Convergent Synthesis of the NS5B Inhibitor GSK8175 Enabled by Transition Metal Catalysis

Article abstract of DOI:10.1021/acs.joc.8b02269

A convergent eight-stage synthesis of the boron-containing NS5B inhibitor GSK8175 is described. The previous route involves 13 steps in a completely linear sequence, with an overall 10% yield. Key issues include a multiday S_NAr arylation of a s

Full text of DOI:10.1021/acs.joc.8b02269

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Article
Convergent Synthesis of the NS5B Inhibitor
GSK8175 Enabled by Transition Metal Catalysis
Kenneth Arrington, Gregg A. Barcan, Nicholas A Calandra, Greg A. Erickson,
Ling Li, Li Liu, Mark G. Nilson, Iulia I. Strambeanu, Kelsey Faith VanGelder, John
L. Woodard, Shiping Xie, C. Liana Allen, John A. Kowalski, and David C. Leitch
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b02269 • Publication Date (Web): 19 Oct 2018
Downloaded from http://pubs.acs.org on October 19, 2018
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The Journal of Organic Chemistry
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Convergent Synthesis of the NS5B Inhibitor GSK8175 Enabled by
Transition Metal Catalysis
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Kenneth Arrington, Gregg A. Barcan, Nicholas A. Calandra, Greg A. Erickson, Ling Li, Li Liu,
Mark G. Nilson, Iulia I. Strambeanu, Kelsey F. VanGelder, John L. Woodard, Shiping Xie, C. Li-
ana Allen, John A. Kowalski,* and David C. Leitch*
API Chemistry, GlaxoSmithKline, King of Prussia PA 19406.
ABSTRACT: A convergent eight-stage synthesis of the boron-containing NS5B inhibitor GSK8175 is described. The previous
route involves 13 steps in a completely linear sequence, with an overall 10% yield. Key issues include a multi-day SNAr
arylation of a secondary sulfonamide using HMPA as solvent, multiple functional group interconversions after all of the
carbon atoms are installed (including a Sandmeyer halogenation), use of carcinogenic chloromethyl methyl ether to install
a protecting group late in the synthesis, and an unreliable Pd-catalyzed Miyaura borylation as the penultimate step. We
have devised an orthogonal approach using a Chan-Lam coupling between a halogenated aryl pinacol boronate ester and
an aryl methanesulfonamide. This reaction is performed using a cationic Cu(I) precatalyst, which can be easily generated
in situ using KPF6 as a halide abstractor. High-throughput screening revealed a new Pd catalyst system to effect the penul-
timate borylation chemistry using simple monodentate phosphine ligands, with PCyPh2 identified as optimal. Reaction
progress analysis of this borylation indicated likely mass-transfer rate limitations under standard conditions using KOAc as
the base. We have devised a K2CO3 / pivalic acid system as an alternative, which dramatically outperforms the standard
conditions. This new synthesis proceeds in eight stages with a 20% overall yield.
Introduction.
Hepatitis C is a potentially life-threatening viral infec-
tion that afflicts ~2% of the world’s population, with
>500,000 deaths per year attributed to complications from
the disease.1 While there is currently no vaccine for the
Hepatitis C virus (HCV), there are several approved treat-
ments for the condition, some of which are able to achieve
cure rates of >90%.2 Because of the need for increasing pa-
tient access, particularly in developing nations, and to
combat potential viral resistance to current medicines, de-
velopment of alternative treatments is imperative.
Figure 1. Structures of two benzofuran-derived NS5B inhibi-
tors containing boronic acid motifs.
One important class of HCV therapeutics is the NS5B in-
hibitors, which operate by blocking the RNA polyermase
activity of the NS5B viral enzyme.3 There are both nucleo-
side analog2a,4 and non-nucleoside analog5 Active Pharma-
ceutical Ingredients (APIs) either in development or ap-
proved for use. Previously, we reported the synthesis of a
non-nucleoside analog NS5B inhibitor based on a substi-
tuted benzofuran scaffold (GSK852A, 1, Figure 1).6 A key
structural feature of this compound is a boronic acid moi-
ety,7 which contributes to the compound’s potency. Here
we report on the synthesis of a more advanced benzofuran-
based NS5B inhibitor, GSK8175 (2), which retains the bo-
ron-containing functionality, but removes the metaboli-
cally labile methylene linker between the sulfonamide ni-
trogen and the pendant arene.8
The initial synthesis of 2 is shown in Scheme 1. The first
half is based heavily on our previously reported route to 1,
and is identical up to the common intermediate 8. At this
point in the synthesis of 1, a reductive amination and me-
sylation of the aryl/alkyl secondary amine completes the
sequence.6b For the preparation of 2, the aniline 8 is first
mesylated prior to installation of the final arene via SNAr
substitution using 10; this affords the advanced intermedi-
ate 11, which contains all of the carbon atoms present in
the API. From this point, there are seven more transfor-
mations required to complete the synthesis, including a
Sandmeyer halogenation and use of the potent carcinogen
chloromethyl methyl ether (MOMCl).
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Scheme 1. Initial synthesis of GSK8175 (2); half of the steps occur after assembling the entire carbon framework.
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Due to this highly atom, step, and redox inefficient se-
quence to convert 11 into 2, we sought an alternative end-
game that would avoid this series of functional group in-
terconversions. Of particular importance was removing the
Sandmeyer sequence, which could be achieved by directly
coupling an appropriately halogenated aromatic substrate
with 9 (or analog thereof). Unfortunately, SNAr reactions
between 9 and fluoroaromatics without the para-nitro
functionality have been unsuccessful. Even the initial SNAr
is difficult, requiring multiple days to reach completion
with HMPA as the solvent; alternative conditions that re-
place HMPA with less toxic solvents are considerably lower
yielding. Palladium- or copper-catalyzed arylation of 9 was
also considered; however, chemoselectivity in the presence
of multiple halides was a significant concern, especially
given the reactivity trends established by Buchwald for
biarylphosphine-based Pd catalysts.9 Furthermore, cata-
lytic C-N coupling using secondary sulfonamides is not
well developed, particularly with N-arylsulfonamides.10 In-
itial attempts to couple even simple aryl-halides to 9 were
not successful. Finally, while we were able to arylate 8 us-
ing Pd-catalysis, mesylation of the resulting diarylamines
proved low yielding due to the propensity of the diarylme-
thanesulfonamides to demesylate when using strong base.11
on 1, we intended to retain/adapt as much of that chemis-
try as possible. Second, because our initial scoping studies
indicated mesylation of a diarylamine would be overly dif-
ficult, mesylation must precede N-arylation. Third, N-ary-
lation would need to be achieved with a reaction that could
function with both a sulfonamide and a multiply-halogen-
ated aromatic; for this we investigated a Cu-catalyzed
Chan-Lam coupling, which is orthogonal to redox-neutral
C-N coupling reactions.12 Finally, Pd-catalyzed borylation
must occur at the end of the synthesis due to the instability
of arylboronate esters toward many reaction and work-up
conditions.13 This borylation would need to be performed
at a hindered position, in the presence of an Ar-Cl group,
with a benzyl alcohol protecting group other than MOM.
Thus, we envisioned a new synthetic sequence with four
general attributes (Figure 2). First, given the efficiency of
the benzofuran synthesis from previous development work
Figure 2. Key disconnection sequence in a new synthesis of 2.
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Following the hydrogenation, mesylation of the primary
Results and Discussion.
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aniline was achieved under analogous conditions to con-
version of 8 to 9; however, rather than isolate this mesyl-
ated intermediate, we opted to directly hydrolyze the ethyl
ester in a one-pot protocol. After the mesylation reaction
is complete, the reaction mixture is concentrated to ~5 vol-
umes, followed by the addition of aqueous KOH (6.75
equiv). An 8 hour reaction time at 70-80 °C is sufficient to
completely saponify the ethyl ester. A simple organic ex-
traction to remove impurities followed by acidification of
the alkaline aqueous solution provides 19 in >95% isolated
yield. This three-step, two-pot sequence allows rapid, reli-
able, and high-yielding access to the key sulfonamide cou-
pling partner for the ensuing Chan-Lam chemistry.
Preparation of Chan-Lam coupling partners. In or-
der to effect the difficult N-arylation chemistry required for
our improved synthesis of 2, we focused our efforts on a
Chan-Lam coupling strategy. The Chan-Lam reaction is an
oxidative C-N coupling between an arylboronic acid (or
boronate ester) and a nitrogen nucleophile that operates
under much milder conditions than redox neutral Pd- or
Cu-catalyzed N-arylations.12 The Chan-Lam is thus an or-
thogonal coupling strategy, allowing use of a halogenated
coupling partner. Our goal was to intercept the current
chemistry at intermediate 14, and therefore we needed to
access the appropriate substrates (equation 1).
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For the aryl boronate coupling partner, we envisioned a
selective Ir-catalyzed C–H borylation14 of methyl-3-bromo-
2-chlorobenzoate (20) as the most efficient synthetic
method. This enables formation of the C-B bond in the
presence of both Ar-Cl and Ar-Br groups, with the required
regiochemistry, in a single step. While the use of an Ir-cat-
alyst is of concern from a cost perspective, the low catalyst
loadings needed for C-H borylation coupled with the lack
of attractive alternative syntheses gave us confidence in
our approach to this material.
While coupling sulfonamide 9 would provide the most
direct method, concerns regarding chemoselectivity of the
N-arylation in the presence of two N-H nucleophiles
prompted the synthesis of the carboxylic acid analogue 19.
This was achieved in >78% yield over two steps from 6 by
hydrogenation of the nitro group to 18, followed by a one-
pot mesylation / saponification sequence (Scheme 2).
