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

Article abstract of DOI:10.1016/j.tet.2011.11.028

Chiral triazolium salts bearing a pyridine ring were developed as N-heterocyclic carbene precursors. In the presence of the chiral triazolium salt and a base, the catalytic asymmetric benzoin condensation proceeded to afford the product in high level of chemical yield and enantioselectivity. A wide range of aromatic aldehydes were applicable to this reaction.

Full text of DOI:10.1016/j.tet.2011.11.028

Tetrahedron 68 (2012) 894e899
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Asymmetric benzoin condensation promoted by chiral triazolium precatalyst
bearing a pyridine moiety
*
*
Takahiro Soeta , Yuhta Tabatake, Katsuhiko Inomata, Yutaka Ukaji
Division of Material Sciences, Graduate School of Natural Science and Technology, Kanazawa University, Kakuma, Kanazawa 920-1192, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Chiral triazolium salts bearing a pyridine ring were developed as N-heterocyclic carbene precursors. In
the presence of the chiral triazolium salt and a base, the catalytic asymmetric benzoin condensation
proceeded to afford the product in high level of chemical yield and enantioselectivity. A wide range of
aromatic aldehydes were applicable to this reaction.
Received 15 September 2011
Received in revised form 5 November 2011
Accepted 8 November 2011
Available online 13 November 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
N-Heterocyclic carbene
Catalytic asymmetric reaction
Benzoin condensation
1. Introduction
previous literature of the asymmetric benzoin condensations,
chemical yield, and enantioselectivity of the product were highly
The broad application of N-heterocyclic carbenes (NHCs) in or-
ganic synthesis has been dramatically demonstrated since Ber-
trand, Arduengo and co-workers reported the first stable
nucleophilic carbene around 1990.1,2 Ukai and co-workers reported
in 1943 that co-factor thiamine (vitamin B1) catalyzed the benzoin
condensation.2a The mechanism of the thiazolium catalyzed ben-
zoin condensation was elucidated by Breslow in 1958.3 The first
catalytic asymmetric benzoin condensation reaction was de-
veloped by Sheehan and Hunnemann in 1966, however, the
enantioselectivity was low.4a Although they reported that the sec-
ond generation thiazolium salt promoted benzoin condensations of
benzaldehyde more selectively, the product was obtained in only
6% yield with 52% ee.4b Even though several groups later attempted
to improve the performance through the design of mono- and bi-
cyclic thiazolium salt derivatives,5 stereoselectivities of the prod-
ucts were lower than that reported by Sheehan. Enders achieved
the dramatic improvement in 1996, which was the first design of
chiral triazolium precatalyst for the benzoin condensation, giving
the product up to 86% ee.6a Leeper also reported a bicyclic carbene
catalyst by synthesizing the chiral triazolium salt.7 Enders made
improvements through a design of conformationally restricted
triazolium salts in 2002.6b Furthermore, they reported the de-
velopment of the pyroglutamic acid-derived precatalyst, which
gave the product in 66% yield with 95% ee in 2008.6c As shown in
dependent on the steric and electronic characteristics of the aro-
matic aldehydes used, that is, aromatic aldehydes bearing electron-
withdrawing group afforded the products in high chemical yield
but with low enantioselectivity. On the other hand, aromatic al-
dehydes bearing electron-donating group showed low reactivity
but realized high enantioselectivity. Very recently, hydrogen bond-
donating carbene catalysts have been developed by Connon and
were applied to benzoin condensation.8 Although a number of
enantioselective variants of the benzoin condensation have been
reported, this reaction remains as a good model to test newly de-
veloped NHC catalysts. To the best of our knowledge, no example of
chiral triazolium precatalyst bearing a pyridine ring has ever been
reported in the literatures.9
2. Results and discussions
In the NHC catalyzed asymmetric benzoin condensation, it was
elucidated that conformational control of the key intermediate, so
called the Breslow intermediate, is significant to obtain the product
with high enantioselectivity.6,7 Thus, we expected that if the chiral
triazolium salt possesses a Lewis basic moiety, OH group of the
Breslow intermediate could make intramolecular hydrogen bond
with the Lewis base affording more rigid intermediate for the
benzoin condensation giving the product with higher stereo-
selectivity (Scheme 1).2f,10 We therefore designed and synthesized
a various kinds of chiral triazolium salts bearing a pyridine ring
(Fig. 1). Our initial attempt of benzoin condensation of
* Corresponding authors. Tel.: þ81 76 264 5732; fax: þ81 76 264 5742; e-mail
address: soeta@se.kanazawa-u.ac.jp (T. Soeta).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.11.028

T. Soeta et al. / Tetrahedron 68 (2012) 894e899
895
Table 2
benzaldehyde (1a) was performed using 10 mol % of triazolium salt
3 and potassium tert-butoxide
Effect of base and additives for the catalytic asymmetric benzoin condensation
O
3 (10 mol%)
O
base (10 mol%)
H
1,4-dioxane (1.4 M), rt
OH
2a
1a
Entry
Base
Additive
Time (h)
Yield (%)
ee (%)
1
2
3
4
5
6
7
8
9
10
n-BuLi
t-BuLi
LHMDS
NaOt-Bu
KOt-Bu
KHMDS
Cs2CO3
DBU
d
d
15
15
16
16
14
22
15
15
22
15
nr
nr
d
d
d
18
42
87
75
38
46
78
87
27
69
65
65
69
54
56
71
Scheme 1. Working hypothesis.
