Synthesis of α,α-Disulfenylated Aldehydes via Oxidative Transformation of Tertiary Amines

Article abstract of DOI:10.1021/acs.orglett.5b02876

A method for the copper-catalyzed regioselective β-functionalization of tertiary amines with thiophenols has been developed. The control experiments and primary studies show that a thiyl radical is involved in the reaction, and the method provides a novel

Full text of DOI:10.1021/acs.orglett.5b02876

Letter
pubs.acs.org/OrgLett
Synthesis of α,α-Disulfenylated Aldehydes via Oxidative
Transformation of Tertiary Amines
Xin Huang, Jichao Wang, Zhangqin Ni, Sichang Wang, and Yuanjiang Pan*
Department of Chemistry, Zhejiang University, Hangzhou 310027, China
*
S Supporting Information
ABSTRACT: A method for the copper-catalyzed regioselective β-function-
alization of tertiary amines with thiophenols has been developed. The control
experiments and primary studies show that a thiyl radical is involved in the
reaction, and the method provides a novel and direct approach to synthesize
3
C(sp )−S bonds without a directing group under ligand-free conditions.
ertiary amine derivatives are widespread in natural products
and are therefore important in the pharmaceutical industry.
Scheme 1. Radical Pathway for the Synthesis of β-
Functionalized Tertiary Amines
T
The functionalization of tertiary amines has become an enduring
challenge that attracts much interest from organic chemists. The
direct α-functionalization of tertiary amines was developed as an
efficient and conventional way to synthesize tertiary amine
1
derivatives. To synthesize α-functionalized tertiary amines, well-
accepted methods involved either the formation of iminium
intermediates oxidized by various oxidants or the activation of
2
the C−H bond adjacent to an N atom by transition metals.
with pyridine as base. To our surprise, treatment of 1a with
copper(I) iodide in DMSO in air at 90 °C afforded 2,2-bis[(4-
chlorophenyl)thio]propanal (3aa) in 61% yield (Table 1, entry
1). To confirm the structure of 3aa, single-crystal X-ray analysis
was performed (see the Supporting Information). A series of
experiments were then examined to optimize the reaction
conditions, as shown in Table 1.
First, different catalysts were tested; copper catalysts showed
catalytic activities for the reaction (Table 1, entries 1−4), and
CuI was found to be the most efficient, whereas iron catalysts or
no catalyst could not afford the desired product (Table 1, entries
5 and 6). Using a 20 mol % amount of catalyst resulted in 34%
yield (Table 1, entry 8), and increasing the amount of catalyst
resulted in a slightly higher 63% yield (Table 1, entry 9). Next, we
investigated the influence of solvent; most solvents such as
More recently, a method utilizing α-amino radical intermediates
formed through single-electron transfer by photoredox catalysts
3
was developed for this transformation.
Compared to the extensive studies of the α-position of tertiary
amines, β-functionalized tertiary amines are mostly limited by
their relatively inert C−H bonds. To date, three major
approaches to synthesize β-functionalized tertiary amines have
been developed: (1) transition-metal-catalyzed selective β-
position functionalization using ligand control or four-
membered-ring cyclometalation complexes; (2) nuclephilic
enamines used as starting materials or key intermediates followed
by reactions with appropriate electrophiles; and (3) the novel
enamine cation radical generated by CAN oxidants or photo-
redox catalysts as a novel synthetic pathway. Recently, the Seidel
group reported a redox-neutral strategy for amine β-functional-
ization under metal-free conditions. These methods are efficient
and useful for the β-functionalization of tertiary amines, but in
most cases, access to the compounds requires multiple steps and
indirect pathways. Furthermore, precious transition-metal
catalysts such as palladium or ruthenium are often required.
Therefore, the direct, convenient, and selective transformation of
aliphatic C−H bonds remains a challenge. Based on recent
9
4
5
6
toluene and CH CN were not effective at producing high yields
3
7
for this reaction (Table 1, entries 10−14), and DMF was the only
solvent that could produce the desired product (Table 1, entry
1
5). Peroxide oxidants were unsuitable for the reaction (Table 1,
entries 16 and 17), and the nitrogen-protected experiment
resulted in no product formation, which indicates that oxygen is
essential for the oxidation (Table 1, entry 7). Thus, we
performed the reaction in an oxygen atmosphere, and the
product was isolated in a higher yield (Table 1, entry 18).
