A convenient synthesis of 2-(alkylamino)pyridines

Article abstract of DOI:10.1021/jo020057z

The synthesis of a series of 2-(alkylamino) pyridines (1) in three steps from 2-aminopyridine (4) is reported. The products were obtained in 67-91% overal yield from 4.

Full text of DOI:10.1021/jo020057z

CHART 1
A Con ven ien t Syn th esis of
2-(Alk yla m in o)p yr id in es
Douglas M. Krein and Todd L. Lowary*
Department of Chemistry, The Ohio State University,
Columbus, Ohio 43210
lowary.2@osu.edu
Received J anuary 24, 2002
SCHEME 1a
Abstr a ct: The synthesis of a series of 2-(alkylamino)-
pyridines (1) in three steps from 2-aminopyridine (4) is
reported. The products were obtained in 67-91% overall
yield from 4.
The asymmetric reduction of prochiral ketones by a
complex formed from lithium aluminum hydride, (1R,2S)-
(-)-N-methylephedrine, and 2-(ethylamino)pyridine (1a ,
Chart 1) is a useful method for the synthesis of optically
pure secondary alcohols.1,2 In the course of other inves-
tigations, we had the need to carry out this reduction
on large scale and thus required significant quantities
of 1a .
a
(a) HCO2H, Ac2O, 0 °C f rt, 73%; (b) CH3CH2I, NaH, DMF,
0 °C f rt 85%; (c) 6 N HCl, 100 °C, 90%.
When choosing among the methods reported for the
preparation of 1a ,1,3,4 it appeared to us that the most
straightforward route would be the one illustrated in
Scheme 1, which uses inexpensive 2-aminopyridine (4)
as the starting material.1 Thus, 4 was treated with acetic
anhydride and formic acid5 to provide the N-formyl
derivative 5 in 73% yield.6 This product was then
alkylated by reaction with sodium hydride and ethyl
iodide affording 6 (85%). Deformylation of 6 by acid
hydrolysis gave 1a in 90% yield. Although the product
could be obtained by this route, the modest yield of the
formylation step, and its problematic purification by
distillation (the distillate often solidified in the con-
denser), led us to explore an alternate route to 1a . We
report here that substitution of 5 with the readily
available N-Boc-protected 2-aminopyridine derivative 2
allows for the efficient preparation of 1a and other
2-(alkylamino)pyridines in high overall yield.
SCHEME 2a
a
(a) (Boc)2O, t-BuOH, rt, 98%.
Alkylation of 2 with various alkyl halides proceeded
efficiently upon treatment with sodium hydride in DMF
(Table 1). The yields of products (3, Chart 1) were, with
one exception, uniformly excellent; only isopropyl iodide
afforded the corresponding alkylated derivative (3d ) in
less than 90% yield. Following purification of 3a -e by
chromatography, cleavage of the Boc group was achieved
by treatment with TFA in CH2Cl2 containing a small
amount of water. In terms of overall efficiency from 4,
compounds 1a -1c and 1e are obtained in yields of 85%
or better. A similar yield of 1a was also obtained when
the crude reaction mixture obtained after the alkylation
of 2 with ethyl iodide was directly treated with TFA/
water in CH2Cl2 (Table 1, entry 6).
To summarize, we describe here an efficient route for
the preparation of 2-(alkylamino)pyridines from 2-ami-
nopyridine (4) via the readily accessible intermediate 2.
Advantages of this route over the one shown in Scheme
1 are (1) the cumbersome purification of the N-formyl
derivative 5 is avoided and (2) the protected aminopyri-
dine intermediate (2) is a solid that can be readily
recrystallized from the crude reaction mixture following
its preparation. Furthermore, the overall yields of the
final products are, in general, higher than those reported
by other methods.1,3,4,8
The preparation of carbamate 2 was achieved by
reaction of 4 with Boc anhydride in tert-butyl alcohol
(Scheme 2).7 Following evaporation of the solvent, the
crude solid was recrystallized from isopropyl alcohol,
providing 2 in 90% yield. Evaporation of the mother
liquors and chromatography of the resulting oil provided
additional product, giving 2 in a 98% total yield.
(1) Kawasaki, M.; Suzuki, Y.; Terashima, S. Chem. Lett. 1984, 239.
