[3+2] Annulation of Donor-Acceptor Cyclopropanes with Vinyl Azides

Article abstract of DOI:10.1055/s-0036-1588703

A Sc(OTf)₃-catalyzed reaction of vinyl azides with donor-acceptor cyclopropanes affords highly functionalized azidocyclopentanes in a diastereoselective fashion. The resulting azidocyclopentanes could be transformed into various cyclic scaffolds.

Full text of DOI:10.1055/s-0036-1588703

SYNLETT
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
©
Georg Thieme Verlag Stuttgart · New York
2017, 28, A–E
A
letter
Synlett
A. Kaga et al.
Letter
[
3+2] Annulation of Donor–Acceptor Cyclopropanes with Vinyl
Azides
Atsushi Kaga
N3
+
R1
Dhika Aditya Gandamana
Sayako Tamura
N3
CO2R3
CO2R3
R1
cat. Sc(OTf)3
R2
CH2Cl2–MeNO2 (4:1)
0 °C
Mesut Demirelli
Shunsuke Chiba*
CO2R3
CO2R3
R2
11 examples
up to 95% yield
dr 71:29 to 91:9
[3+2] annulation
1
2
3
R
R
R
= aryl, alkyl
= aryl, alkenyl, phthalimidyl
= CH2(2,6-Me2C6H3)
Division of Chemistry and Biological Chemistry, School of Physical
and Mathematical Sciences, Nanyang Technological University,
Singapore 637371, Singapore
shunsuke@ntu.edu.sg
Received: 30.11.2016
Accepted after revision: 15.01.2017
Published online: 06.02.2017
a) reactions of vinyl azides with electrophiles (E+)
N2
N2
N
N
DOI: 10.1055/s-0036-1588703; Art ID: st-2016-b0806-l
E+
further
transformations
E
Ph
vinyl azides
Ph
Abstract A Sc(OTf) -catalyzed reaction of vinyl azides with donor–ac-
iminodiazonium
ions
3
ceptor cyclopropanes affords highly functionalized azidocyclopentanes
in a diastereoselective fashion. The resulting azidocyclopentanes could
be transformed into various cyclic scaffolds.
b) with 2-alkylidenemalonates (previous work: ref 2b)
N2
E
N
N2
Ph
E
E
cat. TiCl4
E
N
N
Key words vinyl azides, donor–acceptor cyclopropanes, cyclopen-
tanes, [3+2] annulation, Lewis acids
+
Ph
CH2Cl2
reflux
1,4-addition
R
Ph
(
E = CO2Me)
Vinyl azides have exhibited unique chemical reactivity
in their molecular transformations. Our group recently
disclosed that vinyl azides perform as an enamine-type nu-
cleophile to various carbon or halogen electrophiles [E ] to
E
E
E
Ph
E
E
N2
R
N2
N
E
R
1
Ph
–N2
Ph
N
R
+
I
II
1-pyrroline
2
,3
construct a new C–C or C–X bond. While the Stork enam-
c) with donor-acceptor cyclopropanes (this work)
4
ine reaction forms an iminium ion, the reactions of vinyl
R1
+
N2
azides with [E ] result in generation of an iminodiazonium
N3
CO2R3
CO R3
N
cat. Sc(OTf)3
CO2R3
CO R3
+
ion that undergoes further transformations such as
Schmidt-type rearrangement to form amides and regener-
R1
R2
[3+2] annulation
R2
2
5
2
ation of an azide through trap of the electrophilic C=N bond
with nucleophiles in both intra- and intermolecular man-
ners (Scheme 1, a). As for synthesis of nitrogen heterocy-
[
ScIII
]
N2
E
N
E
S 2-type
ring-opening
N
N2
R1
R1
III
N
cles, synthesis of 1-pyrrolines was enabled by TiCl -cata-
(E = CO2R3)
E
E
4
R2
R2
lyzed reactions of vinyl azides with 2-alkylidenemalonates
IV
2b
(
Scheme 1, b). The process is initiated by conjugate addi-
Scheme 1 Nucleophilic reactivity of vinyl azides
tion of vinyl azides onto 2-alkylidenemalonates to form the
iminodiazonium ions I bearing a γ-carbanion. Subsequent
cyclization generates azidocyclobutanes II that undergoes
strain-release denitrogenative ring expansion to afford the
(Scheme 1, c).6,7 Herein, we report Sc(OTf) -catalyzed [3+2]
3
8
,9
annulation of donor–acceptor cyclopropanes with vinyl
azides for the construction of highly functionalized azido-
cyclopentanes in a diastereoselective fashion.10 Electrophil-
ically activated donor–acceptor cyclopropanes III were at-
1-pyrroline products.