Moreover, other factors such as temperature, reaction time, and
additive were also investigated (see the Supporting Information).
Therefore, the optimal reaction conditions involved treatment of
thiophenol (1) with tertiary amine (2) in a 1:2 ratio in DMSO at
3
8
studies on C(sp )−S coupling and our interest in thiophenols,
we report a copper-catalyzed direct and selective β-sulfenylation
of aliphatic tertiary amines through a radical pathway to obtain
α,α-disulfenylated aldehydes that have emerged as versatile
10,11
reagents in cyclization reactions (Scheme 1).
Our initial intention was to oxidize 4-chlorothiophenol (1a) to
the corresponding sulfinic acid with a copper salt in air in the
presence of a tertiary amine. This could be achieved in low yield
Received: October 4, 2015
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b02876
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a
Table 1. Optimization of Reaction Conditions
Scheme 2. Substrate Scope of Thiophenol with
Tripropylamine
a
b
c
entry
catalyst
oxidant
solvent
yield (%)
1
2
3
4
5
6
CuI
air
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
61
52
CuCl
CuBr
CuCl2
FeCl2
air
air
55
air
49
air
NR
NR
NR
34
air
d
7
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
air
e
8
f
air
9
air
63
10
11
12
13
14
15
16
17
18
air
CH CN
trace
NR
NR
NR
NR
55
3
air
toluene
dioxane
air
air
H O
2
air
THF
air
DMF
TBHP
H O
DMSO
DMSO
DMSO
NR
NR
72
2
2
O2
a
Reaction conditions: 1a (0.5 mmol), 2a (1.0 mmol), catalyst (50 mol
), and solvent (1.5 mL) under air atmosphere at 90 °C for 10 h.
%
b
Other Cu(II) salts are reported in the Supporting Information.
c
d
e
Isolated yields. Under N atmosphere. 20 mol % of CuI was used.
2
f
1
00 mol % of CuI was used.
9
0 °C and catalyst by CuI (50 mol %) in an oxygen atmosphere
for 10 h.
With the optimal reaction conditions determined, we then
investigated the substrate scope of thiophenol (1) with
tripropylamine (2a) as shown in Scheme 2. Both electron-
donating and electron-withdrawing substituents were well-
tolerated to produce aldehydes in moderate to good yields. For
the strong electron-withdrawing group, 4-NO , the desired
2
product was isolated in 34% yield (3qa). Notably, steric
hindrance had a strong effect on the reaction. For example, for
the methoxy-substituted thiols, the yields of the corresponding
aldehydes decreased significantly as substitution changed from
para to meta to ortho (3ka, 3la, 3ma). Similar reactivity patterns
of chloro-substituted thiols were also observed (3aa, 3ba, 3ca).
Furthermore, when the thiophenol (3sa) wa used directly, the
product was isolated in a higher yield than when reactants
containing substituents were used. Moreover, the halide
substituents (Br, Cl, F) including para, meta, and ortho
derivatives were all accessible to allow for the formation of the
corresponding aldehydes, which could then be applied to further
reactions. To our delight, the disubstituted thiophenols were also
well-tolerated under these reaction conditions, and 3ta was
obtained in 57% yield. Moreover, naphthyl, benzyl, and
heterocycle substituents were also examined (3ua, 3va, 3wa),
and the results showed that the thionaphthol (3ua) was suitable
for reaction under the conditions, whereas the benzyl (3va) and
heterocycle (3wa) substituents did not lead to product
formation. These results indicated that aromatic thiols are
essential for the formation of the C−S bond.
a
Reaction conditions: 1 (0.5 mmol), 2a (1.0 mmol), CuI (50 mol %),
and DMSO (1.5 mL) under oxygen balloon at 90 °C for 10 h. Isolated
b
yields. Reaction for 16 h.
