Palladium-catalyzed C-H functionalization using guanidine as a directing group: Ortho arylation and olefination of arylguanidines

Article abstract of DOI:10.1021/ol302533w

Palladium-catalyzed C-H functionalization using guanidine as the directing group was achieved under mild reaction conditions. Various guanidine derivatives were produced in moderate to good yields by using simple unactivated arenes or ethyl acrylate as the source of arylation or olefination, respectively.

Full text of DOI:10.1021/ol302533w

ORGANIC
LETTERS
2012
Vol. 14, No. 21
5452–5455
Palladium-Catalyzed CꢀH
Functionalization Using Guanidine
as a Directing Group: Ortho Arylation
and Olefination of Arylguanidines
Jiaan Shao,† Wenteng Chen,† Marc A. Giulianotti,‡ Richard A. Houghten,‡ and
Yongping Yu*,†,‡
Institute of Materia Medica, College of Pharmaceutical Sciences, Zhejiang University,
Hangzhou 310058, P. R. China and Torrey Pines Institute for Molecular Studies,
11350 SW Village Parkway, Port St Lucie, Florida 34987, United States
yyu@zju.edu.cn
Received September 13, 2012
ABSTRACT
Palladium-catalyzed CꢀH functionalization using guanidine as the directing group was achieved under mild reaction conditions. Various
guanidine derivatives were produced in moderate to good yields by using simple unactivated arenes or ethyl acrylate as the source of arylation or
olefination, respectively.
Palladium-catalyzed CꢀH bond functionalization for the
CꢀC bond formation has emerged as a promising area in
organic synthesis; however, it still remains a tremendous
challenge.1 In particular, the combination of palladium and
directing groups provides an efficient way to facilitate CꢀH
bond cleavage and transform a CꢀH bond to a CꢀC bond.2
In the past years, diverse directing groups, including
pyridyl,3a carbamate,3b pyrazole,3c oxazolyl,3d amide,3e
oxime ether,3f ketones,3g hydroxyl,3h and carboxylic
acids,3i,j havebeen developedtoassistaromatic CꢀH bond
activation.
Guanidines are important structural motifs in a wide
range of molecules with numerous applications such as
histamine receptor agonists,4 antidiabetic,5 adrenoceptor
antagonists,6 as well as chiral catalysts.7 Guanidines also
have been widely used as coordination groups with various
metals in many useful complexes.8 However, to the best of
our knowledge, using guanidine as the directing group to
achieve CꢀH functionalization of substituted aromatics
† Zhejiang University.
‡ Torrey Pines Institute for Molecular Studies.
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r
10.1021/ol302533w
Published on Web 10/24/2012
2012 American Chemical Society

