A convenient one-pot synthesis of homoallylic halides and 1,3-butadienes

Article abstract of DOI:10.1016/j.tetlet.2003.07.006

An efficient one-pot synthetic pathway for the preparation of homoallylic halides by in situ generated MgBrCl-promoted ring opening of cyclopropylcarbinyl acetates has been established. An easily accessible one-pot synthetic protocol of 1,3-butadienes by the elimination of hydrogen halides from the resulting homoallylic halides in the presence of an excess amount of strong base has also been developed.

Full text of DOI:10.1016/j.tetlet.2003.07.006

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 8033–8036
A convenient one-pot synthesis of homoallylic halides and
1,3-butadienes
Ken-Tsung Wong* and Ying-Yueh Hung
Department of Chemistry, National Taiwan University, Taipei 106, Taiwan, ROC
Received 11 April 2003; revised 2 July 2003; accepted 31 July 2003
Abstract—An efficient one-pot synthetic pathway for the preparation of homoallylic halides by in situ generated MgBrCl-pro-
moted ring opening of cyclopropylcarbinyl acetates has been established. An easily accessible one-pot synthetic protocol of
1,3-butadienes by the elimination of hydrogen halides from the resulting homoallylic halides in the presence of an excess amount
of strong base has also been developed.
© 2003 Elsevier Ltd. All rights reserved.
In modern molecular design and synthesis, 1,3-butadi-
ene serves as a versatile building skeleton for the con-
struction of complicated molecule via the famous
Diels–Alder reaction.1 A convenient synthetic protocol
is highly desired for the quick access of this important
precursor. A possible synthetic pathway towards the
1,3-butadiene is the direct elimination of hydrogen
halides from homoallylic halides. However, the syn-
thetic approaches of homoallylic halides to the best of
our knowledge are very limited. One feasible way to
homoallylic halides relies on the direct functional group
transformation from homoallylic alcohols with suitable
reagent such as PBr3.2 Another intriguing approach for
the synthesis of homoallylic bromides is focused on the
ring opening of cyclopropylcarbinols and their deriva-
tives.3 For example, treatment of the cyclopropyl-
carbinols with aqueous HBr or HCl stereoselectively
afforded the E-homoallylic bromides or chlorides as the
major products with reasonable yields respectively.4
However, at lower reaction temperature, direct replace-
ment of the hydroxy group by the Br group led to
cyclopropylcarbinyl bromide as the major product.5
Ring opening of the cyclopropylcarbinol promoted by
PBr3 has also been reported to afford the homoallylic
bromide.6 More recently, this transformation has been
improved from the view point of chemical yields by
treating the a-benzyl-substituted cyclopropylcarbinols
with PPh3·CBr4 complex in a mixed solvent of CH2Cl2
and acetonitrile.5 Lewis acid such as MgBr2 or MgI2
has also been reported to mediate the ring opening of
cyclopropylcarbinols to give the corresponding homoal-
lylic halides. However, a mixture of E/Z alkenes was
obtained upon using these conditions.7 In addition,
ZnBr2-promoted ring opening of cyclopropylcarbinyl
bromide has also been shown to furnish homoallylic
bromide quantitatively.5 The isolation of the starting
compounds such as cyclopropylcarbinols or cyclo-
propylcarbinyl bromide is necessary in the above trans-
formations. We report herein a convenient one-pot
synthetic protocol for the stereospecific synthesis of
homoallylic halides by in situ generated Lewis acid
MgBrCl-promoted ring opening of cyclopropylcarbinyl
acetate, without isolating the cyclopropylcarbinyl ace-
tate. Further treatment of the resulting crude homoal-
lylic halides with a strong base led to a convenient
one-pot procedure for the synthesis of 1,3-butadiene.
The easy access of the starting cyclopropylcarbinyl
acetates renders this one-pot procedure more valuable
for a quick preparation of homoallylic halides and
1,3-butadienes.
The addition of cyclopropylmagnesium bromide to
benzaldehyde should give (cyclopropylphenylmethoxy)
magnesium bromide, and subsequently quenching of
this intermediate with acetyl chloride should provide
the cyclopropylcarbinyl acetate as a single product.
However, a slight change of the work-up procedure led
to a different result. Instead of quenching the addition
mixture with aqueous solution, the resulting reaction
mixture was concentrated by rotary evaporation, and
was followed by extracting with ether. It cleanly
afforded a ring opening product, which was confirmed
by 1H NMR with the absence of the characteristic
Keywords: ring opening; homoallylic halide; 1,3-butadiene; cyclo-
propylcarbinyl acetate.
* Corresponding author. E-mail: kenwong@ccms.ntu.edu.tw
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.07.006

