Bis(imido)vanadium(V)-Catalyzed [2+2+1] Coupling of Alkynes and Azobenzenes Giving Multisubstituted Pyrroles

Article abstract of DOI:10.1021/jacs.8b13390

The combination of VCl₃(THF)₃ and N,N-bis(trimethylsilyl)aniline (1a) is an efficient catalyst for the [2+2+1] coupling reaction of alkynes and azobenzenes, giving multisubstituted pyrroles. A plausible reaction mechanism involves the generation of a mono(imido)vanadium(III) species as an initiation step, where 1a served as an imido source with concomitant release of 2 equiv of ClSiMe₃, followed by a reaction with azobenzene to form a catalytically active bis(imido)vanadium(V) species via N=N bond cleavage.

Full text of DOI:10.1021/jacs.8b13390

Subscriber access provided by WEBSTER UNIV
Communication
Bis(imido)vanadium(V)-Catalyzed [2+2+1] Coupling of
Alkynes and Azobenzenes Giving Multi-Substituted Pyrroles
Kento Kawakita, Evan P. Beaumier, Yuya Kakiuchi, Hayato Tsurugi, Ian A. Tonks, and Kazushi Mashima
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b13390 • Publication Date (Web): 07 Feb 2019
Downloaded from http://pubs.acs.org on February 7, 2019
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a service to the research community to expedite the dissemination
of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in
full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully
peer reviewed, but should not be considered the official version of record. They are citable by the
Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore,
the “Just Accepted” Web site may not include all articles that will be published in the journal. After
a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web
site and published as an ASAP article. Note that technical editing may introduce minor changes
to the manuscript text and/or graphics which could affect content, and all legal disclaimers and
ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or
consequences arising from the use of information contained in these “Just Accepted” manuscripts.
is published by the American Chemical Society. 1155 Sixteenth Street N.W.,
Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 6
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
Bis(imido)vanadium(V)-Catalyzed [2+2+1] Coupling of Alkynes and
Azobenzenes Giving Multi-Substituted Pyrroles
†
‡
†
,†
,‡
Kento Kawakita, Evan P. Beaumier, Yuya Kakiuchi, Hayato Tsurugi,* Ian A. Tonks,* and
Kazushi Mashima*,†
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
†Department of Chemistry, Graduate School of Engineering Science, Osaka University, Toyonaka, Osaka, 560-8531, Japan
‡Department of Chemistry, University of Minnesota—Twin Cities, 207 Pleasant Street SE, Minneapolis, Minnesota 55455,
United States
Supporting Information Placeholder
and oxidation states can potentially play a role in complex, oxida-
tive heterocycle-forming reactions.
3 3
ABSTRACT: The combination of VCl (THF) and N,N-bis(tri-
10
methylsilyl)aniline (1a) is an efficient catalyst for [2+2+1] cou-
pling reaction of alkynes and azobenzenes, giving multi-substituted
pyrroles. A plausible reaction mechanism involves the generation
of a mono(imido)vanadium(III) species as an initiation step, where
Scheme 1. Transition Metal-Catalyzed [2+2+1] Pyrrole
Formation Reactions
1
a served as an imido source with concomitant release of 2 equiv
of ClSiMe , followed by a reaction with azobenzene to form a cat-
3
alytically active bis(imido)vanadium(V) species via N=N bond
cleavage.
Multi-substituted pyrroles are synthetically valuable heteroaro-
matic compounds in terms of their versatility as building blocks of
1
2
3
pharmaceuticals, natural products, functional materials, and
4
dyes. Although cyclocondensation reactions such as the Paal-
5
6
Knorr and Hantzsch reactions are well-established routes for syn-
thesizing multi-substituted pyrroles, transition metal-catalyzed
multicomponent coupling reactions have been recently investigated
7
as potent alternatives. Among them, the [2+2+1] cycloaddition re-
action of alkynes and primary amines is attractive because many
alkynes and primary amines are commercially available or easily
8
synthesized. As shown in Scheme 1, AgBF
4
catalyzed the oxida-
tive coupling of activated alkynes and primary amines in the pres-
ence of stoichiometric amounts of iodobenzene diacetate (Scheme
8
g
1a), Cu(OAc)
coupling of 2-butynedioate and primary amines (Scheme 1b), and
PdCl combined with superstoichiometric amounts of CuCl and
Na CO catalyzed the coupling of diarylalkynes and primary
2 2 3 2
combined with Cs CO under O catalyzed the
8
c
2
2
3
8
d
amines (Scheme 1c). In these [2+2+1] cycloaddition reactions,
activated alkynes bearing ester groups and stoichiometric amounts
of oxidant and base were inevitably required.
