Visible-Light-Mediated Sulfonylimination of Tertiary Amines with Sulfonylazides Involving Csp3-Csp3 Bond Cleavage

Article abstract of DOI:10.1021/acs.orglett.9b00786

Visible-light-induced cross-coupling of arylsulfonyl azides with tertiaryamines in the presence of Eosin Y at room temperature has been achieved. This transformation features alkyl C-C bond cleavage and provides a green approach to N-sulfonylamidines under mild conditions.

Full text of DOI:10.1021/acs.orglett.9b00786

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Visible-Light-Mediated Sulfonylimination of Tertiary Amines with
3
3
Sulfonylazides Involving Csp −Csp Bond Cleavage
Jiao Gui,§ Haisheng Xie,§ Huanfeng Jiang, and Wei Zeng*
Key Laboratory of Functional Molecular Engineering of Guangdong Province, Guangdong Engineering Research Center for Green
Fine Chemicals, School of Chemistry and Chemical Engineering, South China University of Technology, Guangzhou 510641,
China
S
* Supporting Information
ABSTRACT: Visible-light-induced cross-coupling of arylsul-
fonyl azides with tertiaryamines in the presence of Eosin Y at
room temperature has been achieved. This transformation
features alkyl C−C bond cleavage and provides a green
approach to N-sulfonylamidines under mild conditions.
promoter (Scheme 1d).7 However, considering that a trace
midines are often encountered in many natural products
Aand bioactive small molecules, and also serve as useful amount of transition-metal ions will limit their application in
biological pharmaceutical industry,8 the development of metal-
free catalyzed strategies for green synthesis of amidines is
therefore highly desired.
synthons to assemble complex molecules.1 In recent decades,
different synthetic methodologies have been developed to
construct versatile amidines. Among them, the direct
condensation reaction between formamides and sulfonamides
could produce N-sulfonyl amidines in the presence of a
stoichiometric amount of acyl chlorides or oxidants (Scheme
1a).2 To avoid the use of these hazardous reagents and harsh
conditions, Wang,3 Stahl,4 Odell,5 and others6 developed
transition-metal-catalyzed and electrochemical systems for
assembling these compounds (Scheme 1b and 1c). Meanwhile,
Wang also reported an easily available tertiary amine-based
cross-coupling for making amidine derevatives using FeCl3 as a
On the other hand, photoredox catalysis has attracted much
attention because this synthetic strategy provides a low-carbon
platform for chemical transformation at ambient temperatures
and pressures.9 In this regards, double bond (CC, CO,
and CN)-containing substrates could be activated by
photosensitizers to generate radical species, which could be
further captured by other coupling partners.10 In contrast, inert
3
3
Csp −Csp bond activation by visible light or transition-metal
catalysts is more difficulty due to its high bond-dissociation
energy and low polarity.11 Recently, Xu reported that tertiary
amines could be transferred into enamines via a single electron
transfer (SET) process under visible-light conditions, and then
the corresponding enamine species reacted with alkynes to
form highly strained bicycles (Scheme 1e).12 This is in
combination with the fact that the 1,3-diopolar addition
between enamines and sulfonazides could easily occur,
sometimes followed by degradation of triazolines.13 Xu’s
work encouraged us to expect that tertiary amines could
possibly couple with sulfonazides for assembling amidines via
Scheme 1. Synthetic Strategies of N-Sulfonylamidines
3
3
Csp −Csp cleavage of alkanes under a photocatalytical system
(Scheme 1f).
