An efficient indium-mediated 2-bromoallylation of aldehydes at low temperature in aqueous DMF

Article abstract of DOI:10.1016/j.tetlet.2011.04.053

An efficient synthesis of 2-bromohomoallylic alcohols was carried out via an indium-mediated Barbier-type 2-bromoallylation of aldehydes in moderate yields. The reaction was performed at low temperature (-20 °C) in aqueous DMF in order to minimize decompo

Full text of DOI:10.1016/j.tetlet.2011.04.053

Tetrahedron Letters 52 (2011) 3240–3242
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An efficient indium-mediated 2-bromoallylation of aldehydes
at low temperature in aqueous DMF
Yu Mi Kim a, Sangku Lee b, Sung Hwan Kim a, Jae Nyoung Kim a,
⇑
a Department of Chemistry and Institute of Basic Science, Chonnam National University, Gwangju 500-757, Republic of Korea
b Immune Modulator Research Center, KRIBB, Daejeon 305-806, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient synthesis of 2-bromohomoallylic alcohols was carried out via an indium-mediated Barbier-
type 2-bromoallylation of aldehydes in moderate yields. The reaction was performed at low temperature
(ꢀ20 °C) in aqueous DMF in order to minimize decomposition of 2-bromoallylindium reagent to allene.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 30 March 2011
Revised 13 April 2011
Accepted 14 April 2011
Available online 22 April 2011
Keywords:
2-Bromoallylation
Indium
Barbier reaction
Allene
2-Bromoallylation of carbonyl compounds to 2-bromohomoally-
lic alcohols has been the subject of current interest.1–5 2-Bromoho-
moallylic alcohols have been used for the synthesis of various
important substances including 2-methyleneoxetanes,1c homo-
2,3-dihalopropene is a well-known method of allene.9 The decom-
position of 2-bromoallylindium reagent has also been observed by
Minehan and co-workers in their attempted reaction of D-glyceral-
dehyde acetonide and 2,3-dibromopropene in aqueous DMF.8a
Actually, when we ran the reaction in aqueous DMF at room temper-
ature, we observed an exothermic reaction and gas evolution as
Minehan and co-workers have reported. Thus, we examined the
reaction of 4-chlorobenzaldehyde and 2,3-dibromopropene at low
temperature (ꢀ20 °C). To our delight, the desired product 2a was
obtained in 71% yield in short time (3 h).10 However, trace amounts
of 4-chlorobenzaldehyde remained even though excess amounts of
2,3-dibromopropene (3.0 equiv) and indium (2.0 equiv) were em-
ployed. The results clearly state that 2-bromoallylindium reagent
reacted with 1a in part and destroyed in part, even at low tempera-
ture. Although we did not observe a gas evolution apparently at this
propargylic alcohols,1e 2-methyleneazetidines,1f and
a-methy-
lene-c
-butyrolactones.1a,3a,c However, 2-bromoallylation of
carbonyl compounds is rather limited in contrast to the allylation.
2-Bromoallylation of aldehydes with 2,3-dibromopropene could
be effectively achieved using Sn/HBr.2a Besides 2-bromoallyltin re-
agent 2-bromoallylboranes can also be used.3
Although allylindium reagent has received much attention in
recent years,6,7 an indium-mediated 2-bromoallylation of alde-
hydes has not been developed.4 Many research groups examined
the reaction; however, they failed completely or obtained the de-
sired product in very low yield.8 Li and co-workers used
2-chloro-3-bromopropene instead of 2,3-dibromopropene in their
indium-mediated 2-chloroallylation.4a Loh et al. carried out an in-
dium-mediated 2-bromocrotylation in saturated aqueous NH4Cl
solution in the presence of La(OTf)3 under sonication.4b
OH Br
During our studies on the indium-mediated allylations,7 we also
found that indium-mediated 2-bromoallylation of 4-chlorobenzal-
dehyde (1a) with 2,3-dibromopropene afforded the product 2a in
low yield (33%) in the presence of indium in aqueous DMF at room
temperature (3 h). We hypothesized that the unfavorable results
might be due to the decomposition of 2-bromoallylindium reagent
to allene, as shown in Scheme 1. Zinc-mediated dehalogenation of
CHO
Br
In
+
Br
aq DMF
Cl
Cl
2a (33%): rt, 3 h
2a (71%): -20 oC, 3 h
1a
Br
L
decomposition
In
InBr2L
+
Br
⇑
Corresponding author. Tel.: +82 62 530 3381; fax: +82 62 530 3389.
