Palladium(II)-Catalyzed C-H Acylation with Arylglycine Derivatives

Article abstract of DOI:10.1055/s-0034-1380440

A novel palladium(II)-catalyzed ortho acylation of arenes with arylglycines in the presence of Cu(OAc)₂ and K₂S₂O₈ to afford the benzophenones was developed. This direct C-H acylation is suitable for a broad range of substrates. The control experiments suggested a possible oxidative addition mechanism.

Full text of DOI:10.1055/s-0034-1380440

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© Georg Thieme Verlag Stuttgart · New York
2015, 26, 2033–2036
letter
2033
W. Fan et al.
Letter
Synlett
Palladium(II)-Catalyzed C–H Acylation with Arylglycine Deriva-
tives
Weizheng Fan
R1
R1
Jiapeng Su
Pd(OAc)2 (5 mol%)
Bainian Feng*
H2N
COOH
K2S2O8 (2 equiv)
+
N
N
R2
School of Pharmaceutical Science, Jiangnan University,
Wuxi 214122, P. R. of China
fengbainian@jiangnan.edu.cn
R2
Cu(OAc)2 (10 mol%)
DMSO (5% H2O)
H
O
Received; 14.04.2015
Accepted after revision; 17.05.2015
Published online: 25.06.2015
this work
COOH
ref. 13
CO + ArI
H2N
DOI: 10.1055/s-0034-1380440; Art ID: st-2015-w0270-l
Ar
Abstract A novel palladium(II)-catalyzed ortho acylation of arenes
with arylglycines in the presence of Cu(OAc)2 and K2S2O8 to afford the
benzophenones was developed. This direct C–H acylation is suitable for
a broad range of substrates. The control experiments suggested a pos-
sible oxidative addition mechanism.
ref. 5
ref. 6
ArCHO
ArCH2OCH2Ar ref. 12
DG
O
ArCH2OH
ArCH2NH2
ArCOOH
ref. 11
ref. 10
Ar
ref. 7 ArCOCOOH
Key words palladium(II)-catalyzed, ortho acylation, arylglycine, C–H
activation, oxidative addition
ArMe
ref. 8
ArCOOCAr
ref. 9
Transition-metal-catalyzed direct selective functional-
ization of arenes via C–H activation has attracted consider-
able attention due to the ecological and economical advan-
tages in comparison to traditional cross-coupling methods
with the pre-activated starting materials.1 Benzophenones
are prominent structural motifs of many pharmaceuticals,
fragrances, and agrochemicals.2 Regarding their synthesis,
many effective methods have been developed, including the
traditional Friedel–Crafts acylation3 and some catalytic
Friedel–Crafts acylations.4 But these methods showed poor
selectivity with isomeric mixtures. In order to solve the se-
lectivity issue, metal-catalyzed oxidative ortho acylations
were developed bearing conventional directing groups
(Scheme 1).5–13 The acyl sources included aldehydes,5 alco-
hols,6 α-oxocarboxylic acids,7 toluenes,8 diketones,9 carbox-
ylic acids,10 arylmethyl amines,11 benzylic ethers,12 and CO
with PhI.13
Scheme 1 Acyl sources for the preparation of directed benzophenones
tion from phenylglycine to phenylglyoxylic acid, we at-
tempted to employ the same phenylglycine to achieve ortho
acylation. Herein, we present a novel palladium(II)-cata-
lyzed ortho acylation of arenes with arylglycine in the pres-
ence of Cu(OAc)2 and K2S2O8 to afford the benzophenones.
