Tandem ring opening/cyclization of vinylcyclopropanes: A facile synthesis of chiral bicyclic amidines

Article abstract of DOI:10.1002/anie.201100375

An open and shut case: An interesting bromine-catalyzed tandem ring opening/cyclization reaction of bicyclic vinylcyclopropanes with chloramine-T ([TsNCl]Na) has been demonstrated to furnish chiral bicyclic amidine derivatives in good yield. A plausible m

Full text of DOI:10.1002/anie.201100375

Communications
DOI: 10.1002/anie.201100375
Synthetic Methods
Tandem Ring Opening/Cyclization of Vinylcyclopropanes: A Facile
Synthesis of Chiral Bicyclic Amidines**
Venkataraman Ganesh, Devarajulu Sureshkumar, and Srinivasan Chandrasekaran*
Vinylcyclopropanes (VCP) are important synthons in organic
synthesis because of the presence of a highly strained ring
system in conjugation with a carbon–carbon double bond,
thus enabling these compounds to participate in a wide range
of reactions. This structural motif is found in numerous
naturally occurring optically active compounds that are
important intermediates in the biosynthesis of terpenes.[1]
Furthermore, these compounds are prone to pyrolysis,
electrophilic ring opening, and acid-catalyzed rearrangement,
thus leading to structurally interesting compounds.[2,3]
(Scheme 1). It resulted in the serendipitous formation of the
optically pure [4.4.0] bicyclic amidine 4a in good yield, rather
than the expected aziridine derivative A.[7,8] The structure of
4a was confirmed unambiguously by X-ray crystallography
(see Scheme 4). Although, VCP derivatives have been shown
to undergo a Ritter-type reaction under strongly acidic
conditions,[8] the reaction has not been utilized as an approach
for the synthesis of amidines. The reaction was optimized by
varying the electrophilic halogen source, which was used as
the catalyst, to get the bicyclic amidine 4a as the exclusive
product.
Herein, a one-pot synthesis of enantiomerically pure
bicyclic amidines from bicyclic vinylcyclopropanes is reported
(Scheme 1). Amidines have attracted considerable interest
owing to their diverse applications in the fields of chemistry
With iodine[7] and other electrophilic halogen sources,
such as N-bromosuccinimide and N-iodosuccinimide, the
reaction afforded the product in only a moderate yield.
When the reaction was carried out with 10 mol% of
pyridinium hydrobromide perbromide,[9a] the yield of 4a
went up to 73% and further improvement in yield (82%) was
achieved when PTAB[9b] was used as the catalyst (see the
Supporting Information).
To demonstrate the versatility of the reaction as a general
method towards the synthesis of chiral bicyclic amidine
derivatives, it was carried out using various nitriles as the
solvent. In all cases, the reaction proceeded smoothly leading
to the corresponding nitrile-inserted compounds (4b–d) in
good yields (Table 1, entries 2–4).
Scheme 1. Reaction of VCP 3 with chloramine-T. Ts=p-toluenesulfonyl.
and biology.[4] Chiral amidine scaffolds are efficient organo-
catalysts and excellent ligands for transition-metal-based
asymmetric catalysis, thus providing good enantioselectivity.[5]
However, only a few methods are available for the
synthesis of amidines with a wide range of structures.[6]
Shibasaki and co-workers reported an interesting intramo-
lecular cyclization for the efficient synthesis of bicyclic
amidines[6a] and highlighted the challenge in synthesizing
chiral bicyclic amidines. The present study focuses on a ring
opening of the VCP, a Ritter-type reaction, and a subsequent
cyclization in one pot to obtain enantiomerically pure
amidines. In our preliminary studies, we investigated the
reaction of (+)-2-carene (3) with chloramine-T (1) in the
presence of a catalytic amount of phenyltrimethylammonium
tribromide (2; PTAB) using acetonitrile as the solvent
Even with the electron-deficient nitrile pentafluoroben-
zonitrile (Table 1, entry 5), the reaction afforded 4e, albeit in
low yield (25%). Cis- and trans-4-carene (5 and 7, respec-
tively), when treated under similar reaction conditions,
underwent rearrangement readily in acetonitrile to yield the
corresponding amidines 6 and 8 in good yields (Table 1,
entries 6 and 7). The study was then extended to other VCP
derivatives, such as (S)-(+)-caren-5-ol (9) and 5-acetylcarene
(11),[10] which yielded the corresponding amidines 10 (83%)
and 12 (76%) in good yields (Table 1, entries 8 and 9).
The reaction scope was further extended by the study of
the fused five-membered bicyclic VCP 17 to achieve the
synthesis of chiral [4.3.0] bicyclic amidines (see Table 2).
Therefore, 17 was synthesized starting with the dihydroxyla-
tion of 2-carene (3) using OsO4 and NMMO in tBuOH to give
the corresponding cis-diol 13 in 86% yield (Scheme 2).[11a]
The diol was subsequently treated with NaIO4/silica gel[11b] to
furnish the keto aldehyde 14 (97% yield), which after an
intramolecular Aldol reaction gave the corresponding five-
membered a,b-unsaturated ketone 15.[11c] The ketone 15 was
reduced with NaBH4/CeCl3 under Luche conditions to yield
the alcohol 16 as a diastereomeric mixture (85:15). The
diastereomers were separated after conversion into the
benzyl ether (NaH, BnBr and DMF) and the major isomer
17 was used for further studies.
[*] V. Ganesh,[+] Dr. D. Sureshkumar,[+] Prof. S. Chandrasekaran
Department of Organic Chemistry, Indian Institute of Science
Bangalore-560 012, Karnataka (India)
Fax: (+91)80-2360-2423
E-mail: scn@orgchem.iisc.ernet.in
[+] These authors contributed equally.
[**] We thank the CSIR (New Delhi) for the Shyama Prasad Mukherjee
Fellowship (V.G.) and DST for the JC Bose National Fellowship
(S.C.).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201100375.
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Angew. Chem. Int. Ed. 2011, 50, 5878 –5881

