An Evaluation of Multiple Catalytic Systems for the Cyanation of 2,3-Dichlorobenzoyl Chloride: Application to the Synthesis of Lamotrigine

Article abstract of DOI:10.1021/acs.oprd.7b00262

2,3-Dichlorobenzoyl cyanide is a key intermediate in the synthesis of Lamotrigine. An assessment of various catalytic systems for the cyanation of 2,3-dichlorobenzoyl chloride with cyanide salts is described. High-throughput experimentation identified many conditions for effecting the requisite chemistry, including amine bases and phase-transfer catalysts, as well as catalyst-free conditions utilizing acetonitrile as a polar cosolvent. A novel catalyst, CuBr₂, was identified by consideration of the possible oxidation of Cu(I) during high-throughput screening experimentation. CuCN was found to be the best cyanide source for achieving clean conversion; however, the solubility of CuCN was the major factor limiting reaction rate under many conditions. Improving CuCN solubility by using acetonitrile as solvent enhanced the reaction rate even in the absence of the catalysts tested but significantly complicated isolation of the product. With no acetonitrile cosolvent, phase-transfer catalysts such as tetrabutylammonium bromide (TBABr) are effective; however, use of TBABr led to inconsistent reaction profiles from run-to-run, due to an unexpected clumping of the CuCN solid. Switching to cetyltrimethylammonium bromide (CTAB) alleviated this clumping behavior, leading to consistent reactivity. This CTAB-catalyzed process was scaled up, giving 560 kg of 2,3-dichlorobenzoyl cyanide in 77% isolated yield.

Full text of DOI:10.1021/acs.oprd.7b00262

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Full Paper
An Evaluation of Multiple Catalytic Systems for the Cyanation of 2,3-
Dichlorobenzoyl Chloride: Application to the Synthesis of Lamotrigine
David C. Leitch, Matthew P John, Paul Slavin, and Andrew D Searle
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.7b00262 • Publication Date (Web): 17 Oct 2017
Downloaded from http://pubs.acs.org on October 17, 2017
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An Evaluation of Multiple Catalytic Systems for the
Cyanation of 2,3ꢀDichlorobenzoyl Chloride:
Application to the Synthesis of Lamotrigine
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David C. Leitch,†,* Matthew P. John,‡ Paul A. Slavin, § and Andrew D. Searle§
†Chemical Catalysis Group, API Chemistry, GlaxoSmithKline, King of Prussia PA. ‡Highꢀ
§
Throughput Chemistry Group, API Chemistry, GlaxoSmithKline, Stevenage UK. Global
Manufacturing and Supply, GlaxoSmithKline, Stevenage UK.
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Table of Contents artwork
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KEYWORDS: acyl cyanide, cyanation, lamotrigine, catalysis, phaseꢀtransfer catalysis.
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ABSTRACT: 2,3ꢀDichlorobenzoyl cyanide is a key intermediate in the synthesis of
Lamotrigine. An assessment of various catalytic systems for the cyanation of 2,3ꢀ
dichlorobenzoyl chloride with cyanide salts is described. Highꢀthroughput experimentation
identified many conditions for effecting the requisite chemistry, including amine bases and
phaseꢀtransfer catalysts, as well as catalystꢀfree conditions utilizing acetonitrile as a polar coꢀ
solvent. A novel catalyst, CuBr2, was identified by consideration of the possible oxidation of
Cu(I) during high throughput screening experimentation. CuCN was found to be the best
cyanide source for achieving clean conversion; however, the solubility of CuCN was the major
factor limiting reaction rate under many conditions. Improving CuCN solubility by using
acetonitrile as solvent enhanced the the reaction rate even in the absence of the catalysts tested
but significantly complicated isolation of the product. With no acetonitrile coꢀsolvent, phaseꢀ
transfer catalysts such as tetrabutylammonium bromide (TBABr) are effective; however, use of
TBABr led to inconsistent reaction profiles from runꢀtoꢀrun, due to an unexpected clumping of
the CuCN solid. Switching to cetyltrimethylammonium bromide (CTAB) alleviated this
clumping behaviour, leading to consistent reactivity. This CTABꢀcatalyzed process was scaled
up, giving 560 kg of 2,3ꢀdichlorobenzoyl cyanide in 77% isolated yield.
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Introduction.
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Lamotrigine (4), first disclosed in the early 1980s by researchers at the Wellcome
Foundation,1 continues to be a frontꢀline anticonvulsant medicine for the treatment of epilepsy,
bipolar disorder, and other conditions.2 In the intervening years, many syntheses of Lamotrigine
have been reported, with the vast majority following the general route starting from 2,3ꢀ
dichlorobenzoic acid (1) shown in Scheme 1.1,3,4 Among these routes, the reported conditions
for cyanation of the acid chloride intermediate 2 to give the acyl cyanide 3 are the most varied.
