Synthesis of (Z)-N-alkenylazoles and pyrroloisoquinolines from α-N-azoleketones through Pd-catalyzed tosylhydrazone cross-couplings

Article abstract of DOI:10.1002/chem.201301057

Azoles reacting in tandem: The ortho-stereodirecting effect is the key to the stereoselective synthesis of (Z)-N-alkenylazoles I through the tosylhydrazide-mediated Pd-catalyzed cross-coupling reaction of α-N-azoleacetophenones with ortho-substituted aryl halides and nonaflates (see scheme). Additionally, the preorganization of the alkene allowed for the development of an auto-tandem reaction involving an intramolecular C-H arylation leading to pyrroloisoquinolines II. Copyright

Full text of DOI:10.1002/chem.201301057

COMMUNICATION
Domino Reactions
L. Florentino, F. Aznar,
C. Valdꢀs* ..................... &&&& — &&&&
Synthesis of (Z)-N-Alkenylazoles and
Pyrroloisoquinolines from a-N-Azole-
ketones through Pd-Catalyzed Tosyl-
hydrazone Cross-Couplings
Azoles reacting in tandem: The ortho-
stereodirecting effect is the key to the
stereoselective synthesis of (Z)-N-alke-
nylazoles I through the tosylhydrazide-
mediated Pd-catalyzed cross-coupling
reaction of a-N-azoleacetophenones
with ortho-substituted aryl halides and
nonaflates (see scheme). Additionally,
the preorganization of the alkene
allowed for the development of an
auto-tandem reaction involving an
À
intramolecular C H arylation leading
to pyrroloisoquinolines II.
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DOI: 10.1002/chem.201301057
Synthesis of (Z)-N-Alkenylazoles and Pyrroloisoquinolines from a-N-
Azoleketones through Pd-Catalyzed Tosylhydrazone Cross-Couplings
Lucꢀa Florentino, Fernando Aznar, and Carlos Valdꢁs*[a]
In recent years, the chemistry of tosylhydrazones has
gained increasing attention as a result of the development of
new metal-catalyzed and metal-free cross-coupling reac-
tions.[1] In particular, the Pd-catalyzed cross-coupling of to-
sylhydrazones and organic halides represents a very efficient
method to transform a carbonyl compound into the nucleo-
The Z stereoselectivity can be explained by the mechanism
proposed for the coupling process.[2a] Thus, after formation
of Pd–carbene D, migratory insertion gives alkylpalladium
complex E. Next, syn-b-hydride elimination provides the
final olefin. The last step defines the stereochemistry of the
final product. With the aid of DFT computations, it has
been determined that, to avoid steric interactions, the opti-
mal arrangement for the transition state of the syn-b-hy-
dride elimination places the R substituent on the same side
of the incipient double bond as the ortho-substituted
arene.[5a]
The stereoselective synthesis of trisubstituted olefins is a
highly interesting and challenging task that usually requires
stepwise processes to introduce the different substituents in
a sequential manner.[6] Unlike most methodologies, in the
ortho-directed cross-coupling reaction with tosylhydrazones,
no previous stereochemical restrictions are required for the
stereoselective synthesis of the alkenes. Therefore, we en-
À
philic component of a C C bond forming cross-coupling re-
action.[2] Currently, this transformation can be regarded as a
powerful method for the synthesis of polysubstituted olefins.
Moreover, these reactions have been applied in the synthe-
sis of heterocycles through one-pot and auto-tandem Pd-cat-
alyzed cascades.[3,4]
One particular feature of this Pd-catalyzed coupling reac-
tion is the stereoselective formation of Z-trisubstituted ole-
fins if ortho-substituted aromatic halides or sulfonates are
employed (Scheme 1).[5] Thus, in the synthesis of trisubstitut-
ed 1,1-diarylolefins C from hydrazones derived from a-sub-
stituted acetophenones A and ortho-substituted aromatic
electrophiles B, the substituent at C2 in C is placed cis rela-
tive to the ortho-substituted aryl group, and therefore, the
ortho substituent can be regarded as a stereodirecting group.
AHCTUNGTREGvNNNU isioned that this methodology might be useful for the prep-
aration of functionalized trisubstituted olefins not easily
available through conventional methods. In particular, we
focused on 1,1-diaryl-2-N-azoleethylenes F (Scheme 2), a
Scheme 1. Synthesis of Z-trisubstituted olefins by ortho-directed Pd-cata-
lyzed cross-coupling reactions (Ts=tosyl; DG=directing group).
Scheme 2. Stereoselective synthesis of N-alkenylazoles and auto-tandem
À
À
C C/C C reactions reported in this paper.
[a] L. Florentino, Prof. Dr. F. Aznar, Dr. C. Valdꢁs
Instituto Universitario de Quꢂmica Organometꢃlica “Enrique Moles”
Departamento de Quꢂmica Orgꢃnica e Inorgꢃnica
Universidad de Oviedo, c/Juliꢃn Claverꢂa 8. Oviedo. 33006 (Spain)
Fax : (+34) 985-103446
particularly appealing class of alkenes that might find inter-
esting applications in medicinal chemistry,[7] agrochemistry,[8]
and materials science.[9] The synthesis of N-alkenylazoles
E-mail: acvg@uniovi.es
has generally been accomplished by reaction of the corre-
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201301057.
