Gold-catalysis: Highly efficient and regio-selective carbonyl migration in alkynyl-substituted indole-3-carboxamides leading to azepino[3,4-b]indol-1-ones

Article abstract of DOI:10.1002/adsc.201200092

An unprecedented rearrangement/anellation sequence allows the clean synthesis of azepino[3,4-b]indol-1-ones from readily available starting materials. Alkyne-substituted indole-3-carboxamides were prepared and converted to azepino[3,4-b]indol-1-ones by the SPhosAuNTf₂ catalyst (SPhos=2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl). The new connectivity, which involves an unprecedented 3,2-shift of an acylamino group for the product formation, was proven by a crystal structure analysis. Copyright

Full text of DOI:10.1002/adsc.201200092

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DOI: 10.1002/adsc.201200092
Gold-Catalysis: Highly Efficient and Regio-Selective Carbonyl
Migration in Alkynyl-Substituted Indole-3-Carboxamides Leading
to Azepino[3,4-b]indol-1-ones
G
A. Stephen K. Hashmi,a,* Weibo Yang,a and Frank Romingera,b
a
Organisch-Chemisches Institut, Ruprecht-Karls-Universitꢀt Heidelberg, Im Neuenheimer Feld 270, 69120 Heidelberg,
Germany
Fax : (+49)-711-685-4205; e-mail: hashmi@hashmi.de
Crystallographic investigation
b
Received: January 9, 2012; Revised: March 21, 2012; Published online: April 24, 2012
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201200092.
Abstract: An unprecedented rearrangement/anella-
tion sequence allows the clean synthesis of azepino-
ACHTUNGTRENNUNG
activating p-systems and then inducing rearrange-
ments. With respect to selectivity and activity, the
gold catalysts are often superior to related metals like
platinum.[3] Gold is particularly attractive as it not
only can conveniently be employed under experimen-
tally simple ꢁopen flaskꢂ reaction conditions but also
shows an outstanding functional group tolerance.[2]
Natural products and synthetic compounds contain-
ing the indole moiety possess an extraordinary range
of important biological activities. The latter have mo-
tivated organic chemists to synthesize analogous
which could potentially lead to useful drugs.[4]
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
(SPhos=2-dicyclohexylphosphino-2’,6’-dimethoxy-
biphenyl). The new connectivity, which involves an
unprecedented 3,2-shift of an acylamino group for
the product formation, was proven by a crystal
structure analysis.
Keywords: acylamino migration; alkynes; gold; het-
erocycles; indoles
Echavarren et al.[5] have reported the intramolecu-
lar cyclization of indoles with terminal alkynes teth-
ered to the 3-position. The reaction delivers indoles
anellated to other rings and is believed to proceed by
a 3,2-shift of a vinyl substituent in a spirocyclic inter-
mediate B formed by an ipso-attack on the indole
The construction of complex heterocyclic structures (Scheme 1). Recently, Liu and co-workers[6] have re-
involving homogeneous transition metal-catalyzed re- ported related spiro-intermediates B, formed by an
arrangements has emerged as a powerful synthetic ipso-cyclization of internal alkynes. Then a fragmenta-
strategy.[1] Among the methodologies described in the tion of that intermediate provides highly functional-
literature, gold catalysts[2] as ꢁp-acidsꢂ are capable of ized 3-allenylindoles, but a 3,2-migration could not be
Scheme 1. Gold- or platinum-catalyzed selective bond cleavage and migration with indole/alkynes.
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A. Stephen K. Hashmi et al.
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Table 1. Optimization studies on the rearrangement of 1a.[a]
Entry
Catalyst
Solvent
Time
Isolated yield
1
2
3
Ph3PAuNTf2
Ph3PAuCl/AgSbF6
IPrAuCl/AgNTf2
toluene
toluene
toluene
24 h
24 h
24 h
32%
66%
54%
4
toluene
1 h
92%
5
AgNTf2
p-TsOH
SPhosAuNTf2
SPhosAuNTf2
SPhosAuNTf2
toluene
toluene
toluene
DCE
1 h
NR
NR
49%
52%
77%
6
24 h
24 h
24 h
24 h
7[b]
8
9
CH3CN
[a]
Reaction conditions: substrate (100 mmol), [Au] (5 mol%), [Ag] (5 mol%), solvent (2 mL), in air. The reaction was moni-
tored by TLC.
