Lewis acid promoted intramolecular (3 + 2) 'cycloadditions' of methyleneaziridines with alkene and alkyne acceptors

Article abstract of DOI:10.1039/c1ob06578e

2-Methyleneaziridines can be tethered to a variety of alkene or alkyne acceptors through the saturated carbon of the heterocyclic ring by application of a simple lithiation/alkylation sequence (8 examples, 31-59%). Treatment of the resultant alkene bearin

Full text of DOI:10.1039/c1ob06578e

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PAPER
Lewis acid promoted intramolecular (3 + 2) ‘cycloadditions’ of
methyleneaziridines with alkene and alkyne acceptors†
Karen Griffin, Cyril Montagne, Cam Thuy Hoang, Guy J. Clarkson and Michael Shipman*
Received 14th September 2011, Accepted 26th October 2011
DOI: 10.1039/c1ob06578e
2-Methyleneaziridines can be tethered to a variety of alkene or alkyne acceptors through the saturated
carbon of the heterocyclic ring by application of a simple lithiation/alkylation sequence (8 examples,
31–59%). Treatment of the resultant alkene bearing substrates with BF3·OEt2 leads to
cis-octahydrocyclopenta[c]pyrroles in which up to four contiguous stereocentres are created in a
diastereocontrolled manner after reductive work-up. Using an alkyne based substrate, a
2,4,5,6-tetrahydrocyclopenta[c]pyrrole is produced by rapid tautomerisation of the initially formed
bisenamine. Evidence that these (3 + 2) ‘cycloadditions’ proceed in a stepwise manner via a
2-aminoallyl cation is presented.
could be easily transformed into complex nitrogen heterocycles
Introduction
with the creation of up to three contiguous stereocentres in
just two synthetic operations. At the outset, it was felt that the
introduction of an exocyclic double bond on the three membered
ring could have a number of advantages. Firstly, it was expected
that the cycloaddition substrates would be more reactive as a
result of the additional 12–13 kcal mol-1 of ring strain energy.9
Secondly, it is known that 2-methyleneaziridines undergo facile
lithiation/substitution at C–3 with carbon-based electrophiles,10
which was expected to make the synthesis of the requisite
cycloaddition precursors straightforward. Finally, the exocyclic
double bond of the methyleneaziridine increases the amount of
functionality incorporated in the resultant cycloadduct.
Based upon earlier work on the (4 + 3) cycloadditions of
methyleneaziridines with 1,3-dienes,11 treatment of 2 with Lewis
acids such as BF3·OEt2 was expected to generate highly strained
and reactive aziridinium ion 3, which might undergo facile
ring opening by the appended nucleophilic p-bond producing
carbenium ion 4. Subsequent ring closure to yield enamine 5
as the initially formed cycloadduct was anticipated.§ If good
levels of stereocontrol could be achieved in this process, then this
highly asynchronous ‘cycloaddition’ process might serve as a very
direct and attractive route to octahydrocyclopenta[c]pyrroles and
related scaffolds. Here, we report the first examples of this new
cycloaddition, and highlight the scope of this approach to a variety
of nitrogen heterocycles.
Five membered nitrogen heterocycles are found in many natural
products and pharmaceuticals, and there is much interest in the
development of efficient methods for their synthesis.1 Aziridines
often serve as excellent starting materials because of the high
reactivity associated with their ring strain.2 Indeed, aziridines
have been extensively used for the synthesis of five membered
nitrogen heterocycles through application of (3 + 2) cycloaddition
processes.‡3,4 Classically, they have been used as precursors to
azomethine ylides through conrotatory C–C bond cleavage,5 and
also reactions involving zwitterion formation through C–N bond
cleavage have been reported.6 Intramolecular variants of these
reactions offer opportunities to assemble more complex heterocy-
cles. Whilst intramolecular cycloadditions involving azomethine
ylids generated from aziridines have been used extensively in
the synthesis of alkaloids,7 intramolecular (3 + 2) cycloadditions
involving aziridine C–N bond cleavage are much less common.8
In this article, the first examples of intramolecular (3 + 2)
‘cycloadditions’ of 2-methyleneaziridines with alkene and alkyne
acceptors are described through controlled C–N cleavage. The
basic idea behind this investigation is illustrated for generalised
alkene containing substrate 2 in Scheme 1. Using this approach, it
was imagined that readily available methyleneaziridines such as 1
Department of Chemistry, University of Warwick, Gibbet Hill Road,
Coventry, UK, CV4 7AL. E-mail: m.shipman@warwick.ac.uk; Fax: +44
2476 524112; Tel: +44 2476 523186
† Electronic supplementary information (ESI) available: 1H and 13C NMR
spectra for 6–12, 19–24, 26, 27 and 31. CCDC reference number 842811.
For ESI and crystallographic data in CIF or other electronic format see
DOI: 10.1039/c1ob06578e
‡ According to the IUPAC system for the classification of cycloaddition
reactions, square and round brackets denote the number of electrons and
atoms, respectively, involved in the transformation. P. Muller, Pure Appl.
Chem., 1994, 66, 1077.
§ It is conceivable that ring closure might also proceed through the b-
carbon atom of the complexed enamine 4, producing the corresponding
cyclopentanone imine. No products of this type were observed during this
investigation.
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Scheme 1 Generalised depiction of intramolecular Lewis acid promoted (3 + 2) cycloaddition of 2-methyleneaziridines.
Table 1 Preparation of methyleneaziridines 6–9 by lithiation/alkylation
patterns, it was possible to produce related substrates (Z)-6, 7, (E)-
8 and (E)-9 in an identical manner (Table 1, entries 2–5).
Lithiation and alkylation of (S)-N-(1-phenylethyl)-2-
isopropylidineaziridine (1b) with (E)-13 produced the alkylated
aziridine as a 91 : 9 mixture of diastereomers (Scheme 2). The
major isomer 10 was isolated in 56% yield and tentatively assigned
as having the (S,R)-stereochemistry by analogy with related
alkylations.10
Entry
R3
R4
Iodide
Product
Yielda (%)
1
2
3
4
5
H
Ph
H
Ph
(E)-13
(Z)-13
14
(E)-15
(E)-16
(E)-6b
(Z)-6
7
(E)-8
(E)-9
54
57
41
57
59
Ph
Ph
H
4-C6H4OMe
4-C6H4CF3
H
a Isolated yield after column chromatography. b See ref. 10.
Scheme 2 Stereocontrolled synthesis of methyleneaziridine 10.
Results and Discussion
Design and synthesis of cycloaddition precursors
Finally, to introduce alkyne acceptors, 1-(5-iodopent-1-
ynyl)benzene (17) was used as the electrophile. Thus, deprotona-
tion of 1a, or (Z)-N-benzyl-2-ethylideneaziridine (1c), and further
treatment with 17 gave 11 (54%) and (Z)-12 (31%) respectively
(Scheme 3).
Methyleneaziridines possessing at least one substituent on the
exocyclic double bond were used (i.e. R1 and/or R2 π H)
throughout this study. This was because: (i) substitution on the
exocyclic double bond was expected to make enamine 5 less
reactive and hence easier to isolate/manipulate; (ii) substituents
on the exocyclic double bond might encourage ring opening of
aziridinium ion 3 if the chemistry proceeds via a 2-aminoallyl
cation (vide infra); (iii) alkylideneaziridines are relatively stable9a
making the purification of the requisite cycloaddition precursors
straightforward.
A total of eight (3 + 2) cycloaddition precursors were made
for this study. In order to encourage the proposed cycloaddition,
substrates 6–12 capable of stabilising the proposed carbenium
ion 4 through use of an aryl group were selected (Scheme 1).
Both the (Z)- and (E)-diastereoisomer of styrene 6 were made
to ascertain if the alkene geometry would impact the propensity
and/or stereochemical course of the cycloaddition. To gain insight
into the reaction mechanism, 10 possessing a stereocentre of
defined absolute stereochemistry on the aziridine ring was made.
