Identification of monodentate oxazoline as a ligand for copper-promoted ortho-C-H hydroxylation and amination

Article abstract of DOI:10.1039/C6SC03383K

The use of a weakly coordinating monodentate directing group for copper mediated ortho-hydroxylation and amination reactions allows for the identification of an external oxazoline ligand as a promoter.

Full text of DOI:10.1039/C6SC03383K

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Edge Article
Identification of Monodentate Oxazoline as a Ligand for Copper-
Promoted ortho-C–H Hydroxylation and Amination
Ming Shang, a Qian Shao,a Shang-Zheng Sun,c Yan-Qiao Chen,b Hui Xu, a Hui-Xiong Dai, * a and Jin-
Quan Yu* a,b
5
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
DOI: 10.1039/b000000x
The use of a monodentate weakly coordinating directing group for copper mediated orthoꢀhydroxylation
and amination reactions allows for the identification of an external oxazoline ligand as a promoter.
Introduction
10 Over the past decade, directed C–H activation has emerged as a
Recently, copper mediated C–H hydroxylation of benzoic acid
derivatives with the assistance of bidentate auxiliaries have also
been disclosed.11 Guided by the development of Pdꢀcatalyzed C–
useful tool for organic synthesis.1 Diverse carbonꢀcarbon bond
and carbon heteroatom bond forming reactions have been
developed with various transition metals. In this regard, precious 50 H activation reactions enabled by ligands, we set out to explore
metals such as Pd, Rh and Ir have shown superior catalytic
15 reactivity. Notably, Pd catalysts have demonstrated versatility in
both C(sp2)–H activation and C(sp3)–H activation via different
manifolds including Pd(0)/Pd(II), Pd(II)/Pd(0), Pd(II)/Pd(IV) and
the combination of weakly coordinating monodentate directing
groups and ligands for Cuꢀcatalyzed C–H activation reactions.
Herein, we report the first example of copper mediated C–H
hydroxylation and amination using
a weakly coordinating
Pd(II)/Pd(II) catalysis.2 However, replacing these precious metals 55 directing group under the assistance of a monoꢀdentate ligand.
with firstꢀrow transition metals such as Fe and Cu are more
20 desirable due to their high abundance and low toxicity.3,4 In
particular, copper mediated C–H functionalization has made rapid
progress in recent years with various C–H transformations
developed via different redox manifolds corresponding to the
oxidants employed. However, owing to their low reactivity,
25 nearly all of the inexpensive metals, especially copper mediated
C–H activation reactions rely on strongly coordinating directing
groups, for example, pyridine or pyridine based bidentate
auxiliaries (Figure 1).4,5 The advantage of weakly coordinating
directing groups to form the less thermodynamically stable
30 metallacycle thereby kinetically facilitating the subsequent
functionalization step has been demonstrated with only precious
metal catalysts.6 The use of a monoꢀdentate weakly coordinating
directing group in combination of ligand acceleration remains to
be demonstrated with Cu catalysts.
35
Phenols are a class of important structure motifs prevalent
both in natural products and pharmaceuticals.7 Direct C–H
hydroxylation is an appealing method for the synthesis of
functionalized phenols. Pdꢀmediated hydroxylation of excess
benzene at 180 °C was found to give phenol in less than 5% yield
Fig. 1 Auxiliaries used for copper mediated C–H activation.
40 in an early study.8a Recently, directed orthoꢀC–H hydroxylation
of simple substrates has reached synthetically useful yields with
Pd and Ru catalysts.8,9 However, inexpensive metals catalyzed or
mediated C–H hydroxylation reactions remain rare. In 2006, our
group reported a pyridine directed hydroxylation of inert C–H
45 bonds using Cu(OAc)2 as a promoter, which involved the
formation of acetoxylated products and subsequent hydrolysis.10
60
Results and Discussion
Initial Studies and Reaction Optimization
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We commenced our studies with screening a series of weakly
combined additive to generate CsOPiv in situ, the yield of 3a
coordinating amides (Table 1). Although displaying good 45 could be increased to 59% while decreasing the yield of 2a to
reactivity in Pd catalyzed C–H activation reactions, N–OMe
substituted amide gave no product. Other simple amides such as
N–isopropyl, N–phenyl and N–(4ꢀNO2)ꢀphenyl substituted
amides were also unreactive with starting material fully recovered.
