Synthesis of Flubromazepam Positional Isomers for Forensic Analysis

Article abstract of DOI:10.1021/acs.joc.9b01433

Designer benzodiazepines have recently appeared in many forensic cases as legal alternatives to federally scheduled drugs such as diazepam (Valium) and alprazolam (Xanax). Though current forensic instrumental techniques are often sufficient for identifying novel psychoactive substances, they may not readily differentiate between potential positional isomers. Additionally, characterization data for positional isomers of known designer benzodiazepines are widely nonexistent. In this study, flubromazepam, a recognized designer benzodiazepine since 2012, was targeted for synthesis and characterization due to its potential for federal scheduling and current legal status within the United States. A practical synthetic method was developed to prepare purified reference materials for each positional isomer of flubromazepam in which the positions of the bromine and fluorine substituents were varied. Possible isomers (9 of the 12) were successfully prepared and used for further analysis.

Full text of DOI:10.1021/acs.joc.9b01433

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Article
Synthesis of Flubromazepam Positional Isomers for Forensic Analysis
Evelyn S. Ligon, Jason Nawyn, Lonnie V. Jones, B. McKay Allred, Daniel V. Reinhardt, and Stefan France
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b01433 • Publication Date (Web): 20 Jul 2019
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Synthesis of Flubromazepam Positional Isomers for Forensic Analysis
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Evelyn S. Ligona, Jason Nawynb, Lonnie V. Jonesb, B. McKay Allredc, Daniel V. Reinhardt, Jr.b,*,
and Stefan Francea,d,*
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a
School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta, Georgia,
30332, United States
b United States Army Criminal Investigation Laboratory, Defense Forensic Science Center,
Forest Park, Georgia, 30297, United States
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Office of the Chief Scientist, Defense Forensic Science Center, Forest Park, Georgia, 30297,
United States
d
Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta,
Georgia 30332, United States
daniel.v.reinhardt.civ@mail.mil
stefan.france@chemistry.gatech.edu
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ABSTRACT
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Designer benzodiazepines have recently appeared in many forensic cases as legal alternatives to
federally scheduled drugs such as diazepam (Valium®) and alprazolam (Xanax®). Though current
forensic instrumental techniques are often sufficient for identifying novel psychoactive substances
(NPS), they may not readily differentiate between potential positional isomers. Additionally,
characterization data for positional isomers of known designer benzodiazepines are widely
nonexistent. In this study, flubromazepam, a recognized designer benzodiazepine since 2012, was
targeted for synthesis and characterization due to its potential for federal scheduling and current
legal status within the United States. A practical synthetic method was developed to prepare
purified reference materials for each positional isomer of flubromazepam in which the positions
of the bromine and fluorine substituents were varied. Nine of the twelve possible isomers were
successfully prepared and used for further analysis.
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INTRODUCTION
Benzodiazepines constitute a large class of pharmaceutical compounds that exhibit sedative,
depressant, and relaxant properties.1-4 Phenazepam (1), for instance, is currently obtainable in
most states as a research chemical self-prescribed for insomnia, anxiety, and opiate withdrawal
(Figure 1).5,6 Though still prescribed for medicinal purposes, many benzodiazepines, such as
diazepam (Valium®, 2) and alprazolam (Xanax®, 3), have become federally controlled under
Schedule IV due to their abuse and addiction potential.7 As a result, designer benzodiazepines
have entered the recreational market as non-scheduled non-FDA-approved alternatives to
Schedule IV benzodiazepines since the early 2010s. Among them, flubromazepam (4), its triazole
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counterpart
flubromazolam
(5),
and
etizolam
(6),
a
structurally
similar
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triazolothienobenzodiazepine, were listed in the 2017 Drug Enforcement Agency (DEA) Emerging
Threat Report as the benzodiazepine designer drugs most frequently seized and analyzed in the
United States.8
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Figure 1. Representative Pharmaceutical Benzodiazepines
An understudied class of designer benzodiazepines is the positional isomers of federally
controlled parent benzodiazepines. Positional isomers have identical core structures to their
parents but differ by the placement of one or two atoms or substituents. Because of these close
structural similarities, positional isomers are expected to exhibit similar physiological effects to
their parents, making them prime candidates for technically legal alternatives. The Federal
Analogue Act,9 which is part of the Controlled Substances Act (CSA) of 1970,10 allows entire
classes of “substantially similar” compounds to become controlled in one broad sweep.7a,11 The
analogue rule applies only to Schedule I and Schedule II substances, however, so Schedule IV
benzodiazepines, including their positional isomers, are processed individually as distinct
substances.
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At the time of this publication, analytical reference data is not readily available to
differentiate between many illicit benzodiazepines and their corresponding positional isomers. To
address this deficiency, flubromazepam (4) was targeted for synthesis and characterization for two
primary reasons. First, recent incidents have made flubromazepam a candidate for future
scheduling, and its current uncontrolled status facilitates unrestricted research. Second, from a
synthetic perspective, flubromazepam has twelve possible positional isomers (including the
parent), which maximizes the available chemical space for synthetic, analytical, and biological
survey.
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Despite its recent appearance in forensic cases, flubromazepam (4) was first prepared and
studied by Sternbach and co-workers in the early 1960s.12 Flubromazepam was later fully
characterized by Moosmann and co-workers in 2013,13 and initial biological studies showed that
it has anticonvulsant properties and an elimination half-life of 100 hours.14 Flubromazolam (5),
which was first reported in 2016 and is directly prepared from 4, has exhibited even more potent
effects.15 Incidents involving flubromazepam include three hospitalizations from acute exposure
in the last four years in the US,16 thirty-three in Sweden between 2012-2015,17 and a severe case
of poisoning from 4 mixed with synthetic opioid U-47700 which resulted in severe brain damage
followed by patient death.13,18 Additionally, in certain military cases, on-duty personnel in
possession of the drug have been convicted of violating operational readiness, which is an
important threat to national security.19
Flubromazepam is most commonly accessed through Sternbach's published method
(Scheme 1A).12 By their method, p-bromoaniline (7a) undergoes a Friedel-Crafts acylation with
o-fluorobenzoyl chloride (8a) to form the 2-aminobenzophenone 9aa (Scheme 1A).12b Then, a
two-step annulation sequence is employed involving 2-bromoacetyl bromide (10) to first prepare
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the 2-bromoacetamidobenzophenone intermediate, followed by treatment with ammonia and heat
to promote ring closure through imine formation.12c Though other benzodiazepines were also
successfully prepared by Sternbach's method, the scope has been generally limited to products
originating from anilines with electron-withdrawing para-substituents. This is unsurprising given
the synergistic substitution preferences of Friedel-Crafts acylations for 4-halo- or 4-EWG-
substituted anilines (Scheme 1B).20 This is in stark contrast to the expected undesired acylations
that would predominate with the 2- or 3-substituted anilines. Thus, 2-aminobenzophenones with
bromo, chloro, and nitro substituents para to the amino group are highly accessible,21 which
explains the greater abundance of their corresponding benzodiazepines on the recreational drug
market and thus in forensic cases.
