Tandem transformations of nitriles into N-heterocyclic compounds by electrophilic trapping of Blaise reaction intermediates

Article abstract of DOI:10.1055/s-0031-1290814

Tandem transformations of nitriles into various N-heterocycles have been accomplished through the reaction of electrophiles with Blaise reaction intermediates formed in situ. The reaction of the Blaise reaction intermediates with propiolates gives 2-pyridones through consecutive C- and N-nucleophilic reactions. The tandem reactions of the Blaise reaction intermediate with 1,3-enynes proceed through C-nucleophilic addition followed by an electrocyclization-aromatization cascade to give pyridines. Exocyclic enamino esters can be prepared by transformations of ω-chloroalkyl nitriles through chemoselective intramolecular alkylation of the Blaise reaction intermediate. Palladium-catalyzed intramolecular arylations or copper-catalyzed intermolecular cross-coupling reactions of the Blaise reaction intermediate give a range of indole derivatives. Combinations of tandem alkylations and palladium-catalyzed couplings of the Blaise reaction intermediates of ω-chloroalkyl nitriles give N-fused indoles. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0031-1290814

SPECIAL TOPIC
▌1809
special topic
Tandem Transformations of Nitriles into N-Heterocyclic Compounds by
Electrophilic Trapping of Blaise Reaction Intermediates
Tandem Transformations of Nitriles into N-Heterocyclic Compounds
Ju Hyun Kim,a Yu Sung Chun,a Hyunik Shin,*b Sang-gi Lee*a
a
Department of Chemistry and Nano Science (BK21), Ewha Womans University, 120-750 Seoul, Korea
b
Chemical Development Division, LG Life Science, Ltd/R&D, Daejeon 350-380, Korea
Fax +82(2)32774505; E-mail: sanggi@ewha.ac.kr
Received: 24.02.2012; Accepted after revision: 07.03.2012
possible reactions with electrophiles, nucleophiles, or
both. We have explored the intrinsic reactivity and C-/N-
chemoselectivity of the Blaise reaction intermediate
toward various electrophiles,5 and have proved that the
Abstract: Tandem transformations of nitriles into various N-het-
erocycles have been accomplished through the reaction of electro-
philes with Blaise reaction intermediates formed in situ. The
reaction of the Blaise reaction intermediates with propiolates gives
2-pyridones through consecutive C- and N-nucleophilic reactions. selectivity associated with the ambivalent C-/N-nucleo-
The tandem reactions of the Blaise reaction intermediate with 1,3-
enynes proceed through C-nucleophilic addition followed by an
electrocyclization–aromatization cascade to give pyridines. Exocy-
N-heterocyclic compounds (Scheme 1).6 Electrophilic
clic enamino esters can be prepared by transformations of ω-chlo-
roalkyl nitriles through chemoselective intramolecular alkylation of
philic nature of the Blaise reaction intermediate can be
utilized in tandem transformations of nitriles into various
trappings of Blaise reaction intermediates with electro-
philes possessing two electrophilic groups, such as propi-
olates or 1,3-enynes, provide a new tandem one-pot
method for the synthesis of pyridones6a or pyridines,6b
respectively. The chemoselective intramolecular alkyl-
ation,6c palladium-catalyzed arylation, and alkylation/pal-
ladium-catalyzed arylation of Blaise reaction inter-
mediates have been investigated for the development of
tandem transformations of nitriles into exocyclic enamine
esters and indole derivatives.6d Here, we describe the
scope and the limitations of these tandem transformations
of nitriles into N-heterocyclic compounds through elec-
trophilic trapping of Blaise reaction intermediates.
the Blaise reaction intermediate. Palladium-catalyzed intramolecu-
lar arylations or copper-catalyzed intermolecular cross-coupling re-
actions of the Blaise reaction intermediate give a range of indole
derivatives. Combinations of tandem alkylations and palladium-
catalyzed couplings of the Blaise reaction intermediates of ω-chlo-
roalkyl nitriles give N-fused indoles.
Key words: nitriles, tandem reactions, heterocycles, cyclizations,
catalysis
The reaction of a Reformatsky reagent with a nitrile,
known as the Blaise reaction,1 proceeds via the zinc bro-
mide complex of the β-enamino ester. Hydrolytic workup
of this reaction intermediate under acidic or basic condi-
tions provides the corresponding β-keto ester or β-enami-
no ester, respectively. These reactions are among the most
classical and popular transformations of nitriles.2 Recent-
ly, we envisioned that Blaise reaction intermediates could
be considered as functionalized organozinc reagents and
might serve as suitable platforms for tandem transforma-
tion of nitriles into various organic compounds. Despite
the undeniable benefits of tandem reactions in minimizing
the number of synthetic steps, reducing waste generation,
and generating molecular complexity,3 the development
of new tandem methods for transforming nitriles via
Blaise reaction intermediates remains a challenging prob-
lem.4 The potential of the Blaise intermediate as a reagent
for tandem bond-formation reactions has not previously
been recognized, and before our study, no tandem trans-
formations of nitriles by means of the Blaise reaction had
been reported.
