Base-promoted internal redox-cyclisation reactions

Article abstract of DOI:10.1055/s-0033-1339313

A new internal, base-mediated redox-cyclisation reaction has been discovered and developed. In this transformation, the sacrificial reduction of an alkynyl moiety to an alkene allows direct functionalisation of an α-amino C-H bond. This approach allows th

Full text of DOI:10.1055/s-0033-1339313

1722▌
LETTER
letter
Base-Promoted Internal Redox-Cyclisation Reactions
Base-Promoted Internal Redox-Cyclisation Reactions
Saad Shaaban, Bo Peng, Nuno Maulide*
Max-Planck-Institut für Kohlenforschung, Kaiser-Wilhelm-Platz 1, 45470 Mülheim an der Ruhr, Germany
Fax +49(208)3062974; E-mail: maulide@mpi-muelheim.mpg.de
Received: 24.04.2013; Accepted after revision: 05.06.2013
in these early attempts, N,O-acetal (aminal) 4a was ob-
tained in low (but reproducible) isolated yields when NaH
was employed as base. In contrast to well-known Brønst-
ed or Lewis acid catalyzed redox reactions,2 this transfor-
Abstract: A new internal, base-mediated redox-cyclisation reac-
tion has been discovered and developed. In this transformation, the
sacrificial reduction of an alkynyl moiety to an alkene allows direct
functionalisation of an α-amino C–H bond. This approach allows
the preparation of several 1,3-oxazinane derivatives in an atom- mation piqued our interest since it proceeds under
efficient manner.
orthogonal conditions (in the presence of base rather than
acid) and presented the potential to deliver compound 4a
in an atom-economical manner.5 We thus decided to in-
vestigate this unexpected result further.
Key words: C–H activation, C–H functionalisation, redox, cyclisa-
tion, pyrrolidine
Ar
The direct functionalisation of C–H bonds is a current and
highly attractive topic in contemporary organic synthe-
sis.1 Numerous creative and innovative C–H activation
methods have been developed in the past decades. Recent-
ly, a novel approach to the functionalisation of sp3 C–H
bonds through internal hydride transfer has received a
great deal of attention.2 In contrast to traditional C–H
activation reactions, such transformations proceed in the
absence of external oxidants and generally hinge on an in-
ternal 1,5-hydride shift process.
Ar
redox
N
N
O
OH
base
this work
R
R
3
4
Scheme 2 Base-promoted redox cyclisation
Ph
Intrigued by this concept, we have developed a redox-trig-
gered C–H functionalisation strategy (Scheme 1).3 In this
one-pot process, C–H bonds α to a pyrrolidine or piperi-
dine moiety 1 are directly converted into C–C bonds, ac-
companied by concomitant reduction of a neighbouring
carboxaldehyde group. Herein, we report the discovery
and development of a base-promoted redox isomerisation
of α-alkynyl pyrrolidines 3 that allows the deployment of
sequential, iterative C–H functionalisation sequences
(Scheme 2).
N
O
base
5a
Ph
N
not observed
OH
Ph
O
N
NaH
THF, 60 °C
3a
n
n
4a, 10%
Nu
H
Nu
H
redox
N
N
Scheme 3 Discovery of the base-promoted redox cyclisation
CHO
OH
ref. 3
A selection of conditions that were surveyed is depicted in
Table 1. According to our initial discovery, aminal 4a was
obtained in 10% yield, although full conversion of sub-
strate 3a was observed (Table 1, entry 1). Lowering the
temperature from 60 to 50 °C significantly enhanced the
selectivity, leading to a great improvement of the yield of
4a (entry 2). The use of larger amounts of NaH or switch-
ing to potassium tert-butoxide as base did not lead to sig-
nificant improvement (entries 3 and 4). In spite of
numerous additional experiments (not shown), it was not
possible to improve the yield of product 4a further.6
R
R
2
1
Scheme 1 Previously developed internal redox-triggered C–H func-
tionalisation of amines
During our recent studies on redox-triggered C–H func-
tionalisation, we attempted to transform adduct 3a into 5a
by base-promoted 7-exo-dig cyclisation (Scheme 3).4 To
our surprise, while none of the oxepane 5a was observed
SYNLETT 2013, 24, 1722–1724
Advanced online publication: 10.07.2013
DOI: 10.1055/s-0033-1339313; Art ID: ST-2013-D0383-L
© Georg Thieme Verlag Stuttgart · New York
With suitable conditions in hand, we then investigated the
scope of this base-promoted redox reaction. Moderate to
good yields of the desired 1,3-oxazinane derivatives were
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6

