New preparation of benzylic aluminum and zinc organometallics by direct insertion of aluminum powder

Article abstract of DOI:10.1021/ol202733v

The reaction of commercial Al-powder (3 equiv) and InCl₃ (1-5 mol %) with benzylic chlorides provides various functionalized benzylic aluminum sesquichlorides under mild conditions (THF, 20 °C, 3-24 h) without homocoupling (<5%). These new benz

Full text of DOI:10.1021/ol202733v

ORGANIC
LETTERS
2011
Vol. 13, No. 24
6440–6443
New Preparation of Benzylic Aluminum
and Zinc Organometallics by Direct
Insertion of Aluminum Powder
€
Tobias D. Blumke, Klaus Groll, Konstantin Karaghiosoff, and Paul Knochel*
€
Department Chemie, Ludwig-Maximilians-Universitat, Butenandtstrasse, 5-13, 81377
Mu€nchen, Germany
Paul.Knochel@cup.uni-muenchen.de
Received October 12, 2011
ABSTRACT
The reaction of commercial Al-powder (3 equiv) and InCl3 (1ꢀ5 mol %) with benzylic chlorides provides various functionalized benzylic aluminum
sesquichlorides under mild conditions (THF, 20 °C, 3ꢀ24 h) without homocoupling (<5%). These new benzylic organometallics reacted smoothly
with various electrophiles (Pd-catalyzed cross-couplings, or Cu-mediated acylations, allylations, or 1,4-addition reactions). Electron-poor
benzylic chlorides or substrates prone to Wurtz coupling can be converted to benzylic zinc compounds by the reaction of Al-powder in the
presence of ZnCl2.
Benzylic organometallics are important intermediates in
organic synthesis. They can be used to build up diaryl-
methanes present in many natural products or pharmaco-
logically activecompounds.1 Several methods are available
for the preparation of benzylic organometallics.2 Whereas
benzylic lithium and magnesium organometallics do not
tolerate functional groups, benzylic zinc organometallics
are compatible with numerous functionalities and are
readily prepared by direct insertion of zinc dust in the
presence of LiCl.2 Like zinc, aluminum is also a cheap
metal with low toxicity. By comparing the electronegativ-
ities of the metals (Mg, 1.32; Al, 1.61; Zn, 1.65)3 we anti-
cipated that benzylic aluminum organometallics could also
tolerate a number of functional groups.4 Generally, the
preparation of organoaluminums from metal powder is
difficult and requires a proper activation of the metal
surface.4a,5 Reports on the reaction of aluminum powder
with benzylic chlorides are scarce.4a,6 Recently, we found
(1) (a) Ueoka, R.; Fujita, T.; Matsunaga, S. J. Org. Chem. 2009, 74,
4396. (b) Jin, Z. Nat. Prod. Rep. 2005, 22, 196. (c) Hassan, W.; Edrada,
R.; Ebel, R.; Wray, V.; Berg, A.; van Soest, R.; Wiryowidagdo, S.;
Proksch, P. J. Nat. Prod. 2004, 67, 817. (d) Horak, F.; Zieglmayer, U. P.
Expert Rev. Clin. Immunol. 2009, 5, 659. (e) Kaila, N.; Janz, K.; Huang,
A.; Moretto, A.; DeBernardo, S.; Bedard, P. W.; Tam, S.; Clerin, J.;
Keith, J. C.; Tsao, D. H. H.; Sushkova, N.; Shaw, G. D.; Camphausen,
R. T.; Schaub, R. G.; Wang, Q. J. Med. Chem. 2007, 50, 40. For the
preparation of diarylmethanes, see also:(f) Molander, G. A.; Elia, M. D.
J. Org. Chem. 2006, 71, 9198.
(2) For lithium reagents: (a) Reed, J. N. In Science of Synthesis;
Snieckus, V., Ed.; Georg Thieme-Verlag KG: Stuttgart, 2006; Vol. 8a, p 329.
