Cyclopropylidene Derivatives via Low-Valent Titanium-Induced Dehydroxylative Debenzotriazolylation of 1- and 2-(Cyclopropylbenzotriazolyl)carbinols

Full text of DOI:10.1021/jo980617n

6710
J . Org. Chem. 1998, 63, 6710-6711
Notes
(LVT) induced dehydroxylative-debenzotriazolylation
Cyclop r op ylid en e Der iva tives via
Low -Va len t Tita n iu m -In d u ced
Deh yd r oxyla tive Deben zotr ia zolyla tion of
1- a n d
which was demonstrated8 to give alkenes in good to
excellent yields and stereoselectivities. This new meth-
odology exploits the synthetic advantages of benzotria-
zole9 to both (i) stabilize R-carbanions10 and (ii) act as a
leaving group.11 The starting cyclopropylbenzotriazole
derivatives are readily available via the well-prece-
dented12 cyclopropane ring formation by 1,3-intramolecu-
lar nucleophilic substitution cyclopropane ring formation.
2-(Cyclop r op ylben zotr ia zolyl)ca r bin ols
Alan R. Katritzky,* Weihong Du, J ulian R. Levell, and
J ianqing Li
Center for Heterocyclic Compounds,
Department of Chemistry, University of Florida,
Gainesville, Florida 32611-7200
Resu lts a n d Discu ssion
The reaction of 1-bromo-3-chloropropane (1a ) with
sodium benzotriazolate (from benzotriazole and sodium
hydroxide) in DMSO gives 97% of a mixture of 1- and
2-(3-chloropropyl)benzotriazole (2a and 2b) (see Scheme
1). 1-Bromo-3-chloro-2-methylpropane (1b) similarly
yields 99% of a mixture of 1- and 2-(2-chloromethyl)-
propylbenzotriazole (2c and 2d ). The 1- and 2-benzo-
triazolyl isomers are readily separated either by column
chromatography or by acidic extractive workup (see
Experimental Section). Upon treatment at -78 °C with
n-butyllithium (n-BuLi) or lithium diisopropylamide
(LDA), and warming to 20 °C, compounds 2 (whether as
pure 1- or 2-benzotriazolyl isomers, or as a mixture)
undergo quantitative conversion to 1- and/or 2-cyclopro-
pylbenzotriazoles 5. Compounds 5 can be isolated at this
stage, and 5a was characterized by 1H and 13C NMR, but
5 are generally treated with a second equivalent of
n-BuLi/LDA at -78 °C, followed by addition of an
aldehyde/ketone 4, to give carbinols 3a -j in good yields
(as either the 1- or the 2-benzotriazolyl isomers, or as a
mixture, depending upon the nature of the starting
product 2). Cyclopropylbenzotriazole13 and derivatives14
have been previously described and could be used in place
of the in situ generated cyclopropylbenzotriazoles used
herein, thus expanding the range of potentially accessible
(cyclopropylbenzotriazolyl)carbinol intermediates.
Received April 3, 1998
Available general routes to cyclopropylidene com-
pounds include phase transfer catalyzed Wittig reaction
of cyclopropylidenetriphenylphosphorane,1 Peterson ole-
fination,2 additions of carbenes to allenes,3 and Petasis
titanocene methodology.4 While elegant, these methods
often utilize unstable and/or not-readily accessible re-
agents and intermediates. The Wittig methodology is
useful for the introduction of an unsubstituted cyclopro-
pylidene moiety, due to the commercial availability of
cyclopropyltriphenylphosphonium bromide, but other cy-
clopropylidene derivatives are more difficult to access.5
Peterson olefination requires the synthesis of thioacetal/
1-(phenylthio)trimethylsilylcyclopropane intermediates.6
The titanocene methodology succeeds in the conversion
of readily enolizable aldehydes/ketones, as well as esters
and lactones, and the parent dicyclopropyltitanocene
intermediate is easily synthesized. However, complica-
tions arise when substituted cyclopropyl derivatives are
required.
