Enantioselective synthesis of cyclopropylcarboxamides using s-BuLi-sparteine-mediated metallation

Article abstract of DOI:10.1039/b810441g

Enantioselective synthesis of cyclopropylcarboxamides is possible by asymmetric metallation of prochiral starting cyclopropanes using s-BuLi-sparteine. The Royal Society of Chemistry.

Full text of DOI:10.1039/b810441g

View Article Online / Journal Homepage / Table of Contents for this issue
COMMUNICATION
www.rsc.org/chemcomm | ChemComm
Enantioselective synthesis of cyclopropylcarboxamides using
s-BuLi–sparteine-mediated metallationw
Stephanie Lauru,a Nigel S. Simpkins,z*a David Gethinb and Claire Wilsona
Received (in Cambridge, UK) 19th June 2008, Accepted 7th August 2008
First published as an Advance Article on the web 16th September 2008
DOI: 10.1039/b810441g
Enantioselective synthesis of cyclopropylcarboxamides is possi-
ble by asymmetric metallation of prochiral starting cyclo-
propanes using s-BuLi–sparteine.
pected to achieve asymmetric induction using either lithium
amide bases or chiral analogues of the Eaton type of base
highlighted in Scheme 1.
Chiral cyclopropanes are important structures, which are
commonly encountered in natural products, and in synthetic
compounds with significant medicinal properties.1,2 The con-
sequent requirement for access to diverse functionalized and
substituted cyclopropanes, in highly enantioenriched form,
has acted as a driver for research into their asymmetric
synthesis. Important established methods for the enantio-
selective synthesis of cyclopropanes include asymmetric var-
iants of the Simmons–Smith procedure,3 transition-metal
catalysed diazoester cyclopropanation,4 and organocatalysed
approaches using ylide chemistry.5 The area is one of intense
current activity, and new approaches are emerging, such as
asymmetric addition reactions of cyclopropenes.6
Scheme 1 Eaton’s cyclopropane substitution using a magnesium base
i
(R = Et, Pr; R0 = H, Me, Ph).
As a prelude to chiral base studies, and in order to provide
access to racemic cyclopropanes required for analytical work,
we briefly re-examined the Eaton metallation illustrated in
Scheme 1. We decided to employ systems substituted at the
a-position in order to avoid possible equilibration pathways.
Preparation of racemic iodides, such as 3a, was very straight-
forward, although direct C–C bond formation by alkylation or
aldol addition (which was described as requiring CuI)7 was less
satisfactory in our hands, Scheme 2.9
Through our ongoing interest in desymmetrisation reactions
mediated by chiral bases, we became attracted to a new
possibility for the asymmetric synthesis of cyclopropanes,
based on a report from Eaton’s group of the b-metallation
of cyclopropylcarboxamide 1 (Scheme 1).7
Efficient cyclopropane metallation syn to the directing amide
substituent was achieved using BuMgNiPr2 as a base, giving an
intermediate formulated as 2, and subsequent electrophilic
quenching enabled access to variously substituted products 3.
The metallation is remarkable in that predominant b-substitu-
tion is observed, even when an a-hydrogen is available (i.e. when
R0 = H) that would enable competing formation of a metal
enolate type intermediate. This was rationalised as the result of
equilibration to give the more stable b-magnesium amide.
We conceived an asymmetric variant of this cyclopropane
substitution using chiral metal amide bases derived from
amines or diamines, e.g. 4 and 5. These amine motifs, in the
form of lithium amides or bis-lithium amides, have a good
track record for asymmetric induction by deprotonation of
various carbonyl-substituted systems.8 Consequently, we ex-
Scheme 2 Synthesis and lithium–iodine exchange of cyclopropane 3a.
Significantly for our later studies we established that a wide
range of substituted cyclopropanes could be accessed via lithium–
iodine exchange reactions of 3a, followed by addition of
various types of electrophile. These compounds could also
be prepared by metallation using s-BuLi–TMEDA in Et2O at
low temperature.
