NHC-catalyzed reaction of enals with hydroxy chalcones: Diastereoselective synthesis of functionalized coumarins

Article abstract of DOI:10.1021/ol400562z

The N-heterocyclic carbene-catalyzed annulation of enals with 2′-hydroxy chalcones afford cyclopentane-fused coumarin derivatives with an excellent level of diastereocontrol. The reaction tolerates a broad range of functional groups; 25 examples are given, and a preliminary mechanistic investigation is provided.

Full text of DOI:10.1021/ol400562z

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
NHC-Catalyzed Reaction of Enals with
Hydroxy Chalcones: Diastereoselective
Synthesis of Functionalized Coumarins
Anup Bhunia,† Atanu Patra,† Vedavati G. Puranik,‡ and Akkattu T. Biju*,†
Organic Chemistry Division and Centre for Material Characterization, CSIR-National
Chemical Laboratory, Dr. Homi Bhabha Road, Pune 411008, India
at.biju@ncl.res.in
Received February 28, 2013
ABSTRACT
The N-heterocyclic carbene-catalyzed annulation of enals with 20-hydroxy chalcones afford cyclopentane-fused coumarin derivatives with an
excellent level of diastereocontrol. The reaction tolerates a broad range of functional groups; 25 examples are given, and a preliminary
mechanistic investigation is provided.
N-Heterocyclic carbene (NHC)-catalyzed umpolung of
aldehydes represent an important class of organocatalysis
and have established a broad range of applications in
synthetic organic chemistry.1 One of the important modes
of action of NHCs is the generation of homoenolate
equivalents from R,β-unsaturated aldehydes, which has
recently received great attention.2 The concept of NHC-
catalyzed generation of homoenolates from enals was
developed independently by Glorius3 and Bode4 in 2004,
and they intercepted the homoenolate equivalents with
aldehydes leading to the formation of γ-butyrolactones.
Consequently, a number of research groups have explored
homoenolate chemistry for the synthesis of a variety of
cyclic and acyclic compounds.1b,2,5 In 2006, Nair and co-
workers developed an unprecedented NHC-catalyzed
homoenolate annulation with chalcones furnishing 1,3,4-
trisubstituted cyclopentenes in high yields (Scheme 1, eq 1).6
Subsequently, the enantioselective cyclopentene-forming
reactions utilizing chiral NHCs was developed by Bode
and co-workers.7 Moreover, the enantioselective ver-
sion of the Nair reaction was uncovered by Scheidt and
† Organic Chemistry Division.
‡ Centre for Material Characterization.
(5) For selected recent reports, see: (a) Dugal-Tessier, J.; O’Bryan,
E. A.; Schroeder, T. B. H.; Cohen, D. T.; Scheidt, K. A. Angew. Chem.,
Int. Ed. 2012, 51, 4963. (b) Maji, B.; Ji, L.; Wang, S.; Vedachalam, S.;
Ganguly, R.; Liu, X.-W. Angew. Chem., Int. Ed. 2012, 51, 8276. (c)
Zhang, B.; Feng, P.; Sun, L.-H.; Cui, Y.; Ye, S.; Jiao, N. Chem.;Eur. J.
2012, 18, 9198. (d) Fu, Z.; Sun, H.; Chen, S.; Tiwari, B.; Li, G.; Chi, Y. R.
Chem. Commun. 2013, 49, 261.
(6) (a) Nair, V.; Vellalath, S.; Poonoth, M.; Suresh, E. J. Am. Chem.
Soc. 2006, 128, 8736. For related selected reports from the Nair group,
see: (b) Nair, V.; Vellalath, S.; Poonoth, M.; Mohan, R.; Suresh, E. Org.
