Cu-catalyzed transannulation reaction of pyridotriazoles: General access to fused polycyclic indolizines

Article abstract of DOI:10.1039/c5cc07598j

An efficient intramolecular transannulation reaction of pyridotriazoles using internal alkynes en route to various fused polycyclic indolizines has been developed. For the first time it is shown that in addition to the well-established Rh- or Cu-catalyzed carbene mechanism, the transannulation reaction could also follow a Lewis acid-mediated electrophilic pathway.

Full text of DOI:10.1039/c5cc07598j

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Cu-Catalyzed Transannulation Reaction of Pyridotriazoles:
General Access to Fused Polycyclic Indolizines
Received 00th January 20xx,
Accepted 00th January 20xx
Yi Shi and Vladimir Gevorgyan*
DOI: 10.1039/x0xx00000x
www.rsc.org/
An efficient intramolecular transannulation reaction of general with respect to arylalkyne moiety (entries 1-10). Thus,
pyridotriazoles with internal alkynes en route to various fused a variety of tethered internal arylalkynes bearing electron-
polycyclic indolizines has been developed. For the first time it was neutral,
shown that in addition to the well-established Rh- or Cu-catalyzed substituents at ortho-, meta- and para-positions participated
carbene mechanism, the transannulation reaction could also well in this transannulation reaction toward fused indolizine
electron-withdrawing,
and
electron-donating
2
.
follow a Lewis acid-mediated electrophilic pathway.
It was also found that this reaction is not limited to aryl
alkynes. Thus, alkenyl (ak), as well as alkyl (al) alkynes, could
also be utilized in this transformation to produce the
corresponding indolizines. Moreover, an electron-deficient
alkyne 2am was found to be a competent substrate, as well.
Notably, the reaction of alkynyl pyridotriazole bearing a silyl
substituent proceeded smoothly to afford 3-TBS-indolizine 2an
in good yield, which upon desilylation offers an access to C3-
nonsubstituted indolizine.
Transition metal-catalyzed denitrogenative transannulation of
triazoles1-4 represents
a powerful tool for synthesis of
nitrogen-containing heterocycles. Previously, our group
developed the transannulation reaction of pyridotriazoles
proceeding via the reaction of rhodium carbene intermediate
C
with alkynes.2a It was shown that Cl, Br, or OMe substituents
at C7 (AG = activating group) were requisite for efficient
formation of the cyclization product (eq. 1). Recently, we
reported the Cu-catalyzed version of this reaction, which
addressed the above mentioned limitations (eq. 2).2d Despite a
much broader reaction scope and employment of cheap
copper catalyst, this transformation was still limited to
terminal alkynes, which precluded the possibility of an
intramolecular transannulation reaction toward valuable fused
N-heterocycles.5 Herein, we report the first general and
efficient Cu-catalyzed intramolecular transannulation of
pyridotriazoles with tethered internal alkynes to produce a
wide range of fused polycyclic indolizines (eq. 3).
Previous work:
Terminal Alkynes only
EWG
N2 Rh(II)
EWG
R
EWG
EWG
R
Rh
N
N
(1)
N
N
N
N
-N2
AG
AG
AG
B
C
AG
A
D
AG = Cl, Br, OMe
R1
R1
Cu(MeCN)4PF6, 15 mol %
PhMe, 130 °C
+
N
(2)
R2
N
N
N
R2
Aiming at the development of efficient intramolecular
transannulation reaction, an extensive screening of various
transition metal catalysts was performed.6 It was found that
this reaction could efficiently be accomplished in the present
of Cu-catalyst. Thus, pyridotriazole 1aa was converted to the
desired tetracyclic δ-valerolactone-fused indolizine product in
This work:
Internal Alkynes
X
X
CuBr SMe2, 15 mol %
(3)
DCE, 140 o
C
N
N
N
N
R
R
1
2
X = C(O), C(O)O, CONMe
83% yield employing 15 mol % of CuBrꢀSMe in dichloroethane
(Table 1, entry 1). This transformation appeared to be quite
Scheme 1 Transannulation reactions of pyridotriazoles.
