Asymmetric cross-benzoin condensation promoted by a chiral triazolium precatalyst bearing a pyridine moiety

Article abstract of DOI:10.1016/j.tet.2017.05.001

Cross-benzoin condensation catalyzed by NHC, prepared from chiral triazolium salts bearing a pyridine ring, afforded α-hydroxy ketones with reasonable chemical yields and enantioselectivities. A wide range of aliphatic and aromatic aldehydes were successf

Full text of DOI:10.1016/j.tet.2017.05.001

Accepted Manuscript
Asymmetric cross-benzoin condensation promoted by a chiral triazolium precatalyst
bearing a pyridine moiety
Takahiro Soeta, So Mizuno, Yuichi Hatanaka, Yutaka Ukaji
PII:
S0040-4020(17)30467-2
10.1016/j.tet.2017.05.001
TET 28667
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 1 March 2017
Revised Date: 28 April 2017
Accepted Date: 1 May 2017
Please cite this article as: Soeta T, Mizuno S, Hatanaka Y, Ukaji Y, Asymmetric cross-benzoin
condensation promoted by a chiral triazolium precatalyst bearing a pyridine moiety, Tetrahedron (2017),
doi: 10.1016/j.tet.2017.05.001.
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to
our customers we are providing this early version of the manuscript. The manuscript will undergo
copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please
note that during the production process errors may be discovered which could affect the content, and all
legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT
Graphical Abstract
To create your abstract, type over the instructions in the template box below.
Fonts or abstract dimensions should not be changed or altered.
Asymmetric cross-benzoin condensation promoted by chiral
triazolium precatalyst bearing a pyridine moiety
Leave this area blank for abstract info.
Takahiro Soeta*, So Mizuno, Yuichi Hatanaka, Yutaka Ukaji*
Division of Material Chemistry, Graduate School of Natural Science and Technology, Kanazawa University, Kakuma, Kanazawa 920-
1
192, Japan

1
ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
Asymmetric cross-benzoin condensation promoted by a chiral triazolium
precatalyst bearing a pyridine moiety
Takahiro Soeta*, So Mizuno, Yuichi Hatanaka, Yutaka Ukaji*
Division of Material Sciences, Graduate School of Natural Science and Technology, Kanazawa University, Kakuma, Kanazawa 920-1192, Japan
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Cross-benzoin condensation catalyzed by NHC, prepared from chiral triazolium salts bearing a
pyridine ring, afforded α-hydroxy ketones with reasonable chemical yields and
enantioselectivities. A wide range of aliphatic and aromatic aldehydes were successfully used in
the reaction.
Available online
2
009 Elsevier Ltd. All rights reserved.
Keywords:
Keyword_1 N-Heterocyclic carbene
Keyword_2 Catalytic asymmetric reaction
Keyword_3 Cross-benzoin condensation
11
asymmetric reactions. These are just some of the many
examples of benzoin condensation, and particularly promising
examples of cross-benzoin condensation have been studied
1
. Introduction
In 1943, Ukai reported that thiamine catalyzed benzoin
condensation,
1
2
1
a
independently by Zeitler, Cannon, Gravel, Glorius and Yang.
and the mechanism of thiazolium-catalyzed
2
However, there are still limitations associated with general cross-
benzoin condensation between two different aldehydes catalyzed
benzoin condensation was elucidated by Breslow in 1958. The
introduction of NHCs as an organocatalyst led to a breakthrough
in this area. Since the first stable nucleophilic carbene was
reported by Bertrand, Arduengo and coworkers in 1990, broad
application of N-heterocyclic carbenes (NHCs) in organic
synthesis has been dramatically demonstrated. The first catalytic
asymmetric benzoin condensation reaction was developed by
Sheehan and Hunnemann in 1966, although the enantioselectivity
12,13
by NHC, especially in terms of enantioselectivity.
1,3
We recently developed a family of chiral triazolium salts bearing
a pyridine moiety, which have been shown to catalyze benzoin
condensation and intramolecular Stetter reactions to give
14
products with high enantioselectivity.
Herein, we report
catalytic asymmetric cross-benzoin condensation between two
different aldehydes to afford the corresponding α-
hydroxyketones with good enantioselectivity.
4
was low. Recently, several successful catalysts were reported in
the reaction of two identical aldehydes, yet cross-benzoin
5
condensation is still a significant challenge. The first example of
cross-benzoin condensation catalyzed by a thiazolium salt as an
NHC precursor was reported by Stetter in 1977. Imines and
2
. Results and Discussion
6
In NHC-catalyzed asymmetric reactions, conformational control
of the Breslow intermediate is crucial in order to obtain products
with a high degree of enantioselectivity. In the view of these
points, we anticipated that a chiral triazolium salt with a Lewis
basic moiety would undergo intramolecular hydrogen bonding
with the OH group of the Breslow intermediate, giving a more
rigid intermediate in the umpolung reaction and giving products
with greater stereoselectivity (Scheme 1). We designed and
synthesized a variety of chiral triazolium salts bearing a pyridine
ring (Figure 1). Our initial reactions attempted cross-benzoin
condensation of 1.5 equiv of 3-phenylpropanal (1a) and
benzaldehyde (2a) using 5 mol% of triazolium salt 4, with 1.0
equiv of diisopropylethylamine (DIPEA) as a base to generate a
iminium salts are also good acceptors for cross-benzoin-type
condensation reactions, affording α-aminoketones with high
7
chemoselectivities. In 2005, an asymmetric version of cross-
benzoin-type condensation between aldehydes and imine
precursors was developed by Miller using a thiazolium-derived
8
catalyst with a peptide backbone. Meanwhile, acylsilanes and
acylphosphonates were found to be suitable substrates for
9
aldehyde ketone cross-coupling catalyzed by cyanide ions.
Ketones including α-keto esters were also found to be good
10
substrates, thereby largely avoiding chemoselectivity issues.
Intramolecular cross-benzoin condensation between different
aldehydes and ketones has also been developed, including

2
Tetrahedron
edEDα- MA
carbene catalyst, in THF at 70 °C.
hydroxyketone 3aa was obtained in 43% ee with a yield of 24%
eq 1). To determine the importance of the pyridine ring of the
precatalyst, we then carried out the reaction using triazolium salt
A
Th
C
e
C
d
E
es
P
ir
T
K
N
Ot
U
-BuSCwa
R
s
I
used as a base at 70 °C, the chemical yield of 3aa
P
T
increased to 54%, but enantioselectivity was lower (entry 6).
When the reaction temperature was decreased to 50 °C and 40 °C,
an increase in enantioselectivity, rather than a decrease in
chemical yield, was observed (entries 6–8). Finally, we found
that the desired product 3aa was obtained with 60% ee and a
yield of 62% when the reaction was carried out at 40 °C using
KHMDS as a base and dioxane/HMPA/2-MeTHF (4/1/1) as a
solvent (entry 9). 2-MeTHF is a useful solvent for this reaction,
as it dissolves solid KHMDS.
(
15
5
, with no pyridine ring. The reaction proceeded smoothly, but
the product 3aa was obtained in 24% ee with a yield of 14%.
This result clearly indicated that the pyridinyl group plays an
important role in achieving higher enantioselectivity.
Table 1. Optimization of reaction conditions
6
(10 mol%)
O
O
H
Ph
Base (10 mol%)
Ph
+
H
O
solv.,70 °C, 24 h
Bn
Bn OH
1
a
2a
3aa
(1.5 equiv)
Scheme 1. Working hypothesis
a
–
BF
entry
base
solv.
THF
yield/%
56
ee/%
60
79
46
55
80
60
80
87
60
–
–
BF
4
N
+
4
BF
4
N
N
+
+
N
N
N
N
N
N
1
2
3
4
5
6
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
KOt-Bu
KOt-Bu
KOt-Bu
KHMDS
Ph
Ph
Ph OTMS
Ph
N
N
Ph
Ph
MeCN
13
4
5
6
–
BF
–
–
BF
CH Cl2
15
4
BF
4
2
N
N
+
N
N
N
4
+
+
N
N
N
N
toluene
12
N
N
N
OTBS
OTIPS
b
dioxane/HMPA
19
7
8
9
b
–
–
BF
4
BF
N
+
4
dioxane/HMPA
54
N
+
N
N
N
N
c
b
–
7
dioxane/HMPA
38
BF
4
N
N
N
+
N
N
d
b
8
dioxane/HMPA
13
N
OTBDPS
d
1
0
11
12
9
dioxane/HMPA/
62
–
e
–
BF
–
BF
N BF
4
2-MeTHF
N
4
N
+
N
4
+
N
N
+
N
N
N
a
The absolute configuration of (R)-3aa was determined by
comparison of the specific rotation with the reported value.
The solvent ratio was 1/1 (volume/volume). Reaction was
carried out at 50 °C. Reaction was carried out at 40 °C. The
solvent ratio was 4/1/1 (volume/volume).
N
N
N
16a b
c
d
e
1
3
14
15
Figure 1. Chiral triazolium salts bearing a pyridine ring
chiral triazolium salt
4 or 5 (5 mol%)
DIPEA (1.0 equiv)
We then turned our attention to the structure of the chiral
triazolium salt (Table 2). The chiral triazolium salt 7, bearing an
isopropyl group at the stereocenter, gave a higher chemical yield
of 83% (entry 2). Based on this result, the catalytic efficiency of
the chiral triazolium salt is highly dependent on the bulkiness of
the substituent on the chiral center. The introduction of a TBS-
protected methanol group onto the pyrrolidine ring (8) gave the
product with high chemical yield, but the enantioselectivity was
47% (entry 3). When the reaction was carried out at room
temperature, the reaction still proceeded, affording the product
with moderate chemical yield and enantioselectivity (entry 4).