At 508C.
[b]
observed. In contrast, Beller et al.[7] with internal and the latter is rarely utilized. Thus we envisioned
propargylic indole-2-carboxamide in most examples that a 3,2-shift of the acylamino substitutent in deriva-
of platinum- or gold-catalyzed cyclization did not tives of indole-3-carboxylic acid would be a highly de-
detect a shift of the carbonyl group but of the vinyl sirable entry to the pharmaceutically important indo-
group (to deliver F), only in two cases as a side-reac- loazepinones[10] which have attracted significant atten-
tion was a 2,3-shift of the acylamino substitutent in tion from synthetic chemists.[11]
the spiro-intermediate E observed.
In order to achieve this, alkyne-substituted indole-
We recently documented a novel gold(I)-catalyzed 3-carboxamide (1a) was used as a model substrate to
rearrangement reaction which, under mild conditions, screen different parameters including catalyst, tem-
provides a rapid and efficient access to benzo[b]fur- perature and solvent. Substrate 1a was subjected to
ans from simple, readily available 3-silyloxy-1,5- 5 mol% Ph3PAuNTf2 in toluene at 808C without an
enynes.[8] The intriguing mechanism involved a new inert atmosphere. The desired product indeed was ob-
2,3-shift in a spirocyclic Wheland-type intermediate. tained, albeit in 32% isolated yield (Table 1, entry 1).
Here we now report the first gold-catalyzed 3,2-car- The counter-ion can play an important role in gold
bonyl shift which – in alkynyl-substituted indole-3-car- catalysis.[12] Switching to Ph3PAuCl/AgSbF6 resulted in
boxamides – provides a highly efficient and regiose- a positive effect on the reactivity and delivered the
lective access to azepinoACTHNUTRGENNUG[3,4-b]indol-1-ones. After the azepinoACHTUNTGREN[NUGN 3,4-b]indol-1-one (2a) in 66% yield after 24 h
initial submission of this manuscript a paper appeared (entry 2). In the presence of Nolanꢂs catalyst, 2a was
which reported a related 3,2-carbonyl shift in palladi- isolated in a moderate yield of 54% (entry 3). To our
um/copper-catalyzed reactions of indoles with alkenes delight, employing SPhosAuNTf2 (SPhos=2-dicyclo-
under one atmosphere of CO in methanol, leading to hexylphosphino-2’,6’-dimethoxybiphenyl) in toluene
six-membered rings anellated to the indole and bear- at 808C resulted in the novel 3,2-carbonyl migration
ing a methyl ester group.[9]
product 2a in excellent yield in 1 h without any other
The starting materials for the route via D, E and F, by-product (entry 4). This gold-catalyzed rearrange-
namely indole-2-carboxylic amides, are much less ment involving a carbonyl shift represents a superior
readily available and thus much more expensive than alternative to previously reported related platinum-
the corresponding amides of indole-3-carboxylic acid. catalyzed reactions in terms of the regioselectivity as
Surprisingly, the former is more attractive to employ well as efficiency. The control experiments with silver
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Gold-Catalysis: Highly Efficient and Regio-Selective Carbonyl Migration
Table 2. Scope and limitations of the Au(I)-catalyzed rearrangement of indoles with alkynes.[a]
Entry
Substrate
Product
Time
1 h
Isolated yield
92%
1
1a
1b
2a
2b
2
3
4
5
0.5 h
98%
61%
81%
85%
1c
1d
1e
2c
2d
2e
2 h
6 h
2 h
6
7
1f
1g
2f
2g
2 h
63%
0.5 h; 20 h
95%; 93%[b]
8
9
1h
1i
2h
2i
2 h
1 h
94%
98%
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A. Stephen K. Hashmi et al.
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Table 2. (Continued)
Entry
Substrate
Product
Time
Isolated yield
84%
10
1j
2j
1.5 h
[a]
Reaction conditions: substrate (100 mmol), SPhosAuNTf2 (5 mol%), toluene (2 mL), 808C, in air. The reaction was moni-
tored by TLC.
SPhosAuNTf2 (1 mol%).