In seeking to develop a new type of molecular transfor-
mation by taking advantage of the nucleophilic reactivity of
vinyl azides, we became interested in use of donor–accep-
tor cyclopropanes as a potential 3-atom unit electrophile
tacked by vinyl azides in an S 2-type fashion as a predomi-
N
nant pathway,11 forming iminodiazonium ions IV bearing a
©
Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E

B
Synlett
A. Kaga et al.
Letter
δ-carbanion. Further cyclization delivered azidocyclopen-
tanes. Several conversions of azidocyclopentanes into use-
ful carbo- and heterocyclic scaffolds were also demonstrated.
We commenced our study to optimize the reaction set-
tings using vinyl azide 1a and cyclopropropanes 2a–5a (Ta-
Using the optimized reaction conditions (Table 1, entry
7), we investigated the substrate scope for the diastereose-
lective [3+2] annulation of cyclopropanes 5 with vinyl
1
azides 1 (Scheme 2). As for substituent R on vinyl azides 1,
several aryl groups such as 4-tolyl (for 1b), 2-naphthyl (for
1c), and 4-bromophenyl (for 1d) groups could be used for
the reaction with the cyclopropane 5a to afford the corre-
sponding cyclopentanes 9ba–da with good diastereoselec-
12
ble 1). Extensive screening of acid activators revealed that
use of Sc(OTf) in MeNO is optimal to realize the desired
3
2
[
3+2] annulation of cyclopropane 2a for the construction of
1
cyclopentane 6aa in good yield albeit in poor diastereose-
tivity, whereas installation of an alkyl group as R on vinyl
13
lectivity (Table 1, entry 1). We assumed that the steric ef-
fect of the ester moiety should affect the diastereoselectivi-
ty. Indeed, bulkier esters 3a–5a resulted in better diastereo-
selectivity (Table 1, entries 2–4) and 2,6-dimethylbenzyl
ester 5a provided the best result (dr = 82:18, Table 1, entry
azide 1e resulted in the moderate diastereoselectivity in cy-
2
clopentane 9ea. Next, the effect of substituent R on cyclo-
propanes 5 was examined using vinyl azide 1d. The process
allowed for the use of cyclopropanes having electron-rich
4-methoxyphenyl (for 5b), sterically bulky aryl (for 5c and
5d), and thienyl (for 5e) moieties, forming the correspond-
ing cyclopentanes 9db–de in good yields and diastereose-
lectivity. Moreover, cinnamyl (for 5f) and phthalimido (for
5g)6 groups were also well tolerated in the present annu-
lation process, forming the corresponding cyclopentanes
9df and 9dg, respectively.