R2
CO2R3
R1
C
N
+
Br
classical Blaise
transformation of nitrile
Zn
O
CO2R3
Br
R1
Zn
R2
or
Blaise reaction intermediate
C-/N-nucleophilic enamine
electrophilic ester C=O
HN
O
NH2
R1
OR3
CO2R3
R2
R1
R2
divalent
C-/N-nucleophile
intramolecular
alkylation
intramolecular
alkylation/
Pd-catalyzed
arylation
intramolecular
Pd-catalyzed
arylation
R4
CO2R5
R4
R5
NH
CO2R3
R4
R2
R3O2C
R3O2C
R1
R3O2C
R3O2C
R4
R5
N
H
O
R1
The Blaise reaction intermediate has unique features in
that it combines an ambivalent C-/N-nucleophilic en-
amine moiety with an electrophilic ester group, permitting
n
N
R1
N
N
H
H
C-C/N-C/N-C
bond formation
C-C/N-C
bond formation
C-C/C-C/N-C
bond formation
SYNTHESIS 2012, 44, 1809–1817
Advanced online publication: 17.04.2012
Scheme 1 Tandem Blaise transformations of nitriles into heterocy-
clic compounds
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0031-1290814; Art ID: SS-2012-C0191-ST
© Georg Thieme Verlag Stuttgart · New York

1810
J. H. Kim et al.
SPECIAL TOPIC
covered, reflecting the ease of proton transfer from the
acidic acetylenic proton to the Blaise reaction intermedi-
Tandem Transformation of Nitriles into 2-Pyridones
Pyridones are embedded as structural units in many natu- ate.
ral products and biologically active compounds.7 Al-
The formation of a 2-pyridone ring clearly demonstrated
though various effective methods have been developed
for the synthesis of pyridone derivatives, most require
multiple steps.8 We have devised a tandem one-pot syn-
thesis of 2-pyridone derivatives from nitriles by electro-
philic trapping of Blaise reaction intermediates with
propiolates as terminal electrophiles (Scheme 2).6a A wide
range of aromatic, heteroaromatic, and aliphatic nitriles
can be transformed efficiently into the corresponding 4-
phenyl-2-pyridones in good-to-excellent yields (≤98%)
through the tandem reaction of Blaise reaction intermedi-
ates with ethyl phenylpropiolates.
the ambivalent nucleophilic nature of the Blaise reaction
intermediate 2, as both the α-carbon and the β-nitrogen
atoms can act as nucleophiles. As shown in Scheme 3, the
Michael addition of the Blaise reaction intermediate to the
propiolate gives the vinyl zinc bromide A, which isomer-
izes to the α-vinylated zinc bromide complex B, through
intermolecular and/or intramolecular proton transfer of
the acidic α-proton. Rearrangement of B to the C(sp3)–
ZnBr complex C, followed by intramolecular cyclization,
leads to the 2-pyridone structure. Careful monitoring and
quenching of the reaction in the early stage permitted the
isolation of appreciable amounts of the α-vinylated β-en-
amino ester 5, which supports our proposed reaction
mechanism. Although, it is not possible to introduce a
substituent on C3, which is a limitation of this tandem
transformation, the technique still provides a rapid build-
up of a wide range of pyridine derivatives that are inacces-
sible by other methods.
R2
Zn (2.0 equiv)
BrCH2CO2Et
(1.5 equiv)
Br
R2
CO2Et
Zn
EtO2C
R1
3 (1.1 equiv)
R1
C
N
HN
R1
O
THF, reflux
3–8 h
THF, reflux
1 h (>98%)
1
N
H
O
OEt
2
4
Br
EtO2C
EtO2C
EtO2C
Br
Zn
Zn
R1
N
O
HN
R1
O
N
O
N
H
O
CO2Et
H
H
HN
R1
O
H
HN
BrZn
X
X = F: 4b (97%)
X = CF3: 4c (95%)
X = OMe: 4d (95%)
OEt
o-: 4e (56%)
m-:4f (81%)
p-: 4g (89%)
Me
'H'
transfer
OEt
CO2Et
4a (98%)
R2
H
2
R2
CO2Et
R2
CO2Et
3
A
B
R1
R2
EtO2C
EtO2C
Ph
EtO2C
O
EtO2C
CO2Et
R2
EtO2C
R1
NH2
O
HN
EtO
O
N
H
O
N
H
O
N
O
N
H
O
Ph
OEt
H
N
H
4
O
N
4k (92%)
Ph
4h (83%)
4j (92%)
4i (90%)
BrZn
CO2Et
C
F
5
X = F: 4m (92%)
X = OMe: 4n (94%)
X = Bu: 4o (90%)
X = Cy: 4p (91%)
Scheme 3 Proposed reaction pathway for tandem synthesis of 2-pyr-
idones
H
EtO2C
EtO2C
EtO2C
N
H
O
N
H
O
N
O
H
Tandem Transformation of Nitriles into Pyridines
4l (88%)
4q (35%)
Scheme 2 Tandem transformations of nitriles into 2-pyridones
The pyridine moiety is also an important component of
various natural products, pharmaceuticals, and functional
materials.9 Consequently, the development of a new syn-
thetic method for the construction of pyridines is always
important. We have recently developed a method for the
tandem transformation of nitriles into pyridines 7 through
the tandem reaction of the Blaise reaction intermediate 2
with 1,3-enynes 6.6b This transformation is based on the
propensity of the Blaise reaction intermediate 2 to play the
dual role of a carbon nucleophile and a Lewis acid in re-
acting with nonactivated terminal alkynes for regio- and
chemoselective α-vinylation.5c We reasoned that if identi-
cal tandem reactions were conducted with a 1,3-enyne 6,
the resulting α-dienylated β-enaminozincate 10 might be
capable of undergoing isomerization to form the N-zinc-
In general, the electronic properties of the nitriles did not
affect their reactivity. However, sterically demanding 2-
methylbenzonitrile showed a diminished reactivity, re-
sulting in a relatively lower yield of 2-pyridone 4e (56%).
