N-Heterocyclic carbene-catalyzed enantioselective annulations: A dual activation strategy for a formal [4+2] addition for dihydrocoumarins

Article abstract of DOI:10.1039/c4cc09590a

A highly efficient asymmetric formal [4+2] annulation for the synthesis of dihydrocoumarins has been developed via an in situ activated NHC catalysis. Both electrophilic and nucleophilic species are generated in situ simultaneously whereby acyl imidazoles facilitated rapid formation of an NHC-enolate intermediate to afford the [4+2] dihydrocoumarin adducts.

Full text of DOI:10.1039/c4cc09590a

ChemComm
View Article Online
View Journal
COMMUNICATION
N-Heterocyclic carbene-catalyzed enantioselective
annulations: a dual activation strategy for a formal
[4+2] addition for dihydrocoumarins†
Cite this:DOI: 10.1039/c4cc09590a
Received 1st December 2014,
Accepted 15th January 2015
Anna Lee‡ and Karl A. Scheidt*
DOI: 10.1039/c4cc09590a
www.rsc.org/chemcomm
A highly efficient asymmetric formal [4+2] annulation for the synthesis of 2-hydroxynitrostyrene and 2-oxocyclohexanecarbaldehyde.6 More
dihydrocoumarins has been developed via an in situ activated NHC recently, the Jørgensen group reported an asymmetric synthesis
catalysis. Both electrophilic and nucleophilic species are generated of 3,4-dihydrocoumarins by merging aminocatalysis with an
in situ simultaneously whereby acyl imidazoles facilitated rapid formation NHC-catalyzed internal redox process.7 Lastly, the deracemiza-
of an NHC-enolate intermediate to afford the [4+2] dihydrocoumarin tion process of a-aryl hydrocoumarins using chiral phosphoric
adducts.
acids was reported by the List group.8 However, a convergent and
efficient asymmetric strategy for the synthesis of the dihydro-
Coumarins and their substituted derivatives are found in coumarin scaffold staring from simple starting compounds is
numerous natural products and pharmaceuticals.1 In particular, currently underdeveloped: reports for straightforward approaches
3,4-dihydrocoumarins are prevalent in nature and have shown such as enantioselective a-alkylations or a-allylations are surpris-
interesting biological activities such as aldose reductase and pro- ingly limited.9
tein kinase inhibition, as well as anti-herpetic, anti-inflammatory,
N-Heterocyclic carbenes represent a potent class of catalysts
anti-oxidative, anti-aging and anti-cancer properties.2 Given the for the formation of key C–C and C–X bonds via nontraditional
significance of these compounds as important structural scaffolds Umpolung reactivity.10 The development of novel approaches
in natural products and drug candidates, the synthesis of chiral using NHC catalysis by employing activation strategies has
dihydrocoumarin derivatives through catalytic and stereoselective drawn significant attention over the last few years. For example,
processes is a high value endeavor. Most currently deployed the Chi group has demonstrated the ability to access NHC
conventional approaches for the synthesis of dihydrocoumarins enolates through the acylation of carbenes with highly activated
require the use of transition metal catalysis.3 However, there are aryl esters.11 Recently, our group has employed a strategy which
opportunities to go beyond these processes and generate new, invokes the in situ formation of acyl azolium enolates12,13
potentially more sustainable and selective approaches with for the synthesis of dihydroquinolones.14,15 In this study,
complementary substrate scope and/or activation strategies. carboxylic acids as simple and accessible starting materials
Within the area of organocatalysis, the Zeitler group reported provided an intermediate acyl imidazole for subsequent addi-
an N-heterocyclic carbene (NHC)-catalyzed redox lactonization tion of an NHC.16 By using an acyl imidazole generated in situ,
for the synthesis of unsubstituted, achiral dihydrocoumarins the undesired enal dimerization pathway that is a common
using o-hydroxycinnamaldehydes.4 Our group has also reported concern in NHC catalysis can be avoided.17 Additionally, this
an NHC-catalyzed domino elimination/conjugate addition/ approach offers a complimentary and potentially more general
acylation process for the synthesis of substituted coumarins.5 strategy vs. NHC-enolate generation via disubstituted ketenes
Recently, the Hong group synthesized dihydrocoumarin deriva- reported by Ye.18 Encouraged by this work and our continuing
tives including quaternary carbon center via asymmetric domino interest in the synthesis of bioactive-relevant heterocyclic
Michael/acetalization reactions and oxidation reaction using compounds employing asymmetric NHCs catalysis, we have
explored an enantioselective formal [4+2] annulation reaction for
Department of Chemistry, Center for Molecular Innovation and Drug Discovery,
Chemistry of Life Processes Institute, Northwestern University, Silverman Hall,
Evanston, Illinois 60208, USA. E-mail: scheidt@northwestern.edu
† Electronic supplementary information (ESI) available. See DOI: 10.1039/
c4cc09590a
the synthesis of dihydrocoumarins. Herein, we report the first
general method for the highly efficient asymmetric synthesis of
substituted dihydrocoumarins from simple precursors (Scheme 1).
