Preparative resolution of bromocyclopropylcarboxylic acids

Article abstract of DOI:10.1016/j.tetasy.2014.10.017

A general and efficient method for the preparative resolution of α- and β-bromocyclopropylcarboxylic acids has been developed. This protocol involves a sequence of two crystallizations with pseudo-enantiomeric amines, cinchonine, and cinchonidine, which yield both enantiomers of the acid in highly enriched form. Both alkaloids can be easily recovered and reused multiple times without any loss of efficacy.

Full text of DOI:10.1016/j.tetasy.2014.10.017

Tetrahedron: Asymmetry 25 (2014) 1537–1549
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Preparative resolution of bromocyclopropylcarboxylic acids
Andrew Edwards a, Pavel Ryabchuk a, Alexey Barkov b, Marina Rubina a, Michael Rubin a,
⇑
a Department of Chemistry, University of Kansas and Center for Environmentally Beneficial Catalysis, 1251 Wescoe Hall Drive, Room 5088, Lawrence, KS 66045-7582, USA
b Department of Chemistry, Ural Federal University, pr. Lenina 51, 620000 Ekaterinburg, Russian Federation
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 5 October 2014
Accepted 27 October 2014
A general and efficient method for the preparative resolution of
a- and b-bromocyclopropylcarboxylic
acids has been developed. This protocol involves a sequence of two crystallizations with pseudo-enantio-
meric amines, cinchonine, and cinchonidine, which yield both enantiomers of the acid in highly enriched
form. Both alkaloids can be easily recovered and reused multiple times without any loss of efficacy.
Ó 2014 Elsevier Ltd. All rights reserved.
1. Introduction
steric factors at the quaternary stereogenic center of cyclopropene
intermediate 7 dictate the configuration of the newly installed
Chiral halocyclopropanes are useful building blocks and
convenient precursors for chiral cyclopropyl anions 2 (Scheme 1,
path a),1 cyclopropylidenes 3 (path b),2 and cyclopropenes 4 (path
c).3 They can also be engaged in transition-metal catalyzed cross-
coupling reactions (path d).4 These synthons are also important
for the assembly of cyclopropane-containing targets.2,5,6 Their abil-
ity to participate in highly stereoselective ring-opening transfor-
mations7 may be advantageously employed in the installation of
stereodefined three carbon atom fragments.
In continuation of our long-standing interests in additions
across strained C@C bonds of cyclopropenes8,9 and the formal
nucleophilic substitution of halocyclopropanes, we have recently
reported on a new mode for the highly diastereoselective formal
nucleophilic substitution of chiral cyclopropylbromides 6 with alk-
oxides.10 This reaction involves dual control of selectivity, in which
stereocenter at C-1. The stereochemistry of the third stereogenic
center at C-3 is set by a thermodynamically driven epimerization
of enolate 8 (Scheme 2).10 This strategy allows for rapid access to
densely functionalized chiral cyclopropanes 9 with three contigu-
ous stereogenic centers; however, the poor availability of the cor-
responding enantiomerically enriched precursors 6, derivatives of
bromocyclopropylcarboxylic acids (BCCA), has been the bottleneck
of this methodology.
The most efficient known approach to chiral b-BCCAs 10 is the
catalytic asymmetric [2+1]-cycloaddition of diazoacetates 12 to
vinylbromides 11 (Scheme 3, Mode I). This strategy, however, has
only been successfully employed for intramolecular cyclopropana-
tions,11 since the lowered
p-density in the vinyl bromide makes
the intermolecular version of this reaction rather ineffective.
Cyclopropanation of olefins 14 via carbenoid transfer from
2-bromo-2-diazoacetates 15 by Hansen12 permits access to race-
mic a-BCCA derivatives 13; an asymmetric version of this method-
ology, however, is still to be developed (Scheme 3, Mode II). It has
also been shown that enantiomerically enriched derivatives of
b-BCCA 18 can be obtained via the transition metal-catalyzed
asymmetric hydro- and carbometallation of cyclopropenes 16
followed by metal–halogen exchange (Scheme 4).13,14 Several
examples of diastereoselective cyclopropanations of homochiral
olefins with halo- and dihalocarbenes have also been reported.15
All of these strategies, however, have not found significant syn-
thetic applications, mainly due to substrate or catalyst limitations.
The lack of suitable enantio- and diastereoselective syntheses
and cost-prohibitive or non-scalable preparative enzymatic16 and
chromatographic methods5,17 have prompted us to develop a
new approach for the resolution of racemic bromocyclopropylcarb-
oxylic acids via crystallization of diastereomeric salts with pseudo-
enantiomeric bases, cinchonine, and cinchonidine. This method
*
*
(a)
(d)
TM-cat.
R-M
*
*
*
X
*
R
2
1
5
(b)
(c)
*
*
4
3
Scheme 1.
⇑
Corresponding author. Tel.: +1 (785)864 5071; fax: +1 (785)864 5396.
E-mail address: mrubin@ku.edu (M. Rubin).
http://dx.doi.org/10.1016/j.tetasy.2014.10.017
0957-4166/Ó 2014 Elsevier Ltd. All rights reserved.

1538
A. Edwards et al. / Tetrahedron: Asymmetry 25 (2014) 1537–1549
Me
Me
O
t-BuOK
PhCH2O
O
N
H
18-crown-6
steric control
(S)
(R)
(S)
DMSO, 40 oC
Me
Me
Br
HN
7
6
Me
O
(S)
Ph
Me
O
(R)
(S)
Ph
H
O
O
Me (R)
thermodynamic control
(S)
Me
HN
HN
9
8
Scheme 2.
was the relatively poor stability of the free amine. Commercially
available technical grade amine 20 has only 60% assay, and must
be purified prior to use. The purified product in a free form has a
limited shelf live, but can be stored in the form of hydrochloride
or acetate, which adds steps to the resolution routine. Freshly puri-
fied amine can be recycled and reused but every successive cycle
gives a lower purity material and eventually requires re-purifica-
tion therefore increasing the cost of this already expensive reagent.
It should also be mentioned that (+)-DHAA is very substrate
specific and can only be used for the efficient separation of 2,2-dib-
romocyclopropanecarboxylic acids. Other types of cyclopropyl-
carboxylic acids tested with (+)-DHAA provided inferior results.
We therefore carried out a search for alternative, efficient, and
more stable resolving agents that would allow for a multigram-
scale preparation of a variety of enantiomerically pure BCCAs.
R1
R2
CO2R
R1
X
R2
N2
CO2R
CO2R
+
+
Mode I
Mode II
R3
R3
X
10
11
12
R1
R3
R2
R1
R3
R2
CO2R
N2
X
X
14
15
13
Scheme 3.
R1
R2
R1
R2
R1
R3
R2
Hal2
TM-cat, chiral ligand
R3-M
R3
M
Hal
17
18
16
2.1. Preparation of racemic acids
Scheme 4.
A straightforward approach to racemic BCCA 24 was envisioned
via Hoffman’s22 mono-lithiation of gem-dibromocyclopropanes 22
with n-BuLi, followed by trapping with CO2 (Scheme 6). To this
end, a multigram synthesis of the starting geminal dibromides
22, was carried out via the addition of dibromocarbene to styrenes
28 under phase-transfer catalytic conditions according to our pre-
viously published procedure23 (Table 1).
provides high yields of both enantiomers of the acid in nearly
enantiopure form after a single recrystallization with the corre-
sponding base, which can be easily recycled and reused.
2. Results and discussion
With a series of geminal dibromocyclopropanes 22 in hand, we
evaluated the scalability of Hoffman’s mono-lithiation procedure.
Successful known attempts at the resolution of halocyclopro-
pylcarboxylic acids via the crystallization of diastereomeric salts
include the use of (+)-dehydroabietylamine 20 (DHAA)18,19 and
Although the preparation of
a-bromocyclopropane carboxylic
acids 24 via this protocol was previously used in synthesis,24 most
of the reported examples were carried out on a relatively small
scale and provided marginal yields. The main challenge in achiev-
ing high selectivity in the mono-lithiation was the accurate moni-
toring of the reaction temperature, which must be maintained
within a narrow range between ꢀ60 and ꢀ65 °C. Lowering the
brucine20 for b- and
a-BCCA, respectively. We have previously
employed crystallization with (+)-DHAA in a scale-up preparation
of both individual enantiomers of 2,2-dibromo-1-methylcyclopro-
panecarboxylic acid 19 in the synthesis of chiral cyclopropylphos-
phine ligands 21 (Scheme 5).6,21 Our experience with amine 20
revealed several disadvantages of this reagent. The main issue
Me
CO2H
Br
Me
CO2
Br
Me
CO2H
Br
+
+
Br
Br
Br
NH2
rac-19
19
(S) , 57%
(R)-19, 55%
ee 99%
-
(+)-DHAA 20
ee 99%
>
>
Me
R32P
O
chiral cyclopropane-based
PHOX-ligands for intramolecular
asymmetric Heck reaction
N
21
R2
R1
Scheme 5.