Table 1: Synthesis of [4.4.0] bicyclic amidines from carene derivatives.[a]
Entry
Reactant
Solvent
t
[h]
Product
Yield
[%][b]
1
CH3CN
5
5
5
8
82
78
74
62
3
3
4a
4b
4c
4d
2
3
4
EtCN
PrCN
PhCN
Scheme 2. Synthesis of five-membered bicyclic VCP 17. Bn=benzyl,
DMF=N,N’-dimethylformamide, NMMO=N-methylmorpholine-N-
oxide.
3
3
starting from 1,3-cyclohexadiene and a-phenyl diazoacetate
using a AgSbF6-catalyzed cyclopropanation.[12] The cyclo-
propyl ester was reduced to the corresponding alcohol 18
using LiAlH4 in THF, and a subsequent reaction with NaH
and MeI at 08C furnished 19. Compound 19 was subjected to
Sharpless aziridination reaction conditions in acetonitrile to
afford exclusively the desired bicyclic amidine 20 in good
yield (72%). The stereochemistry of compound 20 was
confirmed by analysis of 1H-1H COSY, HMQC, and
NOESY spectra (nOe of the bridgehead protons and the
phenyl ring protons; Scheme 3). We observed a complete
inversion at the phenyl-substituted cyclopropane carbon
5
3
15
25
4e
6
6
7
8
CH3CN
CH3CN
CH3CN
5
5
7
73
82
83
5
7
9
Table 2: Synthesis of [4.3.0] bicyclic amidines from 17.[a]
Entry
Reactant
Solvent
t
[h]
Product
Yield
[%][b]
8
1
CH3CN
5
5
5
8
5
5
92
90
85
83
91
81
10
17
17
17a
17b
17c
17d
17e
17 f
9
CH3CN
7
76
2
3
4
5
6
EtCN
PrCN
iPrCN
11
12
[a] Reaction conditions: VCP (3 mmol), chloramine-T (3.3 mmol), PTAB
(0.3 mmol), solvent (15 mL), 5-15 h, RT. [b] Yield is of the isolated
product.
17
17
17
17
Compound 17 was subjected to the rearrangement
reaction with chloramine-T and PTAB in acetonitrile at
room temperature for 5 hours to yield the corresponding
amidine 17a in excellent yield (92%; Table 2, entry 1). To
show the general applicability of the method, compound 17
was treated with chloramine-T and PTAB using a variety of
nitriles as the solvent to furnish the corresponding bicyclic
amidines 17b–f in good yield (Table 2, entries 2–6).
While the present method has been shown to be effective
for the synthesis of chiral bicyclic amidines from vinylcyclo-
propanes that bear gem dimethyl groups, it was of interest to
study the reactivity of phenyl-substituted vinylcyclopropane
19 (Scheme 3). Accordingly, compound 19 was synthesized
PhCN
[a] Reaction conditions: 17 (1 mmol), chloramine-T (1.1 mmol), PTAB
(0.1 mmol), solvent (5 mL), 5-8 h, RT. [b] Yield is of the isolated product.
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Communications
pathway to form 4a (path a). Compound 4a was thus
obtained without any compromise to the enantiomeric purity.
The intermediate Id can follow an alternate pathway
(path b; Scheme 4), which involves the attack of the alkene at
the nitrogen atom of N-chlorosulfonamide Id with the
expulsion of chloride, thus leading to If. Decomplexation of
If leads to the formation of product 4a.[15]
À
Chiral amidines with free N H have a wide scope of
applications as organocatalysts and chiral bases,[6] and this
feature encouraged us to attempt the removal of the tosyl
group. Since the removal of a tosyl group often requires harsh
reaction conditions, various attempts were unsuccessful (HBr/
phenol, SmI2/Et3N). Finally, the use of N-sodio-N-chloro
benzyloxycarbamate (chloramine-Cbz), instead of chlor-
amine-T, for the reaction with 3 (PTAB, PhCN), led to the
desired amidine 21 in 76% yield (Scheme 5). The removal the
of Cbz group in 21 was carried out successfully using
methanolic KOH (40%) under reflux to furnish chiral
amidine 22 in 63% yield.
