T3P-Mediated N-N Cyclization for the Synthesis of 1,2,4-Triazolo[1,5- a]pyridines

Article abstract of DOI:10.1021/acs.oprd.9b00396

Propylphosphonic anhydride has been shown to be an effective reagent for the synthesis of substituted [1,2,4]triazolo[1,5-a]pyridines from the corresponding N′-hydroxy-N-formimidamides. The reactions worked under mild conditions and exhibited wide functional group tolerance, delivering the triazolopyridines in good to excellent yields and purities.

Full text of DOI:10.1021/acs.oprd.9b00396

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Cite This: Org. Process Res. Dev. XXXX, XXX, XXX−XXX
T3P-Mediated N−N Cyclization for the Synthesis of 1,2,4-
Triazolo[1,5‑a]pyridines
†
†
†
‡
̈
Rajaram Ayothiraman, Durgarao Bandaru, Ranjitha Paranthaman, Michael Fenster,
Martin D. Eastgate,‡ and Rajappa Vaidyanathan*,†
†Chemical Development and API Supply, Biocon Bristol-Myers Squibb Research and Development Center, Biocon Park, Jigani Link
Road, Bommasandra IV, Bengaluru 560099, India
‡Chemical and Synthetic Development, Bristol-Myers Squibb, 1 Squibb Drive, New Brunswick, New Jersey 08903, United States
ABSTRACT: Propylphosphonic anhydride has been shown to be an effective reagent for the synthesis of substituted
[1,2,4]triazolo[1,5-a]pyridines from the corresponding N′-hydroxy-N-formimidamides. The reactions worked under mild
conditions and exhibited wide functional group tolerance, delivering the triazolopyridines in good to excellent yields and
purities.
KEYWORDS: propylphosphonic anhydride, N−N bond formation, 1,2,4-triazole, 1,2,4-triazolo[1,5-a]pyridine
exacerbated when Eaton’s reagent6 was used (entry 3, Table
1), prompting us to explore nonacidic conditions for the
cyclization reaction.
INTRODUCTION
We sought to explore the use of [1,2,4]triazolo[1,5-a]pyridines
1 as key building blocks in the discovery of novel
■
medications.1,2 We envisioned that this class of compounds
We envisioned that the cyclization could be accomplished
with a suitable nonacidic desiccant5 and sought to examine
could be readily accessed by the treatment of commercially
available substituted 2-aminopyridines 2 with dimethylforma-
mide−dimethylacetal (DMF−DMA) and hydroxylamine
hydrochloride to afford the corresponding N′-hydroxy-N-
some of the commonly used peptide coupling agents for this
transformation. As anticipated, reagents such as HATU, EDCI,
PyBOP, CDI, and DCC circumvented the formation of the
formimidamides 3,3 which could then be dehydrated to form
hydrolyzed impurity 4 but, at the same time, afforded only
modest conversions to the desired triazole 1j (entries 4−8,
the 1,2,4-triazole ring through an intramolecular cyclization
Table 1).
(Scheme 1). Several dehydrative conditions such as poly-
phosphoric acid (PPA)4 and trifluoroacetic anhydride
In recent times, 1-propanephosphonic acid anhydride (T3P)
(TFAA)5 have been effectively utilized for the cyclization
has emerged as a mild dehydrating agent for the direct
coupling of acids with amines.7,8 We hypothesized that this
reaction.
reagent could be effective for the cyclization of 3j to 1j as well.
It was gratifying to note that exposure of 3j to T3P cleanly
furnished 1,2,4-triazole 1j, with nondetectable levels of
Scheme 1. General Synthesis of [1,2,4]Triazolo[1,5-
a]pyridines
carboxylic acid 4 (entry 9, Table 1). A quick solvent screen
revealed that the reaction worked effectively in 2-MeTHF,
THF, toluene, and ethyl acetate, but was much less efficient in
acetonitrile and dichloromethane (entries 9−14, Table 1).
These results proved general and could be used to synthesize
a range of [1,2,4]triazolo[1,5-a]pyridines from N′-hydroxy-N-
formimidamides. Several substituted 2-aminopyridines were
converted to the corresponding N′-hydroxy-N-formimida-
mides by treatment with DMF−DMA and then subjected to
the T3P-mediated cyclization conditions; our results are
summarized in Scheme 2. In most cases, the reactions
proceeded to completion and the products were isolated in
good to excellent yields. The reaction worked well in the case
of alkoxy- (1a, 1k, 1l), phenyl- (1b), chloro- (1g, 1h), nitro-
(1e), cyano- (1i), and 5-trifluoromethyl (1f)-substituted
analogues, demonstrating that electron-withdrawing as well
as electron-donating substituents on the pyridine ring were
well tolerated in the cyclization. The reactions with the 6-
RESULTS AND DISCUSSION
■
Our initial studies were performed using methyl-2-amino-
isonicotinate 2j as the test substrate (Table 1). The formation
of the corresponding N′-hydroxy-N-formimidamide 3j through
treatment with DMF−DMA worked smoothly providing the
desired product in 94% yield. However, our attempts to effect
the cyclization of 3j to form 1j using PPA4 or TFAA5 based on
literature precedent were met with only modest success. While
the cyclization reaction afforded 1j using either of these
reagents, the product was contaminated with a significant
amount of carboxylic acid 4 arising from hydrolysis of the
methyl ester under the reaction conditions (entries 1 and 2,
Table 1). The levels of the carboxylic acid impurity were
Received: September 16, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.oprd.9b00396
Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development
Article
a
Table 1. Screening of Various Dehydrating Agents for the Cyclization of 3j
entry
dehydrating agent (equiv)
solvent
1j (HPLC area %)
4 (HPLC area %)
1
2
3
4
5
6
7
8
TFAA (3.0)
2-MeTHF
2-MeTHF
2-MeTHF
2-MeTHF
2-MeTHF
2-MeTHF
2-MeTHF
2-MeTHF
2-MeTHF
EtOAc
76
80
37
3
4
35
1
30
92
96
99
92
5
24
20
63
polyphosphoric acid (3.0)
Eaton’s reagent (3.0)
HATU (1.5)
EDCl (1.5)
PyBOP (1.5)
<0.05
<0.05
<0.05
<0.05
<0.05
<0.05
<0.05
<0.05
<0.05
<0.05
<0.05
CDI (1.5)
DCC (1.1)
9
50% T3P in EtOAc (1.5)
50% T3P in EtOAc (1.5)
50% T3P in EtOAc (1.5)
50% T3P in EtOAc (1.5)
50% T3P in EtOAc (1.5)
10
11
12
13
14
THF
PhMe
MeCN
CH2Cl2
b
50% T3P in EtOAc (1.5)
10
a
b
All reactions were conducted on a 1 g scale. Carried out at 40 °C.
