Highly regioselective AgNTf2-catalyzed intermolecular hydroamination of alkynes with anilines

Article abstract of DOI:10.1055/s-0031-1290341

A facile and economic method for the fully regioselective and high-yielding protocol for the hydroamination of unsymmetrical internal alkynes under mild reaction conditions with AgNTf₂ was developed. The materials are easily available from comm

Full text of DOI:10.1055/s-0031-1290341

622
LETTER
Highly Regioselective AgNTf2-Catalyzed Intermolecular Hydroamination of
Alkynes with Anilines
A
gN
T
f
-Catalyzed
u
I
ntermolecular
H
y
Z
droamination o
h
f
A
lkynes ang, Bin Yang, Guangzhao Li, Xin Shu, Divyesh C. Mungra, Jin Zhu*
2
Department of Polymer Science and Engineering, School of Chemistry and Chemical Engineering, State Key Laboratory of Coordination
Chemistry, Nanjing National Laboratory of Microstructures, Nanjing University, Nanjing 210093, P. R. of China
Fax +86(25)83317761; E-mail: jinz@nju.edu.cn
Received 12 November 2011
nucleophile. However, problems still exhibit in the
Abstract: A facile and economic method for the fully regioselec-
present known catalytic systems. First, to the best of our
tive and high-yielding protocol for the hydroamination of unsym-
knowledge, no general hydroamination procedure for a
metrical internal alkynes under mild reaction conditions with
wide scope of substrates is known.1,2 Terminal alkynes are
AgNTf2 was developed. The materials are easily available from
commercial vendors, to give synthetically useful enamine deriva- usually utilized, and the products are thus limited to the
tives efficiently. This strategy is efficient to build complex struc-
Markovnikov pattern while unsymmetrical (internal)
alkynes are rarely reported.10 Second, all of the aforemen-
tures from simple starting materials in an environmentally
compatible fashion.
tioned group III and lanthanide catalysts display limited
functional group tolerance and high moisture sensitivity,
making their routine preparation and application in syn-
Key words: AgNTf2 catalysis, intermolecular hydroamination, in-
ternal alkyne, enamine
thesis problematic. Therefore, effective catalysts for the
hydroamination reaction are demanded.
Herein, we report a high-yielding hydroamination proto-
Catalyzed intermolecular hydroamination of alkynes by
primary amines have attracted much attention.1 It repre-
sents one of the most atom-economic synthetic methods
for substituted amines, imines, and enamines, which are
important building blocks for organic compounds used as
pharmaceuticals, detergents, technical additives, and
dyes.2 Catalysts derived from both early and late transi-
tion metals as well as lanthanides have shown significant
activity for the addition of N–H bonds across a variety of
alkyne moieties.1,2 To be of particular interest catalysts
have been incorporating Pd, Ru, Au, Pt, Ir, Rh, Ni, and
Ag.3–9 While hydroamination catalyzed by lanthanide, al-
kali metal, and early transition metal complexes typically
take place through activation of an N–H bond, those cata-
lyzed by late transition metal complexes, including Pd,
Ru, Au, Pt, Ir, Rh, Ni, and Ag, occur through activation of
C–C multiple bonds, followed by the attack of the N-
col of internal alkynes (represented by propionate) cata-
lyzed by AgNTf2 under mild conditions (Scheme 1)
which yields products with (Z)-enamines. The starting
materials are easily available from simple commercial
sources, thus affording synthetically enamine derivatives
efficiently.
Table 1 Optimization of Reaction Conditionsa
COOMe
H
NH2
+
N
AgNTf2
Ph
COOMe
toluene, 4 h
Ph
1
2
3
Entry
Catalyst
AgNTf2
AgNTf2
AgNTf2
AgNTf2
AgNTf2
Solvent
toluene
toluene
THF
Temp (°C) Yield (%)b
1
2
3
4
5
6
7
8
9
25
60
60
60
60
60
60
60
60
60
92
75
56
48
n.r.
79
27
47
R3
H
R2 R3
(1.0 equiv)
N
MeOH
CCl4
R1
R2
NH2
AgNTf2
(5 mol%)
R1
toluene
toluene
toluene
toluene
toluene,
60 °C, 4 h
R2
R3
R3
R3
(1.0 equiv)
R3 = COOR
AgOTf
AgCl
H
(2.0 equiv)
N
R1
R2
R2
AgNO3
Scheme 1 AgNTf2-catalyzed intermolecular hydroamination of al-
kynes with substituted anilines
a All reactions were carried out by employing aniline (1.0 mmol),
alkyne (1.0 mmol), and AgNTf2 (5.0 mmol%).
b Yields after column chromatographic purification with silica gel,
n.r. denotes that no reaction has occurred.
SYNLETT 2012, 23, 622–626
x
x
.
x
x
.
2
0
1
1
Advanced online publication: 08.02.2012
DOI: 10.1055/s-0031-1290341; Art ID: W65911ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
AgNTf2-Catalyzed Intermolecular Hydroamination of Alkynes
623
This strategy is efficient to build complex structures from Under the optimized conditions, the aniline was initially
simple starting materials in an environmentally compati- used as a moderator for exploring the alkyne substrate
ble fashion.
scope (Scheme 2, 3a and 3b). It could be seen that the
alkynes with an electron-withdrawing group could give
the corresponding products in good yields. Only the (Z)-
enamines were observed as products.10 The stereochemis-
try of the structure was also determined by NOESY spec-
tra, which showed the cross peaks of the alkene proton
with the adjacent aromatic ring. Alkynes with an electron-
donating group also gave the products. However, the
product was a mixture of regioisomers, and the yield was
low. The regioselectivity of electron-poor alkynes was a
result of the electronic effect and steric repulsion of
alkynes and might primarily depend on the electronic ef-
fect.10 The scope of aniline was also demonstrated. A va-
riety of substituted anilines – substituted with Me (ortho),
NO2 and Me (meta), and Me, OMe, and NO2 (para) –
could afford the corresponding products in good yields, as
shown in Scheme 2. The electronic properties of the sub-
stituents on the aniline slightly affect the yield; aniline
To begin our study, we performed the reaction of aniline
(1.0 mmol) and alkyne (1.0 mmol) in the presence of
AgNTf2 (5 mmol%) in toluene. We were pleased to find
that the reaction in toluene at 25 °C for four hours afford-
ed the desired product in 60% yield (Table 1, entry 1).
Surprisingly, when the temperature was raised to 60 °C,
the yield increased to 92% (Table 1, entry 2). Continued
optimization revealed that other solvents (THF, CCl4, and
MeOH) all afforded the desired product, but the yields
were comparatively low (Table 1, entries 3, 4, 5). When
the catalyst was changed to AgOTf, the yield of the prod-
uct decreased to 79% (Table 1, entry 7). Other silver cat-
alysts (AgCl and AgNO3), both afforded the product
(Table 1, entries 8, 9). To ascertain the influence of
AgNTf2, the reaction was performed without catalyst
(Table 1, entry 6), and no product was detected. Follow-
ing these general conditions, we examined the scope of
this reaction, and the results are summarized in Scheme 2.
COOR3
H
NH2
N
AgNTf2
R1
R2
COOR3
COOMe
R1
+
R2
toluene
3
1
2
COOMe
COOMe
COOMe
H
N
H
H
H
N
N
N
Hex
Ph
Ph
Hex
3c; 87%
3b; 92%
3d; 94%
3a; 85%
COOEt
COOMe
COOMe
H
H
H
N
N
N
Ph
Ph
3f; 70%
3g; 95%
3e; 94%
COOMe
COOEt
COOEt
H
N
H
N
H
O2N
O2N
N
Ph
Ph
Ph
3h; 82%
3i; 83%
3j; 97%
COOMe
COOMe
COOEt
H
N
H
N
H
N
Ph
Hex
Ph
MeO
MeO
3k; 97%
3l; 87%
3m; 98%
COOEt
COOEt
COOMe
H
H
N
H
N
N
Ph
Ph
O2N
MeO
O2N
3n; 72%
3o; 82%
3p; 82%
Scheme 2 Examples of hydroamination reactions. All reactions were carried out by employing aniline (1.0 mmol), alkyne (1.0 mmol), and
AgNTf2 (5.0 mmol%) at 60 °C for 4 h. Yields after column chromatographic purification with silica gel.
© Thieme Stuttgart · New York
Synlett 2012, 23, 622–626

