High-yield synthesis of novel imidazoles and triazoles from alcohols and phenols

Article abstract of DOI:10.1055/s-2000-8722

A variety of alcohols and phenols are converted into their corresponding imidazoles and triazoles in high yields by a facile reaction with N,N¹-carbonyldiimidazole (CDI) or N,N¹-carbonylditriazole (CDT) in acetonitrile. The reactions of allylic alcohols, enols and phenols with CDI or CDT are unprecedented. Evidence is provided which suggests that the reaction with alcohols proceeds via the corresponding carbamates by an S(N)i mechanism.

Full text of DOI:10.1055/s-2000-8722

PAPER
2019
High-Yield Synthesis of Novel Imidazoles and Triazoles from Alcohols and
Phenols
Vincent C. O. Njar*
Department of Pharmacology and Experimental Therapeutics, School of Medicine, University of Maryland, Baltimore, MD 21201-1559,
USA
Fax +1(410)7060032; E-mail: vnjar001@umaryland.edu
Received 2 May 2000; revised 12 July 2000
temperature and then refluxing for 1.5 hours. However,
Abstract: A variety of alcohols and phenols are converted into their
following the addition of CDI to a stirred solution of
4-OHMR in anhydrous MeCN at room temperature, we
observed an intense color change (from yellow to red) of
corresponding imidazoles and triazoles in high yields by a facile re-
action with N,N1-carbonyldiimidazole (CDI) or N,N1-carbonylditri-
azole (CDT) in acetonitrile. The reactions of allylic alcohols, enols
and phenols with CDI or CDT are unprecedented. Evidence is pro- the reaction mixture within ca 5 minutes. Analysis of the
vided which suggests that the reaction with alcohols proceeds via
the corresponding carbamates by an SNi mechanism.
reaction mixture by TLC revealed no trace of starting al-
cohol, but a more polar product which following workup
Key words: alcohols, imidazoles, triazoles, carbonyl diazole re-
agents, substitution nucleophilic internal reaction, steroids, retin-
oids, heterocycles
was identified as the desired 4-imidazole 2, obtained in
near quantitative yield.
Prior to this work, carbonyldiazole reagents (mainly, CDI
and carbonylditriazole, CDT) were not the reagents of
choice for the synthesis of imidazoles and triazoles from
their corresponding alcohols, due to the low to good yields
of products obtained and also due to the long reaction pe-
riods (up to 7 days) and/or high reaction temperatures. For
example, Jones et al.7b reported the reaction of a benzhy-
drol with CDI in CH2Cl2 under reflux for 3 days to give a
mediocre 7% of the corresponding imidazole. Two excep-
tions include the reaction of a benzylic alcohol with CDI
mentioned earlier10 and the recent report by Le Borgne et
al.12 in which a number of indolic alcohols were treated
with CDI in THF to give the corresponding imidazoles in
yields ranging from 31% to 84%.
Introduction
The azole moiety is an important and frequent structural
feature of many biologically active compounds such as
cytochrome P450 enzyme inhibitors1 and peptide analog
inhibitors of human immunodeficiency virus (HIV-1)
protease.2 A number of these compounds are useful as
drugs for the treatment of many diseases, including can-
cer,3 acquired immune deficiency syndrome (AIDS)2 and
also as cholesterol lowering4 and antifungal agents.5
In connection with our recent interest aimed at synthesis
of potential inhibitors of retinoic acid metabolism en-
zyme(s),6 we required an azolyl retinoid 2 (Table, Entry
1). Although a number of azoles have been synthesized di-
rectly from alcohols or from their corresponding halides7
or sulfonates,8 we expected difficulties in the present case
because of the allylic nature of the 4-hydroxy group of
(±)-4-hydroxy methyl retinoate (1, 4-OHMR), a key inter-
mediate in our projected synthetic scheme. Literature pre-
cedent for the conversion of benzylic alcohols9 into the
corresponding imidazole (in 69% yield) involves treat-
ment of the alcohol with N,N1-carbonyldiimidazole (CDI)
in refluxing CH2Cl2 for 1 hour.10 However, only a trace
(~ 3%) of the desired product together with many intrac-
table byproducts were observed on applying these condi-
tions to 4-OHMR. Furthermore, attempts to transform 4-
OHMR to the corresponding sulfonate or halide failed.
In this paper we report further extension of the utility of
CDI or CDT in MeCN to include reactions with nearly all
types of alcohols (except 3o alcohols), i.e., 1o, 2o, allylic,
homoallylic, enolic, and benzylic alcohols and also phe-
nols to produce their corresponding imidazoles or triaz-
oles in near quantitative isolated yields. Furthermore, we
provide evidence which suggest that the reaction of these
agents with alcohols proceeds via their corresponding car-
bamates by the rare SNi mechanism.
