N-Heterocyclic carbene catalyzed ring expansion of formylcyclopropanes: Synthesis of 3,4-dihydro-α-pyrone derivatives

Article abstract of DOI:10.1021/ol9002898

N-Heterocyclic carbene catalyzed ring expansion of readily accessible 2-acyl-1-formylcyclopropanes was developed. With 5 mol % of triazolium salt 5 and 30 mol % of DBU, ring expansion of various 2-acyl-1-formylcyclopropanes led to 3,4-dihydro-α-pyrones in

Full text of DOI:10.1021/ol9002898

ORGANIC
LETTERS
2009
Vol. 11, No. 7
1623-1625
N-Heterocyclic Carbene Catalyzed Ring
Expansion of Formylcyclopropanes:
Synthesis of 3,4-Dihydro-r-pyrone
Derivatives
Gong-Qiang Li, Li-Xin Dai, and Shu-Li You*
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai 200032, China
slyou@mail.sioc.ac.cn
Received February 11, 2009
ABSTRACT
N-Heterocyclic carbene catalyzed ring expansion of readily accessible 2-acyl-1-formylcyclopropanes was developed. With 5 mol % of triazolium
salt 5 and 30 mol % of DBU, ring expansion of various 2-acyl-1-formylcyclopropanes led to 3,4-dihydro-r-pyrones in good to excellent yields.
Reversing the reactivity of aldehydes (also known as
umpolung1) by N-heterocyclic carbenes (NHCs) has become
an intense area, providing an unconventional access to some
important target molecules.2 In recent years, NHCs were also
found to catalyze various redox-type transformations of
functionalized aldehydes containing reducible functional-
ities.3 Remarkably, Bode and co-workers reported that
formyl-substituted three-membered rings such as epoxides,
aziridines, and cyclopropanes underwent ring opening during
redox esterifications.4 Inspired by their findings, we devel-
oped the ring expansion of 4-formyl-ꢀ-lactams, a class of
four-membered ring compounds, catalyzed by a N-hetero-
cyclic carbene5 and its kinetic resolution version by a chiral
N-heterocyclic carbene.6 Very recently, Gravel and co-
(3) (a) Reynolds, N. T.; Read de Alaniz, J.; Rovis, T. J. Am. Chem.
Soc. 2004, 126, 9518. (b) Sohn, S. S.; Rosen, E. J.; Bode, J. W. J. Am.
Chem. Soc. 2004, 126, 14370. (c) Burstien, C.; Glorius, F. Angew. Chem.,
Int. Ed. 2004, 43, 6205. (d) Reynolds, N. T.; Rovis, T. J. Am. Chem. Soc.
2005, 127, 16406. (e) Sohn, S. S.; Bode, J. W. Org. Lett. 2005, 7, 3873. (f)
Chan, A.; Scheidt, K. A. Org. Lett. 2005, 7, 905. (g) Nair, V.; Vellalath,
S.; Poonoth, M.; Mohan, R.; Suresh, E. Org. Lett. 2006, 8, 507. (h) Zeitler,
K. Org. Lett. 2006, 8, 637. (i) He, M.; Uc, G. J.; Bode, J. W. J. Am. Chem.
Soc. 2006, 128, 15088. (j) Phillips, E. M.; Wadamoto, M.; Chan, A.; Scheidt,
K. A. Angew. Chem., Int. Ed. 2007, 46, 3107. (k) Chiang, P.-C.;
Kaeobamrung, J.; Bode, J. W. J. Am. Chem. Soc. 2007, 129, 3520. (l) Bode,
J. W.; Sohn, S. S. J. Am. Chem. Soc. 2007, 129, 13798. (m) He, M.; Bode,
J. W. J. Am. Chem. Soc. 2008, 130, 418. (n) Phillips, E. M.; Reynolds,
T. E.; Scheidt, K. A. J. Am. Chem. Soc. 2008, 130, 2416. (o) Chan, A.;
Scheidt, K. A. J. Am. Chem. Soc. 2008, 130, 2740. (p) Rommel, M.;
Fukuzumi, T.; Bode, J. W. J. Am. Chem. Soc. 2008, 130, 17266. (q) Seayad,
J.; Patra, P. K.; Zhang, Y.; Ying, J. Y. Org. Lett. 2008, 10, 953. (r) Maki,
B. E.; Scheidt, K. A. Org. Lett. 2008, 10, 4331. (s) Maki, B. E.; Chan, A.;
Scheidt, K. A. Synthesis 2008, 1306. (t) Kaeobamrung, J.; Bode, J. W. Org.
