Ligand-enabled cross-coupling of C(sp 3)-H bonds with arylboron reagents via Pd(II)/Pd(0) catalysis

Article abstract of DOI:10.1038/nchem.1836

There have been numerous developments in C-H activation reactions in the past decade. Attracted by the ability to functionalize molecules directly at ostensibly unreactive C-H bonds, chemists have discovered reaction conditions that enable reactions of C(sp 2)-H and C(sp 3)-H bonds with a variety of coupling partners. Despite these advances, the development of suitable ligands that enable catalytic C(sp 3)-H bond functionalization remains a significant challenge. Herein we report the discovery of a mono-N-protected amino acid ligand that enables Pd(II)-catalysed coupling of γ-C(sp 3)-H bonds in triflyl-protected amines with arylboron reagents. Remarkably, no background reaction was observed in the absence of ligand. A variety of amine substrates and arylboron reagents were cross-coupled using this method. Arylation of optically active substrates derived from amino acids also provides a potential route for preparing non-proteinogenic amino acids.

Full text of DOI:10.1038/nchem.1836

ARTICLES
PUBLISHED ONLINE: 5 JANUARY 2014 | DOI: 10.1038/NCHEM.1836
Ligand-enabled cross-coupling of C(sp3)–H bonds
with arylboron reagents via Pd(II)/Pd(0) catalysis
Kelvin S. L. Chan, Masayuki Wasa, Ling Chu, Brian N. Laforteza, Masanori Miura and Jin-Quan Yu
*
There have been numerous developments in C–H activation reactions in the past decade. Attracted by the ability to
functionalize molecules directly at ostensibly unreactive C–H bonds, chemists have discovered reaction conditions that
enable reactions of C(sp2)–H and C(sp3)–H bonds with a variety of coupling partners. Despite these advances, the
development of suitable ligands that enable catalytic C(sp3)–H bond functionalization remains a significant challenge.
Herein we report the discovery of a mono-N-protected amino acid ligand that enables Pd(II)-catalysed coupling of
g-C(sp3)–H bonds in triflyl-protected amines with arylboron reagents. Remarkably, no background reaction was observed
in the absence of ligand. A variety of amine substrates and arylboron reagents were cross-coupled using this method.
Arylation of optically active substrates derived from amino acids also provides a potential route for preparing
non-proteinogenic amino acids.
ransition-metal-catalysed C–H activation directed by hetero- formation, cross-coupling of C(sp3)–H bonds with organoboron
atom directing groups has rapidly emerged as a fertile field reagents is generally limited to substrates derived from carboxylic
T
for developing a diverse range of catalytic carbon–carbon acids14,19,34,35. The synthetic importance of amines guided us to
and carbon–heteroatom bond-forming reactions1–10. During our focus on the development of cross-coupling of C(sp3)–H bonds
efforts towards the development of Pd(II)-catalysed C–H activation in alkylamines with arylboron reagents. In particular, we envisioned
reactions using a broad range of synthetically useful substrates, it that rapid generation of a library of non-proteinogenic amino
became evident that controlling the reactivity and selectivity of cat- esters could be achieved via g-C(sp3)–H functionalization of
alysts through the use of external ligands, such as amino acids11–16
,
substrates derived from amino acids such as 1. Encouraged by
pyridines and quinolines17,18, is crucial to realizing their full poten- our previous studies on triflamide-directed C(sp2)–H olefination,
tial as useful tools for synthesis. Previously, we demonstrated that
weak coordinating functional groups, such as –COOH, –OH,
a
H
Ar
5 mol% Pd(OAc)2
N
N
–CN and –OMe, can cooperate with a mono-N-protected amino
acid (MPAA) ligand on the Pd(II) centre to lower the transition-
state energy and drastically accelerate the aromatic C(sp2)–H acti-
vation step12–16. On the contrary, typically C(sp3)–H activation
reactions are promoted by a strong coordinating directing group
without ligand assistance19–24, except for a rare example of
moderate rate enhancement by MPAA ligands in the lactonization
of benzylic C(sp3)–H bonds25. Therefore we embarked on the devel-
opment of a ligand scaffold that can promote C(sp3)–H activation of
amine derivatives, a major class of synthetically useful compounds.