Finally, to establish if the chemistry could be extended to other
p-systems, two alkyne bearing substrates 11 and 12 were used.
All the substrates used in this study were made in a very direct
manner by reaction of known methyleneaziridines 1a–c12 with
iodides 13–17 containing the requisite alkene or alkyne acceptors.
The synthesis of all these iodides has been described previously.
Lithiation of N-benzyl-2-isopropylidineaziridine (1a) with sec-
butyllithium and tetramethylethylenediamine (TMEDA) followed
by addition of 1-[(E)-5-iodopent-1-enyl)]benzene (13) provided
aziridine (E)-6 in 54% yield after column chromatography (Table 1,
entry 1).10 Using electrophiles bearing different alkene substitution
Scheme 3 Preparation of alkyne based substrates 11 and 12.
Lewis acid promoted (3 + 2) cycloadditions involving alkenes
As stoichiometric quantities of BF3·OEt2 are known to effect
intramolecular (4 + 3) cycloadditions of methyleneaziridines with
1,3-dienes,11b this Lewis acid was selected for the initial study, using
(E)-6 bearing a disubstituted alkene. Upon addition of excess
BF3·OEt2 (150 mol%) in CH2Cl2 at -30 ◦C, followed by slow
warming to room temperature over 15 h, (E)-6 was converted
to the iminium ion 18 as essentially a single diastereomer (Scheme
4). Further treatment of 18 with NaBH4/AcOH in THF provided
separated diastereomers 19 and 20 in a combined yield of 48%.
The stereochemistry of 18 is inferred from that of 19 and 20, whose
assignments were deduced by NOE experiments. These revealed
the same stereochemical relationship at C–3, C–3a and C–6a in
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Scheme 5 Synthesis of cis-octahydrocyclopenta[c]pyrroles 21–24.
Scheme 4 Lewis acid promoted (3 + 2) cycloaddition/reduction sequence
to cis-octahydrocyclopenta[c]pyrroles 19 and 20.
each compound, as well as the relative configurations at C–1.¶
These assignments were reinforced by an X-ray crystal structure
of a related cycloadduct (vide infra). Gratifyingly, this (3 + 2) cy-
cloaddition proceeds with good levels of diastereocontrol although
the facial selectivity in the final reduction is modest (crude dr:
41 : 59). Evidently, hydride delivery from the Re face of iminium
ion 18 is favoured leading to 19, as approach from the concave
Si face is sterically hindered. Preliminary attempts to improve
the diastereoselectivity of this step using other hydride sources
Scheme 6 cis-Octahydrocyclopenta[c]pyrrole 26 from aziridine 7.
25 is hindered by the additional endo phenyl ring (cf. Scheme
4).** Efforts to improve the yield of this cycloaddition/reduction
sequence by screening alternative Lewis acids (Sc(OTf)3, SnCl4,
AgSbF6), Brønsted acids [p-TsOH, (PhO)2P(O)OH)] and solvents
(CH2Cl2, DCE, PhH, CH3CN, Et2O) was largely unsuccessful.
However, a modest improvement to 27% was realised using
stoichiometric amounts of Sc(OTf)3 (150 mol%) in place of
BF3·OEt2. In all the cyclisations studied, the integral for the
aromatic region in the 1H NMR spectrum immediately after work-
up was higher than expected. One can speculate that this might
indicate competitive debenzylation under the reaction conditions
although further proof in support of this hypothesis has yet to be
obtained.
R
(Et3SiH/TFA, NaBH3CN/AcOH and L-Selectrideꢀ) led to lower
yields with little improvement in selectivity. The cyclisation of the
corresponding (Z)-isomer of 6 is discussed later.
To determine the impact of electronic effects on the efficiency
of this (3 + 2) cycloaddition/reduction sequence, the reactivity
of aziridines (E)-8 and (E)-9 bearing electron donating –OMe
and withdrawing –CF3 groups respectively on the phenyl ring
were explored (Scheme 5). Both substrates behaved very similarly
to (E)-6, yielding cis-octahydrocyclopenta[c]pyrroles 21 and 23
possessing the (1S*,3R*,3aR*,6aS*)-configuration as the major
product. In both cases, the products were produced as an epimeric
mixture at C–1 in a combined 32% yield (crude dr: 21/22 =
60 : 40; 23/24 = 58 : 42). These findings suggest that the electronic
nature of the aromatic substituent exerts little influence on the
ease of the cycloaddition. In the case of (E)-8, crystallisation
of the major diastereomer 21 provided a single crystal suitable
for X-ray diffraction, allowing its gross structure and relative
stereochemistry to be confirmed.ꢀ
To determine if difficulties with hydride delivery to iminium
ions 18 and 25 might be responsible in part for the low yields,
and to extend the usefulness of this chemistry, capture of the
intermediate iminium ion 18 with cyanide was investigated. Using
HCN, generated in situ from trimethylsilyl cyanide and glacial
AcOH, a-aminonitrile 27 was produced as a single stereoisomer
from (E)-6 in 29% yield (Scheme 7). Based upon this and other
evidence, we conclude that it is the (3 + 2) reaction and not the
iminium ion capture that is the low-yielding step. Unexpectedly, in
27 strong NOE enhancements were seen between all the hydrogens
Treatment of trisubstituted alkene 7 with BF3·OEt2 under
the same conditions followed by reduction with NaBH4/AcOH
provided pyrrolidine 26 in 23% yield (Scheme 6). Only one
diastereomer was observed in this reaction, presumably because
hydride delivery to the concave Si face of the iminium ion
i
of the Pr group and H–6a revealing a syn-relationship between
the isopropyl group and the hydrogens of the ring junction. This
implies that cyanide delivery occurs to the more hindered Si face
of the iminium ion 18. To account for this observation, we suggest
that because cyanide is a good leaving group, the formation of 27
is under thermodynamic control, and at equilibrium the smaller
cyano group (A-values: C N = 0.17; iPr = 2.15)13 prefers to reside
in the sterically congested endo position. In contrast, the formation
¶ In major diastereomer 19, reciprocal NOEs were observed between H–1,
H–3a, H–6a and the ortho-hydrogens of the Ph group located at C–3. These
data led us to conclude that H–1, H–3a, H–6a and the C–3 phenyl group
reside on the same face of 19. For minor diastereomer 20, irradiation
of H–6a led to NOE enhancements of H–3a and the isopropyl methyl
groups. Moreover, reciprocal NOEs were seen between H–1 and H–3 in
this compound but not 19. These findings led us to deduce that 20 is
epimeric at C–1. All other NOEs were consistent with these assignments.
ꢀ Crystal Data for 21. CCDC 842811. C24H31NO, M = 349.50, monoclini◦c,
˚
˚
˚
a = 11.4815(14) A, b = 17.5731(15) A, c = 10.4720(10) A, b = 105.993(11) ,
** Reciprocal NOEs in 26 between the ring junction hydrogens (H–3a and
H–6a) and between H–3 and H–3a indicated that the three hydrogens of
the pyrrolidine ring reside on the same face. Note: ring numbering priorities
changed relative to 19/20 due to an additional Ph group.
3
˚
U = 2031.1(4) A , T = 100(2), space group P21/c (no. 14), Z = 4, m(CuKa)
= 0.523, 10496 reflections measured, 3819 unique (Rint = 0.0901) which
were used in all calculations. The final wR(F2) was 0.2554 (all data).
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Scheme 7 (3 + 2) Cycloaddition/cyanide capture sequence.
of 19/20 is under kinetic control with preferential attack of hydride
from the less hindered Re face.
Scheme 9 Evidence for the involvement of a 2-aminoallyl cation.
Lewis acid promoted (3 + 2) cycloadditions involving alkynes
(3 + 2) proceeds in a concerted manner, or involves SN2 attack
of the appended alkene onto aziridinium ion 3 as depicted
in Scheme 1, the resultant iminium ion would be expected to
be formed as a single stereoisomer. Alternatively, if cyclisation
proceeds through a planar 2-aminoallyl cation, such as 32, then
partial or complete loss of the stereochemical information at
C–3 of the starting aziridine would be expected (Scheme 9).
