BBDFA: A Practical Reagent for Trifluoromethylation of Allylic and Benzylic Alcohols on Preparative Scale

Article abstract of DOI:10.1021/acs.oprd.9b00201

We report a safe and readily prepared reagent [1,1′-biphenyl]-4-yl 2-bromo-2,2-difluoroacetate (BBDFA) for Cu-catalyzed trifluoromethylation of allylic or benzylic alcohols. An operationally simple and column-chromatography-free process to prepare BBDFA was developed and demonstrated on >100 g scale. Detailed reaction calorimetry and thermal analysis of the deoxytrifluoromethylation were performed using cinnamyl alcohol as a model substrate, demonstrating that the reactions could be safely implemented on preparative scale.

Full text of DOI:10.1021/acs.oprd.9b00201

Communication
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Cite This: Org. Process Res. Dev. XXXX, XXX, XXX−XXX
BBDFA: A Practical Reagent for Trifluoromethylation of Allylic and
Benzylic Alcohols on Preparative Scale
Chong Han,*,† Lady Mae Alabanza,† Sean M. Kelly,† Douglas L. Orsi,‡ Francis Gosselin,†
and Ryan A. Altman*,‡
†Department of Small Molecule Process Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, United
States
‡Department of Medicinal Chemistry, The University of Kansas, Lawrence, Kansas 66045, United States
available and inexpensive industrial byproducts,7 to selectively
ABSTRACT: We report a safe and readily prepared
reagent [1,1′-biphenyl]-4-yl 2-bromo-2,2-difluoroacetate
(BBDFA) for Cu-catalyzed trifluoromethylation of allylic
or benzylic alcohols. An operationally simple and column-
chromatography-free process to prepare BBDFA was
developed and demonstrated on >100 g scale. Detailed
reaction calorimetry and thermal analysis of the
deoxytrifluoromethylation were performed using cinnamyl
alcohol as a model substrate, demonstrating that the
reactions could be safely implemented on preparative
scale.
convert activated electrophiles to trifluoromethanes. This
strategy, pioneered by Chen and co-workers,8 relies on in
situ conversion of a difluorocarbene intermediate9 and fluoride
to an active Cu-CF3 species, only generating CO2 and halogen
salts as byproducts (Figure 1b). However, application of this
strategy for the conversion of activated alcohols to trifluoro-
methanes historically required isolation and purification of the
intermediate bromodifluoroacetate esters and the use of
stoichiometric Cu salts, which are undesirable for large-scale
applications from the standpoints of operational simplicity and
waste disposal.10 In recent years, catalytic variants of this
strategy have been developed, although these reactions still
required isolation and purification of the intermediate ester to
remove byproducts (Figure 1b).11 To overcome this necessary
isolation step and provide a one-pot deoxytrifluoromethylation
reaction, phenyl bromodifluoroacetate (PhBDFA) was intro-
duced as a deoxytrifluoromethylation reagent, enabling the
direct conversion of alcohols to trifluoromethanes under Cu-
catalyzed conditions (Figure 1c).12 Beneficial aspects of this
catalytic variant include fewer synthetic steps (1 vs 4), mild
reaction temperatures, and a short reaction time. Though this
process converted a variety of benzyl, allyl, and propargyl
alcohols into the corresponding trifluoromethanes, the liquid
physical state of PhBDFA limits its isolation and purification in
a practical manner on large scale. Furthermore, process safety
characterization for the Cu-catalyzed step remains unaddressed
(Figure 2a). To further explore the large-scale feasibility of this
catalytic deoxytrifluoromethylation process, we present a new,
stable, and crystalline biphenyl bromodifluoracetate (BBDFA)
reagent and related process safety data to ensure its
applicability on preparative scale (Figure 2b) using the
conversion of cinnamyl alcohol to cinnamyl−CF3 as a model
reaction.
KEYWORDS: trifluoromethylation, RC1 calorimetry,
thermal stability, process safety, copper catalysis
INTRODUCTION
■
Fluorination of organic molecules is an important strategy in
the pharmaceutical and agrochemical industries, as incorpo-
ration of fluorinated groups typically modulates pharmacody-
namic, pharmacokinetic, distribution, metabolism, and toxicity
profiles.1 As such, >30% of marketed drugs contain at least one
fluorine atom. One of the most common fluorinated functional
groups exploited in drug discovery is the trifluoromethyl group,
which can (1) block metabolic oxidation, (2) alter lipophilicity
and permeability profiles, (3) adjust the pKa of vicinal
functional groups, (4) perturb conformational dynamics, and
(5) reduce the electron density of nearby π-systems.2 As such,
strategies for introducing trifluoromethyl groups from simple
and ubiquitous functional groups are highly desirable.