The reaction efficiency was not markedly affected by the
structure of the propiolate, so that the aryl and alkyl pro-
piolates reacted with the Blaise reaction intermediate to
afford the corresponding 2-pyridones in high yields. How-
ever, under the same reaction condition, the reaction of
ethyl propiolate (R2 = H) gave a low yield (18%) of 2-pyr-
idone 4q, although this rose to 35% when 2.2 equivalents
of propiolate were allowed to react for 24 hours. A signif-
icant amount of the β-enamino ester Blaise adduct was re-
Synthesis 2012, 44, 1809–1817
© Georg Thieme Verlag Stuttgart · New York

SPECIAL TOPIC
Tandem Transformations of Nitriles into N-Heterocyclic Compounds
1811
ated 1-azatriene 11, which could facilitate a 6π-electrocy-
clization and/or cycloaddition to produce pyridines 7 after
elimination of zinc hydrogen bromide (HZnBr) (Scheme
4).10
Zn (2.0 equiv)
BrCH2CO2R2
(1.5 equiv)
R2O2C
R1
6 (1.1 equiv)
R1
C
1
N
1,4-dioxane
110 °C
1,4-dioxane
75 °C
N
7
i)
Zn
ii)
R2
R3
BrCH2CO2R4
X = o-Me: 7ba (89%)
X = m-Me: 7ca (83%)
X = p-Me: 7da (80%)
X = o-OMe: 7ea (72%)
X = p-OMe: 7fa (80%)
EtO2C
EtO2C
R4O2C
R1
R2
R3
6
N
R1
C
N
N
X
1
N
7aa (90%)
EtO2C
7
Br
X = F: 7ha (80%)
X = CF3: 7ia (70%)
X = Br: 7ja (70%)
X = CO2Et: 7ka (72%)
X = CN: 7la (60%)
EtO2C
Zn
NH2
O
HN
O
R1
OR4
N
R5
N
Br
R1
OR4
Zn
R5
MeO
X
R5
HN
O
7ga (73%)
HZnBr
R1
OR4
OR4
EtO2C
EtO2C
EtO2C
O
OR4
2
R2
R3
R2
R3
O
Ph
O
N
N
N
R2
R3
R1
N
N
H
R1
Zn
N
Br
7oa (75%)
7na (83%)
ZnBr
11
7ma (77%)
10
6
NH2
MeO2C
i-PrO2C
EtO2C
CO2Et
Ph
N
N
N
7ab (75%)
7pa (66%)
7ac (92%)
12
Scheme 5 Tandem transformations of various nitriles to tetrahydro-
quinolines
Scheme 4 Proposed reaction pathway for tandem transformation of
nitriles to pyridines
good yields. Acyclic 1,3-enynes with two phenyl, phenyl
and methyl, phenyl and hydrogen, or two propyl substitu-
ents reacted smoothly with the Blaise reaction intermedi-
ate 2a to give the corresponding polysubstituted
pyridines. However, their yields were lower than those
obtained from cyclic 1,3-enynes, which was attributed to
the entropic effects (Scheme 6).
To test our hypothesis, we commenced our investigation
with the Blaise reaction intermediate 2a, formed from the
reaction of benzonitrile (1a) with a Reformatsky reagent
generated in situ from ethyl bromoacetate (1.5 equiva-
lents) and zinc (2.0 equivalents) in tetrahydrofuran; over
96% of 1a was converted into 2a. The tandem reaction of
2a with commercially available 1-ethynylcyclohexene
(6a; 1.1 equivalents) was carried out in refluxing tetrahy-
drofuran for two hours to afford the tetrahydroquinoline
7aa in 70% yield, along with the α-dienylated β-enamino
ester 12 (13%). This result clearly showed that the zincat-
ed aminotriene 10 was formed as an intermediate. When
the tandem reaction was carried out in 1,4-dioxane at
110 °C, the yield of 7aa was increased to 90%. Under
standard conditions, various aromatic nitriles with elec-
tron-donating or -withdrawing groups such as methyl,
methoxy, halides, and ester groups were readily converted
into the corresponding tetrahydroquinolines 7aa–la in
good-to-excellent yields (Scheme 5). Heteroaromatic and
aliphatic nitriles were also readily converted into the cor-
responding tetrahydroquinoline derivatives 7ma–pa in
high yields (66–83%). The use of Reformatsky reagents
with different R2 groups did not diminish the yield, thus
allowing the preparation of the 3-methyl ester 7ab (75%)
and the 3-isopropyl ester 7ac (92%) in high yields.
R2
R3
Zn (2.0 equiv)
EtO2C
R2
R3
BrCH2
CO2Et
6
(1.5 equiv)
(1.1 equiv)
Ph
C
N
N
1,4-dioxane
75 °C, 1 h
1a
7
EtO2C
EtO2C
EtO2C
N
N
N
7ad (82%)
7ae (70%)
7af (62%)
EtO2C
EtO2C
EtO2C
N
N
N
7ah (40%)
7aj (49%)
7ag (53%)
This tandem transformation protocol could also be suc-
cessfully applied to different types of cyclic 1,3-enynes to
afford the corresponding carbacycle-fused pyridines in
Scheme 6 Tandem transformations of benzonitrile to pyridines by us-
ing various 1,3-enynes as terminal electrophiles
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 1809–1817

1812
J. H. Kim et al.
SPECIAL TOPIC
Significantly, the stereochemistry of the enyne did not af-
fect the reactivity of the reactions. Thus, tandem reactions
with the enynes (E)-6i and (Z)-6i afforded the same pyri-
dine 7ai with almost the same yield (Scheme 7a). Howev-
er, the 1,3-enynes with internal alkynes such as 1-prop-1-
ynylcyclohexene and (cyclohex-1-enylethynyl)benzene
were not suitable substrates for this tandem reaction
(Scheme 7b). Furthermore, the tandem reaction with cy-
clohex-1-enyl propiolate gave the cyclohexenyl-substitut-
ed pyridine 4r in 80% yield (Scheme 7c).
