Cascade reaction including a formal [5?+?2] cycloaddition by use of alkyne-Co2(CO)6 complex

Article abstract of DOI:10.1016/j.tetlet.2019.01.045

A new cascade reaction including formal [5 + 2] cycloaddition was developed. Treatment of homocinnamyl alcohol and Co₂(CO)₆-complexed arylpropynal with BF₃·OEt₂ resulted in the generation of hydrobenzocyclohepta

Full text of DOI:10.1016/j.tetlet.2019.01.045

Accepted Manuscript
Cascade reaction including a formal [5+2] cycloaddition by use of alkyne-
Co2(CO)6 complex
Yuki Sakata, Eiko Yasui, Megumi Mizukami, Shinji Nagumo
PII:
S0040-4039(19)30063-2
https://doi.org/10.1016/j.tetlet.2019.01.045
TETL 50578
DOI:
Reference:
Tetrahedron Letters
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20 November 2018
8 January 2019
18 January 2019
Please cite this article as: Sakata, Y., Yasui, E., Mizukami, M., Nagumo, S., Cascade reaction including a formal
[5+2] cycloaddition by use of alkyne-Co2(CO)6 complex, Tetrahedron Letters (2019), doi: https://doi.org/10.1016/
j.tetlet.2019.01.045
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Cascade reaction including a formal [5+2]
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Yuki Sakataa , Eiko Yasuia , Megumi Mizukamib and Shinji Nagumoa

1
Tetrahedron Letters
Cascade reaction including a formal [5+2] cycloaddition by use of alkyne-Co2(CO)6
complex
Yuki Sakataa , Eiko Yasuia , Megumi Mizukamib and Shinji Nagumoa
a Department of Chemistry and Life Science, Kogakuin University, Nakano 2665-1, Hachioji, Tokyo 192-0015, Japan.
b
Department of Medicinal Chemistry, Faculty of Pharmaceutical Sciences, Hokkaido University of Science, Maeda 7-15-4-1, Teine, Sapporo, Hokkaido 006-
8585, Japan.
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A new cascade reaction including formal [5+2] cycloaddition was developed. Treatment of
homocinnamyl alcohol and Co2(CO)6-complexed arylpropynal with BF3･OEt2 resulted in the
generation of hydrobenzocycloheptafuran having an alkyne-Co2(CO)6 complex. The reaction
consists of 5-membered ring selective Prins cyclization and subsequent Friedel-Crafts
cyclization. The cascade reaction was applied to a further multi-step cascade cyclization, which
resulted in the formation of more complex polycyclic hydrofurans.
Available online
Keywords:
formal [5 + 2] cycloaddition
alkyne-Co2(CO)6 complex
seven-membered carbocycle
Prins cyclization
cascade cyclization
Since new two bonds are formed in one operation,
being formed in one operation, this reaction can be categorized as
a formal [3+2] cycloaddition. We then expected as an extension
of the cascade reaction that arylpropanals might react with
homocinnamyl alcohol to afford furans fused with a cycloheptane
ring. However, it was thought that the planning would not be so
easy because an intramolecular Friedel-Crafts reaction of
arylpropanal might occur alone to give indanol. It should be
possible to avoid such a five-membered ring formation by using
the substrates with alkyne-Co2(CO)6 complex. We report here a
new cascade reaction involving formal [5+2] cycloaddition of
Co2(CO)6-complexed propynals linked to a benzene ring and/or
alkene and homocinnamyl alcohol
cycloaddition reactions continue to attract much interest as a
method for rapid construction of highly substituted cyclic
molecules. Notably, a [5+2] cycloaddition has the potential for
synthesis of cycloheptane derivatives found in a number of
natural products.1 This type of cycloaddition necessitates an
elaborate design of C5-component. In pioneer works in this field,
pentadienyl cation derived from some kind of quinone (perezone
type)2 and oxidopyrylium ylide3 were utilized as the coupling
partner. The reactions generate bridgehead skeleton involving a
seven-membered carbocycle. Thereafter, Wender et al. developed
a transition-metal catalyzed [5+2] cycloaddition using
vinylcyclopropane and -systems.4 The cycloaddition proceeds
concomitantly with ring cleavage of a cyclopropane to afford a
non-bridgehead-type polysubstituted cycloheptane molecules.
Tanino et al. reported a more straightforward construction of
non-bridgehead-type cycloheptanes on the basis of a formal
[5+2] cycloaddition utilizing the characteristics of alkyne-
Co2(CO)6 complex.5 The cobalt complex fits the cyclization of a
medium-membered ring due to the large bond angle6 and
stabilizes the neighboring carbocation.7 We also reported
aromatic cyclizations of an iminium ion and a vinylepoxide to
generate molecules containing medium rings with the aid of
alkyne-Co2(CO)6 complex.8,9 Incidentally, we recently reported a
novel cascade reaction consisting of a five-membered selective
Prins cyclization of benzaldehydes with a homocinnamyl alcohol
and subsequent intramolecular Friedel-Crafts reaction (Scheme
Scheme 1. Cascade reaction consisting of 5-membered selective
Prins cyclization and intramolecular Friedel-Crafts reaction.
Prior to cascade reaction utilizing alkyne-Co2(CO)6 complex,
we investigated the reaction of arylpropanals 4 with 2 (Table 1).
Treatment of phenylpropanal 4a with BF3･OEt2 at 0 oC in
CH2Cl2 resulted in complex mixture. Aldehyde 4b having 3,5-
dimethylbenzene reacted well with 2 to generate cis-
benzocycloheptafuran 6b (62%) and its trans-isomer 5b (26%)
after separation by column chromatography with silica gel. The
cascade reaction of 4c and 2 proceeded more smoothly to afford a
mixture of cis-isomer 6c and its trans-isomer 5c with a ratio of
1).10,11 Based on the characteristic feature of two C-C bonds
———
 Corresponding author. Tel.: +0-000-000-0000; fax: +0-000-000-0000; e-mail: author@university.edu

