Enantioselective synthesis of substituted pyrans via amine-catalyzed Michael addition and subsequent enolization/cyclisation

Article abstract of DOI:10.1039/c2cc31445b

An organocatalytic construction of optically enriched substituted pyran derivatives via amine-catalyzed Michael addition and subsequent enolization/cyclisation has been described starting from electronically poor alkenes. Functionalized pyrans were obtain

Full text of DOI:10.1039/c2cc31445b

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COMMUNICATION
Enantioselective synthesis of substituted pyrans via amine-catalyzed
Michael addition and subsequent enolization/cyclisationwz
Utpal Das, Chan-Hui Huang and Wenwei Lin*
Received 27th February 2012, Accepted 9th April 2012
DOI: 10.1039/c2cc31445b
An organocatalytic construction of optically enriched substituted
pyran derivatives via amine-catalyzed Michael addition and
subsequent enolization/cyclisation has been described starting
from electronically poor alkenes. Functionalized pyrans were
obtained in high enantioselectivities (up to 96%) and good yields
(up to 90%) having three contiguous chiral centers.
Scheme 1 A general strategy for the organocatalytic enantioselective
synthesis of substituted pyrans.
Substituted pyran rings are an important class of core structures
found in a number of naturally occurring and biologically
active molecules.1 Accordingly, several methods have been
developed for the synthesis of substituted pyrans.2 In recent
years organocatalysis has emerged as a promising synthetic tool in
organic synthesis to challenge various synthetic problems.3 Hence,
the development of organocatalytic asymmetric approaches
allowing the construction of these structural frameworks in
optically active forms remains an attractive goal in organic
synthesis.4 Literature survey reveals that trans-trisubstituted
electron-poor alkenes such as trans-2-aroyl-3-arylacrylonitriles5
(1) are restricted substances in organocatalysis, given the fact that
very limited literature reports are available on these substances
although their functionalities offer possibility of additional
transformations.
Fig. 1 Catalysts screened for this study.
were screened under the same conditions to find out the most
suitable one. From the preliminary screening it was found that
the catalyst IV was superior to others in terms of enantio-
selectivity and yield. Only a trace amount of the desired
product could be detected when secondary amine catalyst VI
was used in neat conditions (entry 6). To further optimize the
reaction conditions, a series of solvents and additives were
examined, and the key results are presented in Table 1.
Although the reactions proceed readily in various solvents
(for details see ESIz) and also under solvent-free conditions,
dichloromethane seems to be the better one. The use of various
acidic co-catalysts (entries 9–11, for details see ESIz) revealed
that the enantioselectivity (96% ee) can be finely tuned using
2-fluorobenzoic acid (entry 10) accompanied by fair diastereo-
selectivity (5.4 : 1) and good yield. Importantly, the major
diastereomer can be easily isolated by simple flash column
chromatography. Using our protocol, it is also possible to
obtain ent-3 albeit with lower ee (87%, entry 3).
Herein, we wish to report a practical solution by using an
organocatalyst to address the problem of using electron poor
alkenes to construct pyran derivatives having three contiguous
chiral centers. Our strategy was an amine-catalyzed Michael
reaction of cyclohexanone (or anals) with trans-2-aroyl-3-aryl-
acrylonitriles 1 and subsequent enolization and hemi-ketalization/
acetalization to give pyran derivatives (Scheme 1).6
We began our investigation using trans-2-benzoyl-3-(4-benzo-
nitrile)acrylonitrile (1a) and cyclohexanone (2) as the model
substrates in the presence of Cinchona-based primary amine7
catalysts (Fig. 1). Gratifyingly, substituted pyran 3a was obtained
with 80% ee in 79% yield (Table 1, entry 1) using I as catalyst.
Encouraged by this result, a series of catalysts II–V (entries 2–5)
Department of Chemistry, National Taiwan Normal University,
88, Sec. 4, Tingchow Road, Taipei 11677, Taiwan, R.O.C.