Such intermediates have been suggested in the related (4 + 3)
cycloadditions of methyleneaziridines with 1,3-dienes.11 Treatment
of 10 with BF3·OEt2 provided two diastereomeric iminium ions in
a 64 : 36 mixture, assigned as 33 and 34. This finding supports
the hypothesis that the major reaction pathway involves a planar
2-aminoallyl cation.14
Based upon the work with alkene acceptors, it seemed likely that
reactions involving alkynes might generate bisenamines as the
initial (3 + 2) products. Such molecules might be expected to be
rather unstable, and undergo isomerisation to aromatic pyrroles
under the reaction conditions. To test this concept, aziridine 11
was treated with BF3·OEt2 without recourse to NaBH4 work-up.
Analysis of the mixture by NMR suggested that dienamine 28 had
been formed although the exocyclic tetrasubstituted double bond
proved reluctant to isomerise to pyrrole 29. Attempts to reduce
28 (NaBH4/AcOH or H2, Pd/C), or catalyse its isomerisation
to pyrrole 29 (AcOH, reflux) were undertaken without success.
Reasoning that a less substituted bisenamine such as 30 might
more readily tautomerise to the pyrrole, the chemistry was
repeated with aziridine (Z)-12 bearing a single methyl group on
the exocyclic double bond of the methyleneaziridine. Gratifyingly,
treatment of (Z)-12 with BF3·OEt2 afforded pyrrole 31 in 38% yield
after chromatography (Scheme 8). In this case, isomerisation of
exocyclic olefin occurs spontaneously with no trace of bisenamine
30 seen in the mixture.
Conclusions
The first examples of Lewis acid promoted (3 + 2) cycload-
ditions of methyleneaziridines are reported which provide new
insights into the reactivity of this highly strained ring system.
The reaction is used in an intramolecular manifold to produce
cis-octahydrocyclopenta[c]pyrroles and 2,4,5,6-tetrahydrocyclo-
penta[c]pyrroles through reaction with tethered alkenes and
alkynes respectively. Evidence is obtained that suggests this (3
+ 2) most likely proceeds in an asynchronous manner through the
involvement of a planar 2-aminoallyl cation. In combination with
a reductive work-up, this new ‘cycloaddition’ is used to provide
a very direct route to highly functionalised, stereodefined cis-
octahydrocyclopenta[c]pyrroles. The intermediate iminium ions
can also be captured with cyanide to generate heterocycles
containing fully substituted stereocentres. Using alkyne acceptors,
tautomerisation of the initially formed bisenamines to 2,4,5,6-
tetrahydrocyclopenta[c]pyrroles is possible. The modest yields
from the (3 + 2) cycloaddition (yields up to 48%) are offset, in
part, by the fact that the substrates can be assembled in a very
direct manner, and that the (3 + 2) creates considerable molecular
complexity. Ongoing work is focused on identifying improved
reaction conditions and applying this new methodology in target
synthesis.
Scheme 8 Synthesis of 2,4,5,6-tetrahydrocyclopenta[c]pyrroles.
Mechanism of the (3 + 2) ‘cycloaddition’
At first glance, the observation that 18 is formed from (E)-6 implies
a stereospecific (3 + 2) process in which the geometry of the alkene
is relayed into the stereochemistry at C–3 of the cycloadduct. If this
is the case, (Z)-6 should produce the iminium ion with the opposite
stereochemistry at this centre. However, treatment of (Z)-6 under
identical conditions to those used for (E)-6 proceeded very poorly,
with the only detectable iminium ion 18 being formed in trace
amounts. As such, no significant conclusions can be drawn from
these experiments other than that cyclisation to 18 is more facile
than that to its C–3 epimer. The fact that (E)-8 and (E)-9 cyclise
with equal propensity (based upon product yields) suggests that
the reaction is not especially sensitive to electronic effects.
Experimental
General
Anhydrous solvents were purchased in Sure/SealTM bottles from
Sigma-Aldrich. 1-Benzyl-2-(1-methylethylidene)aziridine (1a), 1-
[(S)-1-phenylethyl]-2-(propan-2-ylidene)aziridine (1b), and (Z)-
1-benzyl-2-ethylideneaziridine (1c) were prepared according to
As a further mechanistic probe, cyclisation of homochiral
isopropylideneaziridine 10 was examined (Scheme 9). If the
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published procedures.12 Similarly, all the iodide electrophiles used
in this study are known: 1-[(E)-5-iodopent-1-enyl]benzene [(E)-
13],10 1-[(Z)-5-iodopent-1-enyl]-benzene [(Z)-13],15 5-iodo-1,1-
diphenylpent-1-ene (14),16 1-[(E)-5-iodopent-1-enyl]-4-methoxy-
benzene [(E)-15],17 1-[(E)-5-iodopent-1-enyl]-4-trifluorotoluene
[(E)-16],17 and 1-(5-iodopent-1-ynyl)benzene (17).18 All other
solvents and reagents were used as received or purified by standard
protocols. Petroleum ether refers to the fraction of petroleum ether
having a boiling point between 40–60 ◦C. All experiments were
performed under an inert atmosphere (N2) and moisture sensitive
reactions were conducted in oven- or flame-dried glassware. Flash
chromatography was carried out using Matrex silica 60. Thin
layer chromatography was performed on pre-coated aluminium-
backed plates and developed using UV fluorescence (254 nm)
and/or potassium permanganate, followed by heating. Infrared
spectra were recorded neat or as thin films on NaCl plates using
a PerkinElmer Spectrum One FT-IR spectrometer with internal
calibration. 1H and 13C NMR spectra were recorded at 300 MHz
and 75 MHz respectively on a Bruker DPX-300; at 400 MHz and
100 MHz respectively on a Bruker DPX-400; and at 600 MHz
and 150 MHz respectively on a Bruker AV-600 spectrometer. High
resolution mass spectra were obtained on a Bruker MicroTOF
instrument. Melting points were recorded on a Gallenkamp
MPD350 apparatus.
1-Benzyl-2-((Z)-5-phenylpent-4-enyl)-3-(propan-2-
ylidene)aziridine [(Z)-6]
(Z)-6 was prepared from 1a (148 mg, 0.85 mmol), TMEDA
(0.16 mL, 1.03 mmol), sec-BuLi (1.16 mL, 1.63 mmol) in THF
(8 mL) and a solution of 1-((Z)-5-iodopent-1-enyl)benzene [(Z)-
13] (280 mg, 1.03 mmol) in THF (1 mL) in accordance with the
general procedure. Work-up followed by purification on silica
(0.5% Et3N and 2% EtOAc in petroleum ether) afforded (Z)-6
(154 mg, 0.49 mmol, 57%) as a pale yellow oil, as an inseparable
91 : 9 (Z : E) mixture of geometrical isomers. nmax (neat) 2923, 1798,
1601, 1494, 1447, 1128, 731, 696 cm-1; dH (400 MHz, CDCl3) 7.35–
7.18 (10H, m), 6.37 (1H, d, J = 11.7 Hz), 5.55 (1H, dt, J = 11.7, 6.7
Hz), 4.13 (1H, d, J = 13.3 Hz), 3.17 (1H, d, J = 13.3 Hz), 2.25 (2H,
q, J = 7.4 Hz, 1.97 (1H, t, J = 5.8 Hz), 1.74 (3H, s), 1.72 (3H, s),
1.63–1.47 (2H, m), 1.44–1.36 (2H, m); dC (100 MHz, CDCl3) 139.1
(C), 137.7 (C), 132.7 (CH), 129.9 (C), 129.0 (CH), 128.8 (2 ¥ CH),
128.5 (2 ¥ CH), 128.3 (2 ¥ CH), 128.1 (2 ¥ CH), 127.1 (CH), 126.5
(CH), 104.0 (C), 62.0 (CH2), 44.0 (CH), 31.9 (CH2), 28.3 (CH2),
27.8 (CH2), 20.6 (CH3), 19.1 (CH3); HRMS (ESI) calculated for
C23H28N [M + H]: 318.2216, found 318.2218.