Results and Discussion
Our reaction conditions were tested on a variety of sub-
strates (alcohols and phenols), and the results are summa-
rized in the Table. For most of the reactions, the products
were simply obtained following precipitation, by addition
of cold water to the reaction mixtures, filtration, and dry-
ing under vacuum at room temperature or 40-50 °C. All
the products were fully characterized by 1H NMR, HRMS
and elemental analyses.
During an attempted preparation of 4-bromo methyl retin-
oate from 4-OHMR following the procedure of Kamijo et
al.11 we made a serendipitous discovery. The reaction in-
volved addition of allyl bromide to a solution of the alco-
hol (in this case, 4-OHMR) and CDI in anhydrous
acetonitrile, followed by stirring for 30 minutes at room
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2020
V. C. O. Njar
Table Imidazole or Triazoles from Alcohols or Phenols Using CDI or CDT
PAPER
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High-Yield Synthesis of Novel Imidazoles and Triazoles from Alcohols and Phenols
2021
Table (continued)
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V. C. O. Njar
Table (continued)
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a
Reactions were carried out on scales ranging from 0.1735-16.56 mmol of the hydroxy com-
pounds, with 1.3 equiv of either CDI or CDT.
b Purity of reaction products was established by TLC, 1H NMR and elemental analyses.
c Isolated yields.
d These products were isolated by extraction with EtOAc.
e Compound 25 was found to be unstable in aqueous solution and was immediately isolated (ex-
tracted) from the aqueous reaction mixture.
f This reaction was extremely sluggish with 1.3 equiv of CDI and was incomplete after 76 h. Re-
action with 2.6 equiv of CDI was complete in 6 h. NR = No reaction. R = C10H13O2.
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High-Yield Synthesis of Novel Imidazoles and Triazoles from Alcohols and Phenols
2023
ed to their imidazoles, 19, 21 and 23, respectively (Entries
14-16). It should be noted that for each of these chiral
secondary alcohols, the reactions with either CDI or CDT
to give their corresponding azolyl compounds occur with
Reaction of Allylic Alcohols
The reaction of 1 with CDT gave the corresponding triaz-
ole regioisomers, 1H-1,2,4-triazole 3 and 4H-1,2,4-triaz-
ole 4 in the ratio of 1.8:1, respectively, in quantitative
yield (Entry 3). We then examined the reaction of the ste-
roidal allylic alcohol 5, with CDI in MeCN (Entry 4). It
was found that unlike the reaction of 1 with CDI which oc-
curred readily at room temperature (vide supra), this sub-
strate required refluxing for 5 hours. The reaction also
proceeded smoothly in CH2Cl2 at reflux (Entry 5), in
sharp contrast to results obtained with 1 under similar re-
action conditions. The differences in reaction times and
product yields of the reactions of these two allylic alco-
hols with CDI in either MeCN or CH2Cl2 may be due to
the specific nature of the alcohols. Given that nucleophilic
substitution reactions involving allylic alcohols are usual-
ly plagued with rearrangements,13 the facile and high yield
reactions described above are particularly interesting and
are unprecedented to the best of our knowledge.
1
100% retention of configuration as determined by H
NMR studies. The implications of this significant obser-
vation on the mechanism of reaction will be discussed in
detail below. The assignment of stereochemistries to the
3- or 17- substituents of steroidal compounds such as
these on the basis of chemical shifts and resonance pat-
terns of 3- or 17- protons is firmly established.14, 15 The as-
signments in the present study were based by direct
comparison with the spectra of corresponding hydroxy- or
amino steroids.14, 15 In the 1H NMR spectrum of 17b-(1H-
imidazol-1-yl)androst-4-en-3-one (14) the 17a-hydrogen
appears as a triplet (d 4.85, J = 8.0 Hz), while in the spec-
trum of 17a-(1H-imidazol-1-yl)androst-4-en-3-one (17),
the 17b-H appears as a doublet (d 5.03, J = 6.1 Hz). Fur-
thermore, in these reactions, i.e., 13 Æ 14 and 16 Æ 17,
there was no trace of any contaminating 17-isomers (1H
NMR and TLC evidence) in either of the isolated prod-
ucts. Similar results were also obtained for reactions of all
of the other chiral secondary alcohols in this study, thus
providing firm evidence that these transformations occur
with complete retention of configuration at the secondary
alcohol chiral center.
Reaction of Primary Alcohols
We investigated the reaction of primary alcohols with
CDI. All primary alcohols tested, reacted readily with
CDI in MeCN to give the corresponding imidazoles in
quantitative yields. While the reaction of compounds 7
and 11 (Entries 6 and 8) occurred readily at room temper-
ature, that of the sterically hindered primary alcohol 9
(Entry 7) was sluggish at room temperature, but it did pro-
ceed to completion within 1 hour at reflux.
The chiral indan-1-ol (24) reacted with CDI in MeCN at
reflux, to give the corresponding 1-indanyl imidazole (25)
within 1 hour in 90% yield (Entry 17). The reactions in ei-
ther CH2Cl2 or THF at reflux also proceeded smoothly,
but required longer times (5 h each) (Entries 18 and 19).
