LiCl-mediated preparation of highly functionalized benzylic zinc chlorides

Article abstract of DOI:10.1021/ol7030697

In the presence of zinc dust (1.5-2.0 equiv) and LiCI(1.5-2.0 equiv), various benzylic chlorides bearing functional groups (iodide, cyanide, ester, ketone) are smoothly converted at 25°C to the corresponding zinc reagents without homo-coupling (≤5%). The utility of these benzylic zinc reagents is demonstrated by a short synthesis of papaverine.

Full text of DOI:10.1021/ol7030697

ORGANIC
LETTERS
2008
Vol. 10, No. 6
1107-1110
LiCl-Mediated Preparation of Highly
Functionalized Benzylic Zinc Chlorides
Albrecht Metzger, Matthias A. Schade, and Paul Knochel*
Department Chemie und Biochemie, Ludwig-Maximilians-UniVersita¨t,
Butenandtstrasse 5-13, 81377, Mu¨nchen, Germany
Paul.Knochel@cup.uni-muenchen.de
Received December 20, 2007
ABSTRACT
In the presence of zinc dust (1.5−2.0 equiv) and LiCl (1.5−2.0 equiv), various benzylic chlorides bearing functional groups (iodide, cyanide,
ester, ketone) are smoothly converted at 25
°
C to the corresponding zinc reagents without homo-coupling (<5%). The utility of these benzylic
zinc reagents is demonstrated by a short synthesis of papaverine.
Zinc organometallics are important intermediates since they
combine an excellent functional group compatibility with a
high reactivity (in the presence of the appropriate catalyst).1
Especially functionalized benzylic zinc halides occupy a
unique place since the high reactivity of related benzylic
lithium and magnesium compounds preclude the presence
of most functional groups in these organometallics. Benzylic
zinc reagents can be prepared by the direct zinc insertion to
benzylic bromides but may require elevated temperatures and
the addition of polar cosolvents.2 These drawbacks hamper
a more general application of these organometallics. Re-
cently, we have reported that LiCl facilitates considerably
the rate of zinc insertion.3 Herein, we report an efficient
preparation of functionalized benzylic zinc chlorides of type
1 using the LiCl-mediated insertion of commercial zinc dust
to functionalized benzylic chlorides of type 2 (Scheme 1 and
Scheme 1. LiCl-Mediated Insertion into Functionalized
Benzylic Chlorides
(1) (a) Knochel, P.; Singer, R. D. Chem. ReV. 1993, 93, 2117. (b)
Knochel, P.; Millot, N.; Rodriguez, A.; Tucker, C. E. Org. React. 2001,
58, 417. (c) Knochel, P. In Handbook of Functionalized Organometallics;
Wiley-VCH: New York, 2005. (d) Knochel, P.; Calaza, M. I.; Hupe, E.
Carbon-Carbon Bond-Forming Reactions Mediated by Organozinc Reagents.
In Metal-Catalyzed Cross-Coupling Reactions, 2nd ed.; de Meijere, A.,
Diederich, F., Eds.; Wiley-VCH: New York, 2004.
(2) (a) Yuguchi, M.; Tokuda, M.; Orito, K. J. Org. Chem. 2004, 69,
908. (b) Piazza, C.; Millot, N.; Knochel, P. J. Organomet. Chem. 2001,
624, 88. (c) Wang, J. X.; Fu, Y.; Hu, Y. L. Chin. Chem. Lett. 2002, 5, 405.
(d) Berk, S. C.; Yeh, M. C. P.; Jeong, N.; Knochel, P. Organometallics
1990, 9, 3053. (e) Harada, T.; Kaneko, T.; Fujiwara, T.; Oku, A. J. Org.
Chem. 1997, 62, 8966. (f) Gaudemar, M. Bull. Soc. Chim. Fr. 1962, 5,
974. For the use of benzylic zinc, see also: (g) Fellahi, Y.; Mandin, D.;
Dubois, P.; Ombetta-Goka, J. E.; Guenzet, J.; Chaumont, J. P.; Frangin, Y.
Eur. J. Med. Chem. 1996, 31, 77. (h) Wang, J.-X.; Fu, Y. Angew. Chem.,
Int. Ed. 2002, 41, 2757. (i) Krasovskiy, A.; Gavryushin, A.; Knochel, P.
Synlett 2006, 5, 792. (j) Thorn, S. N.; Gallagher, T. Synlett 1997, 185. (k)
Negishi, E.; King, A. O.; Okukado, N. J. Org. Chem. 1977, 42, 185.
Table 1). Their reaction with various electrophiles (3)
provides a range of polyfunctional products of type 4. Thus,
the addition of 2-chlorobenzyl chloride (2a, 1.0 equiv) to
(3) Krasovskiy, A.; Malakhov, V.; Gavryushin, A.; Knochel, P. Angew.
Chem., Int. Ed. 2006, 45, 6040.
10.1021/ol7030697 CCC: $40.75
© 2008 American Chemical Society
Published on Web 02/21/2008

