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This Feature Article showcases the use of pyridynes and indolynes to construct functionalized heterocycles and complex natural products.
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Pyridynes and Indolynes as Building Blocks for Functionalized Heterocycles and Natural Products
Cite this: DOI: 10.1039/x0xx00000x
Adam E. Goetz, Tejas K. Shah and Neil K. Garg* Heterocyclic arynes, or hetarynes, have been studied for over 100 years. However, challenges associated with observing these reactive species, as well as developing synthetically useful methods for their generation and trapping, have limited their use. This review provides a brief historical perspective on the field of hetarynes, in addition to a discussion of pyridyne and indolyne methodologies. Moreover, this review highlights the use of pyridynes, indolynes, and related strained intermediates in natural product synthesis.
Received 00th January 2012, Accepted 00th January 2012 DOI: 10.1039/x0xx00000x www.rsc.org/
Introduction and Historical Perspective The importance of heterocyclic compounds in modern chemistry cannot be overstated. Methods for the synthesis of functionalized heterocyclic compounds are highly prized because of their applications in pharmaceutical chemistry, materials chemistry, natural products synthesis, organometallic chemistry, and many other fields. Among the various methods for functionalizing heterocycles, the use of highly reactive heterocyclic arynes, or hetarynes,1 offers a strategically different approach compared to many conventional methods. Arynes have a rich history, and despite being studied experimentally for over 60 years, many of these species are still treated as scientific curiosities rather than as useful synthetic intermediates. The majority of studies related to arynes focus on carbocyclic arynes, such as ortho-benzyne (1),2 rather than heterocyclic arynes (e.g., 2–6, Figure 1).
ethoxide to give 8. This proposal, despite its influence on the field of aryne chemistry, has been called into question.1b In the original report, compound 8 was not isolated, but rather was inferred based on the formation of 9a and 9b, which were thought to arise from ring opening of 8. Alternative proposals suggest that contamination of precursor 7 with the isomeric 2bromobenzofuran (11) would readily give the proposed intermediate 8 through an SNAr pathway.1b Given that bromide 7 was prepared through elimination of dibromide 10, the alternate mechanism is certainly plausible.
Examples of Heterocyclic Arynes
N H
O
o-benzyne (1)
N
3
2
4
N N
N
5
6
Fig. 1 Examples of Arynes
The first appearance of any type of aryne in the literature comes from Stoermer and Kahlert’s 1902 report invoking 2,3benzofuranyne (2) as an intermediate (Figure 2).3 The authors proposed that treatment of 3-bromobenzofuran (7) with sodium ethoxide led to hetaryne 2, which was trapped by excess
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FEATURE ARTICLE
ChemComm DOI: 10.1039/C4CC06445C
Original 2,3-Benzofuranyne Proposal Br
R 2N
LG
3
NaOEt
2
EtOH
O
NR 2 4
7
N
NR 2
LG
O
addition
H
2
13
4
elimination
3
3
N
N
proposed intermediate
NR 2
12 O
NR 2
elimination
OH
14
addition N
O
OR
Fig. 3 Competing Aryne and Non-‐Aryne Mechanisms
9a; R = H 9b; R = Et isolated products
8 not isolated
Alternative Proposal for Observed Products mixture of isomers
Br KOH
7
Br
+
Br O
O
11
10
O NaOEt EtOH
OH
OEt O OR
8
9a; R = H 9b; R = Et
Fig. 2 Initial Proposal of 2,3-‐Benzofuranyne Formation
This example highlights one of the inherent challenges with the study of arynes and hetarynes; specifically, the fact that they cannot be readily observed. Typically, the strongest evidence for the presence of an aryne intermediate is the identity of the products obtained. However, even this can lead to incorrect conclusions. As shown in Figure 3, it is possible to arrive at socalled “aryne products” through pathways that do not involve aryne formation. This possibility is especially relevant when strong bases, which are also nucleophilic, are employed to generate arynes through dehydrohalogenation, as is demonstrated using pyridine 12. In what is termed the addition/elimination pathway, nucleophilic attack by the amide on the electrophilic C4 position generates stabilized adduct 13, which then