The reaction of 24 with CDT also proceeded readily to
give the corresponding triazole (data not shown).
Reaction of Secondary Alcohols
The reactions of secondary alcohols with the azole re-
agents were the most extensively studied. For the most
part, we chose those secondary alcohols of known chiral
centers to enable us to determine the stereochemistry at
the chiral center of the resulting azoly products. This ap-
proach proved very useful, as it provided experimental ev-
idence suggesting a mechanism for the reaction (vide
infra). The reaction of testosterone (17b-hydroxyandrost-
4-en-3-one, 13) with CDI in MeCN at reflux afforded
17b-(1H-imidazol-1-yl)androst-4-en-3-one (14) in 95%
yield after 5 hours (Entry 9). In solvents such of CH2Cl2
or THF, the product yield were not affected (Entries 10
and 11). The reaction of 13 with CDT in MeCN afforded
17b-(1H-1,2,4-triazole-1-yl)androst-4-en-3-one (15) ex-
clusively in 94% yield (Entry 12). This result is in contrast
with the reaction of the allylic secondary alcohol 1 with
CDT which afforded the two triazole regioisomer prod-
ucts (vide supra). The 17a-epimer of testosterone (epites-
tosterone or (17a-hydroxyandrost-4-en-3-one, 16) was
also smoothly converted to 17a-(1H-imidazole-1-yl)an-
drost-4-en-3-one, 17) in 95% yield (Entry 13). The steroi-
dal 3-hydroxy epimers, epiandrosterone (3b-hydroxy-5a-
androstan-17-one, 18) and androsterone (3a-hydroxy-5a-
androstane-17-one, 20) and also the homoallylic second-
ary alcohol, cholesterol were each also smoothly convert-
The reactions of various benzhydrols with CDI in reflux-
ing CH2Cl2 have previously been reported to give their
corresponding imidazoles in yields ~7%7b and 69%,10 re-
spectively. In this study, the reaction of diphenylmethanol
(26) with CDI in MeCN, CH2Cl2, or THF gave the corre-
sponding imidazole (27) in quantitative yields.
Reaction of Tertiary Alcohols
The tertiary alcohols 28-30 resisted reaction when sub-
jected to similar treatments with CDI in refluxing MeCN
even after 3 days (Entries 24-26). The inability of these
tertiary alcohols to undergo this transformation may be
due to the lack of formation of the corresponding interme-
diate carbamates (precursors of the azolyl products) under
these reaction conditions hindrance.
Reaction of Enolic Alcohol
The enolic steroid, 4-hydroxyandrostenedione (31), an ar-
omatase inhibitor currently used for the treatment of
breast cancer3c reacted with CDI in refluxing MeCN to
give the corresponding imidazole, 32 in 85% yield (Entry
26). The reaction in CH2Cl2 with the usual amount of CDI
(1.3 equiv) was sluggish and was incomplete after
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V. C. O. Njar
PAPER
76 hours. However, when 2.6 equivalents of CDI was uti-
lized, the reaction was completed in approximately
6 hours.
Reaction with Phenols
Although it has previously been reported that CDI reacts
with phenols on heating to form diesters of carbonic ac-
id,16 it was of interest to test their behavior under our re-
action conditions. Thus, when estrone (33) was treated
with CDI in refluxing MeCN, the corresponding N-arylat-
ed imidazole 34 was obtained in 95% yield within 1 hour
(Entry 28). The reaction also proceeds smoothly in
CH2Cl2 (Entry 29). Estradiol (35) and 2,6-dimethylphenol
(37) were also each cleanly converted to their correspond-
ing imidazoles, 36 and 38, respectively (Entries 30 and
31). The formation of these N-arylated imidazoles is un-
precedented by this reaction given the fact that attempted
synthesis of an N-aryl imidazole by thermal (up to 270 °C)
decarbonylation of 1-carbophenoxy-2-ethylimidazole
was unsuccessful.17
Proposed Mechanism for the Conversion Alcohols to Azoles
Scheme 1
The reaction proceeds through an initial formation of
1-alkoxycarbonylazoles or carbamates (e.g. 40) from al-
cohols (e.g. testosterone, 13) with CDI or CDT, followed
by decarboxylation (at r.t. or with heating) to give the cor-
responding azolyl products 14. Furthermore, we suggest
that decomposition of 40 involves the heterolysis of the
alkyl-oxygen bond to give an intimate ion pair (I) which
decomposes with the azolyl ion (part of the leaving group)
attacking necessarily from the front side since it is unable
to get to the rear. This results in retention of configuration,
designated as SNi mechanism. The proposed mechanism
is supported by the results that: (i) chiral secondary alco-
hols give the corresponding azoles with 100% retention of
stereochemistry (Entries 9-16), and (ii) 17b-carbamyl-an-
drost-4-en-3-one [40, synthesized from testosterone (13)
via 17b-chloroformate (39)21 as outlined in Scheme 2] un-
derwent smooth decarbonylation in refluxing MeCN to
give 17b-(1H-imidazol-1-yl)androst-4-ene-3-one (14) in
quantitative yield.