Although a number of examples of arylation of g-C(sp3)–H bonds
in amines using strong coordinating auxiliaries have been reported
(Fig. 1a)26–30, ligand-enabled activation of g-C(sp3)–H bonds in
amines remains to be established. Herein we report the first
example of Pd-catalysed cross-coupling of g-C(sp3)–H bonds of
triflyl-protected amines (R–NHTf) with arylboron reagents
through the use of a MPAA ligand. Remarkably, no background
reaction is observed in the absence of the MPAA ligand (Fig. 1b),
which thus implies the feasibility of using MPAA as a ligand to
control the regioselectivity and enantioselectivity in the activation
of C(sp3)–H bonds. This reaction also allows for rapid generation
of novel amino acids and amino alcohols that are broadly useful
in syntheses of bioactive molecules and chiral compounds31.
H
N
H
N
ArI, AgOAc, 130 °C
O
O
H
Ar
N
N
H
N
H
5 mol% Pd(OAc)2
H
Ar
N
S
S
ArI, AgOAc
HFIP, 150 °C
O
O
O
O
MeO2C
MeO2C
H
b
10 mol% Pd(OAc)2
NHTf
No reaction
R1
ArBPin, Ag2CO3, NaHCO3
1,4-benzoquinone
R2
t-amyl-OH, 100 °C
c
tBu
NHAc
CO2H
Ligand =
H
Ar
10 mol% Pd(OAc)2
NHTf
NHTf
R1
R1
ArBPin, Ag2CO3, NaHCO3
1,4-benzoquinone
R2
R2
t-amyl-OH, 100 °C
25 examples
up to 96%
Results and discussion
Recently, the use of inert C–H bonds as coupling partners for Suzuki Figure 1 | Ligand-enabled C(sp3)–H activation. a, C–H activation of aliphatic
coupling with organoboron reagents has been made possible using amines directed by strong s chelation. b, Unreactive amine substrates in the
Pd(II)/Pd(0) catalysis19,32,33. Although this new catalytic reaction absence of strong s chelation. c, Ligand-enabled g-C(sp3)–H arylation of
provides a variety of new disconnections for carbon–carbon bond amines. HFIP, hexafluoroisopropanol.
Department of Chemistry, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, California 92037, USA. e-mail: yu200@scripps.edu
*
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.1836
ARTICLES
Table 1 | Optimization of reaction conditions.
Table2 | Screening of ligand for the C(sp3)–H cross-coupling
reaction.
CO2Me
CO2Me
cat. Pd(II)
cat. Pd(II)
H
H
cat. Ac-D-tLeu-OH, 3
R
CO2Me
N
CO2Me
NHTf
PG
(S)
NHTf
Ag2CO3, base
H
(S)
CO2H
(S)
1,4-benzoquinone
DMSO, H2O
BPin
CO2Me
CO2Me
1a
NHTf
Ag2CO3, NaHCO3
1,4-benzoquinone
DMSO, H2O
NHTf
1
2
(R)
t-amyl-OH
(R)
BPin
CO2Me
100 °C, N2, 18 h
CO2Me
4a
t-amyl-OH
100 °C, N2, 18 h
2
4
Entry Ligand
Pd(II) catalyst
Base
Yield* (%)
1
Ac-L-Val-OH
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Na2CO3
(2.0 equiv.)
42
Entry
Ligand
Yield* (%)
R
PG
Ac-L-tLeu-OH
Ac-D-Val-OH
Na2CO3
(2.0 equiv.)
46
57
65
1
2
3
4
5
6
7
8
9
10
11
12
13
iPr
iPr
iPr
iPr
iPr
iPr
iPr
H
Me
Formyl
Ac
Boc
Fmoc
Cbz
Troc
Ac
Ac
Ac
Ac
Ac
0
2
3
4
18
68
12
15
9
Na2CO3
(2.0 equiv.)
Ac-D-tLeu-OH Pd(OAc)2
Na2CO3
(2.0 equiv.)
