One-pot selective syntheses of 5-azaindoles through zirconocene-mediated multicomponent reactions with three different nitrile components and one alkyne component

Article abstract of DOI:10.1002/chem.201003119

5-Azaindoles either with three different substituents at their 2-, 4-, and 6-positions or with two identical substituents at their 2-and 6-positions and a different one at the 4-position, were obtained in good to excellent isolated yields by a zirconocene

Full text of DOI:10.1002/chem.201003119

DOI: 10.1002/chem.201003119
One-Pot Selective Syntheses of 5-Azaindoles through Zirconocene-Mediated
Multicomponent Reactions with Three Different Nitrile Components and
One Alkyne Component
Shaoguang Zhang,[a] Wen-Xiong Zhang,[a] Jing Zhao,[b] and Zhenfeng Xi*[a, c]
Abstract: 5-Azaindoles either with
three different substituents at their 2-,
4-, and 6-positions or with two identical
substituents at their 2- and 6-positions
and a different one at the 4-position,
were obtained in good to excellent iso-
lated yields by a zirconocene-mediated
multicomponent process. Each reaction
involved four organic partners, com-
prising a Si-tethered diyne, one tBuCN
component, and two (either different
or identical) nitriles. All these four
components were combined through
the action of a Cp2ZrII species into a
three-ring fused Zr/Si-containing or-
ganometallic complex in a perfectly
chemo- and regioselective manner.
This multicomponent reaction process
consisted of three reaction steps, all of
which were made clear through the iso-
lation and characterization of their cor-
responding organometallic intermedi-
ates: the zirconacyclopropene-azasila-
cyclopentadienes 2, the allenyl-aza-zir-
conacycles 3, and the three-ring fused
complexes 6. X-ray single-crystal struc-
tural analyses of two three-ring fused
Zr/Si-containing intermediates and two
5-azaindoles unambiguously showed
the positions of the different substitu-
ents and the regioselectivity. Iminopyr-
role derivatives could be also highly se-
lectively prepared from a Si-tethered
diyne and two different nitriles.
Keywords: 5-azaindoles
·
multi-
component reactions
·
nitriles ·
nitrogen heterocycles · zirconium
Introduction
the same, but the third one could be different. In these
cases, the reactions generated 5-azaindoles with the same
substituents (R1) at the 2- and 4-positions and a different
substituent (R2) at the 6-position (type II).
The development of synthetic methods for azaindoles and
pyrrole derivatives has attracted much attention because
these heterocyclic compounds are of great importance in
many areas.[1–8] Recently, we have developed a synthetic
method for 5-azaindole derivatives.[9] As shown in Scheme 1,
this method involved zirconocene-mediated intermolecular
couplings of one Si-tethered diyne with three nitriles. Either
three identical nitriles or two different nitriles could be
used. The reactions were found to proceed in step-by-step
fashion. When three identical nitriles were used, the reac-
tions afforded 5-azaindoles with the same substituents (R)
at the 2-, 4-, and 6-positions (type I). When two different ni-
triles were used, the first and the second substituents were
Scheme 1. Previous work on the synthesis of 5-azaindoles of type I (the
same substituents at the 2-, 4-, and 6-positions) and type II (the 2- and 4-
positions with the same substituents and the 6-position with a different
one). Different shapes around R1, R2 represent different substituents.
[a] S. Zhang, Prof. Dr. W.-X. Zhang, Prof. Dr. Z. Xi
Beijing National Laboratory for Molecular Sciences
Key Laboratory of Bioorganic Chemistry and
Molecular Engineering of Ministry of Education
College of Chemistry, Peking University
Beijing 100871 (PR China)
We have very recently disclosed a coordination-induced
[10]
À
À
Zr C/Si C bond cleavage and reorganization reaction,
starting from the zirconacyclobutene-silacyclobutene ring-
fused compound 1 (Scheme 2), first reported by Takahashi
et al., which could readily be generated in situ in high yields
through zirconocene-mediated reactions of Si-tethered
diynes.[11–13] As shown in Scheme 2, tBuCN was found to
behave both as an initiator and as a brake/release handle for
initiation and control of the reaction process of 1. The
Fax : (+86)10-62751708
E-mail: zfxi@pku.edu.cn
[b] J. Zhao
Institute of Chemistry, CAS, Beijing 100190 (PR China)
[c] Prof. Dr. Z. Xi
State Key Laboratory of Organometallic Chemistry, Shanghai Insti-
tute of Organic Chemistry, Shanghai 200032 (PR China)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201003119.
tBuCN-stabilized
zirconacyclopropene-azasilacyclopenta-
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Chem. Eur. J. 2011, 17, 2442 – 2449

FULL PAPER
diene complexes 2 and the allenyl-aza-zirconacycles 3 were
thus generated in high yields from tBuCN, a different nitrile
RCN, a Si-tethered diyne, and the zirconocene species.[14–17]
We believe that these two reactive organometallic inter-
mediates 2 and 3 should be synthetically useful for the syn-
thesis of heterocyclic compounds. Indeed in this work, as
shown in Scheme 2, further reactions of these intermediates
with nitriles were found to proceed smoothly through inter-
esting insertions and skeletal rearrangements, providing
useful synthetic methods for N-containing heterocyclic com-
pounds. When the tBuCN-stabilized zirconacyclopropene-
azasilacyclopentadiene complex 2 was treated with a single
nitrile (2 equiv), the reaction generated a 5-azaindole with
the same substituents (R2) at the 2- and the 6-positions and
a different substituent (R1 =tBu) at the 4-position (type III).
The allenyl-aza-zirconacycle 3 was found to react with a
third nitrile smoothly at higher temperature. A 5-azaindole
of type IV, with three different substituents at the 2- (R2), 4-
(R1), and 6-positions (R3), was obtained in a high isolated
yield upon hydrolysis of the reaction mixture.
could readily be generated in situ in high yields through zir-
conocene-mediated reactions of Si-tethered diynes.[9–12]
When a compound 1 was treated with tBuCN (2 equiv), a
tBuCN-stabilized
zirconacyclopropene-azasilacyclopenta-
diene complex 2 was generated in high yield, as we had pre-
viously communicated.[10] In this work, treatment of 2a
(Ar=Ph) with CyCN (2 equiv) at 908C in benzene for 1 h
afforded the three ring-fused compound 4a (Ar=Ph, R2 =
Cy) in 81% isolated yield (Scheme 3). The X-ray structure
Scheme 2. This work: synthesis of 5-azaindoles of type III (the 2- and 6-
positions with the same substituents and the 4-position with a different
one) and type IV (2-, 4-, and 6-positions with three different substitu-
ents).
