2-Aminopyridines via reaction of pyridine N-oxides and activated isocyanides

Article abstract of DOI:10.1021/jo402693s

A practical and efficient method for the synthesis of substituted 2-aminopyridines from pyridine N-oxides is reported. Yields of purified, isolated products of up to 84% are observed for the one-pot, two-step process. The reaction involves an in situ depr

Full text of DOI:10.1021/jo402693s

Note
pubs.acs.org/joc
2‑Aminopyridines via Reaction of Pyridine N‑Oxides and Activated
Isocyanides
Mitchell Vamos* and Nicholas D. P. Cosford*
Cell Death & Survival Networks Program and Conrad Prebys Center for Chemical Genomics, Sanford-Burnham Medical Research
Institute, 10901 North Torrey Pines Road, La Jolla, California 92037, United States
S
* Supporting Information
ABSTRACT: A practical and efficient method for the synthesis
of substituted 2-aminopyridines from pyridine N-oxides is
reported. Yields of purified, isolated products of up to 84% are
observed for the one-pot, two-step process. The reaction
involves an in situ deprotection of an isolable N-formylamino-
pyridine intermediate and facilitates the synthesis of 2-
aminopyridines for which other methods fail.
ubstituted aromatic heterocycles constitute a large portion
of the body of pharmaceutical agents. Within that chemical
resulted in a rich chemical history.10 Given that some pyridine
N-oxide derivatives have shown poor or zero reactivity in prior
methods,4a,11 or were not reported in another,7 we sought to
expand the synthetic arsenal for the synthesis of 2-amino-
pyridines. Also, some previously reported methods yield 2-
aminopyridine amides as products that require harsh conditions
to cleave the amide bond and isolate the desired 2-
aminopyridine derivatives.4,5 Thus, we report here a new
method for the synthesis of 2-aminopyridines by reaction of
activated isocyanides with pyridine N-oxides followed by mild
hydrolysis of the incipient N-formyl-2-aminopyridines.
An initial survey of reaction conditions was conducted with
commercially available methyl isonicotinate N-oxide (1a) and
benzyl isocyanide (2a), shown in Table 1. Microwave
irradiation proved superior to traditional heating in flask, with
a solvent combination of acetonitrile and DMF giving the best
results. Use of DMSO resulted in an isocyanide−DMSO redox
reaction and no product formation (entry 7).12 A variety of
Lewis and Brønsted acids were examined for their ability to
initiate the reaction, which did not occur without the action of
an activator (entry 1). Acyl chlorides such as acetyl chloride
(entry 2) proved only mildly effective, whereas dimethyl sulfate
(entry 6) provided a good level of conversion. Strong Brønsted
acids gave mixed results: while camphorsulfonic acid (CSA,
entry 3) gave virtually zero product conversion, the similar, but
much smaller, analogue methanesulfonic acid (MsOH, entry 4)
gave more promising results. The best results were obtained
with strong silylating agents like trimethylsilyl triflate
(TMSOTf, entries 7−11) and triisopropylsilyl triflate (TIP-
SOTf, not shown). As the initial product formamide 3 was
partially cleaved during workup and purification, it was fully
converted to the amine 4 by mild acidic solvolysis.13 For the
purpose of comparison, the reaction was also run under
S
space exist aminopyridines, which serve as pharmacophores for
many bioactive small molecules in their own right.1 Whereas its
carbon-analogue aniline presents a variety of problematic issues
pharmacologically due to its tendency to be oxidized to a
reactive and toxic nitroso species,2 the heteroaromatic 2-
aminopyridine avoids such problems due to its reduced
oxidation potential, thus rendering it a safer alternative for
drug design. Additionally, 2-aminopyridines possess advanta-
geous absorption and emission spectra and thus have proven
useful as fluorescent tags, particularly in the study of
oligosaccharides.3
It has been previously shown that pyridine N-oxides are
capable of yielding amides of 2-aminopyridines by reaction with
imidoyl chlorides4 or triflates5 and 2-aminopyridines by
reaction with isocyanates (Scheme 1).6 Pyridine N-oxides
Scheme 1. Amination and Amidation of Pyridine N-Oxides
activated with a phosphonium coupling reagent were shown to
react with amines to give 2-aminopyridines by a Reissert−
Henze-type reaction.7 Reissert−Henze-type reactions were also
employed in the synthesis of N-unsubstituted8 and N-triflyl 2-
aminopyridines.9 We were interested in investigating the
unexplored interaction of pyridine N-oxides and isocyanides,
whose unique dual nature of reactivity, their tendency to react
both as nucleophilic carbanions and electrophilic carbenes, has
Received: December 4, 2013
Published: February 3, 2014
© 2014 American Chemical Society
2274
dx.doi.org/10.1021/jo402693s | J. Org. Chem. 2014, 79, 2274−2280

The Journal of Organic Chemistry
Note
Table 1. Optimization of Reaction Conditions*
Table 2. Initial Pyridine N-Oxide Substrate Scope Survey*
e
entry
activator
solvent(s)
relative conversion
1
2
3
4
5
none
3:1 MeCN/DMF
3:1 MeCN/DMF
3:1 MeCN/DMF
3:1 MeCN/DMF
3:1 MeCN/DMF
3:1 MeCN/DMF
DMSO
0
AcCl
0
CSA
0
MsOH
BF3•OEt2
Me2SO4
TMSOTf
TMSOTf
14
6
d
6
35
0
7
f
8
DMF
62 (32%)
a
9
TMSOTf
TMSOTf
TMSOTf
3:1 MeCN/DMF
3:1 MeCN/DMF
3:1 MeCN/DMF
23
b
c
f
10
11
59 (40%)
f
100 (45%)
*
Reaction conditions: 1 equiv of N-oxide, 1 equiv of isocyanide, and 1
equiv of activator in stated solvent in microwave at 150 °C for 15 min,
a
b
c
then 1 M HCl and THF, 50 °C. 0.1 equiv. 0.5 equiv. 1.0 equiv.
d
e
Yields of the methylamide. Relative HPLC yields determined by
peak area analysis of product(s) and N-oxide in crude reaction mixture.
f
Isolated yield in parentheses.
conventional oil bath heating and gave a slightly lower yield
after 4 h.14
Having worked out the optimized reaction conditions, a
survey of substrate scope was initiated using 4-chlorophenyl
isocyanide (2b) and various pyridine N-oxides (Table 2). Yields
were dependent upon the nature of the pyridine N-oxide, with
those bearing electron-withdrawing substituents affording
higher yields (products 6 and 7) than those with less polar
aliphatic groups (product 10) or electron-donating substituents
(products 8 and 11). The low yield (19%) of 4-methoxy-
substituted 8 from the electron-rich pyridine N-oxide 1d is
noteworthy. In addition, the attenuated yield of 3,5-dibromo-N-
(4-chlorophenyl)pyridin-2-amine (11, 41%) may indicate that
coordination of the reactants is sensitive to steric hindrance.