(b) Wakefield, B. J. Organolithium Methods; Academic Press: New York,
1988. (c) Hargreaves, S. L.; Pilkington, B. L.; Russell, S. E.; Worthington,
P. A. Tetrahedron Lett. 2000, 41, 1653. For magnesium reagents: (d)
Burns, T. P.; Rieke, R. D. J. Org. Chem. 1987, 52, 3674. (e) Benkeser,
R. A.; Snyder, D. C. J. Org. Chem. 1982, 47, 1243. (f) Baker, K. V.;
Brown, J. M.; Hughes, N.; Skarnulis, A. J.; Sexton, A. J. Org. Chem.
1991, 56, 698. (g) Harvey, S.; Junk, P. C.; Raston, C. L.; Salem, G. J. Org.
Chem. 1988, 53, 3134. (h) Stoll, A. H.; Krasovskiy, A.; Knochel, P.
Angew. Chem., Int. Ed. 2006, 45, 606. For zinc reagents: (i) Metzger, A.;
Schade, M. A.; Knochel, P. Org. Lett. 2008, 10, 1107. (j) Metzger, A.;
Schade, M. A.; Manolikakes, G.; Knochel, P. Chem.;Asian J. 2008, 3,
1678. (k) Metzger, A.; Piller, F. M.; Knochel, P. Chem. Commun. 2008,
5824.
(3) Lide, D. R. CRC Handbook of Chemistry and Physics: A ready-
reference book of chemical and physical data; Taylor & Francis: Boca
Raton, FL, 2009.
(4) Organoaluminum compounds: (a) Mole, T.; Jeffery, E. A. Orga-
noaluminium Compounds; Elsevier: Amsterdam, 1972. (b) Negishi, E-i.;
Takahashi, T.; Baba, S.; Van Horn, D. E.; Okukado, N. J. Am. Chem. Soc.
1987, 109, 2393. (c) Zweifel, G.; Miller, J. A. In Organic Reactions;
Dauben, W. G., Ed.; Wiley: 1984.
(5) (a) Takai, K.; Ikawa, Y. Org. Lett. 2002, 4, 1727. (b) Uneyama,
K.; Kamaki, N.; Moriya, A.; Torii, S. J. Org. Chem. 1985, 50, 5396. (c)
Tanaka, H.; Nakahara, T.; Dhimane, H.; Torii, S. Tetrahedron Lett.
1989, 30, 4161. (d) Tanaka, H.; Inoue, K.; Pokorski, U.; Taniguchi, S.;
Torii, S. Tetrahedron Lett. 1990, 31, 3023. (e) Saito, S. In Science of
Synthesis; Yamamoto, H., Ed.; Thieme: Stuttgart, 2004.
(6) (a) Prevost, C.; Gaudemar, M. Compt. Rend. 1954, 239, 282. (b)
Kawai, W.; Tsutsumi, S. Nippon Kagaku Zasshi 1960, 81, 109.
r
10.1021/ol202733v
Published on Web 11/18/2011
2011 American Chemical Society

that aluminum powder inserts readily into aromatic ha-
lides in the presence of LiCl and catalytic amounts of
PbCl2, InCl3, TiCl4, or BiCl3.7 Inspired by these results, we
have developed a general method for the preparation of
benzylic aluminum reagents. Herein we report a mild syn-
thesis of functionalized benzylic organoaluminums by the
reaction of benzylic chlorides with Al-powder in the pre-
sence of InCl3 (1ꢀ5 mol %) as well as their reactivity with
various catalysts.
