Tosylhydrazide-promoted palladium-catalyzed reaction of β-aminoketones with o-dihaloarenes: Combining organocatalysis and transition-metal catalysis

Article abstract of DOI:10.1002/anie.201006996

(Chemical Equation Presented) Working in tandem: Mannich adducts obtained by organocatalyzed processes are readily transformed into phenanthridine and quinoline derivatives by a Pd-catalyzed cascade reaction involving tosylhydrazide (TsNHNH₂)-promoted cross-coupling followed by intramolecular amination (see scheme; MW=microwave). The enantioselectivity achieved in the organocatalytic reaction is maintained throughout the process.

Full text of DOI:10.1002/anie.201006996

Communications
DOI: 10.1002/anie.201006996
Tandem Catalysis
Tosylhydrazide-Promoted Palladium-Catalyzed Reaction of
b-Aminoketones with o-Dihaloarenes: Combining Organocatalysis and
Transition-Metal Catalysis**
Josꢀ Barluenga,* Noelia Quiꢁones, Marꢂa-Paz Cabal, Fernando Aznar, and Carlos Valdꢀs*
One of the main challenges of current organic synthesis is the
design of practically simple and increasingly efficient organic
transformations. The sequential formation of various bonds
through tandem or cascade reactions constitutes one
approach to achieving this goal. In these types of reactions,
high molecular complexity can be built from relatively simple
starting materials in a single synthetic operation.[1] Moreover,
among the advantages of these processes are atom, solvent,
and catalyst economy and operational simplicity, as isolation
of intermediates is avoided.
In the context of transition-metal-catalyzed reactions,
processes in which a single, multifunctional metal catalyst
promotes various individual reactions (auto-tandem cataly-
sis)[2] are of great interest. By taking advantage of the wide
scope, high performance, and remarkable stability of state-of-
the-art Pd catalysts, a variety of Pd-catalyzed processes have
been developed based on this principle.[3]
Following our interest in auto-tandem Pd-catalyzed
processes,[3b,c] we decided to investigate whether the new C
À
C bond-forming reaction with tosylhydrazones could be one
of the processes promoted by a multifunctional catalyst.
Following this idea, we designed a possible sequence employ-
ing hydrazones derived from b-aminoketones I and o-
dihalobenzene derivatives II as starting materials. Thus, in
the presence of the Pd catalyst two consecutive processes
À
might occur: a C C cross-coupling reaction (arylation) to give
À
intermediate III, followed by an intramolecular C N bond-
forming reaction (amination)[6] affording substituted tetrahy-
droquinolines IV (Scheme 2). Moreover, taking into account
that a variety of b-aminoketones are accessible in enantio-
merically pure form through asymmetric organocatalyzed
Mannich reactions,[7] our ultimate goal would be to develop a
heterocyclization process that would preserve the configura-
tionally unstable stereogenic center in the a position to the
carbonyl group.[8]
À
We have recently discovered a new Pd-catalyzed C C
bond-forming reaction that employs N-tosylhydrazones as
nucleophilic component in a new type of “stoichiometric
organometallic-free” cross-coupling process.[4] Moreover, the
tosylhydrazone can be generated in situ from a carbonyl
compound and tosylhydrazide, which implies that the car-
bonyl compounds can be directly employed in the cross-
coupling reaction (Scheme 1).[5]
À
À
Scheme 2. Proposed C C/C N cascade reaction.
Scheme 1. Synthesis of polysubstituted alkenes by Pd-catalyzed tosyl-
hydrazide (TsNHNH2)-promoted cross-coupling reaction. Xphos=2-
dicyclohexylphosphino-2’,4’,6’-triisopropylbiphenyl.
We started our study with the model reaction between the
hydrazone 2a, derived from aminoketone 1a, and 1-bromo-2-
chlorobenzene (3a, Scheme 3). The initial experiments were
conducted under standard conditions for the arylation
reaction, but in the presence of an excess of base to also
promote the intramolecular amination, which gave rise to
promising results. The desired tetrahydrophenanthridine 4a
was formed together with significant amounts of cyclohexene
5, which was generated by uncatalyzed thermal degradation
of the hydrazone, and arylated cyclohexene 6, which was
formed by dehalogenation of the intermediate arylated
product.
