New Gilman-type lithium cuprate from a copper(II) salt: synthesis and deprotonative cupration of aromatics

Article abstract of DOI:10.1016/j.tetlet.2009.09.100

Deprotonative cupration of aromatics including heterocycles (anisole, 1,4-dimethoxybenzene, thiophene, furan, 2-fluoropyridine, 2-chloropyridine, 2-bromopyridine, and 2,4-dimethoxypyrimidine) was realized in tetrahydrofuran at room temperature using the Gilman-type amido-cuprate (TMP)₂CuLi in situ prepared from CuCl₂·TMEDA through successive addition of 1 equiv of butyllithium and 2 equiv of LiTMP. The intermediate lithium (hetero)arylcuprates were evidenced by trapping with iodine, allyl bromide, methyl iodide, and benzoyl chlorides, the latter giving the best results. Symmetrical dimers were also prepared from lithium azine and diazine cuprates using nitrobenzene as an oxidative agent.

Full text of DOI:10.1016/j.tetlet.2009.09.100

Tetrahedron Letters 50 (2009) 6787–6790
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
New Gilman-type lithium cuprate from a copper(II) salt: synthesis
and deprotonative cupration of aromatics
*
*
Tan Tai Nguyen, Floris Chevallier, Viatcheslav Jouikov , Florence Mongin
Chimie et Photonique Moléculaires, UMR 6510 CNRS, Université de Rennes 1, Bâtiment 10A, Case 1003, Campus Scientifique de Beaulieu, 35042 Rennes Cedex, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 28 July 2009
Revised 11 September 2009
Accepted 18 September 2009
Available online 24 September 2009
Deprotonative cupration of aromatics including heterocycles (anisole, 1,4-dimethoxybenzene, thiophene,
furan, 2-fluoropyridine, 2-chloropyridine, 2-bromopyridine, and 2,4-dimethoxypyrimidine) was realized
in tetrahydrofuran at room temperature using the Gilman-type amido-cuprate (TMP)2CuLi in situ pre-
pared from CuCl2ꢀTMEDA through successive addition of 1 equiv of butyllithium and 2 equiv of LiTMP.
The intermediate lithium (hetero)arylcuprates were evidenced by trapping with iodine, allyl bromide,
methyl iodide, and benzoyl chlorides, the latter giving the best results. Symmetrical dimers were also
prepared from lithium azine and diazine cuprates using nitrobenzene as an oxidative agent.
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Lithium
Copper
Metalation
Aromatic compound
Heterocycle
Lithium bases have been largely employed for the deproto-
metalation of aromatic rings.1 Even if less nucleophilic hindered
lithium dialkylamides are more suitable for the metalation of aro-
matics bearing reactive functions or sensitive p-deficient heterocy-
cles, low reaction temperatures are required due to the high
We recently accomplished the deproto-metalation of a large
range of aromatics including heterocycles using a newly developed
lithium–cadmium base, (TMP)3CdLi, in situ prepared from
CdCl2ꢀTMEDA and 3 equivalents of LiTMP.14 We here describe the
synthesis of putative (TMP)2CuLi using the same approach, and
its use to deprotonate aromatic substrates.
reactivity of the corresponding (hetero)aryllithiums.
