Gold-Catalyzed Regiospecific Hydration of N-Tosyl Propargylic Amines

Article abstract of DOI:10.1021/acs.organomet.8b00549

A gold-catalyzed regiospecific hydration of N-tosyl propargylic amines has been developed. In the presence of a catalytic amount of the gold catalyst NaAuCl₄·2H₂O, both alkyl and aryl-substituted N-tosyl propargylic amines were smoothly converted into the corresponding β-amino ketones with excellent regioselectivities and high yields (up to 85%). Further transformations of the obtained β-amino ketones to valuable 1,3-amino alcohols were demonstrated as well.

Full text of DOI:10.1021/acs.organomet.8b00549

Communication
pubs.acs.org/Organometallics
Cite This: Organometallics XXXX, XXX, XXX−XXX
Gold-Catalyzed Regiospecific Hydration of N‑Tosyl Propargylic
Amines
Jun Ying,*,†,§ Hai Wang,†,§ Xinxin Qi,†,§ Jin-Bao Peng,†,§ and Xiao-Feng Wu*,†,‡,§
†Department of Chemistry, Zhejiang Sci-Tech University, Xiasha Campus, Hangzhou 310018, People’s Republic of China
‡Leibniz-Institut fu
̈
r Katalyse e. V. an der Universitat Rostock, Albert-Einstein-Straβe 29a, 18059 Rostock, Germany
̈
S
* Supporting Information
ABSTRACT: A gold-catalyzed regiospecific hydration of N-
tosyl propargylic amines has been developed. In the presence
of a catalytic amount of the gold catalyst NaAuCl4·2H2O,
both alkyl and aryl-substituted N-tosyl propargylic amines
were smoothly converted into the corresponding β-amino
ketones with excellent regioselectivities and high yields (up to
85%). Further transformations of the obtained β-amino
ketones to valuable 1,3-amino alcohols were demonstrated
as well.
ropargylic amines represent a class of useful and versatile
Scheme 2. Regioselective Hydration of Propargylic Amines
P
building blocks in organic synthesis.1 For example, α- and
β-amino ketones and the corresponding structural motifs can
be synthesized by hydration of the corresponding propargylic
amines, which are ubiquitous in nitrogen-containing pharma-
ceuticals and biologically active compounds (Scheme 1).2
Scheme 1. Representative Pharmaceuticals and Biologically
Active Compounds
While a considerable number of procedures have been
developed that focus on the hydration of an internal alkyne
unit,3 only limited examples have been reported on the
regioselective hydration of propargylic amines to produce α- or
β-amino ketones (Scheme 2).4−11 In these works, toxic Hg(II)
complexes were commonly used. Propargylic amines were
converted to the β-amino ketones with high regioselectivity in
the presence of Hg(OAc)2 or Hg(OCOCF3)2/HgO.4−7 In
2011, Shi’s group developed the hydration of an alkyl-
substituted propargylic amine catalyzed by AuClPPh3/
AgOTf, which gave a β-amino ketone in good yield.8 The
propargylic amine used in this reaction contains an arylsulfonyl
group on the nitrogen. Recently, Pu’s group reported a
Received: August 1, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.organomet.8b00549
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Communication
Au(III)-catalyzed regiospecific hydration of N-(diphenyl-
phosphinoyl)propargylic amines, affording various β-amino
ketones.11 This method was suitable not only for a series of
alkyl-substituted N-(diphenylphosphinoyl)propargylic amines
but also for a chiral substrate with maintenance of high
enantiomeric purity, which made a great advance in the
asymmetric synthesis of chiral β-amino ketones. Despite this
advance, the reaction gave moderate yields of products due to
the instability of the N-(diphenylphosphinoyl) group. More-
over, the strategy failed in reactions with aryl-substituted
propargylic amines.
The tosyl group is useful as a protecting group for amines in
organic synthesis. Owing to its high stability, N-tosyl
propargylic amines have found broad applications in the
synthesis of valuable nitrogen-containing molecules.12 We
assume that the N-tosyl group in a propargylic amine can
direct the regioselective hydration of the alkyne unit. Herein,
we report a Au(III)-catalyzed regiospecific hydration of both
alkyl- and aryl-substituted N-tosyl propargylic amines to
generate various β-amino ketones. Additionally, synthetic
applications of the obtained β-amino ketones have been
demonstrated.
The reaction with an Au(I) catalyst, Ph3PAuMe, as well as its
combination with AgSbF6 gave only a trace amount of product
(entries 7 and 8). To our delight, the desired product 2a was
obtained in moderate to high yields with the use of Au(III)
catalysts (entries 9−11). The reaction using NaAuCl4·2H2O as
a catalyst gave the best yield of 2a (64%; entry 11). The yield
was improved to 82% when the solvent system was changed to
ethanol, methylene chloride, and water (4/1/1) (entry 12). In
this reaction, only the β-amino ketone product 2a in 80%
isolated yield was obtained with no observation of the α-amino
ketone isomer. When the amount of NaAuCl4·2H2O was
reduced to 5 or 3 mol %, the high yield of 2a was still
maintained (entries 13 and 14). Further decreasing the catalyst
loading to 1 mol % damaged the product yield significantly,
due to decreased conversion of substrate (entry 15).
