Cyclopropanation with dibromomethane under grignard and barbier conditions

Article abstract of DOI:10.1055/S-0029-1216999

Tertiary Grignard reagents and dibromomethane efficiently cyclopropanate allylic (and certain homoallylic) magnesium and lithium alcoholates at ambient temperature in ether solvents. Lithium (homo)allyl alcoholates are directly cyclopropanated with magnes

Full text of DOI:10.1055/S-0029-1216999

3708
PRACTICAL SYNTHETIC PROCEDURES
Cyclopropanation with Dibromomethane under Grignard and Barbier
Conditions
C
yclopropanation
e
with
D
ibro
r
mometha
h
ne ard Brunner, Laura Eberhard, Jürg Oetiker, Fridtjof Schröder*
Research Chemistry Department, Givaudan Schweiz AG, 8600 Dübendorf, Switzerland
Fax +41(44)8242976; E-mail: fridtjof.schroeder@givaudan.com
PSP
Received 22 June 2009
No171
Abstract: Tertiary Grignard reagents and dibromomethane efficiently cyclopropanate allylic (and certain homoallylic) magnesium and lith-
ium alcoholates at ambient temperature in ether solvents. Lithium (homo)allyl alcoholates are directly cyclopropanated with magnesium
and dibromomethane under Barbier conditions at higher temperatures. The reaction rates depend on the substitution pattern of the (homo)al-
lylic alcoholates and on the counterion with lithium giving best results. Good to excellent syn-selectivities are obtained from a-substituted
(homo)allyl alcohols. In tandem reactions, cyclopropyl carbinols are obtained from allyloxylithium or -magnesium intermediates, generated
in situ by alkylation of conjugated aldehydes, ketones, and esters as well as from allyl esters and carbonates or vinyloxiranes.1
Key words: cyclopropanation, Barbier conditions, Grignard addition, alkyllithium addition, dibromomethane
Procedure 1: Deprotonation with t-BuMgCl and cyclopropanation with CH2Br2
OH
OH
CH2Br2 (3 equiv), 10–30 °C, Et2O
t-BuMgCl (4 equiv), THF, 87%
2a (dr = 1:1)
1a
Procedure 2: Sequential Grignard addition / cyclopropanation of conjugated aldehydes
PentylMgBr in THF, 0 °C, then
CH2Br2 (3 equiv), 10–30 °C, then
CHO
5g
2g
t-BuMgCl (3 equiv), Et2O, 95%
OH
Procedure 3: Sequential alkyl lithium addition / cyclopropanation of conjugated ketones
O
Me OH
MeLi, THF, –78 ° to 0 °C,
CH2Br2 (3 equiv), 0 °C,
Me
Me
t-BuMgCl (3 equiv), Et2O, 50%
7c
8c
Et
Et
Procedure 4: Sequential alkyl lithium addition / cyclopropanation of vinyloxiranes
n-BuLi, –78 °C, then
CH2Br2 (4 equiv), t-BuMgCl (4 equiv)
O
OH
THF, Et2O, 16 h
10c
11c (65%, dr = 93:7)
Procedure 5: Barbier mode
LiH, THF, 3 h, 70 °C,
then Mg (4 equiv), 70 °C,
OH
OH
CH2Br2 (4 equiv), 4 h,
3 cycles, 43%
1a
2b
Scheme 1
SYNTHESIS 2009, No. 21, pp 3708–3718
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x
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Advanced online publication: 08.09.2009
DOI: 10.1055/s-0029-1216999; Art ID: Z13309SS
© Georg Thieme Verlag Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
Introduction
Cyclopropanation with Dibromomethane
3709
X
Mg
β
γ
α
OM
XMgCH2X
MXn
O
+
+
.
The Simmons–Smith cyclopropanation has evolved as a
widely used tool for the conversion of alkenes, e.g. allylic
alcohols, into the corresponding cyclopropanes, especial-
ly with carbenoids of the general structure MCH2X
(M = Zn, Al, Sm, Cu).2 However, stoichiometric amounts
of expensive and/or pyrophoric metal reagents as well as
iodinated carbenoid precursors such as diiodomethane or
chloroiodomethane are required to guarantee the neces-
sary reactivity for carbenoid formation,3 which in turn
generates large amounts of waste. Dibromomethane is a
much less expensive and more easily purified and storable
reagent. An efficient cyclopropanation reaction with di-
bromomethane, however, has so far only been reported by
Friedrich,4 who activated zinc and copper(I) chloride in
the presence of dibromomethane and the alkene substrate
either by ultrasound4a or by addition of acetyl halides4b to
facilitate carbenoid formation. An unusual cyclopropana-
tion of allylic alcohols promoted by a Grignard reagent
has been reported by Bolm and Pupowicz,5 who obtained
moderate to good cyclopropanation yields from g- and
a,g-substituted allylic alcohols in the presence of isopro-
pylmagnesium halides (4 equiv)/diiodomethane (3 equiv)
in a mixture of dichloromethane and ether solvents after
2–3 days at –70 °C. Although these conditions can be re-
alized with normal laboratory equipment (cryostat), a
more practical procedure was desired.
Rz
A
B
Rz
n
n
X = Cl, Br
Equation 2
cyclopropanation transition state B, formed from allylic
alcoholate A in the presence of XCH2MgX (Equation 2).7
Without substrate, tert-butylmagnesium chloride and di-
bromomethane react exothermically and vigorously with
each other and a gaseous isobutane/isobutylene/neopen-
tane (4:3:1) mixture is collected from this test reaction (as
well as in the presence of 1a).8 Deprotonation of 1a with
one equivalent of tert-butylmagnesium chloride produces
the expected one equivalent of isobutane, less than one
equivalent of isobutane is collected during the addition of
dibromomethane and the next three equivalents of tert-bu-
tylmagnesium chloride, as well as after aqueous quench of
the mixture. GC/MS of the distillation pre-fractions shows
that the missing isobutane is incorporated into oligomeric
structures.9
The substitution pattern has a profound effect upon the re-
action rates, especially when magnesium alcoholates A
(M = MgX) are cyclopropanated in situ. At least two sub-
stituents, one in the g- (E or Z) and another one in the a-
or b-position I and II (Figure 1), are necessary to achieve
high conversions through subsequent addition of 3–4
equivalents of CH2Br2/t-BuMgCl. Additional substituents
Rz have no detrimental effect.