As a proof of concept, we first evaluated standard litera-
ture15 borylation conditions: 1 mol% [Ir(cod)OMe]2, 2 mol%
4,4′-di-tert-butyl-2,2′-dipyridyl (dtbbipy), with B2pin2 as
the boron source, and a heptane/TBME solvent system to
ensure complete dissolution of 20. After only one hour at
50 °C, conversion to 21 was complete, and no other
borylated products were observed. In order to turn these
initial conditions into a scalable process, we first evaluated
replacing [Ir(cod)OMe]2 with the more widely available
[Ir(cod)Cl]2, and dtbbipy with 2,2’-bipyridine (bipy). Previ-
ous reports have indicated that preactivation of
[Ir(cod)Cl]2/ligand mixtures with B2pin2 at elevated tem-
perature in the absence of substrate leads to an active cat-
alyst system.16 Thus, heating [Ir(cod)Cl]2/ dtbbipy/B2pin2 at
85 °C in heptane for 30 minutes prior to introduction of 20
(as a heptane solution) is highly effective; unfortunately,
we did not achieve comparable success with bipy as the lig-
and. At these temperatures, TBME (or another co-solvent)
is not required to maintain solubility of 20, enabling max-
imum catalyst efficiency (various co-solvents were ob-
served to decrease reactivity). Notably, we observed that
grinding the crystalline [Ir(cod)Cl]2 into a fine powder
prior to use resulted in a more active catalyst, likely due to
faster solubilization in heptane during the activation pe-
riod.17 This allowed us to reduce the catalyst loading to 0.4
Scheme 2. Three-step, two-pot sequence for the prep-
aration of 19.
Initially, we planned to adapt the existing hydrogenation
conditions for the conversion of 7 to 8 to the reduction of
6 (Scheme 1); however, using the previously identified 5%
Pt/Al2O3 catalyst required long reaction times to reach
completion (>48 hours). We therefore screened twenty dif-
ferent Pt-based hydrogenation catalysts on 0.1 mmol scale
under a number of reaction conditions, and identified sev-
eral Pt/C alternatives capable of achieving completion in
<8 hours without competing hydrogenolysis of the cyclo-
propane ring. The use of a 2% Pt/1% V/C catalyst (Noblyst
P8071, 2.5 wt% loading) and the addition of 3 equivalents
of acetic acid were deemed optimal. These conditions were
validated on 35-65 g scale in multiple runs to give a com-
bined isolated yield of 82%.
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mol% [Ir(cod)Cl]2 and 0.8 mol% dtbbipy. The optimized
reaction conditions are shown in equation 2, and have been
demonstrated on >225 g scale with 91% isolated yield after
crystallization from acetonitrile/water.
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Development of the Chan-Lam coupling. With relia-
ble synthetic routes to both 19 and 21 in place, we focused
considerable effort on developing the Chan-Lam coupling
reaction. Figure 3 summarizes the key findings of a series
of preliminary small-scale screening experiments that ex-
plored the effect of Cu source, base, and reaction solvent
on the conversion of 19 into 22. In all cases, an excess of the
arylboronate 21 was required, generally ≥2 equivalents.
From these experiments, we selected acetonitrile and tri-
ethylamine as the preferred solvent and base, and estab-
lished that the reaction must be run in the presence of O2.
We also discovered that cationic Cu(I) salts generally out-
perform other Cu(I) or Cu(II) sources in the Chan-Lam ar-
ylation of secondary sulfonamides.18 Standard Chan-Lam
conditions typically employ a stoichiometric amount of
Cu(OAc)2, which acts as both catalyst and oxidant. In the
coupling of 19 and 21, all Cu(II) sources achieved relatively
poor conversion.
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Figure 4. Potential byproducts of Chan-Lam couplings result-
ing from decomposition of 21.
We attribute the superiority of cationic Cu(I) sources to
the absence of potentially competing X-type ligands
(AcO-, Cl-, etc.) that could inhibit coordination of the sul-
fonamide. Subsequent experiments indicated that both
[Cu(ACN)4]OTf and [Cu(ACN)4]PF6 can be used inter-
changably in this transformation. Adding ligands (such as
2,2’-bipyridine), reducing the Cu loading below 0.5 equiv-
alents, and using alternative oxidants (such as Ag2CO3 or
H2O2/urea) all led to lower conversions of 19.
es correspond to biaryl 24 and/or the diarylether 25 (such
oxidative coupling products are commonly observed in
Chan-Lam couplings12). These protonolytic or oxidative by-
products explain both the need for excess 21, and for the
premature termination of reaction progress. Reducing the
reaction temperature to ≤10 °C improved the solution yield
to 70%; however, the reaction time needed increased to
>48 hours (equation 3).
Despite these initial promising results, we quickly iden-
tified a key issue with the conditions in equation 3. Using
only 10 volumes of solvent (4:1 acetonitrile/triethylamine),
the reaction mixture is heterogeneous. Both compound 21
and [Cu(ACN)4]PF6 are highly soluble in acetonitrile (>100
mg/mL), whereas 19 is poorly soluble (2.7 mg/mL). Fur-
thermore, under these conditions the initial rates and over-
all extents of reaction are invariant when the charges of 19,
21, or [Cu(ACN)4]PF6 are changed.
In order to improve the outcome and the scalability of
this reaction, we explored the solution behavior of 19 in a
series of control and solubility experiments. As noted
above, 19 has only 2.7 mg/mL solubility in acetonitrile;
however, in the presence of excess triethylamine it should
predominantly exist as the triethylammonium carboxylate.
We therefore determined the solubility of 19 in a 4:1 mix-
ture of acetonitrile and triethylamine, mirroring the Chan-
Lam reaction solvent system. Upon addition of triethyla-
mine to a slurry of 19 in acetonitrile, all of the solid dis-
solves quickly, but a tan precipitate forms shortly thereaf-
ter. HPLC analysis of the supernatant after stirring this
mixture for >1 hour reveals the solution concentration of 19
(and/or the corresponding triethylammonium carbox-
ylate) is only 2.8 mg/mL.
Figure 3. Summary of preliminary screening experiments,
with most effective materials highlighted in blue. See Support-
ing Information for further details.
Even using the best reaction conditions identified from
screening, we were unable to achieve >60% conversion of
19 into 22 before the reaction progress stalled. We did ob-
serve that in many cases all of the boronate ester 21 was
consumed despite the excess charge, and that multiple by-
products were formed during the course of the reaction.
We observed both compound 20 and the phenol 23, and
hypothesize that non-polar byproducts seen in HPLC trac-
A series of observations during Chan-Lam reaction set-
up led us to investigate the solubility of 19 in the presence
immediately turns dark green. We attribute this behavior
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Figure 6. Initial rate of Chan-Lam coupling (left axis, blue
Figure 5. Solubility of compound 19 in a 4:1 ACN/NEt3 solvent
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points) and solution yield of 22 at 8 hours (right axis, red
points) versus equiv [Cu(ACN)4]PF6.
mixture versus amount of [Cu(ACN)4]PF6 added, with maxmi-
mum possible solubilities denoted based on charge of 19. The
slope of the line indicates 19 forms a 2:1 complex with Cu.
study is required to elucidate the reaction mechanism, it is
clear that the optimal amount of Cu is 0.5-0.6 equiv.
to the oxidation of Cu(I) by air to generate a 2:1 complex
between the anion of 19 and a Cu(II) center. This has the
effect of dramatically increasing the amount of 19 in solu-
tion: quantitative HPLC analysis of a saturated solution of
19 (250 mg) with 0.6 equiv [Cu(ACN)4]PF6 (143 mg) in
ACN/NEt3 (4/1 mL) indicates 188.5 mg 19 is dissolved (sol-
ubility = 37.7 mg/mL, 0.0968 M). Notably, no color change
or solubilization is observed when 19 and [Cu(ACN)4]PF6
are stirred in ACN/NEt3 under N2, confirming the necessity
of O2 to oxidize the Cu(I) source to Cu(II).
After establishing the appropriate reaction concentra-
tion to produce a homogeneous solution, and the optimal
Cu charge of 0.5-0.6 equivalents, several additional fea-
tures of the Chan-Lam reaction required process improve-
ments. Due to safety concerns with using air, we explored
the use of 5% O2 (balance N2) as an alternative. Previous
work has established the limiting oxygen concentration
(LOC) for acetonitrile to be 12-13%;19 thus, a 5% O2 (balance
N2) gas stream is >2-fold below the LOC for combustion of
the reaction solvent. In addition, use of 5% O2 instead of
air performs well on multigram scale with overhead stir-
ring: using a 10 g charge of 19, a 75% solution yield of 22
was obtained after 20 hours (equation 4), which is a very
similar extent of reaction to that achieved using air. Given
these promising results, all further development work was
conducted using 5% O2.20
To further test our hypothesis of 2:1 complex formation
between an in situ generated Cu(II) center and the anion
of 19, we measured the solution concentration of 19 in 4:1
ACN/NEt3 in the presence of varying amounts of
[Cu(ACN)4]PF6 (Figure 5). These experiments were done
with two different charges of 19 (20 mg and 40 mg per mL
of solvent), and each of these had three different loadings
of [Cu(ACN)4]PF6. A plot of the concentration of
[Cu(ACN)4]PF6 (based on amount charged) versus the con-
centration of 19 (obtained by quantitative HPLC of the su-
pernatant) is linear with a slope of 1.9, clearly indicating a
2:1 ratio of 19 to Cu in solution. The highest concentration
of 19 observed, 39.6 mg/mL or 0.102 M, is within experi-
mental error of the maximum solubility (37.7 mg/mL).
Given the correlation between the Cu loading and
amount of dissolved 19, we also assessed the influence of
Cu loading on the Chan-Lam reaction itself (Figure 6).
Both the initial rate of product formation and the extent of
reaction after complete consumption of 21 (8 h time point)
increase with amount of [Cu(ACN)4]PF6 added up to 0.6
equiv; increasing the charge to 1.2 equiv has little impact
on either the initial rate or yield. While a detailed kinetic
Another issue that needed to be addressed is the use of
[Cu(ACN)4]PF6, especially since large quantities are costly
and only available from a few suppliers. In order to access
a cationic Cu(I) species in situ, we explored a number of
options with Cu(I) salts and halide abstracting reagents.
Traditional means of halide abstraction using Ag(I) salts
such as AgBF4 or AgOTf were deemed not suitable due to
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cost issues, and the need to remove the resultant silver amine would intercept the existing synthetic route at in-
termediate 14. Initially, we employed TBTU22 (1.6 equiv) as
the coupling reagent using 22 as the free acid, along with
methylammonium hydrochloride (1.5 equiv) and DIPEA (3
equiv), which gave 14 in >70% isolated yield on gram scale.
However, switching to 22-NH2Me as isolated from the pre-
vious stage (along with extra methylammonium chloride)
led to incomplete conversion. Screening other coupling re-
agents identified only COMU23 as an equally effective alter-
nate system, but still only partial conversion was observed.