(2) Daverio, P.; Zanda, M. Tetrahedron: Asymmetry 2001, 12, 2225.
(3) Kemal, O¨ .; Reese, C. B. J . Chem. Soc., Perkin Trans. 1 1981,
1569.
(4) Watanabe, Y.; Morisaki, Y.; Kondo, T.; Mitsudo, T. J . Org. Chem.
1996, 61, 4214.
(5) Sheehan, J . C.; Yang, D.-D. H. J . Am. Chem. Soc. 1958, 80, 1154.
(6) An alternate formylation method, involving heating 4 in formic
acid at reflux (Tschitschibabin, A. E.; Knunjanz, I. L. Chem. Ber. 1931,
64, 2841) provided 5 in only a 43% yield.
(7) Venuti, M. C.; Stephenson, R. A.; Alvarez, R.; Bruno, J . J .;
Strosberg, A. M. J . Med. Chem. 1988, 31, 2136.
10.1021/jo020057z CCC: $22.00 © 2002 American Chemical Society
Published on Web 05/17/2002
J . Org. Chem. 2002, 67, 4965-4967
4965

TABLE 1. Alk yla tion of 2 a n d Su bsequ en t Dep r otection
alkylation
yield (%)a
alkylation
product
deprotection
yield (%)a
final
product
overall yield
from 2 (%)
entry
RX
1
2
3
4
5
6
CH3CH2I
CH3I
CH3CH2CH2I
(CH3)2CHI
PhCH2Br
CH3CH2I
95
91
94
74
96
-
3a
3b
3c
3d
3e
-
97
95
96
93
97
-
1a
1b
1c
1d
1e
1a
92
87
90
69
93
88b
a
b
Isolated yield following chromatography. Overall yield when intermediate alkylated Boc derivative (3a ) is not purified.
(vigorous stirring is required to keep the suspension fluid). Upon
complete addition, the suspension was stirred vigorously for an
additional 20 min while maintaining the temperature below 5
°C and then ethyl iodide (1.79 g, 11.5 mmol) was added dropwise.
After stirring for 30 min, the reaction mixture was brought to
room temperature over a 1 h period, before water (5 mL) was
added. The mixture was then diluted with water (20 mL) and
Et2O (100 mL). The organic layer was separated and extracted
with water, 0.1 M HCl, a sat. aqueous NaHCO3 solution, and
brine, before being dried and concentrated. The resulting residue
was then purified by chromatography (hexanes/EtOAc, 4:1) to
afford 6 (1.28 g, 85%) as a clear, colorless oil. Rf 0.29 (hexanes/
EtOAc, 2:1); IR νmax (neat): 3059, 2976, 1679, 1589, 1477, 1442
Exp er im en ta l Section
Gen er a l. Solvents were distilled from the appropriate drying
agents before use. Unless stated otherwise, all reactions were
carried out under
a positive pressure of argon and were
monitored by TLC on silica gel 60 F254 (0.25 mm, E. Merck).
Spots were detected under UV light. Solvents were evaporated
under reduced pressure and below 40 °C (bath). Organic solu-
tions of crude products were dried over anhydrous MgSO4.
Column chromatography was performed on silica gel 60 (40-
60 µM). The ratio between silica gel and crude product ranged
from 100 to 50:1 (w/w). Melting points are uncorrected. 1H NMR
spectra were recorded at 500.12 MHz and chemical shifts are
referenced to TMS (0.00 ppm). 13C NMR spectra were recorded
at 125.75 MHz and 13C chemical shifts are referenced to CDCl3
(77.0 ppm). Electrospray mass spectra were recorded on samples
suspended in 1:1 THF:MeOH containing NaCl. Elemental
analyses were carried out in house.
1
cm-1; H NMR (500 MHz, CDCl3, δ) 9.19 (s, 1 H), 8.41 (ddd, 1
H, J ) 4.9, 1.9, 0.7 Hz), 7.73 (ddd, 1 H, J ) 8.4, 7.2, 1.9 Hz),
7.12 (ddd, 1 H, J ) 7.2, 4.9, 0.7 Hz), 7.04 (ddd, 1 H, J ) 8.4, 0.7,
0.7 Hz), 4.00 (q, 2 H, J ) 7.2 Hz), 1.24 (t, 3 H, J ) 7.2 Hz); 13C
NMR (125 MHz, CDCl3, δ) 161.9, 153.4, 148.8, 138.5, 120.2,
112.4, 37.0, 13.0. Anal. Calcd for C8H10N2O: C, 63.98; H, 6.71.