1-Benzyl-2-(5,5-diphenylpent-4-enyl)-3-(propan-2-ylidene)aziridine
(7)
7 was prepared from 1a (201 mg, 1.16 mmol), TMEDA (0.21 mL,
1.39 mmol), sec-BuLi (1.58 mL, 2.21 mmol) in THF (10 mL) and
a solution of 5-iodo-1,1-diphenylpent-1-ene (14) (486 mg, 1.39
mmol) in THF (1 mL) in accordance with the general procedure.
Work-up followed by purification on silica (1% Et3N in petroleum
ether) afforded 7 (188 mg, 0.48 mmol, 41%) as a yellow oil. nmax
(neat) 2919, 1796, 1596, 1493, 1442, 1129, 1028, 760, 698 cm-1; dH
(400 MHz, CDCl3) 7.35–7.10 (15H, m), 5.97 (1H, t, J = 7.5 Hz),
4.10 (1H, d, J = 13.4 Hz), 3.15 (1H, d, J = 13.4 Hz), 2.04 (2H,
q, J = 7.4 Hz), 1.93 (1H, t, J = 5.8 Hz), 1.73 (3H, s), 1.71 (3H,
s), 1.58–1.35 (4H, m); dC (100 MHz, CDCl3) 142.8 (C), 141.7 (C),
140.2 (C), 139.1 (C), 130.0 (C), 129.9 (2 ¥ CH), 129.8 (CH), 128.5
(2 ¥ CH), 128.3 (2 ¥ CH), 128.2 (2 ¥ CH), 128.1 (2 ¥ CH), 127.2 (2
¥ CH), 127.1 (CH), 126.9 (CH), 126.8 (CH), 104.0 (C), 62.0 (CH2),
44.0 (CH), 31.9 (CH2), 29.4 (CH2), 27.8 (CH2), 20.6 (CH3), 19.1
(CH3); HRMS (ESI) calculated for C29H32N [M + H]: 394.2529,
found 394.2539.
General procedure for the synthesis of (3 + 2) cycloaddition
precursors 6–12
To a stirred solution of the methyleneaziridine (1.0 equiv.) in
THF at -78 ◦C, was added TMEDA (1.2 equiv.) and sec-
BuLi (1.4 M in hexane, 1.9 equiv.) dropwise. The reaction was
stirred at -78 ◦C for 6 h, then quenched with a solution of the
electrophile (1.2–2.0 equiv.) in THF and allowed to warm to room
temperature overnight. Water was added, the layers separated, and
the aqueous phase extracted with Et2O (3¥). The combined organic
extracts were washed with brine, dried over MgSO4, filtered and
concentrated in vacuo. Purification by column chromatography
afforded the title compounds.
1-Benzyl-2-((E)-5-phenylpent-4-enyl)-3-(propan-2-
ylidene)aziridine [(E)-6]
1-Benzyl-2-((E)-5-(4-methoxyphenyl)pent-4-enyl)-3-(propan-2-
ylidene)aziridine [(E)-8]
(E)-6 was prepared from 1a (198 mg, 1.14 mmol), TMEDA
(0.21 mL, 1.37 mmol), sec-BuLi (1.55 mL, 2.17 mmol) in THF
(10 mL) and a solution of 1-((E)-5-iodopent-1-enyl)benzene [(E)-
13] (373 mg, 1.37 mmol) in THF (1 mL) in accordance with the gen-
eral procedure. Work-up followed by purification on silica (0.5%
Et3N and 2% EtOAc in petroleum ether) afforded (E)-6 (197 mg,
0.62 mmol, 54%) as a yellow oil. dH (400 MHz, CDCl3) 7.37–7.24
(9H, m), 7.20–7.15 (1H, m), 6.28 (1H, d, J = 15.8 Hz), 6.11 (1H, dt,
J = 15.8, 6.8 Hz), 4.17 (1H, d, J = 13.3 Hz), 3.18 (1H, d, J = 13.3
Hz), 2.14–2.10 (2H, m), 2.02 (1H, t, J = 5.8 Hz), 1.77 (3H, s), 1.74
(3H, s), 1.66–1.38 (4H, m); dC (100 MHz, CDCl3) 139.1 (C), 137.9
(C), 130.7 (CH), 130.0 (C), 129.9 (CH), 128.5 (2 ¥ CH), 128.4 (2
¥ CH), 128.3 (2 ¥ CH), 127.1 (CH), 126.8 (CH), 125.9 (2 ¥ CH),
104.0 (C), 62.1 (CH2), 44.1 (CH), 32.7 (CH2), 31.9 (CH2), 27.2
(CH2), 20.7 (CH3), 19.1 (CH3). Spectral data were in accordance
with literature data.10
(E)-8 was prepared from 1a (149 mg, 0.86 mmol), TMEDA (0.16
mL, 1.03 mmol), sec-BuLi (1.17 mL, 1.64 mmol) in THF (8 mL)
and a solution of 1-((E)-5-iodopent-1-enyl)-4-methoxybenzene
[(E)-15] (312 mg, 1.03 mmol) in THF (1 mL) in accordance with
the general procedure. Work-up followed by purification on silica
(0.5% Et3N and 2% EtOAc in petroleum ether) afforded (E)-8 (170
mg, 0.49 mmol, 57%) as a pale yellow oil. nmax (neat) 2924, 1797,
1607, 1509, 1453, 1244, 1174, 1034, 964, 698 cm-1; dH (400 MHz,
CDCl3) 7.36–7.21 (7H, m), 6.82 (2H, d, J = 8.6 Hz), 6.23 (1H,
d, J = 15.8 Hz), 5.96 (1H, dt, J = 15.8, 6.9 Hz), 4.16 (1H, d, J =
13.3 Hz), 3.77 (3H, s), 3.18 (1H, d, J = 13.3), 2.10 (2H, q, J = 7.1
Hz), 2.02 (1H, t, J = 5.7 Hz), 1.76 (3H, s), 1.73 (3H, s), 1.65–1.35
(4H, m); dC (100 MHz, CDCl3) 158.7 (C), 139.2 (C), 130.7 (C),
130.0 (C), 129.3 (CH), 128.5 (2 ¥ CH) 128.5 (CH), 128.3 (2 ¥ CH),
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127.1 (CH), 127.0 (2 ¥ CH), 113.9 (2 ¥ CH), 104.0 (C), 62.1 (CH2),
55.3 (CH3), 44.1 (CH), 32.7 (CH2), 31.9 (CH2), 27.3 (CH2), 20.6
(CH3), 19.1 (CH3); HRMS (ESI) calculated for C24H30NO [M +
H]: 348.2322, found 348.2324.
4.18 (1H, d, J = 13.3 Hz), 3.19 (1H, d, J = 13.3 Hz), 2.31 (2H, t,
J = 7.0 Hz), 2.06 (1H, t, J = 5.7 Hz), 1.78 (3H, s), 1.74 (3H, s),
1.67–1.48 (4H, m); dC (100 MHz, CDCl3) 139.1 (C), 131.6 (2 ¥
CH), 129.7 (C), 128.5 (2 ¥ CH), 128.4 (2 ¥ CH), 128.2 (2 ¥ CH),
127.5 (CH), 127.2 (CH), 124.0 (C), 104.2 (C), 89.9 (C), 80.8 (C),
62.1 (CH2), 43.7 (CH), 31.4 (CH2), 26.5 (CH2), 20.7 (CH3), 19.1
(CH3), 19.1 (CH2); HRMS (ESI) calculated for C23H26N [M + H]:
316.2060, found 316.2061.
