D. W. Hopper et al. / Tetrahedron Letters 49 (2008) 137–140
139
Table 3.
Cl
S
N
N
HN
N
O
3R4RN
CN
1R2RN
n
Compound
n
NR1R2
NR3R4
Yielda (%)
Temp (°C)
20
21
22
23
24
25
26
27
28
29
30
31
32
33
2
2
2
1
1
1
1
1
1
2
2
2
2
2
Pyrrolidine
Pyrrolidine
Pyrrolidine
Morpholine
N-Methylpiperazine
N-Ethylpiperazine
1-Methyl-1,4-diazepane
Pyrrolidine
Piperidine
Pyrrolidine
Piperidine
Pyrrolidine
Piperidine
1-Methyl-1,4-diazepane
N-Ethylpiperazine
1-Methyl-1,4-diazepane
Pyrrolidine
39
54
58
62
62
94
77
59
45
60
60
50
55
40
120
120
120
70
70
70
70
70
70
110
115
115
75
Morpholine
Thiomorpholine
Thiomorpholine
N-Methylpiperazine
N-Methylpiperazine
Morpholine
N-Methylpiperazine
N-Methylpiperazine
N-Ethylpiperazine
N-Ethylpiperazine
1-Methyl-1,4-diazepane
110
a Isolated yields.
5.2 and 3.0-fold, respectively, higher than morpholine in
the aminolysis of methyl 4-nitrobenzene sulfonate. This
is consistent with our finding that the different amines
displaced the alkyl chloride under similar conditions.
In contrast, the amines with b-heteroatoms were signi-
ficantly less reactive than piperidine and pyrrolidine in
the SNAr reaction at 70 °C. Consistent with this obser-
vation, Caswell and Goldsmith9 have reported that the
uncatalyzed reaction rate constant for morpholine was
106 times less than pyrrolidine and 25 times less than
piperidine in an SNAr reaction with 3-fluoro-N-methyl-
phthalimide in acetonitrile. In this work,9 it was con-
cluded that these rate differences were attributable to
molecular size and basicity, with the smaller, strongly
basic pyrrolidine providing the fastest reaction rates
for the nucleophilic addition and base-catalyzed decom-
position of the Meisenheimer adduct. In contrast, the
less basic morpholine reacted significantly more slowly
in the initial nucleophilic addition step, and apparently
did not show evidence of base catalysis in the decompo-
sition step. We believe that the same factors are respon-
sible for the rate differences observed in our fluoro-
substituted quinoline ring system, which has allowed
us to selectively perform the SN2 displacement reactions
only with the less basic b-heteroatom containing cyclic
amines.
mediate 19 was further reacted with different amines at
C-7 (Scheme 2, Step D) to provide target compounds
20–22 (Table 3).
In conclusion, we observed a divergence in reactivity for
pyrrolidine and piperidine vs amines that contain b
heteroatoms in competing SN2 and SNAr reactions on
substituted quinoline-3-carbonitrile intermediates
5
and 6. By utilizing the appropriate reaction conditions,
we were able to distinguish between SN2 and SNAr reac-
tions and rapidly synthesize a diverse library of 34 target
compounds possessing amine groups attached at C-6
and C-7 to explore the structure–activity relationships
of this series. Several of these analogs proved to be
potent inhibitors of MEK kinase. These results will be
published elsewhere in due course.
Acknowledgments
The authors acknowledge the Wyeth Discovery Analyt-
ical Chemistry Department for providing the spectral
data. Additionally, we thank Dr. Tarek Mansour for
his support.
References and notes
To overcome the lack of selectivity of pyrrolidine and
piperidine with regard to the SN2 and SNAr reactions,
it was necessary to implement a new strategy to provide
the desired target compounds. We hypothesized that C-7
fluoride displacement could be inhibited by adding
sodium hydride to the reaction mixture. The strong base
would deprotonate the quinolinecarbonitrile ring sys-
tem, thereby adding electron density to intermediates 5
and 6, and inhibiting attack by a nucleophile. This
approach proved to be successful using pyrrolidine
(Scheme 2, Step C), providing intermediate 19 (Table
2) in acceptable yield. The pyrrolidine-substituted inter-
1. (a) Zhang, N.; Wu, B.; Powell, D.; Wissner, A.; Floyd, M.
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