ARTICLE Received 9 Feb 2014 | Accepted 15 Jul 2014 | Published 20 Aug 2014
DOI: 10.1038/ncomms5707
Silver-catalysed direct amination of unactivated C–H bonds of functionalized molecules Mingyu Yang1, Bo Su1, Yang Wang1, Kang Chen1, Xingyu Jiang1, Yun-Fei Zhang1, Xi-Sha Zhang1, Guihua Chen1, Ye Cheng1, Zhichao Cao1, Qing-Yun Guo1, Lushun Wang2 & Zhang-Jie Shi1,3,4
Carbon–nitrogen bond formation from inert C–H bonds is an ideal organic transformation and a highly desirable method for the synthesis of N-containing molecules due to its high efficiency and atom economy. In this report, we develop a general reaction to achieve an unprecedented selective intramolecular amination of unactivated C–H bond in the absence of complex directing groups. Functionalized heterocyclic products are built up from readily available linear amines through simple and reliable silver catalysis, representing a new silver-based C–H functionalization. This method displays preference for primary sp3 C–H bonds and exhibits distinct chemo- and regioselectivity compared to existing methods of direct amination (Hofmann–Lo¨ffler–Freytag reaction and nitrene insertion). The study highlights the manipulation of unfunctionalized groups in organic molecules to furnish complex structural units in the natural and bioactive molecules.
1 Beijing National Laboratory of Molecular Sciences (BNLMS) and Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education,
College of Chemistry and Green Chemistry Center, Peking University, Beijing 100871, China. 2 Shenzhen Graduate School of Peking University, Shenzhen 518055, China. 3 State Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin 300071, China. 4 State Key Laboratory of Organometallic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China. Correspondence and requests for materials should be addressed to Z.-J.S. (email: [email protected]). NATURE COMMUNICATIONS | 5:4707 | DOI: 10.1038/ncomms5707 | www.nature.com/naturecommunications
& 2014 Macmillan Publishers Limited. All rights reserved.
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ARTICLE
NATURE COMMUNICATIONS | DOI: 10.1038/ncomms5707
D
irect functionalization of inert C–H bonds is of great importance with the potential to fundamentally change the strategy of organic synthesis1–3. This chemistry can directly convert simple, cheap and readily available raw materials into highly valuable and useful products by the manipulation of inert unfunctionalized groups4–8. The greatest challenge in this field is therefore to achieve the chemo- and regioselectivity in C–H functionalization among many C–H bonds in organic molecules, while keeping an array of functional groups intact. In addition to the issue of selectivity, there are more challenges toward the direct functionalization of sp3 C–H bonds, including: their high bond dissociation energy, inaccessibility of the independent C–H bonding and antibonding orbitals as well as steric hindrance. In the past decades, great progress has been made in such fields to convert aliphatic sp3 C–H bonds to C–C, C–O and C–B bonds in either stoichiometric or catalytic manner based on transition-metal catalysis9–15. The present article focuses on the direct amination of inert Csp3–H bonds, especially primary C–H bonds to construct aza-heterocycles. Nitrogen-containing heterocycles, such as pyrrolidines, oxazolidines and tetrahydroquinolines, are dominant both in naturally occurring and man-made compounds, which often exhibit high levels of biological activity. In particular, the pyrrolidine and tetrahydroquinoline derivatives are privileged structural units in natural products and pharmaceuticals as exemplified by the structures of strychnine, folicanthine and mesembrine and so on (Fig. 1a)16–20. Many chemists have devoted themselves to searching for practical and convenient synthetic methods for accessing such ubiquitous structural units by direct oxidative amination of C–H bonds21–38. In fact, efforts toward such a goal can be traced back to the historical Hofmann–Lo¨ffler–Freytag reaction in early 19th century and its advanced versions-the Baldwin and Doll modification and the Sua´rez modification21–29. Another effective method for approaching direct amination of sp3 C–H bonds is to utilize nitrene insertion via transition-metal catalysis (Fig. 1b)30–33. Amongst these, silver complexes were first founded to promote the nitrene insertion34,35. Recently, Hennessy and Betley36 developed a successful example for carrying out such transformation via Fe catalysis under mild
conditions. The power of this strategy has also been demonstrated in the synthesis of the natural product tetrodotoxin37. Notably, the selectivity in these two elegant transformations is highly dependent on the nature of C–H bonds. In general, secondary and tertiary C–H bonds are much more reactive than the primary one for both reactions. Primary C–H bonds could be accessed only in cases of conformational bias38,39. To approach the primary selectivity of direct amination, Chen and Daugulis groups successfully developed a Pd-catalysed cyclization to specific ring systems by using a directing strategy while the manipulation of protecting group by multistep transformations limited its applications40–42.
H
N
H
Tf N
NHTf
H
H H
O
Strychnine
b
R3
R1 R2
Rh, Cu, Fe, etc
R1 R2
H
R1
R3 This chemistry NHTf
H
R2
R1 R2
3
R2
R1
Primary C–H amination H H
N Tf
R3
Figure 1 | Pyrroline structural active compounds and synthetic methods. (a) Diversified structures of alkalines containing semi-unsubstituted pyrroline structural units. (b) Secondary and tertiary aliphatic C–H amination through transition-metal catalyzed nitrene insertion and Hofmann–Lo¨ffler–Freytag reaction (HLF reaction). (c). Rational design on direct primary C–H amination via transition-metal catalysis. 2
2n (54%, dr = 93/7)c
1n (dr = 93/7)
Tf N
NHTf
Me Tf N
NHTf
1o (dr = 60/40) 2o (60%, dr = 60/40)a
Me Me
NHTf H
2g (66%, dr = 86/14)a
1g H
Me
Me Tf N
NHTf
Me
Me
H
Me
NTf
Tf N
2p (trace)d
1p
+
NHTf Me
Et
Tf N
H
2h (70%, 1:2, dr = 1:1)a NHTf
Et
2q (trace)d
1q
Tf N
OCOtBu
H
H
Tf N
NHTf
Et
H
2i (71%)c NHTf
nPr
1r
Tf N
Et
nPr
2r (24%, dr = 1:0.8)a Tf N
H
OCOPh
NHTf
OCOPh
Ph
Et
2j (72%)c
1j NHTf
1k
1s
2s (65%)c
H
Tf N
iPr
NHTf MeO
OTs
OTs Et
HLF reaction Better for 2° and 3° C–H
Me
2f (52%)a
1f
Nitrene insertion R3 Better for 2° and 3° C–H
N H
R N R R1 and/or R2 = alkyl, aryl
NXR
c H H
R1 R2
Strong acidic and thermo condition
R3
H X = CO; (–)-Mesembrine X = CH2; Mesembrane
OAc
OAc
OCOtBu
N Me
NHTf
H
H
2m (20%)a Tf N
Me
Tf N
NHTf
H
N3 H
X
H
2c 2d 2e (25%)b
Me
OMe
N N H CH3 R R = H, (+)-Chimonanthine R = Me, (+)-Folicanthine
O
R
(57%)b (43%)b
H
Tf N
H
NHTf
1m
1c (R = Me) 1d (R = n-Pr) 1e (R = Ph)
H
H
H
R
H
2l (28%)c
1l
O
Tf N
NHTf
NTf TfN
H
R
2a (70%)a 2b (66%)a
1i N
NHTf
H
R
1a (R = Me) 1b (R = Et)
R1 R2
R3
TfHN
OMe
H
O
K2CO3, PhCl/DCE
R2
1h R H3C H N N
AgOAc-dtbpy, PhI(OTFA)2,
R1
R3
H
a
Tf N
NHTf
MeO
Et
2k (73%)c
Tf N
iPr
1t
2t (73%)c
Figure 2 | Direct amination of primary and benzylic C–H bonds. The reaction scheme is shown above the table. aUnless otherwise noted, the reaction conditions were as follows: sulphonamide (0.25 mmol), AgOAc (20 mol%), PhI(OTFA)2 (2.0 equiv), ligand (20 mol%), K2CO3 (2.0 equiv), PhCl/dichloroethane (DCE) (1.5 ml/1.5 ml), 120 °C, 12 h. The isolated yield was shown in the parentheses. bSulphonamide (0.25 mmol), AgOAc (20 mol%), PhI(OTFA)2 (2.0 equiv), ligand (20 mol%), K2CO3 (4.0 equiv), PhF/Trichloroethane (1.5 ml/1.5 ml), 120 °C, 2 h; then another PhI(OTFA)2 (2.0 equiv) was added and the reaction was continued for another 2 h. cSulphonamide (0.10 mmol), AgOAc (20 mol%), PhI(OTFA) (2.0 equiv), 2 ligand (20 mol%), K2CO3 (2.0 equiv), PhCl/DCE (1.0 ml/1.0 ml), 120 °C, 12 h. dThe yield was determined by 1H NMR of the crude reaction mixture.
