Multicomponent Pyrazole Synthesis from Alkynes, Nitriles, and Titanium Imido Complexes via Oxidatively Induced N-N Bond Coupling

Article abstract of DOI:10.1021/jacs.9b13173

Pyrazoles are an important class of heterocycles found in a wide range of bioactive compounds and pharmaceuticals. Pyrazole synthesis often requires hydrazine or related reagents where an intact N-N bond is conservatively installed into a pyrazole precursor fragment. Herein, we report the multicomponent oxidative coupling of alkynes, nitriles, and Ti imido complexes for the synthesis of multisubstituted pyrazoles. This modular method avoids potentially hazardous reagents like hydrazine, instead forming the N-N bond in the final step via oxidation-induced coupling on Ti. The mechanism of this transformation has been studied in-depth through stoichiometric reactions of the key diazatitanacyclohexadiene intermediate, which can be accessed via multicomponent coupling of Ti imidos with nitriles and alkynes, ring opening of 2-imino-2H-azirines, or direct metalation of 4-azadiene-1-amine derivatives. The critical transformation in this reaction is the 2-electron oxidation-induced N-N coupling on Ti. This is a rare example of formal N-N coupling on a metal center, which likely occurs through an electrocyclic mechanism analogous to a Nazarov cyclization. Conveniently, these 2-electron-oxidized diazatitanacyclohexadiene intermediates can be accessed via disproportionation of the 1-electron-oxidized species, which allows utilization of weak oxidants such as TEMPO

Full text of DOI:10.1021/jacs.9b13173

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Article
Multicomponent Pyrazole Synthesis from Alkynes, Nitriles,
and Ti Imidos via Oxidatively Induced N-N Bond Coupling
Adam J Pearce, Robin P Harkins, Benjamin R Reiner,
Alexander C Wotal, Rachel J Dunscomb, and Ian A. Tonks
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 11 Feb 2020
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Page 1 of 11
Journal of the American Chemical Society
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Multicomponent Pyrazole Synthesis from Alkynes, Nitriles, and Ti
Imidos via Oxidatively Induced N-N Bond Coupling
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†
Adam J. Pearce, Robin P. Harkins, Benjamin R. Reiner, Alexander C. Wotal, Rachel J. Dunscomb, and Ian A.
Tonks*
Department of Chemistry, University of Minnesota−Twin Cities, 207 Pleasant Street SE, Minneapolis, Minnesota 55455, United
States
ABSTRACT: Pyrazoles are an important class of heterocycles found in a wide range of bioactive compounds and pharmaceuticals.
Pyrazole synthesis often requires hydrazine or related reagents where an intact N-N bond is conservatively installed into a pyrazole
precursor fragment. Herein, we report the multicomponent oxidative coupling of alkynes, nitriles, and Ti imidos for the synthesis of
multisubstituted pyrazoles. This modular method avoids potentially hazardous reagents like hydrazine, instead forming the N-N bond
in the final step via oxidation-induced coupling on Ti. The mechanism of this transformation has been studied in-depth through
stoichiometric reactions of the key diazatitanacyclohexadiene intermediate, which can be accessed via multicomponent coupling of
Ti imidos with nitriles and alkynes, ring opening of 2-imino-2H-azirines, or through direct metalation of 4-azadiene-1-amine deriva-
tives. The critical transformation in this reaction is the 2-electron oxidation-induced N-N coupling on Ti. This is a rare example of
formal N-N coupling on a metal center, which likely occurs through an electrocyclic mechanism analogous to a Nazarov cyclization.
Conveniently, these 2-electron oxidized diazatitanacyclohexadiene intermediates can be accessed via disproportionation of the 1-
electron oxidized species, which allows utilization of weak oxidants such as TEMPO.
3
3
Introduction
nucleophilic coupling. Other aerobically-triggered reductive elim-
inations have been reported for the synthesis of hydrazines and
Pyrazoles are an important class of N-N bond containing heterocy-
cles found in flagship pharmaceuticals such as Eliquis, Viagra, Cele-
brex and Acomplia. Multisubstituted pyrazoles are most com-
monly synthesized via the Knorr condensation of hydrazines onto
3
4
0
azoarenes, and there is also an example of air oxidation of a d yt-
trium triamide complex that liberates aminyl radicals competent for
1–3
3
5
N-N coupling.
4–6
1,3-diketones or through a 1,3-dipolar cycloaddition of hydra-
Our group has produced several examples of early transition metal-
zones with alkynes or electron-deficient alkenes after autooxida-
catalyzed oxidative aminations of alkynes for the synthesis of pyr-
7
–15
36–40
tion. Direct N-N bond formation is an attractive alternative to
these classical methods, as it would remove the need to use poten-
tially toxic and/or explosive hydrazine reagents. However, N-N
bond forming methods are limited, particularly those proceeding
through formal reductive elimination at a transition metal center.
