Lithiation of 1-chloromethylbenzotriazole: Generation and elaboration of benzotriazolyloxiranes

Article abstract of DOI:10.1021/jo026400h

1-Benzotriazolylchloromethyllithium generated from 1-chloromethylbenzotriazole (1) and LDA reacts with enolizable and nonenolizable ketones to give benzotriazolyloxiranes 2a-g in good yields. The oxiranyllithiums 4a-d generated from 2a-d and n-BuLi at -78 °C were trapped by a variety of electrophiles to give oxiranyl derivatives 5a-j in good to excellent yields. Lewis-acid-promoted nucleophilic ring opening of benzotriazolyloxiranes 2a,f,g with allyltrimethylsilane gave the corresponding 1,7-octadien-4-ols 6a-c in 68-75% yield. Hydrolysis of α-acylbenzotriazolyloxiranes 5g,h provided 3-hydroxy-1,2-diones 7a and 7b in 73 and 86% yield, respectively.

Full text of DOI:10.1021/jo026400h

Lith ia tion of 1-Ch lor om eth ylben zotr ia zole: Gen er a tion a n d
Ela bor a tion of Ben zotr ia zolyloxir a n es
Alan R. Katritzky,*,§ Kavita Manju,§ and Peter J . Steel‡
Center for Heterocyclic Compounds, Department of Chemistry, University of Florida,
Gainesville, Florida 32611-7200, and Department of Chemistry, University of Canterbury,
Christchurch, New Zealand
katritzky@chem.ufl.edu
Received September 5, 2002
1-Benzotriazolylchloromethyllithium generated from 1-chloromethylbenzotriazole (1) and LDA reacts
with enolizable and nonenolizable ketones to give benzotriazolyloxiranes 2a -g in good yields. The
oxiranyllithiums 4a -d generated from 2a -d and n-BuLi at -78 °C were trapped by a variety of
electrophiles to give oxiranyl derivatives 5a -j in good to excellent yields. Lewis-acid-promoted
nucleophilic ring opening of benzotriazolyloxiranes 2a ,f,g with allyltrimethylsilane gave the
corresponding 1,7-octadien-4-ols 6a -c in 68-75% yield. Hydrolysis of R-acylbenzotriazolyloxiranes
5g,h provided 3-hydroxy-1,2-diones 7a and 7b in 73 and 86% yield, respectively.
In tr od u ction
reported.10 However, many oxiranes with anion stabiliz-
ing aromatic,11 heteroaromatic,12 unsaturated,13 silicon-
linked,14 or electron-withdrawing substituents15-17 are
lithiated and trapped efficiently to give substituted
oxiranes.
Benzotriazolyloxiranes have earlier been prepared by
the epoxidation of 1-(1-alkenyl)benzotriazoles using
m-CPBA18a and dimethyldioxirane.18b The hydrolysis of
R-alkyl- and R-(R-hydroxyalkyl)-benzotriazolyloxiranes
gives the corresponding R-hydroxy ketones.18a We now
report another convenient and general method for the
preparation of benzotriazolyloxiranes and their further
transformations to octa-1,7-dien-4-ols and 3-hydroxy-1,2-
diones. Such dienes are useful substrates for ring-closing
The synthetic potential of carbenoids, in particular
R-haloalkyllithiums, is well documented.1 R-Haloorgano-
metals and metalloids derived from alkyl2 and allyl
halides,3 R-halo-esters, -amides, and -nitriles,4 2-halo-
methylbenzothiazoles,5 2-halomethyloxazoles,6 and 2- and
3-halomethylpyridines7 can be trapped effectively with
carbonyl compounds to give oxiranes.
Oxiranes are versatile synthetic intermediates.8 Oxi-
ranes can be deprotonated by a strong base to give highly
reactive oxiranyl anions, which frequently spontaneously
ring open to diverse products.9 Rare examples of the
trapping of nonstabilized oxiranyl anions have been
§ University of Florida.
(9) (a) Hodgson, D. M.; Gras, E. Synthesis 2002, 1625. (b) Doris, E.;
Dechoux, L.; Mioskowski, C. Synlett 1998, 337. (c) Satoh, T. Chem.
Rev. 1996, 96, 3303. (d) Crandall, J . K.; Apparu, M. Org. React. 1983,
29, 345.
(10) (a) Satoh, T.; Kobayashi, S.; Nakanishi, S.; Horiguchi, K.; Irisa,
S. Tetrahedron 1999, 55, 2515. (b) Lohse, P.; Loner, H.; Acklin, P.;
Sternfeld, F.; Pfaltz, A. Tetrahedron Lett. 1991, 32, 615.
(11) (a) Capriati, V.; Florio, S.; Luisi, R.; Salomone, A. Org. Lett.
2002, 4, 2445. (b) Eisch, J . J .; Galle, J . E. J . Organomet. Chem. 1976,
121, C10.
‡ University of Canterbury.
(1) (a) Brown, H. C.; Phadke, A. S.; Bhat, N. G. Tetrahedron Lett.
1993, 34, 7845. (b) Brown, H. C.; J ayaraman, S. Tetrahedron Lett.
1993, 34, 3997. (c) Taylor, K. G. Tetrahedron 1982, 38, 2751. (d)
Villieras, J .; Rambaud, M. Synthesis 1980, 644. (e) Ko¨brich, G. Angew.
Chem., Int. Ed. Engl. 1972, 11, 473.
(2) (a) Hoffmann, R. W.; Brumm, K.; Bewersdorf, M.; Mikolaiski,
W.; Kusche, A. Chem. Ber. 1992, 125, 2741. (b) Sadhu, K. M.; Matteson,
D. S. Tetrahedron Lett. 1986, 27, 795.
(3) (a) Florio, S.; Troisi, L. Tetrahedron Lett. 1996, 37, 4777. (b) J ulia,
M.; Verpeaux, J .-N.; Zahneisen, T. Bull. Soc. Chim. Fr. 1994, 131, 539.
(c) Mallaiah, K.; Satyanarayana, J .; Ila, H.; J unjappa, H. Tetrahedron
Lett. 1993, 34, 3145.
