Lithiation and functionalization of 1-alkynylimidazoles at the 2-position

Article abstract of DOI:10.1016/j.tetlet.2009.06.133

Functionalization reactions of 1-alkynylimidazoles involving the formation of their 2-lithio derivatives followed by addition of various electrophiles are presented. This allows access to previously unreported 1,2-dialkynylimidazoles via 1-alkynyl-2-iodoi

Full text of DOI:10.1016/j.tetlet.2009.06.133

Tetrahedron Letters 50 (2009) 5194–5197
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Tetrahedron Letters
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Lithiation and functionalization of 1-alkynylimidazoles at the 2-position
*
Christophe Laroche, Sean M. Kerwin
Division of Medicinal Chemistry, College of Pharmacy and Department of Chemistry, The University of Texas at Austin, TX 78712, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Functionalization reactions of 1-alkynylimidazoles involving the formation of their 2-lithio derivatives
followed by addition of various electrophiles are presented. This allows access to previously unreported
1,2-dialkynylimidazoles via 1-alkynyl-2-iodoimidazoles. The use of an aldehyde or sulfonimine electro-
philes allows the direct formation of bicyclic ring systems.
Received 1 April 2009
Revised 17 June 2009
Accepted 29 June 2009
Available online 4 July 2009
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
2. Result and discussion
Imidazoles and benzimidazoles are molecules of wide interest
and importance due to their utilization as key scaffolds in nat-
ure1–4 and pharmaceutical products.5–7 We recently reported a
coupling reaction between imidazoles and bromoalkynes mediated
by copper complexes.8 This methodology allows efficient access to
1-alkynylimidazoles. The rapid elaboration of polycyclic heterocy-
cles from a variety of N-substituted alkynes has been reported re-
cently.9–13 Application of these strategies, or alternative strategies
involving the thermal cyclization of 1,2-dialkynylimidazoles,14 re-
quires functionalization of the readily available 1-alkynylimidaz-
oles at the 2-position. Functionalization of 1-protected
imidazoles at the 2-position has been reported many times in the
literature. One methodology is based on the quaternarization of
the pyridine-like nitrogen (typically with Boc2O), allowing the for-
mation of an intermediate ylide which can be trapped by different
electrophiles.15 An alternative and widely used methodology con-
sists of the generation of the lithiated intermediate16 at the 2-posi-
tion by the action of a strong base (typically n-BuLi) followed by
addition of an electrophile reagent.17 Using this process, observed
yields vary significantly with reaction conditions and the nature of
protected group on the pyrrole-like nitrogen. The main issues in
applying this strategy on 1-alkynylimidazoles concern the un-
known stability of the ynamine moiety under strong basic condi-
tions and potential instability of the resulting lithiated
intermediate. We are aware of only one previous report of depro-
tonation/lithiation of a heterocycle adjacent to an N-alkynyl substi-
tuent.18 The work described here reports the successful application
of this strategy in the functionalization of 1-alkynylimidazoles to
2-substituted-1-alkynylimidazoles.
The deprotonation of 1-alkynylimidazole 1 (Table 1) was stud-
ied by deuterolysis experiment. Addition of n-BuLi (2.5 M in hex-
Table 1
Iodination of 1-alkynylimidazoles
i) n-BuLi, -78 ºC, 15 min
ii) I2, -78 ºC, 30 min
N
N
N
N
X
X
I
THF
R
R
1—4
5—8
Entry
1
Starting material
n-BuLi equiv
I2 equiv
0.9
Product, yield
N
N
1.2
5, 50%
Ph
1
2
3
1
1
1.0
1.2
1.0
1.2
5, 87%
5, 74%
N
N
4
1.0
1.0
6, 77%
TIPS
2
Ph
N
N
5
6
1.0
1.0
1.0
1.0
7, 61%
8, 82%
TIPS
3
N
N
OTBDMS
4
* Corresponding author. Tel.: +1 512 471 5074/5264; fax: +1 512 232 2606.
