Dealkylative functionalization of tertiary amines with electron deficient heteroaryl chlorides

Article abstract of DOI:10.1016/j.tetlet.2006.01.104

The selective dealkylative arylation of trialkyl amines, N-alkyl pyrrolidines, N-alkyl piperidines and dialkyl anilines with electron deficient heteroaryl chlorides was investigated. Efficient and practical reaction conditions were determined for a range

Full text of DOI:10.1016/j.tetlet.2006.01.104

Tetrahedron Letters 47 (2006) 2229–2231
Dealkylative functionalization of tertiary amines with
electron deficient heteroaryl chlorides
Gregory L. Hamilton and Bradley J. Backes*
Metabolic Disease Research, Global Pharmaceutical Research and Development, Abbott Laboratories,
100 Abbott Park Road, Abbott Park IL 60064-6098, USA
Received 15 December 2005; revised 17 January 2006; accepted 18 January 2006
Available online 7 February 2006
Abstract—The selective dealkylative arylation of trialkyl amines, N-alkyl pyrrolidines, N-alkyl piperidines and dialkyl anilines with
electron deficient heteroaryl chlorides was investigated. Efficient and practical reaction conditions were determined for a range of
substrates.
Ó 2006 Elsevier Ltd. All rights reserved.
During the course of our research in the metabolic dis-
ease area, N-aryl or N-heteroaryl pyrrolidines were
developed as leads for promising development targets.
Fortuitously, powerful and mild synthetic methods such
as dipolar additions employing azomethine ylides1 can
give access to pyrrolidines that are decorated with a
range of substituents and functional groups. However,
these methods often leave products with an undesired
methyl or benzyl group on the nitrogen. On occasions,
our efforts to remove these nitrogen substituents to pro-
vide substrates for nucleophilic aromatic substitution
chemistry or metal-mediated cross-couplings met with
limited success due to the presence of sensitive function-
ality displayed upon the pyrrolidine. For example, the
reductive removal of N-benzyl groups can be difficult
in the presence of aryl halides or nitro groups.2 The
use of chloroformates to quaternize and dealkylate the
pyrrolidine nitrogen to give carbamates for subsequent
deprotection worked moderately well for some sub-
strates.3 However, the efficiency of this process was very
much dependent on the nature of the amine.4
X
_
X
R3
N
R2
R2
N
R3
N
EW
N
R1
+R1-X
R2
R3
N
N
EW
EW
R1
Figure 1. Quaternization of 3° amines with electron deficient hetero-
aromatic halides and dealkylation.
and have focused on the reactions of triazinyl,5 pyrimid-
inyl and quinazolinyl chloride substrates6 with simple 3°
amines. Attempts to extend these methods to a wider
range of heteroaryl chloride electrophiles has required
the use of high pressures and reaction times that extend
over days.7 Here we report our efforts to identify reactiv-
ity trends and practical reaction conditions to make this
transformation a viable option for a wide range of
substrates.
An early report detailing the substitution of 2,4,6-
trichlorotriazine with 3° amines at high temperatures
identified over-addition as a major side product.5
Accordingly, 1,8 for which over-addition is not an issue,
was chosen to explore this transformation in more detail
(Table 1). Treatment of 1 (1.2 equiv) with N-methyl-
piperidine (0.5 M in CH3CN) at 22 °C resulted in a near
quantitative yield of 2a (98%) after 12 h. N-Benzyl- and
N-ethylpiperidine reacted more slowly and required
heating (60 °C) to give complete conversion to 2a in
96%, and 98% yield, respectively. The reactivity trend
for N-substituents (Me > Bn) is the opposite of that
By analogy to the aforementioned chloroformate-medi-
ated process, we were curious whether N-alkyl pyrroli-
dines could be directly substituted with aryl and
heteroaryl halides to provide N-aryl and N-heteroaryl
pyrrolidines in a single step (Fig. 1). Reports detailing
useful applications of this transformation are limited,
Keywords: Quaternization; Dealkylation; Microwave synthesis.
*
Corresponding author. Tel.: +1 847 938 3521; fax: +1 847 938
1674; e-mail: bradley.backes@abbott.com
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.01.104

