Organoaluminum-Mediated Direct Cross-Coupling Reactions

Article abstract of DOI:10.1002/anie.201412249

We present a direct cross-coupling reaction between arylaluminum compounds (ArAlMe₂·LiCl) and organic halides RX (R=aryl, alkenyl, alkynyl; X=I, Br, and Cl) without any external catalyst. The reaction takes place smoothly, simply upon heating, thereby enabling the efficient and chemo-/stereoselective formation of biaryl, alkene, and alkyne coupling products with broad functional group compatibility.

Full text of DOI:10.1002/anie.201412249

Angewandte
Chemie
DOI: 10.1002/anie.201412249
Cross-Coupling Very Important Paper
Organoaluminum-Mediated Direct Cross-Coupling Reactions**
Hiroki Minami, Tatsuo Saito, Chao Wang,* and Masanobu Uchiyama*
Abstract: We present a direct cross-coupling reaction between
arylaluminum compounds (ArAlMe2·LiCl) and organic hal-
ides RX (R = aryl, alkenyl, alkynyl; X = I, Br, and Cl) without
any external catalyst. The reaction takes place smoothly, simply
upon heating, thereby enabling the efficient and chemo-/
stereoselective formation of biaryl, alkene, and alkyne cou-
pling products with broad functional group compatibility.
the coordination of aluminum (by using heteroleptic
ligands,[7] triarylaluminum compounds such as Ar3Al,[8,9] or
a more reactive organoaluminate complex[10]), 2) by using
another transition-metal catalyst such as Ni[11] or Fe,[9,12] and
3) notably, by using aryl- or benzylaluminum reagents freshly
prepared in situ with proper Pd catalysts and ligands.[13] Now,
we have discovered a direct cross-coupling reaction of
organoaluminum that does not require any external catalyst.
This reaction offers many advantages over transition-metal-
catalyzed reactions, including 1) low halogen-metal exchange
ability, so that side dehalogenation reactions are minimized,
2) applicability to a wide range of organic halides, including
aryl/alkenyl/alkynyl iodide, bromide, and even chloride, and
3) excellent chemoselectivity for carbon–halogen and
carbon–pseudohalogen coupling partners with broad func-
tional group compatibility.
A
luminum is the most abundant metal (and the third most
abundant element) in the Earthꢀs crust. It also provides the
worldꢀs largest tonnage organometallic reagent, AlMe3.[1a]
Since the discovery of organoaluminum in 1859,[1b] various
[1,2]
ꢀ
methods have been developed to create C Al bonds.
example, in 2010, the direct oxidative insertion of aluminium
For
ꢀ
metal into a C X (X = halogen) bond in the presence of LiCl
was reported by Knochel and co-workers.[3] Organoaluminum
reagents occupy a central position in synthetic organic and
organometallic chemistry because of their low cost, ready
availability, low toxicity, and exceptional Lewis acidity.[1–3]
However, the utilization of organoaluminum compounds
in modern transition-metal-catalyzed cross-coupling reac-
tions[1a] has been largely neglected in favor of organoboron
(Suzuki–Miyaura reaction), organozinc (Negishi reaction),
organomagnesium (Kumada–Tamao reaction), and organotin
(Stille reaction) reagents,[4] despite the fact that Pd-catalyzed
cross-coupling with organoaluminum reagents was first
reported by Negishi et al. as early as in 1976.[5] The initial
methods for cross-coupling with organoaluminum usually
required a co-catalyst such as zinc or indium salts to
accelerate the reaction.[2,6] However, in recent years, new
coupling procedures that do not require those additives have
also been developed: for example, 1) by appropriately tuning
Initially, we focused on the reaction between dimethyl-p-
tolylaluminum (1a, easily prepared from p-tolyllithium and
dimethylaluminum chloride)[14] and 2-iodonaphthalene (2a).
After extensive studies,[15] we identified the optimum con-
ditions for direct coupling to be heating at 1108C in THF. We
then examined the scope and limitations of the cross-coupling
reaction between various aryl aluminum compounds 1 and
aryl iodides 2 (Scheme 1). The steric and electronic properties
of functional groups on the aromatic rings, such as ester (!
