Preparation of Carbamates, Esters, Amides, and Unsymmetrical Ureas via Br?nsted Acid-Activated N-Acyl Imidazoliums

Article abstract of DOI:10.1021/acs.oprd.0c00445

We report the application of Br?nsted acid-activated N-acyl imidazoliums as versatile intermediates in carbonyl transformations. The efficient and scalable procedure was validated on a diverse set of carbamates, esters, amides, and unsymmetrical ureas (21 examples, up to 91% yield). Additionally, we exemplify this method on multikilogram scale for the synthesis of an electron-deficient carbamate.

Full text of DOI:10.1021/acs.oprd.0c00445

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Preparation of Carbamates, Esters, Amides, and Unsymmetrical
Ureas via Brønsted Acid-Activated N‑Acyl Imidazoliums
Rebecca B. Watson,‡ Todd W. Butler, and Jacob C. DeForest*,‡
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ABSTRACT: We report the application of Brønsted acid−activated N-acyl imidazoliums as versatile intermediates in carbonyl
transformations. The efficient and scalable procedure was validated on a diverse set of carbamates, esters, amides, and unsymmetrical
ureas (21 examples, up to 91% yield). Additionally, we exemplify this method on multikilogram scale for the synthesis of an electron-
deficient carbamate.
KEYWORDS: imidazolium, carbamate, electron deficient, alkoxycarbonyl, Brønsted acid
To achieve the desired transformation on scale, we
considered reactions which proceed through either a
carbamoyl cation7,12 (Figure 2A) or an alkoxycarbonyl
INTRODUCTION
■
Carbonyls are among the most ubiquitous functional groups in
organic synthesis. In particular, the carbamate functional group
is a common structural motif in pharmaceutical drug
substances,1 agricultural chemicals,2 and functional materials.3
This prevalence is in part due to its hybrid nature containing
both amide and ester functionalities, which provide carbamates
with good hydrolytic and proteolytic stability.1 Many common
methods for carbamate synthesis include the use of potentially
toxic or high energy reagents such as chloroformates,4
phosgene,5 phosgene derivatives,6 methylated carbamoyl
imidazolium salts,7 isocyanates,8 and acyl azides.9,10 A recent
review by Chaturvedi on the carbamation of amines11 provides
additional methods for the synthesis of carbamates including,
but not limited to, amine carbonylation, reductive carbon-
ylation of nitroaromatics, and carbamate metathesis. Many of
these methods face obstacles on scale, including availability
and stability of commercial materials, worker safety concerns
for handling toxic reagents, manufacturing capabilities
associated with the utilization of gas, and the need to avoid
a buildup of high-energy intermediates. As part of an early
development program within Pfizer, a multikilogram synthesis
of an electron-deficient aryl carbamate (represented by general
structure 3) was required (Figure 1). As a result, an
operationally simplistic, one-pot protocol was developed that
avoids high-energy intermediates, while utilizing easily
accessible phenol (1) and amine (2) starting materials.
Figure 2. Activated intermediates for carbamate synthesis.
cation13−16 equivalent (Figure 2B). With carbamoyl cation
equivalents, the amine starting material is activated to generate
a reactive intermediate (4−6), and following the addition of
the phenol starting material, the desired carbamate is obtained.
Conversely, with alkoxycarbonyl cation equivalents, the phenol
is activated first to form the cation equivalent (7−9), and upon
addition of amine, the desired carbamate is generated.
Carbamoyl cation equivalents 4 and 5 were not used in our
investigations, as preparing carbamoyl chloride 4 requires the
use of toxic phosgene or triphosgene, and the requisite
isocyanate 5 is challenging to prepare and not available on
scale. The last carbamoyl cation considered was carbamoyl
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istry
Received: October 1, 2020
Figure 1. Synthesis of an electron-deficient aryl carbamate from
amine and phenol starting materials.
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A

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imidazolium salt 6, which is easily accessed utilizing 1,1′-
carbonyldiimidazole (CDI)17 and methyl iodide. While
imidazolium 6 successfully reacted with the electron-deficient
phenol needed for the final drug substance, it required forcing
conditions and a stepwise generation of the methylated
imidazolium (6) using methyl iodide, both of which were
undesirable. We instead sought to invert the reactivity of the
system by generating an alkoxycarbonyl cation equivalent (7−
9, Figure 2B). This strategy was thought to both enhance the
electrophilicity of the resulting carbonyl species compared with
the carbamoyl cation derivatives and further benefited from the
use of a more active amine as the nucleophile rather than the
electron-deficient phenol.
