Copper Triflate Catalyzed Oxidative α-Allylation of Glycine Derivatives

Article abstract of DOI:10.1055/s-0036-1588158

Copper triflate catalyzed oxidative C-H functionalization of glycine derivatives with allyltributyltin has been established using oxygen or tert -butyl hydroperoxide as oxidant. Various glycine esters and glycine amides were suitable substrates for this oxidative allylation reaction and afforded the desired homoallylic amines in moderate to good yields.

Full text of DOI:10.1055/s-0036-1588158

SYNLETT
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
© Georg Thieme Verlag Stuttgart · New York
2017, 28, A–E
letter
A
T.-T. Chen, C. Cai
Letter
Synlett
Copper Triflate Catalyzed Oxidative α-Allylation of Glycine Deriva-
tives
O
Ting-Ting Chen
H
O
Cu(OTf)2, oxidant
DCE
N
H
Chun Cai*
SnBu3
Ar
R
N
Ar
R
R = OR1, NHR2
20 examples
41–73% yield
College of Chemical Engineering, Nanjing University of Science
& Technology, 200 Xiaolingwei, Nanjing, 210094, P. R. of China
c.cai@njust.edu.cn
Received: 07.01.2017
Accepted after revision: 26.02.2017
Published online: 15.03.2017
can be furtherly modified into various functional groups.9
The most commonly used pathway for the synthesis of ho-
moallylic amines is the addition of allyl metal reagents to
imine substrates.10 However, since some imine substrates
are difficult to prepare or unstable, this method still suf-
fered from some shortages. Due to the importance of these
structural motifs, there is a continuing demand for the de-
velopment of new and convenient pathways for the synthe-
sis of homoallylic amine compounds, such as the oxidative
cross-coupling between C–H bonds. In 2010, Kumaraswamy
et al.11 firstly reported the oxidative α-allylation of N-aryl
tetrahydroisoquinoline with allyltributyltin catalyzed by
FeCl3·6H2O in the presence of TBHP. Inspired by this work,
in 2016, Wang et al.12 disclosed a silver triflate catalyzed
cascade of in situ oxidation and allylation of arylbenzyl-
amines employing 2,2,6,6-tetramethylpiperidine-1-oxoam-
monium tetrafluoroborate as oxidant. However, reports
about the oxidative allylation of glycine derivatives are still
rare.13 Owing to the biological importance of homoallylic
amines and α-amino acid derivatives, we carried out the in-
vestigation on oxidative C–H functionalization reaction of
glycine derivatives with allyltributyltin catalyzed by a cop-
per salt to produce α-allyl glycine derivatives.
Initially, N-PMP (p-methoxyphenyl) glycine ester (1a)
and allyltributyltin (2) were chosen as model substrates to
explore and optimize the experimental conditions. When
the reaction was performed in the presence of 10 mol%
CuCl2 under an oxygen atmosphere at 40 °C, the desired α-
allyl glycine ester 3a was isolated in 36% yield (Table 1, en-
try 1). Then, several other copper salts were investigated to
improve the reaction yields and Cu(OTf)2 proved to be best
with 73% yield (Table 1, entries 2–4). Notably, replacing mo-
lecular oxygen with air gave an inferior result (Table 1, en-
try 5). A number of other oxidants were subsequently
screened (Table1, entries 6–8) and a stoichiometric amount
of TBHP exhibited superior yields than O2 (75% vs. 73%).
DOI: 10.1055/s-0036-1588158; Art ID: st-2017-w0016-l
Abstract Copper triflate catalyzed oxidative C–H functionalization of
glycine derivatives with allyltributyltin has been established using oxy-
gen or tert-butyl hydroperoxide as oxidant. Various glycine esters and
glycine amides were suitable substrates for this oxidative allylation re-
action and afforded the desired homoallylic amines in moderate to
good yields.