In preliminary experiments, 3-chlorobenzyl chloride
(1a) was treated with Al-powder (3.0 equiv) and different
metal salt additives (Table 1). No reaction was observed
in the absence of the metal salts (Table 1, entry 1), whereas
the addition of PbCl2 (3 mol %) or BiCl3 (3 mol %) lead
to the formation of the 3-chlorobenzylaluminum reagent8
2a in 20% and 64% yield along with the homodimer 3
(entries 2 and 3).9
The resulting benzylic reagent 2a underwent a smooth
Pd-catalyzed cross-coupling reaction11 in the presence of
Zn(OAc)2 (1.5 equiv) and PEPPSI-iPr (1.7 mol %)12 with
ethyl 3-iodobenzoate (4a, 0.7 equiv) furnishing the func-
tionalized diarylmethane 5a in 89% yield (Table 2, entry 1).13
Using the same conditions, 2-bromobenzyl chloride (1b)
afforded the corresponding aluminum reagent (3 h, 20 °C)
which reacted well with 4-chlorobenzoyl chloride (2b,
0.7 equiv) after transmetalation with Zn(OAc)2 (1.5 equiv)
and addition of CuCN 2LiCl, 20 mol %.14 The expected
3
ketone 5b was obtained in 83% yield (entry 2). Several
fluorine-substituted benzylic chlorides (1cꢀf) could be
readily converted to the aluminum reagents (20 °C, 6ꢀ24 h)
and reacted with various unsaturated halides in Pd-cata-
lyzed cross-couplings (Zn(OAc)2 (1.5 equiv); PEPPSI-iPr
(1.7 mol %)) giving the functionalized diarylmethanes
5cꢀf in 71ꢀ98% yields (entries 3ꢀ6). Besides electron-
deficient benzylic chlorides, also electron-rich chlorides
suchas4-methoxybenzyl chloride (1g) or 3-methoxybenzyl
chloride (1h) reacted with Al-powder (3.0 equiv) in the
presence of InCl3 (3 mol %) within 5ꢀ12 h at 20 °C pro-
viding the expected intermediate aluminum reagents. Tran-
smetalation with Zn(OAc)2 (1.5 equiv) and subsequent
cross-coupling reactions produced the diarylmethanes
5gꢀh in 78% and 82% yields (entries 7, 8). Even 3,4,5-
trimethoxybenzyl chloride (1i) or the thiomethyl substi-
tuted benzyl chloride 1j could be readily used in this
procedure, and after a Cu(I)-mediated allylation reaction
Table 1. Catalyst Screening for the Preparation of Benzylic
Organoaluminums
(Zn(OAc)2 (1.5 equiv), CuCN 2LiCl, ꢀ30 °C, 20 mol %)
3
with ethyl (2-bromomethyl)acrylate15 (4i, 0.7 equiv) or
3-bromocyclohexene (4j, 0.7 equiv) the functionalized
alkenes 5i and 5j were isolated in 75% and 92% yields
(entries 9, 10).
Inthecaseof benzylicchloridesbearing anester or nitrile
functionality, as well as secondary benzylic systems, the
experimental procedure had to be modified. Although
these benzylic chlorides reacted with Al-powder in the
presence of InCl3, the reaction resulted in low yields of
the aluminum reagent, or dimerization. Nevertheless,
the addition of ZnCl2 proved to be beneficial.16 Thus,
time
[h]a
yield
yield
entry
catalyst
[%] (2a)b
[%] (3)b
1
2
3
4
5
ꢀ
24
22
12
3.5
24
n.r.c
20
n.r.c
5
PbCl2
BiCl3
InCl3
TiCl4
64
36
0
n.r.c
90
n.r.c
a Reaction time at 20 °C. b The yield was determined by iodolysis of
reaction aliquots and subsequent GC analysis. c No reaction took place.
InCl3 proved to be the best choice, and 3-chlorobenzyl
chloride reacted with Al (3.0 equiv) in the presence of
TMS-Cl (3 mol %)10 and InCl3 (3 mol %) within 3.5 h at
20 °C furnishing the aluminum reagent 2a in 90% yield
without the formation of 3 (entry 4). Interestingly no
reaction was observed when TiCl4 was used as a catalyst
although it is an effective additive for the preparation of
arylaluminums (entry 5).7
(11) (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.
(12) (a) Organ, M. G.; Calimsiz, S.; Sayah, M.; Hoi, K. H.; Lough,
A. J. Angew. Chem., Int. Ed. 2009, 48, 2383. (b) O Brien, C. J.; Kantchev,
E. A. B.; Valente, C.; Hadei, N.; Chass, G. A.; Lough, A.; Hopkinson,
A. C.; Organ, M. G. Chem.;Eur. J. 2006, 12, 4743. (c) Nasielski, J.;
Hadei, N.; Achonduh, G.; Kantchev, E. A. B.; O Brien, C. J.; Lough, A.;
Organ, M. G. Chem.;Eur. J. 2010, 16, 10844.
