Synthesis of pyrroloazepinones: platinum- and gold-catalyzed cyclization reactions of alkynes

Article abstract of DOI:10.1016/j.tet.2010.02.091

The synthesis of potentially bioactive pyrroloazepinones based on the catalytic intramolecular cyclization of alkyne-substituted 1H-pyrrole-2-carboxylic acid amides has been developed. In the presence of either H₂PtCl₆·6H₂

Full text of DOI:10.1016/j.tet.2010.02.091

Tetrahedron 66 (2010) 3341–3352
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of pyrroloazepinones: platinum- and gold-catalyzed cyclization
reactions of alkynes
Marina Gruit, Dirk Michalik, Karolin Kru¨ger, Anke Spannenberg, Annegret Tillack,
*
Anahit Pews-Davtyan, Matthias Beller
¨
Leibniz-Institut fu¨r Katalyse e.V. an der Universitat Rostock, Albert-Einstein-Strasse 29a, 18059 Rostock, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis of potentially bioactive pyrroloazepinones based on the catalytic intramolecular cyclization
of alkyne-substituted 1H-pyrrole-2-carboxylic acid amides has been developed. In the presence of either
H2PtCl6$6H2O at 120 ꢀC or AuCl3 at room temperature pyrrolo[3,2-c]azepin-4-ones are formed.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 14 January 2010
Received in revised form 20 February 2010
Accepted 24 February 2010
Available online 1 March 2010
Keywords:
Cyclization
Platinum
Gold
Pyrroles
Alkynes
1. Introduction
Consequently, derivatives are promising candidates for treat-
ment of a range of diseases including Cohn’s disease or psoriasis.6,7
Pyrroloazepinones represent an important structural motif fre-
quently found in a variety of bioactive compounds, such as Hyme-
nialdisine,1 Stevensine,2 LatonduineA,3 andthe Paullones,4 which have
been originally isolated from marine sponges (Fig. 1). So far, pyrro-
loazepinone derivatives have been identified to inhibit various protein
kinases, such as cyclin-dependant kinase (CDK1) or mitogen-activated
protein kinase (MEK1).1,5 These properties offer interesting potential
for the development of novel small molecule drugs for cancer, Alz-
heimer’s disease, arthritis, etc.1–6 Moreover, Hymenialdisine inhibits
the production of cytokine resulting in anti-inflammatory effects.
As shown in Figure 1 all compounds related to the Hymenialdisine
family share the structural element of a fused bicyclic pyrroloaze-
pinone in common (Fig. 1)8
The key step for the synthesis of pyrroloazepinone derivatives
is the construction of the bicyclic ring system. In general, cycli-
zation reactions have been used for this purpose. For example,
typical electrophilic aromatic substitution reactions using phos-
phorus pentoxide9 or trifluoroacetic acid (TFA) are known.10 More
recently, intramolecular Heck reactions were described by Van der
Eycken to give benzazepinones and by Joseph et al. for the
preparation of Lantoduine derivatives.11 In addition, Taddei et al.
synthesized (pyrroloazepinyl)acetamides by classic Beckmann
rearrangement.12
In the last decade transition metal-catalyzed cyclizations of
aryl-and heteroaryl-substituted alkynes have attracted significant
attention. Among these reactions especially intramolecular hydro-
arylations,13,14 cycloisomerizations,15 and cycloadditions16 offer
new and efficient ways for construction of biologically interesting
carbo- and heterocycles. Elegant examples include the work of
Echavarren et al., who reported the intramolecular cyclization of
indoles with alkynes in the presence of gold catalysts to give six- to
eight-membered rings.17 Complementary, England and Padwa
developed an AuCl3-catalyzed cycloisomerization of N-prop-
argylindole-2-carboxamides.18
NH2
N
N
H2N
H2N
O
N
O
R
N
HN
HN
Br
NH
Br
Br
NH
NH
NH
N
H
Br
Br
N
N
N
H
H
H
O
O
O
Paullones
Hymenialdisine
Lantonduine A
Stevensine
Figure 1. Natural products with a pyrroloazepinone core structure.
* Corresponding author. E-mail address: matthias.beller@catalysis.de.
0040-4020/$ – see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.02.091

3342
M. Gruit et al. / Tetrahedron 66 (2010) 3341–3352
Table 1
Since some years we are interested in the application of catalytic
Variation of different metal salts for the intramolecular cyclization reactiona
coupling and amination reactions for the synthesis of novel bio-
active compounds.8,19 In this respect, recently we envisioned the
synthesis of pyrroloazepinone derivatives by metal-catalyzed cy-
clizations of alkyne-substituted pyrrolecarboxamides (Scheme 1).
Based on a preliminary communication,20 here we present a full
account of our work on this topic.
[cat]
N
(5 mol%)
N
N
N
N
N
N
N
Toluene
120 °C
O
O
O
O
Ar
5a
2a
3a
4a
Ar
R2
N
R
R
catalyst
N
Entry
Catalyst
Convb [%]
Yieldb [%] 3a
Yieldb [%] 4a
R2
N
N
1
2
3
4
5
6
7
8
AuCl3
AuCl
AuCl(PPh3)
H2PtCl6$6H2O
K2PtCl6
Pt(PPh3)4
PtCl2(COD)
Fe(OAc)2
FeCl3
RuCl3
Rh(acac)3
IrCl3
Zn(OTf)2
TsOH
76
41
11
100
100
88
100
19
d
13
2
0
7
5
6
6
0
0
0
0
0
0
0
40
19
0
78
74
26
75
0
0
0
0
0
O
R1
R1
O
Scheme 1. Strategy for the synthesis of pyrroloazepinones from 2-propargylamide-
substituted pyrroles.
2. Results and discussion
9
Our initial investigations aimed at the straightforward synthesis
of the pyrrolo[2,3-c]azepin-8-one 3 (Scheme 2). Hence, 1-methyl-
1H-pyrrole-2-carboxylic acid methyl-prop-2-ynyl-amide (1) was
prepared in 91% yield by addition of N-methylpropargylamine to N-
methyl-1H-pyrrole-2-carboxylic acid. Amide formation took place
in the presence of 4-(dimethylamino)pyridine (DMAP) and 1,10-
carbonyldiimidazole (CDI) in tetrahydrofurane (THF) at 40 ꢀC over
night.21 Subsequent palladium-catalyzed Sonogashira coupling in
the presence of a commercial Pd/Cu-catalyst system with aryl and
heteroaryl halides (I, Br) gave different aryl-substituted alkynes 2.22
Next, the key step of the sequence, which is the intramolecular
cyclization of 2, was studied in the presence of different metal salts
and complexes.
10
11
12
13
14
d
8
d
18
89
0
0
a
Reaction conditions: 5 mol % catalyst, 0.2 mmol compound 2a, 10 mL toluene,
20 h at 120 ꢀC.
b
Determined by GC with hexadecane as internal standard.
a small amount of the other isomer 1,7-dimethyl-4-p-tolyl-6,7-
dihydro-1H-pyrrolo[2,3-c]azepin-8-one (3a) is observed (Table 1).
Apart from Pt and Au, all other catalysts showed no activity for
the cyclization process (Table 1, entries 8–14). However, when we
used p-toluenesulfonic acid (Table 1, entry 14), 1H NMR and GC–MS
analysis of the reaction mixture confirmed the formation of the
corresponding pyrrolo[2,3-c]pyridin-7-one derivative 5a, which
corresponds to the six-membered ring cyclization product. Ap-
parently, this product is formed by an 6-exo-dig process.17,18 In few
cases also in the presence of Pt or Au catalysts traces (<1% yield) of
this third product were observed.
DMAP (5 mol%)
H
N
OH
N
N
N
CDI, THF
O
O
1
40 °C, overnight
[PdCl2(PPh3)2], CuI
THF/TEA, Ar-X
60 °C, 20 h
After the initial catalyst screening, we investigated the influence
of different solvents and temperatures on the H2PtCl6$6H2O- and
AuCl3-catalyzed cyclization of 2 (Table 2).
The model reaction proceeded in good yield and selectivity (78%
or 70% of product 4a) in the presence of H2PtCl6$6H2O in toluene at
120 ꢀC (Table 2, entry 1) or AuCl3 in CH2Cl2 at room temperature
Ar = Aryl
X = I or Br
Ar
Ar
Ar
[cat]
N
(5 mol%)
N
N
N
N
N
O
O
O
3
2
4
Scheme 2. General synthesis of pyrroloazepinones 3 and 4.
Table 2
According to the work of Echavarren et al. the best catalysts for
the formation of the seven-membered azepinone derivatives
should be AuIII complexes. In accordance with previously per-
formed cyclizations, the expected product should have been the
pyrrolo[2,3-c]azepin-8-one 3 formed by an 7-endo-dig process.17
Surprisingly, we obtained two intramolecular cyclization prod-
ucts: the pyrrolo[2,3-c]azepin-8-one 3 and the pyrrolo[3,2-c]aze-
pin-4-one 4 as major product (Scheme 2).20
In Table 1 the testing of different catalysts for the model reaction
of 1-methyl-1H-pyrrole-2-carboxylic acid methyl-(3-p-tolyl-prop-
2-ynyl)-amide (2a) is shown. In general, we used 5 mol % of the
respective gold, platinum, iron, ruthenium, rhodium, iridium, zinc
complexes or p-toluenesulfonic acid as classic Broenstedt catalyst.
High activity and full conversion are observed in the presence of
either H2PtCl6$6H2O, K2PtCl6 or PtCl2(COD) (Table 1, entries 4, 5 and
7) as catalyst in toluene at 120 ꢀC. Under these conditions 1,5-di-
methyl-8-p-tolyl-5,6-dihydro-1H-pyrrolo[3,2-c]azepin-4-one (4a)
is obtained in 74–78% yield, while the AuCl3-catalyzed reactions led
to the same product in 40% yield. Notably, in these cases only
Variation of reaction conditions in the presence of AuCl3 and H2PtCl6$6H2O
catalystsa
Entry Catalyst Solvent
T [ꢀC] Conv.b [%] Yieldb [%] 3a Yieldb [%] 4a
1
2
3
4
5
6
7
8
H2PtCl6 Toluene 120
100
19
0
7
0
0
78
3
0
H2PtCl6 Toluene
H2PtCl6 Toluene
60
0
H2PtCl6 Dioxane 120
100
100
21
36
35
5
60
64
5
H2PtCl6 Dioxane
H2PtCl6 Dioxane
H2PtCl6 CH2Cl2
60
20
20
9
0
8
AuCl3
AuCl3
AuCl3
AuCl3
AuCl3
AuCl3
AuCl3
AuCl3
Toluene 120
Dioxane 120
76
13
31
51
19
7
6
1
60
40
55
48
10
70
39
40
9
9
100
100
29
77
58
10
11
12
13
14
15
Dioxane
Dioxane
CH2Cl2
DMF
DMF
DMAc
60
20
20
140
120
120
41
69
a
Reaction conditions: 5 mol % catalyst, 0.2 mmol compound 2a, 10 mL solvent,
20 h.
b
Determined by GC with hexadecane as internal standard.