d
d
d
Bn Bn
d
N
N
BF4
N
N
BF4
N
d
KBra
BF4
N
N
N
N
N
N
KOt-Bu
KOt-Bu
N
HMPAb
Ph
Ph
Ph
N
Ph
Ph
a
3
4
5
KBr (100 mol %) was added.
HMPA (50 mol %) was used.
Ph
b
BF4
N
N
N
N
N
N
BF4
N
BF4
N
N
N
N
2-Tol
2-Tol
Ph
Ph
Ph
Ph
N
afforded the product with moderate yield and enantioselectivity
(entry 8). From these results, KOt-Bu proved to be a base of choice
for this reaction system (entry 5). To assess the effect of potassium
cation that comes from the base, some additives were examined.
When 100 mol % of KBr was added to the reaction, the yield and
enantioselectivity were decreased to give the product in 78% yield
with 56% ee (entry 9). The use of 50 mol % HMPA coordinatable to
the potassium cation improved the enantioselectivity to 71% ee
(entry 10).
7
8
6
OH
OTMS
PF6
N
Cl
Br
N
N
N
N
N
N
N
N
Ph
Ph
Ph
Ph
Ph
Ph
N
N
OTMS
OTMS
OTMS
9
10
11
Fig. 1. Chiral triazolium salts bearing a pyridine ring.
(KOt-Bu) as a base to generate a carbene catalyst in toluene, and the
corresponding benzoin 2a was obtained in 10% yield with 34% ee in
the preference of (R)-enantiomer after 19 h (Table 1, entry 1). In the
case of dichloromethane or diethyl ether was used as a solvent, the
reaction proceeded more efficiently to afford the product 2a in 80%
and 99% yields, respectively. However, enantioselectivity was still
low (43% ee, 18% ee) (entries 2 and 3). Remarkable improvement of
the enantioselectivity was observed when cyclic ether, such as THF
or 1,4-dioxane was used to furnish 2a with 51% ee and 65% ee, re-
spectively (entries 4 and 5). Polar solvents (DMF and DMSO) were
also effective in this reaction, giving the product with moderate
enantioselectivity (entries 6 and 7).
We turned our attention to the structure of chiral triazolium
salts (Table 3). Introduction of a methyl group onto the C6-position
of the pyridine ring (4), dibenzyl group onto the pyrrolidine ring
(5), and replacement of the phenyl groups in 3 to 2-tolyl groups (6)
lowered the enantioselectivity (entries 2e4). We found that cata-
lytic efficiency of chiral triazolium salt is highly dependent on the
bulkiness of the substituent on the diphenylmethyl group. Dra-
matic improvement of the enantioselectivity was realized up to 98%
ee with the precatalyst 7, in which a hydroxyl group was introduced
on the diphenylmethyl carbon (entry 5). Finally, it was found that
the enantioselectivity was enhanced to 99% ee when 10 mol % O-
silylated triazolium salt 8 was used together with KOt-Bu in the
presence of HMPA (entry 6). We have found that BFꢀ4 is suitable as
a counter anion of the triazolium salt in this reaction, whereas the
reaction using the chiral triazolium salts bearing PFꢀ6 9, Clꢀ 10, and
Brꢀ 11 lowered chemical yields and/or enantioselectivities (entries
7e9).
Table 1
Effect of solvents for the catalytic asymmetric benzoin condensation
3 (10 mol%)
O
O
KOt-Bu (10 mol%)
H
solvent (1.4 M), rt
OH
2a
Table 3
Effect of precatalyst
1a
precatalyst (10 mol%)
Entry
Solv
Time (h)
Yield (%)
ee (%)
O
KOt-Bu (10 mol%)
O
HMPA (50 mol%)
1
2
3
4
5
6
7
Toluene
CH2Cl2
Et2O
THF
1,4-Dioxane
DMF
19
24
20
17
14
18
18
10
80
99
32
87
58
91
34
43
18
51
65
56
58
H
1,4-dioxane (1.4M), rt
OH
1a
2a
Entry
Precatalyst
Time (h)
Yield (%)
ee (%)
DMSO
1
2
3a
4
5
6
7
8
9
3
4
5
6
7
8
9
10
11
15
15
15
21
22
14
24
18
17
87
89
8
96
64
75
15
61
61
71
66
42
22
98
99
97
88
98
Based on the above results, other bases beside KOt-Bu were then
evaluated to generate carbene for the asymmetric benzoin con-
densation in 1,4-dioxane as a solvent (Table 2). The organolithium
reagents and lithium amide were ineffective in this reaction (en-
tries 1e3). In the cases of NaOt-Bu, KHMDS, and CsCO3, benzoin 2a
was obtained with the comparable enantioselectivity as in the case
of KOt-Bu, but yields were lower (entries 4e7). The use of DBU
a
HMPA was not employed in this reaction.