E-mail: wenweilin@ntnu.edu.tw; Fax: +886229324249
With an effective protocol for the enantioselective synthesis of
pyran derivatives in hand, the substrate scope and generality of
the method were examined (Table 2). A variety of substituents
on both the aryl rings of 1 were well tolerated in our catalytic
system, providing the desired substituted pyran adducts in
w This article is part of the joint ChemComm–Organic & Biomolecular
Chemistry ‘Organocatalysis’ web themed issue.
z Electronic supplementary information (ESI) available: Experimental
procedure, spectral data of new compounds. CCDC 865351 (3b) and
865350 (5d). For ESI and crystallographic data in CIF or other
electronic format see DOI: 10.1039/c2cc31445b
c
5590 Chem. Commun., 2012, 48, 5590–5592
This journal is The Royal Society of Chemistry 2012

Table 1 Optimization of enantioselective synthesis of substituted pyransa
optimized protocol, achieving high stereocontrol (93, 95% ee)
in the products 3i, j in much shorter time (entries 9 and 10). We
have also observed slight decrease in ee but with significantly
diminished yield when an ortho-Br substituent was used in Ar2
compared to a para-Br substituent (entry 2 vs. 12). Poor
enantioselectivity was also obtained in the case of para sub-
stituents in the benzoyl moiety (Ar1) of 1 (entries 13 and 14).
Instead of Ar2, a less reactive group like cyclohexyl showed no
product formation under the optimized reaction conditions.9
Meanwhile, in preparative synthesis, the reaction (3b) can also
be performed with a fourfold excess without any significant
loss of selectivity (98% ee) or yield (80%). The absolute
configuration of 3b10 was determined by single crystal X-ray
data analysis and those of others were assigned by analogy.
After successfully demonstrating the utility of our protocol
to synthesize substituted pyrans using cyclohexanone, we
turned our attention towards anals for our study. We have chosen
1a and butyraldehyde (4a) as reaction partners for optimization
of reaction conditions (some representative results are sum-
marized in Table 3; for details, see ESIz). In our preliminary
study, the use of catalyst IV was not encouraging as it led to
very poor chemical yield of our desired product 5a (Table 3,
entry 1). Then we switched to a pyrrolidine based catalyst11
and carried out the same reaction with the most promising
diphenylprolinol trimethylsilyl ether as catalyst (VI) leading to
the successful formation of product 5a in good yield (73%)
and ee (90, 80%) (entry 2). The catalytic ability was further
examined by using a,a-bis[3,5-bis(trifluoromethyl)phenyl]-
2-pyrrolidinemethanol trimethylsilyl ether (VII), but surpris-
ingly no product formation was observed (entry 3). The use of
catalyst VIII was also not much interesting (entry 4). Further
optimizations of the reaction conditions by changing molar
ratio of reactants, solvents and employing neat conditions
(entries 5–8, for details see ESIz) were not beneficial. The
screening of acidic co-catalysts revealed that both the amount
and nature of the acid influenced the results (see ESIz).
Entry Catalyst Solvent
t/h
36
18
20
24
40
24
drb
Yieldc (%) eed (%)
1
2
3
4
5
6
I
II
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
Neat
4.6 : 1 79
2.8 : 1 72
3.0 : 1 67
3.5 : 1 95
4.2 : 1 99
80
ꢀ77
ꢀ87
92
III
IV
V
VI
IV
IV
IV
IV
IV
ꢀ83
nde
93
—
Trace
7
8
CHCl3
Toluene
CH2Cl2
CH2Cl2
CH2Cl2
48f 2.7 : 1 70
48
36
60
120
4.6 : 1 95
5.6 : 1 94
5.4 : 1 97
6.6 : 1 67
90
90
96
94
9g
10h
11i
a
1a (0.15 mmol), 2 (0.3 mmol) and cat. (20 mol%) were used in 0.15 mL
solvent. b The diastereomeric ratio was measured by 1H-NMR analysis of
the crude reaction mixture. c Determined by 1H NMR analysis of the crude
d
reaction mixture using CH2Br2 as an internal standard. Enantiomeric
excess determined by HPLC analysis. e Not determined. f 90% conversion.
g
C6H5CO2H (20 mol%) used as an additive. h 2-FC6H4CO2H (20 mol%)
used as an additive (85% ee for the minor diastereomer).8 i 2-NO2C6H4-
CO2H (20 mol%) used as an additive.