This is due to the unfavorable thermodynamics of N-N bond reduc-
tive elimination, which results in a weak N-N bond at the expense of
two strong metal-N bonds. Despite this challenge, there are a few el-
egant examples of late transition metal facilitated N–N bond reduc-
tive eliminations: (1) Cu-catalyzed or -mediated synthesis of pyra-
roles,
which proceeds through an electrocyclic reductive elimi-
nation to form a C-N bond from an azatitanacyclohexadiene inter-
4
1
mediate (Figure 1c, bottom right). We envisioned that reaction of
42,43
an analogous diazatitanacyclohexadiene –formed from the reac-
tion between a nitrile and the common azatitanacyclobutene inter-
44,45,54,46–53
mediate
–could result in a formal N-N bond reductive elim-
ination to produce multisubstituted pyrazoles, either through cata-
lytic turnover with azobenzene as an oxidant or by further reaction
with an exogenous oxidant (Figure 1c, bottom left). Herein, we re-
port an example of oxidation-induced N–N bond reductive elimina-
tion, yielding pyrazoles from diazatianacyclohexadienes (Figure 1c,
top). These diazatianacyclohexadienes can be generated from the
coupling of an alkyne and a nitrile with a Ti imido, providing a prac-
tical and simple multicomponent [2+2+1] route to pyrazoles. Mech-
anistic studies indicate that N-N coupling is triggered by 2-electron
oxidation of the diazatianacyclohexadiene, which generates an inter-
mediate that can undergo electrocyclic ring closure in analogy to a
Nazarov-type cyclization.
1
6,17
zoles from nitriles and enamines (Figure 1a), as well as a few re-
8–22
1
lated transfromations
a binuclear Ni complex which couples triazabicyclodecene ligands
and (2) a stoichiometric example featuring
2
3
after oxidation with hypervalent iodine reagent PhICl (Figure 1b).
2
In the pyrazole examples, the aromaticity gained provides driving
force to overcome the otherwise weak N-N bond (approximately 24
24
kcal/mol for the parent pyrazole ). In the binuclear Ni example,
generation of high valent metal centers makes reductive elimination
more favorable. Oxidatively-induced reductive elimination is a com-
mon strategy employed in late transition-metal organometallic
2
5–32
chemistry to overcome otherwise challenging couplings.
More-
over, increasing the oxidation state of the system as a whole has been
shown to increase the electrophilicity of the ligands towards
ACS Paragon Plus Environment

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Page 2 of 11
a) Glorius, 2010:
Ph
N
R1
R2
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
N
CN
Et
N
R2
N
Cu(OAc)
2
R1
N
+
N
H
0.5 PhNNPh
110-120 oC, air
R4
Me
+
10% [py TiCl (NPh)]
2
p-tol
Et
R3
CO
2
R4
CO R3
2
2
2
Et
Br, 145 o
20 h
1 (16%)
Ph
N
C
6
D
5
C
1
NPh
Cu
R
Et
Et
+
N
N
+
Et
Et
Et
R4
R2
Et
Et
3 (9%)
CO
2
R3
2 (57%)
via
b) Diao, 2016:
Figure 2. Multicomponent coupling of p-tolunitrile, 3-hexyne and
azobenzene catalyzed by py TiCl (NPh).
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
2
N
N
Ni
N
N
N
N
2 equiv PhICl
z
2
N
N
N
N
N
A potential mechanism for the multicomponent catalytic reaction
was computed in analogy to our previous multicomponent synthesis
of pyrroles (Figure 3). Computations indicate that the key interme-
diate diazatitanacyclohexadiene IM5-pyz is very stable (ΔG = -17.4
TiCl (NPh)) and the barrier to N-N reduc-
tive elimination (TS3-pyz 46 kcal/mol from IM5-pyz) is over-
Ni
N
N
N
N
Ni
Cl Cl
0
.5 equiv
PhICl
Cl
1.5 equiv
PhICl2
N
2
N
Ni
N
kcal/mol relative to py
3
2
N
N
N
N
Ni
N
1
N
whelmingly high. In fact, H NMR monitoring of the reaction shows
the formation of a new species consistent with the structure of IM5-
pyz at 90% yield relative to catalyst within 10 min, suggesting the sta-
bility of IM5-pyz is inhibitive for productive catalysis. While the for-
mation of 1a demonstrates that diazatitanacyclohexadiene IM5-pyz
or another analogous species is capable of N-N coupling, we suspect
that the high barrier to ring closure likely facilitates competitive
acid/base chemistry to occur, ultimately leading to hydroamination.
In fact, protonated diazatitanacycles crystallize from the reaction
mixture (see Supporting Information). Thus, unlike previous exam-
ples of Ti-catalyzed nitrene transfer, PhNNPh may not be a strong
enough oxidant to drive productive N-N bond forming catalysis.
c) This Work: Multicomponent Pyrazole Synthesis via Oxidation-Induced N-N Coupling:
py
Cl
py
Cl
Ph
R
R
then,
2 equiv. TEMPO
Ti
R
Ph
R
[py
2
TiCl
2
(NPh)]
2
N
N
N
N
2
R CN +
R
C
6
D
5
Br, 115 oC, 1 h
C D Br, 50 oC, 2 h
R2
6
5
R2
R
Ph
N
R
Ph
N
nitrene
oxidant
N
R
R
R2
R
II
[L
n
Ti ]
II
Oxidation-
Induced
N-N Coupling
n
[L Ti ]
R
R
L
n
Ti
N
Ph
This Work:
2+2+1] Pyrazole
Synthesis
Prior Work:
[2+2+1] Pyrrole
Synthesis
[
RCCR
Ph
L
n
Ln
Ti
Ti
Ph
R
Ph
R
N
N
L
n
Ti
N
N
R2
R
R
N
R
R
R
R
R
Key Intermediate:
Diazatitanacyclohexadiene
R2
R
Figure 1. a) Cu-catalyzed oxidation-induced formal N-N reductive elim-
ination for the synthesis of pyrazoles from electron-poor enamines and
nitriles. b) Ni-mediated N-N bond reductive elimination. c) Formal
2+2+1] multicomponent synthesis of pyrazoles via oxidation-induced
N-N coupling, and a proposed catalytic cycle for pyrazoles compared to
the previously reported [2+2+1] synthesis of pyrroles.
