Construction of monocyclic eight-membered rings: Intermolecular rhodium(I)-catalyzed [6+2] cycloaddition of 4-allenals with alkynes

Article abstract of DOI:10.1002/anie.201206508

Rounding up: A Rh^I-catalyzed intermolecular cycloaddition of 4-allenals with alkynes has been developed that provides various monocyclic eight-membered rings in good to high yields in a stereoselective manner (see scheme). In addition, the chirality of the starting allene is transferred in this reaction, thereby giving optically active monocyclic eight-membered ring compounds. Copyright

Full text of DOI:10.1002/anie.201206508

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Angewandte
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DOI: 10.1002/anie.201206508
Cycloaddition
Construction of Monocyclic Eight-Membered Rings: Intermolecular
Rhodium(I)-Catalyzed [6+2] Cycloaddition of 4-Allenals with
Alkynes**
Yoshihiro Oonishi,* Akihito Hosotani, and Yoshihiro Sato*
Eight-membered carbocyclic compounds are widely found in
natural products that have unique medical and biological
activities.[1]
Transition-metal-catalyzed [m+n]
and/or
[m+n+o] cycloadditions (e.g., [4+4], [6+2], and [4+2+2])
are the most promising strategies for the construction of
polycyclic eight-membered-ring compounds.[2,3] However, the
construction of a simple but functionalized monocyclic eight-
membered carbocyclic system is still difficult even when using
transition-metal-catalyzed cycloadditions, and only a few
examples have so far been reported.[4] Herein we report
RhI-catalyzed intermolecular [6+2] cycloadditions of 4-alle-
nals and alkynes to give functionalized monocyclic eight-
membered-ring compounds.[4f,5–8]
Scheme 1. RhI-catalyzed intramolecular [6+2] cycloaddition. L=ligand.
We recently reported a RhI-catalyzed intramolecular
[6+2] cycloaddition of 4-allenals with tethered alkynes and
alkenes (Scheme 1).[5c] In this reaction, the rhodacycle A is
initially formed through hydroacylation[9] of the 4-allenal
À
moiety of 1 followed by insertion into a C C mutiple bond in
the tether to afford bicyclic eight-membered-ring compound
2.
We envisaged that if this intramolecular [6+2] cyclo-
addition could be expanded to an intermolecular reaction
between 4-allenal 3 and alkyne 4, monocyclic octanone
derivative 5 would be obtained (Scheme 2).[10] However, the
application of the intramolecular reaction to an intermolec-
ular version is generally difficult because of unfavorable
entropy and the high probability of side reactions (e.g.,
formation of 6 through hydroacylation of allenal 3[5c] and
formation of 7 by trimerization of alkyne 4).
Scheme 2. Plan for intermolecular [6+2] cycloaddition.
To examine the feasibility of the plan, the cyclization of 4-
allenal 3a with terminal alkyne 4a in the presence of various
RhI complexes was initially investigated (Table 1). The use of
[Rh(IMes)(cod)]ClO4, which is the most effective for the
above-mentioned intramolecular cyclization (Scheme 1),
afforded the desired eight-membered ring 5aa in 61% yield
along with six-membered ring 8aa in 19% yield (entry 1).[11] It
was found that [Rh(SIMes)(cod)]ClO4 was also effective in
this intermolecular reaction, and the cyclic compound 5aa
was produced selectively in 68% yield (entry 2). Lowering the
reaction temperature from room temperature to 08C
improved the yield of the eight-membered-ring compound
5aa up to 83% (entry 3). Furthermore, the catalyst loading
could be reduced to 2 mol% under similar reaction con-
ditions, thereby giving 5aa in 84% yield (entry 4). On the
other hand, [RhCl(PPh3)3] and [Rh(dppe)]ClO4 did not
promote the desired reaction at all, and the starting material
3a was recovered in 69% and 78% yield, respectively
(entries 5 and 6).
[*] Dr. Y. Oonishi, A. Hosotani, Prof. Dr. Y. Sato
Faculty of Pharmaceutical Sciences, Hokkaido University
Nishi 6, Kita 12, Kita-ku Sapporo 060-0812 (Japan)
.
E-mail: biyo@pharm.hokudai.ac.jp
Homepage: http://gouka.pharm.hokudai.ac.jp/FSC/jpn/page/
top_page.htm
[**] This work was financially supported by Grants-in-Aid for Young
Scientist (B) (no. 20790002) and for Scientific Research (B) (no.
23390001) from the Japan Society for the Promotion of Science
(JSPS) and also by a Grant-in-Aid for Scientific Research on
Innovative Areas “Molecular Activation Directed toward Straight-
forward Synthesis (no. 23105501)” from the Ministry of Education,
Culture, Sports, Science, and Technology (Japan). Y.O. acknowl-
edges the Akiyama Foundation for financial support. A.H. thanks
the JSPS for providing a Research Fellowship for Young Scientists.
