General and efficient insertions of carbons carrying aryl and heteroaryl groups: Synthesis of α-Aryl- And α-heteroaryl-substituted ketones

Article abstract of DOI:10.1021/jo960841h

Anions formed from the lithiation of a variety of 1-(arylmethyl)- and 1-(heteroarylmethyl)-benzotriazoles 1 with n-BuLi underwent addition to aliphatic and aromatic aldehydes and cyclic and acyclic ketones. Subsequent in situ thermal rearrangements of the intermediates in the presence of zinc bromide provided one-carbon chain-extended or ring-expanded α-aryl- and α-heteroaryl-substituted ketones 2 in moderate to excellent yields in simple one-pot operations with excellent regioselectivity in most cases. Substituent effects on the relative migration rates were investigated in the insertion reactions of 1-(4-methoxybenzyl)benzotriazole (1e) with XC₆H₄-COPh. The small and negative Hammett ρ⁺ value (-0.92) suggested that the rearrangements proceed via early, reagent-like, electron deficient transition states.

Full text of DOI:10.1021/jo960841h

J . Org. Chem. 1996, 61, 7571-7577
7571
Gen er a l a n d Efficien t In ser tion s of Ca r bon s Ca r r yin g Ar yl a n d
Heter oa r yl Gr ou p s: Syn th esis of r-Ar yl- a n d
r-Heter oa r yl-Su bstitu ted Keton es
Alan R. Katritzky,* Dorin Toader, and Linghong Xie
Center for Heterocyclic Compounds, Department of Chemistry, University of Florida,
Gainesville, Florida 32611-7200
Received May 7, 1996X
Anions formed from the lithiation of a variety of 1-(arylmethyl)- and 1-(heteroarylmethyl)-
benzotriazoles 1 with n-BuLi underwent addition to aliphatic and aromatic aldehydes and cyclic
and acyclic ketones. Subsequent in situ thermal rearrangements of the intermediates in the
presence of zinc bromide provided one-carbon chain-extended or ring-expanded R-aryl- and
R-heteroaryl-substituted ketones 2 in moderate to excellent yields in simple one-pot operations
with excellent regioselectivity in most cases. Substituent effects on the relative migration rates
were investigated in the insertion reactions of 1-(4-methoxybenzyl)benzotriazole (1e) with XC6H4-
COPh. The small and negative Hammett F+ value (-0.92) suggested that the rearrangements
proceed via early, reagent-like, electron deficient transition states.
In tr od u ction
selenoxides14-16 and arylmethylene insertions via the
rearrangement of halohydrins, derived from the addition
of benzylmagnesium chloride to carbonyl compounds,
followed by R-bromination;17 and (iv) other approaches
include ring expansions of cyclic ketones via radical
processes18-20 and more complex pathways.21
Carbon chain extension or ring expansion of carbonyl
compounds by a one-carbon unit is a frequently encoun-
tered synthetic objective and has attracted widespread
and continuing interest (for recent examples, see refs
1-5). Carbon insertion is the most straightforward and
most commonly used strategy for this purpose. The
numerous procedures for the insertions of carbons bear-
ing C-linked substituents into aldehydes and ketones
available in the literature can be classified into the
following categories: (i) diazo insertion reactions utilizing
ethyl diazoacetate,6-8 R-diazo ketones and aldehydes,9
diazoalkanes,2 and aryl diazomethanes;10,11 (ii) â-oxido
carbenoid chemistry as initiated by Yamamoto using
dihalomethyllithiums12 and recently extensively devel-
oped by Yamakawa1 with chloromethyl sulfoxides as
advantageous reagents for the insertions of carbons
bearing an alkyl1c,13 and an aryl13 groups into aldehydes
and ketones; (iii) semipinacol-type rearrangements, alky-
lidene insertions utilizing R-lithioalkyl sulfoxides14 and
While several arylmethylene insertion routes to one-
carbon-homologated R-aryl-substituted ketones are avail-
able as mentioned above, insertions of carbons carrying
heteroaryl groups into carbonyl compounds were previ-
ously unknown. Moreover, all the previous approaches
possess limitations: (i) Direct insertions of the corre-
sponding aryl diazomethanes10-11 are not suitable for
large-scale preparations and often suffer from epoxide
formation and multiple homologation. (ii) The original
â-oxido carbenoid route is limited by the extreme thermal
instability of the (R,R-dibromobenzyl)lithium reagent.16a
(iii) Sisti’s semipinacol-type rearrangement17 involves
three steps and is limited to cyclic ketones.
Since our preliminary paper,22 we have undertaken a
systematic investigation of the benzotriazole-mediated
insertion route to one-carbon-chain extended or ring-
expanded R-functionalized ketones. In the preceding
paper,23 we have described the efficient benzotriazole-
mediated insertions of carbons carrying O-, S-, and
N-linked substituents to give R-alkoxyalkyl-, R-(alkyl-
thio)alkyl-, and R-(carbazol-9-yl)alkyl-substituted ke-
tones. We now provide full details for the insertions of
carbons carrying aryl and heteroaryl groups to furnish
one-carbon-homologated R-aryl- and R-heteroaryl-substi-
tuted ketones and comment on the generality of and
X Abstract published in Advance ACS Abstracts, October 1, 1996.
(1) (a) Satoh, T.; Mizu, Y.; Kawashima, T.; Yamakawa, K. Tetrahe-
dron 1995, 51, 703. (b) Satoh, T.; Itoh, N.; Gengyo, K.; Yamakawa, K.
Tetrahedron Lett. 1992, 33, 7543. (c) Satoh, T.; Hayashi, Y.; Mizu, Y.;
Yamakawa, K. Tetrahedron Lett. 1992, 33, 7181. (d) Satoh, T.; Fujii,
T.; Yamakawa, K. Bull. Chem. Soc. J pn. 1990, 63, 1266.
(2) (a) Maruoka, K.; Concepcion, A. B.; Yamamoto, H. J . Org. Chem.
1994, 59, 4725. (b) Maruoka, K.; Concepcion, A. B.; Yamamoto, H.
Synthesis 1994, 1283.
(3) Montana, J . G.; Phillipson, N.; Taylor, R. J . K. J . Chem. Soc.,
Chem. Commun. 1994, 2289.
(4) Trost, B. M.; Mikhail, G. K. J . Am. Chem. Soc. 1987, 109, 4124.
(5) Krow, G. R. Tetrahedron 1987, 43, 3.
(6) Holmquist, C. R.; Roskamp, E. J . J . Org. Chem. 1989, 54, 3258.
(7) Nagao, K.; Chiba, M.; Kim, S.-W. Synthesis 1983, 197.
(8) Mock, W. L.; Hartman, M. E. J . Org. Chem. 1977, 42, 459.
(9) Padwa, A.; Hornbuckle, S. F.; Zhang, Z.; Zhi, L. J . Org. Chem.
1990, 55, 5297.
(15) Gadwood, R. C. J . Org. Chem. 1983, 48, 2098.
(16) (a) Labar, D.; Laboureur, J . L.; Krief, A. Tetrahedron Lett. 1982,
23, 983. (b) Krief, A.; Dumont, W.; Laboureur, J . L. Tetrahedron Lett.