3hc), amide (< Pr3hd), benzyl ether (!3ee), trifluoromethyl
(!3ef), silyl ether (!3 fg), and heterocycles (!3ah), had
little influence on the reactivity, and the desired coupling
[*] H. Minami, Dr. T. Saito, Dr. C. Wang, Prof. Dr. M. Uchiyama
Graduate School of Pharmaceutical Sciences
The University of Tokyo
7-3-1 Hongo, Bunkyo-ku, Tokyo-to 113-0033 (Japan)
E-mail: chaowang@mol.f.u-tokyo.ac.jp
uchiyama@mol.f.u-tokyo.ac.jp
Dr. C. Wang, Prof. Dr. M. Uchiyama
The Advanced Elements Chemistry Research Team
Center for Sustainable Resource Science
and the Elements Chemistry Laboratory, RIKEN
2-1 Hirosawa, Wako-shi, Saitama-ken, 351-0198 (Japan)
E-mail: chaowang@riken.jp
uchi_yama@riken.jp
[**] This work was supported by the JSPS KAKENHI (S) (24229011 to
M.U.), a JSPS Grant-in-Aid for Young Scientists (B) (24790035 to
C.W.). We thank Dr. Xuan Wang (our group) and Dr. Kazuya
Takahashi (Nishina Center for Accelerator-Based Science, RIKEN)
for ICP-MS analysis.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201412249.
Scheme 1. Direct cross-coupling between arylaluminum 1 (2.5 equiv)
and aryl iodide 2 (1.0 equiv).
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products were obtained in high yields without the formation
of detectable amounts of dehalogenated side product.
Next, the reaction with aryl bromides 4 was investigated
(Scheme 2). Under the same conditions, aryl bromides
carrying various functional groups reacted with aluminum
reagents 1 to form biaryl products 3 in high yields. Multiple
coupling with dibromo substituents (4k) and reaction at
sterically congested sites (4l) proceeded smoothly to give the
desired terphenyl (3hk) and 9-phenylanthracene products in
high yields. Therefore, this procedure is potentially applicable
for the synthesis of functional molecules with extended p-
conjugated systems.
To further investigate the chemoselectivity of this cross-
coupling reaction, the reactions with aromatic iodides or
bromides bearing tosylate, triflate, and carbamate groups
were next examined (Scheme 3). It is well known that
sulfonate usually shows reactivity similar to, or even higher
than, that of halides in transition-metal-catalyzed cross-
couplings reactions. Recently, aryl carboxylates (ester, carba-
mate, etc.) have also been reported to be good coupling
partners in the presence of transition-metal catalysts.[16] The
functional-group specificity of our coupling was very high,
with tosylate, carbamate, and especially the highly reactive
triflate not reacting at all. In competitive reactions, cross-
coupling at iodide (surprisingly, also at bromide versus OTf)
proceeded in excellent yield with more than 99% selectivity.
This is in sharp contrast with transition-metal-catalyzed
procedures, and opens up new possibilities for the diversified
synthesis of multifunctionalized aromatic compounds with
high chemoselectivity.
This reaction also proceeded with alkenyl iodides 5 and
bromides 6 (Scheme 4). In all cases, the stereochemistry of the
starting materials was retained in the products. Therefore, this
coupling reaction is expected to be a powerful tool for the
region-/stereocontrolled synthesis of multisubstituted olefins.
This finding also strongly suggests that no free radical process
is involved in the present reaction.
Another highly attractive feature of this reaction is its
applicability to organic chlorides. According to previous
reports, aryl and vinyl chlorides are much less reactive toward
both Grignard[17] and organozinc[18] reagents. However, the
reaction of aryl or vinyl chloride (8 or 9) with aluminum
reagent 1 enabled formation of coupling products 3 or 11,
respectively, albeit in moderate yield (Scheme 5).
Transition-metal-catalyst-free coupling of alkynyl halides
with organometallic compounds has not been previously
reported. Here, we found that the direct cross-coupling of
alkynyl iodides or bromides with aluminum reagent 1 afforded
the aryl–alkynyl cross-coupling product in low yield as
a mixture with free alkyne and the aryl–aryl homocoupling
Scheme 2. Direct cross-coupling between arylaluminum 1 (2.5 equiv)
and aryl bromides 4 (1.0 equiv). For 3eg, the reaction was maintained
for 48 h. For 3hk, 3.5 equiv of 1h was used.
Scheme 4. Direct cross-coupling between arylaluminum 1 (2.5 equiv)
=
and alkenyl iodides 5 or bromides 6 (1.0 equiv). No C C bond isomers
were observed by both GC and NMR spectroscopic analysis of the
crude products.
Scheme 3. Direct cross-coupling between arylaluminum 1 (2.5 equiv)
and aryl iodide 2 or bromides 4 (1.0 equiv). The reaction exhibits
different chemoselectivity from transition-metal-catalyzed reactions.
