Formal diels-alder reactions of chalcones and formylcyclopropanes catalyzed by chiral n-heterocyclic carbenes

Article abstract of DOI:10.1021/ol202250s

Highly enantioselective (formal) hetero-Diels-Alder reactions between chalcones and formylcyclopropanes are disclosed. The challenging N-heterocyclic carbene (NHC)-bounded enolate intermediates from formylcyclopropanes were captured for new C-C bond formi

Full text of DOI:10.1021/ol202250s

ORGANIC
LETTERS
2011
Vol. 13, No. 19
5366–5369
Formal DielsꢀAlder Reactions of
Chalcones and Formylcyclopropanes
Catalyzed by Chiral N-Heterocyclic
Carbenes
Hui Lv, Junming Mo, Xinqiang Fang, and Yonggui Robin Chi*
Division of Chemistry & Biological Chemistry, School of Physical & Mathematical
Sciences, Nanyang Technological University, Singapore 637371, Singapore
robinchi@ntu.edu.sg
Received August 19, 2011
ABSTRACT
Highly enantioselective (formal) hetero-DielsꢀAlder reactions between chalcones and formylcyclopropanes are disclosed. The challenging
N-heterocyclic carbene (NHC)-bounded enolate intermediates from formylcyclopropanes were captured for new CꢀC bond forming reactions.
The reaction products were obtained with high diastereo- and enantioselectivities and could be easily transformed to optically pure
multisubstituted cyclohexane derivatives.
The catalytic generation of chiral ester enolates or their
equivalents with small organic catalysts for enantioselec-
tive carbonꢀcarbon bond-forming reaction is a powerful
strategy in reaction discovery and synthesis.1ꢀ4 One well-
studied approach is to generate enolates from ketenes by
employing nucleophilic catalysts, such as planar-chiral
DMAP derivatives,2 cinchona alkaloids,3 and chiral
N-heterocyclic carbenes (NHCs).4 With NHCs as the
catalysts, the chiral ester enolate equivalents can also be
generated from R-heteroatom-functionalized aldehydes
(such as R-chloro aldehydes) and recently simple enals.5
These NHC-bounded enolate equivalents have been ex-
plored as dienophiles for (formal) reverse-electron-
demand DielsꢀAlder reactions.5cꢀe Highly activated het-
erodienes, such as ketoenones5d,e,6 and R,β-unsaturated
N-sulfonylimines,5c,7 were widely used for the DielsꢀAlder
reactions (eq 1).8 However, chalcones were rarely used
in NHC-mediated5f,9 or other catalytic intermolecular
(1) (a) Chiang, P.-C.; Bode, J. W. In N-Heterocyclic Carbenes; The
Royal Society of Chemistry: 2011; p 399; (b) Moore, J.; Rovis, T. Top.
Curr. Chem. 2010, 291, 77. (c) Enders, D.; Balensiefer, T. Acc. Chem.
ꢀ
Res. 2004, 37, 534. (d) Marion, N.; Dıez-Gonzalez, S.; Nolan, S. P.
Angew. Chem., Int. Ed. 2007, 46, 2988. (e) Nair, V.; Vellalath, S.; Babu,
B. P. Chem. Soc. Rev. 2008, 37, 2691. For a recent review on the related
“chiral enol equivalents” (enamine catalysis), see: (f) Mukherjee, S.;
Yang, J. W.; Hoffmann, S.; List, B. Chem. Rev. 2007, 107, 5471.
(2) (a) Wurz, R. P. Chem. Rev. 2007, 107, 5570. (b) Fu, G. C. Acc.
Chem. Res. 2000, 33, 412. (c) Fu, G. C. Acc. Chem. Res. 2004, 37, 542.
(3) (a) Gaunt, M. J.; Johansson, C. C. C. Chem. Rev. 2007, 107, 5596.
(b) France, S.; Guerin, D. J.; Miller, S. J.; Lectka, T. Chem. Rev. 2003,
103, 2985. (c) France, S.; Weatherwax, A.; Taggi, A. E.; Lectka, T. Acc.
Chem. Res. 2004, 37, 592.
(4) (a) Enders, D.; Niemeier, O.; Henseler, A. Chem. Rev. 2007, 107,
5606. (b) Zhang, Y.-R.; He, L.; Wu, X.; Shao, P.-L.; Ye, S. Org. Lett.
2007, 10, 277. (c) Lv, H.; Zhang, Y.-R.; Huang, X.-L.; Ye, S. Adv. Synth.