[
Results and Discussion
Multicomponent coupling for the synthesis of pyrazoles. Initial cat-
alytic multicomponent coupling attempts of azobenzene, alkynes
and nitriles catalyzed by [py TiCl (NPh)] , were met with limited
2
2
2
success. For example, reaction of p-tolunitrile, 3-hexyne and azoben-
zene for 20 h at 145 ˚C yields 16% of the desired 4,5-diethyl-N-phe-
nyl-3-p-tolylpyrazole (
animine ( ) and 9% 2,3,4,5-tetraethyl-N-phenylpyrrole (
Scheme 1). Although the yield of is lower than the catalyst load-
ing, we were able to demonstrate catalytic turnover using a labeled
azobenzene, ArNNAr (Ar = p-(CF O)C ), which showed incor-
1
) in addition to 57% N-phenyl-3-hex-
2
3
)
(
1
Figure 3. Computed cycle for pyrazole formation via direct N-N bond
coupling (M06/6-311G(d,p)/SMD, 145 °C, C
N bond formation in the analogous multicomponent pyrrole synthesis
(M06/6-311G(d,p)/SMD, 115 °C, PhCF ) by Ti-imido catalysts.
6
D
5
Br) compared to C-
3
6
H
4
poration of both Ph (from the precatalyst) and Ar into the pyrazole
product (Table S2, Supporting Information).
3
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Page 3 of 11
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Pyrrole computations and intermediate labels adapted from ref. 37. All
free energies are referenced to py TiCl (NPh) = 0.0 kcal/mol.
ligands. Treatment of 6a and 6b with pyridine generates
py TiCl
(ADA) (7a 7b) in 30% crystallized yield. The x-ray crystal
structures for 5a and 7a are shown in Figure 4. 5a 7a and 7b all have
similar solid-state metrics, and contain a titanium vinylimido with a
pendent imine donor. For example, 7a has a Ti1–N1 distance of
1.768(1) Å, indicative of Ti-N imido multiple bonding, and a Ti1–
N2 distance of 2.126(1) Å, indicative of a Ti-N imine dative bond.
These bond lengths are consistent with the computed values for
IM5-pyz (Figure 3, bottom), where Ti1–N1 and Ti-N2 to were
computed to be 1.71701 Å and 2.10562 Å, respectively. Further re-
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
3
2
2
2
,
,
Diazatitanacyclohexadiene synthesis. We next synthesized several
diazatitanacyclohexadiene model complexes in order to study po-
tential routes to productive N-N bond formation with other oxidants
beyond PhNNPh (Figure 4). Protonolysis of TiCl
-azadiene-1-amine (H
ADA) (4a) gives (HNMe
5a) in 46% isolated yield. Reaction of H ADA (4a
TiCl (THF)
LiHMDS (HMDS = hexamethyldisilazide) produces the dinuclear
2
(NMe
2
) with a
(ADA )
2
Ph
4
2
2
)TiCl
2
(
2
,
4b) with
4
2
in THF followed by the addition of 2 equivalents of
actions were carried out with 7a and 7b because the HNMe
2
ligand
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
species [TiCl
(ADA)]
(
6a
,
6b), which is bridged through the imido
2
2
in 5a can potentially participate in deleterious acid/base reactions.
2.125(2) Å
H
4
2
ADAR
a R = Ph
4b R = Et
Me HN
Cl
2
Cl
TiCl (NMe )
2
2
2
Ti
1.740(1) Å
.338(2) Å
N
N
NH
2
N
C H
6
6
-
HNMe
2
Ph
1.334(2) Å
1
R
Me
Me
Me
Me
5a
4 2
1.) TiCl (THF)
1.437(2) Å
THF
1.391(3) Å
2.) 2 LiHMDS
- 2 LiCl, - 2 HMDS
Me
Me
Ti
py
py
Cl
R
2.126(1) Å
Cl
N
Ti
Cl
Cl
2
pyridine
N
N
N
N
0
.5 Ph
Ti
Ph
R
1.768(1) Å
.322(2) Å
Cl
N
6 6
C H
Cl
R
1.333(2) Å
1
Me
Me
Me
Me
6a-b
7a-b
1.426(2) Å
1.400(2) Å
,
Figure 4. Syntheses of diazatitanacyclohexadienes 5a 7a, and 7b and ORTEP diagrams of 5a and 7a. Thermal ellipsoids are drawn at 50% probablility
and hydrogen atoms omitted for clarity. Full crystallographic data for 5a
,
7a, and 7b is available in the supporting information.
Diazatitanacyclohexadiene oxidation. Although 7a and 7b are both
amounts of 1a. N-N bond coupling was not observed when react-
IV
Ti , we hypothesized that ligand-based oxidation could increase
ing with several common oxidants such as I
Me NO, instead leading to intractable mixtures.
Table 1. Oxidation of 7a with various oxidants.