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Scheme 1. (A) Sternbach Synthesis of Flubromazepam and (B) its Limitations for o- and p-
Substituted Anilines
Preparative methods for positional isomers of benzodiazepines, on the other hand, are
limited in the scientific literature. Though many studies have investigated efficient routes to
various benzodiazepine precursors,22,23 most fall short of at least one of three important criteria: 1)
they do not showcase precursors with substitution patterns that would lead to positional isomers
of the more common parents; 2) they do not tolerate halo- and nitro-substituted benzodiazepines
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most frequently surveyed in forensic cases; and 3) they have failed to follow through in the actual
preparation of the corresponding benzodiazepine products. Consequently, the characterization data
to accompany these benzodiazepines, both analytical and biological, are nonexistent.
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To address this gap in knowledge, we set out to develop a uniform synthetic method to
access the positional isomers of flubromazepam (Scheme 2).24 An ideal synthesis would employ
commercially available precursors and tolerate a variety of substituents and substitution patterns.
Herein, we report a generalized approach to access the twelve possible positional isomers of
flubromazepam by developing a complementary approach to the substituted benzophenones that
bypasses the issues associated with Friedel-Crafts regioselectivity. Both successful and
unsuccessful approaches will be described, culminating in access to nine of the twelve isomers.
This study serves as a proof of concept while establishing a roadmap for synthesizing and
characterizing the isomers of additional benzodiazepines of interest.
Scheme 2. Synthetic Roadmap to Flubromazepam Positional Isomers
RESULTS AND DISCUSSION
For the proposed synthesis of the positional isomers of flubromazepam, three different
approaches were outlined in the retrosynthetic analysis shown in Figure 2. In Approach 1, an
oxidative cross-coupling of bromoanilines 7 with fluorobenzaldehydes 11 was envisioned to
access the 2-aminobenzophenones 9. Approach 2 explored the potential of decarboxylative cross-
coupling reactions between bromoisatins 12 (via its hydrolysis products, X-bromo-2-(2-
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aminophenyl)-2-oxoacetates) and fluorophenylboronic acids 13. Finally, Approach 3 targeted
benzophenones 9 via acylation of X'-fluorophenyllithiums 15 with the Weinreb 2-
aminobenzamides 14.
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Figure 2. Retrosynthetic Analysis for the Synthesis of Flubromazepam Isomers
Approach 1- Oxidative Cross-Coupling. Initial attempts to access the functionalized
benzophenones explored a Pd-catalyzed oxidative C-H bond coupling of acetanilides and
aldehydes that was reported by Li and Kwong (Scheme 3A).25 This strategy was appealing due to
the commercial availability of each of the bromoanilines and fluorobenzaldehydes. The acetyl
substituent serves as a directing group for the ortho C-H functionalization to access the desired
benzophenones. Moreover, if successful, this strategy would be particularly appealing since two
distinct sets of regioisomeric cross-coupling adducts (17ba-17bc and 17da-17dc) should be
accessible from reactions with 3-bromoacetanilide (16b), which would streamline isomer
synthesis (Scheme 3B).
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Scheme 3. (A) Li and Kwong's Oxidative Coupling of Acetanilides and Aldehydes and (B) the
Proposed Divergent Coupling of 3-Bromoacetanilide
As a starting point, 4-bromoaniline 7a was N-acetylated with acetic anhydride then
separately treated with 2, 3, or 4-fluorobenzaldehyde (11a, 11b, or 11c) under the published
conditions (Scheme 4). In each case, however, the reactions afforded a complex mixture of
products and yields of the desired benzophenones 17 were low (8-12%). These results were
partially attributed to deactivation of the substitution reaction by the bromine substituent.
Additionally, a test reaction with 3-bromoacetanilide 16b and 2-fluorobenzaldehyde 11a only gave
only one benzophenone regioisomer (17ba) in low yield, signifying that all twelve flubromazepam
isomers would not be accessible by this route.
Scheme 4. Pd-catalyzed Oxidative Cross-Couplings Between N-Acetyl-4-bromoaniline (7a) and
Fluorobenzaldehydes 11 and Attempted End-Game to [7,X']-Flubromazepams
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Sufficient amounts of material (~10-20 mg) were isolated from the 4-bromoacetanilide
reactions to attempt the syntheses of three flubromazepam isomers- the (7,2')-, (7,3')-, and (7,4')-
isomers. Based on previous benzodiazepine syntheses through Friedel-Crafts acylation, these three
isomers were already expected to be the most accessible by distributors, as the fluorine substitution
would likely not drastically affect reaction outcomes. Thus, it was appealing to obtain the
corresponding characterization data early in the project. From the 2-acetamido-4-bromo-X'-
fluorobenzophenones 17aa-ac, acid-promoted N-deprotection was attempted, followed by
annulation of the crude product using glycine ethyl ester via an alternative Sternbach method
(Scheme 4).26 No desired product could be obtained as only a trace amount of each isomer was
detected by 1H NMR. Ultimately, this approach was deemed not viable to access the isomers.
As a last-ditch effort in using the bromoanilines, an alternative directed ortho-C-H
functionalization approach was envisioned involving Sugasawa coupling27 of 3-bromoaniline 7b
with 4-fluorobenzonitrile 18c in the presence of BCl3 and AlCl3 (Scheme 5).28 We anticipated that
the use of 7b in the Sugasawa reaction would give a mixture of the regiosiomeric benzophenones.
However, the reaction afforded 22% of 9bc as the only benzophenone isomer. Due to both the
poor yield and the inability to access the other regioisomer, this approach was similarly abandoned.
Scheme 5. Attempted Sugasawa Coupling
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Approach 2- Decarboxylative Coupling. Changing tactics, we were inspired by the work of Qi
and co-workers29 who demonstrated a Ag-catalyzed decarboxylative acylation of phenylglyoxylic
acids 20 with phenylboronic acids 21 to afford substituted benzophenones 22 (Scheme 6). The
authors particularly highlighted the method's tolerance for both halo- and amino-substituted
phenylglyoxylic acids and boronic acids. Employing (2-amino-X-bromophenyl)glyoxylic acids
would set the isomer substitution pattern at the beginning of the synthesis, thus simplifying
purification and characterization throughout the sequence.
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Scheme 6. Qi's Glyoxylic Acid Decarboxylative Cross-Couplings
However, given that (2-amino-5-bromophenyl)glyoxylic acid 23a is the only
commercially-available isomer, the synthesis of the remaining glyoxylic acids presented a
challenge. To address this, 4-, 5-, 6-, and 7-bromoisatins (12a-d) were explored as precursors to
the glyoxylic acids (Scheme 7). Each bromoisatin is commercially-available and should be readily
hydrolyzed to generate the glyoxylic acid salt. Starting with a model system, saponification of
unsubstituted isatin (12e) with NaOH in methanol readily afforded the ring-opened 2-
aminophenylglyoxylate salt (23e-Na),30 but acidic workup (to pH 3) drove the reaction
predominantly back to isatin. Hypothesizing that an electron-withdrawing substituent might hinder
this process by making the amine less nucleophilic, the saponification-acidification sequence was
attempted with 12a, but mixtures of glyoxylic acid (23a) and isatin were obtained. Methods to
separate the acid from the isatin by either chromatography (flash or preparative), extraction, or
recrystallization failed.