1-Benzyl-2-((E)-5-(4-trifluoromethylphenyl)pent-4-enyl)-3-
(propan-2-ylidene)aziridine [(E)-9]
(E)-9 was prepared from 1a (186 mg, 1.08 mmol), TMEDA (0.19
mL, 1.29 mmol), sec-BuLi (1.46 mL, 2.04 mmol) in THF (8 mL)
and a solution of 1-((E)-5-iodopent-1-enyl)-4-trifluorotoluene
[(E)-16] (439 mg, 1.29 mmol) in THF (1 mL) in accordance with
general procedure. Work-up followed by purification on silica
(0.5% Et3N and 2% EtOAc in petroleum ether) afforded (E)-9
(244 mg, 0.63 mmol, 59%) as a pale yellow oil. nmax (neat) 2924,
1652, 1615, 1495, 1453, 1323, 1162, 1118, 1066, 967, 699 cm-1;
dH (500 MHz, CDCl3) 7.45 (2H, d, J = 8.1 Hz), 7.36–7.17 (7H,
m), 6.22 (1H, d, J = 16.0 Hz), 6.13 (1H, dt, J = 16.0, 6.6 Hz),
4.11 (1H, d, J = 13.3 Hz), 3.09 (1H, d, J = 13.3 Hz), 2.06 (2H,
q, J = 7.1 Hz), 1.95 (1H, t, J = 6.0 Hz), 1.69 (3H, s), 1.67 (3H,
s), 1.60–1.29 (4H, m); dC (125 MHz, CDCl3) 141.3 (C), 139.1
(C), 133.5 (2 ¥ CH), 129.8 (2 ¥ C), 128.8 (CH), 128.5 (CH),
128.3 (CH), 127.1 (CH), 126.0 (CH), 125.5 (CH), 125.4 (3 ¥
CH), 122.2 (CF3, JC–F = 273.3 Hz), 104.1 (C), 62.1 (CH2), 43.9
(CH), 32.7 (CH2), 31.8 (CH2), 26.9 (CH2), 20.6 (CH3), 19.1 (CH3);
HRMS (ESI) calculated for C24H27F3N [M + H]: 386.2090, found
386.2087.
(Z)-1-Benzyl-2-ethylidene-3-(5-phenylpent-4-ynyl)aziridine
[(Z)-12]
(Z)-12 was prepared from 1c (212 mg, 1.33 mmol), TMEDA
(0.24 mL, 1.60 mmol), sec-BuLi (1.80 mL, 2.53 mmol) in THF
(11 mL) and a solution of 1-(5-iodopent-1-ynyl)benzene (17) (431
mg, 1.60 mmol) in THF (2 mL) in accordance with the general
method. Work-up followed by purification on silica (0.5% Et3N
and 0–1% EtOAc in petroleum ether) afforded (Z)-12 (125 mg,
0.41 mmol, 31%) as a yellow oil. nmax (film) 2936, 1780, 1598, 1490,
1454, 1303, 1130, 756, 692 cm-1; dH (400 MHz, CDCl3) 7.39–7.23
(10H, m), 5.12 (1H, q, J = 6.7 Hz), 4.20 (1H, d, J = 13.4 Hz), 3.29
(1H, d, J = 13.4 Hz), 2.32 (2H, t, J = 7.0 Hz), 2.03 (1H, t, J = 5.9
Hz), 1.78–1.47 (7H, m); dC (100 MHz, CDCl3) 138.7 (C), 135.3(C),
131.6 (2 ¥ CH), 128.5 (2 ¥ CH), 128.4 (2 ¥ CH), 128.2 (2 ¥ CH),
127.5 (CH), 127.3 (CH), 124.0 (C), 94.9 (CH), 89.9 (C), 80.9 (C),
61.8 (CH2), 42.9 (CH), 31.2 (CH2), 26.3 (CH2), 19.0 (CH2), 13.3
(CH3); HRMS (ESI) calculated for C22H24N [M + H]: 302.1903,
found 302.1906.
1-((S)-1-Phenylethyl)-2-((E)-5-phenylpent-4-enyl)-3-(propan-2-
ylidene)aziridine (10)
General procedure for boron trifluoride promoted intramolecular
(3 + 2) cycloaddition/hydride reduction
10 was prepared from 1b (202 mg, 1.08 mmol), TMEDA (0.20 mL,
1.29 mmol), sec-BuLi (1.46 mL, 2.05 mmol) in THF (10 mL) and
a solution of 1-((E)-5-iodopent-1-enyl)benzene [(E)-13] (587 mg,
2.16 mmol) in THF (1 mL) in accordance with the general method.
Work-up followed by purification on silica (0.25% Et3N and 1%
EtOAc in petroleum ether) afforded 10 (202 mg, 0.61 mmol, 56%)
as a yellow oil. nmax (neat) 2926, 1718, 1448, 1132, 964, 745, 697
cm-1; dH (400 MHz, CDCl3) 7.40–7.16 (10H, m), 6.40 (1H, d,
J = 15.8 Hz), 6.24 (1H, dt, J = 15.8, 6.8 Hz), 2.91 (1H, q, J =
6.6 Hz), 2.32–2.26 (2H, m), 2.04–1.93 (1H, m), 1.78–1.51 (4H,
m), 1.66 (3H, s), 1.46 (3H, d, J = 6.6 Hz), 1.03 (3H, s); dC (100
MHz, CDCl3) 145.2 (C), 137.8 (C), 130.7 (CH), 130.1 (CH), 129.6
(CH), 128.5 (2 ¥ CH), 128.3 (2 ¥ CH), 127.6 (2 ¥ CH), 127.1 (CH),
126.9 (CH), 126.0 (2 ¥ CH), 104.1 (C), 68.3 (CH), 43.1 (CH), 33.1
(CH2), 32.3 (CH2), 27.7 (CH2), 23.6 (CH3), 21.1 (CH3), 19.1 (CH3);
HRMS (ESI) calculated for C24H30N [M + H]: 332.2373, found
332.2376.
To a stirred solution of aziridine (1.0 equiv.) in CH2Cl2 at -30 ◦C
was added BF3·OEt2 (2.2 equiv.). The mixture was allowed to
warm slowly to room temperature over 15 h, then quenched by
the addition of saturated aq. NaHCO3 solution. The mixture was
extracted with EtOAc (3¥), and the combined organic extracts
dried over MgSO4, filtered and concentrated in vacuo. The crude
iminium ion was taken up in THF and added to a stirred solution
of NaBH4 (3 equiv.) in glacial AcOH. The mixture was stirred at
room temperature for 12 h, then basified by the addition of 2 M
aq. NaOH solution. The mixture was extracted with EtOAc (3¥),
dried over MgSO4, filtered and concentrated in vacuo to give the
crude product. Purification by column chromatography afforded
the title compounds.
(1S*,3R*,3aR*,6aS*)-2-Benzyl-octahydro-1-isopropyl-
3-phenylcyclopenta[c]pyrrole (19) and (1R*,3R*,
3aR*,6aS*)-2-benzyl-octahydro-1-isopropyl-3-
phenylcyclopenta[c]pyrrole (20)
1-Benzyl-2-(5-phenylpent-4-ynyl)-3-(propan-2-ylidene)aziridine
(11)
To a stirred solution of (E)-6 (178 mg, 0.56 mmol) in CH2Cl2
(11 mL) at -30 ◦C was added BF3·OEt2 (0.16 mL, 1.23 mmol) in
accordance with the general method, then the crude mixture was
dissolved in THF (4 mL) and added to a stirred solution of NaBH4
(65 mg, 1.68 mmol) in glacial AcOH (10 mL). Work-up followed by
purification on silica (0.5–1.5% Et2O in petroleum ether) afforded
successively 20 (30.7 mg, 0.10 mmol, 17%) as a colourless oil and
19 (55.4 mg, 0.17 mmol, 31%) as a yellow oil. Compound 19: nmax
(neat) 2952, 1690, 1452, 697 cm-1; dH (400 MHz, C6H6) 7.33 (2H,
11 was prepared from 1a (202 mg, 1.17 mmol), TMEDA (0.21
mL, 1.40 mmol), sec-BuLi (1.57 mL, 2.19 mmol) in THF (9 mL)
and a solution of 1-(5-iodopent-1-ynyl)benzene (17) (374 mg, 1.39
mmol) in THF (1 mL) in accordance with the general method.
