2,2,2-Trifluoroethoxy Aromatic Heterocycles: Hydrolytically Stable Alternatives to Heteroaryl Chlorides

Article abstract of DOI:10.1021/acs.joc.8b02453

Herein we describe the 2,2,2-trifluoroethoxy group as an alternative leaving group for hydrolytically unstable heteroaryl chlorides. This group provides improved shelf stability by years while maintaining reactivity toward nucleophiles in S_NAr

Full text of DOI:10.1021/acs.joc.8b02453

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Note
2,2,2-Trifluoroethoxy Aromatic Heterocycles:
Hydrolytically Stable Alternatives to Heteroaryl Chlorides
ETHAN L. FISHER, Christopher W. am Ende, and John M. Humphrey
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b02453 • Publication Date (Web): 19 Oct 2018
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2,2,2-Trifluoroethoxy Aromatic Heterocycles: Hydrolytically Stable Alternatives to Heteroaryl
Chlorides
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Ethan L. Fisher,* Christopher W. am Ende, and John M. Humphrey
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Pfizer Worldwide Research and Development, Eastern Point Road, Groton, Connecticut 06340, United
States
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TOC/Abstract Graphic:
OMe
OMe
MeO
N
O
MeO
N
N
N
F3C
Cl
Hydrolytically unstable
• Bench stable >3 years
• Facile preparation
• SNAr electrophiles
Abstract: Herein we describe the 2,2,2-trifluoroethoxy group as an alternative leaving group for
hydrolytically unstable heteroaryl chlorides. This group provides improved shelf stability by years while
maintaining reactivity toward nucleophiles in SNAr reactions. A highlighted trifluoroethyl ether was
shown to be tolerant to aqueous Suzuki conditions, permitting sequential Suzuki/SNAr processes
inaccessible to the heterocyclic chlorides. The strategic use of trifluoroethyl ethers enables storage of
otherwise unstable heterocyclic chlorides and limits costly decomposition..
Nucleophilic aromatic substitution (SNAr) is among the most prevalent chemical reactions in
pharmaceutical research.1 In the course of our work on quinazoline based PDE1 inhibitors,2 SNAr between
the heterocyclic chloride (Het-Cl) 1 and the amine 2, returned inconsistent yields (45–85%) of adduct 3
(Scheme 1). The variable yields were later attributed to the quality of the Het-Cl, with production lots
from different sources found to contain varying amounts of the quinazoline hydrolysis product 4. Further
experimentation demonstrated that the Het-Cl 1 can undergo hydrolysis to the quinazolone 4 upon
extended storage under ambient conditions or repeated manipulation in an acid-catalyzed process.3 Thus,
the HCl by-product of the hydrolysis catalyzes further decomposition of the substrate.
Scheme 1. Synthesis of Quinazoline 3
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H2N
OMe
5
6
7
8
MeO
N
OMe
NH
N
MeO
N
X
N
2
N
HN
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45-85%
yield
3
1
4
(X = Cl)
(X = OH)
HN
N
While limited amounts of Het-Cl hydrolysis during storage may prove of little consequence for
many exploratory studies, the problem is exacerbated on larger reaction scale where cost must be
minimized. In the manufacture of a pharmaceutical API, consistency in feedstock composition is a
considerable concern that can be adversely affected by shipping and storage conditions. Even for
medicinal chemistry discovery, which typically involves smaller quantities, the presence of labile Het-Cl
functionality in advanced intermediates can complicate structure-activity relationship (SAR) exploration.
In order to address this relatively common problem, we sought to identify a hydrolytically stable leaving
group alternative to chloride that would be applicable to quinazolines as well as other reactive Het-Cl’s.
Thus, we have selected for discussion three other Het-Cl systems from our research programs that
suffered significant hydrolysis during storage (chlorides 5, 6, and 7, Scheme 2). In order to crudely
quantify the extent of hydrolysis that occurred during typical storage, a freshly prepared sample of each
chloride was placed in a capped vial under air and stored at room temperature. After one month, analysis
by 1H NMR indicated pyrazolopyrimidine 54 and imidazotriazene 65, cores found in PDE inhibitors 86 and
97, had hydrolyzed by ~20% and ~60%, respectively. A freshly prepared sample of reactive
chloroquinoline 7, an early intermediate in the synthesis of Imiquimod,8 had fully degraded to the
hydroxyquinoline over the same period of time.
Scheme 2. Decomposition of Heterocyclic Chlorides
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7
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9
N
Hydrolysis at 1 month
~20%
N
Cl
Br
N
N
N
Ar
8
N
N
PDE2 inhibitor
N
N
N
N
N
5
F
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N
Cl
N
Br
N
N
N
9
~60%
Ar
PDE2 inhibitor
N
N
N
N
N
6
Cl
N
NO2
Imiquimod
TLR7 agonist
N
~99%
N
N
NH2
7
In order to address this problem, we considered attributes of potential chloride replacements such
as ease of installation, availability, and conjugate acid pKa. Based on these factors we identified the 2,2,2-
trifluoroethoxy group as a competent substitute (Scheme 3).9 Preparation of ether 10 was accomplished
by the reaction of the chloroquinazoline with t-BuOK and trifluoroethanol (TFE) in THF. Analysis of the
1
ether showed complete shelf stability under ambient conditions with no measureable hydrolysis by H
NMR after two years. Conversely, a freshly prepared sample of chloride 1 had undergone 75%
decomposition to the quinazolone 4 after one month. Upon application, displacement of the trifluoroethyl
ether 10 with the amine 2 (Et3N, DMSO, 90 °C) afforded adduct 3 in high yield. Trifluoroethanol is
commercially available in bulk quantities and its physical properties (water miscible, bp 77–80 °C),
facilitates its removal post reaction. Furthermore, the trifluoroethyl ether mitigates the risk of
autocatalytic hydrolysis as trifluoroethanol is weakly acidic (pKa 12.4 in H2O)10 in contrast to chloride
(pKa HCl = –5.9 in H2O).11 While this strategy requires an additional step for the conversion of the
chloride into the ether, it assures the integrity of the material during storage and shipment. The latter
points are of critical concern as one increases scale from research quantities to bulk lots for API
manufacture. The ability to store SNAr precursors at room temperature is also of value in a medicinal
chemistry program for rapid SAR generation.