However, many current trifluoromethylation reactions require
specialized/functionalized substrates and/or expensive or
unsafe reagents3 to access this important functional group,4
which limit their utility for large-scale preparation.
RESULTS AND DISCUSSION
Current methods to convert alcohols into trifluoromethanes
unfortunately require four-step synthetic sequences that lead to
low overall yields and generate large quantities of waste.
Further, the sequences require the use of strong nucleophilic
reagents (TMS−CF3), oxidants, and reductants that limit the
scope of accessible molecules (Figure 1a).5,6 Thus, despite the
potential significance of this reaction, the efficient conversion
of alcohols to trifluoromethanes on large scale remains
challenging.
■
Preparation of BBDFA. In the search for a bromo-
difluoroacetate reagent amenable to large scale synthesis via
the disclosed deoxytrifluoromethylation protocol, we surveyed
a variety of bromodifluoroacetate reagents reported previ-
ously12 and selected the 4-phenylphenol analog BBDFA for
Special Issue: Honoring 25 Years of the Buchwald-Hartwig
Amination
An alternate strategy via nucleophilic substitution exploits
halodifluoroacetate-derived reagents, which are prepared in
two steps from 1,1-difluoro-2,2-dihaloethylene, or other readily
Received: May 2, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.oprd.9b00201
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Figure 1. Functional group interconversion of alcohols to trifluoromethanes.
Figure 2. Design of new deoxytrifluoromethylating reagents
Scheme 1. Synthesis of BBDFA on 100 g Scale
further evaluation because of its comparable reactivity to
PhBDFA and desirable solid form that enables isolation via
crystallization. In the simple and practical sequence illustrated
in Scheme 1, bromodifluoroacetic acid (1) was subjected to
oxalyl chloride in the presence of a catalytic amount of DMF,
and the resulting acid chloride 2 was reacted with 4-
phenylphenol to afford the corresponding ester BBDFA.
After aqueous workup, the product solution in toluene was
solvent-switched to n-heptane, and the product was isolated as
a white crystalline solid in 93% yield and 99.3% purity by GC
B
DOI: 10.1021/acs.oprd.9b00201
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Figure 3. PXRD of crystalline BBDFA.
Figure 4. DVS analysis of crystalline BBDFA.
analysis. The powder X-ray diffraction (PXRD) pattern of the
isolated crystalline BBDFA is illustrated in Figure 3. Dynamic
vapor sorption (DVS) data showed the BBDFA absorbed up to
only 0.15% (w/w) water at approximately 90% relative
humidity. Therefore, this material is deemed nonhygroscopic
and can be weighed and stored on the bench without special
handling requirements (Figure 4).
etry (DSC, Figure 5). The reagent showed good thermal
stability with endothermic melting starting at 75 °C and the
major exothermic decomposition event with an onset temper-
ature of 325 °C and energy release of 285 J/g. The
introduction of a thermal runaway event is unlikely if a 100
°C safety margin from the handling temperature to the onset
temperature of the exothermic event can be established. Given
the high onset temperature of the thermal decomposition and
Safety Assessment of BBDFA. The thermal stability of
BBDFA was investigated using differential scanning calorim-
C
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Figure 5. DSC curve (range: 25−400 °C) of BBDFA.
a
Table 1. Key Parameters for RC1 Experiment
a
b
stage
operation
total enthalpy of reaction (kJ/mol) total adiabatic temp rise (K)
reaction temp (°C) MTSR (°C)
1
2
3
4
5
6
first dose of BBDFA (0.67 equiv)
second dose of BBDFA (0.67 equiv)
third dose of BBDFA (0.67 equiv)
formation of active ester at 40 °C
reaction at 70 °C
10.4
−3.5
−16.8
2.1
132
56
3.6
25
25
25
40
70
20
28.6
23.9
20
40.6
108.9
24.7
−1.1
−5.0
0.6
38.9
4.7
addition of water
a
Total adiabatic temperature rise (ΔTad): Adiabatic temperature rise of the synthesis reaction (temperature increase under adiabatic conditions in
b
case of cooling failure). MTSR: Maximum temperature of the synthesis reaction (max temperature attainable under adiabatic conditions after
cooling failure; Reaction Temperature + Total Adiabatic Temperature Rise).
very low hygroscopicity, BBDFA is considered as a safe reagent
for storage, shipping, and routine handling.