E-mail address: kimjn@chonnam.ac.kr (J.N. Kim).
Scheme 1.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.04.053

Y. M. Kim et al. / Tetrahedron Letters 52 (2011) 3240–3242
3241
Table 1
In
+
-
In-mediated Barbier-type-2-bromoallylation of aldehydesa
Br
In2R3X3
InR2
(R = allyl, X = Br)
+
InRX3
solvent
2,3-dibromopropene (3.0 equiv)
In powder (2.0 equiv)
OH Br
H
OH
InR2(solv)
R-CHO
X3In
DMF/H2O (1:1), -20 oC, 3 h
R'
O
R
R'
1a-j
2a-j
Scheme 2.
OH Br
OH Br
Cl
Cl
to a mixture of indium in aqueous DMF at ꢀ20 °C and let the reac-
tion mixture for 3 h at this temperature, and then 1a was added
and the reaction progress was monitored (entry 1). However, de-
sired product 2a was produced in trace amount (<5%) even after
15 h. The result stated that 2-bromoallylindium reagent was de-
stroyed almost completely within 3 h at ꢀ20 °C in aqueous DMF.
When we used aqueous THF instead of aqueous DMF as a reaction
medium at ꢀ20 °C, 2a was formed in trace amount (<5%), as shown
in entry 2. The result stated that the reaction of 2-bromoallylindi-
um reagent and 1a was not effective in aqueous THF at ꢀ20 °C. But,
decomposition of 2-bromoallylindium reagent at ꢀ20 °C was
found to be negligible based on the experiment in entry 3. Actually,
a moderate yield of 2a (47%) was isolated at 20 °C when we added
1a to a pre-generated 2-bromoallylindium reagent at ꢀ20 °C after
3 h. However, most of 2-bromoallylindium reagent was destroyed
at 20 °C within 3 h even in aqueous THF, as can be seen in entry 4;
however, decomposition rate of 2-bromoallylindium reagent is
slower in aqueous THF than in aqueous DMF.
2a (71)
OH Br
2b (85)
OH Br
Me
2c (55)
OH Br
MeO
2d (76)
OH Br
MeO
2e (60)
OH Br
2f (39)
OH Br
Cl
Cl
Ph
2g (64)
2h (40)
OH Br
OH Br
Very recently, Koszinowski reported a brilliant study on the het-
erolytic dissociation of allylindium reagent.11 As shown in Scheme
2, an allylindium reagent In2R3X3 undergoes heterolytic dissocia-
tion to yield ions such as InRþ2 and InRXꢀ3 , and the extent of disso-
ciation is greater in DMF than in THF. According to the report, the
reactivity of allylindium reagent toward an aldehyde is great in
DMFꢀdue to high concentration of nucleophilic allylindate anions,
InRX3 . Based on the study of Koszinowski11 and our own observa-
tions, the successful results of 2-bromoallylation in aqueous DMF
could be understood as follows. 2-Bromoallylation of aldehyde is
faster in aqueous DMF than in aqueous THF although a decompo-
sition of 2-bromoallylindium reagent to allene is also faster in
aqueous DMF.12
In summary, an indium-mediated 2-bromoallylation of alde-
hydes was carried out successfully to produce the corresponding
2-bromohomoallylic alcohols in moderate yields. The reaction
was carried out at low temperature (ꢀ20 °C) in aqueous DMF in or-
der to minimize the decomposition of 2-bromoallylindium reagent
to allene.
MeOOC
2j (57)
2i (57)
a
Isolated yield (%).
Table 2
Competetive decomposition and reaction of 2-bromoallylindium reagenta
Entry Conditionsb
2ac (%)
1
(i) 2,3-Dibromopropene, indium, aqueous DMF, ꢀ20 °C, 3 h <5
(ii) Then add 1a, ꢀ20 °C (3 h), 20 °C (12 h)
2
3
1a, 2,3-dibromopropene, indium, aqueous THF, ꢀ20 °C, 3 h <5
(i) 2,3-Dibromopropene, indium, aqueous THF, ꢀ20 °C, 3 h
(ii) Then add 1a, 20 °C, 12 h
47
4
(i) 2,3-Dibromopropene, indium, aqueous THF, ꢀ20 °C, 3 h
18
(ii) Then add 1a, 20 °C, 12 h
a
b
c
Compound 1a was used as a model substrate.
