Highly efficient synthesis of spirocyclic (1R)-camphor-derived triazolium salts: Application in the catalytic asymmetric benzoin condensation

Article abstract of DOI:10.1016/j.tet.2014.06.066

New (1R)-camphor-derived triazolium salts, incorporating a spirocyclic system, are described. Benzoin condensation of aromatic aldehydes, mediated by these salts affords α-hydroxyketones in good yields and moderate enantiomeric excesses.

Full text of DOI:10.1016/j.tet.2014.06.066

Tetrahedron 70 (2014) 5739e5745
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Highly efficient synthesis of spirocyclic (1R)-camphor-derived
triazolium salts: application in the catalytic asymmetric benzoin
condensation
*
ꢀ
ꢀ
Zbigniew Rafinski , Anna Kozakiewicz, Katarzyna Rafinska
Faculty of Chemistry, Nicolaus Copernicus University, 7 Gagarin Street, 87-100, Poland
a r t i c l e i n f o
a b s t r a c t
Article history:
New (1R)-camphor-derived triazolium salts, incorporating a spirocyclic system, are described. Benzoin
Received 1 March 2014
Received in revised form 3 June 2014
Accepted 17 June 2014
condensation of aromatic aldehydes, mediated by these salts affords
and moderate enantiomeric excesses.
a-hydroxyketones in good yields
Ó 2014 Elsevier Ltd. All rights reserved.
Available online 24 June 2014
Keywords:
N-Heterocyclic carbenes
Benzoin condensation
Asymmetric synthesis
Terpenoids
1. Introduction
In the area of rapidly expanding organocatalysis, N-heterocyclic
carbenes (NHCs) have received considerable attention due to their
capability of catalyzing a broad range of synthetic transformations.1
The attractive ability of NHCs to invert the reactivity of aldehydes
(umpolung) has led to intensive research in the area, providing an
unconventional access to designed target molecules.2
3
€
Since the first report by Liebig and Wohler on the dimerization
of benzaldehyde to benzoin in the presence of cyanide, a lot of ef-
fort has been devoted towards further development of this re-
action. More than 100 years later, Ukai and co-workers showed that
a catalytic amount of thiazolium salts could achieve the same
transformation.4 The mechanism of the thiazolium catalyzed ben-
zoin condensation was elucidated by Breslow in 1958.5 Initial at-
tempts to develop an asymmetric variant of the reaction using
chiral thiazolium precatalysts, designed by Sheehan resulted in
a low to moderate enantiomeric excess (Fig. 1).6 The real break-
through, achieved by Enders7 and then Leeper and Knight,8 dem-
onstrated the clear superiority of chiral triazolium-derived NHCs in
terms of thiazolium analogues. Further catalyst optimization by
Enders allowed the condensation of benzaldehyde to benzoin in
greater than 90% ee.9
Fig. 1. Chiral N-heterocyclic carbene precursors.
More recently, Connon reported the first example of bi-
functional catalysts, employing hydrogen bond donation as a con-
trol element, providing stabilizing interactions in the transition
state, leading to >99% ee.10
Chiral carbene catalysts (NHCs) were shown to be powerful
organocatalysts in various kinds of asymmetric reactions. However,
only a limited number of NHCs backbone scaffolds are effective in
highly enantioselective reactions. Many of them suffer from in-
tricate synthetic procedures and relatively high cost of enantiopure
starting materials.
ꢀ
* Corresponding author. E-mail address: payudo@chem.umk.pl (Z. Rafinski).
http://dx.doi.org/10.1016/j.tet.2014.06.066
0040-4020/Ó 2014 Elsevier Ltd. All rights reserved.

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Z. Rafinski et al. / Tetrahedron 70 (2014) 5739e5745
5740
Consequently, the design of new catalysts from readily available
chiral sources with improved reactivity profiles having fine-tuning
of the steric and electronic environment around the carbene centre
is still in great demand. On the basis of our previous success uti-
lizing b-pinene-derived triazolium salts as very efficient and se-
lective carbene precatalysts in Stetter reaction,11 we report the
synthesis of chiral spirocyclic triazolium salts derived from (1R)-
camphor and their evaluation in the benzoin condensation. To the
best of our knowledge, this is the first example of the synthesis of
chiral spirocyclic triazolium NHCs.
2. Results and discussion
Camphor as a natural source of chirality has been widely used in
asymmetric synthesis.12 The readily available enantiomers of
camphor guarantee access to either enantiomer of the chiral
products. We started our investigation by the synthesis of a series
triazolium salts as outlined in Scheme 1. The synthesis commences
from the highly diastereoselective addition TMSCN to (1R)-cam-
phor 1, according to the reported method.13 The reduction of
cyanohydrin silyl ether 2 by LiAlH4 proceeded smoothly to the
corresponding aminoalcohol 3 in quantitative yield. Conversion
into the lactam 5 was achieved using an optimized two-step pro-
cedure involving the formation of amide 4, followed by cyclization
with potassium tert-butoxide in excellent overall yields. Then, the
diastereo- and enantiopure lactam 5 was methylated with the
Meerwein’s reagent to form the corresponding amidate. It was
treated in situ with arylhydrazines to yield tetrafluoroborate
hydrazonium salts, which were directly cyclized with triethyl
orthoformate to give the tetracyclic triazolium salts AeC in high
yield as crystalline solids. The configuration of triazolium salt B was
confirmed by X-ray crystallographic analysis as shown in Fig. 2.
Fig. 2. ORTEP drawing structure of molecular structure of B. Thermal ellipsoids are set
at the 30% probability level.
group of the spirocyclic triazolium salts A, B, D showed that the
enantiomeric excess was constant over time regardless of the
catalysts used. In the case of N-C6F5 triazolium precatalyst, re-
action monitoring showed that after 15 min most of benzaldehyde
was consumed to afford the racemic acryloin product. We suppose
that the differences in the enantioselectivity results from re-
versibility of the benzoin reaction by using the N-C6F5 triazolium
precatalyst. Insightful studies from Smith described the effect of
the aryl substituent of azolium salts on the reactivity and re-
versibility in benzoin condensation.15
The reaction parameters were further examined in the presence
of D, and the results are summarized in Table 2. Several tested bases
(entries 1e5) were found tolerable and DIPEA was optimal in terms
Scheme 1. Synthesis of triazolium salts from (1R)-camphor.
The tetracyclic triazolium salt D was then obtained as a white
solid in 64% overall yield from 5 by a modified three-step procedure
developed by Bode (Scheme 2).14 The structure of triazolium salt D
was confirmed by X-ray structural analysis (Fig. 3).
of both yield and er of the product (entry 2). Other organic and
inorganic bases, such as t-BuOK, K2CO3, Cs2CO3, DBU and phos-
phazene bases, also gave the desired product with high to excellent
yields but as racemates. We suppose that this results from in-
complete conversion to carbene, so that free base might racemize
the product. To confirm this, the catalytic process was repeated
with enantioenriched benzoin 9a (55% ee) replacing benzaldehyde
as the starting material. After stirring 20 min, the acryloin 9a was
recovered as the racemate (Scheme 3).16
Subsequently, various solvents were also examined and found to
be tolerated, affording the desired product with good to excellent
yields and moderate selectivity (entries 1e8, Table 3). However,
using solvents, such as dimethoxyethane, dichloromethane and
octafluorotoluene, a significant drop in yield was observed but with
the same level of selectivity (entries 9e11). Finally, the reaction in
THF led to an optimal combination of yield (93%) and enantiomeric
ratio, 77.5:22.5 (entry 1, Table 3).