Lett. 2006, 8, 507. (c) Nair, V.; Vellalath, S.; Poonoth, M.; Suresh, E.;
Viji, S. Synthesis 2007, 3195. (d) Nair, V.; Babu, B. P.; Vellalath, S.;
Suresh, E. Chem. Commun. 2008, 747. (e) Nair, V.; Sinu, C. R.; Babu,
B. P.; Varghese, V.; Jose, A.; Suresh, E. Org. Lett. 2009, 11, 5570. (f)
Nair, V.; Paul, R. R.; Seethalakshmi, K. C.; Menon, R. S.; Jose, A.; Sinu,
C. R. Tetrahedron Lett. 2011, 52, 5992.
(1) For selected recent reviews on NHC catalysis, see: (a) Bugaut, X.;
Glorius, F. Chem. Soc. Rev. 2012, 41, 351. (b) Nair, V.; Menon, R. S.;
Biju, A. T.; Sinu, C. R.; Paul, R. R.; Jose, A.; Sreekumar, V. Chem. Soc.
Rev. 2011, 40, 5336. (c) Chiang, P.-C.; Bode, J. W. In N-Heterocyclic
Carbenes; The Royal Society of Chemistry: London, 2011; pp 399. (d)
Grossmann, A.; Enders, D. Angew. Chem., Int. Ed. 2012, 51, 314. (e)
Cohen, D. T.; Scheidt, K. A. Chem. Sci 2012, 3, 53. (f) Vora, H. U.;
Wheeler, P.; Rovis, T. Adv. Synth. Catal. 2012, 354, 1617. (g) Biju, A. T.;
Kuhl, N.; Glorius, F. Acc. Chem. Res. 2011, 44, 1182. (h) Enders, D.;
Niemeier, O.; Henseler, A. Chem. Rev. 2007, 107, 5606. (i) Izquierdo, J.;
Hutson, G. E.; Cohen, D. T.; Scheidt, K. A. Angew. Chem., Int. Ed. 2012,
51, 11686.
(2) (a) Nair, V.; Vellalath, S.; Babu, B. P. Chem. Soc. Rev. 2008, 37,
2691. For a highlight on homoenolate chemistry, see: (b) Zeitler, K.
Angew. Chem., Int. Ed. 2005, 44, 7506.
(3) (a) Burstein, C.; Glorius, F. Angew. Chem., Int. Ed. 2004, 43, 6205.
(b) Burstein, C.; Tschan, S.; Xie, X.; Glorius, F. Synthesis 2006, 2418.
(4) (a) Sohn, S. S.; Rosen, E. L.; Bode, J. W. J. Am. Chem. Soc. 2004,
126, 14370. (b) He, M.; Bode, J. W. Org. Lett. 2005, 7, 3131.
(7) (a) Chiang, P.-C.; Kaeobamrung, J.; Bode, J. W. J. Am. Chem.
Soc. 2007, 129, 3520. For a related homoenolate annulation with
unsaturated N-sulfonyl ketimines, see: (b) He, M.; Bode, J. W. J. Am.
Chem. Soc. 2008, 130, 418.
r
10.1021/ol400562z
XXXX American Chemical Society

Table 1. Optimization of the Reaction Conditionsa
Scheme 1. NHC-Catalyzed Reaction of Enals with Chalcones
and 20-Hydroxy Chalcones
variation of the
standard conditionsa
yield of
3ac (%)
entry
drb
1
None
>20:1
nd
88 (86)
<1
2
5 instead of 4
co-workers utilizing the cooperative NHC/Lewis acid
strategy.8 We envisaged that if the reaction is carried
out using hydroxy chalcones, there is a possibility of δ-
lactonization to furnish functionalized coumarin deriva-
tives (Scheme 1, eq 2). The results of our studies leading to
a highly diastereoselective synthesis of cyclopentane-fused
coumarins are presented herein. Notably, functionalized
coumarin derivatives are important synthetic targets due
to their biological properties and some of them are endowed
with important fluorescent properties.9,10
Our present study commenced with the treatment of 20-
hydroxy chalcone 1a and cinnamaldehyde 2a with 10 mol %
of imidazolium salt 4 and 20 mol % of 1,8-diazabicyclo-
[5.4.0] undec-7-ene (DBU) as the base in THF as the
solvent. Delightfully, a facile reaction occurred leading to
the formation of the cyclopentane-fused coumarin deriva-
tive 3a in 88% yield with an excellent diastereoselectivity of
>20:1 (based on 1H NMR spectroscopy, Table 1, entry 1).