The pyridine N-oxide 1e possessing a 4-carboxaldehyde
substituent proved unstable and/or unreactive and resulted in
degradation of starting material, with reduction of the N-oxide
and aldehyde functional groups evident by LCMS analysis.
Further elucidation of substrate scope was conducted with a
variety of pyridine N-oxides and isocyanides (Table 3). In
general, yields were good (40−76%) with regioselectivity
depending on the nature of both the pyridine N-oxide and the
isocyanide. The 2-aminopyridines arising from aromatic
isocyanides (save for 2d due to sterics) and 1h were produced
in good yields and (generally) favored the 2,3-disubstituted
pyridine (i.e., 12b−14b) by a slight margin (relative to 2,5-
disubstituted 12a−14a). The combination of 3-cyano-sub-
stituted pyridine N-oxide 1h and isocyanide 2b (entry 1)
showed a particularly high bias (3:1) for the 2,3-disubstituted
product 12b, in 74% yield. In general, aliphatic isocyanides
(2a,e−f) tended to give slightly lower yields than their aromatic
counterparts (2b−d). Reaction efficiency also appears to be
dependent upon the degree of steric congestion at the
isocyanide reactive center, which is evident when comparing
products 15 and 16 (entries 4 and 5); appendage of a methyl
group at the benzylic position of the isocyanide resulted in a
lower yield of 16 and increased propensity for the 2,5-
*
Reaction conditions: 1 equiv of N-oxide, 1 equiv of isocyanide, and 1
equiv of TMSOTf in 3:1 MeCN/DMF microwaved at 150 °C for 15
min, then 1 M HCl and THF, 50 °C. No product detected.
a
disubstituted regioisomer. Isocyanides possessing bulky ali-
phatic groups proved ineffective in this procedure; tert-butyl
isocyanide (2g) and diphenylmethyl isocyanide (2h)15 (entries
11 and 12) yielded negligible product when reacted with
pyridine N-oxide 1h. It should be noted that pyridine N-oxides
with electron-withdrawing cyano or nitro substituents, as in 1h
(Table 3), 1c (Table 2, entry 3), and 1k (Table 3, entry 9),
have shown no reactivity in previously published methods
involving isocyanates and imidoyl chlorides as dipolaro-
philes.4a,11
Based on the data in Table 3, some trends can be inferred
concerning the regioselectivity of reaction between 3-
substituted pyridine N-oxides and isocyanides. Pyridine N-
oxides (1h−j) possessing electron-withdrawing substituents
gave a larger proportion of the 2,3-disubstituted isomer (12−
14, 18, 19) when reacted with an aryl isocyanide than would
otherwise be expected based on steric effects alone. Addition-
ally, yields reflected the favorability of this interaction, with the
nearly 2-fold difference in yield of 18 (Table 3, entry 7) and 21
(Table 3, entry 10) proving illustrative. Regioselectivity was
most pronounced for compound 19 (Table 3, entry 8), for
which none of the alternative regioisomer was observed. One
notable exception to the trend, however, is compound 20
2275
dx.doi.org/10.1021/jo402693s | J. Org. Chem. 2014, 79, 2274−2280

The Journal of Organic Chemistry
Note
Table 3. Substrate Scope and Regiochemical Trends
a
Minor amount of product detected after workup, which was not isolated.
(Table 3, entry 9), which favored by a 5:1 margin the 2,5-
disubstituted isomer.
Scheme 2. Possible Reaction Pathways
A plausible reaction mechanism is presented in Scheme 2A.
Addition of the N-oxide to the activated isocyanide A16 would
give imidate intermediate B, from which further reaction can
occur at either C2 or C6 of the activated aromatic ring to give
oxadiazoline C (by reaction at C2). The regioselectivity of this
addition can be rationalized as a balance between the partial
charge distribution about the aromatic ring and steric effects
imposed by the 3-substituent. The nitrile group in the 3-
position of intermediate C has a relatively minor steric impact
(given its linear geometry) on attack of the nucleophile at the
2-position. Thus, given that there is a larger accumulation of
partial positive charge at C2 relative to C6, electrostatic effects
dictate selective formation of the 2,3-isomer 12b. For product
18, although the electron-withdrawing ability of the 3-
carbomethoxy group places a larger partial positive charge at
C2, its greater steric demand (relative to nitrile) shifts the
regioselectivity to favor 2,5-isomer 18a. A similar charge
distribution calculation for the intermediate leading to 21
reveals a much narrower gap between the C2−C6 partial
charges, increasing the importance of the steric effect of the 3-
methyl group and leading to the highest ratio of 2,5-isomer
(21a) in Table 3. A more detailed analysis of these factors is
included as Figure SI-1 in the Supporting Information. The
impact of the size of the isocyanide must be taken into account
as well; a trend in entries 1−6 can be seen such that larger bulk
about the isocyanide reactive center equates to a larger ratio of
2276
dx.doi.org/10.1021/jo402693s | J. Org. Chem. 2014, 79, 2274−2280

The Journal of Organic Chemistry
Note
the 2,5-isomer. Rearomatization would give D, and hydrolysis17
would lead to 2-aminopyridine 12b. Interestingly, the order of
reagent addition proved inconsequential; identical results were
obtained even when the pyridine N-oxide and TMSOTf were
premixed. Also, no reaction was observed at the 4-position of
the pyridine N-oxide, as was demonstrated with the example
shown in Scheme 3.
by a quick Florisil column if necessary (the product tends to elute last
on this adsorbent). Otherwise, the crude product was purified by flash
chromatography on Florisil to yield 4. See specific examples for
purification conditions. In some cases, preparative TLC was used to
separate the 2,3- from the 2,5-isomer. It is possible to substitute 7 M
NH3 in MeOH to cleave the formamide 3 to give 4.
In-Flask Procedure for the 2-Amination of Pyridine N-
Oxides. Pyridine N-oxide 1a (30 mg, 0.196 mmol, 1.0 equiv), benzyl
isocyanide (2a, 24 μL, 0.196 mmol, 1.0 equiv), and TMSOTf (19 μL,
0.196 mmol, 1.0 equiv) in MeCN/DMF (3:1, 0.1 M based on N-
oxide) were heated to 105 °C for 4 h under nitrogen atmosphere. The
crude reaction mixture was concentrated to remove volatile organics
(DMF remains), then 1 M HCl (5 mL) and THF (5 mL) were added,
and the mixture was stirred at 50 °C until complete conversion of
formamide 3 to aminopyridine 4 (see below for analytical data). Ethyl
acetate (15 mL) was added, and the organics were washed with water
(2 × 10 mL) and brine (10 mL), dried over Na2SO4, filtered, and
concentrated in vacuo. Purification involved flash chromatography on
Florisil (DCM → 5% EtOAc/DCM) to give 4 (15 mg, 37%).
