Enantioselective and rapid Rh-catalyzed arylation of N -tosyl- and N -nosylaldimines in methanol

Article abstract of DOI:10.1021/jo5012653

Enantiomerically enriched tosyl-protected diarylmethylamines were rapidly prepared by the asymmetric addition of arylboronic acids to N-tosylaldimines under mild conditions in the presence of a catalyst prepared in situ from Rh(I) and a chiral diene ligand. This methodology offers access to diarylmethylamines in good yields with excellent chiral purity at room temperature using MeOH as a solvent and NEt₃ as a base. Its synthetic utility was demonstrated by the preparation of (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline (14), an antagonist of the N-methyl-d-aspartate (NMDA) receptor.

Full text of DOI:10.1021/jo5012653

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Article
Enantioselective and Rapid Rh-Catalyzed Arylation
of N-Tosyl and N-Nosyl Aldimines in Methanol
Chun-Chih Chen, Balraj Gopula, Jin-Fong Syu, Jhih-Han Pan, Ting-
Shen Kuo, Ping-Yu Wu, Julian P Henschke, and Hsyueh-Liang Wu
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo5012653 • Publication Date (Web): 22 Aug 2014
Downloaded from http://pubs.acs.org on August 26, 2014
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Enantioselective and Rapid Rh-Catalyzed Arylation of N-
Tosyl and N-Nosyl Aldimines in Methanol
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Chun-Chih Chen,a Balraj Gopula,a Jin-Fong Syu,a Jhih-Han Pan,a Ting-Shen Kuo,a
Ping-Yu Wu,b Julian P. Henschkeb and Hsyueh-Liang Wua*
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aDepartment of Chemistry, and Instrumentation Center, National Taiwan Normal
University, No. 88, Section 4, Tingzhou Rd. Taipei, 11677, Taiwan, Republic of
China
email address: hlw@ntnu.edu.tw
bScinoPharm Taiwan, No. 1, Nan-Ke 8th Road, Tainan Science-Based Industrial Park,
Shan-Hua, Tainan County, 74144, Taiwan, Republic of China
KEYWORDS: rhodium-catalyzed; chiral diarylmethylamine; chiral diene ligand;
enantioselective arylation
TOC:
[RhCl(C2H4)2]2 (1 mol % of Rh)
R
H
R
2e (1.2 mol %)
N
HN
Ar1
Ar2B(OH)2
+
Ar1
Ar2
For R = Ts, NEt3 (2.4 equiv), MeOH, 30 °C, 1h
For R = Ns, NEt3 (2.4 equiv), MeOH, 60 °C, 1h
33 examples
56-99% yield
90-99% ee
Ar
Ar
2e : Ar = 4-NO2-C6H4
ABSTRACT: Enantiomerically enriched tosyl-protected diarylmethylamines were
rapidly prepared by the asymmetric addition of arylboronic acids to N-tosyl aldimines
under mild conditions in the presence of a catalyst prepared in situ from Rh(I) and a
chiral diene ligand. This methodology offers access to diarylmethylamines in good
yields with excellent chiral purity at room temperature using MeOH as a solvent and
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NEt3 as a base. Its synthetic utility was demonstrated by the preparation of (S)-1-
phenyl-1,2,3,4-tetrahydroisoquinoline (14), an antagonist of the N-methyl-D-aspartate
(NMDA) receptor.
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Introduction: The chiral diarylmethylamine 1 moiety is seen in many
pharmacologically active compounds,1 such as (+)BW373U862 (1a) and cetirizine
hydrochloride3 (1b, Zyrtec®); the former exhibits potent analgesic and antidepressant
effects while the later shows selective antagonistic activity toward histamine H1-
receptors (Figure 1).
OH
R
CO2H
O
R
R
N
N
N
N
*
N
R
2 HCl
2 HBr
Cl
(Et)2N
(+)BW373U86 (1a)
Cetirizine dihydrochloride (1b)
1
O
Figure 1. Selected Pharmacologically Active Compounds Containing Chiral
Diarylmethylamine Moiety.
Consequently, the development of efficient enantioselective syntheses of
diarylmethylamines has received much interest amongst synthetic organic chemists
resulting in several useful methodologies. Although nucleophilic additions of
arylmetallic reagents to chiral auxiliary-based N-aryl imines,4a oxazolidines4b-d and N-
tert-butanesulfinyl imines4g-i proceed in a highly diastereoselective manner,4 more
effort has been focused on the development of metal-catalyzed enantioselective
protocols. For example, the Ir-catalyzed asymmetric hydrogenation of imines derived
from substituted benzophenones provides direct access to unprotected chiral
diarylmethylamine, although high enantioselectivities are only observed for ortho-
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substituted substrates.5 In contrast, the Rh-catalyzed asymmetric 1,2-addition of aryl
nucleophiles to arylaldimines offers an attractive route to the preparation of chiral
diarylmethylamines with high enantio-excesses. Various nucleophilic organometallics
such as arylstanne,6 aryltitanium,7 arylboron,8 and arylzinc reagents9 can be used as
nucleophiles for this purpose, whilst by simply selecting which of the aryl groups
appear in the nucleophilic reaction partner and the electrophilic reaction partner,
respectively, both the (R)- and (S)-chiral amines can be synthesized using only a
single chiral catalyst. Among the Rh-catalyzed enantioselective addition reactions
available to synthetic and process chemists, utilization of arylboron reagents as the
aryl source is most attractive due to the ready availability of a diverse range of aryl
boronic acids, combined with their relatively low toxicity and wide tolerance of
functional groups within the same molecule. Recently, in this field, chiral dienes have
been found to be excellent ligands in the Rh-catalyzed asymmetric transformations,
prompting significant effort toward the design and investigation of new chiral diene
ligands in catalytic asymmetric transformations.10 The utilization of chiral diene
ligands11 in conjunction with Rh(I) salts in the arylation of a variety of N-tosyl
aldimines allows high catalytic efficiency and enantioselectivity similar to that
achieved by the use of chiral phosphorous-based ligands.8a,b These Rh/chiral diene
catalyzed asymmetric arylations, however, have to be conducted at above room
temperature (50–60 °C) and can require up to about 12 hours to complete. Given this,
we were interested to develop a catalyst system that could be used for the rapid
preparation of enantio-enriched diarylmethylamines under mild reaction conditions.
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Recently we reported the synthesis and application of a series of novel and stable
C1-symmetric chiral 2,5-diarylsubstituted bicyclo[2.2.1]heptadiene ligands 2 for
Rh(I)-catalyzed asymmetric conjugate addition of arylboronic acids to electron-
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deficient acceptors.12 These reactions provide the corresponding addition adducts in
high yield with high ee values whilst using low catalyst loadings.12a Encouraged by
our earlier results, we subsequently investigated the employment of chiral dienes 2 as
ligands in the Rh(I)-catalyzed asymmetric addition of arylboronic acids to N-tosyl
aldimines. Herein, we report the results of this work that comprises an efficient
methodology for access to chiral diarylmethylamines of high optical purity.
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Results and Discussion: Investigations were initiated with an evaluation of the
catalytic activity of chiral dienes 2 in the Rh(I)-catalyzed asymmetric addition of p-
tolylboronic acid (4a) to N-tosyl protected imine 3a in aqueous dioxane with KOH as
base (Table 1). At 60 °C in the presence of 3 mol % of Rh/2a, the asymmetric addition
reaction was complete within 1 h furnishing diarylmethylamine 5aa in 84% yield with
94% ee (entry 1). The only moderately high yield was a result of partial hydrolysis of
imine 3a, and it was therefore anticipated that a better chemical yield would be
achieved at lower temperatures. Indeed, at only 30 °C the asymmetric addition
reaction proceeded smoothly, albeit less rapidly (24 h), providing amine 5aa in a
much-improved 99% yield with 93% ee (entry 2). Subsequently, a variety of our
ligands with various substituents at the 2,5-position of the bicyclo[2.2.1] skeleton
were tested. Ligands bearing 4-methyl-phenyl (2b) and 4-biphenyl (2c) substituents
gave excellent yields with slightly less enantioselectivity (entries 3 and 4), and while
chiral diene 2d was optimal in the enantioselective 1,4-addition of arylboronic acids
to acyclic α,β-unsaturated carbonyl compounds,12a it failed to show comparable
catalytic activity in this study, giving rise to amine 5aa in only 41% yield (entry 5).