E-mail address: skerwin@mail.utexas.edu (S.M. Kerwin).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.06.133

C. Laroche, S. M. Kerwin / Tetrahedron Letters 50 (2009) 5194–5197
5195
Table 2
ane) to 1-(2-phenylethynyl)-imidazole (1) in THF at À78 °C was
Reaction of 1-alkynylimidazoles with different electrophiles
followed by quenching of reaction mixture aliquots with D2O at
different time periods (15, 30, and 60 min). 1H NMR spectra of
the quenched reaction products showed an almost complete disap-
pearance of the signal for the proton at the 2-position on the imid-
azole ring after 15 min at À78 °C (95% deuterium incorporation).
The 1H NMR spectra obtained after 30 min and 1 h at À78 °C were
similar to the those of the 15 min sample, indicating that the 2-
lithiated intermediate is stable under these conditions; however,
after warming the reaction mixture, we noticed the formation of
an oligomeric product at approximately À40 °C.
i) n-BuLi, -78 ºC, 15 min
N
N
N
E
ii) Electrophile, -78 ºC, 30 min
N
THF
Ph
Ph
1
10—14
Entry
1
Electrophile
Product
Yield
N
Me
N
MeI
10, 96%
11, 60%
12, 61%
13, 60%
14, 65%
Initial attempts to access 2-substituted-1-alkynylimidazoles fo-
cused on trapping the 2-lithio species with iodine. After deproto-
nation of 1 with n-BuLi at À78 °C for 15 min, solid iodine was
added at À78 °C and the reaction mixture was stirred for an addi-
tional 30 min at À78 °C. Gratifyingly, this led to the isolation of the
2-iodo-1-(phenylethynyl)imidazole (5) in moderate yield (Table 1,
entry 1). Optimization of the equivalents of base and iodine indi-
cated that the use of excess reagent is detrimental to reaction yield
(Table 1, entries 1 and 3). We are assuming that the excess of base
or iodine may react with the carbon–carbon triple bond. When ex-
actly one equivalent of each reagent was used, the yield of 5 in-
creased from 50% to 87% (Table 1, entry 2).
Under the optimized conditions, three different substrates
afforded iodinated products in moderate to good yields (Table 1,
entries 4–6). The methodology showed good tolerance toward
variations in the imidazole ring system (benzimidazole and 4-
phenylimidazole, Table 1, entries 4 and 5) and carbon–carbon tri-
ple bond substitution (Ph, TIPS, and CH2OTBDMS, Table 1, entries
3, 4, and 6). Thus, despite some limitations due to the stability of
the 2-lithio derivative and the reactivity of the triple bond, the yna-
mine moiety of 1-alkynylimidazoles acts as an efficient blocking
group of the pyrrole-like nitrogen, enabling iodination at the 2-
position.
To demonstrate the utility of this new strategy, the compound 3
was engaged in coupling reaction with 4-methoxyphenylacetylene
and trimethylsilylacetylene (Scheme 1). In both cases, the 4-substi-
tuted-1,2-dialkynylimidazoles 9a and 9b, respectively, were ob-
tained in good yields after Sonogashira coupling and silyl
deprotection. This strategy represents a significant advance since
4-substituted-1,2-dialkynylimidazoles cannot be produced using
our previous strategy.19
We have investigated the use of electrophiles other than iodine
to intercept the 2-lithio derivative of 1-phenylethynylimidazole
(Table 2). Iodomethane gave the expected methylated compound
10 in almost quantitative yield (Table 2, entry 1). When phen-
ylethylbromide, -iodide,20 -tosylate,21 and -triflate22 were exam-
ined as electrophiles, the triflate derivative was the only one to
afford the 2-alkylated product 11 (60% yield, Table 2, entry 2).