896
T. Soeta et al. / Tetrahedron 68 (2012) 894e899
Under the optimized reaction conditions using the highly active
The absolute stereochemistry of the major isomer of the benzoin
2a was determined to be R by comparison of its optical rotation
with that reported in the literature.6a
and selective precatalyst 8, the scope of the catalytic enantiose-
lective benzoin condensation was demonstrated with various aro-
matic aldehydes (Table 4). We were delighted to find that our
catalytic system was applicable to a wide range of aromatic alde-
hydes when the reactions were conducted by using 10 mol % of 8
and 10 mol % of KOt-Bu in the presence of 50 mol % HMPA in 1,4-
dioxane at room temperature. 2-Naphthaldehyde (1b) was found
to be a good substrate, and the product 2b was obtained in 56%
yield with 93% ee (entry 2). We examined the substituted benzal-
dehydes bearing an electron-withdrawing group at the para-posi-
tion of the phenyl group. 4-Bromobenzaldehyde (1c) and 4-
chlorobenzaldehyde (1d) showed almost same reactivities, but
the enantioselectivities were completely different (30% ee and 85%
ee, respectively) (entries 3 and 4).11 4-Fluorobenzaldehyde (1e)
bearing a stronger electron-withdrawing group on the aromatic
ring showed low reactivity but high stereoselectivity was achieved
(entry 5). In the case of 4-(trifluoromethyl)benzaldehyde (1f), the
racemic product was obtained in 74% yield (entry 6). 2-
Chlorobenzaldehyde (1g) showed poor reactivity and selectivity,
probably due to the steric factor of the substituent at the ortho-
position (entry 7). The reactions of relatively deactivated 4-
methylbenzaldehyde (1h) and 4-methoxybenzaldehyde (1i) were
sluggish to furnish the corresponding products 2h and 2i in lower
yields but with excellent enantioselectivities (entries 8 and 9).
Heteroaromatic aldehyde, furfural (1j), showed moderate reactivity
to afford the product in 69% yield with 39% ee (entry 10).
The diphenylmethyl group shields the Re face of the Breslow
intermediate, whose geometry was controlled by intramolecular
hydrogen bonding between hydroxyl group and pyridine ring.
Therefore, the attack to the incoming second aldehyde molecule
occurs from the less hindered Si face, that is, the Breslow in-
termediate favorably approaches to the Si face of the second alde-
hyde leading to an R configuration at the newly formed stereogenic
center.2f On the other hand, Re face attack by the Breslow in-
termediate may be disfavored due to the steric repulsion between
the heterocyclic moiety of the Breslow intermediate and the aro-
matic ring of the second aldehyde (Scheme 2).
Table 4
Scope of substrates
Scheme 2. Stereochemical model for benzoin condensation.
8 (10 mol%)
O
O
KOt-Bu (10 mol%)
HMPA (50 mol%)
Ar
OH
3. Conclusion
Ar
Ar
H
1,4-dioxane (1.4 M), rt
1a-j
2a-j
In summary, we have developed the chiral triazolium salts
bearing a pyridine ring and could optimize the reaction procedure,
which led to the catalytic asymmetric benzoin condensation in an
excellent level. A wide range of aromatic aldehydes were applicable
to this reaction. The precise mechanism of the stereoinduction is
now further investigated in our laboratory.
Entry
Ar
Time (h)
Yield (%)
ee (%)
1
2
3
Ph (1a)
15
16
23
19
12
22
23
14
17
16
75 (2a)
56 (2b)
83 (2c)
80 (2d)
31 (2e)
74 (2f)
11 (2g)
10 (2h)
3 (2i)
99
93
30
85
99
0
67
95
99
39
2-Naphthyl (1b)
4-BrC6H4 (1c)
4-ClC6H4 (1d)
4-FC6H4 (1e)
4-CF3C6H4 (1f)
2-ClC6H4 (1g)
4-MeC6H4 (1h)
4-MeOC6H4 (1i)
2-Furyl (1j)
4
5a
6
4. Experimental section
7
8
9
10
4.1. General
69 (2j)
1H NMR was recorded on a JEOL ECS 400 (400 MHz) NMR spec-
trometer. Chemical shifts
a
Catalyst 8 (30 mol %) and KOt-Bu (30 mol%) were used.
d are reported in parts per million using
TMS as an internal standard. Data are reported as follows: chemical
shift, multiplicity (s¼singlet, d¼doublet, t¼triplet, q¼quartet,
m¼multiplet), coupling constant (J) and integration.13C NMR spectra
were recorded on JEOL ECS 400 (100 MHz) NMR spectrometer. The
To reveal the efficiency of the pyridine ring of the precatalyst, we
conducted the asymmetric benzoin condensation of benzaldehyde
(1a) by using the triazolium salt 12.6c The reaction proceeded
smoothly giving the product 2a in 90% yield with 8% ee and this
result clearly indicated that the pyridinyl group plays an important
role to realize the high stereoselectivity (Eq. 1).