Enantio-induction equivalent to that with ligand 2a was observed when the catalytic
reaction was carried out in the presence of ligand 2e12b within 4.5 h at 30 °C (entry 6),
but a slightly lower yield (80%) was observed. The absolute configuration of the
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stereogenic center was determined to be R by X-ray crystallographic analysis of
compound 5aa.13
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Table 1. Ligand Effect on the Asymmetric Addition of p-Tolylboronic Acid (4a) to
Aldimine 3a
[RhCl(C2H4)2]2 (3 mol % of Rh)
ligand 2 (3.6 mol %)
Ts
H
Ts
B(OH)2
N
HN
+
Ph
KOH(aq) (20 mol %), dioxane / H2O
temp, time
Ph
5aa
3a (1.0 equiv)
4a (2.0 equiv)
2a: Ar = C6H5
2b: Ar = 4-Me-C6H4
2c: Ar = 4-Ph-C6H4
2d: Ar = 1-Naphthyl
2e: Ar = 4-NO2-C6H4
Ar
Ar
entrya
ligand
2a
temp (°C)
time (h)
yield (%)b
ee (%)c
94
1
2
3
4
5
6
60
30
30
30
30
30
1.0
24
24
24
24
4.5
84
99
99
98
41
80
2a
93
2b
92
2c
87
2d
92
2e
94
a The reaction was conducted with 0.1 mmol of imine 3a. b Calibrated GC
yield using n-decane as an internal standard. c Determined by chiral HPLC,
see experimental section.
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Next, a base and solvent study was conducted using ligand 2e at 30 °C (Table 2).
Whereas the reaction carried out in THF using 20 mol % of aqueous KOH solution
gave amine 5aa in a poor 23% yield with 94% ee after 24 h (entry 2), moderately
improved chemical yields with high selectivity were obtained in alcohol solvents
(entries 3 and 4). Replacing the base with aqueous CsOH, triethylamine (NEt3) or
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diisopropylamine (DIPA) in dioxane still did not meet our yield expectation (entries
4i,14
5–7). Pleasingly, however, when the reaction was carried out employing NEt3
as
the base in MeOH, consumption of the starting material was very rapid (within 1 h),
furnishing the desired amine 5aa in excellent chemical yield (96%) with 96% ee
(entry 8); notably, no negative impact on the asymmetric induction was observed
when 1 mol % of the Rh/2e complex was utilized (entry 9).15 Since the use of dioxane
as a solvent in pharmaceutical manufacturing is highly undesirable due to its
relatively high toxicity, it was pleasing that the comparatively less toxic alcohol,
MeOH, could be used as a solvent in this reaction giving this methodology industrial
applicability.16 Whilst the Rh(I) catalyst comprising ligand 2a was found to provide a
similar level of selectivity as did that of ligand 2e in the screening tests conducted in
dioxane, (Table 1, entry 2 vs entry 6) the former, however, produced less asymmetric
induction than did the latter when the Rh(I)-catalysed asymmetric reaction was
carried out in MeOH using Et3N as a base at 30 °C, yielding 86% of adduct 5aa in a
diminished 90% ee (Table 2, entry 10).
To test the generality of the optimized reaction conditions, commercially available
chiral diene ligands were employed in the enantioselective 1,2-addition of p-
tolylboronic acid (4a) to N-tosyl protected imine 3a (entries 11–14). In the presence
of 1.0 mol % of Rh-catalysts comprising ligands 611c and 711d that bear a
bicyclo[2.2.2] skeleton, and ligand 8 possessing a bicyclo[3.3.0] framework,
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compound 5aa was obtained in 67%, 85% and only trace yield with 97%, 90% and
non-determined ee, respectively (entries 11–13). When the reaction using ligand 8
was repeated using 3 mol % of Rh-catalyst a much improved 85% yield and 98% ee
was noted (entry 14). When evaluated based on a combination of both yield and
enantioselectivity, this comparison of ligands 2e, 6, 7 and 8 under identical conditions
suggests that ligands 2e exhibits equal or better performance in this reaction.
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Table 2. Optimization of Reaction Conditions
Ts
[RhCl(C2H4)2]2 (x mol % of Rh)
ligand (1.2x mol %)
Ts
H
HN
Ph
B(OH)2
N
+
solvent, base, 30 °C, time
Ph
5aa
3a (1.0 equiv)
4a (2.0 equiv)
Ph
H
Ph
O
O
Ph
H
Me
Ph
7
6
8
yield
entrya ligand
x
solvent
base
time (h)
ee (%)c
(%)b
1
2
2e
2e
2e
2e
2e
2e
3.0
3.0
3.0
3.0
3.0
3.0
Dioxane
THF
KOH
KOH
KOH
KOH
CsOH
NEt3
4.5
24
6.0
24
24
24
80
94
94
93
92
95
94
23
3
MeOH
EtOH
61
4
43
5
Dioxane
Dioxane
85
6d
70
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7d
2e
2e
2e
2a
6
3.0
3.0
1.0
1.0
1.0
1.0
1.0
3.0
Dioxane
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
DIPA
NEt3
NEt3
NEt3
NEt3
NEt3
NEt3
NEt3
24
1.0
1.0
1.0
1.0
1.0
1.0
1.0
45
96
95
96
8d
9d,e
84f
86f
67f
85f
trace
85f
96
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10d,e
11d,e
12d,e
13d,e
14d
90
−97
90
7
8
N.D.g
−98
8
a The reaction was conducted with 0.1 mmol of imine 3e. Calibrated GC yield
b
using n-decane as an internal standard. c Determined by chiral HPLC, see
experimental section. d 2.4 equivalents of base were used. The reaction was
e
conducted with 0.3 mmol of imine 3a. f Isolated yield. g N.D. = Not Determined
After establishing the optimal reaction conditions specified in Table 2, entry 9 for
the asymmetric addition reaction of p-tolylboronic acid (4a) to benzaldehyde-derived
N-tosyl aldimine 3a, the scope was further examined with a diverse array of
arylboronic acids and N-tosyl aldimines (Table 3). Reactions between p-tolylboronic
acid (4a) and various arylimines 3a–3l furnished chiral N-tosyl protected
diarylmethylamines 5aa–5la in good to excellent yields (68–93%) along with
excellent enantioselectivities (92–98% ee), regardless of the electronic properties of
the arylimines being investigated (entries 2–12). Good chemical yields and enantio-
induction were observed for substrates derived from 2-naphthaldehyde (entry 10), 2-
furaldehyde (entry 11), and 2-thienylaldehyde (entry 12). In addition, high catalytic
activity and enantioselectivity were also observed in the enantioselective additions of
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arylboronic acids substituted with either electro-withdrawing or electro-donating
groups, to aldimines (3a, 3m and 3n) (entries 13–25). Notably, although a longer
reaction time was required and a correspondingly inferior yield was witnessed for the
reaction of o-tolyboronic acid (4g) with benzaldehyde derived aldimine 3a, an
excellent 97% ee was still obtained (entry 18). Presumably the poorer conversion rate
was the result of steric hindrance of the ortho-substituted aryl-nucleophile, and
although not yet examined, further optimisation of the conditions might provide an
improved result. A key advantage of applying this approach to chiral
diarylmethylamine synthesis is that either enantiopode can be accessed by appropriate
assignment of each of the aryl groups to either the nucleophilic or electrophilic
reaction component whilst only requiring a single chiral catalyst. For example, by
comparison of entry 1 and 24, entry 3 and 20, entry 7 and 19, entry 10 and 22, and
entry 18 and 25, it can be seen that the same catalyst was able to provide both pairs of
enantiomers with comparable ee’s despite the requisite reversed assignment of the
aryl groups.
