Carbometalation-carboxylation of 2,3-allenols with carbon dioxide: A dramatic effect of halide anion

Article abstract of DOI:10.1021/ol4000197

The cyclic organometallic intermediates formed via CuCl-mediated highly regio- and stereoselective carbomagnesiation of 2,3-allenols with Grignard reagents may smoothly react with carbon dioxide to afford 2(5H)-furanones. A dramatic effect of the halide anion from the Grignard reagent (Br vs Cl) for CO₂ activation was observed. The reaction proceeded smoothly under mild conditions to afford the products in 58-93% yields.

Full text of DOI:10.1021/ol4000197

ORGANIC
LETTERS
2013
Vol. 15, No. 5
977–979
CarbometalationÀCarboxylation
of 2,3-Allenols with Carbon Dioxide:
A Dramatic Effect of Halide Anion
Suhua Li,† Bukeyan Miao,‡ Weiming Yuan,‡ and Shengming Ma*,†,‡
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, 345 Lingling Lu, Shanghai 200032,
P. R. China, and Shanghai Key Laboratory of Green Chemistry and Chemical Process,
Department of Chemistry, East China Normal University, 3663 North Zhongshan Lu,
Shanghai 200062, P. R. China
masm@sioc.ac.cn
Received January 3, 2013
ABSTRACT
The cyclic organometallic intermediates formed via CuCl-mediated highly regio- and stereoselective carbomagnesiation of 2,3-allenols with Grignard
reagents may smoothly react with carbon dioxide to afford 2(5H)-furanones. A dramatic effect of the halide anion from the Grignard reagent (Br vs Cl)
for CO2 activation was observed. The reaction proceeded smoothly under mild conditions to afford the products in 58À93% yields.
Muchattention has been paid tothe development of new
and efficient methodologies for the synthesis of 2(5H)-
furanones,1 a class of important heterocycles with a broad
range of potential biological activities.2 On the other hand,
carbon dioxide is one of the most attractive C1 synthons in
organic synthesis as it is a type of renewable, nontoxic,
abundant, and economical resource.3 There are a few reports
on the synthesis of 2(5H)-furanones from the reaction of
alkynols with Grignard reagents with or without Cp2TiCl2
followed by quenching with inletting CO2 gas or pouring
into dry ice.4 Recently, we have developed an efficient regio-
and stereospecific CuCl-mediated carbomagnesiation of
differently substituted 2,3-allenols with primary, secondary
alkyl, or aromatic Grignard reagents followed by iodination
to synthesize fully substituted allylic alcohols (Scheme 1).5
We envisioned that the cyclic intermediates A formed in
situ in the reaction would react with CO2 to form γ-hydroxy
Z-alkenoic carboxylic acid, which would be followed by
lactonization to produce butenolides. Herein, we report such
a transformation in which a dramatic halide anion effect for
CO2 activation was observed and a CO2 balloon was used
without continuous release of CO2 to the environment.
After the CuCl-mediated carbometalation of n-BuMgBr
with allenol 1a, CO2 was introduced into reaction vessel by
† Chinese Academy of Sciences.
‡ East China Normal University.
(1) For recent reviews, see: (a) Romeo, G.; Iannazzo, D.; Piperno, A.;
Romeo, R.; Corsaro, A.; Rescifina, A.; Chiacchio, U. Mini-Rev. Org.
Chem. 2005, 2, 59. (b) Langer, P. Synlett 2006, 3369. (c) Bruckner, R.
Curr. Org. Chem. 2001, 5, 679. (d) Ma, S. Acc. Chem. Res. 2003, 36, 701.
(e) Ma, S. Pure Appl. Chem. 2004, 76, 651.
(2) (a) Otsuka, H.; Kotani, K.; Bando, M.; Kido, M.; Takeda, Y.
Chem. Pharm. Bull. 1998, 46, 1180. (b) Juan Hikawczuk, V. E.; Roberto
´ ´ ´
Saad, J.; Giordano, O. S.; Garcıa, C.; Martın, T.; Martın, V. S.; Sosa,
M. E.; Tonn, C. E. J. Nat. Prod. 2008, 71, 190. (c) Parvatkar, R. R.;
D’Souza, C.; Tripathi, A.; Naik, C. G. Phytochemistry 2009, 70, 128.
ꢀ
(d) Pour, M.; Spulak, M.; Buchta, V.; Kubanova, P.; Marie Voprsalova,
ꢁ
ꢁ
ꢁ
ꢀ
ꢁ
M.; Wsol, V.; Fakova, H.; Koudelka, P.; Pourova, H.; Schiller, R.
ꢁ
ꢁ
ꢁ
J. Med. Chem. 2001, 44, 2701.
(3) For recent reviews, see: (a) Louie, J. Curr. Org. Chem. 2005, 9,
605. (b) Sakakura, T.; Choi, J.-C.; Yasuda, H. Chem. Rev. 2007, 107,
2365. (c) Aresta, M.; Dibenedetto, A. Dalton Trans. 2007, 2975.
(4) (a) Tan, Z.; Negishi, E.-i. Org. Lett. 2006, 8, 2783. (b) Ito, T.;
Okamoto, S.; Sato, F. Tetrahedron Lett. 1990, 31, 6399. (c) Tani, K.;
Sato, Y.; Okamoto, S.; Sato, F. Tetrahedron Lett. 1993, 34, 4975.
(d) Ishino, Y.; Wakamoto, K.; Hirashima, T. Chem. Lett. 1984, 765.
(e) Forgione, P.; Wilson, P. D.; Fallis, A. G. Tetrahedron Lett. 2000, 41, 17.
(5) Lu, Z.; Ma, S. Adv. Synth. Catal. 2007, 349, 1225.
(d) Correa, A.; Martı
Riduan, S. N.; Zhang, Y. Dalton Trans. 2010, 39, 3347. (f) Huang, K.;
Sun, C.; Shi, Z. Chem. Soc. Rev. 2011, 40, 2435. (g) Martın, R.; Kleij, A.
ChemSusChem. 2011, 4, 1259. (h) Cokoja, M.; Bruckmeier, C.; Rieger,
´
n, R. Angew. Chem., Int. Ed. 2009, 48, 6201. (e)
´
€
B.; Herrmann, W. A.; Kuhn, F. E. Angew. Chem., Int. Ed. 2011, 50, 8510.
r
10.1021/ol4000197
2013 American Chemical Society
Published on Web 02/08/2013