The most direct alkoxycarbonyl cation to utilize would be an
aryl chloroformate (7); however, that option was eliminated
because of the lack of commercial sources and reagent
instability. Inspired by the enhanced reactivity of carbonyl
imidazoliums,18−20 we were confident that methylated acyl
imidazolium 8 could be generated and used productively.
However, this transformation would require the use of highly
acutely toxic methyl iodide. Instead, we believed that a similar
reactivity profile could be achieved by generating alkoxylcar-
bonyl cation 9 under Brønsted acidic conditions, as acyl
imidazoliums generated through acid additives have been
shown to increase the rate of amidation reactions when
compared to neutral acyl imidazoles.21
RESULTS AND DISCUSSION
Initial exploration of the reaction conditions is summarized in
Table 1. As a model substrate, p-trifluoromethyl phenol (14)
■
a
Table 1. Optimization of Reaction Conditions
entry
additive
temp (°C) time (h) 15 (%) 16 (%)
1
2
3
4
5
6
7
8
9
none
22
22
22
22
22
22
22
22
50
50
50
50
50
50
50
18
18
18
18
18
18
18
18
2
2
2
2
2
28
34
23
80
86
91
87
90
28
58
74
83
90
89
87
72
66
77
20
14
9
13
10
72
42
26
17
10
11
13
HOPO (1.0 equiv)
Et3N (2.0 equiv)
Py-HCl (2.0 equiv)
HCl (2.0 equiv)
PPTS (2.0 equiv)
CSA (2.0 equiv)
MsOH (2.0 equiv)
none
MsOH (0.5 equiv)
MsOH (1.0 equiv)
MsOH (1.5 equiv)
MsOH (2.0 equiv)
MsOH (2.5 equiv)
MsOH (3.0 equiv)
10
11
12
13
14
15
2
2
In addition, we were interested in evaluating imidazolium 9
because of undesired reactivity observed under neutral, “non-
ionized” conditions (Figure 3). Specifically, after activation of
a
Conditions: All reactions were performed using p-trifluoromethyl-
phenol (100 mg, 1.0 equiv), CDI (1.0 equiv), and piperidine (1.0
equiv) in CH3CN (10 mL/g). Product distributions were determined
by UPLC analysis at 210 nm applying a response factor of 1.2549 for
16.
was selected with piperidine as the amine nucleophile and CDI
as the activating agent. CDI was chosen because of its low cost,
availability on scale, and relatively benign byproducts. As a
control experiment, the phenol (14) was treated with one
equivalent of CDI followed by one equivalent of piperidine.
UPLC analysis showed an intrinsic 28:72 selectivity favoring
the formation of urea 16 rather than desired carbamate 15
(Table 1, entry 1), confirming that under neutral conditions, p-
trifluoromethyl phenol was a better leaving group than
imidazole (Figure 3). To enhance the desired reactivity,
various additives were introduced after the addition of CDI,
given the hypothesis that activating the imidazole may facilitate
preferential formation of carbamate 15. As expected, addition
of Et3N did not improve the selectivity, while the nucleophilic
additive 2-hydroxypyridine-N-oxide (HOPO) afforded a 34:66
product ratio favoring urea 16, a modest improvement upon
the control experiment (Table 1, entries 2 and 3). Acid
additives were evaluated next; two equivalents of each acid
were utilized to fully protonate both imidazole equivalents of
CDI, presumably resulting in the formation of the desired
alkoxycarbonyl imidazolium intermediate 12 (Figure 3). Both
pyridine hydrochloride and HCl in dioxane had a drastic
influence on selectivity, resulting in 80:20 and 86:14 product
ratios, respectively, completely reversing the intrinsic selectivity
observed without using an acid additive (Table 1, entries 4 and
5). The addition of pyridinium p-toluenesulfonate (PPTS),
camphorsulfonic acid (CSA), or methanesulfonic acid
(MsOH) were also effective, achieving product ratios of
Figure 3. Acid activation hypothesis for selectivity reversal.
the starting electron-deficient phenol 1 with CDI to yield acyl
imidazole intermediate 10, we observed the reaction with
amine 2 favored the formation of undesired urea 11. This
suggests that under neutral conditions, the electron-deficient
phenol is a better leaving group than imidazole. To avoid this
undesired reactivity, we hypothesized that upon addition of an
acid additive, the imidazole would protonate to form the
intermediate alkoxycarbonyl cation (12), rendering the
imidazolium a better leaving group and favoring carbamate
(3) formation upon reaction with amine 2. Herein we report
the results of our investigation for the synthesis of various
additional electron-deficient carbamates. The resulting, opera-
tionally simplistic protocol was found to be very practical and
was subsequently expanded to include the synthesis of a variety
of carbonyl compounds including esters, amides, and unsym-
metrical ureas.