With these four novel chiral carbene precursors in hand, the
model intermolecular benzoin condensation of benzaldehyde was
evaluated. As shown in Table 1, when triazolium salts AeD
(10 mol %) and triethylamine (10 mol %) in THF were used, D gave
the best results, affording the benzoin product in 98% yield and
71.5:28.5 enantiomeric ratio (entry 4). Under the same condition
precatalyst A showed slightly lower selectivity (71:29 er) and
provided the product with a much lower yield (entry 1). Tri-
azolium salt B bearing a pentafluorophenyl moiety gave the de-
sired benzoin in excellent yields but only with 52:48 er. The
carbene generated from C was found to be ineffective leading to
a trace amount of the desired benzoin. Monitoring the enantio-
meric excess of benzoins with time and with variation in the aryl

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Z. Rafinski et al. / Tetrahedron 70 (2014) 5739e5745
5741
Scheme 2. Preparation of spirocyclic triazolium salt D.
Fig. 3. X-ray crystal structure of triazolium salt D. Thermal ellipsoids are set at the 30% probability level.
Table 1
selectivities but with relatively low yields. The best result was ob-
tained for the p-methoxybenzaldehyde 8f affording the acryloin in
82:18 er. The absolute configuration of the acryloin product was
determined to be R by comparison of its optical rotation with that
reported in the literature.9a
Screening of the chiral NHC catalystsa
3. Conclusion
Entry
NHC
Yieldb (%)
erc
1
2
3
4
A
B
C
31
99
<5
98
71:29
52:48
d
In summary, we have developed a series of novel spirocyclic
triazolium salts from readily available and inexpensive (1R)-cam-
phor. The catalyst derived from D and DIPEA was successfully
employed in the asymmetric benzoin condensation. The resulting
acryloins were obtained in moderate to excellent yields and ac-
ceptable enantioselectivities. Further structural modification of the
spirocyclic triazolium salts derived from (1R)-camphor and their
application in other asymmetric reactions are currently under way.
D
71.5:28.5
a
Reaction conditions: 8a (1 mmol), catalyst (10 mol %), triethylamine (10 mol %)
in THF (1.1 mL).
b
Yields of isolated benzoin.
Determined by chiral HPLC (Daicel Chiralcel OD-H).
c
Under optimized conditions using carbene precatalyst D, the
scope of the intermolecular benzoin reaction was demonstrated
with various aromatic aldehydes 8aef (Table 4). In general, con-
densation of aldehydes occurred smoothly affording the corre-
4. Experimental section
4.1. General methods
sponding
acryloins
in
good
yields
and
acceptable
enantioselectivities. Generally, the reaction of aldehydes bearing
electron-donating groups led to their desired products with higher
All chemicals used in this study were obtained from commer-
cial sources and used without further purification. Reactions

ꢀ
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Z. Rafinski et al. / Tetrahedron 70 (2014) 5739e5745
Table 2
Table 4
Screening of different basesa
Substrate scope for enantioselective intermolecular benzoin condensationa
Entry
Base
Yieldb (%)
erc
Entry
Ar
Yieldb (%)
erc
1
2
3
4
5
6
7
8
NEt3
98
93
92
62
69
75
73
72
93
80
95
71.5:28.5
77.5:22.5
74:26
78:22
74:26
Racemate
Racemate
Racemate
Racemate
Racemate
Racemate
1
2
3
4
5
6
Ph (8a)
93 (9a)
54 (9b)
28 (9c)
51 (9d)
20 (9e)
28 (9f)
77.5:22.5
74:26
72:28
79:21
62:38
DIPEA
DCyEA
DMAP
DABCO
t-BuOK
P2eEt
P2et-Bu
K2CO3
Cs2CO3
DBU
2-Naphthyl (8b)
4-MeC6H4 (8c)
2-MeOC6H4 (8d)
2-ClC6H4 (8e)
4-MeOC6H4 (8f)
82:18
a
Reaction conditions: 8aef (1 mmol), D catalyst (10 mol %), DIPEA (10 mol %) in
THF (1.1 mL).
9
10
11
b
c
Yields of isolated benzoin.
Determined by chiral HPLC (Daicel Chiralcel OD-H).
a
Reaction conditions: 8a (1 mmol), catalyst (10 mol %), base (10 mol %) in THF
Reactions were monitored by thin layer chromatography using
(1.1 mL).
b
c
UV light to visualize the course of reaction. Purification of reaction
products was carried out by column chromatography on silica gel.
Chemical yields refer to pure isolated substances.
Yields of isolated benzoin.
Determined by chiral HPLC (Daicel Chiralcel OD-H). P2eEt, P2et-Bu¼phospha-
zene bases, DCyEA¼dicyclohexylethylamine.
1H and13H NMR spectrawere obtainedusing a Bruker DPX-400 or
Bruker DPX-700 spectrometer. Chemical shifts are reported in parts
per million from tetramethylsilane with the solvent resonance as the
internal standard. The following abbreviations were used to desig-
nate chemical shift multiplicities: s¼singlet, d¼doublet, t¼triplet,
q¼quartet, h¼heptet, m¼multiplet, br s¼broad singlet. The melting
points were determined on a Buchi SPM-20 melting point apparatus.
Elementalanalyses were performed ona Vario MACRO CHNanalyzer.
Optical rotations ([a]D) were measured on a PolAAr 3000 (Optical
Scheme 3. Racemization of 9a under the reaction conditions.
Activity LTD) polarimeter. IR spectra were recorded on PerkineElmer
Spectrum Two spectrometer and are reported in terms of frequency
of absorption cmꢀ1. Mass spectra were collected on a Shimadzu High
Performance Liquid Chromatograph/Mass Spectrometer LCMS-8030
(ESI, operating both in positive and negative mode). Enantiomeric
excesses were determined by HPLC analysis on chiral stationary
phase using 4.6 mmꢁ250 mm Daicel Chiralcel OD-H with n-hexane,
2-propanol as eluent.
Table 3
Screening of different solventsa
The X-ray data for reported structure were collected at 293(2) K
with an Oxford Sapphire CCD diffractometer using Mo K
a
radiation
ꢁ
l¼0.71073 A and
u-2q method. The numerical absorption correc-
tion was applied with CrysAlis171 package of programs, Oxford
Diffraction, 2000.17 Structure was solved by direct methods and
refined with the full-matrix least-squares method on F2 with the
use of SHELX-97 program package.18 The hydrogen atoms have
been located from the difference electron density maps and con-
strained during refinement. The absolute configuration was de-
termined by the Flack method.19 CCDC No. 988374 for X-ray crystal
structure B, and CCDC No. 988376 for X-ray crystal structure D.
