Three step, one-pot process to prepare thiophene-2-carbonyl chloride (TCC), a key raw material in the manufacture of tioxazafen (Nemastrike)

Article abstract of DOI:10.1016/j.tetlet.2019.02.015

Nematodes are parasitic organisms that cause significant damage to crops. Tioxazafen (Nemastrike), is a proprietary seed treatment being developed by Bayer AG as a broad-spectrum nematicide. Thiophene-2-carbonyl chloride (TCC) is the key raw material in the manufacture of tioxazafen. Current manufacturing routes to TCC suffer from byproduct formation and significant waste generation, which leads to high manufacturing cost. A potentially more cost-effective process for preparing TCC from commercial thiophene has been developed. The advantages of this new chemical approach are illustrated in the processing details described in this Letter.

Full text of DOI:10.1016/j.tetlet.2019.02.015

Accepted Manuscript
Three step, one-pot process to prepare thiophene-2-carbonyl chloride (TCC), a
key raw material in the manufacture of tioxazafen (Nemastrike ® )
Daniel P. Walker, Charles R. Graham, William H. Miller, Kevin J. Koeller
PII:
S0040-4039(19)30136-4
https://doi.org/10.1016/j.tetlet.2019.02.015
TETL 50609
DOI:
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
9 January 2019
2 February 2019
7 February 2019
Please cite this article as: Walker, D.P., Graham, C.R., Miller, W.H., Koeller, K.J., Three step, one-pot process to
prepare thiophene-2-carbonyl chloride (TCC), a key raw material in the manufacture of tioxazafen (Nemastrike® ),
Tetrahedron Letters (2019), doi: https://doi.org/10.1016/j.tetlet.2019.02.015
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers
we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and
review of the resulting proof before it is published in its final form. Please note that during the production process
errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Corresponding author. Tel.: 1 314 694 2675; fax: 1 314 694 1259
E-mail address: daniel.walker@bayer.com (D.P. Walker).
Graphical Abstract
To create your abstract, type over the instructions in the template box below.
Fonts or abstract dimensions should not be changed or altered.
Three step, one-pot process to prepare
thiophene-2-carbonyl chloride (TCC), a key
raw material in the synthesis of tioxazafen
(Nemastrike®)
Leave this area blank for abstract info.
Daniel P. Walker*, Charles R. Graham, William H. Miller, Kevin J. Koeller

1
Tetrahedron Letters
Three step, one-pot process to prepare thiophene-2-carbonyl chloride (TCC), a key
raw material in the manufacture of tioxazafen (Nemastrike®)
Daniel P. Walker1, Charles R. Graham, William H. Miller, Kevin J. Koeller
Bayer AG, Crop Science Division, 800 N. Lindbergh Blvd, St. Louis, MO 63167
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Nematodes are parasitic organisms that cause significant damage to crops. Tioxazafen
(Nemastrike®), is a proprietary seed treatment being developed by Bayer AG as a broad-
spectrum nematicide. Thiophene-2-carbonyl chloride (TCC) is the key raw material in the
manufacture of tioxazafen. Current manufacturing routes to TCC suffer from byproduct
formation and significant waste generation, which leads to high manufacturing cost. A
potentially more cost-effective process for preparing TCC from commercial thiophene has been
developed. The advantages of this new chemical approach are illustrated in the processing
details described in this Letter.
Available online
2009 Elsevier Ltd. All rights reserved.
,
Keywords:
thiophene
tioxazafen
acylation
chlorosulfonyl isocyanate (CSI)
Introduction
Nematodes are active, flexible, elongated organisms that live
on moist surfaces or in aquatic environments, including films of
water within soil and moist tissues within other organisms. Many
species of nematodes have evolved to be very successful
parasites of plants and animals and, as a result, are responsible
for significant economic losses in agriculture and livestock.
