Platinum-catalyzed intramolecular cyclizations of alkynes: efficient synthesis of pyrroloazepinone derivatives

Full text of DOI:10.1002/anie.200902937

Communications
DOI: 10.1002/anie.200902937
Catalytic Cycloisomerization
Platinum-Catalyzed Intramolecular Cyclizations of Alkynes: Efficient
Synthesis of Pyrroloazepinone Derivatives**
Marina Gruit, Dirk Michalik, Annegret Tillack, and Matthias Beller*
Dedicated to Professor Hans Jꢀrgen Wernicke on the occasion of his 60th birthday
Transition-metal-catalyzed cyclizations of aromatic and het-
eroaromatic compounds with alkynes have attracted much
attention in the last decade. In particular, intramolecular
gold- and platinum-catalyzed hydroarylations,[1] cycloisome-
rizations,[2] and cycloadditions[3] offer new ways for the
efficient construction of biologically interesting carbo- and
heterocycles. Recent elegant examples also include the use of
N-heterocycles; for example, Echavarren et al.[4] and England
and Padwa[5] reported intramolecular cyclizations of indol
derivatives in the presence of gold catalysts. Inspired by this
work and our interest in the application of catalytic coupling
and amination reactions for the synthesis of bio-active
compounds,[6] we started a program on the catalytic synthesis
of novel pyrroloazepinone derivatives.
preparation of Latonduine derivatives in five steps with a
intramolecular Heck reaction as the key step.[17] In addition,
Taddei et al. synthesized (pyrroloazepinyl)acetamides by a
Beckmann rearrangement.[18]
Our initial investigations aimed at the straightforward
synthesis of the pyrrolo[2,3-c]azepin-8-one 3a (Scheme 2).
N,N’-Dimethyl-N-(prop-2-ynyl)-1H-pyrrole-2-carboxamide
The pyrroloazepinone motif (Scheme 1)[7] is present in a
variety of natural and pharmaceutical products, such as
hymenialdisine,[8] stevensine,[9] latonduine,[10] and the paul-
Scheme 1. Planned formation of pyrroloazepinones from propargyl-
amide-substituted pyrroles.
Scheme 2. Synthesis of pyrroloazepinones 3a and 4a.
lones.[11] From a biological point of view, pyrroloazepinones
have been found to selectively inhibit a number of different
kinases and cytokines.[12–14] Therefore, these kinase inhibitors
have emerged as promising therapeutic molecules for treat-
ment of a range of diseases, including cancer.[13,15] Some of the
pyrrole-based alkaloid intermediates were shown to have also
neuroprotective activity against the agonists serotonin and
glutamate in vivo.[16] It is thus not surprising that this class of
compounds has become an important target for organic
synthesis. For example, Joseph and co-workers reported the
(1) was formed in 91% yield by addition of N-methylpro-
pargylamine to N-methyl-1H-pyrrole-2-carboxylic acid acti-
vated by 4-(dimethylamino)pyridine and 1,1’-carbonyldiimi-
dazole in tetrahydrofuran at 408C.[19] A subsequent palla-
dium-catalyzed Sonogashira reaction in the presence of the
[PdCl2(PPh3)2] and CuI catalyst system gave N,N’-dimethyl-
N-(3-p-tolylprop-2-ynyl)-1H-pyrrole-2-carboxamide (2a) in
73% yield.[20] The intramolecular cyclization of 2a was then
examined in the presence of different metal salts and
complexes of Au, Pt, Pd, Cu, Zn, Fe, Ru, and others. High
activity and full conversion were observed only in the
presence of AuCl3 and H2PtCl6·6H2O as catalysts.
According to the work of Echavarren et al., the best
catalyst for the formation of azepinone derivatives by an
endo-dig process should be an gold(III) complex, and the
expected product should have been the pyrrolo[2,3-c]azepin-
8-one 3a.[4] Surprisingly, an intramolecular hydroarylation
reaction gave 1,5-dimethyl-8-p-tolyl-5,6-dihydropyrrolo[3,2-
c]azepin-4-one (4a) as the major product (Scheme 2). To our
knowledge, this type of alkyne cyclization, including rear-
[*] Dr. M. Gruit, Dr. D. Michalik, Dr. A. Tillack, Prof. M. Beller
Leibniz-Institut fꢀr Katalyse e.V. an der Universitꢁt Rostock
Albert-Einstein-Strasse 29a, 18059 Rostock (Germany)
Fax: (+49)381-1281-51113
E-mail: matthias.beller@catalysis.de
Homepage: http://www.catalysis.de
[**] 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. Fisher, S. Buchholz, and S. Schareina (all LIKAT) for
their excellent analytical support, and acknowledge discussions with
Dr. Michael Arlt (Merck KgA) at the start of this project.