M. Gruit et al. / Tetrahedron 66 (2010) 3341–3352
3343
(Table 2, entry 12). Notably, in both cases only a small amount (7%)
of 3a is observed. It appears that the gold catalyst is more easily
deactivated and temperature sensitive compared to the platinum
system.
As shown in Table 2, the ratio of 3a and 4a depends strongly
upon the reaction conditions. For example, the use of H2PtCl6$6H2O
in 1,4-dioxane at 60 ꢀC gave a ratio of 3a:4a of approximately 1:2
(Table 2, entry 5). Furthermore, in the presence of AuCl3 under the
same conditions a 1:1 ratio is obtained (Table 2, entry 10). It is in-
teresting to note that when we used AuCl3 in dimethylacetamide
(DMAc) at 120 ꢀC (Table 2, entry 5) 3a is formed as major product in
60% yield (9% of 4a).
Figure 2. Relevant NOE (double arrows) and HMBC (single arrow) correlations of
compounds 3a and 4a.
In Scheme 3 the proposed mechanism of this Au- and Pt-
catalyzed cycloisomerization reaction is shown. In agreement
with earlier reports in the literature,13,17,18,23 the pyrrole-substituted
alkyne 2 should be activated at the triple bond by coordination to
the electrophilic AuIII, PtIV or PtII catalysts. Then, several modes of
cycloisomerization reactions are possible depending on the re-
action conditions (Table 2 and Scheme 3). It appears that the
pyrrolo-azepinones 3 and 4 are obtained by a 7-endo-dig process
from 2.
a correlation of the b-pyrrole-proton to the carbonyl group is seen
(Fig. 2). In addition, we obtained single crystals of compound 4a
suitable for X-ray structure analysis, which confirmed the given
structure (Fig. 3).
Next, we were interested in the scope and limitations of the
procedure applying different arylated substrates (Table 3). For this
purpose, Sonogashira reactions of N-(prop-2-ynyl)-1H-pyrrole-2-
carboxamides 1a–d with various aryl halides were performed in
presence of [PdCl2(PPh3)2] and CuI.22 The resulting Sonogashira
products 2a–r were obtained in good yield (up to 90%). Products 2q
and 2r were formed by Sonogashira reaction follow by protection
reaction from compound 2o (Table 3, entries 17 and 18).24,25 For the
intramolecular cyclization reactions to afford pyrrolo[3,2-c]azepin-
4-ones 4a–r we always tested two conditions: 1. H2PtCl6$6H2O in
toluene at 120 ꢀC and 2. AuCl3 in CH2Cl2 at room temperature. As
shown in Table 3, in general the first set of conditions in the pres-
ence of the platinum catalyst gave superior yields of the corre-
sponding pyrroloazepines in up to 76% (Table 3, entries 1, 4–10, 12,
15, and 18). The cycloisomerization process of substituted alkynes
with tolyl, o-xylyl, anisyl, chlorophenyl, p-acetylphenyl, and
naphthyl groups afforded the corresponding products 4a–d, 4g, i
and 4r (Table 3, entries 1–4, 7, 9, and 18) in good yields. However,
trifluoromethylbenzene, cyanobenzene, ethyl benzoate, benzofu-
ran, furan or thiophen substituents (Table 3, entries 5, 6, 8, and 10–
12) led to lower yields of the desired coupling products. In addition,
we tested heteroaryl-substituted alkynes but no conversion was
observed (Table 3, entry 13).
Ar
Ar
Ar
N
[MX ]
n
N
N
N
N
N
O
2
O
O
3
4
[MX ]
n
[MX ]
n
[MX ]
n
Ar
[MX ]
n
MX
N
n-1
O
Ar
N
H
H
X-
N
MX
N
n-1
N
N
O
Ar
O
C
A
D
X-
M = AuIII, PtIV
or PtII
Ar
MX
n-1
N
N
O
B
Scheme 3. Proposed mechanism for the formation of 3 and 4.
Following the initial activation of the triple bond, cation C is
formed either directly from intermediate A or via cation B. Sub-
sequent protonolysis of the carbon–metal bond and deprotonation
leads to 3. On the other hand, the reactive spiro intermediate B,
already described in literature,14,17 might form cation D by rear-
rangement, which after deprotonation followed by demetalation
provides the seven-membered ring compound 4.
Structures of the cyclization products 3a and 4a have been
unambiguously confirmed by 1D and 2D NMR spectroscopy. In the
1H, 1H NOESY spectrum of 4a correlations are found between the
aryl protons and the protons of the N-methyl group of the pyrrole
moiety (Fig. 2). Due to the anisotropic effect of the aryl ring,
which is twisted out of the plane of the molecule, the signal of
this N-methyl group is shifted at about 1 ppm to higher field in
the 1H NMR spectrum, compared to the spectrum of compound
3a.20 For compound 3a a correlation of the aryl protons with the
Figure 3. ORTEP view of the molecular structure of 1,5-dimethyl-8-p-tolyl-5,6-dihy-
dro-1H-pyrrolo[3,2-c]azepin-4-one (4a). The thermal ellipsoids correspond to 30%
probability.
b
-pyrrole-proton is observed in the 1H, 1H NOESY spectrum. On
the other hand in the HMBC spectrum of compound 4a,

3344
M. Gruit et al. / Tetrahedron 66 (2010) 3341–3352
Table 3
Sonogashira and cyclization reactions with various arylated substratesa
R3
R3
R1
N
R2
R2
N
H2PtCl6·6H2O (5 mol%)
Toluene, 120 °C, 20 h
[PdCl2(PPh3)2], CuI
N
N
R2
N
N
or AuCl3 (5 mol%)
CH2Cl2, RT, 20 h
THF/TEA, 60 °C, 20 h
O
R1
O
R1
O
R3-X
1a-c
2a-r
4a-r
1a: R1 = CH3, R2 = CH3
R
3 = Aryl
X = I or Br
1b: R1 = CH3, R2 = H
1c: R1 = H, R2 = CH3
1d: R1 = H, R2 = H
Entry
Substrate
Product 2
Yield of 2 [%]b
Product 4
Yield of 4 [%]b
4a
76
2a
1
73
I
70c
N
N
N
N
N
O
O
O
4b
4c
2
75
75
2b
2c
I
N
N
N
O
MeO
OMe
3
52
68
I
OMe
N
N
N
N
O
O
Cl
Cl
54
4d
4e
4f
4
82
I
Cl
<10c
2d
2e
2f
N
N
N
N
O
O
F3C
CF3
18
5
81
I
CF3
Tracec
N
N
N
N
O
O
NC
CN
17
6
77
I
CN
Tracec
N
N
N
N
O
O
O
O
O
58
7
80
4g
Tracec
N
2g
N
I
N
N
O
O

M. Gruit et al. / Tetrahedron 66 (2010) 3341–3352
3345
Table 3 (continued)
Entry Substrate
Product 2
Yield of 2 [%]b
Product 4
Yield of 4 [%]b
OEt
O
O
OEt
O
30
4h
8
OEt
85
10c
2h
N
N
I
N
O
N
N
O
I
70
2i
4i
9
72
19c
N
O
N
N
O
O
33
O
4j
2j
Br
10
11
78
Tracec
O
N
N
O
N
N
N
O
O
S
2k
O
Br
42
10
N
N
N
4k
N
O
O
N
N
N
O
S
2l
29
I
12
13
65
18c
4l
4m
4n
N
O
S
N
O
N
2m
N
0
I
90
0c
N
N
N
O
O
0
14
50
I
I
0c
H
N
2n
HN
NH
N
H
O
O
40
0c
4o
15
66
2o
H
N
N
NH
N
O
O
4p
16
72
35
I
2p
N
HN
N
N
H
O
(continued on next page)
O

3346
Table 3 (continued)
M. Gruit et al. / Tetrahedron 66 (2010) 3341–3352
Entry
Substrate
Product 2
Yield of 2 [%]b
Product 4
Yield of 4 [%]b
0 (21% of 4q)
Boc
N
4q
4r
17
64d
I
I
2q
10c
N
N
N
N
Boc
O
O
68
Bn
N
18
52d
53c
2r
N
N
Bn
O
O
a
Sonogashira conditions: 2 mol % [PdCl2(PPh3)2], 4 mol % CuI, 1.15 mmol compound 1, 1.27 mmol aryl halogenide, 8 mL THF/TEA (1:1), 60 ꢀC, 20 h. Cyclization conditions:
5 mol % H2PtCl6$6H2O, 0.2 mmol compound 2, 10 mL toluene, 120 ꢀC, 20 h.
b
Yield of isolated product.
c
5 mol % AuCl3, 0.2 mmol compound 2, 10 mL CH2Cl2, rt, 20 h.
Total yield of isolated product after Sonogashira (to give 2o) and protection reaction.
d
By comparing the reactivity of N,N0-dialkyl pyrroles 2a and 2q, r
(Table 3, entries 1, 17, and 18) with N-methyl-derivatives 2o, p
(Table 3, entries 15 and 16) and 2n (Table 3, entry 14), it became
clear that protection of the nitrogen atoms is beneficial for the
cyclization reaction. Notably, in all cases the major product is
compound 4 and 3 is obtained only in traces (<5%). Finally non-
arylated alkynes have been tested, however under these condi-
tions no cyclization took place.
on MAT 95XP (Thermo ELECTRON CORPORATION). GC was per-
formed on Agilent 6890 chromatograph with a 30 m HP5 column.
HRMS was performed on MAT 95XP (EI) and Agilent 6210 Time-of-
Flight LC/MS (ESI). GC–MS was performed on Agilent 5973 chro-
matograph Mass Selective Detector. All yields reported in Table 3
refer to isolated yields. The analysis of compounds 1a, 1b, 1c, 2a,
3a and 4a have been already described in earlier publication.20,21
It should be noted that apart from being mechanistically in-
teresting, this cycloisomerization protocol provides straightfor-
4.2. X-ray diffraction
ward access of an original
attractive motif for novel biologically active compounds.
b-amino acid scaffold, which is an
Diffraction Data were collected on a STOE IPDS diffractometer
using graphite-monochromated Mo Ka radiation. The structure was
solved by direct methods (SHELXS-97)26 and refined by full-matrix
least-squares techniques on F2 (SHELXL-97)26. XP (Bruker AXS) was
used for graphical representation. Crystallographic data for the
structure in this paper has been deposited with the Cambridge
Crystallographic Data Centre as supplementary publication number
CCDC 730340 [4a]. The copy of the data can be obtained free of
charge from www.ccdc.cam.ac.uk/data_request/cif or from the
Cambrigde Crystallographic Data Centre,12 Union Road, Cambridge
CB2 1EZ, UK; fax: þ44 1223 336033.
3. Conclusion
In summary, a biologically interesting scaffold can be synthe-
sized in few steps from commercially available starting materials.
Au- and Pt-catalyzed cyclization reactions gave a number of pyr-
rolo[3,2-c]azepin-4-one derivatives in good yield. The formation of
the products proceeds via a 7-endo-dig cyclization process with
concomitant rearrangement of the amidocarbonyl group from the
2- to the 3-position of the pyrrole ring. H2PtCl6$6H2O is the more
general catalyst for the formation of seven-membered pyrrolo[3,2-
c]azepin-4-one derivatives. Further extensions of this chemistry
towards indoles and other heterocycles are currently explored in
our laboratory.
Crystal data for 4a C17H18N2O, Mr¼266.33, monoclinic, space
group P21/c, a¼9.358(2), b¼10.587(2), c¼14.841(3) Å,
b
¼105.18(3)ꢀ,
V¼1419.0(5) Å3, Z¼4, rcalcd¼1.247 g cmꢁ3
,
m
¼0.078 mmꢁ1, T¼200 K,
4994 reflections collected, 2773 independent (Rint¼0.0325) and
1890 observed reflections [I>2
s
(I)], final R indices [I>2
s(I)]:
R1¼0.0416, wR2¼0.0994,
R
indices (all data): R1¼0.0700,
wR2¼0.1074, 184 refined parameters.
4. Experimental section
4.1. General methods
4.3. General procedure for the synthesis of 1-methyl-1H-
pyrrole-2-carboxylic acid methyl-prop-2-ynyl-amide (1a) and
1-methyl-1H-pyrrole-2-carboxylic acid prop-2-ynylamide (1b)
All reactions were carried out under argon atmosphere. Chem-
icals were purchased from Aldrich, Fluka and Acros and unless
otherwise noted were used without further purification. All com-
pounds were characterized by 1H NMR, 13C NMR, GC–MS, HRMS
and IR spectroscopy. 1H and 13C NMR spectra were recorded on
Bruker AV 300 and AV 500 spectrometers with chloroform solu-
1-Methylpyrrole-2-carboxilic acid (5 g, 40 mmol, 1 equiv), 4-
dimethylaminopyridine DMAP (0.24 g, 2 mmol) and 1,10-carbon-
yldiimidazole CDI (6.49 g, 40 mmol, 1 equiv) were introduced in
100 mL of tetrahydrofuran (THF). The solution was stirred 90 min at
room temperature and N-methylpropargylamine (4 mL, 48 mmol,
1.2 equiv) or propargylamine (4.11 mL, 48 mmol, 1.2 equiv) was
then added. The brown mixture was stirred overnight at 40 ꢀC (for
1a) or room temperature (for 1b). After removal of the solvent in
vacuo, the residue was purified by column chromatography (hep-
tane/ethyl acetate 1:1) to give pyrroles 1a (4.53 g, 91%, yellow oil)
or 1b (6.25 g, 96%, white powder).
tions of the compounds at a temperature of 300 K. The 1H and 13
NMR chemical shifts are reported relative to the chloroform reso-
C
nances (
d
(1H)¼7.26,
d
(
13C)¼77.0). Due to dynamic effects (re-
stricted rotation in the amide moiety) some signals of compounds 2
appeared in the spectra at room temperature as broadened or were
not displayed. IR spectra were recorded on FT-IR ALPHA (Bruker)
with Platinum-ATR (Bruker). EI (70 eV) mass spectra were recorded