for the C−S coupling. Surprisingly, 3aa was isolated in good yield
when triallylamine (2b) instead of tripropylamine (2a) was used
as a reactant. This result revealed that the saturated bond in the
aliphatic tertiary amine might convert to an unsaturated bond
during the reaction. When triethylamine (2c) was used as a short
carbon chain, the desired product (3ab) was obtained in 75%
yield, which is higher than the yield obtained when long carbon
chains were used. Notably, the product 3ab as the key reactant
has been applied for the synthesis of β-lactams like
thienamycin. Moreover, we also chose amines with different
R groups, such as N-ethylmorpholine (2d) and N-ethyl-
piperidine (2e), as reactants, and the product 3ab was isolated
in yields of 64% and 69%, respectively. This outcome indicates
that the C−S bond was previously formed at the terminal β-
position with less steric hindrance. We also tested other long-
carbon-chain amines, and the yields of the aldehydes decreased as
the carbon chain length increased on the tertiary amines (3ac,
3ad, 3ae). However, when a branched tertiary amine (2i) was
12
Next, we examined the reactions of different tertiary amines
with 4-chlorothiophenol (1a) as shown in Table 2. The results
clearly showed that various aliphatic tertiary amines are suitable
B
DOI: 10.1021/acs.orglett.5b02876
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Table 2. Substrate Scope of Tertiary Amines with 4-
Chlorothiophenol
under standard conditions, but 3aa was not detected (Scheme
3c). These results illustrate that the formation of the C−S bond
occurred prior to the formation of the aldehyde. When the
reaction between triethylamine and thiophenol was treated with
basic alumina, the enamine product was isolated in good yield
a
(
Scheme 3d). On the basis of this result, it is likely that aldehydes
are converted from enamines hydrolysis.
On the basis of the control experiments and previous reports
on the β-functionalized tertiary amines, a plausible mechanism is
proposed in Scheme 4. Initially, the thiophenol is oxidized to a
entry
1
2, R
2b, allyl
3, R4
yield (%)
15
3aa, Me
3ab, H
59
75
64
69
54
43
35
n.r.
b
2
2c, Et
3
4
5
6
2d, see below
2e, see below
2f, n-Bu
3ab, H
3ab, H
Scheme 4. Proposed Mechanism
3ac, Et
2g, n-pentyl
2h, n-hexyl
2i, isopentyl
3ad, n-Pr
3ae, n-Bu
3af, i-Pr
c
7
8
a
Reaction conditions: 1a (0.5 mmol), 2 (1.0 mmol), CuI (50 mol %),
and DMSO (1.5 mL) under oxygen balloon at 90 °C for 10 h, unless
b
otherwise noted. Isolated yields. Cooled to room temperature after
c
the reaction, then added silica gel for 10 h. Reaction for 16 h.
used, no desired product was obtained. These results indicated
that steric hindrance greatly impacts this reaction.
To explore the reaction mechanism, radical-trapping experi-
13
ments have been performed. First, 2 equiv of TEMPO (2,2,6,6-
tetramethyl-1-piperidinyloxy) as a radical inhibitor was added to
the standard reaction conditions, and less than 10% yield of 3aa
was obtained. We isolated the TEMPO adduct with thiophenol
in 27% yield. No desired product was isolated when 2 equiv of
butylated hydroxytoluene (BHT) was used. The oxidation of the
BHT product was obtained in 75% yield. From these results, we
believe that a radical pathway is involved in the reaction process.
To gain insight into the reaction mechanism, a series of control
experiments were performed as shown in Scheme 3. First, when
disulfide, which can produce the thiol radical A and thiol cation J.
Moreover, the copper−oxygen species are used as single-
electron-transfer agents, and imine intermediate B is formed
from the tertiary amine. Enamine C is then generated after a
deprotonation process. Next, the cationic radical species D and E
are produced through single-electron transfers. Once the radical
intermediates A and E are formed, a radical coupling reaction
occurs to form the monosulfenylated ion F. After a
deprotonation process, enamine intermediate G is produced.
Two possible pathways are involved in the next stage. Path a
proceeds via another radical process as follows: A different
cationic radical species H is produced through single-electron
transfer from G, and H coupling with thiol radical A generats the
disulfenylated ion I. Path b is also reasonable because the
Scheme 3. Control Experiments To Determine the Reaction
Mechanism
I
16
disulfide could coordinate with Cu to generate thiol cation J.
