Multisubstituted N-fused heterocycles via transition metal-catalyzed cycloisomerization protocols

Article abstract of DOI:10.1016/j.tet.2008.04.023

Two complementary protocols for assembly of multisubstituted N-fused heterocycles have been developed. It was demonstrated that 1,3-disubstituted N-fused heterocycles, including indolizines, pyrroloquinoxalines, and pyrrolothiazoles can easily be synthesized via an exceptionally mild and efficient method involving a novel silver-catalyzed cycloizomerization of propargyl-containing heterocycles. Alternatively, 1,2-disubstituted heterocycles can be accessed through the novel cascade transformation involving an alkyne-vinylidene isomerization with concomitant 1,2-shift of hydrogen, silyl, stannyl, or germyl groups. This mild and simple method allows for selective and highly efficient synthesis of indolizines, pyrroloisoquinolines, pyrroloquinoxalines, pyrrolopyrazines, and pyrrolothiazoles.

Full text of DOI:10.1016/j.tet.2008.04.023

Tetrahedron 64 (2008) 6876–6883
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Multisubstituted N-fused heterocycles via transition metal-catalyzed
cycloisomerization protocols
*
Ilya V. Seregin, Alex W. Schammel, Vladimir Gevorgyan
Department of Chemistry, University of Illinois at Chicago, 845 W. Taylor Street, Chicago, IL 60607-7061, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Two complementary protocols for assembly of multisubstituted N-fused heterocycles have been de-
veloped. It was demonstrated that 1,3-disubstituted N-fused heterocycles, including indolizines, pyrro-
loquinoxalines, and pyrrolothiazoles can easily be synthesized via an exceptionally mild and efficient
method involving a novel silver-catalyzed cycloizomerization of propargyl-containing heterocycles. Al-
ternatively, 1,2-disubstituted heterocycles can be accessed through the novel cascade transformation
involving an alkyne–vinylidene isomerization with concomitant 1,2-shift of hydrogen, silyl, stannyl, or
germyl groups. This mild and simple method allows for selective and highly efficient synthesis of in-
dolizines, pyrroloisoquinolines, pyrroloquinoxalines, pyrrolopyrazines, and pyrrolothiazoles.
Ó 2008 Elsevier Ltd. All rights reserved.
Received 21 February 2008
Received in revised form 2 April 2008
Accepted 4 April 2008
Available online 10 April 2008
1. Introduction
migration, which allows for the efficient synthesis of 1,3-di-
substituted indolizines and other heterocycles (Eq. 2).12
Heteroaromatic molecules containing N-fused pyrrole unit,
along with their partially or completely reduced analogues, are
pharmaceutically significant scaffolds.1,2 Structural fragments of
this family are widely found in naturally occurring, as well as in
synthetic biologically active molecules. Among diverse indolizine-
containing biologically active molecules, the most prominent are:
the potent topoisomerase I inhibitor, marine alkaloid Lamellarin
R
1
(A)
(A)
CuI
50-93%
2
ð1Þ
ð2Þ
N
N
3
R
R = H, Alk, OTBS
D,3,4 the anti-HIV integrase agent, Lamellarin
a
20-sulfate,5 15-
7
lipoxigenase,6 and sPLA2 inhibitors. More recently, the potent
indolizine-containing cardiovascular agent8 and anti-inflammatory
CRTH2 receptor modulator9 have also been reported. Although few
routes toward fused pyrroloheterocycles exist,10 there is a high
demand for the effective and general methods for selective con-
struction of heterocycles with alternative substitution pattern.
Recently, we reported two protocols for the synthesis of C-3
substituted and 1,3-disubstituted fused and non-fused pyrrole-
containing heterocycles (Eqs. 1 and 2). The first approach, which
operates via a copper-assisted cycloisomerization of conjugated
alkynyl imines (Eq. 1), has been demonstrated to be very general
and efficient for synthesis of C-3 monosubstituted heterocycles.
This method, however, is not applicable for synthesis of C-2- and/or
C-3-substituted heterocycles.11 We also disclosed a set of cyclo-
isomerization methodologies of imines and alkynyl ketones with
concomitant acyloxy, phosphatyloxy, or sulfonyloxy group
OP(O)(OEt)2
OP(O)(OEt)2
R
1
2
3
CuI
68-96%
N
N
R
R1
R1
R1
(B)
(B)
(B)
[Ag]
R2
52-100%
[Au]
A
A
A
R2
N
56-94%
N
N
ð3Þ
R2
R1 = OP(O)(OEt)2, OTBS, OAc
R2 = H, Alk, Ar, Het,
Alkenyl, Alkynyl
R
2 = H, Si, Sn, Ge
Aiming at the development of alternative methods toward
heterocyclic units with different substitution pattern, as well as at
expanding the scope of heterocyclic cores, we have developed two
complementary protocols for cycloisomerization of propargyl-
containing heterocycles (Eq. 3). These methods, being mild and
* Corresponding author. Tel.: þ1 312 355 3579; fax: þ1 312 355 0836.
E-mail address: vlad@uic.edu (V. Gevorgyan).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.04.023

I.V. Seregin et al. / Tetrahedron 64 (2008) 6876–6883
6877
Table 1
Catalyst optimization for synthesis of 1,3-disubstituted heterocycles
2. Results and discussion
OAc
2.1. Mild cycloisomerization of propargylic heterocycles
OAc
Cat., 3 mol %
DCM, r.t.
N
We anticipated that the triple bond of a propargyl-substituted
heterocycle may be rendered reactive toward intramolecular nu-
N
Ph
Ph
cleophilic attack of heterocyclic nitrogen by coordination of a
p-
1a
2a
philic metal, such as Cu, Ag, or Au. First, we tested easily available
propargylic derivative of pyridine 1a under the previously elabo-
rated copper/base-promoted cycloizomerization conditions.11 It
was found that 1a underwent smooth cycloizomerization furnish-
ing indolizine 2a in good yield. Notably, the cycloisomerization of
‘skipped’ propargyl pyridine 1a did not require elevated tempera-
tures, as it was necessary for cycloisomerization of the conjugated
substrates (Eq. 1). Thus, we were able to obtain 2 in good yield on
performing the reaction at room temperature. Moreover, we found,
that base is not required for this transformation, hence, it can be
omitted, as well as dimethylacetamide solvent can be substituted
with easier to handle dichloromethane. At the same time, the
catalyst load was dropped from 30 to to 3 mol %. Employment of
Cu(I) salts under these conditions resulted in a very facile conver-
sion of 1a, both copper iodide and chloride led to high yields of 2a,
affording 77 and 83% yields, respectively (Table 1). Gold catalysts
were found to be efficient in this transformation, as well. Thus,
Au(I) iodide and Au(III) chloride furnished 2a in 71% and 95% yields,
respectively, though the reaction was substantially slower. Con-
trary, only moderate yields of 2a were obtained in the presence of
other metals, such as Al, Sn, In, Mg, Pt, and Pd (Table 1). Recently,
several reports appeared, which debated the role of eventual
Brønsted acid as the true catalyst in transition metal-catalyzed
transformations.16 To address this issue, we tested this reaction in
the presence of triflic acid, and found that only negligible amounts
of 2a were produced (entry 15). In contrast, switching to AgBF4 and
AgPF6 led to virtually quantitative yields of 2a (entries 12 and 13)!