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Table 1 Scope of copper catalyzed transannulation reaction of pyridotriazoles. – synthesis of 3-5 cyclic Indolizines.a,b
X
C
X
D
CuBr SMe2, 15 mol %
DCE, 140 o
A
B
N
N
C
N
N
R
R
2
1
Entry
1
Product
Yield, %
83
Entry
13
Product
Yield, %
50
Entry
21
Product
Yield, %
91
O
O
O
O
O
N
N
N
Ph
Ph
Ph
O
2aa
2ba
O
2am
2an
2
3
4
5
6
7
2ab, R = p-Me
2ac, R = p-OMe
2ad, R = p-CF3
2ae, R = p-F
75
85
80
73
78
58
O
67c
O
N
14
15
22
23
87
73
N
O
TBS
O
2bb
2bc
N
O
O
O
R
2af, R = p-C(O)Me
2ag, R = m-Cl
78
71
N
N
Me
Ph
O
n-Bu
2ao
O
O
O
O
N
Me
8
76
16
24
90
N
Me
N
p-OPhC6H4
TBS
2bd
2be
2ap
OMe
2ah
O
O
O
O
O
N
9
81
64
17
18
60d
25
26
23
95
N
N
Ph
2aq
OMe
2ai
O
O
O
O
O
N
10
68
N
N
Ph
O
Ph
O
TIPS
2ar
2bf
S
2aj
O
O
O
N
11
12
47
41
19
20
60
52
27
28
85
40
N
N
Ph
O
Ph
2as
2at
2bg
2ak
2al
O
O
O
NMe
O
N
N
N
(84[e]
)
Ph
Ph
2bh
a Conditions: pyridotriazole 1 (0.20 mmol) and CuBrꢀSMe2 (15 mol %) were heated in 2 mL of dry DCE at 140 °C until completion (in general, 24 h for entries 1-
20, 27; 2 h for entries 21-26, 28). b Isolated yields. c 5 mol % [Rh*CpCl2]2 in 2 mL of dry mesitylene at 140 °C. d Performed at 180 °C in PhCl. e 1.0 mol % Rh2(esp)2
in 2 mL of dry Toluene at 120 °C.
2 | J. Name., 2012, 00, 1-3
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Next, the scope of rings A and D was examined (Table 1, of a 5-membered ring (Table 1, entries 21-28). We were
entries 15-19). To our delight, substituents at ring A (2ao 2ap pleased to find that, aryl (2ba), alkenyl (2bb), alkyl (2bc) and
,
)
were tolerated under these reaction conditions, which for the silyl (2bd) group at the alkyne moiety were all perfectly
first time, enabled the synthesis of C6-substituted indolizines compatible under these reaction conditions to efficiently
in a selective manner.7 Notably, the reaction proceeded afford the corresponding indanone-fused indolizines.
smoothly to construct pentacyclic fused systems 2aq and 2ar
In addition, tetracyclic indolizine with non-aromatic ring D 2be, although in a low yield. Remarkably, 1,3-strained C3,5-
2as) could also be produced in good yield. Moreover, disubstituted fused indolizines 2bf
2bg9 were efficiently
pyridotriazole processing an amide tether underwent constructed by this method. In addition to the above-
transannulation reaction to afford the corresponding lactam- mentioned indanone-fused indolizines, tricyclic γ-
fused product 2at, albeit in a moderate yield.8
butyrolactone-fused indolizine 2bh could also be obtained
.
Surprisingly, terminal alkyne could also be utilized to produce
(
,
a
After developing the transannulation reaction to form 6- albeit in moderate yield.
membered C ring, we turned our attention to the construction
[3+2]
X
Carbene Mechanism
X
[2+1]
[M]=Cu
N
Cu
-N2
4
R
X
N
3
R
Metathesis
X
X
X
N
R
5
Cu
N
N
N
N
N
N
N
R
X
X
[M]
[M]
R
R
1
1'
2
-[M]
N
-N2
Lewis Acid
Mechanism
N
N
N
R
R
7
6
-[M]
[M]
X
N
X
X
N
aza-Nazarov
N
M
N
-N2
N
M
M
R
R
R
8
9
10
Scheme 2 Proposed mechanism for the copper catalyzed transannulation reaction of pyridotriazoles.