washes. In particular, the cyclization of 3l to 1l was carried out
on a 1.6 kg scale (see Experimental Section), affirming the
scalability of the T3P-mediated reaction.
Scheme 2. Synthesis of Various [1,2,4]Triazolo[1,5-
a]pyridines Using T3P
The methodology was extended to the cyclization of N′-
hydroxy-N-formimidamides derived from other α-aminoheter-
oarenes as well. The N′-hydroxy-N-formimidamides synthe-
sized from 3-amino-6-methoxypyridazine (5 → 6), 2-amino-
pyrazine (8 → 9), and 3-aminoisoquinoline (11 → 12)
underwent efficient ring closure to provide the corresponding
1,2,4-triazoles 7, 10, and 13 (Scheme 3).
In summary, we have developed a general methodology for
the cyclization of N′-hydroxy-N-formimidamides derived from
α-aminoheteroarenes using T3P. The reactions proceeded
under mild conditions, exhibited wide functional group
tolerance, and provided the corresponding heteroaryl-fused
1,2,4-triazoles in moderate to excellent yields.
EXPERIMENTAL SECTION
■
General Information. All reactions were performed under
a nitrogen atmosphere. All compounds were purified by flash
chromatography using silica gel (20−40 μm) as needed.
Chemical shifts for protons are reported in parts per million
downfield from tetramethylsilane and are referenced to
residual protium in the NMR solvent (CDCl3 = δ 7.26;
(CD3)2SO = δ 2.50). Chemical shifts for carbons are reported
in parts per million downfield from tetramethylsilane and are
referenced to the carbon resonances of the solvent (CDCl3 = δ
77.16; (CD3)2SO = δ 39.50). Melting points were obtained
using a Stuart SMP10 instrument. HRMS was recorded on a
Thermo Velos Orbitrap mass spectrometer (ESI and APCI
source).
General Procedure for the Synthesis of N′-Hydroxy-
N-formimidamides (3a−k, 6, 9, and 12). To an oven-dried
three-neck round-bottom flask fitted with a thermocouple and
reflux condenser, 2-propanol (10 mL per g of the amine) was
added under a nitrogen atmosphere. Dimethyl formamide−
dimethylacetal (2.6 equiv) and the amine (1.0 equiv) were
fluoro- and 6-trifluoromethyl-substituted N′-hydroxy-N-formi-
midamides (1c, 1d) provided slightly lower yields, in line with
the results reported with TFAA for formimidamines derived
from 6-substituted pyridines.5 Compounds 1g, 1h, and 1l were
of particular interest since the presence of the halo substituents
in these compounds would allow for further elaboration via
appropriate cross-coupling reactions. In general, all of these
reactions worked under fairly mild conditions, and most
importantly, the residues from the coupling agent (T3P) were
water-soluble and could be removed via simple aqueous
B
DOI: 10.1021/acs.oprd.9b00396
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Scheme 3. Synthesis of Various [1,2,4]Triazole-Fused Heteroarenes Using T3P
added to the flask. The reaction mixture was stirred for 3 h at
80 °C. Hydroxylamine hydrochloride (1.5 equiv) was added to
the reaction mass and stirred for 12 h at 50 °C. The reaction
was quenched with 10% aqueous NaHCO3. The layers were
separated, and the aqueous layer was extracted with 2-MeTHF
(1 × 10 mL per g of the amine). The combined organic layer
was dried over Na2SO4, filtered, and concentrated in vacuo.
The residue was purified by column chromatography to furnish
the desired product.
N′-Hydroxy-N-(6-methoxypyridin-2-yl)formimidamide
(3a). The reaction was conducted on a 5.0 g scale using the
general procedure. The product was purified by column
chromatography using EtOAc/n-heptane (1:3) as eluent to
afford 2.1 g (31%) of compound 3a as a pale brownish solid
(mp 164−166 °C). 1H NMR (400 MHz, (CD3)2SO): δ 10.03
(s, 1H), 9.29 (d, J = 10.0 Hz, 1H), 7.86 (d, J = 10.0 Hz, 1H),
7.50 (t, J = 8.0 Hz, 1H), 6.59 (d, J = 8.0 Hz, 1H), 6.23 (d, J =
7.6 Hz, 1H), 3.81 (s, 3H). 13C NMR (100 MHz, (CD3)2SO):
δ 163.0, 151.5, 141.3, 136.2, 101.9, 101.4, 53.3. HRMS (ESI)
(m/z): calcd for C7H9N3O2 168.0768 [M + H]+, found
168.0765.