(13) In the absence of stoichiometric amounts of Zn(OAc)2 almost no
cross-coupling was observed. Both the acetate anion and the zinc cation
seem to be important. We speculate that the acetate anion is reducing the
Lewis acidity of the aluminum species whereas the zinc cation favors the
transfer of the aryl group to palladium.
€
(7) Blumke, T. D.; Chen, Y.-H.; Peng, Z.; Knochel, P. Nat. Chem.
2010, 2, 313.
(14) Knochel, P.; Yeh, M. C. P.; Berk, S. C.; Talbert, J. J. Org. Chem.
1988, 53, 2390.
(8) An almost 1:1 mixture of RAlCl2 and R2AlCl is obtained as
shown by NMR spectroscopy (see Supporting Information).
(9) The yield was determined by iodolysis of reaction aliquots and
subsequent GC analysis. The use of LiCl leads to dimerization in almost
quantitative yield.
(10) For the metal surface activation with TMS-Cl, see also: Takai,
K.; Ueda, T.; Hayashi, T.; Moriwake, T. Tetrahedron Lett. 1996, 37,
7049.
ꢀ
(15) (a) Villieras, J.; Rambaud, M. Synthesis 1982, 11, 924. (b)
ꢀ
Villieras, J.; Rambaud, M. Org. Synth. 1988, 66, 220.
(16) (a) Piller, F. M; Appukkuttan, P.; Gavryushin, A.; Helm, M.;
Knochel, P. Angew. Chem., Int. Ed. 2008, 47, 6802. (b) Piller, F. M.;
Metzger, A.; Schade, M. A.; Haag, B. H.; Gavryushin, A.; Knochel, P.
€
Chem.;Eur. J. 2009, 15, 7192. (c) Blumke, T. D.; Piller, F. M.; Knochel,
P. Chem. Commun. 2010, 46, 4082.
Org. Lett., Vol. 13, No. 24, 2011
6441

Table 2. InCl3 Catalyzed Aluminum Insertion into Functiona-
lized Benzyl Chlorides and Reaction with Various Electrophiles
Scheme 1. in Situ Trapping of Aluminum Reagents with ZnCl2
and aluminum reagent 2k0 (Scheme 1). This has been
varified by 1H, 13C, and 27Al NMR studies (see Support-
ing Information).
This benzylic organometallic was allylated with ethyl
(2-bromomethyl)acrylate15 (4i, 0.7 equiv) yielding the ester
derivative 5k in 93% yield (Table 3, entry 1). Interestingly,
a cyano group in the para position is also compatible with
these reaction conditions and 4-cyanobenzyl chloride (1l)
is converted to the expected organometallic which reacted
with S-4-fluorophenyl benzenesulfonothioate (4l, 0.7 equiv)
forming the thioether 5l in 74% yield (entry 2).
In the case of ester substituted benzylic chlorides (1mꢀn)
the Al/ZnCl2 method produced the expected benzylic
organometallics which could be cross-coupled or allylated
affording the functionalized ester derivatives (5mꢀn) in
83% and 75% yield (entries 3, 4). Piperonyl moieties are
found in many pharmacologically active substances.17
Thus, the reaction of 5-chloro-6-(chloromethyl)benzo-
[d][1,3]dioxole (1o) with Al-powder and InCl3 was per-
formed (20 °C, 10 h). Without the presence of ZnCl2
the Wurtz-coupling product is formed almost quantita-
tively. However the use of a stoichiometric amount of
ZnCl2 allowed the formation of the intermediate organo-
metallic within 8 h at 20 °C, and after a Cu(I)-mediated
1,4-addition with cyclohexenone (4o) in the presence of
TMS-Cl (2.5 equiv), the ketone 5o was isolated in
68% yield (entry 5).18 Secondary benzylic chlorides like
1p or 1q were also prone to dimerization during the
insertion conditions, but the use of ZnCl2 prevented the
dimerization and within 22h fullconversion tothebenzylic
reagents was readily achieved. Quenching with ethyl
(2-bromomethyl)acrylate15 (4i, 0.7 equiv) or S-methyl
benzenesulfonothioate (4q, 0.7 equiv) afforded the
ester 5p and the thioether 5q in 76% and 65% yields
(entries 6, 7).