M. Gruit et al. / Tetrahedron 66 (2010) 3341–3352
3347
4.4. Procedure for the synthesis of 1H-pyrrole-2-carboxylic
acid methyl-prop-2-ynyl-amide (1c) and 1H-pyrrole-2-
carboxylic acid prop-2-ynylamide (1d)
(br, OCNCH3). FT-IR (ATR, cmꢁ1): 3108, 2980, 2957, 2930,1710,1605,
1532, 1406, 1389, 1267, 1102, 1069, 1018, 858, 769, 729, 696, 608.
GC–MS (EI, 70 eV): m/z (%): 282 (28) [Mþ], 267 (36), 254 (50), 240
(69), 225 (69), 210 (22), 196 (9), 175 (21), 158 (20), 145 (34), 130 (11),
108 (100), 102 (17), 89 (5), 81 (22), 76 (5), 63 (4), 53 (24), 39 (14).
HRMS (ESI, [MþH]þ): calcd for C17H19O2N2: 283.1441; found:
283.14411.
N-Methylpropargylamine (0.81 mL, 14.22 mmol, 1.5 equiv) or
propargylamine (0.63 mL, 14.22 mmol, 1.5 equiv) was introduced to
a solution of 2-trichloroacetylpyrrole (2 g, 9.48 mmol, 1 equiv) in
3 mL of triethylamine (TEA). The reaction mixture was then stirred
at 60 ꢀC overnight. After removal of the solvent in vacuo, the resi-
due was purified by column chromatography (heptane/ethyl ace-
tate 1:1) to give pyrroles 1c as white powder (1.15 g, 75%) or 1d as
light yellow powder (1.06 g, 76%).
4.5.4. 1-Methyl-1H-pyrrole-2-carboxylic acid [3-(4-chloro-phenyl)-
prop-2-ynyl]-methyl-amide (2d). Yellow syrup, 82%. 1H NMR
(300.13 MHz; CDCl3):
d
¼7.38 (m, 2H); 7.30 (m, 2H); 6.72 (dd, J¼2.5,
1.8 Hz, 1H); 6.59 (br, 1H); 6.10 (dd, J¼3.8, 2.5 Hz, 1H); 4.54 (s, 2H,
CH2); 3.81 (s, 3H, NCH3); 3.25 (s, 3H, OCNCH3). 13C NMR (75.5 MHz,
4.5. General procedure for Sonogashira reactions
CDCl3):
d
¼163.7 (CO); 134.5 (C); 133.0 (2CH); 128.7 (2CH); 126.9
(CH); 124.6 (C); 121.1 (C); 113.7 (CH); 107.0 (CH); 85.4 (C^C); 36.0
(NCH3); not displayed: CH2, C^C, OCNCH3. FT-IR (ATR, cmꢁ1): 3104,
2930, 1701, 1618, 1532, 1487, 1390, 1243, 1089, 1069, 1013, 827, 729,
607. GC–MS (EI, 70 eV): m/z (%): 286 (12) [Mþ], 258 (53), 244 (21),
229 (59), 215 (15), 194 (9), 175 (8), 149 (17), 108 (100), 97 (3), 81
(28), 63 (4), 53 (23), 39 (14). HRMS (ESI, [MþH]þ): calcd for
C16H16ON2Cl: 287.09457; found: 287.09453.
[PdCl2(PPh3)2] (16 mg, 0.023 mmol, 2 mol %) and CuI (9 mg,
0.046 mmol, 4 mol %) were placed in an ACE pressure tube under an
argon atmosphere. The aryl halogenide (1.27 mmol, 1.1 equiv) and
a solution of N,N0-dimethyl-N-(prop-2-ynyl)-1H-pyrrole-2-carbox-
amide (1a) (202.7 mg, 1.15 mmol, 1 equiv) in THF/TEA (1:1, 8 mL)
were then added. The pressure tube was sealed and the reaction
mixture was heated at 60 ꢀC for 20 h. After removal of the solvent in
vacuo, the residue was purified by column chromatography (hep-
tane/ethyl acetate 1:1) to give pyrroles 2a–r.
4.5.5. 1-Methyl-1H-pyrrole-2-carboxylic acid methyl-[3-(4-
trifluoromethyl-phenyl)-prop-2-ynyl]-amide (2e). Yellow syrup,
81%. 1H NMR (500.13 MHz; CDCl3):
d
¼7.58 (m, 4H); 6.73 (dd, J¼2.5,
4.5.1. 1-Methyl-1H-pyrrole-2-carboxylic acid methyl-(3-p-tolyl-
1.8 Hz, 1H); 6.60 (br, 1H); 6.11 (dd, J¼3.8, 2.5 Hz, 1H); 4.58 (s, 2H,
prop-2-ynyl)-amide (2a). Yellow
(500.13 MHz; CDCl3):
syrup,
73%. 1H
NMR
CH2); 3.82 (s, 3H, NCH3); 3.26 (s, 3H, OCNCH3). 13C NMR
d
¼7.34 (m, 2H); 7.14 (m, 2H); 6.70 (dd,
(125.8 MHz, CDCl3):
d¼167.8 (CO); 132.0 (2CH); 130.4 (C); 130.3 (q,
J¼2.5, 1.8 Hz, 1H); 6.61 (br, 1H); 6.09 (dd, J¼3.8, 2.5 Hz, 1H); 4.53
JC,F¼33.0 Hz, C–CF3); 130.0 (C); 127.0 (CH); 126.4 (C); 125.2 (q,
JC,F¼3.9 Hz, 2CH); 124.4 (C); 123.8 (q, JC,F¼272 Hz, CF3); 113.7 (CH);
107.0 (CH); 87.0 (C^C); 82.8 (br, C^C); 39.1 (br, CH2); 36.0 (NCH3);
35.1 (br, OCNCH3). FT-IR (ATR, cmꢁ1): 3350, 3108, 3041, 3000, 2960,
2920, 1681, 1618, 1600, 1532, 1389, 1323, 1259, 1243, 1066, 837, 750,
728, 592. GC–MS (EI, 70 eV): m/z (%): 320 (18) [Mþ], 301 (6), 292
(66), 278 (14), 263 (81), 249 (13), 211 (5), 194 (5), 183 (16), 175 (6),
147 (6), 133 (8), 118 (3), 108 (100), 94 (23), 81 (27), 53 (21), 39 (12).
HRMS (ESI, [MþH]þ): calcd for C17H16ON2F3: 321.12092; found:
321.12107.
(s, 2H, CH2); 3.80 (s, 3H, NCH3); 3.23 (br, 3H, OCNCH3); 2.34 (s,
3H, CH3(aryl)). 13C NMR (125.8 MHz, CDCl3):
d
¼163.8 (CO); 138.6
(C); 131.6 (2CH); 129.0 (2CH); 126.7 (CH); 124.8 (C); 119.6 (C);
113.5 (CH); 106.9 (CH); 84.4 (br, C^C); 83.6 (C^C); 40.3 (br,
CH2); 35.9 (NCH3); 34.8 (br, OCNCH3); 21.4 (CH3). FT-IR (ATR,
cmꢁ1): 3109, 3029, 2921, 1706, 1619, 1532, 1509, 1476, 1444, 1409,
1389, 1243, 1069, 1013, 816, 750, 729, 608. GC–MS (EI, 70 eV):
m/z (%): 266 (22) [Mþ], 251 (27), 238 (65), 224 (43), 209 (91), 194
(27), 175 (12), 156 (13), 129 (28), 115 (15), 108 (100), 91 (4), 81
(30), 63 (6), 53 (29), 39 (20). HRMS (EI): calcd for C17H18ON2:
266.14136; found: 266.140787.
4.5.6. 1-Methyl-1H-pyrrole-2-carboxylic acid [3-(4-cyano-phenyl)-
prop-2-ynyl]-methyl-amide (2f). Yellow syrup, 77%. 1H NMR
4.5.2. 1-Methyl-1H-pyrrole-2-carboxylic acid [3-(3,4-dimethyl-phe-
(300.13 MHz; CDCl3):
d
¼7.61 (m, 2H); 7.53 (m, 2H); 6.73 (dd, J¼2.5,
nyl)-prop-2-ynyl]-methyl-amide (2b). Yellow syrup, 75%. 1H NMR
1.8 Hz, 1H); 6.58 (dd, J¼3.8, 1.8 Hz, 1H); 6.11 (dd, J¼3.8, 2.5 Hz, 1H);
(500.13 MHz; CDCl3):
d
¼7.24 (d, J¼1.9 Hz, 1H); 7.20 (dd, J¼7.7,
4.58 (s, 2H, CH2); 3.82 (s, 3H, NCH3); 3.26 (s, 3H, OCNCH3). 13C NMR
1.9 Hz, 1H); 7.07 (d, J¼7.7 Hz, 1H); 6.71 (dd, J¼2.5, 1.8 Hz, 1H); 6.62
(br, 1H); 6.10 (dd, J¼3.8, 2.5 Hz, 1H); 4.54 (s, 2H, CH2); 3.81 (s, 3H,
NCH3); 3.24 (s, 3H, OCNCH3); 2.26 (s, 3H, CH3(aryl)); 2.24 (s, 3H,
(75.5 MHz, CDCl3):
d¼163.7 (CO); 132.3 (2CH); 132.0 (2CH); 127.5
(C); 127.0 (CH); 124.3 (C); 118.3 (C); 113.7 (CH); 111.8 (C); 107.0
(CH); 89.1 (C^C); 82.6 (br, C^C); 36.0 (NCH3); not displayed: CH2,
OCNCH3. FT-IR (ATR, cmꢁ1): 3106, 3043, 2922, 2225, 1617, 1603,
1531, 1409, 1389, 1243, 1069, 838, 750, 728, 608, 555. GC–MS (EI,
70 eV): m/z (%): 277 (19) [Mþ], 262 (7), 249 (66), 235 (14), 220 (68),
206 (22), 192 (3), 175 (7), 140 (15), 108 (100), 94 (2), 81 (26), 63 (4),
53 (21), 39 (13). HRMS (ESI, [MþH]þ): calcd for C17H16ON3:
278.12879; found: 278.12885.
CH3(aryl)). 13C NMR (125.8 MHz, CDCl3):
d
¼163.7 (CO); 137.3 (C);
136.6 (C); 132.7 (CH); 129.6 (CH); 129.1 (CH); 126.6 (CH); 124.7 (C);
119.8 (C); 113.5 (CH); 106.9 (CH); 84.5 (br, C^C); 83.3 (C^C); 40.6
(br, CH2); 35.8 (NCH3); 34.8 (br, OCNCH3); 19.6 (CH3); 19.5 (CH3).
FT-IR (ATR, cmꢁ1): 3119, 3023, 2920, 1704, 1605, 1534, 1447, 1384,
1254, 1070, 1022, 818, 735, 609. GC–MS (EI, 70 eV): m/z (%): 280
(28) [Mþ], 265 (39), 252 (63), 238 (43), 223 (95), 208 (33), 194 (8),
175 (18), 143 (23), 128 (25), 115 (19), 108 (100), 91 (6), 81 (31), 65
(3), 52 (4), 39 (15). HRMS (ESI, [MþH]þ): calcd for C18H21ON2:
281.16484; found: 281.16479.
4.5.7. 1-Methyl-1H-pyrrole-2-carboxylic acid [3-(4-acetyl-phenyl)-
prop-2-ynyl]-methyl-amide (2g). Yellow syrup, 80%. 1H NMR
(500.13 MHz; CDCl3):
d
¼7.92 (m, 2H); 7.53 (m, 2H); 6.72 (dd, J¼2.5,
1.9 Hz, 1H); 6.60 (br, 1H); 6.11 (dd, J¼3.9, 2.5 Hz, 1H); 4.58 (s, 2H,
4.5.3. 1-Methyl-1H-pyrrole-2-carboxylic acid [3-(4-methoxy-phe-
CH2); 3.82 (s, 3H, NCH3); 3.26 (s, 3H, OCNCH3); 2.60 (s, 3H, CH3CO).
nyl)-prop-2-ynyl]-methyl-amide (2c). Yellow syrup, 52%. 1H NMR
13C NMR (125.8 MHz, CDCl3):
d¼197.2 (CH3CO); 163.7 (CO); 136.4
(300.13 MHz; CDCl3):
d
¼7.39 (m, 2H); 6.84 (m, 2H); 6.71 (dd, J¼2.5,
(C); 131.9 (2CH); 128.2 (2CH); 127.5 (C); 126.9 (CH); 124.5 (C); 113.7
(CH); 107.0 (CH); 87.9 (C^C); 83.5 (br, C^C); 40.0 (br, CH2); 36.0
(NCH3); 35.0 (br, OCNCH3); 26.7 (CH3CO). FT-IR (ATR, cmꢁ1): 3108,
3078, 2931,1712,1615,1533,1408,1321,1244,1164,1121,1105, 1065,
1016, 842, 732, 597. GC–MS (EI, 70 eV): m/z (%): 294 (20) [Mþ], 266
(65), 252 (15), 237 (86), 223 (17), 194 (24), 170 (9), 143 (11), 129 (4),
1.8 Hz, 1H); 6.62 (br, 1H); 6.10 (dd, J¼3.8, 2.5 Hz, 1H); 4.53 (s, 2H,
CH2); 3.81 (s, 6H, 2CH3); 3.24 (s, 3H, CH3). 13C NMR (75.5 MHz,
CDCl3):
d
¼163.7 (C]O); 159.7 (COCH3); 133.2 (2CH); 126.7 (CH);
124.7 (C); 114.7 (C); 114.0 (2CH); 113.6 (CH); 106.9 (CH); 83.0 (br,
C^C); 82.8 (C^C); 55.3 (OCH3); 39.0 (br, CH2); 35.9 (NCH3); 34.5