This article focuses on experimental procedures and the
results of a (tandem) cyclopropanation with dibromo-
methane under Grignard and Barbier conditions devel-
oped in our laboratories, to provide a basis for the rapid
reproduction of this reaction on our, and related, sub-
strates (Scheme 1). A more detailed discussion, the theo-
retical background, and analytical data of all compounds
produced already by this method is available.1
Rβ
Rγ
OMgX
Rγ
OMgX
or
Rz
Rα
Rz
n
n
II
I
Figure 1 Substituents necessary for high conversions of magnesi-
um alcoholates A to the corresponding cyclopropyl carbinols with 3–
4 equiv CH2Br2/t-BuMgCl; higher substitution grades (n = 1–3) are
possible.
Scope and Limitations
After an investigation of the influence of substituent R in
RMgX upon the cyclopropanation of allylic alcohol 1a,
we found that yield and reaction rate correlate with the or-
der R = tert-alkyl > sec-alkyl >> n-alkyl. To avoid decom-
position, carbenoid XMgCH2X has to be generated in the
presence of the allylic alcohol to be cyclopropanated
(Equation 1).5,6
Allyl alcoholates A lacking this substitution pattern give
only partial conversions under these conditions. These can
be brought to completion by subjecting the crude sub-
strate/product mixture (after workup) to another cyclopro-
panation cycle. More substituents such as those in tri- or
tetrasubstituted alkenes are tolerated. In case of less reac-
tive or sensitive substrates the generation of allyloxylithi-
ums prior to cyclopropanation is generally recommended
(vide infra).
RMgX + CH2X2 → RX + XMgCH2X
(with X = I >> Br > Cl)
Equation 1
The cyclopropanation under Grignard conditions gives (in
case of substrates with substituents in the a-position)
higher syn-selectivities at ambient or higher temperatures
than by other methods which are run at lower (–10 °C) or
much lower temperatures (–78 °C).10 anti-Byproducts
(<20%) were detected in the case of the smallest substitu-
ent (Ra = Me). Already with the first higher substituent
Ra = Et, this effect was negligible.
Dibromomethane was found to be the ideal carbenoid pre-
cursor, which at 25 °C and in combination with three
equivalents of a tertiary magnesium chloride such as tert-
butylmagnesium chloride completely converted allylic al-
cohol 1a into cyclopropane carbinol 2a within a few hours
(Scheme 1, Procedure 1). The selectivity for the proximal
(allylic) double bond of 1a follows from intramolecular
Synthesis 2009, No. 21, 3708–3718 © Thieme Stuttgart · New York

3710
G. Brunner et al.
PRACTICAL SYNTHETIC PROCEDURES
Cyclopropanation of differently substituted allylic alco- gave also good cyclopropanation rates (entries 5–12).
hols 1 with CH2Br2 (3 equiv)/t-BuMgCl (3 equiv) gave af- These substitution patterns are abundant in various ter-
ter deprotonation with t-BuMgX or MeMgX the penic alcohols. Less-substituted allylic alcohols, which
corresponding cyclopropanes 2 with good to very good gave only 30–60% conversions under these conditions,11
yields and purities (Procedure 1). Clean and extensive could be nevertheless completely cyclopropanated using
conversions under these conditions were obtained from more CH2Br2/t-BuMgCl or by application of a further re-
substrates 1 that were at least a,g- or b,g-substituted action cycle.
(Table 1, entries 1–4). More substituents such as in 1e–l
Table 1 Procedure 1: CH2Br2/t-BuMgCl-Promoted Cyclopropanation of Allylic Alcohols 1a
RMgCl, THF, then
CH2Br2 (3 equiv), 10–30 °C
H2C
β
α
H
γ
OH
α
β
γ
t-BuMgCl (3 equiv), Et2O
OH
H
Rz
Rz
n
2
1
n
Entry
1
Substrateb
Subst. pattern
Product
Conv.c (%) Yieldd (%) Ratioe syn/anti (dr)
OH
OH
OH
OH
b,g
91f,g
87
89
68
66i
(1:1)
(1:1)
(1:1)
1a
2a
2b
2
3
4
b,g
b,g
b,g
94
1b
quant.
73h
Z
cis
OH
OH
1c
2c
OH
OH
2d
1d
5
a,b,g
94
94
97:3
OH
OH
1e
1f
2e
2f
OH
OH
6
7
a,g,g
a,b,g
quant.
91
95
96
>99:1
>99:1
OH
OH
1g
1h
1i
2g
2h
2i
OH
OH
8
9
a,b,g
a,g
91
96
80
>99:1
81:19
87j
OH
OH
Synthesis 2009, No. 21, 3708–3718 © Thieme Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
Cyclopropanation with Dibromomethane
3711
Table 1 Procedure 1: CH2Br2/t-BuMgCl-Promoted Cyclopropanation of Allylic Alcohols 1a (continued)
RMgCl, THF, then
CH2Br2 (3 equiv), 10–30 °C
H2C
β
α
H
γ
OH
α
β
γ
t-BuMgCl (3 equiv), Et2O
OH
H
Rz
Rz
n
2
1
n
Entry
10
Substrateb
Subst. pattern
Product
Conv.c (%) Yieldd (%) Ratioe syn/anti (dr)
HO
HO
a,b,g,g
quant.k
97
70
>99:1
(98:2)
1j
2j
11
12
b,g,g-D
92k
OH
OH
1k
2k
OH
(dr = 60:40)
OH
a,b-D,g,g
94l
57
39:61m
2l
1l
a Rzn = H, alkyl, cyclopropyl, n = 2–4. R = t-Bu, Me. Conditions as given unless otherwise stated.
b Substrates 1 were prepared according to the literature.12
c Total conversion syn + anti, determined by GC/MS of the crude product after workup.
d Yields after distillation.
e Diastereomeric ratio, relative to substrate stereocenter(s), in brackets. Configuration determined by GC/MS retention times (tR), NMR, and/
or X-ray crystal structure analysis (see below).
f CH2Br2 (2.5 equiv) and t-BuMgCl (2.5 equiv) after deprotonation.
g Contains 1–4% of remote cyclopropanation product 2b.
h CH2Br2 (4 equiv) and t-BuMgCl (4 equiv) after deprotonation.
