Catalytic asymmetric α-alkylation of ketones and aldehydes with N-benzylic sulfonamides through carbon-nitrogen bond cleavage

Article abstract of DOI:10.1021/jo2014142

A range of ketones and aldehydes smoothly undergo asymmetric S_N1 α-alkylation with N-benzylic sulfonamides in the presence of 10 mol % of a chiral imidazolidinone and trifluoroacetic acid to give the corresponding products in good to excellent

Full text of DOI:10.1021/jo2014142

NOTE
pubs.acs.org/joc
Catalytic Asymmetric α-Alkylation of Ketones and Aldehydes with
N-Benzylic Sulfonamides through CarbonÀNitrogen Bond Cleavage
Zhen-Tao Weng, Yuan Li, and Shi-Kai Tian*
Joint Laboratory of Green Synthetic Chemistry, Department of Chemistry, University of Science and Technology of China, Hefei,
Anhui 230026, China
S Supporting Information
b
ABSTRACT: A range of ketones and aldehydes smoothly undergo
asymmetric SN1 α-alkylation with N-benzylic sulfonamides in the presence
of 10 mol % of a chiral imidazolidinone and trifluoroacetic acid to give the
corresponding products in good to excellent yields and with good
enantioselectivity. This chemistry has been successfully extended to the
asymmetric desymmetrization of 4-substituted cyclohexanones, which
exhibits greater than 99:1 diastereoselectivity and good enantioselectivity.
-Benzylic sulfonamides have recently emerged as useful sp3
carbon electrophiles to couple with a range of nucleophiles,
sulfonamides under acidic conditions. Since this reaction would
occur through the cleavage of carbonÀnitrogen bonds rather
than carbonÀsulfur, carbonÀoxygen, and carbonÀbromide
bonds, new reactivity and selectivity were expected to extend
the scope for the catalytic asymmetric α-alkylation of ketones
and aldehydes.
N
such as aromatic compounds, active methylene compounds,
alkynes, thiols, sulfinic acids, and silanes, through acid-catalyzed
carbonÀnitrogen bond cleavage in an SN1 manner.1,2 Since such
reactions yield primary sulfonamides as neutral byproducts,
N-benzylic sulfonamides have been demonstrated to serve as
unique alkylating agents with regard to reducing undesired side
reactions, such as overalkylation and elimination, when com-
pared to benzylic halides that are commonly employed but
inevitably lead to the formation of hydrogen halides as strongly
acidic byproducts.3 It is noteworthy that in 2010 You and co-
workers disclosed a chiral phosphoric acid-catalyzed asymmetric
FriedelÀCrafts alkylation reaction of indoles with N-sulfonyl(3-
indolyl)methanamines in moderate enantioselectivity.1g To our
knowledge, nucleophiles other than aromatic compounds have
not been reported previously to be alkylated with N-benzylic
sulfonamides in a catalytic asymmetric fashion. Herein, we
report, for the first time, a chiral amine-catalyzed asymmetric
α-alkylation reaction of ketones and aldehydes with N-benzylic
sulfonamides through carbonÀnitrogen bond cleavage.
Initially, N-(9H-thioxanthen-9-yl)-p-toluenesulfonamide (1a)
was selected as the alkylating agent for the catalytic asymmetric
α-alkylation of ketones. It was not reported previously for the
introduction of a 9H-thioxanthen-9-yl group to the α-position of
a ketone in a catalytic asymmetric manner. Moreover, the
thioxanthene moiety is present in some potent inhibitors of
acetyl- and butyrylcholinesterase with potential for treatment of
Alzheimer’s disease.11 To our delight, the α-alkylation of cyclo-
hexanone (2a, 3.0 equiv) with N-benzylic sulfonamide 1a
proceeded smoothly in the presence of L-cysteine (4a)/trifluoro-
acetic acid (1:1, 35 mol %) in dichloromethane at room
temperature and gave product 3a in 74% yield and with 44%
ee (Table 1, entry 1). Encouraged by this result, a range of
solvents were examined, but no better enantioselectivity was
obtained (Table 1, entries 2À5). While a weaker acid, such as
acetic acid or benzoic acid, failed to promote the alkylation
reaction, a stronger acid, such as p-toluenesulfonic acid or
trifluoromethanesulfonic acid, failed to induce enantioselectivity
(Table 1, entries 6À9). Further studies revealed that the
enantioselectivity was significantly affected by the structure of
chiral amine catalysts (Table 1, entries 10À16), and gratifyingly,
the employment of imidazolidinone 4h resulted in the formation
of product 3a in 98% yield and with 72% ee (Table 1, entry 16).