Scheme 5. Direct cross-coupling of arylaluminum 1 (2.5 equiv) with
aryl or alkenyl chloride 8 or 9 (1.0 equiv).
2
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[2] For reviews on the applications of organoaluminum reagents in
products, presumably as a result of halogen–aluminum
exchange. However, alkynyl chlorides 10 were found to be
good substrates for the present reaction, affording the desired
aryl–alkynyl cross-coupled 11 as the sole product in moderate
to good yields without exchange-associated side reactions
(Scheme 6). These results demonstrate the broad scope, high
organic synthesis, see also a) K. Maruoka, H. Yamamoto,
Tetrahedron 1988, 44, 5001 – 5032; b) C. Wang, Z. Xi, Chem.
Soc. Rev. 2007, 36, 1395 – 1406; c) W. Uhl, Coord. Chem. Rev.
2008, 252, 1540 – 1563.
[3] T. Blꢁmke, Y.-H. Chen, Z. Peng, P. Knochel, Nat. Chem. 2010, 2,
313 – 318. We also reported on the preparation of organoalumi-
num compounds thorough deprotonative alumination as well as
its synthetic application in Pd-catalyzed cross-coupling reactions
with organic halides, see Ref. [10].
[4] For selected reviews, see a) C. C. C. Johansson Seechurn, M. O.
Kitching, T. J. Colacot, V. Snieckus, Angew. Chem. Int. Ed. 2012,
51, 5062 – 5085; Angew. Chem. 2012, 124, 5150 – 5174; b) E.
Negishi, Angew. Chem. Int. Ed. 2011, 50, 6738 – 6764; Angew.
Chem. 2011, 123, 6870 – 6897; c) A. Suzuki, Angew. Chem. Int.
Ed. 2011, 50, 6722 – 6737; Angew. Chem. 2011, 123, 6854 – 6869;
d) R. Jana, T. P. Pathak, M. S. Sigman, Chem. Rev. 2011, 111,
1417 – 1492; e) Metal-Catalyzed Cross-Coupling Reactions, 2nd
ed. (Eds.: A. de Meijere, F. Diederich), Wiley-VCH, Weinheim,
2004.
[5] a) E. Negishi, S. Baba, J. Chem. Soc. Chem. Commun. 1976,
596b – 597b; b) E. Negishi, S. Baba, J. Am. Chem. Soc. 1976, 98,
6729 – 6731.
Scheme 6. Direct cross-coupling of arylaluminum 1 (2.5 equiv) with
alkynyl chloride 10 (1.0 equiv).
[6] a) E. Negishi, N. Okukado, A. O. King, D. E. van Horn, B. I.
Spiegel, J. Am. Chem. Soc. 1978, 100, 2254 – 2256; b) M. Qian, Z.
Huang, E. Negishi, Org. Lett. 2004, 6, 1531 – 1534; c) A. Unsinn,
S. H. Wunderlich, A. Jana, K. Karaghiosoff, P. Knochel, Chem.
Eur. J. 2013, 19, 14687 – 14696; d) T. D. Blꢁmke, K. Groll, K.
Karaghiosoff, P. Knochel, Org. Lett. 2011, 13, 6440 – 6443;
e) S. H. Wunderlich, P. Knochel, Angew. Chem. Int. Ed. 2009,
48, 1501 – 1504; Angew. Chem. 2009, 121, 1530 – 1533.
[7] a) J. Blum, D. Gelman, W. Baidossi, E. Shakh, A. Rosenfeld, Z.
Aizenshtat, B. C. Wassermann, M. Frick, B. Heymer, S. Schutte,
S. Wernik, H. Schumann, J. Org. Chem. 1997, 62, 8681 – 8686;
b) H. Schumann, J. Kaufmann, H.-G. Schmalz, A. Bçttcher, B.
Gotov, Synlett 2003, 1783 – 1788; c) T. Cooper, A. Novak, L. D.
Humphreys, M. D. Walker, S. Woodward, Adv. Synth. Catal.
2006, 348, 686 – 690.
selectivity, and diverse applicability of this transition-metal-
catalyst-free cross-coupling reaction.