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Chemie
rangement of carbonyl groups, has not been previously
reported.[4,18]
The yields of products 3a and 4a varied significantly
depending on the catalysts, solvents, and reaction temper-
ature used (Table 1). H2PtCl6·6H2O and toluene as solvent
Table 1: Variation of reaction conditions in the presence of AuCl3 and
H2PtCl6·6H2O catalysts.[a]
Entry Catalyst Solvent
T [8C] Conv.[b] [%] Yield[b]
Yield[b]
3a [%] 4a [%]
1
2
3
4
5
6
7
8
9
AuCl3
AuCl3
AuCl3
AuCl3
H2PtCl6
H2PtCl6
H2PtCl6
H2PtCl6
H2PtCl6
toluene
dioxane 120
dioxane
dioxane
toluene
toluene
dioxane 120
dioxane
CH2Cl2
120
76
100
100
29
100
19
100
100
9
13
31
51
19
7
40
55
48
10
78
3
60
64
8
60
20
120
60
0
36
35
0
60
20
[a] Reaction conditions: catalyst (5 mol%), N,N’-dimethyl-N-(3-p-tolyl-
prop-2-ynyl)-1H-pyrrole-2-carboxamide (2a; 0.2 mmol), solvent (10 mL),
20 h. [b] Determined by GC with hexadecane as internal standard.
turned out to be the optimal catalyst at higher temperatures,
and product 4a is formed in 78% yield (Table 1, entry 5).
Notably, in this case only a small amount (7%) of the
originally expected cyclization isomer 3a is observed. How-
ever, in 1,4-dioxane in the presence of both gold or platinum
catalysts, the regioselectivity is low. In these cases, the
pyrroloazepinones 3a and 4a were formed in a ratio that
ranged from 1:1 to 1:2 (Table 1, entries 2, 3, 7–8).
In few cases, traces of other compounds apart from 3a and
4a and degradation products were detected in the crude
reaction mixture. Indeed, we observed pyrrolo[2,3-c]pyridin-
7-one derivatives (< 1% yield) corresponding to the product
with a six-membered ring, which was probably formed by an
6-exo-dig process.[5] A simplified proposal for the mechanism
of this novel gold- and platinum-catalyzed cycloisomerization
reaction is shown in Scheme 3.
Scheme 3. Proposed mechanism for the formation of seven-mem-
bered-ring-containing compounds 3 and 4.
different arylated substrates. Selected examples of the newly
synthesized pyrroles 2a–i and azepinones 4a–i are listed in
Table 2. The first step, the Sonogashira reaction of N-
propargylpyrrole-2-carboxamide 1 with various substituted
aryl or heteroaryl iodides and bromides proceeded smoothly
in a 1:1 mixture of tetrahydrofuran and triethylamine at 608C
in presence of [PdCl2(PPh3)2] and CuI.[19] We typically
obtained the desired pyrroles 2 in 70–80% yield. Next, the
cyclization of pyrroles 2a–i was performed using 5 mol% of
H2PtCl6·6H2O in toluene at 1208C to afford pyrrolo[3,2-
c]azepin-4-ones 4a–i with yields of isolated products between
18 and 76%. If the alkyne moiety is substituted with tolyl, o-
xylyl, anisyl, chlorophenyl, p-acetylphenyl, or naphthyl
groups, the cycloisomerization process afforded the corre-
sponding products 4a–d and 4 f,g (Table 2, entries 1–4, 6, 7) in
good yields. With trifluoromethylbenzene, benzofuran, or
thiophene substituents (Table 2, entries 5, 8, 9), the desired
coupling products were obtained in lower yields. Obviously
the electronic and steric nature of the attached aryl group
influences the reactivity; however, is no clear trend is
observed between reactivity and electronic nature of the
aryl substituent. It is important to note that in all cases, the
major cycloisomerization product was compound 4, and the
regioisomer 3 was obtained only in traces (< 5%).