The enantioselectivity was enhanced to 82% ee by performing
the reaction at 10 °C (Table 1, entry 17), but further lowering the
temperature did not lead to better enantioselectivity (Table 1,
entry 18). Replacementof the p-toluenesulfonyl groupof substrate
The asymmetric α-alkylation of ketones and aldehydes has
long been recognized as a powerful tool for chemical synthesis
and has usually been realized by attacking carbon electrophiles in
an SN2 manner.4 To extend the scope of carbon electrophiles,
catalytic asymmetric SN1 α-alkylation of aldehydes has recently
been realized through enamine activation with a range of chiral
amines.5 3-(1-Arylsulfonylalkyl)indoles, benzylic alcohols, and
benzylic bromides have been employed as effective alkylating
agents by Melchiorre,6 Cozzi,7 and Jacobsen,8 respectively.
Moreover, Luo and Cheng described an asymmetric SN1
α-alkylation reaction of ketones with benzylic alcohols in mod-
erate to good enantioselectivity catalyzed by pyrrolidine-derived
functionalized chiral ionic liquids.9,10 Inspired by these findings,
we envisaged that chiral amine-activated ketones and aldehydes
could undergo asymmetric SN1 α-alkylation with N-benzylic
Received: July 8, 2011
Published: August 25, 2011
r
2011 American Chemical Society
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dx.doi.org/10.1021/jo2014142 J. Org. Chem. 2011, 76, 8095–8099
|

The Journal of Organic Chemistry
NOTE
Scheme 1. Proposed Catalytic Cycle
Table 1. Optimization of Reaction Conditionsa
1a or
catalyst
acid
yieldb eec
entry
1ab
(mol %)
(mol %)
solvent
(%)
(%)
1d
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1ab
1a
1a
4a (35) TFA (35)
4a (35) TFA (35)
4a (35) TFA (35)
4a (35) TFA (35)
4a (35) TFA (35)
CH2Cl2
CHCl3
74
68
44
22
37
14
2
3
(ClCH2)2 93
1a with a methanesulfonyl group slightly decreased the enantio-
selectivity (Table 1, entry 19). Finally, reducing the amount of
ketone 2a from 3.0 to 1.2 equiv and the catalyst loading from 35
to 10 mol % resulted in the formation of product 3a in 92% yield
and with 81% ee (Table 1, entry 21).
4
toluene
solvente
75
trace
0
5
6
4a (35) MeCO2H (35) CH2CI2
4a (35) PhCO2H (35) CH2Cl2
7
8d
9d
0
4a (35) PTS (35)
4a (35) TfOH (35)
4b (35) TFA (35)
4c (35) TFA (35)
4d (35) TFA (35)
4e (35) TFA (35)
4f (35) TFA (35)
4g (35) TFA (35)
4h (35) TFA (35)
4h (35) TFA (35)
4h (35) TFA (35)
4h (35) TFA (35)
4h (35) TFA (35)
4 h(10) TFA (10)
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2CI2
CH2Cl2
CH2Cl2
CH2Cl2
67
53
79
86
90
39
93
94
98
97
60
97
95
92
1
0
Other than cyclohexanone (2a), a range of cyclic ketones were
found to serve as suitable substrates. Either 4-oxotetrahydropyr-
an (2b) or 4-oxothiane (2c) was reacted with sulfonamide 1a in
the presence of 10 mol % of imidazolidinone 4h and trifluor-
oacetic acid to give the corresponding alkylation product in an
excellent yield and with good enantioselectivity (Table 2, entries
2 and 3). In contrast, lower enantioselectivity was obtained from
the reaction with 1-tosyl-4-piperidone (2d) or 1,4-cyclohexane-
dione monoethyleneketal (2e) (Table 2, entries 4 and 5). This
chemistry was successfully extended to the asymmetric desym-
metrization of 4-substituted cyclohexanones such as 2f, 2g, and
2h, which exhibited greater than 99:1 diastereoselectivity and
good enantioselectivity (Table 2, entries 6À8). Although cyclo-
pentanone, cyclooctanone, and 1-tetralone were found to react
well with sulfonamide 1a under the same conditions, less than
10% ee was observed. Moreover, acyclic ketones, such as acetone
and 5-nonanone, failed to undergo α-alkylation. A few other N-
benzylic sulfonamides were able to undergo catalytic asymmetric
α-alkylation with cyclohexanone (2a) to give the correspond-
ing products in moderate to good enantioselectivity (Table 2,
entries 9À11). Nevertheless, this reaction was not applicable to
less reactive N-benzylic sulfonamides such as N-benzhydryl-p-
toluenesulfonamide and N-benzyl-p-toluenesulfonamide.12
According to the previous studies on the acid-catalyzed
carbonÀnitrogen bond cleavage1,2 and enamine catalysis,5 we
propose the following catalytic cycle for the chiral amine-
catalyzed asymmetric α-alkylation of ketones with N-benzylic
sulfonamides under acidic conditions (Scheme 1). Enamine 6 is
initially generated from imidazolidinone 4h and ketone 2 via
iminium 5 in the presence of trifluoroacetic acid, which also
catalyzes the transformation of N-benzylic sulfonamide 1 into
carbocation 7 through carbonÀnitrogen bond cleavage. Diaster-
eoselective attack of enamine 6 to carbocation 7 predominantly
10
11
12
13
14
15d
16d
17f
18g
19f
20f,h
21h,i
37
0
11
2
53
69
72
82
82
80
80
81
a Reaction conditions: sulfonamide 1a or 1ab (0.20 mmol), ketone 2a
(0.60 mmol), catalyst, acid, solvent (1.0 mL), rt, 2 d. b Isolated yield.