(4) (a) Arai, S.; Suzuki, Y.; Tokumaru, K.; Shioiri, T. Tetrahedron
Lett. 2002, 43, 833. (b) Hirashita, T.; Kinoshita, K.; Yamamura, H.;
Kawai, M.; Araki, S. J . Chem. Soc., Perkin Trans. 1 2000, 825. (c)
Takagi, R.; Kimura, J .; Shinohara, Y.; Ohba, Y.; Takezono, K.; Hiraga,
Y.; Kojima, S.; Ohkata, K. J . Chem. Soc., Perkin Trans. 1 1998, 689.
(5) (a) Florio, S.; Capriati, V.; Russo, V. Tetrahedron Lett. 1997, 38,
5843. (b) Florio, S.; Troisi, L. Tetrahedron Lett. 1992, 33, 7953.
(6) (a) Florio, S.; Capriati, V.; Luisi, R. Tetrahedron Lett. 2000, 41,
5295. (b) Florio, S.; Capriati, V.; Luisi, R.; Abbotto, A. Tetrahedron
Lett. 1999, 40, 7421.
(12) (a) Florio, S.; Capriati, V.; Martino, S. D.; Abbotto, A. Eur. J .
Org. Chem. 1999, 409. (b) Florio, S.; Ingrosso, G.; Troisi, L.; Lucchini,
V. Tetrahedron Lett. 1993, 34, 1363.
(13) (a) Grandjean, D.; Pale, P.; Chuche, J . Tetrahedron: Asymmetry
1993, 4, 1991. (b) Eisch, J . J .; Galle, J . E. J . Org. Chem. 1990, 55,
4835.
(14) (a) Molander, G. A.; Mautner, K. J . Org. Chem. 1989, 54, 4042.
(b) Eisch, J . J .; Galle, J . E. J . Organomet. Chem. 1988, 341, 293. (c)
Burford, C.; Cooke, F.; Roy, G.; Magnus, P. Tetrahedron 1983, 39, 867.
(15) (a) Mori, Y.; Furuta, H.; Takase, T.; Mitsuoka, S.; Furukawa,
H. Tetrahedron Lett. 1999, 40, 8019. (b) Mori, Y.; Yaegashi, K.;
Furukawa, H. J . Org. Chem. 1998, 63, 6200. (c) Dunn, S. F. C.; J ackson,
R. F. W. J . Chem. Soc, Perkin Trans. 1 1992, 2863. (d) Ashwell, M.;
Clegg, W.; J ackson, R. F. W. J . Chem. Soc., Perkin Trans. 1 1991, 897.
(16) Dubuffet, T.; Sauveˆtre, R.; Normant, J . F. Tetrahedron Lett.
1988, 29, 5923.
(7) (a) Florio, S.; Troisi, L. J . Org. Chem. 1996, 61, 4148. (b) Florio,
S.; Troisi, L. Tetrahedron Lett. 1994, 35, 3175.
(8) (a) Erden, I. In Comprehensive Heterocyclic Chemistry II; Katritz-
ky, A. R., Rees, C. W., Scriven, E. F. V., Eds.; Pergamon Press: Oxford,
1996; Vol. 1A, p 97. (b) Wong, H. N. C.; Fok, C. C. M.; Wong, T.
Heterocycles 1987, 26, 1345. (c) Smith, J . G. Synthesis 1984, 629.
(17) Yamauchi, Y.; Katagiri T.; Uneyama, K. Org. Lett. 2002, 4, 173.
(18) (a) Katritzky, A. R.; Heck, K. A.; Li, J .; Wells, A.; Garot, C.
Synth. Commun. 1996, 26, 2657. (b) Katritzky, A. R.; Maimait, R.;
Denisenko, A.; Denisenko, S. N. Arkivoc 2001, V, 68 (MT-194B).
10.1021/jo026400h CCC: $25.00 © 2003 American Chemical Society
Published on Web 12/05/2002
J . Org. Chem. 2003, 68, 407-411
407

Katritzky et al.
TABLE 1. Rea ction of Ben zotr ia zolyloxir a n yllith iu m s
w ith Electr op h iles
SCHEME 1
oxiranyl
entry lithium
product
Y (%)a
E+
R
R1
E
1
2
3
4
5
6
7
8
9
4a
4a
4b
4c
4a
4a
4a
4c
4d
MeI
BuBr
Me3SiCl
Ph Ph Me
Ph Ph Bu
5a (82)
5b (76)
5c (69)
Et
Et
SiMe3
PhCHdNPh -(CH2)5- PhCH(NHPh) 5d (78)b
PhCHO
Et2CO
PhCO2Et
PhCO2Et
PhCO2Et
Ph Ph PhCHOH
Ph Ph Et2CHOH
Ph Ph COPh
5e (92)c
5f (83)
5g (72)
5h (76)
5i (68)
-(CH2)5- COPh
Ph Et
COPh
a
b
Isolated yields. Product is a mixture of isomers in a 2:1:1
ratio. c Product is a mixture of syn/anti isomers in a 1:1 ratio.
as electrophiles. An obvious solution to this problem
would be to use a slight excess of benzophenone, which
should increase the yield of the desired product 2a due
to an increase in the concentration of this electrophile.
Indeed, when 1.5 equiv of benzophenone was used, 2a
could be obtained in 68% yield without the formation of
3. This procedure worked well with a variety of aromatic
and aliphatic ketones but remained unsuccessful in the
case of aldehydes (Scheme 1). Reactions with propiophen-
one and p-methylbenzophenone gave the benzotriazolyl-
oxiranes 2d and 2g as a mixture of diastereomers in the
ratios 3.3/1 and 1.3/1, respectively. The major isomers
were separated and studied by X-ray crystallography.
Crystals of the major isomer of 2d were all severely
twinned. Nevertheless, a partial structure solution could
be extracted from a twinned data set, and this showed
that it is the trans isomer. The X-ray crystal structure
of the major isomer of 2g showed that it is the cis isomer.