The approach toward propargyl-substituted heterocycles 1, in-
cluding 1a employed in our initial optimization, is general for all
substrates (Scheme 1). This two-step procedure proved to be more
efficient compared to the same sequence of steps performed in
‘‘one-pot’’. It was found, that upon column purification on silica gel,
#
Catalyst
Reaction time
Yield, %a
1
2
3
4
5
6
7
8
CuI
CuCl
AuCl3
AuI
AlCl3
Sn(OTf)2
Mg(OTf)2
In(OTf)2
PtCl2
PdCl2(PPh3)2
Pd(OAc)2
AgBF4
3 h
77
83
71
30 min
30 min
3 h
48 h
48 h
48 h
48 h
48 h
30 min
30 min
30 min
30 min
30 min
72 h
95
64b
31
52
33
41
61
9
10
11
12
13
14
15
74
>99
>99
52
AgPF6
AgSbF6
No catalyst
<20c
a
GC–MS yields.
10 mol % of catalyst was used.
Reaction was performed at 50 ꢀC.
b
c
effective, allow for selective preparation of 1,3- or 1,2-di-
substituted N-fused heterocycles. We demonstrated that in the
presence of Ag, Cu or Au catalyst, 2-propagyl pyridines, qui-
noxalines, and thiazoles undergo smooth and facile cyclo-
isomerization
resulting
in
1,3-disubstituted
indolizines,
pyrroloquinoxalines, and pyrrolothiazoles, in good to excellent
yields.13,14 In addition, we showed that 1,2-disubstituted hetero-
cycles can be accessed via a novel alkyne–vinylidene isomeriza-
tion cascade with concomitant 1,2-shift of various groups such as
H, SiR3, SnR3, and even previously unknown migration of germyl
group, and allows for the efficient synthesis of various fused
pyrroloheterocycles functionalized at C-2 (Eq. 3).15 Herein, we
summarize our recent developments in this area, and provide
a more detailed discussion of the scope and mechanisms of these
novel transformations.
propargyl alcohols 10 undergo facile isomerization into
a,b-un-
saturated ketones (Eq. 4),17 therefore, compounds 10 were used
without additional purification in the next step. In a typical pro-
OR1
(B)
OH
O
(B)
R1Cl
A
(B)
BrMg
H
R2
A
A
R2
N
R2
N
N
a
1'
1a-l
OAc
OP(O)(OEt)2
OTBS
OAc
S
N
R
N
N
R
N
R
1i, R = Ph, 80%b
1d, R = H, 82%
1e, R = Ph, 79%
1a, R = Ph, 76%
1b, R = nHex, 59%
1f, R = H, 62%
1j, R = nHex, 81%b
1c, 73%
N
OTBS
OTBS
S
N
OTBS
S
N
N
OAc
N
N
( )5
N
( )3
1g, 97%b
1h, 66%b
1k, 69%b
1l, 53%b
Scheme 1. Preparation of heterocycles 1; (a) isolated yields over two steps; (b) isolated yields from 10.

6878
I.V. Seregin et al. / Tetrahedron 64 (2008) 6876–6883
cedure, heterocyclic aldehydes were treated with magnesium
acetylides to afford the corresponding propargyl alcohols 10, which
were further converted to acetyloxy-, phosphatyloxy-, or silyloxy-
containing compounds 1 in good to very high yields (Scheme 1).
Further, the scope of this cycloisomerization with regard to the
heterocyclic core was examined. It was found that disubstituted
indolizines (2a–f), pyrroloquinoxalines (2g, 2h), and pyrrolothia-
zoles (2i–k) can also be synthesized through this cyclo-
isomerization in preparative yields (Scheme 2).
We propose the following mechanistic rationale for this novel
cycloizomerization (Scheme 3). First, an intramolecular nucleo-
philic attack of the heterocyclic nitrogen19 at the metal-activated-
triple bond takes place (3) to produce zwitterionic adduct 4, which
then rearomatizes into the product 6 (Scheme 3). The rear-
omatization may proceed via two alternative pathways: through
a proton transfer sequence (path A), or by a hydride shift (path B).
In the deprotonation–protonation scenario, heterocyclic nitrogen
of 3 would play a role of the base, as no other base is present in the
O
OH
(B)
(B)
A
SiO2
ð4Þ
A
N
R
N
R
Next, the scope of this cycloisomerization has been examined.
To this end, a series of propargyl-substituted heterocycles 1a–l
were synthesized and tested under the optimized conditions
(Scheme 2). We were pleased to find, that acetyloxy-, dieth-
ylphosphatyloxy-, and O-TBS-protected propargylic substrates 1a–
k, possessing alkyl (1b, 1j, 1l, 1h), aryl (1a, 1e, 1i), heteroaryl (1k),
and alkenyl (1c, 1g) substituents at the triple bond, as well as those
possessing terminal alkyne moiety (1f, 1d), underwent smooth
cycloizomerization to give corresponding heterocycles 2a–k in
good to excellent yields (Scheme 2). In contrast, diyne-containing
substrate 1l furnished pyrrolothiazole 2l in a very moderate yield.
Of note, alkynyl N-fused heterocycles can be alternatively accessed
via the recently developed direct C–H alkynylation approach.18
reaction. Accordingly, we reasoned that if
a deprotonation–
protonation event, indeed, takes place (path A), a severe deuterium–
hydrogen exchange in isotope-labeled substrate would be
observed.20 Conversely, if a hydride shift is the key step of the
rearomatization (path B), a clean deuterium incorporation at C-2 of
the product 6 would be expected.21 To address this question, a deu-
terium-labeled propargyl pyridine 7 was subjected to the cyclo-
isomerization conditions (Eq. 5).22 A substantial proton–deuterium
R1
R1
(B)
(B)
A
AgBF4, 3 mol %
DCM, r.t.
A
R2
N
N
R2
a
1 a-l
2a-l
OAc
R
OTBS
OP(O)(OEt)2
OAc
S
N
N
N
N
R
R
2a, R = Ph, 95%
2b, R = nHex, 76%
2f, R = H, 87%
2i, R = Ph, 82%
2d, R = H, 64%
2e, R = Ph, 94%
2j, R = nHex, 85%c
2c, 83%
OTBS
OTBS
OTBS
OAc
N
S
S
N
N
N
N
N
( )
N
5
( )3
2k, 89%b,c
2l, <10%c
2g, 52%
2h, 72%
Scheme 2. Synthesis of 1,3-disubstituted N-fused pyrrole-containing heterocycles; (a) isolated yields; (b) 10% of catalyst was used; (c) reaction was performed at 40 ꢀC.
OP
R
H
OP
[M]
[1,2]H~
or [1,5]H~
Path B
(B)
(B)
H
A
A
N
N
[M]
R
4
5
OP
R
OP
[M]
(B)
(B)
A
A
N
N
R
3
6
B
H
OP
[M]
(B)
A
N
Path A
R
4
Scheme 3.

I.V. Seregin et al. / Tetrahedron 64 (2008) 6876–6883
6879
exchange (ca. 50%) was observed. It is believed that this observation
strongly supports the deprotonation–protonation pathway A. Ob-
viously, path B is in a contradiction with this result (Scheme 3).
or Au(III) catalyst,30 underwent smooth cycloisomerization into C-1
monosubstituted indolizine 10.31 It is reasonable to propose that
this transformation may operate through diverse mechanistic
pathways: via a zwitterionic intermediate i, similar to 4 (Scheme
1),13 or, alternatively, through an allenyl intermediate v, resulting
from the formal 1,3-hydride shift.11 Finally, the reaction may pro-
ceed via the gold–vinylidene intermediate iv (Scheme 4).