LETTER
Base-Promoted Internal Redox-Cyclisation Reactions
1723
Table 1 Optimisation of the Redox Reaction of 3aa
Ar
Ar
Ph
O
N
N
Ph
NaH (1.0 equiv)
THF, 50 °C, 24 h
O
N
N
OH
Ph
base
OH
THF, temp, 24 h
R
R
3
4
Ph
3a
4a
Ph
O
Entry
Base
Temp (°C)
Yield (%)b
N
O
N
O
N
1
2
3
4
NaH (1.0 equiv)
NaH (1.0 equiv)
NaH (2.0 equiv)
t-BuOK (1.0 equiv)
60
50
50
50
10
52
Cl
OMe
4b, 47%a
4c, 32%
4a, 52%
trace
30
t-Bu
Et
Ph
obtained for a range of substrates (Scheme 4). Substrate
3b, bearing a para-methoxy substituent, proved to be un-
reactive under the optimised conditions. However, in-
creasing the temperature to 100 °C led to a good yield of
desired oxazinane 4b. When substrates 3c and 3d, con-
taining electron-deficient aromatic rings, were subjected
to the redox cyclisation conditions, the desired 1,3-oxazi-
nane derivatives 4c and 4d were also obtained albeit in
lower yields. Substituents on the benzene of phenyl
alkynes 3e–h also led to slightly lower yields.
O
N
O
N
O
N
F3C
4f, 38%
4d, 33%
4e, 29%
F3C
OMe
CF3
To acquire further insight into the mechanism of this reac-
tion, a deuterium labelling experiment was performed as
shown in Scheme 5. When the reaction of 3a was conduct-
ed with NaH (1.0 equiv) and deuterium oxide
(2.0 equiv),7 the product d-4a was isolated containing
20% of the deuterium label at the indicated position.
Based on this experiment, we can tentatively propose a
mechanism for this base-promoted redox-cyclisation
(Scheme 6).
O
O
N
N
4g, 39%
4h, 33%
Scheme 4 Substrate scope for the base-promoted redox C–H func-
tionalisation. Reagents and conditions: amino alcohol 2 (0.1 mmol),
THF (2.5 mL), NaH (4.0 mg), 50 °C, 24 h.7 a Reaction performed at
100 °C in a microwave reactor for 16 h.
At the outset, deprotonation of the alcohol functionality in
3a gives alkoxide A, which may trigger an internal depro-
tonation of the propargylic α-amine moiety, leading to the
formation of intermediate B. The allenic anion B (bearing
an OH or OD residue) thus generated is internally
quenched by the alcohol, providing allenamine intermedi-
ate C.8 Isomerisation of allenamine C (assisted by D2O)
then leads to iminium intermediate D, the nucleophilic
trapping of which furnishes deuterated oxazinane deriva-
tive d-4a.
20% D
D
Ph
H
Ph
O
N
N
H
NaH (1.0 equiv), D2O (2.0 equiv)
THF, µw, 100°C
OH
3a
d-4a
Scheme 5 Labelling experiment
D2O
D
Ph
H
D
Ph
H
Ph
Ph
Ph
Ph
+
N
N
H
O
N
N
N
N
H
H
O
base
OH
O
O
OH/D
3a
A
B
C
D
d-4a
Scheme 6 Plausible mechanism for the base-promoted redox C–H functionalisation
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 1722–1724