Catal. 2008, 350, 2715. (d) Duguet, N.; Campbell, C. D.; Slawin,
A. M. Z.; Smith, A. D. Org. Biomol. Chem. 2008, 6, 1108. (e) Lv, H.;
You, L.; Ye, S. Adv. Synth. Catal. 2009, 351, 2822. (f) Lv, H.; Chen, X.-
Y.; Sun, L.-H.; Ye, S. J. Org. Chem. 2010, 75, 6973.
(5) (a) Ling, K. B.; Smith, A. D. Chem. Commun. 2011, 47, 373. (b)
Scheidt, K. A.; Kawanaka, Y.; Phillips, E. M. J. Am. Chem. Soc. 2009,
131, 18028. (c) Bode, J. W.; He, M.; Struble, J. R. J. Am. Chem. Soc.
2006, 128, 8418. (d) Bode, J. W.; Kaeobamrung, J.; Kozlowski, M. C.
Proc. Natl. Acad. Sci. U.S.A. 2010, 107, 20661. (e) Bode, J. W.; He, M.;
Uc, G. J. J. Am. Chem. Soc. 2006, 128, 15088. (f) Scheidt, K. A.; Phillips,
E. M.; Wadamoto, M.; Chan, A. Angew. Chem., Int. Ed. 2007, 46, 3107.
(g) Vora, H. U.; Rovis, T. J. Am. Chem. Soc. 2010, 132, 2860. (h) Glorius,
F.; Burstein, C.; Tschan, S.; Xie, X. Synthesis 2006, 2006, 2418. (i)
Kobayashi, S.; Kinoshita, T.; Uehara, H.; Sudo, T.; Ryu, I. Org. Lett.
2009, 11, 3934. (j) Fang, X.; Chen, X.; Chi, Y. R. Org. Lett. 2011,
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(6) (a) He, M.; Beahm, B. J.; Bode, J. W. Org. Lett. 2008, 10, 3817. (b)
Zhang, Y.-R.; Lv, H.; Zhou, D.; Ye, S. Chem.;Eur. J. 2008, 14, 8473. (c)
Belmessieri, D.; Morrill, L. C.; Simal, C.; Slawin, A. M. Z.; Smith, A. D.
J. Am. Chem. Soc. 2011, 133, 2714.
r
10.1021/ol202250s
Published on Web 08/30/2011
2011 American Chemical Society

hetero-DielsꢀAlder reactions, as indicated through litera-
ture survey and recently pointed out by Feng and co-
workers.10
You et al.14a had reported the facile intramolecular trap-
ping of the activated ester by the ketone enol oxygen.
However, a further evaluation of the system let us hy-
pothesize that the reactivity (and/or stability) of the en-
olate A might be modulated through intramolecular
noncovalent interactions (B) and/or formation of cyclic
We reasoned that one difficulty of using the relatively
less-activated chalcones as oxodienes for NHC-catalyzed
intermolecular DielsꢀAlder reactions might be that the
catalytically generated enolates could undergo rapid con-
versions to the corresponding activated esters and subse-
quently end up as carboxylic acids (when trace water was
present) or their derivatives suchas amides and esters when
alcohols and amines were present.11 When enals were used
as the enolate precursors, additional complications came
from the competing NHC-bounded homoenolate equiva-
lent intermediates.5f,9,12 One solution to overcome this
difficulty is perhaps to minimize the conversion of the
enolate to the activated ester intermediates through some
kind of stabilizing or buffering.
1
adduct C.15 Our efforts with H NMR studies did not
detect these interactions or intermediates; nevertheless we
decided to evaluate the reactions of formylcyclopropanes
with chalcones and other electrophiles. Described here are
our highly enantioselective intermolecular DielsꢀAlder
reactions between simple chalcones and formylcyclopro-
panes (eq 2).
Our attention was turned to formylcyclopropanes as
enolate precursors for formal DielsꢀAlder reactions with
chalcones. In 2006, Bode et al. reported the pioneering
NHC-mediated ring opening of formylcyclopropanes to
give activated carboxylate esters that were trapped inter-
molecularly by alcohols or amines to afford the corre-
sponding esters and amides (eq 1).13 The groups of You
and Wang have then applied this chemistry to synthesize
heterocyclic compounds via intra- or intermolecular
trapping of the activated ester intermediates (eq 1).14 To
the best of our knowledge, no reaction through trapping of
the possible enolate intermediates A (eq 2) has been
developed.14d At first glance trapping the enolate inter-
mediates seemedtobedifficult especiallygiven the factthat
Our condition optimization for a model reaction be-
tween formylcyclopropane 1a and chalcone 2a is summar-
ized in Table 1. The reaction using 10 mol % of 4a NHC
precatalyst and 30 mol % DBU successfully afforded
product 3a with 68% yield but poor dr (Table 1, entry 1).