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Table 3. Substrate Scope of Enantioselective Addition Reaction to N-Tosyl
Aldimines
[RhCl(C2H4)2]2 (1 mol % of Rh)
2e (1.2 mol %)
Ts
H
Ts
N
HN
Ar1
Ar2B(OH)2
+
MeOH, NEt3, 30 °C, 1h
Ar1
Ar2
5
3 (1.0 equiv)
4 (2.0 equiv)
Entrya
Ar1
Ar2
Yield (%)b
Ee (%)c
1
C6H5 (3a)
4-Me-C6H4 (4a)
4-Me-C6H4 (4a)
84 (5aa)
70 (5ba)
96
2
3-Cl-C6H4 (3b)
95
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4-Cl-C6H4 (3c)
4-Me-C6H4 (4a)
4-Me-C6H4 (4a)
4-Me-C6H4 (4a)
4-Me-C6H4 (4a)
4-Me-C6H4 (4a)
4-Me-C6H4 (4a)
4-Me-C6H4 (4a)
4-Me-C6H4 (4a)
4-Me-C6H4 (4a)
4-Me-C6H4 (4a)
4-F-C6H4 (4b)
4-Cl-C6H4 (4c)
4-MeO-C6H4 (4d)
2-Naphthyl (4e)
4-Ph-C6H4 (4f)
2-Me-C6H4 (4g)
4-F-C6H4 (4b)
4-Cl-C6H4 (4c)
4-MeO-C6H4 (4d)
2-Naphthyl (4e)
4-Ph-C6H4 (4f)
C6H5 (4h)
83 (5ca)
75 (5da)
92 (5ea)
94
94
94
94
96
94
97
93
99
92
96
97
94
96
98
97
97
96
96
96
96
95
2,4-Cl2C6H3 (3d)
3,4-Cl2C6H3 (3e)
3-F-C6H4 (3f)
4-F-C6H4 (3g)
3-Br-C6H4 (3h)
3-Me-C6H4 (3i)
2-Naphthyl (3j)
2-Furyl (3k)
5
10
11
12
13
14
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6
74 (5fa)
7
93 (5ga)
83 (5ha)
88 (5ia)
8
9
10
11
12
13
14
15
16
17
18d
19
20
21
22
23
24
91 (5ja)
68 (5ka)
91 (5la)
2-Thienyl (3l)
C6H5 (3a)
95 (5ab)
76 (5ac)
C6H5 (3a)
C6H5 (3a)
89 (5ad)
89 (5ae)
C6H5 (3a)
C6H5 (3a)
74 (5af)
C6H5 (3a)
56 (5ag)
82 (ent-5ga)
81 (ent-5ca)
80 (5md)
97 (ent-5ja)
99 (5mf)
91 (ent-5aa)
4-Me-C6H4 (3m)
4-Me-C6H4 (3m)
4-Me-C6H4 (3m)
4-Me-C6H4 (3m)
4-Me-C6H4 (3m)
4-Me-C6H4 (3m)
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25e
2-Me-C6H4 (3n)
C6H5 (4h)
96 (ent-5ag)
98
4
5
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7
8
a The reaction was conducted with 0.3 mmol of imine 3 and 2.4 equiv. of NEt3 was
used. b Isolated yield. c Determined by chiral HPLC, see experimental section. d The
reaction was carried for 3 h. e The reaction was carried out for 2 h.
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The more readily cleaved 4-nitrophenyl sulfonyl protecting group was also
examined as an alternative to the 4-tosyl analogue (Table 4).17 While no desired
product was observed under the optimal conditions established above, apparently due
to insolubility in MeOH at 30 °C, the enantioselective reactions of N-nosylaldimines
(9a–9c) and arylboronic acids (4a–4i) furnished the corresponding 1,2-addition
adducts (10aa–10cd) with excellent enantioselectivities (90–99% ee) and with
generally good yields when the reaction was conducted at 60 °C rather than at 30 °C.
Table 4. Substrate Scope of Enantioselective Addition Reaction to N-Nosyl
Aldimines
[RhCl(C2H4)2]2 (1 mol % of Rh)
2e (1.2 mol %)
Ns
H
Ns
N
HN
Ar1
Ar2B(OH)2
+
MeOH, NEt3, 60 °C, 1 h
Ar1
Ar2
9 (1.0 equiv)
4 (2.0 equiv)
10
Entrya
Ar1
Ar2
Yield (%)b
78 (10aa)
68 (10ad)
93 (10ai)
67 (10aj)
Ee (%)c
95
1
2
3
4
C6H5 (9a)
C6H5 (9a)
C6H5 (9a)
C6H5 (9a)
4-Me-C6H4 (4a)
4-MeO-C6H4 (4d)
3-Me-C6H4 (4i)
3-Cl-C6H4 (4j)
99
90
99
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7
4-Cl-C6H4 (9b)
C6H5 (4h)
C6H5 (4h)
83 (10bh)
87 (ent-10aa)
57 (10cd)
92
97
99
4-Me-C6H4 (9c)
4-Me-C6H4 (9c)
4-MeO-C6H4 (4d)
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a The reaction was conducted with 0.3 mmol of imine 9 and 2.4 equiv. of NEt3 were
used. b Isolated yield. c Determined by chiral HPLC, see experimental section.
Finally, to demonstrate the synthetic utility of this methodology, the
enantioselective synthesis of (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline (14), a more
potent antagonist of the NMDA receptor18 than its (R)-enantiomer was conducted
(Scheme 1). In the key step, asymmetric 1,2-addition of phenylboronic acid (4h) to N-
tosylaldimine 1119 catalysed by the Rh(I)/2e complex furnished chiral
diarylmethylamine 12 in 96% yield with 95% ee, despite the presence of an ortho-
substituent in imine 11. Subsequent fluoride mediated removal of the TBDPS
protecting group gave alcohol 13 in 86% yield, which due to sufficient pKa
augmentation of the amino group resulting from the N-tosyl substituent, cyclized
under Mitsunobu20 conditions. Ensuing reductive deprotection of the N-tosyl group
yielded (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline (14)21 with 96% ee in 71% yield
over two steps from alcohol 13.
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Scheme
1.
Enantioselective
Synthesis
of
(S)-1-Phenyl-1,2,3,4-
4
5
6
Tetrahydroisoquinoline (14)
7
8
9
Ts
N
Ts
HN
[RhCl(C2H4)2]2 (1 mol % of Rh)
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60
2e (1.2 mol %)
H
Ph
+
PhB(OH)2
MeOH, NEt3, 30 °C, 1h
OTBDPS
OTBDPS
12
11
4h
(96%, 95% ee)
(2.0 equiv)
Ts
TBAF, THF, 0 °C to rt,
overnight
1) DEAD (3.0 equiv)
PPh3 (3.0 equiv), THF, rt,
HN
HN
Ph
Ph
OH
2) Na / Naphthalene, THF, -78 °C
13
14
86%
71% yield, 96% ee
(over two steps)
In summary, a rapid and efficient protocol for the enantioselective addition of
arylboronic acids to N-tosyl aldimines catalyzed by rhodium complexes of novel
chiral diene ligands under mild conditions has been developed. Although a range of
diene ligands were applicable, ligand 2e was preferred. For N-tosyl aldimines, the
asymmetric addition proceeded at room temperature (30 °C) offering high yields of
N-tosyl protected diarylmethylamines with high optical purity, whereas N-nosyl
aldimines reacted at 60 °C, due to the lower solubility of these analogues.
Additionally, this methodology allows ready access to both enantiomers of
diarylmethylamines with comparable enantio-enrichment whilst using the same single
chiral catalyst. To demonstrate the synthetic usefulness, the enantioselective synthesis
of (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline (14) was conducted. The use of
acceptably low loadings of the catalyst, methanol as solvent, an ambient reaction
temperature, the use of a non-corrosive base, and the rapid rate of reaction lends this
reaction system to industrial applications. Probing the structure of the active catalytic
species for this catalytic system and its further expansion for the synthesis of enantio-
enriched amines is currently under intensive investigation in our laboratory.
