Biomimetic aerobic oxidation of amino alcohols to lactams

Article abstract of DOI:10.1002/chem.201202080

The right path: N-Protected amino alcohols undergo aerobic and biomimetic oxidation to the corresponding lactams in the presence of a ruthenium catalyst and a combination of electron-transfer mediators under air (see scheme). The reaction was used for the synthesis of five-, six-, and seven-, membered lactams and showed good tolerance to a number of N-protecting groups. Copyright

Full text of DOI:10.1002/chem.201202080

COMMUNICATION
DOI: 10.1002/chem.201202080
Biomimetic Aerobic Oxidation of Amino Alcohols to Lactams
Beneesh P. Babu, Yoshinori Endo, and Jan-E. Bꢀckvall*[a]
The demand for environmentally benign methods in or-
recent years, metal-catalyzed reactions between an alcohol
and an amine and in which only hydrogen is produced as
the byproduct are the most atom economical and environ-
mentally friendly.[8,9c]
ganic synthesis is increasing,[1] and hence the aerobic oxida-
tion of organic molecules catalyzed by metal complexes is
an important area in current research.[2,3] Our laboratory
has been involved in this research field and during the past
two decades we have developed various biomimetic meth-
ods for aerobic oxidation.[3b,4] In these methods, a coupled
catalytic system promotes electron transfer from the catalyst
to the oxidant, which usually is air/O2 or hydrogen peroxide
(Scheme 1). Electron-transfer mediators (ETMs) in the cou-
We recently reported an efficient aerobic lactonization of
diols using a biomimetic approach.[4g] Encouraged by these
results, we were interested in extending this methodology to
amino alcohols; the use of these substrates in an analogous
ruthenium-catalyzed biomimetic oxidation may give lactams.
This method for forming lactams would involve an amino–
aldehyde intermediate II, which would be generated by the
biomimetic oxidation of the amino alcohol; intermediate II
would then transform into hemiaminal III, which would un-
dergo subsequent oxidation to give product IV (path 1,
Scheme 2). Intramolecular N-alkylation, via the iminium-ion
Scheme 1. Biomimetic aerobic oxidation.
pled catalytic system play the key role of driving the reac-
tion through low-energy pathways. This method has been
successfully used for the dehydrogenation of alcohols,[4c]
amines,[4d,e,f] and diols.[4g] The ruthenium-based Shvo catalyst
was the best metal catalyst for these reactions and a combi-
nation of 2,6-dimethoxy-1,4-benzoquinone (DMBQ) and
a cobalt complex were used as the ETMs.
Amide bonds are fundamental linkages in chemistry as
well as in biology and hence methods for their synthesis are
of interest.[5] Direct coupling between an activated carboxyl-
ic acid and an amine is the major approach for amide forma-
tion; this method suffers from several limitations such as the
production of a large amount of waste, tedious work-up, and
difficulties in avoiding racemization/epimerization.[6] The
continuous demand for improved methods for amide forma-
tion has led to the development of a number of transition-
metal-catalyzed methods[7] starting from alcohols,[8,9,10] alde-
hydes,[11] nitriles,[12] aryl halides,[13] aldoximes,[14] alkenes, and
alkynes.[15] Among the catalytic methods developed in
Scheme 2. Aerobic lactamization of amino alcohols.
intermediate V, leading to VI may be a competing side reac-
tion (path 2, Scheme 2). Dehydrogenative lactam formation
from 1,5-amino alcohols (with H2 evolution) was recently re-
ported and the switch between amide- and amine-forming
pathways was discussed (see products IV and VI,
Scheme 2).[10a]
[a] Dr. B. P. Babu, Dr. Y. Endo, Prof. J.-E. Bꢁckvall
Department of Organic Chemistry, Arrhenius Laboratory
Stockholm University, 106 91, Stockholm (Sweden)
Fax : (+46)8-154-908
Preliminary attempts to cyclize 1,4-amino alcohols accord-
ing to the procedure used for 1,4-diols failed. Thus, stirring
a solution of 4-amino-1-butanol (1 mmol) with Shvoꢀs cata-
lyst
1a
(1 mol%),
2,6-dimethoxybenzoquinone
2
E-mail: jeb@organ.su.se
(20 mol%), and cobalt complex 3 (2 mol%) in toluene
(2 mL) under air at 1008C for 18 hours failed to yield
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201202080.
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Table 2. Screening of protecting groups.[a]
Protecting group (PG)
lactam. When substituted amino alcohols, such as 4-benzyl-