Solvent Effects
Except for the reactions with allylic and enolic alcohols,
there was no significant solvent effects on the rates of re-
action and on the yield of products (see Table). However,
MeCN is the solvent of choice for these transformations
as reaction in this solvent resulted in higher yields of prod-
ucts. This lack of solvent effects points to a concerted
mechanism being operative in which the transition state of
the reaction has no appreciable ionic character (vide in-
fra).
Mechanisms of Reactions
The reaction of alcohols with carbonyldiazole reagents,
i.e., CDI and CDT are thought to proceed via the carbam-
ate intermediates,16 which undergo subsequent decarbox-
ylation to give the corresponding azolyl products. This
general view is supported by the facts that: i) some alco-
hols
react
with
CDI
to
form
N-alkoxy-
carbonylimidazoles,16,18 and ii) thermal decomposition of
N-alkoxy-carbonylimidazoles (synthesized by the reac-
tion of imidazoles with ethyl chroloformate) results in the
formation of the corresponding 1-alkylimidazoles in good
yields.17 Whereas the mechanism of the first step of this
reaction is well understood, that for the second step is
poorly understood and has not been given much attention.
It has been suggested17 that this reaction may be regarded
as an O Æ N shift, comparable with the Chapman rear-
rangement.19 In addition, an SNi mechanism involving ra-
cemization has also been suggested for the thermal
decomposition of aralkyl carbamates.20
Synthesis of 17b-(1H-Imidazol-1-yl)androst-4-en-3-one (14) via
17b-Choloroacetate (39) and 17b-Carbamate (40)
Our present studies sheds light on the probable mecha-
nism of this reaction. The process may be viewed as oc-
curring through the sequence outlined in Scheme 1.
Scheme 2
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High-Yield Synthesis of Novel Imidazoles and Triazoles from Alcohols and Phenols
2025
However, we find it difficult to extend the same mecha- respect to the allylic, enolic and phenolic hydroxyl com-
nism to the transformation with the phenols. Furthermore, pounds, as it provides a simple and unprecedented method
most of the typical aromatic substitution reactions mech- for direct conversion to the corresponding imidazoles and
anisms, i.e., SNAr, SN1, and benzyne mechanism are con- triazoles. In addition, we have provided evidence which
sidered unlikely on theoretical grounds based on the strongly suggest that transformation of alcohols to the
nature of the reactants involved and also on the reaction azolyl products via the intermediate carbamates under-
conditions. Clearly, we know that the reaction does not goes decarbonylation by the relatively rare SNi mecha-
proceed via a benzyne mechanism because if it did, then nism.
the phenol 37, which contains two ortho methyl substitu-
ents would resist the transformation. Our transformation
reaction is similar to the conversion of phenols (through
Melting points (mp) were determined with a Fischer-Johns melting
point apparatus and are uncorrected. 1H NMR Spectra were record-
their diethyl phosphate esters) to aromatic primary amines
ed in CDCl3 at 300 MHz or 600 MHz with TMS as an internal stan-
(anilines).22 However, this mechanism involves radical
dard. HRMS were obtained using a Karatos-Aspect Systems
and radical anion intermediates and is designated an SRN1
mechanism. We consider the SRN1 mechanism to be un-
likely in our case considering the nature of reactants and
reaction conditions utilized and also because we have
found that a radical scavenger (2-methyl-2-nitrosopro-
pane dimer, 1-2 equiv) did not affect the reaction of es-
trone (33) with CDI in MeCN. Assuming that the reaction
with phenols also proceeds through their carbamates, the
mechanism might be regarded as an O Æ N shift (Scheme
3), comparable with the Chapman rearrangement.19 This
mechanism may also be envisioned for the reaction with
the enol 31.
Instrument, EI mode. Elemental analyses were performed by
Chemisar Laboratories Inc, Guelph, Ontario, Canada.
All the alcohols and phenolic compounds unless otherwise indicat-
ed were purchased either from Aldrich Chemical Co. Inc. or from
Sigma. 1,1-Diphenylmethanol (26) was synthesized from ben-
zophenone by reduction with NaBH4 in MeOH at r.t. Analytical
TLC was done on silica gel GHLF precoated plates (250 mm) pur-
chased from Analtech.
Reaction of Hydroxy Compounds with CDI or CDT; 17b-(1H-
Imidazol-1-yl)androst-4-ene-3-one (14, Table, Entry 9); Typical
Procedure
A solution of testosterone (13; 150 mg, 0.5208 mmol) and CDI
(110 mg, 0.6771 mmol, 1.3 equiv) in anhyd MeCN (5 mL) was re-
fluxed for 5 h (reactions were usually monitored by TLC and termi-
nated after complete consumption of the hydroxy compound). The
mixture was diluted with cold H2O (20-30 mL) and the resulting
precipitate was collected, washed thoroughly with H2O, and dried
under vacuum at 40-50 °C to give pure 17b-imidazolyl steroid 14
(168 mg, 95%); mp 168-169 °C.