i Completely converted after a second reaction cycle.
j Addition of t-BuMgCl (5 equiv) to substrate in CH2Br2 (5 equiv).
k Addition of t-BuMgCl (4–5 equiv) to substrate in CH2Br2 (4 equiv).
l MeLi deprotonation.
m For a discussion of the unusual anti-selectivity see ref.1
The cyclopropanation of homoallylic alcohols gave either The direct conversion of conjugated aldehydes 5 into the
no or only disappointing conversions under these condi- corresponding cyclopropyl carbinols 2 demonstrates pow-
tions. Nevertheless, some of these substrates, such as ter- erfully the advantages of cyclopropanation under Grig-
pinen-4-ol (3a) and to a certain extent also (Z)-hept-4-en- nard conditions (Procedure 2). a,g-, a,b,g- or a,g,g-
2-ol (3b), underwent cyclopropanation surprisingly well Substituted allylic alcoholates I are the reactive interme-
(Scheme 2).
diates, which are further cyclopropanated. Thus, (E)-citral
(5f) or (E)-2-methylpent-2-enal (5g) (Table 2, entries 1
and 2) gave, after pretreatment with appropriate Grignard
reagents und subsequent cyclopropanation with excess
t-BuMgCl/CH2Br2, the corresponding cyclopropanes 2f
and 2g in nearly the same yields and purities as obtained
already from the allylic alcohols 1f and 1g (Table 1). Oth-
er conjugated aldehydes 5m–t underwent this tandem
alkylation/cyclopropanation with similar efficiency
(Table 2).
CH2Br2 (3 equiv),
t-BuMgCl (4 equiv)
i-Pr
OH
i-Pr
OH
Et2O, THF, 2 h
89%
3a
4a (dr > 99:1)
as above but
2 cycles
Z
cis
55%
OH
OH
4b (dr = 83:17)
By reverse addition of alkenylmagnesium halides to satu-
rated aldehydes the same intermediate 6 is cyclopropan-
ated. Thus, after pretreatment with (E,Z)-propenyl-
magnesium bromide and subsequent cyclopropanation,
octanal gave 2t (as E/Z-mixture) with a comparable yield
to that obtained from crotonaldehyde (5t) and heptylmag-
nesium bromide (Scheme 3).
3b
Scheme 2 Cyclopropanation of homoallylic alcohols 3a and 3b13
under Grignard conditions (yields after distillation)
Synthesis 2009, No. 21, 3708–3718 © Thieme Stuttgart · New York

3712
G. Brunner et al.
PRACTICAL SYNTHETIC PROCEDURES
Table 2 Procedure 2: CH2Br2/t-BuMgCl-Promoted Cyclopropanation of Conjugated Aldehydes 5 via Intermediate Ia
β
R2MgX
γ
H2C
β
CH2Br2 (3 equiv)
R1
OMgX
α
R1
α
OH
CHO
γ
R1
t-BuMgCl (3 equiv)
10–30 °C, 20 h
ether solvents
R2
R2
Rz
Rz
I
Rz
5
2
n
n
n
Entry Substratesb
R2MgX
Subst.
pattern I
Product
Conv.c
(%)
Yieldd
(%)
Ratioe
syn/anti (dr)
OH
1
MeMgCl
a,g,g
quant.
93
73
95
>99:1
>99:1
CHO
5f
2f
2
pentylMgBr
a,b,g
CHO
OH
OH
5g
2g
3
EtMgBr
a,g
a,g
90
84
36
86
98:2
CHO
CHO
5m
2m
OH
4
MeMgCl
79:21
5n
2n
Ph
OH
CHO
5
6
7
MeMgCl
MeMgCl
MeMgCl
a,g
a,g
a,g
quant.
97f
83
77
77
82:18
83:17
88:12
Ph
5o
2o
2p
2q
CHO
OH
5p
5q
93f
CHO
OH
8
9
MeMgCl
MeMgCl
a,g-D
a,b,g
80f
95f
98g
81
75:25
CHO
OH
5r
2r
2s
OH
CHO
>99:1 (1:1)
5s
5t
10
heptylMgBr
a,g
91
76
> 99:1
CHO
OH
2t
a R1 = H, alkyl, alkenyl, aryl; R2 = alkyl; X = Cl, Br; Rzn = H, Me
b E-Alkenes. Substrates 5 are commercial available, except 5r and 5s which were prepared according to the literature.14
c Total conversion syn + anti, determined by GC/MS of the crude product after workup.
d Yields after distillation.
e Diastereomeric ratio, relative to substrate stereocenter(s), in brackets. Configuration determined by GC/MS retention times (tR), NMR, and/
or X-ray crystal structure analysis.1
f CH2Br2 (4–5 equiv) and t-BuMgCl (4–5 equiv) after Grignard addition.
g Crude yield, 24% after distillation, not optimized.
Synthesis 2009, No. 21, 3708–3718 © Thieme Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
Cyclopropanation with Dibromomethane
3713
OH
heptylMgBr +
CHO
CO2Me
MeLi (2 equiv), then
MgBr
+ octanal
CH2Br2, t-BuMgCl
65%
6
5t
OMgBr
7f
8f
CH2Br2, t-BuMgCl
Et2O, THF
same
conditions
CO2Et
48%
7g
OH
8g
2t
OH
Scheme 4 Tandem methyllithium alkylation/cyclopropanation of
conjugated esters; 7g was prepared as described19 (yields after distil-
lation).
Scheme 3 Addition of heptylmagnesium bromide to crotonaldehy-
de (5t) and inverse addition of prop-1-enylmagnesium bromide to oc-
tanal, followed by cyclopropanation of the common intermediate 6
under Grignard conditions
detected. Methylation/tandem cyclopropanation of 7c–e
proceed via an intermediate III with the highest substitu-
tion grade (a,a,b,g,g) possible (Table 3, entries 3–5).
tert-Allylic alcoholates are unstable cyclopropanation
substrates because of their sensitivity to elimination.15,16
Nevertheless, under Grignard conditions conjugated ke-
tones 7 underwent a relatively smooth tandem 1,2-methy-
lation/cyclopropanation (Procedure 3). Methyllithium
addition/cyclopropanation gave yields and purities, which
were 15–30% better than those obtained from the corre-
sponding methylmagnesium chloride addition/cyclopro-
panation sequence. trans-Isomers were generally not
tert-Allylic alcoholates III are also accessible by exhaus-
tive (2 equiv) methyllithium addition to conjugated esters
such as 7f and 7g. In situ cyclopropanation of the tertiary
allylic alcoholate III gave the corresponding cyclopropyl
carbinols 8f and 8g (Scheme 4).