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Scheme 7. Attempted Isatin Saponification-Acidification Sequence and Unsuccessful
Decarboxylative Coupling Using Glyoxylate Salts
Next, the direct use of glyoxylate salts were employed for the decarboxylative cross
coupling reaction (Scheme 7). Similar to the sodium salt, the lithium salt was prepared by isatin
treatment with LiOH. The potassium salt was prepared using K2CO3. Finally, since the cross-
coupling procedure is catalyzed by Ag(I) salts, the silver glyoxylate salt was generated from Ag2O.
Each salt was then subjected to the cross coupling conditions with the unsubstituted phenylboronic
acid (24). In all cases, no desired product was detected.
In a final attempt to effect cross-coupling, several N-protection protocols were evaluated
with hopes of stabilizing the glyoxylic acid for isolation. Methyl chloroformate and di-tert-butyl
dicarbonate (Boc2O) protections were unproductive, but a two-step protection/saponification
protocol employing ethyl chloroformate and Na2CO3 afforded the desired glyoxylic acid 26 in high
yield (Scheme 8).31 Unfortunately, the subsequent cross coupling of 12e with 2-
fluorophenylboronic acid (27) did not give any observable products.
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Scheme 8. Failed Coupling of N-Protected Glyoxylic Acid 26
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Approach 3- Benzoylation of Fluoro-substituted Phenyllithiums. Following the failed cross-
coupling approaches, an alternative strategy was undertaken involving benzoylation of fluoro-
substituted phenyl anions 15 (Grignards or lithiates) with 2-amino-X-bromo-N-methoxy-N-
methylbenzamides 28 (Scheme 9).
NH2
O
NH2
O
M
OMe
N
F
Br
Br
F
Me
28
15
(M = MgX or Li)
9
Scheme 9. Proposed Benzoylation Strategy
Preparation of each Weinreb amide involved a two-step sequence starting from a bromo-
substituted isatin 12a-d (Scheme 10). Isatins 12 were treated with hydrogen peroxide under
strongly basic conditions to produce 2-amino-X-bromobenzoic acids 29a-d,32 which were
collected in moderate to high yields as the hydrochloride salts after acidification. Amidation of
29a-d with N,N,'-dimethylhydroxylamine hydrochloride was then effected in the presence of
HBTU33 and N-methylmorpholine to give Weinreb amides 30a-c in moderate to high yields.
Unfortunately, obtaining 30d proved particularly troublesome. Though crude NMR validated its
formation, 30d was inseparable from the complex mixture that was formed. In hopes of still
accessing the desired benzophenone isomer, the crude mixture of 30d was taken forward.
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MeO
Me
N
• HCl
N-methylmorpholine
HBTU, DMF
H
30% aq. H2O2
5% aq. NaOH
O
NH2
O
NH2
O
OMe
OH
N
O
Br
Br
Br
O
N
Me
• HCl
Br
H
12
NH2
29
30
NH2
O
O
NH2
O
NH2
OH
OH
OH
OH
9
Br
• HCl
OMe
Br
• HCl
• HCl
• HCl
29b, 72%
Br
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29a, 66%
29c, 86%
29d, 87%
NH2
O
NH2
O
NH2
O
N
NH2
O
OMe
Br
OMe
OMe
N
N
N
Me
Me
Me
Me
Br
Br
Br
30a, 97%
30b, 99%
30c, 74%
30d
inseparable
mixture
Scheme 10. Two-step Synthesis to Prepare 2-Amino-X-bromobenzoic Acids 29a-d and Weinreb
Amides 30a-d from Bromoisatins 12a-d
Next, the conditions for benzophenone formation were explored (Scheme 11). Initial test
reactions between amides 30a-c and phenylmagnesium bromide were promising (see Supporting
Information).34 However, in situ preparation of the fluorophenylmagnesium bromides from the
various fluoro-substituted bromobenzenes gave inconsistent results. Several reagents for
magnesium-halogen exchange were tested, including Turbo Grignard35 (i-PrMgCl•LiCl), with no
success. Lithium-halogen exchange was then examined as a potential protocol. Gratifyingly,
lithiation of 1-bromo-4-fluorobenzene (31c) with n-butyllithium proceeded smoothly at -78 ˚C.
Upon transferring the lithiate solution dropwise via syringe to a solution of the Weinreb amide
30a, the desired 2-amino-3-bromo-4’-fluorobenzophenone (9ac) was formed and, ultimately,
isolated in 78% yield.
Mg-halogen
exchange
poor conversions
undesired side reactions
NH2
Br
O
OMe
Br
N
Me
NH2
Br
O
F
nBuLi
(2.0 equiv)
(2.1 equiv)
31c
30a
THF, -78 ˚C
F
9ac (78%)
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Scheme 11. Exploratory Benzoylation Reactions
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Given the success with the Li-halogen exchange of 1-bromo-4-fluorobenzene, the same
approach was first applied to accessing the benzophenone isomers containing the 4'-fluoro
substituent (Scheme 12). Addition of the lithiate to amides 30b and 30c gave the desired
benzophenones 9bc and 9cc in 49% and 62% yield, respectively. Next, the lithium-halogen
exchange reactions of 1-bromo-3-fluorobenzene 31b were conducted. The reactions generated the
respective benzophenone isomers (9ab, 9bb, and 9cb) in 60%, 55%, and 63% yield.
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NH2
O
NH2
O
nBuLi
(2.1 equiv)
Br
OMe
N
Br
F
F
Br
THF, -78 ˚C
Me
31 (2 equiv)
30
9
NH2
O
F
NH2
O
NH2
O
F
F
Br
Br
Br
9aa, 65%a
9ac, 78%
9ab, 60%
NH2
NH2
O
F
O
NH2
O
F
F
Br
Br
Br
F
9ba, 50%a
NH2
9bb, 55%
NH2
9bc, 49%
NH2
O
O
F
O
Br
Br
Br
F
9ca, 56%a
9cb, 63%
9cc, 62%
NH2
O
F
NH2
O
NH2
O
F
Br
Br
Br
F
9da, 0%b
9db, 0%b
9dc, 0%b
a Reactions performed at -100 ˚C
b No desired product formed
Scheme 12. Synthesis of 2-Amino-X-bromo-X'-fluorobenzophenones 9 via Benzoylation
For 1-bromo-2-fluorobenzene 31a, lithiation was not successful at -78 ˚C as the lithiate
appeared to degrade as immediately as it was formed. A quick literature search revealed that
lithiation of 31a could be accomplished at temperatures as low as -110 ˚C,36 so the reaction was
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attempted again at -100 ˚C. Addition of the benzamide solutions to the lithiate at -100 ˚C afforded
benzophenone precursors 9aa, 9ba, and 9ca with yields of 65%, 50%, and 56%, respectively. The
yields were modest due to the nucleophilic attack of the Weinreb amide by n-butyllithium, forming
an n-butyl phenone adduct (see Supporting Information). A test reaction with t-butyllithium to
promote lithium-halogen exchange and reduce nucleophilic activity of the lithiating agent gave a
lower yield along with a number of uncharacterized side products (see Supporting Information).