The use of bimetallic bases in order to get more efficient and/or
more chemoselective reactions is a challenging field. LIC–KOR
(LIC = butyllithium, KOR = potassium tert-butoxide) first described
by Schlosser2 and Lochmann,3 and BuLi–LiDMAE (DMAE = 2-dim-
ethylaminoethoxide) introduced by Caubère4 and developed fur-
ther by Gros and Fort in the pyridine series5 are well-known
examples of synergic (or superbasic) mixtures of organolithiums
and alkali metal alkoxides. By combining soft organometallic com-
pounds with alkali (or alkaline-earth metal) additives, bases have
been more recently prepared and used to generate functionalized
aromatic compounds including heterocycles.6 Examples are
R2Zn(TMP)Liꢀ(TMEDA) (R = tBu, Bu; TMP = 2,2,6,6-tetramethyl
piperidino, TMEDA = N,N,N0,N0-tetramethylethylenediamine) (de-
scribed by the groups of Kondo, Uchiyama, Mulvey, and Hevia),7
(TMP)2Znꢀ2MgCl2ꢀ2LiCl8 and TMPZnClꢀLiCl9 (Knochel), iBu3Al
(TMP)Li (Uchiyama and Mulvey),10 Al(TMP)3ꢀ3LiCl (Knochel),11
(Me3SiCH2)2Mn(TMP)LiꢀTMEDA (Mulvey),12 and MeCu(TMP)(CN)
Li2 (Uchiyama and Wheatley).13
Wheatley and Uchiyama documented in 2007 the first direct
metalation using a lithium cuprate.13 The authors showed that Gil-
man-type amidocuprates prepared from CuI were less efficient
bases than Lipshutz-type amidocuprates prepared from CuCN. Me-
Cu(TMP)(CN)Li2 was identified as the best base when used at the
rate of 2 equiv in tetrahydrofuran (THF) at 0 °C.
Our approach was based on the in situ generation of putative
(TMP)2CuLi from CuCl2ꢀTMEDA15 by (i) reduction of Cu(II) to
Cu(I) and (ii) formation of the lithium cuprate by addition of
2 equiv of LiTMP. The reaction of copper(II) chloride with lithium
bis(trimethylsilyl)amide at the reflux temperature of THF being
known to produce the corresponding copper(I) amide,16 the gener-
ation of (TMP)2CuLi starting from CuCl2ꢀTMEDA and using 3 equiv
of LiTMP was first considered. Electron paramagnetic resonance
(EPR) response of Cu(II) was used in order to check the validity
of the reduction step using LiTMP. To this purpose, the EPR spec-
trum of a THF solution prepared from CuCl2ꢀTMEDA and LiTMP
(2ꢀ10ꢁ3 M each) was collected, and was compared with a spectrum
recorded from a THF solution of CuCl2ꢀTMEDA (2.10ꢁ3 M). It was
observed that the reduction to Cu(I) was not quantitative, even
after 20 h at room temperature, and that TEMPO was formed, prob-
ably by reaction between LiTMP and dissolved oxygen17 (Fig. 1).18
It was then decided to attempt the use of butyllithium for the
* Corresponding authors. Fax: +33 (0) 2 2323 6955 (F.M.).
E-mail addresses: viatcheslav.jouikov@univ-rennes1.fr (V. Jouikov), florence.
mongin@univ-rennes1.fr (F. Mongin).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.09.100

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T. T. Nguyen et al. / Tetrahedron Letters 50 (2009) 6787–6790
Scheme 1, and recorded again the spectra of the solution. The only
observable signal being attributed to TEMPO,19 the reactivity of
such prepared (TMP)2CuLi was studied toward various aromatics.
With anisole (1a) and the 4-methoxy derivative 1b as substrates,
the metalation reactions performed in THF at room temperature by
using 1 equiv of in situ prepared (TMP)2CuLi, followed by subse-
quent trapping with elemental iodine after 2 h, proceeded in low
yields (compounds 2a20 and 2b,21 Table 1, entries 1 and 2). Concom-
itant formation of 2,20-dimethoxybiphenyl22 and N-(2-methoxy-
phenyl)-2,2,6,6-tetramethylpiperidine23 was observed from
Figure 1. EPR spectra of (i) a THF solution prepared from CuCl2ꢀTMEDA and LiTMP
(2.10ꢁ3 M each), (ii) the same solution 20 h later, and (iii) a THF solution of TEMPO
(g = 2.007, aN = 15.54 G).
