Preparation of 4-alkyl-2-[N-(tert-butoxycarbonyl)amino]pyridines by alkylation, nucleophilic addition, and acylation of 2-[N-(tert-butoxycarbonyl)amino]-4-picoline

Full text of DOI:10.1021/jo960184t

4
810
J . Org. Chem. 1996, 61, 4810-4811
P r ep a r a tion of
found to be suitable in terms of its stability to anionic
reaction conditions and ease of protecting group removal.
5
4
2
-Alk yl-2-[N-(ter t-bu toxyca r bon yl)a m in o]-
p yr id in es by Alk yla tion , Nu cleop h ilic
Ad d ition , a n d Acyla tion of
Resu lts a n d Discu ssion
-[N-(ter t-Bu toxyca r bon yl)a m in o]-4-p icolin e1
The Boc protection of 2-aminopyridines requires un-
usual acylation conditions. Typically, in halogenated or
ethereal solvents di-tert-butyl dicarbonate reacts to pro-
Nathan C. Ihle* and Amy E. Krause
6
vide significant amounts of N,N′-di-2-pyridylureas. These
Medicinal Chemistry Department, Merck & Co.,
West Point, Pennsylvania 19486
byproducts can be minimized by slow addition of the
aminopyridine to a solution of di-tert-butyl dicarbonate
or, more conveniently, by carrying out the reaction using
tert-butyl alcohol as solvent. Under these conditions, 1
was cleanly protected to provide 2 in 94% yield.
A solution of 2 in THF at -78 °C was treated with 2.5
equiv of n-BuLi, and the resulting solution was allowed
to warm to room temperature for 30 min. Quenching the
2
Received J anuary 29, 1996
As part of an ongoing drug discovery project, we sought
a mild and general method for the preparation of
structurally diverse 4-alkyl-2-aminopyridines. While a
number of simple 2-aminopyridines are commercially
available, methods for preparation of 4-substituted de-
rivatives are limited. The Chichibabin reaction, in which
a pyridine is allowed to react with sodium amide, is
conceptually simple, but the reaction conditions are
harsh.2 A milder approach relies on the nucleophilic
displacement reaction between an amine and a 2-halo-
reaction with D O resulted in clean regeneration of 2 with
7
>95% incorporation of deuterium in the methyl group,
indicating successful formation of the presumed dianion
2a . This dianion has limited solubility in THF (<0.1 M)
and generally precipitates from the bright orange solu-
tion, even at room temperature. In spite of this low
solubility, 2a reacted readily at low temperature after
the reaction flask was returned to a -78 °C bath.
Addition of allyl bromide led to rapid discharge of the
orange color and dissolution of the precipitate. After 5
min, the reaction was quenched and worked up, and
product 3a was isolated in 77% yield.
3
pyridine, but the preparations of 2-halopyridines typi-
cally involve multistep sequences. In this paper we
report a new method for the preparation of 4-alkyl-2-
aminopyridines by the alkylation, nucleophilic addition,
and acylation of 2-[N-(tert-butoxycarbonyl)amino]-4-pi-
coline (2).
To explore the scope of this method, a variety of
electrophiles were investigated (Table 1). In addition to
allyl bromide, benzyl bromide reacted rapidly. In this
1
case, the crude yield of 3b was >90% by H NMR, but
separation from unreacted 2 was difficult. Recrystalli-
zation from hexanes/ethyl acetate provided pure 3b,
albeit in low yield. In addition to the activated halides,
primary alkyl bromides (Table 1, entry 3) and even
epoxides (Table 1, entry 4) will alkylate the dianion of 2,
although higher temperatures and/or longer reaction
times were required. With the epoxide, no sign of the
regioisomeric product was detected.
Carbonyl electrophiles will also react with 2a . Benz-
aldehyde undergoes an addition reaction within 10 min,
providing the alcohol 3e in 63% yield. A clean, selective
acylation was accomplished using a Weinreb amide as
electrophile (Table 1, entry 6).8 In this case, ketone 3f
was isolated and no polyacylation products were detected.
In each condensation reaction, NMR analysis of the
crude product indicated the presence of 10-30% of 2,
along with the expected 3. Because of the high efficiency
of the deprotonation step, as indicated by the deuterium
quench experiment, this suggests inappropriate proto-
nation of 2a prior to its reaction with the carbon elec-
trophiles. The source of this undesirable quenching
remains uncertain.
