Copper-catalyzed oxidative α-alkylation of α-amino carbonyl compounds with ethers via dual C(sp3)-H oxidative cross- coupling

Article abstract of DOI:10.1002/adsc.201301091

A novel copper-catalyzed oxidative alkylation of α-amino carbonyl compounds with ethers has been established for the selective synthesis of α-etherized α-amino carbonyl compounds. This oxidative alkylation is achieved by dual C(sp³)-H bond oxidative cross-coupling, and its scope is expanded to α-amino ketones, α-amino esters and α-amino amides.

Full text of DOI:10.1002/adsc.201301091

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DOI: 10.1002/adsc.201301091
Copper-Catalyzed Oxidative a-Alkylation of a-Amino Carbonyl
Compounds with Ethers via Dual C
(sp3)-H Oxidative Cross-
Coupling
AHCTUNGTRENNUNG
Wen-Ting Wei,a Ren-Jie Song,a and Jin-Heng Lia,*
a
State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, Hunan
University, Changsha 410082, Peopleꢀs Republic of China
Fax : (+86)-731-8871-3642; phone: (+86)-731-8871-3642; e-mail: jhli@hnu.edu.cn
Received: December 6, 2013; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201301091.
Abstract: A novel copper-catalyzed oxidative alky-
lation of a-amino carbonyl compounds with ethers
has been established for the selective synthesis of
a-etherized a-amino carbonyl compounds. This oxi-
could be alkylated with malonates by Cu-catalyzed
dual C H functionalization. However, the reaction
was carried out under rather harsh conditions
[20 mol% CuACTHUNRGTNEUNG(OAc)2 at 1508C]; moreover, a catalytic
[4]
À
3
À
dative alkylation is achieved by dual C
N
amount of bases combined with a ligand was still
needed to facilitate the reaction. Subsequently, Huang
and Xie have illustrated a new, mild cross dehydro-
genative coupling strategy for a-alkylation of a-amino
esters with ketones through a Cu/aminocatalyst-cata-
bond oxidative cross-coupling, and its scope is ex-
panded to a-amino ketones, a-amino esters and a-
amino amides.
À
Keywords: alkylation; a-amino carbonyl com-
pounds; tert-butyl hydrogen peroxide (TBHP);
lyzed oxidative dual C H functionalization process
under neutral conditions.[5] To the best of our knowl-
3
À
copper; C
N
edge, however, oxidative a-alkylation of a-amino car-
À
bonyl compounds with ethers using the dual C H
functionalization strategy has not been exploited. The
reason may be that in the cross dehydrogenative cou-
pling reactions both a-amino carbonyl com-
a-Amino carbonyl compounds are ubiquitous sub-
units in biologically active natural products, biomole- to react with a wide range of nucleophiles.[7]
cules and therapeutic agents.[1] The development of
Herein we report a novel and mild Cu-catalyzed
pounds[2l–o,4,5] and ethers[6] are utilized as electrophilies
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
efficient strategies for their assembly has been a long- oxidative alkylation of a-amino carbonyl compounds
standing hot topic in organic and bioorganic synthesis. with ethers for selective synthesis of a-etherized a-
In this context, a-C H functionalization of the preex- amino carbonyl compounds[8,9] in the presence of tert-
À
isting a-amino carbonyl structures has attracted con- butyl hydrogen peroxide (TBHP; Scheme 1); this oxi-
3
À
siderable efforts due to its direction and site-specifici- dative alkylation is achieved by dual C
G
ty.[2–5] Despite impressive progress in the field, there oxidative cross-coupling, and its scope is extended to
remains a great need for new strategies. In particular, a-amino ketones, a-amino esters and a-amino amides.
[3]
À
the traditional a-C H alkylation is more limited: To the best of our knowledge, this work represents
À
the reaction usually requires expensive organohalides the first example of metal-catalyzed oxidative a-C H
with the aid of a strong base leading to a mass of un-
wanted wastes; moreover, any NH2 group should be
À
pre-protected to avoid free N H bond functionaliza-
tion side-reactions.
Recently, a fascinating transition metal-catalyzed
cross dehydrogenative coupling strategy was estab-
À
lished for a-C H alkylation of a-amino esters, where-
in a carbon-hydrogen bond at the a-position of ke-
tones is used to replace the traditional carbon-halo-
[4,5]
À
gen bond, and free N H bonds are tolerated.
