Isoprene-mediated lithiation of 1-alkylimidazoles: Chiral induction of the alkyl substituent

Article abstract of DOI:10.2174/157017810791514850

The isoprene-mediated lithiation of imidazoles bearing a secondary alkyl substituent at the nitrogen (7, 8 and 13) and the subsequent nucleophilic addition to different electrophiles allows the preparation of the corresponding 2-functionalized imidazoles

Full text of DOI:10.2174/157017810791514850

Letters in Organic Chemistry, 2010, 7, 373-376
373
Isoprene-Mediated Lithiation of 1-Alkylimidazoles: Chiral Induction of
the Alkyl Substituent
Isidro M. Pastor*, Rosario Torregrosa and Miguel Yus*
Departamento de Química Orgánica, Facultad de Ciencias and Instituto de Síntesis Orgánica (ISO), Universidad de
Alicante, Apdo. 99, 03080 Alicante, Spain
Received January 25, 2010: Revised April 22, 2010: Accepted April 23, 2010
Abstract: The isoprene-mediated lithiation of imidazoles bearing a secondary alkyl substituent at the nitrogen (7, 8 and
13) and the subsequent nucleophilic addition to different electrophiles allows the preparation of the corresponding 2-
functionalized imidazoles 10, 11 and 14. The presence of a stereogenic center in the alkyl substituent induces
diastereoselection during the nucleophilic addition step with a prochiral electrophile (i.e. pivalaldehyde), producing the
expected imidazole derivative with excellent overall yield, but low de (up to 26%).
Keywords: Isoprene-mediated lithiation, imidazole derivatives, nucleophilic addition, lithium.
1. INTRODUCTION
Albeit the generation of 2-lithioimidazole derivatives bearing
methyl or primary alkyl groups in the nitrogen has been
extensively studied, the preparation of this type of
organolithium intermediates with a secondary alkyl moiety
has not been yet reported. Herein, we describe the use of the
isoprene-mediated lithiation methodology in the preparation
and reactivity of N-cyclohexyl- and N-(1-methylheptyl)-2-
lithioimidazole. Additionally, it has been considered the
influence of a stereogenic center in the alkyl substituent
About half of the registered chemical compounds contain
a heterocyclic moiety. Imidazoles, and azoles in general, are
an important family of those heterocyclic compounds with a
broad interest due to their bioactive properties [1].
Consequently, the synthesis of imidazole derivatives
constitutes a wide field of interest in synthetic organic and
medicinal research [2]. Imidazole derivatives can be
obtained by different routes, the employment of metalated
imidazole derivatives being one of them [3].
[using
1-(1-cyclohexylethyl)imidazole]
during
the
nucleophilic addition reaction to a prochiral electrophile [9].
X
R1
R1
a-c
2. RESULTS AND DISCUSSION
N
N
N
N
N-Cyclohexyl- (7) and N-(1-methylheptyl)imidazole (8)
were respectively obtained from cyclohexylamine and 2-
octylamine, in their reaction with formaldehyde, glyoxal and
ammonia. Thus, an equimolecular mixture of the four
1 (R1 = Me)
2 (R1 = Ph)
3 [R1 = CH(OEt)2]
4 (77-99%, R1 = Me)
5 (64-89%, R1 = Ph)
6 (48-93%, R1 = H)
components was heated at 75 ºC in
water/methanol during 3 hours producing imidazoles 7 and 8
in good isolated yields (Scheme 2) [10].
a mixture of
Scheme 1. Reagents and conditions: (a) Li, isoprene, THF, 25 ºC;
(b) Electrophile, THF, 25 ºC; (c) H2O (or HCl 0.1 M for compound
3).