Scheme 3. Formation of 5-azaindoles with the same substituents at the 2-
and 6-positions and a different substituent at the 4-position (type III).
Iminopyrrole derivatives with all different substituents
could also be prepared highly selectively. Two of the impor-
tant three-ring fused Zr/Si-containing intermediates, each
composed of a Cp2ZrII species, a Si-tethered diyne, one
tBuCN, and two (different or identical) nitrile units, were
isolated in high yields and characterized by single-crystal X-
ray structural analysis, which unambiguously showed the po-
sitions of the different substituents and the regioselectivity.
of 4a clearly revealed that the tBu group was located on the
six-membered azasilacycle, adjacent to the N-silyl imine
moiety (Figure 1). Hydrolysis of 4a afforded the 5-azaindole
derivative 5a in 69% isolated yield. As well as CyCN, other
nitriles such as the aromatic nitrile 2-ThCN or the aliphatic
nitriles iPrCN and nPrCN could be also applied to afford
good to high yields of the 5-azaindoles 5b, 5c, 5d, and 5e,
with the same substituents (R2) at the 2- and the 6-positions
and a different substituent (tBu) at the 4-position (type III).
The mechanism of the hydrolysis of the intermediates 4 to
afford the 5-azaindoles 5 can be related to that proposed in
our previous communication.[9c] The single-crystal X-ray
structure of 5c (Figure 2) again confirmed the location of
the tBu group at the 4-position of the azaindole, and the
two cyclohexyl groups at the 2- and the 6-positions.
Results and Discussion
Formation of 5-azaindoles
i) 5-Azaindoles of type III from one Si-tethered diyne, one
tBuCN component, and two identical nitrile units: The zirco-
nacyclobutene-silacyclobutene fused-ring compounds
1
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2443

Z. Xi et al.
Figure 1. ORTEP drawing of 4a with 30% thermal ellipsoids. Hydrogen
atoms are omitted for clarity. Selected bond lengths [ꢁ]: Zr1–N1
2.262(6), Zr1–N3 1.999(6), Si1–N2 1.762(6), Si1–C6 1.967(7), C7–N3
1.231(8), C4–N2 1.283(9), C1–C2 1.374(9), C2–C3 1.422(9), C3–C5
1.415(9), C3–C4 1.497(10), C5–C6 1.575(9), C6–C7 1.546(9).
Scheme 4. Formation of 5-azaindoles with three different substituents at
the 2-, 4-, and 6-Positions (type IV).
Figure 2. ORTEP drawings of 5c with 30% thermal ellipsoids. Hydrogen
À
atoms are omitted for clarity except for the polar N H bond. Selected
bond lengths [ꢁ]: N1–C1 1.378(3), N1–C7 1.371(3), N2–C4 1.340(3), N2–
C5 1.362(3), C1–C2 1.371(3), C2–C3 1.461(3), C3–C7 1.417(3), C3–C4
1.427(3). C5–C6 1.386(3), C6–C7 1.386(3).
ii) 5-Azaindoles of type IV from one Si-tethered diyne, one
tBuCN, and two different nitriles: When the allenyl-aza-zir-
conacycle 3a (Ar=Ph, R2 =Th, generated in situ) was treat-
ed with a third nitrile—CyCN—at 908C in benzene for 1 h,
the reaction afforded the three ring-fused Zr/Si-containing
compound 6a (Ar=Ph, R2 =Th, R3 =Cy) in 72% isolated
yield (Scheme 4). The structure of 6a was characterized by
single-crystal X-ray structural analysis (Figure 3), which
clearly showed the positions of the three different nitriles.
Hydrolysis of 6a afforded the 5-azaindole derivative 7a in
59% isolated yield. The structure of 7a was also confirmed
by single-crystal X-ray structural analysis (Figure 4). The
tBu group from the first nitrile was fixed at the 4-position,
the thienyl group from the second nitrile was found at the 2-
position on the pyrrole ring, and the cyclohexyl group from
the third nitrile was bonded at the 6-position on the pyridine
ring.
Figure 3. ORTEP drawings of 6a with 30% thermal ellipsoids. Hydrogen
atoms are omitted for clarity. Selected bond lengths [ꢁ]: Zr1–N1
2.250(5), Zr1–N3 1.990(5), Si1–N2 1.752(5), Si1–C22 1.941(6), C29–N3
1.251(7), C15–N2 1.284(7), C1–C2 1.392(8), C2–C3 1.416(8), C3–C15
1.490(7), C3–C4 1.409(7), C4–C22 1.531(8), C22–C29 1.523(8).
As well as CyCN, other nitriles, either aromatic or ali-
phatic, could also be applied as the third different nitrile to
afford the 5-azaindoles 7b–f (Scheme 4) in good to high
yields upon hydrolysis of the reaction mixtures. In each of
these cases only one regioisomer was obtained. These results
clearly demonstrate that the 5-azaindoles are each substitut-
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Chem. Eur. J. 2011, 17, 2442 – 2449

One-Pot Syntheses of 5-Azaindoles
FULL PAPER
Figure 4. ORTEP drawings of 7a with 30% thermal ellipsoids. Hydrogen
À
atoms are omitted for clarity except for the polar N H bond. Selected
bond lengths [ꢁ]: N1–C1 1.400(5), N1–C7 1.383(5), N2–C4 1.329(4), N2–
C5 1.351(4), C1–C2 1.371(5), C2–C3 1.470(5), C3–C7 1.413(5), C3–C4
1.434(5), C5–C6 1.385(5), C6–C7 1.377(5).
ed with three different substituents at the 2-, 4-, and 6-posi-
tions (type IV).