We began our investigation by allowing 2-phenylpyri-
dine (1a) and phenylglycine (2a) to react in the presence of
different palladium catalysts, oxidants, additives, and sol-
vents. To our delight, when the reaction was conducted
with Pd(OAc)2 (5 mol%) and K2S2O8 (2 equiv) in DMSO (in-
cluding 5% H2O) at 120 °C, 3a was formed in 52% yield (Ta-
ble 1, entry 1). Other palladium catalysts gave lower yields
(Table 1, entries 2–4). Oxygen, the ideal oxidant, was also
tested to replace K2S2O8, but only a trace amount of the
product was detected (Table 1, entry 5). Using other oxi-
dants did not afford good results (Table 1, entries 6–10). A
slightly higher yield was observed when Cu(OAc)2 was in-
troduced into the reaction (Table 1, entry 12), compared
with other additives (Table 1, entries 11, 13 and 14). Com-
pound 3a was not obtained in the absence of Pd(OAc)2 (Ta-
Despite the significant advances made with respect to
the substrate scope, the quest for new methods of unacti-
vated C–H acylations remains a challenge. Inspired by
Wang’s recent work,14 which used amino acids as the direct
arylation source to construct the benzothiazoles and sug-
gested an oxidative mechanism involving the transforma-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 2033–2036

2034
W. Fan et al.
Letter
Synlett
R1
R1
Pd(OAc)2 (5 mol%)
K2S2O8 (2 equiv)
H2N
COOH
+
Cu(OAc)2 (10 mol%)
DMSO (5% H2O)
N
N
R2
R2
H
O
2
1
3
MeO
F3C
N
N
N
Ph
N
Ph
Ph
3a, 81%
t-Bu
Ph
O
O
O
O
3d, 73%
3c, 80%
3b, 75%
OMe
CF3
N
N
N
N
Ph
Ph
Ph
Ph
O
O
3e, 15%
O
O
3h, 68%
3g, 72%
3f, 84%
Cl
OMe
N
N
N
Ph
Ph
Ph
O
O
3k, 79%
O
3j, 82%
3i, 70%
CF3
F
Br
N
N
N
Ph
Ph
Ph
O
O
O
3n, 78%
3m, 68%
3l, 65%
3o, R2 = 4-FC6H4, 84%
3p, R2 = 4-ClC6H4, 87%
3q, R2 = 4-MeC6H4, 51%
3r, R2 = 2-FC6H4, 79%
3s, R2 = 2-MeC6H4, 62%
3t, R2 = Me, 0
3u, R2 = n-Bu, 0
3v, R2 = i-Pr, 0
N
R2
O
Scheme 2 Evaluation of the substrate scope. Reagents and conditions: 1a (0.5 mmol), 2a (0.6 mmol), Pd(OAc)2 (5 mol%), K2S2O8 (2 equiv), Cu(OAc)2
(10 mol%) in DMSO (5 mL) at 120 °C for 24 h under Ar atmosphere (1 atm).
ble 1, entry 15). When dry DMSO was used as solvent (Ta-
ble 1, entry 16), a very poor yield of 3a was obtained, sug-
gesting that water was the O-atom source. The use of other
solvents or increasing the catalyst loading led to no signifi-
cant improvement in yield (see Supporting Information, SI-
Tables 1, 2).
With the optimized reaction conditions in hand
[Pd(OAc)2, K2S2O8, and Cu(OAc)2], we turned our attention
to the evaluation of the substrate scope. The results of the
compatibility studies with respect to the substituted 2-
phenylpyridines 1a–v are presented in Scheme 2. A series
of functional groups including methyl, methoxyl, chloro,
trifluoromethyl, bromo, and fluoro on the phenyl ring were
compatible under standard conditions, affording the target
products 3a–n in good yields.18 There was no significant
electronic effect observed, but the presence of an ortho-po-
sitioned tert-butyl group in 1e reduced the yield of 3e to
15%, indicating a steric effect.
(3o,p,r > 3q,s). Aliphatic amino acids afforded no products
(3t–v).
More experiments were carried out to gain a better un-
derstanding of the mechanism of this transformation. First-
ly, addition of the radical scavenger TEMPO did not reduce
the yield under standard conditions. This suggests that a
radical process is not involved (Scheme 3, eq. 1). Secondly,
TEMPO (2 equiv)
1a
2a
+
2a
3a, 79%
(1)
(2)
standard conditions
standard conditions
CHO
COOH
+
Ph
56%
Ph
15%
standard conditions
CHO
Ph
1a
1a
+
+
3a, 48%
3a, 3%
(3)
(4)
COOH
Ph
standard conditions
Subsequently, the substituent effects of phenylglyoxylic
acid on this transformation were studied. In summary, elec-
tron-withdrawing substituents showed higher activity
Scheme 3 Control experiments
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 2033–2036

2035
W. Fan et al.
Letter
Synlett
Table 1 Optimization of the Conditions
In summary, we have developed a novel palladium(II)-
catalyzed ortho acylation of arenes with arylglycine in the
presence of Cu(OAc)2 and K2S2O8 to afford benzophenones.