By charging excess NH2Me-HCl (1.7 equiv) and TBTU (3
equiv), full conversion and 90% isolated yield was obtained
on gram scale. This requirement for excess coupling rea-
gent was traced to adventitious water in the batches of 22-
NH2Me prepared via Chan-Lam coupling (Karl-Fisher ti-
tration indicated >6% water by weight). A simple re-slurry
of 22-NH2Me in acetonitrile at 50 °C for several hours is
able to dehydrate 22-NH2Me. By using dry input material,
only modest excesses of NH2Me-HCl (1.5 equiv) and TBTU
(1.7 equiv) are required to achieve complete conversion,
giving 14 in 83% yield on 30 g scale (equation 6).
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waste. Small-scale experiments led to the identification of
KPF6 in combination with CuCl as an effective replacement
for [Cu(ACN)4]PF6. This system relies on the high solubility
of KPF6 in acetonitrile, and the insolubility of KCl, to drive
the anion metathesis forward; accordingly, CuCl and KPF6
were typically stirred in acetonitrile for ~30 minutes to
complete halide abstraction. Unfortunately, this CuCl/
KPF6 system failed to reach acceptable solution yields of 22
upon scale-up, where we suspected the poor solubility of
CuCl leads to slow halide abstraction. Use of CuX2 (X = Cl,
Br, I) instead of CuCl resulted in more consistent outcomes
on multigram scales; however, we observed a significant
new byproduct resulting from halogenation of the Ar-Bpin
bond.21 Iterative optimization led us to a mixed CuCl/CuCl2
system in conjunction with KPF6, which performs well on
scale without the need to pre-mix the inorganics. While
the exact nature of this catalyst system is still under inves-
tigation, we postulate that in the presence of O2, 19, and
NEt3, all of the Cu is oxidized to Cu(II) and complexed to
anionic deprotonated 19, while the chloride counterions
are brought out of solution as KCl.
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The final aspect of this Chan-Lam coupling that required
development was the workup and isolation, particularly
due to the formation of the decomposition byproducts
(Figure 4). We determined that crystallization of an am-
monium carboxylate salt of 22 would be the best method
to reject the non-polar byproducts. Because the next syn-
thetic step is amidation to form the N-methylamide 14
(vide infra), we targetted the N-methylammonium salt 22-
NH2Me; this would avoid the need to completely remove
an alternative amine that could interfere with the subse-
quent amidation. During optimization of the workup pro-
cedure, we discovered that unreacted 19 could be extracted
into aqueous ammonia, leaving 22 (likely as its ammonium
salt) in the organic phase. Further optimization estab-
lished that 40% methylamine in water is also capable of ex-
tracting 19 into the aqueous phase, removing residual Cu,
and forming the required ammonium salt with a single
wash. Crystallization of 22-NH2Me purges the remaining
byproducts, providing the desired product in >60% iso-
lated yield and >95% purity (equation 5).
With the development of this amidation chemistry, our
new synthesis has intercepted a common intermediate (14)
from the previous route in only six linear steps rather than
nine. From 14, the only required transformations are re-
duction of the methyl ester group, and installation of the
boron moiety. The previously developed reduction condi-
tions for the conversion of 14 to 15 (LiBH4 in MeOH/ THF,
Scheme 1) performed well, and so we focused our attention
on developing a more robust borylation protocol.
Previous work had identified the methoxymethyl ether
(MOM) protecting group as optimal for the borylation
chemistry, which was carried out using a Pd(OAc)2/dppb
catalyst system under standard Miyaura borylation condi-
tions (excess B2pin2, KOAc as base).24 Conversion of 16 to
17 required multiple catalyst charges (up to 15 mol% Pd),
and resulted in a significant degree of desbromination as a
side pathway (up to 30%). Furthermore, the reaction out-
come was variable even when using the same batches of
input material. In order to address both the identity of the
protecting group (to avoid the use of MOMCl), and the un-
reliable catalytic conditions, we designed a parallel-in-par-
allel set of screens to evaluate four different protecting
groups and 48 different mono- and bidentate phosphine
ligands using KOAc / toluene (Figure 7).
The 48 reaction set for each of the four substrates reveals
several key insights into the Miyaura borylation chemistry.
First, it is clear that protecting groups other than MOM are
viable, with 2-tetrahydropyranyl (THP) emerging as the
most attractive from these studies: not only does 26 prove
Completion of the synthesis with an improved
borylation protocol. In order to elaborate the Chan-Lam
coupling product 22 into the API (2), several additional
steps required optimization. Amidation of 22 with methyl-
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Figure 7. Parallel-in-parallel screening design to investigate the effect of both protecting group and phosphine ligand in the
Miyaura borylation shown. The screening data are visualized with the size of the points corresponding to % product (larger is
greater % product), and the color corresponding to % debromination observed (color gradient as follows: red: 100% desbromo;
yellow: 25% desbromo; green: 0% desbromo). Ligands identified as hits are denoted with a-l in the visualization, with structures
at right. See Supporting Information for full table of conditions and results.
more effective than the acetate (27), pivalate (28), or tert-
butyldimethylsilyl (29) in the borylation, but installation
and removal of the THP group can be readily achieved (vide
infra). Second, while dppb is clearly the best bidentate lig-
and among the 24 investigated, there are several relatively
simple monodentate ligands that are highly effective, in-
cluding PPh3 and P(iPr)Ph2. Finally, debromination is ob-
served in nearly every case, with many systems giving ex-
clusively the desbromo byproduct; however, borylation of
the Ar-Cl is not observed using these ligands.
adjacent Ar-Cl. Therefore, the ideal Pd(0) center is rela-
tively unhindered, and will not readily undergo oxidative
addition of an Ar-Cl bond. The suitability of phosphines
such as PCyPh2 and the others pictured in Figures 7 and 8
is consistent with these requirements.
Further studies identified Pd2dba3-CHCl3 as the most ac-
tive Pd source in combination with either P(iPr)Ph2 or
PCyPh2. As observed elsewhere, the quality of the “Pd-dba”
used is critical to the success of the reaction.26 Commercial
sources of “Pd2dba3”, or “Pd(dba)2” lead to lower conversion
of starting material, and increased debromination as well
as other byproducts. The chloroform solvate outperformed
the alternatives.27
In a follow-up screen focused on the THP-protected sub-
strate (26), we assessed an expanded set of 33 monodentate
ligands with different solvent and base combinations
drawn from standard Miyaura borylation conditions in the
literature (Figure 8).25 Switching from toluene to CPME
had little effect, while using NaOtBu led to undesirable re-
activity regardless of the ligand used. The best ligand class
emerging from these experiments is alkyldiphenylphosph-
ine, with P(iPr)Ph2 and PCyPh2 as equally effective under
screening conditions. All of the phosphines that show good
reactivity are modestly electron rich, and not sterically
bulky. That these features are desirable for this transfor-
mation is entirely consistent with the nature of the aryl hal-
ide substrate: the borylation must occur with high
chemoselectivity for the hindered Ar-Br position over the
Having identified a suitable set of reaction conditions
from high-throughput screening, our attention turned to
reaction optimization on larger scale. A borylation reaction
on 4 g scale was monitored over time using the Pd2dba3-
CHCl3 / P(iPr)Ph2 catalyst system, with toluene and KOAc
as the solvent and base respectively. A plot of reaction pro-
gress over time reveals linear kinetics for the consumption
of starting material and generation of both desired product
and desbromo byproduct (Figure 9). Despite a large cata-
lyst charge (5 mol% Pd), complete conversion requires
nearly 24 hours at 90 °C. Given both the linear kinetics
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Figure 9. Reaction profile for conversion of 26 to 30 on gram-
scale using either crystalline KOAc (conditions above arrow;
light-colored points), or 325 mesh K2CO3 / PivOH (conditions
below arrow; dark-colored points). The rate difference be-
tween the two sets of conditions is >10-fold.
Figure 8. Expanded monodentate ligand screen for the con-
version of 26 to 30 (THP protecting group), with additional
ligand hits denoted m-p. The screening data are visualized
with the size of the points corresponding to % product (larger
is greater % product), and the color corresponding to %
debromination observed (color gradient as follows: red: 100%
desbromo; yellow: 25% desbromo; green: 0% desbromo). See
Supporting Information for full table of results.
with 10-13% debromination. While these reaction endpoint
results are very similar to those obtained with KOAc, use
of pivalate has a striking effect on reaction rate: simply sub-
stituting as-received KOPiv for crystalline KOAc under
otherwise identical conditions results in a >4-fold increase
in rate, while grinding the KOPiv leads to an even greater
rate increase. With powdered KOPiv, a 90% solution yield
can be obtained after only 60 minutes.
observed, and the heterogeneous nature of the reaction
mixture, our hypothesis is that solid/liquid mass-transfer
is rate limiting in this case. KOAc has low solubility in tol-
uene, even at elevated temperatures, and the crystallinity
of as-received KOAc likely results in slow dissolution ki-
netics. This hypothesis was validated by performing the re-
action with KOAc that was ground in a mortar and pestle
under nitrogen, resulting in a >3-fold rate increase. Given
that grinding a hygroscopic solid would be undesirable on
larger scale, we sought to identify an alternative base that
would alleviate mass-transfer issues. A variety of acetate
salts were evaluated, with only KOAc and CsOAc achieving
good solution yields of product.
In order to retain the reaction rates observed with pow-
dered KOPiv without the need to mill the solid base, we
investigated the use of a pivalic acid/K2CO3 system. In con-
trast to KOAc and KOPiv, K2CO3 is readily available in a
number of particle sizes. We chose 325 mesh K2CO3, and
validated our small-scale results on gram scale using over-
head stirring (to prevent any inadvertent grinding of the
base by a magnetic stir bar). The solvent system was also
modified to include THF as a cosolvent in order to solubil-
ize 26 (and avoid another potential mass-transfer issue).