Remarkably, using the same conditions it was also
possible to generate benzylic bimetallic compounds. Only
a few preparative methods of bimetallic species of this type
are known. Usually high dilution (<0.1 M) and dropwise
addition of the benzylic substrate are needed to achieve
a good yield of the organometallic.19 However, 1,2-
bis(chloromethyl)benzene 1r reacted readily with Al
(3.0 equiv), InCl3 (3 mol %), and ZnCl2 (2.2 equiv) within
a Insertion time at 20 °C. b 0.7 equiv of electrophile was used; Cross-
coupling conditions: PEPPSI-iPr (1.7 mol %), THF/NMP (1:1), 50 °C,
2 h. c Isolated yields. d CuCN 2LiCl (20 mol %) was added.
(17) (a) Burton, W. H.; Budde, W. L.; Cheng, C.-C. J. Med. Chem.
1970, 13, 1009. (b) Cahlikova, L.; Opletal, L.; Kurfurst, M.; Macakova,
K.; Kulhankova, A.; Host’alkova, A. Nat. Prod. Commun. 2010, 5, 1751.
3
~
ꢀ
(c) Monge, A.; del Carmen Pena, M.; Palop, J. A.; Caldero, J. M.; Roca,
J.; Garcia, E.; Romero, G.; del Rio, J.; Lasheras, B. J. Med. Chem. 1994,
37, 1320.
3-cyanobenzyl chloride (1k) reacted with Al-powder
(3.0 equiv), InCl3 (3 mol %), and ZnCl2 (1.0 equiv)
within 5 h forming a mixture of the functionalized zinc
(18) Nakamura, E.; Matsuzawa, S.; Horiguchi, Y.; Kuwajima, I.
Tetrahedron Lett. 1986, 34, 4029.
6442
Org. Lett., Vol. 13, No. 24, 2011

Table 3. InCl3 Catalyzed Aluminum Insertion into Functiona-
lized Benzyl Chlorides and Subsequent Trapping with ZnCl2
and Various Electrophiles
Scheme 2. Preparation of a Bimetallic and Subsequent Reaction
with an Electrophile
Subsequent reaction with ethyl (2-bromomethyl)acrylate15
(4i, 0.7 equiv) furnished the bis-functionalized benzene
derivative 5r in 74% yield (Scheme 2). The substitution
pattern is not important as 1,3- and 1,4-bis-(chloromethyl)-
benzene reacted equally leading to 5s and 5t in 69% and
74% yields (Scheme 2).20
In summary we have reported a mild and general
method for the preparation of benzylic aluminum sesqui-
chlorides starting from benzylic chlorides using commer-
cially available aluminum powder and catalytic amounts
of InCl3. The aluminum reagents are obtained in good
yields without formation of homocoupling byproducts. In
the case of secondary benzylic chlorides or electron-poor
benzylic substrates being prone to Wurtz coupling, the use
of Al/ZnCl2 for the insertion reaction proved to be ad-
vantageous. Extensions of this work are currently under-
way in our laboratories.
Acknowledgment. The research leading to these results
has received funding from the European Research Council
under the European Community’s Seventh Framework
Programme (FP7/2007ꢀ2013) ERC Grant Agreement
No. 227763. We thank Chemetall GmbH (Frankfurt)
and BASF SE (Ludwigshafen) for the generous gift of
chemicals.
a Insertion time at 20 °C. b 0.7 equiv of electrophile was used; Cross-
coupling conditions: PEPPSI-iPr (1.7 mol %), THF/NMP (1:1), 50 °C,
2 h. c Isolated yield. d CuCN 2LiCl (20 mol %) was used. e CuCN 2LiCl
3
3
(1.0 equiv) and TMS-Cl (2.5 equiv) were used.
1.5 h at 20 °C (THF, 0.5 M) generating the bimetallic 2r
without the need for dropwise addition (Scheme 2).
Supporting Information Available. Experimental de-
tails and full spectroscopic data for all new compounds is
given in the Supporting Information. This material is
available free of charge via the Internet at http://pubs.
acs.org.
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under the same reaction conditions, and the best results were observed
with Al, InCl3, and ZnCl2.
Org. Lett., Vol. 13, No. 24, 2011
6443