To verify this hypothesis, the mixture of TsN3 (1a), N-ethyl-
N-isopropylpropan-2-amine (2a), Eosin Y (2.0 mol %), and
Na2CO3 (1.0 equiv) in CH3CN (2.0 mL) was irradiated with
blue LEDs (446 nm, 30 W) for 3 h under an air atmosphere at
room temperature. N,N-Diisopropyl-N′-tosylformimidamide
(3-1a) was obtained in 91% yield after chromatogaphic
isolation (Table 1, entry 1). In comparison, the use of organo-
or noble-metal photocatalysts including TPT, [Mes-Acr]ClO4,
[Ir(dtbbpy)(ppy)2][PF6], and Ru(bpy)3Cl2 gave considerably
Received: March 4, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b00786
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
a b
,
Table 1. Optimization of the Reaction Parameters
Scheme 2. Sulfonylazide Scope
b
entry
changes to standard conditions
3-1a yield (%)
c
1
none
91/88
2
3
4
5
6
7
8
9
10
11
12
13
TPT (2 mol %)
[Mes-Acr]ClO4 (2 mol %)
[Ir(dtbbpy)(ppy)2][PF6]
Ru(bpy)3Cl2 (2 mol %)
Cs2CO3
K2CO3
NaOMe
no base
no light
39
46
63
51
50
80
75
40
0
THF
DMF
toluene
47
51
41
a
Reaction conditions: 0.2 mmol of TsN3 1a, 0.1 mmol of tertiary
amine 2a, photocatalysts eosin Y (5 mol %), and Na2CO3 (1.0 equiv)
in CH3CN (0.2 M) under an air atmosphere at room temperature for
b
c
3 h, blue LED light. Isolated yield. 1.0 mmol of 2a was employed.
lower yields (entries 2−5, 39−51%). The coupling reaction
between 1a and 2a in the presence of Cs2CO3, K2CO3, or
NaOMe also proceeded with inferior conversions under our
optimized conditions (entries 6−8). It should be noted that
the transformation only produced 40% yield of 3-1a in the
absence of bases (entry 9), and no desired product 3-1a was
observed when the mixture was subjected to the standard
reaction conditions without the photoirradiation (entry 10).
Finally, the change of solvent to THF, DMF, and toluene did
not show any promising results (entries 11−13).
a
All the reactions were performed using sulfonylazides 1 (0.20
mmol), tertiaryamine 2a (0.1 mmol), and Na2CO3 (0.1 mmol) with
photocatalyst Eosin Y (5 mol %) in CH3CN (1.0 mL) at room
temperature for 3 h under air atmosphere irradiation using 30 W blue
LEDs in a sealed reaction tube. Followed by flash chromatography on
We next examined the scope of sulfonylazides and
tertiaryamines (Scheme 2 and Scheme 3). In general, kinds
of arylsulfonylazides including phenylsulfonyl azides and
heteroarylsulfonyl azides could smoothly couple with N-
ethyl-N-isopropylpropan-2-amine (2a) to produce the target
b
SiO2. Isolated yield.
Subsequently, we evaluated the coupling reaction of TsN3
(1a) with different tertiaryamines and found different lengths
of linear trialkylamines proceeded smoothly to furnish the
desired products (3-2a−3-2d) in acceptable yields. Compared
with tri-n-propylamine and triethylamine (76% for 3-2b, 80%
for 3-2c), longer or shorter linear tri-n-butyl- and trimethyl-
substituted tertiaryamines made the transformation a little
sluggish, providing lower yields of 3-2a (23%) and 3-2d
(27%), respectively. Although diverse linear alkyl chain-
substituted tertiaryamines (2f, 2g, 2h, 2i, and 2j) could
efficiently react with 1a with excelent overall yields (81−86%),
the carbon−carbon activation occurred mainly at the ethyl
moiety, and different regioselectivity was still observed (entries
4−6). Interestingly, except N-methyl morpholine (2o) which
only produced N-Tos-N-morpholinoamidine 3-2o (41%),
