Efficient C-3 functionalization of 4-dimethylaminopyridine (DMAP). A straightforward access to new chiral nucleophilic catalysts

Article abstract of DOI:10.1016/j.tetlet.2012.04.068

Herein, the straightforward C-3 functionalization of 4- dimethylaminopyridine (DMAP) backbone is disclosed. An efficient halogen-metal exchange procedure from 3-bromo DMAP 1 is reported providing a large panel of C-3 functionalized DMAPs. In addition, a Pd-catalysed C-N cross-coupling reaction is also described furnishing new 3-amino DMAPs. These new functionalization pathways led to the resolution-free synthesis of three new chiral DMAP catalysts in few steps and a good overall yield. These new catalysts were evaluated into the Steglich rearrangement giving modest enantioselectivities (up to 20% ee).

Full text of DOI:10.1016/j.tetlet.2012.04.068

Tetrahedron Letters 53 (2012) 3284–3287
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Efficient C-3 functionalization of 4-dimethylaminopyridine (DMAP).
A straightforward access to new chiral nucleophilic catalysts
Thomas Poisson a,b,c, , Sylvain Oudeyer a,b,c, Vincent Levacher a,b,c,
⇑
⇑
a INSA de Rouen, Avenue de l’Université, 76800 St Etienne du Rouvray, France
b Université de Rouen, Laboratory COBRA UMR 6014 & FR 3038, IRCOF, 1 Rue Tesnière, 76821 Mont St Aignan Cedex, France
c CNRS Délégation Normandie, 14 Rue Alfred Kastler, 14052 Caen Cedex, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Herein, the straightforward C-3 functionalization of 4-dimethylaminopyridine (DMAP) backbone is dis-
closed. An efficient halogen-metal exchange procedure from 3-bromo DMAP 1 is reported providing a
large panel of C-3 functionalized DMAPs. In addition, a Pd-catalysed C–N cross-coupling reaction is also
described furnishing new 3-amino DMAPs. These new functionalization pathways led to the resolution-
free synthesis of three new chiral DMAP catalysts in few steps and a good overall yield. These new cat-
alysts were evaluated into the Steglich rearrangement giving modest enantioselectivities (up to 20% ee).
Ó 2012 Elsevier Ltd. All rights reserved.
Received 29 February 2012
Revised 12 April 2012
Accepted 16 April 2012
Available online 22 April 2012
Keywords:
4-Dimethylaminopyridine (DMAP)
Halogen-metal exchange reaction
Steglich rearrangement
Buchwald–Hartwig cross-coupling reaction
Since the middle of the 1960s, 4-dimethylaminopyridine
(DMAP) is well known as a powerful nucleophilic organocatalyst.1
Indeed, since the first report dealing with the observation of the
enhancement of esterification reaction rate, DMAP appeared as
one of the most versatile nucleophilic organocatalyst.2 Surpris-
ingly, the first report dealing with the synthesis and application
of a chiral DMAP catalyst was reported in 1996 by Vedejs and
Chen.3 They developed a chiral analog bearing a stereogenic center
at the C-2 position of the pyridine moiety. However, its use as a
catalyst in the resolution of secondary alcohol was significantly
hampered by the C-2 substitution,4 actually a stoichiometric
amount of chiral DMAP was required to ensure decent yields. Over
the past two decades several strategies have been developed to
introduce a chiral moiety on the DMAP backbone. Among all these
strategies, the C-3 functionalization position of the pyridine ring by
a substituent bearing a stereogenic center,5 a chiral axis6 or a chiral
relay7 was mainly explored, while few reports dealt with the intro-
duction of a chiral substituent at the C-4 position.8 At last but not
least, we have to mention the remarkable performances of ferro-
cene-based planar chiral DMAP analogs developed by Fu.9 Interest-
ingly, the C-2 functionalization of the pyridine ring does not
disrupt the catalyst turnover and its impressive efficiency was de-
scribed in a broad range of asymmetric processes (Fig. 1).
Although numerous efficient chiral catalysts have been reported,
their synthesis remained laborious and usually required a final
resolution step. Basically, two strategies have emerged on the prep-
aration of chiral DMAP catalysts; the introduction of a chiral pattern
in C-4 position was achieved by a SNAr strategy with halogenated
pyridine derivative,8 while the chiral C-2 and C-3 substituted deriv-
atives were synthesized according to multi-step sequences from
pyridine derivatives, followed by a tricky resolution step.3,5,6,9
Surprisingly, the direct functionalization of the DMAP backbone
and more interestingly the straightforward introduction of chiral
⇑
Corresponding authors. Tel.: +33 2 35 52 24 11; fax: +33 2 35 52 29 62 (T.P.);
tel.: +33 2 35 52 24 85; fax: +33 2 35 52 29 62 (V.L.).
E-mail addresses: thomas.poisson@insa-rouen.fr (T. Poisson), vincent.levacher@
insa-rouen.fr (V. Levacher).
Figure 1. An overview of the most popular chiral DMAP catalysts previously
reported.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.04.068

