Enantio- and diastereoselective cross-annulation of enal and ketone with new chiral bicyclic N-heterocyclic carbene catalysts

Article abstract of DOI:10.1246/cl.151116

The enantio- and diastereoselective cross-annulation of cinnamaldehyde (6) and 2,2,2-trifluoroacetophenone (7) was examined to evaluate the performance of newly developed chiral bicyclic imidazolium salts 3 and 4 as catalyst precursors. The reaction proce

Full text of DOI:10.1246/cl.151116

CL-151116
Received: December 3, 2015 | Accepted: December 24, 2015 | Web Released: January 8, 2016
Enantio- and Diastereoselective Cross-annulation of Enal and Ketone
with New Chiral Bicyclic N-Heterocyclic Carbene Catalysts
Momo Hasegawa,1 Kazuhiro Yoshida,*1,2 and Akira Yanagisawa*1,2
1Department of Chemistry, Graduate School of Science, Chiba University, Yayoi-cho, Inage-ku, Chiba 263-8522
2Molecular Chirality Research Center, Chiba University, Yayoi-cho, Inage-ku, Chiba 263-8522
(E-mail: kyoshida@faculty.chiba-u.jp, ayanagi@faculty.chiba-u.jp)
The enantio- and diastereoselective cross-annulation of
cinnamaldehyde (6) and 2,2,2-trifluoroacetophenone (7) was
examined to evaluate the performance of newly developed
chiral bicyclic imidazolium salts 3 and 4 as catalyst precursors.
The reaction proceeded to give desired γ-lactone 8 with high
diastereoselectivities (up to 10/1) and moderate enantioselectiv-
ities (up to 71% ee) when the sterically demanding catalyst
precursors were used.
compounds to afford γ-lactones still presents a challenge.11 Here,
we report our investigation of this reaction to form γ-lactone
8 catalyzed by N-alkyl bicyclic NHCs generated from newly
prepared imidazolium salts (S)-3 and (R)-4.
At the outset, we synthesized chiral imidazolium salts (S)-3
and (R)-4 having flexibility at substituents R1 and R3 from
pyrrolidine-fused imidazoles 1, which were prepared from
urocanic acid, and oxazolidine-fused imidazole 2, which was
prepared from amino acids, with various electrophiles (R3X)
(Figure 2).12
According to the reaction conditions reported by Ishida and
Saigo,8 we first carried out the cross-annulation of cinnamalde-
hyde (6) and 2,2,2-trifluoroacetophenone (7) in the presence of
imidazolium salt (S)-3at (20 mol %) and KN(SiMe3)2 (20 mol %)
in THF at room temperature (Table 1, Entry 1). However, the
desired γ-lactone was not generated under those conditions.
Then, we screened bases DBU, Cs2CO3, and t-BuOK and
found that t-BuOK was the best option, generating 8 in 49%
isolated yield with good diastereoselectivity (8a/8b = 5.7/1)
and enantioselectivity (55% ee (8a), 50% ee (8b)) (Entries 2-4).
Keywords: N-Heterocyclic carbene (NHC)
| Cross-annulation |
Chiral bicyclic NHC catalyst
Chiral N-heterocyclic carbenes (NHCs) have become an
indispensable tool in the fields of coordination chemistry and
asymmetric catalysis.1,2 In 2010, we reported a modular synthe-
sis of chiral bicyclic imidazolium salts 3-5 based on the
alkylation of newly prepared imidazoles 1 and 2 with the intent
of applying them to NHC/metal-catalyzed asymmetric reactions
(Figure 1).3 One of the advantages of the method is the rapid
preparation of a diverse array of imidazolium salts simply by
changing the combinations of imidazoles and alkylating agents.
In fact, very recently, we have synthesized many NHC/Ir
complexes by using this method and succeeded in finding an
excellent catalyst precursor for the asymmetric transfer hydro-
genation of ketones.4
Although NHCs generated from structurally similar bicyclic
triazolium salts and imidazolium salts to 3 and 4 are well-known
chiral organocatalysts,2,5 most of them have aryl groups on the
nitrogen atom.6 The use of analogs having alkyl groups on the
nitrogen atom is rather limited.7 In 2008, Ishida and Saigo
prepared various chiral N-alkyl bicyclic imidazolium salts by
the alkylation of their own morpholine-fused imidazole, and
reported that one of those salts could be used as a catalyst
precursor for the asymmetric cross-annulation of cinnamalde-
hyde (6) and 2,2,2-trifluoroacetophenone (7).8 Since the seminal
reports by the groups of Glorius9a and Bode,9b the chemistry of
NHC-catalyzed homoenolates has greatly developed, enabling
the synthesis of many useful molecules.2,10 However, the
asymmetric version of the reaction between enals and carbonyl
Figure 1. Modular synthesis of chiral bicyclic imidazolium
salts 3-5.
Figure 2. Structures of chiral bicyclic imidazolium salts 3 and
4 for enantio- and diastereoselective cross-annulation.
294 | Chem. Lett. 2016, 45, 294–296 | doi:10.1246/cl.151116
© 2016 The Chemical Society of Japan

