Personal Account DOI: 10.1002/tcr.201500212
THE CHEMICAL RECORD
An Efficient Amide-Aldehyde-Alkene Condensation: Synthesis for the N-Allyl Amides Zheng-Jun Quan* and Xi-Cun Wang*[a]
Chem. Rec. 2016, 16, 435–444
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ABSTRACT: The allylamine skeleton represents a significant class of biologically active nitrogen compounds that are found in various natural products and drugs with well-recognized pharmacological properties. In this personal account, we will briefly discuss the synthesis of allylamine skeletons. We will focus on showing a general protocol for Lewis acid-catalyzed N-allylation of electron-poor N-heterocyclic amides and sulfonamide via an amide-aldehydealkene condensation reaction. The substrate scope with respect to N-heterocyclic amides, aldehydes, and alkenes will be discussed. This method is also capable of preparing the Naftifine motif from N-methyl-1-naphthamide or methyl (naphthalene-1-ylmethyl)carbamate, with paraformaldehyde and styrene in a one-pot manner. Keywords: allylation, allylamines, amide-aldehyde-alkene condensation, Lewis acids, multicomponent reactions
1. Introduction The allylamine skeleton represents a significant class of biologically active nitrogen compounds that are found in various natural products and drugs.[1] In particular, they are the most promising therapeutic drugs, such as antifungal agents (Figure 1). Moreover, allylamines are fundamental building blocks in organic chemistry, and they have been used as starting materials for the synthesis of numerous compounds, such as amino acids, different alkaloids, and carbohydrate derivatives.[2] Therefore, developing chemical synthesis methods for allylamines is an important industrial and synthetic goal. Generally, there are three typical procedures for the synthesis of allylamines, which are outlined in Scheme 1. The first type, delivering allylamines by the transition metal-catalyzed allylic amination of allylic alcohols and their derivatives, as one of the most important approaches, has been studied intensively.[3] Before the discovery of the palladium-catalyzed Tsuji-Trost allylic alkylation, synthesis of allylamines from alkyl halides or mesylates and amines by Gabriel-type reactions were available.[2] In the last two decades, the direct nucleophilic substitution of free allylic alcohols with amines has been intensively studied using acids and various transition metals. The mechanism for the palladium-catalyzed allylic amination is generally accepted to occur via a neutral or cati-
[a]
Z.-J. Quan, X.-C. Wang Key Laboratory of Eco-Environment-Related Polymer Materials, Ministry of Education, China Gansu 730070 (P. R. China) and Key Laboratory of Polymer Materials, College of Chemistry and Chemical Engineering, Northwest Normal University Gansu 730070 (P. R. China) Fax: (186) 931-7972626, E-mail: [email protected], E-mail: [email protected]
Chem. Rec. 2016, 16, 435–444
onic p-allylpalladium intermediate, followed by nucleophilic attack on the amine. The second type is metal-catalyzed vinylation of imines via the addition of activated alkene substrates (such as halogenation and subsequent metalation) into the C5N bond, which also is one of the most commonly used processes. However, the corresponding activated substrates have to be prepared in additional steps for such elegant methods, because of the poor nucleophilicity of simple alkenes.[4] As a highly valuable alternative synthetic pathway, Rh- or Pd-catalyzed direct vinylation of imines or aminals via C-H functionalization of alkenes has been reported.[5] The third type is the direct allylic amination of alkenes, including catalytic hydroamination of 1,3-dienes.[2b, 6] More recently, Beller et al. described a general and regioselective 1,4addition of electron deficient amines into 1,3-dienes catalyzed by Pd catalysts, combined with phosphine ligands to deliver allylamines.[7] As compared with analogous reactions of amines, the studies on the selective N-allylization of electron-deficient N-heterocycles, amides, and sulfonamides via olefins or dienes has rarely been investigated. Recently, notable progress was made by some groups, such as the Beller, Shibasaki, Mashima, and Zhu groups, via the allylic substitution of allylic alcohols with amides.[8] In 2014, Beller et al. reported the Pd-catalyzed intermolecular hydroamination of electrondeficient N-heterocyclic amides and sulfonamides with 1,3dienes and vinyl pyridines.[9] The hydroamination performed well to give the allylic amides in good to excellent yield with high regioselectivity. The studies indicated that the use of cyclic dienes showed good reactivity to yield the addition product in higher yields than the acyclic dienes. They assumed that the catalytic cycle for the addition started initially by forming a transient Pd-H species, which subsequently reacted with the diene to produce a cationic intermediate p-allyl Pd complex. The nucleophilic attack of the amide on the less-substituted carbon atom gave the linear 1,4-addition products.
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OMe
MeO
Me N
Ar
O
OMe
O Me N
EtO
N
1, Naftifine
2, Terbinafine
Fig. 1. Examples of allylamine-containing pharmaceuticals.
Ar
O
path (a)
R
LG +
LG = OH, OAc, OCO2Me, Cl path (b) R
path (c)
R
MX + R3CH=NR2
+ HNR1R2
allylic amination nuceophilic addition
N H 8
Me
R1 R
N R2
O N
EtO
HNR1R2
i) (CH2O)n 5, TMS-Cl ii) NuH or NaNu 6 CH2Cl2 X = S, O
Nu
N
EtO
X
N H 7
Me
(CH2O)n TMSCl
3, Abamine
F
X
N H 4
Me
Ar
O NH
Cl O
Me
nitrogen nucleophiles = HN , NaN3 , O
HN
hydroamination
Scheme 1. Synthesis of allylamine derivatives.
Alternatively, a lot of direct or indirect methods to obtain allylamines have been reported by some groups.[10]
5
N
EtO N H 9
Ar
O
Ar
O
N
EtO Me
N H 7
Nu O
oxygen nucleophiles = MeOH, EtOH, i-PrOH, t-BuOH, C6H5SO2Na, p-Me-C6H4SO2Na MeCO2H, ArylCO2H
Scheme 2. Three-component reaction of DHPM, paraformaldehyde, and nucleophiles.
The introduction of an aminomethyl group into an organic structure can be carried out by the reaction of an imine (I) or an iminium salt (II) with a nucleophile, which is called a Mannich reaction. This consideration reflects the availability of the corresponding starting materials, whereas compounds I and II are easily available.[11] On the other hand, reactions between N-acyliminium ions and a nucleophile have been frequently used to introduce substituents at the a-carbon of an amine.[11] To our surprise, almost no intermolecular reaction of nucleophilic styrene into iminium cations for the construction of allylamine is known. Although the allylation of imines has been reported, most of these existing methods require electron-rich precursors (allylboronic acid ester and cyclic boronates), strong bases, involve the use of additives for the addition reaction, or are accompanied by the formation of unexpected by-products.[12]
Our initial interest focused on the construction of N3substituted 3,4-dihydropyrimidinones (DHPMs), as DHPMs (termed Biginelli compounds) have received considerable attention in the past decades, due to their heterocyclic scaffold and their interesting pharmacological properties.[13,14] Our thinking at the time was that N3-substitued DHPMs 7 could be regioselectively obtained by reaction of a DHPM 4 with paraformaldehyde 5 and a nucleophile 6 by a one-pot strategy.[15] This regioselective reaction was observed in our initial examination of the reaction of DHPM with paraformaldehyde and alcohols in the presence of TMSCl. A series of alkyloxymethyl, aminomethyl, arylsulfonylmethyl, azidomethyl, and acyloxymethyl groups were regioselectively introduced into the N3 positon of DHPMs over their isomeric N1 compounds (Scheme 2).[16] Mechanistically, it is expected that this reaction proceeds through a N-chloromethyl DHPM 8, in which nucleophilic substitution subsequently occurred to give the product 7.[15] Alternatively, an N-acyliminium ion 9 might also be one of the possible intermediates of this reaction, provided that the Nmethylation of DHPMs was run under like Mannich-type
Dr. Zheng-Jun Quan was born in 1978 in Gansu, China. He received his BS and PhD with Professor Xi-Cun Wang from Northwest Normal University in 2004 and 2007. After his BS, he joined the chemistry faculty of Northwest Normal University, where he was promoted to associate professor in 2007 and professor in 2014. His current research interests focus on transition-metal-catalyzed cross-coupling reactions, and multicomponent reactions for synthesis of biologically important heterocycles.
