Enantioselective benzoin condensation catalyzed by spirocyclic terpene-based N-heterocyclic carbenes

Article abstract of DOI:10.1016/j.tet.2016.02.049

The synthesis of new chiral spirocyclic triazolium salts, derived from (1S)-fenchone and (1R)-camphorquinone, are described. These salts, which are N-heterocyclic carbene precatalysts, were successfully employed in the catalytic asymmetric benzoin condensation affording acyloins with good yields and moderate enantioselectivities.

Full text of DOI:10.1016/j.tet.2016.02.049

Tetrahedron xxx (2016) 1e8
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Enantioselective benzoin condensation catalyzed by spirocyclic
terpene-based N-heterocyclic carbenes
Zbigniew Rafi nꢀ ski
Faculty of Chemistry, Nicolaus Copernicus University in Toru nꢀ , 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:
The synthesis of new chiral spirocyclic triazolium salts, derived from (1S)-fenchone and (1R)-cam-
phorquinone, are described. These salts, which are N-heterocyclic carbene precatalysts, were successfully
employed in the catalytic asymmetric benzoin condensation affording acyloins with good yields and
moderate enantioselectivities.
Received 14 November 2015
Received in revised form 8 February 2016
Accepted 22 February 2016
Available online xxx
Ó 2016 Elsevier Ltd. All rights reserved.
Keywords:
N-Heterocyclic carbenes
Benzoin condensation
Asymmetric synthesis
Acyloins
Terpenoids
1. Introduction
Bifunctional chiral NHC precursors derived from L-pyroglu-
tamic acid, pioneered by Connon, proved to be efficient catalysts
7
Over the past decade, N-heterocyclic carbene (NHC) catalysts
have been extensively studied due to their ability to the invert
natural electrophilic nature of the carbonyl group. They offer un-
conventional access to a set of umpolung reactions and emerged
as a powerful tool for synthesis. The NHC-catalyzed benzoin re-
action leads to known, optically active a-hydroxyketones which
leading to >99% ee. Very recently, Connon and Zeitler disclosed
the first chemoselective, intermolecular crossed acyloin con-
densation between two different aldehyde partners involving
8
triazolium precatalysts. In related work, Gravel also demon-
strated a very elegant general approach to chemoselective cross-
benzoin reactions which relied on the NHC catalyst rather than
1
9
are valuable synthons for the synthesis of wide range of natural
substrate control. A change from the traditional pyrrolidinone-
2
and unnatural products. The first asymmetric benzoin conden-
based salt to the piperidinone-based triazolium catalyst resul-
ted in a dramatic improvement of chemoselectivity. Despite
these advances, only a handful of scaffolds is available via tedious
procedures from relatively expensive enantiopure starting ma-
terials. Consequently, the development of novel NHC catalysts
from readily available chiral sources, and the extension of their
application to various asymmetric organic transformations, is
desired.
sation employing a chiral thiazolium salt was reported by Sheenan
3
and co-workers in the 70s of the last century. During the fol-
lowing years, various NHC carbene precursors were developed
and investigated for this type of reaction. However, these carbene
catalysts worked poorly producing acyloins with low-moderate
stereocontrol. Finally, chiral triazolium salts independently de-
veloped by Enders and Leeper, opened an access to a variety of
aromatic acyloins with high yields and enantioselectivity up to
9
Although a number of enantioselective variants of the benzoin
condensation has been reported, this reaction remains a good
model to test newly developed N-heterocyclic carbene catalysts.
A very recent report on the use of the tetracyclic triazolium
0% ee.4 In 2008, You and co-workers developed a novel catalyst,
,5
generated from chiral bis-triazolium salts, which could catalyze
the asymmetric intermolecular benzoin condensation in high ef-
ficiency, and the yields and enantioselectivities could be greatly
improved with low catalyst loading (1 mol % for most reactions)
derived from (1S)-b-pinene and (1R)-camphor in the acyloin
condensation, Stetter reaction, and cross-benzoin reaction
Fig. 1).6
prompted us to disclose our results in this field (Fig. 2).
10,11
(
Herein, we report the synthesis of chiral spirocyclic triazolium
salts derived from (1R)-fenchone and (1R)-camphorquinone and
their use in the benzoin condensation.
E-mail address: payudo@chem.umk.pl.
http://dx.doi.org/10.1016/j.tet.2016.02.049
040-4020/Ó 2016 Elsevier Ltd. All rights reserved.
0
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Z. Rafi nꢀ ski / Tetrahedron xxx (2016) 1e8
Fig. 1. Selected chiral azolium salts.
Fig. 2. Chiral triazolium salts derived from (1S)-b-pinene and (1R)-camphor.
2
. Results and discussion
4
refluxing with LiAlH . Treatment with chloroacetyl chloride, fol-
lowed by potassium tert-butoxide gave the corresponding mor-
pholinone 5. With the amide 5 in hand, a one-pot procedure was
used for the three-step conversion into triazolium salts 6aeb.
Methylation of 6 with Meerwein’s reagent produced the desired
amidate, which was treated in situ with phenyl- or per-
fluorophenylhydrazine to generate the desired cyclization pre-
cursor. Finally, treatment with triethyl orthoformate in
Inspired by the successful application of catalyst G in the
intramolecular benzoin condensation, we continued the prepara-
tion of new pre-carbene salts bearing the spirocyclic system. We
turned attention to rigid bicyclic terepene structures based on the
norcamphor backbone (Fig. 3). Among the terpene systems, fen-
chone and camphorquinone were selected.
ꢀ
chlorobenzene at 110 C gave triazolium salts 6aeb (Scheme 1).
In efforts to prepare the mesityl analogue of catalyst 6a, the
12
protocol developed by Bode was used (Scheme 2). The synthesis
of the desired bicyclic N-mesityl triazolium salt 6c commenced
from morpholinone 5. Methylation was executed using trimethy-
loxonium tetrafluoroborate, and liberation of the free base upon
3
treatment with NaHCO provided the iminoether 7, which was used
without further purification. The condensation of 2-
mesitylhydrazinium hydrochloride and the iminoether 7 led to
the desired amidrazone hydrochloride 8 in good yield. The final
ring closure with triethyl orthoformate in the presence of a stoi-
chiometric amount of anhydrous HCl at elevated temperature
afforded the desired triazolium salt 6c.
Fig. 3. Structure of the terpenes used in this study.
In the second step, the synthesis of camphor-derived triazolium
salts functionalized in the 3-position of camphor backbone was
developed. Thus, camphorquinone 9 was implemented to provide
the aliphatic part of the bicyclic skeleton (Scheme 3). A variety of
attempts to carry out selective monoketalization of 9 met with no
success. Fortunately, the desired monoprotected ketal 10 was pre-
pared using ethylene glycol in refuxing cyclohexane using a Dean-
The synthesis of fenchone-derived triazolium salts commences
from the highly diastereoselective exo-addition of TMSCN to (1S)-
10c
fenchone 1, according to the reported method. Then, silyl ether 2
was transformed into the aminoalcohol 3 in excellent yield by
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Z. Rafi nꢀ ski / Tetrahedron xxx (2016) 1e8
3
Scheme 1. Preparation of the fenchone-derived triazolium salts 6aeb.
Scheme 2. Synthesis of the pre-carbene catalyst 6c.
Scheme 3. Preparation of chiral triazolium salt 16a.
