Copper Catalyzed sp3 C-H Etherification with Acyl Protected Phenols

Article abstract of DOI:10.1021/jacs.6b09057

A variety of acyl protected phenols AcOAr participate in sp³ C-H etherification of substrates R-H to give alkyl aryl ethers R-OAr employing ^tBuOO^tBu as oxidant with copper(I) β-diketiminato catalysts [Cu^I]. Although 1°, 2°, and 3° C-H bonds may be functionalized, selectivity studies reveal a preference for the construction of hindered, 3° C-OAr bonds. Mechanistic studies indicate that β-diketiminato copper(II) phenolates [Cu^II]-OAr play a key role in this C-O bond forming reaction, formed via transesterification of AcOAr with [Cu^II]-O^tBu intermediates generated upon reaction of [Cu^I] with ^tBuOO^tBu.

Full text of DOI:10.1021/jacs.6b09057

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Communication
3
Copper Catalyzed sp C-H Etherification with Acyl Protected Phenols
Tolani Kuam Salvador, Charles H. Arnett, Subrata Kundu, Nicholas G.
Sapiezynski, Jeffery A. Bertke, Mahdi Raghibi Boroujeni, and Timothy H. Warren
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.6b09057 • Publication Date (Web): 28 Nov 2016
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Copper Catalyzed sp3 C-H Etherification with Acyl Protected
Phenols
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Tolani K. Salvador,a,b Charles H. Arnett,a Subrata Kundu,a Nicholas G. Sapiezynski,a Jeffrey A.
Bertke,a Mahdi Raghibi Boroujeni,a and Timothy H. Warrena,*
aDepartment of Chemistry, Georgetown University, Box 571227-1227, Washington, D. C. 20057 United States
bDepartment of Chemistry, Purdue University, 560 Oval Drive, West Lafayette, IN 47907, United States
Supporting Information Placeholder
Scheme 1. Catalytic C-H Etherification and Esteri-
ABSTRACT: A variety of acyl-protected phenols AcOAr
fication.
participate in sp3 C-H etherification of substrates R-H to
a
b
directed C-H etherification
Kharasch-Sosnovsky
C-H esterification
t
give alkyl aryl ethers R-OAr employing BuOOtBu as oxi-
O
H
DG
RO
DG
dant with copper(I) β-diketiminato catalysts [CuI].
While 1°, 2°, and 3° C-H bonds may be functionalized,
selectivity studies reveal a preference for the construction
of hindered, 3° C-OAr bonds. Mechanistic studies indi-
cate that β-diketiminato copper(II) phenolates [CuII]-
OAr play a key role in this C-O bond forming reaction,
formed via transesterification of AcOAr with [CuII]-OtBu
intermediates generated upon reaction of [CuI] with
tBuOOtBu.
