Efficient synthesis of benzofuranones: N-heterocyclic carbene (NHC)/base-catalyzed hydroacylation-stetter-rearrangement cascade

Article abstract of DOI:10.1021/ol2023483

A N-heterocyclic carbene/base-catalyzed cascade reaction leading to the formation of functionalized benzofuranones is reported. The reaction proceeds via an intramolecular hydroacylation of unactivated alkynes followed by an intermolecular Stetter reactio

Full text of DOI:10.1021/ol2023483

ORGANIC
LETTERS
2011
Vol. 13, No. 20
5624–5627
Efficient Synthesis of Benzofuranones:
N-Heterocyclic Carbene (NHC)/
Base-Catalyzed HydroacylationÀStetterÀ
Rearrangement Cascade
Mohan Padmanaban,† Akkattu T. Biju,*,‡ and Frank Glorius*,†
€
€
Westfalische Wilhelms-Universitat, NRW Graduate School of Chemistry,
Organisch-Chemisches Institut, Corrensstrasse 40, 48149 Mu€nster, Germany and
Organic Chemistry Division, National Chemical Laboratory (CSIR), Dr. Homi Bhabha
Road, Pune-411008, India
at.biju@ncl.res.in; glorius@uni-muenster.de
Received August 30, 2011
ABSTRACT
A N-heterocyclic carbene/base-catalyzed cascade reaction leading to the formation of functionalized benzofuranones is reported. The reaction
proceeds via an intramolecular hydroacylation of unactivated alkynes followed by an intermolecular Stetter reaction and a base-catalyzed
chromanone to benzofuranone rearrangement.
Benzofuran-3(2H)-ones are attractive synthetic targets,
primarily due to the range of antifungal, antipsychotic,
and anticancer properties associated with them.1 The 2,2-
disubstituted benzofuranone core is found in various
natural products including griseofulvin (antifungal agent)
and Sch 202596 (Alzheimer’s disease) (Figure 1).2
Consequently, a number of methods for the synthesis of
benzofuranones containing a quaternary stereocenter at C2
have been developed.3,4 N-Heterocyclic carbene (NHC)-
catalyzed approaches toward the synthesis of 2,2-disub-
stituted benzofuranones have been uncovered by the re-
search group of Rovis and She.4,5 Although many of
Figure 1. Selected biologically active benzofuranones.
the known strategies for benzofuranone synthesis provide
the products in good yield, multiple steps are required for
the substrate synthesis. To address thisproblem, Rovis and
co-workers recently developed an elegant and highly en-
antioselective NHC-catalyzed benzofuranone synthesis
using commercially available starting materials via a multi-
catalytic cascade reaction.6
†
€
€
Westfalische Wilhelms-Universitat M€unster, Germany.
‡ National Chemical Laboratory (CSIR), India.
(1) For selected reports, see: (a) Charrier, C.; Clarhaut, J.; Gesson, J.;
Estiu, G.; Wiest, O.; Roche, J.; Bertrand, P. J. Med. Chem. 2009, 52,
3112. (b) Sheng, R.; Xu, Y.; Hu, C.; Zhang, J.; Lin, X.; Li, J.; Yang, B.;
He, Q.; Hu, Y. Eur. J. Med. Chem. 2009, 44, 7.
(2) (a) Pirrung, M. C.; Brown, W. L.; Rege, S.; Laughton, P. J. Am.
Chem. Soc. 1991, 113, 8561. (b) Rønnest, M. H.; Rebacz, B.;
Markworth, L.; Terp, A. H.; Larsen, T. O.; Kramer, A.; Clausen,
M. H. J. Med. Chem. 2009, 52, 3342. (c) Katoh, T.; Ohmori, O.; Iwasaki,
K.; Inoue, M. Tetrahedron 2002, 58, 1289.
(3) (a) Karthikeyan, K.; Perumal, P. T. Synlett 2009, 2366.