Triazolium salts (9 or 10) bearing a TIPS group or a TBDMS
group on the alcohol moiety gave the product 3aa with almost
same enantioselectivity as 8 (entries 5 and 6). We found that the
use of a chiral triazolium salt bearing a benzyl group (11)
resulted in improved chemical yield and enantioselectivity,
giving the product with 65% ee and a yield of 69% at room
temperature (entry 7). The use of chiral imidazolium salts bearing
more bulky benzyl groups such as mesitylmethyl (12),
triisopropylphenylmethyl (13), 1-naphthylmethyl (14), and 2-
naphthylmethyl (15) resulted in lower enantioselectivities and/or
chemical yields (entries 8–11). Enantioselectivities did not
O
O
H
Ph
Ph
+
(1)
H
O
THF, 70 °C , 24 h
Bn
Bn OH
1
a
2a
3aa
(
1.5 equiv)
4
5
: 24%, 43% ee
: 14%, 24% ee
To optimize the reaction conditions, we examined the reaction
solvent, base, and reaction temperature using chiral triazolium
salt 6, which has been demonstrated to be useful in benzoin
condensation. The results are shown in Table 1. Cross-benzoin
condensation of 1a and 2a was carried out using 10 mol% of
triazolium salt 6 with 10 mol% of DIPEA as a base in THF at
1
4a
7
5
0 °C, giving α-hydroxyketone 3aa with 60% ee and a yield of
6% (entry 1). When other solvents such as MeCN,
dichloromethane, and toluene were used, the desired product 3aa
was obtained with moderate enantioselectivity but the chemical
yields were lower (entries 2–4). A dramatic improvement in
enantioselectivity was achieved—up to 80% ee—by using a
dioxane/HMPA (1/1) solvent system (entry 5). To improve the
chemical yield, we examined the optimum base and reaction
temperature for efficient generation of the carbene catalyst. When
1
4a

3
change when the reactions ran for shorter and lo
A
ng
C
er
C
ti
E
me
P
(
T
en
E
tr
D
ies MA
a
N
hig
U
he
S
r
C
en
R
an
I
tioselectivity (77% ee) was achieved (entry 14).
P
T
7
, 12 and 13).
Next, we examined substituted benzaldehydes bearing an
electron-donating group (entries 16–21). In all cases except one,
the reaction proceeded to afford the corresponding α-
hydroxyketone with 64–69% enantioselectivity. The exception
was 2-methylbenzaldehyde (2m), which was possibly due to
steric hindrance (entry 19).
Table 2. Effects of various precatalysts
Table 3. Reactions with various substrates
1
1 (10 mol%)
O
O
H
Ar
KHMDS (10 mol%)
a
Ar
OH
entry
chiral
triazolium
salt
yield/%
ee/%
absolute
+
R
R
H
O
dioxane/HMPA/2-MeTHF
b
configuration
(
4/1/1)
1
2
rt, 24 h
3
c
(
1.5 equiv)
1
6
62
83
99
46
48
63
69
42
50
48
38
26
55
60
43
47
63
61
62
65
37
40
69
62
66
64
R
S
c
2
7
a
entry
R
Ar
yield/%
ee/
b
%
c
3
8
R
R
R
R
S
4
5
6
7
8
9
8
1
2
BnCH
2
(1a)
CH
C
C
6
6
H
5
5
(2a)
(2a)
69 (3aa)
66 (3ba)
65
56
9
4-MeC
6
H
4
2
H
(
1b)
10
11
12
13
14
15
11
11
3
4-MeOC H CH
C H (2a)
31 (3ca)
67
6
4
2
6
5
(
1c)
R
R
S
c
4
5
6
7
8
9
Et (1d)
n-Hept (1e)
i-Bu (1f)
i-Pr (1g)
C H (2a)
23 (3da)
55 (3ea)
24 (3fa)
trace
60
59
17
nd
64
67
69
39
69
64
77
43
6
5
C H (2a)
6
5
1
0
1
C H (2a)
6
5
1
R
S
C H (2a)
6
5
d
1
2
3
BnCH (1a)
1-naphtyl (2b)
2-naphtyl (2c)
2-ClC H (2d)
28 (3ab)
76 (3ac)
41 (3ad)
50 (3ae)
43 (3af)
30 (3ag)
46 (3ah)
40 (3ai)
2
e
1
S
BnCH (1a)
2
a
3
-Phenylpropanal (1a) (1.5 equiv) and benzaldehyde (2a)
b
1.0 equiv) were used as substrates. The absolute configuration
of 3aa was determined by comparison of the specific rotation
with the reported value.
1
0
BnCH (1a)
2
6
4
(
11
12
BnCH
BnCH
(1a)
(1a)
3-ClC
H
(2e)
(2f)
2
2
6
4
1
6a c
The reaction was carried out at 40
d
e
4-ClC
H
6 4
°
C. Reaction time was 4 h. Reaction time was 48 h.
1
1
3
4
BnCH (1a)
2-BrC H (2g)
6 4
2
BnCH (1a)
4-BrC H (2h)
6 4
2
Under the optimized reaction conditions using the active and
selective precatalyst 11, the scope of the catalytic
enantioselective cross-benzoin condensation reaction was
demonstrated using various aliphatic and aromatic aldehydes
15
BnCH (1a)
4-MeO CC H
2
2
6
4
(2i)
1
6
BnCH (1a)
2-MeOC H4
39 (3aj)
66 (3ak)
19 (3al)
nd
69
68
64
nd
2
6
(
Table 3). We were delighted to find that our catalytic system
(
2j)
was applicable to a wide range of aldehydes using 10 mol% of 11
and 10 mol% of KHMDS in 1,4-dioxane/HMPA/2-MeTHF at
room temperature. 3-Phenylpropanal (1a) and its derivatives 1b
and 1c were good substrates for the reaction, affording the
products with moderate enantioselectivity (entries 1–3). In the
case of linear aliphatic aldehydes such as propionaldehyde (1d)
and n-octanal (1e), the products were obtained with reasonable
enantioselectivities; however, branched aldehydes were not
effective in this reaction system, possibly due to steric hindrance
17
BnCH (1a)
3-MeOC H4
2
6
(2k)
1
1
2
8
9
BnCH (1a)
4-MeOC H4
2
6
(
2l)
BnCH (1a)
2-MeC H4
2
6
(2m)
0
1
BnCH (1a)
3-MeC H (2n)
46 (3an)
52 (3ao)
70
64
(
entries 4–7). Next, we examined the reactions of various types
2
6
4
of aromatic aldehyde with 3-phenylpropanal (1a), again using
chiral triazolium salt 11. 1-Naphthaldehyde (2b) showed lower
reactivity, but with moderate enantioselectivity (entry 8). In
contrast, 2-naphthaldehyde (2c) was a good substrate, affording
the product 3ac with 67% ee and a yield of 76% (entry 9). We
also examined substituted benzaldehydes bearing an electron-
withdrawing group (entries 10–15). Products 3ad–3ai were
obtained with moderate enantioselectivities, except for 3ae and
2
BnCH (1a)
4-MeC H (2o)
6 4
2
a
Aliphatic aldehydes 1 (1.5 equiv) and aromatic aldehydes 2
1.0 equiv) were used as substrates. The absolute configurations
b
(
c
of 3 were assigned based on the analogous reactions in Table 2.
The absolute configuration of (S)-3da was determined by
1
6b
comparison of the specific rotation with the reported value.
3
ai (entries 11 and 15). In the case of 4-bromobenzaldehyde (2h),

4
Tetrahedron
1
7
By comparison of its optical rotation with th
A
at
C
re
C
po
E
rte
P
d
T
in
E
t
he MASy
D
N
nt
U
he
S
si
C
s o
R
f c
IPT
hiral lactams 16 and 17
literature, the absolute stereochemistry of the major isomer of
benzoin 3aa prepared using the chiral triazolium salt 11 was
To a solution of corresponding benzyl bromide derivative (6.5
mmol) in THF (20 mL), t-BuLi (8.0 mL, 1.63 M in pentane) was
added dropwise at –78 °C, and the whole was stirred at 0 °C for
10 min. To the reaction mixture, CuCN (292 mg, 3.26 mmol)
was added one portion and the whole was stirred at 0 °C for 20
min. To the reaction mixture, (S)-5-(tosylmethyl)pyrrolidin-2-
16a
determined to be S. Based on the determined stereochemistry, a
transition state model, as shown in Scheme 2, was proposed. The
benzyl group shields the Si face of the Breslow intermediate,
whose geometry is controlled by hydrogen bonding between the
hydroxyl group and the pyridine ring. Therefore, the attack of the
incoming aromatic aldehyde molecule occurs from the less
hindered Re face; that is, the Breslow intermediate predominantly
approaches the Re face of the aromatic aldehyde, leading to an S
configuration at the newly formed stereogenic center. Si attack by
the Breslow intermediate may be disfavored due to steric
repulsion between the heterocyclic moiety of the intermediate
and the aromatic ring of the aldehyde. The precise mechanism of
stereoinduction is now under further investigation in our
laboratory.