This direct C–H acylation is suitable for a broad range of
substrates. The control experiments suggested a possible
oxidative addition mechanism. Further studies concerning
the detailed mechanism and a broader investigation of sub-
strate scope are currently in progress in our laboratory.
Pd catalyst
COOH
oxidant
H2N
+
N
N
additive
DMSO (5% H2O)
Ph
Ph
H
O
1a
2a
3a
Entrya
Catalyst
(5 mol%)
Oxidant
(2 equiv)
Additive
(10 mol%)
Yield
(%)b
standard
conditions
CHO
Ph
H2N
COOH
1
2
Pd(OAc)2
PdCl2
K2S2O8
K2S2O8
K2S2O8
K2S2O8
O2 (1 atm)
PhI(OAc)2
TBHP
–
52
8
–
Ph
3
Pd2(dba)3
Pd(OTf)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
–
–
0
Pd(OAc)2
4
–
47
<5
0
C–H activation
N
N
H
5
–
Pd(II)
1a
I
6
–
OAc
CHO
7
–
<5
33
41
28
61
81
43
49
0
8
Na2S2O8
Oxone
–
Ph
Pd(II)
9
–
elimination
10
11
12
13
14
15
16c
Ag2CO3
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
–
N
N
AgOTf
Cu(OAc)2
CuCl
Ph
3a
Pd(IV)
O
II
Ph
O
Scheme 4 Proposed mechanism
HOAc
Cu(OAc)2
Cu(OAc)2
Acknowledgment
Pd(OAc)2
<5
a Reaction conditions: 1a (0.5 mmol), 2a (0.6 mmol), catalyst (5 mol%), ox-
idant (2 equiv), additive (10 mol%), in DMSO (5 mL) at 120 °C for 24 h un-
der Ar atmosphere (1 atm).
This work was supported financially by grants from the National Nat-
ural Science Foundation of China (grants 21302066) and Young Pro-
gram, SCF of Jiangsu Province (BK20130129).
b Isolated yields.
c Dry DMSO solvent.
Supporting Information
when 2a reacted under standard conditions for only for one
hour, 56% yield of PhCHO and 15% yield of PhCOOH were
isolated, respectively (Scheme 3, eq. 2). This result is in
agreement with the fact that the α-amino acids are easily
oxidized to aldehydes.14,15 Moreover, 1a reacted with
PhCHO affording compound 3a in 48% yield, but PhCOOH
showed poor reactivity (Scheme 3, eq. 3 and 4).14 Finally,
the additional parallel experiments to oxidize the α-amino
acids with or without Cu(OAc)2 in the presence of K2S2O8
suggested that Cu(OAc)2 accelerated the oxidation of 2a
(Supporting Information, Scheme 1D).
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0034-1380440.
S
u
p
p
ortiInfogrmoaitn
S
u
p
p
o
nrtogI
f
rmoaitn
References and Notes
(1) For recent reviews, see: (a) Mousseau, J. J.; Charette, A. B. Acc.
Chem. Res. 2013, 46, 412. (b) Kuhl, N.; Hopkinson, M. N.;
Wencel-Delord, J.; Glorius, F. Angew. Chem. Int. Ed. 2012, 51,
10236. (c) Bras, J. L.; Muzart, J. Chem. Rev. 2011, 111, 1170.
(d) McMurray, L.; O’Hara, F.; Gaunt, M. J. Chem. Soc. Rev. 2011,
40, 1885. (e) Baudoin, O. Chem. Soc. Rev. 2011, 40, 4902.