We have been exploring new strategies to enhance NHC reac-
tivity and selectivity through the integration of Lewis base catalysis
with other activation modes, including Lewis acids,11b,19,20
‡ Current address: Department of Chemistry, Myongji University, Myongji-Ro 116,
Cheoin-Gu, Yongin, Gyeonggi-Do, 449-728, Korea
This journal is ©The Royal Society of Chemistry 2015
Chem. Commun.

View Article Online
Communication
ChemComm
Table 1 Optimization of asymmetric reaction conditionsa
Entry
Base
Equiv.
Yieldb (%)
e.r.c
1
2
3
4
5
6
7
8
Cs2CO3
CsOAc
CsOAc
CsOAc
K2CO3
KOAc
KOAc
KOAc
NaOAc
NaOAc
NaOAc
KOAc
2.5
2.5
1.0
0.5
1.0
1.5
1.0
0.5
1.0
0.5
2.5
1.0
1.0
65
70
68
32
60
74
75
40
40
11
44
No rxn
No rxn
50 : 50
50 : 50
67 : 33
84 : 16
59 : 41
67 : 33
85 : 15
85 : 15
85 : 15
85 : 15
85 : 15
—
9
10
11
12d
13e
KOAc
—
a
Conditions: 1a (0.05 mmol, 1.0 equiv.), 2a (2.0 equiv.), triazolium A
(0.2 equiv.), 18-crown-6 (2.0 equiv.), CsF (2.0 equiv.) at 4 1C for 15 h.
b
Determined by NMR analysis with 1,3,5-trimethoxybenzene as an inter-
c
d
nal standard. Determined by HPLC analysis. Reaction conducted in
the absence of CsF and 18-crown-6. Reaction conducted in the absence
e
Scheme 1 Dual activation NHC strategy.
of 18-crown-6.
more labile silyl groups (TMS, TES) result in very poor yields,
presumably due to the balance of generating both electrophile
and nucleophile at productive concentrations. Further investiga-
tions are ongoing.
Brønsted acids21,22 and additional Lewis bases.23 In this endeavour,
we have developed additional activation modes such as Lewis base-
promoted in situ electrophile generation. A key aspect of this ‘‘dual
activation’’ approach is to productively integrate the in situ creation
of reactive electrophiles during the NHC process (e.g., see
o-quinone methide, or o-QM, formation, Scheme 1A). Using
this concept, we demonstrated a formal [4+3] annulation reac-
tion for the synthesis of enantioenriched 2-benzoxepinones
using enals and o-QMs via dual Lewis base activation strategy
(see Scheme 1B).23,24 The desired products were obtained in
high yields and excellent enantioselectivities (up to 99 : 1 e.r.),
however, it was found that the enal-derived NHC-homoenolate
species25 were unable to undergo a formal [4+2] process after
protonation to afford the dihydrocoumarins (Scheme 1B).