0
31
50
68
57
75
82
5
6
Ac-D-tLeu-OH Pd(OAc)2
Ac-D-tLeu-OH Pd(OAc)2
None
0
Me
nPr
iBu
tBu
Na2HPO4
(2.0 equiv.)
72
Ac-D-tLeu-OH Pd(OAc)2
Ac-D-tLeu-OH Pd(OAc)2
Ac-D-tLeu-OH Pd(OAc)2
Ac-D-tLeu-OH Pd(OAc)2
Ac-D-tLeu-OH Pd(OAc)2
Ac-D-tLeu-OH Pd(OAc)2
Ac-D-tLeu-OH Pd(TFA)2
K2HPO4
(2.0 equiv.)
41
Me
7
Ac
Me
8
K2CO3
(2.0 equiv.)
41
Experiments were performed with 4 (0.2 mmol), 2 (0.4 mmol), Pd(OTf)2(MeCN)4 (0.02 mmol),
ligand (0.04 mmol), NaHCO3 (1.2 mmol), Ag2CO3 (0.4 mmol), 1,4-benzoquinone (0.1 mmol),
DMSO (0.08 mmol), H2O (1.1 mmol) in t-amyl-OH (1 ml) for 18 hours at 100 8C under
N2 atmosphere. *Yields were determined by 1H NMR spectroscopy using CH2Br2 as an
internal standard.
9
Li2CO3
(2.0 equiv.)
69
63
70
74
73
82
46†
0
10
11
KHCO3
(4.0 equiv.)
imidate-like moietyas aweak coordinating sdonor when deprotonated
under basic conditions. We therefore began screening of conditions in
the presence of MPAA ligands to achieve the cross-coupling of 1 with
arylboron reagent 2.
NaHCO3
(4.0 equiv.)
12
13
14
15
16
NaHCO3
(6.0 equiv.)
To our delight, when we introduced N-acetyl-L-valine (Ac-L-Val-
OH) into the reaction mixture, we obtained the desired g-arylation
product in 42% yield (Table 1, entry 1). Further screening of MPAA
ligands revealed that L-amino ester 1 gave a higher yield when
D-enantiomers of the MPAA ligands were used (Table 1, entries
1–4). For example, the L-enantiomer of N-acetyl-tert-leucine
(Ac-tLeu-OH) gave a yield of only 46%, but the D-enantiomer
improved the yields to 65%. This provides evidence for the spatial
(steric) impact of MPAA ligands on the reactivity of the catalytic
system. Encouraged by these results, we proceeded to optimize the
reaction conditions using Ac-L-tLeu-OH, and found that the use
of mild bases, such as NaHCO3, was crucial to the reactivity. In
general, sodium salts performed better than their corresponding
potassium counterparts (Table 1, entries 6 and 7). Among the
bases screened, carbonates and bicarbonates were found to be
NaHCO3
(6.0 equiv.)
Ac-D-tLeu-OH Pd(OTf)2(MeCN)4 NaHCO3
(6.0 equiv.)
Ac-D-tLeu-OH Pd(OTf)2(MeCN)4 NaHCO3
(6.0 equiv.)
Ac-D-tLeu-OH None
NaHCO3
(6.0 equiv.)
Experiments were performed with
1 (0.2 mmol), 2 (0.4 mmol), Pd(II) catalyst (0.02 mmol),
3 (0.04 mmol), base, Ag2CO3 (0.4 mmol), 1,4-benzoquinone (0.1 mmol), DMSO (0.08 mmol),
H2O (1.1 mmol) in t-amyl-OH (1 ml) for 18 hours at 100 8C under N2 atmosphere. *Yields were
determined by 1H NMR spectroscopy using CH2Br2 as an internal standard. †Performed with
Pd(OTf)2(MeCN)4 (0.01 mmol) and 3 (0.02 mmol). BPin, boronic acid pinacol ester.
