Controlled β-protonation and [4+2] cycloaddition of enals and chalcones via N-heterocyclic carbene/acid catalysis: Toward substrate independent reaction control

Article abstract of DOI:10.1039/c2cc36564b

A substrate-independent selective generation of enolates over homoenolate equivalents in NHC-catalyzed reactions of enals and chalcones is disclosed. Acid co-catalysts play vital roles in control of the reaction pathways, allowing for individual access to diverse products from identical substrates.

Full text of DOI:10.1039/c2cc36564b

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Controlled b-protonation and [4+2] cycloaddition of
enals and chalcones via N-heterocyclic carbene/acid
catalysis: toward substrate independent reaction
control†
Cite this: DOI: 10.1039/c2cc36564b
Received 10th September 2012,
Accepted 9th November 2012
a
b
Zhenqian Fu,z Hui Sun,z Shaojin Chen,a Bhoopendra Tiwari,a Guohui Li*b and
DOI: 10.1039/c2cc36564b
Yonggui Robin Chi*a
www.rsc.org/chemcomm
A substrate-independent selective generation of enolates over
homoenolate equivalents in NHC-catalyzed reactions of enals and
chalcones is disclosed. Acid co-catalysts play vital roles in control of
the reaction pathways, allowing for individual access to diverse
products from identical substrates.
When multiple reactive intermediates generated from the same
substrate are possible, the use of identical substrates may allow for
individual access to a diverse set of different products. However,
controlling these reaction pathways in a precise and selective
manner remains challenging, and thus the observed reaction
pathways (and products) are often substrate-dependent. In the
arena of N-Heterocyclic Carbene (NHC) catalysis,1 the activation
Fig. 1 Substrate combinations in intermolecular enal reactions via enolate
pathways: partially substrate-dependent reaction control.
of enals can lead to at least three different reactive intermediates: Nair and co-workers reported enolate products from enals in the
homoenolates,2 enolates,3,4 and acyl anion equivalents.5 Protona- reaction with b-unsubstituted vinyl ketones as the electrophiles.4d
tion (on the enal b-carbon) of homoenolate intermediates could We recently reported that by using alkylidene diketones as the
produce enolate intermediates for new intra-3 and intermolecular electrophiles, enals predominantly undergo enolate reaction path-
reactions,4 as envisioned and realized by the groups of Bode,4a ways in the presence of strong bases.4e
Glorius,4b Scheidt,3a,b Nair,4d You,3c ourselves,4e and others.6–9 As
A further analysis of these otherwise very impressive results
for intermolecular reactions, in 2006, Bode and co-workers reported (Fig. 1) indicated that access to the enolate pathways (competing
intermolecular Diels–Alder reactions of a,b-unsaturated imines with the homoenolate pathways) is somewhat substrate-dependent,
with enals bearing electron-withdrawing groups (EWGs) with respect to either the enals or the electrophiles. For instance,
(Fig. 1).4a In the same year, the Glorius group described the the reactions of simple enals (bearing no EWG) with chalcones
formation of b-lactones in 22–48% yields by reacting enals and predominantly went through homoenolate pathways to give cyclo-
activated ketones.4b In 2010, by using enones bearing additional pentenes, as disclosed by the groups of Nair,2b Bode2c and
EWGs as the electrophiles, Bode and co-workers developed efficient Scheidt,2g under NHC or NHC/Lewis acid cooperative catalysis.
enolate generation from enals in the presence of weak bases.4c Here we report selective access to enolate products using similar
enals and chalcones as the substrates (Scheme 1). This work was in
a Division of Chemistry & Biological Chemistry, School of Physical & Mathematical
part encouraged by our recent success in selective generation of
Sciences, Nanyang Technological University, 637371, Singapore.
enolate and acyl anion intermediates from the same enal for
E-mail: robinchi@ntu.edu.sg; Fax: +65 67911961; Tel: +65 65927769
b State key Laboratory of Molecular Reaction Dynamics, Dalian Institute of
Diels–Alder and Stetter reactions respectively.4e,5e We hope the
present study, built on the progress of others,4 will provide useful
Chemical Physics, Chinese Academy of Sciences, 457 Zhongshan Rd, Dalian,
116023, P. R. China. E-mail: ghli@dicp.ac.cn; Fax: +86 411-84675584;
Tel: +86 411-84379593
insights into substrate-independent control of reaction pathways.
