Palladium-Catalyzed Aminocyclization-Coupling Cascades: Preparation of Dehydrotryptophan Derivatives and Computational Study

Article abstract of DOI:10.1021/acs.joc.1c00636

Dehydrotryptophan derivatives have been prepared by palladium-catalyzed aminocyclization-Heck-type coupling cascades starting from o-alkynylaniline derivatives and methyl α-aminoacrylate. Aryl, alkyl (primary, secondary, and tertiary), and alkenyl substituents have been introduced at the indole C-2 position. Further variations at the indole benzene ring, as well as the C-2-unsubstituted case, have all been demonstrated. In the case of C-2 aryl substitution, the preparation of the o-alkynylaniline substrate by Sonogashira coupling and the subsequent cyclization-coupling cascade have been performed in a one-pot protocol with a single catalyst. DFT calculations have revealed significant differences in the reaction profiles of these reactions relative to those involving methyl acrylate or methacrylate, and between the reactions of the free anilines and their corresponding carbamates. Those calculations suggest that the nature of the alkene and of the acid HX released in the HX/alkene exchange step that precedes C-C bond formation could be responsible for the experimentally observed differences in reaction efficiencies.

Full text of DOI:10.1021/acs.joc.1c00636

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Article
Palladium-Catalyzed Aminocyclization−Coupling Cascades:
Preparation of Dehydrotryptophan Derivatives and Computational
Study
́
Belén Vaz, Claudio Martínez, Francisco Cruz, J. Gabriel Denis, Angel R. de Lera, José M. Aurrecoechea,*
́
and Rosana Alvarez*
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ABSTRACT: Dehydrotryptophan derivatives have been prepared
by palladium-catalyzed aminocyclization-Heck-type coupling cas-
cades starting from o-alkynylaniline derivatives and methyl α-
aminoacrylate. Aryl, alkyl (primary, secondary, and tertiary), and
alkenyl substituents have been introduced at the indole C-2
position. Further variations at the indole benzene ring, as well as
the C-2-unsubstituted case, have all been demonstrated. In the case
of C-2 aryl substitution, the preparation of the o-alkynylaniline
substrate by Sonogashira coupling and the subsequent cyclization−
coupling cascade have been performed in a one-pot protocol with a
single catalyst. DFT calculations have revealed significant differ-
ences in the reaction profiles of these reactions relative to those
involving methyl acrylate or methacrylate, and between the reactions of the free anilines and their corresponding carbamates. Those
calculations suggest that the nature of the alkene and of the acid HX released in the HX/alkene exchange step that precedes C−C
bond formation could be responsible for the experimentally observed differences in reaction efficiencies.
heterocyclization from the Pd(0) generated during the
coupling and, after intramolecular nucleopalladation, an acid
molecule HX has to be released and exchanged for the
coupling partner. As a result, in addition to the ligand ability of
the alkene coupling partner, the acidity of HX becomes also an
important consideration. Perhaps not surprisingly, cyclo-
isomerization of the acyclic starting material, a well-established
Pd-catalyzed transformation,48 has often been reported as a
side-reaction, particularly in the case of alkyne-tethered
substrates.5,6,11,17,27,42 Within the context of Scheme 1b, one
particular field of application of cascade reactions has been the
preparation of 3-alkenyl indoles by Pd-catalyzed amino-
cyclization-Heck-type coupling between 2-alkynylanilines and
alkenes.14,21,27 It was envisaged that the application of this
methodology to the particular use of an α-acetamidoacrylate as
the alkene partner would be advantageous in the preparation of
the expected dehydrotryptophan products (Scheme 1c). These
compounds have attracted interest as precursors of the
INTRODUCTION
■
Palladium complexes are extensively utilized as catalysts in
nucleophilic additions to unsaturated systems1 as well as in
cross-coupling reactions.2 These two abilities have been
combined in heterocyclization−coupling cascades involving
nucleophile-tethered unsaturated systems and suitable cou-
pling agents (Scheme 1a). In this manner, the cascade strategy
has provided a practical access to heterocyclic systems with an
appended alkene, alkyne, or aryl group, depending on whether
heterocyclization is strategically designed to be followed by
Heck-,3−30 Sonogashira-31−41 or Suzuki-type7,42−46 couplings,
respectively.47 Compared with an alternative two-step protocol
where a precursor is functionalized (typically as halide) before
performing a palladium-catalyzed coupling,2 the use of those
reaction cascades provides a more direct, expeditious and
convergent method, as they use simpler acyclic substrates as
starting materials and do not require the isolation of a cyclic
functionalized intermediate.47 Taking the case of an alkene
coupling agent as example, in mechanistic terms the cascade
reaction can be thought of as proceeding via Pd(II)-promoted
nucleopalladation and alkene complexation steps leading to a
typical Heck reaction intermediate Pd(II) complex (Scheme
1b). However, relative to the conventional coupling reaction
from a prefunctionalized precursor, the cascade reaction
features two important distinctions. Thus, oxidative conditions
are needed to regenerate the Pd(II) species that promote the
Received: March 17, 2021
Published: June 14, 2021
https://doi.org/10.1021/acs.joc.1c00636
© 2021 American Chemical Society
J. Org. Chem. 2021, 86, 8766−8785
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with potential use in therapeutic applications.64−71 Access to
dehydrotryptophans has been gained, among other method-
ologies,65 via Heck reaction of preformed 3-haloindoles72,73
and α-acetamidoacrylate derivatives.74−78 In this contribution,
we report a more direct access to dehydrotryptophans from
acyclic 2-alkynylaniline and α-acetamidoacrylate substrates
using a Pd-catalyzed aminocyclization−Heck-type-coupling
cascade. Additionally, with a combination of experimental
and computational data, we have inquired into the effects of
the alkene, phosphine ligand, and the aniline precursor on the
overall efficiency of the cascade coupling reaction, and on the
competition between coupling and cycloisomerization.
Scheme 1. Palladium-catalyzed Oxidative
Heterocyclization−Coupling Cascades and Application to
the Preparation of Dehydrotrytophans
RESULTS AND DISCUSSION
■
Initially, the reaction conditions previously developed for
related reactions with acrylate esters14 were tested on methyl
α-acetamidoacrylate (3) and representative o-alkynylaniline
substrates 1 variable at the terminal alkynyl position (aryl or
alkyl). The corresponding carbamates 2 were also tried since
on occasion their use had proven more advantageous.27 Results
are shown in Table 1. Thus, heating o-alkynylaniline 1a derived
from p-tolylacetylene with an excess (6 equiv) of alkene 3 in
DMF in the presence of a catalytic amount of PdCl2 and KI
(0.5 equiv) under an air atmosphere provided the expected
dehydrotryptophan product 4a in moderate yield (entry 1).
Cycloisomerization of the starting N-unsubstituted alkynylani-
line 1a was found to be an important side-reaction leading to
the formation of the 3-unsubstituted indole 6a. The use of a
phosphine ligand had been found beneficial in cases where
cycloisomerization was a problem,14 and this was also the case
here, as the use of PdCl2(PPh3)2 (entry 2) resulted in a
considerable increase in the yield of 4a (63%) and a much
more favorable 4a/6a ratio (4:1). Other phosphines were also
tested but gave inferior overall results (entries 3−4). For
example, with (p-MeOC6H4)3P a further increase of the 4a/6a
ratio was observed (perhaps pointing to a possible effect of the
important family of tryptophan derivatives,49−63 and also
because of their presence in natural and non-natural substances
Table 1. Survey of Reaction Conditions for Aminocyclization−Heck Coupling Between o-Alkynylaniline Derivatives 1 and 2
a
and Methyl α-Acetamidoacrylate (3)
b
c
Entry
1
R1, R2
H, p-tolyl
H, p-tolyl
H, p-tolyl
H, p-tolyl
H, p-tolyl
H, n-hexyl
H, tert-butyl
CO2Et, p-tolyl
CO2Et, n-hexyl
CO2Et, tert-butyl
[Pd], L
t (h)
4a/5a
Yield of 4/5
4−5/6 Ratio
1
2
3
4
5
6
7
8
9
10
1a
1a
1a
1a
1a
1b
1c
2a
2b
2c
PdCl2
18
7
18
18
18
4
4a
4a
4a
4a
4a
4b
4c
5a
4b, 5b
−
39
63
54
33
36
20
43
72
1:1
4:1
5:1
2:1
2:1
d
d
only 5a
only 4b, 5b
e
PdCl2(PPh3)2
PdCl2, (p-MeOC6H4)3P
PdCl2, (o-furyl)3P
Pd(OAc)2, PPh3
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
5
31
31
43
PdCl2(PPh3)2
PdCl2(PPh3)2
18, 40
−
a
Taken (in part) from Cruz, F. Development of cascade reactions catalyzed by Palladium and their application to the synthesis of heterocycles, Ph.D.
Thesis, Universidade de Vigo, 2019. Reaction conditions: Alkynylaniline derivative 1 or 2, alkene 3 (6 equiv), a Pd complex (5 mol %), a phosphine
ligand (where appropriate, 10 mol %), and KI (0.5 equiv) were heated in DMF (10 mL/mmol) at 100 °C under air for the indicated time.
b
c
d
e
Isolated yield (%). Measured in the crude reaction mixture. Not determined due to signal overlap. No reaction.
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a
Table 2. Preparation of 2-Aryldehydrotryptophans 4a, 4d−n (R2 = Ar) from 2-Iodoarylcarbamates 7
b
c
Entry
7
R3
R4
R2
t (h)
4
Yield of 4
1
2
3
4
5
6
7
8
7a
7a
7a
7b
7c
7d
7e
7a
7a
7a
7a
7a
H
H
H
Br
H
CO2Me
OMe
H
H
H
H
H
H
H
H
H
Br
H
H
H
H
H
H
H
p-tolyl
6, 31, 4
6, 30, 4
6, 40, 4
5, 41, 3
4, 40, 3
4, 40, 3
4, 40, 3
21, 48, 6
21, 48, 5
21, 48, 4
21, 48, 5
21, 48, 5
4a
4d
4e
4f
4g
4h
4i
4j
4k
4l
62
73
59
68
62
49
55
58
50
59
58
51
(p-MeO)C6H4
(p-CO2Me)C6H4
p-tolyl
p-tolyl
p-tolyl
p-tolyl
(m-Cl)C6H4
(m-F)C6H4
(m-OMe)C6H4
(3,4-diF)C6H3
3-thienyl
9
10
11
12
4m
4n
a
Taken (in part) from Cruz, F. Development of cascade reactions catalyzed by Palladium and their application to the synthesis of heterocycles, Ph. D.
Thesis, Universidade de Vigo, 2019. Reaction conditions. Step 1: Iodide 7, alkene 3 (6 equiv), alkyne 8 (2 equiv), PdCl2 (5 mol %), polymer-
bound PPh3 (10 mol % of PPh3 relative to 7), CuI (20 mol %), Et3N (4.5 equiv) in DMF (10 mL/mmol) at 60 °C under Ar. Step 2:120 °C under
b
c
air. Step 3: t-BuNH2 (30 equiv), MeOH (21 mL/mmol), reflux. Reaction times for steps 1−3. Isolated yield (%).
phosphine electron-donating ability) but at the expense of an
overall lower yield of 4a (entry 3). The use of Pd(OAc)2 in
place of PdCl2 was also less effective (entry 5). Next, the
reaction conditions of entry 2 were applied to alkynylanilines
1b and 1c with alkyl groups at the terminal alkynyl position,
but the results were much less successful (entries 6 and 7).
Finally, the reactions of carbamates 2 were tested (entries 8−
10). Relative to the N-unsubstituted anilines 1, carbamates 2
were less reactive, as indicated by longer reaction times
(entries 8 and 9) and complete lack of reactivity in the case of
the t-Bu-substituted substrate 2c (entry 10). Nevertheless,
when reactive enough, carbamates led to the best results in
terms of both yield and selectivity (72% for 5a, entry 8), as the
formation of a 3-unsubstituted indole analogous to 6 was not
observed in those cases. In the case of the alkyl-substituted
substrate 2b partial carbamate cleavage took place, resulting in
the formation of the N-unsubstituted indole 4b, in addition to
the corresponding carbamate 5b.79 In any case, the overall
yield of cyclization−coupling (58%) was a substantial
improvement over the result of entry 6.
Preparation of N-Unsubstituted Dehydrotrypto-
phans. The extension of the cascade reaction to other
carbamate substrates 2 was then studied. Additionally, the
possibility of incorporating the preparation of the alkynyl
carbamate substrate 2 into a one-pot protocol to perform a
Sonogashira-cyclization−coupling sequence was sought. In this
manner, the dehydrotryptophan derivatives would be prepared
from 2-iodoarylcarbamates 7, terminal alkynes 8, and alkene 3
in a one-pot Pd-catalyzed sequence,21 using a single catalyst,
without isolation of the Sonogashira intermediate 2 (Table 2).
In practice, it was found that only alkynes with terminal aryl
substituents took part effectively. The resulting aryl-substituted
dehydrotryptophan products are endowed with particular
interest, as the 2-phenylindole moiety is considered a
privileged structure in medicinal chemistry.80 In the event,
iodides 7, arylalkynes 8, and alkene 3 were reacted under
typical Sonogashira conditions under argon, until complete
consumption of the starting aryl iodide, whereupon air was
allowed into the system and the mixture was heated to 120 °C
(Table 2). Under these conditions, the expected dehydro-
tryptophan carbamate products 5 were formed, but it was
noticed that, in line with previous observations (Table 1, entry
9), partial carbamate cleavage took place to yield also variable
amounts of the N-unsubstituted dehydrotryptophans 4.79 As a
result, the experimental procedure was modified to include a
carbamate-cleaving step. Accordingly, after a simple workup,
the crude dehydrotryptophan product mixture (5 and 4) was
treated with tert-butylamine81 to complete the conversion of 5
into 4. This three-step procedure afforded dehydrotryptophan
products 4 in good overall yields without the need for
purification of intermediates. It was also found advantageous to
use a polymer-bound PPh3.82 In this manner, a simple filtration
facilitated the removal of catalyst residues that otherwise made
chromatographic purification of some of the products difficult.
As shown in Table 2, the procedure is effective for a variety of
substituted arylalkynes 8 and 2-iodoarylcarbamates 7. Electron-
donating and electron-withdrawing substituents were tolerated
in both sets of reactants, and the presence of bromine
substituents at alternative positions of the aryl group of 7 did
not interfere with the desired reaction sequence (entries 4 and
5).
As indicated above, the one-pot Sonogashira-cyclization−
coupling sequence did not provide satisfactory results when
applied to alkyl-substituted terminal alkynes. Alternatively, a
cyclization−coupling−carbamate-cleavage protocol was effi-
cient with such alkynes (Scheme 2). Still, these alkynyl
carbamates had a rather sluggish reactivity in the Pd-catalyzed
process, resulting in long reaction times and recovery of some
starting material. This prompted the use of a higher Pd load
(10 mol %), and in the case of the c-hexyl-substituted substrate
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the incorporation of a cyclohexenyl substituent was also
successful (entries 7 and 10). The particular examples of
entries 4−6 and 8−9 provide a precedent for the introduction
of tertiary alkyl groups, prevalent in natural and otherwise
interesting dehydrotryptophan derivarives.64−67,69 Further-
more, the reaction could also be applied to the triethylsilyl
(TES)-substituted substrate 9k (Scheme 3) to yield a C-2-
Scheme 2. Preparation of 2-Alkyldehydrotryptophans from
2-Alkynylaniline Carbamates
Scheme 3. Preparation of a 2-Unsubstituted
Dehydrotryptophan Derivative
a
Reaction conditions: (i) alkene 3 (6 equiv), PdCl2(PPh3) 2 (10 mol
%), KI (0.5 equiv), DMF, air, 100 °C (2b and 2p) or 120 °C (2o).
(ii) t-BuNH2 (30 equiv), MeOH, 90 °C.
2o, a higher temperature (120 °C) was also needed for
practical results. As shown in Scheme 2, both primary- and
secondary-alkyl groups, as well as an alkenyl substituent, were
successfully used to afford the corresponding N-unsubstituted
dehydrotryptophans (4b, 4o, and 4p) after carbamate
deprotection.
Preparation of N-(PMB)dehydrotryptophans. To ex-
plore also the possibility of using Csp3-substituents at the
aniline N atom, p-methoxybenzyl (PMB) dehydrotryptophans
were targeted as representative of the interesting subclass of
benzyl-substituted indoles83−86 (Table 3). In line with the
results of Scheme 2, modifications of the reaction conditions
were introduced in order to improve the performance of these
aniline substrates. This implied increasing again the catalyst
loading to 10 mol % and, for consistent results, also
incorporating triphenylphosphine oxide (TPPO, 10 mol %)
as an additive.87
unsubstituted dehydrotryptophan 12 as a result of an
aminocyclization−alkenylation cascade and concomitant desi-
lylation. The use of a silyl substituent as a H surrogate was
prompted by unsuccessful attempts to use directly simple o-
ethynylaniline featuring a terminal alkyne. In general, some
cycloisomerization of the starting alkynylaniline, with for-
mation of the uncoupled 3-unsubstituted indoles (11), was
observed as a side reaction in the cases shown in Table 3. For
example, the 2-(tert-butyl) derivative 11d (R1 = H; R2 = t-Bu)
was isolated in 17% yield (entry 4, Table 3), and the formation
of analogous products could also be inferred in the remaining
1
entries of Table 3 (and Scheme 3) from inspection of the H
NMR of the crude products (singlet at δ 6.3−6.8), although
these products were not further characterized.