Unfortunately, applying any of the reaction conditions to the crude mixture of 30d failed
to deliver the desired benzophenones. It is hypothesized that the purification issues with 30d, the
steric hindrance at the site of nucleophilic addition, and potential cross lithium-halogen exchange
may have prevented the transformation from occurring.
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Synthesis of the Isomers from the Prepared Benzophenones. With nine of the twelve possible
benzophenone precursors in hand, the conversions to the desired flubromazepam positional
isomers were performed using the known literature procedures12 (Scheme 13). For each
benzophenone, N-acylation was first effected using 2-bromoacetyl bromide (10). Subsequently,
the crude product was dissolved in 7M ammonia in methanol and stirred overnight to afford the
parent flubromazepam (4) and eight other positional isomers 19. Most yields were good (49-98%),
though isomers 19ca and 19cc were isolated with lower yields (<40%) than expected. This
chemistry was not further optimized, however, as sufficient quantities of each positional isomer
were obtained for analysis.
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Scheme 13. Synthesis of Flubromazepam Positional Isomers
CONCLUSIONS
In this study, nine of the twelve positional isomers of flubromazepam were successfully
synthesized. The synthetic route developed was a three-step saponification, amidation, and lithiate
addition and has not been used previously to access the 2-amino-X-bromo-X’-fluorobenzophenone
precursors to the flubromazepam positional isomers. The chemical characterization data (e.g.,
spectra) acquired from this study will be made available to forensic scientists. This method may
be adapted to synthesize and characterize other benzodiazepines of interest. Future efforts will
involve comparing the potency of the isomers versus the parent. Alternative approaches to
synthesize the final three flubromazepam isomers will also be explored.
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EXPERIMENTAL SECTION
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General Information. Chromatographic purification was performed via flash chromatography
with Silicycle SiliaFlash P60 silica gel (40-63 µm) or preparative thin-layer chromatography (prep-
TLC) with Analtech silica gel F254 (1000 µm) plates and solvents indicated as eluent with 0.1-0.5
bar pressure. For quantitative flash chromatography, technical grades solvents were utilized.
Analytical thin-layer chromatography (TLC) was also used to separate and purify reaction
products using Silicycle SiliaPlate TLC silica gel F254 (250 µm) TLC glass plates. Products on
the TLC plates were visualized under UV light (254 nm).
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Proton, carbon, and fluorine nuclear magnetic resonance spectra (1H NMR, 13C NMR, and
19F NMR, respectively) were recorded on a Bruker 500 MHz spectrometer in all but one case-
compound 16a was analyzed using a Bruker 300 MHz spectrometer. The solvent resonances were
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used the internal standards (1H NMR: CDCl3 at 7.26 ppm, DMSO-d6 at 3.50 ppm; C NMR:
CDCl3 at 77.0 ppm, DMSO-d6 at 39.5 ppm; 19F NMR: locked to CDCl3 or DMSO-d6).
MestReNova (v. 11.0) was used to analyze NMR spectra. 1H NMR data are reported as follows:
chemical shift (ppm), multiplicity (s = singlet, d = doublet, dd = doublet of doublets, dt = doublet
of triplets, ddd = doublet of doublet of doublets, t = triplet, m = multiplet, br = broad), coupling
constants (Hz), and integration. 13C NMR data were recorded as proton-decoupled spectra, and 19F
NMR data were recorded as proton-coupled spectra. High-resolution accurate mass-mass
spectrometry (HRAM-MS) was performed using a ThermoFisher Q-Exactive quadrupole Orbitrap
tandem Mass Spectrometer (MSD) coupled to a ThermoFisher Vanquish Liquid Chromatograph
(LC). Thermo QualBrowser (Xcalibur 4.1.31.9) was employed for data processing, including
integrations and background subtractions. Infrared (IR) spectra were recorded using a Spectra
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Analysis DiscovIR-GC coupled with an Agilent 7890A Gas Chromatograph. Data were processed
in Grams (version 9.1) for baseline correction and exported to Microsoft Excel for plotting. The
IR bands were characterized as broad (br), weak (w), medium (m), and strong (s).
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Procedures for Approach 1.
Synthesis of 2-Amino-N-(4-bromophenyl)acetamide (16a). Following the published procedure
from Fagnou et al.:37 In a flame-dried flask under nitrogen atmosphere, 4-bromoaniline 7a (500
mg, 2.907 mmol) was stirred with acetic anhydride (0.33 mL, 3.488 mmol) in anhydrous CH2Cl2
(7.3 mL) at room temperature. After 16 h, the reaction was quenched with saturated aqueous
Na2CO3. The aqueous layer was extracted three times with CH2Cl2, then the combined organic
layers were dried over anhydrous magnesium sulfate, filtered through Celite under reduced
pressure, and concentrated by rotary evaporation. Compound 16a was collected (25%
EtOAc/hexanes, Rf = 0.07) without further purification as a white solid (609.1 mg, 97% yield). 1H
NMR (300 MHz, CDCl3) δ 7.42 (d, J = 2.2 Hz, 4H), 2.18 (s, 3H).
General Procedure for the Oxidative Coupling. Following the published procedure:25 In a dry flask
open to air, 2-amino-N-(4-bromophenyl)acetamide 16a (75 mg, 0.350 mmol) and Pd(TFA)2 (5.8
mg, 0.0175 mmol) were dissolved in anhydrous toluene (0.7 mL). After 5 min, X'-
fluorobenzaldehyde 11 (0.07 mL, 0.700 mmol) and TBHP (0.34 mL, 1.40 mmol, 4.13 M solution
in toluene) were added, then the reaction was heated at 90 ˚C using an oil bath and stirred for 24
h. After cooling to room temperature, the reaction was quenched with saturated aqueous K2CO3.
The aqueous layer was extracted three times with EtOAc, then the combined organic layers were
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dried over anhydrous Na2SO4, filtered through celite under reduced pressure, and concentrated by
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rotary evaporation. Compound 17 was isolated by silica preparatory thin-layer chromatography.