Found: C, 63.93; H, 6.99. HRMS (ESI) calcd for (M + Na+)
C8H10N2O: 173.0685. Found: 173.0695.
2-(F or m yla m in o)p yr id in e (5). To an ice-cooled solution of
dry formic acid, 99% (115.07 g, 2.50 mol), was added 2-aminopy-
ridine (23.53 g, 0.25 mol) in portions. Caution: This process is
very exothermic and should be performed with care. This
solution was then cooled to 0 °C with vigorous stirring while
Ac2O (38.28 g, 0.38 mol) was slowly added over 1 h at such a
rate that the internal temperature never exceeded 10 °C. Upon
complete addition, the mixture was brought to room temperature
and allowed to stir for 48 h. The mixture was then diluted with
water (100 mL) and Et2O (500 mL). The organic layer was
separated and extracted with water, a sat. aqueous NaHCO3
solution, and brine, before being dried and concentrated. The
resulting residue was then purified by vacuum distillation to
afford 5 (22.28 g, 73%) as a clear, colorless oil that immediately
solidified to a white solid upon cooling. Note: During the
distillation, the distillate may solidify in the condenser. Rf 0.35
(hexanes/EtOAc, 1:1); mp 70-71 °C [lit.6 mp 71 °C]; IR νmax
(KBr): 3265, 3059, 2968, 1700, 1588, 1462 cm-1. All peaks in
2-(Eth yla m in o)p yr id in e (1a ). Compound 6 (1.0 g, 6.7 mmol)
was dissolved in 6 M HCl (10 mL) and heated at reflux for 6 h.
The mixture was cooled to room temperature, carefully neutral-
ized with 3 M NaOH to pH ∼ 9, and then diluted with Et2O
(100 mL). The organic layer was separated and extracted with
water and brine before being dried and concentrated. The
resulting residue was purified by chromatography (hexanes/
EtOAc, 4:1) to afford 1a (0.74 g, 90%) as a clear, colorless oil. Rf
0.36 (hexanes/EtOAc, 2:1); IR νmax (neat): 3263, 3088, 2971,
1603, 1515, 1447 cm-1; 1H NMR (500 MHz, CDCl3, δ) 8.07 (ddd,
1 H, J ) 5.0, 2.0, 0.8 Hz), 7.40 (ddd, 1 H, J ) 8.4, 7.1, 2.0 Hz),
6.54 (ddd, 1 H, J ) 7.1, 5.0, 0.8 Hz), 6.38 (ddd, 1 H, J ) 8.4, 0.8,
0.8 Hz), 4.57 (br. s, 1 H), 3.28 (dq, 2 H, J ) 7.2, 6.3 Hz), 1.25 (t,
3 H, J ) 7.2 Hz); 13C NMR (125 MHz, CDCl3, δ) 158.9, 148.2,
137.4, 112.6, 106.4, 36.9, 14.9. Anal. Calcd for C7H10N2: C, 68.83;
H, 8.25. Found: C, 68.71; H, 8.06. HRMS (ESI) calcd for (M +
H+) C7H10N2: 123.0917: Found: 123.0919.
1
the H and 13C NMR spectra were doubled. This is presumably
1
due to restricted rotation about the amide bond. H NMR (500
MHz, CDCl3, δ) 10.20 (br. s, 1 H), 9.99 (br. s, 1 H), 9.34 (d, 1 H,
J ) 10.6 Hz), 8.54 (s, 1 H), 8.34 (br. t, 2 H, J ) 5.0 Hz), 8.27 (d,
1 H, J ) 8.4 Hz), 7.75 (dt, 1 H, J ) 9.0, 1.8 Hz), 7.68 (dt, 1 H,
J ) 7.8, 1.8 Hz), 7.12-7.05 (m, 2 H), 6.94 (d, 1 H, J ) 8.2 Hz);
13C NMR (125 MHz, CDCl3, δ) 163.1, 159.6, 151.1, 151.0, 148.6,
147.4, 138.9, 138.7, 120.2, 119.8, 115.2, 110.6. Anal. Calcd for
C6H6N2O: C, 59.01; H, 4.95. Found: C, 58.96; H, 5.31. HRMS
(ESI) calcd for (M + Na+) C6H6N2O: 145.0372. Found: 145.0373.
