Zirconium-catalyzed multistep reaction of hydrazines with alkynes: A non-fischer-type pathway to indoles

Article abstract of DOI:10.1002/anie.201101070

Dominos at zirconium: A cascade of N-N and C-H scissions and C-C and C-N coupling steps in the coordination sphere of zirconium directly converts alkynes and hydrazines into indoles. The reaction pathway differs fundamentally from that of the Fischer indo

Full text of DOI:10.1002/anie.201101070

DOI: 10.1002/anie.201101070
Indole Synthesis
Zirconium-Catalyzed Multistep Reaction of Hydrazines with Alkynes:
A Non-Fischer-Type Pathway to Indoles**
Thorsten Gehrmann, Julio Lloret Fillol, Solveig A. Scholl, Hubert Wadepohl, and Lutz H. Gade*
The combined formation and scission of several chemical
bonds in one process, frequently referred to as a “domino
reaction”, is the key to the assembly of complex molecules in
just a few reaction steps.[1,2] For these transformations there
are relatively few examples of early-transition-metal catalysts,
in particular from Group 4. Examples include the titanium-
catalyzed syntheses of N-heterocycles reported by Odom,
Beller, and others,[3–6] involving a catalytic hydrohydrazina-
tion of an alkyne and subsequent transformations of the
resulting hydrazones, which may either occur by direct
coupling with other unsaturated organic substrates[3] or a
Fischer-type conversion to indoles.[5] Little is known about the
reaction mechanisms of these transformations although the
stoichiometric reactivity of titanium hydrazides is the subject
of growing interest.[7] The reactivity of their zirconium
ꢀ
analogues is dominated by facile N N bond scission which
appears to precede C–N and related coupling steps, as first
demonstrated by Bergman and co-workers in 1991 for
[Cp2Zr(N2Ph2)(dmap)] (Cp = C5H5, dmap = 4-dimethylami-
nopyridine).[8] We explored the scope of the hydrazinediido-
zirconium complex [Zr(N2 Npy)(NNPh2)(py)] (1)[9] in stoi-
TBS
chiometric and catalytic transformations of alkynes and other
unsaturated substrates analogous to those reported for
titanium. We observed strikingly different reaction pathways,
Scheme 1. Reaction of the hydrazinediido complex 1 or alternatively
characterized by the absence of a hydrohydrazination step in
the zirconium hydrazide, which is formed in situ from 5 and Ph2NNH2,
with alkynes to yield the metallacyclic compounds 2a,b and 6a,b;
these undergo hydrazinolysis to give the bis(hydrazides) 3a,b and
indoles 4a,b. TBS=tert-butyldimethylsilyl, mes=mesityl.
ꢀ
favor of early N N bond cleavage. Here we report the
catalytic transformation of alkynes and diarylhydrazines to
indoles through a non-Fischer-type reaction cascade.
TBS
Reaction of one equivalent of [Zr(N2 Npy)(NNPh2)(py)]
(1)[9a] with the disubstituted alkynes R-C C-R (R = Me, Et)
the (bis)dimethylamido complex 5[10] with one molar equiv-
alent of both the alkyne and diphenylhydrazine.
ꢁ
leads to the formation of seven-membered diazazirconacycles
2a,b (Scheme 1), which are closely related to the Cp2Zr-
derived complexes reported by Bergman et al.[8] The zircona-
The molecular structures of the metallacyclic complexes
were established by X-ray diffraction for complexes 2b and
6a (Figure 1).[11] The coordination geometry of the complexes
is best described as distorted trigonal bipyramidal. The
chelating bisamide fragment within the puckered metallacy-
clic unit, which is generated by the N–N cleavage and C–C
coupling of the alkyne and one of the N-phenyl groups of the
hydrazinediide, occupies one equatorial and one axial posi-
tion at the metal; the bulky diarylamide is bonded in the
equatorial position and the small primary amide in the
sterically more crowded axial position. The C–C and C–N
distances are consistent with the structural assignment in
Scheme 1.
