N-tosylhydrazones as reagents for cross-coupling reactions: A route to polysubstituted olefins

Article abstract of DOI:10.1002/anie.200701815

Metal-free partner: No organometallic coupling partner is required for a Pd-catalyzed cross-coupling reaction that employs N-tosylhydrazones as the nucleophilic component (see scheme; Ts = 4-toluenesulfonyl).

Full text of DOI:10.1002/anie.200701815

Angewandte
Chemie
DOI: 10.1002/anie.200701815
Cross-Coupling Reactions
N-Tosylhydrazones as Reagents for Cross-Coupling Reactions: A
Route to Polysubstituted Olefins**
JosØ Barluenga,* Patricia Moriel, Carlos ValdØs, and Fernando Aznar
Pd-catalyzed cross-coupling reactions can be considered
nowadays to be the most reliable methodology for the
employment of arene carboxylic acids in decarboxylative Pd-
catalyzed synthesis of biaryls (Scheme 1e).[13] The common
feature of all these methodologies is that no stoichiometric
organometallic reagent is employed in the reaction.
During recent years we have been studying the employ-
ment of different types of nitrogenated reagents in Pd-
catalyzed cross-coupling reactions.[14] In this context, we
discovered that N-tosylhydrazones behave as a nucleophilic
component in a new type organometallic-free Pd-catalyzed
formation of C(sp ) C(sp ) bonds.[1] These types of reactions
find increasing application in the synthesis of complex organic
molecules.[2] In a cross-coupling reaction, an electrophile is
combined with a nucleophile to provide the corresponding
coupling product (Scheme 1a). Organometallic reagents such
2
2
À
[15,16]
À
C C-bond-forming reaction.
Herein we present our
preliminary results, which have led to the development of a
new methodology for the synthesis of polysubstituted olefins.
We started our study with the model reaction between the
acetophenone N-tosylhydrazone (1a) and p-bromotoluene
(2a; Scheme 2). In initial experiments employing different
À
Scheme 1. General strategies for Pd-catalyzed C C bond-forming reac-
tions.
as organomagnesium,[3] -zinc,[4] -tin,[5] -silicon,[6] and -boron[7]
compounds among others, are generally employed as the
nucleophilic component. In spite of the wide applicability of
these methodologies, a limitation of the general approach is
the requirement of a stoichiometric amount of the organo-
metallic reagent, which in many cases has to be prepared
through expensive, moisture-sensitive, and multistep proce-
dures.
Scheme 2. Formation of diaryl olefin 3a by coupling between aryl
halide 2a and acetophenone hydrazone 1a.
The Heck reaction (Scheme 1b) can be considered as the
reaction conditions, ligands, and bases we never observed
formation of either C- or N-arylation products. Instead, we
obtained variable amounts of the disubstituted olefin 3a.
After some experimentation, we concluded that [Pd2(dba)3]
(dba = trans,trans-dibenzylideneacetone), Xphos (2-dicyclo-
hexylphosphino-2’,4’,6’-triisopropylbiphenyl) as ligand, and
LiOtBu as base in dioxane at 708C provided the coupling
product 3a in quantitative yield. Having these efficient
experimental conditions in hand, we studied the scope of
the reaction regarding both coupling partners, the hydrazone
and the aryl halide. Representative examples are presented in
Table 1.
The reaction can be carried out with N-tosylhydrazones
derived from both ketones and aldehydes, giving rise to the
corresponding di- or trisubstituted olefins. Hydrazones
derived from cyclohexanone (Table 1, entries 5–7) and cyclo-
hexane carboxaldehyde (Table 1, entries 13–15) required
more-demanding experimental conditions. Thus, an increase
in the temperature or the catalyst loading was required to
achieve high conversions.
À
earliest example of a C C bond-forming reaction that does
not require stoichiometric amounts of the organometallic
coupling partner.[8] In recent years, some other examples have
been discovered which differ from cross-coupling: the direct
[9]
À
activation of C H bonds (Scheme 1c), the a-arylation of
ketones,[10] esters,[11] and amides[12] (Scheme 1d), and the
[*] Prof. J. Barluenga, P. Moriel, Dr. C. ValdØs, Prof. F. Aznar
Instituto Universitario de Química Organometµlica “Enrique
Moles”
Unidad Asociada al CSIC
Universidad de Oviedo
Juliµn Clavería 8, 33071 Oviedo (Spain)
Fax: (+34)985-103-450
E-mail: barluenga@uniovi.es
[**] Financial support of this work by the Fundación Ramón Areces and
the DGI, as well as an FPU predoctoral fellowship for P.M. is
gratefully acknowledged.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
Angew. Chem. Int. Ed. 2007, 46, 5587 –5590
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
5587