Stark apparatus in the presence of a catalytic amount of p-TsOH, in
4% yield. The minor diketal 11 was easy separated from 10 using
single column chromatography. This process is highly reliable and
can be performed to give up to 50 g of 10 in a single chromato-
graphic run.
In contrast to the fenchone backbone, the addition of TMSCN
to 10 proceeded in a highly diastereoselective fashion with ex-
clusive endo-selectivity to give 12. The reduction of its cyano
group, followed by two-step cyclization using procedure
employing chloroacetyl chloride afforded the lactam 15 in an
overall 83% yield. With the 15 in hand, a one-pot-procedure, in-
volving methylation, the phenylhydrazine coupling reaction and
a final triethylorthoformate ring closure, gave the triazolium salt
16a with 49% yield. Unfortunately, when perfluorophenyl hy-
drazine was used, only trace amount of the corresponding tri-
azolium salt was obtained.
6
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4
Z. Rafi nꢀ ski / Tetrahedron xxx (2016) 1e8
The enantiopure spirocyclic triazolium salt 16b was prepared in
a similar manner as described above for the precatalyst 6c (Scheme
). The triazolium salt could be precipitated from diethyl ether
increasing the catalyst loading (20 mol %) and amount of base
(100 mol %) resulted in slightly higher yield, whereas the selectivity
of 6a remained at the same level. Prolonging the reaction time also
did not increase the yield. Then the catalytic activities of chiral
4
affording a white crystalline solid.
Scheme 4. Synthesis of mesityl analogue of the 16a.
The potential of the new catalysts in the intermolecular benzoin
condensation was tested with benzaldehyde (Table 1).
spirocyclic camphor-based triazolium salts 16a,b were examined.
The catalyst generated from 16a and triethylamine led to a moder-
ate conversion and stereocontrol (entry 8). To our delight, in-
creasing the nucleophility of the catalyst had a positive effect on
both the yield and enantioselectivity (entry 9). Triazolium salt 16b
bearing a mesityl moiety gave the desired benzoin in very high
yield and promising enantioselectivity (70:30 er).
Table 1
a
Screening of the chiral NHC catalysts in the benzoin condensation of benzaldehyde
Solvents and bases screening revealed that ethanol and octa-
fluorotoluene led to much lower yields with slightly decreased
enantioselectivity (Table 2, entries 7 and 9). Various tested bases
(entries 1e6) were found tolerable and dicyclohexylethylamine
was optimal in terms of both the yield and er of the product (Table
2, entry 2). When the catalyst was generated by DBU, almost full
conversion of benzaldehyde was observed but the enantiose-
lectivity dramatically decreased (entry 6). Racemization of the
product in the presence of DBU is possible.
ꢀ
Yield (%)b
erc
Entry
1
2
NHC$HX
T [ C]
6a
6a
6a
6a
6b
6b
6c
16a
16b
rt
rt
40
rt
rt
0
rt
rt
rt
42
56
52
48
99
88
98
48
89
70:30
65:35
65:35
70:30
56:44
60:40
54:46
64.5:35.5
70:30
d
3
4
e
Under the optimized conditions using the carbene precatalyst
5
6
7
8
9
16b, the scope of the intermolecular benzoin reaction was dem-
onstrated with various aromatic aldehydes 19aee (Table 3). We
were delighted to find that our catalytic system was capable of
tolerating relatively different aromatic aldehydes when the re-
actions were conducted in the presence of 10 mol % of 16b and
10 mol % of dicyclohexylethylamine in THF at room temperature for
a
Reaction conditions: 19a (1 mmol), precatalyst (10 mol %), triethylamine
(
10 mol %) in THF (1.1 mL).
b
Yields of isolated benzoin.
20 h. As is evident from Table 3, in all cases the condensation of
c
Determined by chiral HPLC (Daicel Chiralcel OD-H).
aromatic aldehydes 19aee led to the corresponding -hydoxy ke-
a
d
NEt
3
(100 mol %) was used.
e
tones 20aee with reasonable product yields and acceptable enan-
tioselectivities. The reactions of relatively less active 4-
methylbenzaldehyde 19c, 2-methoxybenzaldehyde 19d and 4-
methoxybenzaldehyde 19e were sluggish to furnish the corre-
sponding products 20c, 20d and 20e in lower yields but showed
better enantioselectivities. It is known that electron-rich aromatic
aldehydes are less active, but give better asymmetric induction
than electron-deficient aldehydes. The best result was obtained for
the 4-methoxybenzaldehyde 19e affording the acyloin in 80:20 er.
The R-configuration of the acyloin product was determined by
comparison of its optical rotation with that reported in the litera-
NHC$HBF 6a (20 mol %) was used.
4
Comparison of the benzoin condensation of benzaldehyde 19a
catalyzed by a series of chiral spirocyclic carbenes generated from
triazolium salts 6aec, 16aeb showed a diverse catalytic activity. It
is well known that the N-aryl NHC substituents strongly affects
upon the rate of adduct formation, selectivity and catalyst
As shown in Table 1, when triazolium salts 6aec
10 mol %) derived from fenchone and triethylamine (10 mol %) in
THF was used, 6a gave the promising results affording the benzoin
product in 42% yield and 70:30 enantiomeric ratio (entry 1). Under
the same conditions, catalysts 6b,c showed much higher catalytic
activity provided the product with high yields, however the er
value dropped dramatically (entries 5 and 7). Furthermore,
activity.1
3e15
(
16
ture. It is worth noting, that the ketal group can be easy modified
using different hindered diols or even deprotect the ketal moiety to
ketone, and its further transformations onto bifunctional N-het-
erocyclic carbene catalysts.
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Z. Rafi nꢀ ski / Tetrahedron xxx (2016) 1e8
5
Table 2
Reactions were monitored by thin layer chromatography using
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.
Screening of different bases and solvents in the benzoin condensation of
benzaldehydea
1
13
H and H NMR spectra were obtained using a Bruker DPX-400
or Bruker DPX-700 spectrometer. Chemical shifts are reported in
ppm from tetramethylsilane with the solvent resonance as the in-
ternal standard. The following abbreviations were used to desig-
nate chemical shift multiplicities: s¼singlet, d¼doublet, t¼triplet,
q¼quartet, h¼heptet, m¼multiplet, bs¼broad singlet. The melting
points were determined on a Buchi SPM-20 melting point appa-
ratus. Elemental analyses were performed on a Vario MACRO CHN
Entry
Solvent
Base
NEt
DIPEA
DCyEA
DMAP
DABCO
DBU
DCyEA
DCyEA
DCyEA
Yield (%)b
erc
1
2
3
4
5
6
7
8
9
THF
THF
THF
THF
THF
THF
EtOH
CPME
OFT
3
89
87
92
46
52
95
23
90
10
70:30
analyzer. Optical rotations ([
Optical Activity LTD) polarimeter. IR spectra were recorded on
Perkin Elmer Spectrum Two spectrometer and are reported in
D
a] ) were measured on a PolAAr 3000
71.5:21.5
74.5:25.5
70:30
74:26
Racemate
68:32
(
ꢁ1
terms of frequency of absorption cm . 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 mmꢂ250 mm Daicel
Chiralcel OD-H with n-hexane, 2-propanol as eluent.
