Approaches to the synthesis of 2,3-dihaloanilines. Useful precursors of 4-functionalized-1 H-indoles

Article abstract of DOI:10.1021/jo200406f

2,3-Dihaloanilines have been proved as useful starting materials for synthesizing 4-halo-1H-indoles. Subsequent or in situ functionalization of the prepared haloindoles allows the access to a wide variety of 2,4- or 2,3,4-regioselectively functionalized indoles in good overall yields. As no efficient synthetic routes to 2,3-dihaloanilines have been described in the literature, different approaches to the preparation of these 1,2,3-functionalized aromatic precursors are now presented. The most general one involves a Smiles rearrangement from the corresponding 2,3-dihalophenols and allows the preparation of 2,3-dihaloanilides in a straightforward and synthetically useful manner.

Full text of DOI:10.1021/jo200406f

ARTICLE
pubs.acs.org/joc
Approaches to the Synthesis of 2,3-Dihaloanilines. Useful Precursors
of 4-Functionalized-1H-indoles§
Verꢀonica Guilarte, M. Pilar Castroviejo, Patricia García-García, Manuel A. Fernꢀandez-Rodríguez, and
Roberto Sanz*
ꢀ
Departamento de Química, Area de Química Orgꢀanica, Facultad de Ciencias, Universidad de Burgos, Pza. Misael Ba~nuelos s/n,
09001-Burgos, Spain
S Supporting Information
b
ABSTRACT: 2,3-Dihaloanilines have been proved as useful
starting materials for synthesizing 4-halo-1H-indoles. Subse-
quent or in situ functionalization of the prepared haloindoles
allows the access to a wide variety of 2,4- or 2,3,4-regioselec-
tively functionalized indoles in good overall yields. As no
efficient synthetic routes to 2,3-dihaloanilines have been de-
scribed in the literature, different approaches to the preparation
of these 1,2,3-functionalized aromatic precursors are now
presented. The most general one involves a Smiles rearrange-
ment from the corresponding 2,3-dihalophenols and allows the preparation of 2,3-dihaloanilides in a straightforward and
synthetically useful manner.
Scheme 1. Retrosynthetic Analysis of 4-Haloindoles and 2,3-
Dihaloanilines
’ INTRODUCTION
Indole derivatives are usually referred to as privileged struc-
tures due to their excellent binding ability to many receptors and
so, the indole core represents one of the ubiquitous heterocyclic
scaffolds in biologically active compounds.1 This prevalence in
bioactive molecules has prompted the development of efficient
and practical syntheses of indoles bearing a variety of substitution
patterns, which provides a continual challenge to organic
chemists.2 In this field, considerable efforts are needed to obtain
valuable 4-substituted indoles and few methods have been
described. Some reported examples involve the metalation of
adequately 3-functionalized indoles,3 regioselective hydrodebro-
mination of 4,6-dibromoindoles,4 CꢀH activation of 4-acetoxy-
6,7-dihydroindoles,5 and selective lithiation of 4,7-dibromo-
indoles.6 In recent years, a few particular examples of 4-haloindoles
have also been prepared by different metal-catalyzed processes.7
Nevertheless, the most general strategy to prepare these 4-func-
tionalized-1H-indoles involves the construction of the hetero-
cyclic ring using an annelative method from properly substituted
aromatic precursors.8 Its main disadvantage is the requirement of
specifically functionalized benzene derivatives that are in general
difficult to get. Within the current approach, we reasoned that
one of the most direct entries to 4-haloindoles, which are valuable
precursors for further functionalization, could involve a selective
Sonogashira cross coupling with the appropriate 2,3-dihaloani-
line derivative and a subsequent heteroannulation reaction
(Scheme 1). However, this easy approach to 4-haloindoles has
not been previously reported probably due to the fact that no
direct routes are known for accessing to 2,3-dihaloanilines.9
Among 3-halo-2-iodoanilines, only 3-bromo-2-iodoaniline has
been described although its preparation requires a sequence
involving diazotation/iodide displacement/reduction from
2-bromo-6-nitroaniline, which is obtained as the minor isomer
in the nitration of 2-bromoaniline.10 In the same way, the
syntheses of 2-bromo-3-chloroaniline11 and 2,3-dibromoaniline12
have been performed by using analogous multistep and ineffi-
cient strategies.
Taking into account the foreseeable potential of 2,3-dihaloa-
nilines as precursors of 4-haloindoles, we decided to develop an
efficient synthesis of these 1,2,3-functionalized benzene deriva-
tives. We envisaged three different pathways to access these
substrates. As shown in Scheme 1, route a would involve an ortho-
metalation reaction of a 3-haloaniline derivative. To the best of
our knowledge, the only reported example of this approach is due
Received: February 23, 2011
Published: March 28, 2011
r
2011 American Chemical Society
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|

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Scheme 2. Synthesis of 3-Fluoro-2-halotrifluoroacetanilides
3 and 3-Fluoro-2-haloanilines 6
Scheme 3. Unsuccessful Synthesis of 3-Chloro-2-iodoaniline
from 3-Chloroaniline Derivatives 1b and 8
to Soll and co-workers, who reported the ortho-lithiation of
N-trifluoroacetyl-3-fluoroaniline (1a) and were able to prepare
2-bromo-3-fluoroaniline.13 Alternatively, the desired anilines
could be prepared by reduction of the corresponding 2,3-dihalo-
nitrobenzenes (Scheme 1, route b).14 However, the only efficient
and direct route to these latter compounds is limited to
the synthesis of 2-bromo-3-fluoronitrobenzene by a base-
mediated halogenation reaction.15 Finally, taking advantage
of the efficient synthesis of 2,3-dihalophenols that we have
previously developed,16 we also reasoned that the corresponding
2,3-dihaloanilines could be obtained from their phenol coun-
terparts through a “Smiles rearrangement” strategy (Scheme 1,
route c).17 Herein, we report our results on the synthesis of
2,3-dihaloanilines and their application to the preparation of
4-halo-1H-indoles and different regioselectively functionalized
indoles.18
electrophilic quenching, the iodinated benzoxazole 4 in moder-
ate yield (Scheme 2). This observation has been previously
described by Clark and Caroon in the directed metalation of
3-fluoroaniline bearing pivaloyl, N-Boc, or benzoyl as directing
groups.20 In an analogous way, the addition of bromine or
hexachloroethane as electrophilic reagents to 2a afforded the
corresponding 3-fluoro-2-halo-trifluoroacetanilides 3ab and 3ac
in 45% and 30% yield. Moreover, the basic hydrolysis of some of
these trifluoroacetanilides 3 furnished 3-fluoro-2-haloanilines
6aa and 6ab in high yields (Scheme 2).
However, when we tried to apply the ortho-lithiation strategy,
under the same reaction conditions used for the metalation of 1a
(t-BuLi/TMEDA, THF, ꢀ78 °C), to 3-chlorotrifluoroacetani-
lide 1b we could not obtain the corresponding 3-chloro-2-
iodoaniline derivative and the starting material was recovered.
When the reaction mixture was allowed to reach higher tem-
peratures (over ꢀ40 °C), the addition of t-BuLi to the trifluor-
oacetamido moiety was observed and N-(3-chlorophenyl)-
pivalamide (7) could be isolated (Scheme 3).21 The use of n-
BuLi instead of t-BuLi precludes the addition reaction but no
metalation was observed below ꢀ30 °C.22 On the other hand,
the use of LDA as metalating agent did not give satisfactory
results either. Thus, below ca. ꢀ40 °C, no reaction occurred,
whereas allowing the reaction mixture to reach higher tempera-
tures led to decomposition products (Scheme 3).23 Then, we
attempted to exploit the well-known ortho-directing ability of the
Boc group24 for the synthesis of 3-chloro-2-iodoaniline starting
from N-(Boc)-3-chloroaniline (8). In this case, treatment with
LDA in THF gave rise to a different result. At low temperature,
the starting material remained intact, but upon warming the
reaction mixture N-(Boc)-aniline (9) started to form and at 0 °C
it could be isolated in high yield (Scheme 3).25 It is known that
t-BuLi is able to abstract the proton from the double activated
’ RESULTS AND DISCUSSION
As established above, the ortho-lithiation of N-trifluoroacetyl-
3-fluoroaniline (1a) has been previously described.13 Its treat-
ment with t-BuLi in the presence of TMEDA gives rise to the
generation of the organolithium intermediate 2a, which was
trapped with methyl disulfide or bromine. This ortho-metalation
reaction has not been further used in synthesis in spite of the
potential interest in the resulting 2,3-difunctionalized aniline
derivatives for the preparation of fluorine-containing indoles.
So, first we tried to apply the reported reaction conditions to
get 3-fluoro-2-iodotrifluoroacetanilide (3aa) from 1a employing
iodine as an electrophile. Thus, using a slight excess of t-BuLi/
TMEDA in THF at ꢀ78 °C, we were able to generate the
dilithiated species 2a and trap it with iodine, allowing the
isolation of 3aa in 63% yield (Scheme 2). We also observed
that working at temperatures over ca. ꢀ60 °C a competitive
lithium fluoride elimination takes place affording benzyne19
intermediate 5 that intramolecularly evolves to afford, after
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ARTICLE
Scheme 4. Synthesis of 2-Halo-3-nitrofluorobenzenes 14 and
Alternative Preparation of 3-Fluoro-2-haloanilines 6ab and
6ac
Scheme 5. Smiles Rearrangement
Taking into account that only 2-halo-3-fluoroanilines 6aaꢀac
could be accessed by the first two of our envisaged approaches
(Scheme 1, routes a and b), we then examined the use of 2,
3-dihalophenol derivatives as starting materials (Scheme 1, route c).
The direct conversion of phenols into anilines represents an
intriguing organic transformation and few general methods have
been reported for this reaction. Some of them include the
conversion of phenols to aryl diethyl phosphates and subsequent
treatment with KNH2,30 their activation with 4-chloro-2-phe-
nylquinazoline and further thermal rearrangement,31 as well as
the Bucherer reaction of phenols with ammonium sulfite that is
generally limited to naphthols and hydroxy- and aminophenols.32
More recently, the Pd-catalyzed coupling of amines with aryl
triflates or tosylates has meant an important advance in this
field.33 However, aryl halides are also useful partners for these
metal-catalyzed CꢀN bond forming reactions,34 so the use of
this strategy is precluded for our halophenol derivatives. Besides
the Pd- and Cu-catalyzed processes, Smiles rearrangement,
which works especially well with an activated phenoxy compo-
nent bearing at least one halogen subsituent, could be considered
a complementary and valuable alternative for the preparation of
N-arylamines from phenols (Scheme 5).35 This methodology
requires the initial conversion of the corresponding phenol into a
substituted aryloxyacetamide derivative in which oxygen and
nitrogen atoms are connected by a COC(R)2 group. The phenol
is usually alkylated with 2-bromo-2-methylpropionamide afford-
ing a 2-aryloxy-2-methylpropanamide that undergoes rearrange-
ment to give an N-aryl-2-hydroxypropionamide under basic
conditions.36 The formation of the final product must involve a
nucleophilic attack of the amide anion leading to a spiro inter-
mediate followed by its breakdown and protonoation (Scheme 5).
For this two-step sequence, some one-pot procedures have been
reported in literature avoiding the isolation of the intermediate
2-aryloxy-2-methylpropanamide.37 In addition, subsequent hy-
drolysis of the generated anilide could afford the corresponding
aniline.
position in the meta isomers of N-(Boc)fluoro- and chloroani-
lines already at low temperature, and also it has been shown that
the subsequent elimination of lithium halide and generation of a
benzyne intermediate is not possible to prevent, thus leading to
7-lithiobenzoxazole derivatives.26 However, as this reaction has
not been carried out with 8, we decided to check its metalation
with t-BuLi and further trapping with iodine. As expected from
previous results, 7-iodobenzoxazole derivatives 10 and 11,27
whose formation could be understood through generation of
an aryne intermediate, such as 12, were obtained in a moderate
combined yield (Scheme 3).
Having seen that the directed ortho-metalation strategy for the
synthesis of 2,3-dihaloanilines is only useful for preparing
3-fluoro-2-haloanilines, we turned our attention to the prepara-
tion of 2,3-dihalonitrobenzenes. Daugulis and co-workers re-
ported the base-mediated halogenation of acidic sp2 CꢀH bonds
and described the synthesis of 2-bromo-3-nitrofluorobenzene
(14ab) by treatment of 3-nitrofluorobenzene (13a) with lithium
tert-butoxide and carbon tetrabromide in DMF.15 We were able
to reproduce this result and moreover, we explored the extension
of this protocol to the preparation of other 2,3-dihalonitroben-
zenes 14. Therefore 2-chloro-3-nitrofluorobenzene (14ac) was
formed in high yield with use of hexachloroethane as the
electrophile. However, the employment of iodine as the halogen
electrophile in order to prepare 2-iodo-3-nitrofluorobenzene
(14aa) gave rise to low conversion to the desired adduct
(<7%) (Scheme 4). With a suitable method for the preparation
of 2,3-dihalonitrobenzenes 14ab and 14ac from commercially
available 3-nitrofluorobenzene (13a), the corresponding anilines
6ab and 6ac were readily synthesized in high yields by reduction
with iron (Scheme 4). Nevertheless, when we applied this strategy
to 3-nitrochlorobenzene (13b), only a 13% yield of the corre-
sponding 2-bromo-3-nitrochlorobenzene (14bb)28 was ob-
tained, showing that the deprotonation of 13b was not
efficient (Scheme 4). In addition, we tried to metalate this arene
derivative by using (tmp)2Zn 2MgCl2 2LiCl as the base, which
As we had reported, a new and efficient synthesis of 2,
3-dihalophenols from 3-halophenols using the O-carbamate-
directed metalation methodology,16a we thought that the Smiles
rearrangement could be suitable for our initial purpose of develop-
ing an efficient approach to 2,3-dihaloanilines. The required 2,
3-dihalophenols 16 were obtained by basic hydrolysis of the
corresponding O-2,3-dihalophenyl carbamates 15, which in turn
were efficiently accessed from 3-halophenyl carbamates by ortho-
lithiation and trapping with halogen electrophiles (Scheme 6).16a
For the introduction of bromine, better yields have been obtained
by using carbon tetrabromide as the electrophilic reagent compared
to the use of 1,2-dibromoethane, which was used in our previous
3
3
has been described by Knochel and co-workers for the chemo-
selective zincation of sensitive arenes and heteroarenes, such as
2-nitrobenzo[b]furan.29 However, 13b was not zincated with this
base even at 0 °C (Scheme 4).
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Scheme 6. Synthesis of N-(2,3-Dihalophenyl)-2-hydroxy-2-
methylpropanamides 18
Scheme 7. Alternative Synthesis of N-(3-Halo-2-
iodophenyl)-2-hydroxy-2-methylpropanamides 18ba
and 18caa
a Reagents and conditions: (a) (1) t-Bu2Zn(tmp)Li, THF, ꢀ45 °C (for
X = Cl) or ꢀ30 °C (for X = Br); (2) I2, THF; (b) (1) BBr3, CH2Cl2; (2)
NaHCO3, MeOH; (c) (1) NaOH (3 equiv), DMF, rt; (2) BrC-
(Me)2CONH2 (3 equiv), rt; (d) NaOH (9 equiv), 60 °C.
Table 2. Synthesis of 2,3-Dihaloanilines 6
Table 1. Preparation of Propanamides 17 and Dihaloanilides
18 from O-2,3-Dihalophenyl Carbamates 15
entry starting material X1 X2 17 yielda (%) 18 yielda (%)
entry
starting material
X1
X2
product
yielda (%)
1
2
15aa
15ab
15ac
15ba
15bb
F
I
17aa
86
83
82
86
80
87
85
86
82
83
80
79
18aa
18ab
18ac
18ba
18bb
18bc
18ca
18cb
18cc
18da
18db
18dc
83
77
76
82
78
84
81
83
77
79
77
75
1
2
3
4
5
6
18ab
18ac
18bb
18bc
18cb
18cc
F
Br
Cl
Br
Cl
Br
Cl
6aa
6ab
6bb
6bc
6cb
6cc
89
66b
94
90
89
95
F
Br 17ab
Cl 17ac
F
3
F
Cl
Cl
Br
Br
4
Cl
I
17ba
5
Cl Br 17bb
Cl Cl 17bc
b
6
ꢀ
7
15ca
15cb
15cc
15da
15db
15dc
Br
I
17ca
a Isolated yield based on the starting material 18. b Lower yield probably
due to volatility of this aniline.
8
Br Br 17cb
Br Cl 17cc
9
10
11
12
I
I
I
I
17da
(19b) by ortho-zincation of the corresponding 3-haloanisoles
with lithium di-tert-butyltetramethylpiperidinozincate,40 and further
treatment with iodine of the intermediate arylzincate.16b These
2,3-dihaloanisoles 19 also proved to be useful starting materials
to afford 2,3-dihaloanilides 18ba and 18ca in high yields by an
analogous three-step (BBr3-mediated deprotectionꢀphenol al-
kylationꢀrearrangement), two-pot process (Scheme 7).
Once we have developed a reliable procedure for accessing
2,3-dihaloanilides 18 and due to the lack of methods for the
preparation of 2,3-dihaloanilines, we tried to synthesize 2,3-
dihaloanilines 6 by hydrolysis of the corresponding anilides
18. We found that, in general, their reaction with ethanolic
6 M HCl at 90 °C for 6 h afforded 6 in high yields (Table 2).
However, iodine-containing rearranged amides 18 did not
cleanly furnish the expected haloiodoanilines as partial loss
of the iodine atom occurred under the reaction conditions.
For instance, 2,3-diiodoanilide 18da led to 2,3-diiodoaniline
(6da) and 3-iodoaniline in a ca. 1:2 ratio (78% combined yield),
whereas 3-chloro-2-iodoanilide 18ba afforded a 2:3 mixture of
3-chloro-2-iodoaniline (6ba) and 3-chloroaniline in 80% overall
yield.41
Br 17db
Cl 17dc
a Isolated yield referred to starting material 15. b Commercially available
2,3-dichlorophenol was used as starting material.
report.38 The crude phenols 16 were treated with an excess of
2-bromo-2-methylpropionamide39 and NaOH in DMF at room
temperature forming 2-aryloxy-2-methylpropionamides 17 that
were isolated in high yields by simple addition of water to the reaction
mixture and filtration of the crystallized compound (Scheme 6
and Table 1). Interestingly, without isolation of these derivatives 17,
the addition of an excess of NaOH to their DMF solution and
subsequent warming to 60 °C for 2 h afforded N-aryl-2-hydroxypro-
pionamides 18 in high overall yields relative to the starting carba-
mates 15 (Scheme 6 and Table 1). In this way, 2,3-dihaloanilides
18 can be efficiently synthesized from 2,3-dihalophenyl carbamates
15 in a three-step (carbamate hydrolysisꢀphenol alkylationꢀ
rearrangement), two-pot process. Furthermore, simple addition
of water at the end of the rearrangement leads to crystallization of
anilides 18 from the reaction solution, which proved to be pure
enough without further chromatographic purification.
Considering our retrosynthetic analysis for the synthesis of
4-haloindoles (Scheme 1), and having developed convenient
routes for accessing 2,3-dihaloanilides 3 and 18, then we tackle
On the other hand, we have also established an alternative syn-
thesis of 3-chloro-2-iodoanisole (19a) and 3-bromo-2-iodoanisole
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Scheme 8. Synthesis of 4-Fluoro-2-substituted-1H-indoles
20
Scheme 9. Synthesis of 3-Aryl-4-fluoro-2-substituted-1H-in-
dole 21i
Table 3. Synthesis of 3-Aryl-4-fluoro-2-substituted-1H-in-
doles 21aꢀh
iodide was used instead of the corresponding bromide for the
introduction of the aryl group at the C-3 position of the indole
ring. Interestingly, although the addition of an inorganic base,
such as K2CO3 or Cs2CO3, is usually required for the Cacchi
reaction, in our hands this microwave-irradiated process
works efficiently under the exclusive influence of Et3N as base
(Scheme 9).
To prepare 4-chloro- and 4-bromo-1H-indoles we decided to
check the suitability of the 3-halo-2-iodoanilides 18ba and 18ca
for a selective Sonogashira coupling with terminal alkynes.
Gratifyingly, we found that under standard conditions (PdꢀCu
catalysis), and without the use of special phosphine ligands, these
2,3-dihaloanilides underwent selective coupling at the iodine
atom despite this position being the most sterically crowded one.
However, to avoid dialkynylation processes in the case of 18ca,
bearing a bromo substituent, a careful control of the reac-
tion temperature should be exerted. A broad array of terminal
alkynes, including aryl-, alkyl-, heteroaryl-, alkenyl-, and trialk-
ylsilyl-substituted ones, were efficiently coupled with anilides 18,
providing 2-alkynyl-3-haloanilides 22 in high yields (Table 4).
With these o-alkynylanilides 22 in our hands and taking advan-
tage of our previously reported methodology for the synthesis of
indoles through NaOH-mediated cyclization of o-alkynylaniline
derivatives,45 we obtained 4-chloro-1H-indoles 23 and 4-bromo-
1H-indoles 24 in usually high yields by treatment of 22 with an
excess of NaOH at high temperature (Table 4).46 It is interesting
to note that N-deprotection also occurred under the reaction
conditions. In addition, starting from o-trimethylsilylethynylani-
lides 22be or 22ce, 2-unsubstituted 4-halo-1H-indoles 23e and
24e were respectively obtained, showing that the cleavage of the
silyl group also takes place under the reaction conditions
(Table 4, entries 5 and 10).
We had also shown that 2-substituted-1H-indoles could be
prepared in a one-pot manner starting from o-iodoaniline
derivatives and terminal alkynes, involving an initial Sonogashira
coupling, followed by NaOH-mediated cyclization, without the
need for isolation of the intermediate o-alkynylaniline.45 In this
way 4-fluoro-, 4-chloro-, and 4-bromo-1H-indoles 20, 23, and
24, respectively, were synthesized from 3-halo-2-iodoanilides
18aaꢀca and a selection of terminal alkynes by a one-pot, two-
step procedure (Table 5). With use of this procedure, 4-fluor-
oindoles 20 (Table 5, entries 1 and 2) as well as 4-chloroindoles
23 (Table 5, entries 3ꢀ8) were obtained in overall good yields
based on the starting materials 18, whereas 3-bromo-2-iodoani-
lide 18ca formed the corresponding 4-bromoindoles 24 in lower
yields (Table 5, entries 9ꢀ11). As in this one-pot protocol, Pd
salts are not removed after the Sonogashira coupling and prior to
the subsequent cyclization step; the isolation of these indole
derivatives 24 in lower yields could be due to competitive Pd-
catalyzed processes involving the CꢀBr bond, which could lead
entry
R
Ar
product
yielda (%)
1
Ph
2-O2NC6H4
2-O2NC6H4
3-MeOC6H4
4-MeO-3-MeC6H3
3-NCC6H4
21a
21b
21c
21d
21e
21f
72
80
84
56
86
85
90
46
2
n-Bu
Ph
3b
4b
5
n-C6H13
3-Th
6
c-C6H9
4-O2NC6H4
3-O2NC6H4
2-O2NC6H4
7
4-MeOC6H4
21g
8
n-C6H13
21h
a Isolated yield based on starting material 3aa. b The aryl bromide was
added from the beginning of the reaction.
the preparation of a wide range of different 4-haloindoles.
First, an efficient preparation of 4-fluoro-2-substituted-1H-
indoles 20 was achieved by reaction of 3-fluoro-2-iodotrifluor-
oacetanilide (3aa) with terminal aromatic and aliphatic
alkynes through a domino Pd/Cu-catalyzed coupling-cyclization
process (Scheme 8).42
On the other hand, the aminopalladationꢀreductive elimina-
tion domino reaction, mainly developed by Cacchi and co-workers,43
has been employed as a useful strategy for the regioselective
construction of 2,3-disubstituted indole rings from o-alkynyltri-
fluoroacetanilides. Interestingly, some methodologies have
been reported for the one-pot, three-component (o-haloani-
lide, terminal alkyne, aryl halide) synthesis of 2,3-disubstituted-1H-
indoles.44 On the basis of the report of Lu and co-workers,44b we
have been able to prepare a wide variety of 3-aryl-4-fluoro-2-
substituted-1H-indoles 21 from 3-fluoro-2-iodotrifluoroacetani-
lide (3aa), terminal alkynes, and aryl bromides in a one-pot pro-
cess through tandem SonogashiraꢀCacchi reactions (Table 3).
Moderate to high yields were obtained for a selection of
terminal alkynes and aryl bromides, which could be added
after the starting iodoanilide 3aa was consumed (Table 3,
entries 1, 2, and 5ꢀ8) or from the beginning of the reaction
(Table 3, entries 3 and 4).
In addition, we have also prepared trisubstituted indole 21i by
a microwave-assisted one-pot, three-component coupling reac-
tion described by Larock and co-workers.44c In this case, an aryl
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Table 4. Selective Sonogashira Couplings from 3-Halo-2-iodoanilides 18 and Synthesis of 4-Halo-1H-indoles 23 and 24 from
2-Alkynyl-3-haloanilides 22
entry
starting material
X
alkyne (R)
time (h)
product
yielda (%)
time (h)
product
yieldb (%)
1
2
18ba
18ba
18ba
18ba
18ba
18ca
18ca
18ca
18ca
18ca
18ca
Cl
Cl
Cl
Cl
Cl
Br
Br
Br
Br
Br
Br
Ph
2
22ba
22bb
22bc
22bd
22be
22ca
22cb
22cc
22 cd
22ce
22cf
86
90
81
80
81
80
85
79
86
71
74
4
23a
23b
23c
23d
23ee
24a
24b
24c
24d
24ef
24f
79
86
84
81
73
83
80
82
76
75
71
n-Bu
2.5
2.5
3
5.6d
3.5
3.5
3.5
5
2.5
2.5
2.5
4
3
n-C5H11
c
4
c-C6H9
5
SiMe3
Ph
6
5
7
n-Bu
3
8
n-C5H11
2.5
4
c
9
c-C6H9
10
11
SiMe3
3d
5
3-thienyl
3.5
3
a Isolated yield based on the corresponding starting material 18. b Isolated yield based on the corresponding starting material 22. 1-Cyclohexenyl.
c
d Conducted at 40 °C for 6 h. e 4-Chloro-1H-indole (R = H). f 4-Bromo-1H-indole (R = H).
