One-step assembly of functionalized γ-butyrolactones from benzoins or benzaldehydes via an N-heterocyclic carbene-mediated tandem reaction

Article abstract of DOI:10.1021/ol051422m

(Chemical Equation Presented) We describe here a direct, efficient, one-step construction of γ,γ-difunctionalized γ-butyrolactones from benzoins or benzaldehydes via a tandem reaction promoted by 1,3-dimethyl imidazolin-2-ylidene, an N-heterocyclic carbene (NHC).

Full text of DOI:10.1021/ol051422m

ORGANIC
LETTERS
2
005
Vol. 7, No. 17
769-3771
One-Step Assembly of Functionalized
-Butyrolactones from Benzoins or
Benzaldehydes via an N-Heterocyclic
Carbene-Mediated Tandem Reaction
3
γ
Wei Ye,†,‡ Guanliang Cai, Zeyang Zhuang, Xueshun Jia, and Hongbin Zhai*
‡
†,§
§
,†
Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai,
China 200032, Analytical Center, Institute of Chemical Defense, Beijing, China
102205, and Department of Chemistry, Shanghai UniVersity, Shanghai, China 200436
zhaih@mail.sioc.ac.cn
Received June 19, 2005
ABSTRACT
We describe here a direct, efficient, one-step construction of
γ,γ-difunctionalized γ-butyrolactones from benzoins or benzaldehydes via a
tandem reaction promoted by 1,3-dimethyl imidazolin-2-ylidene, an N-heterocyclic carbene (NHC).
Since the isolation and characterization of the stable N-
multicomponent reactions (MCRs) were reported by Nair6
and Ma, respectively.
Having been fascinated by the attractive characteristics of
NHCs, we decided to investigate the reaction of benzoin (1a,
Scheme 1) and methyl acrylate in the presence of 1,3-
1
7
heterocyclic carbene (NHC) species by Arduengo in 1991,
2
there has been considerable attention given to exploring and
developing NHC-mediated organic transformations such as
3
4
benzoin condensation, Stetter reaction, and transesterifi-
5
cation. Recently, several successful cases of NHC-triggered
(4) For selected examples, see: (a) Kerr, M. S.; Read de Alaniz, J.; Rovis,
T. J. Am. Chem. Soc. 2002, 124, 10298. (b) Mattson, A. E.; Bharadwaj, A.
R.; Scheidt, K. A. J. Am. Chem. Soc. 2004, 126, 2314. (c) Kerr, M. S.;
Rovis, T. J. Am. Chem. Soc. 2004, 126, 8876. (d) Kerr, M. S.; Rovis, T.
Synlett 2003, 1934. (e) Ciganek, E. Synthesis 1995, 1311. (f) Pesch, J.;
Harms, K.; Bach, T. Eur. J. Org. Chem. 2004, 2025. (g) Barrett, A. G. M.;
Love, A. C.; Tedeschi, L. Org. Lett. 2004, 6, 3377.
(5) For selected examples, see: (a) Nyce, G. W.; Lamboy, J. A.; Connor,
E. F.; Waymouth, R. M.; Hedrick, J. L. Org. Lett. 2002, 4, 3587. (b) Grasa,
G. A.; G u¨ veli, T.; Singh, R.; Nolan, S. P. J. Org. Chem. 2003, 68, 2812.
(c) Kano, T.; Sasaki, K.; Maruoka, K. Org. Lett. 2005, 7, 1347. (d) Singh,
R.; Kissling, R. M.; Letellier, M.-A.; Nolan, S. P. J. Org. Chem. 2004, 69,
209.
†
Shanghai Institute of Organic Chemistry.
Institute of Chemical Defense.
Shanghai University.
‡
§
(
1) Arduengo, A. J., III; Harlow, R. L.; Kline, M. J. Am. Chem. Soc.
991, 113, 361.
2) For recent reviews on NHCs, see: (a) Enders, D.; Balensiefer, T.
1
(
Acc. Chem. Res. 2004, 37, 534. (b) Nair, V.; Bindu, S.; Sreekumar, V.
Angew. Chem., Int. Ed. 2004, 43, 5130. (c) C e´ sar, V.; Bellemin-Laponnaz,
S.; Gade, L. H. Chem. Soc. ReV. 2004, 33, 619. (d) Herrmann, W. A. Angew.
Chem., Int. Ed. 2002, 41, 1290.
(3) For selected examples, see: (a) Knight, R. L.; Leeper, F. J. J. Chem.
Soc., Perkin Trans. 1 1998, 1891. (b) Enders, D.; Kallfass, U. Angew. Chem.,
Int. Ed. 2002, 41, 1743. (c) Dvorak, C. A.; Rawal, V. H. Tetrahedron Lett.
(6) (a) Nair, V.; Bindu, S.; Sreekumar, V.; Rath, N. P. Org. Lett. 2003,
5, 665. (b) Nair, V.; Sreekumar, V.; Bindu, S.; Suresh, E. Org. Lett. 2005,
7, 2297.
1998, 39, 2925. (d) Linghu, X.; Johnson, J. S. Angew. Chem., Int. Ed. 2003,
42, 2534. (e) Pesch, J.; Harms, K.; Bach, T. Eur. J. Org. Chem. 2004, 2025.
(7) Ma, C.; Yang, Y. Org. Lett. 2005, 7, 1343.
1
0.1021/ol051422m CCC: $30.25
© 2005 American Chemical Society
Published on Web 07/29/2005

