Mild aminoacylation of indoles and pyrroles through a three-component reaction with ynol ethers and sulfonyl azides

Article abstract of DOI:10.1021/ja5058967

An effective method for aminoacylation of indoles and pyrroles has been achieved. The transformation involves a multicomponent one-pot cascade reaction between indoles or pyrroles, ynol ethers, and sulfonyl azides, creating four different bonds regioselectively through N-sulfonyltriazole intermediates. The oxo-tryptamines and oxo-pyrroloethanamines are generated in moderate to high yields under mild reaction conditions.

Full text of DOI:10.1021/ja5058967

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Communication
Mild Aminoacylation of Indoles and Pyrroles through a Three-
component Reaction with Ynol Ethers and Sulfonyl Azides
Joshua S Alford, and Huw M. L. Davies
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/ja5058967 • Publication Date (Web): 06 Jul 2014
Downloaded from http://pubs.acs.org on July 13, 2014
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Mild Aminoacylation of Indoles and Pyrroles through a Three-
component Reaction with Ynol Ethers and Sulfonyl Azides.
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Joshua S. Alford and Huw M. L. Davies*
Department of Chemistry, Emory University, 1515 Dickey Drive, Atlanta, Georgia, 30322
Supporting Information Placeholder
alkyl triazole counterparts. They decompose thermally at
55 °C in the absence of catalyst to generate a transient do-
nor/acceptor carbene,8 leading to a ready access to cyclo-
propaneamino acids.3 These studies prompted us to explore
the chemistry of 4-alkoxy N-sulfonyltriazoles 8,9 which has
led to the discovery of a novel cascade sequence between
ynol ethers 6, sulfonyl azides 7 and electron rich heterocy-
cles such as indoles 9 and pyrroles 10 (Scheme 2). The
resulting enol ethers 11 and 12 were readily converted to
the amino ketones 13 and 14, resulting in a facile method
for α-aminoacylation of electron rich heterocycles.10,11
ABSTRACT: An effective method for aminoacylation
of indoles and pyrroles has been achieved. The trans-
formation involves a multicomponent one-pot cascade
reaction between indoles or pyrroles, ynol ethers and
sulfonyl azides, creating four different bonds regioselec-
tively through N-sulfonyltriazole intermediates. The
oxo-tryptamines and oxo-pyrroloethanamines are gener-
ated in moderate to high yields under mild reaction con-
ditions.
The metal-catalyzed decomposition of diazo compounds
to generate transient metal carbenes has broad application
in organic synthesis.1 In recent years, donor/acceptor-
substituted metallocarbenes 3 have been extensively stud-
ied because their reactivity is attenuated compared to the
more traditional transient metallocarbenes lacking a donor
group (Scheme 1).2 In order for this chemistry to reach its
full potential, however, a broader range of donor groups
need to be developed. Particularly attractive systems would
be those in which the donor group is amino3 or alkoxy,4 but
these types of carbenes cannot be accessed from preformed
diazo compounds 2 because of their inherent instability.
Therefore, we have become interested in the use of N-
sulfonyltriazoles 4, which Fokin, Gevorgyan and Muraka-
mi have shown could be used as alternative precursors to
rhodium carbenes 5 in the presence of an appropriate dir-
hodium tetracarboxylate catalyst.5 Since these initial stud-
ies, a majority of the work with N-sulfonyltriazoles has
centered on the use of 4-aryl or 4-alkyl N-sulfonyltriazoles
as carbene precursors.6,7 We have been intrigued by the
possibility of developing new chemistry of N-
sulfonyltriazoles by incorporation of other types of donor
groups into the N-sulfonyltriazole scaffold.