Tioxazafen, the active ingredient in Nemastrike®, is a proprietary
seed treatment being developed by Bayer Crop Science for the
control of nematodes in corn and soy.[1] The synthesis of
tioxazafen utilizes thiophene-2-carbonyl chloride (TCC) as a key
raw material (Scheme 1).[2]
Scheme 1. Synthesis of tioxazafen. Reagents and conditions: (a)
NH2OH•HCl, MeOH, 50% aq. NaOH, 60 °C, 2h, (b) 50% aq. NaOH,
Bu4N+OH- (cat.), 2-MeTHF-water, 70 °C, 1 h.
Currently, TCC is manufactured by two different processes:
The Aldehyde Process and the Acetyl Process (Scheme 2). Both
processes rely on chlorination of a common intermediate,
thiophene-2-carboxylic acid (TCA), as a final step. In the
Aldehyde Process, TCA is prepared via a Vilsmeier-Haack
formylation of thiophene,[3] followed by oxidation of the
corresponding aldehyde (TCAL) using modified Pinnick[4]
conditions. In the Acetyl Process, TCA is prepared via
acetylation[5]a of thiophene, followed by subjecting the product,
Both processes produce TCC in reasonable overall yield (60-
65%). Also, both processes utilize inexpensive reagents and can
be used to generate large volumes of TCC. However, there are
drawbacks associated with each of these processes. For the
Aldehyde Process, the formylation step requires an aqueous
workup to hydrolyze the initially formed iminium ion, followed
by a distillation of the aldehyde to separate byproducts. In
addition, the oxidation step generates sodium hypochlorite as a
byproduct that must be scavenged. While effective scavengers do
exist, small quantities of chlorinated thiophenes are still
2-acetylthiophene (AcT), to a haloform reaction.Error! Bookmark not
defined.b
generated, leading to impurity issues. For the Acetyl Process, a 2-
3-fold excess of acetic anhydride is required for the acetylation,

2
Tetrahedron
and the oxidation step generates an organic byproduct
60%
(chloroform) of similar mass to the desired product (TCA),
which creates environmental and waste disposal concerns. The
Acetyl Process also suffers from ring-chlorinated byproducts. In
both processes, the above issues add significantly to the overall
manufacturing cost of TCC. The commercial success of any
agricultural product highly depends on achieving a low cost of
goods. In our hands, the existing routes were expensive and did
not offer a clear path to lowering the cost of TCC; hence, we
became interested in developing a new process to prepare this
material. We detail below our efforts to develop a commercially
viable and lower cost process to prepare TCC.[6]
50%
40%
30%
20%
10%
0%
In Toluene
in MTBE
in DnBE
in MeTHF
in Water
30
40
50
60
70
80
90
Temperature, o
C
Figure 1. Solubility of TCA in various solvents.
Armed with these earlier studies, our first task in developing a
new TCC process was to identify a suitable solvent replacement
for ether-benzene used in Graf’s original procedure. Ether and
benzene were not acceptable solvents in our process due to their
flammability and toxicity, respectively. Furthermore, in choosing
a solvent, we envisioned a telescoped process wherein a single
solvent would be utilized in CSI adduct formation, hydrolysis
and chlorination steps. Telescoping reactions can offer
tremendous cost savings, and it is an important aspect of green
chemistry.[16] Besides the above flammability and toxicity
concerns, the best solvent would promote the desired chemistry,
be non-reactive, readily available and easy to recycle. In
addition, it would be beneficial if the solvent was inexpensive,
possessed low water solubility and formed a water azeotrope.[17]
Based on these criteria, we identified four test solvents for our
process, 2-methyltetrahydrofuran (2-MeTHF), methyl tert-butyl
ether (MTBE), toluene and di-n-butyl ether (DnBE).[18] Before
screening these solvents in the process, we determined the
solubility of TCA, the precursor to TCC, in each solvent. Prior
to chlorination, an aqueous-organic phase separation needed to
take place. To avoid any loss, TCA would need to be completely
dissolved in solution at the time of the phase separation.
