Preparation and reactions of some 2,2-difunctional 1,1-dibromocyclopropanes

Article abstract of DOI:10.1016/j.tet.2007.04.104

The synthesis of 2,2-dibromocyclopropane-1,1-dicarboxylic acids is described. Reaction of substituted 1,1-dibromo-2-acyloxymethylcyclopropanes with methyl lithium at low temperature leads to a bromine-lithium exchange and then either formal protonation to

Full text of DOI:10.1016/j.tet.2007.04.104

Tetrahedron 63 (2007) 7717–7726
Preparation and reactions of some 2,2-difunctional
1,1-dibromocyclopropanes
Mark S. Baird,a Vitali M. Boitsov,b Alexander V. Stepakov,b Alexander P. Molchanov,b
Jurgen Kopf,c Mohanathas Rajaratnama and Rafael R. Kostikovb,
*
aSchool of Chemistry, University of Wales, Bangor, Gwynedd LL57 2UW, UK
bChemistry Department, Saint-Petersburg State University, Universitetsky prosp. 26, St.-Petersburg 198504, Russian Federation
cInstitut fu€r Anorganische Chemie, Universita€t Hamburg, Martin-Luther-King platz 6, D 20146 Hamburg, Germany
Received 15 January 2007; revised 4 April 2007; accepted 26 April 2007
Available online 13 May 2007
Abstract—The synthesis of 2,2-dibromocyclopropane-1,1-dicarboxylic acids is described. Reaction of substituted 1,1-dibromo-2-acyloxy-
methylcyclopropanes with methyl lithium at low temperature leads to a bromine–lithium exchange and then either formal protonation to give
the corresponding monobromocyclopropanes or intramolecular cyclisation to give a substituted 3-oxabicyclo[3.1.0]hexane. Oxidative ring
opening of these compounds leads stereoselectively to 1,1,2,2-tetrasubstituted cyclopropanes with four functionalities on the ring.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
the 1,3-elimination of HBr from 1,1-dibromo-2-(halogeno-
methyl)cyclopropanes on reaction with methyl lithium.10,11
We recently reported that reaction of 2,2-dibromo-1-acyl-
oxymethylcyclopropanes with methyl lithium leads to hemi-
acetals, apparently derived by cyclisation of an intermediate
lithiobromide (Scheme 1).12
The cyclopropane ring is a key structural element of many
natural products1 and the synthesis of specifically substituted
cyclopropanes has therefore grown important. Dibromo-
cyclopropanes, which are normally readily available by addi-
tion of dibromocarbene to alkenes, undergo a range of
useful transformations many of which can be used to produce
other cyclopropanes in a stereocontrolled manner.2 One ex-
ample is their reaction with methyl lithium, which is known
to lead to a very rapid lithium–bromine exchange, followed
in most cases by formal elimination of lithium bromide to
produce a cyclopropylidene (or a related carbenoid), which
often rearranges efficiently to form an allene.3 At low tem-
perature or, in some cases, if there is a coordinating group
present in the molecule, the organolithium may be trapped
in intermolecular processes by reaction with electrophiles.3
There are also many examples of intramolecular trapping
of the cyclopropylidene. Thus, insertion into CH bonds is of
considerable synthetic potential.4,5 For example, in ethers,6
amines,7 sulfides8 and acetals9 insertion occurs exclusively
at the C–H bond adjacent to the heteroatom and 5,6-related
to the carbenic carbon (1,5-insertion) to give bicyclic hetero-
cycles. There are fewer cases of similar intramolecular reac-
tions of the lithiobromides acting as nucleophiles; one such is
Br
Li
R
R1
Br
R1
Br
R
HO
R1
MeLi
Et2O
Br
R
O
O
O
O
O
Scheme 1.
2. Results and discussion
The reaction of a,b-unsaturated esters with bromoform and
base under phase transfer conditions (probably proceeding
by addition of the tribromomethyl anion rather than the
carbene) provides 1,1-dibromocyclopropane-2-carboxylates
that can be resolved to provide useful chiral building blocks
for synthesis.13 This reaction has also been applied to alkyl-
idenemalonates to produce esters of 3-alkyl-2,2-dibromo-
cyclopropane-1,1-dicarboxylic acid.14 In this work, the
preparation and reactions of some 1,1-dibromocyclopro-
panes having two functional groups at the 2-position were
studied. The synthesis of cyclopropanes 1a–c was carried
out according to Scheme 2. Treatment of di-tert-butyl
methylenemalonate15 with bromoform and aqueous sodium
Keywords: Dibromocyclopropanes; Monobromocyclopropanes; Hemiace-
tals; Lithiation; Cyclisation.
* Corresponding author. Tel.: +7 812 428 4047; e-mail: rkost@rk1198.spb.
edu
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.04.104

7718
M. S. Baird et al. / Tetrahedron 63 (2007) 7717–7726
hydroxide in the presence of a phase transfer catalyst pro-
duced di-tert-butyl ester 1a in 27% yield. The 1H NMR spec-
trum of ester 1a contains signals of the methylene protons at
2.32 ppm and the methyl groups at 1.52 ppm. The 13C NMR
spectrum consists of signals for the three-membered ring
carbon atoms at 23.3 ppm (CBr2), 32.6 ppm (CH2) and
44.4 ppm (C) and carboxylate groups. The structure of com-
pound 1a was confirmed by X-ray diffraction studies
(Fig. 1).
Cyclopropanes 5a,b were synthesised as in Scheme 3.
Treatment of ethyl acrylate with formaldehyde and DABCO
as catalyst produced ethyl a-hydroxymethylacrylate 2.16
Protection of the hydroxyl group with 2-methoxy-1-propene
or 3,4-dihydro-2H-pyran to give esters 3a,b (yields 75% or
53% correspondingly) and subsequent cyclopropanation
led to compounds 4a,b in yields 95% or 79%. The 1H NMR
spectrum of cyclopropane 4a included the cyclopropane
methylene group as two doublets at 1.84 and 2.45 ppm, the
oxymethylene group as two doublets at 3.97 and 4.07 ppm,
two singlets for methyl groups at 2.17 and 3.49 ppm, and
the signals of the ethyl group. Cyclopropane 4b was obtained
as a mixture of diastereomers in 1:1 ratio. Reaction of
cyclopropane 4a with aqueous methanol in the presence of
p-toluenesulfonic acid led to compound 5a in 67% yields.
CO2t-Bu
CO2t-Bu
Br
Br
CO2R
CO2R
i
27%
1a R = t-Bu
1b R = H
ii, 99%
iii, 83%
1c R = Me
A selective reduction of ester 4b with DIBAL-H at ꢀ78 ꢁC
gave THP protected alcohol 5b in 48% yield. Reduction of
ester 1c with lithium aluminium hydride afforded 1-bromo-
2,2-bis(hydroxymethyl)cyclopropane 6 with a yield of 69%.
Thus, reduction of the ester group and also one of C–Br bond
has occurred. The 1H NMR spectrum of compound 6 showed
the signals for the cyclopropane ring protons as double dou-
blets at 0.93 (J¼6.6 and 4.4 Hz), 1.21 (J¼7.5 and 6.6 Hz)
and 3.10 ppm (J¼7.5 and 4.4 Hz). Using a mixture of
lithium aluminium hydride–aluminium chloride allowed se-
lective reduction only of the ester groups of esters 1c and 5a
to give 1,1-dibromo-2,2-bis(hydroxymethyl)cyclopropane
Scheme 2. Reagents and conditions: (i) CHBr3, 40% aq NaOH, TEBA,
CH2Cl2; (ii) TFA; (iii) CH2N2.
Hydrolysis of cyclopropane 1a with trifluoroacetic acid led
to diacid 1b in 99% yield. Dimethyl 2,2-dibromocyclo-
propane-1,1-dicarboxylate 1c was obtained by treatment of
the acid 1b with an ethereal solution of diazomethane in
1
83% yield. The H NMR spectrum of the ether 1c showed
the signals of the methylene group protons at 2.52 ppm
and the methyl group protons at 3.87 ppm.
7
17 with a yield of up to 65%. Deprotection of 5b was carried
out with PTSA in methanol at 50 ꢁC to give diol 7 in 98%
yield (Scheme 4). The H NMR spectrum of compound 7
1
showed singlets at 1.64 ppm (CH2 of the cyclopropane
ring) and at 2.44 ppm (OH), and two doublets at 3.94 and
4.13 ppm (CH2O).
CH2OH
CH2OH
Br
i
1c
69%
H
6
CH2OH
CH2OH
Br
iii
ii
1c, 5a
5b
98%
63-65%
Br
7
Scheme 4. Reagents and conditions: (i) LiAlH4, Et2O; (ii) LiAlH4–AlCl3,
Et2O; (iii) MeOH, PTSA.