As displayed in Table 3, the reaction has been applied to
substrates 9 with primary-, secondary-, and tertiary-alkyl
groups at the alkynyl terminal position. Additionally, both
protected and unprotected carbinol-type substituents were
tolerated at that position, leading to the expected 2-
indolylmethanols88 in moderate yields (entries 2, 5−6), and
In all the cases under study (Tables 1−3 and Schemes 2−3)
the exocyclic trisubstituted double bond of dehydrotrypto-
phans 4, 10, and 12 was generated with high stereoselectivity,
as only one geometric isomer was isolated. The configuration
was determined to be Z in product 10c by X-ray analysis (see
Figure S1 in Supporting Information), and the same geometry
a
Table 3. Preparation of 2-Alkyl- and 2-Alkenyldehydrotryptophans 10 from N-(PMB)-2-Alkynylanilines 9
b
Entry
9
R1
R2
t (h)
10
Yield of 10
1
2
3
4
5
6
7
8
9
9a
9b
9c
9d
9e
9f
9g
9h
9i
H
H
H
H
H
H
H
n-hexyl
CH2OAc
c-hexyl
15
5
10a
10b
10c
10d
10e
10f
10g
10h
10i
40
41
50
16
24
20
16
23
18
17
19
c
c
tert-butyl
82
C(Me)2CH2OTBDPS
C(Me)2OH
cyclohexenyl
tert-butyl
tert-butyl
cyclohexenyl
72
41
67
53
48
50
Me
CO2Me
Me
10
9j
10j
a
Taken (in part) from Cruz, F. Development of cascade reactions catalyzed by Palladium and their application to the synthesis of heterocycles, Ph.D.
Thesis, Universidade de Vigo, 2019. Reaction conditions: N-PMB-2-alkynylaniline 9, alkene 3 (6 equiv), PdCl2(PPh3)2 (10 mol %), TPPO (10 mol
b
c
%), and KI (0.5 equiv) in DMF (10 mL/mmol) under air. Isolated yield (%). A 3-unsubstituted indole 11d (R1 = H; R2 = t-Bu) was also
obtained in 17% yield.
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a
Table 4. Effect of the Alkene and PPh3 on Yields and Coupling/Cycloisomerization Ratios
b
c
entry
Y
R2
[Pd]
PdCl2
PdCl2(PPh3)2
PdCl2
T (° C)
t (h)
4, 13−14
Yield of 4, 13−14
4 or 13−14/6 Ratio
1
2
3
4
5
6
7
8
9
NHAc
NHAc
H
p-tolyl
p-tolyl
p-tolyl
p-tolyl
p-tolyl
p-tolyl
n-hexyl
n-hexyl
p-tolyl
p-tolyl
p-tolyl
p-tolyl
100
100
80
100
80
100
100
100
60
100
100
100
18
7
4a
4a
13a
13a
13a
39
63
56
85
90
91
20
52
67
g
1:1
4:1
1.4:1
e
de
,
20
20
19
18
4
18
20
20
20
4
e
e
e
e
H
H
H
PdCl2
only 13a
only 13a
only 13a
f
e
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2
e
13a
NHAc
H
Me
NHAc
NHAc
NHAc
4b
e
e
13b
only 13b
e
e
14
only 14
g
10
11
g
g
h
g
g
h
h
12
a
Reaction conditions: Unless otherwise indicated, 1a or 1b, a Pd complex (5 mol %), KI (0.5 equiv) and alkene (6 equiv) in DMF under air
b
c
d
e
f
atmosphere. Isolated yield (%). Measured in the crude reaction mixture. Ratio of isolated yields. Reference 14. Not determined due to signal
g
overlap. Reaction run in the absence of alkene. The cycloisomerization product 6a was obtained in 28% yield (entry 10) or 15% yield (entry 11).
h
Experiment run in the absence of alkene and Pd catalyst: No reaction.
Scheme 4. Expected Catalytic Cycle
was assigned by analogy to the remaining products. This result
is in line with previous literature examples where the formation
of the (Z)-isomers of dehydrotryptophans was also reported in
Heck-type reactions between indole and α-aminoacrylate
derivatives.58,74,76,78
Formation of Cycloisomerization Products. Relative to
the related heterocyclization−coupling reactions of 2-alkyny-
lanilines with n-butyl acrylate and methyl methacrylate (α-
unsubstituted- and α-Me-substituted analogs, respectively, of
acrylate 3),14 the α-acetamidoacrylate reactions appear to be
less effective, as indicated by their often lower isolated yields
and higher incidence of cycloisomerization products (the main
observed side reaction for N-unsubstituted and N-PMB-
substituted anilines; see also Table 4 below), although that
type of product was not observed in the carbamate series
(Tables 1−2 and Scheme 2). The relative importance of that
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Table 5. Energy Differences [in kcal/mol; WB97XD/def2SVPP_LANL2DZ(SMD, DMF)//B97XD/def2TZVP (SMD, DMF)]
for the Stepwise Transformation of B to G
Aminopalladation HCl/alkene exchange
Carbopalladation
Rotation-BHE HCl RE
ΔG# ΔG°E−F ΔG#
ΔG°F−G
F−G
entry
R1, R2
H, Ph
H, Ph
H, Ph
H, Ph
H, Me
H, t-Bu
CO2Me, Ph
CO2Me, t-Bu
L
Y
ΔG#
ΔG°B−C
ΔG°C−D
ΔG#
ΔG°D−E ΔG#
B−C
D−E
C−E
E−F
1
2
3
4
5
6
7
8
PPh3
DMF
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
H
H
18.7
−10.1
−33.6
−10.1
−10.1
−9.0
−8.2
9.2
−0.7
10.5
2.2
6.0
7.7
10.0
−6.3
2.9
7.5
12.7
6.7
16.9
16.6
14.9
18.1
16.3
−27.2
−14.8
−23.0
−26.0
−32.8
−32.6
−27.1
−28.6
6.8
23.2
8.9
28.2
15.2
18.4
6.2
7.3
17.3
0.3
12.9
13.9
18.7
18.7
19.1
17.8
20.4
21.8
Me
a
NHAc
NHAc
NHAc
NHAc
NHAc
22.9
24.3
24.9
10.8
19.2
26.5
29.9
29.1
31.1
30.2
18.3
24.2
24.5
24.1
26.2
4.4
4.9
3.5
2.7
2.1
1.3
−2.9
−1.8
−1.9
−4.9
b
12.5
a
b
27.0 kcal/mol from the lowest energy intermediate Erot (see Figure 1). 18.1 kcal/mol from D (see Figure 2).
Figure 1. (a) Reaction profile starting from complexes B derived from Aa (R1 = H, R2 = Ph in Scheme 4) and methyl α-acetamidoacrylate (Y =
NHAc) or methyl acrylate (Y = H) in a reaction promoted by PdCl2/L (L = PPh3 or DMF) [energy values in kcal/mol; WB97XD/
def2SVPP_LANL2DZ(SMD, DMF)//B97XD/def2TZVP (SMD, DMF)]. (b) Ground state structures of intermediates involved in the reaction
profile.
competing cycloisomerization reaction is also strongly depend-
ent on the presence or absence of PPh3, as seen in Table 1. In
order to have a more precise picture of the alkene- and
phosphine-dependence of the coupling/cycloisomerization
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Figure 2. (a) Reaction profile starting from complexes B derived from Aa‑carb (R1 = CO2Me, R2 = Ph, L = PPh3 in Scheme 4) and methyl α-
acetamidoacrylate in a reaction promoted by PdCl2(PPh3)2 [energy values in kcal/mol; WB97XD/def2SVPP_LANL2DZ(SMD, DMF)//B97XD/
def2TZVP (SMD, DMF)]. (b) 3-D structures of TSs, as representative of those involved in the different series.
ratio, we have run some control experiments that have enabled
comparisons, under the same reaction conditions, between α-
acetamidoacrylate (3), n-butyl acrylate, and methyl meth-
acrylate. These results are displayed in Table 4, where entries
1, 2, and 7 have been taken from Table 1.
alkene showed that the 3-unsubstituted indole 6a was formed
(albeit in a low 15−28% yield)89 (Table 4, entries 10−11) but
was not detected when the Pd catalyst was also omitted (Table
4, entry 12). This indicated that, at least in part, cyclo-
isomerization is a Pd-catalyzed reaction.
The results in Table 4 confirm that, under comparable
conditions, cycloisomerization is a more important competing
side reaction in the α-acetamidoacrylate case relative to the
other acrylates. Notably, the disubstituted alkene of entry 9
reacts without observable formation of cycloisomerization
products. It is also apparent that the effect of the phosphine
ligand PPh3 on cycloisomerization is not exclusive of α-
acetamidoacrylates. Thus, while cycloisomerization is subdued
in the α-acetamidoacrylate reaction in the presence of PPh3
(entries 1 and 2), it appears to be completely suppressed with
the simpler acrylates under similar reaction conditions (see
entry 3 vs entries 5 and 9). Control reactions in the absence of
Computational Studies. In order to gain further insights
into the above-mentioned differences in reactivity, we have
studied computationally the aminocyclization−coupling reac-
tions using DFT methods. We have evaluated the effect of the
alkene and PPh3 ligand on the energetics of the reaction
pathway, as well as the differences between N-unsubstituted 2-
alkynylanilines and their corresponding carbamates. The
expected catalytic cycle is shown in Scheme 4, where product
formation is the result of four major steps, namely cyclization
(intramolecular aminopalladation), HCl/alkene exchange,
carbopalladation (insertion), and β-hydride elimination
(BHE). To complete the catalytic cycle, oxidation of the
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Pd(0) released by reductive elimination (RE) of HCl after
BHE regenerates the Pd(II) species needed to activate the C−
C triple bond and reinitiate the cycle.
(Y = H, cf. entry 1, Table 5) and methyl methacrylate (Y = Me,
cf. entry 3) have a more favorable HCl/alkene exchange energy
than the corresponding methyl α-acetamidoacrylate (Y =
NHAc, cf. entries 4−6), indicating that the former have a
higher affinity for that particular palladium moiety. This
exchange is also more favorable for carbamates, relative to the
N-unsubstituted anilines; for example, for the carbamate of
entry 7 (R2 = Ph, Y = NHAc) HCl/alkene exchange is
exergonic (by 6.3 kcal/mol), whereas in the corresponding
aniline it is endergonic by approximately the same amount (6.0
kcal/mol, cf. entry 4). It is reasonable to expect that, in this
case, the same substituent effects discussed above would make
the carbamate zwitterion C (R1 = CO2Me) more acidic,
leading to a more favorable HCl/alkene exchange. A final note
on this step has to do with the phosphine-free complex (C, L =
DMF, cf. entry 2), where the exchange is found to be much
less favorable (by 11.2 kcal/mol) than in the corresponding
PPh3-ligated case (C, L = PPh3, cf. entry 1); however, these
latter data would be difficult to interpret in the foregoing
context of substituent effects because both the acidity of C and
the affinity of the HCl-free Pd complex for the alkene are
affected by the change at L in this case.
Next, from complexes D carbopalladation leads to
intermediates E, which display a trans-relationship between
the Cl−Pd and newly formed σ−Pd-Cα bonds, while the 5-
membered indole π-system occupies the remaining vacant
position at Pd. This step is predicted to be very exergonic in all
cases and irreversible, as a result. However, differences are
clearly observed in the activation energies. Thus, both methyl
acrylate and methyl methacrylate are predicted to have
substantially lower insertion barriers when compared with
methyl α-acetamidoacrylate (cf. entries 1 and 3 vs 4−8). From
the carbopalladation product E, an energy sink, the reaction
proceeds to the BHE TS by detachment of the indole π-ligand
from palladium and Cα−Cβ rotation to first reach rot-E
(Figures 1−2 and S3) and allow the interaction between
palladium and one of the C−H bonds at the original alkene’s
β-position. The overall activation energy for BHE leading to
the experimentally obtained Z-isomer is relatively high (26.5−
31.1 kcal/mol), again with the exception of the PPh3-free
complex (L = DMF, ΔG#E‑F = 15.2 kcal/mol, entry 2), whereas
the barrier for the unobserved E-isomer is 7 kcal/mol higher in
the calculated case (R1 = H; R2 = Ph; L = PPh3; Y = NHAc)
(see Table S5 in Supporting Information). The BHE step is
reversible in all cases, and in this scenario, product release and
completion of the catalytic cycle require a relatively facile and
irreversible regeneration of the starting PdX2 catalyst.93
According to the literature,93,94 this could take place from
HPdX by initial rate-determining H atom abstraction by O2
(HAA pathway) or an alternative reductive elimination of HX,
followed by facile oxidation by O2 of the resulting Pd(0)
species (HXRE pathway), leading in both cases to the
formation of a Pd(II) hydroperoxide intermediate. While the
actual oxidation mechanism has not been subject to study in
our particular system, in the context of the more generally
considered HXRE mechanism93 we have determined that
reductive elimination of HCl from complexes F (L = PPh3),
where the H and Cl atoms already have the required cis
arrangement, has indeed a relatively low activation energy
(2.7−7.3 kcal/mol, Table 5, Figures 1−2 and S3).
Furthermore, the subsequent Pd(0) oxidation is expected to
be facilitated by the participation of molecular iodine formed
According to this general scheme, we have compared the
reaction profiles of cyclization−coupling cascades involving
palladium complexes B originating from o-alkynylaniline
derivatives A, variable at the nitrogen and alkynyl substituents
(R1 and R2, respectively), and acrylate esters where variations
were introduced at Cα (substituent Y). For reactions run in the
absence of PPh3, the vacant position at Pd has been filled with
a molecule of solvent (DMF).90 A summary of results is
displayed in Table 5, where the energy differences (ΔG, kcal/
mol) between species (intermediates and transition states)
have been collected for cyclization, HCl/alkene exchange,
insertion, BHE, and RE steps starting from complex B. Full
energy profiles are displayed in Figures 1−2 and S3 (see
Supporting Information).
Formation of palladium complexes B from o-alkynylaniline
derivatives A and PdCl2(PPh3)2 is an endergonic process in all
cases (15.6−16.8 kcal/mol; see also Tables S2−S4 in
Supporting Information), and almost insensitive to substituent
effects. However, it is noticed that this estimate is probably
realistic only in the early stages of the reaction, when PPh3 has
to be displaced from Pd by the o-alkynylaniline A. Indeed,
under the experimental oxidative conditions, some PPh3 is
oxidized to the corresponding triphenylphosphine oxide
(TPPO),91,92 and this should make complexation of the o-
alkynylaniline A more favorable, as TPPO is a weaker Pd-
ligand than PPh3. In any event, the activated triple bond and
internal amino group of B then engage in a 5-endo-dig
cyclization leading to zwitterions C (where the palladium trans
geometry is maintained) with moderate activation energies,
which are in the range 17.8−21.8 kcal/mol, with the exception
of the phosphine-free cyclization, which has a significantly
lower cyclization barrier (13.9 kcal/mol). It is interesting that
this step appears to be insensitive to the steric bulk of the t-Bu
group in the N-unsubstituted series. On the other hand,
carbamates have somewhat higher barriers (by 1.7 and 4 kcal/
mol, for R2 = Ph and t-Bu, respectively) than the
corresponding amines. However, a much more substantial
difference is observed in the reaction energies, as the
cyclization of the carbamate substrates (B, R1 = CO2Me)
proceeds uphill (by 9.2−12.5 kcal/mol) whereas for the N-
unsubstituted substrates (B, R1 = H) the cyclizations are all
exergonic (by 8.2−33.6 kcal/mol). Again, differences are
noticed between the PPh3-ligated complexes (B, L = PPh3),
which maintain cyclization exergonicity within a narrow range
(8.2−10.1 kcal/mol), and the much more favorable phosphine-
free case (B, L = DMF; ΔG°B−C = −33.6 kcal/mol). Those
calculated differences between N-unsubstituted anilines and
their carbamates are understood as a consequence of the effect
of the electron-withdrawing group on N that, relative to the
unsubstituted aniline (B, R1 = H), renders the carbamate (B,
R1 = CO2Me) a less reactive nucleophile and reduces the
stability of the zwitterionic cyclization product C (R1
=
CO2Me). In any case, from zwitterions C the loss of HCl is
accompanied by the incorporation of an alkene molecule to
arrive at intermediates D, where the alkene ligand occupies the
position of the released chloride anion. Complexes D are the
starting point for the C−C-bond forming carbopalladation step
eventually leading to the coupling product. Some interesting
information emerges from the HCl/alkene exchange data.
Thus, for reactions catalyzed by PdCl2(PPh3)2, methyl acrylate
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from the KI additive under the oxidizing (air) reaction
conditions.14,95
preparation of the indolyl N-unsubstituted dehydrotrypto-
phans (through the corresponding carbamates), as well as for
N-PMB derivatives. Aryl, alkenyl, and alkyl (primary,
secondary, and tertiary) substituents have all been incorpo-
rated at the indole C-2 position, and the presence of both
electron-donating and electron-withdrawing groups at the
aniline benzene ring has been shown to be well tolerated. DFT
calculations have been performed on these and related
reactions using model methyl acrylates. The computed data
indicate that the presence of the amino substituent on the
alkene tends to disfavor both HCl/alkene exchange and alkene
insertion steps, whereas the presence of PPh3 and the use of a
carbamate of the alkynylaniline have the opposite effect. These
findings are in line with the experimentally observed higher
incidence of competing cycloisomerization in those cases
where HCl/alkene exchange and alkene insertion are
disfavored (use of α-acetamidoacrylates, absence of PPh3,
and use of N-unsubstituted alkynylanilines).