Recently, we reported a formal [2+2+1] coupling of alkynes and
azobenzenes that was catalyzed by (imido)titanium complexes, ei-
We have proposed that the previous Ti catalyst system for
[
2+2+1] pyrrole formation reaction involved (imido)titanium as the
ther preformed or in situ generated from TiCl
4
(THF)
2
and reductant
9
9
catalytically active species. Accordingly, we sought to find an-
other effective catalyst system by varying transition metal chlorides
upon activation by N,N-bis(trimethylsilyl)aniline (1a), since some
imido complexes of early transition metals have been synthesized
by treating metal chlorides with 1a with concomitant loss of 2 equiv
(Scheme 1d). In an effort to expand the classes of catalysts and
utility of this type of oxidative coupling, we herein report that va-
nadium complexes facilitate the [2+2+1] coupling of alkynes and
azobenzenes, where an in situ generated catalyst system of
3 3
VCl (THF) combined with N,N-bis(trimethylsilyl)aniline (1a)
9
b,11
of ClSiMe
2+2+1] pyrrole formation by reacting 5-decyne (2a) and azoben-
zene (3a) in the presence of various metal chlorides (10 mol%) and
3
.
Thus, we searched for the best catalyst system for
showed the best catalytic activity (Scheme 1e). Furthermore, we
confirmed that an in situ generated mono(imido)vanadium(III) in-
termediate cleaves the N=N double bond of azobenzene to give a
bis(imido)vanadium(V) active species, which is responsible for the
catalytic reaction, in contrast to the previously-reported mono(im-
ido)titanium(IV) active species for the Ti(II)/Ti(IV) catalytic cycle.
These results highlight that diverse catalyst metals, architectures,
[
1
a (10 mol%) in o-dichlorobenzene at 170 °C for 16 h.
The results of our initial catalyst screening are summarized in Ta-
ble 1. The [2+2+1] coupling product, N-phenyl-2,3,4,5-tetra(n-bu-
tyl)pyrrole (4aa), was obtained in 23% yield with TiCl (THF) and
3
3
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 2 of 6
1
a, whereas the yield of 4aa was 4% for TiCl
4
(THF)
tries 1 and 2); both reactions produced a small amount of alkyne-
trimerization product, hexa(n-butyl)benzene. In contrast,
VCl (THF) quantitatively gave 4aa without any contamination of
hexa(n-butyl)benzene (entry 3). CrCl (THF) and MnCl
resulted in no reaction (entries 4 and 5). In the absence of 1a, the
reactivity of VCl (THF) was significantly suppressed, giving 4aa
in 9% yield (entry 6). Among other early transition metal chlorides
2
and 1a (en-
2i produced significant amounts of alkyne cyclotrimerization by-
1
2
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
products, even in the presence of excess amount of azobenzene in
1
4
the case of 2i. We further tested the effect of various additives
for synthesizing 4aa: ether, iodoarene, nitrile, amide, and phos-
phine (1 equiv with respect to the catalyst) were tolerated in the
reaction, an improved scope compared to the original Ti system
3
3
3
3
2
(THF)1.5
15
3
3
(Table S4).
6
showed moderate catalytic activity
Table 2. Scope and Limitations of Alkynesa
we screened in Table S1, WCl
to give 4aa in 65% yield.
Noteworthy was that the yield of 4aa by a preformed (imido)va-
nadium(V) complex, V(=NPh)Cl , was sensitively affected by the
addition of 1a: in the presence of 1a, V(=NPh)Cl produced 4aa in
quantitative yield, whereas in the absence of 1a, V(=NPh)Cl re-
sulted in poor yield of 4aa (entries 7 and 8). This result indicates
that the formation of bis(imido)vanadium(V) species may be im-
portant for catalysis (vide infra). Bulkiness of the substituent on
3
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
3
3
b
entry
alkyne
yield [%](4:5:6)
74
1
2
the imido group of the precatalyst was another factor to control the
1
2
R = R = Et (2b)
t
1
2
n
catalytic yield: V(=N Bu)Cl
3
/1a showed high yield, while bulkier
R = R = Pr (2c)
92
16c
i
1
2
V(=N(2,6- Pr
2
C
6
H
3
))Cl
3
/1a resulted in significantly lower yield
3
R = R =Ph (2d)
1
2
i
(
entries 9 and 10). We thus selected VCl
3
13
(THF)
3
/1a as the best
4
R = Me, R = Pr (2e)
54 (72:17:11)
34 (53:47:0)
42 (100:0:0)
53 (100:0:0)
1
2
catalytic system for further substrate scope.