2,3-Dibromopropene (3.0 equiv) and indium (2.0 equiv) were used.
Isolated yield.
temperature, 2-bromoallylindium reagent must be destroyed
slowly (vide infra).
Acknowledgments
Encouraged by the above results we examined an indium-med-
iated 2-bromoallylation of various aldehydes 1a–j, and the results
are summarized in Table 1. We used 2,3-dibromopropene
(3.0 equiv) and indium (2.0 equiv) throughout all the entries
although starting materials remained in appreciable amounts in
some cases. As shown in Table 1, the yields of products (2a–e, g,
i, and j) were moderate to good (55–85%). However, the yields of
products (2f and h) were relatively low with p-anisaldehyde (1f)
and p-phenylbenzaldehyde (1h). The reaction of 5-methylfurfural
produced intractable complex mixtures and unfortunately we
failed to isolate the desired product in an appreciable amount.
In order to get more insights we ran the reaction of 1a under
various conditions, and the results are summarized in Table 2.
Firstly, we examined a decomposition of 2-bromoallylindium re-
agent in aqueous DMF at ꢀ20 °C. 2,3-Dibromopropene was added
This work was supported by the National Research Foundation
of Korea Grant funded by the Korean Government (2010-0015675).
Spectroscopic data were obtained from the Korea Basic Science
Institute, Gwangju branch.
References and notes
1. For the synthetic applications of 2-halohomoallylic alcohols, see: (a) Corey, E.
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Marek, I.; Normant, J. F.; Platzer, N. J. Org. Chem. 1995, 60, 2488–2501; (c) Fang,
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Lu, H.; Li, C. Org. Lett. 2006, 8, 5365–5367.
2. For 2-haloallylation of aldehydes with 2-haloallyltin reagents, see: (a) Mandai,
T.; Nokami, J.; Yano, T.; Yoshinaga, Y.; Otera, J. J. Org. Chem. 1984, 49, 172–174;
(b) Lei, M.-Y.; Fukamizu, K.; Xiao, Y.-J.; Liu, W.-M.; Twiddy, S.; Chiba, S.; Ando,

3242
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K.; Narasaka, K. Tetrahedron Lett. 2008, 49, 4125–4129; (c) Studer, A.; Bossart,
M.; Vasella, T. Org. Lett. 2000, 2, 985–988.
NMR (CDCl3, 300 MHz) d 2.26 (br s, 1H), 2.66–2.83 (m, 2H), 4.97–5.02 (m, 1H),
5.53 (d, J = 1.8 Hz, 1H), 5.65 (d, J = 1.8 Hz, 1H), 7.30 (d, J = 8.4 Hz, 2H), 7.33 (d,
3. For 2-haloallylation of aldehydes with 2-haloallylboranes, see: (a) Hara, S.;
Suzuki, A. Tetrahedron Lett. 1991, 32, 6749–6752; (b) Hara, S.; Yamamoto, Y.;
Fujita, A.; Suzuki, A. Synlett 1994, 639–640; (c) Rauniyar, V.; Hall, D. G. J. Org.
Chem. 2009, 74, 4236–4241.
4. For the indium-mediated 2-haloallylation of aldehydes, see: (a) Yi, X.-H.; Meng,
Y.; Li, C.-J. Tetrahedron Lett. 1997, 38, 4731–4734; (b) Loh, T.-P.; Cao, G.-Q.; Pei,
J. Tetrahedron Lett. 1998, 39, 1453–1456; (c) Kwon, J. S.; Pae, A. N.; Chio, K. I.;
Koh, H. Y.; Kim, Y.; Cho, Y. S. Tetrahedron Lett. 2001, 42, 1957–1959.
5. For the other methods of 2-haloallylation of aldehydes, see: (a) Kurosu, M.; Lin,
M.-H.; Kishi, Y. J. Am. Chem. Soc. 2004, 126, 12248–12249; (b) Knochel, P.; Rao,
S. A. J. Am. Chem. Soc. 1990, 112, 6146–6148.
6. For the leading references on indium-mediated reactions, see: (a) Auge, J.;
Lubin-Germain, N.; Uziel, J. Synthesis 2007, 1739–1764; (b) Kargbo, R. B.; Cook,
G. R. Curr. Org. Chem. 2007, 11, 1287–1309; (c) Lee, P. H. Bull. Korean Chem. Soc.
2007, 28, 17–28; (d) Li, C.-J.; Chan, T.-H. Tetrahedron 1999, 55, 11149–11176;
(e) Pae, A. N.; Cho, Y. S. Curr. Org. Chem. 2002, 6, 715–737; (f) Kim, S. H.; Lee, H.
