Deprotonative metalation of five-membered aromatic heterocycles using mixed lithium-zinc species

Article abstract of DOI:10.1021/jo7020345

(Equation Presented) Deprotonation of benzoxazole, benzothiazole, benzo[b]thiophene, benzo[b]furan, N-Boc-protected indole and pyrrole, and N-phenylpyrazole using an in situ mixture of ZnCl₂·TMEDA (0.5 equiv) and lithium 2,2,6,6-tetramethylpipe

Full text of DOI:10.1021/jo7020345

Deprotonative Metalation of Five-Membered Aromatic Heterocycles
Using Mixed Lithium-Zinc Species
Jean-Martial L’Helgoual’ch,† Anne Seggio,† Floris Chevallier,† Mitsuhiro Yonehara,‡
Erwann Jeanneau,§ Masanobu Uchiyama,*,‡ and Florence Mongin*,†
Synthe`se et ElectroSynthe`se Organiques, UMR 6510 CNRS, UniVersite´ de Rennes 1, Baˆtiment 10A,
Case 1003, Campus Scientifique de Beaulieu, 35042 Rennes, France, The Institute of Physical and
Chemical Research, RIKEN, 2-1 Hirosawa, Wako-shi, Saitama 351-0198, Japan, and Centre de
Diffractome´trie Henri Longchambon, UniVersite´ Claude Bernard Lyon 1, 69622 Villeurbanne, France
florence.mongin@uniV-rennes1.fr; uchi_yama@riken.jp
ReceiVed September 20, 2007
Deprotonation of benzoxazole, benzothiazole, benzo[b]thiophene, benzo[b]furan, N-Boc-protected indole
and pyrrole, and N-phenylpyrazole using an in situ mixture of ZnCl2‚TMEDA (0.5 equiv) and lithium
2,2,6,6-tetramethylpiperidide (1.5 equiv) in THF at room temperature is described. The reaction was
evidenced by trapping with iodine, regioselectively giving the expected functionalized derivatives in
52-73% yields. A mixture of mono- and disubstituted derivatives was obtained starting from thiazole.
Cross-coupling reactions of 2-metalated benzo[b]thiophene and benzo[b]furan with heteroaromatic chlorides
proved possible under palladium catalysis. A reaction pathway where the lithium amide and zinc diamide
present in solution behave synergically was proposed for the deprotonation reaction, taking account of
NMR and DFT studies carried out on the basic mixture.
Introduction
temperatures.4 Nevertheless, because of the limited reactivity
of the magnesium amide or diamide used to deprotonate
functionalized substrates, an excess has, in general, to be
employed to ensure good yields.5 In addition, even if the use
of mixed lithium-magnesium amides seems more promising,6
it is still not extendable to very sensitive substrates.
Substituted five-membered aromatic heterocycles are struc-
tural units present in many natural products and pharmaceutical
synthetic intermediates.1 Among the methods used to function-
alize them,1 deprotonation reactions using lithiated bases have
been developed.2 This methodology often requires low temper-
atures and cannot be used when reactive functional groups are
present. In addition, unlike organoboron, organotin, organozinc,
and organomagnesium compounds, organolithiums can hardly
be involved in cross-coupling reactions.3 Organomagnesium
compounds have been prepared by deprotonation at higher
The deprotonation reactions of sensitive aromatics such as
alkyl benzoates, ethyl thiophenecarboxylates, ethyl 2-furancar-
t
boxylate, pyridine, quinoline, and isoquinoline using Bu2Zn-
(4) (a) Metzger, J.; Koether, B. Bull. Chem. Soc. Fr. 1953, 702-707.
(b) Marxer, A.; Siegrist, M. HelV. Chim. Acta 1974, 57, 1988-2000. (c)
Boga, C.; Del Vecchio, E.; Forlani, L.; Milanesi, L.; Todesco, P. E. J.
Organomet. Chem. 1999, 588, 155-159. (d) Rao, P. D.; Littler, B. J.; Geier,
G. R., III; Lindsey, J. S. J. Org. Chem. 2000, 65, 1084-1092.
(5) (a) Eaton, P. E.; Lee, C.-H.; Xiong, Y. J. Am. Chem. Soc. 1989,
111, 8016-8018. (b) Schlecker, W.; Huth, A.; Ottow, E.; Mulzer, J. J.
Org. Chem. 1995, 60, 8414-8416. (c) Schlecker, W.; Huth, A.; Ottow, E.;
Mulzer, J. Liebigs Ann. 1995, 1441-1446. (d) Schlecker, W.; Huth, A.;
Ottow, E.; Mulzer, J. Synthesis 1995, 1225-1227. (e) Kondo, Y.; Yoshida,
A.; Sakamoto, T. J. Chem. Soc., Perkin Trans. 1 1996, 2331-2332. (f)
Shilai, M.; Kondo, Y.; Sakamoto, T. J. Chem. Soc., Perkin Trans. 1 2001,
442-444. (g) Ooi, T.; Uematsu, Y.; Maruoka, K. J. Org. Chem. 2003, 68,
4576-4578.
† Universite´ de Rennes 1.
‡ RIKEN.
§ Universite´ Claude Bernard Lyon 1.
(1) (a) Katritzky, A. R. Handbook of Heterocyclic Chemistry, 1st ed.;
Pergamon: New York, 1985. (b) Eicher, T.; Hauptmann, S.; Speicher, A.
The Chemistry of Heterocycles, 2nd ed.; Wiley-VCH: Weinheim, Germany,
2003.
