Acylation of N-p-toluenesulfonylpyrrole under Friedel-Crafts conditions: evidence for organoaluminum intermediates

Article abstract of DOI:10.1016/j.tet.2007.12.043

The Friedel-Crafts acylation of N-p-toluenesulfonylpyrrole under Friedel-Crafts conditions has been reinvestigated. Evidence is presented in support of the hypothesis that when AlCl₃ is used as the Lewis acid, acylation proceeds via reaction of

Full text of DOI:10.1016/j.tet.2007.12.043

Available online at www.sciencedirect.com
Tetrahedron 64 (2008) 2104e2112
www.elsevier.com/locate/tet
Acylation of N-p-toluenesulfonylpyrrole under FriedeleCrafts
conditions: evidence for organoaluminum intermediates
*
John W. Huffman , Valerie J. Smith, Lea W. Padgett
Department of Chemistry, Clemson University, Clemson, SC 29634-0973, United States
Received 8 November 2007; received in revised form 13 December 2007; accepted 14 December 2007
Available online 23 December 2007
Abstract
The FriedeleCrafts acylation of N-p-toluenesulfonylpyrrole under FriedeleCrafts conditions has been reinvestigated. Evidence is presented
in support of the hypothesis that when AlCl3 is used as the Lewis acid, acylation proceeds via reaction of an organoaluminum intermediate with
the acyl halide. This leads to the production of the 3-acyl derivative as the major product. With weaker Lewis acids (EtAlCl2, Et2AlCl) or less
than 1 equiv of AlCl3 the relative amount of 2-acyl product is increased. A mechanistic rationalization is presented to explain these data.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Acylpyrrole; Organoaluminum intermediates; FriedeleCrafts reaction; Reaction mechanism
1. Introduction
etherate produces the 2-isomer as the major product.4b Also,
FriedeleCrafts alkylation of N-benzenesulfonylpyrrole using
tert-butyl chloride gave an excellent yield of the 3-isomer, while
isopropyl chloride under the same conditions gave a mixture of
2- and 3-isomer.3b Kakushima et al. considered several possible
explanations for the regiochemistry observed in the acylation of
N-benzenesulfonylpyrrole including initial acylation at C-2 fol-
lowed by rearrangement to the 3-isomer and steric or electronic
effects.4b Evidence was presented that the observed regiochemi-
stry could be explained neither by rearrangement of a 2-sub-
stitued compound nor by steric effects. It was suggested that
with AlCl3 charge control prevailed to give 3-acylation via
a highly polarized species formed by interaction of the Lewis
acid with acyl chloride. With weaker Lewis acids, a less polari-
zed species reacts by orbital control to provide the 2-acyl com-
pound as the major product. Although the authors favored
this hypothesis over the others they stated that none of these
explanations is completely consistent with their experimental
results.
It has been known for many years that electrophilic substi-
tution reactions of pyrrole and many substituted pyrroles occur
predominantly at the 2-position.1 Historically, in order to pre-
pare 3-substituted pyrrole derivatives, a variety of multi-step
indirect syntheses were employed. However, in work carried
out in 1980s, it was found that an easily removable bulky
nitrogen substituent, triisopropylsilyl1,2 or, alternatively, an
N-benzenesulfonyl group1,3,4 provided acylation primarily at
the 3-position of the N-substituted pyrrole under Friedele
Crafts conditions.
The regioselectivity observed in the case of N-triisopropyl-
silylpyrrole was attributed to steric hindrance at the pyrrole
2-position,2b however, the reactions of N-benzenesulfonylpyr-
role are less straightforward than those of N-triisopropylsilyl-
pyrrole.1,3,4 In particular, while acylation under FriedeleCrafts
conditions using relatively simple acyl halides with AlCl3 pro-
duces the 3-acyl compound with good regioselectivity,3,4 the
use of weaker Lewis acids, such as SnCl4 or boron trifluoride
Several years ago, we reported the synthesis and pharma-
cology of a series of cannabimimetic 1-alkyl-3-(1-naphthoyl)-
pyrroles (1, R¼n-C3H7 to n-C7H15).5 Based upon the
assumption that cannabimimetic pyrroles interact with the
CB1 receptor by aromatic stacking in a manner similar to
* Corresponding author. Tel.: þ1 864 656 3133; fax: þ1 864 656 6613.
E-mail address: huffman@clemson.edu (J.W. Huffman).
0040-4020/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.12.043

J.W. Huffman et al. / Tetrahedron 64 (2008) 2104e2112
2105
indoles and indenes,6 it was concluded that the addition of an-
other aromatic substituent to naphthoylpyrroles 1 could lead
to compounds with increased receptor affinity. Accordingly,
the synthesis of a series of 1-alkyl-2-aryl-4-(1-naphthoyl)-
pyrroles (2, Ar¼phenyl and substituted aryl, R¼n-alkyl) was
carried out.7 The initial synthetic approach to these com-
pounds included as a key step the FriedeleCrafts acylation
of an N-p-toluenesulfonyl-2-arylpyrrole, which was success-
fully applied to the synthesis of N-p-toluenesulfonyl-
2-phenyl-4-(1-naphthoyl)pyrrole (2, Ar¼C6H5, R¼Ts) by the
AlCl3 catalyzed reaction of 1-naphthoyl chloride with N-p-tol-
uenesulfonyl-2-phenylpyrrole (3, Ar¼C6H5) under standard
FriedeleCrafts conditions in which the substrate is added to
a mixture of AlCl3 and the acyl halide. These conditions are
similar to those of reaction conditions A (see Section 5) in
which the acyl chloride is stirred with the catalyst and the sub-
strate is then added.
approximately equal amounts of N-p-toluenesulfonyl-2-phe-
nyl-4-(1-naphthoyl)pyrrole (2, Ar¼C6H5, R¼Ts) and N-p-tol-
uenesulfonyl-2-phenyl-5-(1-naphthoyl)pyrrole (4, Ar¼C6H5).
Under conditions B with AlCl3 catalysis, reaction of pyrrole
3 (Ar¼C6H5) with 1-naphthoyl chloride gave a 9:1 mixture
of the 2,4-isomer (2, Ar¼C6H5, R¼Ts) and the 2,5-isomer
(4, Ar¼C6H5). The 1H NMR spectrum of pyrrole 2 (Ar¼C6H5,
R¼Ts) shows one of the pyrrole protons as a doublet
(J¼1.8 Hz) at d 6.72. The other pyrrole proton is obscured
by the peaks due to the naphthoyl and toluenesulfonyl protons.
The structures of pyrroles 2 (Ar¼C6H5, R¼Ts) and 4
(Ar¼C6H4OCH3) were confirmed by X-ray crystallography.12
In our synthesis of N-alkylpyrroles 1, it was found that the
AlCl3 catalyzed FriedeleCrafts reaction of N-p-toluenesulfo-
nylpyrrole with 1-naphthoyl chloride in dichloromethane
gave mixtures of N-p-toluenesulfonyl-3-(1-naphthoyl)pyrrole
(1, R¼Ts) and N-p-toluenesulfonyl-2-(1-naphthoyl)pyrrole
(5) with ratios of 3-acylpyrrole to the 2-isomer ranging from
2:1 to 4:3.5,13 These acylations were carried out under condi-
tions essentially identical to procedure A using 1.2 equiv of
AlCl3 and 1.2 equiv of 1-naphthoyl chloride, however, the re-
actions were carried out at ambient temperature rather than
0 ꢀC. Acylation with 1-naphthoyl chloride in 1,2-dichloroeth-
ane again provided a mixture of the 2- and 3-isomer. These
results contrast with those of other workers described above
and those of Sattambolo et al.3,4,14 We were unable to explain
neither these variable results nor the acylation experiments us-
ing N-p-toluenesulfonylpyrroles 3 (Ar¼C6H5 and C6H4OCH3)
and a systematic reinvestigation of the acylation reactions of
N-p-toluenesulfonylpyrrole was undertaken.