3348
M. Gruit et al. / Tetrahedron 66 (2010) 3341–3352
114 (12), 108 (100), 81 (29), 63 (3), 53 (21), 39 (12). HRMS (ESI,
(36),142 (7), 130 (7),108 (99), 94 (5), 81 (17), 65 (4), 53 (26), 39 (17).
HRMS (EI): calcd for C14H14O2N2: 242.10498; found: 242.105288.
[MþH]þ): calcd for C18H19O2N2: 295.1441; found: 295.14387.
4.5.8. 4-{3-[Methyl-(1-methyl-1H-pyrrole-2-carbonyl)-amino]-
4.5.12. 1-Methyl-1H-pyrrole-2-carboxylic acid methyl-(3-thiophen-
prop-1-ynyl}-benzoic acid ethyl ester (2h). Yellow syrup, 85%. 1H
2-yl-prop-2-ynyl)-amide (2l). Red syrup, 65%. 1H NMR
NMR (300.13 MHz; CDCl3):
d
¼7.99 (m, 2H); 7.50 (m, 2H); 6.72 (d,
(500.13 MHz; CDCl3):
d
¼7.25 (dd, J¼5.0, 1.2 Hz, 1H); 7.23 (dd, J¼3.5,
J¼2.5, 1.8 Hz, 1H); 6.60 (br, 1H); 6.11 (dd, J¼3.9, 2.5 Hz, 1H); 4.58 (s,
2H, CH2); 4.38 (q, J¼7.1 Hz, 2H, OCH2); 3.82 (s, 3H, NCH3); 3.26 (s,
3H, OCNCH3); 1.10 (t, J¼7.1 Hz, 3H, CH3). 13C NMR (75.5 MHz,
1.2 Hz, 1H); 6.98 (dd, J¼5.0, 3.5 Hz, 1H); 6.71 (dd, J¼2.5, 1.9 Hz, 1H);
6.58 (br, 1H); 6.10 (dd, J¼3.9, 2.5 Hz, 1H); 4.57 (s, 2H, CH2); 3.82 (s,
3H, NCH3); 3.24 (s, 3H, OCNCH3). 13C NMR (125.8 MHz, CDCl3):
CDCl3):
d¼166.0 (CO); 163.7 (CO); 131.6 (2CH); 130.1 (C); 129.4
d¼163.7 (CO); 132.3 (CH); 127.2 (CH); 126.9 (CH); 126.8 (CH); 124.6
(2CH); 127.1 (C); 126.9 (CH); 124.5 (C); 113.7 (CH); 107.0 (CH); 87.4
(C^C); 86.0 (br, C^C); 61.1 (OCH2); 36.0 (NCH3); 14.3 (CH3); not
displayed: NCH2, OCNCH3. FT-IR (ATR, cmꢁ1): 3107, 3038, 3001,
2933, 2837, 1705, 1603, 1532, 1508, 1410, 1243, 1171, 1069, 1037, 832,
750, 730, 607, 534. GC–MS (EI, 70 eV): m/z (%): 324 (26) [Mþ], 296
(69), 279 (15), 267 (86), 253 (13), 238 (14), 210 (10), 194 (24), 175
(10), 143 (11), 108 (100), 88 (3), 81 (30), 63 (3), 53 (21), 39 (12).
HRMS (ESI, [MþH]þ): calcd for C19H21O3N2: 325.15467; found:
325.15506.
(C); 122.5 (C); 113.6 (CH); 106.9 (CH); 88.3 (C^C); 77.5 (br, C^C);
40.3 (br, CH2); 35.9 (NCH3); 35.0 (br, OCNCH3). FT-IR (ATR, cmꢁ1):
3102, 2919, 2222, 1615, 1531, 1475, 1443, 1409, 1386, 1306, 1242,
1189, 1066, 847, 725, 700, 606. GC–MS (EI, 70 eV): m/z (%): 258 (12)
[Mþ], 243 (15), 230 (20), 216 (38), 201 (99), 187 (14), 168 (12), 148
(5), 135 (3), 121 (22), 108 (100), 94 (5), 81 (20), 63 (5), 53 (25), 39
(16). HRMS (ESI, [MþH]þ): calcd for C14H15ON2S: 259.08996;
found: 259.09012.
4.5.13. 1-Methyl-1H-pyrrole-2-carboxylic acid methyl-(3-pyridin-2-
4.5.9. 1-Methyl-1H-pyrrole-2-carboxylic acid methyl-(3-naphthalen-
yl-prop-2-ynyl)-amide (2m). Orange syrup, 90%. 1H NMR
1-yl-prop-2-ynyl)-amide (2i). Yellow syrup, 72%. 1H NMR
(300.13 MHz; CDCl3):
d
¼8.58 (ddd, J¼4.9, 1.9, 1.0 Hz, 1H); 7.66 (d0t0,
(500.13 MHz; CDCl3):
d
¼8.30 (m, J¼8.2 Hz, 1H); 7.85 (m, 2H); 7.69
J¼7.7, 1.9 Hz, 1H); 7.45 (d0t0, J¼7.7, 1.1 Hz, 1H); 7.24 (ddd, J¼7.7, 4.9,
1.2 Hz, 1H); 6.71 (dd, J¼2.6, 1.9 Hz, 1H); 6.59 (br, 1H); 6.09 (dd,
J¼3.8, 2.6 Hz, 1H); 4.60 (s, 2H, CH2); 3.80 (s, 3H, NCH3); 3.26 (s, 3H,
(dd, J¼7.3, 1.2 Hz, 1H); 7.57 (ddd, J¼8.2, 7.1, 1.2 Hz, 1H); 7.52 (ddd,
J¼8.2, 7.1, 1.2 Hz, 1H); 7.43 (dd, J¼8.2, 7.1 Hz, 1H); 6.74 (dd, J¼2.5
1.8 Hz, 1H); 6.69 (br, 1H); 6.12 (dd, J¼3.9, 2.5 Hz, 1H); 4.72 (s, 2H,
CH2); 3.84 (s, 3H, NCH3); 3.34 (s, 3H, OCNCH3). 13C NMR
OCNCH3). 13C NMR (75.5 MHz, CDCl3):
d¼163.7 (CO); 150.0 (CH);
142.8 (C); 136.2 (CH); 127.2 (CH); 126.8 (CH); 124.4 (C); 123.1 (CH);
113.7 (CH); 106.9 (CH); 84.5 (C^C); 83.6 (br, C^C); 35.9 (NCH3);
not displayed: CH2, OCNCH3. FT-IR (ATR, cmꢁ1): 3105, 3078, 3051,
2952, 2921, 2230,1734, 1617,1581, 1531,1461,1427, 1410,1387, 1243,
1068, 778, 736, 540. GC–MS (EI, 70 eV): m/z (%): 253 (18) [Mþ], 238
(6), 224 (15), 210 (19), 196 (63), 182 (27), 175 (11), 145 (43), 129 (4),
117 (29), 108 (100), 89 (9), 81 (23), 63 (5), 42 (8), 39 (18). HRMS (ESI,
[MþH]þ): calcd for C15H16ON3: 254.12879; found: 254.12885.
(125.8 MHz, CDCl3):
d¼163.8 (CO); 133.3 (C); 133.1 (C); 130.7 (CH);
128.9 (CH); 128.3 (CH); 126.9 (CH); 126.8 (CH); 126.4 (CH); 126.0
(CH); 125.2 (CH); 124.7 (C); 120.3 (C); 113.7 (CH); 107.0 (CH); 89.3
(C^C); 82.4 (C^C); 40.4 (br, CH2); 36.0 (NCH3); 34.8 (br, OCNCH3).
FT-IR (ATR, cmꢁ1): 3104, 3055, 2921, 1616, 1531, 1476, 1443, 1409,
1388, 1306, 1242, 1067, 799, 773, 749, 726. GC–MS (EI, 70 eV): m/z
(%): 302 (31) [Mþ], 273 (30), 260 (60), 245 (73), 230 (17), 192 (14),
178 (8), 165 (49), 152 (14), 108 (100), 94 (3), 81 (17), 63 (3), 53 (21),
39 (19). HRMS (ESI, [MþH]þ): calcd for C20H19ON2: 303.14919;
found: 303.14915.
4.5.14. 1H-Pyrrole-2-carboxylic acid (3-p-tolyl-prop-2-ynyl)-amide
(2n). Light yellow powder, 50%. 1H NMR (300.13 MHz; CDCl3):
d
¼9.59 (br, 1H, NH); 7.32 (m, 2H); 7.11 (m, 2H); 6.93 (m, 1H); 6.61
4.5.10. 1-Methyl-1H-pyrrole-2-carboxylic acid (3-benzofuran-2-yl-
(m, 1H); 6.24 (m, 1H); 6.10 (br t, J¼5.3 Hz, 1H, OCNH); 4.44 (d,
prop-2-ynyl)-methyl-amide (2j). Yellow syrup, 78%. 1H NMR
J¼5.3 Hz, 2H, CH2); 2.34 (s, 3H, CH3). 13C NMR (75.5 MHz, CDCl3):
(300.13 MHz; CDCl3):
d
¼7.56 (m, 1H); 7.45 (m, 1H); 7.34 (m, 1H);
d¼160.6 (CO); 138.6 (C); 131.6 (2CH); 129.0 (2CH); 125.4 (C); 121.7
7.25 (m, 1H); 6.96 (d, J¼0.8 Hz, 1H); 6.73 (dd, J¼2.6, 1.8 Hz, 1H);
6.59 (br, 1H); 6.11 (dd, J¼3.9, 2.6 Hz, 1H); 4.64 (s, 2H, CH2); 3.82 (s,
3H, NCH3); 3.23 (s, 3H, OCNCH3). 13C NMR (75.5 MHz, CDCl3):
(CH); 119.4 (C); 109.9 (CH); 109.2 (CH); 84.1 (C^C); 83.6 (C^C);
30.1 (CH2); 21.6 (CH3). FT-IR (ATR, cmꢁ1): 3357, 3296, 3120, 3079,
3026, 2917, 2858, 1625, 1554, 1523, 1509, 1316, 1125, 816, 741, 526.
GC–MS (EI, 70 eV): m/z (%): 238 (100) [Mþ], 223 (7), 209 (59), 194
(14),180 (13),167 (4),144 (86),130 (27),115 (25),102 (7), 94 (54), 91
(8), 77 (8), 66 (26), 51 (6), 39 (18). HRMS (ESI, [MþH]þ): calcd for
C15H15ON2: 239.11789; found: 239.11768.
d
¼163.8 (C]O); 154.7 (C–O); 138.0 (C–O); 127.4 (C); 127.0 (CH);
125.7 (CH); 124.4 (C); 123.3 (CH); 121.3 (CH); 113.8 (CH); 112.0
(CH); 111.2 (CH); 107.0 (CH); 90.7 (C^C); 74.8 (C^C); 39.8 (br,
CH2); 36.0 (NCH3); 35.3 (br, OCNCH3). FT-IR (ATR, cmꢁ1): 3103,
3056, 3036, 2921, 1702, 1617, 1531, 1447, 1409, 1387, 1306, 1243,
1068, 748, 730. GC–MS (EI, 70 eV): m/z (%): 292 (24) [Mþ], 277 (21),
263 (25), 250 (26), 235 (100), 220 (14), 184 (9), 169 (6), 155 (20),
144 (7), 126 (8), 108 (81), 94 (5), 80 (15), 63 (4), 53 (21), 39 (12).
HRMS (ESI, [MþH]þ): calcd for C18H17O2N2: 293.12845; found:
293.12878.
4.5.15. 1-Methyl-1H-pyrrole-2-carboxylic acid (3-p-tolyl-prop-2-
ynyl)-amide (2o). Light yellow powder, 66%. 1H NMR (300.13 MHz;
CDCl3):
d
¼7.33 (m, 2H); 7.11 (m, 2H); 6.73 (dd, J¼2.6, 1.7 Hz, 1H);
6.60 (dd, J¼3.9, 1.7 Hz, 1H); 6.09 (dd, J¼3.9, 2.6 Hz, 1H); 6.04 (br, 1H,
NH); 4.39 (d, J¼5.3 Hz, 2H, CH2); 3.96 (s, 3H, NCH3); 2.34 (s, 3H,
CH3). 13C NMR (75.5 MHz, CDCl3):
d¼161.4 (CO); 138.5 (C); 131.6
4.5.11. 1-Methyl-1H-pyrrole-2-carboxylic acid (3-furan-2-yl-prop-2-
(2CH); 129.0 (2CH); 128.2 (CH); 125.1 (C); 119.5 (C); 111.9 (CH);
107.3 (CH); 84.4 (C^C); 83.4 (C^C); 36.7 (NCH3); 29.8 (CH2); 21.4
(CH3). FT-IR (ATR, cmꢁ1): 3324, 3082, 3025, 2920, 2865, 1634, 1542,
1507, 1462, 1409, 1324, 1273, 1259, 1157, 816, 726, 592. GC–MS (EI,
70 eV): m/z (%): 252 (58) [Mþ], 237 (15), 223 (23), 210 (41), 196 (20),
180 (3), 167 (2), 161 (14), 128 (13), 115 (14), 108 (100), 102 (5), 91 (5),
80 (13), 63 (4), 53 (20), 39 (14). HRMS (ESI, [MþH]þ): calcd for
C16H17ON2: 253.13354; found: 253.13374.
ynyl)-methyl-amide (2k). Yellow syrup, 42%. 1H NMR (300.13 MHz;
CDCl3):
d¼7.38 (m, 1H); 6.71 (dd, J¼2.6, 1.7 Hz, 1H); 6.60 (dd, J¼3.4,
0.6 Hz, 1H); 6.57 (br, 1H); 6.39 (dd, J¼3.4, 1.9 Hz, 1H); 6.10 (dd,
J¼3.8, 2.6 Hz, 1H); 4.58 (s, 2H, CH2); 3.82 (s, 3H, NCH3); 3.23 (s, 3H,
OCNCH3). 13C NMR (75.5 MHz, CDCl3):
d
¼163.7 (CO); 143.6 (CH);
136.4 (C); 126.8 (CH); 124.4 (C); 115.5 (CH); 113.7 (CH); 110.8 (CH);
106.9 (CH); 88.8 (C^C); 35.9 (NCH3); not displayed: CH2, OCNCH3,
C^C. FT-IR (ATR, cmꢁ1): 3110, 2957, 2924, 1701, 1617, 1532, 1480,
1410, 1388, 1244, 1210, 1068, 730, 593. GC–MS (EI, 70 eV): m/z (%):
242 (12) [Mþ], 227 (11), 214 (22), 201 (16), 185 (100), 170 (17), 156
4.5.16. 1H-Pyrrole-2-carboxylic acid methyl-(3-p-tolyl-prop-2-ynyl)-
amide (2p). Light yellow powder, 72%. 1H NMR (300.13 MHz;