(2) Schlosser, M. In Organometallics in Synthesis, 2nd ed.; Schlosser,
M., Ed.; Wiley: New York, 2002; Chapter I.
(3) Stanforth, S. P. Tetrahedron 1998, 54, 263-303.
10.1021/jo7020345 CCC: $40.75 © 2008 American Chemical Society
Published on Web 12/05/2007
J. Org. Chem. 2008, 73, 177-183
177

L’Helgoual’ch et al.
(TMP)Li (TMP ) 2,2,6,6-tetramethylpiperidino) as a base were
corresponding lithium phenolate, even at extremely low tem-
perature.12 We therefore focused on the stability of intermediary
aromatic zincates (relative to their lithium analogues), which is
well-known to prevent subsequent rearrangement13 or side
reactions.14 We assumed that it might allow the regioselective
zincation of five-membered aromatic heterocycles and the
isolation of 2-zincate intermediates without any successive side
reactions.
first described in 1999.7 More recently, the use of the aluminum
i
ate base Bu3Al(TMP)Li and the copper ate bases R(TMP)Cu-
(CN)Li2 (R ) alkyl, aryl, or TMP) has been developed in order
to generate functionalized aromatic compounds including
heterocycles.8 The reactions performed in tetrahydrofuran (THF)
proved to be chemoselective, but require 1 or 2 equiv of base.9
Several examples of deprotonation using lithium amidozin-
cates in hexane have been reported by Mulvey since 2005.10
The term alkali-metal-mediated zincation has been introduced
to depict these reactions because the reactivity (“synergy”)
exhibited by the zincates cannot be attained by the homometallic
compounds on their own.11
Previous NMR studies on 2-metallobenzoxazole have shown
the equilibrium was completely on the side of the open isomer
with lithium, whereas transmetalation to the organozinc deriva-
tive favored the ring closure.15 Then, we performed a prelimi-
nary DFT study on the stability of 2-metallobenzoxazoles and
their rearrangement pathways by means of the B3LYP/6-31+G*
method. Figure 1 shows the energy changes for each path and
the geometries of the transition states, intermediates, and
products. While the transition state (TS) and the product (PD)
of 2-lithio derivatives were kinetically and thermodynamically
stable, those of the 2-zincio compounds were found to be more
unstable compared with 2-zincio reactant (RT), which was
consistent with the experimental observations. These big
energetic changes by the difference of metal species prompted
us to further survey whether the zincate bases could be used
for chemoselective metalation of aromatic heterocycles.
The deprotonation reaction of 1 was then examined using
various zincate reagents (Table 1). The addition of 1 molar equiv
(per lithium) of TMEDA or THF to a bulk nonpolar hydrocarbon
in order to increase the opportunity for crystal growth proved
to favor the deprotonation reactions of N,N-diisopropy-
lcarboxamide10b,c and anisole10d using lithium amidozincates.
We therefore decided to prepare bases from ZnCl2‚TMEDA,16
much less hygroscopic than ZnCl2, and 3 (or 4) equiv of
alkyllithium or lithium dialkylamide and to study their ability
to deprotonate benzoxazole (1) (Table 1).
The first experiments were carried out with bases obtained
by mixing 1 equiv of ZnCl2‚TMEDA and 3 equiv of methyl-
or butyllithium and were assumed to be lithium trimethylzincate
and lithium tributylzincate, respectively.17 When used in THF
at room temperature for 2 h, these mixed Li-Zn compounds
hardly metalated benzoxazole (1), giving the 2-substituted
derivative 2 in low yields of 28 and 10%, respectively, after
trapping with iodine (entries 1 and 2). Since dilithium tetraalky-
lzincates have been shown to exhibit a reactivity higher than
that of lithium trialkylzincates in various reactions including
halogen-metal exchange,18 we decided to use 4 equiv of
Herein, we report a new chemoselective deprotonation tool
for regiocontrolled functionalization of five-membered aromatic
heterocycles using a basic mixture obtained from a lithium base
and TMEDA-chelated zinc chloride.
Results and Discussion
To develop new chemoselective deprotonation reactions of
five-membered aromatic heterocycles, our approach capitalizes
on the high chemoselectivity of organozincate reagents, which
allows flexible design and fine-tuning by modifying the ligation
environment. In the initial screening of suitable zincates,
benzoxazole (1) was selected as a model substrate because this
substrate can be readily metalated by alkyllithiums, but the
2-lithiated species is well-known to be in equilibrium with the
(6) (a) Awad, H.; Mongin, F.; Tre´court, F.; Que´guiner, G.; Marsais, F.;
Blanco, F.; Abarca, B.; Ballesteros, R. Tetrahedron Lett. 2004, 45, 6697-
6701. (b) Awad, H.; Mongin, F.; Tre´court, F.; Que´guiner, G.; Marsais, F.
Tetrahedron Lett. 2004, 45, 7873-7877. (c) Krasovskiy, A.; Krasovskaya,
V.; Knochel, P. Angew. Chem. 2006, 118, 3024-3027; Angew. Chem. Int.
Ed. 2006, 45, 2958-2961. (d) Clososki, G. C.; Rohbogner, C. J.; Knochel,
P. Angew. Chem. 2007, 119, 7825-7828; Angew. Chem. Int. Ed. 2007, 46,
7681-7684.
(7) (a) Kondo, Y.; Shilai, M.; Uchiyama, M.; Sakamoto, T. J. Am. Chem.
