Non-directed copper-catalyzed regioselective C-H sulfonylation of phenothiazines

Article abstract of DOI:10.1039/c9ob00705a

We develop a simple and general method for sulfonylation of phenothiazines under Cu(i) catalysis. The broad scope of aryl/alkyl sulfonyl chlorides was applicable to produce C3 sulfonylation products of phenothiazines in moderate to good yields. The further transformation of the sulfonylation products was successful, which afforded valuable polyheterocycles.

Full text of DOI:10.1039/c9ob00705a

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DOI: 10.1039/C9OB00705A
ARTICLE
Non-Directed Copper-Catalyzed Regioselective C-H Sulfonylation
of Phenothiazines
Caiyan Liu, Yongli Shen and Kedong Yuan*
Received 00th January 20xx,
Accepted 00th January 20xx
We develop a simple and general method for sulfonylation of phenothiazines under Cu(I) catalysis. The broad scope from
aryl/alkyl sulfonyl chlorides was applicapable to produce C3 sulfonylation products of phenothiazines in moderate to good
yields. The further transformation of the sulfonylation products was successful, which afforded valuable polyheterocycles.
DOI: 10.1039/x0xx00000x
optical materials.7 In the last decade, arylsulfonyl chlorides are
popular sulfonylation reagents owing to the commercial
availability and inexpensive cost. Though the specific
Introduction
Phenothiazine derivatives (PTZs) are privileged structures that
have been explored for many uses in drug discovery, functional
materials, and photo-redox catalysis (Scheme 1a).1
Incorporation of diverse functional groups into the
phenothiazine skeleton imparts more applications, for instance,
regioselectivities obtained, the directing groups increased extra
a. Representative applications of Phenothiazine derivatives
C8H17
N
N-aryl phenothiazine derivatives as
a
new type of
N
BuO
OBu
photosensitizer have been applied in photo-dehalogenation
and polymerization reactions with good catalytic performance.2
Thus, substantial efforts have been devoted to functionalize
PTZs. Recently, N-arylation of phenothiazines using phenol
derivatives by either cross-dehydrogenative coupling or
electrochemical approaches were reported,3 and some
sensitive functional groups, such as NH2 and OH, which are
useful bioisosteres in drug design, were well tolerated. In
contrast with widely known N-H transformations, C-H bond
functionalization of PTZs was scarcely reported. Some strategies
relied on classical coupling reactions using prefunctionalized
PTZs, which often took several steps to obtain the desired
products.4 Recently, transition metal-catalyzed direct C-H bond
functionalization has emerged as a reliable approach allowing
rapid access to complex compounds.5 Such a strategy minimizes
the synthetic steps and expands the substrate scope as well.
Specifically, inexpensive copper catalysts also showed efficiency
in carbon-carbon and carbon-heteroatom bonds formations.6 It
is desirable to incorporate more diverse functional groups into
the biorelevant PTZs using an economical and efficient strategy.
S
BuO
OBu
N
S
S
S
N
S
Cl
NC
CN
HOOC
COOH
Thorazine
Antiphsycotics drug
Donor-(p-acceptor) dye
Photosensitizer 4b
Ph-PTZ
Photoredox catalyst 2
b. Cu(I) catalyzed non-directed regioselective sulfonylation of heteroarenes 9a
Copper-catalysis
CuI, K2CO3
R1
R1
+
ClO2S-Ar
+
Ar
+
N
N
S
O
O
O
O
16 examples
c. Previous work for regioselective sulfonylation of phenothiazines 10
R1
R1
N
Photo-catalysis
N
Me
[Ir], K2S2O8
NaO
S
+
Me
S
S
O
Blue LEDs
S
O
O
2 examples
d. Our work:
R1
N
R1
N
Copper-catalysis
CuI, Li2CO3
R2
R2
+
S
R3
ClO2
R3
S
S
S
O
O
Scheme 1. Application of PTZs and Sulfonylation of PTZs
(Hetero)Aryl sulfones, on the other hand, represent as
important building blocks in both medicinal chemistry and
synthetic steps. Recently, Wu and Pan groups respectively
reported copper catalyzed non-directive C-H sulfonylation of
quinoline derivatives at C2 position (Scheme 1b).9 In addition,
photo-catalyzed sulfonylation of (hetero)arenes with
arylsulfinate salts10 or arylsulfonyl chlorides,11 various
heteroarenes, including aniline derivatives, N-heteroarenes and
thiophenes were regioselectively sulfonylated in good yields.