NATURE COMMUNICATIONS | 5:4707 | DOI: 10.1038/ncomms5707 | www.nature.com/naturecommunications
& 2014 Macmillan Publishers Limited. All rights reserved.
ARTICLE
NATURE COMMUNICATIONS | DOI: 10.1038/ncomms5707
R3
R1
R3
AgOAc-dtbpy, PhI(OTFA)2
NHTf
R H
K2CO3, PhCl/DCE
R2
NHTf H
F
N Tf
4a (73%)a
3a
H1
H
R2 R N Tf NHTf H2
F
H
NHTf
AgOAc (20 mol%) dtbpy (20 mol%) PhI(OTFA)2 (2.0 eq.)
NHTf
+
R1
Et
nPr
SM1 0.125 mmol
SM2 0.125 mmol
H1
64%
N Tf
H
3b
4b (53%)b
3e
NHTf
NHTf H2
+ Recovery SM2
Et
nPr
45%
35%
N Tf
H D NHTf
Tf N +
K2CO3 (2.0 eq.) PhCl/DCE (1.5 ml/1.5 ml) 12 h
4d (35%a, H1:H2 = 76:24c )
3d
Tf N
N Tf
4e (73%a, H1:H2 = 88:12c )
H2
Tf N
AgOAc (20 mol%) dtbpy (20 mol%)
H/D
PhI(OTFA)2 (2.0 eq.) K2CO3 (2.0 eq.) PhCl/DCE (1.0 ml/1.0 ml) 75 min, 15%
kH/kD = 2.8
H H
F
NHTf
F
H1
N Tf
3c O
4c
(44%a,c,
H1:H2
Me
=
1:0.3c )
O
O
H1
O
NHTf
H1
H
Me
4f
3f
Me
NHTf H2
(43%a,
4h
(57%)a
3g
4g
N Tf
H1:H2
=
H1:H2
=
88:12c )
NHTf H
3i
D D NHTf
kH/kD = 1.4
75 min, 13%
D N Tf
(50%a,
Tf N
H/D
PhI(OTFA)2 (2.0 eq.) K2CO3 (2.0 eq.) PhCl/DCE (1.0 ml/1.0 ml)
+
88:12c )
Me
N Tf
3h
AgOAc (20 mol%) dtbpy (20 mol%)
NHTf
NHTf H2
Figure 4 | Competition experiment and kinetic isotope effect. (a) Intermolecular competition experiment. (b) Intra/intermolecular kinetic isotope effect at benzylic position.
N Tf
Figure 3 | Direct amination of aromatic C–H bonds. aUnless otherwise noted, the reaction conditions were as follows: sulphonamide (0.25 mmol), AgOAc (1.0 equiv), PhI(OTFA)2 (2.0 equiv), ligand (20 mol%), K2CO3 (2.0 equiv), PhCl/dichloroethane (DCE) (1.5 ml/1.5 ml), 120 °C, 12 h. The isolated yield was shown in the parentheses. bSulphonamide (0.25 mmol), AgOAc (1.0 equiv), PhI(OTFA)2 (2.0 equiv), ligand (20 mol%), K2CO3 (2.0 equiv), PhCl/DCE(1.0 ml/1.0 ml), 120 °C, 2 h; then another PhI(OTFA)2 (2.0 equiv) was added and the reaction was continued for 2 h. cThe ratio was determined by crude 1H NMR of the crude reaction mixture.
To achieve the primary selectivity to construct the abundant five-membered heterocyclic products from easily available amine derivatives without the requirement of complicated directing groups, new strategies and new catalytic systems are highly desirable43,44. Notably, the compatibility with an array of the functionalities, the availability of the starting materials and the reliability of the new reaction system are important for potential applications. Herein, we report an unprecedented Ag-catalysed direct amination of primary sp3 C–H, secondary benzylic C–H and aryl C–H bonds from linear triflamide (1,1,1trifluoromethanesulfonamide) under simple conditions. This represents a powerful approach to access structures widely existing in natural products and druggable molecules. Results C–H cyclizations. We chose the sulphonamides as the substrates due to their easy availability and broad application in organic synthesis. After extensive screening of a variety of transitionmetal catalysts, oxidants, bases and ligands, we found that the combination of AgOAc, K2CO3, 4,40 -di-t-butyl-2,20 -bipyridine and PhI(OTFA)2 gave the best results and the desired pyrolidines were isolated from linear alkyltriflamide (Supplementary Tables 1–3). This method was successfully applied to a variety of triflamide derivatives, providing the cyclized products in fair to good yields (Fig. 2). Notably, the presence of substituents at the b-position is favourable for the transformation of products and good yields of 2a and 2b were obtained. a-Substitution decreased the yields and the examples indicate steric hindrance playing a key role in these annulations (2c–e). g-Substituted linear triflamide afforded the pyrrolidine product in a fair yield (2f).
H
OTFA
AcO
4i (< 10%)a
NHTf
Ag
N Tf
N
OAc N CF3COOH
N N TFAO Ag Tf N
N Ag N
OAc
H
TfN OAc
CF3COOH
PhI(OTFA)2
CF3 O
O
H
Ag
Ln Tf N
OAc
N TFAO Ag N H TfN OTFA
PhI
OAc
Figure 5 | The proposed catalytic cycle of direct amination via Ag catalysis. A concerted metallation/deprotonation (CMD) process.
