Construction of 1-pyrroline skeletons by Lewis acid-mediated conjugate addition of vinyl azides

Article abstract of DOI:10.1039/c5cc10299e

Lewis acid-mediated conjugate addition of vinyl azides to electron-deficient alkenes led to the efficient construction of 1-pyrroline skeletons. The reactions of vinyl azides with 3-alkylidene-2-oxoindolines afford 3′,4′-dihydrospiro[indoline-3,2′-pyrrol]-2-ones in a diastereoselective fashion, whereas those with dimethyl 2-alkylidenemalonates provide 4,5-dihydro-3H-pyrroles.

Full text of DOI:10.1039/c5cc10299e

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Construction of 1-Pyrroline Skeletons by Lewis Acid-Mediated
Conjugate Addition of Vinyl Azides
Xu Zhua and Shunsuke Chiba*a
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
Lewis acid-mediated conjugate addition of vinyl azides to
electron-deficient alkenes led to the efficient construction of 1-
pyrroline skeletons. The reactions of vinyl azides with 3-
alkylidene-2-oxoindolines afford 3',4'-dihydrospiro[indoline-3,2'-
pyrrol]-2-ones in diastereoselective fashion, whereas those with
dimethyl 2-alkylidenemalonates provide 4,5-dihydro-3H-pyrroles.
a) 1,2-addition of vinyl azides: amide synthesis
H
N
Ph
BF3•OEt2
H2O
Ph
Ph
Ts
Ph
+
N
N
NH
O
N2
Ts
vinyl azides
H2O
Ph
Ph
Ts
Ph
N2
Ph
Ph
N2
In seeking to develop new and efficient methods for nitrogen-
containing molecules, vinyl azides have been recently
employed as the source of three-atom unit including one
nitrogen.1 As one of their unique chemical reactivities, of
particular interest to us is that they perform as an enamine-
type nucleophile to various carbon electrophiles such as
imines, aldehydes, and carbocations derived from alcohols,
constructing the new C-C bond in the presence of
Lewis/Brønsted acid activators.2 Unlike the Stork enamine
reaction that concurrently forms an iminium ion,3 the C-C bond
formation with vinyl azides generates a distinct reactive
intermediate, namely, an iminodiazonium ion. For example,
the reactions of vinyl azides with N-Ts imines proceed
N
N
NH
N
NH
Ph
N
Ts
Ts
iminodiazonum ions
b) 1,4-addition of vinyl azides (hypothesis of this work)
R
O
i
HN
EWG
R
Ph
R'
Ph
R
Ph
or
R'
R
N
N
EWG
EWG
N2
N2
R'
ii
EWG
Ph
N2
R'
N
c) Construction of 1-pyrroline skeletons (this work)
EtO2C
Ph
EtO2C
Ph
O
N
N
Ph
smoothly in the presence of BF3•OEt2 to form β-amino amides
E
E
N
Bn
Ph
Ph
via the Schmidt type rearrangement4 of iminodiazonium ion
intermediates (Scheme 1-a).2a,5
N
cat. TiCl4
CH2Cl2
40 °C
BF3•OEt2 or
cat. TiCl4
O
N2
N
E
E
Bn
CH2Cl2, rt
(E = CO2Me)
We became interested in using this enamine-type
nucleophilic reactivity of vinyl azides for conjugate addition
Scheme 1 Enamine-type nucleophilic reactivity of vinyl azides.
onto
iminodiazonium ion bearing the
α,β
-unsaturated carbonyl compounds.6 In this case, the
sequence of Lewis-acid promoted conjugate addition of vinyl
azides and denitrogenative ring-expansion of transient
azidocyclobutane intermediates (Scheme 1-c).8 Changing the
conjugate electrophiles uniquely switched the atom
composition of the resulting 1-pyrroline skeletons derived
from vinyl azides.