Our previous research found that simple Pd(II) precatalyst
Tianjin Key Laboratory of Advanced Functional Porous Materials, Institute for New
Energy Materials & Low-Carbon Technologies, School of Materials Science and
Engineering, Tianjin University of Technology, Tianjin 300384, P. R. China.
* Kedong.yuan@tjut.edu.cn
Electronic Supplementary Information (ESI) available: Experimental details and 1H,
13C NMR spectral data of all new compounds. CCDC 1856159, 1856160. See
DOI: 10.1039/x0xx00000x
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Organic & Biomolecular Chemistry
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ARTICLE
associated with a base catalyzed the arylation of electron-rich
Journal Name
Then, reactions between various arylsulfonyl chlorides and 1a
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heteroarenes with arylsulfonyl chlorides in high regioselectivity were surveyed by using the optimal condDitOioI:n1s0.(1S0c3h9e/Cm9eOB20).07T0w5Ao
and with broad substrate scope.12 Inspired by the electron-rich arylsulfonyl chlorides (4-MeO, 4-NHAc) were initially
aforementioned efforts, we attempted to study the reactivity employed in the reaction, affording 3b, 3c in 71% and 91% isolated
between electron-rich PTZs and arylsulfonyl chlorides for yield, respectively. 2-Naphtylsulfonyl chloride, as well as electron-
diverse functionalization of PTZs in a non-directive fashion.
deficient ones (4-CN, 4-CF3), also smoothly reacted with 1a to form
the corresponding products 3d-f in good yields. Notably, no obvious
electronic effect was observed. Halogen-substituted arylsulfonyl
chlorides were tolerated in the transformation, even C-I, C-Br bonds
remained untouched at high temperature, which allowed late-stage
functionalizations. With 4-chlorobenzenesulfonyl chloride as
coupling partner, both mono- and di-substituted products were
formed, and the symmetrical disulfonylated product was isolated in
12% yield. The sterically hindered arylsulfonyl chlorides were also
reactive to give 3k, 3l in moderate to good yields. Notably, the
disulfonylated product from 2-bromobenzenesulfonyl chloride was
obtained in 15% yield, and a low ratio rotational isomer (6.8:1) was
observed by 1H NMR spectroscopy in 3k due to the steric effect.
Incorporation of heteroarene-sulfones (quinoline, coumarin,
thiophene, pyrazole) to PTZs were successful, giving moderate to
high yields (3m-3p), which made such procedure more attractive for
potential applications. Moreover, we studied the reactivity of 1a with
alkylsulfonyl chlorides. Product 3q bearing a cyclopropane motif was
obtained in 71% yield with a higher loading of CuI (50 mol%) catalyst.
No reaction occurred when trifluoromethylsulfonyl chloride was
used. It is worthy to mention that in all the cases, the sulfonylation
occurred exclusively at electron-rich C3 position of the phenothiazine
ring.
Results and discussion
Initially, N-butylphenothiazine 1a and para-tolylsulfonyl
chloride 1b were investigated for reaction discovery.
Surprisingly, the previous desulfitative arylation catalytic
system [Pd(CH3CN)2Cl2/Li2CO3/1,4-dioxane],12 showed less
reactivity, and phenothiazine 1a was recovered almost
quantitatively (Table 1. entry 1).
Table 1. Reaction Discovery and Optimization a
Me
nBu
N
nBu
N
Me
Cat.
+
Base,solvent
temp.
ClO2
S
S
S
S
H
O
O
H
H
1a
2a
3a
Catalyst
(mol%)
Pd(CH3CN)2Cl2(5)
Pd(CH3CN)2Cl2(5)
CuBr (50)
-
Base
Temp.
(oC)
140
Yield b
Entry
Solvent
(2.0equiv.)
Li2CO3
(%)
0
1
2 c
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
DEC
Li2CO3
Li2CO3
Li2CO3
Li2CO3
Li2CO3
Li2CO3
Li2CO3
Li2CO3
Li2CO3
Li2CO3
K2CO3
Li2CO3
Li2CO3
140
120
120
120
120
120
120
100
120
120
120
120
120
79(71)
81
3
4
0
5
CuI (50)
94
6
CuCl (50)
CuBr2 (50)
CuI (10)
89
7
7
8
36
nBu
N
nBu
N
R
9
CuI (20)
78
20 mol% CuI
Het
O
Het
R
+
ClO2
S
Li2CO3 (2 equiv.)
