Highly enantioselective synthesis of (diarylmethyl)amines by rhodium-catalyzed arylation of N-nosylimines using a chiral bicyclo[3.3.0]diene ligand

Article abstract of DOI:10.1055/s-0030-1258210

A highly efficient asymmetric arylation of N-nosylimines with arylboronic acids catalyzed by a rhodium-diene complex is described. A wide range of enantiopure (98-99% ee) N-(diarylmethyl)nosylamides, as well as (3S)-2-(4-nosyl)-3-phenylisoindolin-1-one, were obtained in high yields (83-99%) under very mild conditions. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0030-1258210

SPECIAL TOPIC
3263
Highly Enantioselective Synthesis of (Diarylmethyl)amines by Rhodium-
Catalyzed Arylation of N-Nosylimines Using a Chiral Bicyclo[3.3.0]diene Ligand
E
nantioselective
i
Synthesis of
W
(Diarylmethyl)amines ang,a Zhi-Qian Wang,b Ming-Hua Xu,*a,b Guo-Qiang Lin*b
a
Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, P. R. of China
Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
345 Lingling Road, Shanghai 200032, P. R. of China
b
E-mail: xumh@mail.shcnc.ac.cn; fax +86(21)50807388; E-mail: lingq@mail.sioc.ac.cn
Received 7 May 2010
Ph
H
H
Ph
Abstract: A highly efficient asymmetric arylation of N-
nosylimines with arylboronic acids catalyzed by a rhodium–diene
complex is described. A wide range of enantiopure (98–99% ee) N-
(diarylmethyl)nosylamides, as well as (3S)-2-(4-nosyl)-3-phenyl-
isoindolin-1-one, were obtained in high yields (83–99%) under very
mild conditions.
Ph
Ph
O
Ph
Ph
1c
1a
1b
Key words: asymmetric catalysis, amines, arylations, rhodium, di-
arylmethylamines
Ar
Ar
O
Ar
Chiral (diarylmethyl)amines are essential components of
a many biologically interesting or pharmacologically ac-
tive compounds. Simple methods for the preparation of
these substances are therefore of great interest to synthetic
and medicinal chemists.1 To access these attractive mate-
rials in highly enantiomerically enriched forms, the asym-
metric addition of a diverse range of arylmetal reagents,
including those of lithium,2 zinc,3 magnesium,4 tin,5 tita-
nium,6 or boron7–9 to arylimines has been extensively ex-
plored in recent years. Among the methods that have been
developed, the transition metal-catalyzed asymmetric ad-
dition of arylboroxines or arylboronic acids to imines ap-
1e
1d
Figure 1 Chiral dienes used for asymmetric arylation of arylimines
In 2007, we reported our discovery of a new family of C2-
symmetric chiral diene ligands bearing a simple bicyclic
[3.3.0] backbone, and their successful application in the
rhodium-catalyzed enantioselective arylation of N-tosyl-
arylimines with arylboronic acids.8c A broad range of
highly enantiomerically enriched N-(diarylmethyl)tosyl-
amides (98–99% ee) were obtained in good-to-excellent
yields (Scheme 1a). For example, treatment of the N-to-
sylimine 2a with phenylboronic acid in the presence of
bis[(chloro)(diethenyl)rhodium] (3 mol)%, diene ligand
1c (3.3 mol%), and triethylamine in toluene at 55 °C gave
the desired amide 3a in 81% yield with an extremely high
enantioselectivity (99% ee). Unfortunately, when pheny-
lation of the N-nosylimine of 4-chlorobenzaldehyde (2b)
was carried out under the same conditions, the corre-
sponding N-(diarylmethyl)nosylamide 3b was obtained in
a significantly reduced yield (35%), although the excel-
lent enantioselectivity (98.5% ee) was maintained. Here,
we report our development of a practical new reaction
system that solves this problem of a low yield, and which
allows the addition of arylboronic acids to N-nosylimines
in high yields and excellent enantioselectivities.
pears to be one of the most efficient and practical.7–9
A
variety of chiral ligands have been used successfully, and
a few examples of arylation with high enantioselectivities
have been documented. Despite the considerable progress
in this field, the use of N-tosylimines as substrates can
sometimes limit the range of application of the reaction
because harsh conditions are required for the subsequent
removal of the N-tosyl group from the product.10 To ad-
dress this problem, several other aryl aldimines, such as
N-tert-butoxycarbonyl,7e N-nosyl,7h,i,8b,d or N-diphenyl-
phosphinoyl imines7f,g have been examined as substrates
for arylation. As a result, there is a need for the develop-
ment of new chiral ligands or reaction systems.