2
Tetrahedron
2.3 : 1 in 91% yield after 30 min. The reaction of 4d having
can be ascertained by several silyl-Prins reactions. Silyl-Prins
reaction of allylsilane 9 generates tetrahydrofuran 11 with 2,3-
cis-selectivity (Scheme 3).12 Also, oxidative silyl-Prins reaction
of allylsilane 12 proceeds cis-selectively to afford 13.13
Incidentally, Sakaguchi and Ohfune et al. reported that also silyl-
Prins cyclization of allenylsilane 14 with several aldehydes
including 4a proceeded cis-selectively in most cases.14 The
stereoselection in the last example was explained by a plausible
mechanism through a synclinal transition state model in which an
oxonium ion takes a thermodynamically stable E-configuration.15
We adapted their explanation to the stereochemical trend
observed in the cascade reaction of 4 and 2 including 5-
membered selective Prins cyclization as shown in Scheme 4.
Thus, cyclization of an oxonium ion formed by condensation of 4
and 2 favors a transition state (E) with an E-form oxonium ion
over another one (F).
3,4,5-trimethoxybenzene under the same conditions resulted in
the generation of tetrahydrofuranyl indane 7d (20%) in addition
to a mixture of 6d and 5d (64%, 6d : 5d = 2.6 : 1). Compound 7d
was a mixture of two stereo isomers, but their relative
configurations have not been determined yet. In the case of 4e
having 3,5-dimethoxybenzene, the combined yield of 6e and 5e
was very low and 7e became the main product. Formation of 7
seems to increase as reactivity of the aromatic ring increases. The
stereochemistry of major stereo isomer 6c was determined by
NOE NMR measurement of a mixture with 5c as shown in Table
1. On the other hand, the stereochemistry of minor isomer 5c was
determined by synthetic transformation from 17c and the details
are to be mentioned later (Scheme 5).
Table 1. Reaction of arylpropanal with homocinnamyl alcohol
Scheme 3. Several silyl Prins cyclizations generating hydrofuran
The formation of 5 and 6 should start with the occurrence of
oxonium ion A by condensation of 2 and 4 (Scheme 2, route a).
Subsequently, 5-ring selective Prins cyclization of A proceeds to
give hydrofuranyl-benzyl cation B, which is further converted to
two isomeric products 5 and 6. On the other hand, the formation
of 7 should start with intramolecular Friedel-Crafts reaction of 4
as we anticipated in advance (Scheme 2, route b). Subsequently,
dehydroxylation of the resulting C occurs to generate benzylic
cation D, which is further converted to 7 by alkene attack of 2
concomitant with hydrofuran ring formation. In fact, separately
synthesized indanol 8e was confirmed to react with 2 to give 7e
under the same acidic conditions.
Scheme 4. Stereochemical consideration for reaction of 2 and 4c
The side reaction triggered by intramolecular Friedel-Crafts
reaction of arylpropanals 4d and 4e was a serious problem of the
cascade reaction. We thus tried the cascade reaction using cobalt-
complexed arylpropynals 16 because alkyne-Co2(CO)6 complex
was known to resist a five-membered ring formation due to its
wide bond angle of ca. 140o (Table 2).16 Treatment of 16a and 2
with BF3･OEt2 at 0 oC resulted in the formation of a complex
mixture (Entry 1). However, the cascade reaction of 16b and 2
proceeded gradually under the same conditions to give a mixture
of 17b and 18b in 39% yield with a ratio of 30 : 1 after 3 h (Entry
2). Furthermore, when the reaction was performed at room
temperature, the mixture was obtained in 62% yield with a ratio
of 7 : 1 (Entry 3). Aldehyde 16c reacted smoothly with 2 under
the same conditions to give trans-Co2(CO)6-complexed
Scheme 2. Tentative mechanism for the formation of 5-7
cycloheptafuran 17c and cis-one 18c in 92% as a mixture with a
ratio of 3 : 1 (at 0 oC, 1.5 h) or 4 : 1 (at rt, 0.5 h) (Entry 4 and 5).
These stereo isomers were separated by careful column
chromatography, and their relative configurations were
determined by NOE correlations as shown in Table 2.
It should be noted that somewhat preferential formation of cis-
fused products 6 was observed in all cascade reactions. The
stereochemical trend is attributed to the cis/trans selectivity of
Prins cyclization. A general stereochemical trend of 5-membered
ring selective Prins cyclization of disubstituted homoallyl alcohol