Substrate 1g afforded 2g in a good yield with the expected preference for the trans isomer (86:14). Substrate scope. We further expanded the substrate scope containing heteroatom functional groups. To our satisfaction, we found that O-containing functional groups are well-tolerated (2i, 2j, 2k). Remarkably, the excellent leaving group –OTs (4-toluylsulfonoxyl) was compatible. The spirocyclic 2l was obtained from substrate 1l through double cyclization, albeit in relatively low yield. The 1,2-amino alcohol derivative 1m afforded oxazolidine 2m, indicating the enhanced reactivity of the C–H bond adjacent to the heteroatom in spite that the reaction leaves much room for the improvement. The protected amino alcohol 1n well proceeded the cyclization, with the retention of the stereogenic centres, providing an efficient method to produce unnatural proline derivatives. The five–six fused-ring compound 2o was formed in a satisfactory yield, and the diastereoselectivity was controlled by the starting materials. Compared with primary C–H bonds, secondary or tertiary C–H bonds exhibit poor reactivity, which is distinct from Hofmann–Lo¨ffler–Freytag reactions or nitrene insertions, thus probably pointing out the different mechanistic pathway 1p and 1q (after 12 h, 59% of 1p and 51% of 1q were recovered). Moreover, five-membered ring is
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ARTICLE
NATURE COMMUNICATIONS | DOI: 10.1038/ncomms5707
NHTf H
COOMe
1) AgOAc (1.0 eq.), dtbpy (20 mol%) PhI(OTFA)2 (2.0 eq.), K2CO3 (4.0 eq.) PhCl/DCE (1.0 ml/1.0 ml), 2 h
COOMe N Tf 6, 50%
2) PhI(OTFA)2 (2.0 eq.), 2 h
L-isoleu-5
NHTf COOMe
1) AgOAc (1.0 eq), dtbpy (20 mol%) PhI(OTFA)2 (2.0 eq.), K2CO3 (4.0 eq.) PhCl/DCE (1.0 ml/1.0 ml), 2 h
H
N Tf
2) PhI(OTFA)2 (2.0 eq.), 2 h
7 (±)
COOMe
8, 62%
NH N H
Me N MeO
N
HOOC OH
N H (–)-Martinellic acid
(–)-Codonopsinine TfHN H
9 H
NHTf
NH
N 12 Tf F2
C5
F5
F6
C6
C9 F2
X-ray for compound 10
C7
C8
F3
F2
03
F1
05
C13
04
C5
F1
C12
C9
C13 03
X-ray for compound 9
51
C11
C16
C16
F4
C10
N2
C14 F3
C5
N1
S2
S1
C7 04
C6
C3
04
C15
C4
05
C10
C13 C4
03 C15
N1
C9
C11 N1
C8
01
C3
C3
C2 C8
C14
S1
02
C4
C2
C1
02
F3
C12
01 02
C1
01
C6
C12
F1
C10
C2
10 TfN
C7
C11
O
O
PhCl/DCE (1.0 ml/1.0 ml), 10 h One step, 30%
11
C1
Tf N
AgOAc (2.0 eq.), 3,4,7,8-Tetramethyl-Phen (40 mol%) PhI(OTFA)2 (4.0 eq.), K2CO3 (4.0 eq.)
NHTf
H
H N
AgOAc (1.0 eq.) 4,4′-dimethoxy-2,2′-bipyridine (20 mol%) MeO O PhI(OTFA)2 (2.0 eq.), K2CO3 (2.0 eq.) PhCl/DCE (1.0 ml/1.0 ml), 12 h One step, 36%
O
MeO
H N
OH
X-ray for compound 12
Figure 6 | Direct amination of linear amino acids derivatives. (a) Direct amination to produce substituted proline and tetrahydroquinolyl carboxylic acid derivatives from linear amino acids. (b) Applications to the synthesis of natural structural scaffolds.
much favoured even in the presence of more reactive primary C–H bonds for the formation of six-membered ring (24% of the 1r was recovered). In contrast, the more reactive benzylic secondary C–H bonds in 1s and 1t could be addressed, expanding the scope for further applications. Due to the distinct proposed pathway of such an amination from previous methods, we envisioned that this chemistry could be applicable for direct amination of aromatic C–H bonds. Thus, we extended this chemistry to build up the structurally important tetrahydroquinoline scaffolds from 3-arylpropyl triflamide 3 (Fig. 3). A series of g-aryl substituted sulphonamides were examined and it was found that: (1) substituented aliphatic motifs at different positions do not obviously affect the efficiency; (2) electron-rich aromatics react preferentially; (3) compared with the inert primary sp3 C–H bond, the sp2 C–H bond on the aromatic ring is more reactive; and (4) notably, functionalized substrate 3h also exhibited good reactivity, thus indicating great potential for their applications. Competition experiments. Competition experiment between primary C–H bonds and secondary C–H bonds was carried 4
out (Supplementary Fig. 1). As predicted, the preference for amination is CMe–H4 4Cmethylene H (Fig. 4a). The KIE experiments have been conducted and we found that the intramolecular and intermolecular kinetic isotopic effect values at the benzylic position were 2.8 and 1.4, respectively (Supplementary Figs 2 and 3). On the basis of all these results, we proposed that this transformation was preferred to a proton abstraction pathway. With the assistance of strong s-donor chelating N-ligands, the silver complex could be oxidized to Ag(III) after the ligand exchange. The hyperelectrophilic Ag(III) centre attacks the less steric hindered the primary C–H bonds, followed by electrophilic deprotonation, which probably goes through a concerted metallation/deprotonation process in the presence of TFAO (1,1,1-trifluoroacetate anion) as a base. Afterwards, the reductive elimination produced the desired product, releasing Ag(I) to fulfil the catalytic cycle (Fig. 5). The steric and electronic outcomes based on different substrates are consistent with this hypothesis. In some cases, a small amount of the desired product is also observed in the absence of the Ag catalyst, indicating the competitive existing radical pathway, which may induce the low KIE in kinetic studies.