[10]
À
sponding N H-free azoles with alkynes or carbonyl com-
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Synthesis of (Z)-N-Alkenylazoles and Pyrroloisoquinolines
COMMUNICATION
pounds,[11] under harsh conditions and without stereochemi-
cal control, or by Pd-catalyzed cross-couplings with vinyl
bromides or triflates.[12] Furthermore, the introduction of a
potentially reactive ortho-stereodirecting group might allow
for additional transformations to occur in a cascade. In par-
ticular, and continuing with our interest in auto-tandem-cat-
alyzed processes,[13,14] we wanted to explore the combination
of tosylhydrazone cross-coupling with an intramolecular
À
(1) to provide the corresponding N-alkenylazoles (4) with
high yields and Z stereoselectivities (Table 1, entries 1–9).
The reaction has been tested with a variety of azoles, includ-
ing indoles, pyrroles, and imidazoles. With regard to the di-
recting ortho substituent, alkyl, alkoxy, and chlorine sub-
stituents were able to drive the reaction to form the Z
isomer, although a drop in selectivity was observed for an
ortho-cyano substituent (Table 1, entry 6). The reaction in
C H arylation reaction that might lead to complex pyr
rolo-
the presence of a chlorine substituent is noteworthy
iso
R
N
N
(Table 1, entry 2) because it may enable further modification
of the stereodirecting substituent. As expected, further di-
versity can be incorporated by the use of acetophenones
with substituents on the aryl group (Table 1, entries 7 and
9).
Herein, we wish to report our initial progress towards these
goals.
In a preliminary experiment, we studied the coupling re-
action between tosylhydrazone 3a, obtained from a-N-in-
A
N
U
The cross-coupling reaction was then studied with aryl
bromides 5 instead of nonaflates (2). After some experimen-
tation, we found that for these systems the coupling product
could be obtained by employing the same {Pd}/Xphos cata-
lytic system, but with LiOtBu as the base and without an ad-
ditional additive. In this manner, and again in a one-pot
process from the carbonyl compounds, N-alkenylazoles 4
were obtained in very high Z stereoselectivities and good
yields in most cases. It is noteworthy that both ortho-chloro
and ortho-bromo substituents are compatible with the cou-
pling reaction, allowing for further modifications of the di-
recting group. To test the functional group tolerance of the
reaction, the coupling process was conducted with ethyl
ortho-bromobenzoate, leading to the corresponding alkene
in good yield and stereoselectivity (Table 1, entry 12).
Again, the reaction is compatible with a variety of azoles,
including indoles, pyrroles, imidazoles, indazoles, and tri-
(2a; Scheme 3). After some experimentation, we found that,
AHCTUNGTREGaNNUN zoles (Table 1, entries 10–21). Notably, the use of 2-bromo-
3-chlorothiophene as a coupling partner also led to the cor-
responding trisubstituted alkene (Table 1, entry 22), widen-
ing the scope of the method to include heterocyclic deriva-
tives.
As a result of the Z stereoselectivity of the coupling reac-
tion, the systems that feature a halogen substituent as the di-
recting group are properly preorganized to participate in a
Scheme 3. Cross-coupling between tosylhydrazone 3a and nonaflate 2a
and the one-pot reaction from 1a.
À
under reaction conditions similar to those previously report-
ed for the coupling of other classes of tosylhydrazone with
aryl nonaflates,[4,5a] the trisubstituted alkene 4a could be ob-
tained in high yield. As expected, the Z isomer was obtained
as the major isomer in very high stereoselectivity. Moreover,
the reaction could be carried out directly from carbonyl
compound 1a, without isolation of tosylhydrazone 3a. Thus,
(Z)-N-alkenyl azole 4a was obtained in high yield and very
high stereoselectivity by stirring a solution of ketone 1a
(1.5 equiv) and tosylhydrazide (1.65 equiv) in dioxane at
1108C for 6 h and then adding nonaflate 2a (1 equiv) and
Pd-catalyzed intramolecular cyclization through a C H aryl-
A
E
U
Thus, we set out to investigate this transformation in order
to develop a new auto-tandem-catalyzed process. It is worth
noting that auto-tandem Pd-catalyzed reactions involving to-
À
À
sylhydrazones have previously been included in C C/C N
cascades,[3,17] but not in the more challenging C C/C C
À
À
auto-tandem processes.[18] Furthermore, this cascade process
would lead to pyrrolo
ACHTUNGTRENUN[NG 2,1-a]isoquinoline derivatives, a het-
A
ACHTUNGTRENNUNG
products with biological activity.
all components for the coupling reaction ([Pd
(dba)3] (3%
Our initial experiments were conducted with 4b, the
indole derivative featuring a chlorine atom in the ortho posi-
tion. However, this molecule turned out to be extremely un-
reactive, and the starting material was recovered unaltered
mol) as metal source, 2-dicyclohexylphosphino-2’,4’,6’-triiso-
propylbiphenyl (Xphos; 6% mol) as ligand, LiOH as base
(3 equiv), and LiCl (3 equiv) and stirring for a further 12 h
at 1108C.