71:29
60:40
a
Reaction conditions: 19a (1 mmol), 16b precatalyst (10 mol %), base (10 mol %),
solvent (1.1 mL).
b
Yields of isolated benzoin.
Determined by chiral HPLC (Daicel Chiralcel OD-H). CMPE¼cyclopentyl methyl
c
4.1. General
ether; DCyEA¼Dicyclohexylethylamine; OFT¼octafluorotoluene.
4
.1.1. (1S,2S,4R)-1,3,3-Trimethyl-2-((trimethylsilyl)oxy)bicyclo[2.2.1]
Table 3
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
a
Substrate scope for enantioselective intermolecular benzoin condensation
(
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 (1S)-fenchone 1 was added. The reaction mixture was
stirred at rt until all the starting material was consumed. After
completion, the reaction was quenched with 10% Na CO (100 mL),
2
3
and extracted with tert-butyl methyl ether (3ꢂ100 mL). The com-
bined 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 2ꢂ25 mL of acetonitrile. The hexane layer was
Entry
Ar
Yield (%)b
erc
separated, and concentrated to afford 17.6 g (yield 99%) of the de-
1
2
3
4
5
Ph (19a)
2-Naphthyl (19b)
4-MeC
2-MeOC
4-MeOC
92 (20a)
48 (20b)
29 (20c)
26 (20d)
47 (20e)
74.5:25.5
72:28
70:30
76:24
80:20
22
sired product as a colorless liquid; [
a]
D
¼ꢁ1.8 (c¼2.6, CHCl
3
); IR
ꢁ1
(
ATR) ṽ (cm ): 2942, 2220, 1474, 1454, 1258, 1155, 1104, 990, 922;
6
H
4
(19c)
1
H NMR (400 MHz, CDCl
1.10 (dt, J¼3.2, 12.8 Hz, 1H), 1.16 (t, J¼9.6 Hz, 1H), 1.23 (m, 6H;
2ꢂCH ), 1.38e1.46 (m, 1H), 1.62e1.70 (m, 1H), 1.73e1.79 (m, 2H),
1.84e1.90 (m, 1H); C NMR (100 MHz, CDCl
3
)
d
0.26 (s, 9H; 3ꢂCH
3 3
), 0.90 (s, 3H; CH ),
6
H
4
(19d)
(19e)
6
H
4
a
3
Reaction conditions: 19aee (1 mmol), 16b precatalyst (10 mol %), DCyEA
13
(
10 mol %) in THF (1.1 mL).
3
)
d
1.1 (3ꢂC), 17.9, 21.9,
b
Yields of isolated benzoin.
Determined by chiral HPLC (Daicel Chiralcel OD-H).
25.7, 26.5, 29.5, 40.4, 43.5, 48.5, 54.2, 83.6, 120.1; LRMS (ESI): m/z
c
þ
calcd for C14
H
25NOSiNa [MþNa] , 274.2; found, 274.2; Anal. Calcd
for C14
H25NOSi (251.44): C, 66.88; H, 10.02; Found: C, 66.73; H,
3
. Conclusion
10.10%.
In summary, a series of novel spirocyclic triazolium salts was
4.1.2. (1S,2S,4R)-2-(Aminomethyl)-1,3,3-trimethylbicyclo[2.2.1]hep-
obtained from readily available and inexpensive (1R)-camphor and
1S)-fenchone. The catalyst derived from 16b and dicyclohex-
tan-2-ol (3). To a suspension of LiAlH (3.0 g, 79.5 mmol) in 200 mL
4
(
of anhydrous diethyl ether was added dropwise a solution of 2
ꢀ
ylethylamine was successfully employed in the asymmetric ben-
zoin condensation. The resulting acyloins were obtained in
moderate to excellent yields and acceptable enantioselectivities.
Further structural modification of the spirocyclic triazolium salts
derived from (1R)-camphor and their application in other asym-
metric reactions is currently under way.
(10.0 g, 39.8 mmol) in 200 mL of anhydrous diethyl ether at ꢁ10 C
over 45 min. The mixture was stirred for 3 h at this temperature,
then was heated under reflux for 72 h. The reaction mixture was
then carefully hydrolyzed with 4N NaOH solution (20 mL) and
water (40 mL). The precipitate was filtered off and washed with
ether (3ꢂ100 mL). The combined organic layers were concentrated
under vacuum to give aminoalcohol 3 in very good purity as a white
solid and was carried on without further purification (7.2 g, yield
ꢀ
22
ꢁ1
4
. Experimental
99%); mp¼59e61 C. [
a
]
D
¼þ1.2 (c¼3.1, CHCl
3
); IR (ATR) ṽ (cm ):
1
3
338, 2944, 2870, 1704, 1376, 1360, 1155, 1108, 1016; H NMR
All syntheses and manipulations were carried out under argon
(400 MHz, CDCl
CH ), 0.92 (s, 3H; CH
1.47e1.56 (m, 3H), 1.65e1.75 (m, 1H), 2.01e2.11 (m, 1H), 2.66 (d,
3
)
d
0.80e0.89 (m, 2H), 0.89 (s, 3H; CH
3
), 0.91 (s, 3H;
atmosphere using standard vacuum line techniques. All solvents
and liquid reagents used for catalytic as well as stoichiometric ex-
periments were dried with standard procedures and distilled under
argon atmosphere prior to use.
3
3
), 0.97e1.02 (m, 1H), 1.28e1.41 (m, 1H),
13
J¼12.8 Hz, 1H), 2.77 (d, J¼12.8 Hz, 1H); C NMR (100 MHz, CDCl
3
)
d
17.8, 23.0, 25.5, 26.7, 30.2, 41.0, 43.6, 44.9, 49.6, 51.5, 78.0; LRMS
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6
Z. Rafi nꢀ ski / Tetrahedron xxx (2016) 1e8
þ
ꢀ
22
(
ESI): m/z calcd for C11
H
21NONa [MþNa] , 206.2; found, 206.1;
a white solid; yield 77%; mp¼151e154 C; [
a
]
D
¼þ3.0 (c¼2.3,
), 1.05 (s, 3H;
1
Anal. Calcd for C11
7
H
21NO (183.30): C, 72.08; H, 11.55; Found: C,
CHCl
CH
.65e1.77 (m, 2H), 1.85e2.03 (m, 3H), 4.54 (d, J¼14.0 Hz, 1H), 4.86
(d, J¼14.0 Hz, 1H), 5.07 (d, J¼17.2 Hz, 1H), 5.22 (d, J¼17.2 Hz, 1H),
3
); H NMR (400 MHz, CDCl
3
)
d
0.98 (s, 3H; CH
3
2.22; H, 11.63%.