Preliminary tests showed that TCA had limited solubility in
some of the solvents; hence, a TCA solubility curve was
generated for each solvent (Figure 1). TCA showed similar
solubility properties in DnBE and toluene, whereas TCA was
significantly more soluble in both MTBE and 2-MeTHF at all
temperatures. Higher solubility would lead to higher payloads,
which was attractive from an economic standpoint. Nonetheless,
at 50 °C, TCA showed at least 10 wt% solubility in each solvent,
which was acceptable for our process.
Scheme 2. Industrial syntheses of TCC. Reagents and conditions, Aldehyde
Process: (a) DMF, POCl3, <40 °C, 1 h; add thiophene, 100 °C, 20 h; (b)
NaClO2, 35% aq. H2O2, NaH2PO4, acetonitrile-water, <10 °C, 1 h; Acetyl
Process: (c) Ac2O (3.0 equiv.), H3PO4 (cat.), 60→100 °C, 3 h; (d) NaOCl, aq.
NaOH, 55-70 °C, 3 h; (e) SOCl2, DMF (cat.), 60 °C, 2 h; distillation.
Results and Discussion:
While searching for a new process to prepare TCC, we came
across a report by Graf[7] who showed that thiophene reacts in a
highly regio-selective[8] manner with chlorosulfonyl isocyanate
(CSI)[9],[10] without a catalyst to afford adduct 1 in high yield
(Scheme 3). While we could find no specific examples for the
direct conversion of adduct 1 into TCA, there was literature
precedent for the acidic[11] hydrolysis of an N-chlorosulfonyl
amide to the corresponding carboxylic acid.[12] Indeed, when
adduct 1 was subjected to aqueous mineral acids, TCA was
produced in high yield (vide infra). Based on these findings, the
reaction sequence in Scheme 3 became of interest to us because
adduct 1 is in the same oxidation state as TCA, thus, avoiding the
costly oxidation step needed in the current Aldehyde and Acetyl
manufacturing processes. Although CSI itself does not possess
good atom economy as only two of the seven atoms of CSI get
incorporated into the product, the overall atom economy of
preparing TCC from thiophene utilizing CSI is 30%, which is
surprisingly better than either the Aldehyde Process (26%) or the
Acetyl Process (22%).[13] Also, while CSI is more expensive
than either acetic anhydride (Acetyl Process) or the combination
of N,N-dimethylformamide and phosphorus oxychloride
Solvent
MTBE
Stability Toward CSI
Reacts with CSI
Comments
Low conversion to 1 due to
reaction with solvent
(Aldehyde Process), reagent cost can be secondary to operational
costs in the overall manufacturing process.[14],[15]
2-MeTHF
Reacts with CSI
ca. 20% thiophene unreacted
due to CSI reaction with solvent
Low conversion to 1
toluene
DnBE
Stable to CSI
Stable to CSI
High conversion to 1
Table 1. Reaction of thiophene with CSI in various solvents.
We next tested each solvent for its ability to promote the
formation of adduct 1 (Table 1). MTBE reacted vigorously with
CSI,[19] so it was eliminated. Initial studies showed that
2-MeTHF was stable towards CSI, even at 60 °C. However, after
hydrolysis of 1, analysis of crude TCA revealed that it was
contaminated with byproducts stemming from tetrahydrofuran
ring opening.[20] Thus, 2-MeTHF was also eliminated. While
toluene was stable towards CSI, it was a poor solvent for
promoting the formation of adduct 1. After several hours, there
Scheme 3. Graf’s preparation of adduct 1.

3
was essentially no reaction between thiophene and CSI; only
after adding 20% DnBE did the reaction initiate. Still, after 24h,
only about 70% of 1 had formed, and heating the reaction did not
improve the outcome. Fortunately, DnBE showed good stability
towards CSI,[21] and it promoted complete consumption of
thiophene.
CSI Addition
Continuous or 1/3
+ 2/3 Delay
Ratio of
adduct 1 to
adduct 2
Addition
Protocol
Temp.