c Determined by chiral stationary-phase HPLC analysis. d The reaction
was run for 1 d. e Et2O, THF, dioxane, EtOAc, DMF, DMSO, MeCN,
f
g
or MeOH. The reaction was run at 10 °C. The reaction was run at
i
0 °C. h 0.24 mmol of ketone 2a was used. The reaction was run in
0.80 mL of CH2Cl2 at 10 °C for 3 d.
results in the formation of iminium 8, which is subjected to
hydrolysis to give product 3 via hemiaminal 9 and meanwhile
release the chiral amine catalyst. This catalytic cycle is substan-
tially supported by ESI-MS (positive mode) spectroscopic
analysis of the reaction mixture of N-benzylic sulfonamide 1a
and ketone 2a in the presence of 10 mol % of imidazolidinone 4h
and trifluoroacetic acid, from which enamine 6a and hemiaminal
9a were identified as critical intermediates (Table 3).
Although imidazolidinone 4h could catalyze the α-alkyla-
tion of aldehyde 2i with N-benzylic sulfonamide 1a under the
same conditions, hardly any enantioselectivity was observed.
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dx.doi.org/10.1021/jo2014142 |J. Org. Chem. 2011, 76, 8095–8099

The Journal of Organic Chemistry
NOTE
Table 2. Catalytic Asymmetric α-Alkylation of Ketones with
N-Benzylic Sulfonamidesa
Table 3. High-Resolution Mass Data of Intermediates De-
tected in the Reaction Mixture of Sulfonamide 1a and Ketone 2a
entry species mass (calcd) mass (found)
formula
[6a + H]+ 403.18386 403.18369 C25H27N2OS
[9a + H]+ 617.22910 617.22839 C38H37N2O2S2
error (ppm)
1
2
0.4
1.2
with N-benzylic sulfonamides through carbonÀnitrogen bond
cleavage. A range of cyclic ketones are reacted with N-benzylic
sulfonamides in the presence of 10 mol % of a chiral imidazo-
lidinone and trifluoroacetic acid to give the corresponding
alkylation products in good to excellent yields and with good
enantioselectivity. This chemistry has been successfully extended
to the asymmetric desymmetrization of 4-substituted cyclohex-
anones, which exhibits greater than 99:1 diastereoselectivity and
good enantioselectivity. A plausible catalytic cycle is proposed
and substantially supported by ESI-MS spectroscopic analysis of
the reaction mixture. Moreover, this method is applicable to
aliphatic aldehydes by switching the chiral amine catalyst.
entry
1
2
product
yieldb (%)
drc
eed (%)
’ EXPERIMENTAL SECTION
1
1a
1a
1a
1a
1a
1a
1a
1a
1b
1c
1d
2a
2b
2c
2d
2e
2f
3a
3b
3c
3d
3e
3f
92
94
95
96
83
93
95
96
81
82
96
81
1
General Information. H and 13C NMR spectra were recorded
2
80
using tetramethylsilane as an internal reference. Chemical shifts (δ) and
coupling constants (J) are expressed in ppm and Hz, respectively. High-
pressure liquid chromatography (HPLC) analyses were performed on
an instrument equipped with an isostatic pump, using a chiral stationary-
phase column (250 Â 4.6 mm), and the UV detection was monitored at
254 nm. Optical rotations were measured on a polarimeter with a
sodium lamp at λ = 589 nm and reported as [α]T(°C)D (c = g/100 mL,
solvent). Melting points were uncorrected. Chiral imidazolidinone
catalysts were prepared according to known procedures.13
3
84
4
5e
60
62
6
99:1
99:1
99:1
80
7
2g
2h
2a
2a
2a
3g
3h
3i
81
8f
9e
10g
11
80
60
3j
50
82 (80)h
Preparation of N-Benzylic Sulfonamides.