O
O
Ar
N
R
N
R
1
2
Ar
Ar
N
N
O
Ts
Ts
3
4
N
2. Results
O
Ts
5
Initially, the effects of solvent and concentration upon the
course of the AlCl3 catalyzed acylation of N-p-toluenesulfo-
nylpyrrole with 1-naphthoyl chloride under standard Friedele
Crafts conditions (method A) were investigated. The results of
these experiments are summarized in Table 1 and show that in
both dichloromethane and 1,2-dichloroethane, N-(p-toluene-
sulfonyl)-3-(1-naphthoyl)pyrrole (1, R¼Ts) comprised at least
98% of the product mixture. The use of chloroform as the
reaction solvent increased the amount of the 2-(1-naphthoyl)
When this approach was extended to the AlCl3 catalyzed
reaction of 1-naphthoyl chloride with N-p-toluenesulfonyl-2-
(4-methoxyphenyl)pyrrole (3, Ar¼C6H4OCH3) a complex mix-
ture of products was obtained. We have successfully employed
a modified FriedeleCrafts acylation procedure developed by
Okauchi et al. and Ottoni et al. in the synthesis of a number
of 3-acylindoles.8e10 In this method the substrate is stirred
with the catalyst for approximately 30 min and the acyl halide
is added subsequently. These are experimental conditions B
(see Section 5). Reaction of pyrrole 3 (Ar¼C6H4OCH3) with
Et2AlCl followed by the addition of 1-naphthoyl chloride
gave a single product in 47% unoptimized yield. This com-
pound was identified as N-p-toluenesulfonyl-2-(4-methoxy-
phenyl)-5-(1-naphthoyl)pyrrole (4, Ar¼C6H4OCH3) on the
basis of its 1H NMR spectrum, which showed the pyrrole
protons as doublets (J¼3.4 Hz) at d 6.12 and d 6.68. These
chemical shifts and coupling constants are consistent with those
of a 2,5-disubstituted pyrrole.11
Table 1
Effect of solvent on acylation (method A) of N-p-toluenesulfonylpyrrole using
a
excess 1-naphthoyl chloride and AlCl3
Solvent
Concnb (M)
1 R¼Ts
5
N-Tsepyrrole
ClCH2CH2Cl
ClCH2CH2Cl
CHCl3
0.159
0.422
0.411
0.514
0.799
0.211
0.422
>98
>99
83
<2
<1
17
<1
<1
1
0
0
0
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
a
>98
>99
98
<1
0
1
98
2
0
Acylation performed in designated solvent system with 2 equiv of AlCl3
and 1.18 equiv of 1-naphthoyl chloride for 2 h. Product ratios determined by
1H NMR.
Repetition of the reaction of N-p-toluenesulfonyl-2-phenyl-
pyrrole (3, Ar¼C6H5) with 1-naphthoyl chloride under condi-
tions A with AlCl3 catalysis gave a product mixture containing
b
Concentration relative to N-p-toluenesulfonylpyrrole.

2106
J.W. Huffman et al. / Tetrahedron 64 (2008) 2104e2112
isomer (5) to 17% of the product mixture. This increase in the
relative amount of 5 may be due to the difference in polarity
between chloroform and either dichloromethane or 1,2-
dichloroethane.
were investigated. Aliquots were taken at 5, 30, 60, 90, and
120 min to examine changes in relative amounts of reaction
products with respect to time. The reaction was monitored
1
by H NMR and GC/MS. The data show that the relative
The effect of the relative amount of AlCl3 under reaction
conditions A was explored and the results are summarized in
Table 2. Decreasing the relative amount of AlCl3 from 2 to
1 equiv increased the relative amount of the 2-(1-naphthoyl)
isomer to 15% of the product mixture. Reducing the amount
of AlCl3 to 0.9 equiv increased the amount of the 2-isomer
to 25%. A further decrease in the amount of catalyst to
0.1 equiv resulted in 95% recovery of the starting material
and the formation of an approximately equimolar mixture of
the 2- and 3-isomer. When the reaction was carried out at
room temperature under conditions duplicating as nearly as
possible to those of Lainton et al.,5,13 the product mixture con-
tained 90% of the 3-isomer (1, R¼Ts) and 10% of the 2-iso-
mer (5). At room temperature with 0.9 equiv of AlCl3 the
relative amount of the 2-isomer was increased to 32%. Chang-
ing the catalyst to 2 equiv of AlBr3 gave results indistinguish-
able from those with AlCl3. When a milder Lewis acid, SnCl2,
was employed as catalyst the major product (72% of the prod-
uct mixture) was the 2-(1-naphthoyl) isomer (5). The product
mixture from this reaction also contained 6% of the 3-(1-naph-
thoyl) isomer (1, R¼Ts) and 22% recovered starting material.
These results are in accord with those of Kakushima et al. who
reported that acylation of N-benzenesulfonylpyrrole using
mild Lewis acids, such as SnCl4, ZnCl2 or BF3$OEt2, led to
predominant formation of the 2-acyl product.4b
The results presented in Table 1 in which acylation of
N-p-toluenesulfonylpyrrole was carried out with 2 equiv of
AlCl3 were generally reproducible and it was found that the
amount of AlCl3 could be reduced to 1.2 equiv without loss
of regioselectivity. However, in some experiments this proce-
dure afforded up to 20% of the 2-naphthoyl isomer (5). In an
effort to explain this decline in regioselectivity the effect of the
purity of the AlCl3 was explored. A series of reactions were
performed at a pyrrole concentration of 0.422 M in dry
dichloromethane using 2.0 equiv of AlCl3 and 1.17 equiv of
1-naphthoyl chloride for 2 h. Samples of AlCl3 from different
suppliers of different labeled purities and of different ages
amount of the 2-naphthoyl isomer remains constant at
1e10% throughout the reaction and as would be expected
the amount of starting material decreases as the reaction pro-
ceeds. All samples of AlCl3 tested provided at least 90% of
3-(1-naphthoyl)-N-p-toluenesulfonylpyrrole (1, R¼Ts). There
was no significant difference between very high purity
(99.9% under argon) AlCl3 and material of 98% purity, or
between materials from different suppliers. It was observed
that older samples of AlCl3 gave proportionately larger
amounts of the 2-isomer (5) and that the reaction was some-
what slower than when fresh AlCl3 was used. This is consis-
tent with the observation that fewer equivalents of AlCl3
enhance the formation of the 2-isomer (5). Regioselective for-
mation of the 3-isomer (1, R¼Ts) was achieved with the older
samples of AlCl3 when an excess (at least 2 equiv) was used.