chemical shifts were determined in the
d-scale relative to CDCl3
(d¼77.0 ppm). The IR spectra were measured on JASCO FT/IR-230
spectrometer. The MS spectra were recorded with Hitachi M-80
and JEOL SX-102A mass spectrometers. HPLC was performed using
chiral column with JASCO PU2800 plus, HITACHI 650A and HITACHI
D2500 chromato-integrater. Optical rotations were measured on
a JASCO DIP370. All of the melting points were measured with
YANAGIMOTO micro melting point apparatus. Toluene was dried and
distilled over sodium. THF, Et2O, and 1,4-dioxane were freshly dis-
tilled from sodium diphenylketyl. All other solvents were distilled
and stored over drying agents. All anhydrous solvents used in the
present experiment were degassed by freeze-thaw (3 cycles) prior to
use. Thin-layer chromatography (TLC) and flash column chroma-
tography were performed by using Merck silica gel 60 PF254 (Art.
7749) and silica gel 60N, spherical neutral (37563-84), respectively.
N
BF4–
N
N
Ph
H
Ph
12 (10 mol%)
KOt-Bu (10 mol%)
O
O
(1)
1,4-dioxane (1.4 M), rt
OH
2a
1a
90%, 8% ee

T. Soeta et al. / Tetrahedron 68 (2012) 894e899
897
4.2. Catalytic asymmetric benzoin condensation; general
procedure
7.45 (d, J¼8.0 Hz, 2H), 7.60 (d, J¼8.0 Hz, 2H), 7.69 (d, J¼8.4 Hz, 2H),
8.00 (d, J¼8.4 Hz, 2H).
To a suspension of chiral triazolium salt (0.1 mmol, 10 mol %),
hexamethylphosphoramide (HMPA) (0.09 mL, 50 mol %) and aro-
matic aldehyde (1.0 mmol) in 1,4-dioxane (0.3 mL), the suspension
of KOt-Bu (10 mol %) in 1,4-dioxane (0.4 mL) was added dropwise at
room temperature. The reaction mixture was stirred at room
temperature, quenched by adding water (2 mL) and diluted by
CHCl3 (5 mL). Aqueous layer was separated and extracted with
CHCl3 (5 mLꢁ3). Combined organic layers were dried over Na2SO4
and concentrated. The residue was purified by silica gel flash col-
umn chromatography.
4.2.7. (R)-1,2-Bis(2-chlorophenyl)-2-hydroxyethanone (2g)8b. Silica
gel column chromatography (hexane/ethyl acetate¼10/1e4/1) gave
2g (16 mg,11% yield) as a yellow solid of mp¼60.6e61.2 ꢂC and ½a D25
ꢃ
ꢀ36.6 (c 0.13, CHCl3). The ee was determined to be 67% by HPLC
(Daicel Chiralpac IA, hexane/i-PrOH¼9/1, 0.5 mL/min, 254 nm,
major 21.3 min and minor 19.1 min). 1H NMR (CDCl3): 4.39 (br s,
1H), 6.35 (s, 1H), 7.17e7.36 (m, 8H).
4.2.8. (R)-2-Hydroxy-1,2-di(p-tolyl)ethanone (2h)8b. Silica gel col-
umn chromatography (hexane/ethyl acetate¼10/1e4/1) gave 2h
Chiral triazolium salt 8 was used as a precatalyst in the following
experiments.
(12 mg, 10% yield) as a yellow solid of mp¼88.5e89.1 ꢂC and ½a D25
ꢃ
ꢀ65.4 (c 0.14, CHCl3). The ee was determined to be 95% by HPLC
(Daicel Chiralpac IA, hexane/i-PrOH¼9/1, 0.5 mL/min, 254 nm,
major 16.1 min and minor 20.7 min). 1H NMR (CDCl3): 2.28 (s, 3H),
2.35 (s, 3H), 4.57 (br s, 1H), 5.89 (s, 1H), 7.11 (d, J¼8.0 Hz, 2H),
7.17e7.22 (m, 4H), 7.81 (d, J¼8.0 Hz, 2H).
4.2.1. (R)-2-Hydroxy-1,2-diphenylethanone (2a)6a. Silica gel column
chromatography (hexane/ethyl acetate¼10/1e4/1) gave 2a (79 mg,
75% yield) as a white solid of mp¼131.0e131.9 ꢂC and ½a D25
ꢀ150.1
ꢃ
(c 0.56, MeOH). Lit.6a: ½a D25
ꢀ108.4 (c 1.0, MeOH) for R enantiomer
ꢃ
with 75% ee. The ee was determined to be 99% by HPLC (Daicel
Chiralpac IA, hexane/i-PrOH¼9/1, 0.5 mL/min, 254 nm, major
28.9 min and minor 31.7 min). 1H NMR (CDCl3): 4.57 (br s, 1H), 5.96
(s, 1H), 7.27e7.33 (m, 7H), 7.52 (t, J¼8.2 Hz, 1H), 7.92 (d, J¼8.2 Hz,
2H).