Methyl 2-(Benzylamino)isonicotinate (4). 0.196 mmol scale: 21
mg, 45% yield. Purification involved flash chromatography on Florisil
(DCM→5% EtOAc/DCM) to give 4 as a crystalline solid (mp = 118−
120 °C). Rf = 0.24 (5:1 hexanes/EtOAc). 1H NMR (400 MHz,
CD3CN) δ: 8.12 (d, 1H, J = 5.6 Hz), 7.36−7.30 (m, 5H), 7.25 (d, 1H,
J = 6.8 Hz), 6.99 (s, 1H), 6.98 (d, 1H, J = 2.0 Hz), 5.94 (bs, 1H), 4.55
(d, 2H, J = 6.4 Hz), 3.84 (s, 3H). 13C NMR (100 MHz, CD3CN) δ:
166.9, 160.4, 149.8, 141.1, 139.5, 129.4, 128.2, 127.8, 111.9, 108.4,
53.0, 45.8. HRMS calcd for C14H15N2O2 [M + H]+: 243.1128, found
243.1112.
Scheme 3. Failure of a 2,6-Disubstituted Pyridine N-Oxide
To React
An alternative reaction pathway, which consumes 0.5 equiv
of pyridine N-oxide 1l through oxidation of the isocyanide to
isocyanate via F,12,18 could be a minor source of product
formation (Scheme 2B). This pathway would proceed through
cycloaddition with the isocyanate H to ultimately give 2-
aminopyridine 21a after decarboxylation of cycloadduct I. Side
product G, resulting from reduction of the N-oxide, was
observed by LCMS in cases of poor reactivity. However, it is
notable that the use of 2 equiv of pyridine N-oxide in our
reaction afforded no improvement in yield. Also, this alternative
pathway does not give rise to the formamide (ie. 24b, Scheme
2A), which we observed as the major initial product in every
instance (see Figure SI-2A, Supporting Information). Thus, this
pathway is not a major contributor to product formation.
In conclusion, a new method for the synthesis of 2-
aminopyridines from pyridine N-oxides and activated iso-
cyanides has been developed. Isolated yields of purified
products were generally good and a variety of functional
groups were tolerated. Importantly, in contrast with previously
reported methods, substituted pyridines bearing strongly
electron-withdrawing substituents (-NO2, −CN) reacted
efficiently to provide the desired products in good yield.
Reaction output, yield, and regioselectivity were dependent
upon the nature of the starting materials (aliphatic vs aromatic,
presence of electron-donating vs -withdrawing substituents,
substitution pattern), with regioselectivity being controlled by a
combination of steric and electronic factors in the imidate
intermediate.
N-(4-Chlorophenyl)pyridin-2-amine (5). 0.557 mmol scale: 81
mg, 71% yield. Purification involved addition of 5:1 hexanes/EtOAc
and washing with water (3 × 10 mL) and brine (10 mL) The organics
were dried over sodium sulfate and concentrated in vacuo to give 5 as
1
an amorphous solid. Rf = 0.28 (5:1 hexanes/EtOAc). H NMR (400
MHz, CD3CN) δ: 8.16 (dd, 1H, J = 2.0, 5.6 Hz), 7.63 (d, 2H, J = 8.8
Hz), 7.55 (td, 1H, J = 2.0, 8.0 Hz), 7.50 (bs, 1H), 7.27 (d, 2H, J = 8.8
Hz), 6.79−6.75 (m, 2H). 13C NMR (100 MHz, CD3CN) δ: 156.7,
148.3, 141.5, 138.4, 129.4, 125.9, 120.7, 116.0, 111.4. HRMS calcd for
C11H10ClN2 [M + H]+: 205.0527, found 205.0518.
Methyl 2-((4-Chlorophenyl)amino)isonicotinate (6). 0.326
mmol scale: 51 mg, 60% yield. Purification involved addition of 5:1
hexanes/EtOAc with 5% DCM (just enough to dissolve) and washing
with water (3 × 10 mL) and brine (10 mL). The organics were dried
over sodium sulfate and concentrated in vacuo to give 6 as an
amorphous solid. Rf = 0.38 (5:1 hexanes/EtOAc). 1H NMR (400
MHz, CD3CN) δ: 8.29 (dd, 1H, J = 0.4, 5.2 Hz), 7.74 (bs, 1H), 7.65
(d, 2H, J = 9.2 Hz), 7.29 (d, 1H, J = 8.8 Hz), 7.26 (dd, 1H, J = 0.8 1.2
Hz), 7.21 (dd, 1H, J = 1.6, 5.2 Hz), 3.89 (s, 3H). 13C NMR (100 MHz,
CD3CN) δ: 166.6, 157.3, 149.5, 140.9, 139.9, 129.5, 126.6, 121.0,
114.3, 111.1, 53.2. HRMS calcd for C13H12ClN2O2 [M + H]+:
263.0582, found 263.0578.
EXPERIMENTAL SECTION
■
N-(4-Chlorophenyl)-4-nitropyridin-2-amine (7). 0.500 mmol
scale: 83 mg, 67% yield. Purification involved addition of 5:1 hexanes/
EtOAc and washing with water (3 × 10 mL) and brine (10 mL). The
organics were dried over sodium sulfate and concentrated in vacuo.
The mostly pure material was then subjected to flash chromatography
on Florisil (DCM→5% EtOAc/DCM) to give 7 as a crystalline solid
General Procedure for the 2-Amination of Pyridine N-
Oxides: Synthesis of Methyl 2-(Benzylamino)isonicotinate (4).
Pyridine N-oxide 1a (30 mg, 0.196 mmol, 1.0 equiv) benzyl isocyanide
(2a, 24 μL, 0.196 mmol, 1.0 equiv), and TMSOTf (19 μL, 0.196
mmol, 1.0 equiv) were mixed in MeCN/DMF (3:1, 0.1 M based on N-
oxide) in a 10 mL capped microwave reaction tube. The contents were
stirred and microwave-irradiated to a set temperature of 150 °C for 15
min. The crude reaction mixture was concentrated to remove volatile
organics (DMF remains), 1 M HCl (5 mL) and THF (5 mL) were
added, and the mixture was stirred at 50 °C until complete conversion
of formamide 3 to aminopyridine 4. Saturated aqueous sodium
bicarbonate (10 mL) was added to neutralize the solution to
approximately pH 7, and then the volatile organics were removed.