1988, 29, 3265. (c) Laboureur, J . L.; Krief, A. Tetrahedron Lett. 1984,
25, 2713.
(17) (a) Sisti, A. J . Tetrahedron Lett. 1967, 5327. (b) Sisti, A. J . J .
Org. Chem. 1970, 35, 2670. (c) Sisti, A. J .; Rusch, G. M.; Sukhon, H.
K. J . Org. Chem. 1971, 36, 2030.
(10) Loeschorn, C. A.; Nakajima, M.; McCloskey, P. J .; Anselme, J .-
P. J . Org. Chem. 1983, 48, 4407.
(11) Gutsche, C. D.; J ohnson, H. E. J . Am. Chem. Soc. 1955, 77,
109.
(12) (a) Taguchi, H.; Yamamoto, H.; Nozaki, H. J . Am. Chem. Soc.
1974, 96, 6510. (b) Taguchi, H.; Yamamoto, H.; Nozaki, H. Tetrahedron
Lett. 1976, 2617.
(13) Villieras, J .; Perriot, P.; Normant, J . F. Synthesis 1979, 968.
(14) Gadwood, R. C.; Mallick, I. M.; DeWinter, A. J . J . Org. Chem.
1987, 52, 774.
(18) Kim, S.; Lee, S. Tetrahedron Lett. 1991, 32, 6575.
(19) Dowd, P.; Choi, S.-C. J . Am. Chem. Soc. 1987, 109, 3493.
(20) Boger, D. L.; Mathvink, R. J . J . Org. Chem. 1990, 55, 5442.
(21) Bunce, R. A.; Schilling, C. L., III. J . Org. Chem. 1995, 60, 2748.
(22) Katritzky, A. R.; Xie, L.; Toader, D.; Serdyuk, L. J . Am. Chem.
Soc. 1995, 117, 12015.
(23) Katritzky, A. R.; Xie, L.; Serdyuk, L. J . Org. Chem. 1996, 61,
7564.
S0022-3263(96)00841-9 CCC: $12.00 © 1996 American Chemical Society

7572 J . Org. Chem., Vol. 61, No. 21, 1996
Katritzky et al.
a
Sch em e 1
r-Ar yl an d- r-Heter oar yl-Su bstitu ted Keton es. Treat-
ment of the deep green solutions of 4 prepared in situ
with aldehydes or ketones at -78 °C for 4 h gave the
intermediate products 5 (Scheme 1). The intermediates
5 thus produced were shown in each case to be capable
of in situ rearrangement promoted by a ca. 3-fold molar
excess of zinc bromide upon heating to furnish one-
carbon-homologated R-aryl- and R-heteroaryl-substituted
ketones 2a -u in moderate to excellent yields (Tables 1
and 2). All compounds prepared showed the expected
NMR spectra, and all new compounds were further
characterized by elemental analyses (see Experimental
Section).
As discussed in our preceding paper,23 zinc bromide is
necessary for the departure of the benzotriazolyl group.
An excess of the Lewis acid and complete coordination
of the oxygen anion with zinc cation were found to be
crucial to suppress the tendency of intermediates 5 to
revert back to the starting materials. The reaction
temperatures necessary for the rearrangement vary as
listed in Tables 1 and 2. As expected, the greater the R
group stabilization (Scheme 1) of the transient cation,
the lower the temperature needed to complete the rear-
rangement. In those cases where the required temper-
ature was higher than the boiling point of THF, the THF
was distilled off and an appropriate solvent (or no
solvent) was added for the rearrangement stage.
Of special importance is the general applicability of
these insertions to diverse aldehydes and ketones. While
Table 1 shows examples of insertions into aliphatic and
aromatic aldehydes and acyclic ketones to give chain-
extended products, Table 2 illustrates the successful
insertions into cyclic ketones to provide ring-expanded
ketones. The regioselectivity of these insertions is also
significant. In most cases (entries 1-11 in Table 1 and
entries 1-7 in Table 2), single regioisomers were pro-
duced by migration of the group (R1, see Scheme 1) that
can best stabilize an electron deficiency in the transition
state, i.e., in general, H > Ar > alkyl; tert-alkyl > sec-
alkyl > n-alkyl. Similar migration aptitudes were found
in other pinacol-type rearrangements.29 Although the
yields of 2e and 2g were only moderate, no other
regioisomers were detected according to GCMS analysis
of the crude products; the relatively low yields of 2e and
2g were due either to the partial recovery of the inter-
mediates 5 or to the reverse reaction of 5 to the starting
materials. In the case of 2l (entry 12 in Table 1), the
alternative regioisomer 3l, derived from the migration
of the trifluorophenyl group (R2, see Scheme 1), was
formed in 27% yield based on the GCMS and NMR
results of the crude product, although its separation was
not achieved.
a
Bt ) benzotriazol-1-yl; R ) aryl, heteroaryl (see Tables 1 and
2 for the designation of R).
significant exceptions to the scope of this synthetic
transformation. Substituent effects on relative migration
rates are also described.
Resu lts a n d Discu ssion
P r epa r a tion of 1-(Ar ylm eth yl)- a n d 1-(Heter oa r yl-
m eth yl)ben zotr ia zoles 1a -f a n d in Situ P r ep a r a -
tion of Th eir Lith io Der iva tives 4a -f. 1-(4-Methyl-
benzyl)benzotriazole (1a ),24 1-[4-(N,N-dimethylamino)-
benzyl]benzotriazole (1b),25 1-[(1-methylindol-3-yl)meth-
yl]benzotriazole (1d ),26 and 1-(4-methoxybenzyl)benzo-
triazole (1e)27 were made according to previously reported
procedures. 1-[(5-Methylthien-2-yl)methyl]benzotriazole
(1c) was produced by treatment of 1-(hydroxymethyl)-
benzotriazole with 2-methylthiophene in refluxing acetic
acid in 50% yield. 1-(4-Chlorobenzyl)benzotriazole (1f)
was prepared in good yield from the reaction of 4-chlo-
robenzyl chloride with benzotriazole in refluxing toluene.
All these benzotriazole derivatives 1a -f can easily be
prepared on a large scale; novel compound 1c was
characterized by NMR spectroscopy and elemental analy-
ses.
Two different insertion reagents each reacted with
2-methylcyclohexanone (entries 8 and 9 in Table 2) to
afford two regioisomers (2 and 3) in each case. In the
case of entry 8, 2t and 3t were separated in yields of 81%
and 3%, and the GCMS analysis of the crude reaction
mixture indicated that they were formed in a ratio of 11:
1. In the case of entry 9, 2u and 3u were formed in a
ratio of 5:1 according to the GCMS of the crude product,
although only 2u was separated in 66% yield. These
results again reveal preferential migrations of the most
substituted alkyl group.