4). Screening of the solvent systems (Table 1, entries 5–7)
revealed that use of CH Cl –MeNO co-solvent (4:1) system
2
2
2
at 0 °C improved the yield of 9aa with further improvement
of the diastereoselectivity (Table 1, entries 6 and 7).
e,8o
Table 1 Optimization of the Reaction Conditionsa
Ph
N3
R1
N3
Sc(OTf)3
(15–30 mol%)
N3
E
E
E
CO2R
R1
+
R2
Ph
CH2Cl2–MeNO2
(4:1)
R2
CO2R
N3
1
5
E
Sc(OTf)3
a major isomer
(0.50 M)
0 °C
9
(10 mol%)
(2 equiv)
CO2R
CO2R
+
Ph
+
E = CO CH (2,6-Me C H )
2
2
2 6 3
Ph
solvent
temp, time
1
a
Ph
(
2 equiv)
cyclopropanes
scope of vinyl azides 1 with 5a
N3
CO2R
CO2R
Me
Br
cyclopropanes
a: R = Me
a: R = i-Pr
Ph
2
4a: R = CH2Ph
5a: R = CH2(2,6-Me2C6H3)
Ph
3
a minor isomer
N3
E
N3
N3
E
N3
E
Entry Cyclopropane Solvent
Temp Time Yield drc
E
b
Ph
Ph
Ph
Ph
(
°C)
(h)
(%)
E
E
E
E
9
ba
9ca
(95%, 91:9)
9da
(89%, 90:10)
9ea
(73%, 71:29)
1
2a
3a
4a
5a
5a
5a
5a
MeNO
MeNO
MeNO
MeNO
2
2
2
2
23
5
6aa
53:47
77:23
71:29
82:18
84:16
89:11
88:12
a
a
a
b
(
82%, 86:14)
94
scope of cyclopropanes 5 with 1d (Ar = 4-BrC6H4)
2
23
23
23
23
0
10
10
24
24
24
24
7aa
Ar
Ar
Ar
81
N3
E
Me
N3
E
N3
3
8aa
E
77
E
E
E
MeO
4
9aa
9dcb
9
db
9dd
(89%, 88:12)
Ar
55
(94%, 86:14)
(86%, 91:9)
5
CH
2
Cl
2
–MeNO
–MeNO
–MeNO
2
2
2
9aa
72
Ar
Ar
(
4:1)
O
N3
E
N3
N3
E
6d
CH
Cl
9aa
80
E
N
2
2
2
Ph
E
(
4:1)
E
E
S
O
7d,e
CH Cl
0
9aa
95
2
9
de
9df
9dg
(83%, 78:22)
(
4:1)
(
92%, 88:12)
(83%, 90:10)
a
Unless otherwise stated, the reactions were carried out using 0.3–0.5
Scheme 2 Substrate scope. Unless otherwise noted, the reactions
mmol of cyclopropanes with vinyl azide 1a (2 equiv) in the presence of 10
were conducted using 0.5 mmol of cyclopropanes 5 and 1 mmol vinyl
azides 1 in the presence of Sc(OTf) (15 mol%) in CH Cl –MeNO (4:1, 1
mol% of Sc(OTf)
3
in the solvent (0.3 M).
b
Isolated yields based on cyclopropanes.
3
2
2
2
c
1
Diastereoselectivities (major/minor) were determined by H NMR analysis
mL) under an Ar atmosphere. Isolated yields based on cyclopropanes 5
of isolated mixture of cyclopentanes.
a
and diastereoselectivities were recorded above. 20 mol% of Sc(OTf)3
d
Reaction was conducted in 0.50 M.
b
e
used. 30 mol% of Sc(OTf) used.
3
3
15 mol% of Sc(OTf) was used.
©
Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E

C
Synlett
A. Kaga et al.
Letter
Finally, we demonstrated versatility of the azidocyclo-
pentane products by transforming 6aa and 9aa into a vari-
ety of synthetically useful derivatives (Schemes 3 and 4).
This work demonstrated that nucleophilic attack of vi-
nyl azides onto donor–acceptor cyclopropanes in the pres-
ence of Sc(OTf) as a Lewis acid activator enables an effi-
3
The reaction of 6aa with LiCl in the presence of H O in
cient construction of azidocyclopentanes.17 Further study
in exploration of other types of bond-forming processes us-
ing vinyl azides is in progress.
