Asymmetric synthesis of diarylmethyl amines by rhodium-catalyzed asymmetric addition of aryl titanium reagents to imines

Article abstract of DOI:10.1002/anie.200461338

A rational tuning of the arene sulfonamide moiety (by introducing isopropyl groups onto the phenyl ring) brought about high enantioselectivity in the asymmetric synthesis of diarylmethyl amines by the title reaction (see scheme). Ar¹ = 4-CF₃C₆H₄, 4-ClC ₆H₄, 4-FC₆H₄, 3-MeOC ₆H₄, 4-MeOC₆H₄, 2-MeC ₆H₄, 1-naphthyl, Ph; Ar² = Ph, 4-FC ₆H₄, 3-MeOC₆H₄, 4-MeOC ₆H₄.

Full text of DOI:10.1002/anie.200461338

Angewandte
Chemie
Amine Synthesis
Asymmetric Synthesis of Diarylmethyl Amines by
Rhodium-Catalyzed Asymmetric Addition of
Aryl Titanium Reagents to Imines**
Tamio Hayashi,* Masahiro Kawai, and
Norihito Tokunaga
Asymmetric synthesis of diarylmethyl amines has attracted
growing attention owing to their importance in biological
[
1]
activity. Among several methods for performing the asym-
[
2,3]
metric synthesis,
catalytic asymmetric addition of aryl
metal reagents to imine derivatives seems to be most
promising, provided that both high enantioselectivity and
[
4]
high catalytic activity are realized. After our publication on
the rhodium-catalyzed asymmetric addition of aryl stannanes
[
5]
to N-sulfonylimines, two reports appeared on catalytic
asymmetric arylation: 1) Bräse, Bolm, and co-workers descri-
bed the addition of a phenylzinc reagent to masked N-
[
6]
formylimines in the presence of a chiral ketimine catalyst,
and 2) Tomioka illustrated the rhodium-catalyzed addition of
aryl boroxines to N-tosylimines in which high enantioselec-
[
7]
tivity was observed for sterically tuned aryl imines. Herein
we report another rhodium-catalyzed asymmetric arylation in
which the addition of aryl titanium reagents to sulfonylimines
proceeds with high enantioselectivity under mild conditions
(208C, 1 h) to give diarylmethyl amines with up to 96% ee.
During our studies on rhodium-catalyzed asymmetric 1,4-
[
8]
additions to a,b-unsaturated ketones, we found that the
phenyltitanium reagent PhTi(OiPr) is highly reactive toward
3
transmetalation and forms a phenyl–rhodium bond. In the
presence of a rhodium/(S)-binap catalyst in THF at 208C, the
catalytic 1,4-addition gives titanium enolates as 1,4-addition
[
9]
products with high enantioselectivity. Under similar reac-
[
10]
tion conditions (Scheme 1), the addition of PhTi(OiPr)3
(
4a) to N-tosylarylimine 1a, which was prepared from 4-
[
11]
trifluoromethylbenzaldehyde and 4-toluenesulfonamide,
took place rapidly to give the tosylamide of diarylmethyl
amine 5aa after aqueous workup, unfortunately with only
[
12]
2
8% ee (Table 1, entry 1). The use of (S)-H -binap and (S)-
8
[
13]
[14]
segphos in place of (S)-binap improved the enantiose-
lectivity up to 43% and 76% ee, respectively (Table 1,
entries 4 and 6). The relatively narrow dihedral angle of the
biaryl bisphosphine ligand segphos is considered to exert a
positive influence on the enantioselectivity in the present
[
14]
[
*] Prof. T. Hayashi, M. Kawai, N. Tokunaga
Department of Chemistry, Graduate School of Science
Kyoto University
Sakyo, Kyoto 606-8502 (Japan)
Fax: (+81)75-753-3988
E-mail: thayashi@kuchem.kyoto-u.ac.jp
[
**] This work was supportedby a Grant-in-Aidfor Scientific Research,
the Ministry of Education, Culture, Sports, Science, and Technology,
Japan. N.T. thanks the Japan Society for the Promotion of Science
for the award of a fellowship for graduate students.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
Angew. Chem. Int. Ed. 2004, 43, 6125 –6128
DOI: 10.1002/anie.200461338
ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
6125