Soc. 1999, 121, 3539-3540. See also: (b) Imahori, T.; Uchiyama, M.;
Sakamoto, T.; Kondo, Y. Chem. Commun. 2001, 2450-2451. (c) Uchiyama,
M.; Miyoshi, T.; Kajihara, Y.; Sakamoto, T.; Otani, Y.; Ohwada, T.; Kondo,
Y. J. Am. Chem. Soc. 2002, 124, 8514-8515. (d) Uchiyama, M.;
Matsumoto, Y.; Nobuto, D.; Furuyama, T.; Yamaguchi, K.; Morokuma,
K. J. Am. Chem. Soc. 2006, 128, 8748-8750. (e) Uchiyama, M.; Kobayashi,
Y.; Furuyama, T.; Nakamura, S.; Kajihara, Y.; Miyoshi, T.; Sakamoto, T.;
Kondo, Y.; Morokuma, K. J. Am. Chem. Soc. 2007, 129, in press.
(8) Al-ate base: (a) Uchiyama, M.; Naka, H.; Matsumoto, Y.; Ohwada,
T. J. Am. Chem. Soc. 2004, 126, 10526-10527. (b) Garc´ıa-AÄ lvarez, J.;
Graham, D. V.; Kennedy, A. R.; Mulvey, R. E.; Weatherstone, S. Chem.
Commun. 2006, 3208-3210. (c) Naka, H.; Uchiyama, M.; Matsumoto, Y.;
Wheatley, A. E. H.; McPartlin, M.; Morey, J. V.; Kondo, Y. J. Am. Chem.
Soc. 2007, 129, 1921-1930. Cu-ate base: (d) Usui, S.; Hashimoto, Y.;
Morey, J. V.; Wheatley, A. E. H.; Uchiyama, M. J. Am. Chem. Soc. 2007,
129, in press.
(9) Knochel has just published a new mixed lithium-magnesium-zinc
base, (TMP)2Zn‚2MgCl2‚2LiCl, that can be used stoichiometrically: Wunder-
lich, S. H.; Knochel, P. Angew. Chem. 2007, 119, 7829-7832; Angew.
Chem., Int. Ed. 2007, 46, 7685-7688.
(10) (a) Barley, H. R. L.; Clegg, W.; Dale, S. H.; Hevia, E.; Honeyman,
G. W.; Kennedy, A. R.; Mulvey, R. E. Angew. Chem. 2005, 117, 6172-
6175; Angew. Chem., Int. Ed. 2005, 44, 6018-6021. (b) Clegg, W.; Dale,
S. H.; Hevia, E.; Honeyman, G. W.; Mulvey, R. E. Angew. Chem. 2006,
118, 2430-2434; Angew. Chem., Int. Ed. 2006, 45, 2370-2374. (c) Clegg,
W.; Dale, S. H.; Harrington, R. W.; Hevia, E.; Honeyman, G. W.; Mulvey,
R. E. Angew. Chem. 2006, 118, 2434-2437; Angew. Chem., Int. Ed. 2006,
45, 2374-2377. (d) Clegg, W.; Dale, S. H.; Drummond, A. M.; Hevia, E.;
Honeyman, G. W.; Mulvey, R. E. J. Am. Chem. Soc. 2006, 128, 7434-
7435.
(12) (a) Schro¨der, R.; Scho¨llkopf, U.; Blume, E.; Hoppe, I. Liebigs Ann.
Chem. 1975, 533-546. Reviews: (b) Gilchrist, T. L. AdV. Heterocycl. Chem.
1987, 41, 41-74. (c) Rewcastle, G. W.; Katritzky, A. R. AdV. Heterocycl.
Chem. 1993, 56, 155-302. (d) Iddon, B. Heterocycles 1994, 37, 1321-
1346.
(13) Kondo, Y.; Takazawa, N.; Yoshida, A.; Sakamoto, T. J. Chem. Soc.,
Perkin Trans. 1 1995, 1207-1208.
(14) Uchiyama, M.; Furuyama, T.; Kobayashi, M.; Matsumoto, Y.;
Tanaka, K. J. Am. Chem. Soc. 2006, 128, 8404-8405.
(15) (a) Crowe, E.; Hossner, F.; Hughes, M. J. Tetrahedron 1995, 51,
8889-8900. (b) Hilf, C.; Bosold, F.; Harms, K.; Marsch, M.; Boche, G.
Chem. Ber./Recl. 1997, 130, 1213-1221. (c) Boche, G.; Bosold, F.;
Hermann, H.; Marsch, M.; Harms, K.; Lohrenz, J. C. W. Chem.sEur. J.
1998, 4, 814-817. At room temperature, a quick precipitation of the
organozinc derivative was observed in THF.
(16) Concerning the synthesis of a lithium zincate from ZnCl2‚TMEDA,
see: Kjonaas, R. A.; Hoffer, R. K. J. Org. Chem. 1988, 53, 4133-4135.
(17) Isobe, M.; Kondo, S.; Nagasawa, N.; Goto, T. Chem. Lett. 1977,
679-682.
(18) Uchiyama, M.; Kameda, M.; Mishima, O.; Yokoyama, N.; Koike,
M.; Kondo, Y.; Sakamoto, T. J. Am. Chem. Soc. 1998, 120, 4934-4946.
(11) For reviews, see: (a) Mulvey, R. E. Organometallics 2006, 25,
1060-1075. (b) Mulvey, R. E.; Mongin, F.; Uchiyama, M.; Kondo, Y.
Angew. Chem. 2007, 119, 3876-3899; Angew. Chem., Int. Ed. 2007, 46,
3802-3824.