3 3
), 1.10 (s, 3H; CH ), 1.21e1.31 (m, 2H), 1.54e1.65 (m, 1H),
1
4
[
.1.3. 2-Chloro-N-(((1S,2S,4R)-2-hydroxy-1,3,3-trimethylbicyclo
2.2.1]heptan-2-yl)methyl)-acetamide (4). A solution of chloroacetic
chloride (2.4 mL, 30.0 mmol) in 60 mL of dichloromethane was
13
7.53e7.62 (m, 3H), 7.86e7.93 (m, 2H), 10.38 (s, 1H; CH); C NMR
(100 MHz, CDCl 19.5, 21.5, 25.5, 25.7, 28.8, 43.7, 46.8, 47.3, 48.4,
3
) d
added dropwise to a biphasic solution of aminoalcohol 3 (5.0 g,
52.0, 58.7, 81.2, 120.8 (2ꢂCH), 130.2 (2ꢂCH), 130.9, 135.0, 139.9,
ꢁ1
2
7.6 mmol) in 30 mL of dichloromethane and NaOH in water (0.5N,
149.8; IR (ATR) ṽ (cm ): 2940, 1595, 1430, 1220, 1089, 1055, 979,
ꢀ
þ
120 mL) over 45 min at 0 C. The reaction mixture was warmed to rt
761; LRMS (ESI): m/z calcd for C20
H
26
N
3
O [MꢁBF
4
] , 324.2; found,
and stirred for 4 h at that temperature. The biphasic solution was
transferred to a separatory funnel, the organic phase was separated
324.2; Anal. Calcd for C20
Found: C, 58.39; H, 6.32%.
H26BF
4
N
3
O (411.24): C, 58.41; H, 6.37;
and the aqueous phase was extracted with CH
combined organics were washed 10% aqueous solution of sodium
bicarbonate (100 mL), dried over MgSO , filtered, and concentrated
2
Cl
2
(2ꢂ60 mL). The
0
0
0
4.1.6. (1S,2S,4R)-1,3,3-Trimethyl-2 -(perfluorophenyl)-5 H,8 H-spiro
0
0
4
[bicyclo[2.2.1]heptane-2,6 -[1,2,4]triazolo[3,4-c][1,4]oxazin]-2 -ium
tetrafluoroborate (6b). Following the procedure as described for the
6a using pentafluorophenylhydrazine, the product 6b was obtained
under reduced pressure. The product (7.05 g, yield 99%) was ob-
tained in very good purity as a white solid and was carried on
ꢀ
22
ꢀ
22
without further purification; mp¼58e60 C; [
a
]
D
¼þ1.4 (c¼2.3,
in 72% yield as a white solid; mp¼231e234 C; [
a
]
D
¼þ3.1 (c¼3.1,
1
1
CHCl
CH
.43e1.53 (m, 1H), 1.64e1.73 (m, 3H), 1.82e1.89 (m, 1H), 1.90 (s, 1H),
3
); H NMR (400 MHz, CDCl
3
)
d
0.99 (s, 3H; CH
3
), 1.06 (s, 3H;
CHCl
CH
3
); H NMR (700 MHz, CDCl
3
)
d
0.91 (s, 3H; CH
3
), 1.04 (s, 3H;
3
), 1.07 (s, 3H; CH
3
), 1.10e1.12 (m, 1H), 1.17e1.22 (m, 1H),
3
), 1.10 (s, 3H; CH
3
), 1.20e1.27 (m, 2H), 1.55e1.61 (m, 3H),
1
1.70e1.75 (m, 1H), 1.84e1.97 (m, 3H), 4.56 (d, J¼14.7 Hz, 1H), 4.84
3
2
2
.35 (dd, J¼4.8, 14.0 Hz, 1H), 3.54 (dd, J¼6.0, 14.0 Hz, 1H), 4.06 (s,
(d, J¼14.7 Hz, 1H), 5.06 (d, J¼16.8 Hz, 1H), 5.21 (d, J¼16.8 Hz, 1H),
13
13
H; CH
2
), 7.11 (br s, 1H; NH); C NMR (100 MHz, CDCl
3
)
d
17.5, 22.3,
10.21 (s,1H); C NMR (100 MHz, CDCl
3
)
d
18.5, 21.2, 24.9, 25.0, 28.5,
5.0, 26.4, 30.2, 41.1, 42.7, 44.0, 44.8, 49.4, 52.0, 80.2, 165.9; IR (ATR)
43.0, 46.4, 47.4, 48.0, 51.6, 58.2, 81.0, 110.5, 136.9, 138.4, 141.9, 143.4,
146.1, 150.3; IR (ATR) ṽ (cm ): 2926, 1590, 1527, 1438, 1075, 1059,
1028, 1006, 857; LRMS (ESI): m/z calcd for C20
414.2; found, 414.2; Anal. Calcd for C20
H, 4.22; Found: C, 47.81; H, 4.16%.
ꢁ
1
ꢁ1
ṽ (cm ): 3310, 2935, 2870, 1648, 1567, 1424, 1255, 1097, 1074, 856,
3
5
þ
þ
7
80; LRMS (ESI): m/z calcd for C13
H
22ClNO
2
Na [MþNa] , 282.1;
H
21
F
5
N
3
O [MꢁBF
4
] ,
found, 282.2; Anal. Calcd for C13
H
22ClNO
2
(259.77): C, 60.11; H,
9 3
H21BF N O (501.20): C, 47.93;
8
.54; Found: C, 60.16; H, 8.46%.
0
4
.1.4. (1S,2S,4R)-1,3,3-Trimethylspiro[bicyclo[2.2.1]heptane-2,2 -
4.1.7. (Z)-2-Mesityl-1-((1S,2S,4R)-1,3,3-trimethylspiro[bicyclo[2.2.1]
0
0
0
morpholin]-5 -one (5). To a solution of chloroamide 4 (5.0 g, 19.4) in
4 mL of anhydrous dichloromethane was added dropwise a solu-
tion of potassium tert-butoxide (8.6 g, 76.8 mmol) in i-propanol
over 45 min at 0 C. The solution was allowed to warm to ambient
temperature and stirred for 24 h. After that time all volatile ma-
terials were evaporated under reduced pressure. Water (200 mL)
was added and mixture was extracted with ethyl acetate
heptane-2,2 -morpholin]-5 -ylidene)hydrazin-1-ium chloride (8). To
a dry dichloromethane solution (50 mL) of morpholinone 5 (3.0 g,
13.5 mmol) was added trimethyloxonium tetrafluoroborate (2.5 g,
13.5 mmol,1.0 equiv), and the resulting mixture was stirred at room
temperature for 20 h under an argon atmosphere. The solution was
9
ꢀ
ꢀ
cooled to 0 C and quenched by the slow, portion-wise addition of
3
saturated aqueous solution of NaHCO (30 mL) over a period of
(
3ꢂ100 mL). The combined organic phases were washed with
30 min, stirring was maintained for an additional 1 h. The biphasic
solution was transferred to a separatory funnel, the organic phase
water and brine, dried over MgSO , filtered, and concentrated un-
4
der reduced pressure. Purification by crystallization (Petroleum
ether/ethyl acetate) provided the title compound as a white solid
separated, and the aqueous phase extracted with CH
(3ꢂ50 mL). The combined organic fractions were dried over
Mg SO , filtered, and concentrated to afford the crude iminoether 7
2 2
Cl
ꢀ
22
1
(
4.0 g, yield 93%); mp¼158e161 C. [
a
]
D
¼þ6.5 (c¼2.6, CHCl
), 1.02 (s, 3H; CH ), 1.12 (dt,
),
.44e1.56 (m, 1H), 1.61e1.69 (m, 2H), 1.76e1.87 (m, 1H), 1.94e2.04
m, 1H), 3.28 (dd, J¼4.0, 12.8 Hz, 1H), 3.56 (dd, J¼1.6, 12.8 Hz, 1H),
3
); H
2
4
NMR (400 MHz, CDCl
3
)
d
1.00 (s, 3H; CH
3
3
(3.15 g, 99%) as a colorless solid which was used without further
purification. A flame-dried 50-mL round-bottomed flask was
charged with 2-mesitylhydrazinium chloride (2.0 g, 10.6 mmol,
1.00 equiv), iminoether 7 (2.5 g, 10.6 mmol, 1.00 equiv) and MeOH
(42 mL) resulting in a light orange solution. After 5 min stirring at
ambient temperature, a catalytic amount of anhydrous HCl (4 M in
1,4-dioxane, 0.26 mL, 0.03 mmol) was added, and the resulting
J¼4.4, 12.4, 1H), 1.17 (dd, J¼2.0, 10.4 Hz, 1H), 1.21 (s, 1H, CH
3
1
(
4
.18 (d, J¼17.6 Hz, 1H), 4.23 (d, J¼17.6 Hz, 1H), 6.80 (br s, 1H; NH);
1
3
C NMR (100 MHz, CDCl
3
) d 20.1, 21.9, 25.3, 26.1, 28.9, 43.4, 43.7,
ꢁ
1
4
5.5, 48.9, 51.6, 65.0, 79.7, 170.3; IR (ATR) ṽ (cm ): 3062, 2918,
ꢀ
1
681, 1427, 1334, 1120, 1088, 1062, 905, 836, 767; LRMS (ESI): m/z
solution was heated at 60 C and stirred for 4 h. The reaction was
þ
calcd for C13
for C13 21NO
H
21NO
2
Na [MþNa] , 246.2; found, 246.2; Anal. Calcd
allowed to cool to ambient temperature and the concentrated un-
der reduced pressure to afford a crude orange solid. The crude
material was suspended in EtOAc (25 mL) and stirred vigorously in
H
2
(223.32): C, 69.92; H, 9.48; Found: C, 70.06; H, 9.36%.
