Consecutive gold(I)-catalyzed cyclization reactions of o -(buta-1,3-diyn-1-yl-)-substituted N-aryl ureas: A one-pot synthesis of pyrimido[1,6- a ]indol-1(2 H)-ones and related systems

Article abstract of DOI:10.1021/ol4007986

Treatment of readily available o-(buta-1,3-diyn-1-yl-)-substituted N-aryl ureas such as 1 with the Au(I)-catalyst 11 affords, via a twofold cyclization process, the isomeric pyrimido[1,6-a]indol-1(2H)-one 3 in good yield.

Full text of DOI:10.1021/ol4007986

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Consecutive Gold(I)-Catalyzed Cyclization
Reactions of o‑(Buta-1,3-diyn-1-yl-)-
Substituted N‑Aryl Ureas: A One-Pot
Synthesis of Pyrimido[1,6‑a]indol-
1(2H)‑ones and Related Systems
Phillip P. Sharp,† Martin G. Banwell,*,† Jens Renner,‡ Klaas Lohmann,‡ and
Anthony C. Willis†
Research School of Chemistry, Institute of Advanced Studies, The Australian National
University, Canberra ACT 0200, Australia, and Global Research Agricultural Products,
BASF SE, GVA/FO ꢀ A030, 67056 Ludwigshafen, Germany
mgb@rsc.anu.edu.au
Received March 25, 2013
ABSTRACT
Treatment of readily available o-(buta-1,3-diyn-1-yl-)-substituted N-aryl ureas such as 1 with the Au(I)-catalyst 11 affords, via a twofold cyclization
process, the isomeric pyrimido[1,6-a]indol-1(2H)-one 3 in good yield.
o-Alkynylanilines and certain related systems readily
cyclize under various conditions to give the corresponding
indoles, and these types of processes have found extensive
application in the synthesis of a wide range of biologically
relevant systems.1ꢀ3 Surprisingly, and despite the pro-
spects they offer for rapidly assembling polyfused hetero-
aromatic systems, extensions of this type of process to
substrates incorporating ortho-related diynes and bis-het-
eroatom-based nucleophiles do not appear to have been
investigated.4 The prototypical process we envisaged is
shown in Figure 1 and involves the conversion of the
monocyclic o-disubstituted arene 1 or 2 into their tricyclic
and thermodynamically more stable isomer 3 or 4, re-
spectively.5 Herein we report the successful implementation
† The Australian National University.
‡ Global Research Agricultural Products, BASF SE.
(1) See, for example: (a) Koradin, C.; Dohle, W.; Rodriguez, A. L.;
Schmid, B.; Knochel, P. Tetrahedron 2003, 59, 1571 and references cited
ꢀ
therein. (b) Barluenga, J.; Trincado, M.; Rubio, E.; Gonzalez, J. M.
Angew. Chem., Int. Ed. 2003, 42, 2406. (c) Arcadi, A.; Bianchi, G.;
Marinelli, F. Synthesis 2004, 610. (d) Kamijo, S.; Sasaki, Y.; Yamamoto,
Y. Tetrahedron Lett. 2004, 45, 35. (e) Hashmi, A. S. K.; Ramamurthi,
T. D.; Rominger, F. Adv. Synth. Catal. 2010, 352, 971. (f) Alsabeh, P. G.;
Lundgren, R. J.; Longobardi, L. E.; Stradiotto, M. Chem. Commun.
2011, 47, 6936. (g) Wang, H.; Li, Y.; Jiang, L.; Zhang, R.; Jin, K.; Zhao,
D.; Duan, C. Org. Biomol. Chem. 2011, 9, 4983. (h) Hirano, K.; Inaba,
Y.; Takasu, K.; Oishi, S.; Takemoto, Y.; Fujii, N.; Ohno, H. J. Org.
Chem. 2011, 76, 9068. (i) Chen, C.-C.; Yang, S.-C.; Wu, M.-J. J. Org.
Chem. 2011, 76, 10269. (j) Wetzel, A.; Gagosz, F. Angew. Chem., Int. Ed.
2011, 50, 7354.
(4) For examples of monocyclization processes involving related
diynes, see: (a) Fiandanese, V.; Bottalico, D.; Marchese, G.; Punzi, A.
Tetrahedron 2008, 64, 53. (b) Vinogradova, O. V.; Sorokoumov, V. N.;
Balova, I. A. Tetrahedron Lett. 2009, 50, 6358. (c) Danilkina, N. A.;
(2) “Double-barrelled” versions of such processes leading to 2,20-
biindolyls are known: (a) Shin, K.; Ogasawara, K. Synlett 1995, 859. (b)
Saulnier, M. G.; Frennesson, D. B.; Deshpande, M. S.; Vyas, D. M.
Tetrahedron Lett. 1995, 36, 7841. (c) Abbiati, G.; Arcadi, A.; Beccalli, E.;
Bianchi, G.; Marinelli, F.; Rossi, E. Tetrahedron 2006, 62, 3033.
(3) For a useful review on the electrophile-promoted nucleophilic
ring closure reactions of alkynes, see: Godoi, B.; Schumacher, R. F.;
Zeni, G. Chem. Rev. 2011, 111, 2937.
€
Brase, S.; Balova, I. A. Synlett 2011, 517. (d) Vinogradova, O. V.;
Balova, I. A.; Popik, V. V. J. Org. Chem. 2011, 76, 6937.
(5) 1-(o-Ethynylaryl)ureas have been shown to undergo either 6-exo-
dig or 5-endo-dig cyclization reactions depending on the choice of
ꢀ
catalyst and reaction conditions: Gimeno, A.; Medio-Simon, M.;
Ramırez de Arellano, C.; Asensio, G.; Cuenca, A. B. Org. Lett. 2010,
12, 1900.
´
r
10.1021/ol4007986
XXXX American Chemical Society