T. Poisson et al. / Tetrahedron Letters 53 (2012) 3284–3287
3285
Table 1
halogen-metal exchange reaction and a Pd-catalyzed C–N cross-
coupling reaction.
Halogen-metal exchange with DMAP 1a
Firstly, we developed a straightforward halogen-metal ex-
change in order to introduce relevant functionalities at C-3 posi-
tion of the pyridine ring within one step (Table 1).13
Initial experiments were performed using usual lithium bases,
well known to promote smooth bromine–lithium exchange
reactions. Unfortunately, all attempts to use t-BuLi, as previously
reported by Vedejs and co-workers,5a failed. The best results were
obtained when conducting the bromine–lithium exchange at
À78 °C for 1 h. Subsequent deuteration of the intermediate lithiat-
ed species with EtOD afforded only 60% of the desired 3-deuterated
DMAP 2a along with significant amounts of unidentified side-prod-
ucts (entry 1). Under the same reaction conditions, n-BuLi fur-
nished the corresponding deuterated product 2a in somewhat
higher yield (80%) but still with several by-products difficult to
eliminate (entry 2). Finally, we tested i-PrMgCl, previously used
by Knochel and others in bromide–magnesium exchange reactions
for the preparation of pyridyl Grignard reagents.14 To our delight,
the room temperature exchange procedure gave the corresponding
deuterated product 2a, which was isolated in quantitative yield
(entry 3). With this efficient halogen-metal exchange procedure
in hand, several functional groups could be introduced straightfor-
wardly on the DMAP scaffold. This methodology was successfully
applied to the introduction of numerous substituents leading to
the formation of ethyl ester 2b (entry 4), trimethylsilyl derivative
2c (entry 5), azide 2d (entry 6) or aldehyde 2e (entry 7), or tin
derivative 2g (entry 9) in good to excellent yields. Remarkably, a
chiral sulfoxide group could be readily introduced in one step using
Entry
R-M
Electrophile
E, Product
Yieldb (%)
1
2
3
4
5
6
7
8
9
t-BuLi
n-BuLi
EtOD
EtOD
EtOD
CNCO2Et
TMSCl
Trisyl azide
DMF
TsCN
n-Bu3SnCl
Ar-CHO
A
D, 2a
D, 2a
D, 2a
60c
80c
99
86
98
55
81
74
55
75
56d
40
i-PrMgCl
i-PrMgCl
i-PrMgCl
i-PrMgCl
i-PrMgCl
i-PrMgCl
i-PrMgCl
i-PrMgCl
i-PrMgCl
i-PrMgCl
CO2Et, 2b
TMS, 2c
N3, 2d
CHO, 2e
CN, 2f
Sn(n-Bu)3, 2g
CH(OH)Ar, 2h
(R)-2i
10
11
12
Pd(PPh3)4, PhI
Ph, 2j
a
Conditions: 1 (1 mmol), i-PrMgCl (1.2 mmol) in THF (7 mL), rt, 3 h, then elec-
trophile (1.1 mmol). Ar = 3,4,5-trimethoxybenzaldehyde, A = (1R,2S,5R)-(—)-men
thyl para-toluenesulfinate.
b
Isolated yield.
Determined by 1H NMR.
c
d
Product was obtained as a single enantiomer see Ref. 13.
(L)-para-toluenementhylsulfinate A as the electrophile under stan-
dard conditions giving access to the enantiomerically pure chiral
catalyst 2i without any resolution step in 56% yield (entry 11).13 Fi-
nally, the synthetic utility of the Grignard reagent was also high-
lighted in the course of a Pd-catalyzed Corriu–Kumada cross-
coupling with iodobenzene, affording the C-3-arylated DMAP 2j
in 40% yield (entry 12).
Then, with the aim of developing a straightforward access to
new chiral nucleophilic catalysts, we decided to use aldehyde 2e
to introduce a stereogenic center at C-3 position. Our strategy re-
lies on the use of the powerful Ellman’s chiral auxiliary.15 The cor-
responding chiral DMAP sulfinimine 7 was obtained in 98% yield
under standard conditions (Scheme 1) and was then allowed to re-
act with various Grignard reagents (Table 2).
Scheme 1. Synthesis of sulfinimine 7.
substituents at C-3 still remained unexplored.10 Herein, new C-3
functionalization pathways of the DMAP scaffold are disclosed as
well as the synthesis of new non-racemic chiral DMAP derivatives
without having to implement a resolution step. A preliminary eval-
uation of their performance in the course of asymmetric Steglich
rearrangement will also be reported.11
Our strategy focused on the use of the readily available 3-bro-
mo-4-dimethylaminopyridine
1 as a
key intermediate.12 We
decided to highlight the versatility of this intermediate through a
Table 2
Addition of Grignard reagents to sulfinimine 7a
Entry
RMgX
Product
Y
X
Solvent
T (°C)
% Conv.b
Dr.c
1
2
Ph
Ph
Ph
Ph
Ph
Ph
8a
8a
8a
8a
8a
8a
8b
8b
THF
THF
1.2
1.2
1.2
1.2
2.4
2.4
2.4
3.6
THF
À78
À78
À78
À78
À78
À100
À78
À78
100
100
53
52
100
82:18
75:25
91:9
94:6
92:8
92:8
>95:5
>95:5
Toluene
DCM
DCM
DCM
DCM
DCM
DCM
3
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
4d
5
6
7
8
100
9-Phenanthrenyl
9-Phenanthrenyl
90
100 (91)e
a
b
c
Conditions: 7 (0.91 mmol), RMgX (1.09 mmol), DCM (5 mL).
Determined by 1H NMR.
Determined by 1H NMR on the crude reaction mixture.
Reaction was performed at 0.08 M instead of 0.16 M.
Isolated yield.
d
e