Table 1. LiCl-Mediated Insertion into Functionalized Benzylic Chlorides and Reaction with Various Electrophiles
a Reaction time at 25 °C. b Yield as determined by iodometric titration. c Zn (2.0 equiv), LiCl (2.0 equiv). d Isolated yield of analytically pure product.
e Catalytic CuCN‚2LiCl. f Stoichiometric CuCN‚2LiCl. g Pd(PPh3)4 (cat.). h In this case, the limiting reagent is the benzylic zinc chloride 1a.
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Org. Lett., Vol. 10, No. 6, 2008

zinc dust4 (1.5 equiv) and LiCl (1.5 equiv) at 0 °C followed
by 2 h of stirring at 25 °C provides almost quantitatively
2-chlorobenzylzinc chloride 1a (in 99% yield as deter-
mined by iodometric titration).5 In the absence of LiCl, only
a slow and incomplete reaction is observed under these
reaction conditions. The benzylic zinc reagent 1a undergoes
a range of useful reactions with electrophiles. Thus, Cu(I)-
catalyzed cross-couplings with allylic and benzylic bromide
such as 3-bromo-1-cyclohexene (3a, 1.3 equiv) or 4-ni-
trobenzyl bromide (3b, 0.8 equiv) afford the cross-coupling
products 4a and 4b in 89-94% yield (entries 1 and 2 of
Table 1).
such as 3,4,5-trimethoxybenzyl chloride are easily converted
within 3 h at 25 °C (zinc dust 2.0 equiv, LiCl 2.0 equiv) to
the benzylic zinc compound (1k, 78%). The allylation of
1k with ethyl (2-bromomethyl)acrylate8 (0.8 equiv) affords
the desired product 4r in 98% yield (entry 18). Also, the
electron-rich benzylic chloride 2l is readily converted to the
corresponding zinc compound 1l within 1 h (zinc dust 1.5
equiv, LiCl 1.5 equiv) in 93% yield. Acylation of 1l leads
to the ketone 4s in 93% yield (entry 19). Phenylacetic acid
derivatives are common targets in pharmaceutical research.9
They are readily prepared in two ways using benzylic zinc
species of type 1 (Scheme 2). Thus, the Negishi Pd-catalyzed
Also, Negishi6 cross-coupling of ethyl 4-iodobenzoate (3c,
0.8 equiv) in the presence of Pd(PPh3)4 (2 mol %, 60 °C, 5
h) gives the diarylmethane derivative 4c in 97% yield (entry
3). A copper(I)-mediated 1,4-addition of cyclohexenone (0.8
equiv) using CuCN‚2LiCl4 (1 equiv, -40 °C to 25 °C,
overnight) and TMSCl7 (2 equiv) provides the Michael
adduct 4d in 93% yield (entry 4). Similarly the 4-fluoro-,
3-bromo, and 2-iodobenzylic zinc chlorides (1b-d) were
prepared in 87-99% yield. The Cu(I)-mediated reaction of
the benzylic zinc chloride 1b with 3,3-dimethylbutyryl
chloride (3e, 0.7 equiv) in the presence of CuCN‚2LiCl (1.0
equiv, -40 °C to 25 °C, overnight) leads to the ketone 4e
in 95% yield. The high reactivity of benzylic zinc chlorides
allows an efficient addition to various aldehydes in the
absence of any catalyst. Thus, the addition of the substituted