With acetophenone and p-chlorobenzophenone, the re-
spective products 2e and 2f were each formed as single
diene metathesis,19 and vicinal carbonyl systems play a
vital role in the therapeutic activity of a number of
immunosuppressants.20
Resu lts a n d Discu ssion
P r ep a r a tion of Ben zotr ia zolyloxir a n es. Lithiation
of 1-chloromethylbenzotriazole (1) with LiHMDS at -40
°C and trapping with benzophenone under Barbier condi-
tions gave the desired oxirane 2a in 18% yield along with
the alcohol 3 in 62% yield (Scheme 1).21 The structure of
1
diastereomers as indicated by the H NMR spectra.
Gen er a t ion a n d Tr a p p in g of Oxir a n yl An ion s.
While other oxiranyl anions are generated and trapped
from -90 to -110 °C,9a,c addition of n-BuLi to 3,3-
diphenylbenzotriazolyloxirane (2a ) at -78 °C followed by
addition of methyl iodide or n-butyl bromide gave the
alkylated products 5a and 5b in 82 and 76% yield,
respectively. Similarly, coupling of 3,3-diethylbenzotri-
azolyloxiranyllithium (4b) with trimethylsilyl chloride
gave 5c in 69% yield. The procedure worked well with a
variety of electrophiles to give the corresponding R-sub-
stituted products in 68-92% yield (Scheme 1, Table 1).
To the best of our knowledge, use of Schiff’s bases to
trap oxiranyl anions has not previously been reported.
However, reaction of N-(phenylmethylidene)aniline with
oxiranyllithium 4c gave 5d in 78% yield as a mixture of
three isomers in a 2:1:1 ratio. The major isomer of 5d
was separated by silica gel column chromatography, and
its structure was determined as anti by single-crystal
X-ray crystallography. Compound anti-5d crystallizes
with two independent molecules in the asymmetric unit,
which differ in the orientation of the phenyl substituents
and the conformation of the cyclohexane ring.
1
alcohol 3 is supported by H NMR and 13C NMR spec-
troscopy and also by X-ray crystallography. Compound
3 arises from a base-promoted reaction involving two
molecules of 1-chloromethylbenzotriazole,22 and its for-
mation was reduced to a large extent by using LDA as a
base at -78 °C, when 2a was obtained in an improved
yield of 40%.
Formation of the side product 3 indicated a competition
between 1-chloromethylbenzotriazole and benzophenone
(19) (a) Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413. (b)
Armstrong, S. K. J . Chem. Soc., Perkin Trans. 1 1998, 371.
(20) (a) Goulet, M.; Sinclair, P. J .; Wong, F.; Wyvratt, M. J . U.S.
Patent 5,247,076, 1994; Chem. Abstr. 1995, 122, 105528. (b) Tanaka,
H.; Kuroda, A.; Marusawa, H.; Hatanaka, H.; Kino, T.; Goto, T.;
Hashimoto, M.; Taga, T. J . Am. Chem. Soc. 1987, 109, 5031.
(21) (a) For an earlier report on lithiation of 1-chloromethylbenzo-
triazole with LiHMDS/HMPA at -20 °C and coupling with Schiff’s
bases, see: Katritzky, A. R.; Yao, J .; Bao, W.; Qi, M.; Steel, P. J . J .
Org. Chem. 1999, 64, 346. (b) For similar deprotonation-substitutions
of activated and unactivated Bt-CH, see: Katritzky, A. R.; Lan, X.;
Yang, J . Z.; Denisko, O. V. Chem. Rev. 1998, 98, 409.
(22) (a) BtCH2X compounds are known to equilibrate to Bt-CH2
)
Reaction of oxiranyllithium 4a with benzaldehyde gave
the desired epoxy alcohol 5e as a mixture of syn and anti
isomers in a 1:1 ratio. One of the isomers was separated
by recrystallization and was assigned as anti-5e by X-ray
analysis; again, anti-5e crystallizes with two molecules
in the asymmetric unit, but these have almost identical
X+ or Bt+ ) CH2X- depending upon the substituent X,21b and BtCH2-
Cl reacts with Bt-M+ to give BtCH2Bt.26 Alcohol 3 is derived by the
reaction of BtCH(Li)Bt and benzophenone. For other base-promoted
couplings of 2-chloromethyl-benzothiazole or -oxazoline, see: (b) Ca-
priati, V.; Florio, S.; Luisi, R.; Rocchetti, M. T. J . Org. Chem. 2002,
67, 759. (c) Florio, S.; Capriati, V.; Solimini, M. C.; Troisi, L.
Tetrahedron Lett. 1994, 35, 8481.
408 J . Org. Chem., Vol. 68, No. 2, 2003

Lithiation of 1-Chloromethylbenzotriazole
SCHEME 2
SCHEME 3
SCHEME 4
1
structures and conformations. The H NMR spectrum of
anti-5e displayed signals for CH(O) and OH protons at
4.85 and 4.35 ppm, respectively, whereas the correspond-
ing signals for the syn-5e isomer appeared at 5.16 and
2.59 ppm, respectively.
R-Acyloxiranes are versatile building blocks capable of
functionalization at both the ketone and the oxirane
moieties.23 Reaction of oxiranyllithiums 4a or 4c with
ethyl benzoate gave the R-acylated products 5g and 5h
in 72 and 76% yield, respectively. Lithiation of the trans
isomer of benzotriazolyloxirane 2d provided configura-
tionally stable oxiranyllithium 4d , which was trapped
with ethyl benzoate to give exclusively the trans product
5i in 68% yield. The trans stereochemistry for 5i was
unambiguously determined by X-ray analysis; once again,
there are two independent molecules in the asymmetric
unit.
SCHEME 5
Acylbenzotriazoles are good acylating agents,24 and an
attempt was made to prepare acylbenzotriazoles via base-
promoted rearrangement of benzotriazolyloxiranyllithi-
um 4a . However, this resulted in the formation of 5j. A
possible explanation is that the base and 2a generate the
corresponding enolate and the ketene by the loss of the
benzotriazolyl group. The oxiranyllithium 4a is appar-
ently stable enough to be trapped by the ketene thus
generated in situ giving R-acylated benzotriazolyloxirane
5j in 71% yield (Scheme 2).