[Pd] / ox
ROH
H
O
R
R
[Cu]
Ar
t
H
DG
O
DG
[Pd] / ox
BuOOC(O)R
or
Cu(OAc)
2
Ar-Si(OR')
t
t
BuOO Bu / HOC(O)R
3
O
c
undirected C-H etherification
t
H
O Bu
H
O
[Cl NN]Cu
2
[Cu]
t
t
t
t
BuOO Bu
BuOO Bu /
HOC(O)R
with the mild oxidant BuOOtBu. Interestingly, many
saturated C-H substrates such as cyclohexane undergo
tandem dehydrogenation to give to allylic esters.12
Demonstrating that related protocols could lead to undi-
rected C-H etherification, we reported that the β-
diketiminato catalyst [Cl2NN]Cu (1b) provides the hin-
dered dialkyl ether Cy-OtBu in good yield from cyclohex-
ane and tBuOOtBu (Scheme 1c).13
t
Alkyl aryl ether linkages R-OAr are ubiquitous in natu-
ral and synthetic substances, particularly in bioactive
molecules targeted as pharmaceuticals.1 While the
Williamson ether synthesis represents a classic approach
involving phenols and alkyl halides, it often suffers from
elimination, especially when targeting hindered carbon
centers. The Mitsunobu reaction partially addresses this
limitation through the coupling of alkyl and aryl alco-
hols, but generates significant waste with phosphine and
Mechanistic studies of related C-H amination proto-
cols catalyzed by [Cl2NN]Cu that employ alkyl and aryl
diazocarboxylate
co-reagents.2
Metal
catalyzed
t
amines along with BuOOtBu as oxidant provide a con-
approaches employ alkyl alcohols in the Buchwald-
Hartwig coupling with aryl halides1,3 or the Chan-Lam
coupling with aryl boronic acids4 or aryltrifluoroborates.5
In a metal-free protocol, hindered aryl alkyl ethers Ar-
OR may be prepared from diaryliodonium salts [Ar2I]X
and alkyl alcohols HOR.6
ceptual platform to develop new classes of C-H function-
alization reactions.13-14 tBuOOtBu reacts swiftly with
[Cl2NN]Cu to give [CuII]-OtBu and the t-butoxy radical
(Scheme 2a)13 that readily reacts via H-atom abstraction
with sp3 C-H bonds in substrates R-H to generate the C-
based radical R• (Scheme 2b).15 Acid-base exchange
While methods exist to directly oxidatively convert sp2
C-H bonds to aryl ethers C-OR via alcohols and phenols
HOR,7 the corresponding etherification of sp3 C-H bonds
have progressed much more slowly.7a Directing groups,
often based on pyridyl- or quinolinyl-substituted amides,
allow for the installation of dialkyl ether linkages at sp3
C-H sites with alkyl alcohols under Pd catalysis (Scheme
1a).7e,8 The related formation of alkyl aryl ethers R-OAr
requires the separate incorporation of the O and Ar
groups through Cu(OAc)2 and ArSi(OR)3 reagents,
respectively.9 On the other hand, the copper catalyzed
Kharasch-Sosnovsky reaction10 has been long known to
convert sp3 C-H bonds (especially allylic) to esters via
Scheme 2. Catalytic C-H Amination with H-NR1R2
and C-H Etherification with AcOAr.
cat. [CuI]
tBuOOtBu
X
R-H + H-FG
R-FG
R-FG
- 2 HOBut
X
N
tBuOOtBu
a
[CuI]
Cu
N
d
HAA
b
X
OtBu
R
X
HOtBu R-H
[CuII] FG
[CuII]-OtBu [Cu] = [Cl2NN]Cu
c
EOtBu
E-FG = H-NR1R2
refs 14a-c
(1b, X = Cl)
E-FG
t
E-FG = Ac-OAr
[(MeO)2NN]Cu
peroxyesters BuOOC(O)R (Scheme 1b).11 More recent
this work
(1d, X = OMe)
variations allow the use of carboxylic acids HOC(O)R
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Table 2. Copper catalyzed etherification of cyclo-
between [CuII]-OtBu and H-NR1R2 forms copper(II)
amides [CuII]-NR1R2 (Scheme 2c) capable of efficient
capture of organic radicals R• to form a new C-N bond in
R-NR1R2 (Scheme 2d).14c Coupled with pioneering
studies by Kochi who demonstrated that many copper(II)
species containing anions X (X = O2CR, Cl, Br, I, SCN,
N3, CN) are capable of capturing radicals R• to give new
R-X species,16 we anticipated that this mechanistic
scheme could be applied to other functional groups in
complexes [CuII]-FG.14c Unfortunately, this protocol did
not deliver alkyl aryl ethers R-OAr upon substitution of
HOAr for amines using cyclohexane as the C-H sub-
strate.
1
2
3
4
5
6
7
8
hexane with acyl protected phenols ArOAc.