(f) Wencel-Delord, J.; Dröge, T.; Kiu, F.; Glorius, F. Chem. Soc. Rev.
2011, 40, 4740. (g) Ackermann, L. Chem. Rev. 2011, 111, 1315.
(h) Cho, S. H.; Kim, J. Y.; Kwak, J.; Chang, S. Chem. Soc. Rev. 2011,
40, 5068. (i) Lyons, T. W.; Sanford, M. S. Chem. Rev. 2010, 110,
1147. (j) Colby, D. A.; Bergman, R. G.; Ellman, J. A. Chem. Rev.
2010, 110, 624. (k) Chen, X.; Engle, K. M.; Wang, D.-H.; Yu, J.-Q.
Angew. Chem. Int. Ed. 2009, 48, 5094. (l) Li, B.-J.; Yang, S.-D.; Shi,
Z.-J. Synlett 2008, 949. (m) Kakiuchi, F.; Kochi, T. Synthesis 2008,
3013.
Based upon the experimental and literature results,5–13
a mechanism is proposed in Scheme 4. The active palladi-
um catalyst reacts with 2a by chelation-directed C–H acti-
vation to generate intermediate I.16 Meanwhile, 2a is oxi-
dized to PhCHO,14,15 followed by oxidative addition to form
acyl palladium(IV) intermediate II.17 Finally, elimination
results in 3a and the active palladium(II) species is regener-
ated.
(2) (a) McGrath, N. A.; Brichacek, M.; Njardarson, J. T. J. Chem. Educ.
2010, 87, 1348. (b) Gmouh, S.; Yang, H.; Vaultier, M. Org. Lett.
2003, 5, 2219. (c) Harrington, P. J.; Lodewijk, E. Org. Process Res.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 2033–2036

2036
W. Fan et al.
Letter
Synlett
Dev. 1997, 1, 72. (d) Harvey, G.; Mader, G. Collect. Czech. Chem.
Commun. 1992, 57, 862. (e) Sheldon, R. A. Chem. Ind. 1992, 903.
(f) Furniss, B. S.; Hannaford, A. J.; Smith, P. W. G.; Tatchell, R.
Vogel’s Textbook of Practical Organic Chemistry; Addison Wesley
Longman: England, 1989, 5th ed. 1006.
Sharma, S.; Park, E.; Kim, A.; Lee, S. H.; Kwak, J. H.; Jung, Y. H.;
Kim, I. S. Chem. Commun. 2013, 49, 1654. (f) Sharma, S.; Kim, A.;
Park, E.; Park, J.; Kim, M.; Kwak, J. H.; Lee, S. H.; Jung, Y. H.; Kim,
I. S. Adv. Synth. Catal. 2013, 355, 667. (g) Yu, L.; Li, P.; Wang, L.
Chem. Commun. 2013, 49, 2368. (h) Li, H.; Li, P.; Zhao, Q.; Wang,
L. Chem. Commun. 2013, 49, 9170. (i) Miao, J.; Ge, H. Org. Lett.
2013, 15, 2930. (j) Kim, M.; Mishra, N. K.; Park, J.; Han, S.; Shin,
Y.; Sharma, S.; Lee, Y.; Lee, E.-K.; Kwak, J. H.; Kim, I. S. Chem.
Commun. 2014, 50, 14249.
(3) (a) Heaney, H. In Comprehensive Organic Synthesis; Vol. 2; Trost,
B. M.; Fleming, I., Eds.; Pergamon Press: Oxford, 1991, 733.
(b) Olah, G. A. Friedel–Crafts Chemistry; Wiley: New York, 1973.
(c) Gore, P. H. Aromatic Ketone Synthesis, In Friedel–Crafts and
Related Reactions; Olah, G. A., Ed.; John Wiley: London, 1964,
Part 1, Vol. 3 1. (d) Gore, P. H. Chem. Rev. 1955, 55, 229.
(4) Selected references, see: (a) Sharghi, H.; Jokar, M.; Doroodmand,
M. M.; Khalifeh, R. Adv. Synth. Catal. 2010, 352, 3031. (b) de
Noronha, R. G.; Fernandes, A. C.; Romao, C. C. Tetrahedron Lett.