iii) Mechanistic aspects: In our previous communication,[10]
we had isolated and characterized the Zr/Si-containing inter-
mediates 2 and 3. Here we have successfully isolated and
characterized the third type of important Zr/Si-containing
intermediates: 4a and 6a, the X-ray structures of which
clearly showed the positions of the three different nitriles. A
proposed possible mechanism for the formation of com-
pounds 4 or 6 from compounds 2, based on the above exper-
imental evidence, is shown in Scheme 5. For the first step, it
is proposed that one R2CN unit replaces the bulky tBuCN
and revives the reactivity of the zirconacyclopropene
moiety. The coordinating R2CN, which is generally smaller
than tBuCN, can insert into the zirconacyclopropene moiety
in 8 to form its corresponding azazirconacyclopentadiene
moiety in 8’. Skeletal rearrangement of 8 or 8’ would then
generate the allenyl-aza-zirconacycle 3. The third R3CN unit
Scheme 5. Proposed reaction mechanism for the formation of the three-
ring fused compounds 4 and 6.
each functionalized with an imino group and substituted
with all different substituents. It is proposed that the forma-
tion of the pyrroles 13 takes place through nucleophilic-
attack-induced hydroamination cyclizations of the iminoal-
lene species 12.[18]
À
could then insert into the Zr C bond of the allenyl-aza-zir-
conacycle 3 to generate the nine-membered allenyl-aza-zir-
conacycle 9. This cyclic intermediate 9 would be unstable
and would undergo intramolecular nucleophilic attack or a
1,3-silyl shift to give the final three-ring fused compound 6.
When R2 =R3, this gives the corresponding compound 4.
Formation of iminopyrroles with all different substituents
through hydrolysis of the allenyl-aza-zirconacycles 3: The
development of synthetic methods for pyrrole derivatives
has been an ongoing major research topic in synthetic
chemistry, because pyrrole derivatives are of great impor-
tance in many areas.[6–8] The synthesis of pyrrole derivatives
with functional groups and all different substituents on the
ring remains a great challenge.[6,7] When the allenyl-aza-zir-
conacycles 3, each generated in situ from two different ni-
triles and a Si-tethered diyne, were hydrolyzed with water, a
wide variety of iminopyrrole derivatives—13a–e—were ob-
tained in 67–90% yields (Scheme 6). These pyrroles 13 are
Scheme 6. Formation of iminopyrroles with all different substituents
through hydrolysis of the allenyl-aza-zirconacycles 3.
Chem. Eur. J. 2011, 17, 2442 – 2449
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2445

Z. Xi et al.
the preparation of 4-tert-butyl-2,6-dicyclohexyl-3,7-diphenyl-1H-pyrrolo-
AHCTUNGERTG[NNUN 3,2-c]pyridine (5a): nBuLi (1.6m, 2.1 mmol, 1.32 mL) was added drop-
Conclusion
wise by syringe at À788C (dry ice/acetone) to a toluene (10 mL) solution
of Cp2ZrCl2 (1.05 mmol, 307 mg) in a 20 mL Schlenk tube. After the ad-
dition was complete, the reaction mixture was stirred at À788C for 1 h.
Bis(phenylethynyl)dimethylsilane (1 mmol) was then added, and the re-
action mixture was warmed up to 508C and stirred at this temperature
for 1 h. After trimethylacetonitrile (2.0 mmol, 166 mg, 220 mL) had been
added, the reaction mixture was stirred at the same temperature for 2 h.
Cyclohexanecarbonitrile (3.0 mmol, 327 mg, 356 mL) was then added and
the reaction mixture was stirred at 908C for 2 h. The reaction mixture
was quenched with saturated aqueous NaHCO3 and the resulting mixture
was extracted three times with diethyl ether and then washed with water
and brine. The extract was dried over anhydrous MgSO4. The solvent was
evaporated in vacuo to give a yellow solid, which was subjected to SiO2
column chromatography with hexane/diethyl ether/triethylamine
(100:5:1) as the eluent.
In summary, here we report a selective synthesis of 5-azain-
doles with a diverse range of substituents through zircono-
cene-mediated multicomponent reactions. 5-Azaindoles of
two new types—5-azaindoles with three different substitu-
ents at their 2-, 4-, and 6-positions or 5-azaindoles with two
identical substituents at their 2- and 6-positions and a differ-
ent one at the 4-position—are synthesized in good to excel-
lent isolated yields by this method. This work represents a
new synthetic strategy for achieving selectivity in multicom-
ponent reactions. Single-crystal X-ray structural analyses of
the important three-ring fused Zr/Si-containing intermedi-
ates, each consisting of a Cp2ZrII species, a Si-tethered
diyne, one tBuCN, and two different nitriles, unambiguously
showed the positions of the different nitriles and the high
regioselectivity. In addition, iminopyrrole derivatives could
be prepared in high yields from a Si-tethered diyne and two
different nitriles.
4-tert-Butyl-2,6-dicyclohexyl-3,7-diphenyl-1H-pyrroloACTHNUGRTENUNG[3,2-c]pyridine (5a):
Pale yellow solid, isolated yield 69% (338 mg). 1H NMR (400 MHz,
CDCl3, 258C, TMS): d=1.19–1.90 (m, 29H; CH2, CMe3), 2.19–2.26 (m,
1H; CH), 2.59–2.66 (m, 1H; CH), 7.34–7.54 (m, 10H; C6H5), 7.74 ppm
(brs, 1H; NH); 13C NMR (100 MHz, CDCl3, 258C, TMS): d=23.59,
24.77, 25.21, 25.79, 26.22, 27.50, 29.01, 30.30, 32.48, 32.65, 35.23, 38.87,
41.08, 112.93, 115.30, 118.64, 122.17, 126.52, 126.99, 127.09, 128.54, 129.51,
132.54, 136.01, 138.47, 139.33, 141.10, 150.39, 159.73 ppm; HRMS: m/z:
calcd for C35H43N2: 491.3426 [M+H]+; found: 491.3428; elemental analy-
sis calcd (%) for C35H42N2: C 85.66, H 8.63, N 5.71; found: C 85.60, H
8.82, N 5.59.
Experimental Section
General methods: All reactions were conducted under a slightly positive
pressure of dry nitrogen by standard Schlenk line techniques or under ni-
trogen in a glovebox (Mikrouna Super 1220/750). The nitrogen in the glo-
vebox was constantly circulated through a catalyst unit (copper/molecular
sieves). The oxygen and moisture concentrations in the glovebox atmos-
phere were monitored with an O2/H2O Combi-Analyzer to ensure both
were always below 1 ppm. Unless otherwise noted, all starting materials
were commercially available and were used without further purification.