NATURE COMMUNICATIONS | 5:4707 | DOI: 10.1038/ncomms5707 | www.nature.com/naturecommunications
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ARTICLE
NATURE COMMUNICATIONS | DOI: 10.1038/ncomms5707
Use of amino esters. To show the power of this method, the protected linear amino acid esters 5 and 7 were submitted to the standard condition, and both 3-methylproline 6 and 2-tetrahydroquinonylcarboxilic ester 8 were obtained in satisfying yield. Moreover, more complicated 9 is also converted into tetrasubstituted pyrrolidine 10 as the epimer of natural ( )codonopsinine with a sole diastereoisomer in a single operation. To our satisfaction, tricyclic scaffold 12, containing the core structure of the natural product martinellic acid, can be also constructed via double aminations, in which both primary Csp3–H and aromatic CAr–H are aminated in a single operation, showing the beauty of this chemistry in organic synthesis. In conclusion, we first developed an unprecedented siteselective amination of C–H bonds without the requirement of special complicated directing groups. N-heterocyclic products bearing complex functionalities were constructed from simple and easily available linear triflamines via reliable and easily handled Ag catalysis. The method displayed unique chemo- and regioselectivities that differed from the existing methods. This study highlighted the manipulation of unfunctionalized groups in organic molecules to furnish the complex privileged structural units in the synthesis of natural products and bioactive molecules using a new pathway that is broadly applicable in organic synthesis. Methods Materials. Materials were obtained from commercial suppliers or prepared according to standard procedures unless otherwise noted. AgOAc and PhI(OTFA)2 were purchased from J&K Chemical Co., Ltd. 4,40 -Di-tert-butyl-2,20 -dipyridyl was purchased from Sigma-Aldrich. Potassium carbonate, anhydrous (K2CO3) was purchased from Alfa Aesar used without any further purification. All the solvents and other reagents were directly used from the purchased without any further purification unless otherwise specified. General spectroscopic methods. For NMR and X-ray analysis of compounds in this paper, see Supplementary Figs 1–140 and Supplementary Tables 4–6. NMR spectra were recorded on Bruker 400 and 500 M nuclear resonance spectrometers unless otherwise specified. CDCl3 as solvent and tetramethylsilane (TMS) as the internal standard were employed. Chemical shift values for 1H NMR and 13C NMR are referenced to residual solvent peaks (CHCl3 in CDCl3: 7.26 p.p.m. for 1H, 77.00 p.p.m. for 13C). Chemical shifts are reported in d p.p.m. All coupling constants (J values) were reported in Hertz (Hz). Data for 1H NMR spectra are reported as follows: chemical shift (p.p.m., referenced to TMS; s ¼ singlet, d ¼ doublet, t ¼ triplet, q ¼ quartet, dd ¼ doublet of doublets, dt ¼ doublet of triplets, m ¼ multiplet), coupling constant (Hz) and integration. 19F NMR data was obtained on Varian 300 M nucleus resonance spectrometers. Column chromatography was performed on silica gel 200–300 mesh. HRMS (high-resolution mass spectra) were recorded on a Bruker Apex IV FTMS mass spectrometer (ESI) in the State-authorized Analytical Center at Peking University. 1H NMR, 13C NMR and ESI spectra are provided for all compounds. See the Supplementary Methods for the characterization data for compounds not listed in this section. Synthesis of 3-Methyl-1-(trifluoromethyl)sulfonyl-pyrrolidine 2a. Silver acetate (AgOAc, 8.3 mg, 0.05 mmol), 4,40 -Di-tert-butyl-2,20 -dipyridyl (dtbpy, 13.4 mg, 0.05 mmol), [Bis(trifluoroacetoxy)iodo]benzene (PhI(OTFA)2, 215 mg, 0.5 mmol) and potassium carbonate (K2CO3, 69 mg, 0.5 mmol) were placed in a vial under air. Chlorobenzene (PhCl, 1.5 ml), triflamide 1a (54.8 mg, 0.25 mmol), dichloroethane (1.5 ml) were sequentially added. The mixture was stirred at room temperature for 5 min and then was stirred for 12 h at 120 °C. After the reaction mixture was cooled to room temperature, direct flash silica gel column purification (eluent: 100 ml of PE; then PE/DCM/Et2O 250/20/5) of the reaction solution provided 2a (40 mg, 0.17 mmol) in 70% isolated yield. (Because the boiling point of desired product is low, the solvent should be evaporated under low temperature). Colourless oil. 1H NMR (400 MHz, CDCl3) d 3.63–3.71 (m, 2H), 3.52 (q, J ¼ 8.0 Hz, 1H), 3.06 (t, J ¼ 8.0 Hz, 1H), 2.40 (octet, J ¼ 8.0 Hz, 1H), 2.13 (sext, J ¼ 8.0 Hz, 1H), 1.65 (tq, J ¼ 8.0, 12.0 Hz, 1H), 1.11 (d, J ¼ 4.0 Hz, 3H). 13C NMR (100 MHz, CDCl3) d 120.44 (q, J ¼ 322.0 Hz), 55.32, 48.56, 33.90, 33.57, 17.00. HRMS–ESI (m/z): [M þ Na] þ calcd for C6H10F3NNaO2S, 240.02765; found, 246.02789.
References 1. Gutekunst, W. R. & Baran, P. S. C–H functionalization logic in total synthesis. Chem. Soc. Rev. 40, 1976–1991 (2011).
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33. Davies, H. M. L. & Manning, J. R. Catalytic C–H functionalization by metal carbenoid and nitrenoid insertion. Nature 451, 417–424 (2008). 34. Cui, Y. & He, C. A Silver-catalyzed intramolecular amidation of saturated C–H bonds. Angew. Chem. Int. Ed. 43, 4210–4212 (2004). 35. Li, Z., Capretto, D. A., Rahaman, R. & He, C. Silver-catalyzed intermolecular amination of C–H groups. Angew. Chem. Int. Ed. 46, 5184–5186 (2007). 36. Hennessy, E. T. & Betley, T. A. Complex N-heterocycle synthesis via iron-catalyzed, direct C–H bond amination. Science 340, 591–595 (2013). 37. Ahrendt, K. A., Bergman, R. G. & Ellman, J. A. Synthesis of a tricyclic mescaline analogue by catalytic C–H bond activation. Org. Lett. 5, 1301–1303 (2003). 38. Corey, E. J. & Hertler, W. R. A study of the formation of haloamines and cyclic amines by the free radical chain decomposition of N-haloammonium ions (Hofmann-Lo¨ffler Reaction)1. J. Am. Chem. Soc. 82, 1657–1668 (1960). 39. Huard, K. & Lebel, H. N-tosyloxycarbamates as reagents in rhodium-catalyzed C–H amination reactions. Chemistry 14, 6222–6230 (2008). 40. He, G., Zhao, Y., Zhang, S., Lu, C. & Chen, G. Highly efficient syntheses of azetidines, pyrrolidines, and indolines via palladium catalyzed intramolecular amination of C(sp3)–H and C(sp2)–H bonds at g and d positions. J. Am. Chem. Soc. 134, 3–6 (2012). 41. Nadres, E. T. & Daugulis, O. Heterocycle synthesis via direct C–H/N–H coupling. J. Am. Chem. Soc. 134, 7–10 (2012). 42. Zhang, S.-Y., He, G., Zhao, Y., Wright, W. A. & Chen, G. Efficient alkyl ether synthesis via palladium-catalyzed, picolinamide-directed alkoxylation of unactivated C(sp3)–H and C(sp2)–H bonds at remote positions. J. Am. Chem. Soc. 134, 7313–7316 (2012). 43. Li, J.-J., Mei, T.-S. & Yu, J.-Q. Synthesis of indolines and tetrahydroisoquinolines from arylethylamines by PdII-catalyzed C–H activation reactions. Angew. Chem. Int. Ed. 47, 6452–6455 (2008). 44. Mei, T.-S., Wang, X. & Yu, J.-Q. Pd(II)-catalyzed amination of C–H bonds using single-electron or two-electron oxidants. J. Am. Chem. Soc. 131, 10806–10807 (2009).