Computational Details. All calculations were carried out
using the Gaussian 09 program package100 and ωB97XD
functional developed by Chai and Head-Gordon.101 The
def2SVPP basis set developed by Ahlrichs and co-workers was
used for nonmetals and LANL2DZ for Pd.102 Single-point
energy calculations were carried out with a triple ζ basis
(def2TZVPP) for all atoms.103 The SMD model104 was used
to include the solvent (DMF) in both optimizations and
single-point calculations. The nature of the different saddle
points were determined by the number of imaginary
frequencies, and these structures were connected via IRC. All
3D representations were created using the Chemcraft
software.105
The analysis of the data in Table 5, Figures 1−2 and S3
(Supporting Information) reveals that the carbamate reactions
transit through a higher energy pathway than the N-
unsubstituted cases, and this would be in line with the
experimental observation of a longer reaction time required for
substrate 2a relative to 1a (Table 1). Nevertheless, the
carbamate reactions are higher yielding than those of their
corresponding amines, possibly because the former benefit
from an exergonic HCl/alkene exchange (with the exception of
the t-Bu-substituted case; see below) between the zwitterion C
and the key insertion precursor D. As a result, intermediate D
(that leads irreversibly to E) is much more populated than C,
while the insertion barrier is kept lower than that of the N-
unsubstituted aniline (18.1 kcal/mol from D vs 22.9 kcal/mol
from C, entries 7 and 4, respectively; Table 5). On the other
hand, the lack of reactivity of the t-Bu-substituted carbamate
2c (entry 10, Table 1) could be ascribed to the endergonicity
of both cyclization and HCl/alkene exchange steps, resulting in
a total insertion barrier of 31.7 kcal/mol starting from B. This,
together with a similarly high barrier for BHE (30.2 kcal/mol,
entry 8, Table 1) would lead to a slow reaction.
Further examination of Tables 4−5 also indicates that
cycloisomerization of the starting alkynylaniline derivative,
leading to products 6, is absent in cases with low insertion
energy and/or favorable HCl/alkene exchange energy. As
suggested in the literature,96 protodepalladation is a possible
cycloisomerization mechanism and, in the context of the
catalytic cycle of Scheme 4, this could be taking place from an
intermediate of an undetermined structure, originating from C
or D.97 In this scenario, reactions of n-butyl acrylate or methyl
methacrylate, with low insertion activation energies, would be
expected to compete more efficiently with that cycloisomeriza-
tion pathway than those of α-acetamidoacrylates, where
insertion has a much higher barrier.98 As for the effect of
PPh3, it is noticed that protodepalladation would be dependent
on the availability of HCl (released upon formation of D and
also after BHE), which is in turn limited by its consumption
during the final Pd(0) oxidation (Scheme 4), and possibly by
interaction with TPPO produced as a result of PPh3 air
oxidation.91,92 In fact, the formation of the hydrochloride
HClTPPO99 from TPPO and HCl is a very favorable process,
calculated to release 13.7 kcal/mol. As a result, TPPO could
have a regulatory effect on the available amount of HCl.
Interestingly, upon following the reaction of 1a and 3 by
HPLC-MS, it was found that the ratio 4a/6a increased as the
reaction progressed (and presumably more HClTPPO was
formed).92 This possible regulatory role of TPPO could
explain its beneficial effect in the reactions of N-PMB
derivatives (Table 3), as indicated above, and perhaps also
the higher incidence of cycloisomerization in the PPh3-free
reactions (entries 1 and 3 in Tables 1 and 4, respectively),
where that regulatory effect is absent.
EXPERIMENTAL SECTION
■
General Information. THF and MeOH were dried using a
Puresolv solvent purification system. Commercial DMF (≥99.8%)
was kept over 4 Å MS. A polymer-bound PPh3 (100−200 mesh; 1.6
mmol/g PPh3 loading; diphenylphosphino polystyrene cross-linked
with divinylbenzene) was purchased from Aldrich. All other reagents
were commercial compounds of the highest purity available. For
reactions that require heating we used the Heat-On block system of
radleys. New compounds were fully characterized by their 1H and 13
C
NMR, IR, and HRMS spectral properties. Unless otherwise indicated,
routine NMR spectra were obtained at 25 °C on a Bruker ARX-400
1
spectrometer (400.16 MHz for H and 100.62 MHz for 13C) using
CDCl3, acetone-d6, CD3OD, and DMSO-d6 as solvents and internal
reference (CDCl3 δ 7.26 for 1H and δ 77.0 for 13C, acetone-d6 δ 2.05
for 1H and δ 29.84 for 13C, CD3OD δ 3.31 for 1H and δ 49.0 for 13C,
1
DMSO-d6 δ 2.50 for H and δ 39.5 for 13C). Chemical shifts (δ) are
reported in ppm, and coupling constants (J) are given in hertz (Hz).
The proton spectra are reported as follows: multiplicity, coupling
constant J, number of protons. The DEPT sequence was routinely
used for 13C multiplicity assignment. Additionally, a combination of
COSY, HSQC, and HMBC NMR experiments were used for
structural assignments. Infrared spectra (IR) data were obtained
from a thin film deposited onto a NaCl glass and were measured on a
Jasco FT/IR 4100 in the interval between 4000 and 600 cm−1 with a 4
cm−1 resolution; data include only characteristic absorptions.
Electrospray ionization (ESI) mass spectra were obtained on a
micrOTOF focus mass spectrometer (Bruker Daltonics) using an
ApolloII (ESI) source with a voltage of 4500 V applied to the
capillary. Electron impact (EI) mass spectra were obtained on a
Hewlett-Packard HP59970 instrument operating at 70 eV. For
UPLC-QTOF, chromatographic separation was done with an Acquity
UPLC BEH C18 1.7 μm, 50 mm × 2.1 mm column, and H2O/
HCO2H (99.9:0.1, v/v) or MeOH/HCO2H (99.9:0.1, v/v) as eluent
mixture; the ionization source was electrospray in positive mode
CONCLUSIONS
■
The preparation of structurally diverse dehydrotryptophans has
been developed using palladium-catalyzed oxidative amino-
cyclization−coupling cascade reactions involving 2-alkynylani-
line derivatives and methyl α-acetamidoacrylate. In this direct
manner, moderate-to-high yields of products are realized and,
relative to alternative strategies, the isolation and purification
of intermediates is minimized. The method is effective for the
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(ESI+) with a voltage of 15 V; the range of masses in acquisition was
50−1200 u in SCAN mode. Flash-column chromatography was
carried out in an automated system, using silica gel (230−400 mesh),
cyano-functionalized silica gel (CN-silica gel, 20 to 40 μm particle
size, spherical) or C18-derivatized silica gel (C18-silica, 40 to 63 μm,
particle size). Analytical thin layer chromatography (TLC) was
performed on aluminum plates with Merck Kieselgel 60F254 and
visualized by UV irradiation (254 nm). Melting points were measured
NMR (100.62 MHz, CDCl3): δ 165.3, 153.0, 142.5, 140.4, 130.9,
126.2, 118.4, 87.1, 62.0, 52.3, 14.5 ppm. FTIR (NaCl): ν 3380 (s, N−
H), 2976 (m, C−H), 1748 (s, CO), 1709 (s, CO), 1520 (s),
1242 (s), 759 (s, C−Br) cm−1. HRMS (ESI) m/z: [M + H]+ calcd for
C11H13INO4 349.9884; found 349.9889.
Ethyl (2-Iodo-4-methoxyphenyl)carbamate (7e). Following the
general procedure for carbamate formation described above the
reaction of 2-iodo-4-methoxyaniline (0.20 g, 0.80 mmol), ethyl
chloroformate (0.09 mL, 0.96 mmol), and K2CO3 (0.14 g, 1.04
mmol) in THF (4 mL) at 25 °C for 22 h afforded 0.21 g (81%) of 7e
in a Buchi B-540 apparatus in open capillary tubes.
̈
X-ray Crystallographic Analysis of 10c. The crystals were
grown in hexane/EtOAc by warming for 2 days at 5−7 °C.
Crystallographic data were collected on a Bruker Smart 1000 CCD
diffractometer at CACTI (Universidade de Vigo) at 20 °C using
graphite monochromated Mo Kα radiation (λ = 0.71073 Å), and were
corrected for Lorentz and polarization effects. The software SMART1
was used for collecting frames of data, indexing reflections, and the
determination of lattice parameters and SAINT2 for integration of
intensity of reflections and scaling and SADABS3 for empirical
absorption correction. The structure (Figure 1) was solved by direct
methods using the program SHELXS97.4. Non-hydrogen atoms were
refined with anisotropic thermal parameters by full-matrix least-
squares calculations on F2 using the program SHELXL97.5.
Hydrogen atoms were inserted at calculated positions and constrained
with isotropic thermal parameters. The crystallographic data of 10c
were deposited in the Cambridge Crystallographic Data Centre with
the deposition number CCDC 1939395.
1
as a white solid. Mp: 79−80 °C (hexane/EtOAc). H NMR (400.16
MHz, CDCl3): δ 7.81 (d, J = 9.0 Hz, 1H), 7.30 (d, J = 2.9 Hz, 1H),
6.90 (dd, J = 9.0, 2.9 1H), 6.65 (s, 1H), 4.23 (q, J = 7.1 Hz, 2H), 3.76
(s, 3H), 1.32 (t, J = 7.1 Hz, 3H) ppm. 13C{1H} NMR (100.62 MHz,
CDCl3): δ 156.4, 154.0), 132.1, 123.9, 122.2, 115.1, 90.9, 61.6, 55.8,
14.7) ppm. FTIR (NaCl): ν 3279 (s, N−H), 2978 (w), 2938 (w),
2904 (w), 2838 (w), 1697 (s, CO), 1528 (s, N−CO), 1401 (w),
1283 (s, C−O−C), 1240 (s, C−O), 1216 (s, C−O), 1034 (w), 1024
(w), 854 (w) cm−1. HRMS (ESI) m/z: [M + H]+ calcd for
C10H13INO3 321.9935; found 321.9931.
tert-Butyl[(2,2-dimethylbut-3-yn-1-yl)oxy]diphenylsilane (8n).
To a cooled (0 °C) solution of 4-hydroxy-3,3-dimethylbutan-2-
one108 (5.5 g, 47 mmol) in DMF (95 mL), TBDPSCl (18.5 mL, 71
mmol) and imidazole (8.1 g, 118 mmol) were added. The resulting
mixture was stirred at 25 °C for 20 h under argon. Then, the mixture
was poured over a 1:1 NaHCO3 (sat)/water solution, and the mixture
was extracted with CH2Cl2 (3×). The combined organic layers were
washed with water (3×), dried (Na2SO4), and concentrated. The
residue was purified by flash-column chromatography (silica gel, 95:
hexane/EtOAc) to afford 8.0 g (68%) of the silyl ether 4-[(tert-
butyldiphenylsilyl)oxy]-3,3-dimethylbutan-2-one. 1H NMR (400.16
MHz, CDCl3): δ 7.68−7.62 (m, 4H), 7.48−7.36 (m, 6H), 3.65 (s,
2H), 2.18 (s, 3H), 1.13 (s, 6H), 1.06 (s, 9H) ppm. 13C{1H} NMR
(100.62 MHz, CDCl3): δ 213.0, 135.8 (4×), 133.3 (2×), 129.9 (2×),
127.8 (4×), 70.9, 50.0, 27.0 (3×), 26.2, 21.7 (2×), 19.4 ppm. FTIR
(NaCl): ν 2961 (m, C−H), 2932 (m, C−H), 2859 (m, C−H), 1710
(s), 1472 (m), 1427 (m), 1392 (m), 1360 (m), 1109 (s), 703 (s)
cm−1. HRMS (ESI) m/z: [M + H]+ calcd for C22H31O2Si 355.2088;
found 355.2082. This material was processed as follows: n-BuLi (1.77
M in hexanes, 1.2 mL, 2.07 mmol) was added to a cooled (0 °C)
solution of diisopropylamine (0.307 mL, 2.17 mmol) in THF (3.9
mL), and the resulting mixture was stirred at 0 °C for 30 min. Then,
this solution was cooled down to −78 °C, and a solution of 4-[(tert-
butyldiphenylsilyl)oxy]-3,3-dimethylbutan-2-one (1.00 g, 1.97 mmol)
in THF (2.0 mL) was added. After stirring for 1 h at the same
temperature, diethyl chlorophosphate (0.314 mL, 2.17 mmol) was
added, and the reaction mixture was allowed to warm up to 25 °C
over a period of 90 min. Then, a second LDA solution was prepared
by the addition of n-BuLi (1.77 M in hexanes, 2.5 mL, 4.44 mmol) to
a solution of diisopropylamine (0.642 mL, 4.54 mmol) in THF (3.9
mL) at 0 °C and further stirring for 30 min at the same temperature.
Then, the previous reaction mixture was added to this freshly
prepared LDA solution at −78 °C, and stirring was continued at this
temperature for 1 h. After additional stirring for 1 h at 25 °C, the
reaction mixture was quenched at 0 °C by the addition of a saturated
aqueous solution of NH4Cl. Then Et2O was added, the layers were
separated, and the aqueous layer was extracted with Et2O (3×). The
combined organic layers were washed with a saturated aqueous
solution of NaHCO3 and dried (Na2SO4), and the solvent was
evaporated. The residue was purified by flash-column chromatog-
raphy (silica gel, gradient from hexane to 95:5 hexane/EtOAc) to
Carbamate Preparation from o-Iodoanilines. General
Procedure. To a suspension of K2CO3 (0.36 g, 2.61 mmol) and
the appropriate 2-iodoaniline (2.01 mmol) in THF (10 mL) at 0 °C
was added dropwise ethyl chloroformate (0.23 mL, 2.41 mmol), and
the mixture was stirred either at room temperature or at 80 °C for
12−22 h. The reaction mixture was poured over H2O (10 mL), and
the mixture was extracted with CH2Cl2 (3×). The combined organic
layers were washed with a saturated aqueous solution of NaHCO3 and
dried (Na2SO4). The solvent was evaporated, and the residue was
purified by flash-column chromatography (silica gel; solvent A,
hexane; solvent B, EtOAc; gradient from 100:0 to 80:20 A/B) to
afford the product.
Ethyl (4-Bromo-2-iodophenyl)carbamate (7b).27,106 Following
the general procedure for carbamate formation described above, the
reaction of 4-bromo-2-iodoaniline (0.50 g, 1.68 mmol), ethyl
chloroformate (0.19 mL, 2.01 mmol), and K2CO3 (0.30 g, 2.18
mmol) in THF (8.4 mL) at 80 °C for 19 h provided 0.55 g (88%) 7b
as a white solid. Mp: 105−106 °C (hexane/EtOAc).106
Ethyl (5-Bromo-2-iodophenyl)carbamate (7c).106 To a cooled (0
°C) solution of 5-bromo-2-iodoaniline (1.5 g, 5.03 mmol) in pyridine
(6.6 mL) was added ethyl chloroformate (0.67 mL, 7.05 mmol). The
mixture was warmed up to 25 °C and stirred for 20 h. The reaction
was poured into a mixture of EtOAc and brine (100 mL, 1:1 v/v).
The layers were separated, the aqueous layer was extracted with
EtOAc (3×), and the combined organic layers were washed
successively with a saturated aqueous solution of CuSO4 (2×) and
brine (2×) and dried (Na2SO4). The solvent was evaporated, and the
residue was purified by flash-column chromatography (silica gel, 95:5
hexane/EtOAc) to afford 1.80 g (97%) of 7c as a white solid. Mp
1
108−109 °C (hexane/EtOAc). H NMR (400.16 MHz, CDCl3): δ
8.30 (d, J = 2.4 Hz, 1H), 7.58 (d, J = 8.4 Hz, 1H), 6.93 (dd, J = 8.3,
2.5 Hz, 2H), 4.26 (q, J = 7.1 Hz, 2H), 1.34 (t, J = 7.1 Hz, 3H)
ppm.106 13C{1H} NMR (100.62 MHz, CDCl3): δ 153.2, 139.8, 139.7,
128.0, 123.5, 122.9, 86.3, 62.0, 14.6 ppm. FTIR (NaCl): ν 3291 (s,
N−H), 1690 (s, CO), 1565 (s), 1518 (s), 1075 (s, C−Br) cm−1.
Methyl 4-[(Ethoxycarbonyl)amino]-3-iodobenzoate (7d).107 Fol-
lowing the general procedure for carbamate formation described
above the reaction of methyl 4-amino-3-iodobenzoate (0.78 g, 2.82
mmol), ethyl chloroformate (0.32 mL, 3.38 mmol), and K2CO3 (0.51
g, 3.66 mmol) in THF (14.1 mL) at 80 °C for 12 h provided 0.98 g
(69%) of 7d as a white solid. Mp: 113−114 °C (hexane/EtOAc). 1H
NMR (400.16 MHz, CDCl3): δ 8.40 (d, J = 1.9 Hz, 1H), 8.18 (d, J =
8.7 Hz, 1H), 7.96 (dd, J = 8.7, 2.0 Hz, 1H), 7.16 (s, 1H), 4.25 (q, J =
7.1 Hz, 2H), 3.87 (s, 3H), 1.33 (t, J = 7.1 Hz, 3H) ppm. 13C{1H}
1
afford 0.34 g (52%) of 8n as a yellow oil. H NMR (400.16 MHz,
CDCl3): δ 7.72−7.66 (m, 4H), 7.46−7.35 (m, 6H), 3.52 (s, 2H), 2.08
(s, 1H), 1.26 (s, 6H), 1.08 (s, 9H) ppm. 13C{1H} NMR (100.62
MHz, CDCl3): δ 135.9 (4×), 133.8 (2×), 129.8 (2×), 127.8 (4×),
90.6, 71.8, 68.4, 33.7, 27.0 (3×), 25.7 (2×), 19.6. FTIR (NaCl): ν
3066 (m, C−H), 2948 (m, C−H), 2929 (m, C−H), 1690 (s), 1632
(m), 1466 (m), 1387 (m), 1247 (m), 1107 (s), 746 (s) cm−1. HRMS
(ESI) m/z: [M + H]+ calcd for C22H29OSi 337.1982; found 337.1984.
