Single-step preparation of a 4-(dimethylamino)pyridine analogue bearing a sulfoxide as new chiral inducer. Preliminary evaluation as nucleophilic catalyst

Article abstract of DOI:10.1055/s-2005-872256

A one-step synthesis of a new chiral DMAP-1a equivalent is reported by bromine-magnesium exchange reaction of the 3-bromo-4-(dimethylamino)pyridine (2). The chiral sulfoxide appendage is introduced by trapping the resulting Grignard intermediate with (1R,

Full text of DOI:10.1055/s-2005-872256

LETTER
2285
Single-Step Preparation of a 4-(Dimethylamino)pyridine Analogue Bearing
a Sulfoxide as New Chiral Inducer. Preliminary Evaluation as Nucleophilic
Catalyst
Single-Step
Pre
h
paration of
a
o
4-(Dimethyl
m
amino)pyridine An
a
Vincent Levacher*a
a
Laboratoire de Chimie Organique Fine et Hétérocyclique, UMR 6014, IRCOF, CNRS, Université et INSA de Rouen, B.P. 08,
76131 Mont-Saint-Aignan Cédex, France
b
Laboratoire de chimie, URCOM, Faculté des Sciences et Techniques de l’Université du Havre, 76620 Le Havre, France
Fax +33(2)35522962; E-mail: vincent.levacher@insa-rouen.fr
Received 10 June 2005
R2N
Abstract: A one-step synthesis of a new chiral DMAP-1a equiva-
lent is reported by bromine–magnesium exchange reaction of the 3-
bromo-4-(dimethylamino)pyridine (2). The chiral sulfoxide ap-
NR2
N
R'
Fe
pendage is introduced by trapping the resulting Grignard intermedi-
ate with (1R,2S,5R)-(–)-(S)-menthyl p-toluenesulfinate affording
(S)-1a in 60% yield and high optical purity. A preliminary evalua-
tion of 1a as nucleophilic catalyst has demonstrated promising se-
lectivity (s = 4.5) during acylative kinetic resolution of various
alcohols.
R'
R'
Ar
R'
N
R'
A. C. Spivey (ref. 1e)
G. C. Fu (ref. 1a)
H
Key words: chiral DMAP, sulfoxide, kinetic resolution, alcohol
OH
NMe2
H
N
CAr3
OAc
H
Chiral 4-(dimethylamino)pyridine (DMAP) analogues
have received considerable attention in recent years. A
number of these chiral DMAP have already demonstrated
to be highly effective chiral nucleophilic catalysts in a
wide range of synthetically useful catalytic processes.1
These include, as the main illustrative examples, acylative
kinetic resolution of secondary alcohols and amines, C-
arylations of silyl ketene acetals and additions of 2-cyano-
pyrrole to ketenes. In spite of the high potential exhibited
by these chiral DMAP reagents, they have not yet gained
full popularity due to the multi-step sequences and resolu-
tion techniques such as semi-preparative HPLC or crystal-
lization required during their preparation (Figure 1).
N
E. Vedejs (ref. 1d)
N
K. Fuji (ref. 1b)
Figure 1 Chiral DMAP analogues previously reported.
comment on the preliminary investigation of its potential
during acylative kinetic resolution of various alcohols. By
analogy with previous observations reported by Vedejs,1d
it was anticipated that the proximity of the dimethylamino
group would prevent the free rotation of the chiral sulfox-
ide inducer. A molecular modeling3 study of DMAP ana-
logue 1a revealed that the most stable conformation
would place the lone pair of the sulfoxide and the pyridine
ring in a coplanar arrangement (Figure 2, b). This confor-
mational constraint is expected to be the main driving
force in the stereodifferentiation of both faces of the pyri-
dine ring.
The lack of straightforward and general existing methods
for the preparation of these attractive synthetic tools stim-
ulated us to develop an approach for the easy access of an
array of new chiral DMAP derivatives, in which the chiral
appendages would be installed in a single-step operation.