In agreement with earlier reports,[1,4,5,21] we assume that
pyrrole derivative 2 is initially activated at the triple bond by
coordination to the electrophilic gold(III) or platinum(IV)
catalyst. Several modes of cycloisomerization reactions are
then possible depending on reaction conditions (Table 1 and
Scheme 3).
It appears that the pyrroloazepinone 3 is obtained by a 7-
endo-dig process from compound 2. Following the initial
activation of the triple bond, cation C is formed either directly
from intermediate A or via cation B. Subsequent protonolysis
of the carbon–metal bond and deprotonation leads to 3. In
contrast, cation D might be formed from B by rearrangement.
After deprotonation followed by demetalation, compound 4
is obtained.
Apart from being mechanistically interesting, our new
cycloisomerization procedure provides an original b-amino
acid scaffold in only two steps, which is an attractive motif for
novel biologically active compounds. Therefore, we were
interested in the scope and limitations of the procedure with
In summary, a series of biologically interesting scaffolds
were synthesized in a straightforward fashion in only two
steps. For the first time, gold- and platinum-catalyzed intra-
molecular cyclization reactions that give pyrrolo[3,2-c]azepin-
4-one derivatives have been performed. Interestingly, the 7-
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Table 2: General synthesis of pyrroloazepin-4-one products.[a]
Entry
1
Substrate
Product 2
Yield of 2 [%][b]
Product 4
Yield of 4 [%][b]
2a
2b
2c
73
4a
4b
4c
76
2
3
4
5
75
52
82
81
75
68
54
18
2d
2e
4d
4e
6
7
2 f
80
72
4 f
58
70
2g
4g
8
9
2h
2i
78
65
4h
33
29
4i
[a] Sonogashira conditions: [PdCl2(PPh3)2] (2 mol%), CuI (4 mol%), 2 (1.15 mmol), THF/triethylamine (1:1; 8 mL), 608C, 20 h. Cyclization
conditions: H2PtCl6·6H2O (5 mol%), 4 (0.2 mmol), toluene (10 mL), 1208C, 20 h. [b] Yield of isolated product.
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Chemie
21.1 ppm (aryl CH3). GC-MS (EI, 70 eV): m/z (%) 266 (100) [M+],
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):
C17H18ON2 calcd 266.14136, found 266.141372.
endo-dig cyclization process involved a concomitant rear-
rangement of the amidocarbonyl group from the 2- to the 3-
position of the pyrrole ring. H2PtCl6·6H2O is the best catalyst
for the formation of seven-membered pyrrolo[3,2-c]azepin-4-
one derivatives; the corresponding products 4a–i were
obtained in up to 76% isolated yield. Further extensions of
this chemistry towards indoles and other heterocycles can be
easily envisioned, and are being currently explored in our
laboratory.
Received: June 1, 2009
Published online: August 28, 2009
Keywords: alkynes · cyclization · gold · platinum · pyrroles
.
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Experimental Section
N,N’-Dimethyl-N-(3-p-tolylprop-2-ynyl)-1H-pyrrole-2-carboxamide
(2a): [PdCl2(PPh3)2] (0.023 mmol, 16 mg, 2 mol%) and CuI
(0.046 mmol, 9 mg, 4 mol%) were placed in an ACE pressure tube
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ynyl)-1H-pyrrole-2-carboxamide (1; 1.15 mmol, 202.7 mg) in THF/
TEA (1:1; 8 mL) was then added. The pressure tube was sealed and
the reaction mixture was heated at 608C for 20 h. After removal of
the solvent in vacuo, the residue was purified by column chromatog-
raphy (heptane/ethyl acetate 1:1) to give pyrrole 2a as yellow liquid
(223 mg, 73%). 1H NMR (500.13 MHz; CDCl3; numbering according
to Table 2): d = 7.34 (m, 2H, o-Ph); 7.14 (m, 2H, m-Ph); 6.70 (dd, 3Ja,b
= 2.5 Hz, 4Ja,b’ = 1.8 Hz, 1H, H-a); 6.61 (br, 1H, H-b’); 6.09 (dd,
3Jb,b’ = 3.8 Hz, 3Ja,b = 2.5 Hz, 1H, H-b); 4.53 (s, 2H, CH2); 3.80 (s, 3H,
NCH3); 3.23 (br, 3H, OCNCH3); 2.34 ppm (s, 3H, aryl CH3).