4-tert-Butyl-3,7-diphenyl-2,6-bis(thiophen-2-yl)-1H-pyrroloACTHNUTRGNEUGN[3,2-c]pyridine
(5b): White solid, isolated yield 77% (377 mg). 1H NMR (400 MHz,
CDCl3, 258C, TMS): d=1.31 (s, 9H; CMe3), 6.40 (d, J=3.5 Hz, 1H;
C4H3S), 6.70–6.82 (m, 3H; C4H3S), 7.06 (d, J=5.2 Hz, 1H; C4H3S), 7.16
(d, J=5.2 Hz, 1H; C4H3S), 7.44 (s, 5H; C6H5), 7.50–7.60 (m, 5H; C6H5),
8.05 ppm (brs, 1H; NH); 13C NMR (100 MHz, CDCl3, 258C, TMS): d=
30.60, 39.55, 114.56, 116.05, 120.86, 124.64, 125.16, 126.17, 126.34, 126.72,
127.37, 128.20, 128.31, 128.61, 129.87, 130.04, 130.98, 133.58, 134.16,
135.52, 137.36, 138.84, 141.71, 147.21, 161.69 ppm; HRMS: m/z: calcd for
C31H27N2S2: 491.1616 [M+H]+; found: 491.1608.
Solvents were purified with
a
solvent purification system
(MBRAUN SPS-800) and dried over fresh Na chips in the glovebox.
nBuLi was obtained from Acros. Organometallic samples for NMR spec-
troscopic measurements were prepared in the glovebox by use of valve
NMR tubes (J. Young, Wilmad 528-JY). 1H and 13C NMR spectra were
4-tert-Butyl-2,6-diisopropyl-3,7-bis-p-tolyl-1H-pyrroloACTHUNRTGNEUNG[3,2-c]pyridine (5c):
White solid, isolated yield 71% (310 mg). 1H NMR (300 MHz, CDCl3,
258C, TMS): d=1.05 (d, J=6.9 Hz, 6H; CHMe2), 1.23 (d, J=6.9 Hz, 6H;
CHMe2), 1.24 (s, 9H; CMe3), 2.43 (s, 3H; CMe), 2.47 (s, 3H; CMe),
2.59–2.69 (m, 1H; CHMe2), 3.00–3.08 (m, 1H; CHMe2), 7.18–7.34 (m,
8H; C6H4), 7.72 ppm (brs, 1H; NH); 13C NMR (75 MHz, CDCl3, 258C,
TMS): d=21.33, 22.50, 23.16, 25.65, 30.75, 31.10, 39.33, 113.08, 115.54,
119.21, 128.31, 129.72, 129.80, 132.84, 133.34, 135.80, 136.48, 137.12,
139.98, 142.05, 151.40, 160.31 ppm; HRMS: m/z: calcd for C31H39N2:
439.3108 [M+H]+; found: 439.3100; elemental analysis calcd (%) for
C31H38N2: C 84.88, H 8.73, N 6.39; found: C 84.72, H 8.79, N 6.21. Single
crystals of 5c suitable for X-ray analysis were grown in hexane/diethyl
ether at room temperature for one day.
recorded with
a
Bruker 400 spectrometer (FT, 400 MHz for 1H;
1
100 MHz for 13C) or a JEOL-AL 300 spectrometer (FT, 300 MHz for H;
75 MHz for 13C) at room temperature, unless otherwise noted. Elemental
analyses were performed with an Elemental Analyzer vario EL appara-
tus.
Isolation of the reactive intermediate 4a from one bisACHTNUTRGNEUNG(alkynyl)silane, one
tBuCN, and two CyCN components: A compound 2 was isolated by the
method we reported previously.[10] In a 20 mL Schlenk tube, cyclohexane-
carbonitrile (178 mL, 1.50 mmol) was added to a benzene (3 mL) solution
of compound 2 (Ar=Ph, 318 mg, 0.50 mmol) by syringe. After the reac-
tion mixture had been stirred at 908C for 1 h, it was concentrated and
dried under vacuum and the residue was extracted with hexane. After fil-
tration and concentration, the solid was dried under vacuum to provide
4a as an orange powder (312 mg, 0.405 mmol, 81%). Single crystals of
4a suitable for X-ray analysis were grown in benzene/hexane at room
temperature for one week. 1H NMR (300 MHz, C6D6, 258C): d=0.29 (s,
3H; SiMe2), 1.01 (s, 9H; CMe3), 1.02 (s, 3H; SiMe2), 1.23–2.18 (m, 20H;
C6H11), 2.28–2.36 (m, 1H; C6H11), 2.71–2.77 (m, 1H; C6H11), 6.11 (s, 5H;
C5H5), 6.26 (s, 5H; C5H5), 7.12–7.46 (m, 6H; C6H5), 7.66 (d, J = 7.8 Hz,
2H; C6H5), 7.90 ppm (d, J = 7.5 Hz, 2H; C6H5); 13C NMR (75.4 MHz,
C6D6, 258C): d=À3.35, 2.95, 15.54, 25.76, 26.31, 27.82, 28.16, 29.74, 31.33,
32.09, 32.22, 37.45, 41.42, 46.44, 46.86, 60.53, 111.29, 111.41, 119.54,
125.82, 126.47, 126.94, 127.50, 127.68, 130.70, 132.45, 134.66, 140.07,
141.24, 142.02, 144.23, 181.56, 194.26 ppm; elemental analysis calcd (%)
for C47H57N3SiZr: C 72.07, H 7.33, N 5.36; found: C 72.00, H 7.56, N
5.00.
