Palladium-catalyzed trifluoroacetate-promoted mono-arylation of the β-methyl group of alanine at room temperature: Synthesis of β-arylated α-amino acids through sequential C-H functionalization

Article abstract of DOI:10.1039/c4sc01545b

We report a highly efficient and practical protocol for palladium-catalyzed N-quinolylcarboxamide (AQ)-directed arylation of the unactivated β-C(sp³)-H bonds of alanine with aryl iodides at room temperature. For the first time, a broad range of easily accessible aryl iodides can be installed onto the β-methyl group of AQ-coupled phthaloyl alanine mono-selectively, providing both natural and unnatural aromatic α-amino acids. Access to these mono-arylated compounds enables subsequent AQ-directed diastereoselective C-H functionalization, allowing the preparation of various β-disubstituted aromatic α-amino acids in a programmable manner.

Full text of DOI:10.1039/c4sc01545b

Chemical
Science
View Article Online
View Journal | View Issue
EDGE ARTICLE
Palladium-catalyzed trifluoroacetate-promoted
mono-arylation of the b-methyl group of alanine at
room temperature: synthesis of b-arylated a-amino
acids through sequential C–H functionalization†
Cite this: Chem. Sci., 2014, 5, 3952
*
Bo Wang, William A. Nack, Gang He, Shu-Yu Zhang and Gong Chen
We report a highly efficient and practical protocol for palladium-catalyzed N-quinolylcarboxamide (AQ)-
directed arylation of the unactivated b-C(sp3)–H bonds of alanine with aryl iodides at room temperature.
For the first time, a broad range of easily accessible aryl iodides can be installed onto the b-methyl
group of AQ-coupled phthaloyl alanine mono-selectively, providing both natural and unnatural aromatic
a-amino acids. Access to these mono-arylated compounds enables subsequent AQ-directed
diastereoselective C–H functionalization, allowing the preparation of various b-disubstituted aromatic a-
amino acids in a programmable manner.
Received 26th May 2014
Accepted 16th June 2014
DOI: 10.1039/c4sc01545b
www.rsc.org/chemicalscience
Daugulis demonstrated that the ArS auxiliary enables mono-
selective C–H arylation of Ala (see 6).6c However, a slight loss in
Introduction
the enantiopurity of the AA products was observed. More
a-Amino acids (AAs) bearing aromatic side chains are an
important class of building blocks for synthesis of peptide-
based natural products and drug molecules (Scheme 1A).
Compared with b-mono-substituted aromatic AAs such as Phe,
Tyr and Trp, b-disubstituted aromatic AAs, e.g. b-methylated
Phe and Trp found in many natural products, exhibit even
greater inuence on the structural and biophysical properties of
their parent peptide backbone.1 Stereoselective synthesis of
these b-disubstituted a-AAs remains a signicant challenge.2
While the synthesis of these compounds has been achieved with
limited success via conventional methods such as asymmetric
conjugate addition and hydrogenation, metal-catalyzed
sequential C–H functionalization could potentially provide a
much more convergent and streamlined strategy, beginning
from easily accessible alanine precursors (see 1).3–5 Over the past
few years, several aniline-based auxiliary groups, including
Daugulis' 8-aminoquinoline (AQ)
2 (ref. 6a) and 2-thio-
methylaniline (ArS) 3 (ref. 6c) as well as Yu's uorinated aniline
(ArF) 4,7 have been successfully employed for palladium-cata-
lyzed b-C(sp3)–H arylation of Ala with aryl iodides, producing b-
arylated a-AAs (Scheme 1B).6–12 In 2006, Corey rst applied the
AQ auxiliary for Pd-catalyzed b-C–H arylation of Ala.8 Despite
the high efficiency of this AQ-directed arylation reaction, it
cannot be stopped at the mono-arylation stage and predomi-
nantly forms homo-di-arylated products (see 5). In 2012,
Department of Chemistry, The Pennsylvania State University, 104 Chemistry Building,
University Park, PA 16802, USA. E-mail: guc11@psu.edu
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c4sc01545b
Scheme 1 Synthesis of b-arylated a-amino acids via Pd-catalyzed
carboxamide-directed C–H arylation of Ala.