Scheme 1: Donor/Acceptor Metallocarbenes
[MLn]
N2
N3-R2
base
MLn
EDG
EWG
EDG
EWG
EDG
EWG
1
2
3
N2
EDG = aryl, alkenyl, alkyl stable; OR, NR2 unstable
[MLn]
N
N2
N
MLn
N2
Δ
N
SO2R1
SO2R1
N
SO2R1
N
EDG
EDG
EDG
4
4'
5
EDG = aryl, alkenyl, alkyl, OR, NR2 stable
Scheme 2: Acylation Variant for Indoles and Pyrroles
N3 SO2R2
R1O
7
6
Cu(I)
R1O
R1O
N
R3
N
R3
H
N
N
N
N
10
9
SO2R2
SO2R2
N
R3
N
R1O
Δ
Δ
R2O2S
H
N
8
11
R3
12
N-Sulfonyltriazole
intermediate
Pyrrole Amino
Acylation
Indole Amino
Acylation
H3O+
-HOR1
SO2R2
H3O+
-HOR1
O
O
H
N
H
N
R2O2S
In our early exploratory studies to expand the range of N-
sulfonyl triazole derivatives, we showed that 4-alkenyl tria-
zoles underwent a formal [4+3] cycloaddition with dienes7f
and an electrocyclization reaction to provide fused pyrroles
and substituted indoles.7g The stability of the N-
sulfonyltriazole was found to be greatly influenced by the
N
R3
N
R3
14
13
Four New Bonds Regioselectively Introduced
Into the Alkyne Backbone
We began our investigations with the synthesis of vari-
ous 4-alkoxy-1-sulfonyl triazoles 8 from the corresponding
sulfonyl azides 7 and commercially available or easily pre-
nature of the C(4) substituent.3
4-Phthalimido N-
sulfonyltriazoles are more labile than their 4-aryl and 4-
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pared ynol ethers 6.12,13 These electron rich triazoles were
was observed. This reaction was found to be less sensitive
1
2
3
4
5
6
7
8
submitted to a metal-free thermal denitrogenative reaction
with indole 9a at 0.2 mmol scale under microwave irradia-
tion in which rapid evolution of gas occurred and the reac-
tion proceeded to completion within 15 min. The interme-
diate enol ether product 11 was subsequently hydrolyzed in
situ to provide the α-amino ketone product (see Table 1). A
range of alkoxy and phenolic substituents were compatible
with the reaction as well as many different sulfonyl groups
including the easily deprotected SES group (13c, entry 5).
The reaction can also be conducted at larger scale (5.0
mmol) using conventional heating conditions at 70 °C with
similar performance (entry 4).
to steric effects as both bulkier sulfonyl groups (e.g. 1-Ts,
16b and 18b) and substituents at C(2) were tolerated.7e At-
tempted hydrolysis of the enol ether 16a and 16b failed to
provide the desired pyrroloindolone products.14
Table 2. Scope of Indole Componenta
CuTC, 0 °C, 4h
then 80 °C/MW
1,2-DCE, 15 min
O
H
N
R2
N
R1
R3
Ms
R3
PhO
6c
then
Amberlyst 15
50 °C, 2-4 h
9
9
N
R1
R2
10
11
12
13
14
15
16
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N3 Ms
13
7a
1
2
3
O
O
H
O
H
N
H
N
N
Ms
Ms
Ms
Table 1. Scope of the Oxygen Surrogatea
N
N
N
Me
Bn
H
13a
87% yield
13d
71% yield
13e
57% yield
O
80 °C/MW
1,2-DCE, 15 min
H
N
(79% yield)b,c
N
N
4
5
6
SO2R2
SO2R2
N
Br
MeO
Me
R1O
then
Amberlyst 15
N
N
O
H
O
H
O
H
8
9a Me
13
Me
N
N
N
Ms
Ms
Ms
N
R1
Et
-SO2R2
Ms
product 14
N
N
entry triazole 8
% yieldb
Me
Me
Me
13f
80% yield
13g
83% yield
13h
86% yield
1
2
3
4
8a
13a
53
83
8b
8c
Et
Ts
13b
13a
7
8
9
81
Cy
Ms
O
H
O
H
O
H
91(87)b
N
N
N
8d
8e
Ph
Ph
Ms
13a
13c
Ms
Ms
Ms
TMS
5
6
7
84
90
87
Me
N
N
N
Me
Ph
8f
Ph
Ts
13b
13a
Me
Me
Me
13i
89% yield
13j
83% yield
13k
71% yield
8g
2-Naph
Ms
aTriazole 8 (0.20 mmol, 1.0 equiv) and indole 9a (0.30 mmol, 1.5
equiv) were combined in solvent (2.0 mL) and heated at 80 ºC for
15 min; then Amberlyst 15 was added and heated at 50 ºC for 2-4
10
11
MeO
12
Br
Me
O
H
O
H
O
H
N
N
N
Ms
Ms
Ms
b
h. Isolated yields. Reaction was conducted under conventional
N
N
N
Me
Me
Me
heating at 70 ºC for 12 h on a 5.0 mmol scale.