Dr. Xi-Cun Wang was born in 1965 in Gansu, China. He obtained his PhD with Professor E. Ya. Borisova in the Moscow College of Fine Chemical Engineering in 1993. After his PhD, he joined the chemistry faculty of Northwest Normal University in 1994, where he was promoted to associate professor in 1996 and professor in 2001. His current research interests focus on transitionmetal-catalyzed cross-coupling reactions, multicomponent reactions, tandem approaches, and green chemistry.
2. Synthesis Planning
Chem. Rec. 2016, 16, 435–444
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R1
R1
NH N H 4
I2 (20 mol%)
+ (CH2O)n +
N
EtO
N H 12
o
dioxane, 110 C R2 12 h
O
N H
Me
10
R2
O
11 16 examples, 52-82% E:Z > 25:1
Cl
R2 N
EtO N H
1
R = H, 4-Me, 4-MeO, 3-MeO, 2-MeO = 4-Cl, 2-Cl, 4-F, 4-NO2, 3-NO2;
O
2
Me
R = H, Me, Br
EtO
N
EtO N H
Me
R2
O
Scheme 3. Three-component reaction of DHPMs, paraformaldehyde, and styrenes.
R
R O
O NH + (CH2O)n + N H 12
Ar
O 10
I2 (20 mol%) dioxane 110 oC, 12 h
Ar
N N H
O 13
Scheme 4. Three-component reaction of quinazoline-2,5-diones, paraformaldehyde, and styrenes.
conditions (Scheme 2). This hypothesis was subsequently proven by the N3-ethoxymethylation of heterocyclic compounds with paraformaldehyde and diethyl phosphite in the absence of TMSCl.[16b] The formation of iminium ion 8 was supported by the LC-MS experimental results. 2.1. Direct Allylation of the Biginelli Compounds via the Amide-Aldehyde-Alkene Condensation On the basis of our studies on the synthesis of DHPM derivatives via iminium ions,[16] we were curious whether we could access allylamine fragments, such as 11, through the threecomponent reaction of a DHPM, paraformaldehyde, and an unactivated styrene 10 (Scheme 3). When DHPM 4a (R1 5 H), paraformaldehyde, and styrene 10a (R2 5 H) were subjected to the previously mentioned conditions in the presence of TMSCl, the desired N3-allylic DHPM 11a (R1 5 R2 5 H) was obtained, along with both unreacted starting materials. Although only a trace amount of 11a was observed, the reaction still provided an opportunity to develop a general method for N3-allylic DHPM.[17] Thus, optimization of the formation of N3-allylic DHPM 11a was pursued. We found p-toluenesulfonic acid (p-TSA), trifluoroacetic acid (TFA), and trifluoromethanesulfonic acid (TfOH) gave the desired product 11a (R1 5 R2 5 H) in 35–45% yield. Good reaction yield and regioselectivity were observed when using I2 as the catalyst (75% yield), and I2/FeCl3 or FeCl3/ TfOH catalytic systems (76 or 72% yields, respectively). Thus,
Chem. Rec. 2016, 16, 435–444
Ar2
NH N H 4
O
O OEt
N N H
O
O
15a, R = 3-NO2 (18%) 15b, R = 4-NO2 (15%)
or Cl
R = H, 4-Me, 4-Cl, 4-Br R = 3-NO2, 4-NO2, 2-Cl
O
O
O
,
OEt I2 (40 mol%), dioxane 110 oC, 36 h
or
R1
R1
N O H 14, 39-64%
O O
+ Ar2
N
O
NO2
CO2Et
NH
(CH2O)n
Me
R O
O
EtO Me
R O
O
CO2Et
O EtO Me
Ph
N N O H 16, 41%
Scheme 5. Three-component reaction of heterocyclic amides, ethyl glyoxalate, and styrenes.
we optimized the conditions for the formation of the N3-allylated DHPM using 0.2 equivalents of molecular iodine as the catalyst in 1,4-dioxane as the solvent at 110 8C for 12 h. The choice of solvent was critical in the presence of I2 as the catalyst: less polar solvents, such as toluene and dioxane, promoted the allylation reaction, whereas dipolar aprotic solvents, such as dimethylformamide (DMF), were ineffective. Varying DHPM and styrene reaction partners, good yields of N3allylated DHPMs 11 were obtained with high regio- and stereochemical control in favour of the E-isomer. To further expand the scope of DHPM, paraformaldehyde, and styrene condensation, we examined octahydroquinazoline2,5-diones 12 as the amide partner in the three-component reaction. A series of N-allylic derivatives 13 were obtained in moderate to good yield with high regioselectivity (Scheme 4).[18] Then we became interested in the formation of more challenging allylic amides. Glycinates are fascinating precursors for the synthesis of multifunctional heterocycles.[19] Therefore, we performed the direct N-allylation of DHPM 4 or quinazoline2,5-diones 12 with ethyl glyoxalate and alkenes. The three amidealdehyde-alkene substrates condensed smoothly to yield the glycinate group-functionalized allylic products, 14 and 16. Moderate yield and high regioselectivity were also observed (Scheme 5). Unexpected results were also observed, i.e., the 4-NO2- or 3-NO2 phenyl ring-substituted quinazoline-2,5-diones delivered the allylic products with a minor amount of by-product as 15a and 15b. The reaction of quinazoline-2,5-dione with a 2Cl substituted phenyl ring showed poor reactivity, yielding a trace amount of product. Furthermore, the use of methylglyoxal 17 as the aldehyde partner yielded an unexpected product 13, which was the same as those from using paraformaldehyde (Scheme 6). Little was known about the observed chemistry. Other limitations were also observed in the case of 1-octene, 4vinyl pyridine, and 2-vinyl pyridine; they were unreactive in this reaction. Nonetheless, we found an interesting three-component procedure, using readily available DHPMs (like amides),
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O
O
Ar
O NH
N H 12
Me +
+ H
O
O
I2 (40 mol%) Ph dioxane 110 oC, 36 h
Ar Ph
N N H
17
O
13
Me
Cl NO2
O
O N N H
O
Ph O
N O H 13b, 23%
13a, 28%
O
Ph
N
Ph
N
N
N O H 13c, 31%
Ph
N O H 13d, 19%
Scheme 6. Reaction of quinazoline-2,5-dione with methylglyoxal and styrenes.
NH
I2 (30 mol%) TfOH (2 mol%)
+ (CH2O)n +
O
Me
O
H N
NH O
H N
O Me
Me
O
O O
Ph
20
NH Ph
NH
Me
Bn
Me
Scheme 7. Three-component reaction of amides, paraformaldehyde, and styrenes.
paraformaldehyde, and alkenes (unactivated styrenes) as starting materials. The reaction is atom-economical, as water is the sole by-product and does not need any additives.