Ethyl acetate (15 mL) was added, and the organics were washed with
water (2 × 10 mL) and brine (10 mL), dried over Na2SO4, filtered,
and concentrated in vacuo. For some aminopyridines (see particular
examples below), purification can be accomplished by dissolving in a
hexane/EtOAc mixture (using highest ratio possible of hexane
allowing solubility) and washing with water (3 × 10 mL), followed
1
(mp = 168−170 °C). Rf = 0.40 (5:1 hexanes/EtOAc). H NMR (400
MHz, CD3CN) δ: 8.41 (dd, 1H, J = 0.4, 5.6 Hz), 8.00 (bs, 1H), 7.64
(d, 2H, J = 9.2 Hz), 7.41 (dd, 1H, J = 0.8, 2.0 Hz), 7.39 (dd, 1H, J =
2.0, 5.2 Hz), 7.33 (d, 2H, J = 8.8 Hz). 13C NMR (100 MHz, CD3CN)
δ: 158.1, 156.2, 151.1, 140.2, 129.7, 127.6, 121.6, 107.7, 104.3. HRMS
calcd for C11H9ClN3O2 [M + H]+: 250.0378, found 250.0379.
N-(4-Chlorophenyl)-4-methoxypyridin-2-amine (8). 0.426
mmol scale: 19 mg, 19% yield. Purification involved addition of 5:1
hexanes/EtOAc and washing with water (3 × 10 mL) and brine (10
mL). The organics were dried over sodium sulfate, concentrated in
vacuo, and then subjected to flash chromatography on silica gel
(DCM→5% EtOAc/DCM) to give 8 as an amorphous solid. Rf = 0.37
(3:1 hexanes/EtOAc). 1H NMR (400 MHz, CD3CN) δ: 7.98 (d, 1H, J
2277
dx.doi.org/10.1021/jo402693s | J. Org. Chem. 2014, 79, 2274−2280

The Journal of Organic Chemistry
Note
= 6.0 Hz), 7.59 (d, 2H, J = 9.2 Hz), 7.43 (bs, 1H), 7.26 (d, 1H, J = 8.8
Hz), 6.41 (dd, 1H, J = 2.0, 5.6 Hz), 6.28 (d, 1H, J = 2.0 Hz), 3.80 (s,
3H); 13C NMR (100 MHz, CD3CN) δ: 167.02, 157.46, 148.65,
140.65, 128.56, 125.11, 120.03, 103.84, 93.86, 54.88. HRMS calcd for
C12H11ClN2O [M + H]+: 235.0633, found 235.0632.
6-((2,6-Dimethylphenyl)amino)nicotinonitrile and 2-((2,6-
Dimethylphenyl)amino)nicotinonitrile (14a and 14b). 0.500
mmol scale: 50 mg, 45% combined yield. Purification involved flash
chromatography on Florisil (DCM → 5% EtOAc/DCM) to give 14a
as a crystalline solid (mp = 117−119 °C) and 14b as an amorphous
1
solid. Rf = (14a) 0.22 and (14b) 0.31 (5:1 hexanes/EtOAc). 14a. H
N-(4-Chlorophenyl)-6-methylpyridin-2-amine (10). 0.596
mmol scale: 63 mg, 48% yield. Purification involved addition of 5:1
hexanes/EtOAc with 5% DCM (just enough to dissolve) and washing
with water (3 × 10 mL) and brine (10 mL). The organics were dried
over sodium sulfate and concentrated in vacuo. The semipure material
was then subjected to flash chromatography on Florisil (DCM → 5%
EtOAc/DCM) to give 10 as an amorphous solid. Rf = 0.36 (5:1
NMR (400 MHz, CD3CN) δ: 8.35 (bs, 1H), 7.65 (dd, 1H, J = 2.0, 8.8
Hz), 7.34 (bs, 1H), 2.15 (s, 6H). 13C NMR (100 MHz, CD3CN) δ:
160.6, 154.2, 141.1, 137.7, 129.3, 128.9, 128.3, 119.3, 100.9, 98.1, 18.3.
14b. 1H NMR (400 MHz, CD3CN) δ: 8.14 (dd, 1H, J = 1.6, 4.8 Hz),
7.86 (dd, 1H, J = 2.0, 7.6 Hz), 7.13 (s, 3H), 7.09 (bs, 1H), 6.72 (dd,
1H, J = 4.8, 7.6 Hz), 2.16 (s, 6H). 13C NMR (100 MHz, CD3CN) δ:
158.8, 153.7, 143.4, 138.0, 137.0, 128.9, 128.1, 117.4, 113.9, 92.2, 18.5.
HRMS calcd for C14H14N3 [M + H]+: 224.1182, found 224.1177.
6-(Benzylamino)nicotinonitrile and 2-(Benzylamino)-
nicotinonitrile (15a and 15b). 0.416 mmol scale: 53 mg, 61%
combined yield. Purification involved addition of 5:1 hexanes/EtOAc
with 5% DCM (just enough to dissolve) and washing with water (3 ×
10 mL) and brine (10 mL). The organics were dried over sodium
sulfate and concentrated in vacuo. The isomers were separated by flash
chromatography on Florisil (DCM→5% EtOAc/DCM) to give 15a as
a crystalline solid (mp = 105−107 °C) and 15b as an amorphous solid.
1
hexanes/EtOAc). H NMR (400 MHz, CD3CN) δ: 7.66 (d, 2H, J =
8.8 Hz), 7.46−7.41 (m, 2H), 7.25 (d, 2H, J = 8.8 Hz), 6.65 (dd, 1H, J
= 0.4, 7.2 Hz), 6.58 (d, 1H, J = 8.0 Hz), 2.39 (s, 3H). 13C NMR (100
MHz, CD3CN) δ: 157.4, 156.1, 141.7, 138.8, 129.4, 125.7, 120.6,
115.0, 108.1, 24.4. HRMS calcd for C12H12ClN2 [M + H]+: 219.0684,
found 219.0670.