1
8
one (584 mg, 2.2 mmol) in THF (2.0 mL) was added dropwise
at –78 °C and the whole was stirred at –78 °C for 1 h, and
warmed to room temperature. After 24 h, 1 M HCl was added
and the organic solvents were removed in vacuo. The aqueous
layer was extracted with CHCl
organic layers were washed with water and brine, then, dried
over Na SO . Condensation and the subsequent purification by
(10 mL x 3). The combined
3
2
4
silica gel flash column chromatography gave the corresponding
chiral lactam.
(S)-5-(2,4,6-Trimethylbenzyl)pyrrolidin-2-one (16)
Silca gel column chromatography (hexane/ethyl acetate =
Scheme 2. Stereochemical model of cross-benzoin
condensation
2
1
1
2
2
1
1
0/1~3/1) gave 16 (193 mg, 41%) as a white solid of mp = 144–
25
1
45 °C and [α] –41.5 (c 0.54, EtOH). H NMR (CDCl ): 1.78–
D
3
.85 (m, 1H), 2.18 (s, 3H), 2.22 (s, 6H), 2.25–2.41 (m, 3H),
.75–2.81 (m, 2H), 3.78–3.85 (m, 1H), 5.25 (brs, 1H), 6.79 (s,
13
H). C NMR (CDCl ): 20.4, 20.7, 27.5, 30.0, 35.8, 53.9, 129.4,
3
31.3, 136.1, 136.4, 177.6. IR (KBr): 2960, 1710, 1460, 1380,
–1
360, 1250, 1050 cm . HRMS–DART (m/z): Calcd for
+
C H NO [M+H] : 218.1545. Found: 218.1551.
14
20
(S)-5-(2,4,6-Triisopropylbenzyl)pyrrolidin-2-one (17)
Silca gel column chromatography (hexane/ethyl acetate =
2
1
0/1~2/1) gave 17 (271 mg, 41%) as a white solid of mp = 158–
25
1
59 °C and [α] –38.6 (c 0.11, CHCl ). H NMR (CDCl ): 1.14
D
3
3
(d, J = 6.8 Hz, 6H), 1.17 (d, J = 6.8 Hz, 6H), 1.18 (d, J = 6.8 Hz,
6
2
H), 1.82–1.87 (m, 1H), 2.24–2.30 (m, 2H), 2.32–2.42 (m, 1H),
.73–2.89 (m, 3H), 3.08–3.10 (m, 2H), 3.70–3.77 (m, 1H), 5.23
13
(brs, 1H), 6.93 (s, 2H). C NMR (CDCl ): 23.7, 23.9, 24.1, 26.6,
3
2
9.1, 29.9, 32.2, 33.8, 55.3, 120.9, 127.9, 147.7, 146.8, 177.4. IR
–1
(
KBr): 2970, 1700, 1450, 1390, 1360, 1250, 1060 cm HRMS–
3
. Conclusion
+
DART (m/z): Calcd for C H NO [M+H] : 302.2484. Found:
In summary, we have developed a cross-benzoin condensation
reaction catalyzed by NHC prepared from chiral triazolium salts
bearing a pyridine ring, giving α-hydroxy ketones with
reasonable chemical yields and enantioselectivities. A wide range
of aliphatic and aromatic aldehydes were successfully used in the
reaction.
20 32
3
02.2470.
(R)-5-(Naphthalen-1-ylmethyl)pyrrolidin-2-one (18)
Chiral lactam 18 was synthesized following the reported
method
Silca gel column chromatography (hexane/ethyl acetate =
19
25
5
/1~ethyl acetate ) gave 18 as a yellow oil of [α] +18.7 (c 0.19,
D
1
4
. Experimental Section
CHCl ). H NMR (CDCl ): 1.66–1.73 (m, 1H), 1.89–1.98 (m,
3
3
1
3
2
1
H), 2.12–2.19 (m, 1H), 2.23–2.28 (m, 1H), 3.00–3.05 (m, 1H),
.22 (dd, J = 7.2, 14.0 Hz, 1H), 3.89–3.92 (m, 1H), 7.19–7.26 (m,
H), 7.29–7.33 (m, 1H), 7.38–7.46 (m, 2H), 7.67 (d, J = 8.4 Hz,
General Method
H NMR spectra were recorded on a 400 MHz NMR
1
1
3
spectrometer. Chemical shifts δ are reported in ppm using TMS
as an internal standard. Data are reported as follows: chemical
shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet,
m = multiplet), coupling constant (J) and integration. C NMR
spectra were recorded on 100 MHz NMR spectrometer. The
chemical shifts were determined in the δ-scale relative to CDCl3
H), 7.77 (d, J = 8.4 Hz, 1H), 7.93 (d, J = 8.4 Hz, 1H). C NMR
(CDCl ): 26.3, 29.7, 39.0, 54.3, 123.0, 124.9, 125.2, 125.6, 126.7,
3
1
1
27.0, 128.3, 131.3, 133.1, 133.4, 177.7. IR (KBr): 3060, 1700,
–1
13
600, 1510, 1400, 1280, cm . HRMS–DART (m/z): Calcd for
+
C H NO [M+H] : 226.1232. Found: 226.1234.
15
16
(
δ = 77.0 ppm). The wave numbers of maximum absorption
General procedures for the synthesis of chiral triazolium salts
−1
peaks of IR spectroscopy are presented in cm . HRMS (FAB
positive, DART) was measured with a quadrupole mass
spectrometer and TOF mass spectrometers. All melting points
were measured using
a micro melting point apparatus.
Dehydrated solvents were purchased for the reactions and used
without further desiccation.
Scheme 3. General synthesis of precatalysts (Method A).
14a
General procedures for the synthesis of chiral lactams 16–18
Method A

5
1
To a solution of the corresponding lactam in CH Cl ,
59.5 (c 0.12, CHCl ). H NMR (CDCl ): –0.06 (s, 3H), 0.00 (s,
ACCEPTE
2
D
2
MANUSCRIPT
3
3
Lawesson reagent (1.0 equiv) was added in one portion. The
reaction mixture was stirred at room temperature for 24 h. The
whole was filtered through silica gel on celite and the filtrate was
concentrated. The residue was purified by silica gel flash columm
chromatography to afford the corresponding thiolactam (Scheme
3H), 0.75 (s, 9H), 2.54–2.62 (m, 1H), 2.97–3.07 (m, 1H), 3.14–
3.22 (m, 2H), 3.80 (dd, J = 4.8, 12.0 Hz, 1H), 4.20 (dd, J = 2.8,
12.0 Hz, 1H), 5.19–5.22 (m, 1H), 7.43–7.47 (m, 1H), 7.87–7.97
(m, 2H), 8.47 (d, J = 3.2 Hz, 1H), 10.1 (s, 1H). C NMR
(CDCl ): 17.9, 22.2, 25.6, 29.7, 62.5, 64.4, 113.8, 125.8, 136.4,
1
3
3
3
, Step 1). To a solution of the thiolactam in benzene, excess
140.0, 147.4, 149.2, 163.7. IR (KBr): 2950, 1590, 1470, 1420,
–1
mount of iodomethane (15 equiv) was added dropwise at room
temperature. The whole was stirred at room temperature. After
consumption of the starting thiolactam (monitored by TLC), the
solvent and the remaining unreacted iodomethane were removed
under reduced pressure. The residue was used without further
purification (Scheme 3, Step 2). To a THF solution of the
thioimidium iodide obtained above, 2-hydrazinopyridine (1.0
equiv) in THF was added dropwise and the whole was stirred at
room temperature. The solvent was removed in vacuo and the
residue was purified by silica gel flash column chromatography
1380, 1260, 1200, 1120 cm . HRMS–DART (m/z): Calcd for
+ –
C H N OSi [M – BF ]: 331.1954. Found: 331.1961.
17
27
4
4
(S)-2-(Pyridin-2-yl)-5-(((triisopropylsilyl)oxy)methyl)-6,7-
4
dihydro-5H-2λ -pyrrolo[2,1-c][1,2,4]triazole,
tetrafluoroborate salt (9)
Method
B
(11.0 mmol scale): Silca gel column
chromatography (CHCl /MeOH = 10/1) gave 9 (580 mg, 11%) as
3
2
5
a white solid of mp = 171–172 °C (ethyl acetate) and [α]
52.1 (c 0.15, CHCl ). H NMR (CDCl ): 0.96 (d, J = 4.8 Hz, 9H),
–
D
1
3
3
(
Scheme 3, Step 3). A suspension of the resulting iminohydrazine
0.97 (d, J = 4.8 Hz, 9H), 1.02–1.11 (m, 3H), 2.64–2.72 (m, 1H),
3.04–3.14 (m, 1H), 3.2–3.29 (m, 2H), 3.95 (dd, J = 3.6, 11.5 Hz,
1H), 4.36 (dd, J = 2.0, 11.5 Hz, 1H), 5.33–5.37 (m, 1H), 7.47–
7.51 (m, 1H), 7.93 (d, J = 8.4 Hz, 1H), 7.99 (td, J = 2.0, 8.4 Hz,
1H), 8.54 (d, J = 4.8 Hz, 1H), 10.2 (s, 1H). C NMR (CDCl3):
11.6, 17.7, 17.8, 22.2, 29.6, 62.6, 64.9, 113.8, 125.9, 136.4, 140.0,
and ammonium tetrafluoroborate (1.05 equiv) in trimethyl
orthoformate (40 equiv) was stirred at 90 °C for 12 h.