NC
CN
1l
Zn (4.0 equiv)
BrCH2CO2Et
(3.0 equiv)
1,4-dioxane
75 °C
Br
OEt
Zn
NH
O
O
6a (1.1 equiv)
HN
Zn
Br
then
EtO
2l
6a
Ph
CO2Et
(1.1 equiv)
(2.2 equiv)
1,4-dioxane
110 °C
Ph
O
CO2Et
EtO2C
CO2Et
EtO2C
H
(E)-
Zn (2.0 equiv)
NH
N
N
N
Ph
BrCH2CO2Et
(1.5 equiv)
EtO2C
Ph
H
1,4-dioxane
110 °C, 12 h
7lb (56%)
13 (39%)
(a)
Ph
C
N
1,4-dioxane
75 °C, 1 h
1a
N
Ph
Scheme 8 Double tandem transformation of a bisnitrile for a one-pot
construction of a biheterocyclic compound
H
from (E)-isomer: 53%
from (Z)-isomer: 51%
(Z)-
Ph
products.11 Synthetic approaches to exocyclic enamine es-
ters rely mainly on the use of existing N-heterocycles.12 In
contrast, construction of the N-heterocyclic moiety
though intramolecular ring-closure reactions has been
rarely reported, and most of them require multistep syn-
theses of the cyclization precursors.13 To provide a more-
general synthetic route towards exocyclic enamine esters
from readily available compounds, we investigated the
tandem transformation of ω-chloroalkyl nitriles into exo-
cyclic enamine esters through chemoselective intramolec-
ular N-alkylation of the various Blaise reaction
intermediates (Scheme 9).6c
R
R = Me, Ph
(1.1 equiv)
no reaction
(b)
Zn (2.0 equiv)
BrCH2CO2Et
(1.5 equiv)
1,4-dioxane
110 °C, 12 h
Ph
C
N
1,4-dioxane
75 °C, 1 h
1a
EtO2C
(c)
N
O
MeO2C
H
4r (80%)
The reactivity and N/C selectivity of the Blaise reaction
intermediate were insufficient to provide an entry to exo-
cyclic enamine esters. The N/C cyclization selectivity is
determined mainly by the substituent at the C-2 position.
Scheme 7 (a) Pyridines from (E)- and (Z)-3-enynes; (b) and (c) lim-
itations on tandem transformations of benzonitrile to pyridines
Finally, extension to divergent tandem reactions allowed
the construction of a molecule containing both a pyridine
and a pyridone ring. Both nitrile groups of terephthaloni-
trile can react with an excess of a Reformatsky reagent to
generate the bisenaminozincate intermediate 2l, which
can subsequently react with 2.1 equivalents of 6a to form
the two pyridine rings in the bipyridyl compound 7lb in
56% yield (Scheme 8). The chemoselectivity of the Blaise
reaction intermediate 2a towards activated alkynes and
1,3-enynes permitted divergent tandem one-pot construc-
tions of two different heterocyclic rings, a pyridine ring
and a pyridine ring, in one molecule. Thus, the bisenami-
nozincate 2l reacted sequentially with the 1,3-enyne 6a
and phenylpropiolate to afford 13 in 39% yield along with
bispyridine 7lb in 15% yield (Scheme 8).
Cl
R
CO2Et
+
Br
CN
n
Zn
Br
C-alkylation
N-alkylation
NH
Zn
Cl
CO2Et
R
HN
O
OEt
n
R
R = H, Me, Ph
isolated as
NH2
O
NH
CO2Et
CO2Et
R
n
CO2Et
14 (when R = H)
when R = H
n
n
R
15
16
in the presence of NaHMDS
when R = H
n = 1: 14 (29%) + 16 (6%)
n = 2: 14 (37%) + 16 (-)
when R = Me
n = 1: 14 (<5%) + 16 (46%)
n = 2: 14 (45 %) + 16 (<5%)
when R = Ph
n = 1: 14 (-) + 16 (93%)
n = 2: 14 (42%) + 16 (10%)
when R = Me
Tandem Transformation of Nitriles into Exocyclic
Enamino Esters
n = 1: 14 (<5%) + 16 (74%)
n = 2: 14 (- ) + 16 (67%)
when R = Ph
n = 1: 14 (<5%) + 16 (71%)
n = 2: 14 (-) + 16 (67%)
n = 1: 14 (<5%) + 16 (42%)
n = 2: 14 (25 %) + 16 (20%)
Exocyclic enamine esters are highly versatile intermedi-
ates for the synthesis of the N-heterocyclic fragments that
are embedded in many useful pharmaceuticals and natural
Scheme 9 The tandem transformations of ω-chloroalkyl nitriles into
exocyclic compounds
Synthesis 2012, 44, 1809–1817
© Georg Thieme Verlag Stuttgart · New York

SPECIAL TOPIC
Tandem Transformations of Nitriles into N-Heterocyclic Compounds
1813
Thus, Blaise reaction intermediates with no α-substituent of solvent, the reaction temperature, the ligand, and the
(R2 = H) cyclized C-selectively, whereas N-cyclization base, we found that the N-arylative trapping of the Blaise
was dominant with the Blaise reaction intermediate hav- reaction intermediate 17a (R1 = Ph) did occur in the pres-
ing α-substituents (R2 ≠ H). The low reactivity and poor ence of tetrakis(triphenylphosphine)palladium (7.4
N/C selectivity could be overcome by addition of sodium mol%) and potassium tert-butoxide (1.3 equiv) in 1:10 v/v
hexamethyldisilazide, which significantly enhanced the tetrahydrofuran/N,N-dimethylformamide to give the cor-
N-nucleophilicity and permitted the tandem synthesis of responding indole 19a in 84% yield (Scheme 11). Under
the exocyclic enamine esters from nitriles. In terms of the the optimized conditions, various aromatic nitriles with
yield and the control of N/C selectivity, this modification electron-donating and electron-withdrawing substituents,
is sufficient to permit the use of the current protocol as a as well as heteroaromatic nitriles and aliphatic nitriles,
general method for the construction of N-heterocyclic could be converted into the corresponding indoles 19a–k
exocyclic enamino esters.