The lack of reactivity of 1-dimethylaminomethyl-protected imid-
azole anion with phenylethyliodide and -tosylate has been previ-
ously reported.23 Moreover, the 2-lithio species derived from 1-
alkynylimidazoles may be also limited by ring fragmentation as
is observed for 2-lithiated oxazole species.24 In the literature, the
limited reactivity of the 2-lithio imidazole species toward these
Ph
N
N
Ph
2
3
4
Ph(CH2)2OTf
ClCO2Me
Ph
N
N
O
OMe
Ph
O
N
N
Me
EtOAc
Ph
O
H
N
N
5a
(CH3)2NCHO
Ph
a
The reaction was quenched with 5 mL of 1 M HCl solution.
electrophiles has led to alternative routes to the 2-(2-arylethyl)
derivatives involving either deprotonation of a 2-methyl derivative
and alkylation of the resulting 2-lithiomethyl species23 or a Wittig-
based strategy where an (arylmethyl)triphenylphosphonium salt
and 2-formylimidazole were coupled followed by reduction.25 In
our case, 11 can be prepared directly by employing the correspond-
ing triflate electrophile. The successful synthesis of 2-alkyl-1-alky-
nylimidazoles constitutes the starting point for structure–activity
relationship studies. Although a number of biologically active 1-al-
kyl-2-alkynylimidazoles are known,26 the regioisomeric 2-alkyl-1-
alkynylimidazoles such as compounds 10 and 11 are new. These
can be used as model compounds to evaluate the biological rele-
vance of the regiochemistry of the carbon–carbon triple bond of
the previously reported alkynylimidazoles.
Other electrophiles can also be used to trap the 2-lithio species.
Methylchloroformate, ethyl acetate, and dimethylformamide can
all be employed to afford ester 12, ketone 13, and aldehyde 14 in
60%, 61%, and 65% yield, respectively (Table 2, entries 3–5).
Finally, when benzaldehyde was employed, a different type of
product was formed in 50% yield. The 13C NMR of this product
showed the disappearance of the carbon–carbon triple bond sig-
nals and the 1H NMR spectrum showed a signal at 6.5 ppm attrib-
uted to an olefinic proton. Although these observations are
consistent with a product in which the intermediate alcoholate
adds to the ynamine moiety, the structure could not be unambig-
i) Pd(PPh3)4 (5 mol %)
CuI (10 mol %)
alkyne (1.1 equiv.)
Et3N, 50 ºC
Ph
N
N
Ph
N
N
I
R
i) n-BuLi, -78 ºC, 15 min
ii) PhCHO, -78 ºC, 30 min
N
N
N
N
Ph
ii) TBAF (1 equiv.)
THF, -78 ºC
O
TIPS
H
THF
Ph
Ph
9a: R = p-MeOPh (78 %)
3
1
9b: R = H (from TMS-acetylene) (79 %)
15
Scheme 1. Synthesis of new 4-substituted-1,2-dialkynylimidazoles.
Scheme 2. Direct route to dihydroimidazo[1,2-c]oxazole.

5196
C. Laroche, S. M. Kerwin / Tetrahedron Letters 50 (2009) 5194–5197
dazo[1,5-a]imidazole structure 16 based on comparison of its
NMR spectral properties with that of 15. The 7,8-dihydroimi-
dazo[1,2-a]pyrazine structure of 17, obtained in 23% yield, was
determined by X-ray crystallography (Fig. 2).
Interestingly, in this case, the presumed intermediate sulfon-
amide anion undergoes both 5-exo-dig and 6-endo-dig cyclization
with no apparent selectivity for one mode versus the other.
3. Conclusion
The synthesis of 1-alkynylimidazoles with various substituents
on the 2-position has been accomplished.29 The strategy employed
allows the presence of different substituents on the carbon–carbon
triple bond and the imidazole core. In the case of 2-iodo deriva-
tives, a subsequent Sonogashira coupling was realized to achieve
the synthesis of previously inaccessible 1,2-dialkynylimidazoles.
The method developed in this Letter also provides a new, concise
route to the synthesis of the 5,7-dihydroimidazo[1,2-c]oxazole, 5-
benzylidine-6,7-dihydromidazo[1,5-a]imidazole, and 7,8-dihydro-
imidazo[1,2-a]pyrazine bicyclic ring systems.
Figure 1. Structure of 15 determined by X-ray crystallography. One of two non-
centrosymmetric molecules of 15 from the unit cell is shown. Displacement
ellipsoids are scaled to the 50% probability level.
uously assigned based on spectral data. Fortunately, the product
was crystalline and the structure solved by X-ray crystallography
was assigned as the 5,7-dihydroimidazo[1,2-c]oxazole 15 (Scheme
2, Fig. 1).