Key words copper triflate, glycine derivatives, allylation, homoallylic
amines, oxygen, TBHP
The oxidative coupling-cross of C–H bonds has emerged
as an effective and straightforward protocol to construct
new C–C bonds as it avoids prefunctionalization of sub-
strates and is more atom economic and environmentally
friendly.1 In particular, the oxidative C–H functionalization
of glycine derivatives with various nucleophiles has proved
to be a convenient way to synthesize diverse α-substituted
α-amino derivatives, which are of great importance and
have applications in the synthesis of biologically active
drugs and natural products.2 The prominent route appears
to be the selective oxidation of C–H bond adjacent to the ni-
trogen atom to generate a reactive iminium ion, which
upon deprotonation gives the imine intermediate and then
reacts with a nucleophile to form a new C–C bond. In 2008,
Li et al.2a reported the pioneering work on the copper-com-
plex-catalyzed α-alkylation of glycine derivatives with
malonates. Then structurally diverse nucleophiles, such as
ketones,3 ethers,4 indoles,5 phenols,6 alkynes,7 and meth-
ylquinolines8 have also been successfully explored for this
transformation in suitable catalytic systems.
Homoallylic amines are useful building blocks for many
biologically active compounds and nitrogen-containing
natural products, because their double bond of allylic group
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E

B
T.-T. Chen, C. Cai
Letter
Synlett
However, given the economic and environmental factors,
molecular oxygen was chosen as the terminal oxidant for
the oxidative C–H functionalization of glycine derivatives
with allyltributyltin. Lowering the temperature to 25 °C or
raising the temperature to 60 °C was not beneficial to the
oxidative reaction (Table 1, entries 9 and 10). Examination
of solvent effects showed that DCE was the best solvent and
gave 73% yield of the corresponding product. Based on
above results, the optimized reaction should be performed
with 10 mol% of Cu(OTf)2 in DCE at 40 °C using molecular
oxygen (1.0 atm) as terminal oxidant.
yield than that on the para and meta position, indicating
that steric effects had an obvious effect on the yields of the
allylation reaction (Table 2, entries 2 vs. 7 vs. 8). The steric
substituent effects of the ester moiety were then investigat-
ed. When the corresponding methyl ester 1i was employed
instead of ethyl ester 1a, coupling products 3i were also iso-
lated in 72% yield (Table 2, entry 9). However, when a tert-
butyl ester 1j was utilized, the reaction did not proceed at
all under the optimal conditions, which could be attributed
to the steric hindrance of tert-butyl group (Table 2, entry
10).
After the scope of N-aryl glycine esters was examined, a
series of N-aryl glycine amides were investigated. Unfortu-
nately, only 14% yield of the desired product 3k was ob-
served when N-PMP glycine amide 1k was applied under
the optimized conditions. Replacing molecular oxygen with
TBHP led to a significant improvement on the yield when
lowering the reaction temperature to 25 °C (Table 3, entry
1). Thus the oxidative allylation of N-glycine amides was
conducted in the presence of Cu(OTf)2 and TBHP.15 The elec-
tronic and steric variations in the N-aryl moiety of glycine
amides were also tested. Similarly to glycine esters, both
electron-rich and electron-deficient glycine amides reacted
well and afforded the corresponding products in 63–75%
yields (Table 3, entries 1–5). Gratifyingly, the presence of a
methyl group at the para, meta, or ortho position was toler-
ated and afforded the desired α-allyl glycine amides in sat-
isfactory yields (Table 3, entries 6 and 7). To establish the
scope of this transformation further, various secondary am-
ides were next investigated. The oxidative cross-coupling
reaction of allyltributyltin with secondary amides, except
the corresponding tert-butyl derivative, resulted in the de-
sired N-aryl glycine amides in moderate yields (Table 3, en-
tries 8–12).
Some control experiments were carried out in order to
reveal the mechanism of this transformation (Table 4).
When 2,6-di-tert-butyl-4-methylphenol (BHT), a radical
scavenger, was added into the reaction system of N-PMP
glycine derivatives 1a and 1k (Table 4, entries 1 and 4), the
yields of coupling products 3a and 3k both dramatically de-
creased. This result suggests that reactions may undergo a
radical mechanism. N-PMP glycine derivatives 1a and 1k
could converted into the imine intermediates 4a and 4k in
the presence of Cu(OTf)2 and oxidant, respectively (Table 4,
entries 2 and 5). The result in Table 4 (entry 3) indicated
that Cu(OTf)2 is involved in the oxidation process and the
only role of oxygen is to reoxidative the reduced copper.16
However, the result in Table 4 (entry 6) indicated that the
terminal oxidant THBP not only involved in the reoxidation
of copper but also in the oxidative process. With respect to
the reaction with imine 4, a diminished yield was observed
in the absence of Cu(OTf)2, implying that Cu(OTf)2 should
activate 4 for the nucleophilic attack (Table 4, entries 7 and
8).