in a one-pot manner. Although 4-fluorobenzonitrile and
propionitrile were converted into the corresponding in-
doles 19d and 19j in slightly diminished yields, the elec-
tronic nature of the substituents on the aromatic nitriles
did not significantly affect the reactivity. One nitrile
group of terephthalonitrile could be transformed into an
Tandem Transformation of Nitriles into Indoles and
N-Fused Indoles
Many elegant approaches have been developed for pre- indole ring to afford 19g in 62% yield.
paring the indole ring moiety.14 However, because most of
these approaches start from anilines, arylhydrazines, or
CO2Et
Zn +
amine derivatives, the development of new methods for
the synthesis of indoles from simple and readily available
Br
H
N
Pd(PPh3)4 (7.4 mol%)
Br
R1
t-BuOK (1.3 equiv)
R1
C
1
N
non-amino compounds is of great interest. In this context,
we envisioned a novel tandem transformation of nitriles
into indoles through palladium-catalyzed N-arylative cou-
pling reaction of the Blaise reaction intermediate. We hy-
pothesized that a Blaise reaction intermediate possessing
an o-bromophenyl group at the α-carbon should undergo
oxidative addition of palladium(0) to generate electrophil-
ic an palladium(2+) species that might be trapped by the
nucleophilic β-nitrogen atom to form an indole ring
(Scheme 10).6d
THF, reflux
1.5 h
THF–DMF (1:10, v/v)
120 °C, 15 h
EtO2C
19
H
H
N
H
N
N
X
Me
EtO2C
EtO2C
m-: 19b (74%)
p-: 19c (72%)
EtO2C
X = OMe: 19c (84%)
X = F: 19d (51%)
X = OCF3: 19e (72%)
X = CO2Et: 19f (71%)
X = CN: 19g (62%)
19a (84%)
H
H
N
O
N
N
EtO2C
19i (64%)
EtO2C
19h (76%)
H
N
On the basis of an analogy with the recently disclosed pal-
ladium-catalyzed cross couplings of Reformatsky re-
agents with aryl halides under base-free conditions,15 we
initially hypothesized that the nucleophilic nature of the
intermediate would induce palladium-catalyzed intramo-
lecular N-arylation in the absence of a base. However, the
tandem reactions did not proceed at all in refluxing tetra-
hydrofuran in the presence of bis(dibenzylideneace-
tone)palladium/dicyclohexyl(2′,6′-dimethoxybiphenyl-2-
yl)phosphine (Sphos) or tetrakis(triphenylphosphine)pal-
ladium as the catalyst. These results suggested that the nu-
cleophilicity of the Blaise reaction intermediate might not
be sufficient for the intramolecular transmetalation of the
electrophilic palladium(II) species formed by oxidative
addition of the o-bromide with palladium(0). After exten-
sive screening of the reaction conditions, such as the type
H
Ph
N
EtO2C
19j (58%)
EtO2C
19k (72%)
Scheme 11 Tandem transformation of nitriles into indoles
Fortunately, these reaction conditions are also useful for
the tandem transformation of ω-chloroalkyl nitriles into
N-fused indoles through chemoselective intramolecular
N-alkylation/palladium-catalyzed N-arylation of the
Blaise reaction intermediate. Trapping experiments at
lower reaction temperatures suggested that the N-alkyla-
tion reaction precedes N-arylation (Scheme 12).
Br
Br
Zn
Zn
H
R1
C N
HN
R1
O
N
HN
R1
O
R1
Pd(0)
+
OR2
CO2R2
ZnBr
OR2
Br
+
R2O2C
Pd2
Br
19
electrophilic
Pd2+ species
Br
18
17
Scheme 10 Strategy for tandem transformation of nitriles into indoles through palladium-catalyzed N-arylative trapping
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 1809–1817

1814
J. H. Kim et al.
SPECIAL TOPIC
CO2Et
Zn +
form C, which has sufficient nucleophilicity to permit in-
tramolecular transmetalation of D to form E. Reductive
elimination then gives the N-fused indole 19.