(°C)
Entrya
1b
2
Normal
Normal
Normal
Inverse
Normal
Inverse
delay
35→50 12:1
continuous
continuous
continuous
delay
50
80
50
4:1
4:1
4:1
3
4c
5
6d
35→65 9:1
35→65 9:1
delay
Table 2. Conditions for the formation of adduct 1. (a) Unless otherwise
noted, reactions consisted of mixing thiophene (1.0 equiv.) with CSI (1.05
equiv.) in Bu2O; (b) Graf’s original conditions using ether-benzene; (c) A
significant induction period was observed prior to reaction initiation; (d) Only
84% of thiophene was converted to products.
Scheme 4. Unoptimized process to prepare TCC from thiophene. Reagents
and conditions: (a) ClSO2NCO, Bu2O, 50 °C, 2 h; (b) 20% aq. H2SO4, Bu2O,
40 °C, 30 min; 100 °C, 12 h; (c) separate aqueous and organic layers, 60 °C;
wash aqueous layer with Bu2O (2x) (d) azeotropic distillation, 50 °C, 25 mm
Hg; (e) SOCl2, DMF (cat.), Bu2O, 65 °C, 2h; (f) distillation (5-25 mm Hg, 40-
65 °C vapor).
Prior to addressing the nitrile impurity in TCC, we focused
our attention on minimizing the formation of adduct 2 (Table 2).
The absence of compound 6 suggested that adduct 2 was formed
directly from adduct 1. Attempting to suppress the formation of
2, we minimized the concentration of available thiophene via an
inverse addition[27] protocol (i.e., adding thiophene to CSI,
Entry 4). Surprisingly, this procedure produced the same amount
of adduct 2 as the normal addition. Furthermore, unlike the
normal addition, the inverse addition had a long induction period
where most of the thiophene had been added prior to initiation,
which may explain why the adduct ratio did not change. Adding
the CSI at different reaction temperatures did not affect the ratio.
At this point, we suspected that the role of benzene in Graf’s
original conditions was to lower the solvent polarity to help
facilitate the precipitation of adduct 1 as it forms, which would
minimize its susceptibility to further reaction with thiophene.
Indeed, repeating Graf’s conditions afforded an improved 12:1
ratio of adducts 1 and 2 (Entry 1). Nonetheless, aside from the
concerns stated earlier on using ether-benzene (vide supra), this
reaction was not scalable due to the formation of thick mixtures
that were difficult to stir. However, by applying Graf’s addition
protocol to our process using DnBE solvent, we were able
minimize the formation of adduct 2. Thus, rapid treatment of a
solution of thiophene in DnBE with 1/3 of the CSI charge,
followed by a slow addition of the remaining CSI charge led to
an 9:1 ratio of adducts 1 and 2 (Entry 5). The improved ratio was
likely due to partial precipitation of adduct 1, which began to
occur after the initial 1/3 CSI charge was added. In this case, the
resulting DnBE slurry did not become too thick as to adversely
affect stirring. While inverse addition coupled with slow addition
also decreased the formation of adduct 2, the conversion of
thiophene was only 84% (Entry 6).
Having selected DnBE as the preferred solvent, we evaluated
it in our telescoped process (Scheme 4). Toward this end,
treatment of a DnBE solution of thiophene with CSI resulted in
the formation of desired adduct 1 and an unknown byproduct in a
4:1 ratio. The structure of the byproduct was confirmed by
LCMS and 1H NMR spectroscopy as adduct 2 resulting from the
addition of a second molecule of thiophene to adduct 1. The
solution of adducts 1 and 2 was directly subjected to hydrolysis
conditions, which afforded a mixture of five products [TCA
(80%), TCAm (4%), 2(10%), 3 (1%) and 4 (5%)]. The numbers
in parentheses indicate the HPLC area percentages of each
compound. The structures of compounds 3 and 4 were confirmed
by LCMS and presumably were hydrolysis byproducts originated
from adduct 2.[22] Due to the limited solubility of TCA in
DnBE, separation of the organic and aqueous layers was carried
out at 60 °C, which avoided precipitation of TCA. On a
laboratory scale, the heated separation was conveniently carried
out by running the reaction in a jacketed reactor containing a
bottom drain. Initially, there was some concern that at the
elevated temperature significant amounts of TCA would be lost
to the aqueous layer. However, as shown in Figure 1, TCA has
low aqueous solubility up to 70 °C. After two washes with DnBE,
the aqueous layer contained less than 2 wt% of TCA. The
organic layer was azeotropically dried by distilling a portion of
the DnBE.[23],[24] The chlorination of TCA was accomplished
using thionyl chloride and a catalytic amount of DMF,[25],[26]
followed by subsequent distillation. Analysis of our distilled
TCC showed that it was 97% pure and contained a major
byproduct in 2.7%. The structure of the impurity was confirmed
by GCMS and 1H NMR spectroscopy as 2-thiophenecarbonitrile
(5, Scheme 4). Also, the overall yield of TCC by our new
process was 40%, which was lower than the existing TCC
manufacturing processes. Nonetheless, we were confident that
the overall yield would improve as the impurities, such as adduct
2 and nitrile 5, were minimized.