2
14
DMSO promoted decarboxylation and subsequent elimi-
nation of the azido ion to afford cyclopentene 10, whereas
treatment of 6aa with TfOH gave another regioisomeric cy-
clopentene 11 (Scheme 3, a and b).1 Furthermore, denitro-
genative ring expansion of 6aa was enabled by the reaction
5
Acknowledgment
with SnCl , forming tetrahydropyridines 12 and 13 (that is
formed through subsequent decarboxylation) in 39% and
4
This work was supported by funding from Nanyang Technological
University (NTU) and the Singapore Ministry of Education (Academic
Research Fund Tier 1: 2015-T1-001-040). S.T. is grateful to Yokohama
National University and MHPS Mirai Scholarship for the financial sup-
port. M.D. is grateful to UPMC Sorbonne Universités for the financial
support. We acknowledge to Dr. Yongxin Li and Dr. Rakesh Ganguly
34% yields, respectively (Scheme 3, c). Similarly with our
previous 1-pyrroline formation (Scheme 1, b), migration of
the secondary carbon occurred dominantly over that of the
quaternary carbon, which is deactivated by the two me-
thoxycarbonyl groups.
(Division of Chemistry and Biological Chemistry, School of Physical
and Mathematical Sciences, NTU) for assistance in X-ray crystallo-
graphic analysis.
Ph
Ph
Ph
a. LiCl, H2O
DMSO
N3
E
b. TfOH
E
Ph
E
DCE
0 °C
Ph
Ph
Supporting Information
1
30 °C
E
E
10 97%
6aa
11 94%
Supporting information for this article is available online at
(
E = CO2Me)
http://dx.doi.org/10.1055/s-0036-1588703.
S
u
p
p
o
nrtIo
i
g
f
rm oaitn
S
u
p
p
ortioIgnfmr oaitn
c. SnCl4
DCE, 60 °C
H
References and Notes
N
Ph
E
N
Ph
E
+
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E
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2 39%
13 34%
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16
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3
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(
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N
N
a.
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Ph
9
aa
NH
b. PMe3, H2O
THF, 0 °C
E = CO2-(2,6-Me2C6H3)
E
Ph
(
then Ac2O
pyridine, rt
E
15 49%
Scheme 4 Derivatization of azidocyclopentane 9aa. Reagents and con-
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equiv), DMF, 80 °C, 50 h; b) PMe (2 equiv), THF–H O (20:1), 0 °C, then
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2
2
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Synlett
A. Kaga et al.
Letter
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9) For recent reports on other types of annulation reactions with
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Chattaraj, P. K.; Banerjee, P. Org. Lett. 2016, 18, 4940.
(b) Varshnaya, R. K.; Banerjee, P. Eur. J. Org. Chem. 2016, 4059.
(c) Chidley, T.; Vemula, N.; Carson, C. A.; Kerr, M. A.; Pagenkopf,
B. L. Org. Lett. 2016, 18, 2922. (d) Alajarin, M.; Egea, A.; Orenes,
R.-A.; Vidal, A. Org. Biomol. Chem. 2016, 14, 10275. (e) Das, S.;
Chakrabarty, S.; Daniliuc, C. G.; Studer, A. Org. Lett. 2016, 18,
(17) Procedure for the Synthesis of Cyclopentane 9aa
To a stirred solution of cyclopropane 5a (218 mg, 0.493 mmol)
and vinyl azide 1a (144 mg, 0.993 mmol) in CH Cl (0.8 mL) and
2
784. (f) Ivanova, O. A.; Budynina, E. M.; Khrustalev, V. N.;
Skvortsov, D. A.; Trushkov, I. V.; Melnikov, M. Y. Chem. Eur. J.
016, 22, 1223. (g) Sabbatani, J.; Maulide, N. Angew. Chem. Int.