In
2008, Li and Zhao firstly reported that a-amino esters Scheme 1. Cu-catalyzed oxidative a-alkylation.
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Wen-Ting Wei et al.
Table 1. Screening for optimal conditions.[a]
alytic activity for the reaction, but they were inferior
to CuCl2. However, the reaction cannot take place
without metal catalysts (entry 14). Among the
amounts of both CuCl2 and TBHP examined, it
turned out that the reaction at 2 mol% CuCl2 and
1.2 equiv. TBHP provided the best results (entry 15
vs. entries 4, 16 and 17). Extensive screening revealed
that the reaction temperature affected the reaction,
and the yield was lowered at either 258C or 708C (en-
tries 18 and 19 vs. entry 15). It is noteworthy that
a good yield is still achieved using toluene as the
medium (entry 20). Gratifyingly, a large scale reac-
tion, 10 mmol of 1-phenyl-2-(phenylamino)ethanone
(1a), proceeded smoothly, furnishing product 3aa in
good yield (entry 21).
With the optimal conditions in hand, the scope of
both a-amino carbonyl compounds 1 and ethers 2 in
the a-etherized a-amino carbonyl compound synthesis
was examined (Table 2 and Table 3). As shown in
Table 2, all of the tested ethers and a thioether acted
as excellent substrates to react with 1-phenyl-2-(phe-
nylamino)ethanone (1a), CuCl2 and TBHP, furnishing
the corresponding products 3ab–ag in moderate to
good yields. Tetrahydro-2H-pyran (2b), for instance,
could successfully undergo the oxidative cross-cou-
pling reaction with substrate 1a in 61% yield (product
3ab). However, 3,4-dihydro-2H-pyran (2c) selectively
gave the desired product 3ac in low yield. Using 1,4-
dioxane (2d), diethyl ether (2e) or 1,2-dimethoxy-
ethane (2f), the corresponding products 3ad–af were
isolated in 75%, 52% and 51% yields, respectively.
Entry [M] [mol%]
[O] [equiv.]
T [oC] Yield [%][b]
1
CuCl2 (5)
CuCl2 (5)
CuCl2 (5)
CuCl2 (5)
CuCl2 (5)
CuCl2 (5)
CuCl2 (5)
CuCl2 (5)
CuBr2 (5)
air (1 atm)
O2 (1 atm)
–
TBHP (1.2)
DTBP (1.2)
50
50
50
50
50
40
10
trace
76
61
25
10
36
53
24
48
53
11
0
76
41
74
30
65
75
78
2
3[c]
4
5
6
7
8
m-CPBA (1.2) 50
DDQ (1.2)
oxone (1.2)
TBHP (1.2)
50
50
50
50
50
50
50
50
50
50
50
25
70
50
50
9
10
11
12
13
14
15
16
17
18
19
20[d]
21[e]
Cu
Cu
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
CuCl (5)
FeCl3 (5)
–
CuCl2 (2)
CuCl2 (1)
CuCl2 (2)
CuCl2 (2)
CuCl2 (2)
CuCl2 (2)
CuCl2 (2)
TBHP (1.2)
TBHP (1.2)
TBHP (1.2)
TBHP (1.2)
TBHP (1.2)
TBHP (2)
TBHP (1.2)
TBHP (1.2)
TBHP (1.2)
TBHP (1.2)
[a]
Reaction conditions: 1a (0.5 mmol), 2a (7.5 mmol), [M]
and [O] at 508C under air atmosphere for 12 h. TBHP=
tert-butyl hydrogen peroxide (anhydrous, 5M in decane),
DTBP=di-tert-butyl peroxide.
Yield of 3aa (dr is about 1.5:1).
Under an argon atmosphere.
[b]
[c]
[d]
[e]
Table 2. Scope of substrates 2.[a]
In toluene (0.5 mL).
1a (10 mmol, 2.11 g).
alkylation of a-amino carbonyl compounds with a
3
À
C
G
or a sulfur atom).
We initiated our investigation on the reaction be-
tween 1-phenyl-2-(phenylamino)ethanone (1a) and
tetrahydrofuran (THF; 2a), and the results are sum-
marized in Table 1. Interestingly, substrate 1a could
react with THF 2a in the presence of CuCl2 and air,
providing the desired product 3aa in 40% yield
(entry 1). However, the use of O2 instead of air result-
ed in a poor yield (entry 2), and no product 3aa was
detectable in argon (entry 3). The results suggest that
the reaction is highly dependent on the oxidant. A
number of other oxidants were subsequently screened
(entries 4–8): they effected the reaction, among which
TBHP proved to be superior (76% yield; entry 4).