undergoes ejection of the leaving group to give product 14. This is in contrast to the elimination/addition pathway. In this route, pyridine 12 can undergo deprotonation at C3 followed by elimination of the leaving group to generate 3,4-pyridyne (4). Attack on this species by a nucleophile at C4 followed by protonation then provides product 14. Additionally, it is also possible that both aryne and non-aryne mechanisms are operating competitively in a given reaction. Since many of the early aryne studies relied on this method of aryne generation, not all claims of aryne generation are likely accurate, and care must be taken in interpretation of results. Previous reviews have sought to identify certain aryne precursors that are prone to favor one mechanism over the other.1
2 | J. Name., 2012, 00, 1-‐3
Despite uncertainty over the generation of arynes such as 2, solid evidence for the intermediacy of these highly reactive species was obtained in the 1950s. Following several reports of unexplained “rearrangements” in reactions of halobenzenes with amide bases,4 Roberts demonstrated that treatment of 14Clabeled chlorobenzene (15) with potassium amide gave an equimolar mixture of products 16a and 16b (Figure 4).5 This was rationalized by the presence of the symmetrical “benzyne” (1) intermediate. Shortly thereafter, Huisgen demonstrated that treating either 2- or 3-fluoroanisole (17a or 17b) with phenyllithium followed by CO2 led to the isolation of compounds 19a and 19b with a strong preference for 19a (Figure 4).6 Similar to Roberts’ reasoning, Huisgen noted that since the two isomeric starting materials gave the same major product with similar ratios, a common intermediate, 18, was likely involved. He also noted that the π-system of the proposed intermediate 18 would be orthogonal to the aromatic system. Finally, Wittig demonstrated that treatment of dihalobenzene 20 with lithium amalgam in furan led to the isolation of cycloadduct 21, which further suggested the intermediacy of benzyne (1).7 These three studies represent the first solid evidence for the intermediacy of any aryne and inspired the development of much of the hetaryne chemistry reported since. Roberts' 14C Labeling Study (1953)
•
Cl
•
KNH2 NH3, –33 ºC
15
(43% yield)
•=
•
NH2
•
+
NH2
1
16a
16b 1 : 1
14C
Huisgen's Study using Isomeric Substrates (1955) OMe
OMe i. PhLi Et2O, 35 ºC
X
OMe CO2H
Ph +
ii. CO2
Y
OMe
Ph
18
17a; X=F, Y=H 17b; X=H, Y=F
CO2H
19a
19b >15 : 1
Wittig's Benzyne Cycloaddition (1955) F Br
20
Li(Hg) O
furan (76% yield)
1
21
Fig. 4 Early ortho-‐Benzyne Studies
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Hetaryne Experimental Results Throughout the years, many heterocyclic arynes have been proposed as intermediates. As discussed above, it is likely that some of the reported reactions do not actually involve the reported aryne as an intermediate.1 Additionally, aryne reactions frequently give low yields of products, likely due to a combination of the high instability of these intermediates, as well as the harsh conditions that have been traditionally used to generate these species. As a result, the following sections focus on the aryne derivatives of pyridines and indoles, two of the most well-studied classes of hetarynes. Both of these families of hetarynes have undergone an evolution from their initial discovery to their current uses as versatile intermediates for organic synthesis. Emphasis is placed on developments that have sought to address key challenges related to the utility of these species. This article also highlights the application of hetarynes in the total synthesis of natural products, including our own laboratory’s recent syntheses of tubingensin A, the [4.3.1]-bicyclic welwitindolinones, and several indolactam alkaloids. Pyridyne Methodology Considering all classes of heterocyclic arynes, pyridynes have been the most intensely studied over the past 60 years. Of the three pyridyne isomers shown in Figure 5, 3,4-pyridyne (4) is suggested computationally8 to be the most stable, followed by 2,3-pyridyne (22). Attempts to study 1,2-pyridyne (23, alternatively represented as the 2-pyridyl cation) in solution have been unsuccessful,9 however, studies in the gas phase have shown evidence of this species.10 All of these isomers have long been recognized as promising intermediates for the preparation of substituted pyridines and, collectively, have been the target of much synthetic effort.11,12 Pyridyne Isomers
