Cu-catalyzed transannulation reaction of pyridotriazoles with terminal alkynes under aerobic conditions: Efficient synthesis of indolizines

Article abstract of DOI:10.1039/c4sc03358b

A Cu(i)-catalyzed denitrogenative transannulation reaction of pyridotriazoles with terminal alkynes en route to indolizines was developed. Compared to the previously reported Rh-catalyzed transannulation reaction, this Cu-catalyzed method features aerobic conditions and a much broader scope of pyridotriazoles and alkynes.

Full text of DOI:10.1039/c4sc03358b

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Cu-Catalyzed Transannulation Reaction of
Pyridotriazoles with Terminal Alkynes under
Aerobic Conditions: Efficient Synthesis of
Indolizines†
Cite this: DOI: 10.1039/x0xx00000x
Received 00th January 2014,
Accepted 00th January 2014
V. Helan, A. V. Gulevich and V. Gevorgyan*
DOI: 10.1039/x0xx00000x
The Cu(I)ꢀcatalyzed denitrogenative transannulation reaction of pyridotriazoles with terminal
alkynes en route to indolizines was developed. Compared to the previously reported Rhꢀ
catalyzed transannulation reaction, this Cuꢀcatalyzed method features aerobic conditions and
much broader scope of pyridotriazoles and alkynes.
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Transitionꢀmetalꢀcatalyzed denitrogenative transannulation of Herein, we report the first general and efficient Cuꢀcatalyzed
pyridotriazoles represent an efficient method for the synthesis transannulation of pyridotriazoles with terminal alkynes to
of fused nitrogenꢀcontaining heterocycles.1 This method is form indolizines
(eq. 2). This newly developed method
based on the ability of pyridotriazole to exist in the features several important advantages over the previously
equilibrium with diazoꢀform A 2,3 which can be trapped with reported Rhꢀcatalyzed protocol.1a Thus, it is highly practical as
Rh(II) to form the reactive pyridyl carbene intermediate it employs cheap Cuꢀcatalyst and efficiently operates unꢀder
capable to react with terminal alkynes1a to produce valuable aerobic conditions. It is also more general demonstrating a
indolizines
(Scheme 1).4,5 However, this transannulation much broader reaction scope, as unactivated pyridotriazoles
1
2
3
1
,
B
,
3
1
reaction has several shortcomings.
and aliphatic alkynes
partners (eq. 2).
2 now became competent reaction
Previous work:
The abovementioned transannulation reaction of
pyridotriazoles
(eq. 1),1 as well as the further developed and
EWG
EWG
EWG
Rh
R
EWG
1
[Rh]
N2
N
(1)
widely used transannulation reactions of
Nꢀsulfonyl 1,2,3ꢀ
N
N
N
N
-N2
RT
N
6 examples
up to 85%
triazoles,7 require the use of Rhꢀcatalyst,8 which is one of the
RT
R
AG
AG
AG
AG
A
1
B
3
Table 1 Optimization of the Cuꢀtransannulation reaction conditions.a
AG = Cl
EWG = CO2Me
= Ar only
[Rh] = Rh2(C3F7CO2)4 (1 mol %)
R
This work:
R1
R1
Yield[b]
N.R.
38%
25%
50%
96%
99%
99%
N.R.
N.R.f
-
Cu instead of Rh!
Cu(MeCN)4PF6
(15 mol %)
Entry
1
2
3
Catalyst, mol %
CuCl, 15%
CuOTf•0.5C6H6, 15%
Cu(OTf)2, 15%
Cu(MeCN)4PF6 , 15%
Cu(MeCN)4PF6, 15%
Cu(MeCN)4PF6, 15%
Cu(MeCN)4PF6, 15%
No catalyst
T (°C)
100
100
100
100
120
130
130
100
100
N
- No AG required!
+
(2)
N
N
N
R
PhMe, 130 o
C
- No EWG required!
R
1
2
3
-
R = Alk, Ar
R1 = CO2Et, Ph, Me, H
21 examples
up to 94%
4
5c
6c
7d,e
8
Scheme 1 Metal-catalyzed transannulation reactions of pyridotriazoles with
terminal alkynes.