Similarly allylic acetate 9a, and allylic carbonate 9b were
converted into the cyclopropyl carbinol 2f (Scheme 5).
Table 3 Procedure 3: Sequential Methyllithium Addition/Cyclopropanation of Conjugated Ketones 7a
CH2Br2 (2.5–4 equiv), 0 °C
t-BuMgCl (2.5–4 equiv), Et2O
H2C
β
MeLi, THF,
–78 to 0 °C
γ
α
α
R
O
OLi
Me
β
γ
Me
OH
R
R
Rz
n
8
7
Rz
Rz
n
III
n
Entry Substrate 7b
Subst. pattern III CH2Br2 and t-BuMgCl Product
Conv.c (%) Yieldd (%) Ratio cis/trans (dr)
i-Pr
O
OH
1
a,a,g,g
a,a,b,g
4 equiv
4 equiv
quant.
93
45
60
>99:1
94:6
i-Pr
7a
8a
O
OH
n-hexyl
2
3
n-hexyl
8b
8c
7b
O
OH
a,a,b,g,g
3 equiv
quant.
70
>99:1
Et
Et
7c
4
5
a,a,b,g,g
a,a,b,g,g
3 equiv
quant.
98
65
53
>99:1
>99:1
O
OH
7d
7e
8d
8e
O
OH
2.5 equiv
a R = alkyl; Rzn = H, alkyl; n = 2–3.
b Substrates 7 are commercial available (7b)17 or were prepared by known procedures.18
c Determined by GC/MS of the crude product after work-up.
d Yields after flash chromatography or distillation.
Synthesis 2009, No. 21, 3708–3718 © Thieme Stuttgart · New York

3714
G. Brunner et al.
PRACTICAL SYNTHETIC PROCEDURES
RLi, hexane, –78 °C, then
CH2Br2 (4 equiv), t-BuMgCl (4 equiv)
MeMgBr (2–3 equiv)
THF, then CH2Br2/
t-BuMgCl, Et2O, 16 h
O
OH
R
OH
OR
THF, Et2O, 16 h
86–88%
10a
11a R = n-Bu 83%
(cis/trans = 85:15)
11b R = i-Pr 84%
(cis/trans = 75:25)
9a R = Ac
9b R = CO2Et
2f
syn/anti > 99:1
+ t-BuOH
OH
Scheme 5 Sequential ester cleavage/cyclopropanation of allyl
esters and carbonates 9a,b20,21
n-BuLi
O
same conditions
11c (65%, dr = 93:7)
An interesting extension of the tandem alkylation/cyclo-
propanation method is the SN2¢ allylic substitution and
cyclopropanation of vinyloxiranes (Procedure 4). Alkyl-
lithium reagents are known to open isoprene oxide 11a
without additives by 1,3-allylic substitution, giving main-
ly Z-configurated 4-alkyl-2-methylbut-2-en-1-ols.12d,22
The allyloxylithium intermediates of this reaction were
cleanly cyclopropanated under Grignard conditions giv-
ing the corresponding cyclopropyl carbinols 12 with the
expected cis,syn-configuration (Scheme 6).
10c
Scheme 6 Procedure 4: SN2¢ allylic substitution of vinyloxiranes 10a
and 10c,23 and cyclopropanation of the corresponding (Z)-allyloxy-
lithium intermediates (yields after distillation)
cyclopropanation occurs here at a temperature (70 °C)
more than 100 °C above the reported decomposition tem-
perature (–55 °C) of carbenoid bromomethylmagnesium
bromide.6
Cyclopropanation of substrate 1a under Grignard condi-
tions (CH2Br2/t-BuMgCl, Table 2) had not only given al-
lylic cyclopropanation product 2a, but also traces (1–4%)
of the remote cyclopropanation product 2b. Under Barbier
conditions, a much higher content (20%) of remote cyclo-
propanation product 2b was obtained. The 2a/2b mixture
could be completely converted into 2b through another
two reaction cycles (Procedure 5). The same bis-cyclopro-
panation strategy was applied to geraniol (1u), which
gave biscyclopropanation product 2u¢ via cyclopropyl
carbinol 2u after three reaction cycles.
Cyclopropanation with bromomethylmagnesium bro-
mide, directly formed from magnesium and dibromo-
methane (Barbier conditions), in the presence of the
alkene substrate, is also possible (Procedure 5). For this
purpose, 1b was deprotonated with 1 equivalent of butyl-
lithium or lithium hydride prior to the addition of magne-
sium turnings.24 Subsequent dropwise addition of
dibromomethane at reflux (70 °C) kept the reaction con-
trollable. After complete conversion and workup, this
gave 2a/2b (75:20) in 65% yield (Table 4, entry 1). Other
substrates were cyclopropanated with similar efficiency
under these conditions (Table 4). It should be noticed that
Encouraged by the better performance of lithiated rather
than magnesiated tertiary allylic alcoholates III (Table 3)
Table 4 Procedure 5: Cyclopropanation under Barbier Conditionsa,b
Entry
Substratec
Mg and CH2Br2 Product
Yieldd
(%)
Puritye
(%)
Ratio syn/anti
(mono/bis)
OH
OH
1
3 equiv
65
68
91 (3)
(75:20)
97:3
1a
2a/2b
2
6 equiv
84 (16)
OH
OH
1g
1u
2g
OH
OH
3
4
4 equiv
66
68
85 (5)
93 (3)
(71:24)
73:27
2u/2u¢
cis
6 equiv
Z
OH
OH
3b
4b
a For the precise structures of 2a, 2b, and 2u see Tables 1 and 5. 2u¢ indicates the bis-cyclopropanation product.
b Deprotonation with BuLi (0 °C, 30 min) or LiH (THF, 70 °C, 3 h) followed by addition of Mg and CH2Br2 at 70 °C. Stirred at this temperature
until no further conversion detected by GC.
c Substrates are either commercially available (1u) or were prepared by literature procedures (1a, 1g11 and 3b12).
d Yields after distillation corrected by purity.
e Determined by GC/MS of the crude product after workup for syn + anti. Percentage of unconverted substrate in brackets.