In order to elucidate if this reaction, indeed, can proceed via
a vinylidene intermediate iv, we examined cycloisomerization of
TMS-substituted propargyl pyridine 11a in the presence of Au
catalyst. A prototropic isomerization through intermediate v,32 as
well as formation of a zwitterionic intermediate i, would result in
the formation of C-3-silyl indolizine, whereas C-2-substituted iso-
mer would be the expected product if the alkyne–vinylidene
isomerization takes place. After initial experimentation, it was
found that 11a in the presence of AuBr3 (2.0 mol %) in toluene at
50 ꢀC underwent smooth cycloisomerization to afford indolizine
12a with TMS group residing at the C-2 as the sole regioisomer in
63% yield (Eq. 8). Employment of Cu(I) salts led to trace amount of
products, whereas various Ag, Pt, and Pd sources tested did not
catalyzed this reaction at all. Of note, the C-2 position in indolizines,
as well as in related fused heterocycles, has long been considered as
‘unfunctionalizable’, as a substituent generally has to be introduced
prior to cyclization.10
OTBS
TBSO
N
D (> 99%D)
( )5
AgBF4 3 mol%
(51%D)
D
ð5Þ
N
toluene, r.t.
15 min
( )5
7
8
2.2. Gold-catalyzed cascade 1,2-migration/cycloisomerization
Encouraged by the successful development of cyclo-
isomerization toward 1,3-disubstituted N-fused ring systems, we
reasoned that propargylic heterocycles can serve as precursors for
1,2-disubstituted products as well, if migratory cyclo-
isomerization22 is achieved. Thus, we turned our attention to the
development of an alternative cycloisomerization protocol, which
would allow for a complementary substitution pattern at the fused
pyrrole ring. Particularly, alkyne–vinylidene isomerization has
drawn our attention. This rearrangement has long been recognized
as a synthetically useful23 and mechanistically interesting24 trans-
formation. In elegant series of works, McDonald employed this
transformation as the key step in the efficient synthesis of oxygen,
nitrogen, and sulfur-containing heterocycles, as well as in the
synthesis of carbocycles (Eq. 6).25 Moreover, it was exemplified by
a number of research groups, that a 1,2-migration of certain groups
can occur upon alkyne–vinylidene isomerization. For instance,
Iwasawa and Miura26 and Fu¨rstner et al.27 have shown that halo-
gens undergo 1,2-shift in the presence of tungsten and gold com-
plexes. Furthermore, Katayama demonstrated the Ru-catalyzed
migration of silicon,28 and Kawakami et al.29 reported an analogous
transformation with trialkyl tin (Eq. 7). Hence, we reasoned, that
alkyne–vinylidene isomerization with a concurrent 1,2-shift of the
groups other than hydrogen, can potentially be employed in the
synthesis of heterocycles, though no such examples have been
reported.
OTBS
OTBS
1
AuBr3 (2 mol %)
ð8Þ
SiMe3
2
N
N
SiMe3
toluene, 60 °C
63%
3
11a
12a
To examine the scope of this novel cascade migratory cyclo-
isomerization, a series of substrates have been prepared (Scheme
5). Thus, H- and TMS-containing propargyl heterocycles were
prepared using the protocol discussed above (Scheme 1). Whereas,
stannyl and germyl groups have been installed by deprotonation of
the terminal alkynes 110 furnishing lithium acetylides, which were
quenched with stannyl and germyl halides to form compounds 11b
and 11c, respectively (Scheme 5).
Next, migratory cycloisomerization of 11a–j in the presence of
gold catalysts was examined. Thus, similarly to the silyl-containing
substrate 11a, its stannyl counterpart 11b underwent smooth
cycloisomerization to afford 2-stannyl indolizine 12b.29 It was also
found that previously unprecedented 1,2-migration of a germyl
group can occur: cyclization of the corresponding propargylic
3
R2
3
R2
2
2
[M]
1
n
R3
n
R3
n
Nu
R1
R3
R2
•
1
Nu
R1
ð6Þ
Nu
R1
[M]
Nu = O, NR, S, C
[M]
[1,2] G~
R
G
•
[M]
R
G
OR1
1. nBuLi
O
OR1
ð7Þ
2. Bu3SnCl
or Me3GeBr
(B)
(B)
(B)
A
G = Hal, SiR3, SnR3
A
H
A
for R2= H
N
N
9', 11'a-j
R2
N
9, 11a-j
G
a
see, Scheme 1
First, we turned our attention to the cycloisomerization of easily
available skipped propargyl pyridine 9 (Scheme 4). Brief screening
of transition metal catalysts revealed that 9, in the presence of Au(I)
G = SnBu3, GeMe3
OTBS
OTBS
OTBS
N
OTBS
OTBS
N
R
N
R
N
AuI or AuIII
H
9, R = H, 70%
N
N
H
toluene, 60°C
11f, R = H, 50%
11g, R = SiMe3, 37%
11e, 96%
11a, R = SiMe3, 61%
11b, R = SnBu3, 68%
11c, R = GeMe3, 54%
H
10
9
Possible intermediates:
OTBS
OTBS
S
H
OTBS
[M]
OTBS
OTBS
•
N
N
N
H
R
SiMe3
H
H
N
N
N
11h, R = H, 60%
11i, R = SiMe3, 57%
11j, 38%
R
[M]
i
v
iv
Scheme 5. (a) Isolated yields over two steps.
Scheme 4.

6880
I.V. Seregin et al. / Tetrahedron 64 (2008) 6876–6883
substrate 11c furnished 2-germyl indolizine 12c in excellent yield. It
was also demonstrated that this protocol is efficient for construc-
tion of other related N-fused heterocyclic systems, such as pyrro-
loisoquinoline (12e), quinoxaline (12f, 12g), pyrazine (12h, 12i), and
thiazole (12j). The corresponding substrates 11e–j reacted
smoothly, producing fused bicyclic and tricyclic molecules in good
to excellent yields (Scheme 6).
undergo a sequence of 1,2-hydride shifts (path A), or proton
transfer processes (path B), to give 12. In order to verify, which
pathway operates, we examined cycloisomerization of deuterium-
labeled propargyl pyridine 9-d, under the standard cyclo-
isomerization conditions (Eq. 10). The reaction produced indolizine
10-d with equal distribution of deuterium between positions C-2
and C-3, thus strongly supporting path A (Scheme 7).33 Logically,
equal distribution of the deuterium between positions C-2 and C-3
is possible via the path A if there is no H/D kinetic isotope effect in
the transformation 16 to 12. Obviously, path B cannot explain the
observed scrambling of deuterium at C-2.
OTBS
OTBS
(B)
(B)
AuBr3 2 mol %
toluene
A
A
G
N
G
N
OTBS
OTBS
a
11 a-j
12a-j
AuBr3 2 mol%
toluene, 50 °C
2.5 h
(43%D)
D
2
OTBS
OTBS
R
N
ð10Þ
OTBS
N
D
3
(>99%D)
(43%D)
D
H
N
N
R
N
9-d
10-d; 73%
Br
10, R = H, 62%
12a, R = SiMe3, 63%b
Furthermore, we considered a possibility of Au-catalyzed 1,2-
trimethylsilyl shift, which may occur after cyclization.34 However,
the test experiment with 14, an isomer of pyrroloquinoxaline 12i,
ruled out this possibility (Eq. 11).