Entry
Aldehyde
Yieldb (%)
erc
1
2
3
4
THF
Toluene
DMF
MeCN
EtOH
CMPE
TAME
MTBE
CH2Cl2
DME
93
54
98
76
85
51
49
56
28
28
26
77.5:22.5
76.5:23.5
63.5:36.5
62:38
72:28
79:21
78:22
79:21
72:28
77:23
5
6d
7d
8d
9
10
4.2. Experimental procedure and characterization data for
compounds
11d
OFT
74:26
a
Reaction conditions: 8a (1 mmol), catalyst (10 mol %), DIPEA (10 mol %) in THF
(1.1 mL).
4.2.1. (1R,2R,4R)-2-Cyano-2-trimethylsilanyloxy-1,3,3-trimethyl
[2.2.1bicyclo]heptane-2-carbonitrile (2). To a solution of lithium
methoxide (158 mg, 4.2 mmol, 0.05 equiv) in 140 mL of anhydrous
THF was added a trimethylsilylcyanide (10.4 mL, 83 mmol). The
resulting clear yellow solution was stirred at rt for 20 min and
10.7 g (70 mmol) of (1R)-(þ)-camphor 1 was added. The reaction
mixture was stirred at rt until all the starting material was con-
sumed. After completion, the reaction was quenched with 10%
Na2CO3 (100 mL), and extracted with tert-butyl methyl ether
b
c
Yields of isolated benzoin.
Determined by chiral HPLC (Daicel Chiralcel OD-H).
MTBE¼methyl tert-butyl ether, CPME¼cyclopentyl methyl ether, TAME¼tert-
d
amyl methyl ether, OFT¼octafluorotoluene.
utilizing air- or moisture-sensitive reagents were carried out in
flame-dried glassware under a dry Ar atmosphere. All solvents
were purified and dried according to standard methods prior to
use.

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Z. Rafinski et al. / Tetrahedron 70 (2014) 5739e5745
5743
(3ꢁ100 mL). The combined organic layers were concentrated in
vacuo to afford a crude liquid. The crude product was diluted with
200 mL of hexanes and washed twice with 2ꢁ25 mL of acetonitrile.
The hexane layer was separated, and concentrated to afford 17.6 g
in 94 mL of anhydrous dichloromethane was added dropwise
a solution of potassium tert-butoxide (8.6 g, 76.8 mmol) in iso-
propanol over 45 min at 0 ꢂC. The solution was allowed to warm to
ambient temperature and stirred for 24 h. After that time all
volatile materials were evaporated under reduced pressure. Water
(200 mL) was added and mixture was extracted with ethyl acetate
(3ꢁ100 mL). The combined organic phases were washed with
water and brine, dried over MgSO4, filtered and concentrated
under reduced pressure. Purification by crystallization (petroleum
(yield 99%) of the desired product as a colourless liquid 1. [
a
]
22 ꢀ2.2
D
(c 1.2, CH2Cl2). 1H NMR (400 MHz, CDCl3)
d
0.25 (s, 9H; 3ꢁ CH3),
0.89 (s, 3H; CH3), 0.97 (s, 3H; CH3), 1.00 (s, 3H; CH3), 1.14e1.22 (m,
1H), 1.56e1.67 (m, 1H), 1.71e1.80 (m, 2H), 1.83 (t, J¼4.0 Hz, 1H), 2.07
(d, J¼13.6 Hz, 1H), 2.19e2.24 (m, 1H). 13C NMR (100 MHz, CDCl3)
d
1.1 (3ꢁ CH3), 10.6 (CH3), 20.4 (CH3), 21.1 (CH3), 26.5 (CH2), 31.7
ether/ethyl acetate) provided the title compound as a white solid
22
(CH2), 45.2 (CH), 47.9 (C), 48.7 (CH2), 54.1 (C), 78.6 (C), 122.1 (C). IR
(4.0 g, yield 93%). Mp¼139e141 ꢂC. [
a]
ꢀ105.4 (c 1.0, CHCl3). 1H
D
(ATR)
n
(cmꢀ1): 2947, 2228, 1482, 1457, 1254, 1150, 1104, 990, 922,
NMR (400 MHz, CDCl3) d 0.87 (s, 3H; CH3), 0.88 (s, 3H; CH3), 0.98
~
881, 844, 751. LRMS (ESI): m/z calcd for C14H25NOSi [MþNa]þ,
274.2; found, 274.2. Anal. Calcd for C14H25NOSi (251.44): C, 66.87;
H, 10.02; N, 5.57. Found: C, 66.75; H, 10.14; N, 5.69%.
(s, 3H; CH3), 1.05 (ddd, J¼5.2, 9.2, 12.4 Hz, 1H), 1.30 (ddd, J¼3.2, 9.2,
12.4 Hz, 1H), 1.29 (d, J¼13.2 Hz, 1H), 1.44 (ddd, J¼5.6, 12.0, 13.6 Hz,
1H), 1.70e1.80 (m, 1H), 1.83 (t, J¼4.8 Hz, 1H), 2.22e2.30 (m, 1H),
2.99 (dd, J¼4.8, 11.6 Hz, 1H), 3.52 (d, J¼11.6 Hz, 1H), 4.05 (d,
J¼17.6 Hz, 1H), 4.15 (d, J¼17.6 Hz, 1H), 7.66 (br s, 1H; NH). 13C NMR
4.2.2. (1R,2R,4R)-2-(Aminomethyl)-1,7,7-trimethylbicyclo[2.2.1]hep-
tan-2-ol (3). To a suspension of LiAlH4 (2.3 g, 59.6 mmol) in 150 mL
of anhydrous diethyl ether was added dropwise a solution of 2
(7.5 g, 29.8 mmol) in 150 mL of anhydrous diethyl ether at ꢀ10 ꢂC
over 45 min. The mixture was stirred for 3 h at this temperature,
then allowed to warm to rt and stirred additionally for 20 h The
reaction mixture was then carefully hydrolyzed with 4 N NaOH
solution (10 mL) and water (20 mL). The precipitate was filtered off
and washed with ether (3ꢁ75 mL). The combined organic layers
were concentrated under vacuum to give aminoalcohol in very
good purity as a white solid and was carried on without further
(100 MHz, CDCl3)
d 10.2 (CH3), 20.2 (CH3), 20.8 (CH3), 26.7 (CH2),
29.9 (CH2), 37.7 (CH2), 45.1 (CH), 48.2 (CH2), 49.0 (C), 51.7 (C), 60.7
(cmꢀ1): 3062, 2918, 1681,
~
n
(CH2), 80.1 (C), 170.0 (C]O). IR (ATR)
1427, 1334, 1120, 1088, 1062, 905, 836, 767. LRMS (ESI): m/z calcd
for C13H21NO2 [MþNa]þ, 246.2; found, 246.2. Anal. Calcd for
C13H21NO2 (223.31): C, 69.92; H, 9.48; N, 6.27. Found: C, 70.01; H,
9.39; N, 6.35%.