2.2. Direct Allylation of Simple Amides via the AmideAldehyde-Alkene Condensation However, we faced some problems when other amides 18 were used instead of DHPM in the condensation of amide-aldehydealkene (Scheme 7). The reaction of simplified amides with paraformaldehyde and styrene only gave the desired product 19 in about 20% yield under the previously mentioned conditions. Using xylene as the solvent slightly enhanced the yield, up to 43%. We finally applied a combined catalyst system of 30 mol% I2 and 2 mol% of TfOH in xylene at 110 8C for 24 h, giving various N-allylic amides 19 in good yields (70–83%) (Scheme 7). More loading of the TfOH reduced the reaction yield, because of the polymerization of styrene. In an effort to extend this protocol from amides to carbamate, we prepared Naftifine derivatives via the threecomponent reaction. Naftifine is a commercial drug with high antifungal activity.[1a, 1b] Compounds 21a and 21b were synthesized in yields of 65 and 70%, respectively, by the amidealdehyde-alkene condensation of carbamate 20, paraformaldehyde, and styrene or 4-methyl-substituted styrene catalyzed by I2/TfOH system (Scheme 8). These compounds can be
Chem. Rec. 2016, 16, 435–444
OMe
O
R
N (CH2O)n styrenes
R
19 9 examples, 70-83%
10 R = H, Br, Me
amides:
OMe NH
o
110 C R xylene, 24h
O 18
NH
O
N
R
Me N
LiAlH4
ref. 18 I2 (20 mol%) TfOH (2 mol%) R = H, 21a, 65%, E:Z > 20:1 o 24h = xylene, 110 C, R Me, 21b, 70%, E:Z > 25:1
Naftifine
Scheme 8. Synthesis of the Naftifine derivatives by the amide-aldehydealkene condensation.
reduced by LiAlH4, giving Naftifine derivatives via procedures in the literature.[20] The reaction of electron-deficient N-phenylbenzamide 22a with paraformaldehyde and styrene provided, to our surprise, only trace amounts of the allylic product, but gave a cyclization product 3,4-dihydroquinoline 23a in 70% yield (Scheme 9). This result suggested the formation of a carbocation intermediate and subsequent occurrence of an addition/ intramolecular Friedel-Crafts reaction. When we attempted to explore the origins of the observed domino reaction, we met some difficulties. We found the reaction of Nphenylbenzamide with paraformaldehyde and (4-bromophenyl)styrene could give the desired product 23b in moderate yield (56%). However, the N-naphthybenzamide 22b only gave product 23c in 18% yield. Although we tried to optimize the reaction conditions by changing various Brønsted and Lewis acids or solvents, we could not obtain a satisfactory result. Unexpectedly, the use of more electron-rich amide 22c resulted in a novel benzoxazine cyclic product 23d.[21] 2.3. Direct Allylation of N-Heterocyclic Amides via the Amide-Aldehyde-Alkene Condensation To further illustrate the use of the amide-aldehyde-alkene condensation for the synthesis of allylic amides, we investigated the Lewis-acid-catalyzed direct N-allylation of N-heterocyclic amides with aldehydes and alkenes.[22] Five-membered heterocycles, such as oxazolidinone and imidazolidinone, are found in a broad range of synthetically and biologically interesting compounds, displaying a broad spectrum of biological
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O I2 (20 mol%) TfOH (2 mol%) o xylene,110 C 24h
O a)
(CH2O)n
N H
R
22a
b)
N R 23a, R = H, 70% 23b, R = 4-Br, 56%
I2 (20 mol%) TfOH (2 mol%)
O (CH2O)n
N H 22b
O N
o
xylene,110 C 24h
23c, 18%
c) OCH3
O
O
(CH2O)n, styrene
OCH3
N H
N
I2 (20 mol%) TfOH (2 mol%) o
xylene,110 C 24h
22c
OCH3
O
OCH3 23d, 22%
Scheme 9. Aza-Prins and intramolecular Friedel-Crafts reaction of N-aryl amides with paraformaldehyde and styrene.
Table 1. Optimization of conditions for the acid-catalyzed direct allylation reaction.
O O
O
NH + (CH2O)n 24a
Entry 1 2 3 4 5 6
conditions
Ph
O
O
N
toluene
Ph
N
O
Bi(OTf)3 (20 mol%) O
N 26
Scheme 10. Reaction of oxazolidin-2-one with paraformaldehyde and toluene.
25a
10a
Catalyst (mol%)
Solvent
Isolated yield (%)
I2 (30) I2(5)/TfOH (20) FeCl3 (30)/TfOH (5) I2(20)/Fe(OTf )3 (5) Bi(OTf )3 (20) Bi(OTf )3 (20)
dioxane dioxane dioxane dioxane dioxane toluene
67 trace 10 75 88 85
activities. They have also shown pharmacological activity as treatments for depression and psychosis.[23] First, we examined the effect of different catalysts in the reaction of oxazolidin-2-one with paraformaldehyde and styrene in dioxane at 110 8C, and found that the reaction catalyzed by Bi(OTf )3 gave product 25a in a high yield of 88% (Table 1, entry 5). However, the use of our previous catalyst conditions gave the desired allylic product in a lower yield of 67% (Table 1, entry 1). The use of I2/Fe(OTf )3 as the catalyst system also gave a good result (Table 1, entry 4). When we examined toluene as the solvent, it worked well, giving the product in high yield; however, toluene also added into the 3methylene-2-oxooxazolidin-3-ium ion intermediate, forming 3-(4-methylbenzyl)oxazolidin-2-one 26 (Scheme 10) (Table 1, entry 6). This result is similar to the amidoalkylation reactions reported by Manolikakes et al. and Ruengsangtongkul et al.[24]
Chem. Rec. 2016, 16, 435–444
O
24a
O
O
NH
(CH2O)n
Next, we applied the optimized conditions for the allylation of oxazolidinone and imidazolidinones with paraformaldehyde and various alkenes. Typical examples are summarized in Table 2.[22] The reaction of oxazolidinone performed smoothly to deliver the N-allylic product in high yield (Table 2, entries 1 and 2); however, the use of 1-tert-butylimidazolidin-2-one and 1-methylimidazolidin-2-one formed the product in lower yields (Table 2, entries 4–6). Fortunately, the combination of I2 (20 mol%) with Fe(OTf )3 (5 mol%), instead of Bi(OTf )3, as catalysts efficiently improved the yield to 65–76%. From Table 2, we can see that different Lewis acids provide different reactivities for different classes of substrates. The overall conversions to product were better with I2/ Fe(OTf )3, although with the Bi(OTf )3 perhaps showing better yields for the oxazolidinone substrate (the same results were also observed for the reaction of unsubstituted imidazolidinone and tetrahydropyrimidin-2(1H)-one, shown in Scheme 11). Luckily, long-chain olefins, such as 1-octene 10g, as the alkene partner obtained allylation products (Table 2, entries 7 and 8); however, pent-4-en-2-one (10h) provided the corresponding product in low yield (Table 2, entry 9). The I2/Fe(OTf)3 catalyzed-allylation of N-methylbenzenesulfonamide 24d with paraformaldehyde and styrenes was also investigated due to the sulfonamide structural motif presenting in several drugs and pharmacological agents. Delightfully, the desired allylic sulfonamides were obtained in 61–70% yield,
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Table 2. Different Lewis acid-catalyzed amide-aldehyde-alkene reactions. O N
H
Bi(OTf)3 (20% mol ) o dioxane, 110 C, 24 h
+ R1CHO + Ar(R2)
24
O
amides:
24a
24b
alkenes:
N
NH PhSO2NHMe 24c
24d
10a (R2 = H); 10b (R2 = 4-Cl); C6H13 10c (R2 = 4-Br); 10d (R2 = 4-Me); 10e (R2 = 4-tert-butyl); 10f (R2 = 2-Me) 10g
R2
(R )Ar
O NH
N
2
N 25
O NH
O
R1
O
O 10h
Yield (%) Entry
Aldehyde/R1
Amide
1 2 4 5 6 7 8 9 10 11 12 13 14
H H H H H H H H H CO2Et CO2Et CO2Et CO2Et
I2 (20 mol %) Fe(OTf)3 (5 mol %) dioxane R2 110 oC, 36 h
R1
O
O H N
24a 24a 24b 24c 24c 24a 24b 24a 24d 24a 24a 24b 24c
N H n
R1
H R2
N
N
R1 N n
R2
26 O
O R2
O
R2
N
N
N
R2
R2
26a: R2 = C6H5, 61% 26b: R2 = 4-Cl-C6H4, 65% 26c: R2 = 4-Br-C6H4, 52% EtO Ph
O
26d: R2 = C6H5, 53% 26e: R2 = 4-Cl-C6H4, 54% 26f: R2 = 4-Me-C6H4, 51% O
N
O
OEt
N Ph
26g, 61%
Scheme 11. The bis-allylation of imidazolidinone and tetrahydropyrimidin2(1H)-one.