3 LiTMP
R
CuCl2
(TMP)2CuLi
1) (TMP)2CuLi (1 equiv)
THF, rt, 2 h
- 1/2 Bu-Bu
- LiCl
BuLi
LiTMP
TMPCu
2) C6H5COCl
or
4-ClC6H4COCl
X
X
O
LiTMP
- LiCl
6a (X = S)
6b (X = O)
7a (X = S, R = H): 48%
8a (X = S, R = Cl): 48%
7b (X = O, R = H): 53%
CuCl
Scheme 1. Synthesis of (TMP)2CuLi from CuCl2ꢀTMEDA as copper(II) source.
Scheme 2. Deproto-cupration of 6a,b followed by trapping with benzoyl chlorides.
Table 1
Deproto-cupration of 1a,b followed by trapping with electrophiles
Table 2
Deproto-cupration of 9a–c followed by trapping with electrophiles or oxidation
1) (TMP)2CuLi (1 equiv)
THF, rt, 2 h
OMe
OMe
E
1) (TMP)2CuLi (1 equiv)
E
2) Electrophile
R
R
THF, rt, 2 h
1a (R = H)
1b (R = OMe)
2) Electrophile or C6H5NO2
N
X
N
X
9a (X = F)
9b (X = Cl)
9c (R = Br)
Entry
Substrate
Electrophile
I2
Product, yield (%)
OMe
Entry
Substrate
Electrophile or
oxidative agent
Product, yield %
1
1a
1b
2a, 20
I
O
OMe
1
2
3
4
5
6
9a
9b
9c
9a
9a
9a
C6H5COCl
C6H5COCl
C6H5COCl
4-ClC6H4COCl
I2
10a, 85
10b, 78
10c, 20
11a, 83
12a, 31
13a, 84
Ph
Ph
Ph
2
3
I2
2b, 19
3b, 41
MeO
MeO
I
N
N
N
F
O
OMe
1b
1b
CH2@CHCH2Br
Cl
O
OMe
O
4
C6H5COCl
4b, 53
Br
O
MeO
MeO
Ph
OMe
O
N
N
F
Cl
5
1b
4-ClC6H4COCl
5b, 57
I
F
Cl
F
N
reduction of CuCl2ꢀTMEDA at 0 °C, and the EPR spectrum of a THF
solution prepared from CuCl2ꢀTMEDA and BuLi (2.10ꢁ3 M each)
was recorded. The spectrum showing a complete reduction of
Cu(II), we prepared the mixed lithium–copper base as depicted in
C6H5NO2
N
F

T. T. Nguyen et al. / Tetrahedron Letters 50 (2009) 6787–6790
6789
OMe
N
MeO
N
14
(TMP)2CuLi (1 equiv)
THF, rt, 2 h
OMe O
N
OMe
OMe
N
PhCOCl
PhNO2
)
Cu(TMP)Li
2
N
Ph
N
N
MeO
MeO
N
MeO
15:35 45%
19:35 22%
MeI
4-ClC6H4COCl
OMe O
CH2=CHCH2Br
OMe
N
OMe
Me
N
N
N
MeO
N
Cl
MeO
MeO
N
16:35 52%
18:36 24%
17:35 19%
Scheme 3. Deproto-cupration of 14 followed by trapping with electrophiles or oxidation. (See above-mentioned references for further information.)
anisole (1a), probably through reactions occurring during the trap-
ping step with iodine. Indeed, it was noted that carrying out the reac-
tion using water as electrophile instead of iodine resulted in
recoveredanisole. Whereastheuse of ethylacrylateandenonessuch
as 2-cyclohexen-1-one and 2-cyclopenten-1-one did not allow any
trapping products, reactions proved successful when performed
with allyl bromide and benzoyl chlorides at the reflux temperature
of THF (entries 3–5) to afford the allylated derivative 3b,24 and the
benzophenones 4b25 and 5b26 in yields ranging from 41% to 57%.