4.2.9. (R)-2-Hydroxy-1,2-bis(4-methoxyphenyl)ethanone
(2i)8b
.
Silica gel column chromatography (hexane/ethyl acetate¼10/1e4/
1) gave 2i (4 mg, 3% yield) as a yellow solid of mp¼119.0e119.9 ꢂC
and ½a 2D5
ꢀ43.8 (c 0.05, CHCl3). The ee was determined to be 99% by
ꢃ
HPLC (Daicel Chiralpac IA, hexane/i-PrOH¼4/1, 0.95 mL/min,
254 nm, major 26.5 min and minor 29.1 min). 1H NMR (CDCl3): 3.76
(s, 3H), 3.82 (s, 3H), 5.84 (s, 1H), 6.83e6.87 (m, 4H), 7.26 (m, 2H),
7.90 (d, J¼9.1 Hz, 2H). OH proton was not observed clearly.
4.2.2. (R)-2-Hydroxy-1,2-di(naphthalen-2-yl)ethanone (2b)8b. Silica
gel column chromatography (hexane/ethyl acetate¼10/1e4/1) gave
2b (88 mg, 56% yield) as a white solid of mp¼117.2e117.8 ꢂC and
½
a 2D5
ꢃ
þ52.4 (c 0.37, MeOH). The ee was determined to be 93% by
4.2.10. (R)-1,2-Di(furan-2-yl)-2-hydroxyethanone (2j)8b. Silica gel
column chromatography (hexane/ethyl acetate¼4/1e1/1) gave 2j
HPLC (Daicel Chiralpac IA, hexane/i-PrOH¼4/1,1.0 mL/min, 254 nm,
major 21.5 min and minor 15.1 min). 1H NMR (CDCl3): 4.82 (br s,
1H), 6.27 (s, 1H), 7.39e7.54 (m, 5H), 7.72e7.99 (m, 8H), 8.48 (s, 1H).
(66 mg, 69% yield) as a yellow solid of mp¼135.1e135.7 ꢂC and ½a D25
ꢃ
ꢀ13.7 (c 0.47, CHCl3). The ee was determined to be 39% by HPLC
(Daicel Chiralpac IA, hexane/i-PrOH¼9/1, 0.8 mL/min, 254 nm,
major 26.0 min and minor 17.6 min). 1H NMR (CDCl3): 4.15 (br s,
1H), 5.80 (s, 1H), 6.35 (m, 1H), 6.49 (m, 1H), 6.53 (dd, J¼1.8, 3.6 Hz,
1H), 7.25 (m, 1H), 7.37 (m, 1H), 7.61 (m, 1H).
4.2.3. (R)-1,2-Bis(4-bromophenyl)-2-hydroxyethanone (2c)6a. Silica
gel column chromatography (hexane/ethyl acetate¼10/1e4/1) gave
2c (149 mg, 83% yield) as a white solid of mp¼96.8e97.5 ꢂC and
½
a 2D5
ꢃ
ꢀ4.4 (c 0.63, CHCl3). The ee was determined to be 30% by HPLC
(Daicel Chiralpac IA, hexane/i-PrOH¼9/1, 0.5 mL/min, 254 nm,
major 31.2 min and minor 33.5 min). 1H NMR (CDCl3): 4.50 (br s,
1H), 5.85 (s, 1H), 7.18 (d, J¼8.2 Hz, 2H), 7.46 (d, J¼8.2 Hz, 2H), 7.55
(d, J¼8.2 Hz, 2H), 7.73 (d, J¼8.2 Hz, 2H).
4.3. Preparation of chiral triazolium salts
To a solution of the corresponding lactam in CH2Cl2, 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 column chromatography to
afford the corresponding thiolactam (Scheme 3, step 1).
4.2.4. (R)-1,2-Bis(4-chlorophenyl)-2-hydroxyethanone (2d)8b. Silica
gel column chromatography (hexane/ethyl acetate¼10/1e4/1) gave
2d (85 mg, 80% yield) as a white solid of mp¼89.6e90.1 ꢂC and ½a D25
ꢃ
ꢀ30.5 (c 0.66, CHCl3). The ee was determined to be 85% by HPLC
(Daicel Chiralcel OJ-H, hexane/i-PrOH¼95/5, 0.6 mL/min, 220 nm,
major 46.4 min and minor 42.0 min). 1H NMR (CDCl3): 4.55 (br s,
1H), 5.92 (s, 1H), 7.25 (d, J¼8.2 Hz, 2H), 7.30 (d, J¼8.2 Hz, 2H), 7.39
(d, J¼8.2 Hz, 2H), 7.82 (d, J¼8.2 Hz, 2H).
4.2.5. (R)-1,2-Bis(4-fluorophenyl)-2-hydroxyethanone (2e)6a. Silica
gel column chromatography (hexane/ethyl acetate¼10/1e4/1) gave
2e (26 mg, 31% yield) as a yellow solid of mp¼80.5e80.9 ꢂC and
Scheme 3. General synthesis of precatalysts.