Scheme 3. Preparation and Reaction of Trifluoroethyl ether 10
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OMe
OMe
t-BuOK, TFE
MeO
N
O
MeO
N
THF
N
N
87% yield
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9
CF3
Cl
OMe
MeO
1
10
N
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N
2
Et3N, DMSO 90 °C
HN
93% yield
3
NH
N
Trifluoroethyl ethers 11–18 were easily prepared from the corresponding chlorides via
displacement with trifluoroethoxide in either trifluoroethanol or THF as described in the Experimental
Section (Table 1). To demonstrate the long term stability of select heterocycles, samples of trifluoroethyl
ethers 11 and 12 were stored on the bench in screw capped vials under air. 1H NMR analysis of the ethers
after three years indicated no-detectible hydrolysis, thus demonstrating superior stability on storage
compared to the corresponding chlorides (cf. 5 and 6, Scheme 2).
Table 1. Substrate Table
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R1
R2
N
H
R1
R2
Et3N, DMSO, heat
HetAr
O
CF3
HetAr
19-26
temp (°C) yield (%)
N
7
8
9
11-18
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TFE ether
Product
F3C
O
N
Br
N
Br
11
19
N
23
23
23
99
95
96
N
N
N
N
N
N
F
F3C
12[a]
O
Br
N
N
Br
N
N
20
21
N
N
N
N
N
F3C
O
N
NH
N
NO2
13
NO2
CF3
84[b]
F3C
N
O
120
80
F3C
O
N N
N
N N
N
14
15
22
CF3
O
N
23
92
NO2
NO2
CF3
CF3
N
N
N
O
O
80
16
17
18
24
25
26
93
89
92
CN
CN
N
N
N
120
80
N
N
Ph
Ph
CF3
O
N
O
N
N
O
O
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aDBU used as base. b55% conversion at 24 hours, yield is BRSM
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The reactivity of trifluoroethyl ethers 11–18 toward substitution was examined with various
nitrogen nucleophiles as illustrated in Table 1. In general, each reacted smoothly (DMSO, Et3N or DBU,
rt to 120 °C) to afford the products in high yield (84–99%).12 One particularly reactive system is
represented by the nitroquinoline 13. For this system, the chloride (7, Scheme 2) was found to be
exceedingly unstable and even the corresponding trifluoroethyl ether suffered significant hydrolysis
during storage.13 In this case, the methyl ether 27 proved to be a more stable alternative capable of later
displacement under mild conditions (Scheme 4).
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Scheme 4. Tempering Reactivity of 13
OMe
N
F3C
O
N
modulate
nucleofuge
NO2
NO2
13
27
NH2
NH
N
NO2
Et3N, DMSO, 23 °C
97% yield
21
To demonstrate the utility of the trifluoroethyl ether as a latent electrophile, we chose to explore a
Suzuki coupling/SNAr sequence. Bromide 11 was coupled with the pyrazole boronate under a standard set
of Suzuki reaction conditions in the presence of water (Scheme 5). The coupling product 28 was obtained
in high yield with no observable ether hydrolysis, whereas the corresponding chloride did not survive
similar coupling conditions. Subsequent reaction with azetidine afforded the SNAr product 29 without
issue. This strategy was effectively exploited in the synthesis of the of pyrazolopyrimidine class of PDE2
inhibitors exemplified by 8.
Scheme 5. Trifluoroethyl Ether Stability in Suzuki Coupling
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N
CF3
F3C
N
N
N
PinB
O
O
N
Br
N
azetidine, Et3N
DMSO, 80 °C
PdCl2(dppf), K3PO4
dioxane, H2O, 80 °C
N
N
N
80% yield
85% yield
N
N
N
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N
N
N
N
N
N
Ar
ref 6
N
N
N
N
N
N
N
N
29
8
In conclusion, we have presented a general strategy to address the instability of heteroaryl
chlorides during storage by use of trifluoroethyl ether surrogates. Heteroaryl trifluoroethyl ethers exhibit
improved hydrolytic stability as compared to the corresponding Het-Cl’s under ambient conditions
permitting storage without special requirements, yet maintain reactivity toward nitrogen nucleophiles in
SNAr reactions. The trifluoroethyl group is introduced under mild conditions and excess trifluoroethanol
is easily removed from the reaction with an aqueous workup or evaporation. Use of the trifluoroethyl
ether as a latent electrophile, exemplified in a sequential cross coupling-SNAr protocol, permits the use of
reactions not accessible to the corresponding Het-Cl’s. This method should prove useful for mitigating the
risk of heterocyclic feedstock hydrolysis for both medicinal and process scale efforts.