The reaction reached completion in <75 minutes (Figure
9), consistent with the results obtained with powdered
KOPiv. With confidence that our reaction conditions
would be scalable, we finalized the reagent and catalyst
charges, and proceeded to refine the scale-up and isolation
protocols to access both 26 and 30. As previously men-
tioned, reduction of 14 with LiBH4 easily furnished the ben-
zyl alcohol 15. Rather than isolate 15 prior to THP protec-
tion, we developed a telescoped reduction/protection se-
quence that produced 26 in 81% isolated yield on 23 g scale
At this point, we drew inspiration from synthetic and
mechanistic studies in Pd-catalyzed direct arylation chem-
istry.28 The proposed mechanisms for both the Miyaura
borylation and direct arylation proceed through Pd(car-
boxylate) intermediates,29,30 and it has been shown that
pivalate ligands have a pronounced positive effect on direct
arylation chemistry.31 We therefore investigated both
KOPiv and CsOPiv as bases, either as the discrete carbox-
ylate salts, or generated in situ using a mixture of pivalic
acid and K2CO3 or Cs2CO3. All of these pivalate-derived ba-
ses performed very well, giving 86-89% solution yield of 30,
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Scheme 3. Conversion of 14 to 30 in 59% overall yield. HPLC), which results mainly from carry-through of 34
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from the prior stage borylation. An initial crystallization of
2 after concentration of the acetonitrile solution and addi-
tion of water as an anti-solvent unfortuantely does not re-
move 35 to a significant extent. Instead, we took advantage
of the acidity of 2 to extract it into a 10% KOH aqueous
solution, leaving 35 in a THF/TBME organic layer. Washing
the alkaline aqueous layer with a second portion of
THF/TBME completely removes 35, and recrystallization
of 2 can be achieved by acidification of the aqueous solu-
tion. This affords GSK8175 (2) in 89% isolated yield, and
>99% purity as judged by HPLC analysis. Importantly, the
levels of residual Pd were determined to be <20 ppm with-
out any further re-work of the material, despite the Pd-cat-
alyzed borylation late in the synthesis.
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(Scheme 3).
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For all of the screening and reaction progress studies of
the key borylation chemistry, compound 26 was sourced
from a stockpile of intermediate 14 prepared using the pre-
vious synthetic route (Scheme 1). Unfortuantely, our initial
attempts to utilize 26 as-prepared using our new route led
to poor results in the borylation reaction. Using 3 mol%
Pd2dba3-CHCl3 resulted in <10% product after a 2 hour rea
ction time; however, the borylation could be ‘re-started’ by
further addition of catalyst. This behavior led us to suspect
a low-level impurity in our newly synthesized 26 that leads
to catalyst decomposition, with residual copper remaining
after the Chan-Lam reaction as a likely culprit. Screening
various methods to remove copper from 26 revealed that
washing a MeTHF solution of 26 with EDTA (0.5 M) fol-
lowed by 30% aqueous NH3 provided material that per-
formed well in use tests under our optimized borylation
conditions. This re-work resulted in 95% recovery, bring-
ing the overall yield for converting 14 to 26 to 76%. A mul-
tigram scale borylation was performed on the re-worked 26
according to Scheme 3, giving a 77% isolated yield after
work-up and treatment with Darco to remove the residual
palladium.
Conclusions.
Through judicious use of transition-metal catalyzed
transformations, a new and more efficient synthetic route
to GSK8175 (2) has been devised and demonstrated on
multi-gram scale (Scheme 4). This route includes an regi-
oselective Ir-catalyzed C–H borylation to generate a 1,3,4,5-
tetrasubstituted aromatic, Cu-catalyzed oxidative aryla-
tion of a secondary sulfonamide using a cationic Cu precat-
alyst system, and a chemoselective Miyaura borylation at a
2,6-disubstituted position as the penultimate step. The to-
tal number of steps from readily available starting materi-
als has been cut from 13 to 10. In terms of the newly devel-
oped chemistry, the route is only 8 stages (7 longest linear)
starting from intermediates 6 and 17 with 20% overall yield.
In addition to providing a more efficient protocol for ac-
cessing GSK8175 (2), newly developed conditions for both
the Chan-Lam coupling18 and the Miyaura borylation
should find broad applicability in effecting these transfor-
mations. Work to assess the generality of these systems in
other contexts is ongoing, and will be reported in due
course.
With the borylation chemistry demonstrated on multi-
gram scale, the only remaining step in the synthesis is re-
moval of the THP protecting group with concomitant hy-
drolysis of the pinacol boronate ester. Previous conditions
to effect the deprotection/hydrolysis sequence with a
MOM protecting group used excess 1 N HCl in an
MeOH/THF solvent system. This required elevated tem-
peratures for 5-10 hours, which raises the risk of proto-
deborylation of 2 to generate 35. Switching solvents to ac-
etonitrile facilitates complete hydrolysis using 1 N HCl af-
ter only 2-3 hours at 60 °C (equation 7). The major impurity
observed after the hydrolysis is compound 35 (up to 10% by
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Scheme 4. Newly developed synthetic route to GSK8175 (2), in eight stages and 20% overall yield from 6 and 20.
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Experimental Section.
Acquity SQD, positive ion mode, scan time 0.1 s) detectors.
Chromatography method: Column: Waters CSH (C18), 1.7
μm, 2.1 x 30 mm; column temp: 45 °C; flow rate: 1.3 mL/min;
solvent gradient: ACN (0.05% TFA v/v) / H2O (0.05% TFA
v/v), from 97/3 to 2/98 over 1.9 min.
General. All jacketed reactors were heated and cooled
using Syltherm silicone fluid circulated by a Huber Mini-
chiller with internal temperature feedback control. Agita-
tion was achieved with overhead stirring.
HRMS (m/z) was measured using an Exactive Plus
(Thermo) orbitrap mass spectrometer equipped with a
heated electrospray ionization (HESI) ion source.
Materials. All common reagents and solvents were pur-
chased from commercial sources and used as received.
Analytical. All NMR spectra were acquired at ambient
temperature on a Bruker 400 MHz spectrometer. Solvents
and frequencies for specific data acquisitions are noted for
each case in the following sections. Chemical shifts were
calibrated relative to residual protio solvent (1H and 13C) or
to external standards (19F). Data were processed using Top-
Spin and reports generated using ACD SpecManager.
Melting points were obtained using a Mettler Toledo
MP90 instrument, with a 4 °C min-1 temperature ramp up
to 250 °C.
Synthesis of ethyl 6-amino-5-cyclopropyl-2-(4-fluor-
ophenyl)benzofuran-3-carboxylate
(18).
SAFETY
NOTE: Pressurized hydrogenation reactions should always
be carried out in well-maintained, leak-checked pressure
equipment located in a well-ventilated environment, pre-
ferrably a dedicated pressure laboratory. Hydrogenation
catalysts are pyrophoric materials, particularly when dry,
and especially after being exposed to hydrogen. Care
should be taken in handling the catalyst material after re-
action completion. Never letting the catalyst cake dry dur-
ing filtration, and prompt quenching of the spent catalyst
in a dilute aqueous oxidant such as sodium bisulfite are
critical to ensuring safe operation.
HPLC analysis was performed on Agilent 1260 or 1290 se-
ries instruments with diode array detectors, though analy-
sis was typically done with traces from a single wavelength.
Two HPLC methods were utilized during the course of this
work: Method A (1260 series): Column: Zorbax SB-C18, 1.8
μm, 3 x 50 mm; column temp: 60 °C; flow rate: 1.5 mL/min;
solvent gradient: ACN (0.05% TFA v/v) / H2O (0.05% TFA
v/v), from 100/0 to 5/95 over 2.7 min; detection wave-
length: 220 nm. Method B (1290 series): Column: Waters
X-Select CSH, 2.5 μm, 2.1 x 30mm; column temp: 45 °C; flow
rate: 1.6 mL/min; solvent gradient: ACN (0.05% TFA v/v) /
H2O (0.05% TFA v/v), from 97/3 to 5/95 over 1.9 min; de-
tection wavelength: 220 nm.
To a 1 L jacketed BuchiGlas glass-walled pressure reactor
was charged 2% Pt, 1% V/C catalyst (Evonik Noblyst P8071,
1.625 g, 0.167 mmol) followed by a well-mixed slurry of 6
(65 g, 176 mmol) in THF (650 mL, 10 vol) / acetic acid (10.07
mL, 176 mmol). The reactor headspace was evacuated and
backfilled with N2 three times to remove dissolved O2. The
LCMS analysis was performed on a Waters Acquity sys-
tem equipped with UV (Waters Acquity PDA, 210-360 nm),
ELS (Waters Acquity ELSD, 50 °C), and MS (ESI, Waters
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reaction mixture was stirred and heated to 45 °C prior to
159.5, 163.6 (d, J=249.00 Hz), 164.9. HRMS (ESI): m/z calcu-
lated for C19H17FNO5S [M+H]+: 390.0806; found: 390.0806.
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7
8
pressurization with 5 bar (72 psi) H2. The mixture was
stirred under these conditions overnight. The reaction
mixture was then cooled to 25 °C, followed by filtration
through GFC filter paper to remove the catalyst. The fil-
trate was then distilled under vacuum to ~3 vol. TBME (325
mL, 5 vol) was added over 30 minutes, and the mixture was
vacuum distilled down to ~3 vol. This put-and-take was re-
peated once more to yield a red-orange slurry. The slurry
was vacuum filtered to collect the solid, and the cake was
washed with TBME (195 mL, 3 vol). The wet cake was dried
overnight in a vacuum oven at 50 °C to give 18 as an orange
solid (48.9 g, 82% yield). M.p. 141-142 °C. 1H NMR (400
MHz, DMSO-d6) δ ppm 0.46 - 0.56 (m, 2 H), 0.88 - 0.98 (m,
2 H), 1.32 (t, J=7.09 Hz, 3 H), 1.70 - 1.81 (m, 1 H), 4.30 (q,
J=7.04 Hz, 2 H), 5.38 (s, 2 H), 6.83 (s, 1 H), 7.29 - 7.39 (m, 2
H), 7.45 (s, 1 H), 7.93 - 8.03 (m, 2 H). 19F{1H} NMR (376 MHz,
DMSO-d6) δ ppm -110.81. 13C{1H} NMR (101 MHz, DMSO-d6)
δ ppm 6.2, 12.0, 14.5, 60.7, 94.7, 109.0, 115.7 (d, J=21.8 Hz),
115.9, 120.3, 125.0, 126.6 (d, J=3.3 Hz), 131.6 (d, J=8.5 Hz),
147.8, 154.1, 155.8, 163.9, 163.1 (d, J=248.0 Hz). HRMS (ESI):
m/z calculated for C20H19FNO3 [M+H]+: 340.1343; found:
340.1339.