2
, NBS, NOBF and
4
the electrophilicity of N
α
and promote N-N coupling in analogy to
3
late transition metal-based oxidations that induce reductive elimi-
nation. In fact, several oxidants promote facile, room temperature
N-N coupling with 7a and 7b (Table 1). Reaction of 7a and 7b
with 2 equiv TEMPO resulted in 80% isolated yield of the N-N
coupled pyrazole product 1a or 1b after 2 hours (Table 1, entry 1),
respectively. When the reaction is performed with 1 equiv
TEMPO, a 1:1 mixture of unreacted 7a and pyrazole 1a is ob-
served, which is indicative of a net 2-electron stoichiometry re-
quirement for the reaction (Table 1, entry 2). Likewise, hyperva-
a
py
Cl
py
Cl
Ph
Ti
Oxidant
N
N
N
N
Ph
6 6
C D
Ph
p-tol
Me
Me
Me
7
a
1a
Entry Oxidant
time
T (˚C)
% Yield
lent iodine reagents PhICl
sulted in good yields of 1a or 1b (Table 1, entries 3-5). Interest-
ingly, oxidation of 7a by PhI(OAc)
(Table 1, entry 5) results in an
2
, PhI(TFA)
2
, and PhI(OAc) all re-
2
(h)
b
1
2
3
4
5
6
7
8
TEMPO (2 equiv)
TEMPO (1 equiv)
2
50
50
rt
87 (80 )
40
2
initial mixture of 1a with a kinetic azirine product (8a), which
slowly converts to 1a over time. Intermediacy of 8a could indicate
2
c
c
c
PhICl
PhI(O
PhI(OAc)
2
3
70
5
5–57
potential free nitrene reactivity
or transmetallation to I, but
2
CCF
3
)
2
3
rt
76
control experiments rule out these possibilities (Figure S90 and
S96, Supporting Information). The intermediacy of 8a was not ev-
ident in any other reaction. Other oxidants also engender produc-
2
3
rt
44
FcPF
6
(2 equiv)
(2 equiv)
16
70
3
rt
32
+
tive N-N coupling, including FcPF
6
(Fc = Cp
2
Fe ) and even O
2
,
FcPF
6
rt
50
albeit in lower yields. Prolonged exposure of 7a to PhNNPh even
at elevated temperatures (up to 145 ˚C) did not furnish tractable
amounts of 1a, consistent with early catalytic attempts. Thermoly-
sis of 7a in the absence of any oxidant also only led to trace
O
2
(1 atm)
60
17
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Journal of the American Chemical Society
Conditions: 7a (0.02 M), oxidant (1-2 equiv), 0.5 mL benzene.
Page 4 of 11
a
1
Yields are determined in situ via H NMR against internal TMB
standard. Isolated yield. Yields are determined via H NMR
against internal TCE standard added after the reaction.
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Table 2. Substrate scope of 1-pot in situ pyrazole synthesis from
alkynes and nitriles.
b
c
1
a
py
Cl
py
Cl
In situ multicomponent pyrazole synthesis. One-pot multicompo-
nent synthesis via alkynes and nitriles is an attractive, unrealized
and simple route to pyrazoles, Given that diazatitanacycles have
been observed as long-lived intermediates in our initial catalytic re-
action attempts, it seemed plausible that they could be generated
in situ by reaction of an alkyne and nitrile with a Ti imido and then
oxidized to generate the desired pyrazole product in a one-pot pro-
cedure (Table 2). Indeed, diazatitanacycles analogous to 7a and 7b
R3
Ph
0.5 equiv
TiCl (NPh)]
then,
2 equiv. TEMPO
Ti
Ph
R3
[py
2
2
2
N
N
N
N
1
R3
R CN +
C D Br, 115 oC, 4 h
C D Br, 50 oC, 2 h
6
5
6
5
R1
R1
R2
2
R2
R
in situ generated
c.f. IM5-pyz or 7a/b
1b - 1l
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
Entry
R
R
R
Product % Yield
1
1
can be synthesized in 81% in situ yield ( H NMR) by reaction of
b
c
1
4-Me-
C
Et
Et
1
75%
[
py
with respect to [Ti]) and 3-hexyne (6 equiv) in C
hour at 115 ˚C (Table 2, entry 1). C Br solvent was chosen be-
cause it is an affordable-to-access polar NMR solvent, and was suc-
2
TiCl
2
(NPh)]
2
with an excess of p-tolunitrile (6 equiv; 3 equiv
6
H
4
6
D
5
Br after an
b
c
2
Ph
Ph
4-
Et
Et
Et
Et
Et
Et
1b
1b
1c
79%
56%
52%
6
D
5
3
4
4
1
cessful for our previous [2+2+1] pyrrole cyclizations. Addition of
TEMPO after diazatitanacyclohexadiene formation, followed by
MeO-
C
heating at 50 ˚C for 2 hours affords pyrazole
1
in 75% yield with
6
H
4
respect to [py TiCl (NPh)]
2
2
2
(98% yield with respect to IM5-pyz).