12% respectively (Table 3, entry 1). 1ꢀAdꢀCOOH proved to be a
better acid which lead to the product 3a in 61% yield (Table 3,
entry 2). The yield could be slightly improved to 63% when
increasing the amount of 1ꢀAdꢀCOOH to 1.8 equiv (Table 3,
5
Encouragingly, when Nꢀ(3,5ꢀdiꢀtrifluoromethyl)ꢀphenyl amide 50 entry 3). The reaction proceeded in the presence of 1.5 equiv
was employed as substrate, trace product was observed. Further
decreasing the electron density of the Nꢀaryl group by using
10 2,3,5,6ꢀtetrafluoroꢀ4ꢀ(trifluoromethyl) substituent increased the
yield to 11%.12 Using 0.8 equiv CuBr as an additive, the yield
Cu(OAc)2, 0.4 equiv ligand and 0.5 mL DMSO to provide the
product in 67% yield (Table 3, entry 4ꢀ6). After a brief survey of
Cu(II) salts, we found that using Cu(OPiv)2 could inhibit the
undesired product completely and increase the product yield to
was improved to 23%. However, side product (2a) arising from 55 75% (Table 3, entry 7ꢀ9). Finally, slightly increasing the
nucleophilic attack of the hydroxyl group to the C–F bond on the
directing group was observed in 10% yield.
temperature to 105oC improved the yield to 80%.