Me
Me
Me
13l
78% yield
13m
84% yield
13n
88% yield
aYnol ether 6c (0.24 mmol, 1.2 equiv), MsN3 (0.20 mmol, 1.0
equiv), CuTC (0.006 mmol, 0.03 equiv), and indole 9 (0.40 mmol,
2.0 equiv) were combined in solvent (2.0 mL) and stirred at 0 ºC
for 4 h, then heated at 80 ºC for 15 min. Amberlyst 15 was added
The next series of experiments were directed towards de-
termining whether a one-pot, three-step procedure was fea-
sible starting with the ynol ether, indole, and sulfonyl az-
ide. A mixture of ynol ether 6c, indole 9 and mesyl azide
7a was stirred at 0 °C for 4 h in the presence of CuTC
(copper(I) thiophene-2-carboxylate; 3 mol%), then warmed
to 80 °C for 15 min under microwave irradiation, which
was followed by the addition of Amberlyst 15 to provide
the hydrolyzed product 13. As shown in Table 2, a broad
range of indole derivatives reacted to provide the corre-
sponding aminoacylated products in good to excellent
yields. An evaluation of the substituents on the indolic ni-
trogen revealed that N-H, N-alkyl, and N-benzyl are com-
patible with this transformation (13a,13d-e, entries 1-3);
however, electron-withdrawing groups on the indolic nitro-
gen are not tolerated (e.g. 1-Ts, 1-Boc). An array of elec-
tron-rich and electron-deficient indoles substituted at C(5)
or C(7) of the indolic core also provided the corresponding
aminoacylated products in excellent yields (13f-i, entries 4-
7). The reaction was found to be applicable to a range of
C(2)-alkyl and aryl indoles as well (13j-n, entries 8-12).
b
and heated at 50 ºC for 2-4 h. Isolated yields. Reaction was con-
ducted under conventional heating at 70 ºC for 4 h on a 12.0
mmol scale. cTsOH hydrate (30 mol%) used for hydrolysis.
Scheme 3: Reaction with C(3)-Substituted Indoles
R1O
Me
Me
80 °C/MW
CHCl3, 15 min
N
N
N
N
SO2R2
SO2R2
R1O
N
H
N
Me
Me
Me
16a: R1 = Ph, R2 = Ms; 93% yield
16b: R1 = Et, R2 = Ts; 86% yield
8
15
R1O
Me
80 °C/MW
CHCl3, 15 min
N
N
N
SO2R2
Me
N
SO2R2
R1O
N
N
Me
Me
Me
8
17
18a: R1 = Ph, R2 = Ms; 67% yield
18b: R1 = Et, R2 = Ts; 71% yield
Further investigation into substituted indoles with C(3)-
substituents revealed that these were also reactive sub-
strates; however, instead of the expected C(2)-acylated
product, the dearomatized [3+2] annulation product 16a
The amino acylation reaction was also applicable to elec-
tron-rich pyrroles giving either the C(2) or C(3) amino ac-
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Journal of the American Chemical Society
ylated products as shown in Table 3. Starting from 4- indole moiety. Hydrolysis of the enol ether leads to the
1
2
3
4
5
6
7
8
phenoxy-1-sulfonyl triazoles 8d,f, a range of pyrrole deriv-
atives 5 reacted under metal-free thermal conditions to pro-
vide the corresponding amino acylated products 14 in mod-
erate to excellent yields. Similar to the results with indole
derivatives, N-H, alkyl and aryl are well tolerated, but pyr-
roles with electron withdrawing groups failed to provide
the desired products. The use of the bulkier sulfonyl group
is also well tolerated (14b, entry 2) as well as various sub-
stitutions of the pyrrole (entries 3-5). Interestingly, both
the starting pyrrole derivatives in entries 3 and 4 can be
derived from N-sulfonyl triazoles,7g,o further showcasing
the applicability of the N-sulfonyl triazole chemistry. Last-
ly, the C(3) aminoacylated product 14f is obtained when
both the C(2) and C(5) positions of the pyrrole derivative
are substituted (entry 6).
amino acylated product 13a. We have proposed a similar
initial cyclopropanation step with C(3)-substituted indoles
in our previous studies on [3+2] annulation with 4-aryl N-
sulfonyltriazoles.7e It is presumed that a similar mechanism
operates with electron-rich pyrroles.