S.; Kim, K. H.; Kim, S. H.; Kim, J. N. Tetrahedron 2010, 66, 7065–7076; (g) Li, C.-J.;
Chan, T.-H. Tetrahedron Lett. 1991, 32, 7017–7020.
7. For our recent contributions on indium-mediated Barbier-type allylations, see:
(a) Kim, S. H.; Lee, H. S.; Kim, K. H.; Kim, J. N. Tetrahedron Lett. 2009, 50, 1696–
1698; (b) Kim, S. H.; Kim, S. H.; Lee, K. Y.; Kim, J. N. Tetrahedron Lett. 2009, 50,
5744–5747; (c) Kim, S. H.; Lee, H. S.; Kim, K. H.; Kim, J. N. Tetrahedron Lett.
2009, 50, 6476–6479; (d) Kim, S. H.; Kim, S. H.; Kim, K. H.; Kim, J. N. Tetrahedron
Lett. 2010, 51, 860–862; (e) Kim, S. H.; Kim, S. H.; Kim, T. H.; Kim, J. N.
Tetrahedron Lett. 2010, 51, 2774–2777; (f) Kim, Y. M.; Lee, S.; Kim, S. H.; Kim, K.
H.; Kim, J. N. Tetrahedron Lett. 2010, 51, 5922–5926.
J = 8.4 Hz, 2H); 13C NMR (CDCl3, 75 MHz)
d 51.25, 70.90, 120.33, 127.17,
128.62, 129.56, 133.45, 141.18; ESIMS m/z 243 (M++H-H2O), 245 (M++H+2-
H2O), 247 (M++H+4-H2O). Anal. Calcd for C10H10BrClO: C, 45.92; H, 3.85. Found:
C, 45.75; H, 3.91.
Compound 2b: 85%; colorless oil; IR (film) 3424, 1630, 1431, 1275, 1261 cmꢀ1
;
1H NMR (CDCl3, 300 MHz) d 2.42 (d, J = 3.0 Hz, 1H), 2.66–2.82 (m, 2H), 4.95–
5.00 (m, 1H), 5.53 (d, J = 1.8 Hz, 1H), 5.65 (d, J = 1.8 Hz, 1H), 7.18–7.29 (m, 3H),
7.37 (s, 1H); 13C NMR (CDCl3, 75 MHz) d 51.16, 70.89, 120.35, 123.93, 125.94,
127.88, 129.47, 129.73, 134.35, 144.78; ESIMS m/z 243 (M++H-H2O), 245
(M++H+2-H2O), 247 (M++H+4-H2O). Anal. Calcd for C10H10BrClO: C, 45.92; H,
3.85. Found: C, 46.07; H, 3.79.
Compound 2d: 76%; colorless oil; IR (film) 3420, 1631, 1275, 1261 cmꢀ1 1H
;
NMR (CDCl3, 300 MHz) d 2.28 (d, J = 2.7 Hz, 1H), 2.34 (s, 3H), 2.67–2.84 (m, 2H),
4.93–4.98 (m, 1H), 5.51 (d, J = 1.5 Hz, 1H), 5.65 (d, J = 1.5 Hz, 1H), 7.06–7.25 (m,
4H); 13C NMR (CDCl3, 75 MHz) d 21.37, 51.14, 71.48, 119.80, 122.80, 126.41,
128.34, 128.49, 130.14, 138.09, 142.76; ESIMS m/z 223 (M++H-H2O), 225
(M++H+2-H2O). Anal. Calcd for C11H13BrO: C, 54.79; H, 5.43. Found: C, 54.86; H,
5.15.
Compound 2e: 60%; colorless oil; IR (film) 3450, 1630, 1601, 1488, 1263 cmꢀ1
;
1H NMR (CDCl3, 300 MHz) d 2.23 (br s, 1H), 2.70–2.86 (m, 2H), 3.81 (s, 3H),
4.98–5.02 (m, 1H), 5.53 (d, J = 1.8 Hz, 1H), 5.68 (d, J = 1.8 Hz, 1H), 6.80–6.84 (m,
1H), 6.94–6.96 (m, 2H), 7.24–7.29 (m, 1H); 13C NMR (CDCl3, 75 MHz) d 51.20,
55.21, 71.46, 111.21, 113.29, 118.05, 119.99, 129.53, 130.03, 144.52, 159.70;
ESIMS m/z 239 (M++H-H2O), 241 (M++H+2-H2O). Anal. Calcd for C11H13BrO2: C,
51.38; H, 5.10. Found: C, 51.71; H, 4.94.