Lithio derivatives 4a -f were prepared in situ as deep
green solutions in THF under argon by stirring com-
pounds 1 with n-butyllithium at -78 °C for ca. 30 min
(Scheme 1). Anions 4d and 4e have been previously
documented to react readily with electrophiles followed
by the displacement of the benzotriazolyl group to furnish
functionalized indoles,26 carbazoles,28 and methoxyben-
zenes.27
Ar ylm eth ylen e a n d Heter oa r ylm eth ylen e In ser -
tion s in to Ald eh yd es a n d Keton es: P r ep a r a tion of
In the preceding paper, it was demonstrated that the
(24) Gibson, M. S. J . Chem. Soc. 1956, 1076.
(25) Katritzky, A. R.; Lan, X.; Lam, J . N. Synthesis 1990, 341.
(26) Katritzky, A. R.; Xie, L.; Cundy, D. Synth. Commun. 1995, 25,
539.
(27) Katritzky, A. R.; Lan, X.; Lam, J . N. Chem Ber. 1991, 124, 1819.
(28) Katritzky, A. R.; Xie, L. J . Org. Chem. 1995, 60, 3707.
(29) Hanson, J . R. (Section 3.1); Rickborn, B. (Section 3.2 and 3.3);
Coveney, D. J . (Section 3.4) In Comprehensive Organic Synthesis; Trost,
B. M., Fleming, I., Eds.; Pergamon Press: New York, 1991; Vol. 3, p
705.

Synthesis of R-Aryl- and R-Heteroaryl-Substituted Ketones
J . Org. Chem., Vol. 61, No. 21, 1996 7573
Ta ble 1. Ar ylm eth ylen e a n d Heter oa r ylm eth ylen e In ser tion s in to Ald eh yd es a n d Acyclic Keton es: P r ep a r a tion of
On e-Ca r bon Ch a in -Exten d ed Keton es
alkoxymethylene and (alkylthio)methylene insertions
proceeded through the epoxide intermediates by success-
ful isolation of the latter.23 Epoxide intermediates seem
unlikely in most of the present reactions, since in not one
of the cases described in Tables 1 and 2 were any of the
regioisomers 9 and 10 (Scheme 1) detected. If epoxides
6 were intermediates, formation of compounds 9 and 10
would be expected alongside insertion products 2 and 3,
especially in the cases of entries 7-9 and 12 of Table 1
where the corresponding tertiary cationic species 8
should be more stable than secondary cationic species 7.
However, the epoxide mechanism was implicated in one
experiment as shown in Scheme 2. Treatment of the
anion of 1-(4-methoxybenzyl)benzotriazole (1e) with p-
tolualdehyde, followed by zinc bromide-assisted rear-
rangement, gave an inseparable mixture of ketones 2w
and 9w together with aldehyde 10w in the ratio of 3:1:
12 in total 88% yield based on the NMR and GCMS
results of the crude product. These results suggest that
epoxide 6 is the intermediate (Scheme 1), which can open
up from both sides to give cationic intermediates 7 and
8. While 7 leads to the “normal” insertion product 2w
(via path a, hydride migration), subsequent hydride (path
a) and 4-methoxyphenyl (path b) migrations of 8 furnish
ketone 9w and aldehyde 10w . It is noteworthy that in
this case the 4-methoxyphenyl group migrates preferen-
tially over the hydrogen due to the existence of the
electron-donating methoxy group, which reflects a sig-
nificant substituent effect on the migration aptitude. The
reason for the different behavior in the case of 1e from
all those in Tables 1 and 2 has not yet been fully clarified.
However, the diastereoselectivity of the initial addition
does not determine product structures since for the
reaction described in Scheme 2 the same products were
obtained in the same proportions when the two diaste-
reoisomers of adduct intermediate 11 were isolated and
treated with ZnBr2 separately.
To explore further the generality of this insertion
methodology, 1-(3-phenylallyl)benzotriazole (1g) was pre-
pared from the reaction of cinnamyl bromide with ben-
zotriazole in the presence of sodium ethoxide in ethanol
in 52% yield. The scope of this methodology was thus
extended to vinyl-substituted methylene insertions as
exemplified by the successful preparation of 2-(2-phen-

7574 J . Org. Chem., Vol. 61, No. 21, 1996
Katritzky et al.
Ta ble 2. Ar ylm eth ylen e a n d Heter oa r ylm eth ylen e In ser tion s in to Cyclic Keton es: P r ep a r a tion of On e-Ca r bon
Rin g-Exp a n d ed Keton es
Sch em e 2
terminal to assist the departure of the benzotriazolyl
group in 5 (Scheme 1) was found to be essential since
the simple allyl analog 1-allylbenzotriazole failed to give
homologation products: even at 220 °C for 10 h, the
intermediate 5 was still present, while higher tempera-
tures caused tar formation. Vinyl-substituted methylene
homologations of ketones have previously been accom-
plished by direct insertion of the corresponding diazo
compounds2 and a rather complex radical process.18
Su bstitu en t Effects on Rela tive Migr a tion Ra tes.
To gain insight into the mechanism of this reaction, we
examined the electronic effects of the substituents on the
transition state. 1-(4-Methoxybenzyl)benzotriazole (1e)
was used for insertion into a series of p-substituted
benzophenones according to our methodology (Scheme 3).
The reaction conditions were the ones used for the
synthesis of 2l (Table 1, entry 12), i.e., heating at 155 °C
for 3 h without solvent. Under these conditions, solvent
and steric influences upon variation in the migration
rates are minimized. The crude mixture of products was
ylvinyl)cycloheptanone (2v) from 1-(3-phenylallyl)benzo-
triazole (1g) and cyclohexanone (Table 2, entry 10).
However, a stabilizing group such as phenyl at the vinylic

Synthesis of R-Aryl- and R-Heteroaryl-Substituted Ketones
J . Org. Chem., Vol. 61, No. 21, 1996 7575
Sch em e 3
in many cases, ready availability of starting materials,
and simple one-pot procedures.
Exp er im en ta l Section
Gen er a l P r oced u r es. Melting points were determined
with a hot-stage apparatus and are uncorrected. NMR spectra
were taken in CDCl3 with tetramethylsilane as the internal
1
standard for H (300 MHz) or solvent as the internal standard
for 13C (75 MHz). Tetrahydrofuran was distilled under nitro-
gen immediately prior to use from sodium/benzophenone. All
reactions with air-sensitive compounds were carried out under
an argon atmosphere. Column chromatography was conducted
with silica gel 230-400 mesh. 1-(4-Methylbenzyl)benzotria-
zole (1a),24 1-[4-(N,N-dimethylamino)benzyl]benzotriazole (1b),25
1-[(1-methylindol-3-yl)methyl]benzotriazole (1d ),26 and 1-(4-
methoxybenzyl)benzotriazole (1e)27 were prepared according
to previously reported procedures.