1724
S. Shaaban et al.
LETTER
(4) (a) Xu, M.; Miao, Z.; Bernet, B.; Vasella, A. Helv. Chim.
Acta 2005, 88, 2918. (b) Saha, J.; Lorenc, C.; Surana, B.;
Peczuh, M. W. J. Org. Chem. 2012, 77, 3846.
The obtained 1,3-oxazinane derivatives possess an addi-
tional N,O-acetal moiety, which suggests further possibil-
ities for functionalisation. To this end, we attempted to
further elaborate product 4b by reaction with another nu-
cleophile (Scheme 7). In the event, it was found that lith-
ium alkynyltrifluoroborate 6 reacted smoothly with 4b,
affording the aminoenyne 6b in 81% yield. Notably, 6b
contains both alkynyl- and alkenyl fragments at the
α-position of the pyrrolidine moiety, introduced sequen-
tially in a redox-based fashion.
(5) (a) Bottini, A. T.; Mullikin, J. A.; Morris, C. J. J. Org. Chem.
1964, 29, 373. (b) Phadtare, S.; Zemlicka, J. J. Am. Chem.
Soc. 1989, 111, 5925. (c) Wei, L.-L.; Hsung, R. P.; Xiong,
H.; Mulder, J. A.; Nkansah, N. T. Org. Lett. 1999, 1, 2145.
(6) The remainder of the mass balance in these reactions was
typically composed of a mixture of oligomeric material,
decomposition products and (occasionally) small amounts of
cyclisation products isomeric or akin to 5a (Scheme 3).
(7) No reaction occurred under the optimised conditions;
however, when the reaction temperature was raised to
100 °C, the product d-4a was isolated containing 20%
deuterium at the indicated position.
Ph
Ph
N
O
N
Ph
OH
(8) Wei, L.-L.; Xiong, H.; Douglas, C. J.; Hsung, R. P.
Tetrahedron Lett. 1999, 40, 6903.
Ph
BF3Li (6)
THF, –78 °C to r.t., 1 h
(9) Typical Procedure; Synthesis of 1,3-Oxazine 4a: To a
solution of amino alcohol 3a (62 mg, 0.22 mmol) in THF
(5 mL) was added NaH (60% w/w, 1.0 equiv, 8.8 mg, 0.22
mmol) under argon at room temperature and the mixture was
stirred at 50 °C overnight. The reaction mixture was then
cooled to room temperature, quenched with sat. aq NH4Cl,
extracted with EtOAc (3×), dried (Na2SO4), and
OMe
OMe
6b, 81%
4b
Scheme 7 Elaboration of compound 4b
In summary, we have discovered and developed a base-
promoted redox cyclisation providing a series of 1,3-oxa-
zinane derivatives in moderate to good yields.9 In this pro-
cess, a C–H bond α to an amine moiety is transformed into
a C–O bond through a redox process whereupon an alkyne
fragment is simultaneously reduced to an alkene. Further
mechanistic investigations, exploration of synthetic appli-
cations, and development of redox reactions as tools for
C–H functionalisation are ongoing in our group.
concentrated under reduced pressure. Purification by
column chromatography (pentane–EtOAc, 9:1) afforded the
desired product 1,3-oxazinane 4a.
3a-Styryl-2,3,3a,5-tetrahydro-1H-benzo[d]pyrrolo[2,1-
b][1,3]oxazine (4a): Yield: 52%. 1H NMR (400 MHz,
CDCl3): δ = 7.36–7.33 (m, 2 H), 7.30–7.27 (m, 2 H), 7.23–
7.16 (m, 2 H), 6.88 (d, J = 7.2 Hz, 1 H), 6.74 (d, J = 8.1 Hz,
1 H), 6.71–6.67 (m, 1 H), 6.41 (d, J = 15.7 Hz, 1 H), 6.19 (d,
J = 15.7 Hz, 1 H), 4.88 (d, J = 14.6 Hz, 1 H), 4.62 (d,
J = 14.6 Hz, 1 H), 3.79 (td, J = 8.9, 1.8 Hz, 1 H), 3.36 (ddd,
J = 9.8, 8.8, 6.7 Hz, 1 H), 2.25–2.20 (m, 1 H), 2.16–2.09 (m,
1 H), 2.05–1.91 (m, 2 H). 13C NMR (100 MHz, CDCl3): δ =
142.4, 136.1, 133.8, 130.4, 128.5, 127.8, 127.7, 126.8,
124.5, 120.1, 116.7, 113.3, 93.6, 63.5, 50.0, 39.3, 21.3. IR
(neat): 3024 (w), 2970 (w), 2841 (w), 1881 (w), 1607 (s),
1497 (s), 1361 (s), 1196 (m), 1029 (m), 973 (m), 747 (s) cm–1.
HRMS: m/z calcd for [C19H19NO + H]+: 278.1545; found:
278.1539.
Acknowledgment
We are highly indebted to the Max-Planck Society and the Max-
Planck-Institut für Kohlenforschung for generous funding of our re-
search programs.
Typical Procedure; Synthesis of 1,3-Oxazine 4f: To a
solution of amino alcohol 3f (50 mg, 0.15 mmol) in THF (4
mL), NaH (60% w/w, 1.0 equiv, 6.2 mg, 0.15 mmol) was
added under argon at room temperature and the mixture was
stirred at 50 °C overnight. The reaction mixture was cooled
to room temperature, quenched with sat. aq NH4Cl, extracted
with EtOAc (3×), dried (Na2SO4), and concentrated under
reduced pressure. Purification by column chromatography
(pentane–EtOAc, 19:1) afforded the desired 1,3-oxazinane
4f.
3a-[4-(tert-Butyl)styryl]-2,3,3a,5-tetrahydro-1H-
benzo[d]pyrrolo[2,1-b][1,3]oxazine (3f): Yield: 38%. 1H
NMR (400 MHz, CDCl3): δ = 7.28–7.25 (m, 4 H), 7.12–7.09
(m, 2 H), 6.81–6.77 (m, 1 H), 6.80 (d, J = 7.6 Hz, 1 H), 6.72
(d, J = 8.2 Hz, 1 H), 6.62–6.59 (m, 1 H), 6.31 (d,
J = 15.7 Hz, 1 H), 6.08 (d, J = 15.4 Hz, 1 H), 4.80 (d,
J = 14.8 Hz, 1 H), 4.54 (d, J = 15.8 Hz, 1 H), 3.71 (td,
J = 8.5 Hz, J = 8.4 Hz, 1 H), 3.36 (m, 1 H), 2.16–2.11 (m,
1 H), 2.08–2.02 (m, 1 H), 1.91–1.95 (m,1 H), 1.89–1.82 (m,
1 H), 1.25–1.22 (s, 9 H). 13C NMR (100 MHz, CDCl3): δ =
133.6, 133.1, 129.7, 127.8, 126.8, 125.7, 124.5, 120.3,
116.7, 113.2, 96.6, 93.8, 63.5, 50.3, 39.4, 34.6, 30.9, 21.2. IR
(neat): 3024 (w), 2970 (w), 2841 (w), 1830 (w), 1698 (s),
1498 (s), 1362 (s), 1263 (m), 1029 (m), 815 (m), 749 (s) cm–1.
HRMS: m/z calcd for [C23H27NO + H]+: 334.2167; found:
334.2165.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SnoIufproig
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References and Notes
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