Table 1. Screening of The Reaction Condition of Ortho-Arylationa
Scheme 1. Scope of The Orytho-Arylation Reactiona
entry
oxidant (equiv)
additive (s)
yield (%)b
1
2
Ag2CO3 (2)
Ag2O (2)
10 equiv of TFA
10 equiv of TFA
10 equiv of TFA
10 equiv of TFA
10 equiv of TFA
10 equiv of TFA
10 equiv of TFA
10 equiv of TFA
10 equiv of HOAc
10 equiv of TFA
10 equiv of TFA
10 equiv of TFA
0
0
3
Cu(OAc)2 (2)
p-benzoquinone (2)
air
0
4
trace
0
5
6
K2S2O8 (2)
K2S2O8 (3)
K2S2O8 (4)
K2S2O8 (3)
K2S2O8 (3)
K2S2O8 (3)
K2S2O8 (3)
61
72
70
0
7
8
9
10c
11d
12e
53
66
58
a Reaction conditions: phenyguanidine carbonate salt (0.5 mmol, 1.0
equiv), Pd(OAc)2 (10 mol %), benzene (1 mL), TFA (5 mmol, 10 equiv),
K2S2O8, 65 °C, 48 h. The most successful entry is highlighted in bold.
b Determined by high-performance liquid chromatography. c 5 mmol %
Pd(OAc)2 was used. d Reaction was performed at 80 °C for 48 h.
e Reaction was performed at 65 °C for 36 h.
has not been explored in the literature. The important
applications of guanidine derivatives in drug discovery and
natural product synthesis prompted us to develop a Pd-
catalyzed CꢀH functionalization of aryl guanidines.
The biaryl linkageisanimportantstructural motif thatis
prevalent in numerous organic compounds, including
natural products,9a pharmaceuticals,9b privileged ligands9c
and conjugated materials.9d Palladium-catalyzed direct
oxidative functionalization of CꢀH bonds of two arene
coupling partners constitutes an important and desirable
process for the synthesis of biaryls.10 So the attempt using
phenylguanidine as a test substrate to react with benzene
under various conditions toform a CꢀC biaryllinkagewas
carried out as the primary case study. By surveying various
reaction parameters, we obtained key results shown in
Table 1.
First, the reaction was carried out by using Pd(OAc)2
(10 mol %) as the catalyst in the presence of different oxidants
with TFA. However, no conversation was observed at
65°C for 48h whenAg2CO3, Ag2O or Cu(OAc)2 were used
as the oxidant (Table 1, entry 1, 2 and 3). There was also no
conversion observed when the reaction was exposed to the
a Reaction conditions: guanidine carbonate salts (0.5 mmol,
1.0 equiv), Pd(OAc)2 (10 mol %), arene (1 mL), TFA (5 mmol, 10 equiv),
b
K2S2O8(1.5 mmol, 1.0 equiv), 65 °C, 48 h. Reaction was performed at
80 °C for 64 h. c The ratio of the regioisomers was detemined by 1H NMR,
products were isolated as their HCl saits, isolated yield.
air without any oxidant (Table 1, entry 5). A trace amount
of the conversion occurred when BQ (p-benzoquinone)
was used as the oxidant (Table 1, entry 4). To our delight,
the conversion was improved significantly when BQ was
replaced by potassium persulfate (K2S2O8), and the ideal
amount of K2S2O8 was determined to be 3 equivelants to 1
equivalent of guanidine (Table 1, entry 4, 6ꢀ8). When the
same reaction was carried out in the absence of K2S2O8 or
TFA, no desired product was observed. And if TFA was
replaced by acetic acid, no desired product was observed
ꢀ
(9) (a) Baudoin, O.; Gueritte, F. Stud. Nat. Prod. Chem. 2003, 29,
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Buchwald, S. L. Org. Lett. 2008, 10, 2207.
Org. Lett., Vol. 14, No. 21, 2012
5453

Scheme 2. Ortho-Arylation of Protected Phenylguanidine
Scheme 4. Plausible Catalyic Mechanisms for the CꢀH Bond
Activation
Scheme 3. Ortho-Olefination of Phenylguanidines with Ethyl
Acrlatea
a Reaction conditions: guanidine carbonate salts (0.5 mmol, 1.0
equiv), ethyl acrylate (0.75 mmol, 1.5 equiv), Pd(OAc)2 (10 mol %),
BQ (0.75 mmol, 1.5 equiv), HOAc (1.5 mL), 65 °C, 5 h, products were
isolated as their HCl saits, isolated yield. b 2.5 equiv of ethyl acrylate was
used, reaction was performed at 80 °C for 17 h c Reaction was performed
at 80 °C for 24 h.
regioisomeric products obtained when toluene was used as
the arylation source (2b, 2b0 and 2g, 2g0). High regioselec-
tivity was observed in the reaction of 1-m-tolylguanidine
leading to arylation only at the CꢀH bond para to the
methyl substituent presumably due to steric reasons
(2n). However, if the guanidine group was protected
by methyl or acetyl, there was no desired product
observed under the standard reaction conditions. No
desired product generated when 1H-benzo[d]imidazol-
2-amine was applied under the standard conditions,
either (Scheme 2).
In order to investigate the versatility of the guanidine
directing group in CꢀH activation, we also explored the
ortho-olefination reactionof substitutedphenylguanidines
with ethyl acrylate. After optimization of the reaction
conditions, it was found that the olefination reaction could
proceed successfully in the presence of Pd(OAc)2 (10 mol
%), and BQ (1.5 equiv) using acetic acid as the solvent at
65 °C for 5 h.
either (Table 1, entry 9). The results showed that both
K2S2O8 and TFA were required for the formation of the
desired product. The reaction was also assessed at a higher
temperature (Table 1, entry 11) but with a slight decrease
in the yield. The amount of catalyst was also studied as
well as the reaction time (Table 1, entry 10 and 12). On the
basis of this initial study, the reaction was considered
proceeding most efficiently when 3 equivalents of K2S2O8,
10 mol % Pd(OAc)2 were applied in the presence of TFA at
65 °C for 48 h.
With the optimized conditions in hand, we next exam-
ined the scope of the substrates as displayed in Scheme 1.
Screening of arenes demonstrated that only electron-neu-
tral or electron-rich arenes could take part in the arylation
reaction efficiently. Electron-deficient arenes such as 1,
2-dichlorobenzene resulted in notably low conversion even
under harsher reaction conditions (2m). Both electron-rich
and electron-deficient phenylguanidines could be efficiently
arylated using our protocol. However, the electron-rich
phenylguanidines were more reactive, giving higher yields.
Notably, most products were obtained as the monoarylated
compounds as well as only one regioisomer. There were two
The optimized olefination reaction conditions were ap-
plied to additional substituted phenylguanidines (Scheme 3).
Most of the substituted phenylguanidines reacted cleanly
with ethyl acrylate to give the corresponding alkenyla-
tion products in moderate to good yields with excellent
5454
Org. Lett., Vol. 14, No. 21, 2012