Cyclopropylidene derivatives are increasingly impor-
tant as building blocks for organic synthesis,7 and new
routes for their synthesis are relevant. We herein report
an efficient synthesis of cyclopropylidene derivatives
utilizing our recently introduced low-valent titanium
In contrast to the facile rearrangements observed for
phenylthio-derived cyclopropane carbinols,15 the inter-
mediate carbinols 3a -j do not readily rearrange and
hydrolyze to the cyclobutanone derivatives 6. However,
LVT methodology readily achieves the simultaneous loss
of both the hydroxyl and benzotriazolyl moieties. Thus,
treatment of 1- or 2-(1-cyclopropylbenzotriazolyl)carbinol
(1) Stafford, J . A.; McMurry, J . E. Tetrahedron Lett. 1988, 29, 2531.
(2) (a) Cohen, T.; J ung, S.-H.; Romberger, M. L.; McCullough, D.
W. Tetrahedron Lett. 1988, 29, 25. (b) Cohen, T.; Sherbine, J . P.; Matz,
J . R.; Hutchins, R. R.; McHenry, B. M.; Willey, P. R. J . Am. Chem.
Soc. 1984, 106, 3245.
(3) (a) Creary, X.; Mehrsheikh-Mohammadi, M. E.; McDonald, S.
J . Org. Chem. 1987, 52, 3254. (b) Billups, W. E.; Lin, L.-J .; Casserly,
E. W. J . Am. Chem. Soc. 1984, 106, 3698. (c) Staley, S. W.; Norden, T.
D. J . Am. Chem. Soc. 1984, 106, 3699.
(4) Petasis, N. A.; Bzowej, E. I. Tetrahedron Lett. 1993, 34, 943.
(5) Ollivier, J .; Piras, P. P.; Stolle, A.; Aufranc, P.; de Meijere, A.;
Salau¨n, J . Tetrahedron Lett. 1992, 33, 3307.
(6) Cohen, T.; Sherbine, J . P.; Mendelson, S. A.; Myers, M. Tetra-
hedron Lett. 1985, 26, 2965.
(7) (a) Brandi, A.; Goti, A. Chem. Rev. 1998, 98, 589. (b) Kasatkin,
A.; Sato, F. Angew. Chem., Int. Ed. Engl. 1996, 35, 2848. (c) De Meijere,
A.; Teichmann, S.; Seyed-Mahdavi, F.; Kohlstruk, S. Liebigs Ann. 1996,
1989 and references therein. (d) Nemoto, H.; Shiraki, M.; Nagamochi,
M.; Fukumoto, K. Tetrahedron Lett. 1993, 34, 4939. (e) Zefirov, N. S.;
Kozhushkov, S. I.; Ugrak, B. I.; Lukin, K. A.; Kokoreva, O. V.; Yufit,
D. S.; Struchkov, Y. T.; Zoellner, S.; Boese, R.; De Meijere, A. J . Org.
Chem. 1992, 57, 701. (f) Reissig, H.-U. In The Chemistry of the
Cyclopropyl Group; J ohn Wiley & Sons: New York, 1987; Part 1, pp
307-374. (g) Rousseau, G.; Le Perchec, P.; Conia, J . M. Tetrahedron
1978, 34, 3475. (h) Trost, B. M.; Bogdanowicz, M. J . J . Am. Chem.
Soc. 1973, 95, 5311.
(8) (a) Katritzky, A. R.; Li, J . J . Org. Chem. 1997, 62, 238. (b)
Katritzky, A. R.; Cheng D.; Li, J . J . Org. Chem. 63, 3438. (c) Katritzky,
A. R.; Cheng D.; Henderson, S. A.; Li, J . J . Org. Chem. 1998, 63, 6704.
(9) Katritzky, A. R.; Denisko, O.; Lan, X. Chem. Rev. 1998, 98, 409.
(10) Katritzky, A. R.; Yang, Z.; Cundy, D. J . Aldrichimica Acta 1994,
27, 31.