Under reaction conditions A, using AlCl3 as catalyst, the
only variable that appreciably affected the relative amounts
of 2- and 3-acylation product was the number of equivalents
of AlCl3 that were used. It appears probable that the product
distribution that we reported earlier was caused by the use
of impure or aged AlCl3, with perhaps a small increase in
the amount of the 2-isomer (5) caused by carrying out the
reaction at room temperature, rather than 0 ꢀC.5,13
The results of the acylation of N-p-toluenesulfonylpyrrole
with 1-naphthoyl chloride under conditions B using AlCl3,
EtAlCl2 or Et2AlCl in 1,2-dichloroethane are summarized in
Table 3. With an initial N-p-toluenesulfonylpyrrole concentra-
tion of 0.075 M, AlCl3 gave a product mixture containing
greater than 98% of the 3-(1-naphthoyl) isomer (1, R¼Ts).
EtAlCl2 provided a 2.5 to 1 ratio of the 2-(1-naphthoyl) isomer
(5) to the 3-isomer (1, R¼Ts). With Et2AlCl these ratios in-
creased to greater than 16 to 1. With both EtAlCl2 and Et2AlCl
from 6% to 14% of starting material was recovered. At a con-
centration of N-p-toluenesulfonylpyrrole of 0.221 M the reac-
tions using EtAlCl2 and Et2AlCl are considerably more
regioselective than those carried out at the lower concentration
of starting material. With EtAlCl2 the ratio of 2-naphthoyl
isomer 5 to the 3-naphthoyl isomer (1, R¼Ts) was greater
than 15 to 1 and with Et2AlCl greater than 95% of 5 was
Table 2
Acylation of N-p-toluenesulfonylpyrrole with 1.18 equiv of 1-naphthoyl chlo-
ride using varying amounts of AlCl3 (method A)
Table 3
Effect of Lewis acid and concentration upon acylation of N-p-toluenesulfonyl-
Lewis acid (equiv)
Solvent
1 R¼Tsa
98
5a
N-Tsepyrrolea
pyrrole via method Ba
AlCl3 (2.0)
AlCl3 (1.2)b
AlCl3 (1.2)c
AlCl3 (1.1)
AlCl3 (1.1)
AlCl3 (1.0)
AlCl3 (0.9)
AlCl3 (0.9)c
AlCl3 (0.1)
a
ClCH2CH2Cl
CH2Cl2
CH2Cl2
2
0
0
90
90
10
10
Concentration of
N-Tsepyrrole (M)
Lewis acid
1 R¼Tsb
5
N-Tsepyrrole
0
ClCH2CH2Cl
CH2Cl2
>98
>88
85
<2
<2
15
0
10
0
0.075
0.221
0.075
0.221
0.075
0.221
a
AlCl3
AlCl3
>98
>99
27
<2
<1
67
0
0
ClCH2CH2Cl
CH2Cl2
CH2Cl2
75
68
25
32
0
EtAlCl2
EtAlCl2
Et2AlCl
Et2AlCl
6
0
95
6
93
80
<1
15
0
ClCH2CH2Cl
<3
<2
<5
<5
>95
Ratios determined by 1H NMR.
b
Reaction was carried out at room temperature, following the procedure of
Lainton et al. (Ref. 5).
Acylation performed in 1,2-dichloroethane with the indicated Lewis acid
and 2.18 equiv of 1-naphthoyl chloride for 2 h at 0 ꢀC.
c
b
Reaction was carried out at room temperature.
Ratios determined by 1H NMR.

J.W. Huffman et al. / Tetrahedron 64 (2008) 2104e2112
2107
obtained. In none of these experiments was a significant
amount of starting material recovered. The reactions summa-
rized in Table 3 were also carried out in dichloromethane,
however, there were no significant differences in product
distribution from those carried out in 1,2-dichloroethane
(data not shown).
48% of 3-acetyl-N-p-toluenesulfonylpyrrole, 37% of the
2-isomer, and 15% starting material. Decreasing the amount
of AlCl3 further to 1.2 equiv gave a product mixture contain-
ing 19% of the 3-acyl product, 61% of the 2-isomer, and 20%
recovered N-p-toluenesulfonylpyrrole. With 1 equiv of AlCl3
acetic anhydride gave a product mixture that contained 12%
of 3-acetyl-N-p-toluenesulfonylpyrrole, 36% of the 2-isomer,
and 52% starting material.
Under acylation conditions B using AlCl3 and acetyl chlo-
ride, N-p-toluenesulfonylpyrrole gave the 3-acetyl compound
as the predominant product (Table 4). However, when the
acylation was carried out using EtAlCl2 as the Lewis acid,
the product mixture consisted of 59% of the 3-acyl product,
34% of 2-acetyl-N-p-toluenesulfonylpyrrole, and 7% N-p-
toluenesulfonylpyrrole.
In our earlier work, we obtained somewhat different results
when benzoyl chloride was used in place of 1-naphthoyl chlo-
ride to acylate N-p-toluenesulfonylpyrrole.5,13 In particular,
when dichloromethane was used as solvent a mixture of
2- and 3-acylation products was obtained. However, in 1,2-di-
chloroethane, 3-benzoyl-N-p-toluenesulfonylpyrrole was the
only detectable product. With the exception of temperature,
the reactions described in Refs. 5 and 13 were carried out
under conditions virtually identical to those of acylation
method A. In the current study, acylation of N-p-toluenesulfo-
nylpyrrole with benzoyl chloride or acetyl chloride using
procedure A and 2 equiv of AlCl3 gave as the only product
3-acyl-N-p-toluenesulfonylpyrrole, plus a trace of recovered
starting material (Table 4). Similar results were obtained
with acetyl chloride and 2 equiv of AlCl3, however, the prod-
uct mixture contained 5% of starting material. When acetic
anhydride was employed as the acylating agent under the
same conditions with 2 equiv of AlCl3, the product mixture
contained 80% of 3-acetyl-N-p-toluenesulfonylpyrrole, less
than 3% of the 2-isomer, and 17% recovered N-p-toluenesulfo-
nylpyrrole. This result contrasts with that reported by
Kakushima et al., who reported that the AlCl3 catalyzed reac-
tion of acetic anhydride with N-p-benzenesulfonylpyrrole gave
predominantly (>98%) the 3-isomer.4b However, the results
reported by Kakushima et al. were obtained using 6 mol equiv
of catalyst rather than the 2 equiv used in the present work. It
has been established that acid anhydrides react with 1 equiv of
AlCl3 to give the acyl chloride plus an aluminum salt of a carb-
oxylic acid.15 As would be predicted, our results with acetic
anhydride and 2 equiv of AlCl3 are similar to those using
acetyl chloride and 1 equiv of AlCl3. When the acylation of
N-p-toluenesulfonylpyrrole with acetic anhydride was re-
peated using 1.5 equiv of AlCl3 the product mixture contained
A qualitative estimate of the rate of the AlCl3 catalyzed
reaction of N-p-toluenesulfonylpyrrole with 1-naphthoyl chlo-
ride under acylation conditions A was carried out by removing
aliquots from the reaction mixture at timed intervals throughout
1
the procedure. Analysis of the aliquots by H NMR showed
that the mixture of acylation products contained >98%
3-(1-naphthoyl)-N-p-toluenesulfonylpyrrole (1, R¼Ts) and <2%
2-(1-naphthoyl)-N-p-toluenesulfonylpyrrole (5) after 5 min.