Table 5. One-Pot Synthesis of 4-Halo-1H-indoles 20, 23, and 24 from 2,3-Dihalonanilides 18
entry
starting material
X
R
time1 (h)
time2 (h)
product
yielda (%)
1
2
18aa
18aa
18ba
18ba
18ba
18ba
18ba
18ba
18ca
18ca
18ca
F
Ph
3
4
3
4
3
3
3
3
4
4
3
4
20a
20c
23a
23b
23d
23ec
23f
85
77
81
71
82
61
75
72
49
55
48
F
n-Bu
Ph
3
3
Cl
Cl
Cl
Cl
Cl
Cl
Br
Br
Br
3
4
n-Bu
2.5
2
b
5
c-C6H9
6
SiMe3
5.5
2
7
3-ClC6H4
4-F-3-MeC6H3
Ph
8
2
23g
24a
24b
24g
9
3
10
n-Bu
2
11
3-ClC6H4
2
a Isolated yield based on the corresponding starting material 18. b 1-Cyclohexenyl. c 4-Chloro-1H-indole (R = H).
to different side products. So, for accessing 4-bromoindoles the
two-step sequence involving isolation of intermediates 22 proved
more appropriate.
Although selective Sonogashira couplings of 3-halo-2-iodoa-
nilides 18aaꢀca have been efficiently achieved (Tables 4 and 5),
the presence of two halogen atoms in the starting anilides 18
prompted us to attempt the synthesis of 4-alkynyl-2-substituted-
1H-indoles 26 (Scheme 10). First we chose 2,3-dichloroanilide
18bc as the starting material and performed the dialkynylation
reaction47 with different terminal alkynes using the catalytic
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Scheme 10. Synthesis of 4-Alkynyl-2-substituted-1H-indoles
26 from 2,3-Dichloroanilides 1c and 18bc, and 4-Bromoin-
dole 24a
Scheme 11. Synthesis of 4-Halo-3-phenylthio-2-substituted-
1H-indoles 27
Scheme 12. 4-(Hetero)aryl-2-substituted-1H-indoles 28 and
29 from 4-Haloindoles 23 and 24
system described by Buchwald and Gelman for the Sonogashira
coupling of aryl chlorides.48 In this way, 2,3-dialkynylanilides 25
were obtained in good yields. Further cyclization reaction of the
former substrates under basic conditions afforded 4-alkynyl-1H-
indoles 26 bearing the same substituent at the terminal position
of the triple bond and at C-2 (Scheme 10). As 2,3-dichloroaniline
is commercially available, we also decided to check the usefulness
of easily available trifluoroacetamide 1c for the synthesis of the
same type of indoles 26. Due to the presence of the trifluor-
oacetamido group on the nitrogen atom, the corresponding
intermediates 25 could not be isolated and the final indole
derivatives 26e,f were obtained in a one-pot process though with
similar overall yield compared with the two-step protocol. More-
over, other 2,3-dihaloanilides, such as 18ca, are suitable sub-
strates for the preparation of 4-alkynylindoles 26. In this case,
26a was synthesized in moderate yield by using a copper- and
solvent-free methodology49 for the Sonogashira couplings
(Scheme 10). Finally, to prepare a 4-alkynylindole with different
substituents at C-2 and at the terminal position of the triple bond,
4-bromoindole 24a was used as starting material and treated
under standard Sonogashira conditions. Using this approach,
4-hex-1-ynyl-2-phenyl-1H-indole (26g) was obtained in good
yield (Scheme 10).
With the aim of getting highly functionalized indole deriva-
tives from our 2,3-dihaloanilides 18, we tried to introduce an
arylthio group at C-3 under the reaction conditions employed for
the synthesis of haloindoles 24.50 Starting from 3-halo-2-iodoa-
nilides 18aa and 18ba and two different terminal alkynes we were
able to prepare 4-halo-3-phenylthio-2-substituted-1H-indoles 27
in a one-pot, three-step protocol involving the addition of
diphenyl disulfide after the NaOH-mediated cyclization step. It
should be noted that these 2,3,4-functionalized indole derivatives
27 have been prepared in high yield from easily available 2,
3-dihaloanilides 18 without the isolation of any intermediate
(Scheme 11). Also, this type of trifunctionalized indoles 27 could
be accessed from 2-alkynyl-3-haloanilides 22 by their treat-
ment with NaOH and subsequent addition of the disulfide
(Scheme 11).
Finally, we decided to explore the synthetic utility of the
obtained 4-haloindoles 23 and 24 as precursors of other 4-func-
tionalized-1H-indoles using Pd-catalyzed coupling reactions. For
instance, 4-heteroarylindoles 28 were formed in high yields by
Stille coupling of 4-chloroindoles 23 with 2-(tributylstannyl)furan
(Scheme 12, eq 1).51 In addition, 4-phenyl-2-substituted-1H-indoles
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29 also have been prepared in high yields by Suzuki coupling of
4-bromoindoles 24 with phenylboronic acid (Scheme 12, eq 2).52
1H); 13C NMR (75.4 MHz, CDCl3) δ 162.9 (d, J = 246.6 Hz, C), 155.3
(q, J = 37.8 Hz, C), 136.5 (d, J = 10.6 Hz, C), 130.7 (d, J = 9.2 Hz, CH),
116.2 (d, J = 3.2 Hz, CH), 115.7 (q, J = 288.4 Hz, C), 113.5 (d, J = 21.2
Hz, CH), 108.5 (d, J = 26.6 Hz, CH); EI-LRMS m/z 207 (Mþ, 100), 138
(45), 110 (36), 95 (32), 83 (18).
’ CONCLUSIONS
In summary, we have studied different approaches to the
synthesis of 2,3-dihaloanilines and we have found that the most
general and efficient route involves a Smiles rearrangement from
2,3-dihalophenols. By using this strategy, 2,3-dihaloanilides were
obtained in high yields from O-2,3-dihalophenyl N,N-diethylcar-
bamates or 3-halo-2-iodoanisoles without any chromatographic
purification. 3-Halo-2-iodoanilides have been shown as useful
precursors for the synthesis of 4-halo-1H-indoles through their
coupling with terminal alkynes, followed by cyclization under
treatment with NaOH. In this way, a wide variety of challen-
ging and interesting 4-haloindoles have been prepared, usually
in high yields. In addition, the usefulness of these 4-haloin-
doles as intermediates for further transformations has been
briefly outlined, including reactions that afford 2,4- and 2,3,4-
functionalized indoles.
N-(3-Chlorophenyl)-2,2,2-trifluoroacetamide (1b): Purifica-
tion by recrystallization in hexane afforded 1b (7.15 g, 80%) as a white
solid: mp 68ꢀ70 °C (lit.53 mp 66ꢀ68 °C); 1H NMR (300 MHz,
CDCl3) δ 8.24 (br s, 1H), 7.66 (t, J = 2.0 Hz, 1H), 7.42 (ddd, J = 8.0, 2.0,
1.1 Hz, 1H), 7.31 (t, J = 8.0 Hz, 1H), 7.22 (ddd, J = 8.0, 2.0, 1.1 Hz, 1H);
13C NMR (75.4 MHz, CDCl3) δ 155.3 (q, J = 37.8 Hz, C), 136.2 (C),
135.2 (C), 130.5 (CH), 126.7 (CH), 121.0 (CH), 118.8 (CH), 115.7 (q,
J = 288.5 Hz, C); EI-LRMS m/z 225 (Mþ þ 2, 33), 223 (Mþ, 100), 154
(51), 126 (19).
General Procedure for the Synthesis of N-(3-Fluoro-2-
halophenyl)-2,2,2-trifluoroacetamides 3. t-BuLi (2.5 equiv of a
1.5 M solution in hexane) was added slowly to a solution of N,N,N0,
N0-tetramethylethylenediamine (TMEDA) (2.5 equiv) in anhydrous
THF (3.5 mL/mmol) at ꢀ80 °C. After 5 min a solution of 1a (1 equiv)
in THF (1 mL/mmol) was added dropwise avoiding temperatures
exceeding ꢀ70 °C. After 40 min at ꢀ80 °C, a solution of iodine,
bromine, or hexachloroethane (1.4 equiv) in THF (1 mL/mmol) was
added dropwise. The resulting solution was stirred for 40 min at ꢀ80 °C.
Then, the reaction mixture was allowed to reach rt and was quenched
with H2O (a solution of aqueous Na2S2O3 in the case of using iodine as
electrophile). The aqueous phase was extracted with Et2O, and the
combined organic layers were washed with 1 M HCl and dried over
anhydrous Na2SO4, then the solvents were evaporated under reduced
pressure. The crude was purified by column chromatography (hexane/
EtOAc, 8/1) on silica gel to afford the title compounds 3.
2,2,2-Trifluoro-N-(3-fluoro-2-iodophenyl)acetamide (3aa):
The reaction of 1a (2.48 g, 12 mmol) with iodine (4.26 g, 16.8 mmol)
afforded 3aa (2.51 g, 63%) as a whiteꢀpale reddish solid: mp 104ꢀ
106 °C; 1H NMR (300 MHz, CDCl3) δ 8.39 (br s, 1H), 8.05 (d, J = 8.3
Hz, 1H), 7.40 (td, J = 8.3, 2.1 Hz, 1H), 7.01ꢀ6.94 (m, 1H); 13C NMR
(75.4 MHz, CDCl3) δ 161.9 (d, J = 245.6 Hz, C), 155.0 (q, J = 37.7 Hz,
C), 137.4 (d, J = 3.6 Hz, C), 130.9 (d, J = 8.9 Hz, CH), 117.5 (d, J =
3.1 Hz, CH), 115.7 (q, J = 288.5 Hz, C), 113.3 (d, J = 23.8 Hz, CH), 79.0
(d, J = 28.8 Hz, C); EI-LRMS m/z 333 (Mþ, 53), 206 (100), 186 (26),
137 (13), 109 (22); IR (KBr) 3218, 3061, 1717, 1580, 1548, 1463, 1207,
1165, 788, 733 cmꢀ1; HRMS calcd for C8H4F4INO 332.9274, found
332.9283.
N-(2-Bromo-3-fluorophenyl)-2,2,2-trifluoroacetamide (3ab):
The reaction of 1a (414 mg, 2 mmol) with bromine (447 mg, 2.8 mmol)
afforded 3ab (256 mg, 45%) as a white solid: mp 55ꢀ57 °C (lit.13 mp
55ꢀ56 °C); 1H NMR (300 MHz, CDCl3) δ 8.48 (br s, 1H), 8.14 (dt, J =
8.4, 1.3 Hz, 1H), 7.38 (td, J = 8.4, 6.0 Hz, 1H), 7.04 (td, J = 8.4, 1.3 Hz, 1H);
13C NMR (75.4, CDCl3) δ159.3 (d, J= 247.9 Hz, C), 154.9 (q, J= 37.9 Hz,
C), 134.8 (C), 129.6 (d, J = 8.7 Hz, CH), 117.3 (d, J = 3.3 Hz, CH), 115.6
(q, J = 288.9 Hz, C), 113.8 (d, J = 22.0 Hz, CH), 102.0 (d, J = 24.1 Hz, C);
EI-LRMS m/z 287 (Mþ þ 2, 21), 285 (Mþ, 21), 206 (100), 186 (20), 109
(22); HRMS calcd for C8H4BrF4NO 284.9412, found 284.9414.
N-(2-Chloro-3-fluorophenyl)-2,2,2-trifluoroacetamide (3ac):
The reaction of 1a (1.03 g, 5 mmol) with hexachloroethane (1.66 g,
7 mmol) afforded 3ac (362 mg, 30%) as a pale brown solid: mp
38ꢀ40 °C; 1H NMR (300 MHz, CDCl3) δ 8.07 (d, J = 8.4 Hz, 1H),
7.97 (br s, 1H), 7.07 (td, J = 8.4, 5.9 Hz, 1H), 7.04 (td, J = 8.4, 1.3 Hz,
1H); 13C NMR (75.4, CDCl3) δ 158.3 (d, J = 249.4 Hz, C), 154.9 (q, J =
37.9 Hz, C), 133.7 (C), 128.5 (d, J = 8.6 Hz, CH), 117.5 (C), 117.4 (d,
J = 3.5 Hz, CH), 113.8 (d, J = 20.7 Hz, CH), 112.0 (d, J = 20.6 Hz, C);
EI-LRMS m/z 243 (Mþ þ 2, 11), 241 (Mþ, 35), 206 (100), 144 (27), 117
(18), 69 (13); HRMS calcd for C8H4ClF4NO 240.9918, found 240.9924.
Synthesis of 2-(Trifluoromethyl)-7-iodobenzo[d]oxazole
(4). t-BuLi (16.2 mL of a 1.5 M solution in hexane, 27.5 mmol) was
’ EXPERIMENTAL SECTION
All reactions involving air-sensitive compounds were carried out
under a N2 atmosphere in oven-dried glassware with magnetic stirring.
Temperatures are reported as bath temperatures. Solvents used in
extraction and purification were distilled prior to use. TLC was
performed on alumina-backed plates coated with silica gel 60 with
F254 indicator; the chromatograms were visualized by UV light (254 nm)
and/or by staining with a Ce/Mo reagent, anisaldehyde, or phospho-
molybdic acid solution and subsequent heating. Rf values refer to silica
gel. Flash column chromatography was carried out on silica gel 60,
230ꢀ400 mesh. Melting points were obtained with open capillary tubes
and are uncorrected. 1H NMR spectra were recorded at 400 or 300 MHz.
Chemical shifts are reported in ppm with the residual solvent resonance
as the internal standard (CHCl3: δ 7.26; acetone-d6: δ 2.05; DMSO-d6:
δ 2.50). Data are reported as follows: chemical shift, multiplicity
(s: singlet, br s: broad singlet, d: doublet, dd: doublet of doublets, dt:
doublet of triplets, ddd doublet of doublet of doublets, t: triplet, appt:
apparent triplet, td: triplet of doublets, tdd triplet of doublet of doublets,
q: quartet, m: multiplet), coupling constants (J in Hz), and integration.
13C NMR spectra were recorded at 100.6 or 75.4 MHz, using broadband
proton decoupling. Chemical shifts are reported in ppm with the solvent
resonance as internal standard (CDCl3: δ 77.16; acetone-d6: δ 29.84;
DMSO-d6: δ 39.51). Low-resolution electron impact mass spectra
(EI-LRMS) were obtained at 70 eV on a mass spectrometer and only
the molecular ions and/or base peaks as well as significant peaks in MS
are given. High-resolution mass spectrometry (HRMS) was carried out
on a mass spectrometer. Infrared spectra were recorded with a FT-IR
spectrophotometer. The microwave heating was performed in a Micro-
wave, CEM Discover S-Class single-mode microwave cavity producing
continuous irradiation (temperature measurements were conducted
with use of an IR sensor located below the microwave cavity floor,
and reaction times refer to the total hold time at the indicated
temperature; the maximum wattage supplied was 300 W). All commer-
cially available reagents were used without purification unless otherwise
indicated and were purchased from standard chemical suppliers.
Synthesis of Trifluoroacetamides 1. These compounds were
prepared following a reported procedure.13
2,2,2-Trifluoro-N-(3-fluorophenyl)acetamide (1a): Purifica-
tion by recrystallization in hexane afforded 1a (6.37 g, 77%) as a white
solid: 67ꢀ69 °C (lit.13 mp 68ꢀ70 °C); 1H NMR (300 MHz, CDCl3)
δ 8.38 (br s, 1H), 7.48 (dt, J = 10.2, 2.1 Hz, 1H), 7.34 (td, J = 8.2, 2.1 Hz,
1H), 7.26 (ddd, J = 8.2, 2.1, 1.1 Hz, 1H), 6.95 (tdd, J = 8.2, 2.5, 1.1 Hz,
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added slowly to a solution of TMEDA (4.2 mL, 27.8 mmol) in
anhydrous THF (40 mL) at ꢀ78 °C. After 5 min a solution of 1a
(2.27 g, 11 mmol) in THF (10 mL) was added at ꢀ78 °C. After 40 min
at ꢀ60 °C, a solution of iodine (3.91 g, 15.4 mmol) in THF (10 mL) was
added dropwise. The resulting solution was stirred for 40 min at ꢀ60 °C.
Then, the reaction mixture was allowed to reach rt and was quenched
with a solution of aqueous Na2S2O3. The aqueous phase was extracted
with Et2O (3 ꢁ 30 mL), and the combined organic layers were washed
with 1 M HCl and dried over anhydrous Na2SO4, then the solvents were
evaporated under reduced pressure. The crude was purified by column
chromatography (hexane/EtOAc, 12/1) on silica gel affording 4 (1.13 g,
33%) as a red solid: mp 64ꢀ66 °C; 1H NMR (300 MHz, CDCl3) δ 7.77
(t, J = 7.6 Hz, 2H), 7.17 (t, J = 8.0 Hz, 1H); 13C NMR (75.4 MHz,
CDCl3) δ 152.3 (C), 151.1 (q, J = 44.4 Hz, C), 138.7 (C), 136.9 (CH),
127.5 (CH), 121.7 (CH), 116.6 (q, J = 272.1 Hz, C), 72.9 (C); EI-LRMS
m/z 313 (Mþ, 44), 294 (6), 186 (6), 127 (50), 69 (100); HRMS calcd
for C8H3F3INO 312.9211, found 312.9211.
General Procedure for the Synthesis of 3-Fluoro-2-haloa-
nilines 6aa and 6ab. To a solution of the corresponding N-(3-fluoro-
2-halophenyl)-2,2,2-trifluoroacetamide 3aa or 3ab (1 equiv) in EtOH
(10 mL/mmol) was added a large excess of NaOH (10 equiv) and the
mixture was refluxed for 2 h (completion of the hydrolysis was
monitored by GC-MS). After the mixture was cooled to rt, most of
the EtOH was removed under reduced pressure and the residue was
diluted with EtOAc and water. The aqueous solution was extracted with
EtOAc (3 ꢁ 20 mL), and the combined organic layers were washed with
brine and dried over anhydrous Na2SO4, then the solvents were
evaporated under reduced pressure. The crude was purified by column
chromatography on silica gel to afford the title compounds.
3-Fluoro-2-iodoaniline (6aa): Treatment of 3aa (666 mg, 2 mmol)
with NaOH (800 mg, 20 mmol) followed by purification by column
chromatography (hexane/EtOAc, 6/1) gave 6aa (407 mg, 86%) as a white
solid: mp 52ꢀ54 °C; 1H NMR (300 MHz, CDCl3) δ 7.07 (td, J = 8.1,
1.6 Hz, 1H), 6.53ꢀ6.48 (m, 1H), 6.45 (td, J = 8.1, 1.3 Hz, 1H), 4.29 (br s,
2H); 13C NMR (75.4 MHz, CDCl3) δ 162.2 (d, J = 242.2 Hz, C), 148.8
(d, J = 4.6 Hz, C), 130.0 (d, J = 10.0 Hz, CH), 109.9 (d, J = 2.4 Hz, CH),
104.6 (d, J = 24.4 Hz, CH), 71.8 (d, J = 28.2 Hz, C); EI-LRMS m/z 237
(Mþ, 100), 110 (12), 83 (12); IR (KBr) 3399, 3299, 3184, 1616, 1553,
1456, 1242, 1020, 771 cmꢀ1; HRMS calcd for C6H5FIN 236.9451, found
236.9455. Anal. Calcd for C6H5FIN: C, 30.41; H, 2.13; N, 5.91. Found: C,
30.52; H, 2.16; N, 5.87.
2-Bromo-3-fluoroaniline (6ab): Treatment of 3ab (285 mg,
1 mmol) with NaOH (400 mg, 10 mmol) followed by purification by
column chromatography (hexane/EtOAc, 6/1) gave 6ab (160 mg, 85%)
as a white solid: mp 32ꢀ34 °C; 1H NMR (300 MHz, CDCl3) δ 7.04
(tdd, J = 8.1, 6.1, 0.7 Hz, 1H), 6.55ꢀ6.47 (m, 2H), 4.23 (br s, 2H); 13C
NMR (75.4 MHz, CDCl3) δ 159.9 (d, J = 244.2 Hz, C), 146.1 (d,
J = 3.1 Hz, C), 128.6 (d, J = 9.8 Hz, CH), 110.8 (d, J = 2.7 Hz, CH), 105.3
(d, J = 22.6 Hz, CH), 96.4 (d, J = 23.6 Hz, C); EI-LRMS m/z 191 (Mþ þ
2, 88), 189 (Mþ, 100), 110 (22), 90 (14), 83 (28); IR (KBr) 3443, 3317,
1625, 1464, 763, 582 cmꢀ1; HRMS calcd for C6H5BrFN 188.9589,
found 188.9592.
by 1H NMR and GC-MS, the crude resulted to be a ca. 1:1 mixture of
7 and 1b. After purification by column chromatography (hexane/
EtOAc, 10/1) on silica gel, 7 was isolated as a white solid: mp
1
124ꢀ126 °C (lit.54 mp 124ꢀ126 °C); H NMR (300 MHz, CDCl3)
δ 7.67 (t, J = 2.0 Hz, 1H), 7.43 (br s, 1H), 7.37ꢀ7.32 (m, 1H), 7.21 (t, J =
8.0 Hz, 1H), 7.08ꢀ7.03 (m, 1H), 1.30 (s, 9H); 13C NMR (75.4 MHz,
CDCl3) δ 176.9 (C), 139.2 (C), 134.6 (C), 130.0 (CH), 124.3 (CH),
120.3 (CH), 118.1 (CH), 39.8 (C), 27.6 (3 ꢁ CH3); EI-LRMS m/z 213
(Mþ þ 2, 11), 211 (Mþ, 34), 168 (5), 127 (49), 57 (100); HRMS calcd
for C11H14ClNO 211.0764, found 211.0764.
Synthesis of N-(tert-Butoxycarbonyl)-3-chloroaniline (8).
The title compound was prepared according to a published procedure.24a
The residue was recrystallized from hexane to give 8 as a white solid:
1
mp 67ꢀ69 °C (lit.55 mp 69ꢀ70 °C); H NMR (300 MHz, CDCl3)
δ 7.51 (br s, 1H), 7.19ꢀ7.12 (m, 2H), 6.98 (dt, J = 7.2, 1.7 Hz, 1H), 6.58
(br s, 1H), 1.50 (s, 9H); 13C NMR (75.4 MHz, CDCl3) δ 152.6 (C),
139.7 (C), 134.8 (C), 130.0 (CH), 123.1 (CH), 118.6 (CH), 116.5
(CH), 81.1 (C), 28.4 (3 ꢁ CH3); EI-LRMS m/z 227 (Mþ, 3), 171 (16),
153 (26), 129 (33), 127 (100).
Synthesis of N-(tert-Butoxycarbonyl)aniline (9). n-BuLi
(0.7 mL of a 1.6 M solution in hexane, 1.1 mmol) was added to a
solution of i-Pr2NH (154 μL, 1.1 mmol) in THF (4 mL) at 0 °C. After
30 min at 0 °C, the LDA solution was cooled to ꢀ78 °C, and 8 (114 mg,
0.5 mmol) was added. The resulting solution was stirred for 30 min at
0 °C and then iodine (178 mg, 0.7 mmol) was added at ꢀ78 °C. After 1 h
at 0 °C, the reaction mixture was allowed to warm to rt and was
quenched with aqueous Na2S2O3. The aqueous phase was extracted with
EtOAc (3 ꢁ 30 mL), the combined organic layers were dried over
anhydrous Na2SO4, and the solvents were evaporated under reduced
pressure. The crude was purified by column chromatography (hexane/
EtOAc, 12/1) on silica gel affording 9 (72 mg, 75%) as a white solid: mp
135ꢀ137 °C (lit.24a mp 136ꢀ137 °C); 1H NMR (300 MHz, CDCl3)
δ 7.36 (d, J = 8.0 Hz, 2H), 7.31ꢀ7.25 (m, 2H), 7.06ꢀ6.99 (m, 1H), 6.56
(br s, 1H), 1.52 (s, 9H); 13C NMR (75.4 MHz, CDCl3) δ 152.9 (C),
138.4 (C), 129.1 (2 ꢁ CH), 123.1 (2 ꢁ CH), 118.6 (CH), 80.6 (C),
28.5 (3 ꢁ CH3); EI-LRMS m/z 193 (Mþ, 5), 137 (26), 119 (20), 93
(100).
Synthesis of 2-tert-Butoxy-2-tert-butyl-7-iodo-2,3-dihydro-
benzo[d]oxazole (10) and 2-tert-butyl-7-iodobenzo[d]oxa-
zole (11). t-BuLi (1.6 mL of a 1.6 M solution in pentane, 2.5 mmol) was
added to a solution of 8 (227 mg, 1 mmol) in THF (5 mL) at ꢀ78 °C. The
reaction mixture was allowed to reach ꢀ20 °C for 1 h. Iodine (355 mg,
1.4 mmol) was added at ꢀ78 °C and the reaction was stirred at ꢀ20 °C for
1 h. After this time, the reaction mixture was allowed to warm to rt and was
quenched with aqueous Na2S2O3. The aqueous phase was extracted with
EtOAc (3 ꢁ 30 mL), the combined organic layers were dried over anhydrous
Na2SO4, and the solvents were evaporated under reduced pressure. The crude
was purified by column chromatography (hexane/EtOAc, 12/1) on silica gel
affording a ca. 1:2 mixture of 10 (67 mg, 18%) and 11 (114 mg, 38%).
2-tert-Butoxy-2-tert-butyl-7-iodo-2,3-dihydrobenzo[d]-
1
oxazole (10): white solid; mp 134ꢀ136 °C; H NMR (300 MHz,
CDCl3) δ 7.94 (d, J = 7.8 Hz, 1H), 7.21 (d, J = 7.8 Hz, 1H), 6.71 (t, J = 7.8
Hz, 1H), 6.28 (br s, 1H), 1.64 (s, 9H), 1.47 (s, 9H); 13C NMR (75.4 MHz,
CDCl3) δ 154.1 (C), 145.2 (C), 143.4 (CH), 136.2 (C), 131.0 (CH), 127.6
(CH), 95.9 (C), 80.4 (C), 38.2 (C), 32.4 (3 ꢁ CH3), 28.5 (3 ꢁ CH3);
EI-LRMS m/z 375 (Mþ, 6), 319 (99), 275 (77), 260 (99), 232 (25), 127
(67), 57 (100); HRMS calcd for C15H22INO2 375.0695, found 375.0693.
2-tert-Butyl-7-iodobenzo[d]oxazole (11): colorless oil; Rf 0.48
(hexane/EtOAc, 7/1); 1H NMR (300 MHz, CDCl3) δ 7.61 (dd, J = 7.9,
0.9 Hz, 1H), 7.59 (dd, J = 7.9, 0.9 Hz, 1H), 7.03 (t, J = 7.9 Hz, 1H), 1.49
(s, 9H); 13C NMR (75.4 MHz, CDCl3) δ 173.2 (C), 152.5 (C), 140.5
(C), 133.4 (CH), 125.8 (CH), 119.7 (CH), 72.3 (C), 34.4 (C), 28.5
(3 ꢁ CH3); EI-LRMS m/z 301 (Mþ, 90), 286 (100), 259 (35), 245
(39), 127 (17); HRMS calcd for C11H12INO 300.9964, found 300.9969.