Undaunted by this lack of specific reactivity, we envisaged that
the [4+2] annulation pathway could be promoted by the use of acyl
imidazoles as NHC-enolate precursors. To test this hypothesis, we
designed a model reaction using acyl imidazole 1a and benzyl
bromide derivate 2a as nucleophilic and electrophilic precursors,
respectively (Table 1). Various NHC pre-catalysts were screened,
and the chiral 5,5-triazolium catalyst A was found to most
effectively catalyze the addition of acyl imidazole 1a to 2a (data
not shown, see ESI† for more detail).
Interestingly, the choice of chloride and bromide leaving
groups on substrate 2a is essentially insignificant in terms of
reactivity and enantioselectivity (see ESI† for more detail).
However, the measurement of enantiomeric excess over the
course of the reaction in the presence of strong bases such as
Cs2CO3 and CsOAc revealed slow racemization of the products
(Fig. 1). Consequently, the principal synthetic challenges
associated with these compounds are derived from both the
difficulty associated with effective control of o-QM formation
and sensitivity of the products to racemization.
To address this racemization, we speculated that altering
base strength and/or stoichiometry would likely improve
Acyl imidazole 1a underwent decomposition at 23 1C under the
reaction conditions, therefore the reaction was carried out at 4 1C.
Various silyl protecting and desilylating reagents were evaluated
on 2a, and optimal rate of o-QM generation was achieved with the
use of an equimolar combination of crown ether and cesium
fluoride in conjunction with the tert-butyldimethylsilyl (TBS)-
protected phenol substrate (see ESI† for more detail). The use of
Fig. 1 Racemization in the presence of 1.0 equiv. of CsOAc as the base
(Table 1, entry 3).
Chem. Commun.
This journal is ©The Royal Society of Chemistry 2015

View Article Online
ChemComm
Communication
enantioselectivity. While the product was fully racemized when (3d–3f, 3h–3i, 3k–3l) and hetero alkyl (3o) substituted acyl imida-
we employed 2.5 equivalents of Cs2CO3 and CsOAc as the base zoles. In most cases, similar reactivity and enantioselectivity were
(entries 1 and 2), decreasing the amounts of base improved the observed, although slightly improved enantioselectivity was
enantioselectivity at the expense of yield (entries 3 and 4). obtained with isovaleryl acyl imidazole 3e (92 : 8 e.r.).
However, by employing weaker bases, we were able to improve
Tolerance to substitution on the benzyl bromide derivative 2
both the yield and enantioselectivity (entries 6 and 7). Optimal was also investigated. Various substituents were tolerated at the
results were obtained in terms of reactivity and enantio- C-3, C-4, and C-5 positions affording the desired products
selectivity when we introduced 1.0 equivalent of potassium acetate 3g–3n in good to high yields and high enantioselectivities.
as the base; the desired product was obtained in 75% yield and However, the bromides including electron-withdrawing groups
85 : 15 e.r. (entry 7). Sodium acetate also provided the product with at C-5 positions were not suitable substrates, and no desired
high enantioselectivity (85 : 15 e.r.), however, the reaction yield products were obtained (see ESI† for more details). In addition,
was low and did not improve with additional equivalents of base no product was isolated when using C-6 substituted benzyl
(entries 9–11). To little surprise, the reaction did not proceed in bromides since many of these potential substrates were not stable
the absence of 18-crown-6 and/or CsF (entries 12 and 13), both under the reaction conditions. The products derived from
necessary for the formation of the o-QM.23,26
electron-rich substituted bromides were obtained with slightly
With the optimized reaction conditions in hand, the scope of higher enantioselectivity (3g vs. 3j or 3m, 3h vs. 3k), however, the
this formal [4+2] annulation was explored (Table 2). The reaction reaction yields of both electron rich and deficient substituted
was found to be tolerant of both electron-rich and electron- bromides were similar. In the case of chloro-substituted benzyl
deficient acyl imidazoles (1). The desired dihydrocoumarins were bromide 3m, diminished yields and enantioselectivities were
obtained in good yield (56–80%) and high enantioselectivity observed along with the generation of several unknown by-
(up to 93 : 7 e.r.) with benzyl (3a–3c, 3g, 3j, 3m–3n), aliphatic products. We assumed that the formation of o-QM does not take
place properly under the reaction condition and this might be a
main reason for the diminished yield. The absolute configuration
of compound 3d was determined to be (S)-configuration by
comparison with the reported optical rotation value.27
Table 2 Substrate scope
The proposed reaction pathways are shown in Scheme 2.