Scheme 3. Rearrangement of the phenyl-substituted VCP 19 with
inversion of the phenyl substituent, thus supporting an intimate ion
pair pathway. THF=tetrahydrofuran.
center, thus providing support to the intermediacy of an
intimate ion pair (or delocalized charge), rather than a free-
carbocation pathway with the subsequent attack of acetoni-
trile in a concerted fashion. This observation is supported by
the pioneering work of Cram and Ratajczak[13a] on the
stereochemical course of solvolysis in strained ring systems,[13]
and that of others reported recently.[13c,d]
Based on the extensive work of Komastu and co-work-
ers[7] and Sharpless and co-workers,[9b] on the chloramine-T/
halogen-mediated aziridination of olefins, a plausible mech-
anism has been proposed for the formation of 4a from 3
(Scheme 4). It is reasonable to visualize the in situ generation
of BrX during the reaction of chloramine-T with PTAB, thus
catalyzing the reaction further. BrX thus formed can add to
the alkene double bond of 3 to form a p-complex intermedi-
Scheme 5. Chloramine-Cbz-mediated rearrangement and deprotection
to give free amidine 22. Cbz=benzyloxycarbonyl.
In conclusion, we have demonstrated an interesting
bromine-catalyzed tandem ring opening/cyclization of vinyl-
cyclopropane derivatives through a Ritter-type rearrange-
ment to give enantiomerically pure [4.4.0] and [4.3.0] bicyclic
amidine derivatives in good yield. The use of these easily
accessible chiral amidines as organocatalysts and chiral bases
is under investigation.
À
ate Ia, and subsequent polarization of the cyclopropane C C
bond gives the intimate ion pair Ib. This intermediate Ib gets
trapped in
a
concerted fashion by the nitrile, which
À
approaches from the direction opposite to the polarized C
C bond of the cyclopropane,[13] thus following a Ritter-type
reaction pathway to provide the intermediate Ic. A subse-
quent reaction with chloramine-T generates the intermediate
Id, which after the abstraction of chlorine facilitates an
intramolecular cyclization through an allylic-substitution
Experimental Section
General procedure for the synthesis of cyclic N-sulfonylamidines:
Chloramine-T (1.1 equiv) and phenyltrimethylammonium tribromide
(PTAB; 10 mol%) were added to the stirred solution of the olefin
(1 equiv) in the respective nitrile (ca. 2m concentration). The mixture
was stirred at room temperature (258C) until the reaction was
Scheme 4. The X-ray crystal structure of 4a and the proposed catalytic cycle for its formation.[14]
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complete (5–18 h; monitored by TLC). Then the solvent was removed
under reduced pressure. The solid residue was directly purified by
flash column chromatography on silica gel (eluent: petroleum ether/
ethyl acetate 7:3).
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Received: January 16, 2011
Revised: March 25, 2011
Published online: May 10, 2011
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Keywords: cyclization · organocatalysis · Ritter-type reaction ·
synthetic methods · vinylcyclopropane
.
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[14] CCDC 748917 (4a) contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via www.
ccdc.cam.ac.uk/data_request/cif.
[15] The authors thank one of the reviewers for suggesting the
alternate pathway shown as path b in Scheme 4.
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