In summary, we have developed an efficient method for
aminoacylation of indoles and pyrroles through 4-alkoxy
N-sulfonyltriazole intermediates from readily available
starting materials. The oxo-tryptamine and oxo-
pyrroloethanamine products are synthesized in a multicom-
ponent one-pot cascade reaction. As previously observed
with amino-substituted triazoles, the alkoxy-substituted
triazoles undergo nitrogen extrusion under relatively mild
conditions without requiring the use of a dirhodium cata-
lyst. These studies further demonstrate that meal free do-
nor/acceptor carbenes are capable of selective high-
yielding transformations.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
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29
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34
35
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40
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42
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60
Table 3. Scope of Pyrrole Componenta
R6
R6
R5
N
N
O
80 °C/MW
1,2-DCE, 15 min
N
H
N
R4
Scheme 4: Proposed Mechanistic Pathways
SO2R2
SO2R
N
R5
PhO
then
Amberlyst 15
50 °C, 2-4 h
R4
14
R3
N
R3
8d,f
10
N
Ms
1
2
3
O
PhO
PhO
O
O
H
A
N
N
N
H
N
H
N
PhO
6c
N2
Δ
Cu(I)
N
Ms
N
Ms
Ms
Ms
Ts
Ph
PhO
PhO
N
N
N
•
N
N2
Ms
8d
Me
Me
14a
Me
8d'
A'
N3 Ms
Ms
14b
89% yield
14c
68% yield
93% yield
N
H
4
5
6
Friedel-
Crafts
pathway
MsHN
O
H
O
O
OPh
H
N
H
N
OPh
N
H3O+
-HOPh
Ms
Ms
Ms
Me
13a
pathway
A
N
N
N
N
Me
Me
Me
N
MeO2C
Me
Ph
B
Me
11a
14d
84% yield
14e
82% yield
14f
86% yield
MsN
cyclopropa-
nation
pathway
NMs
OPh
aTriazole 8 (0.20 mmol, 1.0 equiv) and pyrrole 10 (0.30 mmol, 1.5
equiv) were combined in solvent (2.0 mL) and heated at 80 ºC for
15 min; then Amberlyst 15 was added and heated at 50 ºC for 2-4
h. Isolated yields.
H
H
OPh
pathway
B
N
N
H
Me
Me
D
C
A proposed mechanism for the one-pot formation of the
amino acylated product 13a from alkyne 6c and indole 9a
is depicted in Scheme 4. Initially, a copper(I)-catalyzed
cycloaddition reaction of the alkoxy alkyne 6c with mesyl
azide occurs, resulting in the formation of 4-alkoxy-1-
mesyl triazole 8d.11b Subsequent microwave irradiation
causes the triazole to isomerize to the α-diazo imine 8d’
which then undergoes a thermal nitrogen extrusion furnish-
ing the resonance-stabilized carbene intermediate A.4,9,15 At
this point, there are two possible reaction pathways. In
pathway A, the intermediate A is engaged by the electron-
rich indole derivative at C(3) in a Friedel-Crafts-type sub-
stitution to furnish the zwitterionic intermediate B, fol-
lowed by a subsequent re-aromatization of the indole moie-
ty to form enol ether 11a. However, with the observation of
the formal [3+2] product 16a, we propose that intermediate
A undergoes a thermal cyclopropanation reaction with the
electron-rich indole (intermediate C, pathway B).3,7e,16 An
immediate ring opening of the strained cyclopropylindoline
intermediate leads to intermediate D, which tautomerizes to
the enol ether 11a with subsequent re-aromatization of the
ASSOCIATED CONTENT
Synthetic detail and spectral data. This material is available
free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
hmdavie@emory.edu
Notes
No competing financial interests have been declared.
ACKNOWLEDGMENT
This work was supported by the National Science Founda-
tion (CHE 1213246).