9
Rh2(hfb)4, 1%
Thus, Cl substituent at Cꢀ7 position (AG, activating group)
and electronwithdrawing ester group (EWG) at Cꢀ3 position of
aTriazole (1 equiv), Alkyne (3 equiv), Cu cat. (15 mol %), toluene (1M) in a
pyridotriazoles were requisite to facilitate the formation of a Wheaton Vꢀvial capped with a mininert syringe valve. bGC/MS yields are
given. c1.2 equiv of alkyne was used. d In air with 1.2 equiv of alkyne. e
sufficient amount of an openꢀform of triazole
A
even at room
In
Lower catalyst loading led to decreased reaction yields.11 fPolymerization of
the alkyne was observed; hfb = heptafluorobutyrate.
temperature and subsequently generate indolizines 3 2,3,6
.
addition, the reaction was limited to aryl alkynes only (eq. 1).1a
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Table 2 Scope of the Cuꢀcatalyzed transannulation reaction of pyridotriazoles with alkynes.a
Entry
1
Product
Yield, %
70%
Entry
9
Product
Yield, %
78%
Entry
17
Product
Yield, %
82%
2
3
74%
65%
10
11
75%
33%
18
19
66%
77%
4
70%
12
67%
20
80%
5
6
48%
57%
13
14
68%
82%
21
22
67%
50%
7
8
60%
94%
15
16
83%
53%
23
24
41%
54%
a Isolated yields.
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most expensive and rare metals used in catalysis. Naturally, the reasonable yields (entries 19ꢀ23). Remarkably, even a nonꢀ
development of alternative catalysts for transannulation substituted pyridotriazole (R1
H) reacted with
=
reactions of triazoles would dramatically increase a synthetic phenylacetylene to form indolizine 3x in moderate yield.
applicability of this methodology.9 Accordingly, aiming at the Noteworthy, trialkylsilylꢀsubstituted alkynes were either
discovery of a cheaper catalyst and at expanding the scope of unstable (TMS, TES) or stayed intact (TIPS) under the reaction
transannulation reactions of pyridotriazoles, we turned our conditions.
attention to potential employment of copper catalysts.10 To
ensure sufficient amounts of an openꢀform of the unactivated transannulation reaction (Scheme 2). First, the copper catalyst
pyridotriazole, we tested the potential transannulation reaction can react with the terminal alkyne to form copper acetylide
at elevated temperatures.3 Thus, we tested various copper which would react with αꢀimino diazo compound
to generate
catalysts in the reaction of unactivated pyridotriazole 1a with the Cuꢀcarbene complex (path ). Alternatively, the copper
phenylacetylene 2a (Table 1). While CuCl was found to be carbene can be formed via the reaction of alkyne with
inefficient (entry 1), the use of Cu(I) and Cu(II) triflates led to copper carbene , which is produced from the diazo compound
the formation of the corresponding indolizine 3a in moderate and Cuꢀcatalyst (path ). Next, migratory insertion of the
yield (entries 2, 3).11 Delightfully, more electrophilic alkynyl group at the carbene Cꢀatom of
would form the
Cu(MeCN)4PF6 catalyst turned out to be even more efficient for propargyl intermediate D 13
The latter would undergo
We envision two alternative pathways for this Cuꢀcatalyzed
A
2
4,
A
C
a
C
2
B
A
b
C
.
the formation of 3a (entry 4). Finally, after optimization of cyclization via a nucleophilic attack of the pyridine nitrogen at
temperature (entries 5, 6), virtually quantitative yield of 1a was the triple bond activated by electrophilic Cuꢀspecies14 to
achieved (entry 7). Moreover, we were pleased to find that this produce a triazolylꢀcopper intermediate
reaction works equally efficient under aerobic conditions (entry exclude formation of propargylic
G
. Also, one cannot
E) or allenic F)
protiodemetalation of
would form intermediate G 15
subsequent protiodemetalation of would lead to the
(
(
D.