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General Experimental Information:
4
5
6
7
8
General Methods. All commercial chemicals and solvents were reagent grade and
were used without further treatment unless otherwise noted. All reactions were carried
out under an atmosphere of argon gas. Reactions were monitored by TLC using silica
gel plates; zones were detected visually under ultraviolet irradiation (254 nm) or by
spraying with 2,4-dinitrophenylhydrazine solution followed by heating. Flash column
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1
chromatography was done using silica gel. H NMR spectra were obtained on 400
MHz or 500 MHz spectrometers. 13C NMR spectra were obtained on 100 MHz or 125
MHz spectrometers. Chemical shifts were recorded in parts per million (ppm, δ) and
were reported relative to the solvent peak. High-resolution mass spectra were
obtained using EI, ESI, FAB or MALDI ionization methods. Optical purity of the
final compounds were determined using chiral HPLC. Optical rotations were
measured on a polarimeter. Melting points were measured on a melting points
apparatus. Phenylboronic acid (4h), chiral dienes 6 and 8 were purchased and used
directly. Chiral diene 7,11d chiral bicyclo[2.2.1] diene ligands (2a–e)12a and substituted
arylboronic acids21 were prepared according to the reported procedures. The absolute
configuration of the stereogenic center of compound 5aa was determined by X-ray
crystallographic analysis data obtained from a single crystal diffractometer.
General Procedures for Rhodium-Catalyzed Arylation of N-Tosyl-Aldimines:
A solution of N-tosyl aldimine (0.3 mmol), arylboronic acid (0.6 mmol),
[RhCl(C2H4)2]2 (0.58 mg, 1.5 µmol, 1 mol % of Rh) and chiral diene ligand 2e (1.35
mg, 3.6 µmol, 1.2 mol %) in MeOH (2.4 mL) was stirred at 30 °C for 5 min. Et3N was
then added, and the resulting solution was stirred for an additional 1 h at 30 °C. After
removing the volatiles at reduced pressure, the resulting residue was purified by
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column chromatography over silica gel (Hexanes / EtOAc = 8 / 1), furnishing the
4
5
6
desired chiral N-tosyl diarylmethylamines.
7
8
9
(R)-4-methyl-N-(phenyl(p-tolyl)methyl)benzenesulfonamide (5aa)11e
Yield: 89 mg, 84%. The ee was determined on a Chiralpak IB column with hexanes :
2-propanol = 80 : 20, flow = 1 mL/min. Retention times: 6.85 min [(S)-enantiomer],
8.03 min [(R)-enantiomer]. 96% ee [α]3D1 +11.53 (c 1.03, CHCl3)
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60
FTIR (Neat) 3278, 1598, 1445, 1325, 1158, 1090, 1052, 700, 667, 568 cm-1
1H NMR (400 MHz, CDCl3): δ 7.55 (d, J = 7.6 Hz, 2H), 7.22–7.16 (m, 3H), 7.15–
7.08 (m, 4H), 7.03–6.94 (m, 4H), 5.52 (d, J = 6.8 Hz, 1H), 5.24 (d, J = 6.8 Hz, 1H),
2.36 (s, 3H), 2.27 (s, 3H).
13C NMR (100 MHz, CDCl3): δ 143.1, 140.7, 137.7, 137.4, 137.3, 129.3, 129.2, 128.4,
127.4, 127.28, 127.25, 127.18, 61.1, 21.4, 21.0.
HRMS (FAB+): m/z Calcd for [C21H21NO2S+H]+ 352.1366, found 352.1381 [M+H]+.
M.p. 116–118 °C
(S)-N-((3-chlorophenyl)(p-tolyl)methyl)-4-methylbenzenesulfonamide (5ba)
Yield: 81 mg, 70%. The ee was determined on a Chiralpak IB column with hexanes :
2-propanol = 80 : 20, flow = 1 mL/min. Retention times: 7.07 min [(R)-enantiomer],
9.79 min [(S)-enantiomer]. 95% ee [α]2D6 +6.38 (c 0.96, CHCl3)
FTIR (Neat) 3269, 1596, 1439, 1330, 1159, 1093, 1056, 811, 666, 573 cm-1
1H NMR (400 MHz, CDCl3): δ 7.55 (d, J = 8.0 Hz, 2H), 7.15–7.11 (m, 4H), 7.02 (d, J
= 8.0 Hz, 4H), 6.93 (d, J = 8.0 Hz, 2H), 5.48 (d, J = 7.2 Hz, 1H), 5.28 (d, J = 7.2 Hz,
1H), 2.38 (s, 3H), 2.27 (s, 3H).
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13C NMR (100 MHz, CDCl3): δ 143.4, 142.6, 137.7, 137.2, 137.0, 134.3, 129.7, 129.4,
127.5, 127.5, 127.18, 127.15, 125.5, 60.7, 21.4, 21.0.
HRMS (MALDI-TOF): m/z Calcd for [C21H20ClNO2S+Na]+ 408.0795, found
408.0813 [M+Na]+.
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60
M.p. 95–97 °C
(S)-N-((4-chlorophenyl)(p-tolyl)methyl)-4-methylbenzenesulfonamide (5ca)23
Yield: 96 mg, 83%. The ee was determined on a Chiralpak IB column with hexanes :
2-propanol = 80 : 20, flow = 1 mL/min. Retention times: 8.37 min [(R)-enantiomer],
9.31 min [(S)-enantiomer]. 94% ee [α]3D0 +7.71 (c 0.99, CHCl3)
FTIR (Neat) 3277, 1598, 1448, 1326, 1158, 1091, 1052, 811, 668, 568 cm-1
1H NMR (500 MHz, CDCl3): δ 7.55 (d, J = 8.5 Hz, 2H), 7.19–7.14 (m, 4H), 7.06 (d, J
= 8.5 Hz, 2H), 7.02 (d, J = 8.0 Hz, 2H), 6.91 (d, J = 8.0 Hz, 2H), 5.49 (d, J = 7.0 Hz,
1H), 4.93 (d, J = 7.0 Hz, 1H), 2.40 (s, 3H), 2.28 (s, 3H).
13C NMR (125 MHz, CDCl3): δ 143.4, 139.2, 137.7, 137.23, 137.18, 133.3, 129.4,
128.7, 128.54, 127.2, 60.5, 21.5, 21.0.
HRMS (MALDI-TOF): m/z Calcd for [C21H20ClNO2S+Na]+ 408.0795, found
408.0815 [M+Na]+.
M.p. 118–120 °C
(S)-N-((2,4-dichlorophenyl)(p-tolyl)methyl)-4-methylbenzenesulfonamide (5da)
Yield: 95 mg, 75%. The ee was determined on a Chiralpak IB column with hexanes :
2-propanol = 80 : 20, flow = 1 mL/min. Retention times: 6.80 min [(R)-enantiomer],
8.56 min [(S)-enantiomer]. 94% ee [α]2D6 +12.67 (c 1.02, CHCl3)
FTIR (Neat) 3281, 1591, 1470, 1439, 1332, 1160, 1069, 812, 666, 580 cm-1
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1H NMR (500 MHz, CDCl3): δ 7.61 (d, J = 8.0 Hz, 2H), 7.35 (d, J = 8.5 Hz, 1H),
7.24 (d, J = 2.0 Hz, 1H), 7.19 (d, J = 8.0 Hz, 2H), 7.13 (dd, J = 8.5, 2.0 Hz, 1H), 7.03
(d, J = 7.5 Hz, 2H), 6.89 (d, J = 8.5 Hz, 2H), 5.80 (d, J = 6.5 Hz, 1H), 5.33 (d, J = 6.5
Hz, 1H), 2.41 (s, 3H), 2.28 (s, 3H).
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13C NMR (125 MHz, CDCl3): δ 143.6, 138.0, 136.7, 136.4, 135.7, 134.0, 133.4, 130.1,
129.48, 129.5, 127.21, 127.16, 127.09, 57.9, 21.5, 21.0.
HRMS (FAB+): m/z Calcd for [C21H19Cl2NO2S+H]+ 420.0586, found 420.0595
[M+H]+.
M.p. 116–118 °C
(S)-N-((3,4-dichlorophenyl)(p-tolyl)methyl)-4-methylbenzenesulfonamide (5ea)
Yield: 116 mg, 92%. The ee was determined on a Chiralpak IB column with hexanes :
2-propanol = 80 : 20, flow = 1 mL/min. Retention times: 8.80 min [(R)-enantiomer],
11.79 min [(S)-enantiomer]. 94% ee [α]2D6 +18.22 (c 1.09, CHCl3)
FTIR (Neat) 3280, 1597, 1447, 1327, 1158, 1093, 1047, 811, 666, 572 cm-1
1H NMR (400 MHz, CDCl3): δ 7.53 (d, J = 8.0 Hz, 2H), 7.25 (d, J = 8.4 Hz, 1H),
7.16–7.12 (m, 3H), 7.03–6.96 (m, 3H), 6.91 (d, J = 8.0 Hz, 2H), 5.46 (s, 2H), 2.39 (s,
3H), 2.27 (s, 3H).