12e, 81%
12d, 62%
12b, R = SnBu3, 64%d
12c, R = GeMe3, 92%
OTBS
N
OTBS
OTBS
N
R
N
OTBS
TMS
OTBS
S
N
SiMe3
AuBr3, 2 mol%
N
R
N
N
toluene 50 °CX
N
ð11Þ
N
12f, R = H, 94%
12g, R = SiMe3, 78%
12h, R = H, 72%
TMS
12i, R = SiMe3, 87%c
12j, 52%
14
12i
Scheme 6. Synthesis of 1,2-disubstituted N-fused pyrrole-containing heterocycles; (a)
3. Conclusions
isolated yields; (b) NMR yield; (c) yields over two steps; (d) AuCl was used as a catalyst.
Additionally, this transformation was tested under catalyst-free
conditions. It was found that in the absence of gold catalyst,
propargylic substrate 13 at 60 ꢀC underwent thermal cyclo-
isomerization into 14, expectably, with no 1,2-silicon shift (Eq. 9).
Two complementary protocols for the preparation of multi-
substituted N-fused heterocycles have been developed. It was
demonstrated that 1,3-disubstituted N-fused heterocycles, in-
cluding indolizines, pyrroloquinoxalines, and pyrrolothiazoles can
be easily prepared via an exceptionally mild, and efficient method
involving a novel silver-catalyzed cycloizomerization of propargyl-
containing heterocycles. Alternatively, 1,2-disubstituted heterocy-
cles can be accessed through the Au-catalyzed cascade
cycloisomerization of propargylic derivatives of N-containing het-
erocycles into pyrrole-fused heterocycles. This cascade trans-
formation involves 1,2-migration of silyl, stannyl, and germyl
groups. This mild and simple method allows for selective and
highly efficient synthesis of indolizines, pyrroloisoquinolines, pyr-
roloquinoxalines, pyrrolopyrazines, and pyrrolothiazoles, not
available via existing cycloisomerization techniques.
OTBS
OTBS
N
N
no catalyst
toluene, 60 °C
47%
N
ð9Þ
TMS
N
TMS
13
14
The mechanism of the gold-catalyzed cascade transformation
can be rationalized as following (Scheme 7). First, alkyne 9 un-
dergoes isomerization to form vinylidene intermediate iv (Scheme
4). A nucleophilic attack of the nitrogen lone pair at the vinylidene
carbon results in the formation of zwitterion 15, which can either
4. Experimental
4.1. General
R
R
Ha
Ha
G
[1,2]H~
Path A:
G
N
N
Sequential hydride shifts
NMR spectra were recorded on Bruker Avance DRX-500
(500 MHz) and DPX-400 (400 MHz) instruments. GC/MS analyses
were performed on a Hewlett Packard Model 6890 GC interfaced to
[1,2]H~
[M]
[M]
15
16
R
R
Ha
R
Ha
a
Hewlett Packard Model 5973 mass selective detector
(15 mꢁ0.25 mm capillary column, HP-5MS). Column chromatog-
raphy was carried out employing Silicycle silica gel (43–60 m).
G
G
m
N
N
N
G
9
Ha
[M]
HRMS (EI) analysis was performed on a JEOL GCmate II instrument.
All manipulations with transition metal catalysts were conducted
under inert atmosphere using a combination of glovebox and
standard Schlenk techniques. Anhydrous toluene, tetrahydrofuran,
and dichloromethane, purchased from Aldrich, were additionally
purified on PureSolv PS-400-4 by Innovative Technology, Inc. pu-
rification system. All other chemicals and solvents were purchased
from Aldrich, Fisher, Acros Organics, TCI, and Alfa Aesar and used
without additional purification.
iv
12
:B
Path B:
Deprotonation-protonation
R
R
Ha
G
G
N
N
Ha
[M]
B
[M]
15
17
Scheme 7.

I.V. Seregin et al. / Tetrahedron 64 (2008) 6876–6883
6881
4.2. General procedures for Ag-catalyzed cycloisomerization
4.2.7. 1-(Cyclohexenyl)-3-((tert-butyldimethyl)-
silanyloxy)pyrrolo[1,2]quinoxaline (2g)
1H NMR (500.13 MHz, CDCl3)
ppm 8.63 (1H, s), 7.97 (1H, d,
In a glovebox under nitrogen atmosphere, to a 5.0 mL Wheaton
microreactor equipped with a spin vane and screw cap with a PTFE
faced silicone septum was added 3–10 mol % of AgBF4. The micro-
reactor was removed from the glovebox, propargyl heterocycles
1a–l and anhydrous toluene (0.10 M) were successively added and
the mixture was stirred until completion (as monitored by TLC and/
or GC/MS). The solvent was removed under reduced pressure and
the residue was purified using flash-column chromatography using
hexane or hexane/ethyl acetate mixture as eluent to afford pure
fused pyrroloheterocycles 2a–2l.
d
J¼4.7 Hz), 7.82 (1H, d, J¼5.0 Hz), 7.28–7.38 (2H, m), 6.10 (1H, s),
5.99–6.08 (1H, m), 2.17–2.34 (3H, m), 1.68–1.90 (5H, m), 1.03 (9H, s),
0.25 (6H, s); 13C NMR (125.76 MHz, CDCl3)
d ppm 143.7, 139.5,137.4,
131.9, 131.8, 130.7, 129.2, 129.1, 126.3, 124.4, 116.6, 116.1, 109.5, 105.7,
28.9, 25.6, 25.5, 22.5, 21.7, 18.2, ꢂ4.5. HREIMS m/z 378.2125, calcd
for C23H30N2OSi 378.2127.
4.2.8. 1-(Hexyl)-3-(acetyloxy)pyrrolo[1,2]quinoxaline (2h)
1H NMR (500.13 MHz, CDCl3)
d ppm 8.65 (1H, s), 8.08 (1H, d,
J¼8.2 Hz), 7.92 (1H, d, J¼7.6 Hz), 7.35–7.53 (2H, m), 6.68 (1H, s),
3.08–3.33 (2H, m), 2.39 (3H, s),1.72–1.95 (2H, m),1.43–1.60 (2H, m),
1.27–1.44 (4H, m), 0.91 (3H, t, J¼7.02 Hz); 13C NMR (125.76 MHz,
4.2.1. 1-(Acetyloxy)-3-(phenyl)indolizine (2a)
1H NMR (500.13 MHz, CDCl3)
d
ppm 8.18 (1H, d, J¼7.3 Hz), 7.56
CDCl3)
d ppm 168.6, 142.8, 137.5, 132.8, 131.6, 130.1, 129.4, 127.0,
(2H, dd, J¼8.3, 1.3 Hz), 7.44–7.50 (2H, m), 7.32–7.37 (1H, m), 7.29
124.9, 116.6, 116.1, 106.4, 31.6, 30.8, 29.1, 28.1, 22.5, 21.0, 14.0.
HREIMS m/z 310.1693, calcd for C19H22N2O2 310.1681.
(1H, d, J¼9.0 Hz), 6.83 (1H, s), 6.65 (1H, dd, J¼9.2, 6.4 Hz), 6.44 (1H,
dd, J¼8.4, 6.4 Hz), 2.37 (3H, s); 13C NMR (125.76 MHz, CDCl3)
d ppm
172.4, 131.8, 128.9, 128.1, 127.3, 123.0, 122.0, 121.6, 116.5, 116.3, 110.9,
109.5, 106.6, 20.9.