. A
9). As expected, under thermal conditions no reaction occurred intermediates
(entry 8). Moreover, it was found that Rh2(hfb)4 is not a capable Cycloisomerization of
catalyst for this reaction (entry 9).
upon
E
and
F
G
Having in hands the optimized conditions, we investigated indolizine
the scope of this Cu–catalyzed transannulation reaction of
pyridotriazoles with terminal alkynes (Table 2). A variety of
aryl alkynes bearing electronꢀneutral, electron withdrawing, and
3.
electron donating substituents at orthoꢀ, metaꢀ and para
ꢀ
position produced the corresponding indolizines in high
3
yields upon the reaction with pyridotriazole 1a (Table 2, entries
1ꢀ10).12 Heteroaromatic alkynes, such as 3ꢀthienyl acetylene,
and enyne led to indolizines 3k-l in reasonable yields (entries
11,12). We were pleased to find that in contrast to the
previously reported Rhꢀcatalyzed reaction, aliphatic alkynes
were also competent reactants. Thus, benzylꢀ, nꢀbutyl, and cꢀ
hexyl acetylenes reacted smoothly to produce the
corresponding indolizines in good yields (entries 13ꢀ15). To our
delight, functional groups including benzyloxyꢀ and
Nꢀ
phthalimido were perfectly tolerated under the reaction
conditions (entries 16,17). Moreover, while our group
previously reported the Rhꢀcatalyzed transannulation reaction
of pyridotriazoles with nitriles,1a the Cuꢀcatalyzed
transannulation showed strong preference for the alkyneꢀ over
the nitrile group. Thus, the reaction of pyridotriazole 1a with 5ꢀ
hexynenitrile furnished indolizine 3r with nitrile group stayed
intact (entry 18). Notably, pyridotriazoles which did not contain
electron withdrawing groups at Cꢀ3 position were found to be
reactive substrates as well. Hence, the indolizines derived from
3ꢀphenyl and 3ꢀmethyl pyridotriazoles were produced in
Scheme 2 Proposed mechanism for the Cu-catalyzed transannulation reaction of
pyridotriazoles with alkynes.
In order to verify a potential involvement of the Cuꢀ
acetylide
4 in this transformation, we performed several testꢀ
experiments. First, it was found that the reaction of
pyridotriazole 1a with
4
did not produce indolizine 3a (Scheme
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DOI: 10.1039/C4SC03358B
3, entry 1). However, the reaction of 1a with
4 can be catalyzed
Rearrangements and Transformations of 1,2,3ꢀTriazoles” in Top.
Heterocycl. Chem. SpringerꢀVerlag, BerlinꢀHeidelberg, 2014.
For selected recent reviews on bioactive indolizines, see: (a) V.
Sharma and V. Kumar, Med. Chem. Res., 2014, 23, 3593; (b) G. S.
Singh and E. E. Mmatli, Eur. J. Med. Chem., 2011, 46, 5237.
by both Cu(MeCN)4PF6 (entry 2)16 and HPF6(aq.) (entry 3). This
observation suggests that the presence of electrophilic Cuꢀ
species is required to activate the alkyne during the cyclization
4
5
of
pyridotriazole towards the reactive αꢀimino diazo compound
A 19
Although more detailed studies are required to elucidate
D , and potentially to shift the equilibrium of the
into G 17,18
For selected methods towards indolizines, see: (a) A. E.
Tschitschibabin, Ber. Dtsch. Chem. Ges., 1927, 60, 1607; (b) A. R.
.
Katritzky, G. Qiu , B. Yang and H.ꢀY. He, J. Org. Chem., 1999, 64
7618; (c) D. Basavaiah and A. J. Rao, Chem. Commun., 2003, 604;
(d) I. Seregin and V. Gevorgyan, J. Am. Chem. Soc., 2006, 128
12050; (e) A. R. Hardin and R. Sarpong, Org. Lett. 2007, , 4547; (f)
,
,
9
J. Barluenga, G. Lonzi, L. Riesgo, L. A. López and M. Tomás, J. Am.
Chem. Soc., 2010, 132, 13200; (g) D. Chernyak, C. Skontos and V.
Gevorgyan, Org. Lett. 2010, 12, 3242; (h) D. Chernyak and V.