Synthesis of methyl 2-bromo-3-chloro-5-(4,4,5,5-tet-
ramethyl-1,3,2-dioxaborolan-2-yl)benzoate (21). To a 6
L jacketed glass reactor equipped with overhead stirring
and thoroughly purged with N2 was charged the following
solids: finely ground [Ir(cod)Cl]2 (2.453 g, 3.65 mmol, 0.4
mol%); dtbbpy (1.961 g, 7.31 mmol, 0.8 mol%); B2pin2 (209
g, 822 mmol, 0.9 equiv). Heptane (1.14 L, 5 vol) was added,
and stirring commenced at 350 rpm. The reactor headspace
was evacuated and backfilled with N2 three times to re-
move dissolved O2. The reaction mixture was heated to 85
°C to give a dark maroon solution. Compound 20 (227.8 g,
913 mmol, 1.0 equiv) was added portionwise as a solid to
the reactor (addition can also be achieved by dissolving 20
in 1 vol heptane and added dropwise). After addition was
complete, the reaction mixture was stirred at 85 °C for 1
hour, and then cooled to room temperature (20-25 °C).
TBME (1.37 L, 6 vol) was charged, followed by a slow addi-
tion of water (400 mL, 2 vol) to quench the reaction. 20%
NaCl in water (400 mL, 2 vol) was then charged, and the
biphasic mixture agitated for at least 15 minutes. After the
layers settled, the aqueous phase was removed, and the or-
ganic layer heated to 45 °C. Solvent was distilled (125-150
mbar, 45-55 °C, 200 rpm stirring) to give a concentrated
solution of ~3 vol. Once distillation was complete, the so-
lution was heated to 50 °C, followed by the sequential ad-
dition of acetonitrile (912 mL, 4 vol) and water (1.37 L, 6
vol). The mixture was then cooled at ~1 °C min-1 to 5 °C, and
held at 5 °C for at least 30 minutes. The slurry was then
vacuum filtered, and the residual solid in the reactor
washed onto the filter cake with 1:1 acetonitrile/water (100
mL) using a spray ball. After filtration, the off-white solid
was dried in a vacuum oven at 50 °C to give 311.8 g of 21
(91% yield). M.p. 83-85 °C. 1H NMR (400 MHz, DMSO-d6)
δ ppm 1.31 (s, 12 H), 3.88 (s, 3 H), 7.83 (d, J=1.47 Hz, 1 H),
7.88 (d, J=1.47 Hz, 1 H). 13C{1H} NMR (101 MHz, DMSO-d6)
δ ppm 25.1, 53.4, 85.1, 123.9, 130.2, 134.3, 135.6, 136.0, 137.9,
166.2. HRMS (ESI): m/z calculated for C14H17BBrClO4
[M+H]+: 375.0165; found: 375.0162.
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Synthesis of 5-cyclopropyl-2-(4-fluorophenyl)-6-
(methylsulfonamido)benzofuran-3-carboxylic
acid
(19). A 3 L flask equipped with an overhead stirrer was
charged with 18 (85.0 g, 250 mmol), acetonitrile (1317.5 mL,
15.5 vol), and pyridine (101 mL, 1252 mmol). With stirring,
a solution of methanesulfonyl chloride (38.8 mL, 501
mmol) in acetonitrile (170 mL) was added dropwise over 40
min; the internal temperature was monitored during the
addition to ensure the mixture did not go above 25 °C. Af-
ter addition was complete, the reaction mixture was stirred
at 20-25 °C for 6 hours. The reaction mixture was then vac-
uum distilled to ~370 mL (4.4 vol). Water was added (850
mL, 10 vol), followed by solid potassium hydroxide (100 g,
1778 mmol, NOTE: exothermic; solid added portionwise).
The reaction mixture was then heated to 75 °C and stirred
at that temperature for 3 hours. The reaction mixture was
then cooled to 30 °C over 1 hour. TBME (425 mL, 6.5 vol)
was added to give a biphasic mixture. The layers were
mixed, then separated. The organic layer was discarded.
The aqueous layer was diluted with water (1870 mL, 22 vol)
followed by a slow addition of 6 N HCl (403 mL, 4.7 vol)
over 1 hour to acidify to pH ~1 and yield a white suspension.
The suspension was stirred for one hour while cooling from
30 to 20 °C. The solid was then collected by vacuum filtra-
tion, and the wet cake washed with water (2 x 850 mL, 10
vol) and acetonitrile (255 mL, 3 vol). The solid was then
dried overnight in a vacuum oven at 55 °C to give a 19 as a
Synthesis of methylammonium 6-(N-(4-bromo-3-
chloro-5-(methoxycarbonyl)phenyl)methylsulfon-
amido)-5-cyclopropyl-2-(4-fluorophenyl)benzofuran-
3-carboxylate (22-NH2Me). SAFETY NOTE: Mixtures of
oxygen and organic solvents pose a significant risk of com-
bustion and potential explosion. Operating below the lim-
iting oxygen concentration of the reaction solvent(s) is
critical to mitigating the risk of combustion.19,20
To a 1 L jacketed glass reactor equipped with a tempera-
ture probe, overhead stirrer, gas inlet, and gas outlet to an
oil bubbler was added acetonitrile (150 mL, 4.3 vol) and
CuCl2 (1.21 g, 8.99 mmol). The mixture was stirred at 20 °C
for 10 min to give a yellow brown suspension. Solid CuCl
(4.45 g, 44.9 mmol) was added to give a brown suspension,
followed by KPF6 (23.16 g, 126 mmol) to give an orange-
brown slurry. Compound 19 (35 g, 90 mmol) was added as
a solid, followed by acetonitrile (150 mL, 4.3 vol) to ensure
quantitative transfer and to wash down walls of reactor.
Triethylamine (200 mL, 5.7 vol) was added to give a light
1
pale yellow solid (94.9 g, 97% yield). M.p. 241-244 °C. H
NMR (400 MHz, DMSO-d6) δ ppm 0.58 - 0.72 (m, 2 H), 0.97
- 1.09 (m, 2 H), 2.25 - 2.39 (m, 1 H), 3.07 (s, 3 H), 7.30 - 7.45
(m, 2 H), 7.58 (s, 1 H), 7.63 (s, 1 H), 7.99 - 8.14 (m, 2 H), 9.34
(s, 1 H), 13.21 (br s, 1 H). 19F{1H} NMR (376 MHz, DMSO-d6)
13
δ ppm -109.70. C{1H} NMR (101 MHz, DMSO-d6) δ ppm
8.9, 12.0, 40.8, 108.6, 109.5, 115.8 (d, J=22.00 Hz) 118.8, 125.4,
126.1 (d, J=3.10 Hz), 132.3 (d, J=8.80 Hz), 134.6, 135.4, 151.8,
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green slurry. The reaction mixture was then cooled to 0 °C
ppm 53.3, 108.3, 116.4, 119.9, 135.7, 136.7, 157.8, 166.6. HRMS
(ESI): m/z calculated for C8H7ClBrO3 [M+H]+: 264.9262;
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8
over 20 minutes, followed by the addition of solid 21 (84 g,
225 mmol) and acetonitrile (150 mL, 4.3 vol). Sub-surface
bubbling of 5% O2 (balance N2) through a stainless steel
tube was commenced at a flow rate between 0.40-0.45
L/min. After stirring under these conditions for 42 hours,
the reaction mixture was warmed to 20 °C and the solvent
removed by vacuum distillation to 120 mL total volume.
The solution was transferred into a 1 L separatory funnel,
and the reactor washed with 2-MeTHF (90 mL, 2.6 vol) into
the same separatory funnel. The organic phase was washed
with 1 N HCl (180 mL, 5.2 vol), 5% aqueous NaCl (60 mL,
1.7 vol), and 1 N HCl (90 mL, 2.6 vol). The aqueous pH was
confirmed to be <1. To the organic phase was added 40 wt%
aqueous methylamine (19.45 mL, 225 mmol) and 10% aque-
ous NaCl (60 mL, 1.7 vol). The layers were mixed, allowed
to settle, and separated. The organic phase was washed
twice with 10% aqueous NaCl (90 mL, 2.6 vol), and then
returned to the 1 L reactor. This solution was seeded with
a small amount of crystalline 22-NH2Me, followed by vac-
uum distillation with stirring to a total volume of ~200 mL
(5.7 vol). Once the desired volume was reached, the sus-
pension was stirred slowly overnight to complete the crys-
tallization. The solid was then collected by vacuum filtra-
tion, and the residual solid from the reactor rinsed onto the
filter cake with toluene (90 mL, 2.6 vol). The solid was
dried by suction, and then in a vacuum oven overnight at
50 °C to give 37.1 g of 22-NH2Me (62% yield). M.p. not de-
termined.1H NMR (400 MHz, DMSO-d6) δ ppm 0.30 (br m,
1 H) 0.78 (br m, 2 H) 0.96 (br m, 1 H) 2.07 (quin, J=6.70 Hz,
1 H) 2.38 (s, 3 H) 3.84 (s, 3 H) 7.26 - 7.35 (m, 2 H) 7.59 (d,
J=2.74 Hz, 1 H) 7.67 (s, 1 H) 7.78 (d, J=2.74 Hz, 1 H) 7.96 (s,
found: 264.9260.