Encouraged by these results, the cyclization of 4-allenal
3a with various terminal alkynes 4 was examined (Table 2).
Cyclization of 3a with terminal alkynes 4b, 4c, and 4d, having
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201206508.
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Table 1: Cyclization using various RhI complexes.
sulfonamide moiety, afforded 5ae in 61% yield as the sole
product (entry 4). On the other hand, the use of propargyl
alcohol (4 f) afforded 5af along with its regioisomer 5af’ in
yields of 64% and 10%, respectively (entry 5). When 1-
hexyne (4g) was used in this cyclization, the eight-membered
rings 5ag and 5ag’ were obtained in yields of 68% and 5%,
respectively, along with the six-membered ring 8ag in 11%
yield (entry 6). In the case of 4h, having an electron-with-
drawing group, 5ah and 5ah’ were obtained in yields of 56%
and 22%, respectively (entry 7).
Next, we investigated the cyclization of various 4-allenals
3 with terminal alkyne 4a (Table 3). Cyclizations of 3b–3d
with 4a proceeded in a stereoselective manner to afforded
eight-membered rings 5ba–5da in good to high yields
(entries 1–3). 4-Allenal 3e, having a TMS moiety on the
allene unit, gave the desired cyclic compound 5ea in 82%
yield as the sole product (entry 4). On the other hand, when
3 f, having a phenyl group on the allene part, was employed in
this cyclization, 5 fa and its regioisomer 5 fa’ were obtained in
yields of 51% and 23%, respectively (entry 5). The reaction
of 3g or 3h, having groups between the aldehyde and allene,
gave 5ga or 5ha in yields of 37% or 44%, respectively
(entries 6 and 7).[12]
Entry
RhI complex
Conditions
Yields [%][a]
5aa
8aa
[b]
1
2
3
4
[Rh(IMes)(cod)]ClO4
RT, 9 h
RT, 2 h
08C, 12 h
08C, 24 h
RT, 24 h
RT, 24 h
61 (57)
68
83 (81)
84
–
19 (17)
[b]
[b]
[c]
[Rh(SIMes)(cod)]ClO4
[Rh(SIMes)(cod)]ClO4
[Rh(SIMes)(cod)]ClO4
[RhCl(PPh3)3]
–
–
–
–
–
5[d]
6[d]
[e]
[Rh(dppe)]ClO4
–
[a] Yields were determined by NMR spectroscopy using 1,3,5-trime-
thoxybenzene as an internal standard. Yields of isolated products are
given in parenthesis. [b] Reactions were carried out using 10 mol%
[Rh(NHC)(cod)]ClO4 generated in situ from [Rh(NHC)(cod)]Cl
(10 mol%) and AgClO4 (10 mol%) in ClCH2CH2Cl (0.1m solution with
respect to 3a). [c] The reaction was carried out using 2 mol% [Rh-
(NHC)(cod)]ClO4 generated in situ from [Rh(NHC)(cod)]Cl (2 mol%)
and AgClO4 (2 mol%) in ClCH2CH2Cl (1.0m solution with respect to 3a).
[d] The starting material 3a was recovered in yields of 69% (entry 4) and
78% (entry 5). [e] The reaction was carried out using 10 mol% [Rh-
(dppe)]ClO4 generated in situ from [Rh(dppe)(nbd)]ClO4 (10 mol%)
under an atmosphere of hydrogen in ClCH2CH2Cl (0.1m solution with
respect to 3a). Bn=benzyl, MOM=methoxymethyl, IMes=1,3-dime-
sitylimidazol-2-ylidene, cod=cycloocta-1,5-diene, dppe=ethane-1,2-
diylbis(diphenylphosphane).
Table 3: Cyclizations using various 4-allenals.[a]
Entry Allenal 3
t [h]
Yield [%]
Table 2: Cyclizations using various alkynes.[a]
1
2
3
3b: (R1 =CH2OBn)
21 5ba: 69
18 5ca: 81
14 5da: 72
5ba’: –
5ca’: –
5da’: –
8ba: -
8ca: –
8da: –
3c: (R1 =CH2CH2Ph)
3d:
(R1 =CH2CH2NMeTs)
3e: (R1 =TMS)
3 f: (R1 =Ph)
4[b]
5[b]
1
1
5ea: 82
5 fa: 51
5ea’: –
5 fa’: 23
8ea: –
8 fa: –
Entry
Alkyne 4
t [h]
Yield [%]
5
5’
8
6[c]
15 5ga: 37
5ga’: –
8ga: 28
3g (R1 =CH2CH2OBn)
1
2
17
39
82
74
–
–
–
–
7[b]
21 5ha: 44
5ha’: –
8ha: 17
3[b]
24
75
–
–
3h (R1 =CH2CH2OBn)
4[b]
15
61
–
–
[a] All reactions were carried out in the presence of [Rh(SIMes)-
(cod)]ClO4 (10 mol%) in ClCH2CH2Cl (0.1m solution with respect to 3) at
08C. R2 =CH2OMOM. [b] Carried out at RT. [c] Hydroacylation product
6g was obtained in 8% yield. TMS=trimethylsilyl.