Despite the fact that the one-step synthesis of diol 7 is pos-
sible from ester 1c, this way is not optimal as far as ester 1c
itself is the product of three-step synthesis (from methylene-
malonate) with summarised yield around 23% (the summar-
ised yield of diol 7 from methylenemalonate is around
Figure 1. The X-ray crystal structure of compound 1a.
CO2Et
CO2Et
OCMe2OMe
CO2Et
CO2Et
OH
Br
Br
Br
Br
i
ii
iii
OCMe2OMe
4a, 95%
CH2OH
3a, 75%
5a, 67%
2
iv
CO2Et
CO2Et
CH2OH
OTHP
Br
Br
4b, 79%
Br
Br
ii
v
OTHP
OTHP
3b, 53%
5b, 48%
Scheme 3. Reagents and conditions: (i) Me(MeO)C]CH2, PPTS; (ii) CHBr3, aq NaOH, TEBA, CH2Cl2; (iii) H+/aq MeOH; (iv) 3,4-dihydro-2H-pyran, PPTS;
(v) DIBAL, ꢀ78 ꢁC, 12 h.

M. S. Baird et al. / Tetrahedron 63 (2007) 7717–7726
7719
14%). Therefore, we attempted two additional ways to
prepare the diol 7 from hydroxymethylacrylates. The
summarised yield of diol 7 is around 31% and 20% (using
2-methoxy-1-propene and 3,4-dihydro-2H-pyran, respec-
tively, as protecting group) (Schemes 3 and 4).
the reaction was kept at low temperature. By an analogous
process hemiacetals 11b–d,g were prepared by reaction of
esters 8b–d, respectively, with a slight excess of methyl
lithium (Scheme 6). Moreover, methyl esters 11b,c,g were
obtained as a result of transesterification of ethyl esters.
Treatment of compounds 5a and 7 with a series of acid chlo-
rides in pyridine led to the formation of esters 8a–f (Scheme
5) with yields of 62–85%.
Reaction of cyclopropane 8e with methyl lithium in tetra-
hydrofuran at ꢀ110 ꢁC to ꢀ100 ꢁC for 30 min followed by
quenching at this temperature with water led to the forma-
tion of monobromocyclopropane 12 (24%) as a mixture of
cis- and trans-isomers in a 7:1 ratio, respectively, whereas
warming to 0 ꢁC immediately after the addition of methyl
lithium, and stirring at this temperature for 20 min afforded
hemiacetal 11e (Scheme 7). The reaction of cyclopropane 8f
with methyl lithium generally followed a similar pattern. It is
interesting to note that quenching the reaction mixture in the
last case with saturated aqueous ammonium chloride af-
forded a mixture of protected and unprotected compounds,
whereas quenching with methanol afforded only compounds
unprotected on the second hydroxymethyl group.
R1
i
Br
Br
5a,7
CH2OCOR
8a R1 = CO2Et, R = Me, 62%
8b R1 = CO2Et, R = Pr, 68%
8c R1 = CO2Et, R = i-Pr, 63%
8d R1 = CO2Et, R = Ph, 71%
8e R1 = CH2OCOPr, R = Pr, 85%
8f R1 = CH2OCOMe, R = Me, 73%
Scheme 5. Reagents and conditions: (i) RCOCl, Py.
O
O
O
O
The reaction of esters 8a–f with methyl- or butyl lithium was
investigated under various conditions. Reaction of ester 8a
with methyl lithium in tetrahydrofuran at ꢀ109 ꢁC to
ꢀ100 ꢁC for 30 min followed by quenching with water at
this temperature produced only a mixture of cis- and trans-
monobromides 9 (23%, 3:1 ratio by 1H NMR spectroscopy)
and 10—as a single cis-isomer (15%) (Scheme 6). When the
reaction mixture was warmed to ꢀ30 ꢁC, ꢀ10 ꢁC or 0 ꢁC and
kept at this temperature for a range of times, formation of
hemiacetal 11a was observed after quenching. Reaction of
ester 8a with a slight excess of n-butyl or methyl lithium at
ꢀ100 ꢁC, warming to 0 ꢁC and maintaining at 0–1 ꢁC for
a further 20–30 min, then quenching with methanol led to
formation of hemiacetal 11a (up to 21%) and cyclopropane
9 in a 8:1 ratio. Additional reactions were carried out with
compound 8a under different conditions with butyl lithium
in order to increase the yield of 11a. In all cases, a decrease
in the mass was noticed after reaction mixtures were
worked-up (chromatography), but attempts to isolate other
compounds from the mixtures were unsuccessful. The
amount of monobromocyclopropanes (determined from the
1H NMR spectra of crude products) depended on how long
Pr
Pr
Pr
O
O
i
Br
Br
Br
H
H
OH
O
Br
OH
Pr
trans-12, 6%
cis-12, 18%
8e
O
ii
Br
R
OH
8e, f
O
HO
11e R = Pr, 51%
11f R = Me, 69%
O
O
Me
Me
Me
O
O
Br
Br
Br
Me
iii
11f, 21%
O
O
HO
O
11h, 37%
8f
Scheme 7. Reagents and conditions: (i) (a) MeLi, THF, ꢀ100 ꢁC to ꢀ95 ꢁC,
30 min, (b) H2O; (ii) (a) MeLi, Et2O, ꢀ100 ꢁC to 0 ꢁC, 20 min, (b) MeOH;
(iii) (a) MeLi, Et2O, ꢀ100 ꢁC to 0 ꢁC, 20 min, (b) aq NH4Cl.
The configurations of compounds 9 and 10 were determined
on the basis of chemical shifts. A comparison of the signal
protons H1, H2 and the protons of the CH2-group of com-
pounds 5a and 7 showed H1 to be 0.81 (2.45–1.64) ppm
lower field in the ester and H2 to be 0.2 (1.84–1.64) ppm
lower field while the protons of the geminal SO2-group
were at ꢀ0.01ꢂ0.01 ppm. A comparison of the signals of
the protons H1, H2 and the protons of CH2-group of com-
pounds 5 and its acylated analogue 8a showed the effect of
acetylation to be +0.03 ppm for H1, +0.10 ppm for H2 and
+0.56ꢂ0.22 ppm for the protons of CH2-group. In the
same way the influence of the bromine atom was determined
by comparison of the mono- and dibromodiols. The effect of
the bromine atom is +0.71 ppm for H1, +0.42 ppm for H2,
+0.35ꢂ0.01 ppm for the trans-related CH2-group and
+0.06ꢂ0.05 ppm for the cis-related CH2-group.
Br
CO2Et
O
Br
CO2Et
OH
i
H
H
Me
O
10, 15%
9, 23%
8a_d
Br
R
R1
ii
O
HO
11a R1= CO2Et, R = Me, 21%
11b R1= CO2Me, R = Pr, 10%
11c R1= CO2Me, R = i-Pr, 10%
11d R1= CO2Et, R = Ph, 6%
11g R1= CO2Me, R = Ph, 3%
A plausible mechanism for transformation of lithiation
products of dibromocyclopropanes into monobromocyclo-
propanes and hemiacetals is shown below (Scheme 8).
On alkyl lithium attack one of the bromine atoms (the one
Scheme 6. Reagents and conditions: (i) (a) MeLi, THF, ꢀ109 ꢁC to
ꢀ100 ꢁC, 30 min, (b) H2O; (ii) (a) MeLi or BuLi, Et2O, ꢀ100 to 0 ꢁC,
20 min, (b) MeOH.

7720
M. S. Baird et al. / Tetrahedron 63 (2007) 7717–7726
R1
Br
RCH2
R1
R''OH
Br
RCH2
O
O
a
HO
LiO
R1
Br
R1
Br
Li
O
Br
H
LiO
R1
Br
R1
OH
R''OH
b
RCH2CO2Li
a
H
b
H
O
O
O
O
H
R
H
RH2C
R
H
Br
Br
R1
I
R'Li
R1
O
H
R1
Li
Br
R''OH
O
c
RH2C
Br
O
O
O
O
RH2C
RH2C
Scheme 8. A plausible mechanism of formation of products 9–12.