15
Table 2 Ligand effect on C(sp2)–H hydroxylation.a, b
Table 1 Weakly coordinating directing groups screeninga, b
O
O
O
F
O
NH
F
O
Cu(OAc)2, CuBr,
CsOAc, ligand
ArF
ArF
+
Cu(OAc)2, CsOAc
DMSO,100 oC, air
N
N
R
R
N
H
H
N
F
O
H
DMSO, 100 oC, air
H
H
OH
H
OH
CF3
ArF = 4-(CF3)C6F4
1a
3a
2a
NO2
O
O
O
O
OMe
iPr
N
N
N
H
N
H
no ligand
N-Ac-Leu
N-Boc-Gly
H
H
O
O
L3, 24%+9%
23%+10%
L2, 22%+6%
L1, 26%+8%
0%
0%
0%
F
0%
F
O
O
N
CF3
F
F
F
F
F
F
CF3
F
N
O
O
O
N
N
F
N
CF3
N
H
N
H
H
L4, 22%+12%
L5, 23%+11%
L6,33%+17%
L7,37%+17%
F
trace
7%
11% (23%)c
O
N
N
O
O
N
O
N
MeO
OMe
a Reaction conditions: 1a (0.1 mmol), Cu(OAc)2 (0.2 mmol), CsOAc (0.2
mmol), DMSO (1.0 mL), 100 oC, air, 6 h. b Yield determined by 1H NMR
analysis of crude reaction mixture using CH2Br2 as an internal standard. c
Bn
iPr
20 CuBr (0.8 eq) as an additive.
L8, 32%+13%
L9, 30%+ 12%
L10, 28%+12%
L11,32%+10%
O
N
O
N
O
O
N
During the past several years, we have developed two kinds
Ph
N
of ligands, Nꢀprotected amino acid ligand and pyridine or
quinolineꢀbased ligand, for accelerating or promoting Pd
25 catalyzed C(sp2)–H and C(sp3)–H bond activation.13 Based on
these results, we next tested the ligand effect on this reaction. Nꢀ
protected amino acids such as NꢀAcꢀLeu (L1), NꢀBocꢀGly (L2)
and pyridine (L4), quinolineꢀbased ligands (L5) are found to have
negligible effect on the yield. Considering that oxazoline ligands
30 have been demonstrated effective in various copperꢀmediated
reactions, we subsequently focused on investigating theses
ligands. To our delight, with ligand L6 as an additive, the yield of
3a could be increased to 33% though it also promoted the
nucleophilic attack process affording 2a in 17% yield
35 correspondingly. Modifying the phenyl moiety on the oxazoline
L12, 36%+18%
L13, 42%+18%
L14, 48%+20%
L15, 55%+15%
Ph
O
Ph
Ph
O
O
O
N
N
N
N
Ph
L16, 40%+12%
L17, 45%+24%
L18, 32%+10%
L19, 38%+11%
a
Reaction conditions: 1a (0.1 mmol), Cu(OAc)2 (0.2 mmol), CuBr (0.08
o
60 mmol), CsOAc (0.2 mmol), ligand (0.1 mmol), DMSO (1.0 mL), 100 C,
air, 6 h. b Yield determined by 1H NMR analysis of crude reaction mixture
using CH2Br2 as an internal standard.
ligand with
a biaryl framework (L8-L11) provided no
improvement. Interestingly, employing readily available
oxazoline L15 as ligand, the yield was improved to 55%. Further
optimization by changing the steric bulk and electronꢀdonating
40 ability of the ligands proved ineffective (L16-L19, and see SI).
Having identified the optimal ligand, we next performed the
further optimization of reaction conditions to suppress the
undesired product 2a (Table 3). Using Cs2CO3 and PivOH as a
65 Substrate Scope
With the optimal conditions in hand, we next investigated the
substrate scope. Arenes containing oꢀmethyl and pꢀmethyl
substitutions gave yields of 41% and 65% respectively (3b and
3d), whereas mꢀmethylꢀsubstituted arene afforded two
2
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regioisomers in a total of 60% yield (3c). Other electronꢀdonating
electron donating and electron withdrawing groups gave
groups such as tertꢀbutylꢀ, methoxyl and phenyl were also well 35 acceptable yields (5b-5g). Different cyclic alkyl amines also
tolerated to give the corresponding products in 56ꢀ84% yields
(3e-3g). Arene with mꢀfluoro substitution afforded a mixture of
hydroxylation product at the Cꢀ2 and Cꢀ3 positions with sterically
less hindered Cꢀ3 position as the major product (3h), while pꢀ
fluoroarene proceeded smoothly to give the product in 84% yield
(3i). Importantly, this reaction was also compatible with Clꢀ, Brꢀ,
and Iꢀ substituted arenes, which left synthetic handles for further
10 functionalization (3j-3m). Arenes bearing strong electronꢀ
withdrawing functional groups underwent C–H activation
efficiently, thus providing the hydroxylated products in good to
excellent yields (3n-3q). Notably, this hydroxylation protocol
could also be compatible with vinylꢀsubstituted arene, which was
15 rare in noble metals catalyzed C–H activation reactions.
showed good compatibility with this reaction (5h-5k).