We next focused our attention on minimizing nitrile 5 in
distilled TCC. Due to the similarities in boiling points of 5 (192
°C) and TCC (206 °C), separation of the two compounds by
distillation was going to be challenging and would likely add to
the overall cost of TCC. Hence, the formation of nitrile 5 needed
to be minimized, which necessitated an understanding of how 5
was being formed in the process. Upon closer inspection of the
impurity profiles in crude TCA versus crude TCC, nitrile 5
appeared to be formed from TCAm and adduct 2 during the
chlorination step (Scheme 4). A quick check of the literature
showed that both carboxamides as well as sulfonylamides can be
easily converted into nitriles using thionyl chloride on closely

4
Tetrahedron
related systems.[28],[29] The presence of both TCAm and
the amount of remaining TCAm was significantly reduced in the
optimized process, which lowered the formation of nitrile 5 in
distilled TCC from 2.7% to less than 0.4% (Table 3). The overall
reduction in byproducts improved the overall yield of TCC from
40% to 64%. Finally, the overall purity of TCC improved from
97% to >99%.
adduct 2 in the chlorination step was a direct result of incomplete
hydrolysis in the prior step. With respect to TCAm, our initial
hydrolysis conditions called for heating the mixture to 100 °C in
the presence of 20% aqueous sulfuric acid (Scheme 4). After 6
hours, typically 3-5% TCAm remained. Additional heating did
slowly convert more TCAm into TCA; however, the actual yield
of TCA dropped due to the formation of other impurities.
Fortunately, switching to 18% aqueous hydrochloric acid resulted
in >99.8% hydrolysis of TCAm in 8 hours. A scatterplot of the
conversion of TCAm over time illustrates how hydrochloric acid
is more efficient than sulfuric acid in catalyzing the hydrolysis of
TCAm (Figure 2). Hydrochloric acid was also more efficient at
hydrolyzing adduct 2. After 8 hours <1% of 2 remained versus
3.4% using sulfuric acid.
%
%
%
TCC
97
Process
%2 %3
%4
%5
TCA TCAm
80
Unoptimizeda
Optimizedb
4
10
0.5
5
2.7
0.4
96
<0.1
1.2
<0.1
1.7
>99
Table 3. HPLC analysis of product (TCA) and byproducts in the DnBE layer
following acidic hydrolysis of adducts 2 and 3, and GC-FID analysis of
product (TCC) and byproduct 5 following distillation of crude TCC.
Numbers refer to area percentages. (a) Refer to conditions described in
Scheme 4; (b) Refer to conditions described in Scheme 5.
120
100
in 20% aq. sulfuric acid
In summary, we have developed a new process for preparing
TCC, the key raw material in the manufacture of tioxazafen. The
new process avoids an oxidation step, a costly component of the
existing TCC manufacturing routes, and our process features a
fully telescoped process, which is not feasible in the current
manufacturing processes. The telescoped process minimizes
solvent usage and in-line processing, resulting in a lower cost
process. Furthermore, our process prepares TCC in similar yield
and purity to the existing manufacturing routes.
