An asymmetric SNAr reaction using the molecular chirality in a crystal

Article abstract of DOI:10.1039/b706426h

An asymmetric S_NAr reaction was performed by using molecular chirality generated and amplified by the spontaneous crystallization of achiral naphthamides; the chirality was retained in a cold solution, caused by slow racemization, and was transferred to stable axially chiral materials with high enantiomeric excesses. The Royal Society of Chemistry.

Full text of DOI:10.1039/b706426h

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An asymmetric S Ar reaction using the molecular chirality in a crystal{
N
Masami Sakamoto,* Atsushi Unosawa, Shuichiro Kobaru, Kazuyuki Fujita, Takashi Mino and
Tsutomu Fujita
Received (in Cambridge, UK) 27th April 2007, Accepted 4th July 2007
First published as an Advance Article on the web 26th July 2007
DOI: 10.1039/b706426h
An asymmetric S Ar reaction was performed by using
N
temperature. We have now found that the apparent molecular
chirality in a crystal could be fixed by an S Ar reaction, leading to
molecular chirality generated and amplified by the spontaneous
crystallization of achiral naphthamides; the chirality was
retained in a cold solution, caused by slow racemization, and
was transferred to stable axially chiral materials with high
enantiomeric excesses.
N
stable axial chirality with a high enantiomeric excess. This reaction
provides the first example of an asymmetric S Ar reaction using
N
chirality generated by the spontaneous crystallization of achiral
materials.
Previously, we reported that achiral naphthamide 1b, prepared
Asymmetric generation influenced by a chiral crystalline environ-
ment is considered an attractive methodology for obtaining
from 2-methoxy-1-naphthalenecarboxylic acid and piperidine,
5
(Fig. 2). We also
crystallized in a chiral space group, P2
1
2
1
2
1
1,2
found that 1a crystallized in a chiral fashion in space group
optically active compounds from achiral compounds. In recent
years, solid-state reactions using chiral crystals in a variety of new
systems has progressed to such an extent that it can now be
P2 2 2 , and X-ray crystallographic analyses of the crystals
1 1 1
revealed that both amides 1a and 1b have almost the same
3
molecular conformation; remarkably, each carbonyl group twists
7
almost orthogonally to the naphthalene plane.
regarded as an important branch of organic chemistry.
Furthermore, recently, a new methodology using molecular
chirality in a crystal as a source of chiral memory in solution
was explored (Fig. 1). The chirality can be effectively transferred to
optically active products by asymmetric reactions involving
The rate of racemization was measured according to changes in
the circular dichroism (CD) spectra using a cryostat apparatus,
{
and the activation free energy (DG ) and half-life (t1/2) were
4
calculated. When the crystals of 1a were dissolved in THF at 15 uC,
the t1/2 of enantiomerization was 973 s. The t1/2 increased as the
temperature was lowered; t1/2 was 1546 and 2445 s at temperatures
nucleophilic carbonyl addition and intermolecular photochemi-
5
,6
cal reactions. Asymmetric synthesis becomes possible with two
requirements; one is spontaneous crystallization of achiral
materials and the other is slow racemization at a controlled
{
of 10 and 5 uC, respectively. DG was calculated as a temperature
2
4 21
dependence of the kinetic rate constant (5 uC: 1.42 6 10
s ,
24
21
24 21
1
0 uC: 2.24 6 10
s
, 15 uC: 3.56 6 10 s ) to be 21.2 ¡
.2 kcal mol . In the case of 1b, derived from piperidine, the
21
0
racemization showed a slightly lower activation free energy and
5
exhibited a t1/2 of 707 s at 15 uC. These facts indicate that the
racemization of both amides 1a and 1b is too fast to be resolved in
the usual manner; however, it can be controlled by lowering the
temperature, and the lifetime becomes long enough for utilization
in asymmetric synthesis.
Next, we tried to lock the bond rotation that affects the
8
Ar reaction. The racemization
racemization of amides 1 by an S
N
should be suppressed by substitution of the methoxy group at the
-position of the naphthalene ring with a more bulky group. Chiral
crystals of 1a were added to a toluene solution containing
.0 equiv. of n-BuLi at 280 uC. After the reaction mixture had
2
3
been stirred for 1 h at the same temperature, a saturated aqueous
solution of ammonium chloride was added to quench the reaction,
and the organic layer was washed with brine and dried over
Fig. 1 Chiral crystallization and asymmetric synthesis using chiral
memory.
Department of Applied Chemistry and Biotechnology, Graduate School
of Engineering, Chiba University, Yayoi-cho, Inage-ku, Chiba 263-8522,
Japan. E-mail: sakamotom@faculty.chiba-u.jp; Fax: +81 43 290 3401;
Tel: +81 43 290 3387
{
1
Electronic supplementary information (ESI) available: Crystal data for
a and experimental data. See DOI: 10.1039/b706426h
Fig. 2 Racemization of 2-methoxy-1-naphthamides.
