Preparation of N-hydroxysuccinimido esters via palladium-catalyzed carbonylation of aryl triflates and halides

Article abstract of DOI:10.1016/S0040-4039(03)00337-X

N-Hydroxysuccinimido esters of aromatic carboxylic acids (a.k.a. active esters) can be made using a potentially general, one-step procedure via Pd-catalyzed carbonylation of an aryl triflate or aryl iodide with CO and N-hydroxysuccinimide. Excellent yields (up to 94%) were observed when the reaction was done in DMSO at 70°C and 1 atmosphere of CO pressure.

Full text of DOI:10.1016/S0040-4039(03)00337-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 2477–2480
Preparation of N-hydroxysuccinimido esters via
palladium-catalyzed carbonylation of aryl triflates and halides
ꢀ
Rongliang Lou,* Melissa VanAlstine, Xufeng Sun and Mark P. Wentland*
Department of Chemistry, Rensselaer Polytechnic Institute, 110 8th Street, Troy, NY 12180, USA
Received 9 January 2003; accepted 3 February 2003
Abstract—N-Hydroxysuccinimido esters of aromatic carboxylic acids (a.k.a. active esters) can be made using a potentially general,
one-step procedure via Pd-catalyzed carbonylation of an aryl triflate or aryl iodide with CO and N-hydroxysuccinimide. Excellent
yields (up to 94%) were observed when the reaction was done in DMSO at 70°C and 1 atmosphere of CO pressure. © 2003
Elsevier Science Ltd. All rights reserved.
1
1
Carboxylic acid esters of N-hydroxysuccinimide (NHS)
have been widely used in organic synthesis as reactive
acylating reagents (a.k.a. active esters). These active
esters are especially useful as intermediates in the syn-
presence of dicyclohexylcarbodiimide or azodicar-
12
boxylate/triphenylphosphine. The reaction of bis(N-
succinimidyl) carbonate with carboxylic acids also
affords the corresponding active esters in high yield.
Additionally, acylation of NHS with mixed anhydrides
1
3
2
thesis of peptides and proteins via N-acylation. In
14
addition, a number of biologically important molecules
has been used.
3
4
such as receptor antagonists, nucleotides and labeling
5
reagents have been chemically modified using N-
However, these methods are limited in their utility if the
required carboxylate is not readily available. Therefore,
we envisioned a process (Scheme 1) whereby an N-
hydroxysuccinimido ester 2 could be made in one-step
from readily available starting materials, namely aryl
triflates or halides (1). Specifically, we wanted to apply
known Pd-catalyzed carbonylation chemistries in a
novel way by reacting the aryl triflate (or halide) with
CO and NHS. Several reports have appeared where
aryl triflates and halides have been converted to aryl
hydroxysuccinimido ester intermediates. More recently,
N-hydroxysuccinimido esters have been used to acylate
6
other nucleophiles such as alcohols and a hydroxyl-
7
amine. Thorough investigations (e.g., mechanism,
scope, preparation) on the chemistry of N-hydroxysuc-
8,9
cinimido esters have been reported.
The classical method for making N-hydroxysuccin-
imido esters involves the reaction of the sodium, potas-
sium, silver or thallium salt of NHS with an acyl
15,16
amides and esters,
however, to our knowledge, we
have not seen this process used to make active esters.
This new method would be very useful in, for example,
1
0
chloride. Other common methods of preparation
involve esterifying a carboxylic acid with NHS in the
Scheme 1.
Keywords: Pd-catalyzed carbonylation; active ester; N-hydroxysuccinimide.
ꢀ
A preliminary account of this work has appeared, see Ref. 1.
*
Corresponding authors. Tel.: +1-518-276-2234; fax: +1-518-276-4887; e-mail: wentmp@rpi.edu
0
040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)00337-X