Table 1 Optimization of Conditionsa
O
O
H
H
N
N
OEt
[Cu], oxidant
solvent
OEt
SnBu3
MeO
MeO
1a
2
Entry
Catalyst
Oxidant
Solvent
Yield (%)b
1
2
CuCl2
CuBr2
O2
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
CH2Cl2
PhMe
THF
36
41
47
73
17
75
44
63
25
64
67
58
51
46
O2
3
Cu(OAc)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
O2
4
O2
5
air
6
TBHP
DTBP
DDQ
O2
7
8
9c
10d
11
12
13
14
O2
O2
O2
O2
O2
MeCN
a Reaction conditions: 1a (0.2 mmol) and catalyst (10 mol%) in solvent (1.0
mL) at 40 °C for 4 h, under O2 (1 atm) or using oxidant (1.0 equiv); followed
by the addition of 2 (0.24 mmol) for another 6 h.
b Isolated yield.
c At 25 °C.
d At 60 °C.
With the optimal conditions in hand, the scope of N-
aryl glycine esters for the Cu(OTf)2-catalyzed aerobic α-al-
lylation was explored (Table 2).14 The electronic effect of
substituents on the N-aryl moiety of glycine esters was ini-
tially studied. A range of N-aryl glycine esters 1a–1b bear-
ing electron-donating groups and those bearing electron-
withdrawing groups on the N-aryl ring (1d–f) were all tol-
erated and afforded the desired coupling products 3a–f in
satisfactory yields (Table 2, entries 1–6). Gratifyingly, halo-
gen atoms (F, Cl, and Br) could be tolerated well, thereby
making this methodology more useful for further transfor-
mations at the halogenated position (Table 2, entries 4–6).
The methyl group on the ortho position resulted in lower
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E

C
T.-T. Chen, C. Cai
Letter
Synlett
Table 2 Scope of N-Aryl-Glycine Estersa
O
H
N
O
H
N
OR2
Cu(OTf)2,O2
DCE, 40 °C
R1
OR2
SnBu3
R1
1
3
2
Entry
R1
4-MeO
R2
Product
Yield (%)b
1
2
Et
3a
3b
3c
3d
3e
3f
73
70
59
68
67
62
66
43
72
0
4-Me
H
Et
Et
Et
Et
Et
Et
Et
3
4
4-F
5
4-Cl
6
4-Br
7
3-Me
2-Me
4-MeO
4-MeO
3g
3h
3i
8
9
Me
10
t-Bu
3j
a Reaction conditions: glycine ester (0.2 mmol) and Cu(OTf)2 (10 mol%) in DCE (1.0 mL) at 40 °C under O2 (1.0 atm) for 4 h, followed by the addition of 2 (1.2
equiv) for another 6 h.
b Isolated yield.
Consequently, based on experimental observations and
the literatures,16 the plausible mechanism for this copper
triflate catalyzed oxidative allylation of glycine derivatives
in the presence of oxidant is illustrated (Scheme 1). In the
catalytic system of Cu(OTf)2 and molecular oxygen, initial
oxidation of 1 by Cu(II) via single-electron transfer (SET)
Table 3 Scope of N-Aryl Glycine Amidesa
O
H
O
H
N
R3
Cu(OTf)2,
TBHP
R3
N
H
N
R1
SnBu3
N
R1
H
DCE, 25 °C
1
3
2
Entry
R1
4-MeO
R3
Product
Yield (%)b
1
2
Me
3k
3l
73(14c)
68
4-Me
H
Me
3
Me
3m
3n
3o
3p
3q
3r
63
4
4-F
Me
71
5
4-Cl
Me
75
6
3-Me
2-Me
4-MeO
4-MeO
4-MeO
4-MeO
4-MeO
Me
67
7
Me
65
8
Et
57
9
n-Bu
C12H25
C6H11
t-Bu
3s
3t
63
10
11
12
70
3u
3v
41
traced
a Reaction conditions: glycine amides (0.2 mmol), TBHP (1.0 equiv 5.5 M in decane), and Cu(OTf)2 (10 mol%) in DCE (1.0 mL) at r.t for 4 h, followed by the addition
of 2 (1.2 equiv) for another 6 h.