Interestingly, in this process, many selectivity issues arose,
and the competing cyclopentene formation as well as the
redox esterification was largely suppressed under the present
reaction conditions.11,12 Remarkably, in contrast to the
NHC derived from 4, other common NHCs derived from
precursors 5ꢀ8 are far less effective (entries 2ꢀ6). Other
bases such as NaOAc, KOt-Bu, NEt3, and dimethylamino
pyridine (DMAP) furnished the desired product in
3
6 instead of 4
nd
<1
4
7a instead of 4
nd
<1
5
7b instead of 4
>20:1
nd
67
6
8 instead of 4
<1
7
NaOAc instead of DBU
KO-t-Bu instead of DBU
Et3N instead of DBU
DMAP instead of DBU
1,4-dioxane instead of THF
toluene instead of THF
CH2Cl2 instead of THF
DME instead of THF
7 mol % of 4, 14 mol %
of DBU in DME
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
46
8
86
9
10
10
11
12
13
14
15
6
89
49
50
99 (98)d
72
a Standard conditions: 1a (0.25 mmol), 2a (0.25 mmol), NHC HX
3
(10 mol %), DBU (20 mol %), THF (1.0 mL), 25 °C and 24 h.
b Determined by 1H NMR analysis of crude products. c The yields were
determined by 1H NMR analysis of crude products using CH2Br2 as the
internal standard, isolated yield in 1.0 mmol scale in parentheses. d The
reaction was completed in 12 h.
reduced yields, but maintaining the diastereoselectivity
(entries 7ꢀ10). Among the various solvents screened, 1,4-
dioxane resulted in comparable result (entry 11), whereas
the reaction carried out in other solvents such as toluene
and CH2Cl2 resulted in inferior yields of 3a (entries 12
and 13). Gratifyingly, the reaction carried out in dimethoxy
ethane (DME) afforded the trans-diastereomer 3a in 98%
yield with a selectivity of >20:1 (entry 14).13,14 Furthermore,
lowering the amount of catalyst 4below 10 mol % resulted in
reduced yield of the product (entry 15).15
(8) (a) Cardinal-David, B.; Raup, D. E. A.; Scheidt, K. A. J. Am.
Chem. Soc. 2010, 132, 5345. See also: (b) Wadamoto, M.; Phillips, E, M.;
Reynolds, T. E.; Scheidt, K. A. J. Am. Chem. Soc. 2007, 129, 10098.
(9) For selected reports, see: (a) Riveiro, M. E.; Kimpe, N. D.;
Moglioni, A.; Vazquez, R.; Monczor, Shayo, C.; Davio, C. Curr.
Med. Chem. 2010, 17, 1325. (b) Garazd, M. M.; Garazd, Y. L.; Shilin,
S. V.; Panteleimonova, T. N.; Khilya, V. P. Chem. Nat. Compd. 2002, 38,
230. (c) Liu, X.; Cole, J. M.; Waddell, P. G.; Lin, T.-C.; Radia, J.;
Zeidler, A. J. Phys. Chem. A 2012, 116, 727. (d) Jung, H. S.; Kwon, P. S.;
Lee, J. W.; Kim, J. I.; Hong, C. S.; Kim, J. W.; Yan, S.; Lee, J. Y.; Lee,
J. H.; Joo, T.; Kim, J. S. J. Am. Chem. Soc. 2009, 131, 2008.
(10) For selected reports on NHC-catalyzed methods for synthesis of
coumarins, see: (a) Phillips, E. M.; Wadamoto, M.; Roth, H. S.; Andrew,
W. O.; Scheidt, K. A. Org. Lett. 2009, 11, 105. (b) Nair, V.; Sinu, C. R.;
Rejithamol, R.; Seethalakshmi, K. C.; Suresh, E. Org. Biomol. Chem.
2011, 9, 5511. (c) Ding, D.; Wang, Z. Eur. J. Org. Chem. 2008, 4949. (d)
Sinu, C. R.; Padmaja, D. V. M; Ranjini, U. P.; Seetha Lakshmi, K. C.;
Suresh, E.; Nair, V. Org. Lett. 2013, 15, 68.