Using Bolm’s method from the alkylation of N-tosyl imines,
we prepared various alkyl-substituted N-tosyl propargylic
amines that were subjected to the optimal conditions of
gold-catalyzed hydration (Table 1, entry 14). The results are
shown in Scheme 3. It shows that propargylic amines
Scheme 3. Gold-Catalyzed Hydration of Alkyl-Substituted
a
At the outset of this study, N-tosyl propargylic amine 1a was
selected as a model substrate. We investigated the reaction of
1a with water in the presence of various catalysts, and the
results are summarized in Table 1. It shows that the reaction
N-Tosyl Propargylic Amines
Table 1. Screening of Catalysts and Reaction Conditions for
a
the Hydration of Propargylic Amine
b
entry
catalyst
HgSO4
solvent
yield (%)
1
MeOH/H2O (5/1)
53
2
Cu(OAc)2
MeOH/H2O (5/1)
nr
3
CuCl
MeOH/H2O (5/1)
nr
4
PdCl2
MeOH/H2O (5/1)
nr
5
6
RuCl3·xH2O
AgOAc
MeOH/H2O (5/1)
MeOH/H2O (5/1)
nr
nr
7
8
9
Ph3PAuMe
Ph3PAuMe/AgSbF6
AuCl3
MeOH/H2O (5/1)
MeOH/H2O (5/1)
MeOH/H2O (5/1)
trace
trace
48
10
11
12
HAuCl4·3H2O
NaAuCl4·2H2O
NaAuCl4·2H2O
NaAuCl4·2H2O
NaAuCl4·2H2O
NaAuCl4·2H2O
MeOH/H2O (5/1)
MeOH/H2O (5/1)
EtOH/DCM/H2O (4/1/1)
EtOH/DCM/H2O (4/1/1)
EtOH/DCM/H2O (4:1:1)
EtOH/DCM/H2O (4/1/1)
53
64
82 (80 )
81
82 (81 )
41
c
a
Reaction conditions unless specified otherwise: 1 (0.2 mmol),
d
13
NaAuCl4·2H2O (3 mol %), EtOH/DCM/H2O (4/1/1) (3 mL), 60
°C, 24 h. Isolated yields. 48 h.
e
c
b
14
f
15
a
Reaction conditions unless specified otherwise: 1a (0.2 mmol),
b
1
substituted with both electron-donating and electron-with-
drawing groups can undergo hydration to give the correspond-
ing β-amino ketone products 2b−e in 59−85% yields. The
reaction of compounds containing an o- or m-Me substituent
afforded the desired products 2f,g in high yields. Compounds
bearing a linear alkyl group or a carbocycle on the triple bond
also gave good yields of products 2h−n. Additionally, the
hydration of substrates having a vinyl group on the triple bond
furnished the expected products 2o,p in 53% and 55% yields,
respectively.
catalyst (10 mo%), solvent (3 mL). Yields were determined by H
c
NMR analysis using CH2Br2 as an internal standard. Isolated yield.
d
e
5 mol % of the catalyst was used. 3 mol % of the catalyst was used.
f
1 mol % of the catalyst was used.
catalyzed by HgSO4 gave the β-amino ketone product 2a in
53% yield at 60 °C in a mixed solvent of methanol and water
(5/1) (entry 1). To avoid the use of toxic Hg catalysts, other
metal catalysts including AgOAc, Cu(OAc)2, CuCl, PdCl2, and
RuCl3·xH2O were tested. Disappointingly, no reaction
occurred (entries 2−6). Previously, gold catalysts were
reported to be more effective for the hydration of propargylic
amines due to their higher affinity toward the alkyne unit.10,11
Notably, the reaction conditions with slight modification
could be successfully applied to aryl-substituted N-tosyl
propargylic amines, as shown in Scheme 4. When a compound
B
DOI: 10.1021/acs.organomet.8b00549
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Communication
Scheme 4. Gold-Catalyzed Hydration of Aryl-Substituted N-
Tosyl Propargylic Amines
Scheme 5. Complexes A and B as Plausible Intermediates
for the Gold-Catalyzed Hydration
a
generated from the chelation of the N-tosyl group and the
alkyne unit with the Au(III) center. Nucleophilic attack of
H218O at the C3 position of A from the back side leads to the
formation of a more favorable six-membered-ring intermediate
(with gold at the C2 position). Subsequent elimination of the
Au(III) unit, protonation, and tautomerization give the β-
amino ketone product 2a-18O. In the intermediate B, the
oxygen atom of the N-tosyl group activates the C3 position of
the alkyne unit and the Au(III) catalyst occupies the C2
position simultaneously. Nucleophilic attack of H218O at the
C3 position followed by hydrolysis furnishes the final product.