Table 1. Optimization of reaction conditions for enantio- and
diastereoselective cross-annulation of cinnamaldehyde (6) and
2,2,2-trifluoroacetophenone (7) with (S)-3ata
Table 2. Enantio- and diastereoselective cross-annulation of
cinnamaldehyde (6) and 2,2,2-trifluoroacetophenone (7) with
various imidazolium salts (S)-3 and (R)-4a
Temp Yieldb
drc
eed
Entry Base
Solvent
/°C
/% (8a/8b) (8a/8b)
Yieldb
/%
drc
(8a/8b)
eed
(8a/8b)
Entry
3 or 4
1
2
3
4
5
6
7
8
9
KN(SiMe3)2 THF
rt
rt
rt
rt
0
¹40
rt
rt
rt
rt
0
17
34
49
33
16
50
13
14
12
®/®
5.3/1
5.3/1
5.7/1
6.7/1
3.6/1
7.3/1
4.0/1
6.7/1
3.8/1
®/®
51/51
39/67
55/50
58/65
35/38
57/16
52/36
46/38
35/26
DBU
THF
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
(S)-3at
(S)-3au
(S)-3av
(S)-3aw
(S)-3ax
(S)-3ay
(S)-3az
(R)-4au
(R)-4av
(S)-3bt
(S)-3ct
(S)-3cu
(S)-3cv
(S)-3dt
(S)-3dz
(S)-3et
(S)-3ez
49 (0)
56 (1)
44 (2)
64 (0)
47 (0)
23 (0)
27 (1)
51 (0)
60 (13)
62 (6)
31 (1)
42 (1)
53 (10)
52 (12)
35 (8)
39 (24)
39 (19)
5.7/1
5.7/1
3.2/1
4.0/1
6.3/1
4.3/1
10/1
4.9/1
2.0/1
4.8/1
6.7/1
4.8/1
2.9/1
7.7/1
8.3/1
10/1
55/50
34/31
35/50
18/40
50/54
33/24
49/40
25/20
22/26
33/18
61/30
45/24
42/27
62/37
62/72
64/28
71/36
Cs2CO3
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
THF
THF
THF
THF
Et2O
toluene
CH2Cl2
MeOH
10 t-BuOK
aThe cross-annulation was carried out with cinnamaldehyde (6)
and 2,2,2-trifluoroacetophenone (7) (4 equiv) in the presence of
imidazolium salt (S)-3at (20 mol %) and base (20 mol %) in
solvent (0.1 mol L¹1) for 24 h. Isolated yield. cDiastereomeric
b
ratios were determined by 1H NMR analysis of the crude
reaction mixture. dDetermined by HPLC analysis using a chiral
stationary phase column (Chiralcel AS-H).
7.1/1
aThe cross-annulation was carried out with cinnamaldehyde (6)
and 2,2,2-trifluoroacetophenone (7) (4 equiv) in the presence
of imidazolium salt (S)-3 or (R)-4 (20 mol %) and t-BuOK
(20 mol %) in THF (0.1 mol L¹1) at room temperature for 24 h.
bIsolated yield and numbers in parenthesis indicate the yield
of recovered 6. cDiastereomeric ratios were determined by
Lowering the reaction temperature to 0 °C improved both
diastereo- and enantioselectivities, but the isolated yields of
the products decreased (Entry 4 vs. 5). Further lowering of the
temperature to ¹40 °C worsened the situation: Not only the
isolated yield but also the selectivities decreased (Entry 4 vs. 6).
Several solvents were then screened to further optimize the
reaction conditions. With Et2O as the solvent, the reaction
proceeded with better diastereoselectivity, whereas the enantio-
selectivity of 8b decreased (Entry 4 vs. 7). Other solvents,
toluene, CH2Cl2, and MeOH, were found to significantly
decrease the isolated yields of the products (Entries 8-10).
The results of catalyst screening for the enantio- and
diastereoselective cross-annulation are shown in Table 2, in
which all reactions were performed in the presence of t-BuOK as
the base at room temperature in THF.13 First, using the structure
of (S)-3at (Entry 1), the influence of the steric hindrance of
substituent R3 was inspected. It was found that neither
decreasing (Entries 2-4) nor increasing (Entries 5-7) the steric
hindrance improved the enantioselectivity of 8a. On the other
hand, in regard to diastereoselectivity, (S)-3az, which has a
rather bulky R3 substituent, the di(2-naphthalenyl)methyl group
showed the best result (8a/8b = 10/1) (Entry 7). Unfortunately,
oxazolidine-fused imidazolium salts (R)-4 were found to be
inferior to pyrrolidine-fused imidazolium salts (S)-3 in terms of
both diastereo- and enantioselectivities (Entry 2 vs. 8; Entry 3
vs. 9). A measurable improvement in enantioselectivity was
d
1H NMR analysis of the crude reaction mixture. Determined
by HPLC analysis using a chiral stationary phase column
(Chiralcel AS-H).
observed when substituent R1 of (S)-3 was changed. Although
the introduction of two tert-butyl groups on the 3,5-positions of
the phenyl ring decreased both diastereo- and enantioselectiv-
ities (Entry 1 vs. 10), the introduction of bulkier substituents
on the 2,6-positions of the phenyl ring clearly led to higher
enantioselectivity in 8a (Entry 1 vs. 11, 14, and 16; Entry 2 vs.
12; Entry 3 vs. 13; Entry 7 vs. 15 and 17). In these cases,
however, the reaction rates tended to slow down and a certain
amount of starting cinnamaldehyde (6) was recovered.14 The
highest enantioselectivity of 8a (71% ee) was observed when
(S)-3ez, which has a 2,4,6-tricyclohexylphenyl group as the
R1 substituent and a di(2-naphthalenyl)methyl group as the R3
substituent, was used (Entry 17).15
In conclusion, we have conducted the enantio- and
diastereoselective cross-annulation of cinnamaldehyde (6) and
2,2,2-trifluoroacetophenone (7), which is known as a challeng-
Chem. Lett. 2016, 45, 294–296 | doi:10.1246/cl.151116
© 2016 The Chemical Society of Japan | 295

