Pd-Catalyzed Autotandem Reactions with N-Tosylhydrazones. Synthesis of Condensed Carbo- and Heterocycles by Formation of a C-C Single Bond and a C-C Double Bond on the Same Carbon Atom

Article abstract of DOI:10.1021/acs.orglett.7b00613

A new Pd-catalyzed autotandem reaction is introduced that consists of the cross-coupling of a benzyl bromide with a N-tosylhydrazone followed by an intramolecular Heck reaction with an aryl bromide. During the process, a single and a double C-C bond are formed on the same carbon atom. Two different arrangements for the reactive functional groups are possible, rendering great flexibility to the transformation. The same strategy led to 9-methylene-9H-fluorenes, 9-methylene-9H-xanthenes, 9-methylene-9,10-dihydroacridines, and also dihydropyrroloisoquinoline and dihydroindoloisoquinoline derivatives.

Full text of DOI:10.1021/acs.orglett.7b00613

Letter
pubs.acs.org/OrgLett
Pd-Catalyzed Autotandem Reactions with N‑Tosylhydrazones.
Synthesis of Condensed Carbo- and Heterocycles by Formation of a
C−C Single Bond and a CC Double Bond on the Same Carbon
Atom
Miguel Paraja and Carlos Valdes*
́
Departamento de Química Organ
́ ́ ́
ica e Inorganica and Instituto Universitario de Química Organometalica “Enrique Moles”,
Universidad de Oviedo, c/Julian Clavería 8, Oviedo 33006, Spain
́
S
* Supporting Information
ABSTRACT: A new Pd-catalyzed autotandem reaction is introduced that
consists of the cross-coupling of a benzyl bromide with a N-tosylhydrazone
followed by an intramolecular Heck reaction with an aryl bromide. During
the process, a single and a double C−C bond are formed on the same
carbon atom. Two different arrangements for the reactive functional
groups are possible, rendering great flexibility to the transformation. The
same strategy led to 9-methylene-9H-fluorenes, 9-methylene-9H-xan-
thenes, 9-methylene-9,10-dihydroacridines, and also dihydropyrroloisoquinoline and dihydroindoloisoquinoline derivatives.
Scheme 1. (1) Synthesis of Spirofluorenes by Pd-Catalyzed
Autotandem Reaction; (2) This Work
ascade reactions are very powerful methodologies for the
1
Csynthesis of complex carbocyclic structures. In cascade
processes, two or more bonds are formed in one single synthetic
operation, enabling cyclization processes from two independent
subunits and, therefore the development of highly convergent
synthetic methodologies. Within the widely studied field of
metal-catalyzed cascade reactions, Pd-catalyzed processes can be
regarded as some of the most versatile methodologies.2
In the context of our interest in Pd-catalyzed C−C bond-
forming reactions based on N-sulfonylhydrazones,3,4 we have
recently focused on the development of new cascade reactions
oriented to the synthesis of carbo- and heterocycles.5−7 Within
this research program, we described a new method for the
synthesis of spirofluorenes through a Pd-catalyzed cascade
between N-tosylhydrazones and 2,2′-dibromobiphenyls
(Scheme 1, eq 1).8 In this process, two different C−C bonds
are formed on the hydrazonic carbon atom. First, the cross-
coupling reaction between the N-tosylhydrazone and one of the
bromides leads to an intermediate D that experiences an
intramolecular Heck reaction, which provides the final
spirofluorene structure C. Interestingly, the process involves
two separate catalytic cycles that are promoted by the same Pd
catalysta so-called autotandem catalysis.9,10 We envisioned
that this approach, which combines the formation of an alkene by
the cross-coupling reaction with a N-tosylhydrazone followed by
the cyclization by carbopalladation of the newly formed double
bond, features considerable potential for the synthesis of
polycyclic aromatic hydrocarbons upon selection of the proper
coupling partners. Thus, we decided to explore a similar cascade,
employing dibromobiphenyls with the general structure E, which
feature a benzylic bromide and an aryl bromide in the proper
positions to undergo an autotandem cascade sequence (Scheme
1, eq 2).