Condensation and the subsequent purification by silica gel flash
column chromatography gave the corresponding chiral triazolium
salt (Scheme 3, Step 4).
13
1
1
47.4, 149.3, 163.7. IR (KBr): 2940, 1600, 1470, 1380, 1190,
–
1
+
–
060 cm . HRMS–DART (m/z): Calcd for C H N OSi [M –
20
33
4
BF ]: 373.2424. Found: 373.2410.
4
(
6
S)-5-(((tert-Butyldiphenylsilyl)oxy)methyl)-2-(pyridin-2-yl)-
,7-dihydro-5H-2λ -pyrrolo[2,1-c][1,2,4]triazole,
4
tetrafluoroborate salt (10)
Method (8.76 mmol scale): Silca gel column
chromatography (CHCl /MeOH = 10/1) gave 10 (210 mg, 42%)
Scheme 4. General synthesis of precatalysts (Method B).
B
3
15
2
5
Method B
To a solution of the corresponding lactam in CH Cl (0.5 M),
as a brown solid of mp = 118–119 °C (ethyl acetate) and [α]
–
D
1
2
2
39.6 (c 0.15, CHCl ). H NMR (CDCl ): 1.01 (s, 9H), 2.63–2.67
3
3
trimethyloxonium tetrafluoroborate (1.1 equiv) was added in one
portion. The reaction mixture was stirred at room temperature for
2 h (Scheme 4, Step 1). To the reaction mixture, 2-
hydrazinopyridine (1.1 equiv) in THF (ca. 1 mL) was added at
room temperature and stirred for 12 h (Scheme 4, Step 2). After
removing the solvent in vacuo, trimethyl orthoformate (20 equiv)
was added and the whole was stirred at 120 °C for 12 h (Scheme
, Step 3). Condensation and the subsequent purification by silica
gel flash column chromatography gave the corresponding chiral
triazolium salt.
(
=
(
m, 1H), 3.01–3.07 (m, 1H), 4.24 (t, J = 6.8 Hz, 2H), 3.96 (dd, J
4.0, 12.0 Hz, 1H), 4.25 (dd, J = 3.6, 12.0 Hz, 1H), 5.31–5.32
m, 1H), 7.28–7.37 (m, 5H), 7.45–7.53 (m, 6H), 7.91 (d, J = 6.0
Hz, 1H), 8.00 (td, J = 1.6, 8.0 Hz, 1H), 8.54–8.56 (m, 1H), 9.84
1
13
(s, 1H). C NMR (CDCl ): 18.9, 21.9, 26.7, 29.1, 62.1, 64.7,
3
1
1
1
13.6, 125.9, 127.8, 127.9, 130.0, 130.1, 131.2, 131.8, 135.1,
35.2, 135.7, 140.0, 147.0, 148.9, 163.3. IR (KBr): 2930, 1590,
–1
4
470, 1430, 1380, 1190, 1060 cm . HRMS–DART (m/z): Calcd
+
–
for C H N OSi [M – BF ]: 455.2267. Found: 455.2273.
27
31
4
4
4
(
R)-5-Benzyl-2-(pyridin-2-yl)-6,7-dihydro-5H-2λ -
pyrrolo[2,1-c][1,2,4]triazole, tetrafluoroborate salt (11)
Method (9.06 mmol scale): Silca gel column
chromatography (CHCl /MeOH = 10/1) gave 11 (660 mg, 20%)
4
(
R)-5-Isopropyl-2-(pyridin-2-yl)-6,7-dihydro-5H-2λ -
pyrrolo[2,1-c][1,2,4]triazole, tetrafluoroborate salt (7)
Method (7.23 mmol scale): Silca gel column
chromatography (CHCl /MeOH = 10/1) gave 7 (462 mg, 20%) as
B
B
3
25
3
as a colorless solid of mp = 177–178 °C (MeOH) and [α]
D
1
25
a brown solid of mp = 170–172 °C (MeOH) and [α] +30.1 (c
D
+30.5 (c 0.20, CHCl ). H NMR (CDCl ): 2.53–2.61 (m, 1H),
3 3
1
0
.11, CHCl ). H NMR (CDCl ): 0.97 (d, J = 6.8 Hz, 3H), 1.11 (d,
3
3
2.96–3.04 (m, 1H), 3.18–3.22 (m, 2H), 3.29 (dd, J = 7.2, 14.0 Hz,
J = 6.8 Hz, 3H), 2.35–2.43 (m, 1H), 2.51–2.60 (m, 1H), 2.96–
.06 (m, 1H), 3.16–3.20 (m, 1H), 3.26–3.30 (m, 1H), 5.05–5.10
m, 1H), 7.49 (t, J = 6.0 Hz, 1H), 7.93–8.01 (m, 2H), 8.54 (d, J =
1
5
H), 3.42 (d, J = 4.4 Hz, 1H), 5.23–5.73 (m, 1H), 7.19–7.32 (m,
H), 7.38–7.42 (m, 1H), 7.84–7.88 (m, 1H), 7.90 (td, J = 2.0, 8.4
3
(
3
2
13
Hz, 1H), 8.04–8.41 (m, 1H), 9.58 (s, 1H). C NMR (MeCN-d3):
13
.6 Hz, 1H), 10.1 (s, 1H). C NMR (CDCl ): 16.8, 18.4, 21.7,
3
22.5, 33.7, 40.5, 63.5, 115.1, 127.5, 128.9, 130.4, 130.7, 136.8,
8.9, 31.5, 66.4, 113.9, 126.0, 136.6, 140.1, 147.4, 149.2, 162.9.
1
1
37.3, 142.1, 148.8, 150.6, 164.7. IR (KBr): 3030, 1600, 1510,
–1
–1
IR (KBr): 2970, 1590, 1500, 1460, 1410, 1380, 1200, 1070 cm .
470, 1390, 1200, 1060 cm . HRMS–DART (m/z): Calcd for
+
–
+
–
HRMS–DART (m/z): Calcd for C H N [M – BF ]: 229.1453.
13
17
4
4
C H N [M – BF ]: 277.1453. Found: 277.1450.
17 17 4 4
Found: 229.1457.
(
S)-2-(Pyridin-2-yl)-5-(2,4,6-trimethylbenzyl)-6,7-dihydro-
4
(
S)-5-(((tert-Butyldimethylsilyl)oxy)methyl)-2-(pyridin-2-yl)-
5
(
H-2λ -pyrrolo[2,1-c][1,2,4]triazole, tetrafluoroborate salt
12)
Method
chromatography (CHCl /MeOH = 10/1) gave 12 (30 mg, 27%) as
4
6
,7-dihydro-5H-2λ -pyrrolo[2,1-c][1,2,4]triazole,
tetrafluoroborate salt (8)
Method (2.49 mmol scale): Silca gel column
chromatography (CHCl /MeOH = 10/1) gave 8 (93 mg, 9%) as a
A
(0.28 mmol scale): Silca gel column
A
3
25
3
a white solid of mp = 195–196 °C (CHCl /hexane) and [α]
3 D
1
25
colorless solid of mp = 181–183 °C (ethyl acetate) and [α]
–
D
+64.4 (c 0.07, CHCl ). H NMR (CDCl ): 2.16 (s, 6H), 2.29 (s,
3 3

6
Tetrahedron
ACCEPTED MANUSCRIPT
3
H), 2.54–2.62 (m, 1H), 3.14 (dd, J = 10.0, 14.0 Hz, 1H), 3.23–
To a suspension of chiral triazolium salt (0.05 mmol, 10
3
7
1
1
1
2
.31 (m, 3H), 3.35–3.41 (m, 1H), 5.35–5.37 (m, 1H), 6.91 (s, 2H),
.43–7.46 (m, 1H), 7.90 (d, J = 8.0 Hz, 1H), 7.95 (t, J = 8.0 Hz,
H), 8.44 (d, J = 4.8 Hz, 1H), 8.72 (s, 1H). C NMR (CDCl3):
9.8, 20.9, 21.4, 33.1, 33.4, 60.2, 113.9, 125.8, 128.4, 129.9,
36.0, 136.8, 137.6, 140.0, 147.3, 149.0, 162.7. IR (KBr): 3410,
mol%), aliphatic aldehyde 1 (0.75 mmol), aromatic aldehyde 2
(0.5 mmol) in 1,4-dioxane-hexamethylphosphoramide (HMPA)
(0.5 mL, 4/1), a suspension of KHMDS (0.05 mmol, 10 mol%) in
2-methylTHF (0.1 mL) was added dropwise at room temperature.
The reaction mixture was stirred at room temperature. After 24 h,
the whole was though silica gel and washed with ethyl acetate,
then, the solvent was removed in vacuo. The residue was purified
by silica gel column chromatography.
13
–1
940, 1600, 1470, 1420, 1380, 1200, 1060 cm . HRMS–DART
+
–
(m/z): Calcd for C H N [M
–
BF ]: 319.1923. Found:
20
23
4
4
3
19.1919.
