Thieme Chemistry Journal Awardees - Where are they now? Aerobic oxidative coupling of tertiary amines with silyl enolates and ketene acetals

Article abstract of DOI:10.1055/s-0029-1217336

Cyclic tertiary amines can be oxidatively coupled with a variety of silyl enol ethers or ketene acetals to furnish tertiary Mannich bases. The reactions are catalyzed by simple copper salts employing elemental oxygen as the oxidant. Georg Thieme Verlag St

Full text of DOI:10.1055/s-0029-1217336

1558
LETTER
Thieme Chemistry Journal Awardees – Where Are They Now?
Aerobic Oxidative Coupling of Tertiary Amines with Silyl Enolates
and Ketene Acetals
O
xidative Couplin
e
g
of
A
mine
v
s
arajulu Sureshkumar, Abhishek Sud, Martin Klussmann*
Max-Planck-Institut für Kohlenforschung, Kaiser-Wilhelm-Platz 1, 45470 Mülheim an der Ruhr, Germany
Fax +49(208)3062980; E-mail: klusi@mpi-muelheim.mpg.de
Received 16 March 2009
Abstract: Cyclic tertiary amines can be oxidatively coupled with a
variety of silyl enol ethers or ketene acetals to furnish tertiary Man-
nich bases. The reactions are catalyzed by simple copper salts em-
ploying elemental oxygen as the oxidant.
Key words: amines, C–H bond functionalization, copper, oxidative
cross-coupling, oxidations
Oxidative coupling allows the forging of new carbon–
carbon (C–C) bonds by direct functionalisation of car-
bon–hydrogen (C–H) bonds.1 Such reactions have the po-
tential to significantly reduce the number of steps and
waste products in a reaction sequence as no special leav-
ing groups have to be introduced.
Martin Klussmann studied chemistry at the universities of Mainz,
Jena, and Darmstadt, Germany, and North Carolina in Chapel Hill. He
obtained his PhD in 2004 with Prof. Michael Reggelin in Darmstadt
on helically chiral polymeric ligands for transition-metal-catalysed
asymmetric reactions. In 2004 he joined the group of Prof. Donna
G. Blackmond at Imperial College London, UK, as a postdoctoral re-
searcher to work on mechanistic studies of organocatalytic reactions.
Since 2007 he is a junior research group leader at the Max Planck In-
stitute für Kohlenforschung, working on his Habilitation with Prof.
Benjamin List. His research group is interested in the development of
new reactions and the study of their mechanisms, especially catalytic
oxidative coupling reactions to form C–C bonds.
The oxidative coupling with amines has received special
interest recently; in these reactions, the amines are gener-
ally believed to be oxidized to iminium ions which subse-
quently react with a nucleophile in a similar fashion as the
classical Mannich reaction (Scheme 1).2
[Ox]
H
Nu
N+
N
N
Nu
We became interested in the oxidative coupling of cyclic
amines with carbonyl compounds. These reactions have
the exciting potential to generate natural product-like
structures in a single step.3h However, the known method-
ologies are still limited to activated carbonyl substrates or
to a few simple ketones. In this communication, we report
the use of various enol ethers and ketene acetals as nucleo-
philes in oxidative coupling reactions with tertiary
amines, employing elemental oxygen as the oxidant.
Scheme 1 Oxidative coupling reactions with amines
In most cases, metal catalysts are used together with or-
ganic peroxides as the terminal oxidant,3 less commonly,
environmentally benign oxidants like hydrogen peroxide
or elemental oxygen are used.4 The reactions with organic
peroxides are known to proceed via a-oxygenated inter-
mediates.3a,4a,5
We focused on elemental oxygen as a cheap and easy-to-
use oxidant. We expected simple copper salts to be effec-
tive catalysts for the oxidation of amines whilst easily re-
oxidizable by oxygen, but we also screened some other
metal compounds for comparison. As a test reaction, we
chose the coupling of tetrahydroisoquinoline 1a3a,4b,c with
silyl enol ether 2 at room temperature in methanol
(Table 1).
Such oxidative Mannich-type reactions have been used to
functionalise tertiary amines with good carbon nucleo-
philes such as malonates,3b,c,4b nitroalkanes,3d indoles,3e
naphthols,2c or cyanide anion.3f,g,4c–e The activation of less
nucleophilic carbonyl compounds has been achieved at el-
evated temperatures,4f by using amine organocatalysts to
activate enones2c or simple ketones.3h Alternatively, pre-
formed siloxyfurans have been used to introduce a
butenolide moiety.3a,4a Other silyl enol ethers and organo-
metallic reagents have also been used successfully in oxi-
dative coupling reactions with cyclic ethers.6
Among the metal salts, FeCl3 and RuCl3 proved to be
active catalysts (entries 1–3) but less active than most of
the copper salts tested (entries 4–8). Among these,
CuCl2·2H2O afforded the fastest conversions and the
