Novel one-pot method for chemoselective bromination and sequential sonogashira coupling

Article abstract of DOI:10.1021/ol101110v

(Equation Presented). An efficient one-pot method for bromination- elimination of allyl alcohol derivatives and sequential Sonogashira coupling has been developed. A highlight of the method is chemoselective DBU-promoted elimination of vicinal dibromoalka

Full text of DOI:10.1021/ol101110v

ORGANIC
LETTERS
2010
Vol. 12, No. 15
3316-3319
Novel One-Pot Method for
Chemoselective Bromination and
Sequential Sonogashira Coupling
Noriki Kutsumura,* Kentaro Niwa, and Takao Saito*
Department of Chemistry, Faculty of Science, Tokyo UniVersity of Science,
Kagurazaka, Shinjuku-ku, Tokyo 162-8601, Japan
nkutsu@rs.kagu.tus.ac.jp; tsaito@rs.kagu.tus.ac.jp
Received May 14, 2010
ABSTRACT
An efficient one-pot method for bromination-elimination of allyl alcohol derivatives and sequential Sonogashira coupling has been developed.
A highlight of the method is chemoselective DBU-promoted elimination of vicinal dibromoalkanes having an adjacent O-functional group.
Carbon-carbon bond-forming reactions of organometallic
reagents, such as the Sonogashira1 and Suzuki-Miyaura2
coupling processes, play key roles in the total synthesis of
natural products1d-g and as a result in investigations of
biologically active compounds. The applicability of these
C-C bond-forming reactions to the synthesis of complex
molecules is heightened by the fact that they require simple
and mild reaction conditions and that they tolerate an array
of potentially labile functionalities. Alkenyl halides are useful
building blocks in a wide range of transition-metal-catalyzed
C-C coupling reactions as well as in the preparation of
vinyllithiums3 and vinyl Grignard reagents, substrates of
radical reactions,4 and precursors of R-haloketones5 and
heterocycles.6
Pawluc´ et al. recently reported a one-pot synthesis of trans-
1-bromo-1-alkenes from styrenes by sequential ruthenium-
catalyzed silylative coupling followed by an N-halosuccin-
imide-mediated halodesilylation reaction.7 Moreover, Rault
(3) (a) Poss, C. S.; Rychnovsky, S. D.; Schreiber, S. L. J. Am. Chem.
Soc. 1993, 115, 3360. (b) Paqutte, L. A.; Hofferberth, J. E. J. Org. Chem.
2003, 68, 2266.
(1) (a) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975,
16, 4467. (b) Ireland, R. E.; Wipf, P. J. Org. Chem. 1990, 55, 1425. (c)
Izzo, I.; De Caro, S.; De Riccardis, F.; Spinella, A. Tetrahedron Lett. 2000,
41, 3975. For total syntheses of natural products, see: (d) Marshall, J. A.;
DuBay, W. J. J. Org. Chem. 1994, 59, 1703. (e) Nicolaou, K. C.; Koide,
K. Tetrahedron Lett. 1997, 38, 3667. (f) Koyama, Y.; Lear, M. J.;
Yoshimura, F.; Ohashi, I.; Mashimo, T.; Hirama, M. Org. Lett. 2005, 7,
267. (g) Hakuba, H.; Kitagaki, S.; Mukai, C. Tetrahedron 2007, 63, 12639.
(2) (a) Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95, 2457. (b) Yamada,
Y. M. A.; Takeda, K.; Takahashi, H.; Ikegami, S. J. Org. Chem. 2003, 68,
7733.
(4) Yokota, M.; Toyota, M.; Ihara, M. Chem. Commun. 2003, 422.
(5) (a) Vanbrunt, M. P.; Ambenge, R. O.; Weinreb, S. M. J. Org. Chem.
2003, 68, 3323. (b) Novikov, Y. Y.; Sampson, P. J. Org. Chem. 2005, 70,
10247.
(6) (a) Ohno, H.; Yamamoto, M.; Iuchi, M.; Tanaka, T. Angew. Chem.,
Int. Ed. 2005, 44, 5103. (b) Miyamoto, H.; Okawa, Y.; Nakazaki, A.;
Kobayashi, S. Tetrahedron Lett. 2007, 48, 1805. (c) Suzuki, H.; Sakai, N.;
Iwahara, R.; Fujiwara, T.; Satoh, M.; Kakehi, A.; Konakahara, T. J. Org.
Chem. 2007, 72, 5878.
(7) Pawluc´, P.; Hreczycho, G.; Szudkowska, J.; Kubicki, M.; Marciniec,
B. Org. Lett. 2009, 11, 3390.
10.1021/ol101110v  2010 American Chemical Society
Published on Web 07/01/2010

