Chromium(0)-catalyzed tandem cyclization of α,β-unsaturated thioimidates containing an enyne moiety

Article abstract of DOI:10.1002/anie.201201505

Bicyclic: The diastereoselective synthesis of functionalized 1-azabicyclo[5.3.0]decane derivatives proceeds through 1,7-electrocyclization of the zwitterionic intermediates that are formed in the cyclization of α,β-unsaturated thioimidates containing an e

Full text of DOI:10.1002/anie.201201505

Angewandte
Chemie
DOI: 10.1002/anie.201201505
Synthetic Methods
Chromium(0)-Catalyzed Tandem Cyclization of a,b-Unsaturated
Thioimidates Containing an Enyne Moiety**
Yusuke Karibe, Hiroyuki Kusama, and Nobuharu Iwasawa*
1-Azabicyclo[n.3.0] ring systems have been attracting much
attention of organic chemists as a variety of important
bioactive molecules contain these azabicyclic skeletons.[1] In
contrast to the abundant approaches to the construction of 1-
azabicyclo[3.3.0]octane and 1-azabicyclo[4.3.0]nonane sys-
tems, the construction of the 1-azabicyclo[5.3.0]decane skel-
eton has not been extensively developed, although this ring
system constitutes the basic core skeleton of the stemona
alkaloids, some of which showed promising insecticide and
antitussive activities.[2] The central 1-azabicyclo[5.3.0]decane
nucleus was formed by 7-membered-ring formation of
pyrrolidine derivatives or 5-membered-ring formation of
azepine derivatives in most of the previous synthetic strat-
egies,[3] and there were only a few reports[4] on the one-step,
stereoselective synthesis of these compounds by tandem
cyclization of acyclic precursors (Scheme 1).
imidates[5] containing an enyne moiety 1 with an electrophilic
transition-metal catalyst, zwitterionic complexes would be
generated by 5-endo nucleophilic addition of the nitrogen
atom to the electrophilically activated alkyne,[6] followed by
ring closure to give 1-azabicyclo[5.3.0]decane derivatives 2,
the core skeleton of stemona alkaloids. Herein we describe
successful realization of this type of reaction.
We first examined the reaction of a,b-unsaturated thio-
imidate 1a containing an enyne moiety[7] with [W(CO)6]
(10 mol%) under photoirradiation (250W super high-pres-
sure Hg lamp; Table 1, entry 1). The reaction proceeded as
Table 1: Catalyst screening.
Entry
Catalyst
Condition
Yield [%]
1
2
3
4
5
6
7
8
9
10
[W(CO)6]
AuCl
AuCl3
[AuCl(PPh3)]-AgSbF6
[PtCl2(CH2CH2)][a]
[ReCl(CO)5]
[Mo(CO)6]
[Cr(CO)6]
hn
54
67
10
trace
43
19
74
86
92
808C
808C
RT
808C
hn
hn
hn
[Cr(CO)6]
hn[b]
hn[b]
[Cr(CO)6][a]
15
[a] 5 mol% of catalyst was used. [b] THF was used as solvent.
Scheme 1. Synthetic strategies toward the 1-azabicyclo[5.3.0]decane
skeleton.
expected, and 1-azabicyclo[5.3.0]decane product, pyrrole 2a,
was obtained in 54% yield after double-bond migration. We
further examined various electrophilic transition-metal cata-
lysts to carry out the reaction more efficiently. AuCl, AuCl3,
[PtCl2(C2H4)], and [ReCl(CO)5] also showed moderate
catalytic activity for this transformation (Table 1, entries 2,
3, 5, 6), but a cationic gold(I) complex, which was widely used
as a powerful catalyst for the electrophilic activation of
alkynes,[8] failed to promote this reaction (entry 4). Among
the group VI metal catalysts, [Cr(CO)6] was found to show
the highest activity (Table 1, entries 7, 8), and use of THF as
solvent gave the best result (entry 9). Further reduction of the
catalyst loading to 5 mol% lowered the yield of the product
considerably (Table 1, entry 10).