Table 4 Scope of C–H hydroxylation a, b
5
O
O
Cu(OPiv)2, CuBr,
ArF
ArF
Cs2CO3, 1-AdCOOH, ligand
N
N
X
X
H
H
DMSO, 105 oC, air
H
OH
ArF = 4-(CF3)C6F4
N
1a-1r
3a-3r
L =
O
O
Me
O
O
2
ArF
ArF
Me
ArF
N
H
N
N
H
H
6
OH
OH
OH
3c, 60%
C2:C6 = 25:35
O
3a, 79%
3b, 41%
O
O
ArF
ArF
ArF
Table 3 Further optimization of C(sp2)–H hydroxylation.a, b
N
N
H
N
H
H
Me
OH
t-Bu
OH
MeO
OH
O
O
O
ArF
ArF
F
3d, 65%
3e, 56%
3f, 67%
NH
N
N
+
Conditions
O
O
O
H
H
2
F
ArF
ArF
ArF
F
ArF
ArF
H
OH
O
N
O
N
N
N
ArF = 4-(CF3)C6F4
L =
H
H
H
6
CF3
F
Ph
Cl
OH
OH
F
OH
1a
3a
2a
3h, 75%
C2:C6 = 16:59
O
3g, 84%
3i, 84%
O
O
yield
2
Entry
copper salts
base
acid
PivOH
ArF
ArF
ArF
ArF
ArF
ArF
N
N
H
N
3a
2a
H
H
6
Cu(OAc)2+CuBr
Cu(OAc)2+CuBr
Cu(OAc)2+CuBr
Cu(OAc)2+CuBr
Cu(OAc)2+CuBr
Cu(OAc)2+CuBr
Cu(OPiv)2+CuBr
59
1
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
12
OH
Cl
OH
Br
OH
3j, 70%
C2:C6 = 41:29
O
3k, 78%
3l, 72%
1-Ad-COOH
1-Ad-COOH
1-Ad-COOH
1-Ad-COOH
1-Ad-COOH
1-Ad-COOH
1-Ad-COOH
1-Ad-COOH
61
63
63
66
67
2
13
12
11
8
O
O
F3C
3c
N
N
N
H
H
H
I
OH
OH
F3C
OH
4c,d
5c,d,e
6c,d.e,f
7c,d,e,f
3m, 71%
3n, 59%
3o, 71%
O
O
O
ArF
N
N
N
8
H
H
H
Ph
OH
NC
OH
OH
75(80)g
68
0
O
3p, 88%
3q, 72%
3r, 72%
8c,d.e,f Cu(OCOiPr)2+CuBr
0
9c,d,e,f
0
a
Cu(OCO)2+CuBr
45
Reaction conditions: 1a-1r (0.1 mmol), Cu(OPiv)2 (0.15 mmol), CuBr
(0.08 mmol), Cs2CO3 (0.15 mmol), 1ꢀAdꢀCOOH (0.18 mmol), ligand
40 (0.04 mmol), DMSO (0.5 mL), 105 oC, air, 6 h. b Isolated yield.
a
Reaction conditions: 1 (0.1 mmol), Cu(OAc)2 (0.2 mmol), CuBr (0.08
mmol), base (0.15 mmol), acid (0.15 mmol), ligand (0.1 mmol), DMSO
o
b
1
20 (1.0 mL), 100 C, air, 6 h. Yield determined by H NMR analysis of
Conclusions
c
crude reaction mixture using CH2Br2 as an internal standard. acid (0.18
mmol). CuX2 (0.15 mmol). DMSO (0.5 mL). ligand (0.04 mmol).
105 oC.
d
e
f
g
In conclusion, we have developed a Cuꢀpromoted C–H
hydroxylation and amination of weakly coordinating amides with
the assistance of an external oxazoline ligand. This finding
45 provides guidance for further ligand development in promoting
copper catalyzed C–H activation reactions in the future.
25
With the success of achieving C–H hydroxylation of weakly
coordinating amides, we wondered whether this newly developed
external ligand promoted C–H activation protocol could be
compatible with C–H amination reactions using a free alkyl
amine donor, which is still an unsolved problem with weakly
Acknowledgements
30 coordinating auxiliaries.14 To our delight, using unprotected
morpholine as the amine coupling partner, C–H amination
reaction proceeded smoothly providing the desire product in
moderate yields. A variety of substituents on arenes containing
We gratefully acknowledge Shanghai Institute of Organic
50 Chemistry, Chinese Academy of Sciences, the CAS/SAFEA
International Partnership Program for Creative Research Teams,
NSFCꢀ21121062, NSFCꢀ21472211, NSFCꢀ21421091
, Youth
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organic fraction was dried over Na2SO4, evaporated and purified by
preparative TLC (EtOAc/hexane) to provide the corresponding products
as white solids.