Acknowledgments
5,7-Dihydroimidazo[1,2-c]oxazoles have been reported a few
times in the literature for their biological properties and are gener-
ally prepared by a condensation reaction between 2-hydroxyme-
thylimidazoles and aldehydes.27 The formation of 15 can be
classified as a 5-exo-dig ring closure reaction of the intermediate
alcoholate onto the imidazole 1-alkynyl substituent.
The 2-lithio-1-phenylethynyl-1H-imidazole was also allowed to
react with N-benzylidenebenzenesulfonamide28 at À78 °C. The
solution was allowed to warm to À60 °C after the addition of the
sulfonimine and the reaction was quenched by the addition of
water (Scheme 3).
We are grateful to the Robert Welch Foundation (F-1298) and
the Texas Advanced Research Program (3658-003) for financial
support of this research. We want to thank M. Allison and E. N.
Chugh for their contributions to this work.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2009.06.133.
References and notes
Two products were formed, one of these products, obtained in
24% yield, was assigned the 5-benzylidine-6,7-dihydromi-
1. Cianchi, F.; Vinci, C. M.; Masini, E. Cancer Biol. Ther. 2008, 7, 36–37.
2. De Luca, L.; Curr. Med. Chem. 2006, 13, 1–23.
3. Haas, H. L.; Sergeeva, O. A.; Selbach, O. Physiol. Rev. 2008, 88, 1183–1241.
4. Masahiko, S. Med. Res. Rev. 2006, 26, 434–482.
5. Michnovicz, J. J.; Galbraith, R. A. Metabolism 1991, 40, 170–174.
6. Saeki, T.; Umezawa, H.; Tokieda-Fujishige, T.; Hori, M. J. Antibiot. 1974, 27, 225–
227.
7. Peixoto, F.; Camargos, A.; Duarte, G.; Linhares, I.; Bahamondes, L.; Petracco, A.
Int. J. Gynecol. Obstet. 2008, 102, 287–292.
8. Laroche, C.; Li, J.; Freyer, M. W.; Kerwin, S. M. J. Org. Chem. 2008, 73, 6462–6465.
9. Zhang, Y.; Hsung, R. P.; Zhang, X.; Huang, J.; Slafer, B. W.; Davis, A. Org. Lett.
2005, 7, 1047–1050.
i) n-BuLi, -78 ºC, 15 min
N
N
Ph
N
N
N
N
ii) PhCHNSO2Ph
-78 to -60 ºC
Ph
NSO2Ph
Ph
+
NSO2Ph
THF
Ph
Ph
17
16
1
Scheme 3. Direct route to 5-benzylidine-6,7-dihydromidazo[1,5-a]imidazole 16
and 7,8-dihydroimidazo[1,2-a]pyrazine 17.
10. Hoffmann, R. W.; Brüchner, D. B. New J. Chem. 2001, 25, 369–373.
11. Zhang, X.; Zhang, Y.; Huang, J.; Hsung, R. P.; Kutz, K. C. M.; Oppenheimer, J.;
Petersen, M. E.; Sagamanova, I. K.; Shen, L.; Tracey, M. R. J. Org. Chem. 2006, 71,
4170–4177.
12. Marion, F.; Couirillon, C.; Malacria, M. Org. Lett. 2003, 5, 5095–5097.
13. Couty, S.; Liegault, B.; Meyer, C.; Cossy, J. Tetrahedron 2006, 62, 3882–3895.
14. (a) Nadipuram, A. K.; Kerwin, S. M. Org. Lett. 2002, 4, 4543–4546; (b)
Nadipuram, A. K.; Kerwin, S. M. Synlett 2004, 8, 1404–1408; (c) Nadipuram,
A. K.; Kerwin, S. M. Tetrahedron Lett. 2006, 47, 353–356; (d) Nadipuram, A. K.;
Kerwin, S. M. Tetrahedron 2006, 62, 3798–3808.