4-tert-Butyl-2,6-dipropyl-3,7-bis-p-tolyl-1H-pyrrolo
G
(5d):
White solid, isolated yield 46% (201 mg). 1H NMR (300 MHz, CDCl3,
258C, TMS): d=0.77 (t, J=6.6 Hz, 3H; CH2CH3), 0.86 (t, J=7.2 Hz, 3H;
CH2CH3), 1.24 (s, 9H; CMe3), 1.38–1.46 (m, 2H; CH2CH2CH3), 1.74–1.81
(m, 2H; CH2CH2CH3), 2.25 (t, J=7.1 Hz, 2H; CH2CH2CH3), 2.42 (s, 3H;
CMe), 2.46 (s, 3H; CMe), 2.64 (t, J=6.8 Hz, 2H; CH2CH2CH3), 7.16–
7.33 (m, 8H; C6H4), 7.76 ppm (brs, 1H; NH); 13C NMR (75 MHz,
CDCl3, 258C, TMS): d=13.85, 14.19, 21.35, 22.92, 22.99, 28.44, 30.71,
36.35, 38.96, 114.58, 116.72, 119.39, 128.24, 129.67, 129.83, 132.85, 133.43,
135.72, 136.39, 137.07, 137.09, 140.31, 146.62, 160.09 ppm; HRMS: m/z:
calcd for C31H39N2: 439.3108 [M+H]+; found: 439.3102.
4-tert-Butyl-2,6-dicyclohexyl-3,7-bis-p-tolyl-1H-pyrroloACTHNUTRGENUGN[3,2-c]pyridine
(5e): White solid, isolated yield 93% (483 mg). 1H NMR (300 MHz,
CDCl3, 258C, TMS): d=1.09–1.93 (m, 29H; CH2, CMe3), 2.19–2.27 (m,
1H; CH), 2.42 (s, 3H), 2.47 (s, 3H), 2.61–2.68 (m, 1H; CH), 7.15–7.37
(m, 8H), 7.72 ppm (brs, 1H); 13C NMR (75 MHz, CDCl3, 258C, TMS):
d=21.37, 25.71, 26.24, 26.67, 30.78, 32.97, 33.12, 35.60, 39.32, 41.43,
Formation of the 5-azaindoles 5 (type III) from one Si-tethered diyne,
one tBuCN, and two identical nitrile components—typical procedure for
2446
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ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2011, 17, 2442 – 2449

One-Pot Syntheses of 5-Azaindoles
FULL PAPER
113.24, 115.66, 119.15, 128.27, 129.72, 129.79, 132.78, 133.33, 135.71,
136.37, 136.98, 139.84, 141.55, 150.85, 160.03 ppm; HRMS: m/z: calcd for
C31H39N2 [M+H]+: 519.3739; found: 519.3736.
514.3217 [M+H]+; found: 514.3216; elemental analysis calcd (%) for
C36H39N3: C 84.17, H 7.65, N 8.18; found: C 84.12, H 7.77, N 8.10.
4-tert-Butyl-6-isopropyl-2-(thiophen-2-yl)-3,7-bis-p-tolyl-1H-pyrroloACHTUNGTRENNUNG[3,2-
c]pyridine (7c): White solid, isolated yield: 53% (253 mg). 1H NMR
(300 MHz, CDCl3, 258C, TMS): d=1.24 (d, J=7.2 Hz, 6H; CHMe2),
1.26 (s, 9H; CMe3), 2.45 (s, 3H; CMe), 2.47 (s, 3H; CMe), 3.03–3.12 (m,
1H; CHMe2), 6.67 (d, J=3.6 Hz, 1H; C4H3S), 6.79–6.82 (m, 1H; C4H3S),
7.03 (d, J=5.1 Hz, 1H; C4H3S), 7.21–7.35 (m, 8H; C6H4), 8.02 ppm (brs,
1H; NH); 13C NMR (75 MHz, CDCl3, 258C, TMS): d=21.33, 21.49,
23.05, 30.81, 31.22, 39.49, 115.55, 120.12, 124.09, 125.64, 126.57, 128.97,
129.78, 129.81, 132.86, 133.36, 134.64, 134.79, 137.39, 137.65, 140.89,
152.58, 161.28 ppm; HRMS: m/z: calcd for C32H35N2S: 479.2521 [M+H]+;
found: 479.2518; elemental analysis calcd (%) for C32H34N2S: C 80.29, H
7.16, N 5.85; found: C 80.31, H 7.08, N 5.95.
Isolation of the reactive intermediate 6a from one bisACHTNUTRGNEUNG(alkynyl)silane, one
tBuCN, one thiophene-2-carbonitrile and one CyCN component: Thio-
phene-2-carbonitrile (47 mL, 0.50 mmol) was added by syringe to a ben-
zene (3 mL) solution of compound 2 (Ar=Ph, 318 mg, 0.50 mmol) in a
20 mL Schlenk tube. After the reaction mixture had been stirred at room
temperature for 1h, cyclohexanecarbonitrile (118 mL, 1.0 mmol) was
added and the reaction mixture was stirred at 908C for 1h; it was then
concentrated and dried under vacuum and the residue was extracted with
hexane. After filtration and concentration, the solid was dried under
vacuum to provide 6a as an orange powder (277 mg, 0.36 mmol, 72%).
Single crystals of 6a suitable for X-ray analysis were grown in hexane at
room temperature for one week. 1H NMR (300 MHz, C6D6, 258C): d=
0.20 (s, 3H; SiMe2), 0.88 (s, 3H; SiMe2), 1.04 (s, 9H; CMe3), 1.21–1.91
(m, 10H; C6H11), 2.73–2.81 (m, 1H; C6H11), 5.62 (s, 5H; C5H5), 6.20 (s,
5H; C5H5), 6.77–7.44 (m, 11H; C6H5, C4H3S), 7.74 ppm (d, J = 8.1 Hz,
2H; C6H5); 13C NMR (75.4 MHz, C6D6, 258C): d=À3.8, 3.0, 26.32, 30.28,
31.21, 32.16, 42.00, 46.33, 59.91, 108.41, 110.41, 111.62, 111.98, 125.62,
126.01, 126.15, 126.69, 127.80, 129.18, 130.36, 130.82, 132.81, 132.84,
140.12, 141.65, 143.20, 145.50, 179.71, 195.99 ppm; elemental analysis
calcd (%) for C45H49N3SSiZr: C 69.00, H 6.31, N 5.36; found: C 68.92, H
6.41, N 5.18.
