Efficient chiral amidophosphine ligand for copper-catalyzed asymmetric addition of diethylzinc to N-sulfonylimines

Article abstract of DOI:10.1246/cl.2002.8

Structure study of a chiral amidophosphine ligand for copper-catalyzed asymmetric addition reaction of diethylzinc with the N-tosylimine reached to the new chiral phosphine bearing the bulky substituent on the pyrrolidine ring, which significantly improved catalytic performance to give the adduct in 96% yield and 93% ee after 3 h.

Full text of DOI:10.1246/cl.2002.8

8
Chemistry Letters 2002
Efficient Chiral Amidophosphine Ligand for Copper-catalyzed
Asymmetric Addition of Diethylzinc to N-Sulfonylimines
Kazushige Nagai, Hidetaka Fujihara, Masami Kuriyama, Ken-ichi Yamada, and Kiyoshi Tomiokaꢀ
Graduate School of Pharmaceutical Sciences, Kyoto University, Yoshida, Sakyo-ku, Kyoto 606-8501
(Received September 21, 2001; CL-010942)
Structure study of a chiral amidophosphine ligand for copper-
was also in the similar and unsatisfactory level, 58–65% ee.
catalyzed asymmetric addition reaction of diethylzinc with the N-
tosylimine reached to the new chiral phosphine bearing the bulky
substituent on the pyrrolidine ring, which significantly improved
catalytic performance to give the adduct in 96% yield and 93% ee
after 3 h.
Production of a reduced sulfonamide 4 was observed in a
significant yield, 10–22%. Amidophosphine 1f bearing more
bulky pivaloyl group behaved as a better ligand for copper
accelerating the reaction and gave 3 in 79% yield after 4 h, while
adamantylcarbonylphosphine 1e did not show any benefit giving
3 in 64% yield (entries 5 and 6). The enantioselectivity was also in
the unsatisfactory level, 51%by 1e and 63%by 1f. Production of 4
was not suppressed. One of the common features of these
reactions was precipitate derived from amidophosphine-copper
complex, which was probably responsible for lower catalytic
activity compared with the soluble complex derived from 1h.7
Next, we examined influence of the substituent on the
pyrrolidine ring of pivaloylphosphine 1 (R1 ¼ t-Bu). A pivaloyl-
phosphine 1g bearing two methyl groups on the pyrrolidine ring
promoted the reaction within 5 h giving the product 3 in 79%
yield. Enantioselectivity was improved to 79% ee (entry 7).
Undesirable reduction was not suppressed to give 4 in 19% yield.
It was so delightful to learn that pivaloylphosphine 1h bearing two
benzyl substituents gave 3 after 2 h in 94% yield and 90% ee
(entry 8).7 Production of 4 was suppressed into 5% yield.
Comparison of three pivaloylphosphines 1f-h bearing no
substitution, methyl, and benzyl groups on the pyrrolidine ring
apparently indicated that the bulkier substituent gave better
catalytic performance; the reaction selectivity giving 3 versus 4,
yield of 3, and enantioselectivity of 3 (entries 6–8). It is also
important to note that solubility was in the order of 1h-copper, 1g-
copper, and 1f-copper complex.
Considerably energetic approaches toward catalytic asym-
metric addition of organometallic reagents to C¼N of imines
have appeared in this decade.1 Among these, chiral amino
alcohol-catalyzed addition of zinc acetylide2 and organozinc,3
chiral allylpalladium-catalyzed allylation with allylstannane or
allylsilane,4 and rhodium-monophosphine-catalyzed arylation
with arylstannanes5 showed impressive success.6 Recently we
have documented the highly enantioselective addition of
diethylzinc to C¼N of a broad range of N-sulfonylimines in the
presence of catalytic amount (1 mol%) of copper(II) triflate and a
chiral amidophosphine 1h (1.3 mol%).7 We describe herein the
structure-efficiency relationships of 1 and, as a result of the
studies, highly efficient chiral amidophosphines 1l.
At the outset of the study on the structure and catalytic
performance relationships of the amidophosphines, a series of
ligands 1a-f bearing various length and size of acyl groupon a
nitrogen atom of a simple pyrrolidine skeleton was prepared,8 and
their catalytic activity was examined. A hexane solution of 2
equiv of diethylzinc was added to a mixture of 1 mol% of
copper(II) triflate and 1.3 mol% of a phosphine ligand 1 in
toluene. The whole was stirred at room temperature for 20 min
ꢁ
and then cooled to 0 C. Then, a toluene solution of N-tosylimine
2 of benzaldehyde was added. The whole was stirred till
Table 1. Catalytic asymmetric ethylation of N-tosylimine 2
giving 3 and reduction product 4 using amidophosphines 1.a
ꢁ
completion at 0 C for the requisite time. Usual workupand
purification by column chromatography gave an addition product
3 and a reduction product 4 (Scheme 1).
Entry 1 R1
R2
Time Yield eeb Yield
/h 3/% 3/% 4/%
1
2
3
4
5
6
7
8
a Me
b Et
c n-Bu
H
H
H
24
24
24
24
24
4
5
5
7
77 58
82 61
81 65
69 58
64 51
79 63
79 79
94 90
83 69
62 52
53 41
96 93
18
14
10
22
30
20
19
5
16
32
40
4
Amidophosphines 1a-d bearing normal acyl groupvarying
from acetyl to nonanoyl on the pyrrolidine nitrogen atom showed
the similar level of catalytic activity giving 3 in 69–82% chemical
yield after 24 h (Table 1, entries 1–4). The enantioselectivity of 3
d n-Oct H
e 1-Adc
f t-Bu
H
H
R2
R2
g t-Bu Me
h t-Bu PhCH2
i Me2N PhCH2
j i-Pr2N PhCH2
k C6F5 PhCH2
l t-Bu 2,4,6-Me3C6H2CH2
N
H
9
PPh2
N
Ph
R1
O
1a-l
Ts
Ts
10
11
12
24
24
3
Et
3
N
Ph
+ Et2Zn
Ts
H
N
aTwo equiv of diethylzinc were used. For entries 6 and 7, three
equiv of diethylzinc were used. The ee was determined by
Ph
4
2
b
HPLC analysis of 3 with a chiral stationary phase column
(Daicel Chiralcel OD-H, hexane/i-PrOH (10/1), 254 nm,
0.6 mL/min). c1-Adamantyl.
Scheme 1. Copper-catalyzed asymmetric ethylation of N-tosy-
limine 2 using amidophosphines 1a-l.
Copyright Ó 2002 The Chemical Society of Japan