8775
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Article
Preparation of 2-Alkynylaniline Derivatives 2 and 9 by
Sonogashira Reaction. Procedure A: In a typical experiment, to a
solution of an appropriate o-iodoaniline derivative (0.29 mmol) and
alkyne 8 (1.18 mmol) in Et3N (0.2 mL) and DMF (2.9 mL) were
added PdCl2(PPh3)2 (4.2 mg, 0.006 mmol) and CuI (2.3 mg, 0.012
mmol), and the mixture was stirred at 25 °C under argon. After
reaction completion, a saturated aqueous solution of NH4Cl was
added, and the mixture was extracted with CH2Cl2 (3×). The
combined organic layers were dried (Na2SO4), and the solvent was
evaporated. The residue was purified by flash-column chromatog-
raphy to afford product 2 or 9. Procedure B: In a typical experiment, to
a solution of an appropriate o-iodoaniline derivative (1.18 mmol) and
alkyne 8 (4.72 mmol) in Et3N (2.6 mL) were added PdCl2(PPh3)2
(16.8 mg, 0.024 mmol) and CuI (4.6 mg, 0.024 mmol), and the
mixture was stirred at 25 °C under argon. It then proceeded as in
procedure A to afford product 2 or 9. Procedure C: In a typical
experiment, to a solution of an appropriate o-iodoaniline derivative
(0.29 mmol) and alkyne 8 (0.35 mmol) in Et3N (0.6 mL) and DMF
(0.3 mL) were added PdCl2(PPh3)2 (4.2 mg, 0.006 mmol) and CuI
(0.6 mg, 0.003 mmol), and the mixture was stirred at 25 °C under
argon. It then proceeded as in procedure A to afford product 2 or 9.
Procedure D: In a typical experiment, to a solution an appropriate o-
iodoaniline derivative (0.34 mmol) and alkyne 8 (0.69 mmol) in a
mixture of THF/Et3N (6.4 mL, 4:1 v/v) were added PdCl2(PPh3)2
(4.8 mg, 0.007 mmol) and CuI (2.6 mg, 0.014 mmol), and the
mixture was stirred at 25 °C under argon. It then proceeded as in
procedure A to afford product 2 or 9.
Ethyl [2-(Oct-1-yn-1-yl)phenyl]carbamate (2b). The Sonogashira
Procedure A was followed from ethyl (2-iodophenyl)carbamate27,107
(7a) (500 mg, 1.72 mmol) and oct-1-yne (8b) (1.0 mL, 6.87 mmol)
(reaction time 20 h) to afford, after purification by flash-column
chromatography (silica gel; solvent A, n-hexane; solvent B, EtOAc;
gradient from 100:0 to 80:20 A/B), 413 mg (88%) of 2b as a yellow
oil. 1H NMR (400.16 MHz, CDCl3): δ 8.13 (d, J = 8.4 Hz, 1H), 7.42
(s, 1H, NH), 7.34 (dd, J = 7.7, 1.5 Hz, 1H), 7.32−7.22 (m, 1H), 6.95
(td, J = 7.6, 1.2 Hz, 1H), 4.24 (q, J = 7.1 Hz, 2H), 2.49 (t, J = 7.0 Hz,
2H), 1.70−1.57 (m, 2H), 1.54−1.43 (m, 2H), 1.37−1.31 (m, 7H),
0.92 (t, J = 7.1 Hz, 3H) ppm. 13C{1H} NMR (100.62 MHz, CDCl3):
δ 153.4, 139.1, 131.7, 128.9, 122.3, 117.4, 112.2, 97.8, 75.9, 61.4, 31.5,
28.7 (2×), 22.7, 19.7, 14.7, 14.2 ppm. FTIR (NaCl): ν 3398 (s, N−
H), 2956 (w), 2931 (w), 2858 (w), 1741 (s, CO), 1580 (s), 1521
(s), 1452 (s), 1230 (w), 1210 (w) cm−1. HRMS (ESI) m/z: [M +
H]+ calcd for C17H24NO2 274.1803; found 274.1802.
101.9, 75.9, 61.4, 32.7 (2×), 29.8, 25.9 (2×), 24.8, 14.7 ppm. FTIR
(NaCl): ν 3395 (s, N−H), 2979 (w), 2930 (s), 2854 (s), 1741 (s,
CO), 1581 (s), 1521 (s), 1451(s), 1307 (w), 1227 (s), 1207 (s)
cm−1. HRMS (ESI) m/z: [M + H]+ calcd for C17H22NO2 272.1646;
found 272.1645.
Ethyl [2-Cyclohex-1-en-1-ylethynyl)phenyl]carbamate (2p). The
Sonogashira Procedure A was followed from 7a27,107 (500 mg, 1.72
mmol) and 1-ethynylcyclohex-1-ene (8l) (0.81 mL, 6.87 mmol)
(reaction time 20 h) to afford, after purification by flash-column
chromatography (silica gel; solvent A, n-hexane; solvent B, EtOAc;
gradient from 100:0 to 80:20 A/B), 460 mg (99%) of 2p as a yellow
oil. 1H NMR (400.16 MHz, CDCl3): δ 8.15 (d, J = 8.4 Hz, 1H), 7.38
(dd, J = 7.7, 1.7 Hz, 2H), 7.33−7.27 (m, 1H), 6.99 (tt, J = 7.6, 1.0 Hz,
1H), 6.32−6.25 (m, 1H), 4.27 (q, J = 7.1 Hz, 2H), 2.27 (ddt, J = 5.9,
4.4, 2.4 Hz, 2H), 2.23−2.15 (m, 2H), 1.77−1.69 (m, 2H), 1.69−1.62
(m, 2H), 1.36 (t, J = 7.1 Hz, 3H) ppm. 13C{1H} NMR (100.62 MHz,
CDCl3): δ 153.4, 138.9, 136.2, 131.6, 129.3, 122.4, 120.3, 117.6,
111.9, 98.3, 81.7, 61.4, 29.3, 25.9, 22.4, 21.5, 14.7 ppm. FTIR (NaCl):
ν 3398 (s, N−H), 2979 (w), 2932 (m), 2859 (w), 2837 (w), 1740 (s,
CO), 1579 (m), 1520 (s), 1452 (m), 1208 (s), 1060 (w) cm−1.
HRMS (ESI) m/z: [M + H]+ calcd for C17H20NO2 270.1488; found
270.1489.
N-(4-Methoxybenzyl)-2-(oct-1-yn-1-yl)aniline (9a). The Sonoga-
shira Procedure A was followed from 2-iodo-N-(4-methoxybenzyl)-
aniline109 (100 mg, 0.29 mmol) and 8b (0.174 mL, 1.18 mmol) at 60
°C (reaction time 16 h) to afford, after purification by flash-column
chromatography (silica gel; solvent A, hexane; solvent B, EtOAc;
gradient from 100:0 to 80:20 A/B), 52 mg (55%) of 9a as an oil. 1H
NMR (400.16 MHz, CDCl3): δ 7.30 (d, J = 8.7 Hz, 2H), 7.27 (dd, J =
7.5, 1.5 Hz, 1H), 7.12 (ddd, J = 7.7, 7.0, 1.5 Hz, 1H), 6.89 (d, J = 8.7
Hz, 2H), 6.62 (td, J = 7.5, 1.0 Hz, 1H), 6.57 (d, J = 8.1 Hz, 1H), 4.94
(t, J = 5.6 Hz, 1H), 4.34 (d, J = 5.6 Hz, 2H), 3.81 (s, 3H), 2.45 (t, J =
7.0 Hz, 2H), 1.63−1.53 (m, 2H), 1.47−1.37 (m, 2H), 1.33−1.23 (m,
4H), 0.90 (t, J = 7.0 Hz 3H) ppm. 13C{1H} NMR (100.62 MHz,
CDCl3): δ 158.9, 148.8, 132.0, 131.4, 129.2, 128.6 (2×), 116.5, 114.1
(2×), 109.8, 108.7, 96.4, 77.2, 55.4, 47.4, 31.5, 29.0, 28.7, 22.7, 19.8,
14.2 ppm. FTIR (NaCl): ν 3396 (m, N−H), 2924 (s, C−H), 2858 (s,
C−H), 1605 (m), 1508 (s), 1246 (s), 741 (m) cm−1. HRMS (ESI)
m/z: [M + H]+ calcd for C22H28NO 322.2165; found 322.2161.
3-[2-(4-Methoxybenzylamino)phenyl]prop-2-yn-1-yl Acetate
(9b). The Sonogashira Procedure B was followed from 2-iodo-N-(4-
methoxybenzyl)aniline109 (400 mg, 1.18 mmol) and prop-2-yn-1-yl
acetate (8m) (0.468 mL, 4.72 mmol) in Et3N (2.6 mL) (reaction
time 24 h) to afford, after purification by flash-column chromatog-
raphy (silica gel; solvent A, hexane; solvent B, EtOAc; gradient from
100:0 to 80:20 A/B), 170 mg (47%) of 9b as a yellow solid. Mp: 59−
60 °C (hexane/EtOAc). 1H NMR (400.16 MHz, CDCl3): δ 7.31 (dd,
J = 7.5, 1.5 Hz, 1H), 7.29 (d, J = 8.7 Hz, 2H), 7.16 (ddd, J = 8.3, 7.4,
1.6 Hz, 1H), 6.89 (d, J = 8.7 Hz, 2H), 6.62 (td, J = 7.5, 1.1 Hz, 1H),
6.57 (d, J = 8.3 Hz, 1H), 5.05 (br s, 1H), 4.92 (s, 2H), 4.36 (s, 2H),
3.80 (s, 3H), 2.09 (s, 3H) ppm. 13C{1H} NMR (100.62 MHz,
CDCl3): δ 170.4, 158.9, 149.4, 132.6, 131.1, 130.6, 128.4 (2×), 116.4,
114.1 (2×), 110.0, 106.3, 89.0, 83.6, 55.3, 53.1, 47.1, 20.9 ppm. FTIR
(NaCl): ν 3398 (m, N−H), 3000 (w, C−H), 2936 (w), 2836 (w),
2223 (w, CC), 1741 (s, CO), 1507 (s), 1229 (s), 1028 (s), 743
(m) cm−1. HRMS (ESI) m/z: [M + H]+ calcd for C19H20NO3
310.1438; found 310.1429.
Ethyl [2-(3,3-Dimethylbut-1-yn-1-yl)phenyl]carbamate (2c). The
Sonogashira Procedure B was followed from 7a27,107 (200 mg, 0.69
mmol) and tert-butylacetylene (8c) (0.10 mL, 0.83 mmol) (reaction
time 3 h) to afford, after purification by flash-column chromatography
(silica gel; solvent A, n-hexane; solvent B, EtOAc; gradient from 100:0
1
to 90:10 A/B), 165 mg (98%) of 2c as a colorless oil. H NMR
(400.16 MHz, CDCl3): δ 8.12 (d, J = 8.4 Hz, 1H), 7.39 (s, 1H), 7.32
(ddd, J = 7.7, 1.6, 0.5 Hz, 1H), 7.26 (dddd, J = 8.2, 7.4, 1.6, 0.5 Hz,
1H), 6.94 (td, J = 7.6, 1.2 Hz, 1H), 4.24 (q, J = 7.1 Hz, 2H), 1.37 (s,
9H), 1.32 (t, J = 7.1 Hz, 3H) ppm. 13C{1H} NMR (100.62 MHz,
CDCl3): δ 153.4, 139.0, 131.3, 128.9, 122.2, 117.4, 112.1, 106.0, 74.5,
61.3, 31.1 (3×), 28.4, 14.6 ppm. FTIR (NaCl): ν 3399 (m, N−H),
2970 (m, C−H), 1742 (s, CO), 1582 (m), 1522 (s), 1454 (m),
1216 (s) cm−1. HRMS (ESI) m/z: [M + H]+ calcd for C15H20NO2
246.1488; found 246.1486.
Ethyl [2-Cyclohexyl)ethynyl)phenyl]carbamate (2o). The Sono-
gashira Procedure A was followed from 7a27,107 (500 mg, 1.72 mmol)
and 1-ethynylcyclohexane (8k) (0.90 mL, 6.87 mmol) (reaction time
20 h) to afford, after purification by flash-column chromatography
(silica gel; solvent A, n-hexane; solvent B, EtOAc; gradient from 100:0
to 80:20 A/B), 357 mg (77%) of 2o as a yellow oil. 1H NMR (400.16
MHz, CDCl3): δ 8.11 (d, J = 8.4 Hz, 1H), 7.44 (s, 1H, NH), 7.34
(dd, J = 7.9, 1.4 Hz, 1H), 7.29−7.24 (m, 1H), 6.95 (td, J = 7.6, 1.2
Hz, 1H), 4.24 (q, J = 7.1 Hz, 2H), 2.70 (tt, J = 8.4, 3.7 Hz, 1H),
1.98−1.84 (m, 2H), 1.80−1.74 (m, 2H), 1.64−1.52 (m, 3H), 1.47−
1.36 (m, 3H), 1.33 (t, J = 7.1 Hz, 3H) ppm. 13C{1H} NMR (100.62
MHz, CDCl3): δ 153.5, 139.1, 131.5, 128.9, 122.3, 117.4, 112.2,
2-(Cyclohexylethynyl)-N-(4-methoxybenzyl)aniline (9c). The So-
nogashira Procedure C was followed from 2-iodo-N-(4-
methoxybenzyl)aniline109 (100 mg, 0.29 mmol) and 8k (0.046 mL,
0.35 mmol) (reaction time 24h) to afford, after purification by flash-
column chromatography (silica gel; solvent A, hexane; solvent B,
EtOAc; gradient from 100:0 to 80:20 A/B), 58 mg (62%) of 9c as an
oil. 1H NMR (400.16 MHz, CDCl3): δ 7.31 (d, J = 8.7 Hz, 2H), 7.28
(dd, J = 7.6, 1.6 Hz, 1H), 7.13 (ddd, J = 8.2, 7.4, 1.6 Hz, 1H), 6.89 (d,
J = 8.7 Hz, 2H), 6.62 (td, J = 7.5, 1.1 Hz, 1H), 6.58 (d, J = 8.2 Hz,
1H), 4.95 (br s, 1H), 4.34 (s, 2H), 3.81 (s, 3H), 2.66 (tt, J = 8.6, 3.8
Hz, 1H), 1.88−1.79 (m, 2H), 1.75−1.64 (m, 2H), 1.58−1.45 (m,
3H), 1.40−1.26 (m, 3H) ppm. 13C{1H} NMR (100.62 MHz,
CDCl3): δ 159.0, 148.8, 131.8, 131.4, 129.1, 128.6 (2×), 116.5,
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114.1 (2×), 109.7, 108.7, 100.6, 77.2), 55.4, 47.5, 32.9 (2×), 29.9,
26.0 (2×), 24.8 ppm. FTIR (NaCl): ν 3400 (m, N−H), 3006 (m, C−
H), 2928 (s, C−H), 2851 (s, C−H), 1603 (s), 1508 (s), 1454 (s),
1246 (s), 744 (s) cm−1. HRMS (ESI) m/z: [M + H]+ calcd for
C22H26NO 320.2009; found 320.2004.
129.6, 128.5 (2×), 120.9, 116.7, 114.2 (2×), 110.0, 108.3, 97.4, 83.3,
55.4, 47.4, 29.6, 25.9, 22.5, 21.7 ppm. FTIR (NaCl): ν 3400 (m, N−
H), 2926 (s, C−H), 2853 (s, C−H), 2190 (w, CC), 1601 (m),
1507 (s), 1454 (m), 1244 (s), 1034 (m), 747 (m) cm−1. HRMS
(ESI) m/z: [M + H]+ calcd for C22H24NO [(M+H)+] 318.1852;
found 318.1857.
2-(3,3-Dimethylbut-1-yn-1-yl)-N-(4-methoxybenzyl)aniline (9d).
The Sonogashira Procedure B was followed from 2-iodo-N-(4-
methoxybenzyl)aniline109 (100 mg, 0.29 mmol) and 8c (0.044 mL,
0.35 mmol) (reaction time 4 h) to afford, after purification by flash-
column chromatography (silica gel, solvent A: hexane; solvent B:
EtOAc; gradient from 100:0 to 80:20 A/B) 84 mg (98%) of 9d as a
yellow solid. Mp: 30−31 °C (hexane/EtOAc). 1H NMR (400.16
MHz, CDCl3): δ 7.32 (d, J = 8.4 Hz, 2H), 7.28 (dd, J = 7.5, 1.5 Hz,
1H), 7.14 (ddd, J = 8.2, 7.4, 1.6 Hz, 1H), 6.91 (d, J = 8.4 Hz, 2H),
6.63 (td, J = 7.5, 1.1 Hz, 1H), 6.59 (dd, J = 8.2, 1.0 Hz, 1H), 4.92 (s,
1H), 4.35 (s, 2H), 3.82 (s, 3H), 1.32 (s, 9H) ppm. 13C{1H} NMR
(100.62 MHz, CDCl3): δ 158.9, 148.7, 131.7, 131.4, 129.2, 128.5
(2×), 116.5, 114.1 (2×), 109.8, 108.6, 104.9, 75.7, 55.4, 47.5, 31.4
(3×) 28.4 ppm. FTIR (NaCl): ν 3401 (m, N−H), 3064 (m, C−H),
2967 (s, C−H), 2903 (m, C−H), 2841 (m, C−H), 1607 (s), 1579
(s), 1506 (s), 1457 (s), 1247 (s), 741 (s) cm−1. HRMS (ESI) m/z:
[M + H]+ calcd for C20H24NO 294.1852; found 294.1850.