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2-Acetamido-5-bromo-2'-fluorobenzophenone (17aa). The general decarboxylative coupling
procedure was followed using 2-fluorobenzaldehyde 11a (0.07 mL, 0.700 mmol). The product
17aa was isolated by silica preparatory thin-layer chromatography (25% EtOAc/hexanes, Rf =
0.37) to afford a yellow solid (14.8 mg, 12% yield). 1H NMR (500 MHz, CDCl3) δ 11.17 (s, 1H),
8.68 (d, J = 9.1 Hz, 1H), 7.67 (dd, J = 9.0, 2.3 Hz, 1H), 7.61 – 7.55 (m, 2H), 7.48 – 7.44 (m, 1H),
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7.30 (td, J = 7.5, 1.0 Hz, 1H), 7.21 (ddd, J = 9.6, 8.4, 1.0 Hz, 1H), 2.26 (s, 3H). C{1H} NMR
(126 MHz, CDCl3) δ 195.9, 169.4, 159.5 (d, J = 253.0 Hz), 140.1, 138.1, 136.0 (d, J = 2.1 Hz),
133.6 (d, J = 8.3 Hz), 130.2 (d, J = 2.3 Hz), 126.8 (d, J = 14.4 Hz), 124.5 (d, J = 3.6 Hz), 123.9,
122.6, 116.6 (d, J = 21.4 Hz), 114.6, 25.5. 19F NMR (471 MHz, CDCl3) δ -111.61 (dtd, J = 9.8,
7.1, 6.3, 3.6 Hz). HRAM-MS (EI) m/z [M+H]+ Calcd for C15H12BrFNO2 336.0030; Found
336.0025.
2-Acetamido-5-bromo-3’-fluorobenzophenone (17ab). The general decarboxylative coupling
procedure was followed using 3-fluorobenzaldehyde 11b (0.07 mL, 0.700 mmol). The product
17ab was isolated by silica preparatory thin-layer chromatography (10% EtOAc/hexanes, Rf =
1
0.30) to afford a yellow oil (13.1 mg, 11% yield). H NMR (500 MHz, CDCl3) δ 10.55 (s, 1H),
8.55 (d, J = 9.0 Hz, 1H), 7.67 (dd, J = 9.0, 2.5 Hz, 1H), 7.62 (d, J = 2.4 Hz, 1H), 7.50 (td, J = 7.9,
5.3 Hz, 1H), 7.48 – 7.38 (m, 2H), 7.33 (tdd, J = 8.2, 2.7, 1.2 Hz, 1H), 2.22 (s, 3H). 13C{1H} NMR
(126 MHz, CDCl3) δ 196.81 (d, J = 2.2 Hz), 169.1, 162.5 (d, J = 249.4 Hz), 139.8 (d, J = 6.4 Hz),
139.5, 137.2, 135.3, 130.3 (d, J = 7.8 Hz), 125.7 (d, J = 3.1 Hz), 124.3, 123.4, 120.1 (d, J = 21.4
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Hz), 116.5 (d, J = 22.7 Hz), 114.6, 25.2. 19F NMR (471 MHz, CDCl3) δ -110.96 (td, J = 8.6, 5.5
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6
Hz). HRAM-MS (EI) m/z [M+H]+ Calcd for C15H12BrFNO2 336.0030; Found 336.0025.
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2-Acetamido-5-bromo-4'-fluorobenzophenone (17ac). The general decarboxylative coupling
procedure was followed using 4-fluorobenzaldehyde 11c (0.07 mL, 0.700 mmol). The product
17ac was isolated by silica preparatory thin-layer chromatography (10% EtOAc/hexanes, Rf =
1
0.33) to afford a yellow solid (9.4 mg, 8% yield). H NMR (500 MHz, CDCl3) δ 10.44 (s, 1H),
8.52 (d, J = 9.0 Hz, 1H), 7.79 – 7.72 (m, 2H), 7.66 (dd, J = 9.0, 2.3 Hz, 1H), 7.61 (d, J = 2.4 Hz,
1H), 7.23 – 7.18 (m, 2H), 2.21 (s, 3H). 13C{1H} NMR (126 MHz, CDCl3) δ 196.6, 169.0, 165.7
(d, J = 255.8 Hz), 139.1, 136.8, 135.0, 134.0 (d, J = 3.1 Hz), 132.6 (d, J = 9.4 Hz), 124.9, 123.5,
115.9 (d, J = 21.8 Hz), 114.6, 25.2. 19F NMR (471 MHz, CDCl3) δ -104.32 (tt, J = 8.3, 5.4 Hz).
HRAM-MS (EI) m/z [M+H]+ Calcd for C15H12BrFNO2 336.0030; Found 336.0023.
General Deprotection Procedure of N-Acetylbenzophenones. In a flask equipped with a stir bar
and a condenser under nitrogen atmosphere, 2-acetamido-5-bromo-X'-fluorobenzophenone 17
(14.8 mg, 0.0440 mmol) was stirred with hydrochloric acid (0.15 mL, 37 wt% H2O) at 125 ˚C
using an oil bath. After 3 h, the reaction was cooled to 0 ˚C, diluted with EtOAc, and quenched
with saturated aqueous NaHCO3. The aqueous layer was extracted three times with EtOAc, then
the combined organic layers were washed with H2O, dried over anhydrous Na2SO4, filtered
through celite under reduced pressure, and concentrated by rotary evaporation.
General Glycine Ethyl Ester Annulation Procedure. The crude deprotection product was re-
dissolved in pyridine (0.09 mL) in a flask equipped with a stir bar and a condenser under nitrogen
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atmosphere, then stirred at reflux using an oil bath with glycine ethyl ester hydrochloride (18.4
mg, 0.132 mmol) and piperidine (1 drop) for 15 h. The reaction mixture was concentrated by rotary
evaporation, then diluted with CH2Cl2. The organic layer was washed with H2O, dried over
anhydrous MgSO4, filtered through celite under reduced pressure, and concentrated by rotary
evaporation.
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Flubromazepam (4) from 2-acetamido-5-bromo-2’-fluorobenzophenone 17aa. The general
deprotection and annulation procedures were followed using N-(5-bromophenyl)acetamido-2’-
fluorobenzophenone (14.8 mg, 0.0440 mmol) in 0.15 mL of HCl (37 wt% H2O), then glycine ethyl
ester hydrochloride (18.4 mg, 0.132 mmol) and piperidine (1 drop) in 0.09 mL of pyridine.
Compound 4 was not isolated.
(7,3’)-Isomer (19ab) from 2-acetamido-5-bromo-3’-fluorobenzophenone 17ab. The general
deprotection and annulation procedures were followed using N-(5-bromophenyl)acetamido-3’-
fluorobenzophenone 17ab (13.1 mg, 0.0390 mmol) in 0.13 mL of HCl (37 wt% H2O), then glycine
ethyl ester hydrochloride (16.3 mg, 0.117 mmol) and piperidine (1 drop) in 0.08 mL of pyridine.
Compound 19ab was not isolated.
(7,4’)-Isomer (19ac) from 2-acetamido-5-bromo-4’-fluorobenzophenone 17ac. The general
deprotection and annulation procedures were using N-(5-bromophenyl)acetamido-4’-
fluorobenzophenone 17ac (9.3 mg, 0.0277 mmol) in 0.09 mL of HCl (37 wt% H2O), then glycine
ethyl ester hydrochloride (11.6 mg, 0.0831 mmol) and piperidine (1 drop) in 0.3 mL of pyridine.
