Rhodium-Catalyzed Enantioselective Addition of Tricyclopropylboroxin to N -Sulfonylimines

Article abstract of DOI:10.1055/s-0035-1561605

A hydroxorhodium complex coordinated with a chiral diene ligand efficiently catalyzed the asymmetric addition of tricyclopropylboroxin to N-sulfonylimines in high yields and high enantioselectivities.

Full text of DOI:10.1055/s-0035-1561605

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2016, 48, A–G
A
special topic
T. Nishimura et al.
Special Topic
Synthesis
Rhodium-Catalyzed Enantioselective Addition of Tricyclopropyl-
boroxin to N-Sulfonylimines
Takahiro Nishimura*
Tomotaka Nagai
Ryosuke Takechi
Yusuke Ebe
SO2R
[Rh(OH)((S,S)-L*)]2
(5 mol% of Rh)
SO2R
H
F
HN
F
N
+
OB
F
3
tert-amyl alcohol
1,4-dioxane
Ar
Ar
18 examples (72–98%)
F
up to 98% ee
Department of Chemistry, Graduate School of Science,
Kyoto University, Sakyo, Kyoto 606-8502, Japan
tnishi@kuchem.kyoto-u.ac.jp
[Rh(OH)((S,S)-L*)]2
(5 mol% of Rh)
K3PO4
O
O
O
S
O
(S,S)-L*
S
N
NH
OB
+
3
tert-amyl alcohol
1,4-dioxane
Ar
Ar
3 examples (56–75%)
99% ee
Received: 05.01.2016
Accepted after revision: 10.03.2016
Published online: 14.04.2016
alytic conditions can be applied to the asymmetric cyclo-
propylation of N-sulfonylimines in a highly enantioselective
manner. To the best of our knowledge, the catalytic enan-
tioselective addition of cyclopropylated metal species to
imines has not previously been reported.
DOI: 10.1055/s-0035-1561605; Art ID: ss-2016-c0007-st
Abstract A hydroxorhodium complex coordinated with a chiral diene
ligand efficiently catalyzed the asymmetric addition of tricyclopropyl-
boroxin to N-sulfonylimines in high yields and high enantioselectivities.
Our initial studies focused on the addition of various cy-
clopropylboron reagents to the N-tosylimine 1a in the pres-
ence of various rhodium complexes in an attempt to find a
suitable cyclopropyl transfer reagent (Table 1). Treatment of
imine 1a with cyclopropylboronic acid (2a, 3 equiv) in the
presence of [Rh(OH)(cod)]2 (cod = 1,5-cyclooctadiene; 5
mol% of Rh) in 1,4-dioxane at 80 °C for 20 hours gave the
cyclopropylated product 3a in 14% yield (Table 1, entry 1).
The use of tricyclopropylboroxin (2b) with tert-amyl alco-
hol as a proton source improved the yield of 3a to 33% (en-
try 2), whereas neither the cyclopropylboronate 2c nor the
trifluoroborate 2d gave the cyclopropylated product (en-
tries 3 and 4). A chlororhodium complex with K3PO4 as a
base was not effective and gave a low yield of 3a (entry 5).
Enantioselective addition was achieved by the use of chiral
diene ligands.9 Among various chiral diene ligands based on
a tetrafluorobenzobarrelene (tfb) framework10,11 (entries 6–
11), the neopentyl-substituted tfb ligand L27 showed a high
enantioselectivity (93% ee) and gave 3a in 59% yield (entry
10). Reaction for a prolonged reaction time (40 h) gave 3a in
92% yield and 92% ee (entry 12). The rhodium-bisphos-
phine complex {Rh(OH)[(R)-BINAP]}2, reported to be one of
the most efficient catalysts for the enantioselective addi-
tion of arylboronic acids,12 did not give the addition prod-
uct at all (entry 13).
Key words asymmetric catalysis, addition reactions, rhodium, imines,
cyclopropylation, ligands
α-Chiral amines are important core units, often found in
drugs and natural products, and their synthesis by enanti-
oselective addition of organometallic reagents to imines
has been developed as one of the most valuable transfor-
mations in organic synthesis.1 There have been many re-
ports on catalytic enantioselective alkylations and aryla-
tions of imines by organometallic reagents catalyzed by
transition-metal complexes.2 In this regard, the catalysis by
rhodium complexes of the enantioselective addition of or-
ganoboron reagents to imines permits the synthesis of di-
verse α-chiral amines substituted with aryl or alkenyl
groups with high enantioselectivity.2f–q,3
α-Cyclopropylbenzylamines are important core units of
many biologically active compounds,4 and their diastereo-
selective synthesis by using chiral auxiliaries on the imine
nitrogen has been reported.4 Asymmetric hydrogenation
and hydrosilylation of ketimines are alternative approaches
to chiral α-cyclopropylbenzylamines with high levels of en-
antioselectivity.5 Recently, a palladium-catalyzed enanti-
oselective addition of phenylboronic acid to imines gener-
ated in situ from cyclopropanecarbaldehyde to give α-cy-
clopropylbenzylamines was reported.6 In this context, we
recently reported that rhodium–chiral diene complexes
catalyze the asymmetric 1,4-addition of cyclopropylboronic
acid to electron-deficient alkenes, without suffering from
β-hydrogen elimination.7,8 Here, we report that similar cat-
Besides the N-tosylimine 1a, the N-mesylimine 1b, the
N-(4-nitrobenzenesulfonyl)imine 1c, and the sulfamidate
imine 1d also reacted well to give the corresponding addi-
tion products 3b–d in good to high yields and high enan-
tioselectivities (Scheme 1).13
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–G

B
T. Nishimura et al.
Special Topic
Synthesis
Table 1 Rhodium-Catalyzed Asymmetric Addition of Cyclopropylbo-
ron Reagents to Imine 1aa
functional groups in the ortho-, meta-, and para-positions
of the phenyl group (Table 2, entries 1–10), as well as those
containing a naphthyl group (entries 11 and 12) or a ferro-
cenyl group (entry 13), gave the corresponding addition
products in good to high yields and over 91% ee. The reac-
tion of the 2-furyl-substituted imine 1r gave the addition
product 3r in 75% ee (entry 14).