B
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91:9, 87:13, and 90:10, respectively, all favoring carbamate 15
formation (Table 1, entries 6−8).
Table 2. Carbamate (15, 17−19): Urea (16) Selectivity with
§
and without MsOH as an Additive
With all the acids screened exhibiting excellent selectivity for
carbamate (15) formation, MsOH was chosen for further
optimization because of its low cost, availability on commercial
scale, atom economic properties, and nonhygroscopic nature.
Additionally, the imidazolium methanesulfonate salt (13,
Figure 3) formed as a byproduct in the reaction has low
organic and high aqueous solubility, offering the opportunity to
remove it via filtration or through an aqueous workup.
Further optimization focused on the evaluation of acid
equivalents and reaction temperature. Two additional control
experiments were conducted at 50 °C under neutral and acidic
conditions (Table 1, entries 9 and 13), both of which
demonstrated an increase in reaction rate when compared with
the analogous room temperature reactions (Table 1, entries 1
and 8). With that information in hand, MsOH was added at
room temperature in 0.5 equiv portions from 0 to 3.0 equiv,
and then the reaction vessel was heated to 50 °C. Selectivity
for carbamate 15 gradually improved with increasing
equivalents of acid until a product ratio of 90:10 was achieved
(Table 1, entry 13, 2.0 equiv of MsOH). Furthermore, the
product distribution at 50 °C mirrored the selectivity achieved
with 2.0 equiv of MsOH at room temperature, and the reaction
reached completion in only 2 h (Table 1, entries 8 and 13). No
benefit was apparent when 2.5 or 3.0 equiv of acid was utilized
(Table 1, entries 14 and 15). Overall, the addition of 2.0 equiv
of acid as well as an elevated reaction temperature maximized
selectivity while minimizing reaction time.
The preference for carbamate formation over the undesired
urea upon the addition of acid confirmed our initial hypothesis
(Figure 3). Mechanistically, the first equivalent of acid leads to
the protonation of the free imidazole generated after the
phenol-CDI activation; filtering the slurry following the
addition of 1.0 equiv of MsOH leads to the isolation of
imidazolium methanesulfonate 13. The second equivalent of
acid protonates the neutral acyl imidazole to form
alkoxycarbonyl cation 12, which results in the highly reactive
protonated imidazole leaving group and is the active species
responsible for the reversal of product distribution.
§
Conditions: Phenol (200 mg, 1.0 equiv), CDI (1.0 equiv), MsOH
(2.0 equiv), and piperidine (1.0 equiv) in CH3CN (15 mL/g) at 50
°C. Yields were determined by H NMR analysis utilizing mesitylene
as an internal standard. Isolated yields.
1
a
importance of a Brønsted acid additive for efficiently
synthesizing electron-deficient carbamates (Figure 3).
With optimized conditions in hand, the reaction was probed
for its ability to scale, versatility in substrate scope, and utility
for the synthesis of other substrate classes, specifically amides,
esters, and unsymmetrical ureas (Figure 4). To demonstrate
the practicality of this method on larger scale, all substrates
shown in Figure 4 were run on 1 g scale. To begin, electron-
deficient carbamates 15, 17, and 19 were synthesized with
isolated yields of 74%, 60%, and 55%, respectively, all of which
correspond closely to the 1H NMR yields observed in Table 2.
Acid-sensitive N-Boc piperazine was utilized to make
carbamate 20 in 88% yield with no observed degradation.
Furthermore, carbamate 21 generated from electron rich 4-
methoxyphenol was isolated in 86% yield. Finally, 6-
methylpyridin-3-ol was converted to alkyl carbamate 22 in
68% yield, demonstrating the tolerance of both alkyl amines
and basic heterocycles under the optimized reaction
conditions.