5 % [(MeO)2NN]Cu
1.2 equiv tBuOOtBu
O
H
OAr
+
ArO
2
OAc
OAc
OAc
OAc
MeO
9
2a. 74%
2e. 66%
2b. 53%
OAc
2c. 83%
OAc
2d. 56%
OAc
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OAc
Table 1. Copper catalyzed C-H etherification of
cylclohexane with 2-napthyl acetate.
2f. 82%
OAc
2g. 70%
OAc
2h. 60%
OAc
OAc
O
H
O
[Cu]
+
O
1.2 tBuOOtBu
Ac
Ph
2a
OAc
2l. 64%
OAc
E1/2
(mV)
Catalyst
(R1, R2, X)
Loading Cy-H Yield
(mol %) (equiv.) (%)
R2
2i. 76%
2j. 68%
OAc
2k. 41%
AcO
OAc
[Cl2NNF6]Cu
(Cl, H, CF3)
[Cl2NN]Cu
(Cl, H, CH3)
[Me3NN]Cu
(Me, Me, CH3)
1a +220
1b -140
1c -390
10
10
10
0
OAc
20
20
20
R1
X
R1
Cu
R1
44
68
NC
CN
F3C
N
N
OAc
2m. 73%
OAc
2n. 37%
2o. 32%
2p. 55%
Cl
[(MeO)2NN]Cu 1d -480
(OMe, H, CH3)
10
10
10
50
20
1
76
72
74
83
81
20
10
5
20
20
20
OAc
OAc
R1
X
OAc
general conditions:
90 °C, neat, 24 h
F
Cl
Cl
Cl
Cl
R2
1
(oxidation potentials
vs. Fc+/Fc in MeCN)
2q. 66%
2r. 70%
2s. 55%
2t. 58%
trace
Conditions: 10 equiv. cyclohexane, neat, 90 oC, 24 h
We turned our attention to acyl protected phenols
AcOAr that would not potentially suffer from the rela-
tively acidic (pKa = 7 - 11)17 and weak O-H bond (BDE ~
85 - 93 kcal/mol)18 present in phenols. Gratifyingly,
[Cl2NN]Cu catalyzes the C-H etherification of cyclohex-
ane (10 equiv.) with 2-napthyl acetate in 44% yield
Substrates containing multiple aryl acetate functionali-
ties (2l and 2m) undergo single C-H functionalization
under these conditions.
A range of 2° and 3° sp3 C-H bonds undergo C-H
etherification with AcOPh (Table 3). Cyclohexene,
ethylbenzene, and indane (3a - 3c) gave slightly lower
yields (58% - 74%) than cyclohexane (2c: 83%). Cumene
(3d) and diisopropyl ketone (3e) undergo efficient, se-
lective C-H functionalization at their 3° C-H bonds (83
and 81% yield, respectively). The 2° benzylic C-H bonds
in 2-ethylfuran (3f) and 2-ethylthiofuran also participate
in C-H etherification. Saturated heterocycles (3h and 3i)
undergo functionalization at the heteroatom α-C-H bond
similar to anisole (3j).
t
employing BuOOtBu (1.2 equiv.) as oxidant (Table 1).
Screening
a small set of copper(I) β-diketiminato
complexes revealed that increasing the electron-richness
of the β-diketiminate supporting ligand increases the C-
H etherification yield (Table 1 and S1). Under the same
conditions, the [Me3NN]Cu (1c) and [(MeO)2NN]Cu (1d)
catalysts provided a 68% and 76% yield, respectively,
while the electron-poor catalyst [Cl2NNF6]Cu gave no
product. Since further attempts at optimization of this
reaction with [(MeO)2NN]Cu led only to marginal
increases in yield (e.g. 83% with 50 equiv. cyclohexane),
we opted to examine the phenol and C-H substrate scope
of this new protocol employing 10 equiv. cyclohexane
with 5 mol% [(MeO)2NN]Cu.
Table 3. Copper catalyzed etherification of cyclo-
hexane with acyl protected phenols ArOAc.