4.2.9. 5-(Phenyl)-7-(acetyloxy)pyrrolo[1,2]thiazole (2i)
1H NMR (500.13 MHz, CDCl3)
d
ppm 7.63 (1H, d, J¼4.2 Hz), 7.45–
7.50 (2H, m), 7.39–7.45 (2H, m), 7.24–7.32 (1H, m), 6.63 (1H, d,
4.2.2. 1-(Acetyloxy)-3-(hexyl)indolizine (2b)
J¼4.2 Hz), 6.54 (1H, s), 2.31 (3H, s); 13C NMR (125.76 MHz, CDCl3)
1H NMR (500.13 MHz, CDCl3)
d
ppm 7.61 (1H, d, J¼7.0 Hz),
d
ppm 168.1,132.4,128.9,126.7,126.2,122.5,119.2,119.0,119.0,112.3,
7.22 (1H, d, J¼9.1 Hz), 6.56 (1H, dd, J¼9.1, 6.4 Hz), 6.53 (1H, s),
6.45 (1H, dd, J¼8.5, 7.0 Hz), 2.76 (2H, d, J¼7.6 Hz), 2.34 (3H, s),
1.66–1.79 (2H, m), 1.37–1.49 (2H, m), 1.29–1.37 (4H, m), 0.90 (3H,
105.4, 20.8. HREIMS m/z 257.0500, calcd for C14H11NO2S 257.0511.
4.2.10. 5-(Hexyl)-7-(acetyloxy)pyrrolo[1,2]thiazole (2j)
t, J¼5.6 Hz); 13C NMR (125.76 MHz, CDCl3)
d ppm 167.3, 121.5,
1H NMR (500.13 MHz, CDCl3)
d
ppm 7.16 (1H, d, J¼4.2 Hz), 6.54
121.0, 120.9, 116.0, 114.8, 110.0, 110.0, 104.4, 31.6, 29.2, 27.1, 25.8,
(1H, d, J¼4.2 Hz), 6.11 (1H, s), 2.58–2.72 (2H, m), 2.26 (3H, s), 1.57–
22.6, 20.9, 14.1. HREIMS m/z 259.1575, calcd for
259.1572.
C16H21NO2
1.67 (2H, m), 1.34–1.42 (2H, m), 1.26–1.34 (2H, m), 0.89 (3H, t,
J¼6.9 Hz); 13C NMR (125.76 MHz, CDCl3)
d ppm 168.2, 127.7, 121.9,
117.7, 115.3, 111.3, 103.7, 31.6, 28.9, 28.3, 26.8, 22.6, 20.8, 14.1.
4.2.3. 1-((tert-Butyldimethyl)silanyloxy)-3-(cyclohexenyl)-
indolizine (2c)
HREIMS m/z 265.1130, calcd for C14H19NO2S 265.1137.
1H NMR (500.13 MHz, CDCl3)
(1H, d, J¼9.1 Hz), 6.35 (1H, dd, J¼8.9, 6.3 Hz), 6.27 (1H, dd, J¼7.0,
5.7 Hz), 6.03 (1H, t, J¼3.8 Hz), 2.29–2.38 (2H, m), 2.20–2.30 (2H, m),
1.75–1.85 (2H, m), 1.65–1.75 (2H, m), 1.02 (9H, s), 0.19 (6H, s); 13C
d
ppm 8.03 (1H, d, J¼7.9 Hz), 7.24
4.2.11. 5-(3-Pyridyl)-7-((tert-butyldimethyl)-
silanyloxy)pyrrolo[1,2]thiazole (2k)
1H NMR (500.13 MHz, CDCl3)
d ppm 8.74 (1H, s), 8.44 (1H, d,
J¼3.7 Hz), 7.73 (1H, d, J¼7.9 Hz), 7.58 (1H, d, J¼4.2 Hz), 7.31 (1H, dd,
NMR (125.76 MHz, CDCl3)
d ppm 132.2, 128.9, 124.9, 122.5, 121.9,
J¼7.8, 4.9 Hz), 6.64 (1H, d, J¼3.5 Hz), 6.35 (1H, s), 1.01 (9H, s), 0.23
(6H, s); 13C NMR (125.76 MHz, CDCl3)
d ppm 146.6, 146.4, 134.2,
120.8, 117.0, 112.7, 109.7, 103.3, 29.1, 25.8, 25.5, 23.0, 22.2, 18.2, ꢂ4.5.
HREIMS m/z 327.2010, calcd for C20H29NOSi 327.2018.
132.4, 129.1, 123.7, 118.8, 118.4, 118.1, 111.8, 106.6, 25.7, 18.1, ꢂ4.4.
HREIMS m/z 324.1660, calcd for C19H24N2OSi 324.1658.
4.2.4. 1-(Diethylphosphatoxy)indolizine (2d)
1H NMR (500.13 MHz, CDCl3)
d
ppm 7.72 (1H, d, J¼7.0 Hz), 7.39
4.3. General procedures for Au-catalyzed cycloisomerization
(1H, d, J¼9.1 Hz), 7.06 (1H, d, J¼2.2 Hz), 6.69 (1H, d, J¼2.9 Hz),
6.58 (1H, dd, J¼9.4, 6.4 Hz), 6.38 (1H, dd, J¼8.5, 2.2 Hz), 4.21
(4H, q, J¼8.2 Hz), 1.34 (6H, t, J¼7.0 Hz); 13C NMR (125.76 MHz,
In a glovebox under nitrogen atmosphere, to a 3.0 mL Wheaton
microreactor equipped with a spin vane and screw cap with a PTFE
faced silicone septum was added 2 mol % of AuBr3. The microreactor
was removed from the glovebox, propargylic heterocycle 9 or 11a–j
and anhydrous toluene (0.5 M) were successively added and the
mixture was stirred until completion (as monitored by TLC and/or
GC/MS). The solvent was removed under reduced pressure and the
residue was purified using flash-column chromatography using
hexane as eluent to afford pure fused pyrroloheterocycles 10, 12a–j.
CDCl3)
d ppm 130.8, 128.8, 124.6, 116.2, 116.0, 110.4, 108.5,
105.2, 64.5, 16.1. HREIMS m/z 269.0816, calcd for C12H16NO4P
269.0817.
4.2.5. 1-(Diethylphosphatoxy)-3-(phenyl)indolizine (2e)
1H NMR (500.13 MHz, acetone-d6)
d
ppm 8.26 (1H, d, J¼7.3 Hz),
7.55–7.63 (2H, m), 7.45–7.53 (3H, m), 7.37 (1H, d, J¼6.5 Hz), 6.85
(1H, s), 6.70 (1H, dd, J¼8.2, 7.3 Hz), 6.53 (1H, dd, J¼7.0, 6.4 Hz), 4.22
(4H, q, J¼4.0 Hz), 1.32 (6H, t, J¼7.0 Hz); 13C NMR (125.76 MHz, ac-
4.3.1. 1-((tert-Butyldimethyl)silanyloxy)indolizine (10)
Prepared in 62% yield. 1H NMR (500.13 MHz, acetone-d6)
d 7.87
etone-d6)
d ppm 131.6, 129.0, 127.8, 127.3, 121.5, 121.4, 116.4, 116.3,
111.2, 105.4, 105.4, 64.2, 64.1, 15.6, 15.6. HREIMS m/z 345.1131, calcd
for C18H20NO4P 345.1130.