Communications
Scheme 1. Rhodium-catalyzed asymmetric arylation of imines 1a–3a
with PhTi(OiPr) (4a).
Scheme 2. Stereochemical pathway in the catalytic asymmetric
3
arylation of imines.
Table 1: Rhodium-catalyzed asymmetric arylation of imines 1a–3a with
[
a]
PhTi(OiPr) (4a).
sponding phenylation products 6aa and 7aa with 49 and
71% ee, respectively (Table 1, entries 2 and 3). The higher
enantioselectivity in the asymmetric addition to triisopropyl-
benzenesulfonamide (3a) was also observed in the reaction
3
[
b]
[c,d]
Entry
Imine
[ %L i g] andYield
ee [%]
1
2
3
4
5
6
7
8
1a
2a
3a
1a
3a
1a
2a
3a
(S)-binap
(S)-binap
(S)-binap
97 (5aa)
71 (6aa)
58 (7aa)
96 (5aa)
86 (7aa)
99 (5aa)
97 (6aa)
98 (7aa)
28 (R)
49 (R)
71 (R)
43 (R)
82 (R)
76 (R)
88 (R)
93 (R)
catalyzed by the rhodium complexes of (S)-H -binap and (S)-
8
segphos (Table 1, entries 5 and 8). The combination of (S)-
segphos and triisopropylbenzenesulfonamide 3a gave the
diarylmethylamine (R)-7aa with 93% ee (Table 1, entry 8).
The present asymmetric phenylation with phenyltitanium
(S)-H -binap
8
(S)-H -binap
8
(S)-segphos
(S)-segphos
(S)-segphos
4
a catalyzed by rhodium/(S)-segphos was also successful for
[
a] The reaction was carriedout in THF at 20 8C for 1 h with 4a (2 equiv)
triisopropylbenzenesulfonamides of other aromatic imines 3.
The aromatic imines substituted with chloro (3b), fluoro (3c),
and methoxy (3d) at the 4-position of the phenyl and the
imines 3e–g derived from 2-MeC H CHO, 3-MeOC H CHO,
and 1-naphthaldehyde, respectively, gave the corresponding
sulfonamides of diarylmethyl amines (R)-7 in high yields
(Scheme 3). The enantioselectivity ranged from 86 to 96% ee
in the presence of the catalyst generatedfrom [{RhCl(C H ) } ] anda
2
4 2 2
chiral phosphine ligand. [b] Yields of isolated amines (column chroma-
tography: silica gel, hexane/EtOAc (2:1)). [c] Determinedby HPLC
analysis with a chiral stationary phase column (Chiralcel OD-H: hexane/
2
7
6
4
6
4
-propanol=80:20 for 5aa and 6aa; hexane/2-propanol=98:2 for
aa.). [d] The configurations of the amines were assigned by consid-
eration of the stereochemical reaction pathway (see text).
asymmetric phenylation, although the enantioselectivity is
still not satisfactory.
For the asymmetric 1,4-addition to a,b-unsaturated
[
15]
[16]
[17]
ketones,
esters,
and alkenylphosphonates
catalyzed
by a rhodium complex coordinated with (S)-binap, we have
proposed stereorecognition models that successfully ration-
alize the absolute configuration of the products. By applying
this type of model to the present reaction of N-alkylidene
[
18]
sulfonamides, it is evident that the enantioface of the imine
is recognized by steric repulsions between one of the phenyl
rings on the diphenylphosphino group and the aromatic ring
on the arene sulfonamide (Scheme 2). Steric tuning of the
arene sulfonamide moiety by introduction of sterically bulky
groups onto the aromatic ring actually brought about
enhancement of the enantioselectivity to an acceptable
level. Thus, the asymmetric addition of phenyltitanium 4a
to mesitylenesulfonamide 2a and triisopropylbenzenesulfon-
amide 3a catalyzed by rhodium/(S)-binap gave the corre-
Scheme 3. Asymmetric arylation of imines 3 with ArTi(OiPr) (4)
catalyzedby rho di um/( S)-segphos.
3
6
126
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Angew. Chem. Int. Ed. 2004, 43, 6125 –6128