To examine whether any transition metals were present,
ICP-MS analysis was performed on the solvents, aluminum
reagents, and aryl halides. No transition metals were detected
at the level of 1 ppb (the detection limit). Although this result
may not entirely rule out the participation of transition
metals, the present findings indicate the low possibility of the
involvement of a transition-metal-mediated process.[19]
In conclusion, we have developed a direct cross-coupling
reaction between organoaluminum and aryl halides without
any external catalyst. This reaction is efficient, selective, and
applicable to a wide range of substrates, including aryl/
alkenyl/alkynyl halides. Further studies to further expand the
scope of this reaction and its synthetic utility, including its
applicability to functional molecules with extended p-con-
jugated systems is in progress. We are also further investigat-
ing the reaction properties/mechanisms with the help of
theoretical and spectroscopic methods.[20]
[8] S. L. Ku, X. P. Hui, C. A. Chen, Y. Y. Kuo, H. M. Gau, Chem.
Commun. 2007, 3847 – 3849.
[9] a) S. Kawamura, K. Ishizuka, H. Takaya, M. Nakamura, Chem.
Commun. 2010, 46, 6054 – 6056; b) S. Kawamura, T. Kawabata,
K. Ishizuka, M. Nakamura, Chem. Commun. 2012, 48, 9376 –
9378.
[10] a) H. Naka, J. V. Morey, J. Haywood, D. J. Eisler, M. McPartlin,
F. Garcꢂa, H. Kudo, Y. Kondo, M. Uchiyama, A. E. H. Wheatley,
J. Am. Chem. Soc. 2008, 130, 16193 – 16200; b) H. Naka, M.
Uchiyama, Y. Matsumoto, A. E. H. Wheatley, M. McPartlin,
J. V. Morey, Y. Kondo, J. Am. Chem. Soc. 2007, 129, 1921 – 1930;
c) M. Uchiyama, H. Naka, Y. Matsumoto, T. Ohwada, J. Am.
Chem. Soc. 2004, 126, 10526 – 10527; for reviews, see d) F.
Mongin, A. Harrison-Marchand, Chem. Rev. 2013, 113, 7563 –
7727; e) R. E. Mulvey, F. Mongin, M. Uchiyama, Y. Kondo,
Angew. Chem. Int. Ed. 2007, 46, 3802 – 3824; Angew. Chem.
2007, 119, 3876 – 3899.
[11] a) E. Negishi, T. Takahashi, S. Baba, D. E. van Horn, N.
Okukado, J. Am. Chem. Soc. 1987, 109, 2393 – 2401; b) B. H.
Lipshutz, G. Bulow, R. F. Lowe, K. L. Stevens, Tetrahedron 1996,
52, 7265 – 7276; c) B. H. Lipshutz, P. Mollard, S. S. Pfeiffer, W.
Chrisman, J. Am. Chem. Soc. 2002, 124, 14282 – 14283; d) D. B.
Biradar, H. M. Gau, Chem. Commun. 2011, 47, 10467 – 10469.
Received: December 21, 2014
Published online: && &&, &&&&
ꢀ
Keywords: C C bond formation · cross-coupling ·
organic halides · organoaluminum · selectivity
.
[1] a) “Modern organoaluminum reagents: preparation, structure,
reactivity and use”: Topics in Organometallic Chemistry, Vol. 41
(Eds.: S. Woodward, S. Dagorne), Springer, Berlin, 2013, pp. 1 –
322, for the synthesis of organoaluminum compounds, see
pp. 173 – 186, in the chapter on Preparation of organoalanes
for organic synthesis, by P. Knochel, T. Blꢁmke, K. Groll, Y.-H.
Chen; for cross-coupling reactions of organoaluminum com-
pounds, see pp. 267 – 276, in chapter on Organoaluminum
couplings to carbonyls, imines, and halides, by A. Kolb, P.
Zezschwitz; b) W. Hallwachs, A. Schafarik, Justus Liebigs Ann.
Chem. 1859, 109, 206 – 209.
ˇ
[12] D. Necas, P. Drabina, M. Sedlꢃk, M. Kotora, Tetrahedron Lett.
2007, 48, 4539 – 4541.
[13] a) B. Wang, M. Bonin, L. Micouin, Org. Lett. 2004, 6, 3481 –
3484; b) H. Gao, P. Knochel, Synlett 2009, 1321 – 1325; c) K.
Groll, T. D. Blꢁmke, A. Unsinn, D. Haas, P. Knochel, Angew.
Chem. Int. Ed. 2012, 51, 11157 – 11161; Angew. Chem. 2012, 124,
Angew. Chem. Int. Ed. 2015, 54, 1 – 5
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www.angewandte.org
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.
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Communications
11319 – 11323; d) T. Klatt, K. Groll, P. Knochel, Chem. Commun.
