Imidazole transfer from 1,1'-carbonyldimidazole and 1,1'- (thiocarbonyl)diimidazole to alcohols. A new protocol for the conversion of alcohols to alkylheterocycles

Article abstract of DOI:10.1021/jo9708811

The transfer of imidazole from 1,1'-carbonyldimidazole (CDI) and 1,1'- (thiocarbonyl)diimidazole in modest to excellent yields under mild conditions was observed with activated alcohols, unactivated alcohols generally providing the expected carbonylimidazole esters. Reasonable mechanisms for the transfer are proposed. 1,1'-Carbonyldi-1,2,4-triazole was found to work as well, providing a new heterocycle in good yield. Chemists should be aware of this reaction when treating benzylic, vinylogous benzylic, and benzhydryl alcohols with CDI-type reagents, expecting elimination of heterocycle rather than incorporation of heterocycle and elimination of CO₂.

Full text of DOI:10.1021/jo9708811

J . Org. Chem. 1997, 62, 7319-7323
7319
Im id a zole Tr a n sfer fr om 1,1′-Ca r bon yld im id a zole a n d
,1′-(Th ioca r bon yl)d iim id a zole to Alcoh ols. A New P r otocol for th e
Con ver sion of Alcoh ols to Alk ylh eter ocycles
1
Michael J . Totleben, J eremiah P. Freeman, and J acob Szmuszkovicz*
Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana 46556
Received May 19, 1997X
The transfer of imidazole from 1,1′-carbonyldimidazole (CDI) and 1,1′-(thiocarbonyl)diimidazole in
modest to excellent yields under mild conditions was observed with activated alcohols, unactivated
alcohols generally providing the expected carbonylimidazole esters. Reasonable mechanisms for
the transfer are proposed. 1,1′-Carbonyldi-1,2,4-triazole was found to work as well, providing a
new heterocycle in good yield. Chemists should be aware of this reaction when treating benzylic,
vinylogous benzylic, and benzhydryl alcohols with CDI-type reagents, expecting elimination of
2
heterocycle rather than incorporation of heterocycle and elimination of CO .
In tr od u ction
Sch em e 1
The imidazole group is a common functionality found
in a number of biologically active and medicinally im-
1
portant molecules. Examples of such imidazole-contain-
ing compounds include histidines, histamines, and an-
tifungal agents such as miconazole, clotrimazole, and
2
ketoconazole; histamine H -receptor antagonists such as
cimetidine; and the hypnotic etomidate.2
New ways of preparing heterocycles are always of
interest, especially if they employ mild methods which
can tolerate many functional groups present in more
complex molecules. During the course of our studies, we
observed that (thiocarbonyl)diimidazole (TCDI) and car-
3
bonyldiimidazole (CDI) transfer imidazole to benzylic,
vinylogous benzylic, and benzhydryl carbinol carbons in
modest to excellent yields.
Resu lts a n d Discu ssion
In connection with other studies, we needed to prepare
1
,2,3,5,10,10a-hexahydrobenz[f]indolizine, 3, and decided
to examine the deoxygenation of 10-hydroxy-1,2,3,5,10,10a-
4
5a,b
hexahydrobenz[f]indolizine, 1, by Barton’s method.
We attempted to prepare the (thiocarbonyl)imidazole of
according to the literature5b by treatment of 1 with
which suggest an axial relationship between the benzylic
and ring junction protons (see Experimental Section for
spectroscopic evidence).
1
excess TCDI in refluxing THF (Scheme 1). The product
of this reaction failed to react with tri-n-butyltin hydride/
AIBN. Carbon NMR and FAB mass spectroscopy indi-
cated that we did not obtain the (thiocarbonyl)imidazole
To examine the generality of this reaction, we tested
some representative substrates. The results are tabu-
lated in Table 1. We also studied the use of CDI for this
transformation in place of TCDI. As shown in Table 1,
the more reactive CDI performs the transfer in higher
yields. Other advantages of CDI are the higher purity
of commercially available CDI, lower cost of the reagent,
and cleaner products. (Combustion analysis of chro-
matographed 4 obtained from the reaction with TCDI
showed the presence of 0.62% sulfur.) CDI thus is the
preferred reagent.