[b]
or an acidic catalyst gave no conversion of the sub- the introduction (Scheme 1). This further highlights
strate (entries 5 and 6). Furthermore, the temperature the scope of our method.
effect was also investigated, and it turned out that
The structure of the products was unambiguously
conducting the reaction at 508C is inferior (entry 7). confirmed by the single crystal X-ray structure analy-
Further optimization of the reaction conditions re- sis of 2h (Figure 1).[13] This also nicely confirms Bel-
vealed that this reaction proceeded most efficiently in lerꢂs[7] assignments. Due to the neighbouring indole
the non-polar solvent toluene, whereas reactions in ring, the 2-fluorophenyl group is rotated out of conju-
solvents of high polarities such as DCE or CH3CN af- gation with the double bond by 488. The seven-mem-
forded only moderate yields of 2a (entries 8 and 9).
bered lactam ring is puckered, the olefinic double
Upon optimization of the reaction conditions, we bond and the amide partial double bonds are slightly
explored the generality of this novel 3,2-acylamino tilted with regard to the plane of the indole ring and
migration transformation with a series of alkyne-sub- the methylene group points up.
stituted indole-3-carboxamides (Table 2). We were de-
In an attempt to investigate the mechanism of the
lighted to see that the reaction conditions proved to 3,2-acylamino migration, we monitored the reaction
1
be general, not only electron-rich arylalkynes but also of 1g by H NMR spectroscopy (Figure 2) and of 1a
electron-deficient arylalkynes delivered the azepino- by React-IR. No intermediate could be detected, indi-
ACHTUNGTRENNUNG[3,4-b]indol-1-ones in good to excellent yields. As dis- cating that the first step is rate-limiting. As the spec-
cussed before, the thiophene-substituted alkyne 1a tra clearly show, the conversion is highly selective, no
gave an excellent 92% yield (previously only 45% significant amount of any side-product is visible.
yield from the more expensive starting material had
With regard to the mechanism,[14] the 3,2-shift ob-
been reported,[7] entry 1). A quantitative yield of the served points towards the following steps: after the
desired product was obtained when the phenyl-substi- initial p-coordination of the alkyne (G), the spirocy-
tuted alkyne 1b was used (entry 2). On the other clic cationic intermediate H is formed by the electro-
hand, the nitro compound 1c gave only 61% of 2c
(entry 3). For the bromo and the methoxy derivatives
again yields in the 80% range were realized (entries 4
and 5). When we tested the substrate with a naphthyl
substituent, it gave a moderate yield of 63% (entry 6).
With the electron-donating methyl group on the
arene, it was even possible to decrease the catalyst
loading to 1 mol%, the conversion was complete after
20 h and afforded 93% of 2g (compared to 95% with
5 mol% of SPhosAuNTf2, entry 7). In light of the im-
portance of fluorine in medicinal chemistry, we intro-
duced 2-fluorobenzene as a functional group on the
alkyne. To our delight, 1h gave exclusively the expect-
ed migration product in 94% yield (entry 8). In addi-
tion, the disubstituted arylalkyne resulted in a 98%
yield of 2i after only 1 h (entry 9). Importantly, even
when the NH-unprotected indole/alkyne was subject-
ed to the standard conditions, the corresponding
product was formed in good yield after 2 h (entry 10).
The similar NH-unprotected indole/alkynes were not
at all mentioned in Bellerꢂs investigation discussed in Figure 1. Solid state molecular structure of 2h.
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Gold-Catalysis: Highly Efficient and Regio-Selective Carbonyl Migration
1
Figure 2. Monitoring the conversion of 1g from Table 2 by in situ H NMR spectroscopy (bottom trace: 1g; middle trace:
during the conversion; top trace: crude product 2g).
philic ipso-attack of the activated alkyne to the most cycle.[15] The lone pair at nitrogen can stabilize the mi-
nucleophilic position of the indole system (Scheme 2). grating acylamino group (H to I), the two mesomeric
Now the migration of the acylamino group is clearly formulas I1 and I2 symbolize the keteniminium-type
preferred to a migration of the vinyl substituent, of stabilization of the migrating group and might
which delivers intermediate I. Now elimination of serve as an explanation for the higher migratory apti-
a proton and protodeauration of J close the catalytic tude of this group.
In conclusion, a new and highly selective gold-cata-
lyzed 3,2-shift of an acylamino substituent on indole
has been discovered. This will provide new impulses
for pharmaceutical chemists working on indole sys-
tems and even for the pharmaceutical industry, as the
starting materials for this route are more readily
available and affordable than the starting materials
for the previously known metal-catalyzed synthesis of
such products. With regard to homogeneous gold cat-
alysis, the new migratory preference opens new per-
spectives for future research.