6
Acknowledgements We gratefully acknowledge the financial support by the ‘973’ Project from the MOST of China (2013CB228102, 2009CB825300) and NSFC (Nos 20925207 and 21002001). M.Y. thanks China Postdoctoral science foundation Grant (2013M530465). We thank Professor E.P. Ku¨ndig for assistance on the manuscript revision.
Author contributions Z.-J.S. directed the research. M.Y. performed the experiments and analysed the data. B.S. worked on the synthesis of scaffold 12. Y.W. worked on the synthesis of scaffold 10 and some other starting materials. K.C., X.J., Y.-F.Z., X.-S.Z., G.C., Y.C., Z.C., Q.-Y.G. and L.W. worked on product isolation, purification and starting materials preparation. M.Y. and Z.-J.S. wrote the paper. M.Y. wrote the Supplementary Information and contributed other related materials.
Additional information Accession codes: The X-ray crystallographic structures for 9,10,12 reported in this article have been deposited at the Cambridge Crystallographic Data Centre (CCDC), under deposition number CCDC 1005416, 1005417,1005418. These data can be obtained free of charge from the Cambridge Crystallographic Data Centre via http://www.ccdc.cam. ac.uk/ data_request/cif. Supplementary Information accompanies this paper at http://www.nature.com/ naturecommunications Competing financial interests: The authors declare no competing financial interests. Reprints and permission information is available online at http://npg.nature.com/ reprintsandpermissions/ How to cite this article: Yang, M. et al. Silver-catalysed direct amination of unactivated C–H bonds of functionalized molecules. Nat. Commun. 5:4707 doi: 10.1038/ncomms5707 (2014).
NATURE COMMUNICATIONS | 5:4707 | DOI: 10.1038/ncomms5707 | www.nature.com/naturecommunications
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DOI: 10.1038/ncomms5707
Silver-catalysed direct amination of unactivated C–H bonds of functionalized molecules Mingyu Yang1, Bo Su1, Yang Wang1, Kang Chen1, Xingyu Jiang1, Yun-Fei Zhang1, Xi-Sha Zhang1, Guihua Chen1, Ye Cheng1, Zhichao Cao1, Qing-Yun Guo1, Lushun Wang2 & Zhang-Jie Shi1,3,4
Carbon–nitrogen bond formation from inert C–H bonds is an ideal organic transformation and a highly desirable method for the synthesis of N-containing molecules due to its high efficiency and atom economy. In this report, we develop a general reaction to achieve an unprecedented selective intramolecular amination of unactivated C–H bond in the absence of complex directing groups. Functionalized heterocyclic products are built up from readily available linear amines through simple and reliable silver catalysis, representing a new silver-based C–H functionalization. This method displays preference for primary sp3 C–H bonds and exhibits distinct chemo- and regioselectivity compared to existing methods of direct amination (Hofmann–Lo¨ffler–Freytag reaction and nitrene insertion). The study highlights the manipulation of unfunctionalized groups in organic molecules to furnish complex structural units in the natural and bioactive molecules.
1 Beijing National Laboratory of Molecular Sciences (BNLMS) and Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education,
College of Chemistry and Green Chemistry Center, Peking University, Beijing 100871, China. 2 Shenzhen Graduate School of Peking University, Shenzhen 518055, China. 3 State Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin 300071, China. 4 State Key Laboratory of Organometallic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China. Correspondence and requests for materials should be addressed to Z.-J.S. (email: [email protected]). NATURE COMMUNICATIONS | 5:4707 | DOI: 10.1038/ncomms5707 | www.nature.com/naturecommunications
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ARTICLE
NATURE COMMUNICATIONS | DOI: 10.1038/ncomms5707
D
irect functionalization of inert C–H bonds is of great importance with the potential to fundamentally change the strategy of organic synthesis1–3. This chemistry can directly convert simple, cheap and readily available raw materials into highly valuable and useful products by the manipulation of inert unfunctionalized groups4–8. The greatest challenge in this field is therefore to achieve the chemo- and regioselectivity in C–H functionalization among many C–H bonds in organic molecules, while keeping an array of functional groups intact. In addition to the issue of selectivity, there are more challenges toward the direct functionalization of sp3 C–H bonds, including: their high bond dissociation energy, inaccessibility of the independent C–H bonding and antibonding orbitals as well as steric hindrance. In the past decades, great progress has been made in such fields to convert aliphatic sp3 C–H bonds to C–C, C–O and C–B bonds in either stoichiometric or catalytic manner based on transition-metal catalysis9–15. The present article focuses on the direct amination of inert Csp3–H bonds, especially primary C–H bonds to construct aza-heterocycles. Nitrogen-containing heterocycles, such as pyrrolidines, oxazolidines and tetrahydroquinolines, are dominant both in naturally occurring and man-made compounds, which often exhibit high levels of biological activity. In particular, the pyrrolidine and tetrahydroquinoline derivatives are privileged structural units in natural products and pharmaceuticals as exemplified by the structures of strychnine, folicanthine and mesembrine and so on (Fig. 1a)16–20. Many chemists have devoted themselves to searching for practical and convenient synthetic methods for accessing such ubiquitous structural units by direct oxidative amination of C–H bonds21–38. In fact, efforts toward such a goal can be traced back to the historical Hofmann–Lo¨ffler–Freytag reaction in early 19th century and its advanced versions-the Baldwin and Doll modification and the Sua´rez modification21–29. Another effective method for approaching direct amination of sp3 C–H bonds is to utilize nitrene insertion via transition-metal catalysis (Fig. 1b)30–33. Amongst these, silver complexes were first founded to promote the nitrene insertion34,35. Recently, Hennessy and Betley36 developed a successful example for carrying out such transformation via Fe catalysis under mild
conditions. The power of this strategy has also been demonstrated in the synthesis of the natural product tetrodotoxin37. Notably, the selectivity in these two elegant transformations is highly dependent on the nature of C–H bonds. In general, secondary and tertiary C–H bonds are much more reactive than the primary one for both reactions. Primary C–H bonds could be accessed only in cases of conformational bias38,39. To approach the primary selectivity of direct amination, Chen and Daugulis groups successfully developed a Pd-catalysed cyclization to specific ring systems by using a directing strategy while the manipulation of protecting group by multistep transformations limited its applications40–42.