ing asymmetric reaction, to evaluate the performance of newly
developed NHC precursors (S)-3 and (R)-4. Although the cross-
annulation was not entirely successful in terms of satisfying all
requirements, namely, yield, diastereoselectivity, and enantio-
selectivity, some NHC catalysts produced desired γ-lactone 8
with good diastereo- and enantioselectivities.
9
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6205. b) S. S. Sohn, E. L. Rosen, J. W. Bode, J. Am. Chem.
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10 R. S. Menon, A. T. Biju, V. Nair, Chem. Soc. Rev. 2015, 44,
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We appreciate the financial support in the form of a Grant-
in-Aid for Scientific Research (Grant #15K05494) from the
Ministry of Education, Culture, Sports, Science and Technology,
Japan. We also gratefully acknowledge financial support from
the next generation training program in Chiba University.
References and Notes
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12 For experimental details, see refs 3 and 4. (S)-3aw was
prepared from (S)-3a with benzyne generated by mixing
2-(trimethylsilyl)phenyl imidazolsulfonate and cesium fluo-
ride.
13 General procedures for the enantio- and diastereoselective
cross-annulation: To a suspension of t-BuOK (0.02 mmol)
in THF (1.0 mL) was added a THF solution of imidazolium
salt (S)-3 or (R)-4 (0.02 mmol) at ¹78 °C. The mixture was
stirred at the same temperature for 1 h, and then cinnamal-
dehyde (6) (0.100 mmol) and 2,2,2-trifluoroacetophenone (7)
(0.400 mmol) were added. After being stirred for 30 min,
the mixture was allowed to warm to room temperature and
stirred for 24 h. The resulting mixture was poured into water
(20 mL) and extracted with CH2Cl2 (5 mL © 3). The organic
phases were dried over Na2SO4, filtered, and concentrated
under reduced pressure. The residue was chromatographed
on silica gel (hexane/CH2Cl2 = 2/1) to give a mixture of
8a and 8b. The products were characterized by comparison
of spectroscopic data with those reported previously (ref 8).
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The desired γ-lactone was obtained as a mixture of trans-
and cis-isomers (8a: 23% yield (66% ee), 8b: 5% yield (59%
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1
The diastereomeric ratio of 8 was determined by H NMR
analysis of the crude reaction mixture. The enantiomeric
excess of the products was determined by HPLC analysis
with a chiral stationary phase column (Daicel Chiralcel; AS-
6
7
H, hexane/i-PrOH = 90/10, 0.9 mL min¹1, 8a (t4R,5R(minor)
=
6.8 min, t4S,5S(major) = 9.7 min), 8b (t4R,5S(minor) = 10.8 min,
4S,5R(major) = 16.8 min). The absolute configurations of the
t
major enantiomers were assigned as (4S,5S) for 8a and
(4S,5R) for 8b by comparison of the HPLC retention time
with literature data, see ref 11b.
14 In the present reaction, the self-annulation of 6 affording
another γ-lactone is known as the major side reaction. In
our case, a diastereomeric mixture of the side products was
likewise produced. The yields were 0-32%, see: Y. Ishida,
K. Kawatsu, Y. Matsuoka, K. Yamada, R. Ikariya, J.
Sawayama, S. Hirao, N. Nishiwaki, K. Saigo, Asian J.
Org. Chem. 2013, 2, 140.
15 Higher enantioselectivities (74% ee (8a), 94% ee (8b)) have
been achieved using a chiral cyclophane-type NHC, see
ref 11b.
8
296 | Chem. Lett. 2016, 45, 294–296 | doi:10.1246/cl.151116
© 2016 The Chemical Society of Japan