13C NMR (100 MHz, CDCl3): δ 143.6, 140.8, 137.9, 137.0, 136.6, 132.4, 131.5, 130.3,
129.5, 129.4, 129.3, 127.11, 127.09, 126.75, 60.2, 21.5, 21.0.
HRMS (FAB+): m/z Calcd for [C21H19Cl2NO2S+H]+ 420.0586, found 420.0596
[M+H]+.
M.p. 118–120 °C
(S)-N-((3-fluorophenyl)(p-tolyl)methyl)-4-methylbenzenesulfonamide (5fa)
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8
Yield: 82 mg, 74%. The ee was determined on a Chiralpak IB column with hexanes :
2-propanol = 80 : 20, flow = 1 mL/min. Retention times: 7.17 min [(R)-enantiomer],
8.93 min [(S)-enantiomer]. 94% ee [α]2D8 +21.76 (c 1.06, CHCl3)
9
FTIR (Neat) 3276, 1593, 1487, 1446, 1328, 1159, 1091, 1054, 668, 574 cm-1
1H NMR (500 MHz, CDCl3): δ 7.57 (d, J = 8.0 Hz, 2H), 7.20–7.10 (m, 3H), 7.02 (d, J
= 8.0 Hz, 2H), 6.95–6.90 (m, 3H), 6.87 (ddd, J = 8.0, 8.0, 2.0 Hz, 1H), 6.81 (d, J =
9.5 Hz, 1H), 5.50 (d, J = 7.0 Hz, 1H), 5.18 (d, J = 7.0 Hz, 1H), 2.39 (s, 3H), 2.28 (s,
3H).
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13C NMR (125 MHz, CDCl3): δ 162.7 (d, J = 245.0 Hz), 161.7, 143.4, 143.2 (d, J =
6.3 Hz), 137.7, 137.2, 137.1, 130.0 (d, J = 8.8 Hz), 129.4, 127.2, 122.9 (d, J = 2.5 Hz),
114.4 (d, J = 2.5 Hz), 114.3, 60.6, 21.4, 21.0.
HRMS (FAB+): m/z Calcd for [C21H20FNO2S+H]+ 370.1272, found 370.1277
[M+H]+.
M.p. 106–108 °C
(S)-N-((4-fluorophenyl)(p-tolyl)methyl)-4-methylbenzenesulfonamide (5ga)23
Yield: 103 mg, 93%. The ee was determined on a Chiralpak IB column with hexanes :
2-propanol = 80 : 20, flow = 1 mL/min. Retention times: 7.55 min [(R)-enantiomer],
8.72 min [(S)-enantiomer]. 96% ee [α]3D1 +15.98 (c 1.04, CHCl3)
FTIR (Neat) 3277, 1602, 1508, 1442, 1326, 1226, 1159, 814, 666, 561 cm-1
1H NMR (500 MHz, CDCl3): δ 7.55 (d, J = 8.0 Hz, 2H), 7.15 (d, J = 8.0 Hz, 2H),
7.11–7.06 (m, 2H), 7.02 (d, J = 8.0 Hz, 2H), 6.93 (d, J = 8.0 Hz, 2H), 6.88 (t, J = 8.5
Hz, 2H), 5.50 (d, J = 7.0 Hz, 1H), 5.11 (d, J = 7.0 Hz, 1H), 2.39 (s, 3H), 2.28 (s, 3H).
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13C NMR (125 MHz, CDCl3): δ 162.0 (d, J = 245.0 Hz), 143.3, 137.6, 137.4, 137.3,
4
5
6
136.5 (d, J = 3.8 Hz), 129.4, 129.3, 129.0 (d, J = 7.5 Hz), 127.19, 127.15, 115.3 (d, J
7
8
= 21.3 Hz), 60.5, 21.5, 21.0.
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HRMS (FAB+): m/z Calcd for [C21H20FNO2S+H]+ 370.1272, found 370.1284
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[M+H]+.
M.p. 114–116 °C
(S)-N-((3-bromophenyl)(p-tolyl)methyl)-4-methylbenzenesulfonamide (5ha)
Yield: 107 mg, 83%. The ee was determined on a Chiralpak IB column with hexanes :
2-propanol = 80 : 20, flow = 1 mL/min. Retention times: 7.44 min [(R)-enantiomer],
10.19 min [(S)-enantiomer]. 94% ee [α]2D8 +4.78 (c 1.11, CHCl3)
FTIR (Neat) 3272, 1595, 1439, 1359, 1159, 1092, 1055, 811, 665, 573 cm-1
1H NMR (500 MHz, CDCl3): δ 7.55 (d, J = 8.0 Hz, 2H), 7.32–7.27 (m, 1H), 7.16–
7.13 (m, 3H), 7.08 (d, J = 5.0 Hz, 2H), 7.04 (d, J = 8.0 Hz, 2H), 6.94 (d, J = 8.0 Hz,
2H), 5.48 (d, J = 7.0 Hz, 1H), 5.16 (d, J = 7.0 Hz, 1H), 2.40 (s, 3H), 2.29 (s, 3H).
13C NMR (125 MHz, CDCl3): δ 143.5, 142.8, 137.8, 137.1, 137.0, 130.5, 130.3, 130.0,
129.4, 127.2, 127.1, 126.0, 122.6, 60.6, 21.5, 21.0.
HRMS (MALDI-TOF): m/z Calcd for [C21H20BrNO2S+Na]+ 452.0290, found
452.0318 [M+Na]+.
M.p. 101–103 °C
(S)-4-methyl-N-(m-tolyl(p-tolyl)methyl)benzenesulfonamide (5ia)
Yield: 97 mg, 88%. The ee was determined on a Chiralpak IB column with hexanes :
2-propanol = 80 : 20, flow = 1 mL/min. Retention times: 5.71 min [(R)-enantiomer],
7.81 min [(S)-enantiomer]. 97% ee [α]2D6 +15.69 (c 1.03, CHCl3)
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FTIR (Neat) 3280, 1559, 1449, 1327, 1159, 1094, 1048, 812, 667, 573 cm-1
1H NMR (500 MHz, CDCl3): δ 7.55 (d, J = 8.0 Hz, 2H), 7.20–7.07 (m, 4H), 7.05 (d, J
= 7.5 Hz, 2H), 7.00 (d, J = 8.0 Hz, 2H), 6.93 (d, J = 8.0 Hz, 2H), 5.74 (d, J = 7.0 Hz,
1H), (d, J = 6.0 Hz, 1H), 2.37 (s, 3H), 2.28 (s, 3H), 2.14 (s, 3H).
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13C NMR (125 MHz, CDCl3): δ 143.1, 138.3, 137.5, 137.3, 137.0, 135.4, 130.6,
129.24, 129.19, 127.43, 127.37, 127.09, 127.07, 126.1, 57.8, 21.4, 21.0, 19.3.
HRMS (FAB+): m/z Calcd for [C22H23NO2S+H]+ 366.1522, found 366.1522 [M+H]+.
M.p. 120–122 °C
(S)-4-methyl-N-(naphthalen-2-yl(p-tolyl)methyl)benzenesulfonamide (5ja)
Yield: 110 mg, 91%. The ee was determined on a Chiralpak IB column with hexanes :
2-propanol = 80 : 20, flow = 1 mL/min. Retention times: 8.43 min [(R)-enantiomer],
10.61 min [(S)-enantiomer]. 93% ee [α]3D1 −4.79 (c 0.99, CHCl3)
FTIR (Neat) 3274, 1597, 1439, 1327, 1158, 1093, 1055, 813, 668, 558 cm-1
1H NMR (500 MHz, CDCl3): δ 7.76–7.73 (m, 1H), 7.67–7.62 (m, 2H), 7.54 (d, J =
8.5 Hz, 2H), 7.51 (s, 1H), 7.45–7.41 (m, 2H), 7.17 (dd, J = 8.5, 1.5 Hz, 1H), 7.04–
7.01 (m, 6H), 5.69 (d, J = 7.5 Hz, 1H), 5.18 (d, J = 7.5 Hz, 1H), 2.28 (s, 3H), 2.27 (s,
3H).