5
4-CF
C
3
-
Et
Et
1d
49%
Based off of this result, comparative reactions were next carried out
at a 3:3:1 and 1:1:1 stoichiometry of benzonitrile, 3-hexyne and
Ti=NR (Table 2, entries 2 and 3). While the 1:1:1 stoichiometry
results in a lower conversion to the metalacyclic intermediate (Fig-
ure S54 and S57, Supporting Information), 1b is still generated in
6
H
4
i
6
Pr
Me
Me
Ph
Ph
Ph
Et
Et
1
e
54%
43%
28%
54%
52%
37%
7
Et
Et
1f
1g
1h
1i
8
Ph
Ph
Me
Me
Me
Me
56% overall yield with respect to alkyne (Table 2, entry 3). This
9
reaction could be performed at 1 mmol scale, resulting in 65% yield
of 1b (see Supporting Information). Inferring that the alkyne and
nitrile fragment may often be the more precious components of
this reaction, we next briefly explored the scope of this reaction at
the 1:1:1 stoichiometry. In all cases, the desired pyrazole products
were furnished in moderate to good yield. This method can toler-
ate both electron-rich and electron-poor nitriles (entries 3-5). p-
10
11
4-t-
BuC
4-t-
BuC
1j
6
H
4
6
H
4
a
Conditions: 0.025 mmol [py
2
TiCl
2
(NPh)] , 0.05 mmol (2 equiv)
2
alkyne, 0.05 mmol (2 equiv) nitrile, 0.5 mL PhBr, 115 ˚C, 4 hr;
1
yields with respect to alkyne are determined in situ via H NMR
(trifluoromethyl)benzonitrile effects a slightly lower yield (49%)
b
against internal 1,3,5-trimethoxybenzene standard. Conditions:
which is explained by detectable amounts of titanacycle decompo-
sition (entry 5). Alkyl nitriles (entries 6-8) are also effective cou-
pling partners in the reaction; however, the yield of diazatitana-
cycle oxidation is poor when coupling acetonitrile to 1-phenyl-1-
propyne (entry 8). 1-Phenyl-1-propyne couples with both ace-
tonitrile and benzonitrile affording the 5-methyl-4-phenyl regioi-
somers selectively (entry 8 and 9); notably, 5-alkyl-3-arylpyrazoles
are challenging to access via Knorr pyrazole synthesis due to the
regioselectivity of the hydrazine condensation step. Tetraarylpyra-
zoles, which have shown the enhancement of aggregation-induced
0
.025 mmol [py
2
TiCl
2
(NPh)] , 0.15 mmol (6 equiv) alkyne, 0.15
2
c
mmol (6 equiv) nitrile, 0.5 mL PhBr, 115 ˚C, 1 hr. Yields reported
with respect to [py
under condition B.
2
TiCl
2
(NPh)] , which is the limiting reagent
2
Mechanistic studies of N-N coupling. N-N coupling on Ti could
plausibly occur through one (or more) of 3 possible oxidation
states—either the “default” oxidation state, 1-electron oxidized, or
2-electron oxidized (Figure 5, top). In order to determine the sys-
58,59
emission, are accessible in 37% in situ yield for pyrazole 1j (en-
tem oxidation state that triggers N-N coupling on Ti, we sought to
conduct N-N coupling reactions with the entire redox series. Pre-
vious work in our group has shown that Cp Ti(BTMSA) (BTMSA
try 11) or 42% isolated yield when diphenylacetylene is used (see
Supporting Information). This scope demonstrates that multisub-
stituted pyrazoles can be accessed directly and generally in a single
step through multicomponent coupling of Ti imidos, while avoid-
ing prerequisite hydrazine or hydrazine-derived coupling partners.
2
61–65
=
bis(trimethylsilyl)acetylene)
6
rapidly ring-opens 2H-azirines
6
at the C–N bond. Thus, we hypothesized 2-imino-2H-azirine 8a
II
–
an isomer of pyrazole 1a – could react with a Ti source to give a
diazatitanacyclohexadiene in the “default” oxidation state. By ex-
Conveniently, [py
prepared in a single pot from TiCl
demonstrated benchtop-compatible Ti imido generation. Thus,
access to these multicomponent coupling reactions does not re-
quire specialized equipment or protocols.
2
TiCl
2
(NPh)]
2
and derivatives thereof can be
(THF) , and we have recently
III
tension of this logic, reacting 2-imino-2H-azirines with Ti and
4
2
6
0
IV
Ti precursors could allow for interrogation of 1- and 2-electron
oxidized diazatitanacyclohexadiene species, respectively.
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Which species undergo N-N coupling?
1
2
3
4
5
6
7
8
9
py
Cl
py
Cl
py
Cl
X
X
X
Cl
Cl
Cl
Ti
Ph
1 e-
Ti
Ph
-1 e
-
Ti
Ph
-
N
N
N
N
N
N
+ X-
+
X-
Ph
Ph
Ph
p-tol
p-tol
p-tol
Me
Me
7a-1e-
Me
7a-2e-
7a
“
default”
oxidation state
1 e- oxidized
2 e- oxidized
diazatitanacycle
diazatitanacycle
TMS
reaction II
2
Cp Ti
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Ph
Cp
Ti
2
“TiII”
Ph
N
TMS
N
N
N
stable
Ph
(some 1a + decomp at high T)
C
1
6
H
6
p-tol
p-tol
p-tol
Ph
p-tol
7a
0 min
BTMSA
Me
Me
-
9
a
2 py
N
isomers
89%
reaction III
TiIIICl
(THF)
X
3
Ph
N
Cl
Ti
2
Ph
Ph
Ti
Ph
Ph
Ph
N
N
N
disproportionation
N
N
3
3
N
TiIVCl
4
Ph
+
+
50% 7a-0e-
C D , 40 min
6
6
p-tol
Ph
not
p-tol
+
p-tol
Me
-
characterized
Me
c.f. 7a-1e-
50% 7a-2e
Me
1a (from 7a-2e-)
Me
7a-0e
42%
-
8
a
5
0%
2
H-azirines:
known to undergo
C-N ring opening
reaction IV
TiIVCl
(THF)
X
3
Ph
Ti
Ph
Ph
N
4
2
N
N
N
Ph
+
TiIVCl4
C
6
D
6
, 50 o
5 h
C
p-tol
not
X
Me
Me
characterized
1
a
7a-Cl-2e-
c.f. 7a-2e
full conversion
sole product
-
II
III
IV
Figure 5. Reaction of 8a with a series of Ti complexes spanning Ti , Ti , and Ti oxidation states.