Table 1. Yields of cyclisation products
cis- to the acyloxymethyl group) is replaced selectively by
lithium with formation of the organolithium species, pro-
moted by coordination of lithium to the oxygens of the ester
group.18 This can undergo two transformations: a—intramo-
lecular attack by the anionic carbon atom of the ring at the
carbon atom of the carboxylic group with the formation of
bicyclic acetal; b and c—replacement of the lithium atom
by a hydrogen with the formation of monobromide. If the
quenching of the reaction mixture with methanol proceeds
faster than transformation of the lithium carbenoid (the reac-
tion proceeds at low temperature; R1¼CO2Et, CH2OCOR),
a stereoisomeric mixture of monobromides is formed (reac-
tions b and c). If the transformation of the lithium carbenoid
proceeds faster than quenching of the reaction mixture with
methanol (the reaction proceeds at higher temperature;
R1¼H, Alk, CH2OCOR), a corresponding cyclisation prod-
uct is formed (reaction a). In case R1¼CO2Et the same car-
benoid is formed at the first step but due to its unstability the
yields of corresponding cyclisation product are low and
polymer products are formed. This scheme explains also
the predominated formation of carbenoid 13 and both the
stereochemistry of cyclisation and reduction of one of the
bromine atoms in the initial dibromide (preferentially cis-
H substitution to acyloxymethyl group).
Br
Br
R
R1
R1
Br
R
MeLi / BuLi
Et2O
O
O
HO
O
R1
R
Yielda (%) R1
R
Yield (%)
21
H
H
H
H
H
Me
n-Pr
CF3
Ph
55
46
90
64
CO2Et
Me
n-Pr 10
i-Pr
Ph
Ph
Me
Pr
CO2Et
CO2Et
CO2Et
CO2Me
CH2OH
CH2OH
CH2OH
10
6b
3b
69
–CH]CH2 39
Me Me
Me n-Pr
Me Ph
60
74
82
51
Me
21c
37c
Me –CH]CH2 68
CH2OCOMe Me
Me i-Pr
Me t-Bu
80
81
a
Data from Ref. 12.
b
As a mixture from ethyl 2,2-dibromo-1-(phenylcarbonyloxymethyl)-
cyclopropane-1-carboxylic acid (8d).
As a mixture from 1,1-di(acetoxymethyl)-2,2-dibromocyclopropane (8f).
c
prepared from hemiacetal 11a (Scheme 9). Tandem transfor-
mation of 1-acyloxymethyl-2,2-dibromocyclopropanes to 2-
keto-2-bromocyclopropane-1-carboxylates can therefore be
successfully used in the synthesis of various 1,2,3,4-tetra-
substituted cyclopropanes.
Table 1 summarises data on the influence of substituents on
the cyclisation products’ yields, both from the literature12
and found in this work. The yield of cyclisation products
strongly depends on the substituent and decreases in the or-
der R1¼MeꢃHꢃCH2OCOR>CO2Et. This suggests that the
carboxylate group and acyloxymethyl group more strongly
promote substitution of the cis-bromine by lithium with
formation of carbenoid, which cannot in the former case
rearrange to bicycle.
Br
Me
R
i
11a, f
CO2Me
O
13 R = CO2Me, 31%
14 R = CO2Et, 38%
Scheme 9. Reagents and conditions: (i) (a) H5IO6, RuCl3, (b) CH2N2.
Some applications of the products of cyclisation were exam-
ined. Oxidative ring opening of 11f using periodic acid and
catalytic ruthenium trichloride gave the corresponding 2-
acetyl-2-bromocyclopropane-1,1-dicarboxylic acid, which
was isolated as methyl ester 13 (Scheme 9). The 13C NMR
spectrum of the product showed the expected signal for the
ester carbonyl group in the region of 166 ppm and the ketone
at 198 ppm. By an analogous process, cyclopropane 14 was
3. Conclusion
Two new synthetic blocks, dialkyl 2,2-dibromocyclo-
propane-1,1-dicarboxylates and 2,2-dibromo-1-hydroxy-
methylcyclopropane-1-carboxylates, were used for synthesis
of cyclopropanes containing three C substituents. Reaction

M. S. Baird et al. / Tetrahedron 63 (2007) 7717–7726
7721
of 1-acyloxymethyl-2,2-dibromocyclopropanes with alkyl
lithium is sensitive to the substituents on the ring.
was added to a stirred solution of ethyl a-(hydroxymethyl)-
acrylate 216 (3.13 g, 24 mmol) and 2-methoxy-1-propene
(6.9 mL, 72 mmol) in dry ether at below 0 ꢁC. After 1 h, so-
dium bicarbonate (1 g) was added and the mixture was
stirred for 10 min, filtered and washed with ether. The sol-
vent was removed and residue was distilled under vacuum
giving ether 3a (3.44 g, 70%), bp 74–84 ꢁC (1 mmHg). IR
(CHCl3) 851, 950, 1054 s, 1084 s, 1153 s, 1214, 1273,
4. Experimental
4.1. General methods
1
Infrared spectra were obtained as KBr discs or as liquid films
on a Perkin–Elmer 1600 FTIR spectrometer or for 2% solu-
tions in chloroform on a Carl Zeiss UR-20 spectrometer and
data are given in cmꢀ1. Melting points were determined on
a Boetius instrument or a Gallenkamp melting point appara-
1303, 1381, 1460, 1640, 1718 v.s, 2829, 2992 s smꢀ1; H
NMR (250 MHz, CDCl3) d 1.31 (3H, t, J¼7.0 Hz, CH3),
1.39 (6H, s, CH3), 3.20 (3H, s, CH3), 4.16 (2H, m, CH2),
4.22 (2H, q, J¼7.0 Hz, CH2), 5.89 (1H, d, J¼1.6 Hz,
CH2), 6.26 (1H, d, J¼1.6 Hz, CH2); 13C NMR (62.9 MHz,
CDCl3) d 14.3 (CH3), 24.4 (CH3), 48.6 (CH3), 59.2 (CH2),
60.6 (CH2), 100.3 (C), 124.8 (CH2), 138.0 (C), 166.0
(C]O); MS (ESI) m/z: 225 (M++Na). Anal. Calcd for
C10H18O4: C, 59.39; H, 8.97. Found: C, 59.2; H, 8.9.
1
tus and are uncorrected. H and 13C NMR spectra were
recorded in CDCl3 or DMSO-d6 as solvent using a Bruker
1
AC250 (250 and 62.9 MHz for H and 13C, respectively),
Bruker DPX-300 (300 and 75 MHz), or a Bruker Avance500
(500 and 125 MHz). Elemental analyses were performed on
a Hewlett-Packard 185B apparatus or on a Carlo Erba Model
1106 CHN analyser. Low-resolution mass spectra were mea-
sured using electron impact (EI) at 70 eVon a Finnigan MAT
8340 spectrometer. The X-ray diffraction data were mea-
sured with a Hilger and Watts (Y290) diffractometer. Reac-
tions were monitored by TLC analysis using silica gel 60 F254
thin layer plates. Organic solutions were dried over anhy-
drous magnesium sulfate.
4.2.4. Ethyl 2-(tetrahydropyran-2-yloxymethyl)acrylate
(3b). 3,4-Dihydro-2H-pyran (3.2 g, 3.4 mL, 40.0 mmol)
was added to a stirred solution of ethyl a-(hydroxymethyl)
acrylate 2 (2.2 g, 15.0 mmol) in dry dichloromethane and
PPTS (0.2 g, 0.8 mmol) at 0 ꢁC. The mixture was stirred
for 12 h, then quenched with satd aq sodium bicarbonate
(10 mL) and extracted with dichloromethane (3ꢄ20 mL).
The combined organic layers were dried, filtered and the
solvent evaporated in vacuo to give the crude product as
a pale yellow liquid. Chromatography on silica gel eluting
with petrol–ether (5:3) gave a colourless liquid, ester (3b)
(2.78 g, 13.1 mmol, 53%). IR (CHCl3) 817, 870, 907, 979,
1037 s, 1068, 1122 s, 1180, 1202, 1271, 1325, 1387, 1455,
4.2. Experimental procedures
4.2.1. Di-tert-butyl 2,2-dibromocyclopropane-1,1-dicarb-
oxylate (1a). Di-tert-butyl methylenemalonate15 (0.5 g,
2.2 mmol), bromoform (0.3 mL, 3.4 mmol), TEBA (0.05 g)
and dichloromethane (4 mL) were put in a flask equipped
with a magnetic stirrer and thermometer. A 50% solution
of sodium hydroxide (0.26 g) was added dropwise with cool-
ing in an ice-salt bath (T<5 ꢁC). The mixture was stirred for
12 h at ambient temperature and quenched with water.
The organic layer was separated and washed with water.