Synthesis 2009, No. 21, 3708–3718 © Thieme Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
Cyclopropanation with Dibromomethane
3715
as well as by the much better conversions obtained from Because of the higher sterical congestion of the anti-dias-
lithiated (homo)allylic alcoholates under Barbier condi- tereomers, mixtures of syn- and anti-cyclopropyl
tions (compared to the corresponding magnesiated ones), carbinols show the typical elution order tR (anti) < tR (syn)
some less reactive (homo)allylic alcohols were deproto- on polar GC columns.27 This analytical method has been
nated with butyllithium (1.3 equiv) and cyclopropanated used by others for the determination of the relative config-
in situ with the CH2Br2/t-BuMgCl system (Table 5). uration of these compounds.10 We routinely found the
Again, this gave much better and often complete conver- same elution order on a less polar GC column.28 The rela-
sions.25
tive configuration of all cyclopropyl carbinols was also
routinely analyzed by NOESY (together with COSY,
HMBC, HMQC). This was necessary in case of exocyclic
syn/anti mixtures, e.g., 2e and 11c, which were insepara-
ble by our GC method, and in case of diastereopure cyclo-
propyl carbinols. If the NOESY experiment in water-free
dimethyl sulfoxide (to detect the OH proton)29 gave am-
Cyclopropanation of a,g-substituted allyl alcoholates I
gave cyclopropyl carbinols, which were mainly (>80%)
or exclusively (>99%) syn-configurated.26 The (nearly)
identical mass spectra of the syn- and anti-diastereomers
allow the detection of the minor isomer (anti) by GC/MS.
Table 5 Cyclopropanation of Lithium Allylic Alcoholates in Comparison to the Cyclopropanation of the Corresponding Magnesium ‘Ate’
Complexesa
then portionwise
CH2Br2, t-BuMgCl
A) BuLi (1.3 equiv),
hexane, THF or
OH
β
β
H2C
γ
γ
OH
OM
α
α
B) MeMgCl (1.2 equiv),
THF
Rz
Rz
Rz
Et2O
n
n
n
1
IV
2
Entry Substrateb
Subst. pattern Product
IV
Conversion (%)
after deprotonation
Yieldd (%)
Method B
A: with MeMgClc B: with BuLic
OH
OH
1
g,g
60 (4 equiv)
29 (6 equiv)
93 (4 equiv) 73
1u
2u
2
g
93 (6 equiv) 94
OH
OH
1v
2v
OH
OH
3
a
g
95 (5 equiv)
44 (5 equiv)
100 (6 equiv) 98
81 (4 equiv) 54
1w
2w
OH
OH
4
1x
2x
2y
OH
OH
5
a,a
a,a
47 (5 equiv)
41 (5 equiv)
100 (5 equiv) 80
100 (5 equiv) 85
1y
OH
OH
6
1z
2z
4b
4c
7
homoallylic
homoallylic
75 (6 equiv)
15 (4 equiv)
100 (5 equiv) 98
91 (6 equiv)e 59
OH
OH
3b
cis
OH
Z
OH
8
3c
a M = MgCl or Li. Rzn = H, alkyl, aryl, n = 1, 2.
b Substrates 1 are commercially available, for the preparation of 3b see ref.13
c Equiv CH2Br2 and t-BuMgCl in brackets.
d Yield after distillation.
e 50% conversion after addition of 4 equiv CH2Br2/t-BuMgCl.
Synthesis 2009, No. 21, 3708–3718 © Thieme Stuttgart · New York

3716
G. Brunner et al.
PRACTICAL SYNTHETIC PROCEDURES
to give an oily residue that was bulb-to-bulb-distilled (110 °C/0.133
mbar) to give 2a (12.5g, 87% after purification) as a colorless oil;
dr 1:1. The analytical data (NMR, MS, IR, odor) for 2a were con-
sistent with those in the literature.12
biguous results, ethylation or benzylation of the hydroxy
function furnished more encumbered derivatives, whose
relative configuration was tentatively assigned by this
method. If that was not possible (e.g., on 2e or 4b), the
corresponding camphanates were analyzed by X-ray crys-
tal structure analysis after crystallization.1 The syn-con-
figuration of g-alkenylcyclopropyl carbinols 2p and 2q
(where all these methods failed) was determined after
conversion to known derivatives.1
Procedure 2: Sequential Grignard Addition/Cyclopropanation
of Conjugated Aldehydes; Typical Procedure for 2g
A 2 M soln of pentylmagnesium bromide in Et2O (75 mL, 0.15 mol)
was added dropwise to (E)-2-methylpent-2-enal (12.6 g, 0.15 mol)
in THF under N2 with cooling and stirring. CH2Br2 (77 g, 0.44 mol)
was added to the Grignard product followed by dropwise addition
of 2 M t-BuMgCl in Et2O (220 mL, 0.44 mol) at 10–20 °C; the mix-
ture was stirred at 25 °C for 16 h. Then 2 M HCl was added and the
mixture was extracted with t-BuOMe, and the combined extracts
were washed with concd NaHCO3, H2O, and concd NaCl. The soln
Conclusion
Tertiary Grignard reagents such as tert-butylmagnesium was dried (MgSO4), filtrated, and concentrated to give an oily resi-
due (30.3 g), which was distilled (45 °C/0.04 mbar) to give 2g (24.4
chloride and dibromomethane efficiently cyclopropanate
allylic (and certain homoallylic) magnesium and lithium
alcoholates at ambient temperature in ether solvents. The
reaction rates depend on the substitution pattern of the
(homo)allyl alcoholates and on the counterion. Lithium
allyl alcoholates gave best cyclopropanation rates, e.g. un-
der Barbier conditions or in the cyclopropanation of rela-
tively unsubstituted allyl or sensitive a-tertiary allyl
alcoholates, which are less reactive. Under these relative-
ly simple conditions good to excellent syn-selectivities are
obtained, which are higher than the ones obtained from
other cyclopropanation methods, which are carried out at
lower temperatures. In conclusion we provide a new cy-
clopropanation method, which proceeds simply and rapid-
ly with relatively inexpensive reagents, and which has
relatively positive environmental and safety aspects. This
method can be integrated into the sequential conversion of
conjugated aldehydes and ketones, allylic acetates, and
carbonates, as well as vinyloxiranes. We are confident
that this methodology will find use in preparative organic
chemistry.
