Cu(i)-Catalyzed oxidative homo-coupling of thiazoline-4-carboxylates: Synthesis of 4,4′-bithiazoline derivatives

Article abstract of DOI:10.1039/c6ob01471b

Cu(i)-Catalyzed oxidative homo-coupling of thiazoline-4-carboxylates with good functional group tolerance has been developed. The methodology presented an efficient method to directly construct vicinal carbon-hetero quaternary centers existing in numerous functional molecules and could be applied to the synthesis of 4,4′-bithiazoles which are difficult to prepare by direct C-H activation.

Full text of DOI:10.1039/c6ob01471b

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DOI: 10.1039/C6OB01471B
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COMMUNICATION
Cu(I)-Catalyzed Oxidative Homo-Coupling of Thiazoline-4-
Carboxylates: Synthesis of 4,4’-Bithiazoline Derivatives
Xinxin Fanga, Kaifan Zhanga, Hequan Yaoa* and Yue Huangb*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
The Cu(I)-catalyzed oxidative homo-coupling of thiazoline-4-
carboxylates with good functional group tolerance has been
developed. The methodology presented an efficient method
to directly construct vicinal carbon-hetero quaternary centers
existing in numerous functional molecules and could apply to
the synthesis of 4,4’-bithiazoles which are difficult to be
prepared by direct C−H activation.
Dehydrogenative coupling is an efficient tool to rapidly
construct C-C bonds, which satisfies the requirement of atom
economy,
environment
protection
and
avoids
prefunctionalized starting materials as well as unwanted
stoichiometric amounts of chemical waste.1 Among those, the
homo-coupling of tertiary carbon, which involves a radical
coupling sequence, is particular suitable for the building of
vicinal quaternary centers attributing to the strong tendency
Scheme 1. Recent strategies for the synthesis of 4,4'-
of radical to form C-C bond and the sterically favourable effect bithiazoline.
of the coupling reaction.2 The oxidative coupling of tertiary
noble metals, copper is inexpensive and readily available and
carbon represents one of the most straightforward methods to
synthesize this kind of compounds. Many catalytic systems
have been developed including Co(I),2a V2O5,2b CAN/aqueous
KOH,2c, 2d and KOtBu/I2.2e 4,4'-Bithiazoline derivatives as a kind
of important heterocylic compounds bearing vicinal carbon-
hetero quaternary centers have broad applications in the field
of medicinal chemistry and material chemistry,3 such as
yersiniabactin derivative ulbactin E, which is an antibacterial
agent. However, the developed synthetic methods of 4,4'-
bithiazolines are limited (Scheme 1, eq.(1)(2)).4 Compared to
usually used to mediate various oxidative homo-coupling.5 To
the best of our knowledge, no systematic study is reported for
the copper salt catalyzed dehydrogenative homo-coupling of
tertiary carbon.
4,4'-Bithiazole derivatives are also important nitrogen-
containing heterocylic skeletons which have broad applications
in the field of medicinal chemistry and ligand chemistry.6
Current methods for building of 4,4'-bithiazole skeleton, the
carbon atoms of material are required to be pre-activated or
special functional materials are needed.7 Actually, it’s difficult
to be functionalized on C4-position of thiazole ring via direct
C−H activation.8 Concerning our continuing interest in the
functionalization of azoles,8f-8h,9 herein we report a Cu(I)-
catalyzed homo-coupling of tertiary carbon to provide a facile
approach for construction of 4,4'-bithiazolines, and the
coupling products could easily generate 4,4’-bithiazoles
through hydrolysis and oxidative decarboxylation progress
which are difficult to be prepared by direct C−H activation.
To achieve our assumption, we chose methyl 2-phenyl-4,5-
dihydrothiazole-4-carboxylate (1a) as model substrate to
optimize reaction conditions. We screened a number of
a.State Key Laboratory of Natural Medicines and department of medicinal
Chemistry, China Pharmaceutical University, Nanjing, 24 Tong Jia Xiang, 210009,
P. R. China.
b.Department of Organic Chemistry, China Pharmaceutical University, Nanjing, 24
Tong Jia Xiang, 210009, P. R. China.
E-mail: hyao@cpu.edu.cn, yhuang@cpu.edu.cn
† Footnotes relating to the title and/or authors should appear here.