At this stage we probed for asymmetric induction in the
synthesis of cyclopropanes, especially 3a, by use of a range of
basic reagents, including those which can be formulated
as 4–Li, 5–Li, 5–Li2, BuMg–4, BuMg–5, etc., but with no
success.10
a School of Chemistry, The University of Nottingham, University
Park, Nottingham, UK NG7 2RD. E-mail: n.simpkins@bham.ac.uk;
Fax: +44 121 4144403; Tel: +44 121 4148905
b Pfizer Central Research, Ramsgate Road, Sandwich, Kent
UK CT13 9NJ
w Electronic supplementary information (ESI) available: Spectro-
scopic data for new compounds. CCDC reference numbers 691338,
691339 and 695941. For ESI and crystallographic data in CIF or other
electronic format see DOI: 10.1039/b810441g
z Current address: School of Chemistry, University of Birmingham,
Edgbaston, Birmingham, UK, B15 2TT
ꢀc
This journal is The Royal Society of Chemistry 2008
5390 | Chem. Commun., 2008, 5390–5392

View Article Online
Table 1 Asymmetric metallation-substitution of cyclopropanes
In the case of the iodo-derivative 3i, we were able to
recrystallise the sample and obtain enantiomerically pure
crystals suitable for X-ray analysis, Fig. 2.z
Yield
Product (%)
Ee
(%)
Entry
Cyclopropane Electrophile
1
2
3
4
5
6
7
8
9
1a R = Me
1a
1a
1a
1a
1a
1a
1a
1b R = Ph
1b
1b
1b
1b
1b
I2
MeI
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
3q
3r
58
29
69
52
61
67a
56
52
66
31
89
32
83
52
75
48
75
75
88
90
90
90
PhSSPh
PhCOCl
Prenyl bromide
PhCHO
Cyclohexanone
Acetone
I2
MeI
PSSPh
PhCOCl
Prenyl bromide
Cyclohexanone
I2
90
80b
88
90
85
88
10
11
12
13
14
15
16
17
18
a
90
ndc
ndc
79
1c R = Bn
1c
1d R = CF3
1d
ndc
88
Fig. 2 A view of one of the two independent molecules of 3i in the
asymmetric unit. Displacement ellipsoids are drawn at the 50%
probability level.
PhSSPh
I2
PhSSPh
ndc
77
b
ca. 2:1 Mixture of diastereomers. Average ee of two diastereomers
The structure shows the arrangement of the congested
amide function with respect to the cyclopropane, and confirms
both the relative configuration and the proposed sense of
absolute asymmetric induction. We assume that all of the
compounds generated using (ꢁ)-sparteine will be of the same
enantiomeric series. It is not too surprising that the ee values
for the different series of cyclopropanes should be similar,
since the deprotonation event occurs syn to the same amide
function in each case, and anti to the substituent which
is varied.
(the individual ee values were 82% for the major product and 78% for
c
the minor one). Not determined.
At last we turned to the s-BuLi–(ꢁ)-sparteine combination
for the asymmetric metallation,11 using diethyl ether as sol-
vent, and immediately found interesting levels of asymmetric
induction. By optimizing the stoichiometry of the reaction
process and other reaction parameters such as length of
reaction time and dilution we were able to establish a general
protocol for the asymmetric substitution of several prochiral
cyclopropanes with good enantiomeric excess levels, usually in
the 88–90% range, Table 1.y
Chemical yields are rather variable, which could be due to
the known tendency of lithiated cyclopropanes to undergo
decomposition and self-condensation.12 However, we were
able to demonstrate moderate to good yields with a range
of carbon electrophiles, including additions to enolisable
carbonyl partners, and also in iodination and sulfenylation
reactions.
We expected that this process would proceed by an asym-
metric deprotonation mechanism, involving kinetically con-
trolled selection between the two enantiotopic hydrogens
orientated syn to the carboxamide. The above selectivity results
support this proposal, but we also considered an alternative
asymmetric substitution type of mechanism, which in our case
would require equilibration between the diastereomeric orga-
nolithium–ligand pairs 8a and 8b, with the latter reacting faster
to give the major enantiomeric product, Scheme 3.11,14
The sense of asymmetric induction is proposed to be as
shown above for 3a–3r, based on analogy with the well-known
N-Boc pyrrolidine deprotonations—i.e. comparing 6 with 7,
Fig. 1.13
Scheme 3 Alternative asymmetric substitution mechanism.
In order to eliminate this possibility we generated the
lithiated cyclopropane, starting from 3a, by lithium–iodine
exchange, as mentioned above, followed by addition of spar-
teine and then quenching with various electrophiles. As
expected, the products obtained in this way were racemic,
which lends further support to the asymmetric deprotonation
mechanism.