M. Gruit et al. / Tetrahedron 66 (2010) 3341–3352
3349
CDCl3):
6.77 (br, 1H); 6.27 (m, 1H); 4.62 (s, 2H, CH2); 3.35 (br, 3H, OCNCH3);
2.35 (s, 3H, CH3). 13C NMR (75.5 MHz, CDCl3):
¼162.3 (CO); 138.5
d
¼9.95 (br,1H, NH); 7.34 (m, 2H); 7.11 (m, 2H); 6.96 (m,1H);
342 (10) [Mþ], 314 (32), 300 (3), 251 (49), 223 (5), 209 (100), 194
(21), 170 (12), 129 (14), 108 (65), 91 (23), 81 (9), 65 (4), 53 (10), 39
(5). HRMS (ESI, [MþH]þ): calcd for C23H23ON2: 343.18049; found:
343.18069.
d
(C); 131.6 (2CH); 129.0 (2CH); 124.5 (C); 121.4 (CH); 119.5 (C); 112.9
(CH); 109.8 (CH); 83.3 (C^C); 21.4 (CH3); not displayed: CH2, C^C,
OCNCH3. FT-IR (ATR, cmꢁ1): 3247, 3081, 3029, 2917, 2866, 1596,
1487, 1402, 1299, 1135, 1116, 812, 780, 736, 608. GC–MS (EI, 70 eV):
m/z (%): 252 (100) [Mþ], 237 (53), 223 (82), 209 (11), 194 (42), 180
(41), 158 (60), 144 (10), 129 (41), 115 (17), 102 (5), 94 (52), 77 (8), 66
(25), 51 (5), 39 (13). HRMS (ESI, [MþH]þ): calcd for C16H17ON2:
253.13354; found: 253.1338.
4.8. General procedure for cyclization reactions
H2PtCl6$6H2O or AuCl3 (0.01 mmol, 5 mol %) was placed in an
ACE pressure tube under an argon atmosphere. A solution of
product 2a–r (0.2 mmol, 1 equiv) in 10 ml of toluene (for [Pt]) or
10 ml of dichloromethane (for [Au]) was then injected into the tube.
The pressure tube was sealed and the reaction mixture was heated
at 120 ꢀC (for [Pt]) or room temperature (for [Au]) for 20 h. Solvent
was removed under reduced pressure and the residue purified by
column chromatography (heptane/ethyl acetate) to give pyr-
rolo[3,2-c]azepin-4-ones 4a–r.
4.6. Procedure for the synthesis of (1-methyl-1H-pyrrole-2-
carbonyl)-(3-p-tolyl-prop-2-ynyl)-carbamic acid tert-butyl
ester (2q)
To a solution of compound 2o (200 mg, 0.783 mmol, 1 equiv)
and DMAP (32.3 mg, 0.159 mmol) in acetonitrile (20 mL) was added
4.8.1. 1,5-Dimethyl-8-p-tolyl-5,6-dihydro-1H-pyrrolo[3,2-c]azepin-
(Boc)2O (365
mL 1.585 mmol, 2 equiv) under an argon atmosphere.
4-one (4a). Beige powder, 76%. 1H NMR (500.13 MHz; CDCl3):
The orange suspension was stirred at room temperature overnight.
The reaction mixture was quenched with a saturated solution of
aqueous NH4Cl (50 mL) and extracted with ethyl acetate
(2ꢂ100 mL). The combined organic layer was dried over anhydrous
Na2SO4. The solvent was removed under reduced pressure and the
residue purified by column chromatography (heptane/ethyl acetate
1:1) affording the pyrrole 2q as yellow oil (271 mg, 97%).
d
¼7.14 (m, 2H); 7.09 (m, 2H); 6.73 (d, J¼2.9 Hz, 1H); 6.61 (d,
J¼2.9 Hz,1H); 6.09 (t, J¼7.5 Hz, 1H); 3.71 (d, J¼7.5 Hz, 2H, CH2); 3.15
(s, 3H, OCNCH3); 3.07 (s, 3H, NCH3); 2.35 (s, 3H, CH3). 13C NMR
(125.8 MHz, CDCl3):
d¼166.0 (CO); 137.9 (C); 137.7 (C); 136.6 (C);
131.6 (C); 129.3 (2CH); 127.4 (2CH); 124.6 (CH); 123.8 (CH); 123.5
(C); 109.6 (CH); 47.5 (CH2); 36.4 (NCH3); 35.2 (OCNCH3); 21.1 (CH3).
FT-IR (ATR, cmꢁ1): 3138, 3043, 2995, 2921, 2853, 1609, 1494, 1238,
1066, 838, 811, 730, 702, 521. GC–MS (EI, 70 eV): m/z (%): 266 (100)
[Mþ], 251 (14), 237 (48), 224 (29), 210 (29), 194 (11), 175 (20), 165
(4), 152 (9), 115 (5), 91 (3), 77 (3), 63 (3), 51 (2), 42 (11). HRMS (EI):
calcd for C17H18ON2: 266.14136; found: 266.141372.
4.6.1. (1-Methyl-1H-pyrrole-2-carbonyl)-(3-p-tolyl-prop-2-ynyl)-
carbamic acid tert-butyl ester (2q). 1H NMR (300.13 MHz; CDCl3):
d
¼7.30 (m, 2H); 7.08 (m, 2H); 6.79 (dd, J¼2.5, 1.7 Hz, 1H); 6.65 (dd,
J¼4.0, 1.7 Hz,1H); 6.10 (dd, J¼4.0, 2.5 Hz,1H); 4.65 (s, 2H, CH2); 3.86
(s, 3H, NCH3); 2.32 (s, 3H, CH3); 1.38 (s, 9H, 3 CH3). 13C NMR
4.8.2. 8-(3,4-Dimethyl-phenyl)-1,5-dimethyl-5,6-dihydro-1H-pyr-
(75.5 MHz, CDCl3):
d
¼164.3 (CO); 153.3 (CO); 138.2 (C); 131.7
rolo[3,2-c]azepin-4-one (4b). Orange powder, 75%. 1H NMR
(2CH); 129.3 (CH); 128.9 (2CH); 127.8 (C); 119.9 (C); 117.7 (CH);
107.9 (CH); 84.1 (C); 82.8 (C); 82.6 (C); 36.0 (CH3); 35.9 (CH2); 27.8
(3 CH3); 21.4 (CH3). FT-IR (ATR, cmꢁ1): 3029, 2977, 2930, 1722, 1663,
1510, 1410, 1366, 1332, 1220, 1140, 947, 816, 764, 734, 528. HRMS
(ESI, [MþNa]þ): calcd for C21H24O3N2Na: 375.16791; found:
375.1679.
(300.13 MHz; CDCl3):
d¼7.09 (d, J¼7.7 Hz,1H); 6.95 (m, 2H); 6.75 (d,
J¼2.9 Hz, 1H); 6.62 (d, J¼2.9 Hz, 1H); 6.09 (t, J¼7.4 Hz, 1H); 3.70 (d,
J¼7.4 Hz, 2H, CH2); 3.15 (s, 3H, OCNCH3); 3.08 (s, 3H, NCH3); 2.26 (s,
3H, CH3); 2.23 (s, 3H, CH3). 13C NMR (75.5 MHz, CDCl3):
d¼166.0
(CO); 137.9 (C); 137.1 (C); 136.9 (C); 136.6 (C); 131.7 (C); 129.9 (CH);
128.7 (CH); 125.0 (CH); 124.6 (CH); 123.7 (CH); 123.5 (C); 109.6
(CH); 47.5 (CH2); 36.5 (NCH3); 35.2 (OCNCH3); 19.7 (CH3); 19.5
(CH3). FT-IR (ATR, cmꢁ1): 3114, 3041, 3014, 2919, 2859, 1703, 1598,
1499, 1394, 1241, 827, 810, 729. GC–MS (EI, 70 eV): m/z (%): 280
(100) [Mþ], 264 (2), 251 (44), 238 (23), 224 (38), 208 (9), 194 (10),
180 (5), 175 (21), 165 (6), 152 (5), 132 (6), 115 (3), 96 (3), 77 (3), 63
(2), 51 (1), 42 (8). HRMS (ESI, [MþH]þ): calcd for C18H21ON2:
281.16484; found: 281.16507.
4.7. Procedure for the synthesis of 1-methyl-1H-pyrrole-2-
carboxylic acid benzyl-(3-p-tolyl-prop-2-ynyl)-amide (2r)
To a solution of product 2o (318 mg, 1.26 mmol, 1 equiv) in DMF
(30 mL) was added in three times NaH (60% dispersion in mineral
oil, 126 mg, 3.15 mmol, 2.5 equiv) at 0 ꢀC under an argon atmo-
sphere. After 1 h, benzylbromide (375 mL, 3.15 mmol, 2.5 equiv) was
then added and the yellow suspension was stirred 2 h at room
temperature. The reaction mixture was quenched with a saturated
solution of aqueous NH4Cl (50 mL) and extracted with ethyl acetate
(2ꢂ 100 mL). The combined organic layer was dried over anhydrous
Na2SO4. The solvent was removed under reduced pressure and the
residue purified by column chromatography (heptane/ethyl acetate
70:30) affording the pyrrole 2r as yellow oil (335 mg, 78%).
4.8.3. 8-(4-Methoxy-phenyl)-1,5-dimethyl-5,6-dihydro-1H-pyr-
rolo[3,2-c]azepin-4-one (4c). Brown powder, 68%. 1H NMR
(500.13 MHz; CDCl3):
d
¼7.14 (m, 2H); 6.87 (m, 2H); 6.74 (d,
J¼2.9 Hz, 1H); 6.62 (d, J¼2.9 Hz, 1H); 6.05 (t, J¼7.4 Hz, 1H); 3.80 (s,
3H, OCH3); 3.70 (d, J¼7.4 Hz, 2H, CH2); 3.15 (s, 3H, OCNCH3); 3.08 (s,
3H, NCH3). 13C NMR (75.5 MHz, CDCl3):
d
¼166.0 (C]O); 159.5 (C–O);
137.4 (C); 132.1 (C); 131.7 (C); 128.7 (2CH); 124.7 (CH); 123.6 (C);
123.1 (CH); 114.1 (2CH); 109.6 (CH); 55.3 (OCH3); 47.5 (CH2); 36.4
(NCH3); 35.3 (OCNCH3). FT-IR (ATR, cmꢁ1): 3118, 3033, 2999, 2951,
2931, 2838, 1611, 1497, 1391, 1237, 1176, 1030, 829, 730, 535. GC–MS
(EI, 70 eV): m/z (%): 282 (100) [Mþ], 267 (12), 253 (36), 240 (35),
226 (28), 210 (16), 197 (8), 182 (5), 175 (17), 147 (4), 133 (5), 121 (6),
105 (4), 89 (2), 77 (4), 63 (3), 51 (1), 42 (9). HRMS (ESI, [MþH]þ):
calcd for C17H19O2N2: 283.1441; found: 283.14447.
4.7.1. 1-Methyl-1H-pyrrole-2-carboxylic acid benzyl-(3-p-tolyl-prop-
2-ynyl)-amide (2r). Yellow syrup, 52%. 1H NMR (300.13 MHz;
CDCl3):
d
¼7.38–7.30 (m, 7H); 7.14 (m, 2H); 6.74 (dd, J¼2.6, 1.8 Hz,
1H); 6.68 (br, 1H); 6.09 (dd, J¼3.8, 2.6 Hz, 1H); 4.95 (s, 2H, CH2);
4.47 (s, 2H, CH2); 3.86 (s, 3H, NCH3); 2.37 (s, 3H, CH3). 13C NMR
(75.5 MHz, CDCl3):
d
¼163.9 (CO); 138.5 (C); 136.9 (C); 131.6 (2CH);
129.0 (2CH); 128.7 (2CH); 127.7 (br, 2CH); 127.4 (CH); 127.0 (CH);
124.6 (C); 119.5 (C); 113.1 (CH); 107.0 (CH); 84.4 (br, C^C); 83.7
(C^C); 36.0 (NCH3); 21.4 (CH3); not displayed: CH2, CH2. FT-IR (ATR,
cmꢁ1):3108, 3060, 3028, 2920, 2869, 1621, 1509, 1449, 1418, 1242,
1139, 976, 816, 749, 725, 696, 607, 527. GC–MS (EI, 70 eV): m/z (%):
4.8.4. 8-(4-Chloro-phenyl)-1,5-dimethyl-5,6-dihydro-1H-pyr-
rolo[3,2-c]azepin-4-one (4d). Beige powder, 54%. 1H NMR
(300.13 MHz; CDCl3):
J¼2.9 Hz, 1H); 6.63 (d, J¼2.9 Hz, 1H); 6.12 (t, J¼7.4 Hz, 1H); 3.72 (d,
d
¼7.32 (m, 2H); 7.15 (m, 2H); 6.75 (d,

