The Divergent Synthesis of Nitrogen Heterocycles by Rhodium(I)-Catalyzed Intermolecular Cycloadditions of Vinyl Aziridines and Alkynes

Article abstract of DOI:10.1021/jacs.6b00386

Catalyst-controlled divergent intermolecular cycloadditions of vinylaziridines with alkynes have been developed. By using [Rh(NBD)₂]BF₄ as the catalyst, a [3 + 2] cycloaddition reaction was achieved with broad substrate scope and high stereoselectivity under mild reaction conditions. Moreover, the chirality of vinylaziridines can be completely transferred to the [3 + 2] cycloadducts. When the catalyst was changed to [Rh(η⁶-C₁₀H₈) (COD)]SbF₆, the alternative [5 + 2] cycloadducts were selectively formed under otherwise identical conditions.

Full text of DOI:10.1021/jacs.6b00386

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Communication
The Divergent Synthesis of Nitrogen Heterocycles by Rhodium(I)-
Catalyzed Intermolecular Cycloadditions of Vinyl Aziridines and Alkynes
Jian-Jun Feng, Tao-Yan Lin, Chao-Ze Zhu, Huamin Wang, Hai-Hong Wu, and Junliang Zhang
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.6b00386 • Publication Date (Web): 09 Feb 2016
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The Divergent Synthesis of Nitrogen Heterocycles by Rhodi-
um(I)-Catalyzed Intermolecular Cycloadditions of Vinyl Aziri-
dines and Alkynes
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Jian-Jun Feng,‡ Tao-Yan Lin,‡ Chao-Ze Zhu, Huamin Wang, Hai-Hong Wu, and Junliang Zhang*
Shanghai Key Laboratory of Green Chemistry and Chemical Processes, Department of Chemistry, East China Nor-
mal University, 3663 N. Zhongshan Road, Shanghai 200062, P. R. China
Supporting Information Placeholder
Scheme 1. Intermolecular [3+2] and [5+2] cycloadditions of vi-
nylaziridines
ABSTRACT: Catalyst-controlled divergent intermolecular
cycloadditions of vinylaziridines with alkynes have been de-
veloped. By using [Rh(NBD)2]BF4 as the catalyst, a [3+2] cy-
cloaddition reaction was achieved with broad substrate scope
a) [3+2] and [5+2] cycloaddition of vinylaziridines with activated alkenes and alkynes
previous work:
[3+2]: Yamamoto, Aggarwal, Hou & Ding,
[5+2]: Stogryn, Hassner, Yudin
[5+2]
CF3
et al.
et al.
and high stereoselectivity under mild reaction conditions.
Moreover, the chirality of vinylaziridines can be completely
transferred to the [3+2] cycloadducts. When the catalyst was
changed to [Rh(η6-C10H8)(COD)]SbF6, the alternative [5+2]
cycloadducts were selectively formed under otherwise iden-
tical conditions.