3952 | Chem. Sci., 2014, 5, 3952–3957
This journal is © The Royal Society of Chemistry 2014

View Article Online
Edge Article
Chemical Science
recently, Yu reported that the ArF auxiliary 4 can effect Pd- of unactivated C(sp3)–H bonds of phthaloyl alanine with aryl
catalyzed C–H arylation of Ala under the control of pyridine- iodides at room temperature.
based ligands, selectively forming either mono or hetero-di-
arylated products (see 7).7b
Results and discussion
Among reported auxiliaries, the N,N-bidentate AQ group is
arguably the most effective and versatile for the metal-catalyzed
Our investigation commenced with the C–H arylation of
functionalization of unactivated methyl and methylene C(sp3)–
phthaloyl Ala 10 with 3 equiv. of PhI under the catalysis of
H bonds, enabling regio and diastereoselective C–H arylation,
Pd(OAc)2 (eqn (1), Table 1). In accordance with results from
alkynylation, alkylation, oxygenation and even amination.13,14
AQ-coupled compound 8 appears to be a more versatile inter-
mediate than 6 and 7 bearing ArS and ArF directing groups, and
can potentially be sequentially functionalized at the remaining
b-C–H position with a wider range of substituents, enabling the
synthesis of a broad range of b-disubstituted AAs. However, to
realize this AQ-directed sequential C–H functionalization
strategy, we rst needed to attain a method for the AQ-directed
mono-selective C–H arylation of Ala, a long-standing challenge.
Herein, we report a highly efficient protocol for the Pd-catalyzed
triuoroacetate-promoted AQ-directed mono-selective arylation
Corey and others,8,6c arylation of 10 mainly gave the di-arylated
product 12 when the reaction was conducted above 80 ꢀC, even
when PhI was used as limiting reagent (entries 1 and 2).
Compared with the initial methyl arylation, subsequent meth-
ylene C–H arylation at the benzylic position of the mono-ary-
lated product Phe 11 is highly favorable, presumably due to its
reduced C–H bond strength. We reasoned that the unwanted
methylene arylation is sterically disfavored, and thus mono-
selectivity might be obtained under kinetic control by carrying
out the arylation at lower temperature, ideally at room
temperature (RT). However, forming C–C bonds via metal-
Table 1 Mono arylation of b-C(sp3)–H of Ala with PhI at RT
Yielda (%)
Entry
Additives (equiv.) atmosphere
Solvent
t (ꢀC)/time (h)
11
12
1
AgOAc (2), Ar
AgOAc (2), Ar
Ag2CO3 (2), Ar
Ag2CO3 (2), o-PBA (1), Ar
Ag2CO3 (2), TFA (1), Ar
AgTFA (2), Ar
Toluene
Toluene
tBuOH
tBuOH
tBuOH
TCE
TCE
TCE
100/12
100/12
50/24
50/24
50/24
25/48
25/48
25/48
25/48
25/48
25/48
25/48
25/48
25/48
25/24
45/24
<2
10
4
93
21
10
17
3
<2
<2
<2
<2
<2
<2
<2
<2
<2
<2
7
2b
3
4
5
6
7
8
9
10
11
12
13
14
15c
16
2
60
80
13
21
64
82
81
82
NaTFA (2), Ar
AgTFA (2), TFA (4), Ar
AgTFA (2), AcOH (4), Ar
AgTFA (2), KHCO3 (2), Ar
AgTFA (2), Ar
AgTFA (2), air
AgTFA (2), air
AgOAc (2), air
Pd(TFA)2 (0.1), AgTFA (2), air
AgTFA (2), air
TCE
TCE
Dioxane–H2O (9 : 1)
Dioxane–H2O (9 : 1)
TCE–H2O (1 : 1)
TCE–H2O (1 : 1)
TCE–H2O (1 : 1)
TCE–H2O (1 : 1)
92 (88)d
9
70
91
a
Yields are based on 1H-NMR analysis of the reaction mixture on a 0.1 mmol scale. b 0.5 equiv. of PhI. c 10 mol% of Pd(TFA)2 as catalyst. d Isolated
yield on a 3 mmol scale (1 gram of 10) under an air atmosphere.