Synthesis of methyl 2-bromo-3-chloro-5-(N-(5-cyclo-
propyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)ben-
zofuran-6-yl)methylsulfonamido)benzoate (14). A 1 L
reactor equipped with a temperature probe, gas inlet and
outlet, and overhead stirrer was charged with 22-NH2Me
(31.0 g, 46.4 mmol) and ethyl acetate (280 mL, 9 vol). The
headspace was swept with nitrogen and stirring com-
menced. TBTU (25.3 g, 79.0 mmol) was added, followed by
methylamine hydrochloride (4.70 g, 69.6 mmol) and diiso-
propylethylamine (18.0 g, 24.3 mL, 139 mmol). Ethyl acetate
(31 mL, 1 vol) was used to rinse the reactor walls to ensure
a quantitative transfer. The reaction mixture was stirred at
30 °C for 2 hours, during which time the solids dissolved
and the solution clarified. The reaction mixture was cooled
to room temperature, followed by the addition of 10%
aqueous NaHCO3 (155 mL, 5 vol). The layers were mixed for
15 minutes and then allowed to settle. The aqueous phase
was removed, and the organic phase washed with saturated
NH4Cl (155 mL, 5 vol). After mixing for 15 minutes and al-
lowing to settle, the aqueous phase was removed. The or-
ganic phase was washed with 10% aqueous NaCl (155 mL, 5
vol). After mixing for 15 minutes and allowing to settle, the
aqueous phase was removed. The organic phase was
heated to 45 °C, followed by solvent removal by vacuum
distillation to a total volume of ~125 mL (4 vol). Ethyl ace-
tate (120 mL, 4 vol) was added, followed by a second vac-
uum distillation to a total volume of ~80 mL (2.6 vol). With
stirring, the reactor contents were heated to 50 °C, fol-
lowed by the addition of heptane (220 mL, 7 vol) over 30
minutes. The solution was then cooled to 20 °C over 60
minutes, and held at this temperature for a further 60
minutes. The resulting solid was collected by filtration, and
residual solid rinsed onto the filter cake using heptane (2 x
90 mL, 3 vol). The solid was dried in a vacuum oven over-
night at 50 °C to give 24.9 g of 14 (83% yield). M.p. 236-237
°C. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.30 - 0.47 (m, 1
H), 0.71 - 0.84 (m, 1 H), 0.84 - 0.93 (m, 1 H), 0.93 - 1.05 (m,
1 H), 2.03 - 2.15 (m, 1 H), 2.84 (d, J=4.60 Hz, 3 H), 3.34 (s, 2
H), 3.85 (s, 3 H), 7.23 (s, 1 H), 7.35 - 7.46 (m, 2 H), 7.63 (d,
J=2.74 Hz, 1 H), 7.78 (d, J=2.74 Hz, 1 H), 7.92 - 8.02 (m, 2 H),
8.15 (s, 1 H), 8.50 (q, J=4.53 Hz, 1 H). 19F{1H} NMR (376 MHz,
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
19
1 H) 8.36 - 8.44 (m, 2 H). F{1H} NMR (376 MHz, DMSO-
13
d6) δ ppm -112.12. C{1H} NMR (101 MHz, DMSO-d6) δ 7.9
(br), 9.6 (br), 12.2, 24.7, 41.0, 53.6, 113.2, 115.5 (d, J=21.6 Hz),
116.1, 117.7, 119.6, 124.0, 127.5 (d, J=3.1 Hz), 127.6, 131.0 (d,
J=8.5 Hz), 131.3, 134.9, 135.7, 136.7, 137.7, 142.0, 151.4, 154.2,
162.8 (d, J=248.0 Hz), 166.2, 167.2, 173.6. HRMS (ESI): m/z
calculated for C27H21BrClFNO7S [M+H]+: 635.9895; found:
635.9879.
Synthesis
of
methyl
2-bromo-3-chloro-5-hy-
droxybenzoate (23). A 100 mL jacketed reactor equipped
with an overhead stirrer was charged with 21 (5.05 g, 13.45
mmol) and acetone (30 mL). With stirring and maintaining
reaction temperature between 20-30 °C, an aqueous solu-
tion of oxone (8.27 g, 13.45 mmol, 40 mL water) was added
dropwise over 40 minutes. Once addition was complete,
the reaction mixture was stirred overnight at 20 °C. The
mixture was then transferred to a separatory funnel, and
diluted with aqueous 10% NaHSO3 (90 mL) and EtOAc (90
mL). The layers were mixed and then allowed to settle and
separated. The organic phase was washed with aqueous 5%
NaCl (50 mL), then with water (50 mL), and finally dried
over MgSO4. After filtration and concentration, the crude
phenol was purified by silica gel chromatography using a
MeOH/DCM gradient (0-1% MeOH) to give 23 (2.0 g, 55%
13
DMSO-d6) δ ppm -110.34. C{1H} NMR (101 MHz, DMSO-
d6) δ ppm 7.5, 9.2, 11.8, 26.2, 40.6, 53.1, 113.6, 113.7, 115.9, 116.1
(d, J=22.0 Hz), 116.8, 123.7, 125.5 (d, J=3.0 Hz), 127.3, 128.2,
129.4 (d, J=8.9 Hz), 135.3, 135.5, 136.3, 138.5, 141.3, 150.9, 153.7,
162.9, 162.8 (d, J=248.0 Hz), 165.7. HRMS (ESI): m/z calcu-
lated for C28H24BrClFN2O6S [M+H]+: 649.0206; found:
649.0207.
Synthesis of 6-(N-(4-bromo-3-chloro-5-(hydroxyme-
thyl)phenyl)methylsulfonamido)-5-cyclopropyl-2-(4-
fluorophenyl)-N-methylbenzofuran-3-carboxamide
(15). To a 1 L jacketed reactor equipped with overhead stir-
ring was added 14 (70.6 g, 109 mmol), 2-MeTHF (425 mL, 6
vol) and methanol (50 mL). With stirring (500 rpm), the
reaction mixture was cooled to 10 °C. LiBH4 (7.89 g, 326
mmol) was charged portionwise, maintaining reaction
1
yield). M.p. 133-134 °C. H NMR (400 MHz, DMSO-d6) δ
ppm 3.85 (s, 3 H), 7.03 (d, J=2.84 Hz, 1 H), 7.17 (d, J=2.84
Hz, 1 H), 10.57 (s, 1 H). 13C{1H} NMR (101 MHz, DMSO-d6) δ
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The Journal of Organic Chemistry
temperature between 10-12 °C. Once addition was com-
H), 7.68 (br s., 1 H), 7.92 - 8.01 (m, 2 H), 8.07 - 8.15 (br m, 1
H), 8.48 (br d, J=3.91 Hz, 1 H). 19F{1H} NMR (376 MHz,
1
2
3
4
5
6
7
8
plete, the mixture was warmed to room temperature (23
°C) and stirred for 2 hours. Analysis of an aliquot by HPLC
indicated reaction completion. The mixture was again
cooled to 10 °C, and water (150 mL, 2 vol) was added care-
fully to quench the reaction. 1 M HCl was then added until
the aqueous phase pH was less than 5. The biphasic mix-
ture was diluted to a total volume of 1 L with EtOAc. The
phases were separated, and the organic phase concen-
trated to dryness. The crude product was purified on silica
gel using an EtOAc/hexanes gradient to give 15 (46.0 g,
13
DMSO-d6) δ ppm -110.37. C{1H} NMR (101 MHz, DMSO-
d6) δ ppm 8.3, 9.4, 12.3, 18.9, 19.0, 25.3, 26.7, 30.3, 40.8, 61.6,
61.8, 68.1, 97.8, 97.9, 113.9, 114.0, 116.5 (d, J=22.0 Hz), 117.3,
122.1, 122.12, 123.3, 126.0 (d, J=3.2 Hz), 128.6, 129.9 (d, J=8.4
Hz), 134.4, 136.4, 139.2, 141.6, 141.8, 151.5, 154.2, 163.3 (d,
J=248.0 Hz), 163.4. HRMS (ESI): m/z calculated for
C32H32BrClFN2O6S [M+H]+: 705.0832; found: 705.0830.
9
Re-work of 6-(N-(4-bromo-3-chloro-5-(((tetrahydro-
2H-pyran-2-yl)oxy)methyl)phenyl)methylsulfon-
amido)-5-cyclopropyl-2-(4-fluorophenyl)-N-
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
68% yield). M.p. 229-230 °C. H NMR (400 MHz, DMSO-
d6) δ ppm 0.40 - 0.53 (m, 1 H), 0.75 - 0.92 (m, 2 H), 0.92 -
1.05 (m, 1 H), 2.05 - 2.17 (m, 1 H), 2.84 (d, J=4.69 Hz, 3 H),
3.34 (s, 3 H), 4.47 (d, J=5.58 Hz, 2 H), 5.64 (t, J=5.60 Hz, 1
H), 7.22 (s, 1 H), 7.37 - 7.46 (m, 2 H), 7.53 (d, J=2.74 Hz, 1
H), 7.58 (d, J=2.84 Hz, 1 H), 7.93 - 8.03 (m, 2 H), 8.12 (s, 1
H), 8.51 (q, J=4.66 Hz, 1 H). 19F{1H} NMR (376 MHz, DMSO-
d6) d ppm -110.41 (s, 1 F). 13C{1H} NMR (101 MHz, DMSO-d6)
d ppm 8.3, 9.5, 12.3, 26.7, 40.8, 63.6, 113.9, 114.0, 116.5 (d,
J=22.0 Hz) 117.1, 117.2, 122.0, 123.8, 126.0 (d, J=3.1 Hz) 128.5,
129.9 (d, J=8.7 Hz) 134.0, 136.6, 139.2, 141.7, 145.2, 151.4, 154.0,
163.4, 163.3 (d, J=249.0 Hz). HRMS (ESI): m/z calculated for
C27H24BrClFN2O5S [M+H]+: 621.0256; found: 621.0257.
methylbenzofuran-3-carboxamide (26). A 1 L reactor
was charged with 26 (16.5 g, 23.37 mmol), 2-MeTHF (600
mL, 36 vol), and 0.5 M EDTA in water (250 mL, 15 vol). The
biphasic mixture was stirred for 90 minutes, and then the
layers separated. The organic phase was washed with water
(100 mL, 6 vol) and saturated aqueous NaCl (100 mL, 6 vol).
The organic phase was then stirred for 90 minutes with
30% aqueous ammonia (300 mL, 18 vol), followed by sepa-
ration of the layers. The organic phase was washed with
water (100 mL, 6 vol), saturated aqueous NaCl (100 mL, 6
vol), and then concentrated under reduced pressure to re-
cover 26 (15.7 g, 95% recovery), which was used directly in
the following stage to synthesize 30.