15. (a) Deng, Y.; Hlasta, D. J. Tetrahedron Lett. 2002, 43, 189–192; (b) Deng, Y.;
Hlasta, D. J. Org. Lett. 2002, 4, 4017–4020; (c) Zificsak, C. A.; Hlasta, D. J.
Tetrahedron Lett. 2005, 46, 4789–4792.
16. For review see: Tertov, B. A.; Koshchienko, Y. V. Chem. Heterocycl. Compd. 1988,
24, 117–131.
17. (a) Kirk, K. L. J. Org. Chem. 1978, 43, 4381–4383; (b) Traylor, T. G.; Hill, K. W.;
Tian, Z.-Q. JACS 1988, 110, 5571–5573; (c) Knapp, S.; Albaneze, J.; Schugar, H. J.
J. Org. Chem. 1993, 58, 997–998; (d) Bahnu Prasad, A. S.; Stevenson, T. M.;
Citineni, J. R.; Nyzam, V.; Knochel, P. Tetrahedron 1997, 53, 7237–7254; (e)
Eriksen, B. L.; Morel, P. V. S.; Begtrup, M. J. Org. Chem. 1998, 63, 12–16; (f)
Schlegel, J.; Maas, G. Synthesis 1999, 1, 100–106; (g) Lang, P.; Magnin, G.;
Mathis, G.; Burger, A.; Biellman, J.-F. J. Org. Chem. 2000, 65, 7825–7832; (h)
Wang, B. B.; Smith, P. J. Tetrahedron Lett. 2003, 44, 8967–8969; (i) Park, S. B.;
Alper, H. Org. Lett. 2003, 5, 3209–3212; (j) Hamm, M. L.; Rajguru, S.; Downs, A.
M.; Cholera, R. JACS 2005, 127, 12220–12221; (k) Zhang, X.; Bernet, B.; Vasella,
A. Helv. Chim. Acta 2006, 89, 2861–2917; (l) Moreau, C.; Wagner, G. K.; Weber,
K.; Guse, A. H.; Potter, B. V. L. J. Med. Chem. 2006, 49, 5162–5176; (m) Cisar, J. S.;
Ferreras, J. A.; Soni, R. K.; Quadri, L. E. N.; Tan, D. S. JACS 2007, 129, 7752–7753;
Figure 2. Structure of 17 determined by X-ray crystallography. Displacement
ellipsoids are scaled to the 50% probability level.

C. Laroche, S. M. Kerwin / Tetrahedron Letters 50 (2009) 5194–5197
5197
(n) Collman, J. P.; Yang, Y.; Decréau, R. A. Org. Lett. 2007, 9, 2855–2858; (o) Jin,
C.; Burgess, J. P.; Rehder, K. S.; Brine, G. A. Synthesis 2007, 2, 219–224.
18. Mal’kina, A. G.; den Besten, R.; van der Kerk, A. C. H. T. M.; Brandsma, L.;
Trofimov, B. A. J. Organomet. Chem. 1995, 493, 271–273.
19. Inacomparativestudy,4-phenylimidazoleand(triisopropylsilyl)ethynyliodonium
triflate were engaged under our previous conditions.14 However, we did not
observe any conversion to the 4-phenyl-1-alkynylimidazole derivative.
20. Waske, P. A.; Mattay, J. Tetrahedron 2005, 61, 10321–10330.
21. Das, B.; Saidi Reddy, V.; Ravinder Reddy, M. Tetrahedron Lett. 2004, 45, 6717–
6719.
22. (a) Nishigichi, I.; Kita, Y.; Watanabe, M.; Ishino, Y.; Ohno, T.; Maekawa, H.
Synlett 2000, 7, 1025–1027; (b) Aubert, C.; Bégué, J.-P. Synthesis 1984, 759–760.
23. Tarnchompoo, B.; Thebtaranonth, C.; Thebtaranonth, Y. Tetrahedron Lett. 1990,
31, 5779–5780.
24. Vedejs, E.; Monahan, S. J. J. Org. Chem. 1996, 61, 5192–5193.
25. Shafiee, A.; Morteza-Senani, K.; Foroumadi, A. J. Heterocycl. Chem. 1996, 33,
671–673.