2
as expected, but rather the imidazole 4 in 54% yield.
Interestingly, the transfer occurred with retention of
stereochemistry! This assessment was based on the large
coupling constants for the benzylic proton in 1 and 4,
X
Abstract published in Advance ACS Abstracts, September 15, 1997.
(1) For a review of the chemistry of imidazoles, see: Katritzky, A.
R.; Rees, C. W. Comprehensive Heterocyclic Chemistry; Potts, K. T.,
Ed.; Pergamon: New York, 1984; Vol. 5, Part 4A, p 345, 373, 457.
R-Tetralol (entry 2) produced both the expected car-
bonylimidazole 6 in 55% yield (28% when TCDI used)
(
2) For a review of medicinally important imidazoles, see: Roth, H.
J .; Kleeman, A. Pharmaceutical Chemistry; J ohn Wiley: New York,
988; p 218.
3) For reviews of CDI and TCDI, see: (a) Staab, H. A. Angew.
1
6
and the imidazole 5 in an unoptimized yield of 26% (13%
(
with TCDI). Also isolated was an undetermined amount
of 1,2-dihydronaphthalene, which likely resulted from
Chem., Int. Ed. Engl. 1962, 1, 351. (b) Staab, H. A.; Rohr, W. In Newer
Methods of Preparative Organic Chemistry; Foerst, W., Ed.; Academic
Press: New York, 1968; Vol. 5, p 61. (c) Encyclopedia of Reagents for
Organic Synthesis; Paquette, L. A., Ed.; J ohn Wiley: New York, 1995;
Vol. 7, p 1006, 4862.
7
elimination of the thiocarbonyl imidazole group. An
interesting case was provided by 4,4′-dimethoxybenzhy-
(
(
4) Rigo, B.; Kolocouris, N. J . Heterocycl. Chem. 1983, 20, 893.
5) (a) Barton, D. H. R.; McCombie, S. W. J . Chem. Soc., Perkin
Trans. 1 1975, 1574. (b) Barton, D. H. R.; Motherwell, W. B. Pure Appl.
Chem. 1981, 53, 15 and references cited therein.
(6) Compound previously reported: Hirsch, K. S.; J ones, C. D.;
Taylor, H. M. U.S. Patent 4 659 730, 1987.
S0022-3263(97)00881-5 CCC: $14.00 © 1997 American Chemical Society

7
320 J . Org. Chem., Vol. 62, No. 21, 1997
Ta ble 1. Rea ction s of Alcoh ols w ith CDI a n d TCDI in Reflu xin g THF
Totleben et al.
drol (entry 3). We obtained the benzhydrylimidazole 7
in a modest yield of 35% using TCDI in refluxing THF.
Compound 7 was an oil, and the assigned structure was
consistent with the spectral data. Also isolated was a
mixture that appeared to contain some 8 and some other
minor compounds that have not been clearly identified
yet. A small amount of unreacted benzhydrol was
detected, but was not isolated. In stark contrast, it has
been reported that when the reaction is done with TCDI
at room temperature in the solid state (grinding), the
imidazole (9)10 in 69% yield as a yellow oil which solidified
on standing after several days, along with what appeared
to be a mixture of mainly cinnamyl alcohol plus unidenti-
fied impurities.
Both cyclohexanol (entry 5) and ethyl (S)-lactate (entry
6
) yielded the expected carbonylimidazolides 10 and 11,
respectively, in good yields. 2-(N,N-Dimethylamino)cy-
clohexan-1-ol (entry 7 and Scheme 2) gave none of the
imidazole 13 but did give the ester 12 which proved to
be unusually reactive. Thus, when the reaction was
worked up with chloroform containing 0.75% ethanol
stabilizer, ethyl 2-(N,N-dimethylamino)cyclohexyl car-
bonate, 14, was obtained in 67% yield. When the work-
up is limited to solvent removal only, IR and FAB mass
expected (thiocarbonyl)imidazole 8 was isolated as a solid
in 85% yield.8 As expected, the yield of 7 was substan-
tially higher, 95%, when CDI was employed for the
reaction.9 Cinnamyl alcohol (entry 4) gave cinnamyl-
(
7) The material still contained impurities after chromatography.