On the application side, it is important to note that the enol
lactones obtained in this work cannot be easily accessed using
other methods. For example, the related enantioselective enamine
catalysis approach using aldehyde pre-nucleophiles worked well
only with enones bearing additional EWGs as the electrophiles.10
† Electronic supplementary information (ESI) available: Experimental
procedures and spectral data for all new compounds. CCDC 870337 (3c). For ESI
and crystallographic data in CIF or other electronic format see DOI: 10.1039/
c2cc36564b
‡ These authors contributed equally to this work.
c
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is critical to ensure effective generation of the free NHC catalysts.
The use of catalytic amounts (e.g., 20 mol%) of DBU in the
presence of various amounts of acid led to little formation of 3a
and/or 4a. Weaker organic bases4c such as DABCO resulted in
improved, but still unsatisfactory formation of 3a after optimiza-
tion (see ESI†). We subsequently found that inorganic bases such
as K3PO4, in combination with HOAc, performed much better
(entries 3 and 4). Triazolium-based NHC B led to more selective
formation of enolate product 3a (entry 5) than the imidazolium-
based catalyst A, as previously observed by Bode and co-workers.4c
Finally, a combination of KOAc, HOAc, and chiral NHC pre-catalyst
C could afford 3a in excellent yield, high dr and ee (Table 1, entry
8). It is worth noting that Rovis and co-workers2i have previously
used acetic acid salts as bases in NHC-catalyzed homoenolate
addition to imines to form lactams, in which enolate pathway
products were not formed and the conjugate acids were believed
to activate the imine electrophiles.11
Both b-(hetero)aryl and alkyl enals were effective substrates
to react with chalcone 2a to give the enolate products (3) with
good yields, excellent dr and ee (Table 2). Substitutions on the
enal b-aryls were tolerated (entries 1–6). One observation of
notable mechanistic interest is the effect of the substituents of
the b-aryls on the ratios of enolate/homoenolate products. For
example, enal 1d with an ortho-Br-substituent on the b-phenyl
group showed a better enolate/homoenolate product ratio than
enal 1c with a para-Br-substituted phenyl unit. The ortho-Br
substituent provides steric bulkiness that makes homoenolate
b-addition to the chalcones less favorable than the corres-
ponding b-carbon protonation. Similar trends were observed
for enals 1a and 1b. Enals with b-alkyl-substituents were
effective substrates as well (Table 2, entries 9 and 10). In all
these reactions, a combined use of acids and bases is necessary.
Next, chalcones (2) with various Ar and Ar0 substituents were
examined to react with enals smoothly (Table 3). In general,
chalcones with electron-donating substituents (Me or MeO) on
Ar or Ar0 (entries 1–3 and 6–7) gave higher enolate/homoenolate
product ratios than those with slight electron-withdrawing
Scheme 1 Control of the reaction pathways of enals and chalcones to give
enolate products.
Two apparent approaches may be used to achieve selective access
to the enolate pathway products by controlling the two competing
reactions of the homoenolate intermediate (Scheme 1). One is to
decrease the reactivity of the electrophile (e.g., enone) toward the
homoenolate b-carbon by decreasing its electrophilicity and/or
increasing the steric bulkiness. We attributed the predominant
enolate pathways in our earlier reactions4e to the increased steric
bulkiness of the alkylidene diketones. Another and more desired
approach is to promote the enal b-protonation by increasing the
effective proton concentration (Scheme 1).4c At the same time, an
increase in proton concentration should not lead to NHC deactiva-
tion or other undesired side reactions such as enolate protonation
and self-redox reaction.6
With this qualitative working hypothesis in mind, we first
evaluated the reaction between enal 1a (200 mol%) and chalcone
2a (100 mol%) using NHC pre-catalyst A (12 mol%) (Table 1). In
the presence of 50 mol% of HOAc and 200 mol% of DBU, a small
but encouraging amount of enolate pathway product 3a could be
obtained, in comparison to no detectable formation of 3a in the
absence of HOAc (entries 1 and 2). Further adjustment of acid
loading led to little improvement in the formation of 3a. It is
important to note that the use of stoichiometric amounts of base
Table 1 Model reaction optimization
Table 2 Scope of the enals 1a
Entry
Condition
Conva (%)
3a : 4ab
drb
1
2
3
4
A, DBU (no acid)
A, DBU, HOAc
85
81
>95
51
>95
>95
o1 : 99
1 : 13
1 : 8
1.3 : 1
9 : 1
5.6 : 1
4 : 1
10 : 1
n.d.
n.d.
n.d.
n.d.