2-(3,3-Dimethylbut-1-yn-1-yl)-N-(4-methoxybenzyl)-4-methyla-
niline (9h). The Sonogashira Procedure D was followed from 2-iodo-
N-(4-methoxybenzyl)-4-methylaniline110 (710 mg, 2.04 mmol) and
8c (0.50 mL, 4.07 mmol) (reaction time 16 h) to afford, after
purification by flash-column chromatography (silica gel; solvent A,
acetonitrile; solvent B, water; gradient from 50:50 to 100:0 A/B), 593
1
mg (95%) of 9h as a yellow oil. H NMR (400.16 MHz, CDCl3): δ
7.29 (d, J = 8.8 Hz, 2H), 7.08 (d, J = 2.2 Hz, 1H), 6.94−6.89 (m,
1H), 6.87 (d, J = 8.7 Hz, 2H), 6.47 (d, J = 8.3 Hz, 1H), 4.72 (t, J = 5.5
Hz, 1H, NH), 4.30 (d, J = 5.6 Hz, 2H), 3.80 (s, 3H), 2.18 (s, 3H),
1.28 (s, 9H) ppm. 13C{1H} NMR (100.62 MHz, CDCl3): δ 158.8,
146.6, 139.3, 132.1, 131.6, 129.8, 128.5 (2×), 125.6, 114.0 (2×),
109.9, 108.5, 104.5, 75.7, 55.4, 47.7, 31.4 (3×), 20.3 ppm. FTIR
(NaCl): ν 3397 (w, N−H), 2965 (w), 2925 (w), 2864 (w), 2834 (w),
1511 (s), 1248 (w) cm−1. HRMS (ESI) m/z: [M + H]+ calcd for
C21H26NO 308.2009; found 308.2011.
Methyl 3-(3,3-Dimethylbut-1-yn-1-yl)-4-[(4-methoxybenzyl)-
amino]benzoate (9i). The Sonogashira Procedure D was followed
from methyl 3-iodo-4-[(4-methoxybenzyl)amino]benzoate109 (500
mg, 1.26 mmol) and 8c (0.31 mL, 2.52 mmol) (reaction time 16 h) to
afford, after purification by flash-column chromatography (silica gel;
solvent A, n-hexane; solvent B, EtOAc; gradient from 100:0 to 90:10
2-{4-[(tert-Butyldiphenylsilyl)oxy]-3,3-dimethylbut-1-yn-1-yl}-N-
(4-methoxybenzyl)aniline (9e). The Sonogashira Procedure C was
followed from 2-iodo-N-(4-methoxybenzyl)aniline109 (500 mg, 1.47
mmol) and 8n (595 mg, 1.77 mmol) (reaction time 48 h) to afford,
after purification by flash-column chromatography (C18-silica gel;
solvent A, acetonitrile; solvent B, water; gradient from 70:30 to 100:0
1
1
A/B), 428 mg (95%) of 9i as a brown oil. H NMR (400.16 MHz,
A/B), 580 mg (72%) of 9e as a yellow oil. H NMR (400.16 MHz,
CDCl3): δ 7.95 (d, J = 2.1 Hz, 1H), 7.80 (dd, J = 8.5, 1.8 Hz, 1H),
7.27 (d, J = 8.5 Hz, 2H), 6.89 (d, J = 8.6 Hz, 2H), 6.54 (d, J = 8.7 Hz,
1H), 5.29 (t, J = 5.3 Hz, 1H, NH), 4.37 (d, J = 5.3 Hz, 2H), 3.84 (s,
3H), 3.81 (s, 3H), 1.28 (s 9H) ppm. 13C{1H} NMR (100.62 MHz,
CDCl3): δ 167.0, 159.1, 151.7, 133.7, 131.3, 130.2, 128.5 (2×), 117.8,
114.4, 114.2 (2×), 108.6, 108.0, 105.4, 74.6, 55.4, 51.7, 47.0, 31.2
(3×) ppm. FTIR (NaCl): ν 3397 (m, N−H), 2967 (w), 2900 (w),
2866 (w), 2837 (w), 1709 (s, CO), 1604 (s), 1514 (s), 1302 (s),
1249 (s), 1176 (w), 1131 (w) cm−1. HRMS (ESI) m/z: [M + H]+
calcd for C22H26NO3 352.1910; found 352.1907.
2-(Cyclohex-1-en-1-ylethynyl)-N-(4-methoxybenzyl)-4-methyla-
niline (9j). The Sonogashira Procedure D was followed from 2-iodo-
N-(4-methoxybenzyl)-4-methylaniline110 (600 mg, 1.70 mmol) and 8l
(0.40 mL, 3.40 mmol) (reaction time 16 h) to afford, after
purification by flash-column chromatography (silica gel; solvent A,
acetonitrile; solvent B, water; gradient from 50:50 to 100:0 A/B), 231
mg (41%) 9j as a yellow oil. 1H NMR (400.16 MHz, CDCl3): δ 7.29
(d, J = 8.8 Hz, 2H), 7.16−7.09 (m, 1H), 6.93 (ddd, J = 8.3, 2.2, 0.8
Hz, 1H), 6.88 (d, J = 8.7 Hz, 2H), 6.47 (d, J = 8.3 Hz, 1H), 6.15 (tt, J
= 3.9, 1.8 Hz, 1H), 4.82 (br s, 1H, NH), 4.33 (s, 2H), 3.81 (s, 3H),
2.24−2.17 (m, 5H), 2.14 (tdd, J = 6.1, 4.0, 2.1 Hz, 2H), 1.72−1.59
(m, 4H) ppm. 13C{1H} NMR (100.62 MHz, CDCl3): δ 158.8, 146.5,
134.7, 132.2, 131.6, 130.2, 128.4 (2×), 125.6, 120.8, 114.1 (2×),
110.1, 108.2, 97.1, 83.5, 55.4, 47.5, 29.6, 25.9, 22.5, 21.6, 20.3 ppm.
FTIR (NaCl): ν 3398 (w, N−H), 3021 (w), 2928 (w), 2857 (w),
2834 (w), 1611 (w), 1509 (s), 1437 (w), 1246 (m), 1034 (w) cm−1.
HRMS (ESI) m/z: [M + H]+ calcd for C23H26NO 332.2004; found
332.2008.
CDCl3): δ 7.72−7.66 (m, 4H), 7.44−7.37 (m, 2H), 7.38−7.30 (m,
4H), 7.25−7.19 (m, 3H), 7.10 (ddd, J = 8.3, 7.4, 1.6 Hz, 1H), 6.83 (d,
J = 8.0 Hz, 2H), 6.59 (td, J = 7.5, 1.1 Hz, 1H), 6.52 (d, J = 8.2 Hz,
1H), 4.94 (br s, 1H), 4.26 (d, J = 3.9 Hz, 2H), 3.79 (s, 3H), 3.58 (s,
2H), 1.30 (s, 6H), 1.07 (s, 9H) ppm. 13C{1H} NMR (100.62 MHz,
CDCl3): δ 158.8, 148.8, 135.8 (4×), 133.7, 131.9, 131.4 (2×), 129.8
(2×), 129.3, 128.3 (2×), 127.8 (4×), 116.4, 114.1 (2×), 109.8, 108.4,
102.2, 77.4, 72.1, 55.4, 47.3, 34.8, 27.0 (3×), 26.1 (2×), 19.6 ppm.
FTIR (NaCl): ν 3398 (w, N−H), 3067 (w, C−H), 2960 (s, C−H),
2927 (s, C−H), 2863 (s, C−H), 1606 (m), 1509 (s), 1464 (m), 1246
(m), 1106 (s) cm−1. HRMS (ESI) m/z: [M + H]+ calcd for
C36H42NO2Si 548.2979; found 548.2995.
4-[2-(4-Methoxybenzylamino)phenyl]-2-methylbut-3-yn-2-ol
(9f). The Sonogashira Procedure D was followed from 2-iodo-N-(4-
methoxybenzyl)aniline109 (400 mg, 1.18 mmol) and 2-methylbut-3-
yn-2-ol (8o) (0.23 mL, 2.36 mmol) (reaction time 12 h) to afford,
after purification by flash-column chromatography (silica gel, solvent
A: hexane; solvent B: EtOAc; gradient from 90:10 to 80:20 A/B), 340
1
mg (98%) of 9f as a brown oil. H NMR (400.16 MHz, CDCl3): δ
7.31−7.25 (m, 3H), 7.18−7.12 (m, 1H), 6.88 (d, J = 8.6 Hz, 2H),
6.62 (td, J = 7.5, 1.0 Hz, 1H), 6.57 (d, J = 8.2 Hz, 1H), 4.87 (br s, 1H,
NH), 4.34 (s, 2H), 3.81 (s, 3H), 1.60 (s, 6H), 1.53 (br s, 1H, OH)
ppm. 13C{1H} NMR (100.62 MHz, CDCl3): δ 158.8, 148.8, 132.1,
131.1, 129.9, 128.3 (2×), 116.5, 114.1 (2×), 110.0, 107.1, 100.1, 78.9,
65.8, 55.3, 47.2, 31.7, 31.1 ppm. FTIR (NaCl): ν 3600−3000 (br, O−
H), 2979 (m, C−H), 2932 (m, C−H), 2835 (m, C−H), 1509 (s),
1248 (s), 1173 (s), 772 (s) cm−1. HRMS (ESI) m/z: [M + H]+ calcd
for C19H22NO2 296.1645; found 296.1639.
N-(4-Methoxybenzyl)-2-[(triethylsilyl)ethynyl]aniline (9k). The
Sonogashira Procedure D was followed from 2-iodo-N-(4-
methoxybenzyl)aniline109 (400 mg, 1.18 mmol) and triethyl-
(ethynyl)silane (8p) (0.42 mL, 2.36 mmol) (reaction time 12 h) to
afford, after purification by flash-column chromatography (silica gel,
solvent A: hexane; solvent B: EtOAc; gradient from 95:5 to 90:10 A/
2-(Cyclohex-1-en-1-ylethynyl)-N-(4-methoxybenzyl)aniline (9g).
The Sonogashira Procedure B was followed from 2-iodo-N-(4-
methoxybenzyl)aniline109 (100 mg, 0.29 mmol) and 8l (0.042 mL,
0.35 mmol) (reaction time 6 h) to afford, after purification by flash-
column chromatography (silica gel, solvent A: hexane; solvent B:
EtOAc; gradient from 100:0 to 80:20 A/B), 91 mg (98%) of 9g as a
yellow solid. Mp: 38−39 °C (hexane/EtOAc). 1H NMR (400.16
MHz, CDCl3): δ 7.29 (d, J = 8.7 Hz, 2H), 7.28 (dd, J = 7.6, 1.6 Hz,
1H), 7.12 (ddd, J = 8.3, 7.4, 1.6 Hz, 1H), 6.88 (d, J = 8.7 Hz, 2H),
6.62 (td, J = 7.5, 1.1 Hz, 1H), 6.56 (d, J = 8.4 Hz, 1H), 6.15 (tt, J =
3.9, 1.8 Hz, 1H), 5.00 (br s, 1H), 4.35 (s, 2H), 3.81 (s, 3H), 2.23−
2.17 (m, 2H), 2.17−2.10 (m, 2H), 1.72−1.57 (m, 4H) ppm. 13C{1H}
NMR (100.62 MHz, CDCl3): δ 158.9, 148.6, 134.9, 132.0, 131.3,
1
B), 214 mg (52%) of 9k as a yellow oil. H NMR (400.16 MHz,
CDCl3): δ 7.32 (dd, J = 7.6, 1.6 Hz, 1H), 7.29 (d, J = 8.8 Hz, 2H),
7.21−7.13 (m, 1H), 6.88 (d, J = 8.6 Hz, 2H), 6.65−6.56 (m, 2H),
4.97 (br s, 1H, NH), 4.31 (s, 2H), 3.81 (s, 3H), 0.97 (t, J = 7.9 Hz,
9H), 0.62 (q, J = 7.9 Hz, 6H) ppm. 13C{1H} NMR (100.62 MHz,
CDCl3): δ 159.1, 149.4, 132.2, 131.0, 130.2, 128.8 (2×), 116.4, 114.2
2×), 109.7, 107.8, 103.3, 97.9, 55.4, 47.5, 7.6 (3×), 4.6 (3×) ppm.
8777
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FTIR (NaCl): ν 3398 (s, N−H), 2953 (s, C−H), 2933 (m, C−H),
2909 (m, C−H), 2873 (m, C−H), 2834 (w, C−H), 2141 (w, CC),
1602 (s), 1510 (s), 1458 (s), 1249 (s), 1038 (s) cm−1. HRMS (ESI)
m/z: [M + H]+ calcd for C22H30NOSi 352.2091; found 352.2085.
Preparation of Dehydrotryptophans 4a−c or 5a−b from
1a−c or 2a−b and 3 (Table 1). In a typical experiment, to a
solution of the appropriate alkynylaniline derivative 1 or 2 (0.24
mmol) and methyl α-acetamidoacrylate (3) (207.2 mg, 1.45 mmol) in
DMF (2.4 mL) were added PdCl2(PPh3)2 (8.5 mg, 0.012 mmol) and
KI (20.0 mg, 0.121 mmol). The resulting mixture was stirred at 100
°C with the flask open to air. After reaction completion, a saturated
aqueous solution of NaHCO3 was added, and the mixture was
extracted with EtOAc (3×). The combined organic layers were dried
(Na2SO4), and the solvent was evaporated. The residue was purified
by flash-column chromatography to afford products 4 and/or 5.
Methyl (Z)-2-Acetamido-3-[2-(p-tolyl)-1H-indol-3-yl]acrylate
(4a). The reaction of 2-(p-tolylethynyl)aniline (1a)14,111 (50.0 mg,
0.24 mmol) and methyl 2-acetamidoacrylate (3) (207.2 mg, 1.45
mmol) in 7 h afforded, after purification by flash-column
chromatography (CN-silica gel, solvent A: hexane; solvent B:
EtOAc; gradient from 100:0 to 50:50 A/B), 50.4 mg (63%) of 4a
and 9.8 mg (20%) of 6a.111,112 Data for 4a: Yellow solid. Mp: 158−
EtOAc; gradient from 100:0 to 50:50 A/B), 54.2 mg (72%) of 5a as a
yellow solid. Mp: 85−86 °C (hexane/EtOAc). 1H NMR (400.16
MHz, Acetone-d6): δ 8.62 (s, 1H), 8.22 (dt, J = 8.4, 0.9 Hz, 1H), 7.52
(d, J = 7.9 Hz, 1H), 7.42−7.33 (m, 3H), 7.33−7.23 (m, 3H), 6.89 (s,
1H), 4.21 (q, J = 7.1 Hz, 2H), 3.71 (s, 3H), 2.41 (s, 3H), 1.84 (s,
3H), 1.03 (t, J = 7.1 Hz, 3H) ppm. 13C{1H} NMR (100.62 MHz,
Acetone-d6): δ 168.7, 165.8, 151.9, 140.4, 139.0, 137.4, 130.8 (2×),
130.8, 129.2 (2×), 128.8, 127.8, 125.4, 123.9, 123.3, 121.4, 116.7,
116.0, 63.9, 52.4, 22.8, 21.4, 13.8 ppm. FTIR (NaCl): ν 3400−3200
(m, N−H), 2991 (m, C−H), 2955 (m, C−H), 1727 (s, CO), 1681
(s, CO), 1508 (m), 1221 (s), 751 (s) cm−1. HRMS (ESI) m/z: [M
+ H]+ calcd for C24H25N2O5 421.1758; found 421.1749.
Methyl (Z)-2-Acetamido-3-(2-hexyl-1H-indol-3-yl)acrylate (4b)
and Ethyl (Z)-3-(2-Acetamido-3-methoxy-3-oxoprop-1-en-1-yl)-2-
hexyl-1H-indole-1-carboxylate (5b). The reaction of 2b (48.9 mg,
0.18 mmol) and 3 (153.7 mg, 1.07 mmol) in 31 h afforded, after
purification by flash-column chromatography (CN-silica gel, solvent
A: hexane; solvent B: EtOAc; gradient from 95:5 to 0:100 A/B), 29.8
mg (40%) of 5b and 11.2 mg (18%) of 4b.
Data for 5b: Pale yellow solid. Mp: 136−137 °C (hexane/EtOAc).
1H NMR (400.16 MHz, CDCl3): δ 8.11 (d, J = 8.3, 1H), 7.33−7.28
(m, 2H), 7.26 (dd, J = 8.3, 1.5 Hz, 1H), 7.20 (td, J = 7.4, 1.1 Hz, 1H),
6.87 (s, 1H), 4.51 (q, J = 7.1 Hz, 2H), 3.89 (s, 3H), 3.02 (app t, J =
7.7 Hz, 2H), 1.91 (s, 3H), 1.66−1.56 (m, 2H), 1.50 (t, J = 7.1 Hz,
3H), 1.42−1.26 (m, 6H), 0.88 (t, J = 7.0 Hz, 3H) ppm. 13C{1H}
NMR (100.62 MHz, CDCl3): δ 168.3, 165.3, 151.6, 142.7, 136.1,
126.9, 126.8, 124.3, 123.3, 122.0, 119.8, 116.0, 113.9, 63.6, 52.8, 31.7,
29.9, 29.5, 28.0, 23.3, 22.8, 14.4, 14.2 ppm. FTIR (NaCl): ν 3263 (m,
N−H), 2954 (w, C−H), 2928(w, C−H), 2856 (w, C−H), 1735 (s,
CO), 1457 (m), 1325 (m), 1223 (m), 1122 (w), 756 (w) cm−1.
HRMS (ESI) m/z: [M + H]+ calcd for C23H31N2O5 415.2227; found
415.2238.