0
0
0
ꢀ
4
[
.1.5. (1S,2S,4R)-1,3,3-Trimethyl-2 -phenyl-5 H,8 H-spiro[bicyclo
a at 70 C for 30 min causing a light yellow precipitate to form. The
0
0
2.2.1]heptane-2,6 -[1,2,4]triazolo[3,4-c][1,4]oxazin]-2 -ium
tetra-
suspension was allowed to cool to ambient temperature with vig-
ꢀ
fluoroborate (6a). A flame-dried 50 mL round-bottomed flask was
charged with morpholinone 5 (1.0 g, 4.5 mmol) and dichloro-
methane (22 mL). Trimethyloxonium tetrafluoroborate (0.67 g,
orous stirring and immersed in an ice/water bath at 0 C with
vigorous stirring. The precipitate was collected by suction filtration
and washed with EtOAc (3ꢂ3 mL) affording the amidrazone hy-
4
.5 mmol, 1.0 equiv) was added and stirred under atmosphere of Ar
drochloride
mp¼129e131 C; [
CDCl 0.96 (s, 3H; CH
8
(2.7 g, 64%) as
a
light yellow powder;
ꢀ
22
1
for 12 h. The phenylhydrazine 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 evapo-
rated and the triethyl orthoformate (40 equiv) was added. The
a
]
D
¼L0.6 (c¼2.3, CHCl
3
); H NMR (400 MHz,
), 1.06 (s, 3H; CH ),
3
)
d
3
), 1.04 (s, 3H; CH
3
3
1.38e1.46 (m, 1H), 1.58e1.60 (m, 1H), 1.64e1.68 (m, 1H), 1.69e1.72
(m, 1H), 1.86e1.91 (m, 1H), 2.19 (s, 3H), 2.21 (s, 6H), 3.43 (dd, J¼4.9,
14.0 Hz, 1H), 3.57 (dd, J¼2.1, 14.0 Hz, 1H), 4.42 (d, J¼16.1 Hz, 1H),
4.49 (d, J¼16.1 Hz, 1H), 6.85 (s, 2H), 7.05 (s, 1H), 10.31 (br s, 1H),
ꢀ
mixture was then heated to 110 C 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
13
11.21 (br s, 1H); C NMR (100 MHz, CDCl
3
)
d
18.5, 18.6 (2ꢂC), 20.7,
Please cite this article in press as: Rafi nꢀ ski, Z., Tetrahedron (2016), http://dx.doi.org/10.1016/j.tet.2016.02.049

Z. Rafi nꢀ ski / Tetrahedron xxx (2016) 1e8
7
2
2.2, 25.1, 26.2, 29.3, 40.6, 41.7, 45.5, 49.2, 52.4, 59.1, 83.3, 129.8
1H NMR (400 MHz, CDCl
3
)
d
0.86 (s, 6H; 2ꢂCH
3
), 1.26 (s, 3H; CH
3
),
ꢁ
1
(
2
2ꢂC), 132.0 (2ꢂC), 134.3, 138.8, 162.2; IR (ATR) ṽ (cm ): 3205,
1.29e1.37 (m, 2H), 1.44 (ddd, J¼3.6, 9.2, 13.3 Hz, 1H), 1.50e1.59 (m,
1H), 1.67e1.74 (m, 2H), 2.47 (d, J¼12.4 Hz, 1H), 3.13 (d, J¼12.4 Hz,
1H), 3.75e3.80 (m, 1H), 3.85e3.93 (m, 1H), 3.94e4.00 (m, 2H), 4.11
959, 1726, 1684, 1483, 1339, 1120, 1089, 1045; LRMS (ESI): m/z
þ
calcd for C22
C
34
H N
3
O [MꢁCl] , 356.3; found, 356.3. Anal. Calcd for
13
22
H34ClN
3
O (391.98): C, 67.41; H, 8.74; Found: C, 67.49; H, 8.80%.
(br s, 1H, NH); C NMR (100 MHz, CDCl
3
) d 10.7, 20.9, 21.3, 21.9,
ꢁ
1
28.9, 44.0, 47.6, 52.1, 52.9, 64.3, 64.8, 80,1, 116.5; IR (ATR) ṽ (cm ):
0
0
0
4
.1.8. (1S,2S,4R)-2 -Mesityl-1,3,3-trimethyl-5 H,8 H-spiro[bicyclo
3388, 3038, 2863, 1028; LRMS (ESI): m/z calcd for C13
3
H23NO Na
0
0
þ
[
2.2.1]heptane-2,6 -[1,2,4]triazolo[3,4-c][1,4]oxazin]-2 -ium chloride
6c). To a solution of 8 (2.0 g, 5.1 mmol, 1.00 equiv), triethylor-
thoformate (6.8 mL, 40.9 mmol, 8.0 equiv) in chlorobenzene
5.5 mL), anhydrous HCl (4 M in 1,4-dioxane, 1.28 mL, 5.1 mmol,
[MþNa] , 264.2; found, 264.2; Anal. Calcd for C20
H26BF N O
4 3
(
(241.3): C, 64.70; H, 9.61; Found: C, 64.76; H, 9.74%.
(
4.1.12. 2-Chloro-N-(((1S,3R,4R)-3-hydroxy-4,7,7-trimethylspiro[bicy-
0
1.00 equiv) was added under an argon atmosphere and the reaction
clo[2.2.1]heptane-2,2 -[1,3]dioxolan]-3-yl)methyl)acetamide
ꢀ
mixture was heated for 2 h at 120 C. The solvent was removed
(14). Following the procedure as described for the 4, the product 14
ꢀ
under reduced pressure and the diethyl ether was added (20 mL).