This journal is © The Royal Society of Chemistry 2014
Chem. Sci., 2014, 5, 3952–3957 | 3953

View Article Online
Chemical Science
Edge Article
catalyzed functionalization of unactivated C(sp3)–H bonds at RT
With our optimized RT mono-selective C–H arylation
remains a signicant challenge.15 In our previous study, we conditions in hand, we proceeded to evaluate the substrate
discovered that linear N-quinolyl alkylcarboxamides such as scope of aryl and heteroaryl iodides with Ala 10 (Scheme 2). In
compound 13 (eqn (2)) underwent intramolecular C–H arylation
at the b-methylene position to form cyclic products e.g. 14 in
good yield at 50 ꢀC in tBuOH.16 Unfortunately, application of
ortho-phenylbenzoic acid (oPBA), which promotes the intra-
molecular C–H arylation of 13, showed little promoting effect
on this intermolecular reaction (entry 4). However, the addition
of 1 equiv. of triuoroacetic acid (TFA), which suppressed the
intramolecular arylation of 13, was uniquely effective (entry 5).
Furthermore, we were delighted to nd that AgTFA successfully
effects the desired C–H arylation of 10 in 1,1,2,2-tetrachloro-
ethane (TCE) at RT with both mono-selectivity and excellent
conversion (entry 6).17 While triuoroacetate is required for this
C–H arylation reaction to proceed at RT, excess TFA (4 equiv.)
signicantly decreased the reactivity (entry 8). As shown in entry
11, the reaction was very tolerant of water and air. Finally, we
found that a bi-phasic mixture of TCE and H2O (1 : 1)18 provided
the best solvent system and we obtained an 88% isolated yield
of Phe 11 in 48 hours (ref. 19) at RT on a 1 gram scale (entry 13).
The enantiopurity of Phe product 11 was conserved based on
HPLC analysis (>98% ee).
Scheme 3 Synthesis of b-disubstituted a-amino acids via AQ-directed
a
Scheme 2 Substrate scope of aryl iodides. Isolated yield on a 0.2 sequential C–H functionalization of Ala. Isolated yield on 0.2 mmol
a
b
c
mmol scale. b Conditions B: 45 ꢀC, 24 h, on a 1 mmol scale. c Isolated scale. Conditions A; tBuOH/DCE, ethyl a-bromoacetate, 75 ꢀC;
yield on a 3 mmol scale.
tAmylOH/DCE, 90 ꢀC. See ESI† for experimental details.
3954 | Chem. Sci., 2014, 5, 3952–3957
This journal is © The Royal Society of Chemistry 2014

View Article Online
Edge Article
Chemical Science
general, aryl iodides carrying electron-donating groups (see 15)
are more reactive and gave excellent yield and superior mono-
selectivity (>30/1) under the standard RT conditions A. Aryl
iodides carrying electron-withdrawing groups (see 21) are rela-
tively less reactive and performed better at slightly elevated
temperature (45 ꢀC, 24 h, conditions B, with typical >20/1 mono/
di-selectivity). Notably, aryl iodides bearing delicate motifs such
as diethyl phosphate and Bn-protected O-mannose (see 16 and
17) also worked well. These reactions provide a convenient
method for synthesis of various post-translationally modied
tyrosine building blocks.20 Other common functional groups
such as bromo-(see 24), acetyl (see 23), even pinacolborane (see
26) were well tolerated. Furthermore, we were delighted to nd
that unprotected 4-iodophenol (see 18) and 5-iodoindole (see
22), challenging substrates in similar previously reported reac-
tion systems,9a cleanly gave mono-arylated products in excellent
yield. 3-Iodoindole did not react under the standard conditions
A to give Trp product 19; however, Ts-protected 3-iodoindole
provided Trp 20 in good yield.
Scheme 4 Removal of auxiliaries under mild conditions.