1H NMR (600 MHz, CDCl3): d = 0.96 (s, 3 H, 18-CH3), 1.21 (s, 3
H, 19-CH3), 4.85 (t, 1 H, J = 8.0 Hz, 17a-H), 5.75 (s, 1 H, 4-H), 7.08
(s, 1 H, 41-H), 7.42 (s, 1 H, 51-H), 8.13 (s, 1 H, 21-H).
HRMS: m/z (M+) calcd 338.2358, obsd 338.2348.
Anal. calcd for C22H30N2O: C, 78.05; H, 8.94; N, 8.28. Found C,
78.10; H, 8.91; N, 8.25.
Compound 14 was also readily synthesized from 17b-imidazolcar-
bamylandrost-4-ene-3-one (40) by refluxing in MeCN for 5 h (see
Scheme 2).
Plausible Mechanism for the Conversion of Phenols to Azoles
4x-(1H-Imidazol-1-yl)methyl Retinoate (2, Table, Entry 1)
Yellow semisolid.
Scheme 3
1H NMR (300 MHz, CDCl3): d = 1.09 (s, 3 H, 16-H), 1.12 (s, 3 H,
17-H), 1.60 (s, 3 H, 18-CH3), 2.02 (s, 3 H, 19-CH3), 2.36 (s, 3 H, 20-
CH3), 3.72 (s, 3 H, OCH3), 4.53 (s, 1H, 4x-H), 5.80 (s, 1 H, 14-H)
6.25 (m, 4 H, 7-, 8-, 10- and 12-H), 6.91 (s, 1 H, 41-H), 6.98 (t, 1 H,
J = 14.7 Hz, 11-H), 7.07 (s, 1 H, 51-H), 7.50 (s, 1 H, 21-H).
Biological Studies
The free acids of compounds 2, 3, and 4 have been found
to be potent inhibitors of hamster liver microsomal cyto-
chrome P-450 dependent ATRA 4-hydroxylase enzyme.6
The other prospective inhibitors of other target P-450 en-
zymes remain to be examined for enzyme activity.
HRMS: m/z (M+) calcd 380.2464, obsd 380.2451.
4x-(1H-1,2,4-Triazol-1-yl)methyl Retinoate (3, Table, Entry 3)
Mp 105-108 °C.
1H NMR (300 MHz, CDCl3): d = 1.10 (s, 3 H, 16-H), 1.13 (s, 3 H,
17-H), 1.63 (s, 3 H, 18-CH3), 2.02 (s, 3 H, 19-CH3), 2.36 (s, 3 H, 20-
CH3), 3.72 (s, 3 H, OCH3), 4.82 (s, 1 H, 4x-H), 5.80 (s, 1 H, 14-H)
6.30 (m, 4 H, 7-, 8-, 10- and 12-H), 6.99 (t, 1 H, J = 14.7 Hz, 11-H),
7.99 (s, 1 H, 31-H), 8.02 (s, 1 H, 51-H)
Conclusion
In summary, we have uncovered a facile and useful proce-
dure for the preparation of imidazoles and triazoles in near
quantitative yields from a variety of alcohols and phenols,
thus broadening the scope of reactions with CDI and
CDT. Indeed, this discovery has its greatest novelty with
HRMS: m/z (M+) calcd 381.2416, obsd 381.2422.
Anal. calcd for C23H31N3O2: C, 72.41; H, 8.19; N, 11.01. Found C,
72.45; H, 8.51; N, 10.97.
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4x-(4H-1,2,4-Triazol-4-yl)methyl Retinoate (4, Table, Entry 3)
Mp 62-65 °C.
17a-(1H-Imidazol-1-yl)androst-4-ene-3,17-dione (17, Table,
Entry 13)
Mp 184-186 °C.
1H NMR (300 MHz, CDCl3): d = 1.10 (s, 3 H, 16-H), 1.13 (s, 3 H,
17-H), 1.64 (s, 3 H, 18-CH3), 2.02 (s, 3 H, 19-CH3), 2.36 (s, 3 H, 20-
CH3), 3.72 (s, 3 H, OCH3), 4.64 (s, 1 H, 4x-H), 5.81 (s, 1 H, 14-H)
6.25 (m, 4 H, 7-, 8-, 10- and 12-H), 6.98 (t, 1 H, J = 14.7 Hz, 11-H),
8.15 (s, 2 H, 31- and 51-H).
1H NMR (600 MHz, CDCl3): d = 0.88 (s, 3 H, 18-CH3), 1.21 (s, 3
H, 19-CH3), 5.03 (d, 1 H, J = 6.1 Hz, 17b-H), 5.75 (s, 1 H, 4-H),
7.07 (s, 1 H, 41-H), 7.40 (s, 1 H, 51-H), 8.11 (s, 1 H, 21-H).
HRMS: m/z (M+) calcd 338.2358, obsd 338.2354.