Work-up followed by purification on silica (0.5% Et3N and 5%
EtOAc in petroleum ether) afforded 11 (198 mg, 0.63 mmol, 54%)
as a pale yellow oil. nmax (neat) 3028, 2923, 2361, 1796, 1598, 1490,
1452, 755, 693 cm-1; dH (400 MHz, CDCl3) 7.38–7.25 (10H, m),
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d, J = 7.5 Hz), 7.20 (2H, t, J = 7.5 Hz), 7.15–7.04 (4H, m), 6.98
(2H, d, J = 7.5 Hz), 3.92 (1H, d, J = 3.9 Hz), 3.76 (1H, d, J = 14.5
Hz), 3.19–3.13 (2H, m), 2.57–2.51 (1H, m), 2.47–2.39 (1H, m),
1.90–1.77 (3H, m), 1.68–1.60 (1H, m), 1.52–1.43 (1H, m), 1.40–
1.24 (2H, m), 1.06 (3H, d, J = 6.8 Hz), 0.99 (3H, d, J = 7.0 Hz); dC
(100 MHz, C6D6) 141.9 (C), 139.8 (C), 128.0 (2 ¥ CH), 127.0 (2 ¥
CH), 126.9 (2 ¥ CH), 126.6 (2 ¥ CH), 125.4 (CH), 125.3 (CH), 70.8
(CH), 66.7 (CH), 49.6 (CH2), 48.8 (CH), 46.2 (CH), 33.3 (CH2),
28.4 (CH2), 27.1 (CH2), 27.1 (CH), 19.2 (CH3), 17.4 (CH3); HRMS
(ESI) calculated for C23H30N [M + H]: 320.2373, found 320.2370.
Compound 20: nmax (neat) 2950, 1718, 1453, 1246, 1166, 699 cm-1;
dH (600 MHz, DMSO-d6) 7.42 (2H, d, J = 7.1, Hz), 7.35 (2H, t,
J = 7.6 Hz), 7.25–7.22 (3H, m), 7.18–7.15 (1H, m), 7.03 (2H, d, J
= 7.1 Hz), 3.62 (1H, d, J = 14.5 Hz), 3.29 (1H, d, J = 14.5 Hz),
3.04 (1H, d, J = 8.7 Hz), 2.31–2.26 (1H, m), 2.23 (1H, dd, J = 3.5,
6.5 Hz), 2.15 (1H, q, J = 8.4 Hz), 1.96–1.89 (1H, m), 1.58–1.25
(6H, m), 0.88 (3H, d, J = 6.7 Hz), 0.85 (3H, d, J = 7.0 Hz); dC (150
MHz, DMSO-d6) 144.3 (C), 137.5 (C), 129.5 (2 ¥ CH), 128.9 (2 ¥
CH), 128.2 (2 ¥ CH), 128.1 (2 ¥ CH), 127.5 (CH), 127.1 (CH), 74.8
(CH), 74.4 (CH), 54.0 (CH2), 52.8 (CH), 41.3 (CH), 33.9 (CH2),
29.5 (CH2), 27.8 (CH), 25.0 (CH2), 20.6 (CH3), 15.6 (CH3); MS
(ES+) m/z 320 [M + H+]; HRMS (ES+) calcd. for C23H30N [M +
H+]: 320.2373; found 320.2373.
[M + H+]; HRMS (ES+) calcd. for C24H32NO [M + H+]: 350.2478,
found 350.2479.
(1S*,3R*,3aR*,6aS*)-2-Benzyl-octahydro-1-isopropyl-3-(4-
trifluoromethylphenyl)cyclopenta[c]pyrrole (23) and (1R*,3R*,
3aR*,6aS*)-2-benzyl-octahydro-1-isopropyl-3-(4-
trifluoromethylphenyl)cyclopenta[c]pyrrole (24)
To a stirred solution of (E)-9 (202 mg, 0.53 mmol) in CH2Cl2
(10 mL) at -30 ◦C was added BF3·OEt2 (0.14 mL, 1.15 mmol) in
accordance with the general method, then the crude mixture was
dissolved in THF (5 mL) and added to a stirred solution of NaBH4
(60 mg, 1.57 mmol) in glacial AcOH (10 mL). Work-up followed
by purification on silica (2% Et2O in petroleum ether) afforded a
58 : 42 diasteromeric mixture of 23 and 24 (74 mg, 0.19 mmol, 32%)
as a colourless oil. nmax (film) 2954, 2869, 1692, 1618, 1323, 1162,
1120, 1066, 1017, 827, 804, 740 cm-1; HRMS (ESI) calculated for
C24H29F3N [M + H]: 388.2247, found 388.2247. Compound 23: dH
(400 MHz, CDCl3) 7.39 (2H, d, J = 8.0 Hz), 7.22–7.08 (5H, m),
7.01 (2H, d, J = 8.0 Hz), 3.80 (1H, d, J = 14.2 Hz), 3.78 (1H, d,
J = 2.7 Hz), 3.15 (1H, d, J = 14.2 Hz), 3.06 (1H, t, J = 6.1 Hz),
2.63–2.48 (2H, m), 2.02–1.89 (2H, m), 1.87–1.67 (3H, m), 1.52–
1.32 (2H, m), 1.07 (3H, d, J = 6.8 Hz), 0.95 (3H, d, J = 7.0 Hz);
dC (100 MHz, CDCl3) 147.9 (C), 139.4 (C), 136.0 (C), 128.5 (2 ¥
CH), 127.1 (2 ¥ CH), 126.9 (CH), 125.6 (CH), 124.5 (CH), 124.2
(2 ¥ CH), 123.4 (CF3, JC–F = 272.1 Hz), 70.4 (CH), 67.4 (CH),
50.0 (CH2), 49.5 (CH), 46.7 (CH), 33.5 (CH2), 28.5 (CH2), 27.1
(CH2), 26.9 (CH), 19.5 (CH3), 17.9 (CH3). Compound 24: dH (400
MHz, CDCl3) 7.48–7.38 (5H, m), 7.09 (2H, d, J = 7.6 Hz), 6.91
(2H, d, J = 7.6 Hz), 3.54 (1H, d, J = 14.3 Hz), 3.35 (1H, d, J =
14.3 Hz), 3.16 (1H, d, J = 8.6 Hz), 2.32–2.22 (2H, m), 2.13 (1H, q,
J = 8.1 Hz), 2.02–1.89 (1H, m), 1.59–1.11 (6H, m), 0.90 (3H, d,
J = 6.9 Hz), 0.86 (3H, d, J = 7.1 Hz); dC (100 MHz, CDCl3) 146.7
(C), 139.5 (C), 136.0 (C), 127.8 (2 ¥ CH), 127.1 (2 ¥ CH), 126.9
(CH), 126.7 (CH), 125.4 (CH), 123.5 (2 ¥ CH), 123.4 (CF3, JC–F
= 272.1 Hz), 73.6 (CH), 73.2 (CH), 53.1 (CH2), 52.1 (CH), 40.4
(CH), 32.8 (CH2), 28.3 (CH2), 26.8 (CH), 24.0 (CH2), 19.2 (CH3),
14.2 (CH3).