R1
N
N
a
R1NH2
Lithium metal is a widely used lithiation agent for the
preparation of organolithium reagents. Additionally, the use
of an arene as catalyst has been extensively employed as a
very practical methodology [4]. A variety of functionalized
organolithium intermediates has been prepared, employing
metal lithium as lithiating agent, by means of this
methodology [5]. More recently, we have reported the use of
a diene (i.e. isoprene) as a promoting lithiation agent in the
generation of lithio-imidazole derivatives. Thus, isoprene-
mediated lithiation of different imidazole derivatives, such as
N-methyl- (1) [6], N-phenyl- (2) [7] and N-(diethoxy-
methyl)imidazole (3) [8] has been reported (Scheme 1).
7 (80%, R1 = cyclohexyl)
8 (75%, R1 = 1-methylheptyl)
Scheme 2. Reagents and conditions: (a) NH3 (25% aq.),
[(CHO)2]3·(H2O)2, CH2O (36% aq.), H2O/MeOH, 75 ºC.
Imidazole derivatives 7 and 8 were treated with lithium
powder in the presence of isoprene [11] at room temperature,
producing the corresponding organolithium intermediates 9
which underwent nucleophilic addition to different
aldehydes and ketones giving, after hydrolysis, the
corresponding 2-functionalized imidazoles 10 and 11 (Table
1) [12]. The final products 11 were obtained as diastereo-
isomeric mixtures, when the reactions were performed with
prochiral electrophiles, due to the presence of a stereogenic
center in the N-substituent of compound 8 (Table 1, entries
*Address correspondence to these authors at the Departamento de Química
Orgánica, Facultad de Ciencias and Instituto de Síntesis Orgánica (ISO),
Universidad de Alicante, Apdo. 99, 03080 Alicante, Spain; Fax: + 34 965
903549; E-mails: ipastor@ua.es, yus@ua.es
1570-1786/10 $55.00+.00
© 2010 Bentham Science Publishers Ltd.

374 Letters in Organic Chemistry, 2010, Vol. 7, No. 5
Pastor et al.
Table 1. Isoprene-Mediated Lithiation of Imidazoles 7 and 8a
R2
HO
R1
R3
N
Li
R1
R1
Li, isoprene
a) Electrophile
b) H2O
N
N
N
N
N
THF, 25 ˚C
7-8
9
10-11
Product
Entry
Substrate
Electrophile
No.
10a
Structure
Yield (%)
HO
Et
Et
1
7
Et2CO
82
53
N
N
HO
N
Me
Ph
2
3
4
5
6
7
8
7
7
7
8
8
8
8
PhCOMe
ButCHO
10b
10c
10d
11a
11b
11c
11d
N
HO
N
But
N
65
HO
N
Pri
PriCH2CHO
75
N
HO
Et
Et
Et2CO
65
N
N
5
HO
Me
Ph
PhCOMe
ButCHO
82b
94c
72b
N
N
5
HO
But
N
N
5
HO
N
Pri
PriCH2CHO
N
5
aReactions performed with the corresponding imidazole (2 mmol), lithium (6 mmol), isoprene (4 mmol) in THF (5 mL), and then the electrophile (2.2 mmol).
bThis compound was obtained as a mixture of diastereoisomers (0% de, 1H-NMR).
cThis compound was obtained as a mixture of diastereoisomers (9% de, 1H-NMR).

Isoprene-Mediated Lithiation of 1-Alkylimidazoles
Letters in Organic Chemistry, 2010, Vol. 7, No. 5
375
HO
N
But
N
HO
N
But
N
a-c
N
N
Cy
+
Cy
Cy
14
13
90% yield (26% de)
Scheme 3. Reagents and conditions: (a) Li, isoprene, THF, 25 ºC; (b) ButCHO, THF, 25 ºC; (c) H2O.
[3]
(a) Iddon, B. Metalation and metal-halogen exchange reactions of
imidazoles. Heterocycles, 1985, 23, 417-443; (b) Iddon, B.;
Ngochindo, R. I. Synthesis and reactions of lithiated monocyclic
azoles containing two or more hetero-atoms. Part IV. Imidazoles.
Heterocycles, 1994, 38, 2487-2568; (c) Zificsak, C. A.; Hlasta, D.