13C NMR (125.8 MHz, CDCl3): d = 163.8 (CO); 138.6 (C-p); 131.6
(C-o); 129.0 (C-m); 126.7 (C-a); 124.8 (C-a’); 119.6 (C-i); 113.5 (C-
b’); 106.9 (C-b); 84.4 (br), 83.6 (H2C-C, C-i’); 40.3 (br, CH2); 35.9
(NCH3); 34.8 (br, OCNCH3); 21.4 ppm (aryl CH3). GC-MS (EI,
70 eV): m/z (%) 266 (22) [M+], 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): C17H18ON2 calcd 266.14136,
found 266.140787.
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1,7-Dimethyl-4-p-tolyl-6,7-dihydropyrrolo[2,3-c]azepin-8(1H)-one
(3a) and 1,5-dimethyl-8-p-tolyl-5,6-dihydropyrrolo[3,2-c]azepin-4(1H)-
one (4a): H2PtCl6·6H2O (0.01 mmol, 5.2 mg, 5 mol%) was placed in
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was then added. The pressure tube was sealed and
the reaction mixture was heated at 1208C for 20 h.
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was purified by column chromatography (ethyl
acetate) to give pyrroloazepinones 3a and 4a as
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brown powders (5% and 76%, respectively). 3a:
1H NMR (500.13 MHz; CDCl3): d = 7.27 (m, 2H, o-
Ph); 7.14 (m, 2H, m-Ph); 6.71 (d, 3Ja,b = 2.7 Hz, 1H,
3
=
H-a); 6.03 (t, JCH,CH = 7.0 Hz, 1H, CH); 5.94 (d,
2
3Ja,b = 2.7 Hz, 1H, H-b); 3.98 (s, 3H, NCH3); 3.75
3
(d, JCH,CH = 7.0 Hz, 2H, CH2); 3.15 (s, 3H,
2
OCNCH3); 2.36 ppm (s, 3H, CH3(aryl)). 13C NMR
(75.5 MHz, CDCl3): d = 162.2 (CO); 142.4 (C-i’); 137.6, 137.6 (C-i,p);
=
128.8 (C-m); 128.4 (C-o); 127.1, 126.8 (C-a’,b’); 126.7 (C-a); 119.0 (
CH); 107.7 (C-b); 47.5 (CH2); 36.6 (NCH3); 34.6 (OCNCH3);
21.1 ppm (aryl CH3). GC-MS (EI, 70 eV): m/z (%) 266 (100) [M+],
251 (20), 237 (31), 224 (23), 209 (52), 194 (10), 175 (18), 165 (5), 152
(8), 115 (5), 91 (3), 77 (3), 63 (3), 51 (2), 42 (9). HRMS (EI):
C17H18ON2 calcd 266.14136, found 266.141082.
4a: 1H NMR (500.13 MHz; CDCl3; numbering according to
Table 2): d = 7.14 (m, 2H, m-Ph); 7.09 (m, 2H, o-Ph); 6.73 (d, 3Ja,b
=
=
3
3
2.9 Hz, 1H, H-b); 6.61 (d, Ja,b = 2.9 Hz, 1H, H-a); 6.09 (t, JCH,CH
7.5 Hz, 1H, CH); 3.71 (d, JCH,CH = 7.5 Hz, 2H, CH2); 3.15 (s, 3H,
2
3
=
2
OCNCH3); 3.07 (s, 3H, NCH3); 2.35 ppm (s, 3H, aryl CH3). 13C NMR
(125.8 MHz, CDCl3): d = 166.0 (CO); 137.9, 137.7 (C-i’,p); 136.6 (C-i);
=
131.6 (C-a’); 129.3 (C-m); 127.4 (C-o); 124.6 (C-a); 123.8 ( CH);
123.5 (C-b’); 109.6 (C-b); 47.5 (CH2); 36.4 (NCH3); 35.2 (OCNCH3);
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