Pd-catalyzed autotandem C-C/C-C bond-forming reactions with tosylhydrazones: Synthesis of spirocycles with extended π-conjugation

Article abstract of DOI:10.1021/ol500778u

A new Pd-catalyzed autotandem process is presented by the reaction of tosylhydrazones of cyclic ketones and 2,2′-dibromobiphenyls and related systems. The process involves cross-coupling with tosylhydrazone followed by an intramolecular Heck reaction and gives rise to spirocyclic structures. Noteworthy, two C-C_Ar bonds are formed on the hydrazonic carbon during the process. Depending on the starting dibromide, an array of spirofluorenes, spirodibenzofluorenes, spiroacridines, and spiroanthracenes have been prepared. Thus, this methodology may be applied for the preparation of interesting structures useful in the development of optoelectronic materials.

Full text of DOI:10.1021/ol500778u

Letter
pubs.acs.org/OrgLett
Pd-Catalyzed Autotandem C−C/C−C Bond-Forming Reactions with
Tosylhydrazones: Synthesis of Spirocycles with Extended
π‑Conjugation
Raquel Barroso, Rocío A. Valencia, María-Paz Cabal, and Carlos Valdes*
́
Instituto Universitario de Química Organometal
́ ́ ́
ica “Enrique Moles” and Departamento de Química Organica e Inorganica,
Universidad de Oviedo, c/Julian Clavería 8, Oviedo 33006, Spain
́
S
* Supporting Information
ABSTRACT: A new Pd-catalyzed autotandem process is presented
by the reaction of tosylhydrazones of cyclic ketones and 2,2′-
dibromobiphenyls and related systems. The process involves cross-
coupling with tosylhydrazone followed by an intramolecular Heck
reaction and gives rise to spirocyclic structures. Noteworthy, two
C−CAr bonds are formed on the hydrazonic carbon during the
process. Depending on the starting dibromide, an array of
spirofluorenes, spirodibenzofluorenes, spiroacridines, and spiro-
anthracenes have been prepared. Thus, this methodology may be
applied for the preparation of interesting structures useful in the
development of optoelectronic materials.
ascade reactions are among the most attractive methods
Scheme 1. Examples of Typical Pd-Catalyzed Autotandem
Reactions of Ambidentate Nucleophiles (eqs 1 and 2),3b,7a
This Work’s Approach (eq 3) (New Bonds Are Represented
in Bold)
C
for the construction of molecular complexity. A particular
type of transition-metal-catalyzed cascade process is the so-
called “autotandem” process.1 In these transformations, the
same catalyst is able to promote various independent bond-
forming reactions, which proceed through distinct catalytic
cycles. Over the past decade, a considerable number of
examples of Pd-catalyzed autotandem processes have been
developed, mainly oriented to the synthesis of heterocycles.
These reactions generally rely on the concatenation of
sequential C−heteroatom and C−C bond-forming cross-
couplings.2−4 An advantage of these approaches is that the
adequate selection of the coupling partners permits the
construction of relatively complex cyclic structures from
properly functionalized simple materials in one single
operation. The vast majority of these reactions are based on
the employment of complementary bifunctionalized reagents,
either a species with two electrophilic positions toward an
ambidentate nucleophile or two coupling partners, both
featuring an electrophilic and a nucleophilic reacting point
(Scheme 1, eqs 1 and 2).
In the context of our interest in the Pd-catalyzed cross-
coupling reactions employing tosylhydrazones,5,6 we reported
recently the first autotandem process through a C−C/C−N
sequence7a and, more recently, the first autotandem C−C/C−
C process with participation of tosylhydrazones as a coupling
partner.8 Nevertheless, all of these examples follow the usual
pattern presented in eq 1 of Scheme 1: all reacting functional
groups are already present in the starting coupling partners.
We envisioned a different approach by designing a reaction
sequence in which the functionality generated in the first step
would react in the second step of the autotandem process. In
particular, considering the cross-coupling of tosylhydrazones,
the double bond formed in the first Pd-catalyzed cross-coupling
might participate in an intramolecular Heck reaction to render
cyclic systems through a C−C/C−C autotandem sequence
(Scheme 1, eq 3).