3
586 | Chem. Commun., 2007, 3586–3588
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a
Table 1
S
N
Ar reaction of amides 1a and 1b with n-BuLi and t-BuLi
Table 2 Kinetic parameters for the racemization of amides 2 and 3 in
n-nonane
a
DG{/
1/2/s kcal mol
DH{/
kcal mol
DS /cal
21
K
{
Temperature/
uC
2
1
21
21
Amide
t
mol
2
2
3
3
a
a
b
a
b
40
40
100
100
5585 24.39
1057 23.35
11184 29.71
3182 28.78
21.72
20.01
28.91
24.34
28.53
210.69
22.13
211.90
The Arrhenius parameters (E values) were 22.34, 20.63, 29.65 and
5.08 kcal mol for 2a, 2b, 3a and 3b, respectively.
2
1
2
Yield of ee of
Temperature/ Conversion 2 or 3 2 or 3
b
(%)
Entry Amide RLi
uC
(%)
(%)
9
(
17.6 min) at 40 uC. These results clearly show the reason why the
c
e
1
2
3
4
5
6
7
8
9
1
a
1a
1b
1a
1a
1a
1a
1b
1b
1b
1b
n-BuLi 280
n-BuLi 280
32
35
92
92
92
94
97
82
99
85
28
65
36
0
ee values of 2a and 2b were low (Table 1, entries 1 and 2). On the
other hand, both amides 3a and 3b have stable axial chirality and
did not racemize at room temperature for several months. The t1/2
of 3a racemization was about 11184 s (186 min) at 100 uC, and
that of 3b was 3182 s (53.0 min).
c
e
f
d
d
d
d
d
d
d
d
t-BuLi
t-BuLi
20
0
43
68
71
72
52
87
98
97
43
58
81
85
12
31
79
85
f
f
f
f
f
f
f
t-BuLi 240
t-BuLi 280
t-BuLi
t-BuLi
20
0
Bulk crystals of naphthamides 1a and 1b used for the
asymmetric reaction were prepared by stirred crystallization from
10
the melt. The samples melted completely at 120 uC, well over
their melting points (mp: 1a, 103–105 uC; 1b, 110–112 uC), and
were cooled and solidified by lowering the temperature with
stirring to 95 uC for 1a and 100 uC for 1b. In five crystallization
t-BuLi 240
t-BuLi 280
0
Powdered crystals of 1 (0.5 mmol) were added to a cooled toluene
solution (5.0 mL) containing butyllithium (1.5 mmol), and the
reaction mixture was stirred for 1 h at the same temperature under
an argon atmosphere. The ee was determined by HPLC using a
CHIRALCEL-IA column. Isolated yield of 2. Isolated yield of 3.
ee of 2. ee of 3.
b
c
d
experiments of 1a followed by an S Ar reaction, product 3a
N
e
f
showed optical activities of 90, 85, 84, 89 and 85% ee, respectively.
High reproducibility of both chiral crystallization and asymmetric
reaction were achieved by this method; however, the direction of
the optical rotation of the photoproduct was inconsistent and
appeared random. This is because the first-generated enantio-
morphic crystal acts as a seed in the crystallization step, and all the
crystals in the batch turn out with the same absolute configuration;
three experiments yielded (2)-3a and two gave (+)-3a. As a matter
of course, a large quantity of the desired crystals can be prepared
by seeding the desired crystal through crystallization.
magnesium sulfate. The organic solvent was removed in vacuo and
the residual mixture was subjected to chromatography on silica gel.
Analysis of the reaction product showed the formation of
2
-n-butyl derivatives 2a and 2b, as shown in Table 1, entries 1–2.
The S Ar product 2a was obtained in an optically active form
N
with 36% ee; on the other hand, in the case of the reaction of 1b,
racemic 2b was isolated. Furthermore, it was observed that the ee
value of 2a decreased gradually as time passed. Even if an optically
active product was yielded, these results show that racemization
had occurred in the work-up process.
In conclusion, we have provided an example of the generation
of chirality by the spontaneous crystallization and hitherto
unknown absolute asymmetric synthesis of axially chiral com-
pounds by locking the apparent molecular chiral conformation via
The n-butyl group was not bulky enough to lock the bond
rotation along Ar–C(LO). Therefore, a reaction with t-BuLi was
tried. A toluene solution containing 3.0 equiv. of t-BuLi was
cooled to 280 uC and was followed by the addition of chiral
crystals of 1a. After reaction for 1 h at the same temperature, the
mixture was treated in the same way as the reaction with n-BuLi.
Analysis of the reaction product showed the formation of 2-tert-
butyl derivatives 3a in 72% yield and in an optically active form
with 85% ee (Table 1, entry 6). With rises in temperature, ee values
decreased (Table 1, entries 4–6); however, even at 20 uC, a 43% ee
of the product was obtained (Table 1, entry 3). When chiral
an S Ar reaction.
N
This work was supported by a Grant-in-Aid for Scientific
Research on Priority Area (417) and a Grant-in-Aid for Scientific
Research (no 1720511) from the Ministry of Education, Culture,
Sports, Science and Technology (MEXT) of the Japanese
Government.