With the optimized reaction conditions in hand, we then
examinedthe scope of thisunique homoenolate annulation
reaction (Scheme 2). The parent system worked well, and a
(13) To get insight into the reversibility of the reaction and to test the
stability of the product 3a under the reaction conditions, 3a was treated
with 4 and DBU. The reaction returned 3a quantitatively, demonstrat-
ing that the product is stable under the reaction conditions and that the
reaction is irreversible.
(14) It is noteworthy that the same yield was obtained from a 10.0
mmol scale reaction.
(15) See the Supporting Information for details.
(11) CCDC-918307 (3a) contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
(12) Chan, A.; Scheidt, K. A. Org. Lett. 2004, 7, 905.
B
Org. Lett., Vol. XX, No. XX, XXXX

variety of electron-donating and -withdrawing groups at
the 4-position of the aromatic ring at β-position of 1 are
well tolerated leading to the formation of cyclopentane-
fused coumarin derivatives in 89ꢀ98% yields and excellent
diastereoselectivity of >20:1 in all cases (3aꢀ3e). More-
over, substitution at 3-position and 2-position of β-aro-
matic ring resulted in a smooth conversion to the product
(3fꢀ3h). Additionally, disubstitution and the naphthyl
moiety at β-position of 1 afforded the desired product in
excellent yield (3i,j).
the product in high yields (3pꢀs) maintaining the diaste-
reoselectivity. Additionally, substitution at 3-position and
2-position as well as disubstitution resulted in smooth
conversion to the desired product (3tꢀv). Interestingly,
heterocyclic R,β-unsaturated aldehyde as well as alkyl
substituents at the β-position of 2 resulted in the formation
of the cyclopentane-fused coumarin derivatives thus de-
monstrating the versatility of the present reaction (3wꢀy).
It may be noted that in the reaction with crotonaldehyde,
the 2-phenylchroman-4-one 9 was also isolated in 22%
yield.
Scheme 2. Substrate Scope for the Synthesis of Functionalized
Coumarins. Variation of the 20-Hydroxy Chalcones Moiety
Scheme 3. Variation of the Enal Moiety
a General reaction conditions: 1a (1.0 mmol), 2 (1.0 mmol), 4 (10.0
mol %), DBU (20.0 mol %) in DME (4.0 mL) at 25 °C for 12 h.
b Determined by 1H NMR analysis of crude products. c Reaction run on
0.50 mmol scale. d Reaction run on 0.25 mmol scale. e 2-Phenylchroman-
4-one 9 was isolated in 22% yield.
The mechanistic rationale for this homoenolate annula-
tion reaction may be advanced as follows (Scheme 4). The
reaction proceeds via the generation of homoenolate
equivalent A from the enal and the NHC. The con-
jugate addition of A to the 20-hydroxy chalcone 1 followed
by the proton transfer generates the enolate B, which under-
goes intramolecular aldol reaction generating intermediate
C. The intermediate C instead of high energy β-lactoniza-
tion6a may undergo a proton transfer to afford phenoxide D
followed by δ-lactonization and dehydration to furnish the
coumarin derivative 3.
To gain mechanistic insight on this reaction, a series of
experiments were carried out. When the ꢀOH group at
20-position was protected (substrate 10), the reaction did
not work at all under the optimized conditions. Interest-
ingly, however, when the reaction was carried out at 45 °C,
the cyclopentene derivative 11 was formed in 55% yield
(Scheme 5, eq 3). No detectable formation of 3a was
observed and this indicates the importance of free ꢀOH
group at 20-position for the δ-lactonization leading to 3a.
Moreover, to evaluate the role of an additional proton
source in the proton transfer events, the reaction was
a General reaction conditions: 1 (1.0 mmol), 2a (1.0 mmol), 4 (10.0
mol %), DBU (20.0 mol %) in DME (4.0 mL) at 25 °C for 12 h.
b Determined by 1H NMR analysis of crude products. c Reaction run on
0.25 mmol scale.
Interestingly, challenging substituents such as hetero-
aromatic group and ferrocenyl moiety at β-position also
furnished excellent yields of the tricyclic compound,
further expanding the scope of this homoenolate annula-
tion reaction (3k,l). Furthermore, it was observed that
additional conjugation at β-position has no effect in the
course of the reaction and the corresponding product 3m
was formed in 79% yield. Finally, the substitution at the
benzoyl moiety of 1 was well tolerated leading to the
formation of the desired products (3n,o) in good yields.