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
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Table1. Optimization of the reaction conditionsa
Figure 1. X-ray structures of 2a (left) and 2a’ (right)
View Article Online
DOI: 10.1039/C6OB01471B
Entr
Cat. (mol%)
Oxidant
Yield (%)b
drb
y
1
2
3
4
CuCl (10)
Cu2O (10)
CuCN (10)
Ph2I+OTf-
Ph2I+OTf-
Ph2I+OTf-
Ph2I+OTf-
40
70
ND
40
1.3:1
1.2:1
/
Based on the above optimization, the substrate scope for
this Cu(I)-catalyzed oxidative homo-coupling of thiazoline-4-
carboxylates was investigated (Table 2). The reaction of 4,5-
Cu(CH3CN)4PF6 (10)
Copper(II) 2-
ethylhexanoate (10)
1.9:1
5
Ph2I+OTf-
38
1.2:1
dihydrothiazole-4-carboxylates
(
1
)
with
electron-rich
-
Ph2I+BF4
67
40
82
1.2:1
1.1:1
1.3:1
1.2:1
1.5:1
/
substituents such as methyl at para-/meta- position of phenyl
ring reacted smoothly giving good to excellent yields of 2b and
6
7
8
Cu2O (10)
Cu2O (10)
Cu2O (15)
Cu2O (20)
Cu2O (15)
Cu2O (15)
/
PhI(OAc)2
Ph2I+OTf-
Ph2I+OTf-
Ph2I+OTf-
Ph2I+OTf-
Ph2I+OTf-
/
2c
. 4,5-Dihydrothiazole-substituted benzene possessing a
methyl on ortho-position offered a relatively low yield of 2d
,
9
69
which may be due to the steric effect. Strong electron-
donating substituent such as methoxyl and electron-
withdrawing substituents such as methoxycarbonyl and acetyl
groups decreased the reaction conversion and produced
10c
11e
12
13
14f
84 (86)d
NR
Trace
24
Trace
/
Cu2O (15)
Cu2O (15)
1.2:1
/
moderate yields of 2e
groups (F, Cl, Br, I) on para-position of the phenyl ring were
well tolerated, affording the corresponding 2h 2k in good
-2g. The substrates bearing halogen
/
a Reaction conditions: 1a (0.4 mmol, 1.0 equiv), catalyst, L1
-
(0.12 mmol), oxidant (0.08 mmol), CsOAc (0.4 mmol), 1,4-
yields and providing synthetically useful functionalities for
further transformations. Moreover, substrates possessing two
substituents on the phenyl ring worked well and produced 2l
and 2m in yield of 89% and 64%, respectively. Compared to
the methyl ester derivative 2a, ethyl ester derivative 2n was
generated in relatively low yield of 61% attributing to the
steric effect. 4,5-Dihydrothiazole-4-carboxylate bearing thienyl
substituent was able to furnish the corresponding product 2o
in 41% yield. However, the present system was not applicable
for pyridyl and alkyl derivatives; in both cases starting
substrates were recovered, while 2p was obtained in trace and
2q was not observed. 4,5-Dihydrooxazole-4-caboxylate was
also examined, and the corresponding product 2r was
obtained with yield of 31%. In addition, when this reaction was
performed on a larger scale (6 mmol, 1.33 g), 2a could still be
achieved in 72% isolated yield (958 mg).
o
dioxane (1.0 mL), air atmosphere, 70 C, 26 h. b Yield and
diastereoselectivity ratio were determined by 1H NMR using
c
o
dibromomethane (δ = 4.80) as an internal standard. 75 C.
f
d Isolated yield of two diastereoisomers. e Without base.
Under Ar atmosphere.
conditions including copper salts, ligands, oxidants, bases,
solvents (see the Supporting Information) and some typical
results were summarized in Table 1. Our initial attempt began
with a catalytic amount of CuCl (10 mol%), 6-methylpicolinic
acid (L1), Ph2I+OTf-, 1,4-dioxane at 70 oC under air atmosphere,
and the desired homo-coupling product 2a was obtained in 40%
yield with 1.3:1 dr (Table 1, entry 1). The isolated
diastereoisomer structures were determined by X-ray crystal
structure analysis (Figure 1).10 Then a series of copper salts
were tested, the results indicated that Cu2O could remarkably
enhance the yield to 70% (Table 1, entries 2-5). When the
oxidants were replaced with Ph2I+BF4- and PhI(OAc)2, the yields
were reduced to 67% and 40%, respectively (Table 1, entries 6-
7). A yield of 82% was obtained after increasing the amount of
Cu2O to 15 mol% equivalent, while adding the catalytic loading
from 10 to 20 mol% did not affect the overall outcome of the
Table 2. Scope of 4,5-dihydroazole-4-carboxylatesa,b
o
reaction (Table 1, entries 8-9). Moreover, 75 C was found to
be the best temperature for this reaction (Table 1, entry 10).
Control experiments indicated that no reaction took place or
only trace product was obtained in the absence of the base or
catalyst (Table 1, entries 11-12). Without oxidant the yield of
coupling product was decreased to 24% (Table 1, entry 13),
and trace product was produced without oxidant and under
argon atmosphere (Table 1, entry 14).