J. Current methods for the synthesis of 2-substituted azoles.
Tetrahedron, 2004, 60, 8991-9016.
(a) Yus, M. Arene-catalyzed lithiation reactions. Chem. Soc. Rev.,
1996, 25, 155-161; (b) Ramón, D. J.; Yus, M. New methodologies
based on arene-catalyzed lithiation reactions and their application
to synthetic organic chemistry. Eur. J. Org. Chem., 2000, 225-237;
(c) Yus, M. From arene-catalyzed lithiation to other synthetic
adventures. Synlett, 2001, 1197-1205; (d) Yus, M. The Chemistry
of Organolithium Compounds; Chapter 11. Rappoport, Z.; Marek,
I. Eds.; J. Wiley & Sons: Chichester, 2004.
(a) Nájera, C.; Yus, M. Functionalized organolithium compounds
in synthetic organic chemistry. Trends Org. Chem., 1991, 2, 155-
181; (b) Nájera, C.; Yus, M. Acyl main group metal and metalloid
derivatives in organic synthesis: a review. Org. Prep. Proced. Int.,
1995, 27, 383-457; (c) Nájera, C.; Yus, M. Recent developments in
the chemistry of functionalized organolithium compounds. Recent
Res. Dev. Org. Chem., 1997, 1, 67-96; (d) Yus, M.; Foubelo, F.
Reductive opening of saturated oxa-, aza- and thia-cycles by means
of an arene-promoted lithiation: synthetic applications. Rev.
Heteroatom Chem., 1997, 17, 73-107; (e) Guijarro, D.; Yus, M.
Non-deprotonating methodologies for organolithium reagents
starting from non-halogenated materials. Recent Res. Dev. Org.
Chem., 1998, 2, 713-744; (f) Yus, M.; Foubelo, F. In Targets
Heterocycl. Syst.; Attanasi, O. A.; Spinelli, D. Eds.; Italian Society
of Chemistry: Rome, 2002; pp. 136-171; (g) Nájera, C.; Sansano, J.
M.; Yus, M. Recent synthetic uses of functionalized aromatic and
heteroaromatic organolithium reagents prepared by non-
deprotonating methods. Tetrahedron, 2003, 59, 9255-9303; (h)
Nájera, C.; Yus, M. Functionalized organolithium compounds:
New synthetic adventures. Curr. Org. Chem., 2003, 7, 867-926; (i)
Yus, M. Ring opening of heterocycles by an arene-catalyzed
lithiation. Pure Appl. Chem., 2003, 75, 1453-1475; (j) Chinchilla,
R.; Nájera, C.; Yus, M. Functionalized organolithium compounds
in total synthesis. Tetrahedron, 2005, 61, 3139-3176.
Torregrosa, R.; Pastor, I. M.; Yus, M. Isoprene-catalyzed lithiation
of imidazole: synthesis of 2-(hydroxyalkyl)- and 2-
(aminoalkyl)imidazoles. Tetrahedron, 2005, 61, 11148-11155.
Torregrosa, R.; Pastor, I. M.; Yus, M. Isoprene-promoted lithiation
of 1-phenylimidazole. ARKIVOC, 2008, vii, 8-15.
Torregrosa, R.; Pastor, I. M.; Yus, M. Isoprene-catalysed lithiation:
deprotection and functionalisation of imidazole derivatives.
Tetrahedron, 2007, 63, 947-952.
A part of this study was preliminary presented: Torregrosa, R.;
Pastor, I. M.; Yus, M. Isoprene-mediated lithiation of chiral N-
alkylimidazoles. ECSOC-11, 2007, communication [a005]
(http://www.mdpi.org/ecsoc-11).