3k
59:41
a Reaction conditions: sulfonamide 1 (0.20 mmol), ketone 2 (0.24
mmol), imidazolidinone 4h (10 mol %), TFA (10 mol %), CH2Cl2
(0.80 mL), 10 °C, 3 d. b Isolated yield. c Determined by 1H NMR
spectroscopic analysis. d Determined by chiral stationary-phase HPLC
analysis. e The reaction was run at 0 °C for 4 d. f The absolute
configuration of product 3h was determined by single-crystal X-ray
analysis and that of the rest of new products was assigned by analogy.
g The reaction was run at 40 °C. h The ee of the minor diastereomer is
shown in the parentheses.
To a solution of p-toluenesulfonamide (2.05 g, 12.0 mmol) and a
ketone (10.0 mmol) in 1,2-dichloroethane (40 mL) under nitrogen at
room temperature were added dropwise titanium tetrachloride (1.14 g,
0.66 mL, 6.0 mmol) and triethylamine (2.02 g, 2.78 mL, 20.0 mmol).
The mixture was heated at reflux for 10 h and cooled to room
temperature. The resulting N-sulfonylimine was collected by filtration
and purified by recrystallization from ethyl acetate and petroleum
ether.14 To a solution of the N-sulfonylimine (5.0 mmol) in ethanol
(20 mL) at 0 °C was added sodium borohydride (378 mg, 10.0 mmol).
The mixture was stirred at room temperature for 8 h, quenched with
iceÀwater (20 mL), and extracted with dichloromethane (3 Â 30 mL).
The combined organic extracts were dried over anhydrous magnesium
sulfate and concentrated. The residue was recrystallized from dichloro-
methane and petroleum ether to give N-benzylic sulfonamide 1. Sulfona-
mides 1a, 1ab, 1b, and 1c were obtained in 63%, 59%, 60%, and 47% yields
(two steps), respectively. These sulfonamides are known compounds.
Gratifyingly, alternative use of imidazolidinone 4f as the
catalyst led to the formation of product 3l in 83% yield and
with 65% ee (eq 1).
In summary, we have developed an unprecedented catalytic
asymmetric SN1 α-alkylation reaction of ketones and aldehydes
8097
dx.doi.org/10.1021/jo2014142 |J. Org. Chem. 2011, 76, 8095–8099

The Journal of Organic Chemistry
NOTE
General Procedure for the Catalytic Asymmetric α-Alkyla-
tion of Ketones and Aldehydes with N-Benzylic Sulfonamides.
To a solution of trifluoroacetic acid (2.3 mg, 10 mol %) in dichloromethane
(0.80 mL) under nitrogen at 10 °C was added catalyst 4h (6.5 mg,
10 mol %). The mixture was stirred for 10 min, and ketone (or aldehyde)
2(0.24mmol) andN-benzylic sulfonamide 1(0.20 mmol) were added. The
resulting mixture was stirred at 10 °C for 3 d and purified by flash column
chromatography on silica gel, eluting with dichloromethane/petroleum
ether (1:1 to 8:1), to give product 3.
127.3, 127.2, 126.9, 126.5, 107.6, 64.7, 64.5, 47.1, 46.9, 39.8, 38.8, 35.2;
IR (film) ν 3021, 2975, 1713, 1523, 1469, 1439 cmÀ1; HRMS (EI) calcd
for C21H20O3S (M) 352.1133, found 352.1132. The ee was determined
to be 62% by HPLC analysis on a Chiralpak OD column, λ = 254 nm,
n-hexane/i-PrOH (90:10), flow rate = 0.50 mL/min; tR = 11.41 min
(major), 13.01 min (minor).
(2R,4R)-4-Methyl-2-(9H-thioxanthen-9-yl)cyclohexanone (3f):
white solid; mp 155À156 °C; [α]20D +63.6 (c 0.5, CHCl3); 1H NMR
(400 MHz, CDCl3) δ 7.45À7.33 (m, 3H), 7.29À7.12 (m, 5H), 4.57 (d,
J = 10.4 Hz, 1H), 3.21À3.13 (m, 1H), 2.51À2.42 (m, 1H), 2.37À2.30
(m, 1H), 2.21À2.13 (m, 1H), 2.01À1.92 (m, 1H), 1.62À1.44 (m, 2H),
1.21À1.12 (m, 1H), 0.98 (d, J = 6.8 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 212.6, 137.3, 136.0, 133.6, 132.9, 130.0, 129.5, 127.5, 126.9,
126.8, 126.6, 126.3, 48.5, 47.0, 39.4, 38.6, 35.1, 27.0, 19.8; IR (film) ν
3020, 2962, 1706, 1524, 1465, 1441 cmÀ1; HRMS (EI) calcd for
C20H20OS (M) 308.1235, found 308.1239. The ee was determined to
be 80% by HPLC analysis on a Chiralpak AD column, λ = 254 nm,
n-hexane/i-PrOH (99:1), flow rate = 0.70 mL/min; tR = 14.87 min
(major), 17.13 min (minor).