(b) Morton, G. J.; Kwon, D. L.; Freeman, D. J.; Njardarson, T. J.
Tetrahedron Lett. 2009, 50, 1684. (c) Capuzzi, M.; Perdicchia, D.;
Jørgensen, K. A. Chem.;Eur. J. 2008, 14, 128. (d) Gerard, B.; Sangji,
S.; O’Leary, J. D.; Porco, A. J., Jr. J. Am. Chem. Soc. 2006, 128, 7754.
€
r
10.1021/ol2023483
Published on Web 09/16/2011
2011 American Chemical Society

During the course of our endeavor on NHC-
organocatalysis,7 we recently disclosed an NHC-catalyzed
unique cascade reaction involving the hydroacylation8 of
unactivated alkynes followed by an intermolecular Stetter
reaction leading to the formation of chromanones with a
valuable 1,4-diketone moiety.9 The chromanone forma-
tion took place in spite of various selectivity issues includ-
ing the undesired benzoin and Stetter pathways, and the
key to success was the right choice of NHC and base. It was
surmised that when the reaction is carried out using a
relatively strong base, the initially formed chromanone will
be poised for a retro-Michael reaction leading to phenol A,
which upon a 1,3-H shift to B followed by an intramole-
cular oxa-Michael reaction leads to the formation of 2,2-
disubstituted benzofuranones (Scheme 1).10 Herein, we
report a unique cascade reaction comprising an NHC-
catalyzed hydroacylation followed by an intermolecular
Stetter reaction and a subsequent base-catalyzed chroma-
none to benzofuranone rearrangement (Scheme 2).11,12
Our present study commenced with the NHC/base-
catalyzed reaction of 2-propargyloxy 1-naphthaldehyde
Scheme 1. Cascade Catalysis Using NHC
Scheme 2. Proposed Mechanism of Base-Catalyzed Rearran-
gement of Chromanones to Benzofuranones
(4) (a) Kerr, M. S.; Rovis, T. J. Am. Chem. Soc. 2004, 126, 8876.
(b) Moore, J. L.; Kerr, M. S.; Rovis, T. Tetrahedron 2006, 62, 11477.
(c) He, J.; Zheng, J.; Liu, J.; She, X.; Pan, X. Org. Lett. 2006, 8, 4637.
(5) For recent reviews on NHC-organocatalysis, see: (a) Nair, V.;
Menon, R. S.; Biju, A. T.; Sinu, C. R.; Paul, R. R.; Jose, A.; Sreekumar,
V. Chem. Soc. Rev. 2011, 40, DOI: 10.1039/c1cs15139h. (b) Biju, A. T.;
Kuhl, N. Glorius, F. Acc. Chem. Res. 2011, 44, DOI: 10.1021/ar2000716.
(c) Hirano, K.; Piel, I.; Glorius, F. Chem. Lett. 2011, 40, 786. (d) Chiang,
P.-C.; Bode, J. W. In RSC Catalysis Series; Royal Society of Chemistry:
Cambridge, 2010; p 339. (e) Moore, J. L.; Rovis, T. Top. Curr. Chem.
2009, 291, 77. (f) Phillips, E. M.; Chan, A.; Scheidt, K. A. Aldrichimica
Acta 2009, 42, 55. (g) Enders, D.; Niemeier, O.; Henseler, A. Chem. Rev.
ꢀ
2007, 107, 5606. (h) Marion, N.; Dıez-Gonzalez, S.; Nolan, S. P. Angew.
Chem., Int. Ed. 2007, 46, 2988. For a recent review on physicochemical
(1a) with 4-chlorobenzaldehyde (2a) leading to the forma-
tion of chromanone 3a and benzofuranone 4a. After a
series of experiments, we found that treatment of 1a and 2a
with the carbene generated by the deprotonation of the
thiazolium salt 513 with 1,8-diazabicyclo[5.4.0]undec-7-ene
(DBU) resulted in the exclusive formation of the benzo-
€
properties of NHCs, see: (i) Droge, T.; Glorius, F. Angew. Chem., Int.