3350
M. Gruit et al. / Tetrahedron 66 (2010) 3341–3352
J¼7.4 Hz, 2H, CH2); 3.16 (s, 3H, OCNCH3); 3.08 (s, 3H, NCH3). 13C
2905, 1710, 1603, 1499, 1269, 1176, 1100, 1019, 775, 732, 709. GC–MS
(EI, 70 eV): m/z (%): 324 (100) [Mþ], 295 (52), 279 (9), 267 (22), 254
(9), 222 (4), 210 (15), 194 (5), 175 (24), 152 (8), 139 (5), 89 (2), 77 (2),
63 (2), 42 (8). HRMS (ESI, [MþH]þ): calcd for C19H21O3N2:
325.15467; found: 325.15473.
NMR (75.5 MHz, CDCl3):
d¼165.9 (CO); 138.0 (C); 136.8 (C); 134.1
(C); 130.9 (C); 129.0 (2CH); 128.9 (2CH); 125.0 (CH); 124.9 (CH);
123.9 (C); 109.9 (CH); 47.5 (CH2); 36.6 (NCH3); 35.4 (OCNCH3). FT-IR
(ATR, cmꢁ1): 3130, 3095, 3044, 2918, 1615, 1492, 1392, 1237, 1090,
1068, 1012, 830, 818, 764, 730, 703. GC–MS (EI, 70 eV): m/z (%): 286
(100) [Mþ], 271 (10), 257 (63), 244 (29), 229 (20), 210 (8), 194 (6),
175 (28), 152 (13), 139 (8), 125 (11), 111 (4), 96 (5), 75 (4), 63 (4), 51
(2), 42 (14). HRMS (ESI, [MþH]þ): calcd for C16H16ON2Cl:
287.09457; found: 287.09467.
4.8.9. 1,5-Dimethyl-8-naphthalen-1-yl-5,6-dihydro-1H-pyrrolo[3,2-
c]azepin-4-one (4i). Brown powder, 30%. 1H NMR (300.13 MHz;
CDCl3):
d
¼7.84 (d, J¼8.6 Hz, 2H); 7.44 (m, 4H); 7.32 (m, 2H); 6.82
(d, J¼2.9 Hz, 1H); 6.50 (d, J¼2.9 Hz, 1H); 6.19 (t, J¼7.4 Hz, 1H);
3.92 (dd, J¼14.3, 7.4 Hz, 1H, CH2); 3.80 (dd, J¼14.3, 7.4 Hz, 1H,
CH2); 3.21 (s, 3H, OCNCH3); 2.72 (s, 3H, NCH3). 13C NMR
4.8.5. 1,5-Dimethyl-8-(4-trifluoromethyl-phenyl)-5,6-dihydro-1H-
pyrrolo[3,2-c]azepin-4-one (4e). Beige powder, 18%. 1H NMR
(75.5 MHz, CDCl3):
d
¼165.9 (CO); 137.3 (C); 136.5 (C); 133.6 (C);
(300.13 MHz; CDCl3):
d
¼7.62 (m, 2H); 7.35 (m, 2H); 6.78 (d,
132.4 (C); 131.3 (C); 128.8 (CH); 128.3 (CH); 127.2 (CH); 126.8
(CH); 126.1 (CH); 126.1 (CH); 125.5 (CH); 124.9 (CH); 124.8 (CH);
122.9 (C); 110.1 (CH); 47.6 (NCH2); 35.9 (NCH3); 35.5 (OCNCH3).
FT-IR (ATR, cmꢁ1): 3100, 3042, 2922, 2853, 1729, 1610, 1495,
1392, 1241, 1071, 804, 778, 728. GC–MS (EI, 70 eV): m/z (%): 302
(100) [Mþ], 287 (9), 273 (25), 260 (15), 244 (13), 230 (8), 217 (7),
202 (8), 189 (9), 175 (14), 161 (9), 141 (4), 128 (3), 101 (3), 77 (1),
63 (1), 42 (7). HRMS (ESI, [MþH]þ): calcd for C20H19ON2:
303.14919; found: 303.14917.
J¼2.9 Hz, 1H); 6.66 (d, J¼2.9 Hz, 1H); 6.20 (t, J¼7.5 Hz, 1H); 3.76 (d,
J¼7.5 Hz, 2H, CH2); 3.17 (s, 3H, OCNCH3); 3.07 (s, 3H, NCH3). 13C
NMR (75.5 MHz, CDCl3):
d
¼165.8 (CO); 143.0 (C); 136.8 (C); 130.7
(C); 130.3 (q, JC,F¼33.0 Hz, C–CF3); 127.8 (2CH); 126.1 (CH); 125.7 (q,
JC,F¼3.9 Hz, 2CH); 125.1 (CH); 124.1 (q, JC,F¼274 Hz, CF3); 123.8 (C);
110.1 (CH); 47.5 (CH2); 36.6 (NCH3); 35.5 (OCNCH3). FT-IR (ATR,
cmꢁ1): 3108, 2957, 2923, 2854, 1733, 1678, 1599, 1496, 1355, 1263,
1240, 1070, 956, 842, 734, 605, 593. GC–MS (EI, 70 eV): m/z (%): 320
(100) [Mþ], 291 (72), 278 (29), 263 (24), 248 (8), 209 (3), 175 (21),
147 (5), 125 (9), 75 (2), 63 (3), 42 (9). HRMS (ESI, [MþH]þ): calcd for
C17H16ON2F: 321.12092; found: 321.12099.
4.8.10. 8-Benzofuran-2-yl-1,5-dimethyl-5,6-dihydro-1H-pyrrolo[3,2-
c]azepin-4-one (4j). Beige powder, 33%. 1H NMR (300.13 MHz;
CDCl3):
d
¼7.56 (m, 2H); 7.54 (m, 2H); 7.27 (m, 3H); 6.78 (d,
4.8.6. 4-(1,5-Dimethyl-4-oxo-1,4,5,6-tetrahydro-pyrrolo[3,2-c]aze-
J¼2.9 Hz, 1H); 6.72 (d, J¼2.9 Hz, 1H); 6.65 (s, 1H); 6.63 (t, J¼7.6 Hz,
pin-8-yl)-benzonitrile (4f). Yellow powder, 17%. 1H NMR
1H); 3.78 (d, J¼7.6 Hz, 1H, CH2); 3.37 (s, 3H, OCNCH3); 3.18 (s, 3H,
(300.13 MHz; CDCl3):
d
¼7.65 (m, 2H); 7.34 (m, 2H); 6.77 (d,
NCH3). 13C NMR (75.5 MHz, CDCl3):
d¼165.8 (C]O); 154.7 (CO);
J¼2.9 Hz, 1H); 6.67 (d, J¼2.9 Hz, 1H); 6.23 (t, J¼7.4 Hz, 1H); 3.77 (d,
153.8 (CO); 129.4 (C); 128.5 (C); 127.2 (C); 125.6 (CH); 125.2 (CH);
124.9 (CH); 124.0 (C); 123.2 (CH); 121.2 (CH); 111.3 (CH); 110.1
(CH); 105.3 (CH); 47.2 (NCH2); 36.0 (NCH3); 35.4 (OCNCH3). FT-IR
(ATR, cmꢁ1): 3108, 3052, 3013, 1950, 1922, 1613, 1496, 1450, 1392,
1253, 1240, 975, 861, 821, 731, 613. GC–MS (EI, 70 eV): m/z (%):
292 (100) [Mþ], 275 (35), 263 (18), 250 (23), 220 (8), 199 (5), 165
(4), 152 (4), 131 (3), 115 (2), 96 (2), 77 (2), 63 (3), 42 (8). HRMS
(ESI, [MþH]þ): calcd for C18H17O2N2: 293.12845; found:
293.12852.
J¼7.4 Hz, 2H, CH2); 3.17 (s, 3H, OCNCH3); 3.07 (s, 3H, NCH3). 13C
NMR (75.5 MHz, CDCl3):
d
¼165.7 (CO); 144.0 (C); 136.4 (C); 132.6
(2CH); 130.1 (C); 128.1 (2CH); 126.8 (CH); 125.2 (CH); 124.2 (C);
118.4 (C); 111.8 (C); 110.1 (CH); 47.4 (CH2); 36.5 (NCH3); 35.4
(OCNCH3). FT-IR (ATR, cmꢁ1): 3108, 3035, 2923, 2226, 1731, 1599,
1496, 1393, 1239, 1070, 854, 826, 733, 607, 568, 543. GC–MS (EI,
70 eV): m/z (%): 277 (100) [Mþ], 262 (12), 248 (74), 235 (32), 220
(23), 205 (14), 192 (11), 175 (25), 164 (7), 151 (6), 140 (7), 127 (2), 96
(3), 76 (2), 63 (3), 51 (2), 42 (13). HRMS (ESI, [MþH]þ): calcd for
C17H16ON3: 278.12879; found: 278.12866.
4.8.11. 8-Furan-2-yl-1,5-dimethyl-5,6-dihydro-1H-pyrrolo[3,2-c]aze-
pin-4-one (4k). Brown powder, <10%. 1H NMR (500.13 MHz;
4.8.7. 8-(4-Acetyl-phenyl)-1,5-dimethyl-5,6-dihydro-1H-pyrrolo[3,2-
CDCl3):
d
¼7.42 (dd, J¼1.9, 0.9 Hz,1H); 6.74 (d, J¼2.8 Hz,1H); 6.68 (d,
c]azepin-4-one (4g). Yellow powder, 58%. 1H NMR (500.13 MHz;
J¼2.8 Hz, 1H); 6.44 (dd, J¼3.3, 1.9 Hz, 1H); 6.36 (t, J¼7.5 Hz, 1H);
CDCl3):
d
¼7.95 (m, 2H); 7.32 (m, 2H); 6.77 (d, J¼2.9 Hz, 1H); 6.66 (d,
6.32 (dd, J¼3.3, 0.9 Hz, 1H); 3.72 (d, J¼7.5 Hz, 1H, CH2); 3.31 (s, 3H,
J¼2.9 Hz, 1H); 6.23 (t, J¼7.4 Hz, 1H); 3.76 (d, J¼7.4 Hz, 2H, CH2); 3.17
OCNCH3); 3.17 (s, 3H, NCH3). 13C NMR (125.8 MHz, CDCl3):
d¼165.9
(s, 3H, OCNCH3); 3.07 (s, 3H, NCH3); 2.61 (s, 3H, COCH3). 13C NMR
(CO); 151.9 (CO); 142.4 (CH); 129.9 (C); 127.2 (C); 125.0 (CH); 123.6
(C); 122.9 (CH); 111.5 (CH); 109.9 (CH); 108.7 (CH); 47.1 (NCH2);
35.6 (NCH3); 35.4 (OCNCH3). FT-IR (ATR, cmꢁ1): 3111, 2922, 2852,
1602, 1501, 1461, 1396, 1241, 1095, 1016, 808, 730, 596. GC–MS (EI,
70 eV): m/z (%): 242 (100) [Mþ], 227 (3), 213 (96), 200 (20),185 (44),
170 (19), 156 (8), 144 (16), 130 (7), 115 (11), 103 (4), 89 (6), 77 (6), 63
(6), 51 (6), 42 (17), 32 (6). HRMS (ESI, [MþH]þ): calcd for
C14H15O2N2: 243.1128; found: 243.11264.
(125.8 MHz, CDCl3):
d
¼197.4 (CH3CO); 165.8 (CO); 144.2 (C); 137.0
(C); 136.6 (C); 130.7 (C); 128.8 (2CH); 127.7 (2CH); 126.1 (CH); 125.0
(CH); 124.0 (C); 110.0 (CH); 47.5 (CH2); 36.5 (NCH3); 35.4 (OCNCH3);
26.6 (COCH3). FT-IR (ATR, cmꢁ1): 3110, 3062, 3042, 2994, 2923,
1679, 1600, 1498, 1398, 1356, 1265, 1242, 957, 825, 736, 606. GC–MS
(EI, 70 eV): m/z (%): 294 (100) [Mþ], 265 (47), 252 (15), 237 (13), 220
(2), 210 (20), 194 (6), 175 (22), 167 (6), 152 (8), 125 (3), 89 (2), 77 (2),
63 (3), 42 (10). HRMS (ESI, [MþH]þ): calcd for C18H19O2N2:
295.1441; found: 295.14414.
4.8.12. 1,5-Dimethyl-8-thiophen-2-yl-5,6-dihydro-1H-pyrrolo[3,2-
c]azepin-4-one (4l). Brown powder, 29%. 1H NMR (500.13 MHz;
4.8.8. 4-(1,5-Dimethyl-4-oxo-1,4,5,6-tetrahydro-pyrrolo[3,2-c]aze-
CDCl3):
d
¼7.26 (dd, J¼5.0, 1.0 Hz, 1H); 7.01 (dd, J¼5.0, 3.5 Hz, 1H);
pin-8-yl)-benzoic acid ethyl ester (4h). Brown powder, 30%. 1H NMR
6.86 (dd, J¼3.5, 1.0 Hz, 1H); 6.75 (d, J¼2.8 Hz, 1H); 6.66 (d, J¼2.8 Hz,
(300.13 MHz; CDCl3):
d
¼8.02 (m, 2H); 7.29 (m, 2H); 6.76 (d,
1H); 6.23 (t, J¼7.3 Hz, 1H); 3.70 (d, J¼7.3 Hz, 1H, CH2); 3.25 (s, 3H,
J¼2.9 Hz, 1H); 6.65 (d, J¼2.9 Hz, 1H); 6.21 (t, J¼7.4 Hz, 1H); 4.37 (q,
J¼7.1 Hz, 2H, OCH2); 3.75 (d, J¼7.4 Hz, 2H, NCH2); 3.17 (s, 3H,
OCNCH3); 3.05 (s, 3H, NCH3); 1.39 (t, J¼7.1 Hz, 3H, CH3). 13C NMR
OCNCH3); 3.17 (s, 3H, NCH3). 13C NMR (125.8 MHz, CDCl3):
d¼165.9
(CO); 141.7 (CS); 131.2 (C); 130.7 (C); 127.6 (CH); 126.3 (CH); 125.5
(CH); 125.2 (CH); 124.4 (CH); 123.5 (C); 109.9 (CH); 47.4 (NCH2);
36.3 (NCH3); 35.4 (OCNCH3). FT-IR (ATR, cmꢁ1): 3430, 3100, 3068,
2923, 1710, 1608, 1495, 1391, 1239, 1067, 833, 809, 728, 695. GC–MS
(EI, 70 eV): m/z (%): 258 (100) [Mþ], 243 (7), 229 (28), 216 (28), 202
(28), 186 (10), 173 (7), 161 (4), 147 (5), 133 (3), 115 (5), 97 (3), 77 (3),
(75.5 MHz, CDCl3):
d¼166.1 (CO); 165.8 (CO); 143.9 (C); 137.1 (C);
130.7 (C); 130.1 (C); 130.0 (2CH); 127.5 (2CH); 125.9 (CH); 124.9
(CH); 123.9 (C); 109.9 (CH); 61.1 (OCH2); 47.4 (NCH2); 36.5 (NCH3);
35.4 (OCNCH3); 14.3 (CH3). FT-IR (ATR, cmꢁ1): 3112, 2957, 2927,

