N-heterocyclic carbene catalyzed nucleophilic substitution reaction for construction of benzopyrones and benzofuranones

Article abstract of DOI:10.1021/ol061924f

N-Heterocyclic carbene as an efficient organic catalyst was employed to catalyze an intramolecular nucleophilic substitution reaction. When R ² was a phenyl group, the cyclization process underwent isomerization, leading to generation of benzofuranone.

Full text of DOI:10.1021/ol061924f

ORGANIC
LETTERS
2006
Vol. 8, No. 20
4637-4640
N-Heterocyclic Carbene Catalyzed
Nucleophilic Substitution Reaction for
Construction of Benzopyrones and
Benzofuranones
Jinmei He,† Jiyue Zheng,† Jian Liu,† Xuegong She,*,†,‡ and Xinfu Pan*,†
Department of Chemistry, State Key Laboratory of Applied Organic Chemistry,
Lanzhou UniVersity, Lanzhou, 730000, P. R. China, and State Key Laboratory for
Oxo Synthesis and SelectiVe Oxidation, Lanzhou Institute of Chemical Physics,
Chinese Academy of Sciences, Lanzhou 730000, P. R. China
shexg@lzu.edu.cn
Received August 3, 2006
ABSTRACT
N-Heterocyclic carbene as an efficient organic catalyst was employed to catalyze an intramolecular nucleophilic substitution reaction. When
R2 was a phenyl group, the cyclization process underwent isomerization, leading to generation of benzofuranone.
Efficient and selective organocatalytic transformations have
been intensely investigated and have attracted a great deal
of attention in the past decades.1 They are becoming powerful
tools in the construction of complex molecular skeletons.
N-Heterocyclic carbenes (NHCs) generated in situ from
thiazolium salts and triazolium salts in the presence of a weak
base have been known for a long time.2 Established catalytic
reactions include the benzoin3 and Stetter reactions4 in which
carbonyl units of aldehydes are converted into nucleophiles
upon the addition of a nucleophilic catalyst. Although the
development of these carbonyl anion addition reactions has
received significant attention,5,6 nucleophilic substitution
reactions catalyzed by NHC have received considerably less.
There have been only a few reports on the application of
NHCs to these types of organocatalytic transformations.7
Herein, we report a facile route of nucleophilic substitution
reaction catalyzed by NHC to construction of benzopyrones
(4) For the Stetter reaction, see: (a) Kerr, M. S.; Read de Alaniz, j.;
Rovis, T. J. Am. Chem. Soc. 2002, 124, 10298. (b) Kerr, M. S.; Rovis, T.
J. Am. Chem. Soc. 2004, 126, 8876. (c) Liu, Q.; Rovis, T. J. Am. Chem.
Soc. 2006, 128, 2552. (d) Mattson, A. E.; Bharadwaj, A. R.; Scheidt, K. A.
J. Am. Chem. Soc. 2004, 126, 2314. (e) Mennen, S. M.; Glpson, J. D.;
Kim, Y. R.; Miller, S. J. J. Am. Chem. Soc. 2005, 127, 1654. (f) Mattson,
A. E.; Zuhl, A. M.; Reynolds, T. E.; Scheidt, K. A. J. Am. Chem. Soc.
2006, 128, 4932.
(5) Enders, D.; Balensiefer, T. Acc. Chem. Res. 2004, 37, 534.
(6) Other reaction have been developed. For internal redox of unsaturated
aldehydes, see: (a) Sohn, S. S.; Rosen, E. L.; Bode, J. W. J. Am. Chem.
Soc. 2004, 126, 14370. (b) Chan, A.; Scheidt, K. A. Org. Lett. 2005, 7,
905. (c) He, M.; Bode, J. W. Org. Lett. 2005, 7, 3131. For internal redox
of epoxyaldehydes, see: (d) Chow, K. Y.; Bode, J. W. J. Am. Chem. Soc.
2004, 126, 8126. for internal redox of haloaldehydes, see: (e) Reynolds,
N. T.; Read de Alaniz, J.; Rovis, T. J. Am. Chem. Soc. 2004, 126, 9518.
For umpolung of Michael acceptors, see: Fischer, C.; Smith, S. W.; Powell,
D. A.; Fu, G. C. J. Am. Chem. Soc. 2006, 128, 1472.
† Lanzhou University.
‡ Chinese Academy of Sciences.
(1) For reviews on organocatalytic transformations, see: (a) Dalko, P.
I.; Moisan, L. Angew. Chem., Int. Ed. 2004, 43, 5138. (b) Tian, S. K.; Chen,
Y. G.; Hang, J. F.; Tang, L.; Mcdaid, P.; Deng, L. Acc. Chem. Res. 2004,
37, 621. (c) France, S.; Guerin, D. J.; Miller, S. J.; Leclka, T. Chem. ReV.
2003, 103, 2985. (d) Notz, W.; Tanaka, F.; Barbas, C. F. Acc. Chem. Res.
2004, 37, 580. (e) Allemann, C.; Gordillo, R.; Clemente, F. R.; Cheong, P.
H.; Houk, K. N. Acc. Chem. Res. 2004, 37, 558.
(2) (a) Ukai, T.; Tanaka, R.; Dokawa, T. J. Pharm. Soc. Jpn. 1943, 63,
296. (b) Mizuhara, S.; Handler, P. J. Am. Chem. Soc. 1954, 76, 571. (c)
Breslow, R. J. Am. Chem. Soc. 1958, 80, 3719.
(3) For the benzoin condensation, see: (a) Sheehan, J. C.; Hara, T. J.
Org. Chem. 1974, 39, 1196. (b) Enders, D.; Kallfass, U. Angew. Chem.,
Int. ed. 2002, 41, 1743. (c) Hachisu, Y.; Bode, J. W.; Suzuki, K. J. Am.
Chem. Soc. 2003, 125, 8432. (d) Enders, D.; Niemeier, O.; Balensiefer, T.
Angew. Chem., Int. Ed. 2006, 45, 1463.
10.1021/ol061924f CCC: $33.50
© 2006 American Chemical Society
Published on Web 08/31/2006