Notes and references
1 L. Addadi and M. Lahav, in Origins of Optical Activity in Nature, ed.
D. C. Walker, Elsevier, New York–Basel, 1979; S. F. Mason, Nature,
crystals of 1b were used for the S Ar reaction, similar results were
N
1984, 311, 19–23; W. E. Wlias, J. Chem. Educ., 1972, 49, 448–454.
obtained. The reaction at 20 uC gave a 12% ee of product 3b
Table 1, entry 7), and a high ee product (85%) was obtained in a
2
3
J. Jacques, A. Collet and S. H. Wilen, Enantiomers, Racemates and
Resolutions, Wiley, New York, 1981; M. Sakamoto, Chem.–Eur. J.,
1997, 3, 384–389; J. Crusats, S. Veintemillas-Verdaguer and J. M. Ribo,
Chem.–Eur. J., 2006, 12, 7776–7781.
For reviews, see: V. Ramamurthy and K. Venkatesan, Chem. Rev.,
1987, 87, 433–481; J. R. Scheffer, M. Garcia-Garibay and O. Nalamasu,
(
reaction at 280 uC (Table 1, entry 10). When crystals of (+)-1a/1b
were used for the S Ar reaction, (+)-2 and (+)-3 were obtained;
N
however, their absolute configurations could not be determined.
The rate of racemization of all amides 2a/2b and 3a/3b were
in Organic Photochemistry, ed. A. Padwa, Marcel Dekker, New York–
Basel, 1987, vol. 8, pp. 249–338; M. Vaida, R. Popovitz-Biro,
L. Leiserowitz and M. Lahav, in Photochemistry in Organized and
Constrained Media, ed. V. Ramamurthy, VCH, New York, 1991,
pp. 249–302; B. L. Feringa and R. Van Delden, Angew. Chem., Int. Ed.,
1999, 38, 3419–3438; M. Sakamoto, in Chiral Photochemistry, ed.
measured on the basis of changes to their [a]D value in n-nonane,
and their DG{ and t1/2 were calculated (Table 2). The t1/2 of
racemization of 2a was about 5585 s (93.1 min) at 40 uC; however,
that of 2b was rather shorter than that of 2a, and was 1057 s
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Y. Inoue and V. Ramamurthy, Marcel Dekker, New York, 2004, pp.
15–461; M. Sakamoto, J. Photochem. Photobiol., C, 2007, 7, 183–196.
We previously reported an asymmetric carbonyl addition using the
chirality of crystals: M. Sakamoto, T. Iwamoto, N. Nono, M. Ando,
W. Arai, T. Mino and T. Fujita, J. Org. Chem., 2003, 68, 942–946;
M. Sakamoto, S. Kobaru, T. Mino and T. Fujita, Chem. Commun.,
for 2991 reflections (Rint = 0.0188). CCDC 638448. For crystallographic
data in CIF or other electronic format see DOI: 10.1039/b706426h.
8 Aromatic amides of stable axial chirality are utilized in many
asymmetric reactions. For example: J. Clayden, A. Lund, L. Vallverdu
and M. Hellwell, Nature, 2004, 431, 966–971; J. Clayden, Angew. Chem.,
Int. Ed. Engl., 1997, 35, 949–951; H. Koide and M. Uemura,
Tetrahedron Lett., 1999, 40, 3443–3446.
4
4
2004, 2002–2003.
5
6
M. Sakamoto, A. Unosawa, S. Kobaru, A. Saito, T. Mino and
T. Fujita, Angew. Chem., Int. Ed., 2005, 44, 5523–5526.
A diastereoselective reaction was also performed: M. Sakamoto,
A. Unosawa, S. Kobaru, Y. Hasegawa, T. Mino, Y. Kasashima and
T. Fujita, Chem. Commun., 2007, 1632–1634.
9 The racemization of several 1-naphthlenecarboxamides with a sub-
stituent at the 2-position was also studied: A. Ahmed, R. A. Bragg,
J. Clayden, L. W. Lai, C. McCarthy, J. H. Pink, N. Westlund and
S. A. Yasin, Tetrahedron, 1998, 54, 13277–13294.
10 Effective stirred crystallization has been reported: R. E. Pincock,
R. R. Perkins, A. S. Ma and K. R. Wilson, Science, 1971, 174,
1018–1020; D. K. Kondepudi, J. Laudadio and K. Asakura, J. Am.
Chem. Soc., 1999, 121, 1448–1451; M. Sakamoto, T. Utsumi, M. Ando,
M. Saeki, T. Mino, T. Fujita, A. Katoh, T. Nishio and C. Kashima,
Angew. Chem., Int. Ed., 2003, 42, 4360–4363.
7
Crystal data for 1a (recrystallized from a mixture of CHCl
17NO , M = 255.31, orthorhombic, space group P2
a = 7.6281(15), b = 11.856(2), c = 14.408(3) s, V = 1303.0(4) s , Z =
3
and hexane):
16
C H
2
r
1 1 1
2 2 ,
3
2
3
2
4
, r = 1.301 Mg m ; in the final least-squares refinement cycles on F ,
the model converged at R = 0.0339, wR2 = 0.0937, and GOF = 0.735
1
3
588 | Chem. Commun., 2007, 3586–3588
This journal is ß The Royal Society of Chemistry 2007