2009, 50, 1407. (c) Nishimoto, Y.; Babu, S. A.; Yasuda, M.; Baba,
A. J. Org. Chem. 2008, 73, 9465. (d) Gopalakrishnan, M.;
Sureshkumar, P.; Kanagarajan, V.; Thanusu, J. Catal. Commun.
2005, 6, 753. (e) Hosseini Sarvari, M.; Sharghi, H. J. Org. Chem.
2004, 69, 6953. (f) Bartoli, G.; Bosco, M.; Marcantoni, E.;
Massaceri, M.; Rinaldi, S.; Sambri, L. Tetrahedron Lett. 2002, 43,
6331. (g) Reetz, M. T.; Giebel, D. Angew. Chem. Int. Ed. 2000, 39,
2498.
(8) (a) Guin, S.; Rout, S. K.; Banerjee, A.; Nandi, S.; Patel, B. K. Org.
Lett. 2012, 14, 5294. (b) Wu, Y.; Choy, P. Y.; Mao, F.; Kwong, F. Y.
Chem. Commun. 2013, 49, 689.
(9) Zhou, W.; Li, H.; Wang, L. Org. Lett. 2012, 14, 4594.
(10) Lu, J.; Zhang, H.; Chen, X.; Liu, H.; Jiang, Y.; Fu, H. Adv. Synth.
Catal. 2013, 355, 529.
(11) Zhang, Q.; Yang, F.; Wu, Y. Chem. Commun. 2013, 49, 6837.
(12) Han, S.; Sharma, S.; Park, J.; Kim, M.; Shin, Y.; Mishra, N. K.; Bae,
J. J.; Kwak, J. H.; Jung, Y. H.; Kim, I. S. J. Org. Chem. 2014, 79, 275.
(13) Tlili, A.; Schranck, J.; Pospech, J.; Neumann, H.; Beller, M. Angew.
Chem. Int. Ed. 2013, 52, 6293.
(14) Wang, R.; An, C.-H.; Li, Y.; Zhao, Y.; Wang, T.; Li, A. Tetrahedron
Lett. 2015, 56, 2077.
(5) For selected examples of C–H acylation using aldehydes, see:
(a) Jia, X.; Zhang, S.; Wang, W.; Luo, F.; Cheng, J. Org. Lett. 2009,
11, 3120. (b) Park, J.; Park, E.; Kim, A.; Lee, Y.; Chi, K.-W.; Kwak,
J. H.; Jung, Y. H.; Kim, I. S. Org. Lett. 2011, 13, 4390. (c) Sharma,
S.; Park, E.; Park, J.; Kim, I. S. Org. Lett. 2012, 14, 906. (d) Sharma,
S.; Park, J.; Park, E.; Kim, A.; Kim, M.; Kwak, J. H.; Jung, Y. H.;
Kim, I. S. Adv. Synth. Catal. 2013, 355, 332. (e) Chan, C.-W.; Zhou,
Z.; Chan, A. S. C.; Yu, W.-Y. Org. Lett. 2010, 12, 3926. (f) Yang, Y.;
Zhou, B.; Li, Y. Adv. Synth. Catal. 2012, 354, 2916. (g) Sharma, S.;
Kim, A.; Park, J.; Kim, M.; Kwak, J. H.; Jung, Y. H.; Park, J. S.; Kim,
I. S. Org. Biomol. Chem. 2013, 11, 7869. (h) Baslé, O.; Bidange, J.;
Shuai, Q.; Li, C.-J. Adv. Synth. Catal. 2010, 352, 1145. (i) Shin, Y.;
Sharma, S.; Mishra, N. K.; Han, S.; Paek, J.; Oh, H.; Ha, J.; Yoo, H.;
Jung, Y. H.; Kim, I. S. Adv. Synth. Catal. 2015, 357, 594.
(6) For selected examples of C–H acylation using alcohols, see:
(a) Xiao, F.; Shuai, Q.; Zhao, F.; Baslé, O.; Deng, G.; Li, C.-J. Org.