HRMS: m/z (M+) calcd 381.2416, obsd 381.2423.
Anal. calcd for C22H30N2O: C, 78.05; H, 8.94; N, 8.28. Found C,
78.15; H, 8.92; N, 8.26.
Anal. calcd for C23H31N3O2 C, 72.41; H, 8.19; N, 11.01. Found C,
72.55; H, 8.10; N, 11.00.
3b-(1H-Imidazol-1-yl)-5a-androstan-17-one (19, Table, Entry
14)
Mp 195-197 °C.
1H NMR (300 MHz, CDCl3): d = 0.88 (s, 3 H, 18-CH3), 0.91 (s, 3
H, 19-CH3), 4.91 (s, 1 H, 3a-H), 7.07 (s, 1 H, 41-H), 7.42 (s, 1 H, 51-
H), 8.13 (s, 1 H, 21-H).
20x-(1H-Imidazol-1-yl)pregna-5,16-diene-3b-acetate (6, Table,
Entry 4)
Mp 175-176 °C (dec.).
1H NMR (300 MHz, CDCl3): d = 0.95 (s, 3 H, 18-CH3), 1.05 (s, 3
H, 19-CH3), 1.55 (d, 3 H, J = 6.6 Hz, 21-CH3), 4.59 (m, 1 H, 3a-H),
5.38 (s, 1 H, 6-H), 5.64 (d, 1 H, J = 6.0 Hz, 20x-H), 5.80 (s, 1 H, 16-
H), 7.07 (s, 1 H, 41-H), 7.43 (s, 1 H, 51-H), 8.15 (s, 1 H, 21-H).
HRMS: m/z (M+) calcd 340.2515, obsd 340.2510.
Anal. calcd for C22H32N2O: C, 77.59; H, 9.48; N, 8.23. Found C,
77.52; H, 9.46; N, 8.24.
HRMS: m/z (M+) calcd 408.2777, obsd 408.2796.
Anal. calcd for C26H36N2O2: C, 76.42; H, 8.89, N, 6.86. Found C,
76.35; H, 8.80; N, 6.85.
3a-(1H-Imidazol-1-yl)-5a-androstan-17-one (21, Table, Entry
15)
21-(1H-Imidazol-1-yl)preg-4-ene-3,20-dione (8, Table, Entry 6)
Mp 95-95 °C.
1H NMR (300 MHz, CDCl3): d = 0.76 (s, 3 H, 18-CH3), 1.20 (s, 3
H, 19-CH3), 4.90 (ABq, 2 H, dAB = 60.0 Hz, JAB = 16.5 Hz, 21-
CH2), 5.75 (s, 1 H, 4-H), 7.10 (s, 1 H, 41-H), 7.46 (s, 1 H, 51-H), 8.18
(s, 1 H, 21-H).
Mp 143-144 °C.
1H NMR (300 MHz, CDCl3): d = 0.88 (s, 3 H, 18- and 19-CH3),
5.28 (s, 1 H, 3b-H), 7.09 (s, 1 H, 41-H), 7.44 (s, 1 H, 51-H), 8.15 (s,
1 H, 21-H).
HRMS: m/z (M+) calcd 340.2515, obsd 340.2517.
Anal. calcd for C22H32N2O: C, 77.59; H, 9.48; N, 8.23. Found C,
77.50; H, 9.45; N, 8.25.
HRMS: m/z (M+) calcd 380.2464, obsd 380.2469.
Anal. calcd for C24H32N2O2: C, 75.74; H, 8.46; N, 7.37. Found C,
75.70; H, 8.42; N, 7.40.
3b-(1H-Imidazole-1-yl)cholest-5-ene (23, Table, Entry 16)
Mp 133-135 °C.
1H NMR (300 MHz, CDCl3): d = 0.69 (s, 3 H, 18-CH3), 0.86, 0.88
(2 s 6 H,, 26- and 27-CH3), 0.92 (d, 3 H, J = 6.3 Hz, 21-CH3), 1.07
(s, 3 H, 19-CH3), 4.82 (m, 1 H, 3a-H), 5.44 (s, 1 H, 5-H), 7.07 (s, 1
H, 41-H), 7.43 (s, 1 H, 51-H), 8.14 (s, 1 H, 21-H).
19-(1H-Imidazol-1-yl)androst-4-ene-3,17-dione (10, Table, En-
try 7)
mp 155-156 °C.
1H NMR (300 MHz, CDCl3): d = 0.94 (s, 3 H, 18-CH3), 4.57 (d, 1
H, J = 11.0 Hz, 19-H), 4.89 (d, 1 H, J = 11.0 Hz, 19-H), 6.01 (s, 1
H, 4-H), 7.07 (s, 1 H, 41-H), 7.26 (s, 1 H, 51-H), 8.04 (s, 1 H, 21-H).
HRMS: m/z (M+) calcd 436.3818, obsd 436.3818.