Intermediates A and B both indicate that the N-tosyl group of
the propargylic amines can direct the hydration to occur
specifically at the C3 position of the starting propargylic
amines.
a
Reaction conditions unless specified otherwise: 1 (0.2 mmol),
NaAuCl4·2H2O (10 mo%), EtOH/DCM/H2O (4/1/1) (3 mL), 60
°C, 48 h. Isolated yields. 60 °C,72 h. 90 °C, 24 h.
b
c
with a phenyl substituent (R1 = Ph) was treated with 10 mol %
NaAuCl4·2H2O at 60 °C in a mixed solvent of ethanol,
methylene chloride, and water (4/1/1) for 48 h, the desired
product 2q was achieved in 49% yield. For compounds with an
electron-donating substituent on the phenyl ring, moderate to
good yields (44−73%) of the products 2r−v were obtained. It
was noted that the lower yield of the product 2s (44%) could
be attributed to the steric hindrance of the o-Me substituent. It
was also found that compounds with an electron-withdrawing
substituent could be converted the products 2w,x in moderate
yields. Additionally, a N-tosyl propargylic amine prepared from
2-ethynylpyridine was tested under our standard conditions as
well, but only less than 5% of the desired product could be
detected.
To demonstrate the scalability of hydration, we treated 1.0 g
of propargylic amine 1a with 5 mol % of NaAuCl4-·2H2O at 60
°C in a mixed solvent of ethanol, methylene chloride, and
water (4/1/1) for 24 h. The resulting product 2a was obtained
in 77% yield (Scheme 6).
Scheme 6. Scale-up Reaction of Propargylic Amine 1a
In order to gather more evidence on the mechanism of the
Au(III)-catalyzed hydration, an 18O-labeling experiment was
conducted. The hydration of 1a in the presence of H218O gave
the resulting product 2a-18O, whose 13C NMR spectra
indicated that the 18O was incorporated into the ketone
group but not in the N-tosyl group, as an upfield shift of the
13C NMR signal for the carbonyl carbon of 2a-18O from δ
209.08 to δ 209.21 was observed. The high-resolution mass
spectrum of 2a-18O gave the molecular ion for 2a-18O + Na+ at
m/z 412.1819 (calcd for C22H29NNO218OS + Na+ 412.1803),
indicating the incorporation of one 18O atom. In addition, the
peak for the fragment 2a-18O − C7H8NO2S at m/z 219.1636
(calcd for C15H2118O 219.1635) with significant 18O
incorporation, and the peak for the fragment 2a-18O −
C8H1518O at m/z 260.0747 (calcd for C14H14NO2S 260.0745)
with insignificant 18O incorporation. These results are
consistent with those observed by 13C NMR analyses and
confirm that the carbonyl oxygen of the β-amino ketone
product is derived from water.
Finally, a few transformations of the β-amino ketone product
2a were tested in order to show the synthetic utility of our
process (Scheme 7). When 2a was treated with NaBH4, the
1,3-amino alcohol product 3 was obtained in 85% yield with a
3:2 diastereoselectivity. It should be noted that the tertiary
amino alcohol 4 was achieved in 81% yield as a single isomer
by the treatment of a phenyl Grignard reagent at 0 °C. These
Scheme 7. Transformations of the β-Amino Ketone 2a
On the basis of previous reports11,13 and the above
experimental results, a plausible intermediate A or B is
proposed to account for the Au(III)-catalyzed regiospecific
hydration of 1a (Scheme 5). The intermediate A can be
C
DOI: 10.1021/acs.organomet.8b00549
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In conclusion, we have disclosed that N-tosyl propargylic
amines can undergo regiospecific hydration to produce various
β-amino ketones in the presence of a gold catalyst, NaAuCl4·
2H2O. In this reaction, the N-tosyl group of the propargylic
amines can direct the hydration to occur specifically at the C3
position of the alkyne unit. A mechanistic study reveals that the
carbonyl oxygen of the β-amino ketone product is derived from
water rather than the N-tosyl group. Additionally, we have
discovered that reduction and phenyl addition of a β-amino
ketone can provide 1,3-amino alcohols with moderate to good
diastereoselectivity.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.organo-
met.8b00549.
General comments, general procedures, analytical data,
and NMR spectra (PDF)
(4) Colombo, F.; Benaglia, M.; Orlandi, S.; Usuelli, F.; Celentano, G.
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AUTHOR INFORMATION
Corresponding Authors
*E-mail for J.Y.: yingjun@zstu.edu.cn.
*E-mail for X.-F.W.: xiao-feng.wu@catalysis.de.
■
ORCID
Xiao-Feng Wu: 0000-0001-6622-3328
Author Contributions
§X.-F.W. and J.Y. conceived and supervised the project. H.W.
performed the experiments, analyzed and prepared the
supporting information. X.Q. and J.-B.P. participated in
discussions. X.-F.W. and J.Y. wrote and revised the manuscript.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We acknowledge the Zhejiang Natural Science Fund for Young
Scholars (LQ18B020008) and Zhejiang Sci-Tech University
(17062078-Y) for financial support.
(10) Liu, R. − R.; Zhu, L.; Hu, J. − P.; Lu, C. − J.; Gao, J. − R.; Lan,
Y.; Jia, Y. − X. Enantioselective alkynylation of N-sulfonyl α-
ketiminoesters via a Friedel-Crafts alkylation strategy. Chem. Commun.
2017, 53, 5890−5893.
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