involving a newly formed copper carbene intermediate 5. During
optimization, we unexpectedly found that Lewis acids, such as
In(OTf)3 or TIPSOTf, could also catalyze this transformation (Scheme
3). Based on this observation, we envisioned an alternative Lewis
acid activation pathway, according to which, the diazo form 1’ can
be metallated to produced intermediate 6, which would then
X
X
Catalyst (15 mol %)
DCE, 140 o
N
N
C
N
N
Ph
2
Ph
1
undergo
a denitrogenative cyclization to form a cationic
X = C(O), 2ba, 64%
X = C(O)O, 2aa, 10%
Cat. In(OTf)3:
Cat. TIPSOTf:
intermediate 7. A subsequent cyclization and a metal loss of the
latter would form the fused indolizine product 2. Also, the reaction
could be triggered by a nucleophilic attack of the diazo carbon at
the Lewis acid-activated triple bond to form intermediate 8. The
latter, upon exclusion of dinitrogen, aza-Nazarov cyclization,11 and a
metal loss, would be converted into indolizine 2.
X = C(O), 2ba,
30%
Scheme 3. Lewis acid - catalyzed transannulation reaction of pyridotriazoles.
Naturally, after establishing the scope of this intramolecular
transannulation reaction, we were eager to clarify the reaction
pathway (Scheme 2). Apparently, the pyridotriazole 1 exists in
equilibrium with the diazo form 1’, which can react with copper
catalyst to generate copper carbene intermediate 3.10 Next, a direct
[3+2] cyclization would lead to the indolizine product 2.2a
Alternatively, a [2+1] cycloaddition would produce a cyclopropene
intermediate 4, which would then isomerize into indolizine 2.2b
Also, one cannot exclude the carbene-alkyne metathesis pathway3m
In summary, we developed an efficient copper catalyzed
intramolecular transannulation reaction of pyridotriazoles with
internal alkynes. This first intramolecular transannulation reaction
of pyridotriazoles provides expeditious and general access to
various tri-, tetra-, and pentacyclic fused indolizines, including C6-
substituted fused indolizines that cannot be synthesized selectively
via known cycloaddition methods. For the first time it was shown
that this reaction could also be triggered by Lewis acids.
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Acknowledgements
The support of the National Science Foundation (CHE-
1362541) is gratefully acknowledged.
Notes and references
1
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6
7
See Supporting Information for details.
Alternatively, fused indoizines can be accessed via direct
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Zhang, F. Liang, L. Sun, Y. Hu and H. Hu, Synthesis, 2000, 12,
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Xu, Tetrahedron, 2007, 63, 2024.
3
For transannulation reactions of N-sulfonyl triazoles, see: (a)
T. Horneff, S. Chuprakov, N. Chernyak, V. Gevorgyan and V.
V. Fokin, J. Am. Chem. Soc., 2008, 130, 14972; (b) T. Miura,
M. Yamauchi and M. Murakami, Chem. Commun., 2009
,
However, cyclization of meta-substituted pyridinium salt is
not selective.7b
1470; (c) B. Chattopadhyay and V. Gevorgyan, Org. Lett.,
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Chem., Int. Ed., 2013, 52, 10044; (h) M. Zibinsky and V. V.
CN
CO2Et
CO2Et
NC
Br
Cu(OAc)2 H2O, 3 equiv.
NaOAc, 4 equiv.
+
CO2Et
+
N
N
N
NC
DMF, 80 °C
Ph
C(O)Ph
C(O)Ph
O
39%
50%
8
9
Attempts on employment of alkynyltriazole possessing ether
tether were not successful.
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10 For the Cu-catalyzed reactions involving copper carbene
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4
For other reactions of N-sulfonyl triazoles, see: (a) N.
Grimster, L. Zhang and V. V. Fokin, J. Am. Chem. Soc., 2010,
132, 2510; (b) S. Chuprakov, S. W. Kwok, L. Zhang, L. Lercher
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11 For aza-Nazarov cyclization reaction on pyridine ring, see: (a)
R. R. Naredla, C. Zheng, S. O. Nilsson Lill and D. A. Klumpp, J.
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4 | J. Name., 2012, 00, 1-3
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Table of Contents
X
X
CuBr SMe2, 15 mol %
DCE, 140 o
N
N
C
N
N
R
R
X = C(O), C(O)O, CONMe
An efficient intramolecular transannulation reaction of pyridotriazoles with internal alkynes en route to various fused polycyclic indolizines
has been developed. For the first time it was shown that in addition to the well-established Rh- or Cu-catalyzed carbene mechanism, the
transannulation reaction could also follow a Lewis acid-mediated electrophilic pathway.
This journal is © The Royal Society of Chemistry 20xx
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