Synthesis of enol ethers and enamines by Pd-catalyzed tosylhydrazide- promoted cross-coupling reactions

Article abstract of DOI:10.1002/chem.200902718

"Chemical Equation Presented" α-Substitution is fine: α-Alkoxycarbonyl and α-aminocarbonyl compounds are good substrates for the recently developed tosylhydrazide-promoted Pd-catalyzed cross-coupling of carbonyls with aryl halides. The reac-tion gives ris

Full text of DOI:10.1002/chem.200902718

COMMUNICATION
DOI: 10.1002/chem.200902718
Synthesis of Enol Ethers and Enamines by Pd-Catalyzed Tosylhydrazide-
Promoted Cross-Coupling Reactions
Josꢀ Barluenga,* Marꢁa Escribano, Patricia Moriel, Fernando Aznar, and
Carlos Valdꢀs*[a]
Pd-catalyzed cross-coupling reactions are very powerful
[1]
À
methodologies for the creation of C C bonds. While most
of these methodologies rely on the combination of an organ-
ic halide with an organometallic reagent, great efforts have
been devoted in the recent years towards the development
À
of C C bond-forming processes that do not employ stoichio-
metric organometallic reagents.[2–5] In this context, we have
À
recently described a new Pd-catalyzed C C bond-forming
reaction between aryl halides and tosylhydrazones.[6,7] This
process gives rise to substituted olefins and can be regarded
as a very efficient method for employing carbonyl com-
pounds as nucleophilic partners in cross-coupling reactions
Scheme 2. Pd-catalyzed cross-coupling reactions of a-functionalized car-
bonyls, which are mediated by tosylhydrazide. dba=trans,trans-dibenzyli-
deneacetone, XPhos=2-dicyclohexylphoshino-2’,4’,6’-triisopropylbiphen-
yl.
(Scheme 1).
prototype to develop proper reaction conditions. After some
experimentation, we observed that the coupling could be
best accomplished by employing 0.5% mol of [Pd2ACHTUNGTRENNUNG(dba)3],
Xphos as the supporting ligand for Pd, two equivalents of
LiOtBu as base, and dioxane as solvent at 908C. Under
these conditions, the enol ether 3a was obtained as a 1:1
mixture of Z/E diastereoisomers in very high yield. Like in
our previous work, we observed that the tosylhydrazone can
be generated in situ from the carbonyl compound 1 and to-
sylhydrazide. Thus, stirring the a-methoxy ketone 1 with to-
sylhydrazide for 2 h in dioxane at 708C, followed by the ad-
dition of the rest of the reagents at 908C, provided the cou-
pling product in good yield (Table 1, entry 1).
These methodologies were applied to a variety of aryl
bromides and chlorides, giving rise to the corresponding
enol ethers and enamines with very high yields in most of
the cases (Scheme 2, Table 1). As expected, reactions of de-
rivatives containing bromo and chloro substituents give rise
exclusively to the substitution of the more reactive bromide
(Table 1, entries 5 and 6), and the reaction with 1,2-dibro-
mobenzene provides exclusively the o-bromo-substituted
enol ether (Table 1, entry 4). The coupling process is com-
patible with a variety of substituents at the ortho position,
including some bulky substituents. We focused on the intro-
duction of nitrogenated functionalities at the ortho position
Scheme 1. Pd-catalyzed cross-coupling reactions of carbonyls, which are
mediated by tosylhydrazide.
We have initiated a research program to explore the syn-
thetic usefulness of this reaction in different chemical sce-
narios. In this context, we have investigated the reactions of
a-functionalized ketones and aldehydes, with the aim of syn-
thesizing functionalized olefins, such as enol ethers or enam-
ines (Scheme 2). Herein, we report our results.
The reaction between tosylhydrazone 2a (R=Ph, Y=
OMe) (Scheme 2) and p-bromotoluene was selected as a
[a] Prof. J. Barluenga, M. Escribano, Dr. P. Moriel, Prof. F. Aznar,
Dr. C. Valdꢀs
Instituto Universitario de Quꢁmica Organometꢂlica “Enrique Moles”
Universidad de Oviedo, c/Juliꢂn Claverꢁa 8. Oviedo 33006 (Spain)
Fax : (+34)985103450
E-mail: barluenga@uniovi.es
acvg@uniovi.es
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200902718.
Chem. Eur. J. 2009, 15, 13291 – 13294
ꢃ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Table 1. Enol ethers and enamines prepared by the cross-couplings given in Scheme 2.[a]
À
Ar X
Entry
R
Y
T [8C]
t [h]
Pd (% mol)
Product 3
Yield
[method A/B] [%][b]
1[c]
Ph
Ph
OMe
OMe
90
90
4
4
1
1
3a
3b
99/92
99/91
2[c]
3[c]
4[c]
5[c]
Ph
Ph
Ph
OMe
OMe
OMe
90
90
90
4
4
4
1
1
1
3c
3d
3e
99/98
80/79
99/92
6[c]
p-MeO-C6H4
OMe
OMe
90
14
14
1
1
3 f
3g
99/–
–/82
7[c]
Ph
110
8[c]
Ph
OMe
OMe
110
5
4
3h
80/–
9[c]
Ph
Ph
110
90
14
14
4
1
3i
3j
84/–
88/–
10[c]
11[c]
Ph
110
14
2
3k
82/–
12[d]
H
H
OBn
OBn
90
90
3
2
4
3l
77/65
70/56
13[d]
14[d]
14
3m
H
OBn
OBn
90
14
4
4
2
3n
3o
75/69
80/70
15[d]
H
110
À
[a] Method A: Ar X, 0.5 mmol; 2, 0.5 mmol; [Pd
N
À
0.5 mmol; Ar X, 0.5 mmol; [Pd
2A
drazone; Method B: based on the starting carbonyl compound. [c] Obtained as an approximate 1:1 mixture of E/Z isomers. [d] Obtained as a 7:1 mixture
of E/Z isomers.
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Chem. Eur. J. 2009, 15, 13291 – 13294