ACHTUNGTRENNUNGamino-1-butanol and 4-phenylamino-1-butanol, were em-
ployed, intramolecular N-alkylation occurred to give N-
benzyl pyrrolidine and N-phenyl pyrrolidine (see. Path 2,
Scheme 2). This observation prompted us to protect the
amino group with an electron-withdrawing group so that for-
mation of imine V from intermediate hemiaminal III
(Scheme 2) would be prevented.
We chose N-tosylated 4-amino-1-butanol (4a, 1 mmol) as
the substrate and it was stirred with Shvoꢀs catalyst 1a
(1 mol%), 2,6-dimethoxybenzoquinone 2 (20 mol%), and
cobalt complex 3 (2 mol%) in toluene (2 mL) under air at
1008C for 18 hours. Gratifyingly, intramolecular amide for-
mation was observed exclusively and the corresponding N-
tosylated pyrrolidinone 5a was isolated as a white crystalline
solid in 75% yield. Encouraged by this result, we repeated
the reaction in the presence of different ruthenium com-
plexes (Table 1). The use of monomeric catalyst 1b and
Product
Yield
[%][b]
1
2
3
4
5
6
4-methylbenzenesulfonyl (Ts) 4a
tert-butoxycarbonyl (Boc) 4b
2-nitrobenzenesulfonyl (Ns) 4c
methanesulfonyl (Ms) 4d
5a 75
5b 58
5c 46
5d 77
5e 81
5 f 35
4-methoxylbenzenesulfonyl (Mbs)
4e
Table 1. Screening of catalyst and reaction conditions.[a]
acetyl (Ac) 4 f
7
8
benzoyl (Bz) 4g
5g 78
Ru catalyst
Yield 5a [%][b]
9-fluorenylmethoxcarbonyl (Fmoc)
n.r.
–
4h
1
2
1a
1b
75
[a] Substrate (1 mmol), 1a (1 mol%), 3 (2 mol%), 2 (20 mol%), toluene
(2 mL), air (1 atm), 1008C, 18 h; n.r.=no reaction. [b] Yield of isolated
product.
n.r.[c]
rivative 4g afforded an intermolecular oxidative-esterifica-
tion product 5g whereas Fmoc-protected amino alcohol 4h
decomposed under the reaction conditions.
3
4
5
G
E
1c
1d
1a
n.r.[c]
n.r.[c]
68[d]
ACHTUNGTRENNUNG
On the basis of these results, we next examined the scope
of this reaction for the synthesis of other N-tosylated lac-
tams. Various N-tosylated amino alcohols, both acyclic as
well as benzofused, were selected as substrates and the
method was quite successful in transforming them into their
corresponding products, which included N-protected five-,
six-, and seven-membered lactams, in good to high yields.
All these reactions were performed under air and the results
are given in Table 3. The subjection of N-tosylated 5-amino-
1-pentanol (6) to these reaction conditions afforded the ex-
pected N-tosylpiperidin-2-one (7) as a white crystalline solid
in 72% yield (Table 3, entry 2). N-Tosylated derivatives of
isoindolin-1-one (9) and indolin-2-one (11) were obtained in
98% and 80% yield from the corresponding amino alcohols
8 and 10, respectively (Table 3, entries 3 and 4). Similarly,
N-tosylated 3-(2-aminophenyl)propan-1-ol (12) afforded 3,4-
[a] 4a (1 mmol), Ru catalyst (1 mol%), 3 (2 mol%), 2 (20 mol%), tolu-
ene (2 mL), air (1 atm), 1008C, 18 h. [b] Yield of isolated product; n.r.=
no reaction. [c] K2CO3 (2 mol%) was added. [d] In chlorobenzene, under
O2 (1 atm), at 1208C.
commercially available catalysts 1c and 1d did not lead to
lactamization (Table 1, entries 2–4). When the reaction was
performed at an elevated temperature in chlorobenzene,
under pure oxygen, the yield of 5a was slightly decreased
(Table 1, entry 5).
We next examined the influence of different N-protecting
groups in the reaction and the results are summarized in
Table 2. In addition to substrates containing the tosyl group
(4a), those containing a methanesulfonyl group (Ms, 4d)
and a 4-methoxybenzenesulfonyl group (Mbs, 4e) also gave
good yields of the corresponding lactam (Table 2, entries 4
and 5). On the other hand, a substrate containing the 2-ni-
trobenzenesulfonyl group (Ns, 4c; Table 2, entry 3) gave
a low yield of the corresponding lactam. Interestingly, N-
Boc derivative 4b and N-acyl derivative 4 f also afforded the
expected lactam in moderate yield. However, N-benzoyl de-
dihydroquinolin-2ACTHNUTRGNEUNG(1H)-one derivative 13 as a white solid in
78% yield (Table 3, entry 5). Biologically important mor-
pholin-2-one and piperazin-2-one derivatives, 15 and 17,
could also be synthesized by this method using the corre-
sponding amino alcohol derivatives 14 and 16, respectively
(Table 3, entries 6 and 7).[16] 4-Phenyl-substituted 5-amino-1-
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Aerobic Oxidation of Amino Alcohols
COMMUNICATION
Table 3. Aerobic lactamization of N-tosylated amino alcohols.[a]
Substrate
Product
Yield