Preparation of 2-Aryldehydrotryptophans 4a and 4d−n
from o-Iodoaryl Carbamates 7, Alkynes 8, and Alkene 3
(Table 2). In a typical experiment, to a solution of an o-iodoaryl
carbamate 7 (0.21 mmol), an alkyne 8 (0.41 mmol), and 3 (177 mg,
1.24 mmol) in DMF (2.1 mL, previously degassed with freeze−thaw
cycles under argon) were added PdCl2 (1.8 mg, 0.010 mmol),
polymer-bound PPh3 (13.1 mg, 1.6 mmol/g PPh3 loading, 0.021
mmol of PPh3), CuI (7.9 mg, 0.041 mmol), and Et3N (0.129 mL, 0.93
mmol). The resulting mixture was stirred at 60 °C under argon. After
reaction completion, air was allowed into the system, and the mixture
was stirred at 120 °C. Then, a saturated aqueous solution of NaHCO3
was added, and the mixture was extracted with EtOAc (3×). The
combined organic layers were dried (Na2SO4) and filtered over silica
gel (230−400 mesh). After removal of the solvent by evaporation, the
residue was dissolved in methanol (4.3 mL) in the presence of tert-
butylamine (0.64 mL, 6.1 mmol), and the mixture was heated at
reflux. The solvent was removed under reduced pressure, and the
crude product was purified by flash-column chromatography (silica
gel, solvent A: hexane; solvent B: EtOAc; gradient from 20:80 to
0:100 A/B) to afford products 4a and 4d−n. Reaction times are those
given in Table 2.
1
159 °C (hexane/EtOAc). H NMR (400.16 MHz, Acetone-d6): δ
10.88 (s, 1H), 8.40 (s, 1H), 7.57 (d, J = 8.1 Hz, 1H), 7.56 (d, J = 8.1
Hz, 2H), 7.44 (dt, J = 8.0, 1.0 Hz, 1H), 7.39 (s, 1H), 7.30 (d, J = 8.1
Hz, 2H), 7.18 (ddd, J = 8.1, 7.0, 1.2 Hz, 1H), 7.10 (ddd, J = 8.1, 7.1,
1.1 Hz, 1H), 3.74 (s, 3H), 2.39 (s, 3H), 1.82 (s, 3H) ppm. 13C{1H}
NMR (100.62 MHz, Acetone-d6): δ 169.0, 166.4, 140.3, 139.2, 137.6,
130.4, 130.2 (2×), 129.4 (2×), 127.8, 126.0, 125.7, 123.1, 121.4,
120.9, 112.4, 108.2, 52.2, 22.8, 21.3 ppm. FTIR (NaCl): ν 3284 (br,
m, N−H), 3013 (m, CC), 2950 (m, C−H), 2866 (m, C−H), 1680
(s, CO), 1671 (s, CO), 1507 (s), 1246 (s), 754 (s) cm−1. HRMS
(ESI) m/z: [M + H]+ calcd for C21H21N2O3 349.1547; found
349.1546.
Methyl (Z)-2-Acetamido-3-(2-hexyl-1H-indol-3-yl)acrylate (4b).
The reaction of 2-(oct-1-yn-1-yl)aniline113 (1b) (40.3 mg, 0.20
mmol) and 3 (171.8 mg, 1.20 mmol) in DMF (2.0 mL) in 4 h
afforded, after purification by flash-column chromatography (silica gel,
solvent A: hexane; solvent B: EtOAc; gradient from 90:10 to 20:80 A/
B) 14.0 mg (20%) of 4b as a brown solid. Mp: 122−123 °C (hexane/
1
EtOAc). H NMR (400.16 MHz, CDCl3): δ 8.65 (s, 1H), 7.53 (s,
1H), 7.46 (d, J = 7.7 Hz, 1H), 7.29−7.26 (m, 1H), 7.17−7.06 (m,
2H), 6.95 (s, 1H), 3.87 (s, 3H), 2.61 (t, J = 7.8 Hz, 2H), 2.04 (s, 3H),
1.64−1.51 (m, 2H), 1.38−1.20 (m, 6H), 0.87 (t, J = 7.0 Hz, 3H)
ppm. 13C{1H} NMR (100.62 MHz, CDCl3): δ 168.4, 166.2, 143.6,
135.9, 125.9, 125.9, 122.0, 120.8, 120.6, 120.4, 111.4, 107.4, 52.5,
31.7, 29.4, 29.1, 26.8, 23.5, 22.7, 14.2 ppm. FTIR (NaCl): ν 3271 (s,
N−H), 2924 (s, C−H), 2858 (m), 1674 (s, CO), 1625 (s, CO),
1460 (s), 1239 (s), 749 (s) cm−1. HRMS (ESI) m/z: [M + H]+ calcd
for C20H27N2O3 343.2016; found 343.2027.
Methyl (Z)-2-Acetamido-3-[2-(tert-butyl)-1H-indol-3-yl]acrylate
(4c). The reaction of 2-(3,3-dimethylbut-1-yn-1-yl)aniline113 (1c)
(34.7 mg, 0.20 mmol) and 3 (171.8 mg, 1.20 mmol) in 5 h afforded,
after purification by flash-column chromatography (silica gel, solvent
A: hexane; solvent B: EtOAc; gradient from 90:10 to 20:80 A/B),
27.0 mg (20%) of 4c as a white solid. Mp: 107−108 °C (hexane/
Methyl (Z)-2-Acetamido-3-[2-(p-tolyl)-1H-indol-3-yl]acrylate
(4a). Starting from ethyl (2-iodophenyl)carbamate (7a)27,107 (60
mg, 0.21 mmol) and p-tolylacetylene (8a) (0.052 mL, 0.41 mmol)
afforded 44 mg (62%) of 4a.
1
EtOAc). H NMR (400.16 MHz, CDCl3): δ 8.65 (s, 1H), 7.59 (s,
1H), 7.32 (d, J = 8.1 Hz, 1H), 7.26 (d, J = 7.7 Hz, 2H), 7.14 (ddd, J =
8.1, 7.0, 1.3 Hz, 1H), 7.08 (t, J = 7.6 Hz, 1H), 6.73 (s, 1H), 3.87 (s,
3H), 1.88 (s, 3H), 1.47 (s, 9H) ppm. 13C{1H} NMR (100.62 MHz,
CDCl3): δ 168.8, 165.7, 147.6, 134.3, 126.3, 125.4, 124.3, 121.9,
120.6, 119.8, 111.2, 104.8, 52.6, 33.4, 30.3 (3×), 23.3 ppm. FTIR
(NaCl): ν 3321 (s, N−H), 2967 (s, C−H), 1709 (s, CO), 1674 (s,
CO), 1432 (s), 1257 (s), 752 (s) cm−1. HRMS (ESI) m/z: [M +
H]+ calcd for C18H23N2O3 315.1703; found 315.1701.
Ethyl (Z)-3-(2-Acetamido-3-methoxy-3-oxoprop-1-en-1-yl)-2-(p-
tolyl)-1H-indole-1-carboxylate (5a). The reaction of ethyl [2-(p-
tolylethynyl)phenyl]carbamate114 (2a) (50.0 mg, 0.18 mmol) and 3
(153.7 mg, 1.07 mmol) for 31 h afforded, after purification by flash-
column chromatography (CN-silica gel, solvent A: hexane; solvent B:
Methyl (Z)-2-Acetamido-3-[2-(4-methoxyphenyl)-1H-indol-3-yl]-
acrylate (4d). Starting from 7a27,107 (60 mg, 0.21 mmol) and 1-
ethynyl-4-methoxybenzene (8d) (55 mg, 0.41 mmol) afforded 55 mg
(73%) of 4d as a solid. Mp: 165−166 °C (hexane/EtOAc). 1H NMR
(400.16 MHz, CDCl3): δ 8.84 (s, 1H), 7.53−7.48 (m, 2H), 7.44 (d, J
= 8.5 Hz, 2H), 7.22 (d, J = 7.6 Hz, 1H), 7.18−7.09 (m, 2H), 6.93 (d,
J = 8.5 Hz, 2H), 6.89 (s, 1H), 3.84 (s, 3H), 3.83 (s, 3H), 1.85 (s, 3H)
ppm. 13C{1H} NMR (100.62 MHz, CDCl3): δ 168.0, 166.0, 160.1,
139.3, 136.3, 129.9 (2×), 126.9, 125.7, 124.6, 122.8, 122.7, 120.8,
120.2, 114.6 (2×), 111.5, 107.5, 55.5, 52.6, 23.3 ppm. FTIR (NaCl):
ν 3500−3100 (br, s, N−H), 3012 (m, C−H), 2950 (m, C−H), 2837
(m, C−H), 1706 (s, CO), 1670 (s, CO), 1611 (m), 1502 (s),
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1250 (s), 752 (s) cm−1. HRMS (ESI) m/z: [M + H]+ calcd for
C21H21N2O4 365.1496; found 365.1489.
C−H), 1701 (s, CO), 1668 (s, CO), 1624 (s), 1488 (s), 1256
(s), 754 (s) cm−1. HRMS (ESI) m/z: [M + H]+ calcd for
C22H23N2O4 379.1652; found 379.1660.
Methyl (Z)-4-[3-(2-Acetamido-3-methoxy-3-oxoprop-1-en-1-yl)-
1H-indol-2-yl]benzoate (4e). Starting from 7a27,107 (60.0 mg, 0.21
mmol) and methyl 4-ethynylbenzoate (8e) (66.0 mg, 0.41 mmol)
afforded 48.0 mg (59%) of 4e as a yellow solid. Mp: 111−112 °C
Methyl (Z)-2-Acetamido-3-[2-(3-chlorophenyl)-1H-indol-3-yl]-
acrylate (4j). Starting from 7a27,107 (75.0 mg, 0.26 mmol) and 8d
1
(0.063 mL, 0.52 mmol) afforded 55 mg (58%) of 4j as a foam. H
1
(hexane/EtOAc). H NMR (400.16 MHz, DMSO-d6): δ 12.05 (s,
NMR (400.16 MHz, CD3OD, 323 K): δ 7.90 (s, 1H), 7.55−7.53 (m,
2H), 7.50 (d, J = 8.1 Hz, 1H), 7.45−7.41 (m, 3H), 7.20 (t, J = 7.6 Hz,
1H), 7.11 (t, J = 7.5 Hz, 1H), 3.82 (s, 3H), 1.80 (s, 3H) ppm.
13C{1H} NMR (100.62 MHz, CD3OD, 323 K): δ 172.1, 167.4, 139.3,
1H), 9.38 (s, 1H), 8.10 (d, J = 8.5 Hz, 2H), 7.74 (d, J = 8.5 Hz, 2H),
7.47 (d, J = 8.2 Hz, 1H), 7.44 (d, J = 8.1 Hz, 1H), 7.24 (s, 1H), 7.22
(ddd, J = 8.1, 7.1, 1.1 Hz, 1H), 7.09 (ddd, J = 8.1, 7.1, 1.1 Hz, 1H),
3.89 (s, 3H), 3.71 (s, 3H), 1.70 (s, 3H). 13C{1H} NMR (100.62
MHz, DMSO-d6): δ 168.5, 165.9, 165.4, 137.3, 136.8, 136.4, 129.5
(2×), 128.8, 128.5 (2×), 126.2, 125.4, 124.4, 122.8, 120.5, 120.1,
111.9, 108.2, 52.3, 51.9, 22.3 ppm. FTIR (NaCl): ν 3500−3100 (br,
m, N−H), 3009 (m, C−H), 2949 (m, C−H), 1713 (s, CO), 1670
(s, CO), 1435 (m), 1276 (s), 751 (s) cm−1. HRMS (ESI) [M +
H]+: calcd for C22H21N2O5 393.1445; found 393.1433.
138.3, 135.7, 135.6, 131.4, 129.3 (2×), 128.6, 128.3, 127.8, 124.7,
123.9, 121.5 (2×), 112.8, 109.1, 52.8, 22.4 ppm. FTIR (NaCl): ν
3263 (s, N−H), 3058 (w), 3001 (w), 2950 (w), 1704 (s, CO),
1669 (s, CO), 1435 (s), 1243 (s) cm−1. HRMS (ESI) m/z: [M +
H]+ calcd for C20H18ClN2O3 [(M+H)+] 369.1000; found 369.1000.
Methyl (Z)-2-Acetamido-3-[2-(3-fluorophenyl)-1H-indol-3yl]-
acrylate (4k). Starting from 7a27,107 (75.0 mg, 0.26 mmol) and 8e
(0.060 mL, 0.52 mmol) afforded 45.0 mg (50%) of 4k as a foam. 1H
NMR (400.16 MHz, CD3OD, 323 K): δ 7.90 (s, 1H), 7.53−7.41 (m,
4H), 7.38 (ddd, J = 10.0, 2.6, 1.5 Hz, 1H), 7.23−7.08 (m, 3H), 3.82
(s, 3H), 1.80 (s, 3H) ppm. 13C{1H} NMR (100.62 MHz, CD3OD,
323 K): δ 172.2, 167.4, 164.2 (1JCF = 245.1 Hz), 139.5, 138.3, 135.9
(3JCF = 8.3 Hz), 131.7 (3JCF = 8.6 Hz), 128.8, 127.8, 125.8 (4JCF = 3.0
Methyl (Z)-2-Acetamido-3-[5-bromo-2-(p-tolyl)-1H-indol-3-yl]-
acrylate (4f). Starting from 7b27,106 (200 mg, 0.54 mmol) and 8a
(0.137 mL, 1.08 mmol) afforded 157 mg (68%) of 4f as a yellow
1
solid. Mp: 163−164 °C (hexane/EtOAc). H NMR (400.16 MHz,
CD3OD): δ 7.62 (d, J = 1.9 Hz, 1H), 7.49 (d, J = 8.0 Hz, 2H), 7.49
(s, 1H), 7.33 (d, J = 8.6 Hz, 1H), 7.30 (d, J = 8.0 Hz, 2H), 7.26 (dd, J
= 8.6, 1.8 Hz, 1H), 3.80 (s, 3H), 2.40 (s, 3H), 1.91 (s, 3H) ppm.
13C{1H} NMR (100.62 MHz, CD3OD): δ 172.4, 167.4, 143.4, 140.3,
Hz), 124.7, 123.9, 121.5 (2×), 116.3 (2JCF = 18.3 Hz), 116.1 (2JCF
=
16.8 Hz), 112.7, 109.0, 52.8, 22.4 ppm. FTIR (NaCl): ν 3260 (s, N−
H), 3050 (w), 3029 (w), 2950 (w), 1698 (s, CO), 1669 (s, CO),
1436 (s), 1270 (s), 1243 (s) cm−1. HRMS (ESI) m/z: [M + H]+
calcd for C20H18FN2O3 353.1298; found 353.1296.
136.8, 130.5 (2×), 130.1, 129.9 (2×), 129.4, 129.1, 126.0, 124.2,
123.9, 114.4, 114.2, 107.7, 52.8, 22.5, 21.3 ppm. FTIR (NaCl): ν
3400−3100 (br, m, N−H), 3013 (w, CC), 2949 (w, C−H), 1684
(s, CO), 1672 (s, CO), 1433 (s), 1245 (s), 753 (s) cm−1. HRMS
(ESI) m/z: [M + H]+ calcd for C21H2079BrN2O3 427.0652; found
427.0637.
Methyl (Z)-2-Acetamido-3-[2-(3-methoxyphenyl)-1H-indol-3-yl]-
acrylate (4l). Starting from 7a27,107 (75.0 mg, 0.26 mmol) and 1-
ethynyl-3-methoxybenzene (8f) (0.065 mL, 0.52 mmol) afforded 55.0
1
Methyl (Z)-2-Acetamido-3-[6-bromo-2-(p-tolyl)-1H-indol-3-yl]-
acrylate (4g). Starting from 7c106 (200 mg, 0.54 mmol) and 8a
(0.137 mL, 1.08 mmol) afforded 144 mg (62%) of 4g as a yellow
mg (59%) of 4l as a foam. H NMR (400.16 MHz, DMSO-d6, 333
K): δ 9.23 (s, 1H), 7.50−7.42 (m, 3H), 7.32 (s, 1H), 7.23−7.16 (m,
3H), 7.09 (d, J = 8.1 Hz, 1H), 7.08−6.99 (m, 1H), 3.84 (s, 3H), 3.72
(s, 3H), 1.77 (s, 3H) ppm. 13C{1H} NMR (100.62 MHz, DMSO-d6,
333 K): δ 168.3, 165.4, 159.2, 138.9, 136.3, 132.9, 129.6, 126.0, 125.6,
124.2, 122.0, 120.8, 120.3, 119.7, 114.0, 113.8, 111.5, 107.0, 55.0,
51.6, 22.1 ppm. FTIR (NaCl): ν 3274 (s, N−H), 3058 (w), 3006 (w),
2951 (w), 2836 (w), 1708 (s, CO), 1670 (s, CO), 1491 (s),
1435 (s), 1240.0 (s), 1042 (w) cm−1. HRMS (ESI) m/z: [M + H]+
calcd for C21H21N2O4 365.1480; found 365.1496.
1
solid. Mp: 157−158 °C (hexane/EtOAc). H NMR (400.16 MHz,
CD3OD): δ 7.50 (s, 1H), 7.46 (s, 1H), 7.40 (d, J = 7.9 Hz, 2H), 7.31
(d, J = 8.6 Hz, 1H), 7.16 (d, J = 7.9 Hz, 2H), 7.12 (d, J = 8.6 Hz, 1H),
3.72 (s, 3H), 2.28 (s, 3H), 1.76 (s, 3H) ppm. 13C{1H} NMR (100.62
MHz, CD3OD): δ 172.1, 167.4, 142.3, 140.0, 138.8, 130.4 (2×),
130.1, 129.6 (2×), 129.1, 126.8, 124.3, 124.0), 122.6, 116.6, 115.4,
108.0, 52.8, 22.5, 21.4 ppm. FTIR (NaCl): ν 3500−3100 (br, m, N−
H), 3017 (m, CC), 2953 (m, C−H), 1685 (s, CO), 1671 (s,
CO), 1434 (m), 1246 (s), 757 (s) cm−1. HRMS (ESI) m/z: [M +
H]+ calcd for C21H2079BrN2O3 427.0652; found 427.0644.