80
60
in 18% aq. hydrochloric acid
40
20
0
0
1
2
3
4
5
6
7
Time (h)
Acknowledgment
Figure 2. Hydrolysis of thiophene-2-carboxamide (TCAm) in Bu2O-aq.
mineral acid (1:2, vol/vol) at 100 °C.
We thank Wensheng Li for analytical support. We thank Bayer
Crop Science St. Louis Chemistry Leadership for encouraging
the publication of this work.
Supplementary data
Supplementary data (experimental procedures and
characterization data for new compound 2) associated with this
article can be found, in the on-line version, at:
Scheme 5. Optimized telescoped process for preparing TCC from thiophene.
Reagents and conditions: (a) ClSO2NCO (0.33 equiv.), Bu2O, 35 °C, 15 min;
ClSO2NCO (0.67 equiv.) dropwise, 35→50 °C, 1 h; 50 °C, 3 h (b) 10% aq.
HCl (2.7 equiv.), 20 °C; (c) 100 °C, 7 h; (d) Separate organic and aqueous
layers, 60 °C; wash aqueous layer with Bu2O (2x), 60 °C; (e) azeotropic
distillation, 50 °C, 25 mm Hg; (f) SOCl2 (1.15 equiv.), DMF (cat.), 65 °C, 1 h;
(g) fractional distillation, 30 mm Hg, 40-45 °C vapor (DnBE); 5 mm Hg, 55-
65 °C (TCC). 1Assayed via the corresponding methanesulfonyl derivative.
Scheme 5 illustrates our telescoped process after
implementing the above process improvements. Following the
hydrolysis step, the organic and aqueous layers were separated,
and the organic layer was washed twice with DnBE.[30] Table 3
shows HPLC area percentages of TCA and byproducts in the
DnBE layer for our unoptimized and optimized processes. The
amount of adduct 2 and its corresponding hydrolysis products (3
and 4) were significantly reduced in the optimized process. Also,

5
References and notes
[20]
GCMS and GC-FID analysis of crude TCA showed
that it was contaminated with a mixture of chloropentene
isomers (25wt%), which are ring-opened byproducts of
2-MeTHF. Further analysis demonstrated that ring opening
occurred during the CSI addition step.
References
[1]
(a) Slomczynska, U. J.; Dimmic, M. W.; Haakenson,
W. P., jr.; Wideman, A. S. US Patent 9,051,309, June 9th,
2015; (b) Slomczynska, U.; South, M. S.; Bunkers, G.;
Edgecomb, D.; Wyse-Pester, D.; Selness, S.; Ding, Y.;
Christiansen, J.; Ediger, K.; Miller, W.; Charumilind, P.;
Hartmann, G.; Williams, J.; Dimmic, M.; Shortt, B.;
Haakenson, W.; Wideman, A:; Crawford, M.; Hresko, M.;
McCarter, J. 248th ACS National Meeting & Exposition, San
Francisco, CA, United States, August 10–14, 2014 (2014),
AGRO-39.
[21]
Analysis by GCMS of the TCC distilling bottoms
showed 1% of butyl thiophene-2-carboxylate, which indicated
that a small amount of DnBE solvent had degraded during the
process.
[22]
It was later confirmed that under the stated
hydrolysis conditions, adduct 2 is hydrolyzed into TCA and
sulfonamide 4, with only a small (1-2%) amount of 2 being
hydrolyzed into TCAm and sulfonic acid 3.
DnBE (bp 143 °C) possesses a 33% water azeotrope
[2]
(a) Miller, W. H.; Graham, C. R.; Brown, D. L. US
[23]
Patent 9,040,711, May 26th, 2015; (b) Miller, W. H.; Graham,
C. R.; Brown, D. L. US Patent 9,273,037, March 1st, 2016.
at 93 °C, see: Horsley L. In Azeotropic Data, 3rd ed.; Gould,
R. F. Ed.; Advances in Chemistry Series; American Chemical
Society: Washington, D.C., 1973; 116, p. 37.
[3]
Weston, A. W. US Patent 2,853,493, September 23rd,
Water solubility in DnBE at 25 °C = 0.14% (w/w) as
1958.