4-tert-Butyl-2-(furan-2-yl)-6-hexyl-3,7-bis-p-tolyl-1H-pyrroloACTHUNTGRNEUNG[3,2-c]pyri-
dine (7d): Yellow solid, isolated yield: 41% (206 mg). 1H NMR
(400 MHz, CDCl3, 258C, TMS): d=0.84 (t, J=6.5 Hz, 3H; CH3), 1.20–
1.27 (m, 4H; CH2), 1.29 (s, 9H; CMe3), 1.73–1.76 (m, 2H; CH2), 2.34–
2.42 (m, 2H; CH2), 2.47 (s, 3H; CMe), 2.48 (s, 3H; CMe), 2.69 (t, J=
7.6 Hz, 2H; CH2), 5.02 (d, J=3.4 Hz, 1H; C4H3O), 6.16–6.17 (m, 1H;
C4H3O), 7.27 (d, J=4.1 Hz, 1H; C4H3O), 7.28 (s, 4H; C6H4), 7.31 (s, 4H;
C6H4), 8.43 ppm (brs, 1H; NH); 13C NMR (100 MHz, CDCl3, 258C,
TMS): d=14.10, 21.33, 21.43, 22.60, 29.13, 29.55, 30.79, 31.78, 34.28,
39.06, 106.86, 111.89, 114.27, 117.06, 119.83, 127.10, 128.94, 129.22, 129.75,
129.84, 132.52, 133.04, 135.29, 137.27, 137.38, 140.72, 140.85, 146.87,
148.07, 161.14 ppm; HRMS: m/z: calcd for C35H41N2O: 505.3213; found:
505.3210.
Formation of the 5-azaindoles 7 (type IV) from one Si-tethered diyne,
one tBuCN, and two different nitrile components—typical procedure for
the preparation of 4-tert-butyl-6-cyclohexyl-3,7-diphenyl-2-(thiophen-2-
4-tert-Butyl-6-propyl-2-(pyrazin-2-yl)-3,7-bis-p-tolyl-1H-pyrroloACHTUNGTRENNUNG[3,2-c]pyr-
yl)-1H-pyrroloACHTUNGTRENNUNG[3,2-c]pyridine (7a): nBuLi (1.6m, 2.1 mmol, 1.32 mL) was
idine (7e): White solid, isolated yield: 72% (341 mg). 1H NMR
(400 MHz, CDCl3, 258C, TMS): d=0.86 (t, J=7.2 Hz, 3H; CH2CH3),
1.27 (s, 9H; CMe3), 1.77–1.83 (m, 2H; CH3CH2CH2), 2.48 (s, 3H; CMe),
2.49 (s, 3H; CMe), 2.69 (t, J=7.6 Hz, 2H; CH3CH2CH2), 7.29–7.35 (m,
4H; C6H4), 7.37 (s, 4H; C6H4), 7.51 (d, J=1.6 Hz, 1H; C4H3N2), 8.21 (d,
J=2.5 Hz, 1H; C4H3N2), 8.35–8.36 (m, 1H; C4H3N2), 9.35 ppm (brs, 1H;
NH); 13C NMR (100 MHz, CDCl3, 258C, TMS): d=14.14, 21.36, 21.46,
22.74, 30.88, 36.46, 39.25, 117.34, 118.75, 120.72, 129.62, 129.78, 129.81,
130.92, 132.33, 132.88, 134.80, 137.30, 138.22, 141.24, 141.55, 142.48,
143.15, 146.28, 148.84, 162.51 ppm; HRMS: m/z: calcd for C32H35N4:
475.2862 [M+H]+; found: 475.2858; elemental analysis calcd (%) for
C32H34N4: C 80.98, H 7.22, N 11.80; found: C 80.90, H 7.36, N 11.54.
added dropwise by syringe at À788C (dry ice/acetone) to a toluene
(10 mL) solution of Cp2ZrCl2 (1.05 mmol, 307 mg) in a 20 mL Schlenk
tube. After the addition was complete, the reaction mixture was stirred
at À788C for 1 h. Bis(phenylethynyl)dimethylsilane (1 mmol) was then
added, and the reaction mixture was warmed up to 508C and stirred at
this temperature for 1 h. After trimethylacetonitrile (2.0 mmol, 166 mg,
220 mL) had been added, the reaction mixture was stirred at the same
temperature for 2 h. Thiophene-2-carbonitrile (0.9 mmol, 98 mg, 84 mL)
was then added and the reaction mixture was stirred at room tempera-
ture for 1 h. Cyclohexanecarbonitrile (2.0 mmol, 218 mg, 238 mL) was
then added, and the reaction mixture was stirred at 908C for 2 h. The re-
action mixture was quenched with saturated aqueous NaHCO3. The re-
sulting mixture was extracted three times with diethyl ether and then
washed with water and brine. The extract was dried over anhydrous
MgSO4. The solvent was evaporated in vacuo to give a yellow solid,
which was subjected to SiO2 column chromatography with hexane/diethyl
ether/triethylamine (100:5:1) as the eluent.
4-tert-Butyl-2-(pyridin-2-yl)-6-(thiophen-2-yl)-3,7-bis-p-tolyl-1H-pyrrolo-
AHCTUNGTRENNUNG
[3,2-c]pyridine (7 f): White solid, isolated yield: 49% (251 mg). 1H NMR
(400 MHz, CDCl3, 258C, TMS): d=1.31 (s, 9H; CMe3), 2.50 (s, 3H;
CMe), 2.53 (s, 3H; CMe), 6.34 (d, J=8.3 Hz, 1H; C5H4N), 6.45 (d, J=
3.2 Hz, 1H; C4H3S), 6.79–6.81 (m, 1H; C4H3S), 7.18–7.42 (m, 9H; C5H4N,
C6H4), 8.43 (d, J=4.8 Hz, 1H; C5H4N), 9.57 ppm (brs, 1H; NH);
13C NMR (100 MHz, CDCl3, 258C, TMS): d=21.47, 21.52, 30.74, 39.62,
115.05, 117.36, 120.91, 121.59, 121.66, 125.25, 126.19, 127.37, 129.33,
129.91, 130.47, 132.60, 132.65, 134.18, 135.07, 136.01, 137.75, 138.08,
139.04, 141.25, 148.77, 149.74, 162.35 ppm; HRMS: m/z: calcd for
C34H32N3S: 514.2311; found: 514.2305.