[3+2]
CO2Me
Y
alkenes
activated
alkynes
EWG
R1
activated
R
or
CF3
N
metal-free
R = H
[Pd]
CO2Me
N
N
H
N
R = Ts
Y= H, EWG
Ts
b) [3+2] and [5+2] cycloaddition of vinylaziridines with general alkynes (with or without EWG)
this work:
R2
R1
R2
[5+2]
[3+2]
R2
general alkynes:
R1
R
+
N
[Rh]
R1
[Rh]
N
N
R
R
R = Ts, Ns, Ms
A preeminent goal of organic synthesis is to complete control
over the product distribution of a catalytic reaction. Efforts
to realize this goal would enable the divergent synthesis of
different valuable products from common versatile starting
materials. Heterocycles such as pyrrolidine and azepine de-
rivatives are ubiquitous structural motifs found in an array of
natural products and pharmaceuticals with diverse biological
and medicinal properties (Figure 1).1 Therefore, the develop-
ment of highly efficient synthetic methods to access these
compounds has been intensively pursued by synthetic com-
munity.2 Among them, intermolecular [3+2] and [5+2] cy-
cloaddition is a viable strategy to synthesis of these valuable
aza-heterocycles in an atom-economical fashion.3,4 While
such a strategy has been widely utilized for the formation of
pyrrolidine and azepine skeletons from different starting
materials, only scarce and specific examples have been re-
ported for the divergent synthesis of different aza-
heterocycles from common versatile reactants solely con-
trolled by different catalysts.4i
with or without EWG
Switchable process
General substrate scope Complete chirality transfer
addition with heterocumulenes or other activated two-
carbon components.5 Among them, transition-metal-
catalyzed formal [3+2] cycloadditions of vinylaziridines with
electron-deficient alkenes represent powerful tools enabling
quick and efficient access to multi-substituted pyrrolidines.6
For example, the research group of Yamamoto has done pio-
neering work on the palladium-catalyzed [3+2] cycloaddition
of N-tosylvinylaziridines and alkenes with two activators in
2002.7 Subsequently, Aggarwal and co-workers disclosed an
elegant palladium-catalyzed [3+2] cycloaddition of enanti-
oenriched vinylaziridines with monoactivated alkenes for the
stereospecific synthesis of substituted pyrrolidines. The sig-
nificance of this reaction has been highlighted in the formal
synthesis of (-)-α-kainic acid.8 Recently, the more challeng-
ing enantioselective [3+2] cycloaddition of racemic vinyl-
aziridines with monoactivated alkenes was reported by Hou
and Ding (Scheme 1b).9 However, previous reports on the
intermolecular [3+2] cycloadditions of vinylaziridines are
limited to those two-carbon components with one or two
activators .10 Morover, the examples of vinylaziridines as five-
atom components in [5+2] cycloaddition with general al-
kynes is rare (scheme 1a). 11 Therefore, discovering new in-
termolecular [3+2] and [5+2] cycloadditions involving general
alkynes will advance the vinylaziridine chemistry.
As a part of our continual program in the discovery of new
hetero-[5+2] cycloaddition reactions of strained rings,11a-b, 12
we recently developed a Rh(I)-catalyzed intramolecular het-
ero-[5+2] cycloaddition of vinyl aziridine-alkyne substrates
for synthesis of enantioenriched fused 2,5-dihydro-azepines
through chirality transfer strategy.11a Hence, we became in-
terested in whether vinylaziridines could be employed in
Figure 1. Biologically active natural products containing pyr-
rolidine and azepine skeletons
Vinylaziridines are increasingly being exploited as versatile
building blocks in organic synthesis, such as nucleophilic
ring-opening, rearrangements, carbonylation and [3+2] cylo-
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more challenging intermolecular cycloaddition with general
1d proceeded smoothly in current transformation, providing
options for N-protection and deprotection. The R5 group in 1
1
2
3
4
alkynes. Herein we report our efforts to selective synthesis of
the optically active 2,3-dihydropyroles and valuable 2,5-
dihydroazepines from identical starting materials (vinylaziri-
dines and alkynes), by switching the cycloaddition mode
with different rhodium(I) catalysts (Scheme 1b).