Next, we examined the effect of varying the substituents
on the R,β-unsaturated aldehyde 2 (Scheme 3). Various
electronically different substituents at the 4-position of the
aromatic ring at β-position of 2 are well tolerated affording
Org. Lett., Vol. XX, No. XX, XXXX
C

Scheme 4. Plausible Reaction Mechanism
Scheme 5. Mechanistic Experiments
carried out with stoichiometric amounts of phenol. Grat-
ifyingly, even in the presence of additional proton source,
the desired product 3a was formed in 52% yield and no
detectable amounts of the redox esterification product 12
was observed (Scheme 5, eq 4).12,16 This result tends to
indicate that the proton transfer events are intramolecular
(Scheme 4) and the nucleophilic attack of homoenolate
equivalent A onto 1 is more important than its protonation
(leading to redox-esterification product).17
To get insight into the kinetics of the reaction as well as
to investigate the ease of δ-lactonization over β-lactoniza-
tion, competition experiments were carried out. Intermo-
lecular competition experiments carried out between 20-
hydroxy chalcone 1a and chalcone 1a0 revealed that 1a
reacted ∼75 times faster than 1a0 indicating the preferential
formation of 3a (Scheme 5, eq 5). The low rate of forma-
tion of 3a0 may be due to the fact that this reaction
proceeds via the high energy β-lactone intermediate.
These observations indicate that the thermodynamically
more feasible δ-lactonization proceeds over the high energy
β-lactonization.18,19 Alternatively, the H-bonding interac-
tion in 1 can also enhance its reactivity with homoenolate
equivalent A.
In conclusion, we have developed a metal-free and
scalable NHC-organocatalyzed homoenolate annulation
with hydroxy chalcones to furnish functionalized couma-
rin derivatives in good to excellent yields. The key to success
of the present reaction is the ease of δ-lactonization over
the β-lactonization. Moreover, broad substrate scope,
high yields of products, and mild reaction conditions
are the notable features of the present reaction. Further
studies on developing an enantioselective version of this
reaction and the related NHC-organocatalyzed annula-
tion reactions are ongoing in our laboratory.
(16) When the reaction was performed in methanol, intramolecular
cyclization of 1a leading to 2-phenyl chroman-4-one 9 was observed.
Interestingly, just stirring 1a in methanol in the presence of 20 mol %
DBU for 12 h afforded 9 in 62% yield indicating that this cyclization is
catalyzed by base only. Moreover, in DME the blank reaction afforded
20% of 9.
Acknowledgment. Generous financial support from
CSIR-NCL (start-up grant, MLP022426), CSIR-New
Delhi (Network project ORIGIN, CSC0108), and CSIR-
OSDD (HCP0001) is gratefully acknowledged. A.B. and
A.P. thank CSIR-New Delhi for the award of Junior
Research Fellowship. We thank Dr. P. R. Rajamohanan
(CSIR-NCL) for the NMR spectra and Ms. B. Santhakumari
(CSIR-NCL) for the HRMS data.
(17) For a related report on interception of homoenolates with
chalcones in methanol, see: Nair, V.; Babu, B. P.; Vellalath, S.; Varghese,
V.; Raveendran, A. E.; Suresh, E. Org. Lett. 2009, 11, 2507.
(18) Notably, the formation of functionalized coumarin 3 can also be
rationalized by invoking the β-lactone intermediate E generated from
cyclopentane intermediate C (Scheme 4) followed by the intramolecular
opening of the β-lactone E to generate δ-lactone F and subsequent
elimination of water. However, based on the apparent preference of δ-
lactonization over β-lactonization as revealed by the competition ex-
periments, this possibility can be ruled out at this point. For a related
report, see: Kaeobamrung, J.; Bode, J. W. Org. Lett. 2009, 11, 677
Supporting Information Available. Detailed experimen-
tal procedures, single-crystal X-ray data of 3a, mecha-
nistic experiments, and characterization data of all com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
.
(19) Monitoring the kinetics of the reaction revealed that 3a was
formed in 11% yield after 15 min and 25% after 30 min under optimized
conditions. For details, see the Supporting Information.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX