Direct N- sec -Alkylation of Amides by Reaction of α-Halohydroxamates and Sulfonylindoles: An Approach to 3-Indolyl Methanamines

Article abstract of DOI:10.1055/s-0037-1611754

A catalyst-free, base-mediated N- sec -alkylation of amides by reaction of sulfonylindoles and α-halohydroxamates has been developed. The N- sec -alkylation of amides reaction is based on an intermolecular nucleophilic addition of vinylogous imine with N

Full text of DOI:10.1055/s-0037-1611754

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© Georg Thieme Verlag Stuttgart · New York
2019, 30, A–F
letter
A
en
Y. Chen et al.
Letter
Synlett
Direct N-sec-Alkylation of Amides by Reaction of -Halohydroxam-
ates and Sulfonylindoles: An Approach to 3-Indolyl Methanamines
Yuan Chena,b
O
Xiaoqiang Guoa
Chuang Zhoua
Lianmei Chena
Tairan Kang*a,b
R1
PhO2S
N
R1
R3
Na2CO3
O
OR4
1,4-dioxane
OR4
N
R2
+
R3
R2
H
80 °C
N
Br
0
0
0
0-0
0
0
1-6
8
5
1-
2
9
6
7
N
H
H
22 examples
up to 92% yield
containing an acrylamide group
polyfunctional indole
a College of Pharmacy and Biological Engineering, Chengdu
University, Chengdu City 610106, P. R. of China
b College of Chemistry and Chemical Engineering, China West
Normal University, Nanchong City 637002, P. R. of China
kangtairan@sina.com
Received: 29.11.2018
Accepted after revision: 20.02.2019
Published online: 28.03.2019
mary halides could provide amides in good yields, the
yields of the desired amides are very poor when inactivated
secondary halides are used as substrate.6 In 2014, a break-
through study was reported by Peters, Fu and co-workers,
in which a copper-catalyzed coupling of amides with sec-
ondary alkyl bromides and iodides provided N-sec-alkyla-
tion amides in good yield (Scheme 1a).7 Therefore, the de-
velopment of an efficient method to give N-sec-alkylation
of amide is a worthwhile objective.7
DOI: 10.1055/s-0037-1611754; Art ID: st-2018-v0776-l
Abstract A catalyst-free, base-mediated N-sec-alkylation of amides by
reaction of sulfonylindoles and -halohydroxamates has been devel-
oped. The N-sec-alkylation of amides reaction is based on an intermo-
lecular nucleophilic addition of vinylogous imine with N-(benzyl-
oxy)meth-acrylamide/azaoxyallyl cations formed in situ and represents
a simple way to give polyfunctionalized 3-indolyl methanamines in
good to excellent yields.
Previous work
Key words 3-indolyl methanamines, azaoxyallyl cations, vinylogous
imine, sulfonylindoles, -halohydroxamates
O
R1
O
R1
(a)
(b)
copper-catalyzed
photoinduced
+
R
N
H
R2
R
NH2
X
R2
X = Br, I; R1, R2, = alkyl
R1
3-Indolyl methanamine derivatives are widely found in
many natural and unnatural products with unique biologi-
cal activities.1 They are also important building blocks for
constructing complex molecules.1 Thus, the synthesis of 3-
indolyl methanamine derivatives has attracted attention
during the past years.2 The most prominent approach to 3-
indolyl methanamine relies on the Lewis or Brønsted acid
catalyzed Friedel–Crafts reaction of imines with indoles.3
However, alkyl imine is usually ineffective for this Friedel–
Crafts reaction because it can tautomerize to the corre-
sponding enamine.3 Frequently, the competing bisindole
by-product limits the versatility of these strategies.3 There-
fore, the development of an efficient method to synthesize
3-indolyl methanamines is of importance.
During recent years, metal-catalyzed methods for C–N
bond formation, such as Buchwald–Hartwig couplings,4 ole-
fin hydroamination and reductive amination,5 have been
fully developed. However, there are few reports of N-sec-al-
kylation of amides with electrophiles. The N-alkylation re-
action (formation of a Csp3–N bond) between an amide and
an alkyl halide is a classic method for providing functional
amides through a substitution process (SN2). Although pri-
R1
O
O
Na2CO3
HFIP
OBn
N
N
+
N
H
N
R2
OBn
Br
R2
This work
O
OBn
R
N
O
O
H
BnO
R
Br
standard
conditions
Na2CO3
1,4-dioxane
N
R
(c)
+
N
OBn
PhO2S
X
cyclization
N
N
H
N
22 examples
85–92% yield
expected
H
Scheme 1 Reaction of amide with alkyl halide or indole derivatives
As a versatile 1,3-dipole, the azaoxyallyl cation generat-
ed in situ from -bromohydroxamate has been widely ap-
plied to synthesize various heterocycles.8,9 Jeffrey,8a Wu,8b
and Liao8c realized [3+2] cycloaddition reactions between
© Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–F

B
Y. Chen et al.
Letter
Synlett
electron-rich 3-substituted indoles and azaoxyallyl cations
to construct pyrroloindolines, respectively (Scheme 1b). Jef-
frey’s group developed aza-[4+3] annulation of azaoxyallyl
cation intermediates with electron-rich dienes for synthe-
sizing seven-membered heterocycles.9a–d Chen realized
[3+1] or [3+2] cycloaddition reactions between azaoxyallyl
cations and electron-rich sulfur ylides for the synthesis of
-lactams and -lactams.9f Wu and Xia also described a
base-mediated [3+3] cycloaddition reaction of azaoxyallyl
cations with electron-rich isoquinoline N-oxides.9g Very re-
cently, Huang and Lin reported that a new [3+3] cycloaddi-
tion reaction between azaoxyallyl cations and electron-rich
2-alkenylindoles provided tetrahydro--carbolinones in
good yields.9h
Cycloaddition reactions between the electron-deficient
reactants and azaoxyallyl cations have also been reported
during recent years. In 2016, the groups of Lin10a and Jef-
frey,10b respectively, reported a [3+2] cycloaddition reaction
of the electron-deficient carbonyl reactant with azaoxyallyl
cations. In 2018, the group of Jiang and Zhu reported a pal-
ladium-catalyzed coupling reaction between N-tosylhydra-
zones and electron-deficient benzo-1,2-quinones leading to
the formation of two C–O bonds on the carbenic carbon.10c
The electron-deficient vinylogous imines are usually gener-
ated in situ from sulfonylindoles by leaving the sulfonyl
group in situ under basic conditions, and has intriguing po-
tential for organic synthesis.11 We envisioned that a cyc-
loaddition reaction of vinylogous imines with azaoxyallyl
cations might occur to provide 3,3-spiroindolines (for a pos-
sible mechanism, see Scheme 4 below). To our disappoint-
ment, the reaction of -bromohydroxamates with sulfo-
nylindoles stopped at the aza-Michael step, and only 3-in-
dolyl methanamines were obtained in the course of the
experiment (Scheme 1c). The development of new cycliza-
tion strategies making use of the 3-indolyl methanamines
is ongoing in our laboratory. To our knowledge, the azaoxy-
allyl cations being employed as a nucleophile reagent has
not been reported to date. Herein, we report a metal-free
N-alkylation reaction between -bromohydroxamates and
sulfonylindoles to synthesize 3-indolyl methanamines
bearing an acrylamide group, which could be used for di-
verse transformation in organic synthesis.12
Table 1 Optimization of Reaction Conditionsa
O
PhO2S
Ph
Ph
O
N
base, solvent
OBn
OBn
+
temp
N
H
N
H
Br
2a
N
H
3a
1a
Entry
Base
Solvent
T (°C)
Yield (%)b
1
2
Et3N
TFE
25
25
60
60
60
60
60
60
60
60
60
80
10
15
20
26
35
41
47
62
55
46
27
91
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
K2CO3
HFIP
TFE
3
4
HFIP
5
isopropanol
MeCN
6
7
toluene
8
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
9
10
11
12
Cs2CO3
NaOtBu
Na2CO3
a Reaction conditions: 1a (0.1 mmol, 1.0 equiv), 2a (0.15 mmol, 1.5 equiv),
base (0.3 mmol, 3.0 equiv) in solvent (1 mL) for 8 h.
b Isolated yield.
and 26% yields, respectively (entries 3 and 4). Better results
(35–62% yield of 3a) were obtained when the solvent was
changed to isopropanol, MeCN, toluene, or 1,4-dioxane (en-
tries 5–8). The best choice was 1,4-dioxane (62% yield, en-
try 8). When the base Na2CO3 was replaced with K2CO3,
Cs2CO3 or NaOtBu in 1,4-dioxane solvent, no better results
were obtained (entries 9–11). To our delight, the best result
(91% yield of 3a) was obtained by increasing the tempera-
ture from 60 to 80 °C for 8 hours (entry 12).
With the optimized conditions in hand, a range of sulfo-
nylindoles 1 were examined. The results are summarized in
Table 2. Generally, in these 2-methyl substituted sulfonylin-
doles 1a–l, R1 could be different substituents with aryl and
alkyl groups (entries 1–12).14 Those substrates with elec-
tron-withdrawing (CN, NO2) and electron-donating (MeO)
group at the 4-position of the substituted phenyl ring (R1)
had no effect on this transformation, and the products 3b–d
were obtained in good to excellent yields (89–90%, entries
2–4). Both ortho- and meta-substituted phenyl (R1) were
well tolerated to give the products 3e–i in good yields (87–
92% yield, entries 5–9). Notably, substrates with heteroaro-
matic groups (R1), such as 2-thienyl and 3-pyridyl, could
also provide the desired products 3j, 3k in 87% and 90%
yields (entries 10 and 11). Fortunately, alkyl substituted
(R1) sulfonylindole was also tolerated, giving 3l in satisfac-
tory yield (entry 12). In addition, the R2 group with various
electronic nature (Cl, Br, Me or MeO) at different positions
At the outset of this project, a model reaction of 2-
methyl substituted sulfonylindole 1a (1.0 equiv) with -
bromohydroxamate 2a (1.5 equiv) at room temperature
was initially studied under Föhlisch’s,13 Jeffrey’s,8a and
Wu’s8b conditions {[Et3N, trifluoroethanol (TFE)] or [Na2CO3,
hexafluoroisopropanol (HFIP)]}. Only the 3-indolyl meth-
anamine 3a containing an acrylamide group was obtained
in very low yield (Table 1, entries 1 and 2, <15% yield), and
the pyrroloindoline products reported in the previous
works8 were not observed. Increasing the reaction tem-
perature from 25 to 60 °C, using Na2CO3 as base in TFE or
HFIP, the 3-indolyl methanamine 3a was obtained in 20%
© Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–F

