Rh(I)-catalyzed formal [6 + 2] cycloaddition of 4-allenals with alkynes or alkenes in a tether

Article abstract of DOI:10.1021/ja203824v

Rh(I)-catalyzed formal [6 + 2] cycloaddition of allenal 6 having an alkyne or alkene in a tether proceeded smoothly, giving 5-8- and 6-8-fused bicyclic ketone derivatives 7 in good to excellent yields. It was also found that cyclization of enantiomerically enriched (S)-6a (94% ee) gave cyclic ketone derivative (S)-7a in high yield with reasonable chirality transfer (86% ee). This result indicates that this cyclization proceeds through stereoselective formation of rhodacycle H′ followed by insertion of a multiple bond.

Full text of DOI:10.1021/ja203824v

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Rh(I)-Catalyzed Formal [6 + 2] Cycloaddition of 4-Allenals with Alkynes
or Alkenes in a Tether
Yoshihiro Oonishi,* Akihito Hosotani, and Yoshihiro Sato*
Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan
S Supporting Information
b
Scheme 1. Rh(I)-Catalyzed Cycloadditions
ABSTRACT: Rh(I)-catalyzed formal [6 + 2] cycloaddition
of allenal 6 having an alkyne or alkene in a tether proceeded
smoothly, giving 5ꢀ8- and 6ꢀ8-fused bicyclic ketone
derivatives 7 in good to excellent yields. It was also found
that cyclization of enantiomerically enriched (S)-6a (94%
ee) gave cyclic ketone derivative (S)-7a in high yield with
reasonable chirality transfer (86% ee). This result indicates
that this cyclization proceeds through stereoselective for-
mation of rhodacycle H0 followed by insertion of a
multiple bond.
Scheme 2. Rh(I)-Catalyzed Cycloaddition through
Hydroacylation
ransition-metal-catalyzed [m + n] and/or [m + n + o]
cycloadditions represent an important class of reactions
T
because of their ability to construct complex polycyclic skeletons
in one reaction in a highly stereoselective1 and step-economical
fashion.2 Various types of cycloaddition (e.g., [4 + 1], [4 + 2],
[2 + 2 + 1], [2 + 2 + 2], etc.) using rhodium catalysts have been
extensively studied, and highly enantioselective variants have also
been developed.3 The trigger of most of the reactions is stereo-
selective formation of rhodacycle intermediate A via oxidative
cycloaddition of two CꢀC multiple bonds to a low-valent
rhodium complex, and cyclized products are produced through
insertion of a multiple bond (e.g., alkene, alkyne, carbon mon-
oxide, etc.) into intermediate A followed by reductive elimination
(Scheme 1).
Recently, another type of Rh(I)-catalyzed [m + n] cycloaddi-
tion has been reported by Fu,4 Tanaka,5 and Morehead,6 in which
oxo-rhodacycle intermediate C or D would be formed from
4-alkenals or 4-alkynals 1 through hydroacylation (eq 1 in Scheme 2).
In these reactions, C and D are in equilibrium via intemediate B,
and insertion of a CꢀC multiple bond into D would be more
favorable than that into C, affording cyclic compound 3 selec-
tively. In contrast to extensive studies of rhodium-catalyzed
hydroacylation7 of 4-alkenals8 and 4-alkynals,9 including the
reactivity of oxo-rhodacycle intermediates such as C and D4,6
and asymmetric variants,5 there has been no report on intramo-
lecular hydroacylation between allene and aldehyde or the reac-
tivity of oxo-rhodacycle intermediates derived from allenals toward
CꢀC multiple bonds (eq 2 in Scheme 2).10 In the reaction of
4-allenal 4 with a rhodium complex, it is possible to produce four
oxo-rhodacycle intermediates (EꢀH). If the stereoselective
formation of Eꢀ H and the reaction of the intermediate with
CꢀC multiple bonds were established, a novel [m + n] cycload-
dition producing a polycyclic skeleton containing a medium-
sized ring would be realized. We herein report a Rh(I)-catalyzed
11
formal [6 + 2] cycloaddition of 4-allenals with CꢀC mul-
tiple bonds.