Synthesis of N-(3-Chlorophenyl)pivalamide (7). t-BuLi
(1.6 mL of a 1.6 M solution in pentane, 2.5 mmol) was slowly added
to a solution of TMEDA (0.38 mL, 2.52 mmol) in anhydrous THF
(3 mL) at ꢀ80 °C. After 5 min a solution of 1b (223 mg, 1 mmol) in
THF (2 mL) was added dropwise at this temperature. The reaction
mixture was allowed to reach ꢀ45 °C and, after 1 h at this temperature,
iodine (355 mg, 1.4 mmol) was added. The resulting solution was stirred
for 40 min at ꢀ45 °C. Then, the reaction mixture was allowed to reach rt
and was quenched with a solution of aqueous Na2S2O3. The aqueous
phase was extracted with Et2O (3 ꢁ 30 mL), and the combined organic
layers were washed with 1 M HCl and dried over anhydrous Na2SO4,
then the solvents were evaporated under reduced pressure. As analyzed
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Synthesis of 2-Halo-3-nitrofluorobenzenes 14 from 3-Ni-
trofluorobenzene (13a). t-BuOLi (2.5 equiv) was added to a flask
charged under N2 with 3-nitrofluorobenzene (1 equiv), the halogenating
reagent (1.5ꢀ2.0 equiv), and dry DMF (1 mL/mmol). The resulting
mixture was heated at 60 °C for the indicated time and then was allowed
to cool to rt. The crude was subjected to flash chromatography on silica
gel (hexane/EtOAc, 10/1) to afford the title compounds.
(completion of the hydrolysis was monitored by GC-MS). After the
mixture was cooled to rt, most of the EtOH was removed under reduced
pressure and the residue was diluted with Et2O and water. The organic
phase was rejected and then the aqueous solution was carefully
neutralized with a 1 M HCl solution. The aqueous solution was extracted
with Et2O (3 ꢁ 10 mL), and the combined organic layers were washed
with brine and dried over anhydrous Na2SO4, then solvents were
evaporated under reduced pressure. Without further purification, the
crude product was dissolved in dry DMF (1.5 mL/mmol) under N2 and
NaOH (3 equiv) was added. After 1 h at rt, 2-bromo-2-methylpropa-
namide (3 equiv) was added and the reaction was stirred for an additional
2 h (completion of the reaction was monitored by GC-MS). The reaction
was quenched with H2O and propanamides 17 were filtrated and
recovered as solids that were not further purified.
2-(3-Fluoro-2-iodophenoxy)-2-methylpropanamide (17aa):
Reaction of O-3-fluoro-2-iodophenyl N,N-diethylcarbamate (15aa, 168
mg, 0.5 mmol) afforded 17aa (138 mg, 86%) as a white solid: mp
100ꢀ102 °C; 1H NMR (300 MHz, CDCl3) δ 7.23 (td, J = 8.2, 6.6 Hz,
1H), 6.85 (br s, 1H), 6.84ꢀ6.76 (m, 2H), 5.84 (br s, 1H), 1.65 (s, 6H);
13C NMR (75.4 MHz, CDCl3) δ 177.0 (C), 163.0 (d, J = 245.8 Hz, C),
156.1 (d, J = 4.9 Hz, C), 129.9 (d, J = 9.6 Hz, CH), 114.8 (d, J = 3.0 Hz,
CH), 110.4 (d, J = 24.1 Hz, CH), 83.8 (C), 80.3 (d, J = 25.7 Hz, C), 25.0
(2 ꢁ CH3); EI-LRMS m/z 323 (Mþ, 1), 279 (41), 238 (81), 196 (60),
152 (19), 112 (19), 86 (100); IR (KBr) 3451, 3416, 1673, 1458, 1237,
1152, 600 cmꢀ1. Anal. Calcd for C10H11FINO2: C, 37.17; H, 3.43; N,
4.34. Found: C, 37.34; H, 3.48; N, 4.40.
2-Bromo-1-fluoro-3-nitrobenzene (14ab): Reaction of 13a
(350 mg, 2.5 mmol) with CBr4 (1.25 g, 3.75 mmol) and t-BuOLi
(500 mg, 6.25 mmol) for 4 h afforded 14ab (279 mg, 51%) as a yellow
1
solid: mp 43ꢀ45 °C (lit.15 mp 42ꢀ44 °C); H NMR (300 MHz,
CDCl3) δ 7.63 (dt, J = 8.1 1.4 Hz, 1H), 7.47 (td, J = 8.1, 5.2 Hz, 1H),
7.36 (td, J = 8.1, 1.4 Hz, 1H); 13C NMR (75.4 MHz, CDCl3) δ 159.8
(d, J = 251.1 Hz, C), 151.0 (C), 129.2 (d, J = 8.4 Hz, CH), 121.0 (d,
J = 3.5 Hz, CH), 120.1 (d, J = 23.4 Hz, CH), 103.6 (d, J = 25.5 Hz, C);
EI-LRMS m/z 219 (Mþ, 81), 189 (26), 175 (68), 163 (31), 94 (100).
2-Chloro-1-fluoro-3-nitrobenzene (14ac):56. Reaction of 13a
(350 mg, 2.5 mmol) with C2Cl6 (1.18 g, 5 mmol) and t-BuOLi (500 mg,
6.25 mmol) for 6 h afforded 14ac (323 mg, 74%) as a colorless oil:
Rf 0.43 (hexane/EtOAc, 10/1); 1H NMR (300 MHz, CDCl3) δ 7.75ꢀ
7.65 (m, 1H), 7.50ꢀ7.39 (m, 2H); 13C NMR (75.4 MHz, CDCl3)
δ 158.8 (d, J = 252.9 Hz, C), 148.9 (C), 128.1 (d, J = 8.3 Hz, CH), 121.0
(d, J = 3.7 Hz, CH), 120.5 (d, J = 21.9 Hz, CH), 116.0 (d, J = 21.8 Hz, C);
EI-LRMS m/z 177 (Mþ þ 2, 23), 175 (Mþ, 72), 145 (21), 131 (35), 129
(77), 117 (36), 84 (80), 49 (100); HRMS calcd for C6H3ClFNO2
174.9836, found 174.9837.
2-(2-Bromo-3-fluorophenoxy)-2-methylpropanamide (17ab):
Reaction of O-2-bromo-3-fluorophenyl N,N-diethylcarbamate (15ab,
870 mg, 3 mmol) afforded 17ab (684 mg, 83%) as a white solid: mp
91ꢀ93 °C; 1H NMR (300 MHz, CDCl3) δ 7.19 (td, J = 8.3, 6.5 Hz,
1H), 6.98 (br s, 1H), 6.91ꢀ6.82 (m, 2H), 6.48 (br s, 1H), 1.60 (s, 6H);
13C NMR (75.4 MHz, CDCl3) δ 177.4 (C), 160.2 (d, J = 247.7 Hz, C),
153.4 (d, J = 3.0 Hz, C), 128.2 (d, J = 9.5 Hz, CH), 116.4 (d, J = 3.2 Hz,
CH), 111.2 (d, J = 22.4 Hz, CH), 104.9 (d, J = 21.2 Hz, C), 83.9 (C),
24.8 (2 ꢁ CH3); EI-LRMS m/z 277 (Mþ þ 2, 1), 275 (Mþ, 1), 233
(27), 231 (28), 196 (52), 192 (39), 190 (39), 86 (100); IR (KBr)
3428, 3212, 1683, 1463, 1018, 794, 596 cmꢀ1; HRMS calcd for
C10H11BrFNO2 274.9957, found 274.9953.
2-(2-Chloro-3-fluorophenoxy)-2-methylpropanamide (17ac):
Reaction of O-2-chloro-3-fluorophenyl N,N-diethylcarbamate (15ac, 122mg,
0.5 mmol) afforded 17ac (95 mg, 82%) as a white solid: mp 92ꢀ94 °C; 1H
NMR (300 MHz, CDCl3) δ 7.13 (td, J = 8.3, 6.3 Hz, 1H), 6.98 (br s, 1H),
6.92ꢀ6.84 (m, 2H), 6.73 (br s, 1H), 1.56 (s, 6H); 13C NMR (75.4 MHz,
CDCl3) δ 177.5 (C), 159.2 (d, J = 249.2 Hz, C), 152.2 (d, J = 2.2 Hz, C),
127.1 (d, J = 9.4 Hz, CH), 117.0 (d, J = 3.2 Hz, CH), 115.3 (d, J = 18.1 Hz,
C), 111.4 (d, J = 21.2 Hz, CH), 83.9 (C), 24.7 (2 ꢁ CH3); EI-LRMS m/z
231 (Mþ, 1), 196 (20), 187 (49), 146 (53), 86 (100), 58 (29); IR (KBr)
3425, 3214, 1684, 1465, 1452, 1140, 1020, 795, 605 cmꢀ1; HRMS calcd for
C10H11ClFNO2 231.0462, found 231.0469.
2-Bromo-1-chloro-3-nitrobenzene (14bb): Reaction of 13b
(788 mg, 5 mmol) with CBr4 (2.49 g, 5 mmol) and t-BuOLi (1000 mg,
12.5 mmol) for 17 h afforded 14bb (154 mg, 13%) as a white solid: mp
83ꢀ85 °C (lit.11a mp 83ꢀ84 °C); 1H NMR (300 MHz, CDCl3) δ 7.67
(dd, J = 8.1, 1.5 Hz, 1H), 7.61 (dd, J = 8.1, 1.5 Hz, 1H), 7.41 (t, J = 8.1 Hz,
1H); 13C NMR (75.4 MHz, CDCl3) δ 137.6 (C), 133.3 (CH), 128.7
(CH), 123.1 (CH), 115.4 (C); EI-LRMS m/z 239 (Mþ þ 4, 26), 237
(Mþ þ 2, 100), 235 (Mþ, 76), 191 (89), 179 (63), 110 (71), 75 (74);
HRMS calcd for C6H3ClBrNO2 234.9036, found 234.9025.
Synthesis of 3-Fluoro-2-haloanilines 6ab and 6ac from
Nitroaromatics 14. Powder Fe (3 equiv) was added to a solution of
the corresponding 2-halo-3-nitrofluorobenzene 14 (1 equiv) in HCl:
EtOH (1:7) and the mixture was refluxed for 2 h (completion of the
reduction was monitored by GC-MS). After the mixture was cooled to rt,
most of the EtOH was removed under reduced pressure and the residue
was diluted with EtOAc and water. The aqueous solution was carefully
neutralized with a 1 M NaOH solution. The aqueous solution was
extracted with EtOAc (3 ꢁ 15 mL), the combined organic layers were
dried over anhydrous Na2SO4, and solvents were evaporated under
reduced pressure. The crude was purified by column chromatography on
silica gel to afford the title compounds (data for 6ab have been reported
above).
2-Chloro-3-fluoroaniline (6ac):56. Treatment of 14ac (175 mg,
1 mmol) with Fe (168 mg, 3 mmol) followed by purification by column
chromatography (hexane/EtOAc, 6/1) gave 6ac (123 mg, 85%) as a
colorless oil: Rf 0.35 (hexane/EtOAc, 5/1); 1H NMR (300 MHz,
CDCl3) δ 7.00 (td, J = 8.2, 6.0 Hz, 1H), 6.57ꢀ6.49 (m, 2H), 4.18
(br s, 2H); 13C NMR (75.4 MHz, CDCl3) δ 159.0 (d, J = 245.6 Hz, C),
144.9 (d, J = 2.4 Hz, C), 127.6 (d, J = 9.7 Hz, CH), 110.8 (d, J = 2.8 Hz,
CH), 106.5 (d, J = 20.3 Hz, C), 105.4 (d, J = 21.3 Hz, CH); EI-LRMS
m/z 147 (Mþ þ 2, 31), 145 (Mþ, 100), 118 (7), 110 (9), 83 (18); IR
(KBr) 3390, 1622, 1470, 987, 767 cmꢀ1; HRMS calcd for C6H5ClFN
145.0095, found 145.0103.
General Procedure for the Synthesis of 2-(2,3-Dihalophenoxy)-
2-methylpropanamides 17 from O-2,3-Dihalophenyl N,
N0-Diethylcarbamates 15. To a solution of the corresponding
carbamate 1516a (1 equiv) in EtOH (10 mL/mmol) was added a large
excess of NaOH (10 equiv) and the mixture was refluxed for 5ꢀ8 h
2-(3-Chloro-2-iodophenoxy)-2-methylpropanamide (17ba):
Reaction of O-3-chloro-2-iodophenyl N,N-diethylcarbamate (15ba, 176
mg, 0.5 mmol) afforded 17ba (145 mg, 86%) as a white solid: mp
1
101ꢀ103 °C; H NMR (300 MHz, CDCl3) δ 7.26ꢀ7.16 (m, 2H),
6.89ꢀ6.82 (m, 2H), 5.71 (br s, 1H), 1.65 (s, 6H); 13C NMR (75.4 MHz,
CDCl3) δ 177.1 (C), 156.2 (C), 140.1 (C), 129.5 (CH), 124.1 (CH),
116.8 (CH), 97.3 (C), 83.9 (C), 25.1 (2 ꢁ CH3); EI-LRMS m/z 339
(Mþ, 1), 295 (12), 254 (42), 212 (44), 128 (17), 86 (100), 58 (24); IR
(KBr) 3453, 3418, 1673, 1563, 1439, 1151, 1134, 980, 958, 771,
576 cmꢀ1; HRMS calcd for C10H11ClINO2 338.9523, found 338.9524.
2-(2-Bromo-3-chlorophenoxy)-2-methylpropanamide (17bb):
Reaction of O-2-bromo-3-chlorophenyl N,N-diethylcarbamate (15bb,
153 mg, 0.5 mmol) afforded 17bb (116 mg, 80%) as a white solid: mp
84ꢀ86 °C; 1H NMR (300 MHz, CDCl3) δ 7.26ꢀ7.13 (m, 2H),
7.01ꢀ6.94 (m, 2H), 6.11 (br s, 1H), 1.61 (s, 6H); 13C NMR (75.4
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ARTICLE
MHz, CDCl3) δ 177.2 (C), 153.4 (C), 136.1 (C), 128.1 (CH), 125.1
(CH), 118.9 (CH), 118.1 (C), 84.0 (C), 24.9 (2 ꢁ CH3); EI-LRMS m/z
291 (Mþ, 1), 249 (12), 214 (10), 212 (33), 168 (11), 86 (100), 58 (26);
387 (16), 346 (88), 304 (100), 260 (10), 218 (11), 86 (59), 58 (18); IR
(KBr) 3465, 3263, 1682, 1429, 1141, 953, 564 cmꢀ1; HRMS calcd for
C10H11I2NO2 430.8879, found 430.8891.
IR (KBr) 3467, 3156, 1698, 1570, 1445, 1260, 1149, 963, 544 cmꢀ1
;
2-(2-Bromo-3-iodophenoxy)-2-methylpropanamide (17db):
Reaction of O-2-bromo-3-iodophenyl N,N-diethylcarbamate (15db, 199 mg,
0.5 mmol) afforded 17db (153 mg, 80%) as a white solid: mp 134ꢀ136 °C;
1H NMR (400 MHz, CDCl3) δ 7.58 (d, J = 7.6 Hz, 1H), 7.02 (d, J = 7.9 Hz,
1H), 6.98ꢀ6.92 (m, 2H), 6.27 (br s, 1H), 1.59 (s, 6H); 13C NMR
(100.6 MHz, CDCl3) δ 177.4 (C), 152.4 (C), 134.9 (CH), 129.2 (CH),
124.8 (C), 120.3 (CH), 102.8 (C), 84.2 (C), 24.9 (2 ꢁ CH3); EI-LRMS
m/z385 (Mþ þ 2, 1), 383 (Mþ, 1), 341 (17), 339 (18), 304 (100), 300 (50),
298 (53), 86 (96); IR (KBr) 3444, 3184, 1680, 1566, 1437, 1154, 966, 764,
584 cmꢀ1; HRMS calcd for C10H11BrINO2 382.9018, found 382.9001.
2-(2-Chloro-3-iodophenoxy)-2-methylpropanamide (17dc):
Reaction of O-2-chloro-3-iodophenyl N,N-diethylcarbamate (15dca, 176
mg, 0.5 mmol) afforded 17dc (133 mg, 79%) as a white solid: mp
130ꢀ132 °C; 1H NMR (400 MHz, CDCl3) δ 7.58 (dd, J = 8.1, 1.1 Hz,
1H), 7.06 (dd, J = 8.1, 1.1 Hz, 1H), 6.95 (br s, 1H), 6.90 (t, J = 8.1 Hz, 1H),
6.24 (br s, 1H), 1.57 (s, 6H); 13C NMR (100.6 MHz, CDCl3) δ 177.3 (C),
151.0 (C), 134.9 (CH), 132.2 (C), 128.4 (CH), 121.4 (CH), 99.6 (C),
84.1 (C), 24.9 (2 ꢁ CH3);EI-LRMSm/z339 (Mþ, 1), 304 (38), 295 (25),
256 (19), 254 (59), 86 (100); IR (KBr) 3454, 3175, 1680, 1568, 1442,
1155, 968, 765, 586 cmꢀ1; HRMS calcd for C10H11ClINO2 338.9523,
found 338.9524. Anal. Calcd for C10H11ClINO2: C, 35.37; H, 3.27; N, 4.12.
Found: C, 35.46; H, 3.31; N, 4.09.
General Procedure for the Synthesis of N-(2,3-Dihalophenyl)-
2-hydroxy-2-methylpropanamides 18 from O-2,3-Dihalo-
phenyl N,N0-Diethylcarbamates 15. To a solution of the corre-
sponding carbamate 1516a (1 equiv) in EtOH (10 mL/mmol) was added
a large excess of NaOH (10 equiv) and the mixture was refluxed for 5ꢀ
8 h (completion of the hydrolysis was monitored by GC-MS). After the
mixture was cooled to rt, most of the EtOH was removed under reduced
pressure and the residue was diluted with Et2O and water. The organic
phase was rejected, and then the aqueous solution was carefully
neutralized with a 1 M HCl solution. The aqueous solution was extracted
with Et2O (3 ꢁ 30 mL), the combined organic layers were washed with
brine, dried over anhydrous Na2SO4, and the solvents were evaporated
under reduced pressure. Without further purification, the corresponding
crude phenol 16 was dissolved in dry DMF (1.5 mL/mmol) under N2
and NaOH (3 equiv) was added to the mixture. After 1 h at rt, 2-bromo-
2-methylpropanamide (3 equiv) was added and the reaction was stirred
for 2 h at rt. After complete formation of the corresponding propana-
mide 17 (monitored by GC-MS), an excess of NaOH (9 equiv) was
added and the mixture was heated at 60 °C for 2 h. The reaction was
quenched with H2O and the corresponding propanamide 18 was
recovered as a solid after filtration, which was not further purified.
N-(3-Fluoro-2-iodophenyl)-2-hydroxy-2-methylpropana-
mide (18aa): Reaction of O-3-fluoro-2-iodophenyl N,N-diethylcarba-
mate (15aa, 674 mg, 2 mmol) afforded 18aa (536 mg, 83%) as a white
solid: mp 95ꢀ97 °C; 1H NMR (300 MHz, CDCl3) δ 9.31 (br s, 1H),
8.13 (d, J = 8.3 Hz, 1H), 7.35ꢀ7.26 (m, 1H), 6.83 (t, J = 8.3 Hz, 1H),
2.71 (s, 1H), 1.58 (s, 6H); 13C NMR (75.4 MHz, CDCl3) δ 175.0 (C),
161.8 (d, J = 243.7 Hz, C), 139.8 (d, J = 3.5 Hz, C), 130.5 (d, J = 9.0 Hz,
CH), 116.5 (d, J = 2.9 Hz, CH), 111.2 (d, J = 23.8 Hz, CH), 78.1 (d, J =
27.9 Hz, C), 74.7 (C), 28.1 (2 ꢁ CH3); EI-LRMS m/z 323 (Mþ, 27),
265 (33), 237 (100), 138 (19), 59 (81); IR (KBr) 3420, 3368, 3289,
1661, 1462, 1416, 776 cmꢀ1; HRMS calcd for C10H11FINO2 322.9819,
found 322.9812.
HRMS calcd for C10H11BrClNO2 290.9662, found 290.9650. Anal.
Calcd for C10H11BrClNO2: C, 41.05; H, 3.79; N, 4.79. Found: C, 40.89;
H, 3.77; N, 4.75.
2-(2,3-Dichlorophenoxy)-2-methylpropanamide (17bc):
2,3-Dichlorophenol (81 mg, 0.5 mmol) (commercially available) was
dissolved in dry DMF (0.75 mL) under N2 and NaOH (60 mg, 1.5 mmol)
was added. After 1 h at rt, 2-bromo-2-methylpropanamide (250 mg,
1.5 mmol) was added and the reaction was stirred for 2 h at rt
(completion of the reaction was monitored by GC-MS). The reaction
was quenched with H2O and 17bc (107 mg, 87%) was recovered as a
1
white solid after filtration: mp 100ꢀ102 °C; H NMR (300 MHz,
CDCl3) δ 7.26ꢀ7.09 (m, 2H), 7.05ꢀ6.89 (m, 2H), 6.21 (br s, 1H), 1.58
(s, 6H); 13C NMR (75.4 MHz, CDCl3) δ 177.3 (C), 152.1 (C), 134.1
(C), 127.2 (CH), 126.7 (C), 125.3 (CH), 119.8 (CH), 84.1 (C), 24.8
(2 ꢁ CH3); EI-LRMS m/z 249 (Mþ þ 2, 1), 247 (Mþ, 1), 212 (23), 203
(30), 162 (50), 126 (14), 86 (100), 58 (25); IR (KBr) 3474, 3155, 1699,
1450, 1264, 1145, 783, 550 cmꢀ1. Anal. Calcd for C10H11Cl2NO2: C,
48.41; H, 4.47; N, 5.65. Found: C, 48.59; H, 4.52; N, 5.60.
2-(3-Bromo-2-iodophenoxy)-2-methylpropanamide (17ca):
Reaction of O-3-bromo-2-iodophenyl N,N-diethylcarbamate (15ca, 199
mg, 0.5 mmol) afforded 17ca (162 mg, 85%) as a white solid: mp
114ꢀ116 °C; 1H NMR (300 MHz, CDCl3) δ 7.35 (dd, J = 8.1, 1.1 Hz,
1H), 7.14 (t, J = 8.1 Hz, 1H), 6.89 (dd, J = 8.1, 1.1 Hz, 1H), 6.83 (br s, 1H),
5.82 (br s, 1H), 1.64 (s, 6H); 13C NMR (75.4 MHz, CDCl3) δ 177.3 (C),
156.2 (C), 131.2 (C), 129.8 (CH), 127.4 (CH), 117.2 (CH), 100.3 (C),
83.9 (C), 25.0 (2 ꢁ CH3); EI-LRMS m/z 341 (Mþ ꢀ CONH2 þ 2, 6),
339 (Mþ ꢀ CONH2, 6), 300 (25), 298 (25), 258 (25), 256 (26), 207 (14),
86 (100), 58 (27); IR (KBr) 3461, 3146, 1674, 1434, 1146, 966, 911,
575 cmꢀ1; HRMS calcd for C10H11BrINO2 382.9018, found 382.9005.
2-(2,3-Dibromophenoxy)-2-methylpropanamide (17cb):
Reaction of O-2,3-dibromophenyl N,N-diethylcarbamate (15cb, 174
mg, 0.5 mmol) afforded 17cb (144 mg, 86%) as a white solid: mp
111ꢀ113 °C; 1H NMR (300 MHz, CDCl3) δ 7.35 (d, J = 7.8 Hz, 1H),
7.14ꢀ6.94 (m, 3H), 6.42 (br s, 1H), 1.60 (s, 6H); 13C NMR (75.4 MHz,
CDCl3) δ 177.3 (C), 153.2 (C), 128.6 (CH), 128.4 (CH), 126.3 (C),
120.3 (C), 119.5 (CH), 84.0 (C), 24.9 (2 ꢁ CH3); EI-LRMS m/z 295
(Mþ ꢀ CONH2 þ 4, 5), 293 (Mþ ꢀ CONH2 þ 2, 11), 291 (Mþ ꢀ
CONH2, 5), 252 (26), 86 (100), 58 (22); IR (KBr) 3467, 3147, 1698,
1440, 1260, 1147, 953, 779, 548 cmꢀ1; HRMS calcd for C10H11Br2NO2
334.9157, found 334.9150. Anal. Calcd for C10H11Br2NO2: C, 35.64; H,
3.29; N, 4.16. Found: C, 35.55; H, 3.27; N, 4.12.
2-(3-Bromo-2-chlorophenoxy)-2-methylpropanamide (17cc):
Reaction of O-3-bromo-2-chlorophenyl N,N-diethylcarbamate (15cc,
153 mg, 0.5 mmol) afforded 17cc (120 mg, 82%) as a white solid: mp
117ꢀ119 °C; 1H NMR (300 MHz, CDCl3) δ 7.37 (dd, J = 6.7, 2.7 Hz,
1H), 7.23ꢀ7.04 (m, 2H), 6.94 (br s, 1H), 5.67 (br s, 1H), 1.59 (s, 6H);
13C NMR (75.4 MHz, CDCl3) δ 177.2 (C), 151.9 (C), 128.5 (CH),
127.7 (CH), 124.0 (CH), 120.4 (CH), 84.1 (C), 24.8 (2 ꢁ CH3); EI-
LRMS m/z 293 (Mþ þ 2, 1), 291 (Mþ, 1), 258 (11), 249 (19), 247 (14),
208 (33), 206 (24), 86 (100), 58 (23); IR (KBr) 3471, 3153, 1699, 1446,
1263, 1149, 953, 912, 548 cmꢀ1; HRMS calcd for C10H11ClBrNO2
290.9662, found 290.9667.