The aqueous layer was extracted with dichloromethane. The
combined organic layers were dried. The solvent was re-
moved and the residue was crystallised from hexane giving
ester 1a as a colourless solid (0.24 g, 27%), mp 94–96 ꢁC;
IR (CHCl3) 1130, 1170, 1340, 1370, 1740 v.s, 2980,
1
1638, 1724 s, 2872, 2943 s cmꢀ1; H NMR (500 MHz,
CDCl3) d 1.31 (3H, t, J¼7.2 Hz, CH3), 1.85–1.51 (6H, m,
CH2), 3.54 (1H, br dt, J¼11.4, 4.4 Hz, OCH2), 3.89 (1H, ddd,
J¼11.4, 8.8, 2.9 Hz, OCH2), 4.20 (1H, dt, J¼14.2, 1.4 Hz,
OCH2), 4.23 (2H, q, J¼7.2 Hz, CH2), 4.46 (1H, dt, J¼14.2,
1.6 Hz, OCH2), 4.70 (1H, t, J¼3.5 Hz, OCHO), 5.89 (1H,
br d, J¼1.6 Hz, ]CH2), 6.30 (1H, br d, J¼1.6 Hz, ]CH2);
13C NMR (125 MHz, CDCl3) d 14.2 (CH3), 19.2 (CH2),
25.4 (CH2), 30.5 (CH2), 60.6 (CH2), 62.0 (CH2), 65.3
(CH2), 98.2 (CH), 125.4 (CH2), 137.5 (C), 165.8 (C]O).
ESI-MS: 237 (M++Na), 68 (M+ꢀOTHP, OEt). Anal. Calcd
for C11H18O4: C, 61.66; H, 8.47. Found: C, 62.0; H, 8.4.
1
3050 cmꢀ1; H NMR (300 MHz, CDCl3) d 1.52 (18H, s,
SO3), 2.32 (2O, s, SO2); 13C NMR (75 MHz, CDCl3)
d 23.3 (S), 28.3 (SO3), 32.6 (SO2), 44.4 (S), 83.9 (S),
163.9 (S]O). Anal. Calcd for C13H20Br2O4: C, 39.03; H,
5.04. Found: C, 38.9; H, 5.1.
4.2.5. Ethyl 2,2-dibromo-1-(1-methoxy-1-methylethoxy-
methyl)cyclopropane-1-carboxylate (4a). Ester 3a (30.0 g,
0.148 mol), bromoform (75.1 g, 26.6 mL, 0.30 mol), cetri-
mide (2.5 g), triethylamine (20 drops) and dichloromethane
(50 mL) were stirred and sodium hydroxide (95.0 g) in water
(95.0 mL) was added dropwise with cooling in an ice-salt
bath. The mixture was stirred vigorously for 20 h at ambient
temperature. The layers were separated and the aqueous
layer was extracted with dichloromethane (3ꢄ50 mL). The
combined organic layers were washed with brine (50 mL),
dried and evaporated under reduced pressure. To the residue
was added the same volume of hexane; after stirring for
15 min the mixture was filtered. Removing the solvent
gave cyclopropane 4a (52.9 g, 95%). IR (CHCl3) 858,
1024 s, 1096, 1156 s, 1180 s, 1223 s, 1266 s, 1326, 1371,
4.2.2. 2,2-Dibromocyclopropane-1,1-dicarboxylic acid
(1b). Ester 1a (0.4 g, 1 mmol) and trifluoroacetic acid
(0.5 mL) were allowed to stand for 1 h at ambient tempera-
ture. The product was filtered and washed with hexane to
give acid 1b as a colourless solid (0.29 g, 99%), mp 180–
183 ꢁC; IR (CHCl3) 690 s, 770, 790, 900 s, 1040, 1160,
1250 s, 1300 s, 1410 s, 1680 v.s, 1720 v.s, 3000 br s smꢀ1
;
1H NMR (300 MHz, DMSO) d 2.31 (2O, s, SO2), 10.43
(2O, br s, PO); 13C NMR (300 MHz, DMSO) d 23.8 (S),
32.6 (SO2), 43.8 (S), 166.5 (S]O). Anal. Calcd for
C5H4Br2O4: C, 20.86; H, 1.40. Found: C, 20.8; H, 1.4.
1
1444, 1465, 1730 v.s, 2981, 3088, 3428 br smꢀ1; H NMR
(250 MHz, CDCl3) d 1.34 (3H, t, J¼7.0 Hz, CH3), 1.84
(1H, d, J¼8.2 Hz, CH2), 2.17 (6H, s, CH3), 2.45 (1H, d,
J¼8.2 Hz, CH2), 3.49 (3H, s, CH3), 3.97 (1H, d,
4.2.3. Ethyl 1-(1-methoxy-1-methyl-ethoxymethyl)acryl-
ate (3a). Pyridinium-p-toluene sulphonate (PPTS) (7 mg)

7722
M. S. Baird et al. / Tetrahedron 63 (2007) 7717–7726
J¼12.2 Hz, CH2), 4.07 (1H, d, J¼12.2 Hz, CH2), 4.29 (1H,
q, J¼7.0 Hz, CH2), 4.30 (1H, q, J¼7.0 Hz, CH2); 13C NMR
(62.9 MHz, CDCl3) d 15.7 (CH3), 26.8 (CBr2), 32.3 (CH2),
32.4 (CH3), 40.9 (C), 52.4 (CH3), 63.9 (CH2), 67.7 (CH2),
142.5 (C), 170.0 (C]O); MS m/z: M+ (not observed), 130,
113, 101, 85, 73, 53.
0.99 mL, 1.0 M, 0.99 mmol) was added slowly to a stirred
solution of the dibromide 4b (76.0 mg, 0.19 mmol) in dry di-
chloromethane at ꢀ78 ꢁC under argon. The mixture was
allowed to reach room temperature for 2 h. TLC and GLC
showed starting material was still present. The mixture
was stirred for a further 10 h and then quenched with satd
aq sodium bicarbonate (1 mL) and extracted with dichloro-
methane (3ꢄ10 mL). The combined organic layers were
dried and evaporated in vacuo to give a light brown solid.
This was purified by chromatography on silica gel eluting
with petrol–ethyl acetate (1: 1) to give a colourless liquid al-
cohol 5b as a mixture of diastereomers (32.5 mg, 0.1 mmol,
48%). IR (CHCl3) 688, 868, 904, 1032 s, 1062, 1122, 1201,
4.2.6. Ethyl 2,2-dibromo-1-(tetrahydropyran-2-yloxy-
methyl)cyclopropane carboxylate (4b). Sodium hydroxide
solution (4.2 g in 4.2 mL water) was added slowly to a rap-
idly stirred solution of the ester 3b (2.24 g, 10.5 mmol), tri-
ethylamine (0.25 mL), bromoform (3.96 g, 15.7 mmol) and
TEBACl (0.2 g, 1.1 mmol) in dichloromethane (25 mL) at
0 ꢁC. The mixture was allowed to reach room temperature,
stirred for 6 h, monitored by GLC and TLC, then cooled to
0 ꢁC, water (2 mL) and dichloromethane (20 mL) were
added. The organic layer was separated and washed with
brine (3ꢄ20 mL). The combined organic layers were dried,
filtered and evaporated in vacuo to give a dark brown oil.
Chromatography on silica eluting with petrol–ether (5:2)
gave a colourless liquid, bromide (4b) (0.98 g, 2.52 mmol,
79%) as a mixture of diastereomers. IR (CHCl3) 682, 816,
871, 904, 1029 s, 1067, 1183, 1260, 1351, 1442, 1454,
1
1353, 1385, 1440, 1455, 2871, 2943 s, 3406 br s cmꢀ1; H
NMR (500 MHz, CDCl3) d 1.60 (1H, d, J¼7.6 Hz, CH2),
1.64–1.55 (2H, m, CH2), 1.65 (1H, d, J¼7.8 Hz, CH2),
1.69* (1H, d, J¼7.6 Hz, CH2), 1.90–1.74 (2H, m, CH2), 2.96
(2H, quintet, J¼6.9 Hz, CH2), 3.59–3.54 (2H, m, CH2), 3.69
(1H, d, J¼10.7 Hz, OCH2), 3.78* (1H, dd, J¼12.0, 7.2 Hz,
CH2), 3.83 (1H, d, J¼10.7 Hz, OCH2), 3.90 (1H, m, CH2),
4.01 (1H, m, CH2), 4.08* (1H, d, J¼10.7 Hz, OCH2), 4.14
(1H, dd, J¼12.0, 6.3 Hz, CH2), 4.23* (1H, d, J¼10.7 Hz,
OCH2), 4.66* (1H, dd, J¼5.3, 2.4 Hz, OCHO), 4.69 (1H,
dd, J¼4.6, 3.0 Hz, OCHO); 13C NMR (125 MHz, CDCl3)
d 19.6 (CH2), 19.9* (CH2), 25.1 (CH2), 25.2 (CH2), 30.5*
(CH2), 30.6* (CH2), 30.6 (CH2), 31.8* (C), 31.9 (C), 33.7
(C), 34.0* (C), 62.9* (CH2), 63.2 (CH2), 66.9 (CH2),
67.0* (CH2), 71.4 (CH2), 71.5* (CH2), 99.4 (CH), 99.8*
1
1466, 1740 s, 2873, 2943 s cmꢀ1; H NMR (500 MHz,
CDCl3, minor diastereomer was marked by asterisk *)
d 1.33 (3H, t, J¼7.3 Hz, CH3), 1.35* (3H, t, J¼7.3 Hz, CH3),
1.84–1.52 (6H, m, CH2), 1.93 (1H, dd, J¼9.9, 8.8 Hz, CH2),
2.47 (1H, ddd, J¼7.9, 4.6, 1.3 Hz, CH2), 3.46 (1H, d, J¼
10.7 Hz, CH2), 3.68 (1H, d, J¼10.4 Hz, CH2), 3.82 (1H, t,
J¼11.4 Hz, CH), 3.83* (1H, t, J¼11.4 Hz, CH), 4.34–4.24
(2H, m, CH2), 4.40 (1H, dd, J¼10.7, 1.3 Hz, CH2), 4.62
(1H, dd, J¼10.7, 1.3 Hz, CH2), 4.64* (1H, t, J¼3.8 Hz,
OCHO), 4.70 (1H, t, J¼3.2 Hz, OCHO); 13C NMR
(125 MHz, CDCl3) d 14.1* (SO3), 14.3 (SO3), 18.7*
(CH2), 19.2 (CH2), 24.9 (C), 25.3 (CH2), 30.2* (CH2),
30.4 (CH2), 30.7 (CH2), 31.0* (CH2), 38.5 (C), 38.8* (C),
61.6* (CH2), 62.0 (CH2), 62.1 (CH2), 62.2* (CH2), 69.6
(CH2), 71.3* (CH2), 97.8 (CH), 99.5* (CH), 167.7 (C]O),
167.8* (C]O). ESI-MS: 409 (M++Na). Anal. Calcd for
C12H18Br2O4: C, 37.33; H, 4.70. Found C, 37.6; H, 4.8.