Experimental
General. All reagents and solvents were obtained from commercial sources and used without
further purification. Reactions requiring heat were performed in aluminum heating blocks. Reaction
progress was monitored by UPLC-MS (Waters Acquity, ESCI ±, APCI ±) or TLC (Analtech, Inc. silica
gel GF 250 μm plates). H NMR, 19F NMR, and 13C{1H} NMR spectra were obtained on Bruker or
1
Varian instruments (400, 376, and 100 MHz respectively). 1H and 13C chemical shifts are reported in ppm
relative to chloroform (7.26 ppm and 77.00 ppm, respectively) or DMSO (2.50 ppm and 39.51 ppm,
respectively). NMR multiplicities are reported as: s, singlet; d, doublet; t, triplet; quint, quintet; m,
multiplet; br, broadened; ddd, doublet of doublet of doublets. IR (infrared) spectra were obtained on a
Thermo Nicolet Avatar 360 FT-IR. High resolution mass spectra (HRMS) were obtained on an Agilent
model 6220 MS (ESI-TOF). Melting points were recorded on a Sanford Research Systems OptiMelt and
are uncorrected.
Synthesis of Trifluoroethyl Ethers, General Procedure A: To a solution of heteroaryl chloride
(1 equiv) in 2,2,2-trifluoroethanol (0.2 M) at 0 °C was added potassium tert-butoxide (2 equiv). After 5
minutes the ice bath was removed and the reaction stirred at the indicated temperature. After complete
conversion of the reaction (monitored by LCMS or TLC), all organics were evaporated. The crude residue
was diluted with EtOAc or DCM, washed with water × 3, brine, dried over Na2SO4 or MgSO4, filtered and
concentrated. The product was purified as described.
General Procedure B: To a solution of heteroaryl chloride (1 equiv) and 2,2,2-trifluoroethanol
(2 equiv) in THF (0.2 or 0.4 M) at 0 °C was added potassium tert-butoxide (1.2 equiv). After 5 minutes
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the ice bath was removed and the reaction stirred at the indicated temperature. After complete conversion
of the reaction (monitored by LCMS or TLC), all organics were evaporated. The crude residue was
diluted with EtOAc or DCM, washed with water × 3, brine, dried over Na2SO4 or MgSO4, filtered and
concentrated. The product was purified as described.
7
8
9
7,8-Dimethoxy-4-(2,2,2-trifluoroethoxy)quinazoline (10). Following General Procedure B, 4-chloro-7,8-
dimethoxyquinazoline (595 mg, 2.65 mmol), 2,2,2-trifluoroethanol (0.38 mL, 5.30 mmol), THF (6 mL),
and t-BuOK (357 mg, 3.18 mmol) at room temperature for 1 hour resulted in the desired product as an
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off-white solid after recrystallization from hot heptane (650 mg, 2.26 mmol, 87% yield). H NMR (400
MHz, CDCl3)  8.78 (s, 1H), 7.98 (d, J = 9.0 Hz, 1H), 7.35 (d, J = 9.4 Hz, 1H), 4.98 (q, JHF = 8.6 Hz, 2H),
19
4.11 (s, 3 H), 4.05 (s, 3H); F NMR (376 MHz, CDCl3)  –73.57 (t, JHF = 8.0 Hz); 13C{1H} NMR (100
MHz, DMSO-d6)  164.7, 155.8, 153.3, 146.1, 141.9, 125.3 (q, JCF = 227.3 Hz), 119.8, 119.1,
115.9, 110.2. 62.2 (q, J = 35.2 Hz), 61.5, 56.7; IR (thin film) max 1611, 1565, 1474 cm−1; HRMS
(ESI/QTOF) m/z: [M+H]+ Calcd for C12H12F3N2O3 289.0795; Found 289.0802; Melting point 81.7–82.1
°C
3-Bromo-1-methyl-4-(2,2,2-trifluoroethoxy)-1H-pyrazolo[3,4-d]pyrimidine (11). Following General
Procedure A, 3-bromo-4-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidine (7.03 g, 28.4 mmol), 2,2,2-
trifluoroethanol (140 mL), and t-BuOK (6.37 g, 56.8 mmol) at room temperature for 18 hour resulted in
the desired product as an off-white solid without further purification (8.22 g, 26.2 mmol, 93% yield)
Following General Procedure B, 3-bromo-4-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidine (500 mg,
2.02 mmol), 2,2,2-trifluoroethanol (0.291 mL, 4.04 mmol), THF (10 mL), and t-BuOK (378 mg, 2.53
mmol) at room temperature for 19 hours resulted in the desired product as an off-white solid after silica
1
gel chromatography (0–10% EtOAc:heptane) (565 mg,1.82 mmol, 90% yield). H NMR (400 MHz,
CDCl3)  8.54 (s, 1H), 5.00 (q, JHF = 8.2 Hz, 2H), 4.08 (s, 3H); 19F NMR (376 MHz, CDCl3)  –73.60 (t,
13
JHF = 8.0 Hz); C{1H} NMR (100 MHz, CDCl3)  161.6, 155.6, 155.3, 123.0 (q, JCF = 276 Hz), 117.9,
102.7, 62.5 (q, JCF = 37 Hz), 34.5; IR (thin film) max 1606, 1558, 1465 cm−1; HRMS (ESI/QTOF) m/z:
[M+H]+ Calcd for C8H7BrF3N4O 310.9750 and 312.9730; Found 310.9741 and 312.9717; Melting point
156.0–156.1 °C.