13C NMR (125 MHz, CDCl3): δ 143.2, 137.7, 137.53, 137.50, 137.4, 133.0, 132.6,
129.28, 129.25, 128.4, 128.0, 127.5, 127.4, 127.2, 126.3, 126.2, 126.1, 125.2, 61.3,
21.3, 21.0.
HRMS (FAB+): m/z Calcd for [C25H23NO2S]+ 401.1444, found 401.1447 [M]+.
M.p. 139–141 °C
(S)-N-(furan-2-yl(p-tolyl)methyl)-4-methylbenzenesulfonamide (5ka)
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Yield: 70 mg, 68%. The ee was determined on a Chiralpak IB column with hexanes :
2-propanol = 80 : 20, flow = 1 mL/min. Retention times: 7.63 min [(R)-enantiomer],
8.03 min [(S)-enantiomer]. 99% ee [α]2D6 +22.5 (c 1.09, CHCl3)
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FTIR (Neat) 3272, 2923, 1597, 1434, 1330, 1158, 1059, 812, 666, 577 cm-1
1H NMR (500 MHz, CDCl3): δ 7.58 (d, J = 8.0 Hz, 2H), 7.21 (d, J = 1.0 Hz, 1H),
7.15 (d, J = 8.0 Hz, 2H), 7.05–7.04 (m, 4H), 6.18 (dd, J = 3.0, 1.5 Hz, 1H), 5.99 (d, J
= 3.0 Hz, 1H), 5.56 (d, J = 7.5 Hz, 1H), 5.23 (d, J = 7.5 Hz, 1H), 2.38 (s, 3H), 2.29 (s,
3H).
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13C NMR (125 MHz, CDCl3): δ 152.4, 143.1, 142.5, 137.8, 137.4, 135.3, 129.3, 129.2,
127.10, 127.09, 110.2, 108.2, 55.3, 21.4, 21.0.
HRMS (FAB+): m/z Calcd for [C19H19NO3S+H]+ 342.1158, found 342.1156 [M+H]+.
M.p. 125–127 °C
(S)-4-methyl-N-(thiophen-2-yl(p-tolyl)methyl)benzenesulfonamide (5la)
Yield: 98 mg, 91%. The ee was determined on a Chiralpak IB column with hexanes :
2-propanol = 80 : 20, flow = 1 mL/min. Retention times: 7.89 min [(S)-enantiomer],
8.93 min [(R)-enantiomer]. 92% ee [α]2D8 +7.38 (c 1.04, CHCl3)
FTIR (Neat) 3272, 1598, 1438, 1328, 1159, 1093, 1050, 706, 666, 574 cm-1
1H NMR (500 MHz, CDCl3): δ 7.58 (d, J = 8.5 Hz, 2H), 7.16–7.12 (m, 3H), 7.07–
7.00 (m, 4H), 6.82 (dd, 5.0, 4.0 Hz, 1H), 6.68 (d, J = 3.5 Hz, 1H), 5.74 (d, J = 7.5 Hz,
1H), 5.30 (d, J = 7.5 Hz, 1H), 2.38 (s, 3H), 2.30 (s, 3H).
13C NMR (125 MHz, CDCl3): δ 145.1, 143.3, 137.8, 137.4, 137.2, 129.4, 129.2, 127.2,
127.0, 126.7, 126.0, 125.6, 57.3, 21.5, 21.1.
HRMS (MALDI-TOF): m/z Calcd for [C19H19NO2S2+Na]+ 380.0749, found 380.0768
[M+Na]+.
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M.p. 114–116 °C
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(R)-N-((4-fluorophenyl)(phenyl)methyl)-4-methylbenzenesulfonamide (5ab)23
Yield: 101 mg, 95%. The ee was determined on a Chiralpak IB column with hexanes :
2-propanol = 80 : 20, flow = 1 mL/min. Retention times: 15.15 min [(S)-enantiomer],
16.61 min [(R)-enantiomer]. 96% ee [α]2D8 −1.78 (c 1.00, CHCl3)
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FTIR (Neat) 3268, 1601, 1447, 1327, 1226, 1159, 1092, 814, 668, 567 cm-1
1H NMR (500 MHz, CDCl3): δ 7.55 (d, J = 8.0 Hz, 2H), 7.22–7.21 (m, 3H), 7.15 (d, J
= 8.0 Hz, 2H), 7.10–7.03 (m, 4H), 6.89 (t, J = 8.5 Hz, 2H), 5.55 (d, J = 7.0 Hz, 1H),
5.13 (d, J = 7.0 Hz, 1H), 2.39 (s, 3H).
13C NMR (125 MHz, CDCl3): δ 162.1 (d, J = 245.0 Hz), 143.4, 140.3, 137.3, 136.3 (d,
J = 3.8 Hz), 129.4, 129.1 (d, J = 8.8 Hz), 128.7, 127.8, 127.3, 127.2, 115.4 (d, J =
21.3 Hz), 60.7, 21.5.
HRMS (FAB+): m/z Calcd for [C20H18FNO2S+H]+ 356.1115, found 356.1118
[M+H]+.
M.p. 109–111 °C
(R)-N-((4-chlorophenyl)(phenyl)methyl)-4-methylbenzenesulfonamide (5ac)11c
Yield: 85 mg, 76%. The ee was determined on a Chiralpak IB column with hexanes :
2-propanol = 80 : 20, flow = 1 mL/min. Retention times: 7.33 min [(S)-enantiomer],
8.43 min [(R)-enantiomer]. 97% ee [α]2D8 +4.01 (c 1.03, CHCl3)
FTIR (Neat) 3267, 1598, 1490, 1447, 1328, 1159, 1090, 701, 665, 568 cm-1
1H NMR (500 MHz, CDCl3): δ 7.55 (d, J = 8.0 Hz, 2H), 7.22–7.19 (m, 3H), 7.18–
7.12 (m, 4H), 7.07–7.03 (m, 4H), 5.53 (d, J = 7.0 Hz, 1H), 5.26 (d, J = 7.5 Hz, 1H),
2.39 (s, 3H).
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13C NMR (125 MHz, CDCl3): δ 143.4, 140.1, 139.0, 137.2, 133.5, 129.4, 128.8, 128.7,
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128.6, 127.8, 127.3, 127.2, 60.7, 21.5.
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HRMS (FAB+): m/z Calcd for [C20H18ClNO2S+H]+ 372.0820, found 372.0819
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[M+H]+.
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M.p. 125–127 °C
(R)-N-((4-methoxyphenyl)(phenyl)methyl)-4-methylbenzenesulfonamide (5ad)11c
Yield: 98 mg, 89%. The ee was determined on a Chiralpak IB column with hexanes :
2-propanol = 80 : 20, flow = 1 mL/min. Retention times: 8.56 min [(S)-enantiomer],
11.04 min [(R)-enantiomer]. 94% ee [α]2D8 +16.00 (c 1.19, CHCl3)
FTIR (Neat) 3227, 2924, 1607, 1512, 1447, 1326, 1252, 1158, 668, 567 cm-1
1H NMR (500 MHz, CDCl3): δ 7.56 (d, J = 8.0 Hz, 2H), 7.21–7.18 (m, 3H), 7.14 (d, J
= 8.0 Hz, 2H), 7.12–7.08 (m, 2H), 6.99 (d, J = 9.0 Hz, 2H), 6.73 (d, J = 8.5 Hz, 2H),
5.52 (d, J = 7.0 Hz, 1H), 5.06 (d, J = 7.0 Hz, 1H), 3.75 (s, 3H), 2.38 (s, 3H).
13C NMR (125 MHz, CDCl3): δ 159.0, 143.1, 140.7, 137.4, 132.7, 129.3, 128.6, 128.5,
127.5, 127.4, 127.3, 127.2, 113.9, 60.8, 55.2, 21.4.
HRMS (FAB+): m/z Calcd for [C21H21NO3S]+ 367.1237, found 367.1239 [M]+.