JC‑F = 11.0 Hz), 135.5, 107.5 (d, JC‑F = 5.5 Hz), 99.7 (d, JC‑F =
47.6 Hz), HRMS (ESI) (m/z): calcd for C6H6FN3O 156.0568
[M + H]+, found 156.0557.
N′-Hydroxy-N-(6-(trifluoromethyl)pyridin-2-yl)-
formimidamide (3d). The reaction was conducted on a 4.0 g
scale using the general procedure. The product was purified by
column chromatography using CH2Cl2/CH3OH (9:1) as
eluent to afford 4.7 g (74%) of compound 3d as a pale
brownish solid (mp 178−180 °C). 1H NMR (400 MHz,
(CD3)2SO): δ 10.33 (s, 1H), 9.83 (d, J = 10.0 Hz, 1H), 7.86
(t, 8.0 Hz, 1H), 7.79 (d, J = 9.6 Hz, 1H), 7.29−7.34 (m, 2H).
13C NMR (100 MHz, (CD3)2SO): δ 153.2, 144.9 (q, JC‑F
=
33.6 Hz), 139.9, 135.4, 121.7 (q, JC‑F = 272 Hz), 114.6, 112.7.
HRMS (ESI) (m/z): calcd for C7H6F3N3O 206.0536 [M +
H]+, found 206.0528.
N′-Hydroxy-N-(5-nitropyridin-2-yl)formimidamide (3e).
The reaction was conducted on a 5.0 g scale using the general
procedure. At the end of the reaction, the precipitated solids
were isolated by filtration. The filter cake was transferred to a
clean round-bottom flask, slurried in MTBE (25 mL), filtered,
and dried to afford 4.2 g (64%) of compound 3e as a pale
greenish solid (mp 186−188 °C). 1H NMR (400 MHz,
(CD3)2SO): δ 10.62 (s, 1H), 10.35 (d, J = 9.6 Hz, 1H), 9.02
(d, J = 2.8 Hz, 1H), 8.39 (dd, J = 9.2 Hz, 2.8 Hz, 1H), 7.93 (d,
J = 9.6 Hz, 1H), 7.21 (d, J = 9.2 Hz, 1H). 13C NMR (100
MHz, (CD3)2SO): δ 156.7, 145.8, 138.5, 134.9, 134.1, 110.7.
HRMS (ESI) (m/z): calcd for C6H6N4O3 183.0531 [M + H]+,
found 183.0512.
N′-Hydroxy-N-(5-(trifluoromethyl)pyridin-2-yl)-
formimidamide (3f). The reaction was conducted on a 5.0 g
scale using the general procedure. The product was purified by
column chromatography using CH2Cl2/CH3OH (9:1) as
eluent to afford 4.7 g (74%) of compound 3f as a pale
brownish solid (mp 181−183 °C). 1H NMR (400 MHz,
(CD3)2SO): δ 10.37 (s, 1H), 9.91 (d, J = 9.6 Hz, 1H), 8.50 (s,
1H), 7.95 (dd, J = 8.8 Hz, 2.4 Hz, 1H), 7.87−7.90 (m, 1H),
7.22 (d, J = 8.8 Hz, 1H). 19F NMR (376.4 MHz, (CD3)2SO):
δ 60.1. 13C NMR (100 MHz, (CD3)2SO) δ 155.4, 145.2 (q,
N′-Hydroxy-N-(6-phenylpyridin-2-yl)formimidamide (3b).
The reaction was conducted on a 4.0 g scale using the general
procedure. The product was purified by column chromatog-
raphy using EtOAc/n-heptane (1:3) as eluent to afford 2.4 g
(48%) of compound 3b as an off-white solid (mp 157−159
1
°C). H NMR (400 MHz, (CD3)2SO): δ 10.09 (s, 1H), 9.41
(d, J = 10.0 Hz, 1H), 8.07 (d, J = 10.0 Hz, 3H), 7.70 (t, J = 8.0
Hz, 1H), 7.39−7.49 (m, 4H), 7.02 (d, J = 8.0 Hz, 1H). 13C
NMR (100 MHz, (CD3)2SO): δ 154.4, 152.7, 139.5, 139.0,
136.2, 129.4, 129.1, 126.9, 112.9, 109.7. HRMS (ESI) (m/z):
calcd for C12H11N3O 214.0975 [M + H]+, found 214.0964.
N-(6-Fluoropyridin-2-yl)-N′-hydroxyformimidamide (3c).
The reaction was conducted on a 5.0 g scale using the general
procedure. The product was purified by column chromatog-
raphy using CH2Cl2/CH3OH (9:1) as eluent to afford 4.8 g
(69%) of compound 3c as an off-white solid (mp 164−166
1
°C). H NMR (400 MHz, (CD3)2SO): δ 10.23 (s, 1H), 9.65
(d, J = 10.0 Hz, 1H), 7.76 (dd, J = 16.4 Hz, 8.0 Hz, 1H), 7.65
(d, J = 10.0 Hz, 1H), 6.95 (dd, J = 8.0 Hz, 2.0 Hz, 1H), 6.53
(dd, J = 7.6 Hz, 2.4 Hz, 1H). 19F NMR (376.4 MHz,
(CD3)2SO): δ 69.52. 13C NMR (100 MHz, (CD3)2SO): δ
162.5 (d, JC‑F = 312.2 Hz), 152.3 (d, JC‑F = 20.7 Hz), 143.7 (d,
JC‑F = 4.3 Hz), 135.1 (q, JC‑F = 2.8 Hz), 135.2, 124.5 (q, JC‑F =
269 Hz), 117.6 (q, JC‑F = 32.3 Hz), 110.5. HRMS (ESI) (m/
z): calcd for C7H6F3N3O 206.0536 [M + H]+, found 206.0528.