(1S*,3R*,3aR*,6aS*)-2-Benzyl-octahydro-1-isopropyl-
3-(4-methoxy-phenyl)cyclopenta[c]pyrrole (21) and
(1R*,3R*,3aR*,6aS*)-2-benzyl-octahydro-1-isopropyl-3-(4-
methoxy-phenyl)cyclopenta[c]pyrrole (22)
To a stirred solution of (E)-8 (167 mg, 0.48 mmol) in CH2Cl2
(10 mL) at -30 ◦C was added BF3·OEt2 (0.13 mL, 1.05 mmol) in
accordance with the general method, then the crude mixture was
dissolved in THF (4 mL) and added to a stirred solution of NaBH4
(56 mg, 1.44 mmol) in glacial AcOH (10 mL). Work-up followed
by purification on silica (2% Et2O in petroleum ether) afforded
successively 22 (20.6 mg, 0.06 mmol, 12%) as a colourless oil and
21 (33.2 mg, 0.10 mmol, 20%) as a colourless oil. Compound 21:
nmax (film) 2953, 1608, 1510, 1453, 1250, 1038, 822 cm-1; dH (400
MHz, CDCl3) 7.19–7.18 (4H, m), 7.14–7.09 (1H, m), 6.79 (2H, d,
J = 8.6 Hz), 6.69 (2H, d, J = 8.6 Hz), 3.74–3.69 (5H, m), 3.03 (1H,
t, J = 5.8 Hz), 2.98 (1H, d, J = 14.5 Hz), 2.60–2.50 (2H, m), 1.97–
1.86 (2H, m), 1.83–1.64 (3H, m), 1.45–1.31 (2H, m), 1.03 (3H, d,
J = 6.8 Hz), 0.93 (3H, d, J = 7.0 Hz); dC (75 MHz, CDCl3) 157.1
(C), 140.0 (C), 133.8 (C), 129.1 (2 ¥ CH), 127.0 (4 ¥ CH), 125.1
(CH), 111.9 (2 ¥ CH), 69.6 (CH), 66.3 (CH), 54.2 (CH3), 49.4
(CH2), 48.5 (CH), 46.2 (CH), 33.6 (CH2), 28.6 (CH2), 27.2 (CH2),
27.1 (CH), 19.4 (CH3), 17.5 (CH3); HRMS (ESI) calculated for
C24H32NO [M + H]: 350.2478, found 350.2479. Compound 22:
nmax (film) 2952, 1611, 1511, 1453, 1247, 1038, 826 cm-1; dH (400
MHz, CDCl3) 7.27 (2H, d, J = 8.6 Hz), 7.17–7.06 (3H, m), 6.98–
6.96 (2H, m), 6.80 (2H, d, J = 8.6 Hz), 3.73 (3H, s), 3.60 (1H, d, J =
14.4 Hz), 3.27 (1H, d, J = 14.4 Hz), 2.91 (1H, d, J = 8.5 Hz), 2.26–
2.10 (3H, m), 1.94–1.86 (1H, m), 1.54–1.22 (6H, m), 0.84 (3H, d,
J = 6.7 Hz), 0.82 (3H, d, J = 7.0 Hz); dC (75 MHz, CDCl3) 158.0
(C), 137.0 (C), 135.8 (C), 128.9 (2 ¥ CH), 128.4 (2 ¥ CH), 127.0
(2 ¥ CH), 125.8 (CH), 113.1 (2 ¥ CH), 74.0 (CH), 73.2 (CH), 54.6
(CH3), 53.1 (CH2), 52.1 (CH), 40.6 (CH), 33.3 (CH2), 28.9 (CH2),
27.2 (CH), 24.4 (CH2), 19.7 (CH3), 14.6 (CH3); MS (ES+) m/z 350
(3S*,3aS*,6aR*)-2-Benzyl-octahydro-3-isopropyl-1,1-
diphenylcyclopenta[c]pyrrole (26)
To a stirred solution of 7 (169 mg, 0.43 mmol) in CH2Cl2 (9 mL) at
-30 ◦C was added BF3·OEt2 (0.12 mL, 0.94 mmol) in accordance
with the general method, then the crude mixture was dissolved in
THF (4 mL) and added to a stirred solution of NaBH4 (49 mg,
1.28 mmol) in glacial AcOH (10 mL). Work-up followed by
purification on silica (2% Et2O in petroleum ether) affo◦rded 26
(39 mg, 0.10 mmol, 23%) as a white solid. mp 119–122 C; nmax
(film) 2956, 1601, 1493, 1443, 1262, 1028, 909, 734 cm-1; dH (600
MHz, CDCl3) 7.34–7.12 (15H, m), 4.29 (1H, d, J = 16.0 Hz), 3.68
(1H, d, J = 16.0 Hz), 3.28–3.27 (1H, m), 3.22–3.17 (1H, m), 2.75–
2.71 (1H, m), 2.01–1.96 (1H, m), 1.74–1.69 (1H, m), 1.58–1.36
(4H, m), 1.12–1.08 (1H, m), 0.57 (3H, d, J = 6.8 Hz), 0.11 (3H, d,
J = 6.8 Hz); dC (150 MHz, CDCl3) 147.1 (C), 146.8 (C), 141.0 (C),
129.0 (2 ¥ CH), 128.6 (2 ¥ CH), 128.2 (2 ¥ CH), 127.5 (2 ¥ CH),
127.3 (2 ¥ CH), 127.1 (2 ¥ CH), 126.2 (CH), 126.2 (CH), 125.7
(CH), 76.1 (C), 73.0 (CH), 55.4 (CH), 50.0 (CH2), 41.6 (CH), 34.0
(CH2), 31.3 (CH2), 28.2 (CH), 26.2 (CH2), 20.5 (CH3), 17.0 (CH3);
1038 | Org. Biomol. Chem., 2012, 10, 1032–1039
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HRMS (ESI) calculated for C29H34NO [M + H]: 396.2686, found
396.2683.
University of Warwick. The Oxford Diffraction Gemini XRD
system was obtained through the Science City Advanced Materials
project: Creating and Characterising Next Generation Advanced
Materials, with support from Advantage West Midlands.
(1R*,3R*,3aR*,6aS*)-2-Benzyl-octahydro-1-isopropyl-3-
phenylcyclopenta[c]pyrrole-1-carbonitrile (27)
To a stirred solution of (E)-6 (152 mg, 0.48 mmol) in CH2Cl2
(10 mL) at -30 ◦C was added BF3·OEt2 (0.13 mL, 1.05 mmol). The
resulting mixture was allowed to warm slowly to room temperature
over 15 h, and then quenched by the addition of saturated aq.
NaHCO3 solution. The mixture was extracted with EtOAc (3¥)
and the combined organic layers were dried over MgSO4, filtered
and concentrated in vacuo. The residue was taken up in THF
(5 mL) and cooled to 0 ◦C. In a separate flask, glacial AcOH (0.07
mL, 1.20 mmol) was added to a solution of TMSCN (0.09 mL, 0.72
mmol) in THF (1 mL) at 0 ◦C (CAUTION: HCN must be handled
with extreme caution). After stirring at 0 ◦C for 2 h, this mixture
was added to the stirred solution of the crude iminium ion. The
resultant mixture was warmed to room temperature and stirred for
15 h. Water followed by saturated aq. NaHCO3 were added and
the mixture extracted with Et2O (3¥). The combined organic layers
were washed with saturated aq. NaHCO3 then brine, were dried
over MgSO4, filtered and concentrated in vacuo. Purification on
silica (2% Et2O in petroleum ether) afforded 27 (48 mg, 0.14 mmol,
29%) as a white solid. mp 109–110 ◦C; nmax (film) 2956, 1601, 1493,
1443, 1262, 1028, 909, 734 cm-1; dH (600 MHz, CDCl3) 7.39 (2H,
d, J = 7.3 Hz), 7.29 (2H, t, J = 7.6 Hz), 7.22 (1H, t, J = 7.3 Hz),
7.15–7.08 (5H, m), 3.66 (2H, s), 3.30 (1H, d, J = 8.9 Hz), 2.64 (1H,
dt, J = 2.9, 9.6 Hz), 2.47 (1H, m), 1.98–1.86 (2H, m), 1.76–1.66
(3H, m), 1.57–1.54 (1H, m), 1.47–1.40 (1H, m), 0.98 (3H, d, J =
6.7 Hz), 0.84 (3H, d, J = 6.7 Hz); dC (150 MHz, CDCl3) 142.2
(C), 138.9 (C), 129.3 (2 ¥ CH), 128.5 (2 ¥ CH), 128.3 (2 ¥ CH),
127.8 (2 ¥ CH), 127.7 (CH), 126.8 (CH), 118.9 (C), 77.4 (C), 76.6
(CH), 54.5 (CH2), 52.2 (CH), 44.2 (CH), 33.1 (CH), 32.2 (CH2),
29.0 (CH2), 25.7 (CH2), 19.0 (CH3), 15.1 (CH3); HRMS (ESI)
calculated for C24H29N2 [M + H]: 345.2325, found 345.2322.