C
Y. Chen et al.
Letter
Synlett
Table 2 Reactions of Sulfonylindoles with -Bromohydroxamate 2aa
We explored the scope of the reaction with -halohy-
droxamates 2 (Table 3). Replacing the benzyl group with
methyl or ethyl groups (2b, 2c), the desired 3-indolyl meth-
anamines 4a and 4b were delivered in 89% and 88% yield,
respectively. The -bromohydroxamate with a methyl
group (2d) also provided 4c in 90% yield.
O
R1
PhO2S
R1
N
O
4
Na2CO3
OBn
R3
OBn
N
H
+
R3
R2
R2
6
1,4-dioxane
80 °C
Br
N
N
H
H
Table 3 Substrate Scope of the Reaction with -Halohydroxamate 2a
1a–s
2a
3a–s
Entry
R1
R2
R3
3
Yield (%)b
O
Ph
Ph
SO2Ph
+
R2
O
1
2
Ph
4-CNC6H4
H
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
H
3a
91
90
89
90
89
92
92
90
87
87
90
87
85
86
91
86
86
91
89
N
Na2CO3
OR3
R1
R2
OR3
H
3b
3c
3d
3e
3f
N
1,4-dioxane
80 °C
H
N
X
3
4-NO2C6H4
4-OMeC6H4
3-ClC6H4
H
H
N
H
1a
2
4
4
H
5
H
-Halohydroxamate 2
Product
Yield (%)b
6
3-MeC6H4
2-ClC6H4
H
O
7
H
3g
3h
3i
Ph
O
N
8
2-CNC6H4
H
OMe
NHOMe
Br
9
3,4,5-(OMe)3 C6H2
H
N
H
10
11
12
13
14
15
16
17
18
19
2-thienyl
3-pyridyl
propyl
Ph
H
3j
H
3k
3l
2b
4a
4b
4c
89
88
90
H
O
4-Cl
5-Br
6-Cl
7-Br
7-Me
4-Br
5-OMe
3m
3n
3o
3p
3q
3r
O
Ph
N
Ph
H
OEt
NHOEt
Br
Ph
H
N
H
Ph
H
Ph
H
2c
Ph
Me
Me
O
Ph
3s
Ph
O
N
a Reaction conditions: 1 (0.1 mmol, 1.0 equiv), 2a (0.15 mmol, 1.5 equiv),
Na2CO3 (0.3 mmol, 3.0 equiv) in 1, 4-dioxane (1 mL) at 80 °C for 8–12 h.
b Isolated yield.
OBn
NHOBn
Br
N
H
2d
a Reaction conditions: sulfonylindole 1a (0.1 mmol, 1.0 equiv), -halohy-
droxamate 2 (0.15 mmol, 1.5 equiv), Na2CO3 (0.3 mmol, 3.0 equiv) in 1,4-
dioxane (1 mL) at 80 °C for 8–12 h.
(4, 5, 6 and 7) of the indole core had no apparent effect on
the yield of 3m–s (85–91% yields, entries 13–19), irrespec-
tive of R3 being a hydrogen or methyl group. The relative
configuration of 3g was determined unambiguously by X-
ray crystallography (Figure 1, see Supporting Informa-
tion).15
b Isolated yield.
This reaction could be carried out on a multigram scale.
The product 3a (1.74 g) and 3g (1.80 g) were afforded in 85%
and 81% yield, respectively (Scheme 2, see the Supporting
Information for details).
To gain insight into the mechanism, a number of control
experiments were carried out (Scheme 3). No desired prod-
uct was detected when the N-Boc protected arenesulfo-
nylindole was employed under the standard conditions
(Scheme 3a), which suggested that the reaction mechanism
is not an SN2 substitution process. Although the -halohy-
droxamates can be transformed into the corresponding
product N-(benzyloxy)methacrylamide in 95% yield under
the standard conditions (Scheme 3b), the aza-Michael addi-
tion reaction between the N-(benzyloxy)methacrylamide
O
N
Cl
OBn
N
H
3g
CCDC 1546337
Figure 1 Relative configuration of compound 3g
© Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–F