ꢀ
cycles result from a scission of the N N bond and the coupling
of the alkyne with one of the phenyl rings of the diphenylhy-
drazinediide, involving a formal C–H activation step. The
corresponding metallacyclic complexes 6a,b containing an N-
arylated ancillary tripod ligand were obtained by reaction of
[*] T. Gehrmann, Dr. J. Lloret Fillol, S. A. Scholl, Prof. Dr. H. Wadepohl,
Prof. Dr. L. H. Gade
Anorganisch-Chemisches Institut, Universitꢀt Heidelberg
Im Neuenheimer Feld 270, 69120 Heidelberg (Germany)
Fax: (+49)6221-545-609
Reaction of compounds 2a,b and 6a,b with two molar
equivalents of diphenylhydrazine gave the corresponding
bis{hydrazido(1ꢀ)} complexes 3a,b as well as one equivalent
of 1-phenyl-2,3-dimethylindole (4a) and 1-phenyl-2,3-diethyl-
indole (4b). Since bis(hydrazido) complexes such as 3a,b may
be employed as precursors in the generation of hydrazine-
E-mail: lutz.gade@uni-hd.de
[**] We thank the Deutsche Forschungsgemeinschaft for financial
support (SFB 623, TP A7) and the EU for the award of a Marie Curie
EIF postdoctoral fellowship (to J.L.F.).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201101070.
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Table 1: Catalytic indole syntheses of diphenylhydrazine with various
alkynes.[a]
Entry Alkyne
Indole
r.r.[b]
Yield
[%][c]
Figure 1. Molecular structures of complexes 2b (left) and 6a (right).
The asymmetric unit of 6a contains two independent molecules.
Because of their similarity only one of the two independent molecules
is shown. Bond lengths and angles of the second molecule are given
in square brackets. Selected bond lengths [ꢁ] and angles [8] for 2b:
Zr(1)–N(4) 2.0983(15), Zr(1)–N(5) 2.1304(15), C(1)–N(4) 1.3925(19),
C(1)–C(2) 1.359(2); N(3)-Zr-N(4) 171.30(4), N(4)-Zr-N(5) 87.40(5), Zr-
N(4)-C(1) 137.02(10), Zr-N(4)-C(1)-C(2) ꢀ44.1(2). Selected bond
lengths [ꢁ] and angles [8] for 6a: Zr(51)–N(54) 2.106(2) [2.112(2)],
Zr(51)–N(55) 2.113(9) [2.113(2)], C(85)–N(54) 1.394(3) [1.388.3],
C(84)–C(85) 1.350(3) [1.348(3)]; N(53)-Zr(51)-N(54) 160.73(7)
[160.73(7)], N(54)-Zr(51)-N(55) 84.72(7) [84.22(7)], Zr(51)-N(54)-
C(85) 135.26(16) [135.13(15)], Zr(51)-N(54)-C(85)-C(84) ꢀ43.9(3)
[ꢀ34.7(3)]. Hydrogen atoms, except those on the amido N atoms, are
omitted for clarity.
1
–
84
2
3
2:1[d] 59
–
36
diido compounds,[12] the reaction sequence leading to the
indoles was thought to be potentially part of a catalytic cycle
for the direct generation of substituted indoles from alkynes
and hydrazines via metallacyclic intermediates such as 2a,b
and 6a,b, thus without involving hydrazones and subsequent
Fischer-type transformations. Reaction of 1.2 equivalents of
diphenylhydrazine and various substituted alkynes (1 equiv)
at ambient temperature in the presence of 10 mol% [Zr-
4
5
>9:1[d] 74
xyl
(N2 Npy)(NMe2)2] (7), the more reactive N-xylylated ana-
logue of 5, gave the corresponding indole derivatives listed in
Table 1. For nonsymmetrical disubstituted alkynes the indole
with the bulkier substituent in the 3-position was the major
product (entries 2 and 5), whilst terminal alkynes exclusively
gave the indole substituted in 3-position (entries 4 and 6).
A non-Fischer reaction pathway to the indoles, which does
not involve hydrazone intermediates, raised the question of
the mechanism of the transformation of the hydrazinediide 1
to metallacycles of the type represented by 2a,b in Scheme 1.
The reaction of the perdeuterated diphenylhydrazinediide,
2:1[d] 56
6
7
>9:1[d] 56
which was also 15N-labeled in the Na position, with EtC CEt
ꢁ
cleanly gave the corresponding metallacycle with the enam-
ido N atom fully 15N-labeled and completely deuterated, thus
clarifying the origin of the NH group (see the Supporting
Information). Since exchange with solvent hydrogen or
deuterium atoms was not observed, this rearrangement is
assumed to be intramolecular.