With this initial idea, we considered first the reaction
between an appropriate tosylhydrazone and 2,2′-dibromobi-
phenyl 2a. We expected that, after the initial cross-coupling
Received: March 14, 2014
Published: April 7, 2014
© 2014 American Chemical Society
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Letter
reaction, a 5-exo-trig Heck-type cyclization9 might occur to
provide the corresponding spirofluorene derivatives (Scheme
2).10,11 To avoid regioselectivity problems, we chose the
regarding the structure of the tosylhydrazone was examined. As
presented in Scheme 3, the reaction could be carried out with
Scheme 3. Synthesis of Spirofluorenes 4 by Reaction
between Cyclic N-Tosylhydrazones 1 and 1,1′-
Scheme 2. Initial C−C/C−C Pd-Catalyzed Autotandem
Reaction Considered and Some Optimization Results
ab
,
Dibromobiphenyl 2a
reaction between cyclohexanone tosylhydrazone 1a and 2,2′-
dibromobiphenyl 2a as a model to investigate the feasibility of
the process and develop proper experimental conditions
(Scheme 2).
a
Reaction conditions: dibromide 2 (0.2 mmol, 1 equiv), tosyl-
hydrazone 1 (0.4 mmol, 2 equiv), t-BuOLi (4 equiv), Pd2(dba)3 (4
As a starting point for the optimization, we employed the
standard reaction conditions developed for the cross-coupling
reactions with tosylhydrazones: t-BuOLi as base and the
Pd2(dba)3·Xphos catalytic system.5 The initial experiments
employing a 1:1 ratio of both coupling partners and 2 mol % of
Pd2(dba)3 led to the obtention of a mixture of the cross-
coupling product 3a and the desired spirocycle 4a. Delightfully,
upon increasing of the catalyst loading and the 1a/2a ratio, the
spirocyclic derivative 4a could be obtained as the only reaction
product with an excellent isolated yield of 93%. The structure
b
mol %), Xphos (8 mol %), dioxane (2 mL), 110 °C, 24 h. Isolated
c
d
yields after column chromatography. Reaction time 48 h. Yield
determined by 1H NMR employing triphenylmethane as internal
e
reference. Structure confirmed by X-ray diffraction.
an array of tosylhydrazones derived from cyclic ketones to
provide a collection of spirofluorene derivatives 4 with
unprecedented structures. The reaction proceeded with the
tosylhydrazone of cyclohexanone, 4-substituted cyclo-
hexanones, and also cycloheptanone but failed with cyclo-
pentanone. Moreover, tetralone tosylhydrazone was also an
appropriate substrate for the reaction leading to the interesting
spiro derivatives 4e and 4f which feature an additional aromatic
ring. Similarly, the reaction with the hydrazone of 4,4-
dimethylcyclohexenone led to the symmetric spirofluorene 4g
featuring two unconjugated double bonds. Interestingly, the
cascade reaction could be achieved also with the tosyl-
hydrazones of N-benzyl-4-piperidone and 4-piranone, which
led to the corresponding spiro derivatives 4h and 4i featuring
enamine and enol ether functionalities, respectively. In
particular, the structure of 4i was confirmed by X-ray
crystallographic analysis (Figure 1). Finally, the reaction with
the hydrazone of 2-methoxycyclohexanone furnished spiro
compound 4j in a complete regioselective manner.5d
1
4a could be assigned based on the 13C, H NMR, and MS
spectra. In particular, the presence of two dt at 5.35 (3J = 9.9
Hz, 4J = 2.1 Hz) and 6.12 ppm (3J = 9.9 Hz, 3J = 3.8 Hz) in the
1H NMR spectrum was a clear indication of the presence of the
endocyclic double bond. Moreover, the spirocyclic structure
was later confirmed by X-ray crystallographic analysis in
another member of this family of spiro compounds (Figure
1). Interestingly, during the autotandem reaction, the unusual
formation of two C−CAr bonds on the same carbon atom has
taken place.4b,11,12
This result prompted us to study the scope of this novel
process regarding both coupling partners, the tosylhydrazone
and the dibromide derivative. First, the scope of the reaction
It is worth noting the interest of spirofluorene structures,
which are currently employed in the development of electro-
luminescent and optoelectronic materials.13 This approach may
offer the opportunity to build structurally diverse and
functionalized derivatives of this family of compounds.
Encouraged by these results, the autotandem reaction was
then examined employing other dibrominated scaffolds to
explore the versatility of this approach in the synthesis of
structurally diverse spiro compounds. Thus, we selected a series
of dibrominated scaffolds, binaphthyl 2b, diarylanilines 2c−2g,
diarylmethane 2h, and arylbenzylether 2i (Figure 2).
Figure 1. ORTEP representation of the molecular structure of 4i
determined by X-ray crystallographic analysis (see Supporting
Information).