Chemistry Letters 2002
9
Dimethylcarbamoyl and diisopropylcarbamoylphosphines
1i,j were designed as better ligands for copper, because their
carbonyl oxygen atoms were anticipated to coordinate more
efficiently to copper. However, the reactions using 1i,j as ligands
gave 3 in unsatisfactory yields and reduced enantioselectivities,
69% ee and 52% ee (entries 9 and 10). Production of 4 was 16%
and 32% yields. On the other hand, pentafluorobenzoylphosphine
1k bearing an electron-withdrawing groupwas much more
unsatisfactory giving 3 in 53% yield and 41% ee along with
production of 4 in 40% yield (entry 11). These systematic
examinations of N-acyl groupand catalytic behavior relation-
ships indicated that a pivaloyl group on the nitrogen atom and
bulky substituent on the pyrrolidine ring are beneficial for high
catalytic performance.
Based on the above structure-performance relationships, a
pivaloylphosphine 1l bearing two mesitylmethyl substituents on
the pyrrolidine ring was designed and synthesized, and its
catalytic activity was examined. To our delightful, 1l-copper
complex was soluble in toluene and performed the highest
catalysis giving 3 after 3 h in 96% yield and 93% ee (entry 12).
Production of 4 was suppressed to 4% yield.
It is possible to speculate that phosphorus and carbonyl oxygen
atoms coordinate to copper or zinc and form a chelate, which is
available only when the carbonyl group and phosphorus atom
point to the same direction as shown in the structure 1, but not in 5
and 6. The bulky substituent effectively shields the one face of the
chelate, which may prohibit the approach of tosylimine 2 from
this face and is responsible for the high enantioselectivity.
It is also important to note that higher catalytic performance
in yield and enantioselectivity was observed only when the
reagent complex was soluble in toluene. The complexes
generated from 1h,l, copper, and diethylzinc were soluble in
toluene at the initial stage of the reaction. A reaction mixture
gradually became turbid as the reaction proceeded, probably
because of formation of zinc salt of 3. In contrast, the reagent
mixture generated from other phosphines 1, 5, and 6 was a
suspension or a turbid solution with brown gum, giving poor
catalytic performance. However, solubility was not sufficient
condition for the performance. The reagent generated from
pentafluorobenzoylphosphine 1k formed a clear solution, while
the performance was quite poor.
In summary, systematic steric tuning of the amidophosphine
ligand successfully and significantly improved the catalytic
activity of the copper-catalyzed asymmetric addition. Rational
will be the study of the next stage toward practical and reasonably
efficient catalytic asymmetric reactions.
These structure-catalytic performance relationships are
understandable. The poor catalytic performance by 1a-d is
ascribable to the presence of rotamers. Because of less bulkiness
of the normal acyl groupon the nitrogen atom, rotation of the N–
CO sigma bond is possible to allow the rotamer.9 The rotamer
fixes the carbonyl group to the direction opposite to phosphorus