D
Y. Chen et al.
Letter
Synlett
R
PhO2S
O
Ph
O
PhO2S
standard
conditions
OBn
N
O
N
Na2CO3
OBn 1,4-dioxane
80 °C
+
R
(a)
H
no desired product
95% yield
OBn
Br
N
+
N
Boc
H
N
Br
O
N
O
H
H
standard
conditions
(b)
OBn
OBn
Ph
1
2a
3
N
H
N
H
Br
R = H 3a 1.74 g (85%)
= Cl 3g 1.80 g (81%)
5 mmol
7.5 mmol
PhO2S
standard
conditions
O
Scheme 2 Gram-scale experiments
OBn
(c)
(d)
3a 35% yield
+
N
H
12 h
N
H
and arenesulfonylindole 1a resulted in the 3-indolyl meth-
anamine 3a only in 35% yield under the standard conditions
(Scheme 3c). The -bromohydroxamate with an electron-
donating group (-OBn) replacing a benzyl (-Bn) group failed
to transform the corresponding N-benzylmethacrylamide
(Scheme 3d) and failed to react with the arenesulfonylin-
dole (Scheme 3e). Using acetamide, N-methylacetamide,
benzamide, and N-methylbenzamide as substrates, it was
found that they failed to react with -halohydroxamates
under the standard conditions (Scheme 3e). The reactions
(Scheme 3b–e) indicate that the electron-donating group
(-OBn) plays a key role in realizing this aza-Michael addi-
tion reaction.
O
O
standard
conditions
not obtained
Bn
Bn
N
H
N
H
Br
O
Bn
standard
conditions
N
H
PhO2S
Br
no desired product
(e)
Ph
or
O
+
R1 = CH3 or Ph
R2 = H or Bn
R2
R1
N
N
H
H
Scheme 3 Control experiments
Based on the previous work,8,11 a plausible mechanism
is proposed as illustrated in Scheme 4. The sulfonyl group of
1a acts as a leaving group under basic conditions, which en-
ables the formation of vinylogous imines intermediates A.
The azaoxyallyl cation B is formed from -bromohydrox-
amate 2a under the basic conditions. Subsequently, from B,
two pathways are possible: (a) a zwitterionic intermediate
C, which is generated from B, reacts with vinylogous imines
Ph
Ph
SO2Ph
base
N
N
H
1a
vinylogous imine A
O
proton
migration
OBn
N
2a
Br
H
3a
path a
O
Ph
OBn
N
OBn
base
–HBr
N
O
N
O
cyclization
X
Ph
A
OBn
path a
N
O
N
OBn
C
E
N
spiro[indole-3,3'-
pyrrolidin]-5'-ones
azaoxyallyl
cation B
protonation
O
3a
path b
OBn
O
A
Ph
N
O
N
OBn
H
BnO
path b
N
D
cyclization
X
Ph
N
F
N
spiro[indole-3,3'-
piperidin]-6'-ones
Scheme 4 Possible mechanism for the cycloaddition reaction.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–F