178 J. Org. Chem., Vol. 73, No. 1, 2008

Metalation of FiVe-Membered Aromatic Heterocycles
FIGURE 1. Calculated structures for the reactants, transition states and products, and energy changes. Bond lengths and energy changes at the
B3LYP/6-31+G* level are shown in Å and kcal/mol, respectively.
TABLE 1. Deprotonation of Benzoxazole (1) Using in situ
Prepared Mixtures of ZnX2‚TMEDA and 3 (or 4) equiv of
Alkyllithium or Lithium Dialkylamide
attempts resulted in slightly improved yields of 38 and 44%,
respectively. The moderate 44% yield obtained by employing
Me2Zn(TMP)Li was partly attributed to the conversion step to
the iodo compound 2 and its isolation;21 indeed, monitoring the
1
reaction by H NMR indicated a complete conversion after
2 h.22 This result was not satisfying, however, since 1 equiv of
zincate is required. It was therefore decided to replace all the
alkyl groups with TMP in order to reduce the amount of base.
The experiment carried out with 0.5 equiv of ZnCl2‚TMEDA
and 1.5 equiv of LiTMP under the reaction conditions used
before furnished the iodide 2 in 57% yield (entry 7). A similar
result was obtained using 1/3 equiv of ZnCl2‚TMEDA and 1
equiv of LiTMP (entry 8, 60% yield), with a 1H NMR spectrum
indicating a 90% conversion after 2 h.23 Since examples of
efficient deprotonation using lithium zincates in hexane have
been reported,10b-d experiments using hexane instead of THF
were performed and ended in similar yields (entries 9 and 10).
It was finally decided to see the influence of the zinc source on
the result of the reaction. It was found that zinc bromide (entry
11, 58%) and zinc chloride (entry 8, 60%) could be equally
employed.
yield
(%)
entry
X
n1
R
n2
R′
n3
solvent
1
2
3
4
5
6
7
8
9
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Br
1.0
1.0
1.0
1.0
1.0
1.0
0.50
0.33
0.40
0.40
0.33
Me
Bu
Bu
3.0
3.0
4.0
2.0
2.0
2.0
1.5
1.0
1.2
1.2
1.0
THF
THF
THF
THF
THF
THF
THF
THF
THF
hexane
THF
28
10
32
35
38
44
57
60
55
55
58
Bu
TMP
TMP
TMP
1.0
1.0
1.0
sBu
Me
TMP
TMP
TMP
TMP
TMP
10
11
In order to obtain additional information about the active
species of a basic mixture obtained from a THF solution of 1/3
equiv of ZnCl2‚TMEDA and 1 equiv of LiTMP, NMR and DFT
studies were then carried out. Since (TMP)2Zn (1 equiv) and
LiTMP (1 equiv) give lower conversions when used separately
under the same reaction conditions, both of them play a role in
the deprotonation mechanism. However, even if alkali-metal
triamidozincates have been evidenced,24 sterically hindered
lithium dialkylamide and diamidozinc (e.g., LiN(SiMe3)2 and
butyllithium instead of 3. Admittedly, the yield was higher using
4 equiv (32%, entry 3) instead of 3 but was still low.
Considering the preference for dialkylamino over alkyl transfer
in THF,7d we then decided to replace one of the butyl groups
with a TMP. The heteroleptic base was prepared by successively
adding 2 equiv of butyllithium and 1 equiv of LiTMP to a
solution of ZnCl2‚TMEDA. Since the base prepared similarly
by successively adding 2 equiv of tert-butyllithium and 1 equiv
of LiTMP to a solution of ZnCl2 in THF proved to be tBu2Zn-
(TMP)Li,7d we assumed the base we prepared was a zincate.19
Using the latter (1 equiv) in THF at room temperature for 2 h
to metalate benzoxazole (1) resulted in a moderate 35% yield
of the iodide 2 after interception with iodine (entry 4). Similar
bases were prepared by replacing butyllithium with either sec-
butyllithium (entry 5) or methyllithium (entry 6).20 Metalation
(20) The use of tert-butyllithium was not attempted. Indeed, it has been
shown that methyl and tert-butyl groups in R2Zn(TMP)Li behave similarly
when deprotonation is concerned, with the nature of these dummy ligands
on Zn only influencing the stability of the generated metalated substrates.7c
(21) Compound 2 rapidly decomposes at room temperature.
(22) A 90% yield of lithium 2-(isocyano)phenolate was estimated from
the NMR spectrum using 1,2-dimethoxyethane as internal standard.
(23) Fifteen and 5% yields of lithium 2-(isocyano)phenolate and ben-
zoxazole, respectively, were estimated from the NMR spectrum using 1,2-
dimethoxyethane as internal standard. The 2-zincated species of benzoxazole
which form (about 80% yield) are insoluble in the reaction mixture.
(19) The base prepared by successively adding 1 equiv of LiTMP and 1
equiv of TMEDA to a solution of dibutylzinc in hexane proved to be Bu2-
Zn(TMP)Li(TMEDA).10a
J. Org. Chem, Vol. 73, No. 1, 2008 179

L’Helgoual’ch et al.