3,4-pyridyne (4)
N
N
N
N
are derived from analogous precursors to o-benzyne, illustrating that similar strategies could be applicable for the generation of other hetarynes. For example, 3,4-pyridyne (4) is accessible from 3-halopyridines upon treatment with strong base (24→4),13 oxidation of aminotriazoles with Pb(OAc)4 (25→4),14 photolysis of anhydrides (26→4),15 magnesiumsulfur exchange followed by elimination (27→4),16 thermolysis of diazonium carboxylates (28→4),17 or fluoride-induced elimination of ortho-trialkylsilyl pyridyl triflates (29→4).18 Of note, this latter method, which was first pioneered by Kobayashi for o-benzyne generation,19 has demonstrated the most functional group tolerance in terms of both the trapping agents that can be utilized and the substituents present on the precursors. Although there is always the possibility that some precursors may react through non-aryne mechanisms, the isolation of pyridyne 4 in an N2 matrix and subsequent characterization by IR spectroscopy20 demonstrated that pyridyne 4 is a valid intermediate. The 3,4-pyridyne has been demonstrated to be useful for the preparation of 3- and 4-substituted pyridines as well as 3,4disubstituted derivatives.21 Leake and Levine reported the first generation of 3,4-pyridyne (4) utilizing 3-bromopyridine (30),22 which upon treatment with acetophenone and sodium amide in liquid ammonia gave low yields of 4-aminopyridine (31) and adduct 32, the latter of which arises from attack by the enolate of acetophenone (Figure 6). Many early studies that relied on dehydrohalogenation for pyridyne generation were limited in the scope of the trapping agent employed. In order to minimize the byproducts resulting from attack by the base used for pyridyne generation, strongly nucleophilic groups such as alkoxides, amide salts, and thiolates were often employed. In an example of the latter reported by Zoltewicz, treatment of bromopyridine 30 with sodium methanethiolate and sodium amide led to an equimolar mixture of adducts 33a and 33b.23 This lack of regioselectivity is characteristic of pyridyne 4, and has limited the synthetic utility of this intermediate.
2,3-pyridyne (22)
Original 3,4-Pyridyne Example
1,2-pyridyne (23) Br
Known 3,4-Pyridyne Precursors SiR3 X
30
Ph
NH2
4 3
+ N
N
N
4
31
32
(10% yield) (14% yield)
N
N
3,4-pyridyne (4)
24
Me Ph NaNH2 NH3, –33 ºC
N OTf
N
O
O
Typical Selectivity of 3,4-Pyridyne
29
SCH3 H 2N
O
N N N
Br
O N2
O
O
O N
S
Ph Br
O
25 26
N
NH3, –33 ºC
30
(67% yield)
28 N
N
N
NaNH2, NaSCH3
27
Fig. 5 Pyridyne Isomers and Methods of Generation
The 3,4-pyridyne can be used to illustrate the wide range of methods typically used to generate arynes. Most of the methods
This journal is © The Royal Society of Chemistry 2012
4
SCH3 3
+
N
33a
N
1 : 1
33b
Fig. 6 Examples of 3,4-‐Pyridyne Studies
Several studies have focused on the development of methods to control regioselectivity in reactions of 3,4pyridynes,18,24 and include a report by our laboratory in 2013, which systematically explored the use of substituents to control
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selectivity via aryne distortion.25 We prepared three pyridyne precursors, 34, 36, and 38, and then performed a series of pyridyne generation and trapping experiments (Figure 7). For example, using 3,4-pyridyne precursor 34 in a nitrone cycloaddition yielded products 35a and 35b in a 1.9 to 1 ratio. However, by employing the sulfamoylated precursor 36 in the corresponding reaction, higher regioselectivity could be achieved favoring attack at C4. In a complementary sense, selectivity could be reversed by use of the brominated precursor 38 in the aryne trapping experiment to now favor attack at C3. Of note, after performing aryne trapping experiments of silyltriflates 36 and 38, the sulfamate and bromides remaining may be used in Ni- or Pd-catalyzed cross-coupling experiments.26,27 For example, after performing pyridyne trapping experiments with 1,3-dimethyl-2-imidazolidinone,28 similar to trapping experiments recently report by Sato and coworkers,29 40 and 41 were obtained using catalytic C–C and C–N bond forming processes. Pyridyne precursors 34 and 38 are now available commercially.30