The starting material was completely consumed within 2 h,
however, with highly active AlCl3 the reaction was complete
within 30 min. In earlier work, Kakushima et al. reported that
the AlCl3 catalyzed reaction of N-benzenesulfonylpyrrole
with acetyl chloride at ꢁ78 ꢀC went to completion in 12 min
to afford almost exclusively the 3-acyl isomer.4b
Pyrroles normally undergo electrophilic substitution at the
2-position and a possible route for the acylation of N-arylsulfo-
nylpyrroles at C-3 would involve initial acylation at C-2, fol-
lowed by rearrangement to the 3-acyl isomer. Although
migrations of 2-acyl, sulfinyl, and sulfonyl groups to the corres-
ponding 3-isomers have been observed in substituted pyrroles
under acidic conditions at mild temperatures,16 Kakushima
et al. considered that this was an unlikely reaction path for the
formation of 3-isomers in the FriedeleCrafts reaction of N-benz-
enesulfonylpyrrole.4b This conclusion was based upon the
observation that 2-acetyl-N-benzenesulfonylpyrrole formed
a stable complex with AlCl3 from which it could be recovered
unchanged after aqueous work up. In our hands similar results
were obtained with 2-(1-naphthoyl)-N-p-toluenesulfonylpyr-
role (5), which after stirring with AlCl3 in dichloromethane
for 2 h was recovered unchanged. Similar treatment of the
3-isomer (1, R¼Ts) also provided unchanged starting material.
The OkauchieOttoni modification of the FriedeleCrafts
acylation of indoles differs from the classical procedure in
that the substrate is stirred with the Lewis acid for some time,
usually 30 min, prior to the addition of the acylating agent.8
This is similar to our acylation procedure B, while procedure
A is a normal FriedeleCrafts procedure. Although Okauchi
et al. did not comment upon the mechanism of the modified
procedure,8a Ottoni et al. suggested that an intermediate or-
ganometallic complex was formed between the indole and the
Lewis acid.8b In earlier work, we obtained evidence for such
an intermediate when 1-pentylindole was treated with
Table 4
Effect of acylating agents upon the acylation of N-p-toluenesulfonylpyrrolea
Acylating agent
1 R¼Tsb
5b
N-Tsepyrroleb Acylation method
Benzoyl chloride
Acetyl chloride
Acetyl chloridec
Acetic anhydride
Acetic anhydrided
Acetic anhydridee
Acetic anhydridec
Acetyl chloride
Acetyl chloridef
a
>99
>99
>95
80
0
0
<1
<1
A
A
A
A
A
A
A
B
B
Trace <5
<3
37
61
36
1
17
15
20
52
15
7
48
19
12
84
59
34
Acylation performed in 1,2-dichloroethane with 2 equiv of AlCl3 and
1.2 equiv of 1-naphthoyl chloride for 2 h.
b
Ratios determined by 1H NMR.
AlCl3 (1 equiv).
c
d
AlCl3 (1.5 equiv).
AlCl3 (1.2 equiv).
EtAlCl2 used as Lewis acid.
e
f

2108
J.W. Huffman et al. / Tetrahedron 64 (2008) 2104e2112
dimethylaluminum chloride and subsequently quenched with
D2O to afford a 3-deuterio compound.10 In contrast to the results
of Ottoni et al.,8b who found that their organotin intermediates
were insoluble in dichloromethane in the absence of nitrometh-
ane, the organoaluminum intermediates in our work and presum-
ably those of Okauchi et al. are soluble in dichloromethane.8a,10
Kakushima et al. reported that a mixture of N-benzenesul-
fonylpyrrole and AlCl3 in 1,2-dichloroethane remains hetero-
geneous and that there is no evidence of complex formation
by 1H NMR and UV.4b However, in our hands the stirred
mixture of N-toluenesulfonylpyrrole and 0.9 equiv of AlCl3
in 1,2-dichloroethane provides a homogeneous green solution
within 4 min, which fades to pale tan over time. In our hands
N-benzenesulfonylpyrrole behaves similarly. D2O quenching
experiments similar to those carried out on 1-pentylindole
were carried out with the solution of N-p-toluenesulfonylpyr-
role and AlCl3 in 1,2-dichloroethane. In this procedure,
1.5 equiv of AlCl3 was added to a solution of N-p-toluenesul-
fonylpyrrole in 1,2-dichloroethane at 0 ꢀC and the reaction
was stirred at that temperature for 30 min. After quenching
AlCl3 in 1,2-dichloroethane with water provided only recovered
N-p-toluenesulfonylpyrrole. When a solution of N-p-toluene-
sulfonylpyrrole in 1,2-dichloroethane was treated with EtAlCl2
or Et2AlCl and the mixturewas quenched with D2O the products
showed no incorporation of deuterium as indicated by the H
NMR spectrum.
1
3. Discussion
The data summarized in Tables 1e4 and presented above
indicate that the mechanism of acylation of N-p-toluenesulfo-
nylpyrrole with AlCl3 is different from that with weaker Lewis
acids. In particular, the observation that quenching a 1,2-
dichloroethane solution of N-p-toluenesulfonylpyrrole and
AlCl3 with D2O results in the incorporation of deuterium at
C-2 and C-3, combined with the fact that these solutions are
1
homogeneous with an H NMR spectrum different from that
of N-p-toluenesulfonylpyrrole provides strong evidence for
the intermediacy of organoaluminum compounds derived
from N-p-toluenesulfonylpyrrole in the acylation reactions.
This is in direct contrast to the results reported by Kakushima
et al. and we have no explanation for the differences in our
results and those reported previously.4b The deuterium incor-
poration reactions were carried out several times as was the
observation that the AlCl3, N-p-toluenesulfonylpyrrole, and
1,2-dichloroethane system was homogeneous. Thus, the mech-
anism of this reaction is probably similar to that of the
Okauchi and Ottoni indole acylation procedure.8,10
As depicted in Scheme 1, reaction of N-p-toluenesulfonyl-
pyrrole with AlCl3 leads reversibly to a mixture of 2- (6) and
3-organoaluminum (7) species via cations 8 and 9, respec-
tively. Alternatively, organoaluminum species 6 and 7 may
interconvert via an intramolecular process.16 The acid
1
with D2O the H NMR spectra of the reaction products were
1
examined. The H NMR signals at d 6.28 and d 7.15, which
are assigned to the pyrrole protons of N-p-toluenesulfonylpyr-
role, were considerably diminished. The AlCl3 reaction with
D2O quench was carried out three times and in all cases the
13C NMR signals for both pyrrole carbons were diminished.
1
Qualitatively, it was observed that in the H NMR spectra of
the products of all three runs the intensity of the pyrrole C-2
protons was diminished more than those at C-3. An effort
was made to obtain quantitative data by integration of the
1H NMR spectra. The results were highly variable over the
three runs, with substitution at C-2 of 40ꢂ27% and at C-3
of 28ꢂ14%. In one run aliquots were taken at 30 s, 2, 10,
20, and 60 min with substitution at C-2 of 30ꢂ6% and at
C-3 of 21ꢂ4%, with essentially no change in substitution
pattern over the course of the reaction.