P r ep a r a tion of 5,5-Dia r yl-1,7-octa d ien -4-ols. Nu-
cleophilic ring opening of 3,3-diarylbenzotriazolyloxiranes
2a ,f,g on treatment with allyltrimethylsilane and BF3‚
OEt2 gave the corresponding 5,5-diarylocta-1,7-dien-4-
ols 6a -c in 68-75% yield (Scheme 3). Similar ring
openings tried with 1-(3-ethyl-3-phenyl-2-oxiranyl)-1H-
1,2,3-benzotriazole (2d ) or 1-(2-methyl-3,3-diphenyl-2-
oxiranyl)-1H-1,2,3-benzotriazole (5a ) yielded a mixture
of rearranged products along with the desired 1,7-
octadiene-4-ols in low yields.
anone25e (Scheme 4). R-Alkyl and R-( R-hydroxyalkyl)-
benzotriazolyloxiranes of the type 5a ,b,e,f have already
been utilized for the synthesis of corresponding R-hydroxy
ketones.18a Similarly, treatment of R-acylbenzotriazolyl-
oxiranes 5g,h with perchloric acid readily gave 3-hy-
droxy-1,2-diones 7a and 7b in 73 and 86% yield, respec-
tively (Scheme 5). Thus, a general and efficient route is
now available for the preparation of 3,3-dialkyl or -aryl
substituted acylbenzotriazolyloxiranes and the corre-
sponding 3-hydroxy-1,2-diones.
Con clu sion s
In summary, we have shown that R-anion stabilization
by the benzotriazolyl group can also be utilized for the
preparation of 3,3-disubstituted benzotriazolyloxiranes
and 2,3,3-trisubstituted benzotriazolyloxiranes. Further,
nucleophilic ring opening of benzotriazolyloxiranes pro-
P r ep a r a tion of 3-Hyd r oxy-1,2-d ion es. 3-Hydroxy-
1,2-diones have earlier been prepared by either the
oxidation of 2-hydroxy-2-ene-1-ones,25a the hydrolysis of
the corresponding imines25b or ring opening of diepoxy
ketones,25c the oxidation and subsequent hydrolysis of
R-acetoxyacetylenes,25d or the oxidation of 3(2H)-fur-
(25) (a) Gonza´lez, A. G.; Alvarenga, N. L.; Este´vez-Braun, A.; Ravelo,
A. G.; Este´vez-Reyes, R. Tetrahedron 1996, 52, 10667. (b) Murakami,
M.; Masuda, H.; Kawano, T.; Nakamura, H.; Ito, Y. J . Org. Chem. 1991,
56, 1. (c) Zvonok, A. M.; Kuz’menok, N. M.; Stanishevskii, L. S. Khim.
Geterotsikl. Soedin. 1989, 1172; Chem. Abstr. 1990, 112, 157451. (d)
Fiesselmann, H.; Sasse, K. Chem. Ber. 1956, 89, 1791. (e) Kohler, E.
P. J . Am. Chem. Soc. 1925, 47, 3030.
(23) Lauret, C. Tetrahedron: Asymmetry 2001, 12, 2359.
(24) (a) Katritzky, A. R.; Abdel-Fattah, A. A. A.; Wang, M., unpub-
lished results. (b) Evans, D. A.; Trotter, B. W.; Coleman, P. J .; Cote,
B.; Dias, L. C.; Rajapakse, H. A.; Tyler, A. N. Tetrahedron 1999, 55,
8671.
J . Org. Chem, Vol. 68, No. 2, 2003 409

Katritzky et al.
132.3, 129.7, 129.3, 129.0, 128.8, 128.0, 126.8, 124.4, 119.8,
111.6, 73.6, 67.7. Anal. Calcd for C20H14ClN3O: C, 69.07; H,
4.06; N, 12.08. Found: C, 69.27; H, 3.91; N, 11.86.
vides easy access to 1,7-octadien-4-ols and 3-hydroxy-1,2-
diones.
1-[3-(4-Met h ylp h en yl)-3-p h en yl-2-oxir a n yl]-1H -1,2,3-
ben zot r ia zole (2g). White needles (from CH2Cl2/hexanes);
yield, 69%; mp 122-124 °C; cis isomer: 1H NMR δ 7.92-7.89
(m, 1H), 7.43-7.39 (m, 6H), 7.22-7.19 (m, 2H), 7.08 (d, J )
8.0 Hz, 2H), 6.89 (d, J ) 7.8 Hz, 2H), 6.12 (s, 1H), 2.16 (s,
3H); 13C NMR δ 145.7, 138.8, 137.8, 132.7, 130.7, 129.2, 129.0,
128.8, 128.3, 127.6, 126.8, 124.2, 119.6, 112.0, 74.1, 68.1, 21.3.
Anal. Calcd for C21H17N3O: C, 77.04; H, 5.23; N, 12.83.
Found: C, 77.07; H, 5.28; N, 12.84.
Exp er im en ta l Section
All of the reactions were carried out under N2. THF was
distilled from sodium/benzophenone prior to use. 1H NMR (300
MHz) and 13C NMR (75 MHz) spectra were recorded in CDCl3
(with TMS for 1H and chloroform-d for 13C as the internal
reference). Column chromatography was performed on silica
gel 200-425 mesh.
Gen er a l P r oced u r e for th e P r ep a r a tion of Ben zotr ia -
zolyloxir a n es 2. To a solution of 1-chloromethylbenzotriazole
(1)26 (0.50 g, 3 mmol) and ketone (4.5 mmol) in THF (10 mL)
at -78 °C was added LDA [freshly prepared from n-BuLi (1.5
M in hexanes, 3 mL, 4.5 mmol) and diisopropylamine (0.7 mL,
5 mmol) at 0 °C in THF (20 mL)]. The reaction mixture was
stirred for 1 h at -78 °C and then allowed to warm to 20 °C.
After the mixture was stirred for 3 h, aqueous NH4Cl was
added, and the aqueous layer was extracted with diethyl ether.
The combined organic layer was washed with brine, dried (Na2-
SO4), and concentrated in vacuo. The residue was purified by
flash column chromatography using hexanes/EtOAc (95:5) as
eluent to give 2a -g.
1-(3,3-Diph en yl-2-oxir an yl)-1-H-1,2,3-ben zotr iazole (2a).