Table 2. Effect of Halide Anion
Scheme 1. Our Previous Work and Proposed Synthesis of
2(5H)-Furanones
entry
R
n-BuMgX
time (h)
yield of 2 (%)
1a
2b
3a
4b
5c
CH3 (1b)
CH3 (1b)
H (1c)
nC4H9MgBr
nC4H9MgCl
nC4H9MgBr
nC4H9MgCl
nC4H9MgI
13
14
13
13
24
48d (2ba)
72 (2ba)
44d (2ca)
78 (2ca)
H (1c)
H (1c)
complicated
installation of a CO2 balloon and 2aa was formed in 45%
yield (Table 1, entry 1). We believed that the reason for the
low yield might be the low reactivity of the intermediate A
toward CO2. When HMPA or CsF was added as an additive
before quenching of the intermediate A with CO2, the yield
of 2aa dropped to 23% (Table 1, entries 2 and 3). To our
delight, when LiCl was used, the yield of 2aa was raised to
79% (Table 1, entry 4). With such an observation of the
unique effect of halide anion, we further used n-BuMgCl
instead of n-BuMgBr: interestingly, the yield was further
improved to 87% (Table 1, entry 5)!
a The reaction was conducted using 1 mmol of 1, 2 mmol of CuCl,
5 mmol of nBuMgBr (2 M in Et2O), and a CO2 balloon in 6 mL of Et2O.
b The reaction was conducted with 1 mmol of 1, 2 mmol of CuCl, 5 mmol
of BuMgCl (2 M in Et2O), and a CO2 balloon in 6 mL of Et2O. c The
reaction was conducted using 1 mmol of 1, 2 mmol of CuCl, 5 mmol of
nBuMgI (2 M in Et2O), and a CO2 balloon in 6 mL of Et2O. d NMR
yield.
The results show in Table 3 indicatedthat 2(5H)-furanones
were formed in moderate to excellent yields: R1 can be
alkyl, phenyl, benzyl, or H; R2 may be alkyl, phenyl, methyl,
or H. Primary (Table 3, entries 1À3), secondary (Table 3,
entries 4À13), and tertiary 2,3-allenols (Table 3, entry 14) all
produced the lactones in moderate to good yields. Grignard
reagents such as CyMgCl (entry 4), i-PrMgCl (entry 5), and
PhMgCl (entry 6) were examined in this reaction producing
moderate to good yields of 2(5H)-furanones. To check the
practicality, this reaction was scaled up to 1.12 g (7 mmol)
Table 1. Optimization of Reaction Conditions for the Synthesis
of 2(5H)-Furanone 2aaa
Table 3. Synthesis of 2(5H)-Furanonesa
entry
X
additive (equiv)
NMR yield of 2aa (%)
1
Br
Br
Br
Br
Cl
none
45
2
HMPA (2)
CsF (2)
LiCl (2)
none
23
3
23
4
5b
79
85 (87)c
entry
R1/R2/R3
R4 MgCl time (h) isolated yield (%)
a The reaction was conducted using 1 mmol of 1, 2 mmol of CuCl,
5 mmol of n-BuMgBr (2 M in Et2O), and a CO2 balloon in 6 mL of Et2O.
b The reaction was conducted with 1 mmol of 1, 2 mmol of CuCl, 5 mmol
of n-BuMgCl (2 M in Et2O), and a CO2 balloon in 6 mL of Et2O. The first
step finished after 15 h. c Isolated yield in parentheses.
1
nC6H13/H/H (1d)
nC4H9/H/H (1e)
Bn/H/H (1f)
nC4H9
nC4H9
nC4H9
Cy
10
10
12
13
13
13
12
13.5
12
14
13
11
75 (2da)
73 (2ea)
88 (2fa)
68 (2cb)
58 (2cc)
75 (2cd)
76 (2ga)
61 (2ha)
65 (2ia)
67 (2ja)
76 (2ka)
81 (2ka)
82 (2la)
64 (2ma)
2
3
4
H/Ph/H (1c)
5
H/Ph/H (1c)
iPr
Subsequently, other organomagnesium chlorides and
organomagnesium bromides were compared (Table 2).
When n-C4H9MgBr was used, lactone 2ba was obtained
in low yield (Table 2, entry 1) while with n-C4H9MgCl, 2ba
was isolated in 72% yield (Table 2, entry 2); the halide anion
effect also exists in the reaction of secondary 2,3-allenol 1c
(Table 2, entries 3 and 4).6
6
H/Ph/H (1c)
Ph
nC4H9
7
H/4-ClC6H4/H (1g)
H/1-naphthyl/H (1h) nC4H9
8
9
H/nC5H11/H (1i)
H/Cy/H (1j)
nC4H9
nC4H9
nC4H9
nC4H9
nC4H9
nC4H9
10
11
Ph/Me/H (1k)
12b Ph/Me/H (1k)
13
14
Ph/Ph/H (1l)
14
13
On the basis of these results, the scope of this reaction
was then studied using organomagnesium chlorides.
H/nC6H13/Me (1m)
a The reaction was conducted with 1 mmol of 1, 2 mmol of CuCl,
5 mmol of R4 MgCl (2 M in Et2O), and a CO2 balloon in 6 mL of Et2O.
b The reaction was conducted using 7 mmol of 1k (1.12 g scale).
(6) Metzger, A.; Bernhardt, S.; Manolikakes, G.; Knochel, P. Angew.
Chem., Int. Ed. 2010, 49, 4665.
978
Org. Lett., Vol. 15, No. 5, 2013