Innovation Promotion Association CAS (No.2014229), and The
Recruitment Program of Global Experts for financial support. We
gratefully acknowledge The Scripps Research Institute, for
financial support. This work was supported by NSF under the
CCI Center for Selective C−H Functionalization, CHEꢀ1205646,
and Novartis for an unrestricted grant.
35
40
45
50
55
60
65
70
75
80
85
90
95
100
1
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5
Table 5 Scope of C–H amination a ,b
O
O
Cu(OAc)2, CuBr,
ArF
ArF
N
N
CsOAc, LiOAc, ligand
X
X
H
H
R1R2NH
+
DMSO, 100 oC, air
H
NR1R2
ArF = 4-(CF3)C6F4
N
2
For Pdꢀcatalyzed C–H functionalizations via various redox manifolds, see:
(a) O. Baudoin, A. Herrbach, F. Guéritte, Angew. Chem., Int. Ed. 2003, 42,
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L =
5a-5k
4a-4e
1
O
O
O
O
ArF
ArF
ArF
O
N
H
N
H
N
H
N
Me
N
F
N
O
O
5a, 52%
5b, 46%
5c, 57%
O
O
O
For iron catalyzed sp2 and sp3 C–H functionalizations, see: (a) A.
Matsumoto, L. Ilies, E. Nakamura, J. Am. Chem. Soc. 2011, 133, 6557ꢀ
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14349ꢀ14352; (f) R. Shang, L. Ilies, E. Nakamura, J. Am. Chem.
Soc. 2015, 137, 7660ꢀ7663.
ArF
ArF
ArF
3
N
H
N
H
N
H
Cl
N
F3C
N
N
O
O
O
5d, 51%
5e, 53%
5f, 47%
O
O
O
ArF
O
ArF
ArF
N
H
N
H
N
H
Ph
N
Cl
N
Cl
N
O
4
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Me
5g, 55%
5h, 51%
5i, 47%
O
N
O
ArF
ArF
N
N
H
H
Cl
Cl
N
N
Boc
COOEt
5j, 43%
5k, 48%
a
Reaction conditions: 1 (0.1 mmol), 4a-4e (0.3 mmol), Cu(OAc)2 (0.2
10 mmol), CuBr (0.1 mmol), CsOAc (0.2 mmol), LiOAc (0.1 mmol), ligand
(0.05 mmol), DMSO (1.0 mL), 100 oC, air, 6 h. b Isolated yield.
Notes and references
15 a State Key Laboratory of Organometallic Chemistry, Shanghai Institute
of Organic Chemistry, Shanghai 20032, China. E-mail:hxdai@sioc.ac.cn;
yu200@scripps.edu
b Department of Chemistry, The Scripps Research Institute, 10550 N.
Torrey Pines Road, La Jolla, California 92037, USA;
20 c Department of Chemistry, Innovative Drug Research Center, Shanghai
University, 99 Shangda Road, 200444, China.
† Electronic Supplementary Information (ESI) available: Data for new
compounds and experimental procedures. See DOI: 10.1039/b000000x/
25 ‡ General procedure for Copper Promoted orthoꢀC–H Hydroxylation: To
a 15 mL sealed tube was added substrates 1 (0.1 mmol, 1.0 equiv),
Cu(OPiv)2 (0.15 mmol), CuBr (0.08 mmol), Cs2CO3 (0.15 mmol), 1ꢀAdꢀ
COOH (0.18 mmol), ligand L15 (0.04 mmol) and DMSO (0.5 mL). The
reaction tube was then placed into a preꢀheated oil bath and stirred at 105
30 oC for 6 h under air. Upon completion, EtOAc was added to dilute the
mixture and then washed with NH3·H2O and saturated NaCl(aq). The
5
For few examples of Fe, Co catalyzed C–H functionalizations with a
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