N-(5-Chloropyridin-2-yl)-N′-hydroxyformimidamide (3g).
The reaction was conducted on a 5.0 g scale using the general
C
DOI: 10.1021/acs.oprd.9b00396
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procedure. The product was purified by column chromatog-
raphy using EtOAc/n-heptane (1:3) as eluent to afford 5.0 g
(75%) of compound 3g as an off-white solid (mp 189−191
120.4, 54.4. HRMS (ESI) (m/z): calcd for C6H8N4O2
169.0720 [M + H]+, found 169.0710.
N′-Hydroxy-N-(pyrazin-2-yl)formimidamide (9). The re-
action was conducted on a 4.0 g scale using the general
procedure. The product was purified by column chromatog-
raphy using CH2Cl2/CH3OH (9:1) as eluent to afford 5.5 g
(95%) of compound 9 as an off-white solid (mp 201−203 °C).
1H NMR (400 MHz, (CD3)2SO): δ 10.34 (s, 1H), 9.79 (d, J =
10.0 Hz, 1H), 8.45 (d, J = 1.6 Hz, 1H), 8.14 (d, J = 1.2, 1H),
8.06 (d, J = 2.8 Hz, 1H), 7.79 (d, J = 10.0 Hz, 1H). 13C NMR
(100 MHz, (CD3)2SO): δ149.5, 141.9, 136.7, 135.2, 134.9.
HRMS (ESI) (m/z): calcd for C5H6N4O, 139.0614 [M + H]+
found, 139.0611.
1
°C). H NMR (400 MHz, (CD3)2SO): δ 10.17 (s, 1H), 9.54
(d, J = 10.0 Hz, 1H), 8.16 (d, J = 2.8 Hz, 1H), 7.78 (d, J = 10.0
Hz, 1H), 7.70 (dd, J = 8.8 Hz, 2.8 Hz, 1H), 7.09 (d, J = 8.8 Hz,
1H). 13C NMR (100 MHz, (CD3)2SO): δ 151.8, 146.0, 138.4,
135.8, 122.7, 112.2. HRMS (ESI) (m/z): calcd for
C6H6ClN3O 172.0272 [M + H]+, found 172.0261.
N-(4-Chloropyridin-2-yl)-N′-hydroxyformimidamide (3h).
The reaction was conducted on a 2.0 g scale using the general
procedure. The product was purified by column chromatog-
raphy using EtOAc/n-heptane (1:3) as eluent to afford 1.4 g
(52%) of compound 3h as an off-white solid (mp 155−157
N′-Hydroxy-N-(isoquinolin-3-yl)formimidamide (12). The
reaction was conducted on a 5.0 g scale using the general
procedure. The product was purified by column chromatog-
raphy using EtOAc/n-heptane (1:3) as eluent to afford 6.0 g
(92%) of compound 12 as an off-white solid (mp 146−148
1
°C). H NMR (400 MHz, (CD3)2SO): δ 10.22 (s, 1H), 9.55
(t, J = 4.8 Hz, 1H), 8.11 (d, J = 5.2 Hz, 1H), 7.82 (d, J = 9.6
Hz, 1H), 7.16 (d, J = 1.6 Hz, 1H), 6.94 (dd, J= 5.6 Hz, 1.6 Hz,
1H). 13C NMR (100 MHz, (CD3)2SO): δ 153.8, 149.0, 143.6,
135.1, 116.2, 109.6. HRMS (ESI) (m/z): calcd for
C6H6N3OCl 172.0272 [M + H]+, found 172.0267.
1
°C). H NMR (400 MHz, (CD3)2SO): δ 10.05 (br s, 1H),
9.31 (d, J = 10.0 Hz, 1H), 9.01 (d, J = 12.8 Hz, 1H), 7.94−
7.99 (m, 2H), 7.67 (d, J = 8.0 Hz, 1H), 7.58−7.61 (m, 1H),
7.35 (dd, J = 15.2 Hz, 7.6 Hz, 2H). 13C NMR (100 MHz,
(CD3)2SO): δ 156.5, 153.7, 143.1, 141.6, 136.1, 133.1, 130.5,
129.8, 129.3, 106.6. HRMS (ESI) (m/z): calcd for C10H9N3O
188.0818 [M + H]+, found 188.0816.
N-(4-Cyanopyridin-2-yl)-N′-hydroxyformimidamide (3i).