Ts
H
Ts
N
HN
*
Rh catalyst
(5 mol% of Rh)
+
[B]
tert-amyl alcohol
1,4-dioxane
80 °C, 20 h
1a
2
3a
O
B
(HO)2B
OB
KF3B
Table 2 Rhodium-Catalyzed Asymmetric Addition of Tricyclopropyl-
boroxin to Imines 1a
3
O
2c
2a
2b
2d
R = Ph
Fc
F
F
Ts
H
Ts
[Rh(OH)((S,S)-L2)]2
(5 mol% of Rh)
N
HN
F
Bn
PPh2
PPh2
+
OB
Ar
3
Ar
tert-amyl alcohol
1,4-dioxane
80 °C, 40 h
(L1)
(L2)
F
1
2b
3
R
R
Entry Ar
Product
Yieldb (%) eec (%)
(R)-BINAP
Ph
R-tfb*
(L3)
1
2
4-FC6H4 (1e)
3e
3f
80
76
52
91
95
83
94
94
77
65
92
95
61
90
92
91
93
94
92
91
92
96
91
94
94
98
91
75
Entry
Catalyst
Reagent
Yieldb (%) eec (%)
4-ClC6H4 (1f)
4-BrC6H4 (1g)
4-F3CC6H4 (1h)
4-Tol (1i)
3
3g
3h
3i
1d
2
[Rh(OH)(cod)]2
[Rh(OH)(cod)]2
[Rh(OH)(cod)]2
[Rh(OH)(cod)]2
2a
2b
2c
14
33
0
–
4
–
5
3
–
6
4-MeOC6H4 (1j)
3-MeOC6H4 (1k)
2-MeOC6H4 (1l)
3j
4
2d
2b
2b
2b
2b
2b
2b
2b
2b
2b
0
–
7
3k
3l
e
5
[RhCl(cod)]2/K3PO4
3
–
8
6
{Rh(OH)[(R,R)-Ph-tfb*]}2
{Rh(OH)[(S,S)-Fc-tfb*]}2
{Rh(OH)[(S,S)-Bn-tfb*]}2
{Rh(OH)[(R,R)-L1]}2
{Rh(OH)[(R,R)-L2]}2
{Rh(OH)[(R,R)-L3]}2
{Rh(OH)[(R,R)-L2]}2
{Rh(OH)[(R)-BINAP]}2
70
91
75
67
59
48
92
0
27
63
82
88
93
93
92
–
9
3,4,5-(MeO)3C6H2 (1m)
3m
3n
3o
3p
3q
3r
7
10
11
12
13
14
1,3-benzodioxol-5-yl (1n)
2-naphthyl (1o)
1-naphthyl (1p)
Fc (1q)
8
9
10
11
12f
13
2-furyl (1r)
a Reaction conditions: 1a (0.20 mmol), tricyclopropylboroxin (2b, 0.20
mmol), {Rh(OH)[(S,S)-L2]}2 (5 mol% of Rh), tert-amyl alcohol (0.60 mmol),
1,4-dioxane (0.8 mL), 80 °C, 40 h.
a Reaction conditions: 1a (0.10 mmol), cyclopropylboron reagent (0.30
mmol of B), Rh catalyst (5 mol% of Rh), tert-amyl alcohol (0.30 mmol), 1,4-
dioxane (0.4 mL), 80 °C, 20 h; for details, see Supporting Information.
b Isolated yield.
b Isolated yield.
c Determined by chiral HPLC.
c Determined by chiral HPLC.
d Without tert-amyl alcohol.
The present catalytic system can also be applied to ad-
dition reactions of ketimines to give the corresponding α-
tert-chiral amines (Scheme 2). Thus, the reaction of cyclic
N-sulfonyl ketimine 4a with boroxin 2b in the presence of
K3PO4 as a base gave the α-tert-chiral amine 5a in 75% yield
with 99% ee.14 A high enantioselectivity was also observed
with ketimines 4b and 4c containing substituted phenyl
groups.
e K3PO4 (0.10 mmol).
f For 40 h.
R
H
R
N
HN
[Rh(OH)((S,S)-L2)]2
(5 mol% of Rh)
+
OB
3
tert-amyl alcohol
1,4-dioxane
80 °C, 40 h
1a: R = Ts
1b: R = Ms
1c: R = p-Ns
2b
3a: 94%, 92% ee
3b: 75%, 94% ee
3c: 72%, 94% ee
O
O
O
O
[Rh(OH)((S,S)-L2)]2
(5 mol% of Rh)
K3PO4 (1 equiv)
S
S
N
NH
SO N
2
O
1d: R =
3d: 98%, 96% ee
2b
+
Ar
tert-amyl alcohol
1,4-dioxane
Ar
Scheme 1 Effects of the substituent on the imine nitrogen
80 °C, 40 h
4a: Ar = Ph
4b: Ar = 4-ClC6H4
4c: Ar = 4-MeC6H4
5a: 75%, 99% ee
5b: 56%, 99% ee
5c: 60%, 99% ee
The results obtained in enantioselective additions of tri-
cyclopropylboroxin (2b) to several imines 1 are summa-
rized in Table 2. Aromatic imines substituted with various
Scheme 2 Asymmetric additions to ketimines
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–G

C
T. Nishimura et al.
Special Topic
Synthesis
We tried to use alkylboron reagents other than tricyclo-
propylboroxin (2b) in the addition reactions of imines, but
these reactions failed to give the corresponding addition
products.15,16 For example, no reaction was observed for cy-
clobutyl- or cyclopentylboronic acid. Butylboronic acid re-
duced the imine 1a to give the benzylamine 7 in 49% yield
(Scheme 3), probably through reduction of imine 1a with a
hydridorhodium species generated by β-hydrogen elimina-
tion from a butylrhodium complex.7 In contrast, the forma-
tion of the reduced product 7 was not observed in the reac-
tion using cyclopropylboronic acid (2a), implying that β-hy-
drogen elimination from the cyclopropylrhodium species
does not take place under the present reaction conditions.