DCE, 120 oC, 18 h
10
11 d
12 e
13
14 f
CuI (20)/EDTA
CuI (20)
12
S
S
S
H
O
1a
2b-q
nBu
3b-q
95(79)
27
OMe
NHAc
nBu
N
nBu
N
CuI (20)
N
CuI (20)
58
S
S
S
S
S
S
O
O
O
O
O
O
CuI (20)
DCE
93(83)
3b 71%
3c 91%
3d 76%
a conditions: 1a 0.25 mol, 2a 0.375 mmol, base 0.5 mmol in 1 mL 1,4-dioxane (0.25 M)
CN
CF3
X
nBu
N
nBu
nBu
b
reflux for 18 h under N2 atmosphere; yields of 3a based on 1H NMR analysis and
N
S
N
X= F, 3g 77%
Cl, 3h 51%b
Br, 3i 65%
I, 3j 58%
isolated yield of product was given in parentheses; c 50 mol% of CuBr was used as
additives; d the reaction performed under air in sealed tubes; e Na2CO3, Cs2CO3, K3PO3
showed lower reactivity than K2CO3; f reaction performed on 2 mmol scale under air in
a sealed tube. DEC: diethylcarbonate; DCE: 1,2-dichloroethane.
S
S
S
S
S
O
O
O
O
O
O
3e 76%
3f 79%
nBu
N
nBu
N
nBu
N
S
S
Br
S
S
OCF3
S
S
N
O
O
O
O
O
O
3k 58%c
3l 73%
3m 69%d
O
nBu
N
However, the addition of 50 mol% of CuBr as an additive
significantly improved the conversion of 1a, providing 3a in 71%
isolated yield as a single isomer (entry 2). Analysis of crystal structure
revealed that the sulfonylation occurred at electron-rich C3 position
of the phenothiazine ring (see SI). Surprisingly, no desulfitative
arylation product was observed in this case, possibly due to the high
reactivity of PTZs. No reaction occurred in the absence of Cu(I)
catalyst (entry 4). Finally, by evaluation of different metal species,
bases, solvents, (entry 5-13), we found that the reaction was
performed using CuI (20%), Li2CO3 (2 equiv.) in DCE at 120 oC reflux
for 18 hours under air, affording 3a in 84% isolated yield even on 2
mmol scale (entry 14).
O
nBu
Br
N
S
S
S
O
S
S
O
O
O
3n 81%
nBu
3o 79%
Me
nBu
N
nBu
N
N
N
N
CF3
S
O
O
S
S
S
S
S
O
O
O
O
3q 71%e
3p 72%
0
a Reactions were performed on 0.5 mmol scale based on 1a, isolated yields were given in
all cases, b12% of disulfonylation product isolated. c15% of disulfonylation product
isolated. d crystal structure of 3m, hydrogens were omitted for clarity. e 50 mol% CuI
loading at 130 oC.
Scheme 2. Scope Study of Ar-SO2Cl with PTZ 1a
2 | J. Name., 2012, 00, 1-3
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Journal Name
Subsequently, we randomly studied the reactivity between Scheme 4. Post-functionalization of 3k and 3u.
ARTICLE
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DOI: 10.1039/C9OB00705A
different PTZs and arylsulfonyl chlorides (Scheme 3). The
products 3r, 3s were formed in moderate yields from two
arylsulfonyl chlorides. Substrate 1c, previously utilized as
photocatalyst, was highly reactive under catalytic conditions to
generate 3t in 95% isolated yield. Product 3u was prepared from
PTZs 1d in 53% yield, which contained an Ar-Br motif on N-alkyl
unit. The reactivity of complex C2 substituted PTZs 1e, 1f were
further investigated. As shown in scheme 3, with the reaction
from 3-chloro-N-propylphenothiazine 1e, two isolable
regioisomers obtained (3v 54%, 3w 30%, ratio 1.8:1), the
sulfonylation preferred to occur at more electron rich benzene
ring to form 3v rather than the electronegative Cl substituted
benzene ring. Only one regioisomer 3x was obtained when 1f
was employed, possibly due to the presence of electron-rich
thiomethyl substituent. With N-Boc or N-Ac protected
phenothiazines, the reaction does not proceed.