3
Interestingly, the formation of 17c seemed to be more selective at
the early stage according to careful TLC monitoring of the
reaction mixture. We thus quenched the reaction mixture of 16c
and 2 after being stirred in the presence of BF3･OEt2 at 0 oC for 3
min, at which time much aldehyde and homocinnamyl alcohol
remained. The ratio of 17c and 18c at that time was 5 : 1. This
finding indicated that the Prins cyclization at the first step
kinetically favored trans-formation over cis-one with a ratio of
>5 : 1 and then trans-product 17c was gradually isomerized to
cis-one 18c via a Co2(CO)6-complexed propargyl cation formed
by C-O bond cleavage of the hydrofuran ring.17 In order to
confirm such an isomerization, isolated 17c was treated with BF3
･OEt2 in CH2Cl2 at room temperature for 3 h. As a result, 17c
and 18c were obtained as a mixture with a ratio of ca. 2.5 : 1. On
the other hand, isomerization of 18c proceeded gradually to
afford a mixture of 17c and 18c with the same ratio after 12 h.
The cascade reaction of 16d and 16e having more reactive
benzene rings proceeded smoothly at 0 oC to generate mixtures of
17d-e and 18d-e with ratios of 7 : 1 and 4 :1 (Entry 6 and 7). It
should be noted that the cascade reaction of 16 shows the
opposite stereochemical preference from that of 4. Sakaguchi and
Ohfune et al. mentioned their silyl-Prins reaction would take also
antiperiplanar transition state to give a mixture of the cis- and
trans-isomers in the case of using 3,4-dimethoxybenzaldehyde
which has an electron donating group (Scheme 3).14 In the
cascade cyclization of 16, alkyne-Co2(CO)6 complex would guide
antiperiplanar transition state (G) shown in right side of Table 2
to afford trans-isomer 17. Two C-C bond formations might occur
almost simultaneously since the hydrogen at the benzyl position
and the neighboring hydrogen remained trans configuration.
NOE correlations that major product 20a has trans-cis-trans
configurations for hydrogens at the sequential 12a-6a-7-7a
bonds, whereas 22a has trans-trans-trans configurations.
These results indicate that both double bonds in 19a and 2
connect with other parts in an anti-parallel fashion in the
formation of both 20a and 22a. Also aldehydes 19b-j having
various substituted benzene rings reacted with 2 to generate
trans-cis-trans products 20b-j in 40-70% yields. The reactions
of 19c, 19d and 19g afforded slight amounts of regional
isomers 21c, 21d and 21g. The preferential formation of 20
might be explained by a nearly concerted mechanism through
a transition state H involving antiperiplanar coformation
between an oxonium ion and a styrene double bond.
Table 3. Further multi-step cascade reaction of 19
Table 2. Reaction of 16 with homocinnamyl alcohol 2
Finally, we transformed Co2(CO)6-complexed polycyclic
hydrofuran 17c to the saturated cycloheptafuran 5c in order to
confirm the relative configuration of 5c that had not been
detected by NOE correlation (Table 1). Treatment of 17c with
(EtO)3SiH in the presence of bis(trimethylsilyl)acetylene at 60 oC
resulted in decomplexation of Co2(CO)6-complex concomitant
with regioselective hydrosilylation to give vinylsilane 23 in 85%
yield.20 Desilylation of 23 with TBAF proceeded smoothly to
afford 24 in 98% yield. Catalytic hydrogenation of 24 with Pd/C
in MeOH afforded 5c in 85% yield, of which 1H and 13C NMR
spectroscopic data accorded with those of minor product obtained
in the cascade reaction of 4c and 2. Also decomplexation of 20h
concomitant with hydrosilylation gave vinylsilane 25 in 80%
yield upon treatment with (EtO)3SiH and
It is well known that the cobalt complex activates neighboring
alkenes.18 With the expectation of establishing a new method for
construction of a polycyclic framework by a single operation,
we tried a more multi-step cascade cyclization of aldehydes
19 having an internal alkene linked to alkyne-Co2(CO)6
complex and a terminal benzene ring. A survey of optimized
conditions was first carried out using 19h. Treatment of 19h
with BF3･OEt2 (3 eq. or 6 eq.) in CH2Cl2 at 0 oC afforded 20h
in 37% or 36% yield with recovery of starting materials after
3 hours. Meanwhile, the reaction with TMSOTf (3 eq. or 6
eq.) proceeded more rapidly to give 20h in 51% or 49% yield
after 20 min. Interestingly, maximum yield was obtained by
using TMSOTf (3 eq.) and BF3･OEt2 (3 eq.) (Table 3, entry
8).19 With the best conditions in hand, the scope of the cacade
reactions was examined using various aldehydes (Table 3).
The reaction of 19a with 2 afforded polycyclic furan 20a
(41%) and 22a (8%). It was confirmed from observation of
bis(trimethylsilyl)acetylene at 60 oC. Compound 25 was
efficiently transformed to 27 through a removal of silyl group
and the subsequent catalytic hydrogenation.