Colorless cubes (from EtOAc/hexanes); yield, 68%; mp 135-
137 °C; 1H NMR δ 7.89-7.86 (m, 1H), 7.37 (s, 6H), 7.20-7.14
(m, 4H), 7.06-7.05 (m, 3H), 6.14 (s, 1H); 13C NMR δ 145.3,
137.1, 133.3, 132.3, 128.7, 128.6, 128.5, 128.2, 128.1, 127.3,
126.5, 123.8, 119.2, 111.6, 73.7, 67.8. Anal. Calcd for C20H15N3O:
C, 76.66; H, 4.82; N, 13.41. Found: C, 76.62; H, 4.61; N, 13.38.
1-(3,3-Dieth yl-2-oxir a n yl)-1H-1,2,3-ben zotr ia zole (2b).
Yellow oil; yield, 72%; 1H NMR δ 8.06 (d, J ) 8.4 Hz, 1H),
7.80 (d, J ) 8.4 Hz, 1H), 7.52-7.47 (m, 1H), 7.41-7.36 (m,
1H), 5.52 (s, 1H), 1.93-1.85 (m, 2H), 1.49-1.41 (m, 2H), 1.12
(t, J ) 7.5 Hz, 3H), 0.93 (t, J ) 7.5 Hz, 3H); 13C NMR δ 145.7,
133.7, 128.1, 124.5, 120.0, 111.5, 70.8, 68.4, 25.5, 22.7, 9.0, 8.7.
Anal. Calcd for C12H15N3O: C, 66.34; H, 6.96; N, 19.34.
Found: C, 66.46; H, 7.13; N, 19.28.
2,2-Di(1H-1,2,3-ben zotr ia zol-1-yl)-1,1-d ip h en yl-1-eth a -
n ol (3). White cubes (from EtOAc); yield, 62%; mp 235-237
1
°C; H NMR δ 8.53 (s, 1H), 7.96 (d, J ) 8.2 Hz, 2H), 7.74 (d,
J ) 8.4 Hz, 2H), 7.48-7.42 (m, 2H), 7.38-7.31 (m, 6H), 7.18-
7.16 (m, 6H), 6.21 (s, 1H); 13C NMR δ 145.9, 142.3, 132.7, 129.1,
128.7, 128.2, 125.6, 125.1, 120.4, 111.1, 82.6, 76.4; HRMS Calcd
for C26H20N6O (M+ + 1) 433.1771, found 433.1746.
Gen er a l P r oced u r e for th e P r ep a r a tion of Ben zotr ia -
zolyloxir a n es 5. To a stirred solution of 2 (0.15 g, 0.5 mmol)
in THF (5 mL) at -78 °C was added n-BuLi (1.5 M in THF,
0.4 mL, 0.6 mmol). After 5 min, electrophile (0.6 mmol) was
added, and the reaction mixture was stirred for 30 min at -78
°C and then allowed to warm to 20 °C. After the mixture was
stirred for 2 h, aqueous NH4Cl was added. The aqueous layer
was extracted with diethyl ether, and the combined organic
extracts were washed with brine, dried (Na2SO4), and concen-
trated in vacuo. The residue was purified by flash column
chromatography using EtOAc/hexanes (5:95) to give 5a -j.
1-(2-Met h yl-3,3-d ip h en yl-2-oxir a n yl)-1H -1,2,3-b en zo-
1
tr ia zole (5a ). Colorless oil; yield, 82%; H NMR δ 7.85 (d, J
) 8.2 Hz, 1H), 7.78 (d, J ) 8.4 Hz, 1H), 7.61 (d, J ) 7.3 Hz,
2H), 7.44-7.39 (m, 2H), 7.36-7.25 (m, 2H), 7.20-7.15 (m, 3H),
6.95-6.90 (m, 3H), 1.98 (s, 3H); 13C NMR δ 145.2, 137.1, 135.9,
132.9, 128.8, 128.4, 128.0, 127.9, 127.4, 127.2, 126.9, 123.9,
119.5, 112.0, 78.6, 72.6, 20.5. Anal. Calcd for C21H17N3O: C,
77.04; H, 5.23; N, 12.83. Found: C, 77.35; H, 5.29; N, 12.81.
1-(2-Bu tyl-3,3-d ip h en yl-2-oxir a n yl)-1H-1,2,3-ben zotr ia -
zole (5b). White needles (from Et2O/pentane); yield, 76%; mp
1-(1-Oxa sp ir o[2.5]oct-2-yl)-1H-1,2,3-ben zotr ia zole (2c).
White cubes (from CH2Cl2/hexanes); yield, 70%; mp 103-105
1
65-67 °C; H NMR δ 7.85-7.81 (m, 2H), 7.62 (d, J ) 7.3 Hz,
2H), 7.43-7.38 (m, 2H), 7.35-7.30 (m, 2H), 7.23-7.14 (m, 3H),
6.90-6.88 (m, 3H), 2.76-2.67 (m, 1H), 1.80-1.72 (m, 1H),
1.48-1.42 (m, 1H), 1.17-1.16 (m, 3H), 0.70 (t, J ) 6.9 Hz, 3H);
13C NMR δ 145.0, 137.2, 136.1, 133.8, 128.7, 128.4, 127.9,
127.8, 127.5, 127.1, 126.8, 123.8, 119.4, 112.0, 81.3, 72.8, 32.9,
25.9, 22.3, 13.8. Anal. Calcd for C24H23N3O: C, 78.02; H, 6.27;
N, 11.37. Found: C, 77.82; H, 6.60; N, 11.50.
1
°C; H NMR δ 8.06 (d, J ) 8.4 Hz, 1H), 7.79 (d, J ) 8.4 Hz,
1H), 7.51-7.46 (m, 1H), 7.40-7.35 (m, 1H), 5.45 (s, 1H), 1.87-
1.75 (m, 4H), 1.66-1.57 (m, 4H), 1.48-1.47 (m, 2H); 13C NMR
δ 145.7, 133.7, 128.1, 124.5, 120.0, 111.4, 71.2, 66.4, 33.2, 29.1,
25.3, 24.7, 24.4. Anal. Calcd for C13H15N3O: C, 68.10; H, 6.59;
N, 18.33. Found: C, 68.35; H, 6.71; N, 18.29.