2230
G. L. Hamilton, B. J. Backes / Tetrahedron Letters 47 (2006) 2229–2231
Table 1. Triazinyl chloride 1 reaction with amines and aniline
Table 2. Treatment of 3 with various heteroaromatic chlorides
OEt
N
N
OEt
N
N
R2
N
R2
O
N
Cl
N
O
Ph
HET
N
N
N
Ph
R1
R3
R3
HET-Cl (1.2 equiv)
1 (1.2 equiv)
2a-c
Entry
R1NR2R3
Product
Yielda
98b
3
4a-i
Br
Br
N
N
Entry
1
HET-Cl
Prod
Conditions
Yielda
1
2
3
4
N
Ph
N
N
Me
1
4a
22 °C, 2 h,
86
CH3CNb
2a
N
N
N
N
2
3
4b
4b
22 °C, 1 h,
45c
2a
2a
79b (96)c
71b (98)c
92b
N
Cl
Cl
Cl
N
N
N
Cl
Cl
N
THFb
Bn
N
N
22 °C, 1 h,
0.25 M LiCl
THFb
96
N
Et
N
N
4
5
6
4c
4d
4e
80 °C, 7 h,
80
85
68
CH3CNd
N
Ph
N
N
N
2b
N
N
N
N
N
150 °C
N
N
Cl
Cl
(lW), 0.5 h,
96d
CH3CNe
5
N
Ph
N
2c
200 °C
a Yields of analytically pure material based upon amine equivalent.
b Conditions: CH3CN (0.5 M), 22 °C, 12 h.
Cl
Cl
(lW), 0.5 h,
N
NMPe
c Conditions: CH3CN (0.5 M), 60 °C, 3 h.
7
4f
220 °C
Trace
d Conditions: CH3CN (0.5 M), 80 °C, 12 h.
N
(lW), 0.5 h,
NMPe
NO2
N
N
observed for the quaternization and dealkylation of 3°
amines with chloroformates.9 These results may suggest
that for dealkylative substitution with heteroaryl chlo-
rides, reversible quaternization is the rate-limiting step
with the reactivity profile reflecting the steric availability
of the nitrogen lone pairs. Triethylamine substitution of
1 occurred at room temperature to give 2b in 92% yield
while less nucleophilic aniline required more forcing
conditions (80 °C) to give 2c (96%).
8
4g
4h
4i
180 °C
80
58
16
(lW), 0.5 h,
Cl
Cl
NMPe
CN
9
220 °C
(lW), 0.5 h,
NMPe
CF3
N
10
220 °C
(lW), 0.5 h,
Cl
NMPe
A representative substrate, pyrrolidine 3, was employed
to examine the reactivity of several heteroaryl chloride
partners (Table 2). Reaction of 1 (1.2 equiv) with 3
(0.2 M in CH3CN) at 22 °C gave 4a in 86% yield.10
Treatment of 2,6-dichlorotriazine with 3 under similar
conditions resulted in a poor yield of 4b due to the for-
mation of a significant amount of di-addition product 6
(Fig. 2). The use of lower reaction temperatures or sol-
vents of varying character did not improve this result.
It is likely that intermediate 5 is more reactive to substi-
tution than is 2,6-dichlorotriazine, and that a second
addition of 3 competes with dealkylation. It is doubtful
that the formation of 6 is due to a second addition to 4b,
due to the reduced reactivity of amine-substituted chlo-
rotriazines. This is evident since the reaction of (N,N-di-
methyl)amino-chlorotriazine and 3 required the use of
more forcing conditions (80 °C, 0.5 M CH3CN, 7 h) to
provide 4c in 80% yield. We hypothesized that the yield
of 4b could be improved with the inclusion of a chloride
ion source to increase the rate of dealkylation of 5 versus
the rate of addition of a second equivalent of 3. After
a Yields of analytically pure material based upon amine equivalent.
b Reaction performed at 0.2 M in 3.
c Di-addition gave 6 (16%) as a side product (Fig. 2).
d Reaction performed at 0.4 M in 3.
e Reaction performed at 2 M in 3.
profiling a number of such reagents, LiCl (0.25 M) in
THF was found to dramatically reduce the formation
of 6 to give 4b in 96% yield.11
Previous reports employed high reaction pressures and
multi-day reaction times to expand the scope of this
transformation.7 We found that microwave-assisted syn-
thesis provided practical reaction conditions for a range
of substrates.12 Treatment of 4,6-dichloropyrimidine
with 3 (2 M in CH3CN, 150 °C, 0.5 h) gave 4d in 80%
yield. Unlike the disubstitution that was observed for
2,6-dichlorotriazine (entry 2) substitution, over-addition
to 4,6-dichloropyrimidine was presumably not observed
because the quaternized intermediate formed is short-