H
N
H
Tf N
NHTf
H
H H
O
Strychnine
b
R3
R1 R2
Rh, Cu, Fe, etc
R1 R2
H
R1
R3 This chemistry NHTf
H
R2
R1 R2
3
R2
R1
Primary C–H amination H H
N Tf
R3
Figure 1 | Pyrroline structural active compounds and synthetic methods. (a) Diversified structures of alkalines containing semi-unsubstituted pyrroline structural units. (b) Secondary and tertiary aliphatic C–H amination through transition-metal catalyzed nitrene insertion and Hofmann–Lo¨ffler–Freytag reaction (HLF reaction). (c). Rational design on direct primary C–H amination via transition-metal catalysis. 2
2n (54%, dr = 93/7)c
1n (dr = 93/7)
Tf N
NHTf
Me Tf N
NHTf
1o (dr = 60/40) 2o (60%, dr = 60/40)a
Me Me
NHTf H
2g (66%, dr = 86/14)a
1g H
Me
Me Tf N
NHTf
Me
Me
H
Me
NTf
Tf N
2p (trace)d
1p
+
NHTf Me
Et
Tf N
H
2h (70%, 1:2, dr = 1:1)a NHTf
Et
2q (trace)d
1q
Tf N
OCOtBu
H
H
Tf N
NHTf
Et
H
2i (71%)c NHTf
nPr
1r
Tf N
Et
nPr
2r (24%, dr = 1:0.8)a Tf N
H
OCOPh
NHTf
OCOPh
Ph
Et
2j (72%)c
1j NHTf
1k
1s
2s (65%)c
H
Tf N
iPr
NHTf MeO
OTs
OTs Et
HLF reaction Better for 2° and 3° C–H
Me
2f (52%)a
1f
Nitrene insertion R3 Better for 2° and 3° C–H
N H
R N R R1 and/or R2 = alkyl, aryl
NXR
c H H
R1 R2
Strong acidic and thermo condition
R3
H X = CO; (–)-Mesembrine X = CH2; Mesembrane
OAc
OAc
OCOtBu
N Me
NHTf
H
H
2m (20%)a Tf N
Me
Tf N
NHTf
H
N3 H
X
H
2c 2d 2e (25%)b
Me
OMe
N N H CH3 R R = H, (+)-Chimonanthine R = Me, (+)-Folicanthine
O
R
(57%)b (43%)b
H
Tf N
H
NHTf
1m
1c (R = Me) 1d (R = n-Pr) 1e (R = Ph)
H
H
H
R
H
2l (28%)c
1l
O
Tf N
NHTf
NTf TfN
H
R
2a (70%)a 2b (66%)a
1i N
NHTf
H
R
1a (R = Me) 1b (R = Et)
R1 R2
R3
TfHN
OMe
H
O
K2CO3, PhCl/DCE
R2
1h R H3C H N N
AgOAc-dtbpy, PhI(OTFA)2,
R1
R3
H
a
Tf N
NHTf
MeO
Et
2k (73%)c
Tf N
iPr
1t
2t (73%)c
Figure 2 | Direct amination of primary and benzylic C–H bonds. The reaction scheme is shown above the table. aUnless otherwise noted, the reaction conditions were as follows: sulphonamide (0.25 mmol), AgOAc (20 mol%), PhI(OTFA)2 (2.0 equiv), ligand (20 mol%), K2CO3 (2.0 equiv), PhCl/dichloroethane (DCE) (1.5 ml/1.5 ml), 120 °C, 12 h. The isolated yield was shown in the parentheses. bSulphonamide (0.25 mmol), AgOAc (20 mol%), PhI(OTFA)2 (2.0 equiv), ligand (20 mol%), K2CO3 (4.0 equiv), PhF/Trichloroethane (1.5 ml/1.5 ml), 120 °C, 2 h; then another PhI(OTFA)2 (2.0 equiv) was added and the reaction was continued for another 2 h. cSulphonamide (0.10 mmol), AgOAc (20 mol%), PhI(OTFA) (2.0 equiv), 2 ligand (20 mol%), K2CO3 (2.0 equiv), PhCl/DCE (1.0 ml/1.0 ml), 120 °C, 12 h. dThe yield was determined by 1H NMR of the crude reaction mixture.
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NATURE COMMUNICATIONS | DOI: 10.1038/ncomms5707
R3
R1
R3
AgOAc-dtbpy, PhI(OTFA)2
NHTf
R H
K2CO3, PhCl/DCE
R2
NHTf H
F
N Tf
4a (73%)a
3a
H1
H
R2 R N Tf NHTf H2
F
H
NHTf
AgOAc (20 mol%) dtbpy (20 mol%) PhI(OTFA)2 (2.0 eq.)
NHTf
+
R1
Et
nPr
SM1 0.125 mmol
SM2 0.125 mmol
H1
64%
N Tf
H
3b
4b (53%)b
3e
NHTf
NHTf H2
+ Recovery SM2
Et
nPr
45%
35%
N Tf
H D NHTf
Tf N +
K2CO3 (2.0 eq.) PhCl/DCE (1.5 ml/1.5 ml) 12 h
4d (35%a, H1:H2 = 76:24c )
3d
Tf N
N Tf
4e (73%a, H1:H2 = 88:12c )
H2
Tf N
AgOAc (20 mol%) dtbpy (20 mol%)
H/D
PhI(OTFA)2 (2.0 eq.) K2CO3 (2.0 eq.) PhCl/DCE (1.0 ml/1.0 ml) 75 min, 15%
kH/kD = 2.8
H H
F
NHTf
F
H1
N Tf
3c O
4c
(44%a,c,
H1:H2
Me
=
1:0.3c )
O
O
H1
O
NHTf
H1
H
Me
4f
3f
Me
NHTf H2
(43%a,
4h
(57%)a
3g
4g
N Tf
H1:H2
=
H1:H2
=
88:12c )
NHTf H
3i
D D NHTf
kH/kD = 1.4
75 min, 13%
D N Tf
(50%a,
Tf N
H/D
PhI(OTFA)2 (2.0 eq.) K2CO3 (2.0 eq.) PhCl/DCE (1.0 ml/1.0 ml)
+
88:12c )
Me
N Tf
3h
AgOAc (20 mol%) dtbpy (20 mol%)
NHTf
NHTf H2
Figure 4 | Competition experiment and kinetic isotope effect. (a) Intermolecular competition experiment. (b) Intra/intermolecular kinetic isotope effect at benzylic position.
N Tf
Figure 3 | Direct amination of aromatic C–H bonds. aUnless otherwise noted, the reaction conditions were as follows: sulphonamide (0.25 mmol), AgOAc (1.0 equiv), PhI(OTFA)2 (2.0 equiv), ligand (20 mol%), K2CO3 (2.0 equiv), PhCl/dichloroethane (DCE) (1.5 ml/1.5 ml), 120 °C, 12 h. The isolated yield was shown in the parentheses. bSulphonamide (0.25 mmol), AgOAc (1.0 equiv), PhI(OTFA)2 (2.0 equiv), ligand (20 mol%), K2CO3 (2.0 equiv), PhCl/DCE(1.0 ml/1.0 ml), 120 °C, 2 h; then another PhI(OTFA)2 (2.0 equiv) was added and the reaction was continued for 2 h. cThe ratio was determined by crude 1H NMR of the crude reaction mixture.