12f
(S)-1-Hydroxy-1,4-diphenylbutan-2-one (3aa)
(
S)-2-(Pyridin-2-yl)-5-(2,4,6-triisopropylbenzyl)-6,7-dihydro-
Silica gel column chromatography (hexane/ethyl acetate = 10/1)
4
25
5
H-2λ -pyrrolo[2,1-c][1,2,4]triazole, tetrafluoroborate salt
13)
Method
chromatography (CHCl /MeOH = 10/1) gave 13 (56 mg, 5%) as
gave 3aa (83 mg, 69% yield) as a colorless oil of [α] +49.6 (c
D
16a
25
(
0.67, acetone) [lit . [α] –77.6 (c 1.5, acetone) for 85% ee, R-
D
A
(2.28 mmol scale): Silca gel column
isomer]. The ee was determined to be 65% by HPLC (Daicel
3
Chiralpac IB, hexane/i-PrOH = 50/1, 1.0 mL/min, 220 nm, major
25
1
a white solid of mp = 196–197 °C (CHCl /n-hexane) and [α]
+
18.3 min and minor 20.3 min). H NMR (CDCl ): 2.57–2.68 (m,
3
D
3
1
63.1 (c 0.12, CHCl ). H NMR (CDCl ): 1.04 (d, J = 6.4 Hz,
2H), 2.70–2.78 (m, 1H), 2.84–2.91 (m, 1H), 4.28 (brs, 1H), 5.02
3
3
1
3
3
=
(
H), 1.24 (d, J = 6.4 Hz, 3H), 1.27 (d, J = 5.2 Hz, 6H), 1.29 (d, J
5.2 Hz, 6H), 2.60–2.63 (m, 1H), 2.73–2.81 (m, 1H), 2.87–2.92
m, 1H), 3.12–3.18 (m, 2H), 3.20–3.46 (m, 4H), 5.21–5.24 (m,
(s, 1H), 7.03 (d, J = 7.2 Hz, 2H), 7.13–7.40 (m, 8H). C NMR
(CDCl ): 29.6, 39.5, 79.9, 126.3, 127.4, 128.1, 128.5, 128.7,
3
129.0, 137.7, 140.1, 208.6.
1
1
2
1
2
H), 7.05 (s, 2H), 7.40–7.44 (m, 1H), 7.86–7.96 (m, 2H), 8.23 (s,
13
H), 8.37 (d, J = 4.4 Hz, 1H). C NMR (CDCl ): 21.3, 23.7, 24.2,
(S)-1-Hydroxy-1-phenyl-4-(p-tolyl)butan-2-one (3ba)
3
4.4, 29.7, 31.2, 33.3, 34.3, 61.8, 113.9, 121.8, 125.8, 135.5,
40.0, 147.1, 147.1, 147.5, 148.8, 149.1, 162.7. IR (KBr): 3420,
Silica gel column chromatography (hexane/ethyl acetate = 5/1)
gave 3ba (83 mg, 66% yield) as a white solid of mp = 67–68 °C
–1
25
960, 1590, 1470, 1420, 1380, 1190, 1070 cm . HRMS–DART
and [α] +83.3 (c 0.70, CHCl ). The ee was determined to be
D
3
+
–
(m/z): Calcd for C H N [M
–
BF ]: 403.2862. Found:
56% by HPLC (Daicel Chiralpac IB x 2, hexane/i-PrOH = 50/1,
1.0 mL/min, 220 nm, major 37.4 min and minor 34.2 min). H
26
35
4
4
1
4
03.2867.
NMR (CDCl ): 2.21 (s, 3H), 2.48–2.66 (m, 3H), 2.67–2.79 (m,
3
(
R)-5-(Naphthalen-1-ylmethyl)-2-(pyridin-2-yl)-6,7-dihydro-
1H), 4.25 (d, J = 4.0 Hz, 1H), 4.95 (d, J = 4.0 Hz, 1H), 6.86 (d, J
4
13
5
(
H-2λ -pyrrolo[2,1-c][1,2,4]triazole, tetrafluoroborate salt
14)
Method
chromatography (CHCl /MeOH = 10/1) gave 14 (125 mg, 11%)
= 7.2 Hz, 2H), 6.97 (d, J = 7.2 Hz, 2H), 7.18–7.34 (m, 5H).
C
NMR (CDCl ): 20.9, 29.2, 39.6, 79.8, 127.3, 128.0, 128.6, 128.9,
3
B
(2.85 mmol scale): Silca gel column
129.1, 135.7, 137.0, 137.7, 208.7. IR (KBr): 3460, 2920, 1720,
–1
3
1520, 1450, 1360, 1190, 1060 cm . HRMS–DART (m/z): Calcd
25
+
as a white solid of mp = 198–199 °C (MeOH) and [α] +51.5 (c
0
for C H O [M+H] : 255.1385. Found: 255.1394.
D
17 19
2
1
.30, MeCN). H NMR (CDCl ): 2.57–2.66 (m, 1H), 2.98–3.08
3
(
5
(
m, 2H), 3.20–3.26 (m, 2H), 3.33 (dd, J = 7.2, 10.0 Hz, 1H),
.34–5.42 (m, 1H), 7.24–7.36 (m, 7H), 7.42–7.50 (m, 1H), 7.90
d, J = 7.6 Hz, 1H), 7.94 (td, J = 1.6, 8.0 Hz, 1H), 8.45 (d, J = 8.0
(S)-1-Hydroxy-4-(4-methoxyphenyl)-1-phenylbutan-2-one
(3ca)
Silica gel column chromatography (hexane/ethyl acetate = 5/1)
13
25
Hz, 1H), 9.64 (s, 1H). C NMR (MeCN-d ): 22.4, 34.2, 37.7,
gave 3ca (25 mg, 31% yield) as a colorless oil and [α] +74.2
3
D
4
1
1.3, 62.5, 115.0, 116.1, 120.0, 124.6, 126.9, 127.1, 127.5, 128.0,
29.2, 129.7, 130.3, 132.9, 137.6, 142.1, 148.7, 150.5, 164.6. IR
(c 0.77, CHCl ). The ee was determined to be 67% by HPLC
3
(Daicel Chiralpac IA, hexane/ethyl acetate = 20/1, 1.0 mL/min,
–1
1
(
KBr): 3420, 2960, 1590, 1460, 1420, 1380, 1190 cm . HRMS–
254 nm, major 54.8 min and minor 69.2 min). H NMR (CDCl ):
3
+
–
DART (m/z): Calcd for C H N [M – BF ]: 327.1610. Found:
3
2.51–2.71 (m, 3H), 2.78–2.82 (m, 1H), 3.74 (s, 3H), 4.29 (d, J =
4.0 Hz, 1H), 5.00 (d, J= 4.0 Hz, 1H), 6.75 (d, J = 8.8 Hz, 2H),
21
19
4
4
27.1609.
13
6
.93 (d, J = 8.8 Hz, 2H), 7.24–7.31 (m, 5H). C NMR (CDCl ):
3
(S)-5-(Naphthalen-2-ylmethyl)-2-(pyridin-2-yl)-6,7-dihydro-
28.7, 39.7, 55.1, 79.8, 113.8, 127.3, 128.6, 128.9, 129.0, 132.1,
137.7, 157.9, 208.6. IR (KBr): 3450, 2930, 1720, 1510, 1250,
4
5
H-2λ -pyrrolo[2,1-c][1,2,4]triazole, tetrafluoroborate salt
15)
Method
chromatography (CHCl /MeOH = 10/1) gave 9 (100 mg, 37%) as
–1
+
(
1040 cm . HRMS–DART (m/z): Calcd for C H O [M+H] :
17 19 3
B
(0.66 mmol scale): Silca gel column
271.1334. Found: 271.1332.
3
25
12f
a white solid of mp = 217–218 °C (CHCl /MeOH) and [α]
–
(S)-1-Hydroxy-1-phenylbutan-2-one (3da)
3
D
1
2
3
1
0.0 (c 0.12, CHCl ). H NMR (MeCN-d ): 2.76–2.84 (m, 1H),
Silica gel column chromatography (hexane/ethyl acetate = 10/1)
3
3
25
.01–3.08 (m, 1H), 3.29–3.31 (m, 2H), 3.47 (dd, J = 8.0, 14.4 Hz,
H), 3.64 (dd, J = 6.8, 14.4 Hz, 1H), 5.23–5.30 (m, 1H), 7.58 (dd,
gave 3da (19 mg, 23% yield) as a pale yellow oil and [α]
D
1
6b
25
+
153.4 (c 0.05, CHCl ) [lit . [α] –301.4 (c 1.5, CHCl ) for
3 D 3
J = 2.0, 8.8 Hz, 1H), 7.64–7.67 (m, 2H), 7.69–7.73 (m, 2H), 7.92
9
1% ee, R-isomer]. The ee was determined to be 60% by HPLC
(s, 1H), 7.96–7.99 (m, 1H), 8.03–8.08 (m, 2H), 8.21–8.25 (m,
(
Daicel Chiralpac IB, hexane/i-PrOH = 50/1, 1.0 mL/min, 220
13
1
1
3
1
3
H), 8.61–8.62 (m, 1H), 9.77 (s, 1H). C NMR (MeCN-d ): 22.5,
3
nm, major 10.7 min and minor 12.5 min). H NMR (CDCl ): 0.93
3
3.9, 40.8, 63.3, 115.1, 127.5, 127.6, 127.9, 128.5, 129.0, 129.1,
29.6, 130.2, 134.0, 134.4, 137.5, 142.1, 150.6, 164.7. IR (KBr):
(
1
1
t, J = 7.6 Hz, 3H), 2.21–2.38 (m, 2H), 4.28 (brs, 1H), 5.03 (s,
13
H), 7.24–7.33 (m, 5H). C NMR (CDCl ): 7.6, 31.2, 79.4, 128.7,
3
–1
420, 3140, 1590, 1500, 1470, 1420, 1370, 1190, 1060 cm .