In order to obtain preliminary information on oxo-rhodacycle
intermediates derived from alleneꢀaldehydes, hydroacylation
of allenal 4a using various rhodium complexes was examined
(Scheme 3). It was found that the use of [Rh(IMes)(cod)]ClO4,
Received: April 26, 2011
Published: June 13, 2011
r
2011 American Chemical Society
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dx.doi.org/10.1021/ja203824v J. Am. Chem. Soc. 2011, 133, 10386–10389
|

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Scheme 3. Rh(I)-Catalyzed Cyclization of Allenal 4a
Table 1. Reaction Using Various Rh(I) Complexes
yield (%)
8a
run
Rh(I) complex
time (h)
7a
1a
2a
3a
4
[Rh(IMes)(cod)]ClO4
2
16
16
5
76
23
14
72
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
27
c
[Rh(IiPr)(cod)]ClO4
c
[Rh(IPr)(cod)]ClO4
RhCl(PPh3)3
5b
[Rh(dppe)]ClO4
1
a Reactions were carried out using 6a (0.25 mmol) in ClCH2CH2Cl
(2.5 mL) and 10 mol % [Rh(NHC)(cod)]ClO4, which was generated
in situ from [Rh(NHC)(cod)]Cl (10 mol %) and AgClO4 (10 mol %).
b The reaction was carried out using 10 mol % [Rh(dppe)]ClO4
generated in situ from [Rh(dppe)(nbd)]ClO4 (10 mol %) under a
hydrogen atmosphere. c Structures of IiPr and IPr:
Scheme 4. Rh(I)-Catalyzed Formal [6 + 2] Cycloaddition
reactions of 6e, 6f, and 6g containing a heteroatom in the chain,
the corresponding heterocycles 7e, 7f, and 7g were produced in
good to excellent yields (runs 4ꢀ6). Elongation of the tether
between the alkyne and allene moieties by one carbon was
tolerated in the reaction, and 6ꢀ8-fused bicyclic ketone deriva-
tive 7h was produced from 6h in 70% yield (run 7). Notably, the
cyclization of substrates 6i and 6j having an alkene instead of an
alkyne in the tether also proceeded in a stereoselective manner to
afford the bicyclic ketones 7i and 7j in 86 and 72% yield,
respectively.16
A possible reaction mechanism for the formation of 7 from 6 is
shown in Scheme 5. Initially, a CꢀH bond of the aldehyde
moiety of 6 would be oxidatively added to the Rh(I) complex,
after which insertion of the CdC bond of the allene moiety into
the RhꢀH bond would give oxo-rhodacycle E0, which might
isomerizeto oxo-rhodacycle H0 via π-allylrhodium intermediateK.
Insertion of an alkyne or alkene in the tether into the RhꢀC bond
in H0 would occur, producing rhodacycle L, from which reductive
elimination would lead to bicyclic ketone derivative 7 along with
regeneration of the Rh(I) complex.17
On the other hand, the formation of bicyclic alcohol 8a from
6a using [Rh(dppe)]ClO4 as a catalyst (Table 1, run 5) cannot be
explained by the mechanism shown in Scheme 5, and a distinct
mechanism is shown in Scheme 6. Here, rhodacycle N would be
initially formed by oxidative cycloaddition of the alkyne part and
the external CdC bond of the allene moiety of 6a to the Rh(I)
complex.18 Insertion of the aldehyde moiety of 6a into N would
then give rhodacycle P. β-Hydride elimination from P followed
by reductive elimination from the resultant intermediate Q
would give bicyclic alcohol 8a.
which was generated from Rh(IMes)(cod)Cl and AgClO4, was
effective for the hydroacylation process, affording cyclic com-
pound 5a in 20% yield. This result indicates that oxo-rhodacycle
intermediate H (eq 2 in Scheme 2) was preferentially produced
from 4a to give 5a through reductive elimination from inter-
mediate H.