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(14) Hydrolysis resulted in the cleavage of the N,N-aminal bond
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(15) Examples of thermally induced diazo decompositions: a)
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4284-4287; b) Hansen, S. R.; Spangler, J. E.; Hansen, J. H.; Davies,
H. M. L. Org. Lett., 2012, 14, 4626-4629.
(16) When the 4-phenoxy-1-mesyltriazole was warmed in the pres-
ence of styrene, a cyclopropane product was formed in moderate yield
(66%), but low d.r. (7:3).
(3) Alford, J. S.; Davies, H. M. L. Org. Lett., 2012, 14, 6020-6023
(4) A single example of a methoxytrifluoromethylcarbene derived
from 3-methoxy-3-trifluoromethyldiazirine has been reported, see:
Moss, R. A.; Zdrojewski, T.; Ho, G. J. Chem. Soc., Chem. Commun.
1991, 946-947.
(5) a) Chuprakov, S; Hwang, F. W.; Gevorgyan, V. Angew. Chem.
Int. Ed., 2007, 46, 4757-4759; b) Horneff, T.; Chuprakov, S.;
Chernyak, N.; Gevorgyan, V.; Fokin, V. V. J. Am. Chem. Soc., 2008,
130, 14972-14974; c) Miura, T.; Yamauchi, M.; Murakami, M.;
Chem. Commun., 2009, 1470-1471.
(6) For reviews, see: a) Chattopadhyay, B.; Gevorgyan, B. Angew.
Chem., Int. Ed., 2012, 51, 862-872; b) Gulevich, A. V.; Gevorgyan,
V. Angew. Chem., Int. Ed., 2013, 52, 1371-1373; c) Davies, H. M. L.;
Alford, J. S. Chem. Soc. Rev., 2014, Advance Article DOI:
10.1039/c4cs00072b.
(7) For recent examples, a) Zibinsky, M.; Fokin, V. V. Angew.
Chem. Int. Ed., 2013, 52, 1507-1510; b) Parr, B. T.; Green, S. A.;
Davies, H. M. L. J. Am. Chem. Soc., 2013, 135, 4716-4718; c)
Schultz, E. E.; Sarpong, R. J. Am. Chem. Soc., 2013, 135, 4696-4699;
d) Chuprakov, S.; Kwok, S. W.; Fokin, V. V. J. Am. Chem. Soc.,
2013, 135, 4652-4655; e) Spangler, J. E.; Davies, H. M. L. J. Am.
Chem. Soc., 2013, 135, 6802-6805; f) Parr, B. T.; Davies, H. M. L.
Angew. Chem. Int. Ed., 2013, 52, 10044-10047; g) Alford, J. S.;
Spangler, J. E.; Davies, H. M. L. J. Am. Chem. Soc., 2013, 135,
11712-11715; h) Miura, T.; Hiraga, K.; Biyajima, T.; Nakamuro, T.;
Murakami, M. Org. Lett., 2013, 15, 3298-3301; i) Miura, T; Tanaka,
Hiraga, K.; Stewart, S. G.; Murakami, M. J. Am. Chem. Soc., 2013,
135, 13652-13655; j) Shi, Y.; Gevorgyan, V. Org. Lett., 2013, 15,
5394-5396; k) Chuprakov, S.; Worrell, B. T.; Selander, N.; Sit, R. K.;
Fokin, V. V. J. Am. Chem. Soc., 2014, 136, 195-202; l) Miura, T.;
Funakoshi, Y.; Murakami, M J. Am. Chem. Soc., 2014, 136, 2272-
2275; m) Kwok, S. W.; Zhang, L.; Grimster, N. P.; Fokin, V. V.
Angew. Chem. Int. Ed., 2014, 53, 3452-3456. n) Boyer, A. Org. Lett.,
2014, 16, 1660-1663; o) Kim, C.; Park, S.; Eom, D.; Seo, B.; Lee, P.
H. Org. Lett., 2014, 16, 1900-1903; p) Jung, D. J.; Jeon, H. J.; Kim, J.
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Indole
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Indole
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aminoacylation
14 examples
57-91% yield
SO2R2
R1O
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Cu(I)
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H
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Pyrrole
SO2R2
aminoacylation
6 examples
68-93% yield
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Pyrrole
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