Colorless solid; yield: 56.7 mg (94%); [α]D20 –21 (c 0.99, CHCl3) for 92%
ee (S).
HPLC [Chiralpak AD-H (hexane–i-PrOH, 9:1), flow: 0.5 mL/min, 254
nm]: tR = 28.0 min (R), 30.0 min (S).
1H NMR (600 MHz, CDCl3): δ = 7.54 (d, J = 8.1 Hz, 2 H), 7.18–7.11 (m, 7
H), 4.95 (d, J = 5.4 Hz, 1 H), 3.70 (dd, J = 8.9, 5.4 Hz, 1 H), 2.37 (s, 3 H),
1.12–1.08 (m, 1 H), 0.52–0.45 (m, 2 H), 0.30–0.21 (m, 2 H).
N-[(S)-Cyclopropyl(phenyl)methyl]methanesulfonamide (3b)
[CAS Reg. No. 1376332-88-5 for rac-3b]
Colorless solid; yield: 33.8 mg (75%); [α]D20 –6 (c 1.01, CHCl3) for 94%
ee (S).
HPLC [Chiralcel OD-H (hexane–i-PrOH, 9:1), flow: 0.5 mL/min, 254
nm]: tR = 20.9 min (R), 23.0 min (S).
Ts
N
1H NMR (500 MHz, CDCl3): δ = 7.40–7.28 (m, 5 H), 4.73 (br s, 1 H),
3.23 (dd, J = 10.7, 6.5 Hz, 1 H), 2.63 (s, 3 H), 1.26–1.20 (m, 1 H), 0.74–
0.66 (m, 1 H), 0.59–0.50 (m, 2 H), 0.40–0.36 (m, 1 H).
Ts
Ts
HN
HN
[Rh(OH)((S,S)-L2)]2
(5 mol% of Rh)
H
R
+
1a
tert-amyl alcohol
1,4-dioxane
80 °C, 40 h
+
(HO)2B
2
N-[(S)-Cyclopropyl(phenyl)methyl]-4-nitrobenzenesulfonamide
(3c)
Colorless solid; yield: 47.9 mg (72%); [α]D20 +32 (c 1.02, CHCl3) for 94%
6: 0% (R = Bu)
3a: 47% (R = c-Pr)
7: 49%
7: 0%
R
Scheme 3 Reduction caused by β-hydrogen elimination
ee (S).
HPLC [Chiralcel OD-H (hexane–i-PrOH, 9:1), flow: 0.5 mL/min, 254
nm]: tR = 60.4 min (R), 73.5 min (S).
1H NMR (600 MHz, CDCl3): δ = 8.09 (d, J = 8.9 Hz, 2 H), 7.71 (d, J = 8.1
Hz, 2 H), 7.17–7.11 (m, 3 H), 7.04 (d, J = 8.1 Hz, 2 H), 5.28–5.23 (m, 1
H), 3.82 (dd, J = 9.1, 5.4 Hz, 1 H), 1.18–1.12 (m, 1 H), 0.61–0.50 (m, 2
H), 0.38–0.30 (m, 2 H).
In summary, by using a chiral diene ligand, we have de-
veloped a rhodium-catalyzed asymmetric addition of tricy-
clopropylboroxin to various aromatic imines with high en-
antioselectivity.
13C NMR (150 MHz, CDCl3): δ = 149.5, 146.7, 139.2, 128.4, 128.2,
127.9, 127.0, 123.7, 63.3, 18.0, 4.8, 3.9.
HRMS (ESI): m/z [M + Na]+ calcd for C16H16N2NaO4S: 355.0723; found:
355.0717.
All anaerobic and moisture-sensitive manipulations were carried out
by standard Schlenk techniques under dry N2. NMR spectra were re-
corded on a JEOL JNM ECA-600 spectrometer (600 MHz for 1H; 150
MHz for 13C) or a JEOL JNM LA-500 spectrometer (500 MHz for 1H;
125 MHz for 13C). Chemical shifts are referenced to the residual peaks
N-[(S)-Cyclopropyl(phenyl)methyl]morpholine-4-sulfonamide
(3d)
Colorless solid; yield: 58.1 mg (98%); [α]D20 +26 (c 1.01, CHCl3) for 96%
ee (S).
of CDCl3 (δ = 7.26 ppm) for 1H NMR and CDCl3 (δ = 77.00 ppm) for 13
C
NMR. High-resolution mass spectra (TOF-MS) were obtained with a
Bruker micrOTOF spectrometer. Flash column chromatography was
performed on Silica Gel 60 N (spherical, neutral, Cica-Reagent). Pre-
parative TLC was performed on Silica Gel 60 PF254 (Merck). Alumina
(activated 200) for column chromatography was purchased from
Nacalai Tesque.
HPLC [Chiralcel OD-H (hexane–i-PrOH, 9:1), flow: 0.5 mL/min, 254
nm]: tR = 23.4 min (R), 26.2 min (S).
1H NMR (600 MHz, CDCl3): δ = 7.37–7.29 (m, 5 H), 4.78 (br, 1 H), 3.68
(dd, J = 8.8, 4.8 Hz, 1 H), 3.43–3.33 (m, 4 H), 2.95–2.88 (m, 4 H), 1.23–
1.17 (m, 1 H), 0.69–0.64 (m, 1 H), 0.57–0.48 (m, 2 H), 0.38–0.33 (m, 1
H).