Synthesis of Enol Ethers and Enamines
COMMUNICATION
(Table 1, entries 7–9), since they can be further cyclized to
the corresponding heterocycles by intramolecular cleavage
of the enol ether. For instance, the o-cyano-substitued enol
ether 3g, which has been previously employed in the synthe-
sis of quinolines,[8] can be efficiently synthesized from o-bro-
mobenzonitrile (Table 1, entry 7).
The same reaction was also applied to benzyloxyacetalde-
hyde (R=H, Table 1, entries 12–15). As expected, the corre-
sponding enol ethers were obtained successfully. The reac-
tions proceeded with moderate stereoselectivity, and the
trans isomer was obtained as the major diastereoisomer.
Furthermore, the coupling process was also applied to the
synthesis of enamines, by employing a-morpholino-substitut-
ed tosylhydrazone (Table 1, entries 10 and 11).
Scheme 4. The lack of selectivity in the b-hydrogen elimination step leads
to a mixture of allyl ether 5 and enol ether 6. [a] The conversion is mea-
sured based on the disappearance of the aryl halide.
As we have previously proposed, the coupling process can
be explained through the catalytic cycle depicted in
Scheme 3,[6a] which features the following main steps: i) oxi-
hexanone 4. The reaction, under the standard conditions, af-
forded a mixture of the four possible olefins, the isomeric
enol ethers 5 and the isomeric allyllic ethers 6 in a 1:1 ap-
proximate ratio (Scheme 4), which indicates that the heter-
oatom does not influence the b-hydrogen elimination step.
The enol ether functionality on compounds 3 could be hy-
drolyzed to provide the corresponding unsymmetrical a,a-
diarylacetaldehydes 7. However, aldehydes 7 are highly un-
stable and the hydrolysis requires very controlled reaction
conditions.[9] Nevertheless, treatment of enol ethers 3 with
an aqueous HCl:toluene mixture under microwave heat-
ing[10] provided the diaryl aldehydes 7 in good yields
(Table 2). These type of aldehydes are interesting synthetic
Table 2. Synthesis of a,a-diarylacetaldehydes 7 by controlled hydrolysis
of the enol ethers 3.
Scheme 3. Proposed mechanism for the Pd-catalyzed cross-coupling of a-
substituted N-tosylhydrazones with aryl halides.
Compound 7
Ar
t [min]
Yield [%][b]
80
a
1
dative addition of the aryl halide to the Pd0 catalyst I to give
the arylpalladium complex IV; ii) reaction of the diazo com-
pound III (generated in situ from the tosylhydrazone II)
with the arylpalladium complex IV to produce the Pd–car-
bene complex V; iii) migratory insertion of the aryl group to
give the alkylpalladium complex VI; iv) syn b-hydrogen
elimination on the alkylpalladium complex VI leading to
the release of the arylated olefin VII and the regeneration
of the Pd0 catalyst.
In the examples presented so far, based on aldehydes or
arylketones, only one regioisomer can be formed from the
alkylpalladium complex VI (Scheme 4a). However, if the
starting ketone features hydrogen atoms at both a-carbon
atoms, two different regioisomers could be generated by b-
hydrogen elimination from the alkylpalladium complex VIII
(Scheme 4b). As we wanted to investigate whether the pres-
ence of the heteroatom exerts any influence on the b-hydro-
gen elimination, we studied the reaction of 1-methoxy-2-
b
c
1
1
90
(99)[c] 74
d
e
f
3
3
3
5
(92)[c] 89
(97)[c] 85
(90)[c] 58
63
g
[a] Reaction conditions for the hydrolysis step: Enol ether 3, 0.2 mmol;
water, 0.25 mL, conc. HCl, 0.25 mL; toluene 1 mL. MW, 1808C.
[b] Overall yield for the two steps. [c] Yield for the first step, not de-
scribed in Table 1, is indicated in parentheses.
Chem. Eur. J. 2009, 15, 13291 – 13294
ꢃ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
13293