6
7
occurs after C-N bond cleavage. By analogy, 2-imino-2H-azirines
-
II
III
IV
likely undergo similar reactivity to form 7a-Cl-2e , which can then
The reaction of Ti , Ti , and Ti precursors with the 2-imino-2H-
azirine 8a is shown in Figure 6. Reaction of 8a and
Cp Ti(BTMSA) rapidly gives the expected diazatitanacyclohexa-
undergo N-N coupling upon chloride loss. Consistent with this
mechanism, there are examples of late transition metal-catalyzed
2-acyl-2H-azirine or 2-imino-2H-azirine rearrangements to isoxa-
zoles or pyrazoles, respectively, that may proceed through similar
vinyl-nitrenoid intermediates.
Ph
Reactivity of Cp
2
Ph
diene Cp
Ti(ADA ) (9a) in 89% yield (Figure 5, Reaction II). In-
2
terestingly, XRD analysis of 9a (Figure 6) shows a Ti1–N1 bond
distance of 1.857(1) Å and a Ti1-N2 distance of 2.121(1) Å, indi-
cating an iminyl-enamide bonding description for this complex,
6
8–71
2
Ti(ADA ) (9a) with PhICl .
The 2H-azirine
2
contrasting the vinylimido-imine resonance form in complexes 5a
,
ring-opening redox series in Figure 5 strongly suggests that N-N
coupling to form pyrazoles occurs through the 2-electron oxidized
7
a
and 7b (Figure 4). Consistent with earlier results with 7a and
-
7b
, no N-N coupling occurs from 9a in this oxidation state.
diazatitanacycle of the form 7a-2e . We next aimed to synthesize
-
II
analogues of the 7a-2e intermediate and observe their direct N-N
coupling reactivity. We hoped that the stability imbued by the ti-
tanocene moiety in 9a would allow for isolation of an intermediate
in the PhICl
dark claret C
immediately furnishes a bright yellow solution, yielding 10a quan-
titatively (Figure 6), which exists as two isomers. The solid-state
structure of 10a (Figure 6) reveals chlorination of Ti and the C
position of the diazatitanacyclohexadiene ring. 10a is a “2-electron
oxidized” organic moiety, similar to the proposed azirine ring-
opened product from TiCl
Having shown that Ti reacts cleanly with 8a to give diazatitana-
cyclohexadiene 9a, we moved to investigate the in situ formation
of a diazatitanacycle radical via radical ring opening of 8a by
2
oxidations of diazatitanacyclohexadienes. Mixing a
solution of 9a with PhICl
at room temperature
TiCl
acts instantaneously with a benzene slurry of TiCl
ing a 1:1 mixture of pyrazole 1a and presumably the “default” oxi-
3
(THF)
3
(Figure 5, Reaction III) A benzene solution of 8a re-
6
D
6
2
3
(THF) yield-
3
Ph
-
dation state diazatitanacycle, (THF)
tion of 2 equiv pyridine generates 7a with the gradual precipitation
of a yellow solid presumed to be (py) TiCl . The formation of
equal parts pyrazole 1a 7a, and TiCl
strongly suggest the initial
formation of diazatitanacycle radical TiCl
x
TiCl
(ADA ) 7a-0e . Addi-
2
γ
2
4
,
4
-
Ph
-
4
(THF)
2
7a-Cl-2e - (Figure 5, Reaction
3
(ADA •) (7a-1e ), fol-
IV) and Alper’s earlier observations of γ-chlorination. However,
steric encumbrance imposed by the Cp rings in 10a likely prevents
imine coordination to Ti. Interestingly, 9a does not react with
TEMPO, which may indicate that reaction of TEMPO with 7a in-
itially requires coordination to Ti.
lowed by disproportionation into the “default” oxidation state and
-
the 2-electron oxidized species 7a-2e , which then couples to form
pyrazole.
III
Given the disproportionation reactivity with Ti , we then tested
IV
the reactivity of 2-imino-2H-azirines with Ti (Figure 5, Reaction
IV). Treatment of azirine 8a with TiCl
4
(THF) generates an uni-
2
dentified intermediate species, which upon heating to 50 ˚C re-
sults in conversion to 1a as the major product. Alper demonstrated
that TiCl will ring open 2H-azirines, in which γ-chlorination
4
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Ph
Ph
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Ph
Me
N
Cl Me
N
Ti
PhICl2
Ti
reflux
N
N
Cl Ph
Ph
N
N
C
6
D
6
C
6
D
6
, 22 h
p-tol
-PhI
- Cp TiCl (11)
2
2
Me
9
a
Me
10a
quantitative
c.f. 7a -2e-
Me
1a
79%
c.f. 7a
2
.121(1) Å
1
.890(2) Å
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
.407(2) Å
1.527(3) Å
1.560(3) Å
1.429(2) Å
1.857(1) Å
Figure 6. Oxidation of 9a to 10a by PhICl
2
nation of Cp TiCl
2
followed by thermal elimi-
2
to give 1a, and ORTEP diagrams of 9a and 10a
Thermal ellipsoids are drawn at 50% probability, and hydrogen atoms
are omitted for clarity. One crystallographically independent mole-
O have also been omitted. Full crystallo-
graphic data is available in the supporting information.
.
Figure 7. Cyclic voltammogram of 9a (DCM solvent, 3.5 mM 9a, 0.1
M NBu BPh ) at scan rates 1 – 200 mV/s (red – blue). Inset displays
pa/ipc as a function of scan rate.