P r ep a r a tion of 5-Meth yl-2-(ben zotr ia zol-1-ylm eth yl)-
th iop h en e (1c). A mixture of (hydroxymethyl)benzotriazole
(4.5 g, 30 mmol) and 2-methylthiophene (3.4 g, 35 mmol) in
glacial acetic acid (50 mL) was refluxed for 48 h. After the
acetic acid was distilled off under reduced pressure, aqueous
sodium hydroxide (5%, 30 mL) and chloroform (50 mL) were
added. The organic layer was separated, washed with water
(50 mL), and dried (MgSO4). After the solvent was removed,
the residue was crystallized from methylene chloride and
hexanes to give the pure product as a brownish solid (3.4 g,
50%): mp 108-109 °C; 1H NMR δ 2.40 (s, 3 H), 5.92 (s, 2 H),
6.60 (d, J ) 3.4 Hz, 1 H), 6.90 (d, J ) 3.4 Hz, 1 H), 7.35 (dd,
J 1 ) J 2 ) 6.7 Hz, 1 H), 7.46 (m, 2 H), 8.05 (d, J ) 8.3 Hz, 1 H);
13C NMR δ 15.4, 47.2, 109.6, 120.0, 123.8, 125.0, 127.3, 127.4,
132.3, 134.0, 141.3, 146.2. Anal. Calcd for C12H11N3S: C,
62.86; H, 4.84; N, 18.33. Found: C, 62.52; H, 4.79; N, 18.33.
P r ep a r a tion of 1-(4-Ch lor oben zyl)ben zotr ia zole (1f).
A solution of benzotriazole (23.8 g, 200 mmol) and 4-chlo-
robenzyl chloride (22.5 g, 140 mmol) in toluene (200 mL) was
refluxed for 48 h. After being cooled to room temperature, the
solution was washed with aqueous sodium hydroxide (5%, 2
× 100 mL) and water (100 mL) to remove excess benzotriazole.
The toluene solution was then extracted with cold hydrochloric
acid (25%, 5 × 50 mL) to allow complete extraction of the
product into the aqueous layer. To the combined aqueous
extract was added water (500 mL), and the solution was then
extracted with benzene (3 × 100 mL). The combined benzene
solution was washed with water (2 × 50 mL) and dried
(MgSO4). After the solvent was removed, the residue was
crystallized from methanol to give a white solid (22.5 g, 66%):
mp 101-102 °C (lit.33 mp 90 °C); 1H NMR δ 5.78 (s, 2 H), 7.18
(d, J ) 8.3 Hz, 2 H), 7.27 (d, J ) 8.3 Hz, 2 H), 7.33-7.42 (m,
3 H), 8.04 (d, J ) 8.0 Hz, 1 H); 13C NMR δ 51.2, 109.4, 119.8,
123.9, 127.4, 128.8, 129.0, 132.5, 133.1, 134.2, 146.1. Anal.
Calcd for C13H10ClN3: C, 64.07; H, 4.14; N, 17.24. Found: C,
64.02; H, 3.88; N, 17.36.
analyzed by GCMS, and the identities of the two products
2 and 3 were assigned according to their fragmentation
patterns: a peak at m/z 105 was diagnostic for the
product containing an unsubstituted benzoyl group. The
migration ratio of substituted phenyl to give product 2
and of unsubstituted phenyl to form product 3 was
calculated. This ratio represents the relative migration
aptitude of a substituted phenyl free of steric and solvent
effects. The data are presented in Table 3. When log(kX/
kH) was plotted against the corresponding σ and σ+
values,30 the corresponding F and F+ values were obtained
(Table 3). The linear correlation is better for F+ (correla-
tion coefficient 0.982) than for F (correlation coefficient
0.931). The negative value for the selectivity parameter
(F+) signifies that electron-donating substituents acceler-
ate the migration rate and suggests that bond making
(of bond a ) is further advanced in the transition state 12
than bond breaking (of bond b)(see Scheme 3).
A
correlation is with σ+ rather than with σ, indicating that
conjugative electronic interaction in the transition state
between ring substituent and the cationic center domi-
nates over field effects. The small |F+| value indicates
(i) an early, reagent-like transition state,31 similar to a
phenonium ion where â-aryl group assists leaving of the
benzotriazole,32 and (ii) a small contribution from cationic
structures of types 8 to the transition state (Scheme 1)
since if 8 was important, the |F+| value should have been
much higher (higher than 3) due to strong interaction
between the CR carbocation and the substituent.
Thus, the Hammett correlation implicates an early
reagent-like transition state with cationic character for
this process.
P r ep a r a tion of (E)-3-(Ben zotr ia zol-1-yl)-1-p h en yl-1-
p r op en e (1g). To a solution of sodium ethoxide prepared from
sodium metal (2.3 g, 100 mmol) in ethanol (200 mL) were
added benzotriazole (13.1 g, 110 mmol) and cinnamyl bromide
(19.7 g, 100 mmol). The mixture was refluxed overnight. After
the ethanol was removed, benzene (200 mL) was added, and
the solution was washed with aqueous sodium hydroxide (5%,
2 × 100 mL) and water (100 mL) to remove excess benzotria-
zole. The benzene solution was then extracted with cold
hydrochloric acid (25%, 3 × 100 mL) to allow complete
extraction of the product into the aqueous solution. To the
combined aqueous extract was added water (500 mL), and the
solution was then extracted with benzene (3 × 100 mL). The
combined benzene solution was washed with water (2 × 50
Con clu sion
Various 1-(arylmethyl)- and 1-(heteroarylmethyl)ben-
zotriazoles are excellent insertion reagents for the trans-
formations of aldehydes and ketones into one-carbon
chain-extended or ring-expanded R-aryl- and R-het-
eroaryl-substituted ketones. Advantages of this meth-
odology include wide generality, excellent regioselectivity
mL) and dried (MgSO4
). Removal of the solvent gave white
prisms (12.2 g, 52%): mp 79 °C (lit.34 mp 75-76 °C); 1H NMR
δ 5.37 (dd, J ) 6.2, 1.4 Hz, 2 H), 6.34 (dt, J ) 15.8, 6.2 Hz, 1
H), 6.62 (dt, J ) 15.8, 1.4 Hz, 1 H), 7.21-7.35 (m, 6 H), 7.41
(30) Hansch, C.; Leo, A.; Taft, R. W. Chem. Rev. 1991, 91, 165.
(31) Ruasse, M.-F.; Dubois, J .-E. J . Am. Chem. Soc. 1984, 106, 3230.
(32) Lancelot, C. J .; Cram, D. J .; Schleyer, P. v. R. Phenonium Ions.
in Carbonium Ions; Olah, G. A., Schleyer, P. v. R., Eds.; Wiley: New
York, 1972; Vol. III.
(33) Kreutzberger, A.; Stratmann, J . Arch. Pharm. (Weinheim) 1979,
312, 806.
(34) Arnau, N.; Arredondo, Y.; Moreno-Manas, M.; Pleixats, R.;
Villarroya, M. J . Heterocycl. Chem. 1995, 32, 1325.

7576 J . Org. Chem., Vol. 61, No. 21, 1996
Katritzky et al.