[*] Prof. J. Barluenga, N. Quiꢀones, Dr. M. P. Cabal, Prof. F. Aznar,
Dr. C. Valdꢁs
Instituto Universitario de Quꢂmica Organometꢃlica “Enrique
Moles”, Universidad de Oviedo
c/Juliꢃn Claverꢂa 8, 33006 Oviedo (Spain)
Fax: (+34)98-510-3446
E-mail: barluenga@uniovi.es
acvg@uniovi.es
[**] This work was financially supported by the DGI of Spain (CTQ2007-
61048/BQU) and the Consejerꢂa de Educaciꢄn y Ciencia of
Principado de Asturias (IB08-088). A FICYT predoctoral fellowship
to N.Q. is gratefully acknowledged.
These results prompted us to carry out a very exhaustive
study of both steps of the cascade reaction to find the optimal
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201006996.
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Angew. Chem. Int. Ed. 2011, 50, 2350 –2353

source for this transformation. Again, very fine tuning of
the reaction conditions was required. After extensive exper-
imentation on the model reaction of Scheme 3, a very
convenient protocol was identified for the cascade process.
Thus, upon treating the mixture of hydrazone 2a (0.27 mmol)
and o-bromochlorobenzene (0.25 equiv) in dioxane (1.5 mL)
in the presence of H2O (10 mL), [Pd2(dba)3] (4 mol%), Xphos
(16 mol%), and LiOtBu (4 equiv) at 1508C for 30 min, the
phenanthridine 4a was obtained in a 67% yield upon
isolation (Table 2, entry 1, method A). Some points regarding
À
À
À
À
Table 2: Microwave (MW)-promoted Pd-catalyzed C C/C N cascade
Scheme 3. Preliminary results for the C C/C N cascade reaction.
PMP=p-methoxyphenyl, dba=dibenzylidene acetone.
reaction.[a]
conditions for the formation of 4a. No improvement was
found by changing either the ligand or the base. However, it
was observed that the presence of an excess of base in the
arylation step increased the amount of undesired cyclohexene
5. To avoid the uncatalyzed decomposition of 2a, a one-pot
two-step sequence was devised. Moreover, it was found that
the employment of a Pd0/Xphos preformed catalyst, as
recently reported by Buchwald et al.,[9] allowed a slight
reduction of the catalyst loading. Thus, the best conditions
found for the formation of the phenanthridine comprised two
operations in a one-pot fashion: 1) treatment of the amino-
Entry
Product
Yield [%][b]
1
2
3
4
4a (R=MeO)
4b (R=Me)
4c (R=H)
67 (70)
76 (73)
60
hydrazone
2 and o-bromochlorobenzene with LiOtBu
(1.1 equiv) and the Pd0/Xphos catalyst (8 mol%) in dioxane
at 1108C; and 2) once the arylation is complete (GC–MS
4d (R=Me2N)
76 (75)
monitoring), addition of
a second portion of LiOtBu
(2.4 equiv). These conditions were applied to a set of cyclic
b-aminohydrazones 2 leading to the corresponding tricyclic
compounds 4 with moderate yields (Table 1). It must be
pointed out that the time required for the arylation step
before the addition of the second potion of the base had to be
optimized independently for each particular reaction.
5
4e
52
These moderately successful results prompted us to
investigate microwave heating as an alternative energy
6
4 f
4g
4h
4i
72 (61)
41
Table 1: Synthesis of phenanthridines by a one-pot reaction.[a]
7
8
55
9
77
Substrate
X
R
t [min]
Yield [%][b]
2a
2b
2c
2d
2e
2 f
CH2
CH2
CH2
CH2
(CH2)2
O
4-MeOC6H4
4-tol
Ph
4-Me2NC6H4
4-MeOC6H4
4-MeOC6H4
75
75
150
120
120
75
65
47
48
44
37
30
10
11
4j
41
[a] Reaction conditions: 2, 0.55 mmol; 3a, 0.5 mmol; [Pd(Xphos)],
8 mol%; dioxane, 2 mL; 1108C. [b] Yield of isolated compounds 4.