Compound 19ac was not isolated.
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Sugasawa Procedure: Modified from the published procedure:28a To a flame-dried flask under
nitrogen equipped with a stir bar was added BCl3 (0.76 mL, 0.755 mmol, 1 M solution in CH2Cl2).
After cooling to 0 ˚C, 3-bromoaniline (100 mg, 0.581 mmol) was added dropwise, followed by
AlCl3 (100.7 mg, 0.755 mmol), 4-fluorobenzonitrile (140.7 mg, 1.162 mmol), and anhydrous
benzene (1.2 mL). The reaction was heated to 80 ˚C using an oil bath for 12 h then cooled back to
0 ˚C. HCl (2.5 mL, 1 M solution) was added, then the nitrogen line was removed and the reaction
was warmed to 80 ˚C for 30 min. After cooling to room temperature, the aqueous layer was
extracted three times with CH2Cl2, then the combined organic layers were washed with saturated
aqueous NaCl, dried over MgSO4, filtered through Celite under reduced pressure, and concentrated
by rotary evaporation. After purification by preparatory TLC, benzophenone 9bc was afforded as
a yellow solid (38.5 mg, 22%) along with unreacted starting materials.
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Procedures for Approach 2.
Standard Isatin Ring-opening Procedure: In a round-bottom flask, a 30% KOH/H2O (or 30%
NaOH/H2O) solution was prepared. MeOH was added, then isatin was added and dissolved. After
24 h, the reaction was brought to pH ~3 with 1 M HCl, then the aqueous layer was extracted with
EtOAc and the combined organic extracts were dried over anhydrous Na2SO4, filtered through
celite under reduced pressure, and concentrated.
Synthesis of (2-Ethoxycarbonylaminophenyl)glyoxylic Acid (26). Following the published
procedure from Kraus and Guo:31 In a flame-dried flask under nitrogen equipped with a stir bar,
isatin (500 mg, 3.398 mmol) was dissolved in dry tetrahydrofuran (8.5 mL), then Et3N (0.66 mL,
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4.757 mmol) was added. After stirring for 30 min, the reaction was cooled to 0 ˚C, and ethyl
chloroformate (0.33 mL, 3.398 mmol) was added slowly. The reaction was allowed to warm to
room temperature. After 45 min, Na2CO3 (540.2 mg, 5.097 mmol) and H2O (8.5 mL) were added
and the reaction was heated to reflux. After 1 h, the reaction was cooled to 0 ˚C and the solution
pH adjusted to 1-2 with 0.5 M HCl. The aqueous layer was extracted three times with Et2O. The
combined organic layers were washed once with H2O, then dried over anhydrous Na2SO4, filtered
through celite under reduced pressure, and concentrated by rotary evaporation. The product 26 was
isolated by silica column chromatography (10% MeOH/CH2Cl2, Rf = 0.06) to afford a yellow solid
(670.8 mg, 88% yield). 1H NMR (500 MHz, DMSO-d6) δ 10.82 (s, 1H), 8.20 (d, J = 8.3 Hz, 1H),
7.73 (d, J = 7.6 Hz, 1H), 7.63 (t, J = 7.8 Hz, 1H), 7.15 (t, J = 7.3 Hz, 1H), 4.16 (q, J = 7.1 Hz, 2H),
1.25 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (126 MHz, DMSO-d6) δ 197.0, 166.8, 153.1, 141.0, 135.0,
133.5, 122.0, 119.0, 118.6, 61.0, 14.4. HRAM-MS (EI) m/z [M-H]- Calcd for C11H10NO5
236.0564; Found 236.0561.
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Procedures for Approach 3.
General Saponification Procedure for the Synthesis of 2-Amino-X-bromobenzoic Acids 29.
Following the published procedure32, X-bromoisatin 12 (1.00 g, 4.42 mmol) was charged to a
round-bottom flask equipped with a stir bar. NaOH (5% H2O, 22 mL) was added, and the solution
was warmed to 50 ˚C using an oil bath. Then, H2O2 (30 wt%/H2O, 1.1 mL, 11.06 mmol) was added
in one shot. After 30 min stirring, the solution was brought to pH ~ 4 with 1 M HCl. The product
29 was collected under reduced pressure on a Buchner funnel, rinsed with cold water, and used
without further purification as the hydrochloride salt.
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2-Amino-5-bromobenzoic acid (29a). The general saponification procedure was followed using 5-
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compound 29a was afforded as an off-white solid (mp 217°C) (594.3 mg, 53% yield). H NMR
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(500 MHz, DMSO-d6) δ 7.74 (d, J = 2.5 Hz, 1H), 7.34 (dd, J = 8.9, 2.5 Hz, 1H), 6.73 (d, J = 8.8
Hz, 1H). 13C{1H} NMR (126 MHz, DMSO-d6) δ 168.4, 150.6, 136.1, 132.8, 118.7, 111.1, 104.5.
GC-FTIR νmax (cm-1): 3500, 3384, 3010, 2885, 1671, 1615, 1584, 1549, 1482, 1424, 1316, 1291,
1231, 1161, 689. HRAM-MS (EI) m/z: [M+H]+ Calcd. for C7H7BrNO2 215.9655; Found
215.9652..
2-Amino-4-bromobenzoic acid (29b). The general saponification procedure was followed using 6-
bromoisatin (1.00 g, 4.424 mmol). After workup and purification (10% MeOH/CH2Cl2, Rf = 0.59),
compound 29b was afforded as an off-white solid (mp 236°C) (799.8 mg, 72% yield). 1H NMR
(500 MHz, DMSO-d6) δ 7.59 (d, J = 8.5 Hz, 1H), 6.97 (d, J = 2.0 Hz, 1H), 6.64 (dd, J = 8.5, 2.0
Hz, 1H). 13C{1H} NMR (126 MHz, DMSO-d6) δ 168.9, 152.5, 133.1, 127.34, 118.1, 117.3, 108.8.
GC-FTIR νmax (cm-1): 3502, 3384, 2908, 2717, 1667, 1609, 1580, 1547, 1482, 1428, 1312, 1237,
1156, 1094, 899. HRAM-MS (EI) m/z: [M+H]+ Calcd. for C7H7BrNO2 215.9655; Found
215.9652.