Known systems differ in cyanide source, solvent, reaction temperature, and additive / catalyst.
Classic methods for the cyanation of acyl chlorides involve highꢀtemperature (>150 °C)
treatment with CuCN, often conducted neat.5 A milder approach for largeꢀscale preparations of
Lamotrigine intermediate 3 involves the use of a stoichiometric amount of KI in conjuction with
CuCN at lower reaction temperatures.3a Because of the simplicity of the organic starting
materials, and the high molecular weight of KI, this one additive can constitute an inordinately
high proportion of the overall cost of goods. In addition, the correspondingly large mass of
iodineꢀcontaining waste generated makes the process undesirable from an environmental
standpoint. Thus, an inexpensive catalyst capable of achieving comparable or better cyanation
activity would greatly improve this process.
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Scheme 1. General synthetic sequence for the preparation of Lamotrigine (4) from 1.
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A number of potential catalyst systems for the formation of aroyl cyanides have been
reported both in the academic and patent literature.4,6ꢀ8 One common approach is the use of
phaseꢀtransfer catalysts, generally tetraalkylammonium salts such as tetrabutylammonium
bromide or iodide.4a,d,7 Potassium iodide could also potentially be made catalytic, with iodide
acting as a nucleophilic catalyst to activate the acid chloride toward cyanation. Finally,
combining alternative cyanide sources such as NaCN, Zn(CN)2, or K4Fe(CN)6 with various
catalysts has also been reported previously for cyanation of aroyl chlorides.3e,4b,8
Herein we describe our efforts to evaluate multiple catalyst systems for the cyanation of 2
to generate 3, without increased processing to remove said catalyst, or formation of byproducts.
This was achieved by a combined highꢀthroughput screening and reaction profiling approach to
ascertain the features and limitations of each system. These experiments led to the discovery of
CuBr2 as a previously unreported catalyst for this transformation, as well as identification of
cetyltrimethylammonium bromide (CTAB) as a superior phaseꢀtransfer catalyst. Informed by
smallꢀscale reaction progress experiments, the synthesis of 3 was accomplished using the CTAB
system on large scale with a 77% isolated yield.
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Results and Discussion.
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High throughput screening. In order to rapidly evaluate several sets of reaction
conditions for the synthesis of 3, two highꢀthroughput screens (~0.1 mmol scale) were designed
using a qualitative Design of Experiments approach to simultaneously examine three cyanide
sources (CuCN, NaCN and Zn(CN)2; data for CuCN and NaCN shown in Figure 1), five coꢀ
solvents paired with pꢀxylene (acetonitrile (ACN), 1,2ꢀdimethoxyethane (DME), N,Nꢀ
dimethylformamide (DMF), Nꢀmethylꢀpyrrolidinone (NMP), and sulfolane), and fifteen
catalysts. The reactions with NaCN were also run with four different Cu(I) coꢀcatalysts (CuCl,
CuBr, CuI, and Cu[ACN]4OTf). To simplify this process, 2,3ꢀdichlorobenzoyl chloride (2) was
synthesized on a preparative scale9 and used directly, rather than being generated in situ from
2,3ꢀdichlorobenzoic acid (1) and thionyl chloride as for the manufacturing process. From these
highꢀthroughput experiments, multiple hits were identified (>95% conversion of 2 determined by
GC, Figure 1).
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Cl
O
Cl
O
cyanide source (1.2 equiv.)
p-xylene / co-solvent
(150 uL total)
Cl
Cl
+
CN
OH
110-130 oC, 4-6 h
Cl
O
catalyst (0-1.0 equiv.)
1
Cl
3
Cl
Cl
Cl
9
~450 combinations
down to 61 reactions
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2
Cl
O
O
Cl
Cl
Cl
+
Cl
O
O
O
Cl
CN
CN
5
6
Figure 1. Data visualization of highꢀthroughput experimentation results for reactions with CuCN
(left) and NaCN / Cu cat. (right). The yꢀaxis is coꢀsolvent used in conjunction with pꢀxylene,
while the xꢀaxis is catalyst (including Cu coꢀcatalyst for NaCN reactions; TMEDA: N,N,N’,N’ꢀ
tetramethylethylenediamine; TBAI: tetrabutylammonium iodide; TBABr: tetrabutylammonium
bromide; NMI: Nꢀmethylimidazole; DMBA: N,Nꢀdimethylbenzylamine; DMAP: 4ꢀ
dimethylaminopyridine; DMA: N,Nꢀdimethylaniline; DIPEA: N,Nꢀdiisopropylethylamine;
Bbipy: 4,4’ꢀdiꢀtertꢀbutylbipyridine). Catalyst charges were typically 10 mol%, with some
variability between 5ꢀ100 mol%. The size of the points corresponds to % conversion of starting
acid chloride 1 (large is high conversion), while the colour of the points represents % product 3
(gradient from red = 0%; to yellow = 50%; to green = 100%). Multiple points under the same set
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of conditions represent either repeats, or in the case of KI for cyanation with CuCN and no coꢀ
solvent, different equivalents of KI: green point: 1.0 equiv.; yellow point: 0.5 equiv.; red point:
0.1 equiv. Blank areas represent runs not performed. See SI for full numeric table of results,
including detailed reagent/catalyst charges for each case.