1
g, 90%) as colorless oil. The H NMR data were (within limits)
identical to those described in ref.30 Odor: green, fresh, spicy, choc-
olate. The syn-configuration confirmed by NMR analysis of the cor-
responding benzyl ether.1
IR (film): 3373 (br, OH), 2957 (s), 2930 (s), 2859 (m), 1456 (m),
1377 (w), 1310 (w), 1120 (w), 1060 (w), 1023 cm–1 (s).
1H NMR (CDCl3): d = –0.05 (m, 1 H), 0.5 (2 H), 0.9 (t, 3 H), 0.99
(t, 3 H), 1.01 (s, 3 H), 1.25–1.35 and 1.35–1.6 (11 H), 2.7 (dd, 1 H).
13C NMR (CDCl3): d = 11.6 (q), 14.0 (q), 14.3 (q), 17.8 (t), 22.0 (t),
22.6 (t), 24.0 (d), 24.9 (s), 26.0 (t), 32.0 (t), 33.9 (t), 80.9 (d).
MS (EI): m/z (%) = 166 ([M – 18]+, 3), 141 (5), 128 (15), 113 (10),
99 (32), 84 (35), 72 (85), 71 (100), 69 (60), 55 (70), 43 (75).
Anal. Calcd for C12H24O: C, 78.20; H, 13.12. Found: C, 78.05; H,
13.04.
Procedure 3: Sequential Alkyllithium Addition/Cyclopropana-
tion of Conjugated Ketones; Typical Procedure for 8c
Prepared from 7c (4 g, 32 mmol)18 using 1.6 M MeLi in Et2O (28
mL, 45 mmol) at –20 °C, followed by dropwise addition of CH2Br2
(2 × 8.4 g, 97 mmol) and 2 M t-BuMgCl in Et2O (2 × 24.3 mL, 97
mmol) at 0–10 °C. After 18 h at 25 °C the mixture was inversely
quenched with concd NH4Cl. Extraction with t-BuOMe and bulb-
to-bulb distillation gave 8c (0.23 g, 45%) as a colorless oil. cis-con-
figuration assigned by COSY, HMBC, HSQC, NOESY in DMSO-
d6.
Reagents and solvents were purchased from commercial suppliers
and used without further purification. Solvents for moisture-sensi-
tive reactions contained < 0.1% H2O. Moisture-sensitive reactions
were conducted under argon and in oven-dried (130 °C) glassware.
The given temperatures refer to reaction thermometers. All reac-
tions were carried out under stirring. The silica gel used for flash
chromatography was Sorbsil, 0.04–0.063 mm. 1H and 13C NMR: all
spectra were recorded at 400 MHz and in CDCl3 or C6D6 relative to
TMS. 13C NMR peaks were assigned with q (CH3), t (CH2), d (CH)
and s (C). GC/MS: nonpolar column: 5% diphenyl/95% Dimeth-
ylpolysiloxan 30 × 250 × 0.2. Program: 50 °C/3 min, 10 °C/min to
60 °C, 6 °C/min to 240 °C, 30 °C/min to 270 °C. Conditions: injec-
tor: 240 °C; split 1:50; flow: 1.0 mL/min; transferline: 250 °C. MS
Quadrupole: 106 °C; source: 230 °C; carrier gas: He. IR: samples
were measured neat in ATR modus. For preparative procedures and
analytical data of all compounds see ref.1
IR (film): 3297 (br, OH), 2959 (s), 2933 (m), 2859 (m), 1453 (s),
1365 (s), 1300 (w), 1200 (m), 1115 (s), 993 (s), 938 (s), 926 cm–1
(s).
1H NMR (CDCl3): d = –0.1 (d, 1 H), 0.75 (d, 1 H), 0.95 (t, 3 H), 1.1
(s, 3 H), 1.25 (s, 3 H), 1.3 (1 H), 1.4 (2 H), 1.55 (2 H), 1.8 (1 H).
13C NMR (CDCl3): d = 11.4 (q), 12.7 (q), 18.4 (t), 24.9 (q), 25.8 (t),
28.5 (t), 32.35 (s), 34.6 (s), 36.5 (t), 81.3 (s).
MS (EI): m/z (%) = 154 (M+, 1), 139 ([M – 15]+, 36), 136 (55), 125
(34), 121 (27), 107 (85), 96 (58), 81 (100), 67 (30), 57 (42), 55 (36),
43 (84).
HRMS: m/z [M – CH3] calcd for C9H15O: 139.11229; found:
139.11031.
Procedure 1: Deprotonation with t-BuMgCl and Cyclopropana-
tion with CH2Br2; Typical Procedure for 2a
Procedure 4: Sequential Alkyllithium Addition/Cyclopropana-
tion of Vinyloxiranes; Typical Procedure for 11c
nor-Radjanol (1a, 12.6 g, 65 mmol)12 was added with cooling and
stirring to 2 M t-BuMgCl in Et2O (33 mL, 66 mol) under N2. This
was followed by 3 additions of both CH2Br2 (3 × 10 g, 0.17 mol)
and 2 M t-BuMgCl in Et2O (3 × 28 mL, 0.17 mol) each time in that
order at 10–20 °C. The mixture was quenched with concd NH4Cl,
extracted with t-BuOMe, and the combined extracts were washed
with H2O until pH 7. The soln was dried (MgSO4) and concentrated
Oxirane 10c (3 g, 18 mmol)23 was added dropwise to 1.6 M BuLi in
hexane (11 mL, 18 mmol) in Et2O (20 mL) at –78 °C, after 1 h at
this temperature it was slowly warmed up to r.t. CH2Br2 (12.5 g, 72
mmol) was added followed by dropwise addition of t-BuMgCl (36
mL, 72 mmol) at 10–20 °C. After 24 h at 25 °C, it was poured into
2 M HCl. The mixture was extracted with t-BuOMe and the com-
Synthesis 2009, No. 21, 3708–3718 © Thieme Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
Cyclopropanation with Dibromomethane
3717
bined extracts were washed with concd NaHCO3 and concd NaCl,
dried (MgSO4), filtered, and the solvent evaporated to give a residue
that was purified by bulb-to-bulb distillation (98 °C/0.05 mbar) to
give 11c (2.6 g, 65%) as a colorless oil; dr 93:7. D3-cis-configura-
tion assigned by COSY, HMBC, HSQC, NOESY in DMSO-d6.