Similar to previously reported Pd-catalyzed N,N-bidentate
auxiliary-directed C–H functionalization systems, this AQ-
directed arylation reaction likely proceeds through a PdII/IV
catalytic cycle involving C–H palladation, oxidative addition
(OA) of aryl iodides, and reductive elimination (RE).6b,23 As
shown in Scheme 5A, a small deuterium kinetic isotope effect
(KIE z 1.2)24 was observed for the arylation of Ala 10 vs. Me-
deuterated Ala 42 in TCE at RT (see entry 9, Table 1). This
indicates that the reversible C–H palladation, in contrast to
many metal-catalyzed AQ-directed C–H functionalization
systems,25 may proceed at a rate faster than or similar to the
irreversible oxidative addition of aryl iodides.26 Although not
critical, H2O slightly enhances the reaction rate. We suspect
that it may assist the protonolysis of the Pd-complexed arylation
product (see 47) and facilitate catalyst turnover. The biphasic
solvent system might also assist the removal of inhibitory ions
such as IÀ and excess H+ (ref. 18) from the organic phase. Both
Ag+ cation and triuoroacetate anion are critical for the high
reactivity of this C–H arylation at RT. While Ag+ likely acts as an
With access to these mono-arylated amino acid intermedi-
ates, we could now explore the scope of sequential AQ-directed
transformations under various known Pd-catalyzed con-
ditions6c,14g,14j (Scheme 3). For example, Phe 11 can undergo
another Pd-catalyzed
b
C–H arylation with 3-methox-
yiodobenzene to give the hetero-di-arylated product 28 in
excellent yield and diastereoselectivity (>30/1) under the stan-
dard conditions C14g at 110 ꢀC (Scheme 3A). The stereochemistry
at Cb of 28 is presumably dictated by the trans-a,b-substituted
palladacycle intermediate 27. To give the complementary dia-
stereomer 29, mono-arylated compound 15 was C–H arylated
with iodobenzene. As shown in Scheme 3B, mannosyl Tyr 17
was alkylated at the b-position with a-iodoacetate 30 (ref. 14g) to
give product 31 in excellent yield and diastereoselectivity.
Similarly, reaction of Ala 10 using the reverse sequence of C–H
alkylation then arylation provided the complementary diaste-
reomers 33 in good yield and diastereoselectivity.
Heteroatoms such as O and N can also be stereoselectively
introduced at the b position of mono-arylated compounds
under Pd catalysis. For example, compound 25 can undergo
C–H acetoxylation6c,8,9b with PhI(OAc)2 to give b-acetoxylated
product 34 (Scheme 3C). As shown in Scheme 3D, Ala 35
equipped with our recently introduced 5-methoxyl-8-amino-
quinoline (MQ) auxiliary21 can rst be mono-arylated to give
compound 36. Compound 36 was then subjected to MQ-
directed intramolecular C–H amidation under conditions
adapted from Wu14j to give the b-lactam product 37 in low yield22
with excellent diastereoselectivity. The MQ auxiliary of 37 can be
easily removed by treatment with cerium ammonium nitrate
(CAN) at RT to give 38 in good yield.
The MQ and AQ groups of mono-arylated AA products can be
removed under mild conditions. As shown in Scheme 4A, the
MQ group of compound 36 can be readily removed by treatment
with CAN at RT to give primary amide products e.g. 39.21 As
shown in Scheme 4B, treatment of Trp 17 with Boc2O and DMAP
at RT gave Boc-protected intermediate 40.14a Treatment of 40
with LiOH–H2O2 at RT gave free carboxylic acid 41 in excellent
yield.
Scheme 5 Mechanistic considerations.
This journal is © The Royal Society of Chemistry 2014
Chem. Sci., 2014, 5, 3952–3957 | 3955

View Article Online
Chemical Science
Edge Article
IÀ scavenger, the functional role of the triuoroacetate ion is
puzzling at the moment. Compared with OAc, triuoroacetate is
a less effective but competent ligand for AQ-directed C–H ary-
lation at RT (entry 15, Table 1). We speculate that Ala–Pd
complex 43 bearing either OAc or triuoroacetate ligand can
undergo C–H palladation to form palladacycle intermediate 44
via a concerted metalation–deprotonation mechanism.27 The
higher electrophilicity of the triuoroacetate-bound PdII
complex might partially compensate for the weaker basicity of
triuoroacetate ligand. To account for the unusual reactivity at
RT, we suspect that triuoroacetate may serve as a unique
ligand to stabilize the PdII palladacycle intermediate (see 44) or
even facilitate the oxidative addition of ArI (see 45).28 Relative to
OAc (AcOH), the weaker basicity of triuoroacetate may disfavor
the reverse C–H palladation process (44 to 43).29
C. J. Moody, Org. Lett., 2006, 8, 1975; (d) B. Banerjee,
S. G. Capps, J. Kang, J. W. Robinson and S. L. Castle, J.
Org. Chem., 2008, 73, 8973.
3 For selected reviews on C–H functionalizations in organic
synthesis: (a) K. Godula and D. Sames, Science, 2006, 312,
67; (b) H. M. Davies and J. R. Manning, Nature, 2008, 451,
417; (c) T. R. Newhouse and P. S. Baran, Angew. Chem., Int.