1.7 : 1
20 : 1
19 : 1
20 : 1 (>98)f
Entry
R
Yieldb (%)
dr
ee (%)
3 : 4
A, K3PO4 (no acid)
A, K3PO4, HOAc
B, K3PO4, HOAc
C, K3PO4, HOAc
C, KOAc (no acid)
C, KOAc, HOAc
1
4-MeOC6H4 (1a)
2-MeOC6H4 (1b)
4-BrC6H4 (1c)
2-BrC6H4 (1d)
4-Me2NC6H4 (1e)
2-Naphthyl (1f)
2-Furyl (1g)
Ph (1h)
n-C5H11 (1i)
n-C3H7 (1j)
86 (3a)
89 (3b)
73 (3c)
83 (3d)
81 (3e)
84 (3f)
69 (3g)
88 (3h)
79 (3i)
77 (3j)
20 : 1
20 : 1
20 : 1
20 : 1
20 : 1
19 : 1
20 : 1
20 : 1
20 : 1
9 : 1
>98
>98
>98
>98
>98
>98
>98
>98
>98
>98
10 : 1
26 : 1
6 : 1
21 : 1
5 : 1
9 : 1
n.d.
10 : 1
9 : 1
10 : 1
5
2
3c
4c
5
6
7c
8c,d
>95
>95 (86)e
6c
7c
8c
9c
10c
a
Conversion based on 2a, determined via 1H NMR analysis of the crude
reaction mixture. Determined via 1H NMR analysis of the crude
reaction mixture. 20 mol% of cat. C, 250 mol% of KOAc, 4 Å MS, THF
(0.5 mL). 25 mol% of HOAc. The number in parentheses indicates
the isolated yield of 3a (single diastereomer). ee (%) of 3a, determined
via chiral phase HPLC analysis; the absolute configuration of the major
diastereomer was assigned based on X-ray structure of 3c (Table 2).
n.d. = not determined. MS = molecular sieve.
b
c
d
e
f
a
Reaction conditions similar to Table 1, entry 8: 0.75 mmol of 1 was
used except for entries 1, 2 and 5 where 0.5 mmol of 1 was used.
Isolated yield of 3. THF (0.25 mL) was used. n.d. = not determined.
b
c
c
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Table 3 Scope of the chalcones 2a
Angew. Chem., Int. Ed., 2012, 51, 314; (k) X. Bugaut and F. Glorius,
Chem. Soc. Rev., 2012, 41, 3511.
2 For selected examples, see: (a) C. Burstein and F. Glorius, Angew.
Chem., Int. Ed., 2004, 43, 6205; (b) V. Nair, S. Vellalath, M. Poonoth
and E. Suresh, J. Am. Chem. Soc., 2006, 128, 8736; (c) P. C. Chiang,
J. Kaeobamrung and J. W. Bode, J. Am. Chem. Soc., 2007, 129, 3520;
(d) Y. Li, Z. A. Zhao, H. He and S. L. You, Adv. Synth. Catal., 2008,
350, 1885; (e) J. Kaeobamrung and J. W. Bode, Org. Lett., 2009,
11, 633; ( f ) D. E. A. Raup, B. C. David, D. Holte and K. A. Scheidt,
Nat. Chem., 2010, 2, 766; (g) B. C. David, D. E. A. Raup and
K. A. Scheidt, J. Am. Chem. Soc., 2010, 132, 5345; (h) X. Q. Fang,
K. Jiang, C. Xing, L. Hao and Y. R. Chi, Angew. Chem., Int. Ed., 2011,
50, 1910; (i) X. D. Zhao, D. A. DiRocco and T. Rovis, J. Am. Chem. Soc.,
2011, 133, 12466; ( j) Y. M. Zhao, Y. Tam, Y. J. Wang, Z. Li and J. Sun,
Org. Lett., 2012, 14, 1398.
Entry Ar
Ar0
Yieldb (%) dr (ee (%))
3 : 4
1
4-MeOC6H4 Ph
79 (3k)
82 (3l)
50 (3m)
60 (3n)
66 (3n)
16 : 1 (>98) 12 : 1
20 : 1 (>98) 18 : 1
20 : 1 (>98) 17 : 1
9 : 1 (>98)
20 : 1 (>98)
2
4-MeC6H4
2-MeC6H4
4-ClC6H4
4-ClC6H4
Ph
Ph
Ph
Ph
Ph
3c
4
4 : 1
6 : 1
3 For intramolecular examples, see: (a) E. M. Phillips, M. Wadamoto,
A. Chan and K. A. Scheidt, Angew. Chem., Int. Ed., 2007, 46, 3107;
(b) M. Wadamoto, E. M. Phillips, T. E. Reynolds and K. A. Scheidt,
J. Am. Chem. Soc., 2007, 129, 10098; (c) Y. Li, X. Q. Wang, C. Zheng
and S. L. You, Chem. Commun., 2009, 5823.