[c] The catalyst is prepared as described in Ref. [9].
4k
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Communications
Table 2: (Continued)
different types of cyclic ketones, including 4-substituted
cyclohexanones, cycloheptanone, and heterocyclic derivatives
of 4-piperidone, dihydro-2H-pyran-4-one, and dihydro-2H-
thiopyran-4-one. Finally, the reaction could also be carried
out with b-branched systems (4p, 4q).[10] Of note, the
diastereomeric ratio was not altered in the reaction.[11]
Furthermore, we investigated whether it might be possible
to carry out the coupling reaction starting directly from the
ketone 1, and generate the hydrazone 2 in situ, in a
multicomponent fashion under microwave conditions. To
our delight, after a new optimization process, a microwave-
promoted sequence hydrazone formation (30 min, 468C) and
Pd-catalyzed auto-tandem reaction (2 h, 1508C) allowed the
preparation of the tricyclic systems 4 directly from the
Mannich adducts 1 in yields comparable to those of the
two-step process (Table 2, method B).
The Mannich adducts 1, which are the starting materials
for the cascade reaction, can be synthesized in enantiomer-
ically enriched form by l-proline a-aminomethylation of
ketones either by classical heating[12] or by microwave
activation.[13] However, these adducts are configurationally
unstable, and usually have to be isolated after reduction of the
carbonyl compound. Since the arylation of tosylhydrazones
derived from a-chiral ketones proceeds with preservation of
the a chirality,[8] we decided to pursue a combined organo-
catalysis/Pd catalysis sequence to prepare the enantiomeri-
cally enriched phenanthridines 4.
It was soon discovered that dimethyl sulfoxide (DMSO),
the solvent required to achieve the enantioselective Mannich
reaction, was not appropriate for the formation of the
hydrazone. Nevertheless, the hydrazones could be obtained
in fairly good yields upon aqueous workup and extraction
with ether, by direct treatment of the ethereal organic layer
with tosylhydrazide.[14] When the methodology mentioned
above for the Pd-catalyzed cascade reaction was applied to
the enantiomerically enriched hydrazones, the tetrahydro-
phenanthridines 4 were obtained with high enantiomeric
excess (ee; Scheme 4). Very importantly, in spite of the known
configurational instability of the stereogenic center of the
Entry
Product
Yield [%][b]
90 (60)
12
4l
13
4m
41
14
15
4n
4o
71 (40)
35 (20)
16
17
4p (R=H)
4q (R=Me)
77 (40)
55
[a] Method A: hydrazone 2, 0.27 mmol, 1.1 equiv; bromochloroarene,
0.25 mmol, 1 equiv; method B: Mannich adduct 1, 0.27 mmol,
1.1 equiv; tosylhydrazide, 0.27 mmol, bromochloroarene, 0.25 mmol,
1 equiv. [b] Yield of isolated product for method A; the yield for method B
is indicated in parentheses. Bn=benzyl, Boc=tert-butoxycarbonyl.
the optimized reaction conditions are worth noting. 1) The
concentration of the reagents and the amount of H2O added
are crucial for the success of the reaction. A variation in the
amount of water added (500, 100, 60, 40, and 5 mL) leads to an
increase in the elimination product 5. 2) The use of the
preactivated Pd0/Xphos catalyst is no longer necessary, and in
fact is detrimental to the yield of the reaction. 3) The total
reaction times are remarkably reduced. 4) The LiOtBu is
added in one portion at the beginning of the reaction. This is
an important advantage when compared with the conven-
tionally heated one-pot reaction. Therefore, the microwave-
heated process can be considered a real cascade reaction.
These reaction conditions (Table 2, method A) were
applied to an expanded set of systems by variation of the
substituents of the amine (4a–d), the cyclic ketone skeleton
(4e–k), and the ortho-dihalogenated aromatic system (4l–o).
