Formation of Seven-Membered Carbocycles via 7-endo Mode Cyclization of Lithioheptatrienes

Article abstract of DOI:10.1021/acs.orglett.6b02956

The highly selective synthesis of triene derivatives was achieved by a zirconocene-mediated three-component coupling reaction, and the trienes were efficiently subjected to 7-endo mode cyclization. The reaction of unsymmetrical zirconacyclopentadienes prepared from two different alkynes with N-bromosuccinimide (NBS) followed by treatment with allyl halides in the presence of CuCl afforded the corresponding heptatrienes in good yields. When the trienes reacted with an organolithium reagent, 7-endo mode cyclization occurred smoothly to give the corresponding cycloheptadiene.

Full text of DOI:10.1021/acs.orglett.6b02956

Letter
pubs.acs.org/OrgLett
Formation of Seven-Membered Carbocycles via 7-endo Mode
Cyclization of Lithioheptatrienes
Ken-ichiro Kanno,† Eri Igarashi,† Yuki Mizukami,† Kiyohiko Nakajima,∥ Zhiyi Song,†
and Tamotsu Takahashi*,†
†Institute for Catalysis and Graduate School of Life Science, Hokkaido University, Kita-ku, Sapporo 001-0021, Japan
∥Department of Chemistry, Aichi University of Education, Igaya, Kariya 448-8542, Japan
S
* Supporting Information
ABSTRACT: The highly selective synthesis of triene
derivatives was achieved by a zirconocene-mediated three-
component coupling reaction, and the trienes were efficiently
subjected to 7-endo mode cyclization. The reaction of
unsymmetrical zirconacyclopentadienes prepared from two
different alkynes with N-bromosuccinimide (NBS) followed by
treatment with allyl halides in the presence of CuCl afforded the corresponding heptatrienes in good yields. When the trienes
reacted with an organolithium reagent, 7-endo mode cyclization occurred smoothly to give the corresponding cycloheptadiene.
ntramolecular carbometalation to multiple C−C bonds is a
Ifundamental tool for the construction of carbocyclic
skeletons.1,2 A number of metal-mediated or catalyzed
carbocyclization reactions have been developed as synthetic
methodologies. That said, some exceptions have been reported,
where the intramolecular carbometalation reaction proceeds in
exo fashion.1 For example, when heptenylmetal 1 is cyclized,
the 6-exo product 2 is obtained exclusively or predominantly
(Scheme 1), and the 7-endo cyclization product 3 is not formed.
corresponding 7-endo cyclization product, cycloheptadiene 8 in
high yield (Scheme 2).
Scheme 2. 7-endo Mode Cyclization of Bromoheptatrienes 7
Scheme 1. Intramolecular Carbometalation
We recently reported a selective coupling reaction of
different alkynes to give linear oligoene derivatives.7 This
method prompted us to synthesize suitable substrates to
examine the above-mentioned novel carbolithiation reaction.
Scheme 3 shows the synthesis of the cyclization precursors.
Scheme 3. Synthesis of Bromoheptatriene 7a
Our group previously reported zirconium-mediated eight-
membered ring formation.3 The key point of our strategy was
the introduction of a conjugated diene moiety into the
substrate to decrease the flexibility of the molecule; otherwise,
no eight-membered ring product was obtained at all. We
hypothesized that this methodology would also be applied to
the regioselective intramolecular carbometalative cyclization of
4 to affording the 7-endo product 6.
Two different alkynes were selectively coupled on Zr using
Cp2ZrEt2 to give the corresponding unsymmetrical zirconacy-
clopentadiene 9a, as we reported previously.8 Bromination of
one Zr−C bond by addition of NBS9 followed by the reaction
with allyl chloride in the presence of CuCl furnished the
corresponding bromoheptatriene 7a in high yield after the usual
workup.3,10
Herein, we report 7-endo carbolithiation4−6 of 1-bromohep-
tatrienes 7, which can be conveniently prepared from
zirconacyclopentadienes. To a THF solution of bromotriene
7 was added 2 equiv of t-BuLi at −78 °C, and the mixture was
stirred for 1 h. Acid treatment of the mixture gave the
Received: September 30, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b02956
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 1 summarizes the results of the synthesis of
bromoheptatrienes 7 from various substrates and their 7-endo
entry 6). Silyl-substituted cycloheptadiene 8g was synthesized
in 63% yield (Table 1, entry 7). Fused seven- and six-
membered-ring carbocycle 8h was synthesized by this method
(Table 1, entry 8). The structure of cycloheptadiene 8a was
unambiguously confirmed by X-ray crystallographic analysis
(see the Supporting Information).