2-(F or m yl(eth yl)a m in o)p yr id in e (6). Compound 5 (1.22 g,
10.0 mmol) was dissolved in anhydrous DMF (30 mL), and the
solution was cooled to 0 °C in an ice/water bath. Sodium hydride
(0.50 g, 60% suspension in oil, 12.5 mmol) was added in portions
such that the internal temperature was maintained <5 °C
2-[N-(ter t-Bu toxyca r bon yl)a m in o]p yr id in e (2). To a solu-
tion prepared from freshly distilled tert-butyl alcohol (1.3 L) and
di-tert-butyl dicarbonate (48.02 g, 0.22 mol) was slowly added
2-aminopyridine (18.82 g, 0.20 mol). This mixture was then
allowed to stir for 24 h at 25 °C, and the solvent was then
evaporated to an off-white semisolid. Recrystallization from hot
2-propanol (50 mL) afforded 2 (35 g, 90%) as a white needlelike
solid. The mother liquor was concentrated to an yellow oil that
was purified by chromatography (hexanes/EtOAc, 6:1) giving an
additional 3 g (98% total yield) of 2. Rf 0.44 (hexanes/EtOAc,
4:1); mp 95-97 °C [lit.7 mp 96-97 °C]; IR νmax (KBr): 3184, 2983,
1721, 1591, 1442, 1234, 1063 cm-1; 1H NMR (500 MHz, CDCl3,
δ) 9.28 (br. s, 1 H), 8.34 (ddd, 1 H, J ) 5.0, 1.9, 0.8 Hz), 7.99
(ddd, 1 H, J ) 8.6, 0.8, 0.8 Hz), 7.66 (ddd, 1 H, J ) 8.6, 7.4, 1.9
Hz), 6.94 (ddd, 1 H, J ) 7.4, 5.0, 0.8 Hz), 1.55 (s, 9 H); 13C NMR
(125 MHz, CDCl3, δ) 152.7, 147.8, 146.8, 138.3, 118.1, 112.5, 80.8,
(8) Bernardi, P.; Dembech, P.; Fabbri, G.; Ricci, A.; Seconi, G. J .
Org. Chem. 1999, 64, 641.
4966 J . Org. Chem., Vol. 67, No. 14, 2002

28.4. Anal. Calcd for C10H14N2O2: C, 61.84; H, 7.26. Found: C,
61.89; H, 7.45. HRMS (ESI) calcd for (M + H+) C10H14N2O2:
195.1128. Found: 195.1143.
for C17H20N2O2: C, 71.81; H, 7.09. Found: C, 71.91; H, 7.03.
HRMS (ESI) calcd for (M + H+) C17H20N2O2: 285.1598: Found:
285.1615.
Gen er a l P r oced u r e for Alk yla tion of 2. Compound 2 (1.94
g, 10.0 mmol) was dissolved in anhydrous DMF (30 mL), and
the solution was cooled to 0 °C in an ice/water bath. Sodium
hydride (0.50 g, 60% suspension in oil, 12.5 mmol) was added
in portions such that the internal temperature was maintained
<5 °C (vigorous stirring is required to keep the suspension fluid).
The suspension was stirred vigorously for an additional 20 min
while maintaining the temperature below 5 °C, and then the
alkyl halide (11.5 mmol) was added dropwise. After stirring for
30 min, the reaction mixture was brought to room temperature
over a 1 h, and then water (5 mL) was added. The reaction
mixture was further diluted with water (20 mL) and Et2O (150
mL). The organic layer was separated and extracted with water,
0.1 M HCl, a sat. aqueous NaHCO3 solution, and brine, before
being dried and concentrated. Chromatography (hexanes/EtOAc,
8:1) of the resulting residue afforded the pure product. The
product yields for 3a -e are given in Table 1. This procedure is
amenable to scale-up by 10-fold; however, a mechanical stirrer
should be used to keep the suspension fluid.