TABLE 2. Deprotonation of Five-Membered Aromatic
SCHEME 1. Bond Lengths at the B3LYP/6-31G* Level are
Shown in Angstroms
Heterocycles Using the 1:3 in situ Prepared Mixture of
ZnCl2‚TMEDA and LiTMP
Zn[N(SiMe3)2]2) rarely stabilize as a lithium triamidozincate.25
In addition, the in situ prepared 1:3 mixture of ZnCl2‚TMEDA
and LiTMP in THF was studied by NMR, and the analysis of
the 13C spectra revealed that the main species in solution were
LiTMP and (TMP)2Zn.26 This was confirmed by the B3LYP-
calculated equilibrium between LiTMP and (TMP)2Zn on one
side and (TMP)3ZnLi on the other side (Scheme 1), which is
interestingly in sharp contrast to dialkylamidozincate (TMP-
zincates).7a,d,10a,b
On this basis, one can assume a reaction pathway where the
deprotonation proceeds with LiTMP, and the resultant aryl-
lithium intermediate converts smoothly and quickly by in situ
trapping with (TMP)2Zn (or ArZnTMP) to the more stabilized
arylzinc species, as depicted in Scheme 2. Further studies on a
structural study of this basic mixture and a mechanistic
investigation of this novel metalation are in progress with the
help of ab initio calculations and spectroscopies.27
SCHEME 2. Proposed Pathway for the Metalation of
Benzoxazole (1) Using an in situ Prepared 1:3 Mixture of
ZnCl2‚TMEDA and LiTMP
a Using 1/3 equiv of ZnCl2‚TMEDA and 1 equiv of LiTMP. b Lower
conversions of 10 and 20% were obtained using (TMP)2Zn (1 equiv) and
LiTMP (1 equiv), respectively, under the same reaction conditions.
evaluate the scope of the reaction under the reaction conditions
used before (Table 2).
Lithiation of benzothiazole (3) has been reported using
phenyl- and butyllithium in ethers at very low temperatures.28
When treated with the in situ prepared mixture of 0.5 equiv of
ZnCl2‚TMEDA and 1.5 equiv of LiTMP, metalation also
occurred at the 2 position, as demonstrated by quenching with
iodine to afford the iodide 4 in a medium 52% yield (entry 2).
Benzo[b]thiophene (5) can be easily metalated using butyl-
lithium in THF at 0 °C.29 Our basic mixture furnished after
trapping with iodine the expected derivative 6 in 73% yield. A
similar result was observed from benzo[b]furan (7). The latter
has previously been deprotonated using tert-butyllithium in
diethyl ether at -78 °C.30 The metalation with the in situ
Having obtained the active species and mechanism that is
likely to be experimentally relevant, metalation of other
substrates using the in situ prepared mixture of 0.5 equiv of
ZnCl2‚TMEDA and 1.5 equiv of LiTMP was attempted to
(24) (a) Putzer, M. A.; Neumuller, B.; Dehnicke, K. Z. Anorg. Allg.
Chem. 1997, 623, 539-544. (b) Forbes, G. C.; Kennedy, A. R.; Mulvey,
R. E.; Rodger, P. J. A. Chem. Commun. 2001, 1400-1401. (c) Clegg, W.;
Forbes, G. C.; Kennedy, A. R.; Mulvey, R. E.; Liddle, S. T. Chem. Commun.
2003, 406-407.
(25) Mulvey, R. E. Chem. Commun. 2001, 1049-1056 (special page
1053).
(26) Seggio, A.; Lannou, M.-I.; Chevallier, F.; Nobuto, D.; Uchiyama,
M.; Golhen, S.; Roisnel, T.; Mongin, F. Chem.sEur. J. 2007, 13, 9982-
9989.
(28) (a) Metzger, J.; Koether, B. Bull. Chem. Soc. Fr. 1953, 708-709.
(b) Pinkerton, F. H.; Thames, S. F. J. Heterocycl. Chem. 1971, 8, 257-
259. (c) Jutzi, P.; Hoffmann, H. J. Chem. Ber. 1973, 106, 594-605. (d)
Okuhara, K. J. Org. Chem. 1976, 41, 1487-1494.
(29) Jen, K.-Y.; Cava, M. P. J. Org. Chem. 1983, 48, 1449-1451.
(30) Zhang, H.; Larock, R. C. J. Org. Chem. 2002, 67, 7048-7056.
(27) An alternative mechanism is to assume that (TMP)3ZnLi‚TMEDA
is the catalytic deprotonating species.26
180 J. Org. Chem., Vol. 73, No. 1, 2008

Metalation of FiVe-Membered Aromatic Heterocycles
SCHEME 3. Metalation/Cross-Coupling Sequences of Benzo[b]thiophene (5) and Benzo[b]furan (7)
prepared basic mixture was attempted using both 0.5 equiv of
ZnCl2‚TMEDA and 1.5 equiv of LiTMP, and 1/3 equiv of
ZnCl2‚TMEDA and 1 equiv of LiTMP without any important
change (69 and 64% yields of 8, respectively).
We next turned to N-Boc-indole (9). The lithiation of the
latter has been described using tert-butyllithium in THF at
-75 °C.31 Our method allowed the metalation to take place at
room temperature, with the iodide 10 being isolated in 67%
yield. Whereas tert-butyllithium proved not suitable, LiTMP
can be used at -80 °C in THF for the deprotonation of N-Boc-
pyrrole (11).31 No degradation was observed using our proce-
dure, and the iodide 12 was given in 68% yield.
1-Phenylpyrazole (13) has been metalated using butyllithium
at -65 °C.32 In diethyl ether, substitution occurs in the 5 and
2′ positions in a ratio of about 4:1. Reaction carried out at room
temperature using 0.5 equiv of ZnCl2‚TMEDA and 1.5 equiv
of LiTMP provided the iodide 14 in 56% yield after electrophilic
trapping.