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With pꢀxylene as the solvent and CuCN as the cyanide source, efficient catalysts included
the reportedly effective PTCs tetrabutylammonium bromide and iodide (TBABr and TBAI),4a,d
and aliphatic amines triethylamine and diisopropylethylamine;4c notably, these tertiary amines
outperformed the common nucleophilic catalyst DMAP. With acetonitrile as a coꢀsolvent (1:1
v/v), no added catalyst was required.4b Finally, the combination of NaCN and 10 mol% CuX (X
= Cl, Br, I) in 1:1 pꢀxylene/acetonitrile was also effective. Analysis of the crude reaction
mixtures by GC revealed the formation of the desired acid cyanide (3, 65ꢀ75%), and also the
carboxylic acid (1), anhydride (5), and bis(cyanohydrin)ꢀderived ester 6 when using
NaCN/CuX.3e,7 Compounds 1 and 5 were also observed when using stoichiometric KI on highꢀ
throughput scale as a positive control, suggesting that adventitious water from atmospheric
exposure during reaction setꢀup is responsible for the hydrolysis side reactivity. Notably,
reduction of KI equivalents to 0.5 or 0.1 resulted in only 35% and 7% GC yield respectively.
This suggests that iodide is not simply acting as a nucleophilic catalyst in these cases, as the
yield is directly proportional to, and never exceeds, the amount of KI added.
Scale up inconsistencies and CuCN solubility. Once several sets of conditions were
identified, we prioritized scaling these reactions to ~5 mmol under anhydrous and anaerobic
conditions, and developing reaction profiles by using in situ ReactIR monitoring of the carbonyl
stretches of both 2 (1790 cmꢀ1) and 3 (1700 cmꢀ1). Not only are these two peaks well resolved,
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they also have the same absorption coefficient (i.e. 2 and 3 have the same response factor) as
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confirmed by GC analysis of several timepoints along the profile.10
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CuCN (1.1 equiv.)
NEt3 (10 mol%)
toluene / acetonitrile
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Cl
O
Cl
O
100 C, 3 hours
Cl
Cl
Cl
CN
2
3
Figure 2. Reaction monitoring data for the cyanation of 1 with CuCN (1.1 equiv.) and NEt3 (10
mol%) in toluene/acetonitrile (1:1 v/v). A: Solutionꢀphase IR spectrum at reaction start, with
C=O stretch for 1 indicated. B: Solutionꢀphase IR spectrum at one hour reaction time, with C=O
stretch for 2 indicated. C: Contourꢀplot of reaction progress as judged by disappearance of C=O
stretch at 1790 cmꢀ1, and growth of C=O stretch at 1700 cmꢀ1. D: Reaction profile curve, with
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h/h0 plotted versus time for both 2 (blue) and 3 (red) (h is peak height to singleꢀpoint baseline, h0
is initial peak height). E: GC trace of reaction mixture after 3 hours (92.4% area for 2).
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Initially, NEt3 was investigated as a catalyst using toluene as the reaction solvent. In
contrast to screening results, at ~5 mmol scale, no conversion was observed after one hour at 100
°C; over this period, it was evident that the CuCN did not dissolve. Distillation of approximately
half of the toluene and addition of an equal volume of acetonitrile initiated the reaction as
observed by ReactIR, and complete dissolution of the CuCN was observed after approximately
30 minutes. Since screening had also identified “catalystꢀfree” conditions with a pꢀxyleneꢀ
acetonitrile solvent system, the cyanation was repeated on ~5 mmol scale with 1:1
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toluene/acetonitrile with no added NEt3. Again in contrast to the screening results, no
conversion was observed after one hour; visually, CuCN had again failed to dissolve. Addition
of 10 mol% NEt3 to this stirring suspension resulted in immediate formation of 3, and dissolution
of CuCN over about 30 minutes. The toluene/acetonitrile/NEt3 conditions were repeated to
generate the reaction data shown in Figure 2; importantly, the degree of hydrolysis to 1 and 5 is
greatly diminished under these conditions, as shown in the GC trace (Figure 2, E).