Asymmetric Addition of Tricyclopropylboroxin (2b) to Imines 1;
General Procedure
13C NMR (150 MHz, CDCl3): δ = 141.4, 128.6, 127.8, 127.0, 65.9, 63.2,
{Rh(OH)[(S,S)-L2]}2 (4.8 mg, 0.010 mmol of Rh) and imine 1 (0.20
mmol) were placed in a Schlenk tube under N2. A 0.50 M stock solu-
tion of tricyclopropylboroxin (2b) in 1,4-dioxane (0.40 mL, 0.20
mmol) together with t-amyl alcohol (66 μL, 0.60 mmol) and 1,4-diox-
ane (0.60 mL) were added to the Schlenk tube, and the mixture was
stirred at 80 °C for 40 h. The mixture was then passed through a short
column of alumina with EtOAc as eluent. The solvent was removed on
a rotary evaporator and the residue was subjected to preparative TLC
[silica gel, hexane–EtOAc] to give 3. The ee of 3 was determined by
chiral HPLC analysis.
45.6, 18.5, 4.8, 4.1.
HRMS (ESI): m/z [M + Na]+ calcd for C14H20N2NaO3S: 319.1087; found:
319.1082.
N-[(S)-Cyclopropyl(4-fluorophenyl)methyl]-4-toluenesulfon-
amide (3e)
[CAS Reg. No. 1108697-86-4 for rac-3e]
Colorless solid; yield: 51.1 mg (80%); [α]D20 –20 (c 1.02, CHCl3) for 92%
ee (S).
HPLC [Chiralcel OD-H (hexane–i-PrOH, 9:1), flow: 0.5 mL/min, 254
nm]: tR = 22.4 min (R), 26.1 min (S).
N-[(S)-Cyclopropyl(phenyl)methyl]-4-toluenesulfonamide (3a)
[CAS Reg. No. 1797442-90-0 for (R)-3a]
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–G

D
T. Nishimura et al.
Special Topic
Synthesis
1H NMR (600 MHz, CDCl3): δ = 7.54 (d, J = 8.1 Hz, 2 H), 7.15 (d, J = 8.1
Hz, 2 H), 7.10–7.07 (m, 2 H), 6.84 (t, J = 8.5 Hz, 2 H), 5.17 (br s, 1 H),
3.66 (dd, J = 8.9, 5.4 Hz, 1 H), 2.38 (s, 3 H), 1.09–1.03 (m, 1 H), 0.53–
0.45 (m, 2 H), 0.29–0.18 (m, 2 H).
1H NMR (600 MHz, CDCl3): δ = 7.56 (d, J = 8.1 Hz, 2 H), 7.14 (d, J = 8.1
Hz, 2 H), 7.00 (d, J = 8.1 Hz, 2 H), 6.98 (d, J = 8.1 Hz, 2 H), 5.10–5.02 (m,
1 H), 3.65 (dd, J = 8.5, 5.8 Hz, 1 H), 2.38 (s, 3 H), 2.28 (s, 3 H), 1.12–1.06
(m, 1 H), 0.52–0.43 (m, 2 H), 0.28–0.19 (m, 2 H).
13C NMR (150 MHz, CDCl3): δ = 142.9, 137.8, 137.5, 137.1, 129.2,
128.9, 127.1, 126.8, 62.2, 21.4, 21.0, 18.0, 4.4, 3.6.
N-[(S)-(4-Chlorophenyl)(cyclopropyl)methyl]-4-toluenesulfon-
amide (3f)
HRMS (ESI): m/z [M + Na]+ calcd for C18H21NNaO2S: 338.1185; found:
338.1183.
Colorless solid; yield: 50.9 mg (76%); [α]D20 –20 (c 1.01, CHCl3) for 91%
ee (S).
HPLC [Chiralcel OD-H (hexane–i-PrOH, 9:1), flow: 0.5 mL/min, 254
nm]: tR = 21.9 min (R), 24.6 min (S).
N-[(S)-Cyclopropyl(4-methoxyphenyl)methyl]-4-toluenesulfon-
amide (3j)
1H NMR (600 MHz, CDCl3): δ = 7.54 (d, J = 8.1 Hz, 2 H), 7.14 (d, J = 8.2
Hz, 2 H), 7.11 (d, J = 8.2 Hz, 2 H), 7.01 (d, J = 8.1 Hz, 2 H), 5.35 (br, 1 H),
3.64 (dd, J = 8.1, 6.1 Hz, 1 H), 2.39 (s, 3 H), 1.10–1.02 (m, 1 H), 0.54–
0.44 (m, 2 H), 0.27–0.17 (m, 2 H).
13C NMR (150 MHz, CDCl3): δ = 143.2, 139.0, 137.5, 133.1, 129.3,
128.3, 128.2, 127.1, 61.9, 21.4, 18.0, 4.4, 3.7.
[CAS Reg. No. 1108697-85-3 for rac-3j]
Colorless solid; yield: 55.1 mg (83%); [α]D20 –28 (c 1.03, CHCl3) for 91%
ee (S).
HPLC [Chiralpak AD-H (hexane–i-PrOH, 9:1), flow: 0.5 mL/min, 254
nm]: tR = 44.5 min (R), 47.7 min (S).
1H NMR (600 MHz, CDCl3): δ = 7.55 (d, J = 8.2 Hz, 2 H), 7.16 (d, J = 8.1
Hz, 2 H), 7.03 (d, J = 8.2 Hz, 2 H), 6.70 (d, J = 8.1 Hz, 2 H), 4.87 (br, 1 H),
3.76 (s, 3 H), 3.66 (dd, J = 8.8, 5.5 Hz, 1 H), 2.38 (s, 3 H), 1.11–1.05 (m,
1 H), 0.52–0.42 (m, 2 H), 0.27–0.20 (m, 2 H).
HRMS (ESI): m/z [M + Na]+ calcd for C17H18ClNNaO2S: 358.0639;
found: 358.0637.
N-[(S)-(4-Bromophenyl)(cyclopropyl)methyl]-4-toluenesulfon-
amide (3g)
N-[(S)-Cyclopropyl(3-methoxyphenyl)methyl]-4-toluenesulfon-
amide (3k)
Colorless solid; yield: 39.4 mg (52%); [α]D20 –13 (c 0.49, CHCl3) for 93%
ee (S).
Colorless solid; yield: 63.3 mg (94%); [α]D20 –26 (c 1.00, CHCl3) for 92%
HPLC [Chiralcel OD-H (hexane–i-PrOH, 9:1), flow: 0.5 mL/min, 254
nm]: tR = 25.6 min (R), 29.7 min (S).