Lithiation of thiazole (15) has been reported using butyl-
lithium in diethyl ether at very low temperatures.28a,33 When
treated with a mixture of 0.5 equiv of ZnCl2‚TMEDA and 1.5
equiv of LiTMP in THF at room temperature for 2 h, both the
monoiodide 16 and the diiodide 17 were obtained after
interception with iodine (22 and 17%, respectively). Reducing
the amount of base to 1/3 equiv of ZnCl2‚TMEDA and 1 equiv
of LiTMP favored formation of the monoiodo derivative 16
(30%) over the diiodo 17 (9%).34 The formation of dizincated
arenes has been recently reported in the course of deprotonation
reactions using a zincate: naphthalene was dimetalated at both
2 and 6 positions,35 and benzene at both 1 and 4 positions,36
when treated with tBu2Zn(TMP)Na‚TMEDA in hexane. Whereas
the generation of dilithiums and disodiums is generally pre-
cluded by using a stoichiometric amount of base in a solvent
of sufficient polarity such as THF,37 the dizincated derivatives
are still present after long reaction times, a result that could be
attributed to their relative stability compared to that of the
corresponding bis(alkali metal) compounds.
2-deprotonated benzo[b]thiophene and benzo[b]furan were
attempted under palladium catalysis using 1,1′-bis(diphenylphos-
phino)ferrocene (dppf) as ligand.38 When the intermediates were
subjected to reaction with 2-chloropyridine and 2,4-dichloro-
pyrimidine, respectively, in THF at 55 °C, the bis(heterocycles)
18 and 19 were isolated in 67 and 49% yields (Scheme 3).
Conclusion
Activation of organometallic compounds in order to get more
efficient and chemoselective bases for the deprotonation of
sensitive substrates such as aromatic heterocycles is a challeng-
ing area. Our approach is based on the synergy exhibited by a
mixture of (TMP)2Zn (0.5 equiv) and LiTMP (0.5 equiv), in
situ prepared from LiTMP and ZnCl2‚TMEDA in a 3:1 ratio.
The reaction could proceed by metalation with LiTMP, stabi-
lization of the deprotonated aromatic by trapping with (TMP)2Zn
(or ArZnTMP), and regeneration of the deprotonating species
from sterically congested zincate intermediates. The main
advantage of the method developed is the relative stability of
the organometallic species formed, allowing cross-coupling
reactions to be performed without transmetalation to more stable
organometallics. Indeed, whereas hydrogen-lithium exchange
of aromatic heterocycles often has to be performed at low
temperature in order to prevent side nucleophilic addition, the
protocol described here can be conducted at room temperature.
The method could find synthetic applications in the deproto-
nation of aromatic heterocycles including sensitive substrates.39
Experimental Section
General Procedure 1 for the Deprotonation-Iodination of
Heterocycles. To a stirred, cooled (0 °C) solution of 2,2,6,6-
tetramethylpiperidine (1.1 mL, 6.0 mmol) in THF (5 mL) were
successively added BuLi (about 1.6 M hexanes solution, 6.0 mmol)
and, 5 min later, ZnCl2‚TMEDA17 (0.50 g, 2.0 mmol). The mixture
was stirred for 15 min at 0 °C before introduction of the substrate
(4.0 mmol) at 10 °C. After 2 h at room temperature, a solution of
I2 (1.5 g, 6.0 mmol) in THF (10 mL) was added. The mixture was
stirred overnight before addition of an aqueous saturated solution
of Na2S2O3 (4 mL) and extraction with EtOAc (3 × 20 mL). The
combined organic layers were dried over MgSO4, filtered, and
concentrated under reduced pressure.
2-Iodobenzoxazole (2). 2 was obtained according to the general
procedure 1 from benzoxazole (1, 0.48 g) and isolated after
purification by chromatography on silica gel (eluent: heptane/
AcOEt 90/10) as a pale yellow powder, which rapidly turns brown
upon standing (0.56 g, 57%): mp 86-90 °C (dec); 1H NMR
Subsequent cross-coupling of 2-metalated substrates was then
considered in order to get bis(heterocycles). Reactions of
(31) Hasan, I.; Marinelli, E. R.; Lin, L.-C.; Fowler, F. W.; Levy, A. B.
J. Org. Chem. 1981, 46, 157-164.
(32) (a) Alley, P. W.; Shirley, D. A. J. Am. Chem. Soc. 1958, 80, 6271-
6274. (b) Marxer, A.; Siegrist, M. HelV. Chim. Acta 1974, 57, 1988-2000.
(33) Beraud, J.; Metzger, J. Bull. Chem. Soc. Fr. 1962, 2072-2074.
(34) The structure of 17 was unambiguously determined by X-ray
diffraction analysis (see presented ORTEP figure in the Supporting
Information).
(35) Clegg, W.; Dale, S. H.; Hevia, E.; Hogg, L. M.; Honeyman, G.
W.; Mulvey, R. E.; O’Hara, C. T. Angew. Chem. 2006, 118, 6698-6700;
Angew. Chem., Int. Ed. 2006, 45, 6548-6550.
(38) These conditions proved convenient for the reaction between lithium
2-furylzincates and chloropyridines: Gauthier, D. R., Jr.; Szumigala, R.
H., Jr.; Dormer, P. G.; Armstrong, J. D., III; Volante, R. P.; Reider, P. J.
Org. Lett. 2002, 4, 375-378.
(39) Synthetic applications for the functionalization of diazines have been
recently published: Seggio, A.; Chevallier, F.; Vaultier, M.; Mongin, F. J.
Org. Chem. 2007, 72, 6602-6605.
(36) Armstrong, D. R.; Clegg, W.; Dale, S. H.; Graham, D. V.; Hevia,
E.; Hogg, L. M.; Honeyman, G. W.; Kennedy, A. R.; Mulvey, R. E. Chem.