Table 1. Scope with respect to various alkynes 2
5
6
7
8
Initially, our investigation began with phenylacetylene 2a
and N-tosyl vinylaziridine substrate (R)-1a, which can be
prepared in 98% ee from commercially available (L)-serine
methyl ester hydrochloride.5 After many attempts, gratifying-
ly, with the use of [Rh(NBD)2]BF4, the [3+2] cycloaddition
provided the desired 2,3-dihydropyrole 3aa in 90% NMR
yield without loss of chirality information. Interestingly, the
reaction favors the formation of [5+2]-cycloadduct 4aa rather
than 3aa when using [Rh(COD)Cl]2/AgSbF6, [Rh(COD)Cl]2/
AgBF4 or [Rh(η6-C10H8) (COD)]SbF6 containing a COD lig-
and as the catalyst, and the structure of 4aa was further con-
firmed by X-ray crystallographic analysis.13 Other commonly
used metal catalysts such as Pd2(dba)3,8a AgSbF6,3g FeCl3,3h
entry R1/R2
Cond. Ac
Cond. Bc
Yield(%)
Yield(ee)(%)
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1
Ph/H(2a)
3aa, 80 (97)
3ab, 70 (98)
3ac, 93 (96)
3ad, 72 (97)
3ae, 78 (98)
3af, 90 (98)
3ag, 91 (98)
3ah, 82 (96)
3ai, 86 (94)
3aj, 70 (97)
3ak, 65 (98)
3al, 87 (94)
3am, 88 (99)
3an, 82 (98)
3ao, 89 (98)
3ap, 66 (97)
4aa, 90
4ab, 94
4ac, 93
4ad, 90
4ae, 97
4af, 97
4ag, 91
4ah, 75
4ai, 60
4aj, 17
2
4-EtOC6H4/H(2b)
4-t-BuC6H4/H(2c)
4-MeC6H4/H(2d)
3-MeC6H4/H(2e)
2-MeC6H4/H(2f)
4-FC6H4/H(2g)
3
4
5
6
3j
7
and Sc(OTf)3 showed almost no catalytic activity (see Table
S1, in the supporting information).
8
4-ClC6H4/H(2h)
4-BrC6H4/H(2i)
4-AcC6H4/H(2j)
4-MeCO2C6H4/H(2k)
1-naphthyl/H(2l)
2-naphthyl/H(2m)
2-thienyl/H(2n)
2-benzofuranyl/H(2o)
cyclohexenyl/H(2p)
n-C3H7/H(2q) i
With the optimal reaction conditions in hand, various al-
kynes 2 were explored to investigate the generality of these
product-switchable cycloadditions (Table 1). Firstly, the
scope of the [3+2] cycloaddition was examined under condi-
tions A. A wide range of alkynes, not only terminal alkynes
but also internal alkynes are suitable substrates, leading to
the corresponding [3+2] cycloadduct as a single regioisomer
in most cases (Table 1, entries 1-15). The chirality of (R)-1a
can be efficiently or completely transferrred to the valuable
2,3-dihydropyroles with 90-99% ee in moderate to high
yields. The structure and absolute configuration of the cy-
cloadduct (R)-3am was unambiguously determined by X-ray
crystallographic analysis.13 Aliphatic alkynes can give the
corresponding [3+2] cycloadducts in moderate to high NMR
yield, but it is very unstable as a result of the hydrolytically
labile property of the enamine skeleton during purification
(Table 1, entries 16-26).14 Gratifyingly, the [5+2] cycloadduct
4az together with [3+2] cycloadduct 3az was obtained when
we subjected symmetric internal alkyne 2z to conditions A.
The reaction remained efficient when nonsymmetric internal
alkyne 2aa and 2bb was used as substrate, providing the cor-
responding 3aaa and 3abb as a single regioisomer. Notably,
the reaction is not limited to alkynes without electron-
withdrawing group. Monoactivated alkyne 2cc was also com-
patible, delivering the [3+2] cycloadduct 3acc under condi-
tions A and B.