confirming the general applicability of the protocol (for example, see Table 2, entry 10). To demonstrate the generality of this one-pot allylation protocol, we tested ethyl glyoxalate as the aldehyde partner in
Chem. Rec. 2016, 16, 435–444
Alkene
Bi(OTf )3
I2/Fe(OTf )3
10a 10b 10a 10a 10b 10g 10g 10h 10a 10a 10b 10a 10a
88 76 45 50 45 62 56 – – 65 61 52 –
62 60 65 76 66 – 72 < 25 64 56 50 74 60
the amide-aldehyde-alkene condensation reaction. In general, good yields of the desired products were obtained catalyzed by Bi(OTf )3 in dioxane at 110 8C for 24 h. As in the previous case, N-substituted imidazolidin-2-one led to consistently 10– 22% lower yields. The use of I2/Fe(OTf )3 catalyzed allylation of N-substituted imidazolidin-2-one with ethyl glyoxalate and styrenes formed the allylation products in good yields (for example, see Table 2, entries 11–14). The scope of this three-component reaction was further investigated by using unsubstituted imidazolidinone and tetrahydropyrimidin-2(1H)-one as available amide partners. Both paraformaldehyde and ethyl glyoxalate as aldehyde substrate gave the desired bis-allylated imidazolidinones in moderate yields (Scheme 11). The protocol was also applied to the synthesis of the key intermediate for Naftifine (Scheme 12). Overall, compared with our previous studies,[17,18] the substrate scope in this study was significantly expanded into N-methyl sulfonamide, carbamates, and carboxamide, and allowed the use of long-chain olefins and ethyl glyoxalate as the reagents.
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O
OH
O
NHMe
O
Me N
Ph
(CH2O)n, 10a I2 (20 mol %)
1) SOCl2 2) MeNH2 28
27
Fe(OTf)3 (5 mol %) dioxane 110 °C, 24 h
29, 85%
Scheme 12. Synthesis of the Naftifine motif by the amide-aldehyde-alkene reaction. S
S N
H (CH2O)n
Ar
I2 (20 mmol%) TfOH (10 mmol%)
N
Ar
dioxane o 110 C, 24 h
30 31 Ar = C6H5, 31a, 82%; Ar = 4-ClC6H4, 31b, 35%; Ar = 4-MeOC6H4, 31c, 29%; Ar = t-BuC6H4, 31d, 39%; Ar = nathphyl, 31f, 80%
Scheme 13. Lewis acid-catalyzed thioamide-aldehyde-alkene condensation.
R (CH2O)n
NH
N
O
N
R
M
R
33
34 -H
R O
O N
EtO N H
Me 32a
M
O
O
O 32
amide
N
M
O
N N
+
32b
O
O minor product kinetic control
O
R
N
major product thermodynamic control
M = Bi(OTf)2, Fe(OTf)2 or I2
Scheme 14. The proposed mechanism of amide-aldehyde-alkene condensation.
2.4. Direct Allylation of Thioamides via the AmideAldehyde-Alkene Condensation Finally, the utility of the amide-aldehyde-alkene reaction for stereoselective synthesis of allylic amide derivatives is now well established, with this chemistry being employed in our laboratories to accomplish synthesis of allylic thioamide derivatives, i.e., I2/TfOH-catalyzed direct N-allylations of azepane-2thione with paraformaldehyde and alkenes were successfully performed to yield allylated thioamides, confirming the general applicability of the protocol (Scheme 13). 2.5. The Initial Mechanistic Proposal for the AmideAldehyde-Alkene Condensation We present the mechanistic pathway to explain the formation of the N-allylated product by the amide-aldehyde-alkene
Chem. Rec. 2016, 16, 435–444
condensation (Scheme 14). Generally, we propose that the reaction is performed in a Lewis acid-promoted intermolecular aza-Prins-type reaction.[25] The aldehyde, upon reaction with an amide, forms the cationic Bi or Fe species 32 from the interaction between an acyliminium ion and the carbonyl C5O double bond of amide, which is the important intermediate species for the reaction. Then 32 undergoes nucleophilic attack by the alkene moiety to produce cationic intermediate 34 through the transition state 33. Finally, intermediate 34, on subsequent deprotonation,[26] should be sterically favoured to afford the thermodynamically controlled (E)-type product as the dominant reaction, compared with the formation of (Z)type product. We assumed that both Bi(OTf )3 and an in situ generated Brønsted acid, TfOH, are important for the catalytic system, although using sole I2 as the Lewis acid catalyst was applicable
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in most cases. The combination of I2 with TfOH or Fe(OTf )3 (5 mol% TfOH) was a practicable method to improve the product yield, which indicates that a small amount of strong Brønsted acid (such as 2–5 mol% TfOH) is needed in this reaction. The presence of TfOH or Fe(OTf )3 was especially important for those amides which are less basic. The formation of an acyliminium ion 32 is supported by the HRMS experimental results (32a and 32b were detected at m/z [M 1 H]1 273, 274, and 100, respectively, for the reaction of DHPM 4a (Ar 5 Ph) and 24a with paraformaldehyde and styrene). Finally, we have to stress that the exact mechanism is yet to be established with more experimental and theoretical studies, although the proposed mechanism can explain some experimental results.
3. Conclusion In summary, we have briefly described our synthetic method for the N-allylation of N-heterocyclic amides via an amide-aldehydealkene condensation. A variety of N-heterocyclic compounds and amides, including pyrimidin-2(1H)-ones, oxazolidinone, imidazolidinone, N-substituted imidazolidinones, quinazoline-2,5diones, piperidin-2-one, azepan-2-one, N-phenylacetamide, N-(2,6-dimethylphenyl) acetamide, N-methylbenzamide, and N-benzylbenzamide, have been used as substrates to give the Nallylic products. N-allylic thioamides, such as azepane-2-thione, were also applied in the reaction. We assume that both a Lewis acid and a Brønsted acid are important for the catalytic system, although using sole I2 as the catalyst was applicable in most cases (albeit in a lower yield). It is clear that the detailed reaction mechanism of amide-aldehyde-alkene condensation is very complicated, particularly the behaviour of different Lewis acids in different type of amides. In this regard, studies of the reaction mechanism, particularly the role of Lewis acids in the allylation reactions, are ongoing. A more generally catalytic system is needed for the threecomponent reaction, including amides, aldehydes, and alkenes. Due to the ubiquity of enantio-enriched amine having remained an important goal in chemistry for decades, the ability to be enantioselective in the allylation of amides by catalytic asymmetric amide-aldehyde-alkene condensation is an important goal. Ultimately, we aim to extend our research on amidealdehyde-alkene condensation into an amine-aldehyde-alkene condensation to access allylic amines.
Acknowledgements Financial support was provided by the financial support from the NSF of China (Nos. 21362032 and 21362031), and the Gansu Provincial Department of Finance.