b Isolated yield.
c The reaction was conducted under O2 (1.0 atm) at 40 °C.
d Detected by GC–MS.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E

D
T.-T. Chen, C. Cai
Letter
Synlett
Table 4 Control Experiments
In summary, a facile approach for copper triflate cata-
lyzed oxidative C–H functionalization of glycine derivatives
with allyltributyltin has been established using molecular
oxygen or TBHP as oxidant catalyzed by a simple copper
salt. Various glycine derivatives bearing electron-donating
groups as well as electron-withdrawing groups underwent
the oxidative allylation reaction smoothly and afforded the
desired homoallylic amines in moderate to good yields.
Entry
Substrate
Conditionsa
Yield (%)b
1
2
3
4
5
6
7
A
B
trace
74c
0
O
H
N
Et
PMP
O
C
D
E
trace
74c
43
O
O
H
N
Me
Et
PMP
N
H
F
Supporting Information
G
11
Supporting information for this article is available online at
N
8
H
84
PMP
O
http://dx.doi.org/10.1055/s-0036-1588158.
S
u
p
p
ortiInfogrmoaitn
S
u
p
p
o
nrtogI
f
rmoaitn
a Conditions A: 1a (0.2 mmol), BHT (2.0 equiv), Cu(OTf)2 (10 mol%) in DCE
(1.0 mL) at 40 °C under O2 (1.0 atm) for 4 h, followed by the addition of 2
(1.2 equiv) for another 6 h; conditions B: 1a (0.2 mmol), Cu(OTf)2 (10
mol%) in DCE (1.0 mL) at 40 °C under O2 (1.0 atm) for 4 h; conditions C: 1a
(0.2 mmol) in DCE (1.0 mL) at 40 °C under O2 (1.0 atm) for 4 h; conditions
D: 1k (0.2 mmol), TBHP (1.0 equiv), BHT (2.0 equiv), Cu(OTf)2 (10 mol%) in
DCE (1.0 mL) at r.t. for 4 h, followed by the addition of 2 (1.2 equiv) for
another 6 h; conditions E: 1k (0.2 mmol), TBHP (1.0 equiv), Cu(OTf)2 (10
mol%) in DCE (1.0 mL) at r.t. for 4 h; conditions F: 1k (0.2 mmol), TBHP (1.0
equiv) in DCE (1.0 mL) at r.t. for 4 h; conditions G: 4a (0.2 mmol), 2 (1.2
equiv) in DCE (1.0 mL) at r.t. for 6 h; conditions H: 4a (0.2 mmol), 2 (1.2
equiv), Cu(OTf)2 (10 mol%) in DCE (1.0 mL) at r.t. for 6 h.
References and Notes
(1) (a) Li, C. J.; Li, Z. Pure Appl. Chem. 2006, 78, 935. (b) Campos, K. R.
Chem. Soc. Rev. 2007, 36, 1069. (c) Li, C. J. Acc. Chem. Res. 2009,
42, 335. (d) Liu, C.; Zhang, H.; Shi, W.; Lei, A. Chem. Rev. 2011,
111, 1780. (e) Yeung, C. S.; Dong, V. M. Chem. Rev. 2011, 111,
1215. (f) Girard, S. A.; Knauber, T.; Li, C. J. Angew. Chem. Int. Ed.
2014, 53, 74.
(2) (a) Zhao, L.; Li, C. J. Angew. Chem. Int. Ed. 2008, 47, 7075.