Gevorgyan, Org. Lett. 2010, 12, 5558; (i) Z. Li, D. Chernyak and V.
Gevorgyan, Org. Lett. 2012, 14, 6056; (j) X. Meng, P. Liao, J. Liua
and X. Bi, Chem. Commun., 2014, 50, 11837; (k) M. Gao, J. Tian and
Scheme 3 The reactions of Cu-acetylide with triazole 1a
.
the exact mechanism for this transformation, based on literature
data20,21 and the mentioned above observations, it is believed
that the reaction most likely proceeds via the path
2).
A. Lei, Chem. Asian J., 2014, 9, 2068; (l) C. Feng, Y. Yan, Z. Zhang,
K. Xu and Z. Wang, Org. Biomol. Chem., 2014, 12, 4837; (m) J. Sun,
F. Wang, H. Hu, X. Wang, H. Wu and Y. Liu, J. Org. Chem., 2014,
79, 3992; (n) J. Liu, L. Zhou, W. Ye, C. Wang, Chem Commun.,
2014, 50, 9068; (o) R. R. Jha, A. K. Danodia and A. K. Verma,
Tetrahedron Lett., 2014, 55, 4724 and refs 1 and 13.
a (Scheme
Conclusions
6
7
For formation of rhodium carbene from unactivated pyridotriazole,
see: Y. Shi, A. V. Gulevich and V. Gevorgyan, Angew. Chem., Int.
Ed., 2014, 53, 14191.
We have developed practical and efficient copperꢀcatalyzed
denitrogenative transannulation reaction of pyridotriazoles with
terminal alkynes into indolizines. Compared to the known Rhꢀ
catalyzed transannulation reaction, this newly developed
method features not only the use of cheap Cuꢀcatalyst and
aerobic conditions, but also much broader scope of
multisubstituted indolizines that now can be accessed from
unactivated pyridotriazoles and diverse terminal alkynes.
For reviews on reactions of iminocarbenes derived from
Nꢀsulfonyl
1,2,3ꢀtriazoles, see: (a) H. M. L. Davies and J. S. Alford, Chem. Soc.
Rev., 2014, 43, 5151; (b) A. V. Gulevich and V. Gevorgyan, Angew.
Chem., Int. Ed., 2013, 52, 1371; (c) B. Chattopadhyay and V.
Gevorgyan, Angew. Chem., Int. Ed
. 2012, 51, 862.
8
9
For rare examples of Niꢀcatalyzed transannulation of
Nꢀsulfonyl
1,2,3ꢀtriazoles, see: (a) T. Miura, M. Yamauchi and M. Murakami,
Chem. Commun. 2009, 1470; (b) T. Miura, K. Hiraga, T. Biyajima,
T. Nakamuro and M. Murakami, Org. Lett. 2013, 15, 3298.
Acknowledgements
The support of the National Institutes of Health (GM 64444) and
National Science Foundation (CHEꢀ1401722) is gratefully
acknowledged. We also thank Dr. S. Chuprakov for initial
experiments.
For selected recent reviews on reactions of metalꢀcarbenes, see: (a) F.
Z. Dörwald, in Metal Carbenes in Organic Synthesis, WileyꢀVCH,ꢁ
Weinheim, 1999; (b) Metal Carbenes in Organic Synthesis, (Ed: K.
H. Dotz), SpringerꢀVerlag, Berlin Heidelberg, 2004; (c) J. Egger and
E. M. Carreira, Nat. Prod. Rep., 2014, 31, 449; (d) Q. Xiao, Y. Zhang
and J. Wang, Acc. Chem. Res., 2013, 46, 236.
Notes and references
Department of Chemistry, University of Illinois at Chicago, 845 W
Taylor St., Room 4500, Chicago, Illinois 60607, USA. Eꢀmail:
vlad@uic.edu
10 For recent review on Cuꢀcatalyzed reactions of diazocompounds, see:
(a) X. Zhao, Y. Zhang and J. Wang, Chem. Commun., 2012, 48
,
†
Electronic Supplementary Information (ESI) available: Experimental
10162. For relevant examples, see: (b) E. Lourdusamy, L. Yao and
C.ꢀM. Park, Angew. Chem., Int. Ed., 2010, 49, 7963; (c) R. Liu, M.