Chem. Rec. 2016, 16, 435–444
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[17] Z.-J. Quan, W.-H. Hu, Z. Zhang, X.-D. Jia, Y.-X. Da, X.-C. Wang, Adv. Synth. Catal. 2013, 355, 891–900. [18] Z. Zhang, Y.-S. Zhang, Z.-J. Quan, Y.-X. Da, X.-C. Wang, Tetrahedron 2014, 70, 9093–9098. [19] a) Y. Yamamoto, H. Hayashi, T. Saigoku, H. Nishiyama, J. Am. Chem. Soc. 2005, 127, 10804–10805; b) Y. Luo, X. Lu, Y. Ye, Y. Guo, H. Jiang, W. Zeng, Org. Lett. 2012, 14, 5640– 5643. [20] P. Prediger, L. F. Barbosa, Y. Genisson, C. R. D. Correia, J. Org. Chem. 2011, 76, 7737–7749. [21] Unpublished work. The structure of 17d was determined by X-ray crystallographics, CCDC No. CCDC 944759. [22] X.-X. Wang, Z.-J. Quan, X.-C. Wang, Asian J. Org. Chem. 2015, 4, 54–61. [23] a) W. A. Gregory, D. R. Brittelli, C. L. J. Wang, M. A. Wuonola, R. J. McRipley, D. C. Eustice, V. S. Eberly, P. T. Bartholomew, A. M. Slee, M. Forbes, J. Med. Chem. 1989, 32, 167321681; b) C. H. Park, D. R. Brittelli, C. L. J. Wang, F. D. Marsh, W. A. Gregory, M. A. Wuonola, R. J. McRipley, V. S. Eberly, A. M. Slee, M. Forbes, J. Med. Chem. 1992, 35, 115621165. [24] a) J. Halli, G. Manolikakes, Eur. J. Org. Chem. 2013, 7471– 7475; b) A. E. Schneider, G. Manolikakes, Synlett 2013, 2057–2060; c) J. Jaratjaroonphong, S. Tuengpanya, S. Ruengsangtongkul, J. Org. Chem. 2015, 80, 5592567. [25] R. M. Carballo, G. Valdomir, M. Purino, V. S. Martın, J. I. Padron, Eur. J. Org. Chem. 2010, 2304–2313. [26] A. P. Dobbs, S. J. J. Guesne, R. J. Parker, J. Skidmore, R. A. Stephensond, M. B. Hursthoused, Org. Biomol. Chem. 2010, 8, 1064–1080.
Received: July 7, 2015 Published online: January 25, 2016
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An Efficient Amide-Aldehyde-Alkene Condensation: Synthesis for the N-Allyl Amides Zheng-Jun Quan* and Xi-Cun Wang*[a]
Chem. Rec. 2016, 16, 435–444
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ABSTRACT: The allylamine skeleton represents a significant class of biologically active nitrogen compounds that are found in various natural products and drugs with well-recognized pharmacological properties. In this personal account, we will briefly discuss the synthesis of allylamine skeletons. We will focus on showing a general protocol for Lewis acid-catalyzed N-allylation of electron-poor N-heterocyclic amides and sulfonamide via an amide-aldehydealkene condensation reaction. The substrate scope with respect to N-heterocyclic amides, aldehydes, and alkenes will be discussed. This method is also capable of preparing the Naftifine motif from N-methyl-1-naphthamide or methyl (naphthalene-1-ylmethyl)carbamate, with paraformaldehyde and styrene in a one-pot manner. Keywords: allylation, allylamines, amide-aldehyde-alkene condensation, Lewis acids, multicomponent reactions
1. Introduction The allylamine skeleton represents a significant class of biologically active nitrogen compounds that are found in various natural products and drugs.[1] In particular, they are the most promising therapeutic drugs, such as antifungal agents (Figure 1). Moreover, allylamines are fundamental building blocks in organic chemistry, and they have been used as starting materials for the synthesis of numerous compounds, such as amino acids, different alkaloids, and carbohydrate derivatives.[2] Therefore, developing chemical synthesis methods for allylamines is an important industrial and synthetic goal. Generally, there are three typical procedures for the synthesis of allylamines, which are outlined in Scheme 1. The first type, delivering allylamines by the transition metal-catalyzed allylic amination of allylic alcohols and their derivatives, as one of the most important approaches, has been studied intensively.[3] Before the discovery of the palladium-catalyzed Tsuji-Trost allylic alkylation, synthesis of allylamines from alkyl halides or mesylates and amines by Gabriel-type reactions were available.[2] In the last two decades, the direct nucleophilic substitution of free allylic alcohols with amines has been intensively studied using acids and various transition metals. The mechanism for the palladium-catalyzed allylic amination is generally accepted to occur via a neutral or cati-
[a]
Z.-J. Quan, X.-C. Wang Key Laboratory of Eco-Environment-Related Polymer Materials, Ministry of Education, China Gansu 730070 (P. R. China) and Key Laboratory of Polymer Materials, College of Chemistry and Chemical Engineering, Northwest Normal University Gansu 730070 (P. R. China) Fax: (186) 931-7972626, E-mail: [email protected], E-mail: [email protected]
Chem. Rec. 2016, 16, 435–444
onic p-allylpalladium intermediate, followed by nucleophilic attack on the amine. The second type is metal-catalyzed vinylation of imines via the addition of activated alkene substrates (such as halogenation and subsequent metalation) into the C5N bond, which also is one of the most commonly used processes. However, the corresponding activated substrates have to be prepared in additional steps for such elegant methods, because of the poor nucleophilicity of simple alkenes.[4] As a highly valuable alternative synthetic pathway, Rh- or Pd-catalyzed direct vinylation of imines or aminals via C-H functionalization of alkenes has been reported.[5] The third type is the direct allylic amination of alkenes, including catalytic hydroamination of 1,3-dienes.[2b, 6] More recently, Beller et al. described a general and regioselective 1,4addition of electron deficient amines into 1,3-dienes catalyzed by Pd catalysts, combined with phosphine ligands to deliver allylamines.[7] As compared with analogous reactions of amines, the studies on the selective N-allylization of electron-deficient N-heterocycles, amides, and sulfonamides via olefins or dienes has rarely been investigated. Recently, notable progress was made by some groups, such as the Beller, Shibasaki, Mashima, and Zhu groups, via the allylic substitution of allylic alcohols with amides.[8] In 2014, Beller et al. reported the Pd-catalyzed intermolecular hydroamination of electrondeficient N-heterocyclic amides and sulfonamides with 1,3dienes and vinyl pyridines.[9] The hydroamination performed well to give the allylic amides in good to excellent yield with high regioselectivity. The studies indicated that the use of cyclic dienes showed good reactivity to yield the addition product in higher yields than the acyclic dienes. They assumed that the catalytic cycle for the addition started initially by forming a transient Pd-H species, which subsequently reacted with the diene to produce a cationic intermediate p-allyl Pd complex. The nucleophilic attack of the amide on the less-substituted carbon atom gave the linear 1,4-addition products.
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OMe
MeO
Me N
Ar
O
OMe
O Me N
EtO
N
1, Naftifine
2, Terbinafine
Fig. 1. Examples of allylamine-containing pharmaceuticals.
Ar
O
path (a)
R
LG +
LG = OH, OAc, OCO2Me, Cl path (b) R
path (c)
R
MX + R3CH=NR2
+ HNR1R2
allylic amination nuceophilic addition
N H 8
Me
R1 R
N R2
O N
EtO
HNR1R2
i) (CH2O)n 5, TMS-Cl ii) NuH or NaNu 6 CH2Cl2 X = S, O
Nu
N
EtO
X
N H 7
Me
(CH2O)n TMSCl
3, Abamine
F
X
N H 4
Me
Ar
O NH
Cl O
Me
nitrogen nucleophiles = HN , NaN3 , O
HN
hydroamination
Scheme 1. Synthesis of allylamine derivatives.
Alternatively, a lot of direct or indirect methods to obtain allylamines have been reported by some groups.[10]
5
N
EtO N H 9
Ar
O
Ar
O
N
EtO Me
N H 7
Nu O
oxygen nucleophiles = MeOH, EtOH, i-PrOH, t-BuOH, C6H5SO2Na, p-Me-C6H4SO2Na MeCO2H, ArylCO2H
Scheme 2. Three-component reaction of DHPM, paraformaldehyde, and nucleophiles.