3,5-Dibromo-N-(4-chlorophenyl)pyridin-2-amine (11). 0.316
mmol scale: 47 mg, 41% yield. Purification involved addition of 5:1
hexanes/EtOAc and washing with water (3 × 10 mL) and brine (10
mL). The organics were dried over sodium sulfate and concentrated in
vacuo. The mostly pure material was then subjected to flash
chromatography on Florisil (DCM → 5% EtOAc/DCM) to give 11
as a crystalline solid (mp = 98−100 °C). Rf = 0.69 (5:1 hexanes/
1
Rf = (15a) 0.18 and (15b) 0.44 (5:1 hexanes/EtOAc). 15a. H NMR
(400 MHz, CD3CN) δ: 8.33 (d, 1H, J = 2.4 Hz), 7.59 (dd, 1H, J = 2.0,
8.8 Hz), 7.35−7.32 (m, 4H), 7.26 (sext, 1H, J = 4.4 Hz), 6.53 (d, 1H, J
= 8.8 Hz), 6.43 (bs, 1H), 4.57 (d, 2H, J = 6.0 Hz). 13C NMR (100
MHz, CD3CN) δ: 161.1, 154.1, 141.2, 140.1, 129.4, 128.2, 128.0,
119.5, 97.2, 45.4. 15b. 1H NMR (400 MHz, CD3CN) δ: 8.21 (dd, 1H,
J = 1.6, 4.8 Hz), 7.77 (dd, 1H, J = 2.0, 7.6 Hz), 7.36−7.29 (m, 4H),
7.26−7.21 (m, 1H), 6.64 (dd, 1H, J = 5.2, 7.6 Hz), 6.28 (bs, 1H), 4.67
(d, 2H, J = 6.0 Hz). 13C NMR (100 MHz, CD3CN) δ: 159.3, 153.5,
142.9, 140.9, 129.3, 128.1, 127.8, 117.4, 113.1, 92.4, 45.0. HRMS calcd
for C13H12N3 [M + H]+: 210.1026, found 210.1015.
1
EtOAc). H NMR (400 MHz, CD3CN) δ: 8.17 (d, 1H, J = 2.4 Hz),
8.03 (d, 1H, J = 2.0 Hz), 7.59 (d, 2H, J = 8.8 Hz), 7.37 (bs, 1H), 7.32
(d, 2H, J = 9.2 Hz). 13C NMR (100 MHz, CD3CN) δ: 152.0, 147.6,
143.2, 139.6, 129.4, 128.2, 123.3, 123.3, 109.1, 107.4. HRMS calcd for
C11H8Br2ClN2 [M + H]+: 362.8716, found 362.8714.
6-((4-Chlorophenyl)amino)nicotinonitrile and 2-((4-
Chlorophenyl)amino)nicotinonitrile (12a and 12b). 0.666 mol
scale: 111 mg, 73% combined yield. Purification involved addition of
5:1 hexanes/EtOAc and washing with water (3 × 10 mL) and brine
(10 mL). The organics were dried over sodium sulfate and
concentrated in vacuo. Compound 12a is an amorphous solid and
12b is a crystalline solid (mp = 129−131 °C). If any minor impurities
remain flash chromatography on Florisil (DCM→5% EtOAc/DCM)
can be used. Rf = (12a) 0.14 and (12b) 0.40 (5:1 hexanes/EtOAc).
(S)-6-((1-Phenylethyl)amino)nicotinonitrile and (S)-2-((1-
Phenylethyl)amino)nicotinonitrile (16a and 16b). 0.333 mmol
scale: 40 mg, 54% combined yield. Purification involved addition of
5:1 hexanes/EtOAc with 5% DCM (just enough to dissolve) and
washing with water (3 × 10 mL) and brine (10 mL). The organics
were dried over sodium sulfate and concentrated in vacuo. The mostly
pure material was then subjected to flash chromatography on Florisil
(DCM → 5% EtOAc/DCM) to give the isomer mixture as an
amorphous solid. Rf = (16a) 0.23 and (16b) 0.53 (5:1 hexanes/
1
12a. H NMR (400 MHz, CD3CN) δ: 8.48 (d, 1H, J = 2.4 Hz), 8.04
(bs, 1H), 7.75 (dd, 1H, J = 2.4, 8.8 Hz), 7.62 (d, 2H, J = 8.8 Hz), 7.33
(d, 2H, J = 8.8 Hz), 6.81 (d, 1H, J = 8.8 Hz). 13C NMR (100 MHz,
CD3CN) δ: 158.4, 153.5, 140.7, 139.6, 129.7, 128.1, 122.4, 119.0,
1
EtOAc). 16a. H NMR (400 MHz, CD3CN) δ: 8.27 (d, 1H, J = 2.4
1
Hz), 7.55 (dd, 1H, J = 2.4, 8.8 Hz), 7.38−7.30 (m, 4H), 7.25−7.21 (m,
1H), 6.47 (d, 1H, J = 8.8 Hz), 6.40 (bs, 1H), 5.04 (bs, 1H), 1.49 (d,
3H, J = 6.8 Hz). 13C NMR (100 MHz, CD3CN) δ: 160.4, 154.0, 145.8,
140.1, 129.5, 127.9, 126.9, 119.5, 100.9, 97.2, 51.7, 23.6. 16b. 1H NMR
(400 MHz, CD3CN) δ: 8.16 (dd, 1H, J = 2.0, 5.2 Hz), 7.76 (dd, 1H, J
= 2.0, 7.6 Hz), 7.41−7.38 (m, 2H), 7.34−7.30 (m, 2H), 7.22 (tt, 1H, J
= 1.2, 7.2 Hz), 6.62 (dd, 1H, J = 4.8, 7.6 Hz), 5.88 (bs, 1H), 5.31
(quint, 1H, J = 6.8 Hz), 1.55 (d, 3H, J = 7.2 Hz). 13C NMR (100
MHz, CD3CN) δ: 158.6, 153.5, 146.0, 143.0, 129.4, 127.8, 127.0,
117.4, 113.2, 92.5, 51.5, 23.1. HRMS calcd for C14H14N3 [M + H]+:
224.1182, found 224.1144.
111.1, 99.9. 12b. H NMR (400 MHz, CD3CN) δ: 8.33 (dd, 1H, J =
2.0, 4.8 Hz), 7.92 (dd, 1H, J = 2.0, 7.6 Hz), 7.59 (d, 2H, J = 8.8 Hz),
7.33 (d, 2H, J = 8.8 Hz), 6.88 (dd, 1H, J = 4.8, 7.6 Hz). 13C NMR
(100 MHz, CD3CN) δ: 156.9, 153.0, 143.6, 139.2, 129.4, 128.7, 123.9,
116.9, 115.7, 94.7. HRMS calcd for C12H9ClN3 [M + H]+: 230.0480,
found 230.0480.