A. Edwards et al. / Tetrahedron: Asymmetry 25 (2014) 1537–1549
1539
performed to obtain a diastereomerically pure product. The high
R1
R2
Br
R1
R2
Br
R1
R2
CO2H
trans-selectivity has been attributed27 to the thermodynamically
CO2
-61 oC
n-BuLi
Li
THF
more favored trans-a-halocyclopropyl lithium species 23, in which
-78 to -61oC
Br
Br
the bromide and the bulky aromatic ring are located on the
opposite sides of the small ring plane (Scheme 7). The reduced dia-
stereoselectivity observed in the reaction of 22c (Table 2, entry 3)
can be rationalized by the increased steric demands imposed by
the ethyl substituent as compared to methyl, which made facial
differentiation less efficient. We believe that excessive steric hin-
drance of the aromatic substituent in anionic species trans-23d
may reduce a relative kinetic rate of electrophilic trapping at the
syn-phase, which could explain the observed lower dr (Table 2,
entry 4). The lowest diastereoselectivity in the series obtained in
the reaction of 22e (Table 2, entry 5) could be explained by a desta-
bilizing stereoelectronic effect of the electron-donating aromatic
substituent. Apparently, this effect could only be realized in the
trans-23 anionic species, in which the dihedral angle Ar-C-C-Li is
close to 0°. In cis-23 species this angle approaches 120°, which does
not allow for efficient orbital overlap.
23
- LiBr
22
24
> -50 oC
R1
R1
R2
R1
R2
R2
H
OR
OR
25
26
Scheme 6.
27
Table 1
Synthesis of dibromocyclopropanes 22 via [2+1] cycloaddition of dibromocarbene to
styrenes
R1
R2
CHBr3/NaOH
cetrimide-cat.
R1
R2
Br
Br
CH2Cl2, 40 o
C
22
28
2.2. Resolution of a-BCCAs
28
R1
R2
Scale (mmol)
22
Yielda (%)
We first attempted the resolution of acid 24a by employing (+)-
DHAA 20.26 Taking into account the reported tendency of the latter
to form acidic salts with cyclopropylcarboxylic acids, several crys-
tallizations of diastereomeric salts have been probed using 4:1, 2:1,
and 1:1 acid-to-amine ratios. However in all cases, the samples of
acid recovered by extraction from acidified solutions of the corre-
sponding crystalline crops were racemic (Table 3, entries 1–3).
Carlier’s method for the resolution of acid 24j with brucine 29
proved to be efficient,20 however, analogous treatment of
methyl-substituted acid 24a gave racemic product (Table 3, entries
4 and 5), thus confirming that brucine is also a very substrate-sen-
sitive resolving agent.
1
2
3
4
5
6
7
8
9
10
28a
28b
28c
28d
28e
28f
28g
28h
28i
Me
Me
Et
Me
Me
H
Me
Me
Me
Ph
Ph
4-MeC6H4
Ph
2-Naphthyl
4-MeOC6H4
Ph
3-MeC6H4
3,4-Me2C6H4
4-EtC6H4
Ph
500
117
88
110
67
500
116
120
128
55
22a
22b
22c
22d
22e
22f
22g
22h
22i
80
73
69
66
74
88
68
78
71
66
28j
22j
a
Isolated yields of purified dibromocyclopropanes.
Having achieved no success with the above established litera-
ture protocols, we began screening alternative chiral amine-based
resolving agents. Our attention was drawn to the cinchona alka-
loids, currently one of the most powerful and versatile chirality-
inducing agents for synthetic28,29 and analytical30 applications.
These chiral amines are very inexpensive and readily available in
both pseudo-enantiomeric forms. Initial attempts at crystallization
of quinine salts produced marginal results: employment of 0.5 and
1.0 equiv of chiral base afforded acid (ꢀ)-24a in 16% and 33% ee,
respectively (Table 3, entries 6 and 7). A second crystallization with
1.0 equiv of quinine allowed for an improved enantiomeric purity
up to 55% (Table 3, entry 8), but was still inadequate for prepara-
tive method development. Another problem associated with using
quinine 30 as a resolving agent was the relatively high solubility of
both diastereomeric salts, which produced poorly separable, loose,
and flaky crystalline crops. In contrast, crystallization of the corre-
sponding salts with cinchonine 31 afforded a visibly dense and
much less soluble needle-like crystalline precipitate. The enantio-
meric purity of dextrorotatory acid 24a, isolated after a single
crystallization, exceeded 95% (Table 3, entry 9). Re-crystallization
of the acid recovered from the mother liquor with cinchonidine
32 afforded a second crystalline crop, acidic digestion and extrac-
tion of which provided the levorotatory enantiomer with high
enantiomeric purity (Table 3, entry 10).
temperature reduces the efficiency of the lithium–halogen
exchange and the subsequent electrophilic trapping of species
23, whereas increasing it beyond these limits may trigger a-elim-
ination to cyclopropylidene species 26. The latter can subsequently
rearrange into allene 2525 or undergo C–H insertion to afford
cyclopropane derivatives 2726 (Scheme 6).
Having studied several different solvents and temperature reg-
imens, we found that the recently reported Carlier’s method for the
preparation of diphenyl derivative 24j20 reproduced well upon
scale-up and afforded good yields for all gem-dibromides (Table 2).
It should be pointed out that in most cases, the corresponding
acids were obtained as individual diastereomers (Table 2, entries
1, 2 and 6–9), or with high trans-diastereoselectivity (Table 2,
entries 3 and 4). When necessary, a single crystallization was
Table 2
Synthesis of racemic
a-bromocyclopropylcarboxylic acids 24 via mono-lithiation of
gem-dibromocyclopropanes 22
#
22
R1
R2
Scale (mmol)
24
dra
Yieldb (%)
1
2
3
4
5
6
7
8
9
10
22a
22b
22c
22d
22e
22f
22g
22h
22i
Me
Me
Et
Me
Me
H
Me
Me
Me
Ph
Ph
4-MeC6H4
Ph
2-Naphthyl
4-MeOC6H4
Ph
3-MeC6H4
3,4-Me2C6H4
4-EtC6H4
Ph
70
70
56
70
49
70
79
75
70
34
24a
24b
24c
24d
24e
24f
24g
24h
24i
100:0
100:0
89:11
86:14
67:33
100:0
100:0
100:0
100:0
—
90
75
76
42
88c
56
76
71
46
84d
With a pair of powerful resolving reagents in hand, we focused
on the development of a preparative resolution protocol that
would allow for material recycling and reuse (Scheme 8). The opti-
mized routine involves dissolving equimolar amounts of racemic
acid 24a and cinchonine 31 in the minimal amount of boiling
acetone, hot filtration, after which the hot solution was allowed
to cool to room temperature, and then further chilled to +4 °C.
The crystalline precipitate obtained provided, after routine acid–
22j
24j
a
b
c
Ratio of trans/cis was determined in the crude reaction mixture.
Isolated yields of purified trans-diastereomer, unless specified otherwise.
Isolated yields of a mixture of diastereomers.
d
Isolated yield of purified product 24j.

1540
A. Edwards et al. / Tetrahedron: Asymmetry 25 (2014) 1537–1549
R
R
Li
CO2H
Br
CO2
R1
Br
trans-23
R1
trans-24, major
R
n-BuLi
Br
Br
R1
22
R
R
Br
Br
CO2
R1
CO2H
R1
Li
cis-23
cis-24, minor
Scheme 7.
Table 3
Resolution of 24a: optimization of resolving agent
N
N
N
N
OH
OH
OH
MeO
H
O
N
H
MeO
O
H
N
N
N
O
cinchonidine 32
cinchonine 31
quinine 30
brucine 29
Resolving agent
Equivalentsa
Enantiomerb
eec (%)
1
2
3
4
5
6
7
8
9
10
(+)-DHHA 20
20
20
Brucine 29
29
Quinine 30
30
0.25
0.5
1.0
0.5
1.0
0.5
1.0
1.0
1.0
1.0
—
—
—
—
0
0
0
0
0
16
33
55d
98
91e
—
(ꢀ)
(ꢀ)
(ꢀ)
(+)
(ꢀ)
30
Cinchonine 31
Cinchonidine 32
a
b
c
Amine to acid ratios. All of the test experiments were performed on a 500 mg scale.
Signs of the specific rotation of the recovered enantiomer 24a obtained after acid–base extraction.
Determined by chiral GC of the corresponding methyl esters.
Second crystallization of the acid (33% ee), obtained in entry 7.
Re-crystallization of acid 24a recovered from the mother liquor obtained in the experiment shown in entry 9.
d
e
base extraction, enantiomerically pure (+)-24a and recovered cin-
chonine. Acid base extraction of the concentrated mother liquor
afforded an additional amount of recovered cinchonine along with
partially enriched crude acid (ꢀ)-24a. The latter was next re-crys-
tallized from hot acetone with an equimolar amount of cinchoni-
dine 32. The crystalline precipitate formed upon cooling of the
hot acetone solution was digested with aqueous acid followed by
acid–base extraction to provide enantiomerically pure (ꢀ)-24a
and recovered cinchonidine 32. The mother liquor from this crys-
tallization was also subjected to acid base-extraction to provide
an additional amount of alkaloid 32 and a small amount of nearly
racemic 24a (Scheme 8, see Section 4 for details). Overall, the
described protocol afforded a good material balance of acid and
allowed for the recovery of both alkaloids in a purity sufficient
enough for further reuse without additional purification. Thus, in
the frame of this project, the same 25 g of each alkaloid was reused
multiple times to obtain all of the described enantiomerically
enriched carboxylic acids. Furthermore, in many cases it was found
that the amount of the resolving agent could be reduced down to
0.7–0.5 equiv without deterioration of the resolution efficiency
(see Table 4 and Section 4 for details).
acids. Acid 24a was successfully resolved on a 13 g scale, providing
more than 4 g of each enantiomer. Swapping the order in which
the alkaloids were applied did not affect the efficacy of the separa-
tion. When cinchonidine 32 was used first, the corresponding (ꢀ)-
enantiomer was afforded with 91% ee. Subsequent crystallization
with cinchonine 31 provided (+)-30a with 98% ee. When alkaloid
31 was used first, followed by 32, the corresponding enantiomers
(+)-24a and (ꢀ)-24a were also obtained with 98% and 91% ee,
respectively (Table 3, entries 9 and 10; Table 4, entries 1 and 2).
The introduction of a small substituent at the para- or meta-
position of the phenyl ring (substituent R2) in acid 24 improved
the resolution efficiency. Both enantiomers of acids bearing p-tolyl
24b (entries 3 and 4), m-tolyl 24g (entries 11 and 12), or p-ethyl-
phenyl 24i (entries 15 and 16) substituents were obtained in pure
form according to the described protocol. At the same time, the
resolution of acids possessing a large R2 group with cinchonidine
32 was found to be rather problematic. Thus, the purity of levoro-
tatory acids (ꢀ)-24d (R2 = 2-naphthyl, entry 8) and (ꢀ)-24h
(R2 = 3,4-Me2C6H3, entry 14) barely exceeded 50%, while the corre-
sponding dextrorotatory acids (+)-24d and (+)-24h were obtained
in enantiomerically pure form after crystallization with cinchonine
31 (entries 7 and 13). Increased steric hindrance of R1 (trans-sub-
stituent with respect to the carboxylic function) improved the
The optimized protocol was applied to the preparation of vari-
ous enantiomerically enriched
a-bromocyclopropanecarboxylic

A. Edwards et al. / Tetrahedron: Asymmetry 25 (2014) 1537–1549
1541
R2
(R)
R1
CO2H
(S)
pure
(+)-24
Br
acid-base
extraction
(31-H)
(+)-24
crystalline crop
cinchonine 31
recovery
R2
R1
CO2H
Br
rac-24
cinchonine 31
acetone
(31-H)
(-)-24
acid-base
extraction
mother liquor
acid-base
extraction
(32-H)
rac-24
cinchonidine 32
recovery
mother liquor
R2
(S)
R1
CO2H
(R)
cinchonidine 32
acetone
Br
acid-base
extraction
(-)-24
crude
(32-H)
(-)-24
R2
(S)
R1
CO2H
(R)
crystalline crop
Br
(-)-24
pure
Scheme 8.
Table 4
Chiral resolution of
a
-bromocyclopropanecarboxylic acidsa
R1, R2
Resolving agent
RA (equiv)
24
Yieldb (%) (ee, %)c
1
2
3
4
5
6
7
8
Me, Ph
Me, Ph
Me, p-MeC6H4
Me, p-MeC6H4
Et, Ph
Cinchonine 31
Cinchonidine 32
Cinchonine 31
Cinchonidine 32
Cinchonine 31
Cinchonidine 32
Cinchonine 31
Cinchonidine 32
Cinchonine 31
Cinchonidine 32
Cinchonine 31
Cinchonidine 32
Cinchonine 31
Cinchonidine 32
Cinchonine 31
Cinchonidine 32
Cinchonine 31
Cinchonidine 32
1.0
0.70
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
0.5
1.0
0.6
0.5
0.5
0.75
0.75
(+)-24a
(ꢀ)-24a
(+)-24b
(ꢀ)-24b
(+)-24c
(ꢀ)-24c
(+)-24d
(ꢀ)-24d
(+)-24f
(ꢀ)-24f
(+)-24g
(ꢀ)-24g
(+)-24h
(ꢀ)-24h
(+)-24i
(ꢀ)-24i
(+)-24j
(ꢀ)-24j
62 (98)d
53 (91)
50 (>99)
34 (>99)
57 (>99)
40 (>99)
51 (99)
73 (54)
32 (>99)
70 (90)
23 (>99)
11 (>99)
34 (92)
66 (52)
33 (99)
35 (>99)
22 (99)
19 (98)
Et, Ph
Me, 2-Napthyl
Me, 2-Napthyl
H, Ph
9
10
11
12
13
14
15
16
17
18
H, Ph
Me, 3-MeC6H4
Me, 3-MeC6H4
Me, 3,4-Me2C6H3
Me, 3,4-Me2C6H3
Me, 4-EtC6H4
Me, 4-EtC6H4
Ph, Ph
Ph, Ph
a
Resolutions were performed on a 4–5 g scale unless specified otherwise.
Isolated yields of enantiomerically enriched acid, obtained in a single crystalline crop.
Enantiomeric excesses determined by chiral GC or HPLC techniques after conversion of the carboxylic acids into the corresponding methyl esters, see Table 5.
Resolution was performed on a 13 g scale.
b
c
d
resulting ee in both cinchonidine (entries 6 and 18) and cinchonine
(entries 1, 5, 9, and 17) with crystallizations up to 98–99%.
The absolute configurations of both enantiomers of compound
24a were unambiguously assigned by single crystal X-ray
crystallography. (ꢀ)-(1R,2S)-24a and (+)-(1S,2R)-24a were
characterized in a form of cinchonidine salt and diethylamide
(+)-(1S,2R)-33, respectively. The latter derivative was obtained as
depicted in Scheme 9 upon sequential treatment of the parent acid
with oxalyl chloride and diethylamine.
2.3. Resolution of b-BCCA
The described above general protocol was also applied toward
the resolution of 2,2-dibromo-1-methylcyclopropanecarboxylic
acid 19. First crystallization of rac-19 with cinchonine 31 afforded
(ꢀ)-(S)-19 in high yield and with excellent enantiomeric purity
(Scheme 10). The absolute configuration of this enantiomer was
established by X-ray analysis of the corresponding cinchonine salt.
Subsequent single crystallization of the crude, partially enriched
(+)-acid recovered from the mother liquor, with cinchonidine 32
provided (+)-(R)-19 in good isolated yield and with 72% ee
(Scheme 10). Trituration of the partially enriched (+)-(R)-19 (in a
free acid form) in hexane at rt allowed for nearly quantitative pre-
cipitation of a hardly soluble acid rac-19, whereas the more soluble
(+)-enantiomer remained in the solution and was recovered upon
concentration to give (+)-(R)-19 in 50% overall yield and with ee
>99%.
Ph
Me
Br
CONEt2
Ph
Me
Br
CO2H
1. (COCl)2/CH2Cl2, 0oC
2. HNEt2/THF, RT
87%
(+)-(1S,2R)-33
(+)-(1S,2R)-24a
Scheme 9.