Additional studies revealed that the low dr was mainly
caused by the base (DBU)-induced postreaction epimer-
ization of 3a. Thus decreasing the DBU loading from 30 to
10 mol % led to a higher dr (14:1; Table 1, entry 2) without
loss of the yield. The use of a slight excess of aldehyde 1a
(1.2 to 1.5 equiv) was necessary to ensure high yields as
side reactions via the previously reported activated ester
intermediates14a could not be completely suppressed.
Further screenings of solvents and bases suggested that
the combination of DBU and THF gave the best results in
terms of both yields and stereoselectivities (Table 1, entries
3ꢀ8).The use of 4A molecular sieve could improve the
reaction yield but with a dropped dr (Table 1, entry 10).
Finally, switching the counteraꢀnions16 of the NHC pre-
cursors from Clꢀ (4a) to BF4 (4b) could consistently
afford the product with high yields and excellent enantios-
electivities (Table 1, entries 11ꢀ12).
(7) Jian, T.-Y.; Shao, P.-L.; Ye, S. Chem. Commun. 2011, 47, 2381.
(8) The same type of highly activated heterodiene substrates were
also widely used in other catalytic hetero-DielsꢀAlder reactions. See: (a)
Juhl, K.; Jørgensen, K. A. Angew. Chem., Int. Ed. 2003, 42, 1498. (b)
Han, B.; He, Z.-Q.; Li, J.-L.; Li, R.; Jiang, K.; Liu, T.-Y.; Chen, Y.-C.
Angew. Chem. 2009, 121, 5582–5589. (c) Angew. Chem., Int. Ed. 2009,
58, 5474.
(9) For examples of NHC-bounded enolates involved in intramole-
cular DielsꢀAlder reactions (or possible Michael additions) with chal-
cones, see ref 5f and Fang, X.; Jiang, K.; Xing, C.; Hao, L.; Chi, Y. R.
Angew. Chem., Int. Ed. 2011, 50, 1910.
(10) For one example of guanidine-catalyzed intermolecular
DielsꢀAlder reactions with chalcones, see: Dong, S.; Liu, X.; Chen,
X.; Mei, F.; Zhang, Y.; Gao, B.; Lin, L.; Feng, X. J. Am. Chem. Soc.
2010, 132, 10650. It should be noted that stepwise pathways via Michael-
type additions to chalcones followed by enol ester formatons cannot be
ruled out. So these (ref 5cꢀ5e, 6, 7, 10) and our reactions might be
considered as “formal” DielsꢀAlder reactions.
(11) (a) Rovis, T.; Reynolds, N. T.; Read de Alaniz, J. J. Am. Chem.
Soc. 2004, 126, 9518. (b) Rovis, T.; Vora, H. U. J. Am. Chem. Soc. 2007,
129, 13796. (c) Bode, J. W.; Chow, K. Y.-K. J. Am. Chem. Soc. 2004, 126,
8126.
(12) (a) Nair, V.; Vellalath, S.; Poonoth, M.; Suresh, E. J. Am. Chem.
Soc. 2006, 128, 8736. (b) Bode, J. W.; Chiang, P.-C.; Kaeobamrung, J. J.
Am. Chem. Soc. 2007, 129, 3520.
(13) (a) Bode, J. W.; Sohn, S. S. Angew. Chem., Int. Ed. 2006, 45,
6021. (b) Bode, J. W.; Sohn, S. S. J. Am. Chem. Soc. 2007, 129, 13798. (c)
ꢀ
Vesely, J.; Zhao, G.-L.; Bartoszewicz, A.; Cordova, A. Tetrahedron Lett.
With the optimized conditions (Table 1, entry 12) in
hand, the scope of the chalcone substrates was examined
2008, 49, 4209.
(14) (a) You, S.-L.; Li, G.-Q.; Dai, L.-X. Org. Lett. 2009, 11, 1623. (b)
Du, D.; Li, L.; Wang, Z. J. Org. Chem. 2009, 74, 4379. (c) Li, L.; Du, D.;
Ren, J.; Wang, Z. Eur. J. Org. Chem. 2011, 2011, 614. (d) Du, D.; Wang,
Z. Eur. J. Org. Chem. 2008, 2008, 4949. In Wong’s work (ref 14d) the
formation of an ester intermediate (via trapping of the NHC-bounded
activated ester) was followed by an intramolecular condensation of the
ester with an aldehyde to form the product; no direct trapping of an
NHC-bounded enolate intermediate was observed/proposed.