The introduction of an aminomethyl group into an organic structure can be carried out by the reaction of an imine (I) or an iminium salt (II) with a nucleophile, which is called a Mannich reaction. This consideration reflects the availability of the corresponding starting materials, whereas compounds I and II are easily available.[11] On the other hand, reactions between N-acyliminium ions and a nucleophile have been frequently used to introduce substituents at the a-carbon of an amine.[11] To our surprise, almost no intermolecular reaction of nucleophilic styrene into iminium cations for the construction of allylamine is known. Although the allylation of imines has been reported, most of these existing methods require electron-rich precursors (allylboronic acid ester and cyclic boronates), strong bases, involve the use of additives for the addition reaction, or are accompanied by the formation of unexpected by-products.[12]
Our initial interest focused on the construction of N3substituted 3,4-dihydropyrimidinones (DHPMs), as DHPMs (termed Biginelli compounds) have received considerable attention in the past decades, due to their heterocyclic scaffold and their interesting pharmacological properties.[13,14] Our thinking at the time was that N3-substitued DHPMs 7 could be regioselectively obtained by reaction of a DHPM 4 with paraformaldehyde 5 and a nucleophile 6 by a one-pot strategy.[15] This regioselective reaction was observed in our initial examination of the reaction of DHPM with paraformaldehyde and alcohols in the presence of TMSCl. A series of alkyloxymethyl, aminomethyl, arylsulfonylmethyl, azidomethyl, and acyloxymethyl groups were regioselectively introduced into the N3 positon of DHPMs over their isomeric N1 compounds (Scheme 2).[16] Mechanistically, it is expected that this reaction proceeds through a N-chloromethyl DHPM 8, in which nucleophilic substitution subsequently occurred to give the product 7.[15] Alternatively, an N-acyliminium ion 9 might also be one of the possible intermediates of this reaction, provided that the Nmethylation of DHPMs was run under like Mannich-type
Dr. Zheng-Jun Quan was born in 1978 in Gansu, China. He received his BS and PhD with Professor Xi-Cun Wang from Northwest Normal University in 2004 and 2007. After his BS, he joined the chemistry faculty of Northwest Normal University, where he was promoted to associate professor in 2007 and professor in 2014. His current research interests focus on transition-metal-catalyzed cross-coupling reactions, and multicomponent reactions for synthesis of biologically important heterocycles.
Dr. Xi-Cun Wang was born in 1965 in Gansu, China. He obtained his PhD with Professor E. Ya. Borisova in the Moscow College of Fine Chemical Engineering in 1993. After his PhD, he joined the chemistry faculty of Northwest Normal University in 1994, where he was promoted to associate professor in 1996 and professor in 2001. His current research interests focus on transitionmetal-catalyzed cross-coupling reactions, multicomponent reactions, tandem approaches, and green chemistry.
2. Synthesis Planning
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R1
R1
NH N H 4
I2 (20 mol%)
+ (CH2O)n +
N
EtO
N H 12
o
dioxane, 110 C R2 12 h
O
N H
Me
10
R2
O
11 16 examples, 52-82% E:Z > 25:1
Cl
R2 N
EtO N H
1
R = H, 4-Me, 4-MeO, 3-MeO, 2-MeO = 4-Cl, 2-Cl, 4-F, 4-NO2, 3-NO2;
O
2
Me
R = H, Me, Br
EtO
N
EtO N H
Me
R2
O
Scheme 3. Three-component reaction of DHPMs, paraformaldehyde, and styrenes.
R
R O
O NH + (CH2O)n + N H 12
Ar
O 10
I2 (20 mol%) dioxane 110 oC, 12 h
Ar
N N H
O 13
Scheme 4. Three-component reaction of quinazoline-2,5-diones, paraformaldehyde, and styrenes.
conditions (Scheme 2). This hypothesis was subsequently proven by the N3-ethoxymethylation of heterocyclic compounds with paraformaldehyde and diethyl phosphite in the absence of TMSCl.[16b] The formation of iminium ion 8 was supported by the LC-MS experimental results. 2.1. Direct Allylation of the Biginelli Compounds via the Amide-Aldehyde-Alkene Condensation On the basis of our studies on the synthesis of DHPM derivatives via iminium ions,[16] we were curious whether we could access allylamine fragments, such as 11, through the threecomponent reaction of a DHPM, paraformaldehyde, and an unactivated styrene 10 (Scheme 3). When DHPM 4a (R1 5 H), paraformaldehyde, and styrene 10a (R2 5 H) were subjected to the previously mentioned conditions in the presence of TMSCl, the desired N3-allylic DHPM 11a (R1 5 R2 5 H) was obtained, along with both unreacted starting materials. Although only a trace amount of 11a was observed, the reaction still provided an opportunity to develop a general method for N3-allylic DHPM.[17] Thus, optimization of the formation of N3-allylic DHPM 11a was pursued. We found p-toluenesulfonic acid (p-TSA), trifluoroacetic acid (TFA), and trifluoromethanesulfonic acid (TfOH) gave the desired product 11a (R1 5 R2 5 H) in 35–45% yield. Good reaction yield and regioselectivity were observed when using I2 as the catalyst (75% yield), and I2/FeCl3 or FeCl3/ TfOH catalytic systems (76 or 72% yields, respectively). Thus,
Chem. Rec. 2016, 16, 435–444
Ar2
NH N H 4
O
O OEt
N N H
O
O
15a, R = 3-NO2 (18%) 15b, R = 4-NO2 (15%)
or Cl
R = H, 4-Me, 4-Cl, 4-Br R = 3-NO2, 4-NO2, 2-Cl
O
O
O
,
OEt I2 (40 mol%), dioxane 110 oC, 36 h
or
R1
R1
N O H 14, 39-64%
O O
+ Ar2
N
O
NO2
CO2Et
NH
(CH2O)n
Me
R O
O
EtO Me
R O
O
CO2Et
O EtO Me
Ph
N N O H 16, 41%
Scheme 5. Three-component reaction of heterocyclic amides, ethyl glyoxalate, and styrenes.
we optimized the conditions for the formation of the N3-allylated DHPM using 0.2 equivalents of molecular iodine as the catalyst in 1,4-dioxane as the solvent at 110 8C for 12 h. The choice of solvent was critical in the presence of I2 as the catalyst: less polar solvents, such as toluene and dioxane, promoted the allylation reaction, whereas dipolar aprotic solvents, such as dimethylformamide (DMF), were ineffective. Varying DHPM and styrene reaction partners, good yields of N3allylated DHPMs 11 were obtained with high regio- and stereochemical control in favour of the E-isomer. To further expand the scope of DHPM, paraformaldehyde, and styrene condensation, we examined octahydroquinazoline2,5-diones 12 as the amide partner in the three-component reaction. A series of N-allylic derivatives 13 were obtained in moderate to good yield with high regioselectivity (Scheme 4).[18] Then we became interested in the formation of more challenging allylic amides. Glycinates are fascinating precursors for the synthesis of multifunctional heterocycles.[19] Therefore, we performed the direct N-allylation of DHPM 4 or quinazoline2,5-diones 12 with ethyl glyoxalate and alkenes. The three amidealdehyde-alkene substrates condensed smoothly to yield the glycinate group-functionalized allylic products, 14 and 16. Moderate yield and high regioselectivity were also observed (Scheme 5). Unexpected results were also observed, i.e., the 4-NO2- or 3-NO2 phenyl ring-substituted quinazoline-2,5-diones delivered the allylic products with a minor amount of by-product as 15a and 15b. The reaction of quinazoline-2,5-dione with a 2Cl substituted phenyl ring showed poor reactivity, yielding a trace amount of product. Furthermore, the use of methylglyoxal 17 as the aldehyde partner yielded an unexpected product 13, which was the same as those from using paraformaldehyde (Scheme 6). Little was known about the observed chemistry. Other limitations were also observed in the case of 1-octene, 4vinyl pyridine, and 2-vinyl pyridine; they were unreactive in this reaction. Nonetheless, we found an interesting three-component procedure, using readily available DHPMs (like amides),
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O
O
Ar
O NH
N H 12
Me +
+ H
O
O
I2 (40 mol%) Ph dioxane 110 oC, 36 h
Ar Ph
N N H
17
O
13
Me
Cl NO2
O
O N N H
O
Ph O
N O H 13b, 23%
13a, 28%
O
Ph
N
Ph
N
N
N O H 13c, 31%
Ph
N O H 13d, 19%
Scheme 6. Reaction of quinazoline-2,5-dione with methylglyoxal and styrenes.
NH
I2 (30 mol%) TfOH (2 mol%)
+ (CH2O)n +
O
Me
O
H N
NH O
H N
O Me
Me
O
O O
Ph
20
NH Ph
NH
Me
Bn
Me
Scheme 7. Three-component reaction of amides, paraformaldehyde, and styrenes.
paraformaldehyde, and alkenes (unactivated styrenes) as starting materials. The reaction is atom-economical, as water is the sole by-product and does not need any additives.