5
6d
R = Me, R = Ph (2f)
1
2
n
R = SiMe
3
, R = Bu (2g)
1
2
t
Table 1. Catalyst Screeninga
7
8e
R = H, R = Bu (2h)
1
2
n
R = H, R = Bu (2i)
17 (53:35:12)
aReaction condition: 2; 0.988 mmol, 3a; 0.165 mmol, C
D
Br; 0.5 mL. NMR yield
based on 3a using 1,3,5-trimethoxybenzene (internal standard). Isolated yield. For
b
6
5
c
d
e
4
0 h. The reaction was performed using 1 equiv of 2i and 6 equiv of 3a.
We next examined the effect of the para-substituents of azoben-
zenes. The coupling reaction with 4,4’-dimethoxyazobenzene (3b)
or 4,4’-dimethylazobenzene (3c) afforded the corresponding pyr-
roles 4ab and 4ac in 66% and 69% yield, whereas reaction with
4,4’-dibromoazobenzene (3d) or 4,4’-bis(trifluoromethoxy)azo-
benzene (3e) resulted in the formation of 4ad or 4ae in 91% and
94% yield, respectively (Table S5). Hammett analysis of the cata-
lytic reaction using 3a-e revealed that the reaction rate was accel-
erated by the electron-withdrawing substituents ( = 1.97, Figure
yield [%]b
entry
cat.
additive
1
2
3
4
5
6
7
8
9
TiCl
3
(THF)
3
2
PhN(SiMe
PhN(SiMe
PhN(SiMe
PhN(SiMe
PhN(SiMe
-
3
3
3
3
3
)
)
)
)
)
2
2
2
2
2
(1a)
23
TiCl
4
(THF)
(1a)
(1a)
(1a)
(1a)
4
>99 (71)c
VCl
3
(THF)
(THF)
(THF)1.5
(THF)
3
CrCl
3
3
trace
n.d.d
9
MnCl
2
VCl
3
3
V(=NPh)Cl
3
PhN(SiMe
-
)
3 2
(1a)
>99
6
S38), being in good accordance with the tendency observed for the
V(=NPh)Cl
3
9d,15
Ti-catalyzed system.
In addition, a good positive correlation
t
V(=N Bu)Cl
3
PhN(SiMe
PhN(SiMe
3
3
)
2
2
(1a)
(1a)
98
was observed between the initial reaction rate and reduction poten-
tials of azobenzenes, indicating that the reduction potential of azo-
benzenes is significant to determine the reaction rate (Figure
i
1
0
V(=N(2,6- Pr
2
C
6
H
3
))Cl
3
)
33
a
; 2.5 mL. bDeter-
Reaction condition: 2a; 3.00 mmol, 3a; 0.500 mmol, o-C
6
H
4
Cl
2
mined by GC using pentadecane (internal standard). cIsolated yield. Not detected
d
1
5
S40).
To gain insight into a reaction mechanism, we carried out a ki-
netic study for pyrrole formation under the optimized reaction con-
ditions where the catalyst was in situ generated by treating
VCl (THF) with 1a, and analyzed the resulting data by variable
3 3
time normalization analysis. The obtained rate law is provided in
Equation 1. The reaction obeyed a second-order with respect to the
concentration of VCl (THF) , which was in sharp contrast to the
3 3
half-order rate dependence on the catalyst concentration for the Ti-
catalyzed system, suggesting the involvement of a dimeric vana-
dium species for azobenzene N=N double bond cleavage. For the
substrates, we found a first-order rate dependence for the concen-
tration of 5-decyne, while the dependency of the concentration of
azobenzene was slightly deviated from a first-order rate, being 0.8.
With the best catalytic system in hand, we explored the scope and
limitations of alkynes for the vanadium-catalyzed pyrrole synthesis
with 3a in C D Br, and the results of the NMR yields are shown in
6 5
Table 2. Coupling reactions of symmetrical aliphatic alkynes such
as 3-hexyne (2b) and 4-octyne (2c) afforded the corresponding pyr-
roles 4ba and 4ca in 74% and 92% yield, respectively (entries 1
and 2), whereas the yield of 4da from diphenylacetylene (2d) and
1
6
3
a was low (entry 3). The unsymmetrical alkyne, 4-methyl-2-
9d
pentyne (2e), produced a mixture of 4ea, 5ea, and 6ea in 54% total
yield with the ratio of 72:17:11 for the regioisomers (entry 4).
When 1-phenyl-1-propyne (2f) was used as a substrate, the corre-
sponding regioisomers of 4fa and 5fa were formed in the ratio of
5
3:47 in 34% total yield (entry 5). Regioselectivity of this reaction
9
c
is assumed to be derived from the electronic effect of 2f. In con-
3 3
Rate ∝ [VCl (THF)
]2[5-decyne][azobenzene]0.8 (1)
trast, good steric control of the regioselectivity was observed when
1
-trimethylsilyl-1-hexyne (2g) was applied to the reaction, in which
During the catalytic reaction, an imidovanadium(III) species is
assumed to be responsible for the N=N bond cleavage, giving a
bis(imido)vanadium(V) species. We thus examined an in situ gen-
erated ‘V(=NPh)Cl’ species for the catalytic reaction. V(=NPh)Cl
4
was treated with an organosilicon reducing reagent, Si-Me -DHP,
the single regioisomer 4ga was obtained in 42% yield (entry 6).