29.0, 138.3, 210.1.
+
–
HRMS–DART (m/z): Calcd for C H N [M – BF ]: 327.1610.
Found: 327.1602.
21
19
4
4
12f
(S)-1-Hydroxy-1-phenylnonan-2-one (3ea)
Silica gel column chromatography (hexane/ethyl acetate = 10/1)
2
5
General procedure for the catalytic asymmetric cross-
benzoin condensation reactions
gave 3ea (64 mg, 55% yield) as a colorless oil and [α] +119.0
D
(
c 0.35, CHCl ). The ee was determined to be 59% by HPLC
3

7
(
Daicel Chiralpac IC, hexane/i-PrOH = 50/1, 1.0 mL/min, 220
Silica gel column chromatography (hexane/ethyl acetate =
10/1) gave 3ae (66 mg, 50% yield) as a colorless oil and [α]
ACCEPTED MANUSCRIPT
1
25
D
nm, major 16.2 min and minor 15.2 min). H NMR (CDCl ): 0.77
3
(
2
t, J = 7.2 Hz, 3H), 1.04–1.19 (m, 8H), 1.37–1.46 (m, 2H), 2.18–
.33 (m, 2H), 4.32 (brs, 1H), 5.01 (s, 1H), 7.14–7.33 (m, 5H). C
+48.0 (c 0.08, CHCl ). The ee was determined to be 39% by
3
13
HPLC (Daicel Chiralpac ID, hexane/i-PrOH = 10/1, 1.0 mL/min,
1
NMR (CDCl ): 14.0, 22.5, 23.6, 28.8, 28.9, 31.5, 37.6, 79.6,
220 nm, major 21.4 min and minor 19.9 min). H NMR (CDCl ):
3
3
1
27.4, 128.6, 128.9, 138.1, 209.7.
2.52–2.66 (m, 2H), 2.74–2.87 (m, 2H), 4.26 (d, J = 4.0 Hz, 1H),
4
7
1
.92 (d, J = 4.0 Hz, 1H), 6.98 (d, J = 6.8 Hz, 2H), 7.06–7.23 (m,
13
H). C NMR (CDCl ): 29.5, 39.5, 79.1, 125.5, 126.4, 127.5,
3
28.1, 128.5, 128.9, 130.2, 134.9, 139.6, 139.9, 207.8.
12f
(S)-1-Hydroxy-4-methyl-1-phenylpentan-2-one (3fa)
(S)-1-(4-Chlorophenyl)-1-hydroxy-4-phenylbutan-2-one (3af)
Silica gel column chromatography (hexane/ethyl acetate = 5/1)
Silica gel column chromatography (hexane/ethyl acetate = 10/1)
25
25
gave 3ea (23 mg, 24% yield) as a colorless oil and [α] +69.3
gave 3af (60 mg, 43% yield) as a colorless oil and [α] +82.6 (c
D
D
(
c 0.11, CHCl ). The ee was determined to be 17% by HPLC
0.32, CHCl ). The ee was determined to be 69% by HPLC
3
3
(
Daicel Chiralpac IC, hexane/i-PrOH = 50/1, 1.0 mL/min, 220
(Daicel Chiralpac IC, hexane/i-PrOH = 10/1, 1.0 mL/min, 230
1
1
nm, major 32.8 min and minor 31.5 min). H NMR (CDCl ): 0.67
nm, major 22.7 min and minor 19.5 min). H NMR (CDCl ):
3
3
(
d, J = 6.4 Hz, 3H), 0.80 (d, J = 6.4 Hz, 3H), 1.97–2.23 (m, 3H),
2.50–2.60 (m, 2H), 2.69–2.84 (m, 2H), 4.22 (brs, 1H), 4.92 (s,
1H), 6.96 (d, J = 6.8 Hz, 2H), 7.09–7.27 (m, 7H). C NMR
1
3
4
5
1
.32 (d, J = 4.4 Hz, 1H), 4.97 (d, J = 4.4 Hz, 1H), 7.22–7.31 (m,
13
H).
C NMR (CDCl ): 22.2, 22.5, 24.6, 46.7, 80.0, 127.5,
(CDCl ): 29.6, 39.4, 79.2, 126.3, 128.1, 128.5, 128.7, 129.2,
3
3
28.6, 128.9, 137.9, 209.1.
134.6, 136.2, 140.0, 208.0. IR (neat): 3450, 2930, 1720, 1590,
–
1
1
490, 1460, 1400, 1190, 1090 cm . HRMS–DART (m/z): Calcd
+
(S)-1-Hydroxy-1-(naphthalen-1-yl)-4-phenylbutan-2-one
for C H ClO [M+H] : 275.0839. Found: 275.0847.
16 16 4
(3ab)
Silica gel column chromatography (hexane/ethyl acetate = 10/1)
1(2Sf)-1-(2-Bromophenyl)-1-hydroxy-4-phenylbutan-2-one (3ag)
25
gave 3ab (36 mg, 28% yield) as a colorless oil and [α] +54.5
D
(
c 0.30, CHCl ). The ee was determined to be 64% by HPLC
Silica gel column chromatography (hexane/ethyl acetate = 10/1)
3
2
5
(Daicel Chiralpac ID, hexane/i-PrOH = 50/1, 1.0 mL/min, 254
gave 3ag (47 mg, 30% yield) as a colorless oil and [α] +52.0
D
1
nm, major 37.5 min and minor 34.2 min). H NMR (CDCl ):
(c 0.08, CHCl ). The ee was determined to be 64% by HPLC
3
3
2
4
7
7
7
1
3
.42–2.52 (m, 1H), 2.64–2.79 (m, 2H), 2.84–2.92 (m, 1H), 4.36–
.39 (m, 1H), 5.53 (d, J = 2.4 Hz, 1H), 6.97 (d, J = 7.2 Hz, 2H),
.16–7.28 (m, 3H), 7.40–7.45 (m, 2H), 7.48–7.52 (m, 2H), 7.83–
(Daicel Chiralpac IB, hexane/i-PrOH = 10/1, 1.0 mL/min, 240
1
nm, major 25.0 min and minor 31.6 min). H NMR (CDCl ):
3
2.53–2.61 (m, 1H), 2.72–2.88 (m, 3H), 4.33 (d, J = 4.0 Hz, 1H),
5.50 (d, J = 4.0 Hz, 1H), 7.00 (d, J = 7.2 Hz, 2H), 7.06–7.21 (m,
13
.90 (m, 2H), 7.94–7.97 (m, 1H). C NMR (CDCl ): 29.7, 39.5,
3
13
9.1, 123.4, 125.3, 126.0, 126.2, 126.9, 127.8, 128.1, 128.4,
29.0, 129.7, 131.0, 133.1, 134.2, 140.0, 209.8. IR (KBr): 3450,
6H), 7.52 (dd, J = 1.6, 8.0 Hz, 1H). C NMR (CDCl ): 29.6, 39.5,
3
78.3, 123.7, 126.3, 128.2, 128.4, 129.1, 130.2, 133.4, 137.1,
140.0, 207.9.
–1
030, 1710, 1600, 1510, 1500, 1450, 1350, 1170, 1050 cm .
+
HRMS–DART (m/z): Calcd for C H O [M+H] : 291.1385.
20
19
2
Found: 291.1396.
(S)-1-(4-Bromophenyl)-1-hydroxy-4-phenylbutan-2-one (3ah)
Silica gel column chromatography (hexane/ethyl acetate = 10/1)
2
5
(
S)-1-Hydroxy-1-(naphthalen-1-yl)-4-phenylbutan-2-one
gave 3ah (68 mg, 46% yield) as a colorless oil and [α] +19.0
D
(3ac)
(c 0.16, CHCl ). The ee was determined to be 77% by HPLC
3
Silica gel column chromatography (hexane/ethyl acetate = 5/1)
gave 3ac (111 mg, 76% yield) as a pale yellow oil and [α]
(Daicel Chiralpac IC, hexane/i-PrOH = 10/1, 1.0 mL/min, 220
25
1
D
nm, major 21.1 min and minor 18.8 min). H NMR (CDCl ):
3
+
84.5 (c 0.52, CHCl ). The ee was determined to be 67% by
2.51–2.60 (m, 2H), 2.71–2.84 (m, 2H), 4.23 (brs, 1H), 4.91 (s,
3
HPLC (Daicel Chiralpac ID, hexane/i-PrOH = 10/1, 1.0 mL/min,
1H), 6.95 (d, J = 6.8 Hz, 2H), 7.05 (d, J = 8.4 Hz, 2H), 7.09–7.24
1
13
2
2
1
2
1
1
1
54 nm, major 36.2 min and minor 30.0 min). H NMR (CDCl ):
(m, 3H), 7.39 (d, J = 8.4 Hz, 2H). C NMR (CDCl ): 29.6, 39.4,
3
3
.57–2.97 (m, 4H), 4.45 (d, J = 4.0 Hz, 1H), 5.20 (d, J = 4.0 Hz,
H), 7.01 (d, J = 6.8 Hz, 2H), 7.11–7.34 (m, 3H), 7.48–7.52 (m,
79.2, 122.8, 126.4, 128.1, 128.5, 128.9, 132.1, 136.7, 139.9,
–
1
207.9. IR (neat): 3450, 2910, 1720, 1560, 1510, 1490, 1070 cm .
13
+
H), 7.78–7.89 (m, 5H). C NMR (CDCl ): 29.5, 39.5, 79.9,
HRMS–DART (m/z): Calcd for C H BrO [M+H] : 319.0334.