5-Bromo-7-methyl-4-(2,2,2-trifluoroethoxy)imidazo[5,1-f][1,2,4]triazine (12). Following General
Procedure A, 5-bromo-4-chloro-7-methylimidazo[5,1-f][1,2,4]triazine (2.00 g, 8.08 mmol), 2,2,2-
trifluoroethanol (40 mL), and t-BuOK (1.81 g, 16.2 mmol) at room temperature for 18 hour resulted in
1
the desired product as an off-white solid without further purification (2.10 g, 6.75 mmol, 84% yield) H
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NMR (400 MHz, CDCl3)  7.98 (s, 1H), 4.95 (q, JHF = 8.2 Hz, 2H), 2.70 (s, 3H); F NMR (376 MHz,
CDCl3)  –73.49 (t, JHF = 8.0 Hz); 13C{1H} NMR (100 MHz, CDCl3)  160.8, 147.5, 142.1, 131.7 (q, JCF
= 277 Hz), 112.0, 109.4, 62.5 (q, JCF = 37 Hz), 11.9; IR (thin film) max 1606, 1520, 1474 cm−1; HRMS
(ESI/QTOF) m/z: [M+H]+ Calcd for C8H7BrF3N4O 310.9750 and 312.9730; Found 310.9743 and
312.9717; Melting point 107.1–107.6 °C.
3-Nitro-4-(2,2,2-trifluoroethoxy)quinolone (13). Following General Procedure A, 3-Nitro-4-
chloroquinoline (742 mg, 3.56 mmol), 2,2,2-trifluoroethanol (17.8 mL), and t-BuOK (798 mg, 7.11
mmol) at room temperature for 20 hours resulted in the desired product as a beige amorphous solid
1
without further purification (938 mg, 3.45 mmol, 97% yield). H NMR (400 MHz, DMSO-d6)  9.40 (s,
1H), 8.30 (d, J = 7.8 Hz, 1H), 8.17 (d, J = 8.2 Hz, 1H), 8.04 (ddd, J = 1.4, 7.0, 8.4 Hz, 1H), 7.87 (t, J = 7.3
Hz, 1H), 5.14 (q, JHF = 9.0 Hz, 2H); 19F NMR (376 MHz, DMSO-d6)  –73.56 (t, JHF = 8.0 Hz); 13C{1H}
NMR (100 MHz, DMSO-d6)  155.8, 150.3, 146.4, 133.7, 133.3, 129.4, 128.8, 123.5, 123.2 (q, JCF = 277
Hz), 122.0, 70.8 (q, JCF = 35.2 Hz); IR (thin film) max 1590, 1574, 1525, 1374, 1344, 1279, 1182 cm−1;
HRMS (ESI/QTOF) m/z: [M+H]+ Calcd for C11H8F3N2O3 273.0482; Found 273.0475.
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3-(2,2,2-Trifluoroethoxy)-6-(trifluoromethyl)pyridazine (14). Following General Procedure A, 3-chloro-6-
(trifluoromethyl)pyridazine (670 mg, 3.67 mmol, 75% pure), 2,2,2-trifluoroethanol (18.3 mL), and t-
BuOK (823 mg, 7.33 mmol) at 60 °C for 6 hours resulted in the desired product as a light pink oil after
silica gel chromatography (0–20% EtOAc:heptane) (500 mg, 2.03 mmol, 74% yield based on purity of
chloride). 1H NMR (400 MHz, CDCl3)  7.80 (d, J = 8.0 Hz, 1H), 7.30 (d, J = 8.0 Hz, 1H), 5.03 (q, JCF
=
8.0 Hz, 2H); 19F NMR (376 MHz, CDCl3)  –66.48 (s), –73.80 (t, JHF = 8.0 Hz); 13C{1H} NMR (100
MHz, CDCl3)  164.4, 149.0 (q, JCF = 35 Hz), 127.3 (q, JCF = 2 Hz), 122.9 (q, JCF = 275 Hz), 121.2 (q,
JCF = 273 Hz), 118.0, 63.89 (q, JCF = 37 Hz); IR (thin film) max 1594, 1466, 1450 cm−1; HRMS
(ESI/QTOF) m/z: [M+H]+ Calcd for C7H4F6N2O 247.0301; Found 247.0300.
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3-Nitro-2-(2,2,2-trifluoroethoxy)pyridine (15). Following General Procedure A, 2-chloro-3-nitropyridine
(2.00 g, 12.6 mmol), 2,2,2-trifluoroethanol (63 mL), and t-BuOK (2.83 g, 25.2 mmol) at 75 °C for 8
hours resulted in the desired product as a yellow waxy solid after silica gel chromatography (0–25%
EtOAc:heptane) (2.51 g, 11.3 mmol, 90% yield). 1H NMR (400 MHz, CDCl3)  8.40 (dd, J = 4.7, 2.0 Hz,
1H), 8.34 (dd, J = 7.8, 2.0 Hz, 1H), 7.19 (dd, J = 8.0, 4.9 Hz, 1H), 4.93 (q, JCF = 8.0 Hz, 2H); 19F NMR
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(376 MHz, CDCl3)  –73.56 (t, JHF = 8.0 Hz); C{1H} NMR (100 MHz, CDCl3)  154.1, 151.2, 135.6,
123.1 (q, JCF = 275 Hz), 118.4, 118.1, 63.0 (q, JCF = 37 Hz); IR (thin film) max 1613, 1577, 1437 cm−1;
HRMS (ESI/QTOF) m/z: [M+H]+ Calcd for C7H6F3N2O3 223.0320; Found 223.0324.
4-(2,2,2-Trifluoroethoxy)nicotinonitrile (16). Following General Procedure A, 4-chloronicotinonitrile
(1.00 g, 7.2 mmol), 2,2,2-trifluoroethanol (36 mL), and t-BuOK (722 mg, 14.4 mmol) at 70 °C for 17
hours resulted in the desired product as a colorless oil after silica gel chromatography (0–60%
EtOAc:heptane) (1.36 g, 6.73 mmol, 93% yield). 1H NMR (400 MHz, CDCl3)  8.65 (s, 1H), 8.64 (d, J =
8.0 Hz, 1H), 6.95 (d, J = 8.0 Hz, 1H), 4.56 (q, JCF = 8.0 Hz, 2H); 19F NMR (376 MHz, CDCl3)  –73.60
(t, JHF = 7.5 Hz); 13C{1H} NMR (100 MHz, CDCl3)  163.9, 154.8, 154.3, 122.2 (q, JCF = 277 Hz), 113.1,
107.2, 100.3, 65.4 (q, JCF = 37 Hz); IR (thin film) max 2235, 1731, 1590 cm−1; HRMS (ESI/QTOF) m/z:
[M+H]+ Calcd for C8H6F3N2O 203.0427; Found 203.0423.