We have become interested in developing a new method
for the stereoselective construction of the 1-azabicyclo-
[5.3.0]decane skeleton by using tandem cyclization of easily
available compounds. Our basic strategy is shown at the
bottom of Scheme 1. By treatment of a,b-unsaturated thio-
[*] Y. Karibe, Dr. H. Kusama, Prof. Dr. N. Iwasawa
Department of Chemistry, Tokyo Institute of Technology
2-12-1, O-okayama, Meguro-ku, Tokyo 152-8551 (Japan)
E-mail: niwasawa@chem.titech.ac.jp
[**] This research was partly supported by a Grant-in-Aid for Scientific
Research from the Ministry of Education, Culture, Sports, Science,
and Technology of Japan. Y.K. was granted a Research Fellowship of
the Japan Society for the Promotion of Science for Young Scientists.
As the deactivation of the catalyst was thought to be due
to the coordination of the metal to the sulfur atom of 1a and/
or 2a,[9] we then expected that the use of thioimidates
containing a bulky substituent on the sulfur atom would
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201201505.
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Table 3: Generality of the reaction.
inhibit the coordination of the catalyst to the sulfur atom,
thereby resulting in acceleration of the reaction (Table 2).
Although the benzyl group was not suitable for this reaction
(Table 2, entry 2), the reaction with the (trimethylsilyl)-
methyl-substituted substrate was found to be very efficient
(entry 3). The reaction proceeded even with 2 mol% of
[Cr(CO)6] to give the cyclized product in 92% yield (Table 2,
entry 4).
Entry
X
Substrate
Yield [%] (product)
Table 2: Effect of the sulfur substituent.
1
2
3
4
5
2
5
5
5
5
R1 =Me (1d)
94 (2d)
74 (2e)
94 (2 f)[b]
80 (2g)
88 (2h)
R1 =TMS (1e)
R1 =CH3CHCH (1 f)[a]
R1 =CO2Me (1g)
R1 =2-furyl (1h)
Entry
R
Yield [%]
1
2
CH3(1a)
Bn(1b)
Me3SiCH2(1c)
Me3SiCH2(1c)
38
16
80
92
3
4[a]
6
7
8
5
5
5
(1i)
90 (2i)
95 (2j)
75 (2k)
[a] 2 mol% of catalyst was used. Reaction time was 12 h.
(1j)[a]
After having established that complexes of the composi-
tion Cr(CO)5(L) efficiently catalyzed the seven-membered-
ring formation, the reaction was examined by employing
several types of substrates with the results being summarized
in Table 3. Monosubstituted a,b-unsaturated thioimidates
having a methyl, trimethylsilyl, propenyl, methoxycarbonyl,
2-furyl group (1d, 1e, 1 f, 1g, 1h) also underwent seven-
membered-ring formation smoothly in good yields. Even the
reactions of disubstituted a,b-unsaturated thioimidates (1i,
1j) proceeded to afford the corresponding products in
moderate to good yields. We next applied this reaction to
a concise synthesis of tricyclic compounds possessing a seven-
membered ring moiety. The reaction of thioimidate 1k having
a cyclohexenyl group with a catalytic amount of [Cr(CO)6]
gave the tricyclic compound 2k in good yield. Furthermore,
the reaction of cyclohexylidene derivative 1l also underwent
seven-membered-ring formation smoothly to give spiro com-
pound 2l in good yield. Finally, the reaction of aniline
derivatives 1m, 1n was examined. In these cases, formation of
indole derivatives 2m, 2n, which contain a seven-membered
ring, was found to proceed smoothly through deprotonation–
protonation of an a,b-unsaturated carbene complex inter-
mediate in the presence of NEt3.[10]
(1k)
9
5
(1l)
71 (2l)
10[c]
11[c]
10
10
R5 =H(1m)
71 (2m)
78 (2n)
R5 =Me (1n)
[a] Mixture of geometrical isomers. [b] E/Z=85:15. [c] NEt3 (10 mol%)
was added. Reaction time was 8 h. TMS=trimethylsilyl.