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Table 3. Scope of 4,4’-bithiazolinesa,b,c
View Article Online
DOI: 10.1039/C6OB01471B
a Reaction conditions: (1)
2
(0.2 mmol, 1.0 equiv), NaOH (1.6
mmol), MeOH/H2O (1:1, 3.0 mL); (2) DDQ (0.6 mmol, 3.0
equiv), toluene (2.0 ml), 110 oC, 24h. b 1H NMR yields using
dibromomethane (δ = 4.80) as an internal standard. c Isolated
yields.
Scheme 3. Control experiments
a Reaction conditions: 1 (0.4 mmol, 1.0 equiv), Cu2O (0.06 mmol), L1
(0.12 mmol), Ph2I+OTf- (0.08 mmol), CsOAc (0.4 mmol), 1,4-dioxane
b
(1.0 mL), air atmosphere, 75 oC.
diastereoisomers.
Isolated yields of two
c
One diastereoisomer could be isolated,
diastereoselectivity ratio was determined by H NMR. d Cs2CO3 was
used, Ph2I+OTf- (0.16 mmol), 80 oC.
1
Scheme 2. Further transformation of 4,4'-bithiazoline-4-
carboxylates
To shed light on the synthetic application of the homo-
coupling products, selected 4,4'-bithiazoline was subjected to
further functionalization (Scheme 2). 4,4'-Bithiazoline (R=Br, 2j
smoothly underwent C-O coupling with p-methoxyphenol to
)
tolerated (5b-5e), and heteroaromatic ring was also suitable
for this transformation (5f). This transformation to construct
4,4'-bithiazole derivatives could be an alternative route to this
kind of derivatives.
furnish
gave the corresponding C-C coupling product
3
in 56% yield.11 In addition, 2j with phenylboronic acid
4
in 71% yield.12
Furthermore, 4,4'-bithiazoline products could be further
transformed to 4,4'-bithiazole derivatives which were difficult
to be prepared by direct C−H activation. First, treatment of the
To gain further insights into the mechanism of the homo-
coupling process, control experiments were performed
(Scheme 3). When the radical scavenger TEMPO was added,
no desired product was detected and starting material was
recovered (Scheme 3, eq.(1)). The experimental result
indicated that this coupling reaction might contain radical
mechanism process. When the equivalent of Ph2I+OTf- was
homo-coupling product
2 with NaOH provided hydrolysis
intermediates in almost quantative yields.13 Then 4,4'-
bithiazole derivatives
5 was furnished with DDQ as oxidant in
o
toluene at 110 C.14 Substrates bearing methyl on para-/meta-
/ortho- positions or two substituents of phenyl ring were
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increased to 1.5 equiv. and reaction was conducted under
argon atmosphere, 2a was obtained in yield of 71%, which
indicated that Ph2I+OTf- could be the oxidant in this coupling
(Scheme 3, eq.(2)). Moreover, only 23% coupling product 2a
was obtained with the optimized condition under argon
atmosphere instead of air (Scheme 3, eq.(3)). Finally, the
reaction was proceeded without Ph2I+OTf- under argon
atmosphere, 2a was produced in yield of 29%. The two
experimental results suggested that air might play a role as
oxidation as same as Ph2I+OTf-.
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Based on the control experiment results and literatures,1a, 15
the possible mechanism for this oxidative homo-coupling is
proposed in Scheme 4. The first step of this transformation is
enolization of
1 to afford enolate ions 6
. Meanwhile the CuI is
oxidized in situ to active CuII/CuIII species by Ph2I+OTf- and air.
(e) S. Ghosh, S. Chaudhuri and A. Bisai, Org. Lett., 2015, 17
,
Subsequently enolate ions
transfer to provide radical
6
7
further undergoes single electron
. Finally, radicial-radicial coupling
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Scheme 4. Proposed mechanism of oxidative homo-coupling
4
5
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In summary, we have established a practical protocol for the
homo-coupling of thiazoline-4-carboxylates to construct vicinal
carbon-hetero quaternary centers with a copper catalytic
system. A variety of functional groups and heterocycles were
tolerated. A radical-mediated mechanism was tentatively
proposed. Further utilization of the method could generate
functionalized 4,4'-bithiazoline-4-carboxylate derivatives and
provided a facile and efficient approach for the construction of
4,4'-bithiazole derivatives by oxidative decarboxylation of
homo-coupling products. Further efforts to the applications of
this method are currently underway.
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Generous financial support from the National Natural
Science Foundation of China (NSFC21272276) and the Natural
Science Foundation of Jiangsu Province (BK20130645) is
gratefully acknowledged.
6
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Organic & Biomolecular Chemistry
Page 6 of 6
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DOI: 10.1039/C6OB01471B
The Cu(I)-catalyzed oxidative homo-coupling of thiazoline-4-carboxylates with
good functional group tolerance has been developed.