The reaction was conducted on a 5.0 g scale using the general
procedure. The product was purified by column chromatog-
raphy using EtOAc/n-heptane (1:3) as eluent to afford 4.2 g
(62%) of compound 3i as an off-white solid (mp 175−177
1
°C). H NMR (400 MHz, (CD3)2SO): δ 10.34 (s, 1H), 9.78
N-(5-Bromo-3-methoxypyridine-2-yl)-N′-hydroxyformimi-
damide (3l). To a clean 60 L glass reactor, 2-propanol (21 L)
and 5-bromo-3-methoxypyridin-2-amine (3.0 kg, 14.8 mol, 1.0
equiv) were sequentially added at 20−35 °C under a nitrogen
atmosphere. DMF−DMA (4.3 kg, 34.5 mol, 2.4 equiv) was
added at 20−35 °C, and the mixture was stirred for 2 h at 70−
80 °C. After reaction completion, the reaction mass was cooled
to 20−35 °C. Hydroxylamine hydrochloride (1.5 kg, 19.2 mol,
1.3 equiv) was charged, and the mixture was stirred for 16 h at
50−55 °C. After reaction completion, the contents of the
reactor were cooled to 20−35 °C, and 10% aqueous NaHCO3
(30 L) was charged and stirred for 15 min. The mass was then
cooled to 0−10 °C and allowed to granulate for 1 h. The
resulting slurry was filtered through a Nutsche filter, and the
filter cake was washed with water (30 L). The wet solid was
dried under vacuum at 45−50 °C to afford compound 3l as a
pale brown solid (3.5 kg, 99.98% purity by HPLC, 94.30%
(d, J = 9.6 Hz, 1H), 8.36 (d, J = 5.2 Hz, 1H), 7.83 (d, J = 9.6
Hz, 1H), 7.40 (d, J = 1.2 Hz, 1H), 7.23 (dd, J = 5.2 Hz, 1.2 Hz,
1H). 13C NMR (100 MHz, (CD3)2SO): δ 153.0, 149.3, 134.7,
120.7, 117.0, 116.8, 112.7. HRMS (ESI) (m/z): calcd for
C7H6N4O 163.0614 [M + H]+, found 163.0617.
Methyl 2-(N′-Hydroxyformimidamido)isonicotinate (3j).
The reaction was conducted on a 25.0 g scale using the general
procedure. The product was purified by column chromatog-
raphy using EtOAc/n-heptane (1:3) as eluent to afford 21.3 g
(66%) of compound 3j as an off-white solid (mp 185−187
°C). 1H NMR (400 MHz, (CD3)2SO): δ 10.4 (s, 1H), 9.90 (d,
J = 9.6 Hz, 1H), 8.68 (s, 1H), 8.04 (d, J = 8.0 Hz, 1H), 7.91
(d, J = 9.6 Hz, 1H), 7.11 (d, J = 8.4 Hz, 1H), 3.81 (s, 3H). 13
C
NMR (100 MHz, (CD3)2SO): δ 165.7, 155.9, 150.3, 139.1,
135.3, 118.4, 110.4, 52.3. HRMS (ESI) (m/z): calcd for
C8H9N3O3 196.0717 [M + H]+, found 196.0710.
N-(3-(Benzyloxy) Pyridin-2-yl)-N′-hydroxyformimidamide
(3k). The reaction was conducted on a 5.0 g scale using the
general procedure. The product was purified by column
chromatography using EtOAc/n-heptane (1:3) as eluent to
afford 4.7 g (77%) of compound 3k as an off-white solid. (mp
1
assay by HPLC, 95% yield, mp 193−195 °C). H NMR (400
MHz, (CD3)2SO): δ 10.53 (s, 1H), 7.94 (d, J = 10.0 Hz, 1H),
7.85 (d, J = 9.6 Hz, 2H) 7.55 (br s, 1H), 3.93 (s, 3H). 13C
NMR (100 MHz, (CD3)2SO): δ 142.9, 141.6, 138.7, 135.2,
120.5, 110.7, 56.9. HRMS (ESI) (m/z): calcd for C7H8BrN3O2
245.9873 [M + H]+, found 245.9874.
1
175−177 °C.) H NMR (400 MHz, (CD3)2SO): δ 10.39 (s,
1H), 8.02 (d, J = 10.0 Hz, 1H), 7.93 (d, J = 10.0 Hz, 1H), 7.78
(dd, J = 4.8 Hz, 1.2 Hz, 1H), 7.36−7.49 (m, 6H), 6.89 (dd, J =
8.0 Hz, 5.2 Hz, 1H), 5.23 (s, 2H). 13C NMR (100 MHz,
DMSO-d6): δ 142.7, 141.2, 139.0, 136.7, 135.6, 129.1, 128.7,
128.2, 119.3, 117.1, 70.3. HRMS (ESI) (m/z): calcd for
C13H13N3O2 244.1081 [M + H]+, found 244.1076.
General Procedure for the Synthesis of Heteroaryl-
Fused 1,2,4-Triazoles (1a−k, 7, 10, and 13). To an oven-
dried three-neck round-bottom flask fitted with a thermocou-
ple and reflux condenser, THF (10 mL per g of the N′-
hydroxy-N-formimidamide) was added under a nitrogen
atmosphere, followed by the appropriate N′-hydroxy-N-
formimidamide (1.0 equiv). The resultant mixture was stirred
for 10 min at 25−30 °C. Once complete dissolution was
achieved, T3P (50% solution in EtOAc, 1.5 equiv) was added
slowly into the reaction vessel and stirred for 2−16 h at 55−60
°C. Then, the reaction mass was quenched with 10% aqueous
NaHCO3 and extracted with EtOAc (2 × 10 mL per g of the
N′-hydroxy-N-formimidamide). The organic layer was dried
over Na2SO4, filtered, and concentrated in vacuo. The residue
N′-Hydroxy-N-(6-methoxypyridazin-3-yl)formimidamide
(6). The reaction was conducted on a 4.0 g scale using the
general procedure. The product was purified by column
chromatography using EtOAc/n-heptane (1:3) as eluent to
afford 2.8 g (52%) of compound 6 as an off-white solid (mp
1
169−171 °C). H NMR (400 MHz, (CD3)2SO): δ 10.19 (s,
1H), 9.36 (d, J = 10.0 Hz, 1H), 7.86 (d, J = 10.0 Hz, 1H), 7.38
(d, J = 9.6 Hz, 1H), 7.12 (d, J = 9.6 Hz, 1H), 3.22 (s, 3H). 13
C
NMR (100 MHz, (CD3)2SO): δ 161.7, 151.8, 135.6, 121.6,
D
DOI: 10.1021/acs.oprd.9b00396
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Organic Process Research & Development
Article
was purified by column chromatography to furnish the desired
product.