(15) For a recent example of related intramolecular nucleophilic
addition to triazoliums in an NHC-catalyzed living polymerization,
see: Guo, L.; Zhang, D. J. Am. Chem. Soc. 2009, 131, 18072.
(16) For a discusion on counteranion effects, see: Wei, S.; Wei, X.-G.;
Su, X.; You, J.; Ren, Y. Chem.;Eur. J. 2011, 17, 5965.
Org. Lett., Vol. 13, No. 19, 2011
5367

Table 1. Optimization of Reaction Conditionsa
Table 2. Scope of Chalconesa
yield,
entry
Ar1
Ar2
yield %
ee (dr)
b
entry
cat.
conditions
%
drc
2:3
eed
1
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
86(3a)
95(3b)
95(3c)
95(3d)
32(3e)
44(3f)
57(3g)
93(3h)
83(3i)
95(3j)
95(3k)
92(3l)
39(3m)
52(3n)
94(3o)
99(3p)
93(3q)
37(3r)
81(3s)
86(3t)
>99(20:1)
>99(12:1)
>99(11:1)
>99(10:1)
>99(20:1)
>99(20:1)
>99(15:1)
>99(12:1)
>99(20:1)
>99(11:1)
99(14:1)
1
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4b
4b
DBU (30 mol %), THF
DBU, THF
68
68
39
52
50
28
12
20
83
93
81
86
>99e
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
2
p-ClC6H4
p-BrC6H4
m-BrC6H4
o-BrC6H4
p-MeOC6H4
p-MeC6H4
3-Py
2
14:1
12:1
4:1
3
3
DBU, Toluene
DBU, DCM
KOtBu, THF
4
4
5
5
16:1
12:1
>20:1
>20:1
13:1
4:1
6
6
Cs2CO3, THF
NMM, THF
7
7
8
8
DMAP, THF
9
Ph
Cinnamyl
p-ClC6H4
p-BrC6H4
m-BrC6H4
p-MeOC6H4
p-MeC6H4
3-Py
9f
10f
11f
12g
DBU, THF
10
11
12
13
14
15
16
17
18
19
20
Ph
DBU, THF, 4A MS
DBU, THF, 4A MS
DBU, THF, 4A MS
Ph
>20:1
>20:1
Ph
>99(19:1)
>99(20:1)
>99(17:1)
>99(19:1)
>99(6:1)
Ph
Ph
a Reaction conditions: 1a (1.2 equiv), 2a (0.2 mmol, 1 equiv), 4a
(10 mol %; for entries 11ꢀ12, 12 mol % 4b), 10 mol % base (except entry
1), 1 mL of solvent, 2ꢀ3 h. b Isolated yield based on 2a. c Diastereos-
electivtiy of 3a, determined via 1H NMR analysis of unpurified reaction
mixtures. Absolute configuration of products was determined via X-ray
of 3p (see Table 2 and SI). d Enantiomeric excess of 3a, determined via
chiral-phase HPLC analysis. e >99% ee for both diastereomers. f 1.5
equiv 1a. g 1a (1.5 equiv) was added in two portions (see Supporting
Information (SI)).
Ph
p-BrC6H4
p-ClC6H4
p-MeC6H4
p-BrC6H4
p-MeC6H4
p-BrC6H4
p-ClC6H4
p-MeC6H4
p-MeC6H4
p-BrC6H4
>99(11:1)
>99(13:1)
>99(12:1)
>99(15:1)
a Conditions as in Table 1 (entry 12); reaction time: 3ꢀ24 h (see SI).