γ
-carbanion might be
generated (Scheme 1-b). We wondered if this iminodiazonium
intermediates might undergo formation of amides via the
Schmidt rearrangement (path-i) or azidocyclobutanes through
cyclization of the carbanion onto the C=N bond7 (path-ii). We
herein report construction of 1-pyrroline skeletons enabled by
To elucidate our hypothesis, 3-alkylidene-2-oxoindoline 1a
was first chosen as the conjugate electrophile for the reactions
of vinyl azide 2a. Extensive screening of acid-promoters and
solvents reveled two complementary reaction conditions using
BF3•OEt2 (2 equiv, conditions
A) or TiCl4 (10 mol%, conditions
B
)
in CH2Cl2 are optimal (Scheme 2), providing 3',4'-
dihydrospiro[indoline-3,2'-pyrrol]-2-one 3aa as
a
single
diastereomer in excellent yields.9,10 The process could
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construct a 1-pyrroline scaffold as the part of the spiro
structure of 3aa. As the molecules having 2,3’-pyrrolidinyl
spirooxindole skeletons exhibit a wide spectrum of biological
activities,11,12 this finding stimulated us further to investigate
the substrate scope. The process did not require protection
(R1) on the nitrogen of 2-oxoindoline 1b, giving N-H product
3ba in good yields. By changing R2 on the alkene of
1, the
present method allowed for installation of benzoyl and cyano
groups to give the corresponding azaspirocyclic products 3ca
and 3da, respectively in good yields, whereas the reaction with
Scheme 3 The reactions with 1-azidocyclooctene 2h. The chemical structure of
the major isomer is shown.
terminal alkene (1e, R1 = H) resulted in poor yields of 3ea
Investigation of the substituent compatibility (R3) on the
benzene ring of 2-oxoindoline revealed that methoxy, chloro,
and trifluoromethyl groups were well tolerated (for 3fa 3ha).
Next, we examined the scope of vinyl azides in the reactions
with 1a
As the substituent R4, a variety of aromatic groups
could be introduced without diminution of the chemical yields
for 3ab 3af except for nitro-substituted 3af under the TiCl4-
catalyzed reaction conditions . It is worthy to note that alkyl
.
reaction conditions
diastereomers.
B resulted in formation of a mixture of the
Interestingly, the reaction of 1-azidocyclooctene 2h with 3-
alkylidene-2-oxoindoline 1a under the BF3-mediated reaction
conditions delivered unique polycyclic system 3ah in highly
diastereoselective manner (Scheme 3), whereas that with
1
-
2
.
chlorine-substituted
1g
somehow
lowered
the
diastereoselectivity of 3gh
.
-
To further broaden the scope of the present 1-pyrroline
synthesis, we turned our attention to use 2-
B
substituted vinyl azide 2g was amenable to the present
process for synthesis of 3ag under BF3-mediated reaction
alkylidenemalonates
4 (Scheme 4). It was found that the
reaction of dimethyl 2-benzylidenemalonate 4a with vinyl
azide 2a was enabled only by TiCl4-catalyzed reaction
conditions in CH2Cl2 at 40 °C, providing 1-pyrroline 5aa in 75%
yield (see ESI for optimization of the reaction conditions).13,14
Elucidation of the chemical structure of 5aa revealed that the
reaction process unambiguously involves C-C bond fission of
the vinyl moiety of 2a (marked in blue and green), which is
conditions
A
.
In the general trend, the reactions under the
provided single
BF3-mediated reaction conditions
A
diastereomers of
3, whereas those under the TiCl4-catalzyed
–conditions A
BF3•OEt2 (2 equiv)
or
–conditions B
TiCl4 (10 mol%)
R2
R2
R4
R4
N2
R3
R3
N
+
N
O
N
distinct from the formation of azaspirocycle
substituent R4 on vinyl azides
, various aryl motifs could be
5af 15
3. By varying the
O
CH2Cl2, 0 °C–rt
N
R1
2
2
R1
1 (0.3 mmol)
(1.2 equiv)
3
introduced for efficient construction of 1-pyrrolines 5aa
-
.