Taking advantage of the higher reactivity of benzyl bromides
compared to aryl bromides in the oxidative addition step, we
expected the initial formation of stilbene F by reaction with the
N-tosylhydrazone,11 followed by the 5-exo-trig intramolecular
Heck reaction, which would provide the final 9-fluorenylidene
G12 (Scheme 1, eq 2). If this approach was successful, it would
represent a novel and convergent route to an important class of
fluorenyl derivatives.13 Moreover, it would consist of a rare
example of the formation of a C−C single bond and a CC
double bond on the same carbon atom in a single reaction.
Received: February 28, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b00613
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
In this paper, we describe our progress toward this goal, which
has led to the development of new cascade reactions that take
place with formation of two consecutive C−C bonds and enable
the straightforward synthesis of a variety of carbo- and
heterocyclic structures.
complete conversion, indicating that 4 is indeed an intermediate
in the autotandem-catalyzed cascade.
The optimized reaction conditions were applied to the
coupling of dibromide 1 with a set of different N-tosylhydrazones
2 to establish the scope of the reaction (Table 2). Thus, a wide
We initiated our study with the reaction between 2-bromo-2′-
(bromomethyl)-1,1′-biphenyl 1 and the N-tosylhydrazone of 4-
chlorobenzaldehyde 2a. In an initial experiment, we chose a set of
catalytic conditions similar to those described by Wang for the
Pd-catalyzed cross-couplings between N-tosylhydrazones and
benzyl bromides,11 which should be the first step of the
autotandem process: Pd2dba3 (5 mol %)/P(2-Furyl)3 (20 mol
%), in toluene at 80 °C, but employing 6 equiv of t-BuOLi as
base, as an additional load of base would be necessary for the
second step of the cascade process. Under these conditions, the
cross-coupling proceeded with excellent conversion leading to
stilbene 4, but formation of the desired benzylidenefluorene 3a
was not detected (Table 1, entry 1). Nevertheless, formation of
Table 2. Pd-Catalyzed Synthesis of 9-Methylene-9H-fluorenes
3 by Reaction of Dibromide 1 with N-Tosylhydrazones 2
a
Table 1. Selected Optimization Experiments for the C−C/C−
a
C Pd-Catalyzed Autotandem Reaction
f
b
entry
base 1/base 2 (6 equiv)
T (°C)
3/4
c
1
2
t-BuOLi/−
t-BuOLi/−
t-BuOLi/−
t-BuOLi/−
80
100
100
100
100
100
100
100
100
120
0:1
1:4
1:1
2:3
2:1
0:1
1:4
7:3
4:1
e
3
d
4
a
5
t-BuOLi/K2CO3
Reaction conditions: dibromide 1, (0.1 mmol), N-tosylhydrazone 2,
(1 equiv), Pd2(dba)3 (5 mol %), P(2-Furyl)3 (30 mol %), t-BuOLi (3
6
K2CO3/−
b
equiv), Cs2CO3 (3 equiv), 1,4-dioxane (2 mL), 12 h, 120 °C. Isolated
7
t-BuOLi/Na2CO3
t-BuOLi/Li2CO3
t-BuOLi/Cs2CO3
t-BuOLi/Cs2CO3
yield after column chromatography.
8
9
g
10
1:0 (79%)
a
number of fluorenes 3 were obtained with excellent to moderate
yields through the reactions with N-tosylhydrazones derived
from aromatic aldehydes bearing both electron-donating (3c, 3d,
3j) or electron-withdrawing (3b, 3h) functional groups as well as
heterocycles 3g. Moreover, ortho-substitution is also tolerated, as
represented by the highly sterically hindered 3j. The N-
tosylhydrazone of trans-p-methoxycinnamaldehyde provided
the 2-propenyl-1-ylidene-9H-fluorene 3k in excellent yield.
Finally, the reaction was also attempted with the N-
tosylhydrazone derived from 4-methoxyacetophenone, leading
to the fluorene featuring a tetrasubstituted double bond 3l.
Next, the cascade reaction was applied to diphenyl ether 5,
which should provide xanthenes 6, after the cross-coupling/6-
exo-trig Heck cyclization. However, under the experimental
conditions described above, the reaction furnished the
intermediate stilbene in which the cross-coupling reaction with
the N-tosylhydrazone, but not the Heck reaction, had taken
place. After some experimentation, we observed that the
employment of a mixture of t-BuOLi (3 equiv) and t-BuONa
(3 equiv) as base combination allowed for the complete
transformation into the desired xanthenes 6. Under these
conditions, the reaction showed a scope similar to that for the
synthesis of fluorenes 3, including N-tosylhydrazones derived
from aromatic aldehydes featuring a variety of functional groups
(Table 3).
