Intramolecular substitution reaction of alkylidene-lithium carbenoids: Regioselective synthesis of indenes

Article abstract of DOI:10.1002/1522-2675(200210)85:10<3130::AID-HLCA3130>3.0.CO;2-E

Intramolecular substitution reaction of geminal dibromo alkenes proceeds to afford indenes, dihydronaphthalenes, dihydrofurans, and dihydropyran via in sint generated lithium alkylidene carbenoids, which have a carbon or oxygen nucleophilic moiety. This reaction provides a regioselective method for the preparation of polysubstituted indenes.

Full text of DOI:10.1002/1522-2675(200210)85:10<3130::AID-HLCA3130>3.0.CO;2-E

3130
Helvetica Chimica Acta Vol. 85 (2002)
Intramolecular Substitution Reaction of Alkylidene-Lithium Carbenoids:
Regioselective Synthesis of Indenes
by Hideyuki Yanagisawaa), Kasei Miuraa), Mitsuru Kitamuraa), Koichi Narasaka*a), and Kaori Andob)
a) Department of Chemistry, Graduate School of Science, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku,
Tokyo 113-0033 Japan (fax: ‡81-3-5800-6891; e-mail: narasaka@chem.s.u-tokyo.ac.jp)
b) College of Education, University of the Ryukyus, Nishihara-cho, Okinawa 903-0213 Japan
Dedicated to Professor Dieter Seebach on the occasion of his 65th birthday
Intramolecular substitution reaction of geminal dibromo alkenes proceeds to afford indenes, dihydronaph-
thalenes, dihydrofurans, and dihydropyran via in situ generated lithium alkylidene carbenoids, which have a
carbon or oxygen nucleophilic moiety. This reaction provides a regioselective method for the preparation of
polysubstituted indenes.
Introduction. Recently, we reported the unusual intramolecular substitution at
the sp2-N-atom of oximes [1]. For example, O-methylsulfonyl oximes with an active
CH group are converted to cyclic imines by treatment with 1,8-diazabicyclo[5.4.0]un-
dec-7-ene (DBU; Scheme 1) [1d,e]. Experimental investigation on the stereospeci-
ficity [1d,e] and a theoretical study [2] revealed that this reaction proceeds via
an unusual Sn2-type reaction at the sp2-N-atom of oximes, i.e., backside attack at the
sp2-N-atom.
Scheme 1
It was expected that Sn2 reaction would also occur at alkylidene-metal carbenoids,
due to the structural similarity between oximes and alkylidene carbenoids, both of
which have an electron pair (negative charge) and a leaving group on an sp2-atom.
Actually, there are several examples of nucleophilic substitution of alkylidene-lithium
carbenoids. For instance, inversion of the configuration is observed to some extent
when an optically active chloroalkene is treated with t-BuLi [3]. Benzofurans are

Helvetica Chimica Acta Vol. 85 (2002)
3131
obtained from o-hydroxy-b,b-dichlorostyrenes by treatment with BuLi [4]. Although
these results suggest an Sn2 mechanism at the carbenoid sp2-C-atom, other possibilities
still remain. In this communication, we describe the study of intramolecular
nucleophilic substitution of lithium sp2 carbenoids and the utilization of this reaction
for organic synthesis.
Results and Discussion. 4,4-Dibromobut-3-en-1-ol 1a was treated with 2.2 mol
amounts of BuLi to generate alkylidene-lithium carbenoid A, and dihydrofuran 2a was
obtained after quenching with MeOH. After some experiments, 2a was obtained in
81% yield when the reaction was carried out in toluene at room temperature and
quenched with MeOH (Table 1, Run 1). Although both isomers of alkylidene
carbenoid A would be generated by lithiation and only the (E)-isomer of A could
participate in the Sn2 mechanism, it is known that (E)/(Z)-isomerization of alkylidene-
lithium carbenoids occur with co-existence of LiBr [5]. Since deuterated [D]-2a (D
50%) was obtained by quenching with MeOD, the cyclization definitely afforded
alkenyllithium B. Dialkyldihydrofuran 2b was also obtained from 1b in 82% yield
(Run 2). In addition to the dihydrofurans, dihydropyran 2c was prepared from 1c in
48% yield along with acetylene 3c1) and alcohol 4c2) (Run 3).
Table 1. Nucleophilic Substitution at Alkylidene Carbenoids with O Nucleophiles
Yield/%
Run
1
n
R
2
3
4
1
2
3
1a
1b
1c
1
1
2
Ph
81
82
48
7
0
23
0
0
12
PhCH2CH2
Ph
1
)
Acetylene 3 was produced as a consequence of 1,2-migration of alkylidene carbenoid A (Fritsch-
Buttenberg-Wiechell rearrangement) [6].
Alcohol 4 was probably formed by the addition reaction of BuLi to ketone, which was generated via the
intramolecular hydride attack at carbenoid A [7].
2
)