Table 2 Enantioselective synthesis of substituted pyrans using 1 and 2a
Yield of
Entry Ar1
Ar2
t/days drb
3c (%) eed (%)
1
2
3
4
5
6
7
8
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
4-CNC6H4 2.5
5.4 : 1 90 (3a) 96
4-BrC6H4 2.5
4-NO2C6H4 2.0
4-ClC6H4 2.5
3-NO2C6H4 4.0
4.8 : 1 84 (3b) 94
5.6 : 1 77 (3c) 96
3.7 : 1 85 (3d) 94
5.4 : 1 79 (3e) 92
4.9 : 1 78 (3f) 95
5.0 : 1 81 (3g) 93
4.5 : 1 78 (3h) 94
Table 3 Evaluation of the reaction conditiona
Ph
4-MeC6H4
3.5
4.0
4-OMeC6H4 4.0
9
Ph
Ph
Ph
Ph
2-Furyl
2-Thienyl
2-Naphthyl 4.0
1.0
2.0
5.2 : 1 88 (3i)
3.2 : 1 85 (3j)
4.3 : 1 82 (3k) 60
3.6 : 1 32 (3l) 86
4.6 : 1 81 (3m) 65
9.0 : 1 86 (3n) 75
93
95
10
11
12
13
14
2-BrC6H4
4-BrC6H4
4-OMeC6H4 4-BrC6H4
4.0
2.0
4.0
4-BrC6H4
Entry Cat.
Solvent
t/days drb
Yieldc (%) eed (%)
nde
a
1
2
IV
VI
CH2Cl2
CH2Cl2
CH2Cl2
3.0
3.5
3.0
4.0
3.0
1 : 1.2 21
1 : 0.9 73
—
1 : 1.7 45
1 : 1.1 69
1 : 1.2 66
1 : 1.1 63
1 : 1.0 40
1 : 1.3 75
1 : 1.8 20
1 (0.25 mmol), 2 (0.5 mmol), IV (20 mol%) and 2-FC6H4CO2H
b
(20 mol%) were used in 0.25 mL CH2Cl2. Determined by 1H NMR
90, 80
—
3
VII
—
analysis of the crude reaction mixture.8 c Isolated yields of the mixture
4
VIII CH2Cl2
36, 86
88, 75
88, 72
88, 76
84, 72
90, 87
80, 60
d
of isomers. Determined by HPLC analysis.
5f
6
VI
VI
VI
VI
VI
VI
CH2Cl2
Toluene 2.5
CHCl3
Neat
CH2Cl2
CH2Cl2
7
8
2.5
3.5
2.5
7.0
moderate to high yields (up to 90%), high diastereoselectivity
(up to 9.0 : 1) and excellent enantioselectivities (up to 96%).
The electronic feature of the aryl substituents Ar2 seems to
have little effect on the stereoselectivity or the chemical yield.
As a result, the compounds 3a–e with electron-withdrawing
substituents (entries 1–5) and the compounds 3g, h (entries 7
and 8) having electron-donating substituents were obtained
in excellent enantioselectivity ranging from 92 to 96% ee.
Heteroaromatic residues as Ar2 were also applied well in our
9g
10h
a
1a (0.1 mmol), 4a (0.2 mmol), catalyst (20 mol%) and 2-FC6H4CO2H
b
(20 mol%) were used in 0.1 mL solvent. Determined by 1H NMR
analysis of the crude reaction mixture.8 c Isolated yields of the mixture
d
of isomers. Determined by HPLC analysis. Not determined.
e
f
g
5 equiv. of 4a was used. 40 mol% 2-FC6H4CO2H was used.
h
10 mol% VI and 20 mol% 2-FC6H4CO2H were used.
Chem. Commun., 2012, 48, 5590–5592 5591
c
This journal is The Royal Society of Chemistry 2012

Table 4 Enantioselective synthesis of substituted pyrans using 1 and 4a
2 For reviews, see: (a) I. Larrosa, P. Romea and F. Urpi, Tetrahedron,
2008, 64, 2683; (b) P. A. Clarke and S. Santos, Eur. J. Org. Chem.,
2006, 2045.