M. Gruit et al. / Tetrahedron 66 (2010) 3341–3352
3351
63 (3), 42 (10). HRMS (ESI, [MþH]þ): calcd for C14H15ON2S:
(5), 152 (3), 134 (5), 125 (3), 105 (3), 91 (2), 77 (2), 65 (1), 42 (2).
HRMS (ESI, [MþH]þ): calcd for C23H23ON2: 267.14919; found:
267.14911.
259.08996; found: 259.08993.
4.8.13. 1-Methyl-8-p-tolyl-5,6-dihydro-1H-pyrrolo[3,2-c]azepin-4-
one (4o). Beige powder, 40%. 1H NMR (300.13 MHz; CDCl3):
(m, 4H); 6.77 (d, J¼2.9 Hz, 1H); 6.66 (d, J¼2.9 Hz, 1H); 6.34 (t,
JNH,CH¼5.5 Hz, 1H); 6.06 (t, J¼7.4 Hz, 1H); 3.59 (dd, J¼7.4, 5.5 Hz, 2H,
CH2); 3.09 (s, 3H, NCH3); 2.36 (s, 3H, CH3). 13C NMR (75.5 MHz,
d
¼7.12
Acknowledgements
This work has been funded by the State of Mecklenburg–
Western Pomerania, the BMBF, and the DFG (Leibniz Prize). We
thank Drs. W. Baumann, C. Fischer, and Mrs. S. Buchholz, Mrs. S.
Schareina, Mrs. A. Lehmann and Mrs. K. Mevius (all LIKAT) for their
excellent analytical support and acknowledge discussions with Dr.
Michael Arlt (Merck KGaA) at the start of this project.
CDCl3):
d
¼164.1 (CO); 137.9 (C); 137.6 (C); 136.9 (C); 131.0 (C); 129.5
(2CH); 127.4 (2CH); 125.3 (CH); 124.9 (C); 124.9 (CH); 109.5 (CH);
38.8 (CH2); 36.6 (NCH3); 21.2 (CH3). FT-IR (ATR, cmꢁ1): 3246, 3160,
3108, 3023, 2949, 2917,1631,1496, 1460,1439,1274,1198,1087, 928,
816, 733, 519. GC–MS (EI, 70 eV): m/z (%): 252 (100) [Mþ], 237 (28),
224 (23), 209 (28), 194 (9), 180 (8), 161 (10), 152 (7), 133 (5), 115 (4),
104 (3), 91 (2), 77 (2), 63 (2), 51 (1), 42 (2). HRMS (ESI, [MþH]þ):
calcd for C16H17ON2: 253.13354; found: 253.13348.
References and notes
1. (a) Wan, Y.; Hur, W.; Cho, C. Y.; Liu, Y.; Adrian, F. J.; Lozach, O.; Bach, S.;
Meijer, T.; Gray, N. S. Chem. Biol. 2004, 11, 247–259; (b) Cimino, G.; De Rosa,
S.; De Stephano, S.; Mazzarella, L.; Puliti, R.; Sodano, G. Tetrahedron Lett.
1982, 23, 767–768.
2. (a) Eder, C.; Proksch, P.; Wray, V.; Steube, K.; Bringmann, G.; Van Soest, R. W. M.;
Sudarsono, S.; Ferdinandus, E.; Pattisina, L. A.; Wiryowidagdo, S.; Moka, W.
J. Nat. Prod. 1999, 62, 184–187; (b) Marchais, S.; Al Mourabit, A.; Ahond, A.;
Poupat, C.; Potier, P. Tetrahedron Lett. 1999, 40, 5519–5522.
3. Linington, R. G.; Williams, D. E.; Tahir, A.; Van Soest, R. W. M.; Andersen, R. J.
Org. Lett. 2003, 5, 2735–2738.
4. Schultz, C.; Link, A.; Leost, M.; Zaharevitz, D. W.; Gussio, R.; Sausville, A. A.;
Meijer, L.; Kunick, C. J. Med. Chem. 1999, 42, 2909–2919.
5. (a) Tasdemir, D.; Mallon, R.; Greenstein, M.; Feldberg, L. R.; Kim, S. C.; Collins,
K.; Wojciechowicz, D.; Mangalindan, G. C.; Concepcion, G. P.; Harper, M. K.;
Ireland, C. M. J. Med. Chem. 2002, 45, 529–532; (b) Meijer, L.; Thunnissen, A. M.;
White, A. W.; Garnier, M.; Nikolic, M.; Tsai, L. H.; Walter, J.; Cleverley, K. E.;
Salinas, P. C.; Wu, Y. Z.; Biernat, J.; Mandelkow, E. M.; Kim, S. H.; Pettit, G. R.
Chem. Biol. 2000, 7, 51–63; (c) Cowan-Jacob, S. W.; Mo¨bitz, H.; Fabbro, D. Curr.
Opin. Cell Biol. 2009, 21, 280–287; (d) Chen, P. Nat. Rev. Drug Discov. 2002, 1,
309–315.
4.8.14. 5-Methyl-8-p-tolyl-5,6-dihydro-1H-pyrrolo[3,2-c]azepin-4-
one (4p). Brown powder, 35%.1H NMR (500.13 MHz; CDCl3):
d
¼8.17
(br, 1H, NH); 7.21 (m, 4H); 6.85 (‘t’, JCH,CH¼JNH,CH¼2.8 Hz, 1H); 6.79
(‘t’, JCH,CH¼JNH,CH¼2.8 Hz, 1H); 6.07 (t, J¼7.1 Hz, 1H); 3.79 (d,
J¼7.1 Hz, 2H, CH2); 3.17 (s, 3H, OCNCH3); 2.38 (s, 3H, CH3). 13C NMR
(125.8 MHz, CDCl3):
d¼166.0 (CO); 138.6 (C); 138.2 (C); 135.4 (C);
131.2 (C); 129.6 (2CH); 128.4 (2C H); 122.2 (C); 121.6 (CH); 118.6
(CH); 111.6 (CH); 47.6 (CH2); 35.5 (NCH3); 21.2 (CH3). FT-IR (ATR,
cmꢁ1): 3260, 3198, 3046, 3022, 2960, 2921, 2853, 1598, 1491, 1391,
1259, 1081, 1021, 876, 798, 746, 693, 606, 513. GC–MS (EI, 70 eV):
m/z (%): 252 (100) [Mþ], 237 (10), 223 (34), 210 (27), 196 (15), 180
(9), 167 (11), 161 (8), 152 (7), 139 (4), 115 (4), 96 (3), 77 (2), 63 (2), 51
(1), 42 (4). HRMS (ESI, [MþH]þ): calcd for C16H17ON2: 253.13354;
found: 253.13353.
6. Bridges, A. J. Chem. Rev. 2001, 101, 2541–2571.
7. Sharma, V.; Lansdell, V. A.; Jin, G.; Tepe, J. J. J. Med. Chem. 2004, 47, 3700–3703.
8. For other work on this motif see: (a) Mangu, N.; Kaiser, H. M.; Kar, A.; Span-
nenberg, A.; Beller, M.; Tse, M. K. Tetrahedron 2008, 64, 7171–7177; (b) Kaiser,
H. M.; Zenz, I.; Lo, W. F.; Spannenberg, A.; Schro¨der, K.; Jiao, H.; Go¨rdes, D.;
Beller, M.; Tse, M. K. J. Org. Chem. 2007, 72, 8847–8858; (c) Kaiser, H. M.; Lo,
W. F.; Riahi, A. M.; Spannenberg, A.; Beller, M.; Tse, M. K. Org. Lett. 2006, 8,
5761–5764.
4.8.15. 1-Methyl-4-oxo-8-p-tolyl-4,6-dihydro-1H-pyrrolo[3,2-c]aze-
pine-5-carboxylic acid tert-butyl ester (4q). Brown solid, 10%. 1H
NMR (500.13 MHz; CDCl3):
6.63 (d, J¼2.9 Hz, 1H); 6.30 (t, J¼7.4 Hz, 1H); 4.73, 3.72 (2br s, 2H,
CH2); 3.08 (s, 3H, NCH3); 2.37 (s, 3H, CH3); 1.52 (s, 9H, 3 CH3). 13
NMR (125.8 MHz, CDCl3):
d
¼7.16 (m, 4H); 6.84 (d, J¼2.9 Hz, 1H);
C
´
9. (a) Parmentier, J.-G.; Portevin, B.; Golsteyn, R. M.; Pierre, A.; Hickman, J.;
d
¼164.9 (CO); 152.2 (CO); 138.2 (C); 137.9
Gloanec, P.; De Nanteuil, G. Bioorg. Med. Chem. Lett. 2009, 19, 841–844; (b) He,
Q.; Chen, W.; Qin, Y. Tetrahedron Lett. 2007, 48, 1899–1901; (c) Papeo, G.; Pos-
teri, H.; Borghi, D.; Varasi, M. Org. Lett. 2005, 7, 5641–5644; (d) Chacun-Lefe`vre,
L.; Joseph, B.; Me´rour, J.-M. Tetrahedron 2000, 56, 4491–4499.
(C); 136.5 (C); 132.2 (C); 129.5 (2CH); 127.4 (2CH); 126.7 (CH); 125.0
(CH); 123.1 (C); 111.3 (CH); 82.6 (C); 42.8 (CH2); 36.9 (NCH3); 28.1
(3CH3); 21.2 (CH3). FT-IR (ATR, cmꢁ1): 3138, 3115, 3057, 3033, 2962,
2921, 2851, 1707, 1666, 1329, 1259, 1239, 1152, 1076, 1019, 790, 743,
702. HRMS (ESI, [MþH]þ): calcd for C21H25O3N2: 353.18597; found:
353.18596.
10. (a) Cincinelli, R.; Dallavalle, S.; Merlini, L.; Nannei, R.; Scaglioni, L. Tetrahedron
2009, 65, 3465–3472; (b) Xu, Y.-Z.; Yakushijin, K.; Horne, D. A. J. Org. Lett. 1997,
62, 456–464.
11. (a) Donets, P. A.; Van der Eycken, E. V. Org. Lett. 2007, 9, 3017–3020; (b) Putey,
A.; Joucla, L.; Picot, L.; Besson, T.; Joseph, B. Tetrahedron 2007, 63, 867–879; (c)
Joucla, L.; Putey, A.; Joseph, B. Tetrahedron Lett. 2005, 46, 8177–8179.
12. Piras, L.; Genesio, E.; Ghiron, C.; Taddei, M. Eur. J. Org. Chem. 2008, 2789–2800.
13. (a) Fu¨ rstner, A.; Davies, P. W. Angew. Chem., Int. Ed. 2007, 46, 3410–3449; Angew.
Chem. 2007, 119, 3478–3519; (b) Hashmi, A. S. K.; Kurpejovic, E.; Frey, W.; Bats,
J. W. Tetrahedron 2007, 63, 5879–5885; (c) Hashmi, A. S. K. Chem. Rev. 2007, 107,
3180–3211; (d) Fu¨rstner, A.; Kennedy, J. W. J. Chem.dEur. J. 2006, 12, 7398–
7410; (e) Furstner, A.; Mamane, V.; Seidel, G.; Laurich, D. Org. Synth. 2006, 83,
103; (f) Nevado, C.; Echavarren, A. M. Chem.dEur. J. 2005, 11, 3155–3164; (g)
Nevado, C.; Echavarren, A. M. Synthesis 2005, 2, 167–182; (h) Mamane, V.;
Hannen, P.; Fu¨rstner, A. Chem.dEur. J. 2004, 10, 4556–4575; (i) Pastine, S. J.;
Youn, S. W.; Sames, D. Org. Lett. 2003, 5, 1055–1058; (j) Fu¨rstner, A.; Mamane, V.
Chem. Commun. 2003, 2112–2113; (k) Fu¨ rstner, A.; Mamane, V. J. Org. Chem.
2002, 67, 6264–6267.
4.8.16. 5-Benzyl-1-methyl-8-p-tolyl-5,6-dihydro-1H-pyrrolo[3,2-
c]azepin-4-one (4r). Brown powder, 68%. 1H NMR (300.13 MHz;
CDCl3):
d
¼7.27 (m, 5H); 7.12 (m, 4H); 6.82 (d, J¼2.9 Hz, 1H); 6.65 (d,
J¼2.9 Hz, 1H); 6.0 (t, J¼7.4 Hz, 1H); 4.79 (s, 2H, CH2); 3.66 (d,
J¼7.4 Hz, 2H, CH2); 3.08 (s, 3H, NCH3); 2.36 (s, 3H, CH3). 13C NMR
(75.5 MHz, CDCl3):
d¼166.1 (CO); 138.4 (C); 137.9 (C); 137.7 (C);
136.7 (C); 131.7 (C); 129.4 (2C H); 128.5 (2CH); 128.0 (2CH); 127.5
(2CH); 127.2 (CH); 124.7 (CH); 124.5 (CH); 123.2 (C); 110.0 (CH);
50.6 (CH2); 45.0 (CH2); 36.6 (NCH3); 21.2 (CH3). FT-IR (ATR, cmꢁ1):
3109, 3059, 3027, 2955, 2922, 2855, 1602, 1495, 1452, 1427, 1409,
1244, 1080, 816, 730, 697. GC–MS (EI, 70 eV): m/z (%): 342 (16) [Mþ],
251 (20), 238 (100), 224 (23), 209 (11), 194 (8), 181 (5), 165 (3), 152
(6), 129 (3), 115 (3), 91 (15), 77 (3), 63 (4), 42 (3). HRMS (ESI,
[MþH]þ): calcd for C23H23ON2: 343.18049; found: 343.18066.
14. (a) Lu, Y.; Du, X.; Jia, X.; Liu, Y. Adv. Synth. Catal. 2009, 351, 1517–1522; (b)
Buchgraber, P.; Domostoj, M. M.; Scheiper, B.; Wirtz, C.; Mynott, R.; Rust, J.;
Fu¨rstner, A. Tetrahedron 2009, 65, 6519–6534.
´
´ ˜
15. (a) Jimenez-Nunez, E.; Raducan, M.; Lauterbach, T.; Molawi, K.; Solorio, C. R.;
Echavarren, A. Angew. Chem., Int. Ed. 2009, 48, 6152–6155; Angew. Chem. 2009,
121, 6268–6271; (b) Hashmi, A. S. K.; Loos, A.; Littmann, A.; Braun, I.; Knight, J.;
Doherty, S.; Rominger, F. Adv. Synth. Catal. 2009, 351, 576–582; (c) Jime´nez-
Nu´ n˜ez, E.; Echavarren, A. Chem. Rev. 2008, 108, 3326–3350; (d) Hashmi, A. S. K.;
Rudolph, M.; Bats, J. W.; Frey, W.; Rominger, F.; Oeser, T. Chem.dEur. J. 2008, 14,
6672–6678; (e) Fu¨ rstner, A.; Morency, L. Angew. Chem., Int. Ed. 2008, 47, 5030–
5033; Angew. Chem. 2008, 120, 5108–5111; (f) Fu¨ rstner, A.; Heimann, E. K.;
Davies, P. W. Angew. Chem., Int. Ed. 2007, 46, 4760–4763; Angew. Chem. 2007,
119, 4844–4847; (g) Hashmi, A. S. K.; Blanco, M. C.; Kurpejovic, E.; Frey, W.;
Bats, J. W. Adv. Synth. Catal. 2006, 348, 709–713; (h) Hashmi, A. S. K.; Haufe, B.;
Schmid, C.; Rivas Nass, N.; Frey, W. Chem.dEur. J. 2006, 12, 5376–5382; (i)
4.8.17. 1,6-Dimethyl-4-(4-methyl-benzyl)-1,6-dihydro-pyrrolo[2,3-
c]pyridin-7-one (5a). 1H NMR (500.13 MHz; CDCl3):
d¼7.71 (d,
J¼8.2 Hz, 2H); 7.14 (m, 2H); 6.91 (d, J¼2.9 Hz, 1H); 6.59 (s, 1H); 6.14
(d, J¼2.9 Hz, 1H); 4.15 (s, 3H, NCH3); 3.86 (s, 2H, CH2); 3.55 (s, 3H,
CONCH3); 2.33 (s, 3H, CH3). GC–MS (EI, 70 eV): m/z (%): 366 (100)
[Mþ], 251 (11), 237 (7), 224 (3), 209 (3), 194 (3),180 (4),175 (18),161