4.2.5. (1R,2R,4R)-50-Methoxy-1,7,7-trimethyl-30,60-dihydrospiro[bi-
cyclo[2.2.1]-heptane-2,20-[1,4]oxazine] (6). A flame-dried 50 mL
round-bottomed flask was charged with morpholinone 5 (1.0 g,
4.5 mmol), anhydrous dichloromethane (22 mL) and trimethy-
loxonium tetrafluoroborate (0.67 g, 4.5 mmol, 1.0 equiv). The white
suspension was stirred at ambient temperature under an atmo-
sphere of Ar for 6 h. The solution was cooled to 0 ꢂC and quenched
by slow, portion-wise addition of saturated aqueous NaHCO3
(15 mL) over 15 min. Stirring was maintained for an additional 1 h.
The biphasic solution was transferred to a separatory funnel, the
organic phase separated and the aqueous phase extracted with
CH2Cl2 (3ꢁ50 mL). The combined organic fractions were dried over
MgSO4, filtered and concentrated to afford the crude iminoether 6
as a yellowish liquid. Purification by column chromatography on
silica gel (petroleum ether/ethyl acetate, 95:5) afforded the title
purification (5.35 g, yield 99%). Mp¼100e102 ꢂC. [
a
]
22 ꢀ18.2 (c 1.1,
D
CHCl3). 1H NMR (700 MHz, CDCl3), 0.85 (s, 3H; CH3), 0.88 (s, 3H;
CH3), 0.96e1.01 (m, 1H), 1.13 (s, 3H; CH3), 1.25 (d, J¼12.6 Hz, 1H),
1.29e1.34 (m, 1H), 1.38e1.44 (m, 1H), 1.66e1.74 (m, 2H), 1.95 (dt,
J¼3.5, 12.6 Hz, 1H), 2.69 (d, J¼12.6 Hz, 1H), 2.77 (d, J¼12.6 Hz, 1H).
13C NMR (176 MHz, CDCl3)
d 11.2 (CH3), 20.4 (CH3), 21.2 (CH3), 27.2
(CH2), 29.9 (CH2), 45.0 (CH), 45.1 (CH2), 49.1 (CH2), 49.6 (C), 51.1 (C),
(cmꢀ1): 3338, 2940, 2874, 1700, 1389, 1369, 1149,
~
n
78.7 (C). IR (ATR)
1099, 1011, 945, 908, 855. LRMS (ESI): m/z calcd for C11H21NO
[Mþ1]þ, 184.2; found, 184.2. Anal. Calcd for C11H21NO (183.29): C,
72.08; H, 11.55; N, 7.64. Found: C, 72.16; H, 11.67; N, 7.76%.
4.2.3. 2-Chloro-N-(((1R,2R,4R)-2-hydroxy-1,7,7-trimethylbicyclo
[2.2.1]heptan-2-yl)methyl) acetamide (4). A solution of chloroacetic
chloride (3.1 mL, 39.0 mmol) in 78 mL of dichloromethane was
added dropwise to a biphasic solution of aminoalcohol 3 (6.5 g,
35.5 mmol) in 39 mL of dichloromethane and NaOH in water (0.5 N,
156 mL) over 45 min at 0 ꢂC. The reaction mixture was warmed to rt
and stirred for 4 h at that temperature. The biphasic solution was
transferred to a separatory funnel, the organic phase was separated
and the aqueous phase was extracted with CH2Cl2 (2ꢁ75 mL). The
combined organics were washed 10% aqueous solution of sodium
bicarbonate (100 mL), dried over MgSO4, filtered and concentrated
under reduced pressure. The product (10.0 g, yield 99%) was ob-
tained in very good purity and was carried on without further pu-
compound as a colourless liquid (1.0 g, yield 97%). [
a
]
22 ꢀ86.8 (c 1.7,
D
CHCl3). 1H NMR (400 MHz, CDCl3)
d
0.86 (s, 3H; CH3), 0.88 (s, 3H;
CH3), 1.01 (s, 3H; CH3), 1.06e1.14 (m, 1H), 1.17 (d, J¼13.2 Hz, 1H),1.41
(d, J¼7.6 Hz, 1H), 1.43 (d, J¼7.6 Hz, 1H), 1.71e1.78 (m, 1H), 1.80 (t,
J¼4.8 Hz, 1H), 2.24 (dt, J¼3.2, 13.2 Hz, 1H), 3.35 (dd, J¼2.0, 15.2 Hz,
1H), 3.58 (d, J¼15.2 Hz, 1H), 3.70 (s, 3H; OCH3), 3.97 (d, J¼16.8 Hz,
1H), 4.12 (dt, J¼2.0, 16.8 Hz, 1H). 13C NMR (100 MHz, CDCl3)
d 10.3
(CH3), 20.2 (CH3), 21.0 (CH3), 27.0 (CH2), 29.8 (CH2), 38.4 (CH2), 45.3
(CH), 48.9 (C), 51.7 (C), 52.0 (OCH3), 52.5 (CH2), 56.9 (CH2), 79.2 (C),
(cmꢀ1): 2946, 1682, 1448, 1427, 1335, 1088,
~
n
161.4 (C). IR (ATR)
1048, 1063, 838, 465. LRMS (ESI): m/z calcd for C14H23NO2
[MþNa]þ, 260.2; found, 260.2. Anal. Calcd for C14H23NO2 (237.34):
C, 70.85; H, 9.77; N, 5.90. Found: C, 70.96; H, 9.68; N, 5.97%.
rification. White solid, mp¼42e46 ꢂC. [
a
]
22 ꢀ26.7 (c 1.2, CHCl3). 1H
D
NMR (400 MHz, CDCl3)
d 0.89 (s, 3H; CH3), 0.94 (s, 3H; CH3),
1.07e1.12 (m, 1H), 1.10 (s, 3H; CH3), 1.38e1.54 (m, 3H), 1.60e1.90 (br
s, 1H; OH), 1.70e1.78 (m, 2H), 1.98 (dt, J¼4.0, 13.6 Hz, 1H), 3.30 (dd,
J¼4.8, 13.6 Hz, 1H), 3.54 (dd, J¼6.8, 13.6 Hz, 1H), 4.09 (s, 2H; CH2),
4.2.6. (Z)-2-Mesityl-1-((1R,2R,4R)-1,7,7-trimethylspiro[bicyclo[2.2.1]
heptane-2,20-morpholin]-50-ylidene)hydrazin-1-ium chloride (7). A
flame-dried 50 mL round-bottomed flask was charged with
7.08 (br s, 1H; NH). 13C NMR (100 MHz, CDCl3)
d 10.8 (CH3), 20.6
a
magnetic stir bar, 2-mesitylhydrazinium chloride (0.79 g,
(CH3), 21.2 (CH3), 26.7 (CH2), 30.2 (CH2), 42.6 (CH2), 44.4 (CH2), 44.7
4.2 mmol, 1.0 equiv) and MeOH (17 mL) resulting in a light red/
orange solution. To this solution was added 6 (1.0 g, 4.2 mmol,
1.00 equiv) and the stirred at ambient temperature for 5 min. A
catalytic amount of anhydrous HCl (4 M in 1,4-dioxane, 0.1 mL) was
added, the reaction flask equipped with a water-jacketed con-
denser and the solution stirred at 60 ꢂC under an inert atmosphere
for 4 h. The reaction was allowed to cool to ambient temperature
and concentrated under reduced pressure to afford a crude orange
~
(CH), 47.9 (CH2), 49.5 (C), 51.6 (C), 80.6 (C), 166.7 (C]O). IR (ATR)
n
(cmꢀ1): 3317, 2943, 2875, 1655, 1560, 1432, 1255, 1101, 1074, 851,
788, 726, 689, 588. LRMS (ESI): m/z calcd for C13H2235ClNO2
[MþNa]þ, 282.1; found, 282.2. Anal. Calcd for C13H22ClNO2 (259.77):
C, 60.11; H, 8.54; N, 5.39. Found: C, 60.02; H, 8.50; N, 5.47%.