Then, J acting as an electrophile could react with enamine
intermediate G to form the disulfenylated ion I. Finally, the
intermediate I is hydrolyzed to form the final aldehyde product
3
under acidic conditions. It is worth noting that when the R
group is hydrogen, enamine product K is reasonably generated
under alkaline conditions as confirmed in our control experi-
ment.
In conclusion, we have developed a novel and efficient method
for the synthesis of aldehyde derivatives using copper-catalyzed
3
tertiary amines were replaced by the corresponding primary and
secondary amine (Scheme 3a,b), the desired product was not
obtained. These results indicate that tertiary amines are necessary
C(sp )−S coupling. This transformation shows the ideal β-
selectivity of aliphatic tertiary amines under ligand- and additive-
free conditions. Although aliphatic thiols are limited under the
reaction system, various aromatic thiols and tertiary amines are
suitable, and the corresponding aldehydes of potential value are
isolated in moderate to good yields. Moreover, a series of control
experiments and radical-trapping experiments confirm that a
14
for the reaction to proceed. According to previous reports,
copper−oxygen systems are efficient for the formation of
aldehydes decomposed from tertiary amines, so we used
propanal instead of tripropylamine as the source of aldehyde
C
DOI: 10.1021/acs.orglett.5b02876
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Letter
radical procedure is involved in the reaction process. Further
mechanistic studies and determination of the application of this
reaction are in progress in our laboratory.
(9) (a) Xu, R.; Wan, J.-P.; Mao, H.; Pan, Y. J. Am. Chem. Soc. 2010, 132,
5531. (b) Huang, X.; Wang, J.; Ni, Z.; Wang, S.; Pan, Y. Chem.
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ASSOCIATED CONTENT
Supporting Information
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(b) Kobatake, T.; Yoshida, S.; Yorimitsu, H.; Oshima, K. Angew. Chem.,
Int. Ed. 2010, 49, 2340. (c) Pan, L.; Bi, X.; Liu, Q. Chem. Soc. Rev. 2013,
*
S
4
(
2, 1251.
11) (a) Welker, M.; Woodward, S.; Veiros, L. F.; Calhorda, M. J.
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.5b02876.
Chem. - Eur. J. 2010, 16, 5620. (b) Fang, Z.; Liu, J.; Liu, Q.; Bi, X. Angew.
Chem., Int. Ed. 2014, 53, 7209. (c) Liu, C.; Gu, Y. J. Org. Chem. 2014, 79,
9619.
X-ray data for 3aa (CIF)
Experimental details, characterization of new compounds,
and NMR spectra (PDF)
(
12) Ishibashi, H.; Kameoka, C.; Iriyama, H.; Kodama, K.; Sato, T.;
Ikeda, M. J. Org. Chem. 1995, 60, 1276.
13) For details of the radical-trapping experiment, see the Supporting
(
AUTHOR INFORMATION
Corresponding Author
■
*
Information.
(14) (a) Guo, S.; Qian, B.; Xie, Y.; Xia, C.; Huang, H. Org. Lett. 2011,
1
3, 522. (b) Xiong, B.; Zhu, L.; Feng, X.; Lei, J.; Chen, T.; Zhou, Y.; Han,
E-mail: panyuanjiang@zju.edu.cn.
L.-B.; Au, C.-T.; Yin, S.-F. Eur. J. Org. Chem. 2014, 2014, 4244.
(15) (a) Tian, J. S.; Loh, T. P. Angew. Chem., Int. Ed. 2010, 49, 8417.
Notes
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b) Rao, H.; Wang, P.; Wang, J.; Li, Z.; Sun, X.; Cao, S. RSC Adv. 2014, 4,
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16) (a) Taniguchi, N. J. Org. Chem. 2006, 71, 7874. (b) Mohan, D. C.;
The authors declare no competing financial interest.
(
ACKNOWLEDGMENTS
■
Rao, S. N.; Ravi, C.; Adimurthy, S. Asian J. Org. Chem. 2014, 3, 609.
We are grateful to the National Natural Science Foundation of
China (21327010 and 21372199) for financial support.
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DOI: 10.1021/acs.orglett.5b02876
Org. Lett. XXXX, XXX, XXX−XXX