1542
A. Edwards et al. / Tetrahedron: Asymmetry 25 (2014) 1537–1549
Me
CO2H
(S)
Me
CO2H
cinchonine 31
[α]D25 = -47.5 (c 0.554, CH2Cl2)
yield 75%, ee 98%
Br
Br
crystallization
form acetone
Br
Br
(-)-(S)-
19
rac-19
Me
CO2H
partially enriched
(R)
cinchonidine (32)
25
[α]D = +34.6 (c 0.130, CH2Cl2)
crystallization
form acetone
Br
Br
yield 69%, ee 72%
(+)-(R)-19
trituation in hexanes
soluble in hexanes
insoluble in hexanes
Me
CO2H
(R)
25
[α]D = +49.3 (c 0.130, CH2Cl2)
Br
Br
yield 50%, ee >99%
(+)-(R)-19
Scheme 10.
Table 5
Synthesis of methyl carboxylates from carboxylic acids
2.4. Synthesis of cyclopropylcarboxylates
R1, R2
Acid
Ester
Yielda (%) Rt, minb (T) [
a
]
(c)c
D
25
For analytical and characterization purposes, all of the synthe-
sized racemic and enantiomerically enriched carboxylic acids were
converted into the corresponding methyl esters with preservation
of their stereoconfiguration by treatment of the carboxylic acids
with methyl iodide in DMF in the presence of K2CO3 (Scheme 11).
Chiral GC analyses of the esters were used to determine the enan-
tiomeric purities of the parent carboxylic acids, and the overall effi-
ciency of the featured resolution routine. Chemical yields and
chiral GC data are summarized in Table 5.
1
2
3
4
Me, Ph
rac-24a rac-34a
(+)-24a (+)-34a
(ꢀ)-24a (ꢀ)-34a
rac-24b rac-34b
(+)-24b (+)-34b
(ꢀ)-24b (ꢀ)-34b
rac-24c rac-34c
(+)-24c (+)-34c
(ꢀ)-24c (ꢀ)-34c
71
70
71
49.72 (120) +34.6 (0.220)
50.57 (120) ꢀ32.3 (0.820)
Me, p-MeC6H4
80
80
80
45.08 (131) +42.6 (0.620)
45.62 (131) ꢀ38.3 (0.300)
Et, Ph
91
90
91
34.64 (134) +29.3 (0.244)
34.97 (134) ꢀ30.9 (0.800)
Me, 2-Naphthyl rac-24d rac-34d
(+)-24d (+)-34d
71
75
73
R1
R2
Br
R1
R2
CO2Me
14.40d
16.29d
+90.0 (0.600)
ꢀ39.8 (0.560)
MeI, K2CO3
DMF
(ꢀ)-
(ꢀ)-
CO2H
24d
34d
Br
24
34
5
6
7
H, Ph
rac-24f rac-34f
(+)-24f (+)-34f
(ꢀ)-24f (ꢀ)-34f
90
91
89
12.23 (150) +122.4 (0.840)
12.76 (150) ꢀ109.4 (0.900)
Me
CO2H
Br
Me
CO2Me
Br
MeI, K2CO3
DMF
Me, m-MeC6H4 rac-24g rac-34g
(+)-24g (+)-34g
65
65
65
Br
Br
52.91 (125) +29.3 (0.820)
53.99 (125) ꢀ30.2 (0.420)
19
Scheme 11.
35
(ꢀ)-24g (ꢀ)-34g
Me, 3,4-Me2C6H3 rac-24h rac-34h
(+)-24h (+)-34h
85
85
89
8.87d
+35.4 (0.820)
ꢀ20.4 (0.940)
(ꢀ)-
(ꢀ)-
10.66d
3. Conclusion
24h
34h
8
Me, p-EtC6H4
rac-24i rac-34i
(+)-24i (+)-34i
(ꢀ)-24i (ꢀ)-34i
73
73
80
In conclusion, we have developed a highly efficient protocol for
the resolution of - and b-BCCAs employing two consecutive crys-
71.88 (131) +42.6 (0.660)
72.69 (131) ꢀ40.3 (0.340)
a
tallizations of racemic materials with cinchonine and cinchonidine.
A single crystallization with each of the resolving agents was
required to afford both enantiomers of the acids with high enantio-
meric purity. It was demonstrated that both alkaloids employed as
resolving agents could be cleanly recovered and reused multiple
times, which makes this approach very cost-efficient. The
described method is also more general with respect to substitution
patterns in bromocyclopropylcarboxylic acids as compared to pre-
viously reported procedures.
9
Ph, Ph
rac-24j rac-34j
(+)-24j (+)-34j
(ꢀ)-24j (ꢀ)-34j
rac-19 rac-35
(+)-19 (+)-35
(ꢀ)-19 (ꢀ)-35
84
77
75
19.79d
23.27d
+85.6 (0.820)
ꢀ85.4 (0.900)
e
10
—
69
75
28.51 (120) +45.1 (0.500)
27.79 (120) ꢀ62.0 (0.512)
a
Isolated yields of purified esters.
Retention times from chiral GC analyses, unless specified otherwise. Temper-
atures of GC oven in °C are provided in parentheses. For partially enriched com-
pounds the Rt value of the major component is provided.
b
c
Concentrations in CH2Cl2 in g/100 mL are provided in parentheses.
Retention times from Chiral HPLC analyses.
d
4. Experimental
4.1. General
e
Authentic sample of rac-35 was obtained according to the previously reported
procedure.32
(CPDUL). 13C NMR spectra were registered with broad-band decou-
pling. The (+) and (ꢀ) designations represent positive and negative
intensities of signals in 13C DEPT-135 experiments. GC analyses
NMR spectra were recorded on
equipped with a quadruple-band gradient probe (H/C/P/F QNP)
or a 500 MHz instrument with a dual carbon/proton cryoprobe
a 400 MHz instrument,