(1:3) as eluent to afford 820 mg (88%) of compound 1f as an
off-white solid (mp 100−102 °C). 1H NMR (400 MHz,
(CD3)2SO): δ 9.69 (s, 1H), 8.72 (s, 1H), 8.07 (d, J = 9.2 Hz,
1H), 7.96 (dd, J = 9.6 Hz, 2 Hz, 1H). 19F NMR (376.4 MHz,
(CD3)2SO): δ 60.1. 13C NMR (100 MHz, (CD3)2SO): δ
155.7, 150.7, 129.0 (q, JC‑F =5.5 Hz), 126.1 (q, JC‑F =2.7 Hz),
123.2 (q, JC‑F =269.6 Hz), 117.4, 116.8 (q, JC‑F = 34.1 Hz).
HRMS (ESI) (m/z): calcd for C7H4F3N3, 188.0430 [M + H]+,
found 188.0435.
5-Methoxy-[1,2,4]triazolo[1,5-a]pyridine (1a). The reac-
tion was conducted on a 1.0 g scale using the general
procedure and was complete within 16 h. The product was
purified by column chromatography using EtOAc/n-heptane
(1:3) as eluent to afford 700 mg (78%) of compound 1a as an
off-white solid (mp 113−115 °C). 1H NMR (400 MHz,
(CD3)2SO): δ 8.44 (s, 1H), 7.67 (dd, J = 8.8 Hz, 8.0 Hz, 1H),
7.42 (dd, J = 8.8 Hz, 0.8 Hz, 1H), 6.67 (d, J = 8.0 Hz, 1H),
4.14 (s, 3H). 13C NMR (75 MHz, (CD3)2SO): δ 154.1, 151.9,
151.5, 132.1, 107.9, 92.4, 57.8. HRMS (ESI) (m/z): calcd for
C7H7N3O, 150.0662 [M + H]+, found 150.0662.
6-Chloro-[1,2,4]triazolo[1,5-a]pyridine (1g). The reaction
was conducted on a 1.0 g scale using the general procedure and
was complete within 5 h. The product was purified by column
chromatography using EtOAc/n-heptane (1:3) as eluent to
afford 850 mg (95%) of compound 1g as an off-white solid
5-Phenyl-[1,2,4]triazolo[1,5-a]pyridine (1b). The reaction
was conducted on a 1.0 g scale using the general procedure and
was complete within 5 h. The product was purified by column
chromatography using EtOAc/n-heptane (1:3) as eluent to
afford 640 mg (70%) of compound 1b as an off-white solid
1
(mp 114−116 °C). H NMR (400 MHz, (CD3)2SO): δ 9.35
(q, J = 0.8 Hz, 1H), 8.56 (s, 1H), 7.91 (dd, J = 9.6 Hz, 0.8 Hz,
1H), 7.76 (dd, J = 9.6 Hz, 2.0 Hz, 1H). 13C NMR (100 MHz,
(CD3)2SO): δ 155.0, 149.3, 131.8, 128.2, 121.5, 117.3 HRMS
(ESI) (m/z): calcd for C6H4ClN3, 154.0167 [M + H]+, found
154.0172.
1
(mp 103−105 °C). H NMR (400 MHz, (CD3)2SO): δ 8.54
(s, 1H), 7.99−8.01 (m, 2H), 7.88 (dd, J = 8.8 Hz, 1.2 Hz, 1H),
7.77 (dd, J = 8.8 Hz, 7.2 Hz, 1H), 7.39−7.60 (m, 3H), 7.37 (d,
J = 1.2 Hz, 1H). 13C NMR (100 MHz, (CD3)2SO): δ 153.9,
151.3, 140.6, 132.5, 130.8, 130.4, 129.6, 129.0, 115.7, 114.8.
HRMS (ESI) (m/z): calcd for C12H9N3, 196.0869 [M + H]+,
found 196.0871.
7-Chloro-[1,2,4]triazolo[1,5-a]pyridine (1h). The reaction
was conducted on a 1.0 g scale using the general procedure and
was complete within 5 h. The product was purified by column
chromatography using EtOAc/n-heptane (1:1) as eluent to
afford 760 mg (85%) of compound 1h as an off-white solid
1
5-Fluoro-[1,2,4]triazolo[1,5-a]pyridine (1c). The reaction
was conducted on a 0.5 g scale using the general procedure and
was complete within 5 h. The product was purified by column
chromatography using EtOAc/n-heptane (1:1) as eluent to
afford 265 mg (60%) of compound 1c as an off-white solid
(mp 111−113 °C). H NMR (400 MHz, (CD3)2SO): δ 9.03
(dd, J = 10.0 Hz, 0.8 Hz, 1H), 8.56 (s, 1H) 8.1 (dd, J = 2.8 Hz,
0.8 Hz, 1H), 7.31 (dd, J = 10.0 Hz, 3.2 Hz, 1H). 13C NMR (75
MHz, (CD3)2SO): δ 155.3, 150.7, 135.8, 130.6, 115.8, 115.8.
HRMS (ESI) (m/z): calcd for C6H4ClN3, 154.0167 [M + H]+,
found 154.0171.