The design of chiral dienes as ligands for transition metal-
mediated reactions has recently attracted a considerable
amount of attention.11,12 There have been several reports
regarding the use of rhodium complexes of chiral dienes
1a–e in asymmetric aryl-transfer reactions (Figure 1).8
Initially, we were puzzled by the surprisingly low yield of
similar aryl addition reactions of N-nosylimines under
these conditions. Optimization of the reaction conditions
by changing the temperature and solvent were not suc-
cessful. To understand this result, we performed several
control experiments. We found that, unlike N-tosylimines,
the N-nosylimine substrates decomposed rapidly upon the
addition of triethylamine, probably because of the differ-
ence in electronic structure. Because the use of the chiral
SYNTHESIS 2010, No. 19, pp 3263–3267
x
x.
x
x
.
2
0
1
0
Advanced online publication: 13.08.2010
DOI: 10.1055/s-0030-1258210; Art ID: C03910SS
© Georg Thieme Verlag Stuttgart · New York

3264
L. Wang et al.
SPECIAL TOPIC
a.
Ar2B(OH)2
[RhCl(C2H4)2]2/1c
Table 1 Optimization of the Reaction Conditions for the Rhodium-
Catalyzed Phenylation of N-Nosylimine 2b
NHTs
Ar2
Ts
Ar1
N
toluene, Et3N
55 °C, 4–5h
Ar1
NHNs
Ns
98–99% ee
N
[RhCl(C2H4)2]2/1c
PhB(OH)2
+
toluene–H2O (4:1)
KHF2
Cl
NHR
PhB(OH)2
[RhCl(C2H4)2]2/1c
b.
Cl
R
3b
2b
N
toluene, Et3N
55 °C
Entrya
PhB(OH)2 KHF2
Temp
Time
(h)
Yield
(%)b
ee
Cl
Cl
(equiv)
(equiv) (°C)
(%)c
3a R = Ts, 81% yield, 99% ee
3b R = Ns, 35% yield, 98.5% ee
2a R = Ts
2b R = Ns
1e
2
2.0
0
100
100
100
60
1
n.r.d
88
–
Scheme 1 Rhodium-catalyzed asymmetric arylation using diene 1c
3.0
5.0
3.0
3.0
3.0
3.0
0
1
97
97
98
99
99
97
–
as a chiral ligand
3
2.0
1
89
4
2.0
2.5
3.5
16
98
diene 1c has proved to be effective (98.5% ee), we turned
our attention to other additives that might facilitate the re-
action outcome. The reaction of N-nosylimine 2b with
phenylboronic acid catalyzed by the rhodium complex of
1c was carried out in the presence of additives such as po-
tassium hydroxide, lithium hydroxide, sodium carbonate,
tripotassium phosphate, potassium fluoride, and potassi-
um bifluoride (KHF2) under various reaction conditions.
To our delight, the reactions using potassium bifluoride as
the additive in toluene–water (4:1) gave the required prod-
uct 3b in a very good yield,13 whereas the use of other ad-
ditives was less effective.
5
2.0
40
94
6
2.0
rt
82
7
1.0f
1.0f
100
100
1
1
77
8e
0
n.r.d
a Unless otherwise noted, the reaction was performed with 2b (0.5
mmol), [RhCl(C2H4)2]2 (0.015 mmol), diene 1c (0.017 mmol), and
KHF2 (as indicated) in toluene (2 mL) and H2O (0.5 mL).
b Isolated yield.
c Determined by HPLC analysis on a Chiracel OD-H column.
d No reaction.
Results of further optimization of the reaction using potas-
sium bifluoride are summarized in Table 1. When three
equivalents of potassium bifluoride were used as the addi-
tive at 100 °C, the reaction proceeded smoothly to give an
excellent yield of 89%, as well as a very high enantiose-
lectivity (97% ee) in one hour (entry 3). An increase in
yield to 98% was observed at a lower reaction temperature
(60 °C, entry 4). Gratifyingly, when the reaction was per-
formed at 40 °C, 3b was obtained in a similar yield (94%)
and an even better enantioselectivity (99% ee) in a slightly
longer time (3.5 hours) (entry 5). Because we were aware
that potassium bifluoride reacts with organoboronic acids
in aqueous conditions to form potassium organotrifluo-
roborates,14,15 we investigated the direct use of potassium
trifluoro(phenyl)borate (PhBF3K) for phenylation. The
yield and enantiomeric excess were almost identical to
those obtained by using phenylboronic acid and potassi-
um bifluoride (compare entries 7 and 3), suggesting that
potassium bifluoride may act as a reagent for generation
of trifluoroborate in situ within the system. Also notewor-
thy is that water is of great importance for this process; no
reaction occurred under anhydrous conditions (entries 1
and 8).