2.2. Direct Allylation of Simple Amides via the AmideAldehyde-Alkene Condensation However, we faced some problems when other amides 18 were used instead of DHPM in the condensation of amide-aldehydealkene (Scheme 7). The reaction of simplified amides with paraformaldehyde and styrene only gave the desired product 19 in about 20% yield under the previously mentioned conditions. Using xylene as the solvent slightly enhanced the yield, up to 43%. We finally applied a combined catalyst system of 30 mol% I2 and 2 mol% of TfOH in xylene at 110 8C for 24 h, giving various N-allylic amides 19 in good yields (70–83%) (Scheme 7). More loading of the TfOH reduced the reaction yield, because of the polymerization of styrene. In an effort to extend this protocol from amides to carbamate, we prepared Naftifine derivatives via the threecomponent reaction. Naftifine is a commercial drug with high antifungal activity.[1a, 1b] Compounds 21a and 21b were synthesized in yields of 65 and 70%, respectively, by the amidealdehyde-alkene condensation of carbamate 20, paraformaldehyde, and styrene or 4-methyl-substituted styrene catalyzed by I2/TfOH system (Scheme 8). These compounds can be
Chem. Rec. 2016, 16, 435–444
OMe
O
R
N (CH2O)n styrenes
R
19 9 examples, 70-83%
10 R = H, Br, Me
amides:
OMe NH
o
110 C R xylene, 24h
O 18
NH
O
N
R
Me N
LiAlH4
ref. 18 I2 (20 mol%) TfOH (2 mol%) R = H, 21a, 65%, E:Z > 20:1 o 24h = xylene, 110 C, R Me, 21b, 70%, E:Z > 25:1
Naftifine
Scheme 8. Synthesis of the Naftifine derivatives by the amide-aldehydealkene condensation.
reduced by LiAlH4, giving Naftifine derivatives via procedures in the literature.[20] The reaction of electron-deficient N-phenylbenzamide 22a with paraformaldehyde and styrene provided, to our surprise, only trace amounts of the allylic product, but gave a cyclization product 3,4-dihydroquinoline 23a in 70% yield (Scheme 9). This result suggested the formation of a carbocation intermediate and subsequent occurrence of an addition/ intramolecular Friedel-Crafts reaction. When we attempted to explore the origins of the observed domino reaction, we met some difficulties. We found the reaction of Nphenylbenzamide with paraformaldehyde and (4-bromophenyl)styrene could give the desired product 23b in moderate yield (56%). However, the N-naphthybenzamide 22b only gave product 23c in 18% yield. Although we tried to optimize the reaction conditions by changing various Brønsted and Lewis acids or solvents, we could not obtain a satisfactory result. Unexpectedly, the use of more electron-rich amide 22c resulted in a novel benzoxazine cyclic product 23d.[21] 2.3. Direct Allylation of N-Heterocyclic Amides via the Amide-Aldehyde-Alkene Condensation To further illustrate the use of the amide-aldehyde-alkene condensation for the synthesis of allylic amides, we investigated the Lewis-acid-catalyzed direct N-allylation of N-heterocyclic amides with aldehydes and alkenes.[22] Five-membered heterocycles, such as oxazolidinone and imidazolidinone, are found in a broad range of synthetically and biologically interesting compounds, displaying a broad spectrum of biological
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O I2 (20 mol%) TfOH (2 mol%) o xylene,110 C 24h
O a)
(CH2O)n
N H
R
22a
b)
N R 23a, R = H, 70% 23b, R = 4-Br, 56%
I2 (20 mol%) TfOH (2 mol%)
O (CH2O)n
N H 22b
O N
o
xylene,110 C 24h
23c, 18%
c) OCH3
O
O
(CH2O)n, styrene
OCH3
N H
N
I2 (20 mol%) TfOH (2 mol%) o
xylene,110 C 24h
22c
OCH3
O
OCH3 23d, 22%
Scheme 9. Aza-Prins and intramolecular Friedel-Crafts reaction of N-aryl amides with paraformaldehyde and styrene.
Table 1. Optimization of conditions for the acid-catalyzed direct allylation reaction.
O O
O
NH + (CH2O)n 24a
Entry 1 2 3 4 5 6
conditions
Ph
O
O
N
toluene
Ph
N
O
Bi(OTf)3 (20 mol%) O
N 26
Scheme 10. Reaction of oxazolidin-2-one with paraformaldehyde and toluene.
25a
10a
Catalyst (mol%)
Solvent
Isolated yield (%)
I2 (30) I2(5)/TfOH (20) FeCl3 (30)/TfOH (5) I2(20)/Fe(OTf )3 (5) Bi(OTf )3 (20) Bi(OTf )3 (20)
dioxane dioxane dioxane dioxane dioxane toluene
67 trace 10 75 88 85
activities. They have also shown pharmacological activity as treatments for depression and psychosis.[23] First, we examined the effect of different catalysts in the reaction of oxazolidin-2-one with paraformaldehyde and styrene in dioxane at 110 8C, and found that the reaction catalyzed by Bi(OTf )3 gave product 25a in a high yield of 88% (Table 1, entry 5). However, the use of our previous catalyst conditions gave the desired allylic product in a lower yield of 67% (Table 1, entry 1). The use of I2/Fe(OTf )3 as the catalyst system also gave a good result (Table 1, entry 4). When we examined toluene as the solvent, it worked well, giving the product in high yield; however, toluene also added into the 3methylene-2-oxooxazolidin-3-ium ion intermediate, forming 3-(4-methylbenzyl)oxazolidin-2-one 26 (Scheme 10) (Table 1, entry 6). This result is similar to the amidoalkylation reactions reported by Manolikakes et al. and Ruengsangtongkul et al.[24]
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O
24a
O
O
NH
(CH2O)n
Next, we applied the optimized conditions for the allylation of oxazolidinone and imidazolidinones with paraformaldehyde and various alkenes. Typical examples are summarized in Table 2.[22] The reaction of oxazolidinone performed smoothly to deliver the N-allylic product in high yield (Table 2, entries 1 and 2); however, the use of 1-tert-butylimidazolidin-2-one and 1-methylimidazolidin-2-one formed the product in lower yields (Table 2, entries 4–6). Fortunately, the combination of I2 (20 mol%) with Fe(OTf )3 (5 mol%), instead of Bi(OTf )3, as catalysts efficiently improved the yield to 65–76%. From Table 2, we can see that different Lewis acids provide different reactivities for different classes of substrates. The overall conversions to product were better with I2/ Fe(OTf )3, although with the Bi(OTf )3 perhaps showing better yields for the oxazolidinone substrate (the same results were also observed for the reaction of unsubstituted imidazolidinone and tetrahydropyrimidin-2(1H)-one, shown in Scheme 11). Luckily, long-chain olefins, such as 1-octene 10g, as the alkene partner obtained allylation products (Table 2, entries 7 and 8); however, pent-4-en-2-one (10h) provided the corresponding product in low yield (Table 2, entry 9). The I2/Fe(OTf)3 catalyzed-allylation of N-methylbenzenesulfonamide 24d with paraformaldehyde and styrenes was also investigated due to the sulfonamide structural motif presenting in several drugs and pharmacological agents. Delightfully, the desired allylic sulfonamides were obtained in 61–70% yield,
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Table 2. Different Lewis acid-catalyzed amide-aldehyde-alkene reactions. O N
H
Bi(OTf)3 (20% mol ) o dioxane, 110 C, 24 h
+ R1CHO + Ar(R2)
24
O
amides:
24a
24b
alkenes:
N
NH PhSO2NHMe 24c
24d
10a (R2 = H); 10b (R2 = 4-Cl); C6H13 10c (R2 = 4-Br); 10d (R2 = 4-Me); 10e (R2 = 4-tert-butyl); 10f (R2 = 2-Me) 10g
R2
(R )Ar
O NH
N
2
N 25
O NH
O
R1
O
O 10h
Yield (%) Entry
Aldehyde/R1
Amide
1 2 4 5 6 7 8 9 10 11 12 13 14
H H H H H H H H H CO2Et CO2Et CO2Et CO2Et
I2 (20 mol %) Fe(OTf)3 (5 mol %) dioxane R2 110 oC, 36 h
R1
O
O H N
24a 24a 24b 24c 24c 24a 24b 24a 24d 24a 24a 24b 24c
N H n
R1
H R2
N
N
R1 N n
R2
26 O
O R2
O
R2
N
N
N
R2
R2
26a: R2 = C6H5, 61% 26b: R2 = 4-Cl-C6H4, 65% 26c: R2 = 4-Br-C6H4, 52% EtO Ph
O
26d: R2 = C6H5, 53% 26e: R2 = 4-Cl-C6H4, 54% 26f: R2 = 4-Me-C6H4, 51% O
N
O
OEt
N Ph
26g, 61%
Scheme 11. The bis-allylation of imidazolidinone and tetrahydropyrimidin2(1H)-one.