3 For reviews, see: (a) F. Giacalone, M. Gruttadauria, P. Agrigento
and R. Noto, Chem. Soc. Rev, DOI: 10.1039/c1cs15206h;
(b) A. Moyano and R. Rios, Chem. Rev., 2011, 111, 4703;
(c) M. Nielsen, D. Worgull, T. Zweifel, B. Gschwend,
S. Bertelsen and K. A. Jørgensen, Chem. Commun., 2011,
47, 632; (d) D. R. Lopez, D. Sadaba, I. Delso, R. P. Herrera,
T. Tejero and P. Merino, Tetrahedron: Asymmetry, 2010, 21, 2561;
(e) S. Bertelsen and K. A. Jørgensen, Chem. Soc. Rev., 2009,
38, 2178; (f) P. Melchiorre, M. Marigo, A. Carlone and
G. Bartoli, Angew. Chem., Int. Ed., 2008, 47, 6138; (g) B. List,
Chem. Rev., 2007, 107, 5413; (h) P. I. Dalko and L. Moisan,
Angew. Chem., Int. Ed., 2004, 43, 5138.
4 For selected examples on organocatalytic stereoselective formation
of pyran rings, see: (a) X. Wang, T. Fang and X. Tong, Angew.
Chem., Int. Ed., 2011, 50, 5361; (b) H. Uehara, R. Imashiro,
G. H. Torres and C. F. Barbas III, Proc. Natl. Acad. Sci. U. S. A.,
2010, 107, 20672; (c) S. Dong, X. Liu, X. Chen, F. Mei, Y. Zhang,
B. Gao, L. Lin and X. Feng, J. Am. Chem. Soc., 2010, 132, 10650;
(d) J. Kaeobamrung, J. Mahatthananchai, P. Zheng and J. W.
Bode, J. Am. Chem. Soc., 2010, 132, 8810; (e) H. Gotoh,
D. Okamura, H. Ishikawa and Y. Hayashi, Org. Lett., 2009, 11,
4056; (f) D. Hazelard, H. Ishikawa, D. Hashizume, H. Koshino
and Y. Hayashi, Org. Lett., 2008, 10, 1445; (g) T. Tozawa,
H. Nagao, Y. Yamane and T. Mukaiyama, Chem.–Asian J.,
2007, 2, 123; (h) K. Juhl and K. A. Jørgensen, Angew. Chem.,
Int. Ed., 2003, 42, 1498; (i) Y. Huang, A. K. Unni, A. N. Thadani
and V. H. Rawal, Nature, 2003, 424, 146.
Entry R1 Ar2
t/days drb
Yield of 5c (%) eed (%)
1
2
3
4
5
Et 4-CNC6H4 2.5 1 : 1.3 75 (5a)
90, 87
89, 83
88, 87
55, 95
61, 87
Et 4-BrC6H4 2.5 1 : 1.6 87 (5b)
Et 4-NO2C6H4 3.0
Me 4-BrC6H4 1.5
Me 4-CNC6H4 1.5
1 : 1.6 84 (5c)
1 : 3.0 81 (5d)
1 : 3.0 79 (5e)
a
1 (0.25 mmol), 4 (0.5 mmol), VI (20 mol%) and 2-FC6H4CO2H
b
(40 mol%) were used in 0.25 mL CH2Cl2. Determined by 1H NMR
analysis of the crude reaction mixture.8 c Isolated yields of the mixture
d
of isomers. Determined by HPLC analysis.
In fact, higher loading of 2-fluorobenzoic acid (40 mol%) led
to slight increase in ee for both the diastereomers (90%, 87%)
and yield (75%) in shorter time, but reducing the catalyst
loading led to considerable loss of selectivity and yield (entries 9
and 10).
Having suitable conditions, the scope of the enantioselective
synthesis of pyran derivatives using aldehydes (4a,b) and trans-2-
aroyl-3-arylacrylonitriles (1a–c) was further demonstrated and is
given in Table 4. Both butyraldehyde (4a) and propionaldehyde
(4b) were successfully employed with the differently aryl-substituted
1 thus affording desired products 5a–e in high chemical yields
(up to 87%) and enantiomeric excess (up to 95% ee). Although
the products 5a–c generated from 4a were afforded with poor
diastereomeric ratios, the enantioselectivities of both isomers were
comparably good (entries 1–3). But in the case of 4b, the products
5d and 5e were obtained in better diastereomeric ratios and
high enantioselectivities (95%, 87%) only for major isomers
(entries 4 and 5). The absolute configuration of 5d10 was
determined by single crystal X-ray data analysis and those of
others were assigned by analogy.