5[b]
15
64
10
–
6[c]
7[b]
46
4
68
56
5
11
–
It is noteworthy that gaseous acetylene can be utilized as
an alkyne in this cyclization. Thus, treatment of 3a with
10 mol% [Rh(SIMes)(cod)]ClO4 in an acetylene atmosphere
afforded the corresponding compound 5ai in 84% yield as the
sole product (Scheme 3). The reactions of 3c, 3d, and 3 f with
gaseous acetylene also proceeded smoothly, giving 5ci, 5di,
and 5 fi in high yields. The reactions of 3g and 3h also gave the
eight-membered-ring compounds 5gi and 5hi in yields of
74% and 62%, respectively.
22
[a] All reactions were carried out in ClCH2CH2Cl (0.1m solution with
respect to 3a). [b] Carried out at RT. [c] Carried out in 0.5m solution with
respect to 3a. Ts=toluene-4-sulfonyl.
a benzyloxy or benzoate moiety, proceeded in a steroselective
manner to give cyclic compounds 5ab–5ad in high yields
(entries 1–3). The cyclization of 3a with 4e, having a tethered
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Scheme 5. Mechanistic studies.
Scheme 3. Cyclization under acetylene. All reactions were carried out
in ClCH2CH2Cl (0.1m solution with respect to 3). [a] 8hi was obtained
in 12% yield.
subjected to the above optimal conditions (10 mol% [Rh-
(SIMes)(cod)]ClO4, ClCH2CH2Cl, 08C), the product 7a was
obtained in a high yield with a high chirality transfer
(89% ee). The absolute configuration of 7a was assigned to
be S [Eq. (2)],[14] which indicates that this reaction proceeds
through the enantioselective formation of C from the chiral
starting material, followed by a stereospecific p-allyl rear-
rangement to A’.
A possible reaction mechanism for the formation of 5 and
À
8 is depicted in Scheme 4. Initially, a C H bond of the
aldehyde moiety oxidatively adds to the RhI complex, and this
=
is followed by insertion of the C C bond of the allene moiety
to give the rhodacycle intermediate C. The rhodacycle
intermediate C would be in equilibrium with the rhodacycle
intermediate A’ through the p-allylrhodium intermediate D.
Eight-membered ring 5 would be produced through insertion
of terminal alkyne 4 into seven-membered rhodacycle
intermediate A’, while six-membered ring 8 would be
formed through insertion of teminal alkyne 4 into five-
membered rhodacycle intermediate C.[10] The cyclization of 3
afforded eight-membered ring 5 in preference to six-mem-
bered ring 8.[13] These results suggest that the equilibrium
between A’ and C lies towards A’ or that the rate of the
reaction between A’ and 4 is faster than that between C and 4.
In conclusion, we have succeeded in developing a RhI-
catalyzed intermolecular [6+2] cycloaddition between 4-
allenals and alkynes to afford various monocyclic eight-
membered-ring compounds in high yields. Eight-membered
rings are found in a wide variety of natural products, and the
present reaction should provide a new way for constructing
functionalized monocyclic eight-membered-ring compounds.
Further studies to determine the scope, limitations, and the
detailed mechanism of this reaction are in progress.
Received: August 13, 2012
Published online: October 11, 2012
Keywords: alkynes · allenals · cycloaddition ·
.
eight-membered rings · rhodium
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mechanistic insights into the present reaction (Scheme 5).
First, the reaction of [D]-3a, which was deuterated at the
À
formyl C H bond, with 4a gave the corresponding product
[D]-5aa, having a deuterium on the alkene moiety, in a high
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completely consistent with the mechanism shown in
Scheme 4. Second, when the substrate (S)-3a (91% ee) was
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11550 www.angewandte.org
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À
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[11] The structures of 5aa and 8aa were determined by 2D NMR
spectroscopy (see the Supporting Information).
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J. E. Robinson, E. W. Baum, A. N. Fazal, J. Am. Chem. Soc. 2002,
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[12] The six-membered ring 6g was produced through hydroacyla-
tion of 3g, and see also Ref. [5c].
[13] The same tendency has been observed for RhI-catalyzed
[4+2+2] cycloaddition reported by Wender and Christy, see
Ref. [7e].
[14] The absolute configuration of (S)-5aa was assigned by a modified
Mosherꢂs method after chemical degradation (see the Support-
ing Information).
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