Lett. 2009, 11, 677.
(1) (a) Grobel, B. T.; Seebach, D. Synthesis 1977, 357. (b) Seebach, D.
Angew. Chem., Int. Ed. 1979, 18, 239.
(2) For reviews, see: (a) Enders, D.; Balensiefer, T. Acc. Chem. Res.
2004, 37, 534. (b) Johnson, J. S. Angew. Chem., Int. Ed. 2004, 43, 1326.
(c) Nair, V.; Bindu, S.; Sreekumar, V. Angew. Chem., Int. Ed. 2004, 43,
5130. (d) Christmann, M. Angew. Chem., Int. Ed. 2005, 44, 2632. (e) Zeitler,
K. Angew. Chem., Int. Ed. 2005, 44, 7506. (f) Marion, N.; Díez-Gonza´lez,
S.; Nolan, S. P. Angew. Chem., Int. Ed. 2007, 46, 2988. (g) Enders, D.;
Niemeier, O.; Henseler, A. Chem. ReV. 2007, 107, 5606. (h) Nair, V.;
Vellalath, S.; Babu, B. P. Chem. Soc. ReV. 2008, 37, 2691. For recent
examples, see: (i) Wong, F. T.; Patra, P. K.; Seayad, J.; Zhang, Y.; Ying,
J. Y. Org. Lett. 2008, 10, 2333. (j) Zhao, H.; Foss, F. W., Jr.; Breslow, R.
J. Am. Chem. Soc. 2008, 130, 12590. (k) Liu, Q.; Perreault, S.; Rovis, T.
J. Am. Chem. Soc. 2008, 130, 14066. (l) Phillips, E. M.; Wadamoto, M.;
Roth, H. S.; Ott, A. W.; Scheidt, K. A. Org. Lett. 2009, 11, 105. (m) Yang,
L.; Tan, B.; Wang, F.; Zhong, G. J. Org. Chem. 2009, 74, 1744.
(4) (a) Chow, K. Y.-K.; Bode, J. W. J. Am. Chem. Soc. 2004, 126, 8126.
(b) Sohn, S. S.; Bode, J. W. Angew. Chem., Int. Ed. 2006, 45, 6021.
10.1021/ol9002898 CCC: $40.75
Published on Web 03/09/2009
2009 American Chemical Society

workers realized the ring-expansion lactonization of oxacy-
cloalkane-2-carboxaldehydes, providing functionalized five-,
six-, and seven-membered lactones.7 Both of the above two
reactions feature the expansion of the ring size by one.
Given the fact that 3,4-dihydro-R-pyrones are useful
intermediates for the synthesis of γ-lactones, substituted
benzenoids, pyridones, etc.8 and their efficient syntheses are
however still limited,8d,9 we decided to contribute a facile
synthesis of 3,4-dihydro-R-pyrones during our work toward
NHC catalysis.10 This work is also inspired by the elegant
work from Bode and Sohn, where in the presence of a NHC
catalyst 2-acyl-1-formylcyclopropanes underwent ring open-
ing during redox esterifications.4b The idea originated from
the answer to the following question: how does the reaction
proceed in the absence of the external nucleophile during
Bode’s ring opening of 2-acyl-1-formylcyclopropanes? We
envisioned that 2-acyl-1-formylcyclopropanes in the presence
of a NHC catalyst might also undergo the ring expansion
affording 3,4-dihydro-R-pyrones, since the ketone enolate
generated from the ring opening would serve as nucleophile
(Figure 1). If so, this would provide a new reaction model
less effective.12 Notably, Du and Wang recently reported a
similar ring expansion reaction.13 NHC derived from 3 was
found efficient in their case since the more reactive substrate,
ethyl 1-acetyl-2-formylcyclopropanecarboxylate, was used
therein.
Further examination of the solvents, temperature, and
catalyst loading led to the optimal reaction conditions: 5 mol
% 5, 30 mol % DBU, and 4 Å MS in dioxane at 65 °C.
Under these conditions, various 2-acyl-1-formylcyclopro-
panes were tested to investigate the generality of the reaction.