4
4
i
cule of 10a and a solvent Et
2
Discussion of the mechanism of oxidatively induced N–N cou-
pling mediated by Ti. We propose the mechanism for N-N cou-
pling in Figure 8 based on the stoichiometric oxidations of 7a-b
,
Refluxing 10a in C for 22 h gives pyrazole 1a and Cp
the major products (Figure 6), consistent with 2-imino-2H-azirine
ring-opening by TiCl (THF) . The slower rate of decomposition
6
D
6
2
TiCl
2
as
the 2H-azirine 8a ring-opening reactivity with various Ti oxidation
states, and the reactivity and electrochemistry of 9a. First, multi-
component coupling of a Ti imido with an alkyne and nitrile via
4
2
of 10a into pyrazole compared to the reaction of 8a and TiCl
is
4
44,49
likely due to the hindered approach of the imine during N-N cou-
pling. Further, cyclic voltammetry of 9a features a quasireversible
the previously established [2+2]/insertion mechanism gives di-
azatitanacycle , arbitrarily considered to be in the “default” oxi-
dation state of this system. As demonstrated in the series of redox
experiments above (Figure 5, Reaction II), can also be accessed
via ring-opening of 2-imino-2H-azirines by a Ti precursor such as
Cp Ti(BTMSA). The barrier for N-N reductive elimination from
is too high, facilitating entry into competitive decomposition
pathways. Single-electron oxidation of leads to the 1-electron ox-
idized diazatitanacycle , which is unstable. From , there are two
possible reaction pathways: (1) disproportionation to and 2-
electron oxidized , which undergoes rapid N-N coupling to form
and a TiX coproduct, or (2) further oxidation to , as seen in
the oxidation of 9a to 10a by PhICl . The reaction of 8a with
TiCl (THF)
which results in 50% N-N coupled 1a and 50% of the
default” oxidation state 7a (Figure 5, Reaction III) provides evi-
dence for disproportionation. Further, weak oxidants such as
TEMPO or FcPF result in product formation despite an inability
A
0/+
1-electon oxidation at -0.55 mV vs. Fc which exhibits fully re-
versible behavior at scan rates ³ 200 mV/s (Figure 7). A linear de-
A
II
1
/2
pendence of ipa on n was observed, consistent with a mass trans-
fer limited process. This suggests that the quasireversiblity of 9a
oxidation at low scan rates arises from a chemical event coupled to
oxidation, which, based on the 2-imino-2H-azirine reactivity
above, is likely related to disproportionation of the 1-electron oxi-
dized Cp
Ti(ADA •) en route to 1a formation. Notably, no other
2
A
A
B
B
Ph
A
2
C
current deflection is observed in the anodic sweep before oxidation
of the supporting electrolyte at ~700 mV.
1
4
D
2
3
3
“
6
to oxidize 7a by 2-electrons, indicating that a disproportionation
mechanism is likely in play.
ACS Paragon Plus Environment

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Journal of the American Chemical Society
oxidation-induced formal N-N reductive elimination
1
2
3
4
5
6
7
8
9
2 e- oxidized
rapid N-N coupling
“
default”
1 e- oxidized
oxidation state
X
2
X3
X
Ti
4
Ph
L
n
X
2
Ti
N
Ph
Ti
Ph
Ti
Ph
Ph
R
N
N
N
X•
N
N
disproportionation
N
N
N
R
R
+
+
N
0
.5
R
oxidation
R
R
R
R
R
R
R
R
R
R
R
(X• = TEMPO,
0.5 A
TiX
4
1
A
PhIX
2
, etc)
B
C
entrypoint:
N-N coupled
pyrazole product
multicomponent
coupling
II
TiIIICl
Cp
2
Ti (BTMSA)
3
(THF)
3
X•
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
oxidation
e.g. reaction II
e.g. reaction III
C-X dissociation
Ph
R
X3
Ti
N
TiIVCl
e.g. reaction IV
(THF)
Ph
R
N
4
2
N
N
R
R
R
X
R
e.g. 8
X = Cl- or anion equivalent from oxidant
D
entrrypoint:
azirine ring-opening
c.f. 10a
Figure 8. Proposed mechanism for pyrazole formation from diazatitanacyclohexadienes.
Although is also 2-electron oxidized like , C-X dissociation to Based on the above evidence, the two-electron oxidized diaza-
D
C
C
is likely necessary for rapid N-N coupling to occur. Evidence for titanacycle is likely responsible for rapid N-N bond formation,
this can be seen in several reactions. For example, reaction of
TiCl (THF)
with 8a (Figure 5, Reaction IV) results in full con-
version to 1a, but the reaction is slower than TiCl
(THF) and re-
quires heat to drive to completion. Based on work from Alper, re-
action IV likely generates an intermediate analogous to . Thus,
C
which depending on oxidant strength can be accessed either
through disproportionation of a one-electron oxidized species or
directly through two-electron oxidation. We have previously es-
tablished in related [2+2+1] pyrrole syntheses that C-N bond re-
ductive elimination from a 6-membered azatitanacycle proceeds
through an electrocyclic mechanism. Here, oxidation of the diaza-
4
2
3
3
D
the major difference between the oxidized diazatitanacycles in re-
actions III and IV is the presence of an extra equivalent of Cl in IV;
-
titanacycle should make the a-N significantly more electrophilic,
prompting ring-closure in analogy to a Nazarov-like electrocycliza-
tion (Figure 9). The kinetic slowdown in the presence of coordi-
nating anions is further evidence for an electrocyclic mechanism:
indicating that dissociation of halide from
cationic diazatitanacycle is likely kinetically relevant. Further ev-
idence for the role of X dissociation from may also be seen in
the overall yields with hypervalent iodine oxidants presented in
Table 1: reactions with anion equivalents that would be poor leav-
D
to make the carbo-
C
-
D
intermediate , with full p-conjugation, undergoes rapid reaction,
C
whereas intermediate
for electrocyclization.