affording 2ka in 81% yield (Table 3, entry 12). It should be
noted that in some cases the premature protonation product
was observed as the minor byproduct and the reaction of 1c
with 3 equiv of n-C4H9MgCl afforded a lower yield of 2ca
after 24 h.
Scheme 3. Synthesis of 2(5H)-Furanones 2ea and 2aa in One
Step from 4-Chlorobut-2-yn-1-ol
When the optically active 2,3-allenols S-1k S-1c, S-1n4,
and S-1o were applied, optically active 2(5H)-furanones
S-2ka, S-1ca, S-2na, and R-2oa were prepared in 70À92%
yields without obvious racemization (Scheme 2).
Scheme 2. Synthesis of Optically Active 2(5H)-Furanones
It should be noted that three carbonÀcarbon bonds and a
carbonÀoxygen bond were formed in this transformation.
In conclusion, we have developed a very convenient
method to synthesize 2(5H)-furanones using 2,3-allenols,
organomagnesium chlorides, and carbon dioxide provided in
the form of a balloon as the starting materials. It is interesting
to observe a dramatic chloride effect of the Grignard reagents
for this carboxylation with CO2: the yields with RMgCl are
much higher than those with RMgBr. Optically active 2(5H)-
furanones were synthesized from optically active 2,3-allenols.
As a result of usefulness of the products and the easy
availability of various 2,3-allenols,5,7,8 the reaction may be
potentially useful in organic and medicinal chemistry.
Further studies in this area are in progress in our laboratory.
Acknowledgment. Financial support from the Shanghai
Municipal Committee of Science and Technology (12JC1-
403700), National Basic Research Program of China (2011-
CB808705), and National Natural Science Foundation of
China (21232006) is greatly appreciated. We thank Pengbin
Li in our group for reproducing the results of 2cb and 2ma in
Table 3 and S-2na in Scheme 2.
2(5H)-Furanones 2ea and 2aa may also be synthesized
directly from 4-chlorobut-2-yn-1-ol (3) with the in situ
synthesis of the allenol,7 carbomagnesiation, carboxyla-
tion with CO2, and lactonization in one pot (Scheme 3).
Supporting Information Available. Spectroscopic data,
1
(7) Li, J.; Kong, W.; Fu, C.; Ma, S. J. Org. Chem. 2009, 74, 5104.
(8) (a) Xu, D.; Li, Z.; Ma, S. Chem.;Eur. J. 2002, 21, 5012. (b)
Kuang, J.; Ma, S. J. Org. Chem. 2009, 74, 1763. (c) Kuang, J.; Ma, S.
J. Am. Chem. Soc. 2010, 132, 1786. (d) Kuang, J.; Luo, H.; Ma, S. Adv.
Synth. Catal. 2012, 354, 933. (e) Ye, J.; Li, S.; Chen, B.; Fan, W.; Kuang,
J.; Liu, J.; Liu, Y.; Miao, B.; Wan, B.; Wang, Y.; Xie, X.; Yu, Q.; Yuan,
W.; Ma, S. Org. Lett. 2012, 14, 1346.
general procedure, and H/13C NMR spectra of all the
products. This material is available free of charge via the
Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 5, 2013
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