Our approach is based on methodology reported for the
preparation of 4-alkylpyridines that involves the alky-
lation of the 4-picolyllithium anion. We sought to extend
4
this technology to include 2-amino-4-picolyl anions.
2
-Amino-4-picoline (1) serves as a convenient, com-
mercially available starting material. To facilitate the
anion chemistry, we introduced a protecting group on the
amine nitrogen. The Boc-protected derivative 2 was
The anion chemistry of 2 provides a convenient ap-
proach for the construction of 4-alkyl-2-aminopyridines.
*
To whom correspondence should be addressed. Tel.: (215) 652-
530. Fax: (215) 652-7310. E-mail: nathan ihle@merck.com.
1) Dedicated to Clayton H. Heathcock on the occasion of his 60th
birthday.
4
(5) A phthalimide-protected derivative decomposed under the depro-
tonation conditions. The Boc protecting group is easily removed by
treatment with TFA or anhydrous HCl.
(
(
2) McGill, C. K.; Rappa, A. In Advances in Heterocyclic Chemistry;
(6) Venuti, M. D.; Stephenson, R. A.; Alvarez, R.; Bruno, J . J .;
Strosberg, A. M. J . Med. Chem. 1988, 31, 2136.
Katritzky, A. R., Ed.; Academic Press: San Diego, 1988; Vol. 44, pp
-82. Cislak, F. E. U.S. Patent 2 807 619, 1957; Chem. Abstr. 1958,
2, 2932e. Case, F. H.; Butte, W. A. J . Org. Chem. 1961, 26, 4415.
2
5
(7) Determined by integration of the methyl signal in the 1H-NMR
spectrum.
(
3) Vorbr u¨ ggen, H. In Advances in Heterocyclic Chemistry; Katritzky,
A. R., Ed.; Academic Press: San Diego, 1990; Vol. 49, pp 118-193.
4) Chung, J . Y. L.; Zhao, D.; Hughes, D. L.; Grabowski, E. J . J .
Tetrahedron 1993, 49, 5767.
(8) For an example of acylation of the dianion of 2-[N-(tert-butoxy-
carbonyl)amino]-3-picoline by DMF, see: Clark, R. D.; Muchowski, J .
M.; Fisher, L. E.; Flippin, L. A.; Repke, D. B.; Souchet, M. Synthesis
1991, 871.
(
S0022-3263(96)00184-3 CCC: $12.00 © 1996 American Chemical Society

Notes
J . Org. Chem., Vol. 61, No. 14, 1996 4811
1
Ta ble 1. Alk yla tion of
-[N-(ter t-Bu toxyca r bon yl)a m in o]-4-m eth ylp yr id in e (2)
°C; R
f
0.21 (10% EtOAc/hexanes); H NMR (300 MHz, CDCl
3
) δ
2
8.11 (d, J ) 5 Hz, 1H), 7.79 (s, 1H), 7.40 (br s, 1H), 6.80 (dd, J
5, 1 Hz, 1H), 5.82 (ddt, J ) 13, 10, 7 Hz, 1H), 5.08-4.97 (m,
H), 2.70 (t, J ) 7 Hz, 2H), 2.40 (m, 2H), 1.53 (s, 9H). Anal.
Calcd for C14 : C, 67.76; H, 8.12; N, 11.28. Found: C,
7.72; H, 8.09; N, 11.37.
-[N-(ter t-Bu toxyca r bon yl)a m in o]-4-(2-p h en yleth yl)p y-
)
2
20 2 2
H N O
6
2
r id in e (3b). Following the general procedure, 2 (214 mg, 1.03
mmol) was alkylated with benzyl bromide (184 µL, 1.55 mmol)
for 5 min at -78 °C. The product 3b was inseparable from
unreacted 2 by silica gel chromatography under several condi-
tions, but recrystallization from hot 10% EtOAc/hexanes pro-
vided 3b (67 mg, 22%) as colorless needles: mp 145-148 °C; R
f
1
0
.40 (20% EtOAc/hexanes); H NMR (300 MHz, CDCl
d, J ) 5 Hz, 1H), 7.85 (s, 1H), 7.46 (s, 1H), 7.31-7.17 (m, 5H),
.76 (dd, J ) 5, 1 Hz, 1H), 2.92 (s, 4H), 1.54 (s, 9H). Anal. Calcd
for C18 : C, 72.46; H, 7.43; N, 9.39. Found: C, 72.30;
H, 7.49; N, 9.53.