+
H
+
+
AlCl3
HCl
or
AlCl2
D2O
AlCl2
1
-
N
N
Ts
N
Ts
N
S
Ar
AlCl3
Some difficulty was encountered in obtaining the H NMR
spectrum of the homogeneous solution of N-p-toluenesulfonyl-
pyrrole and AlCl3 in 1,2-dichloroethane-d4. However, when the
Ts
O
O
6
8
1
sample was prepared in a dry, inert atmosphere the H NMR
O
14
-
RCCl
AlCl3
spectrum was obtained. This spectrum was not particularly
well resolved, but clearly showed the loss of the signals at
d 6.29 and d 7.17, which are assigned to the protons at C-3
and C-2, respectively, of N-p-toluenesulfonylpyrrole. The doub-
lets at d 7.30 and d 7.74 (J¼8 Hz), assigned to two of the pro-
tons on the phenyl ring of N-p-toluenesulfonylpyrrole are no
longer present. Several pairs of doublets with J¼7e8 Hz are
present in the aromatic region of the spectrum, the most promi-
nent of which appear at d 7.80 and d 7.83. The bulk of the aro-
matic protons appear as a broad multiplet and it was not
possible to obtain integration data, nor was it possible to assign
any of these signals to specific protons. Also, in addition to the
aromatic methyl peak at d 2.36 there was a second peak of
slightly greater intensity at d 2.46. An attempt was made to ob-
tain a 13C spectrum of this solution, however, the compound
slowly decomposed during the time required to obtain the spec-
trum. Quenching the solution of N-p-toluenesulfonylpyrrole and
H
+
COR
D
N
Ts
N
Ts
N
Ts
11
9
12
O
RCCl
AlCl2
+
COR
HCl
D2O
N
Ts
N
Ts
7
10
D
N
Ts
13
Scheme 1.

J.W. Huffman et al. / Tetrahedron 64 (2008) 2104e2112
2109
catalyzed equilibration of substituted pyrroles is exceedingly
facile and there is evidence both in favor of and against an
intramolecular process. Reaction of organoaluminum interme-
diate 7 with the acyl chloride leads to the 3-acylpyrrole deriva-
tive (10). The reaction of organoaluminum compounds with
acyl halides to provide ketones is a known reaction, which is
facilitated in the presence of AlCl3 or organoaluminum
halides.17 Under the conditions that provide 3-acylpyrrole de-
rivatives regioselectively there is either excess AlCl3 present
or the organoaluminum intermediates may serve to enhance
the reaction of 7 with the acyl chloride. Reactions of organo-
aluminum intermediate 6 with the acyl chloride will lead to the
2-substituted pyrrole derivative (11). Quenching the homoge-
neous solution of organoaluminum intermediates with D2O
leads to a mixture of 2- and 3-deuteriopyrrole derivatives
(12 and 13, respectively) in which the 2-deuterio isomer
prevails in an approximately 3:2 ratio.
Although in principle the path outlined in Scheme 1 would
lead to a mixture of 2- and 3-acylation products, the rate of
conversion of the 2-substituted organoaluminum intermediate
6 to pyrrole 11 would be expected to be slower than the cor-
responding conversion of the 3-substituted intermediate 7 to
pyrrole 10. In analogy to steric effects invoked to explain
the high regioselectivity in reactions of N-triisopropylsilylpyr-
role, it would be anticipated that the rate of reaction of the
2-organoaluminum intermediate (6) with an acyl chloride
would be slower than the rate of reaction of the less sterically
encumbered 3-isomer (7) with the acyl chloride. Also, there
may be a direct electronic interaction of the electrophilic alu-
minum atom of 6 with an oxygen of the sulfonyl group via
a five-membered structure as depicted in 13 (Scheme 1).
Such an interaction would stabilize the 2-organoaluminum in-
termediate (6) and decrease the rate of reaction with the acyl
halide. A combination of these factors provides a rationaliza-
tion for the regioselective formation of the 3-acyl isomers in
the acylation of N-p-toluenesulfonylpyrrole using AlCl3.
Thus, the regioselective acylation of N-p-toluenesulfonylpyr-
role with AlCl3 is not a FriedeleCrafts acylation, but is rather
the reaction of an organoaluminum intermediate with an acyl
chloride. In the absence of at least 1 equiv of AlCl3, excess
N-p-toluenesulfonylpyrrole will be present and will be acyl-
ated with organoaluminum compounds 6 and/or 7 acting as
catalyst. The regiochemistry of this acylation would be similar
to that of the acylation of N-p-toluenesulfonylpyrrole using
a Lewis acid that did not form an organometallic intermediate
prior to acylation.
with this complex for AlCl3, which will lead to cations 8
and 9, which are in turn converted into organoaluminum com-
pounds 6 and 7. It is not necessary to postulate a sequence of
this sort under acylation conditions B because species 6 and 7
are formed prior to the addition of the acyl halide.
In the presence of weaker Lewis acids,21 such as EtAlCl2
and Et2AlCl (Table 3), or as reported by Kakushima who em-
ployed SnCl4, TiCl4, ZnCl2, and FeCl3 as catalysts the reaction
is considerably less regioselective.4b With BF3$Et2O as cata-
lyst Kakushima obtained 2-acylpyrrole as the major product.
In the case of EtAlCl2, Et2AlCl, and presumably the other
weaker Lewis acids, these acylations do not involve organo-
metallic pyrrole derivatives. Bigi et al. found that in relatively
nonpolar solvents, such as dichloromethane and 1,2-dichloro-
ethane, a polarized Lewis acid (AlCl3) acyl halide complex is
formed with no NMR indication of a significant concentration
of acylium ion.20 For the series RCOCl in which R was CH3,
CH2Cl, CHCl2, and CCl3, these authors found that the degree
of Lewis acid induced polarization of the complex between the
acyl halide and the Lewis acid decreased incrementally with
the inductively electron withdrawing effect of the a-halogens.
These authors also found that the rate of acylation was reduced
by electron withdrawing substituents on the acyl halide. Simi-
lar effects would be expected with decreasing strength of the
Lewis acid while holding the electronegativity of the alkyl
or aryl substituent on the acyl halide relatively constant.
A number of years ago, Olah suggested that in aromatic sub-
stitution reactions, strongly electrophilic reagents provide early
transition states resembling a p-complex, while less electro-
philic reagents provide a transition state similar to the resonance
stabilized Wheland intermediate.22 Although this suggestion
has been criticized,23 ab initio calculations indicate that electro-
philic aromatic substitution reactions may proceed through
a single transition state, which would vary from an early p-com-
plex-like with reactive electrophiles to s-complex-like with less
reactive electrophiles.24 This in effect is an application of the
Hammond postulate to electrophilic aromatic substitution reac-
tions in which a reactive electrophile provides a reactant-like
transition state, while a less reactive electrophile leads to a prod-
uct-like transition state. For the addition of an electrophile to an
aromatic compound the product-like transition state will resem-
ble a delocalized cation (Wheland intermediate).