1
H NMR spectrum matches Sadtler Standard Spectra 18210M (1974).
(10) Compound previously reported: Baggaley, K. H.; Heald, M.;
Hindley, R. M.; Morgan, B.; Tee, J . L.; Green, J . J . Med. Chem. 1975,
18, 833.
(
(
8) Hagiwara, H.; Ohtsubo, S.; Kato, M. Tetrahedron 1997, 53, 2415.
9) 4,4′-Dimethoxybenzhydrol (5%) was recovered.

Imidazole Transfer from 1,1′-Carbonyldimidazoles
J . Org. Chem., Vol. 62, No. 21, 1997 7321
Sch em e 2
17. The aziridinium intermediate alone is not sufficient
to explain this reaction, as demonstrated by the results
of entry 7. However, the combination of the benzylic
carbon coupled with the aziridinium intermediate allows
us to explain the retention of stereochemistry noted in
entry 1.
Another explanation for the retention of stereochem-
1
3
istry in 1 f 4 would be to invoke the S
N
i mechanism.
We were curious about whether other carbonyl dihet-
erocycles could transfer aromatic heterocyclic groups
other than imidazole. To explore this possibility, we
1
4
treated alcohol 1 with 1,1′-carbonyldi-1,2,4-triazole in
refluxing THF (Scheme 4). The reaction produced a
gratifying 87% yield of N-alkyl-1,2,4-triazole 18. This
result demonstrates the potential of generating other
heterocyclic compounds from activated alcohol under mild
conditions.
Subsequent to this study, we became aware that this
direct conversion of alcohols to alkylimidazoles had been
observed previously albeit in poor yields after long
reaction times1 or treatment at elevated temperature.
5a
15b
Con clu sion
A new route to N-alkyl aromatic heterocycles has been
explored. The transfer of imidazole and 1,2,4-triazole to
activated alcohols was accomplished under mild condi-
tions under 6 h, in moderate to excellent yields, and
apparent retention of stereochemistry. The process
employs a relatively inexpensive, commercially available
reagent and produces fairly innocuous byproducts. Ef-
forts to extend the generality, scope, and mechanism of
the reaction will be conducted in due course.
spectroscopy of the crude mixture indicated that 12 and
imidazole are the only products.11
A possible explanation for the reactivity of 12 is offered
in Scheme 2. Compound 12 may form the ammonium
salt shown. This salt should be very susceptible to
nucleophilic attack by EtOH present in the CHCl ,
3
yielding the ethyl carbonate 14. (The carbonate was also
observed when the residue from THF removal was
digested in CH Cl and treated with absolute EtOH.)
2 2
From the data in Table 1, we note that the transfer of
imidazole from CDI or TCDI occurs only with the benzylic
or vinylogous benzylic alcohols. Simple alcohols such as
cyclohexanol, or alcohols with adjacent electron-with-
drawing groups, yield only the expected carbonylimida-
zole. This suggests that groups adjacent to the alcohol
which stabilize positive charge allow the transfer to occur
facilely (i. e., “activating” the alcohol carbon). A periph-
erally related example to our studies by Ford and Ley,12
which showed the conversion of hemiketals to ketals in
the presence of CDI and alcohols, offers some support for
this suggestion as well.
We can propose four mechanisms to account for our
observations (Scheme 3), using alcohol 1 as a model
substrate. In mechanism A, 1 attacks CDI to give the
tetrahedral intermediate 15. Intermediate 15 would
then collapse to the carbonylimidazole 16 and imidazole.