(11) Katritzky, A. R.; Rachwal, S.; Hitchings, G. J . Tetrahedron
1991, 47, 2683.
(12) Tsuji, T.; Nishida, S.; The Chemistry of the Cyclopropyl Group;
J ohn Wiley & Sons: New York, 1987; Part 1, pp 375-445.
(13) Diehl, R. E.; Kendall, R. V. US Patent 4,086,242; Chem. Abstr.
1978, 89, 109512.
(14) (a) Katritzky, A. R.; Gordeev, M. F. Synlett 1993, 213. (b)
Katritzky, A. R.; Wu, H.; Xie, L.; J iang, J . J . Heterocycl. Chem. 1995,
32, 595.
(15) Krief, A.; Laval, A.-M. Acros Acta 1995, 49.
(16) Salaun, J .; Hanack, M. J . Org. Chem. 1975, 40, 1994.
S0022-3263(98)00617-3 CCC: $15.00 © 1998 American Chemical Society
Published on Web 09/02/1998

Notes
J . Org. Chem., Vol. 63, No. 19, 1998 6711
Ta ble 1. (Cyclop r op ylben zotr ia zolyl)ca r bin ols 3 a n d
Cyclop r op ylid en e Der iva tives 7
Sch em e 1
compound 3
compound 7
substituents
Bt
isomer
yield,
%
mp,
°C
yield,
%
mp,
°C
R1
R2
a
b
c
d
e
f
g
h g
i
H
H
H
H
H
H
H
H
p-BrC6H4
p-MeC6H4
p-ClC6H4
p-ClC6H4
p-ClC6H4
3,4-Cl2C6H4
1-naphthyl
p-ClC6H4
1
1
1
2
71
62
60
154-6 51c
152-4 37c
179-80 48c
106-7 46c
48-50
oilf
oil
oil
oil
72
1 + 2
75a
65
55b,c
2
1
1
1
1
111-3 35c
131-3 40c
oil
oil
44
64
217-9 15,c 30d 112-4
Me p-ClC6H4
Me p-BrC6H4
52d,e
53d,e
42d,e
41d,e
oil
oil
j
a
b
Based on combined GC yield of Bt1 and Bt2 isomers. Based
on crude 3 being 75% yield. c Method D.8c Method E.8c e Mixture
d
of isomers. f Lit.16 bp 58 °C/0.2 mmHg. R3 ) p-ClC6H4, in other
g
cases R3 ) H.
Sch em e 2
silica with 100 mL portions of ethyl acetate:hexanes ) 10:100
until all the Bt2 isomer (2b or 2d ) was removed. The polarity
was increased, and 100 mL portions of ethyl acetate:hexanes )
20:100 were used to remove the Bt1 isomer (2a or 2c). The
separation could be carried out by extracting organic phase A
into 5 N HCl, washing with ether, neutralizing with saturated
aqueous NaHCO3, extracting into ether, drying, and concentrat-
ing to give >95% pure Bt1 isomer (2a or 2c). Residual, initially
extracted, organic phase A could be washed with saturated
aqueous NaHCO3, dried, and concentrated to give >95% pure
Bt2 isomer.
Gen er a l Meth od for th e Syn th esis of (Ben zotr ia zolyl-
cyclop r op yl)ca r bin ols 3a -i. n-BuLi (10 mmol of 1.6 M in
hexanes) was added dropwise to a solution of BtCH2CH2CH2Cl
(2a or 2b or mixture) (10 mmol) or BtCH2CH(Me)CH2Cl (2c or
2d or mixture) (10 mmol) dissolved in THF (200 mL) at -78 °C,
under argon. The reaction mixture was left stirring at this
temperature for 35 min, warmed to room temperature over 15
min, left for 5 min (sample taken and analyzed by GC to show
complete conversion of the starting material), and recooled to
-78 °C before adding n-BuLi (10 mmol of 1.6 M in hexanes).