A. Edwards et al. / Tetrahedron: Asymmetry 25 (2014) 1537–1549
1543
were performed using 30 m ꢁ 0.25 mm ꢁ 0.25
umn (polydimethylsiloxane, 5% Ph, helium carrier gas, 1 mL/min).
CYCLODEX-B 30 m ꢁ 0.25 mm ꢁ 0.25 m column was used for chi-
l
m capillary col-
were washed with brine, dried over MgSO4, filtered, and concen-
trated. The residue was purified by flash column chromatography
on silica gel with hexanes as the mobile phase to afford (2,2-
dibromo-1methylcyclopropyl)-1,2-dimethylbenzene as a light yel-
low oil. Yield 29.7 g (93.3 mmol, 78%). 1H NMR (400 MHz, CDCl3): d
7.18–7.01 (m, 3H), 2.29 (s, 3H), 2.27 (s, 3H), 2.15 (d, J = 7.5 Hz, 1H),
1.76 (d, J = 7.5 Hz, 1H), 1.71 (s, 3H); 13C (126 MHz, CDCl3): d 139.9,
136.7, 135.7, 129.8 (+), 129.7 (+), 125.9 (+), 37.4 (ꢀ), 35.6, 33.8,
28.0 (+), 20.0 (+), 19.7 (+); FTIR (KBr, cmꢀ1): 2980, 2966, 2924,
2864, 2359, 1504, 1447, 1427, 1062, 1022, 822, 692; HRMS (TOF
l
ral GC-chromatography (hydrogen carrier gas, 1 mL/min). Helium
(99.96%) or hydrogen (99.99%) additionally purified by passing
consecutively through oxygen/moisture/hydrocarbon traps and
oxygen/moisture traps, were used as a carrier gases. Chiral HPLC
was performed employing 30 mm ꢁ 5 mm Chiralcel OD-H column
and UV-detector tuned for 254 nm band. High resolution mass-
spectra were obtained using electrospray ionization and time of
flight detection techniques. Glassware employed in moisture-free
syntheses was flame-dried in vacuum prior to use. Water was puri-
fied by dual stage deionization, followed by dual stage reverse
osmosis. Anhydrous THF was obtained by passing degassed com-
mercially available HPLC-grade inhibitor-free solvent consecu-
tively through two columns filled with activated alumina.
Anhydrous triethylamine was obtained by distillation of ACS-grade
commercially available materials over calcium hydride in a nitro-
gen atmosphere. All other commercially available reagents were
used as received. Dibromocyclopropanes 28 were synthesized
according to the general procedure, as described in our earlier
reports.23 Physical and spectroscopic properties of compounds
22a,b,e,g,23a 22c,9f 22d,23b and 22f,j31 were identical to those pre-
viously reported in the literature. Syntheses of carboxylic acids
rac-24a, rac-24b, and rac-24c were described in our preliminary
communication.10 Syntheses of acids rac-24j20 and rac-1931 were
also previously reported. Physical and spectroscopic properties of
chiral acids (+)-19 and (ꢀ)-196 as well as their methyl esters (+)-
35 and (ꢀ)-3518 were identical to those previously reported in
the literature.
ES): Found 314.9389, calcd for
(1.6 ppm).
C
12H13Br2 (MꢀH) 314.9384
4.4. (2,2-Dibromo-1-methylcyclopropyl)-4-ethylbenzene 22i
Compound was obtained via the same procedure using 1-ethyl-
4-(prop-1-en-2-yl)benzene 28i (18.68 g, 127.7 mmol, 1.0 equiv) as
the starting material. The tiled compound was obtained as a clear
oil in a yield of 31.1 g (97.9 mmol, 77%). 1H NMR (400 MHz, CDCl3):
d 7.25–7.18 (m, 4H), 2.66 (q, J = 7.6 Hz, 2H), 2.15 (d, J = 7.5 Hz, 1H),
1.77 (d, J = 7.5 Hz, 1H), 1.71 (s, 3H), 1.26 (t, J = 7.6 Hz, 3H); 13C
(126 MHz, CDCl3): 143.3, 139.7, 128.5 (+, 2C), 128.0 (+, 2C), 37.3,
35.6, 33.8 (ꢀ), 28.6 (ꢀ), 27.9 (+), 15.5 (+); FTIR (KBr, cmꢀ1): 3022,
2962, 2928, 2893, 2870, 1512, 1445, 1427, 1377, 1082, 1063,
1051, 1018, 831, 692, 573; HRMS (TOF ES): Found 314.9386, calcd
for C12H13Br2 (MꢀH) 314.9384 (0.6 ppm).
4.5. (1R⁄,2S⁄)-1-Bromo-2-(3,4-dimethylphenyl)-2-methylcyclo-
propanecarboxylic acid rac-24h, typical procedure
A solution of (2,2-dibromo-1methylcyclopropyl)-1,2-dimethyl-
benzene 22h (23.7 g, 74.5 mmol, 1.0 equiv) in dry THF (200 mL)
was placed under a nitrogen atmosphere into a 500 mL oven dried
two neck flask. The solution was cooled to ꢀ78 °C and 2.5 M solu-
tion of n-BuLi (28.3 ml, 70.8 mmol, 0.950 equiv) in hexane was
added dropwise over the course of 15 min. Immediately following
the addition of n-BuLi, the reaction mixture was warmed to ꢀ61 °C
and stirred for 20 min. The mixture was then cannulated into a 1 L
three neck flask containing freshly condensed dry carbon dioxide
and allowed to warm to room temperature with moderate stirring
while a constant flow of dry CO2 gas was maintained. The mixture
was partitioned between water (140 mL) and chloroform (100 mL)
and acidified with 4 M HCl (210 mL). The aqueous layer was
extracted with chloroform (3 ꢁ 40 mL). The combined organic
phases were then extracted with saturated sodium bicarbonate
(3 ꢁ 40 mL). The remaining aqueous solution was washed with
20 mL of chloroform. The combined aqueous phases were then
acidified to pH < 1 and extracted with chloroform (3 ꢁ 40 mL).
The combined organic layers were dried over MgSO4, filtered,
and concentrated to afford the product as light yellow crystals,
mp 127–129 °C. Yield 14.2 g (50.1 mmol, 71%). 1H NMR
(500 MHz, CDCl3): d 7.05–6.86 (m, 3H), 2.42 (d, J = 6.3 Hz, 1H),
2.21 (s, 3H), 2.20 (s, 3H), 1.70 (s, 3H), 1.36 (d, J = 6.3 Hz, 1H); 13C
NMR (126 MHz, CDCl3): d 174.0, 137.5, 136.7, 135.6, 129.8 (+),
129.1 (+), 125.2 (+), 39.6, 36.9, 28.8 (ꢀ), 28.0 (+), 19.8 (+), 19.6
(+); FTIR (KBr, cmꢀ1): 3084, 3015, 2982, 2968, 2924, 2885, 2866,
2652, 1699, 1445, 1418, 1302, 1281, 1250, 1221, 1061, 878, 820,
696; HRMS (TOF ES): Found 281.0179, calcd for C13H14BrO2
(MꢀH) 281.0177 (0.7 ppm).
4.2. 1,2-Dimethyl-4-(prop-1-en-2-yl)benzene 28h
A
solution of potassium tert-butoxide (7.71 g, 68.7 mmol,
0.955 equiv) in dry THF (75 mL) was added dropwise to a stirred
suspension of methyltriphenylphosphonium bromide (41.16 g,
115.2 mmol, 1.6 equiv) in dry THF (175 mL) at 0 °C. The resulting
yellow mixture was stirred for one hour at 0 °C and then a solution
of 30,40-dimethylacetophenone (10.7 g, 10.7 mL, 72.0 mmol,
1.0 equiv) in THF was added dropwise and stirred overnight. The
mixture was then quenched with saturated aqueous NH4Cl and
partitioned between water (25 mL) and diethyl ether (3 ꢁ 75 mL).
The combined ether phases were washed with brine, dried over
MgSO4, filtered, and concentrated. The residue was purified by
short column chromatography using silica gel and a hexane mobile
phase to afford the title compound as a clear oil. Yield 8.6 g
(59 mmol, 82%). 1H NMR (500 MHz, CDCl3): d 7.18–7.01 (m, 3H),
5.25 (s, 1H), 4.94 (s, 1H), 2.20 (s, 3H), 2.18 (s, 3H), 2.06 (s, 3H);
13C NMR (126 MHz, CDCl3): d 143.4, 139.0, 136.4, 136.0, 129.6
(ꢀ), 126.9 (ꢀ), 123.1 (ꢀ), 111.6 (+), 22.0 (ꢀ), 20.1 (ꢀ), 19.6 (ꢀ); FTIR
(KBr, cmꢀ1): 3084, 3020, 2970, 2941, 2918, 2887, 2862, 1630, 1566,
1504, 1450, 1371, 1020, 995, 881, 822, 733; HRMS (TOF ES): Found
153.1253, calcd for C11H14Li (M+Li) 153.1256 (2.0 ppm).
4.3. (2,2-Dibromo-1methylcyclopropyl)-1,2-dimethylbenzene
22h
To
119.5 mmol), bromoform (45.2 g, 15.6 mL, 179 mmol, 1.50 equiv),
tetradecyltrimethylammonium bromide (TDTAB) (750 mg,
a vigorously stirred mixture of styrene 28h (17.48 g,
2.23 mmol, 1.9 mol %), and dichloromethane (200 mL) was added
dropwise 50% aqueous solution of sodium hydroxide (12 g NaOH
in 12 mL H2O). The mixture was stirred at 900–1100 rpm overnight
at 30–35 °C. When GC analysis indicated full conversion of the ole-
fin, the mixture was quenched with water (300 mL) and extracted
with dichloromethane (3 ꢁ 50 mL). The combined organic phases
4.6. (1R⁄,2S⁄)-1-Bromo-2-methyl-2(naphthalene-2-yl)cyclopro-
panecarboxylic acid rac-24d
This compound was obtained as a dark brown highly viscous oil
via the typical procedure starting from 2-(2,2-dibromo-1-methyl-
cyclopropyl)naphthalene 22d (23.8 g, 70.0 mmol). Yield 9.06 g