26. (a) Thomas, A.; Lincam, V. S. P. R.; Phatangare, S. K.; Khairatkar-Joshi, N.; Shah,
D. M.; Ukirde, D. V.; More, D. A. PCT Int. Patent Appl. WO 2008062276, 2008;
Chem. Abstr. 2008, 149, 10026.; (b) Buettelmann, B.; Knust, H.; Thomas, A. PCT
Int. Patent Appl. WO 2007137954, 2007; Chem. Abstr. 2007, 148, 11205.; (c)
Luke, R. W. A.; Jones, C. D.; McCoull, W.; Hayter, B. R. PCT Int. Patent Appl. WO
2004013141, 2004; Chem. Abstr. 2004, 140, 163889.; (d) Mutel, V.; Peters, J.-U.;
Wichmann, J. PCT Int. Patent Appl. WO 2002046166, 2002; Chem. Abstr. 2002,
137, 33292.; (e) Wadsworth, S. A.; Cavender, D. E.; Beers, S. A.; Lalan, P.;
Schafer, P. rH.; Malloy, E. A.; Wu, W.; Fahmy, B.; Olini, G. C.; Davis, J. E.;
Pellegrino-Gensey, J. L.; Wachter, M. P.; Siekierka, J. J. J. Pharmacol. Exp. Ther.
1999, 291, 680–687; (f) Ross, W. J.; Jamieson, W. B.; McCowen, M. C. J. Med.
Chem. 1972, 15, 1035–1040.
27. (a) Katritzky, A. R.; Aslan, D. C.; Leeming, P.; Stell, P. J. Tetrahedron: Asymmetry
1997, 8, 1491–1500; (b) Katritzky, A. R.; Aslan, D. C.; Oniciu, D. C. Tetrahedron:
Asymmetry 1998, 9, 2245–2251; (c) Chimirri, A.; Monforte, P.; Zappalà, M.;
Monforte, A. M.; De Sarro, G.; Pannecouque, C.; Witvrouw, M.; Balzarini, J.; De
Clercq, E. Antiviral Chem. Chemother. 2001, 12, 169–174; (d) Essassi, E. M.;
Fifani, J.; Hamamsi, I. Bull. Soc. Chim. Belg. 1994, 103, 83–84.
28. Jennings, W. B.; Lovely, C. J. Tetrahedron Lett. 1988, 29, 3725–3728.
29. Typical procedure for the synthesis of 2-methyl-1-(2-phenylethynyl)-1H-imidazole
(9): To a solution of 1-(2-phenylethynyl)-1H-imidazole 1 (84 mg, 0.5 mmol) in
THF (5 mL) under argon at À78 °C was added n-BuLi (0.200 mL of 2.5 M
solution in hexane, 0.5 mmol). The reaction mixture was stirred for 15 min
at À78 °C prior to the addition of MeI (0.031 mL, 0.5 mmol). After stirring for
30 min at À78 °C, the mixture was quenched with water (5 mL, method A)
or 1 M HCl solution (5 mL, method B) and the temperature was allowed to
rise to room temperature. The reaction mixture was then extracted with
CH2Cl2 (3 Â 25 mL), the combined organic layers were dried over Na2S04,
and the solvent was evaporated under reduced pressure. The residue was
purified by flash chromatography (0–20% EtOAc/hexane) to afford 88 mg
(96%) of 9 as a colorless liquid. 1H NMR (400 MHz, CDCl3) d 7.52–7.46 (2H,
m), 7.38–7.33 (3H, m), 7.08 (1H, s), 6.90 (1H, s), 2.53 (3H, s); 13C NMR
(100 MHz, CDCl3) d 148.7 (br s), 131.5 (2C), 128.7, 128.4 (2C), 127.7, 121.3,
121.1, 78.0, 72.4, 13.2; IR (neat) 2265, 1547, 1500, 1424, 1285, 1183, 1153,
982 cmÀ1; MS (CI) 183 (M+1, 100%); HRMS (CI) calcd for C12H11N2 (M+H+)
183.0919, found 183.0917.