3132
Helvetica Chimica Acta Vol. 85 (2002)
At this stage, three mechanisms were considered for this cyclization reaction,
namely Sn2-type substitution, insertion of a carbene intermediate, and an addition-
elimination reaction (Scheme 2).
Scheme 2
The addition-elimination mechanism was excluded, because 1a was recovered
completely, without forming the desired bromodihydrofuran 5, when 1a was treated
with NaH or lithium diisopropylamide (LDA) (Scheme 3). By the following experi-
ment, alkylidene carbene insertion to the lithium alkoxide was also neglected as a
major reaction pathway. It is known that the alkylidene carbenes, generated via the
corresponding 1-diazo-4-(trimethylsilyloxy)but-1-ene derivatives, readily undergo
intramolecular insertion to the SiÀO bond to give 2,3-dihydro-5-(trimethylsilyl)furans
in good yields [8]. Dihydrofuran 7, however, was produced in only 10% yield on
treatment of dibromo(trimethylsilyloxy)-alkene 6 with a slight excess of BuLi
(Scheme 4). These results imply that the cyclization may proceed according to Sn2
mechanism analogously to the substitution reaction of oximes, although the detailed
reaction mechanism is still unclear3).
Scheme 3
3
)
Efforts are presently underway to clarify the reaction mechanism by theoretical methods.

Helvetica Chimica Acta Vol. 85 (2002)
3133
Scheme 4
To explore synthetic utility of this substitution reaction, preparation of indene
derivatives was examined by means of 1,1-dibromo-3-(2-bromophenyl)propene
derivatives 8 (Table 2). Because of the high nucleophilicity of carbanions C, the
cyclization proceeded smoothly at À 908 in THF to give 1H-indenes 9a d in 85 86%
yield (Runs 1 4). Furthermore, quenching with electrophiles such as PhCHO and
BrCF2CF2Br afforded polysubstituted indenes 10 and 11 regioselectively (Runs 5 10).
Thus, the generated (1H-inden-3-yl)lithiums D4) apparently existed without isomer-
ization of the CˆC bond at À 908, which is in contrast to the behavior of (1H-inden-1-
yl)lithiums. Generally, the reaction of indenyllithiums having substituents with an
electrophile is prone to afford a mixure of isomers as a result of isomerization5).
Although indenes are known as precursors of indenyl ligands such as Kaminsky-
type catalysts [9], there are only few reports on regioselective synthesis of
polysubstituted indenes. As a consequence, the present method offers a pathway to
(1H-inden-3-yl)lithium to provide useful synthetic method for regioselectively poly-
substituted indenes.
The construction also of six-membered rings was accomplished by this substitution
reaction. Dihydronaphthalenes 13 15 were obtained in good yields from 1-bromo-2-
(4,4-dibromo-3-mehylbut-3-enyl)benzene (12) (Table 3).
Conclusions. Five- or six-membered rings are constructed via the intramolecular
substitution reaction at the C-atom of alkylidene-lithium carbenoids, which are
generated by the treatment of geminal dibromoalkenes with alkyllithium. Dihydrofur-
ans and dihydropyran were obtained when alkoxides were employed as nucleophiles. In
addition, 1H-indenes and 1,2-dihydronaphthalenes were produced when carbanions
were used as nucleophiles. Furthermore, the alkenyllithium intermediates generated
during cyclization react regioselectively with electrophiles to afford polysubstituted
indenes and dihydronaphtalenes.
This research was supported by a Grant-in-Aid for Scientific Research on Priority Areas (A) −Exploitation
of Multi-Element Cyclic Molecules× from the Ministry of Education, Culture, Sports, Science and Technology,
Japan.
4
)
To the best of our knowledge, no (1H-inden-3-yl)lithium was reported. For the addition reaction of 1H-
inden-3-yl anion and electrophile in the gas phase, see [11].
Inseparable isomers of adducts were obtained when 1H-indene 9b was treated with t-BuLi to generate
(1H-inden-1-yl)lithium, followed by addition of PhCHO at À 908. For the isomerization of (1H-inden-1-
yl)lithium, see [10].
5
)