These reaction conditions were applied to a set of ortho-
substituted aryl nonaflates (2) and a-N-azoleacetophenones
when treated under several different reaction conditions
[16]
À
typical for C H arylation reactions. Therefore, we turned
our attention to the more reactive bromo-substituted deriva-
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C. Valdꢁs et al.
Table 1. Stereoselective synthesis of (Z)-N-alkenylazoles.[a]
Entry Electrophile 2, 5 Alkene 4
Z/E
Yield Entry Electrophile 2, 5 Alkene 4
Z/E
Yield
[%][b]
[%][b]
1
2
4a
4b
96:4
93
12
13
4l
84:16 76
85:15 98
4m
91:9
67
51
3
4c
85:15 82
14
4n
95:5
4[c]
4d
4e
4 f
94:6
84
15
16
17
4o
4p
4q
98:2
98:2
65
79
87
5
90:10 97
70:30 70
6
100:0
7
4g
88:12 82
85:15 76
18
4r
100:0
95
8
4h
4i
19
4s
4t
4u
80:20 55
9[c]
100:0
98:2
57
74
20[d]
100:0
100:0
46
58
10
4j
21[d]
11
4k
96:4
85
22
4v
100:0
55
[a] See the Supporting Information for experimental details. [b] Yields after column chromatography. [c] Carried out from the preformed tosylhydrazone.
[d] Carried out from the preformed tosylhydrazone under microwave heating at 1508C.
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Synthesis of (Z)-N-Alkenylazoles and Pyrroloisoquinolines
COMMUNICATION
tives. In this case, preliminary experiments starting from car-
bonyl 1a, tosylhydrazide, and 1,2-dibromobenzene, under
reaction conditions similar to those employed in Table 1, but
with an excess of the base, led to the formation of substan-
tial amounts of cyclization product 6a, together with cou-
pling product 4j, and therefore showed the feasibility of the
À
À
C C/C C auto-tandem process (Scheme 4).
Scheme 5. Indolo- and pyrrolo
Pd-catalyzed tosylhydrazone coupling/C H arylation auto-tandem pro-
cess.
ACHTUNGTRENUN[NG 2,1-a]isoquinolines 6 prepared through the
À
AHCTUNGTRENNUNG
pling reaction. The process is quite general, allowing for the
participation of any azole ring, and opening the door to the
preparation of unprecedented molecules featuring these
privileged heterocyclic structures. Moreover, the preorgani-
zation of the trisubstituted alkene products has permitted
À
À
Scheme 4. Preliminary experiments on the Pd-catalyzed C C/C C auto-
tandem process.
Encouraged by these observations, optimization of the
auto-tandem-catalyzed process was conducted. After a set
À
À
the development of a novel C C/C C auto-tandem process,
giving rise to new compounds featuring the biologically rele-
À
À
of experiments, it was found that to achieve the C C/C C
cascade process with high conversion it was necessary to in-
crease the catalyst loading and reaction time. Under the op-
timized reaction conditions, indoloisoquinoline 6a was iso-
lated in high yield.
vant pyrroloACHTUNTRGNEUNG[2,1-a]isoquinoline substructure.
This methodology could be applied to the synthesis of a
set of polyheterocyclic compounds featuring the pyrroloiso-
quinoline scaffold (Scheme 5). The sequence was carried out
in a one-pot fashion in all cases, leading directly to the poly-
cyclic structures 6 from the carbonyl compounds. The auto-
tandem reaction was conducted with N-indole and N-pyrrole
a-substituted acetophenones, leading to the corresponding
Acknowledgements
Financial support of this work by the DGI of Spain (CTQ-2010-16790) is
acknowledged. A predoctoral fellowship by FICYT (Principado de Astu-
rias, Spain) to L.F. is gratefully acknowledged.
Keywords: auto-tandem catalysis · azoles · cross-coupling ·
domino reactions · palladium · tosylhydrazones
indolo- and pyrrolo
tively, in yields ranging from excellent to moderate.[19,20,21]
It is worth noting that the pyrrolo[2,1-a]isoquinoline sub-
ACHTUNGTRENUN[NG 2,1-a]isoquinoline derivatives, respec-
AHCTUNGTRENNUNG
structure is present in lamellarins, a class of marine natural
products with useful biological properties such as antitumor
and anti-HIV activities.[22] Taking into consideration that the
starting ketones 1 are readily prepared from the correspond-
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undergo the tandem process and compound 4m was the only prod-
uct under the reaction conditions given in Scheme 5.
[21] The reaction with an ortho-bromononaflate led to the formation of
the cross-coupling product by the selective reaction of the bromine,
but no auto-tandem reaction occurred under various conditions (see
the Supporting Information for details).
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cles 2011, 83, 491.
Received: March 19, 2013
Revised: May 23, 2013
Published online: && &&, 0000
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Chem. Eur. J. 0000, 00, 0 – 0
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