Our strategy capitalizes on the expected versatility of the
readily available 3-bromo-4-(dimethylamino)pyridine
(2)2 which, by means of various conventional chemical
transformations should provide access to the desired
structural and chiral diversities. In this communication,
we assess the potential of the above working hypothesis
by reporting the straightforward preparation, based on a
bromine–metal exchange, of a new chiral DMAP equiva-
lent 1a bearing a sulfoxide group (Figure 2, a). We also
Initial attempts to install the chiral sulfoxide by bromine–
lithium exchange reaction turned out to be rather disap-
pointing. Treatment of 3-bromo-4-(dimethylamino)pyri-
dine (2)2 with n-BuLi (1.2 equiv, –70 °C, THF) followed
by deuteriolysis, furnished DMAP 1b with modest deute-
rium incorporation (40%). In addition, a substantial
amount of unidentified by-products was observed making
rather difficult the purification of the crude product
(Table 1, entry 1). The situation was even worse when t-
BuLi was used, affording only traces of the desired deu-
terated DMAP 1b along with a myriad of by-products
(Table 1, entry 2). Speculating that the formation of these
by-products took place because of the low stability of the
SYNLETT 2005, No. 15, pp 2285–2288
1
9
.0
9
.2
0
0
5
Advanced online publication: 29.07.2005
DOI: 10.1055/s-2005-872256; Art ID: D16605ST
© Georg Thieme Verlag Stuttgart · New York

2286
T. Poisson et al.
LETTER
NMe2
NMe2
¨
p-Tol
S
Br
(a)
O
N
N
2
(S)-1a
Scheme 1 A single-step synthesis of DMAP 1a. Reagents and
conditions: (a) i-PrMgCl (1.2 equiv), 20 °C, THF, 3 h then
(1R,2S,5R)-(–)-(S)-menthyl p-toluenesulfinate (1.2 equiv), –78 °C to
20 °C, 18 h.
in two hours, catalyst 1a drives the reaction to completion
within 24 hours. These observed rate differences may be
attributed to the presence of the chiral sulfoxide, which
exhibits an electron-withdrawing full charge dipole. As a
result, the formation of the reactive acylpyridinium salt
intermediate may possibly be hampered (Figure 3).
Figure 2 (a) Design of a new chiral DMAP equivalent 1a bearing a
sulfoxide group as chiral inducer; (b) molecular modeling3 (hydrogen
atoms have been omitted for clarity).
3-lithiated DMAP, we next turned our attention to a bro-
mine–magnesium exchange reaction in order to benefit
from a milder reactivity of the resultant Grignard species.4
The reaction was carried out at room temperature by treat-
ment of 3-bromo-4-(dimethylamino)pyridine (2) with i-
PrMgCl for three hours. As anticipated, quenching the re-
action mixture with EtOD led to the desired DMAP 1b
with high deuterium incorporation (>95%) in a much
cleaner manner (Table 1, entry 3).5
Table 1 Optimization of the Halogen–Metal Exchange Reaction
NMe2
NMe2
D
Br
conditions
N
N
2
1b
Entry Bromine–Metal Exchange Conditions
1b
1
2
3
n-BuLi (1.2 equiv), –78 °C, THF, 30 min
t-BuLi (1.2 equiv), –78 °C, THF, 5 min
i-PrMgCl (1.2 equiv), 20 °C, THF, 3 h
%D = 40%a
%D = 20%a
%D > 95%a
Figure 3 Evaluation of the catalytic activity of 1a by acylation of 1-
phenylethanol. Reagents and conditions: Ac2O, CH2Cl2, r.t., catalyst
(see legend).
a Determined from 1H NMR Spectrum.
We next examined the influence of the solvent on the se-
lectivity of the catalyst 1a during the kinetic resolution of
1-(2-methoxyphenyl)ethanol (3c) at –78 °C for 18 hours.7
A literature survey revealed that CH2Cl2 and toluene re-
main the most commonly used solvents in this kinetic res-
olution process. Whereas both of these solvents have
found to provide moderate selectivity values (s = 3.1 and
3.0, respectively), a slight but significant improvement
could be observed by conducting the kinetic resolution
process in acetone (Table 2, entry 5). It should be noticed
that the catalytic activity at this temperature remains par-
ticularly modest, giving rise to poor conversion rates (3.5
< C < 6.7). The use of Et2O or THF proved to be totally
unproductive at this temperature (Table 2, entries 3, 4).