The imidazole would then displace the carboxyimidazole
Exp er im en ta l Section
Gen er a l. 1,1′-Carbonyldiimidazole (CDI, Aldrich), 90%
1,1′-(thiocarbonyl)diimidazole (TCDI, Aldrich), 1,1′-carbonyldi-
1,2,4-triazole (CDT, Fluka), 4,4′-dimethoxybenzhydrol (Fluka),
cinnamyl alcohol (Aldrich), cyclohexanol (Aldrich), and 1,2,3,4-
tetrahydro-1-naphthol (Aldrich) were commercially available
and used without further purification. 2-(N,N-Dimethylami-
1
6
no)cyclohexanol was prepared by literature methods.
Hydroxy-1,2,3,5,10,10a-hexahydrobenz[f]indolizidine, 1, was
obtained from the LiAlH reduction of 1,2,3,5,10,10a-hexahy-
10-
4
4
drobenz[f]indolizidine-3,10-dione according to the literature.
THF was tested for peroxides (aqueous KI) prior to use and
used without further purification or drying. All reactions were
performed under a nitrogen atmosphere in oven- or flame-dried
glassware unless otherwise noted.
1
H and 13C NMR spectra were recorded on a Varian
spectrometer at 300 MHz for proton and 75 MHz for carbon.
The predicted carbon spectra were obtained from the ACD
Labs CNMR program. Flash column chromatography was
done on silica gel (E. M. Merck silica gel 60, 230-400 mesh)
in the stated solvents. Melting points were obtained on a
Thomas-Hoover apparatus and are uncorrected.
Gen er a l P r oced u r e for Im id a zole Tr a n sfer : The alco-
hol (1 equiv) was dissolved in THF (0.36 M) in a 2-neck flask
equipped with a magnetic stir bar and reflux condenser. CDI
or TCDI (2.1 equiv) was added all at once under a stream of
nitrogen. The reaction was then stirred at reflux (bath
temperature ) 75 °C) for 3.5-7 h (TLC indicated the reactions
group to give 4, CO
this mechanism is the observed retention of stereochem-
istry in 4. If a purely S 2 mechanism were in operation,
2
, and imidazole. The drawback to
N
we would expect inversion. However, the benzylic carbon
of 16 may assume considerable cationic character. Mech-
anism B shows a more concerted pathway and is subject
to the same above comment.
Mechanisms A and B may be operative in the case of
entries 2, 3, and 4. In order to explain entry 1, in which
retention of stereochemistry is observed, we propose
mechanism C, and the intermediacy of aziridinium ion
(13) March, J . Advanced Organic Chemistry, 2nd ed.; McGraw
Hill: New York, 1977; p 302.
(
14) For a review of 1,1′-carbonyldi-1,2,4-triazole, see ref 3c, p 1010.
(
15) (a) J ones, C. D.; Winter, M. A.; Hirsch, K. S.; Stamm, N.; Taylor,
(
11) A peak at m/ z 323 (64%) in the FAB mass spectrum correlates
H. M.; Holden, H. E.; Davenport, J . D.; Krumkalns, E. V.; Suhr, R. G.
J . Med. Chem. 1990, 33, 416. (b) Staab, H. A.; Mannschreck, A. Chem.
Ber. 1962, 95, 1284.
(16) Mandrou, A. M.; Potin, P.; Wylde-Lachazette, R. Bull. Soc.
Chim. Fr. 1962, 1546.
with the M + H of the 4-nitrobenzyl carbonate resulting from reaction
of the carbonylimidazole 12 with 4-nitrobenzyl alcohol used as the FAB
matrix.
(12) Ford, M. J .; Ley, S. V. Synlett 1990, 255.

7
322 J . Org. Chem., Vol. 62, No. 21, 1997
Totleben et al.
Sch em e 3
Sch em e 4
to produce a precipitate. The suspension was allowed to stand
overnight; then the supernatant liquid was carefully removed
by pipette and the solid washed with ether. This procedure
was repeated twice. The material was dried under a stream
of N
solid was 40 mg (52%), mp 190-192 °C dec. Anal. Calcd for
‚2HNO ‚CH OH: C, 48.36; H, 5.83; N, 17.62. Found:
C, 48.74; H, 5.15; N, 17.46.