The resulting white precipitate was collected by suction filtration
and washed with ether (2ꢂ5 mL) to give the desired triazolium salt
was obtained in 90% yield as a yellowish solid; mp¼91e93 C;
2
2
1
[a
]
D
¼þ12.2 (c¼1.0, acetone); H NMR (400 MHz, CDCl
3
) d 0.88 (s,
3 3 3
3H; CH ), 0.93 (s, 3H; CH ), 1.18 (s, 3H; CH ), 1.38e1.51 (m, 2H),
ꢀ
22
(
1.5 g, 72%) as a white solid; mp¼290e292 C; [
a
]
D
¼þ2.9 (c¼2.3,
1.54e1.63 (m, 1H), 1.72 (d, J¼4.8 Hz, 1H), 1.81 (ddd, J¼5.6, 9.2,
1
CHCl
CH
3
); H NMR (400 MHz, CDCl
3
)
d
1.00 (s, 3H; CH
3
), 1.07 (s, 3H;
13.2 Hz, 1H), 3.05 (s, 1H), 3.52 (m, 2H), 3.79e3.88 (m, 2H),
1
3
3
), 1.16 (s, 3H; CH
3
),1.25e1.29 (m, 2H),1.56e1.64 (m,1H),1.75 (m,
3.95e4.01 (m, 2H), 4.05 (d, J¼4.8 Hz, 2H), 7.02 (br s, 1H, NH);
C
1
1
H), 1.86e2.03 (m, 4H), 2.08 (s, 6H), 2.36 (s, 3H), 4.47 (d, J¼14.4 Hz,
NMR (100 MHz, CDCl 10.8, 20.8, 21.6, 21.9, 29.4, 42.5, 42.9, 47.4,
3
) d
ꢁ
1
H), 5.09 (d, J¼17.6 Hz, 1H), 5.23 (d, J¼17.6 Hz, 1H), 5.52 (d,
52.7, 53.0, 65.0, 65.6, 81.8, 115.3, 165.4; IR (ATR) ṽ (cm ): 3315,
13
J¼14.4 Hz, 1H), 7.02 (s, 2H), 12.22 (s, 1H; CH); C NMR (100 MHz,
2995, 2954, 1657, 1013, 680; LRMS (ESI): m/z calcd for
þ
CDCl
4
3
)
d
17.5 (2ꢂC), 19.7, 21.2, 21.6, 25.5, 26.0, 28.7, 43.8, 46.7, 48.0,
C
C
15
H
H
24ClNO
24ClNO
4
Na [MþNa] , 340.1; found, 340.2; Anal. Calcd for
8.3, 52.0, 58.9, 81.4, 129.7 (2ꢂC), 131.1, 134.6 (2ꢂC), 142.0, 144.9,
15
4
(317.81): C, 56.69; H, 7.61; Found: C, 56.78; H, 7.49%.
ꢁ
1
149.6; IR (ATR) ṽ (cm ): 3325, 2951, 1585, 1455, 1379, 1122, 1082,
þ
0
0
0
0
0
0
0
976, 846; LRMS (ESI): m/z calcd for C23
H
32
N
3
O [MꢁCl] , 366.3;
4.1.13. (1 R,2R,4 S)-1 ,7 ,7 -Trimethyldispiro[morpholine-2,2 -bicyclo
00
found, 366.3. Anal. Calcd for C23 32ClN
H
3
O (401.97): C, 68.72; H,
[2.2.1]heptane-3 ,2 -[1,3]dioxolan]-5-one (15). Following the pro-
cedure as described for the 5, the product 15 was obtained in 97%
8
.02; Found: C, 68.64; H, 8.09%.
ꢀ
22
yield as a white solid; mp¼176e178 C; [
a
]
D
¼þ29.4 (c¼1.0,
), 0.90 (s,
), 1.40 (ddd, J¼4.9,
0
1
4.1.9. (1S,4R)-4,7,7-Trimethylspiro[bicyclo[2.2.1]heptane-2,2 -[1,3]di-
CH
2
Cl
2
); H NMR (700 MHz, CDCl
3
)
d
0.89 (s, 3H; CH
3
oxolan]-3-one (10). A stirred solution of camphorquinone 9 (20.0 g,
20 mmol), p-toluenesulfonic acid (1.1 g, 6.6 mmol), and ethylene
3H; CH
3
), 1.23e1.28 (m, 1H), 1.29 (s, 3H; CH
3
1
11.9, 14.0 Hz, 1H), 1.55e1.60 (m, 1H), 1.69 (d, J¼4.9 Hz, 1H), 1.81
(ddd, J¼4.9, 9.1, 14.0 Hz, 1H), 3.35 (d, J¼11.9 Hz, 1H), 3.61 (dd,
J¼5.6, 11.9 Hz, 1H), 3.79e3.83 (m, 1H), 3.86e3.89 (m, 1H),
4.00e4.03 (m, 1H), 4.21 (d, J¼16.8 Hz, 1H), 4.68 (d, J¼16.8 Hz, 1H),
glycol (6.7 mL, 120 mmol) in cyclohexane (160 mL) was heated
under reflux using a Dean-Stark trap. After 24 h, the reaction
mixture was washed with 10% aqueous sodium hydroxide and
brine, dried anhydrous magnesium sulfate, filtered, and the cyclo-
hexane was removed under reduced pressure. The crude product
was separated from the diacetal 11 by using column chromatog-
raphy (EtOAc/hexane 2:8) to provide the desired monoacetal 10 in
13
3
6.1 (br s, 1H, NH); C NMR (100 MHz, CDCl ) d 11.0, 20.4, 21.2,
21.9, 29.6, 43.6, 47.5, 53.1, 54.4, 64.8, 65.1, 65.2, 82.0, 116.7, 169.8;
ꢁ
1
IR (ATR) ṽ (cm ): 3187, 2885, 1686, 1651, 1047; LRMS (ESI): m/z
þ
calcd for C15
H
23NO
4
Na [MþNa] , 304.2; found, 304.2; Anal. Calcd
ꢀ
22
5
CH
CH
1% yield as a white solid; mp¼84e85 C; [
a
]
D
¼þ65.0 (c¼1.0,
0.92 (s, 3H; CH ), 0.99 (s, 3H;
), 1.56e1.61 (m, 1H), 1.65e1.70 (m, 1H),
for C15
8.31%.
4
H23NO (281.35): C, 64.04; H, 8.24; Found: C, 64.12; H,
1
2
Cl
2
); H NMR (700 MHz, CDCl
3
)
d
3
3
), 1.03 (s, 3H; CH
3
0 0 0 0 0
4.1.14. (1 R,4 S,6R)-1 ,7 ,7 -Trimethyl-2-phenyl-5H,8H-dispiro[[1,2,4]
triazolo[3,4-c][1,4]oxazine-6,2 -bicyclo[2.2.1]heptane-3 ,2 -[1,3]diox-
olan]-2-ium tetrafluoroborate (16a). Following the procedure as
described for the 6a, the product 16a was obtained in 49% yield as
1.80e1.85 (m, 1H), 1.97e2.02 (m, 2H), 3.97e4.00 (m, 1H), 4.02e4.05
13
0
0
00
(
m, 1H), 4.18e4.21 (m, 1H), 4.30e4.33 (m, 1H); C NMR (100 MHz,
CDCl 9.1, 19.0, 21.4, 21.5, 30.9, 43.6, 51.6, 58.2, 64.4, 66.1, 106.9,
3
) d
ꢁ
1
2
C
C
17.3; IR (ATR) ṽ (cm ): 2962, 1750, 1023; LRMS (ESI): m/z calcd for
þ
ꢀ
22
12
H
H
18
O
3
Na [MþNa] , 233.1; found, 233.2; Anal. Calcd for
a yellowish solid; mp¼222e224 C; [
a
]
D
¼þ44.1 (c¼1.0, CH
2 2
Cl );
1
16
27NOSi (309.48): C, 68.55; H, 8.63; Found: C, 68.42; H, 8.51%.