4
Tetrahedron
References and notes
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Chem. Front. 2018, 5, 1217-1228. (b) Ylijoki, K. E. O.; Stryker,
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J. G.; Sable, H. Z. In Selective Organic Transformations;
Thyagarajan, B. S., Ed.; Wiley-Interscience: New York, 1972;
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3. Wender, P. A.; McDonald, F. E. J. Am. Chem. Soc. 1990, 112,
4956-4958.
4. Wender, P. A.; Takahashi, H.; Witulski, B. J. Am. Chem. Soc.
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5. (a) Mitachi, K.; Yamamoto, T.; Kondo, F.; Shimizu, T.;
Miyashita, M.; Tanino, K. Chem. Lett. 2010, 39, 630-632. (b)
Tanino, K.; Kondo, F.; Shimizu, T.; Miyashita, M. Org. Lett.
2002, 4, 2217-2219. (c) Tanino, K.; Shimizu, T.; Miyama, M.;
Kuwajima, I. J. Am. Chem. Soc. 2000, 122, 6116-6117.
6. Sly, W. G. J. Am. Chem. Soc. 1959, 81, 18-20.
7. Teobald, B. J. Tetrahedron 2002, 58, 4133-4170.
8. Nagumo, S.; Ishii, Y.; Sato, G.; Mizukami, M.; Imai, M.;
Kawahara, N.; Akita, H. Tetrahedron Lett. 2009, 50, 26-28.
9. Mizukami, M.; Saito, H.; Higuchi, T.; Imai, M.; Bando, H.;
Kawahara, N.; Nagumo, S. Tetrahedron Lett. 2007, 48, 7228-
7231.
10. (a) Suzuki, Y.; Niwa, T.; Yasui, E.; Mizukami, M.; Miyashita, M.;
Nagumo, S. Tetrahedron Lett. 2012, 53, 1337-1340. (b) Sakata,
Y.; Yasui, E.; Takatori, K.; Suzuki, Y.; Mizukami, M.; Nagumo,
S. J. Org. Chem. 2018,83, 9103-9118.
11. For other examples of cascade reaction initiated by the Prins
cyclization, (a) Kato, M.; Saito, A. Org. Lett. 2018, 20,
4709−4712. (b) Abas, H.; Linsdall, S. M.; Mamboury, M.; Rzepa,
H. S.; Spivey, A. C. Org. Lett. 2017, 19, 2486-2489. (c) Barbero,
A.; Diez-Varga, A.; Pulido, F. J. Org. Lett. 2013, 15, 5234-5237.
(d) Reddy, B. V. S.; Borkar, P.; Yadav, J. S.; Sridhar, B.; Grée, R.
J. Org. Chem. 2011, 7677-7690. (e) Spivey, A. C.; Laraia, L.;
Bayly, A. R.; Rzepa, H. S.; White, A. J. P. Org. Lett. 2010, 12,
900-903.
12. Peng, F.; Hall, D. G. J. Am. Chem. Soc. 2007, 129, 3070-3071.
13. Chen, C.; Mariano, P. S. J. Org. Chem. 2000, 65, 3252.
14. Okada, T.; Shimoda, A.; Shinada, T.; Sakaguchi, K. Ohfune, Y.
Org. Lett. 2012, 14, 6130-6133.
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117, 10391-10392.
16. Tanino et al. reported the total synthesis of ingenol utilizing their
original seven-membered carbocyclization of a substrate including
alkyne-Co2(CO)6 complex. The cyclization notably proceeded in
advance of a five-membered ether ring formation. See, (a) Tanino,
K.; Onuki, K.; Asano, K.; Miyashita, M.; Nakamura, T.;
Takahashi, Y.; Kuwajima, I. J. Am. Chem. Soc. 2003, 125, 1498-