et al. reported a one-pot microwave-promoted synthesis of
cis-1-bromo-1-alkenes from anti-2,3-dibromo-3-arylalkanoic
acid followed by Suzuki-Miyaura coupling to afford cis-
stilbenes.8 Kuang et al. also reported a one-pot synthesis of
cis-1-bromo-1-alkenes from anti-2,3-dibromo-3-arylalkanoic
acid followed by Sonogashira coupling to afford the corre-
sponding enynes under microwave irradiation.9 Those one-
pot syntheses are highly efficient.
However, very little is known about the systematic
synthesis of 2-bromo-1-alkenes yet,10a-d although a few
sporadic examples exist of such syntheses.11 Herein, we
disclose a concise one-pot method for highly chemoselective
monobromination of allyl alcohol derivatives and sequential
Sonogashira coupling.
We anticipated that bromine addition to allyl alcohol
derivatives, followed by Ohgiya-Nishiyama’s method for
selective elimination,10 could be suitable for one-pot C2-
selective bromination of allyl alcohol derivatives. Therefore,
we started our investigations with 1-(allyloxy)-4-nitrobenzene
1a as a substrate, pyridinium bromide perbromide (Pyr·HBr3)
as a manageable brominating agent and 1,8-diazabicyclo-
[5.4.0]undec-7-ene (DBU) as a mild base (Table 1). In a
chloroform, concentrated in vacuo, and purified by silica gel
column chromatography. When 3.1 equiv of DBU was used,
the reaction gave the desired 2-bromo-1-alkene 2a together
with tiny amounts of regioisomers in a 99% overall yield
(entry 2). In contrast, when 2.2 equiv of DBU was used, the
reaction gave not only a small amount of 2a but also the
intermediate dibromoalkane as a major product (entry 1).
The solvent effect of acetonitrile on yield is comparable to
that of 1,2-dichloroethane, although the other solvents slow
down the rate of initial bromine addition (entries 2-6).
Significantly, when 1.1 equiv of potassium carbonate, rather
than pyridine, was added as a HBr scavenger before addition
of DBU, the requisite amounts of DBU were successfully
reduced (entries 7-9). Thus, we found that two optimal
conditions (entries 2 and 9) allowed efficient and versatile one-
pot synthesis of 2-bromo allyl alcohol derivatives 2 from allyl
alcohol derivatives 1 (Scheme 1).
Scheme 1
.
One-Pot C2-Selective Bromination of Allyl Alcohol
Derivatives 1
Table 1. Optimization of One-Pot Selective Bromination
condition Ia
condition II
equiv of time ratiob (2-bromo/
To confirm the generality of the one-pot chemoselective
bromination reaction, we examined a variety of allyl alcohol
derivatives 1 using optimized Method A and/or B (Table
2). First, the allyl alcohols (2-propen-1-ol), which are
protected by substituted phenyl (2b-2f), benzyl (2g, 2h),
benzoyl (2i-2k), and silyl (2l) groups, were investigated
(entries 1-15). As explained by Nishiyama et al.,10 the
yields and regioselectivity of the DBU-promoted elimination
reaction seem to be controlled by the inductive electron-
withdrawing effects of O-functional groups at the neighbor-
ing position. However, compound 2g, which has an electron-
donating PMB group, was obtained in high yield and
selectivity (entry 7). Surprisingly, compound 2l, with an
electron-donating bulky triisopropylsilyl group, was also
obtained in moderate yield and satisfactory selectivity (entries
14 and 15). In general, Method B requires a longer time for
the elimination reaction than does Method A.
yield (%);
additive
(equiv)
entry
solvent
DBU
(h)
1-bromo)
1
2
3
4
5
6
7
8
9
(CH2Cl)2
(CH2Cl)2
DMF
THF
CH3CN
toluene
2.2
3.1
3.1
3.1
3.1
3.1
1.1
2.2
1.1
48.0 6c; 45/1
0.2 99; 46/1
0.2 68d; 48/1
1.5 71e; 48/1
0.3 92; 45/1
0.4 64f; 30/1
7.5 0g
pyridine (1.0) (CH2Cl)2
pyridine (1.0) (CH2Cl)2
K2CO3 (1.0) (CH2Cl)2
3.0 88h; 37/1
1.0 91; 39/1
a The typical reaction times for bromination were between 12 and 14 h.
b Ratio of 2-bromoalkene and 1-bromoalkene was determined by 1H NMR.
c Dibromoalkane was obtained (58%). d 1a was recovered (22%). e 1a was
recovered (26%). f 1a was recovered (29%). g Dibromoalkane was obtained
(86%). h 1a was recovered (6%).
Next, we examined more complicated substrates. For
secondary alcohol derivatives 2m, 2p, and 2q, yields and
selectivities were excellent (entries 16, 17, and 21-24),
although tertiary alcohol derivative 2n was produced in only
general procedure, 1a and pyridinium bromide perbromide
(1.1 equiv) were stirred at room temperature for 12-14 h.
DBU was added to the reaction system at 0 °C, and the
system was heated to 60 °C. The reaction was quenched with
saturated aqueous NH4Cl or 1 M aqueous HCl, and the
reaction mixture was extracted with dichloromethane or
(10) For 2-bromo-1-alkenes synthesis, see: (a) Ohgiya, T.; Nishiyama,
S. Chem. Lett. 2004, 33, 1084. (b) Ohgiya, T.; Nishiyama, S. Heterocycles
2004, 63, 2349. (c) Ohgiya, T.; Nishiyama, S. Tetrahedron Lett. 2004, 45,
8273. (d) Ohgiya, T.; Nakamura, K.; Nishiyama, S. Bull. Chem. Soc. Jpn.
2005, 78, 1549. For reviews on the elimination reactions of 1,2-dibromoal-
kanes, see: (e) Ohgiya, T.; Kutsumura, N.; Nishiyama, S. J. Synth. Org.
Chem. Jpn. 2008, 66, 139. (f) Ohgiya, T.; Kutsumura, N.; Nishiyama, S.
Synlett 2008, 3091.
(8) Bazin, M.-A.; Jouanne, M.; El-Kashef, H.; Rault, S. Synlett 2009,
2789.
(9) Kuang, C.; Yang, Q.; Senboku, H.; Tokuda, M. Tetrahedron 2005,
61, 4043.
Org. Lett., Vol. 12, No. 15, 2010
3317