Scheme 1. Reaction of Benzoin with Methyl Acrylate
Table 1. Reaction of Various Benzoins with Methyl Acrylate
Catalyzed by Imidazolin-2-ylidene9
Catalyzed by Imidazolin-2-ylidene
a
entry
R
time (h)
product
yield (%)
1
2
3
4
5
6
7
8
9
H
p-Br
o-Cl
m-Cl
p-Cl
p-F
m-Me
p-Me
p-MeO
6
8
8
8
8
8
8
8
44
2a8a,8b
2b
2c
76
65
60
72
67
70
62
60
32
2d
2e
2f
8
b
2g
2h
2i
dimethyl imidazolin-2-ylidene (20 mol %) generated in situ
by deprotonating 1,3-dimethylimidazolium iodide (DMII)
with an appropriate base. As the original objective, we
speculated that an equilibrium-driven, tandem retro-benzoin
condensation/Stetter reaction would take place to furnish 1,4-
ketoester A. As a matter of fact, when potassium tert-
butoxide was chosen as a base and the reaction was run in
THF containing 4 Å molecular sieves (MS) at room
temperature for 6 h, a formal [3 + 2] cyclization product,
8
b
a
Isolated yield.
results, we tend to believe that the role of DMII should not
be merely to provide a counterion. It is also noteworthy that
an excess of methyl acrylate (20 equiv) was introduced into
the system in order to ensure a reasonably clean transforma-
tion by inhibiting possible side reactions.
To examine the generality of the methodology, another
eight benzoin substrates were scrutinized (Table 1). The
following observations have been made. (i) The benzoins
with substituents of F, Cl, Br, or Me on the phenyl rings
gave the γ-butyrolactone products in similar and moderate
yields (60-72%, entries 2-8) that were slightly lower than
those given by the parent molecule benzoin itself (76%, entry
8
γ-benzoyl-γ-phenyl-γ-butyrolactone (2a), was formed in
76% yield. The 1,4-ketoester A was not isolable at all. Simply
switching the base from potassium tert-butoxide to sodium
hydride caused the chemical yield to drop to 65% after the
mixture was allowed to react for 8 h. In contrast, with
triethylamine used as the base, no desirable γ-butyrolactone
product was generated after 10 h of stirring in THF or
dichloromethane as the solvent. The presence of 4 Å MS
seemed to exert a favorable effect on the NHC-mediated
formal [3 + 2] cyclization. With potassium tert-butoxide as
the base, the γ-lactone was afforded in only 53% (10 h) in
the absence of 4 Å MS. Furthermore, the presence of DMII
was found to be crucial for the formal [3 + 2] cyclization
since potassium tert-butoxide or sodium hydride alone could
not drive the transformation to proceed, which indicated that
the NHC might be the catalytic species required for the
tandem reaction. This was further confirmed by the fact that
no reaction occurred even after 12 h at room temperature in
the presence of DMII without addition of potassium tert-
butoxide or sodium hydride. On the basis of our experimental
1
). The substitution pattern on the phenyl rings apparently
affects the reaction to some extent. With the same substituent
of Cl on the phenyl rings, the chemical yields of the products
were discovered to be slightly different and seemed to follow
a trend of o- < p- < m- (entries 3-5). A similar trend was
observed with methyl-substituted benzoins as well (p- < m-,
entries 7 and 8). (ii) In the case of 4,4′-dimethoxybenzoin,
the transformation was rather sluggish, and the corresponding
γ-butyrolactone was afforded in only 32% yield after
prolonged reaction time (44 h, entry 9). (iii) The reaction
seems to be very sensitive to the identity of the Michael
acceptors. Replacement of methyl acrylate with methyl
methacrylate (3), crotonate (4), or cinnamate (5) resulted in
no formation of the corresponding γ-butyrolactones (Figure
1).
(8) Ruthenium carbonyl-mediated cycloaddition was reported to lead to
the same γ-butyrolactone. See: (a) Chatani, N.; Tobisu, M.; Asaumi, T.;
Fukumoto, Y.; Murai, S. J. Am. Chem. Soc. 1999, 121, 7160. (b) Tobisu,
M.; Chatani, N.; Asaumi, T.; Amako, K.; Ie, Y.; Fukumoto, Y.; Murai, S.
J. Am. Chem. Soc. 2000, 122, 12663.
(
9) General Procedure. A mixture of 1,3-dimethylimidazolium iodide
0.22 mmol) and potassium tert-butoxide (0.2 mmol) in THF (4 mL) was
stirred at room temperature under N2 for 45 min [Note: The reaction time
45 min) for carbene generation was consistent with those reported in the
(
(
literature. The carbene species are reportedly quite stable, and some of them
are actually isolable. See: (i) Ref 5a. (ii) Arduengo, A. J., III; Dias, H. V.
R.; Harlow, R. L.; Kline, M. J. Am. Chem. Soc. 1992, 114, 5530. (iii)
Burstein, C.; Glorius, F. Angew. Chem., Int. Ed. 2004, 43, 6205]. Then, 4
Å MS (500 mg), benzoin (1 mmol), and methyl acrylate (1.8 mL, 20 mmol)
were added, and the resulting mixture was stirred for the indicated time.
The reaction mixture was passed through a short pad of Celite, and the
solvent was evaporated under reduced pressure to afford a residue that was
purified by flash column chromatography on silica gel to give the product.
Figure 1.
At this stage, the precise reaction mechanism for the
current efficient transformation remains puzzling to us. As
3770
Org. Lett., Vol. 7, No. 17, 2005