E-stereoselectivity. The electron-rich phenylguanidines were
more reactive giving higher yields. We also obtained the bis-
substituted alkenylation products by adding additional one
equivalent of ethyl acrylate while the reaction was performed
at 80 °C for 17 h (3b).
furnish the final ortho-arylation products and regenerate
the PdII catalyst.
However, the ortho-olefination CꢀH bond functionali-
zation seems more likely to follow a Pd0/PdII pathway.10b,12
Initially, the electronic attack of PdII into phenylguanidines
formed the intermediate III, which inserted into olefins to
afford the intermediate IV. The subsequent β-hydro elim-
ination resulted in the product and liberates Pd0 as well
as acetic acid. The PdII was regenerated from the oxidation
of Pd0 by BQ.
In summary, we have successfully developed efficient
palladium(II)-catalyzed methods for arylation and olefi-
nation of arenes by the use of guanidine as the directing
group. The two different CꢀH functionalizations could be
achieved by suitable control of the reaction condition.
It is known that acetoxylation and arylation of pallada-
cycle in the presence of a strong oxidant were proposed to
proceed via PdIV. A plausible mechanism for the catalytic
arylation reaction is proposed as shown in Scheme 4.
The proposed mechanism is based on previously reported
chelation-assisted cross-couplings through CꢀH bond
functionalization.11 First, PdII coordinated with the nitro-
gen atom of the guanidine in the presence of TFA, which
induced the formation of a cyclopalladated intermediate I
by chelate-directed CꢀH activation. This PdII intermedi-
ate was oxidized by K2S2O8 in the presence of arenes
to afford a hexacoordinated PdIV intermediate II, which
proceeded through a reductive elimination process to
Acknowledgment. This research was supported by
the National Natural Science Foundation of China
(81072516), Natural Science Foundation of Zhejiang Pro-
vince (No. Z2110655) as well as the National Institute on
Drug Abuse (DA031370) and the State of Florida, Execu-
tiveOfficeof the Governor’sOfficeof Tourism, Trade, and
Economic Development.
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2006, 128, 14047. (d) Rosewall, C. F.; Sibbald, P. A.; Liskin, D. V.;
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Supporting Information Available. Experimental details,
1
and H and 13C NMR spectra of new compounds. This
(12) (a) Wang, L.; Guo, W.; Zhang, X. X.; Xia, X. D.; Xiao, W. J.
Org. Lett. 2012, 14, 740. (b) Cai, G. X.; Li, Y. Z.; Wan, X. B.; Shi, Z. J.
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material is available free of charge via the Internet at
http://pubs.acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 21, 2012
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