J. Barluenga, C. Valdꢀs et al.
intermediates, which have been employed in the preparation
of biologically active heterocyclic systems.[11] However, their
synthesis by other methodologies is not straightforward and
requires multistep sequences.
Finally, as a further application of the masked enol ether
functionality we carried out the coupling reaction of 2-me-
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(Ed.: E. Negishi), Wiley, New York, 2002; b) Metal-Catalyzed Cross-
Coupling Reactions (Eds.: A. de Meijere, F. Diederich,), Wiley-
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Wiley, New York, 2004.
À
[2] For some reviews on metal-catalyzed C H arylations: a) D. Alberi-
co, M. E. Scott, M. Lautens, Chem. Rev. 2007, 107, 174; b) F. Kakiu-
chi, T. Kochi, Synthesis 2008, 3013; c) I. V. Seregin, V. Gevorgyan,
Chem. Soc. Rev. 2007, 36, 1173.
thoxyacetophenone
with
o-bromo-N-methylaniline
(Scheme 5). The coupling reaction proceeded nicely even in
[3] Carbonyl a-arylations: a) J. M. Fox, X. Huang, A. Chieffi, S. L.
Buchwald, J. Am. Chem. Soc. 2000, 122, 1360; b) M. Kawatsura, J. F.
Hartwig, J. Am. Chem. Soc. 1999, 121, 1473; c) R. M. Martꢁn, S. L.
Buchwald, Angew. Chem. 2007, 119, 7374; Angew. Chem. Int. Ed.
2007, 46, 7236; d) G. D. Vo, J. F. Hartwig, Angew. Chem. 2008, 120,
2157; Angew. Chem. Int. Ed. 2008, 47, 2127, and references therein.
[4] Decarboxylative couplings: L. J. Goossen, N. Rodrꢁguez, B. Melzer,
C. Linder, G. Deng, L. M. Levy, J. Am. Chem. Soc. 2007, 129, 4824.
[5] Carbonyl acylation: J. Ruan, O. Saidi, J. A. Iggo, J. Xiao, J. Am.
Chem. Soc. 2008, 130, 10510.
Scheme 5. Synthesis of a 1,3-disubstituted indole by a coupling-intramo-
lecular cyclization sequence.
[6] a) J. Barluenga, P. Moriel, C. Valdꢀs; F. Aznar, Angew. Chem. 2007,
119, 5683; F. Aznar, Angew. Chem. 2007, 119, 5683; Angew. Chem.
Int. Ed. 2007, 46, 5587; b) J. Barluenga, M. Tomꢂs-Gamasa, P.
Moriel, F. Aznar, C. Valdꢀs, Chem. Eur. J. 2008, 14, 4792.
[7] For related Pd-catalyzed processes based on diazo compounds see:
a) K. L. Greenman, D. S. Carter, D. L. Van Vranken, Tetrahedron
2001, 57, 5219; b) K. L. Greenman, D. L. Van Vranken, Tetrahedron
2005, 61, 6438; c) S. K. J. Devine, D. L. Van Vranken, Org. Lett.
2007, 9, 2047; d) R. Kudirka, S. K. J. Devine, C. S. Adams, D. L.
VanVranken, Angew. Chem. 2009, 121, 3731; Angew. Chem. Int. Ed.
2009, 48, 3677; e) C. Peng, Y. Wang, J. Wang, J. Am. Chem. Soc.
2008, 130, 1566; f) Q. Xiao, J. Ma, Y. Yang, Y. Zhang, J. Wang, Org.
Lett. 2009, 11, 4732.
À
À
the presence of the free N H group, showing that the C C
bond-forming reaction is preferred over a Pd-catalyzed aryl
amination. Then, treatment of the crude reaction product
under the hydrolytic conditions afforded indole 8 in an over-
all yield of 94%.
In summary, we have reported a new methodology for the
preparation of enamines and enol ethers by Pd-catalyzed to-
sylhydrazide-promoted cross-coupling of a-functionalized
carbonyls with aryl halides. The resulting compounds, which
are not readily available by other methodologies, are useful
intermediates in heterocyclic synthesis. Moreover, hydrolysis
of the enol ethers leads to diarylacetaldehydes.
[8] a) K. Kobayashi, T. Shiokawa, O. Morikawa, H. Konishi, Chem.
Lett. 2004, 33, 236; b) K. Kobayashi, K. Hayashi, K. Miyamoto, O.
Morikawa, H. Konishi, Synthesis 2006, 2934.
[9] M. Tokunaga, Y. Shirogane, H. Aoyama, Y. Obora, Y. Tsuji, J. Orga-
nomet. Chem. 2005, 690, 5378.
[10] P. Nilsson, M. Larhed, A. Hallberg, J. Am. Chem. Soc. 2001, 123,
8217.
Acknowledgements
[11] a) T. Miki, M. Kori, A. Fujishima, H. Mabuchi, R-i. Tozawa, M. Na-
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Financial support of this work by the DGI of Spain (CTQ2007-61048/
BQU) and Consejerꢁa de Educaciꢄn y Ciencia of Principado de Asturias
(IB08-088) FPU predoctoral fellowships to M.E. and P.M. are gratefully
acknowledged.
Keywords: cross-coupling
hydrazones · palladium
· enamines · enol ethers ·
Received: October 2, 2009
Published online: November 24, 2009
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Chem. Eur. J. 2009, 15, 13291 – 13294