TMS
t-Bu
N
4
OTf 3
O
4
34 t-Bu
1.9 : 1
Ph
4
36
N
OTf
MePhNH, CsF MeCN, 23 ºC (65% yield)
45
3 2
N
22
37a
4
Br 5
OTf 3
Me
N
O
OMe
37b
10.7 : 1
t-Bu N Ph
5
CsF, MeCN
N
4
Br
N Ph
OMe TMS
48
OTf
(80% yield)
5
39a
47
3
OMe O O N
N Me
50
Fig 8 Examples of 2,3-‐Pyridyne Studies
N
1 : 3.3
N
49
O
Br
+
N
(60% yield)
38
N
t-Bu
Ph
O N
O
NMePh
46 only isomer formed
O
N 2 OSO2NMe 2
CsF, 23 ºC t-Bu
TMS
2
N
Recent 2,3-Pyridyne Example
O 3
N 2 OSO2NMe 2
(61% yield)
44
43
t-Bu
+
CsF, MeCN N 2 OSO2NMe 2
N
N
N Ph
3
2
Typical 2,3-Pyridyne Reactivity TMS
35b
Ph
O N
O
22
3
t-Bu N
OTf
(
ChemComm Accepted Manuscript
This article can be cited before page numbers have been issued, to do this please use: A. Goetz, T. K. Shah and N. K. Garg, Chem. Commun., 2014, DOI: 10.1039/C4CC06445C.
This is an Accepted Manuscript, which has been through the Royal Society of Chemistry peer review process and has been accepted for publication. Accepted Manuscripts are published online shortly after acceptance, before technical editing, formatting and proof reading. Using this free service, authors can make their results available to the community, in citable form, before we publish the edited article. We will replace this Accepted Manuscript with the edited and formatted Advance Article as soon as it is available. You can find more information about Accepted Manuscripts in the Information for Authors. Please note that technical editing may introduce minor changes to the text and/or graphics, which may alter content. The journal’s standard Terms & Conditions and the Ethical guidelines still apply. In no event shall the Royal Society of Chemistry be held responsible for any errors or omissions in this Accepted Manuscript or any consequences arising from the use of any information it contains.
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This Feature Article showcases the use of pyridynes and indolynes to construct functionalized heterocycles and complex natural products.
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Pyridynes and Indolynes as Building Blocks for Functionalized Heterocycles and Natural Products
Cite this: DOI: 10.1039/x0xx00000x
Adam E. Goetz, Tejas K. Shah and Neil K. Garg* Heterocyclic arynes, or hetarynes, have been studied for over 100 years. However, challenges associated with observing these reactive species, as well as developing synthetically useful methods for their generation and trapping, have limited their use. This review provides a brief historical perspective on the field of hetarynes, in addition to a discussion of pyridyne and indolyne methodologies. Moreover, this review highlights the use of pyridynes, indolynes, and related strained intermediates in natural product synthesis.
Received 00th January 2012, Accepted 00th January 2012 DOI: 10.1039/x0xx00000x www.rsc.org/
Introduction and Historical Perspective The importance of heterocyclic compounds in modern chemistry cannot be overstated. Methods for the synthesis of functionalized heterocyclic compounds are highly prized because of their applications in pharmaceutical chemistry, materials chemistry, natural products synthesis, organometallic chemistry, and many other fields. Among the various methods for functionalizing heterocycles, the use of highly reactive heterocyclic arynes, or hetarynes,1 offers a strategically different approach compared to many conventional methods. Arynes have a rich history, and despite being studied experimentally for over 60 years, many of these species are still treated as scientific curiosities rather than as useful synthetic intermediates. The majority of studies related to arynes focus on carbocyclic arynes, such as ortho-benzyne (1),2 rather than heterocyclic arynes (e.g., 2–6, Figure 1).
ethoxide to give 8. This proposal, despite its influence on the field of aryne chemistry, has been called into question.1b In the original report, compound 8 was not isolated, but rather was inferred based on the formation of 9a and 9b, which were thought to arise from ring opening of 8. Alternative proposals suggest that contamination of precursor 7 with the isomeric 2bromobenzofuran (11) would readily give the proposed intermediate 8 through an SNAr pathway.1b Given that bromide 7 was prepared through elimination of dibromide 10, the alternate mechanism is certainly plausible.