and benzofuranones. In this process, a carbonyl anion
catalyzed by NHC was utilized to attach to a suitable leaving
group. Benzopyrones and benzofuranones were obtained
when the reaction occurred intramolecularly (Scheme 1).
the activity of catalysts was also examined. The thiazolium
salt 1 was found to be superior to the thiazolium salt 2,9
whereas the Herrmann imidazolium salt 310 proved to be
inactive in the intramolecular nucleophilic substitution reac-
tion (entry 7). Subsequent optimization indicated that DBU
was the optimum base, and the reaction was accelerated by
increased amount of DBU. It was found that the reaction
proceeded better in the presence of 25 mol % catalyst 1 and
70 mol % DBU at 160 °C.11
Scheme 1. Intramolecular Nucleophilic Substitution Reaction
With the optimal experimental conditions, the scope of
the nucleophilic substitution reaction catalyzed by NHC was
explored using a series of aromatic aldehydes (Table 2).
Table 2. Generation of Benzopyrones
According to the traditional approach of analogous nucleo-
philic substitution reaction, the carbonyl anions could be
formed from corresponding aldehydes by thioacetalization.8
However, the conventional methods are mostly noncatalytic
and lack step economy and aesthetic appeal. Our new strategy
for construction of benzopyrones and benzofuranones had
more advantages and can potentially provide a sustainable,
environmentally benign process.
Using aromatic aldehyde 4 as a test substrate, the condi-
tions for this intramolecular nucleophilic substitution reaction
were investigated (Table 1). A number of solvents were
Table 1. Optimization of Reaction Conditions for the
Synthesis of Benzopyrone from Aromatic Aldehyde
entrya solvent base catalyst temp time (h) yield (%)
1
2
3
4
5
6
7
8
9b
10b
THF
THF
CH2Cl2 DBU
CH3OH DBU
benzene DBU
xylene
xylene
xylene
THF
DBU
NEt3
1
1
1
1
1
1
3
2
1
1
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
140 °C
140 °C
24
24
24
24
12
4h
12
12
4
50
46
<5
<5
58
72
0
56
62
<5
DBU
DBU
DBU
DBU
a All reactions were performed on a 0.5 mmol scale at 0.02 M. b When
the leaving group was chlorine or bromine, product 5 was obtained in low
yield.
CH2Cl2 DBU
4
a All reactions were performed on a 0.5 mmol scale at 0.02 M. b The
experiment was conducted in a sealed tube.
Reaction of aldehydes 7 and 9 provided benzopyrones 8 and
10 in moderate yield. In the case of aldehyde 11, the
transformation was rather sluggish, and the corresponding
screened. THF and benzene gave the product in moderate
yield (entries 1, 2, and 5), and the use of CH2Cl2 or CH3OH
as solvents provided little or none of the desired product
(entries 3 and 4). An initial survey of solvents demonstrated
that xylene was the solvent of choice (entry 6). Furthermore,
(7) (a) Suzuki, Y.; Toyota, T.; Imada, F. Chem. Commun. 2003, 1314.
(b) Miyashita, A.; Suzuki, Y.; Iwamoto, K. L.; Oishi, E.; Higashino, T.
Heterocycles 1998, 49, 405. (c) Miyashita, A.; Suzuki, Y.; Iwamoto, K. L.
Chem. Pharm. Bull. 1998, 46, 390.
4638
Org. Lett., Vol. 8, No. 20, 2006