Experimental Section
Gold(I)-Catalyzed Formation of Azepino
1-ones; Representative Procedure for 2,10-Dimethyl-
5-(thiophen-2-yl)-2,3-dihydroazepino[3,4-b]indol-
(10H)-one (2a)
ACHTUNGTREN[NUNG 3,4-b]indol-
AHCTUNGTRENNUNG
1ACHTUNGTRENNUG
To a solution of 1a (30.8 mg, 100 mmol) in toluene (2.0 mL)
was added SPhosAuNTf2 (4.4 mg, 5 mol%), and the mixture
was stirred at 808C until the starting material was complete-
ly consumed. Then the mixture was concentrated under re-
duced pressure. Purification of the residue by flash chroma-
tography on silica gel (dichloromethane-ethyl acetate: 16/1)
Scheme 2. Mechanistic proposal for the new 3,2-acylamino
˜
shift in indoles.
gave 2a; yield: 28.3 mg (93%). IR (KBr): n=3067, 2925,
Adv. Synth. Catal. 2012, 354, 1273 – 1279
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A. Stephen K. Hashmi et al.
COMMUNICATIONS
1375, 1332, 1301, 1265, 1242, 1185, 1166, 1135, 1062, 1019,
767, 745, 633 cmÀ1 1H NMR (CDCl3, 300 MHz): d=8.07–
;
8.11 (dd, J=8.64 Hz, J=2.26 Hz, 1H), 8.00 (s, 1H), 7.36 (d,
J=8.33 Hz, 1H), 7.22–7.27 (td, J=6.90 Hz, J=1.03 Hz, 1H),
6.91 (d, J=8.65 Hz, 1H), 6.80–6.85 (td, J=7.50 Hz, J=
0.96 Hz, 1H), 6.57 (d, J=8.13 Hz, 1H), 6.19 (t, J=6.95 Hz,
1H), 4.08 (s, 3H), 3.88 (s, 3H), 3.84 (d, J=6.83 Hz, 2H),
3.53 (s, 3H), 3.27 (s, 3H); 13C NMR (CDCl3, 75 MHz): d=
32.18 (q), 35.12 (q), 47.61 (t), 52.06 (q), 55.89 (q), 109.94 (d),
110.78 (d), 118.23 (s), 120.20 (d), 121.35 (d), 122.65 (s),
123.69 (d), 124.41 (d), 124.67 (s), 129.85 (s), 131.75 (d),
132.80 (d), 138.5 (s), 160.41 (s), 161.16 (s), 166.99 (s);
HRMS [EI (+), 70 eV]: m/z=390.1552, calcd. for
C23H22N2O4: 390.158.
2404, 1625, 1507, 1467, 1385, 1333, 1294, 1237, 1161, 1073,
1061, 851, 830, 800, 742, 705, 614 cmÀ1 1H NMR (CDCl3,
;
300 MHz): d=7.42 (d, J=8.39 Hz, 1H), 7.27–7.35 (m, 2H),
6.97–7.08 (m, 4H), 6.31 (t, J=7.13 Hz, 1H), 4.09 (s, 3H),
3.78 (br, 2H), 3.25 (s, 3H); 13C NMR (CDCl3, 75 MHz): d
=32.09 (q), 34.94 (q), 47.52 (t), 110.13 (d), 116.68 (s), 120.24
(d), 121.52 (d), 122.76 (d), 124.52 (s), 124.57 (d), 125.26 (d),
127.29 (d), 127.51 (d), 133.48 (s), 135.16 (s), 138.35 (s),
142.80 (s), 162.22 (s); HR-MS [EI (+), 70 eV]: m/z=
308.1000, calcd. for C18H16N2OS: 308.0983.
Acknowledgements
2,10-Dimethyl-5-(4-nitrophenyl)-2,3-dihydro-
azepinoACHTUNGTRENNUNG[3,4-b]indol-1ACHTUNGTRENN(UGN 10H)-one (2c)
W. Yang is grateful to the CSC for a fellowship. Gold salts
were generously donated by Umicore AG & Co. KG.
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˜
(61%). IR (KBr): n=2969, 2929, 1704, 1633, 1595, 1565,
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1
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