Examples of Heterocyclic Arynes
N H
O
o-benzyne (1)
N
3
2
4
N N
N
5
6
Fig. 1 Examples of Arynes
The first appearance of any type of aryne in the literature comes from Stoermer and Kahlert’s 1902 report invoking 2,3benzofuranyne (2) as an intermediate (Figure 2).3 The authors proposed that treatment of 3-bromobenzofuran (7) with sodium ethoxide led to hetaryne 2, which was trapped by excess
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Original 2,3-Benzofuranyne Proposal Br
R 2N
LG
3
NaOEt
2
EtOH
O
NR 2 4
7
N
NR 2
LG
O
addition
H
2
13
4
elimination
3
3
N
N
proposed intermediate
NR 2
12 O
NR 2
elimination
OH
14
addition N
O
OR
Fig. 3 Competing Aryne and Non-‐Aryne Mechanisms
9a; R = H 9b; R = Et isolated products
8 not isolated
Alternative Proposal for Observed Products mixture of isomers
Br KOH
7
Br
+
Br O
O
11
10
O NaOEt EtOH
OH
OEt O OR
8
9a; R = H 9b; R = Et
Fig. 2 Initial Proposal of 2,3-‐Benzofuranyne Formation
This example highlights one of the inherent challenges with the study of arynes and hetarynes; specifically, the fact that they cannot be readily observed. Typically, the strongest evidence for the presence of an aryne intermediate is the identity of the products obtained. However, even this can lead to incorrect conclusions. As shown in Figure 3, it is possible to arrive at socalled “aryne products” through pathways that do not involve aryne formation. This possibility is especially relevant when strong bases, which are also nucleophilic, are employed to generate arynes through dehydrohalogenation, as is demonstrated using pyridine 12. In what is termed the addition/elimination pathway, nucleophilic attack by the amide on the electrophilic C4 position generates stabilized adduct 13, which then undergoes ejection of the leaving group to give product 14. This is in contrast to the elimination/addition pathway. In this route, pyridine 12 can undergo deprotonation at C3 followed by elimination of the leaving group to generate 3,4-pyridyne (4). Attack on this species by a nucleophile at C4 followed by protonation then provides product 14. Additionally, it is also possible that both aryne and non-aryne mechanisms are operating competitively in a given reaction. Since many of the early aryne studies relied on this method of aryne generation, not all claims of aryne generation are likely accurate, and care must be taken in interpretation of results. Previous reviews have sought to identify certain aryne precursors that are prone to favor one mechanism over the other.1
2 | J. Name., 2012, 00, 1-‐3
Despite uncertainty over the generation of arynes such as 2, solid evidence for the intermediacy of these highly reactive species was obtained in the 1950s. Following several reports of unexplained “rearrangements” in reactions of halobenzenes with amide bases,4 Roberts demonstrated that treatment of 14Clabeled chlorobenzene (15) with potassium amide gave an equimolar mixture of products 16a and 16b (Figure 4).5 This was rationalized by the presence of the symmetrical “benzyne” (1) intermediate. Shortly thereafter, Huisgen demonstrated that treating either 2- or 3-fluoroanisole (17a or 17b) with phenyllithium followed by CO2 led to the isolation of compounds 19a and 19b with a strong preference for 19a (Figure 4).6 Similar to Roberts’ reasoning, Huisgen noted that since the two isomeric starting materials gave the same major product with similar ratios, a common intermediate, 18, was likely involved. He also noted that the π-system of the proposed intermediate 18 would be orthogonal to the aromatic system. Finally, Wittig demonstrated that treatment of dihalobenzene 20 with lithium amalgam in furan led to the isolation of cycloadduct 21, which further suggested the intermediacy of benzyne (1).7 These three studies represent the first solid evidence for the intermediacy of any aryne and inspired the development of much of the hetaryne chemistry reported since. Roberts' 14C Labeling Study (1953)
•
Cl
•
KNH2 NH3, –33 ºC
15
(43% yield)
•=
•
NH2
•
+
NH2
1
16a
16b 1 : 1
14C
Huisgen's Study using Isomeric Substrates (1955) OMe
OMe i. PhLi Et2O, 35 ºC
X
OMe CO2H
Ph +
ii. CO2
Y
OMe
Ph
18
17a; X=F, Y=H 17b; X=H, Y=F
CO2H