Commun. 2007, 598-600.
(37) Schlosser, M. Angew. Chem. 2005, 117, 380-398; Angew. Chem.,
Int. Ed. 2005, 44, 376-393.
J. Org. Chem, Vol. 73, No. 1, 2008 181

L’Helgoual’ch et al.
(CDCl3) δ 7.26-7.31 (m, 2H), 7.49-7.53 (m, 1H), 7.65-7.69 (m,
1H); 13C NMR (CDCl3) δ 109.2, 109.9, 118.9, 124.4, 125.1, 142.3,
153.7. These values are consistent with the literature.40
2-Iodobenzothiazole (4). 4 was obtained according to the general
procedure 1 from benzothiazole (3, 0.54 g, 0.44 mL) and isolated
after purification by chromatography on silica gel (eluent: heptane/
AcOEt 80/20) as a yellow powder (0.54 g, 52%): mp 78-82 °C
(dec); 1H NMR (CDCl3) δ 7.35-7.49 (m, 2H), 7.83-7.87 (m, 1H),
8.01-8.06 (m, 1H); 13C NMR (CDCl3) δ 105.8, 120.6, 122.7, 125.8,
126.5, 139.3, 154.4. These values are consistent with the literature.41
2-Iodothiazole (16). 16 was obtained according to the general
procedure 1 from thiazole (15, 0.34 g, 0.28 mL) and isolated after
purification by chromatography on silica gel (eluent: heptane/
AcOEt 90/10) as a yellow-orange oil (0.19 g, 22%): 1H NMR
(CDCl3) δ 7.34 (d, 1H, J ) 3.4 Hz), 7.62 (d, 1H, J ) 3.4 Hz).
These values are consistent with the literature.5f 13C NMR
(CDCl3): δ 100.0, 124.8, 144.3. 2,5-Diiodothiazole 17 was isolated
similarly as a yellow powder (0.23 g, 17%): mp 106-110 °C (lit.48
103-105 °C); 1H NMR (CDCl3) δ 7.61 (s, 1H); 13C NMR (CDCl3)
δ 74.8, 104.0, 152.9.
General Procedure 2 for the Deprotonation-Cross-Coupling
of Heterocycles. To a stirred, cooled (0 °C) solution of 2,2,6,6-
tetramethylpiperidine (1.1 mL, 6.0 mmol) in THF (5 mL) were
successively added BuLi (about 1.6 M hexanes solution, 6.0 mmol)
and, 5 min later, ZnCl2‚TMEDA17 (0.50 g, 2.0 mmol). The mixture
was stirred for 15 min at 0 °C before introduction of the substrate
(8.0 mmol) at 10 °C. After 2 h at room temperature, the heterocyclic
chloride (6.0 mmol), PdCl2 (28 mg, 0.16 mmol), and dppf (89 mg,
0.16 mmol) were added to the mixture, which was stirred for 12 h
at 55 °C. The mixture was cooled before addition of water (0.5
mL) and AcOEt (100 mL), dried over MgSO4, and the solvents
were removed under reduced pressure.
2-Iodobenzo[b]thiophene (6). 6 was obtained according to the
general procedure 1 from benzo[b]thiophene (5, 0.54 g) and isolated
after purification by chromatography on silica gel (eluent: heptane)
as a pale yellow powder (0.76 g, 73%): mp 64 °C (lit.42 64-65
°C); 1H NMR (CDCl3) δ 7.41-7.45 (m, 2H), 7.64 (s, 1H), 7.81-
7.92 (m, 2H); 13C NMR (CDCl3) δ 79.3, 121.3, 122.4, 124.5, 124.6,
133.9, 140.9, 144.5. These values are consistent with the literature.43
HRMS: calcd for C8H5IS (M+•) 259.9157, found 259.9165. Anal.
Calcd for C8H5IS (260.09): C, 36.94; H, 1.94; S, 12.33. Found:
C, 36.90; H, 1.95; S, 12.28.
2-Iodobenzo[b]furan (8). 8 was obtained according to the
general procedure 1 from benzo[b]furan (7, 0.47 g, 0.44 mL) and
isolated after purification by chromatography on silica gel (eluent:
heptane) as a yellow oil (0.67 g, 69%): 1H NMR (CDCl3) δ 6.96
(s, 1H), 7.20-7.24 (m, 2H), 7.46-7.54 (m, 2H); 13C NMR (CDCl3)
δ 96.0, 110.9, 117.3, 119.8, 123.2, 124.3, 129.3, 158.3. These values
are consistent with the literature.44 HRMS: calcd for C8H5IO (M+•)
243.9385, found 243.9370.
N-Boc-2-iodoindole (10). 10 was obtained according to the
general procedure 1 from N-Boc-indole (9, 0.87 g, 0.81 mL) and
isolated after purification by chromatography on silica gel (eluent:
heptane/CH2Cl2 30/70) as a pale yellow oil (0.94 g, 68%): 1H NMR
(CDCl3) δ 1.77 (s, 9H), 7.01 (s, 1H), 7.22-7.30 (m, 2H), 7.48
(dd, 1H, J ) 7.8 and 2.0 Hz), 8.17 (d, 1H, J ) 7.2 Hz). These
values are consistent with the literature.45 13C NMR (CDCl3): δ
28.3 (3C), 74.9, 85.2, 115.4, 119.4, 121.9, 122.8, 124.2, 131.1,
137.5, 149.2. HRMS: calcd for C13H14INO2 (M+•) 343.0069, found
343.0070. Anal. Calcd for C13H14INO2 (343.16): C, 45.50; H, 4.11;
N, 4.08. Found: C, 45.47; H, 4.10; N, 4.16.