2
478
R. Lou et al. / Tetrahedron Letters 44 (2003) 2477–2480
the synthesis of series of aryl carboxamide derivatives
from a common carboxylate-containing core intermedi-
ate. We now wish to describe this novel and convenient
method (Scheme 1) for the preparation of N-hydroxy-
succinimido esters 2 of aromatic carboxylic acids
directly from aryl triflates or aryl iodides under Pd-cat-
alyzed carbonylation conditions.
the optimized conditions identified for Ar=2-naphthyl
20
(entry 1), we found that many triflates reacted with
carbon monoxide and NHS smoothly to give rise to the
corresponding esters in very good yields. For example,
variation of the aromatic core to 1-naphthyl or phenyl
provided the corresponding active esters in 88 and 72%
yields, respectively (entries 2 and 3). However, when the
3
-pyridinyl analogue was used in the reaction (entry 4),
1
7
no desired product was obtained with the only isolable
material being 3-pyridinol which we believe results from
cleavage of the triflate ester by NHS.
The triflate ester 3 of 2-naphthol was used as sub-
strate to optimize conditions. As shown in Scheme 2,
we varied the Pd ligand (Xantphos, DPPF, DPPP,
1
8
BINAP, DCPE, and PPh3), solvent (DMSO, DMF,
toluene and dioxane), and stoichiometry while keeping
Pd source [Pd(OAc) ], base (Et N), temperature (70°C),
When the phenyl substrate were substituted with alkyl
groups (entries 5–9), very good yields were observed
2
3
(
66–91%) with the exception of 2-tolyl (entry 7). Here,
and pressure (1 atmosphere CO) constant. For the
conversion of 3 to the corresponding active ester 4, we
observed that an excellent yield of 94% could be real-
the lower yield observed (47%) may be a consequence
of steric congestion in the intermediates or transition
states of the reaction, however, the 1-naphthyl case
1
9
ized using Xantphos (5 mol%) as Pd ligand with a
(
entry 2) gives an excellent result and contradicts this
1
h.
:1.4:1.5 molar ratio of 3:NHS:Et N in DMSO for 17
3
2
0
steric argument. When the phenyl ring was substituted
with heteroatom-containing groups, variable results
were observed. When the 4-MeO-C H substrate (entry
6
4
When Xantphos was replaced with the following well-
known Pd ligands, lower yields for this conversion were
realized: BINAP (32%), DPPF (40%), DPPP (72%),
PPh3 (no reaction up to 10 mol%) or DCPE (no
reaction up to 10 mol%). With the exception of diox-
ane, yields were considerably lower when DMSO was
replaced with the following solvents known to be useful
in Pd catalyzed reactions: DMF (59%), dioxane (90%),
THF (63%), and toluene (61%). The ability of DMSO
to accelerate Pd-catalyzed carbonylation reactions has
1
0) was used, a moderate yield of 57% was obtained.
When electron-withdrawing substituents such as 4-NO2
or 4-Cl were used (entries 11 and 12, respectively),
however, no product was observed. As was seen with
the 3-pyridinyl substrate (entry 4), only the correspond-
ing phenols were evident. However, when the 4-Cl was
combined with a 3-methyl group (entry 13), an 84%
yield was realized. It is apparent that when substrates
contain electron-withdrawing groups (entries 4, 11 and
1
2), cleavage of the triflate ester by a nucleophile which
2
1
been previously reported and sulfoxides are known to
we assume is NHS, competes with carbonylation due to
the excellent leaving group abilities of these phenols.
Sulfurꢀoxygen bond cleavage in the reaction of aryl
fluoroalkanesulfonate with nucleophiles has been
2
2
form a strong complex with Pd(II). The amount of Pd
ligand and molar ratio of 3:NHS:Et N, are also impor-
3
tant determinants to the success of the reaction. For
example, when 2.5 mol% Xanthpos was used versus the
23
reported previously.
2
0
5
mol% in the optimized conditions, the yield of
product decreased from 94 to 80%. Likewise, when the
ratio of 3:NHS:Et N was varied from the optimized
We also studied the effect of variation of the leaving
group by evaluating iodobenzene (entry 14), bromoben-
zene (entry 23) and chlorobenzene (entry 24) as sub-
strates in the reaction. Replacing the triflate of PhOTf
with iodo has a positive effect with the yield increasing
from 72% (entry 3) to 86% (entry 14). However, using
bromine (entry 23) and chlorine (entry 24) as leaving
groups significantly reduced yields (26% and no
product detectable, respectively). When a variety of
functional groups where introduced into iodobenzene,
all substrates evaluated (entries 15–22) gave very good
results with many yields above 90%. In contrast to the
phenyl triflates shown in entries 3, 11 and 12, introduc-
tion of electron-withdrawing groups into iodobenzene is
not detrimental (entries 16–18) to the success of the
reaction. Here, of course, there is no competing triflate
3
1
1
:1.4:1.5 ratio to, for example, 1:1.05:1.2, 1:1.4:3.0 and
:2.5:1.5, the yields decreased to 87, 74, and 51%,
respectively. Lastly, the success of this reaction was not
highly dependent on time, in that TLC showed little
starting material after 5 h and little or no product
decomposition after 24 h.
20
Using these optimized conditions, we studied the
potential generality of the reaction by varying the
nature of the aromatic group (Ar) and leaving group
(
X) of the substrate. Substrates were selected based on
diversity of physicochemical properties and, coinciden-
tally, most substrates and many products are known.
Results are summarized in Table 1. Using X=OTf and
Scheme 2.