A kinetic analysis10 of this reaction indicates an overall firstꢀorder process, with the rate
law shown in equation 1. The apparent zeroꢀorder dependence on [CuCN] is almost certainly due
to the poor solubility of CuCN in the reaction medium, leading to an effectively constant, low
concentration of CuCN until two halfꢀlives have passed (i.e., the reaction is run effectively under
pseudoꢀfirstꢀorder conditions).
Rate = (6.21 x 10ꢀ4 sꢀ1) [2]1[CuCN]0
(1)
(at 100 °C and 10 mol% NEt3; order in NEt3 not determined)
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The inconsistencies observed between benchtop highꢀthroughput screening experiments
and largerꢀscale anhydrous reactions were disconcerting, as they could indicate the potential for
irreproducibility based on unseen reaction variables. One possible reason for this is the presence
of water and/or air in the screening reactions; a much larger degree of hydrolysis was certainly
observed on smallꢀscale. While trace water would likely be consumed rapidly to generate 1
and/or 5, adventitious oxygen could effect a small degree of oxidation of Cu(I) to Cu(II) in the
CuCN. We hypothesized that a small amount of Cu(II) may be able to catalyze the desired
cyanation reaction. Rather than relying on adventitious O2, CuBr2 was investigated as a possible
catalyst to test this hypothesis. At 5 mol% of CuBr2, the conversion of 2 to 3 occurs with a halfꢀ
life of approximately 30 minutes, which is comparable to rates observed with catalytic NEt3.
While this result supports the hypothesis of a Cu(II)ꢀcatalyzed cyanation reaction in the highꢀ
throughput experiments, the exact role(s) of Cu(II) in this chemistry is not known, and beyond
the scope of the current investigation. Furthermore, we did not identify any clear practical
advantage to using CuBr2 in lieu of other systems identified in our highꢀthroughput screens.
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If CuCN solubility is the key factor in determining a successful reaction, as suggested by
the aforementioned kinetic analysis, there should be a pronounced solvent effect on reaction
rates; therefore, an evaluation of NEt3 and CuBr2 as catalysts in acetonitrile as the sole reaction
solvent was undertaken, and compared to catalystꢀfree conditions (Figure 3). With no added
catalyst, the cyanation has an initial rate of 1.02 x 10ꢀ4 M sꢀ1, whereas use of 5 mol% CuBr2
increases the initial rate by only a factor of 1.3. NEt3 (10 mol%) effects an increase of 2.4ꢀfold
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over the uncatalyzed reaction; however this is in stark contrast to the ordersꢀofꢀmagnitude
increase for both of these catalysts observed in the toluene/acetonitrile solvent mixture. These
data clearly support the hypothesis that CuCN solubility is the key rateꢀlimiting factor, and also
indicate that the catalytic effect of NEt3 or CuBr2 is negligible when using acetonitrile..
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CuCN (1.2 equiv.)
CH3CN, 55 o
C
NEt3 (10 mol%) or
CuBr2 (5 mol%) or
no catalyst
Cl
O
Cl
O
Cl
Cl
Cl
CN
2
3
Figure 3. Reaction monitoring data for the cyanation of 2 with CuCN (1.2 equiv.) and NEt3 (10
mol%, green points), CuBr2 (5 mol%, blue points), or no catalyst (purple points) in acetonitrile at
55 ºC, with initial rates shown. Initial rates were determined by linear regression of the
concentration vs. time curve up to 50% conversion.
Phase-Transfer Catalysis. While using either NEt3 or CuBr2 as a catalyst would be both
economical and rapid relative to stoichiometric KI, one clear disadvantage is the need for
acetonitrile as a coꢀsolvent. A major issue is that use of this coꢀsolvent would complicate Cu salt
removal postꢀreaction. Under the acetonitrileꢀonly conditions, the reaction mixture is
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homogeneous upon complete conversion of 2, with the Cu(I) salt byproducts clearly in solution.
Furthermore, the existing isolation of 3 involves a toluene/petroleum ether crystallization, which
would necessitate a complete solvent swap from acetonitrile to toluene, increasing cycle time and
adding complexity.
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In order to develop the simplest process possible, avoid the aforementioned issues, and
enable efficient solvent recycling by using a single reaction solvent, the phaseꢀtransfer catalyst
TBABr (identified during highꢀthroughput screening) was investigated with toluene as the sole
reaction solvent and monitored on ~1 g scale. The cyanation reaction does proceed under these
conditions; however, the reaction is slow, the kinetic profile is odd, and reactivity is not
consistent from run to run (Figure 4, top shows a representative profile). These issues likely
arise from massꢀtransport limitations: in reactions catalyzed by TBABr, the solid CuCN was
observed to clump together to form a large mass; this clumping occurs regardless of the order of
reagent/solvent addition, and does not appear to be affected by stir rate.