4.2.4. (1R,2R,4R)-1,7,7-Trimethylspiro[bicyclo[2.2.1]heptane-2,20-
morpholin]-50-one (5). To a solution of chloroamide 4 (5.0 g, 19.2)

ꢀ
Z. Rafinski et al. / Tetrahedron 70 (2014) 5739e5745
5744
solid. The crude material was suspended in ethyl acetate (22 mL)
and stirred vigorously at reflux for 30 min causing a light yellow
precipitate to form. The suspension was allowed to cool to ambient
temperature with vigorous stirring and immersed in an ice/water
bath at 0 ꢂC. The precipitate was collected by suction filtration and
A flame-dried 50 mL round-bottomed flask was charged with
morpholinone (1.0 g, 4.5 mmol) and dichloromethane (22 mL). Tri-
methyloxonium tetrafluoroborate (0.67 g, 4.5 mmol, 1.0 equiv) was
added and stirred under atmosphere of Ar for 6 h. The corresponding
aryl hydrazine was added (4.5 mmol,1 equiv) and stirred at ambient
temperature until the starting material was consumed as visualized
by TLC (ca. 6 h). The solvent was evaporated and the triethyl ortho-
formate (40 equiv) was added. The mixture was then heated to 110 ꢂC
and stirred at this temperature for 18 h. After completion, the solvent
was removed in vacuo. The crude product was washed with AcOEt
affording the pure salt as a white or ochre powder.
washed with EtOAc (3ꢁ5 mL) affording the title compound (1.4 g,
22
yield 84%) as a white powder. Mp¼206e208 ꢂC, yield 84%. [
a]
D
ꢀ8.3 (c 1.1, CH3OH). 1H NMR (400 MHz, DMSO-d6)
d 0.86 (s, 3H;
CH3), 0.88 (s, 3H; CH3), 0.96 (s, 3H; CH3), 1.08e115 (m, 1H),
1.24e1.30 (m, 1H), 1.48e1.61 (m, 2H), 1.43 (dt, J¼5.6, 13.2 Hz, 1H),
1.70e1.76 (m, 1H),1.83 (t, J¼4.0 Hz,1H), 2.19 (s, 6H; 2ꢁ CH3), 2.34 (s,
3H; CH3), 3.17 (dd, J¼5.6, 13.2 Hz, 1H), 3.50 (d, J¼13.2 Hz, 1H), 6.86
(s, 2H; 2ꢁ CHAr), 6.89 (s, 1H), 6.98 (s, 1H), 9.6 (br s, 1H, NH), 10.24 (d,
J¼4.4 Hz, 1H; NH), 11.11 (br s, 1H; NH). 13C NMR (100 MHz, DMSO-
4.3.1. (10R,20R,40R)-10,70,70-Trimethyl-2-phenyl-5,8-dihydrospiro
[[1,2,4]-triazolo[3,4-c][1,4]-oxazine-6,20-bicyclo[2.2.1]heptan]-2-ium
22
d6)
d
10.6 (CH3), 18.3 (2ꢁ CH3), 20.6 (CH3), 20.7 (CH3) 21.3 (CH3),
tetrafluoroborate (A). White solid, mp¼255e256 ꢂC, yield 77%. [
a]
D
26.7 (CH2), 29.5 (CH2), 38.6 (CH2), 45.1 (CH), 46.6 (CH2), 49.2 (C),
ꢀ78.0 (c 1.0, CHCl3).1H NMR (700 MHz, DMSO-d6)
d 0.91 (s, 3H; CH3),
52.3 (C), 55.8 (CH2), 81.7 (C), 129.9 (2ꢁ CHAr), 131.3 (2ꢁ C), 134.1 (C),
0.97 (s, 3H; CH3), 1.03 (s, 3H; CH3), 1.16e1.22 (m, 1H), 1.34e1.39 (m,
2H), 1.53e1.59 (ddd, J¼5.6, 11.9, 14.0 Hz, 1H), 1.75e1.82 (m, 1H), 1.88
(t, J¼4.2 Hz, 1H), 2.30e2.36 (m, 1H), 4.33 (s, 2H; CH2), 5.24 (d,
J¼17.5 Hz, 1H), 5.28 (d, J¼17.5 Hz, 1H), 7.65e7.75 (m, 3H), 7.90e7.94
(cmꢀ1): 3205, 2959, 1726, 1684, 1483,
~
n
138.9 (C), 160.1 (C). IR (ATR)
1339, 1120, 1089, 1045, 850, 762. LRMS (ESI): m/z calcd for
C
C
22H34N3O [MꢀCl]þ, 356.3; found, 356.3. Anal. Calcd for
22H34ClN3O (391.98): C, 67.41; H, 8.74; N,10.72. Found: C, 68.79; H,
(m, 2H),10.80 (s,1H; CH).13C NMR (176 MHz, DMSO-d6)
d 10.5 (CH3),
8.11; N, 10.37%.