2-Phenyl-4-(2,2,2-trifluoroethoxy)pyrimidine (17). Following General Procedure A, 4-chloro-2-
phenylpyrimidine (1.00 g, 5.25 mmol), 2,2,2-trifluoroethanol (26 mL), and t-BuOK (1.18 g, 10.5 mmol)
at 75 °C for 17 hours resulted in the desired product as a white solid after silica gel chromatography (0–
10% EtOAc:heptane) (1.25 g, 4.92 mmol, 94% yield). 1H NMR (400 MHz, CDCl3)  8.61 (d, J = 4.0 Hz,
1H), 8.41 (m, 2H), 7.50 (m, 3H), 6.77 (d, J = 4.0 Hz, 1H), 4.95 (q, JCF = 8.0 Hz, 2H); 19F NMR (376
MHz, CDCl3)  –73.51 (t, JHF = 8.0 Hz); 13C{1H} NMR (100 MHz, CDCl3)  167.5, 164.3, 158.5, 136.8,
131.1, 128.6, 128.2, 123.3 (q, JCF = 276 Hz), 106.2, 62.0 (q, JCF = 37 Hz); IR (thin film) max 1565, 1435,
1389 cm−1; HRMS (ESI/QTOF) m/z: [M+H]+ Calcd for C12H10F3N2O 255.07397; Found 255.0733;
Melting point 67.1–67.8 °C.
2-(2,2,2-Trifluoroethoxy)-1,3-benzoxazole (18). Following General Procedure A, 2-chloro-1,3-
benzoxazole (0.20 mL, 1.75 mmol), 2,2,2-trifluoroethanol (8.8 mL), and t-BuOK (393 mg, 3.5 mmol) at
70 °C for 18 hours resulted in the desired product as a colorless oil after silica gel chromatography (0–
10% EtOAc:heptane) (320 mg, 1.47 mmol, 84% yield). 1H NMR (400 MHz, CDCl3)  7.53 (m, 1H), 7.38
(m, 1H), 7.29 (m,1H), 7.24 (m, 1H), 4.93 (q, JCF = 7.8 Hz, 2H); 19F NMR (376 MHz, CDCl3)  –74.20 (t,
JHF = 7.5 Hz); 13C{1H} NMR (100 MHz, CDCl3)  162.2, 148.9, 140.2, 124.1, 123.6, 122.2 (q, JCF = 275
Hz), 118.4, 110.0, 66.9 (q, JCF = 37 Hz); IR (thin film) max 1628, 1579, 1458 cm−1; HRMS (ESI/QTOF)
m/z: [M+H]+ Calcd for C9H7F3NO2 218.0423; Found 218.0422.
1-Methyl-3-(1-methyl-1H-pyrazol-4-yl)-4-(2,2,2-trifluoroethoxy)-1H-pyrazolo[3,4-d]pyrimidine
(28).
Trifluoroethyl ether 11 (200 mg, 0.64 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-
1H-pyrazole (174 mg, 0.84 mmol), potassium phosphate tribasic (410 mg, 1.93 mmol), and PdCl2(dppf)
DCM complex (27 mg, 0.03 mmol) were added to a degassed solution of dioxane (6.4 ml) and water (1.0
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mL) followed by heating to 80 °C for 18 hours. After cooling to room temperature the reaction was
diluted with water and extracted with EtOAc × 3. The combined organics were washed with brine, dried
over Na2SO4, filtered and concentrated. The crude material was purified by silica gel chromatography (0–
1
70% EtOAc:heptane) to afford the adduct as a white solid (170 mg, 0.54 mmol, 85% yield). H NMR
(400 MHz, CDCl3)  8.52 (s, 1H), 8.11 (s, 1H), 8.06 (s, 1H), 5.02 (q, JHF = 8.6 Hz, 2H), 4.08 (s, 3H), 3.96
(s, 3H); 19F NMR (376 MHz, CDCl3)  – 73.23 (t, 8 Hz); 13C{1H} NMR (100 MHz, CDCl3)  161.5,
155.7, 154.5, 138.3, 137.1, 130.1, 123.4 (q, JCF = 277 Hz), 114.3, 99.3, 62.7 (q, JCF = 37 Hz), 39.0, 34.1;
IR (thin film) max 1590, 1562, 1429 cm−1; HRMS (ESI/QTOF) m/z: [M+H]+ Calcd for C12H12F3N6O
313.1019; Found 313.1023; Melting point 161.6–162.4 °C.
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SNAr, General Procedure C: A solution of trifluoroethyl ether (1 equiv) in DMSO (0.2 M) was added
amine nucleophile (1.5 equiv) and Et3N or DBU (1.5 equiv). The reaction was then heated for the
indicated time. Upon completion (monitored by TLC or LCMS), the reaction was cooled to room
temperature, diluted with water, and extracted into EtOAc × 3. The combined organics were washed with
water × 3, brine, dried over Na2SO4 or MgSO4, filtered and concentrated. The product was purified as
described.