Table 1. 7-endo Carbolithiation Reaction Using Various
Trienes
When intermediate 8a-Li was treated with electrophiles, the
corresponding coupling products 10 were obtained in good
yields (Table 2). Silylated cycloheptadiene 10a was obtained by
Table 2. Reaction of 8a-Li with Various Electrophiles
a
NMR yields.
the simple addition of chlorotrimethylsilane. Cu-mediated
allylation and alkylation reactions successively proceeded to
give 10b and 10c, respectively. Benzylated product 10d was
verified by X-ray analysis, which showed the cis configuration
between the introduced benzyl group and the ethyl group at the
7-position (see the Supporting Information).11
Here three reaction pathways are presented for this 7-endo
carbolithiation reaction (Scheme 4). At the beginning of the
Scheme 4. Plausible Reaction Pathway
a
b
NMR yields. Isolated yields are given in parentheses. Ar = p-FC6H4.
c
d
The reaction was carried out at 50 °C. Cycloheptadiene 7f was
obtained as a mixture with the minor isomer 1,2,3,4-tetraethylcyclo-
hepta-1,4-diene in a 4:1 ratio.
mode cyclization. When triene 7a was treated with t-BuLi, the
corresponding cycloheptadiene 8a was obtained in high yield
(Table 1, entry 1). The deuterated product 8a(D) was obtained
by treatment with D2O instead of hydrolysis. This result
showed the position of Li in the final product 8a-Li before
hydrolysis. Two butyl groups were introduced by using 5-
decyne instead of 3-hexyne (Table 1, entry 2). The phenyl
groups could be replaced with p-tolyl and p-fluorophenyl
groups, which gave the corresponding seven-membered-ring
products 8c and 8d (Table 1, entries 3 and 4). Heteroaromatic
rings were also applicable (Table 1, entry 5). Non-arylated
substrate 7f cyclized effectively, but the product 8f was obtained
as a 4:1 mixture of double-bond positional isomers (Table 1,
reaction, Li/Br exchange proceeds to form alkenyllithium I.
After that, addition of the Li−C bond on C1 to the C6−C7
double bond in 7-endo-trig mode affords lithiated carbocycle II
(Scheme 4, path a). The subsequent sigmatropic [1,5]-
hydrogen shift affords 7-endo product 8a-Li. On the other
hand, intermediate I can be converted into III via abstraction of
the acidic proton on C5 (Scheme 4, path b). The allylic
migration of lithium forms intermediate IV, and intramolecular
carbolithiation in 7-endo-trig mode affords product 8a-Li. The
B
DOI: 10.1021/acs.orglett.6b02956
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
cyclization step might be considered as a symmetry-allowed
eight-electron electrocyclic reaction. As the third pathway,
cyclization of intermediate III by metallo-ene reaction to afford
VI is also possible (Scheme 4, path c).12
regioselective carbolithiation giving 8 was achieved by the
introduction of a conjugated diene moiety into the starting
compound. On the other hand, treatment of 7 with a palladium
catalyst gave 6-exo cyclization product 19.
As shown in Scheme 5, when dehalogenated triene 11 was
employed for the reaction, the same cycloheptadiene 8a was
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b02956.
■
S
Scheme 5. Reaction of Trienes 11 and 12 with t-BuLi
Detailed experimental procedures and compound char-
acterization data (PDF)
Crystallographic data for 8a (CIF)
Crystallographic data for 10d (CIF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: tamotsu@cat.hokudai.ac.jp.
ORCID
obtained in 73% yield. Furthermore, chlorinated heptatriene 12
gave the corresponding cycloheptatriene 13 in high yield. With
these trienes, lithiation would occur at C5 instead of C1. These
results strongly indicate the existence of intermediate III.
To show the importance of the conjugate diene moiety,
cyclization reactions of compounds 14 and 16 were examined,
as shown in Scheme 6. When iododiene 14 was subjected to
Tamotsu Takahashi: 0000-0003-4728-6547
Notes
The authors declare no competing financial interest.
REFERENCES
■
(1) For a review, see: (a) Yet, L. Chem. Rev. 2000, 100, 2963.
(b) Ojima, I.; Tzamarioudaki, M.; Li, Z.; Donovan, R. J. Chem. Rev.