8b,8e,8h,14
According to the previous literature research,
we
envision that arylsulfonyl chlorides could undergo two possible
reaction pathways under metal-dependent catalysis: a). Cu(I)
promoted single electron transfer (SET) involving an arylsulfone
radical; b) arylsulfonyl chlorides oxidative addition to transition
metals generate hypervalent metal species, which facilitate the
electrophilic aromatic metalation and sulfonylation reaction. To
clarify the mechanism of this sulfonation reaction, two
experiments were conducted, 1) when the TEMPO was used as
radical scavenger, the reaction (Scheme 5, eq. 3) was
completely inhibited, suggesting a possible radical reaction
pathway; 2). when equal mole reactants, 1a, 2a, 2f, were
submitted to react under optimal conditions (eq. 4), the result
showed there was no significant reactivity difference (yield
3f:3b=13:14) between the two reactants 2a, 2f, which could
rule out the Friedel-Crafts reaction pathway.
R1
R1
N
R3
R2
N
Het
O
R3
20 mol% CuI
Het
2
R2
H
+
ClO2
S
Me
Li2CO3 ( 2 equiv.)
DCE, 120 oC, 18 h
S
S
nBu
N
Me
H
S
nBu
O
H
H
N
20 mol% CuI
1b-f
3r-x
eq. 3
+
Cl
TEMPO (2.0 equiv.)
Li2CO3, DCE,
Br
S
S
S
S
Ph
Bn
N
O
O
O
R
O
120 oC, 18 h
N
Me
3a
0
1a 1 equiv.
2a 1 equiv.
0.2 mmol
N
S
S
S
Br
S
S
O
O
O
O
OMe
nBu
N
OMe
S
3t, 95%
3r, Naphthyl, 42%b
3s, 4-CN, 37%
O
O
3u, 53%
Bn
N
Cl
S
S
S
SMe
O
O
Br
nPr
nBu
N
nPr
N
Br
O
O
O
N
Cl
S
3b 0.13 mmol, 33%
Cl
20 mol% CuI
S
S
2b 1 equiv.
O
eq. 4
+
S
CF3
Li2CO3, DCE,
120 oC, 18 h
CF3
S
S
S
nBu
N
F3CO
O
O
O
O
1a 1 equiv.
0.4 mmol
3x, 46%
3v, 54%
3w, 30%
Cl
S
S
S
O
a Reactions were performed on 0.5 mmol scale based on 1b-1f, isolated yields were given
O
O
O
in all cases. b50 mol% CuI loading at 130 oC.
3f 0.14 mmol, 35%
2f 1 equiv.
R2-SO2Cl
+ Cu(I)
Scheme 3. Scope Study of PTZs
R1
N
R2-SO2Cl
LiCl
+
Cu(II)
R1
R1
N
Poly(hetero)arenes play important roles in drug discovery
and material science. It was interesting to demonstrate the
further transformation of the sulfonylated PTZs products. The
intramolecular cyclization reactions from 3k, 3u were
performed (Scheme 4) using previously reported procedures,13
affording the five-membered heteroarene 3y in 75% isolated
yield (eq. 1). Compound 3u, was cyclized using the palladium
catalytic system under oxygen atmosphere (eq. 2), might
undergo an electrophilic palladation pathway with more
electron rich benzene ring to form 3z in 45% yield.
S
N
·
S
SO2R2
SO2R2
S
H
R1
N
Cu(I)
LiCO3
·
Cu(II)
S
SO2R2
LiHCO3
Scheme 5. Control Experiments and Proposed Mechanism
Based on the experimental results and previous literature
work, a possible mechanism involving radical was proposed.
First, Cu(I) catalyst donates one electron to R-SO2Cl reactant to
nBu
N
nBu
N
.
.
generate R-SO2 radical at high temperature. Second, the R-SO2
Br
H
1 mol% Pd(OAc)2
radical would in-situ electrophilic attack the electron rich C3
position of phenothiazines,15 following with base (Li2CO3)-
assisted deprotonation of the aromatic radical species. Finally,
Cu(II) oxidize the aromatic radical anion intermediates to form
the corresponding sulfonylation product and regenerate of
Cu(I) catalyst.
eq. 1
S
KOAc, DMAc
150 oC, 16 h
S
S
S
O
O
O
O
H
H
3y 75%
Br
Me
Me
H
H
1 mol% Pd(OAc)2
Cs2CO3, BzMe3NBr
H
N
N
S
eq. 2
DMAc, 130 o
C
S
S
S
O
O
O2, 16 h
O
O
3z 45%
Conclusions
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
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ARTICLE
Journal Name
S. Hisanaga, T. Iwatsubo, M. Goedert, and M.VHieawsAertgicalewOan,linJe.
Biol. Chem., 2005, 280, 7614; (d) M. DPOoId: 1d0a.1r0, 3P9./CG9aOuBt0a0m70, 5YA.