(S)-7,8-dimethoxy-N-(1-(3-methyl-1H-pyrazol-5-yl)propan-2-yl)quinazolin-4-amine
(3).2
Following
General Procedure C, trifluoroethyl ether 10 (6.56 g, 22.7 mmol), 1-(3-methyl-1H-pyrazol-5-yl)propan-2-
amine bis-hydrochloride (5.79 g, 27.3 mmol) triethylamine (9.21 g, 91 mmol) in DMSO (23 mL) at 90
°C for 24 hours, and was then diluted with water (65 mL) to dissolve the salts. After continued stirring
with cooling to rt the product precipitated as a white solid. This was stirred for 3 hours at room
temperature and another 1 h in an ice bath. The precipitate was collected via filtration, rinsed with a few
mL of water, and dried overnight under a stream of air to afford the title compound as a white solid (6.96
g, 21.1 mmol, 93% yield).
4-(Azetidin-1-yl)-3-bromo-1-methyl-1H-pyrazolo[3,4-d]pyrimidine (19). Following General Procedure C,
trifluoroethyl ether 11 (80 mg, 0.26 mmol), azetidine (0.026 mL, 0.38 mmol), triethylamine (0.054 mL,
0.38 mmol) in DMSO (1.9 mL) at 80 °C for 5 minutes afforded the desired product as a pale yellow solid
without further purification (68 mg, 0.25 mmol, 99% yield). 1H NMR (400 MHz, CDCl3)  8.33 (s, 1H),
4.56 (br s, 4H), 3.97 (s, 3H), 2.50 (quint, J = 7.7 Hz, 2H); 13C{1H} NMR (100 MHz, CDCl3)  156.1,
155.3, 154.6, 116.9, 100.9, 77.2, 34.1, 17.3; IR (thin film) max 1574, 1554, 1467, 1440, 1315, 1292, 1256
cm−1; HRMS (ESI/QTOF) m/z: [M+H]+ Calcd for C9H11BrN5 268.0190 and 270.0170; Found 268.0193
and 270.0168; Melting point 178.2–178.6 °C
5-Bromo-4-(3-fluoroazetidin-1-yl)-7-methylimidazo[5,1-f][1,2,4]triazine (20). Following General
Procedure C, trifluoroethyl ether 12 (366 mg, 1.18 mmol), 3-fluoroazetidine p-toluenesulfonate (433 mg,
1.75 mmol), triethylamine (0.490 mL, 3.50 mmol) in DMSO (4.0 mL) at 23 °C for 24 hours. The
reaction was diluted with water (8 mL) and stirred for an additional 2 h. The precipitate was collected via
filtration and rinsed with 4 mL water to afford the product as a white powder (320 mg, 1.12 mmol, 95%
1
yield). H NMR (400 MHz, CDCl3)   (s, 1H), 5.45 (app. doublet of heptets, 1 H, J = 3.1, 57.1 Hz),
4.86 (br, 2H), 4.68 (br, 2H), 2.63 (s, 3H); 19F NMR (376 MHz, CDCl3)  –178.8 (m); 13C{1H} NMR (100
MHz, CDCl3)  154.2, 148.0, 141.5, 113.0, 106.7, 82.7 (d, JCF = 200 Hz), 12.0; IR (thin film) max 1449,
1403, 1105 cm−1; HRMS (ESI/QTOF) m/z: [M+H]+ Calcd for C9H10BrFN5, 286.0098 and 288.0078;
found, 286.0094 and 288.0069; melting point 181.0–181.3 °C
N-Isobutyl-3-nitroquinolin-4-amine8 (21). Following General Procedure C, trifluoroethyl ether 13 (100
mg, 0.33 mmol), isobutylamine (48 mg, 0.65 mmol), triethylamine (0.136 mL, 0.65 mmol) in DMSO (1.7
mL) at 80 °C for 5 minutes afforded the desired product as a yellow solid after silica gel purification (0–
50% EtOAc:heptane) (77 mg, 0.31 mmol, 96% yield). 1H NMR (400 MHz, DMSO-d6)  9.15 (br s, 1H),
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9.08 (s, 1H), 8.52 (d, J = 7.8 Hz, 1H), 7.92–7.82 (m, 2H), 7.60 (ddd, J = 1.4, 6.9, 8.5 Hz, 1H), 3.52 (t, J =
5.9 Hz, 2H), 2.01 (td, J = 6.7, 13.6 Hz, 1H), 0.94 (d, J = 6.6 Hz, 6H)
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4-(6-(Trifluoromethyl)pyridazin-3-yl)morpholine (22). Following General Procedure C, trifluoroethyl
ether 14 (125 mg, 0.51 mmol), morpholine (0.066 mL, 0.76 mmol), triethylamine (0.10 mL, 0.76 mmol)
in DMSO (2.5 mL) at 120 °C for 24 hours afforded the desired product as a white solid after silica gel
chromatography (0–50% EtOAc:heptane) (60 mg, 0.26 mmol, 51% yield, 84% BRSM). 50 mg of
trifluoroethyl ether 14 was recovered. 1H NMR (400 MHz, CDCl3)  7.49 (d, J = 9.8 Hz, 1H), 6.92 (d, J =
9.8 Hz, 1H), 3.83 (m, 4H), 3.72 (m, 4H); 19F NMR (376 MHz, CDCl3)  –66.19 (s); 13C{1H} NMR (100
MHz, CDCl3)  160.3, 143.1 (q, JCF = 35 Hz), 124.7 (q, JCF = 2 Hz), 122.0 (q, JCF = 275 Hz), 111.3, 66.3,
