Efficient synthesis of eight-membered nitrogen heterocycles from O-propargylic oximes by rhodium-catalyzed cascade reactions

Article abstract of DOI:10.1002/chem.201403637

Azocine derivatives were successfully synthesized from O-propargylic oximes by means of a Rh-catalyzed 2,3-rearrangement/heterocyclization cascade reaction. Moreover, the chirality of the substrate was maintained throughout the cascade process to afford the corresponding optically active azocines.

Full text of DOI:10.1002/chem.201403637

DOI: 10.1002/chem.201403637
Communication
&
Heterocycles
Efficient Synthesis of Eight-Membered Nitrogen Heterocycles from
O-Propargylic Oximes by Rhodium-Catalyzed Cascade Reactions
Itaru Nakamura,*[a] Yoshinori Sato,[b] Keisuke Takeda,[b] and Masahiro Terada[a, b]
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Abstract: Azocine derivatives were successfully synthe-
sized from O-propargylic oximes by means of a Rh-cata-
lyzed 2,3-rearrangement/heterocyclization cascade reac-
tion. Moreover, the chirality of the substrate was main-
tained throughout the cascade process to afford the cor-
responding optically active azocines.
Eight-membered nitrogenous heterocycles (azocines) can be
found in numerous naturally occurring products, such as
manzamine alkaloids,[1] grandilodines,[2] and otonecines,[3] as
well as biologically active compounds, such as XIAP antago-
nists[4] (Scheme 1). Moreover, azocine derivatives have been
Scheme 2. Rh-catalyzed cascade reactions of O-propargylic oximes in the
syntheses of azepines (n=0) and azocines (n=1, present work).
a 2,3-rearrangement to form N-allenylnitrone intermediate A,
then the formation of azarhodacycle B occurs, followed by ring
expansion of the strained cyclopropyl group. Accordingly, we
envisioned that our methods could be extended to the effi-
cient construction of the elusive monocyclic azocine skeletons,
without the use of high-dilution conditions, starting with
a readily accessible cyclobutyl moiety as the ring-expanding
functional group (Scheme 2, n=1).[13] Herein, we report on the
effective transformation of O-propargylic oximes 1 that possess
a cyclobutyl group at the oxime moiety, in the presence of
a Rh catalyst, into the corresponding azocine oxides 2 in good
to excellent yields [Eq. (1)].
Scheme 1. Selected examples of azocines as natural products or synthetic
intermediates. Cbz=carbobenzyloxy.
utilized as synthetic intermediates providing various alkaloids,
such as loline[5] and FR-900482.[6] Accordingly, the efficient con-
struction of nitrogen-containing eight-membered rings would
contribute greatly toward organic synthetic methods.[7] In par-
ticular, the synthesis of eight-membered nitrogenous hetero-
monocyclic compounds has proven to be a challenge because
the direct cyclization of a linear substrate into the correspond-
ing eight-membered ring is entropically and enthalpically un-
favorable.[8] Accordingly, such monocyclic skeletons are gener-
ally constructed in good to moderate yields by olefin metathe-
sis reactions, which inevitably require high-dilution conditions
(typically 0.002–0.005m).[9,10] We have recently reported the
use of Rh-catalyzed cascade reactions for the efficient con-
struction of seven-membered nitrogen heterocyclic azepine
oxides from O-propargylic cyclopropanecarboaldoximes
(Scheme 2, n=0),[11,12] in which the starting oxime undergoes
Initially, the reaction conditions, as summarized in Table 1,
were optimized by using (E)-1a. In the presence of [RhCl(cod)]2
(2.5 mol%; cod=1,5-cyclooctadiene) and PPh3 (10 mol%), the
reaction was carried out in MeCN at 808C to afford desired
product 2a in 71% yield (entry 1).[14] Among the solvents, the
best results were obtained by using MeCN. Moreover, the mass
balance was improved by lowering the reaction concentration
from 0.2 to 0.1m (entry 2). In contrast, the use of DMF and
DMSO (entries 3 and 4, respectively) decreased the mass bal-
ance, whereas the use of 1,4-dioxane, THF, and toluene (en-
tries 5–7, respectively) resulted in significant formation of the
byproduct, four-membered cyclic nitrone 3a.[15] With regards
to the ligands, the use of electron-poor phosphines (entry 9)
afforded 2a in excellent yield, whereas that of electron-rich li-
gands (entry 8) resulted in the formation of undesired byprod-
uct 3a. The use of a phosphite ligand (triphenylphosphite,
entry 10) gave intermediate results. Bidentate ligands such as
dppp (dppp=1,3-bis(diphenylphosphino)propane; entry 11) re-
sulted in the preferential formation of byproduct 3a. Notably,
product 2a was readily separated from triarylphosphine oxides
by using silica gel chromatography. In contrast, the previous
[a] Prof. Dr. I. Nakamura, Prof. Dr. M. Terada
Research and Analytical Center for Giant Molecules
Graduate School of Science, Tohoku University
6-3 Aramaki Aza Aoba, Aoba-ku, Sendai, 980-8578 (Japan)
Fax: (+81)22-795-6602
E-mail: itaru-n@m.tohoku.ac.jp
[b] Y. Sato, K. Takeda, Prof. Dr. M. Terada
Department of Chemistry, Graduate School of Science
Tohoku University, 6-3 Aramaki Aza Aoba
Aoba-ku, Sendai, 980-8578 (Japan)
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201403637.