20.6 (CH3), 21.2 (CH3), 26.5 (CH2), 29.7 (CH2), 36.2 (CH2), 45.1 (CH),
49.3 (C), 51.4 (CH2), 52.7 (C), 54.5 (CH2), 81.4 (CH), 121.1 (2ꢁ CHAr),
130.8 (2ꢁ CHAr), 131.1 (CHAr), 135.4 (CAr), 142.5 (CH), 149.6 (C). IR
~
521. LRMS (ESI): m/z calcd for C20H26N3O [MꢀBF4]þ, 324.2; found,
324.2. Anal. Calcd for C20H26BF4N3O (411.24): C, 58.41; H, 6.37; N,
10.22. Found: C, 58.46; H, 6.28; N, 10.33%.
4.2.7. (10R,20R,40R)-2-Mesityl-10,70,70-trimethyl-5,8-dihydrospiro
[[1,2,4]-triazolo[3,4-c][1,4] oxazine-6,20-bicyclo[2.2.1]heptan]-2-ium
chloride (D). An oven-dried 50 mL round-bottomed flask was
charged with a magnetic stir bar, 7 (1.2 g, 3.14 mmol), triethyl
orthoformate (5.2 mL, 31.4 mmol, 10 equiv), chlorobenzene (15 mL)
and anhydrous HCl (4 M in 1,4-dioxane, 0.78 mL, 3.14 mmol). The
suspension was stirred at 120 ꢂC for 2 h. The tan-coloured solution
was allowed to cool to ambient temperature, and concentrated
under reduced pressure to afford a crude brown foam. Re-
crystallization from diethyl ether afforded the title compound
(ATR)
n
(cmꢀ1): 2942, 1589, 1438, 1226, 1084, 1048, 979, 761, 686,
4.3.2. (10R,20R,40R)-10,70,70-Trimethyl-2-(perfluorophenyl)-5,8-
dihydrospiro-[[1,2,4]triazolo[3,4-c][1,4]oxazine-6,20-bicyclo[2.2.1]
heptan]-2-ium tetrafluoroborate (B). White solid, mp¼250e252 ꢂC,
yield 72%. [
a
]
22 ꢀ50.0 (c 1.0, acetone). 1H NMR (400 MHz, acetone-
D
(1.0 g, 79%) as a white solid. Mp¼260e262 ꢂC, yield 79%. [
a
]
22 ꢀ45.5
d6)
d
0.96 (s, 3H; CH3), 1.02 (s, 3H; CH3), 1.09 (s, 3H; CH3), 1.25e1.32
D
(c 1.0, CHCl3). 1H NMR (700 MHz, CDCl3)
d
0.92 (s, 3H; CH3), 0.97 (s,
(m, 1H), 1.46e1.53 (m, 1H), 1.56 (d, J¼13.2 Hz, 1H), 1.60e1.68 (m,
1H), 1.79e1.88 (m, 1H), 1.94 (t, J¼4.4 Hz, 1H), 2.45e2.52 (m, 1H),
4.63 (d, J¼13.2 Hz, 1H), 4.86 (d, J¼13.2 Hz, 1H), 5.33 (d, J¼17.6 Hz,
1H), 5.40 (d, J¼17.6 Hz, 1H), 10.45 (s, 1H). 13C NMR (100 MHz, ace-
3H; CH3), 1.04 (s, 3H; CH3), 1.33 (d, J¼12.6 Hz, 1H), 1.40e1.45 (m,
1H), 1.48e1.61 (m, 3H), 1.91 (t, J¼4.2 Hz, 1H), 2.08 (s, 6H; 2ꢁ CH3),
2.20e2.25 (m, 1H), 2.34 (s, 3H; CH3), 4.33 (d, J¼12.6 Hz, 1H), 5.00 (d,
J¼17.5 Hz, 1H), 5.06 (d, J¼17.5 Hz, 1H), 5.33 (d, J¼12.6 Hz, 1H), 6.99
tone-d6)
d 9.4 (CH3), 19.6 (CH3), 20.3 (CH3), 25.9 (CH2), 29.4 (CH2),
(s, 2H; 2ꢁ CHAr), 11.97 (s, 1H; CH). 13C NMR (176 MHz, CDCl3)
d
10.2
36.1 (CH2), 45.4 (CH), 46.8 (C), 52.3 (CH2), 52.7 (C), 54.3 (CH2), 81.5
(cmꢀ1): 2930, 1595, 1522, 1438,
~
n
(CH3), 17.7 (2ꢁ CH3), 20.2 (CH3), 20.7 (CH3), 21.2 (CH3), 26.2 (CH2),
29.8 (CH2), 35.9 (CH2), 45.3 (CH), 49.4 (C), 52.5 (CH2), 52.8 (C), 54.5
(CH2), 82.2 (C), 129.8 (2ꢁ CHAr), 131.2 (C) 134.7 (C), 142.1 (C), 145.5
~
(C), 147.2 (CH), 151.1 (C). IR (ATR)
1075, 1051, 1020, 999, 857, 626, 522. LRMS (ESI): m/z calcd for
C
C
20H21F5N3O [MꢀBF4]þ, 414.2; found, 414.2. Anal. Calcd for
(CH), 145.8 (d, J¼26.4 Hz, CH), 149.3 (C). IR (ATR)
n
(cmꢀ1): 3333,
20H21BF9N3O (501.20): C, 47.93; H, 4.22; N, 8.38. Found: C, 47.81;
2941, 1585, 1448, 1390, 1122, 1082, 976, 846, 580. LRMS (ESI): m/z
calcd for C23H32N3O [MꢀCl]þ, 366.3; found, 366.3. Anal. Calcd for
H, 4.16; N, 8.45%. X-ray crystal structure: C20H21BF9N3O, Mr¼501.20.
Colourless 0.27ꢁ0.16ꢁ0.07 mm crystal obtained from the metha-
C
23H32ClN3O (401.97): C, 68.72; H, 8.02; N, 10.45. Found: C, 68.79;
nol, monoclinic space group P2(1). Cell parameters: a¼10.001(2),
¼96.62(3)ꢂ, V¼1098.9(4) A3,
ꢁ
H, 8.11; N, 10.37%. X-ray crystal structure:
C
23H33ClN3O1.5
,
b¼7.501(2), c¼14.747(3) A,
b
Mr¼410.97. Colourless 0.47ꢁ0.32ꢁ0.26 mm crystal obtained from
Dcalcd¼1.515 mg/m3, Z¼2, F(000)¼512,
m
¼0.146 mmꢀ1. The maxi-
the methanol, triclinic space group P1. Cell parameters:
mum and minimum transmissions of 0.9893 and 0.9606.
ꢁ
a¼12.7769(4), b¼13.5683(4), c¼13.8845(5) A,
a
¼97.978(3),
R1¼0.0533, wR2¼0.1150 for reflections I>2
s(I). The absolute
b
¼93.633(3),
g
¼106.138(3)ꢂ, V¼2276.62(13) A3, Dcalcd¼1.199 mg/
structure Flack parameter x¼0.01(11). The structural data have
been deposited at the Cambridge Crystallographic Data Centre:
(CCDC No. 988374).
m3, Z¼4, F(000)¼884,
m
¼0.188 mmꢀ1. The maximum and minimum
transmissions of 0.9534 and 0.9161. R1¼0.0754, wR2¼0.2097 for
reflections I>2s(I). The absolute structure Flack parameter
x¼0.00(9). The structural data have been deposited at the Cam-
4.3.3. (10R,20R,40R)-10,70,70-Trimethyl-2-(4-nitrophenyl)-5,8-
dihydrospiro-[[1,2,4]triazolo[3,4-c][1,4]oxazine-6,20-bicyclo[2.2.1]
heptan]-2-ium tetrafluoroborate (C). Ochre solid, mp¼316e317 ꢂC,
bridge Crystallographic Data Centre: (CCDC No. 988376).