3
16 15
2
24.2, 126.2, 126.5, 127.2, 127.7, 128.0, 128.1, 128.3, 128.4,
29.0, 133.2, 133.3, 135.1, 140.0, 208.6. IR (neat): 3450, 2930,
Found: 319.0333.
–1
720, 1600, 1560, 1360 cm . HRMS–DART (m/z): Calcd for
1M2fethyl (S)-4-(1-hydroxy-2-oxo-4-phenylbutyl)benzoate (3ai)
+
C H O [M+H] : 291.1385. Found: 291.1396.
20
19
2
Silica gel column chromatography (hexane/ethyl acetate = 5/1)
2
5
(
2Sc)-1-(2-Chlorophenyl)-1-hydroxy-4-phenylbutan-2-one (3ad)
gave 3ai (59 mg, 40% yield) as a pale yellow oil and [α] +30.6
D
1
(
c 0.31, CHCl ). The ee was determined to be 43% by HPLC
3
Silica gel column chromatography (hexane/ethyl acetate = 10/1)
gave 3ad (51 mg, 41% yield) as a pale yellow oil and [α]
(Daicel Chiralpac IB x 2, hexane/i-PrOH = 10/1, 1.0 mL/min,
25
D
1
230 nm, major 82.0 min and minor 77.7 min). H NMR (CDCl ):
3
+
26.8 (c 0.14, CHCl ). The ee was determined to be 69% by
2.52–2.80 (m, 4H), 3.82 (s, 3H), 4.31 (brs, 1H), 5.00 (s, 1H), 6.94
3
HPLC (Daicel Chiralpac IB, hexane/i-PrOH = 10/1, 1.0 mL/min,
(d, J = 6.4 Hz, 2H), 7.09–7.18 (m, 3H), 7.26 (d, J = 8.4 Hz, 2H),
1
13
2
2
1
2
1
20 nm, major 11.5 min and minor 13.7 min). H NMR (CDCl ):
.51–2.59 (m, 1H), 2.66–2.89 (m, 3H), 4.32 (brs, 1H), 5.47 (s,
7.94 (d, J = 8.4 Hz, 2H). C NMR (CDCl ): 29.5, 39.5, 52.2,
3
3
79.5, 126.3, 127.3, 128.1, 128.3, 128.5, 130.2, 139.9, 142.5,
166.5, 207.7.
H), 6.98 (d, J = 7.2 Hz, 2H), 7.08–7.18 (m, 5H), 7.29–7.33 (m,
13
H). C NMR (CDCl ): 29.6, 39.4, 76.2, 126.2, 127.5, 128.1,
3
28.5, 129.1, 129.9, 130.0, 133.4, 135.5, 140.0, 207.9.
(S)-1-Hydroxy-1-(2-methoxyphenyl)-4-phenylbutan-2-one
12f
(3aj)
(
2Sc)-1-(3-Chlorophenyl)-1-hydroxy-4-phenylbutan-2-one (3ae)
Silica gel column chromatography (hexane/ethyl acetate = 5/1)
1
25
gave 3ai (52 mg, 39% yield) as a pale yellow oil and [α] +91.5
D

8
Tetrahedron
(
c 0.20, CHCl ). The ee was determined to be 69% by HPLC
3.6 Hz, 1H), 4.91 (d, J = 3.6 Hz, 1H), 6.80 (d, J = 8.4 Hz, 2H),
3
ACCEPTED MANUSCRIPT
13
(Daicel Chiralpac IB, hexane/ethyl acetate = 20/1, 1.0 mL/min,
6.97 (d, J = 8.4 Hz, 2H), 7.07–7.20 (m, 5H). C NMR (CDCl ):
3
1
2
2
1
1
54 nm, major 38.3 min and minor 41.0 min). H NMR (CDCl ):
.50–2.67 (m, 2H), 2.70–2.86 (m, 2H), 3.71 (s, 3H), 4.14 (brs,
H), 5.25 (s, 1H), 6.81 (d, J = 8.4 Hz, 1H), 6.87 (t, J = 8.4 Hz,
H), 6.99 (d, J = 7.2 Hz, 2H), 7.04–7.42 (m, 5H). C NMR
29.7, 39.4, 55.3, 79.3, 114.4, 126.2, 128.1, 128.5, 126.7, 129.8,
140.2, 159.9, 208.9.
3
13
(S)-1-Hydroxy-4-phenyl-1-(m-tolyl)butan-2-one (3an)
(
1
CDCl ): 29.7, 39.1, 55.4, 75.1, 111.1, 121.1, 126.1, 126.3, 128.1,
28.4, 129.0, 129.3, 130.0, 140.0, 156.8, 208.9.
Silica gel column chromatography (hexane/ethyl acetate = 10/1)
3
2
5
gave 3an (59 mg, 46% yield) as a colorless oil and [α] +69.8
D
(
c 0.14, CHCl ). The ee was determined to be 70% by HPLC
3
(
(
S)-1-Hydroxy-1-(3-methoxyphenyl)-4-phenylbutan-2-one
3ak)
(Daicel Chiralpac IB, hexane/ i-PrOH = 50/1, 1.0 mL/min, 230
nm, major 15.0 min and minor 18.2 min). H NMR (CDCl ): 2.25
12f
1
3
Silica gel column chromatography (hexane/ethyl acetate = 5/1)
(s, 3H), 2.55–2.89 (m, 4H), 4.21 (d, J = 3.6 Hz, 1H), 4.92 (d, J =
25
13
gave 3ak (89 mg, 66% yield) as a pale yellow oil and [α]
3.6 Hz, 1H), 6.96–7.18 (m, 9H). C NMR (CDCl ): 21.4, 29.6,
D
3
+
58.7 (c 0.20, CHCl ). The ee was determined to be 68% by
39.4, 79.8, 124.6, 126.3, 127.9, 128.2, 128.5, 128.8, 129.5, 137.7,
138.8, 140.2, 208.7. IR (neat): 3420, 2910, 1720, 1510, 1380,
3
HPLC (Daicel Chiralpac IB, hexane/ethyl acetate = 20/1, 1.0
mL/min, 254 nm, major 47.3 min and minor 51.3 min). H NMR
1
–1
+
1060 cm . HRMS–DART (m/z): Calcd for C H O [M+H] :
17 19 2
(
CDCl ): 2.66–2.70 (m, 2H), 2.72–2.92 (m, 2H), 3.77 (s, 3H),
255.1385. Found: 255.1383.
3
5
2
.00 (s, 1H), 6.77 (t, J = 2.4 Hz, 1H), 6.85 (dd, J = 2.4, 8.0 Hz,
H), 7.04 (d, J = 6.8 Hz, 2H), 7.14–7.31 (m, 4H). OH proton was
1
2f
(S)-1-Hydroxy-4-phenyl-1-(p-tolyl)butan-2-one (3ao)
Silica gel column chromatography (hexane/ethyl acetate = 10/1)
13
not appeared clearly. C NMR (CDCl ): 29.5, 39.2, 55.1, 79.7,
1
1
3
2
5
12.5, 114.3, 119.8, 126.2, 128.1, 128.2, 128.4, 129.9, 139.2,
40.0, 159.9, 208.4.
gave 3an (66 mg, 52% yield) as a colorless oil and [α] +72.6
D
(c 0.58, CHCl ). The ee was determined to be 64% by HPLC
3
(
Daicel Chiralpac IB, hexane/ i-PrOH = 50/1, 1.0 mL/min, 254
1
(
S)-1-Hydroxy-1-(4-methoxyphenyl)-4-phenylbutan-2-one
nm, major 40.0 min and minor 31.4 min). H NMR (CDCl ): 2.35
3
12f
(3al)
(s, 3H), 2.63–2.99 (m, 4H), 4.30 (brs, 1H), 5.01 (s, 1H), 7.06 (d,
13
Silica gel column chromatography (hexane/ethyl acetate = 5/1)
J = 8.0 Hz, 2H), 7.16–6.30 (m, 7H). C NMR (CDCl ): 21.1,
3
25
gave 3al (26 mg, 19% yield) as a pale yellow oil and [α] +74.2
29.6, 39.3, 79.6, 126.2, 127.3, 128.1, 128.4, 129.6, 134.8, 138.5,
140.1,208
D
(
c 0.17, CHCl ). The ee was determined to be 64% by HPLC
3
(
Daicel Chiralpac IB, hexane/ i-PrOH = 50/1, 1.0 mL/min, 254
1
nm, major 49.4 min and minor 51.6 min). H NMR (CDCl ):
3
2
.49–2.59 (m, 2H), 2.67–2.84 (m, 2H), 3.71 (s, 3H), 4.17 (d, J =

9
ACCEPTED MANUSCRIPT
Supplementary Material
Acknowledgments
1
13
This work was supported by a Grant-in-Aid for Young
Scientists (B) (24750037), a Grant-in-Aid for Scientific Research
A Supplementary Data file ( H and C NMR) of newly
synthesized chiral triazolium salts (7–15) and chiral lactams (16–
(B) from the Japan Society for the Promotion of Science
24350022), the Kanazawa University CHOZEN Project, and the
1
8) is available online.
