Use of cyclic allylic bromides in the zinc-mediated aqueous Barbier-Grignard reaction

Article abstract of DOI:10.3390/60800655

The zinc-mediated aqueous Barbier-Grignard reaction of cyclic allylic bromide substrates with various aldehydes and ketones to afford homoallylic alcohols was investigated. Aromatic aldehydes and ketones afforded adducts in good yields (66-90%) and with good diastereoselectivities. Non-aromatic aldehydes also reacted well under these conditions, but only poor yields were obtained with non-aromatic ketones. Regioselectivity was high when some substituted cyclic allylic bromides were investigated.

Full text of DOI:10.3390/60800655

Molecules 2001, 6, 655-662
molecules
ISSN 1420-3049
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Use of Cyclic Allylic Bromides in the Zinc–Mediated Aqueous
Barbier–Grignard Reaction
Gary W. Breton*, John H. Shugart, Christine A. Hughey, Brian P. Conrad, Suzanne M. Perala
Department of Chemistry, Berry College, Mount Berry, GA 30149, USA. Tel. (706)-290-2661, Fax
(706) 238-7855.
* Author to whom correspondence should be addressed; e-mail: gbreton@berry.edu
Received: 27 February 2001 / Accepted: 12 June 2001 / Published: 31 July 2001
Abstract: The zinc–mediated aqueous Barbier–Grignard reaction of cyclic allylic bromide
substrates with various aldehydes and ketones to afford homoallylic alcohols was
investigated. Aromatic aldehydes and ketones afforded adducts in good yields (66–90%)
and with good diastereoselectivities. Non–aromatic aldehydes also reacted well under these
conditions, but only poor yields were obtained with non–aromatic ketones. Regioselectivity
was high when some substituted cyclic allylic bromides were investigated.
Keywords: Barbier–Grignard reaction, aqueous reactions, organozinc, homoallylic alcohols.
Introduction
The synthesis of homoallylic alcohols via the reaction of cyclic and acyclic allylic organometallic
compounds with aldehydes and ketones is an important process in synthetic organic chemistry [1].
Unfortunately, however, the process typically requires the use of toxic and/or water–sensitive
organometallic compounds. Recently a “greener” allylation method has been developed in which the
reaction is carried out in aqueous media under Barbier–type conditions using allylic halides and metals
such as zinc, tin, and indium [2]. The method is simple, avoids the handling of toxic and water-
sensitive reagents, and generally affords good–to–high yields of products. In addition, examples of
impressive regio–, diastereo–, and (more recently) enantioselectivities have also been reported [2,3].
While acyclic allylic halides have been subjected to detailed investigations in this regard, the reactivity
of cyclic allylic halides—with only a few exceptions [4]—have escaped attention despite the fact that

Molecules 2001, 6
656
the cycloalkenyl–substituted methanols generated from these reactions are of considerable synthetic
importance [1b,5]. We have therefore undertaken a systematic study of the reactivity of a series of
cyclic allylic bromides under Barbier–type conditions with the intention of determining the feasibility
and scope of the method, as well as the regio– and diastereoselectivity of the process.
Results and Discussion
Addition of 2 equivalents of 3–bromocyclohexene (1b) as a solution in THF to a rapidly stirred
mixture of zinc metal (2 eq) and benzaldehyde (1 equiv) in saturated aqueous NH4Cl resulted in rapid
consumption of the zinc metal in a mildly exothermic reaction. The addition product 2b (R = C6H5, R’
= H) was isolated in 87% yield (Table 1).
Br
HO
R'
R
O
Zn°, H2O
THF
+
R
R'(H)
H
n
n
1a n = 0
1b n = 1
1c n = 2
1d n = 3
2a–d
1
The H-NMR spectra of both the crude and purified adduct suggested the presence of
diastereomeric products. Gas chromatographic analysis indicated an 83:17 ratio of the erythro and
threo isomers, respectively, identified by comparison of their 1H- and 13C-NMR spectra with literature
data [5a]. The major by-product from this reaction was a dimeric compound formed from Wurtz–type
coupling of the starting bromide [6].
Bromide 1b reacted with substituted benzaldehydes to afford adducts in good yields and
stereoselectivities (see Table 1). In all cases, erythro adducts were obtained as the predominant
diastereomer as determined by comparison of their 1H- and/or 13C-NMR spectra with those of the same
or similar compounds [5a-b,7]. Reaction with the non–aromatic aldehydes heptaldehyde and
isobutyraldehyde, however, afforded very low stereoselectivity although the mixtures of diastereomers
were obtained in reasonable yield. The change in reactivity from aromatic to non–aromatic aldehydes
was also marked by a change in diastereoselectivity from that favoring formation of erythro adducts to
that favoring threo adducts. A reasonable yield of addition product was also obtained with the
aromatic ketones acetophenone and benzophenone, and with good diastereoselectivity in the case of
acetophenone [8]. However, the non–aromatic ketones 3-pentanone and acetone afforded only poor
yields of adduct (12% and 28% yield, respectively) and were not further pursued.