Fig. 1 Comparison of sense of asymmetric induction with pyrrolidine
outcome.
ꢀc
This journal is The Royal Society of Chemistry 2008
Chem. Commun., 2008, 5390–5392 | 5391

View Article Online
In summary, we have established a new asymmetric access to
various cyclopropylcarboxamides, in synthetically useful yields
and levels of stereoselectivity. Further work is in progress to
explore the flexibility of this approach as a route to varied chiral
cyclopropanes, cyclopropenes, and derived products.
Tetrahedron: Asymmetry, 2007, 18, 1217; (b) A. Reichelt and S. F.
Martin, Acc. Chem. Res., 2006, 39, 433.
3 (a) A. B. Charette, Org. React. (N. Y.), 2001, 58, 1; (b) For a recent
example, see: H. Shitama and T. Katsuki, Angew. Chem., Int. Ed.,
2008, 47, 2450.
4 (a) M. P. Doyle, J. Org. Chem., 2006, 71, 9253, and references
therein; (b) For a more recent example, see: J. R. Denton, K.
Cheng and H. M. L. Davies, Chem. Commun., 2008, 1238.
5 H. Xie, L. Zu, J. Wang and W. Wang, J. Am. Chem. Soc., 2007,
129, 10886, and references therein.
We are grateful to the School of Chemistry, University of
Nottingham, and to Pfizer Central Research, Sandwich, for
joint support of the project through a studentship to SL.
6 (a) I. Marek, S. Simaan and A. Masarwa, Angew. Chem., Int. Ed.,
2008, 47, 1982; (b) N. Yan, X. Liu and J. M. Fox, J. Org. Chem.,
2008, 73, 563; (c) M. Rubin, M. Rubina and V. Gevorgyan, Chem.
Rev., 2007, 107, 3117.
7 M.-X. Zhang and P. E. Eaton, Angew. Chem., Int. Ed., 2002, 41,
2169.
Notes and references
y Typical procedure for asymmetric lithiation–substitution: Under an
atmosphere of argon, a solution of s-BuLi (1.4 M in cyclohexane
1.0 mL, 1.4 mmol, 2.5 eq.) was added dropwise to a stirred solution of
(ꢁ)-sparteine (0.32 g, 1.4 mmol, 2.5 eq.) in dry Et2O (4 mL) at ꢁ78 1C.
Then a solution of cyclopropanecarboxamide (0.55 mmol, 1.0 eq.) in
dry Et2O (1 mL) was introduced slowly via syringe. The mixture was
stirred for 2 h at ꢁ78 1C before addition of the electrophile (4.0 eq.),
and then stirred for a further 1 h at ꢁ78 1C and 1 h at room
temperature. It was then poured into an aqueous solution of 2 M
HCl (3 mL) and extracted with EtOAc (3 ꢂ 3 mL). The combined
organic extracts were washed with brine (2 ꢂ 2 mL), dried over
MgSO4, and concentrated in vacuo. The crude product was purified
by flash column chromatography on silica gel to give the product
cyclopropane in the yields given in Table 1.
8 (a) For a review of chiral lithium amide base reactions, see: P.
O’Brien, J. Chem. Soc., Perkin Trans. 1, 1998, 1439. For our most
recent papers, see: (b) V. Rodeschini, N. S. Simpkins and C.
Wilson, J. Org. Chem., 2007, 72, 4265; (c) V. Rodeschini, N. S.
Simpkins and F. Zhang, Org. Synth., 2007, 84, 306; (d) B. Butler,
T. Schultz and N. S. Simpkins, Chem. Commun., 2006, 3634.
9 We obtained good yields only on the cases of iodination, sulfenyla-
tion (using PhSSPh) and carboxylation (with CO2). Eaton reported
that the addition of 20% of a copper salt was needed to obtain
‘‘reasonable rates in the alkylations’’, which includes the addition
to PhCHO. In ref. 7 the cyclopropane alkylations were done on
cyclopropane 1 where either R0 = H, or R = Et, and the more
hindered nature of our substrates (R0 = alkyl and R = iPr)
perhaps explains why our efforts at cyclopropane alkylation were
ineffective.