8034
K.-T. Wong, Y.-Y. Hung / Tetrahedron Letters 44 (2003) 8033–8036
chemical shifts corresponding to cyclopropyl protons.
After adding the acetyl chloride to the Grignard
reagent adduct of benzaldehyde, the reaction mixture
was heated up to 50°C to lead to the isolation of the
same product (1).8
opening of cyclopropylcarbinols, which led to a mixture
of cis/tans isomers.
(2)
(1)
Initial attempts to eliminate the HX (X=Br or Cl) by
treating the isolated homoallylic halides with KOH in
the presence of 18-crown-69 only resulted in the recov-
ery of the starting homoallylic compounds. Other
organic bases such as Et3N, DBU,10 and EtN(iPr)2 have
also been tested for the elimination of hydrogen halides
from the in situ generated homoallylic halides. How-
ever, no evidence indicated the formation of the desired
1,3-butadienes. The desired 1,3-butadienes can be
obtained by treating the homoallylic halides with a
strong bulky base, tert-BuOK,11 in reflux THF. Thus,
combining the easy and convenient synthesis of
homoallylic halides and the subsequent elimination of
HX, a one-pot synthesis of 1,3-butadiene has been
developed. The in situ generated cyclopropylcarbinyl
acetates were heated to 50°C for 1 h, then an excess
amount of tert-BuOK (3.5 equiv.) was added subse-
quently and the mixture was refluxed overnight to
afford 1,3-butadienes in moderate yields (Eq. (3)).8 The
results are shown in Table 1.
1H NMR analysis of the resulting product indicates two
quartets at 2.80 ppm (stronger intensity) and 2.71 ppm
(weaker intensity), and two triplets at 3.50 ppm
(stronger intensity) and 3.65 ppm (weaker intensity)
with a ratio of 5.6 to 1. However only two types of
olefinic protons with the same intensity were observed
at 6.47 ppm (d, J=16 Hz) and 6.21 ppm (dt, J=7.2, 16
Hz), respectively. The large coupling constant of the
olefinic protons indicates the formation of a trans-olefin
exclusively. Careful analysis of the resulting products
by GC–MS clearly indicated that the minor product
contains a chlorine atom whereas the major product
contains a bromine atom. According to the spectro-
scopic characterization, it is reasonable to assign the
major product as a homoallylic bromide and the minor
counterpart as a homoallylic chloride. The halides in
the product can be assumed to come from the in situ
generated magnesium salt, MgBrCl.
(3)
In order to explore the scope and limitation of this
reaction, different carbonyl compounds, including aryl
aldehydes (entries 2 and 3), cinnamaldehyde (entry 4),
aliphatic aldehydes (entries 5 and 6), and arylketones
(entries 7 and 8) were employed as substrates (Eq. (2)),
the results are summarized in Table 1. In general, the
isolated yields of the resulting homoallylic halides are
better for activated carbonyl compounds. However,
aryl ketones showed much lower reactivity towards this
transformation as compared to that of aryl aldehydes.
For example, starting from benzophenone, only 73% of
the homoallylic halides were obtained with a Br/Cl
ratio of 3.4 (entry 7). The homoallylic halides deriva-
tized from aliphatic aldehydes by our one-pot synthesis
only results in moderate yields (entries 5 and 6). Appar-
ently, only trans isomer was formed that is opposed to
the previous report4 of HBr or MgBr2-promoted ring
This one-pot synthetic protocol displays promising
potential for the preparation of 1-aryl-1,3-butadienes
(entries 1–3). 1-Phenyl-1,3,5-triene can also be isolated
conveniently in 53% yield (entry 4). 1,1-Disubstituted-
1,3-butadienes are also accessible by this method
(entries 7 and 8). However, the product analyses of the
1,3-butadienes derivatized from the corresponding
1
aliphatic homoallylic halides by H NMR and GC–MS
indicated that the product consists of a mixture of
isomers with lower isolation yields (entries 5 and 6).
The complicated product distribution may be attributed
to the presence of allylic protons in the aliphatic buta-
dienes, which isomerized through a deprotonation–pro-
tonation process under strong basic condition.
Table 1. The results of one-pot synthesis of homoallylic halides and 1,3-butadienes
Entry
R1
R2
Br/Cl
1 Yield (%)a
2 Yield (%)a
1
2
3
4
5
6
7
8
Ph
H
H
H
H
H
H
Ph
CH3
5.6
6.4
8.1
4.1
10.4
8.8
3.4
8.0
81
90
83
85
40
50
73
70
63
63
69
53
4-MeO-Ph
4-Ph-Ph
trans-PhCH2ꢀCH2
CH3(CH2)8-
c-C6H11
Ph
33b
23b
58
Ph
56
a All yields are isolated yields.
b A mixture of isomers was detected by GC–MS analysis.