e Anhydrous conditions.
f KPhBF3 was used instead of KHF2 and PhB(OH)2.
grees of steric hindrance can undergo the arylation. In all
cases, the desired N-(diarylmethyl)nosylamides were ob-
tained with extremely high enantiomeric excesses (98–
99%) in excellent yields. Moreover, both enantiomers of
the product can be readily obtained by simply switching
the corresponding aryl acceptor and donor, without
changing the catalyst (entries 2 and 6; 5 and 11; and 7 and
12). These results for the enantioselectivity are fully com-
patible with that observed in our previously reported ary-
lation of N-tosylarylimines.8c
We previously8c demonstrated an efficient catalytic asym-
metric approach to pharmacologically valuable chiral ph-
thalimidines (isoindolinones) by a rhodium-catalyzed
arylation strategy. Accordingly, we examined the synthet-
ic utility of the current method. N-nosylimine 4, which has
an ortho-ester functionality, was subjected to phenylation
by phenylboronic acid and potassium bifluoride. Not sur-
prisingly, the formation of the corresponding N-(diaryl-
methyl)tosylamide, followed by lactamization in situ gave
the chiral 2-nosyl-3-phenylisoindolin-1-one 5 in a good
yield (80%) and excellent enantioselectivity (99% ee)
(Scheme 2).
Having identified the optimal reaction conditions
(Table 1, entry 5), we decided to explore the scope and
generality of the reaction. A wide variety of N-nosyl-
arylimines with various steric and electronic properties
were tested with several arylboronic acids (Table 2). The
electronic natures of the phenyl ring of the imines and of
the boronic acids appeared to have no effect on the enan-
tioselectivity of the reaction, and substrates with high de-
The conversion of the arylation product into the corre-
sponding free (diarylmethyl)amine was also examined.
As exemplified by the amide 3b, the chiral free amine (S)-
1-(4-chlorophenyl)-1-phenylmethanamine can be readily
obtained in quantitative yield without any racemization by
removal of the N-nosyl group under mild conditions by
Synthesis 2010, No. 19, 3263–3267 © Thieme Stuttgart · New York

SPECIAL TOPIC
Enantioselective Synthesis of (Diarylmethyl)amines
3265
of N-nosylarylimines with arylboronic acid and a chiral
bicyclo[3.3.0]diene ligand. This approach has the advan-
tage of great practicability and provides an elegant synthesis
of highly enantiomerically enriched (diarylmethyl)amines
or 3-aryl-substituted phthalimidines in high yields under
very mild conditions. We believe it will find wide appli-
cation in asymmetric synthesis.
Table 2 Catalytic Asymmetric Arylation of N-Nosylarylimines
with Arylboronic Acidsa
NHNs
[RhCl(C2H4)2]2/1c
Ar2B(OH)2
Ns
+
Ar1
N
KHF2, toluene–H2O
40 °C, 3–4 h
Ar1
Ar2
3
2
Entry Ar1
Ar2
Product Yield
ee
(%)b
94
99
92
89
98
96
98
95
96
99
88
83
(%)c,d
99 (S)
98 (S)
98 (S)
98 (S)
99 (S)
98 (R)
98 (R)
98 (S)
99 (S)
98 (S)
99 (R)
98 (S)
Unless otherwise indicated, all chemicals and solvents were used as
received from commercial sources or were purified by standard pro-
cedures. NMR spectra were recorded on a Varian or Bruker spec-
trometer (300 MHz for 1H, and 75 MHz for 13C). Chemical shifts are
referenced to an internal SiMe4 standard for 1H NMR or to CDCl3
(d = 77.05 ppm) for 13C NMR. Mass spectra were measured on a
HP-5989A spectrometer. Elemental analyses were performed on a
Heraus Rapid-CHNO analyzer. HPLC were measured on a Jasco
LC-2000 instrument. Column chromatography was performed on
silica gel (200–300 mesh).