2
2
2
MeNO (0.2 mL) was added Sc(OTf) (37.6 mg, 0.0764 mmol) at
2
3
Ed. 2016, 55, 6780. (h) Garve, L. K. B.; Petzold, M.; Jones, P. G.;
Werz, D. B. Org. Lett. 2016, 18, 564. (i) Liu, J.; Ye, W.; Qing, X.;
Wang, C. J. Org. Chem. 2016, 81, 7970. (j) Garve, L. K. B.;
Pawliczek, M.; Wallbaum, J.; Jones, P. G.; Werz, D. B. Chem. Eur. J.
0 °C under an Ar atmosphere. The solution was stirred at 0 °C
for 24 h and then quenched with sat. aq NaHCO . The mixture
3
was extracted with CH Cl , and the combined extracts were
2
2
washed with brine, dried over MgSO , and concentrated in
4
2016, 22, 521. (k) Xu, H.; Hu, J.-L.; Wang, L.; Liao, S.; Tang, Y.
vacuo. The resulting crude material was purified by flash
J. Am. Chem. Soc. 2015, 137, 8006. (l) Tabolin, A. A.; Novikov, R.
A.; Khomutova, Y. A.; Zharov, A. A.; Stashina, G. A.; Nelyubina, Y.
V.; Tomilov, Y. V.; Ioffe, S. L. Tetrahedron Lett. 2015, 56, 2102.
column chromatography (hexane–Et O, 100:1 to 90:1) to yield
cyclopentane 9aa (275 mg, 0.468 mmol) in 95% yield as a
2
mixture of diastereomer (major/minor = 88:12, which was
1
(m) Ghosh, A.; Pandey, A. K.; Banerjee, P. J. Org. Chem. 2015, 80,
determined by H NMR analysis). The major isomer could be
7235. (n) Liu, H.; Yuan, C.; Wu, Y.; Xiao, Y.; Guo, H. Org. Lett.
recrystallized from CH Cl –hexane as a colorless crystal.
2
2
2015, 17, 4220. (o) Zhang, J.; Xing, S.; Ren, J.; Jiang, S.; Wang, Z.
Bis(2,6-dimethylbenzyl) (2S*,4R*)-2-azido-2,4-diphenylcy-
Org. Lett. 2015, 17, 218. (p) Wang, H.-P.; Zhang, H.-H.; Hu, X.-Q.;
Xu, P.-F.; Luo, Y.-C. Eur. J. Org. Chem. 2015, 3486. (q) Pandey, A.
K.; Ghosh, A.; Banerjee, P. Eur. J. Org. Chem. 2015, 2517.
clopentane-1,1-dicarboxylate (9aa major)
1
Mp 100–101 °C. H NMR (400 MHz, CDCl ): δ = 2.04 (6 H, s),
3
2.16 (6 H, s), 2.52 (1 H, dd, J = 6.8, 14.4 Hz), 2.79–2.91 (2 H, m),
©
Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E

E
Synlett
A. Kaga et al.
Letter
3
.03 (1 H, dd, J = 10.4, 14.4 Hz), 3.57–3.66 (1 H, m), 4.94 (1 H, d,
126.4, 127.3, 127.4, 127.9, 128.09, 128.12 (overlapped), 128.2,
128.7, 128.8, 130.7, 131.1, 138.2, 138.4, 138.5, 144.4, 169.4,
170.1. ESI-HRMS: m/z calcd for C37H38NO4 [M – N2 + H] :
J = 12.0 Hz), 5.08–5.14 (2 H, m), 5.29 (1 H, d, J = 12.0 Hz), 6.93 (2
H, d, J = 7.6 Hz), 6.99 (2 H, d, J = 7.6 Hz), 7.07–7.22 (6 H, m),
+
13
7.27–7.31 (4 H, m), 7.37 (2 H, d, J = 7.2 Hz). C NMR (100 MHz,
560.2801; found: 560.2806.
CDCl ): δ = 19.2, 19.3, 39.9, 43.2, 47.3, 62.2, 62.4, 69.8, 78.3,
3
©
Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E