highest yields (entry 8). It is also the most convenient to
handle, as it is neither prone to oxidation in air nor hygro-
scopic. Without a metal catalyst, the reaction did not oc-
SYNLETT 2009, No. 10, pp 1558–1561
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Advanced online publication: 02.06.2009
DOI: 10.1055/s-0029-1217336; Art ID: S03109ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Oxidative Coupling of Amines
1559
Table 2 Further Optimisation of Reaction Conditionsa
Table 1 Screening of Different Metal Salts as Oxidation Catalystsa
OTMS
CuCl2⋅2H2O
1a + 2
3a
2
O2, r.t.
N
Ph
N
Metal salt (10 mol%)
MeOH, O2, r.t.
Entry Cu (mol%) Solvent
2 (equiv) Time
Yield (%)b
Ph
O
1a
3a
1
2
10
10
10
10
10
10
10
10
10
20
5
CH2Cl2
CHCl3
toluene
DMF
5
4.5 d
4.5 d
5 dc
7 h
72
76
38
82
92d
93d
96d
95
92
94
94
5
Entry
Catalyst
FeCl2·2H2O
FeCl3·6H2O
RuCl3·xH2O
CuCl
Time (h)
Yield (%)b
3
5
1
2
3
4
5
6
7
8
9
18
18
18
18
18
18
5
<5
25
35
69
0
4
5
5
MeOH
acetone
acetone
acetone
acetone
acetone
acetone
5
7 h
6
5
2.5 h
1 h
7
2.5
2.0
1.5
2.5
2.5
CuBr
8
1 h
CuI
0
9
1 h
CuCl2
81
92c
0
10
11
1 h
CuCl2·2H2O
–
5
6 h
24
a Reaction conditions: 1 (0.12 mmol), solvent (1.0 mL), O2 (1.02 bar).
b Isolated yield.
a Reaction conditions: 1 (0.12 mmol), 2 (0.6 mmol), metal salt (0.012
mmol), MeOH (1.0 mL), O2 (1.02 bar).
b Isolated yield.
c Compound 1a not fully converted.
d Average of two experiments.
c Average of two experiments.
achieved, even after one day. Because of the low cost of
CuCl2, we kept the amount at 10 mol% for all further
reactions.
cur (entry 9). Next, we further optimized other reaction
parameters (Table 2).
Among the solvents examined, only acetone proved to be
better than methanol, resulting in essentially the same
yields but faster conversions (entries 1–6). In later reac-
tions with acetone as the solvent (vide infra), we encoun-
tered more difficulties, especially in the case of methoxy-
substituted amine substrates. Accordingly, the reactions
were generally run in acetone as the solvent, while meth-
anol was used in selected cases for amines other than 1a.
With high-yielding conditions in hand, we explored the
substrate scope with respect to the silyl nucleophile and
also with a few other substituted tetrahydroisoquinolines
(Table 3).7
A broad range of nucleophiles can be coupled with the
amines, allowing the introduction of open-chain and cy-
clic ketone and enone functionalities (entries 1–13) as
well as esters and thioesters (entries 14–17). The yields
are generally high, only the introduction of a tert-butyl ac-
etate fragment could not be achieved with more than 26%
(entry 14). With cyclic enolates, the reactions proceeded
without significant diastereoselectivities, giving the iso-
mers of products 14–16 in nearly equal amounts (entries
11–13). In the case of 16, the product diastereomers could
be separated by column chromatography. In the case of di-
enolate 11, a 1,4-addition took place to yield the unsatur-
ated aldehydes 19a and 19b (entries 18 and 19). Other
cyclic amines than the tetrahydroisoquinolines were
found to be less suitable substrates. With N-substituted pi-
peridines, the desired products could not be detected.
Nevertheless, we could obtain the coupling products with
N-aryl pyrrolidines in moderate yields (Scheme 2).
Reduction of the relative amount of TMS enol ether 2
from 5 equivalents to 2.5 equivalents was possible with
keeping the reaction time short and even a slight increase
of product yield (entry 7). Further reducing the amount to
2.0 equivalents or 1.5 equivalents only slightly decreased
the yields (entries 8 and 9). When reducing it even further
to 1.2 equivalents, the reaction no longer reaches full con-
version (not shown). In later studies with different nucleo-
philes, we found that reducing the amount did in fact lead
to a more significant drop in the product yield, probably
in case of more sensitive reagents that decomposed during
the reaction. Therefore, we kept the concentration of the
nucleophile at 2.5 equivalents for all other screenings, but
this parameter could in principle be lowered and opti-
mized for each individual reaction.
In analogy to related reactions,2c,3a,4a we assume a mecha-
nism involving iminium ions as key intermediates, as de-
picted in Scheme 1. Alternatively, one could envision the
oxidation of the amines to radicals which would then at-
tack the double bond of the enolates or ketene acetals.8
A further increase of the catalyst loading to 20 mol% did
not lead to any improvement (entry 10), while reducing it
to 5 mol% led to significantly prolonged reaction times
(entry 11). Upon further reduction of the catalyst loading,
full conversion of the amine substrate was no longer
Synlett 2009, No. 10, 1558–1561 © Thieme Stuttgart · New York