To a solution of the thiolactam in benzene, excess amount 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 (Scheme 3, step 3).
½
a 2D5
ꢃ
ꢀ128.2 (c 0.24, CHCl3). The ee was determined to be 99% by
HPLC (Daicel Chiralpac IA, hexane/i-PrOH¼9/1, 0.5 mL/min,
254 nm, major 27.1 min and minor 29.1 min). 1H NMR (CDCl3): 4.53
(br s, 1H), 5.90 (s, 1H), 6.99e7.10 (m, 4H), 7.29 (m, 2H), 7.93 (m, 2H).
4.2.6. (R)-2-Hydroxy-1,2-bis(4-(trifluoromethyl)phenyl)ethanone
(2f)6a. Silica
gel
column
chromatography
(hexane/ethyl
acetate¼10/1e4/1) gave 2f (128 mg, 74% yield) as a yellow solid of
mp¼90.8e91.2 ꢂC. The ee was determined to be almost 0% by HPLC
(Daicel Chiralpac IA, hexane/i-PrOH¼9/1, 0.5 mL/min, 254 nm,
17.8 min and 19.5 min). 1H NMR (CDCl3): 4.51 (br s, 1H), 6.03 (s, 1H),

898
T. Soeta et al. / Tetrahedron 68 (2012) 894e899
A suspension of the resulting iminohydrazine and ammonium
1470, 1190, 1050 cmꢀ1. HRMSeFAB (m/z): calcd for C26H29N4OSi
[MꢀBF4]þ: 441.2111. Found: 441.2116.
tetrafluoroborate (1.05 equiv) in trimethyl orthoformate (40 equiv)
was stirred at 90 ꢂC for 12 h. Condensation and the subsequent
purification by silica gel flash column chromatography gave the
corresponding chiral triazolium salt (Scheme 3, step 4).
4.3.6. (S)-5-[Hydroxy(diphenyl)methy]-2-(pyridin-2-yl)-6,7-
dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-2-ium tetrafluoroborate (7).
To a solution of 8 (100 mg, 0.19 mmol) in THF (1.0 mL), tetra-
fluoroboric acid (0.95 mmol) was added. The whole was stirred at
room temperature for 3 h, and the solvent was removed under
reduced pressure. The residue was purified by silica gel column
chromatography (CHCl3/MeOH¼10/1) to give 7 (58 mg, 67%) as
4.3.1. (S)-5-Benzhydryl-2-(pyridin-2-yl)-6,7-dihydro-5H-pyrrolo
[2,1-c][1,2,4]triazol-2-ium tetrafluoroborate (3). Silica gel column
chromatography (CHCl3/MeOH¼10/1) gave 3 as a brown viscous
liquid of ½a 2D5
ꢃ
þ12.9 (c 0.23, CHCl3). 1H NMR (CDCl3): 2.57 (m, 1H),
3.07 (m, 1H), 3.21 (m, 1H), 3.37 (m, 1H), 4.20 (d, J¼11.4 Hz, 1H), 6.04
(m, 1H), 7.27e7.53 (m, 12H), 7.92 (m, 1H), 8.36 (s, 1H), 8.38 (d,
J¼4.6 Hz, 1H). 13C NMR (CDCl3): 21.4, 32.9, 56.1, 64.4, 114.0, 125.7,
127.8, 127.9, 128.2, 128.6, 129.4, 129.9, 135.3, 138.8, 139.6, 139.9,
a yellow viscous liquid of ½a D25
ꢃ
ꢀ119.6 (c 0.28, CHCl3). 1H NMR
(CDCl3): 2.52 (m, 1H), 2.78 (m, 1H), 3.01 (m, 1H), 3.23 (m, 1H), 4.14
(br s, 1H), 6.17 (m, 1H), 7.26e7.52 (m, 11H), 7.88 (m, 1H), 7.97 (m,
1H), 8.47 (m,1H), 9.26 (s,1H). 13C NMR (CDCl3): 21.4, 29.7, 67.9, 79.0,
113.8, 125.7, 126.0, 126.4, 128.0, 128.5, 128.7, 129.1, 136.2, 139.9,
141.6, 142.5, 147.2, 148.9, 164.0. IR (neat): 3490, 3040, 2960, 1590,
1470, 1190, 1060 cmꢀ1. HRMSeFAB (m/z): calcd for C23H21N4O
[MꢀBF4]þ: 369.1715. Found: 369.1708.
147.1, 148.9, 163.3. IR (neat): 3030, 2960, 1590, 1470, 1250 cmꢀ1
.
HRMSeFAB (m/z): calcd for C23H21N4 [MꢀBF4]þ: 353.1766. Found:
353.1769.
