Enantioselective Diels-Alder reactions of enals and alkylidene diketones catalyzed by N-heterocyclic carbenes

Article abstract of DOI:10.1021/ol201917u

An electron-withdrawing group was introduced to the α-position of chalcones, and the resulting alkylidene diketones showed new reactivities with enals under the catalysis of N-heterocyclic carbenes (NHCs). Selective activation of enals affords enolate equ

Full text of DOI:10.1021/ol201917u

ORGANIC
LETTERS
2011
Vol. 13, No. 17
4708–4711
Enantioselective DielsÀAlder Reactions
of Enals and Alkylidene Diketones
Catalyzed by N-Heterocyclic Carbenes
Xinqiang Fang, Xingkuan Chen, 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 July 15, 2011
ABSTRACT
An electron-withdrawing group was introduced to the R-position of chalcones, and the resulting alkylidene diketones showed new
reactivities with enals under the catalysis of N-heterocyclic carbenes (NHCs). Selective activation of enals affords enolate equivalents that
undergo highly enantioselective intermolecular DielsÀAlder reactions with the alkylidene diketones. No products that might have resulted
from typical homoenolate pathways were observed.
The selective activation of readily available substrates
with small organic molecule catalysts has become an
increasingly promising approach in reaction discovery
and synthesis.1 In the arena of N-heterocyclic carbene
(NHC) catalysis, the activation of aldehydes, R-functiona-
lized aldehydes, ketenes, and enalshas led toa diverseset of
unique reactive intermediates and new reactions.2 In
particular, enals have been used to generate homoenolate
(3) For selected examples, see: (a) Sohn, S. S.; Rosen, E. L.; Bode,
J. W. J. Am. Chem. Soc. 2004, 126, 14370–14371. (b) Burstein, C.;
Glorius, F. Angew. Chem., Int. Ed. 2004, 43, 6205–6208. (c) Nair, V.;
Vellalath, S.; Poonoth, M.; Mohan, R.; Suresh, E. Org. Lett. 2006, 8,
507–509. (d) Chan, A.; Scheidt, K. A. J. Am. Chem. Soc. 2007, 129, 5334–
5335. (e) Li, Y.; Zhao, Z.-A.; He, H.; You, S.-L. Adv. Synth. Catal. 2008,
350, 1885–1890. (f) Seayad, J.; Patra, P. K.; Zhang, Y.; Ying, J. Y. Org.
Lett. 2008, 10, 953–956. (g) Yang, L.; Tan, B.; Wang, F.; Zhong, G. J.
Org. Chem. 2009, 74, 1744–1746. For selected examples of NHC
mediated enal/enone annulations affording cyclopentene products,
see:(h) Nair, V.; Vellalath, S.; Poonoth, S.; Suresh, E. J. Am. Chem.
Soc. 2006, 128, 8736–8737. (i) Chiang, P.-C.; Kaeobamrung, J.; Bode,
J. W. J. Am. Chem. Soc. 2007, 129, 3520–3521. (j) Cardinal-David, B.;
Raup, D. E. A.; Scheidt, K. A. J. Am. Chem. Soc. 2010, 132, 5345–5347.
Also see reviews (ref 2) for additional examples.
(4) The ester enolate equivalents are typically generated from
R-functionalized aldehydes and ketenes, as initially described by the
groups of Bode, Rovis, Ye, and Smith; see: (a) Reynolds, N. T.; Read de
Alaniz, J.; Rovis, T. J. Am. Chem. Soc. 2004, 126, 9518–9519. (b) He, M;
Uc, G. J.; Bode, J. W. J. Am. Chem. Soc. 2006, 128, 15088–15089. (c)
Zhang, Y. R.; Lv, H.; Zhou, D.; Ye, S. Chem.;Eur. J. 2008, 14, 8473–
8476. (d) Duguet, N.; Campbell, C. D.; Slawin, A. M. Z.; Smith, A. M.