K.-T. Wong, Y.-Y. Hung / Tetrahedron Letters 44 (2003) 8033–8036
8035
Acknowledgements
Mechanistic studies on the MgBr2-promoted ring
opening of cyclopropylcarbinols have suggested a
mechanism involving rapid formation of an ion-pair
intermediate, which successively undergoes ring open-
ing to give homoallylic bromide.7c The coordination
of the -OH group with Lewis acid is the pre-require-
ment for the activation of the CꢁO bond to form the
ion-pair intermediate. In this present investigation, we
believe that the homoallylic halides obtained by our
one-pot synthesis come from the in situ generated
Lewis acid (MgBrCl)-promoted ring opening of the
cyclopropylcarbinyl acetates via the coordination of
Lewis acid on the oxygen of the acetate. Subsequent
attack of the resulting ion-pair intermediate by the
corresponding halides (Br− or Cl−) led to the products
as a mixture. In order to prove this assumption, the
following two experiments have been performed. (1)
Replacement of acetyl chloride by acetyl bromide
could generate MgBr2 in situ as the Lewis acid, which
should subsequently promote the ring opening reac-
tion of the resulting cyclopropylcarbinyl acetate and
lead to the isolation of homoallylic bromide as the
single product. Indeed, treatment of 4-biphenylcarbox-
aldehyde by our one-pot procedure using acetyl bro-
mide as the acetylating agent only afforded the
corresponding homoallylic bromide with an isolated
yield of 82%. This observation depicts that the source
of chloro substitutent found in the products is origi-
nated from the in stiu generated Lewis acid, MgBrCl.
(2) a-Biphenyl cyclopropylcarbinyl acetate 3 was iso-
lated in 78% by aqueous work-up, which afforded the
homoallylic bromide quantitatively by its treatment
with MgBr2 in reflux THF (Eq. (4)). The result of
this stepwise reaction clearly indicates that the cyclo-
propylcarbinyl acetate can serve as a starting material
for the synthesis of homoallyic halides via ring open-
ing transformation promoted by the in situ generated
Lewis acid MgBrX.
We thank the National Science Council of Taiwan
for the financial support.
References
1. (a) Nicolaou, K. C.; Snyder, S. A.; Montagnon, T.;
Vassilikogiannakis, G. Angew. Chem., Int. Ed. 2002, 41,
1668–1698; (b) Quinkert, G.; Del Grosso, M. Stereosel.
Synth. 1993, 109–134; (c) Brocksom, T. J.; Correa, A.
G.; Naves, R. M.; Silva, F., Jr.; Catani, V.; Ceschi, M.
A.; Zukerman-Schpector, J.; Toloi, A. P.; Ferreira, M.
L.; Brocksom, U. Org. Synth. Theory Applic. 2001, 5,
39–87.
2. Glennon, R. A.; Salley, J. J. J. Med. Chem. 1981, 24,
678–683.
3. Sarel, S.; Yovell, J.; Imber, M. S. Angew. Chem., Int.
Ed. Engl. 1968, 8, 577–588.
4. (a) Corey, E. J.; Hartmann, R.; Vatakencherry, P. A. J.
Am. Chem. Soc. 1962, 95, 2611–2614; (b) Hanack, M.;
Eggensperger, H. Chem. Ber. 1963, 96, 1259–1264; (c)
Hanack, M.; Kang, S.; Ha¨ffner, J.; Go¨rler, K. Liebigs
Ann. Chem. 1965, 690, 98–114; (d) Liedtke, R. J.; Ger-