5
6
4-MeOC6H4 70 (3o)
11 : 1 (>98) 10 : 1
20 : 1 (>98) 10 : 1
15 : 1 (>98)
19 : 1 (>98)
8 : 1 (>98) 11 : 1
16 : 1 (>98) 5 : 1
7
8
Ph
Ph
4-MeC6H4
4-ClC6H4
4-ClC6H4
2-Furyl
73 (3p)
65 (3q)
75 (3q)
60 (3r)
70 (3s)
6 : 1
8 : 1
9
10
11
Ph
Ph
4-BrC6H4
4 For intermolecular examples, see: (a) M. He, J. R. Struble and
J. W. Bode, J. Am. Chem. Soc., 2006, 128, 8418; (b) C. Burstein,
S. Tschan, X. L. Xie and F. Glorius, Synthesis, 2006, 2418;
(c) J. Kaeobamrung, M. C. Kozlowski and J. W. Bode, Proc. Natl. Acad.
Sci. U. S. A., 2010, 107, 20661; (d) V. Nair, R. R. Paul, K. C. S. Lakshmi,
R. S. Menon, A. Jose and C. R. Sinu, Tetrahedron Lett., 2011, 52, 5992;
(e) X. Q. Fang, X. K. Chen and Y. R. Chi, Org. Lett., 2011, 13, 4708.
5 For selected examples, see: (a) S. Singh, V. K. Rai, P. Singh and L. D.
S. Yadav, Synthesis, 2010, 2957; (b) L. D. S. Yadav, V. K. Rai, S. Singh
and P. Singh, Tetrahedron Lett., 2010, 51, 1657; (c) L. D. S. Yadav,
S. Singh and V. K. Rai, Synlett, 2010, 240; (d) D. A. DiRocco and
T. Rovis, J. Am. Chem. Soc., 2011, 133, 10402; (e) X. Q. Fang,
X. K. Chen, H. Lv and Y. R. Chi, Angew. Chem., Int. Ed., 2011,
50, 11782; ( f ) G. Liu, P. D. Wilkerson, C. A. Toth and H. Xu, Org.
Lett., 2012, 14, 858.
6 For protonation of enal b-carbons leading to self-redox formation of
esters/amides/acids, see: (a) S. S. Sohn and J. W. Bode, Org. Lett.,
2005, 7, 3873; (b) A. Chan and K. A. Scheidt, Org. Lett., 2005, 7, 905;
(c) K. Zeitler, Org. Lett., 2006, 8, 637; (d) J. W. Bode and S. S. Sohn,
J. Am. Chem. Soc., 2007, 129, 13798; (e) B. E. Maki, E. V. Patterson,
C. J. Cramer and K. A. Scheidt, Org. Lett., 2009, 11, 3942.
7 Enolates are believed to be involved as intermediates in the enal
homoenolate reactions after the enal b-carbon forms the first new
C–C or carbon heteroatom bond; see ref. 1, 2c and g for examples.
8 For selected examples of enolates from a-haloaldehydes and their
equivalents, see: (a) M. He, G. J. Uc and J. W. Bode, J. Am. Chem. Soc.,
2006, 128, 15088; (b) S. Kobayashi, T. Kinoshita, H. Uehara, T. Sudo
and I. Ryu, Org. Lett., 2009, 11, 3934. For enolates from ketenes, see:
(c) Y. R. Zhang, H. Lv, D. Zhou and S. Ye, Chem.–Eur. J., 2008,
14, 8473; (d) N. Duguet, C. D. Campbell, A. M. Z. Slawin and
A. D. Smith, Org. Biomol. Chem., 2008, 6, 1108; For enolates from
a-aryloxy acetaldehydes, see: (e) Y. Kawanaka, E. M. Phillips and
K. A. Scheidt, J. Am. Chem. Soc., 2009, 131, 18028.
9 For other relevant studies, see: (a) E. N. Jacobsen, A. Pfaltz and
H. Yamamoto, Comprehensive Asymmetric Catalysis, Springer, Berlin,
Germany, 1999, vol. 1–3; (b) B. List, Acc. Chem. Res., 2004, 37, 548;
(c) W. Notz, F. Tanaka and C. F. Barbas, III, Acc. Chem. Res., 2004,
37, 580; (d) D. Belmessieri, L. C. Morrill, C. Simal, A. M. Z. Slawin
and A. D. Smith, J. Am. Chem. Soc., 2011, 133, 2714.