The initial addition of the NHC (A) to the acyl imidazole 1
generates NHC-enolate equivalent I after tautomerization. Two
different reaction pathways are hypothesized for the formation
of dihydrocoumarin 3 from enol I: (1) a concerted [4+2] process,
(2) a formal [4+2] process involving a stepwise Michael addition
and annulation. In the [4+2] pathway, concerted addition of
in situ generated o-QM 2 and NHC enolate I via II (via either
endo or exo transition states) could provide the desired
product 3. On the other hand, in the Michael addition/acylation
pathway, carbon–carbon bond formation through the less steri-
cally demanding transition state (III) would take place to afford
Reactions were performed at 0.2 mmol with 1 (1 equiv.), 2 (2 equiv.),
triazolium A (0.2 equiv.), KOAc (1 equiv.), CsF (2 equiv.), and 18-crown-6
(2 equiv.) in CPME (0.125 M). Yields are of isolated product after
column chromatography. Enantiomeric ratio was determined by HPLC
analysis.
Scheme 2 Proposed reaction pathways.14
This journal is ©The Royal Society of Chemistry 2015
Chem. Commun.

View Article Online
Communication
ChemComm
11 (a) L. Hao, Y. Du, H. Lv, X. Chen, H. Jiang, Y. Shao and Y. R. Chi, Org.
Lett., 2012, 14, 2154; (b) X. Chen, S. Yang, B.-A. Song and Y. R. Chi,
Angew. Chem., Int. Ed., 2013, 52, 11134; (c) J. Xu, Z. Jin and Y. R. Chi,
Org. Lett., 2013, 15, 5028.
12 For NHC-catalyzed generation of acyl azolium species using
a,b-unsaturated acid fluorides, see: (a) S. J. Ryan, L. Candish and
D. W. Lupton, J. Am. Chem. Soc., 2009, 131, 14176; (b) S. Ryan,
L. Candish and D. W. Lupton, Synlett, 2011, 2275; (c) S. J. Ryan,
L. Candish and D. W. Lupton, J. Am. Chem. Soc., 2011, 133, 4694;
(d) L. Candish, C. M. Forsyth and D. W. Lupton, Angew. Chem., Int.
Ed., 2013, 52, 9149; (e) L. Candish and D. W. Lupton, J. Am. Chem.
Soc., 2013, 135, 58.
13 Selected reviews for acyl azoliums in organocatalysis, see:
(a) H. U. Vora, P. Wheeler and T. Rovis, Adv. Synth. Catal., 2012,
354, 1617; (b) L. C. Morrill and A. D. Smith, Chem. Soc. Rev., 2014,
43, 6214.
14 A. Lee, A. Younai, C. K. Price, J. Izquierdo, R. K. Mishra and
K. A. Scheidt, J. Am. Chem. Soc., 2014, 136, 10589.
acyl azolium intermediate IV, which then undergoes N-acylation
to provide 3 and the NHC catalyst A ready the next catalytic cycle.
In conclusion, we have developed a highly efficient enantio-
selective formal [4+2] annulation reaction using simple starting
compounds for the synthesis of dihydrocoumarin derivatives
via NHC catalysis. This new method employs a dual activation
strategy using in situ electrophilic and nucleophilic species
generated simultaneously during the course of the reaction.