Br
Ar
CO2Et
Pd(PPh3)4 (7.4 mol%)
t-BuOK (2.3 equiv)
Cl
Br
Ar
n
THF, reflux
1.5 h
THF–DMF(1:10, v/v)
120 °C, 15 h
N
CN
Br
Zn (2.0 equiv)
BrCH2CO2Et
(1.5 equiv)
n
Zn
R1
C
1
N
HN
R1
O
CO2Et
THF, reflux, 1 h
I
CO2Et
CO2Et
CO2Et
OEt
2
N
N
N
N
I
(1.2 equiv)
19l (70%)
19m (74%)
19n (60%)
19o (52%)
CO2Et
R1
CuI (30 mol%)
Phen (60 mol%)
Scheme 12 Tandem transformation of ω-chloroalkyl nitriles into N-
fused indoles
N
t-BuOK (4.0 equiv)
THF–DMF (1:10, v/v),
120 °C, 24 h
H
19
CO2Et
CO2Et
CO2Et
The possible reaction pathways for the formation of in-
doles and N-fused indoles are shown in Scheme 13. De-
protonation of the acidic N–H group and oxidative
addition to palladium(0) gives the palladium(II) bromide
complex A. Intramolecular transmetalation, followed by
reductive elimination of the resulting palladium(II) com-
plex B, regenerates palladium(0) for a subsequent catalyt-
ic cycle and forms the zinc bromide complex of indole 19,
which is subsequently converted into indole 19 after
workup (Scheme 13). For the formation of N-fused in-
doles, the intramolecular N-alkylation of the Blaise reac-
tion intermediate 17 proceeds in the presence of base to
F
OMe
N
N
N
H
H
H
19d (42%)
19a (76%)
19c (71%)
CO2Et
CO2Et
N
N
N
H
H
19j (48%)
19h (42%)
Scheme 14 Copper-catalyzed intermolecular arylative trapping of
the Blaise reaction intermediate
Finally, we envisioned that the C-/N-ambivalent nucleo-
philic nature of the Blaise reaction intermediate might be
utilized in the design of metal-catalyzed intermolecular
C–C/N–C couplings with 1,2-dihaloarenes. Therefore, we
decided to investigate the tandem indolization reaction of
the Blaise reaction intermediates with 1,2-dibromoben-
zene. However, in contrast to intramolecular N-arylation,
palladium catalysts, such as tetrakis(triphenylphos-
phine)palladium or complexes of bis(dibenzylideneace-
tone)palladium with dicyclohexyl(2′,4′,6′-triisopropyl-
biphenyl-2-yl)phosphine (XPhos) or 1,1′-binaphthalene-
2,2′-diylbis(diphenylphosphine) (BINAP), were ineffec-
tive for the tandem indolization reaction. However, cop-
per(I) iodide did catalyze the tandem intermolecular C–
C/C–N coupling reaction of the Blaise reaction intermedi-
ate with 1,2-dibromobenzene. After screening of a num-
ber of conditions, we carried out the tandem reaction out
by using copper(I) iodide (20 mol%), phenanthroline
(Phen; 40 mol%) as a ligand, and potassium tert-butoxide
as the base in 1:10 v/v N,N-dimethylformamide–tetrahy-
drofuran at 120 °C for 24 hours to afford the indole 19a in
54% yield.16 The yield increased to 65% when the catalyst
loading was increased to 30 mol% of copper(I) iodide and
60 mol% of Phen. When the same reaction was carried out
with 1,2-iodobenzene, the yield of indole 19a was further
increased to 76%. Although the yields were slightly lower
than those obtained from the palladium-catalyzed inter-
molecular arylative trapping reactions shown in Scheme
11, a wide diversity of indoles could be synthesized in
moderate-to-good yields by the copper(I) iodide catalyzed
intermolecular C–C/N–C coupling reactions of 1,2-di-
Br
Zn
NH
EtO
O
KO
OEt
R
R
Br
17
N
Pd 2+
ZnBr
t-BuOK
Br
A
Pd(0)
KBr
O
OEt
CO2Et
R
R
N
ZnBr
N
Pd2+
ZnBr
B
workup
19-ZnBr
19
Br
EtO
O
C
Zn
BrZnO
OEt
N
N
n
Br
n
Pd2+
Br
Zn
Br
Cl
D
HN
O
ZnBr2
Pd(0)
OEt
Br
t-BuOK
n
O
OEt
CO2Et
N
17
n
Pd2+
N
E
n
19
Scheme 13 Tandem transformations of ω-chloroalkyl nitriles onto N-
fused indoles
Synthesis 2012, 44, 1809–1817
© Georg Thieme Verlag Stuttgart · New York

SPECIAL TOPIC
Tandem Transformations of Nitriles into N-Heterocyclic Compounds
1815
iodobenzene with the Blaise reaction intermediates In summary, we have developed a series of novel methods
(Scheme 14).
for tandem transformation of nitriles into various N-het-
erocycles. Electrophilic trapping of the Blaise reaction in-
termediate with various electrophiles through alkylation,
addition, and cross-coupling reactions provides a useful
tandem synthetic route to derivatives of pyrid-2-ones, pyr-
idines, enamine esters, and indoles from the appropriate
nitriles. Moreover, we have delineated the reactivity of
Blaise reaction intermediates and their N/C selectivity
profiles, and we have modified these to a useful extent
through the inclusion of additives. These results provide a
platform for future studies on applications of Blaise reac-
tion intermediates as functionalized organozinc nucleo-
philes for metal-catalyzed bond-forming reactions.
Further studies on the tandem transformation of nitriles
with Blaise reaction intermediates are underway in our
laboratory.
To determine the timing of the N-arylation and C-aryla-
tion reactions, we examined the the copper(I) iodide cata-
lyzed intermolecular arylation of the Blaise reaction
intermediate with bromobenzene. The N-arylated product
20 was formed exclusively in 44% yield (Scheme 15),
clearly showing that the copper(I) iodide catalyzed N-ar-
ylation reaction precedes C-arylation.