Gen er a l P r oced u r e for th e Dep r otection of 3a -e. The
Boc-protected 2-alkylaminopyridine 3 (5.0 mmol) was dissolved
in CH2Cl2 (5 mL) and treated with TFA, (95% aqueous solution,
5.0 mL), and the mixture was allowed to stir overnight. Cau-
tion: the initial mixing is exothermic and should be done with
care. The reaction mixture was then cooled to 0 °C and
neutralized with 3 M NaOH to pH ∼ 12 before being diluted
with Et2O (100 mL). The organic layer was separated and
extracted with water and brine and then dried and concentrated.
The products were purified by chromatography using either
hexanes/EtOAc, 4:1 (1a , 1c, 1d , 1e) or hexanes/EtOAc, 2:1 (1b)
as the eluant. The product yields for 1a -e are given in Table 1.
Note: This procedure is amenable to scale-up by 20-fold;
however, complete deprotection may require up to 48 h.
2-(Eth yla m in o)p yr id in e (1a ). Clear, colorless oil. The spec-
tral and analytical data for this compound were identical to 1a
obtained from 6.
2-(Meth yla m in o)p yr id in e (1b). Clear, colorless oil. Rf 0.18
(hexanes/EtOAc, 2:1); IR νmax (neat): 3268, 3042, 2941, 1603,
1520, 1411, 1330, 1289, 1154 cm-1; 1H NMR (500 MHz, CDCl3,
δ) 8.09 (ddd, 1 H, J ) 5.0, 2.0, 0.8 Hz), 7.42 (ddd, 1 H, J ) 8.4,
7.1, 2.0 Hz), 6.56 (ddd, 1 H, J ) 7.1, 5.0, 0.8 Hz), 6.37 (ddd, 1 H,
J ) 8.4, 0.8, 0.8 Hz), 4.64 (br. s, 1 H), 2.91 (d, 3 H, J ) 5.1 Hz);
13C NMR (125 MHz, CDCl3, δ) 159.7, 148.2, 137.4, 112.7, 106.2,
29.1. Anal. Calcd for C6H8N2: C, 66.64; H, 7.46. Found: C, 66.75;
H, 7.12. HRMS (ESI) calcd for (M + H+) C6H8N2: 109.0760:
Found: 109.0769.
2-[N-(ter t-Bu toxyca r bon yl)-N-eth yla m in o]p yr id in e (3a ).
Clear, colorless oil. Rf 0.53 (hexanes/EtOAc, 4:1); IR νmax (neat):
1
3060, 2977, 1708, 1590, 1472, 1390, 1275, 1148 cm-1; H NMR
(500 MHz, CDCl3, δ) 8.38 (ddd, 1 H, J ) 4.9, 1.9, 0.8 Hz), 7.61
(ddd, 1 H, J ) 8.3, 7.6, 1.9 Hz), 7.59 (ddd, 1 H, J ) 8.3, 0.8, 0.8
Hz), 6.99 (ddd, 1 H, J ) 7.6, 4.9, 0.8 Hz), 3.97 (q, 2 H, J ) 7.0
Hz), 1.52 (s, 9 H), 1.22 (t, 3 H, J ) 7.0 Hz); 13C NMR (125 MHz,
CDCl3, δ) 154.7, 154.1, 147.7, 136.8, 119.9, 119.4, 80.8, 42.0, 28.3,
14.2. Anal. Calcd for C12H18N2O2: C, 64.84; H, 8.16. Found: C,
64.71; H, 8.48. HRMS (ESI) calcd for (M + H+) C12H18N2O2:
223.1441: Found: 223.1439.
2-(P r op yla m in o)p yr id in e (1c). Clear, colorless oil. Rf 0.40
(hexanes/EtOAc, 2:1); IR νmax (neat): 3265, 3087, 2961, 1603,
1515, 1445, 1332, 1292, 1152 cm-1; 1H NMR (500 MHz, CDCl3,
δ) 8.06 (ddd, 1 H, J ) 5.0, 1.9, 0.9 Hz), 7.39 (ddd, 1 H, J ) 8.3,
7.1, 1.9 Hz), 6.53 (ddd, 1 H, J ) 7.1, 5.0, 0.9 Hz), 6.35 (ddd, 1 H,
J ) 8.3, 0.9, 0.9 Hz), 4.62 (br. s, 1 H), 3.21 (dt, 2 H, J ) 7.4, 5.5
2-[N-(ter t-Bu toxycar bon yl)-N-m eth ylam in o]pyr idin e (3b).