M.p. 132–134 °C
(R)-4-methyl-N-(naphthalen-2-yl(phenyl)methyl)benzenesulfonamide (5ae)24
Yield: 104 mg, 89%. The ee was determined on a Chiralpak AD-H column with
hexanes : 2-propanol = 80 : 20, flow = 1 mL/min. Retention times: 12.51 min [(R)-
enantiomer], 13.41 min [(S)-enantiomer]. 96% ee [α]2D9 +24.55 (c 1.02, CHCl3)
FTIR (Neat) 3281, 2923, 1598, 1448, 1325, 1159, 762, 700, 669, 573 cm-1
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1H NMR (500 MHz, CDCl3): δ 7.78 (dd, J = 6.0, 3.5 Hz, 1H), 7.67 (d, J = 8.5 Hz,
1H), 7.64 (d, J = 6.0, 3.5 Hz, 1H), 7.55 (d, J = 8.5 Hz, 2H), 7.50 (s, 1H), 7.45 (dd, J =
6.0, 3.5 Hz, 2H), 7.24–7.21 (m, 3H), 7.19–7.13 (m, 3H), 7.04 (d, J = 8.0 Hz, 2H),
5.74 (d, J = 7.5 Hz, 1H), 5.19 (d, J = 7.5 Hz, 1H), 2.27 (s, 3H).
13C NMR (125 MHz, CDCl3): δ 143.2, 140.4, 137.5, 137.3, 133.0, 132.7, 129.3, 128.6,
128.5, 128.0, 127.7, 127.53, 127.47, 127.2, 126.4, 126.3, 126.2, 125.1, 61.5, 21.3.
HRMS (MALDI-TOF): m/z Calcd for [C24H21NO2S+Na]+ 410.1185, found 410.1180
[M+Na]+.
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M.p. 159–161 °C
(R)-N-([1,1'-biphenyl]-4-yl(phenyl)methyl)-4-methylbenzenesulfonamide (5af)8a
Yield: 92 mg, 74%. The ee was determined on a Chiralpak IB column with hexanes :
2-propanol = 80 : 20, flow = 1 mL/min. Retention times: 9.25 min [(R)-enantiomer],
17.36 min [(S)-enantiomer]. 98% ee [α]2D9 +11.64 (c 1.01, CHCl3)
FTIR (Neat) 3274, 2923, 1598, 1447, 1327, 1159, 813, 749, 669, 565 cm-1
1H NMR (500 MHz, CDCl3): δ 7.58 (d, J = 8.5 Hz, 2H), 7.52 (d, J = 8.0 Hz, 2H),
7.45–7.40 (m, 4H), 7.34 (t, J = 7.0 Hz, 1H), 7.25–7.20 (m, 3H), 7.19–7.11 (m, 6H),
5.62 (d, J = 7.0 Hz, 1H), 5.18 (d, J = 7.0 Hz, 1H), 2.36 (s, 3H).
13C NMR (125 MHz, CDCl3): δ 143.2, 140.5, 140.5, 140.4, 139.4, 129.4, 128.8, 128.6,
127.8, 127.7, 127.40, 127.35, 127.2, 127.0, 61.1, 21.5.
HRMS (MALDI-TOF): m/z Calcd for [C26H23NO2S+Na]+ 436.1342, found 436.1362
[M+Na]+.
M.p. 129–131 °C
(R)-4-methyl-N-(phenyl(o-tolyl)methyl)benzenesulfonamide (5ag)24
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Yield: 59 mg, 56%. The ee was determined on a Chiralpak IB column with hexanes:
2-propanol = 80: 20, flow = 1 mL/min. Retention times: 5.68 min [(R)-enantiomer],
6.27 min [(S)-enantiomer]. 97% ee [α]2D5 −6.73 (c 1.22, CH2Cl2)
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FTIR (Neat) 3283, 1598, 1449, 1324, 1158, 1092, 1050, 700, 668 cm-1
1H NMR (400 MHz, CDCl3): δ 7.54 (d, J = 8.2 Hz, 2H), 7.20–7.18 (m, 3H), 7.12–
7.09 (m, 4H), 7.07–7.04 (m, 4H), 5.80 (d, J = 7.1 Hz, 1H), 5.18 (d, J = 7.1 Hz, 1H),
2.36 (s, 3H), 2.16 (s, 3H).
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13C NMR (100 MHz, CDCl3): δ 143.1, 139.9, 138.2, 137.4, 135.4, 130.6, 129.3, 128.5,
127.5, 127.2, 127.1, 126.1, 58.0, 21.4, 19.3.
HRMS (ESI): m/z Calcd for [C21H21NO2S+Na]+ 374.1185, found 374.1221 [M+Na]+.
(R)-N-((4-fluorophenyl)(p-tolyl)methyl)-4-methylbenzenesulfonamide (ent-5ga)
Yield: 91 mg, 82%. The ee was determined on a Chiralpak IB column with hexanes :
2-propanol = 80 : 20, flow = 1 mL/min. Retention times: 7.92 min [(R)-enantiomer],
8.91 min [(S)-enantiomer]. 97% ee [α]3D1 −14.34 (c 1.04, CHCl3)
HRMS (FAB+): m/z Calcd for [C21H20FNO2S+H]+ 370.1272, found 370.1284
[M+H]+.
(R)-N-((4-chlorophenyl)(p-tolyl)methyl)-4-methylbenzenesulfonamide (ent-5ca) 22
Yield: 94 mg, 81%. The ee was determined on a Chiralpak IB column with hexanes :
2-propanol = 80 : 20, flow = 1 mL/min. Retention times: 8.69 min [(R)-enantiomer],
9.44 min [(S)-enantiomer]. 96% ee [α]3D0 −6.80 (c 1.04, CHCl3)
(R)-N-((4-methoxyphenyl)(p-tolyl)methyl)-4-methylbenzenesulfonamide (5md)11e
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Yield: 92 mg, 80%. The ee was determined on a Chiralpak IB column with hexanes :
2-propanol = 80 : 20, flow = 1 mL/min. Retention times: 10.24 min [(S)-enantiomer],
11.28 min [(R)-enantiomer]. 96% ee [α]2D8 +6.27 (c 1.01, CHCl3).
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FTIR (Neat) 3276, 2923, 1609, 1511, 1440, 1325, 1250, 1158, 666, 565 cm-1
1H NMR (500 MHz, CDCl3): δ 7.56 (d, J = 8.0 Hz, 2H), 7.14 (d, J = 8.0 Hz, 2H),
7.03–6.95 (m, 6H), 6.72 (d, J = 9.0 Hz, 2H), 5.47 (d, J = 7.0 Hz, 1H), 5.02 (d, J = 7.0
Hz, 1H), 3.75 (s, 3H), 2.39 (s, 3H), 2.28 (s, 3H).
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13C NMR (125 MHz, CDCl3): δ 158.9, 143.1, 137.8, 137.5, 137.2, 132.9, 129.3, 129.2,
128.5, 127.22, 127.17, 113.8, 60.6, 55.2, 21.5, 21.0.
HRMS (FAB+): m/z Calcd for [C22H23NO3S]+ 381.1393, found 381.1392 [M]+.
M.p. 123–125 °C
(R)-4-methyl-N-(naphthalen-2-yl(p-tolyl)methyl)benzenesulfonamide (ent-5ja)
Yield: 117 mg, 97%. The ee was determined on a Chiralpak IB column with hexanes :
2-propanol = 80 : 20, flow = 1 mL/min. Retention times: 8.80 min [(R)-enantiomer],
11.47 min [(S)-enantiomer]. 96% ee [α]2D6 +5.40 (c 1.04, CHCl3)
HRMS (FAB+): m/z Calcd for [C25H23NO2S]+ 401.1444, found 401.1443 [M]+.