Reaction with a bulky terminal alkyne, tert-butylacetylene (2h),
also afforded the single regioisomer 4ha in 53% yield (entry 7),
whereas all three regioisomers of 4ia, 5ia, and 6ia were detected by
using n-butylacetylene (2i) (entry 8); both terminal alkynes 2h and
3
7
1
2
ACS Paragon Plus Environment

Page 3 of 6
Journal of the American Chemical Society
in the presence of 2a and 3a in C
stoichiometry of this reaction was clarified by the observation of 2
equiv of ClSiMe and 1 equiv of 2,3,5,6-tetramethylpyrazine (Me
pyrazine) by H NMR analysis (Figure S44). Subsequent treat-
ment of the reaction mixture at 145 °C for 20 h resulted in the for-
mation of 4aa in 91% yield, indicating that a similar imidovana-
6
D
5
Br, giving ‘V(=NPh)Cl.’ The
VCl
ping with PMe
3
(THF)
3
to 1a and 3a under the reaction conditions and trap-
. One of two V=N moieties in B reacts with alkyne
1
2
3
4
5
6
7
8
9
3
2
0
3
4
-
via [2+2] addition to form an azavanadacyclobutene C. Next,
subsequent insertion of the second alkyne into the V—C bond af-
fords an azavanadacyclohexadiene intermediate D. The formation
of azametallacyclohexadienes from imidometal complexes and al-
1
15
21b
21b
dium(III) species may be generated from VCl
reaction mixture.
3
(THF)
3
and 1a in the
kynes was already noted for molybdenum, tungsten,
tita-
21a
21c
nium, and zirconium complexes. After the second insertion,
reductive elimination from D forms the corresponding pyrrole and
mono(imido)vanadium(III) species E, in which the low-valent va-
nadium center might be stabilized by the coordination of generated
pyrrole. Odom and co-workers observed the similar reductive
elimination from azamolybda- or azatungstacyclohexadiene, giv-
ing pyrrole derivatives.
generate a mono(imido)vanadium(III) species A. In fact, no reac-
tion was observed for complex 7 and 3-hexyne (2b) at room tem-
We further examined the reaction of the in situ generated im-
idovanadium(III) species ‘V(=NPh)Cl’ with 3a in toluene at 80 °C,
followed by subsequent addition of PMe
dium complex, V(=NPh) Cl(PMe (7), in 63% yield (eq 2). In this
reaction, half an equivalent of 3a with respect to V(=NPh)Cl was
3
to trap a bis(imido)vana-
2
2
2
3
)
2
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
3
21b
consumed. The molecular structure of 7 was confirmed by NMR
Finally, the pyrrole is dissociated to re-
and single crystal X-ray diffraction analysis (Figure 1).18 Complex
6 5 3
7 catalyzed the pyrrole formation in the presence of B(C F ) as a
phosphine scavenger in 88% yield (eq 3), clearly indicating that the
bis(imido)vanadium(V) species is a catalytically relevant species.
We also found that complex 7 was generated by treating
6 5 3
perature in the presence of B(C F ) , while we only found the for-
mation of N-phenyl-2,3,4,5-tetraethylpyrrole (4ba) without any in-
termediates such as C, D, and E upon heating. Based on the kinetic
study, the mono(imido)vanadium(III) A is the resting state for gen-
erating catalytically active bis(imido)vanadium B via bimetallic
mechanism, and further reaction of B with one equiv of alkyne is
the rate-determining step in this catalytic reaction. The key differ-
ences between this V-catalyzed reaction and the previous Ti-cata-
lyzed reaction is low-valent species as a resting state during this
catalytic cycle, which is consistent with the relative reducing ability
of Ti(II) and V(III).
VCl
3 3 6 5
(THF) with 1a in the presence of 3a in C D Br at 145 °C fol-
15
lowed by addition of PMe
3
.
Scheme 2. Plausible Reaction Mechanism for Vanadium-
catalyzed [2+2+1] Coupling of Alkynes and Azobenzenes
Figure 1. Molecular structure of complex 7 with 30% thermal
ellipsoids. All hydrogen atoms are omitted for clarity.