Encouraged by this result, we next turned our attention to the
reaction of the oxo-rhodacycle intermediate derived from 4-alle-
nals with a CꢀC multiple bond in a tether (Scheme 4). That is, if
insertion of a CꢀC multiple bond in a tether into the oxo-
rhodacycle intermediate H0 formed from 4-allenal 6 occurs,
bicyclic compound 7 containing an eight-membered ring should
be produced via a formal [6 + 2] cycloaddition in a one-pot
reaction.1f,11ꢀ13
Surprisingly, in contrast to the above-mentioned simple
hydroacylation of 4a, the cyclization of 6a with 10 mol %
[Rh(IMes)(cod)]ClO4 proceeded smoothly to give a 76% yield
of the desired bicyclic compound 7a,14 whose structure was un-
ambiguously determined by X-ray analysis (Table 1, run 1).15
Screening of Rh(I) complexes in the reaction of 6a was again carried
out, and the use of [Rh(IiPr)(cod)]ClO4 and [Rh(IPr)(cod)]ClO4
instead of [Rh(IMes)(cod)]ClO4 decreased the yield of bicyclic
ketone 7a to 23 and 14%, respectively (runs 2 and 3). On the other
hand, the reaction using RhCl(PPh3)3 also gave the bicyclic ketone
7a in 72% yield, although the reaction needed a longer time to reach
completion than that using [Rh(IMes)(cod)]ClO4. The cyclization
of 6a with 10 mol % [Rh(dppe)]ClO4 did not produce 7a at all but
instead gave bicyclic alcohol 8a in 27% yield.
Next, the cyclization of various substrates using [Rh(IMes)-
(cod)]ClO4 was examined (Table 2). The cyclizations of 6b and
6c having phenyl and TMS groups on the alkyne moiety gave 7b
and 7c in 71 and 90% yield, respectively (runs 1 and 2). Substrate
6d also afforded cyclized product 7d in 68% yield (run 3). In the
To obtain further insight into the reaction course for the for-
mation of bicyclic ketone 7, the reaction of deuterized substrate
6a-D (D content, 97%) with 10 mol % [Rh(IMes)(cod)]ClO4
was carried out at room temperature (Scheme 7). As a result, the
cyclic compound 7a-D having a deuterium on the alkene moiety
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Table 2. Rh(I)-Catalyzed Cyclization of Various Substratesa,b
Scheme 6. Possible Reaction Mechanism for the Formation
of 8a
Scheme 7. Cyclization of 6a-D Having a Deuterium on the
Aldehyde Moiety
a All of the reactions were carried out at 65 °C (except for runs 3, 8,
and 9) in a 0.1 M ClCH2CH2Cl solution of the substrate using 10
mol % [Rh(IMes)(cod)]ClO4, which was generated in situ from
[Rh(IMes)(cod)]Cl (10 mol %) and AgClO4 (10 mol %). b E = CO2Me.
c Run at room temperature. d Run at 50 °C.
Scheme 8. Rh(I)-Catalyzed Cyclization of (S)-6a
Scheme 5. Possible Reaction Mechanism for the Formation
of 7
We conceived that if chiral substrate 6a were to be employed
in this cyclization, cyclic compounds 7a having the corresponding
absolute configuration would be produced via a chirality transfer
process. That is, in the reaction of (S)-6a, the cyclic product (S)-7a
would be produced according to the mechanism in Scheme 5 as a
result of enantioselective formation of E0 followed by stereospecific
π-allyl rearrangement to H0. To investigate this hypothesis,
substrate (S)-6a was prepared in an enantiomerically enriched
form (94% ee). When (S)-6a was subjected to the above optimal
conditions (10 mol % [Rh(IMes)(cod)]ClO4, ClCH2CH2Cl,
65 °C), the desired product 7a was obtained in high yield in an
optically active form with a reasonable chirality transfer (86%
ee), and its absolute configuration was clearly assigned to be S
(Scheme 8).19 The results in Schemes 7and 8 strongly suggest that
the pathway for formation of 7 from 6 is Scheme 5, where the
formal [6 + 2] cycloaddition of allenals proceeds via hydroacyla-
tion followed by insertion of a CꢀC multiple bond in the tether
into the resultant oxo-rhodacycle.
was obtained in high yield and with high D content (97%). This
result is completely consistent with the mechanism in Scheme 5.