benzaldehydes (3f or 3g; 0.8 equiv, 0-25 °C, 5-17 h) gave
the benzylic alcohols 4f and 4g in 87-98% yield (entries 6
and 7). The Cu(I)-mediated Michael addition of 1d to
cyclohexenone furnishes an expected ketone 4h in 72% yield
(entry 8). Various benzylic zinc reagents bearing carbonyl
functions have also been prepared (entries 9-16). Thus, the
reaction of substituted benzylic chlorides bearing a carb-
ethoxy group, a cyanide, and a ketone group in the meta-
position with zinc dust at 25 °C provides smoothly the
corresponding zinc reagents (1e-i; entries 9-16). Remark-
ably, the keto group present in the benzylic zinc chlorides
1g-i is quite stable toward enolization. Thus, the 3-propionyl
benzylic zinc chloride (1h) has a half-life of 27 days at 25
°C. Even the acetyl-substituted benzylic zinc reagent 1i is
stable for several days (t1/2 ) 2 days, 25 °C). These zinc
reagents react smoothly with typical electrophiles, leading
to the functionalized products 4i-p (74-97%; entries 9-16).
Secondary benzylic zinc compounds can be prepared simi-
larly. Thus, the treatment of 1-chloroethylbenzene with zinc
dust (1.5 equiv) and LiCl (1.5 equiv) at 25 °C for 11 h
provides the expected zinc reagent 1j in 85% yield. Its
acylation with the acid chloride 3e provides the ketone 4q
in 96% yield. In contrast, cumyl chloride (a tertiary benzylic
chloride) did not afford the corresponding zinc species due
to competitive elimination. Electron-rich benzylic chlorides,
Scheme 2. Synthesis of Phenylacetic Acid Derivatives of
Type 5
acylation10 of the benzylic zinc chloride 1a with ethyl
chloroformate in the presence of Pd(PPh3)4 (5 mol %, 25
°C, 6.5 h) is leading to the phenylacetic acid ethyl ester 5 in
81% yield. Alternatively, a copper mediated acylation is
possible.
Thus, the reaction of 1a with TMSCH2Li (-30 °C, 30
min) provides a mixed diorganozinc of the type ArCH2-
ZnCH2SiMe3.11 Transmetallation to copper (CuCN‚2LiCl,
-30 °C, 30 min) and addition of Mander’s reagent12 gives
the expected ethyl phenylacetic ester 5 in 77% yield.
As an application, we have prepared papaverine (6)13
starting from the isoquinoline14 7 (Scheme 3). Magnesiation
Scheme 3. Synthesis of Papaverine
(4) See Supporting Information, see also: Knochel, P.; Yeh, M. C. P.;
Berk, S. C.; Talbert, J. J. Org. Chem. 1988, 53, 2390.
(5) Krasovskiy, A.; Knochel, P. Synthesis 2006, 5, 890.
(6) (a) Mingxing, Q.; Negishi, E. Tetrahedron Lett. 2005, 46, 2927. (b)
Metay, E.; Hu, Q.; Negishi, E. Org. Lett. 2006, 8, 5773. (c) Negishi, E.;
Qian, M.; Zeng, F.; Anastasia, L.; Babinski, D. Org. Lett. 2003, 5, 1597.
(7) Nakamura, E.; Matsuzawa, S.; Horiguchi, Y.; Kuwajima, I. Tetra-
hedron Lett. 1986, 27, 5181.
Org. Lett., Vol. 10, No. 6, 2008
1109