Encouraged by the results, the reactions between sub-
strate 1a and THF 2a were examined with respect to
metal catalysts (entries 9–13): metal salts, such as
[a]
Reaction conditions: 1a (0.5 mmol), 2 (7.5 mmol), CuCl2
(2 mol%), and TBHP (1.2 equiv.) at 508C under air at-
CuBr2, CuACHTUNGTRENNUNG(OTf)2 CuCAHUTNGTREN(NUGN OAc)2, CuCl or FeCl3, have cat-
mosphere for 12 h. The dr value is given in parenthesis.
2
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Copper-Catalyzed Oxidative a-Alkylation of a-Amino Carbonyl
Table 3. Scope of the a-amino carbonyl compounds 1.[a]
[a]
Reaction conditions: 1 (0.5 mmol), 2a (7.5 mmol), CuCl2 (2 mol%), and TBHP
(1.2 equiv.) at 508C under an air atmosphere for 12 h. The dr value is given in
parenthesis.
Gratifyingly, tetrahydro-2H-thiopyran (2g) was also (products 3da, 3ea and 3ha). An N-1H-inden-5-yl-
compatible with the oxidative cross-coupling reaction containing substrate was also found to be viable for
with substrate 1a (product 3ag). Unfortunately, terti- the reaction (product 3ia). We next set out to exploit
ary amine 2h cannot react with substrate 1a under the the substitution effect on the aryl group of the 1-aryl-
optimal conditions.
ACHTUNGTRENeNUNG thanone moiety: a number of substituents, such as
The reaction was found to be applicable to a wide Me, Cl, F or MeO, are consistent with the optimal
range of a-amino carbonyl compounds 1 (Table 3). conditions, and the electron-donating groups are su-
Steric and electronic variations in the N-aryl moiety perior to the electron-withdrawing groups (products
of a-amino ketones 1 were initially tested in the pres- 3ja–na). The reaction was readily expanded to an ali-
ence of THF 2a, CuCl2 and TBHP (products 3ba–ia). phatic substrate, 1-(phenylamino)propan-2-one, albeit
Extensive screening revealed that several substituents, with a diminished yield (product 3oa). To our delight,
including Me, MeO, Br, Cl and F groups, on the N- both a-amino esters and a-amino amides were com-
aryl ring were perfectly tolerated under the optimal patible with the oxidative cross-coupling reaction
conditions. For example, substrates bearing an Me (products 3pa–sa). For example, ethyl 2-(phenylami-
group at the para-, ortho- or meta-position had high no)acetate was alkylated with THF 2a smoothly to
reactivity to couple with THF 2a in excellent yields construct product 3pa in 67% yield. When a-amino
(products 3ba, 3ca and 3fa). Gratifyingly, Br, Cl and amides were employed under the optimal conditions,
F groups could be tolerated well, thereby facilitating moderate yields were still obtained (products 3ra–sa).
additional modifications at the halogenated position
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Wen-Ting Wei et al.
Scheme 3. Possible mechanism.
which takes place to afford the desired product 3aa
and regenerate the active Cu species.
In summary, we have illustrated a highly effective
synthesis of a-etherized a-amino carbonyl compounds
from the copper-catalyzed oxidative a-alkylation of a-
amino carbonyl compounds with ethers. The reaction
3
À
features a dual C
G
3
À
pling across both the ether C
to an oxygen atom and the a-amino carbonyl com-
(sp ) H bond to generate a new a-amino
carbonyl nucleus. Studies are currently underway to
apply this oxidative alkylation to the synthesis of
3
À
pound a-C
G
Scheme 2. Control experiments.