Based on the kinetic study and the control experiments, we pro-
pose a plausible catalytic cycle for the vanadium-catalyzed [2+2+1]
coupling of 5-decyne (2a) and azobezene (3a) (Scheme 2). Reac-
tion of VCl
3 3
(THF) with 1a generates an on-cycle mono(imido)va-
In summary, we have demonstrated catalytic [2+2+1] pyrrole for-
mation from alkynes and azobenzenes by VCl (THF) upon activa-
3 3
nadium(III) species A together with a release of 2 equiv of ClSiMe
3
under the reaction conditions. The V(III) species A reductively
tion with 1a as an imido source. Control experiments and kinetic
studies provided a plausible reaction mechanism, in which bis(im-
ido)vanadium(V) species is assumed to be a catalytic active species.
Bimetallic activation of azobenzene by a mono(imido)vana-
dium(III) species is a key step in the catalytic cycle, as evidenced
by the observation of the second-order rate dependence on the con-
centration of the catalyst. Further development of this vanadium-
catalyzed pyrrole formation reaction is ongoing in our laboratories.
cleaves the N=N double bond of 3a upon reaction with half an
equivalent of 3a, giving a bis(imido)vanadium species B,19 presum-
ably through a dimerization process similar to that proposed for Ti
9
d,e
system. This is consistent with the second-order rate dependence
on the concentration of the catalyst and the requirement of the im-
ido ligand for showing high catalytic activity. In addition, for-
mation of B is consistent with the generation of 7 after exposure of
3
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 4 of 6
(8) Selected examples of [2+2+1] pyrrole formation: (a) Matsui, K.;
Shibuya, M.; Yamamoto, Y. Synthesis of Pyrroles via Ruthenium-cat-
alyzed Nitrogen-transfer [2+2+1] Cycloaddition of α,ω-Diynes Using
Sulfoximines as Nitrene Surrogates. Comms. Chem. 2018, 1, 21. (b)
Chong, Q.; Xin, X.; Wang, C.; Wu, F.; Wan, B. Synthesis of Polysub-
stituted Pyrroles via Ag(I)-mediated Conjugate Addition and Cycliza-
tion Reaction of Terminal Alkynes with Amines. Tetrahedron 2014, 70,
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
ASSOCIATED CONTENT
Supporting Information
NMR characterization of complex 7 and the coupling products; full
experimental details regarding the kinetic study; and the .CIF file
for complex 7 are included in the Supporting Information. The
Supporting Information (PDF and CIF) is available free of charge
on the ACS Publications website.
4
2
90. (c) Zhang, L.; Wang, X.; Li, S.; Wu, J. Synthesis of Pyrrole-
,3,4,5-tetracarboxylates via a Copper-catalyzed Reaction of Amine
with But-2-ynedioate. Tetrahedron 2013, 69, 3805. (d) Chen, X.; Li,
X.; Wang, N.; Jin, J.; Lu, P.; Wang, Y. Palladium-Catalyzed Reaction
of Arylamine and Diarylacetylene: Solvent-Controlled Construction of
AUTHOR INFORMATION
Corresponding Author
2
,3-Diarylindoles and Pentaarylpyrroles. Eur. J. Org. Chem. 2012,
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
4380. (e) Chen, X.; Jin, J.; Wang, Y.; Lu, P. Palladium-Catalyzed Syn-
thesis of 7,9-Diaryl-8ꢀH-acenaphtho[1,2-c]pyrroles and Their Applica-
tion in Explosives Detection. Chem. - Eur. J. 2011, 17, 9920. (f) Wu,
T.-C.; Tai, C.-C.; Tiao, H.-C.; Kuo, M.-Y.; Wu, Y.-T. Nickel-Cata-
lyzed, Cascade Cycloadditions of 1-Ethynyl-8-halonaphthalenes with
Nitriles: Synthesis, Structure, and Physical Properties of New Pyr-
roloarenes. Chem. - Eur. J. 2011, 17, 1930. (g) Liu, W.; Jiang, H.;
Huang, L. One-Pot Silver-Catalyzed and PIDA-Mediated Sequential
Reactions: Synthesis of Polysubstituted Pyrroles Directly from Al-
kynoates and Amines. Org. Lett. 2010, 12, 312. (h) Yamamoto, Y.;
Kinpara, K.; Saigoku, T.; Takagishi, H.; Okuda, S.; Nishiyama, H.; Itoh,
K. Cp*RuCl-Catalyzed [2+2+2] Cycloadditions of α,ω-Diynes with
Electron-Deficient Carbon−Heteroatom Multiple Bonds Leading to
Heterocycles. J. Am. Chem. Soc. 2005, 127, 605.