1-(3-E t h yl-3-p h e n yl-2-oxir a n yl)-1H -1,2,3-b e n zot r ia -
zole (2d ). White cubes (from CH2Cl2/hexanes); yield, 68% (cis
and trans); mp 74-76 °C; trans isomer: 1H NMR δ 8.10 (d, J
) 8.4 Hz, 1H), 7.87 (d, J ) 8.4 Hz, 1H), 7.56-7.53 (m, 3H),
7.48-7.37 (m, 4H), 5.56 (s, 1H), 2.25-2.12 (m, 1H), 1.56-1.44
(m, 1H), 0.92 (t, J ) 7.4 Hz, 3H); 13C NMR δ 145.8, 136.7,
133.6, 128.9, 128.7, 128.4, 126.5, 124.7, 120.2, 111.3, 72.6, 68.4,
24.2, 9.1. Anal. Calcd for C16H15N3O: C, 72.43; H, 5.70; N,
15.84. Found: C, 72.72; H, 5.58; N, 15.87.
1-[3,3-Diet h yl-2-(t r im et h ylsilyl)-2-oxir a n yl]-1H -1,2,3-
ben zotr ia zole (5c). Yellow oil; yield, 69%; 1H NMR δ 8.02
(d, J ) 8.4 Hz, 1H), 7.81 (d, J ) 8.2 Hz, 1H), 7.45-7.40 (m,
1H), 7.35-7.30 (m, 1H), 1.87-1.70 (m, 2H), 1.26-1.01 (m, 5H),
0.86 (t, J ) 7.4 Hz, 3H), 0.08 (s, 9H); 13C NMR δ 145.3, 134.0,
127.4, 124.1, 119.7, 112.3, 75.7, 70.8, 24.6, 23.1, 9.4, 8.9, -1.9.
Anal. Calcd for C15H23N3OSi: C, 62.24; H, 8.01; N, 14.52.
Found: C, 62.50; H, 8.51; N, 14.53.
N-[[2-(1H-1,2,3-Ben zotr ia zol-1-yl)-1-oxa sp ir o[2.5]oct-2-
yl](ph en yl)m eth yl]an ilin e (5d). Colorless cubes (from EtOAc/
hexanes); yield, 78%; mp 147-149 °C; anti isomer: 1H NMR
δ 7.88 (d, J ) 8.2 Hz, 1H), 7.16-7.05 (m, 4H), 7.02-6.92 (m,
5H), 6.85 (d, J ) 8.4 Hz, 1H), 6.64 (t, J ) 7.3 Hz, 1H), 6.58 (d,
J ) 8.0 Hz, 2H), 5.72 (d, J ) 7.5 Hz, 1H), 4.95 (d, J ) 7.5 Hz,
1H), 2.13-1.96 (m, 2H), 1.84-1.82 (m, 2H), 1.69-1.65 (m, 1H),
1.53 (s, 3H), 1.20-1.12 (m, 1H), 1.03-0.95 (m, 1H); 13C NMR
δ 145.9, 144.4, 137.0, 134.4, 129.3, 128.5, 128.1, 127.6, 127.0,
124.0, 119.2, 117.9, 113.5, 111.4, 81.2, 72.0, 59.6, 31.1, 30.3,
25.4, 25.1, 24.4. Anal. Calcd for C26H26N4O: C, 76.07; H, 6.38;
N, 13.65. Found: C, 75.68; H, 6.54; N, 13.67.
1-(3-Met h yl-3-p h en yl-2-oxir a n yl)-1H -1,2,3-b en zot r ia -
1
zole (2e). Yellow oil; yield, 62%; H NMR δ 8.10 (d, J ) 8.2
Hz, 1H), 7.87 (d, J ) 8.2 Hz, 1H), 7.57-7.52 (m, 3H), 7.48-
7.40 (m, 4H), 5.54 (s, 1H), 1.66 (s, 3H); 13C NMR δ 145.8, 138.4,
133.4, 128.9, 128.8, 128.4, 125.6, 124.7, 120.2, 111.3, 72.0, 64.0,
17.7. Anal. Calcd for C15H13N3O: C, 71.70; H, 5.21; N, 16.72.
Found: C, 71.99; H, 4.94; N, 16.72.
1-[3-(4-Ch lor op h en yl)-3-p h en yl-2-oxir a n yl]-1H -1,2,3-
ben zotr ia zole (2f). White cubes (from EtOAc/hexanes); yield,
75%; mp 114-116 °C; 1H NMR δ 7.94-7.91 (m, 1H), 7.48-
7.36 (m, 6H), 7.32-7.22 (m, 2H), 7.17-7.14 (m, 2H), 7.10-
7.06 (m, 2H), 6.13 (s, 1H); 13C NMR δ 145.6, 136.9, 135.0, 132.7,
[2-(1H-1,2,3-Ben zotr ia zol-1-yl)-3,3-d ip h en yl-2-oxir a n yl]-
(p h en yl)m eth a n ol (5e). White needles (from CH2Cl2/hex-
anes); yield (syn and anti), 92%; anti isomer; mp 185-187 °C;
1H NMR δ 7.92 (d, J ) 7.0 Hz, 2H), 7.75 (d, J ) 4.9 Hz, 1H),
(26) Burckhalter, J . H.; Stephens, V. C.; Hall, L. A. R. J . Am. Chem.
Soc. 1952, 74, 3868.
410 J . Org. Chem., Vol. 68, No. 2, 2003

Lithiation of 1-Chloromethylbenzotriazole
7.53-7.48 (m, 2H), 7.43 (d, J ) 6.9 Hz, 1H), 7.24-7.05 (m,
10H), 6.93 (s, 3H), 4.84 (d, J ) 8.4 Hz, 1H), 4.32 (d, J ) 8.1
Hz, 1H); 13C NMR δ 144.3, 138.2, 136.2, 135.6, 134.6, 129.1,
129.0, 128.3, 128.1, 127.8, 127.6, 126.6, 125.9, 124.0, 119.4,
111.5, 81.5, 75.0, 73.8. Anal. Calcd for C27H21N3O2: C, 77.31;
H, 5.05; N, 10.02. Found: C, 77.03; H, 4.89; N, 10.08.