2013, 49, 6953 – 6955; e) X. Chen, L. Zhou, Y. Li, T. Xie, S. Zhou,
J. Org. Chem. 2014, 79, 230 – 239.
d) E. Shirakawa, R. Watabe, T. Murakami, T. Hayashi, Chem.
Commun. 2013, 49, 5219 – 5221.
[18] a) H. Minami, X. Wang, C. Wang, M. Uchiyama, Eur. J. Org.
Chem. 2013, 7891 – 7894; b) E. Shirakawa, F. Tamakuni, E.
Kusano, N. Uchiyama, W. Konagaya, R. Watabe, T. Hayashi,
Angew. Chem. Int. Ed. 2014, 53, 521 – 525; Angew. Chem. 2014,
126, 531 – 535.
[19] ICP-MS was performed to analyze 1a, 2a, THF, and Et2O
(solvent for the lithation of the iodide to prepare 1) as
representative reactants and solvents. As a result, the concen-
trations of Fe, Co, Ni, Cu, Ru, Rh, Pd, Ag, Ir, Pt, and Au were
found to be less than 1 ppb (below the detection limit).
[14] C. Hawner, D. Mꢁller, L. Gremaud, A. Felouat, S. Woodward, A.
Alexakis, Angew. Chem. Int. Ed. 2010, 49, 7769 – 7772; Angew.
Chem. 2010, 122, 7935 – 7938.
[15] For details on screening of the conditions, see the Supporting
Information. Note that lithium salts such as LiCl influence many
chemical transformations (see E. Hevia, R. E. Mulvey, Angew.
Chem. Int. Ed. 2011, 50, 6448 – 6450; Angew. Chem. 2011, 123,
6576 – 6578). We are currently investigating salt effects in the
present reaction.
[16] For reviews, see a) J. Cornella, C. Zarate, R. Martin, Chem. Soc.
Rev. 2014, 43, 8081 – 8097; b) S. Z. Tasker, E. A. Standley, T. F.
Jamison, Nature 2014, 509, 299 – 309; c) B. M. Rosen, K. W.
Quasdorf, D. A. Wilson, N. Zhang, A. M. Resmerita, N. K. Garg,
V. Percec, Chem. Rev. 2011, 111, 1346 – 1416; d) B. Li, D. Yu, S.
Sun, Z. Shi, Chem. Eur. J. 2011, 17, 1728 – 1759.
[17] a) E. Shirakawa, Y. Hayashi, K. I. Itoh, R. Watabe, N. Uchiyama,
W. Konagaya, S. Masui, T. Hayashi, Angew. Chem. Int. Ed. 2012,
51, 218 – 221; Angew. Chem. 2012, 124, 222 – 225; b) N.
Uchiyama, E. Shirakawa, T. Hayashi, Chem. Commun. 2013,
49, 364 – 366; c) S. Murarka, A. Studer, Angew. Chem. Int. Ed.
2012, 51, 12362 – 12366; Angew. Chem. 2012, 124, 12528 – 12532;
[20] For a pioneering DFT calculation on the mechanism of a SRN1
substitution between a Grignard reagent and an aryl iodide
induced by single-electron transfer (SET), see a) B. E. Haines,
O. Wiest, J. Org. Chem. 2014, 79, 2771 – 2774; for similar
mechanistic studies, see Refs. [17,18]; for recent reviews on SET-
ꢀ
induced C C bond-formation reactions, see b) A. Studer, D. P.
Curran, Nat. Chem. 2014, 6, 765 – 773; c) C.-L. Sun, Z.-J. Shi,
Chem. Rev. 2014, 114, 9219 – 9280; d) N. Zhang, S. R. Samanta,
B. M. Rosen, V. Percec, Chem. Rev. 2014, 114, 5848 – 5958;
e) T. L. Chan, Y. Wu, P. Y. Choy, F. Y. Kwong, Chem. Eur. J.
2013, 19, 15802 – 15814.
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Cross-Coupling
H. Minami, T. Saito, C. Wang,*
M. Uchiyama*
&&&& — &&&&
Organoaluminum-Mediated Direct
Cross-Coupling Reactions
All in Al: Simply heating an arylaluminum
(ArAlMe2·LiCl) and an organic halide RX
(R=aryl, alkenyl, alkynyl; X=I, Br, Cl)
without any external catalyst results in
a smooth and direct cross-coupling
reaction taking place. This approach
enables the efficient, chemo-/stereose-
lective formation of coupling products
with broad functional group compatibil-
ity.
Angew. Chem. Int. Ed. 2015, 54, 1 – 5
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
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