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CuCN (1.05 equiv.)
TBABr or CTAB (5 mol%)
Cl
O
Cl
O
toluene, 110 o
C
Cl
Cl
Cl
CN
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Figure 4. Representative reaction profile curves, for the cyanation of 2 using CuCN (1.05 equiv.)
and 5 mol% of either TBABr (top, t1/2 ~4 hours) or CTAB (bottom, t1/2 ~40 min, orange line:
firstꢀorder fit to 95% conversion).
Since CuCN clumping was only observed when using TBABr, and not under any of the
previous cyanation conditions, we sought other readilyꢀavailable phaseꢀtransfer catalysts that
would not exhibit this behaviour. Due to the observed hydrolytic sensitivity of both acid
chloride 2 and desired product 3, we required use of anhydrous PTCs; unfortunately, many
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inexpensive PTCs (such as the Aliquat series) are supplied as aqueous solutions or hydrates,
limiting the scope of suitable catalysts. Two inexpensive, (largely) anhydrous, and readily
available PTCs were investigated on 1 g scale: benzyltriethylammonium chloride fared poorly
(42 hours reaction time with 10 mol% BnNEt3Cl), but cetyltrimethylammonium bromide
(CTAB) resulted in rapid, consistent reactivity in toluene (Figure 4, bottom). The kinetics of the
reaction fit very well to a firstꢀorder function up to 95% conversion, with a halfꢀlife of
approximately 40 minutes at 110 °C. This kinetic behaviour is again consistent with a low,
constant concentration of CuCN during the reaction, leading to an apparent zero order in
[CuCN], and first order in [2]. Due to these favourable kinetics at 5 mol% catalyst, lower or
higher CTAB loadings were not explored.
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Isolation of 3 generated using CTAB by a simple filtration of the Cu salts and
evaporation of the solvent gave a 90% isolated yield of crude product, which was 90% pure
based on 1H NMR spectroscopy; the other components were 2 (4%) and 5 (6%). Importantly,
the phaseꢀtransfer catalyst was not carried through the workꢀup procedure, which ensures that
additional catalyst removal steps are not required. In fact, as a result of the smallꢀscale
development work described herein, the preparation of 3 using 5 mol% CTAB was directly
scaled to 768 kg input of 2. For these demonstration runs, the reaction was run at 110 °C for 12
hours to ensure complete conversion. Employing a simple isolation procedure resulted in 77%
isolated yield of 3 with 94% purity (eq. 3; average of three runs); the 6% mass balance is
comprised of 4% of 1 and 2% of 5. This material was then successfully used to produce
Lamotrigine (4).
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Conclusions.
As a result of both highꢀthroughput screening and reaction profiling, multiple catalyst
systems for the cyanation of 2,3ꢀdichlorobenzoyl chloride (2) have been evaluated. While
several effective conditions were identified using NaCN, the formation of the homocoupling
byproduct 6 (Figure 1) led us to focus on CuCN as the cyanide source. Good to excellent
conversion to 3 was effected by the use of simple amines, Cu(II) salts, and phaseꢀtransfer
catalysts, in addition to “catalystꢀfree” conditions using acetonitrile as the reaction solvent. In all
of these systems, the solubility of CuCN is the crucial factor, and the probable main function of
each catalyst or solvent is to influence the rate of CuCN dissolution.
With this in mind, the mechanism of catalysis by NEt3 and DIPEA is somewhat puzzling.
Certainly, one possibility is activation of the acid chloride through formation of a more
electrophilic Nꢀacylammonium species; however, three pieces of evidence are not fully
consistent with this picture. First, DMAP (a generally efficient acylation catalyst) was inferior to
NEt3 and even DIPEA in highꢀthroughput screening; second, catalytic KI (another acylation
catalyst) gave very poor cyanation in highꢀthroughput screening (<10% yield with 10 mol% KI);
and third, NEt3 increases the cyanation rate only by a factor of 2.4 in acetonitrile (where CuCN
solubility is markedly increased) relative to the ordersꢀofꢀmagnitude rate increase in
toluene/acetonitrile. Another possibility is that these aliphatic amines act as ligands for Cu, and
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assist in breaking up the polymeric chains of solid CuCN. Finally, there is the possibility that a
putative Nꢀacylammonium species formed by acylation of the amine could also act as a phaseꢀ
transfer catalyst to bring CuCN into solution. If this is the case, more typical
tetraalkylammonium phaseꢀtransfer catalysts are evidently superior for this purpose. In any
event, it is clear that CTAB is a highly effective PTC, enabling efficient cyanation using CuCN
without the need for a polar coꢀsolvent.