(CH). ESI-MS: 364.9, 366.9, 368.8 (M++Na); HRMS calcd
12
for
C
10
1H1679Br216O3 (M+) 341.9466, found: 341.9466.
4.2.9. 1-Bromo-2,2-dihydroxymethylcyclopropane (6).
An ethereal solution of lithium aluminium hydride (4 mL,
2.9 mmol) was added dropwise with stirring and cooling in
an ice bath to the ester 1c (0.3 g, 1.0 mmol) in ether
(15 mL). The mixture was stirred for 1 h, and then the excess
of lithium aluminium hydride was quenched by addition of
water (0.1 mL), 15% aq sodium hydroxide (0.3 mL) and
water (0.3 mL). The mixture was stirred for 30 min, the pre-
cipitate was filtered off and the solution was dried. Remov-
ing the solvent gave diol 6 as a colourless solid (0.12 g,
69%), mp 52–54 ꢁC. IR (CHCl3) 1130 s, 1150 s, 1260,
4.2.7. Ethyl 2,2-dibromo-1-hydroxymethylcyclopropane-
1-carboxylate (5a). p-Toluenesulfonic acid (0.4 g) was
added to a solution of cyclopropane 4a in aq methanol
(12 mL of water and 60 mL of methanol) and stirred for
30 min. Sodium bicarbonate (1 g) was added and the mixture
was stirred for another 10 min, filtered and the organic layer
was dried and evaporated under reduced pressure. The resi-
due was distilled under vacuum giving ester 5a (30.2 g,
67%), bp 150 ꢁC (0.3 mmHg). IR (CHCl3) 688 s, 858, 1024
s, 1157, 1181 s, 1222, 1268 s, 1329, 1371, 1422, 1464,
1
1320, 1380, 1420, 2890, 2950, 3040, 3610 br s smꢀ1; H
NMR (300 MHz, CDCl3) d 0.93 (1O, dd, J¼6.6, 4.4 Hz,
SO2), 1.22 (1O, dd, J¼7.5, 6.6 Hz, SO2), 2.40 (2O, s,
PO), 3.10 (1O, dd, J¼7.5, 4.4 Hz, SO), 3.60 (1O, d,
J¼9.5 Hz, SO2), 3.77 (1O, d, J¼9.5 Hz, SO2), 3.83 (1O,
d, J¼11.9 Hz, SO2), 4.12 (1O, d, J¼11.9 Hz, SO2); 13C
NMR (75 MHz, CDCl3) d 18.6 (CH2), 25.0 (CH), 28.9
(C), 66.4 (CH2), 66.6 (CH2). Anal. Calcd for C5H9BrO2:
C, 33.17; H, 5.01. Found: C, 33.3; H, 5.2.
1
1731 v.s, 2903, 2980 s, 3089, 3442 br s smꢀ1; H NMR
(500 MHz, CDCl3) d 1.27 (3H, t, J¼7.2 Hz, CH3), 1.77
(1H, d, J¼7.9 Hz, CH2), 2.18 (1H, s, OH), 2.38 (1H, d,
J¼7.9 Hz, CH2), 3.90 (1H, d, J¼12.2 Hz, CH2), 4.01 (1H,
d, J¼12.2 Hz, CH2), 4.22 (1H, dq, J¼10.8, 7.2 Hz, CH2),
4.24 (1H, dq, J¼10.8, 7.2 Hz, CH2); 13C NMR (125 MHz,
CDCl3) d 14.2 (CH3), 25.4 (C), 30.8 (CH2), 39.4 (C), 62.4
(CH2), 66.2 (CH2), 168.5 (C]O). Anal. Calcd for
C7H10Br2O3: C, 27.84; H, 3.34. Found: C, 27.6; H 3.3.
4.2.10. 1,1-Dibromo-2,2-di(hydroxymethyl)cyclopropane
(7). From ester 5a. A solution of aluminium chloride (4.86 g,
36.4 mmol) in ether (15 mL) was added dropwise with stir-
ring and cooling in an ice bath to lithium aluminium hydride
(1.52 g, 40.1 mmol) and dry ether (15 mL), followed by the
ester 5 (5.5 g, 18.2 mmol) in ether (10 mL). The mixture was
stirred for 70 min, then the excess of lithium aluminium
hydride was quenched by addition of water (1 mL), 15% aq
sodium hydroxide (1 mL) and water (2 mL). The precipitate
was filtered off, more water (5 mL) was added and the prod-
uct was extracted with ether. The combined solution was
4.2.8. 2,2-Dibromo-1-(tetrahydropyran-2-yloxymethyl)-
cyclopropylmethanol (5b). DIBAL in hexane (1.42 g,

M. S. Baird et al. / Tetrahedron 63 (2007) 7717–7726
7723
dried; the solvent removed to give diol 717 as a colourless
(0.63 mL, 6.0 mmol) in pyridine. IR (CHCl3) 696, 995 s,
1044, 1090 s, 1172 v.s, 1253 s, 1303, 1382, 1461, 1740 v.s,
solid (3.0 g, 63%), mp 96–98 ꢁC. IR (CHCl3) 1040 s, 1060
s, 1240, 1380, 1420, 2890, 2960, 3040, 3610 br s smꢀ1
;
2875, 2965 s smꢀ1; H NMR (250 MHz, CDCl3) d 0.96
1
1H NMR (300 MHz, CDCl3) d 1.64 (2O, s, SO2), 2.44
(2O, s, PO), 3.94 (2O, d, J¼11.6 Hz, SO2), 4.13 (2O, d,
J¼11.6 Hz, SO2); 13C NMR (75 MHz, CDCl3) d 30.8
(SO2), 32.2 (S), 35.7 (S), 68.3 (SO2). Anal. Calcd for
C5H8Br2O2: C, 23.10; H, 3.10. Found: C, 23.4; H, 3.2.
(6H, t, J¼7.3 Hz, CH3), 1.68 (4H, sextet, J¼7.3 Hz, CH2),
1.75 (2H, s, CH2), 2.35 (4H, t, J¼7.3 Hz, CH2), 4.25 (2H,
d, J¼11.9 Hz, CH2), 4.42 (2H, d, J¼11.9 Hz, CH2); 13C
NMR (62.9 MHz, CDCl3) d 13.6 (CH3), 18.4 (CH2), 29.5
(C), 30.8 (CH2), 30.9 (C), 65.9 (CH2), 173.2 (C]O); MS
(EI) m/z (%): 400 (1.5) [M+], 146 (14), 145 (15), 144 (67),
From alcohol 5b. Methanol (10 mL), PTSA (10 mg) and
the alcohol 5b (20 mg, 0.06 mmol) were stirred at 50 ꢁC
for 6 h giving a crude product. Methanol was evaporated
and the residue purified by column chromatography elution
with petrol–ethyl acetate (1: 1) to give diol 7 (15 mg,
0.06 mmol, 98%). TLC, GLC and NMR of the crude product
were identical to those above.