yield 54%. [
d6)
a
]
22 ꢀ76.6 (c 1.0, acetone). 1H NMR (700 MHz, acetone-
4.3. Preparation of (1R)-camphor-derived triazolium salts AeC
D
d
0.92 (s, 3H; CH3), 0.99 (s, 3H; CH3), 1.05 (s, 3H; CH3), 1.24 (ddd,
J¼4.9, 9.1, 12.6 Hz, 1H), 1.46 (m, 1H), 1.47 (d, J¼13.3 Hz, 1H), 1.60
(ddd, J¼4.9, 11.2, 14.0 Hz, 1H), 1.78e1.83 (m, 1H), 1.89 (t, J¼4.9 Hz,
1H), 2.44 (dt, J¼2.8, 14.0 Hz, 1H), 4.52 (d, J¼12.6 Hz, 1H), 4.70 (d,
J¼12.6 Hz, 1H), 5.30 (d, J¼17.5 Hz, 1H), 5.34 (d, J¼17.5 Hz, 1H),
8.24e8.27 (m, 2H), 8.53e8.56 (m, 2H), 10.67 (s, 1H). 13C NMR
(176 MHz, acetone-d6) d 9.5 (CH3),19.7 (CH3), 20.3 (CH3), 25.9 (CH2),

ꢀ
Z. Rafinski et al. / Tetrahedron 70 (2014) 5739e5745
5745
29.2 (CH2), 35.9 (CH2), 45.3 (CH), 49.1 (C), 51.8 (CH2), 52.6 (C), 54.3
(petroleum ether/ethyl acetate, 7:3) gave (R)-9f (28% yield) as
(CH2), 81.6 (C), 122.6 (2ꢁ CHAr), 125.7 (2ꢁ CHAr), 139.5 (C), 142.8
a yellow solid, mp¼120e121 ꢂC. [
a]
21 ꢀ30.2 (c 0.45, CHCl3). 1H NMR
D
(cmꢀ1): 2953, 2933, 1595, 1528,
(CDCl3) d 3.75 (s, 3H), 3.80 (s, 3H), 4.42 (br s, 1H), 5.84 (s, 1H),
~
n
(CH), 148.8 (C), 150.4 (C). IR (ATR)
1350, 1227, 1049, 972, 854, 749, 523. LRMS (ESI): m/z calcd for
6.80e6.89 (m, 4H), 7.24e7.31 (m, 2H), 7.90 (d, J¼8.8 Hz, 2H). 82:18
C
C
20H25N4O3 [MꢀBF4]þ, 369.2; found, 369.2. Anal. Calcd for
er [Daicel Chiralcel OD-H, hexanes/2-propanol 80:20, v¼0.7 mL/
20H25BF4N4O3 (456.24): C, 52.65; H, 5.52; N, 12.28. Found: C,
minꢀ1
,
l¼254 nm, t (major)¼47.7 min, t (minor)¼64.2 min].
52.60; H, 5.44; N, 12.39%.
Acknowledgements
4.4. Benzoin reaction
We gratefully acknowledge the National Science Centre (grant
No. UMO-2011/03/D/ST5/05626) for financial support.
To a stirred solution of triazolium salt D (0.1 mmol, 10 mol %) in
anhydrous THF (1 mL), was added DIPEA (0.1 mmol, 10 mol %) in
one portion. After 15 min aromatic aldehyde (1 mmol) was added
dropwise at rt under argon. The reaction mixture was stirred for
20 h, then the reaction mixture was directly purified by chroma-
tography (silica gel, petroleum ether/ethyl acetate, 8:2) to give the
desired benzoins as white or yellow solids.
Supplementary data
A supplementary data file (1H and 13C NMR) of newly synthe-
sized compounds (2e7, AeD) is available. Supplementary data re-
lated to this article can be found at http://dx.doi.org/10.1016/
j.tet.2014.06.066.
4.4.1. (R)-2-Hydroxy-1,2-diphenylethanone (9a).10 Purification by
silica gel column chromatography (petroleum ether/ethyl acetate,
21
8:2) gave (R)-9a (93% yield) as a white solid, mp¼130e132 ꢂC. [
a
]
D
References and notes
25
ꢀ82.2 (c 1.2, MeOH). Lit.:20
[a
]
ꢀ150.1 (c 0.56, MeOH), for R en-
D
antiomer with 99% ee. 1H NMR (400 MHz, CDCl3)
d 4.56 (br s, 1H),
1. For recent reviews on NHC-catalyzed transformations, see: (a) Enders, D.;
Balensiefer, T.; Niemeier, O.; Christmann, M. In Enantioselective Organo-
catalysis: Reactions and Experimental Procedures; Dalko, P. I., Ed.; Wiley-VCH:
Weinheim, Germany, 2007; pp 331e355; (b) Enders, D.; Niemeier, O.; Hens-
eler, A. Chem. Rev. 2007, 107, 5606; (c) Moore, J. L.; Rovis, T. Top. Curr. Chem.
2009, 291, 77; (d) Chiang, P.-C.; Bode, J. W. In N-Heterocyclic Carbenes: From
5.94 (s, 1H), 7.27e7.44 (m, 7H), 7.50 (t, J¼8.0 Hz, 1H), 7.94 (d,
J¼8.0 Hz, 2H); 77.5:22:5 er [Daicel Chiralcel OD-H, hexanes/2-
propanol 90:10, v¼0.7 mL/minꢀ1
¼254 nm, t (minor)¼16.6 min,
,
l
t (major)¼23.7 min].
ꢀ
Laboratory Curiosities to Efficient Synthetic Tools; Díez-Gonzalez, S., Ed.; Royal
Society of Chemistry: Cambridge, United Kingdom, 2010; pp 339e445; (e)
Campbell, C. D.; Ling, K. B.; Smith, A. D. In N-Heterocyclic Carbenes in Transition
Metal Catalysis and Organocatalysis; Cazin, C. S. J., Ed.; Springer: Dortrecht,
Germany, 2011; Vol. 32, pp 263e297; (f) Bugaut, X.; Glorius, F. Chem. Soc. Rev.
2012, 41, 3511.
4.4.2. (R)-2-Hydroxy-1,2-di(naphthalen-2-yl)ethanone
(9b).10 Purification by silica gel column chromatography (petro-
leum ether/ethyl acetate, 8:2) gave (R)-9b (54% yield) as a white
21
solid, mp¼116e118 ꢂC. [
a
]
þ26.8 (c 0.9, MeOH). 1H NMR
D
2. For reviews, see: (a) Johnson, J. S. Angew. Chem., Int. Ed. 2004, 43, 1326; (b)
Enders, D.; Balensiefer, T. Acc. Chem. Res. 2004, 37, 534; (c) Zeitler, K. Angew.
Chem., Int. Ed. 2005, 44, 7506; (d) Christmann, M. Angew. Chem., Int. Ed. 2005,
(400 MHz, CDCl3)
d 4.73 (br s, 1H), 6.33 (s, 1H), 7.45e7.65 (m, 5H),
7.74e7.83 (m, 5H), 7.87 (d, J¼8.1 Hz, 1H), 7.94 (s, 1H), 8.05 (d,
ꢀ
44, 2632; (e) Marion, N.; Díez-Gonzalez, S.; Nolan, S. P. Angew. Chem., Int. Ed.
J¼8.1 Hz, 1H), 8.51 (s, 1H); 77.5:22:5 er [Daicel Chiralcel OD-H,
2007, 46, 2988; (f) Nair, V.; Vellalath, S.; Babu, B. P. Chem. Soc. Rev. 2008, 37,
2691; (g) Read de Alaniz, J.; Rovis, T. Synlett 2009, 1189; (h) Phillips, E. M.; Chan,
A.; Scheidt, K. A. Aldrichimica Acta 2009, 42, 55; (i) Biju, A. T.; Kuhl, N.; Glorius, F.
Acc. Chem. Res. 2011, 44, 1182; (j) Hirano, K.; Piel, I.; Glorius, F. Chem. Lett. 2011,
40, 786; (k) Chiang, P.-C.; Bode, J. W. TCIMail 2011, 149, 2; (l) Vora, H. U.; Rovis, T.