2-(2,3-Diiodophenoxy)-2-methylpropanamide (17da):
Reaction of O-2,3-diiodophenyl N,N-diethylcarbamate (15da, 222 mg,
0.5 mmol) afforded 17da (179 mg, 83%) as a white solid: mp
N-(2-Bromo-3-fluorophenyl)-2-hydroxy-2-methylpropa-
namide (18ab): Reaction of O-2-bromo-3-fluorophenyl N,N-diethyl-
carbamate (15ab, 580 mg, 2 mmol) afforded 18ab (425 mg, 77%) as a
white solid: mp 102ꢀ104 °C; 1H NMR (300 MHz, CDCl3) δ 9.47 (br s,
1H), 8.20 (dt, J = 8.3, 1.4 Hz, 1H), 7.25 (td, J = 8.3, 6.2 Hz, 1H), 6.87 (td,
J = 8.3, 1.4 Hz, 1H), 3.01 (s, 1H), 1.56 (s, 6H); 13C NMR (75.4 MHz,
1
131ꢀ133 °C; H NMR (300 MHz, CDCl3) δ 7.59 (dd, J = 7.7, 1.4
Hz, 1H), 7.01 (appt, J = 8.0 Hz, 1H), 6.91 (dd, J = 8.2, 1.4 Hz, 1H), 6.84
(br s, 1H), 6.29 (br s, 1H), 1.63 (s, 6H); 13C NMR (75.4 MHz, CDCl3)
δ 177.2 (C), 155.5 (C), 134.1 (CH), 130.3 (CH), 117.7 (CH), 109.5
(C), 106.4 (C), 83.9 (C), 25.1 (2 ꢁ CH3); EI-LRMS m/z 431 (Mþ, 1),
3426
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The Journal of Organic Chemistry
ARTICLE
CDCl3) δ 175.1 (C), 159.2 (d, J = 245.9 Hz, C), 137.2 (d, J = 2.2 Hz, C),
129.0 (d, J = 8.8 Hz, CH), 116.3 (d, J = 3.2 Hz, CH), 111.6 (d, J = 22.0
Hz, CH), 101.3 (d, J = 23.2 Hz, C), 74.7 (C), 28.0 (2 ꢁ CH3); EI-LRMS
m/z 277 (Mþ þ 2, 12), 275 (Mþ, 13), 219 (15), 217 (15), 191 (61), 189
(73), 59 (100); IR (KBr) 3326, 3310, 1665, 1601, 1469, 1422, 1252,
777 cmꢀ1; HRMS calcd for C10H11BrFNO2 274.9957, found 274.9958.
Anal. Calcd for C10H11Cl2NO2: C, 43.50; H, 4.02; N, 5.07. Found: C,
43.38; H, 4.06; N, 5.05.
(t, J = 8.1 Hz, 1H), 2.55 (s, 1H), 1.57 (s, 6H); 13C NMR (75.4 MHz,
CDCl3) δ 174.9 (C), 140.5 (C), 130.4 (C), 130.1 (CH), 128.5 (CH),
119.4 (CH), 98.2 (C), 74.7 (C), 28.0 (2 ꢁ CH3); EI-LRMS m/z 385
(Mþ þ 2, 3), 383 (Mþ, 3), 325 (4), 299 (24), 297 (25), 240 (10), 238
(10), 200 (15), 198 (15), 59 (100); IR (KBr) 3387, 3285, 1652, 1651,
1525, 1392, 776, 693 cmꢀ1; HRMS calcd for C10H11BrINO2 382.9018,
found 382.9012. Anal. Calcd for C10H11BrINO2: C, 31.28; H, 2.89; N,
3.65. Found: C, 31.38; H, 2.92; N, 3.67.
N-(2-Chloro-3-fluorophenyl)-2-hydroxy-2-methylpropan-
amide (18ac): Reaction of O-2-chloro-3-fluorophenyl N,N-diethyl-
carbamate (15ac, 490 mg, 2 mmol) afforded 18ac (351 mg, 76%) as a
white solid: mp 106ꢀ108 °C; 1H NMR (300 MHz, CDCl3) δ 9.44 (br s,
1H), 8.23 (d, J = 8.4 Hz, 1H), 7.27ꢀ7.16 (m, 1H), 6.90 (t, J = 8.4 Hz,
1H), 2.84 (s, 1H), 1.56 (s, 6H); 13C NMR (75.4 MHz, CDCl3) δ 174.9
(C), 158.2 (d, J = 247.4 Hz, C), 136.0 (d, J = 1.2 Hz, C), 128.0 (d, J =
8.7 Hz, CH), 116.0 (d, J = 3.4 Hz, CH), 111.5 (d, J = 20.7 Hz, CH), 111.0
(d, J = 20.0 Hz, C), 74.7 (C), 28.0 (2 ꢁ CH3); EI-LRMS m/z 233
(Mþ þ 2, 7), 231 (Mþ, 21), 173 (25), 147 (28), 145 (97), 59 (100); IR
(KBr) 3418, 3340, 1677, 1522, 1472, 1253, 1132, 782 cmꢀ1; HRMS
calcd for C10H11ClFNO2 231.0462, found 231.0462.
N-(3-Chloro-2-iodophenyl)-2-hydroxy-2-methylpropana-
mide (18ba): Reaction of O-3-chloro-2-iodophenyl N,N-diethylcarba-
mate (15ba, 3.53 g, 10 mmol) afforded 18ba (2.78 g, 82%) as a white
solid: mp 113ꢀ115 °C; 1H NMR (300 MHz, CDCl3) δ 9.33 (br s, 1H),
8.21 (dd, J = 7.8, 1.5 Hz, 1H), 7.31ꢀ7.21 (m, 2H), 2.47 (s, 1H), 1.58 (s,
6H); 13C NMR (75.4 MHz, CDCl3) δ 175.0 (C), 140.4 (C), 139.1 (C),
129.8 (CH), 125.1 (CH), 118.9 (CH), 95.1 (C), 74.7 (C), 28.0
(2 ꢁ CH3); EI-LRMS m/z 341 (Mþ þ 2, 3), 339 (Mþ, 8), 281 (10),
253 (62), 194 (15), 154 (24), 59 (100); IR (KBr) 3398, 3291, 1662, 1575,
1539, 1444, 1396, 1126, 776 cmꢀ1; HRMS calcd for C10H11ClINO2
338.9523, found 338.9514.
N-(2-Bromo-3-chlorophenyl)-2-hydroxy-2-methylpropa-
namide (18bb): Reaction of O-2-bromo-3-chlorophenyl N,N-diethyl-
carbamate (15bb, 612 mg, 2 mmol) afforded 18bb (454 mg, 78%) as a
white solid: mp 107ꢀ109 °C; 1H NMR (300 MHz, CDCl3) δ 9.48 (br s,
1H), 8.34 (dd, J = 7.5, 2.3 Hz, 1H), 7.28ꢀ7.19 (m, 2H), 2.56 (s, 1H),
1.57 (s, 6H); 13C NMR (75.4 MHz, CDCl3) δ 174.7 (C), 137.5 (C),
134.9 (C), 128.7 (CH), 125.5 (CH), 119.1 (CH), 114.4 (C), 74.8 (C),
28.1 (2xCH3); EI-LRMS m/z 293 (Mþ þ 2, 5), 291 (Mþ, 4), 235 (5),
233 (5), 207 (35), 205 (27), 154 (14), 59 (100); IR (KBr) 3390, 3315,
1663, 1582, 1543, 1450, 1404, 777 cmꢀ1; HRMS calcd for C10H11BrClNO2
290.9662, found 290.9661.
N-(2,3-Dibromophenyl)-2-hydroxy-2-methylpropanamide
(18cb): Reaction of O-2,3-dibromophenyl N,N-diethylcarbamate(15cb,
698 mg, 2 mmol) afforded 18cb (556 mg, 83%) as a white solid: mp
119ꢀ121 °C; 1H NMR (300 MHz, CDCl3) δ 9.51 (br s, 1H), 8.34 (dd,
J = 8.1, 1.4 Hz, 1H), 7.36 (dd, J= 8.1, 1.4 Hz, 1H), 7.15 (t, J = 8.1 Hz, 1H),
3.01(br s, 1H), 1.55 (s, 6H); 13C NMR(75.4 MHz, CDCl3) δ 175.1 (C),
137.4 (C), 129.0 (CH), 128.9 (CH), 125.2 (C), 119.7 (CH), 116.6 (C),
74.6 (C), 28.0 (2 ꢁ CH3); EI-LRMS m/z 339 (Mþ þ 4, 2), 337
(Mþ þ 2, 5), 335 (Mþ, 2), 279 (6), 253 (19), 251 (38), 249 (19), 58
(100); IR (KBr) 3444, 3224, 1668, 1575, 1567, 1515, 780 cmꢀ1; HRMS
calcd for C10H11Br2NO2 334.9157, found 334.9165.
N-(3-Bromo-2-chlorophenyl)-2-hydroxy-2-methylpropan-
amide (18cc): Reaction of O-3-bromo-2-chlorophenyl N,N-diethyl-
carbamate (15cc, 612 mg, 2 mmol) afforded 18cc (448 mg, 77%) as a
white solid: mp 114ꢀ116 °C; 1H NMR (300 MHz, CDCl3) δ 9.51 (br s,
1H), 8.36 (dd, J = 8.2, 1.1 Hz, 1H), 7.34 (dd, J = 8.2, 1.1 Hz, 1H), 7.10
(t, J = 8.2, 1H), 3.22 (s, 1H), 1.55 (s, 6H); 13C NMR (75.4 MHz,
CDCl3) δ 175.2 (C), 135.9 (C), 128.7 (CH), 128.2 (CH), 123.8 (C),
122.7 (C), 119.6 (CH), 74.5 (C), 27.9 (2 ꢁ CH3); EI-LRMS m/z 295
(Mþ þ 4, 2), 293 (Mþ þ 2, 10) 291 (Mþ, 9), 258 (5), 256 (5), 235 (11),
233 (11), 209 (14), 207 (60), 205 (46), 200 (12), 198 (12), 125(9), 90
(12), 59 (100); IR (KBr) 3343, 3323, 1664, 1526, 1406, 1132, 777,
569 cmꢀ1; HRMS calcd for C10H11ClBrNO2 290.9662, found 290.9672.
N-(2,3-Diiodophenyl)-2-hydroxy-2-methylpropanamide
(18da): Reaction of O-2,3-diiodophenyl N,N-diethylcarbamate (15da,
890 mg, 2 mmol) afforded 18da (680 mg, 79%) as a white solid: mp
144ꢀ146 °C; 1H NMR (300 MHz, CDCl3) δ 9.28 (br s, 1H), 8.24 (dd,
J = 8.2, 1.4 Hz, 1H), 7.67 (dd, J = 7.8, 1.4 Hz, 1H), 7.09 (appt, J = 8.0 Hz,
1H), 2.53 (br s, 1H), 1.57 (s, 6H); 13C NMR (75.4 MHz, CDCl3)
δ 175.1 (C), 140.0 (C), 135.4 (CH), 130.4 (CH), 120.2 (CH), 108.8 (C),
104.5 (C), 74.5 (C), 28.0 (2 ꢁ CH3); EI-LRMS m/z 431 (Mþ, 21), 372
(8), 345 (85), 286 (62), 246 (44), 218 (14), 91 (15), 59 (100); IR (KBr)
3318, 1651, 1568, 1523, 1386, 773 cmꢀ1; HRMS calcd for C10H11I2NO2
430.8879, found 430.8873.
N-(2,3-Dichlorophenyl)-2-hydroxy-2-methylpropanamide
(18bc): 2,3-Dichlorophenol (1.63 g, 10 mmol) (commercially available)
was dissolved in dry DMF (15 mL) under N2 and NaOH (1.20 g, 30 mmol)
was added. After 1 h at rt, 2-bromo-2-methylpropanamide (4.98 g, 30 mmol)
was added and the reaction was stirred for 2 h atrt. Aftercompletionofthe
alkylation reaction (monitored by GC-MS), an excess of NaOH (3.60 g,
90 mmol) was added and the mixture was heated at 60 °C for 2 h. The
reaction was quenched with H2O and 18bc (2.08 g, 84%) was isolated
after filtration as a white solid: mp 109ꢀ111 °C; 1H NMR (300 MHz,
CDCl3) δ 9.50 (br s, 1H), 8.37ꢀ8.29 (m, 1H), 7.22ꢀ7.15 (m, 2H),
3.11 (s, 1H), 1.55 (s, 6H); 13C NMR (75.4 MHz, CDCl3) δ 175.1 (C),
136.0 (C), 132.8 (C), 127.8 (CH), 125.4 (CH), 122.0 (C), 118.9 (CH),
74.6 (C), 27.9 (2 ꢁ CH3); EI-LRMS m/z 251 (Mþ þ 4, 2), 249 (Mþ þ
2, 12), 247 (Mþ, 21), 189 (20), 163 (56), 161 (89), 59 (100); IR (KBr)
3422, 3337, 1671, 1509, 1407, 1124, 778, 701 cmꢀ1. Anal. Calcd for
C10H11Cl2NO2: C, 48.41; H, 4.47; N, 5.65. Found: C, 48.49; H, 4.47;
N, 5.67.
N-(2-Bromo-3-iodophenyl)-2-hydroxy-2-methylpropana-
mide (18db): Reaction of O-2-bromo-3-iodophenyl N,N-diethylcarba-
mate (15db, 796 mg, 2 mmol) afforded 18db (591 mg, 77%) as a white
solid: mp 110ꢀ112 °C; 1H NMR (400 MHz, CDCl3) δ 9.47 (br s, 1H),
8.36 (dd, J = 8.1, 1.1 Hz, 1H), 7.60 (dd, J = 8.1, 1.1 Hz, 1H), 7.01 (t, J = 8.1
Hz, 1H), 3.01 (br s, 1H), 1.54 (s, 6H); 13C NMR (100.6 MHz, CDCl3)
δ 175.1 (C), 136.7 (C), 135.5 (CH), 129.5 (CH), 121.1 (C), 120.6 (CH),
101.5 (C), 74.5 (C), 27.9 (2 ꢁ CH3); EI-LRMS m/z 385 (Mþ þ 2, 11),
383 (Mþ, 11), 327 (12), 325 (12), 304 (40), 299 (55), 297 (46), 286 (18),
246 (34), 207 (77), 59 (100); IR (KBr) 3334, 1661, 1578, 1529, 1392,
774 cmꢀ1; HRMS calcd for C10H11BrINO2 382.9018, found 382.9001.
N-(2-Chloro-3-iodophenyl)-2-hydroxy-2-methylpropana-
mide (18dc): Reaction of O-2-chloro-3-iodophenyl N,N-diethylcarba-
mate (15dc, 706 mg, 2 mmol) afforded 18dc (508 mg, 75%) as a white
solid: mp 101ꢀ103 °C; 1H NMR (400 MHz, CDCl3) δ 9.40 (br s, 1H),
8.33 (dd, J = 8.1, 1.2 Hz, 1H), 7.52 (dd, J = 8.1, 1.2 Hz, 1H), 6.89 (t, J =
8.1 Hz, 1H), 2.94 (s, 1H), 1.48 (s, 6H); 13C NMR (100.6 MHz, CDCl3)
δ 175.1 (C), 135.2 (CH), 135.1 (C), 128.8 (CH), 127.5 (C), 120.6
(CH), 98.2 (C), 74.6 (C), 27.9 (2 ꢁ CH3); EI-LRMS m/z 341 (Mþ þ 2,
10), 339 (Mþ, 30), 304 (41), 281 (31), 255 (31), 253 (99), 246 (36), 59
(100); IR (KBr) 3343, 3325, 1662, 1568, 1528, 1397, 776 cmꢀ1; HRMS
calcd for C10H11ClINO2 338.9523, found 338.9522.
N-(3-Bromo-2-iodophenyl)-2-hydroxy-2-methylpropana-
mide (18ca): Reaction of O-3-bromo-2-iodophenyl N,N-diethylcarba-
mate (15ca, 796 mg, 2 mmol) afforded 18ca (620 mg, 81%) as a white
solid: mp 118ꢀ120 °C; 1H NMR (300 MHz, CDCl3) δ 9.33 (br s, 1H),
8.23 (dd, J = 8.1, 1.4 Hz, 1H), 7.40 (dd, J = 8.1, 1.4 Hz, 1H), 7.22
3427
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ARTICLE
General Procedure for the Synthesis of N-(2,3-Dihalophenyl)-
2-hydroxy-2-methylpropanamides 18 from 3-Halo-2-iodoa-
nisoles 19. BBr3 (20 mL of a 1 M solution in CH2Cl2, 20 mmol) was
added dropwise to a solution of the corresponding 3-halo-2-iodoanisole
19a or 19b (4 mmol), prepared as previously described,16b in CH2Cl2
(120 mL) at ꢀ78 °C. The mixture was warmed to rt overnight, and then
NaHCO3 (1.68 g, 20 mmol) was added. The resulting mixture was
cooled to 0 °C, and MeOH (70 mL) was added dropwise. After 30 min
at 0 °C, the mixture was warmed to rt and stirred for 1 h. Most of the
solvent was removed under reduced pressure and the residue was diluted
with water and CH2Cl2. The separated aqueous phase was extracted with
CH2Cl2 (2 ꢁ 30 mL). The combined organic layers were dried over
anhydrous Na2SO4 and concentrated under reduced pressure. Without
further purification, the corresponding crude dihalophenol 16 was
dissolved in anhydrous DMF (6 mL) under N2 and NaOH (480 mg,
12 mmol) was added to the mixture. After 1 h at rt, 2-bromo-2-
methylpropanamide (1.99 g, 12 mmol) was added and the reaction
was stirred for 2 h at rt. After complete alkylation of 16 (monitored by
GC-MS), NaOH (9 equiv) was added and the mixture was heated at
60 °C for 2 h. The reaction was quenched with H2O and the
corresponding propanamide 18ba or 18ca was recovered as a solid after
filtration. Their spectroscopic data have been reported above.
General Procedure for the Synthesis of 2,3-Dihaloanilines
6 from Anilides 18. A solution of the corresponding N-(2,3-dihalo-
phenyl)-2-hydroxy-2-methylpropanamide 18 (1 mmol) in 6 M HCl:
EtOH (1:1) (20 mL) was refluxed for 5ꢀ6 h (completion of the
hydrolysis was monitored by GC-MS). After the mixture was cooled to
rt, most of the EtOH was removed under reduced pressure and the
residue was diluted with EtOAc and water. The aqueous solution was
carefully neutralized with a 1 M NaOH solution. The aqueous solution
was extracted with EtOAc (3 ꢁ 15 mL), the combined organic layers
were dried over anhydrous Na2SO4, and the solvents were evaporated
under reduced pressure. The crude was purified by column chromatog-
raphy on silica gel (hexane/EtOAc, 6/1) to afford the title compounds 6.
2-Bromo-3-fluoroaniline (6ab): Reaction of 18ab (275 mg,
1 mmol) gave 6ab (169 mg, 89%). Spectroscopic and characterization
data are reported above.
48), 251 (Mþ þ 2, 100), 249 (Mþ, 53), 172 (12), 170 (12), 90 (43); IR
(KBr) 3382, 1611, 1455, 1287, 1014, 768, 695 cmꢀ1; HRMS calcd for
C6H5Br2N 248.8789, found 248.8777.
3-Bromo-2-chloroaniline (6cc): Reaction of 18cc (291 mg,
1 mmol) gave 6cc (195 mg, 95%) as a white solid: mp 31ꢀ33 °C; 1H
NMR (400 MHz, CDCl3) δ 6.99 (dd, J = 8.0, 1.5 Hz, 1H), 6.90 (t, J =
8.0 Hz, 1H), 6.67 (dd, J = 8.0, 1.5 Hz, 1H), 4.16 (br s, 2H); 13C NMR
(100.6 MHz, CDCl3) δ 144.6 (C), 128.1 (CH), 123.2 (C), 122.8 (CH),
119.2 (C), 114.4 (CH); EI-LRMS m/z 209 (Mþ þ 4, 22), 207 (Mþ þ 2,
100), 205 (Mþ, 71), 126 (13), 90 (29), 63 (12); IR (KBr) 3480, 3388,
1615, 1462, 1435, 767 cmꢀ1; HRMS calcd for C6H5ClBrN 204.9294,
found 204.9286.
General Procedure for the Synthesis of 4-Fluoro-2-sub-
stituted-1H-indoles 20 from 3aa. A mixture of 3aa (1 equiv), the
corresponding alkyne (1.5 equiv), PdCl2(PPh3)2 (3 mol %), CuI
(5 mol %), and Et2NH (1.5 equiv) in anhydrous DMA (5 mL/mmol)
was heated for 4 h at 80 °C under N2 (cyclization was completed as
monitored by GC-MS). CH2Cl2 (20 mL) and water (20 mL) were
added to the cooled reaction mixture. The separated aqueous phase was
extracted with CH2Cl2 (2 ꢁ 20 mL). The combined organic layers were
washed with water (2 ꢁ 60 mL). The organic layer was dried over
anhydrous Na2SO4 and concentrated at reduced pressure. The remain-
ing residue was purified by column chromatography (hexane/EtOAc,
10/1) on silica gel affording the corresponding 4-fluoro-1H-indoles 20.
4-Fluoro-2-phenyl-1H-indole (20a): Treatment of 3aa (167 mg,
0.5 mmol) with phenylacetylene (77 mg, 0.75 mmol), PdCl2(PPh3)2
(10 mg, 3 mol %), CuI (5 mg, 5 mol %), and Et2NH (54 mg, 0.75 mmol)
afforded 20a (92 mg, 87%) as a brown solid: mp 62ꢀ64 °C (lit.59 mp
65ꢀ67 °C); 1H NMR (300 MHz, CDCl3) δ 8.45 (br s, 1H), 7.70ꢀ7.63
(m, 2H), 7.51ꢀ7.43 (m, 2H), 7.41ꢀ7.33 (m, 1H), 7.21ꢀ7.09 (m, 2H),
6.93 (dd, J = 2.2, 0.7 Hz, 1H), 6.84 (ddd, J = 10.3, 7.4 1.2 Hz, 1H); 13C
NMR (75.4 MHz, CDCl3) δ 156.5 (d, J = 246.8 Hz, C), 139.3 (d, J =
11.2 Hz, C), 138.0 (C), 131.9 (C), 129.2 (2 ꢁ CH), 128.1 (CH), 125.3
(2 ꢁ CH), 122.8 (d, J = 7.6 Hz, CH), 118.6 (d, J = 22.4 Hz, C), 107.1
(d, J = 3.6 Hz, CH), 105.1 (d, J = 18.9 Hz, CH), 95.8 (CH); EI-LRMS
m/z 211 (Mþ, 100), 183 (17), 108 (4); HRMS calcd for C14H10FN
211.0797, found 211.0787.
2-Chloro-3-fluoroaniline (6ac): Reaction of 18ac (231 mg,
1 mmol) gave 6ac (96 mg, 66%). Spectroscopic and characterization
data are reported above.
4-Fluoro-2-hexyl-1H-indole (20b): Treatment of 3aa (200 mg,
0.6 mmol) with 1-octyne (99 mg, 0.9 mmol), PdCl2(PPh3)2 (13 mg, 3
mol %), CuI (6 mg, 5 mol %), and Et2NH (66 mg, 0.9 mmol) afforded
20b (102 mg, 78%) as a brown oil: Rf 0.45 (hexane/EtOAc, 5/1); 1H
NMR (300 MHz, CDCl3) δ 7.93 (br s, 1H), 7.15ꢀ6.93 (m, 2H), 6.79
(ddd, J = 10.4, 6.9, 1.7 Hz, 1H), 6.35 (dd, J = 2.2, 0.8 Hz, 1H), 2.74 (t, J =
7.5 Hz, 2H), 1.80ꢀ1.62 (m, 2H), 1.47ꢀ1.21 (m, 6H), 0.94 (t, J = 6.9 Hz,
3H); 13C NMR (75.4, CDCl3) δ 155.8 (d, J = 245.1 Hz, C), 140.2 (C),
138.5 (d, J = 11.9 Hz, C), 121.3 (d, J = 7.7 Hz, CH), 117.8 (d, J = 22.4 Hz,
C), 106.5 (d, J = 3.4 Hz, CH), 104.5 (d, J = 19.1 Hz, CH), 95.4 (CH),
31.7 (CH2), 29.14 (CH2), 29.08 (CH2), 28.2 (CH2), 22.7 (CH2), 14.2
(CH3); EI-LRMS m/z 219 (Mþ, 27), 162 (32), 148 (100), 101 (9);
HRMS calcd for C14H18FN 219.1423, found 219.1418.
General Procedure for the Synthesis of 3-Aryl-4-fluoro-2-
substituted-1H-indoles 21aꢀh. A mixture of 3aa (166 mg, 0.5
mmol), Pd(OAc)2 (6 mg, 5 mol %), PPh3 (26 mg, 20 mol %), K2CO3
(4 276 mg, 2 mmol), and the corresponding alkyne (0.6 mmol) in DMF
(3 mL) was stirred under N2 at 70 °C until the complete formation of the
2-alkynylacetamide was observed (monitored by GC-MS). Then, the
corresponding aryl bromide (0.6 mmol) was added and the reaction was
stirred overnight at 70 °C. For the synthesis of 21c and 21d, the
corresponding aryl bromide was added from the beginning of the
reaction and the mixture was stirred under N2 at 70 °C until the
complete formation of the corresponding 2,3-disubstituted-4-fluoroin-
dole was observed (monitored by GC-MS). In both cases, the resulting
mixture was quenched with water, and the aqueous solution was
extracted with EtOAc (3 ꢁ 15 mL). The combined organic layers were
2-Bromo-3-chloroaniline (6bb):57. Reaction of 18bb (291 mg,
1 mmol) gave 6bb (193 mg, 94%) as a white solid: mp 41ꢀ43 °C;
1H NMR (300 MHz, CDCl3) δ 7.02 (t, J = 8.0 Hz, 1H), 6.84 (dd, J = 8.0,
1.5 Hz, 1H), 6.63 (dd, J = 8.0, 1.5 Hz, 1H), 4.26 (br s, 2H); 13C NMR
(75.4 MHz, CDCl3) δ 146.1 (C), 135.1 (C), 128.4 (CH), 119.5 (CH),
113.5 (CH), 109.3 (C); EI-LRMS m/z 209 (Mþ þ 4, 23), 207 (Mþ þ 2,
100), 205 (Mþ, 77), 126 (16), 90 (30), 63 (12); IR (KBr) 3473, 3381,
1610, 1462, 1018, 769 cmꢀ1; HRMS calcd for C6H5ClBrN 204.9294,
found 204.9293.
2,3-Dichloroaniline (6bc): Reaction of 18bc (248 mg, 1 mmol)
1
gave 6bc (144 mg, 90%) as a white solid: mp 26ꢀ28 °C; H NMR
(300 MHz, CDCl3) δ 6.97 (t, J = 8.0 Hz, 1H), 6.84 (dd, J = 8.0, 1.5 Hz,
1H), 6.63 (dd, J = 8.0, 1.5 Hz, 1H), 4.20 (br s, 2H); 13C NMR (75.4
MHz, CDCl3) δ 144.6 (C), 132.9 (C), 127.6 (CH), 119.4 (CH), 117.3
(C), 113.7 (CH); EI-LRMS m/z 165 (Mþ þ 4, 9), 163 (Mþ þ 2, 61),
161 (Mþ,100), 126 (9), 90 (17), 63 (9); IR (KBr) 3479, 3390, 1615,
1464, 905, 768 cmꢀ1; HRMS calcd for C6H5Cl2N 160.9799, found
160.9792.