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Finally, from a mass efficiency and cost standpoint, all of the identified systems are
preferrable to the use of stoichiometric KI. While the use of acetonitrile is not desirable due
mainly to difficulties in Cu salt removal and solvent swapping and recyclability complications,
phaseꢀtransfer catalysts are operative in toluene, albeit with markedly different activities. CTAB
is a highly effective catalyst for this cyanation, giving a far more reliable reaction profile than
TBABr. The estimated reduction in material cost by employing 5 mol% CTAB in lieu of
stoichiometric KI is ~60% for this stage and ~20% for the entire synthesis, with no increase in
cycle time or number of unit operations.
Experimental Section.
Materials. All reagents and solvents were purchased from commercial suppliers and
used as received.
NMR Spectroscopy. All NMR spectra were acquired at ambient temperature on a
Bruker 400 MHz or 500 MHz spectrometer. Solvents and frequencies for specific data
acquisitions are noted for each case.
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Gas Chromatography. All GC analyses were conducted using an Agilent 6890 series
instrument equipped with a low thermal mass oven unit. The following generic method was
used: column: DBꢀ5, length 15 m, diameter 250 μm, film thickness 0.1; inlet: temperature 275
°C, pressure 30 psi, split ratio 100:1; main oven: temperature 275 °C; detector: temperature 320
°C, H2 flow 40 mL/min, air flow 450 mL/min, make up N2 flow: 25 mL/min; LTM oven method
program: constant pressure mode, initial temperature 50 °C (hold 0.5 min), ramp temperature at
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75 °C/min up to 320 °C (hold 2.5 min), ramp temperature at 300 °C/min down to 50 °C. Total
run time 7.5 min.
Approximate GC retention times of 1ꢀ3, 5 using method described above: 1: 2.40 min; 2:
2.12 min; 3: 2.21 min; 5: 3.85 min.
SAFETY NOTE: Metal cyanide salts, including but not limited to NaCN, CuCN, and
Zn(CN)2, are extremely toxic and can liberate hydrogen cyanide (HCN) gas if handled
improperly. Great care must be taken when carrying out chemistry using these reagents,
particularly on larger scales. All manipulations including weighing materials, charging
materials, carrying out reactions, performing workup, isolation, and purification procedures, and
quenching of waste, must be performed with sufficient ventilation. In the present case, all
chemical waste from cyanide reactions was quenched by disposal into a caustic aqueous solution
(pH > 12) before waste disposal.
Synthesis of 2. The preparation of this acid chloride was adapted from a literature
procedure.9 A 100 mL pearꢀshaped RBꢀflask containing a stirbar was charged with 25.0 g 1 (131
mmol). The flask was fitted with a waterꢀcooled reflux condenser with a septum on the top joint.
Nitrogen was flushed through the system using a needle attached to a rubber hose. The flask was
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immersed in a sandbath in a heating mantle, with a probe monitoring the sand temperature.
Thionyl chloride (48.9 g, 30.0 mL, 411 mmol, 3.14 equiv.) was added via syringe through the
septum at the top of the condenser. The suspension was heated to reflux (sand bath: 80 °C) for 2
hours, during which time the organic solids dissolved in the thionyl chloride. The reaction
mixture was then cooled to below the boiling point of thionyl chloride, and the reflux condenser
quickly replaced with a hoseꢀadapter connected to a dry ice / isopropanol cold trap preceeding a
vacuum pump. The thionyl chloride was distilled off under reduced pressure. Once the volume
had reduced by an appropriate amount, anhydrous toluene (10 mL) was added to the residue, and
subsequently distilled off under reduced pressure. Once the toluene was removed, the hose
adapter was replaced with a shortꢀpath distillation apparatus. The desired acid chloride product
was isolated by vacuum distillation (sand bath temperature at 150 °C, vacuum at 3ꢀ5 mbar),
giving a colourless oil that crystallized upon standing at room temperature. Yield: 24.0 g, 88%
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yield. H and 13C NMR spectra are consistent with the reported synthesis.9 1H NMR (CDCl3,
500 MHz) δ 7.92 (d, J = 7.9 Hz, 1 H); 7.70 (d, J = 7.9 Hz, 1 H); 7.37 (t, J = 7.9 Hz, 1 H). 13C
NMR (CDCl3, 125 MHz) δ 164.95, 135.69, 135.34, 134.82, 131.35, 130.43, 127.33.