(b) Zhang, G.; Zhang, Y.; Wang, R. Angew. Chem. Int. Ed. 2011, 50,
10429. (c) Gao, X. W.; Meng, Q.-Y.; Xiang, M.; Chen, B.; Feng, K.;
Tung, C. H.; Wu, L. Z. Adv. Synth. Catal. 2013, 355, 2158. (d) Gao,
X. W.; Meng, Q. Y.; Li, J. X.; Zhong, J. J.; Lei, T.; Li, X. B.; Tung, C.
H.; Wu, L. Z. ACS Catal. 2015, 5, 2391. (e) Wei, X. H.; Wang, G.
W.; Yang, S. D. Chem. Commun. 2015, 51, 832. (f) Xie, Z.; Jia, J.;
Liu, X.; Liu, L. Adv. Synth. Catal. 2016, 358, 919.
(3) Xie, J.; Huang, Z. Z. Angew. Chem. Int. Ed. 2010, 49, 10181.
(4) Wei, W. T.; Song, R. J.; Li, J. H. Adv. Synth. Catal. 2014, 356, 1703.
(5) (a) Wang, Z. Q.; Hu, M.; Huang, X. C.; Gong, L. B.; Xie, Y. X.; Li, J.
H. J. Org. Chem. 2012, 77, 8705. (b) Zhu, S.; Rueping, M. Chem
Commun. 2012, 48, 11960. (c) Huo, C.; Wang, C.; Wu, M.; Jia, X.;
Xie, H.; Yuan, Y. Adv. Synth. Catal. 2014, 356, 411.
(6) Salman, M.; Zhu, Z. Q.; Huang, Z. Z. Org. Lett. 2016, 18, 1526.
(7) (a) Zhao, L.; Basle, O.; Li, C. J. Proc. Natl. Acad. Sci. U.S.A. 2009,
106, 4106. (b) Xie, Z.; Liu, X.; Liu, L. Org. Lett. 2016, 18, 2982.
(8) Zhu, Z. Q.; Bai, P.; Huang, Z. Z. Org. Lett. 2014, 16, 4881.
(9) (a) Robl, J. A.; Cimarusti, M. P.; Simpkins, L. M.; Brown, B.;
Ryono, D. E.; Bird, J. E.; Asaad, M. M.; Schaeffer, T. R.; Trippodo,
N. C. J. Med. Chem. 1996, 39, 494. (b) Bosque, I.; González-
Gómez, J. C.; Foubelo, F.; Yus, M. J. Org. Chem. 2012, 77, 780.
(10) (a) Huang, J. M.; Wang, X. X.; Dong, Y. Angew. Chem. Int. Ed.
2011, 50, 924. (b) Beuchet, P.; Marrec, N. L.; Mosset, P. Tetrahe-
dron Lett. 1992, 33, 5959. (c) Yasuda, M.; Sugawa, Y.; Yamamoto,
A.; Shibata, I.; Baba, A. Tetrahedron Lett. 1996, 37, 5951.
(d) Wang, D. K.; Zhou, Y. G.; Tang, Y.; Hou, X. L.; Dai, L. X. J. Org.
Chem. 1999, 64, 4233.
b Isolated yield.
c Isolated yields of intermediate imines.
followed by a sequential proton and electron transfer leads
to an iminium ion 5.17 On the other hand, when TBHP was
utilized as the terminal oxidant, a tert-butoxyl radical gen-
erated by the copper-catalyzed decomposition of TBHP and
then abstracted a hydrogen atom from 1 to form intermedi-
ate radical, which also converted into iminium ion 5 via sin-
gle-electron transfer (SET).3,18 Then iminium ion 5 furnish
to imine 4 by deprotonation. A bidentate intermediate 6
was formed by the coordination of copper triflate to the
imine intermediate 4.7b Further, a trans-metalation takes
place between the allyl-Sn reagent 2 and the intermediate 6
giving allylic copper complex 7, followed by nucleophilic at-
tack of allyl to imine generates the homoallylic amine 3.
Cu(OTf)2
oxidant
Ar
R
Ar
R
Ar
R
N
N
H
N
H
O
O
O
H
4
5
1
Cu(OTf)2
Ar
R
O
R
O
N
(11) Kumaraswamy, G.; Murthy, A. N.; Pitchaiah, A. J. Org. Chem.