6-(Naphthalen-2-ylamino)nicotinonitrile and 2-(Naphtha-
len-2-ylamino)nicotinonitrile (13a and 13b). 0.458 mmol scale:
94 mg, 84% combined yield. Purification involved addition of 5:1
hexanes/EtOAc and washing with water (3 × 10 mL) and brine (10
mL). The organics were dried over sodium sulfate and concentrated in
vacuo. Both isomers were isolated as amorphous solids and could be
separated by flash chromatography on Florisil (DCM5% EtOAc/
DCM). Rf = (13a) 0.12 and (13b) 0.38 (5:1 hexanes/EtOAc). 13a. 1H
NMR (400 MHz, CD3CN) δ: 8.54 (d, 1H, J = 2.4 Hz), 8.28 (d, 1H, J
= 2.4 Hz), 8.19 (bs, 1H), 7.83 (apparent q, 3H, J = 8.0 Hz), 7.77 (dd,
1H, J = 2.4, 9.2 Hz), 7.59 (dd, 1H, J = 2.4, 8.8 Hz), 7.40 (td, 1H, J =
1.2, 7.6 Hz), 6.91 (dd, 1H, J = 0.4, 8.8 Hz). 13C NMR (100 MHz,
CD3CN) δ: 158.7, 153.6, 140.6, 138.2, 135.0, 131.0, 129.5, 128.5,
6-(Pentylamino)nicotinonitrile and 2-(Pentylamino)-
nicotinonitrile (17a and 17b). 0.500 mmol scale: 53 mg, 56%
combined yield. Purification involved addition of 5:1 hexanes/EtOAc
and washing with water (3 × 10 mL) and brine (10 mL). The organics
were dried over sodium sulfate and concentrated in vacuo. The
individual isomers were separated by preparative TLC to give both as
amorphous solids. Rf = (17a) 0.23 and (17b) 0.53 (5:1 hexanes/
1
EtOAc). 17a. H NMR (400 MHz, CD3CN) δ: 8.31 (d, 1H, J = 2.0
1
Hz), 7.56 (d, 1H, J = 8.0 Hz), 6.46 (d, 1H, J = 8.8 Hz), 5.95 (bs, 1H),
3.31 (q, 2H, J = 6.4 Hz), 1.57 (q, 2H, J = 7.2 Hz), 1.35−1.31 (m, 4H),
0.90 (t, 3H, J = 6.4 Hz). 13C NMR (100 MHz, CD3CN) δ: 161.3,
128.1, 127.5, 125.5, 121.9, 119.1, 116.8, 111.0, 99.8. 13b. H NMR
(400 MHz, CD3CN) δ: 8.39 (dd, 1H, J = 2.0, 5.2 Hz), 8.18 (d, 1H, J =
1.6 Hz), 7.95 (ddd, 1H, J = 0.4, 2.0, 7.6 Hz), 7.86−7.80 (m, 3H), 7.69
(bs, 1H), 7.65 (dd, 1H, J = 2.4, 8.8 Hz), 7.48 (t, 1H, J = 8.0 Hz), 7.42
(t, 1H, J = 6.8 Hz), 6.90 (ddd, 1H, J = 0.8, 4.8, 7.6 Hz). 13C NMR
(100 MHz, CD3CN) δ: 157.1, 153.1, 143.6, 138.0, 134.8, 131.2, 129.0,
128.4, 128.1, 127.3, 125.7, 123.1, 117.1, 115.6, 94.7. HRMS calcd for
C16H12N3 [M + H]+: 246.1026, found 246.1030.
1
154.1, 139.9, 139.9, 119.7, 96.4, 42.0, 29.8, 29.5, 23.1, 14.3. 17b. H
NMR (400 MHz, CD3CN) δ: 8.24 (dd, 1H, J = 1.6, 4.8 Hz), 7.72 (dd,
1H, J = 1.6, 7.6 Hz), 6.60 (dd, 1H, J = 4.8, 7.6 Hz), 5.71 (bs, 1H), 3.44
(d, 2H, J = 6.0, 10.0 Hz), 1.60 (quint, 2H, J = 7.2 Hz), 1.36−1.31 (m,
4H), 0.90 (t, 3H, J = 7.2 Hz). 13C NMR (100 MHz, CD3CN) δ: 159.6,
2278
dx.doi.org/10.1021/jo402693s | J. Org. Chem. 2014, 79, 2274−2280

The Journal of Organic Chemistry
Note
153.6, 142.8, 117.6, 112.4, 92.0 41.8, 29.8, 29.8, 23.1, 14.3. HRMS
calcd for C11H16N3 [M + H]+: 190.1339, found 190.1315.
3-(Methoxycarbonyl)pyridine 1-Oxide (1i). The compound
was prepared as previously described. Oxidation of methyl nicotinate
was accomplished with m-CPBA.19
Methyl 6-((4-Chlorophenyl)amino)nicotinate and Methyl 2-
((4-Chlorophenyl)amino)nicotinate (18a and 18b). 0.307 mmol
scale: 61 mg, 76% combined yield. Purification involved addition of
5:1 hexanes/EtOAc and washing with water (3 × 10 mL) and brine
(10 mL). The organics were dried over sodium sulfate and
concentrated in vacuo. Preparative TLC was used to separate the
isomers. Compound 18a is a crystalline solid (mp = 179−180 °C), and
18b is an amorphous solid. Rf = (18a) 0.19 and (18b) 0.53 (5:1
hexanes/EtOAc). 18a. 1H NMR (400 MHz, CD3CN) δ: 8.76 (d, 1H, J
= 2.4 Hz), 8.02 (dd, 1H, J = 2.4, 8.8 Hz), 7.95 (bs, 1H), 7.66 (d, 2H, J
= 8.8 Hz), 7.32 (d, 2H, J = 8.8 Hz), 6.78 (d, 1H, J = 8.8 Hz), 3.84 (s,
3H). 13C NMR (100 MHz, CD3CN) δ: 166.7, 159.3, 151.2, 140.1,
3-Nitropyridine Oxide (1k). The procedure was based on a
previous reaction.20 To 3-nitropyridine (2.0 g, 16.1 mmol, 1 equiv)
and sodium bicarbonate (4.33 g, 51.6 mmol, 3.2 equiv) in MeOH (100
mL) flushed with nitrogen was added Oxone (11.14 g, 18.1 mmol,
1.125 equiv) and then water (50 mL). The mixture was heated to 47
°C under nitrogen for 20 h. The reaction was stopped at partial
completion; the solid was filtered off and washed with MeOH. The
filtrate was concentrated, leaving only water, which was extracted with
DCM (3 × 50 mL) and EtOAc (3 × 30 mL), dried over Na2SO4,
filtered, and concentrated in vacuo. Ether was added, and the resulting
orange amorphous solid was collected as product 1k (396 mg, 18%).
Note: a more efficient method for product isolation may involve
simply concentrating all solvent after filtration, including water, and
purifying the crude product as some product seems to be lost to the
1
138.9, 129.6, 127.6, 122.0, 118.1, 110.5, 52.3. 18b. H NMR (400
MHz, CD3CN) δ: 10.20 (bs, 1H), 8.37 (dd, 1H, J = 2.0, 4.4 Hz), 8.28
(dd, 1H, J = 2.0, 8.0 Hz), 7.75 (d, 2H, J = 8.8 Hz), 7.32 (d, 2H, J = 8.8
Hz), 6.85 (dd, 1H, J = 4.4, 7.6 Hz), 3.91 (s, 3H). 13C NMR (100 MHz,
CD3CN) δ: 168.8, 156.6, 153.8, 141.2, 139.9, 129.4, 127.5, 122.8,
115.1, 108.6, 53.1. HRMS calcd for C13H12ClN2O2 [M + H]+:
263.0582, found 263.0580.