143 (14), 71 (100), 66 (11), 65 (24). HRMS calcd for
1H2179Br216O4 (M++H) 398.9807, found 398.9790;
12
C
calcd for
13
12
C
1H2179Br81Br16O4 (M++H) 400.9786, found
13
12
400.9798; calcd for
found 402.9766.
C
13
1H2181Br216O4 (M++H) 402.9766,
4.2.13. 1,1-Di(acetoxymethyl)-2,2-dibromocyclopropane
(8f). Acetyl chloride (1.54 g, 19.6 mmol) was added drop-
wise to a solution of diol 7 (1.70 g, 6.5 mmol) in pyridine
(15 mL) (T<5 ꢁC). The ice bath was removed and the mix-
ture was stirred for 6 h. The excess of acetyl chloride was
quenched with water (0.5 mL). The mixture was dried, evap-
orated under reduced pressure and the product was extracted
with hexane (3ꢄ30 mL). The organic layer was washed in
turn with 5% sulfuric acid (10 mL), water (10 mL), 5% aq
sodium hydroxide (10 mL), then brine (10 mL) and dried.
Removal of the solvent gave ester 8f (1.66 g, 73%, Rf 0.45,
4:1 hexane–ethyl acetate). IR (CHCl3) 990, 1050, 1270,
From ester 1c. Dry aluminium chloride (0.17 g, 1.3 mmol) in
ether (8 mL) was added dropwise to a stirred suspension of
lithium aluminium hydride (1.55 mL, 1.4 mmol) in ether
(5 mL). The mixture was cooled in an ice bath and ester
1c (0.2 g, 0.64 mmol) in ether (10 mL) was added dropwise
and stirred for 1 h. The excess of lithium aluminium hydride
was quenched by the addition of water (five drops), 15% aq
sodium hydroxide (five drops), water (15 drops) and stirred
for another 20 min. The precipitate was filtered off, and the
resulting solution was dried and evaporated to give a residue
(157 mg), containing 65% of diol 7. It was difficult to sepa-
rate the product from impurities; however, the crude material
could be acylated and the resulting ester purified.
1
1370, 1440, 1470, 1750 v.s, 2970, 3050 smꢀ1; H NMR
(250 MHz, CDCl3) d 1.76 (2O, s, SO2), 2.13 (6O, s,
SO3), 4.24 (2O, d, J¼11.7 Hz, SO2), 4.43 (2O, d,
J¼11.7 Hz, SO2); 13C NMR (62.9 MHz, CDCl3) d 21.2
(CH3), 29.9 (S), 31.2 (SO2), 66.4 (SO2), 171.0 (S]O);
MS (EI) m/z (%): 344 (1) [M+], 244 (23), 242 (27), 240
(23), 212 (20), 205 (20), 203 (23), 162 (25), 161 (25), 160
(24), 133 (27), 131 (21), 117 (29), 116 (100), 115 (58), 99
(44), 98 (36), 81 (52), 74 (61). Anal. Calcd for
C9H12Br2O4: C, 31.42; H, 3.53. Found: C, 31.6; H, 3.5.
4.2.11. Ethyl 2,2-dibromo-1-acetoxymethylcyclopro-
pane-1-carboxylate (8a). Acetyl chloride (1.65 mL,
23.2 mmol) was added dropwise to a solution of ester 5a
(3.5 g, 11.6 mmol) in pyridine (30 mL) and cooled in an
ice bath (T<5 ꢁC). The ice bath was removed and the mixture
was stirred for 6 h. The excess of acetyl chloride was
quenched with water. The mixture was dried, the solvent
was removed under reduced pressure and the product was ex-
tracted with hexane (3ꢄ30 mL). The organic layer was then
washed in turn with 10% hydrochloric acid (20 mL), water
(20 mL), 10% aq sodium hydroxide (20 mL), then brine
(20 mL) and dried. Removal of the solvent gave crude prod-
uct (3.44 g), which was then columned using silica to give
pure ester 8a (2.45 g, 62%, Rf 0.60, 4:1 hexane–ethyl ace-
tate). IR (CHCl3) 1040, 1260 s, 1380, 1740 v.s, 2980,
4.2.14. Ethyl 2-bromo-1-acetoxymethylcyclopropane-1-
carboxylate (9) and ethyl 2-bromo-1-hydroxymethyl-
cyclopropane-1-carboxylate (10). An ethereal solution of
methyl lithium (0.60 mL, 0.9 mmol) was added dropwise
at ꢀ100 to ꢀ109 ꢁC to ester 8a (0.21 g, 0.6 mmol) in dry tet-
rahydrofuran (10 mL). The mixture was stirred for another
30 min at the same temperature and the excess of methyl
lithium was quenched with water (1 mL). The layers were
separated and the product was extracted twice from the
aqueous layer with dichloromethane. The combined organic
phase was washed with brine and dried. Removing the sol-
vent gave crude material (0.127 g, 76%, mixture of 9 and
10 in ratio 61:39, respectively), which was then columned
over silica eluting with petrol–ether (3:2) to afford com-
pounds 9 (41.6 mg, 23%) as a mixture of cis- and trans-
isomers (ratio 3:1, Rf 0.63) and 10 (22.5 mg, 15%, Rf 0.24)
as a single isomer.
1
3030 smꢀ1; H NMR (500 MHz, CDCl3) d 1.34 (3O, t,
J¼7.3 Hz, SO3), 1.94 (1O, d, J¼8.2 Hz, SO2), 2.08 (3O,
s, SO3), 2.48 (1O, d, J¼8.2 Hz, SO2), 4.30 (2O, q,
J¼7.3 Hz, SO2), 4.31 (1O, d, J¼11.6 Hz, SO2), 4.84 (1O,
d, J¼11.6 Hz, SO2); 13C NMR (125 MHz, CDCl3) d 14.6
(SO3), 21.1 (SO3), 25.0 (S), 31.3 (SO2), 38.1 (S), 62.8
(SO2), 67.3 (SO2), 167.5 (S]O), 170.8 (S]O); MS (EI)
m/z (%): 345 (0.5) [M+], 211 (16), 205 (76), 203 (69), 177
(92), 175 (100), 158 (42), 149 (56), 147 (46), 121 (17), 119
(25), 116 (43), 113 (59), 85 (22). HRMS calcd for
1
12C9 H1279Br216O4 341.9102, found 341.9127. Anal. Calcd
4.2.14.1. Compound cis-9. IR (CHCl3) 860, 940, 983,
1033, 1095, 1159, 1181, 1233 s, 1314, 1339, 1370, 1446,
for C9H12Br2O4: C, 31.42; H, 3.53. Found: C, 31.6; H, 3.5.
1738 s, 2934, 2982 smꢀ1 1H NMR (500 MHz, CDCl3)
;
4.2.12. 1,1-Dibromo-2,2-di(butyryloxymethyl)cyclopro-
pane (8e). Compound 8e (0.69 g, 85%, Rf 0.61, 4:1 hex-
ane–ethyl acetate) was prepared in an analogous manner
from diol 7 (0.53 g, 2.0 mmol) and butyryl chloride
d 1.31 (3H, t, J¼7.0 Hz, CH3), 1.51 (1H, dd, J¼7.8,
6.9 Hz, CH2), 1.89 (1H, dd, J¼6.9, 5.7 Hz, CH2), 2.06
(3H, s, CH3), 3.16 (1H, dd, J¼7.8, 5.7 Hz, CH), 3.99 (1H,
d, J¼12.0 Hz, CH2), 4.26 (2H, q, J¼7.0 Hz, CH2), 4.61

7724
M. S. Baird et al. / Tetrahedron 63 (2007) 7717–7726
(1H, d, J¼12.0 Hz, CH2); 13S NMR (125 MHz, CDCl3)
d 14.3 (CH3), 19.9 (CH2), 20.8 (CH3), 22.3 (CH), 25.4 (C),
61.8 (CH2), 65.1 (CH2), 168.4 (C]O), 170.7 (C]O).
methyl lithium was quenched with methanol (10 mL) and
hexane (20 mL) was added. Work up as abovegave crude ma-
terial (0.63 g), which was columned over silica eluting with
2:1 petrol–ethyl acetate to give ester 11b (0.20 g, 10%, Rf
0.66), mp 79–80 ꢁC. IR (CHCl3) 858, 898, 914, 945, 1016,
1046, 1060, 1096, 1129, 1161, 1187, 1246, 1278, 1304,
1324, 1352, 1384, 1408, 1432, 1453, 1708 v.s, 2870, 2890,
4.2.14.2. Compound trans-9. 1H NMR (500 MHz,
CDCl3) d 1.27 (3H, t, J¼7.0 Hz, CH3), 1.89 (1H, dd,
J¼6.9, 5.7 Hz, CH2), 2.08 (3H, s, CH3), 3.60 (1H, dd,
J¼7.8, 5.7 Hz, CH), 4.17 (2H, q, J¼7.0 Hz, CH2), 4.42
(1H, d, J¼12.0 Hz, CH2), 4.59 (1H, d, J¼12.0 Hz, CH2).