Org. Biomol. Chem. 2008, 6, 1108–1113. (e) Wang, X. N.; Lv, H.; Huang,
X. L.; Ye, S. Org. Biomol. Chem. 2009, 7, 346–350. The potential
instability issue of using R-chloroaldehydes for enolate generations was
addressed by Bode and co-workers through the use of bisulfite salts as
precursors; see:(f) He, M.; Beahm, B. J.; Bode, J. W. Org. Lett. 2008, 10,
3817–3820.
(1) For recent reviews, see: (a) Notz, W.; Tanaka, F.; Barbas, C. F.,
III. Acc. Chem. Res. 2004, 37, 580–591. (b) Tian, S.-K.; Chen, Y.; Hang,
J.; Tang, L.; McDaid, P.; Deng, L. Acc. Chem. Res. 2004, 37, 621–631. (c)
€
Erkkila, A.; Majander, I.; Pihko, P. M. Chem. Rev. 2007, 107, 5416–
5470. (d) Doyle, A. G.; Jacobsen, E. N. Chem. Rev. 2007, 107, 5713–
5743. (e) Mukherjee, S.; Yang, J. W.; Hoffmann, S.; List, B. Chem. Rev.
€
2007, 107, 5471–5569. (f) Enders, D.; Grondal, C.; Huttl, M. R. M.
Angew. Chem., Int. Ed. 2007, 46, 1570–1581. (g) Colby Davie, E. A.;
Mennen, S. M.; Xu, Y.; Miller, S. J. Chem. Rev. 2007, 107, 5759–5812.
(h) Akiyama, T. Chem. Rev. 2007, 107, 5744–5758. (i) Dondoni, A.;
Massi, A. Angew. Chem., Int. Ed. 2008, 47, 4638–4660. (j) Melchiorre, P.;
Marigo, M.; Carlone, A.; Bartoli, G. Angew. Chem., Int. Ed. 2008, 47,
6138–6171. (k) MacMillan, D. W. C. Nature 2008, 455, 304–308. (l)
Bertelsen, S.; Jørgensen, K. A. Chem. Soc. Rev. 2009, 38, 2178–2189. (m)
Terada, M. Synthesis 2010, 1929–1982.
(2) Reviews: (a) Enders, D.; Niemeier, O.; Henseler, A. Chem. Rev.
ꢀ
2007, 107, 5606–5655. (b) Marion, N.; Dıez-Gonzalez, S.; Nolan, S. P.
Angew. Chem., Int. Ed. 2007, 46, 2988–3000. (c) Nair, V.; Vellalath, S.;
Babu, B. P. Chem. Soc. Rev. 2008, 37, 2691–2698. (d) Phillips, E. M.;
Chan, A.; Scheidt, K. A. Aldrichimica Acta 2009, 42, 55–66. (e) Biju,
A. T.; Kuhl, N.; Glorius, F. Acc. Chem. Res. 2011, DOI: 10.1021/
ar2000716. (f) Hirano, K.; Piel, I.; Glorius, F. Chem. Lett. 2011, 40, 786–
791. (g) Chiang, P.-C.; Bode, J. W. TCI MAIL 2011, 149, 2–17.
r
10.1021/ol201917u
Published on Web 08/02/2011
2011 American Chemical Society

equivalents for effective reactions, such as enal/enone
annulations affording cyclopentenes, as pioneered by
the groups of Bode, Glorius, Scheidt, Nair, You, and
others.3 The enal β-carbon is involved in the overall
formation of the first CÀC or carbonÀheteroatom bond
of the products (the “homoenolate” pathway).3 A selec-
tive protonation of the NHC-bounded homoenolate
β-carbon of enals leading to ester enolate equivalents4 as
alternative reactive intermediates has also been concep-
tualized and realized by the groups of Bode, Glorius, and
Scheidt.5À7 Pioneering studies on enal enolate formations
have led to self-redox reactions of enals,5 intermolecular
azadiene DielsÀAlder reactions using electron-deficient
enals (such as trans-4-oxo-2-butenoate),6a and nicely
designed intramolecular Michael and aldol reactions.6c,d
The use of simpler enals in the direct generation of enolate
intermediates for intermolecular reactions remained as
an unsolved problem until recently at which point the
Bode group reported elegant DielsÀAlder reactions
between simple enals and ketoenones.8 In Bode’s
work,8 they achieved the selective β-enal protonations
by using triazolium-based chiral NHC catalysts and
weak bases such as DMAP and NMM. The typical
homoenolate pathways were largely suppressed for
most substrates under the optimized conditions using
weak bases. When more electron-deficient enone sub-
strates or strong bases (e.g., DBU) were used, the
homoenolate pathway products could still be formed
to a large extent.