(R)-2-(9H-Thioxanthen-9-yl)cyclohexanone (3a): white solid; mp
142À143 °C; [α]20 +23.6 (c 0.5, CHCl3); 1H NMR (400 MHz,
D
CDCl3) δ 7.62 (dd, J = 7.6, 1.6 Hz, 1H), 7.43À7.35 (m, 2H), 7.25À7.08
(m, 5H), 4.68 (d, J = 9.2 Hz, 1H), 3.15À3.05 (m, 1H), 2.35À2.28 (m,
1H), 2.21À2.14 (m, 1H), 1.98À1.92 (m, 1H), 1.75À1.32 (m, 4H),
1.26À1.13 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 212.0, 138.6,
136.7, 133.8, 132.8, 131.0, 130.3, 127.3, 127.2, 126.7, 126.4, 126.3, 50.5,
47.3, 43.2, 33.9, 28.9, 25.3; IR (film) ν 3020, 2941, 1707, 1523, 1466,
1444 cmÀ1; HRMS (EI) calcd for C19H18OS (M) 294.1078, found
294.1082. The ee was determined to be 81% by HPLC analysis on a
Chiralpak AD column, λ = 254 nm, n-hexane/i-PrOH (99:1), flow rate =
0.60 mL/min; tR = 15.70 min (major), 17.38 min (minor).
(2R,4R)-4-tert-Butyl-2-(9H-thioxanthen-9-yl)cyclohexanone (3g):
white solid; mp 184À185 °C; [α]20D +84.6 (c 0.5, CHCl3); 1H NMR
(400 MHz, CDCl3) δ 7.46À7.40 (m, 2H), 7.38À7.30 (m, 1H),
7.25À7.11 (m, 5H), 4.51 (d, J = 10.8 Hz, 1H), 3.13À3.06 (m, 1H),
2.68À2.57 (m, 1H), 2.37À2.29 (m, 1H), 2.13À2.06 (m, 1H),
1.93À1.84 (m, 1H), 1.60À1.45 (m, 2H), 1.35À1.24 (m, 1H), 0.86 (s,
9H); 13C NMR (100 MHz, CDCl3) δ 213.1, 136.1, 135.2, 133.4, 132.9,
130.3, 128.4, 127.7, 127.2, 127.1, 126.6, 126.1, 49.3, 47.7, 41.3, 39.9, 32.9,
(S)-3-(9H-Thioxanthen-9-yl)-4-oxotetrahydropyran (3b): yellow
solid; mp 172À173 °C; [α]20 +53.4 (c 0.5, CHCl3); 1H NMR (400
D
MHz, CDCl3) δ 7.48À7.39 (m, 3H), 7.34À7.28 (m, 1H), 7.24À7.14
(m, 4H), 4.72 (d, J = 9.6 Hz, 1H), 4.02À3.94 (m,1H), 3.90À3.84 (m,
1H), 3.50À3.39 (m, 2H), 3.24À3.16 (m, 1H), 2.63À2.55 (m, 1H),
2.49À2.40 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 207.3, 136.8,
134.9, 133.8, 133.0, 130.0, 129.8, 127.6, 127.5, 127.3, 127.0, 126.7, 126.6,
30.0, 27.9, 27.6; IR (film) ν 3020, 2963, 1706, 1526, 1466, 1442 cmÀ1
;
71.6, 69.2, 51.3, 46.1, 43.1; IR (film) ν 2919, 1708, 1465, 1417 cmÀ1
;
HRMS (EI) calcd for C23H26OS (M) 350.1704, found 350.1704. The ee
was determined to be 81% by HPLC analysis on a Chiralpak AD column,
λ = 254 nm, n-hexane/i-PrOH (99:1), flow rate = 0.70 mL/min; tR =
21.30 min (major), 27.56 min (minor).
HRMS (EI) calcd for C18H16O2S (M) 296.0871, found 296.0859. The
ee was determined to be 80% by HPLC analysis on a Chiralpak OD
column, λ = 254 nm, n-hexane/i-PrOH (98:2), flow rate = 0.60 mL/min;
tR = 16.80 min (major), 22.27 min (minor).