The desired dihydrocoumarins were obtained in high yields
and enantioselectivities. This platform facilitates rapid access
to chiral a-substituted dihydrocoumarins and further studies
on the synthesis of biologically active heterocycles via in situ
activated NHC catalysis are in progress.
We thank the National Institutes of Health (NIGMS,
GM073072) for support of this work.
15 For an example of the synthesis of indol derivatives using in situ
generated aza-ortho-quinone methides in NHC catalysis, see:
M. T. Hovey, C. T. Check, A. F. Sipher and K. A. Scheidt, Angew.
Chem., Int. Ed., 2014, 53, 9603.
16 J. Douglas, G. Churchill and A. D. Smith, Synthesis, 2012, 2295.
17 D. T. Cohen, B. Cardinal-David, J. M. Roberts, A. A. Sarjeant and
K. A. Scheidt, Org. Lett., 2011, 13, 1068.
Notes and references
1 (a) D. Yu, M. Suzuki, L. Xie, S. L. Morris-Natschke and K.-H. Lee,
Med. Res. Rev., 2003, 23, 322; (b) Y. Gu and K. Xue, Tetrahedron Lett., 18 (a) X.-Y. Chen and S. Ye, Synlett, 2013, 1614; (b) H.-M. Zhang,
2010, 51, 192. Z.-H. Gao and S. Ye, Org. Lett., 2014, 16, 3079.
2 (a) F.-L. Hsu, G.-I. Nonaka and I. Nishioka, Chem. Pharm. Bull., 1985, 19 (a) B. Cardinal-David, D. E. A. Raup and K. A. Scheidt, J. Am. Chem.
33, 3142; (b) M. Takechi, Y. Tanaka, M. Takehara, G.-I. Nonaka and
I. Nishioka, Phytochemistry, 1985, 24, 2245; (c) M. Iinuma, T. Tanaka,
M. Mizuno, T. Katsuzaki and H. Ogawa, Chem. Pharm. Bull., 1989,
37, 1813; (d) D. M. X. Donnelly and G. M. Boland, Nat. Prod. Rep.,
1995, 12, 321; (e) J. Posakony, M. Hirao, S. Stevens, J. A. Simon and
A. Bedalov, J. Med. Chem., 2004, 47, 2635; ( f ) A. Kumar, B. K. Singh,
R. Tyagi, S. K. Jain, S. K. Sharma and A. K. Prasad, Bioorg. Med.
Chem., 2005, 13, 4300; (g) F. Roelens, K. Huvaere, W. Dhooge,
Soc., 2010, 132, 5345; (b) E. M. Phillips, M. Riedrich and K. A.
Scheidt, J. Am. Chem. Soc., 2010, 132, 13179; (c) D. E. A. Raup,
B. Cardinal-David, D. Holte and K. A. Scheidt, Nat. Chem., 2010,
2, 766; (d) D. T. Cohen, B. Cardinal-David and K. A. Scheidt, Angew.
Chem., Int. Ed., 2011, 50, 1678; (e) J. Dugal-Tessier, E. A. O’Bryan,
T. B. H. Schroeder, D. T. Cohen and K. A. Scheidt, Angew. Chem., Int.
Ed., 2012, 51, 4963; ( f ) A. Lee and K. A. Scheidt, Angew. Chem., Int.
Ed., 2014, 53, 7594.
M. V. Cleemput, F. Comhaire and D. D. Keukeleire, Eur. J. Med. 20 Also see: J. Mo, X. Chen and Y. R. Chi, J. Am. Chem. Soc., 2012,
Chem., 2005, 40, 1042. 134, 8810.
3 (a) M. Murakata, T. Jono, Y. Mizuno and O. Hoshino, J. Am. Chem. 21 E. O. McCusker and K. A. Scheidt, Angew. Chem., Int. Ed., 2013,
Soc., 1997, 119, 11713; (b) C. Dong and H. Alper, J. Org. Chem., 2004, 52, 13616.
