Synthesis of aminopyridines via an unprecedented nucleophilic aromatic substitution of cyanopyridines

Article abstract of DOI:10.1016/j.tetlet.2004.01.120

The direct reaction of 2- and 4-cyanopyridines with lithium amides affords good yields of the corresponding aminopyridines via displacement of cyanide. Addition of CsF accelerates the reaction and can lead to significantly higher yields.

Full text of DOI:10.1016/j.tetlet.2004.01.120

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 2667–2669
Synthesis of aminopyridines via an unprecedented nucleophilic
aromatic substitution of cyanopyridines
Jonathan M. Penney*
DSM Pharma Chemicals R&D, 5900 NW Greenville Blvd, Greenville, NC 27834, USA
Received 24 October 2003; revised 5 December 2003; accepted 23 January 2004
Abstract—The direct reaction of 2- and 4-cyanopyridines with lithium amides affords good yields of the corresponding amino-
pyridines via displacement of cyanide. Addition of CsF accelerates the reaction and can lead to significantly higher yields.
Ó 2004 Elsevier Ltd. All rights reserved.
While the study of carbon–carbon bond activation has
N
N
received much attention, it has led to only limited syn-
thetic success.1 Recently it has been shown that the
C–CN bond of benzonitriles can be broken by various
nickel complexes.2 Furthermore, catalytic activation of
a C–CN bond has been employed by us in cross-cou-
pling chemistry.3 Recently we described the nickel-cat-
alyzed amination of benzonitriles with lithium amides
promoted by cesium salts.3a It was initially observed that
reaction of 2- and 4-cyanopyridine with lithium amides
proceeded smoothly and in good yield in the presence of
a nickel catalyst and CsF additive. Through control
reactions it was discovered that the amination of 2- and
4-cyanopyridine also proceeded to a small extent in the
absence of catalyst and additive. Further study of this
reaction showed that addition of the nickel catalyst
without CsF failed to improve the uncatalyzed yield.
Addition of CsF without the nickel catalyst, however,
led to high yields of the desired amination product.
CsF
THF
CN
CN
+
R2NLi
NR2
NR2
CsF
THF
+
N
R2NLi
N
R=alkyl, aryl
Scheme 1. Amination of 2- and 4-cyanopyridine by lithium amides.
of 4-pyrrolidinopiperidine (1.6 mmol).5 Attempts to
couple primary amines in this same manner led to
mixtures of secondary and tertiary amination products
due to addition of the amine to multiple cyanopyridines.
2-Cyanopyridine reacts with lithium amides more slowly
than 4-cyanopyridine to give the corresponding amino-
pyridine. 3-Cyanopyridine, however, does not react to
give any amination products.6 In most cases complete
conversion of the limiting reagent, 2- or 4-cyanopyr-
idine, was observed even when the yield of aminopyr-
idine was low. The fate of the balance of cyanopyridine
is unclear, although it is reasonable to suspect it may lie
in oligomerized products.7
While a variety of substitution reactions of halogens on
halopyridines are known,4 the corresponding substitu-
tion of cyanide ion from cyanopyridines is not. The
scope of this amination reaction is illustrated in Table 1
and Scheme 1. Lithium amides prepared from secondary
amines react with 2- and 4-cyanopyridines in moderate
to good yields. For example, reaction of 4-cyanopyr-
idine (2.0 mmol) with lithium pyrrolidide (4.0 mmol,
prepared in situ from pyrrolidine and n-BuLi) and CsF
(3.0 mmol) in THF at 65 °C for 2 h led to the formation
Amidine formation, illustrated in Scheme 2, is immedi-
ate upon addition of lithium amide to a solution of
cyanopyridine as evidenced by a sudden color change of
the reaction mixture.8 Whether this is a true inter-
mediate in the amination reaction is unknown.
The role of the additive in this reaction is twofold. In
most cases, addition of CsF leads to a sharp increase in
rate of reaction. In some cases, especially with 2-
cyanopyridine, addition of CsF also leads to a large
Keywords: Amination; Cyanopyridine.
* Tel.: +1-252-355-7383; fax: +1-252-707-2568; e-mail: jpenney913@
yahoo.com
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.01.120