2920, 2930, 2958, 3431 cmꢀ1
;
1H NMR (250 MHz,
CDCl3) d 0.75 (3H, t, J¼7.0 Hz, CH3), 1.29 (1H, d,
J¼6.0 Hz, CH2), 1.31–1.39 (2H, m, CH2), 1.45ꢀ1.52 (2H,
m, CH2), 1.63–1.70 (2H, m, CH2), 1.74 (1H, d, J¼6.3 Hz,
CH2), 2.56 (1H, s, OH), 3.58 (3H, s, CH3), 3.62 (1H, d,
J¼8.8 Hz, CH2), 4.30 (1H, d, J¼8.8 Hz, CH2); 13S NMR
(62.9 MHz, CDCl3) d 12.0 (CH3), 14.3 (CH2), 21.7 (CH2),
32.6 (C), 35.4 (CH2), 44.3 (C), 50.2 (CH3), 63.9 (CH2),
102.6 (C), 165.9 (C]O). Anal. Calcd for C10H15BrO4: C,
43.03; H, 5.42. Found: C, 43.2; H, 5.5.
1
4.2.14.3. Compound 10. H NMR (250 MHz, CDCl3)
d 1.34 (3H, t, J¼7.0 Hz, CH3), 1.44 (1H, dd, J¼7.6,
7.0 Hz, CH2), 1.87 (1H, dd, J¼7.0, 5.8 Hz, CH2), 2.60
(1H, s, OH), 3.21 (1H, dd, J¼7.6, 5.8 Hz, CH), 3.57 (1H,
d, J¼12.2 Hz, CH2), 3.85 (1H, d, J¼12.2 Hz, CH2), 4.28
(1H, q, J¼7.0 Hz, CH2), 4.29 (1H, q, J¼7.0 Hz, CH2); 13
S
NMR (62.9 MHz, CDCl3) d 14.3 (CH3), 20.3 (CH2), 22.3
(CH), 32.8 (C), 61.7 (CH2), 65.2 (CH2), 170.4 (C]O).
HRMS calcd for 12C7 H1079Br16O2 (M+ꢀOH) 204.9864,
4.2.17. 1-Bromo-5-hydroxymethyl-2-methyl-3-oxabi-
cyclo[3.1.0]hexane-2-ol (11f) and 1-acetoxy-methyl-5-
bromo-4-methyl-3-oxabicyclo[3.1.0]hexane-4-ol (11h).
An ethereal solution of methyl lithium (5.48 mL, 8.2 mmol)
was added dropwise at ꢀ105 ꢁC to ꢀ90 ꢁC to ester 8f (2.18 g,
6.3 mmol) in dry ether (20 mL). The cooling bath was re-
moved immediately; the temperaturewas allowed to increase
to 0 ꢁC for another 20 min. The excess of methyl lithium was
quenched with satd aq ammonium chloride (4 mL). The or-
ganic layer was separated; the product was extracted with
ether (20 mL) and dried. Removing the solvent gave crude
material (1.64 g), which was then columned over silica
eluting with petrol–ethyl acetate (2:1) to afford compounds
11f (0.29 g, 21%) and 11h (0.61 g, 37%, Rf 0.24).
1
found 204.9878; calcd for 12C7 H1081Br16O2 (M+ꢀOH)
1
206.9844, found 206.9868.
4.2.15. Ethyl 5-bromo-4-hydroxy-4-methyl-3-oxabi-
cyclo[3.1.0]hexane-1-carboxylate (11a). Butyl lithium in
hexane (2.20 mL, 3.5 mmol) was added dropwise at
ꢀ100 ꢁC to ꢀ105 ꢁC to ester 8a (1.01 g, 2.9 mmol) in dry
ether (10 mL). The cooling bath was removed immediately;
the temperature was allowed to increase to 0 ꢁC for 20 min.
The excess of butyl lithium was quenched with methanol
(2 mL) and hexane (10 mL) was added. The layers were sep-
arated and the product was extracted three times with di-
chloromethane. The combined organic layer was dried and
evaporated to give crude material (0.440 g), which was col-
umned on silica eluting with petrol–ethyl acetate (2:1) to af-
ford compound 11a (180 mg, 21%, Rf 0.72). IR (CHCl3) 882,
947, 1018, 1044, 1077, 1182, 1274, 1321, 1381, 1445, 1723
4.2.17.1. Compound 11f. Mp 115–117 ꢁC. IR (CHCl3)
870, 897, 925, 996, 1044, 1056, 1071, 1159, 1214, 1326,
1366, 1421, 2863, 2942, 2974, 2994, 3361 smꢀ1; 1H NMR
(250 MHz, CDCl3) d 1.07 (1H, d, J¼6.0 Hz, CH2), 1.19
(1H, d, J¼6.0 Hz, CH2), 1.51 (3H, s, CH3), 2.89 (1H, s, OH),
3.74 (1H, d, J¼12.2 Hz, CH2), 3.78 (1H, d, J¼8.5 Hz, CH2),
3.98 (1H, s, OH), 4.07 (1H, d, J¼12.2 Hz, CH2), 4.28 (1H, d,
J¼8.5 Hz, CH2); 13S NMR (62.9 MHz, CDCl3) d 23.0
(CH3), 23.8 (CH2), 35.9 (C), 46.3 (C), 63.9 (CH2), 68.5
1
v.s, 2898, 2938, 2985, 3092, 3440 br s smꢀ1; H NMR
(500 MHz, CDCl3) d 1.31 (3H, t, J¼6.6 Hz, CH3), 1.43
(1H, d, J¼6.0 Hz, CH2), 1.53 (3H, s, CH3), 1.94 (1H, d,
J¼6.0 Hz, CH2), 3.04 (1H, s, OH), 3.84 (1H, d, J¼9.1 Hz,
CH2), 4.26 (1H, m, CH2), 4.51 (1H, d, J¼8.8 Hz, CH2);
13S NMR (125 MHz, CDCl3) d 14.2 (CH3), 21.7 (CH3),
23.8 (C), 33.4 (C), 46.7 (C), 61.6 (CH2), 66.2 (CH2), 103.9
(C), 167.7 (C]O); MS (EI) m/z (%): 265 (1) [M+], 219
(13), 206 (14), 185 (14), 178 (77), 177 (16), 176 (81), 175
(25), 173 (18), 141 (15), 139 (44), 113 (21), 111 (27), 97
(100), 95 (14), 86 (16), 69 (48). HRMS calcd for
(CH2), 105.0 (C). HRMS calcd for 12C7 H1079Br16O2 (M+ꢀ
1
OH) 204.9864, found 204.9850; calcd for 12C7 H1081Br16O2
1
(M+ꢀOH) 206.9844, found 206.9832. Anal. Calcd for
C7H11BrO3: C, 37.69; H, 4.97. Found: C, 37.9; H, 4.9.
12C9 H1379Br16O4 (M++Na) 286.9895, found 286.9871.
4.2.17.2. Compound 11h. Mp 59–62 ꢁC. IR (CHCl3)
860, 914, 951, 984, 1011, 1049, 1076, 1118, 1172, 1270,
1328, 1368, 1414, 1709 v.s, 2859, 2938, 2962, 2994, 3079,
1
An ethereal solution of methyl lithium (1.00 mL, 1.5 mmol)
was added dropwise at ꢀ95 ꢁC to ꢀ80 ꢁC to 8a (0.401 g,
1.2 mmol) in ether (10 mL). Work up as above gave crude
material (0.130 g), which was columned over silica eluting
with petrol–ethyl acetate (2:1) to afford compound 11a
(28 mg, 9%).