On the other hand, as substituents R5 on alklidenemalonates
4
,
EtO2C
EtO2C
Ph
Ph
Bz
Ph
NC
Ph
N
N
N
N
the process
O
O
O
O
N
N
H
3ba
N
N
Bn
3aa
A: 95%
B: 92%
Bn
3ca
A: 95%
B: 77%
Bn
3da
A: 79%
B: 79%
R4
N2
R5
N
A: 95%
+
TiCl4 (10 mol%)
CH2Cl2, reflux
N
2
R5
R4
B: 95% (6:1)
MeO2C
(Et)
CO2Me
(Et)
MeO2C CO2Me
EtO2C
EtO2C
EtO2C
Ph
Cl
Ph
MeO
Ph
Ph
(Et)
E
(Et)
(2 equiv)
4 (0.3 mmol)
5
N
N
N
N
N
N
N
O
O
O
O
N
Ph
Ph
Ph
E
Ph
N
N
N
H
F3C
Bn
Cl
Bn
Bn
E
E
E
E
3ga
A: 85%
B: 91% (7:1)
3fa
A: 90%
B: 76% (7:1)
3ha
A: 87%
B: 80% (3:1)
3ea
A: 44%
B: 22%
5aa 75%
(E = CO2Me)
5ab 60%
(E = CO2Me)
5ad 71%
(E = CO2Me)
N
N
N
OMe
Cl
Ph
Ph
Ph
EtO2C
EtO2C
EtO2C
Me
NC
E
E
E
E
E
E
N
N
N
Br
NO2
Ph
5ae 67%
(E = CO2Me)
5af 61%
5ba 75%
(E = CO2Et)
O
O
O
N
N
N
(E = CO2Me)
Cl
Bn
Bn
Bn
N
N
N
3ab
3ac
3ad
A: 91%
B: 94% (10:1)
Ph
Ph
A: 91%
A: 90%
B: 94% (10:1)
B: 96% (3:1)
MeO
E
E
E
E
E
E
5ca 63%
(E = CO2Me)
5da 60%
(E = CO2Me)
5ea 67%
(E = CO2Me)
EtO2C
EtO2C
EtO2C
Ph
Br
NO2
N
N
N
N
N
N
Ph
Ph
O
O
O
Ph
Me
Ph
Ph
N
N
N
E
E
E
E
E E
Bn
Bn
3af
A: 70%
Bn
3ag
A: 70%
B: n.r.
3ae
A: 93%
B: 72% (4:1)
5ga 60%
(E = CO2Et)
5fa 58%
(E = CO2Me)
5ha 61%
(E = CO2Me)
B: 38% (4:1)
Scheme 4 Synthesis of 1-pyrrolines 5.
Scheme 2 Synthesis of 3',4'-dihydrospiro[indoline-3,2'-pyrrol]-2-ones 3.
2 | J. Name., 2012, 00, 1-3
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a)
N
H
H
CO2Me
Ph
N2
EtO2C
EtO2C
Ph
Ph
NaBH3CN
(6 equiv)
TiCl4 (20 mol%)
CH2Cl2, reflux
Ph
CO2Me
+
N
N
NH
O
O
O
O
O
O
N
EtOH-AcOH (10:1)
rt, 22 h
N
2a
(2 equiv)
4i (0.3 mmol)
5ia 83%
R2
R2
3aa (R2 = Bn)
3ea (R2 = H)
6a (R2 = Bn) 93%, dr = 43:1
6e (R2 = H) 92% as a single diastereomer
Scheme 5 The reaction with 2-oxo-2H-chromene-3-carboxylate (4i).
b)
c)
LiCl (2.5 equiv)
H2O (4 equiv)
N
N
allowed for installing not only aryl (for 5ba-5ea) and alkenyl
Ph
Ph
Ph
Ph
(for 5fa) groups but also alkyl groups (for 5ga and 5ha).
The reaction of methyl 2-oxo-2H-chromene-3-carboxylate
DMSO
150 °C, 17 h
MeO2C CO2Me
7 76%
5aa
LiCl (1 equiv)
H2O (2 equiv)
(
4i) with vinyl azide 2a also proceeded well to give 2-
N
N
air (O2)
Ph
Ph
Ph
chromanone-1-pyrroline hybrid 5ia in good yield (Scheme 5).
Ph
Ph
5aa
DMSO
130 °C, 18 h
MeO2C
OH
To elucidate the reaction mechanisms for the formation of
CO2Me
9 86%
8
1-pyrrolines
3 and 5, a series of control experiments were
H
NaBH3CN
(1.5 equiv)
conducted (see ESI for more details). These results as well as
characterization of the side products14 implicated that the
present processes are composed of step-wise sequence
N
Ph
EtOH-AcOH (10:1)
rt, 2 h
MeO2C
OH
10 86%
initiated by conjugate addition of vinyl azides
unsaturated electrophiles or , that is followed by cyclization
to give azidocyclobutane intermediates. For the formation of
3',4'-dihydrospiro[indoline-3,2'-pyrrol]-2-ones (Scheme 6-a),
alignment of alkylidene-2-oxoindolines and vinyl azides in
the 1st 1,4-addition might be controlled by coordination of the
Lewis acids to both and in state A’ to afford
iminodiazonium ions
. In prior to the 2nd cyclization, rotation
of the C -C bond in the states B’ should be necessary to form
in
2 to the α,β-
Scheme 7 Chemical transformations of 3aa, 3ea and 5aa.