[4]
[24]
Dalcanale, E. J. Org. Chem. 1986, 51, 567.
measured by a Metrohm 831 KF Coulometer.
We were aware of a report by Levin (see Ref. 26),
[5]
(a) Hartough, H. D.; Kosak, A. I. J. Am. Chem. Soc.
[25]
1947, 69, 3093; (b) Hartough, H. D.; Coney, L. G. J. Am.
Chem. Soc. 1947, 69, 3096.
who pointed out that thionyl chloride and DMF can form N,N-
dimethylcarbamoyl chloride (DMCC), a known animal toxin.
However, in our process, which used 0.0005 equiv. of DMF,
DMCC was not present in crude or distilled TCC at the limits
of our GC (FID) detector (10 ppm based on a minimum S/N
=3).
[6]
Walker, D. P.; Miller, W. H. Patent Cooperation
Treaty WO 2016/161063, October 6th, 2016.
(a) Graf. R. Justus Liebigs Ann. Chem. 1963, 661,
[7]
111; (b) Gronowitz, S.; Liljefors, S. Acta. Chem. Scand. 1977,
B31, 771.
[26]
Levin, D. Org. Proc. Res. Dev. 1997, 1, 182.
[8]
GC (FID) analysis of crude TCC, prepared
according to Scheme 4, showed it contained <0.1% 3-TCC.
Chlorosulfonyl isocyanate (CSI) is prepared by
[27]
Cf: Floyd, A. J.; Kinsman, R. G.; Roshan-Ali, Y.;
Brown, D. W. Tetrahedron 1983, 39, 3881.
Cf: Zhang, S.-L; Damu, G. L. V.; Zhang, L.; Geng,
R.-X.; Zhou, C.-H. Eur. J. Med. Chem. 2012, 55, 164.
Cf: Mostowicz, D.; Zegrocka, O.; Chmielewski, M.
Carbohydr. Res. 1991, 212, 283.
[9]
[28]
[29]
mixing cyanogen chloride with an equal amount of sulfur
trioxide, and it is readily available in large quantities from
several suppliers.
[10]
For a general review on the chemistry of CSI: see,
Dhar, D. N.; Keshava Murthy, K. S. Synthesis, 1986, 437.
Basic hydrolysis was less attractive to us in that the
[30]
The aqueous layer, after washing twice with DnBE,
contained 1.6 wt% of TCA and 7.1 wt% of sulfonamide 4.
[11]
resulting carboxylate salt of TCA would have to be re-
acidified prior to TCC formation, which would generate
additional inorganic salt waste.
[12]
Vebrel, J.; Carrié, R. Bull. Soc. Chim. Fr., Pt. 2
1982, 3-4, 116.
[13]
(a) Trost, B. M. Science 1991, 254, 1471; (b)
Constable, D.J.C.; Curzons, A.D.; Cunningham, V.L. Green
Chem. 2002, 4, 521.
[14]
Anderson, N. G. Practical Process Research &
Development; Acedemic Press: New York, 2012, pp. 72-75.
Initial cost estimates on the CSI route showed that
[15]
the higher cost of CSI was recouped by avoiding the oxidation
step needed in the existing industrial processes.
[16]
Anderson, N. G. Practical Process Research &
Development; Acedemic Press: New York, 2012, pp. 80, 290.
The solvent is contacted with water during the
[17]
hydrolysis step, and it would need to be dried prior to the
chlorination step. Azeotropic removal of water is a convenient
and effective method for solvent drying on large scale.
[18]
DnBE is a low-cost industrial solvent that is used as
an alternative to THF due to its lower flammability, lower
water solubility and lower rate of peroxide formation.
[19]
Adding CSI to MTBE solvent caused a vigorous
reaction to take place with significant gas evolution,
presumably isobutylene.

6
Tetrahedron
Highlights:
(1) Thiophene-2-carbonyl chloride (TCC) can be
prepared in three steps from CSI.
(2) TCC can be prepared without the need of an
expensive oxidation step.
(3) TCC can be prepared in >99% purity using CSI.