1H NMR (600 MHz, CDCl3): δ = 7.52 (d, J = 8.2 Hz, 2 H), 7.28 (d, J = 8.5
Hz, 2 H), 7.15 (d, J = 8.5 Hz, 2 H), 6.99 (d, J = 8.2 Hz, 2 H), 5.04 (br s, 1
H), 3.62 (dd, J = 8.9, 5.2 Hz, 1 H), 2.40 (s, 3 H), 1.08–1.02 (m, 1 H),
0.55–0.45 (m, 2 H), 0.28–0.19 (m, 2 H).
ee (S).
HPLC [Chiralcel OD-H (hexane–i-PrOH, 9:1), flow: 0.5 mL/min, 254
nm]: tR = 28.2 min (R), 40.3 min (S).
1H NMR (600 MHz, CDCl3): δ = 7.55 (d, J = 8.1 Hz, 2 H), 7.14 (d, J = 8.1
Hz, 2 H), 7.10 (t, J = 8.1 Hz, 1 H), 6.73–6.69 (m, 2 H), 6.60 (s, 1 H), 5.00
(br s, 1 H), 3.68 (s, 3 H), 3.67 (dd, J = 8.9, 6.1 Hz, 1 H), 2.37 (s, 3 H),
1.12–1.06 (m, 1 H), 0.54–0.46 (m, 2 H), 0.32–0.24 (m, 2 H).
13C NMR (150 MHz, CDCl3): δ = 143.3, 139.4, 137.5, 131.3, 129.3,
128.6, 127.1, 121.3, 62.1, 21.5, 18.0, 4.4, 3.8.
HRMS (ESI): m/z [M + Na]+ calcd for C17H18BrNNaO2S: 402.0134;
13C NMR (150 MHz, CDCl3): δ = 159.5, 143.0, 142.0, 137.8, 129.3,
129.2, 127.1, 119.3, 112.9, 112.4, 62.5, 55.0, 21.4, 18.1, 4.4, 3.8.
found: 402.0136.
HRMS (ESI): m/z [M + Na]+ calcd for C18H21NNaO3S: 354.1134; found:
354.1133.
N-{(S)-Cyclopropyl[4-(trifluoromethyl)phenyl]methyl}-4-toluene-
sulfonamide (3h)
Colorless solid; yield: 67.0 mg (91%); [α]D20 –7 (c 1.01, CHCl3) for 94%
N-[(S)-Cyclopropyl(2-methoxyphenyl)methyl]-4-toluenesulfon-
amide (3l)
ee (S).
[CAS Reg. No. 1108697-89-7 for rac-3l]
HPLC [Chiralcel OD-H (hexane–i-PrOH, 9:1), flow: 0.5 mL/min, 254
nm]: tR = 20.8 min (R), 23.7 min (S).
Colorless solid; yield: 62.3 mg (94%); [α]D20 –6 (c 0.99, CHCl3) for 96%
ee (S).
1H NMR (600 MHz, CDCl3): δ = 7.47 (d, J = 8.1 Hz, 2 H), 7.39 (d, J = 8.1
Hz, 2 H), 7.21 (d, J = 8.1 Hz, 2 H), 7.10 (d, J = 8.1 Hz, 2 H), 5.00 (br s, 1
H), 3.67 (dd, J = 7.0, 4.8 Hz, 1 H), 2.35 (s, 3 H), 1.11–1.05 (m, 1 H),
0.55–0.50 (m, 1 H), 0.54–0.49 (m, 1 H), 0.33–0.29 (m, 1 H), 0.27–0.23
(m, 1 H).
13C NMR (150 MHz, CDCl3): δ = 144.3, 143.3, 137.3, 129.5 (q, J = 33
Hz), 129.3, 127.3, 127.1, 125.1 (q, J = 4 Hz), 124.0 (q, J = 271 Hz), 62.3,
21.3, 18.1, 4.5, 3.9.
HPLC [Chiralcel OD-H (hexane–i-PrOH, 9:1), flow: 0.5 mL/min, 254
nm]: tR = 22.4 min (R), 24.4 min (S).
1H NMR (600 MHz, CDCl3): δ = 7.44 (d, J = 8.1 Hz, 2 H), 7.09 (td, J = 7.8,
1.3 Hz, 1 H), 7.00 (d, J = 8.1 Hz, 2 H), 6.83 (dd, J = 7.5, 1.3 Hz, 1 H), 6.72
(t, J = 7.5 Hz, 1 H), 6.62 (d, J = 8.1 Hz, 1 H), 5.68 (br, 1 H), 3.72 (s, 3 H),
3.66 (t, J = 9.2 Hz, 1 H), 2.29 (s, 3 H), 1.35–1.29 (m, 1 H), 0.55–0.49 (m,
1 H), 0.41–0.35 (m, 2 H), 0.24–0.19 (m, 1 H).
HRMS (ESI): m/z [M + Na]+ calcd for C18H18F3NNaO2S: 392.0903;
found: 392.0910.
N-[(S)-Cyclopropyl(3,4,5-trimethoxyphenyl)methyl]-4-toluenesul-
fonamide (3m)
Colorless solid; yield: 60.5 mg (77%); [α]D20 –4 (c 1.00, CHCl3) for 91%
ee (S).
N-[(S)-Cyclopropyl(4-tolyl)methyl]-4-toluenesulfonamide (3i)
Colorless solid; yield: 60.2 mg (95%); [α]D20 –32 (c 1.01, CHCl3) for 92%
ee (S).
HPLC [Chiralcel OD-H (hexane–i-PrOH, 9:1), flow: 0.5 mL/min, 254
nm]: tR = 41.4 min (R), 49.0 min (S).
HPLC [Chiralcel OD-H (hexane–i-PrOH, 9:1), flow: 0.5 mL/min, 254
nm]: tR = 19.8 min (R), 23.0 min (S).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–G

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T. Nishimura et al.