19a
19b >15 : 1
Wittig's Benzyne Cycloaddition (1955) F Br
20
Li(Hg) O
furan (76% yield)
1
21
Fig. 4 Early ortho-‐Benzyne Studies
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Hetaryne Experimental Results Throughout the years, many heterocyclic arynes have been proposed as intermediates. As discussed above, it is likely that some of the reported reactions do not actually involve the reported aryne as an intermediate.1 Additionally, aryne reactions frequently give low yields of products, likely due to a combination of the high instability of these intermediates, as well as the harsh conditions that have been traditionally used to generate these species. As a result, the following sections focus on the aryne derivatives of pyridines and indoles, two of the most well-studied classes of hetarynes. Both of these families of hetarynes have undergone an evolution from their initial discovery to their current uses as versatile intermediates for organic synthesis. Emphasis is placed on developments that have sought to address key challenges related to the utility of these species. This article also highlights the application of hetarynes in the total synthesis of natural products, including our own laboratory’s recent syntheses of tubingensin A, the [4.3.1]-bicyclic welwitindolinones, and several indolactam alkaloids. Pyridyne Methodology Considering all classes of heterocyclic arynes, pyridynes have been the most intensely studied over the past 60 years. Of the three pyridyne isomers shown in Figure 5, 3,4-pyridyne (4) is suggested computationally8 to be the most stable, followed by 2,3-pyridyne (22). Attempts to study 1,2-pyridyne (23, alternatively represented as the 2-pyridyl cation) in solution have been unsuccessful,9 however, studies in the gas phase have shown evidence of this species.10 All of these isomers have long been recognized as promising intermediates for the preparation of substituted pyridines and, collectively, have been the target of much synthetic effort.11,12 Pyridyne Isomers
3,4-pyridyne (4)
N
N
N
N
are derived from analogous precursors to o-benzyne, illustrating that similar strategies could be applicable for the generation of other hetarynes. For example, 3,4-pyridyne (4) is accessible from 3-halopyridines upon treatment with strong base (24→4),13 oxidation of aminotriazoles with Pb(OAc)4 (25→4),14 photolysis of anhydrides (26→4),15 magnesiumsulfur exchange followed by elimination (27→4),16 thermolysis of diazonium carboxylates (28→4),17 or fluoride-induced elimination of ortho-trialkylsilyl pyridyl triflates (29→4).18 Of note, this latter method, which was first pioneered by Kobayashi for o-benzyne generation,19 has demonstrated the most functional group tolerance in terms of both the trapping agents that can be utilized and the substituents present on the precursors. Although there is always the possibility that some precursors may react through non-aryne mechanisms, the isolation of pyridyne 4 in an N2 matrix and subsequent characterization by IR spectroscopy20 demonstrated that pyridyne 4 is a valid intermediate. The 3,4-pyridyne has been demonstrated to be useful for the preparation of 3- and 4-substituted pyridines as well as 3,4disubstituted derivatives.21 Leake and Levine reported the first generation of 3,4-pyridyne (4) utilizing 3-bromopyridine (30),22 which upon treatment with acetophenone and sodium amide in liquid ammonia gave low yields of 4-aminopyridine (31) and adduct 32, the latter of which arises from attack by the enolate of acetophenone (Figure 6). Many early studies that relied on dehydrohalogenation for pyridyne generation were limited in the scope of the trapping agent employed. In order to minimize the byproducts resulting from attack by the base used for pyridyne generation, strongly nucleophilic groups such as alkoxides, amide salts, and thiolates were often employed. In an example of the latter reported by Zoltewicz, treatment of bromopyridine 30 with sodium methanethiolate and sodium amide led to an equimolar mixture of adducts 33a and 33b.23 This lack of regioselectivity is characteristic of pyridyne 4, and has limited the synthetic utility of this intermediate.