Our recent observation of the direct generation of NHC-
bounded enolates from simple enals for intermolecular
reactions came as a somewhat unexpected result during
our studies in employing enal homoenolate intermediates
for cascade reactions.9 We examined chalcones with an
electron-withdrawing group (EWG) at the R-position
(alkylidene diketones) as the electrophiles and found the
reactivity modes of the NHC-activated enals were alter-
nated (eq 1). No typical homoenolate pathway products,
as previously observed when chalcones were the elec-
trophiles,3h,j were formed in our reactions with the mod-
ified chalcone substrates. Instead, a DielsÀAlder product
was formed presumably via an NHC-bounded enolate
intermediate generated from an enal.5À8
Our reactions between cinnamaldehyde 1a and alkyli-
dene diketone 2a in the presence of NHC catalysts are
summarized in Table 1. We initially attempted to generate
products that were proposed to result from a homoenolate
equivalent intermediate through Michael-type addition of
an enal β-carbon to 2a to form the first CÀC bond (e.g.,
5aÀc). Somewhat to our surprise, no such products were
observed. Instead, a DielsÀAlder product 3a was obtained
in excellent yield using imidazolium A as the precatalyst
and DBU as the base (entry 1, Table 1). The product was
formed presumably through an inverse-electron-demand
DielsÀAlder pathway between an enal-derived NHC-
bounded enolate ester intermediate and the alkylidene
diketone.10 It is worth noting that previously imidazo-
lium-based NHC catalyst A has mainly been used for
homoenolate generation.3,11
Further catalyst screening and condition optimization
showed that the electronic properties and steric bulkiness of
carbene catalysts had profound effects on the reaction
outcomes.12 The use of the trizolium catalysts B and C led
to neither DielsÀAlder adducts nor any typical homoeno-
late pathway products; instead a Stetter product 4a was
obtained in low yield (Table 1, entries 2, 3).13 Fortunately we
found that the triazolium-based chiral NHC catalyst D can
mediate our DielsÀAlder reaction with 83% yield and
excellent diastereo- and enantioselectivities (Table 1, entry
4). Decreasing the catalyst loading did not affect the reac-
tion yields and selectivities obviously (Table 1, entry 5). The
Stetter product 4a was also detected but with low yield
(typically less than 5%). Solvent and base screenings in-
dicated that dichloromethane and toluene were not suitable
solvents and weaker bases such as DIPEA resulted in lower
yields (Table 1, entries 6À8). We also conducted our reac-
tions using conditions employed by Bode.8 It is interesting
to note that weak bases (e.g., DMAP, NMM) cannot
mediate our reactions efficiently (Table 1, entries 9À12),
(5) For protonation of the enal β-carbons leading to self-redox
formations of esters/amides/acids, see:(a) Sohn, S. S.; Bode, J. W. Org.
Lett. 2005, 7, 3873–3876. (b) Chan, A.; Scheidt, K. A. Org. Lett. 2005, 7,
905–908. (c) Zeitler, K. Org. Lett. 2006, 8, 637–640. (d) Bode, J. W.;
Sohn, S. S. J. Am. Chem. Soc. 2007, 129, 13798–13799. (e) Maki, B. E.;
Patterson, E. V.; Cramer, C. J.; Scheidt, K. A. Org. Lett. 2009, 11, 3942–
3945.
(6) For protonation of the enal β-carbons leading to enolate inter-
mediates for CÀN and CÀO bond formations of the enal R-carbons, see:
(a) He, M.; Struble, J. R.; Bode, J. W. J. Am. Chem. Soc. 2006, 128, 8418–
8420. (b) Burstein, C.; Tschan, S.; Xie, X. L.; Glorius, F. Synthesis 2006,
2418–2439. (c) Phillips, E. M.; Wadamoto, M.; Chan, A.; Scheidt, K. A.