Synthesis of 5 as an impurity marker. This compound was prepared by a modification
of a literature procedure.11 Compound 2 (515.4 mg, 2.461 mmol) was dissolved in
dichloromethane (10 mL) in a 20 mL vial. In a separate 20 mL vial, sodium hydroxide (253 mg,
6.33 mmol) was dissolved in water (10 mL). A third 20 mL vial was charged with 1 (1207 mg,
6.32 mmol) and pyridine Nꢀoxide (24.7 mg, 0.260 mmol). The NaOH solution was added via
pipette to the 1/pyridine Nꢀoxide solids, and the suspension stirred at room temperature for 30
min to ensure complete dissolution. Once dissolution of 1 into the aqueous NaOH solution was
complete, the DCM solution and the aqueous solution were combined in a 100 mL RB flask
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containing a stirbar. The resulting biphasic mixture was stirred at ~1200 rpm at room
temperature for one hour. The reaction progress was determined by GC analysis of the DCM
layer, indicating complete consumption of 2, and a new peak at later retention time assigned to 5.
The reaction mixture was diluted with 10 mL DCM, and 10 mL water. The mixture was
transferred to a seperatory funnel, and the layers separated. The DCM phase was washed with
with 0.02 M NaOH (20 mL), water (2 x 20 mL), and drired over MgSO4. The suspension was
filtered, and the organic solvent removed via rotovap to give a white solid (773 mg, 86% crude
yield) that was 83% pure by GC analysis. The crude product was recrystallized from refluxing
toluene (10 mL) upon cooling to room temperature. The white crystals were collected by suction
filtration, and washed with iceꢀcold toluene (2 x 3 mL) and hexanes (2 x 10 mL) before drying in
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vacuo. Yield: 575 mg (64%). H NMR (400 MHz, CDCl3) δ 7.37 (t, J=7.97 Hz, 1 H) 7.74 (dd,
J=8.07, 1.52 Hz, 1 H) 7.89 (dd, J=7.83, 1.57 Hz, 1 H). 13C NMR (101 MHz, CDCl3) δ 127.43;
130.31; 132.96; 134.88; 135.39; 159.76. MS (EI): base peak m/z = 173/175 [Cl2C6H3CO+],
consistent with the literature report.10
Synthesis of 3 as a product marker. A 5 mL RB flask containing a stirbar was charged
with 2 (200 mg, 0.955 mmol), CuCN (94 mg, 1.055 mmol, 1.1 equiv), and KI (160 mg, 0.964
mmol, 1.01 equiv.). Toluene (0.5 mL) was added. The flask was fitted with a waterꢀcooled
reflux condenser equipped with a septum at the top joint. The system was flushed with N2. The
mixture was heated to reflux with using a sandbath/heating mantle. The reaction progress was
monitored by periodic aliquots taken via syringe through the reflux condenser and analyzed by
GC. After 3 hours at reflux, the mixture was cooled to room temperature. The suspension was
filtered via suction filtration through a small plug of Celite to remove inorganic salts. The
solvent from the filtrate was removed in vacuo to give the crude product (160 mg, 84% yield).
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1H and 13C NMR spectroscopy and GC analysis reveal the presence of 8 mol% of 5. Further
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purification of this material was not carried out. H NMR (CDCl3, 500 MHz): 3 (rel. integ.: 1.0):
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δ 8.08 (dd, J = 7.78, 1.07 Hz, 1 H); 7.84 (dd, J=7.93, 1.22 Hz, 1 H); 7.49 (t, J=8.09 Hz, 1 H); 5
(rel. integ.: 0.20): δ 7.88 (dd, J=7.93, 1.22 Hz, 1 H); 7.72 (dd, J=7.93, 1.22 Hz, 1 H); 7.36 (t,
J=7.93 Hz, 1 H). 13C NMR (CDCl3, 126 MHz) 3: δ 112.83; 127.92; 132.69; 132.71; 133.59;
136.48; 137.00; 165.15; 5: 127.49; 130.32; 132.91; 134.90; 135.36; 159.70. GC analysis (peak
area%): 3: 92.5%; 5: 7.5%.
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Procedure for high-throughput screening experiments. Smallꢀscale HTS reactions
were carried out with 20 mg (0.1 mmol) of 2, with 0.15 mL solvent ([2] = 0.64 M). Solid
reagents were dosed using a FlexiWeigh (Mettler Toledo) instrument into a 48ꢀwell array of 1.5
mL crimpꢀcap HPLC vials containing micro stirbars. (NOTE: After dispensing metal cyanides,
all potentially contaminated surfaces were thoroughly cleaned with bleach.) All liquid reagents
and solvents were dispensed via micropipette to the appropriate vials according to the
experimental design. Once all materials were charged, each vial was sealed with an aluminum
crimpꢀcap containing a PTFE/silicone/PTFE septum. The septa were pierced with a wideꢀbore
needle to allow gas ingress/egress. The vials (arrayed in a metal plate) were heated to the desired
reaction temperature under 5 barg nitrogen inside a Cat96 pressure reactor (HEL). At the end of
the reaction time, the reactor was cooled to room temperature and vented to atmosphere. The
plate was removed, and the caps removed. Each vial was diluted with 1 mL dichloromethane.