Ta ble 3. Ha m m ett Cor r ela tion s
X
p-OCH3
p-CH3
p-F
p-H
p-Cl
0.74
-0.131
p-Br
0.59
-0.229
p-CF3
kX/kH
5.75
0.760
2.45
0.389
1.24
0.093
1
0
0.37
-0.432
log (kX/kH)
F+(r)
-0.92a (0.982)b
-1.34c (0.931)b
F(r)
log (kX/kH) plotted against σ+ for F+. Constants were taken from ref 30. Correlation coefficient. c log(kX/kH) plotted against σ for F.
a
b
(td, J ) 8.3, 1.0 Hz, 1 H), 7.52 (dd, J ) 8.3, 1.0 Hz, 1 H), 8.05
136.6, 149.5, 198.1. Anal. Calcd for C16H17NO: C, 80.30; H,
7.16; N, 5.85. Found: C, 80.59; H, 7.19; N, 5.75.
(dd, J ) 8.3, 1.0 Hz, 1 H); 13C NMR δ 50.3, 109.6, 119.8, 122.0,
123.7, 126.4, 127.1, 128.1, 128.5, 132.7, 134.2, 135.4, 146.1.
Anal. Calcd for C15H13N3: C, 76.57; H, 5.57; N, 17.86.
Found: C, 76.52; H, 5.55; N, 17.90.
1-(4-Ch lor oph en yl)-2-(1-m eth ylin dol-3-yl)eth an on e (2f).
Hexanes:ethyl acetate (2:1) was used as the eluent to give a
1
white powder: mp 114-115° C; H NMR δ 3.68 (s, 3H), 4.32
Gen er a l P r oced u r e for th e In ser tion s in to Ald eh yd es
a n d Keton es: P r ep a r a tion of r-Ar yl- a n d r-Heter oa r yl-
Su bstitu ted Keton es 2a -u , 3t, a n d 2-((E)-2-P h en yleth en -
yl)cycloh ep ta n on e (2v). To a solution of an appropriate
benzotriazole derivative (5 mmol) in THF (50 mL) at -78 °C
under argon was added n-BuLi (2 M, 2.8 mL, 5.5 mmol). After
30 min, a solution of an appropriate aldehyde or ketone (5.5
mmol) in THF (10 mL) was added. The mixture was stirred
at -78 °C for an additional 4 h and allowed to warm to room
temperature overnight. A solution of zinc bromide (15 mmol)
in THF (15 mL) was then added. As indicated in Table 1, (i)
the mixture was refluxed in THF (for entries 5, 6, and 11 in
Table 1 and entries 3, 6 and 8 in Table 2), (ii) the THF was
removed, an appropriate solvent (15 mL) added, and the
mixture refluxed (for entries 2, 3, and 9 in Table 1 and entries
1, 2, 7, 9, and 10 in Table 2), or (iii) the THF was removed
and the residue was heated at an appropriate temperature (for
entries 1, 4, 7, 8, 10, and 12 in Table 1, 4, and 5 in Table 2).
Ethyl acetate (150 mL) and diethyl ether (100 mL) were added
to the residue, and the mixture was stirred for 1 h at room
temperature. The solid was filtered off, and the solution was
washed with water (2 × 100 mL) and dried (MgSO4). After
the solvent was removed, the residue was subjected to column
chromatography to give the pure product.
(s, 2 H), 6.93 (s, 1H), 7.13 (t, J ) 7.9 Hz, 1H), 7.23 (m, 2H),
7.36 (d, J ) 6.8 Hz, 2H), 7.57 (d, J ) 7.9 Hz, 1H), 7.95 (d, J )
6.8 Hz, 2H); 13C NMR δ 32.6, 35.5, 106.9, 109.3, 118.7, 119.2,
121.8, 127.6, 127.7, 128.8, 130.0, 134.9, 136.9, 139.3, 196.5.
Anal. Calcd for C17H14ClNO: C, 71.96; H, 4.97; N, 4.94.
Found: C, 71.63; H, 4.91; N, 4.79.
1-(4-Meth ylp h en yl)-1-p h en yl-2-p r op a n on e (2g). Hex-
anes:diethyl ether (3:1) was used as the eluent to give a
colorless oil (lit.36 bp 143-148 °C/0.25mm): 1H NMR δ 2.19
(s, 3H), 2.29 (s, 3H), 5.06 (s, 1H), 7.11 (m, 4H), 7.19-7.31 (m,
5H); 13C NMR δ 20.9, 29.8, 64.5, 127.0, 128.5, 128.7, 128.8,
129.3, 135.2, 136.8, 138.4, 206.5; HRMS calcd for C16H16
224.1201, found 224.1211.
O
1-(4-Meth oxyp h en yl)-1-p h en yl-2-p r op a n on e (2h ). Hex-
anes:diethyl ether (3:1) was used as the eluent to give a
colorless oil (lit.37 bp 225 °C/25mm): 1H NMR δ 2.20 (s, 3H),
3.75 (s, 3H), 5.05 (s, 1H), 6.85 (d, J ) 8.8 Hz, 2H), 7.13 (d, J
) 8.8 Hz, 2H), 7.19-7.31 (m, 5H); 13C NMR δ 29.8, 55.1, 64.1,
114.0, 127.0, 128.6, 128.8, 129.9, 130.3, 138.6, 158.7, 206.6;
HRMS calcd for C16H16O2 241.1229 (M + 1), found 241.1227.
1-(5-Meth ylth ien -2-yl)-1-p h en yl-2-p r op a n on e (2i). Hex-
anes:diethyl ether (2:1) was used as the eluent to give a
colorless oil: 1H NMR δ 2.19 (s, 3H), 2.39 (s, 3H), 5.17 (s, 1H),
6.56-6.57 (m, 1H), 6.61-6.63 (m, 1H), 7.26-7.31 (m, 5H); 13
C
1-(4-Meth ylph en yl)-4-ph en yl-2-bu tan on e (2a). Hexanes:
diethyl ether (3:1) was used as the eluent to give a white
NMR δ 15.1, 29.0, 59.9, 124.5, 126.0, 127.4, 128.4, 128.7, 138.1,
138.2, 139.6, 204.7. Anal. Calcd for C14H14OS: C, 73.01; H,
6.13. Found: C, 72.83; H, 6.17.
1
solid: mp 65-66 °C; H NMR δ 2.31 (s, 3 H), 2.70-2.76 (m, 2
H), 2.81-2.87 (m, 2 H), 3.59 (s, 2 H), 7.01-7.26 (m, 9 H); 13C
NMR δ 21.0, 29.7, 43.3, 49.9, 126.0, 128.2, 128.4, 129.2, 129.4,
131.0, 136.5, 140.9, 207.5. Anal. Calcd for C17H18O: C, 85.67;
H, 7.61. Found: C, 86.00; H, 7.74.
3-(4-Met h oxyp h en yl)-4,4-d im et h yl-2-p en t a n on e (2j).
Hexanes:diethyl ether (3:1) was used as the eluent to give a
colorless oil: 1H NMR δ 0.97 (s, 9H), 2.06 (s, 3H), 3.54 (s, 1H),
3.79 (s, 3H), 6.84 (d, J ) 8.8 Hz, 2H), 7.17 (d, J ) 8.8 Hz, 2H);
13C NMR δ 27.8, 32.3, 34.3, 55.1, 67.1, 113.4, 127.9, 131.3,
158.7, 209.1; HRMS calcd for C14H20O2 221.1542 (M + 1), found
221.1541.