1
4
could be achieved by NaBH3CN to give 2,3’-pyrrolidinyl
spirooxiindoles 6a and 6e, respectively, in which hydride
approached from the opposite face from the benzene ring of
the 2-oxoindoline moiety (Scheme 7-a). Decarboxylation of
5aa could be controlled precisely by the reaction
temperature.18 Namely, treatment of 5aa with LiCl in the
presence of H2O in DMSO at 150 °C resulted in double
3
1
2
1
2
B
α
β
B”, leading to the formarion of cyclobutane intermediates
C
diastereoselective manner.16,17 The quaternary carbon on the
2-oxoindoline core finally migrated to the azide nitrogen atom
decarboxylation to give
that at 130 °C gave mono-decarboxylation product to afford
further autooxidation of which under air delivered 3-hydroxy-
1-pyrroline in 86% yield as a single diastereomer (Scheme 7-
c).19 Furthermore, NaBH3CN reduction of the C=N bond of
7 in 76% yield (Scheme 7-b), whereas
8,
to give azaspirocycles
formation of 1-pyrrolines
(Scheme 6-b), similarly formed cyclobutane intermediates
might undergo ring-expansion to give 1-pyrrolines
3
.
On the other hand, as for the
9
5
from 2-alkylidenemalonates
4
E
9
afforded densely functionalized pyrrolidine 10 in 86% yield as a
single diastereomer.
5.
In this
case, migration of the secondary carbon (marked in green) was
predominant over that of the quaternary carbon due to its
deactivation by two methoxycarbonyl groups.
We anticipate that the present methods are capable of
supplying various pyrrolidine-based azaheterocycles of
medicinal importance.20 Further studies are in progress to
elucidate the detailed reaction mechanism and to upgrade the
present transformations to catalytic enantioselective variants.
Finally, we demonstrated concise chemical conversions of
1-pyrroline products 3aa, 3ea, and 5aa (Scheme 7). Highly
diastereoselective reduction of the C=N bond of 3aa and 3ea
a) formation of 3
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).
We thank Dr. Yongxin Li and Dr. Rakesh Ganguly (Division of
Chemistry and Biological Chemistry, School of Physical and
Mathematical Sciences, Nanyang Technological University) for
assistance in X-ray crystallographic analysis.
R2
R2
R2
α
β
Ph
N2
Ph
Ph
γ
N
3
N
N2
N
O
O
–N2
O
N2
N
N
R1
LA
N
2a
R1
R1
1
C
A
B
Ph
Ph
N2
R2
R2
H
R2
H
N
N
N
N
N2
N
H
Ph
H
O
O
O
Notes and references
N
R1
α,β-bond
rotation
N
R1
LA
N
R1
B"
B'
A'
(LA: Lewis acids)
b) formation of 5
Ph
1
For reviews, see: (a) B. Hu and S. G. DiMagno, Org. Biomol.
Chem., 2015, 13, 3844; (b) N. Jung and S. Bräse, Angew.
Chem., Int. Ed., 2012, 51, 12169; (c) S. Chiba, Chimia,, 2012,
66, 377; d) S. Chiba, Synlett, 2012, 23, 21; (d) K. Banert, In
Organic Azides: Syntheses and Applications; S. Bräse and K.
Banert, Eds.; Wiley, 2010; p 115; (e) B. J. Stokes and T. G.
Driver, Eur. J. Org. Chem., 2011, 4071; (f) T. G. Driver, Org.
R
N
N2
N
R
Ph
N2
R
E
Ph
R
Ph
N
N
N2
E
–N2
E
E
E
E
E
E
E
LA
2a
4
D
5
Scheme 6 Proposed reaction mechanisms for the 1-pyrroline formations.
Biomol. Chem., 2010, 8, 3831.
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2
(a) F.-L. Zhang, Y.-F. Wang, G. H. Lonca, X. Zhu and S. Chiba,
Angew. Chem., Int. Ed., 2014, 53, 4390; (b) F.-L. Zhang, X. Zhu
and S. Chiba, Org. Lett., 2015, 16, 6136; (c) X. Zhu, Y.-F.
Scott and J. F. Bower, Chem. Sci., 2014, 5, 2416; (d) J. J.
Badillo, C. J. A. Ribeiro, M. M. Olmstead and A. K. Franz, Org.