Compound 2i: 57%; colorless oil; IR (film) 3478, 1719, 1631, 1435, 1278 cmꢀ1
;
8. For the trials of indium-mediated 2-bromoallylation, see: (a) Moral, J. A.; Moon,
S.-J.; Rodriguez-Torres, S.; Minehan, T. G. Org. Lett. 2009, 11, 3734–3737; (b)
Alcaide, B.; Almendros, P.; Rodriguez-Acebes, R. J. Org. Chem. 2005, 70, 3198–
3204; (c) Alcaide, B.; Almendros, P.; Martinez del Campo, T. Eur. J. Org. Chem.
2008, 2628–2634.
9. For zinc-mediated dehalogenation of 2,3-dihalopropene, see: (a) Blomquist, A.
T.; Verdol, J. A. J. Am. Chem. Soc. 1956, 78, 109–112; (b) Hurd, C. D.; Meinert, R.
N. J. Am. Chem. Soc. 1931, 53, 289–300; (c) Griesbaum, K. Angew. Chem., Int. Ed.
Engl. 1966, 5, 933–946.
1H NMR (CDCl3, 300 MHz) d 2.62 (br s, 1H), 2.70–2.86 (m, 2H), 3.90 (s, 3H),
5.06–5.10 (m, 1H), 5.53 (d, J = 1.8 Hz, 1H), 5.65 (d, J = 1.8 Hz, 1H), 7.44 (d,
J = 8.7 Hz, 2H), 7.99 (d, J = 8.7 Hz, 2H); 13C NMR (CDCl3, 75 MHz) d 51.18, 52.09,
71.09, 120.31, 125.70, 129.41, 129.46, 129.74, 147.94, 166.86; ESIMS m/z 267
(M++H-H2O), 269 (M++H+2-H2O). Anal. Calcd for C12H13BrO3: C, 50.55; H, 4.60.
Found: C, 50.68; H, 4.49.
Compound 2j: 57%; colorless oil; IR (film) 3417, 2928, 2857, 1629, 1124 cmꢀ1
;
1H NMR (CDCl3, 300 MHz) d 0.90 (t, J = 6.6 Hz, 3H), 1.24–1.53 (m, 8H), 1.81 (br
s, 1H), 2.46–2.60 (m, 2H), 3.87–4.00 (m, 1H), 5.54 (d, J = 1.5 Hz, 1H), 5.70 (d,
J = 1.5 Hz, 1H); 13C NMR (CDCl3, 75 MHz) d 14.00, 22.56, 25.23, 31.72, 36.30,
49.35, 69.00, 119.52, 130.84; ESIMS m/z 203 (M++H-H2O), 205 (M++H+2-H2O).
Anal. Calcd for C9H17BrO: C, 48.88; H, 7.75. Found: C, 49.13; H, 7.66.
11. Koszinowski, K. J. Am. Chem. Soc. 2010, 132, 6032–6040.
10. Typical procedure for the synthesis of 2a: To a stirred mixture of 1a (141 mg,
1.0 mmol) and indium (228 mg, 2.0 mmol) in aqueous DMF (1:1, 0.5 mL) was
added dropwise
a solution of 2,3-dibromopropene (Tech. 80%, 600 mg,
3.0 mmol) in aqueous DMF (1:1, 0.5 mL) during 5 min at ꢀ20 °C. The
reaction mixture was stirred at ꢀ20 °C for 3 h. After the usual aqueous
extractive workup and column chromatographic purification process (hexanes/
Et2O, 10:1) compound 2a was obtained as colorless oil, 186 mg (71%). Other
compounds were synthesised similarly, and some selected spectroscopic data
of 2a, b, d, e, i, and j are as follows.
12. Based on the works of Koszinowski11 and our own observations, we assumed
that the reaction in aqueous THF at 20 °C could afford the product in a
reasonable yield. Actually, the reaction of 1a under the conditions (aqueous
THF, 12 h, at 20 °C) gave 62% of 2a. Similarly, the reaction of p-anisaldehyde
afforded 2f in 31% (aqueous THF, 14 h, at 20 °C).
Compound 2a: 71%; colorless oil; IR (film) 3421, 1630, 1490, 1091 cmꢀ1 1H
;