2,3-Dibromoaniline (6cb): Reaction of 18cb (335 mg, 1 mmol)
gave 6cb (223 mg, 89%) as a white solid: mp 41ꢀ43 °C (lit.58 mp
45ꢀ46 °C) ; 1H NMR (300 MHz, CDCl3) δ 7.01 (dd, J = 7.8, 1.8 Hz,
1H), 6.95 (t, J = 7.8 Hz, 1H), 6.68 (dd, J = 7.8, 1.8 Hz, 1H), 4.28 (br s,
2H); 13C NMR (75.4 MHz, CDCl3) δ 146.1 (C), 128.9 (CH), 125.7
(C), 122.9 (CH), 114.1 (CH), 111.5 (C); EI-LRMS m/z 253 (Mþ þ 4,
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washed with water (2 ꢁ 30 mL) and dried over anhydrous Na2SO4. The
solvent was removed under reduced pressure and the residue was puri-
fied by silica gel column chromatography (hexane/EtOAc) on silica gel
to afford the title compounds 21.
(CH3), 31.6 (CH2), 29.9 (CH2), 29.1 (CH2), 26.1 (CH2), 22.7 (CH2),
16.5 (CH3), 14.2 (CH3); EI-LRMS m/z 339 (Mþ, 100), 295 (21), 268
(43), 253 (12), 237 (23), 224 (36); HRMS calcd for C22H26FNO
339.1998, found 339.1996.
4-Fluoro-3-(2-nitrophenyl)-2-phenyl-1H-indole (21a):
Treatment of 3aa with phenylacetylene (61 mg, 0.6 mmol) for 1.5 h,
further reaction with 1-bromo-2-nitrobenzene (121 mg, 0.6 mmol), and
purification by column chromatography (hexane/EtOAc, 5/1) gave 21a
3-(4-Fluoro-2-(thiophen-3-yl)-1H-indol-3-yl)benzonitrile
(21e): Treatment of 3aa with 3-ethynylthiophene (64 mg, 0.6 mmol)
for 2.5 h, further reaction with 3-bromobenzonitrile (108 mg, 0.6 mmol),
and purification by column chromatography (hexane/EtOAc, 10/1)
gave 21e (136 mg, 86%) as a brown solid: 1H NMR (300 MHz, DMSO-
d6) δ 11.95 (br s, 1H), 7.82ꢀ7.73 (m, 2H), 7.69 (ddd, J = 7.8, 3.1,
1.6 Hz, 1H), 7.62ꢀ7.49 (m, 3H), 7.27 (d, J = 8.0 Hz, 1H), 7.11 (td, J =
8.0, 5.1 Hz, 1H), 6.92 (dd, J = 3.9, 2.6 Hz, 1H), 6.77 (dd, J = 11.8, 7.3 Hz,
1H); 13C NMR (75.4 MHz, DMSO-d6) δ 155.9 (d, J = 245.2 Hz, C),
138.3 (d, J = 10.8 Hz, C), 136.7 (C), 135.7 (C), 134.0 (d, J = 1.9 Hz, C),
132.0 (CH), 131.3 (C), 130.4 (CH), 129.3 (CH), 127.0 (CH), 126.8
(CH), 123.8 (CH), 122.5 (d, J = 7.9 Hz, C), 118.9 (CH), 116.0 (d, J =
17.7 Hz, C), 111.2 (CH), 108.9 (d, J = 2.7 Hz, C), 108.0 (d, J = 3.4 Hz,
CH), 104.9 (d, J = 19.4 Hz, CH); EI-LRMS m/z 318 (Mþ, 100), 285
(11), 273 (9); HRMS calcd for C19H11FN2S 318.0627, found 318.0621.
2-Cyclohexenyl-4-fluoro-3-(4-nitrophenyl)-1H-indole (21f):
Treatment of 3aa with 1-ethynylcyclohexene (63 mg, 0.6 mmol) for 2.5
h, further reaction with 4-bromonitrobenzene (120 mg, 0.6 mmol), and
purification by column chromatography (hexane/EtOAc, 5/1) gave 21f
(142 mg, 85%) as an orange solid: mp 239ꢀ241 °C; 1H NMR (300 MHz,
DMSO-d6) δ11.7 (s, 1H), 8.19 (d, J= 8.1 Hz, 2H), 7.62 (d, J= 7.5 Hz, 2H),
7.21 (d, J = 8.1 Hz, 1H), 7.07 (dd, J = 12.7, 7.7 Hz, 1H), 6.76 (dd, J = 11.9,
7.7 Hz, 1H), 5.88 (s, 1H), 2.19ꢀ1.96 (m, 4H), 1.65ꢀ1.46 (m, 4H); 13C
NMR (75.4, DMSO-d6) δ155.7 (d, J= 245.0 Hz, C), 145.3 (C), 143.4 (C),
139.2 (C), 138.0 (d, J = 11.0 Hz, C), 131.1 (d, J = 3.0 Hz, 2 ꢁ CH), 130.7
(CH), 129.0 (CH), 122.9 (2 ꢁ CH), 122.2 (d, J = 8.0 Hz, C), 115.1 (d, J =
17.7 Hz, C), 108.3 (d, J =2.8Hz, C), 108.0(d, J= 3.2 Hz, CH), 105.0 (d, J=
20.0 Hz, CH), 27.5 (CH2), 25.2 (CH2), 22.2 (CH3), 21.4 (CH3); EI-
LRMS m/z 336 (Mþ, 100), 290 (35), 261 (24), 248 (29), 235 (21), 222
(10); HRMS calcd for C20H17FN2O2 336.1274, found 336.1274.
3-(4-Fluoro-2-(4-methoxyphenyl)-1H-indol-3-yl)benzonitrile
(21g): Treatment of 3aa with p-tolylacetylene (79 mg, 0.6 mmol) for
4 h, further reaction with 3-bromobenzonitrile (108 mg, 0.6 mmol), and
purification by column chromatography (hexane/EtOAc, 10/1) gave
21g (153 mg, 90%) as a pale brown solid: mp 186ꢀ188 °C; 1H NMR
(300 MHz, CDCl3) δ 8.43 (br s, 1H), 7.69 (d, J = 1.7 Hz, 1H),
7.67ꢀ7.62 (m, 1H), 7.56ꢀ7.52 (m, 1H), 7.43 (t, J = 7.8 Hz, 1H),
7.25ꢀ7.19 (m, 3H), 7.18ꢀ7.10 (m, 1H), 6.87 (d, J = 8.9 Hz, 2H),
6.83ꢀ6.78 (m, 1H), 3.82 (s, 3H); 13C NMR (75.4, CDCl3) δ 159.9
(C), 156.7 (d, J = 248.0 Hz, C), 138.2 (d, J = 10.7 Hz, C), 136.7 (C),
135.6 (d, J = 2.4 Hz, CH), 134.4 (d, J = 2.6 Hz, CH), 130.0 (CH), 129.8
(2 ꢁ CH), 128.8 (CH), 123.7 (C), 123.1 (d, J = 8.0 Hz, CH), 119.3 (C),
116.8 (d, J = 18.1 Hz, C), 114.6 (2 ꢁ CH), 112.1 (C), 110.1 (C), 107.2
(d, J = 3.7 Hz, CH), 106.2 (d, J = 20.0 Hz, CH), 55.4 (CH3); EI-LRMS
m/z 342 (Mþ, 100), 297 (17), 272 (4); HRMS calcd for C22H15FN2O
342.1168, found 342.1172. Anal. Calcd for C22H15FN2O: C, 77.18; H,
4.42; N, 8.18. Found: C, 76.99; H, 4.46; N, 8.23.
1
(119 mg, 72%) as a yellow-orange solid: mp 177ꢀ179 °C; H NMR
(300 MHz, CDCl3) δ 8.47 (br s, 1H), 8.10ꢀ8.05 (m, 1H), 7.52ꢀ7.42
(m, 2H), 7.38ꢀ7.34 (m, 1H), 7.29 (s, 4H), 7.16 (t, J = 8.2 Hz, 2H),
7.13ꢀ7.06 (m, 1H), 6.74 (dd, J = 11.7, 7.70 Hz, 1H); 13C NMR (75.4
MHz, CDCl3) δ 156.7 (d, J = 247.1 Hz, C), 150.0 (C), 138.2 (d, J = 10.4
Hz, C), 135.2 (d, J = 0.9 Hz, C), 134.6 (CH), 132.6 (CH), 131.4 (C),
130.7 (d, J = 0.6 Hz, C), 129.0 (2 ꢁ CH), 128.4 (CH), 128.1 (2 ꢁ CH),
128.1 (CH), 124.8 (CH), 123.3 (d, J = 8.0 Hz, CH), 116.9 (d, J =
18.6 Hz, C), 108.4 (d, J = 1.7 Hz, C), 107.5 (d, J = 3.7 Hz, CH), 105.9 (d,
J = 19.2 Hz, CH); EI-LRMS m/z 332 (Mþ, 44), 285 (15), 105 (100), 77
(16); HRMS calcd for C20H13FN2O2 332.0961, found 332.0949. Anal.
Calcd for C20H13FN2O2: C, 72.28; H, 3.94; N, 8.43. Found: C, 71.89; H,
4.00; N, 8.38.
2-Butyl-4-fluoro-3-(2-nitrophenyl)-1H-indole (21b): Treat-
ment of 3aa with 1-hexyne (49 mg, 0.6 mmol) for 2.5 h, further reaction
with 1-bromo-2-nitrobenzene (121 mg, 0.6 mmol), and purification by
column chromatography (hexane/EtOAc, 5/1) gave 21b (124 mg,
80%) as an orange solid: mp 85ꢀ87 °C; 1H NMR (300 MHz, CDCl3)
δ 8.19 (br s, 1H), 8.08ꢀ8.03 (m, 1H), 7.65ꢀ7.58 (m, 1H), 7.52ꢀ7.45
(m, 2H), 7.12ꢀ7.08 (m, 1H), 7.08ꢀ7.00 (m, 1H), 6.70 (ddd, J = 11.1,
7.5, 1.2 Hz, 1H), 2.71ꢀ2.54 (m, 2H), 1.64ꢀ1.53 (m, 2H), 1.36ꢀ1.21
(m, 2H), 0.84 (t, J = 7.3 Hz, 3H); 13C NMR (75.4 MHz, CDCl3) δ 156.2
(d, J = 245.7 Hz, C), 150.0 (C), 137.8 (d, J = 11.0 Hz, C), 137.2 (C),
134.2 (CH), 132.3 (CH), 130.5 (C), 127.8 (CH), 124.5 (CH), 122.1 (d,
J = 7.8 Hz, CH), 116.2 (d, J = 18.8 Hz, C), 107.6 (d, J = 1.6 Hz, C), 107.0
(d, J = 3.5 Hz, CH), 105.3 (d, J = 19.3 Hz, CH), 31.5 (CH2), 25.8 (CH2),
22.3 (CH2), 13.8 (CH3); EI-LRMS m/z 312 (Mþ, 100), 253 (86), 228
(71), 199 (25); IR (KBr) 3411, 2953, 2927, 1519, 1351, 1046, 779, 753,
740 cmꢀ1; HRMS calcd for C18H17FN2O2 312.1274, found 312.1276.
4-Fluoro-3-(3-methoxyphenyl)-2-phenyl-1H-indole (21c):
Treatment of 3aa with phenylacetylene (61 mg, 0.6 mmol) and
3-bromoanisole (112 mg, 0.6 mmol) for 5 h followed by purification
by column chromatography (hexane/EtOAc, 10/1) gave 21c (133 mg,
84%) as a brown solid: 120ꢀ122 °C; 1H NMR (300 MHz, CDCl3) δ
8.39 (s, 1H), 7.41ꢀ7.24 (m, 5H), 7.24ꢀ7.10 (m, 3H), 7.03 (s, 2H),
6.92ꢀ6.77 (m, 2H), 3.76 (s, 3H); 13C NMR (75.4 MHz, CDCl3) δ
159.2 (C), 157.1 (d, J = 249.0 Hz, C), 138.3 (d, J = 10.8 Hz, C), 136.3
(C), 134.7 (C), 132.2 (C), 128.9 (CH), 128.7 (2 ꢁ CH), 128.4 (2 ꢁ
CH), 128.0 (CH), 123.6 (d, J = 1.9 Hz, CH), 122.9 (d, J = 8.0 Hz, CH),
117.2 (d, J = 18.0 Hz, C), 116.3 (d, J = 2.6 Hz, CH), 113.1 (d, J = 3.0 Hz,
C), 112.6 (CH), 107.1 (d, J = 3.7 Hz, CH), 105.9 (d, J = 20.1 Hz, CH),
55.2 (CH3); EI-LRMS m/z 317 (Mþ, 100), 285 (10), 272 (20), 259 (4);
HRMS calcd for C21H16FNO 317.1216, found 317.1216.
4-Fluoro-2-hexyl-3-(4-methoxy-3-methylphenyl)-1H-indole
(21d): Treatment of 3aa with 1-octyne (66 mg, 0.6 mmol) and 4-bromo-
2-methylanisole (120 mg, 0.6 mmol) for 6 h, and purification by column
chromatography (hexane/EtOAc, 10/1) gave 21d (95 mg, 56%) as a
brown solid: mp 211ꢀ213 °C; 1H NMR (300 MHz, CDCl3) δ 8.06 (br s,
1H), 7.27 (s, 2H), 7.15ꢀ7.02 (m, 2H), 6.92 (d, J = 8.6 Hz, 1H), 6.77 (dd,
J = 10.0, 7.3 Hz, 1H), 3.91 (s, 3H), 2.76 (t, J = 7.7 Hz 2H), 2.32 (s, 3H),
1.71ꢀ1.61 (m, 2H), 1.40ꢀ1.20 (m, 6H), 0.90 (t, J = 6.6 Hz, 3H); 13C
NMR (75.4 MHz, CDCl3) δ 156.6 (d, J = 247.4 Hz, C), 156.4 (C), 137.9
(d, J = 11.4 Hz, C), 136.3 (C), 132.9 (d, J = 1.9 Hz, CH), 130.5 (d, J =
2.1 Hz, C), 128.8 (d, J = 1.9 Hz, CH), 127.9 (C), 127.1 (C), 125.8 (CH),
121.6 (d, J= 8.0 Hz, CH), 116.6 (d, J= 18.1 Hz, C), 112.4 (d, J=2.6Hz, C),
109.5 (CH), 106.5 (d, J = 3.5 Hz, CH), 105.2 (d, J = 20.2 Hz, CH), 55.4
2-(4-Fluoro-2-hexyl-1H-indol-3-yl)benzonitrile (21h): Treat-
ment of 3aa with 1-octyne (66 mg, 0.6 mmol) for 2.5 h, further reaction
with 2-bromobenzonitrile (108 mg, 0.6 mmol), and purification by column
chromatography (hexane/EtOAc, 10/1) gave 21h (73 mg, 46%) as a pale
brown solid: mp 100ꢀ102 °C; 1H NMR (300 MHz, CDCl3) δ 8.39 (br s,
1H), 7.76 (d, J = 7.5, 1.4 Hz, 1H), 7.62 (td, J = 7.5, 1.4 Hz, 1H), 7.56ꢀ7.49
(m, 1H), 7.43 (td, J = 7.5, 1.4 Hz, 1H), 7.14ꢀ7.00 (m, 2H), 6.76 (ddd, J =
11.2, 7.5, 1.1 Hz, 1H), 2.80ꢀ2.57 (m, 2H), 1.73ꢀ1.46 (m, 2H), 1.34ꢀ1.08
(m, 6H), 0.82 (t, J = 6.9 Hz, 3H); 13C NMR (75.4, CDCl3) δ 156.2 (d, J =
246.6 Hz, C), 139.7 (C), 138.1 (C), 137.8 (d, J = 10.9 Hz, C), 132.7 (CH),
132.4 (d, J = 1.7 Hz, CH), 132.1 (CH), 127.1 (CH), 122.3 (d, J = 7.9 Hz,
CH), 119.1 (C), 116.4 (d, J = 18.5 Hz, C), 114.2 (C), 108.8 (d, J = 2.0 Hz,
C), 107.0 (d, J = 3.6 Hz, CH), 105.6 (d, J = 19.5 Hz, CH), 31.5 (CH2), 29.3
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(CH2), 28.9 (CH2), 26.4 (CH2), 22.6 (CH2), 14.1 (CH3); EI-LRMS m/z
320 (Mþ, 74), 263 (22), 249 (100), 229 (22), 84 (18); HRMS calcd for
C21H21FN2 320.1689, found 320.1691.
(C), 103.7 (C), 74.5 (C), 73.1 (C), 30.7 (CH2), 28.1 (2 ꢁ CH3), 22.1
(CH2), 19.6 (CH2), 13.7 (CH3); EI-LRMS m/z 295 (Mþ þ 2, 17), 293
(Mþ, 51), 207 (48), 193 (41), 178 (64), 164 (88), 59 (100); IR (KBr)
3419, 3322, 1670, 1572, 1516, 1450, 981 cmꢀ1; HRMS calcd for
C16H20ClNO2 293.1183, found 293.1184.
Synthesis of 4-Fluoro-3-(3-methoxyphenyl)-2-thiophen-
3-yl-1H-indole (21i): A mixture of 3aa (100 mg, 0.3 mmol), PdCl2-
(PPh3)2 (6.3 mg, 0.009 mmol), CuI (1.4 mg, 0.006 mmol), and
3-ethynylthiophene (39 mg, 0.36 mmol) in Et3N (1.5 mL) was charged
in a 10 mL sealed tube under N2 and irradiated in the microwave cavity at
60 °C for 25 min. Then, 3-iodoanisole (84 mg, 0.36 mmol) and MeCN
(1.5 mL) were added and the mixture was irradiated for 30 min at 90 °C.
The reaction was cooled to rt and then EtOAc (10 mL) and water
(10 mL) were added. The separated aqueous phase was extracted with
EtOAc (2 ꢁ 10 mL), and the combined organic layers were dried over
anhydrous Na2SO4 and concentrated under reduced pressure. The
crude product was purified by column chromatography on silica gel
(hexane/EtOAc, 10/1) to afford 21i (72 mg, 75%) as a brown oil:
Rf 0.50 (hexane/EtOAc, 5/1); 1H NMR (400 MHz, CDCl3) δ 8.45 (br
s, 1H), 7.31 (d, J = 8.0 Hz, 1H), 7.26ꢀ7.22 (m, 2H), 7.18ꢀ7.05 (m, 4H),
6.98 (ddd, J = 4.2, 2.2, 0.5 Hz, 1H), 6.95ꢀ6.90 (m, 1H), 6.84ꢀ6.77 (m,
1H), 3.79 (s, 3H); 13C NMR (100.8 MHz, CDCl3) δ 159.3 (C), 157.0
(d, J = 248.9 Hz, C), 138.1 (d, J = 10.7 Hz, C), 136.4 (C), 132.9 (C),
130.5 (C), 129.0 (CH), 127.0 (CH), 126.1 (C), 126.0 (CH), 123.6 (d,
J = 1.7 Hz, CH), 123.0 (d, J = 7.9 Hz, CH), 122.4 (CH), 117.4 (d, J =
18.0 Hz, C), 116.3 (d, J = 2.1 Hz, CH), 112.9 (CH), 107.0 (d, J = 3.7 Hz,
CH), 105.8 (d, J = 19.9 Hz, CH), 55.3 (CH3); EI-LRMS m/z 323 (Mþ,
100), 291 (14), 280 (17), 246 (9), 235 (8); HRMS calcd for C19H14-
FNOS 323.0780, found 323.0789.
General Procedure for the Synthesis of 2-Alkynyl-3-ha-
loanilides 22. A mixture of the corresponding N-(3-halo-2-iodophe-
nyl)propanamide 18ba or 18ca (1 equiv), alkyne (1.5 equiv when X =
Cl, or 1.2 equiv when X = Br), PdCl2(PPh3)2 (3 mol %), CuI (5 mol %),
and Et2NH (1.5 equiv) in anhydrous DMF (4 mL/mmol) was stirred
under N2 at 40, 50, or 80 °C until complete consumption of starting
material, as monitored by GC-MS (2ꢀ6 h). CH2Cl2 (20 mL/mmol)
and 0.5 M HCl (20 mL/mmol) were added to the cooled reaction
mixture. The separated aqueous phase was extracted with CH2Cl2
(2 ꢁ 20 mL). The combined organic layers were washed with water
(2 ꢁ 40 mL). The organic layer was dried over anhydrous Na2SO4 and
concentrated at reduced pressure. The remaining residue was purified by
column chromatography on silica gel (hexane/EtOAc, 5/1) to afford the
title products 22.
N-(3-Chloro-2-(hept-1-ynyl)phenyl)-2-hydroxy-2-methyl-
propanamide (22bc): Reaction of 18ba (339 mg, 1 mmol) with
1-hetptyne (144 mg, 1.5 mmol) for 2.5 h at 80 °C afforded 22bc (248
mg, 81%) as a pale brown solid: mp 76ꢀ78 °C; 1H NMR (300 MHz,
CDCl3) δ 9.77 (br s, 1H), 8.32 (dd, J = 7.6, 1.8 Hz, 1H), 7.15ꢀ7.05
(m, 2H), 3.49 (s, 1H), 2.49 (t, J = 7.1 Hz, 2H), 1.68ꢀ1.56 (m, 2H), 1.53
(s, 6H), 1.47ꢀ1.21 (m, 4H), 0.88 (t, J = 7.1 Hz, 3H); 13C NMR (75.4 MHz,
CDCl3) δ 175.3 (C), 140.0 (C), 135.6 (C), 128.8 (CH), 124.0 (CH),
116.6 (CH), 113.6 (C), 103.8 (C), 74.2 (C), 73.0 (C), 31.1 (CH2), 28.2
(CH2), 27.9 (2 ꢁ CH3), 22.2 (CH2), 19.7 (CH2), 14.0 (CH3); EI-
LRMS m/z 309 (Mþ þ 2, 7), 307 (Mþ, 21), 206 (20), 180 (35), 164
(44), 59 (100); IR (KBr) 3311, 2953, 1662, 1569, 1520, 1453, 1139, 790,
731 cmꢀ1; HRMS calcd for C17H22ClNO2 307.1339, found 307.1342.
N-(3-Chloro-2-(2-cyclohexenylethynyl)phenyl)-2-hydroxy-
2-methylpropanamide (22bd): Reaction of 18ba (339 mg, 1 mmol)
with 1-ethynylcyclohexene (159 mg, 1.5 mmol) for 3 h at 80 °C afforded
1
22bd (253 mg, 80%) as a white solid: mp 145ꢀ147 °C; H NMR
(300 MHz, CDCl3) δ 9.67 (br s, 1H), 8.36 (dd, J = 8.1, 1.3 Hz, 1H),
7.17 (t, J = 8.1 Hz, 1H), 7.10 (dd, J = 8.1, 1.3 Hz, 1H), 6.36ꢀ6.30 (m, 1H),
2.80 (s, 1H), 2.30ꢀ2.22 (m, 2H), 2.18ꢀ2.10 (m, 2H), 1.72ꢀ1.57 (m, 4H),
1.55 (s, 6H); 13C NMR (75.4 MHz, CDCl3) δ 174.9 (C), 139.7 (C), 137.0
(CH), 135.4 (C), 129.2 (CH), 124.1 (CH), 120.3 (C), 116.6 (CH), 113.4
(C), 103.8 (C), 79.0 (C), 74.5 (C), 29.0 (CH2), 28.0 (2 ꢁ CH3), 26.0
(CH2), 22.3 (CH2), 21.5 (CH2); EI-LRMS m/z 319 (Mþ þ 2, 23), 317
(Mþ, 72), 281 (25), 231 (57), 207 (100), 180 (26), 59 (55); IR (KBr)
3372, 3320, 1652, 1572, 1532, 1450, 1435, 1197, 1184, 778, 725 cmꢀ1
;
HRMS calcd for C18H20ClNO2 317.1183, found 317.1190.
N-(3-Chloro-2-(2-(trimethylsilyl)ethynyl)phenyl)-2-hydro-
xy-2-methylpropanamide (22be): Reaction of 18ba (339 mg,
1 mmol) with trimethylsilylacetylene (147 mg, 1.5 mmol) for 5.5 h at
40 °C afforded 22be (251 mg, 81%) as a pale brown solid: mp 144ꢀ
146 °C; 1H NMR (300 MHz, CDCl3) δ 9.66 (br s, 1H), 8.37 (dd, J = 8.3,
0.9 Hz, 1H), 7.21 (t, J = 8.3 Hz, 1H), 7.09 (dd, J = 8.3, 0.9 Hz, 1H), 2.60
(br s, 1H), 1.55 (s, 6H), 0.29 (d, J = 0.9 Hz, 9H); 13C NMR (75.4 MHz,
CDCl3) δ 175.0 (C), 140.8 (C), 135.8 (C), 130.0 (CH), 124.1 (CH),
116.8 (CH), 112.8 (C), 108.1 (C), 96.6 (C), 74.6 (C), 28.1 (2 ꢁ CH3),
0.0 (3 ꢁ CH3); EI-LRMS m/z 311 (Mþ þ 2, 10), 309 (Mþ, 29), 236
(100), 208 (39); HRMS calcd for C15H20ClNO2Si 309.0952, found
309.951. Anal. Calcd for C15H20ClNO2Si: C, 58.14; H, 6.51; N, 4.52.
Found: C, 58.35; H, 6.46; N, 4.49.
N-(3-Bromo-2-(2-phenylethynyl)phenyl)-2-hydroxy-2-
methylpropanamide (22ca): Reaction of 18ca (383 mg, 1 mmol)
with phenylacetylene (122 mg, 1.2 mmol) for 3.5 h at 50 °C afforded
22ca (285 mg, 80%) as a white solid: mp 131ꢀ133 °C; 1H NMR (300
MHz, CDCl3) δ 9.86 (br s, 1H), 8.44 (dd, J = 8.2, 1.0 Hz, 1H),
7.63ꢀ7.58 (m, 2H), 7.38ꢀ7.29 (m, 4H), 7.13 (t, J = 8.2 Hz, 1H), 2.87
(s, 1H), 1.55 (s, 6H); 13C NMR (75.4 MHz, CDCl3) δ 175.0 (C), 140.1
(C), 131.7 (2 ꢁ CH), 130.1 (CH), 129.2 (CH), 128.6 (2 ꢁ CH), 127.3
(CH), 125.0 (C), 122.3 (C), 117.3 (CH), 115.0 (C), 101.1 (C), 83.4
(C), 74.7 (C), 28.0 (2 ꢁ CH3); EI-LRMS m/z 359 (Mþ þ 2, 62), 357
(Mþ, 62), 300 (60), 298 (58), 273 (100), 271 (100), 191 (60), 165 (53),
59 (83); IR (KBr) 3372, 3312, 1661, 1566, 1532, 1446, 1200, 1131, 752,
726, 689 cmꢀ1; HRMS calcd for C18H16BrNO2 357.0364, found
357.0368.