1-[4-(N ,N -Dim e t h yla m in o)p h e n yl]-4-p h e n yl-2-b u t a -
n on e (2b). Hexanes:diethyl ether (3:1) was used as the eluent
to give a white solid: mp 42-43 °C; 1H NMR δ 2.71 (t, J ) 8.0
Hz, 2H), 2.83 (t, J ) 8.0 Hz, 2H), 2.89 (s, 6H), 3.52 (s, 2H),
6.65 (d, J ) 8.6 Hz, 2H), 7.01 (d, J ) 8.6 Hz, 2H), 7.08-7.24
(m, 5H); 13C NMR δ 29.7, 40.4, 42.9, 49.4, 112.8, 121.7, 125.8,
128.2, 128.3, 129.8, 141.0, 149.5, 208.2. Anal. Calcd for
C18H21NO: C, 80.86; H, 7.92; N, 5.24. Found: C, 81.11; H,
8.09; N, 4.94.
1-(5-Meth ylth ien -2-yl)-4-p h en yl-2-bu ta n on e (2c). Hex-
anes:diethyl ether (2:1) was used as the eluent to give a white
solid: mp 43-44 °C; 1H NMR δ 2.42 (s, 3H), 2.65-2.92 (m,
4H), 3.73 (s, 2H), 6.57-6.59 (m, 2H), 7.12-7.25 (m, 5H); 13C
NMR δ 15.2, 29.7, 43.0, 44.0, 125.0, 126.0, 126.6, 128.2, 128.4,
132.7, 139.5, 140.8, 206.0. Anal. Calcd for C15H16OS: C, 73.73;
H, 6.60. Found: C, 73.88; H, 6.64.
4,4-Dim eth yl-3-(1-m eth ylin d ol-3-yl)-2-p en ta n on e (2k ).
Hexanes:diethyl ether (3:1) was used as the eluent to give a
1
white solid: mp 65 °C; H NMR δ 1.04 (s, 9 H), 2.10 (s, 3H),
3.73 (s, 3H), 3.96 (s, 1H), 6.99 (s, 1H), 7.12 (dd, J 1 ) J 2 ) 8.0
Hz, 1H), 7.21 (dd, J 1 ) J 2 ) 8.0 Hz, 1H), 7.28 (d, J ) 8.0 Hz,
1H), 7.65 (d, J ) 8.0 Hz, 1H); 13C NMR δ 28.1, 32.5, 32.7, 34.9,
58.1, 109.0, 109.2, 119.0, 119.1, 121.4, 128.8, 129.0, 136.6,
209.7. Anal. Calcd for C16H21NO: C, 78.97; H, 8.70; N, 5.76.
Found: C, 78.96; H, 8.91; N, 5.53.
1-[4-(Tr iflu or om eth yl)p h en yl]-2-(4-m eth oxyp h en yl)-2-
p h en yleth a n on e (2l). Hexanes:diethyl ether (4:1) was used
as the eluent to give colorless prisms: mp 84-85 °C; 1H NMR
δ 3.75 (s, 3H), 5.95 (s, 1H), 6.86 (d, J ) 8.8 Hz, 2H), 7.18 (d, J
) 8.8 Hz, 2H), 7.22-7.35 (m, 5H), 7.64 (d, J ) 8.0 Hz, 2H),
8.07 (d, J ) 8.0 Hz, 2H); 13C δ NMR 55.2, 59.1, 114.3, 123.5
(q, J ) 271.0 Hz), 125.6 (q, J ) 4.8 Hz), 127.3, 128.8, 129.0,
129.2, 130.1, 130.4, 134.1(q, J ) 32.6 Hz), 138.8, 139.5, 158.9,
197.5. Anal. Calcd for C22H17OF3: C, 71.35; H, 4.63. Found:
C, 71.22; H, 4.47.
1-[4-(N,N-Dim et h yla m in o)p h en yl]-3,3-d im et h yl-2-b u -
ta n on e (2d ). Hexanes:diethyl ether (3:1) was used as the
1
eluent to give a white solid: mp 34-36 °C; H NMR δ 1.17 (s,
9H), 2.89 (s, 6H), 3.68 (s, 2H), 6.68 (d, J ) 8.8 Hz, 2H), 7.04
(d, J ) 8.8 Hz, 2H); 13C NMR δ 26.4, 40.6, 42.3, 44.4, 112.7,
122.7, 130.0, 149.4, 213.4. Anal. Calcd for C14H21NO: C,
76.67; H, 9.65; N, 6.39. Found: C, 76.26; H, 9.72; N, 6.36.
1-P h en yl-2-[4-(N,N-d im et h yla m in o)p h en yl]et h a n on e
(2e). Hexanes:diethyl ether (1:1) was used as the eluent to
give a white solid: mp 119-120 °C (lit.35 mp 128 °C); 1H NMR
δ 2.88 (s, 6H), 4.15 (s, 2H), 6.67 (d, J ) 7.0 Hz, 2H), 7.12 (d, J
) 7.0 Hz, 2H), 7.37-7.52 (m, 3H), 7.99 (d, J ) 8.6 Hz, 2H);
13C NMR δ 40.5, 44.5, 112.8, 122.1, 128.4, 128.5, 129.9, 132.8,
2-(4-Meth oxyp h en yl)cycloh ep ta n on e (2m ). Hexanes:
diethyl ether (3:1) was used as the eluent to give colorless
plates: mp 59-60 °C (from petroleum ether) (lit.38 mp 59-60
(36) Gragoe, E. J ., J r.; Pietruszkiewicz, A. M.; Robb, C. M. J . Org.
Chem. 1958, 23, 971.
(37) Levy, J .; Gallais, P.; Abragam, D. Bull. Chem. Soc. Fr. 1928,
43, 868.
(35) J enkins, S. S.; Buck, J . S.; Bigelow, L. A. J . Am. Chem. Soc.
1930, 52, 4495.
(38) Gutsche, C. D.; Strohmayer, H. F.; Chang, J . M. J . Org. Chem.
1958, 23, 1.

Synthesis of R-Aryl- and R-Heteroaryl-Substituted Ketones
J . Org. Chem., Vol. 61, No. 21, 1996 7577
1
°C); H NMR δ 1.39-1.64 (m, 3H), 1.89-2.15 (m, 5H), 2.44 -
for C17H21NO: C, 79.96; H, 8.29; N, 5.49. Found: C, 79.98;
2.52 (m, 1H), 2.61-2.71 (m, 1H), 3.65 (dd, J )11.3, 4.1 Hz,
1H), 3.77 (s, 3H), 6.85 (d, J ) 8.8 Hz, 2H), 7.14 (d, J ) 8.4 Hz,
2H); 13C NMR δ 25.3, 28.4, 29.9, 31.9, 42.3, 55.1, 57.8, 113.8,
128.7, 132.3, 158.4, 213.6.