Having optimized the bromine–magnesium exchange
conditions, we then undertook the introduction of the
chiral sulfoxide appendage by means of (1R,2S,5R)-(–)-
(S)-menthyl p-toluenesulfinate as electrophile. The de-
sired chiral DMAP (S)-1a was obtained in 60% yield. As
revealed by chiral HPLC, the product consisted of a single
enantiomer.6 This single-step approach provides a simple
stereoselective access to 1a and makes, in a certain extent,
this novel chiral DMAP more than ever attractive
(Scheme 1).
The potential of catalyst 1a was then investigated during
the kinetic resolution of various secondary alcohols. Its
catalytic activity was firstly assessed by acylation of 1-
phenylethanol under standard conditions at 25 °C in
CH2Cl2 and compared with that of DMAP (Figure 3).
Whereas acylation of 1-phenylethanol with DMAP occurs
To probe the scope of the catalyst, the chiral DMAP
equivalent 1a was then subjected to a preliminary screen-
Synlett 2005, No. 15, 2285–2288 © Thieme Stuttgart · New York

LETTER
Single-Step Preparation of a 4-(Dimethylamino)pyridine Analogue
2287
Table 2 Influence of the Solvent on the Kinetic Resolution of 1-(2- enhancement of the selectivity was detected when switch-
Methoxy)phenyl Ethanol (3c)
ing the acylation reagent from Ac2O to (i-PrCO)2O
(Table 3, entries 3, 8, 13, 18). Finally, the best selectivity
OMe OAc
OMe OH
catalyst 1a (5%)
solvent, –78 °C
could be attained in acetone at –78 °C. However, the pres-
ence of two equivalents of Ac2O is required to guarantee
an acceptable conversion level (Table 3, entries 9 and 10,
14 and 15).
Ac2O (0.6 equiv)
Et3N (0.6 equiv)
3c
In summary, a chiral DMAP equivalent 1a bearing a sul-
foxide as chiral appendage has been prepared. With the
main goal to provide straightforward access to new chiral
DMAP equivalents, a one-step procedure has been suc-
cessfully developed from the readily available 3-bromo-
4-(dimethylamino)pyridine (2). While DMAP 1a suffers
from a moderate catalytic activity, selectivity up to 4.5
could be achieved during the kinetic resolution of second-
ary alcohols. Although these values are still inferior to the
threshold of s = 7 usually required for synthetic applica-
tions, these preliminary experiments have already demon-
strated encouraging results.
Entry
Solvent
CH2Cl2
C (%)a
eeA (%)b
eeE (%)b
50.3
49.0
–
sd
1
2
3
4
5
5.7
3.0
1.8
–
3.1
3.0
–
Toluene
Et2O
3.5
<1
<1
6.7
THF
–
–
–
Acetone
4.2
61.8
4.4
a Conversion [C = 100 × eeA/(eeA + eeE)].
b The ee of alcohol and ester established by chiral GC (Chiraldex CB
25 m × 0.25).
c Selectivity factor, see ref.8
Acknowledgment
ing of reaction conditions with various secondary alcohols We thank the CNRS, the région Haute-Normandie and the
CRIHAN for financial and technical support.
3a–d (Table 3). Each experiment was duplicated at least
once and showed to be reproducible in terms of selectivity
and conversion. While the selectivity remains modest in
all cases, ranging from 1.6 to 4.5, some interesting trends
are emerging from Table 3 and deserve several com-
ments. As frequently reported in the literature, when the
References
(1) For leading references of chiral DMAP analogues, see:
(a) Fu, G. C. Acc. Chem. Res. 2004, 37, 542. (b) Kawabata,
T.; Nagato, M.; Takasu, K.; Fuji, K. J. Am. Chem. Soc. 1997,
119, 3169. (c) Kawabata, T.; Yamamoto, K.; Momose, Y.;
Yoshida, H.; Nagaoka, Y.; Kaoru, F. Chem. Commun. 2001,
2700. (d) Shaw, S. A.; Aleman, P.; Vedejs, E. J. Am. Chem.