rard, A. F.; Diekman, J.; Djerassi, C. J. Org. Chem.
1972, 37, 776–789; (e) Julia, M.; Paris, J.-M. Tetra-
hedron Lett. 1974, 38, 3445–3446.
5. Matveeva, E. D.; Kvasha, M. P.; Kurts, A. L. Russ. J.
Org. Chem. 1996, 32, 17–20.
6. (a) Maercker, A.; Roberts, J. D. J. Am. Chem. Soc.
1966, 88, 1742–1759; (b) Brady, S. F.; Ilton, M. J. A.;
Johnson, W. S. J. Am. Chem. Soc. 1968, 90, 2882–
2889; (c) Johnson, W. S.; Li, T.; Faulkner, D. J.;
Campbell, S. F. J. Am. Chem. Soc. 1968, 90, 6225–
6226.
7. (a) McCormick, J. P.; Barton, D. L. J. Chem. Soc.,
Chem. Commun. 1975, 303–304; (b) McCormick, J. P.;
Barton, D. L. J. Org. Chem. 1980, 45, 2566–2570; (c)
McCormick, J. P.; Fitterman, A. S.; Barton, D. L. J.
Org. Chem. 1981, 46, 4708–4712.
8. Experimental procedure for the one-pot synthesis of
homoallylic halides and 1,3-butadienes from the corre-
sponding aldehyde and ketone: Cyclopropylmagnesium
bromine (1.0 M, 1.2 equiv.) was freshly prepared by
treating cyclopropyl bromine with Mg turning in THF.
To this Grignard solution, the corresponding aldehyde
or ketone (1.0 equiv.) was added in one portion at 0°C.
The resulting mixture was further added with acetyl
chloride (1.2 equiv.) at room temp. and heated to 50°C
for 1 h. The solvent was removed in vacuo, the crude
product was extracted from the residue with Et2O. Pure
homoallyl product was purified by chromatography on
SiO2 with elution of EtOAc/hexanes (1/9, v/v).
(4)
In summary, by slightly modifying the reaction condi-
tion we have established an efficient one-pot synthetic
pathway for the preparation of homoallylic halides by
in situ generated MgBrCl-promoted ring opening of
cyclopropylcarbinyl acetates. In the presence of an
excess amount of a strong base, elimination of hydro-
gen halides from homoallylic halides gives 1,3-butadi-
enes. An easily accessible one-pot synthetic protocol
of the synthesis of 1,3-butadiene from in situ gener-
ated homoallylic halides has also been developed.
For 1,3-butadienes, the mixture after adding acetyl
chloride was heated at 50°C for 1 h. Excess amount
(3.5 equiv.) of KOtBu was added and the mixture was
refluxed overnight. The crude 1,3-butadiene was iso-
lated according to the general procedure and purified
by chromatography on SiO2 eluing with hexanes.

8036
K.-T. Wong, Y.-Y. Hung / Tetrahedron Letters 44 (2003) 8033–8036
11. (a) Kataoka, F.; Shimizu, N.; Nishida, S. J. Am. Chem.
9. (a) Huang, W.; Pulaski, S. P.; Meinwald, J. J. Org. Chem.
Soc. 1980, 102, 711–716; (b) Kataoka, F.; Nishida, S.;
Tsuji, T.; Murakami, M. J. Am. Chem. Soc. 1981, 103,
6878–6884; (c) Toth, M.; Szoecs, G.; van Nieukerken, E.
J.; Philipp, P.; Schmidt, F.; Francke, W. J. Chem. Ecol.
1995, 21, 13–28.
1983, 48, 2270–2274; (b) Millar, J. G.; Underhill, E. W.
Can. J. Chem. 1986, 64, 2427–2430; (c) Mori, K.;
Takeuchi, T. Liebigs Ann. Chem. 1989, 453–458.
10. Roversi, E.; Monnat, F.; Vogel, P.; Schenk, K.; Roversi,
P. Helv. Chim. Acta 2002, 85, 733–760.