Molecules 2001, 6
657
Table 1. Reaction of Cyclic Allylic Bromides with Various
Aldehydes and Ketones Under Aqueous Barbier–Type
Conditionsa
Ratio of
Cyclic
Bromide
%
Substrate
diastereomers
erythro/threoc
83:17
Yieldb
benzaldehyde
tolualdehyde
87
90
90
77
72
83
66
82e
85
85
1b
87:13
85:15
45:55
34:66
90:10d
_
4-chlorobenzaldehyde
n–heptaldehyde
isobutyraldehyde
acetophenone
benzophenone
tolualdehyde
80:20f
89:11
87:13
1a
1c
1d
tolualdehyde
tolualdehyde
a
Performed according to the General Procedure described in the
b
c
Experimental.
Isolated yields.
Ratio determined by gas
chromatography unless otherwise specified. dRatio determined by
13C-NMR spectroscopy. eReaction conducted at 0 °C. fRatio
determined by 1H-NMR spectroscopy.
In order to determine the scope of the method, a series of cyclic allylic bromides (1a–d) that
differed in ring size was investigated. Utilizing the same experimental protocol as was used with 1b,
with the exception that three equivalents of bromide and zinc were used rather than two, good yields of
addition products were obtained with tolualdehyde as substrate in all cases (Table 1). The
stereoselectivity of the process was found to be nearly independent of the size of the bromide ring. The
reactivity of bromide 1a towards hydrolysis under the aqueous reaction conditions required conducting
the reaction at 0 °C rather than the usual room temperature to limit competing formation of 2–
cyclopenten–1–ol.
Reaction of bromide 3 with benzaldehyde could have conceivably afforded adduct 4 or regioisomer
5 by way of the two possible isomeric organometallic intermediates (see below). We found, however,
that standard reaction conditions yielded only adduct 4 in 61% yield as a 90:10 mixture of
erythro/threo diastereomers, respectively, resulting from reaction at the more highly substituted allylic

Molecules 2001, 6
658
site [7]. This finding is in agreement with those previously reported for acyclic allylic bromides in
which reaction was also generally observed to occur at the more substituted allylic position [2].
ZnBr
Br
ZnBr
Zn°, H2O
THF
3
OH
OH
PhCHO
4
5
61% yield
not detected
Similarly, reaction of bromide 6 with tolualdehyde afforded adduct 7 as the sole product in 82%
yield as a 91:9 mixture of diastereomers [9]. The major diastereomer of 7 is tentatively assigned the
erythro configuration based on two observations: 1) the chemical shift of the carbinol proton of the
1
major diastereomer was found at lower field in the H-NMR (δ 4.67) relative to that of the minor
isomer (at δ=4.52) as was observed for the erythro isomers of the other aromatic adducts 2a–d, and 2)
the GC retention time of the major isomer was shorter than that of the major, and it was observed in all
cases examined by us that the erythro isomer consistently eluted from a carbowax GC column prior to
that of the threo isomer. Given the potential for conversion of compound 7 to ketone 8 via oxidative
cleavage of the exocyclic double bond, this reaction presents itself as a possible aqueous-based
synthetic alternative to the conventional aldol reaction. Studies directed towards the exploitation of
this potential route are underway in our labs.
Br
O
OH
Zn°, H O
2
H
+
THF
6
7
O
OH
8