2-Amino-3-bromobenzoic acid (29c). The general saponification procedure was followed using 7-
bromoisatin 12c (1.00 g, 4.424 mmol). After workup and purification (10% MeOH/CH2Cl2, Rf =
1
0.62), compound 29c was afforded as an off-white solid (mp 180°C) (957.1 mg, 86% yield). H
NMR (500 MHz, DMSO-d6) δ 7.78 (dd, J = 8.0, 1.6 Hz, 1H), 7.63 (dd, J = 7.8, 1.5 Hz, 1H), 6.74
13
(s, 1H), 6.52 (t, J = 7.9 Hz, 1H). C{1H} NMR (126 MHz, DMSO-d6) δ 169.0, 147.8, 137.12,
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131.0, 115.8, 111.8, 109.5. GC-FTIR νmax (cm-1): 3489 (s), 3369 (s), 2998 (br), 2863 (br), 2719
(m), 2638 (m), 1667 (s), 1607 (s), 1576 (s), 1543 (s), 1449, 1418, 1314, 1264, 1244, 1059, 746,
692. HRAM-MS (EI) m/z: [M+H]+ Calcd. for C7H7BrNO2 215.9655; Found 215.9652.
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2-Amino-6-bromobenzoic acid (29d). The general saponification procedure was followed using 4-
bromoisatin (1.00 g, 4.424 mmol), with the following modification: after bringing the solution to
pH ~ 4, compound 29d (10% MeOH/CH2Cl2, Rf = 0.07) was extracted into EtOAc, dried over
anhydrous Na2SO4, filtered through celite under reduced pressure, and concentrated by rotary
evaporation to afford a red solid (mp 139°C) (970.6 mg, 87% yield). 1H NMR (500 MHz, DMSO-
d6) δ 7.00 – 6.96 (m, 1H), 6.76 (dd, J = 7.7, 1.0 Hz, 1H), 6.70 (dd, J = 8.2, 1.0 Hz, 1H). 13C{1H}
NMR (126 MHz, DMSO-d6) δ 168.1, 148.4, 131.4, 120.1, 119.8, 118.7, 114.8. GC-FTIR νmax (cm-
1): 3492, 3382, 3377, 3334, 3008, 2910, 2607, 1673, 1613, 1584, 1553, 1462, 1420, 1385, 1293,
1256, 1235, 1161, 1127, 885, 799, 774, 689. HRAM-MS (EI) m/z [M+H]+ Calcd for C7H7BrNO2
215.9655; Found 215.9653.
General Amidation Procedure for the Synthesis of 2-Amino-X-bromo-N-methoxy-N-
methylbenzamides 30. Following the published procedure:33 To a flame-dried round-bottom flask
equipped with a stir bar and under inert nitrogen atmosphere were charged 2-amino-X-
bromobenzoic acid hydrochloride 29 (1 eq) and N,O-dimethylhydroxylamine hydrochloride (1.5
eq). Anhydrous DMF (0.2 M) was added at room temperature with stirring, then N-
methylmorpholine (4.5 eq) and HBTU (1.5 eq) were added. After 18 h, the mixture was poured
onto water in a separatory funnel. The aqueous layer was extracted three times with EtOAc. The
combined organic extracts were dried over anhydrous Na2SO4, filtered through celite under
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reduced pressure, and concentrated by rotary evaporation. The product 30 was isolated by alumina
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flash chromatography (25% EtOAc/hexanes).
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2-Amino-5-bromo-N-methoxy-N-methylbenzamide (30a). The general amidation procedure was
followed using 2-amino-5-bromobenzoic acid hydrochloride 29a (1.11 g, 4.38 mmol), N,O-
dimethylhydroxylamine hydrochloride (641 mg, 6.57 mmol), N-methylmorpholine (2.2 mL, 19.7
mmol), and HBTU (2.49 g, 6.57 mmol) in 22 mL of anhydrous DMF. Compound 30a was isolated
by alumina flash chromatography (25% EtOAc/hexanes, Rf = 0.10) as an orange solid (1.10 g,
97% yield). 1H NMR (500 MHz, CDCl3) δ 7.50 (d, J = 2.3 Hz, 1H), 7.26 (dd, J = 8.6, 2.3 Hz, 1H),
6.59 (d, J = 8.6 Hz, 1H), 4.67 (s, 2H), 3.59 (s, 3H), 3.34 (s, 3H). 13C{1H} NMR (126 MHz, CDCl3)
δ 168.5, 145.9, 134.1, 131.6, 118.6, 118.2, 108.2, 61.3, 33.9. GC-FTIR νmax (cm-1): 3456, 3354,
3245, 2971, 2935, 1617, 1582, 1488, 1424, 1403, 1383, 1302, 1262, 1210, 1158, 1113, 1084, 1057,
997, 978, 903, 891, 829, 820, 770, 745, 689. HRAM-MS (EI) m/z: [M+H]+ Calcd for C9H12BrN2O2
259.0077; Found 259.0077.
2-Amino-4-bromo-N-methoxy-N-methylbenzamide (30b). The general amidation procedure was
followed using 2-amino-4-bromobenzoic acid hydrochloride 29b (1.14 g, 4.53 mmol), N,O-
dimethylhydroxylamine hydrochloride (662 mg, 6.79 mmol), N-methylmorpholine (2.2 mL, 20.4
mmol), and HBTU (2.58 g, 6.79 mmol) in 23 mL of anhydrous DMF. Compound 30b was isolated
by alumina flash chromatography (25% EtOAc/hexanes, Rf = 0.16) as a red oil (1.16 g, 99% yield).
1H NMR (500 MHz, CDCl3) δ 7.26 (d, J = 8.4 Hz, 1H), 6.86 (d, J = 1.9 Hz, 1H), 6.79 (dd, J = 8.3,
1.9 Hz, 1H), 4.79 (s, 2H), 3.56 (s, 3H), 3.33 (s, 3H). 13C{1H} NMR (126 MHz, CDCl3) δ 169.2,
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148.3, 130.7, 125.5, 119.7, 119.1, 115.5, 61.2, 33.9. GC-FTIR νmax (cm-1): 3454, 3352, 3242,
2971, 2935, 1615, 1578, 1489, 1476, 1459, 1418, 1383, 1318, 1287, 1262, 1215, 1173, 1148, 1071,
995, 976, 903, 860, 804, 760, 721, 689. HRAM-MS (EI) m/z: [M+H]+ Calcd for C9H12BrN2O2
259.0077; Found 259.0073.
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2-Amino-3-bromo-N-methoxy-N-methylbenzamide (30c). The general amidation procedure was
followed using 2-amino-3-bromobenzoic acid hydrochloride 29c (1.83 g, 7.233 mmol), N,O-
dimethylhydroxylamine hydrochloride (1.06 g, 10.9 mmol), N-methylmorpholine (3.6 mL, 32.6
mmol), and HBTU (4.12 g, 10.9 mmol) in 36 mL of anhydrous DMF. Compound 30c was isolated
by alumina flash chromatography (25% EtOAc/hexanes, Rf = 0.29) as a light red oil (1.39 g, 74%
yield). 1H NMR (500 MHz, CDCl3) δ 7.47 (dd, J = 7.9, 1.5 Hz, 1H), 7.32 (dd, J = 7.7, 1.5 Hz, 1H),
6.57 (t, J = 7.8 Hz, 1H), 5.13 (s, 2H), 3.57 (s, 3H), 3.35 (s, 3H). 13C{1H} NMR (126 MHz, CDCl3)
δ 169.1, 144.2, 134.5, 128.4, 118.1, 117.2, 110.7, 61.3, 34.1. GC-FTIR νmax (cm-1): 3446, 3355,
2979, 2935, 1611, 1578, 1549, 1453, 1420, 1383, 1306, 1252, 1210, 1171, 1152, 1067, 980, 791,
750, 733. HRAM-MS (EI) m/z: [M+H]+ Calcd for C9H12BrN2O2 259.0077; Found 259.0073.