1560
D. Sureshkumar et al.
LETTER
Table 3 Oxidative Coupling of Tetrahydroisoquinolines with TMS Enolates and Ketene Acetalsa
Entry Amine
1
2
3
Nucleophile
Product
Solvent
Time (h) Yield (%)b
R
1a
1b
1c
1d
3a, R = H, Ar = Ph
acetone
MeOH
acetone
MeOH
1
1.5
48
1
96
81
91
97
R
OTMS
3b, R = H, Ar = PMP
3c, R = OMe, Ar = Ph
3d, R = H, Ar = DMP
N
2
4
R
Ar
Ar
N
O
4
R
Ar
R
5
6
7
1a
1b
1c
12a, R = H, Ar = Ph
12b, R = H, Ar = PMP
acetone
acetone
15
4
48
87
79
90
N
OTMS
t-Bu
R
12c, R = OMe, Ar = Ph acetone
O
t-Bu
R
8
9
10
1a
1b
1d
13a, R = H, Ar = Ph
13b, R = H, Ar = PMP
13d, R = H, Ar = DMP MeOH
acetone
MeOH
6
1.5
1.5
84
78
75
OTMS
Ph
N
5
6
R
Ar
O
Ph
N
OTMS
OTMS
11
12
1a
1a
14, dr = 1.4:1
15, dr = 1.5:1
acetone
acetone
6
86
87
Ph
Ph
O
O
N
N
N
7
5
8
OTMS
13c
1a
1a
8
9
16, dr = 1:1
acetone
acetone
68
26
Ph
O
O
OTMS
Ot-Bu
Ph
14
17
24
Ot-Bu
R
R
15
16
17
1a
1b
1c
18a, R = H, Ar = Ph
18b, R = H, Ar = PMP
18c, R = OMe, Ar = Ph MeOH
acetone
MeOH
12
3
48
74
95
75
N
OTMS
St-Bu
10
11
Ar
Ar
O
St-Bu
OTMS
18
19
1a
1b
19a, R = H, Ar = Ph
19b, R = H, Ar = PMP
acetone
MeOH
5
3
60
61
N
OHC
a General reaction conditions: amine (0.12 mmol), nucleophile (0.30 mmol), CuCl2·2H2O (0.012 mmol), solvent (1.0 mL), O2 (1.02 bar), r.t.
b Isolated yield.
c Nucleophile (5 equiv) added in aliquots over 2.5 h.
Synlett 2009, No. 10, 1558–1561 © Thieme Stuttgart · New York