In summary, we have developed a Rh(I)-catalyzed formal
[6 + 2] cycloaddition of 4-allenals with alkynes or alkenes in a
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Journal of the American Chemical Society
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tether, giving 5ꢀ8- and 6ꢀ8-fused bicyclic ketone derivatives
in good to high yields. Furthermore, we have revealed that
this cyclization proceeds through the stereoselective formation of
oxo-rhodacycle H0 followed by insertion of a multiple bond. This
is the first example of an [m + n] cycloaddition triggered by the
formation of an oxo-rhodacycle from an alleneꢀaldehyde, and
further studies along this line, including applications to the
synthesis of natural products, are in progress.
(9) For Rh(I)-catalyzed hydroacylation of 4-alkynals, see: Tanaka,
K.; Fu, G. C. J. Am. Chem. Soc. 2001, 123, 11492.
(10) For Rh(I)-catalyzed intermolecular hydroacylation of allenes
and aldehydes, see: (a) Kokubo, K.; Matsumasa, K.; Nishinaka, Y.;
Miura, M.; Nomura, M. Bull. Chem. Soc. Jpn. 1999, 72, 303. (b) Osborne,
J. D.; Randell-Sly, H. E.; Currie, G. S.; Cowley, A. R.; Willis, M. C. J. Am.
Chem. Soc. 2008, 130, 17232. (c) Randell-Sly, H. E.; Osborne, J. D.;
Woodward, R. L.; Currie, G. S.; Willis, M. C. Tetrahedron 2009, 65, 5110.
(11) To date, there is only one example of Rh(I)-catalyzed [6 + 2]
cycloaddition of vinylcyclobutanones with CꢀC multiple bonds. See:
Wender, P. A.; Correa, A. G.; Sato, Y.; Sun, R. J. Am. Chem. Soc. 2000,
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(12) For Rh(I)-catalyzed cycloadditions to give eight-membered
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J. Am. Chem. Soc. 2002, 124, 2876. (b) Evans, P. A.; Robinson, J. E.;
Baum, E. W.; Fazal, A. N. J. Am. Chem. Soc. 2002, 124, 8782. (c)
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Evans, P. A.; Baum, E. W. J. Am. Chem. Soc. 2004, 126, 11150. (e)
Wegner, H. A.; de Meijere, A.; Wender, P. A. J. Am. Chem. Soc. 2005,
127, 6530. (f) Evans, P. A.; Baum, E. W.; Fazal, A. N.; Pink, M. Chem.
Commun. 2005, 63. (g) Wender, P. A.; Christy, J. P. J. Am. Chem. Soc.
2006, 128, 5354. (h) Wang, Y.; Wang, J.; Su, J.; Huang, F.; Jiao, L.; Liang,
Y.; Yang, D.; Zhang, S.; Wender, P. A.; Yu, Z.-X. J. Am. Chem. Soc. 2007,
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2007, 72, 799. (j) Huang, F.; Yao, Z.-K.; Wang, Y.; Wang, Y.; Zhang, J.;
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’ ASSOCIATED CONTENT
S
Supporting Information. Experimental details, charac-
b
terization data, NMR spectral charts, and X-ray crystal data
(CIF). This material is available free of charge via the Internet
at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
oonishi@pharm.hokudai.ac.jp; biyo@pharm.hokudai.ac.jp
’ ACKNOWLEDGMENT
This work was financially supported by Grants-in-Aid for
Young Scientists (B) (20790002) and Scientific Research (B)
(19390001) from the Japan Society for the Promotion of Science
(JSPS). Y.S. acknowledges the Fugaku Foundation for financial
support. A.H. thanks JSPS for providing a Research Fellowship
for Young Scientists.
(13) For the synthesis of cyclooctenone derivatives via Rh(I)-
catalyzed hydroacylation, see: (a) Aloise, A. D.; Layton, M. E.; Shair,
M. D. J. Am. Chem. Soc. 2000, 122, 12610. (b) Crꢀepin, D.; Dawick, J.;
€
Aissa, C. Angew. Chem., Int. Ed. 2010, 49, 620.
(14) When the reaction of 6a was carried out using 5 or 2 mol %
[Rh(IMes)(cod)]ClO4 under the same conditions except for the
catalyst loading, 7a was obtained in a yield of 72% (5 h) or 39%
(36 h), respectively.
(15) See the Supporting Information.
(16) The spectral data of 7i and 7j obtained by us were identical to
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