1
2
4-ClC6H4
Ph
3b
3c
3d
3e
3f
4-MeOC6H4
2-ClC6H4
2-furyl
Ph
3
Ph
4
Ph
5
4-ClC6H4
Ph
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-ClC6H4
4-MeC6H4
6
3c¢
3g
3h
3i
7
4-MeC6H4
2-ClC6H4
2-MeOC6H4
1-naphthyl
4-MeOC6H4
4-MeOC6H4
Chiral N-(Diarylmethyl)-4-nitrobenzenesulfonamides; General
Procedure
8
Toluene (2 mL) was added under N2 to a Schlenk flask charged with
the appropriate arylboronic acid (1 mmol), [RhCl(C2H2)2]2 (2.9 mg,
0.015 mmol, 3 mol%), and chiral diene ligand 3c (4.3 mg, 0.017
mmol, 3.3 mol%). The mixture was heated to 40 °C and stirred for
30 min. Ar1CH=NNs (0.5 mmol) and a 3.0 M aq KHF2 (0.5 mL, 1.5
mmol) were added sequentially, and the mixture was stirred at 40
°C for 3–4 h. The reaction was then quenched with 0.2 M aq HCl
(10 mL). The mixture was extracted with EtOAc (3 × 20 mL), and
the extracts were washed with brine (20 mL). The combined organic
phases were dried (Na2SO4) and concentrated. The residue was pu-
rified by column chromatography (silica gel) to afford the desired
N-(diarylmethyl)amide 3.
9
10
11
12
3j
3f¢
3g¢
a The reaction was carried out with N-nosylarylimine 2 (0.5 mmol),
arylboronic acid (2 equiv) in the presence of KHF2 (3 equiv),
[RhCl(C2H4)2]2 (3 mol% ), and chiral diene 1c (3.3 mol%) at 40 °C in
toluene–H2O (4:1, 2.5 mL).
b Isolated yield.
c Determined by HPLC analysis on a chiral column.
d The stereochemistry of the (diarylmethyl)amine products are as-
signed by comparison of their HPLC chromatograms with those re-
ported previously.8b,c
Determination of the Enantiomeric Excess
Method A: determined by HPLC directly.
Method B: The ee values of compounds 3c, 3e, 3f, and 3j were de-
termined by HPLC analyses of the corresponding tosylimines, ob-
tained by removal of 4-nosyl groups in a manner similar to that
described below, followed by treatment with TsCl and Et3N.
O
COOMe
Method C: The ee of compound 6 was determined by HPLC anal-
ysis of the corresponding acetamide, obtained by treatment of 6
with Ac2O and Et3N.
[RhCl(C2H4)2]2/1c
PhB(OH)2
+
NNs
KHF2, toluene–H2O
40 °C, 5 h
N
Ns
80%
Ph
99% ee
5
4
N-[(S)-(4-Chlorophenyl)(phenyl)methyl]-4-nitrobenzene-
sulfonamide (3b)
White solid; yield: 94%; ee 99% (method A); mp 218–220 °C.
Scheme 2 Synthesis of chiral 2-nosyl-3-phenylisoindolin-1-one 5
1H NMR (300 MHz, CDCl3): d = 5.59 (d, J = 7.2 Hz, 1 H), 5.68 (d,
J = 7.5 Hz, 1 H), 7.04–7.08 (m, 4 H), 7.20–7.27 (m, 5 H), 7.77 (d,
J = 8.7 Hz, 2 H), 8.13 (d, J = 9.0 Hz, 2 H).
13C NMR (75 MHz, CDCl3): d = 61.08, 123.94, 127.28, 128.29,
128.76, 128.89, 128.91, 134.08, 138.14, 138.96, 146.08, 149.76.
NHNs
NH2
4-MeC6H4SH, K2CO3
DMF, r.t., 2 h
98%
Cl
Cl
3b
98% ee
6
HPLC: Chiracel OD-H column (150 mm); detected at 230 nm; hex-
ane–i-PrOH (70:30); flow: 0.7 mL/min; retention times: 15.0 min
(S-enantiomer), 26.3 min (R-enantiomer).
98% ee
Scheme 3 Removal of the nosyl group
N-[(S)-(4-Methoxyphenyl)(phenyl)methyl]-4-nitrobenzene-
sulfonamide (3c)
White solid; yield: 99%; ee 98% (method B); mp 220–222 °C.