The synthesis of N-methylated amides using N-methyl-
imidazolium cations in conjunction with Brønsted acids was
recently disclosed by the Fuse group.22 In addition, amidations
from carboxylic acids using CDI and imidazole hydrochloride
as an acid additive to enhance reaction rate has been
demonstrated, albeit with a limited carboxylic acid substrate
scope.21 Utilizing MsOH as the acid additive, we expanded the
scope of this transformation to include heteroaromatic
carboxylic acids, sterically hindered amines and carboxylic
acids, and aliphatic amines. Fluoroaniline was coupled with 1-
methyl-4-pyrazolecarboxylic acid to afford amide 23 in 74%
yield. The same pyrazole carboxylic acid formed amide 26 in
To demonstrate the advantage of MsOH activation,
additional electron-deficient phenols were subjected to the
optimized conditions and reacted with piperidine (Table 2).
Control experiments without the inclusion of MsOH were also
run in parallel, and the product ratios of desired carbamate
1
(15, 17−19) to urea (16) were determined using H NMR
analysis. In each case, the experiments conducted in the
absence of MsOH revealed a strong preference for urea (16)
formation. Carbamate 17 generated from 2-(trifluoromethyl)-
pyrimidin-5-ol was formed in 4% without acid, increasing to
59% with MsOH present. The carbamate (18) resulting from
5-fluoro-2-hydroxypyridine was observed in 8% under neutral
conditions, favoring the formation of urea 16; however,
selectivity reversal was observed under acidic conditions,
resulting in 72% of carbamate 18. The carbamate (19) arising
from pentafluorophenol was not detected in the absence of
MsOH but was isolated in 49% after incorporation of acid.
Finally, 4-trifluoromethyl phenol adduct 15 achieved complete
suppression of urea 16 formation by the addition of MsOH
and resulted in 74% yield. This stark difference in carbamate
(15, 17−19) versus urea (16) selectivity achieved by the
formation of an alkoxycarbonyl cation (12) versus an
unactivated acyl imidazole (10) further highlights the
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Figure 4. Substrate scope for carbamates, amides, esters, and unsymmetrical ureas.
78% yield after exposure to p-chlorobenzylamine under the
optimized reaction conditions. Employing sterically hindered
2,6-dimethylaniline as a nucleophile in the presence of benzoic
acid provided amide 24 in 91% yield. Picolinic acid was well
tolerated with N-Boc piperazine, with no observed acid-
mediated deprotection of the piperazine (25, Figure 4).
Introduction of steric bulk via an α-quaternary carbon
carboxylic acid was also well tolerated, with the corresponding
benzylamine adduct 27 being generated in 85% yield. Notably,
all the described amidation reactions reached full conversion
within 3 h, with very clean reaction profiles. Furthermore, for
highly crystalline products, direct-drop isolation was possible
simply by the addition of water.
Performing esterifications proved to be more challenging
than the analogous amidation reactions. Reaction times were
significantly longer, and reaction profiles contained more
impurities by UPLC. Of the substrates explored, phenol had
the slowest reaction, requiring 93 h to react with 1-methyl-4-
pyrazolecarboxylic acid to generate ester 28 in 63% yield.
Benzyl alcohol was coupled with a sterically hindered
carboxylic acid to afford ester 29 in 80% yield after 41 h.
The remaining three alcoholscyclohexanol, 4-methoxyphe-
nol, and n-butanolrequired less than 24 h to undergo
esterification, providing the corresponding esters in 60%, 90%,
and 79% yields, respectively (30, 31, and 32, Figure 4).
As a final substrate class, we sought to use the N-acyl
imidazoliums as a method for the chemoselective synthesis of
unsymmetrical ureas. While a variety of methods are available
for the preparation of ureas,23 many rely on the use of harsh
reagents,7,24−28 require preforming potentially unstable high
energy intermediates,24,25,29−32 or proceed via metal-catalyzed
cross couplings.33−37 Two reports for the synthesis of
unsymmetrical ureas that utilize CDI38 or S,S-dimethyl
dithiocarbonate (DMDTC)39 in water as the reaction solvent
have been described. However, we anticipated several
challenges upon scaling these approaches due to the instability
of CDI in water, and the formation of noxious byproduct
methanethiol following DMDTC decomposition. Further-
more, Batey and co-workers described the use of N-methyl
carbamoylimidazole as a methyl isocyante surrogate for the
preparation of N-methyl carbamates and ureas.40 We sought to
explore the utility of the Brønsted acid-activated N-acyl
imidazolium method for the preparation of unsymmetrical
ureas in a one-pot protocol.