3134
Helvetica Chimica Acta Vol. 85 (2002)
Table 2. Preparation of 1H-Indenes 9 11
Run
R1
R2
R3
8
Electrophile
E
Product
Yield/%
1
2
3
4
5
6
7
8
9
H
MeO
H
H
H
MeO
H
H
MeO
H
H
H
CF3
H
H
H
H
H
H
H
H
H
Me
H
H
Me
H
H
Me
8a
8b
8c
8d
8a
8b
8d
8a
8b
8d
MeOH
MeOH
MeOH
MeOH
PhCHO
PhCHO
PhCHO
BrCF2CF2Br
BrCF2CF2Br
BrCF2CF2Br
H
H
H
H
9a
9b
9c
85
85
86
86 a)
84
87
87
83
80
63
9d
CH(OH)Ph
CH(OH)Ph
CH(OH)Ph
Br
Br
Br
10a
10b
10d
11a
11b
11d
10
H
a) A mixture of 9d and 9d' in a ratio of 5 : 1.
Table 3. Preparation of 1,2-Dihydronaphthalenes 13 15
Run
Electrophile
E
Product
Yield/%
1
2
3
MeOH
PhCHO
BrCF2CF2Br
H
13
14
15
76
77
77
CH(OH)Ph
Br

Helvetica Chimica Acta Vol. 85 (2002)
3135
Experimental Part
General. Toluene was distilled and dried over molecular sieves (4 ä). Anh. THF was purchased from Kanto
Chemical Co., Inc., and dried over molecular sieves (4 ä). BuLi (1.6m hexane soln.) was purchased from Aldrich
Co., Inc. and used after titration. Prep. TLC: Wakogel B-5F. M.p.: uncorrected. IR Spectra: Horiba FT 300-S
spectrophotometer. 1H- (500 MHz) Spectra: Bruker DRX-500 and Bruker AVANCE-500 spectrometers in
CDCl3 with CHCl3 (for 1H, d ˆ 7.24) as the internal standard. 13C-NMR (125 MHz) Spectra: were recorded on
Bruker DRX-500 and Bruker AVANCE-500 spectrometers in CDCl3 with CDCl3 (for 13C, d ˆ 77.00) as the
internal standard. Elemental analyses were carried out at The Elemental Analysis Laboratory, Department of
Chemistry, Faculty of Science, The University of Tokyo.
Typical Procedure for the Substitution Reaction with an O-Nucleophile. To a soln. of dibrom-olakenol 1a
(123 mg, 0.38 mmol) in toluene (3.8 ml) was added BuLi (1.6m in hexane, 0.52 ml, 0.81 mmol) at r.t., and the
mixture was stirred for 30 min. The reaction was quenched with MeOH. The mixture was extracted with Et2O
(3 Â 10 ml). The combined org. layers were dried (MgSO4) and concentrated under reduced pressure. The crude
product was purified by prep. TLC to afford 2a (50 mg, 0.32 mmol, 82% yield).
2,3-Dihydro-4-methyl-2-phenylfuran (2a). Colorless oil. IR (KBr): 2964, 1728, 1454, 1022, 997, 758, 700.
1H-NMR: 1.66 1.67 (m, Me); 2.49 2.54 (m, 1 H, CH2); 2.94 3.00 (m, 1 H, CH2); 5.50 (dd, J ˆ 8.3, 10.6,
PhCH); 6.16 (m, CˆCH); 7.25 7.29 (m, 1 arom. H); 7.31 7.35 (m, 4 arom. H). 13C-NMR: 11.1; 42.8; 82.5;