Lett. 2011, 13, 1614. (b) Park, J.; Kim, A.; Sharma, S.; Kim, M.;
Park, E.; Jeon, Y.; Lee, Y.; Kwak, J. H.; Jung, Y. H.; Kim, I. S. Org.
Biomol. Chem. 2013, 11, 2766. (c) Kim, M.; Sharma, S.; Park, J.;
Kim, M.; Choi, Y.; Jeon, Y.; Kwak, J. H.; Kim, I. S. Tetrahedron
2013, 69, 6552. (d) Sharma, S.; Kim, M.; Park, J.; Kim, M.; Kwak,
J. H.; Jung, Y. H.; Oh, J. S.; Lee, Y.; Kim, I. S. Eur. J. Org. Chem.
2013, 6656.
(15) (a) Ditrich, K. Science of Synthesis; Vol. 25; Thieme: Stuttgart,
2007, 523. (b) Srogl, J.; Voltrova, S. Org. Lett. 2009, 11, 843.
(16) (a) Murai, S.; Kakiuchi, F.; Sekine, S.; Tanaka, Y.; Kamatani, A.;
Sonoda, M.; Chatani, N. Nature (London, U.K.) 1993, 366, 529.
(b) Dupont, J.; Consorti, C. S.; Spencer, J. Chem. Rev. 2005, 105,
2527.
(17) (a) Arnold, P. L.; Sanford, M. S.; Pearson, S. M. J. Am. Chem. Soc.
2009, 131, 13912. (b) Baslé, O.; Bidange, J.; Shuai, Q.; Li, C.-J. Adv.
Synth. Catal. 2010, 352, 1145. (c) Hickman, A. J.; Sanford, M. S.
Nature (London, U.K.) 2012, 484, 177. (d) Muñiz, K. Angew.
Chem. Int. Ed. 2009, 48, 9412.
(18) Synthesis of 3a–v
A mixture of 1 (0.5 mmol), 2 (0.6 mmol), DMSO (5% H2O aq, 5
mL), Pd(OAc)2 (5 mol%), Cu(OAc)2 (10 mol%), and K2S2O8 (2
equiv) was stirred at 120 °C under Ar atmosphere for 24 h. The
reaction mixture was washed with H2O, and the aqueous phase
was extracted with EtOAc (3×). The combined organic layer was
washed with brine, dried over Na2SO4, and evaporated under
reduced pressure. The crude product was purified by silica gel
column chromatography to give the corresponding products
(3a–d,7b 3f–k,7b 3n–s7b).
Compound 3e: yield 15%, white solid. 1H NMR (500 MHz,
CDCl3): δ = 8.32 (d, J = 4.6 Hz, 1 H), 7.68 (m, 2 H), 7.52 (m, 2 H),
7.50 (m, 1 H), 7.41 (t, J = 7.2 Hz, 1 H), 7.25 (m, 2 H), 7.18 (m, 2
H), 7.0 (m, 1 H), 1.13 (s, 9 H). 13C NMR (125 MHz, CDCl3): δ =
197.2, 158.0, 155.2, 148.5, 140.2, 136.8, 135.9, 131.5, 129.9,
129.3, 128.4, 127.8, 126,9, 121.3, 119.5, 114.1, 34.5, 15.8. HRMS:
m/z calcd for C22H21NO: 315.1623; found: 315.1626.
(7) For selected examples of C–H acylation using α-oxocarboxylic
acids, see: (a) Fang, P.; Li, M.; Ge, H. J. Am. Chem. Soc. 2010, 132,
11898. (b) Li, M.; Ge, H. Org. Lett. 2010, 12, 3464. (c) Wang, H.;
Guo, L.-N.; Duan, X.-H. Org. Lett. 2012, 14, 4358. (d) Kim, M.;
Park, J.; Sharma, S.; Kim, A.; Park, E.; Kwak, J. H.; Jung, Y. H.;
Kim, I. S. Chem. Commun. 2013, 49, 925. (e) Park, J.; Kim, M.;
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 2033–2036