General procedure for preparation of imidazoles: A solution of the
corresponding amine (10 mmol) and ammonia (25% aq., 10 mmol,
0.75 mL) in MeOH (4 mL) and a solution of glyoxal (trimer
dihydrate, 10 mmol, 0.70 g) and formaldehyde (36% aq., 10 mmol,
0.77 mL) in MeOH (4 mL) and water (4 mL) were slowly and
simultaneously added to a round bottom flask with MeOH (7 mL)
heated to 50 ºC. After the addition was finished, the reaction
mixture was heated to 75 ºC during 3 h. The reaction mixture was
cooled down, diethyl ether and water were added in equal portions
until two phases were observed and the aqueous phase was
extracted with Et2O (3ꢀ10 mL). All the organic phases were dried
over anhydrous magnesium sulphate. The solvents were evaporated
under reduced pressure and the corresponding imidazoles were
6-8, footnotes b and c). Although, compounds 11b and 11d
resulted as a 1:1 mixture of diastereoisomers, compound 11c
was obtained with a slight diastereoisomeric excess.
The selectivity of the nucleophilic addition process seems
to be controlled by the stereogenic center in the N-
substituent. Thus, we prepared (R)-1-(1-imidazolyl)-1-
phenylethane (12) and (S)-1-cyclohexyl-1-(1-imidazolyl)
ethane (13) starting from the corresponding chiral amines by
means of the methodology described above (in Scheme 2)
[10,13]. Lithiation of compound 12 did not give the expected
2-lithioimidazole derivative under any of the reaction
conditions employed, because the reductive cleavage of the
benzylic substituent occurred in the presence of the mixture
lithium/isoprene [14]. However, the lithiation of imidazole
13 employing the same methodology described previously
and the nucleophilic addition to pivalaldehyde gave
compound 14 as a diastereoisomeric mixture in good overall
yield (Scheme 3) [15].
[4]
[5]
CONCLUSIONS
In conclusion, we have reported here that the
lithium/isoprene methodology is applicable to successfully
generate 2-lithio-N-alkylimidazole derivatives bearing
secondary alkyl groups, although higher amounts of isoprene
are needed in comparison with the lithiation of 1-
methylimidazole. Additionally, the reaction of the chiral
organolithium intermediates with a prochiral electrophile
(i.e. pivalaldehyde) gives the corresponding functionalized
imidazoles with a certain degree of diastereoselection, when
a stereogenic center is linked to the N-substituent.
[6]
ACKNOWLEDGEMENTS
[7]
[8]
This work was generously supported by the Spanish
Ministerio de Educación
y Ciencia [CTQ2004-01261,
CTQ2007-65218, and CONSOLIDER INGENIO 2010
(CSD2007-00006)], the Generalitat Valenciana (GRUPOS
03/135, GV05/52, GV/2007/036, GVPRE/2008/278 and
PROMETEO 2009/039) and the Universidad de Alicante.
We also thank Medalchemy S.L. for a gift of chemicals,
especially lithium powder.
[9]
[10]
REFERENCES AND NOTES
[1]
(a) Nebert, D. W.; González, F. J. P450 genes: structure, evolution
and regulation. Annu. Rev. Biochem., 1987, 56, 945-993; (b) Pastor,
I. M.; Yus, M. Bioactive N-phenylimidazole derivatives. Curr.
Chem. Biol., 2009, 3, 65-88.
[2]
(a) Grimmett, M. R. Imidazole and benzimidazole synthesis;
Academic: London, 1997; (b) Grimmett, M. R. Product class 3:
Imidazoles. Sci. Synth., 2002, 12, 325-528.

376 Letters in Organic Chemistry, 2010, Vol. 7, No. 5
Pastor et al.
ꢃ20
ꢄD
purified by column chromatography (silica gel, mixtures of hexane
and ethyl acetate).
= +3.6 (c 2.4, CH2Cl2); tr 15.33; Rf 0.35 (hexane/EtOAc
ꢁ
ꢀ
ꢂ
[11]
[12]
Different amounts of isoprene have been used depending on the
substrate, see ref. 6-8. For these cases it was observed and
improvement of the yield in the final product by increasing the
isoprene amount up to 200% molar, so this amount has been
employed for all the reactions.