G. L. Hamilton, B. J. Backes / Tetrahedron Letters 47 (2006) 2229–2231
2231
Supplementary data
Br
O
Cl
N
Supplementary data including analytical data for 2a–c,
3, 4a–e, 4g–h and 6 is available online with this article
and can be found, in the online version, at doi:10.
1016/j.tetlet.2006.01.104.
O
N
N
_
Cl
N
N
+
Cl
LiCl
4b
N
N
3
5
Cl
References and notes
1. Coldham, I.; Hufton, R. Chem. Rev. 2005, 105, 2765–
2809.
3
Br
2. Green, T. W.; Wuts, P. G. M. Protective groups in Organic
Synthesis, 2nd ed.; Wiley and Sons: New York, 1991, pp
364–365.
O
O
O
3. For a review detailing with the reactions of 3° amines with
acid chlorides and chloroformates see: Cooley, J. H.;
Evain, E. J. Synthesis 1989, 1–7.
N
N
N
Br
O
N
N
4. The forcing conditions that were often needed to achieve a
reasonable level of conversion decomposed the chlorofor-
mate and resulted in an increase in the acidity of the
reaction media. In turn, substrates bearing acid sensitive
groups such as Boc-protected amines decomposed.
5. Kober, E.; Ratz, R. J. Org. Chem. 1962, 27, 2509–
2514.
6. Yoshida, K.; Taguchi, M. J. Chem. Soc., Perkin Trans. 1
1992, 919–922.
7. Matsumoto, K.; Hashimoto, S.; Otani, S. J. Chem. Soc.,
Chem. Commun. 1991, 306–307.
6
Figure 2. LiCl suppresses di-addition to activated 5.
lived at 150 °C. Pyrimidines substituted with chlorine at
the less reactive 2-position reacted with 3 at 200 °C to
give 4e (68%). The substitution of more electron-rich
amine-substituted pyrimidines was unsuccessful, even
at high temperatures (entry 7). Pyridines with electron-
withdrawing groups in the 4-position served as viable
substrates (entries 8–10). In the case of 2-chloro-4-nitro-
pyridine, substitution with 3 gave at 180 °C 4g (80%),
and the substitution of 2-chloro-4-cyanopyridine at
220 °C gave 4h (58%). Finally, the reaction of 3 with
2-chloro-4-trifluoromethylpyridine at 220 °C provided
a low yield of 4i (16%) suggesting that inductive stabil-
ization of the quaternized intermediates is less produc-
8. Harris, R. L. Synthesis 1980, 841–842.
9. For chloroformates, quaternization of 3° amines is rela-
tively fast, with the rates of dealkylation governing the
observed reactivity profiles: Kapnang, H.; Charles, G.
Tetrahedron Lett. 1983, 24, 3233–3236.
10. Pyrrolidine substrates that feature acid labile functionali-
ties such as Boc-protected amines were viable substrates
for this transformation, even when forcing conditions were
employed. Unpublished results.
11. It is possible that more reactive heteroaryl chlorides
such as 2,6-dichlorotriazine may shift the rate-limiting
step to dealkylation accounting for these observa-
tions. However, the addition of LiCl in this transfor-
mation did not dramatically increase the overall rate of the
reaction and suggests that quaternization is still rate
limiting.
12. Representative procedure (4d). To 4,6-dichloropyrimidine
(72 mg, 0.48 mmol) was added 3 (160 mg, 0.40 mmol) as a
solution in CH3CN (0.2 mL). The reaction mixture was
submitted to microwave irradiation for 30 min at 150 °C,
concentrated and purified over silica gel (EtOAc/hexanes,
0:100–30:70 gradient) to give 4 d (140 mg, 85%) as a white
solid. 1H NMR (300 MHz, CDCl3) d 8.31 (s, 1H), 7.48 (d,
J = 8.3 Hz, 2H), 7.16 (d, J = 8.3 Hz, 2H), 6.33 (s, 1H), 4.13
(q, J = 7.3 Hz, 2H), 4.00–4.10 (m, 1H) 3.74–3.80 (m, 2H),
3.40–3.60 (m, 2H), 3.20–3.25 (m, 1H), 1.19 (t, J = 7.3 Hz,
3H). 13C NMR (100 MHz, CDCl3) 171.3, 160.3, 159.5,
158.1, 137.8, 131.9, 128.9, 121.4, 101.9, 61.3, 52.6, 49.8,
49.5, 46.5, 14.0. Anal. Calcd for C17H17BrClN3O2: C,
49.72; H, 4.17; N, 10.23. Found: C, 49.80; H, 3.89; N,
10.07.
tive than resonance stabilization and defining
reactivity limit for pyrimidines using our methods.
a
In conclusion, the dealkylative arylation of sensitive 3°
amine substrates with electron-poor heteroaryl chlorides
is shown to be an effective strategy to prepare a variety
of compounds. In addition, reactivity profiles of a num-
ber of electron-poor heteroaryl chlorides and 3° amine
substituents were determined. Further applications of
this practical and efficient method will be reported in
due course.
Acknowledgements
The authors thank Jan Waters for technical assistance in
the final analytical characterization of reaction prod-
ucts. G.L.H. thanks the Abbott Summer Internship Pro-
gram for sponsorship.