3-[2-(1H-1,2,3-Ben zotr ia zol-1-yl)-3,3-d ip h en yl-2-oxir a -
n yl]-3-p en ta n ol (5f). White needles (from CH2Cl2/hexanes);
yield, 83%; mp 62-64 °C; 1H NMR δ 7.95 (d, J ) 8.5 Hz, 1H),
7.78-7.73 (m, 3H), 7.40-7.34 (m, 3H), 7.28-7.24 (m, 3H), 7.18
(t, J ) 7.8 Hz, 1H), 6.87-6.76 (m, 3H), 1.96 (s, 1H), 1.91-1.82
(m, 2H), 1.56-1.47 (m, 1H), 1.43-1.36 (m, 1H), 1.09 (t, J )
7.4 Hz, 3H), 0.85 (t, J ) 7.4 Hz, 3H); 13C NMR δ 144.5, 137.6,
137.4, 134.2, 128.6, 128.1, 127.7, 127.6, 127.6, 126.7, 125.9,
123.8, 119.4, 112.6, 84.3, 77.8, 73.1, 29.2, 28.8, 8.6, 7.7. Anal.
Calcd for C25H25N3O2: C, 75.16; H, 6.31; N, 10.52. Found: C,
74.90; H, 6.46; N, 10.37.
(MgSO4), and concentrated in vacuo. The residue was purified
by column chromatography using EtOAc/hexanes (5:95) as an
eluent.
5,5-Dip h en yl-1,7-octa d ien -4-ol (6a ). Colorless oil; yield,
75%; 1H NMR δ 7.51-7.46 (m, 10H), 6.19-6.05 (m, 1H), 5.72-
5.59 (m, 1H), 5.32-5.18 (m, 4H), 4.68 (t, J ) 8.4 Hz, 1H), 3.32
(dd, J ) 13.7, 6.9 Hz, 1H), 3.12 (dd, J ) 13.9, 7.1 Hz, 1H),
2.73 (dd, J ) 14.4, 6.3 Hz, 1H), 1.85-1.72 (m, 2H); 13C NMR
δ 144.4, 144.0, 136.1, 134.8, 129.7, 129.7, 127.8, 127.8, 126.5,
126.4, 117.9, 117.5, 73.1, 55.4, 42.9, 37.9; HRMS calcd for
C
20H20 (M+ - H2O) 261.1643, found 261.1667.
5-(4-Ch lor oph en yl)-5-ph en ylocta -1,7-dien -4-ol (6b). Col-
orless oil; yield, 73%; (isomer mixture 1:1): 1H NMR δ 7.51-
7.31 (m, 9H), 6.15-6.01 (m, 1H), 5.68-5.55 (m, 1H), 5.33-
5.17 (m, 4H), 4.66-4.61 (m, 1H), 3.25 (dd, J ) 13.7, 6.6 Hz,
1H), 3.12-3.03 (m, 1H), 2.75-2.62 (m, 1H), 1.82-1.68 (m, 2H);
13C NMR δ 144.1 (one isomer), 143.5 (other isomer), 143.2 (one
isomer), 142.6 (other isomer), 135.8 (one isomer), 135.7 (other
isomer), 134.4 (one isomer), 134.3 (other isomer), 132.3 (one
isomer), 132.2 (other isomer), 131.2, 131.2, 129.6, 129.5, 128.0,
127.9, 127.9, 126.7 (one isomer), 126.6 (other isomer), 118.3
(one isomer), 118.3 (other isomer), 118.0, 73.0 (one isomer),
72.6 (other isomer), 55.1, 43.0 (one isomer), 42.8 (other isomer),
[2-(1H-1,2,3-Ben zotr ia zol-1-yl)-3,3-d ip h en yl-2-oxir a n yl]-
(p h en yl)m eth a n on e (5g). White needles (from CH2Cl2/hex-
anes); yield, 72%; mp 142-144 °C; 1H NMR δ 8.15 (d, J ) 7.7
Hz, 2H), 7.90 (d, J ) 8.2 Hz, 1H), 7.79 (d, J ) 8.4 Hz, 1H),
7.57-7.47 (m, 3H), 7.43-7.23 (m, 9H), 7.10-7.08 (m, 3H); 13
C
NMR δ 189.1, 145.4, 134.6, 134.4, 133.8, 133.2, 130.0, 129.0,
128.6, 128.6, 128.4, 128.3, 128.2, 127.5, 124.5, 120.0, 111.3,
78.7, 72.5. Anal. Calcd for C27H19N3O2: C, 77.68; H, 4.59; N,
10.07. Found: C, 77.62; H, 4.70; N, 10.17.
37.8 (one isomer), 37.7 (other isomer); HRMS Calcd for C20H19
-
Cl (M+ - H2O) 295.1253, found 295.1237.
5-(4-Meth ylp h en yl)-5-p h en ylocta -1,7-d ien -4-ol (6c). Col-
1
[2-(1H-1,2,3-Ben zotr ia zol-1-yl)-1-oxa sp ir o[2.5]oct-2-yl]-
(p h en yl)m eth a n on e (5h ). White needles (from Et2O); yield,
76%; mp 148-150 °C; 1H NMR δ 8.30 (d, J ) 7.4 Hz, 2H),
8.01 (d, J ) 8.4 Hz, 1H), 7.86 (d, J ) 8.4 Hz, 1H), 7.59-7.53
(m, 2H), 7.51-7.44 (m, 2H), 7.39-7.34 (m, 1H), 2.07-1.99 (m,
1H), 1.90-1.84 (m, 2H), 1.79-1.68 (m, 4H), 1.59-1.48 (m, 3H);
13C NMR δ 189.1, 145.7, 134.9, 133.5, 133.1, 130.2, 129.1,
128.9, 124.9, 120.1, 111.4, 71.2, 31.7, 31.2, 25.3, 24.5, 24.3.
Anal. Calcd for C20H19N3O2: C, 72.05; H, 5.74; N, 12.60.
Found: C, 72.08; H, 5.99; N, 12.68.