Rout and R. Misra, Dyes and Pigments, 2017, 146, 368; (e) D.
B. Shinde, J. K. Salunke, N. R. Candeias, F. Tinti, M. Gazzano, P.
P. Wadgaonkar, A. Priimagi, N. Camaioni and P. Vivo, Sci. Rep.,
2017, 7, 46268; (f) J. A. Christensen, B. T. Phelan, S. Chaudhuri,
A. Acharya, V. S. Batista and M. R. Wasielewski, J. Am. Chem.
Soc., 2018, 140, 5290; (g) S. Dadashi-Silab, X. Pan and K.
Matyjaszewski, Eur. J. Chem., 2017, 23, 5972.
2. (a) E. H. Discekici, N. J. Treat, S. O. Poelma, K. M. Mattson,
Z. M. Hudson, Y. Luo, C. J. Hawker and J. Read de Alaniz, Chem.
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N-Arylation of phenothiazines, see: (a) R. Jin and F. W.
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In summary, a simple and inexpensive CuI/Li2CO3 catalytic
system was developed for effective sulfonylation of biorelevant
phenothiazines. The non-directed C-H sulfonylation reaction
presented exclusive regioselectivity at C3 position and broad
substrates from (hetero)arylsulfonyl chlorides, as well as
alkylsulfonyl chlorides were tolerated, offering straightforward
access to useful functionalized phenothiazines. Further
property studies of novel phenothiazines are currently in
progress.
2
3
Experimental section
General information. Unless otherwise noted, all reactions were
handled under air atmosphere, refluxed in 25 mL flame-dried Schlenk
tubes placed in a preheated oil bath. CuI (99.995%, 99.5% purity)
were used for reaction optimization and substrate scope studies.
HPLC grade solvents, 1,4-dioxane, DMF, m-xylene, 1,2-
dichloroethane (DCE), Diethyl carbonate (DEC) were purchased from
4
5
(a) C. S. Krämer and T. J. J. Müller, Eur. J. Org. Chem., 2003,
3534; (b) B. Cecconi, N. Manfredi, R. Ruffo, T. Montini, I.
Romero-Ocana, P. Fornasiero and A. Abbotto, ChemSusChem,
2015, 8, 4216.
1
commercial sources and used without further purification. H NMR
spectra were recorded on a Bruker GPX 400 MHz spectrometer.
Chemical shifts (δ) were reported in parts per million relative to
residual chloroform (7.26 ppm for 1H NMR; 77.0 ppm for 13C NMR),
Coupling constants were reported in Hertz. 1H NMR assignment
abbreviations were the following: singlet (s), broad singlet (bs),
doublet (d), triplet (t), quartet (q), doublet of doublets (dd), doublet
of triplets (dt), and multiplet (m). 13C NMR spectra were recorded at
100 MHz on the same spectrometer and reported in ppm. Melting
point were measured on SGW-4A microscopic melting point
apparatus. Mass spectra were conducted at Agilent Technologies
5973N (EI).
Selected review about C-H functionalizations, (a) D. Alberico,
M. E. Scott, M. Lautens, Chem. Rev., 2007, 107, 174; (b) B.-J.
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6
7
General Procedure for the sulfonylation of PTZs (3a-3w).
Phenothiazines 1a-1f (0.5 mmol, 1.0 equiv.), R-SO2Cl (0.75 mmol, 1.5
equiv.), CuI (19 mg, 0.1 mmol), Li2CO3 (74 mg, 1.0 mmol), 1,2-
dichloroethane (0.25 M, 2 mL) were subsequently added to an oven
dried 25 mL Schlenk tube and sealed with a Teflon screw-cap under
air atmosphere. The resulting solution was allowed to reflux in a
preheated (120 oC) oil bath for 18 h with rigid stirring. Upon the
reaction completed, the crude reaction mixture was concentrated
and directly purified by using silica chromatography (ethyl acetate/
petroleum ether) as eluent to afford 3a-3w.
8
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
The authors thank the National Natural Science Foundation of
China (21702145, 21506148) to sponsor our research.
Notes and references
9
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