-Im idazolo-1,2,3,4-tetr ah ydr on aph th alen e (5).6 1,2,3,4-
2
and then in vacuo for 24 h. The yield of a golden-brown
C
15
H
17
N
3
3
3
1
Tetrahydro-1-naphthol (250 mg, 1.7 mmol) provided 450 mg
of a crude mixture. The mixture was flash chromatographed
first in EtOAc/hexane (4:1) to give R-tetrahydronaphthyl
carbonylimidazole 6, 228 mg (55%) of a white solid, mp 88-
were usually done after 3 h). The reaction was cooled to room
temperature and the THF removed on a rotary evaporator.
The residue was partitioned between 5% NaOH (20 mL) and
an appropriate solvent (ether or ethyl acetate, 20 mL). The
layers were separated, and the aqueous layer was extracted
with solvent (3 × 10 mL). The organic layers were combined,
9
0 °C, then CHCl
mg (26%) of a pale yellow solid, mp 114-115 °C.
For 5. 1H NMR (CDCl
): δ 7.45 (s, 1H), 7.23-7.11 (m, 3H),
.05 (s, 1H), 6.87 (d, J ) 7.58 Hz, 1H), 6.82 (t, J ) 1.18, 2.37
3
/MeOH (15.66:1) + 1% NEt
3
to give 5, 87
3
7
washed with brine (25 mL), dried over Na
concentrated.
2 4
SO , filtered, and
Hz, 1H), 5.34 (t, J ) 6.87, 12.56 Hz, 1H), 2.89 (m, 2H), 2.21
1
3
(m, 1H), 2.12 (m, 1H), 1.88 (m, 2H).
3
C NMR (CDCl ): δ
1
,2,3,5,10,10a -Hexa h yd r o-10-im id a zoloben z[f]in d olizi-
d in e (4). Alcohol 1 (101 mg, 0.53 mmol) gave 115 mg of crude
product. Flash chromatography in CHCl /MeOH (11.5:1) +
% NH OH provided 110 mg (86%) of an orange brown solid,
mp 98.5-110.5 °C. H NMR (CDCl
1
5
9
37.57, 137.28, 134.20, 129.42, 128.61, 128.17, 126.55, 118.47,
6.08, 32.38, 28.99, 20.05. IR (Nujol): 2723, 1227, 1151, 1077,
34, 905, 823, 806, 722 cm . MS (FAB): m/ z 199 (M + H,
3
-
1
1
4
1
100%), 154 (21%), 131 (M + H - imidazole, 86%). HRMS
3
): δ 7.59 (s, 1H), 7.20 (d,
(FAB): for C13
H
15
N
H
2
(M + H), calcd 199.1235, obsd 199.1211.
‚0.11H O: C, 77.97; H, 7.16; N, 13.99.
J ) 6.98 Hz, 1H), 7.09 (s, 1H), 6.81 (s, 1H), 6.74 (d, J ) 7.66
Hz, 1H), 5.07 (d, J ) 9.67 Hz, 1H), 4.18 (d, J ) 15.91 Hz, 1H),
Anal. Calcd for C13
14
N
2
2
Found: C, 77.91; H, 7.24; N, 13.88.
For 6. 1H NMR (CDCl
): δ 8.12 (s, 1H), 7.40 (s, 1H), 7.39
(d, J ) 7.93 Hz, 1H), 7.25 (d, J ) 7.25 Hz, 1H), 7.19 (m, 2H),
.02 (s, 1H), 6.18 (t, J ) 3.90, 8.06 Hz, 1H), 2.95-2.79 (broad
3
2
.60 (d, J ) 14.90 Hz, 1H), 3.30 (t, J ) 8.19, 16.68 Hz, 1H),
.58 (m, 1H), 2.38 (m, 1H), 1.89 - 1.79 (m, 3H), 1.63 (m, 1H).