Concerning the seven-membered-ring formation of this
tandem cyclization, we initially assumed that the reaction
proceeded through Cope rearrangement of the divinylazir-
idine intermediate C[11] (see Scheme 3) as in the previously
investigated tandem cyclization of 3-siloxy-1,3,9-trien-7-ynes
3 catalyzed by complexes of the composition W(CO)5(L)
(Scheme 2).[12] However, it was a big surprise that comparison
of the reactions of (E)-propenyl derivative 1o and (Z)-
propenyl derivative 1p with those of the corresponding
carbon analogues clearly indicated the opposite stereospeci-
ficity of the seven-membered-ring formation (Scheme 2). The
reaction of (E)-propenyl derivative 1o afforded the desired
bicyclic compound 2o as a single diastereomer, the relative
stereochemistry of which was trans between the phenyl and
methyl groups, while the stereochemistry of the product 2p
derived from (Z)-propenyl derivative 1p was cis
(Scheme 2).[13]
When the reactions of (E)-propenyl derivative 1o and
(Z)-propenyl derivative 1p were carried out under thermal
2
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Scheme 4. Structural difference between zwitterions of the thioimidate
and the carbon analogues.
intermediate E[17] occurred to give the methoxylated tricyclic
indole 5m as a single diastereomer (Scheme 5). The stereo-
selectivity of the reaction could be explained by the selective
Scheme 2. Stereoselectivity of the tandem cyclization. TIPS=triisopro-
pylsilyl.
conditions (THF, reflux) using [Cr(CO)5(thf)] as a catalyst,
the same stereoselectivity as under photoirradiation condi-
tions was observed. Thus, photoirradiation did not affect the
stereoselectivity of the seven-membered-ring formation.[14]
We currently believe that the product 2 was produced not
through the divinylaziridine intermediate C but through 1,7-
electrocyclization[15] (conrotatory under thermal conditions)
of zwitterionic intermediate B based on the stereochemistry
of the product (Scheme 3).
Scheme 5. 1,4-Addition of nucleophiles to a,b-unsaturated carbene
complex intermediate. Conditions: a) [Cr(CO)6] (30 mol%), MeOH
(50 equiv), toluene, hn, 8 h; b) [Cr(CO)6] (30 mol%),
=
CH2 C(OTBS)OMe (10 equiv), MeOH (3 equiv), toluene, hn, 8 h. The
ratio given for 6n is the stereoselectivity concerning the -CH2CO2Me
group with the major enantiomer shown here. TBS=tert-butyldimethyl-
silyl.
attack of MeOH from the opposite face of the phenyl
substituent. This method was applicable to stereoselective
construction of three contiguous chiral centers. The reaction
of aniline derivative 1n containing a (Z)-propenyl moiety
afforded the methoxylated tricyclic indole 5n as a single
diastereomer.[18] An a,b-unsaturated carbene complex inter-
mediate, the relative stereochemistry of which was cis
between the phenyl and methyl groups, was generated by
1,7-electrocyclization (conrotatory) and the selective 1,4-
addition of MeOH from the opposite face of the phenyl and
methyl substituents. Furthermore, a carbon nucleophile could
also be employed in this reaction. By carrying out the reaction
of 1m and 1n with O-methyl-O-(tert-butyldimethylsilyl)ke-
tene acetal using [Cr(CO)6] (30 mol%) under photoirradia-
tion in the presence of MeOH as a proton source, tricyclic
indoles 6m and 6n were obtained with high stereoselectivity.
In summary, we have developed the chromium(0)-cata-
lyzed tandem cyclization of a,b-unsaturated thioimidates 1,
Scheme 3. Proposed mechanism.
It is likely that the present reaction could not give the
divinylaziridine intermediate C, because the zwitterionic
intermediates B have the planar structure between the
alkenyl metal moiety and the thioiminium moiety in contrast
to the carbon analogues, where no double-bond character
À
existed at the C C bond that is derived from the silyl enol
ether moiety in the zwitterionic intermediate D (Scheme 4).