2-(2-Benzo[b]thienyl)pyridine (18). 18 was obtained according
to the general procedure 2 from benzo[b]thiophene (5, 1.1 g) and
2-chloropyridine (0.68 g, 0.57 mL) and isolated after purification
by chromatography on silica gel (eluent: heptane/CH2Cl2 50/50 to
1
30/70) as a white powder (0.85 g, 67%): mp 126 °C; H NMR
(CDCl3) δ 7.21 (m, 1H), 7.36 (m, 2H), 7.73 (td, 1H, J ) 8.0 and
1.6 Hz), 7.81 (m, 4H), 8.64 (d, 1H, J ) 5.0 Hz). These values are
consistent with the literature.49 13C NMR (CDCl3): δ 119.6, 121.1,
122.6 (2C), 124.1, 124.5, 125.0, 136.6, 140.5, 140.6, 144.8, 149.7,
152.5.
4-(2-Benzo[b]furyl)-2-chloropyrimidine (19). 19 was obtained
according to the general procedure 2 from benzo[b]furan (7, 0.95
g, 0.88 mL) and 2,4-dichloropyrimidine (0.89 g) and isolated after
purification by chromatography on silica gel (eluent: CH2Cl2/
MeOH 100/0 to 80/20) as a pale yellow powder (0.68 g, 49%):
mp 186 °C; 1H NMR (CD3COCD3) δ 7.37 (br t, 1H, J ) 7.8 Hz),
7.51 (br t, 1H, J ) 7.8 Hz), 7.69 (br d, 1H, J ) 7.8 Hz), 7.82 (br
d, 1H, J ) 7.8 Hz), 7.90 (s, 1H), 7.97 (d, 1H, J ) 5.2 Hz), 8.86 (d,
1H, J ) 5.2 Hz). These values are consistent with the literature.50
13C NMR (CD3COCD3): δ 110.9, 112.4, 115.4, 123.5, 124.7, 128.1,
128.7, 152.2, 156.5, 158.6, 161.8, 162.1.
N-Boc-2-iodopyrrole (12). 12 was obtained according to the
general procedure 1 from N-Boc-pyrrole (11, 0.67 g, 0.67 mL) and
isolated after purification by chromatography on silica gel (eluent:
heptane/CH2Cl2 80/20 to 30/70) as a pale yellow oil (0.79 g,
67%): 1H NMR (CDCl3) δ 1.52 (s, 9H), 6.08 (t, 1H, J ) 3.4 Hz),
6.43 (dd, 1H, J ) 3.4 and 1.8 Hz), 7.30 (dd, 1H, J ) 3.6 and 2.0
Hz). These values are consistent with the literature.46 13C NMR
(CDCl3): δ 27.9 (3C), 63.1, 84.6, 113.5, 124.8, 125.4, 147.9.
Computations: All calculations were carried out with the
Gaussian 03 program package.51 The molecular structures and
harmonic vibrational frequencies were obtained at the B3LYP52
level with the basis set of Ahlrichs’ SVP all-electron basis set53
5-Iodo-1-phenylpyrazole (14).47 14 was obtained according to
the general procedure 1 from 1-phenylpyrazole (13, 0.58 g, 0.53
mL) and isolated after purification by chromatography on silica
gel (eluent: heptane) as a pale brown powder (0.60 g, 56%): mp
(48) Dondoni, A.; Mastellani, A. R.; Medici, A.; Negrini, E.; Pedrini, P.
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1
82-88 °C; H NMR (CDCl3) δ 6.63 (d, 1H, J ) 1.6 Hz), 7.46-
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117.6, 126.4 (2C), 128.8, 129.0 (2C), 140.3, 142.8.
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182 J. Org. Chem., Vol. 73, No. 1, 2008

Metalation of FiVe-Membered Aromatic Heterocycles
for Zn54 and 6-31+G*/6-31G* for the other atoms. Geometry
optimization and vibrational analysis were performed at the same
level. All stationary points were optimized without any symmetry
assumptions and characterized by normal coordinate analysis at the
same level of theory (the number of imaginary frequencies,
NIMAG, was 0 for minima and 1 for TSs). All of the transition
state structures and the reaction coordinates (Hessian eigenvectors
with negative eigenvalues) were examined visually. The intrinsic
reaction coordinate (IRC) method55 was used to track minimum
energy paths from transition structures to the corresponding local
minima.
Acknowledgment. We gratefully acknowledge the financial
support of KAKENHI (Young Scientist (A), Houga, and Priority
Area (Nos. 452 and 459) (to M.U.)), Re´gion Bretagne (J.M.L.
and A.S.), CNRS (A.S.), and GlaxoSmithKline (A.S.). We thank
Ste´phane Golhen and Thierry Roisnel for their contribution to
this study. We thank CRMPO (Universite´ de Rennes 1) for
HRMS analysis. The calculations were performed on the RIKEN
Super Combined Cluster (RSCC).
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Supporting Information Available: General procedures, Car-
1
tesian coordinates, and total electron energies, copies of H and
13C NMR spectra for compounds 2, 4, 6, 8, 10, 12, 14, 16, 17, 18,
and 19, as well as X-ray diffraction analysis of compound 17
including ORTEP figure and CIF file. This material is available
free of charge via the Internet at http://pubs.acs.org.
JO7020345
J. Org. Chem, Vol. 73, No. 1, 2008 183