Synthesis of 6-(N-(4-bromo-3-chloro-5-(((tetrahy-
dro-2H-pyran-2-yl)oxy)methyl)phenyl)methylsulfon-
amido)-5-cyclopropyl-2-(4-fluorophenyl)-N-
Synthesis of 2-bromo-3-chloro-5-(N-(5-cyclopropyl-
2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-
6-yl)methylsulfonamido)benzyl acetate (27). A 100 mL
RB-flask containing a stirbar was charged with 15 (3.81 g,
6.13 mmol), DMAP (7.5 mg, 0.061 mmol), and DCM (30
mL). With stirring, acetyl chloride (0.48 mL, 6.74 mmol)
was added slowly. The reaction mixture was then cooled to
0 °C. Triethylamine (1.71 mL, 12.25 mmol) was added drop-
wise, followed by warming to room temperature. After 2
hours, analysis of an aliquot by HPLC revealed ~5% start-
ing material remaining; an additional 50 μL of acetyl chlo-
ride was added and the reaction mixture stirred for a fur-
ther hour. The solvent was removed, and the residue redis-
solved in EtOAc (150 mL). The organic phase was washed
with water, and the solvent removed from the organic
phase. The resulting white solid was washed with hexanes
three times and dried in a vacuum oven at 50 °C overnight
to give 27 (4.01 g, 99% yield). M.p. 212-215 °C. 1H NMR (400
MHz, DMSO-d6) δ ppm 0.43 (br m, 1 H), 0.86 (br m, 2 H),
0.98 (br m, 1 H), 2.02 (s, 3 H), 2.07 - 2.16 (m, 1 H), 2.84 (d,
J=4.60 Hz, 3 H), 3.46 (s, 3 H), 5.11 (s, 2 H), 7.22 (s, 1 H), 7.37
- 7.44 (m, 2 H), 7.45 (d, J=2.74 Hz, 1 H), 7.64 (d, J=2.64 Hz,
1 H), 7.93 - 8.00 (m, 2 H), 8.13 (s, 1 H), 8.50 (q, J=4.24 Hz, 1
H). 19F{1H} NMR (376 MHz, DMSO-d6) δ ppm -110.37 (s, 1
methylbenzofuran-3-carboxamide (26). A 500 mL reac-
tor equipped with a temperature probe and overhead stir-
rer was charged with 14 (23.0 g, 35.5 mmol), 2-MeTHF (115
mL, 5 vol) and MeOH (16.1 mL). Stirring was commenced
at 300 rpm, and the reaction mixture cooled to 10 °C. LiBH4
(2.0 M in THF, 53.2 mL, 106 mmol) was added dropwise
over 30 minutes. After stirring for 15 minutes, ethyl acetate
(100 mL, 4.3 vol) was added, followed by slow addition of 6
N HCl (10 mL) and water (100 mL, 4.3 vol). The reaction
mixture was allowed to warm to room temperature with
stirring, and then the phases allowed to settle. The layers
were separated, and the aqueous phase was extracted with
ethyl acetate (100 mL, 4.3 vol). The combined organic layer
was washed with water (250 mL, 10.9 vol) and saturated
aqueous NaCl (150 mL, 6.5 vol). Solvent was removed by
vacuum distillation to minimum stir in the 500 mL reactor,
followed by the addition of ethyl acetate (160 mL, 7 vol).
DHP (13.4 g, 14.6 mL, 160 mmol) and pyridinium p-tol-
uenesulfonate (0.89 g, 3.55 mmol) were added with stir-
ring, and then the reactor contents were heated to 55 °C for
three hours. Heptane (160 mL, 7 vol) was added, and the
contents of the reactor cooled to 10 °C at a rate of 0.5 °C
min-1, and held at 10 °C with stirring overnight. The result-
ing solid was collected by filtration, and the residual mate-
rial in the reactor washed onto the filter cake with heptane
(100 mL, 4.3 vol) and water (100 mL, 4.3 vol). The solid was
dried at 50 °C in a vacuum oven to give 26 (25.0 g, 81% iso-
lated yield). M.p. 172-176 °C. 1H NMR (400 MHz, DMSO-d6)
δ ppm 0.45 (br m, 1 H), 0.70 - 0.91 (m, 2 H), 0.98 (br m, 1
H), 1.24 – 1.60 (br m, 6 H), 2.10 (br m, 1 H), 2.84 (d, J=4.60
Hz, 3 H), 3.30 – 3.66 (br m, 2 H), 3.48 (s, 3 H), 4.45 - 4.56
(m, 1 H), 4.56 - 4.72 (m, 2 H), 7.23 (s, 1 H), 7.33 - 7.46 (m, 3
13
F). C{1H} NMR (101 MHz, DMSO-d6) δ ppm 8.2, 9.7, 12.3,
20.9, 26.7, 40.9, 66.0, 114.0, 116.5 (d, J=22.0 Hz), 117.1, 119.3,
124.2, 125.3, 126.0 (d, J=3.2 Hz), 128.6, 129.9 (d, J=8.8 Hz),
134.8, 136.3, 139.0, 139.2, 141.7, 151.4, 154.2, 163.3 (d, J=248.5
Hz), 163.4, 170.3. HRMS (ESI): m/z calculated for
C29H26ClBrFN2O6S [M+H]+: 663.0362; found: 663.0364.
Synthesis of 2-bromo-3-chloro-5-(N-(5-cyclopropyl-
2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-
6-yl)methylsulfonamido)benzyl pivalate (28). A 250
mL RB-flask containing a stirbar was charged with 15 (6.00
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The Journal of Organic Chemistry
Page 14 of 18
g, 9.65 mmol) and DCM (60 mL). With stirring, pivaloyl g, 44.4 mmol), pivalic acid (1.13 g, 11.1 mmol), toluene (250
1
chloride (2.38 mL, 19.3 mmol) was added slowly, followed
by triethylamine (2.96 mL, 21.2 mmol). After 18 hours, the
mixture was diluted with EtOAc (50 mL) and washed with
water (70 mL). The aqueous layer was back-extracted with
EtOAc (50 mL), and the combined organic extracts were
washed with brine (100 mL). The organic phase was dried
with Na2SO4, and the solvent removed to give a yellow oil.
Purification by silica gel chromatography with an
EtOAc/hexanes gradient to give 28 as a tan solid (2.82 g,
41% yield). M.p. 195-198 °C. 1H NMR (400 MHz, DMSO-d6)
δ ppm 0.41 (br. s., 1 H), 0.76 (br. s., 1 H), 0.84 (br. s., 1 H),
0.96 (br. s., 1 H), 1.03 (s, 9 H), 1.96 - 2.12 (m, 1 H), 2.84 (d,
J=4.60 Hz, 3 H), 3.47 (s, 3 H), 5.09 (s, 2 H), 7.16 - 7.29 (m, 2
H), 7.36 - 7.51 (m, 2 H), 7.68 (d, J=2.74 Hz, 1 H), 7.93 - 8.02
(m, 2 H), 8.10 (s, 1 H), 8.38 - 8.56 (m, 1 H). 19F{1H} NMR (376
MHz, DMSO-d6) δ ppm -110.37 (s, 1 F). 13C{1H} NMR (101
MHz, DMSO-d6) δ ppm 8.2, 9.2, 12.3, 26.7, 27.1, 38.7, 40.9,
65.6, 114.0, 116.5 (d, J=22.0 Hz), 117.4, 117.8, 121.9, 123.9, 126.0
(d, J=3.2 Hz), 128.7, 129.9 (d, J=8.8 Hz), 134.8, 136.2, 138.9,
139.3, 141.8, 151.5, 154.2, 163.3 (d, J=248.0 Hz), 163.4, 177.2.
HRMS (ESI): m/z calculated for C32H32ClBrFN2O6S [M+H]+:
705.0832; found: 705.0833.
mL, 16 vol) and THF (63 mL, 4 vol). The resulting mixture
was stirred at 400 rpm. The reactor headspace was flushed
with N2 prior to the introduction of PCyPh2 (0.357 g, 1.33
mmol) and Pd2dba3-CHCl3 (0.609 g, 0.665 mmol). The stir-
ring mixture was heated to 90 °C for four hours, when it
was cooled to 60 °C. The organic phase was washed with
water (3 x 50 mL, 3.2 vol) at this temperature, and then
cooled to room temperature. The organic phase was then
drained into a 1 L Erlenmeyer flask, and the reactor washed
with THF (2 x 40 mL, 2.5 vol). Darco activated carbon (12.4
g) was added, and the mixture stirred for 15 minutes. The
carbon was removed by filtration, and the solid washed
with THF (50 mL, 3.2 vol). The combined organic phase
was concentrated to a total volume of ~150 mL (9.6 vol) by
vacuum distillation at 55 °C. Toluene (150 mL, 9.6 vol) was
added, and the organic phase concentrated to ~150 mL (9.6
vol). The solution was then heated to 80 °C, followed by
the addition of heptane (105 mL, 6.7 vol) with stirring. The
mixture was cooled to 10 °C at a rate of 0.5 °C min-1, and
then held at that temperature overnight. The resulting
solid was collected by filtration, and the residual material
in the reactor washed with 1:1 toluene/heptane (60 mL, 3.8
vol) onto the filter cake. The solid was dried in a vacuum
oven at 50 °C to afford 12.9 g of 30 (77% yield). M.p. 196-
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Synthesis of 6-(N-(4-bromo-3-(((tert-butyldime-
thylsilyl)oxy)methyl)-5-chlorophenyl)methylsulfon-
amido)-5-cyclopropyl-2-(4-fluorophenyl)-N-
1
200 °C. H NMR (400 MHz, DMSO-d6) δ ppm 0.28 - 0.43
(m, 1 H), 0.63 - 0.74 (m, 1 H), 0.74 - 0.84 (m, 1 H), 0.84 -
0.97 (m, 1 H), 1.09 (d, J=3.13 Hz, 1 H), 1.24 (d, J=3.91 Hz, 11
H), 1.27 - 1.57 (m, 6 H), 1.94 - 2.12 (m, 1 H), 2.77 (d, J=4.70
Hz, 3 H), 3.20 - 3.24 (m, 1 H), 3.38 (s, 3 H), 3.41 - 3.63 (m, 1
H), 4.31 - 4.44 (m, 2 H), 4.46 - 4.59 (m, 1 H), 7.10 - 7.21 (m,
2 H), 7.24 - 7.29 (m, 1 H), 7.29 - 7.38 (m, 2 H), 7.85 - 7.94
(m, 2 H), 8.03 (s, 1 H), 8.42 (q, J=4.76 Hz, 1 H). 13C{1H} NMR
spectrum is complex; see the Supporting Information.