Molecules 2001, 6
659
Conclusions
Cyclic allylic bromides behave admirably in the zinc-mediated aqueous Barbier-Grignard reaction
towards aromatic and non–aromatic aldehydes, as well as towards aromatic ketones to afford good
yields of the corresponding homoallylic alcohols. Good diastereoselectivities were observed for
aromatic aldehyde and ketone substrates.
Acknowledgments
Acknowledgment is made to the Donors of The Petroleum Research Fund, administered by the
American Chemical Society, for partial support of this research. We also thank Berry College for
partial support of this work. The FT–NMR upgrade used in this work was made possible by NSF DUE
ILI-IP grant # 9750684.
Experimental
General
Unless otherwise indicated, reagents were obtained from commercial suppliers, and used without
further purification. Column chromatography was conducted on Merck grade 60 (230–400 mesh) silica
1
gel. H- and 13C-NMR spectra were recorded in CDCl3 at 60 and 15 MHz, respectively. Gas
chromatography was conducted using a 6' × 1/8" stainless steel column packed with 10% carbowax
20M on 80/100 Chromosorb W AW. Bromides 1a and 1c–1d were synthesized via standard allylic
bromination of the corresponding alkenes utilizing N–bromosuccinimide followed by distillation at
reduced pressure [10].
3–Bromo–1–methylcyclohexene (3) [11].
A solution of 2–cyclohexenone (5.16 g, 0.0538 mol) in diethyl ether (5 mL) was added dropwise
via syringe at 0 °C under N2 to a stirring solution of a 1.4 M MeLi solution (45 mL, 1.4 mol, 1.2 equiv)
in diethyl ether. The resulting solution was stirred for 30 minutes and then quenched with saturated
aqueous. NH4Cl solution (40 mL). The organic phase was separated, and the aqueous phase washed
with diethyl ether (2 × 20mL). The combined organic phases were dried over Na2SO4, filtered, and
1
concentrated. Column chromatography afforded 1–methyl–2–cyclohexen–1–ol as a colorless oil: H-
13
NMR δ=6.63 (br s, 2H), 2.10–1.90 (m, 3H), 1.63 (br m, 4H), 1.27 (s, 3H); C-NMR δ==133.8, 128.4,
68.4, 38.6, 30.3, 25.9, 20.5; IR (neat) 3361, 3019, 2935, 1125 cm-1.
A portion of the 1–methyl–2–cyclohexen–1–ol (0.79 g, 7 mmol) was added dropwise with stirring
to concentrated HBr (2.9 mL). A second layer formed immediately. To the mixture was added CH2Cl2
(2 mL), the phases were mixed, and the organic layer removed, dried over Na2SO4 filtered, and
concentrated under reduced pressure to afford bromide 3 which was used directly in the zinc reactions;

Molecules 2001, 6
660
1H-NMR δ=5.60 (br d, J = 5 Hz, 1H), 4.90 (br m, 1H), 2.1–1.5 (m, 6H), 1.65 (s, 3H); 13C-NMR
δ==139.1, 123.5, 50.5, 32.1, 29.5, 23.4, 18.5.
1-(Bromomethyl)cyclohexene (6) [12].
A solution of 1-cyclohexene-1-carboxylic acid (2.86 g, 0.024 mol) in ether (30 mL) was added
dropwise to a stirring mixture of LiAlH4 (1.08 g, 0.029 mol) in anhydrous ether (40 mL) in a 100 mL
RBF fitted with a reflux condenser. After full addition, the mixture was stirred for an additional 15
min, and then quenched with H2O (2 mL) followed by 10% H2SO4 (30 mL). The aqueous layer was
separated and washed with ether (2 × 5 mL). The combined organics were dried over Na2SO4, filtered
and concentrated to afford 2.33 g (87% yield) of α–(2–cyclohexen–1–yl)methanol as a colorless liquid;
1H-NMR δ=5.66 (br s, 1H), 3.93 (br s, 2H), 3.26 (br s, 1H, OH), 2.2–1.6 (m, 4H), 1.6–1.3 (m, 4H); 13C-
NMR δ==135.5, 120.3, 64.8, 23.6, 23.0, 20.6, 20.5; IR (neat) 3318, 2926, 1008 cm–1
Bromine (1.2 mL, 0.023 mol) was added to a stirring solution of triphenylphospine (6.0 g, 0.023
mol) in dry acetonitrile (30 mL) at 0 °C. The resulting mixture was stirred while a solution of α–(2–
cyclohexen–1–yl)methanol (2.33 g, 0.021 mol) in acetonitrile (3 mL) was added. The reaction mixture
was stirred for 10 minutes, and the acetonitrile was removed via rotary evaporation. The crude product
was loaded onto a silica gel column and eluted with a 5:1 hexane/ethyl acetate solvent mixture. The
fractions containing the product were concentrated to afford 2.87 g (79% yield) of 6. Final purification
1
was effected via vacuum distillation (b.p. 73 °C at 2 mm Hg); H-NMR δ=5.96(br m, 1H), 3.93 (br s,
2H), 2.2–1.8 (m, 4H), 1.8–1.3 (m, 4H)
General Procedure for the Reaction of Cyclic Allylic Bromides with Aldehydes and Ketones.
A solution of the cyclic bromide (2 or 3 mmol) in THF (2 mL) was added dropwise to a rapidly
stirring mixture of aldehyde or ketone (1 mmol), saturated aqueous NH4Cl (1 mL) and zinc metal (2 or
3 mmol, see text). An immediate reaction was observed to take place with loss of the zinc metal. The
mixture was stirred 3 h, filtered to remove excess zinc and precipitated salts, and the organic layer
separated. The aqueous layer was washed with ether (3 × 1 mL). The combined organics were dried
over Na2SO4, filtered, and concentrated. Reaction products were purified by column chromatography
(SiO2), eluting with a suitable hexane/ethyl acetate solvent mixture. The results are summarized in
Table 1.
NOTE: For the compounds below, the erythro and threo diastereomers were inseparable by column
chromatography. Data is provided for the major (erythro) isomer, but where distinct differences were
discernable, information for the threo isomer is included in square brackets (i.e., [ ]) immediately
following the corresponding data for the erythro isomer.
α–(2-Cycloocten-1-yl)-4-methylbenzenemethanol. Isolated as a colorless viscous liquid. Anal. Calcd
1
for C16H22O: C, 83.43; H, 9.63; Found: C, 83.01; H, 9.83; H-NMR δ=7.09 (br s, 4H), 5.50-5.00 (m,