N-(3-Chloro-2-(2-phenylethynyl)phenyl)-2-hydroxy-2-
methylpropanamide (22ba): Reaction of 18ba (339 mg, 1 mmol)
with 1-phenylacetylene (153 mg, 1.5 mmol) for 2 h at 80 °C afforded
22ba (269 mg, 86%) as a white solid: mp 139ꢀ141 °C; 1H NMR (300
MHz, CDCl3) δ 9.83 (br s, 1H), 8.42 (dd, J = 8.2, 1.1 Hz, 1H),
7.65ꢀ7.57 (m, 2H), 7.40ꢀ7.34 (m, 3H), 7.24 (t, J = 8.2 Hz, 1H), 7.15
(dd, J = 8.2, 1.1 Hz, 1H), 2.35 (br s, 1H), 1.58 (s, 6H); 13C NMR (75.4
MHz, CDCl3) δ 174.7 (C), 140.2 (C), 135.7 (C), 131.8 (2 ꢁ CH),
129.9 (CH), 129.2 (CH), 128.7 (2 ꢁ CH), 124.2 (CH), 122.4 (C),
116.8 (CH), 112.9 (C), 101.7 (C), 81.6 (C), 74.8 (C), 28.1 (2 ꢁ CH3);
EI-LRMS m/z 315 (Mþ þ 2, 17), 313 (Mþ, 51), 254 (54), 229 (33), 227
(100), 190 (27), 59 (41); IR (KBr) 3365, 3321, 1665, 1571, 1534, 1452,
759, 692 cmꢀ1; HRMS calcd for C18H16ClNO2 313.0870, found
313.0857. Anal. Calcd for C18H16ClNO2: C, 68.90; H, 5.14; N, 4.46.
Found: C, 69.13; H, 5.21; N, 4.43.
N-(3-Chloro-2-(hex-1-ynyl)phenyl)-2-hydroxy-2-methyl-
propanamide (22bb): Reaction of 18ba (339 mg, 1 mmol) with
1-hexyne (123 mg, 1.5 mmol) for 2.5 h at 80 °C afforded 22bb (263 mg,
1
90%) as a pale brown solid: mp 66ꢀ68 °C; H NMR (300 MHz,
N-(3-Bromo-2-(hex-1-ynyl)phenyl)-2-hydroxy-2-methyl-
propanamide (22cb): Reaction of 18ca (576 mg, 1.5 mmol) with
1-hexyne (148 mg, 1.8 mmol) for 3.5 h at 50 °C afforded 22cb (429 mg,
CDCl3) δ 9.65 (br s, 1H), 8.37 (d, J = 8.1 Hz, 1H), 7.24ꢀ7.07 (m, 2H),
2.55 (t, J = 6.9 Hz, 2H), 2.45 (br s, 1H), 1.70ꢀ1.46 (m, 4H), 1.56
(s, 6H), 0.95 (t, J = 7.1 Hz, 3H); 13C NMR (75.4 MHz, CDCl3) δ 174.8
(C), 140.2 (C), 135.6 (C), 129.0 (CH), 124.1 (CH), 116.7 (CH), 113.5
1
85%) as a pale brown solid: mp 70ꢀ72 °C; H NMR (300 MHz,
CDCl3) δ 9.76 (br s, 1H), 8.36 (dd, J = 8.2, 1.0 Hz, 1H), 7.25 (dd, J = 8.2,
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ARTICLE
1.0 Hz, 1H), 7.05 (t, J = 8.2 Hz, 1H), 3.42 (s, 1H), 2.50 (t, J = 7.0 Hz,
2H), 1.64ꢀ1.43 (m, 4H), 1.52 (s, 6H), 0.91 (t, J = 7.2 Hz, 3H); 13C
NMR (75.4 MHz, CDCl3) δ 175.3 (C), 140.1 (C), 129.2 (CH), 127.2
(CH), 125.0 (C), 117.1 (CH), 115.6 (C), 103.1 (C), 74.8 (C), 74.2 (C),
30.5 (CH2), 27.9 (2 ꢁ CH3), 22.1 (CH2), 19.5 (CH2), 13.7 (CH3); EI-
LRMS m/z 339 (Mþ þ 2, 37), 337 (Mþ, 36), 253 (29), 251 (30), 226
(50), 210 (51), 157 (25), 129 (26), 59 (100); IR (KBr) 3419, 3319,
1673, 1567, 1520, 1427, 980, 729 cmꢀ1; HRMS calcd for C16H20BrNO2
337.0677, found 337.0676. Anal. Calcd for C16H20BrNO2: C, 56.82; H,
5.96; N, 4.14. Found: C, 56.99; H, 6.00; N, 4.11.
General Procedure for the Synthesis of 4-Halo-2-susti-
tuted-1H-indoles 23 and 24. To a solution of the corresponding
3-halo-2-alkynylpropanamide 22 (1 equiv) in DMF (3 mL/mmol) was
added an excess of freshly powdered NaOH (3 equiv). The resulting
mixture was refluxed under N2 at 140 °C until the cyclization was
completed (2ꢀ5 h), as monitored by GC-MS. CH2Cl2 (10 mL) and
0.5 M HCl (10 mL) were added to the cooled reaction mixture. The
separated aqueous phase was extracted with CH2Cl2 (2 ꢁ 10 mL). The
combined organic layers were washed with water (2 ꢁ 20 mL), dried
over anhydrous Na2SO4, and concentrated at reduced pressure. The
remaining residue was purified by column chromatography on silica gel
(hexane/EtOAc) to afford the corresponding 4-haloindoles 23 and 24.
4-Chloro-2-phenyl-1H-indole (23a): Reaction of 22ba (94 mg,
0.3 mmol) with NaOH (36 mg, 0.9 mmol) for 4 h followed by
purification by column chromatography (hexane/EtOAc, 7/1) afforded
23a (54 mg, 79%) as a white solid: mp 73ꢀ75 °C (lit.60 mp 76ꢀ77 °C);
1H NMR (300 MHz, CDCl3) δ 8.43 (br s, 1H), 7.70ꢀ7.63 (m, 2H),
7.50ꢀ7.43 (m, 2H), 7.39ꢀ7.33 (m, 1H), 7.31ꢀ7.27 (m, 1H),
7.17ꢀ7.08 (m, 2H), 6.94 (dd, J = 2.2, 0.8 Hz, 1H); 13C NMR (75.4
MHz, CDCl3) δ 138.6 (C), 137.4 (C), 131.8 (C), 129.2 (2 ꢁ CH),
128.3 (CH), 128.2 (C), 125.9 (C), 125.4 (2 ꢁ CH), 122.9 (CH), 120.1
(CH), 109.6 (CH), 98.5 (CH); EI-LRMS m/z 229 (Mþ þ 2, 33), 227
(Mþ, 100), 191 (10), 165 (16), 113 (10); IR (KBr) 3449, 2961, 2924,
1452, 1261, 1098, 803, 756, 688 cmꢀ1; HRMS calcd for C14H10ClN
227.0502, found 227.0501.
2-Butyl-4-chloro-1H-indole (23b): Reaction of 22bb (88 mg,
0.3 mmol) with NaOH (36 mg, 0.9 mmol) for 2.5 h followed by
purification by column chromatography (hexane/EtOAc, 7/1) afforded
23b (54 mg, 86%) as a colorless oil: Rf 0.46 (hexane/EtOAc, 6/1); 1H
NMR (300 MHz, CDCl3) δ 7.90 (br s, 1H), 7.18 (dt, J = 7.7, 1.0 Hz,
1H), 7.12 (dd, J = 7.7, 1.0 Hz, 1H), 7.05 (t, J = 7.7 Hz, 1H), 6.38 (dd, J =
2.2, 0.9 Hz, 1H), 2.74 (t, J = 7.6 Hz, 2H), 1.77ꢀ1.66 (m, 2H), 1.51ꢀ1.38
(m, 2H), 0.99 (t, J = 7.3 Hz, 3H); 13C NMR (75.4 MHz, CDCl3) δ 141.0
(C), 136.5 (C), 127.6 (C), 125.0 (C), 121.6 (CH), 119.4 (CH), 109.1
(CH), 98.1 (CH), 31.2 (CH2), 28.0 (CH2), 22.5 (CH2), 14.0 (CH3);
EI-LRMS m/z 209 (Mþ þ 2, 10), 207 (Mþ, 33), 164 (100), 128 (8), 101
(6); IR (KBr) 3417, 2957, 2929, 1575, 1548, 1433, 1330, 1182, 941,
765 cmꢀ1; HRMS calcd for C12H14ClN 207.0815, found 207.0822.
4-Chloro-2-pentyl-1H-indole (23c):60. Reaction of 22bc (154 mg,
0.5 mmol) with NaOH (60 mg, 1.5 mmol) for 2.5 h followed by purification
by column chromatography (hexane/EtOAc, 7/1) afforded 23c (93 mg,
84%) as a pale brown solid: mp 24ꢀ26 °C; 1H NMR (300 MHz, CDCl3)
δ 7.96 (br s, 1H), 7.19 (dd, J = 7.6, 0.9 Hz, 1H), 7.11ꢀ7.00 (m, 2H), 6.36 (d,
J = 0.9 Hz, 1H), 2.75 (t, J = 7.6 Hz, 2H), 1.79ꢀ1.68 (m, 2H), 1.43ꢀ1.25
(m, 4H), 0.93 (t, J = 6.7 Hz, 3H); 13C NMR (75.4 MHz, CDCl3) δ 141.0
(C), 136.5 (C), 127.7 (C), 125.0 (C), 121.6 (CH), 119.4 (CH), 109.0
(CH), 98.1 (CH), 31.6 (CH2), 28.8 (CH2), 28.3 (CH2), 22.6 (CH2), 14.1
(CH3); EI-LRMS m/z 223 (Mþ þ 2, 11), 221, (Mþ, 34), 178 (24), 164
(100), 128 (9), 101 (6); IR (KBr) 3417, 2956, 2928, 1547, 1433, 1329,
1182, 939, 765 cmꢀ1; HRMS calcd for C13H16ClN 221.0971, found
221.0980.
N-(3-Bromo-2-(hept-1-ynyl)phenyl)-2-hydroxy-2-methyl-
propanamide (22cc): Reaction of 18ca (383 mg, 1 mmol) with
1-heptyne (115 mg, 1.2 mmol) for 3.5 h at 50 °C afforded 22cc (277 mg,
1
79%) as a white solid: mp 79ꢀ81 °C; H NMR (300 MHz, CDCl3)
δ 9.78 (s, 1H), 8.35 (dd, J = 8.2, 0.8 Hz, 1H), 7.24 (dd, J = 8.2, 0.8 Hz, 1H),
7.03 (t, J = 8.2 Hz, 1H), 3.58 (s, 1H), 2.47 (t, J = 7.2 Hz, 2H), 1.68ꢀ1.57
(m, 2H), 1.52 (s, 6H), 1.49ꢀ1.24 (m, 4H), 0.87 (t, J = 7.2 Hz, 3H); 13C
NMR (75.4 MHz, CDCl3) δ 175.4 (C), 140.1 (C), 129.1 (CH), 127.1
(CH), 125.0 (C), 117.1 (CH), 115.6 (C), 103.2 (C), 74.8 (C), 74.2 (C),
31.1 (CH2), 28.2 (CH2), 27.8 (2 ꢁ CH3), 22.2 (CH2), 19.7 (CH2), 14.0
(CH3); EI-LRMS m/z 353 (Mþ þ 2, 15), 351 (Mþ, 15), 226 (28), 210
(30), 157 (21), 59 (100); IR (KBr) 3295, 2930, 1661, 1564, 1520, 1449,
1130, 981, 788, 730 cmꢀ1; HRMS calcd for C17H22BrNO2 351.0834,
found 351.0822.
N-(3-Bromo-2-(2-cyclohexenylethynyl)phenyl)-2-hydroxy-
2-methylpropanamide (22cd): Reaction of 18ca (383 mg, 1 mmol)
with 1-ethynylcyclohexene (127 mg, 1.2 mmol) for 5 h at 50 °C afforded
22cd (310 mg, 86%) as a white solid: mp 154ꢀ156 °C; 1H NMR (300
MHz, CDCl3) δ 9.65 (br s, 1H), 8.42 (dd, J = 8.2, 1.1 Hz, 1H), 7.29 (dd, J =
8.2, 1.1 Hz, 1H), 7.12 (t, J = 8.2 Hz, 1H), 6.37ꢀ6.32 (m, 1H), 2.48 (br s,
1H), 2.32ꢀ2.22 (m, 2H), 2.21ꢀ2.12 (m, 2H), 1.77ꢀ1.58 (m, 4H), 1.56 (s,
6H); 13C NMR (75.4 MHz, CDCl3) δ 174.7 (C), 139.9 (C), 137.0 (CH),
129.6 (CH), 127.2 (CH), 124.9 (C), 120.4 (C), 117.2 (CH), 115.4 (C),
103.2 (C), 80.9 (C), 74.7 (C), 29.0 (CH2), 28.1 (2 ꢁ CH3), 26.0 (CH2),
22.3 (CH2), 21.5 (CH2); EI-LRMS m/z 363 (Mþ þ 2, 100), 361 (Mþ,
100), 277 (53), 275 (53), 167 (34), 59 (63); IR (KBr) 3376, 3318, 2929,
1653, 1566, 1530, 1446, 1433, 976, 775, 724 cmꢀ1; HRMS calcd for
C18H20BrNO2 361.0677, found 361.0677.
N-(3-Bromo-2-(2-(trimethylsilyl)ethynyl)phenyl)-2-hydro-
xy-2-methylpropanamide (22ce): Reaction of 18ca (383 mg,
1 mmol) with trimethylsilylacetylene (147 mg, 1.5 mmol) for 3 h at
40 °C afforded 22ce (251 mg, 71%) as a pale brown solid: mp
1
150ꢀ152 °C; H NMR (300 MHz, CDCl3) δ 9.70 (br s, 1H), 8.40
(dt, J = 8.2, 0.9 Hz, 1H), 7.27 (td, J = 8.2, 0.9 Hz, 1H), 7.12 (t, J = 8.2 Hz,
1H), 2.83 (s, 1H), 1.54 (d, J = 0.6 Hz, 6H), 0.28 (d, J = 0.8 Hz, 9H); 13C
NMR (75.4 MHz, CDCl3) δ 175.1 (C), 140.8 (C), 130.3 (CH), 127.2
(CH), 125.0 (C), 117.3 (CH), 114.8 (C), 107.5 (C), 98.3 (C), 74.4 (C),
28.0 (2 ꢁ CH3), ꢀ0.1 (3 ꢁ CH3); EI-LRMS m/z 355 (Mþ þ 2, 28),
353 (Mþ, 27), 282 (100), 280 (100), 254 (37), 252 (37), 238 (19), 236
(18); HRMS calcd for C15H20BrNO2Si 353.0447, found 353.0450.
N-(3-Bromo-2-(2-(thiophen-3-yl)ethynyl)phenyl)-2-hydroxy-
2-methylpropanamide (22cf): Reaction of 18ca (383 mg, 1 mmol)
with 3-ethynylthiophene (129 mg, 1.2 mmol) for 3.5 h at 50 °C afforded
4-Chloro-2-cyclohexenyl-1H-indole (23d): Reaction of 22bd
(94 mg, 0.3 mmol) with NaOH (36 mg, 0.9 mmol) for 2.5 h followed by
purification by column chromatography (hexane/EtOAc, 8/1) afforded
23d (56 mg, 81%) as a pale brown oil: Rf 0.70 (hexane/EtOAc, 6/1); 1H
NMR (300 MHz, CDCl3) δ 8.21 (br s, 1H), 7.21ꢀ7.17 (m, 1H),
7.09ꢀ7.02 (m, 2H), 6.54 (d, J = 2.0 Hz, 1H), 6.17ꢀ6.12 (m, 1H),
2.51ꢀ2.44 (m, 2H), 2.29ꢀ2.21 (m, 2H), 1.85ꢀ1.76 (m, 2H), 1.75ꢀ1.65
(m, 2H); 13C NMR (75.4 MHz, CDCl3) δ 140.1 (C), 136.8 (C), 128.8
(C), 127.8 (C), 125.6 (C), 123.8 (CH), 122.5 (CH), 119.5 (CH), 109.1
(CH), 97.1 (CH), 26.0 (CH2), 25.6 (CH2), 22.5 (CH2), 22.2 (CH2); EI-
LRMS m/z 233 (Mþ þ 2, 32), 231 (Mþ, 100), 203 (35), 164 (34), 151
1
22cf (268 mg, 74%) as a white solid: mp 132ꢀ134 °C; H NMR
(400 MHz, CDCl3) δ 9.82 (br s, 1H), 8.41 (d, J = 8.3 Hz, 1H), 7.63 (dd,
J = 2.9, 1.1 Hz, 1H), 7.31ꢀ7.27 (m, 2H), 7.24 (dd, J = 4.9, 1.1 Hz, 1H),
7.11 (t, J = 8.3 Hz, 1H), 2.90 (s, 1H), 1.53 (s, 6H); 13C NMR (100.6
MHz, CDCl3) δ 175.0 (C), 140.1 (C), 130.0 (CH), 129.9 (CH), 129.8
(CH), 127.3 (CH), 125.9 (CH), 124.7 (C), 121.4 (C), 117.3 (CH),
115.1 (C), 96.3 (C), 83.1 (C), 74.7 (C), 28.0 (2 ꢁ CH3); EI-LRMS m/z
365 (Mþ þ 2, 40), 363 (Mþ, 44), 305 (19), 279 (61), 277 (59), 226
(14), 198 (29), 196 (32), 171 (23), 59 (100); HRMS calcd for
C16H14BrNO2S 362.9929, found 362.9928. Anal. Calcd for C16H14BrNO2S:
C, 52.76; H, 3.87; N, 3.85. Found: C, 52.92; H, 3.90; N, 3.86.
(29); IR (neat) 3433, 2928, 1569, 1432, 1334, 1184, 947, 764, 731 cmꢀ1
;
HRMS calcd for C14H14ClN 231.0815, found 231.0814.
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ARTICLE
4-Chloro-1H-indole (23e): Reaction of 22be (154 mg, 0.5 mmol)
with NaOH (60 mg, 1.5 mmol) for 4 h followed by purification by
column chromatography (hexane/EtOAc, 8/1) afforded 23e (56 mg,
73%) as a brown oil: Rf 0.33 (hexane/AcOEt, 5/1); 1H NMR (300 MHz,
CDCl3) δ 8.25 (br s, 1H), 7.31ꢀ7.21 (m, 2H), 7.16ꢀ7.08 (m, 2H),
6.70ꢀ6.62 (m, 1H); 13C NMR (75.4 MHz, CDCl3) δ 136.6 (C), 126.9
(C), 126.2 (C), 124.9 (CH), 122.7 (CH), 119.7 (CH), 109.8 (CH),
101.4 (CH); EI-LRMS m/z 153 (Mþ þ 2, 31), 151 (Mþ, 100), 116
(18), 89 (27).
75%) as a colorless oil: Rf 0.29 (hexane/EtOAc, 6/1); 1H NMR
(300 MHz, CDCl3) δ 8.28 (br s, 1H), 7.37ꢀ7.23 (m, 3H), 7.06
(t, J = 7.9 Hz, 1H), 6.64ꢀ6.60 (m, 1H); 13CNMR (75.4 MHz, CDCl3)
δ 136.1 (C), 128.8 (C), 124.8 (CH), 123.0 (CH), 122.9 (CH), 114.9 (C),
110.4 (CH), 103.2 (CH); EI-LRMS m/z 197 (Mþ þ 2, 100), 195 (Mþ,
100), 184 (7), 116 (77), 89 (44); HRMS calcd for C8H6BrN 194.9684,
found 194.9679.
4-Bromo-2-(thiophen-3-yl)-1H-indole (24f): Reaction of 22cf
(181 mg, 0.5 mmol) with NaOH (60 mg, 1.5 mmol) for 3 h followed by
purification by column chromatography (hexane/EtOAc, 10/1) af-
4-Bromo-2-phenyl-1H-indole (24a): Reaction of 22ca (178 mg,
0.5 mmol) with NaOH (60 mg, 1.5 mmol) for 5 h followed by purification
by column chromatography (hexane/EtOAc, 8/1) afforded 24a (113 mg,
1
forded 24f (99 mg, 71%) as a pale brown solid: mp 44ꢀ46 °C; H
NMR (300 MHz, CDCl3) δ 8.35 (br s, 1H), 7.47ꢀ7.38 (m, 3H), 7.29
(d, J = 7.7 Hz, 2H), 7.07ꢀ7.00 (m, 1H), 6.75 (d, J = 2.1 Hz, 1H); 13C
NMR (75.4 MHz, CDCl3) δ 136.6 (C), 134.6 (C), 133.5 (C), 129.9
(C), 127.0 (CH), 125.7 (CH), 123.25 (CH), 123.19 (CH), 119.9 (CH),
114.5 (C), 110.0 (CH), 100.2 (CH); EI-LRMS m/z 281 (Mþ þ 2, 100),
279 (Mþ, 96), 198 (38), 171 (61), 154 (27), 126 (32); HRMS calcd for
C12H8BrNS 276.9561, found 276.9576. Anal. Calcd for C12H8BrNS: C,
51.81; H, 2.90; N, 5.04. Found: C, 51.66; H, 2.92; N, 5.06.
1
83%) as a white solid: mp 100ꢀ102 °C; H NMR (300 MHz, CDCl3)
δ 8.42 (br s, 1H), 7.65 (dd, J = 8.4, 1.0 Hz, 2H), 7.49ꢀ7.42 (m, 2H),
7.40ꢀ7.29 (m, 3H), 7.06 (t, J = 7.9 Hz, 1H), 6.91ꢀ6.89 (m, 1H); 13C
NMR (75.4 MHz, CDCl3) δ 138.5 (C), 137.0 (C), 131.7 (C), 130.1 (C),
129.2 (2 ꢁ CH), 128.3 (CH), 125.3 (2 ꢁ CH), 123.2 (CH), 114.6 (C),
110.2 (CH), 100.2 (CH); EI-LRMS m/z 273 (Mþ þ 2, 98), 271 (Mþ,
100), 191 (27), 165 (34), 136 (11); IR (KBr) 3445, 1475, 1452, 1352,
1289, 1181, 916, 758, 691 cmꢀ1; HRMS calcd for C14H10BrN 270.9997,
found 270.9995. Anal. Calcd for C14H10BrN: C, 61.79; H, 3.70; N, 5.15.
Found: C, 61.62; H, 3.67; N, 5.19.
General Procedure for the One-Pot Synthesis of 4-Halo-2-
substituted-1H-indoles 20, 23, and 24 from 2,3-Dihaloani-
lides 18. A mixture of the corresponding 2,3-dihaloanilide 18 (1 equiv),
alkyne (1.5 equiv when X = F, Cl, or 1.2 equiv if X = Br), PdCl2(PPh3)2
(3 mol %), CuI (5 mol %) and Et2NH (1.5 equiv) in DMA (4 mL/
mmol) was stirred under N2 at 80 (for 18aa and 18ba), 50 (for 18ca), or
40 °C (when trimetylsilylacetylene was used as alkyne) until complete
consumption of starting material, as monitored by GC-MS (2ꢀ6 h).
Then, a large excess of freshly powdered NaOH (10 equiv) was added to
the reaction mixture and it was refluxed under N2 at 140 °C until the
cyclization was completed (2ꢀ12 h), as monitored by GC-MS. CH2Cl2
(20 mL) and 0.5 M HCl (20 mL) were added to the cooled reac-
tion mixture. The separated aqueous phase was extracted with CH2Cl2
(2 ꢁ 20 mL). The combined organic layers were washed with water
(2 ꢁ 40 mL). The organic layer was dried over anhydrous Na2SO4 and
concentrated at reduced pressure. The remaining residue was purified by
column chromatography on silica gel (hexane/EtOAc) to afford the
corresponding 4-haloindoles 20, 23, and 24. The characterization data of
20a, 23aꢀe and 24aꢀf have been reported above.
4-Bromo-2-butyl-1H-indole (24b): Reaction of 22cb (101 mg,
0.3 mmol) with NaOH (36 mg, 0.9 mmol) for 3 h followed by
purification by column chromatography (hexane/EtOAc, 7/1) afforded
24b (60 mg, 80%) as a white solid: mp 29ꢀ31 °C; 1H NMR (300 MHz,
CDCl3) δ 7.95 (br s, 1H), 7.26 (dd, J = 7.8, 0.8 Hz, 1H), 7.22 (dt, J = 7.8,
0.8 Hz, 1H), 6.99 (t, J = 7.8 Hz, 1H), 6.32 (dd, J = 2.2, 0.9 Hz, 1H), 2.74
(t, J = 7.6 Hz, 2H), 1.77ꢀ1.66 (m, 2H), 1.50ꢀ1.37 (m, 2H), 0.98 (t, J =
7.3 Hz, 3H); 13C NMR (75.4 MHz, CDCl3) δ 141.0 (C), 136.0 (C),
129.6 (C), 122.5 (CH), 121.9 (CH), 113.7 (C), 109.6 (CH), 99.8 (CH),
31.2 (CH2), 28.0 (CH2), 22.5 (CH2), 14.0 (CH3); EI-LRMS m/z 253
(Mþ þ 2, 37), 251 (Mþ, 37), 210 (100), 208 (98), 129 (32); IR (KBr)
3407, 2958, 2929, 1539, 1430, 1329, 1178, 917, 763, 729 cmꢀ1; HRMS
calcd for C12H14BrN 251.0310, found 251.0309.