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aromatic ring. Alkyl groups, such as propyl (entry 4) and cyclo-
hexyl (entry 5), were effective as the alkyne substituent R1,
whereas the reaction of terminal alkyne 1g afforded unidenti-
fied byproducts (entry 6). Alkyl substituents were also accepta-
ble at the propargylic position (entries 9–11). In terms of the
electronic effects at the propargylic position, the reaction of
1h (entry 7), which involves an electron-deficient aryl group,
proceeded much faster than the substrate with an electron-
rich substituent (entry 8).
Table 1. Optimization of reaction conditions.
Entry
Ligand
Solvent
Time
[h]
2a
[%][a]
3a
[%][a]
1a
[%][a]
[0.2 m]
Using the same reaction conditions as for the E oximes
(Table 1, entry 9), the reaction for the corresponding Z oxime
[(Z)-1a, Eq. (2)] led to complete consumption of the starting
material within a shorter time (12 h), affording the product, 2a,
in an excellent isolated yield.[17] In contrast, the reaction of di-
cyclobutyl ketoxime 1m did not give the azocine; instead, the
four-membered cyclic nitrone 3m was obtained [Eq. (3)].
1
2
3
4
5
6
7
8
9
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
(p-MeOC6H4)3P
(p-F3CC6H4)3P
(PhO)3P
dppp[d]
MeCN
24
36
60
48
72
72
72
36
24
24
24
71
88
28
32
17
19
30
57
trace
7
<1
<1
<1
<1
36
9
28
<1
<1
<1
<1
MeCN[b]
DMF
46
41
35
52
30
23
3
DMSO
dioxane
THF
toluene
MeCN[b]
MeCN[b]
MeCN[b]
MeCN[b]
(93)[c]
76
10
11
20
56
27
[a] Yields were determined by using 1H NMR spectroscopy with 1,2-di-
chloroethane as an internal standard. [b] 0.1m. [c] Isolated yield in paren-
thesis. [d] 5 mol% of dppp was used.
azepine oxide synthesis[11] required the use of water-soluble
phosphine TPPMS (TPPMS=sodium diphenylphosphinoben-
zene-3-sulfonate) because of difficulties in the purification
steps.[16]
Next, the reactions of various E oximes (E)-1 were carried
out, as summarized in Table 2, using the optimized reaction
conditions (Table 1, entry 9). The reaction of 1b (entry 1),
which possesses an electron-donating p-anisyl group at the
alkyne terminus, was faster than those of 1c and 1d (entries 2
and 3, respectively), which both possess an electron-deficient
The reaction of meso-cis-1,3-disubstituted cyclobutane 1n
efficiently afforded the trisubstituted azocine oxide, 2n, in an
excellent yield [Eq. (4)]. Notably, the E and Z oximes simultane-
ously underwent the reaction as a mixture, without the need
to separate the isomers. In contrast, as shown in [Eq. (5)], the
reaction of 1,1-disubstituted cyclobutane (E)-1o afforded multi-
substituted azocine derivative 2o in 40% yield (57% brsm=
based on recovered starting material), along with the four-
membered cyclic nitrone 3o as the byproduct (19%), albeit re-
quiring a longer reaction time.
Table 2. Rh-catalyzed reaction of (E)-1b–l.[a]
Entry
1
R1
R2
Time
[h]
2
Yield
[%][b]
1
2
3
4
5
6
7
8
9
1b
1c
1d
1e
1 f
1g
1h
1i
p-MeOC6H4
p-ClC6H4
p-F3CC6H4
nPr
Cy
H
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
20
45
120
48
72
72
20
60
96
2b
2c
2d
2e
2 f
–
2h
2i
2j
91
68
78
71
73
dec.[c]
90
p-F3CC6H4
p-MeOC6H4
nPr
81[d]
48
1j
Ph
10
11
1k
1l
p-MeOC6H4
Ph
nPr
Cy
72
120
2k
2l
53
34
[a] The reaction of 1 (0.4 mmol) was carried out in the presence of [RhCl-
(cod)]2 (2.5 mol%) and (p-F3CC6H4)3P (10 mol%). in MeCN (4 mL) at 808C.
Cy=cyclohexyl. [b] Isolated yield. [c] dec.=decomposed. [d] PPh3 was
used instead of (p-F3CC6H4)3P.
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nitrone byproduct 3p with sufficient level of chirality transfer
(Scheme 3d). It should be noted that the enantiomeric purity
of the starting material (R,E)-1p was maintained during the Rh-
catalyzed reaction. To date, however, attempts to determine
the absolute configuration of the chiral products have proven
to be unsuccessful.