10 Lithium amides were described as unsatisfactory for a-metallation
of cyclopropylcarboxamides, due to the similar pKa of the cyclo-
propane and typical secondary amines.7 We hoped that the re-
quired b-metallation might still be possible, particularly through
use of a bis-lithium amide, or by addition of LiCl, which had
promoted similar problematic metallations in the past.8 However,
we were unable to achieve effective cyclopropane substitution with
any lithium amides, with or without LiCl, at various temperatures
in THF. Room temperature substitution, along the lines shown in
Scheme 1, was possible with a magnesium base derived from amine
4, but gave only very low yields (ca. 10%) of racemic product.
11 (a) P. Beak, A. Basu, D. J. Gallagher, Y. S. Park and S.
Thayumanavan, Acc. Chem. Res., 1996, 29, 552; (b) See also: M.
J. McGrath, J. L. Bilke and P. O’Brien, Chem. Commun., 2006,
2607, and references therein.
Data for iodo-cyclopropane 3a (58% yield) colourless solid (mp
74–76 1C), [a]1D8 117 (c, 0.97, CHCl3); ee = 88% as determined by
chiral HPLC, chiral support CHIRALPAK AD-H, nhexane : EtOH,
98 : 2, flow rate 1 mL minꢁ1, retention time: 5.5 min (major), 6.2 min
(minor); Found C, 42.68; H, 6.54; N, 4.42%. C11H20INO requires C,
42.73; H, 6.52; N, 4.53%. nmax (CDCl3)/cmꢁ1 2968, 2934, 2875,
1628, 1461, 1370, 1345, 1041; dH (400 MHz, CDCl3) 1.18 (1H, dd,
J 8.0, 6.2), 1.22 (3H, d, J 6.6), 1.37 (3H, s), 1.39 (6H, d, J 6.6), 1.40
(3H, d, J 6.6), 1.41 (1H, dd, J 6.2, 6.2), 2.55 (1H, dd, J 8.0, 6.2), 3.27
(1H, sept, J 6.6), 4.15 (1H, sept, J 6.6); dC (100 MHz, CDCl3) ꢁ6.0
(CHI), 20.1 (CH3), 20.5 (CH3), 21.3 (CH3), 21.7 (CH3), 22.0 (CH3),
24.3 (CH2), 28.3 (C), 46.1 (CH), 48.7 (CH), 169.7 (CQO); HRMS
(ESI+) C11H21INO requires 310.0673; found 310.0671 [MH]+
.
z Crystal data for 3i: C16H22INO, M = 371.25, monoclinic, space
group P21, a = 8.5952(4), b = 23.5395(10), c = 8.7614(4) A, b =
111.232(1)1, U = 1652.34(13) A3, Z = 4 Dc = 1.492 Mg mꢁ3
,
m(Mo-Ka) = 1.932 mm ꢁ1, T = 150(2) K, 7310 unique reflections
(Rint = 0.011). Final R1 [7265 I 4 2s(I)] = 0.0174, wR2 (all data) =
0.0459. The absolute configuration was determined by refinement of
the Flack parameter to a value of ꢁ0.022(10).
12 This is usually a problem with a-metallated systems, see for
example: (a) H. W. Pinnick, Y.-H. Chang, S. C. Foster and M.
Govindan, J. Org. Chem., 1980, 45, 4505; (b) We have observed
similar problems in chiral base reactions in the absence of an in situ
quench, see: D. J. Adams, A. J. Blake, P. A. Cooke, C. D. Gill and
N. S. Simpkins, Tetrahedron, 2002, 58, 4603.
13 S. T. Kerrick and P. Beak, J. Am. Chem. Soc., 1991, 113, 9708.
14 The organolithium interconversion considered here is distinct from
the enantiomerization of systems in which the C–Li bond is the sole
stereogenic feature, see: T. I. Yousaf, R. L. Williams, I. Coldham
and R. E. Gawley, Chem. Commun., 2008, 97.
1 (a) For reviews covering many aspects of cyclopropane synthesis
and chemistry see the special edition of Chemical Reviews 2003,
103, 931, guest editor A. De Meijere, especially a review on
stereoselective cyclopropanation; H. Lebel, J.-F. Marcoux, C.
Molinaro and A. B. Charette, Chem. Rev., 2003, 103, 977; (b) W.
A. Donaldson, Tetrahedron, 2001, 57, 8589.
2 For some leading references, see: (a) V. F. Ferreira, R. A. C.
Leao, F. de C. da Silva, S. Pinheiro, P. Lhoste and D. Sinou,
ꢀc
This journal is The Royal Society of Chemistry 2008
5392 | Chem. Commun., 2008, 5390–5392