4-tert-Butyl-6-cyclohexyl-3,7-diphenyl-2-(thiophen-2-yl)-1H-pyrroloACTHNUTRGNE[UNG 3,2-
c]pyridine (7a): White solid, isolated yield: 59% (289 mg). 1H NMR
(300 MHz, CDCl3, 258C, TMS): d=1.16–1.30 (m, 2H; CH2), 1.25 (s, 9H;
CMe3), 1.62–1.96 (m, 8H; CH2), 2.63–2.71 (m, 1H; CH), 6.67 (d, J=
2.1 Hz, 1H; C4H3S), 6.80 (t, J = 5.4 Hz, 1H; C4H3S), 7.03 (d, J = 5.4 Hz,
1H; C4H3S), 7.42–7.57 (m, 10H; C6H5), 8.02 ppm (brs, 1H; NH);
13C NMR (75 MHz, CDCl3, 258C, TMS): d=26.20, 26.61, 30.81, 32.98,
39.49, 41.65, 115.59, 115.81, 119.97, 124.32, 125.76, 126.63, 127.72, 127.97,
128.21, 129.11, 129.78, 129.93, 133.61, 134.63, 135.95, 137.91, 140.82,
152.09, 161.17 ppm; HRMS: m/z: calcd for C33H35N2S: 491.2521 [M+H]+;
found: 491.2516; elemental analysis calcd (%) for C33H34N2S: C 80.77, H
6.98, N 5.71; found: C 80.54, H 7.03, N 5.55.
Formation of the iminopyrroles 13 with all different substituents by hy-
drolysis of the allenyl-aza-zirconacycles 3—general procedure for the
preparation of 1-[2-benzyl-4-phenyl-5-(thiophen-2-yl)-1H-pyrrol-3-yl]-
2,2-dimethylpropan-1-ylimine (13a): nBuLi (2.1 mmol, 1.6m, 1.32 mL)
was added dropwise by syringe at À788C (dry ice/acetone) to a toluene
(10 mL) solution of Cp2ZrCl2 (1.05 mmol, 307 mg) in a 20 mL Schlenk
tube. After the addition was complete, the reaction mixture was stirred
at À788C for 1 h. Bis(phenylethynyl)dimethylsilane (1 mmol) was then
added, and the reaction mixture was warmed up to 508C and stirred at
this temperature for 1 h. After trimethylacetonitrile (2.0 mmol, 166 mg,
220 mL) had been added, the reaction mixture was stirred at the same
temperature for 2 h. Thiophene-2-carbonitrile (0.9 mmol, 98 mg, 84 mL)
was then added and the reaction mixture was stirred at room tempera-
ture for 1 h. The reaction mixture was quenched with saturated aqueous
NaHCO3. The resulting mixture was extracted three times with diethyl
ether and then washed with water and brine. The extract was dried over
anhydrous MgSO4. The solvent was evaporated in vacuo to give a yellow
4-tert-Butyl-6-cyclohexyl-2-(pyridin-2-yl)-3,7-bis-p-tolyl-1H-pyrroloACTHNUTRGENUG[N 3,2-
c]pyridine (7b): White solid, isolated yield: 63% (323 mg). 1H NMR
(400 MHz, CDCl3, 258C, TMS): d=1.19–1.31 (m, 2H; CH2), 1.26 (s, 9H;
CMe3), 1.63–1.95 (m, 8H; CH2), 2.49 (s, 3H; CMe), 2.50 (s, 3H; CMe),
2.69–2.75 (m, 1H; CH), 6.32 (d, J=8.2 Hz, 1H; C5H4N), 6.94–6.97 (m,
9H; C6H4, C5H4N), 8.40–8.41 (m, 1H; C5H4N), 9.54 ppm (brs, 1H; NH);
13C NMR (75 MHz, CDCl3, 258C, TMS): d=21.38, 21.46, 26.27, 26.64,
30.96, 33.00, 39.54, 41.56, 116.11, 116.88, 120.76, 121.36, 129.24, 129.69,
129.85, 132.67, 133.05, 133.07, 135.63, 135.88, 137.02, 137.48, 140.35,
148.69, 150.13, 152.25, 161.76 ppm; HRMS: m/z: calcd for C36H40N3:
Chem. Eur. J. 2011, 17, 2442 – 2449
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
2447

Z. Xi et al.
solid, which was subjected to SiO2 column chromatography with hexane/
ethyl acetate/triethylamine (100:40:1) as the eluent.
non-hydrogen atoms by the full-matrix, least-squares method. The hydro-
gen atoms were placed at the calculated positions and were included in
the structure calculation without further refinement of the parameters.
Crystal data, data collection, and processing parameters for compounds
4a, 5c, 6a, and 7a are summarized in the Supporting Information.
1-[2-Benzyl-4-phenyl-5-(thiophen-2-yl)-1H-pyrrol-3-yl]-2,2-dimethylpro-
pan-1-imine (13a): Yellow solid, isolated yield: 77% (306 mg). 1H NMR
(300 MHz, CDCl3, 258C, TMS): d=0.89 (s, 9H; CMe3), 3.92 (s, 2H;
CH2), 6.76–6.86 (m, 2H; C4H3S), 7.02–7.05 (m, 1H; C4H3S), 7.26–7.34 (m,
10H; C6H5), 8.22 ppm (brs, 1H; NH); 13C NMR (75.5 MHz, CDCl3,
258C, TMS): d=28.51, 32.60, 40.68, 120.75, 121.66, 123.77, 126.56, 126.78,
127.05, 128.08, 128.63, 128.88, 130.55, 134.68, 135.84, 138.57, 187.77 ppm;
HRMS: m/z: calcd for C26H27N2S: 399.1895 [M+H]+; found: 399.1892; el-
emental analysis calcd (%) for C26H26N2S: C 78.35, H 6.58, N 7.03;
found: C 78.25, H 6.66, N 7.08.
CCDC-797061 (4a), CCDC-797062 (5c), CCDC-797063 (6a), and
CCDC-797064 (7a) contain the supplementary crystallographic data for
this paper. These data can be obtained free of charge from The Cam-
bridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_
request/cif.