Angew. Chem., Int. Ed. 2007, 46, 3107–3110. (d) Wadamoto, M.;
Phillips, E. M.; Reynolds, T. E.; Scheidt, K. A. J. Am. Chem. Soc.
2007, 129, 10098–10099.
(7) Enolates are believed to be involved as intermediates in the enal
homoenolate reactions after the enal β-carbon forms the first new CÀC
or carbonÀheteroatom bonds with the substrate electrophiles; see refs
3h, 3j, and 9.
(8) Kaeobamrung, J.; Kozlowski, M. C.; Bode, J. W. Proc. Natl.
Acad. Sci. U.S.A. 2010, 107, 20661–20665.
(9) Fang, X.; Jiang, K.; Xing, C.; Hao, L.; Chi, Y. R. Angew. Chem.,
(10) Stepwise pathways via Michael reactions followed by intramo-
lecular enol ester formations cannot be ruled out. Thus this reaction may
be considered as a “formal” DielsÀAlder reaction.
(11) For an example of imidazolium-based NHC-mediated enolate
generations in competing with homoenolate generations, see ref 6b.
(12) For selected similar observations, see: (a) Ryan, S. J.; Lisa
Candish, L.; Lupton, D. W. J. Am. Chem. Soc. 2009, 131, 14176–
14177. (b) Hirano, K.; Piel, I.; Glorius, F. Adv. Synth. Catal. 2008,
350, 984–988. (c) Wang, L.; Thai, K.; Gravel, M. Org. Lett. 2009, 11,
891–893. Also see ref 3a, 5c, and 6a.
(13) For a very recent related report of enantioselective Stetter
reactions of enals with nitroalkenes, see: DiRocco, D. A.; Rovis, T. J.
Am. Chem. Soc. 2011, 133, 10402–10405.
Int. Ed. 2011, 50, 1910–1913.
Org. Lett., Vol. 13, No. 17, 2011
4709

which is in contrast to Bode’s observations where weak
bases such as DMAP were optimal and strong bases (e.g.,
DBU) led to significant competing (or even dominated)
homoenolate pathway products. Bases stronger than DBU
(e.g., TBD)14 worked effectively as well in our DielsÀAlder
reactions (Table 1, entry 13). In all conditions studied,
regardless of the bases and solvents used, no homoenolate
pathway products (e.g., 5aÀc) were detected. This absence
of typical homoenolate pathway products is significantly
different from literature reports that use chalcones as sub-
strates in NHC catalysis.3h,j
A variety of β-aryl enals were examined to react with
alkylidene diketone 2a under our standard DielsÀAlder
reaction condition (Table 2, products 3aÀ3i). In all cases the
reactions proceeded with exceptionally high diastereo- and
enantioselectivies, and the products were isolated in good
yields with essentially 100% optical purities. We then
examined the β-substituents (R2) on alkylidene diketones 2.
The electronic properties of R2 aryl substituents showed
little observable effects on the reaction outcomes with
respect to both yields and stereoselectivities (Table 2, pro-
ducts 3jÀ3o). Finally, we found that substrates 2 with
different R3 substituents could also react with enals to afford
the corresponding DielsÀAlder products with consistently
high diastereo- and enantioselectivities (Table 2, products
3pÀ3t). A notable observation was that substrate 2 with an
electron-donating methyl group on the R3 substituent
reacted much slower and a longer reaction time (42 h) was
necessary to achieve an acceptable yield (Table 2, product
3u). More electron-deficient 2 usually behaves as a more
effective substrate for the DielsÀAlder reactions. This
electronic effect appears to be different from Bode’s
reactions9 where more electron-deficient electrophiles
tended to give more homoenolate pathway adducts. It
should be noted that we also checked substrates 2 with
EWGs other than ÀCOAr, such as ÀCO2Et, ÀCN, and a
phenyl group. These substrates failed to give DielsÀAlder
or homoenolate pathway products. Substrate 2 with R2 as
alkyl groups showed low reactivities toward enals as well.