624
X. Zhang et al.
LETTER
R
R
H
NH2
N
AgNTf2
toluene
Me
Ph
R
+
Me
Ph
Ph
1
2
3
R2
R2
R1
R1
R2
R2
R1
R1
H
N
H
H
H
N
N
N
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
3q; 90%
3r; 90%
3s; 80%
3t; 80%
R1
R1
R2
R2
R1
R1
R2
R2
H
N
H
N
H
N
H
N
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
3u; 83%
R1 = COOMe, R2 = COOEt
3v; 84%
3w; 92%
3x; 94%
Scheme 3 Examples of hydroamination reactions. All reactions were carried out by employing aniline (1.0 mmol), alkyne (2.0 mmol), and
AgNTf2 (5.0 % mmol) at 60 °C for 4 h. Yields after column chromatographic purification with silica gel.
COOMe
H
NH2
N
Ph
AgNTf2
68%
5%
(1 mmol)
(1 mmol)
Ph
COOMe
(1 mmol)
+
COOMe
toluene, 40 °C
H
N
NH2
Ph
O2N
O2N
Scheme 4
with electron-withdrawing groups gave lower yield than ed anilines, we first found that AgNTf2 could not coordi-
that with electron-donating groups.
nate with the electron-poor alkynes, as can be seen from
1
the H NMR spectra.11 Obvious change of the chemical
Interestingly, when two equivalents of alkynes were add-
ed, we got products as shown in Scheme 3. The electronic
properties of the substituents on the anilines also affected
the yields. Anilines with electron-donating substituents
could afford the corresponding products in better yields,
and only the (Z)-isomers were observed. Evidence for ste-
reochemistry of the structure was mainly determined by
the NOESY spectra, which showed the cross peaks of the
alkene proton with the adjacent aromatic ring.
shift from protons of aniline was observed after AgNTf2
was added, which indicated that the catalyst might interact
with aniline.11,12 At the same time, a deuterium exchange
experiment was performed. As noted from the 1H NMR,
the integration from the NH2 group of aniline changed
from 2.01 ppm to 0.27 ppm. About 86% of the hydrogen
atoms from the amine group were substituted by deuteri-
um. This indicated that the reaction might occur through
the activation of the N–H bond by AgNTf2, which could
also be seen from the 1H NMR spectra.11 Next, under the
standard conditions except that the temperature was
40 °C, both products of electron-poor p-nitroaniline and
electron-rich p-methylaniline could be observed in the
same reaction (Scheme 4). It could be seen that electron-
richer aniline dominated the product formation, since the
N–H bond on the electron-rich aniline might be activated
more easily. Simultaneously, if AgNTf2 had the similar
nature with other late transition metal complexes, the ac-
tivation of C–C multiple bonds might occur, followed by
the attack of the N-nucleophile. The enamine might also
To gain an insight into the reaction of AgNTf2-catalyzed
intermolecular hydroamination of alkynes with substitut-
R
R
R
H
H
N
N
AgNTf2
toluene
Ph
R
+
Ph
Ph
Ph
0%
R = COOMe or COOEt
Scheme 5
Synlett 2012, 23, 622–626
© Thieme Stuttgart · New York