(7) Hoveyda, A. M.; Evans, D. A.; Fu, G. C. Chem. Rev. 1993,
93, 1307; and references therein.
(8) The formation of these byproducts shows that radical
mechanisms are at least partially involved: (a)Ashby, E. C.;
Deshpande, A. K.; Doctorovich, F. J. Org. Chem. 1994, 59,
6223. (b) Walton, J. C. In Houben-Weyl, Vol. E17c;
de Meijere, A., Ed.; Thieme: Stuttgart, 1997, 2438.
(9) Among other byproducts identified by GC/MS: 2,2,4,4-
tetramethylpentane (CAS 1070-87-7), 2,2,6,6-tetramethyl-
4-methyleneheptane (CAS 141-70-8), 2-tert-butyltetra-
hydrofuran (CAS 38624-45-2), 2,2-dimethyldecane (CAS
17302-37-3), 2,2,8-trimethyldecane (CAS 62238-01-1), 2,2-
dimethylundecane (CAS 17312-64-0), tert-butyl bromide
(CAS 507-19-7), 1-bromo-2,2-dimethylpropane (CAS 630-
17-1), 2-bromotetrahydrofuran (CAS 59253-21-3), 3-
bromo-2,2,4,4-tetramethylpentane (CAS 107713-49-5).
(10) (a) Ratier, M.; Castaing, M.; Godet, J.-Y.; Pereyre, M.
J. Chem. Res., Synop. 1978, 179. (b) Molander, G. A.; Etter,
J. B. J. Org. Chem. 1987, 52, 3942. (c) Molander, G. A.;
Harring, L. S. J. Org. Chem. 1989, 54, 3525.
IR (film): 3362 (br, OH), 2919 (s), 2852 (m), 1456 (m), 1364 (w),
1106 (w), 1029 (m), 989 (m), 811 (w), 741 (w), 726 cm–1 (w).
1H NMR (CDCl3): d = 0.3 (m, 1 H), 0.5 (m, 1 H), 0.8 (m, 1 H), 0.8–
1.1 and 1.2–2.4 (24 H), 3.25 (1 H).
13C NMR (CDCl3): d = 14.1 (q), 20.7 (t), 22.7 (t), 23.3 (t), 23.5 (t),
24.3 (d), 26.5 (t), 26.8 (t), 28.9 (t), 29.4 (s), 29.7 (t), 30.4 (t), 31.2
(t), 31.7 (t), 73.7 (d).
MS (EI): m/z (%) = 224 (M+, 1), 206 ([M – 18]+, 10), 178 (4), 163
(5), 149 (12), 135 (22), 126 (24), 109 (22), 107 (24), 98 (58), 97
(33), 96 (80), 95 (46), 93 (54), 69 (41), 68 (42), 67 (84), 55 (100),
41 (80).
HRMS: m/z calcd for C15H28O: 224.21402; found: 224.21737; calcd
for C15H26: 206.20345; found: 206.20372.
(11) Allylic alcohols, which underwent incomplete conversions
with the system CH2Br2 (3 equiv)/t-BuMgCl (4 equiv) (GC
conversion to the corresponding cyclopropanes after 18 h in
brackets): (E)-hex-2-enol (35%), (Z)-hex-2-enol (65%),
nonadienol (50%), geraniol (50%), nerol (10%), oct-1-en-3-
ol (50%), linalool (40%), and nerolidol (50%).
Procedure 5: Barbier Mode; Typical Procedure for 2b
nor-Radjanol (1a, 200 g, 1 mol)12 and LiH (10 g, 1.24 mol) in THF
(400 mL) were heated with strong stirring and under argon at 65 °C
for 6 h until H2 evolution ceased. Mg turnings (100 g, 4.1 mol) and
THF (500 mL) were added at 25 °C. After addition of CH2Br2 (8.5
g, 50 mmol) the mixture was heated to 65 °C, and CH2Br2 (280 mL,
4 mol) was added over 7 h. After a further 1 h at 65 °C the suspen-
sion was quenched with 2 M HCl with cooling. The mixture was ex-
tracted with t-BuOMe, the combined extracts were washed with
H2O until pH 7, dried (MgSO4), and concentrated to give a crude
mixture of mono- and biscyclopropanes (65% corr., 2a/2b 75:20)
which, after two further reaction cycles and distillation (100 °C/
0.07 mbar) gave pure javanol (2b) (95 g, 43%). The analytical data
(NMR, MS, IR, odor) for 2b were consistent with the literature.31
(12) Preparation of substrates 1 according to the literature:
(a) 1a: Bajgrowicz, J. A.; Frank, I.; Frater, G.; Hennig, M.
Helv. Chim. Acta 1998, 81, 1349. (b) 1b: Schröder, F.
WO 2006,066,436, 2005; Chem. Abstr. 2006, 145, 103855.
(c) 1c: Tamura, M.; Suzukamo, G. Tetrahedron Lett. 1981,
22, 577. (d) 1c: Tamura, M.; Suzukamo, G.; Hirose, K.
EP 0,029,603, 1980; Chem. Abstr. 1981, 95, 204220.
(e) 1d: see ref. 1. (f) 1e: Levorse, A. T. Jr. US 5,234,902,
1992; Chem. Abstr. 1993, 119, 210271. (g) 1f: Bajgrowicz,
J. A.; Bringhen, A.; Frater, G.; Mueller, U. EP 743,297,
1996; Chem. Abstr. 1996, 126, 103856. (h) 1g: Kaiser, R.;
Lamparsky, D. EP 0,045,453, 1982; Chem. Abstr. 1982, 96,
199080. (i) 1h: Berg-Schultz, K.; Bajgrowicz, J. A.; Baudin,
J. WO 2005,026,092, 2005; Chem. Abstr. 2005, 142,
336041. (j) 1i: Jacob, P. III.; Brown, H. C. J. Org. Chem.
1977, 42, 579. (k) 1j: Martin, A. EP 770,671, 1997; Chem.
Abstr. 1997, 126, 334220. (l) 1k: Traas, P. C.; Boelens, H.