confirming the general applicability of the protocol (for example, see Table 2, entry 10). To demonstrate the generality of this one-pot allylation protocol, we tested ethyl glyoxalate as the aldehyde partner in
Chem. Rec. 2016, 16, 435–444
Alkene
Bi(OTf )3
I2/Fe(OTf )3
10a 10b 10a 10a 10b 10g 10g 10h 10a 10a 10b 10a 10a
88 76 45 50 45 62 56 – – 65 61 52 –
62 60 65 76 66 – 72 < 25 64 56 50 74 60
the amide-aldehyde-alkene condensation reaction. In general, good yields of the desired products were obtained catalyzed by Bi(OTf )3 in dioxane at 110 8C for 24 h. As in the previous case, N-substituted imidazolidin-2-one led to consistently 10– 22% lower yields. The use of I2/Fe(OTf )3 catalyzed allylation of N-substituted imidazolidin-2-one with ethyl glyoxalate and styrenes formed the allylation products in good yields (for example, see Table 2, entries 11–14). The scope of this three-component reaction was further investigated by using unsubstituted imidazolidinone and tetrahydropyrimidin-2(1H)-one as available amide partners. Both paraformaldehyde and ethyl glyoxalate as aldehyde substrate gave the desired bis-allylated imidazolidinones in moderate yields (Scheme 11). The protocol was also applied to the synthesis of the key intermediate for Naftifine (Scheme 12). Overall, compared with our previous studies,[17,18] the substrate scope in this study was significantly expanded into N-methyl sulfonamide, carbamates, and carboxamide, and allowed the use of long-chain olefins and ethyl glyoxalate as the reagents.
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O
OH
O
NHMe
O
Me N
Ph
(CH2O)n, 10a I2 (20 mol %)
1) SOCl2 2) MeNH2 28
27
Fe(OTf)3 (5 mol %) dioxane 110 °C, 24 h
29, 85%
Scheme 12. Synthesis of the Naftifine motif by the amide-aldehyde-alkene reaction. S
S N
H (CH2O)n
Ar
I2 (20 mmol%) TfOH (10 mmol%)
N
Ar
dioxane o 110 C, 24 h
30 31 Ar = C6H5, 31a, 82%; Ar = 4-ClC6H4, 31b, 35%; Ar = 4-MeOC6H4, 31c, 29%; Ar = t-BuC6H4, 31d, 39%; Ar = nathphyl, 31f, 80%
Scheme 13. Lewis acid-catalyzed thioamide-aldehyde-alkene condensation.
R (CH2O)n
NH
N
O
N
R
M
R
33
34 -H
R O
O N
EtO N H
Me 32a
M
O
O
O 32
amide
N
M
O
N N
+
32b
O
O minor product kinetic control
O
R
N
major product thermodynamic control
M = Bi(OTf)2, Fe(OTf)2 or I2
Scheme 14. The proposed mechanism of amide-aldehyde-alkene condensation.
2.4. Direct Allylation of Thioamides via the AmideAldehyde-Alkene Condensation Finally, the utility of the amide-aldehyde-alkene reaction for stereoselective synthesis of allylic amide derivatives is now well established, with this chemistry being employed in our laboratories to accomplish synthesis of allylic thioamide derivatives, i.e., I2/TfOH-catalyzed direct N-allylations of azepane-2thione with paraformaldehyde and alkenes were successfully performed to yield allylated thioamides, confirming the general applicability of the protocol (Scheme 13). 2.5. The Initial Mechanistic Proposal for the AmideAldehyde-Alkene Condensation We present the mechanistic pathway to explain the formation of the N-allylated product by the amide-aldehyde-alkene
Chem. Rec. 2016, 16, 435–444
condensation (Scheme 14). Generally, we propose that the reaction is performed in a Lewis acid-promoted intermolecular aza-Prins-type reaction.[25] The aldehyde, upon reaction with an amide, forms the cationic Bi or Fe species 32 from the interaction between an acyliminium ion and the carbonyl C5O double bond of amide, which is the important intermediate species for the reaction. Then 32 undergoes nucleophilic attack by the alkene moiety to produce cationic intermediate 34 through the transition state 33. Finally, intermediate 34, on subsequent deprotonation,[26] should be sterically favoured to afford the thermodynamically controlled (E)-type product as the dominant reaction, compared with the formation of (Z)type product. We assumed that both Bi(OTf )3 and an in situ generated Brønsted acid, TfOH, are important for the catalytic system, although using sole I2 as the Lewis acid catalyst was applicable
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in most cases. The combination of I2 with TfOH or Fe(OTf )3 (5 mol% TfOH) was a practicable method to improve the product yield, which indicates that a small amount of strong Brønsted acid (such as 2–5 mol% TfOH) is needed in this reaction. The presence of TfOH or Fe(OTf )3 was especially important for those amides which are less basic. The formation of an acyliminium ion 32 is supported by the HRMS experimental results (32a and 32b were detected at m/z [M 1 H]1 273, 274, and 100, respectively, for the reaction of DHPM 4a (Ar 5 Ph) and 24a with paraformaldehyde and styrene). Finally, we have to stress that the exact mechanism is yet to be established with more experimental and theoretical studies, although the proposed mechanism can explain some experimental results.
3. Conclusion In summary, we have briefly described our synthetic method for the N-allylation of N-heterocyclic amides via an amide-aldehydealkene condensation. A variety of N-heterocyclic compounds and amides, including pyrimidin-2(1H)-ones, oxazolidinone, imidazolidinone, N-substituted imidazolidinones, quinazoline-2,5diones, piperidin-2-one, azepan-2-one, N-phenylacetamide, N-(2,6-dimethylphenyl) acetamide, N-methylbenzamide, and N-benzylbenzamide, have been used as substrates to give the Nallylic products. N-allylic thioamides, such as azepane-2-thione, were also applied in the reaction. We assume that both a Lewis acid and a Brønsted acid are important for the catalytic system, although using sole I2 as the catalyst was applicable in most cases (albeit in a lower yield). It is clear that the detailed reaction mechanism of amide-aldehyde-alkene condensation is very complicated, particularly the behaviour of different Lewis acids in different type of amides. In this regard, studies of the reaction mechanism, particularly the role of Lewis acids in the allylation reactions, are ongoing. A more generally catalytic system is needed for the threecomponent reaction, including amides, aldehydes, and alkenes. Due to the ubiquity of enantio-enriched amine having remained an important goal in chemistry for decades, the ability to be enantioselective in the allylation of amides by catalytic asymmetric amide-aldehyde-alkene condensation is an important goal. Ultimately, we aim to extend our research on amidealdehyde-alkene condensation into an amine-aldehyde-alkene condensation to access allylic amines.
Acknowledgements Financial support was provided by the financial support from the NSF of China (Nos. 21362032 and 21362031), and the Gansu Provincial Department of Finance.
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Received: July 7, 2015 Published online: January 25, 2016
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