Although in the acylations of N-p-toluenesulfonylpyrrole
with 1-naphthoyl chloride the acyl halide is not varied, the elec-
trophilic character of the Lewis acid complex with 1-naphthoyl
chloride will vary as a function of the Lewis acidity of the cata-
lyst. AlCl3 is the strongest Lewis acid of those used for the acyl-
ation of N-p-toluenesulfonylpyrrole and it reacts directly with
the substrate to form an organoaluminum intermediate with an
approximate ratio of 2- to 3-substitution of 3 to 2. The Merck
group carried out CNDO/2 calculations on the 2- and 3-cations
derived from N-benzenesulfonylpyrrole, and found that the
3-cation, obtained by substitution at C-2, was significantly
more stable than the 2-cation, derived from substitution at
C-3, a conclusion that is also predicted by classical valence
bond theory.4a CNDO/3 calculations for the ground state of
N-benzenesulfonylpyrrole indicated that the electron density
As noted above under conditions B, in which the substrate
is treated with AlCl3 and the acylating agent is subsequently
added, the formation of an organoaluminum species, such as
6 and 7, was confirmed experimentally. This confirmation con-
sists of both the direct determination of the 1H NMR spectrum
of the mixture of organoaluminum intermediates and trapping
them via deuterium quenching. Under acylation conditions A
the acyl halide is stirred with AlCl3, which generates a revers-
ibly formed complex between AlCl3 and the acyl halide in
which the AlCl3 is coordinated with the carbonyl oxygen of
the halide.18e20 N-p-Toluenesulfonylpyrrole may compete

2110
J.W. Huffman et al. / Tetrahedron 64 (2008) 2104e2112
at C-3 is greater than that at C-2, while the HOMO coefficient is
greater at C-2. Similar results would be expected for N-p-tolue-
nesulfonylpyrrole. According to this hypothesis, regioselective
substitution with hard electrophiles will proceed through charge
control to provide substitution at C-3, while soft electrophiles
will lead to the 2-isomer through frontier-orbital effects.4a As
noted by Bray et al. other workers have made similar sugges-
tions regarding electrophilic substitution of pyrrole.2b
4. Conclusions
In summary, acylations of N-p-toluenesulfonylpyrrole with
AlCl3 appear to proceed via reaction of an organoaluminum
intermediate with the acyl chloride. Acylations using weaker
Lewis acids proceed by a normal FriedeleCrafts reaction
through a polarized complex formed from the acylating agent
and the Lewis acid. The electrophilicity of this complex is
determined by a combination of the nature of the acylating
agent and the strength of the Lewis acid. In these reactions
the regiochemistry will be determined by the character of
the transition state leading to the intermediate carbocation.
With highly reactive electrophiles, a reactant-like transition
state will favor the 3-substituted product, while less reactive
electrophiles will provide a product-like transition state that
resembles the more stable cation resulting from attack at
C-2.
An indication of the relative nucleophilicity of C-2 and C-3
1
in N-p-toluenesulfonylpyrrole can be found in the H NMR
chemical shifts of the protons at C-2 (d 7.15) and C-3
(d 6.28).25 For pyrrole the chemical shifts of the C-2 and C-3
protons are d 6.73 and d 6.17, respectively, while for N-triiso-
propylsilylpyrrole the C-2 proton appears at d 6.80 and the C-3
proton at d 6.32.2b N-Triisopropylsilylpyrrole undergoes
FriedeleCrafts acylation exclusively at C-3 and it was
concluded that this was due primarily to steric effects inas-
much as the 1H NMR chemical shifts of N-triisopropylsilylpyr-
role are very similar to those of pyrrole itself. The similarity of
these NMR chemical shifts was considered to be indicative of
no significant electronic effect caused by N-silylation.2b In con-
trast, while the chemical shift of H-3 of N-p-toluenesulfonylpyr-
role is relatively unchanged with respect to those of pyrrole and
N-triisopropylsilylpyrrole, H-2 is shifted quite far downfield,
suggesting an electron withdrawing effect at C-2 caused by
the p-toluenesulfonyl group.
Based upon these considerations, the Hammond postulate
would predict that reaction at the 3-position of N-p-toluenesul-
fonylpyrrole by highly electrophilic species via a reactant-like
transition state would be enhanced relative to pyrrole itself.
Less electrophilic species would be expected to preferentially
attack at C-2 via a product-like transition state to produce the
energetically favored, delocalized 3-carbocation. The evidence
discussed above indicates that the mechanism of reaction of
N-p-toluenesulfonylpyrrole with an acyl halide using AlCl3
is not a FriedeleCrafts acylation, but is instead the reaction
of an intermediate organoaluminum species with the acyl ha-
lide. The weaker Lewis acids, EtAlCl2 and Et2AlCl provide
mixtures of 2- and 3-acylation products (Table 3). With
BF3$Et2O, which forms a very weak complex with acetyl
chloride, the acylation of N-benzenesulfonylpyrrole is reported
to give exclusively the 2-acyl product.4b Similar results were
reported by Kimbaris and Varvounis in the acylation of N-p-
toluenesulfonylpyrrole with 2-nitrobenzoyl chloride.26 With
AlCl3 these authors obtained a 4:1 mixture of 3-acyl to
2-acyl product and with SnCl4 the ratio was 1:5. More recently
Song et al. reported that exclusive 2-acylation of N-p-toluene-
sulfonylpyrrole and substituted N-p-toluenesulfonylpyrroles
could be achieved by employing a mixture of the appropriate
carboxylic acid and trifluoroacetic anhydride.27 Although
these authors do not discuss the mechanism of this reaction,
it almost certainly proceeds via a mixed anhydride, with the
strongly electron withdrawing trifluoroacetyl moiety inducing
enhanced positive character to the carbonyl group derived
from the carboxylic acid to give a weakly electrophilic species
that would be expected to react via a product-like transition
state and provide the 2-acyl product.
5. Experimental
5.1. General
1H and 13C NMR spectra were recorded on a Brucker
300AC or 500 MHz spectrometers or a JEOL 500 MHz spec-
trometer. Mass spectral analyses were performed on a Hew-
lett-Packard 5890A capillary gas chromatograph equipped
with a mass sensitive detector. Ether and THF were distilled
from Naebenzophenone ketyl immediately before use, and
other solvents were purified using standard procedures. Col-
umn chromatography was carried out on Sorbent Technologies
silica gel (32e63 m) using the indicated solvents as eluents.
All new compounds were homogeneous to TLC and/or 13C
NMR. TLC was carried out using 200 mm silica gel plates us-
ing the indicated solvents. GLC analyses were performed on
the Hewlett-Packard 5890A GC/MS using a 60 m carbowax
column and helium gas as a carrier. An initial column temper-
ature of 60 ꢀC was employed and the temperature was in-
creased at a rate of 1.5 ꢀC/min to a maximum temperature
of 300 ꢀC with a total run time of 20 min. Elemental analyses
were performed by Atlantic Microlab, Norcross, GA.