Aldrichimica Acta 2011, 44, 3; (m) Rong, Z.-Q.; Zhang, W.; Yang, G.-Q.; You, S.-L.
Curr. Org. Chem. 2011, 15, 3077; (n) Cohen, D. T.; Scheidt, K. A. Chem. Sci. 2012, 3,
53; (o) Grossmann, A.; Enders, D. Angew. Chem., Int. Ed. 2012, 51, 314; (p) Rovis,
T.; Filloux, C. In Comprehensive Chirality; Carreira, E. M., Yamamoto, H., Eds.;
Elsevier Ltd: Amsterdam, 2012; Vol. 6, pp 318e344; (q) Vora, H. U.; Wheeler, P.;
Rovis, T. Adv. Synth. Catal. 2012, 354, 1617.
hexanes/2-propanol 90:10, v¼0.7 mL/minꢀ1
,
l¼254 nm,
t
(major)¼45.6 min, t (minor)¼49.2 min].
4.4.3. (R)-2-Hydroxy-1,2-di(p-tolyl)ethanone (9c).10 Purification by
silica gel column chromatography (petroleum ether/ethyl acetate,
21
8:2) gave (R)-9c (28% yield) as a yellow solid, mp¼87e89 ꢂC. [
a]
D
ꢀ55.1 (c 1.1, MeOH). 1H NMR (400 MHz, CDCl3)
d 2.28 (s, 3H), 2.37 (s,
3H), 4.60 (br s, 1H), 5.94 (s, 1H), 7.09e7.25 (m, 6H), 7.81 (d, J¼8.0 Hz,
€
3. Wohler, F.; Liebig. J. Ann. Pharm. 1832, 3, 249.
2H); 72:28 er [Daicel Chiralcel OD-H, hexanes/2-propanol 90:10,
v¼0.7 mL/minꢀ1
¼254 nm, t (major)¼26.4min, t (minor)¼33.7 min].
,
l
4. Ukai, T.; Tanaka, S.; Dokawa, S. J. Pharm. Soc. Jpn. 1943, 63, 269.
5. Breslow, R. J. Am. Chem. Soc. 1958, 80, 3719.
6. (a) Sheehan, J. C.; Hunnemann, D. H. J. Am. Chem. Soc. 1966, 88, 3666; (b)
Sheehan, J. C.; Hara, T. J. Org. Chem. 1974, 39, 1196.
7. Enders, D.; Breuer, K.; Teles, J. H. Helv. Chim. Acta 1996, 79, 1217.
8. Knight, R. L.; Leeper, F. J. J. Chem. Soc., Perkin Trans. 1 1998, 1891.
9. (a) Enders, D.; Kallfass, U. Angew. Chem., Int. Ed. 2002, 41, 1743; (b) Enders, D.;
Han, J. Tetrahedron: Asymmetry 2008, 19, 1367.
4.4.4. (R)-2-Hydroxy-1,2-bis(2-methoxyphenyl)ethanone
(9d).10 Purification by silica gel column chromatography (petro-
leum ether/ethyl acetate, 7:3) gave (R)-9d (51% yield) as a white
solid, mp¼98e100 ꢂC. [
a
]
21 ꢀ59.6 (c 1.2, CHCl3). 1H NMR (400 MHz,
D
10. Baragwanath, L.; Rose, C. A.; Zeitler, K.; Connon, S. J. J. Org. Chem. 2009, 74, 9214.
CDCl3)
d 3.73 (3H, s), 3.74 (3H, s), 4.50 (br s, 1H), 6.15 (1H, s),
ꢀ
ꢀ
11. Rafinski, Z.; Kozakiewicz, A.; Rafinska, K. ACS Catal. 2014, 4, 1404.
12. Selected examples: (a) Ye, S.; Huang, Z.-Z.; Xia, C.-A.; Tang, Y.; Dai, L.-X. J. Am.
Chem. Soc. 2002, 124, 2432; (b) Kitamura, M.; Oka, H.; Suga, S.; Noyori, R. Org.
Synth. 2003, 79, 139; (c) Kim, H. Y.; Lurain, A. E.; García-García, P.; Carroll, P. J.;
Walsh, P. J. J. Am. Chem. Soc. 2005, 127, 13138; (d) Kloetzing, R. J.; Thaler, T.;
Knochel, P. Org. Lett. 2006, 8, 1125; (e) Deng, X.-M.; Cai, P.; Ye, S.; Sun, X.-L.;
Liao, W.-W.; Li, K.; Tang, Y.; Wu, Y.-D.; Dai, L.-X. J. Am. Chem. Soc. 2006, 128,
9730.
6.73e6.79 (m, 2H), 6.84e6.88 (m, 1H), 6.90e6.95 (m, 1H), 7.19e7.25
(m, 2H), 7.37e7.41 (m, 1H), 7.70 (d, J¼7.8 Hz, 1H); 79:21 er [Daicel
Chiralcel OD-H, hexanes/2-propanol 85:15, v¼0.5 mL/minꢀ1
,
l¼254 nm, t (minor)¼30.6 min, t (major)¼43.5 min].
4.4.5. (R)-1,2-Bis(2-chlorophenyl)-2-hydroxyethanone
13. Wilkinson, H. S.; Grover, P. T.; Vandenbossche, C. P.; Bakale, R. P.; Bhongle, N. N.;
Wald, S. A.; Senanayake, C. H. Org. Lett. 2001, 3, 553.
14. Struble, J. R.; Bode, J. W. Org. Synth. 2010, 87, 362.
(9e).10 Purification by silica gel column chromatography (petro-
leum ether/ethyl acetate, 8:2) gave (R)-9e (20% yield) as an off-
21
white solid, mp¼61e63 ꢂC. [
a]
ꢀ8.8 (c 0.9, CHCl3). 1H NMR
15. Collett, C. J.; Massey, R. S.; Maguire, O. R.; Batsanov, A. S.; O’Donoghue, A. C.;
D
Smith, A. D. Chem. Sci. 2013, 4, 1514.
16. Racemisation of benzoin products was also observed by Connon. O’Toole, S. E.;
Connon, S. J. Org. Biomol. Chem. 2009, 7, 3584.
(CDCl3): 4.05 (br s, 1H), 6.27 (s, 1H), 7.11e7.39 (m, 8H). 62:38 er
[Daicel Chiralcel OD-H, hexanes/2-propanol 90:10, v¼0.7 mL/
minꢀ1
,
l
¼254 nm, t (major)¼26.6 min, t (minor)¼31.4 min].
17. CrysAlis CCD171 and RED171 Package of Programs, Oxford Diffraction, 2000.
€
18. Sheldrick, G. M. SHELXS97 and SHELXL97; University of Gottingen: Germany,
1997.
4.4.6. (R)-2-Hydroxy-1,2-bis(4-methoxyphenyl)ethanone
19. Flack, H. D. Acta Crystallogr., Sect. A 1983, 39, 876.
20. Soeta, T.; Tabatake, Y.; Inomata, K.; Ukaji, Y. Tetrahedron 2012, 68, 894.
(9f).10 Purification by silica gel column chromatography