5 % [(MeO) NN]Cu
t
O
O
2
R
t
+ R-H
H
1.2 equiv BuOO Bu
O
3
A wide range of acyl protected phenols participate in
the C-H etherification of cyclohexane (Table 2). Com-
mercially available aryl acetates derived from both elec-
tron-neutral (2a - 2c) as well as electron-rich (2d - 2i)
arenols afforded good to excellent yields (63 - 82%)
while those containing electron-withdrawing groups (2k
- 2t) occassionally provided somewhat lower yields (32 -
73%). Noteworthy is the absence of any functionalization
of benzylic C-H bonds present in aryl acetates (2e - 2i).
H
H
H
H
O
3a. 58%
3c. 74%
3d. 83%
3e. 81%
3b. 69%
H
H
O
H
S
O
S
O
H
H
3f. 58%
3g. 53%
3h. 57%
3i. 33%
3j. 79%
o
Conditions: 20 equiv. R-H, neat, 90 C, 24 h
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Scheme 3. Transesterification at [CuII]-OtBu gives
Table 4. Exploration of regiochemistry in copper
catalyzed sp3 C-H etherification with PhOAc.
[CuII]-OAr active in C-H etherification via radical
capture.
1
2
3
5 % [(MeO)2NN]Cu
1.2 equiv tBuOOtBu
O
O
R
+ R-H
O
6
4
5
OPh
H
OPh
H
6
7
8
9
6a. 71%a
6b. 80%
H
OPh
10
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H
OPh
OPh
6c. 69% total (1 : 1.0)
OPh
H
H
6d. 69% total (1 : 1.2)
In analogy to copper(II) anilides [CuII]-NHAr that
serve as intermediates that capture sp3 C-based radicals
R• in C-H amination (Scheme 2d),14c we anticipated the
intermediacy of closely related β-diketiminato copper(II)
phenolates [CuII]-OAr.19 Reaction of [(MeO)2NN]Cu(η2-
toluene) with tBuOOtBu quantitatively generates
[(MeO)2NN]Cu-OtBu (4) (Schemes 2a, 3) via UV-vis
spectroscopy and may be isolated from pentane as purple
crystals in 69% yield. Reaction of 4 with an excess of 4-
chlorophenyl acetate provides the corresponding
copper(II) phenolate [(MeO)2NN]Cu-OAr4Cl (5) in 54%
isolated yield as dark brown crystals. X-ray analysis
reveals the trigonal [(MeO)2NN]Cu-OAr4Cl (5) that
features a short Cu-O bond (1.837(3) Å) with the OAr
ring roughly perpendicular to the β-diketiminato
backbone (Scheme 3). There is a slight distortion, how-
ever, to allow for gentle contact with one the β-
diketiminato methoxy groups (Cu…O2 = 2.840 Å). To
gain insight into the formation of [CuII]-OAr intermedi-
ates (Scheme 2c), we kinetically monitored the trans-
esterification of AcOAr4Cl with [CuII]-OtBu that proceeds
cleanly with activation parameters ꢀH‡ = 9.7(8) kcal/mol
and ꢀS‡ = -34(2) e.u (k60°C = 1.1 × 10-1 M-1s-1). Moreover,
electron-rich phenolates react more swiftly with [CuII]-
OtBu as revealed by a Hammett plot with a modest range
of p-substituted acyl phenolates (X = Me, H, F, Ac) that
gives ρ = -0.51(5) against σ+ (Figure S18).