Ed., 2011, 50, 3362; (d) L. McMurray, F. O'Hara and
M. J. Gaunt, Chem. Soc. Rev., 2011, 40, 1885; (e) J. Wencel-
¨
Delord, T. Droge, F. Liu and F. Glorius, Chem. Soc. Rev.,
2011, 40, 4740; (f) S. H. Cho, J. Y. Kim, J. Kwak and
S. Chang, Chem. Soc. Rev., 2011, 40, 5068; (g) J. Yamaguchi,
A. D. Yamaguchi and K. Itami, Angew. Chem., Int. Ed., 2012,
51, 8960; (h) M. C. White, Science, 2012, 335, 807; (i)
D. Y.-K. Chen and S. W. Youn, Chem.–Eur. J., 2012, 18, 9452.
4 For selected reviews on metal-catalyzed C(sp3)–H
functionalizations: (a) R. Jazzar, J. Hitce, A. Renaudat,
J. Sofack-Kreutzer and O. Baudoin, Chem.–Eur. J., 2010, 16,
2654; (b) H. Li, B.-J. Li and Z.-J. Shi, Catal. Sci. Technol.,
2011, 1, 191; (c) J. F. Hartwig, Chem. Soc. Rev., 2011, 40,
1992; (d) J. L. Roizen, M. E. Harvey and J. Du Bois, Acc.
Chem. Res., 2012, 45, 911.
Conclusions
In summary, we have developed a highly efficient and practical
protocol for the palladium-catalyzed triuoroacetate-promoted
N-quinolylcarboxamide-directed arylation of unactivated
b-C(sp3)–H bonds of phthaloyl alanine with aryl iodides under
very mild conditions. To the best of our knowledge, these
reactions represent the rst example of room temperature
intermolecular C–C coupling via metal-catalyzed functionali-
zation of unactivated C(sp3)–H bonds. A broad range of aryl
iodides, including unprotected phenol and indole derivatives,
can be mono-selectively installed onto the b-methyl group of
AQ-coupled phthaloyl alanine to provide various natural and
unnatural aromatic a-amino acid compounds. From an opera-
tional perspective, these mono-arylation reactions are compat-
ible with sensitive functional groups, tolerant of water and air,
and suitable for gram scale synthesis. Access to these mono-
arylated compounds enables further C–H functionalization,
providing various b-disubstituted aromatic a-amino acids,
difficult to synthesize by other means, in a diastereoselective
and programmable manner.
5 For selected reviews on Pd-catalyzed C(sp3)–H arylation: (a)
X. Chen, K. M. Engle, D.-H. Wang and J.-Q. Yu, Angew.
Chem., Int. Ed., 2009, 48, 5094; (b) L. Ackermann,
R. Vicente and A. R. Kapdi, Angew. Chem., Int. Ed., 2009,
48, 9792; (c) T. W. Lyons and M. S. Sanford, Chem. Rev.,
2010, 110, 1147; (d) O. Baudoin, Chem. Soc. Rev., 2011, 40,
4902.
6 (a) V. G. Zaitsev, D. Shabashov and O. Daugulis, J. Am. Chem.
Soc., 2005, 127, 13154; (b) D. Shabashov and O. Daugulis, J.
Am. Chem. Soc., 2010, 132, 3965; (c) L. D. Tran and
O. Daugulis, Angew. Chem., Int. Ed., 2012, 51, 5188; (d)
E. T. Nadres, G. I. F. Santos, D. Shabashov and
O. Daugulis, J. Org. Chem., 2013, 78, 9689.
7 (a) M. Wasa, K. S. L. Chan, X.-G. Zhang, J. He, M. Miura and
J.-Q. Yu, J. Am. Chem. Soc., 2012, 134, 18570; (b) J. He, S. Li,
Y. Deng, H. Fu, B. N. Laforteza, J. E. Spangler, A. Homs
and J.-Q. Yu, Science, 2014, 343, 1216.
8 B. V. S. Reddy, L. R. Reddy and E. J. Corey, Org. Lett., 2006, 8,
3391.
Acknowledgements
We gratefully thank the Pennsylvania State University, NSF
(CAREER CHE-1055795), and ACS-PRF (51705-DN11) for nan-
cial support of this work. GC is an Amgen Young Investigator.
9 (a) G. He and G. Chen, Angew. Chem., Int. Ed., 2011, 50, 5192;
(b) G. He, Y. Zhao, S.-Y. Zhang, C. Lu and G. Chen, J. Am.