Rec. Trav. Chim. Pays-Bas 1973, 92, 985. (m) 1l: Arbuzov,
B. A.; Isaeva, Z. G.; Timoshina, T. N.; Efremov, Y. Y. Russ.
J. Org. Chem. 1993, 29, 1647.
Acknowledgment
For valuable input we thank Prof. Sir Jack Baldwin (Oxford), Prof.
A. Hoveyda (Boston), Prof. A. Vasella (ETH Zürich), Prof. G. Fra-
ter, Dr. P. Gygax (both Givaudan Dübendorf), Dr. A. Goeke
(Givaudan Shanghai), and Dr. P. Kraft (Givaudan Dübendorf). For
skillful experiments we thank P. Aebersold, B. Bonfils, S. Elmer,
R. Lang, M. Mathys, T. Reinmann, B. Rothmund, and F. Rüthi. For
GC/MS and HRMS measurements we thank Dr. J. Schmid. For
proofreading we thank Dr. S. Derrer (Giraudan Dübendorf). For
further acknowledgments see ref. 1.
(13) Watson, S. C.; Malpass, D. B.; Yeargin, G. S. DE 2,430,287,
1975; Chem. Abstr. 1975, 83, 27544.
(14) Preparation of the substrates: (a) 5r: Ullrich, F. W.;
Rotscheidt, K.; Breitmaier, E. Chem. Ber. 1986, 119, 1737.
(b) 5s: Hall, J. B.; Wiegers, W. J. US 4010207, 1977; Chem.
Abstr. 1977, 87, 5396.
(15) Fanta, W. I.; Erman, W. F. J. Org. Chem. 1968, 33, 1656.
(16) Cheng, D.; Kreethadumrongdat, T.; Cohen, T. Org. Lett.
2001, 3, 2121.
References:
(1) Brunner, G.; Eberhard, L.; Oetiker, J.; Schröder, F. J. Org.
Chem. 2008, 73, 7543.
(2) Review: Charette, A. B.; Beauchemin, A. Org. React. 2001,
58, 1.
(3) The reactivity order of dihalomethanes is in accordance with
that of the radical halogen abstraction from these
compounds.
(4) (a) Friedrich, E. C.; Domek, J. M.; Pong, R. Y. J. Org. Chem.
1985, 50, 4640. (b) Friedrich, E. C.; Lewis, E. J. J. Org.
Chem. 1990, 55, 2491. (c) Friedrich, E. C.; Niyati-
Shirkhodaee, F. J. Org. Chem. 1991, 56, 2202.
(5) (a) Bolm, C.; Pupowicz, D. Tetrahedron Lett. 1997, 38,
7349. (b) Pupowicz, D. Dissertation; Philipps-Universität
Marburg: Germany, 1997.
(17) 2-Hexylcyclopent-2-enone = isojasmone B 11. Commercial
available from Oxford Chemicals.
(18) Preparation of substrates 7 according to the literature: (a)
7a: Jurkauskas, V.; Sadighi, J. P.; Buchwald, S. L. Org. Lett.
2003, 5, 2417. (b) 7c: Berube, G.; Fallix, A. G. Can. J.
Chem. 1991, 69, 77. (c) 7d: Trost, B. M.; Keeley, D. E.
J. Am. Chem. Soc. 1976, 98, 248. (d) 7e: Berthelot, P.;
Vaccher, C.; Devergnies, M.; Flouquet, N.; Debaert, M.
J. Heterocycl. Chem. 1988, 25, 1525.
(19) Rathke, M. W.; Nowak, M. J. Org. Chem. 1985, 50, 2624.
(6) (a) Villiéras, J. C. R. Hebd. Seances Acad. Sci. 1965, 261,
4137. (b) Villiéras, J. Bull. Chem. Soc. Fr. 1967, 5, 1520.
Synthesis 2009, No. 21, 3708–3718 © Thieme Stuttgart · New York

3718
G. Brunner et al.
PRACTICAL SYNTHETIC PROCEDURES
(20) Agarwal, V. K.; Thappa, R. K.; Agarwal, S. G.; Mehra,
M. S.; Dhar, K. L.; Atal, C. K. Indian Perfumer 1983, 27,
112.
(21) Barras, J.-P.; Bourdin, B.; Schröder, F. Chimia 2006, 60,
574.
(22) (a) Tamura, M.; Suzukamo, G. Tetrahedron Lett. 1981, 22,
577. (b) Netland, P. Org. Prep. Proced. Int. 1980, 12, 261;
and references therein.
alcoholates versus the lithium alcoholate ion pair. For
mechanistic details see ref. 1.
(26) The syn-selectivities are in accord with a staggered Houk
model.27
(27) (a) Roquet, F.; Sevin, A.; Chodkiewicz, W. C. R. Seances
Acad. Sci., Ser. C 1970, 848. (b) Ratier, M.; Castaing, M.;
Godet, J.-Y.; Pereyre, M. J. Chem. Res., Miniprint 1978,
2309.
(23) Sakaguchi, T.; Nagashima, K.; Yoshida, T. JP 49,047,345,
1974; Chem. Abstr. 1974, 81, 104862.
(28) GC-analysis on a 5% phenyl–95% dimethylpolysiloxane
column.
(29) Pretsch, E.; Bühlmann, P.; Affolter, C. Structure
Determination of Organic Compounds; Springer Verlag:
Berlin, 2000, 202.
(30) Narula, A. P. S.; Arruda, E. M. US 20060,189,510, 2005;
Chem. Abstr. 2006, 145, 255592.
(31) Bajgrowicz, J. A.; Frater, G. EP 0,801,049, 1997; Chem.
(24) Alternative deprotonation reagents such as NaH or MeMgCl
were less efficient. Alternative dihalides such as ClCH2Br,
ClCH2I, and CH2I converted 1b similarly into 2b but without
remote cyclopropanation to 2a. Evidence for exchange
reactions between lithium alkoxides and Grignard reagents:
Micha-Screttas, M.; Constantinos, G.; Steele, B. R.;
Heropoulos, G. A. Tetrahedron Lett. 2002, 43, 4871.
(25) A possible explanation for this rate enhancement is the more
covalent character of the Mg–O bond of the MgX-
Abstr. 1997, 127, 358652.
Synthesis 2009, No. 21, 3708–3718 © Thieme Stuttgart · New York