1
aqueous layer during extraction. Rf = 0.31 (7% MeOH/DCM). H
NMR (400 MHz, CD3OD) δ: 9.12 (s, 1H), 8.61 (dquint, 1H, J = 0.8,
6.8 Hz), 8.31 (dquint, 1H, J = 0.8, 8.4 Hz), 7.74 (t, 1H, J = 7.6 Hz);
13C NMR (100 MHz, CD3OD) δ: 148.6, 145.2, 136.8, 128.1, 123.8.
HRMS calcd for C5H5N2O3 [M + H]+: 141.0295, found 141.0262.
1-Chloro-4-isocyanobenzene (2b). To a solution of commer-
cially available N-(4-chlorophenyl)formamide (4.0 g, 25.7 mmol, 1.0
equiv) in DCM (200 mL) at 0 °C was added Et3N (10.71 mL, 77.1
mmol, 3 equiv) followed by phosphorus oxychloride (2.83 mL, 30.9
mmol, 1.2 equiv). The mixture was warmed to 23 °C and stirred for 14
h, at which time it was poured into saturated aqueous sodium
bicarbonate (200 mL) and extracted with DCM (2 × 200 mL). The
organic layer was dried over Na2SO4, filtered, and concentrated in
vacuo to yield 2b21 (2.93 g, 83%) as a tan amorphous solid. NMR data
matched those from ref 21.
N-(4-Chlorophenyl)isoquinolin-1-amine (19b). 0.413 mmol
scale: 63 mg, 60% yield. Purification involved subjection to flash
chromatography on Florisil (DCM → 5% EtOAc/DCM) to give 19b
as a crystalline solid (mp = 129−131 °C) and the only observable
1
product. Rf = (19b) 0.47 (5:1 hexanes/EtOAc). 19b. H NMR (400
MHz, CD3CN) δ: 8.19 (d, 1H, J = 8.4 Hz), 7.99 (d, 1H, J = 5.6 Hz),
7.92 (bs, 1H), 7.81 (d, 2H, J = 8.4 Hz), 7.78 (d, 1H, J = 7.6 Hz), 7.67
(td, 1H, J = 1.2, 7.2 Hz); 7.58 (td, 1H, J = 1.2, 7.6 Hz), 7.31 (d, 2H, J =
8.8 Hz), 7.16 (d, 1H, J = 6.0 Hz). 13C NMR (100 MHz, CD3CN) δ:
153.3, 141.4, 141.1, 138.4, 131.1, 129.3, 128.0, 127.5, 127.0, 123.3,
122.8, 119.7, 114.3. HRMS calcd for C15H12ClN2 [M + H]+: 255.0684,
found 255.0694.
ASSOCIATED CONTENT
■
N-(4-Chlorophenyl)-3-nitropyridin-2-amine and N-(4-Chlor-
ophenyl)-5-nitropyridin-2-amine (20a and 20b). 0.314 mmol
scale: 35 mg, 45% combined yield. Purification involved subjection to
flash chromatography on Florisil (DCM → 5% EtOAc/DCM) to give
20a as a crystalline solid (mp = 152−154 °C) and 20b as a crystalline
solid (mp = 126−127 °C). Rf = (20a) 0.14 and (20b) 0.49 (5:1
hexanes/EtOAc). 20a. 1H NMR (400 MHz, CD3CN) δ: 9.04 (d, 1H, J
= 2.8 Hz), 8.31 (bs, 1H), 8.24 (dd, 1H, J = 2.8, 9.2 Hz), 7.67 (d, 2H, J
= 8.8 Hz), 7.37 (d, 2H, J = 9.2 Hz), 6.82 (d, 1H, J = 0.8, 9.2 Hz). 13C
NMR (100 MHz, CD3CN) δ: 159.9, 146.7, 139.2, 133.6, 129.8, 129.5,
S
* Supporting Information
1H and 13C NMR spectra for all new compounds. Partial charge
data for selected intermediates and X-ray structures for SI-6
and 11. This material is available free of charge via the Internet
at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Authors
*E-mail: mvamos@sanfordburnham.org.
*E-mail: ncosford@sanfordburnham.org.
■
1
128.8, 122.8, 110.5. 20b. H NMR (400 MHz, CD3CN) δ: 9.93 (bs,
1H), 8.54 (dd, 1H, J = 2.0, 8.4 Hz), 8.47 (dd, 1H, J = 4.6, 4.4 Hz), 7.68
(d, 2H, J = 8.8 Hz), 7.38 (d, 2H, J = 8.8 Hz), 6.94 (dd, 1H, J = 4.4, 8.0
Hz). 13C NMR (100 MHz, CD3CN) δ: 155.9, 150.9, 138.40, 136.5,
134.7, 129.7, 129.6, 125.2, 115.6. HRMS calcd for C11H9ClN3O2 [M +
H]+: 250.0378, found 250.0376.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by National Institutes of Health grant
R01 AG045933 to N.C. We thank Prof. Arnold Rheingold of
the UCSD X-ray facility for crystal structures.
N-(4-Chlorophenyl)-5-methylpyridin-2-amine and N-(4-
Chlorophenyl)-3-methylpyridin-2-amine (21a and 21b). 0.577
mmol scale: 51 mg, 40% combined yield. Purification involved
addition of 5:1 hexanes/EtOAc and washing with water (3 × 10 mL)
and brine (10 mL). The organics were dried over sodium sulfate and
concentrated in vacuo. The semipure material was then subjected to
flash chromatography on Florisil (DCM → 5% EtOAc/DCM) to give
21a as a crystalline solid (mp = 122−123 °C) and 21b as an
amorphous solid. Rf = 21a: 0.38 and 21b: 0.53 (5:1 hexanes/EtOAc).
REFERENCES
■
(1) (a) Hagmann, W. K.; Caldwell, C. G.; Chen, P.; Durette, P. L.;
Esser, C. K.; Lanza, T. J.; Kopka, I. E.; Guthikonda, R.; Shah, S. K.;
MacCoss, M.; Chabin, R. M.; Fletcher, D.; Grant, S. K.; Green, B. G.;
Humes, J. L.; Kelly, T. M.; Luell, S.; Meurer, R.; Moore, V.; Pacholok,
S. G.; Pavia, T.; Williams, H. R.; Wong, K. K. Bioorg. Med. Chem. Lett.
2000, 10, 1975−1978. (b) May, B. C. H.; Zorn, J. A.; Witkop, J.;
Sherrill, J.; Wallace, A. C.; Legname, G.; Prusiner, S. B.; Cohen, F. E. J.