1-[5-Benzyl-2-(4-methylbenzyl)-4-p-tolyl-1H-pyrrol-3-yl]-2,2-dimethylpro-
pan-1-imine (13b): Yellow solid, isolated yield: 82% (355 mg). 1H NMR
(300 MHz, CDCl3, 258C, TMS): d=0.93 (s, 9H; CMe3), 2.31 (s, 3H;
CMe), 2.33 (s, 3H; CMe), 3.80 (s, 2H; CH2), 3.92 (s, 2H; CH2), 7.01–7.29
(m, 13H; C6H4, C6H5), 7.46 ppm (brs, 1H; NH); 13C NMR (75 MHz,
CDCl3, 258C, TMS): d=21.00, 21.16, 28.70, 29.70, 31.85, 31.94, 40.74,
120.29, 122.83, 125.13, 125.86, 126.30, 128.27, 128.36, 128.59, 128.90,
129.25, 129.35, 133.80, 135.34, 136.04, 139.84, 188.67 ppm; HRMS: m/z:
calcd for C31H35N2: 435.2795 [M+H]+; found: 435.2793; elemental analy-
sis calcd (%) for C31H34N2: C 85.67, H 7.89, N 6.45; found: C 85.54, H
7.66, N 6.58.
Acknowledgements
This work was supported by the National Natural Science Foundation of
China and the Major State Basic Research Development Program
(2011CB808705). Cheung Kong Scholars Program, Dow Corning Corpo-
ration, Qiu Shi Science & Technologies Foundation, and BASF are grate-
fully acknowledged.
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2,2-Dimethyl-1-[2-(4-methylbenzyl)-5-phenyl-4-p-tolyl-1H-pyrrol-3-yl]-
propan-1-imine (13c): White solid, isolated yield: 90% (378 mg).
1H NMR (300 MHz, CDCl3, 258C, TMS): d=0.93 (s, 9H; CMe3), 2.32 (s,
3H; CMe), 2.34 (s, 3H; CMe), 3.90 (s, 2H; CH2), 7.01–7.25 (m, 13H;
C6H4, C6H5), 7.73 ppm (brs, 1H; NH); 13C NMR (75 MHz, CDCl3, 258C,
TMS): d=21.04, 21.20, 28.59, 32.37, 40.85, 126.28, 126.95, 127.00, 128.41,
128.67, 128.91, 129.60, 130.04, 132.92, 133.47, 135.46, 135.61, 136.39,
188.33 ppm; HRMS: m/z: calcd for C30H33N2: 421.2638 [M+H]+; found:
421.2635.
1-[5-(Furan-2-yl)-2-(4-methylbenzyl)-4-p-tolyl-1H-pyrrol-3-yl]-2,2-dime-
thylpropan-1-imine (13d): Yellow solid, isolated yield: 80% (328 mg).
1H NMR (400 MHz, CDCl3, 258C, TMS): d=0.91 (s, 9H; CMe3), 2.34 (s,
3H; CMe), 2.35 (s, 3H; CMe), 3.88 (s, 2H; CH2), 5.98 (d, J=3.3 Hz, 1H;
C4H3O), 6.22–6.23 (m, 1H; C4H3O), 7.12–7.22 (m, 9H; C6H4, C4H3O),
8.23 ppm (brs, 1H; NH); 13C NMR (100 MHz, CDCl3, 258C, TMS): d=
21.00, 21.21, 28.59, 32.26, 40.59, 103.44, 111.34, 119.05, 119.66, 124.67,
127.24, 128.54, 128.87, 129.53, 130.06, 132.88, 135.42, 136.27, 136.31,
139.89, 147.21, 187.68 ppm; HRMS: m/z: calcd for C28H31N2O: 411.2431
[M+H]+; found: 411.2408.
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2,2-Dimethyl-1-[2-(4-methylbenzyl)-5-(thiophen-3-yl)-4-p-tolyl-1H-
pyrrol-3-yl]propan-1-imine (13e): Yellow solid, isolated yield: 67%
(285 mg). 1H NMR (400 MHz, CDCl3, 258C, TMS): d=0.93 (s, 9H;
CMe3), 2.29 (s, 3H; CMe), 2.30 (s, 3H; CMe), 3.89 (s, 2H; CH2), 6.78–
6.79 (m, 1H; C4H3S), 6.93–6.94 (m, 1H; C4H3S), 7.06–7.15 (m, 9H; C6H4,
C4H3S), 7.82 ppm (brs, 1H; NH); 13C NMR (100 MHz, CDCl3, 258C,
TMS): d=21.01, 21.19, 28.60, 32.31, 40.73, 119.21, 123.18, 125.30, 126.56,
128.53, 128.61, 128.74, 128.83, 129.41, 129.45, 129.56, 130.11, 133.39,
133.58, 135.51, 135.82, 136.35, 188.12 ppm; HRMS: m/z: calcd for
C28H31N2S: 427.2202 [M+H]+; found: 427.2205.
X-ray crystallographic studies: Single crystals of 4a, 5c, 6a, and 7a suita-
ble for X-ray analysis were grown as described above. The crystals of 4a
and 6a were manipulated under nitrogen and were sealed in thin-walled
glass capillaries. Data collection for 4a was performed at 208C, for 7a at
258C, and for 5c at À1508C with use of a Rigaku RAXIS RAPID IP dif-
fractometer and graphite-monochromated MoKa radiation (l=
0.71073 ꢁ). Data collection for 6a was performed at À1008C with use of
a RIGAKU CCD SATURN 724 diffractometer and graphite-monochro-
mated MoKa radiation (l=0.71073 ꢁ). The determination of crystal class
and unit cell parameters was carried out with the Rapid-AUTO
(Rigaku 2000) program package for 4a, 5c, and 7a or with CrystalClear
(Rigaku Inc., 2007) for 6a. The raw frame data were processed with the
aid of Crystal Structure (Rigaku/MSC 2000) for 4a, 5c, and 7a or of
CrystalClear (Rigaku Inc., 2007) for 6a to yield the reflection data file.
The structures of 4a, 5c, 6a, and 7a were solved by use of the SHELXTL
program.[19] Refinement was performed on F2 anisotropically for all the
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ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Received: October 29, 2010
Published online: January 24, 2011
Chem. Eur. J. 2011, 17, 2442 – 2449
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
2449