A novel solid-phase chlorinating reagent for the synthesis of acyl chlorides

Article abstract of DOI:10.1016/S0040-4039(02)02190-1

Cyanuric chloride was loaded onto a modified Wang resin, which was successfully used to convert carboxylic acids to their corresponding acyl chlorides. The formation of acyl chlorides were confirmed by condensation with various amines or alcohols to form the corresponding amides or esters.

Full text of DOI:10.1016/S0040-4039(02)02190-1

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TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 8909–8912
A novel solid-phase chlorinating reagent for the synthesis of
acyl chlorides
Guanglin Luo,* Li Xu and Graham S. Poindexter
Bristol-Myers Squibb Pharmaceutical Research Institute, Department of Chemistry, 5 Research Parkway, Wallingford,
CT 06492, USA
Received 18 September 2002; accepted 30 September 2002
Abstract—Cyanuric chloride was loaded onto a modified Wang resin, which was successfully used to convert carboxylic acids to
their corresponding acyl chlorides. The formation of acyl chlorides were confirmed by condensation with various amines or
alcohols to form the corresponding amides or esters. © 2002 Elsevier Science Ltd. All rights reserved.
Cyanuric chloride (2,4,6-trichloro[1,3,5]triazine) has
long been used in different organic transformations,
such as dehydration of amides to nitriles,1 deoxygena-
tion of sulfoxides,2 activation of DMSO for the oxida-
tion of alcohols,3 and conversion of acids to acyl
chlorides.4 Some derivatives of cyanuric chloride, espe-
cially the dimethoxy analog (CDMT), have been
employed as mild coupling reagents in the synthesis of
amides with mixed anhydride intermediates.5
We were interested in a resin-bound chlorinating
reagent capable of directly converting various car-
boxylic acids to acyl chlorides. Reasoning that one
equivalent of cyanuric chloride could convert two
equivalents of carboxylic acid to acyl chloride, and that
the intermediate, 2-hydroxyl-4,6-dichloro[1,3,5]triazine,
is still capable of transferring one chlorine,4 we pro-
posed that an oxygen instead of nitrogen linkage should
be able to convert carboxylic acids to acyl chlorides
other than simply serving as an activating group8
(Fig. 1).
Over the last decade, polymer-supported reagents have
found increasing applications in combinatorial, parallel
or even multistep conventional organic synthesis.6 Con-
tinued interest in the development of new solid-phase
reagents7 has greatly facilitated solution phase library
synthesis with simplified purification procedures that
are applicable to robotic protocols.6 Recently, an
amino resin-supported dichlorotriazine group (DCT)
was reported to serve as a good coupling reagent
between carboxylic acids and amines to produce
amides.8 This was the first example of a polymer-sup-
ported cyanuric chloride, which activates a carboxylic
acid through the mixed anhydride intermediate. How-
ever, the amino group linked DCT was not active
enough to directly convert carboxylic acids to the acyl
chlorides, most likely due to the electron-donating abil-
ity of the amino group.
Because of its commercial availability and high loading,
we first examined the Wang benzyl alcohol resin which
has a hydroxy group for attachment of DCT. The
loading of cyanuric chloride went smoothly on shaking
the resin with excess cyanuric chloride and Et3N in
chloroform. Filtration followed by rinsing with solvents
afforded resin 1 (Scheme 1).9 The formation of resin 1
was verified by the disappearance of the hydroxyl IR
stretching frequency (3200–3700 cm−1), as monitored by
single-bead IR (Fig. 2). Further experimental verifica-
tion was provided by elemental analysis of the chlorine
content (Table 1). More importantly, elemental analysis
provided the relative loading amount of cyanuric chlo-
ride on the resin (Table 1).
* Corresponding author. Tel.: +1-203-677-6640; fax: +1-203-677-7702;
e-mail: guanglin.luo@bms.com
Figure 1. Preparation of acyl chlorides through resin-
supported DCT.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02190-1