Methyl (Z)-2-Acetamido-3-[2-(3,4-difluorophenyl)-1H-indol-3-
yl]acrylate (4m). Starting from 7a27,107 (75.0 mg, 0.26 mmol) and
4-ethynyl-1,2-difluorobenzene (8g) (0.062 mL, 0.52 mmol) afforded
55.0 mg (58%) of 4m as a foam. 1H NMR (400.16 MHz, DMSO-d6,
333 K): δ 9.22 (s, 1H), 7.69−7.54 (m, 2H), 7.45 (dd, J = 7.6, 7.0 Hz,
3H), 7.26 (s, 1H), 7.20 (t, J = 7.6 Hz, 1H), 7.09 (t, J = 8.1 Hz, 1H),
3.73 (s, 3H), 1.72 (s, 3H) ppm. 13C{1H} NMR (100.62 MHz,
DMSO-d6, 333 K): δ 168.1, 165.2, 146.3 (1JCF = 245.4 Hz), 149.2
(1JCF = 246.0 Hz), 136.3 (3JCF = 8.5 Hz), 129.4, 129.3, 126.1, 125.3
Methyl (Z)-3-(2-Acetamido-3-methoxy-3-oxoprop-1-en-1-yl)-2-
(p-tolyl)-1H-indole-5-carboxylate (4h). Starting from 7d107 (200
mg, 0.57 mmol) and 8a (0.145 mL, 1.15 mmol) afforded 115 mg
(49%) of 4h as a yellow solid. Mp: 244−245 °C (hexane/EtOAc). 1H
NMR (400.16 MHz, DMSO-d6): δ 12.27 (s, 1H), 9.56 (s, 1H), 8.22
(d, J = 1.7 Hz, 1H), 7.82 (dd, J = 8.5, 1.7 Hz, 1H), 7.53 (d, J = 8.5 Hz,
1H), 7.52 (d, J = 7.9 Hz, 2H), 7.39 (d, J = 7.9 Hz, 2H), 7.18 (s, 1H),
3.85 (s, 3H), 3.71 (s, 3H), 2.39 (s, 3H), 1.85 (s, 3H) ppm. 13C{1H}
NMR (100.62 MHz, DMSO-d6): δ 168.8, 167.0, 165.6, 141.5, 139.1,
138.6, 129.5 (2×), 128.7 (2×), 128.3, 125.6, 124.8, 124.0, 123.5),
123.0, 121.3, 111.6), 107.6, 51.9, 51.7, 22.2, 20.9 ppm. FTIR (NaCl):
ν 3600−2900 (s, br, N−H), 3040 (w, C−H), 2963 (w, C−H), 2257
(w), 2126 (w), 1708 (s, CO), 1664 (s, CO), 1243 (m), 1025 (s)
cm−1. HRMS (ESI) m/z: [M + H]+ calcd for C23H23N2O5 407.1602;
found 407.1601.
(2×), 124.3, 122.4, 120.2, 119.9, 117.8 (2JCF = 17.4 Hz), 116.9 (2JCF
=
18.1 Hz), 111.6, 107.5, 51.6, 22.0 ppm. FTIR (NaCl): ν 3264 (s, N−
H), 3058 (w), 3019 (w), 2952 (w), 1707 (s, CO), 1669 (s, CO),
1513 (s), 1456 (s), 1436 (s), 1277 (s), 1242 (s), 1202 (w), 1118 (w)
cm−1. HRMS (ESI) m/z: [M + H]+ calcd for C20H17F2N2O3
371.1184; found 371.1201.
Methyl (Z)-2-Acetamido-3-[2-(3,4-thiophen-2-yl)-1H-indol-3-yl]-
acrylate (4n). Starting from 7a27,107 (75.0 mg, 0.26 mmol) and 3-
ethynylthiophene (8h) (0.051 mL, 0.52 mmol) afforded 45.0 mg
(51%) of 4n as a foam. 1H NMR (400.16 MHz, DMSO-d6, 333 K): δ
9.22 (s, 1H), 7.73 (s, 2H), 7.53−7.33 (m, 4H), 7.17 (q, J = 7.3 Hz,
1H), 7.06 (q, J = 7.2 Hz, 1H), 3.74 (s, 3H), 1.82 (s, 3H) ppm.
13C{1H} NMR (100.62 MHz, DMSO-d6, 333 K): δ 168.5, 165.4,
136.1, 134.8), 132.4, 127.0, 126., 125.8, 125.1, 124.4, 124.2, 121.2,
120.3, 119.7, 111.3, 106.7, 51.6, 22.2 ppm. FTIR (NaCl): ν 3275 (s,
N−H), 3105 (w), 3055 (w), 3008 (w), 2950 (w), 1704 (s, CO),
1669 (s, CO), 1514 (w), 1434 (s), 1243 (s), 1131 (w) cm−1.
HRMS (ESI) m/z: [M + H]+ calcd for C18H17N2O3S 341.0938;
found 341.0954.
Methyl (Z)-2-Acetamido-3-[5-methoxy-2-(p-tolyl)-1H-indol-3-yl]-
acrylate (4i). Starting from 7e (200 mg, 0.62 mmol) and 8a (0.158
mL, 1.25 mmol) afforded 130 mg (55%) of 4i as a solid. Mp: 179−
1
180 °C (hexane/EtOAc). H NMR (400.16 MHz, CD3OD): δ 7.54
(s, 1H), 7.46 (d, J = 8.0 Hz, 2H), 7.29 (d, J = 8.8 Hz, 1H), 7.24 (d, J =
8.0 Hz, 2H), 6.96 (d, J = 2.4 Hz, 1H), 6.81 (dd, J = 8.8, 2.4 Hz, 1H),
3.79 (s, 3H), 3.78 (s, 3H), 2.35 (s, 3H), 1.87 (s, 3H) ppm. 13C{1H}
NMR (100.62 MHz, CD3OD): δ 172.4, 167.5, 155.9, 142.3, 139.6,
133.1, 130.7, 130.4 (2×), 130.2, 129.6 (2×), 128.5, 123.4, 113.6,
113.3, 107.9, 103.5, 56.2, 52.7, 22.7, 21.3 ppm. FTIR (NaCl): ν
3400−3100 (br, s, N−H), 3010 (m, C−H), 2950 (m, C−H), 2840 (s,
8779
https://doi.org/10.1021/acs.joc.1c00636
J. Org. Chem. 2021, 86, 8766−8785

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
Preparation of 2-Alkyldehydrotryptophans 4b, 4o, and 4p
from o-Alkynylaryl Carbamates 2 and Alkene 3 (Scheme 2).
The following procedure is representative: To a solution of 2 (0.20
mmol) and 3 (170.9 mg, 1.19 mmol) in DMF (2.0 mL) were added
PdCl2(PPh3)2 (14.0 mg, 0.020 mmol) and KI (16.5 mg, 0.099 mmol).
The resulting mixture was stirred at 100 °C (2b, 45 h; 2p, 45 h) or
120 °C (2o, 44 h) with the flask opened to air. After reaction
completion, water was added, and the mixture was extracted with
EtOAc (3×). The combined organic layers were dried (Na2SO4) and
filtered through a pad of Celite, and the solvent was evaporated. The
residue was dissolved in MeOH (4.2 mL) in the presence of tert-
butylamine (0.63 mL, 6.0 mmol), and the mixture was heated to 90
°C (2b, 16 h; 2o, 18 h; 2p, 45 h). The solvent was removed under
reduced pressure, and the crude product was purified by flash-column
chromatography (silica gel, hexane/EtOAc gradient) to afford
product 4b, 4o, or 4p.
Methyl (Z)-2-Acetamido-3-(2-hexyl-1H-indol-3-yl)acrylate (4b).
Starting from 2b (60.0 mg, 0.22 mmol), purification by flash-column
chromatography (silica gel, solvent A: hexane; solvent B: EtOAc;
gradient from 90:10 to 20:80 A/B) afforded 33.7 mg (45%) of 4b.
Methyl (Z)-2-Acetamido-3-(2-cyclohexyl-1H-indol-3-yl)acrylate
(4o). Starting from 2o (54.0 mg, 0.20 mmol), purification by flash-
column chromatography (silica gel, solvent A: hexane; solvent B:
EtOAc; gradient from 90:10 to 0:100 A/B) afforded 43.8 mg (65%)
of 4o as a yellow foam. 1H NMR (400.16 MHz, CD3OD): δ 7.67 (s,
1H), 7.39 (d, J = 8.0 Hz, 1H), 7.32 (d, J = 8.0 Hz, 1H), 7.09 (ddd, J =
8.1, 7.1, 1.2 Hz, 1H), 7.02 (ddd, J = 8.1, 7.1, 1.2 Hz, 1H), 3.82 (s,
3H), 2.94 (tt, J = 12.2, 3.3 Hz, 1H), 1.97 (s, 3H), 1.93−1.85 (m, 4H),
1.83−1.77 (m, 1H), 1.65 (qd, J = 12.8, 3.6 Hz, 2H), 1.48 (qt, J = 12.8,
3.2 Hz, 2H), 1.43−1.29 (m, 1H) ppm. 13C{1H} NMR (100.62 MHz,
CD3OD): δ 172.8, 167.8, 149.4, 137.8, 129.9, 127.1, 122.5, 121.9,
121.3, 121.0, 112.2, 106.5, 52.7, 37.9, 33.8 (2×), 27.6 (2×), 27.1, 22.6
ppm. FTIR (NaCl): ν 3281 (s, N−H), 2930 (s, C−H), 2853 (s),
1670 (s), 1625 (s) 1455 (s), 1434 (s), 1247 (s), 1223 (s), 751 (s)
cm−1. HRMS (ESI) m/z: [M + H]+ calcd for C20H25N2O3 341.1860;
found 341.1859.
7.64 (s, 1H), 7.49 (d, J = 7.5 Hz, 1H), 7.27 (d, J = 7.8 Hz, 1H), 7.13−
7.05 (m, 2H), 6.93 (d, J = 8.3 Hz, 2H), 6.81 (d, J = 8.6 Hz, 2H), 5.35
(s, 2H), 3.82 (s, 3H), 3.73 (s, 3H), 2.83 (t, J = 7.8 Hz, 2H), 1.97 (s,
3H), 1.54−1.43 (m, 2H), 1.39−1.30 (m, 2H), 1.30−1.20 (m, 4H),
0.86 (t, J = 7.1 Hz, 3H) ppm. 13C{1H} NMR (100.62 MHz, CD3OD,
323 K): δ 172.5, 167.8, 160.6, 146.1, 138.8, 130.9, 129.4, 128.4 (2×),
126.8, 122.9, 122.4, 121.8, 121.5, 115.3 (2×), 111.3, 109.0, 55.8, 52.7,
47.2, 32.5, 30.9, 30.0, 26.1, 23.4, 22.7, 14.3 ppm. FTIR (NaCl): ν
3400−3200 (br, m, N−H), 2933 (s, C−H), 1711 (s, CO), 1678
(s), 1514 (s), 1250 (s) cm−1. HRMS (ESI) m/z: [M + H]+ calcd for
C28H35N2O4 463.2591; found 463.2595.
Methyl (Z)-2-Acetamido-3-[2-(acetoxymethyl)-1-(4-methoxy-
benzyl)-1H-indol-3-yl]acrylate (10b). Following the procedure for
the preparation of N-PMB-dehydrotryptophans 10, starting from 9b
(50 mg, 0.16 mmol) afforded 30 mg (41%) of 10b as a solid. Mp:
139−140 °C (hexane/EtOAc). 1H NMR (400.16 MHz, CD3OD, 323
K): δ 7.83 (s, 1H), 7.72 (s, 1H), 7.52 (d, J = 8.1 Hz, 1H), 7.34 (d, J =
8.3 Hz, 1H), 7.20 (ddd, J = 8.3, 7.6, 1.2 Hz, 1H), 7.12 (app t, J = 7.6
Hz, 1H), 6.94 (d, J = 8.6 Hz, 2H), 6.82 (d, J = 8.6 Hz, 2H), 5.43 (s,
2H), 5.30 (s, 2H), 3.83 (s, 3H), 3.73 (s, 3H), 1.93 (s, 3H), 1.83 (s,
3H) ppm. 13C{1H} NMR (100.62 MHz, CD3OD, 323 K): δ 172.5,
172.0, 167.3, 160.6, 139.1, 136.2, 130.8, 128.4 (2×), 127.4, 126.4,
125.7, 124.3, 122.2, 121.8, 115.2 (2×), 112.1, 111.7, 56.7, 55.8, 52.8,
47.6, 22.6, 20.4 ppm. FTIR (NaCl): ν 3500−3200 (br, m, N−H),
3004 (w, C−H), 2947 (w, C−H), 1731 (s, CO), 1681 (s, CO),
1514 (s), 1246 (s) cm−1. HRMS (ESI) m/z: [M + H]+ calcd for
C25H27N2O6 451.1864, found 451.1870.
(Z)-2-Acetamido-3-[2-cyclohexyl-1-(4-methoxybenzyl)-1H-indol-
3-yl]acrylate (10c). Following the procedure for the preparation of N-
PMB-dehydrotryptophans 10, starting from 9c (70 mg, 0.22 mmol)
afforded 50 mg (50%) of 10c as a white solid. Mp: 176−177 °C
1
(hexane/EtOAc). H NMR (400.16 MHz, CDCl3): δ 7.60 (s, 1H),
7.33 (d, J = 7.5 Hz, 1H), 7.24−7.19 (m, 1H), 7.16−7.07 (m, 2H),
6.93 (d, J = 8.3 Hz, 2H), 6.81 (d, J = 8.4 Hz, 2H), 6.76 (br s, 1H),
5.34 (s, 2H), 3.89 (s, 3H), 3.76 (s, 3H), 2.93−2.80 (m, 1H), 1.93 (s,
3H), 1.84−1.78 (m, 2H), 1.77−1.68 (m, 5H), 1.30−1.21 (m, 3H)
ppm. 13C{1H} NMR (100.62 MHz, CDCl3): δ 168.6, 165.8, 159.1,
146.2, 136.7, 129.5, 127.3 (2×), 125.5, 125.1, 123.6, 121.9, 120.6,
120.2, 114.4 (2×), 110.2, 106.2, 55.4, 52.6, 46.8, 37.7, 32.2 (2×), 27.1
(2×), 25.9, 23.4 ppm. FTIR (NaCl): ν 3400−3100 (w, N−H), 3009
(m, C−H), 2931 (s, C−H), 2852 (m, C−H), 1716 (s, CO), 1679
(s, CO), 1511 (s), 1249 (s), 750 (s) cm−1. HRMS (ESI) m/z: [M
+ H]+ calcd for C28H33N2O4 461.2435; found 461.2453.
Methyl (Z)-2-Acetamido-3-[2-(cyclohex-1-en-yl)-1H-indol-3-yl]-
acrylate (4p). Starting from 2p (60.0 mg, 0.22 mmol), purification
by flash-column chromatography (silica gel, solvent A: hexane;
solvent B: EtOAc; gradient from 90:10 to 0:100 A/B) afforded 51.7
1
mg (68%) of 4p as a yellow foam. H NMR (400.16 MHz, CDCl3,
323 K): δ 8.44 (s, 1H), 7.48 (s, 1H), 7.41 (d, J = 8.1 Hz, 1H), 7.29
(d, J = 7.1 Hz, 1H), 7.16 (t, J = 7.8 Hz, 1H), 7.10 (t, J = 7.4 Hz, 1H),
6.92 (s, 1H), 6.14−6.10 (m, 1H), 3.87 (s, 3H), 2.40−2.34 (m, 2H),
2.32−2.24 (m, 2H), 1.97 (s, 3H), 1.83−1.74 (m, 2H), 1.73−1.67 (m,
2H) ppm. 13C{1H} NMR (100.62 MHz, CDCl3, 323 K): δ 168.3,
165.9, 141.6, 135.4, 132.8, 129.3, 128.7, 126.3, 122.7, 122.5, 120.6,
120.2, 111.4, 106.8, 52.6, 27.4, 26.0, 23.5, 22.6, 21.9 ppm. FTIR
(NaCl): ν 3400−3200 (s, N−H), 3011 (w), 2936 (w), 2865 (w),
2829 (w), 1683 (s, CO), 1666 (s, CO), 1495 (w), 1435 (w),
1247 (s) cm−1. HRMS (ESI) m/z: [M + H]+ calcd for C20H23N2O3
339.1703; found 339.1705.
Preparation of Dehydrotryptophans 10 from N-PMB-o-
Alkynylanilines 9 (Table 3 and Scheme 3). In a typical procedure,
to a solution of an o-alkynylaniline 9 (0.22 mmol) and 3 (188 mg,
1.32 mmol) in DMF (2.1 mL) were added PdCl2(PPh3)2 (15.4 mg,
0.022 mmol), TPPO (6.1 mg, 0.022 mmol), and KI (18.2 mg, 0.11
mmol), and the mixture was stirred at 100 °C for 5−24 h (see Table 3
for details) with the flask opened to air. After reaction completion, a
saturated aqueous solution of NaHCO3 was added, and the mixture
was extracted with EtOAc (3×). The combined organic layers were
dried (Na2SO4), and the solvent was evaporated. The residue was
purified by flash-column chromatography (silica gel, solvent A:
hexane; solvent B: EtOAc; gradient from 20:80 to 80:20 A/B) to
afford products 10.