On the contrary, in the case of the present reaction, electro-
cyclization was possible because of the presence of the C N
=
double-bond character of the thioimidate moiety of the
zwitterionic intermediate B (Scheme 4).[16]
Interestingly, when the reaction of aniline derivative 1m
was carried out in the presence of MeOH, stereoselective 1,4-
addition of MeOH to a,b-unsaturated carbene complex
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occurred easily and there seemed to be no difference in
reactivity between Z and E isomer. See the Supporting Infor-
mation (8).
which contain an enyne moiety; the cyclization proceeded
through 1,7-electrocyclization of the zwitterionic intermedi-
ates. This reaction provides a new method for the diastereo-
selective synthesis of highly useful functionalized 1-
azabicyclo[5.3.0]decane derivatives 2, which constitute the
basic skeleton of stemona alkaloids.
[8] For recent reviews on gold-mediated homogeneous catalysis,
see: a) H. Huang, Y. Zhou, H. Liu, Beilstein J. Org. Chem. 2011,
7, 897 – 936; b) F. López, J. L. MascareÇas, Beilstein J. Org.
Chem. 2011, 7, 1075 – 1094.
[9] When the reaction of thioimidate 1a was carried out with
[Cr(CO)6] (10 mol%) in the presence of 2a or 1,4-diphenyl-2-
methylthio-1-azabuta-1,3-diene, the rate of conversion of 1a
became lower. Furthermore, in the reaction of 2a with
[Cr(CO)6] under photoirradiation, the complex that was
formed by the coordination of chromium to the sulfur atom
was observed. For details, see the Supporting Information (7.1,
7.2).
[10] We reported one example of a similar reaction of imines, where
the reaction proceeded without the thio substituent owing to the
facile ring closure of the rigidity of the aromatic substrate, see:
a) H. Kusama, Y. Suzuki, J. Takaya, N. Iwasawa, Org. Lett. 2006,
8, 895 – 897. See also; b) H. Kusama, J. Takaya, N. Iwasawa, J.
Am. Chem. Soc. 2002, 124, 11592 – 11593; c) J. Takaya, H.
Kusama, N. Iwasawa, Chem. Lett. 2004, 33, 16 – 17; d) H.
Kusama, Y. Miyashita, J. Takaya, N. Iwasawa, Org. Lett. 2006,
8, 289 – 292; e) J. Takaya, Y. Miyashita, H. Kusama, N. Iwasawa,
Tetrahedron 2011, 67, 4455 – 4466.
Experimental Section
General procedure:
A mixture of a,b-unsaturated thioimidate
1 (0.1 mmol) and [Cr(CO)6] (0.002–0.01 mmol) in THF (1 mL) was
stirred for 8–12 h under photoirradiation (250W super high-pressure
Hg lamp). The reaction mixture was concentrated under reduced
pressure. The residue was purified by preparative thin layer
chromatography (PTLC; hexane/AcOEt = 19:1) to give the product
2.
Received: February 23, 2012
Published online: && &&, &&&&
Keywords: alkaloids · chromium · homogeneous catalysis ·
.
synthetic methods · tandem cyclizations
[11] M. Zora, J. Org. Chem. 2005, 70, 6018 – 6026.
[12] a) H. Kusama, Y. Onizawa, N. Iwasawa, J. Am. Chem. Soc. 2006,
128, 16500 – 16501; b) Y. Onizawa, M. Hara, T. Hashimoto, H.
Kusama, N. Iwasawa, Chem. Eur. J. 2010, 16, 10785 – 10796, see
also: c) H. Kusama, H. Yamabe, Y. Onizawa, T. Hoshino, N.
Iwasawa, Angew. Chem. 2005, 117, 472 – 474; Angew. Chem. Int.