(R)-N-([1,1'-biphenyl]-4-yl(p-tolyl)methyl)-4-methylbenzenesulfonamide (5mf)8a
Yield: 127 mg, 99%. The ee was determined on a Chiralpak IB column with hexanes :
2-propanol = 80 : 20, flow = 1 mL/min. Retention times: 10.21 min [(S)-enantiomer],
14.93 min [(R)-enantiomer]. 96% ee [α]2D8 +19.19 (c 1.03, CHCl3)
FTIR (Neat) 3275, 1597, 1445, 1327, 1158, 1054, 811, 758, 666, 574 cm-1
1H NMR (500 MHz, CDCl3): δ 7.58 (d, J = 8.5 Hz, 2H), 7.52 (d, J = 8.5 Hz, 2H),
7.44-7.39 (m, 4H), 7.34 (t, J = 7.5 Hz, 1H), 7.18 (d, J = 8.0 Hz, 2H), 7.14 (d, J = 8.0
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Hz, 2H), 7.06–6.99 (m, 4H), 5.57 (d, J = 7.0 Hz, 1H), 5.12 (br, 1H), 2.36 (s, 3H), 2.30
(s, 3H).
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13C NMR (125 MHz, CDCl3): δ 143.1, 140.5, 140.4, 139.6, 137.6, 137.5, 137.4,
129.32, 129.29, 128.8, 127.8, 127.4, 127.3, 127.2, 127.0, 60.9, 21.5, 21.0.
HRMS (FAB+): m/z Calcd for [C27H25NO2S]+ 427.1601, found 427.1602 [M]+.
M.p. 173–175 °C
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(S)-4-methyl-N-(phenyl(p-tolyl)methyl)benzenesulfonamide (ent-5aa)8a
Yield: 96 mg, 91%. The ee was determined on a Chiralpak IB column with hexanes :
2-propanol = 80 : 20, flow = 1 mL/min. Retention times: 6.83 min [(S)-enantiomer],
8.24 min [(R)-enantiomer]. 95% ee [α]3D0 −10.67 (c 1.03, CHCl3)
(S)-4-methyl-N-(phenyl(o-tolyl)methyl)benzenesulfonamide (ent-5ag)
Yield: 101 mg, 96%. The ee was determined on a Chiralpak IB column with hexanes:
2-propanol = 80: 20, flow = 1 mL/min. Retention times: 5.73 min [(R)-enantiomer],
6.29 min [(S)-enantiomer]. 98% ee [α]2D5 +6.66 (c 1.28, CH2Cl2)
General Procedures for Rhodium-Catalyzed Arylation of N-nosyl-Imine:
A solution of N-nosyl-imine (0.3 mmol), arylboronic acid (0.6 mmol), [RhCl(C2H4)2]2
(0.58 mg, 1.5 µmol, 1 mol %) and chiral diene ligand 2e (1.35 mg, 3.6 µmol, 1.2
mol %) in MeOH (2.4 mL) was stirred for 5 min at 60 °C. Et3N was then added to it,
and the resulting solution was stirred for additional 1 hour at 60 °C. After removing
the volatiles at reduced pressure, the resulting residue was purified by column
chromatography over silica gel (Hexanes / EtOAc = 8 / 1), furnishing the desired
chiral N-nosyl diarylmethylamines.
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Yield: 90 mg, 78%. The ee was determined on a Chiralpak IB column with hexanes :
2-propanol = 80 : 20, flow = 1 mL/min. Retention times: 11.63 min [(S)-enantiomer],
15.15 min [(R)-enantiomer]. 95% ee [α]3D1 +4.40 (c 0.98, CHCl3)
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FTIR (Neat) 3269, 1527, 1346, 1311, 1165, 849, 736, 611, 555, 462 cm-1
1H NMR (500 MHz, CDCl3): δ 8.09 (d, J = 8.5 Hz, 2H), 7.74 (d, J = 8.5 Hz, 2H),
7.22–7.18 (m, 3H), 7.12–7.08 (m, 2H), 7.01 (d, J = 8.0 Hz, 2H), 6.97 (d, J = 8.0 Hz,
2H), 5.68 (d, J = 7.0 Hz, 1H), 5.37 (d, J = 7.0 Hz, 1H), 2.27 (s, 3H).
13C NMR (125 MHz, CDCl3): δ 149.6, 146.3, 139.6, 138.0, 136.5, 129.4, 128.7, 128.3,
127.9, 127.33, 127.31, 123.8, 61.5, 21.0.
HRMS (ESI): m/z Calcd for [C20H18N2O4S−H]− 381.0915, found 381.0901 [M−H]−.
M.p. 172–174 °C
(R)-N-((4-methoxyphenyl)(phenyl)methyl)-4-nitrobenzenesulfonamide (10ad)6
Yield: 81 mg, 68%. The ee was determined on a Chiralpak IB column with hexanes :
2-propanol = 80 : 20, flow = 1 mL/min. Retention times: 14.83 min [(S)-enantiomer],
22.00 min [(R)-enantiomer]. 99% ee [α]2D5 +12.90 (c 0.99, CHCl3)
FTIR (Neat) 3269, 1606, 1527, 1346, 1164, 1026, 842, 735, 611, 551 cm-1
1H NMR (500 MHz, CDCl3): δ 8.11 (d, J = 8.5 Hz, 2H), 7.75 (d, J = 8.5 Hz, 2H),
7.22–7.19 (m, 3H), 7.11–7.08 (m, 2H), 7.01 (d, J = 8.5 Hz, 2H), 6.73 (d, J = 8.5 Hz,
2H), 5.68 (d, J = 6.5 Hz, 1H), 5.24 (d, J = 6.5 Hz, 1H), 3.74 (s, 3H)
13C NMR (125 MHz, CDCl3): δ 159.4, 149.7, 146.4, 139.6, 131.6, 128.7, 128.3, 128.0,
127.3, 123.8, 114.1, 61.2, 55.30.
HRMS (ESI): m/z Calcd for [C20H18N2O5S−H]− 397.0864, found 397.0849 [M−H]−.
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The Journal of Organic Chemistry
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M.p. 192–194 °C
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(R)-4-nitro-N-(phenyl(m-tolyl)methyl)benzenesulfonamide (10ai)
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Yield: 107 mg, 93%. The ee was determined on a Chiralpak IB column with hexanes :
2-propanol = 80 : 20, flow = 1 mL/min. Retention times: 12.48 min [(R)-enantiomer],
14.05 min [(S)-enantiomer]. 90% ee [α]2D5 +3.54 (c 0.99, CHCl3)
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FTIR (Neat) 3255, 1605, 1531, 1424, 1346, 1168, 1085, 1037, 736, 702 cm-1
1H NMR (500 MHz, CDCl3): δ 8.07 (d, J = 8.5 Hz, 2H), 7.73 (d, J = 8.5 Hz, 2H),
7.22–7.18 (m, 3H), 7.12–7.08 (m, 2H), 7.08 (d, J = 7.5 Hz, 1H), 7.00 (d, J = 7.5 Hz,
1H), 6.88 (d, J = 8.0 Hz, 2H), 5.67 (d, J = 7.5 Hz, 1H), 5.59 (d, J = 7.5 Hz, 1H), 2.19
(s, 3H).
13C NMR (125 MHz, CDCl3): δ 149.6, 146.2, 139.3, 139.3, 138.5, 128.68, 128.66,
128.62, 128.3, 128.0, 127.9, 127.3, 124.4, 123.7, 61.7, 21.2.
HRMS (MALDI-TOF): m/z Calcd for [C20H18N2O4S+Na]+ 405.0879, found 405.0924
[M+Na]+.
M.p. 158–160 °C
(R)-N-((3-chlorophenyl)(phenyl)methyl)-4-nitrobenzenesulfonamide (10aj)
Yield: 81 mg, 67%. The ee was determined on a Chiralpak IB column with hexanes :
2-propanol = 80 : 20, flow = 1 mL/min. Retention times: 19.60 min [(S)-enantiomer],
20.35 min [(R)-enantiomer]. 99% ee [α]2D5 −5.11 (c 1.03, CHCl3)
FTIR (Neat) 3255, 1601, 1530, 1432, 1347, 1311, 1165, 739, 701, 612 cm-1
1H NMR (500 MHz, CDCl3): δ 8.12 (d, J = 8.5 Hz, 2H), 7.76 (d, J = 8.5 Hz, 2H),
7.23–7.20 (m, 3H), 7.18–7.14 (m, 2H), 7.09–7.05 (m, 2H), 7.05–7.01 (m, 2H), 5.67 (s,
2H).
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