1544
A. Edwards et al. / Tetrahedron: Asymmetry 25 (2014) 1537–1549
(29.7 mmol, 45%). 1H NMR (500 MHz, CDCl3): d 7.80–7.13 (m, 7H),
2.46 (d, J = 6.4 Hz, 1H), 1.70 (s, 3H), 1.38 (d, J = 6.4 Hz, 1H); 13C NMR
(126 MHz, CDCl3): d 172.6, 137.7, 133.4, 132.6, 128.4 (+), 127.9 (+),
127.8 (+), 126.9 (+), 126.3 (+), 126.1 (+), 126.0 (+), 39.5, 37.3, 29.0
(ꢀ), 27.9 (+); FTIR (KBr, cmꢀ1): 3053, 2359, 2341, 1697, 1420, 1292,
1231, 1061, 856, 818, 748, 681, 444, 424, 411; HRMS (TOF ES):
Found 303.0027, calcd for C15H12BrO2 (MꢀH) 303.0021 (2.0 ppm).
(m, 4H), 2.61 (q, J = 7.6 Hz, 2H), 2.44 (d, J = 6.4 Hz, 1H), 1.71 (s,
3H), 1.37 (d, J = 6.4 Hz, 1H), 1.22 (t, J = 7.6 Hz, 3H); 13C NMR
(126 MHz, CDCl3): d 173.7, 143.3, 137.3, 128.0 (+, 2C), 127.9 (+,
2C), 39.5, 37.0, 28.8 (ꢀ), 28.6 (ꢀ), 27.8 (+), 15.6 (+); FTIR (KBr,
cmꢀ1): 3090, 3049, 3022, 2964, 2928, 2895, 2872, 1701, 1516,
1421, 1377, 1298, 1286, 1250, 1119, 1080, 1063, 1045, 941, 885,
862, 833, 696, 569; HRMS (TOF ES): Found 283.0328, calcd for
C13H16BrO2 (M+H) 283.0334 (2.1 ppm).
4.7. (1R⁄,2S⁄)- and (1R⁄,2R⁄)-1-bromo-2-(4-methoxyphenyl)-2-
methylcyclopropanecarboxylic acid rac-24e
4.11. (+)-(1S,2R)-(+)-24a, and (ꢀ)-(1R,2S)-1-bromo-2-methyl-2-
phenylcyclopropanecarboxylic acids (ꢀ)-24a, typical procedure
This compound was obtained as a dark brown highly viscous oil
via the typical procedure starting from (2,2-dibromo-1-methylcy-
clopropyl)-4-methoxybenzene (15.8 g, 49.4 mmol, 1.0 equiv). Yield
10.7 g (43.5 mmol, 88%) as a mixture of two inseparable diastereo-
mers, 2:1. The unfavorable diastereomeric ratio in combination
with high light sensitivity leading to decomposition prohibited fur-
ther use of this material for resolution. Major: 1H NMR (500 MHz,
CDCl3): d 7.13 (d, J = 8.8 Hz, 2H), 6.79 (d, J = 8.8 Hz, 2H), 3.78 (s,
3H), 2.45 (d, J = 6.4 Hz, 1H), 1.71 (s, 3H), 1.38 (d, J = 6.4 Hz, 1H);
13C (126 MHz, CDCl3): d 173.7, 158.7, 132.1, 129.1 (+, 2C), 114.0
(+, 2C), 55.4 (+), 39.5, 36.4, 28.7 (ꢀ), 27.8 (+). Minor: 1H NMR
(500 MHz, CDCl3): d 7.22–7.16 (m, 2H), 6.93–6.86 (m, 2H), 3.81
(s, 3H), 2.05 (d, J = 6.6 Hz, 1H), 1.74 (d, J = 6.6 Hz, 1H), 1.50 (s,
3H); 13C (126 MHz, CDCl3): d 174.9, 158.8, 134.6, 130.0 (+, 2C),
113.8 (+, 2C), 55.4 (+), 37.9, 36.5, 28.5 (ꢀ), 22.2 (+). HRMS (TOF
At first, rac-24a (13.5 g, 52.9 mmol, 1.00 equiv) and cinchonine
31 (15.9 g, 53.8 mmol, 1.00 equiv) were dissolved in the minimum
amount of hot acetone (ꢂ300 mL) with stirring. The solution was
stirred for 20 min and then filtered while hot into a thermal-insu-
lated Erlenmeyer flask. The flask was capped and the mixture was
allowed to cool to room temperature over two hours. The capped
flask was then placed in the fridge at +3 °C and left overnight.
The recovered crystalline cinchonine salt, [a]
25 = +109.1 (c 0.502,
D
MeOH) was isolated by suction filtration and dissolved in ethyl
acetate (100 mL). The organic phase was added to water and acid-
ified to pH 2 using 6 M hydrochloric acid. The product was
extracted using ethyl acetate (3 ꢁ 50 mL), dried, filtered, and con-
centrated. Individual acid (+)-30 was obtained as a light yellow oil,
[a]
25 = +56.5 (c 0.200, CH2Cl2). Yield 4.20 g (16.5 mmol, 62%, ee
D
ES): Found 282.9986, calcd for
(3.9 ppm).
C
12H12BrO3 (MꢀH) 282.9975
98%). Basification of the aqueous phase to pH 10 followed by
extraction with EtOAc (3 ꢁ 50 mL) afforded a first portion of recov-
ered alkaloid 31.
4.8. (1R⁄,2S⁄)-1-Bromo-2-phenylcyclopropanecarboxylic acid rac-
24f
Concentration of the mother liquor, obtained after the first
crystallization, followed by aqueous treatment and acid–base
extraction, identical to the one described above afforded an
additional portion of recovered 31 and crude partially enriched
(ꢀ)-24a (9.0 g). This acid was re-crystallized with cinchonidine
32 (7.47 g, 25.3 mmol, 0.72 equiv) from hot acetone (ꢂ250 mL). A
This compound was obtained as light yellow crystals (mp 100–
102 °C) via the typical procedure starting from (2,2-dibromocyclo-
propyl)benzene 22f (19.3 g, 70.0 mmol). Yield 6.04 g (25.1 mmol,
38%). 1H NMR (400 MHz, CDCl3): d 7.35–7.17 (m, 5H), 3.15 (dd,
J = 10.0, 8.8 Hz, 1H), 2.35 (dd, J = 8.8, 6.6 Hz, 1H), 1.83 (dd,
J = 10.0, 6.6 Hz, 1H); 13C NMR (126 MHz, CDCl3): d 173.1, 133.8,
128.9 (+, 2C), 128.4 (+, 2C), 127.7 (+), 38.3 (+), 30.8, 23.2 (ꢀ); FTIR
(KBr, cmꢀ1): 3088, 3061, 3028, 2903, 2876, 1697, 1448, 1425, 1306,
1225, 1184, 1126, 957, 935, 870, 849, 783, 725, 696, 525; HRMS
(TOF ES): Found 238.9700, calcd for C10H8BrO2 (MꢀH) 238.9708
(3.3 ppm).
crystalline crop of cinchonidine salt, [
a
]
25 = ꢀ102.2 (c 0.360,
D
MeOH) was isolated by suction filtration, then digested and sub-
jected to acid–base extraction in the same manner as was
described above for cinchonine salt. Acid (ꢀ)-24a was obtained
as a light yellow oil, [
a
]
25 = ꢀ49.4 (c 0.172, CH2Cl2). Yield 3.8 g,
D
(14.1 mmol, 53%, ee 91%). NMR properties of both enantiomerically
enriched acids were identical to those previously reported for rac-
24a.10
4.9. (1R⁄,2S⁄)-1-Bromo-2-methyl-2-(m-tolyl)cyclopropanecar-
boxylic acid rac-24g
4.12. (+)-(1S,2R)-(+)-24b and (ꢀ)-(1R,2S)-1-bromo-2-methyl-2-
(p-tolyl)cyclopropanecarboxylic acids (ꢀ)-24b
This compound was obtained as a yellow oil via the typical
procedure starting from 1-(2,2-dibromo-1-methylcyclopropyl)-3-
methylbenzene 22g (23.9 g, 78.5 mmol). Yield 15.2 g (56.4 mmol,
76%). 1H NMR (400 MHz, CDCl3): d 7.18–6.93 (m, 4H), 2.44
(d, J = 6.3 Hz, 1H), 2.30 (s, 3H), 1.71 (s, 3H), 1.38 (d, J = 6.4 Hz,
1H). 13C NMR (126 MHz, CDCl3): d 172.7, 140.1, 138.2, 128.7 (+),
128.5 (+), 128.2 (+), 125.0 (+), 39.5, 37.1, 28.8 (ꢀ), 27.9 (+), 21.5
(+); FTIR (KBr, cmꢀ1): 3400, 3364, 3225, 3180, 3101, 3020, 2984,
2964, 2926, 2864, 1699, 1418, 1379, 1298, 1248, 1200, 1049,
947, 876, 787, 706, 671; HRMS (TOF ES): Found 269.0184, calcd
for C12H14BrO2 (M+H) 269.0177 (2.6 ppm).
These compounds were obtained according to the typical proce-
dure by recrystallization of rac-24b (5.25 g, 19.5 mmol, 1.0 equiv),
with cinchonine (5.75 g, 19.5 mmol, 1.0 equiv) from hot acetone
(ꢂ300 mL). Crystalline crop of cinchonine salt,
[a]
25 = +103.9
D
(c 0.640, MeOH) was digested to afford (+)-24b a light yellow oil,
[a]
25 = +66.0 (c 0.106, CH2Cl2). Yield 1.3 g (4.8 mmol, 50%, ee
D
>99%). Crystalline crop of cinchonidine salt,
[
a
]
25 = ꢀ139.3
D
(c 0.600, MeOH) was digested to afford (ꢀ)-24b as a cream-colored
oil, [
a
]
25 = ꢀ61.0 (c 0.100, CH2Cl2). Yield 0.879 g (3.27 mmol, 34%,
D
ee >99%). NMR properties of both enantiomerically enriched acids
were identical to those previously reported for rac-24b.10
4.10. (1R⁄,2S⁄)-1-Bromo-2-(4-ethylphenyl)-2-methylcyclopro-
panecarboxylic acid rac-24i
4.13. (+)-(1S,2R)-(+)-24c and (ꢀ)-(1R,2S)-1-bromo-2-ethyl-2-
phenylcyclopropanecarboxylic acids (ꢀ)-24c
This compound was obtained as light brown crystals (mp 109–
111 °C) via the typical procedure starting from 1-(2,2-dibromo-1-
methylcyclopropyl)-4-ethyl benzene 22i (22.4 g, 70.4 mmol). Yield
8.57 g (30.3 mmol, 46%). 1H NMR (500 MHz, CDCl3): d 7.15–7.03
These compounds were obtained according to the typical proce-
dure by recrystallization of rac-24c (5.39 g, 20.0 mmol, 1.0 equiv)
with cinchonine (5.89 g, 20.0 mmol, 1.0 equiv) from hot acetone
(ꢂ300 mL). Crystalline crop of cinchonine salt,
[a]
25 = +93.5
D

A. Edwards et al. / Tetrahedron: Asymmetry 25 (2014) 1537–1549
1545
(c 0.306, MeOH) was digested to afford (+)-24b as a cream colored
solid, mp 75–76.5 °C, [
25 = +69.5 (c 0.118, CH2Cl2). Yield 1.53 g
ee 92%). Crystalline crop of cinchonidine salt,
[
a
]
25 = ꢀ67.4
D
a
]
D
(c 0.328, MeOH) was digested to afford (ꢀ)-24h as a light yellow
(5.68 mmol 57%, ee >99%). Crystalline crop of cinchonidine salt,
oil, [
a
]
25 = ꢀ31.6 (c 0.190, CH2Cl2). Yield 1.65 g (5.83 mmol, 66%,
D
[
a
]
25 = ꢀ74.4 (c 0.418, MeOH) was digested to afford (ꢀ)-24c as a
ee 52%). NMR properties of both enantiomerically enriched acids
D
cream-colored solid, mp 72.5–73.4 °C,
[a
]
D
25 = ꢀ43.1 (c 0.144,
were identical to those listed above for rac-24h.
CH2Cl2). Yield 1.06 g (3.94 mmol, 40%, ee >99%). NMR properties
of both enantiomerically enriched acids were identical to those
previously reported for rac-24c.10
4.18. (+)-(1S,2R)-(+)-24i and (ꢀ)-(1R,2S)-1-bromo-2-(4-ethyl-
phenyl)-2-methylcyclopropanecarboxylic acids (ꢀ)-24i
4.14. (+)-(1S,2R)-(+)-24d and (ꢀ)-(1R,2S)-1-bromo-2-methyl-2-
(naphthalen-2-yl)cyclopropanecarboxylic acids (ꢀ)-24d
These compounds were obtained according to the typical proce-
dure by recrystallization of rac-24i (5.01 g, 17.7 mmol, 1.0 equiv)
with cinchonine (2.5 g, 8.5 mmol, 0.48 equiv) from hot acetone
These compounds were obtained according to the typical proce-
dure by recrystallization of rac-24d (4.68 g, 14.6 mmol, 1.0 equiv)
with cinchonine (4.30 g, 14.6 mmol, 1.0 equiv) from hot acetone
(ꢂ300 mL). Crystalline crop of cinchonine salt,
(c 0.170, MeOH) was digested to afford (+)-24i as a yellowish
brown solid, mp 72.8–74.8 °C, [
25 = +69.8 (c 0.116, CH2Cl2). Yield
[a]
25 = +109.4
D
a]
D
(ꢂ300 mL). Crystalline crop of cinchonine salt,
(c 0.382, MeOH) was digested to afford (+)-30d as a light brown
solid, mp 121.5–123.5 °C, [
25 = +108.2 (c 0.122, CH2Cl2). Yield
[
a]
25 = +112.0
820 mg (2.9 mmol, 33%, ee >99%). Crystalline crop of cinchonidine
D
salt, [
a
]
25 = ꢀ70.2 (c 0.124, MeOH), was digested to afford (ꢀ)-24i
D
a
]
D
as a yellowish-brown solid, mp 71.0–73.2 °C, [
a]
25 = +55.4 (c
D
1.19 g (3.72 mmol, 51%, ee 99%). Crystalline crop of cinchonidine
0.130, CH2Cl2). Yield 870 mg (3.1 mmol, 35%, ee >99%). NMR prop-
erties of both enantiomerically enriched acids were identical to
those listed above for rac-24i.
salt, [a]
25 = ꢀ96.1 (c 0.382, MeOH) was digested to afford (ꢀ)-
D
24d as dark-brown oil, [
a
]
D
25 = ꢀ57.4 (c 0.162, CH2Cl2). Yield
1.70 g (5.30 mmol, 73%, ee 54%). NMR properties of both enantio-
merically enriched acids were identical to those listed above for
rac-24d.
4.19. (+)-(S)-(+)-24j and (ꢀ)-(R)-1-bromo-2,2-diphenylcyclopro-
panecarboxylic acids (ꢀ)-24j
4.15. (+)-(1S,2R)-(+)-24f and (ꢀ)-(1R,2S)-1-bromo-2-phenylcycl-
opropanecarboxylic acids (ꢀ)-24f
These compounds were obtained according to the typical proce-
dure by recrystallization of rac-24j (5.03 g, 15.8 mmol, 1.00 equiv)
with cinchonine (3.48 g, 11.8 mmol, 0.75 equiv) from hot acetone
These compounds were obtained according to the typical proce-
dure by recrystallization of rac-24f (4.61 g, 18.0 mmol, 1.0 equiv)
with cinchonine (5.29 g, 18.0 mmol, 1.0 equiv) from acetone
(ꢂ300 mL). Crystalline crop of cinchonine salt,
(c 0.198, MeOH) was digested to afford (+)-24j as a colorless solid,
mp: 168–169.8 °C, [
25 = +110.3 (c 0.204, CH2Cl2). Yield 570 mg,
[a]
25 = +133.3
D
a]
D
(ꢂ300 mL). Crystalline crop of cinchonine salt,
(c 0.430, MeOH) was digested to afford (+)-30f as a light-brown
solid, mp 78.8–79.9 °C, [
25 = +166.0 (c 0.106, CH2Cl2). Yield
[a
]
25 = +117.7
2.14 mmol, 22%, ee 99%). Crystalline crop of cinchonidine salt,
D
[
a
]
25 = ꢀ111.8 (c 0.386, MeOH), was digested to afford (ꢀ)-24j as
D
a]
a colorless solid, mp 182.0–183.0 °C, [
a]
25 = ꢀ106.1 (c 0.198,
D
D
0.72 g (2.8 mmol, 32%, ee >99%). Crystalline crop of cinchonidine
CH2Cl2). Yield 478 mg (1.5 mmol, 19%, ee >99%). NMR properties
of both enantiomerically enriched acids were identical to those
reported for rac-24j.20
salt, [
24f as
a
]
25 = ꢀ130.5 (c 0.430, MeOH) was digested to afford (ꢀ)-
D
a
light brown solid, mp 68–69.4 °C,
[a]
25 = ꢀ131.2
D
(c 0.138, CH2Cl2). Yield 1.62 g (6.33 mmol, 70%, ee 90%). NMR prop-
erties of both enantiomerically enriched acids were identical to
those listed above for rac-24f.
4.20. (1S,2R)-1-Bromo-N,N-diethyl-2-methyl-2-phenylcyclopro-
pane-1-carboxamide (+)-(1S,2R)-33
4.16. (+)-(1S,2R)-(+)-24g and (ꢀ)-(1R,2S)-1-bromo-2-methyl-2-
(m-tolyl)cyclopropanecarboxylic acids (ꢀ)-24g
A flame dried 100 mL round bottom flask equipped with a dry-
ing tube and magnetic stirrer bar was charged with acid (+)-24a
(1.28 g, 5.00 mmol), anhydrous CH2Cl2 (40 mL), and dry DMF (10
drops). The mixture was stirred at 0 °C and oxalyl chloride
(0.65 mL, 7.5 mmol, 1.5 equiv) was added dropwise. Stirring was
continued for 15 min, then the mixture was warmed up to rt and
stirred for an additional 2 h. The solvent was removed in vacuum
and the crude acyl chloride was dissolved in anhydrous THF
(20 mL), followed by the addition of diethylamine (1.55 mL,
15.0 mmol, 3.0 equiv) solution in dry THF (20 mL). The resulting
mixture was stirred overnight, then the solvent was removed in
vacuum and the residue was partitioned between water (25 mL)
and EtOAc (25 mL). The organic phase was separated, and the
aqueous layer was extracted with EtOAc (2 ꢁ 25 mL). The com-
bined organic phases were dried (MgSO4), filtered, and concen-
trated. Chromatographic purification afforded the title compound
as a yellowish solid, Rf 0.34 (hexane/EtOAc 10:1). Yield 1.34 g
(4.35 mmol, 87%). 1H NMR (500 MHz, CDCl3): d 7.56–7.04 (m,
5H), 3.48 (dt, J = 14.2, 7.1 Hz, 1H), 3.37 (dq, J = 14.2, 7.1 Hz, 1H),
2.71 (dq, J = 14.0, 7.1 Hz, 1H), 2.65 (d, J = 7.3 Hz, 1H), 2.58 (dq,
J = 14.0, 7.0 Hz, 1H), 1.85 (s, 3H), 1.33 (d, J = 7.3 Hz, 1H), 1.00 (t,
7.1 Hz, 3H), 0.47 (t, 7.1 Hz, 3H); 13C NMR (126 MHz, CDCl3): d
165.8, 138.1, 128.1 (+, 2C), 127.0 (+, 2C), 126.7 (+), 42.4, 42.0 (ꢀ),
38.3 (ꢀ), 31.0, 26.9 (ꢀ), 24.3 (+), 12.6 (+), 11.1 (+); FTIR (KBr,
cmꢀ1): 2977, 2933, 1643, 1639, 1498, 1456, 1433, 1380, 1282,
These compounds were obtained according to the typical proce-
dure by recrystallization of rac-24g (4.78 g, 17.6 mmol, 1.0 equiv)
with cinchonine (5.17 g, 17.6 mmol, 1.0 equiv) from hot acetone
(ꢂ300 mL). Crystalline crop of cinchonine salt,
(c 0.418, MeOH) was digested to afford (+)-24g as cream colored
crystals, mp 92.0–93.4 °C, [
25 = +77.5 (c 0.102, CH2Cl2). Yield
[a]
25 = +113.9
D
a
]
D
550 mg, (2.0 mmol, 23%, ee >99%). Crystalline crop of cinchonidine
salt, [
as gray oil,
a
]
25 = ꢀ93.5 (c 0.184, MeOH) was digested to afford (ꢀ)-24g
D
[a
]
D
25 = ꢀ74.6 (c 0.114, CH2Cl2). Yield 270 mg
(1.00 mmol, 11%, ee >99%). NMR properties of both enantiomeri-
cally enriched acids were identical to those listed above for
rac-24g.
4.17. (+)-(1S,2R)-(+)-24h and (ꢀ)-(1R,2S)-1-bromo-2-(3,4-dimeth-
ylphenyl)-2-methylcyclopropanecarboxylic acids (ꢀ)-24h
These compounds were obtained according to the typical proce-
dure by recrystallization of rac-24g (5.00 g, 17.7 mmol, 1.0 equiv)
with cinchonine (5.00 g, 16.9 mmol, 0.96 equiv) from hot acetone
(ꢂ300 mL). Crystalline crop of cinchonine salt,
(c 0.408, MeOH) was digested to afford (+)-24g as a light yellow
oil, [
25 = +54.7 (c 0.172, CH2Cl2). Yield 850 mg (3.00 mmol, 34%,
[a]
25 = +94.1
D
a]
D