Communications
Table 1: Synthesis of di- and trisubstituted olefins by cross-coupling of tosylhydrazones with aryl halides.[a]
Entry
1
Hydrazone 1
Halide 2
T [8C]
t [h]
Olefin 3
Yield [%][b]
98
70
4
2
3
90
90
6
4
96
98
4
70
3
82[c]
5
6
7
8
9
110
110
110
90
15
16
16
15
5
74
90
95
78[d]
80
110
10
90
16
80[e]
11
12
90
90
4
75
68
10
13
14
90
16
17
99[f]
110
62[f,g]
15
16
90
90
17
10
52[h]
67[i]
[a] Reaction conditions: 1 (1 mmol), 2 (1 mmol), [Pd2(dba)3] (1 mol%), Xphos (2 mol%), LiOtBu (2.2 mmol), dioxane (6 mL). [b] Yields of isolated
product. [c] Yield of the combined mixture of esters. [d] A 92:8 E:Z mixture of isomers was obtained. [e] A 1:1 E:Z mixture of isomers was obtained.
[f] 2 mol% [Pd2(dba)3] and 4 mol% Xphos were employed. [g] 88% conversion. [h] 84% conversion. [i] The major regioisomer was obtained as a 78:4
E:Z mixture of isomers.
Stereochemistry is a very important issue in the synthesis
of polysubstitued olefins. In this context, a hydrazone derived
from a linear aldehyde provided exclusively the trans olefins
The reaction is general with respect to the structure of the
aryl halide. Bromides and chlorides can be employed with
similar results (Table 1, entries 1 and 2). Electron-donating
(Table 1, entries 11 and 12). In the case of trisubstituted (Table 1, entries 7, 10, 12, and 14) and electron-withdrawing
olefins, the stereochemical outcome of the reaction seems to groups (Table 1, entries 3, 4, and 8) in benzene rings are
be directed by the size of the substituents (Table 1, entries 8– tolerated in the reaction. Moreover, both p-rich (Table 1,
10).
entry 6) and p-deficient (Table 1, entry 15) heterocycles
5588
www.angewandte.org
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2007, 46, 5587 –5590