1996, 96, 635. (c) Negishi, E.; Coperet, C.; Ma, S.; Liou, S.-Y.; Liu, F.
Chem. Rev. 1996, 96, 365.
Scheme 6. Effect of the Conjugated Diene System on the
Intramolecular Carbolithiation
(2) (a) Alder, K.; Pascher, F.; Schmitz, A. Ber. Dtsch. Chem. Ges. B
1943, 76, 27. (b) Lehmkuhl, H. Bull. Soc. Chim. Fr., Part II 1981, 87.
(3) Takahashi, T.; Kotora, M.; Kasai, K.; Suzuki, N.; Nakajima, K.
Organometallics 1994, 13, 4183.
(4) For reviews of intramolecular carbolithiation, see: (a) Clayden, J.
In Organolithiums: Selectivity for Synthesis; Tetrahedron Organic
Chemistry Series, Vol. 23; Pergamon Press: Oxford, U.K., 2002; pp
273−335. (b) Bailey, W. F.; Ovaska, T. V. In Advances in Detailed
Reaction Mechanisms; Coxon, J. M., Ed.; JAI Press: Greenwich, CT,
1994; Vol. 3, pp 251−273. (c) Mealy, M. J.; Bailey, W. F. J. Organomet.
Chem. 2002, 646, 59. (d) Hogan, A.-M. L.; O’Shea, D. F. Chem.
Commun. 2008, 3839. (e) Lhermet, R.; Ahmad, M.; Hauduc, C.;
the same cyclization conditions, cyclization proceeded in 6-exo
mode to afford the corresponding cyclohexene 15. The same
reaction of iodotriene 16, however, gave the seven-membered-
ring product 17. These results clearly showed the importance of
the conjugated diene system for 7-endo mode cyclization.
Notably, the carbometalation of heptatrienes 7 gave not only
7-endo cyclization products but also 6-exo products when the
metal was changed. The reaction of 7a with a catalytic amount
of Pd(PPh3)4 afforded the 6-exo cyclization product 19 in 60%
yield, and no 7-endo product was observed (Scheme 7). The
organopalladium generated by initial oxidative addition is
coordinated to the C6−C7 double bond, and the subsequent
insertion gives intermediate 18 predominaltly.
Fressigne,
8105.
́
C.; Durandetti, M.; Maddaluno, J. Chem. - Eur. J. 2015, 21,
(5) (a) Bailey, W. F.; Nurmi, T. T.; Patricia, J. J.; Wang, W. J. Am.
Chem. Soc. 1987, 109, 2442. (b) Cheng, D.; Zhu, S.; Liu, X.; Norton, S.
H.; Cohen, T. J. Am. Chem. Soc. 1999, 121, 10241.
(6) For a present report of a 7-endo carbolithiation reaction, see:
Holmeide, A. K.; Skattebøl, L. Tetrahedron Lett. 2007, 48, 1357.
(7) Kanno, K.; Igarashi, E.; Zhou, L.; Nakajima, K.; Takahashi, T. J.
Am. Chem. Soc. 2008, 130, 5624.
(8) (a) Xi, Z.; Hara, R.; Takahashi, T. J. Org. Chem. 1995, 60, 4444.
(b) Takahashi, T.; Kageyama, M.; Denisov, V.; Hara, R.; Negishi, E.
Tetrahedron Lett. 1993, 34, 687.
(9) Ubayama, H.; Xi, Z.; Takahashi, T. Chem. Lett. 1998, 27, 517.
(10) Takahashi, T.; Kotora, M.; Kasai, K.; Suzuki, N. Tetrahedron
Lett. 1994, 35, 5685.
In conclusion, we have developed a highly selective 7-endo
mode cyclization using heptatrienes 7, which can be
conveniently prepared by zirconium-mediated reactions. The
(11) Formation of the anti products would cause steric hindrance
between the two substituents at C5 and C1. We assume that
diastereoselective introduction of electrophiles was achieved by the
steric effect.
Scheme 7. 6-exo Mode Cyclization of 6a with a Pd Catalyst
(12) The conversion of intermediate VI into 8a-Li seems to be very
fast. As we mentioned in Scheme 2, quenching the reaction with D2O
gave 8a(D) in which deuterium was introduced at C5 selectively. No
C1-deuterated product was observed in the studies.
C
DOI: 10.1021/acs.orglett.6b02956
Org. Lett. XXXX, XXX, XXX−XXX