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1H NMR (600 MHz, CDCl3): δ = 7.52 (d, J = 8.1 Hz, 2 H), 7.12 (d, J = 8.1
Hz, 2 H), 6.27 (s, 2 H), 5.34 (br, 1 H), 3.77 (s, 3 H), 3.68 (s, 6 H), 3.67
(dd, J = 8.9, 6.1 Hz, 1 H), 2.35 (s, 3 H), 1.12–1.07 (m, 1 H), 0.57–0.46
(m, 2 H), 0.34–0.29 (m, 2 H).
13C NMR (150 MHz, CDCl3): δ = 152.9, 143.0, 138.0, 137.1, 136.0,
129.1, 127.1, 103.9, 62.8, 60.7, 55.8, 21.4, 18.0, 4.4, 3.9.
HPLC [Chiralcel OD-H (hexane–i-PrOH, 9:1), flow: 0.5 mL/min, 254
nm]: tR = 24.9 min (S), 27.6 min (R).
1H NMR (600 MHz, CDCl3): δ = 7.81 (d, J = 8.1 Hz, 2 H), 7.32 (d, J = 8.1
Hz, 2 H), 4.85 (br s, 1 H), 4.17 (s, 5 H), 4.13 (s, 1 H), 4.11 (s, 1 H), 4.01
(s, 1 H), 3.92 (d, J = 1.3 Hz, 1 H), 3.48 (t, J = 7.8 Hz, 1 H), 2.44 (s, 3 H),
1.13–1.07 (m, 1 H), 0.59–0.53 (m, 1 H), 0.40–0.37 (m, 1 H), 0.31–0.24
(m, 2 H).
HRMS (ESI): m/z [M + Na]+ calcd for C20H25NNaO5S: 414.1346; found:
414.1355.
13C NMR (150 MHz, CDCl3): δ = 143.2, 138.6, 129.6, 127.1, 90.7, 68.5,
68.1, 68.0, 67.5, 66.4, 56.8, 21.5, 16.8, 4.2, 3.5.
HRMS (ESI): m/z [M + Na]+ calcd for C21H23FeNNaO2S: 432.0691;
N-[(S)-1,3-Benzodioxol-5-yl(cyclopropyl)methyl]-4-toluenesul-
fonamide (3n)
found: 432.0687.
Colorless solid; yield: 45.9 mg (65%); [α]D20 –31 (c 1.01, CHCl3) for 94%
ee (S).
N-[(S)-Cyclopropyl(2-furyl)methyl]-4-toluenesulfonamide (3r)
HPLC [Chiralcel OD-H (hexane–i-PrOH, 9:1), flow: 0.5 mL/min, 254
nm]: tR = 34.9 min (R), 41.9 min (S).
Colorless solid; yield: 52.3 mg (90%); [α]D20 –25 (c 1.01, CHCl3) for 75%
ee (S).
1H NMR (600 MHz, CDCl3): δ = 7.56 (d, J = 8.1 Hz, 2 H), 7.17 (d, J = 8.1
Hz, 2 H), 6.63–6.55 (m, 3 H), 5.89 (d, J = 1.4 Hz, 1 H), 5.87 (d, J = 1.4 Hz,
1 H), 5.08 (br s, 1 H), 3.58 (dd, J = 8.5, 5.8 Hz, 1 H), 2.38 (s, 3 H), 1.08–
1.01 (m, 1 H), 0.54–0.44 (m, 2 H), 0.27–0.19 (m, 2 H).
13C NMR (150 MHz, CDCl3): δ = 147.5, 146.8, 143.0, 137.7, 134.4,
129.2, 127.2, 120.4, 107.8, 107.2, 100.9, 62.4, 21.4, 18.1, 4.5, 3.7.
HPLC [Chiralcel OD-H (hexane–i-PrOH, 9:1), flow: 0.5 mL/min, 254
nm]: tR = 21.5 min (R), 24.7 min (S).
1H NMR (600 MHz, CDCl3): δ = 7.63 (d, J = 8.5 Hz, 2 H), 7.19 (d, J = 8.5
Hz, 2 H), 7.14 (s, 1 H), 6.14 (dd, J = 3.1, 1.7 Hz, 1 H), 6.00 (d, J = 3.1 Hz,
1 H), 5.07 (br, 1 H), 3.91 (t, J = 7.8 Hz, 1 H), 2.38 (s, 3 H), 1.23–1.17 (m,
1 H), 0.55–0.47 (m, 2 H), 0.34–0.24 (m, 2 H).
HRMS (ESI): m/z [M + Na]+ calcd for C18H19NNaO4S: 368.0927; found:
13C NMR (150 MHz, CDCl3): δ = 152.7, 142.9, 141.9, 137.8, 129.3,
368.0932.
127.0, 109.9, 106.9, 55.6, 21.4, 15.8, 3.8, 3.5.
HRMS (ESI): m/z [M + Na]+ calcd for C15H17NNaO3S: 314.0821; found:
314.0824.
N-[(S)-Cyclopropyl(2-naphthyl)methyl]-4-toluenesulfonamide
(3o)
Colorless solid; yield: 64.7 mg (92%); [α]D20 –20 (c 1.01, CHCl3) for 94%
(3S)-3-Cyclopropyl-3-phenyl-2,3-dihydro-1,2-benzisothiazole 1,1-
ee (S).
Dioxide (5a)
HPLC [Chiralcel OD-H (hexane–i-PrOH, 9:1), flow: 0.5 mL/min, 254
nm]: tR = 32.5 min (R), 38.8 min (S).
[CAS Reg. No. 1504627-57-9 for (R)-5a]
Colorless solid; yield: 21.4 mg (from the reaction of 0.10 mmol of 4a;
75%); [α]D20 +62 (c 0.53, CHCl3) for 99% ee (S).