The plate was placed on a stirplate to ensure complete dissolution of any organic products. The
resulting suspensions were centrifuged prior to analysis by GC.
Procedure for reaction profiling experiments of the cyanation of 2. An ovenꢀdried,
nitrogenꢀflushed 50 mL, 3ꢀnecked RB flask containing a stirbar was charged with 2 (1.00 g, 4.78
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mmol) and anhydrous reaction solvent(s) (4ꢀ8 mL). The flask was fitted with a waterꢀcooled
reflux condenser, a ReactIR probe, and a septum. The reaction mixture was brought to the
desired temperature using a sandbath/heating mantle. Once reaction temperature had stabilized,
the reflux condenser was quickly removed and CuCN (1.05ꢀ1.2 equiv) was carefully added as a
solid with vigorous stirring. For reactions with a solid catalyst (CuBr2, PTCs), the catalyst was
coꢀmixed with the CuCN. For reactions with a liquid catalyst (NEt3), the catalyst was added via
syringe through the septum. The reaction progress was monitored by IR spectra acquired every
minute, and conversion determined by the relative heights of the carbonyl peaks for 2 (1790 cmꢀ
1) and 3 (1700 cmꢀ1).
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Procedure for large-scale preparation of 3. A glassꢀlined reactor was charged with a
toluene solution of 2 (768 kg, 3667 mol, dissolved in 1 vol toluene), CuCN (360 kg, 4019 mol),
and CTAB (67 kg, 184 mol) at room temperature. The reaction mixture was heated to 110 °C
with stirring for 12 hours. The reactor was then cooled to room temperature. Toluene (2100 L)
was charged, and the suspension filtered to remove the Cu salt byproducts and unreacted CuCN.
These waste salts were washed with an additional portion of toluene (1400 L). Toluene was
distilled from the combined organic solution under vacuum. Petroleum ether (1800 L) was
added to the crude product, and the suspension was stirred for 12 hours at 15ꢀ20 °C. The product
was collected by filtration to yield 560 kg of 3 (77% yield, 94% assay by HPLC, balance is 2,3ꢀ
dichlorobenzoic acid 1 and corresponding anhydride 5, average of three runs).
ASSOCIATED CONTENT
The following files are available free of charge via the Internet at http://pubs.acs.org.
Full table of HTS experimental data, kinetic plots, and representative characterization data (PDF)
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AUTHOR INFORMATION
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Corresponding Author
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* david.c.leitch@gsk.com
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Author Contributions
The manuscript was written through contributions of all authors. All authors have given approval
to the final version of the manuscript.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
The authors thank all of the former members of the Catalysis Center of Excellence at Research
Triangle Park for insightful discussions and assistance throughout the course of this work.
REFERENCES
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Zhang, Z.; Ye, S.; Chen, Z. Process for Preparation of Aroyl Cyanides. CN 101328137,
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Ddichlorophenyl)ꢀ1,2,4ꢀtriazineꢀ3,5ꢀdiamine and its Intermediate in Presence of Potassium
Ferrocyanide, Phase Transfer Catalyst and Metal Iodide. CN 103833660, March 26, 2014.
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C.; Wang, H.; Chen, Y.; Zhang, D.; Cheng, L.; Zhang, C.; Peng, Y.; Guo, C. Process for
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J.; Bielski, R.; Halpern, M. Process for Making Organic Products and Improving the
Quality of NonꢀProduct Streams using PhaseꢀTransfer Catalysis US 20030158435, 21 Aug
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M. R.; Haase, K.; Ismail, Z. M.; Preftitsi, S.; Weber, A. Chem. Ber. 1982, 115, 3880ꢀ5.
(7) Koenig, K. E.; Weber, W. P. Tet. Lett. 1974, 2275ꢀ2278.
(8) For general catalytic approaches to aroyl cyanide formation using nonꢀCuCN cyanide
sources, see: (a) Li, Z.; Shi, S.; YangGansu, J. Synlett 2006, 2495ꢀ2497. (b) Cao, Y.ꢀQ;
Du, Y.ꢀF.; Chen, B.ꢀH.; Li, J.ꢀT. Synth. Commun. 2004, 34, 2951ꢀ2957.
(9) Grunewald, G. L.; Sall, D. J.; Monn, J. A. J. Med. Chem. 1988, 31, 824ꢀ830.
(10) See Supporting Information for further details.
(11) Chang, Y. S.; Jwo, J.ꢀJ. J. Mol. Cat. A. 2000, 160, 357ꢀ366.
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