1
(mp 152−154 °C). H NMR (400 MHz, (CD3)2SO): δ 8.64
(s, 1H), 7.76−7.83 (m, 2H), 7.18−7.21 (m, 1H). 19F NMR
(376.4 MHz, (CD3)2SO): δ 107.7. 13C NMR (100 MHz,
(CD3)2SO): δ 154.4 (d, JC‑F =1.1 Hz), 152.1 (d, JC‑F = 6.4 Hz),
149.5 (d, JC‑F = 268.7 Hz), 131.7 (d, JC‑F = 6.5 Hz), 112.2 (d,
JC‑F = 5.1 Hz), 96.0 (d, JC‑F = 15.0 Hz). HRMS (ESI) (m/z):
calcd for C6H4FN3 138.0462 [M + H]+, found 138.0468.
5-(Trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine (1d).
The reaction was conducted on a 1.0 g scale using the general
procedure, and was complete within 16 h. The product was
purified by column chromatography using EtOAc/n-heptane
(1:3) as eluent to afford 450 mg (49%) of compound 1d as an
off-white solid (mp 117−119 °C). 1H NMR (400 MHz,
(CD3)2SO): δ 8.73 (s, 1H), 8.22−8.24 (m, 1H), 7.84−7.86
(m, 2H). 13C NMR (100 MHz, (CD3)2SO): δ 154.4, 150.7,
129.4, 126.8 (q, JC‑F = 36.7 Hz), 119.7 (q, JC‑F = 270.5 Hz),
114.6 (q, JC‑F = 4.3 Hz), 113.2. HRMS (ESI) (m/z): calcd for
C7H4F3N3 188.0430 [M + H]+, found 188.0420.
[1,2,4]Triazolo[1,5-a]pyridine-7-carbonitrile (1i). The re-
action was conducted on a 1.0 g scale using the general
procedure and was complete within 16 h. The product was
purified by column chromatography using EtOAc/n-heptane
(3:1) as eluent to afford 710 mg (80%) of compound 1i as an
off-white solid (mp 174−176 °C). 1H NMR (400 MHz,
(CD3)2SO): δ 9.23 (dd, J = 7.2 Hz, 0.8 Hz, 1H), 8.77 (s, 1H),
8.68 (dd, J = 1.6 Hz, 0.8 Hz, 1H), 7.6 (dd, J = 7.2 Hz, 2.0 Hz,
1H). 13C NMR (100 MHz, (CD3)2SO): δ 156.0, 149.3, 131.1,
123.3, 117.4, 115.3, 113.0. HRMS (ESI) (m/z): calcd for
C7H4N4, 145.0509 [M + H]+, found 145.0513.
Methyl [1,2,4]Triazolo[1,5-a]pyridine-7-carboxylate (1j).
The reaction was conducted on a 1.5 g scale using the general
procedure and was complete within 16 h. The product was
purified by column chromatography using EtOAc/n-heptane
(3:1) as eluent to afford 1.25 g (92%) of compound 1j as an
off-white solid (mp 124−126 °C). 1H NMR (400 MHz,
(CD3)2SO): δ 9.10 (d, J = 9.6 Hz, 1H), 8.70 (s, 1H), 8.39 (s,
1H), 7.59 (dd, J = 9.6 Hz, 2.4 Hz, 1H), 3.94 (s, 3H). 13C NMR
(100 MHz, (CD3)2SO): δ 164.7, 156.3, 151.7, 132.7, 129.8,
118.1, 116.5, 53.2. HRMS (ESI) (m/z): calcd for C8H7N3O2,
178.0611 [M + H]+, found 178.0602.
8-(Benzyloxy)-[1,2,4]triazolo[1,5-a]pyridine (1k). The re-
action was conducted on a 1.0 g scale using the general
procedure and was complete within 16 h. The product was
purified by column chromatography using EtOAc/n-heptane
(3:1) as eluent to afford 755 mg (82%) of compound 1k as an
off-white solid (mp 151−153 °C). 1H NMR (400 MHz,
(CD3)2SO): δ 8.57 (dd, J = 8.8 Hz, 1.2 Hz, 1H), 8.44 (s, 1H),
7.51−7.54 (m, 1H), 7.43−7.46 (m, 1H), 7.37−7.41 (m, 3H),
7.17−7.2 (m, 1H), 7.08−7.13 (m, 1H), 5.36 (s, 2H). 13C
NMR (100 MHz, (CD3)2SO): δ 153.3, 147.5, 145.1, 136.5,
6-Nitro-[1,2,4]triazolo[1,5-a]pyridine (1e). The reaction
was conducted on a 1.0 g scale using the general procedure
and was complete within 16 h. The product was purified by
column chromatography using EtOAc/n-heptane (1:1) as
eluent to afford 600 mg (67%) of compound 1e as a yellow
1
solid (mp 211−213 °C). H NMR (400 MHz, (CD3)2SO): δ
10.17 (t, J = 1.6 Hz, 1H), 8.83 (s, 1H), 8.39 (dd, J = 9.6 Hz,
2.4 Hz, 1H), 8.05 (dd, J = 9.6 Hz, 0.8 Hz, 1H). 13C NMR (100
MHz, (CD3)2SO): δ 157.7, 152.0, 138.5, 130.0, 125.2, 116.3.
HRMS (ESI) (m/z): calcd for C6H4N4O2, 165.0407 [M + H]+,
found 165.0411.
6-(Trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine (1f). The
reaction was conducted on a 1.0 g scale using the general
procedure and was complete within 2 h. The product was
purified by column chromatography using EtOAc/n-heptane
E
DOI: 10.1021/acs.oprd.9b00396
Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development
Article
129.0, 128.7, 128.5, 122.3, 114.6, 109.1, 70.9. HRMS (ESI)
(m/z) calcd for C13H11N3O, 226.0975 [M + H]+, found
226.0976.