E
Y. Chen et al.
Letter
Synlett
A to give the intermediate E through an aza-Michael addi-
tion process, subsequently affording 3a by a proton migra-
tion. (b) An aza-Michael addition reaction between the N-
(benzyloxy)methacrylamide D, formed from azaoxyallyl
cation B in situ, and vinylogous imines A occurs to give in-
termediate F, affording 3a through a protonation process.
Unfortunately, the cyclization of intermediate E or F to pro-
vide 3,3-spiroindolines such as spiro[indole-3,3′-pyrroli-
din]-5′-ones or spiro[indole-3,3′-piperidin]-6′-ones did not
occur under the standard conditions. Development of new
cyclization strategies making use of these 3-indolyl meth-
anamines is ongoing in our laboratory.
In conclusion, a new procedure involving an N-sec-al-
kylation of amides using sulfonylindoles and -halohydrox-
amates has been successfully developed. This protocol
paves the way to synthesize 3-indolyl methanamines bear-
ing an acrylamide group, which could be transformed into a
diverse array of products via different chemoselective pro-
cesses12 in good to excellent yields. We believe that this N-
sec-alkylation of amides will be widely used in organic syn-
thesis.
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Funding Information
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25. (b) Kikugawa, Y.; Shimada, M.; Kato, M.; Sakamoto, T. Chem.
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1825. (e) Barnes, K. L.; Koster, A. K.; Jeffrey, C. S. Tetrahedron
Lett. 2014, 55, 4690. (f) Li, C.; Jiang, K.; Ouyang, Q.; Liu, T.-Y.;
Chen, Y.-C. Org. Lett. 2016, 18, 2738. (g) An, Y.; Xia, H.; Wu, J.
Chem. Commun. 2016, 10415. (h) Zhang, K.; Xu, X.; Zheng, J.;
Yao, H.; Huang, Y.; Lin, A. Org. Lett. 2017, 19, 2596. (i) Zhao, H.-
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We are grateful for financial support from the National Natural Sci-
ence Foundation of China (NO. 21672172), the project of Youth Sci-
ence and Technology Innovation Team of Sichuan Province, China
(2017TD0008); the Education Department of Sichuan Province (NO.
15CZ0016).
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Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1611754.
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o
n
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© Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–F

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flash column chromatography on silica gel [flash column chro-
matography eluent, petroleum ether/ethyl acetate (6:1–4:1,
v/v)] to give the pure product 3a (37 mg, 91% yield) as an oil. 1H
NMR (400 MHz, CDCl3):  = 7.37–7.34 (m, 3 H), 7.30–7.27 (m,
3 H), 7.23–7.21 (m, 1 H), 7.16–7.13 (m, 3 H), 7.11–7.08 (m, 1 H),
6.96–6.92 (m, 1 H), 6.77 (d, J = 6.94 Hz, 2 H), 5.48 (s, 1 H), 5.35
(s, 1 H), 4.95 (s, 1 H), 4.59 (d, J = 8.68 Hz, 1 H), 3.96 (d, J =
8.70 Hz, 1 H), 2.20 (s, 3 H), 2.06 (s, 3 H). 13C NMR (100 MHz,
CDCl3):  = 171. 4, 141.1, 139.9, 135.1, 134.9, 134.4, 129.5,
129.3, 128.6, 128.5, 128.4, 128.3, 128.1, 127.0, 126.8, 121.3,
119.8, 119.7, 117.3, 110.3, 108.7, 78.6, 57.4, 20.4, 12.5. HRMS:
m/z [M+H]+ calcd for C27H26N2O2: 410.2013; found: 410.2016.
(15) CCDC 1546337 (3g) contains the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data request/cif.
(12) (a) Kong, W.; Wang, Q.; Zhu, J. J. Am. Chem. Soc. 2015, 137,
16028. (b) Wang, M.; Zhang, X.; Zhuang, Y.-X.; Xu, Y.-H.; Loh, T.-
P. J. Am. Chem. Soc. 2015, 137, 1341.
(13) Föhlisch, B.; Gehrlach, E.; Herter, R. Angew. Chem. Int. Ed. Engl.
1982, 21, 137.
(14) Typical procedure and characterization data for 3a: To a solu-
tion of sulfonylindole 1a (0.1 mmol) in 1,4-dioxane (1.0 mL) was
added -halohydroxamates 2a (0.15 mmol) and Na2CO3 (0.3
mmol). The reaction mixture was stirred at 80 °C until the start-
ing material sulfonylindole was consumed (monitored by TLC).
After cooling to room temperature, the solvent was removed
under reduced pressure. The crude product was purified by
© Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–F