The unsymmetrical ureas were prepared through the slow
addition of the less nucleophilic amine to a slurry of CDI in 15
mL/g of acetonitrile. Subsequent addition of MsOH formed
the activated carbamoyl cation equivalent, which, when treated
with the second amine, resulted in the desired unsymmetrical
urea. This method proved to be tolerant of a wide range of
amines, including an aniline bearing an acid sensitive N-Boc
group (36), benzylic amines (34, 37), and acyclic (34) and
cyclic (35) secondary amines. Heterocycles with basic amines
including aminothioazoles (33) and benzimidazoles (35) were
also well tolerated. When added second, 1H-indole-5-amine
was a competent substrate with no competitive reaction
observed at the unprotected indole nitrogen (36, Figure 4).
Conveniently, with the exception of alkyl urea 34, all urea
substrates were easily isolated by direct-drop crystallization
upon the addition of water.
During the substrate scope exploration, we observed that the
reaction slurry mobility was affected by the rate of MsOH
addition. When added rapidly (in <5 min), the resulting slurry
of imidazole methanesulfonate (13) would often lead to
reaction solidification and only mobilize once the correspond-
ing alcohol or amine had been added. While this did not
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appear to have significant detrimental impacts on product
selectivity, it was not ideal for reaction consistency and
scalability. Conversely, when MsOH was added in a controlled
fashion over 15−30 min, keeping the internal reaction
temperature below 30 °C, the reaction rarely solidified. To
investigate, slurry samples were taken from reactions where
MsOH had been intentionally added rapidly, as well as in the
controlled addition protocol, for crystal morphology analysis
(Figure 5A,B). When the samples were analyzed under a
with acetonitrile, the generated reaction slurry was thicker in
CPME. No detrimental effects in reaction rate were observed
with the incoming amine salt, and the reaction reached
completion in 2 h on scale. This campaign afforded 7.86 kg of
the desired electron-deficient carbamate 41 in 88% yield,
highlighting the utility of this reaction on scale.
CONCLUSIONS
■
This research demonstrates that generating alkoxylcarbonyl
cation equivalents using CDI and MsOH is an efficient and
scalable method for the preparation of electron-deficient
carbamates. This one-pot method also enabled facile and
efficient synthesis of electron-rich carbamates, amides, esters,
and unsymmetrical ureas. Overall, the operationally simplistic
reaction protocol, broad functional group tolerance, suitable
reaction rates, and removal of reaction byproducts by filtration
or aqueous workup enable this method to be easily adaptable
for use on both laboratory and industrial scale.
EXPERIMENTAL SECTION
■
Figure 5. Crystal morphology of the slurries generated upon fast and
slow MsOH addition.
General Procedure for the Synthesis of Amides and
Esters. To a 40 mL vial equipped with a X-shaped magnetic
stir bar and temperature probe, was charged respective
carboxylic acid (1.0 equiv) and acetonitrile (10−15 mL/g).
Stirring was set to 700−1000 rpm. Next, 1,1′-carbon-
yldiimidazole (CDI) (1.0 equiv) was added, and the reaction
was stirred for 15−30 min at room temperature. Methane-
sulfonic acid (MsOH) (2.0 equiv) was added dropwise over
15−30 min with vigorous stirring, ensuring the internal
temperature of the reaction was kept below 30 °C. The
respective alcohol or amine (1.0 equiv) was added, and the
reaction was heated in a pie-block to 50 °C. The resulting
mixture was stirred at 50 °C until judged complete by UPLC
analysis. The reaction was cooled to room temperature and
subjected to the general workup protocol.
General Procedure for the Synthesis of Carbamates.
To a 40 mL vial equipped with a X-shaped magnetic stir bar
and temperature probe, was charged respective aryl alcohol
(1.0 equiv) and acetonitrile (10−15 mL/g). Stirring was set to
700−1000 rpm. Next, 1,1′-carbonyldiimidazole (CDI) (1.0
equiv) was added, and the reaction was stirred for 15−30 min
at room temperature. Methanesulfonic acid (MsOH) (2.0
equiv) was added dropwise over 15−30 min with vigorous
stirring, ensuring the internal temperature of the reaction was
kept below 30 °C. The respective amine (1.0 equiv) was added
and the reaction was heated in a pie-block to 50 °C. The
resulting mixture was stirred at 50 °C until judged complete by
UPLC analysis. The reaction was cooled to room temperature
and subjected to the general workup protocol.