moiety like amidophosphines 5 and 6 (Scheme 2).
This research was supported by a Grant-in-aid for Scientific
Research on Priority Areas (A) ‘‘Exploitation of Multi-Element
Cyclic Molecules’’ from the Ministry of Education, Culture,
Sports, Science and Technology, Japan.
Me
Me
5
20 h
6
20 h
Me
O
Me
O
We dedicate this work to Professor Teruaki Mukaiyama on
the occasion of his 75th birthday.
N
N
PPh2
PPh2
Me
Bn
Scheme 2. Influence of the carbonyl groupposition on catalytic
activity producing 3.
References and Notes
1
For reviews, see: a) S. E. Denmark and O. J.-C. Nicaise, J.
Chem. Soc., Chem. Commun., 1996, 999. b) D. Enders and U.
Reinhold, Tetrahedron: Asymmetry, 8, 1895 (1997). c) R.
Bloch, Chem. Rev., 98, 1407 (1998).
Another series of chiral amidophosphines 5 and 610 is
characterized by the position and direction of a carbonyl
functionality. The reactions were not smoothly catalyzed by
these phosphine ligands-copper(II) giving 3 after 20 h in 36% and
38% yields. The enantioselectivity was marginal by 5 and 9% by
6. It is also noteworthy that major product in these reactions was
the reduction product 4 in 59% and 61% yields. The poor
efficiency by 5 and 6 would be ascribed to lack of ability in
forming a soluble chelate with copper or zinc, because
phosphorus and carbonyl oxygen atoms point towards different
directions from each other.
Steric repulsion between the methyl or i-propyl group on
carbamoyl nitrogen and methylene groupof the pyrrolidine ring
of 1i,j destabilizes the planarity around the carbamoyl moiety.
This probably changes the direction of the carbonyl groups and
might be responsible for poor performance by 1i,j. Quite poor
efficiency by 1k also indicated the important role of coordinating
ability of the carbonyl oxygen atom. The electron-withdrawing
pentafluorophenyl group weakens the coordinating ability of the
carbonyl oxygen atom and diminishes the possibility of chelate
formation, although the copper complex was soluble during the
reaction.
2
3
4
5
6
7
8
D. E. Frantz, R. Fassler, and E. M. Carreira, J. Am. Chem.
¨
Soc., 121, 11245 (1999).
J. R. Porter, J. F. Traverse, A. H. Hoveyda, and M. L. Snapper,
J. Am. Chem. Soc., 123, 984 (2001).
M. Bao, H. Nakamura, and Y. Yamamoto, Tetrahedron Lett.,
41, 131 (2000).
T. Hayashi and M. Ishigedani, J. Am. Chem. Soc., 122, 976
(2000).
W. J., III Drury, D. Ferraris, C. Cox, B. Young, and T. Lectka,
J. Am. Chem. Soc., 120, 11006 (1998).
H. Fujihara, K. Nagai, and K. Tomioka, J. Am. Chem. Soc.,
122, 12055 (2000).
Prepared by the analogous procedure to ours reported before,
see: Y. Nakagawa, M. Kanai, Y. Nagaoka, and K. Tomioka,
Tetrahedron, 54, 10295 (1998).
9
A significant amount of rotamers (2:8–3:7) was observed by
31P-NMR as well as 13C-NMR for 1a-d, i-k. Pivaloyl and
adamantylcarbonylphosphines are likely to the structure
shown by 1, because peaks assignable to rotamers were not
observed.
10 Y. Nakagawa, M. Kanai, Y. Nagaoka, and K. Tomioka,
Tetrahedron Lett., 37, 7805 (1996).
The favorite effects of the bulky substituent on the
pyrrolidine ring of 1h and 1l were quite significant and apparent.