(1H, d, J¼7.0 Hz), 7.24 (1H, d, J¼9.2 Hz), 7.17 (1H, d, J¼1.8 Hz), 6.42
(1H, dd, J¼9.0, 6.4 Hz), 6.36 (1H, d, J¼2.6 Hz), 6.29 (1H, dd, J¼6.7,
6.7 Hz), 1.04 (9H, s), 0.20 (6H, s); 13C NMR (125.76 MHz, acetone-d6)
4.2.6. 1-(Acetyloxy)indolizine (2f)
d
133.1, 126.3, 122.7, 117.9, 115.1, 111.0, 109.6, 106.1, 26.9, 19.4, ꢂ3.7.
1H NMR (500.13 MHz, CDCl3)
d
ppm 7.75 (1H, d, J¼7.0 Hz), 7.22
HREIMS calcd for C14H21NOSi [Mþ]: 247.1392. Found: 247.1392.
(1H, d, J¼9.1 Hz), 7.14 (1H, d, J¼2.9 Hz), 6.72 (1H, d, J¼2.9 Hz), 6.60
(1H, dd, J¼9.1, 6.4 Hz), 6.41 (1H, dd, J¼7.0, 5.6 Hz), 2.34 (3H, s); 13
C
4.3.2. 1-(tert-Butyldimethyl)silanyloxy-2-(trimethylsilyl)indolizine
(12a)
NMR (125.76 MHz, CDCl3)
d ppm 169.5, 124.8, 116.4, 115.9, 115.7,
110.4, 110.1, 109.0, 106.3, 20.9. HREIMS m/z 175.0634, calcd for
10H9NO2 175.0633.
Prepared in 63% yield for two steps. 1H NMR (500.13 MHz, ac-
C
etone-d6)
d
7.84 (1H, d, J¼7.2 Hz), 7.23 (1H, d, J¼9.9 Hz), 7.17 (1H, s),

6882
I.V. Seregin et al. / Tetrahedron 64 (2008) 6876–6883
6.39 (1H, dd, J¼10.2, 6.3 Hz), 6.25 (1H, dd, J¼7.3, 6.2 Hz),1.09 (9H, s),
0.32 (9H, s), 0.22 (6H, s); 13C NMR (125.76 MHz, acetone-d6)
137.1,
J¼2.8 Hz), 6.30 (1H, d, J¼2.6 Hz), 0.99 (9H, s), 0.18 (6H, s); 13C NMR
d
(125.76 MHz, CDCl3) d 143.6, 136.5, 126.7, 118.5, 117.4, 111.1, 105.1,
125.4, 122.2, 117.7, 115.1, 114.4, 110.2, 26.4, 18.8, 0.4, ꢂ3.1. HREIMS
25.9, 18.3, ꢂ4.5. HREIMS calcd for C13H20N2OSi [Mþ]: 248.1345.
calcd for C17H29NOSi2 [Mþ]: 319.1788. Found: 319.1782.
Found: 248.1347.
4.3.3. 1-(tert-Butyldimethyl)silanyloxy-2-(tributyl-
stannyl)indolizine (12b)
4.3.10. 7-(Trimethylsilyl)-8-((tert-butyldimethyl)-
silanyloxy)pyrrolo[1,2]pyrazine (12i)
Prepared in 64% yield for two steps (by NMR). 1H NMR
Prepared in 87% yield. 1H NMR (500.13 MHz, CDCl3)
d
8.63 (1H,
s), 7.46 (1H, d, J¼5.0 Hz), 7.18 (3H, d, J¼5.0 Hz), 7.06 (1H, s), 1.05 (9H,
s), 0.30 (9H, s), 0.23 (6H, s); 13C NMR (125.76 MHz, CDCl3)
144.0,
(500.13 MHz, benzene-d6)
d
7.36 (1H, d, J¼9.0 Hz), 7.08 (1H, d,
J¼7.0 Hz), 6.80 (1H, s), 6.22 (1H, dd, J¼9.5, 6.8 Hz), 5.90 (1H, dd,
J¼7.5, 6.4 Hz), 1.67–1.79 (6H, m), 1.42–1.51 (6H, m), 1.25–1.32 (6H,
m),1.14(9H, s), 0.93–1.01(9H, m), 0.21 (6H, s); 13CNMR (125.76 MHz,
d
140.8, 126.2, 118.7, 117.0, 116.6, 115.2, 25.9, 18.3, ꢂ0.1, ꢂ3.6. HREIMS
calcd for C16H28N2OSi2 [Mþ]: 320.1740. Found: 320.1741.
benzene-d6)
d 124.2, 117.2, 115.5, 114.4, 113.5, 109.2, 29.7, 27.8, 26.2,
18.4,13.9,10.5, 2.1, ꢂ3.7. MS m/z (relative intensity) 537 (Mþ, 84), 480
4.3.11. 6-(Trimethylsilyl)-7-((tert-butyldimethyl)-
silanyloxy)pyrrolo[1,2]thiazole (12j)
t
(Mþꢂ Bu, 80), 368 (Mþꢂ3nBu, 210); C26H47NOSiSn.
Prepared in 56% yield. 1H NMR (500.13 MHz, CDCl3)
d
7.11 (1H, d,
J¼4.2 Hz), 6.86 (1H, s), 6.44 (1H, d, J¼4.2 Hz), 1.02 (9H, s), 0.27 (6H,
s), 0.26 (9H, s); 13C NMR (125.76 MHz, CDCl3),
137.2, 119.5, 117.1,
113.4, 112.3, 110.6, 25.9, 25.7, 18.0, ꢂ0.2, ꢂ3.4. HREIMS calcd for
C
15H27NOSSi2 [Mþ]: 325.1352. Found: 325.1347.
4.3.4. 1-(tert-Butyldimethyl)silanyloxy-2-(trimethyl-
germyl)indolizine (12c)
d
1
Prepared in 92% (0.75 mmol) yield. H NMR (500.13 MHz, ace-
tone-d6)
6.40 (1H, dd, J¼9.1, 6.4 Hz), 6.25 (1H, dd, J¼7.2, 6.4 Hz), 1.08 (9H, s),
0.44 (9H, s), 0.20 (6H, s); 13C NMR (125.76 MHz, acetone-d6)
129.8,
d
7.85 (1H, d, J¼7.0 Hz), 7.22 (1H, d, J¼9.1 Hz), 7.12 (1H, s),
d
Acknowledgements
125.5, 122.5, 117.7, 114.5, 114.0, 110.1, 105.6, 26.6, 0.1, ꢂ3.2. HREIMS
calcd for C17H29GeNOSi [Mþ]: 365.1230. Found: 365.1244.
The support of the National Institutes of Health (Grant GM-
64444) and National Science Foundation (Grant CHE 0354613) is
gratefully acknowledged.
4.3.5. 1-(tert-Butyldimethyl)-silanyloxy-5-bromo-indolizine (12d)
Prepared in 62% yield. 1H NMR (500.13 MHz, CDCl3)
d 7.31 (1H, d,
J¼9.9 Hz), 7.28 (1H, d, J¼2.3 Hz), 6.64 (1H, d, J¼6.8 Hz), 6.46 (1H, d,
References and notes
J¼2.9 Hz), 6.34 (1H, dd, J¼8.9, 6.9 Hz), 1.03 (9H, s), 0.20 (6H, s); 13
C
NMR (125.76 MHz, CDCl3)
d 133.6, 123.7, 115.7, 114.2, 113.7, 113.4,
1. For review, see: Michael, J. P. Nat. Prod. Rep. 1999, 16, 675.
2. For pharmacologically important indolizines, see: (a) Schoeffter, P.; Hoyer, D.
Naunyn Schmiedebergs Arch. Pharmacol. 1989, 339, 675; (b) Fujita, T.; Matsu-
moto, Y.; Kimura, T.; Yokota, S.; Sawada, M.; Majima, M.; Ohtani, Y.; Kumagai, Y.