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G. Luo et al. / Tetrahedron Letters 43 (2002) 8909–8912
Scheme 1. Synthesis of different cyanuric chloride resins.
Figure 2. Single-bead IR (Nicolet Prote´ge´ 460) spectra of various resins. Red: Wang resin; purple: resin 1 (Wang loaded with
DCT); blue: resin 2 (with linker); green: resin 3 (loaded with DCT).
Table 1. Chloride contents of resin 1, 2 and 3a
To our disappointment, conversion of benzoic acid to
benzoyl chloride effected by this resin was sluggish
(only up to 30% conversion as monitored by HPLC) in
either acetone or CH2Cl2, even with a large excess of
resin 1. Longer reaction times of 5 h resulted in the
appearance of side products, presumably due to the
instability of the benzyloxy linker of the resin. The
sluggish reactivity is probably due to proximity and
steric hindrance between the DCT units and the resin.
To circumvent this problem, we intended to place
spacer units between the resin and cyanuric chloride
Chlorine (%)
Loading (mmol/g)
Resin 1
Resin 2
Resin 3
13.45
3.00
20.87
1.9 (DCT)
0.85 (Cl)b
1.96 (DCT)c
a Chloride content varies with different preparations.
b It cannot be ruled out that some DCT were bisaminated thus less
chloride.
c Calculated based on monoamination linker.

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G. Luo et al. / Tetrahedron Letters 43 (2002) 8909–8912
8911
Table 2. Synthesis of amide or ester via acyl chloride intermediate using resin 3
such that the reactive center was positioned further
rides using thionyl or oxalyl chloride, the solid-phase
methodology is odorless, and the handling process is
very convenient since purification can be affected by
simple filtration.
away from the resin surface (Scheme 1). Such an exten-
sion we felt would not only allow greater reactivity but
also serve to protect the labile benzyloxy ether linkage
of the Wang resin.
Direct extension of the spacer from the Wang resin is
probably practicable but resin 1 itself provided a good
starting point since it is a good electrophile. Towards
this end, resin 2 was prepared by shaking resin 1 with
excess 2-(2-aminoethoxy)ethanol. Analysis by single-
bead IR (appearance of the hydroxyl group at 3200–
3700 cm−1) and elemental analysis confirmed the
complete conversion of 1 to 2 (Fig. 2 and Table 1).9
Resin 2 is stable and inert to moisture and could be
stored at room temperature. Resin 2 was further con-
verted to resin 3 by shaking with excess cyanuric chlo-
ride in the presence of Et3N in chloroform.9 Resin 3
was again characterized by IR (disappearance of the
hydroxyl group) and elemental analysis (Fig. 2 and
Table 1).
Acknowledgements
The authors are grateful to Drs. Kevin Gillman and
Rich Dalterio for the assistance in using single-bead IR.
Li Xu, from Cornell University, was supported by a
Summer Internship at Bristol-Myers Squibb.
References
1. (a) Olah, G. A.; Narang, S. C.; Fung, A. P.; Gupta, B. G.
B. Synthesis 1980, 657–658; (b) Maetz, P.; Rodriguez, M.
Tetrahedron Lett. 1997, 38, 4221–4222.
2. Olah, G. A.; Fung, A. P.; Gupta, B. G. B.; Narang, S. C.
Synthesis 1980, 221.
3. Albright, J. D. J. Org. Chem. 1974, 39, 1977–1979.
4. Venkataraman, K.; Wagle, D. R. Tetrahedron Lett. 1979,
20, 3037–3040.
5. (a) Kaminski, Z. J. Synthesis 1987, 917–920; (b) De Luca,
L.; Giacomelli, G.; Taddei, M. J. Org. Chem. 2001, 66,
2534–2537.
We were gratified to find that after benzoic acid was
shaken with resin 3 (3 equiv.) and Et3N in either
CH2Cl2 or acetone for 3 h, benzoyl chloride was formed
in 70–80% conversion without any noticeable side prod-
ucts as monitored by HPLC.10 Encouraged by the
results with resin 3, we prepared a limited series of acyl
chlorides using different carboxylic acids.9 After
removal of the resin by filtration, the acyl chlorides
were converted to their corresponding benzyl amides or
esters for characterization and calculation of the yields
(Table 2).
6. For recent reviews, see: (a) Thompson, L. A. Curr.
Opinion Chem. Biol. 2000, 4, 324–337; (b) Suttleworth, S.
J.; Allin, S. M.; Sharma, P. K. Synthesis 1997, 1217.
7. For some recently developed polymer-supported
reagents, see: (a) Chinchilla, R.; Dodsworth, D. J.;
Najera, C.; Soriano, J. M. Tetrahedron Lett. 2001, 42,
7579–7581; (b) Parang, K.; Fournier, E. J.-L.; Hindsgaul,
O. Org. Lett. 2001, 3, 307–309; (c) Annis, I.; Chen, L.;
Barany, G. J. Am. Chem. Soc. 1998, 120, 7226–7238, (d)
Hon, Y.; Lee, C.; Chen, R.; Szu, P. Tetrahedron 2001, 57,
5991–6001.
8. (a) Masala, S.; Taddei, M. Org. Lett. 1999, 1, 1355–1357;
(b) A recent publication showed a soluble PEG-sup-
ported DCT resin as a scavenger for various nucleophiles.
However, it’s not known if it could effect this transforma-
tion of carboxylic acid to acyl chloride. See: Falchi, A.;
Taddei, M. Org. Lett. 2000, 2, 3429–3431.
From the isolated yields of the amide or ester, it can be
inferred that the yields for the corresponding acyl chlo-
rides are generally around 70–90%. However, a chiral
amino acid was completely racemized under this resin
treatment.
In summary,
a new resin-supported chlorinating
reagent based on cyanuric chloride has been developed
and used in the facile preparation of acyl chlorides.
Compared to the conventional synthesis of acyl chlo-