1500. (b) Nakamura, T.; Matsui, T.; Tanino, K.; Kuwajima, I. J.
Org. Chem. 1997, 62, 3032-3033.
Scheme 5. Synthetic transformation of Alkyne-Co2(CO)6
Complex
In conclusion, we developed several cascade reactions
including formal [5+2] cycloaddition. These reactions consist of
5-membered ring selective Prins cyclization and subsequent
seven-membered ring formation by nucleophilic attack of
benzene rings or alkene. In the case of using arylpropanal,
whether the reaction goes well or not was found to depend on the
reactivity of the benzene ring. 3,5-Dimethoxyphenylpropanal 4e
mainly underwent intramolecular Friedel-Crafts reaction prior to
attack by homocinnamyl alcohol 2. The resulting intermediate 8e
immediately reacted with 2 to give an unexpected product 7e.
Alkyne-Co2(CO)6 complex was useful for solving the serious
problem. The cascade reaction of 16e resulted in the generation
of benzocycloheptafuran 17e and 18e in an excellent combined
yield. The reaction of 16 selectively formed trans-fused isomers
17 unlike the cycloheptafuran formation of 4 that proceeded cis-
selectively. A more multi-step cascade cyclization of 19
expectedly proceeded to afford polycyclic furans 20 as major
products in moderate to good yields in total. These new cascade
cyclizations including formal [5+2] cycloaddition would be
applicable to target-oriented synthesis.
17. Olier, C.; Gastaldi, S.; Gil, G.; Bertrand, M. P. Tetrahedron Lett.
2007, 48, 7801-7804.
18. Nagasawa, T.; Kitamura, M.; Suzuki, K. Synlett 1995, 1183-1186.
19. For an unique effect by mixing BF3･OEt2 and TMSOTf, Horita,
K.; Sakurai, Y.; Nagasawa, M.; Yonemitsu, O. Chem. Pharm.
Bull. 1997, 45, 1558-1572.
Acknowledgments
Financial support from the Ministry of Education, Culture,
Sports, Science and Technology, Japan (a grant from the
Strategic Research Foundation Grant-aided Project for Private
Universities (S1411005), a Grant-in-Aid for Scientific Research
(B) (No. 19350027) and Advanced Promotion Research Program
for Education of Graduate School) is gratefully acknowledged.
We wish to dedicate this study to Dr. Kiyoshi Sakai, Professor
Emeritus of Kyushu University, on the occasion of his 88th
birthday (BEIJU).
20. Lin, Y.-T.; Lin, F.-Y.; Isobe, M. Org. Lett. 2014, 16, 5948-5951.
Supplementary Material
Supplementary data to this article can be found online at

5
Highlights
・Cascade cyclization of Co2(CO)6-complexed
arylpropynal gave benzocycloheptafuran.
・It consists of 5-menbered ring selective Prins and
Friedel-Crafts cyclizations.
・The Co2(CO)6-complex suppresses a ring
formation of aldehyde itself.
・Polycyclic furans are obtained by using Cobalt-
complexed alkynal linked to alkene.