4-Bromo-2-pentyl-1H-indole (24c): Reaction of 22cc (123 mg,
0.35 mmol) with NaOH (42 mg, 1.05 mmol) for 2.5 h followed by
purification by column chromatography (hexane/EtOAc, 7/1) afforded
24c (76 mg, 82%) as a pale brown oil: Rf 0.42 (hexane/EtOAc, 6/1); 1H
NMR (300 MHz, CDCl3) δ 7.97 (br s, 1H), 7.28ꢀ7.20 (m, 2H), 6.98
(t, J = 8.0 Hz, 1H), 6.31 (dd, J = 2.2, 0.8 Hz, 1H), 2.74 (t, J = 7.7 Hz, 2H),
1.79ꢀ1.68 (m, 2H), 1.43ꢀ1.34 (m, 4H), 0.93 (t, J= 7.0 Hz, 3H); 13C
NMR (75.4 MHz, CDCl3) δ 141.0 (C), 136.1 (C), 129.6 (C), 122.5
(CH), 121.9 (CH), 113.7 (C), 109.6 (CH), 99.9 (CH), 31.6 (CH2),
28.9 (CH2), 28.3 (CH2), 22.6 (CH2), 14.1 (CH3); EI-LRMS m/z 267
(Mþ þ 2, 41), 265 (Mþ, 42), 224 (19), 210 (100), 208 (98), 129 (32);
2-Butyl-4-fluoro-1H-indole (20c): Treatment of 18aa (161 mg,
0.5 mmol) with 1-hexyne (62 mg, 0.75 mmol) for 3 h and then with
NaOH (200 mg, 5 mmol) for 3 h followed by purification by column
chromatography (hexane/EtOAc, 8/1) afforded 20c (73 mg, 77%) as a
1
pale brown oil: Rf 0.50 (hexane/EtOAc, 4/1); H NMR (300 MHz,
CDCl3) δ 7.92 (br s, 1H), 7.11ꢀ7.00 (m, 2H), 6.78 (ddd, J = 10.4, 6.9,
1.7 Hz, 1H), 6.35 (dd, J = 2.2, 0.8 Hz, 1H), 2.75 (t, J = 7.6 Hz, 2H),
1.77ꢀ1.66 (m, 2H), 1.51ꢀ1.38 (m, 2H), 0.99 (t, J = 7.3 Hz, 3H); 13C
NMR (75.4 MHz, CDCl3) δ 155.9 (d, J = 245.2 Hz, C), 140.1 (C), 138.6
(d, J = 11.8 Hz, C), 121.4 (d, J = 7.6 Hz, CH), 117.8 (d, J = 22.4 Hz, C),
106.5 (d, J = 3.4 Hz, CH), 104.5 (d, J = 19.1 Hz, CH), 95.4 (CH), 31.3
(CH2), 27.9 (CH2), 22.5 (CH2), 14.0 (CH3); HRMS calcd for
C12H14FN 191.1110, found 191.1106.
4-Chloro-2-(3-chlorophenyl)-1H-indole (23f): Treatment of
18ba (170 mg, 0.5 mmol) with 1-chloro-3-ethynylbenzene (102 mg,
0.75 mmol) for 2 h and then with NaOH (200 mg, 5 mmol) for 3 h
followed by purification by column chromatography (hexane/EtOAc,
7/1) afforded 23f (98 mg, 75%) as a brown solid: mp 80ꢀ82 °C; 1H
NMR (300 MHz, CDCl3) δ 8.44 (br s, 1H), 7.62 (t, J = 1.6 Hz, 1H), 7.50
(dt, J = 7.5, 1.6 Hz, 1H), 7.36 (t, J = 7.5 Hz, 1H), 7.32ꢀ7.24 (m, 2H),
7.17ꢀ7.08 (m, 2H), 6.92 (dd, J = 2.2, 0.7 Hz, 1H); 13C NMR (75.4
MHz, CDCl3) δ 137.5 (C), 136.9 (C), 135.1 (C), 133.5 (C), 130.4
(CH), 128.1 (CH), 128.0 (C), 126.1 (C), 125.3 (CH), 123.39 (CH),
123.38 (CH), 120.3 (CH), 109.7 (CH), 99.4 (CH); EI-LRMS m/z 265
(Mþ þ 4, 13), 263 (Mþ þ 2, 62), 261 (Mþ, 100), 226 (13), 199 (30),
190 (35), 164 (30), 89 (49); HRMS calcd for C14H9Cl2N 261.0112,
IR (neat) 3411, 2956, 2928, 1548, 1430, 1327, 1178, 917, 763 cmꢀ1
HRMS calcd for C13H16BrN 265.0466, found 265.0467.
;
4-Bromo-2-cyclohexenyl-1H-indole (24d): Reaction of 22 cd
(180 mg, 0.5 mmol) with NaOH (60 mg, 1.5 mmol) for 4 h followed by
purification by column chromatography (hexane/EtOAc, 10/1) af-
forded 24d (105 mg, 76%) as a colorless oil: Rf 0.5 (hexane/EtOAc,
1
6/1); H NMR (300 MHz, CDCl3) δ 8.27 (br s, 1H), 7.27ꢀ7.20
(m, 2H), 6.99 (t, J = 7.8 Hz, 1H), 6.48 (d, J = 1.9 Hz, 1H), 6.17ꢀ6.12
(m, 1H), 2.51ꢀ2.43 (m, 2H), 2.28ꢀ2.20 (m, 2H), 1.84ꢀ1.75 (m, 2H),
1.75ꢀ1.65 (m, 2H); 13C NMR (75.4 MHz, CDCl3) δ 140.2 (C), 136.4
(C), 129.7 (C), 128.9 (C), 123.8 (CH), 122.8 (CH), 122.7 (CH), 114.3
(C), 109.7 (CH), 98.9 (CH), 26.1 (CH2), 25.6 (CH2), 22.6 (CH2), 22.2
(CH2); EI-LRMS m/z 277 (Mþ þ 2, 98), 275 (Mþ, 100), 247 (24), 195
(23), 167 (38); IR (KBr) 3427, 2927, 1568, 1524, 1429, 1332, 1179, 917,
762, 730 cmꢀ1; HRMS calcd for C14H14BrN 275.0310, found 275.0314.
4-Bromo-1H-indole (24e): Reaction of 22ce (176 mg, 0.5 mmol)
with NaOH (60 mg, 1.5 mmol) for 5 h followed by purification by
column chromatography (hexane/EtOAc, 10/1) afforded 24e (74 mg,
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ARTICLE
found 261.0112. Anal. Calcd for C14H9Cl2N: C, 64.15; H, 3.46; N, 5.34.
Found: C, 64.34; H, 3.49; N, 5.32.
128.1 (CH), 127.0 (CH), 126.6 (C), 117.7 (CH), 115.8 (C), 101.8 (C),
94.4 (C), 79.5 (C), 75.0 (C), 74.4 (C), 31.23 (CH2), 31.17 (CH2),
28.58 (CH2), 28.56 (CH2), 28.0 (2 ꢁ CH3), 22.4 (2 ꢁ CH2), 19.9
(CH2), 19.7 (CH2), 14.11 (CH3), 14.09 (CH3); EI-LRMS m/z 367
(Mþ, 20), 320 (37), 296 (87), 278 (100), 167 (29), 59 (40); HRMS
calcd for C24H33NO2 367.2511, found 367.2518.
4-Chloro-2-(4-fluoro-3-methylphenyl)-1H-indole (23g): Treat-
ment of 18ba (136 mg, 0.4 mmol) with 4-ethynyl-1-fluoro-2-methylbenzene
(80 mg, 0.6 mmol) for 2 h and then with NaOH (160 mg, 4 mmol) for 4 h
followed by purification by column chromatography (hexane/EtOAc, 8/1)
afforded 23g (74 mg, 72%) as a brown solid: mp 114ꢀ116 °C; 1H NMR
(300 MHz, CDCl3) δ 8.41 (br s, 1H), 7.49 (d, J = 7.1 Hz, 1H), 7.46ꢀ7.39
(m, 1H), 7.29ꢀ7.24 (m, 1H), 7.15ꢀ7.03 (m, 3H), 6.84 (d, J = 0.9 Hz, 1H),
2.34 (br s, 3H); 13CNMR(75.4MHz, CDCl3) δ161.4 (d, J= 247.0 Hz, C),
138.0 (C), 137.4 (C), 128.6 (d, J = 5.3 Hz, CH), 128.2 (C), 127.8 (d, J =
3.7 Hz, C), 125.9 (d, J = 7.2 Hz, C), 125.7 (C), 124.4 (d, J = 8.2 Hz, CH),
122.9 (CH), 120.1 (CH), 115.8 (d, J = 22.9 Hz, CH), 109.6 (CH), 98.2
(CH), 14.8 (d, J = 3.4 Hz, CH3); EI-LRMS m/z 261 (Mþ þ 2, 49), 259
(Mþ, 100), 223 (14), 208 (13), 197 (14), 129 (16), 111 (23); HRMS calcd
for C15H11ClFN 259.0564, found 0.259.0561. Anal. Calcd for C15H11ClFN:
C, 69.37; H, 4.27; N, 5.39. Found: C, 69.18; H, 4.30; N, 5.37.
4-Bromo-2-(3-chlorophenyl)-1H-indole (24g): Treatment of
18ca (191 mg, 0.5 mmol) with 1-chloro-3-ethynylbenzene (102 mg,
0.75 mmol) for 2 h and then with NaOH (200 mg, 5 mmol) for 4 h
followed by purification by column chromatography (hexane/EtOAc,
8/1) afforded 24g (73 mg, 48%) as a brown solid: mp 89ꢀ91 °C; 1H
NMR (300 MHz, CDCl3) δ 8.47 (br s, 1H), 7.67ꢀ7.64 (m, 1H), 7.55
(ddd, J = 7.6, 2.8, 1.3 Hz, 1H), 7.43ꢀ7.27 (m, 4H), 7.06 (td, J = 8.1, 1.2
Hz, 1H), 6.90ꢀ6.87 (m, 1H); 13C NMR (75.4 MHz, CDCl3) δ 137.1
(C), 137.0 (C), 135.2 (C), 133.6 (C), 130.5 (CH), 129.9 (C), 128.2
(CH), 125.4 (CH), 123.8 (CH), 123.5 (CH), 123.4 (CH), 114.9 (C),
110.3 (CH), 101.2 (CH); EI-LRMS m/z 309 (Mþ þ 4, 23), 307 (Mþ þ
2, 100), 305 (Mþ, 80), 226 (16), 199 (34), 190 (74), 163 (60); HRMS
calcd for C14H9BrClN 304.9607, found 304.9620.
General Procedure for the Synthesis of N-(2,3-Dialkynyl-
phenyl)-2-methylpropanamides 25. A mixture of 18bc (148 mg,
0.6 mmol), PdCl2(MeCN)2 (3 mg, 2 mol %), XPhos (17 mg, 3 mol %),
and Cs2CO3 (586 mg, 1.8 mmol) in anhydrous MeCN (2 mL) was
stirred under N2 at rt for 25 min. Then, the corresponding alkyne
(1.8 mmol) was added and the reaction was stirred at reflux overnight.
AcOEt and water were added to the cooled reaction mixture. The
separated aqueous phase was extracted with AcOEt (3 ꢁ 15 mL). The
combined organic layers were dried over anhydrous Na2SO4 and
concentrated at reduced pressure. The remaining residue was purified
by column chromatography on silica gel (hexane/EtOAc) to afford the
corresponding title compounds 25.
N-(2,3-Bis(2-phenylethynyl)phenyl)-2-hydroxy-2-methyl-
propanamide (25a): Reaction of 18bc with phenylacetylene (198
μL, 1.8 mmol) followed by purification by column chromatography
(hexane/EtOAc, 5/1) afforded 25a (147 mg, 65%) as a brown solid: mp
162ꢀ164 °C; 1H NMR (300 MHz, CDCl3) δ 9.84 (br s, 1H),
8.53ꢀ8.45 (m, 1H), 7.65ꢀ7.54 (m, 4H), 7.41ꢀ7.33 (m, 6H),
7.34ꢀ7.27 (m, 2H), 2.45 (s, 1H), 1.60 (s, 6H); 13C NMR (75.4,
CDCl3) δ 174.7 (C), 139.0 (C), 131.8 (2 ꢁ CH), 131.6 (2 ꢁ CH),
129.1 (CH), 129.0 (CH), 128.7 (3 ꢁ CH), 128.6 (2 ꢁ CH), 127.0
(CH), 125.8 (C), 123.2 (C), 122.8 (C), 118.5 (CH), 115.1 (C), 100.8
(C), 93.7 (C), 88.2 (C), 83.6 (C), 74.8 (C), 28.1 (2 ꢁ CH3); EI-LRMS
m/z 379 (Mþ, 61), 361 (73), 321 (61), 292 (58), 265 (56), 189 (20), 59
(100); HRMS calcd for C26H21NO2 379.1572, found 379.1569.
N-(2,3-Di(hept-1-ynyl)phenyl)-2-hydroxy-2-methylpropan-
amide (25b): Reaction of 18bc with 1-heptyne (236 μL, 1.8 mmol)
followed by purification by column chromatography (hexane/EtOAc,
5/1) afforded 25b (173 mg, 79%) as a brown oil: Rf 0.48 (hexane/
EtOAc, 3/1); 1H NMR (400 MHz, CDCl3) δ 9.59 (s, 1H), 8.34 (dd, J =
7.9, 1.3 Hz, 1H), 7.15 (t, J = 7.9 Hz, 1H), 7.08 (dd, J = 7.9, 1.3 Hz, 1H),
2.72 (s, 1H), 2.51 (t, J = 7.1 Hz, 2H), 2.43 (t, J = 7.1 Hz, 2H), 1.68ꢀ1.57
(m, 4H), 1.53 (s, 6H), 1.49ꢀ1.41 (m, 4H), 1.39ꢀ1.30 (m, 4H), 0.90 (td,
J = 7.2, 3.8 Hz, 6H); 13C NMR (100.6, CDCl3) δ 174.8 (C), 138.9 (C),
N-(2,3-Bis(2-cyclohexenylethynyl)phenyl)-2-hydroxy-2-
methylpropanamide (25c): Reaction of 18bc with 1-ethynylcyclo-
hexene (212 μL, 1.8 mmol) followed by purification by column chro-
matography (hexane/EtOAc, 5/1) afforded 25c (174 mg, 75%) as a pale
yellow solid: mp 156ꢀ158 °C; 1H NMR (300 MHz, CDCl3) δ 9.60 (br
s, 1H), 8.38 (dd, J = 8.0, 1.3 Hz, 1H), 7.27ꢀ7.19 (m, 1H), 7.17ꢀ7.12 (m,
1H), 6.33ꢀ6.27 (m, 1H), 6.27ꢀ6.22 (m, 1H), 2.50 (br s, 1H),
2.30ꢀ2.21 (m, 4H), 2.20ꢀ2.11 (m, 4H), 1.72ꢀ1.59 (m, 8H), 1.56 (d,
J = 1.1 Hz, 6H); 13C NMR (75.4 MHz, CDCl3) δ 174.7 (C), 138.5 (C),
136.3 (CH), 135.9 (CH), 128.4 (CH), 126.8 (CH), 126.0 (C), 120.9
(C), 120.7 (CH), 117.9 (C), 115.3 (C), 102.6 (C), 95.4 (C), 85.7 (C),
81.0 (C), 74.6 (C), 29.3 (CH2), 29.2 (CH2), 28.1 (2 ꢁ CH3), 26.03
(CH2), 25.98 (CH2), 22.45 (CH2), 22.40 (CH2), 21.61 (CH2), 21.55
(CH2); EI-LRMS m/z 387 (Mþ, 92), 369 (32), 328 (38), 300 (36), 207
(100), 59 (83); HRMS calcd for C26H29NO2 387.2198, found 387.2198.
N-(2,3-Bis(2-(thiophen-3-yl)ethynyl)phenyl)-2-hydroxy-2-
methylpropanamide (25d): Reaction of 18bc with 3-ethynylthio-
phene (211 μL, 1.8 mmol) followed by purification by column chro-
matography (hexane/EtOAc, 5/1) afforded 25d (164 mg, 70%) as a pale
brown solid: mp 206ꢀ208 °C; 1H NMR (400 MHz, acetone-d6) δ 10.1
(s, 1H), 8.56 (dd, J = 8.3, 1.2 Hz, 1H), 7.83 (dd, J = 3.0, 1.2 Hz, 1H), 7.81
(dd, J = 3.0, 1.2 Hz, 1H), 7.57 (dd, J = 5.0, 3.0 Hz, 2H), 7.39 (t, J = 8.0 Hz,
1H), 7.32 (dd, J = 5.0, 1.2 Hz, 1H), 7.30 (dd, J = 2.2, 1.2 Hz, 1H), 7.28
(dd, J = 1.2, 0.4 Hz, 1H), 5.41 (s, 1H), 1.51 (s, 6H); 13C NMR (75.4,
acetone-d6) δ 176.0 (C), 140.6 (C), 130.7 (CH), 130.6 (CH), 130.5
(CH), 130.4 (CH), 129.9 (CH), 127.3 (CH), 127.2 (CH), 127.0 (CH),
126.2 (C), 122.8 (C), 122.4 (C), 118.8 (CH), 115.3 (C), 96.8 (C), 89.6
(C), 88.1 (C), 83.6 (C), 74.6 (C), 28.1 (2 ꢁ CH3); EI-LRMS m/z 391
(Mþ, 82), 372 (20), 345 (100), 305 (76), 277 (57), 245 (23), 207 (78),
59 (47); HRMS calcd for C22H17NO2S2 391.0701, found 391.0701.
Anal. Calcd for C22H17NO2S2: C, 67.49; H, 4.38; N, 3.58. Found: C,
67.65; H, 4.41; N, 3.56.
General Procedure for the Synthesis of 4-Alkynyl-2-sub-
stituted-1H-indoles 26aꢀd. To a solution of the corresponding
2,3-dialkynylpropanamide 25 (1 equiv) in DMF (3 mL/mmol) was
added an excess of freshly powdered NaOH (3 equiv). The resulting
mixture was refluxed under N2 at 140 °C until the cyclization was
completed (6 h), as monitored by GC-MS. CH2Cl2 (10 mL) and 0.5 M
HCl (10 mL) were added to the cooled reaction mixture. The separated
aqueous phase was extracted with CH2Cl2 (2 ꢁ 10 mL). The combined
organic layers were washed with water (2 ꢁ 30 mL). The organic layer was
dried over anhydrous Na2SO4 and concentrated at reduced pressure. The
remaining residue was purified by column chromatography on silica gel
(hexane/EtOAc) to afford the corresponding title compounds 26aꢀd.
2-Phenyl-4-(2-phenylethynyl)-1H-indole (26a): Reaction of
25a (189 mg, 0.5 mmol) with NaOH (60 mg, 1.5 mmol) followed by
purification by column chromatography (hexane/EtOAc, 15/1) af-
forded 26a (106 mg, 73%) as a pale brown solid: mp 132ꢀ134 °C;
1H NMR (300 MHz, CDCl3) δ 8.49 (br s, 1H), 7.73ꢀ7.57 (m, 4H),
7.50ꢀ7.34 (m, 8H), 7.19 (t, J = 7.7 Hz, 1H), 7.10 (d, J = 2.2 Hz, 1H); 13C
NMR (75.4 MHz, CDCl3) δ 138.6 (C), 136.5 (C), 132.1 (C), 131.8
(2 ꢁ CH), 130.9 (C), 129.1 (2 ꢁ CH), 128.5 (2 ꢁ CH), 128.2 (CH),
128.1 (CH), 125.4 (2 ꢁ CH), 124.2 (CH), 123.9 (C), 122.2 (CH),
114.7 (C), 111.6 (CH), 99.8 (CH), 92.1 (C), 88.5 (C); EI-LRMS m/z
293 (Mþ, 100), 207 (12), 189 (10), 146 (12); IR (KBr) 3427, 3056,
1597, 1487, 1451, 1422, 1283, 753, 687 cmꢀ1; HRMS calcd for C22H15N
293.1204, found 293.1205. Anal. Calcd for C22H15CN: C, 90.07; H,
5.15; N, 4.77. Found: C, 89.78; H, 5.17; N, 4.76.
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4-(Hept-1-ynyl)-2-pentyl-1H-indole (26b): Reaction of 25b
(147 mg, 0.4 mmol) with NaOH (48 mg, 1.2 mmol) followed by
purification by column chromatography (hexane/EtOAc, 15/1) af-
forded 26b (78 mg, 70%) as a pale brown oil: Rf 0.50 (hexane/EtOAc,
5/1); 1H NMR (300 MHz, CDCl3) δ 7.88 (br s, 1H), 7.24ꢀ7.13 (m,
2H), 7.03 (t, J = 7.6 Hz, 1H), 6.40 (dd, J = 1.5, 0.6 Hz, 1H), 2.74 (t, J =
7.6 Hz, 2H), 2.52 (t, J = 7.0 Hz, 2H), 1.81ꢀ1.61 (m, 4H), 1.61ꢀ1.45 (m,
2H), 1.45ꢀ1.26 (m, 6H), 0.94 (dt, J = 9.2, 7.2 Hz, 6H); 13C NMR (75.4,
CDCl3) δ 140.6 (C), 135.4 (C), 130.6 (C), 123.2 (CH), 120.8 (CH),
114.7 (C), 110.2 (CH), 99.3 (CH), 92.5 (C), 79.6 (C), 31.6 (CH2), 31.3
(CH2), 28.95 (CH2), 28.86 (CH2), 28.4 (CH2), 22.6 (CH2), 22.4
(CH2), 19.8 (CH2), 14.22 (CH3), 14.16 (CH3); EI-LRMS m/z 281
(Mþ, 89), 238 (24), 224 (100), 167 (53); HRMS calcd for C20H27N
281.2143, found 281.2141.
2-Cyclohexenyl-4-(2-cyclohexenylethynyl)-1H-indole (26c):
Reaction of 25c (116 mg, 0.3 mmol) with NaOH (36 mg, 0.9 mmol)
followed by purification by column chromatography (hexane/EtOAc,
15/1) afforded 26c (51 mg, 57%) as a colorless oil: Rf 0.40 (hexane/
EtOAc, 5/1); 1H NMR (300 MHz, CDCl3) δ 8.15 (br s, 1H), 7.23 (dt,
J = 7.9, 1.0 Hz, 1H), 7.16 (dd, J = 7.4, 1.0 Hz, 1H), 7.09ꢀ7.03 (m, 1H),
6.58 (d, J = 1.8 Hz, 1H), 6.29ꢀ6.25 (m, 1H), 6.17ꢀ6.12 (m, 1H),
2.52ꢀ2.45 (m, 2H), 2.37ꢀ2.22 (m, 4H), 2.21ꢀ2.14 (m, 2H),
1.84ꢀ1.76 (m, 2H), 1.75ꢀ1.60 (m, 6H); 13C NMR (75.4 MHz, CDCl3)
δ 140.0 (C), 135.8 (C), 134.7 (CH), 130.5 (C), 130.0 (C), 129.2 (C),
123.5 (CH), 123.3 (CH), 121.9 (CH), 121.3 (C), 115.0 (C), 110.5
(CH), 98.7 (CH), 93.8 (C), 85.9 (C), 29.7 (CH2), 26.2 (CH2), 26.0
(CH2), 25.7 (CH2), 22.7 (CH2), 22.6 (CH2), 22.3 (CH2), 21.7 (CH2);
EI-LRMS m/z 301 (Mþ, 100), 273 (9), 230 (6), 204 (8), 191 (6);
HRMS calcd for C22H23N 301.1830, found 301.1835.
2-(Thiophen-3-yl)-4-(2-(thiophen-3-yl)ethynyl)-1H-indole
(26d): Reaction of 25d (117 mg, 0.3 mmol) with NaOH (36 mg,
0.9 mmol) followed by purification by column chromatography (hexane/
EtOAc, 15/1) afforded 26d (64 mg, 71%) as a white solid: mp 200ꢀ
202 °C; 1H NMR (300 MHz, acetone-d6) δ 10.92 (s, 1H), 7.88 (dd, J =
2.9, 1.3 Hz, 1H), 7.80 (dd, J = 2.9, 1.3 Hz, 1H), 7.69 (dd, J = 5.0, 1.3 Hz,
1H), 7.59 (ddd, J = 6.7, 5.0, 2.9 Hz, 2H), 7.42 (dt, J = 8.0, 1.0 Hz, 1H),
7.33 (dd, J = 5.0, 1.3 Hz, 1H), 7.22 (dd, J = 7.4, 1.0 Hz, 1H), 7.12 (dd, J =
8.0, 7.4 Hz, 1H), 7.03 (dd, J = 2.3, 1.0 Hz, 1H); 13C NMR (100.6,
acetone-d6) δ 137.5 (C), 136.1 (C), 134.9 (C), 131.4 (C), 130.7 (CH),
129.4 (CH), 127.6 (CH), 126.9 (CH), 126.8 (CH), 124.1 (CH), 123.6
(C), 122.4 (CH), 120.8 (CH), 114.8 (C), 112.5 (CH), 99.4 (CH), 88.8
(C), 87.4 (C); EI-LRMS m/z 305 (Mþ, 100), 281 (27), 253 (12), 207
(98), 191 (10); HRMS calcd for C18H11NS2 305.0333, found 305.0333.
General Procedure for the Synthesis of 4-Alkynyl-2-sub-
stituted-1H-indoles 26eꢀf. A mixture of 1c (231 mg, 0.9 mmol),
PdCl2(MeCN)2 (5 mg, 2 mol %), XPhos (26 mg, 3 mol %), and Cs2CO3
(880 mg, 2.7 mmol) in anhydrous MeCN (3 mL) was stirred under N2 at
rt for 25 min. Then, the corresponding alkyne (2.7 mmol) was added
and the reaction was stirred at reflux for 40 h. AcOEt and water were
added to the cooled reaction mixture. The separated aqueous phase was
extracted with AcOEt (3 ꢁ 15 mL). The combined organic layers were
dried over anhydrous Na2SO4 and concentrated at reduced pressure.
The remaining residue was purified by column chromatography on silica
gel (hexane/EtOAc) to afford the corresponding title compounds 26e,f.
2-p-Tolyl-4-(2-p-tolylethynyl)-1H-indole (26e): Reaction of
1c (231 mg, 0.9 mmol) with p-tolylacetylene (313 mg, 2.7 mmol)
followed by purification by column chromatography (hexane/EtOAc,
15/1) afforded 26e (127 mg, 44%) as a brown oil: Rf 0.40 (hexane/
EtOAc, 5/1); 1H NMR (400 MHz, CDCl3) δ 8.42 (br s, 1H), 7.59 (d,
J = 8.2 Hz, 2H), 7.53 (d, J = 8.2 Hz, 2H), 7.36ꢀ7.30 (m, 2H), 7.25 (d, J =
7.9 Hz, 2H), 7.18 (d, J = 7.9 Hz, 2H), 7.14 (t, J = 7.9 Hz, 1H), 7.02 (d, J =
1.3 Hz, 1H), 2.39 (d, J = 1.8 Hz, 6H); 13C NMR (100.4, CDCl3) δ 138.8
(C), 138.3 (C), 138.1 (C), 136.4 (C), 131.7 (2 ꢁ CH), 131.0 (C), 129.9
(2 ꢁ CH), 129.4 (C), 129.2 (2 ꢁ CH), 125.3 (2 ꢁ CH), 124.1 (CH),
122.0 (CH), 120.9 (C), 114.8 (C), 111.3 (CH), 99.3 (CH), 92.2 (C),
87.9 (C), 21.7 (CH3), 21.4 (CH3); EI-LRMS m/z 321 (Mþ, 100), 281
(10), 207 (31), 160 (7); HRMS calcd for C24H19N 321.1517, found
321.1518.