Zhang, G. WinstonꢀMcPherson and W. Tang, Chem. Commun. 2013,
49, 4376.
procedures and characterization for new compounds are provided. See
DOI: 10.1039/b000000x/
1
2
(a) S. Chuprakov, F. W. Hwang and V. Gevorgyan, Angew. Chem.,
Int. Ed., 2007, 46, 4757; (b) S. Chuprakov and V. Gevorgyan, Org.
11 See Supporting Information for detailed optimization studies.
12 The 7ꢀClꢀsubstituted analog of 1a produced a complex mixture of
products even at lower temperature.
Lett., 2007, 9, 4463.
For general reviews on pyridotriazoles, see: (a) G. Jones, Adv.
Heterocycl. Chem., 2002, 83, 1; (b) B. AbarcaꢀGonzalez, J. Enzym.
Inhib. Med. Chem., 2002, 17, 359; (c) G. Jones and B. Abarca, Adv.
Heterocycl. Chem., 2010, 100, 195.
13 For review on the metal carbene migratory insertion, see: Y. Xia, Y.
Zhang and J. Wang, ACS Catal., 2013,
3, 2586.
14 For activation of copper acetilyde by electrophilic copper species,
see: B. T. Worrell, J. A. Malik and V. V. Fokin, Science, 2013, 340
,
3
For recent review on rearrangement of 1,2,3ꢀtriazoles, see: V.
Bakulev, W. Dehaen and T. B. Beryozkina, “Thermal
457.
4 | J. Name., 2012, 00, 1-3
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15 For Cuꢀcatalyzed cycloismerization reactions of propargyl and
allyenyl pyridines into indolizines, see: (a) B. Yan, Y. Zhou, H.
Zhang, J. Chen, Y. Liu, J. Org. Chem., 72, 7783. (b) D. Chernyak, S.
B. Gadamsetty and V. Gevorgyan, Org. Lett., 2008, 10, 2307; (c) M.
J. Albaladejo, F. Alonso and M. Yus, Chem.–Eur. J., 2013, 19, 5242.
16 Apparently, in this case, intermediate
G was quenched by an eventual
proton source, which was supported by deuterium labeling studies.
See Electronic Supporting Information for details.
17 It is believed that HPF6 liberates catalytic amounts of electrophilic
Cuꢀspecies by protonation of copper acetylide
4 (Scheme 3, entry 3).
18 For selected recent reviews on the formation of heterocycles via
attack of nucleophiles at the metalꢀactivated triple bond, see: (a) B.
Godoi, R. E. Schumacher and G. Zeni, Chem. Rev., 2011, 111, 2937;
(b) A. V. Gulevich, A. S. Dudnik, N. Chernyak and V. Gevorgyan,
Chem. Rev., 2013, 113, 3084, and references therein. For a selected
recent example, see: (c) C. He, J. Hao, H. Xu, Y. Mo, H. Liu, J. Han
and A. Lei, Chem. Commun., 2012, 48, 11073.
19 B. Chattopadhyay and V. Gevorgyan, Org. Lett., 2011, 13, 3746.
20 For the Cuꢀcatalyzed reactions of diazo compounds with alkynes, see:
(a) A. Suárez and G. Fu, Angew. Chem., Int. Ed., 2004, 43, 3580; (b)
L. Zhou, J. Ma, Y. Zhang and J. Wang, Tetrahedron Lett., 2011, 52
,
5484; (c) Q. Xiao, Y. Xia, H. Li, Y. Zhamg and J. Wang, Angew.
Chem., Int. Ed., 2011, 50, 1114; (d) L. Zhou, Y. Shi, Q. Xiao, Y. Liu,
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,
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,
6957; (i) M. L. Hossain, F. Ye, Z. Liu, Y. Xia, L. Zhou, Y. Zhang
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21 For computational studies of the Cuꢀcatalyzed crossꢀcoupling
reaction of diazo compounds with alkynes, see: T. Wang, M. Wang,
S. Fang and J. Liu, Organometallics, 2014, 33, 3941.
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