1H NMR (300 MHz, CDCl3): d = 3.74 (s, 3 H), 5.25 (d, J = 9.0 Hz,
1 H), 5.58 (d, J = 7.5 Hz, 1 H), 6.72 (d, J = 8.4 Hz, 2 H), 7.01 (d,
J = 8.7 Hz, 2 H), 7.09–7.12 (m, 2 H), 7.20–7.22 (m, 3 H), 7.74 (d,
J = 8.4 Hz, 2 H), 8.10 (d, J = 8.4 Hz, 2 H).
treatment with 4-methylbenzenethiol and potassium car-
bonate in N,N-dimethylformamide16 at room temperature
(Scheme 3).
In summary, we have developed a new reaction system for
the efficient enantioselective rhodium-catalyzed arylation
Synthesis 2010, No. 19, 3263–3267 © Thieme Stuttgart · New York

3266
L. Wang et al.
SPECIAL TOPIC
13C NMR (75 MHz, CDCl3): d = 55.30, 61.21, 114.03, 123.78,
127.31, 127.92, 128.30, 128.69, 131.60, 139.66, 146.33, 149.61,
159.31.
13C NMR (75 MHz, CDCl3): d = 20.97, 55.29, 61.00, 113.98,
123.73, 127.23, 128.32, 128.64, 129.31, 131.77, 136.69, 137.84,
146.36, 149.56, 159.25.
HPLC: Chiracel OD-H column (250 mm); detected at 230 nm; hex-
ane–i-PrOH (70:30); flow: 0.7 mL/min; retention times: 10.9 min
(S-enantiomer), 15.6 min (R-enantiomer).
ESI-MS: m/z 411 [M – 1].
Anal. Calcd for C21H20N2O5S: C, 61.15; H, 4.89; N, 6.79. Found: C,
61.33; H, 4.93; N, 6.66.
HPLC: Chiracel OD-H column (250 mm); detected at 230 nm; hex-
ane–i-PrOH (80:20); flow: 0.7 mL/min; retention time: 43.5 min (S-
enantiomer), 56.9 min (R-enantiomer).
N-[(S)-(2-Chlorophenyl)(phenyl)methyl]-4-nitrobenzene-
sulfonamide (3d)
White solid; yield: 96%; ee 98% (method A); mp 219–221 °C.
1H NMR (300 MHz, CDCl3): d = 5.84 (s, 1 H), 6.07 (d, J = 6.6 Hz,
1 H), 7.13–7.24 (m, 9 H), 7.82 (d, J = 8.1 Hz, 2 H), 8.12 (d, J = 9.6
Hz, 2 H).
13C NMR (75 MHz, CDCl3): d = 58.87, 123.88, 127.13, 127.16,
128.16, 128.31, 128.79, 129.33, 129.38, 130.17, 132.98, 136.66,
138.32, 145.88, 149.76.
N-[(S)-(2-Chlorophenyl)(4-methoxyphenyl)methyl]-4-nitro-
benzenesulfonamide (3h)
White solid; yield: 95%; ee: 98% (method A); mp 161–163 °C.
1H NMR (300 MHz, CDCl3): d = 3.76 (s, 3 H), 6.03 (s, 1 H), 6.77
(d, J = 8.7 Hz, 2 H), 7.04 (d, J = 8.7 Hz, 2 H), 7.06–7.28 (m, 4 H),
7.82 (d, J = 9.0 Hz, 2 H), 8.13 (d, J = 9.0 Hz, 2 H).
ESI-MS: m/z 402 [M – 1].
13C NMR (75 MHz, CDCl3): d = 55.29, 58.39, 114.09, 123.85,
127.05, 128.30, 128.54, 129.08, 129.23, 130.11, 130.34, 132.90,
136.84, 145.92, 149.73, 159.35.
Anal. Calcd for C19H15ClN2O4S: C, 56.65; H, 3.75; N, 6.95. Found:
C, 56.65; H, 3.76; N, 6.80.
HPLC: Chiracel OD-H column (250 mm); detected at 230 nm; hex-
ane–i-PrOH (90:10); flow: 0.7 mL/min; retention time: 44.8 min (R-
enantiomer), 53.2 min (S-enantiomer).
ESI-MS: m/z 431 [M – 1].
Anal. Calcd for C20H17ClN2O5S: C, 55.49; H, 3.96; N, 6.43. Found:
C, 55.47; H, 3.91; N, 6.34.
HPLC: Chiracel OD-H column (250 mm); detected at 230 nm; hex-
ane–i-PrOH (70:30); flow: 0.7 mL/min; retention time: 18.6 min (R-
enantiomer), 36.9 min (S-enantiomer).