We next demonstrated that the cuprate base was suitable for
Acknowledgment
We gratefully acknowledge the financial support of MESR of
France (to T.T.N.).
References and notes
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p-excessive and p-deficient aromatic het-
erocycles. Thiophene (6a) and furan (6b) proved to react under
the same reaction conditions to furnish after trapping with benzoyl
chlorides the expected ketones 7a,20 8a,27 and 7b27 (Scheme 2).
2-Halopyridines 9a–c were similarly successively treated with
the amido-cuprate and benzoyl chlorides. Whereas a low 20% yield
(compound 10c)28 was obtained starting from 2-bromopyridine
(9c) and using benzoyl chloride, side reactions were not observed
with its lighter isomers 9a,b, and the expected ketones 10a,29
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comitant formation of the 3,30-dimer 13a.32 The latter was
obtained in a high 84% yield using nitrobenzene,33 which proved
to be in this reaction a better oxidant than iodine (Table 2).
2,4-Dimethoxypyrimidine (14) was finally similarly involved in
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rides, allyl bromide and iodomethane the regioselectively func-
tionalized derivatives 15–18 in yields ranging from 19% to 52%;34
the corresponding 5,50-dimer 19 also formed using nitrobenzene
as an oxidative agent (Scheme 3).
In summary, deprotonative cupration of aromatics was realized
using a Gilman-type amido-cuprate in situ prepared from stable
CuCl2ꢀTMEDA.37 The intermediate lithium arylcuprates were nota-
bly evidenced by trapping with benzoyl chlorides in satisfying
yields.
Further development will notably concern the impact of TEMPO
on reaction yields. Indeed, it is known from the literature that
TEMPO is an excellent ligand for alkali metals, and its presence
in TMP-containing complexes can modify the availability of the
amido groups.38
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13. Usui, S.; Hashimoto, Y.; Morey, J. V.; Wheatley, A. E. H.; Uchiyama, M. J. Am.
Chem. Soc. 2007, 129, 15102–15103.
28. The spectral data are analogous to those previously described: Inamoto, K.;
Katsuno, M.; Yoshino, T.; Arai, Y.; Hiroya, K.; sakamoto, T. Tetrahedron 2007, 63,
2695–2711.
14. (a) L’Helgoual’ch, J.-M.; Bentabed-Ababsa, G.; Chevallier, F.; Yonehara, M.;
Uchiyama, M.; Derdour, A.; Mongin, F. Chem. Commun. 2008, 5375–5377;
(b) Snégaroff, K.; L’Helgoual’ch, J.-M.; Bentabed-Ababsa, G.; Nguyen, T. T.;
Chevallier, F.; Yonehara, M.; Uchiyama, M.; Derdour, A.; Mongin, F. Chem.
Eur. J. 2009, 15, 10280–10290; See also: (c) L’Helgoual’ch, J.-M.; Bentabed-
Ababsa, G.; Chevallier, F.; Derdour, A.; Mongin, F. Synthesis 2008, 4033–
4035; (d) Bentabed-Ababsa, G.; Blanco, F.; Derdour, A.; Mongin, F.;
Trécourt, F.; Quéguiner, G.; Ballesteros, R.; Abarca, B. J. Org. Chem. 2009,
74, 163–169.
15. We chose CuCl2 as copper salt source instead of CuCl because of its higher air
stability. In addition, the presence of TMEDA makes salts less sensitive to
moisture, and sometimes favors deprotonation reactions: see Refs. 7d–f. For
the synthesis of CuCl2ꢀTMEDA, see: Handley, D. A.; Hitchcock, P. B.; Lee, T. H.;
Leigh, G. J. Inorg. Chem. Acta 2001, 316, 59–64.
29. The 1H NMR data are analogous to those described: Güngör, T.; Marsais, F.;
Quéguiner, G. J. Organomet. Chem. 1981, 215, 139–150.