A plausible mechanism for the reaction of (E)-trans-1, cata-
lyzed by the dual-role Rh catalyst, is illustrated in Scheme 4.[19]
Firstly, the Rh catalyst coordinates to the alkyne moiety of
propargyl oxime 1 to form p complex 4, which has an electro-
philic activated CꢀC bond. Complex 4 could undergo an intra-
molecular nucleophilic attack by the oxime nitrogen atom to
form cyclic vinyl rhodium species 5. Cleavage of the CÀO
bond, followed by elimination of the Rh catalyst leads to N-al-
lenylnitrone intermediate (E)-6. Upon isomerization of the ni-
trone moiety, the thermodynamically more-stable Z isomer, (Z)-
6, coordinates again with the Rh catalyst to form h4-complex
7, which subsequently undergoes diarotatory metallacycliza-
tion. b-Carbon elimination takes place in the two configura-
tions, 8 and 8’, of the resulting rhodacyclic intermediate, in
which the proximal CÀC bond of the cyclobutane group and
the Csp3ÀRh bond are syn periplanar.[20] Ring expansion from
configuration 8 affords cis rhodacycle 9, which then undergoes
reductive elimination of the Rh catalyst to give azocine 2. Al-
ternatively, trans rhodacycle 9’ leads to the corresponding
enantiomer ent-2. The fact that both optically active E and Z
oximes give the same enantiomers (Scheme 3a and 3b) is at-
tributed to predominant metallacyclization from the thermody-
namically stable Z nitrone (Z)-6. The result of the reaction of
ketoxime 1m also suggests that the cyclobutyl group directed
to the allene moiety in the N-allenylnitrone 6 interferes with
the metallacyclization process. Presumably, loss of chirality
Scheme 3. Chirality transfer in Rh-catalyzed azocine synthesis.
Next, to gain information on reaction mechanism, we con-
ducted the Rh-catalyzed reaction of optically active O-propar-
gylic oximes (R)-1, as summarized in Scheme 3.[18] Both E
oxime 1n [meso-trans-cyclobutane, (R,E)-trans-1n, Scheme 3a]
and Z oxime 1n [(R,Z)-trans-1n,
Scheme 3b] resulted in the for-
mation of the optically active
azocine (+)-2n with an accepta-
ble level of chirality transfer, that
is, the E/Z configuration at the
oxime moiety of the starting ma-
terial does not affect the chirality
transfer. Notably, alkyl and aryl
substituents were found to be
acceptable at the alkyne termi-
nus (see the Supporting Informa-
tion). In contrast to the reaction
of (R)-trans-1n (Scheme 3a), the
reaction of meso-cis-cyclobutane,
(R)-cis-1n, afforded the opposite
enantiomer [(À)-2n, Scheme 3c],
albeit with a lower level of chi-
rality transfer. The chirality of
(R,E)-1p, which does not possess
an
a proton at the oxime
moiety, was also transferred to
(À)-2p with a similar level to
that of 1n, along with the for-
mation of four-membered cyclic Scheme 4. Proposed reaction mechanism.
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could occur, not only during the competitive ring-expansion
step between 8 and 8’, but during various steps, such as race-
mization of N-allenylnitrone 6 by the p acidic Rh catalyst,[21] ep-
imerization of the a position of the nitrone or iminium groups,
and b-hydrogen elimination (reinsertion into the cyclobutyl-
methylrhodium species 8). Nevertheless, the central chirality of
starting material 1 was efficiently transferred into product 2
through the allene axial chirality.[22]
Keywords: cascade reactions
heterocycles · rearrangement · rhodium
·
chirality
·
nitrogen
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In conclusion, we have successfully developed a synthetic
method to construct eight-membered nitrogenous heterocy-
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2,3-rearrangement/heterocyclization cascade sequence. Fur-
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active oximes, with good levels of chirality transfer.
Experimental Section
General procedure
MeCN (0.2 mL) was added to a mixture of [RhCl(cod)]2 (4.9 mg,
0.01 mmol) and tris(p-trifluoromethylphenyl)phosphine (18.7 mg,
0.04 mmol), in a V-vial, under an argon atmosphere. The mixture
was stirred at 1008C for 1 h. Next, (E)-1a (0.4 mmol) in MeCN
(3.8 mL) was added to this solution, and the resulting mixture was
stirred at 808C for 24 h. The reaction mixture was passed through
a short pad of silica gel with EtOAc (100 mL). The solvents were re-
moved in vacuo and the crude product was purified by using flash
column chromatography, with hexane/EtOAc (1:1) as eluents, to
give pure 2a (107.9 mg, 93%).
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Acknowledgements
This work was supported by a Grant-in-Aid for Scientific Re-
search on Innovative Areas “Molecular Activation Directed
toward Straightforward Synthesis” from the Ministry of Educa-
tion, Culture, Sports, Science and Technology, Japan.
Chem. Eur. J. 2014, 20, 10214 – 10219
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Communication
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oxidative insertion in the presence of redox Rh catalysts.
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Received: May 22, 2014
Published online on July 15, 2014
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