69, 5011; (c) G. Chen, N. Tokunaga and T. Hayashi, Org. Lett., 2005, 22 Also see: (a) X. Zhao, D. A. Dirocco and T. Rovis, J. Am. Chem. Soc.,
7, 2285; (d) T. Matsuda, M. Shigeno and M. Murakami, J. Am. Chem.
Soc., 2007, 129, 12086; (e) T. Nishikata, Y. Yamamoto and N. Miyaura,
Adv. Synth. Catal., 2007, 349, 1759; ( f ) B. D. Gallagher, B. R. Taft and
2011, 133, 12466; (b) G. Liu, P. D. Wilkerson, C. A. Toth and H. Xu,
Org. Lett., 2012, 14, 858; (c) Z. Fu, H. Sun, S. Chen, B. Tiwari, G. Li
and Y. R. Chi, Chem. Commun., 2013, 49, 261.
B. H. Lipshutz, Org. Lett., 2009, 11, 5374; (g) H. Kim and J. Yun, Adv. 23 J. Izquierdo, A. Orue and K. A. Scheidt, J. Am. Chem. Soc., 2013,
Synth. Catal., 2010, 352, 1881; (h) Y. Kuang, X. Liu, L. Chang,
M. Wang, L. Lin and X. Feng, Org. Lett., 2011, 13, 3814.
4 K. Zeitler and C. A. Rose, J. Org. Chem., 2009, 74, 1759.
5 E. M. Phillips, M. Wadamoto, H. S. Roth, A. W. Ott and K. A. Scheidt,
Org. Lett., 2009, 11, 105.
135, 10634.
24 For examples of organocatalyzed reactions using o-QM, see:
(a) E. Alden-Danforth, M. T. Scerba and T. Lectka, Org. Lett., 2008,
10, 4951; (b) H. Lv, L. You and S. Ye, Adv. Synth. Catal., 2009,
351, 2822; (c) H. Lv, W.-Q. Jia, L.-H. Sun and S. Ye, Angew. Chem., Int.
Ed., 2013, 52, 8607.
6 B.-C. Hong, P. Kotame and G.-H. Lee, Org. Lett., 2011, 13, 5758.
7 C. B. Jacobsen, Ł. Albrecht, J. Udmark and K. A. Jørgensen, Org. Lett., 25 (a) C. Burstein and F. Glorius, Angew. Chem., Int. Ed., 2004, 43, 6205;
2012, 14, 5526.
8 J.-W. Lee and B. List, J. Am. Chem. Soc., 2012, 134, 18245.
(b) S. S. Sohn, E. L. Rosen and J. W. Bode, J. Am. Chem. Soc., 2004,
126, 14370; (c) A. Chan and K. A. Scheidt, Org. Lett., 2005, 7, 905.
9 For an example and leading references, see: K. Liu, M. T. Hovey and 26 Also see: (a) T. H. Li and S. E. Rokita, J. Am. Chem. Soc., 1991,
K. A. Scheidt, Chem. Sci., 2014, 5, 4026.
10 (a) D. Enders, O. Niemeier and A. Henseler, Chem. Rev., 2007,
107, 5606; (b) E. M. Phillips, A. Chan and K. A. Scheidt, Aldrichimica
113, 7771; (b) P. Pande, J. Shearer, J. H. Yang, W. A. Greenberg and
S. E. Rokita, J. Am. Chem. Soc., 1999, 121, 6773; (c) A. E. Mattson and
K. A. Scheidt, J. Am. Chem. Soc., 2007, 129, 4508.
Acta, 2009, 42, 55; (c) X. Bugaut and F. Glorius, Chem. Soc. Rev., 2012, 27 M. Murakata, H. Tsutsui, N. Takeuchi and O. Hoshino, Tetrahedron,
41, 3511.
1999, 55, 10295.
Chem. Commun.
This journal is ©The Royal Society of Chemistry 2015