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12
13
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19
4ak, 61
4al, 30
4am,93
4an, 61
4ao, 61
4ap, 82
3aq, 90(97)d,e 4aq, 90f
3ar, 66(98)d,e 4ar, 76f
n-C5H11/H(2r)
C6H5(CH2)2/H(2s)
3as, 71(96)
4as, 74j
4at, 75
4au, 84
4av, 69f
20 (CH3)2CHCH2/H(2t) i
21
Cyclopropyl/H(2u) i
3at, 85(97)d,e
3au, 98(97)e
3av, 70(-)e, g
3aw, 65(97)d,e 4aw, 75f
3ax, 55(90)d,e 4ax, 78f,j
3ay, 77(93)d
3az, 52 (92)
3aaa, 64(96)
22 (CH2)3OTBS/H(2v)
23 (CH2)3OBn/H(2w)
24 (CH2)2CO2Me/H(2x)
25 (CH2)3Phth/H(2y)
26 Et/Et(2z)h
4ay, 67f
4az, 18a
3aaa, 40e
27 TMS/Me(2aa)
28 4-MeOC6H4/CH2OMe
(2bb)
In parallel, the scope of [5+2] cycloadditions was also eval-
uated. A set of 2,5-dihydroazepines were obtained in high
selectivity under conditions B. It was found that various al-
kynes such as aromatic (2a-2m), heteroaromatic (2n-2o), and
aliphatic terminal alkynes (2p-2y) underwent the [5+2] cy-
cloadditions with rac-1a to afford the corresponding [5+2]
cycloadducts in moderate to excellent yields. In most cases,
only one regioisomer is detected, except for aliphatic alkynes
2q, 2r, and 2v-y, affording corresponding azepines 4 and its
regioisomer 4’ in moderate to high ratio. Unfortunately, the
internal alkynes are not applicable to the present [5+2] cy-
cloaddition.
3abb, 69(96) 3abb, 30e
29 Ph/COMe(2cc)
3acc, 75(94)
3acc, 37
a Conditions A: 0.25 mmol (R)-1a, 1.2 equiv. 2, and 5 mol%
[Rh(NBD)2]BF4 in 2.5 mL 1,2-dichloroethane (DCE) at rt
for 15 min. b Conditions B: 0.25 mmol rac-1a, 1.5 equiv. 2,
and 5 mol% [Rh(η6-C10H8)(COD)]SbF6 in 2.5 mL DCE at 0
oC for 30 min then it was stirred at rt for 15 min. c Isolated
d
Yield. The ee value was determined after conversion of 3
f
to γ–amino ketone 5. e NMR yield. 4aq:4aq’ = 14:1, 4ar:
4ar’ = 10:1, 4av:4av’ = 10:1, 4aw:4aw’ = 10:1. 4ax:4ax’ = 3.3:1.
4ay:4ay’ = 6.3:1. g The product is very unstable. h 5.0 equiv.
of 2. i 10.0 equiv. of 2. j 10 mol% catalyst.
To further extend the substrate scope, we next examined
several different substituted vinylaziridines. As depicted in
Table 2, N-nosyl vinylaziridine 1c and N-mesyl vinylaziridine
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could be replaced by H, n-butyl, isopropyl or phenyl groups
pyrroline 7 can be accessed from vinylaziridine 1m with
phthalimido (Phth) group under conditions A or B (eq 2).17
Interestingly, the (R)-1a would undergo racemization rapidly
in the absence of alkyne (eq 3).
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2
3
4
5
6
7
8
without a notable negative effect to the cycloaddition under
conditions A or B (1b-1g). Notably, aziridinyl enolsilanes 1h
and 1i underwent [3+2] and [5+2] cycloadditions with ac-
ceptable yields, albeit that products 3ia and 4ia are moisture-
sensitive.15 Vinylaziridines 1j16 and 1k could also successfully
deliver the desired products, incorporating a quaternary car-
bon into the 2,3-dihydropyroles. Furthermore, 1l is also ap-
plicable to the [3+2] and [5+2] cycloadditions, but gave the
corresponding cycloadducts with lower ee value and yield.