[%][b]
1
2
3
4a
6
5a
7
75
72
98
8
9
4
5
10
12
11
13
80[c]
78[c]
6
7
8
9
14
16
18
20
15
17
19
21
77
74
92
31
Scheme 3. Proposed mechanism for lactam formation.
Regarding the mechanism of the reaction, it presumably
follows the route depicted in Scheme 3 and involves two
successive ruthenium-catalyzed dehydrogenations. Thermal
dissociation of Shvoꢀs catalyst 1a[17] generates the active 16-
electron complex 1e, which dehydrogenates amino alcohol I
to amino aldehyde II whilst itself undergoes reduction to hy-
dride 1 f. ETMs 2 and 3, mediate the hydrogen transfer from
1 f to molecular oxygen and, in doing so, 1e is regenerated.
Aminoaldehyde II subsequently cyclizes to hemiaminal III
followed by a second dehydrogenation, which leads to the
lactam IV.
In conclusion, we have developed a new efficient method
for the conversion of N-protected amino alcohols to five-,
six-, and seven-, membered lactams by biomimetic aerobic
oxidation mediated by Shvoꢀs catalyst. Several N-protecting
groups are compatible with the reaction conditions and the
method was successfully applied to the synthesis of a range
of lactams including piperidinone, morpholinone, piperazi-
none, indolinone, and isoindolinone derivatives.
10
22
23
55[c,d]
11
12
n=1:
n=4:
24
26
n=1:
n=4:
25
27
89
82
28
n.r.
–
[a] Substrate (1 mmol), 1a (1 mol%), 3 (2 mol%), 2 (20 mol%), toluene
(2 mL), air (1 atm), 1008C, 18 h; n.r.=no reaction. [b] Yield of isolated
product. [c] 1a (2 mol%), 3 (4 mol%), 2 (20 mol%), toluene (4 mL), air
(1 atm), 1008C, 24 h. [d] Reaction time: 48 h.
pentanol derivative 18 and 4,4-dimethyl-substituted 5-
amino-1-pentanol derivative 20 afforded piperidin-2-one de-
rivatives 19 and 21, respectively (Table 3, entries 8 and 9);
however, the latter was obtained in only moderate yield. In-
terestingly, benzofused seven-membered lactam 23 could
also be synthesized by this route in 55% yield (Table 3,
entry 10). Attempts to expand this methodology to include
the synthesis of four- and additional seven-membered lac-
tams were unsuccessful because intermolecular oxidative
esterification was preferred over the intramolecular lactam
formation (Table 3, entry 11). Attempts toward the oxidative
cyclization of substrate 28 to prepare a thiomorpholin-2-one
derivative were not successful; the substrate 28 did not react
(Table 3, entry 12).
Experimental Section
General procedure: Shvoꢀs catalyst 1a (10.85 mg, 0.01 mmol), 2,6-di
ACHTUNGTRENNUNGmeth-
AHCTUNGTRENNUNG
0.02 mmol), were added to N-tosyl-4-amino-1-butanol 4a (243 mg,
1 mmol) in a Schlenk tube. The mixture was degassed under reduced
pressure for a few seconds and then air was introduced with a balloon.
Toluene (2 mL) was then added and the mixture was stirred in an oil
bath at 1008C for 18 h. The reaction mixture was then cooled to room
temperature, diluted with CH2Cl2, and filtered through a short pad of
Celite. The filtrate was concentrated and the resulting residue was sub-
jected to silica-gel column chromatography eluting with pentane/ethyl
acetate to afford lactam 5a as a white crystalline solid. m.p. 145–1478C
(180 mg, 75%).
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J.-E. Bꢁckvall et al.
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Acknowledgements
Financial support from the European Research Council (ERC AdG
247014) is gratefully acknowledged.
Keywords: amino alcohols · biomimetic synthesis · lactams ·
oxidation · ruthenium
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Received: June 12, 2012
Published online: && &&, 0000
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Chem. Eur. J. 0000, 00, 0 – 0
ÝÝ
These are not the final page numbers!

Aerobic Oxidation of Amino Alcohols
COMMUNICATION
The right path: N-Protected amino
alcohols undergo aerobic and biomim-
etic oxidation to the corresponding lac-
tams in the presence of a ruthenium
catalyst and a combination of electron-
transfer mediators under air (see
scheme). The reaction was used for the
synthesis of five-, six-, and seven-,
membered lactams and showed good
tolerance to a number of N-protecting
groups.
Oxidation
B. P. Babu, Y. Endo,
J.-E. Bꢀckvall* ................ &&&& — &&&&
Biomimetic Aerobic Oxidation of
Amino Alcohols to Lactams
Chem. Eur. J. 2012, 00, 0 – 0
ꢂ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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These are not the final page numbers!