3
1
3
C NMR (CDCl ): δ 137.16, 135.27, 133.97, 129.53, 127.47,
3
7
1
2
1
26.73, 126.31, 126.23, 117.73, 66.08, 62.33, 55.34, 54.62,
9.01, 21.00. IR (neat film): 3128, 2980, 2815, 1668, 1518,
304, 1248, 1095, 920, 906, 755 cm . MS (FAB): m/ z 240
1
3
m, 2H), 2.25-1.88 (broad m, 4H). C NMR (CDCl
138.13, 137.13, 132.56, 130.54, 129.79, 129.32, 128.97, 117.14,
3
): δ 148.48,
-
1
7
1
2
5.06, 28.93, 28.75, 18.59. IR (Nujol): 2728, 1759, 1738, 1286,
(
M + H, 71), 172 (M + H - imidazole, 100), 143 (11), 115 (6.5).
HRMS (FAB): calcd 240.1500 for C15 (M + H), obsd
40.1491.
The imidazole (50 mg, 0.21 mmol) was dissolved in MeOH
and filtered to remove particulate. The solution was treated
with 1:1 concentrated HNO /H
O (about 20 drops, pH , 2).17
-
1
238, 1172, 1059, 999, 892, 763 720 cm . MS (FAB): m/ z
43 (M + H, 4.4), 199 (46), 154 (10), 131 (100), 115 (35). HRMS
18 3
H N
2
(FAB): calcd 243.1133 for C14
H
15
N
2
O
2
(M + H), obsd 243.1147.
Anal. Calcd for C14
14 2 2
H N O : C, 69.40; H, 5.82; N, 11.56.
Found: C, 69.21; H, 5.82; N, 11.48.
4,4′-Dim et h oxyb en zh yd r yl)im id a zole
3
2
(7).15
4,4′-
The solvents were removed under reduced pressure to give a
dark orange residue. The residue was dissolved in a minimal
amount of MeOH with swirling; then ether was slowly added
Dimethoxybenzhydrol (250 mg, 1 mmol) provided 337 mg of
crude material. Flash chromatography in CHCl /MeOH (49:
) + 0.5% NH OH afforded 281 mg (95%) of the imidazole as
3
1
4
a viscous, pale yellow residue. About 14 mg (5%) of starting
(17) The salts from reaction of 4 with ethereal HCl, maleic, meth-
anesulfonic, and oxalic acids gave only oils or noncrystalline solids.
material was recovered. The 13C spectrum closely matches the

Imidazole Transfer from 1,1′-Carbonyldimidazoles
predicted spectrum. 1H NMR (CDCl
J . Org. Chem., Vol. 62, No. 21, 1997 7323
3
): δ 7.38 (s, 1H), 7.08 (s,
H), 7.01 (d, J ) 8.73 Hz, 4H), 6.88 (d, J ) 8.32 Hz, 4H), 6.85
O-(Im id a zolylca r bon yl)-2-(N,N-d im eth yla m in o)cyclo-
h exa n ol (12). A 2-(N,N-dimethylamino)cyclohexanol (270 mg,
1.88 mmol) reaction mixture was evaporated to give a crude
material as a near white solid. No aqueous workup was
performed. IR (Nujol, crude product): 1755, 1313, 1280, 1173,
1
1
3
(s, 1H), 6.42 (s, 1H), 3.80 (s, 6H). C NMR (CDCl
3
): δ 159.21,
1
37.07, 131.43, 128.95, 119.07, 113.93, 63.69, 55.06. IR (neat
film): 2740, 1610, 1580, 1508, 1305, 1250, 1175, 1110, 1075,
030, 905, 815, 790 cm-1; MS (FAB): m/ z 295 (M + H), 4.8),
27 (M + H - imidazole, 100), 154 (52), 136 (41), 106 (5.4).
1090, 1050, 1000, 820, 735 cm . MS (FAB, crude product):
-1
1
2
1
1
m/ z 238 (M + H, 12), 202 (62), 170 (11), 137 (30), 126 (100).
HRMS (FAB): calcd 295.1446420 for C18
95.1400.