Molecules 2001, 6
661
2H), 4.42 (d, J = 7.2 Hz, 1H) [4.36 (d, J = 7.6 Hz, 1H)], 3.20–2.5 (br m, 1H), 2.29 (s, 3H), 2.20–0.90
13
(m, 11H); C-NMR δ==21.5, 25.9, 27.1, 27.2 [27.3] , 29.7, 32.0 [32.9], 43.4 [44.2], 79.0, 126.1 (2C),
128.3 (2C), 129.2, 129.9, 136.3, 140.1; IR (neat) 3398, 3011, 2925, 2856, 1008 cm–1
α–(2-Cyclohepten-1-yl)-4-methylbenzenemethanol. Isolated as a colorless viscous liquid. Anal. Calcd
1
for C15H20O: C, 83.28; H, 9.32; Found: C, 82.99; H, 9.59; H-NMR δ=7.08 (br s, 4H), 5.80-5.50 (m,
2H), 4.45 (d, J = 6.9 Hz, 1H), 2.27 (s, 3H), 1.2-2.3 (10H); 13C-NMR δ=139.5, 136.0, 133.0, 131.2,
128.1, 126.0, 76.9, 46.9, 30.3, 28.9, 28.7, 27.1, 21.4; IR (neat) 3392, 3020, 2853, 1037 cm–1
α–(2-Cyclopenten-1-yl)-4-methylbenzenemethanol. Isolated as a colorless viscous liquid. Anal. Calcd
1
for C13H16O: C, 82.94; H, 8.57; Found: C, 82.79; H, 8.85; H-NMR δ 7.15 (br s, 4H), 5.90-5.70 (m,
1H), 5.45-5.20 (m, 1H), 4.45 (d, J = 6.8 Hz, 1H) [4.40 (d, J = 6.9 Hz, 1H)], 3.30–2.70 (br m, 1H), 2.31
(s, 3H), 2.50–1.53 (m, 5H); 13C-NMR δ 141.3, 137.4, 133.8, 132.2, 129.5, 127.0, 77.8 [78.0], 54.5
[54.0], 32.8, 26.2 [27.1], 21.7; IR (neat) 3407, 3052, 2932, 1058 cm–1
α–(2-Methylenecyclohexyl)-4-methylbenzenemethanol. Isolated as a white solid, m.p. 87.5–88°C. Anal.
Calcd for C15H20O: C, 83.28; H, 9.32; Found: C, 83.07; H, 9.44; 1H-NMR δ 7.20 (br s, 4H), 4.953 (br
s, 2H), 4.67 (d, J = 10.0 Hz, 1H) [4.52 (d, J = 6.5 Hz, 1H)], 3.30–2.70 (br m, 1H), 2.31 (s, 3H), 2.50–
13
1.53 (m, 5H); C-NMR δ 149.6, 139.5, 137.2, 128.9 [128.6], 126.9 [126.1], 110.7, 72.7 [73.1], 51.8
[50.4], 32.7 [34.9], 29.1, 28.1 [27.2], 22.2 [23.5], 21.0; IR (neat) 3407, 3071, 2937, 1038 cm–1
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Sample Availability: Available from the authors.
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