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Zard, Heterocycles, 2014, 88, 953; (f) K. K. Toh, A. Biswas, Y.-
Wang, F.-L. Zhang and S. Chiba, Chem. Asian J., 2014,
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9,
F. Wang, Y. Y. Tan and S. Chiba, J. Am. Chem. Soc., 2014, 136,
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4
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5
6
The Jiao group applied the protonation of vinyl azides for Au- 14 From the reaction of 2a and 4a in 2 mmol scale, in addition
catalzyed synthesis of amides from alkynes and TMSN3, see:
C. Qin, P. Feng, Y. Ou, T. Chen, T. Wang and N. Jiao, Angew.
Chem., Int. Ed., 2013, 52, 7850.
to the formation of 5aa (73% yield), we could isolate and
characterize another 1-pyrroline 5aa’ and acylic amide 5aa’’
(>1% yields) as shown below. See ESI for the reaction
mechanisms for the formation of 5aa’ and 5aa”.
For general reviews on conjugate addition reactions, see: (a)
P. Perlmutter, Conjugate Addition Reactions in Organic
Synthesis; Pergamon Press: Oxford, 1992; (b) H.-G. Schmalz,
In Comprehensive Organic Synthesis; B. M. Trost, I. Fleming,
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For reviews on construction of spirooxindole skeletons from
3-alkylidene-2-oxoindolines, see: (a) D. Cheng, Y. Ishihara, B.
H
E
Ph
N
E
Ph
N
O
Ph
Ph
E
E
5aa'
5aa"
(E = CO2Me)
7
8
15 The reaction with alkyl-substituted vinyl azide 2g did not
provide the corresponding 1-pyrroline 5ag at all.
16 Similar diastereochemical outcomes have been observed in
Lewis acid-catalyzed carboannulation of 3-alkylidene-2-
oxoindolines with allylsilanes, see: N. R. Ball-Jones, J. J.
Badillo, N. T. Tran and A. K. Franz, Angew. Chem., Int. Ed.,
2014, 53, 9462.
17 Presumably, rotation of the C(
iminodiazonium ion is prevented by the steric hindrance.
18 S. S. More, T. K. Mohan, Y. S. Kumar, U. K. S. Kumar and N. B.
Patel, Beilstein J. Org. Chem., 2011, , 831.
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B
9
7
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2012, 10, 5165.
10 The chemical structures of 3aa, 3ca, 3da, 3gh, 5ia, 6a, and 10
were elucidated by X-ray crystallographic analyses. See ESI
for more details.
11 For
recent
reports
on
synthesis
of
3,2'-
pyrrolidinylspirooxindole derivatives and their biological
activities, see: (a) Y. A. Ivanenkov, S. V. Vasilevski, E. K.
Beloglazkina, M. E. Kukushkin, A. E Machulkin, M. S.Veselov,
N. V. Chufarova, E. S. Chernyaginab, A. S. Vanzcool, N. V. Zyk,
D. A. Skvortsov, A. A. Khutornenko, A. L. Rusanov, A. G.
Tonevitsky, O. A. Dontsova, A. G. Majouga, Bioorg. Med.
Chem. Lett., 2015, 25, 404; (b) W. Tan, X.-T Zhu, S. Zhang, G.-
J. Xing, R.-Y. Zhu and F. Shi, RSC Adv., 2013, 3, 10875; (c) M.
A. Ali,; R. Ismail, T. S. Choon, R. S. Kumar, H. Osman, N.
Arumugam, A. I. Almansour, K. Elumalai and A. Singh, Bioorg.
Med. Chem. Lett., 2012, 22, 508; (d) G. Bhaskar, Y. Arun, C.
Balachandran, C. Saikumar and P. T. Perumal, Eur. J. Med.
Chem., 2012, 51, 79.
12 Several methods for asymmetric construction of 2,3’-
pyrrolidinyl spirooxyindoles have been recently developed,
see: (a) J. P. Macdonald, B. H. Shupe, J. D. Schreiber and A. K.
Franz, Chem. Commun., 2014, 50, 5242; (b) Y.-M. Cao, F.-F.
Shen, F.-T. Zhang and R. Wang, Chem. Eur. J., 2013, 19, 1184;
(c) F. Shi, Z.-L. Tao, S.-W. Luo, S.-J. Tu and L.-Z. Gong, Chem.
Eur. J., 2012, 18, 6885.
13 For recent selected reports on synthesis of 1-pyrrolines, see:
(a) A. Faulkner, J. S. Scott and J. F. Bower, J. Am. Chem. Soc.,
2015, 137, 7224; (b) H. Sun, W. Li, Z. Xuan and W. Yu, Adv.
Synth. Catal., 2015, 357, 64; (c) A. Faulkner, N. J. Race, J. S.
4 | J. Name., 2012, 00, 1-3
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