1546
A. Edwards et al. / Tetrahedron: Asymmetry 25 (2014) 1537–1549
1219, 1064, 719, 696, 582; HRMS (TOF ES): Found 309.0724, calcd
(TOF ES): Found 283.0335, calcd for C13H16BrO2 (M+H) 283.0334
(0.4 ppm); Chiral GC: Rt (131 °C isotherm), 45.10 min (50%),
45.64 min (50%).
for C15H20BrNO (M+) 309.0728 (1.3 ppm); [
a]
25 = +17.0 (c 0.194,
D
CH2Cl2).
4.21. (1R⁄,2S⁄)-Methyl 1-bromo-2-methyl-2-phenylcyclopropan-
ecarboxylate rac-34a (typical procedure)
4.25. (1S,2R)-Methyl 1-bromo-2-methyl-2-(p-tolyl)cyclopropan-
ecarboxylate (+)-34b
A mixture of (1R⁄,2S⁄)-1-bromo-2-methyl-2-phenylcyclopro-
panecarboxylic acid rac-24a (255 mg, 0.947 mmol), potassium car-
bonate (276 mg, 2.00 mmol, 2.0 equiv), and methyl iodide (280 mg,
This ester was obtained according to the typical procedure
employing acid (+)-24b (54 mg, 0.20 mmol, 1.0 equiv), potassium
carbonate (55 mg, 0.40 mmol, 2.0 equiv), and methyl iodide
123
lL, 1.97 mmol, 2.0 equiv) was vigorously stirred in dimethyl
(57 mg, 25 lL, 0.40 mmol, 2.0 equiv) in DMF (5 mL). The title com-
formamide (10 mL) for 12 h at rt. Then, the mixture was quenched
with water (5 mL) and extracted with dichloromethane
(3 ꢁ 10 mL). The combined organic phases were dried (MgSO4),
filtered, and concentrated in vacuum. The crude material was puri-
fied by silica gel chromatography to afford the title compound as a
light yellow oil, Rf 0.22 (hexanes/EtOAc 50:1). Yield 181 mg
(0.672 mmol, 71%). 1H NMR (500 MHz, CDCl3): d 7.56–7.01 (m,
5H), 3.34 (s, 3H), 2.55 (d, J = 6.4 Hz, 1H), 1.75 (s, 3H), 1.40 (d,
J = 6.5 Hz, 1H); 13C NMR (126 MHz, CDCl3): d 168.5, 140.7, 128.5
(+, 2C), 128.1 (+, 2C), 127.2 (+), 52.9 (+), 40.4, 35.9, 27.9 (ꢀ), 27.5
(+); FTIR (KBr, cmꢀ1): 3026, 2986, 2951, 1732, 1603, 1497, 1434,
1379, 1325, 1298, 1285, 1234, 1115, 1094, 1061, 1026, 982, 876,
775, 758, 721, 700, 559, 542; HRMS (TOF ES): Found 269.0177,
calcd for C12H14BrO2 (M+H) 269.0177 (0.0 ppm). Chiral GC: Rt
(120 °C isotherm) 49.72 min (50%), 50.57 min (50%).
pound was obtained as a light yellow oil, with TLC and spectro-
scopic properties identical to those listed above for rac-34b. Yield
44 mg (0.16 mmol, 80%). Chiral GC: Rt (131 °C isotherm),
45.08 min; [a]
25 = +42.6 (c 0.620, CH2Cl2).
D
4.26. (1R,2S)-Methyl 1-bromo-2-methyl-2-(p-tolyl)cyclopropan-
ecarboxylate (ꢀ)-34b
This ester was obtained according to the typical procedure
employing acid (ꢀ)-24b (300 mg, 1.11 mmol, 1.0 equiv), potassium
carbonate (306 mg, 2.22 mmol, 2.0 equiv), and methyl iodide
(315 mg, 138 lL, 2.22 mmol, 2.0 equiv) in DMF (10 mL). The title
compound was obtained as a light yellow oil, with TLC and spectro-
scopic properties identical to those listed above for rac-34b. Yield
251 mg (0.88 mmol, 80%). Chiral GC: Rt (131 °C isotherm),
45.62 min; [
a]
25 = ꢀ38.3 (c 0.300, CH2Cl2).
D
4.22. (1S,2R)-Methyl 1-bromo-2-methyl-2-phenylcyclopropane-
carboxylate (+)-34a
4.27. (1R⁄,2S⁄)-Methyl 1-bromo-2-ethyl-2-phenylcyclopropan-
ecarboxylate rac-34c
This ester was obtained according to the typical procedure
employing acid (+)-24a (50 mg, 0.20 mmol), potassium carbonate
(55 mg, 0.40 mmol, 2.0 equiv), methyl iodide (56.8 mg, 25 lL,
This ester was obtained according to the typical procedure
employing acid rac-24c (100 mg, 0.372 mmol, 1.0 equiv), potas-
sium carbonate (103 mg, 0.744 mmol, 2.0 equiv), and methyl
0.400 mmol, 2.0 equiv), and DMF (5 mL). The title compound was
obtained as a light yellow oil, with TLC and spectroscopic proper-
ties identical to those listed above for rac-34a. Yield 37.7 mg
(0.140 mmol, 70%). Chiral GC: Rt (120 °C isotherm), 49.72 min;
iodide (106 mg, 46 lL, 0.745 mmol, 2.0 equiv) in DMF (5 mL). The
title compound was obtained as a light yellow oil, Rf 0.22 (hex-
ane/EtOAc 50:1). Yield 95.7 mg (0.338 mmol, 91%). 1H NMR
(500 MHz, CDCl3): d 7.33–7.17 (m, 5H), 3.34 (s, 3H), 2.45 (d,
J = 6.4 Hz, 1H), 2.11 (dtd, J = 14.6, 7.3, 1.5 Hz, 1H), 1.92 (dq,
J = 13.7, 7.4 Hz, 1H), 1.35 (d, J = 6.3 Hz, 1H), 0.89 (t, J = 7.4 Hz,
3H); 13C NMR (126 MHz, CDCl3): d 168.6, 138.7, 129.1 (+, 2C),
128.3 (+, 2C), 127.3 (+), 52.9 (+), 40.9, 40.9, 33.4 (ꢀ), 26.9 (ꢀ),
11.2 (+); FTIR (KBr, cmꢀ1): 3026, 2970, 2951, 2934, 1732, 1495,
1435, 1377, 1300, 1286, 1225, 1118, 1090, 1067, 989, 881, 795,
756, 721, 702, 592; HRMS (TOF ES): Found 282.0257, calcd for
[a]
25 = +34.6 (c 0.220, CH2Cl2).
D
4.23. (1R,2S)-Methyl 1-bromo-2-methyl-2-phenylcyclopropane-
carboxylate (ꢀ)-34a
This ester was obtained according to the typical procedure
employing acid (ꢀ)-24a (48 mg, 0.19 mmol), potassium carbonate
(51 mg, 0.37 mmol, 2.0 equiv), methyl iodide (52.8 mg, 23 lL,
0.38 mmol, 2.0 equiv), and DMF (5 mL). The title compound was
obtained as a light yellow oil, with TLC and spectroscopic proper-
ties identical to those listed above for rac-34a. Yield 36.3 mg
(0.135 mmol, 71%). Chiral GC: Rt (120 °C isotherm), 50.57 min;
C13H15BrO2 (M+) 282.0255 (0.7 ppm). Chiral GC: Rt (134 °C iso-
therm) 34.64 min (50%), 34.97 min (50%).
4.28. (+)-(1S,2R)-Methyl 1-bromo-2-ethyl-2-phenylcyclopropan-
ecarboxylate (+)-34c
[a
]
D
25 = +32.3 (c 0.820, CH2Cl2).
4.24. (1R⁄,2S⁄)-Methyl 1-bromo-2-methyl-2-(p-tolyl)cyclopro-
panecarboxylate rac-34b
This ester was obtained according to the typical procedure
employing acid (+)-24c (50 mg, 0.19 mmol, 1.0 equiv), potassium
carbonate (51 mg, 0.37 mmol, 2.0 equiv), and methyl iodide
This ester was obtained according to the typical procedure
employing acid rac-24b (300 mg, 1.11 mmol, 1.0 equiv), potassium
carbonate (307 mg, 2.22 mmol, 2.0 equiv), and methyl iodide
(53 mg, 23 lL, 0.37 mmol, 2.0 equiv) in DMF (5 mL). The title com-
pound was obtained as a light yellow oil with TLC and spectro-
scopic properties identical to those listed above for rac-34c. Yield
(315 mg, 138
lL, 2.22 mmol, 2.0 equiv) in dimethyl formamide
48 mg (0.171 mmol, 90%). [a]
25 = +29.3 (c 0.244, CH2Cl2); Chiral
D
(10 mL). The title compound was obtained as a light yellow oil, Rf
0.22 (hexanes/EtOAc 50:1). Yield 251 mg (0.888 mmol, 80%). 1H
NMR (500 MHz, CDCl3): d 7.14–7.04 (m, 4H), 3.36 (s, 3H), 2.50 (d,
J = 6.4 Hz, 1H), 2.30 (s, 3H), 1.71 (s, 3H), 1.35 (d, J = 6.4 Hz, 1H);
13C NMR (126 MHz, CDCl3): d 168.6, 137.6, 136.8, 129.2 (+, 2C),
127.9 (+, 2C), 53.0 (+), 40.3, 35.6, 27.9 (ꢀ), 27.5 (+), 21.2 (+); FTIR
(KBr, cmꢀ1): 2984, 2951, 2926, 1732, 1516, 1435, 1377, 1325,
1300, 1281, 1232, 1113, 1094, 1063, 1047, 820, 719, 557; HRMS
GC: Rt (134 °C isotherm) 34.64 min.
4.29. (ꢀ)-(1R,2S)-Methyl 1-bromo-2-ethyl-2-phenylcyclopro-
panecarboxylate (ꢀ)-34c
This ester was obtained according to the typical procedure
employing acid (+)-24c (50.0 mg, 0.19 mmol, 1.0 equiv), potassium
carbonate (51 mg, 0.37 mmol, 2.0 equiv), and methyl iodide