The reaction mixture was left at -78 °C for 50 min, and
aldehyde/ketone (10.5 mmol) was added as a solution in THF
(20 mL). The reaction was left at -78 °C for 30 min, warmed
to room temperature, quenched with water (100 mL), extracted
with ethyl acetate, dried (MgSO4), and concentrated. The crude
product was presorbed onto silica and dry flash columned on
silica with ethyl acetate:hexanes, gradient dilution. The relevant
fractions were combined and concentrated, and for pure Bt1 or
Bt2 isomers the residual oil was triturated with ether/hexanes
to give pure products as white crystals.
with Ti0 (generated by method D or E from the preceding
paper8c) gives the desired cyclopropylidene derivatives 7
in good yields, after workup and column chromatography
(see Scheme 2). The synthesis was carried out on purified
1- or 2-benzotriazolyl isomers and on a mixture of both,
and shown to be successful in all cases. Therefore, it is
not necessary to purify at any step other than after final
LVT alkenylation, even though the characterization by
spectral analysis of the intermediates is much easier if
pure 1- or 2-benzotriazolyl isomers are used. Thus, the
overall procedure can be greatly simplified to allow access
to cyclopropylidene derivatives directly from cheap and
readily available starting materials.
In conclusion, we have introduced a new method for
accessing cyclopropylidene derivatives, by utilizing low-
valent titanium-activated dehydroxylative-debenzotri-
azolylation of 1-(1-cyclopropylbenzotriazolyl)carbinols.
The overall procedure involves readily available and
inexpensive starting materials, using standard experi-
mental procedures, wherein all intermediates are stable
and isolatable in good to excellent yields. The method
is complementary to those already available and gives
an alternative route to a variety of synthetically useful
cyclopropylidene derivatives.
Gen er a l P r oced u r e A for th e Syn th esis of Cyclop r op yl-
id en e Der iva tives 7. To a solution of LVT8c were added Et3N
(15 mmol) and (benzotriazolylcyclopropyl)carbinol 3 (3 mmol) in
dry DME (20 mL). The reaction mixture was heated at 60 °C
for 12 h, cooled, diluted with diethyl ether (200 mL), and filtered.
The filtrate was washed with 5% aqueous NaOH (3 H 100 mL)
and brine (100 mL) and dried (MgSO4). After concentration the
residue was purified by column chromatography on silica gel,
using hexanes or pentane as eluent, to afford pure 7 as either a
colorless oil or colorless crystals.
Exp er im en ta l Section
Gen er a l Com m en ts. See the preceding paper.8c
Gen er a l P r oced u r e B for th e Syn th esis of Cyclop r op yl-
id en e Der iva tives 7. Exactly as procedure A above, except that
TiCl4 and Zn-Cu dust were used. Identical molar quantities of
all reagents were employed.
Gen er a l P r oced u r e for th e Syn th esis of 1- a n d 2-(3-
Ch lor op r op yl)ben zotr ia zole (2a ,b) a n d 1- a n d 2-(2-Ch lo-
r om eth yl)p r op ylben zotr ia zole (2c,d ). Benzotriazole (100
mmol) was dissolved in DMSO (200 mL), and finely powdered
NaOH (100 mmol) was added. The resulting suspension was
stirred at room temperature, with CaCl2 drying tube, until a
clear solution was obtained. 1-Bromo-3-chloropropane (1a ) (100
mmol) or 1-bromo-3-chloro-2-methylpropane (1b) (100 mmol)
was added dropwise at room temperature, the reaction mixture
was stirred at this temperature overnight before being poured
into water (500 mL), extracted into ethyl acetate (organic phase
A), and dried (MgSO4), and the solvent was removed. The
residual oil was presorbed onto silica and flash columned on
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
data for all isolated intermediates; combustion analyses, or
HRMS and 1H NMR (and 13C NMR) spectra for all novel
compounds (10 pages). This material is contained in libraries
on microfiche, immediately follows this article in the microfilm
version of the journal, and can be ordered from the ACS; see
any current masthead page for ordering information.
J O980617N