H NMR (700 MHz, CDCl
3
)
d
0.96 (s, 3H; CH
3
), 0.99 (s, 3H; CH ), 1.33
3
3
(s, 3H; CH ), 1.53e1.56 (m, 2H), 1.60e1.64 (m, 1H), 1.73e1.76 (m,
4
.1.10. (1S,3R,4R)-4,7,7-Trimethyl-3-((trimethylsilyl)oxy)spiro[bicy-
1H), 1.79 (d, J¼4.9 Hz, 1H), 3.25e3.28 (m, 1H), 3.71e3.76 (m, 1H),
0
clo[2.2.1]heptane-2,2 -[1,3]dioxolane]-3-carbonitrile (12). Following
the procedure as described for the 2, the product 12 was obtained
3.86e3.90 (m, 1H), 4.26 (d, J¼14.0 Hz, 1H), 5.02 (d, J¼14.0 Hz, 1H),
5.18 (d, J¼16.8 Hz, 1H), 5.73 (d, J¼16.8 Hz, 1H), 7.59e7.64 (m, 3H),
2
2
1
13
in 92% yield as a colorless liquid; [
NMR (700 MHz, CDCl
0.24 (s, 9H; 3ꢂCH
s, 3H; CH ), 1.15 (s, 3H; CH ), 1.56e1.62 (m, 2H), 1.71e1.73 (m, 1H),
.82e1.90 (m, 2H), 3.91e4.05 (m, 3H), 4.07e4.12 (m, 1H); C NMR
100 MHz, CDCl
1.0 (3ꢂC), 11.1, 20.1, 21.2, 21.7, 31.3, 47.8, 53.3,
4.9, 64.2, 65.1, 85.7, 114.4, 118.8; IR (ATR) ṽ (cm ): 2959, 2231,
a
]
D
¼L9.1 (c¼1.0, CH
2
Cl
2
);
H
7.94e7.96 (m, 2H), 10.54 (s, 1H); C NMR (100 MHz, CDCl
3
)
d
10.6,
3
)
d
3
), 0.89 (s, 3H; CH
3
), 0.96
20.0, 21.3, 21.7, 29.4, 47.9, 48.0, 52.9, 53.6, 59.3, 64.5, 82.6, 116.8,
(
1
(
5
3
3
120.6 (2ꢂC), 130.3 (2ꢂC), 131.0, 134.8, 139.8, 150.2; IR (ATR) ṽ
13
ꢁ1
(cm ): 2956, 1689, 1584, 1039; LRMS (ESI): m/z calcd for
þ
3
)
d
C
C
22
H
H
28
N
28BF
3
O
3
[MꢁBF
4
] , 382.2; found, 382.2; Anal. Calcd for
ꢁ1
22
4
N
3
O
3
(469.29): C, 56.31; H, 6.01; Found: C, 56.37; H,
1
472, 1457, 1149; LRMS (ESI): m/z calcd for C16
H
27NO
3
SiNa
6.11%.
þ
[
MþNa] , 332.2; found, 332.2; Anal. Calcd for C16
H27NOSi (309.48):
0
0
0
0
0
C, 62.10; H, 8.79; Found: C, 62.18; H, 8.86%.
4.1.15. (1 R,4 S,6R)-2-Mesityl-1 ,7 ,7 -trimethyl-5H,8H-dispiro[[1,2,4]
0
0
00
triazolo[3,4-c][1,4]oxazine-6,2 -bicyclo[2.2.1]heptane-3 ,2 -[1,3]diox-
olan]-2-ium chloride (16b). Following the procedure as described
for the 6c, the product 16b was obtained in 51% yield as a white
4
.1.11. (1S,3R,4R)-3-(Aminomethyl)-4,7,7-trimethylspiro[bicyclo
0
[2.2.1]heptane-2,2 -[1,3]dioxolan]-3-ol (13). Following the pro-
ꢀ
22
1
cedure as described for the 3, the product 13 was obtained in 95%
yield as a white solid; mp¼71e73 C; [
solid; mp¼276e278 C; [
a]
D
¼L82.3 (c¼1.0, CH
2
Cl
2
); H NMR
ꢀ
22
a
]
D
¼þ1.2 (c¼1.0, CH
2
Cl
2
);
(400 MHz, CDCl
3
)
d
0.95 (s, 3H; CH
3
), 1.00 (s, 3H; CH
3
), 1.33 (s, 3H;
Please cite this article in press as: Rafi nꢀ ski, Z., Tetrahedron (2016), http://dx.doi.org/10.1016/j.tet.2016.02.049

8
Z. Rafi nꢀ ski / Tetrahedron xxx (2016) 1e8
CH
3
), 1.53e1.62 (m, 3H), 1.74e1.80 (m, 2H), 2.10 (s, 6H), 2.37 (s, 3H),
52 ee [Daicel Chiralcel OD-H, hexanes/2-propanol 85:15, v¼0.5 mL/
1
ꢁ
3
.37e3.42 (m, 1H), 3.64e3.75 (m, 2H), 3.89e3.94 (m, 1H), 4.30 (d,
min
,
l
¼254 nm, t (minor)¼30.6 min, t (major)¼43.5 min].
J¼14.0 Hz, 1H), 5.14 (d, J¼17.2 Hz, 1H), 5.36 (d, J¼14.0 Hz, 1H), 5.72
13
(
d, J¼17.2 Hz, 1H), 7.03 (s, 2H), 12.39 (s, 1H); C NMR (100 MHz,
CDCl
10.6, 17.4 (2ꢂC), 20.0, 21.1, 21.3, 21.7, 29.5, 48.0, 48.2, 52.6,
3.5, 59.4, 64.1, 64.3, 82.5, 116.9, 129.8 (2ꢂC), 131.1, 134.3 (2ꢂC),
4.2.5. (R)-2-Hydroxy-1,2-bis(4-methoxyphenyl)ethanone
(20e). Purification by silica gel column chromatography (petro-
3
)
d
5
leum ether/ethyl acetate, 7:3) gave (R)-20e (47% yield) as a yellow
ꢁ
1
1
142.0, 145.3, 149.5; IR (ATR) ṽ (cm ): 2912, 1747, 1037; LRMS (ESI):
solid; H NMR (400 MHz, CDCl
3
)
d
3.75 (s, 3H), 3.80 (s, 3H), 4.42 (br
þ
m/z calcd for C20
for C25 34ClN
H
26
N
3
O [MꢁCl] , 424.3; found, 424.3; Anal. Calcd
s, 1H), 5.84 (s, 1H), 6.80e6.89 (m, 4H), 7.24e7.31 (m, 2H), 7.90 (d,
J¼8.8 Hz, 2H). 60 ee [Daicel Chiralcel OD-H, hexanes/2-propanol
H
3
O
3
(460.02): C, 65.28; H, 7.45; Found: C, 65.19; H,
ꢁ
1
7.59%.