D
lacks the conjugated p-system requisite
-
ing groups (e.g. OAc ) generally result in lower yields than more
weakly coordinating anion equivalents and/or better leaving
-
-
groups (Cl , O
2
CCF ).
3
Electrocyclic N-N Coupling:
X
4
X
2
X
4
X
Ti
4
Ph
Ti Ph
Ti
Ph
Ti
Ph
R
Ph
R
N
N
N
N
N
N
N
N
N
N
- TiX4
2
X
R
R
R
R
R
R
R
R
R
R
R
R
R
R
R
Nazarov Cyclization:
R
R
R
R
R
R
R
R
Lewis
acid
O
O
O
O
O
LA
LA
LA
Figure 9. Analogy between electrocyclic N-N coupling and the electrocyclic Nazarov cyclization of dienones.
Conclusion
potentially electrocyclic process. While oxidatively-induced reduc-
0
tive elimination has been extensively explored, the concept of d
In summary, we have shown that simple titanium-imidos are capa-
ble of selective coupling with alkynes and nitriles to generate diaza-
titanacyclohexadienes, which can be oxidized under mild condi-
tions to generate pyrazoles in good yield. By exploring an electro-
transition metals mediating oxidatively-induced couplings
through ligand-centered oxidations may be a general strategy for
accessing new reactivity and myriad new types of metal-mediated
bond couplings, particularly via these types of electrocyclic path-
ways.
II
III
chemical series of 2-imino-2H-azirine ring openings with Ti , Ti ,
IV
and Ti , we have demonstrated that Ti-mediated N-N coupling
occurs from a 2-electron oxidized diazatitanacyclohexadienes via a
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JoséGómez-Escalonilla, M.; de la Hoz, A.; Langa, F.; Moreno, A.
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2
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1
1
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1
1
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2
2
2
2
2
2
2
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3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
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Deng, X.; Mani, N. S. Reaction of N-Monosubstituted Hydrazones
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Ma, C.; Li, Y.; Wen, P.; Yan, R.; Ren, Z.; Huang, G. Copper(I)-
Catalyzed Synthesis of Pyrazoles from Phenylhydrazones and
Dialkyl Ethylenedicarboxylates in the Presence of Bases. Synlett
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AUTHOR INFORMATION
Corresponding Author
(
14)
15)
*
itonks@umn.edu
2
011, 2011, 1321–1323.
Deng, X.; Mani, N. S. Regioselective Synthesis of 1,3,5-Tri- and
,3,4,5-Tetrasubstituted Pyrazoles from N -Arylhydrazones and
(
Present Address
1
†
Nitroolefins. J. Org. Chem. 2008, 73, 2412–2415.
Department of Chemistry, Yale University, 225 Prospect Street,
(16)
Neumann, J. J.; Suri, M.; Glorius, F. Efficient Synthesis of Pyrazoles:
Oxidative C-C/N-N Bond-Formation Cascade. Angew. Chemie -
Int. Ed. 2010, 49, 7790–7794.
Suri, M.; Jousseaume, T.; Neumann, J. J.; Glorius, F. An Efficient
Copper-Catalyzed Formation of Highly Substituted Pyrazoles
Using Molecular Oxygen as the Oxidant. Green Chem. 2012, 14,
2193.
Ueda, S.; Nagasawa, H. Facile Synthesis of 1,2,4-Triazoles via a
Copper-Catalyzed Tandem Addition−Oxidative Cyclization. J. Am.
Chem. Soc. 2009, 131, 15080–15081.
Tang, X.; Huang, L.; Yang, J.; Xu, Y.; Wu, W.; Jiang, H. Practical
Synthesis of Pyrazoles via a Copper-Catalyzed Relay Oxidation
Strategy. Chem. Commun. 2014, 50, 14793–14796.
Chen, B.; Zhu, C.; Tang, Y.; Ma, S. Copper-Mediated Pyrazole
Synthesis from 2,3-Allenoates or 2-Alkynoates, Amines and Nitriles.
Chem. Commun. 2014, 50, 7677.
Dai, G.; Yang, L.; Zhou, W. Copper-Catalyzed Oxidative
Dehydrogenative N–N Bond Formation for the Synthesis of N,N′-
Diarylindazol-3-Ones. Org. Chem. Front. 2017, 4, 229–231.
Ryan, M. C.; Kim, Y. J.; Gerken, J. B.; Wang, F.; Aristov, M. M.;
Martinelli, J. R.; Stahl, S. S. Mechanistic Insights into Copper-
Catalyzed Aerobic Oxidative Coupling of N–N Bonds. Chem. Sci.
2020, 11, 1170–1175.
New Haven, CT, United States.
Funding Sources
(17)
Financial support was provided by the National Institutes of Health
(1R35GM119457), and the Alfred P. Sloan Foundation (I.A.T. is a
2017 Sloan Fellow). Instrumentation for the University of Minnesota
Chemistry NMR facility was supported from a grant through the Na-
tional Institutes of Health (S10OD011952). X-ray diffraction experi-
ments were performed with a diffractometer purchased through a
grant from NSF/MRI (1229400) and the University of Minnesota.
(18)
(19)
ACKNOWLEDGMENT
(
20)
21)
We acknowledge the Minnesota Supercomputing Institute (MSI) at
the University of Minnesota for providing resources that contributed
to the results reported within this paper. AJP would like to thank Vic-
tor Young Jr. for assistance with XRD analysis, as well as Evan P.
Beaumier and Xin Yi See for enlightening discussions and generously
sharing reagents.
(
(22)
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