Clear, colorless oil. Rf 0.43 (hexanes/EtOAc, 4:1); IR νmax (neat):
1
3060, 2977, 1710, 1590, 1474, 1352, 1279, 1150 cm-1; H NMR
(500 MHz, CDCl3, δ) 8.37 (ddd, 1 H, J ) 4.8, 1.9, 0.8 Hz), 7.66
(ddd, 1 H, J ) 8.3, 0.8, 0.8 Hz), 7.61 (ddd, 1 H, J ) 8.3, 7.1, 1.9
Hz), 6.99 (ddd, 1 H, J ) 7.1, 4.8, 0.8 Hz), 3.40 (s, 3 H), 1.52 (s,
9 H); 13C NMR (125 MHz, CDCl3, δ) 155.3, 154.4, 147.4, 136.8,
119.3, 119.2, 81.1, 34.2, 28.3. Anal. Calcd for C11H16N2O2: C,
63.44; H, 7.74. Found: C, 63.63; H, 7.57. HRMS (ESI) calcd for
(M + H+) C11H16N2O2: 209.1285: Found: 209.1280.
Hz), 1.63 (sextet, 2 H, J ) 7.4 Hz), 0.99 (t, 3 H, J ) 7.4 Hz); 13
C
NMR (125 MHz, CDCl3, δ) 159.0, 148.2, 137.4, 112.6, 106.3, 44.1,
22.8, 11.6. Anal. Calcd for C8H12N2: C, 70.56; H, 8.88. Found:
C, 70.75; H, 8.75. HRMS (ESI) calcd for (M + H+) C8H12N2:
137.1073: Found: 137.1064.
2-(Isop r op yla m in o)p yr id in e (1d ). White solid. Rf 0.49
(hexanes/EtOAc, 2:1); mp 83-85 °C. IR νmax (KBr): 3273, 3023,
2-[N-(ter t-Bu toxycar bon yl)-N-pr opylam in o]pyr idin e (3c).
Clear, colorless oil. Rf 0.55 (hexanes/EtOAc, 4:1); IR νmax (neat):
2959, 1611, 1521, 1488, 1355, 1283, 1150 cm-1 1H NMR (500
;
1
3058, 2969, 1706, 1589, 1471, 1391, 1296, 1147 cm-1; H NMR
MHz, CDCl3, δ) 8.06 (ddd, 1 H, J ) 4.8, 1.8, 0.8 Hz), 7.38 (ddd,
1 H, J ) 8.4, 7.0, 1.8 Hz), 6.52 (ddd, 1 H, J ) 7.0, 4.8, 0.8 Hz),
6.34 (ddd, 1 H, J ) 8.4, 0.8, 0.8 Hz), 4.36 (br. s, 1 H), 3.87
(dsextet, 1 H, J ) 6.4, 5.6 Hz), 1.22 (d, 6 H, J ) 6.4 Hz); 13C
NMR (125 MHz, CDCl3, δ) 158.2, 148.3, 137.3, 112.4, 106.8, 43.0,
23.0. Anal. Calcd for C8H12N2: C, 70.56; H, 8.88. Found: C,
70.27; H, 8.79. HRMS (ESI) calcd for (M + H+) C8H12N2:
137.1073: Found: 137.1069.
(500 MHz, CDCl3, δ) 8.37 (ddd, 1 H, J ) 4.9, 1.9, 0.8 Hz), 7.61
(ddd, 1 H, J ) 8.3, 7.1, 1.9 Hz), 7.55 (ddd, 1 H, J ) 8.3, 0.8, 0.8
Hz), 6.99 (ddd, 1 H, J ) 7.1, 4.9, 0.8 Hz), 3.89 (t, 2 H, J ) 7.4
Hz), 1.62 (sextet, 2 H, J ) 7.4 Hz), 1.52 (s, 9 H), 0.89 (t, 3 H, J
) 7.4 Hz); 13C NMR (125 MHz, CDCl3, δ) 154.9, 154.3, 147.7,
136.8, 120.3, 119.5, 80.7, 48.6, 28.3, 22.2, 11.3. Anal. Calcd for
C13H20N2O2: C, 66.07; H, 8.53. Found: C, 65.83; H, 8.40. HRMS
(ESI) calcd for (M + H+) C13H20N2O2: 237.1598: Found: 237.1609.