obtained, perhaps as a result of the steric congestion that
the carbonyl anion encountered when approaching the
sulfonate unit. In this process, any trace of the corresponding
acyloin dimmers was not observed.
Scheme 2. Survey of Another Aldehyde Substrate
To investigate the impact of structural variations on the
aromatic aldehyde substrate for this process, substrate 15 was
prepared and underwent the reaction (Scheme 2).
A significant exception was noted; when aldehyde 15 was
subjected to these reaction conditions, benzofuranone 16 as
the main product was isolated in 82% yield. None of the
prospective flavanone 17 was observed. The result suggested
that the process underwent an isomerization that delivered
the product benzofuranone.
To examine the generality of the methodology, another
five analogous aldehyde substrates were scrutinized (Table
3). Aldehydes 18, 20, 22, and 24 reacted in a similar fashion
to give satisfactory yields of the product benzofuranones 19,
21, 23, and 25, and none of the flavanones was detected.
Nevertheless, aldehyde 26 still gave product in poor yield.12
Several experiments producing benzofuranones supported
the postulated catalytic cycle outlined in Scheme 3. First,
benzopyrone was afforded in only 48% yield after prolonged
reaction time. Presumably, it was ascribed to the electronic
effects. p-OMe depressed the electrophilicity of aldehyde,
and this made the additon of the catalyst to the carbonyl
disadvantageous. When the R2 group was methyl or phenyl
(entries 6 and 7), the corresponding products were not
Table 3. Generation of Benzofuranones
Scheme 3. Postulated Catalytic Cycle for Benzofuranone
Formation
the ion pair II may be formed under these reaction conditions,
and the carbon cation rearranged to give the more stable
(8) Organic chemists found recourse in the conversion of aldehyde into
umpolung reagents such as dithianes and protected cyanohydrin derivatives,
which may be converted into the derived carbanionic species with a strong
base in traditional way.
a All reactions were performed on a 0.5 mmol scale at 0.02 M.
(9) Stetter, H. Angew. Chem., Int. Ed. 1976, 15, 639.
Org. Lett., Vol. 8, No. 20, 2006
4639

intermediate III. Then, the carbene catalyst V added to
aromatic aldehyde III to form intermediate VI, which
underwent deprotonation to the thiazole-enamine VII. Fi-
nally, the umpolung aldehyde attached to the electrophilic
center, leading to benzofuranone forming IX followed by
catalyst turnover.
In conclusion, we have developed a novel intramolecular
nucleophilic substitution reaction catalyzed by NHC, which
is a more direct and efficient way to construct skeletons of
benzopyrones and benzofuranones. A variety of substrates
underwent the reaction in satisfactory yield, and we presumed
a mechanism of this reaction forming benzofuranone, which
was likely to undergo rearrangement of cation. Further
investigations into the precise mechanism of this reaction
as well as the use of chiral carbenes as organocatalysts in
other asymmetric reaction are currently underway in our
laboratory.
Acknowledgment. We are grateful for the financial
support by the NSFC (nos. 20572037, 20572036, QT
program), the Special Doctorial Program Funds of the
Ministry of Education of China (20040730008), GanSu
Science Foundation (no. 3ZS051-A25-004), Program for
New Century Excellent Talents in University (NCET-05-
0879), and the key grant project of Chinese ministry of
Education (no.105169).
(10) Herrmann, W. A.; Goossen, L. J.; Artus, G. R. J.; Kocher, C.
Organometallics 1997, 16, 2472.
(11) The reaction solution was refluxed intensely, heated by an oil bath
kept at 160-170 °C.
(12) The thermal elimination of the sulfonate 26 was detected (30%);
the elimination reaction was a competitive process with cyclization catalyzed
by NHC
Supporting Information Available: Experimental pro-
cedures and spectral data for all products. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL061924F
4640
Org. Lett., Vol. 8, No. 20, 2006