1
3406 smꢀ1; H NMR (500 MHz, CDCl3) d 1.27 (1H, d,
J¼6.3 Hz, CH2), 1.32 (1H, d, J¼6.3 Hz, CH2), 1.59 (3H,
s, CH3), 2.16 (3H, s, CH3), 2.97 (1H, s, OH), 3.88 (1H, d,
J¼8.8 Hz, CH2), 4.16 (1H, d, J¼8.8 Hz, CH2), 4.40 (1H,
d, J¼12.3 Hz, CH2), 4.44 (1H, d, J¼12.3 Hz, CH2); 13S
NMR (125 MHz, CDCl3) d 18.6 (CH3), 19.4 (CH3), 20.4
(CH2), 28.9 (C), 42.8 (C), 62.8 (CH2), 66.1 (CH2), 101.8
4.2.16. Methyl 5-bromo-4-hydroxy-4-propyl-3-oxabicy-
clo[3.1.0]hexane-1-carboxylate (11b). An ethereal solution
of methyl lithium (6.50 mL, 9.7 mmol) was added dropwise
at ꢀ100 ꢁC to ꢀ95 ꢁC to ester 8b (2.78 g, 7.5 mmol) in dry
ether (25 mL). The cooling bath was removed immediately,
the temperature was allowed to increase to 0 ꢁC and the mix-
ture was stirred at this temperature for 20 min. The excess of
(C), 168.9 (C]O). HRMS calcd for 12C9 H1481Br16O4
1
(M++H) 267.0055, found 267.0043. Anal. Calcd for
C9H13BrO4: C, 40.78; H, 4.94. Found: C, 40.7; H, 4.8.
An ethereal solution of methyl lithium (1.79 mL, 2.7 mmol)
was added dropwise at ꢀ100 ꢁC to ꢀ85 ꢁC to ester 8f

M. S. Baird et al. / Tetrahedron 63 (2007) 7717–7726
7725
(0.71 g, 2.1 mmol) in dry ether (10 mL). The cooling bath
was removed immediately; the temperature was allowed to
reach 0 ꢁC for 20 min. The excess of methyl lithium was
quenched by methanol (1 mL) and hexane (10 mL) was
added. Work up as before gave compound 11f (0.32 g,
69%, Rf 0.23, 4:1.5 hexane–ethyl acetate).
added to ester 11a (0.12 g, 0.4 mmol) in carbon tetrachloride
(3 mL) and acetonitrile (3 mL). The mixture was refluxed for
50 h and then water (10 mL) was added. The layers were
separated and the water layer was extracted with ether
(3ꢄ20 mL). The combined organic layer was washed with
water (20 mL), dried, concentrated to ca. 5 mL and a solution
of diazomethane in ether added (3 mL). The mixture was
stirred for 12 h and then evaporated. Chromatography on sil-
ica eluting with petrol–ethyl acetate (4:1) gave ester 14
(50 mg, 38%, Rf 0.55). IR (CHCl3) 858, 905, 979, 1012,
1065, 1125, 1240, 1286, 1360, 1437, 1732 v.s, 2849, 2907,
4.2.18. 1-Bromo-2-hydroxymethyl-2-(butyryloxyme-
thyl)cyclopropane (12). An ethereal solution of methyl lith-
ium (0.40 mL, 0.6 mmol) was added dropwise at ꢀ100 ꢁC to
ꢀ109 ꢁC to ester 8e (0.20 g, 0.5 mmol) in tetrahydrofuran
(10 mL) and the mixture was stirred for 30 min at that tem-
perature and the excess of methyl lithium was quenched
with water (2 mL). The layers were separated and the product
was extracted twice with dichloromethane. The combined
organic phase was washed with brine, dried and evaporated
to give crude material (0.12 g), which was then columned
on silica eluting with petrol–ether (1:1) to afford compound
12 (30 mg, 24%) as the mixture of cis- and trans-isomers
(ratio 7:1, respectively, Rf 0.36). For cis-/trans-12: IR
(CHCl3) 988, 1045, 1091, 1179, 1257, 1381, 1460, 1732 s,
2876, 2963, 3424 br s cmꢀ1; Found: 250.0216 (98.61).
2959, 2984, 3098 smꢀ1 1H NMR (250 MHz, CDCl3)
;
d 1.33 (3H, t, J¼7.0 Hz, CH3), 2.09 (1H, d, J¼6.7 Hz,
CH2), 2.40 (1H, d, J¼6.7 Hz, CH2), 2.53 (3H, s, CH3),
3.72 (3H, s, CH3), 4.32 (2H, q, J¼7.0 Hz, CH2); 13S NMR
(62.9 MHz, CDCl3) d 14.1 (CH3), 24.9 (CH2), 27.9 (CH3),
41.0 (C), 43.2 (C), 53.2 (CH2), 62.8 (CH2), 164.4 (C]O),
166.1 (C]O), 197.8 (C]O).
4.3. X-ray analysis of ester (1a)
Formula: C13H20Br2O4. Unit cell parameters: a 9.194(8),
b 9.380(6), c 10.360(7); a 86.30(5), b 84.16(6), g
12C9 H1579Br16O3 requires 250.0205. For cis-12: H NMR
(500 MHz, CDCl3) d 0.90 t (3H, J¼7.3 Hz, CH3), 1.20
(1H, t, J¼7.6 Hz, CH2), 1.60–1.75 (3H, m, CH2), 2.10 (1H,
s, OH), 2.30 (2H, t, J¼7.3 Hz, CH2), 2.96 (1H, dd, J¼7.6,
4.6 Hz, CH), 3.36 (1H, d, J¼11.6 Hz, CH2), 3.49 (1H, d,
J¼11.6 Hz, CH2), 4.18 (1H, d, J¼12.1 Hz, CH2), 4.45 (1H,
d, J¼12.1 Hz, CH2); 13S NMR (125 MHz, CDCl3) d 13.7
(CH3), 18.4 (CH2), 18.5 (CH2), 23.6 (CH), 26.9 (C), 36.1
(CH2), 64.9 (CH2), 66.2 (CH2), 174.3 (C]O). For trans-
1
1
˚
66.09(6); space group P-1. Selected bond lengths (A) and
bond angles (degree) were presented: C1–C2 1.516(43),
C1–C3 1.525(38), C2–C3 1.484(29), C1–C7 1.511(23), C10–
C11 1.509(46), Br4–C2 1.908(46), O8–C7 1.200(37), O9–C7
1.327(39), O9–C10 1.485(18); C2C3C1 60.50(44), C2C1C3
58.42(47), C3C2C1 61.08(44), C6C1C7 117.01(51), C7C1C2
115.91(54), C7C1C3 117.34(57), C3C2Br4 116.56(47),
C1C2Br4 116.88(48), Br4C2Br5 110.58(34), O8C7O9
126.12(52), C7O9C10 121.38(47), O8C7C1 123.00(52),
O9C7C1 110.88(51), O9C10C11 109.42(48), C12C10C11
110.41(60). The complete set of crystallographic data was
deposited at the Cambridge Crystallographic Data Centre
(entry no. CCDC 283250).
1
12: H NMR (500 MHz, CDCl3) d 2.25 (2H, d, J¼7.3 Hz,
CH2), 2.99 (1H, dd, J¼7.6, 4.6 Hz, CH2), 3.61 (1H, d,
J¼11.6 Hz, CH2), 3.87 (1H, d, J¼11.6 Hz, CH2), 3.91 (1H,
d, J¼12.1 Hz, CH2), 4.21 (1H, d, J¼12.1 Hz, CH2).
4.2.19. Dimethyl 2-acetyl-2-bromocyclopropane-1,1-di-
carboxylate (13). Water (4 mL), periodic acid (1.79 g,
7.8 mmol) and ruthenium trichloride hydrate (10 mg) were
added to alcohol 11f (0.25 g, 1.1 mmol) in carbon tetrachlo-
ride (4 mL) and acetonitrile (4 mL). The mixture was re-
fluxed for 12 h. Water (10 mL) was added. The water layer
was extracted with ether (4ꢄ25 mL) and the combined
organic layer was washed with water (2ꢄ20 mL), dried, con-
centrated to ca. 5 mL and a solution of diazomethane in ether
was added (8 mL). The mixture was stirred for 12 h and then
evaporated. Chromatography on silica eluting with petrol–
ethyl acetate (3:1) gave ester 13 (98 mg, 31%, Rf 0.45). IR
(CHCl3) 889, 926, 980, 1059, 1125, 1202, 1256, 1308,
Acknowledgements
This work was carried out with the support of a Project
INTAS-2000-0549.
Supplementary data
Supplementary data associated with this article can be found
in the online version, at doi:10.1016/j.tet.2007.04.104.
1355, 1439, 1458, 1744, 2956, 3015 smꢀ1 1H NMR
;
References and notes
(250 MHz, CDCl3) d 2.10 (1H, d, J¼7.0 Hz, CH2), 2.42
(1H, d, J¼7.0 Hz, CH2), 2.52 (3H, s, CH3), 3.72 (3H, s,
CH3), 3.86 (3H, s, CH3); 13S NMR (62.9 MHz, CDCl3)
d 25.1 (CH2), 27.9 (CH3), 40.9 (C), 43.2 (C), 53.3 (CH3),
53.5 (CH3), 164.9 (C]O), 166.0 (C]O), 197.7 (C]O);
MS (EI) m/z (%): 249 (13), 248 (16), 247 (14), 246 (15),
217 (21), 215 (23), 199 (100), 167 (40), 157 (46), 125
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