R. Lou et al. / Tetrahedron Letters 44 (2003) 2477–2480
2479
a
Table 1. Preparation of N-hydroxysuccinimide esters via Pd-catalyzed carbonylation of aryl triflates and aryl halides
Entry
1c
Ar
X
Yield (%)b
2-Naphthyl
1-Naphthyl
C H
OTf
OTf
OTf
OTf
OTf
OTf
OTf
OTf
OTf
OTf
OTf
OTf
OTf
I
I
I
I
I
I
I
I
I
94
88
72
d
2
e
3
4
5
6
7
8
6
5
e
f
3-Pyridinyl
4-Me-C H
3-Me-C H
2-Me-C H
3,4-Me -C H
5,6,7,8-H -2-Naphthyl
4-MeO-C H
4-NO -C H
4-Cl-C H
ND
g
66
88
47
93
91
57
6
4
e
6
4
4
h
6
i
2 6 3
i
9
4
e
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
6
4
e
e
i
f
ND
ND
2
6
4
f
6
4
4-Cl-3-Me-C H
84
86
85
73
93
90
92
72
61
83
26
NDk
6
3
e
e
e
j
C H
6
5
4-MeO-C H
4-NO -C H
4-CN-C H
4-Cl-C H
2-Me-C H
4-MeO-3-MeOCO-C H
6
4
2
6
4
6
4
e
e
i
6
4
6
4
6
3
e
e
e
3-Pyridinyl
2-Thienyl
C H
Br
Cl
6
5
5
C H
6
a
See Ref. 20.
b
1
Refers to isolated yields after purification by flash column chromatography. Spectroscopic data (IR, H NMR, MS) were in agreement with the
assigned structures.
See Ref. 25 for alternative preparation of product.
See Ref. 26 for alternative preparation of product.
Product is commercially available.
Product formation Not Detectable (ND); only the corresponding phenol was observed in the reaction mixture.
See Ref. 27 for alternative preparation of product.
See Ref. 9 for alternative preparation of product.
New compounds gave satisfactory element analysis.
See Ref. 28 for alternative preparation of product.
c
d
e
f
g
h
i
j
k
Product formation Not Detectable (ND); only decomposition to unidentified by-products was observed.
2
4
cleavage reaction possible. Relative to the correspond-
ing triflates or bromides, we observed that aryl iodides
underwent the Pd-catalyzed carbonylation faster and in
higher yields regardless of the presence of electron-with-
drawing or -donating groups on aromatic rings.
CF SO ) to the palladium(0) complex. A variety of
3 3
functional groups on the aromatic ring of the substrate
including alkyl, Cl, NO , CN, MeO, and MeOCO are
2
tolerated by the reaction conditions used to make these
active esters. The reaction appears to be tolerant to
steric effects imparted by either ortho substitution or
1,8-peri interactions. Heteroaromatic substrates such as
3-pyridinyl and 2-thienyl can be successfully used when
the substrate is an aryl iodide. This new method offers
an attractive and potentially general alternative to
make N-succinimidyl esters of aromatic carboxylic
acids to the more standard procedures starting with
aromatic carboxylic acids or acid halides. Further
investigations to expand the scope and utility of this
and related reactions are currently underway.
In conclusion, we have found that readily available aryl
triflates and aryl iodides can be converted to the corre-
sponding N-hydroxysuccinimido activated esters in
high yields using common and inexpensive reagents
under Pd-catalysis. With respect to the leaving group,
the yield and rate of the reaction follows the rank
order: Aryl iodide > aryl triflate > aryl bromide > aryl
chloride. This is in agreement with reported rates of the
oxidative addition process of CꢀX (X=halo or

2
480
R. Lou et al. / Tetrahedron Letters 44 (2003) 2477–2480
14. Anderson, G. W.; Callahan, F. M.; Zimmerman, J. E. J.
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