3286
T. Poisson et al. / Tetrahedron Letters 53 (2012) 3284–3287
Table 4
Steglich rearrangementa
Scheme 2. Preparation of catalyst 9.17b
Table 3
Buchwald–Hartwig cross-coupling with 1a
Entry
Catalyst
Time (h)
Solvent
Yieldb (%)
eec (%)
1
2
3
4
5
2i
9
10d
10d
10d
24
8
6
6
6
t-Amyl-OH
t-Amyl-OH
t-Amyl-OH
THF
60
80
99
86
40
10
<5
20
16
20
DCM
a
Conditions: Azalactone enol carbonate (0.1 mmol), catalyst (5 mol %), solvent
(2 mL).
Entry
Amine
Aniline
Product
Yieldb (%)
b
Isolated yield.
1
2
3
4
5
10a
10b
10c
10d
10e
45
51
c
Determined by HPLC using chiral column.
a-Naphtylamine
(R)-
(R)-
a
a
-Methylbenzylamine
-Methylnaphtylamine
84c
78c
50
Pyrrolidine
As summarized in Table 4 and despite all our efforts, no or poor
enantioselectivities (not exceeding 20% ee) were obtained. Note-
worthy, in all cases a decent turnover of the catalyst was observed,
pointing out the good nucleophilic properties of our DMAP catalysts.
a
Conditions:
1 (1 equiv), amine (1.25 equiv) Pd2(dba)3 (2 mol %), BINAP
(4 mol %), t-BuONa (1.5 equiv), toluene, 110 °C, 16 h.
b
Isolated yield.
Reaction proceeds without racemization.
c
Herein, we described
a new and efficient access to C-3
functionalized DMAPs from the readily available 3-bromo dimeth-
ylaminopyridine 1 thanks to a straightforward room temperature
bromine–magnesium exchange reaction. Several DMAPs bearing
various functional groups at C-3 position as well as relevant chiral
appendages were obtained in good yields. From the same key
intermediate 1, an efficient Pd-catalyzed C–N cross-coupling reac-
tion was also developed leading to new chiral 3-amino DMAP
derivatives. Both halogen-metal exchange and cross-coupling ap-
proaches led to a short- step synthesis of three new chiral catalysts
without any resolution step. These three catalysts were evaluated
in the Steglich rearrangement and despite decent catalytic activi-
ties, the enantiomeric excesses remained modest. However, the
straightforward access to these catalysts prompts us to go further
into and new original applications of these catalysts are currently
underway in our laboratory.
As depicted in Table 2, we first studied the reaction parameters
with phenylmagnesium bromide as the Grignard reagent. After
extensive investigations, we were pleased to find out that the reac-
tion carried out in DCM, with freshly prepared Grignard reagent in
Et2O afforded the corresponding sulfinamine in good yield with
fairly good diastereoselectivity (up to 92:8, entry 6). We should no-
tice that these results are in agreement with the report by Ellman
and co-workers.16
With these optimized conditions in hand, the anthracenyl pat-
tern was successfully introduced in 91% yield with excellent dia-
stereoselectivity (>95:5, entry 8). Then, a one pot deprotection–
acylation reaction sequence gave the corresponding enantiomeri-
cally pure DMAP analog 9 in 63% yield without any erosion of
the optical purity (Scheme 2).17
Then, we turned our attention to the use of the bromo deriva-
tive 1 in metal catalyzed cross-coupling reactions. To the best of
our knowledge, reactions involving 1 as the reaction partner in
cross-coupling reaction are limited to sporadic examples.6 More-
over, the introduction of an amino group through a Buchwald–Har-
twig cross-coupling reaction on the DMAP backbone remains, to
date, unexplored. Thus, this strategy would lead to a new class of
DMAP analogs bearing an amino group at C-3 position.
Acknowledgments
This work was supported by CNRS, INSA-Rouen, the University
of Rouen and Region Haute Normandie. T.P. thanks the MENRT for
a
predoctoral fellowship. Dr. Vincent Gembus is gratefully
acknowledged for helpful comments during the preparation of
the manuscript.
As shown in Table 3, the introduction of an amino group was
successfully achieved using Pd2dba3/BINAP/t-BuONa as a catalytic
system, affording various 3-amino DMAP derivatives 10a–e in
moderate to excellent yields. However, the scope of amine deriva-
tives underlined some limitations. In particular, this process was
found to be highly dependent on the steric hindrance of the amine.
The reaction is restricted to primary and strained secondary
amines (ie., pyrrolidine, entry 5).18 As shown in entries 3 and 4,
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