–
11
ꢁ
A detailed kinetic study of the reaction of 1 with EtC CEt
revealed the pyridine dissociation pre-equilibrium:
[a] Reaction conditions: alkyne (1.2 mmol), diphenylhydrazine
xyl
(1.44 mmol), 10 mol% [Zr(N2 Npy)(NMe2)2], 24 h in 2 mL of toluene
at ambient temperature. [b] r.r.=Ratio of regioisomers determined by
1H NMR spectroscopy. [c] Yields of isolated products determined after
chromatographic workup. [d] Major isomer shown.
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and a subsequent rate-determining step, which is represented
by the following rate law:
The observation of saturation phenomena kinetics for
high concentrations of alkyne (see the Supporting Informa-
tion) confirms the existence of the pre-equilibrium whilst the
activation parameters of the rate-determining step were
determined to be DH° = (11.5 ꢂ 0.7) kcalmolꢀ1 and DS° =
(ꢀ45 ꢂ 10) calmolꢀ1 Kꢀ1 and thus a free enthalpy of activation
for the rate-determining step of DG275° = (24 ꢂ 2) kcalmolꢀ1.
Reaction of a derivative of complex 1, in which one of the two
phenyl rings at Nb was perdeuterated, with 0.5 equivalents of
3-hexyne gave a reaction product with an NH/ND distribution
of 1:1, indicating kH/kD = 1 and thus the absence of a kinetic
ꢀ
Figure 2. Reaction profile (DFT, B3PW91) of the cycloaddition of 2-
butyne to the hydrazinediido unit in 1 (I!IV) and the subsequent
isotope effect. This implied that neither the C H bond
cleavage nor the H-atom rearrangement with formation of
ꢀ
(rate-determining) N N bond scission to give the diphenylamido-
ꢀ
the N H bond are involved in the rate-determining step.
(azaallyl) intermediate V (R=TBS). Energies are given in parentheses,
free energies in square brackets.
In order to obtain deeper insight into the reaction cascade
leading to the key metallacycles 2a,b and 6a,b, and taking the
experimental evidence outlined above into account, we
modeled
the
mechanism
by
DFT
(B3PW91) in detail,[13] exploring the poten-
tial reaction pathways of the reaction of the
TBS
zirconium
complex
[Zr(N2 Npy)-
(NNPh2)(py)] (1) with 2-butyne.
First, the [2+2] cycloaddition of 2-butyne
=
to the {Zr N} unit, a reaction step that has
been studied in detail for Ti hydrazides,[7e]
was modeled (Figure 2: I!IV). This con-
version was found to occur without prohib-
itive energetic barriers, giving rise to the
metallacyclic intermediate IV. In a subse-
quent rate-determining step the N–N bond is
broken and the “azaallyl” species V is
formed; in this step the calculated activation
barrier of DG° = 21 kcalmolꢀ1 for the reac-
tion with 2-butyne is close to the experimen-
Figure 3. Reaction profile (DFT, B3PW91) of the transformation of the [2+2] cycloaddition
product IV to the isomeric azaallyl intermediates V and Va and to the key 2,3-dimethyl-
azirinido species VI (R=TBS). Energies are given in parentheses, free energies in square
brackets.
tal value of (24 ꢂ 2) kcalmolꢀ1 observed for the sterically
more demanding 3-hexyne. No pathways from intermediate V
to the reaction products with a low activation barrier were
found in a systematic search of the active conformational and
configurational space. However, the rearrangement of V to
the energetically only slightly (by DG = 2.6 kcalmolꢀ1) dis-
favored constitutional isomer, the dimethylazirinido complex
VI (Figure 3), allows the subsequent transformation without
prohibitive activation barriers.
We note that a species such as VI has been postulated by
Mindiola to explain the insertion of alkynes into the N–N
bonds of titanium hydrazinediides.[14] Whilst this was not
confirmed in computational studies on the titanium sys-
tems,[7e] it clearly represents a key intermediate for the
reaction sequence involving the zirconium complex reported
in this work. Intermediate VI is converted into the seven-
membered metallacyclic complex VIII (Figure 4) by nucleo-
philic attack of a carbon atom in the ortho position of a phenyl
ring of the NPh2 fragment at one of the (electrophilic) carbon
atoms of the metalated azirine ring to form intermediate VII
(DG = ꢀ20.7 kcalmolꢀ1) via transition-state TS(VI–VII),
which has a relatively low activation barrier (DG° = 19.8 kcal
molꢀ1).