3352
M. Gruit et al. / Tetrahedron 66 (2010) 3341–3352
Bruneau, C. Angew. Chem., Int. Ed. 2005, 44, 2328–2334; Angew. Chem. 2005, 117,
2380–2386.
4528; (k) Khedkar, V.; Tillack, A.; Michalik, M.; Beller, M. Tetrahedron 2005, 61,
7622–7631; (l) Khedkar, V.; Tillack, A.; Michalik, M.; Beller, M. Tetrahedron Lett.
2004, 45, 3123–3126; (m) Kumar, K.; Michalik, D.; Castro, I. G.; Tillack, A.; Zapf,
A.; Arlt, M.; Heinrich, T.; Bo¨ttcher, H.; Beller, M. Chem.dEur. J. 2004, 10, 746–757.
20. Gruit, M.; Michalik, D.; Tillack, A.; Beller, M. Angew. Chem., Int. Ed. 2009, 48,
7212–7216; Angew. Chem. 2009, 121, 7348–7352.
21. (a) La Regina, G.; Silvestri, R.; Artico, M.; Lavecchia, A.; Novellino, E.; Befani, O.;
Turini, P.; Agostinelli, E. J. Med. Chem. 2007, 50, 922–931; (b) Silvestri, R.; La
Regina, G.; De Martino, G.; Artico, M.; Befani, O.; Palumbo, M.; Agostinelly, E.;
Turini, P. J. Med. Chem. 2003, 46, 917–920; (c) Huang, F.-C.; Chan, W.-K.; Warus,
J. D.; Morrissette, M. M.; Moriarty, K. J.; Chang, M. N.; Travis, J. J.; Mitchell, L. S.;
Nuss, G. W.; Sutherland, C. A. J. Med. Chem. 1992, 35, 4253–4255.
16. (a) Yu, Z.-X.; Cheong, P. H.-Y.; Liu, P.; Legault, C. Y.; Wender, P. A.; Houk, K. N.
J. Am. Chem. Soc. 2008, 130, 2378–2379; (b) Fu¨rstner, A.; Majima, K.; Martin, R.;
Krause, H.; Kattnig, E.; Goddard, R.; Lehmann, C. W. J. Am. Chem. Soc. 2008, 130,
1992–2004; (c) Yeh, M.-C. P.; Tsao, W.-C.; Lee, B.-J.; Lin, T.-L. Organometallics
2008, 27, 5326–5332; (d) Bruneau, C.; Dixneuf, P. H. Angew. Chem., Int. Ed. 2006,
45, 2171–2203; Angew. Chem. 2006, 118, 2232–2260.
17. (a) Ferrer, C.; Amijs, C. H. M.; Echavarren, A. M. Chem.dEur. J. 2007, 13, 1358–
1373; (b) Ferrer, C.; Echavarren, A. M. Angew. Chem., Int. Ed. 2006, 45, 1105–
1109; Angew. Chem. 2006, 118, 1123–1127.
18. England, D. B.; Padwa, A. Org. Lett. 2008, 10, 3631–3634.
19. (a) Kru¨ger, K.; Tillack, A.; Beller, M. Chem. Sus. Chem. 2009, 2, 715–717; (b)
Schwarz, N.; Pews-Davtyan, A.; Michalik, D.; Alex, K.; Tillack, A.; Diaz, J. L.;
Beller, M. Eur. J. Org. Chem. 2008, 32, 5425–5435; (c) Alex, K.; Schwarz, N.;
22. (a) Elangovan, A.; Wang, Y.-H.; Ho, T.-I. Org. Lett. 2003, 5, 1841–1844; (b)
Nomak, R.; Snyder, J. K. Tetrahedron Lett. 2001, 42, 7929–7933.
23. (a) Hashmi, A. S. K.; Weyrauch, J. P.; Kurpejovic, E.; Frost, T. M.; Miehlich, B.;
Frey, W.; Bats, J. W. Chem.dEur. J. 2006, 12, 5806–5814; (b) Hashmi, A. S. K.;
Rudolph, M.; Weyrauch, J. P.; Wo¨lfle, M.; Frey, W.; Bats, J. W. Angew. Chem., Int.
Ed. 2005, 44, 2798–2801; Angew. Chem. 2005, 117, 2858–2861.
24. Hudlicky, T.; Rinner, U.; Finn, K. J.; Ghiviriga, I. J. Org. Chem. 2005, 70, 3490–
3499.
25. (a) Zanardi, F.; Curti, C.; Sartori, A.; Rassu, G.; Roggio, A.; Battistini, L.; Burreddu,
P.; Pinna, L.; Pelosi, G.; Casiraghi, G. Eur. J. Org. Chem. 2008, 2273–2287; (b)
Yoshida, M.; Komatsuzaki, Y.; Ihara, M. Org. Lett. 2008, 10, 2083–2086; (c) Adler,
´
Khedkar, V.; Sayyed, I. A.; Tillack, A.; Michalik, D.; Holenz, J.; Dıaz, J. L.; Beller, M.
Org. Biomol. Chem. 2008, 6, 1802–1807; (d) Alex, K.; Tillack, A.; Schwarz, N.;
Beller, M. Angew. Chem., Int. Ed. 2008, 47, 2304–2307; Angew. Chem. 2008, 120,
2337–2340; (e) Alex, K.; Tillack, A.; Schwarz, N.; Beller, M. Org. Lett. 2008, 10,
2377–2379; (f) Sayyed, I. A.; Alex, K.; Tillack, A.; Schwarz, N.; Spannenberg, A.;
Michalik, D.; Beller, M. Tetrahedron 2008, 64, 4590–4595; (g) Pews-Davtyan, A.;
Tillack, A.; Ortinau, S.; Rolfs, A.; Beller, M. Org. Biomol. Chem. 2008, 6, 992–997;
(h) Schwarz, N.; Tillack, A.; Alex, K.; Sayyed, I. A.; Jackstell, R.; Beller, M. Tet-
rahedron Lett. 2007, 48, 2897–2900; (i) Schwarz, N.; Pews-Davtyan, A.; Alex, K.;
Tillack, A.; Beller, M. Synthesis 2007, 3722–3730; (j) Sayyed, I. A.; Alex, K.;
Tillack, A.; Schwarz, N.; Michalik, D.; Beller, M. Eur. J. Org. Chem. 2007, 4525–
´
T.; Bonjoch, J.; Clayden, J.; Font-Bardia, M.; Pickworth, M.; Solans, X.; Sole, D.;
Vallverdu, L. Org. Biomol. Chem. 2005, 3, 3173–3183.
26. Sheldrick, G. M. Acta Crystallogr. 2008, 64, 112–122.