iodination and fluorination reactions36–38
, we attempted to optimal, with 6.0 equiv. sodium bicarbonate affording the highest
cross-couple substrate 1 with 4-methoxycarbonylphenylboronic yield of 74% (Table 1, entries 8–12). To further improve the proto-
acid pinacol ester (2) under various previously established conditions. col, we also screened a variety of Pd(II) catalysts (Table 1, entries 13
However, this failed to give any desired arylation product (Fig. 1b). and 14), and found that Pd(OTf)2(MeCN)4 (OTf ¼ OSO2CF3) gave
Analogous to the decisive role played by phosphine ligands in the highest yield of 82%. The use of 5 mol% Pd catalyst dropped the
Suzuki coupling39–41, we postulated that further development of yield to 46% (Table 1, entry 15). The control experiment carried out
this important transformation in C–H activation reactions would in the absence of a Pd(II) catalyst gave no product (Table 1, entry
critically depend on the introduction and development of ligands. 16). Further comprehensive screening data are presented in the
The ligands would alter the steric and electronic properties of the Supplementary Information.
active catalyst, and could drastically accelerate C(sp3)–H activation
With preliminary conditions for the cross-coupling in hand, we
and subsequent coupling reactions (Fig. 1c). Previously, we demon- proceeded to re-examine systematically the MPAA ligand in an
strated that a combination of weak scoordination from the heteroatom- effort to develop a high-yielding protocol (Table 2). As described
directing group of the substrate and bidentate coordination from a in Table 1, there was an observed increase in yield when the L-enan-
MPAA ligand on the Pd(II) centre could accelerate C(sp2)–H tiomer of the substrate reacted in the presence of the D-enantiomer
activation16. We hypothesized that the triflamide could form an of the MPAA ligand. To screen a variety of MPAA ligands,
2
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.1836
ARTICLES
Table 3 | Scope of arylboron reagents for the C(sp3)–H
cross-coupling reaction.
Table 4 | Substrate scope for the C(sp3)–H cross-coupling
reaction.
R
cat. Pd(OTf)2(MeCN)4
H
cat. Pd(OTf)2(MeCN)4
X
cat. Ac-D-tLeu-OH, 3
R
X
H
cat. Ac-D-tLeu-OH, 3
NHTf
R1
NHTf
Ag2CO3, NaHCO3
1,4-benzoquinone
DMSO, H2O
Ag2CO3, NaHCO3
1,4-benzoquinone
DMSO, H2O
t-amyl-OH
100 °C, N2, 18 h
NHTf
NHTf
CO2Me
1a–q
(S)
R1
R2
(S)
BPin
CO2Me
R2
5a–12a
BPin
t-amyl-OH
5–12
1
100 °C, N2, 18 h
CO2Me
CO2Me
CO2Me
CO2Me
F
CO2Me
Me
H
(R)
CO2Me
CO2Me
NHTf
NHTf
NHTf
NHTf
NHTf
Et
MeO2C
(S)
(S)
(S)
NHTf
NHTf
NHTf
NHTf
CO2Me
H
CO2Me
CO2Me
CO2Me
8a, 57%‡
CO2Me
CO2Me
CO2Me
5a, 96%
(mono:di = 1.5:1)†
6a, 82%
(mono:di = 1.2:1)
7a, 50%
CO2Me
1c, 64%
1d, 66%
1e, 62%
1a, 82%
1b, 73%
CO2Me
CF3
CF3
F
F
CF3
CN
F
NHTf
NHTf
NHTf
NHTf
NHTf
NHTf
NHTf
NHTf
NHTf
CO2Me
TBSO
Et
OBn
10a, 61%§
CO2Me
CO2Me
CO2Me
1h, 73%
CO2Me
9a, 56%§
11a, 54%§
12a, 71%||
1f, 60%
1g, 71%
1j, 50%
1i, 60%
Experiments were performed with substrate (0.2 mmol), ArBPin (0.4 mmol), Pd(OTf)2(MeCN)4
(0.02 mmol), (0.04 mmol), NaHCO3 (1.2 mmol), Ag2CO3 (0.4 mmol), 1,4-benzoquinone
OMe
3
Cl
Br
OMe
NHAc
(0.1 mmol), DMSO (0.08 mmol), H2O (1.1 mmol) in t-amyl-OH (1 ml) for 18 hours at 100 8C
under N2 atmosphere. *Isolated yields. †Diastereomeric ratio 4.7:1. ‡Performed with PhBPin (2.0
equiv.) and Ac-L-tLeu-OH (0.04 mmol). §Performed with PhBPin (2.0 equiv.) and Na2CO3
(2.0 equiv.). ꢀPerformed with Pd(OTf)2(MeCN)4 (0.01 mmol), 3 (0.02 mmol) and at 80 8C for
eight hours.