44.8; IR (thin film) max 1867, 1599, 1451 cm−1; HRMS (ESI/QTOF) m/z: [M+H]+ Calcd for C9H11F3N3O
234.0849; Found 234.0843; Melting point 150.5–153.0 °C
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3-Nitro-2-(pyrrolidin-1-yl)pyridine14 (23). Following General Procedure C, trifluoroethyl ether 15 (50 mg,
0.23 mmol), pyrrolidine (0.028 mL, 0.34 mmol), triethylamine (0.047 mL, 0.34 mmol) in DMSO (1.1
mL) at 80 °C for 20 hours afforded the desired product as an oil after silica gel chromatography (0–20%
EtOAc:heptane) (40 mg, 0.21 mmol, 92% yield). 1H NMR (400 MHz, CDCl3)  8.32 (dd, J = 4.5, 1.8 Hz,
1H), 8.07 (dd, J = 8.0, 1.8 Hz, 1H), 6.64 (dd, J = 8.2, 4.7 Hz, 1H), 3.39 (m, 4H), 1.98 (m, 4H)
4-(Pyrrolidin-1-yl)nicotinonitrile15 (24). Following General Procedure C, trifluoroethyl ether 16 (50 mg,
0.25 mmol), pyrrolidine (0.031 mL, 0.37 mmol), triethylamine (0.052 mL, 0.37 mmol) in DMSO (1.2
mL) at 80 °C for 18 hours afforded the desired product as a white solid after silica gel chromatography
1
(0–100% EtOAc:heptane) (40 mg, 0.23 mmol, 93% yield). H NMR (400 MHz, CDCl3)  8.41 (s, 1H),
8.16 (d, J = 6.2 Hz, 1H), 6.39 (d, J = 6.2 Hz, 1H), 3.64 (m, 4H), 2.02 (m, 4H)
2-Phenyl-4-(pyrrolidin-1-yl)pyrimidine (25). Following General Procedure C, trifluoroethyl ether 17 (75
mg, 0.30 mmol), pyrrolidine (0.037 mL, 0.44 mmol), triethylamine (0.062 mL, 0.44 mmol) in DMSO (1.5
mL) at 120 °C for 20 hours afforded the desired product as a white solid after silica gel chromatography
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(0–20% EtOAc:heptane) (59 mg, 0.26 mmol, 89% yield). H NMR (400 MHz, CDCl3)  8.41 (m, 2H),
8.25 (d, J = 5.9 Hz, 1H), 7.44 (m, 3H), 6.14 (d, J = 5.9 Hz, 1H), 3.52 (br m, 4H), 1.98 (br s, 4H); 13C{1H}
NMR (100 MHz, CDCl3)  163.4, 159.8, 154.9, 138.6, 129.9, 128.1, 127.9, 101.5, 46.1, 25.0; IR (thin
film) max 1569, 1542, 1447 cm−1; HRMS (ESI/QTOF) m/z: [M+H]+ Calcd for C14H16N3 226.1339; Found
226.1337; Melting point 95.4–97.3 °C.
2-Morpholino-1,3-benzoxazole16 (26). Following General Procedure C, trifluoroethyl ether 18 (75 mg,
0.35 mmol), morpholine (0.045 mL, 0.52 mmol), triethylamine (0.072 mL, 0.52 mmol) in DMSO (1.7
mL) at 80 °C for 6 hours afforded the desired product as a white solid after silica gel chromatography (0–
40% EtOAc:heptane) (65 mg, 0.32 mmol, 92% yield). 1H NMR (400 MHz, CDCl3)  7.39 (m, 1H), 7.28
(m, 1H), 7.19 (m,1H), 7.05 (m, 1H), 3.83 (m, 4H), 3.70 (m, 4H)
4-Methoxy-2-nitroquinoline (27). To 4-chloro-3-nitroquinoline 7 (330 mg, 1.58 mmol) in methanol (4
mL) was added portionwise over 1 min. potassium tert-butoxide (213 mg, 1.90 mmol). After 10 min the
mixture was partitioned between EtOAc (1 ×) and water. The combined organic phases were washed with
brine, dried with MgSO4, and concentrated to afford an off white solid. This was recrystallized from
EtOAc/heptane to afford of the title compound as an off white solid (260 mg, 1.27 mmol, 80% yield). 1H
NMR (400 MHz, CDCl3)  9.23 (s, 1 H), 8.33 (d, J = 8.6 Hz, 1H), 8.14 (d, J = 8.2 Hz, 1H), 7.89 (ddd, J =
1.6, 5.5, 7.9 Hz, 1 H), 7.69 (ddd, J = 1.2, 5.6, 8.2 Hz, 1H), 4.23 (s, 3 H); 13C{1H} NMR (100 MHz,
CDCl3)            IR (thin film) max 1573,
1519, 1494 cm−1; HRMS (ESI/QTOF) m/z: [M+H]+ Calcd for C10H9N2O3 205.0610; Found 205.0605;
Melting point 101.2–102.1 °C
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N-Isobutyl-3-nitroquinolin-4-amine8 (21) via 27. To 4-methoxy-3-nitroquinoline 27 (123 mg, 0.60 mmol)
in DMSO (3 mL) was added dropwise isobutylamine (110 mg, 0.15 mmol). The yellow solution was
stirred for 10 min and was then diluted with water (10 mL). The resultant yellow slurry was stirred for 1 h
and the precipitate was collected via filtration, rinsed with water, and dried under a stream of air to of the
title compound as a yellow powder (143 mg, 0.58 mmol, 97% yield).