4.3.2. (S)-5-Benzhydryl-2-(6-methylpyridin-2-yl)-6,7-dihydro-5H-
pyrrolo[2,1-c][1,2,4]triazol-2-ium tetrafluoroborate (4). Silica gel
column chromatography ꢂ(CHCl3/MeOH¼10/1) gave 4 as a brown
4.3.7. (S)-5-[Diphenyl(trimethylsilyloxy)methyl]-2-(pyridin-2-yl)-
6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-2-ium
hexafluorophos-
a 25
solid of mp¼119.7e120.1 C and ½ ꢃD þ4.3 (c 0.28, CHCl3). 1H NMR
phate (9). Silica gel column chromatography (CHCl3/MeOH¼10/1)
(CDCl3): 2.47 (s, 3H), 2.57 (m, 1H), 3.07 (m, 1H), 3.18 (m, 1H), 3.34
(m, 1H), 4.20 (d, J¼11.0 Hz, 1H), 6.03 (m, 1H), 7.25e7.52 (m, 11H),
7.66 (d, J¼7.7 Hz, 1H), 7.79 (t, J¼7.7 Hz, 1H), 8.30 (s, 1H). 13C NMR
(CDCl3): 21.4, 23.8, 32.8, 55.8, 64.4, 110.6, 125.3, 127.8, 128.3, 128.4,
129.3, 129.8, 134.9, 138.9, 146.4, 158.9, 163.2. IR (KBr): 3020, 2960,
1590, 1210, 1060 cmꢀ1. HRMSeFAB (m/z): calcd for C24H23N4
[MꢀBF4]þ: 367.1923. Found: 367.1928.
gave 9 as a brown solid of mp¼189.5e194.2 ꢂC and ½a D25
ꢀ151.2 (c
ꢃ
0.78, CHCl3). 1H NMR (CDCl3): ꢀ0.03 (s, 9H), 2.09 (m, 1H), 2.76 (m,
1H), 2.98 (m, 1H), 3.45 (m, 1H), 6.07 (d, J¼8.5 Hz, 1H), 7.26e7.61 (m,
11H), 7.93 (d, J¼8.5 Hz, 1H), 8.05 (m, 1H), 8.61 (d, J¼3.7 Hz, 1H), 9.43
(s,1H).13C NMR (CDCl3): 1.41, 20.9, 29.4, 68.5, 82.2,113.6,126.1,127.8,
128.0,128.4,128.6,128.9,129.4,135.9,139.1,139.6,140.2,147.0,149.1,
163.4. IR (KBr): 3040, 2960,1590,1470,1260,1070 cmꢀ1. HRMSeFAB
(m/z): calcd for C26H29N4OSi [MꢀPF6]þ: 441.2111. Found: 441.2115.
4.3.3. (S)-3,3-Bis(phenylmethyl)-5-benzhydryl-2-(pyridin-2-yl)-6,7-
dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-2-ium tetrafluoroborate (5).
Silica gel column chromatography (CHCl3/MeOH¼10/1) gave 5 as
4.3.8. (S)-5-[Diphenyl(trimethylsilyloxy)methyl]-2-(pyridin-2-yl)-
6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-2-ium chloride (10).
Silica gel column chromatography (CHCl3/MeOH¼10/1) gave 10 as
a brown solid of ½a D25
ꢃ
þ17.1 (c 0.70, CHCl3) and mp¼68.5e69.0 ꢂC.
1H NMR (CDCl3): 2.47 (dd, J¼5.5, 11.8 Hz, 1H), 2.72 (d, J¼11.8 Hz,
1H), 3.07 (m, 2H), 3.35 (m, 2H), 3.46 (d, J¼13.7 Hz, 1H), 5.45 (m, 1H),
7.00 (d, J¼7.8 Hz, 2H), 7.05 (m, 2H), 7.16 (d, J¼7.8 Hz, 2H), 7.21e7.48
(m, 15H), 7.85 (s, 1H), 7.92 (d, J¼8.2 Hz, 1H), 7.99 (t, J¼8.2 Hz, 1H),
8.40 (d, J¼5.0 Hz, 1H). 13C NMR (CDCl3): 42.0, 43.8, 45.5, 46.9, 54.7,
62.5, 113.9, 125.9, 127.4, 127.5, 127.6, 128.0, 128.1, 128.3, 128.4, 128.8,
129.1, 129.4, 129.6, 130.5, 130.8, 134.8, 135.5, 136.4, 138.7, 139.8,
140.0, 147.1, 148.9, 166.5. IR (KBr): 3030, 2930, 2860, 1570, 1470,
a brown viscous liquid of ½a D25
ꢃ
ꢀ125.5 (c 0.55, CHCl3). 1H NMR
(CDCl3): ꢀ0.11 (s, 9H), 1.92 (m, 1H), 2.61 (m, 1H), 2.90 (m, 1H), 3.51
(m, 1H), 6.48 (d, J¼7.7 Hz, 1H), 7.16e7.36 (m, 10H), 7.44 (m, 1H), 7.80
(d, J¼7.7 Hz, 1H), 7.93 (m, 1H), 8.44 (m, 1H), 9.59 (s, 1H). 13C NMR
(CDCl3): 1.45, 21.1, 29.8, 68.4, 82.2, 125.6, 128.0, 128.2, 128.6, 129.0,
136.6, 139.6, 139.8, 139.9, 147.1, 148.9, 163.5. IR (neat): 3150, 2920,
1590, 1470, 1250, 1070 cmꢀ1
. HRMSeFAB (m/z): calcd for
C26H29N4OSi [MꢀCl]þ: 441.2111. Found: 441.2118.