(
Kanazawa University SAKIGAKE Project.
References and notes
1
1
(a) Hachisu, Y.; Bode, J. W.; Suzuki, K. J. Am. Chem. Soc. 2003,
25, 8432–8433. (b) Takikawa, H.; Hachisu, Y.; Bode, J. W.;
1
Suzuki, K. Angew. Chem., Int. Ed. 2006, 45, 3492–3494. (c) Jia,
M.-Q.; You, S.-L. ACS Catal. 2013, 3, 622–624. (d) Ema, T.;
Namjo, Y.; Shiratori, S.; Terao, Y.; Kumura, R. Org. Lett. 2016,
18, 5764–5767.
1
(a) Ukai, T.; Tanaka, R.; Dokawa, S. J. Pharm. Soc. Jpn. 1943, 63,
96–300. Recent reviews: (b) Johnson, J. S. Angew. Chem., Int.
Ed. 2004, 43, 1326–1328. (c) Christmann, M. Angew. Chem., Int.
Ed. 2005, 44, 2632–2634. (d) Zeitler, K. Angew. Chem., Int. Ed.
2
12 (a) Piel, I.; Pawalczyk, M. D.; Hirano, K.; Frölich, R.; Glorius, F.
Eur. J. Org. Chem. 2011, 5475–5484. (b) Rose, C. A.; Gundala,
S.; Connon, S. J.; Zeitler, K. Synthesis 2011, 190–198. (c)
O’Toole, S. E.; Rose, C. A.; Gundala, S.; Zeitler, K.; Connon, S. J.
J. Org. Chem. 2011, 76, 347–357. (d) Jin, M. Y.; Kim, S. M.; Han,
H.; Ryu, D. H.; Yang, J. W. Org. Lett. 2011, 13, 880–883. (e) Jin,
M. Y.; Kim, S. M.; Mao, H.; Ryu, D. H.; Song, C. E.; Yang, J. W.
Org. Biomol. Chem. 2014, 12, 1547–1550. (f) Langdon, S. M.;
Wilde, M. M. D.; Thai, K.; Gravel, M. J. Am. Chem. Soc. 2014,
136, 7539–7542. (g) Langdon, S. M.; Legault, C. Y.; Gravel, M. J.
Org. Chem. 2015, 80, 3597–3610.
2
005, 44, 7506–7510. (e) Marion, N.; Díez-González, S.; Nolan,
S. P. Angew. Chem., Int. Ed. 2007, 46, 2988–3000. (f) Enders, D.;
Niemeier, O.; Henseler, A. Chem. Rev. 2007, 107, 5606–5665. (g)
Zeitler, K. Ernst Schering Found. Symp. Proc. 2007, 2, 183–206.
Breslow, R. J. Am. Chem. Soc. 1958, 80, 3719–3726. Benzoin
condensation was discovered by Liebig. See, Wöhler, F.; Liebig,
J. Ann. Pharm. 1832, 3, 249–282.
(a) Igau, A.; Grutzmacher, H.; Baceiredo, A.; Bertrand, G. J. Am.
Chem. Soc. 1988, 110, 6463–6466. (b) Arduengo, A. J., III;
Harlow, R. L.; Kline, M. J. Am. Chem. Soc. 1991, 113, 361–363.
2
3
(
c) Enders, D.; Breuer, K.; Raabe, G.; Runsink, J.; Teles, J. H.;
Melder, J.-P.; Ebel, K.; Brode, S. Angew. Chem., Int. Ed. Engl.
995, 34, 1021–1023.
(a) Sheehan, J. C; Hunnemann, D. H. J. Am. Chem. Soc. 1966, 88,
666–3667; (b) Sheehan, J. C; Hara, T. J. Org. Chem. 1974, 39,
196–1199.
13 (a) Haghshenas, P.; Gravel, M. Org. Lett. 2016, 18, 4518–4521.
(b) Haghshenas, P.; Quail, J. W.; Gravel, M. J. Org. Chem. 2016,
81, 12075–12083. (c) He, H.-X.; Yang, L.: Huang, W.; Zhao, Q.;
Pan, X.-L.; Jiang, D.-F.; Yang, M.-C.; Peng, C.; Han, B. RSC Adv.
2016, 6, 28960–28965. (d) Shirke, R. P.; Reddy, V. Anand, R. V.;
Ramasastry, S. S. V. Synthesis 2016, 48, 1865–1871.
14 (a) Soeta, T.; Tabatake, Y.; Inomata, K.; Ukaji, Y. Tetrahedron
2012, 68, 894–899. (b) Soeta, T.; Tabatake, Y.; Ukaji, Y.
Tetrahedron 2012, 68, 10188–10983.
1
4
5
3
1
Recent reviews: (a) Enders, D.; Balensiefer, T. Acc. Chem. Res.
004, 37, 534−541. (b) Enders, D.; Niemeier, O.; Henseler, A.
2
Chem. Rev. 2007, 107, 5606−5655. (c) Marion, N.; Díez-
González, S.; Nolan, S. P. Angew. Chem. Int. Ed. 2007, 46,
2
15 Enders, D.; Han, J. Tetrahedron: Asymmetry 2008, 19, 1367–
1371.
988−3000. (d) Rovis, T. Chem. Lett. 2008, 37, 2−7. (e) Read de
Alaniz, J.; Rovis, T. Synlett 2009, 1189−1207. (f) Biju, A. T.;
Kuhl, N.; Glorius, F. Acc. Chem. Res. 2011, 44, 1182−1195. (g)
Hopkinson, M. N.; Richter, C.; Schedler, M.; Glorius, F. Nature
16 (a) Chen, C.-T.; Kao, J.-Q.; Salunke, S. B.; Lin, Y.-H. Org. Lett.
2011, 13, 26–29. (b) Conceição, G. J. A.; Moran, P. J. S.;
Rodrigues, J. A. R. Tetrahedron: Asymmetry 2003, 14, 43–45.
17 Kawada, H.; Ikoma, A.; Ogawa, N,; Kobayashi, Y. J. Org. Chem.
2015, 80, 9192–9199.
18 Ghosh, A. K.; Leshchenko–Yashchuk, S.; Anderson, D. D.;
Baldridge, A.; Noetzel, M.; Miller, H. B.; Tie, Y.; Wang, Y.-F.;
Koh, Y.; Weber, I. T.; Mitsuya, H. J. Med. Chem. 2009, 52, 3902–
3914.
2
014, 510, 485−496. (h) Flanigan, D. M.; Romanov-Michailidis,
F.; White, N. A.; Rovis, T. Chem. Rev. 2015, 115, 9307−9387.
Stetter, H.; Dämbkes, G. Synthesis 1977, 403–404.
(a) Castells, J.; López-Calahorra, F.; Bassedas, M.; Urrios, P.
Synthesis 1988, 314–315. (b) Murry, J. A.; Frantz, D. E.; Soheili,
A.; Tillyer, R.; Grabowski, E. J. J.; Reider, P. J. J. Am. Chem. Soc.
6
7
2
001, 123, 9696–9697. (c) Frantz, D. E.; Morency, L.; Soheili, A.;
19 Zheng, P.; Gondo, C. A.; Bode, J. W. Chem. Asian J. 2011, 6,
614–620.
Murry, J. A.; Grabowski, E. J. J.; Tillyer, R. D. Org. Lett. 2004, 6,
8
4
2
2
43–846. (d) Mattson, A. E.; Scheidt, K. A. Org. Lett. 2004, 6,
363–4366. (e) Li, G.-Q.; Dai, L.-X.; You, S.-L. Chem. Commun.
007, 852–854. (f) Enders, D.; Henseler, A.; Lowins, S. Synthesis
009, 4125–4128. (g) DiRocco, D. A.; Rovis, T. Angew. Chem.,
Int. Ed. 2012, 51, 5904–5906. (h) DiRocco, D. A.; Rovis, T. J.
Am. Chem. Soc. 2012, 134, 8094–8097. (i) Ueno, T.; Kobayashi,
Y.; Takemoto, Y. Beilstein J. Org. Chem. 2012, 8, 1499–1504.
Mennen, S. M.; Gipson, J. D.; Kim, Y. R.; Miller, S. J. J. Am.
Chem. Soc. 2005, 127, 1654–1655.
(a) Demir, A. S.; Reis, Ö.; İǧdir, Ç, A.; Esiringü, İ.; Eymur, S. J.
Org. Chem. 2005, 70, 10584–10587. (b) Tarr, J. C.; Johnson, J. S.
Org. Lett. 2009, 11, 3870–3873.
8
9
1
0
(a) Enders, D.; Henseler, A. Adv. Synth. Catal. 2009, 351, 1749–
1
752. (b) Enders, D.; Grossmann, A.; Fronert, J.; Raabe, G. Chem.
Commun. 2010, 46, 6282–6284. (d) Rose, C. A.; Gundala, S.;
Fagan, C.-L.; Franz, J. F.; Connon, S. J.; Zeitler, K. Chem. Sci.
2
012, 3, 735–740. (e) Thai, K.; Langdon, S. M.; Bilodeau, F.;
Gravel, M. Org. Lett. 2013, 15, 2214–2217.