Ed. 2010, 49, 6940.
(6) Filloux, C. M.; Lathrop, S. P.; Rovis, T. Proc. Natl. Acad. Sci.
U.S.A. 2010, 107, 20666.
(7) (a) Biju, A. T.; Padmanaban, M.; Wurz, N. E.; Glorius, F. Angew.
Chem., Int. Ed. 2011, 50, 8412. (b) Bugaut, X.; Liu, F.; Glorius, F. J. Am.
Chem. Soc. 2011, 133, 8130. (c) Piel, I.; Steinmetz, M.; Hirano, K.;
€
Frohlich, R.; Grimme, S.; Glorius, F. Angew.Chem., Int. Ed. 2011, 50,
1
4983. (d) Jousseaume, T.; Wurz, N. E.; Glorius, F. Angew. Chem., Int.
Ed. 2011, 50, 1410. (e) Padmanaban, M.; Biju, A. T.; Glorius, F. Org.
Lett. 2011, 13, 98. (f) Kuhl, N.; Glorius, F. Chem. Commun. 2011, 47,
573. (g) Biju, A. T.; Glorius, F. Angew. Chem., Int. Ed. 2010, 49, 9761.
(h) Hirano, K.; Biju, A. T.; Piel, I.; Glorius, F. J. Am. Chem. Soc. 2009,
131, 14190. For a recent highlight review, see: (i) DiRocco, D. A.; Rovis,
T. Angew. Chem., Int. Ed. 2011, 50, 7982.
furanone 4a in 94% yield (based on H NMR spectro-
scopy, Table 1, entry 1). Notably, in contrast to this NHC,
other common NHCs derived from precursors 6À9 are less
effective (entries 2À5). The role of the base was found to be
crucial for the chromanoneÀbenzofuranone rearrange-
ment, and other bases including K2CO3, KOt-Bu, Et3N,
and 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD) furnished
the benzofuranone in reduced yields (entries 6À9). Sol-
vents other than THF resulted in inferior selectivity and
hence are not beneficial (entries 10 and 11). Additionally, 5
and 10 mol % loadings of 5 and DBU, respectively,
reduced the yield of 4a as it affected the rearrangement
step (entry 12). Gratifyingly, reducing the loading of 5 to 5
mol % and increasing the DBU amount to 20 mol %
maintained the reactivity and afforded the desired benzo-
furanone in 90% isolated yield (entry 13).
(8) For a review on transition-metal catalyzed hydroacylations, see:
Willis, M. C. Chem. Rev. 2010, 110, 725.
(9) (a) Biju, A. T.; Wurz, N. E.; Glorius, F. J. Am. Chem. Soc. 2010, 132,
5970. For the hydroacylation of activated alkynes, see: (b) Vedachalam, S.;
Wong, Q.-L.; Maji, B.; Zeng, J.; Ma, J.; Liu, X.-W. Adv. Synth. Catal. 2011,
353, 219. For the hydroacylation of nitriles, see: (c) Vedachalam, S.; Zeng,
J.; Gorityala, B. K.; Antonio, M.; Liu, X.-W. Org. Lett. 2010, 12, 352. For a
related hydroacylation of enol ethers, see: (d) He, J.; Tang, S.; Liu, J.; Su, Y.;
Pan, X.; She, X. Tetrahedron 2008, 64, 8797.
(10) For a base induced rearrangement of aminochromanones to
ꢀ
2-aminobenzofuranones, see: Patonay-Peli, E.; Litkei, G.; Patanay, T.
Synthesis 1990, 511.