5 was slightly exothermic with an inconsequential ΔTad (Table
1, entry 4). After the complete conversion of the starting
alcohol was confirmed by HPLC analysis, the reaction mixture
was heated to 70 °C over 45 min. The formation of the
trifluoromethylated product 6 from the ester intermediate 5 at
70 °C was exothermic with a total enthalpy of reaction of 132
kJ/mol that translated to a total adiabatic temp rise of 38.9 °C
(Table 1, entry 5; Figure 7). The reaction was complete after
approximately 1 h at 70 °C based on the heat flow data. In the
event of cooling failure, the maximum temperature of the
synthesis reaction (MTSR),13 which is the maximum temper-
ature attainable under adiabatic conditions after cooling failure,
would be 108.9 °C, which would exceed the bp of MeCN (82
°C) but be below the bp of DMF (156 °C). In addition, the
release of CO2 as a byproduct was measured by a gas flow
meter. The maximum gas flow rate observed throughout the
course of the reaction was 22 mL/min, of which approximately
10 mL/min was contributed by the baseline N2 flow, which
indicated a mild reaction slowly releasing CO2 from BBDFA.
After the complete disappearance of ester 5 by HPLC
analysis, the reaction was diluted with n-heptane and then
Reaction Calorimetry of the Deoxytrifluoromethyla-
tion Reaction. We commenced our studies on understanding
the process safety profile of the desired deoxytrifluoromethy-
lation reaction through reaction calorimetry (RC1) and other
potential undesired thermal events through differential reaction
calorimetry (DSC) studies.
The key reaction and safety parameters for the reaction
calorimetry experiment conducted in RC1 on 10 g scale were
summarized in Table 1. The reaction was set up by premixing
all components at 25 °C except for BBDFA, which was added
in three portions over the course of approximately 30 min. The
heat flow was measured during the addition (Figure 6). Only
the addition of the first portion (0.67 equiv, relative to 4) was
exothermic with a total enthalpy of 10.4 kJ/mol that translated
to a very minor adiabatic temperature rise (ΔTad) of 3.6 °C
(Table 1, entry 1). The addition of the subsequent two
portions were slightly endothermic (Table 1, entries 2−3).
After the addition of BBDFA, the reaction mixture was heated
to 40 °C over 30 min. The formation of the ester intermediate
D
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Figure 6. Heat flow during BBDFA addition.
Figure 7. Heat flow for the conversion of intermediate 5 to product 6.
water was added over 30 min. The addition of water was
exothermic, with a total enthalpy of 56 kJ/mol and a total
adiabatic temp rise of 4.7 °C (Table 1, entry 6). No noticeable
accumulation was observed, with the heat flow returning back
to baseline after 22% of the total water was added.
Thermal Stability of the Reaction Mixture. The thermal
stability of the reaction mixture was next studied by DSC to
understand if any undesired thermal decomposition might
occur (Figure 8). The DSC analysis was conducted in gold-
plated high-pressure crucibles that are rated up to 220 bar. The
crucible was heated from 25 to 400 °C at a scan rate of 2.5 °C/
min. The first exothermic event was observed at an onset
temperature of 59.6 °C with a total heat release of 251.43 J/g,
consistent with the heat release of the desired transformation
from intermediate 5 to product 6 observed in the RC1
experiment mentioned above. The second exothermic event
was observed at an onset temperature of 186.4 °C with a minor
heat release of 35.23 J/g, which could be characterized as an
E
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Figure 8. DSC curve of the reaction mixture
undesired thermal event. When applying the safety margin of
100 °C from the onset temperature, running the reaction at 70
°C is considered safe.
Table 3. Process Parameters for Criticality Class Definition:
Trifluoromethylation Reaction Using BBDFA
parameter
value
comments
process defined
A suggestion for assessment criteria by Stoessel13 for the
severity of a runaway reaction is presented in Table 2. This
Tp
70 °C
ΔTad
38.9 °C
from reaction calorimetry, worst
case for the batch process
Table 2. Assessment Criteria for the Severity of a Runaway
Reaction
MTSR
108.9 °C from reaction calorimetry, worst
case for the batch process
MTT
156 °C
bp of DMF
severity (simplified)
severity (extended)
ΔTad
Thermal decomposition
onset temperature
186.4 °C DSC on reaction mixture
high
catastrophic
critical
>400 °C
200−400 °C
medium
low
medium
negligible
50−100 °C
<50 °C and no pressure
cinnamyl alcohol allowed the process to be safely implemented
on preparative scale. The delivery of the trifluoroethane
product from readily accessible alcohols complements
preparations from alkenes,16 allyl halides,17 or allyl silanes,18
which have not yet been demonstrated on such scale. We
envision that, with appropriate adjustments/optimization, the
scope of this process should match that of previously reported
small-scale reactions.12
assessment was based on the study that, for any adiabatic
temperature rise of over 200 °C, the temperature increase as a
function of time under adiabatic conditions or cooling failure
becomes very sharp. This results in a violent reaction that
could potentially lead to a thermal explosion. Based on a
maximum adiabatic temperature rise of 38.9 °C for the
trifluoromethylation reaction, the severity of a runaway
scenario is deemed to be low.