(2R,4R)-4-Phenyl-2-(9H-thioxanthen-9-yl)cyclohexanone (3h): yellow
1
(R)-3-(9H-Thioxanthen-9-yl)-4-oxothiane (3c): white solid; mp
solid; mp 179À180 °C; [α]20 +136.4 (c 0.5, CHCl3); H NMR (400
D
166À167 °C; [α]20 +58.4 (c 0.5, CHCl3); 1H NMR (400 MHz,
MHz, CDCl3) δ 7.47À7.37 (m, 3H), 7.33À7.14 (m, 10H), 4.67 (d, J =
10.8 Hz, 1H), 3.41À3.32 (m, 1H), 3.24À3.17 (m, 1H), 2.76À2.66 (m,
1H), 2.44À2.36 (m, 1H), 2.27À2.21 (m, 1H), 2.17À2.05 (m, 1H),
1.84À1.69 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 211.7, 144.0,
136.4, 135.3, 133.5, 132.9, 130.0, 128.9, 128.8, 127.7, 127.6, 127.2, 127.0,
126.8, 126.7, 126.6, 126.5, 49.0, 48.1, 39.9, 37.5, 36.6, 33.8; IR (film) ν 3021,
1709, 1524, 1466, 1442 cmÀ1; HRMS (EI) calcd for C25H22OS (M)
370.1391, found 370.1350. The ee was determined to be 80% by HPLC
analysis on a Chiralpak OD column, λ = 254 nm, n-hexane/i-PrOH (95:5),
flow rate = 1.0 mL/min; tR = 22.55 min (minor), 30.31 min (major).
(R)-2-(9H-Xanthen-9-yl)cyclohexanone (3i):15 yellow solid; mp
D
CDCl3) δ 7.47À7.38 (m, 3H), 7.35À7.29 (m, 1H), 7.24À7.13 (m, 4H),
4.88 (d, J = 10.0 Hz, 1H), 3.48À3.40 (m, 1H), 3.00À2.84 (m, 2H),
2.82À2.74 (m, 1H), 2.63À2.55 (m, 1H), 2.53À2.40 (m, 2H); 13C NMR
(100 MHz, CDCl3) δ 209.3, 136.8, 135.2, 133.8, 133.1, 130.3, 130.0,
127.7, 127.6, 127.2, 126.9, 126.7, 126.6, 51.6, 47.5, 44.8, 35.4, 31.9; IR
(film) ν 3021, 1707, 1524, 1467, 1426 cmÀ1; HRMS (EI) calcd for
C18H16OS2 (M) 312.0643, found 312.0623. The ee was determined to
be 84% by HPLC analysis on a Chiralpak OD column, λ = 254 nm,
n-hexane/i-PrOH (98:2), flow rate = 1.0 mL/min; tR = 9.76 min
(major), 16.83 min (minor).
(S)-3-(9H-Thioxanthen-9-yl)-1-tosyl-4-piperidinone (3d): yellow so-
lid; mp 219À220 °C; [α]20D +34.0 (c 0.5, CHCl3); 1H NMR (400 MHz,
CDCl3) δ 7.57À7.52 (m, 3H), 7.49À7.39 (m, 2H), 7.35À7.23 (m, 5H),
7.21À7.14 (m, 2H), 4.75 (d, J = 9.6 Hz, 1H), 3.64À3.56 (m, 1H),
3.24À3.05 (m. 3H), 2.78À2.65 (m, 2H), 2.42À2.33 (m, 4H); 13C NMR
(100 MHz, CDCl3) δ 206.3, 144.3, 135.6, 134.7, 133.5, 133.3, 133.0,
130.8, 130.0, 129.2, 127.7, 127.6, 127.5, 127.2, 126.8, 49.5, 49.0, 47.1,
110À111 °C; [α]20 +60.8 (c 0.5, CHCl3); 1H NMR (400 MHz,
D
CDCl3) δ 7.41 (dd, J = 7.6, 1.6 Hz, 1H), 7.27À7.16 (m, 3H), 7.09À6.97
(m, 4H), 4.93 (d, J = 3.2 Hz, 1H), 2.55À2.47 (m, 1H), 2.45À2.38 (m,
1H), 2.29À2.18 (m, 1H), 1.96À1.88 (m, 1H), 1.79À1.68 (m, 2H),
1.54À1.36 (m, 2H), 1.16À1.04 (m, 1H); 13C NMR (100 MHz, CDCl3)
δ 210.8, 153.5, 153.2, 130.6, 128.9, 127.9, 127.8, 125.8, 123.6, 123.3,
123.0, 116.4, 116.2, 60.8, 42.2, 36.9, 27.8, 26.8, 24.9. The ee was
determined to be 60% by HPLC analysis on a Chiralpak IC column,
λ = 254 nm, n-hexane/i-PrOH (99:1), flow rate =0.60 mL/min; tR =
14.15 min (major), 18.65 min (minor).