Angewandte
Chemie
participate efficiently in the coupling. Nitrile (Table 1, through a Pd–carbene complex.[23] In this reaction pathway,
entry 3) and carbonyl groups (Table 1, entry 8) are also the stereochemistry of the final olefin would be determined
compatible with the transformation. Furthermore, when the
reaction was performed in the presence of a methyl ester, the
coupling reaction proceeded with very high yield, although a
mixture of the expected product and the transesterified tert-
butyl ester was obtained (Table 1, entry 4).
by the syn b-hydrogen elimination step of complex VI. Thus,
in the transition state for the formation of 1,2-disubstituted
olefins and trisubstituted olefins, the R group would be
eclipsed with the smaller substituent of the vicinal carbon
atom to minimize the steric interactions (Scheme 4). This is
Finally, the reaction with the hydrazone prepared from 4-
phenyl-2-butanone showed
a promising regioselectivity
(Table 1, entry 16): an 82:18 mixture of the trisubstituted
olefin (as a 78:4 mixture of the E and Z isomers) and the
terminal disubstituted olefin was obtained. Further tuning of
the reaction conditions might lead to higher regioselectivities.
It is well known that N-tosylhydrazones in the presence of
alkoxides undergo base-mediated decomposition through the
Bamford–Stevens[17] reaction to generate diazocompounds,
which evolve to produce metal carbenes in the presence of a
transition metal.[18] Thus, it seems reasonable that the trans-
formation presented herein should proceed through the
formation of a transient palladium carbene complex, gener-
ated from the tosylhydrazone.
Scheme 4. The syn b-hydrogen elimination that determines the stereo-
chemistry of the olefins.
indeed the general trend, as hydrazones derived from non-
branched aldehydes provide trans olefins (Table 1, entries 11
and 12), and trisubstituted olefins feature the bulky groups
also in a trans arrangement (Table 1, entries 8 and 9). As
shown by the example in entry 10, when the substituents RS
and RL have similar sizes, a 1:1 mixture of isomers is obtained.
In summary, we have reported a new type of Pd-catalyzed
cross-coupling reaction that employs N-tosylhydrazones as
nucleophilic coupling partners. The main features of this new
methodology are: 1) stoichiometric organometallic reagents
are not required for the coupling reaction; 2) di- and
trisubstituted olefins can be prepared with high stereoselec-
tivity in most cases and with very high functional-group
tolerance; 3) in view of the simple transformation of carbonyl
compounds into tosylhydrazones, this methodology repre-
sents a very simple way to convert aldehydes and ketones into
reagents for Pd-catalyzed cross-coupling reactions; 4) from a
mechanistic point of view, the reaction most likely proceeds
through a Pd–carbene complex in a process that has not yet
been widely exploited, but has great promise, in Pd-catalyzed
cross-coupling reactions. For these reasons, we think that this
reaction will find wide application in target-oriented organic
synthesis. Future work will include detailed mechanistic
investigations, extension of this concept to other transition
metals, optimization of the reaction conditions to achieve
high regio- and stereoselectivities, and extension of the
coupling reaction to other types of halides (vinyl, alkyl) and
pseudohalides.
A plausible catalytic cycle for this coupling reaction might
start with the oxidative addition of the aryl halide to the Pd0
catalyst I to give aryl palladium complex IV (Scheme 3).
Scheme 3. Proposed mechanism for the Pd-catalyzed cross-coupling of
N-tosylhydrazones.
Received: April 24, 2007
Published online: June 19, 2007
Then, reaction of the diazocompound III (generated by the
base-mediated decomposition of the tosylhydrazone II) with
aryl palladium complex IV would produce Pd carbene
complex V.[19] The unstable aryl palladium carbene complex
V may evolve through a migratory insertion of the aryl group
to give the alkyl palladium complex VI. Finally, b-hydrogen
elimination would provide the arylated olefin VII and
regenerate the Pd0 catalyst.
Migratory insertion reactions have been previously pro-
posed for N-heterocyclic-,[20] amino-, and methoxycarbene
palladium complexes.[21,22] Moreover, Van Vranken et al. have
reported the Pd-catalyzed insertion of diazocompounds into
benzyl and vinyl halides, in processes that most likely proceed
Keywords: Bamford–Stevens reaction · cross-coupling ·
hydrazones · olefination · palladium
.
[1] a) Handbook of Organopalladium Chemistry for Organic Syn-
thesis (Ed.: E. Negishi), Wiley, New York, 2002; b) Metal-
Catalyzed Cross-Coupling Reactions (Eds.: A. de Meijere, F.
Diederich), Wiley-VCH, Weinheim, 2004; c) J. Tsuji, Palladium
Reagents and Catalysts, Wiley, Chichester, 2004.
[2] For a recent review see: K. C. Nicolau, P. G. Bulger, D. Sarlah,
Angew. Chem. 2005, 117, 4516; Angew. Chem. Int. Ed. 2005, 44,
4442.
Angew. Chem. Int. Ed. 2007, 46, 5587 –5590
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5589