To achieve the primary selectivity to construct the abundant five-membered heterocyclic products from easily available amine derivatives without the requirement of complicated directing groups, new strategies and new catalytic systems are highly desirable43,44. Notably, the compatibility with an array of the functionalities, the availability of the starting materials and the reliability of the new reaction system are important for potential applications. Herein, we report an unprecedented Ag-catalysed direct amination of primary sp3 C–H, secondary benzylic C–H and aryl C–H bonds from linear triflamide (1,1,1trifluoromethanesulfonamide) under simple conditions. This represents a powerful approach to access structures widely existing in natural products and druggable molecules. Results C–H cyclizations. We chose the sulphonamides as the substrates due to their easy availability and broad application in organic synthesis. After extensive screening of a variety of transitionmetal catalysts, oxidants, bases and ligands, we found that the combination of AgOAc, K2CO3, 4,40 -di-t-butyl-2,20 -bipyridine and PhI(OTFA)2 gave the best results and the desired pyrolidines were isolated from linear alkyltriflamide (Supplementary Tables 1–3). This method was successfully applied to a variety of triflamide derivatives, providing the cyclized products in fair to good yields (Fig. 2). Notably, the presence of substituents at the b-position is favourable for the transformation of products and good yields of 2a and 2b were obtained. a-Substitution decreased the yields and the examples indicate steric hindrance playing a key role in these annulations (2c–e). g-Substituted linear triflamide afforded the pyrrolidine product in a fair yield (2f).
H
OTFA
AcO
4i (< 10%)a
NHTf
Ag
N Tf
N
OAc N CF3COOH
N N TFAO Ag Tf N
N Ag N
OAc
H
TfN OAc
CF3COOH
PhI(OTFA)2
CF3 O
O
H
Ag
Ln Tf N
OAc
N TFAO Ag N H TfN OTFA
PhI
OAc
Figure 5 | The proposed catalytic cycle of direct amination via Ag catalysis. A concerted metallation/deprotonation (CMD) process.
Substrate 1g afforded 2g in a good yield with the expected preference for the trans isomer (86:14). Substrate scope. We further expanded the substrate scope containing heteroatom functional groups. To our satisfaction, we found that O-containing functional groups are well-tolerated (2i, 2j, 2k). Remarkably, the excellent leaving group –OTs (4-toluylsulfonoxyl) was compatible. The spirocyclic 2l was obtained from substrate 1l through double cyclization, albeit in relatively low yield. The 1,2-amino alcohol derivative 1m afforded oxazolidine 2m, indicating the enhanced reactivity of the C–H bond adjacent to the heteroatom in spite that the reaction leaves much room for the improvement. The protected amino alcohol 1n well proceeded the cyclization, with the retention of the stereogenic centres, providing an efficient method to produce unnatural proline derivatives. The five–six fused-ring compound 2o was formed in a satisfactory yield, and the diastereoselectivity was controlled by the starting materials. Compared with primary C–H bonds, secondary or tertiary C–H bonds exhibit poor reactivity, which is distinct from Hofmann–Lo¨ffler–Freytag reactions or nitrene insertions, thus probably pointing out the different mechanistic pathway 1p and 1q (after 12 h, 59% of 1p and 51% of 1q were recovered). Moreover, five-membered ring is
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NHTf H
COOMe
1) AgOAc (1.0 eq.), dtbpy (20 mol%) PhI(OTFA)2 (2.0 eq.), K2CO3 (4.0 eq.) PhCl/DCE (1.0 ml/1.0 ml), 2 h
COOMe N Tf 6, 50%
2) PhI(OTFA)2 (2.0 eq.), 2 h
L-isoleu-5
NHTf COOMe
1) AgOAc (1.0 eq), dtbpy (20 mol%) PhI(OTFA)2 (2.0 eq.), K2CO3 (4.0 eq.) PhCl/DCE (1.0 ml/1.0 ml), 2 h
H
N Tf
2) PhI(OTFA)2 (2.0 eq.), 2 h
7 (±)
COOMe
8, 62%
NH N H
Me N MeO
N
HOOC OH
N H (–)-Martinellic acid
(–)-Codonopsinine TfHN H
9 H
NHTf
NH
N 12 Tf F2
C5
F5
F6
C6
C9 F2
X-ray for compound 10
C7
C8
F3
F2
03
F1
05
C13
04
C5
F1
C12
C9
C13 03
X-ray for compound 9
51
C11
C16
C16
F4
C10
N2
C14 F3
C5
N1
S2
S1
C7 04
C6
C3
04
C15
C4
05
C10
C13 C4
03 C15
N1
C9
C11 N1
C8
01
C3
C3
C2 C8
C14
S1
02
C4
C2
C1
02
F3
C12
01 02
C1
01
C6
C12
F1
C10
C2
10 TfN
C7
C11
O
O
PhCl/DCE (1.0 ml/1.0 ml), 10 h One step, 30%
11
C1
Tf N
AgOAc (2.0 eq.), 3,4,7,8-Tetramethyl-Phen (40 mol%) PhI(OTFA)2 (4.0 eq.), K2CO3 (4.0 eq.)
NHTf
H
H N
AgOAc (1.0 eq.) 4,4′-dimethoxy-2,2′-bipyridine (20 mol%) MeO O PhI(OTFA)2 (2.0 eq.), K2CO3 (2.0 eq.) PhCl/DCE (1.0 ml/1.0 ml), 12 h One step, 36%
O
MeO
H N
OH
X-ray for compound 12
Figure 6 | Direct amination of linear amino acids derivatives. (a) Direct amination to produce substituted proline and tetrahydroquinolyl carboxylic acid derivatives from linear amino acids. (b) Applications to the synthesis of natural structural scaffolds.
much favoured even in the presence of more reactive primary C–H bonds for the formation of six-membered ring (24% of the 1r was recovered). In contrast, the more reactive benzylic secondary C–H bonds in 1s and 1t could be addressed, expanding the scope for further applications. Due to the distinct proposed pathway of such an amination from previous methods, we envisioned that this chemistry could be applicable for direct amination of aromatic C–H bonds. Thus, we extended this chemistry to build up the structurally important tetrahydroquinoline scaffolds from 3-arylpropyl triflamide 3 (Fig. 3). A series of g-aryl substituted sulphonamides were examined and it was found that: (1) substituented aliphatic motifs at different positions do not obviously affect the efficiency; (2) electron-rich aromatics react preferentially; (3) compared with the inert primary sp3 C–H bond, the sp2 C–H bond on the aromatic ring is more reactive; and (4) notably, functionalized substrate 3h also exhibited good reactivity, thus indicating great potential for their applications. Competition experiments. Competition experiment between primary C–H bonds and secondary C–H bonds was carried 4
out (Supplementary Fig. 1). As predicted, the preference for amination is CMe–H4 4Cmethylene H (Fig. 4a). The KIE experiments have been conducted and we found that the intramolecular and intermolecular kinetic isotopic effect values at the benzylic position were 2.8 and 1.4, respectively (Supplementary Figs 2 and 3). On the basis of all these results, we proposed that this transformation was preferred to a proton abstraction pathway. With the assistance of strong s-donor chelating N-ligands, the silver complex could be oxidized to Ag(III) after the ligand exchange. The hyperelectrophilic Ag(III) centre attacks the less steric hindered the primary C–H bonds, followed by electrophilic deprotonation, which probably goes through a concerted metallation/deprotonation process in the presence of TFAO (1,1,1-trifluoroacetate anion) as a base. Afterwards, the reductive elimination produced the desired product, releasing Ag(I) to fulfil the catalytic cycle (Fig. 5). The steric and electronic outcomes based on different substrates are consistent with this hypothesis. In some cases, a small amount of the desired product is also observed in the absence of the Ag catalyst, indicating the competitive existing radical pathway, which may induce the low KIE in kinetic studies.