when other cyclic tertiaryamines such as N-methylpiperidine
(2k), N-methylpyrrolidine (2l), N-benzylpiperidine (2m), and
N-allylpyrrolidine (2n) were subjected to the standard
3
3
N-sulfonylamidines 3-1, in which ethyl Csp −Csp bond of 2a
was cleavaged (Scheme 2). Among them, 4- or 3-alkyl or
halogen-substituted phenylsulfonyl azides could give moderate
to excellent yields of 3-1a, 3-1b, 3-1h, 3-1i, 3-1j, and 3-1l,
repectively. In contrast, ortho-substituted phenylsulfonyl azides
including 2,4,5-trimethylphenylsulfonyl azide led to inferior
conversions due to the adjacent steric hindrance (63% for 3-
1c, 43% for 3-1d, and 21% for 3-1k). Compared with
phenylsulfonyl azide (81% for 3-1g), stronger electron-
donating-group-substituted 4-methoxyphenylsulfonyl azide
only afforded a moderare yield of 3-1e (64%), and 4-
acetylaminophenylsulfonyl azide could not be transformed
into 3-1f at all. Meanwhile, the electron-deficient phenyl-
sulfonyl azides such as 4-nitro, 4-acetyl, or 4-trifluorophenyl-
sulfonyl azides also produced poorer yields of the desired
amidines 3-1m (41%), 3-1n (20%), 3-1o (39%), and 3-1p
(19%). Apart from the phenylsulfonyl azides, other arylsulfonyl
azides such as biphenylsulfonyl azide, naphthylsulfonyl azide,
3-pyridylsulfonyl azide, and 2-thienylsulfonyl azide were well
tolerated in this reaction, giving the target products 3-1q, 3-1r,
3-1s, and 3-1t in moderate to good yields (52−75%).
Unfortunately, the cross-coupling between ethylsulfonyl
azide14 and tertiaryamine 2a did not lead to the formation of
amidine 3-1u.
3
conditions, the N-methylene Csp −H bond could also directly
couple with 1a to furnish complex amidines (3-2i, 3-2k, 3-2l,
and 3-2m), which are possibly derived from 1,2-H migration
accompanied by releasing N2 after 1,3-dipolar addition.15
Disappointingly, N-ethylindoline did not afford the desired
amidine 3-2o,16 and the starting material 2p was almost
completely recovered.
B
DOI: 10.1021/acs.orglett.9b00786
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a b
,
Scheme 3. Tertiary Amine Scope
Scheme 4. Preliminary Mechanism Studies
reaction system to react with 1a, a 57% yield of 3-1a could be
obtained (eq 4d). This result implied that tertiaryamines could
be possibly transferred into vinyl amines under the O2-
mediated photocatalysis system. It should be noted that the
cross-coupling reaction between 1a and 2q still gave a 40%
yield of 3-1a in the absence of Eosin Y (Scheme 4e). In
contrast, no desired product 3-1a could be observed in the
absence of visible light (Scheme 4f), demonstrating that visible
light enhanced the coupling reaction of TsN3 and enamine 2q.
Based on the above-mentioned investigations and recent
reports,18 a possible reaction mechanism for this reaction was
proposed in Scheme 5. The reaction starts with the
Scheme 5. Proposed Mechanism
a
All the reactions were performed using sulfonylazide 1a (0.20
mmol), tertiaryamine 2 (0.1 mmol), and Na2CO3 (0.1 mmol) with
photocatalyst Eosin Y (5 mol %) in CH3CN (1.0 mL) at room
temperature for 3 h under air atmosphere irradiation using 30 W blue
LEDs in a sealed reaction tube. Followed by flash chromatography on
photoexcitation of EosinY (EY) to produce the excited state
EY*, which is reductively quenched by N-ethyl-N-isopropyl-
propan-2-amine to generate the key cation radical intermediate
A and the anion radical EY•−. Meanwhile, molecular oxygen
b
SiO2. Isolated yield.