LETTER
Oxidative Coupling of Amines
1561
CuCl2⋅2H2O
(10 mol%)
References and Notes
O
2
+
(1) For selected reviews, see: (a) Li, C.-J. Acc. Chem. Res.
2009, 42, 335. (b) Kakiuchi, F.; Kochi, T. Synthesis 2008,
3013. (c) Dalko, P. I. Tetrahedron 1995, 51, 7579.
(2) For an overview of oxidative functionalization of amines,
see: (a) Murahashi, S.-I.; Zhang, D. Chem. Soc. Rev. 2008,
37, 1490. (b) Campos, K. R. Chem. Soc. Rev. 2007, 36,
1069. (c) Li, Z.; Bohle, D. S.; Li, C.-J. Proc. Natl. Acad. Sci.
U.S.A. 2006, 103, 8928. (d) Murahashi, S.-I. Angew. Chem.,
Int. Ed. Engl. 1995, 34, 2443.
(3) For selected examples, see: (a) Catino, A. J.; Nichols, J. M.;
Nettles, B. J.; Doyle, M. P. J. Am. Chem. Soc. 2006, 128,
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7075. (c) Li, Z.; Li, C.-J. Eur. J. Org. Chem. 2005, 3173.
(d) Li, Z.; Li, C.-J. J. Am. Chem. Soc. 2005, 127, 3672.
(e) Li, Z.; Li, C.-J. J. Am. Chem. Soc. 2005, 127, 6968.
(f) Chiba, T.; Takata, Y. J. Org. Chem. 1977, 42, 2973.
(g) Sundberg, R. J.; Théret, M.-H.; Wright, L. Org. Prep.
Proced. Int. 1994, 26, 386. (h) Sud, A.; Sureshkumar, D.;
Klussmann, M. Chem. Commun. 2009, in press; DOI:
10.1039/b901282f.
(4) (a) Shen, Y.; Tan, Z.; Chen, D.; Feng, X.; Li, M.; Guo,
C.-C.; Zhu, C. Tetrahedron 2009, 65, 158. (b) Baslé, O.; Li,
C.-J. Green Chem. 2007, 9, 1047. (c) Murahashi, S.-I.;
Komiya, N.; Terai, H.; Nakae, T. J. Am. Chem. Soc. 2003,
125, 15312. (d) Murahashi, S.-I.; Nakae, T.; Terai, H.;
Komiya, N. J. Am. Chem. Soc. 2008, 130, 11005.
(e) Murata, S.; Teramoto, K.; Miura, M.; Nomura, M. Bull.
Chem. Soc. Jpn. 1993, 66, 1297. (f) Shen, Y.; Li, M.; Wang,
S.; Zhan, T.; Tan, Z.; Guo, C.-C. Chem. Commun. 2009, 953.
(5) Murahashi, S.-I.; Naota, T.; Yonemura, K. J. Am. Chem.
Soc. 1988, 110, 8256.
MeOH, O2
N
N
2.5 equiv
Ar
Ar
20a Ar = Ph
20b Ar = PMP
21a Ar = Ph,
40 °C, 3 d, 31%
21b Ar = PMP,
r.t., 1 d, 46%
Scheme 2 Oxidative coupling with N-aryl pyrrolidines. Reagents
and conditions: amine (0.50 mmol), 2 (1.25 mmol), CuCl2·2H2O
(0.05 mmol), MeOH (3 mL), O2 (1.02 bar).
Depending on the catalytic system being used, radical
species have been either ruled out or suggested to be inter-
mediates in the formation of iminium ions by single-elec-
tron transfer.3h,4a As a probe for the possible occurrence of
such radicals, we performed the reaction with 1a using
the stable radical 2,2,6,6-tetramethyl-piperidin-1-oxyl
(TEMPO) instead of a nucleophile. Coupling products be-
tween the amine 1a and TEMPO would indicate radical
formation of 1a.9 No conversion of the substrates oc-
curred for three days, supporting a mechanism without the
involvement of free radicals. Additionally, the coupling of
1a with 2 could be performed in the presence of the radical
inhibitor 2,4,6-tri-tert-butylphenol, again supporting the
absence of free radicals.
In summary, we have developed a high-yielding method
to functionalise C–H bonds in tertiary amines by oxida-
tion with elemental oxygen using a simple copper salt as
catalyst. The reactions are easily performed without the
need of extra purification or drying of the reagents. A va-
riety of preformed silyl enolate or silyl ketene acetal nu-
cleophiles can be coupled with cyclic amines, resulting in
amino ketones, aldehydes, esters, and thioesters.
(6) Xu, Y. C.; Roy, C.; Lebeau, E. Tetrahedron Lett. 1993, 34,
8189.
(7) General Procedure for the Oxidative Coupling of
Amines
To a solution of the appropriate amine (0.12 mmol, 1.0
equiv) in acetone or MeOH (1.0 mL), the TMS enol ether or
silyl ketene acetal (0.30 mmol, 2.5 equiv) and CuCl2·2H2O
(2 mg, 10 mol%) were added, and the mixture was stirred
under an atmosphere of oxygen (1 atm) at r.t. After full
conversion was achieved, H2O and CH2Cl2 were added and
the mixture was extracted with additional CH2Cl2. The
combined organic phases were dried over MgSO4 and
concentrated in vacuo. The crude residue was purified by
flash column chromatography on silica gel (5–10% EtOAc–
pentane), giving the product as a solid or oil.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Acknowledgment
We thank the Alexander von Humboldt-Foundation for support (re-
search scholarship to D.S.) and Esther Böß for the synthesis of sub-
strates.
(8) Jang, H.-Y.; Hong, J.-B.; MacMillan, D. W. C. J. Am. Chem.
Soc. 2007, 129, 7004.
(9) Vogler, T.; Studer, A. Synthesis 2008, 1979.
Synlett 2009, No. 10, 1558–1561 © Thieme Stuttgart · New York

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