Angewandte
Chemie
(
4
Table 2, entries 2–7). The reaction of aryl titanium reagents
b–d (with the fluoro or methoxy group at the 3- or 4-position
lithium in ammonia was accompanied by reduction of the aryl
groups to a considerable extent: 4-ClC H and 1-naphthyl
6
4
on the phenyl ring) also proceeded with high enantioselec-
tivity (Table 2, entries 8–11). The reaction of imine 3h with 4-
fluorophenyltitanium 4b, which is a reverse combination of
the reaction of 3c with 4a, gave the S isomer of (4-
fluorophenyl)(phenyl)methylamine 7ca (93% ee) in quanti-
tative yield (Table 2, entry 8). The reaction of 4-methoxyphe-
nyltitanium 4d with imines 3a and 3b proceeded as well to
give diarylmethyl amines in which both aryl groups are
substituted phenyls (Table 2, entries 10 and 11).
gave phenyl and tetrahydronaphthyl, respectively. The depro-
tection was more selective with samarium iodide in HMPA/
THF and RedAl in toluene for 7ba and 7ga, respectively.
In summary, the asymmetric synthesis of diarylmethyl
amines was realized by rhodium-catalyzed asymmetric addi-
tion of aryl titanium reagents to N-alkylidene sulfonamides. A
rational tuning of the arene sulfonamide moiety by introduc-
ing isopropyl groups onto the phenyl ring brought about high
enantioselectivity (86–96% ee).
Received: July 16, 2004
Table 2: Asymmetric arylation of imines 3 with ArTi(OiPr) (4) catalyzed
by rhodium/(S)-segphos.
3
[
a]
Keywords: amines · arylation · asymmetric catalysis · rhodium ·
[
b]
[c,d]
.
Entry
3
4
T [8C]
Yield[%]
ee [%]
titanium
1
2
3
4
5
6
7
8
9
0
1
3a
3b
3c
3d
3e
3 f
3g
3h
3h
3a
3b
4a
4a
4a
4a
4a
4a
4a
4b
4c
4d
4d
20
20
30
40
40
20
30
20
40
40
40
98 (7aa)
93 (R)
94 (R)
92 (R)
92 (R)
86 (R)
89 (R)
96 (R)
93 (S)
90 (S)
88 (S)
88 (R)
[
e]
95 (7ba)
99 (7ca)
98 (7da)
99 (7ea)
99 (7 fa)
99 (7ga)
96 (7hb)
86 (7hc)
97 (7ad)
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[
f]
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[
g]
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[h]
1
1
94 (7bd)
[
a] The reaction was carriedout in THF at the given temperature for 1 h
with 4 (2 equiv) in the presence of the catalyst (3 mol%) generatedfrom
{RhCl(C H ) } ] and( S)-segphos. [b] Yields of isolated amines (column
[
2
4 2 2
chromatography: silica gel, hexane/EtOAc (2:1)). [c] Determinedby
HPLC analysis with a chiral stationary phase column (Chiralcel OD-H:
hexane/2-propanol=98:2 for 7aa, 7ba, 7ca, 7da, 7hb; hexane/2-
propanol=100:1 for 7ga, 7ad, 7bd. Chiralcel AD-H: hexane/2-prop-
anol=98:2 for 7ea, 7 fa). [d] The absolute configurations of 7ba, 7da,
7
ga were determined by comparison of the specific rotations of free
amines 8 or their derivatives (see text). For other products, the
configurations were assignedby consi de ration of the stereochemical
reaction pathway. [e] The sulfonamide of (phenyl)(4-biphenylyl)methyl-
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7ca.
[h] Enantiomer of 7ea.
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19]
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2
[
20]
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1
6
4
ammonia at À788C gave free amine 8da in quantitative yield
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6
4
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[
[
Scheme 4. Deprotection of the sulfonamide.
Angew. Chem. Int. Ed. 2004, 43, 6125 –6128
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ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
6127

Communications
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[
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6
128
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