*
*
*
tsurugi@chem.es.osaka-u.ac.jp
itonks@umn.edu
mashima@chem.es.osaka-u.ac.jp
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
We thank Mr. Hibiki Ochi for the initial experiment results. K.K.
thanks the financial support by the JSPS Research Fellow-ships for
Young Scientist. H.T. acknowledged the financial support by JSPS
KAKENHI grant No.15KK0185, a Fund for the Promotion of Joint
International Research (Fostering Joint International Research),
and Multidisciplinary Research Laboratory System of Graduate
School of Engineering Science, Osaka University. K.M. acknowl-
edged financial supports by JSPS KAKENHI Grant Numbers
(
9) (a) Chiu, H.-C., See, X. Y.; Tonks, I. A. Dative Directing Group Effects
in Ti-Catalyzed [2+2+1] Pyrrole Synthesis: Chemo- and Regioselec-
tive Alkyne Heterocoupling. ACS Catal. 2019, 9, 216. (b) Davis-Gil-
bert, Z. W.; Kawakita, K.; Blechschmidt, D. R.; Tsurugi, H.; Mashima,
K.; Tonks, I. A. In Situ Catalyst Generation and Benchtop-Compatible
1
5H05808, 15K21707 in Precisely Designed Catalysts with Cus-
II
IV
Entry Points for Ti /Ti Redox Catalytic Reactions. Organometallics
018, 37, 4439. (c) Chiu, H.-C., Tonks, I. A. Trimethylsilyl-Protected
tomized Scaffolding (No. 2702). Financial support was provided
by the National Institutes of Health (1R35GM119457), and the Al-
fred P. Sloan Foundation (I.A.T. is a 2017 Sloan Fellow). Equip-
ment for the UMN Chemistry Department NMR facility was sup-
ported through a grant from the National Institutes of Health
2
Alkynes as Selective Cross-Coupling Partners in Titanium-Catalyzed
[2+2+1] Pyrrole Synthesis. Angew. Chem., Int. Ed. 2018, 57, 6090. (d)
Davis-Gilbert, Z. W.; Wen, X.; Goodpaster, J. D.; Tonks, I. A. Mecha-
nism of Ti-Catalyzed Oxidative Nitrene Transfer in [2+2+1] Pyrrole
Synthesis from Alkynes and Azobenzene. J. Am. Chem. Soc. 2018, 140,
7267. (e) Guo, J.; Deng, X.; Song, C.; Lu, Y.; Qu, S.; Dang, Y.; Wang,
Z.-X. Differences between the Elimination of Early and Late Transition
Metals: DFT Mechanistic Insights into the Titanium-catalyzed Synthe-
sis of Pyrroles from Alkynes and Diazenes. Chem. Sci. 2017, 8, 2413.
(f) Davis-Gilbert, Z. W.; Hue, R. J.; Tonks, I. A. Catalytic Formal
(S10OD011952) with matching funds from the University of Min-
nesota.
REFERENCES
(
1) (a) Bhardwaj, V.; Gumber, D.; Abbot, V.; Dhiman, S.; Sharma, P. Pyr-
role: A Resourceful Small Molecule in Key Medicinal Hetero-aromat-
ics. RSC Adv. 2015, 5, 15233. (b) Baumann, M.; Baxendale, I. R.; Ley,
S. V.; Nikbin, N. An Overview of the Key Routes to the Best Selling
II
IV
[
2+2+1] Synthesis of Pyrroles from Alkynes and Diazenes via Ti /Ti
Redox Catalysis. Nat. Chem. 2016, 8, 63.
(
10)Beaumier, E. P.; Pearce, A. J.; See, X. Y.; Tonks, I. A. Modern Appli-
cations of Low-valent Early Transition Metals in Synthesis and Catal-
ysis. Nat. Rev. Chem. 2019, 3, 15-34.
11)Selected examples of using N,N-bis(trimethylsilyl)aniline derivatives
as an imido source: (a) Benito, J. M.; de Jesús, E.; de la Mata, F. J.;
Flores, J. C.; Gómez, R.; Gómez-Sal, P. Carbosilane Dendrimers Con-
taining Peripheral Cyclopentadienyl Niobium- and Tantalum-imido
Complexes. J. Organomet. Chem. 2006, 691, 3602. (b) Antiñolo, A.;
Dorado, I.; Fajardo, M.; Garcés, A.; Kubicki, M. M.; López-Mar-
domingo, C.; Otero, A.; Prashar, S. Synthesis and Reactivity of New
5
-Membered Ring Heterocyclic Pharmaceuticals. Beilstein J. Org.
Chem. 2011, 7, 442.
(
(2) Walsh, C. T.; Garneau-Tsodikova, S.; Howard-Jones, A. R. Biological
Formation of Pyrroles: Nature’s Logic and Enzymatic Machinery. Nat.
Prod. Rep. 2006, 23, 517.
(3) Novák, P.; Müller, K.; Santhanam, K. S. V.; Haas, O. Electrochemi-
cally Active Polymers for Rechargeable Batteries. Chem. Rev. 1997,
9
7, 207.