We next checked the tolerance of enals with β-alkyl
substituents such as trans-2-pentenal under the standard
conditions used above for the DielsÀAlder reactions. To
our surprise, with trizolium D as the catalyst, only a Stetter
type reaction13 occurred without the detection of any
DielsÀAlder adducts or any products from the typical
homoenolate pathways. We then went back to identify
catalysts and conditions that could mediate DielsÀAlder
reactions using β-alkyl enal substrates as the enolate pre-
cursors. At last achiral imidazolium catalyst A (Table 3,
entry 1) was found to mediate the reaction between β-alkyl
enals with alkylidene diketones to exclusively give DielsÀ
Alder products without the detection of Stetter products or
possible homoenolate pathway products. The scope of the
β-alkyl enal DielsÀAlder reactions was then briefly explored,
as summarized in Table 3. Additional attempts to get an
enantioselective version of the reactions were unsuccessful.
Our postulated reaction pathways are summarized in
Scheme 1.15 The reactions start with the formation of
Breslow intermediate I between enal 1 and an in situ
generated NHC. Protonation of the enal β-carbon of I
results in an NHC-bounded enolate ester intermediate II
that readily undergoes a DielsÀAlder reaction with alky-
lidene diketone to eventually give the products.
Table 1. NHC-Catalyzed Reaction of Enal 1a and Alkylidene
Diketones 2aa
yield %b
entry NHC
base
solvent
3a
4a
drc
ee %d
1
A
B
C
D
D
D
D
D
D
D
D
D
D
DBU
DBU
DBU
DBU
DBU
DBU
DBU
THF
92
0
0
21
33
6
5:1
-
2
THF
-
-
-
-
3
THF
0
4
THF
83
82
0
12:1 >99%
5e
6
THF
<5
<5
9
12:1 > 99%
CH2Cl2
toluene
-
-
7
44
56
0
10:1 >99%
10:1 >99%
8
DIPEA THF
0
9
DMAP
DMAP
NMM
NMM
TBD
THF
0
-
-
10f
11f
12
13e
CH2Cl2
CH2Cl2
THF
0
0
-
-
0
0
-
-
<5
86
0
-
-
THF
<5
11:1
>99%
a 1a (0.2 mmol), 2a (0.1 mmol), NHC (30 mol %), base (30 mol %),
12 h. b Isolated yield. c Diastereoselectivtiy of 3a, determined via
1H NMR analysis of unpurified reaction mixtures; relative stereo-
chemistry was determined via X-ray. d Enantiomeric excess of 3a,
determined via chiral-phase HPLC analysis; absolute configura-
tion was determined via analogy (see SI). e Catalyst (20 mol %),
base (20 mol %). f Reaction temperature was 40 °C. Mes = 2,4,6-
trimethylphenyl, DBU = 1,8-diazabicyclo[5.4.0]undec-7-ene, THF =
tetrahydrofuran, DIPEA = N,N-diisopropylethylamine, DMAP =
4-(dimethylamino)pyridine, NMM = N-methylmorpholine, TBD =
1,5,7-triazabicyclo[4.4.0]dec-5-ene.
In conclusion, we have found by introducing an EWG to
the R-positions of chalcone substrates the typical reactivity
modes of NHC-activated enals can be alternated. The
(14) (a) Raup, D. E. A.; Cardinal-David, B.; Holte, D.; Scheidt, K. A.
Nat. Chem. 2010, 2, 766–771. (b) Cohen, D. T.; Cardinal-David, B.;
Roberts, J. M.; Sarjeant, A. A.; Scheidt, K. A. Org. Lett. 2011, 13, 1068–
1071.
(15) For a recapitulative discussion of further transformations of
Breslow intermediates, see: Struble, J. R.; Kaeobamrung, J.; Bode, J. W.
Org. Lett. 2008, 10, 957–960.