Chem. Soc., 2012, 134, 3; (c) S.-Y. Zhang, G. He, Y.-S. Zhao,
K. Wright, W. A. Nack and G. Chen, J. Am. Chem. Soc.,
2012, 134, 7313; (d) S.-Y. Zhang, G. He, W. A. Nack,
Y. Zhao, Q. Li and G. Chen, J. Am. Chem. Soc., 2013, 135, 2124.
Notes and references
1 (a) S. E. Gibson, N. Guillo and M. J. Tozer, Tetrahedron, 1999,
55, 585; (b) M. Y. Chang, P. P. Sun, S. T. Shui and 10 Q. Zhang, K. Chen, W. Rao, Y. Zhang, F. J. Chen and B. F. Shi,
N. C. Chang, Tetrahedron Lett., 2003, 44, 5271; (c) S. Hajra, Angew. Chem., Int. Ed., 2013, 52, 13588.
A. Karmakar, T. Maji and A. K. Medda, Tetrahedron, 2006, 11 N. Rodrıguez, J. A. Romero-Revilla, M. A. Fernandez-Ibanez
´
´
´
´˜
62, 8959; (d) Y. Liu, L. Zhang and Y. Jia, Tetrahedron Lett.,
2012, 53, 684.
and J. C. Carretero, Chem. Sci., 2013, 4, 175.
12 M. Fan and D. Ma, Angew. Chem., Int. Ed., 2013, 52, 12152.
2 For selected syntheses of b-substituted a-amino acids: (a) 13 G. Rouquet and N. Chatani, Angew. Chem., Int. Ed., 2013, 52,
M. J. O'Donnell, J. T. Cooper and M. M. Mader, J. Am. 11726.
Chem. Soc., 2003, 125, 2370; (b) T. Kanayama, K. Yoshida, 14 For selected examples of Pd-catalyzed AQ-directed C–H
H. Miyabe, T. Kimachi and Y. Takemoto, J. Org. Chem.,
2003, 68, 6197; (c) D. J. Bentley, A. M. Z. Slawin and
functionalizations, see: (a) Y. Feng and G. Chen, Angew.
Chem., Int. Ed., 2010, 49, 958; (b) Y. Ano, M. Tobisu and
3956 | Chem. Sci., 2014, 5, 3952–3957
This journal is © The Royal Society of Chemistry 2014

View Article Online
Edge Article
Chemical Science
N. Chatani, J. Am. Chem. Soc., 2011, 133, 12984; (c)
W. R. Gutekunst, R. Gianatassio and P. S. Baran, Angew.
in ref. 14j, the bulk of the PhthN group of Phe may
hamper Pd-catalyzed b-lactamization.
Chem., Int. Ed., 2012, 51, 7507; (d) K. Chen, F. Hu, 23 For selected reviews on PdIV chemistry: (a) P. Sehnal,
Q. Zhang, S.-Q. Zhang and B.-F. Shi, Chem. Sci., 2013, 4,
3906; (e) G. Shan, X. Yang, Y. Zong and Y. Rao, Angew.
Chem., Int. Ed., 2013, 52, 13606; (f) F. Pan, P. X. Shen,
L. S. Zhang, X. Wang and Z.-J. Shi, Org. Lett., 2013, 15,
R. J. Taylor and I. J. S. Fairlamb, Chem. Rev., 2010, 110,
824; (b) L. Xu, B. Li, Z. Yang and Z. Shi, Chem. Soc. Rev.,
2010, 39, 712; (c) A. J. Hickman and M. S. Sanford, Nature,
2012, 484, 177.
4758; (g) S.-Y. Zhang, L. Qiong, G. He, W. A. Nack and 24 To avoid interference from Pd-catalyzed H/D exchange of
G. Chen, J. Am. Chem. Soc., 2013, 135, 12135; (h) R. Parella,
B. Gopalakrishnan and S. A. Babu, J. Org. Chem., 2013, 78,
11911; (i) L.-S. Zhang, G. Chen, X. Wang, Q.-Y. Guo,
X.-S. Zhang, F. Pan, K. Chen and Z.-J. Shi, Angew. Chem.,
starting material 42, H2O was omitted from this
experiment. Compared with the standard biphasic reaction
conditions A, Ala 10 was arylated at a similar rate under
these anhydrous conditions.