Anal. calcd for C30H48N2: C, 82.50; H, 11.09; N, 6.42. Found C,
82.35; H, 11.12; N, 6.41.
HRMS: m/z (M+) calcd 352.2151, obsd 352.2148.
Anal. calcd for C22H28N2O2: C, 74.95; H, 8.01; N, 7.95. Found C,
74.82; H, 8.00; N, 7.97.
1b-(1H-Imidazol-1-yl)indane (25, Table, Entry 17)
Mp 58-60 °C.
1H NMR (300 MHz, CDCl3): d = 2.33 (m, 1 H, 9-H), 2.61 (m, 1 H,
9-H), 2.97 (m, 1 H, 8-H), 3.18 (m, 1 H, 8-H), 6.42 (s, 1 H, 1a-H),
7.05 (s, 1 H, 41-H), 7.33 (m, 4 H, arom. 3-, 4-, and 6-H), 7.51 (s, 1
H, 51-H), 8.11 (s, 1 H, 21-H).
1-(1H-Imidazol-1-yl)methyl-3,4-dimethylbenzene (12, Table,
Entry 8)
Mp 43-44 °C.
1H NMR (300 MHz, CDCl3): d = 2.29 (s, 6 H, 3- and 4-CH3), 5.35
(s, 2 H, benzyl-H), 7.05 (s, 1 H, 41-H), 7.21 (s, 1 H, 2-H), 7.26 (s, 2
H, 5- and 6-H), 7.43 (s, 1 H, 51-H), 8.14 (s, 1 H, 21-H).
HRMS: m/z (M+) calcd 184.1000, obsd 184.1007.
Anal. calcd for C12H12N2: C, 78.22; H, 6.57; N, 15.21. Found C,
78.06; H, 6.59; N, 15.19.
HRMS: m/z (M+) calcd 186.1157, obsd 186.1163.
Anal. calcd for C12H14N2: C, 77.37; H, 7.58; N, 15.05. Found C,
77.25; H, 7.56; N, 15.03.
1,1-Diphenylmethyl-1H-imidazole (27, Table, Entry 20)
Mp 130-131 °C.
17b-(1H-1,2,4-Triazol-1-yl)androst-4-ene-3,17-dione(15,Table,
Entry 12)
Mp 204-205 °C.
1H NMR (300 MHz, CDCl3): d = 0.99 (s, 3 H, 18-CH3), 1.21 (s, 3
H, 19-CH3), 4.94, (t, 1 H, J = 8.4 Hz, 17a-H), 5.75 (s, 1 H, 4-H),
8.08 (s, 1 H, 31-H), 8.80 (s, 1 H, 51-H).
1H NMR (300 MHz, CDCl3): d = 7.05 (s, 1 H, CHN), 7.10 (s, 1 H,
41-H), 7.40 (s, 10 Harom), 7.50 (s, 1 H, 51-H), 8.22 (s, 1 H, 21-H).
HRMS: m/z (M+) calcd 234.1157, obsd 234.1153.
Anal. calcd for C16H14N2: C, 82.01; H, 6.03; N, 11.96. Found C,
82.12; H, 6.01; N, 11.94.
HRMS: m/z (M+) calcd 339.2311, obsd 339.2308.
4-(1H-Imidazol-1-yl)androst-4-ene-3,17-dione (32, Table, En-
try 26)
Mp 200-201 °C.
Anal. calcd for C21H29N3O: C, 77.48; H, 8.94; N, 8.61. Found C,
77.29; H, 8.96, N, 8.62.
1H NMR (300 MHz, CDCl3): d = 0.94 (s, 3 H, 18-CH3), 1.34 (s, 3
H, 19-CH3), 7.12 (s, 1 H, 41-H), 7.48 (s, 1 H, 51-H), 8.21 (s, 1 H, 21-
H).
Synthesis 2000, No. 14, 2019–2028 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
High-Yield Synthesis of Novel Imidazoles and Triazoles from Alcohols and Phenols
2027
HRMS: m/z (M+) calcd 352.2150, obsd 352.2243.
Acknowledgement
Anal. calcd for C22H28N2O2: C, 74.95; H, 9.08; N, 7.95. Found C,
74.86; 9.10; N, 7.97.
We thank Professor H. L. Holland, Department of Chemistry, Brock
University, St. Catharines, Canada for HRMS and also for useful
discussions. We also thank Dr. Angela M. H. Brodie, Department
of Pharmacology & Experimental Therapeutics, University of
Maryland, Baltimore for her interest in this study.
3-(1H-Imidazol-1-yl)estra-1,3,5(10)-trien-17-one (34, Table,
Entry 28)
Mp 184-186 °C.
1H NMR (300 MHz, CDCl3): d = 0.96 (s, 3 H, 18-CH3), 6.99 (s, 1
H, 4-H), 7.03 (d, 1 H, J = 8.3 Hz, 2-H), 7.15 (s, 1 H, 41-H), 7.37 (d,
1 H, J = 8.5 Hz, 1-H), 7.56 (s, 1 H, 51-H), 8.29 (s, 1 H, 21-H).
References
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HRMS: m/z (M+) calcd 320.1887, obsd 320.1865.