To understand the mechanism, some control experi- other bioactive molecules in our laboratory.
ments were carried out (Scheme 2). Two radical inhib-
itors, TEMPO [Eq. (1)] and 2,6-di-tert-butylphenol,
were added to the a-alkylation reaction: a stoichio-
metric amount of radical inhibitor (2 equiv.) results in
Experimental Section
no conversion of substrate 1a; however, THF was
transferred by TEMPO into 2,2,6,6-tetramethyl-1-(tet-
rahydrofuran-2-yloxy)piperidine (4a). The results
imply that an alkyl radical from diethyl ether is
Typical Experimental Procedure for the Cu-Catalyzed
Oxidative a-Alkylation of a-Amino Carbonyl
Compounds (1) with Ethers (2)
formed. Notably, there is a high kinetic isotope effect
To a Schlenk tube were added a-amino carbonyl compound
(kH/kD =4.0) in the deuterated experiment between 1 (0.5 mmol), ether 2 (7.5 mmol), CuCl2 (2 mol%) and
À
TBHP (anhydrous, 1.2 equiv.). Then the tube was charged
with air, and was stirred at 508C (oil bath temperature) for
the indicated time until complete consumption of starting
material as monitored by TLC and GC-MS analysis. After
the reaction was finished, the reaction mixture was cooled
to room temperature, diluted with diethyl ether, and washed
with brine. The aqueous phase was re-extracted with diethyl
ether. The combined organic extracts were dried over
Na2SO4 and concentrated under vacuum, and the resulting
residue was purified by silica gel column chromatography
THF and THF-d8 [Eq. (2)], suggesting that this C H
oxidative functionalization of ether is an irreversible
step.[7] The results in Eq. (3) demonstrate that the re-
action does not include the direct formation of imine
intermediates from a-amino carbonyl compounds 1:
an imine, 1-phenyl-2-(phenylimino)ethanone (5a),
could not react with THF (2a) under the optimal con-
ditions. Moreover, both an amide and a tertiary
amine are also inert [Eq. (4)].
Consequently, a possible mechanism as outlined in (hexane/ethyl acetate=30:1) to afford the desired product
Scheme 3 is proposed.[2l–o,4–8] Initially, TBHP is split by
3.
Cu+ into a tert-butoxy radical and Cu2+(OH) under
1-Phenyl-2-(phenylamino)-2-(tetrahydrofuran-2-yl)etha-
none (3aa): Yellow oil; 1H NMR (500 MHz, CDCl3): d=
3
À
heating conditions. Subsequently, a C
G
8.03–8.01 (m, 2H), 7.60–7.56 (m, 1H), 7.50–7.46 (m, 2H),
7.17–7.14 (m, 2H), 6.83 (d, J=8.0 Hz, 1H), 6.73–6.69 (m,
2H), 5.21 (d, J=4.5 Hz, 0.6H), 5.11 (d, J=2.5 Hz, 0.4H),
4.86 (brs, 1H), 4.37–4.33 (m, 1H), 3.83–3.80 (m, 1H), 3.78–
3.66 (m, 1H), 2.01–1.98 (m, 1H), 1.92–1.84 (m, 1H), 1.83–
1.79 (m, 2H); 13C NMR (125 MHz, CDCl3): d=199.6, 199.3,
147.7, 147.5, 135.7, 135.6, 133.7, 133.4, 129.3, 129.2, 128.8,
adjacent to an oxygen atom in THF 2a can be readily
cleaved by a tert-butoxy radical, and transfers into an
alkyl radical intermediate A. Finally, radical inter-
mediate
(phenylamino)
radical intermediate B, followed by hydrogen atom
A
adds to a-carbon of 1-phenyl-2-
ACHTUNGTRENNUNGethanone (1a) leading to the cation
abstraction from intermediate B with Cu2+(OH) 128.6 (2), 118.2, 114.2, 113.7, 80.5, 79.2, 69.0, 68.7, 62.4, 61.3,
4
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Copper-Catalyzed Oxidative a-Alkylation of a-Amino Carbonyl
28.1, 26.8, 25.9, 25.8; IR (KBr): n=1681 cmÀ1; LR-MS (EI,
70 eV): m/z (%)=281 (M+, 3), 211 (100), 77 (37); HR-MS
(ESI): m/z=282.1504, calcd. for C18H20NO2 ([M+H]+):
282.1489.
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Acknowledgements
We thank the Specialized Research Fund for the Doctoral
Program of Higher Education (No. 20120161110041), Hunan
Provincial Natural Science Foundation of China (No.
13JJ2018), Natural Science Foundation of China (No.
21172060), and Fundamental Research Funds for the Central
Universities (Hunan University, No. 2011-015) for financial
support.
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6 Copper-Catalyzed Oxidative a-Alkylation of a-Amino
Carbonyl Compounds with Ethers via Dual CACTHNUTRGNEUNG
(sp3)-H
Oxidative Cross-Coupling
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asc.wiley-vch.de
ꢁ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 0000, 000, 0 – 0
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These are not the final page numbers!