(1.0 equiv)
Ph Br
Ph
Ph
BrCH2CO2Et
(1.5 equiv)
CuI (30 mol%), Phen (60 mol%)
NH
t-BuOK (4.0 equiv)
CO2Et
Ph CN
THF, reflux, 1 h
THF–DMF (1:10, v/v)
120 °C, 24 h, 44%
1a
20
Scheme 15 Chemoselective intermolecular copper-catalyzed N-ar-
ylation of Blaise reaction intermediates
Our proposed copper(I)/copper(III)-type mechanism for
the copper(I) iodide catalyzed intermolecular coupling re-
action of a Blaise reaction intermediate with 1,2-diiodo-
benzene is shown in Scheme 16.17 The Blaise reaction
intermediate reacts with copper(I) in the presence of a
base to form the nitrogen-coordinated copper(I) complex
A, which subsequently reacts with 1,2-diiodobenzene to
form the copper(III)-complex B. Reductive elimination of
copper(I) then gives the N-arylated intermediate C, which
reacts with copper(I) at the α-carbon to form D. Intramo-
lecular formation of the copper(III)-complex E and reduc-
tive elimination followed by isomerization of the resulting
imine F gives the indole 19. The regenerated copper(I)
can then participate in subsequent catalytic cycles.
All reactions and manipulations were performed in an argon atmo-
sphere using standard Schlenk techniques. Flasks were flame-dried
under a stream of argon. All solvents were distilled before use and
transferred by oven-dried syringes. All purchased reagents were
used as received without further purification. NMR spectra were re-
corded at 300 MHz (1H) and 75.5 MHz (13C) on a Bruker Avance
III 3000 spectrometer or at 250 MHz (1H) and 62.9 MHz (13C) on a
Bruker 9503 DPX spectrometer. The chemical shifts are reported
relative to TMS as an internal reference for 1H NMR and to the re-
sidual solvent signal (CDCl3; δ = 77.16 ppm) for 13C NMR. HRMS
spectra were recorded on a Micromass QTOF2-MS instrument.
Ethyl 6-Oxo-2,4-diphenyl-1,6-dihydropyridine-3-carboxylate
(4a): Typical Procedure for Tandem Transformation of Nitriles
into 2-Pyridones
MeSO3H (3.7 mg) in anhyd THF (4.0 mL) was added to a stirred
suspension of commercial Zn dust (10 μm, 1.0 g, 15.3 mmol). The
mixture was refluxed for 10 min before PhCN (0.8 mL, 7.6 mmol)
was added. BrCH2CO2Et (1.26 mL, 11.4 mmol) was then added
over 1 h from a syringe pump to the refluxing mixture, and the mix-
ture was refluxed for a further 1 h. PhC≡CCO2Et (1.4 mL, 8.4
mmol) was added and the stirred mixture was refluxed for 3 h. The
reaction was quenched with sat. aq NH4Cl at r.t. and the mixture
was extracted with EtOAc (3 × 30 mL). The combined organic layer
was dried (MgSO4), filtered, and concentrated under reduced pres-
sure to give a residue that was purified by chromatography (silica
gel) to give a yellow solid; yield: 2.65 g (98%); mp 208–210 °C.
Br
Zn
Br
HN
O
Zn
1+
Cu
R
OEt
N
O
2
CuI
t-BuOK
R
OEt
A
HN
N
I
R
R
CO2Et
CO2Et
1H NMR (250 MHz, CDCl3): δ = 0.75 (t, J = 7.1 Hz, 3 H), 3.80 (q,
J = 7.2 Hz, 2 H), 6.45 (s, 1 H), 7.26–7.41(m, 5 H), 7.45–7.52 (m, 5
H), 12.21(br s, 1 H).
13C NMR (63 MHz, CDCl3): δ = 13.2, 61.2, 114.3, 118.5, 127.2,
128.2, 128.4, 128.7, 128.8, 130.3, 132.9, 138.1, 147.2, 154.0, 163.7,
166.7.
I
19
F
Br
I
N
Zn
Cu3+
Cu3+
I
N
O
R
I
CO2Et
R
OEt
B
E
Ethyl 4-Methyl-2-phenyl-5,6,7,8-tetrahydroquinoline-3-car-
boxylate (7aa): Typical Procedure for Tandem Transformation
of Nitriles into Pyridines
CuI
A 1 M soln of MeSO3H in 1,4-dioxane (0.3 mL, 0.3 mmol) was add-
ed to a stirred suspension of commercial Zn dust (392 mg, 6.0
mmol) in 1,4-dioxane (1.2 mL) at a bath temperature of 75 °C. After
10 min, PhCN (306 μL, 3.0 mmol) was added followed, at the same
temperature, by BrCH2CO2Et (0.5 mL, 4.5 mmol), added over 1 h
by using a syringe pump. The mixture was stirred for a further 1 h
before 1-ethynylcyclohexene (388 μL, 3.3 mmol) and 1,4-dioxane
(2.0 mL) were added and the bath temperature was raised to 110 °C.
After 3 h, the mixture was cooled to r.t. and the reaction was
quenched with sat. aq NH4Cl. The mixture was neutralized with sat.
aq Na2CO3 and extracted with EtOAc (3 × 40 mL). The combined
Br
Zn
CuI
N
O
N
O
I
R
OEt
I
R
OEt
ZnBrI
Cu1+
C
D
Scheme 16 Proposed reaction pathway for copper-catalyzed inter-
molecular arylative trapping of the Blaise reaction intermediate
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 1809–1817

1816
J. H. Kim et al.
SPECIAL TOPIC
organic layer was dried (MgSO4), filtered, and concentrated under
reduced pressure to give a residue that was purified by chromatog-
raphy [silica gel, hexane–EtOAc (4:1)] to give a pale-yellow solid:
yield: 796 mg (2.69 mmol, 90%); mp 104–106 °C.