Reaction conditions: dibromide 1, (0.1 mmol), N-tosylhydrazone 2a,
(1 equiv), Pd2(dba)3 (5 mol %), P(2-Furyl)3 (30 mol %), base 1 (6
equiv) or base 1 (3 equiv)/base 2 (3 equiv), 1,4-dioxane (2 mL), 12 h.
b
c
d
Calculated by GS/MS. Carried out in toluene as solvent. Carried
e
out in CH3CN as solvent. Pd2(dba)3 (3 mol %) was used.
f
g
Temperature of the bath in the sealed tube reaction. Isolated yield
of 3a after column chromatography
3a occurred to a considerable extent when the reactions were
conducted under reflux of 1,4-dioxane or CH3CN (Table 1,
entries 2−4). In particular, the reaction in 1,4-dioxane provided a
1:1 mixture of 3a and 4 (Table 1, entry 3). After some
experimentation, it was found that the employment of a
combination of two bases, t-BuOLi (3 equiv) and an alkaline
carbonate (3 equiv), led to an increment on the formation of 3a
(Table 1, entries 5, 7−9). The presence of both bases in the
reaction has a beneficial effect on the conversion, as the reaction
carried out only with the participation of K2CO3 led again to the
exclusive formation of stilbene 4. It was finally determined that
the combination t-BuOLi (3 equiv)/Cs2CO3 (3 equiv) afforded
the best 3a:4 ratio. Finally, running the reaction in a sealed tube
with a bath temperature of 120 °C brought a complete
conversion into the fluorene 3a with an isolated yield of 79%
(Table 1, entry 10). In a separate experiment, 4 was subjected to
the same reaction conditions of entry 10, giving rise to 3a with
B
DOI: 10.1021/acs.orglett.7b00613
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Organic Letters
Letter
Table 3. Pd-Catalyzed Synthesis of 9-Benzylidene-9H-
xantenes 6 by Reaction of Dibromide 5 with N-
Tosylhydrazones 2
Scheme 3. Stereoselective Synthesis of Nonsymmetrically
Substituted 9-Methylene-9H-fluorenes 3
a
b
6
Ar
yield (%)
6a
6b
6c
6d
6e
6f
4-MeOC6H4
Ph
50
56
63
67
64
62
74
55
57
62
59
4-NCC6H4
4-Me2NC6H4
4-Tol
fluorenes 3 have been reported to undergo slow Z/E
isomerization upon heating in the presence of Pd catalysts;13d,e
thus, the presence of a minor amount of the E isomer can be
explained considering partial isomerization under the reaction
conditions.
This approach was then applied for the preparation of 9-
benzylidene-9,10-dihydroacridines 10 from easily available N,N-
diarylaniline 9 and benzyl bromides 8. The reaction conditions
established for the synthesis of 9-methylene-9H-fluorenes 3,
involving the t-BuOLi/Cs2CO3 combination, were most
appropriate for these transformations. Again, the examples
selected include benzyl bromides bearing both electron-donating
or electron-withdrawing functional groups (Table 4) and led to
the obtention of this important class of condensed heterocycles15
in nearly quantitative yields.
3-ClC6H4
4-F3CC6H4
4-ClC6H4
2-MeOC6H4
4-FC6H4
6g
6h
6i
6j
6k
2-naphthyl
a
Reaction conditions: dibromide 5, (0.1 mmol), N-tosylhydrazone 2a,
(1 equiv), Pd2(dba)3 (5 mol %), P(2-Furyl)3 (30 mol %), t-BuOLi (3
equiv), t-BuONa (3 equiv), 1,4-dioxane (2 mL), 12 h, 120 °C.
Isolated yield after column chromatography.
b
The mechanism proposed for the Pd-catalyzed autotandem
reactions involves the formation of an intermediate stilbene F
(Scheme 1, eq 2) by cross-coupling of the N-tosylhydrazone with
the dibromide at the benzylic position followed by the
intramolecular Heck reaction. Interestingly, the same inter-
mediate stilbene could be reached by exchanging the positions of
the reactive functional groups. Indeed, when the reaction of N-
tosylhydrazone 7a and benzyl bromide 8 was conducted under
the conditions described in Table 2, the 9-methylene-9H-
fluorene 3e was obtained in nearly identical yield compared to
the original reaction employing dibromide 1 and the N-
tosylhydrazone of benzaldehyde (Scheme 2).