The results are summarized in Table 1. For the R2 groups,
Table 1. NHC-Catalyzed Ring Expansion of
Formylcyclopropanesa
entry
7
R1, R2
time (h)
8, yield (%)b
1c
2
3
4
5
6
7
8
9
7a
7b
7c
7d
7e
7f
7g
7h
7i
C6H5, C6H5
24
6
6
5
8
3
4
7
8a, 92
8b, 85
8c, 75
8d, 78
8e, 50
8f, 55
8g, 63
8h, 73
8i, 70
8j, 68
8k, 30
C6H5, p-MeO-C6H4
C6H5, p-Br-C6H4
C6H5, m-Cl-C6H4
C6H5, H
C6H5, Me
C6H5, nPr
p-Br-C6H4, C6H5
p-Me-C6H4, C6H5
p-MeO-C6H4, C6H5
tBu, C6H5
10
10
12
Figure 1
by NHC.
. Possible ring expansion of 2-acyl-1-formylcyclopropanes
10
7j
7k
11d
a Reaction conditions: 7 (1.0 mmol), 5 mol % 5, 30 mol % DBU, 4 Å
MS (0.1 g) in dioxane (5.0 mL) at 65 °C. b Isolated yields. c 2 mol % 5 and
5 mol % DBU were used. d 8l was isolated in 30% yield.
with expansion of the ring size by three. Herein, we report
our preliminary results from the study on this subject.
Our studies began with an initial examination of the
catalytic reactivity of several NHCs (Figure 2) for the
substrates 7a-d bearing phenyl with different electronic
properties all underwent the ring expansion smoothly to
afford the dihydro-R-pyrones in good yields (75-92%,
entries 1-4, Table 1). The current method was also suitable
for the aliphatic substituted substrates 7f, 7g (entries 6 and
7, Table 1). For the R1 group, aryl ketones 7 h-j bearing
either an electron-withdrawing or electron-donating substitu-
ent on the phenyl group were well tolerated, with yields
ranging from 68% to 73% (entries 8-10, Table 1). When
an aliphatic ketone substrate such as 7k was used, the
reaction gave 8k in 30% yield together with 8l (30% yield)
(entry 11, Table 1).
(5) Li, G.-Q.; Li, Y.; Dai, L.-X.; You, S.-L. Org. Lett. 2007, 9, 3519.
(6) Li, G.-Q.; Li, Y.; Dai, L.-X.; You, S.-L. AdV. Synth. Catal. 2008,
350, 1258.
Figure 2. Several readily available NHC precursors.
(7) Wang, L.; Thai, K.; Gravel, M. Org. Lett. 2009, 11, 891.
(8) (a) Rosenthal, D.; Grabowich, P.; Sabo, E. F.; Fried, J. J. Am. Chem.
Soc. 1963, 85, 3971. (b) Mandal, A. K.; Jawalkar, D. G. Tetrahedron Lett.
1986, 27, 99. (c) Kume, T.; Iwasaki, H.; Yamamoto, Y.; Akiba, K.
Tetrahedron Lett. 1988, 29, 3825. (d) Mandal, A. K.; Jawalkar, D. J. J.
Org. Chem. 1989, 54, 2364. (e) Robl, J. A. Tetrahedron Lett. 1990, 31,
3421. (f) Thang, S. H.; Rigg, D. J. Synth. Commun. 1993, 23, 2355. (g)
Harrowven, D. C.; Hannam, J. C. Tetrahedron 1999, 55, 9333. (h) Zhang,
F.-Y.; Corey, E. J. Org. Lett. 2000, 2, 1097.
possible ring expansion of formylcyclopropane 7a.11 To our
delight, with 20 mol % triazolium salt 5 and 30 mol % DBU
in THF, the substrate 7a was smoothly converted to 3,4-
dihydro-R-pyrone 8a (65% yield). Under the same condi-
tions, several other NHCs derived from 1-4 and 6 proved
1624
Org. Lett., Vol. 11, No. 7, 2009

Since the enantioenriched 2-acyl-1-formylcyclopropanes
are easily accessed,11a the synthesis of optically active 3,4-
dihydro-R-pyrones was also tested.
Scheme 3. Transformations of 3,4-Dihydro-R-pyrones
As shown in Scheme 1, starting from optically active
substrates (-)-7a and (-)-7b, the reaction gave their
Scheme 1. Synthesis of Optically Active 3,4-Dihydro-R-pyrones
2-one 12 upon treatment by p-anisidine in refluxed dioxane
and chloranil, respectively (eqs 1 and 2). The latter is a very
useful intermediate in organic synthesis.15 In addition, the
reductive ring-opening reaction of 8a to carboxylic acid 13
was accomplished in excellent yield by hydrogenation on
Pd/C.
corresponding ring expansion products (+)-8a and (+)-8b
in 86% and 87% yield, respectively, without notable loss of
the optical purity. The ee values of (-)-7a and (-)-7b were
determined by converting to their corresponding primary
alcohols.11b
As 2-acyl-1-formylcyclopropanes could be synthesized via
a one-pot procedure from allylic alcohol and 2-(dimethyl-
l-sulfanylidene)-λ-phenyl-ethanone in the presence of acti-
vated manganese dioxide, as reported by Taylor and co-
workers,14 we therefore tested the one-pot procedure further
to include the ring expansion. To our delight, starting from
allylic alcohol 9 and ylide 10, 3,4-dihydro-R-pyrone 8g could
be synthesized in 31% yield via a one-pot procedure
involving multiple steps (Scheme 2).