A. Edwards et al. / Tetrahedron: Asymmetry 25 (2014) 1537–1549
1547
(53 mg, 23
l
L, 0.37 mmol, 2.0 equiv) in DMF (5 mL). The title com-
pound was obtained as a light yellow oil with spectroscopic prop-
pound was obtained as a light yellow oil with TLC and spectro-
scopic properties identical to those listed above for rac-34c. Yield
49 mg (0.17 mmol, 91% yield). [
ral GC: Rt (134 °C isotherm) 34.97 min.
erties identical to those reported in the literature for rac-34f.24c
Yield 48 mg (0.19 mmol, 91%). [a]
25 = +122.4 (c 0.840, CH2Cl2); Chi-
D
a]
25 = ꢀ30.9 (c 0.800, CH2Cl2); Chi-
ral GC: Rt (150 °C isotherm) 12.23 min.
D
4.35. (ꢀ)-(1R,2S)-Methyl 1-bromo-2-phenylcyclopropanecarboxy-
late (ꢀ)-34f
4.30. (1R⁄,2S⁄)-Methyl 1-bromo-2-methyl-2-(naphthalen-2-yl)
cyclopropanecarboxylate rac-34d
This ester was obtained according to the typical procedure
employing acid (ꢀ)-24f (50 mg, 0.21 mmol, 1.0 equiv), potassium
carbonate (57 mg, 0.41 mmol, 2.0 equiv), and methyl iodide
This ester was obtained according to the typical procedure
employing acid rac-24d (50 mg, 0.16 mmol, 1.0 equiv), potassium
carbonate (45 mg, 0.33 mmol, 2.0 equiv), and methyl iodide
(59 mg, 26 lL, 0.41 mmol, 2.0 equiv) in DMF (5 mL). The title com-
(46 mg, 20
l
L, 0.33 mmol, 2.0 equiv) in DMF (5 mL). The title com-
pound was obtained as a light yellow oil with spectroscopic prop-
pound was obtained as a light brown oil, Rf 0.22 (hexanes/EtOAc
50:1). Yield 38 mg (0.12 mmol, 71%). 1H NMR (500 MHz, CDCl3):
d 7.94–7.33 (m, 7H), 3.26 (s, 3H), 2.66 (d, J = 6.5 Hz, 1H), 1.81 (s,
3H), 1.47 (d, J = 6.5 Hz, 1H); 13C NMR (126 MHz, CDCl3): 168.5,
138.2, 133.4, 132.6, 128.3 (+), 127.9 (+), 127.8 (+), 126.9 (+),
126.3 (+), 126.1 (+), 126.0 (+), 53.0 (+), 40.4, 36.1, 28.1 (ꢀ), 27.5
(+); FTIR (KBr, cmꢀ1): 2984, 2949, 1734, 1435, 1325, 1294, 1271,
1246, 1227, 1196, 1134, 1101, 1063, 982, 955, 895, 858, 820,
746, 717; HRMS (TOF ES): Found 319.0331, calcd for C16H16BrO2
(M+H) 319.0334 (0.9 ppm). Chiral HPLC: (isocratic 99.5% hexane,
0.5% isopropanol, 0.7 mL/min) 14.40 min (50%), 16.29 min (50%).
erties identical to those reported in the literature for rac-34f.24c
Yield 47 mg (0.18 mmol, 89%). [
Chiral GC: Rt (150 °C isotherm) 12.76 min.
a
]
25 = ꢀ109.4 (c 0.900, CH2Cl2);
D
4.36. (1R⁄,2S⁄)-Methyl 1-bromo-2-methyl-2-(m-tolyl)cyclopro-
panecarboxylate rac-34g
This ester was obtained according to the typical procedure
employing acid rac-24g (50 mg, 0.19 mmol, 1.0 equiv), potassium
carbonate (51 mg, 0.37 mmol, 2.0 equiv), and methyl iodide
(53 mg, 23 lL, 0.37 mmol, 2.0 equiv) in DMF (5 mL). The title com-
pound was obtained as a light yellow oil. Yield 35 mg (0.12 mmol,
65%). 1H NMR (500 MHz, CDCl3): d 7.19–6.98 (m, 4H), 3.34 (s, 3H),
2.50 (d, J = 6.4 Hz, 1H), 2.31 (s, 3H), 1.71 (s, 3H), 1.36 (d, J = 6.4 Hz,
1H); 13C (126 MHz, CDCl3): d 168.6, 140.7, 138.1, 128.8 (+), 128.4
(+), 128.0 (+), 125.1 (+), 52.9 (+), 40.4, 35.9, 28.0 (ꢀ), 27.6 (+),
21.5 (+); FTIR (KBr, cmꢀ1): 2984, 2951, 2926, 1732, 1607, 1489,
1435, 1377, 1329, 1302, 1279, 1242, 1200, 1117, 1094, 1063,
872, 789, 706; HRMS (TOF ES): Found 282.0248, calcd for
4.31. (+)-(1S,2R)-Methyl 1-bromo-2-methyl-2-(naphthalen-2yl)
cyclopropanecarboxylate (+)-34d
This ester was obtained according to the typical procedure
employing acid (+)-24d (50 mg, 0.16 mmol, 1.0 equiv), potassium
carbonate (45 mg, 0.33 mmol, 2.0 equiv), and methyl iodide
(46 mg, 20 lL, 0.33 mmol, 2.0 equiv) in DMF (5 mL). The title com-
pound was obtained as a light brown oil with TLC and spectro-
C13H15BrO2 (M+) 282.0255 (2.5 ppm). Chiral GC: Rt (125 °C iso-
scopic properties identical to those listed above for rac-34d. Yield
therm) 52.91 min (50%), 53.99 min (50%).
38 mg (0.12 mmol, 75%). [a]
25 = +90.0 (c 0.600, CH2Cl2); Chiral
D
HPLC: (isocratic 99.5% hexane, 0.5% isopropanol, 0.7 mL/min)
14.40 min (>99%).
4.37. (+)-(1S,2R)-Methyl 1-bromo-2-methyl-2-(m-tolyl)cyclopro-
panecarboxylate (+)-34g
4.32. (ꢀ)-(1R,2S)-Methyl 1-bromo-2-methyl-2-(naphthalen-2-yl)
cyclopropanecarboxylate (ꢀ)-34d
This ester was obtained according to the typical procedure
employing acid (+)-24g (50 mg, 0.19 mmol, 1.0 equiv), potassium
carbonate (51 mg, 0.37 mmol, 2.0 equiv), and methyl iodide
This ester was obtained according to the typical procedure
employing acid (ꢀ)-24d (50 mg, 0.16 mmol, 1.0 equiv), potassium
carbonate (45 mg, 0.33 mmol, 2.0 equiv), and methyl iodide
(53 mg, 23 lL, 0.37 mmol, 2.0 equiv) in DMF (5 mL). The title com-
pound was obtained as a light yellow oil with spectroscopic prop-
erties identical to those listed above for rac-34g. Yield 35 mg
(46 mg, 20
l
L, 0.33 mmol, 2.0 equiv) in DMF (5 mL). The title com-
(0.12 mmol, 65%). [a]
25 = +29.3 (c 0.820, CH2Cl2); Chiral GC: Rt
D
pound was obtained as a light yellow oil with TLC and spectro-
(125 °C isotherm) 52.91 min.
scopic properties identical to those listed above for rac-34d. Yield
37 mg (0.12 mmol, 73%). [
HPLC: (isocratic 99.5% hexane, 0.5% isopropanol, 0.7 mL/min)
14.40 min (23%), 16.29 min (77%).
a
]
25 = ꢀ39.8 (c 0.560, CH2Cl2); Chiral
4.38. (ꢀ)-(1S,2R)-Methyl 1-bromo-2-methyl-2-(m-tolyl)cyclo-
propanecarboxylate (ꢀ)-34g
D
This ester was obtained according to the typical procedure
employing acid (+)-24g (50 mg, 0.19 mmol, 1.0 equiv), potassium
carbonate (51 mg, 0.37 mmol, 2.0 equiv), and methyl iodide
4.33. (1R⁄,2S⁄)-Methyl 1-bromo-2-phenylcyclopropanecarboxy-
late rac-34f
(53 mg, 23 lL, 0.37 mmol, 2.0 equiv) in DMF (5 mL). The title com-
This compound was obtained according to the same procedure
in 90% yield. All physical and spectroscopic properties of this mate-
rial were identical to those previously reported in the literature.24c
Chiral GC: Rt (150 °C isotherm) 12.23 min (50%), 12.76 min (50%).
pound was obtained as a light yellow oil with spectroscopic prop-
erties identical to those listed above for rac-34g. Yield 34 mg
(0.12 mmol, 65%). [
(125 °C isotherm) 53.99 min.
a
]
25 = ꢀ30.2 (c 0.420, CH2Cl2); Chiral GC: Rt
D
4.34. (+)-(1S,2R)-Methyl 1-bromo-2-phenylcyclopropanecarboxy-
late (+)-34f
4.39. (1R⁄,2S⁄)-Methyl 1-bromo-2-(3,4-dimethylphenyl)-2-methyl-
cyclopropanecarboxylate rac-34h
This ester was obtained according to the typical procedure
employing acid (+)-24f (50 mg, 0.21 mmol, 1.0 equiv), potassium
carbonate (57 mg, 0.41 mmol, 2.0 equiv), and methyl iodide
This ester was obtained according to the typical procedure
employing acid rac-24h (50 mg, 0.18 mmol, 1.0 equiv), potassium
carbonate (49 mg, 0.36 mmol, 2.0 equiv), and methyl iodide
(59 mg, 26
lL, 0.41 mmol, 2.0 equiv) in DMF (5 mL). The title com-
(50 mg, 22 lL, 0.36 mmol, 2.0 equiv) in DMF (5 mL). The title com-