40.4, 27.1; IR (film) ν 3021, 2402, 1719, 1600, 1524, 1468, 1442 cmÀ1
;
HRMS (EI) calcd for C25H23NO3S2 (M) 449.1119, found 449.1102.
The ee was determined to be 60% by HPLC analysis on a Chiralpak
AD column, λ = 254 nm, n-hexane/i-PrOH (80:20), flow rate =
1.0 mL/min; tR = 13.96 min (minor), 15.59 min (major).
(R)-3-(9H-Thioxanthen-9-yl)-1,4-cyclohexanedione monoethylene-
ketal (3e): yellow solid; mp 122À123 °C; [α]20D +33.2 (c 0.5, CHCl3);
1H NMR (400 MHz, CDCl3) δ 7.58 (dd, J = 7.6, 1.6 Hz, 1H), 7.43À7.36
(m, 2H), 7.26À7.10 (m, 5H), 4.75 (d, J = 8.8 Hz, 1H), 3.95À3.78 (m,
4H), 3.45À3.36 (m, 1H), 2.57À2.45 (m, 1H), 2.37À2.29 (m, 1H),
2.00À1.84 (m, 2H), 1.59À1.50 (m, 1H), 1.43À1.35 (m, 1H); 13C NMR
(100 MHz, CDCl3) δ 210.5, 138.4, 136.2, 133.9, 132.9, 130.8, 130.3,
(R)-2-(Bis(4-(dimethylamino)phenyl)methyl)cyclohexanone (3j):9a
yellow solid; mp 168À169 °C; [α]20D +65.0 (c 0.5, CHCl3); 1H NMR
(400 MHz, CDCl3) δ 7.15À7.03 (m, 4H), 6.67À6.09 (m, 4H), 4.17 (d,
J = 10.8 Hz, 1H), 3.27À3.19 (m, 1H), 2.87 (s, 6H), 2.85 (s, 6H),
2.46À2.38 (m, 1H), 2.34À2.25 (m, 1H), 1.94À1.79 (m, 4H),
1.67À1.54 (m, 1H), 1.53À1.42 (m, 1H); 13C NMR (100 MHz, CDCl3)
δ 213.5, 149.2, 149.0, 132.6, 132.0, 129.0, 128.3, 113.0, 55.7, 49.1, 42.2,
40.9, 33.1, 29.3, 23.9. The ee was determined to be 50% by HPLC
analysis on a Chiralpak AD column, λ = 254 nm, n-hexane/i-PrOH
8098
dx.doi.org/10.1021/jo2014142 |J. Org. Chem. 2011, 76, 8095–8099

The Journal of Organic Chemistry
NOTE
(85:15), flow rate = 0.80 mL/min; tR = 11.47 min (major), 12.93 min
(minor).
F.-L.; Yang, K.-F.; Lai, G.-Q.; Xu, L.-W.; Xia, C.-G. Synlett 2010,
1251–1254.
(3) Olah, G. A.; Krishnamurti, R.; Surya, G. K. In Comprehensive
Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon Press:
Oxford, 1991; Vol. 3, pp 293À339.
(2R)-2-((1-Methyl-1H-indol-3-yl)(phenyl)methyl)cyclohexanone (3k):
obtained as a 59:41 mixture of diastereomers; yellow solid; mp 126À
127 °C; [α]20D +143.6 (c 0.5, CHCl3); 1H NMR (400 MHz, CDCl3) δ
7.45À7.41 (m, 1H), 7.37À6.94 (m, 9H), 4.73 (d, J = 10.0 Hz, 1H), 3.73
(s, 3H), 3.25À3.17 (m, 1H), 2.51À2.23 (m, 2H), 2.00À1.47 (m, 6H);
(4) Carey, F. A.; Sundberg, R. J. Advanced Organic Chemistry Part B:
Reactions and Synthesis, 5th ed.; Springer: New York, 2007.
(5) For recent reviews of asymmetric enamine catalysis, see:
(a) Mukherjee, S.; Yang, J. W.; Hoffmann, S.; List, B. Chem. Rev.
2007, 107, 5471–5569. (b) Melchiorre, P.; Marigo, M.; Carlone, A.;
Bartoli, G. Angew. Chem., Int. Ed. 2008, 47, 6138–6171. (c) Pihko, P. M.;
Majander, I.; Erkkil€a, A. Top. Curr. Chem. 2010, 291, 29–75.