2-[N -(t er t -Bu t oxyca r b on yl)-N -isop r op yla m in o]p yr i-
d in e (3d ). Clear, colorless oil. Rf 0.40 (hexanes/EtOAc, 4:1); IR
2-(Ben zyla m in o)p yr id in e (1e). White solid. Rf 0.36 (hex-
anes/EtOAc, 2:1); mp 94-96 °C. IR νmax (KBr): 3225, 3024, 2868,
1600, 1528, 1442, 1334, 1152, 1079 cm-1 1H NMR (500 MHz,
;
ν
max (neat): 3060, 2975, 1700, 1588, 1471, 1392, 1335, 1176 cm-1
;
CDCl3, δ) 8.09 (ddd, 1 H, J ) 4.9, 1.9, 0.9 Hz), 7.38 (ddd, 1 H, J
) 8.4, 7.0, 1.9 Hz), 7.35-7.31 (m, 4 H), 7.28-7.25 (m, 1 H), 6.57
(ddd, 1 H, J ) 7.0, 4.9, 0.9 Hz), 6.35 (ddd, 1 H, J ) 8.4, 0.9, 0.9
Hz), 4.95 (br. s, 1 H), 4.49 (d, 2 H, J ) 5.6 Hz); 13C NMR (125
MHz, CDCl3, δ) 158.7, 148.2, 139.2, 137.4, 128.6, 127.4, 127.2,
113.1, 106.8, 46.3. Anal. Calcd for C12H12N2: C, 78.23; H, 6.56.
Found: C, 78.40; H, 6.68. HRMS (ESI) calcd for (M + H+)
C12H12N2: 185.1073: Found: 185.1062.
1H NMR (500 MHz, CDCl3, δ) 8.47 (ddd, 1 H, J ) 4.9, 2.0, 0.8
Hz), 7.66 (ddd, 1 H, J ) 8.0, 7.4, 2.0 Hz), 7.18 (ddd, 1 H, J )
8.0, 0.8, 0.8 Hz), 7.13 (ddd, 1 H, J ) 7.4, 4.9, 0.8 Hz), 4.53 (septet,
1 H, J ) 6.8 Hz), 1.42 (s, 9 H), 1.26 (d, 6 H, J ) 6.8 Hz); 13C
NMR (125 MHz, CDCl3, δ) 154.3, 154.2, 148.3, 137.0, 123.9,
121.3, 80.3, 49.4, 28.4, 22.4. Anal. Calcd for C13H20N2O2: C,
66.07; H, 8.53. Found: C, 65.81; H, 8.54. HRMS (ESI) calcd for
(M + H+) C13H20N2O2: 237.1598: Found: 237.1597.
2-[N-(ter t-Bu toxycar bon yl)-N-ben zylam in o]pyr idin e (3e).
White solid. Rf 0.57 (hexanes/EtOAc, 4:1); mp 48-50 °C. IR νmax
Ack n ow led gm en t. This work was supported by the
National Science Foundation (CHE-9875163).
(KBr): 3063, 2977, 1696, 1588, 1472, 1388, 1245, 1164 cm-1
;
1H NMR (500 MHz, CDCl3, δ) 8.36 (ddd, 1 H, J ) 4.9, 2.0, 0.8
Hz), 7.66 (ddd, 1 H, J ) 8.3, 0.8, 0.8 Hz), 7.60 (ddd, 1 H, J )
8.3, 7.2, 2.0 Hz), 7.29-7.24 (m, 4 H), 7.21-7.18 (m, 1 H), 6.98
(ddd, 1 H, J ) 7.2, 4.9, 0.8 Hz), 5.19 (s, 2 H), 1.51 (s, 9 H); 13C
NMR (125 MHz, CDCl3, δ) 154.5, 154.3, 147.7, 139.5, 136.9,
128.2, 127.2, 126.7, 119.6, 119.5, 81.3, 50.0, 28.2. Anal. Calcd
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra of 1-3, 5, and 6. This material is available free of
charge via the Internet at http://pubs.acs.org.
J O020057Z
J . Org. Chem, Vol. 67, No. 14, 2002 4967