1548
A. Edwards et al. / Tetrahedron: Asymmetry 25 (2014) 1537–1549
pound was obtained as
a
light yellow oil. Yield 45.5 mg
4.44. (ꢀ)-(1R,2S)-Methyl 1-bromo-2-(4-ethylphenyl)-2-methyl-
cyclopropanecarboxylate (ꢀ)-34i
(0.15 mmol, 85%). 1H NMR (500 MHz, CDCl3): d 7.08–6.90 (m,
3H), 3.38 (s, 3H), 2.48 (d, J = 6.4 Hz, 1H), 2.22 (s, 3H), 2.21 (s, 3H),
1.71 (s, 3H), 1.34 (d, J = 6.3 Hz, 1H); 13C NMR (126 MHz, CDCl3): d
168.6, 138.1, 136.6, 135.5, 129.7 (+), 129.2 (+), 125.4 (+), 53.0 (+),
40.3, 35.6, 27.9 (ꢀ), 27.6 (+), 19.9 (+), 19.6 (+); FTIR (KBr, cmꢀ1):
2982, 2949, 2924, 1732, 1506, 1435, 1377, 1306, 1283, 1236,
1221, 1095, 1063, 874, 822, 717, 600; HRMS (TOF ES): Found
296.0412, calcd for C14H17BrO2 (M+) 296.0412 (0.0 ppm). Chiral
HPLC: (isocratic 99.5% hexane, 0.5% isopropanol, 0.7 mL/min)
8.87 min (50%), 10.66 min (50%).
This ester was obtained according to the typical procedure
employing acid (ꢀ)-24i (50 mg, 0.18 mmol, 1.0 equiv), potassium
carbonate (49 mg, 0.35 mmol, 2.0 equiv), and methyl iodide
(50 mg, 22 lL, 0.35 mmol, 2.0 equiv) in DMF (5 mL). The title com-
pound was obtained as a light yellow oil with spectroscopic prop-
erties identical to those listed above for rac-34i. Yield 43 mg
(0.14 mmol, 80%). [
(131 °C isotherm) 72.69 min.
a
]
25 = ꢀ40.3 (c 0.340, CH2Cl2); Chiral GC: Rt
D
4.40. (+)-(1S,2R)-Methyl 1-bromo-2-(3,4-dimethylphenyl)-2-
4.45. Methyl 1-bromo-2,2-diphenylcyclopropanecarboxylate
methylcyclopropanecarboxylate (+)-34h
rac-34j
This ester was obtained according to the typical procedure
employing acid (+)-24h (50 mg, 0.18 mmol, 1.0 equiv), potassium
carbonate (49 mg, 0.36 mmol, 2.0 equiv), and methyl iodide
(50 mg, 22 lL, 0.36 mmol, 2.0 equiv) in DMF (5 mL). The title com-
pound was obtained as a light yellow oil with spectroscopic prop-
This ester was obtained in 84% yield according to the typical
procedure employing acid rac-24j. All physical and spectroscopic
properties of this material were identical to those previously
reported in the literature.20 1H NMR (500 MHz, CDCl3): d 8.07–
6.92 (m, 10H), 3.51 (s, 3H), 2.82 (d, J = 6.5 Hz, 1H), 2.10 (d,
J = 6.5 Hz, 1H). 13C NMR (126 MHz, CDCl3): d 168.4, 141.4, 140.5,
129.5 (+, 2C), 128.6 (+, 2C), 128.4 (+, 2C), 128.4 (+, 2C), 127.4 (+),
127.3 (+), 53.1 (+), 45.2, 38.7, 27.7 (ꢀ); FTIR (KBr, cmꢀ1): 3057,
3026, 2949, 1732, 1599, 1493, 1448, 1435, 1323, 1310, 1279,
1250, 1190, 1153, 1099, 1067, 1014, 951, 798, 762, 748, 706,
694, 669, 623, 604, 592; HRMS (TOF ES): Found 330.0255, calcd
for C17H15BrO2 (M+) 330.0255 (0.0 ppm); Chiral HPLC: (isocratic
99.5% hexane, 0.5% isopropanol, 0.7 mL/min) 19.79 min (50%),
23.27 min (50%).
erties identical to those listed above for rac-34h. Yield 45 mg
(0.15 mmol, 85%). [a]
25 = +35.4 (c 0.820, CH2Cl2); Chiral HPLC: (iso-
D
cratic 99.5% hexane, 0.5% isopropanol, 0.7 mL/min) 8.87 min.
4.41. (ꢀ)-(1R,2S)-Methyl 1-bromo-2-(3,4-dimethylphenyl)-2-
methylcyclopropanecarboxylate (ꢀ)-34h
This ester was obtained according to the typical procedure
employing acid (ꢀ)-24h (50 mg, 0.18 mmol, 1.0 equiv), potassium
carbonate (49 mg, 0.36 mmol, 2.0 equiv), and methyl iodide
(50 mg, 22
l
L, 0.36 mmol, 2.0 equiv) in DMF (5 mL). The title com-
4.46. (+)-(S)-Methyl 1-bromo-2,2-diphenylcyclopropanecarboxy-
pound was obtained as a light yellow oil with spectroscopic prop-
late (+)-34j
erties identical to those listed above for rac-34h. Yield 47 mg
(0.16 mmol, 89%). [
(isocratic 99.5% hexane, 0.5% isopropanol, 0.7 mL/min) 10.66 min.
a
]
25 = ꢀ20.4 (c 0.940, CH2Cl2); Chiral HPLC:
This ester was obtained according to the typical procedure
employing acid (+)-24j (50 mg, 0.16 mmol, 1.0 equiv), potassium
carbonate (44 mg, 0.32 mmol, 2.0 equiv), and methyl iodide
D
4.42. (1R⁄,2S⁄)-Methyl 1-bromo-2-(4-ethylphenyl)-2-methylcyclo–
propanecarboxylate rac-34i
(45 mg, 20
lL, 0.32 mmol, 2.0 equiv) in DMF (ꢂ5 mL). The title
compound was obtained as a colorless solid with spectroscopic
properties identical to those listed above for rac-34j. Yield 41 mg
This ester was obtained according to the typical procedure
employing acid rac-24i (50 mg, 0.18 mmol, 1.0 equiv), potassium
carbonate (49 mg, 0.35 mmol, 2.0 equiv) and methyl iodide
(0.12 mmol, 77%). [a]
cratic 99.5% hexane, 0.5% isopropanol, 0.7 mL/min) 19.79 min.
25 = +85.6 (c 0.820, CH2Cl2); Chiral HPLC: (iso-
D
(50 mg, 22
l
L, 0.35 mmol, 2.0 equiv) in DMF (5 mL). The title com-
4.47. (ꢀ)-(R)-Methyl 1-bromo-2,2-diphenylcyclopropanecarboxy-
late (ꢀ)-34j
pound was obtained as a light yellow oil. Yield 39 mg (0.13 mmol,
73%). 1H NMR (500 MHz, CDCl3): d 7.16–7.07 (m, 4H), 3.33 (s, 3H),
2.60 (q, J = 7.6 Hz, 2H), 2.50 (d, J = 6.5 Hz, 1H), 1.71 (s, 3H), 1.35 (d,
J = 6.4 Hz, 1H), 1.20 (t, J = 7.6 Hz, 3H); 13C NMR (126 MHz, CDCl3): d
168.6, 143.2, 137.8, 128.0 (+, 2C), 127.9 (+, 2C), 52.9 (+), 40.4, 35.5,
28.6 (ꢀ), 27.8 (ꢀ), 27.5 (+), 15.6 (+); FTIR (KBr, cmꢀ1): 3022, 2962,
2978, 2872, 1732, 1514, 1435, 1377, 1327, 1300, 1286, 1232, 1113,
1094, 1063, 1045, 982, 833, 716, 571; HRMS (TOF ES): Found
295.0334, calcd for C14H16BrO2 (MꢀH) 295.0334, 0.0 ppm; Chiral
GC: Rt (131 °C isotherm) 71.89 min (50%), 72.69 min (50%).
This ester was obtained according to the typical procedure
employing acid (ꢀ)-24j (50 mg, 0.16 mmol, 1.0 equiv), potassium
carbonate (44 mg, 0.32 mmol, 2.0 equiv), and methyl iodide
(45 mg, 20
l
L, 0.32 mmol, 2.0 equiv) in DMF (ꢂ5 mL). The title
compound was obtained as a colorless solid with spectroscopic
properties identical to those listed above for rac-34j. Yield 40 mg
(0.12 mmol, 75%). [
(isocratic 99.5% hexane, 0.5% isopropanol, 0.7 mL/min) 23.27 min.
a
]
25 = ꢀ85.4 (c 0.900, CH2Cl2); Chiral HPLC:
D
4.43. (+)-(1S,2R)-Methyl 1-bromo-2-(4-ethylphenyl)-2-methyl-
Acknowledgments
cyclopropanecarboxylate (+)-34i
Financial support from Center for Environmentally Beneficial
Catalysis (Lawrence, K.S.) and from Russian Ministry of Science
and Education (in a frame of MIG Grant (International Investigative
Groups) at Perm State University, Russia and ‘New Innovation Lab-
oratory’ support program at Ural Federal University) is gratefully
acknowledged. We are also grateful to Dr. Maxim Dmitriev (Perm
State University, Russia) and to Prof. Nikolay Gerasimchuk (Mis-
souri State University, Springfiled, MO, USA) for their assistance
with X-ray crystallography.
This ester was obtained according to the typical procedure
employing acid (+)-24i (50 mg, 0.18 mmol, 1.0 equiv), potassium
carbonate (49 mg, 0.35 mmol, 2.0 equiv), and methyl iodide
(50 mg, 22 lL, 0.35 mmol, 2.0 equiv) in DMF (5 mL). The title com-
pound was obtained as a light yellow oil with spectroscopic prop-
erties identical to those listed above for rac-34i. Yield 38.0 mg
(0.13 mmol, 73%). [
(131 °C isotherm) 71.89 min.
a]
25 = +42.6 (c 0.660, CH2Cl2); Chiral GC: Rt
D

A. Edwards et al. / Tetrahedron: Asymmetry 25 (2014) 1537–1549
1549
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