1H NMR (600 MHz, CDCl3): δ = 7.76–7.75 (m, 1 H), 7.65–7.63 (m, 2 H),
7.49 (d, J = 8.1 Hz, 2 H), 7.45–7.42 (m, 3 H), 7.24 (dd, J = 8.5, 1.7 Hz, 1
H), 6.97 (d, J = 8.1 Hz, 2 H), 5.02 (br s, 1 H), 3.87 (dd, J = 8.5, 5.8 Hz, 1
H), 2.22 (s, 3 H), 1.23–1.17 (m, 1 H), 0.60–0.55 (m, 1 H), 0.53–0.48 (m,
1 H), 0.37–0.29 (m, 2 H).
13C NMR (150 MHz, CDCl3): δ = 142.9, 137.6, 137.5, 133.0, 132.7,
129.1, 128.1, 127.8, 127.5, 127.1, 126.0, 125.9, 125.8, 124.7, 62.7, 21.3,
18.0, 4.5, 3.8.
HPLC [Chiralcel OD-H (hexane–i-PrOH, 4:1), flow: 0.5 mL/min, 254
nm]: tR = 15.7 min (R), 18.1 min (S).
1H NMR (600 MHz, CDCl3): δ = 7.81 (d, J = 7.4 Hz, 1 H), 7.61–7.54 (m, 4
H), 7.37–7.31 (m, 3 H), 7.21 (d, J = 7.4 Hz, 1 H), 4.38 (s, 1 H), 0.90–0.84
(m, 1 H), 0.77–0.71 (m, 1 H), 0.70–0.65 (m, 1 H), 0.60–0.47 (m, 2 H).
(3S)-3-(4-Chlorophenyl)-3-cyclopropyl-2,3-dihydro-1,2-benziso-
thiazole 1,1-Dioxide (5b)
Colorless solid; yield: 35.8 mg (56%); [α]D20 +51 (c 1.05, CHCl3) for 99%
HRMS (ESI): m/z [M + Na]+ calcd for C21H21NNaO2S: 374.1185; found:
374.1176.
ee (S).
N-[(S)-Cyclopropyl(1-naphthyl)methyl]-4-methylbenzenesulfon-
HPLC [Chiralcel OD-H (hexane–i-PrOH, 9:1), flow: 0.5 mL/min, 230
nm]: tR = 27.1 min (S), 36.9 min (R).
1H NMR (600 MHz, CDCl3): δ = 7.80 (d, J = 7.5 Hz, 1 H), 7.61 (t, J = 7.5
Hz, 1 H), 7.56 (t, J = 7.5 Hz, 1 H), 7.51 (d, J = 8.9 Hz, 2 H), 7.32 (d, J = 8.9
Hz, 2 H), 7.20 (d, J = 7.5 Hz, 1 H), 4.44 (s, 1 H), 1.68–1.61 (m, 1 H),
0.89–0.82 (m, 1 H), 0.75–0.68 (m, 1 H), 0.57–0.48 (m, 2 H).
amide (3p)
[CAS Reg. No. 1108697-87-5 for rac-3p]
Colorless solid; yield: 66.8 mg (95%); [α]D20 +18 (c 0.84, CHCl3) for 98%
ee (S).
HPLC [Chiralcel OD-H (hexane–i-PrOH, 9:1), flow: 0.5 mL/min, 254
nm]: tR = 27.8 min (R), 37.6 min (S).
13C NMR (150 MHz, CDCl3): δ = 143.3, 141.5, 134.6, 134.4, 133.6,
1H NMR (600 MHz, CDCl3): δ = 8.04–7.99 (m, 1 H), 7.79–7.76 (m, 1 H),
7.67 (d, J = 7.5 Hz, 1 H), 7.46–7.42 (m, 4 H), 7.34 (d, J = 6.8 Hz, 1 H),
7.27 (t, J = 8.2 Hz, 1 H), 6.92 (d, J = 7.5 Hz, 2 H), 5.30 (br, 1 H), 4.61 (t,
J = 6.5 Hz, 1 H), 2.26 (s, 3 H), 1.43–1.37 (m, 1 H), 0.56–0.50 (m, 1 H),
0.46–0.41 (m, 1 H), 0.34–0.29 (m, 1 H), 0.27–0.23 (m, 1 H).
129.6, 129.1, 128.7, 124.9, 121.3, 67.9, 19.8, 3.1, 1.2.
HRMS (ESI): m/z [M + Na]+ calcd for C16H14ClNNaO2S: 342.0326;
found: 342.0317.
(3S)-3-Cyclopropyl-3-(4-tolyl)-2,3-dihydro-1,2-benzisothiazole
1,1-Dioxide (5c)
N-[(S)-Cyclopropyl(ferrocenyl)methyl]-4-toluenesulfonamide (3q)
Colorless solid; yield: 35.9 mg (60%); [α]D20 +48 (c 0.68, CHCl3) for 99%
ee (S).
20
Yellow solid; yield: 50.5 mg (61%); [α]D –13 (c 1.02, CHCl3) for 91%
ee (S).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–G

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Synthesis
HPLC [Chiralcel OD-H (hexane–i-PrOH, 4:1), flow: 0.5 mL/min, 254
nm]: tR = 21.9 min (R), 33.9 min (S).
(3) For selected examples of Rh-catalyzed asymmetric addition of
organoboron reagents to ketimines, see: (a) Shintani, R.; Takeda,
M.; Tsuji, T.; Hayashi, T. J. Am. Chem. Soc. 2010, 132, 13168.
(b) Nishimura, T.; Noishiki, A.; Tsui, G. C.; Hayashi, T. J. Am.
Chem. Soc. 2012, 134, 5056. (c) Wang, H.; Jiang, T.; Xu, M.-H.
J. Am. Chem. Soc. 2013, 135, 971. (d) Chen, Y.-J.; Chen, Y.-H.;
Feng, C.-G.; Lin, G.-Q. Org. Lett. 2014, 16, 3400. (e) Luo, Y.;
Carnell, A. J.; Lam, H. W. Angew. Chem. Int. Ed. 2012, 51, 6762.
(f) Hepburn, H. B.; Lam, H. W. Angew. Chem. Int. Ed. 2014, 53,
11605.