[2-(1H-1,2,3-Ben zotr ia zol-1-yl)-3-eth yl-3-p h en yloxir a n -
2-yl](p h en yl)m eth a n on e (5i). White cubes (from CH2Cl2/
hexanes); yield, 68%; mp 114-116 °C; trans isomer: 1H NMR
δ 8.05 (d, J ) 8.1 Hz, 3H), 7.94 (d, J ) 8.4 Hz, 1H), 7.60-7.55
(m, 1H), 7.49-7.38 (m, 4H), 7.33-7.17 (m, 5H), 2.78-2.66 (m,
1H), 1.68-1.56 (m, 1H), 0.90 (t, J ) 7.4 Hz, 3H); 13C NMR δ
188.2, 145.7, 134.4, 133.8, 133.5, 133.0, 129.9, 129.0, 128.8,
128.6, 127.1, 125.0, 120.3, 111.3, 78.2, 73.5, 26.9, 9.0. Anal.
Calcd for C23H19N3O2: C, 74.78; H, 5.18; N, 11.37. Found: C,
74.77; H, 5.24; N, 11.44.
1-[2-(1H-1,2,3-Ben zotr ia zol-1-yl)-3,3-d ip h en yl-2-oxir a -
n yl]-2,2-d ip h en yl-1-eth a n on e (5j). White needles (from
EtOAc/hexanes); yield, 71%; mp 168-170 °C; 1H NMR δ 7.86-
7.83 (m, 1H), 7.74-7.72 (m, 2H), 7.51-7.50 (m, 3H), 7.32-
7.30 (m, 3H), 7.20-7.15 (m, 4H), 7.05-6.99 (m, 6H), 6.96-
6.92 (m, 2H), 6.86-6.84 (m, 1H), 6.49 (d, J ) 6.6 Hz, 2H), 5.18
(s, 1H); 13C NMR δ 198.5, 145.0, 136.4, 135.5, 134.6, 134.5,
133.2, 130.0, 129.7, 129.6, 129.5, 129.0, 128.8, 128.8, 128.2,
128.1, 127.9, 127.3, 126.9, 124.1, 119.8, 110.5, 78.3, 73.9, 60.3
Anal. Calcd for C34H25N3O2: C, 80.45; H, 4.96; N, 8.28.
Found: C, 80.44; H, 5.13; N, 8.45.
Gen er a l P r oced u r e for th e P r ep a r a tion of 1,7-Octa -
d ien -4-ols. To a solution of 2a ,f or 2g (1 mmol) and allyltri-
methylsilane (0.48 mL, 3 mmol) in CH2Cl2 (5 mL) at 0 °C was
added BF3‚OEt2 (0.25 mL, 2 mmol), and the reaction mixture
was stirred for 10 h at 20 °C. Aqueous NaHCO3 was added,
and the aqueous layer was extracted with diethyl ether. The
combined organic extracts were washed with brine, dried
orless oil; yield, 68%; (isomer mixture 1:1); H NMR δ 7.31-
7.20 (m, 5H), 7.18-7.08 (m, 4H), 5.92-5.80 (m, 1H), 5.46-
5.34 (m, 1H), 5.06-4.92 (m, 4H), 4.43-4.38 (m, 1H), 3.09-
3.00 (m, 1H), 2.89-2.81 (m, 1H), 2.50-2.42 (m, 1H), 2.33 (one
isomer) (s, 1.5H), 2.32 (other isomer) (s, 1.5H), 1.58-1.48 (m,
2H); 13C NMR δ 144.6 (one isomer), 144.2 (other isomer), 141.1
(one isomer), 140.9 (other isomer), 136.2 (one isomer), 135.9
(other isomer), 134.9 (one isomer), 134.9 (other isomer), 129.7,
129.6, 129.5, 128.6, 128.5, 127.8, 127.8, 126.4, 126.3, 117.8 (one
isomer), 117.4 (other isomer), 73.2 (one isomer), 73.1 (other
isomer), 55.1 (one isomer), 55.1 (other isomer), 43.0, 37.9 (one
isomer), 37.8 (other isomer), 21.1; HRMS Calcd for C21H22 (M+
- H2O) 275.1799, found 275.1799.
3-Hydroxy-1,3,3-triphenyl-1,2-propanedione (7a ) and 1-(1-
hydroxycyclohexyl)-2-phenyl-1,2-ethanedione (7b) were pre-
pared according to the general procedure reported previously.18a
3-Hyd r oxy-1,3,3-tr ip h en yl-1,2-p r op a n ed ion e (7a ). Yel-
low needles (from EtOAc/hexanes); yield, 73%; mp 149-152
°C (lit.25e mp 150 °C); 1H NMR δ 7.81 (d, J ) 7.3 Hz, 3H), 7.65-
7.55 (m, 3H), 7.51-7.47 (m, 5H), 7.41-7.35 (m, 5H); 13C NMR
δ 203.8, 197.0, 141.1, 137.8, 135.0, 132.6, 130.3, 129.9, 129.0,
128.7, 128.5, 127.8, 85.6.
1-(1-Hydr oxycycloh exyl)-2-ph en yl-1,2-eth an edion e (7b).
Yellow needles (from pentane); yield, 86%; mp 50-52 °C (lit.25d
1
mp 52-53 °C); H NMR δ 7.89 (d, J ) 7.4 Hz, 2H), 7.68 (t, J
) 7.4 Hz, 1H), 7.53 (t, J ) 7.8 Hz, 2H), 3.15 (br s, 1H), 2.00-
1.83 (m, 4H), 1.79-1.67 (m, 5H), 1.35-1.25 (m, 1H); 13C NMR
δ 208.3, 196.1, 135.0, 132.7, 129.8, 129.1, 78.5, 34.1, 25.1, 20.7.
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra for compounds 3 and 6a -c; X-ray structures of
compounds 3, 2g, 5d , 5e, and 5i; tables of atomic coordinates,
thermal parameters, bond lengths, bond angles, anisotropic
and isotropic displacement parameters for the X-ray crystal
structures of 2g, 5d ,e, and 5i. This material is available free
of charge via the Internet at http://pubs.acs.org.
J O026400H
J . Org. Chem, Vol. 68, No. 2, 2003 411