Criticality Class: 1 or 2. Based on all the collected safety
assessment data, the one-pot deoxytrifluoromethylation using
BBDFA can be assigned to a criticality class 1 or 2 following
the systematic approach developed by Gygax14 and Stoessel13
(Table 3). For applications beyond preparative scale, it is
recommended to further evaluate the reaction mixture by
EXPERIMENTAL SECTION
■
General Information. All reactions were performed under
a nitrogen atmosphere unless otherwise stated. All reagents and
solvents were used as received from commercial suppliers
without further purification unless otherwise specified. KF was
stored and weighted in a nitrogen-filled glovebox because of its
hygroscopic nature. Reaction calorimetry was conducted on a
Mettler Toledo RC1e RTCal reaction calorimeter equipped
with an HFCal reaction calorimeter module. Differential
scanning calorimetry (DSC) analysis was conducted on the
Mettler Toledo DSC 1 STARe System using high-pressure
gold-plated crucibles. Dynamic vapor sorption (DVS) data
were collected at 25 °C over a range of 0% to 90% relative
humidity using a TA Q5000SA vapor sorption analyzer. NMR
spectra were recorded on a Bruker 300 MHz instrument at
ambient temperature. Melting points were measured by DSC
and reported as the onset temperature.
15
accelerating reaction calorimetry (ARC) to determine TD,24
and perform in-depth material compatibility evaluation.
CONCLUSION
■
In summary, we developed a large-scale preparation, isolation,
and purification of a new crystalline deoxytrifluoromethylating
reagent, BBDFA. The reagent itself is safe, thermally stable,
and stable to storage under ambient conditions. BBDFA
efficiently and directly converts activated alcohols to trifluoro-
methanes on >10 g scale. Detailed reaction calorimetry and
thermal analysis of the deoxytrifluoromethylation reaction of
[1,1′-Biphenyl]-4-yl 2-bromo-2,2-difluoroacetate
(BBDFA). Into a mixture of 2-bromo-2,2-difluoroacetic acid
F
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(2) (308 g, 1.76 mol, 300 mol %) in CH2Cl2 (300 mL), DMF
(13.0 g, 0.178 mol, 30 mol %) and oxalyl chloride (216 g, 1.71
mol, 290 mol %) were added sequentially below 20 °C. The
reaction mixture was stirred for 2 h at 10−20 °C until
complete conversion was confirmed by GC analysis. A mixture
of [1,1′-biphenyl]-4-ol (100 g, 0.588 mol, 100 mol %),
pyridine (139 g, 1.76 mol, 300 mol %), and CH2Cl2 (200 mL)
was stirred at 0 °C for 10 min. The solution of 2 in CH2Cl2
was transferred into the solution of [1,1′-biphenyl]-4-ol in
CH2Cl2 at 0 5 °C, and the resulting reaction mixture was
stirred at 20 5 °C for 2 h until complete conversion was
confirmed by GC analysis. The reaction mixture was then
added to a mixture of water (1.00 L) and toluene (1.00 L)
below 20 °C. The resulting upper organic layer was washed
with water (1.00 L × 2) and brine (1.00 L × 3) sequentially
until the pH reached 7. The organic phase was concentrated to
approximately 3 mL/g under vacuum. Azeotropic distillation
by feeding in anhydrous toluene (1.50 L × 3) was conducted
until the residual water was below 500 ppm by Karl Fischer
(KF) analysis. A solvent switch to n-heptane (0.500 L × 4)
resulted in crystallization of the desired product, which was
filtered and dried under vacuum at 50 °C to give BBDFA as a
white solid (179 g, 93% yield, 99.3% purity by GC analysis);
AUTHOR INFORMATION
Corresponding Authors
*E-mail: han.chong@gene.com.
*E-mail: raaltman@ku.edu.
■
ORCID
Chong Han: 0000-0002-2863-3921
Francis Gosselin: 0000-0001-9812-4180
Ryan A. Altman: 0000-0002-8724-1098
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This paper is dedicated to Professor Stephen L. Buchwald on
the occasion of the 25th anniversary of the Buchwald−Hartwig
Amination. We thank Dr. Haiming Zhang for helpful
discussions, Dr. Antonio DiPasquale for collecting PXRD
data, and Ms. Rebecca Rowe for collecting DVS data
(Genentech, Inc.). We thank the National Science Foundation
(CHE-1455163) for supporting this work.
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Reaction Calorimetry Experiment Using RC1. A clean,
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DOI: 10.1021/acs.oprd.9b00201
Org. Process Res. Dev. XXXX, XXX, XXX−XXX