30. The 1H NMR data are analogous to those described: Trécourt, F.; Marsais, F.;
Güngör, T.; Quéguiner, G. J. Chem. Soc., Perkin Trans. 1 1990, 2409–2415.
31. Compound 11a: yellow powder; mp 90 °C; 1H NMR (300 MHz, CDCl3): d 7.37
(ddd, 1H, J = 7.6, 4.9, and 1.9 Hz), 7.44–7.50 (m, 2H), 7.73–7.79 (m, 2H), 8.04
(ddd, 1H, J = 9.4, 7.5, and 2.0 Hz), 8.43 (ddd, 1H, J = 4.9, 2.1, and 1.2 Hz); 13C
NMR (75 MHz, CDCl3): d 121.3 (d, J = 30 Hz), 121.9 (d, J = 4.5 Hz), 129.2 (s, 2C),
131.1 (d, 2C, J = 1.2 Hz), 135.0 (d, J = 0.9 Hz), 140.7 (s), 142.0 (d, J = 3.3 Hz),
150.9 (d, J = 15 Hz), 160.1 (d, J = 243 Hz), 190.7 (d, J = 4.9 Hz).
32. Compound 13a: beige powder; mp 153 °C; 1H NMR (300 MHz, CDCl3): d 7.31–
7.36 (m, 2H), 7.88–7.96 (m, 2H), 8.30 (dd, 2H, J = 4.9, and 1.9 Hz); 13C NMR
(75 MHz, CDCl3): d 116.7 (m), 121.7 (m), 142.0 (t, J = 3.3 Hz), 148.1 (m), 160.4
(d, J = 241 Hz).
33. Mandeville, W. H.; Whitesides, G. M. J. Org. Chem. 1974, 39, 400–405.
34. Even if the basicity of pyrimidine nitrogens is low compared with that of
pyridine, competitive quaternarization by reaction with allyl bromide and
methyl iodide is not impossible under the conditions used.
16. James, A. M.; Laxman, R. V.; Fronczek, F. R.; Maverick, A. W. Inorg. Chem. 1998,
37, 3785–3791.
17. The reaction of lithiated organics with molecular oxygen is well-documented:
Wheatley, A. E. H. Chem. Soc. Rev. 2001, 30, 265–273. The process is thought to
involve
a radical chain decomposition in which a peroxide intermediate
degrades to an organooxide product.
18. An organic radical was also observed (g = 2.005, aH = 1.096 G, 2H), but was not
35. Compound 15: yellow oil; 1H NMR (300 MHz, CDCl3): d 3.95 (s, 3H), 4.07 (s,
3H), 7.42–7.49 (m, 2H), 7.58 (tt, 1H, J = 7.3 and 1.3 Hz), 7.74–7.78 (m, 2H), 8.46
(br s, 1H); 13C NMR (75 MHz, CDCl3): d 54.5, 55.5, 114.5, 128.5 (2C), 129.7 (2C),
133.3, 137.6, 161.2, 166.3, 169.3, 192.2. Compound 16: yellow powder; mp
145–146 °C; 1H NMR (300 MHz, CDCl3): d 8.48 (s, 1H), 7.68–7.73 (m, 2H), 7.41–
7.46 (m, 2H), 4.08 (s, 3H), 3.96 (s, 3H); 13C NMR (75 MHz, CDCl3): d 54.5, 55.5,
114.1, 128.8 (2C), 130.9 (2C), 136.0, 139.7, 161.3, 166.5, 169.1, 190.9.
Compound 17: yellow oil; 1H NMR (300 MHz, CDCl3): d 3.22 (m, 2H), 3.96 (s,
3H), 3.97 (s, 3H), 5.00–5.08 (m, 2H), 5.82–5.97 (m, 1H), 7.98 (br s, 1H); 13C NMR
(75 MHz, CDCl3): d 29.8, 54.0, 54.8, 113.6, 116.5, 135.2, 157.0, 164.4, 169.4.