Scheme 2
Table 2. Reaction of Various Aromatic Aldehydes with
Methyl Acrylate Catalyzed by Imidazolin-2-ylidene10
a
entry
R
time (h)
product
yield (%)
1
2
3
4
5
6
7
8
9
H
p-Br
o-Cl
m-Cl
p-Cl
p-F
m-Me
p-Me
p-MeO
6
8
8
8
8
8
8
8
44
2a8a,8b
2b
2c
72
54
45
65
60
59
56
53
27
2d
2e
2f
outlined in Scheme 2, the γ-butyrolactone formation might
result either from tandem transesterification/intramolecular
Michael addition (path a, via intermediate 6) or from tandem
Michael addition/lactonization realized by intramolecular
transesterification (path b, via intermediate 7). The isolation
of 6 and/or 7 would be highly useful for us to gain certain
detailed mechanistic insights into the current methodology.
However, this attempt has not proved to be successful so
far despite our active endeavors.
8
b
2g
2h
2i
8
b
a
Isolated yield.
corresponding transformations from benzoins (Table 2), the
overall synthetic efficiency was further enhanced. The
lowered yields might be accounted for in part by the fact
that 6-18% of unreacted benzaldehydes could be recovered
and 4-20% of benzoins could be isolated as well.
In summary, we have described a one-step assembly of
γ,γ-difunctionalized γ-butyrolactones from benzoins or ben-
zaldehydes via a tandem reaction promoted by 1,3-dimethyl
imidazolin-2-ylidene that showcased the unique utility of
N-heterocyclic carbene species. Our direct, efficient, NHC-
mediated protocol should find applications in organic
synthesis.
Since NHC species are known to catalyze benzoin
3
condensation, we next turned our attention to probing the
feasibility of directly converting benzaldehydes into γ-bu-
tyrolactones in the presence of 1,3-dimethyl imidazolin-2-
ylidene and methyl acrylate. To our delight, benzaldehyde
and its derivatives could indeed give rise to γ,γ-difunction-
alized γ-butyrolactones presumably via initial benzoin
formation followed by the above-mentioned tandem reaction.
Although the chemical yields (45-72%, except a 27% yield
obtained for 4-methoxybenzaldehyde as the starting material)
were found to be somewhat lower than those of the
Acknowledgment. We thank NSFC (No. 20372073),
STCSM (“Venus” Program, No. 02QB14058), Ministry of
Human Resources of PRC, and Bureau of Tobacco of PRC
for financial support.
(
10) General Procedure. A mixture of 1,3-dimethyl-imidazolium iodide
(
0.22 mmol) and potassium tert-butoxide (0.2 mmol) in THF (4 mL) was
stirred at room temperature under N2 for 45 min. Benzaldehyde (1.0 mmol)
was added, and the resulting mixture was stirred for 3 h. Then, 4 Å MS
Supporting Information Available: Spectroscopic char-
acterization of compounds 2b-e,g,h. This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
(
500 mg) and methyl acrylate (0.90 mL, 10 mmol) were added, and the
reaction mixture was stirred for the indicated time. The reaction mixture
was passed through a short pad of Celite, and the solvent was evaporated
under reduced pressure to afford a residue that was purified by flash column
chromatography on silica gel to give the product.
OL051422M
Org. Lett., Vol. 7, No. 17, 2005
3771