The notion of an electrophilic attack at the N-phenyl ring
is supported by the observation that the analogous reaction of
2-butyne with a diphenylhydrazine derivative, in which one of
the phenyl rings is para-fluoro-substituted [Eq. (1)], exclu-
sively leads to the metallacyclic product 6c, which results
from the coupling of the more-electron-rich unsubstituted
aryl ring.
Finally, the exergonic 1,4 proton shift (DG = ꢀ59.2 kcal
molꢀ1) via a low-lying transition state gives the metallacyclic
complex VIII (= 2a). The pathway as represented in Fig-
ures 2–4 is consistent with the experimentally observed rate
law, the absence of a kinetic H/D isotope effect, the
magnitude of the activation barrier, and the established
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Scheme 2. Reaction of complex 1 with phenylallene to yield the [2+2]
cycloaddition product 8 and its thermal rearrangement to the metalla-
cyclic compound 9a (+9b as a minor regioisomer).
Figure 4. Reaction profile (DFT, B3PW91) of the transformation of the
2,3-dimethylazirinido species VI to the metallacycle VIII (R=TBS).
Energies are given in parentheses, free energies in square brackets.
intramolecular migration of a hydrogen atom from a phenyl
ring of the hydrazine to the NH unit in metallacycles 2a,b and
6a,b.
A notable variation of the reaction scheme is observed
upon reaction of 1 with phenylallene giving the [2+2]
cycloaddition product 8 (Scheme 2). Its molecular structure,
determined by X-ray diffraction, is depicted in Figure 5.
Complex 8 is the first structurally characterized example of a
[2+2] cycloaddition product to a hydrazinediidozirconium
unit; similar cycloaddition products have been obtained
previously with titanium hydrazides.[7]
Figure 5. Molecular structure of complex 8. Selected bond lengths [ꢁ]
and angles [8]: Zr(1)–N(4) 2.1830(12), Zr(1)–C(22) 2.3341(14), N(4)–
N(5) 1.4150(15), C(22)–C(23) 1.4946(18), C(23)–N(4) 1.3950(16),
C(23)–(C24) 1.3608(18); Zr(1)-C(22)-C(23) 56.0(6), Zr(1)-N(4)-N(5)
139.55(8), C(24)-C(23)-N(4) 124.5(11), N(3)-Zr(1)-N(6) 140.93(4).
Hydrogen atoms are omitted for clarity.
Heating complex 8 for 5 h to 808C yielded the seven-
membered zirconacycle 9a,b as a mixture of regioisomers
(also accessible by reaction of 1 with 1-phenylpropyne) which
could also be converted to the corresponding indole 4c by
reaction with diphenylhydrazine. That the conversion of 8 to
9a,b occurs intramolecularly and not through cycloreversion
was established by a crossover experiment in which the
thermal transformation was carried out in the presence of a
ꢁ
100-fold excess of PhC CCD3; no deuterium was found in the
resulting metallacycle. The reaction of phenylallene with
diphenylhydrazine to give 4c could also be carried out
xyl
catalytically using 10 mol% [Zr(N2 Npy)(NMe2)2] (7). The
observation of the same intermediate 9a and product 4c upon
when 1 was reacted with either 1-phenylpropyne or phenyl-
allene suggests that the common reaction intermediate VIa
leads to the metallacyclic product 9a (Scheme 3). Complex
VIa is the analogue of the zirconated azirine VI in Figures 3
Scheme 3. Proposed pathway for the rearrangement of 8 to the 2-
methyl-3-phenylazirinido species VIa, the key intermediate in the
transformation to the metallacyclic compound 9a.
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[6] Review: A. L. Odom, Dalton Trans. 2005, 225.
and 4. A preliminary computational study has revealed that
the rearrangement of the primary [2+2] cycloaddition
product 8 to a VI-type species is viable.
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In the few examples of zirconium-catalyzed domino
reactions in the literature[15] the metal appears to act primarily
as a Lewis acid, though mechanistic details have not been
established. The reaction of hydrazines with alkynes reported
herein proceeds along a complex pathway in which the metal
stabilizes a range of reactive intermediates distinct from those
found for titanium-catalyzed hydrohydrazinations. This capa-
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Received: February 12, 2011
Published online: May 12, 2011
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ꢀ
Keywords: C N coupling · homogeneous catalysis · indoles ·
reaction mechanism · zirconium
.
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