In summary, we have developed a novel reaction pattern
catalyzed by N-heterocyclic carbene where 3,4-dihydro-R-
pyrones were synthesized efficiently from 2-acyl-1-formyl-
cyclopropanes under mild conditions. The ready accessibility
of the starting materials even in enantiopure form make the
current methodology particularly attractive in organic syn-
thesis. Further transformations of the resulting 3,4-dihydro-
R-pyrones are ongoing.
Acknowledgment. We thank the National Natural Science
Foundation of China (20821001, 20732006), National Basic
Research Program of China (973 Program 2009CB825300),
the Chinese Academy of Sciences, and the Science and
TechnologyCommissionofShanghaiMunicipality(07pj14106,
07JC14063) for generous financial support.
Scheme 2
.
One-Pot Synthesis of 3,4-Dihydro-R-pyrones from
Allylic Alcohols
Supporting Information Available: Experimental pro-
cedures and analysis data for 7, 8, and 11-13. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL9002898
To demonstrate the applications of the current methodol-
ogy, several ready transformations of 3,4-dihydro-R-pyrones
were carried out (Scheme 3). The in situ generated 3,4-
dihydro-R-pyrone 8a from the ring expansion of 7a would
lead to ring opening product 11 and 4,6-diphenyl-2H-pyran-
(10) (a) Li, G.-Q.; Dai, L.-X.; You, S.-L. Chem. Commun. 2007, 852.
(b) Li, Y.; Feng, Z.; You, S.-L. Chem. Commun. 2008, 2263. (c) Li, Y.;
Zhao, Z.-A.; He, H.; You, S.-L. AdV. Synth. Catal. 2008, 350, 1885.
(11) (a) Kunz, R. K.; MacMillan, D. W. C. J. Am. Chem. Soc. 2005,
127, 3240. (b) Hartikka, A.; Arvidsson, P. I. J. Org. Chem. 2007, 72, 5874.
(c) Zhao, Y.-H.; Zhao, G.; Cao, W.-G. Tetrahedron: Asymmetry 2007, 18,
2462.
(12) See Supporting Information for details.
(9) (a) Ruhemann, S. J. Chem. Soc. Trans. 1910, 97, 457. (b) El-Kholy,
I. E.; Rafla, F. K.; Mishrikey, M. M. J. Org. Chem. 1966, 31, 2167. (c)
El-Kholy, I. E.; Mishrikey, M. M.; Abdoul-Ela, S. L. J. Heterocycl. Chem.
1982, 19, 1329. (d) Katritzky, A. R.; Denisko, O. V. J. Org. Chem. 2002,
67, 3104. (e) Tozawa, T.; Nagao, H.; Yamane, Y.; Mukaiyama, T. Chem.
Asian J. 2007, 2, 123. (f) Zhu, M.-K.; Wei, Q.; Gong, L.-Z. AdV. Synth.
Catal. 2008, 350, 1281. (g) Wang, J.; Yu, F.; Zhang, X.-J.; Ma, D.-W.
Org. Lett. 2008, 10, 2561.
(13) Du, D.; Wang, Z. Eur. J. Org. Chem. 2008, 4949.
(14) (a) Oswald, M.; Raw, S. A.; Taylor, R. J. K. Org. Lett. 2004, 6,
3997. (b) McAllister, G. D.; Oswld, M. F.; Paxton, R. J.; Raw, S. A.; Taylor,
R. J. K. Tetrahedron 2006, 62, 6681.
(15) (a) Rickborn, B. Org. React. 1998, 53, 245. (b) Hulce, M.
Encyclopedia of Reagents for Organic Synthesis; Academic Press: New
York, 2001; Vol. 6, p 4378. (c) Alberola, A.; Andre´s, C.; Ortega, A. G.;
Pedrosa, R.; Vicente, M. J. Chem. Soc., Perkin Trans. 1 1987, 2125.
Org. Lett., Vol. 11, No. 7, 2009
1625