Br. J. Clin. Pharmacol. 2002, 54, 283; (c) Nakayama, O.; Hirosumi, J.; Chida, N.;
Takahashi, S.; Sawada, K.; Kojo, H.; Notsu, Y. Prostate 1997, 31, 241.
3. Facompre, M.; Tardy, C.; Bal-Mahieu, C.; Colson, P.; Perez, C.; Manzanares, I.;
Cuevas, C.; Bailly, C. Cancer Res. 2003, 63, 7392.
4. For studies on biological activity of Lamellarin family, see: (a) See Ref. 3. (b)
Reddy, M. V.; Rao, M. R.; Rhodes, D.; Hansen, M. S.; Rubins, K.; Bushman, F. D.;
Venkateswarlu, Y.; Faulkner, D. J. J. Med. Chem. 1999, 42, 1901; (c) Østby, O. B.;
Dalhus, B.; Gundersen, L.-L.; Rise, F.; Bast, A.; Haenen, G. R. M. M. Eur. J. Org.
Chem. 2000, 3763.
108.8, 105.4, 25.7, 18.1, ꢂ4.6. HREIMS calcd for C14H20BrNOSi [Mþ]:
325.0498. Found: 325.0501.
4.3.6. 1-((tert-Butyldimethyl)silanyloxy)pyrrolo[2,1-a]isoquinoline
(12e)
Prepared in 81% yield. 1H NMR (500.13 MHz, CDCl3)
d 8.45 (1H, d,
J¼8.07 Hz), 7.46 (1H, d, J¼7.3 Hz), 7.44 (1H, dd, J¼10.7, 8.0 Hz), 7.42
(1H, dd, J¼11.0, 8.3 Hz), 7.23 (1H, d, 5.0 Hz), 6.95 (1H, d, J¼2.9 Hz),
6.50 (1H, d, J¼7.3 Hz), 6.31 (1H, d, J¼2.9 Hz),1.10 (9H, s), 0.30 (6H, s);
13C NMR (125.76 MHz, CDCl3)
d 136.8,127.5,127.1,126.6,126.3,124.8,
5. See Ref. 4b.
6. (a) Gundersen, L.-L.; Malterud, K. E.; Negussie, A. H.; Rise, F.; Teklu, S.; Østby, O.
B. Bioorg. Med. Chem. 2003, 11, 5409; (b) Teklu, S.; Gundersen, L.-L.; Larsen, T.;
Malterud, K. E.; Rise, F. Bioorg. Med. Chem. 2005, 13, 3127.
124.4, 122.4, 115.9, 110.6, 110.5, 103.9, 26.2, 18.5, ꢂ3.9. HREIMS calcd
for C18H23NOSi [Mþ]: 297.1549. Found: 297.1536.
7. For studies on sPLA2 inhibition activity, see: Hagishita, S.; Yamada, M.; Shir-
ahase, K.; Okada, T.; Murakami, Y.; Ito, Y.; Matsuura, T.; Wada, M.; Kato, T.;
Ueno, M.; Chikazawa, Y.; Yamada, K.; Ono, T.; Teshirogi, I.; Ohtani, M. J. Med.
Chem. 1996, 39, 3636.
8. Gautier, P.; Marchionni, D.; Roccon, A.; Tonnerre, B.; Wagnon, J. FR 2893616,
2007.
4.3.7. 3-((tert-Butyldimethyl)-silanyloxy)pyrrolo[1,2]quinoxaline
(12f)
Prepared in 94% yield. 1H NMR (500.13 MHz, CDCl3)
d 8.68 (1H,
s), 7.83 (1H, d, J¼7.9 Hz), 7.7 (5H, d, J¼8.0 Hz), 7.58 (5H, d, J¼2.9 Hz),
7.38 (1H, dd, J¼8.0, 1.6 Hz), 7.34 (1H, dd, J¼7.9, 1.5 Hz), 6.32 (1H, d,
J¼2.9 Hz), 1.02 (9H, s), 0.22 (6H, s); 13C NMR (125.76 MHz, CDCl3)
9. See Ref. 7.
10. For the most comprehensive review, see: (a) Behnisch, A.; Behnisch, P.;
Eggenweiler, M.; Wallenhorst, T. Indolizine. Houben-Weyl; Thieme: Stuttgart,
Germany, 1994; Vol. E6a/2a, pp 323–450; See also: (b) Marchalin, S.; Baumlova,
B.; Baran, P.; Oulyadi, H.; Daich, A. J. Org. Chem. 2006, 71, 9114; (c) Kaloko, J., Jr.;
Hayford, A. Org. Lett. 2005, 7, 4305.
d
143.6, 139.7, 136.1, 129.7, 127.6, 127.2, 124.8, 116.0, 112.8, 110.8,
109.4, 104.6, 25.6, 18.2, ꢂ4.7. HREIMS calcd for C17H22N2OSi [Mþ]:
298.1501. Found: 298.1503.
11. (a) Kel’in, A. V.; Sromek, A. W.; Gevorgyan, V. J. Am. Chem. Soc. 2001, 123, 2074;
(b) Kel’in, A. V.; Gevorgyan, V. J. Org. Chem. 2002, 67, 95.
12. (a) Sromek, A. W.; Kel’in, A. V.; Gevorgyan, V. Angew. Chem., Int. Ed. 2004, 43,
2280; (b) Schwier, T.; Sromek, A. W.; Yap, D. M. L.; Chernyak, D.; Gevorgyan, V. J.
Am. Chem. Soc. 2007, 129, 9868; For other syntheses of heterocycles proceeding
via 1,2-migrations, see: (c) Kim, J. T.; Kel’in, A. V.; Gevorgyan, V. Angew. Chem.,
Int. Ed. 2003, 42, 98; (d) Dudnik, A. S.; Gevorgyan, V. Angew. Chem., Int. Ed. 2007,
46, 5195; (e) Dudnik, A. S.; Sromek, A. W.; Rubina, M.; Kim, J. T.; Kel’in, A. V.;
Gevorgyan, V. J. Am. Chem. Soc. 2008, 130, 1440.
13. Seregin, I. V.; Schammel, A. W.; Gevorgyan, V. Org. Lett. 2007, 9, 3433.
14. When this project was underway, a report on a related Pt-catalyzed 1,2-mi-
gration/cyclization toward indolizine core appeared, see: Smith, C. R.; Bunnelle,
E. M.; Rhodes, A. J.; Sarpong, R. Org. Lett. 2007, 9, 1169.
15. Seregin, I. V.; Gevorgyan, V. J. Am. Chem. Soc. 2006, 128, 12050.
16. For recent discussions on the role of Brønsted acids in transtion metal-cata-
lyzed transformations, see: (a) Hashmi, A. S. K. Catal. Today 2007, 122, 211; (b)
Li, Z.; Zhang, J.; Brouwer, C.; Yang, C.-G.; Reich, N. W.; He, C. Org. Lett. 2006, 8,
4175; (c) Rosenfeld, D. C.; Shekhar, S.; Takemiya, A.; Utsunomiya, M.; Hartwig,
J. F. Org. Lett. 2006, 8, 4179; (d) Rhee, J. U.; Krische, M. J. Org. Lett. 2005, 7, 2493.
4.3.8. 2-(Trimethylsilyl)-3-((tert-butyldimethyl)-
silanyloxy)pyrrolo[1,2]quinoxaline (12g)
Prepared in 78% yield. 1H NMR (500.13 MHz, CDCl3)
d 8.69 (1H,
s), 7.82 (1H, d, J¼7.7 Hz), 7.75 (1H, d, J¼8.3 Hz), 7.60 (1H, s), 7.44
(1H, d, J¼8.1 Hz), 7.36 (1H, d, J¼8.0 Hz), 7.26 (1H, s),1.09 (9H, s), 0.35
(9H, s), 0.27 (6H, s); 13C NMR (125.76 MHz, CDCl3)
d 144.7, 144.4,
136.1, 129.8, 127.8, 127.6, 125.2, 117.0, 116.8, 115.1, 113.1, 26.2, 25.9,
0.2, ꢂ3.3. HREIMS calcd for C20H30N2OSi2 [Mþ]: 370.1897. Found:
370.1893.