plicability of the three-step reaction sequence (bromine
addition, elimination, Sonogashira coupling) was verified
using 1a as a starting material and 1-heptyne as a coupling
partner by Methods A and B (Scheme 2).
Table 2. Synthesis of 2-Bromo Allyl Alcohol Derivatives 2
Using One-Pot Chemoselective Bromination
Scheme 2. One-Pot C2-Selective Sonogashira Coupling
Reaction of Allyl Alcohol Derivatives 1a
Synthesis of the desired enyne system 3a was ac-
complished in 31% yield by Method B and the following
typical Sonogashira conditions.1 In the general procedure,
Table 3. Synthesis of Enyne Alcohol Derivatives 3 Using
One-Pot Chemoselective Sonogashira Coupling Reaction
a Ratio of 2-bromoalkene and 1-bromoalkene was determined by 1H
NMR. b Dibromoalkane was obtained (9%). c Dibromoalkane was obtained
(27%). d Dibromoalkane was obtained (34%).
34% yield (entry 18). Interestingly, reaction of the internal
double bond takes place in a highly stereoselective manner
involving trans elimination to afford 2o (entries 19 and 20).
Thus, as mentioned above, we developed an efficient and
concise one-pot method for chemoselective bromination of
allyl alcohol derivatives. Our method requires no extra-dry
conditions, expensive reagents, or complex manipulations.
Moreover, the one-pot bromine addition and subsequent
DBU-promoted elimination reactions proceed smoothly even
in the presence of sensitive functional groups.
a Determined by 1H NMR using 1,4-bis(trimethylsilyl)-benzene as
internal standard. b The intermediate 2o was obtained (46%). c 3.0 equiv of
3,3-dimethyl-1-butynes was used.
On the basis of these encouraging results, we focused next
on developing a one-pot method for the sequential Sono-
gashira coupling reaction. In our first attempts, the ap-
3318
Org. Lett., Vol. 12, No. 15, 2010