1H NMR (300 MHz, CDCl3): δ = 0.98 (t, J = 7.2 Hz, 3 H), 1.87–1.89
(m, 4 H), 2.26 (s, 3 H), 2.70 (br s, 2 H), 2.99 (br s, 2 H), 4.09 (q, J =
7.2 Hz, 2 H), 7.32–7.42 (m, 3 H), 7.53–7.56 (m, 2 H).
13C NMR (62.9 MHz, CDCl3): δ = 13.6, 15.8, 22.6, 22.8, 26.1, 33.4,
61.3, 127.3, 128.17, 128.23, 129.6, 140.5, 143.5, 153.2, 157.5,
169.4.
ture was refluxed for 1.5 h then cooled to r.t. Pd(PPh3)4 (198.8 mg,
0.17 mmol), t-BuOK (704 mg, 5.28 mmol), and anhyd DMF (9.0
mL) were added and the mixture was kept for 15 h at 120 °C. The
mixture was then cooled to r.t. and the reaction was quenched with
sat. aq NH4Cl. The mixture was extracted with EtOAc (3 × 20 mL)
and the combined organic layer was dried (Na2SO4), filtered, and
concentrated under reduced pressure. The residue was purified by
chromatography [silica gel, hexane–EtOAc (7:1 to 5:1)] to give the
N-fused indole; yield: 52–74%.
Ethyl 2-Phenyl-1H-indole-3-carboxylate (19a): Typical Proce-
dure for Tandem Transformation of Nitriles into Indoles by
Copper Iodide Catalyzed Intermolecular Cross-Coupling of the
Blaise Reaction Intermediate
HRMS (EI): m/z [M]+ calcd for C19H21NO2: 295.1572; found:
295.1571.
MeSO3H (6.5 mol%) was added to a suspension of commercial Zn
dust (500 mg, 7.65 mmol) in THF (1.2 mL) and the mixture was re-
fluxed for 10 min. PhCN (394 mg, 3.82 mmol) was added to the re-
fluxing mixture, followed by BrCH2CO2Et (958 mg, 5.73 mmol)
added over 1 h by using a syringe pump. After refluxing for 1 h, the
mixture was cooled to r.t. and CuI (218 mg, 1.15 mmol), 1,10-phen-
anthroline (418 mg, 2.29 mmol), t-BuOK (1.72 g, 15.29 mmol), 1,2-
dibromobenzene (1.08 g, 4.59 mmol) and anhyd DMF (12.0 mL)
were added. The mixture was kept for 24 h at 120 °C then cooled to
r.t. The reaction was quenched with sat. aq Na2CO3 and the product
was extracted with EtOAc (3 ×100 mL). The combined organic lay-
er was dried (Na2SO4), filtered, and concentrated under reduced
pressure to give a residue that was purified by chromatography (sil-
ica gel) to give a pale yellow solid; yield: 771mg (76%); mp 150–
152 °C.
Ethyl Pyrrolidin-2-ylideneacetate (16, R = H; n = 1): Typical
Procedure for Tandem Transformation of ω-Chloroalkyl Ni-
triles into Exocyclic Enamine Esters
MeSO3H (6.5 mol%) was added to a suspension of Zn dust (500 mg,
7.65 mmol) in THF (1.5 mL) and the mixture was refluxed for 10
min. To the refluxing mixture was added Cl(CH2)4CN (3.82 mmol),
followed by BrCH2CO2Et (4.97 mmol) added over 1 h from a sy-
ringe pump. The reaction was continued until all the Blaise reaction
intermediate had disappeared (GC). The mixture was then cooled to
0 °C and a 1.0 M soln of NaHDMS in THF (13.37 mL, 13.37 mmol)
was added. The mixture was then stirred for 5 h at r.t. before the re-
action was quenched with sat. aq NH4Cl and the mixture was ex-
tracted with EtOAc (3 × 20 mL). The combined organic layer was
dried (Na2SO4), filtered, and concentrated under reduced pressure.
The residue was purified by column chromatography [silica gel,
hexane–EtOAc (7:1)] to give a white solid; yield: 552 mg (93%);
mp 60–61 °C.
Acknowledgment
1H NMR (250 MHz, CDCl3): δ = 1.24 (t, J = 7.1 Hz, 3 H), 1.97 (tt,
J = 7.3, 7.3 Hz, 2 H), 2.58 (t, J = 7.7 Hz, 2 H), 3.52 (t, J = 6.9 Hz,
2 H), 4.12 (q, J = 7.1 Hz, 2 H), 4.52 (s, 1 H), 7.93 (br s, 1 H).
We thank the National Research Foundation of Korea, funded by
the Ministry of Education, Science, and Technology (NRF-
20110016344), for their financial support.
13C NMR (63 MHz, CDCl3): δ = 14.4, 21.7, 31.9, 46.7, 58.0, 76.2,
166.1, 170.3.
References
Ethyl 2-Phenyl-1H-indole-3-carboxylate (19a): Typical Proce-
dure for Tandem Transformation of Nitriles into Indoles
through Palladium-Catalyzed Intramolecular N-Arylation of
the Blaise Reaction Intermediate
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MeSO3H (6.5 mol%) was added to a suspension of commercial Zn
dust (300 mg, 4.59 mmol) in THF (0.85 mL), and the mixture was
refluxed for 10 min before PhCN (0.32 mL, 2.29 mmol) was added.
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added to the refluxing mixture followed by 2-BrC6H4CH(Br)CO2Et
(960 mg, 2.98 mmol) added over 1 h from a syringe pump. The mix-
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© Georg Thieme Verlag Stuttgart · New York

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1817
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Synthesis 2012, 44, 1809–1817