(4) For selected examples, see: (a) Smith, P. W.; Wyman, P. A.;
Lovell, P.; Goodacre, C.; Serafinowska, H. T.; Vong, A.;
Harrington, F.; Flynn, S.; Bradley, D. M.; Porter, R.; Coggon, S.;
Murkitt, G.; Searle, K.; Thomas, D. R.; Watson, J. M.; Martin, W.;
Wu, Z.; Dawson, L. A. Bioorg. Med. Chem. Lett. 2009, 19, 837.
(b) Tosh, D. K.; Paoletta, S.; Deflorian, F.; Phan, K.; Moss, S. M.;
Gao, Z.-G.; Jiang, X.; Jacobson, K. A. J. Med. Chem. 2012, 55, 8075.
(c) Harrington, P. E.; Bourbeau, M. P.; Fotsch, C.; Frohn, M.;
Pickrell, A. J.; Reichelt, A.; Sham, K.; Siegmund, A. C.; Bailis, J. M.;
Bush, T.; Escobar, S.; Hickman, D.; Heller, S.; Hsieh, F.; Orf, J. N.;
Rong, M.; San Miguel, T.; Tan, H.; Zalameda, L.; Allen, J. G.
Bioorg. Med. Chem. Lett. 2013, 23, 6396.
(5) (a) Li, C.; Wang, C.; Villa-Marcos, B.; Xiao, J. J. Am. Chem. Soc.
2008, 130, 14450. (b) Verdaguer, X.; Lange, U. E. W.; Reding, M.
T.; Buchwald, S. L. J. Am. Chem. Soc. 1996, 118, 6784. (c) Wang,
Z.; Cheng, M.; Wu, P.; Wei, S.; Sun, J. Org. Lett. 2006, 8, 3045.
(d) Malkov, A. V.; Vranková, K.; Stončius, S.; Kočovský, P. J. Org.
Chem. 2009, 74, 5839. (e) Wang, Z.; Wang, C.; Zhou, L.; Sun, J.
Org. Biomol. Chem. 2013, 11, 787.
(6) Beisel, T.; Manolikakes, G. Org. Lett. 2015, 17, 3162.
(7) Takechi, R.; Nishimura, T. Chem. Commun. 2015, 51, 8528.
(8) For selected examples of the use of cyclopropylboronic acid in
Pd- and Cu-catalyzed coupling reactions, see: (a) Hildebrand, J.
P.; Marsden, S. P. Synlett 1996, 893. (b) Wang, X.-Z.; Deng, M.-Z.
J. Chem. Soc., Perkin Trans. 1 1996, 2663. (c) Zhou, S.-M.; Deng,
M.-Z.; Xia, L.-J.; Tang, M.-H. Angew. Chem. Int. Ed. 1998, 37, 2845.
(d) Wallace, D. J.; Chen, C.-y. Tetrahedron Lett. 2002, 43, 6987.
(e) Tsuritani, T.; Strotman, N. A.; Yamamoto, Y.; Kawasaki, M.;
Yasuda, N.; Mase, T. Org. Lett. 2008, 10, 1653.
(9) For reviews, see: (a) Defieber, C.; Grützmacher, H.; Carreira, E.
M. Angew. Chem. Int. Ed. 2008, 47, 4482. (b) Shintani, R.;
Hayashi, T. Aldrichimica Acta 2009, 42, 31. (c) Feng, C. G.; Xu, M.-
H.; Lin, G.-Q. Synlett 2011, 1345.
(10) Nishimura, T.; Kumamoto, H.; Nagaosa, M.; Hayashi, T. Chem.
Commun. 2009, 5713.
(11) For examples of the use of chiral tfb ligands in Rh-catalyzed
asymmetric arylations of imines, see: (a) Takechi, R.; Nishimura,
T. Org. Biomol. Chem. 2015, 13, 4918. (b) Nishimura, T.; Ebe, Y.;
Fujimoto, H.; Hayashi, T. Chem. Commun. 2013, 49, 5504.
(12) Hayashi, T.; Takahashi, M.; Takaya, Y.; Ogasawara, M. J. Am.
Chem. Soc. 2002, 124, 5052.
(13) The absolute configuration of the product 3a formed by using
(S,S)-L2 was determined to be S by comparison of the specific
rotation of 3a {[α]D = –21 (c 0.99, CHCl3)} with the reported
value {[α]D = +21.9 (c 0.9, CHCl3)} for (R)-3a (92% ee); see ref. 6.
Configurations of other products were assigned by analogy to
3a.
1H NMR (600 MHz, CDCl3): δ = 7.79 (d, J = 7.5 Hz, 1 H), 7.58 (t, J = 7.5
Hz, 1 H), 7.54 (t, J = 7.5 Hz, 1 H), 7.44 (d, J = 8.2 Hz, 2 H), 7.21 (d, J = 7.5
Hz, 1 H), 7.16 (d, J = 8.2 Hz, 2 H), 4.37 (s, 1 H), 2.33 (s, 3 H), 1.68–1.62
(m, 1 H), 0.87–0.71 (m, 1 H), 0.74–0.68 (m, 1 H), 0.58–0.53 (m, 1 H),
0.51–0.45 (m, 1 H).
13C NMR (150 MHz, CDCl3): δ = 144.3, 140.2, 138.5, 134.4, 133.5,
129.6, 129.3, 127.1, 124.9, 121.2, 68.3, 21.0, 19.7, 3.2, 0.8.
HRMS (ESI): m/z [M + Na]+ calcd for C17H17NNaO2S: 322.0872; found:
322.0868.
Acknowledgment
This work was supported by JSPS KAKENHI Grant No. 15H03810. Y.E.
thanks the JSPS for a Research Fellowship for Young Scientists.
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1561605.
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(14) The use of K3PO4 slightly improved the yield of the addition
product; 5a was obtained in 68% yield without K3PO4.
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–G

G
T. Nishimura et al.
Special Topic
Synthesis
of asymmetric methylation of ketones, see: (c) Siewert, J.;
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example of the addition of α-amido benzyltrifluoroborates to
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5, 1983.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–G