Cin n a m ylim id a zole (9).10 Cinnamyl alcohol (279 mg, 2.08
mmol) provided 469 mg of crude material. Flash chromatog-
raphy in CHCl /MeOH (24:1) + 0.5% NH OH gave 265 mg
69%) of the imidazole as a light yellow-gold oil that solidifies
on standing several days, mp 70-72 °C (lit. mp 46-48 °C, see
H
19
N
2
O
2
(M + H), obsd
Eth yl (2-(N,N-Dim eth yla m in o)cycloh exyl Ca r bon a te
(14). 2-(N,N-Dimethylamino)cyclohexanol (258 mg, 1.8 mmol)
provided 477 mg of crude product as a moist looking, soft solid
after aqueous workup as described in the general procedure
2
3
4
(used ether for extraction). CHCl
to dissolve the solid, and the resulting solution was chromato-
graphed in CHCl /MeOH (11.5:1) to give 270 mg (67%) of a
light colored oil. The carbon spectrum closely matches the
3
(containing EtOH) was used
(
3
1
ref 10). H NMR (CDCl
7
6
3
): δ 8.15 (s, 1H), 7.43-7.35 (m, 3H),
1
.34-7.26 (m, 3H), 7.05 (s, 1H), 6.73 (d, J ) 15.85 Hz, 1H),
3
calculated spectrum. H NMR (CDCl ): δ 4.63 (dt, J ) 4.44,
1
3
.35 (m, 1H), 4.98 (dd, J ) 1.21, 6.71 Hz, 2H).
): δ 137.03, 136.39, 135.44, 130.52, 128.62, 128.52,
26.71, 126.58, 120.90, 117.06, 68.62. IR (neat film): 3132,
758 (absorption of CO likely), 1474, 1400, 1285, 1096, 1000,
C NMR
9.94, 20.01 Hz, 1H), 4.17 (q, J ) 7.12, 14.23 Hz, 2H), 2.48 (m,
1H), 2.29 (s, 6H), 2.06 (m, 1H), 1.84 (m, 1H), 1.71 (m, 2H),
1.41 (m, 1H), 1.29 (t, J ) 7.12, 14.23 Hz, 4H), 1.20 (m, 2H).
(CDCl
3
1
1
8
1
1
3
2
-
C NMR (CDCl
3
): δ 154.35, 75.78, 65.66, 63.02, 40.56, 31.23,
1
33, 747, 694, 649 cm . MS (FAB): m/ z 185 (M + H, 20),
54 (29), 136 (24), 117 (100), 115 (14), 106 (11). HRMS
24.27, 23.83, 23.46, 13.86. IR (neat film): 2920, 2840, 2812,
-1
2760, 1730, 1443, 1370, 1249, 1005, 870 cm ; MS (FAB): m/ z
216 (M + H, 100), 154 (11), 142 (22), 126 (99). HRMS (FAB):
(
FAB): calcd 185.1078 for C12
-((Cycloh exyloxy)ca r bon yl)im id a zole (10). Cyclohex-
anol (0.18 mL, 1.7 mmol) gave 317 mg of a colorless oil that
crystallized on standing. Flash chromatography in CHCl
13 2
H N (M + H), obsd 185.1116.
1
3
calcd 216.1599 for C11H22NO (M + H), obsd 216.1603.
1,2,3,5,10,10a -Hexa h yd r o-10-(1,2,4)tr ia zoloben z[f]in d -
olizid in e (18). Alcohol (250 mg, 2.8 mmol) afforded 301 mg
3
/
MeOH (49:1) yielded 290 mg (88%) of the expected carbamate
of crude material. Flash chromatography in CHCl
1) + 0.25% NH OH gave 277 mg (86%) of a very pale orange
solid. The product was further purified by crystallization from
CH Cl /n-heptane to give lightly colored plates, mp 176.5-178
°C dec. H NMR (CDCl ): δ 8.09 (s, 1H), 7.89 (s, 1H), 7.12 (d,
3
/MeOH (19:
as a faintly colored oil that crystallized on standing, mp 44-
4
1
4
1
1
1
1
6 °C. H NMR (CDCl
3
): δ 8.14 (s, 1H), 7.43 (s, 1H), 7.05 (s,
H), 4.99 (m, 1H), 1.98 (m, 2H), 1.78 (m, 2H), 1.61 (m, 3H),
.44 (m, 3H).