Methyl (Z)-2-Acetamido-3-[2-(tert-butyl)-1-(4-methoxybenzyl)-
1H-indol-3-yl]acrylate (10d) and 2-(tert-Butyl)-1-(4-methoxyben-
zyl)-1H-indole (11d). Following the procedure for the preparation of
N-PMB-dehydrotryptophans 10, starting from 9d (50 mg, 0.17
mmol) afforded 61 mg (82%) of 10d and 17 mg (17%) of 11d. Data
1
for 10d: Yellow solid. Mp: 82−83 °C (hexane/EtOAc). H NMR
(400.16 MHz, CDCl3): δ 7.63 (s, 1H), 7.25−7.21 (m, 1H), 7.10−
7.02 (m, 2H), 7.02−6.96 (m, 1H), 6.80 (app. s, 4H), 6.65 (s, 1H),
5.59 (s, 2H), 3.89 (s, 3H), 3.75 (s, 3H), 1.82 (s, 3H), 1.50 (s, 9H)
ppm. 13C{1H} NMR (100.62 MHz, CDCl3): δ 168.5, 165.6, 158.8,
146.2, 137.7, 129.6, 127.3, 126.8 (2×), 125.6, 125.3, 122.2, 120.5,
119.5, 114.2 (2×), 110.6, 105.7, 55.3, 52.6, 48.9, 34.7, 32.0 (3×), 23.3
ppm. FTIR (NaCl): ν 3400−3100 (m, N−H), 3000 (m, C−H), 2962
(m, C−H), 1716 (s, CO), 1678 (s, CO), 1510 (s), 1470 (s),
1249 (s), 753 (s) cm−1. HRMS (ESI) m/z: [M + H]+ calcd for
C26H31N2O4 435.2278; found 435.2279. Data for 11d: White solid.
Mp: 135−136 °C (hexane/EtOAc). 1H NMR (400.16 MHz, CDCl3):
δ 7.62−7.54 (m, 1H), 7.10−6.98 (m, 3H), 6.85−6.75 (m, 4H), 6.41
(d, J = 0.8 Hz, 1H), 5.56 (s, 2H), 3.76 (s, 3H), 1.44 (s, 9H) ppm.
13C{1H} NMR (100.62 MHz, CDCl3): δ 158.7, 149.3, 138.4, 130.3,
127.6, 126.9 (2×), 121.2, 120.1, 119.7, 114.1 (2×), 110.1, 98.7, 55.3,
48.2, 32.6, 30.8 (3×) ppm. FTIR (NaCl): ν 3041 (w, C−H), 2964 (s,
C−H), 2871 (w, C−H), 1607 (w), 1512 (s), 1466 (s), 1244 (s), 1175
(m), 738 (m) cm−1. HRMS (ESI) m/z: [M + H]+ calcd for
C20H24NO 294.1852; found 294.1856.
Methyl (Z)-2-Acetamido-3-(2-hexyl-1-(4-methoxybenzyl)-1H-
indol-3-yl)acrylate (10a). Following the procedure for the prepara-
tion of N-PMB-dehydrotryptophans 10, starting from 9a (70 mg, 0.22
mmol) afforded 40 mg (40%) of 10a as a pale brown solid. Mp: 128−
129 °C (hexane/EtOAc). 1H NMR (400.16 MHz, CD3OD, 323 K): δ
Methyl (Z)-2-Acetamido-3-{2-[1-(tert-butyldiphenylsilyloxyl)-2-
methylpropan-2-yl]-1-(4-methoxybenzyl)-1H-indol-3-yl}acrylate
8780
https://doi.org/10.1021/acs.joc.1c00636
J. Org. Chem. 2021, 86, 8766−8785

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
(10e). Following the procedure for the preparation of N-PMB-
dehydrotryptophans 10, starting from 9e (50 mg, 0.091 mmol)
afforded 45 mg (72%) of 10e as a yellow oil. 1H NMR (400.16 MHz,
CD3OD, 323 K): δ 7.77 (s, 1H), 7.46−7.42 (m, 4H), 7.41−7.32 (m,
3H), 7.24−7.22 (m, 5H), 7.06−6.95 (m, 3H), 6.72−6.67 (m, 4H),
5.36 (s, 2H), 3.88 (s, 2H), 3.80 (s, 3H), 3.69 (s, 3H), 1.73 (s, 3H),
1.49 (s, 6H), 1.01 (s, 9H) ppm. 13C{1H} NMR (100.62 MHz,
CD3OD, 323 K): δ 172.3, 167.2, 160.2, 144.8, 139.4, 136.8 (4×),
134.7, 131.2, 130.8 (2×), 128.7 (4×), 127.8 (2×), 127.7, 126.9, 126.8,
123.1, 121.1, 120.7, 115.1 (2×), 115.0, 111.2, 109.5, 72.8, 55.8, 52.7,
49.9, 41.8, 27.6 (2×), 27.5 (3×), 22.4, 20.1 ppm. FTIR (NaCl): ν
3074 (w, C−H), 2994 (m, C−H), 2922 (m, C−H), 2858 (m, C−H),
1697 (s, CO), 1683 (s, CO), 1513 (s), 1250 (s), 1111 (s), 1086
(s) cm−1. HRMS (ESI) m/z: [M + H]+ calcd for C42H49N2O5Si
689.3405, found 689.3379.
Methyl (Z)-2-Acetamido-3-[2-(2-hydroxypropan-2-yl)-1-(4-me-
thoxybenzyl)-1H-indol-3-yl]acrylate (10f). Following the procedure
for the preparation of N-PMB-dehydrotryptophans 10, starting from
9f (50 mg, 0.17 mmol) afforded 30 mg (41%) of 10f as a brown solid.
Mp: 86−87 °C (hexane/EtOAc). 1H NMR (400.16 MHz, CDCl3): δ
7.58−7.50 (m, 1H), 7.18−7.11 (m, 4H), 6.84−6.76 (m, 4H), 6.19 (br
s, 1H, NH), 5.39 (s, 2H), 3.87 (s, 3H), 3.75 (s, 3H), 3.23 (br s, 1H,
OH), 1.88 (s, 3H), 1.66 (s, 3H), 1.61 (s, 3H) ppm. 13C{1H} NMR
(100.62 MHz, CDCl3): δ 170.7, 169.6, 159.2, 138.9, 137.9, 129.6,
127.5, 126.9 (2×), 126.6, 122.6, 122.5, 120.3, 118.3, 114.5 (2×),
110.6, 102.4, 74.6, 55.4, 53.1, 47.9, 30.6, 28.8, 23.2 (CH3) ppm. FTIR
(NaCl): ν 3500−3100 (s, O−H), 2934 (m, C−H), 2928 (m, C−H),
2837 (m, C−H), 1748 (s, CO), 1672 (s, CO), 1513 (s), 1465
(s), 1248 (s), 1034 (w) cm−1. HRMS (ESI) m/z: [M + H]+ calcd for
C25H29N2O5 437.2071; found 437.2065.
(w), 1274 (s), 1248 (s), 1181 (w), 1132 (w) cm−1. HRMS (ESI) m/
z: [M + H]+ calcd for C28H33N2O6 493.2327; found 493.2333.
Methyl (Z)-2-Acetamido-3-[2-(cyclohex-1-en-1-yl)-1-(4-methoxy-
benzyl)-5-methyl-1H-indol-3-yl]acrylate (10j). Starting from 9j (75
1
mg, 0.23 mmol) afforded 53 mg (50%) of 10j as a foam. H NMR
(400.16 MHz, DMSO-d6, 333 K): δ 9.23 (s, 1H, NH), 7.34 (s, 1H),
7.23 (d, J = 8.2 Hz, 2H), 7.03−6.93 (m, 3H), 6.84 (d, J = 8.7 Hz,
2H), 5.86 (t, J = 3.8 Hz, 1H), 5.26 (s, 2H), 3.70 (s, 3H), 2.36 (s, 3H),
2.24−2.18 (m, 2H), 2.10−2.03 (m, 2H), 1.91 (s, 3H), 1.66−1.61 (m,
4H) ppm. 13C{1H} NMR (100.62 MHz, DMSO-d6, 333 K): δ 168.4,
168.3, 165.6, 158.3, 145.8, 134.9, 133.1, 129.6, 128.6, 128.4, 127.5
(2×), 126.3, 125.2, 123.0, 120.9, 113.8 (2×), 110.4, 106.7, 54.9, 51.5,
46.4, 29.3, 24.8, 22.3, 22.0, 21.0, 20.9 ppm. FTIR (NaCl): ν 2931 (s,
N−H), 2856 (w), 2836 (w), 1710 (s, CO), 1665 (s, CO), 1512
(s), 1415 (s), 1249 (s), 1175 (w), 1035 (w) cm−1. HRMS (ESI) m/z:
[M + H]+ calcd for C29H33N2O4, 473.2412; found 473.2434.
Methyl (Z)-2-Acetamido-3-[1-(4-methoxybenzyl)-1H-indol-3-yl]-
acrylate (12). Following the procedure for the preparation of N-
PMB-dehydrotryptophans 10, starting from 9k (25 mg, 0.071 mmol)
afforded 20 mg (75%) of the desilylated 12. Mp: 180−181 °C
(hexane/EtOAc). 1H NMR (400.16 MHz, DMSO-d6): δ 9.63 (s, 1H,
NH), 7.64 (d, J = 7.9 Hz, 1H), 7.55 (d, J = 8.4 Hz, 1H), 7.30 (s, 1H),
7.20 (t, J = 7.7 Hz, 1H), 7.11 (s, 1H), 7.08 (app t, J = 7.5 Hz, 1H),
6.98 (d, J = 8.4 Hz, 2H), 6.84 (d, J = 8.4 Hz, 2H), 5.51 (s, 2H), 3.68
(s, 6H), 2.08 (s, 3H) ppm. 13C{1H} NMR (100.62 MHz, DMSO-d6):
δ 169.7, 165.7, 159.0, 137.8, 132.4, 130.5, 128.0 (2×), 127.8, 127.1,
123.9, 121.6, 120.7, 119.6, 114.5 (2×), 110.9, 106.4, 55.5, 52.6, 45.7,
23.0 ppm. FTIR (NaCl): ν 3001 (w, C−H), 2925 (s, C−H), 2853 (s,
C−H), 1690 (s, CO), 1674 (s, CO), 1514 (s), 1333 (s), 1251
(s), 1032 (s) cm−1. HRMS (ESI) m/z: [M + H]+ calcd for
C22H23N2O4 379.1652; found 379.1644.
Methyl (Z)-2-Acetamido-3-[2-(cyclohex-1-en-1-yl)-1-(4-methoxy-
benzyl)-1H-indol-3-yl]acrylate (10g). Following the procedure for
the preparation of N-PMB-dehydrotryptophans 10, starting from 9g
(50 mg, 0.158 mmol) afforded 48 mg (67%) of 10g as a solid. Mp:
59−60 °C (hexane/EtOAc). 1H NMR (400.16 MHz, CDCl3): δ
7.57−7.49 (m, 1H), 7.43 (s, 1H), 7.18−7.10 (m, 3H), 6.98−6.90 (m,
3H), 6.80 (d, J = 8.4 Hz, 2H), 5.91 (s, 1H), 5.24 (s, 2H), 3.85 (s,
3H), 3.76 (s, 3H), 2.27−2.19 (m, 2H), 2.14−2.07 (m, 2H), 2.02 (s,
3H), 1.77−1.64 (m, 4H) ppm. 13C{1H} NMR (100.62 MHz,
CDCl3): δ 168.3, 165.9, 158.9, 146.0, 136.9, 134.2, 129.5, 129.3,
127.3 (2×), 126.1, 125.6, 122.3, 121.6, 120.7, 120.6, 114.2 (2×),
110.8, 107.7, 55.3, 52.4, 47.4, 29.7, 25.6, 23.3, 22.6, 21.7 ppm. FTIR
(NaCl): ν 3500−3100 (br, m, N−H), 3006 (m, C−H), 2936 (s, C−
H), 2840 (m, C−H), 1708 (s, CO), 1678 (s, CO), 1513 (s),
1250 (s), 750 (s) cm−1. HRMS (ESI) m/z: [M + H]+ calcd for
C28H31N2O4 459.2278; found 459.2296.
Methyl (Z)-2-Acetamido-3-[2-(tert-butyl)-1-(4-methoxybenzyl)-
5-methyl-1H-indol-3-yl]acrylate (10h). Starting from 9h (60 mg,
0.20 mmol) afforded 46 mg (53%) of 10h as a foam. 1H NMR
(400.16 MHz, CDCl3, 323 K): δ 7.61 (s, 1H), 7.01 (s, 1H), 6.89 (d, J
= 1.2 Hz, 2H), 6.80 (s, 4H), 6.60 (s, 1H), 5.56 (s, 2H), 3.89 (s, 3H),
3.75 (s, 3H), 2.38 (s, 3H), 1.83 (s, 3H), 1.49 (s, 9H) ppm. 13C{1H}
NMR (100.62 MHz, CDCl3, 323 K): δ 165.7, 158.9, 146.3, 136.2,
129.9, 129.8, 128.2, 126.8 (2×), 125.8, 125.7, 123.8, 119.2, 114.1,
114.3 (2×), 110.4, 105.3, 55.4, 52.5, 48.9, 34.7, 32.0 (3×), 23.1, 21.4
ppm. FTIR (NaCl): ν 3327 (s, N−H), 2996 (w), 2955 (w), 2874
(w), 2837 (w), 1719 (s, CO), 1676 (s, CO), 1513 (s), 1249 (s),
1181 (w), 1036 (w) cm−1. HRMS (ESI) m/z: [M + H]+ calcd for
C27H33N2O4 449.2422; found 449.2434.
Methyl (Z)-2-Acetamido-)-3-[2-(tert-butyl)-5-methoxycarbonyl-
1-(4-methoxybenzyl)-1H-indol-3-yl]acrylate (10i). Starting from 9i
(90 mg, 0.26 mmol) afforded 60 mg (48%) of 10i as a foam. 1H NMR
(400.16 MHz, CDCl3, 323 K): δ 7.98 (d, J = 2.3 Hz, 1H), 7.76 (s,
1H), 7.74 (dd, J = 8.6, 1.6 Hz, 1H), 6.98 (d, J = 8.1 Hz, 1H), 6.79−
6.76 (m, 4H), 5.60 (s, 2H), 3.90 (s, 3H), 3.89 (s, 3H), 3.75 (s, 3H),
1.75 (s, 3H), 1.54 (s, 9H) ppm. 13C{1H} NMR (100.62 MHz, CDCl3,
323 K): δ 168.2, 165.7, 159.0, 147.6, 140.5, 132.3, 129.9, 129.2, 128.7,
128.6, 126.8 (2×), 124.8, 123.5, 123.3, 114.4 (2×), 110.4, 55.4, 52.7,
51.9, 49.2, 34.9, 31.8 (3×), 23.1 ppm. FTIR (NaCl): ν 3332 (w, N−
H), 2952 (w), 2919 (w), 2841 (w), 1715 (s, CO), 1513 (w), 1436
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.1c00636.
■
sı
X-ray data; monitoring of reaction progress by HPLC-
MS; copies of 1H NMR and 13C NMR spectra;
computational data (PDF)
Accession Codes
CCDC 1939395 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
■
Corresponding Authors
́
Rosana Alvarez − Departamento de Química Orgánica,
Facultad de Química (CINBIO) and Instituto de
Investigación Biomédica de Vigo (IBIV), Universidade de
Vigo, 36310 Vigo, Spain; orcid.org/0000-0001-5608-
7561; Email: rar@uvigo.es
José M. Aurrecoechea − Departamento de Química Orgánica
e Inorgánica, Facultad de Ciencia y Tecnología, Universidad
del País Vasco UPV/EHU, Apartado 644, 48080 Bilbao,
Spain; orcid.org/0000-0002-1523-4593;
Email: jm.aurrecoechea@ehu.eus
Authors
Belén Vaz − Departamento de Química Orgánica, Facultad de
Química (CINBIO) and Instituto de Investigación Biomédica
de Vigo (IBIV), Universidade de Vigo, 36310 Vigo, Spain
Claudio Martínez − Departamento de Química Orgánica,
Facultad de Química (CINBIO) and Instituto de
8781
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J. Org. Chem. 2021, 86, 8766−8785

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
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Investigación Biomédica de Vigo (IBIV), Universidade de
Vigo, 36310 Vigo, Spain
Francisco Cruz − Departamento de Química Orgánica,
Facultad de Química (CINBIO) and Instituto de
Investigación Biomédica de Vigo (IBIV), Universidade de
Vigo, 36310 Vigo, Spain
J. Gabriel Denis − Departamento de Química Orgánica,
Facultad de Química (CINBIO) and Instituto de
Investigación Biomédica de Vigo (IBIV), Universidade de
Vigo, 36310 Vigo, Spain
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Lett. 2009, 11, 5626−5628.
́
́
Angel R. de Lera − Departamento de Química Orgánica,
(14) Alvarez, R.; Martínez, C.; Madich, Y.; Denis, J. G.;
́
Facultad de Química (CINBIO) and Instituto de
Investigación Biomédica de Vigo (IBIV), Universidade de
Vigo, 36310 Vigo, Spain; orcid.org/0000-0001-6896-
9078
Aurrecoechea, J. M.; de Lera, A. R. A General Synthesis of Alkenyl-
Substituted Benzofurans, Indoles, and Isoquinolones by Cascade
Palladium-Catalyzed Heterocyclization/Oxidative Heck Coupling.
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Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.1c00636
(15) Yip, K. T.; Yang, D. Palladium(II)-Catalyzed Oxidative Cascade
Cyclization Reactions of Anilides and Anilines: Scope and
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(16) Martínez, C.; Aurrecoechea, J. M.; Madich, Y.; Denis, J. G.; de
Notes
́
́
Lera, A. R.; Alvarez, R. Synthesis of Tetrahydrodibenzofuran and
Tetrahydrophenanthridinone Skeletons by Intramolecular Nucleopal-
ladation/Oxidative Heck Cascades. Eur. J. Org. Chem. 2012, 2012,
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors thank the Spanish Ministerio de Economía y
Competitividad (MINECO) (grant number CTQ2012-
37734), Fondos Europeos para el Desarrollo Regional
(FEDER), and the Universidad del País Vasco UPV/EHU
(PES18/89) for financial support. We also thank Universidad
de Vigo for technical support (NMR facilities, HRMS and X-
ray analyses). We are grateful to the Centro de Super-
computación de Galicia (CESGA) for generous allocation of
computing resources.115
(18) She, Z.; Niu, D.; Chen, L.; Gunawan, M. A.; Shanja, X.; Hersh,
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