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8912 G. Luo et al. / Tetrahedron Letters 43 (2002) 8909–8912
9. Synthesis of resin 1: To a suspension of Wang resin (250
(12 mL) was added diisopropylethylamine (0.5 mmol).
After shaking at rt for 18 h, the resin was then filtered,
washed with chloroform (3×5 mL) and THF (3×5 mL),
dried in vacuo and charaterized by IR and elemental
analysis.
Preparation of acyl chlorides: To a suspension of resin 3
(200 mg) in CH2Cl2 was added carboxylic acid (0.3
equiv. based on the loading of resin 3) and Et3N (0.5
equiv.). After shaking at rt for 3 h and monitoring the
reaction by TLC, the resin was then filtered and the
solution of the acyl chloride was directly carried onto the
next reaction.
mg, 1.5–2.0 mmol OH/g) and cyanuric chloride (369 mg,
2.0 mmole) in chloroform (6 mL) was added diisopropyl-
ethylamine (0.5 mmol). After shaking at rt for 18 h, the
resin was then filtered, washed with chloroform (3×3 mL)
and THF (3×3 mL), dried in vacuo and characterized by
IR and elemental analysis.
Synthesis of resin 2: To a solution of 6-amino-1-hexanol
(293 mg, 2.5 mmol) in THF (8 mL), 250 mg of resin 1
was added followed by diisopropylethylamine (0.5
mmol). After shaking at rt for 18 h, the resin was filtered,
washed with THF (5×2 mL), dried in vacuo and charater-
ized by IR and elemental analysis.
10. An analogous resin with a hexyl linker (prepared from
6-amino-1-hexanol) provided similar conversion in
CH2Cl2 while little conversion in acetone.
Synthesis of resin 3: To a suspension of resin 2 (250 mg)
and cyanuric chloride (553 mg, 3.0 mmol) in chloroform