H, 8.47; N, 5.40. trans-3t: white plates; mp 83-84 °C; yield
(3%); H NMR δ 1.11 (d, J ) 6.7 Hz, 3H), 1.42-1.92 (m, 6H),
1
2.02-2.21 (m, 2H), 2.91-3.00 (m, 1H), 3.76 (s, 3H), 4.32 (dd,
J ) 9.7, 4.2 Hz, 1H), 7.06-7.11 (m, 1H), 7.16 (s, 1H), 7.17-
7.30 (m, 2H), 7.48 (d, J ) 7.9 Hz, 1H); 13C NMR δ 16.3, 25.4,
28.2, 32.5, 32.7, 33.2, 46.0, 47.9, 109.2, 113.9, 118.5, 118.7,
121.4, 127.0, 127.2, 136.6, 214.9. Anal. Calcd for C17H21NO:
C, 79.96; H, 8.29; N, 5.49. Found: C, 79.56; H, 8.61; N, 5.29.
2-(5-Meth ylth ien -2-yl)cycloh ep ta n on e (2n ). Hexanes:
diethyl ether (3:1) was used as the eluent to give a colorless
oil: 1H NMR δ 1.27-1.62 (m, 3 H), 1.78-2.10 (m, 4 H), 2.15-
2.30 (m, 1H), 2.41 (s, 3H), 2.42-2.50 (m, 1H), 2.65-2.73 (m,
1H), 3.85 (dd, J ) 11.1, 4.7 Hz, 1H), 6.58 (d, J ) 3.5 Hz, 1H),
6.65 (d, J ) 3.5 Hz, 1H); 13C NMR δ 15.1, 25.5, 27.8, 29.8,
32.6, 41.2, 54.2, 124.1, 124.6, 138.6, 139.8, 211.6. Anal. Calcd
for C12H16OS: C, 69.19; H, 7.74. Found: C, 69.33; H, 7.88.
2-(1-Met h ylin d ol-3-yl)cycloh ep t a n on e (2o). Hexanes:
ethyl acetate (2:1) was used as the eluent to give a colorless
oil: 1H NMR δ 1.43-1.50 (m, 2H), 1.55-1.72 (m, 1H), 1.92-
2.04 (m, 4H), 2.24-2.35 (m, 1H), 2.38-2.45 (m, 1H), 2.70-
2.79 (m, 1H), 3.73 (s, 3H), 4.04 (dd, J )11.3, 4.7 Hz, 1H), 7.00
(s, 1H), 7.11 (t, J ) 8.0 Hz, 1H), 7.19-7.28 (m, 2H), 7.67 (d, J
) 9.9 Hz, 1H); 13C NMR δ 25.6, 28.1, 30.0, 31.3, 32.6, 41.2,
50.4, 109.1, 113.3, 119.0, 119.5, 121.7, 126.2, 127.1, 136.9,
213.1. Anal. Calcd for C16H19NO: C, 79.63; H, 7.94; N, 5.80.
Found: C, 79.27; H, 8.03; N, 5.92.
2-[4-(N,N-Dim eth ylam in o)ph en yl]cycloh eptan on e (2p).
Hexanes:diethyl ether (1:1) was used as the eluent to give a
yellowish solid: mp 70-72 °C; 1H NMR δ 1.36-1.60 (m, 3H),
1.85-2.15 (m, 5H), 2.39-2.46 (m, 1H), 2.63-2.72 (m, 1H), 2.90
(s, 6H), 3.59 (dd, J ) 11.3, 4.2 Hz, 1H), 6.68 (d, J ) 8.5 Hz,
2H), 7.11 (d, J ) 8.5 Hz, 2H); 13C NMR δ 25.6, 28.1, 30.1, 31.5,
40.5, 42.0, 57.9, 112.7, 127.8, 128.2, 149.5, 213.8. Anal. Calcd
for C15H21NO: C, 77.88; H, 9.15; N, 6.05. Found: C, 77.63;
H, 9.32; N, 5.80.
2-(4-Ch lor op h en yl)cycloh exa n on e (2q). Hexanes:dieth-
yl ether (3:1) was used as the eluent to give white plates: mp
81-82 °C (lit.38 mp 77-78 °C); 1H NMR δ 1.77-2.50 (m, 8H),
3.57 (dd, J ) 11.9, 5.4 Hz, 1H), 7.05 (d, J ) 8.5 Hz, 2H), 7.28
(d, J ) 8.5 Hz, 2H); 13C NMR δ 25.3, 27.7, 35.2, 42.1, 56.7,
128.4, 129.9, 132.6, 137.2, 209.6. Anal. Calcd for C12H13OCl:
C, 69.07; H, 6.28. Found: C, 68.91; H, 6.25.
2-(1-Met h ylin d ol-3-yl)-3-m et h ylcycloh exa n on e (2r ).
Hexanes:diethyl ether (4:1) was used as the eluent to give a
colorless thick oil as a mixture of cis and trans isomers in a
ratio of 1.35:1 (signals for trans isomer in square brackets):
1H NMR δ 0.81 [0.87] (d, J )7.1 [7.2] Hz, 3H), 1.83-2.58 (m,
7H), 3.70 [3.73] (s, 3H), 4.25 [3.45] (d, J ) 4.8 [11.2] Hz, 1H),
6.86 [7.35] (s, 1H), 7.04-7.28 (m, 3H), 7.53 [7.40] (d, J ) 7.8
Hz, 1H); 13C NMR δ 15.3 [21.5], 23.7 [25.9], 31.2 [29.6], 34.2
[32.6], 38.1 [40.6], 41.1 [41.6], 52.6 [56.0], 109.0 [109.2], 110.5,
118.5 [118.6], 119.4, 121.2 [121.3], 127.9 [127.5], 128.0, 136.1
[136.9], 210.6 [210.5]; HRMS calcd for C16H19NO 242.1545 (M
+ 1), found 242.1517.
3-Met h yl-2-(5-m et h ylt h ien -2-yl)cycloh ep t a n on e (2u ).
Hexanes:diethyl ether (10:1) was used as the eluent to give
pure cis and trans isomers. cis Isomer: colorless oil; yield
(55%); 1H NMR δ 0.92 (d, J ) 7.2 Hz, 3H), 1.50-1.65 (m, 1H),
1.72-1.90 (m, 5H), 2.25-2.35 (m, 1H), 2.40-2.50 (m, 1H), 2.45
(s, 3H), 2.65 (dt, J ) 17.2, 5.0 Hz, 1H), 4.35 (d, J ) 2.8 Hz,
1H), 6.58-6.60 (m, 1H), 6.68 (d, J ) 3.6 Hz, 1H); 13C NMR δ
15.0, 16.2, 23.8, 24.8, 36.2, 37.0, 43.5, 56.8, 123.8, 125.4, 138.5-
(2C), 210.7; HRMS calcd for C13H18OS 222.1078, found 222.1074.
1
trans Isomer: colorless oil; yield (11%); H NMR δ 0.98 (d, J
) 6.7 Hz, 3H), 1.26-1.31 (m, 1H), 1.51-1.58 (m, 2H), 1.77-
2.03 (m, 4H), 2.30-2.36 (m, 1H), 2.43 (s, 3H), 2.77-2.85 (m,
1H), 3.40 (d, J ) 10.7 Hz, 1H), 6.69 (m, 1H), 6.70 (d, J ) 3.3
Hz, 1H); 13C NMR δ 15.2, 21.4, 27.2, 29.2, 36.4, 37.9, 40.4, 62.9,
124.9, 125.1, 138.6, 138.8, 211.1. Anal. Calcd for C13H18OS:
C, 70.23; H, 8.16. Found: C, 70.11; H, 8.41.