Ed. 2005, 44, 468 – 470; d) Y. Onizawa, H. Kusama, N. Iwasawa,
J. Am. Chem. Soc. 2008, 130, 802 – 803; e) H. Kusama, Y. Karibe,
Y. Onizawa, N. Iwasawa, Angew. Chem. 2010, 122, 4365 – 4368;
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Karibe, R. Imai, Y. Onizawa, H. Yamabe, N. Iwasawa, Chem.
Eur. J. 2011, 17, 4839 – 4848.
[13] The structure and relative stereochemistry of 2p were confirmed
by X-ray analysis after hydrolysis of the N,S-keteneacetal
moiety. See the Supporting Information (6.1).
[14] Photoirradiation is important for facile generation of the
catalytically active, coordinatively unsaturated species from
[Cr(CO)6] at ambient temperature. See the Supporting Infor-
mation (7.3).
[1] For recent reviews of 1-azabicyclo[n.3.0] ring systems, see:
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1937; b) R. A. Pilli, M. C. F. de Oliveira, Nat. Prod. Rep. 2000,
17, 117 – 127.
[3] For a recent review of the strategies toward 1-azabicyclo-
[5.3.0]decane skeleton, see: R. Alibꢀs, M. Figueredo, Eur. J. Org.
Chem. 2009, 2421 – 2435, and references therein.
[4] a) T. Taniguchi, G. Tanabe, O. Muraoka, H. Ishibashi, Org. Lett.
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127, 15712 – 15713.
[5] Thioimidates were chosen as substrates because of their higher
stability compared to imidates and higher nucleophilicity
compared to imines.
[15] For reviews of 1,7-electrocyclization, see: a) M. Nyerges, J. Tóth,
P. W. Groundwater, Synlett 2008, 1269 – 1278; b) T. M. V. D.
Pinho e Melo, Eur. J. Org. Chem. 2006, 2873 – 2888; c) G.
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[7] The reactions of 1a–1j, 1m, 1n were examined using a mixture
of Z and E isomers concerning the thioimidate moiety. It was
confirmed that isomerization of the zwitterionic intermediates
[16] In the reaction of w-acetylenic thioimidate 7 with [W(CO)6]
(3 equiv) in toluene under photoirradiation, the zwitterionic
complex 8 was obtained.
We have succeeded in obtaining a single crystal that was suitable
for X-ray analysis for the CF3-substituted complex by recrystal-
4
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lization from pentane/CH2Cl2 in a nitrogen atmosphere. For
details, see the Supporting Information (8).
Crystal data: monoclinic, P21/n, a = 11.4793(4), b = 16.9217(6),
c = 11.5189(4) Š, a = 90.00, b = 106.2280(10), g = 90.008, R-
factor= 3.37 (%).
[17] For an example of 1,4-addition to an a,b-unsaturated carbene
complex, see: E. Nakamura, K. Tanaka, T. Fujimura, S. Aoki,
P. G. Williard, J. Am. Chem. Soc. 1993, 115, 9015 – 9020. For
reviews on catalytic generation of a,b-unsaturated carbene
complex intermediates, see reference [6], see also; K. Saito, H.
Sogou, T. Suga, H. Kusama, N. Iwasawa, J. Am. Chem. Soc. 2011,
133, 689 – 691, and references therein.
[18] The relative configuration of 5 n was determined by observation
of NOE spectra. For details, see the Supporting Information
(6.3).
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Communications
Synthetic Methods
Y. Karibe, H. Kusama,
N. Iwasawa*
&&&& — &&&&
Chromium(0)-Catalyzed Tandem
Cyclization of a,b-Unsaturated
Thioimidates Containing an Enyne Moiety
Bicyclic: The diastereoselective synthesis
of functionalized 1-azabicyclo-
[5.3.0]decane derivatives proceeds
through 1,7-electrocyclization of the
zwitterionic intermediates that are
formed in the cyclization of a,b-unsatu-
rated thioimidates containing an enyne
moiety (see scheme). Furthermore 1,4-
addition of nucleophiles to a,b-unsatu-
rated carbene complex intermediates was
also achieved.
6
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