AUTHOR INFORMATION
Corresponding Author
*E-mail: vaidy@bms.com.
■
6-Methoxy-[1,2,4]triazolo [1,5-b] pyridazine (7). The
reaction was conducted on a 1.0 g scale using the general
procedure and was complete within 16 h. The product was
purified by column chromatography using EtOAc/n-heptane
(1:3) as eluent to afford 600 mg (67%) of compound 7 as a
pale yellow solid (mp 179−181 °C).1H NMR (400 MHz,
(CD3)2SO): δ 8.48 (s, 1H), 8.31 (d, J = 9.6 Hz, 1H), 7.32 (d, J
= 9.6 Hz, 1H), 4.01 (s, 3H). 13C NMR (100 MHz,
(CD3)2SO): δ 160.8, 151.8, 142.0, 127.8, 117.8, 55.6. HRMS
(ESI) (m/z): calcd for C6H6N4O, 151.0614 [M + H]+, found
151.0619.
ORCID
̈
Michael Fenster: 0000-0003-1438-1724
Martin D. Eastgate: 0000-0002-6487-3121
Rajappa Vaidyanathan: 0000-0002-2236-5719
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Analytical support from Naresh Marella, Gopi Vayila, and
Subhrakanti Saha is gratefully acknowledged. The authors
thank Prantik Maity for his valuable suggestions, and Dr.
Robert Waltermire and Dr. David Kronenthal for their support.
[1,2,4]Triazolo[1,5-a]pyrazine (10). The reaction was
conducted on a 1.0 g scale using the general procedure and
was complete within 5 h. The product was purified by column
chromatography using EtOAc/n-heptane (1:3) as eluent to
afford 750 mg (86%) of compound 10 as an off-white solid
REFERENCES
■
(1) Siu, M.; Pastor, R.; Liu, W.; Barrett, K.; Berry, M.; Blair, W. S.;
Chang, C.; Chen, J. Z.; Eigenbrot, C.; Ghilardi, N.; Gibbons, P.; He,
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1
(mp 139−141 °C). H NMR (400 MHz, (CD3)2SO): δ 9.45
(d, J = 0.8 Hz, 1H), 9.13 (dd, J = 4.8 Hz, 1.6 Hz, 1H), 8.77 (s,
1H), 8.29 (d, J = 4.4 Hz, 1H). 13C NMR (100 MHz,
(CD3)2SO): δ 155.0, 153.6, 143.4, 132.2, 123.3. HRMS (ESI)
(m/z): calcd for C5H4N4, 121.0509 [M + H]+, found
121.0512.
[1,2,4]Triazolo[1,5-b]isoquinoline (13). The reaction was
conducted on a 1.0 g scale using the general procedure and was
complete within 5 h. The product was purified by column
chromatography using EtOAc/n-heptane (1:3) as eluent to
afford 510 mg (55%) of compound 13 as a pale brownish solid
(mp 97−99 °C). 1H NMR (400 MHz, (CD3)2SO): δ 10.00 (s,
1H), 8.72 (s, 1H), 8.46 (s, 1H), 8.07 (d, J = 8.8 Hz, 1H), 8.02
(d, J = 8.4 Hz, 1H), 7.56−7.60 (m, 1H), 7.46−7.50 (m, 1H).
13C NMR (100 MHz, (CD3)2SO): δ 156.6, 149.1, 133.7,
129.1, 128.5, 127.2, 126.8, 126.2, 122.4, 111.0. HRMS (ESI)
(m/z): calcd for C10H7N3, 170.0713 [M + H]+ found,
170.0698.
6-Bromo-8-methoxy-[1,2,4]triazolo[1,5-a]pyridine (1l). To
a clean 60 L glass reactor, THF (16 L) and compound 3l (1.6
kg, 6.5 mol, 1.0 equiv) were sequentially added at 20−35 °C
under a nitrogen atmosphere. T3P (50% w/w in EtOAc, 4.4
kg, 6.5 mol, 1.0 equiv) was added at the same temperature, and
the mixture was stirred for 5 h at 50−55 °C. After reaction
completion, the contents of the reactor were cooled to 20−35
°C, and EtOAc (16 L) and purified water (8 L) were charged
and stirred for 15 min. The organic layer was separated and the
aqueous layer was backextracted with EtOAc (8 L). The
combined organic layers were sequentially washed with 10%
aqueous NaHCO3 solution (16 L), purified water (8 L), and
brine (8 L). The organic layer was concentrated under vacuum
at 45 °C to ∼4 L and then n-heptane (24 L) was added. The
mass was then cooled to 20−35 °C and allowed to granulate
for 30 min. The resulting slurry was filtered through a Nutsche
filter, and the filter cake was washed with n-heptane (8 L). The
wet solid was dried under vacuum at 45−50 °C to afford
compound 1l as a pale brown solid (1.2 kg, HPLC purity
99.0%, Assay by HPLC 97.80%, 81% yield, mp 150−151 °C).
1H NMR (400 MHz, (CD3)2SO): δ 8.95 (d, J = 1.2 Hz, 1H),
8.46 (s, 1H), 7.26 (d, J = 1.6 Hz, 1H), 4.02 (s, 3H). 13C NMR
(100 MHz, (CD3)2SO): δ 153.6, 148.4, 144.2, 122.3, 111.3,
108.3, 57.4 HRMS (ESI) (m/z): calcd for C7H6BrN3O,
227.9767 [M + H]+, found 227.9768.
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DOI: 10.1021/acs.oprd.9b00396
Org. Process Res. Dev. XXXX, XXX, XXX−XXX