2668
J. M. Penney / Tetrahedron Letters 45 (2004) 2667–2669
Table 1. Amination of 2- and 4-cyanopyridine with lithium amidesa
Yieldb, % (time)c
W/CsF W/out CsF
Entry
1
Cyanopyridine
Amide
LiN
Product
85 (2)
80 (2)
98 (2)
92 (4)
29 (27)
98 (5)
N
CN
N
N
2
3
LiN
N
N
N
N
LiN
4
5
6
44 (1.5)
28 (2.5)
79 (22)
42 (1.5)
31 (2.5)
42 (22)
LiN
N
N
N
N
N
N
N
Li
Ph
Et
LiNMe2
LiNEt2
N
N
N
N
7
8
66 (2)
74 (2)
56 (<20)d
Et
Bu
LiNBu2
N
N
58 (6)
Bu
N
N
9
65 (<23)d
60 (<29)d
23 (23)
23 (29)
LiN
LiN
CN
N
N
N
N
10
11
12
13
14
74 (47)
87 (4)
34 (95)
LiN
LiN
N
N
N
N
N
N
54 (8)
N
O
Ph
N
N
N
N
O
Ph
69 (<48)d
52 (6)
22 (<48)d
82 (<29)d
LiN
LiNMe2
N
Et
Et
15
LiNEt2
24 (6)
0 (6)
N
a All reactions were carried out with stoichiometries, catalyst loadings, etc., as illustrated in the representative procedures.12;13
b Chemical yields are by GC analysis using an internal reference standard and based on cyanopyridine. Starting cyanopyridine and amidine inter-
mediate adduct were consumed in all cases.
c Reaction time indicates the time required for full conversion of the cyanopyridine or amidine intermediate by GC analysis.
d The actual time needed for full conversion of cyanopyridine or amidine intermediate was not determined in this run.