2-Amino-6-bromo-N-methoxy-N-methylbenzamide (30d, crude mixture). The general amidation
procedure was followed using 2-amino-6-bromobenzoic acid hydrochloride 29d (968 mg, 3.83
mmol), N,O-dimethylhydroxylamine hydrochloride (561 mg, 5.750 mmol), N-methylmorpholine
(1.9 mL, 17.3 mmol), and HBTU (2.18 g, 5.75 mmol) in 19 mL of anhydrous DMF. Compound
30d was not isolated. GC-FTIR νmax (cm-1): 3440, 3352, 3242, 2975, 2937, 1617, 1594, 1565,
1466, 1449, 1420, 1387, 1296, 1215, 1179, 1156, 1117, 1096, 1073, 1042, 984, 878, 781, 752,
708, 662. HRAM-MS (EI) m/z: [M+H]+ Calcd for C9H12BrN2O2 259.0077; Found 259.0075.
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General Lithiate Addition Procedure for the Syntheses of 2-Amino-X-bromo-Y’-
fluorobenzophenones. In a flame-dried flask under nitrogen equipped with a stir bar, 1-bromo-X-
fluorobenzene 31 (0.07 mL, 0.607 mmol) was dissolved in anhydrous THF (0.3 mL). The solution
was cooled to either -78 ˚C or -100 ˚C, then n-butyllithium (0.23 mL, 0.578 mmol, 2.5 M solution
in hexanes) was added slowly. In a separate flame-dried flask under nitrogen, 2-amino-X-bromo-
N-methoxy-N-methylbenzamide 30 (75 mg, 0.289 mmol) was dissolved in anhydrous THF (1.2
mL) and cooled to either -78 ˚C or -100 ˚C. After the lithiate solution had been stirring for 1 h, the
benzamide solution was added dropwise to it. The reaction was quenched after 15 min with
saturated aqueous NH4Cl and allowed to warm gradually to room temperature. The aqueous layer
was extracted with EtOAc, then the combined organic layers were dried over Na2SO4, filtered
through celite under reduced pressure, and concentrated by rotary evaporation. The product 9 was
then isolated by silica flash chromatography.
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2-Amino-5-bromo-2’-fluorobenzophenone (9aa). The general lithiate addition procedure was
followed at -100 ˚C using 2-amino-5-bromo-N-methoxy-N-methylbenzamide 30a (75 mg, 0.289
mmol). Compound 9aa was isolated by silica flash chromatography (25% EtOAc/hexanes, Rf =
0.57) to afford a yellow solid (55.2 mg, 65% yield). 1H NMR (500 MHz, CDCl3) δ 7.50 (dddd, J
= 8.3, 7.2, 5.2, 1.8 Hz, 1H), 7.43 – 7.38 (m, 2H), 7.36 (dd, J = 8.8, 2.4 Hz, 1H), 7.26 (s, 1H +
CDCl3, 6H total), 7.17 (ddd, J = 9.5, 8.3, 1.0 Hz, 1H), 6.63 (d, J = 8.8 Hz, 1H), 6.38 (s, 2H).
13C{1H}NMR (126 MHz, CDCl3) δ 194.3, 159.0 (d, J = 250.3 Hz), 149.9, 137.7, 136.1 (d, J = 2.1
Hz), 132.2 (d, J = 8.1 Hz), 129.7 (d, J = 3.2 Hz), 127.9 (d, J = 16.3 Hz), 124.3 (d, J = 3.6 Hz),
119.3, 118.8, 116.3 (d, J = 21.5 Hz), 106.7. 19F NMR (471 MHz, CDCl3) δ -113.31 – -113.39 (m).
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GC-FTIR νmax (cm-1): 3456, 3346, 1613, 1582, 1538, 1484, 1468, 1451, 1410, 1347, 1318, 1298,
1269, 1240, 1217, 1161, 1144, 1103, 1092, 949, 939, 893, 839, 822, 785, 760, 723, 689. HRAM-
MS (EI) m/z: [M+H]+ Calcd for C13H10BrFNO 293.9924; Found 293.9925.
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2-Amino-5-bromo-3’-fluorobenzophenone (9ab). The general lithiate addition procedure was
followed at -78 ˚C using 2-amino-5-bromo-N-methoxy-N-methylbenzamide 30a (75 mg, 0.289
mmol). Compound 9ab was isolated by silica flash chromatography (25% EtOAc/hexanes, Rf =
1
0.50) to afford a yellow solid (mp 111°C) (51.6 mg, 60% yield). H NMR (500 MHz, CDCl3) δ
7.51 (d, J = 2.4 Hz, 1H), 7.46 (td, J = 7.9, 5.4 Hz, 1H), 7.40 – 7.36 (m, 2H), 7.33 (ddd, J = 9.0,
2.6, 1.5 Hz, 1H), 7.25 (tdd, J = 8.3, 2.6, 1.1 Hz, 1H), 6.65 (d, J = 8.8 Hz, 1H), 6.12 (s, 2H). 13C{1H}
NMR (126 MHz, CDCl3) δ 196.3, 162.4 (d, J = 248.4 Hz), 149.9, 141.3 (d), 137.2, 135.9, 130.0
(d, J = 7.8 Hz), 124.8 (d, J = 3.1 Hz), 118.9, 118.8, 118.5 (d, J = 21.4 Hz), 115.9 (d, J = 22.5 Hz),
106.7. 19F NMR (471 MHz, CDCl3) δ -111.71 – -111.85 (m). GC-FTIR νmax (cm-1): 3467, 3350,
3070, 1634, 1611, 1584, 1538, 1472, 1437, 1408, 1314, 1298, 1271, 1250, 1202, 1161, 1119, 986,
968, 882, 870, 820, 814, 793, 774, 735, 704, 683, 656. HRAM-MS (EI) m/z: [M+H]+ Calcd for
C13H10BrFNO 293.9924; Found 293.9921.
2-Amino-5-bromo-4’-fluorobenzophenone (9ac). The general lithiate addition procedure was
followed at -78 ˚C using 2-amino-5-bromo-N-methoxy-N-methylbenzamide 30a (75 mg, 0.289
mmol). Compound 9ac was isolated by silica flash chromatography (25% EtOAc/hexanes, Rf =
1
0.46) to afford a yellow solid (mp 116°C) (66.7 mg, 78% yield). H NMR (500 MHz, CDCl3) δ
7.67 (dd, J = 8.7, 5.4 Hz, 2H), 7.51 (d, J = 2.4 Hz, 1H), 7.37 (dd, J = 8.9, 2.4 Hz, 1H), 7.17 (t, J =
13
8.6 Hz, 2H), 6.65 (d, J = 8.8 Hz, 1H), 6.01 (s, 2H). C{1H} NMR (126 MHz, CDCl3) δ 196.3,
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