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Use of amino esters. To show the power of this method, the protected linear amino acid esters 5 and 7 were submitted to the standard condition, and both 3-methylproline 6 and 2-tetrahydroquinonylcarboxilic ester 8 were obtained in satisfying yield. Moreover, more complicated 9 is also converted into tetrasubstituted pyrrolidine 10 as the epimer of natural ( )codonopsinine with a sole diastereoisomer in a single operation. To our satisfaction, tricyclic scaffold 12, containing the core structure of the natural product martinellic acid, can be also constructed via double aminations, in which both primary Csp3–H and aromatic CAr–H are aminated in a single operation, showing the beauty of this chemistry in organic synthesis. In conclusion, we first developed an unprecedented siteselective amination of C–H bonds without the requirement of special complicated directing groups. N-heterocyclic products bearing complex functionalities were constructed from simple and easily available linear triflamines via reliable and easily handled Ag catalysis. The method displayed unique chemo- and regioselectivities that differed from the existing methods. This study highlighted the manipulation of unfunctionalized groups in organic molecules to furnish the complex privileged structural units in the synthesis of natural products and bioactive molecules using a new pathway that is broadly applicable in organic synthesis. Methods Materials. Materials were obtained from commercial suppliers or prepared according to standard procedures unless otherwise noted. AgOAc and PhI(OTFA)2 were purchased from J&K Chemical Co., Ltd. 4,40 -Di-tert-butyl-2,20 -dipyridyl was purchased from Sigma-Aldrich. Potassium carbonate, anhydrous (K2CO3) was purchased from Alfa Aesar used without any further purification. All the solvents and other reagents were directly used from the purchased without any further purification unless otherwise specified. General spectroscopic methods. For NMR and X-ray analysis of compounds in this paper, see Supplementary Figs 1–140 and Supplementary Tables 4–6. NMR spectra were recorded on Bruker 400 and 500 M nuclear resonance spectrometers unless otherwise specified. CDCl3 as solvent and tetramethylsilane (TMS) as the internal standard were employed. Chemical shift values for 1H NMR and 13C NMR are referenced to residual solvent peaks (CHCl3 in CDCl3: 7.26 p.p.m. for 1H, 77.00 p.p.m. for 13C). Chemical shifts are reported in d p.p.m. All coupling constants (J values) were reported in Hertz (Hz). Data for 1H NMR spectra are reported as follows: chemical shift (p.p.m., referenced to TMS; s ¼ singlet, d ¼ doublet, t ¼ triplet, q ¼ quartet, dd ¼ doublet of doublets, dt ¼ doublet of triplets, m ¼ multiplet), coupling constant (Hz) and integration. 19F NMR data was obtained on Varian 300 M nucleus resonance spectrometers. Column chromatography was performed on silica gel 200–300 mesh. HRMS (high-resolution mass spectra) were recorded on a Bruker Apex IV FTMS mass spectrometer (ESI) in the State-authorized Analytical Center at Peking University. 1H NMR, 13C NMR and ESI spectra are provided for all compounds. See the Supplementary Methods for the characterization data for compounds not listed in this section. Synthesis of 3-Methyl-1-(trifluoromethyl)sulfonyl-pyrrolidine 2a. Silver acetate (AgOAc, 8.3 mg, 0.05 mmol), 4,40 -Di-tert-butyl-2,20 -dipyridyl (dtbpy, 13.4 mg, 0.05 mmol), [Bis(trifluoroacetoxy)iodo]benzene (PhI(OTFA)2, 215 mg, 0.5 mmol) and potassium carbonate (K2CO3, 69 mg, 0.5 mmol) were placed in a vial under air. Chlorobenzene (PhCl, 1.5 ml), triflamide 1a (54.8 mg, 0.25 mmol), dichloroethane (1.5 ml) were sequentially added. The mixture was stirred at room temperature for 5 min and then was stirred for 12 h at 120 °C. After the reaction mixture was cooled to room temperature, direct flash silica gel column purification (eluent: 100 ml of PE; then PE/DCM/Et2O 250/20/5) of the reaction solution provided 2a (40 mg, 0.17 mmol) in 70% isolated yield. (Because the boiling point of desired product is low, the solvent should be evaporated under low temperature). Colourless oil. 1H NMR (400 MHz, CDCl3) d 3.63–3.71 (m, 2H), 3.52 (q, J ¼ 8.0 Hz, 1H), 3.06 (t, J ¼ 8.0 Hz, 1H), 2.40 (octet, J ¼ 8.0 Hz, 1H), 2.13 (sext, J ¼ 8.0 Hz, 1H), 1.65 (tq, J ¼ 8.0, 12.0 Hz, 1H), 1.11 (d, J ¼ 4.0 Hz, 3H). 13C NMR (100 MHz, CDCl3) d 120.44 (q, J ¼ 322.0 Hz), 55.32, 48.56, 33.90, 33.57, 17.00. HRMS–ESI (m/z): [M þ Na] þ calcd for C6H10F3NNaO2S, 240.02765; found, 246.02789.
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Acknowledgements We gratefully acknowledge the financial support by the ‘973’ Project from the MOST of China (2013CB228102, 2009CB825300) and NSFC (Nos 20925207 and 21002001). M.Y. thanks China Postdoctoral science foundation Grant (2013M530465). We thank Professor E.P. Ku¨ndig for assistance on the manuscript revision.
Author contributions Z.-J.S. directed the research. M.Y. performed the experiments and analysed the data. B.S. worked on the synthesis of scaffold 12. Y.W. worked on the synthesis of scaffold 10 and some other starting materials. K.C., X.J., Y.-F.Z., X.-S.Z., G.C., Y.C., Z.C., Q.-Y.G. and L.W. worked on product isolation, purification and starting materials preparation. M.Y. and Z.-J.S. wrote the paper. M.Y. wrote the Supplementary Information and contributed other related materials.
Additional information Accession codes: The X-ray crystallographic structures for 9,10,12 reported in this article have been deposited at the Cambridge Crystallographic Data Centre (CCDC), under deposition number CCDC 1005416, 1005417,1005418. These data can be obtained free of charge from the Cambridge Crystallographic Data Centre via http://www.ccdc.cam. ac.uk/ data_request/cif. Supplementary Information accompanies this paper at http://www.nature.com/ naturecommunications Competing financial interests: The authors declare no competing financial interests. Reprints and permission information is available online at http://npg.nature.com/ reprintsandpermissions/ How to cite this article: Yang, M. et al. Silver-catalysed direct amination of unactivated C–H bonds of functionalized molecules. Nat. Commun. 5:4707 doi: 10.1038/ncomms5707 (2014).
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