Int. Ed., 2014, 53, 3899; (j) W.-W. Sun, P. Cao, R.-Q. Mei, 25 To the best of our knowledge, a KIE study of Pd-catalyzed AQ-
Y. Li, Y.-L. Ma and B. Wu, Org. Lett., 2014, 16, 480; (k)
C. P. Ting and T. J. Maimone, Angew. Chem., Int. Ed., 2014,
53, 3115.
directed C(sp3)–H functionalization has not been reported.
C–H metalation was suggested as the rate-limiting step in
the following AQ-directed C(sp3)–H functionalization
systems: (a) Fe-catalyzed arylation: R. Shang, L. Ilies,
A. Matsumoto and E. Nakamura, J. Am. Chem. Soc., 2013,
135, 6030; (b) Ni-catalyzed alkylation: X. Wu, Y. Zhao and
H. Ge, J. Am. Chem. Soc., 2014, 136, 1789; (c) Cu-catalyzed
intramolecular amidation: Z. Wang, J. Ni, Y. Kuninobu and
M. Kanai, Angew. Chem., Int. Ed., 2014, 53, 3496.
Interestingly, a small KIE (1.2) was obtained for a similar
Cu-catalyzed intramolecular amidation reaction observed
by Ge et al., indicating non-rate-liming C–H cleavage. See:
(d) X. Wu, Y. Zhao, G. Zhang and H. Ge, Angew. Chem., Int.
Ed., 2014, 53, 3706.
15 For two examples of Pd-catalyzed oxygenation of unactivated
C(sp3)–H bond at RT: (a) R. Giri, J. Liang, J.-G. Lei, J.-J. Li,
D.-H. Wang, X. Chen, I. C. Naggar, C. Guo, B. M. Foxman
and J.-Q. Yu, Angew. Chem., Int. Ed., 2005, 44, 7420; (b)
R. K. Rit, M. R. Yadav and A. K. Sahoo, Org. Lett., 2012, 14,
3724.
16 Y. Feng, Y. Wang, B. Landgraf, S. Liu and G. Chen, Org. Lett.,
2010, 12, 3414. The same reaction can also proceed in mixed
solvent of dioxane–H2O (9/1) at RT at much slower rate.
17 For selected applications of triuoroacetate in Pd-catalyzed
C–H functionalization reactions: (a) C. Wang, I. Piel and
F. Glorius, J. Am. Chem. Soc., 2009, 131, 4194; (b) B. Liu, 26 For an insightful discussion on the interpretation of
H.-Z. Jiang and B.-F. Shi, Org. Biomol. Chem., 2014, 12,
2538; (c) Y. Wei, H. Tang, X. Cong, B. Rao, C. Wu and
X. Zeng, Org. Lett., 2014, 16, 2248; (d) Ref. 7.
deuterium
KIE
in
C–H
functionalization,
see:
E. M. Simmons and J. F. Hartwig, Angew. Chem., Int. Ed.,
2012, 51, 3066. We believe that this AQ-directed C–H
arylation follows a course similar to the fourth scenario in
Fig. 1 of this paper.
18 Excess H+ seems to inhibit the arylation reaction at RT.
Addition of weak base such as KHCO3 or using a biphasic
system may help remove H+
27 (a) D. L. Davies, S. M. A. Donald and S. A. Macgregor, J. Am.
Chem. Soc., 2005, 127, 13754; (b) D. Lapointe and K. Fagnou,
Chem. Lett., 2010, 39, 1118; (c) L. Ackmann, Chem. Rev., 2011,
111, 1315.
19 About 45% conversion of 10 in 5 h.
20 (a) T. Hunter, Curr. Opin. Cell Biol., 2009, 21, 140; (b)
K. Zarschler, B. Janesch, M. Pabst, F. Altmann, P. Messner
¨
and C. Schaffer, Glycobiology, 2010, 20, 787.
28 We suspect that (BnO)2PO2H, used in our Pd-catalyzed AQ
and PA-directed C–H alkylation reactions (see ref. 9c and
d), might play a similar role. Detailed computational
studies will be reported in a separate account.
21 For the development of the MQ auxiliary: G. He, S.-Y. Zhang,
W. A. Nack, L. Qiong and G. Chen, Angew. Chem., Int. Ed.,
2013, 52, 11124.
22 A similar lactamization yield was obtained for the 29 Considering its low pKa, TFA predominately exists as an
corresponding AQ-coupled substrate under the same
conditions. Unlike the less-substituted substrates reported
anion under the standard reaction conditions.
This journal is © The Royal Society of Chemistry 2014
Chem. Sci., 2014, 5, 3952–3957 | 3957