109.0; 125.5; 127.5; 128.5; 139.5; 143.5. Anal. calc. for C11H12O: C 82.46, H 7.55; found: C 82.30, H 7.63.
Typical Procedure for the Substitution Reaction with C Nucleophile. To a soln. of dibromo-alkene 8a
(184 mg, 0.50 mmol) in THF (5.0 ml) was added BuLi (1.6m in hexane, 0.74 ml, 1.2 mmol) at À 908, and the
mixture was stirred for 30 min. The reaction was quenched with MeOH. The mixture was extracted with Et2O
(3 Â 10 ml). The combined org. layers were dried (MgSO4) and concentrated under reduced pressure. The crude
product was purified by prep. TLC to afforded 9a (55 mg, 0.42 mmol, 85% yield).
2-Methyl-1H-indene (9a). Colorless oil. IR (KBr): 1616, 1464, 1392, 750, 715. 1H-NMR: 2.15 2.15 (m, Me);
3.29 (m, CH2); 6.48 (m, CˆCH); 7.09 (ddd, J ˆ 1.3, 7.3, 7.3, arom. H); 7.19 7.25 (m, 2 arom. H); 7.35 7.37 (m,
1 arom. H). 13C-NMR: 16.7; 42.7; 119.7; 123.2; 123.4; 126.2; 127.1; 143.3; 145.9; 146.0.
REFERENCES
[1] a) H. Kusama, Y. Yamashita, K. Narasaka, Chem. Lett. 1995, 5; b) H. Kusama, K. Uchiyama, Y. Yamashita,
K. Narasaka, Chem. Lett. 1995, 715; c) H. Kusama, Y. Yamashita, K. Uchiyama, K. Narasaka, Bull. Chem.
Soc. Jpn. 1997, 70, 965; d) K. Uchiyama, M. Yoshida, Y. Hayashi, K. Narasaka, Chem. Lett. 1998, 607; e) M.
Yoshida, K. Uchiyama, K. Narasaka, Heterocycles 2000, 52, 681.
[2] S. Mori, K. Uchiyama, Y. Hayashi, K. Narasaka, E. Nakamura, Chem. Lett. 1998, 111.
[3] a) M. Duraisamy, H. M. Walborsky, J. Am. Chem. Soc. 1984, 106, 5035; b) M. Topolski, M. Duraisamy, J.
Rachon, J. Gawronski, K. Gawronska, V. Goedken, H. M. Walborsky, J. Org. Chem. 1993, 58, 546.
[4] M. Topolski, J. Org. Chem. 1995, 60, 5588.
[5] a) G. Kˆbrich, F. Ansari, Chem. Ber. 1967, 100, 2011; b) G. Boche, J. C. W. Lohrenz, Chem. Rev. 2001, 101,
697.
[6] E. T. Chernick, S. Eisler, R. R. Tykwinski, Tetrahedron Lett. 2001, 42, 8575, and refs. cit. therein.
[7] A. Oku, T. Harada, K. Hattori, Y. Nozaki, Y. Yamaura, J. Org. Chem. 1988, 53, 3089.
[8] K. Miwa, T. Aoyama, T. Shioiri, Synlett 1994, 461.
[9] −Metallocenes: Synthesis Reactivity Applications× Vol. 1, 2 Eds. A. Togni, R. L. Halterman, Wiley-VCH,
Weinheim, 1998.
[10] W. Spaleck, M. Antberg, J. Rohrmann, A. Winter, B. Bachmann, P. Kiprof, J. Behm, W. A. Herrmann,
Angew. Chem., Int. Ed. 1992, 31, 1347.
[11] K. M. Broadus, S. Han, S. R. Kass, J. Org. Chem. 2001, 66, 99.
ReceivedMay 27, 2002