5 For selected examples, (a) Ref. 4a; (b) C. D. Fusco, C. Tedesco and
A. Lattanzi, J. Org. Chem., 2011, 76, 676.
6 We believe that the reaction proceeds through Michael reaction
followed by enolization and cyclization. However hetero-
Diels–Alder reaction described by Juhl and Jørgensen [see ref. 4h]
cannot be excluded.
7 For reviews, see: (a) L. Jiang and Y.-C. Chen, Catal. Sci. Technol.,
2011, 1, 354; (b) M. Tommaso and H. Henk, Synthesis, 2010, 1229;
(c) L.-W. Xu, J. Luo and Y. Lu, Chem. Commun., 2009, 1807; for
selected recent examples; (d) L. Liu, D. Wu, X. Li, S. Wang, H. Li,
J. Li and W. Wang, Chem. Commun., 2012, 48, 1692;
(e) L.-L. Wang, L. Peng, J.-F. Bai, L.-N. Jia, X.-Y. Luo,
Q.-C. Huang, X.-Y. Xu and L.-X. Wang, Chem. Commun., 2011,
47, 5593; (f) P. Kwiatkowski, T. D. Beeson, J. C. Conrad and
D. W. C. MacMillan, J. Am. Chem. Soc., 2011, 133, 1738;
(g) Q. Cai, C. Zheng, J.-W. Zhang and S.-L. You, Angew. Chem.,
Int. Ed., 2011, 50, 8665, and ref. 11 cited therein; (h) L.-Y. Wu,
G. Bencivenni, M. Mancinelli, A. Mazzanti, G. Bartoli and
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(i) G. Bencivenni, L.-Y. Wu, A. Mazzanti, B. Giannichi,
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Chem., Int. Ed., 2009, 48, 7200.
8 The minor diastereomer of 3 or 5 which is observed in the crude
reaction mixture has the structure with syn stereochemistry resulting
from the Michael addition step.
9 We found that cyclopentanone and cycloheptanone were much less
reactive in our optimized reaction conditions. There was even no
product formation in the case of a-tetralone and 3-pentanone.
10 CCDC 865351 (3b) and 865350 (5d) contains supplementary
crystallographic data for this paper (ESIz).
In conclusion, we have demonstrated an efficient enantio-
selective cascade Michael addition–cyclisation reaction sequence
to generate highly functionalized pyrans of synthetic and bio-
logical importance. Cyclohexanone and aliphatic aldehydes were
successfully employed for the scope of the reaction with various
trans-trisubstituted alkenes (1a–n) to provide the corresponding
adducts in very high enantioselectivities (up to 96%) and very
good yields (up to 90%) having three contiguous chiral centers
one of which is quaternary (3a–n). The synthetic usefulness of
this method lies in the fact that electron-poor alkenes were
efficiently functionalized to access pyrans derivatives.
We thank the NSC of the Republic of China (NSC 99-2119-
M-003-004-MY2) and National Taiwan Normal University
(NTNU100-D-06) for financial support.
11 For reviews, see: (a) A. Mielgo and C. Palomo, Chem.–Asian J.,
2008, 3, 922; (b) C. Palomo and A. Mielgo, Angew. Chem., Int. Ed.,
2006, 45, 7876; for selected recent examples; (c) J. Deng, F. Wang,
W. Yan, J. Zhu, H. Jiang, W. Wang and J. Li, Chem. Commun.,
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and G.-H. Lee, Org. Lett., 2011, 13, 1338; (e) V. Coeffard,
A. Desmarchelier, B. Morel, X. Moreau and C. Greck, Org. Lett.,
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P. H. Poulsen and K. A. Jørgensen, Org. Lett., 2011, 13, 3678;
(g) H. Ishikawa, S. Sawano, Y. Yasui, Y. Shibata and Y. Hayashi,
Angew. Chem., Int. Ed., 2011, 50, 3774; (h) D. Enders, C. Wang,
M. Mukanova and A. Greb, Chem. Commun., 2010, 46, 2447;
(i) X. Companyo, A. Zea, A.-N. R. Alba, A. Mazzanti, A. Moyano
and R. Rios, Chem. Commun., 2010, 46, 6953; (j) J. Jiang, L. He,
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Notes and references
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c
5592 Chem. Commun., 2012, 48, 5590–5592
This journal is The Royal Society of Chemistry 2012