Soc. 2003, 125, 13368. (e) Spivey, A. C.; Zhu, F.; Mitchell,
M. B.; Davey, S. G.; Jarvest, R. L. J. Org. Chem. 2003, 68,
resolution is conducted at low temperature (–78 °C) in
CH2Cl2, some improvement of the selectivity is observed,
however, to the detriment of the conversion rate (Table 3,
entries 1 and 2, 6 and 7, 11 and 12, 16 and 17). By contrast
to what has generally been observed in the literature, no
Table 3 Acylative Kinetic Resolution of 3a–d by Means of Catalyst 1a
Alcohol
Entry
Conditions
C (%)
eeA (%)
eeE (%)
s
1
2
3
4
Ac2O (0.6 equiv), Et3N (0.6 equiv), r.t., CH2Cl2
Ac2O (0.6 equiv), Et3N (0.6 equiv), –78 °C, CH2Cl2
(i-PrCO)2O (0.6 equiv), Et3N (0.6 equiv), r.t., CH2Cl2
Ac2O (2 equiv), Et3N (0.6 equiv), –78 °C, acetone
58
12.6
8.6
5.0
9.2
40.7
8.0
1.3
2.6
1.4
3.4
OH
OH
17.4
38.5
15.56
9.4
51.0
3a
3b
6
7
8
9
10
Ac2O (0.6 equiv), Et3N (0.6 equiv), r.t., CH2Cl2
Ac2O (0.6 equiv), Et3N (0.6 equiv), –78 °C, CH2Cl2
(i-PrCO)2O (0.6 equiv), Et3N (0.6 equiv), r.t., CH2Cl2
Ac2O (0.6 equiv), Et3N (0.6 equiv), –78 °C, acetone
Ac2O (2 equiv), Et3N (0.6 equiv), –78 °C, acetone
54.0
20.0
36.0
6.7
17.3
10.2
10.5
3.6
14.7
41.6
18.6
49.9
46.3
1.6
2.6
1.6
3.1
3.0
18.3
10.4
11
12
13
14
15
Ac2O (0.6 equiv), Et3N (0.6 equiv), r.t., CH2Cl2
Ac2O (0.6 equiv), Et3N (0.6 equiv), –78 °C, CH2Cl2
(i-PrCO)2O (0.6 equiv), Et3N (0.6 equiv), r.t., CH2Cl2
Ac2O (0.6 equiv), Et3N (0.6 equiv), –78 °C, acetone
Ac2O (2 equiv), Et3N (0.6 equiv), –78 °C, acetone
49.5
5.7
27.6
6.36
16.7
20.4
3.0
8.0
4.2
12.0
20.8
50.3
21.0
61.8
59.9
1.8
3.1
1.7
4.4
4.5
OMe OH
3c
16
17
18
19
Ac2O (0.6 equiv), Et3N (0.6 equiv), r.t., CH2Cl2
Ac2O (0.6 equiv), Et3N (0.6 equiv), –78 °C, CH2Cl2
(i-PrCO)2O (0.6 equiv), Et3N (0.6 equiv), r.t., CH2Cl2
Ac2O (2 equiv), Et3N (0.6 equiv), –78 °C, acetone
59.3
16.7
51.2
22.4
20.9
9.6
10.4
12.8
14.3
16.7
9.9
1.6
3.1
1.3
2.9
OH
44.3
Cl
3d
Synlett 2005, No. 15, 2285–2288 © Thieme Stuttgart · New York

2288
T. Poisson et al.
LETTER
7379. (f) Yamada, S.; Misono, T.; Iwai, Y. Tetrahedron Lett.
2005, 46, 2239. (g) Dalaigh, C. O.; Hynes, S. J.; Maher, D.