4.3.9. 8-((tert-Butyldimethyl)silanyloxy)pyrrolo[1,2]pyrazine (12h)
Prepared in 72% yield. 1H NMR (500.13 MHz, CDCl3)
d
8.64 (1H,
s), 7.47 (1H, d, J¼5.0 Hz), 7.23 (1H, d, J¼5.0 Hz), 7.07 (1H, d,

I.V. Seregin et al. / Tetrahedron 64 (2008) 6876–6883
6883
17. For acid-promoted isomerization of propargylic alcohols into
a
,
b-unsaturated
25. See, for example: (a) See Ref. 19i. (b) See Ref. 19j.
systems, see: Erenler, R.; Biellmann, J.-F. Tetrahedron Lett. 2005, 46, 5683.
18. Seregin, I. V.; Ryabova, V.; Gevorgyan, V. J. Am. Chem. Soc. 2007, 129, 7742.
19. For selected examples on nucleophilic attack of heteroatom at alkyne activated
by Au and Ag complexes, see: (a) Gorin, D. J.; Davis, N. R.; Toste, F. D. J. Am.
Chem. Soc. 2005, 127, 11260; (b) Dube´, P.; Toste, F. D. J. Am. Chem. Soc. 2006, 128,
12062; (c) Shapiro, N. D.; Toste, N. D. J. Am. Chem. Soc. 2007, 129, 4160; (d)
Hashmi, A. S. K.; Rudolph, M.; Schymura, S.; Visus, J.; Frey, W. Eur. J. Org. Chem.
2006, 4905; (e) Hashmi, A. S. K.; Weyrauch, J. P.; Frey, W.; Bats, J. W. Org. Lett.
2004, 6, 4391; (f) Belting, V.; Krause, N. Org. Lett. 2006, 8, 4489; (g) Sun, J.;
Kozmin, S. A. Angew. Chem., Int. Ed. 2006, 45, 4991; (h) Wang, S.; Zhang, L. J. Am.
Chem. Soc. 2006, 128, 14274; (i) McDonald, F. E.; Gleason, M. M. J. Am. Chem. Soc.
1996, 118, 6648; (j) McDonald, F. E.; Burova, S. A.; Huffman, L. G. Synthesis 2000,
970.
20. For an example of a base-assisted substantial deuterium scrambling upon cy-
cloisomerization in conjugated propargylic systems, see Ref. 11a.
21. For an example of clean 1,2-deuterium shift upon cycloisomerization, see:
Sromek, A. W.; Rubina, M.; Gevorgyan, V. J. Am. Chem. Soc. 2005, 127, 10500.
22. Deuterium-labeled propargylic substrate 7 was prepared via the following
sequence of steps.
26. Miura, T.; Iwasawa, N. J. Am. Chem. Soc. 2002, 124, 518.
27. Mamane, V.; Hannen, P.; Fu¨ rstner, A. Chem.dEur. J. 2004, 10, 4556.
28. Katayama, H.; Wada, C.; Taniguchi, K.; Ozawa, F. Organometallics 2002, 21, 3285.
29. Shirakawa, E.; Morita, R.; Tsuchimoto, T.; Kawakami, Y. J. Am. Chem. Soc. 2004,
126, 13614.
30. For recent reviews on Au-catalyzed reactions, see: (a) Hoffmann-Ro¨der, A.;
Krause, N. Org. Biomol. Chem. 2005, 3, 387; (b) Hashmi, A. S. K. Gold Bull. 2004,
37, 51; For Au-catalyzed synthesis of heterocycles, see: (c) Hashmi, A. S. K.;
Schwarz, L.; Choi, J.-H.; Frost, T. M. Angew. Chem., Int. Ed. 2000, 39, 2285; (d)
Yao, T.; Zhang, X.; Larock, R. C. J. Am. Chem. Soc. 2004, 126, 11164; (e) Zhang, L.;
Kozmin, S. A. J. Am. Chem. Soc. 2005, 127, 6962; (f) Hoffmann-Ro¨der, A.; Krause,
N. Org. Lett. 2001, 3, 2537; (g) See Ref. 21. For Au-catalyzed carbocyclizations,
see for example: (h) Fu¨ rstner, A.; Hannen, P. Chem. Commun. 2004, 2546; (i) Shi,
X.; Gorin, D. J.; Toste, F. D. J. Am. Chem. Soc. 2005, 127, 5802; (j) Luzung, M. R.;
Markham, J. P.; Toste, F. D. J. Am. Chem. Soc. 2004, 126, 10858; (k) Zhang, L.;
Kozmin, S. A. J. Am. Chem. Soc. 2004, 126, 11806; (l) Nieto-Oberhuber, C.; Lopez,
S.; Echavarren, A. M. J. Am. Chem. Soc. 2005, 127, 6178; See also: (m) Asao, N.;
Takahashi, K.; Lee, S.; Kasahara, T.; Yamamoto, Y. J. Am. Chem. Soc. 2002, 124,
12650; (n) Shi, Z.; He, C. J. Am. Chem. Soc. 2004, 126, 5964; (o) Zhang, L. J. Am.
Chem. Soc. 2005, 127, 16804.
31. Au(I) is most likely the active catalyst. In the case of employment of AuBr3 as
a precatalyst, the latter can be reduced into Au(I) species via various redox
processes. See, Ref. 30b.
32. For discussion on Au-catalyzed propargyl–allenyl prototropic isomerization,
see Ref. 10c.
D
D
D
CO2Et
NaBD4
MnO2
OH
O
N
N
N
MeOH
98%
CHCl3
55%
>99%D
>99%D
33. Control experiment indicated no proton–deuterium scrambling in the cyclized
product.
1. Hexyne
MeMgBr, -78 °C
2. TBSCl, Im
61%
D
N
OTBS
OTBS
OTBS
AuBr3, 2 mol%
D2O 2 equiv.
toluene 50 °C 2 h
( )5
N
N
7
D
(2 steps)
X
>99%D
N
N
D
23. For reviews, see: (a) Wakatsuki, Y. J. Organomet. Chem. 2004, 689, 4092; (b)
Bruneau, C.; Dixneuf, P. H. Acc. Chem. Res. 1999, 32, 311; See also: (c) McDonald,
F. E. Chem.dEur. J. 1999, 5, 3103.
24. For a recent example, see: Grotjahn, D. B.; Zeng, X.; Cooksy, A. L. J. Am. Chem.
Soc. 2006, 128, 2798.
34. For Au-catalyzed migration of alkyl group in indole series, see: Alfonsi, M.;
Arcadi, A.; Aschi, M.; Bianchi, G.; Marinelli, F. J. Org. Chem. 2005, 70, 2265.