5.2. 3-(1-Naphthoyl)-N-(p-toluenesulfonyl)pyrrole
5.2.1. Method A
This procedure is a modification of that reported by
Cadamuro et al.28 To a stirred suspension of 0.600 g
(4.5 mmol) of AlCl3 in 2.35 mL of dry CH2Cl2 under argon
was added 0.4 mL (2.6 mmol) of 1-naphthoyl chloride. The
mixture was stirred for 10 min cooled to 0 ꢀC and 0.500 g
(2.3 mmol) of N-p-toluenesulfonylpyrrole in 3.0 mL of dry di-
chloromethane was added. The mixture was allowed to warm
slowly to ambient temperature with stirring over 2 h. Water was
added to quench the reaction, which was extracted with three
portions of dichloromethane, washed with 2 M aqueous NaOH,
and dried (MgSO4). Concentration in vacuo afforded a brown
oil. Chromatography (petroleum ether/ethyl acetate, 9:1) gave
0.561 g (66%) of 3-(1-naphthoyl)-N-p-toluenesulfonylpyrrole

J.W. Huffman et al. / Tetrahedron 64 (2008) 2104e2112
2111
1
as a yellow oil: H NMR (300 MHz, CDCl3) d 2.33 (s, 3H),
6.83 (dd, J¼1.6, 3.4 Hz, 1H), 7.20e7.25 (m, 2H), 7.47e7.53
(m, 3H), 7.65 (d, J¼7.0 Hz, 1H), 7.72 (d, J¼8.1 Hz, 2H),
7.86 (d, J¼7.0 Hz, 1H), 7.95 (d, J¼8.2 Hz, 1H), 8.16 (d,
J¼8.7 Hz, 1H); 13C NMR (75.5 MHz, CDCl3) d 21.5, 113.4,
121.5, 124.2, 125.3, 126.3, 126.8, 126.9, 127.0, 128.2,
129.6, 130.2, 130.3, 131.2, 133.6, 134.7, 136.4, 145.9, 191.2;
EIMS m/z (rel intensity) 65 (21), 91 (58), 127 (26), 191 (12),
220 (100), 375 (52). The spectroscopic data agree with those
reported previously.5
5.5. 2-Phenyl-4-(1-naphthoyl)-N-p-toluenesulfonylpyrrole
Acylation of 0.100 g (0.3 mmol) of 2-phenyl-N-p-toluene-
sulfonylpyrrole29 was carried out by method A to give, after
chromatography (petroleum ether/ether, 9:1), 0.115 g (76%)
of 2-phenyl-4-(1-naphthoyl)-N-p-toluenesulfonylpyrrole: mp
146e148 ꢀC; 1H NMR (300 MHz, CDCl3) d 2.34 (s, 3H),
6.72 (d, J¼1.8 Hz, 1H), 7.05e7.39 (m, 8H), 7.53e7.57
(m, 3H), 7.75e7.81 (m, 2H), 7.89e7.93 (m, 1H), 8.00 (d,
J¼8.2 Hz, 1H), 8.23e8.27 (m, 1H); EIMS m/z (rel intensity)
451 (61), 296 (100), 155 (10), 127 (29), 91 (9). Anal. Calcd
for C28H21NO2S: C, 74.48; H, 4.69; N, 3.10. Found: C,
74.27; H, 4.70; N, 3.11.
5.2.2. Method B
This procedure is a modification of Okauchi et al.8a To a
solution of 0.100 g (0.5 mmol) of N-p-toluenesulfonylpyrrole
and 1 mL of 1,2-dichloroethane under N2 at 0 ꢀC was added
0.68 mL (0.7 mmol) of 1.0 M ethylaluminum dichloride in
dichloromethane. The mixture was stirred for 30 min and
0.15 mL (1.0 mmol) of 1-naphthoyl chloride dissolved in
1 mL of 1,2-dichloroethane was added. The reaction was stirred
for an additional 2 h at 0 ꢀC, quenched with water and extracted
with three portions of ethyl acetate. After drying (MgSO4) the
solution was concentrated in vacuo to give a brown solid.
Chromatography (petroleum ether/ethyl acetate, 9:1) afforded
0.031 g (18%) of 3-(1-naphthoyl)-N-p-toluenesulfonylpyrrole
as a yellow oil, the spectroscopic data for which are identical
to those reported above.
5.6. 3-Acetyl-N-p-toluenesulfonylpyrrole
Acylation of 0.100 g (0.45 mmol) of N-p-toluenesulfonyl-
pyrrole with 0.04 mL (0.53 mmol) of acetyl chloride by
method A or B gave 0.112 g (95%) of 3-acetyl-N-p-toluene-
1
sulfonylpyrrole: H NMR (500 MHz, CDCl3) d 2.41 (s, 3H),
2.43 (s, 3H), 6.67 (dd, J¼1.4, 3.2 Hz, 1H), 7.13 (dd, J¼3.2,
2.2 Hz, 1H), 7.34 (d, J¼8.2 Hz, 2H), 7.72 (t, J¼1.8 Hz, 1H),
7.80 (d, J¼8.2 Hz, 2H); EIMS m/z (rel intensity) 263 (48),
248 (61), 155 (43), 91 (100), 65 (37). The spectroscopic
data are consistent with those reported previously.14
5.7. 3-Benzoyl-N-p-toluenesulfonylpyrrole
Acylation of N-p-toluenesulfonylpyrrole was carried out by
1
method A: H NMR (300 MHz, CDCl3) d 2.42 (s, 3H), 6.79
5.3. 2-(1-Naphthoyl)-N-(p-toluenesulfonyl)pyrrole
(dd, J¼1.5, 3.0 Hz, 1H), 7.23 (dd, J¼2.3, 3.2 Hz, 1H), 7.28
(d, J¼8.1 Hz, 2H), 7.39e7.56 (m, 3H), 7.71 (t, J¼1.7 Hz,
1H), 7.75e7.82 (m, 4H); EIMS m/z (rel intensity) 325 (82),
248 (34), 155 (50), 91 (100). The spectroscopic data are
consistent with those reported previously.30
Acylation of N-p-toluenesulfonylpyrrole was carried out by
method B, however, using diethylaluminum chloride as cata-
lyst. From 0.100 g (0.5 mmol) of N-p-toluenesulfonylpyrrole
and 0.15 mL (1.0 mmol) of 1-naphthoyl chloride there was
obtained after chromatography (petroleum ether/ethyl acetate,
9:1) 0.098 g (58%) of 2-(1-naphthoyl)-N-p-toluenesulfonylpyr-
Acknowledgements
1
role as a yellow solid: mp 145e146 ꢀC; H NMR (300 MHz,
CDCl3) d 2.45 (s, 3H), 6.26 (t, J¼3.3 Hz, 1H), 6.6 (dd,
J¼1.7, 3.6 Hz, 1H), 7.36e7.50 (m, 5H), 7.60 (d, J¼6.9 Hz,
1H), 7.84e7.85 (m, 1H), 7.86 (d, J¼1.7 Hz, 1H), 7.95 (t, J¼
8.2 Hz, 2H), 8.06 (d, J¼8.3 Hz, 2H); 13C NMR (75.5 MHz,
CDCl3) d 21.7, 110.5, 124.2, 125.4, 126.3, 126.8, 127.2, 127.9,
128.2, 128.7, 129.4, 130.4, 130.9, 131.5, 133.5, 134.5, 135.8,
136.2, 145.0, 186.0; EIMS m/z (rel intensity) 65 (11), 91 (14),
127 (38), 190 (13), 219 (100), 375 (62). The spectroscopic
data agree with those reported previously.5
This work was supported by grants DA03590 and DA15340
to J.W.H. and DA15579 to L.W.P., all from the National Insti-
tute on Drug Abuse. We thank Dr. Rhett C. Smith for his
assistance in obtaining the H NMR spectrum of the mixture
of intermediates 6 and 7.