J.; Connon, S. J. Org. Biomol. Chem. 2005, 3, 981.
graphed on silica gel using EtOAc as eluent to afford 1a in
60% yield. 1H NMR (300 MHz, CDCl3): d = 8.74 (s, 1 H),
8.27 (d, 1 H, J = 6 Hz), 7.37 (d, 2 H, J = 8 Hz), 7.17 (d, 2 H,
J = 8 Hz), 6.56 (d, 1 H, J = 6 Hz), 2.95 (s, 6 H), 2.30 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 20.3, 42.2, 109.7, 124.4,
127.3, 128.9, 140.2, 140.5, 148.4, 150.8, 154.2. IR (KBr):
1580, 1407, 1096, 1073, 1044, 957, 813 cm–1. HRMS
(FAB+): m/z calcd for C14H16N2OS: 260.0903; found:
260.0907. [a]D20 –323 (c 0.011, CH2Cl2). Following the
same procedure, the chiral DMAP (R)-1a was prepared
using (1R,2S,5R)-(–)-(R)-menthyl p-toluenesulfinate. The
optical purity of the DMAP 1a was established by chiral
HPLC analysis using a Chiralcelpak AD (250 × 4.6 mm; 10
mm). Chromatographic conditions: injection: 20 mL (0.5 mg
of a racemic mixture of 1a in 10 mL of heptane). Eluent:
heptane–2-PrOH, 80:20. Flow rate: 1 mL/min. Pressure:
300 psi. Temperature: 22 °C. UV detection: l = 254 nm.
Retention time: 16.9 min (R-enantiomer) and 20.9 min
(S-enantiomer).
(2) Groziak, M. P.; Melcher, L. M. Heterocycles 1987, 26, 2905.
(3) Geometry optimization was performed with the MS
modeling (Accelrys) implementation of the CNFF force
field.
(4) For recent development of bromine–magnesium exchange
reaction, see: Knochel, P.; Dohle, W.; Gommermann, N.;
Kneisel, F. F.; Kopp, F.; Korn, T.; Sapountzis, I.; Vu, V. A.
Angew. Chem. Int. Ed. 2003, 42, 4302.
(5) Preparation of DMAP 1b by Bromine–Magnesium
Exchange.
To a solution of 3-bromo-4-(dimethylamino)pyridine (2,
898 mg, 4.47 mmol) in THF (30 mL) is added a solution of
i-PrMgCl in THF (2.68 mL, 2 M, 5.36 mmol) at r.t. The
resultant solution was stirred at this temperature for 3 h
under a nitrogen atmosphere. The reaction mixture was
quenched with EtOD and the solution stirred for a further 1
h. After adding H2O (40 mL), the resulting aqueous layer
was extracted twice with CH2Cl2 (2 × 10 mL), dried
(MgSO4) and evaporated under vacuum to give 1b in high
deuterium incorporation (>95%) as a yellow oil. 1H NMR
(300 MHz, CDCl3): d = 8.22 (app t, 2 H, J = 6 Hz), 6.48 (d,
1 H, J = 6 Hz), 3.00 (3 H, s). HRMS (FAB+): m/z calcd for
C7H9DN2: 123.0907; found: 123.0910.
(7) Typical Procedure for Catalytic Kinetic Resolution of
Secondary Alcohols.
To a solution of catalyst 1a (13 mg, 0.05 mmol), 1-(2-
methoxyphenyl)ethanol (3c, 152 mg, 1 mmol), Et3N (86 mL,
0.6 mmol) in CH2Cl2 (5 mL) was added Ac2O (57 mL, 0.6
mmol) at –78 °C. The reaction mixture was stirred at this
temperature for 18 h after which time 100 mL was removed
from the reaction mixture via a syringe and poured
immediately in MeOH (2 mL). The conversion and the ee of
both the alcohol and the acetate were determined by
analytical chiral GC (Chiraldex CB 25 m × 0.25) of the
resulting methanolic solution.
(6) Preparation of DMAP (S)-1a by Bromine–Magnesium
Exchange.
DMAP 1a is prepared according to the procedure reported in
ref. 5 by means of (1R,2S,5R)-(–)-(S)-menthyl p-toluene-
sulfinate (1.45 g, 4.91 mmol) as electrophile in the quench-
ing step of the procedure. The residue was chromato-
(8) Kagan, H. B.; Fiaud, J. C. Top. Stereochem. 1998, 249.
Synlett 2005, No. 15, 2285–2288 © Thieme Stuttgart · New York