Table 4. Synthesis of 9-Methylene-9,10-dihydroacridines 10
a
by Reaction of Benzyl Bromides 8 with N-Tosylhydrazones 9
b
10
Ar
yield (%)
Scheme 2. Synthesis of 9-Methylene-9H-fluorene 3e through
the Same Reaction from Different Starting Materials
10a
10b
10c
10d
10e
Ph
90
93
91
98
95
4-Tol
4-FC6H4
4-NCC6H4
4-ClC6H4
a
b
See Table 2 for reaction conditions. Isolated yield after column
chromatography.
The possibility of synthesizing the same products through the
same reaction but from different starting materials is very
interesting, since it may enable access to a wider variety of
structures depending on the availability of the coupling partners.
In particular, N-tosylhydrazones 7 featuring additional sub-
stitution on the aromatic rings are readily available and have been
previously employed by Hamze et al. in the Cu-catalyzed
synthesis of 9H-fluorene-9-amines.14 Thus, we turned our
attention to N-tosylhydrazone 7b as a platform to check the
stereoselectivity of the cascade reaction. As presented in Scheme
3, the reaction between 7b and benzyl bromides 8 provided the
nonsymmetrically substituted 9-methylene-9H-fluorenes 3m
and 3n as a 6:1 mixture of Z/E-diastereoisomers.
Finally, to further illustrate the versatility of the autotandem
process, we chose the heterocyclic N-tosylhydrazones 11 and 13
as substrates for the C−C/CC cascade reaction with benzyl
bromides, which would lead to pyrroloisoquinoline and
indoloisoquinoline derivatives, respectively. In these cases the
employment of Pd(OAc)2 as Pd source provided better results.
Additionally, the participation of two different bases did not
result in any reaction improvement. In this manner,
dihydropyrrolo[1,2-b]isoquinoline 12 and dihydropyrrolo[1,2-
b]isoquinoline 14 were obtained with moderate stereoselectivity
(Scheme 4). In both cases, the major isomer corresponded to
that expected considering the syn-β-hydride elimination on the
last step of the cascade process. These results demonstrate the
wide versatility of this approach for the preparation of
polyaromatic carbo- and heterocyclic structures by combining
in the proper way the three reactive elements required for the Pd-
The major isomer corresponds to the one expected
considering a syn-carbopalladation followed by a syn-β-hydrogen
elimination (Scheme 3). It must be noted that 9-methylene-9H-
C
DOI: 10.1021/acs.orglett.7b00613
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Organic Letters
Letter
A. In Metal-Catalyzed Cross-Coupling Reactions and More; de Meijere, A.,
Scheme 4. Synthesis of Pyrroloisoquinoline 12 and
Indoloisoquinoline Derivatives 14
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̃
As summary, we report herein a new type of Pd-catalyzed
autotandem cyclization that proceeds by formation of a C−C
single bond and a C−C double bond on the same carbon atom.
The cascade process includes the cross-coupling reaction
between N-tosylhydrazones and benzyl bromides followed by
an intramolecular Heck reaction. The cyclization occurs by
reaction of a bifunctional coupling partner with a monofunction-
alized system. Interestingly, two different arrangements for the
reactive groups are possible, greatly enhancing the synthetic
possibilities of the reaction. The versatility has been illustrated
with the synthesis of a variety of carbo- and heterocyclic
structures employing the same synthetic strategy, including
fluorene, xanthene, acridine, pyrroloisoquinoline, and indoloiso-
quinoline derivatives.
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The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.7b00613.
Experimental procedures, compound characterization
data, and NMR spectra for compounds 3, 6, 9−14
(PDF)
AUTHOR INFORMATION
■
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Corresponding Author
*E-mail: acvg@uniovi.es.
ORCID
Carlos Valdes: 0000-0002-6246-2994
́
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support of this work was provided by the Ministerio de
́
Economia y Competitividad (MINECO) of Spain (Grant Nos.
CTQ2013-41336-P and CTQ2016-76794-P (AEI/FEDER,
UE)). An FPI predoctoral fellowship (MINECO) to M.P. is
gratefully acknowledged.
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DOI: 10.1021/acs.orglett.7b00613
Org. Lett. XXXX, XXX, XXX−XXX