2010, 75, 3916.
(12) Wang, J.; Yang, S. Tetrahedron Lett. 2016, 57, 3444.
(13) Yoo, W.-J.; Tanoue, A.; Kobayashi, S. Asian J. Org. Chem. 2014, 3,
1066.
Cu OTf
Ar
R
Cu
TfO
N
N
H
SnBu3
OTf
Ar
O
H
2
7
6
3
Scheme 1 Plausible mechanism for the oxidative allylation of glycine
derivatives
(14) General Procedure for the Allylation of N-Aryl Glycine Esters
3a
N-PMP glycine ester 1a (0.2 mmol) and Cu(OTf)2 (10 mol%)
were reacted under oxygen atmosphere (1.0 atm) in DCE (1.0
mL) at 40 °C. After the glycine ester disappeared (by TLC), allyl-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E

E
T.-T. Chen, C. Cai
Letter
Synlett
tributyltin (2, 0.24 mmol) was added, and the mixture was
stirred for another 6 h. After the reaction finished, the mixture
was directly purified by flash chromatography to afford the
desired product 3a; 73% yield. 1H NMR (500 MHz, CDCl3): δ =
6.77 (d, J = 8.5 Hz, 2 H), 6.60 (d, J = 8.5 Hz, 2 H), 5.80 (td, J = 17.1,
7.2 Hz, 1 H), 5.25–5.11 (m, 2 H), 4.18 (q, J = 7.1 Hz, 2 H), 4.05 (q,
J = 6.3 Hz, 1 H), 3.91 (s, 1 H), 3.74 (s, 3 H), 2.58 (dq, J = 14.0, 6.9
Hz, 2 H), 1.24 (t, J = 7.1 Hz, 3 H). 13C NMR (125 MHz, CDCl3): δ =
172.64, 151.81, 139.75, 131.97, 117.83, 114.23, 113.90, 60.08,
56.27, 54.75, 36.23, 13.33. MS (EI): m/z =249 [M+].
directly purified by flash chromatography to afford desired
product 3k; 73% yield. 1H NMR (500 MHz, CDCl3): δ = 6.89 (s, 1
H), 6.72 (d, J = 8.8 Hz, 2 H), 6.48 (d, J = 8.8 Hz, 2 H), 5.69 (td, J =
17.2, 7.2 Hz, 1 H), 5.21–5.05 (m, 2 H), 3.68 (s, 3 H), 3.66 (s, 1 H),
3.57 (d, J = 8.6 Hz, 1 H), 2.74 (d, J = 5.0 Hz, 3 H), 2.70 (dd, J = 10.0,
4.4 Hz, 1 H), 2.46–2.30 (m, 1 H). 13C NMR (126 MHz, CDCl3): δ =
172.72, 152.31, 139.84, 133.03, 118.21, 114.03, 113.96, 58.15,
54.78, 36.91, 25.05. MS (EI): m/z = 234 [M+].
(16) Boess, E.; Schmitz, C.; Klussmann, M. J. Am. Chem. Soc. 2012,
134, 5317.
(15) General Procedure for the Allylation of N-Aryl Glycine Amide
3k
(17) (a) Scott, M.; Sud, A.; Boess, E.; Klussmann, M. J. Org. Chem.
2014, 79, 12033. (b) Wendlandt, A. E.; Suess, A. M.; Stahl, S. S.
Angew. Chem. Int. Ed. 2011, 50, 11062. (c) Tian, J. S.; Loh, T. P.
Angew. Chem. Int. Ed. 2010, 49, 8417.
(18) Zhi, H.; Ung, S. P. M.; Liu, Y.; Zhao, L.; Li, C. J. Adv. Synth. Catal.
2016, 358, 2553.
N-PMP glycine amide 1k (0.2 mmol), Cu(OTf)2 (10 mol%), and
TBHP (1.0 equiv, 5.5 M in decane) were reacted in DCE (1.0 mL)
at r.t. After the glycine amide disappeared (by TLC), allytribut-
yltin (2, 0.24 mmol) was added, and the mixture was stirred for
another 6 h. After the reaction finished, the mixture was
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E