CuI (10 mol %), PdCl2(PPh3)2 catalyst (5 mol %), Et3N (2.0
equiv), and 1-heptyne (1.5 equiv) were added to the reaction
mixture at 0 °C after the process of Method B and stirred at
room temperature for 12-14 h. Reaction was quenched with
saturated aqueous NH4Cl or 1 M aqueous HCl, and the
reaction mixture was extracted with dichloromethane or chlo-
roform, concentrated in vacuo, and purified by silica gel column
chromatography with hexane/ethyl acetate to afford 3a as a sole
product. In contrast, consecutive Sonogashira coupling did not
proceed at all after the process of Method A.
Satisfied with these results, we carried out three-step
sequential reactions of a variety of allyl alcohol derivatives
1 (Table 3). The allyl alcohols having aryloxy groups were
easily converted to the enyne adducts 3 by chemoselective
bromination and sequential Sonogashira coupling (entries
2-7), except for those having the 4-nitrophenyl group
(entries 1 and 9). The syntheses of 3i and 3l, with a
p-methoxybenzyloxy group and/or a lactone moiety, also
proceeded in good yields (entries 8 and 11). Intriguingly,
the intermediate 2p of the three-step sequential reaction was
converted to 3k in 77% yield, although 3.0 equiv of 3,3-
dimethyl-1-butynes was used as a alkyne unit (entry 10). It
is noteworthy that the expected diyne byproduct was detected
in only trace amounts, and the plausible aromatic alkyne was
not detected at all.
In conclusion, a novel one-pot method for chemoselective
bromination of allyl alcohol derivatives has been developed.
This synthetic approach should be applicable to the total
synthesis of natural products and for use in modern drug-
discovery research. Moreover, an efficient one-pot method
for Sonogashira coupling was also achieved. A highlight of
this study is that the third coupling reaction catalyzed by
the transition-metal-based system in this sequence proceeds
successfully. We believe that this is a good first step toward
achieving diverse chemoselective C-C bond-forming reac-
tions. Further potential applications of this straightforward
method are under investigation.
Acknowledgment. We thank Dr. Tadaaki Ohgiya (Man-
ager, Organic Chemistry Department, Organic Chemistry
Group I, Tokyo New Drug Research Laboratories, Pharma-
ceutical Division, Kowa Company, Ltd.) for chemical
discussions. This work was partly supported by the Sasakawa
Scientific Research Grant from The Japan Science Society.
Supporting Information Available: Spectroscopic data
and experimental procedure. This material is available free
of charge via the Internet at http://pubs.acs.org.
(11) (a) Nakata, M.; Enari, H.; Kinoshita, M. Bull. Chem. Soc. Jpn. 1982,
55, 3283. (b) Andrei, D.; Wnuk, S. F. Org. Lett. 2006, 8, 5093.
OL101110V
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