(11) (a) For recent reviews on cascade catalysis, see: MacMillan,
D. W. C.; Walji, A. M. Synlett 2007, 10, 1477. (b) Chapman, C. J.; Frost,
C. G. Synthesis 2007, 1. (c) Nicolaou, K. C.; Edmonds, D. J.; Bulger,
P. G. Angew. Chem., Int. Ed. 2006, 45, 7134. (d) Wasilke, J. C.; Obrey,
S. J.; Baker, R. T.; Bazan, G. C. Chem. Rev. 2005, 105, 1001.
(12) For the application of NHCs in cascade catalysis, see:
(a) Ozboya, K. E.; Rovis, T. Chem. Sci. 2011, 2, 1835. (b) Lathrop,
S. P.; Rovis, T. J. Am. Chem. Soc. 2009, 131, 13628. (c) Ye, W.; Cai, G.;
Zhuang, Z.; Jia, X.; Zhai, H. Org. Lett. 2005, 7, 3769. (d) Stetter, H.;
Kuhlmann, H. Org. React. 1991, 40, 407.
€
(13) (a) Piel, I.; Pawelczyk, M. D.; Hirano, K.; Frohlich, R.; Glorius,
F. Eur. J. Org. Chem. 2011, DOI: 10.1002/ejoc.201100870. (b) Lebeuf,
R.; Hirano, K.; Glorius, F. Org. Lett. 2008, 10, 4243. (c) Hirano, K.; Piel,
I.; Glorius, F. Adv. Synth. Catal. 2008, 350, 984.
Org. Lett., Vol. 13, No. 20, 2011
5625

carboxaldehyde14 and aliphatic aldehyde15,16 also furn-
ished moderate to good yields of the desired products,
further expanding the scope of this NHC/base-catalyzed
reaction (4m, 4n).
Table 1. Optimization of the Reaction Conditionsa
Scheme 3. NHC/Base-Catalyzed Cascade Reaction: Variation
of the Aldehyde Moietya
variation of the standard
conditionsa
3a, yield
(%)b
4a, yield
(%)b
entry
1
None
<1
6
94
5
2
6 instead of 5
3
7 instead of 5
<1
6
60
6
4
8 instead of 5
5
9 instead of 5
<1
66
27
60
82
74
16
20
20
32
24
<1
6
6
K2CO3 instead of DBU
KOt-Bu instead of DBU
Et3N instead of DBU
TBD instead of DBU
1,4-dioxane instead of THF
DME instead of THF
(5 mol %) 5 and DBU
(10 mol %)
7
8
9
10
11
12
24
82
78
a General conditions: 1a (1.0 mmol), 2 (1.0 mmol), 5 (5 mol %), DBU
(20 mol %), THF (2.0 mL), 80 °C, and 24 h.
13
(5 mol %) 5 and DBU
(20 mol %)
<1
93 (90)c
In view of these interesting results, we further investigated
the scope of the reaction using various differently substi-
tuted 2-propargyloxy benzaldehydes (Scheme 4). The un-
substituted parent system (2-propargyloxy benzaldehyde)17
provided the product in a moderate yield (4o); however,
electron-donating groups at the benzene ring improved the
yield18 (4p, 4q). Additionally, a disubstituted as well as
halogen substituted substrate16 also afforded the corre-
sponding product in good to moderate yields (4r, 4s).
Mechanistically, the reaction proceeds via the formation
of a nucleophilic Breslow intermediate19 by the addition of
carbene generated from 5 to 1 followed by its intramole-
cular nucleophilic addition to an unactivated triple bond
resulting in the formation of the intermediate enone, which
undergoes an intermolecular Stetter reaction with the
Breslow intermediate generated from the aldehyde 2 lead-
ing to the formation of the chromanone. Under basic
conditions, the chromanone undergoes a unique rearran-
gement furnishing the benzofuranones (Scheme 2).
a Standard conditions: 1a (0.25 mmol), 2a (0.25 mmol), NHC HX
3
(10 mol %), DBU (20 mol %), THF (0.5 mL), 80 °C, and 24 h. b The
yields were determined by 1H NMR analysis of crude products using
CH2Br2 as the internal standard. c Isolated yield in parentheses.