Regarding the substitution at the nitrogen atom, the
cascade reaction proceeds efficiently with neutral or electron-
rich aromatic substituents (Table 2, entries 1, 2, and 4);
however, with electron-withdrawing substitution, the cycliza-
tion reaction failed and the intermediate arylation product
was obtained (not shown in Table 2). The reaction can be
applied to diverse 1-bromo-2-chlorobenzene derivatives
bearing electron-donating groups (Table 2, entries 12 and
13), electron-withdrawing groups (Table 2, entry 14), and
even with an aromatic heterocycle (Table 2, entry 15). The
reaction proceeds efficiently with hydrazones derived from
Scheme 4. Synthesis of enantiomerically enriched tetrahydrophenan-
À
À
thridines 4 through an organocatalyzed/Pd-catalyzed C C/C N
sequence. [a] Compounds 1 are not isolated and the ethereal extracts
are directly treated with tosylhydrazide.
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Mannich adducts,[14] no decrease in enantioselectivity was
observed during the whole sequence consisting of formation
of the hydrazone and the Pd-catalyzed reaction.
[1] L. F. Tietze, G. Brasche, K. Gericke, Domino Reactions in
Organic Synthesis, Wiley-VCH, Weinheim, 2006, p. 672.
[2] a) D. E. Fogg, E. N. dos Santos, Coord. Chem. Rev. 2004, 248,
2365; b) N. Shindoh, Y. Takemoto, K. Takasu, Chem. Eur. J.
2009, 15, 12168.
This reaction was also extended to Mannich adducts 7[7b]
derived from acyclic ketones to afford tetrahydroquinoline
derivatives 9 (Scheme 5). As in the cases discussed before, the
[3] For relevant examples of auto-tandem Pd-catalyzed processes,
see: a) M. C. Willis, G. N. Brace, I. P. Holmes, Angew. Chem.
2005, 117, 407; Angew. Chem. Int. Ed. 2005, 44, 403; b) J.
Barluenga, M. A. Fernꢀndez, F. Aznar, C. Valdꢁs, Chem. Eur. J.
2005, 11, 2276; c) J. Barluenga, A. Jimꢁnez-Aquino, C. Valdꢁs, F.
Aznar, Angew. Chem. 2007, 119, 1551; Angew. Chem. Int. Ed.
2007, 46, 1529; d) L. Ackermann, A. Althammer, Angew. Chem.
2007, 119, 1652; Angew. Chem. Int. Ed. 2007, 46, 1627; e) C.
Meyers, G. Rombouts, K. T. J. Loones, A. Coelho, B. U. W.
Maes, Adv. Synth. Catal. 2008, 350, 353; f) Y.-Q. Fang, M.
Lautens, J. Org. Chem. 2008, 73, 538; g) C. S. Bryan, J. A.
Braunger, M. Lautens, Angew. Chem. 2009, 121, 7198; Angew.
Chem. Int. Ed. 2009, 48, 7064; h) C. S. Bryan, M. Lautens, Org.
Lett. 2010, 12, 2754; i) T.-P. Liu, C.-H. Xing, Q.-S. Hu, Angew.
Chem. 2010, 122, 2971; Angew. Chem. Int. Ed. 2010, 49, 2909, and
references therein.
[4] J. Barluenga, P. Moriel, C. Valdꢁs, F. Aznar, Angew. Chem. 2007,
119, 5683; Angew. Chem. Int. Ed. 2007, 46, 5587.
[5] J. Barluenga, M. Tomꢀs-Gamasa, P. Moriel, F. Aznar, C. Valdꢁs,
Chem. Eur. J. 2008, 14, 4792.
Scheme 5. Synthesis of quinoline derivatives 9. [a] Yield of isolated
product for the mixture of diastereoisomers. [b] Yields for method B
are indicated in parentheses.
À
[6] In previous contributions it has been observed that the C C
bond-forming reaction occurs preferentially over a Pd-catalyzed
amination with secondary amines (Ref. [5]).
tosylhydrazone derivatives 8 were successfully isolated from
the reaction using ether as solvent, and then subjected to the
Pd catalysis conditions to afford the isoquinoline derivatives 9
in good yields. Interestingly, the formation of derivatives 9
takes place more easily than the formation of the tetrahy-
drophenanthridines 4: the reactions require shorter times to
reach complete conversion, and tolerate the presence of
electron-withdrawing substituents on the nitrogen atom (9d).