Communications
[3] a) K. Tamao, K. Sumitani, M. Kumada, J. Am. Chem. Soc. 1972,
[14] a) J. Barluenga, F. Aznar, C. Valdꢂs, Angew. Chem. 2004, 116,
347; Angew. Chem. Int. Ed. 2004, 43, 343; b) J. Barluenga, C.
Valdꢂs, G. Beltrꢃn, M. Escribano, F. Aznar, Angew. Chem. 2006,
118, 7047; Angew. Chem. Int. Ed. 2006, 45, 6893; c) J. Barluenga,
P. Moriel, F. Aznar, C. Valdꢂs, Org. Lett. 2007, 9, 275; d) J.
Barluenga, A. Jimꢂnez-Aquino, C. Valdꢂs, F. Aznar, Angew.
Chem. 2007, 119, 1551; Angew. Chem. Int. Ed. 2007, 46, 1529.
[15] Some examples of hydrazones as nucleophiles in Pd-catalyzed
94, 4374; b) R. J. P. Corriu, J. P. Masse, J. Chem. Soc. Chem.
Commun. 1972, 144; c) M. Kumada, Pure Appl. Chem. 1980, 52,
669.
[4] a) O. King, N. Okukado, E. Negishi, J. Chem. Soc. Chem.
Commun. 1977, 683; b) For a recent review see: E. Negishi, Q.
Hu, Z. Huang, M. Qian, G. Wang, Aldrichimica Acta 2005, 38,
71.
[5] J. K. Stille, Angew. Chem. 1986, 98, 504; Angew. Chem. Int. Ed.
Engl. 1986, 25, 508.
[6] a) T. Hiyama, Y. Hatanaka, Pure Appl. Chem. 1994, 66, 1471;
b) For a review see: S. E. Denmark, M. H. Ober, Aldrichimica
Acta 2003, 36, 75.
[7] a) N. Miyaura, A. Suzuki, Chem. Rev. 1995, 95, 2457; b) G. A.
Molander, R. Figueroa, Aldrichimica Acta 2005, 38, 49.
[8] For some recent reviews see: a) M. Beller, A. Zapf, T. H.
Riermeier in Transition Metals for Organic Synthesis, 2nd ed.,
Vol. 1 (Eds.: M. Beller, C. Bohm), Wiley-VCH, Weinheim, 2004,
pp. 271 – 305; b) S. Braese, A. de Meijere in Metal-Catalyzed
Cross-Coupling Reactions, 2nd ed., Vol. 1 (Eds.: A. de Meijere,
F. Diederich), Wiley-VCH, Weinheim, 2004, pp. 217 – 315.
[9] For a recent account see: K. Godula, D. Sames, Science 2006,
312, 67.
À
C N bond-forming reactions: a) S. Wagaw, B. H. Yang, S. L.
Buchwald, J. Am. Chem. Soc. 1998, 120, 6621; b) K. Inamoto, M.
Katsuno, T. Yoshino, I. Suzuki, K. Hiroya, T. Sakamoto, Chem.
Lett. 2004, 1026.
À
[16] The use of hydrazones in a Pd-catalyzed C C bond-forming
reaction: A. Takemiya, J. F. Hartwig, J. Am. Chem. Soc. 2006,
128, 14800.
[17] W. R. Bamford, T. S. Stevens, J. Chem. Soc. 1952, 4735.
[18] For a recent review see: J. R. Fulton, V. K. Aggarwal, J.
de Vicente, Eur. J. Org. Chem. 2005, 1479.
[19] Pd–carbene complex V might also be formed directly from the
tosylhydrazone salt, as suggested by one of the referees,
following the pathway in Equation (1).
[10] a) T. Hamada, A. Chieffi, J. ꢀhman, S. L. Buchwald, J. Am.
Chem. Soc. 2002, 124, 1261; b) M. Kawatsura, J. F. Hartwig, J.
Am. Chem. Soc. 1999, 121, 1473; c) T. Satoh, Y. Kawamura, M.
Miura, M. Nomura, Angew. Chem. 1997, 109, 1820; Angew.
Chem. Int. Ed. Engl. 1997, 36, 1740, and references therein.
[11] X. Liu, J. F. Hartwig, J. Am. Chem. Soc. 2004, 126, 5182.
[12] T. Hama, D. A. Culkin, J. F. Hartwig, J. Am. Chem. Soc. 2006,
128, 4976, and references therein.
[13] a) L. J. Goossen, G. Deng, L. M. Levy, Science 2006, 313, 662;
b) L. J. Goossen, N. Rodrꢁguez, B. Melzer, C. Linder, G. Deng,
L. M. Levy, J. Am. Chem. Soc. 2007, 129, 4824; c) P. Forgione,
M.-C. Brochu, M. St-Onge, K. H. Thesen, M. D. Bailey, F.
Bilodeau, J. Am. Chem. Soc. 2006, 128, 11350; d) O. Baudoin,
Angew. Chem. 2007, 119, 1395; Angew. Chem. Int. Ed. 2007, 46,
1373; e) J.-M. Becht, C. Catala, C. Le Drian, A. Wagner, Org.
Lett. 2007, 9, 1781.
[20] A. A. Danopoulos, N. Tsoureas, J. C. Green, M. B. Hursthouse,
Chem. Commun. 2003, 756.
[21] A. C. Albꢂniz, P. Espinet, R. Manrique, A. Pꢂrez-Mateo, Chem.
Eur. J. 2005, 11, 1565.
[22] M. P. Lꢄpez-Alberca, M. J. Mancheꢅo, I. Fernꢃndez, M. Gꢄmez-
Gallego, M. A. Sierra, R. Torres, Org. Lett. 2007, 9, 1757.
[23] a) K. L. Greenman, D. L. Van Vranken, Tetrahedron 2005, 61,
6438; b) S. K. J. Devine, D. L. Van Vranken, Org. Lett. 2007, 9,
2407.
5590
www.angewandte.org
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2007, 46, 5587 –5590