-[N-(ter t-Bu toxycar bon yl)am in o]-4-[4-(tetr ah ydr opyr an -
3
) δ 8.10
(
6
22 2 2
H N O
2
2
2
-yloxy)bu tyl]p yr id in e (3c). Following the general procedure,
(211 mg, 1.01 mmol) was alkylated with 1-bromo-3-(tetrahy-
dropyranyloxy)propane (340 mg, 1.5 mmol) for 90 min at -78
to -50 °C. Flash chromatography (20 × 150 mm silica, 20%
EtOAc/hexanes) provided 3c (235 mg, 66%) as a white crystalline
1
material: mp 80-81 °C; R
300 MHz, CDCl
H), 6.79 (d, J ) 5 Hz, 1H), 4.57 (m, 1H), 3.86 (m, 1H), 3.76 (dt,
J ) 10, 6 Hz, 1H), 3.50 (m, 1H), 3.40 (dt, J ) 10, 7 Hz, 1H), 2.63
t, J ) 7 Hz, 2H), 1.90-1.50 (m, 10H), 1.53 (s, 9H). Anal. Calcd
for C19 : C, 65.12; H, 8.63; N, 7.99. Found: C, 65.39;
H, 8.58; N, 7.99.
-[N-(ter t-Bu t oxyca r b on yl)a m in o]-4-(3-h yd r oxyb u t yl)-
f
0.20 (20% EtOAc/hexanes); H NMR
(
1
3
) δ 8.10 (d, J ) 5 Hz, 1H), 7.78 (s, 1H), 7.33 (s,
(
30 2 4
H N O
2
p yr id in e (3d ). Following the general procedure, 2 (255 mg, 1.23
mmol) was alkylated with propylene oxide (130 µL, 1.8 mmol)
for 150 min at -78 °C. Flash chromatography (20 × 150 mm
a
b
Isolated yield after chromatography. Isolated yield after
c
recrystallization. This reaction was allowed to warm to -50 °C
over a period of 90 min.
silica, 50% EtOAc/hexanes) provided 3d (187 mg, 57%) as a
1
white solid: mp 123-125 °C; R
f
0.26 (50% EtOAc/hexanes); H
Alkylations can be carried out with activated or unacti-
vated alkyl halides and epoxides. Addition to benzalde-
hyde and acylation by a Weinreb amide are also efficient.
Advantages of this route over existing preparative meth-
ods include relatively mild conditions, high efficiency, and
a minimal number of reaction steps. The application of
this methodology in the preparation of new bioactive
molecules will be described in due course.
NMR (300 MHz, CDCl ) δ 8.57 (s, 1H), 8.17 (d, J ) 5 Hz, 1H),
3
7.85 (s, 1H), 6.81 (d, J ) 5 Hz, 1H), 3.83 (m, 1H), 2.82-2.61 (m,
2
H), 1.82-1.75 (m, 2H), 1.54 (s, 9H), 1.24 (d, J ) 6 Hz, 3H).
Anal. Calcd for C14
Found: C, 62.87; H, 8.24; N, 10.55.
-[N -(t er t -B u t o x y c a r b o n y l)a m in o ]-4-(2-h y d r o x y -2-
22 2 3
H N O : C, 63.14; H, 8.33; N, 10.52.
2
p h en yleth yl)p yr id in e (3e). Following the general procedure,
2 (222 mg, 1.07 mmol) was alkylated with benzaldehyde (163
µL, 1.6 mmol) for 10 min at -78 °C. Flash chromatography (10
×
150 mm silica, 30% EtOAc/hexanes) provided 3e (213 mg,
3%) as a white solid: mp 124-126 °C; R 0.20 (30% EtOAc/
) δ 8.13 (d, J ) 5 Hz, 1H),
.90 (s, 1H), 7.76 (s, 1H), 7.40-7.26 (m, 5H), 6.79 (dd, J ) 5, 1
Hz, 1H), 4.97 (m, 1H), 3.02-2.99 (m, 2H), 1.99 (d, J ) 3 Hz,
H), 1.54 (s, 9H). Anal. Calcd for C18 : C, 68.77; H, 7.05;
N, 8.91. Found: C, 68.90; H, 7.00; N, 8.90.