OPh
OPh
H
6e. 23% total (1 : 1.2)
OPh
H
OPh
H
(2 isomers)
6f. 72% total (8.6 : 1)
OPh
H
(2 isomers)
OPh
H
6g. 67% total (11.1 : 1)
OPh
H
H
H
H
H
H
H
H
H
6h. 77% total (1 : 12.8 : 5)
OPh H
H
H
OPh
H
OPh
H
H
H
H
6i. 68% total (1 : 7.9 : 5.3)
OPh H
OPh
OPh
H
6j. 72%
Conditions: 20 equiv. R-H, neat, 90 oC, 24 h.
a10 equiv. R-H, 1.4 equiv. tBuOOtBu
Importantly, these copper(II) phenolates [CuII]-OAr
efficiently react with radicals R• generated by H-atom
abstraction of C-H substrates R-H (Scheme 2d). Heating
1° C-H bonds (Table 4). Nonetheless, the 1° benzylic sub-
strate p-xylene undergoes etherification (entry 6a) alt-
hough toluene does not. Etherification of 4-ethyltoluene
(entry 6b) illustrates preferential functionalization at 2°
over 1° benzylic positions. Isobutylbenzene (entry 6c)
gave a 1:1.0 mixture of 2° and 3° products while neopen-
tylbenzene (entry 6d) gave a nearly equimolar ratio of 2°
and 1° products (1: 1.2).
t
[(MeO)2NN]Cu-OAr4Cl (5) with BuOOtBu and 20 equiv.
cyclohexane generates the C-H functionalized product
Cy-OAr4Cl in 87% yield, presumably via the intermediacy
of Cy• radicals.13,14c Using UV-vis spectroscopy to follow
the C-H etherification of ethylbenzene with AcOAr4Cl and
tBuOOtBu catalyzed by 1d, we observe initial formation
of [CuII]-OtBu (4) followed by the persistent presence of
[CuII]-OAr4Cl (5) which gradually decays (Scheme S10;
Figures S19-S20). Moreover, reaction of [CuII]-OAr4Cl (5)
Indeed, unactivated 1° C-H bonds undergo H-atom ab-
straction (HAA) as illustrated by the use of t-
butylbenzene (entry 6e). The mixture of 1° and 3° prod-
ucts obtained, however, suggests that the 1° radical in-
termediate PhC(CH3)2CH2• derived from HAA of sp3 C-H
bond undergoes facile rearrangement to the 3° radical
PhCCH2CMe2• as first reported by Kharasch.21 In support
of a common 3° radical intermediate, cis- and trans-1,4-
dimethylcyclohexane give the same predominant 3° C-H
t
t
with 3 equiv. BuN=NtBu at 90 °C provides BuOAr4Cl in
t
71% yield through capture of Bu• radicals generated by
thermal decomposition of this azoalkane.20
A brief survey of regioselective preferences in sp3 C-H
etherification with PhOAc reveals that 2° and especially
3° C-H sites undergo functionalization in the presence of
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M.; Nordmann, G.; Job, G. E.; Buchwald, S. L. Org. Lett. 2002, 4,
etherification product (entries 6f and 6g); competing 2°
C-H functionalization that provides slightly different
product mixtures in good combined yields (72 and 67%,
respectively). The observation of three isomers each for
C-H etherification of n-pentane and n-hexane indicates
competitive H-atom abstraction at the C-1, C-2, and C-3
sites (entries 6h and 6i), with a mild preference the C-2
position. Nonetheless, 2,4-dimethylpentane exclusively
gives the 3° alkyl aryl ether (entry 6j). Curiously, the 1°,
2°, and 3° C-H bonds of this alkane undergo H-atom ab-
straction with tBuO• radical in a 24 : 9 : 67 ratio at 60 °C
in neat substrate based on trapping studies with
TEMPO•.22 We do not observe 1° C-H functionalization
adjacent to 3° sites as reported in C-H amidation with
PhC(O)NH2 by a [(phen)Cu]+ / tBuOOtBu system.23 Thus,
our catalyst system may promote alkyl radical isomeriza-
tion to deliver the most hindered 3° ether product de-
rived from the most stable 3° alkyl radical.