With these optimized reaction conditions in hand, we
then examined the scope of this unique NHC/base-cata-
lyzed hydroacylationÀStetterÀrearrangement cascade
(Scheme 3). The parent system worked well, and a variety
of substituents at the 4-position of the ring are well
tolerated leading to the formation of functionalized ben-
zofuranones in 77À90% yields (4aÀ4f). Moreover, 3-sub-
stituted aldehydes and a disubstituted aldehyde resulted in
a smooth conversion to the product (4gÀ4i). The parent
naphthyl system worked well affording the product in 87%
yield (4j). Moreover, this novel cascade reaction is not
limited to aromatic aldehydes. Gratifyingly, heterocyclic
aldehydes also worked well leading to the formation of
the desired products (4k, 4l) in good to excellent yields.
Furthermore, challenging aldehydes like ferrocene
(17) Substrates 1o and 1s gave only a complex reaction mixture under
the reaction conditions. Therefore, using a slightly modified procedure
involving the separation of the crude chromanone product by simple
filtration gave moderate to acceptable yields. For further details, see the
Supporting Information.
(18) Under the optimized conditions, substrate 1q gave only 40% of
the desired product. However, a slight modification of the conditions
improved the yield to 67%. For details, see the Supporting Information.
(19) For the initial report of the concept, see: (a) Breslow, R. J. Am.
Chem. Soc. 1958, 80, 3719. For initial reports on the formation of the
conjugate Breslow intermediate from R,β-unsaturated aldehydes, see:
(b) Sohn, S. S.; Rosen, E. L.; Bode, J. W. J. Am. Chem. Soc. 2004, 126,
14370. (c) Burstein, C.; Glorius, F. Angew. Chem., Int. Ed. 2004, 43,
6205. Short review: (d) Zeitler, K. Angew. Chem., Int. Ed. 2005, 44, 7506.
(14) When ferrocene carboxaldehyde is employed as a coupling
partner, 19% of corresponding chromanone was also isolated.
(15) 26% of the corresponding chromanone was isolated with the
desired product when cyclohexanecarbaldehyde is used as the coupling
partner.
(16) Simple aliphatic aldehydes like octanal resulted in complex
reaction mixtures.
5626
Org. Lett., Vol. 13, No. 20, 2011

The present transition-metal-free catalysis involves an
intramolecular hydroacylation of unactivated alkynes fol-
lowed by an intermolecular Stetter reaction and a subse-
quent base-catalyzed rearrangement. Further studies on
the use of NHCs in cascade catalysis should be rewarding.
Scheme 4. Variation of 2-Propargyloxy Aldehyde Moietya
Acknowledgment. Generous financial support by the
Fonds der Chemischen Industrie, the International
NRW Graduate School of Chemistry (fellowship for
M.P.), and the Alexander von Humboldt Foundation
(fellowship for A.T.B.) is gratefully acknowledged. The
research of F.G. is supported by the Alfried Krupp Prize
for Young University Teachers of the Alfried Krupp von
Bohlen and Halbach Foundation.
a General conditions: 1 (1.0 mmol), 2a (1.0 mmol), 5 (5 mol %), DBU
(20 mol %), THF (2.0 mL), 80 °C, and 24 h. bChromanone is generated
in first step using (5 mol %) 5 and (10 mol %) K2CO3 in THF at 70 °C for
2 h. The addition of DBU (20 mol %) furnishes the furanone at 80 °C for
22 h in THF (for more details see the Supporting Information).
Supporting Information Available. Experimental pro-
cedures and full spectroscopic data for all compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
In conclusion, we have uncovered an efficient synthesis
of 2,2-disubstituted benzofuranones through a multicata-
lytic process using the combination of NHC and a base.
Org. Lett., Vol. 13, No. 20, 2011
5627