2-((E)-2-P h en yleth en yl)cycloh ep ta n on e (2v). Hexanes:
diethyl ether (6:1) was used as the eluent to give a colorless
oil: 1H NMR δ 1.37-1.99 (m, 8 H), 2.49-2.56 (m, 2H), 3.28-
3.35 (m, 1H), 6.30 (dd, J ) 16.0, 7.1 Hz, 1H), 6.40 (d, J ) 16.0
Hz, 1H), 7.19-7.35 (m, 5H); 13C NMR δ 24.7, 27.8, 29.5, 31.4,
42.3, 56.1, 126.1, 127.2, 128.4, 128.5, 130.7, 137.0, 213.4. Anal.
Calcd for C15H18O: C, 84.07; H, 8.47. Found: C, 83.90; H, 8.54.
P r epar ation of 2-(Ben zotr iazol-1-yl)-2-(4-m eth oxyph en -
yl)-1-(4-m eth ylp h en yl)eth a n ol (11). To a solution of 1-(4-
methoxybenzyl)benzotriazole (1e) (0.239 g, 1 mmol) in THF
(30 mL) at -78 °C under argon was adde dropwise n-BuLi
(2.2 M, 0.5 mL, 1.1 mmol). After 30 min, p-tolualdehyde (0.13
mL, 1 mmol) in THF (10 mL) was added. The mixture was
stirred at -78 °C for an additional 4 h and allowed to warm
to rt overnight. A saturated aqueous NH4Cl solution (30 mL)
was added, and the mixture was extracted with diethyl ether
(3 × 50 mL). The combined organic layer was washed with
brine and dried (MgSO4) and solvent removed under vacuum.
The remaining oil was subjected to column chromatography
(hexane:ether ) 1:1) to give threo (0.155 g, 42%) as the first
fraction and erythro (0.075 g, 21%) as the second fraction.
1
threo: mp 146-147 °C; H NMR δ 2.28 (s, 3H), 3.69 (s, 3H),
2-(5-Met h ylt h ien -2-yl)-3-m et h ylcycloh exa n on e (2s).
Hexanes:diethyl ether (10:1) was used as the eluent to give a
colorless oil in trans form: 1H NMR δ 0.94 (d, J ) 6.2 Hz,
3H), 1.55-2.13 (m, 5H), 2.34-2.56 (m, 2H), 2.46 (s, 3H), 3.44
3.88 (d, J ) 4.4 Hz, 1H), 5.75 (d, J ) 8.7 Hz, 1H), 5.89 (dd, J
) 8.6, 4.1 Hz, 1H), 6.66 (d, J ) 8.8 Hz, 2H), 6.98 (d, J ) 8.8
Hz, 2H), 7.03 (d, J ) 8.2 Hz, 2H), 7.10 (d, J ) 8.0 Hz, 2H),
7.28-7.37 (m, 3H), 8.01-8.04 (m, 1H); 13C NMR δ 21.1, 55.1,
70.0, 76.2, 110.0, 113.9, 119.8, 124.2, 126.9, 126.9, 127.5, 128.2,
128.9, 133.5, 136.4, 137.7, 145.8, 159.4. Anal. Calcd for
C22H21N3O2: C, 73.52; H, 5.89, N, 11.69. Found: C, 73.54, H;
5.85 N, 11.76. erythro: mp 86-87 °C, 1H NMR δ 2.28 (s, 3
H), 3.69 (m, 1 H), 3.75 (s, 3 H), 5.69 (d, J ) 5.4 Hz, 1 H), 5.98
(m, 1 H), 6.79 (d, J ) 8.7 Hz, 2 H), 7.00 (d, J ) 8.0 Hz, 2 H),
7.09-7.32 (m, 7 H), 8.00 (d, J ) 8.0 Hz, 1 H); 13C NMR δ 21.1,
55.2, 68.7, 75.0, 109.7, 113.7, 119.8, 124.1, 126.5, 126.7, 127.4,
128.8, 129.9, 132.9, 136.5, 137.7, 145.4, 159.4. Anal. Calcd
for C22H21N3O2: C, 73.52; H, 5.89, N, 11.69. Found: C, 73.64,
H; 5.97, N, 11.88.
(d, J ) 7.8 Hz, 1H), 6.55 (d, J ) 3.3 Hz, 1H), 6.60 (m, 1H); 13
C
NMR δ 15.2, 21.1, 25.6, 33.9, 41.4, 41.7, 59.8, 124.4, 125.9,
137.4, 138.8, 208.8; HRMS calcd for C12H16OS 209.1000 (M +
1), found 209.1018.
3-Meth yl-2-(1-m eth ylin dol-3-yl)cycloh eptan on e (2t) an d
2-Meth yl-7-(1-m eth ylin dol-3-yl)cycloh eptan on e (3t). Hex-
anes:ethyl acetate (20:1) was used as the eluent to give pure
cis- and trans-2t and trans-3t. cis-2t: yellowish oil, yield
(68%): 1H 0.87 (d, J ) 7.2 Hz, 3H), 1.50-1.64 (m, 1H), 1.83-
2.00 (m, 5H), 2.33-2.50 (m, 2H), 2.68 (dt, J ) 17.2, 4.9 Hz,
1H), 3.78 (s, 3H), 4.56 (d, J ) 2.5 Hz, 1H), 7.06-7.12 (m, 1H),
7.18-7.31 (m, 2H), 7.43 (s, 1H), 7.46 (d, J ) 7.9 Hz, 1H); 13C
NMR δ 15.3, 24.1, 24.3, 32.6, 35.7, 37.0, 44.4, 51.7, 109.1, 111.9,
118.1, 118.6, 121.3, 127.6, 127.8, 136.2, 212.5. Anal. Calcd
for C17H21NO: C, 79.96; H, 8.29; N, 5.49. Found: C, 79.77;
H, 8.47; N, 5.26. trans-2t: white plates; mp 86-87 °C; yield
(13%); 1H NMR δ 1.00 (d, J ) 6.7 Hz, 3H), 1.32-1.67 (m, 3H),
1.80-2.02 (m, 3H), 2.14-2.26 (m, 2H), 2.78-2.86 (m, 1H), 3.58
(d, J ) 10.5 Hz, 1H), 3.77 (s, 3H), 7.04 (s, 1H), 7.10-7.15 (m,
1H), 7.19-7.29 (m, 2H), 7.72 (dd, J ) 7.7, 1.2 Hz, 1H); 13C
NMR δ 21.7, 27.5, 29.6, 32.8, 36.1, 36.6, 40.1, 59.0, 109.1, 112.0,
119.2, 119.8, 121.9, 126.0, 127.8, 137.0, 212.1. Anal. Calcd
Su p p or tin g In for m a tion Ava ila ble: 1H and 13C spectra
for compounds 2g, 2j, 2r , 2s, and cis-2u (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 O960841H