Med. Chem. 2006, 50, 65−73. (c) Schroeder, G. M.; An, Y.; Cai, Z.-W.;
Chen, X.-T.; Clark, C.; Cornelius, L. A. M.; Dai, J.; Gullo-Brown, J.;
Gupta, A.; Henley, B.; Hunt, J. T.; Jeyaseelan, R.; Kamath, A.; Kim, K.;
Lippy, J.; Lombardo, L. J.; Manne, V.; Oppenheimer, S.; Sack, J. S.;
Schmidt, R. J.; Shen, G.; Stefanski, K.; Tokarski, J. S.; Trainor, G. L.;
Wautlet, B. S.; Wei, D.; Williams, D. K.; Zhang, Y.; Zhang, Y.; Fargnoli,
J.; Borzilleri, R. M. J. Med. Chem. 2009, 52, 1251−1254. (d) Younis, Y.;
1
21a. H NMR (400 MHz, CD3CN) δ: 8.00 (s, 1H), 7.59 (d, 2H, J =
8.8 Hz), 7.39 (dd, 1H, J = 2.8, 6.8 Hz), 7.25 (d, 2H, J = 8.8 Hz), 6.71
(d, 1H, J = 8.8 Hz), 2.20 (s, 3H). 13C NMR (100 MHz, CD3CN) δ:
166.7, 159.3, 151.2, 140.1, 138.9, 129.6, 127.6, 122.0, 118.1, 110.5,
52.3. 21b. 1H NMR (400 MHz, CD3CN) δ: 8.01 (dd, 1H, J = 1.6, 4.8
Hz), 7.68 (d, 2H, J = 8.8 Hz), 7.43 (dd, 1H, J = 0.8, 7.6 Hz), 7.27 (d,
2H, J = 8.8 Hz), 6.83 (bs, 1H), 6.75 (dd, 1H, J = 5.2, 7.6 Hz), 2.25 (s,
3H). 13C NMR (100 MHz, CD3CN) δ: 154.9, 145.5, 141.5, 138.9,
129.2, 126.2, 121.9, 120.0, 116.4, 17.5. HRMS calcd for C12H12ClN2
[M + H]+: 219.0684, found 219.0670.
2279
dx.doi.org/10.1021/jo402693s | J. Org. Chem. 2014, 79, 2274−2280

The Journal of Organic Chemistry
Note
Douelle, F.; Feng, T.-S.; Cabrera, D. G.; Manach, C. L.; Nchinda, A.
T.; Duffy, S.; White, K. L.; Shackleford, D. M.; Morizzi, J.; Mannila, J.;
Katneni, K.; Bhamidipati, R.; Zabiulla, K. M.; Joseph, J. T.; Bashyam,
S.; Waterson, D.; Witty, M. J.; Hardick, D.; Wittlin, S.; Avery, V.;
Charman, S. A.; Chibale, K. J. Med. Chem. 2012, 55, 3479−3487.
(2) Coleman, M. D. Role of Metabolism in Drug Toxicity. In Human
Drug Metabolism; John Wiley & Sons, Ltd.: New York, 2010; pp 252−
258.
(3) Araki, Y.; Andoh, A.; Fujiyama, Y.; Hata, K.; Makino, J.; Okuno,
T.; Nakanura, F.; Bamba, T. J. Chromatogr. B 2001, 753, 209−215.
(4) (a) Abramovitch, R. A.; Singer, G. M. J. Am. Chem. Soc. 1969, 91,
5672−5673. (b) Manley, P. J.; Bilodeau, M. T. Org. Lett. 2002, 4,
3127−3129.
(5) Medley, J. W.; Movassaghi, M. J. Org. Chem. 2009, 74, 1341−
1344.
(6) Hisano, T.; Yoshikawa, S.; Muraoka, K. Chem. Pharm. Bull. 1974,
22, 1611−1617.
(7) Londregan, A. T.; Jennings, S.; Wei, L. Org. Lett. 2010, 12, 5254−
5257.
(8) (a) Wachi, K.; Terada, A. Chem. Pharm. Bull. 1980, 28, 465−472.
(b) Kurbatov, Y. V.; Solekhova, M. A. Russ. J. Org. Chem. 2007, 43,
1696−1697. (c) Yin, J.; Xiang, B.; Huffman, M. A.; Raab, C. E.; Davies,
I. W. J. Org. Chem. 2007, 72, 4554−4557.
(9) Keith, J. M. J. Org. Chem. 2012, 77, 11313−11318.
(10) Domling, A. Chem. Rev. 2005, 106, 17−89.
̈
(11) Matsuoka, T.; Shinada, M.; Suematsu, F.; Harano, K.; Hisano, T.
Chem. Pharm. Bull. 1984, 32, 2077−2090.
(12) Johnson, H. W.; Krutzsch, H. C. J. Org. Chem. 1967, 32, 1939−
1941.
(13) The formamide was the initial product formed in every example
and was hydrolyzed under acidic, basic, or nucleophilic conditions to
converge all material to the free aminopyridine. Ammonia in methanol
can also be used to cleave the formamide.
(14) The reaction was run at 105 °C for 4 h and gave a relative
conversion of 48 and 32% isolated yield.
(15) Vamos, M.; Welsh, K.; Finlay, D.; Lee, P. S.; Mace, P. D.; Snipas,
S. J.; Gonzalez, M. L.; Ganji, S. R.; Ardecky, R. J.; Riedl, S. J.; Salvesen,
G. S.; Vuori, K.; Reed, J. C.; Cosford, N. D. P. ACS Chem. Biol. 2013,
8, 725−732.
(16) Substoichiometric use of TMSOTf, such as entries 9 and 10 in
Table 1, is enabled by loss of a proton via rearomatization from
intermediate C, which presumably provides further catalysis of the
reaction.
(17) Orita, A.; Ohe, K.; Murai, S. Organometallics 1994, 13, 1533−
1536.
(18) A single example of reaction of a related N-oxide and an
isocyanide was reported with 1-methylbenzimidazole 3-oxide and
phenyl isocyanide. This distinct reaction did not give the formamide
and was suggested to proceed through the isocyanate. Takahashi, S.;
Kano, H. Chem. Pharm. Bull. 1964, 12, 1290−1295.
(19) Duric, S.; Tzschucke, C. C. Org. Lett. 2011, 13, 2310−2313.
(20) Holler, E. R.; Smart, B. E. Org. Synth. 1990, 69, 226.
(21) Guirado, A.; Zapata, A.; Gom
́ ́ ́
ez, J. L.; Trabalon, L.; Galvez, J.
Tetrahedron 1999, 55, 9631−9640.
2280
dx.doi.org/10.1021/jo402693s | J. Org. Chem. 2014, 79, 2274−2280