4710
Org. Lett., Vol. 13, No. 17, 2011

Table 2. Substrate Scope of NHC Catalyzed Formal
DielsÀAlder Reaction with β-Aryl Enals
Table 3. DielsÀAlder Reaction with β-Alkyl Enal Substrates
6
R1
Me
R2, R3
Ph, Ph
yield %a
drb
yield,
6a
6b
6c
6d
6e
65
57
79
64
53
5:1
5:1
3:1
3:1
5:1
a
3
R1
R2, R3
%
ee %b (dr)c
Et
Ph, Ph
3a
3b
3c
3d
3e
3f
Ph
Ph, Ph
Ph, Ph
Ph, Ph
Ph, Ph
Ph, Ph
Ph, Ph
Ph, Ph
Ph, Ph
Ph, Ph
82
99 (12:1)
99 (16:1)
99 (>20:1)
99 (>20:1)
99 (>20:1)
99 (>20:1)
99 (>20:1)
99 (>20:1)
99 (>20:1)
99 (17:1)
99 (>20:1)
98 (>20:1)
99 (20:1)
99 (>20:1)
99 (20:1)
99 (12:1)
99 (20:1)
99 (17:1)
97 (>20:1)
99 (>20:1)
99 (>20:1)
N.D.
n-C5H11
Et
Ph, Ph
4-Br-Ph
4-F-Ph
3-F-Ph
4-Me-Ph
4-iPr-Ph
2-thienyl
1-naphthyl
2-naphthyl
Ph
85
84
83
75
61
71
76
80
80
63
76
56
88
79
74
65
72
80
84
50
<10
4-Br-Ph, Ph
3-MeO-Ph, Ph
Et
a Isolated yields of both diastereomers based on 2. b Determined via
1H NMR analysis of unpurified reaction mixtures; relative stereochem-
istry was determined via 1H NMR analysis.
3g
3h
3i
3j
4-Br-Ph, Ph
4-Br-Ph, Ph
4-iPr-Ph, Ph
4-iPr-Ph, Ph
3-OMe-Ph, Ph
3-OMe-Ph, Ph
Ph, 4-Br-Ph
Ph, 4-Br-Ph
3-OMe-Ph, 4-Br-Ph
Ph, 4-F-Ph
3k
3l
4-F-Ph
Ph
Scheme 1. Postulated Reaction Pathways
3md
3n
3o
3pd
3q
3r
4-Me-Ph
Ph
3-F-Ph
Ph
4-F-Ph
Ph
3sd
3t
3ue
3v
Ph
Ph
Ph, 4-Cl-Ph
Ph, 4-Me-Ph
Ph, Me
Ph
Ph
a Isolated yield based on 2. b Enantiomeric excess of 3, determined via
chiral phase HPLC, ee >99% is reported as 99%. c Diastereoselectivtiy of
3, determinedvia1H NMR analysis ofunpurified reaction mixtures. d TBD
(20 mol %) was used as the base to get better yields. e Reaction for 42 h.
selective generation of ester enolates from simple enals was
realized to facilitate effective DielsÀAlder reactions with
alkylidene diketones to give fully substituted cyclic enol
esters. The ketone moieties from the EWGs offer addi-
tional possibilities for further transformations of the reac-
tion products. With β-aryl enal substrates, the DielsÀ
Alder products were obtained in essentially 100% optical
purities with good yields. With β-alkyl substrates, the use
of a bulky imidazolium-based NHC catalyst was necessary
to obtain the DielsÀAlder products. More electron-
deficient alkylidene diketones were found to favor this
process. In all cases, no products that might have resulted
from the typical homoenolate pathways were observed
in our reactions. Further investigation of the new reacti-
vities of modified chalcones in the presence of NHC
catalysts is in progress.
Acknowledgment. We thank the Singapore National
ResearchFoundation (NRF), SingaporeEconomicDevel-
opment Board (EDB), GlaxoSmithKline (GSK), and
Nanyang Technological University (NTU) for generous
financial support as well as Dr. Y. Li and Dr. R. Ganguly
(X-ray structure; NTU) and Ms. M.-J. Han (optical rota-
tion measurements; a short-time visitor at NTU). We also
appreciate the comments and suggestions from referees of
this manuscript.
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. 17, 2011
4711