LETTER
AgNTf2-Catalyzed Intermolecular Hydroamination of Alkynes
625
R
H
N
Ph
H
N
H+
NH2
R
Ag
H
Ph
N
Ag+
[Ag+]
R
R
Ag
+
Ph
H
N
+ H+
Ph
R
R
Ph
Ph
Ph
R
H+
Ag+
R
R
R
H
H
N
N
R
Ph
R = COOMe
Ph
Ph
Ph
Scheme 6 Postulated mechanism
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react with alkynes under the standard conditions to pro-
vide diene-substituted anilines (Scheme 5). Unfortunate-
ly, no conversion to the desired product was observed
although the reaction proceeded for a longer time.
In light of these experiments we proposed a tentative
mechanism (Scheme 6). First, the coordination of aniline
with AgNTf2 occurred, and the N–H bond was activated.
The insertion of alkynes led to the generation of interme-
diate species, and the second alkyne could further partici-
pate in the reaction for the formation of the next
intermediate. Then, the catalyst was regenerated, and the
product was obtained.
(3) (a) Mizushima, E.; Hayashi, T.; Tanaka, M. Org. Lett. 2003,
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In conclusion, we have developed a fully regioselective
and high-yielding protocol for the hydroamination of un-
symmetrical internal alkynes under mild reaction condi-
tions catalyzed by AgNTf2. The materials are easily
available from commercial sources, to give synthetically
useful enamine derivatives efficiently. This strategy is an
effective method to build complex structures from simple
starting materials in an environmentally compatible fash-
ion.
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Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
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Acknowledgment
Organometallics 1996, 15, 3773. (c) Straub, T.; Frank, W.;
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2541.
J.Z. acknowledges support from the National Natural Science Foun-
dation of China (20974044, 90923006) and National Basic Re-
search Program of China 2001CB935801.
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LETTER
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Synlett 2012, 23, 622–626
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Copyright of Synlett is the property of Georg Thieme Verlag Stuttgart and its content may not be copied or
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However, users may print, download, or email articles for individual use.