J. M. Penney / Tetrahedron Letters 45 (2004) 2667–2669
2669
N- M+
NR2
1997, 532, 267; (c) Morvillo, A.; Turco, A. J. Organomet.
Chem. 1981, 208, 103.
3. (a) Miller, J. A.; Dankwardt, J. W.; Penney, J. M.
Synthesis 2003, 11, 1643; (b) Miller, J. A.; Dankwardt,
J. W. Tetrahedron Lett. 2003, 44, 1907; (c) Miller, J. A.
Tetrahedron Lett. 2001, 42, 6991.
+
N
CN
R2NM
N
M = Li or Cs
4. Dunn, A. D.; Norrie, R. J. Heterocycl. Chem. 1987, 24, 85,
and references therein.
5. These results were obtained by GC analysis of a reaction
sample (containing tridecane as an internal standard)
quenched in a mixture of 1 M sodium citrate (aq) and
MTBE.
N
NR2
Scheme 2. Formation of the amidine.
6. Nucleophiles preferentially react with the 2- and 4-
positions of pyridine electrophiles, see: (a) Sugimori, A.;
Furihata, T.; Mikayama, S.; Yoshida, M.; Nakanishi, Y.
Bull. Chem. Soc. Jpn. 1982, 55, 2906; (b) Wagenknecht, P.
S.; Penney, J. M.; Hembre, R. T. Organometallics 2003,
increase in yield. The amount of CsF necessary was
optimized at 1.5 equiv based on cyanopyridine. Yields of
amination product and rates of reaction drop signifi-
cantly with use of less CsF; below 0.25 equiv no
enhancements are observed. Other alkali metal salts,
such as Cs2CO3 and KF, are also effective in increasing
the rate and yield of this reaction.9 It appears that
exchange of counterions between the amide and additive
creates a more reactive amide, although there are cases
where having no modifier in the reaction actually gave
better results (entry 14).
ꢀ ꢀ
22, 1180; (c) Le Gall, E.; Gosmini, C.; Nedelec, J.-Y.;
ꢀ
Perichon, J. Tetrahedron 2001, 57, 1923; (d) Ref. 4.
7. Polymerization, oligomerization, and cyclotrimerization
of organonitriles are known to occur in the presence of
various metal salts, see: Kabanov, V. A.; Zubov, V. P.;
Kovaleva, V. P.; Kargin, V. A. J. Polym. Sci. C 1964, 4,
1009.
8. Stability of the cyanopyridine amidines toward aqueous
workup is variable, in contrast to amidines derived from
simple benzonitriles, making quantification of the amidine
concentration during the course of the reaction trouble-
some.
9. For example the reaction of lithium 1-methylpiperazide
with 2-cyanopyridine (entry 11) in the presence of various
modifiers shows: CsF (74% yield, 47 h), Cs2CO3 (48%
yield, 71 h), KF (72% yield, 71 h), no modifier (34% yield,
94 h).
10. For recent reviews, see: (a) Hartwig, J. F. Angew. Chem.,
Int. Ed. 1998, 37, 2046; (b) Muci, A. R.; Buchwald, S. L.
Top. Curr. Chem. 2002, 219, 131.
Polarity of the solvent also plays a role in this reaction.
Polar solvents such as THF, DME, and 1,4-dioxane
gave similar, good yields of amination products. Less
polar solvents such as iPr2O and toluene gave low yields
even at long reaction times.
There are distinct advantages of this direct reaction
between lithium amides and cyanopyridines versus the
increasingly common Ni and Pd catalyzed amination of
aryl halides.10 Obviously, cost savings arise from elimi-
nating the need for transition-metal catalysts. It should
also be noted that cyanopyridines are significantly less
expensive than the corresponding halopyridines.11
11. 2003–2004 Aldrich prices for 2-cyanopyridine ($13/mol),
2-chloropyridine ($16/mol), 2-bromopyridine ($68/mol), 2-
iodopyridine ($2500/mol).
12. Representative procedure with CsF: (4-pyrrolidinopyri-
dine, entry 2). A 0 °C solution of pyrrolidine (0.334 mL,
0.284 g, 4.0 mmol, Aldrich) in 4 mL of THF was treated
with n-butyllithium (1.6 mL, 4.0 mmol, 2.5 M in hexanes)
and allowed to warm to room temperature for 15 min. The
reaction solution was cooled to 0 °C and a solution of 4-
cyanopyridine (0.244 g, 2.0 mmol) and tridecane
(0.244 mL, 0.184 g, 1.0 mmol, internal GC standard) in
THF (1 mL) was added. After warming to room temper-
ature the entire reaction mixture was added to solid cesium
fluoride (0.456 g, 3.0 mmol) and heated to 65 °C for 2 h. A
sample was withdrawn and quenched in a mixture of 1 M
sodium citrate (aq) and MTBE. GC analysis of the organic
phase of the hydrolyzed reaction sample showed the
presence of 1.6 mmol (80% yield) of 4-pyrrolidinopyridine.
13. Representative procedure without CsF: (4-piperidinopyr-
idine, entry 1). A 0 °C solution of piperidine (0.396 mL,
0.341 g, 4.0 mmol, Aldrich) in 4 mL of THF was treated
with n-butyllithium (1.6 mL, 4.0 mmol, 2.5 M in hexanes)
and allowed to warm to room temperature for 15 min.
The reaction solution was cooled to 0 °C and a solution
of 4-cyanopyridine (0.244 g, 2.0 mmol) and tridecane
(0.244 mL, 0.184 g, 1.0 mmol, internal GC standard) in
THF (1 mL) was added and the mixture was heated to
65 °C for 4 h. A sample was withdrawn and quenched in a
mixture of 1 M sodium citrate (aq) and MTBE. GC
analysis of the organic phase of the hydrolyzed reaction
sample showed the presence of 1.83 mmol (92% yield) of
4-piperidinopyridine.
In conclusion, the direct substitution of 2- and 4-
cyanopyridine with lithium amides through a novel
uncatalyzed activation of a C–C bond provides a simple
and cost-effective method for preparation of amino-
pyridines.
Acknowledgements
The author would like to thank J. A. Miller (DSM
Pharma Chemicals) and Professor B. M. Trost (Stan-
ford University) for helpful discussions concerning this
work.
References and notes
1. For recent reviews, see: (a) Jun, C.-H.; Moon, C. W.; Lee,
D.-Y. Chem. Eur. J. 2002, 8, 2422; (b) Milstein, D.;
Rybtchinski, B. Angew. Chem., Int. Ed. 1999, 38, 870, and
references cited therein.
2. (a) Garcia, J. J.; Jones, W. D. Organometallics 2000, 19,
5544; (b) Abla, M.; Yamamoto, T. J. Organomet. Chem.