1190 cmꢀ1
.
HRMSeFAB (m/z): calcd for C37H33N4 [MꢀBF4]þ:
533.2705. Found: 533.2711.
4.3.9. (S)-5-[Diphenyl(trimethylsilyloxy)methyl]-2-(pyridin-2-yl)-6,7-
dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-2-ium bromide (11). Silica
gel column chromatography (CHCl3/MeOH¼10/1) gave 11 as
4.3.4. (S)-5-[Di(o-tolyl)methy]-2-(pyridin-2-yl)-6,7-dihydro-5H-pyr-
rolo[2,1-c][1,2,4]triazol-2-ium tetrafluoroborate (6). Silica gel col-
umn chromatography (CHCl3/MeOH¼10/1) gave 6 as a white solid
a brown viscous liquid of ½a D25
ꢃ
ꢀ81.0 (c 0.55, CHCl3). 1H NMR
(CDCl3): ꢀ0.01 (s, 9H), 2.04 (m, 1H), 2.74 (m, 1H), 3.04 (m, 1H), 3.63
(m, 1H), 6.58 (d, J¼8.0 Hz, 1H), 7.27e7.49 (m, 10H), 7.56 (m, 1H), 7.93
(d, J¼8.0 Hz, 1H), 8.04 (m, 1H), 8.58 (m, 1H), 9.67 (s, 1H). 13C NMR
(CDCl3): 1.39, 21.1, 29.6, 68.5, 82.1, 113.5, 125.7, 127.5, 127.8, 128.2,
128.6, 129.0, 136.3, 139.4, 139.6, 139.9, 146.9, 148.9, 163.4. IR (neat):
3050, 2970, 1590, 1500, 1250, 1100, 1070 cmꢀ1. HRMSeFAB (m/z):
calcd for C26H29N4OSi [MꢀBr]þ: 441.2111. Found: 441.2109.
of mp¼236.1e236.9 ꢂC and ½a D25
ꢃ
þ15.8 (c 0.16, CHCl3). 1H NMR
(CDCl3): 2.08 (s, 3H), 2.29 (s, 3H), 2.58 (m, 1H), 3.25 (m, 2H), 3.37
(m, 1H), 4.58 (d, J¼11.4 Hz, 1H), 5.90 (m, 1H), 7.17e7.54 (m, 9H), 7.94
(m, 2H), 8.22 (s, 1H), 8.41 (d, J¼4.6 Hz, 1H). 13C NMR (CDCl3): 19.9,
27.3, 28.4, 47.9, 62.0, 107.9, 114.3, 126.0, 126.3, 126.6, 127.0, 127.3,
130.7, 131.0, 136.3, 136.7, 138.0, 139.3, 139.6, 146.3, 158.9. IR (KBr):
3060, 2960, 1600, 1470, 1190, 1060 cmꢀ1. HRMSeFAB (m/z): calcd
for C25H25N4 [MꢀBF4]þ: 381.2074. Found: 381.2085.
Acknowledgements
4.3.5. (S)-5-[Diphenyl(trimethylsilyloxy)methyl]-2-(pyridin-2-yl)-
6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-2-ium tetrafluoroborate
(8). Silica gel column chromatography (CHCl3/MeOH¼10/1) gave 8
The present work was financially supported in part by Adaptable
and Seamless Technology Transfer Program through target-driven
R&D (221Z03585) from Japan Science and Technology Agency and
a Grant-in-Aid for Young Scientist from Kanazawa University.
as a viscous liquid of ½a D25
ꢃ
ꢀ138.4 (c 0.51, CHCl3). 1H NMR (CDCl3):
ꢀ0.05 (s, 9H), 2.00 (m, 1H), 2.70 (m, 1H), 2.96 (m, 1H), 3.49 (m, 1H),
6.14 (d, J¼7.7 Hz,1H), 7.22e7.50 (m,11H), 7.92 (d, J¼8.2 Hz,1H), 8.02
(m, 1H), 8.59 (d, J¼4.1 Hz, 1H), 9.49 (s, 1H). 13C NMR (CDCl3): 1.52,
21.0, 29.5, 68.4, 82.3, 113.8, 125.9, 128.4, 128.8, 128.9, 129.3, 136.4,
139.6, 139.8, 140.1, 147.2, 149.1, 163.5. IR (neat): 3040, 2960, 1590,
Supplementary data
A supplementary data file (1H and 13C NMR) of newly synthe-
sized chiral triazolium salts (3e11) is available. Supplementary data

T. Soeta et al. / Tetrahedron 68 (2012) 894e899
899
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partial racemization by deprotonationeprotonation at the
a-position of prod-
ucts 3.