polarized light microscope, crystals were between 20−200 μM
from both conditions; however, the morphology of the crystals
generated under fast MsOH addition were thin dendrites,
which presumably became entangled and caused the observed
stirring complications (Figure 5A). Conversely, small crystal
lathes were observed from slow and controlled MsOH
addition, leading to mobile slurries and uniform stirring
(Figure 5B). Nevertheless, if MsOH is added too quickly and
the reaction seizes, slurry mobility can be achieved by dilution
with acetonitrile (see the Supporting Information for more
details). In addition to crystal morphology, some of the stirring
difficulties can be attributed to the use of magnetic rather than
overhead stirring and the high reaction molarity on 1 g scale
with low-molecular-weight substrates. To elaborate, all
reactions are run on 1 g scale in 10−15 mL/g of acetonitrile
with respect to the nucleophile (phenol or amine depending
on the example); with higher-molecular-weight compounds,
less imidazolium methanesulfonate (13) is generated, and
therefore the slurry thickness is reduced.
Finally, the scalability of the reaction protocol was
demonstrated on multikilogram scale during an internal
campaign at Pfizer. While the exact structures and specific
reaction details are unable to be disclosed at this time, a
generalized reaction scheme is shown below (Figure 6). Two
distinct differences are notable compared with the optimized
reaction conditions described previously. First, cyclopentyl
methyl ether (CPME) was chosen as the reaction solvent
instead of acetonitrile for workup and isolation purposes;
second, a piperidine salt derivative (40) was used rather than
the amine free base. It is important to note, when compared
General Procedure for the Synthesis of Unsym-
metrical Ureas. To a 40 mL vial equipped with a X-shaped
magnetic stir bar and temperature probe, was charged 1,1′-
carbonyldiimidazole (CDI) (1.0 equiv) and acetonitrile (10−
Figure 6. Multikilogram scale carbamate 41 formation using piperidine salt 40.
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15 mL/g). Stirring was set to 700−1000 rpm. Next, the less
nucleophilic amine (1.0 equiv) was added dropwise or
portionwise over 15−30 min, and the resulting mixture was
stirred for 30 min at room temperature. Methanesulfonic acid
(MsOH) (2.0 equiv) was added dropwise over 15−30 min
with vigorous stirring, ensuring the internal temperature of the
reaction was kept below 30 °C. The respective amine (1.0
equiv) was added, and the reaction was heated in a pie-block to
50 °C. The resulting mixture was stirred at 50 °C until judged
complete by UPLC analysis. The reaction was cooled to room
temperature and subjected to the general workup protocol.
General Workup. When the reaction was cooled to room
temperature, the reaction contents were transferred to a larger
vessel with water (80 mL/g). If solids precipitated, the mixture
was stirred for 30 min, and the solids were collected by
filtration and rinsed with water (20 mL/g). If no solids
precipitated or oiling occurred, the reaction mixture was
extracted with EtOAc (2 × 30 mL), washed with brine (30
mL), dried over sodium sulfate, concentrated, and purified by
column chromatography.
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ASSOCIATED CONTENT
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sı
* Supporting Information
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Transformation. J. Org. Chem. 1997, 62, 7054−7057.
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Experimental details and spectroscopic data for all
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AUTHOR INFORMATION
■
Reactifs Hydrosolubles DE tert-Butoxycarbonylation D1′ amines. II.1
Sels Stables DE tert-Butoxycarbonyl-1 Alkyl-3 Imidazolium. Synth.
Commun. 1973, 3, 111−114.
Corresponding Author
Jacob C. DeForest − Groton Laboratories, Pfizer Worldwide
Research and Development, Groton, Connecticut 06340,
United States; orcid.org/0000-0002-0316-6685;
Email: Jacob.DeForest@pfizer.com
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Authors
Rebecca B. Watson − Groton Laboratories, Pfizer Worldwide
Research and Development, Groton, Connecticut 06340,
United States
Todd W. Butler − Groton Laboratories, Pfizer Worldwide
Research and Development, Groton, Connecticut 06340,
United States
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Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.oprd.0c00445
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Author Contributions
‡(R.B.W., J.C.D.) These authors contributed equally. The
manuscript was written through contributions of all authors.
All authors have given approval to the final version of the
manuscript.
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors acknowledge Robert North (Analytical Research
& Development, Pfizer Inc., Groton, CT) for HRMS data
collections. The authors also acknowledge Aran Hubbell
(Pfizer Inc.) and Christopher amEnde (Pfizer Inc.) for their
helpful discussions and proofreading this article.
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Discovery and Medicinal Chemistry. J. Med. Chem. 2020, 63, 2751−
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