In an initial approximation, the reactions were carried out
under reaction conditions similar to those employed for
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tosylhydrazone was necessary to achieve the synthesis of the
spiroacridines 6 with preparatively interesting yields. Note-
worthy, under the proper conditions, the autotandem reaction
proceeded successfully with the N−H-free anilines, leading to
the corresponding spiroacridines 6, also valuable structures for
the development of molecules with electronic properties15 and
amenable for further derivatization through the N−H position.
However, in the case of the N-methylated system 2g, formation
of N-methylcarbazole resulted in the major reaction product4b
even in the presence of excess of the N-tosylhydrazone. Finally,
the reaction with bis(2-bromophenyl)methane 2h allowed for
the synthesis of the spirodihydroanthracenes 7.
In contrast, when the reaction with tosylhydrazone 1a was
carried out under the same conditions employing dibromide 2i,
formation of the spiro compound was not detected. Instead, a
mixture of the products 8 and 9, derived from mono- and
dialkenylation, respectively (Scheme 5), was obtained in
different ratios depending on the reaction conditions, indicating
that the 7-exo-trig cyclization is not a favored reaction pathway.
Figure 2. Bis(bromoaryl) compounds 2 employed in the Pd-catalyzed
autotandem reaction.
biphenyl 2a. However, in some cases, further tuning of the
reaction conditions was required. The results are summarized
in Scheme 4.
Scheme 4. Synthesis of Spiro Compounds 5−7 by Reaction
between Cyclic N-Tosylhydrazones 1 and Dibromides 2b−
ab
,
g
Scheme 5. Reaction with Dibromide 2i Which Does Not
Afford the Spirocyclic Structure
In summary, we reported herein a new Pd-catalyzed
autotandem C−C/C−C bond-forming sequence that involves
a tosylhydrazone cross-coupling followed by an intramolecular
Heck reaction. Interestingly, during the process, two C−CAr
bonds were formed on the same carbon atom. Moreover, these
processes led to the obtainment of rigid spirocyclic structures
featuring extended π-conjugation in one single step from
readily available starting materials. These novel scaffolds may
find application in the development of optoelectronic materials
and also in ligand design and diversity-oriented synthesis. The
examples presented herein already show the versatility of this
approach for the preparation of structurally diverse and
functionalized spirocyclic systems. The development of more
sophisticated structures based on this approach and the study of
their properties are currently in progress in our laboratory.
a
Reaction conditions: dibromide 2 (0.2 mmol, 1 equiv), tosyl-
hydrazone 1 (0.4 mmol, 2 equiv), t-BuOLi (4 equiv), Pd2(dba)3 (4
b
mol %), Xphos (8 mol %), dioxane (2 mL), 110 °C, 24 h. Isolated
yield after column chromatography. Tosylhydrazone (4 equiv) was
employed. Reaction time 48 h. Tosylhydrazone (3 equiv) and t-
BuOLi (5 equiv) were employed. N-Methylcarbazole was obtained as
c
d
e
f
major product.
ASSOCIATED CONTENT
■
S
* Supporting Information
The process is also very efficient for the preparation of
spirodibenzofluorenes 5,14 interesting structures which feature a
more extended π-conjugation, with yields similar to the
reactions with the biphenyl system (Scheme 4). The reactions
of bis(bromoaryl) compounds 2c−h were expected to afford
the corresponding spiro compounds 6 and 7, which feature a
central six-membered ring through a 6-exo-trig cyclization.
However, these reactions turned out to be more challenging. In
our initial experiments, under the typical reaction conditions
described above, the diarylanilines 2c and 2g showed some
tendency to cyclize from carbazoles.4b After some experimen-
tation, it was found that the employ of a higher excess of N-
Detailed experimental procedures, characterization data, and
copies of the 1H and 13C NMR spectra for the compounds 4−7
and 9. X-ray crystallographic data of 4i. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: acvg@uniovi.es.
Notes
The authors declare no competing financial interest.
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Letter
(a) Kudirka, R.; Van Vranken, D. L. J. Org. Chem. 2008, 73, 3585.
(b) Zhou, L.; Ye, F.; Zhang, Y.; Wang, J. J. Am. Chem. Soc. 2010, 132,
13590.
ACKNOWLEDGMENTS
■
Financial support of this work was from DGI of Spain (CTQ-
2010-16790). A “Severo Ochoa” predoctoral fellowship by
FICYT (Principado de Asturias, Spain) to R.B. is gratefully
acknowledged. R.A.V. is grateful to Consejo Nacional de
Ciencia y Tecnologia CONACYT (Mexico) for financial
support.
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