Anal. calcd for C21H24N2O: C, 78.70; H, 7.55; N, 8.75. Found C,
78.79; H, 7.57; N, 8.73.
(b) Vanden Bossche, H.; Koymans, L.; Mooreels, H.
Pharmacol. Ther. 1995, 57, 79.
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3,17b-Di(1H-imidazol-1-yl)estra-1,3,5(10)-triene (36, Table, En-
try 30)
Mp 142-144 °C.
1H NMR (300 MHz, CDCl3): d = 0.96 (s, 3 H, 18-CH3), 4.94 (t, 1
H, J = 7.8 Hz, 17a-H), 6.99 (s, 1 H, 4-H), 7.02 (d, 1 H, J = 8.4 Hz,
2-H), 7.09(s, 1 H, 411-H), 7.15 (s, 1 H, 41-H), 7.36 (d, 1 H, J = 8.1
Hz, 1-H), 7.43 (s, 1 H, 511-H), 7.56 (s, 1 H, 51-H), 8.15 (s, 1 H, 211-
H), 8.29 (s, 1 H, 21-H).
HRMS: m/z (M+) calcd 372.2314, obsd 372.2311.
Anal. calcd for C24H28N4: C, 77.37; H, 7.58; N, 15.05. Found C,
77.26; H, 7.59; N, 15.04.
2,6-Dimethylphenyl-1-imidazole (38, Table, Entry 31)
Viscous oil.
1H NMR (300 MHz, CDCl3): d = 2.23 (s, 6 H, 2- and 6-CH3), 7.14
(s, 3 H, 3-, 4- and 5-H), 7.18 (s, 1 H, 41-H), 7.60 (s, 1 H, 51-H), 8.34
(s, 1 H, 21-H).
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(b) Rodriquez, R. J.; Parks, L. W. Antimicrob. Agents
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HRMS: m/z (M+) calcd 172.1000, obsd 172.1009.
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(b) Njar, V. C. O.; Nnane, I. P.; Brodie, A. M. H. Bioorg. Med.
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Anal. calcd for C11H12N2: C, 76.70; H, 7.03; N, 16.27. Found C,
76.75; H, 7.02; N, 16.25.
17b-Chloroacetylandrost-4-en-3-one (39)
(7) (a) Heeres, J.; Backx, L. J. J.; Mostmans, J. H.; Van Cutsem,
J. J. Med. Chem. 1979, 22, 1003.
A solution of triphosgene (171.5 mg, 0.5779 mmol) and anhyd py-
ridine (137 mg, 1.7335 mmol) in anhyd CH2Cl2 (10 mL) was stirred
at r.t. for 5 min. Thereafter, testosterone (13, 500mg, 1.7335 mmol)
was added to the reaction mixture and after stirring for a further 4 h,
it was washed successively with 1 N HCl and brine and dried
(Na2SO4). Evaporation of the solvent gave pure 39 as a white solid
(560 mg, 92%); mp 140-141 °C.
(b) Jones, C. D.; Winter, M. A.; Hirsch, K. S.; Stamm, N.;
Taylor, H. M.; Holden, H. E.; Davenport, J. D.; Knumkalns,
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1H NMR (300 MHz, CDCl3): d = 0.89 (s, 3 H, 18-CH3), 1.70 (s, 3
H, 19-CH3), 4.58 (t, 1 H, J = 8.1 Hz, 17a-H), 5.74 (s, 1 H, 4-H).
Anal. calcd for C20H27ClO3: C, 68.54; H, 7.77; Cl, 9.99. Found C,
68.44; H, 7.76; Cl, 9.97.
(9) To our knowledge, there is no literature precedent for the
direct conversion of allylic alcohols into their corresponding
azole compounds.
17b-Imidazolcarbamylandrost-4-en-3-one (40)
To a solution of imidazole (38.76 mg, 0.57 mmol) and Et3N
(63.32 mg, 0.627 mmol) in anhyd MeCN (2 mL) was added with
stirring at 10 °C a solution of compound 39 (200 mg, 0.57 mmol) in
anhyd MeCN (2 mL). After stiring at r.t. for 30 min, a white precip-
itate formed. The mixture was then diluted with cold H2O (20 mL),
the precipitate was filtered, washed with H2O, and dried to give pure
17b-imidazolcarbamate 40 (200 mg, 95%); mp 168-170 °C.
1H NMR (300 MHz, CDCl3): d = 0.95 (s, 3 H, 18-CH3), 1.21 (s, 3
H, 19-CH3), 4.84 (t, 1 H, J = 10.0 Hz, 17a-H), 5.75 (s, 1 H, 4-H),
7.08 (s, 1 H, 41-H), 7.41 (s, 1 H, 51-H), 8.13 (s, 1 H, 21-H).
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V. C. O. Njar
PAPER
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Article Identifier:
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