Several control experiments were performed to further
explore the reaction mechanism (Scheme 4). At first, the cross-
coupling between TsN3 (1a) and tertiaryamine (2a) was
carried out under our standard catalytic system in an oxygen
atmosphere, giving 90% yield of 3-1a (eq 4a). In comparison,
this transformation in an Ar atmosphere led to the formation
of 3-1a only in 27% yield (eq 4b), which indicated that
molecular oxygen was possibly invovled in a single-electron-
transfer (SET) process. Subsequently, the use of TEMPO (3.0
equiv) in the cross-coupling between 1a and 2a inhibited the
reaction conversion to some degree (eq 4c), further
demonstrating that radical intermediates were possibly
produced in this transformation. Finally, when N-isopropyl-
N-vinylpropan-2-amine (2q)17 was subjected to our standard
abstracts one electron from the anion radical EY− to regenerate
•−
the photocatalysts EY and superoxide anion radical O2
.
•−
Subsequently, the intermediate A is deprotonated by O2 to
produce radical B and further oxidized to the iminium ion D.
The intermediate D can be further deprotoned to form
vinylamine E. Finally, the visible-light-enhanced 1,3-dipolar
cycloaddition of vinylamine E with TsN3 followed by the
19
release of CH2N2 gives the desired amidine 3a.15
In conclusion, a room-temperature cross-coupling reaction
between sulfonylazides and tertiaryamines for assembly of
amidines was developed via a productive merger of visible-light
photoredox catalysis and 1,3-dipolar cycloaddition. This
transformation features a photocatalyzed C−C d-bond
cleavage using molecular oxygen as the terminal oxidant, and
C
DOI: 10.1021/acs.orglett.9b00786
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(c) Mukherjee, S.; Garza-Sanchez, R. A.; Tlahuext-Aca, A.; Glorius, F.
Angew. Chem., Int. Ed. 2017, 56, 14723. (d) Zhang, X.; MacMillan, D.
W. C. J. Am. Chem. Soc. 2017, 139, 11353.
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(12) Xu, G. Q.; Xu, J. T.; Feng, Z. T.; Liang, H.; Wang, Z. Y.; Qin,
Y.; Xu, P. F. Angew. Chem., Int. Ed. 2018, 57, 5110.
(13) (a) Chuprakov, S.; Kwok, S. W.; Fokin, V. V. J. Am. Chem. Soc.
2013, 135, 4652. (b) Efimov, I.; Bakulev, V.; Beliaev, N.; Beryozkina,
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(14) It should be noted that TsNH2 could not react with
tertiaryamine 2a under our standard conditions.
(15) Xu, X. L.; Li, X. N.; Ma, L.; Ye, N.; Weng, B. J. Am. Chem. Soc.
2008, 130, 14048.
(16) Employing TsN3 to react with diethylamine (3a) under our
standard conditions afforded a 93% yield of N,N-diethyl-4-methyl-
benzenesulfonamide 3-3a (please see SI for more details).
(17) Cai, Y.; Zhang, R.; Sun, D.; Xu, S.; Zhou, Q. Synlett 2017, 28,
1630.
provides a green approach to amidine compounds. Further
investigations of photocatalyzed cross-coupling of N-methyl-
ene C−C d-bonds with different coupling partners are
currently being carried out in our laboratory.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b00786.
Detailed experimental procedures, characterization data,
copies of 1H NMR and 13 C NMR spectra for all isolated
compounds (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: zengwei@scut.edu.cn.
ORCID
Huanfeng Jiang: 0000-0002-4355-0294
Wei Zeng: 0000-0002-6113-2459
Author Contributions
§J.G. and H.X. contributed equally to this work.
Notes
(18) Xu, X.; Ge, Z.; Cheng, D.; Ma, L.; Lu, C.; Zhang, Q.; Yao, N.;
Li, X. Org. Lett. 2010, 12, 897.
(19) Diazomethane could be decomposed under visible-light; see:
Wolf, R. J.; Hase, W. L. J. Phys. Chem. 1978, 82, 1850.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors thank NKRDPC (No. 2016YFA0602900), the
NSFC (No. 21871097), GPSF (No. 2017B090903003), and
the GNSF (No. 2018B030308007) for financial support.
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D
DOI: 10.1021/acs.orglett.9b00786
Org. Lett. XXXX, XXX, XXX−XXX