-[N-(ter t-Bu toxyca r bon yl)a m in o]-4-(2-oxo-2-p h en yleth -
yl)p yr id in e (3f). Following the general procedure, 2 (212 mg,
.02 mmol) was acylated with N-methoxy-N-methylbenzamide
6
f
Exp er im en ta l Section
1
hexanes); H NMR (300 MHz, CDCl
7
3
2
-[N-(ter t-Bu toxyca r bon yl)a m in o]-4-m eth ylp yr id in e (2).
A solution of 2-amino-4-methylpyridine (1, 5.01 g, 46.4 mmol)
in 100 mL of melted t-BuOH was treated with di-tert-butyl
dicarbonate (11.1 g, 51 mmol). After the solution was stirred
overnight, the solvent was evaporated, and the residue was
purified by flash filtration (50 × 150 mm silica, CHCl
as a white crystalline material (8.85 g, 94%). Recrystallization
from hot 10% EtOAc/hexanes provided analytically pure colorless
needles: mp 118-119 °C; R
CDCl ) δ 8.80-8.55 (br s, 1H), 8.16 (dd, J ) 5, 1 Hz, 1H), 7.82
s, 1H), 6.78 (d, J ) 5 Hz, 1H), 2.34 (s, 3H), 1.54 (s, 9H). Anal.
Calcd for C11 : C, 63.44; H, 7.74; N, 13.45. Found: C,
3.57; H, 7.69; N, 13.45.
Rep r esen ta tive P r oced u r e for Dia n ion Rea ction : 2-[N-
ter t-Bu toxyca r bon yl)a m in o]-4-(3-bu ten -1-yl)p yr id in e (3a ).
A solution of 2 (227 mg, 1.09 mmol) in 10 mL of THF was cooled
in a -78 °C bath. n-BuLi (1.6 M in hexanes, 1.7 mL, 2.7 mmol)
was added during 1 min, and then the cooling bath was removed.
After 30 min at room temperature, the orange suspension was
returned to the -78 °C bath. Allyl bromide (140 µL, 1.6 mmol)
was added, and after 5 min, the reaction was quenched by the
1
22 2 3
H N O
2
3
), providing
1
2
(
0.23 mL, 1.5 mmol) for 15 min at -78 °C. Flash chromatog-
1
raphy was not effective in separating product from excess
acylating reagent, but recrystallization from 20% EtOAc/hexanes
f 3
0.15 (CHCl ); H NMR (300 MHz,
3
provided 3f as colorless needles (186 mg, 58%): mp 163-165
(
1
°
8
(
C; R
f
0.52 (40% EtOAc/hexanes); H NMR (300 MHz, CDCl
3
) δ
16 2 2
H N O
.35 (s, 1H), 8.23 (d, J ) 5 Hz, 1H), 8.00 (d, J ) 7 Hz, 2H), 7.93
s, 1H), 7.59 (t, J ) 7 Hz, 1H), 7.48 (t, J ) 8 Hz, 2H), 6.87 (dd,
J ) 5, 1 Hz, 1H), 4.29 (s, 2H), 1.53 (s, 9H). Anal. Calcd for
: C, 69.21; H, 6.45; N, 8.97. Found: C, 69.19; H,
6
(
18 20 2 3
C H N O
6
.47; N, 8.99.
Ack n ow led gm en t. The authors acknowledge Dr.
Mark E. Duggan for helpful discussions, the West Point
analytical chemistry group for combustion analyses, and
Ms. J . Kaysen for assistance in the preparation of this
manuscript.
addition of HOAc in Et
diluted with EtOAc, and then washed with water and brine,
dried over MgSO , filtered, and concentrated. Flash chroma-
tography (20 × 150 mm silica, 10% EtOAc/hexanes) provided
a (207 mg, 77%) as a white crystalline solid: mp 106-108.5
2
O. The mixture was warmed to rt,
4
3
J O960184T