(4) Loudelt, A.; Burgess, K. BODIPY Dyes and Their Derivatives: Syn-
Mono- and Dinuclear Niobium and Tantalum Imido Complexes: X-ray
theses and Spectroscopic Properties. Chem. Rev. 2007, 107, 4891.
5
Crystal
N(SiMe
Structure
of
[Ta( -C
5 4
H
SiMe
3
)Cl
2
{=NC
6
Me
4
-4-
(5) (a) Knorr, L. Synthese von Furfuranderivaten aus dem Diacetbern-
steinsäureester. Ber. 1884, 17, 2863. (b) Paal, C. Ueber die Derivate
des Acetophenonacetessigesters und des Acetonylacetessigesters. Ber.
(
)
3 2
)}]. J. Organomet. Chem. 2006, 691, 1361. (c) Pennington,
D. A.; Horton, P. N.; Hursthouse, M. B.; Bochmann, M.; Lancaster, S.
J. Synthesis and Catalytic Activity of Dinuclear Imido Titanium Com-
plexes: the Molecular Structure of [Ti(NPh)Cl(-Cl)(THF) ] . Polyhe-
2 2
dron 2005, 24, 151. (d) Antiñolo, A.; Dorado, I.; Fajardo, M.; Garcés,
A.; López-Solera, I.; López-Mardomingo, C.; Kubicki, M. M.; Otero,
A.; Prashar, S. Synthesis, Structural Characterisation and Reactivity of
1
884, 17, 2756.
(6) Hantsch, A. Neue Bildungsweise von Pyrrolderivaten. Ber. 1890, 23,
1474.
(
7) Representative reviews for multicomponent pyrrole formation: (a)
Estévez, V.; Villacampa, M.; Menéndez, J. C. Recent Advances in the
Synthesis of Pyrroles by Multicomponent Reactions. Chem. Soc. Rev.
2014, 43, 4633. (b) Gulevich, A. V.; Dudnik, A. S.; Chernyak, N.;
Gevorgyan, V. Transition Metal-Mediated Synthesis of Monocyclic
Aromatic Heterocycles. Chem. Rev. 2013, 113, 3084. (c) Estévez, V.;
Villacampa, M.; Menéndez, J. C. Multicomponent Reactions for the
Synthesis of Pyrroles. Chem. Soc. Rev. 2010, 39, 4402.
New Dinuclear Monocyclopentadienyl Imidoniobium and -tantalum
5
Complexes − X-ray Crystal Structures of [{Nb( -C
5
H
4
SiMe
N)] and [{Ta( -
N)]. Eur. J. Inorg. Chem. 2004,
3 2 2
)Cl } (-
5
5
1,4-NC6H4N)], [{Ta( -C
5
Me
5
)Cl
H
}
2 2
6 4
(-1,4-NC H
C
5
Me )(CH SiMe (-1,4-NC
5
2
3
)
2
}
2
6
4
1299. (e) Antiñolo, A.; Dorado, I.; Fajardo, M.; Garcés, A.; Kubicki,
M. M.; López-Mardomingo, C.; Otero, A. Synthesis and Structural
4
ACS Paragon Plus Environment

Page 5 of 6
Journal of the American Chemical Society
Characterisation of New Organo-diimido Tantalum and Niobium Com-
Minasian, S. G.; Abubekerov, M.; Kozimor, S. A.; Shuh, D. K.; Ty-
liszczak, T.; Arnold, J.; Bergman, R. G.; Toste, F. D. Vanadium Bisi-
mide Bonding Investigated by X-ray Crystallography, V and C Nu-
clear Magnetic Resonance Spectroscopy, and V L3,2-Edge X-ray Ab-
sorption Near-Edge Structure Spectroscopy. Inorg. Chem. 2013, 52,
11650.
plexes. Dalton Trans. 2003, 910. (f) Benito, J. M.; de Jesús, E.; de la
Mata, F. J.; Flores, J. C.; Gómez, R.; Gómez-Sal, P. Arylimido Nio-
bium(V) Complexes: Mononuclear and Dendritic Derivatives. J. Or-
ganomet. Chem. 2002, 664, 258. (g) Dorado, I.; Garcés, A.; López-
Mardomingo, C.; Fajardo, M.; Rodríguez, A.; Antiñolo, A.; Otero, A.
Synthesis and Structural Characterization of New Organo-diimido and
Organo-imido Niobium and Titanium Complexes. J. Chem. Soc., Dal-
ton Trans. 2000, 2375.
1
2
3
4
5
6
7
8
9
51
13
(19)(a) Milsmann, C.; Turner, Z. R.; Semproni, S. P.; Chirik, P. J. Azo N=N
Bond Cleavage with a Redox-Active Vanadium Compound Involving
Metal–Ligand Cooperativity. Angew. Chem., Int. Ed. 2012, 51, 5386.