19F{1H} NMR (376 MHz, DMSO-d6) δ ppm -110.41. HRMS
(ESI): m/z calculated for C38H43BClFN2O8SNa [M+Na]+:
775.2398; found: 775.2399.
methylbenzofuran-3-carboxamide (29). A 100 mL jack-
eted reactor equipped with an overhead stirrer was
charged with 15 (5.10 g, 8.20 mmol) and DMF (30 mL). With
stirring, TBSCl (1.85 g, 12.3 mmol) was added slowly, fol-
lowed by imidazole (0.95 g, 13.9 mmol). After 18 hours, the
mixture was diluted with EtOAc (50 mL) and washed with
water (70 mL). The aqueous layer was back-extracted with
EtOAc (50 mL), and the combined organic extracts were
washed with brine (100 mL). The organic phase was dried
with Na2SO4, and the solvent removed to give a yellow oil.
Purification by silica gel chromatography with an
EtOAc/hexanes gradient to give 29 as a white solid (5.51 g,
91% yield). M.p. 160-163 °C. 1H NMR (400 MHz, DMSO-d6)
δ ppm -0.04 (s, 3 H), 0.00 (s, 3 H), 0.39 - 0.50 (m, 1 H), 0.71
(s, 9 H), 0.73 - 0.79 (m, 1 H), 0.79 - 0.88 (m, 1 H), 0.96 (br.
s., 1 H), 1.97 - 2.08 (m, 1 H), 2.84 (d, J=4.70 Hz, 3 H), 3.46 (s,
3 H), 4.62 (s, 2 H), 7.24 (s, 1 H), 7.29 (d, J=2.84 Hz, 1 H), 7.38
- 7.47 (m, 2 H), 7.72 (d, J=2.84 Hz, 1 H), 7.94 - 8.01 (m, 2 H),
8.08 (s, 1 H), 8.45 (d, J=4.70 Hz, 1 H). 19F{1H} NMR (376
Synthesis of 6-(N-(7-chloro-1-hydroxy-1,3-dihydro-
benzo[c][1,2]oxaborol-5-yl)methylsulfonamido)-5-cy-
clopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-
carboxamide (2). A 500 mL reactor equipped with a tem-
perature probe and overhead stirrer was charged with 30
(12.4 g, 16.5 mmol) and acetonitrile (175 mL, 14 vol). The
mixture was stirred at 400 rpm, followed by the addition of
1 N HCl (8.23 mL, 8.23 mmol). The reactor contents were
heated to 60 °C with stirring for three hours. The mixture
was then cooled to room temperature, and the solvent re-
moved by vacuum distillation to a total volume of ~90 mL
(7.3 vol). Water (175 mL, 14 vol) was added, and the reactor
contents cooled to 10 °C at a rate of 0.5 °C min-1. The mix-
ture was stirred at that temperature for 90 minutes. The
resulting solid was collected by filtration, and the residual
material in the reactor washed on to the filter cake with
water (2 x 40 mL, 3.2 vol). After drying via suction for one
hour, the wet solid was transferred to a second 500 mL re-
actor. The material was dissolved in THF (90 mL, 7.3 vol)
and TBME (125 mL, 10 vol), followed by addition of water
(250 mL, 20 vol). This biphasic mixture was stirred at 400
rpm, and 2 M KOH was added slowly (12.4 mL, 24.8 mmol)
13
MHz, DMSO-d6) δ ppm -110.43 (s, 1 F). C{1H} NMR (101
MHz, DMSO-d6) δ ppm -5.3, 8.3, 9.0, 12.2, 18.0, 25.8, 26.7,
40.8, 64.7, 113.9, 114.0, 116.0, 116.5 (d, J=22.2 Hz) 117.5, 120.6,
122.6, 126.1 (d, J=3.1 Hz), 128.6, 129.9 (d, J=8.7 Hz), 134.1,
136.3, 138.9, 141.8, 143.6, 151.5, 154.2, 163.3 (d, J=248.0 Hz),
163.4. HRMS (ESI): m/z calculated for C33H38ClBrFN2O5SSi
[M+H]+: 735.1121; found: 735.1123.
Synthesis of 6-(N-(3-chloro-5-(((tetrahydro-2H-py-
ran-2-yl)oxy)methyl)-4-(4,4,5,5-tetramethyl-1,3,2-diox-
aborolan-2-yl)phenyl)methylsulfonamido)-5-cyclo-
propyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-
carboxamide (30). A 500 mL reactor equipped with a tem-
perature probe and overhead stirrer was charged with 26
(15.7 g, 22.2 mmol), K2CO3 (9.20 g, 66.5 mmol), B2pin2 (11.3
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The Journal of Organic Chemistry
to reach a target pH ~ 12. Once addition was complete, stir-
Notes
The authors are current or former employees of Glax-
oSmithKline, and may own company stock.
ring was maintained for 20 minutes to ensure complete
2
dissolution of solids. Stirring was stopped, and the layers
allowed to settle for 30 minutes. The layers were separated,
and the aqueous phase back extracted with THF (90 mL,
7.3 vol) / TBME (40 mL, 3.2 vol) to remove 35 and other
minor impurities. After separation of the layers, the aque-
ous phase was concentrated to a total volume of 250 mL
(20 vol). The solution was cooled to 10 °C with stirring, fol-
lowed by addition of 9 wt% H2SO4 in water (11.9 mL, 10.7
mmol) to a target pH ~ 2. The mixture was cooled to 5 °C,
and stirred for 30 minutes. The resulting solid was col-
lected by filtration, and the residual material in the cold
reactor washed with water (110 mL, 8.9 vol) onto the filter
cake. The solid was dried in a vacuum oven at 60 °C to give
8.29 g of 2 (89% yield). M.p. 220-223 °C. 1H NMR (400 MHz,
DMSO-d6) δ ppm 0.48 (br m, 1 H), 0.82 (br m, 2 H), 0.98
(br m, 1 H), 2.02 - 2.13 (m, 1 H), 2.84 (d, J=4.60 Hz, 3 H), 3.34
(s, 3 H), 4.96 (s, 2 H), 7.22 (s, 1 H), 7.27 (d, J=1.76 Hz, 1 H),
7.37 - 7.46 (m, 3 H), 7.93 - 8.01 (m, 2 H), 8.08 (s, 1 H), 8.50
(q, J=4.47 Hz, 1 H), 9.18 (s, 1 H). 19F{1H} NMR (376 MHz,
DMSO-d6) δ ppm -110.41. 13C{1H} NMR (101 MHz, DMSO-d6)
δ ppm 8.5, 9.4, 12.3, 26.7, 41.0, 70.0, 114.1, 115.2, 116.5 (d,
J=22.0 Hz), 117.1, 122.5, 126.0 (d, J=3.0 Hz), 128.5, 129.9 (d,
J=8.51 Hz), 136.6, 136.7, 139.2, 145.3, 151.4, 154.1, 157.5, 163.3
(d, J=248.5 Hz), 163.4. HRMS (ESI): m/z calculated for
C27H24BClFN2O6S [M+H]+: 569.1115; found: 569.1119.
3
4
5
6
7
8
9
ACKNOWLEDGMENT
The authors thank all of the members of the API Chemistry
Department at GSK for insightful discussions and assistance
throughout the course of this work. We also thank Joseph
Reckamp for assistance with gas/liquid mixing in the Chan-
Lam coupling, Dr. Michael Morris for HRMS analysis, and Dr.
Anna Dunn and Dr. Frank Yin for discussions regarding reac-
tion monitoring.
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Isolation of 6-(N-(3-chloro-5-(hydroxymethyl)phe-
nyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluoro-
phenyl)-N-methylbenzofuran-3-carboxamide
(35).
This compound was isolated from the THF/TBME back ex-
tractions of the basic aqueous phase during the prepara-
tion of 2 as described above. An isolated yield was not de-
termined; this material was used to confirm the structure
of 35. M.p. 128 °C (decomp). 1H NMR (400 MHz, DMSO-d6)
δ ppm 0.47 (br m, 1 H), 0.84 (br m, 2 H), 0.99 (br m, 1 H),
2.09 - 2.19 (m, 1 H), 2.84 (d, J=4.60 Hz, 3 H), 3.42 (s, 3 H),
4.47 (br m, 2 H), 5.39 (br m, 1 H), 7.19 (s, 1 H), 7.23 (s, 1 H),
7.32 - 7.38 (m, 2 H), 7.38 - 7.45 (m, 2 H), 7.91 - 8.03 (m, 2 H),
8.11 (s, 1 H), 8.50 (q, J=4.50 Hz, 1 H). 19F{1H} NMR (376 MHz,
13
DMSO-d6) δ ppm -110.44 (s, 1 F). C{1H} NMR (101 MHz,
DMSO-d6) δ ppm 8.4 (br) 9.6 (br) 12.3, 26.7, 40.8, 62.4,
113.9, 114.0, 116.5 (d, J=22.0 Hz), 121.2, 122.8, 123.7, 126.0 (d,
J=3.1 Hz), 128.4, 129.9 (d, J=8.9 Hz), 133.4, 136.9, 139.2, 142.7,
146.5, 151.4, 154.0, 163.2 (d, J=248.0 Hz), 163.5. HRMS (ESI):
m/z calculated for C27H25ClFN2O5S [M+H]+: 543.1151; found:
543.1155.
ASSOCIATED CONTENT
Characterization data (1H, 13C{1H}, and 19F{1H} NMR spectra,
and LCMS traces) for all isolated compounds, and tables of
screening data. This material is available free of charge via the
Internet at http://pubs.acs.org.
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AUTHOR INFORMATION
Corresponding Authors
* john.a.kowalski@gsk.com
* david.c.leitch@gsk.com; dcleitch@uvic.ca
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(27) Under the current reaction conditions, use of Pd(OAc)2 led
to inconsistent results; however, this would likely be overcome by
a thorough study of Pd reduction pathways under the reaction
conditions. For an excellent example of this in the context of
Miyaura borylation, see: Wei, C. S.; Davies, G. H. M.; Soltani, O.;
Albrecht, J.; Gao, Q.; Pathirana, C.; Hsiao, Y.; Tummala, S.; East-
gate, M. D. The Impact of Palladium(II) Reduction Pathways on
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