N-[(S)-2-Furyl(phenyl)methyl]-4-nitrobenzenesulfonamide (3e)
White solid; yield: 89%; ee 98% (method B); mp 161–163 °C.
1H NMR (300 MHz, CDCl3): d = 5.53 (s, 1 H), 5.74 (s, 1 H), 6.00–
6.02 (m, 1 H), 6.18–6.19 (m, 1 H), 7.18–7.26 (m, 7 H), 7.80 (d, J =
8.7 Hz, 2 H), 8.15 (d, J = 8.7 Hz, 2 H).
13C NMR (75 MHz, CDCl3): d = 55.73, 109.01, 110.41, 123.83,
127.31, 128.25, 128.48, 128.75, 137.32, 142.88, 146.21, 149.65,
151.30.
N-[(S)-(2-Methoxyphenyl)(4-methoxyphenyl)methyl]-4-nitro-
benzenesulfonamide (3i)
White solid; yield: 96%; ee: 99% (method A); mp 110–112 °C.
1H NMR (300 MHz, CDCl3): d = 3.60 (s, 3 H), 3.72 (s, 3 H), 5.73
(s, 1 H), 6.36 (s, 1 H), 6.60 (d, J = 8.1 Hz, 1 H), 6.71–6.77 (m, 3 H),
6.98 (d, J = 7.2 Hz, 1 H), 7.08–7.13 (m, 3 H), 7.74 (d, J = 8.1 Hz, 2
H), 8.00 (d, J = 8.1 Hz, 2 H)
13C NMR (75 MHz, CDCl3): d = 55.25, 55.33, 58.93, 111.12,
113.66, 120.74, 123.50, 126.91, 128.06, 128.16, 129.41, 129.44,
131.76, 146.28, 149.46, 156.23, 158.88.
ESI-MS: m/z 357 [M – 1].
Anal. Calcd for C17H14N2O5S: C, 56.98; H, 3.94; N, 7.82. Found: C,
56.54; H, 4.33; N, 7.75.
HPLC: Chiracel OD-H column (250 mm); detected at 230 nm; hex-
ane–i-PrOH (95:5); flow: 0.3 mL/min; retention time: 76.5 min (S-
enantiomer), 81.6 min (R-enantiomer).
ESI-MS: m/z 427 [M – 1].
Anal. Calcd for C21H20N2O6S: C, 58.87; H, 4.70; N, 6.54. Found: C,
58.77; H, 4.60; N, 6.36.
N-[(S)-(4-Chlorophenyl)(4-methoxyphenyl)methyl]-4-nitro-
benzenesulfonamide (3f)
White solid; yield: 96%; ee 99% (method B); mp 180–183 °C.
1H NMR (300 MHz, acetone-d6): d = 3.72 (s, 3 H), 5.73 (s, 1 H),
6.77 (d, J = 9.0 Hz, 2 H), 7.12 (d, J = 8.1 Hz, 2 H), 7.28 (s, 4 H),
7.82 (br s, 1 H), 7.91 (d, J = 8.7 Hz, 2 H), 8.22 (d, J = 9.0 Hz, 2 H).
13C NMR (75 MHz, acetone-d6): d = 54.62, 60.27, 113.71, 123.83,
128.25, 128.34, 128.67, 129.05, 132.17, 132.58, 140.10, 147.14,
149.58, 159.17.
HPLC: Chiracel OD-H column (250 mm); detected at 230 nm; hex-
ane–i-PrOH (70:30); flow: 0.7 mL/min; retention time: 23.0 min (R-
enantiomer), 49.4 min (S-enantiomer).
N-[(S)-(4-Methoxyphenyl)(1-naphthyl)methyl]-4-nitrobenzene-
sulfonamide (3j)
White solid; yield: 99%; ee: 98% (method B); mp 216–218 °C.
1H NMR (300 MHz, CDCl3): d = 3.70 (s, 3 H), 5.98 (s, 1 H), 6.38
(s, 1 H), 6.68 (d, J = 8.4 Hz, 2 H), 7.05 (d, J = 8.7 Hz, 2 H), 7.13–
7.25 (m, 2 H), 7.42–7.45 (m, 2 H), 7.51 (d, J = 8.4 Hz, 2 H), 7.65
(d, J = 7.5 Hz, 1 H), 7.73–7.76 (m, 1 H), 7.81 (d, J = 8.7 Hz, 2 H),
7.90–7.93 (m, 1 H).