973-976. (e) Parrish, C. A.; Buchwald, S. L. J. Org. Chem. 2001, 66,
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This simple copper catalyzed protocol provides 1°, 2°,
and 3° alkyl aryl ethers R-OAr from a wide range of
commercially available, acyl protected phenols AcOAr
and sp3 C-H bonds in substrates R-H. In analogy to C-H
t
amination with BuOOtBu via [CuII]-NHR intermediates,
simple mechanistic studies support H-atom abstraction
of R-H by the tBuO• radical to give R• that is captured by
copper(II) phenolates [CuII]-OAr generated by trans-
esterification of [CuII]-OtBu intermediates with AcOAr.
Besides directly converting C-H to C-OAr bonds, this
radical based C-H functionalization protocol offers op-
portunities for the preparation of hindered 3° alkyl aryl
ethers R-OAr.6 Studies are underway to extend this
methodology for undirected C-H etherification to unpro-
tected alkyl alcohols HOR’ to give dialkyl ethers R-OR’.24
(12) (a) Tran, B. L.; Driess, M.; Hartwig, J. F. J. Am. Chem. Soc.
2014, 136, 17292-17301. (b) Wang, C.-Y.; Song, R.-J.; Wei, W.-T.;
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(13) Gephart, R. T.; McMullin, C. L.; Sapiezynski, N. G.; Jang, E. S.;
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(14) (a) Wiese, S.; Badiei, Y. M.; Gephart, R. T.; Mossin, S.;
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T. H. Angew. Chem. Int. Ed. 2010, 49, 8850-8855. (b) Gephart, R. T.;
Huang, D. L.; Aguila, M. J. B.; Schmidt, G.; Shahu, A.; Warren, T.
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McMullin, C. L.; Käß, M.; Meyer, K.; Cundari, T. R.; Warren, T. H.
J. Am. Chem. Soc. 2014, 136, 10930-10940.
ASSOCIATED CONTENT
Supporting Information. Experimental and characterization
details (PDF) as well as X-ray crystallographic data (CIF). This
material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
(15) Finn, M.; Friedline, R.; Suleman, N. K.; Wohl, C. J.; Tanko, J.
M. J. Am. Chem. Soc. 2004, 126, 7578-7584.
* thw@georgetown.edu
Notes
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87, 1508-1514. (b) Kochi, J. K.; Jenkins, C. L. J. Org. Chem. 1971,
36, 3095-3102. (c) Kochi, K. K.; Jenkins, C. L. J. Org. Chem. 1971,
36, 3103-3111. (d) Jenkins, C. L.; Kochi, J. K. J. Am. Chem. Soc.
1972, 94, 856-865.
(17) Liptak, M. D.; Gross, K. C.; Seybold, P. G.; Feldgus, S.; Shields,
G. C. J. Am. Chem. Soc. 2002, 124, 6421-6427.
(18) Luo, Y.-R. Handbook of Bond Dissociation Energies in Organic
Compounds; CRC Press, Boca Raton, FL, 2002.
(19) Jazdzewski, B. A.; Holland, P. L.; Pink, M.; Victor G. Young, J.;
Spencer, D. J. E.; Tolman, W. B. Inorg. Chem. 2001, 40, 6097-6107.
(20) Engle, P. S. Chem. Rev. 1980, 80, 99-150.
(21) (a) Urry, W. H.; Kharasch, M. S. J. Am. Chem. Soc. 1944, 66,
1438-1440. (b) Lindsay, D. A.; Lusztyk, J.; Ingold, K. U. J. Am.
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(22) Dokolas, P.; Loffler, S. M.; Solomon, D. H. Aust. J. Chem. 1998,
51, 1113-1120.
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The authors declare no competing financial interest.
ACKNOWLEDGMENT
THW is grateful to NSF for support of this work (CHE-
1300774) and for an X-ray diffractometer (CHE-1337975).
THW and SK also thank the Georgetown Environment Initi-
ative. This study is dedicated to the late Richard D. Vorisek
who co-founded the Arenol Chemical Corporation.
REFERENCES
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