(6) Shaikh, R. R.; Mazzanti, A.; Petrini, M.; Bartoli, G.; Melchiorre,
P. Angew. Chem., Int. Ed. 2008, 47, 8707–8710.
1
Partial H NMR (400 MHz, CDCl3) for the minor diastereomer: δ
7.61À7.56 (m, 1H), 6.84 (s, 1H), 4.68 (d, J = 10.0 Hz, 1H), 3.42À3.34
(m, 1H), 3.70 (s, 3H); IR (film) ν 3021, 2941, 1707, 1523, 1477,
1426 cmÀ1; HRMS (EI) calcd for C22H23NO (M) 317.1780, found
317.1799. The ee was determined to be 82% (For the minor diaster-
eomer, 80%) by HPLC analysis on a Chiralpak AD column, λ = 254 nm,
n-hexane/i-PrOH (98:2), flow rate = 1.00 mL/min; tR (major dia-
(7) Cozzi, P. G.; Benfatti, F.; Zoli, L. Angew. Chem., Int. Ed. 2009,
48, 1313–1316.
t
R
stereomer) = 19.85 min (major), 36.98 min (minor);
diastereomer) = 21.99 min (minor), 27.62 min (major).
(minor
(8) Brown, A. R.; Kuo, W.-H.; Jacobsen, E. N. J. Am. Chem. Soc.
2010, 132, 9286–9288.
(9) (a) Zhang, L.; Cui, L.; Li, X.; Li, J.; Luo, S.; Cheng, J.-P. Chem.À
Eur. J. 2010, 16, 2045–2049. (b) Zhang, L.; Cui, L.; Li, X.; Li, J.; Luo, S.;
Cheng, J.-P. Eur. J. Org. Chem. 2010, 4876–4885.
(10) During the preparation of this manuscript, Kim and co-workers
disclosed a chiral diamine-catalyzed asymmetric SN1 α-alkylation reac-
tion of cyclic ketones with benzylic alcohols. See: Lee, H. J.; Kang, S. H.;
Kim, D. Y. Bull. Korean Chem. Soc. 2011, 32, 1125–1126.
(11) Tasso, B.; Catto, M.; Nicolotti, O.; Novelli, F.; Tonelli, M.;
Giangreco, I.; Pisani, L.; Sparatore, A.; Boido, V.; Carotti, A.; Sparatore,
F. Eur. J. Med. Chem. 2011, 46, 2170–2184.
2-(9H-Thioxanthen-9-yl)propanal (3l):7 yellow solid; mp 108À109 °C;
[α]20D +12.8 (c 0.5, CHCl3); 1H NMR (400 MHz, CDCl3) δ 9.54 (d, J =
2.0 Hz, 1H), 7.48À7.40 (m, 2H), 7.32À7.17 (m, 6H), 4.25 (d, J = 9.6 Hz,
1H), 3.23À3.12 (m, 1H), 0.88 (d, J = 6.8 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 204.0, 136.0, 135.5, 133.2, 130.2, 129.9, 127.6, 127.4, 127.2,
126.8, 126.5, 50.6, 45.9, 13.1. The ee was determined to be 65% by HPLC
analysis on a Chiralpak AD column, λ = 254 nm, n-hexane/i-PrOH (100:0),
flow rate = 0.80 mL/min; tR = 11.13 min (minor), 15.86 min (major).
’ ASSOCIATED CONTENT
(12) When compared to the catalytic asymmetric α-alkylation of
ketones with benzylic alcohols,9,10 our results clearly demonstrate
different reactivity and selectivity. The catalyst loading is much lower,
and the use of largely excessive ketones is avoided. Although in general
the same level of enantioselectivity has been achieved, our method
exhibits a complementary scope to the previously reported catalytic
asymmetric α-alkylation of ketones.
(13) (a) Ahrendt, K. A.; Borths, C. J.; Macmillan, D. W. C. J. Am.
Chem. Soc. 2000, 122, 4243–4244. (b) Selk€al€a, S. A.; Koskinen, A. M. P.
Eur. J. Org. Chem. 2005, 1620–1624. (c) Mastracchio, A.; Warkentin,
A. A.; Walji, A. M.; Macmillan, D. W. C. Proc. Natl. Acad. Sci. U.S.A. 2010,
107, 20648–20651.
Supporting Information. 1H NMR, 13C NMR, and
S
b
HPLC spectra for products, ESI-MS spectra for reaction mixture,
and crystal data of compound 3h. This material is available free of
charge via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: tiansk@ustc.edu.cn.
(14) Ran, R. N.; Khan, A. A. Synth. Commun. 2001, 31, 841–846.
(15) For a racemic form, see: Pintꢀer, A.; Sud, A.; Sureshkumar, D.;
’ ACKNOWLEDGMENT
ꢀ
We are grateful for the financial support from the National
Natural Science Foundation of China (20972147 and 20732006)
and the National Basic Research Program of China (973
Program 2010CB833300).
Klussmann, M. Angew. Chem., Int. Ed. 2010, 49, 5004–5007.
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