13C NMR (75 MHz, CDCl3): d = 55.28, 58.53, 114.04, 123.35,
123.39, 124.92, 126.05, 126.20, 126.82, 127.94, 128.83, 128.94,
130.38, 131.01, 133.92, 134.63, 145.88, 149.34, 159.27.
ESI-MS: m/z 431 [M – 1].
Anal. Calcd for C20H17ClN2O5S: C, 55.49; H, 3.96; N, 6.47. Found:
C, 55.32; H, 3.86; N, 6.34.
HPLC: Chiracel OD-H column (250 mm); detected at 230 nm; hex-
ane–i-PrOH (70:30); flow: 0.7 mL/min; retention time: 13.4 min (R-
enantiomer), 16.7 min (S-enantiomer).
N-[(R)-(4-Methoxyphenyl)(4-methylphenyl)methyl]-4-nitro-
benzenesulfonamide (3g)
White solid; yield: 98%; ee 98% (method A); mp 180–182 °C.
HPLC: Chiracel OD-H column (150 mm); detected at 230 nm; hex-
ane–i-PrOH (70:30); flow: 0.7 mL/min; retention time: 23.2 min (R-
enantiomer), 32.6 min (S-enantiomer).
1H NMR (300 MHz, CDCl3): d = 2.27 (s, 3 H), 3.74 (s, 3 H), 5.47
(d, J = 5.4 Hz, 1 H), 5.63 (d, J = 5.7 Hz, 1 H), 6.71 (d, J = 7.8 Hz, 2
H), 6.99–7.02 (m, 6 H), 7.73 (d, J = 8.1 Hz, 2 H), 8.09 (d, J = 7.8
Hz, 2 H).
(3S)-2-[(4-Nitrophenyl)sulfonyl]-3-phenylisoindolin-1-one (5)
White solid; yield: 80%; ee: 99% (method A); mp 219–221 °C.
Synthesis 2010, No. 19, 3263–3267 © Thieme Stuttgart · New York

SPECIAL TOPIC
Enantioselective Synthesis of (Diarylmethyl)amines
3267
1H NMR (300 MHz, CDCl3): d = 6.23 (s, 1 H), 7.00–7.03 (m, 2 H),
7.12–7.22 (m, 3 H), 7.33–7.36 (m, 1 H), 7.49–7.54 (t, J = 7.5 Hz, 1
H), 7.56–7.64 (m, 1 H), 7.70–7.74 (m, 2 H), 7.88–7.91 (d, J = 7.8
Hz, 1 H), 8.11–8.15 (m, 2 H).
13C NMR (75 MHz, CDCl3): d = 65.74, 123.70, 123.88, 124.95,
128.39, 128.91, 129.18, 129.29, 129.38, 134.92, 136.22, 144.23,
146.20, 150.46, 166.27.
(7) For selected examples of Rh(I)-catalyzed arylation, see:
(a) Kuriyama, M.; Soeta, T.; Hao, X.; Chen, Q.; Tomioka, K.
J. Am. Chem. Soc. 2004, 126, 8128. (b) Weix, D. J.; Shi, Y.;
Ellman, J. A. J. Am. Chem. Soc. 2005, 127, 1092. (c) Duan,
H.-F.; Jia, Y.-X.; Wang, L.-X.; Zhou, Q.-L. Org. Lett. 2006,
8, 2567. (d) Jagt, R. B. C.; Toullec, P. Y.; Geerdink, D.;
Vries, J. G.; Feringa, B. L.; Minnaard, A. J. J. Comb. Chem.
2007, 9, 407. (e) Nakagawa, H.; Rech, J. C.; Sindelar, R. W.;
Ellman, J. A. Org. Lett. 2007, 9, 5155. (f) Trincado, M.;
Ellman, J. A. Angew. Chem. Int. Ed. 2008, 47, 5623.
(g) Hao, X.; Kuriyama, M.; Chen, Q.; Yamamoto, Y.;
Yamada, K.; Tomioka, K. Org. Lett. 2009, 11, 4470.
(h) Kurihara, K.; Yamamoto, Y.; Miyaura, N. Adv. Synth.
Catal. 2009, 351, 260. (i) Bishop, J. A.; Lou, S.; Schaus, S.
E. Angew. Chem. Int. Ed. 2009, 48, 4337.
(8) For Rh/diene catalysis: (a) Diene 1a: Tokunaga, N.;
Otomaru, Y.; Okamoto, K.; Ueyama, K.; Shintani, R.;
Hayashi, T. J. Am. Chem. Soc. 2004, 126, 13584. (b) Diene
1b: Otomaru, Y.; Tokunaga, N.; Shintani, R.; Hayashi, T.