4-MeC6H4
a
Reaction conditions similar to Table 1, entry 8, except for entries
5 and 9 where 150 mol% of HOAc and 200 mol% KOAc were used.
Isolated yield. 40 h.
b
c
groups (entries 4, 8 and 11) under previously optimized condi-
tions used in Table 2. After a brief additional optimization with
regard to acid and base loadings, good enolate/homoenolate
product ratios were obtained for these substrates by using
2.0 equiv. of KOAc and 1.5 equiv. of AcOH (entries 5 and 9).
The diastereomeric ratios of the enolate pathway products (3)
were also improved by using a higher acid loading.
In summary, we have achieved a control over reaction pathways
in NHC-mediated reactions of enals and chalcones. Acid co-catalysts
were used to realize selective homoenolate b-protonation and
controlled access to previously unobservable enolate products. The
competing enolate/homoenolate pathways were found to be sensi-
tive to the steric bulkiness of the enal and enone substrates, and
could be nicely controlled by the acid co-catalysts. The synthetically
useful lactone products from our reactions could not easily be
prepared using other approaches. We hope this study will initiate
further investigations into substrate-independent manipulation of
catalytic reaction pathways, and thus allow for individual access to
diverse products from identical substrates.12
We thank the financial support from Singapore National
Research Foundation (NRF) and Nanyang Technological
University (NTU) and Dr Y. Li and Dr R. Ganguly (NTU) for
X-ray structure analysis. Prof. G. Li and Dr H. Sun thank the
National High-tech Research and Development Program of
China and the National NSF of China for funding.
10 (a) K. Juhl and K. A. Jorgensen, Angew. Chem., Int. Ed., 2003,
42, 1498; (b) S. Samanta, J. Krause, T. Mandal and C. G. Zhao,
Org. Lett., 2007, 9, 2745; (c) J. Wang, F. Yu, X. J. Zhang and D. W. Ma,
Org. Lett., 2008, 10, 2561; (d) B. Han, Z. Q. He, J. L. Li, R. Li, K. Jiang,
T. Y. Liu and Y. C. Chen, Angew. Chem., Int. Ed., 2009, 48, 5474.
11 For the use of KOAc (NaOAc) and/or HOAc in NHC catalysis, see:
(a) S. P. Lathrop and T. Rovis, J. Am. Chem. Soc., 2009, 131, 13628;
(b) D. Enders, A. Grossmann, H. Huang and G. Raabe, Eur. J. Org.
Chem., 2011, 4298; (c) C. B. Jacobsen, K. L. Jensen, J. Udmark and
K. A. Jorgensen, Org. Lett., 2011, 13, 4790; (d) K. E. Ozboya and
T. Rovis, Chem. Sci., 2011, 2, 1835; (e) D. A. DiRocco, E. L. Noey,
K. N. Houk and T. Rovis, Angew. Chem., Int. Ed., 2012, 51, 2391;
( f ) Y. Zhao, M. S. Cheung, Z. Lin and J. Sun, Angew. Chem., Int. Ed.,
2012, 51, 10359. Also see ref. 2i, 5d and 5f.
Notes and references
1 For selected reviews, see: (a) D. Enders and T. Balensiefer, Acc.
Chem. Res., 2004, 37, 534; (b) V. Nair, S. Bindu and V. Sreekumar,
Angew. Chem., Int. Ed., 2004, 43, 5130; (c) D. Enders, O. Niemeier and
A. Henseler, Chem. Rev., 2007, 107, 5606; (d) N. Marion, S. Diez-
Gonzalez and I. P. Nolan, Angew. Chem., Int. Ed., 2007, 46, 2988;
(e) E. M. Phillips, A. Chan and K. A. Scheidt, Aldrichimica Acta, 2009,
43, 55; ( f ) J. L. Moore and T. Rovis, Top. Curr. Chem., 2010, 291, 77;
(g) L. Benhamou, E. Chardon, G. Lavigne, S. B. Laponnaz and
V. Cesar, Chem. Rev., 2011, 111, 2705; (h) A. T. Biju, N. Kuhl and
F. Glorius, Acc. Chem. Res., 2011, 44, 1182; (i) P. C. Chiang and
J. W. Bode, TCI Mail, 2011, 149, 2; ( j) A. Grossman and D. Enders,
12 For a related study on achieving different products from identical
substrates via NHC catalysis, see ref. 2e.
c
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