1
References and notes
1. Anderson, H. J.; Loader, C. E. Synthesis 1985, 353.
2. (a) Muchowski, J.; Solas, D. R. Tetrahedron Lett. 1983, 24, 3455; (b)
Bray, B. L.; Mathies, P. H.; Naef, R.; Solas, D. R.; Tidwell, T. T.; Artis,
D. R.; Muchowski, J. J. Org. Chem. 1990, 55, 6317.
5.4. Study on effects of aluminum chloride purity on acylation
3. (a) Xu, R. X.; Anderson, N. J.; Gogan, N. J.; Loader, C. E.; McDonald, R.
Tetrahedron Lett. 1981, 22, 4899; (b) Anderson, H. J.; Loader, C. E.; Xu,
R. X.; Le, N.; Gogan, N. J.; McDonald, R.; Edwards, L. G. Can. J. Chem.
1985, 63, 896.
Reactions were performed according to acylation method
A. Each reaction was carried out in duplicate with samples
of aluminum chloride taken from bottles of different ages
and from Acros, Aldrich, and Alfa-Aesar. Aliquots were taken
at 5, 30, 60, 90, and 120 min and the product mixture was
4. (a) Rokach, J.; Hamel, P.; Kakushima, M.; Smith, G. M. Tetrahedron Lett.
1981, 22, 4901; (b) Kakushima, M.; Hamel, P.; Frenette, R.; Rokach, J.
J. Org. Chem. 1983, 48, 3214.
5. Lainton, J. A. H.; Huffman, J. W.; Martin, B. R.; Compton, D. R. Tetra-
hedron Lett. 1995, 36, 1401.
1
evaluated by H NMR spectroscopy.

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J.W. Huffman et al. / Tetrahedron 64 (2008) 2104e2112
6. (a) Reggio, P. H.; Basu-Dutt, S.; Barnett-Norris, J.; Castro, M. T.; Hurst,
D. P.; Seltzman, H. H.; Roche, M. J.; Gilliam, A. F.; Thomas, B. F.;
Stevenson, L. A.; Pertwee, R. G.; Abood, M. E. J. Med. Chem. 1998,
41, 5177; (b) Huffman, J. W.; Mabon, R.; Wu, M.-J.; Lu, J.; Hart, R.;
Hurst, D. P.; Reggio, P. H.; Wiley, J. L.; Martin, B. R. Bioorg. Med.
Chem. 2003, 11, 539.
J. Org. Chem. 1982, 47, 3668; (c) Carson, J. R.; Davis, N. M. J. Org.
Chem. 1981, 46, 839.
17. (a) Arisawa, M.; Torisawa, Y.; Nakagawa, M. Synthesis 1995, 1371; (b)
Arisawa, M.; Torisawa, Y.; Kawahara, M.; Yamanaka, M.; Nishida, A.;
Nakagawa, M. J. Org. Chem. 1997, 62, 4327; (c) Dieter, R. K. Tetra-
hedron 1999, 55, 4177, provides a review of the reaction of acyl chlorides
with organometallic reagents.
7. Huffman, J. W.; Padgett, L. W.; Wiley, J. L.; Martin, B. R. Bioorg. Med.
Chem. Lett. 2006, 16, 5432.
18. Tan, L. K.; Brownstein, S. J. Org. Chem. 1983, 302.
8. (a) Okauchi, T.; Itonaga, M.; Minami, T.; Owa, T.; Kitoh, K.; Yoshino, H.
Org. Lett. 2000, 2, 1485; (b) Ottoni, O.; Neder, A. V. F.; Dias, A. K. B.;
Cruz, R. P. A.; Aquino, L. B. Org. Lett. 2001, 3, 1005, independently and
simultaneously developed a similar procedure for preparing 3-acylindoles.
9. Huffman, J. W.; Zengin, G.; Wu, M.-J.; Lu, J.; Hynd, G.; Bushell, K.;
Thompson, A.; Bushell, S.; Tartal, C.; Hurst, D. P.; Reggio, P. H.; Selley,
D. E.; Cassidy, M. P.; Wiley, J. L.; Martin, B. R. Bioorg. Med. Chem.
2005, 13, 89.
19. Bigi, F.; Casnati, G.; Sartori, G.; Pridieri, G. J. Chem. Soc., Perkin Trans.
2 1991, 1319.
20. (a) Brown, H. C.; Jensen, F. R. J. Am. Chem. Soc. 1958, 83, 2291; (b)
Brown, H. C.; Marino, G.; Stock, L. M. J. Am. Chem. Soc. 1959, 84, 3310.
21. Childs, R. F.; Mulholland, D. L.; Nixon, A. Can. J. Chem. 1982, 60, 801.
These authors present an experimentally determined scale of Lewis acid
strengths which ranks AlCl3>EtAlCl2>TiCl4>Et2AlCl>SnCl4.
22. (a) Olah, G. A.; Kobayashi, S. J. Am. Chem. Soc. 1971, 93, 6964; (b) Olah,
G. A.; Tashiro, M.; Kobayashi, S. J. Am. Chem. Soc. 1970, 92, 6371; (c)
Olah, G. A. Acc. Chem. Res. 1971, 4, 240.
10. Huffman, J. W.; Szklennik, P. V.; Almond, A.; Bushell, K.; Selley, D. E.;
He, H.; Cassidy, M. P.; Wiley, J. L.; Martin, B. R. Bioorg. Med. Chem.
Lett. 2005, 15, 4110.
23. DeHaan, F. P.; Covey, W. D.; Delker, G. L.; Baker, N. J.; Feigon, J. F.;
Miller, K. D.; Stelter, E. D. J. Am. Chem. Soc. 1979, 101, 1336.
24. Santiago, C.; Houk, K. N.; Perrin, C. L. J. Am. Chem. Soc. 1979, 101, 1337.
25. Padgett, L. W. Ph.D. Dissertation, Clemson University, 2005.
26. Kimbaris, A.; Varvounis, G. Tetrahedron 2000, 56, 9675.
27. (a) Song, C.; Knight, D. W.; Whatton, M. A. Tetrahedron Lett. 2004, 45,
9573; (b) Song, C.; Knight, D. W.; Whatton, M. A. Org. Lett. 2006, 8, 163.
28. Cadamuro, S.; Degani, I.; Dughera, S.; Fochi, R.; Gatti, A. J. Chem. Soc.,
Perkin Trans. 1 1993, 273.
11. Anderson, H. J.; Griffiths, S. J. Can. J. Chem. 1967, 45, 2227.
12. We thank Dr. C. W. Padgett and Dr. W. T. Pennington for carrying out the
X-ray determinations. These data have been filed with the Cambridge
Crystallographic Centre with deposition numbers CCDC 628478
(4, Ar¼4-OCH3C6H4) and CCDC 628479 (2, Ar¼C6H5, R¼Ts).
13. Lainton, J. A. H.; Huffman, J. W. Unpublished work.
14. Sattambolo, R.; Lazzaroni, R.; Messeri, T.; Salvadori, P. J. Org. Chem.
1993, 58, 7899.
15. Baddeley, G.; Voss, D. J. Chem. Soc. 1954, 418.
29. Knight, L. W.; Huffman, J. W.; Isherwood, M. L. Synlett 2003, 1993.
30. Chen, Q.; Wang, T.; Zhang, Y.; Wang, Q.; Ma, J. Synth. Commun. 2002,
32, 1041.
16. (a) Carmona, O.; Greenhouse, R.; Landeros, R.; Muchowski, J. M. J. Org.
Chem. 1980, 45, 5336; (b) DeSales, J.; Greenhouse, R.; Muchowski, J. M.