2:1); ꢀ(KBr) 3660–3019 (OH); ꢁH (400 MHz, CDCl3): 0.84–0.92,
0.98, 1.07, 1.20–1.26, 1.42–1.44, 1.65, 1.76–1.80, 1.84–1.88 [1H,
10H, 3H, 1H, 4H, 2H, 1H and 1H, 8m, 5ꢀCH2 and CH, CH3CH and
C(CH3)3], 3.42 (1H, br s, OH), 3.88–3.92 (1H, m, CHCH3), 4.36
(1H, s, CHOH), 6.85, 7.03 (1H and 1H, 2s, NCHCHN); ꢁC (100
MHz, CDCl3): 18.8 (CH3CH), 25.6 [3C, C(CH3)3], 25.8, 25.9, 25.9,
29.3, 30.0 (5ꢀCH2), 37.0 [C(CH3)3], 45.3 (CH), 56.7 (CHCH3),
73.2 (CHOH), 115.5, 127.3 (NCHCHN), 149.1 (NCN); m/z 265
(M++1, 1%), 264 (4), 208 (12), 207 (76), 97 (100), 69 (20). HRMS
calculated for C16H28N2O 264.2202, found 264.2210.
General procedure for the isoprene-mediated lithiation: The
corresponding imidazole (2 mmol) was added to a suspension of
lithium powder (6 mmol, 0.042 g) and isoprene (4 mmol, 0.404
mL) in THF (5 mL) at room temperature. The mixture was stirred
for 1 hour and then the corresponding electrophile (2.2 mmol) was
added, continuing the stirring during 45 min at the same
temperature. The reaction mixture was hydrolyzed with water (10
mL), extracted with ethyl acetate (3ꢀ10 mL), and the resulting
organic phase was dried over anhydrous magnesium sulfate. After
removing the solvent under reduced pressure (15 Torr), the
resulting crude was purified by column chromatography (silica gel,
mixtures of hexane and ethyl acetate) or by recrystallization.
Imidazoles 12 and 13 were respectively isolated with 70% and 44%
yield after column chromatography (silica gel, hexane/ethyl acetate
mixtures).
ꢁ
ꢃ20
[Diastereoisomer 2]: Colorless solid; m.p. 30–35 ºC;
ꢀ
= +10.5
ꢂ
ꢄD
(c 2.9, CH2Cl2); tr 15.44; Rf 0.29 (hexane/EtOAc 2:1); ꢀ(KBr)
3800–3024 (OH); ꢁH (400 MHz, CDCl3): 0.82–0.91, 1.07, 1.14,
1.26, 1.33–1.34, 1.46–1.49, 1.68, 1.81–1.84, 1.91–1.94 [1H, 10H,
2H, 1H, 3H, 1H, 3H, 1H and 1H, 9m, 5ꢀCH2 y CH, CH3CH and
C(CH3)3], 2.58 (1H, br s, OH), 4.00–4.07 (1H, m, CHCH3), 4,37
(1H, s, CHOH), 6.87, 7.02 (1H and 1H, 2s, NCHCHN); ꢁC (100
MHz, CDCl3): 20.7 (CH3CH), 26.0, 26.1, 26.1, 30.0, 30.4 (5ꢀCH2),
26.2 [3C, C(CH3)3], 36.5 [C(CH3)3], 43.7 (CH), 56.9 (CHCH3),
73.6 (CHOH), 115.7, 127.5 (NCHCHN), 148.4 (NCN); m/z 264
(M+, 4%), 208 (12), 207 (69), 99 (10), 97 (100), 69 (24), 55 (10).
HRMS calculated for C16H28N2O 264.2202, found 264.2192.
[13]
[14]
[15]
The N-benzyl substituent is not stable under isoprene-mediated
lithiation reaction: for the stability of N-substituted imidazoles
under these conditions see ref. 8.
1-[1-(1-Cyclohexylethyl)-1H-imidazol-2-yl]-2,2-dimethylpropan-1-
ol (14). [Diastereoisomer 1]: Colorless solid; m.p. 72–74 ºC;