9
Table 2. Scope with respect to various VAs 1a
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entry
(1)(ee%)
Cond. A
Cond. B
Yield(%)
Yield(ee)(%)
3ba, 75 (97) 4ba, 40b
3ca, 84 (92) 4ca, 70
3da, 50(86) 4da, 62
3ea, 72 (90) 4ea, 92
3fa, 65 (93) 4fa, 91
3ga, 75 (99) 4ga, 90
3ha,84 (95) 4ha, 78
Scheme 2. Proposed mechanism
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2
3
4
5
6
7
8
3ia, 75c (-)
4ia, 76c
9
3ja, 78 (84) 4ja, 48d
3ka, 55 (85)e 4ka, 40f
10
Based on the results above, a plausible mechanism is pro-
posed in Scheme 2. Coordination of rhodium catalyst to vi-
nylaziridine (R)-1 via the olefin and the nitrogen gives com-
plex I. Subsequent oxidative addition with retention gives
enyl (σ+π) rhodium species II and III reported by Evans.18,19
The direct reductive elimination of rhodium species III
would afford the 3-pyrroline 7 when the vinylaziridine 1m
was used as starting material. The competitive β−H elimina-
tion of rhodium species III (or II) derived from 1n (or 1j)
would give the aldehyde 8 (eq 4) or (diene 9)16 after further
reductive elimination. In the presence of alkynes 2, rhodium
species II and III could be regioselectively captured by al-
kynes to deliver another two interconvertible enyl (σ+π) rho-
dium species IV and V, followed by irreversible reductive
elimination to yield [3+2] cycloadduct (R)-3 and [5+2] cy-
cloadduct (+)-4, respectively under the catalysis of two dif-
ferent rhodium catalysts. Although the exact mechanism of
this intriguing transformation remains unclear at this stage,
both the diene ligands (NBD versus COD) and the property
of the substrates play a central role on the mode of the cur-
rent cycloadditions.
11
3la, 53 (32)c 4la,40g
a
Conditions A and Conditions B are the same as those
described in Table 2. Isolated yield. b 3ba was obtained in
20% yield. c NMR yield, the product is very unstable. d 3ja
and 4ja were obtained in 48% total yield together with 9
in 45% yield, see ref. 16, 4ja:3ja=1.0:0.7. e Reaction was run
f
at room temperature with 10 mol% catalyst for 1 h. Reac-
tion was run at room temperature with
5 mol%
[Rh(COD)Cl]2/AgSbF6 for 1 h. g 3la (59% ee) and 4la (72%
ee) were obtained in 40% total yield, 4la:3la=1.0:1.2.
Given the fact that synthesis of chiral azepine is in great
demand in both organic and medicinal chemistry, a method
was developed to convert the [3+2] cycloadducts to chiral
azepines. (R)-1a and 2a can be transformed into a useful
building block, γ–amino ketone 5aa, using a one-pot proto-
col. Subsequently, the transformation of 5aa to the enantio-
merically pure azepines 6aa was accomplished by a sequence
of SN2 reaction followed by ring-closing metathesis (eq 1).
To clarify the mechanism, we examined the reaction of vi-
nylaziridines without the activated sulfonamide group. The
reaction turned out to be messy when the unactivated vinyl-
aziridines were employed in the current cycloadditions (see
Figure S1, in the supporting information), whereas 3-
In summary, a product-switchable rhodium(I)-catalyzed
intermolecular cycloadditions of vinylaziridines and alkynes
has been developed, and enable the efficient and divergent
synthesis of two types of aza-heterocycles, 2,3-dihydropyroles
and 2,5-dihydroazepines from identical starting materials,
respectively through [3+2] and [5+2] cycloadditions. Notably,
the chirality of vinylaziridines can be efficiently transferred
to the [3+2] cycloadducts. The salient features of this trans-
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(4) Representative examples for synthesis of azepines via cycloaddi-
formation include atom-economic and switchable process,
mild reaction conditions, stereospecificity, and general sub-
strate scope. Further mechanism and synthetic application of
this efficient transformation are underway.
tions, see: [5+2]: (a) Wender, P. A.; Pedersen, T. M.; Scanio, M. J. C. J.
Am. Chem. Soc. 2002, 124, 15154. (b) Merced Montero-Campillo, M.;
Cabaleiro-Lago, E. M.; Rodríguez-Otero, J. J. Phys. Chem. A 2008, 112,
9068. (c) Zhou, M.-B.; Song, R.-J.; Wang, C.-Y.; Li, J.-H. Angew.