2-Hexyl-4-(oct-1-ynyl)-1H-indole (26f): Reaction of 1c (231
mg, 0.9 mmol) with 1-octyne (398 μL, 2.7 mmol) followed by
purification by column chromatography (hexane/EtOAc, 20/1) af-
forded 26f (141 mg, 51%) as a brown oil: Rf 0.50 (hexane/EtOAc,
5/1); 1H NMR (400 MHz, CDCl3) δ 7.90 (br s, 1H), 7.19 (dt, J = 8.1,
0.9 Hz, 1H), 7.15 (dd, J = 7.4, 0.9 Hz, 1H), 7.02 (dd, J = 8.1, 7.4 Hz, 1H),
6.39 (dd, J = 2.2, 0.9 Hz, 1H), 2.73 (t, J = 7.7 Hz, 2H), 2.51 (t, J = 7.0 Hz,
2H), 1.77ꢀ1.63 (m, 4H), 1.57ꢀ1.48 (m, 2H), 1.44ꢀ1.18 (m, 10H),
0.96ꢀ0.87 (m, 6H); 13C NMR (100.6, CDCl3) δ 140.6 (C), 135.5 (C),
130.7 (C), 123.2 (CH), 120.8 (CH), 114.8 (C), 110.2 (CH), 99.4 (CH),
92.5 (C), 79.7 (C), 31.8 (CH2), 31.6 (CH2), 29.25 (CH2), 29.18 (CH2),
29.15 (CH2), 28.8 (CH2), 28.5 (CH2), 22.8 (CH2), 22.7 (CH2), 19.9
(CH2), 14.23 (CH3), 14.23 (CH3); EI-LRMS m/z 309 (Mþ, 100), 281
(19), 252 (27), 238 (84), 207 (46), 167 (56); HRMS calcd for C22H31N
309.2457, found 309.2456.
Synthesis of 2-Phenyl-4-(2-phenylethynyl)-1H-indole 26a
from 3-Bromo-2-iodoanilide 18ca. A mixture of anilide 18ca (383
mg, 1 mmol), phenylacetylene (408 mg, 4 mmol), PdCl2(PPh3)2 (70
mg, 10 mol %), and TBAF 3H2O (947 mg, 3 mmol) was stirred under
3
N2 at 60 °C until complete consumption of starting material, as
monitored by GC-MS (5 h). The mixture was washed with water,
extracted with Et2O (3 ꢁ 20 mL), and evaporated under reduced
pressure. To remove Pd salts, the crude was filtered through a short pad
of silica gel. The residue was treated with an excess of freshly powdered
NaOH (120 mg, 3 mmol) in DMA (3 mL) under N2 at 140 °C for 8 h.
The formation of the indole was monitored by GC-MS. CH2Cl2
(20 mL) and 0.5 M HCl (20 mL) were added to the cooled reaction
mixture. The separated aqueous phase was extracted with CH2Cl2
(2 ꢁ 20 mL). The combined organic layers were washed with water
(2 ꢁ 30 mL). The organic layer was dried over anhydrous Na2SO4 and
concentrated under reduced pressure. The remaining residue was
purified by column chromatography on silica gel (hexane/EtOAc, 10/
1) to afford 26a (152 mg, 52%), whose spectroscopic data have been
reported above.
Synthesis of 4-(Hex-1-ynyl)-2-phenyl-1H-indole 26g. A
mixture of 4-bromo-2-phenyl-1H-indole 24a (81 mg, 0.3 mmol),
phenylacetylene (46 mg, 0.45 mmol), PdCl2(PPh3)2 (12 mg, 6 mol
%), CuI (6 mg, 10 mol %), and Et2NH (33 mg, 0.45 mmol) in DMF
(2 mL) was stirred under N2 at 80 °C for 17 h. CH2Cl2 (20 mL) and
0.5 M HCl (20 mL) were added to the cooled reaction mixture. The
separated aqueous phase was extracted with CH2Cl2 (3 ꢁ 10 mL). The
combined organic layers were washed with water (2 ꢁ 20 mL). The
organic layer was dried over anhydrous Na2SO4 and concentrated at
reduced pressure. The remaining residue was purified by column
chromatography on silica gel (hexane/EtOAc, 8/1) to afford 26g (63
mg, 77%) as a brown solid: mp 33ꢀ35 °C; 1H NMR (300 MHz, CDCl3)
δ 8.39 (br s, 1H), 7.69 (d, J = 7.3 Hz, 2H), 7.45 (t, J = 7.7 Hz, 2H), 7.33
(d, J = 7.3 Hz, 2H), 7.21 (d, J = 7.3 Hz, 1H), 7.11 (t, J = 7.7 Hz, 1H),
6.99ꢀ6.97 (m, 1H), 2.55 (t, J = 6.9 Hz, 2H), 1.75ꢀ1.63 (m, 2H),
1.62ꢀ1.50 (m, 2H), 1.00 (t, J = 7.2 Hz, 3H); 13C NMR (75.4 MHz,
CDCl3) δ 138.2 (C), 136.5 (C), 132.3 (C), 131.1 (C), 129.2 (2 ꢁ CH),
128.0 (CH), 125.3 (2 ꢁ CH), 123.9 (CH), 122.3 (CH), 115.8 (C),
110.7 (CH), 99.9 (CH), 93.2 (C), 79.3 (C), 31.2 (CH2), 22.2 (CH2),
19.6 (CH2), 13.9 (CH3); EI-LRMS m/z 273 (Mþ, 89), 258 (16), 244
(38), 230 (100), 202 (29), 127 (23); HRMS calcd for C20H19N
273.1517, found 273.1511. Anal. Calcd for C20H19N: C, 87.87; H,
7.01; N, 5.12. Found: C, 87.55; H, 6.98; N, 5.10.
General Procedure for the Synthesis of 4-Halo-3-
(phenylthio)-2-substituted-1H-indoles 27a,b from Anilides
18. A mixture of the corresponding anilide 18aa or 18ba (0.4 mmol),
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ARTICLE
alkyne (0.6 mmol), PdCl2(PPh3)2 (8 mg, 3 mol %), CuI (4 mg, 5 mol
%), and Et2NH (44 mg, 0.6 mmol) in DMA (2 mL) was stirred for 2 h at
80 °C, and then freshly powdered NaOH (160 mg, 4 mmol) was added.
The resulting mixture was heated under N2 at 140 °C for 3 h (until the
cyclization was completed as monitored by GC-MS). Then, Ph2S2
(105 mg, 0.48 mmol) was added and the reaction mixture was stirred
overnight at 140 °C. Then, CH2Cl2 (10 mL) and 0.5 M HCl (10 mL)
were added to the cooled reaction mixture. The separated aqueous phase
was extracted with CH2Cl2 (3 ꢁ 10 mL). The combined organic layers
were washed with water (2 ꢁ 30 mL), dried over anhydrous Na2SO4,
and concentrated under reduced pressure. The remaining residue was
purified by column chromatography on silica gel (hexane/EtOAc, 6/1)
to afford the title compounds 27.
4-Fluoro-2-pentyl-3-(phenylthio)-1H-indole (27a): Reac-
tion of 18aa (129 mg, 0.4 mmol) with 1-heptyne (58 mg, 0.6 mmol)
and then with Ph2S2 afforded 27a (92 mg, 74%) as a brown solid: mp
78ꢀ80 °C; 1H NMR (300 MHz, CDCl3) δ 8.50 (br s, 1H), 7.26ꢀ7.02
(m, 7H), 6.76 (ddd, J = 10.9, 7.5, 1.1 Hz, 1H), 2.89 (t, J = 7.5 Hz, 2H),
1.70ꢀ1.60 (m, 2H), 1.34ꢀ1.24 (m, 4H), 0.84 (t, J = 7.0 Hz, 3H); 13C
NMR (75.4 MHz, CDCl3) δ 156.4 (d, J = 248.9 Hz, C), 146.1 (C), 140.3
(C), 138.2 (C), 128.7 (2 ꢁ CH), 125.8 (2 ꢁ CH), 124.7 (CH), 122.5 (d,
J = 7.8 Hz, CH), 118.7 (d, J = 17.3 Hz, C), 107.1 (d, J = 3.9 Hz, CH),
106.4 (d, J = 19.2 Hz, CH), 97.0 (d, J = 2.3 Hz, C), 31.5 (CH2), 29.3
(CH2), 26.2 (CH2), 22.5 (CH2), 14.0 (CH3); EI-LRMS m/z 313 (Mþ,
100), 256 (48), 222 (16), 148 (24), 69 (16); HRMS calcd for
C19H20FNS 313.1300, found 313.1291. Anal. Calcd for C19H20FNS:
C, 72.81; H, 6.43; N, 4.47. Found: C, 73.01; H, 6.47; N, 4.45.
4-Chloro-2-phenyl-3-(phenylthio)-1H-indole (27b): Reac-
tion of 18ba (136 mg, 0.4 mmol) with phenylacetylene (61 mg,
0.6 mmol) and then with Ph2S2 afforded 27b (103 mg, 77%) as a white
solid: mp 131ꢀ133 °C; 1H NMR (300 MHz, CDCl3) δ 8.70 (br s, 1H),
7.66 (dd, J = 6.6, 2.9 Hz, 2H), 7.43ꢀ7.38 (m, 3H), 7.36ꢀ7.29 (m, 1H),
7.26ꢀ7.05 (m, 7H); 13C NMR (75.4 MHz, CDCl3) δ 144.3 (C), 141.4
(C), 137.3 (C), 131.0 (C), 129.2 (CH), 128.9 (2 ꢁ CH), 128.7 (4 ꢁ
CH), 127.0 (C), 126.8 (C), 125.3 (2 ꢁ CH), 124.6 (CH), 123.7 (CH),
122.8 (CH), 110.2 (CH), 98.8 (C); EI-LRMS m/z 337 (Mþ þ 2, 22),
335 (Mþ, 51), 299 (16), 267 (15), 223 (100), 190 (12), 121 (22), 119
(23), 77 (86), 51 (67); HRMS calcd for C20H14ClNS 335.0535, found
335.0534.
272 (22), 236 (100), 204 (50), 164 (96), 119 (23), 77 (59); HRMS
calcd for C18H18ClNS 315.0848, found 315.0849.
4-Bromo-2-butyl-3-(phenylthio)-1H-indole (27d): Reaction
of 22cb (101 mg, 0.3 mmol) with NaOH for 2.5 h and then with Ph2S2
afforded 27d (78 mg, 73%) as a pale brown solid: mp 86ꢀ88 °C; 1H
NMR (300 MHz, CDCl3) δ 8.42 (br s, 1H), 7.30 (tdd, J = 8.0, 4.4, 0.9
Hz, 2H), 7.22ꢀ7.15 (m, 2H), 7.09ꢀ6.99 (m, 4H), 2.92 (t, J = 7.7 Hz,
2H), 1.67ꢀ1.56 (m, 2H), 1.41ꢀ1.26 (m, 2H), 0.89 (td, J = 7.1, 0.7 Hz,
3H); 13C NMR (75.4 MHz, CDCl3) δ 147.9 (C), 141.5 (C), 136.7 (C),
128.7 (2 ꢁ CH), 127.3 (C), 125.7 (CH), 125.3 (2 ꢁ CH), 124.4 (CH),
123.0 (CH), 113.9 (C), 110.4 (CH), 99.4 (C), 31.6 (CH2), 26.3 (CH2),
22.5 (CH2), 13.9 (CH3); EI-LRMS m/z 361 (Mþ þ 2, 25), 359 (Mþ,
25), 236 (100), 223 (27), 208 (30), 77 (60), 51 (59); HRMS calcd for
C18H18BrNS 359.0343, found 359.0346. Anal. Calcd for C18H18BrNS:
C, 60.00; H, 5.04; N, 3.89. Found: C, 60.15; H, 5.02; N, 3.91.
General Procedure for the Synthesis of 4-(Furan-2-yl)-2-
substituted-1H-indoles 28. A mixture of premilled Pd(OAc)2
(1.3 mg, 2 mol %) and XPhos (5.7 mg, 4 mol %), CsF (100 mg, 0.66
mmol), the corresponding 4-chloroindole 23a or 23b (0.3 mmol), and
tributyl(furan-2-yl)stannane (118 mg, 0.33 mmol) in DME (0.8 mL)
were stirred under N2 at 80 °C for 3 h (the completion of the coupling
reaction was monitored by GC-MS). The reaction mixture was allowed
to cool to rt and the crude was filtered through Celite and washed with
EtOAc (20 mL). The solvent was concentrated under reduced pressure
and the residue was purified by column chromatography on silica gel
(hexane/EtOAc) to afford the title compounds 28.
4-(Furan-2-yl)-2-phenyl-1H-indole (28a): Reaction of 23a
(68 mg, 0.3 mmol) followed by purification by column chromatography
(hexane/EtOAc, 8/1) afforded 28a (71 mg, 91%) as a colorless oil: Rf
0.31 (hexane/AcOEt, 8/1); 1H NMR (300 MHz, CDCl3) δ 8.43 (br s,
1H), 7.73ꢀ7.64 (m, 3H), 7.58 (dd, J = 6.7, 1.6 Hz, 1H), 7.47 (t, J =
7.6 Hz, 2H), 7.40ꢀ7.35 (m, 2H), 7.31ꢀ7.24 (m, 2H), 6.92 (d, J =
3.3 Hz, 1H), 6.63 (dd, J = 3.3, 1.8 Hz, 1H); 13C NMR (75.4 MHz,
CDCl3) δ 154.6 (C), 141.8 (CH), 138.5 (C), 137.6 (C), 132.1 (C),
129.0 (2 ꢁ CH), 127.9 (CH), 125.3 (2 ꢁ CH), 124.9 (C), 123.0 (C),
122.4 (CH), 116.9 (CH), 111.7 (CH), 110.5 (CH), 106.5 (CH), 100.2
(CH); EI-LRMS m/z 259 (Mþ, 100), 230 (40), 202 (8), 127 (8);
HRMS calcd for C18H13NO 259.0997, found 259.0994.
2-Butyl-4-(furan-2-yl)-1H-indole (28b): Reaction of 23b (62 mg,
0.3 mmol) followed by purification by column chromatography
(hexane/EtOAc, 7/1) afforded 28b (66 mg, 92%) as a white solid: mp
50ꢀ52 °C; 1H NMR (300 MHz, CDCl3) δ 7.85 (br s, 1H), 7.61 (d, J = 1.8
Hz, 1H), 7.56ꢀ7.52 (m, 1H), 7.23ꢀ7.20 (m, 2H), 6.85 (d, J =
3.3 Hz, 1H), 6.75 (s, 1H), 6.60 (ddd, J = 3.3, 1.8, 0.6 Hz, 1H), 2.76 (t,
J = 7.6 Hz, 2H), 1.79ꢀ1.68 (m, 2H), 1.52ꢀ1.39 (m, 2H), 1.01 (t, J= 7.3 Hz,
3H); 13C NMR (75.4 MHz, CDCl3) δ 154.8 (C), 141.5 (CH), 141.0 (C),
136.6 (C), 124.4 (C), 122.1 (C), 121.0 (CH), 116.4 (CH), 111.6 (CH),
110.0 (CH), 106.2 (CH), 99.6 (CH), 31.4 (CH2), 28.1 (CH2), 22.5(CH2),
14.0 (CH3); EI-LRMS m/z 239 (Mþ, 56), 196 (100), 167 (14), 154 (4);
HRMS calcd for C16H17NO, 239.1310 found 239.1319. Anal. Calcd for
C16H17NO: C, 80.30; H, 7.16; N, 5.85. Found: C, 80.17; H, 7.19; N, 5.83.
General Procedure for the Synthesis of 4-Aryl-1H-indoles
29. In a Schlenk tube 4-bromo-1H-indole 24a or 24b (1 equiv),
phenylboronic acid (1.5 equiv), and [Pd(PPh3)4] (3 mol %) were
introduced under N2. Then, DME (15 mL/mmol) was added followed
by the addition of Na2CO3 (1.5 equiv) in H2O (7 mL/mmol). The
reaction mixture was vigorously stirred and heated at 80 °C overnight
(the progress of the reaction was monitored by GC-MS). Then, CH2Cl2
(10 mL) and H2O were added to the cooled reaction mixture. The
separated aqueous phase was extracted with CH2Cl2 (3 ꢁ 20 mL). The
combined organic extracts were dried over anhydrous Na2SO4 and
evaporated under reduced pressure. The residue was purified by column
chromatography (hexane/EtOAc, 8/1) on silica gel to afford the title
compounds 29.
General Procedure for the Synthesis of 4-Halo-3-phenyl-
sulfanyl-1H-indoles 27c,d from 3-Halo-2-alkynylpropana-
mides 22. An excess of freshly powdered NaOH (120 mg, 3 mmol)
was added to a solution of the corresponding 3-halo-2-alkynylpropana-
mide 22bb or 22cb (0.3 mmol) in DMA (1 mL). The resulting mixture
was refluxed under N2 at 140 °C until the cyclization was completed
(2ꢀ3 h) (monitored by GC-MS). Then, Ph2S2 (78 mg, 0.36 mmol) was
added to the mixture and the reaction was stirred overnight at 140 °C.
CH2Cl2 (10 mL) and 0.5 M HCl (10 mL) were added to the cooled
reaction mixture. The separated aqueous phase was extracted with
CH2Cl2 (3 ꢁ 10 mL). The combined organic layers were washed with
water (2 ꢁ 30 mL). The organic layer was dried over anhydrous Na2SO4
and concentrated at reduced pressure. The remaining residue was
purified by column chromatography on silica gel (hexane/EtOAc,
6/1) to afford the title compounds 27.
2-Butyl-4-chloro-3-(phenylthio)-1H-indole (27c): Reaction
of 22bb (88 mg, 0.3 mmol) with NaOH for 3 h at 140 °C and then with
Ph2S2 afforded 27c (74 mg, 79%) as a white solid: mp 76ꢀ78 °C; 1H
NMR (300 MHz, CDCl3) δ 8.47 (br s, 1H), 7.25 (ddd, J = 6.5, 2.4, 0.4
Hz, 1H), 7.22ꢀ7.15 (m, 2H), 7.12ꢀ7.03 (m, 5H), 2.91 (t, J = 7.6 Hz,
2H), 1.68ꢀ1.56 (m, 2H), 1.41ꢀ1.27 (m, 2H), 0.99 (t, J = 7.3 Hz, 3H);
13C NMR (75.4 MHz, CDCl3) δ 147.5 (C), 141.3 (C), 136.9 (C), 128.7
(2 ꢁ CH), 126.3 (C), 126.1 (C), 125.4 (2 ꢁ CH), 124.4 (CH), 122.6
(CH), 122.2 (CH), 109.8 (CH), 98.6 (C), 31.6 (CH2), 26.2 (CH2), 22.5
(CH2), 13.9 (CH3); EI-LRMS m/z 317 (Mþ þ 2, 39), 315 (Mþ, 83),
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ARTICLE
2,4-Diphenyl-1H-indole (29a): Reaction of 24a (81 mg, 0.3 mmol)
with phenylboronic acid (55 mg, 0.45 mmol) and [Pd(PPh3)4] (10 mg,
3 mol %) followed by the addition of Na2CO3 (48 mg, 0.45 mmol) in H2O
(2 mL) afforded 29a (74 mg, 93%) as a white solid: mp 205ꢀ207 °C
1993, 36, 29–32. (e) Chauder, B.; Larkin, A.; Snieckus, V. Org. Lett. 2002,
4, 815–817.
(4) Chae, J.; Buchwald, S. L. J. Org. Chem. 2004, 69, 3336–3339.
(5) Davies, H. M. L.; Manning, J. R. J. Am. Chem. Soc. 2005,
128, 1060–1061.
(6) Li, L.; Martins, A. Tetrahedron Lett. 2003, 44, 5987–5990.
(7) (a) Watanabe, M.; Yamamoto, T.; Nishiyama, M. Angew. Chem.,
Int. Ed. 2000, 39, 2501–2504. (b) Willis, M. C.; Brace, G. N.; Findlay,
T. J. K.; Holmes, I. P. Adv. Synth. Catal. 2006, 348, 851–856. (c) Taber,
D. F.; Tian, W. J. Am. Chem. Soc. 2006, 128, 1058–1059. (d) Sanz, R.;
Escribano, J.; Pedrosa, M. R.; Aguado, R.; Arnꢀaiz, F. J. Adv. Synth. Catal.
2007, 349, 713–718. (e) Barluenga, J.; Jimꢀenez-Aquino, A.; Aznar, F.;
Valdꢀes, C. J. Am. Chem. Soc. 2009, 131, 4031–4041.
(8) See, for instance: (a) Tidwell, J. H.; Buchwald, S. L. J. Am. Chem.
Soc. 1994, 116, 11797–11810. (b) S€oderberg, B. C.; Shriver, J. A. J. Org.
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Fernꢀandez, Y. Chem.—Eur. J. 2002, 8, 2034–2046.
1
(lit.61 mp 209 °C); H NMR (300 MHz, CDCl3) δ 8.42 (br s, 1H),
7.89ꢀ7.82 (m, 2H), 7.67 (d, J = 8.1 Hz, 2H), 7.61 (t, J = 7.7 Hz, 2H),
7.53ꢀ7.44 (m, 3H), 7.43ꢀ7.25 (m, 4H), 7.12 (d, J = 2.2 Hz, 1H); 13C
NMR (75.4 MHz, CDCl3) δ 141.3 (C), 138.3 (C), 137.3 (C), 134.5 (C),
132.2 (C), 129.1 (2 ꢁ CH), 128.9 (2 ꢁ CH), 128.7 (2 ꢁ CH), 127.8
(CH), 127.6 (C), 127.1 (CH), 125.2 (2 ꢁ CH), 122.7 (CH), 120.2 (CH),
110.2 (CH), 99.6 (CH); EI-LRMS m/z 269 (Mþ, 100), 190 (10), 165
(53), 133 (11), 77 (28); HRMS calcd for C20H15N 269.1204, found
269.1204.
2-Butyl-4-phenyl-1H-indole (29b): Reaction of 24b (200 mg,
0.8 mmol) with phenylboronic acid (146 mg, 1.2 mmol) and
[Pd(PPh3)4] (24 mg, 3 mol %) followed by the addition of Na2CO3
(127 mg, 1.2 mmol) in H2O (6 mL) afforded 29b (163 mg, 82%) as a
(9) Only 2,3-dichloroaniline is commercially available.
1
(10) (a) Corbett, J. F.; Holt, J. F. J. Chem. Soc. 1961, 5029–5037.
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(11) (a) Lamm, B.; Liedholm, B. Acta Chem. Scand. 1967,
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(12) Singh, R.; Just, G. J. Org. Chem. 1989, 54, 4453–4457.
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Schmid, J.; Asselin, A. A.; Shaw, C. C.; Noureldin, R.; Gavin, G.
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pale brown oil: Rf 0.64 (hexane/EtOAc, 6/1); H NMR (400 MHz,
CDCl3) δ 7.88ꢀ7.83 (m, 3H), 7.60 (t, J = 7.6 Hz, 2H), 7.48 (t, J =
7.6 Hz, 1H), 7.33ꢀ7.30 (m, 3H), 6.56 (d, J = 1.7 Hz, 1H), 2.77 (t, J = 7.6
Hz, 2H), 1.81ꢀ1.71 (m, 2H), 1.54ꢀ1.44 (m, 2H), 1.05 (t, J = 7.3 Hz,
3H); 13C NMR (100.6 MHz, CDCl3) δ 141.6 (C), 140.6 (C), 136.3
(C), 133.4 (C), 128.8 (2 ꢁ CH), 128.5 (2 ꢁ CH), 127.0 (C), 126.8
(CH), 121.3 (CH), 119.6 (CH), 109.7 (CH), 98.9 (CH), 31.4 (CH2),
28.0 (CH2), 22.5 (CH2), 14.0 (CH3); EI-LRMS m/z 249 (Mþ, 23), 206
(100), 178 (15), 165 (16); HRMS calcd for C18H19N 249.1517, found
249.1528.
’ ASSOCIATED CONTENT
(14) Only 2,3-dichloronitrobenzene is commercially available.
Other 2,3-dihalonitrobenzene derivatives have been prepared as inter-
mediates in the multistep syntheses of some 2,3-dihaloanilines. See refs
11 and 12.
(15) (a) Do, H.-Q.; Daugulis, O. Org. Lett. 2009, 11, 421–423.
(b) Popov, I.; Do, H.-Q.; Daugulis, O. J. Org. Chem. 2009, 74, 8309–8313.
(16) (a) Sanz, R.; Castroviejo, M. P.; Fernꢀandez, Y.; Fa~nanꢀas, F. J.
J. Org. Chem. 2005, 70, 6548–6551. See, also:(b) Sanz, R.; Castroviejo,
M. P.; Guilarte, V.; Pꢀerez, A.; Fa~nanꢀas, F. J. J. Org. Chem. 2007,
72, 5113–5118. (c) Sanz, R.; Guilarte, V.; Hernando, E.; Sanjuꢀan,
A. M. J. Org. Chem. 2010, 75, 7443–7446.
Supporting Information. Copies of H and 13C NMR
1
S
b
spectra of all products. This material is available free of charge via
the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: rsd@ubu.es.
(17) Bunnett, J. F.; Zahler, R. E. Chem. Rev. 1951, 49, 273–412.
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(21) A ca. 1:1 mixture of 7 and 1b was obtained at 0 °C.
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corresponding dilithiated species 2b would be formed. See: Reavill,
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(23) At 0 °C no starting material remained in the crude reaction
mixture, probably due to ortho-lithiation and further benzyne generation
that gives rise to an untreatable mixture.
’ ACKNOWLEDGMENT
We thank the Ministerio de Ciencia e Innovaciꢀon (MICINN)
and FEDER (CTQ2010-15358) and Junta de Castilla y Leꢀon
(BU021A09 and GR-172) for financial support. V.G. thanks
Ministerio de Educaciꢀon y Ciencia for a MEC-FPU predoctoral
fellowship. P.G.-G. and M.A.F.-R. thank MICINN for “Juan de la
Cierva” and “Ramꢀon y Cajal” contracts.
DEDICATION
§This paper is dedicated to the memory of Prof. Rafael Suau.
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