OMe
NHTf
NHTf
NHTf
NHTf
NHTf
CO2Me
CO2Me
1l, 16%
CO2Me
1m, 54%
CO2Me
1n, 43%
CO2Me
1o, 38%
1k, 63%
natural L-amino acid substrate. As Ac-D-Ile-OH is difficult to
access, we decided to use the more economical Ac-D-tLeu-OH (3)
as the ligand, which gave a comparable yield (Table 2, entry 12).
With the optimized reaction conditions in hand, we cross-coupled
L-amino ester 1 with a wide variety of arylboronic acid pinacol
esters (ArBPins) in the presence of ligand 3 (Table 3). Ester
groups at the meta- and para-positions of the phenyl ring gave
yields from 64 to 82% (1a–1c), and the unsubstituted phenyl ring
afforded a moderate yield of 66% (1d). There was no significant
racemization at the chiral centre, as determined by high-perform-
ance liquid chromatography. The reaction conditions were
NHTf
NHTf
CO2Me
CO2Me
1q, 63%
1p, 61%
Experiments were performed with
(0.02 mmol), (0.04 mmol), NaHCO3 (1.2 mmol), Ag2CO3 (0.4 mmol), 1,4-benzoquinone
(0.1 mmol), DMSO (0.08 mmol), H2O (1.1 mmol) in t-amyl-OH (1 ml) for 18 hours at 100 8C
1 (0.2 mmol), ArBPin (0.4 mmol), Pd(OTf)2(MeCN)4
3
amenable to
a variety of fluorinated and trifluoromethyl-
substituted aryls (1e–1j), which yielded from 60 to 73%, although
the presence of a cyano group in 1j lowered the yield to 50%.
under N2 atmosphere. *Isolated yields.
we opted to perform the ligand screening on the more abundant 4-Chlorophenylboronic acid pinacol ester reacted to give 1k in a
L-enantiomer of the amino acids, and the D-enantiomer of the trifla- respectable yield of 63%, but bromo substitution in the coupling
mide substrate (4). Our initial ligand screening focused on identify- partner decreased the yield to only 16% (1l). The coupling
ing the optimal N-protecting group by screening a variety of L-valine partners that contained electron-donating methoxy and acetamide
derivatives. We discovered that N-methyl-L-valine (Me-L-Val-OH, groups provided moderate yields from 38 to 54% (1m–1o).
Table 2, entry 1) gave no product, but N-formyl-L-valine (For-L- 1-Napthyl- and 2-napthylboronic acid pinacol esters, however,
Val-OH, Table 2, entry 2) afforded only 18% yield. Among the pro- performed better and gave yields up to 63% (1p and 1q).
tecting groups screened, Ac-L-Val-OH (Table 2, entry 3) afforded Heteroarylboronates that contained pyridine-, pyrazole- or
the highest yield of 68%, but N-carbamates (Table 2, entries 4–7) furan-type motives were unreactive under these conditions (see
performed poorly. Having identified the acetyl moiety as the best Supplementary Information). In all cases, unreacted substrate
N-protecting group, we proceeded to identify the optimal side chain. was recovered fully and the methylene C(sp3)–H bonds present
N-acetyl-glycine (Ac-Gly-OH) and N-acetyl-L-alanine (Ac-L-Ala-OH) did not react under these reaction conditions. Finally, we
gave modest yields of 31% and 50%, respectively (Table 2, entries 8 found that aryl iodides can replace the ArBPins as coupling part-
and 9). Side chains that were more sterically hindered improved ners, which suggests that the MPAA ligands also promote
the yields, and among the protected amino acids screened, N-acetyl C(sp3)–H arylation through a Pd(II)/Pd(IV) catalytic manifold (see
L-isoleucine (Ac-L-Ile-OH) afforded the highest yield of 82% Supplementary Information).