Moreover, the integrity of the stereogenic centers is again
retained, as the quinoline derivatives 9 are obtained in the
reaction crude in the same diastereomeric ratio as the starting
hydrazones 8.[15]
[7] a) B. List, J. Am. Chem. Soc. 2000, 122, 9336; b) B. List, P.
Porjaliev, W. T. Biller, H. J. Martin, J. Am. Chem. Soc. 2002, 124,
827; c) A. Cꢂrdova, W. Notz, G. Zhong, J. M. Betancort, C. F.
Barbas III, J. Am. Chem. Soc. 2002, 124, 1842; d) N. S. Chowdari,
D. B. Ramachary, C. F. Barbas III, Synlett 2003, 1906; e) H.
Zhang, M. Mifsud, F. Tanaka, C. F. Barbas III, J. Am. Chem. Soc.
2006, 128, 9630; f) I. Ibrahem, W. Zou, J. Casas, H. Sudꢁn, A.
Cꢂrdova, Tetrahedron 2006, 62, 357; g) L. Cheng, X. Han, H.
Huang, M. W. Wong, Y. Lu, Chem. Commun. 2007, 4143; h) H.
Zhang, S. S. V. Ramasastry, F. Tanaka, C. F. Barbas III, Adv.
Synth. Catal. 2008, 350, 791; i) Y. Hayashi, T. Urushima, S.
Aratake, T. Okano, K. Obi, Org. Lett. 2008, 10, 21; j) M.
Pouliquen, J. Blanchet, M.-C. Lasne, J. Rouden, Org. Lett. 2008,
10, 1029.
[8] We have recently reported that the cross-coupling reaction of
tosylhydrazones derived from a-chiral ketones proceeds with
preservation of the chirality: J. Barluenga, M. Escribano, F.
Aznar, C. Valdꢁs, Angew. Chem. 2010, 122, 7008; Angew. Chem.
Int. Ed. 2010, 49, 6856.
[9] B. P. Fors, P. Krattiger, E. Strieter, S. L. Buchwald, Org. Lett.
2008, 10, 3505.
[10] Q.-X. Guo, H. Liu, S. Luo, Y. Gu, L. Z. Gong, J. Am. Chem. Soc.
2007, 129, 3790.
[11] Although the Mannich reaction gives rise to a mixture of two
diastereomers, they could be separated at the tosylhydrazone
stage, and thus the Pd-catalyzed cascade reaction was carried out
with a single diastereoisomer.
[12] I. Ibrahem, J. Casas, A. Cꢂrdova, Angew. Chem. 2004, 116, 6690;
Angew. Chem. Int. Ed. 2004, 43, 6528.
[13] B. Rodrꢃguez, C. Bolm, J. Org. Chem. 2006, 71, 2888.
[14] In our hands, attempts to isolate the Mannich adducts prior to
formation of the hydrazone led to partial epimerization.
[15] The Mannich reaction leads to a mixture of diastereoisomers
that could not be separated, and therefore were employed as a
mixture in the Pd-catalyzed cascade reaction.
In summary, we have developed a new Pd-catalyzed
process which consists in the cross-coupling of the tosylhy-
drazone of a Mannich adduct with a 1,2-dihalogenated
À
aromatic system, followed by an intramolecular C N bond-
forming reaction. Notably, the same Pd catalyst promotes
both independent steps. Moreover, this is the first example in
which the Pd-catalyzed cross-coupling reaction with tosylhy-
drazones is included in an auto-tandem catalysis process,
which opens the door to the development of other appealing
cascade transformations. Finally, we have shown that the
combination of organocatalysis and the Pd-catalyzed cross-
coupling reaction of tosylhydrazones allows the ready trans-
formation of enantiomerically enriched Mannich adducts,
which are otherwise configurationally unstable.
Received: November 8, 2010
Published online: January 31, 2011
Keywords: arenes · cascade reactions · ketones · palladium ·
.
tandem catalysis
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