Chem. Int. Ed. 2013, 52, 10805. (d) Yang, Y.; Zhou, M.-B.; Ouyang, X.-
H.; Pi, R.; Song, R.-J.; Li, J.-H. Angew. Chem. Int. Ed. 2015, 54, 6595. (e)
Iqbal, N.; Fiksdahl, A. J. Org. Chem. 2013, 78, 7885. (f) Shenje, R.;
Martin, M. C.; France, S. Angew. Chem. Int. Ed. 2014, 53, 13907. [4+3]:
(g) Schultz, E. E.; Lindsay, V. N. G.; Sarpong, R. Angew. Chem. Int.
Ed. 2014, 53, 9904. (h) Tian, Y.; Wang, Y.; Shang, H.; Xu, X.; Tang, Y.
Org. Biomol. Chem. 2015, 13, 612. (i) Shang, H.; Wang, Y.; Tian, Y.;
Fang, J.; Tang, Y. Angew. Chem. Int. Ed. 2014, 53, 5662. (j) Shapiro, N.
D.; Toste, F. D. J. Am. Chem. Soc. 2008, 130, 9244. (k) Jeffrey, C. S.;
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2014, 53, 4196.
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ASSOCIATED CONTENT
Supporting Information
Experimental details, characterization data and crystallo-
graphic data. This material is available free of charge via the
Internet at http://pubs.acs.org.
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AUTHOR INFORMATION
Corresponding Author
jlzhang@chem.ecnu.edu.cn
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(10) Vinylaziridine as a three-atom component in the palladium(0)
and gold(I) dual catalyzed intramolecular [3+2] cycloaddition with
general alkene, see: Hirner, J.-J.; Roth, K. E.; Shi, Y.; Blum, S. A. Or-
ganometallics 2012, 31, 6843.
(11) Vinylaziridine as a five-atom component: for rhodium(I) cata-
lyzed intramolecular [5+2] cycloadditions with general alkynes or
alkenes, see: (a) Feng, J.-J.; Lin, T.-Y.; Wu, H.-H.; Zhang, J. J. Am.
Chem. Soc. 2015, 137, 3787. (b) Feng, J.-J.; Lin, T.-Y.; Wu, H.-H.;
Zhang, J. Angew. Chem. Int. Ed. 2015, 54, 15854. For metal free inter-
molecular formal [5+2] cycloaddition with activated alkynes through
a tandem addition/aza-[3,3]-Claisen rearrangement reaction, see: (c)
Stogryn, E. L.; Brois, S. J. J. Am. Chem. Soc. 1967, 89, 605. (d)
Hassner, A.; D’Costa, R.; McPhail, A. T.; Butler, W. Tetrahedron Lett.
1981, 22, 3691. (e) Baktharaman, S.; Afagh, N.; Vandersteen, A.;
Yudin, A. K. Org. Lett. 2010, 12, 240.
(12) Feng, J.-J.; Zhang, J. J. Am. Chem. Soc. 2011, 133, 7304.
(13) CCDC 1435125 (3am), 1435126 (4aa).
(14) (a) Hegedus, L. S.; Holden, M. S. J. Org. Chem. 1986, 51, 1171. (b)
Hegedus, L. S.; Mckearin, J. M. J. Am. Chem. Soc. 1982, 104, 2444.
(15) Lam, S. K.; Lam, S.; Wong, W.-T.; Chiu, P. Chem. Comm. 2014, 50,
1738.
Author Contributions
‡These authors contributed equally to this work.
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
We gratefully acknowledge the funding support of STCSM
(15YF1403600), NSFC (21172074, 21373088, 21425205), 973 Pro-
gram (2011CB808600), and the Program of Eastern Scholar at
Shanghai Institutions of Higher Learning.
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