80:20, v¼0.7 mL/min
4.2 min].
,
l¼254 nm, t (major)¼47.7 min, t (minor)¼
6
4
.2. Benzoin reaction
Acknowledgments
To a stirred solution of triazolium salt 16b (0.1 mmol, 10 mol %)
in anhydrous THF (1 mL), was added DCyEA (0.1 mmol, 10 mol %)
in one portion. After 15 min aromatic aldehyde (1 mmol) was
added dropwise at room temperature under argon. The reaction
mixture was stirred for 20 h, then the reaction mixture was di-
rectly purified by chromatography (silica gel, petroleum ether/
ethyl acetate, 8:2) to give the desired acyloins as white or yellow
solids.
We gratefully acknowledge the National Science Centre (grant
No. UMO-2011/03/D/ST5/05626) for financial support.
Supplementary data
Supplementary data associated with this article can be found in
the online version, at http://dx.doi.org/10.1016/j.tet.2016.02.049.
4.2.1. (R)-2-Hydroxy-1,2-diphenylethanone (20a). Purification by
References and notes
silica gel column chromatography (petroleum ether/ethyl acetate,
1
1
. (a) Enders, D.; Balensiefer, T.; Niemeier, O.; Christmann, M. In Enantioselective
8
:2) gave (R)-20a (92% yield) as a white solid; H NMR (400 MHz,
CDCl 4.56 (br s, 1H), 5.94 (s, 1H), 7.27e7.44 (m, 7H), 7.50 (t,
J¼8.0 Hz, 1H), 7.94 (d, J¼8.0 Hz, 2H); 49 ee [Daicel Chiralcel OD-H,
Organocatalysis: Reactions and Experimental Procedures; Dalko, P. I., Ed.; Wiley-
VCH: Weinheim, Germany, 2007; pp 331e355; (b) Flanigan, D. M.; Romanov-
Michailidis, F.; White, N. A.; Rovis, T. Chem. Rev. 2015, 115, 9307e9387; (c)
Hopkinson, M. N.; Richter, C.; Schedler, M.; Glorius, F. Nature 2014, 510,
3
) d
ꢁ
1
hexanes/2-propanol 90:10, v¼0.7 mL/min
,
l¼254 nm,
t
485e496; (d) Mahatthananchai, J.; Bode, J. W. Acc. Chem. Res. 2014, 47,
696e707; (e) Ryan, S. R.; Candish, L.; Lupton, D. W. Chem. Soc. Rev. 2013, 42,
4906e4917; (f) Izquierdo, J.; Hutson, G. E.; Cohen, D. T.; Scheidt, K. A. Angew.
(
minor)¼16.6 min, t (major)¼23.7 min].
4
.2.2. (R)-2-Hydroxy-1,2-di(naphthalen-2-yl)ethanone
Chem., Int. Ed. 2012, 51, 11686e11698; (g) Biju, A. T.; Kuhl, N.; Glorius, F. Acc.
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. (a) Hanessian, S. Total Synthesis of Natural Products: The “Chiron” Approach;
Pergamon: Oxford, UK, 1983, Chapter 2; (b) Tanaka, T.; Kawase, M.; Tani, S.
Bioorg. Med. Chem. 2004, 12, 501e505.
. (a) Sheehan, J. C.; Hunnemann, D. H. J. Am. Chem. Soc. 1966, 88, 3666e3667; (b)
Sheehan, J. C.; Hara, T. J. Org. Chem. 1974, 39, 1196e1199.
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(20b). Purification by silica gel column chromatography (petro-
2
leum ether/ethyl acetate, 8:2) gave (R)-20b (48% yield) as a white
solid; H NMR (400 MHz, CDCl ) d 4.73 (br s, 1H), 6.33 (s, 1H),
3
1
3
7
1
.45e7.65 (m, 5H), 7.74e7.83 (m, 5H), 7.87 (d, J¼8.1 Hz, 1H), 7.94 (s,
H), 8.05 (d, J¼8.1 Hz,1H), 8.51 (s, 1H); 44 ee [Daicel Chiralcel OD-H,
4
ꢁ
1
hexanes/2-propanol 90:10, v¼0.7 mL/min
,
l¼254 nm, t (major)¼
5. Enders, D.; Kallfass, U. Angew. Chem., Int. Ed. 2002, 41, 1743e1745.
. Ma, Y.; Wei, S.; Wu, J.; Yang, F.; Liu, B.; Lan, J.; Yang, S.; You, J. Adv. Synth. Catal.
008, 350, 2645e2651.
. Baragwanath, L.; Rose, C. A.; Zeitler, K.; Connon, S. J. J. Org. Chem. 2009, 74, 9214e9217.
8. O’Toole, S. E.; Rose, C. A.; Gundala, S.; Zeitler, K.; Connon, S. J. J. Org. Chem. 2011,
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9. Langdon, S. M.; Wilde, M. M. D.; Thai, K.; Gravel, M. J. Chem. Soc. Chem. 2014,
36, 7539e7542.
6
4
5.6 min, t (minor)¼49.2 min].
2
7
4
.2.3. (R)-2-Hydroxy-1,2-di(p-tolyl)ethanone (20c). Purification by
7
silica gel column chromatography (petroleum ether/ethyl acetate,
1
8
:2) gave (R)-20c (29% yield) as a yellow solid; H NMR (400 MHz,
CDCl 2.28 (s, 3H), 2.37 (s, 3H), 4.60 (br s, 1H), 5.94 (s, 1H),
.09e7.25 (m, 6H), 7.81 (d, J¼8.0 Hz, 2H); 40 ee [Daicel Chiralcel OD-
1
3
)
d
10. (a) Rafi nꢀ ski, Z.; Kozakiewicz, A. J. Org. Chem. 2015, 80, 7468e7476; (b)
Rafi nꢀ ski, Z.; Kozakiewicz, A.; Rafi nꢀ ska, K. ACS Catal. 2014, 4, 1404e1408;
(c) Rafi nꢀ ski, Z.; Kozakiewicz, A.; Rafi nꢀ ska, K. Tetrahedron 2014, 70,
7
ꢁ
1
H, hexanes/2-propanol 90:10, v¼0.7 mL/min
,
l¼254 nm, t
5739e5745.
(
major)¼26.4 min, t (minor)¼33.7 min].
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You, S.-L. ACS Catal. 2013, 3, 622e624; (c) Rong, Z.-Q.; Li, Y.; Yang, G.-Q.; You, S.-
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4
.2.4. (R)-2-Hydroxy-1,2-bis(2-methoxyphenyl)ethanone
1
1
(20d). Purification by silica gel column chromatography (petro-
leum ether/ethyl acetate, 7:3) gave (R)-20d (26% yield) as a white
A. D. Angew. Chem., Ind. Ed. 2015, 54, 6887e6892.
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1
solid; H NMR (400 MHz, CDCl
s, 1H), 6.15 (1H, s), 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);
3
) d 3.73 (3H, s), 3.74 (3H, s), 4.50 (br
1
(
Please cite this article in press as: Rafi nꢀ ski, Z., Tetrahedron (2016), http://dx.doi.org/10.1016/j.tet.2016.02.049