2
2
1
3
1
C NMR (CDCl
3
): δ 147.87, 136.85, 130.25,
3
16.88, 77.23, 31.10, 24.91, 23.24. IR (Nujol): 1764, 1487,
J ) 7.05 Hz, 1H), 7.04 (m, 2H), 6.57 (d, J ) 8.33, 16.41 Hz,
1H), 5.30 (d, J ) 9.61 Hz, 1H), 4.09 (d, J ) 14.61 Hz, 1H),
3.53 (d, J ) 14.87 Hz, 1H), 3.21 (t, J ) 8.33, 16.41 Hz, 1H),
2.74 (q, J ) 8.84, 15.25 Hz, 1H), 2.30 (q, J ) 8.21, 16.67 Hz,
396, 1288, 1238, 1001, 826, 770 cm-1. MS (FAB): m/ z 195
(
M + H, 100), 151 (14), 136 (5), 113 (93). HRMS (FAB): calcd
95.1133 for C10 (M + H), obsd 195.1152. Anal. Calcd
for C10 : C, 61.84; H, 7.27; N, 14.42. Found: C, 61.68;
1
15 2 2
H N O
1
3
H
14
N
2
O
2
1H), 1.90-1.45 (broad m, 4H). C NMR (CDCl ): δ 151.96,
3
H, 7.28; N, 14.33.
Eth yl O-(Im id a zolylca r bon yl)-(S)-la cta te (11). The es-
ter (0.20 mL, 1.76 mmol) gave 419 mg of crude material after
143.31, 127.76, 126.86, 126.60, 126.18, 65.18, 64.85, 55.38,
54.62. IR (nujol): 2988, 2824, 1474, 1441, 1372, 1278, 1136,
-
1
1011, 990, 961, 940, 723 cm . MS (FAB): m/ z 241 (M + H,
washing with H
tography in CHCl
solid, mp 71-73 °C. H NMR (CDCl
2
O only (no aqueous NaOH). Flash chroma-
/MeOH (19:1) gave 265 mg (69%) of a white
69, 239 (M - H, 33), 173 (94), 170 (100), 143 (14), 117 (14),
3
115 (14). HRMS (FAB): calcd 241.1453 for C14
H
17
N
4
(M +
1
3
): δ 8.18 (s, 1H), 7.46 (t,
H), obsd 241.1478. Anal. Calcd for C14
H N : C, 69.97; H,
16 4
J ) 1.61, 2.96 Hz, 1H), 7.09 (s, 1H), 5.31 (q, J ) 7.12, 14.23
Hz, 1H), 4.26 (q, J ) 7.12, 14.23 Hz, 2H), 1.67 (d, J ) 7.12 Hz,
6.71; N, 23.31. Found: C, 70.22; H, 6.70; N, 23.44.
1
3
Ack n ow led gm en t. The authors thank American
Biogenetic Sciences for generous support of this work,
especially Mr. Alfred Roach for his interest and encour-
agement. We also thank Dr. J oel Morris and Mr.
Stephen A. Mizsak of Pharmacia and Upjohn Company
for helpful discussions.
3
1
1
1
6
H), 1.30 (t, J ) 7.12, 14.23 Hz, 3H). C NMR (CDCl ): δ
3
69.10, 147.83, 136.99, 130.56, 117.00, 71.74, 61.71, 16.61,
3.83. IR (Nujol): 3141, 3110, 1763 (broad, poor resolution),
532, 1519, 1207, 1170, 1091, 1000, 898, 868, 834, 769, 745,
-
1
54 cm . MS (FAB): m/ z 213 (M + H, 100), 154 (39), 136
(32), 106 (13). HRMS (FAB): calcd 213.0875 for C
9 13 2 4
H N O
(
M + H), obsd 213.0882. Anal. Calcd for C : C, 50.94;
9
12 2 4
H N O
H, 5.70; N, 13.20. Found: C, 51.00; H, 5.60; N, 13.10.
J O9708811