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4-(Azetidin-1-yl)-1-methyl-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidine (29). Following
General Procedure C, trifluoroethyl ether 28 (50 mg, 0.16 mmol), azetidine (0.016 mL, 0.24 mmol), DBU
(0.036 mL, 0.24 mmol) in DMSO (0.80 mL) at 80 °C for 4 minutes afforded the desired product as an oil
without further purification (35 mg, 0.13 mmol, 81% yield). 1H NMR (400 MHz, CDCl3)  8.38 (s, 1H),
7.66 (s, 1H), 7.61 (s, 1H), 4.01 (s, 3H), 3.98 (m, 7 H), 2.27 (quint, J = 7.8 Hz, 2 H); 13C{1H} NMR (100
MHz, CDCl3)  159.0, 155.0, 154.3, 140.2, 136.0, 130.1, 115.3, 99.9, 52.9, 39.1, 33.8, 17.2; IR (thin film)
max 1573, 1558, 1470 cm−1; HRMS (ESI/QTOF) m/z: [M+H]+ Calcd for C13H16N7 270.1462; Found
270.1465
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Supporting Information.
1
Copies of H and 13C NMR spectra are included in the supporting information. This material is available
free of charge via the Internet at http://pubs.acs.org.
Author Information.
Corresponding author email: ethan.l.fisher@pfizer.com
The authors declare no competing financial interest.
Acknowledgements.
The authors are grateful for discussions with Chris Helal (Pfizer) and Prof. E. J. Corey (Harvard
University)
1 Brown, D. G.; Boström, J. Analysis of Past and Present Synthetic Methodologies on Medicinal Chemistry: Where
Have All the New Reactions Gone? J. Med. Chem., 2016, 59, 4443–4458
2 Humphrey J. H.; Movsesian, M.; am Ende, C. W.; Becker, S. L.; Chappie, T. A.; Jenkinson, S.; Liras, J. L.; Liras,
S.; Orozco, C.; Pandit, J.; Vajdos, F. F.; Vandeput, F.; Yang, E.; Menniti, F. S. Discovery of Potent and Selective
Periphery-Restricted Quinazoline Inhibitors of the Cyclic Nucleotide Phosphodiesterase PDE1. J. Med. Chem. 2018,
61, 4635−4640
3 The chloroquinazoline 1 experienced complete solvolysis in the presence of 1 N HCl (1:1 v/v, methanol) within 45
min, whereas little or no solvolysis was noted on treatment with saturated NaHCO3 (1:1 v/v, methanol) over 24 h.
Similar results were noted upon treatment of the pyrazolopyrimidyl chloride 5 under comparable conditions.
4 Axten, J. M.; Faucher, N. E.; Daugan, A. C.-M. WO2017/46738, 2017, A1
5
Tran, T. P.; Fisher, E. L.; Wright, A. S.; Yang, J. Concise Synthesis of Versatile Imidazo[5,1-f][1,2,4]triazin-
4(3H)-ones. Org. Process Res. Dev. 2018, 22, 166–172
6 Pfizer Inc.; Helal, C. J.; Chappie, T. A.; Humphrey, J. M. - WO2012/168817, 2012, A1
7 Zhang, L.; Villalobos, A.; Beck, E. M.; Bocan, T.; Chappie, T. A.; Chen, L.; Grimwood, S.; Heck, S. D.; Helal, C.
J.; Hou, X.; Humphrey, J. M.; Lu, J.; Skaddan, M. B.; McCarthy, T. J.; Verhoest, P. R.; Wager, T. T.; Zasadny, K.
Design and Selection Parameters to Accelerate the Discovery of Novel Central Nervous System Positron Emission
Tomography (PET) Ligands and Their Application in the Development of a Novel Phosphodiesterase 2A PET
Ligand. J. Med. Chem. 2013, 56, 4568–4579
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Gerster, J. F.; Lindstrom, K. J.; Miller, R. L.; Tomai, M. A.; Birmachu, W.; Bomersine, S. N.; Gibson, S. J.;
Imbertson, L. M.; Jacobson, J. R.; Knafla, R. T.; Maye, P. V.; Nikolaides, N.; Oneyemi, F. Y.; Parkhurst, G. J.;
Pecore, S. E.; Reiter, M. J.; Scribner, L. S.; Testerman, T. L.; Thompson, N. J.; Wagner, T. L.; Weeks, C. E.; Andre,
J.-D.; Lagain, D.; Bastard, Y.; Lupu, M. Synthesis and Structure−Activity-Relationships of 1H-Imidazo[4,5-
c]quinolines That Induce Interferon Production. J. Med. Chem. 2005, 48, 3481−3491
9
For examples of the 2,2,2-trifluoroethoxy group as a leaving group in SNAr reactions as a method to effect
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regioselective transformations, see: (a) Kagawa, T.; Shigehiro, D.; Kawada, K. Trifluoroethoxy group as a leaving
group for regioselective sequential substitution reactions of 5-trifluoromethylpyrimidine derivative with heteroatom
nucleophiles. J. Fluorine Chem. 2015, 179, 150–158. (b) Best, W. M.; Fam, M.-A. M.; Gregory, M. J.; Kasum, B.;
Keep, P. L.; Lazzaro, S.; Osner, N.; Stewart, N.; Thang, S. H.; Watson, K. G. Preparation of 4,6-disubstituted 5-
pyrimidinesulfonamides. Synthesis 1998, 1, 36–38. (c) Carrol, F. I.; Berrang, B. D.; Linn, C. P. Synthesis of
naphthyridone derivatives as potential antimalarials. J. Heterocyclic Chem. 1981, 18, 941−946
10 Roberts, C. W.; McBee, E. T.; Hathaway, C. E. The Potentiometric Titration of Fluorinated Alcohols in Aqueous
and Non-Aqueous Systems. J. Org. Chem. 1956, 21, 1369–1370
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Trummal, A.; Lipping, L.; Kaljurand, I.; Koppel, I. A.; Leito, I. Acidity of Strong Acids in Water and Dimethyl
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12
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