of 7 with TMPMgCl‚LiCl15 (TMP ) 2,2,6,6-tetramethyl-
piperidyl; 25 °C, 4 h), followed by iodolysis provides the
isoquinoline 8 in 73% yield. Zinc insertion to the benzylic
chloride 2m (25 °C, 4.5 h) gives the expected benzylic zinc
reagent 1m in 72% yield. Pd-catalyzed cross-coupling using
Pd(OAc)2 (2.5 mol %) and S-Phos16 (5 mol %) provides
papaverine (6) in 68% yield.17
the presence of functional groups including ketones. Further
extension of this work to the preparation of heterocyclic
analogs is underway.
Acknowledgment. We thank the DFG for a financial
support. We thank Umicore AG (Angleur, Belgium) for the
generous gift of zinc powder. We also thank Chemetall
GmbH (Frankfurt), Evonik Industries AG (Hanau) and BASF
AG (Ludwigshafen) for the generous gift of chemicals.
In summary, we have reported a mild method allowing
the preparation of benzylic zinc chlorides from the corre-
sponding benzylic chlorides using zinc dust and LiCl.
Remarkably, these zinc organometallics are compatible with
Supporting Information Available: Experimental pro-
cedures and full characterization of all compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(8) (a) Villieras, J.; Rambaud, M. Synthesis 1982, 11, 924. (b) Villieras,
J.; Rambaud, M. Org. Synth. 1988, 66, 220.
(9) (a) Garcia Martinez, A.; Fernadez, H.; Molero Vilchez, D.; Lardon
Guiterrez, M. L.; Subramanian, L. R. Synlett 1993, 229.
OL7030697
(10) Negishi, E.; Bagheri, V.; Chatterjee, S.; Luo, F.-T.; Miller, J. A.;
Stoll, A. T. Tetrahedron Lett. 1983, 24, 5181.
(11) ArCH2ZnCl is not reactive enough and the mixed reagent ArCH2-
ZnCH2SiMe3 gives better results; see also: Berger, S.; Langer, F.; Lutz,
C.; Knochel, P.; Mobley, T. A.; Reddy, C. K. Angew. Chem., Int. Ed. 1997,
36, 1496.
(14) (a) Ioanaviciu, A.; Antony, S.; Pommier, Y.; Staker, B. L.; Stewart,
L.; Cushman, M. J. Med. Chem. 2005, 48, 4803. (b) Boger, D. L.;
Brotherton, C. E.; Kelley, M. D. Tetrahedron 1981, 37, 5181.
(15) Krasovskiy, A.; Krasovskaya, V.; Knochel, P. Angew. Chem., Int.
Ed. 2006, 45, 2958; see also Supporting Information.
(12) Mander, L. N.; Sethi, S. P. Tetrahedron Lett. 1983, 24, 5425.
(13) (a) Schmauder, H. P.; Gro¨ger, D.; Gru¨ner, H.; Lohmann, D.
Pharmazie 1988, 43, 313. (b) Buzas, A.; Merour, J.-Y.; Lavielle, G.
Heterocycles 1985, 23, 2561. (c) Rae, I. D.; Simmonds, P. M. Aust. J. Chem.
1987, 40, 915. (d) de Lera, A. R.; Aubourg, S.; Suau, R.; Castedo, L.
Heterocycles 1987, 26, 675. (e) Peet, N. P.; Karrick, G. L.; Barbuch, R. J.
J. Heterocycl. Chem. 1987, 24, 715.
(16) (a) Charles, M. D.; Schultz, P.; Buchwald, S. L. Org. Lett. 2005, 7,
3965. (b) Anderson, K. W.; Tundel, R. E.; Ikawa, T.; Altman, R. A.;
Buchwald, S. L. Angew. Chem., Int. Ed. 2006, 45, 6523. (c) Barder, T. E.;
Buchwald, S. L. Org. Lett. 2004, 6, 2649.
(17) The copper-catalyzed cross-coupling with the magnesiated iso-
quinoline (7) and 3,4-dimethoxybenzyl chloride (2m) did not provide the
expected papaverine (6).
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