Org. Lett. 2005, 7, 307. (c) Diene 1c: Wang, Z.-Q.; Feng,
C.-G.; Xu, M.-H.; Lin, G.-Q. J. Am. Chem. Soc. 2007, 129,
5336. (d) Diene 1d: Okamoto, K.; Hayashi, T.; Rawal, V. H.
Chem. Commun. 2009, 4815. (e) Diene 1e: Luo, Y. F.;
Carnell, A. J. Angew. Chem. Int. Ed. 2010, 49, 2750.
(9) For Pd(II)-catalyzed arylation, see: (a) He, P.; Lu, Y.; Hu,
Q. S. Tetrahedron Lett. 2007, 48, 5283. (b) Zhang, Q.;
Chen, J.; Wu, M.; Cheng, J.; Qin, C.; Su, W.; Ding, J. Synlett
2008, 935. (c) Dai, H.-X.; Lu, X.-Y. Tetrahedron Lett. 2009,
50, 3478. (d) Ma, G.-N.; Zhang, T.; Shi, M. Org. Lett. 2009,
11, 875.
HPLC: Chiracel OD-H column (250 mm); detected at 230 nm; hex-
ane–i-PrOH (70:30); flow: 0.7 mL/min; retention time: 7.6 min (R-
enantiomer), 11.3 min (S-enantiomer).
(S)-1-(4-Chlorophenyl)-1-phenylmethanamine (6)
A mixture of the N-(diarylmethyl)amide 3b (0.2 mmol), 4-
MeC6H4SH (0.40 mmol), and K2CO3 (1.0 mmol) in DMF (5 mL)
was stirred at r.t. for 2 h. 2 M HCl (10 ml) was added, and the mix-
ture was washed with Et2O. The pH of the aq layer was adjusted to
14 with 10% NaOH, and the basic aqueous soln was extracted with
Et2O (3 × 20 mL). The combined organic phases were washed with
brine (3 × 20 mL), dried (Na2SO4), and concentrated to give the free
amine as a colorless oil; yield: 98% yield; ee: 98% (method C).
1H NMR (300 MHz, CDCl3): d = 2.09 (s, 2 H), 5.18 (s, 1 H), 7.24–
7.34 (m, 9 H).
HPLC: Chiracel OD-H column (250 mm); detected at 230 nm; hex-
ane–i-PrOH (70:30); flow: 0.7 mL/min; retention time: 17.6 min (S-
enantiomer), 25.9 min (R-enantiomer)
Acknowledgment
We thank the National Natural Science Foundation of China, the
Chinese Academy of Sciences, the Shanghai Rising-Star Program,
the Major State Basic Research Development Program
(2010CB833302), and National Science & Technology Major Pro-
ject (2009ZX09301-001) for their generous financial support.
(10) The conditions required for the reductive removal of a tosyl
group from nitrogen, such as Li/NH3 or SmI2/HMPA/
refuxing THF, are incompatible with electron-accepting
functional groups, e.g. carbonyl, nitro, or halo; see refs. 6,
7g, and 8a.
(11) For leading reviews on chiral diene ligands in asymmetric
catalysis, see: (a) Glorius, F. Angew. Chem. Int. Ed. 2004,
43, 3364. (b) Defieber, C.; Grützmacher, H.; Carreira, E. M.
Angew. Chem. Int. Ed. 2008, 47, 4482. (c) Shintani, R.;
Hayashi, T. Aldrichimica Acta 2009, 42, 31.
(12) For our recent work on chiral dienes in asymmetric
catalysis, see: (a) Ref. 8c. (b) Feng, C.-G.; Wang, Z.-Q.;
Tian, P.; Xu, M.-H.; Lin, G.-Q. Chem. Asian J. 2008, 3,
1511. (c) Feng, C.-G.; Wang, Z.-Q.; Shao, C.; Xu, M.-H.;
Lin, G.-Q. Org. Lett. 2008, 10, 4101.
(13) For our recent discovery of the use of KHF2 under similar
conditions for successful asymmetric conjugate addition of
organoboronic acids to nitroalkenes, see: Wang, Z.-Q.;
Feng, C.-G.; Zhang, S.-S.; Xu, M.-H.; Lin, G.-Q. Angew.
Chem. Int. Ed. 2010, 49, 5780.
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Synthesis 2010, No. 19, 3263–3267 © Thieme Stuttgart · New York