Compound 19: red powder; mp 209 °C; 1H NMR (300 MHz, CDCl3): d 3.97 (s,
6H), 4.03 (s, 6H), 8.20 (s, 2H); 13C NMR (75 MHz, CDCl3): d 54.3 (2C), 55.0 (2C),
108.3 (2C), 158.8 (2C), 165.1 (2C), 168.7 (2C).
identified:
36. The spectral data are analogous to those previously described: Boudet, N.;
Dubbaka, S. R.; Knochel, P. Org. Lett. 2008, 10, 1715–1718.
19. TEMPO is similarly formed by preparing LiTMP in THF.
37. Typical procedure: To a stirred, cooled (0 °C) suspension of CuCl2ꢀTMEDA
(0.25 g, 1.0 mmol) in THF (5 mL) were successively added BuLi (about 1.6 M
hexanes solution, 1.0 mmol) and, 15 min later, a solution of LiTMP prepared in
THF (2 mL) at 0 °C from 2,2,6,6-tetramethylpiperidine (0.34 mL, 2.0 mmol) and
BuLi (about 1.6 M hexanes solution, 2.0 mmol). The mixture was stirred for
15 min at this temperature before introduction of 2,4-dimethoxypyrimidine
20. The spectral data are analogous to those obtained from a commercial sample.
21. The 1H NMR data are analogous to those described: Azadi-Ardakani, M.;
Wallace, T. W. Tetrahedron 1988, 44, 5939–5952.
22. The physical and spectral data are analogous to those previously described:
Yuan, Y.; Bian, Y. Appl. Organomet. Chem. 2008, 22, 15–18.
23. 1H NMR (300 MHz, CDCl3): d 0.78 (s, 6H), 1.23 (s, 6H), 1.49–1.64 (m, 6H), 3.75
(s, 3H), 6.82–6.88 (m, 2H), 7.13–7.19 (m, 1H), 7.29 (dd, 1H, J = 8.3 and 1.9 Hz);
13C NMR (75 MHz, CDCl3): d 18.6, 26.0, 31.5, 41.8, 54.4, 55.1, 111.0, 119.3,
126.4, 134.2, 136.0, 160.3.
(125 lL, 1.0 mmol). After 2 h at room temperature, benzoyl chloride (0.24 mL,
2.0 mmol) was added at 0 °C. The mixture was stirred for 16 h at 60 °C before
the addition of brine (5 mL) and extracted with Et2O (3 ꢂ 10 mL). The
combined organic layers were washed with brine (10 mL), dried over
Na2SO4, filtered, and concentrated under reduced pressure before
purification by column chromatography on silica gel (eluent: heptane/EtOAc
8:2). Compound 15 (0.11 g, 45%) was isolated as a yellow oil.
24. The 1H NMR data are analogous to those described: Ochiai, M.; Fujita, E.;
Arimoto, M.; Yamaguchi, H. Chem. Pharm. Bull. 1982, 30, 3994–3999.
25. The 1H NMR data are analogous to those described: Chen, X.; Yu, M.; Wang, M.
J. Chem. Res. 2005, 80–81.
38. Forbes, G. C.; Kennedy, A. R.; Mulvey, R. E.; Rodger, P. J. A. Chem. Commun. 2001,
1400–1401; See also: Balloch, L.; Drummond, A. M.; García-Álvarez, P.;
Graham, D. V.; Kennedy, A. R.; Klett, J.; Mulvey, R. E.; O’Hara, C. T.; Rodger, P.
J. A.; Rushworth, I. D. Inorg. Chem. 2009, 48, 6934–6944.
26. The spectral data are analogous to those previously described: Waterlot, C.;
Hasiak, B.; Couturier, D.; Rigo, B. Tetrahedron 2001, 57, 4889–4901.
27. The spectral data are analogous to those previously described: Rao, M. L. N.;
Venkatesh, V.; Banerjee, D. Tetrahedron 2007, 63, 12917–12926.