Notes and references
1 (a) A. R. Katritzky, C. A. Ramsden, E. F. V. Scriven and R. J. K.
Taylor (ed.), Comprehensive Heterocyclic Chemistry III, vol 3, Elsevier,
Oxford, 2008; (b) J. S. Russel, E. T. Pelkey and S. J. P. Yoon-Miller, Prog.
Heterocycl. Chem., 2011, 22, 143; (c) A. Mitchinson and A. Nadin, J.
Chem. Soc., Perkin Trans. 1, 2000, 2862.
2 Aziridines and Epoxides in Organic Synthesis, ed. A. K. Yudin, Wiley
VCH, Weinheim, 2006.
3 For an excellent overview, see: P. Dauban and G. Malik, Angew. Chem.,
Int. Ed., 2009, 48, 9026.
4 Aziridines have also been used to construct piperidines through (3 +
3) cycloadditions, see: N. C. Mancey, N. Sandon, A.-L. Auvinet, R. J.
Butlin, W. Czechtizkyc and J. P. A. Harrity, Chem. Commun., 2011, 47,
9804 and references cited therein.
5 For illustrative examples of C–C bond cleavage, see: (a) X. Wu, L. Li
and J. Zhang, Chem. Commun., 2011, 47, 7824; (b) L. Li, X. Wu and
J. Zhang, Chem. Commun., 2011, 47, 5049; (c) F. M. Ribeiro Laia,
A. L. Cardoso, A. M. Beja, M. R. Silva and T. M. V. D. Pinho e
Melo, Tetrahedron Lett., 2009, 50, 6180; (d) F. G. Brunetti, M. A.
Herrero, J. De Munoz, S. Giordani, A. Diaz-Ortiz, S. Filippone, G.
Ruaro, M. Meneghetti, M. Prato and E. Vazquez, J. Am. Chem. Soc.,
2007, 129, 14580; (e) O. Dogan, H. Koyuncu, P. Garner, A. Bulut, W. J.
Youngs and M. Panzner, Org. Lett., 2006, 8, 4687; (f) P. D. Pohlhaus,
R. K. Bowman and J. S. Johnson, J. Am. Chem. Soc., 2004, 126,
2294.
6 For recent examples of C–N bond cleavage, see: (a) X.-Y. Dou, L.-N.
He, Z.-Z. Yang and J.-L. Wang, Synlett, 2010, 2159; (b) B. Kang, A. W.
Miller, S. Goyal and S. T. Nguyen, Chem. Commun., 2009, 3928; (c) P.
A. Wender and D. Strand, J. Am. Chem. Soc., 2009, 131, 7528; (d) J.-Y.
Wu, Z.-B. Luo, L.-X. Dai and X.-L. Hou, J. Org. Chem., 2008, 73,
9137; (e) S. Gandhi, A. Bisai, B. A. B. Prasad and V. K. Singh, J. Org.
Chem., 2007, 72, 2133; (f) M. K. Ghorai and K. Ghosh, Tetrahedron
Lett., 2007, 48, 3191; (g) T. Munegumi, I. Azumaya, T. Kato, H. Masu
and S. Saito, Org. Lett., 2006, 8, 379; (h) J. Wu, X. Sun and H.-G. Xia,
Tetrahedron Lett., 2006, 47, 1509; (i) V. K. Yadav and V. Sriramurthy,
J. Am. Chem. Soc., 2005, 127, 16366.
7 For a review on intramolecular azomethine ylid cycloadditions, see: I.
Coldham and R. Hufton, Chem. Rev., 2005, 105, 2765.
8 (a) W. Zhu, G. Cai and D. Ma, Org. Lett., 2005, 7, 5545; (b) S. C.
Bergmeier, S. J. Katz, J. Huang, H. McPherson, P. J. Donoghue and D.
D. Reed, Tetrahedron Lett., 2004, 45, 5011; (c) R. J. Madhushaw, C.-C.
Hu and R.-S. Liu, Org. Lett., 2002, 4, 4151.
9 For reviews concerning the reactivity of methyleneaziridines, see: (a) M.
Shipman, Synlett, 2006, 3205; (b) K. A. Tehrani and N. De Kimpe, Curr.
Org. Chem., 2009, 13, 854.
2-Benzyl-1-ethyl-2,4,5,6-tetrahydro-3-phenylcyclopenta-[c]pyrrole
(31)
To a stirred solution of (Z)-12 (118 mg, 0.39 mmol) in CH2Cl2
(8 mL) at -30 ◦C was added BF3·OEt2 (0.07 mL, 0.59 mmol).
The resulting mixture was allowed to warm slowly to room
temperature over 15 h, and was then quenched by the addition of
saturated NaHCO3 solution. The resulting mixture was extracted
with EtOAc (3¥). The combined organic extracts were dried over
MgSO4, filtered and concentrated in vacuo to give the crude
product. Purification on silica (0–2% Et2O in petroleum ether)
afforded 31 (45 mg, 0.15 mmol, 38%) as a yellow oil. nmax (film)
2940, 1596, 1494, 1453, 1352, 701 cm-1; dH (600 MHz, CDCl3)
7.30–7.14 (8H, m), 6.98 (2H, d, J = 7.4 Hz), 5.10 (2H, s), 2.76–
2.72 (4H, m), 2.44 (2H, q, J = 7.6 Hz), 2.37–2.33 (2H, m), 1.18
(3H, t, J = 7.6 Hz); dC (100 MHz, CDCl3) 139.9 (2 ¥ C), 133.8
(C), 129.5 (C), 128.6 (2 ¥ CH), 128.4 (2 ¥ CH), 128.3 (2 ¥ CH),
127.1 (C), 126.8 (CH), 125.8 (3 ¥ CH), 124.7 (C), 48.0 (CH2), 31.1
(CH2), 25.8 (CH2), 25.5 (CH2), 19.9 (CH2), 12.9 (CH3); HRMS
(ESI) calculated for C22H24N [M + H]: 302.1903, found 302.1905.
10 C. Montagne, N. Pre´vost, J. J. Shiers, G. Prie´, S. Rahman, J. F. Hayes
and M. Shipman, Tetrahedron, 2006, 62, 8447 and references therein.
11 (a) J. Robertson, G. C. Feast, L. V. White, V. A. Steadman and T. D. W.
Claridge, Org. Biomol. Chem., 2010, 8, 3060; (b) G. Prie´, N. Pre´vost, H.
Twin, S. A. Fernandes, J. R. Hayes and M. Shipman, Angew. Chem.,
Int. Ed., 2004, 43, 6517.
12 1a: ref. 10; 1b: J. F. Hayes, M. Shipman, M. A. M. Z. Slawin and
H. Twin, Heterocycles, 2002, 58, 243; 1c:; J. J. Shiers, M. Shipman,
J. F. Hayes and A. M. Z. Slawin, J. Am. Chem. Soc., 2004, 126,
6868.
13 E. L. Eliel, S. H. Wilen and L. N. Mander, Stereochemistry of Organic
Compounds, Wiley, New York, 1994.
14 For (3 + 2) cycloadditions of 2-amidoallyl cations, see: A. H. Stoll and
S. B. Blakey, J. Am. Chem. Soc., 2010, 132, 2108.
15 K. S. Bloome and E. J. Alexanian, J. Am. Chem. Soc., 2010, 132,
12823.
16 D. M. Smith, M. E. Pulling and J. R. Norton, J. Am. Chem. Soc., 2007,
129, 770.
Acknowledgements
17 G. Be´langer, F. Le´vesque, J. Paˆquet and G. Barbe, J. Org. Chem., 2005,
70, 291.
This work was supported by the Engineering and Physical Sciences
Research Council (GR/R82586/02 and EP/D035384/1) and the
18 M. V. Baker, D. H. Brown, B. W. Skelton and A. H. White, J. Chem.
Soc., Dalton Trans., 2000, 4607.
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