(Table 2). The diastereo- and enantioselectivities were
excellent in all the cases. The yields of the lactone products
3 could be influenced by the electronic properties of the
chalcones. Generally, chalcones with electron-withdraw-
ing substituents on Ar1 and/or Ar2 led tohigher yields (e.g.,
Table 2, entries 2ꢀ4, 10ꢀ12, 18ꢀ19); chalcones with
electron-donating substituents gave lower but still accep-
table yields with a slightly longer reaction time (e.g.,
Table 2, entries 5ꢀ7, 13ꢀ14). Replacing the aryl groups
of 2 with heteroaryl groups (Table 2, entries 8 and 15) and
swapping the phenyl to a cinnamyl group (Table 2, entry 9)
were all tolerated.
key intermediate. The enolate III then undergoes a reverse-
electron-demand DielsꢀAlder reaction with chalcone 2a
to give intermediate IV that eventually leads to product 3a
Table 3. Scope of Formylcyclopropanesa
The scope of the formylcyclopropanes was also explored
(Table 3). It appeared the reaction yields and stereoselectiv-
ities were not sensitive to the formylcyclopropanes examined
here. Formylcyclopropanes with an electron-withdrawing
group and electron-donating substituents on the R1 aryls all
reacted smoothly (Table 3, entries 1ꢀ7). Formylcyclopropane
with bulky R1 groups, such as napthyl and tBu groups, were
also tolerated (Table 3, entries 8ꢀ9, 11).17
entry
R1
Ar1, Ar2
Ph, Ph
yield %
ee (dr)
1
p-MeOC6H4
p-MeC6H4
p-FC6H4
66(3u)
59(3v)
>99(20:1)
>99(20:1)
99(20:1)
2
Ph, Ph
3
Ph, Ph
62(3w)
66(3x)
4
p-ClC6H4
Ph, Ph
>99(20:1)
>99(20:1)
>99(20:1)
99(20:1)
5
p-BrC6H4
Ph, Ph
71(3y)
The postulated reaction pathways are summarized in
Scheme 1. The formation of Breslow intermediate I is
followed by a ring opening and subsequent protonation
and enal-ketone tautomerization to give enolate III as a
6
3,4-Cl2C6H3
3-NO2C6H4
2-Naphthyl
tBu n-C5H11
p-MeOC6H4
2-Naphthyl
Ph, Ph
65(3z)
7
Ph, Ph
69(3aa)
74(3ab)
49(3ac)
87(3ad)
89(3ae)
8
Ph, Ph
>99(20:1)
>99(20:1)
>99(12:1)
>99(20:1)
9
Ph, Ph
10
11
Ph, p-ClC6H4
Ph, p-ClC6H4
(17) A few other formylcyclopropanes with various substitution
patterns that were examined in this study but did not work well are
briefed in the Supporting Information.
a Conditions as in Table 1 entry 12 (see SI).
5368
Org. Lett., Vol. 13, No. 19, 2011

and the NHC catalyst. A stepwise pathway via intermedi-
ate V cannot be ruled out.
under unoptimized conditions. In this way, starting
from 1a and 2a, product 5a was obtained as a formal
[3 þ 3] annulation product in a single operation with
good yield and essentially 100% optical purity (eq 3).
Scheme 1. Postulated Reaction Pathways
In summary, we have captured the likely challenging
NHC-bounded enolate intermediates from formylcyclo-
propanes for highly diastereo- and enantioselective
(formal) reverse-electron-demand hetero-DielsꢀAlder
reactions with chalcones. The resulting functionalized
δ-lactone products can be easily transformed to highly
substituted cyclohexanes with good regio- and stereose-
lectivities. The scope of NHC-catalyzed (formal) hetero-
DielsꢀAlder reactions, previously mainly limited to
highly activated heterodienes, is expanded by using chal-
cone substrates. Mechanistic studies and new reaction
developments of NHC-mediated activation of other con-
strained rings are being pursued in our laboratory.
The DielsꢀAlder products 3 bearing ketone groups are
amenable for further transformations under simple condi-
tions. For example, compound 3a could undergo a trans-
esterification followed by a regio- (>9:1 regioselectivity;
see SI) and stereoselective aldol reaction in the same
reaction mixture to givehighly functionalized cyclohexane
5a as a single stereoisomer with 73% isolated yield
(eq 3). Two new chiral centers were formed with nearly
complete stereocontrols. The NHC catalysis step
before any workup could be combined with the transes-
terification and aldol reaction steps in a single-pot
operation to give 5a with 65% overall isolated yield
Acknowledgment. We are thankful for the generous
financial support from Singapore National Research
Foundation (NRF); Singapore Economic Development
Board (EDB); GlaxoSmithKline (GSK); and Nanyang
Technological University (NTU). X-ray structural analy-
sis was assisted by Dr. Y. Li and Dr. R. Ganguly (NTU).
Supporting Information Available. Experimental de-
tails. This material is available free of charge via Internet
at http://pubs.acs.org.
Org. Lett., Vol. 13, No. 19, 2011
5369