2,3-pyridyne (22)
Original 3,4-Pyridyne Example
1,2-pyridyne (23) Br
Known 3,4-Pyridyne Precursors SiR3 X
30
Ph
NH2
4 3
+ N
N
N
4
31
32
(10% yield) (14% yield)
N
N
3,4-pyridyne (4)
24
Me Ph NaNH2 NH3, –33 ºC
N OTf
N
O
O
Typical Selectivity of 3,4-Pyridyne
29
SCH3 H 2N
O
N N N
Br
O N2
O
O
O N
S
Ph Br
O
25 26
N
NH3, –33 ºC
30
(67% yield)
28 N
N
N
NaNH2, NaSCH3
27
Fig. 5 Pyridyne Isomers and Methods of Generation
The 3,4-pyridyne can be used to illustrate the wide range of methods typically used to generate arynes. Most of the methods
This journal is © The Royal Society of Chemistry 2012
4
SCH3 3
+
N
33a
N
1 : 1
33b
Fig. 6 Examples of 3,4-‐Pyridyne Studies
Several studies have focused on the development of methods to control regioselectivity in reactions of 3,4pyridynes,18,24 and include a report by our laboratory in 2013, which systematically explored the use of substituents to control
J. Name., 2012, 00, 1-‐3 | 3
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ChemComm DOI: 10.1039/C4CC06445C
selectivity via aryne distortion.25 We prepared three pyridyne precursors, 34, 36, and 38, and then performed a series of pyridyne generation and trapping experiments (Figure 7). For example, using 3,4-pyridyne precursor 34 in a nitrone cycloaddition yielded products 35a and 35b in a 1.9 to 1 ratio. However, by employing the sulfamoylated precursor 36 in the corresponding reaction, higher regioselectivity could be achieved favoring attack at C4. In a complementary sense, selectivity could be reversed by use of the brominated precursor 38 in the aryne trapping experiment to now favor attack at C3. Of note, after performing aryne trapping experiments of silyltriflates 36 and 38, the sulfamate and bromides remaining may be used in Ni- or Pd-catalyzed cross-coupling experiments.26,27 For example, after performing pyridyne trapping experiments with 1,3-dimethyl-2-imidazolidinone,28 similar to trapping experiments recently report by Sato and coworkers,29 40 and 41 were obtained using catalytic C–C and C–N bond forming processes. Pyridyne precursors 34 and 38 are now available commercially.30
TMS
t-Bu
N
4
OTf 3
O
4
34 t-Bu
1.9 : 1
Ph
4
36
N
OTf
MePhNH, CsF MeCN, 23 ºC (65% yield)
45
3 2
N
22
37a
4
Br 5
OTf 3
Me
N
O
OMe
37b
10.7 : 1
t-Bu N Ph
5
CsF, MeCN
N
4
Br
N Ph
OMe TMS
48
OTf
(80% yield)
5
39a
47
3
OMe O O N
N Me
50
Fig 8 Examples of 2,3-‐Pyridyne Studies
N
1 : 3.3
N
49
O
Br
+
N
(60% yield)
38
N
t-Bu
Ph
O N
O
NMePh
46 only isomer formed
O
N 2 OSO2NMe 2
CsF, 23 ºC t-Bu
TMS
2
N
Recent 2,3-Pyridyne Example
O 3
N 2 OSO2NMe 2
(61% yield)
44
43
t-Bu
+
CsF, MeCN N 2 OSO2NMe 2
N
N
N Ph
3
2
Typical 2,3-Pyridyne Reactivity TMS
35b
Ph
O N
O
22
3
t-Bu N
OTf
(