(b) Komuro, T.; Matsuo, T.; Kawaguchi, H.; Tatsumi, K. Synthesis of
a Vanadium(III) Tris(arylthiolato) Complex and Its Reactions with Az-
ide and Azo Compounds:ꢀ Formation of a Sulfenamide Complex via
Cleavage of an Azo N=N Bond. Inorg. Chem. 2005, 44, 175.
(20)DeWith, J.; Horton, A. D.; Orpen, A. G. Unusual [2 + 2] Cycloaddition
Adducts of an Imidovanadium Complex with Alkynes and Ethene:
(12)Titanium chloride/1a catalyzed the pyrrole formation over 70% yield
under higher concentration of the substrates ([2a] = 2.4 M, [3a] = 0.4
M).
13)Effects of additional reaction parameters such as solvent, temperature,
other metal chlorides, and other additives were included in the Support-
ing Information.
(
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
3
(
14)The result of three-component coupling reaction is shown in the Sup-
porting Information.
Conversion to  -1-Azaallyl and Ethenyl Complexes. Organometallics
1993, 12, 1493.
(15)See the Supporting Information.
(21)(a) Vujkovic, N.; Ward, B. D.; Maisse,-François,A.; Wadepohl, H.;
Mountford, P.; Gade, L. H. Imido-Alkyne Coupling in Titanium Com-
plexes: New Insights into the Alkyne Hydroamination Reaction. Or-
ganometallics 2007, 26, 5522. (b) Lokare, K. S.; Ciszewski, J. T.;
Odom. A. L. Group-6 Imido Activation by a Ring-Strained Alkyne.
Organometallics 2004, 23, 5386. (c) Walsh, P. J. The Synthesis and
Reactivity of Zirconium-Nitrogen Double and Single Bonds. Ph.D.
Thesis, University of California, Berkeley, 1990.
(22) (a) Glueck, D. S.; Wu, J.; Hollander, F. J.; Bergman, R. G. Monomeric
(Pentamethylcyclopentadienyl)iridium Imido Compounds: Synthesis,
Structure, and Reactivity. J. Am. Chem. Soc. 1991, 113, 2041. (b) Kuhn,
N.; Horn, E.-M.; Zauder, E.; Bläser, D.; Boese, R. Stable Sandwich
Complexes with Pentamethylpyrrole Ligands. Angew. Chem., Int. Ed.
Engl. 1988, 27, 579. (c) Huttner, G.; Mills, O. S. Übergangsme-
tallkomplexe cyclischer -Liganden, III. Kristall- und Molekülstruktur
von Tricarbonyl(N-methyl-pyrrol)chrom(0). Chem. Ber. 1972, 105,
(
16)(a) Burés, J. A Simple Graphical Method to Determine the Order in
Catalyst. Angew. Chem., Int. Ed. 2016, 55, 2028. (b) Burés, J. Variable
Time Normalization Analysis: General Graphical Elucidation of Reac-
tion Orders from Concentration Profiles. Angew. Chem., Int. Ed. 2016,
55, 16084.
(
17)(a) Tsurugi, H.; Mashima, K. A New Protocol to Generate Catalytically
Active Species of Group4–6 Metals by Organosilicon-Based Salt-Free
Reductants. Chem. - Eur. J. 2019, 25, 913. (b) Saito, T.; Nishiyama,
H.; Kawakita, K.; Nechayev, M.; Kriegel, B.; Tsurugi, H.; Arnold, J.;
t
Mashima, K. Reduction of ( BuN=)NbCl
3
(py)
2
in a Salt-Free Manner
for Generating Nb(IV) Dinuclear Complexes and Their Reactivity to-
ward Benzo[c]cinnoline. Inorg. Chem. 2015, 54, 6004. (c) Saito, T.;
Nishiyama, H.; Tanahashi, H.; Kawakita, K.; Tsurugi, H.; Mashima, K.
1,4-Bis(trimethylsilyl)-1,4-diaza-2,5-cyclohexadienes as Strong Salt-
Free Reductants for Generating Low-Valent Early Transition Metals
with Electron-Donating Ligands. J. Am. Chem. Soc. 2014, 136, 5161.
18)(a) La Pierre, H. S.; Arnold, J.; Toste, F. D. Z-Selective Semihydro-
genation of Alkynes Catalyzed by a Cationic Vanadium Bisimido
Complex. Angew. Chem., Int. Ed. 2011, 50, 3900. (b) La Pierre, H. S.;
301. (d) Öfele, K.; Dotzauer, E. Cr(CO) --komplexe von Pyrrol und
3
(
Pyrrolderivaten. J. Organomet. Chem. 1971, 30, 211.
5
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 6 of 6
Table of Contents artwork
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
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
6
ACS Paragon Plus Environment