(Table 2, entries 10–13).
We then explored the amine substrate scope of the ligand-
Although we identified Ac-L-Ile-OH (Table 2, entry 13) as the enabled cross-coupling protocol (Table 4). Gratifyingly, we were
most-effective MPAA ligand for the D-enantiomer of the substrate, able to functionalize valine and t-leucine derivatives (5 and 6)
we needed a D-enantiomer of the MPAA ligand to arylate the to give a mixture of mono- and diarylated products in 96%
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.1836
ARTICLES
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Conclusion
In summary, we have developed Pd(II)-catalysed cross-coupling of
g-C(sp3)–H bonds in R–NHTf with arylboron reagents using a
MPAA ligand. g-C(sp3)–H bonds in a variety of alkyl amines,
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coupled with a diverse range of arylboron reagents. The dem-
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12236–12239 (2011).
Methods
In a 50 ml Schlenk tube, starting material 1 (49.8 mg, 0.2 mmol), 4-methoxy
carbonylphenylboronic acid pinacol ester (2) (104.8 mg, 0.4 mmol),
Pd(OTf)2(MeCN)4 (11.4 mg, 0.02 mmol), Ac-D-tLeu-OH (3) (6.9 mg, 0.04 mmol),
NaHCO3 (100.8 mg, 1.2 mmol), Ag2CO3 (110.3 mg, 0.4 mmol) and 1,4-benzo
quinone (10.8 mg, 0.1 mmol) were combined. The flask was evacuated and
backfilled with N2 three times, before a solution of dimethylsulfoxide (DMSO,
6.0 mg, 0.076 mmol), water (20 mg, 1.1 mmol) and t-amyl-OH (1 ml, 0.2 M) was
added. The reaction mixture was then stirred at 100 8C for 18 hours. After being
allowed to cool to room temperature, the mixture was diluted with a 1:1 mixture of
hexanes:ethyl acetate, and filtered through a pad of celite. The filtrate was
concentrated in vacuo, and the resulting residue purified by column
chromatography using an eluent of hexanes:ethyl acetate. The product, 1b, was
obtained as a light-yellow liquid (62.9 mg, 82%).
The above procedure to prepare 1b is generally representative for all the products
shown in Tables 3 and 4. Any deviations from this protocol are specified in the
footnotes of the tables.
26. Zaitsev, V. G., Shabashov, D. & Daugulis, O. Highly regioselective arylation of
sp3 C–H bonds catalyzed by palladium acetate. J. Am. Chem. Soc. 127,
13154–13155 (2005).
Received 23 August 2013; accepted 25 November 2013;
published online 5 January 2014
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28. He, G., Zhao, Y., Zhang, S., Lu, C. & Chen, G. Highly efficient syntheses of
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Acknowledgements
This work was supported by The Scripps Research Institute and the National Institutes of
Health (NIGMS, 2R01GM084019). K.S.L.C. thanks the Agency for Science, Technology
and Research (A*STAR) Singapore for a predoctoral fellowship. M.W. thanks Bristol Myers
Squibb for a predoctoral fellowship. M.M. thanks Astellas Pharma Inc. for a postdoctoral
fellowship. This is The Scripps Research Institute (TSRI) manuscript no. 25049.
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Author contributions
K.S.L.C. conceived the study, principally performed the experiments and wrote the
manuscript, M.W. helped with conceiving the study and preparing the manuscript, L.C.
and B.N.L. performed experiments on coupling-partner scope, M.M. helped with
identifying the deprotection strategy and J-Q.Y. provided overall supervision. All the
authors discussed the results and commented on the manuscript.
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Additional information
Supplementary information and chemical compound information are available in the
online version of the paper. Reprints and permissions information is available
online at www.nature.com/reprints. Correspondence and requests for materials should
be sed to J-Q.Y.
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Competing financial interests
The authors declare no competing financial interests.
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