of this twofold cyclization process, thereby providing
various analogues of the ABC-heterotricyclic framework
associated with, for example, the potent antitumor agent
variolin B (5).6,7
respectively, conditions were readily established (5 mol
% 11, THF, 100 °C, microwave radiation, 1 h) for obtain-
ing the latter product exclusively and in 78% yield. The
structure of pyrimido[1,6-a]indol-1(2H)-one (3) was con-
firmed by single-crystal X-ray analysis.9 Furthermore,
subjection of compound 12 to the reaction conditions
defined above gave product 3 in 75% yield.
Scheme 1
Figure 1. Proposed twofold cyclization process.
The substrate 1 required for initial studies of the pro-
posed twofold cyclization process was readily prepared
according to the reaction sequence shown in Scheme 1.
Thus, the commercially available diyne 6 was treated with
MeLi•LiBr and the lithium diacetylide 7 so-formed was
subjected to Sonogashira cross-coupling with o-iodoani-
line (8) and thereby generating the o-(buta-1,3-diyn-1-yl-)-
substituted aniline 9 (81%).8 Reaction of compound 9
withtrichloroacetylisocyanateaffordedthe corresponding
N-acyl-N0-arylurea 10 (96%), the structure of which was
confirmed by single-crystal X-ray analysis.9 Upon treat-
ment with sodium bicarbonate in aqueous methanol,
compound 10 was converted into the target 1 (76%), the
spectral data for which were in complete accord with the
assigned structure. A variety of conditions were then
examined in an effort to effect the conversion of this
compound into isomer 3.10 Echavarren’s gold(I) catalyst
1111 proved most useful in this regard12 [see the Supporting
Information (SI) for details]. While initial experiments lead
to a chromatographically separable mixture of mono-
and bis-cyclized materials, viz. compounds 12 and 3
This novel conversion was readily extended to a range
ofo-(buta-1,3-diyn-1-yl-)-substitutedN-aryl ureas (13ꢀ28,
Figure 2), thereby giving the corresponding pyrimido-
[1,6-a]indol-1(2H)-ones (29ꢀ41)9 or the related 1H-imidazo-
[1,5-a]indol-3(2H)-ones (42 and 43)13 in uniformly accep-
table yields (Table 1). The substrates used in these studies
were prepared by methods similar to those shown in
Scheme 1. Full details are provided in the SI. There are
several noteworthyoutcomesassociatedwiththetabulated
results. In particular, a range of substituents are tolerated
at the C4 and C5 positions on the substrate (entries 1ꢀ9,
Table 1). Furthermore, the phenyl-capped diynes 22 and
25, which can be prepared by Sonogashira cross-coupling
of compounds 1 and 16 with iodobenzene, also engage
in the anticipated twofold cyclization process (entries 10
and 13) and thereby forming the 3-phenylpyrimido-
[1,6-a]indol-1(2H)-ones 38 and 39, respectively. The corre-
sponding TMS-capped systems 23 and 24, which are read-
ily derived from aniline 9 or its 4-tert-butyl analogue using
minor variations on the reaction sequence shown in
Scheme 1, also undergo the expected cyclization process
(6) (a) Perry, N. B.; Ettouati, L.; Litaudon, M.; Blunt, J. W.; Munro,
M. H. G.; Parkin, S.; Hope, H. Tetrahedron 1994, 50, 3987. (b)
Trimurtulu, G.; Faulkner, D. J.; Perry, N. B.; Ettouati, L.; Litaudon,
M.; Blunt, J. W.; Munro, M. H. G.; Jameson, G. B. Tetrahedron 1994,
50, 3993.
(7) Walker, S. R.; Carter, E. J.; Huff, B. C.; Morris, J. C. Chem. Rev.
2009, 109, 3080.
(8) Liao, H.-Y.; Cheng, C.-H. J. Org. Chem. 1995, 60, 3711.
(9) Details are provided in the Supporting Information (SI).
(10) The parent compound 3 has not been reported previously, but
various derivatives, including biologically active ones, have been de-
scribed; see, for example: (a) Capito, E.; Brown, J. M.; Ricci, A. Chem.
Commun. 2005, 1854. (b) Facoetti, D.; Abbiati, G.; d’Avolio, L.;
Ackermann, L.; Rossi, E. Synlett 2009, 2273. (c) Nakamura, I.; Sato,
Y.; Terada, M. J. Am. Chem. Soc. 2009, 131, 4198. (d) Wang, Z.-J.;
Yang, J.-G.; Yang, F.; Bao, W. Org. Lett. 2010, 12, 3034.
ꢀ
ꢀ
(11) Herrero-Gomez, E.; Nieto-Oberhuber, C.; Lopez, S.; Benet-
Buchholz, J.; Echavarren, A. M. Angew. Chem., Int. Ed. 2006, 45, 5455.
(12) For useful points-of-entry into the literature on gold-catalyzed
cyclization reactions of alkynes, see: (a) Rudolph, M.; Hashmi, A. S. K.
Chem. Soc. Rev. 2012, 41, 2448. (b) Hashmi, A. S. K.; Braun, I.;
Rudolph, M.; Rominger, F. Organometallics 2012, 31, 644. (c) Hashmi,
€
A. S. K.; Lauterbach, T.; Nosel, P.; Vilhelmsen, M. H.; Rudolph, M.;
Rominger, F. Chem.;Eur. J. 2013, 19, 1058. (d) Hansmann, M. M.;
Rudolph, M.; Rominger, F.; Hashmi, A. S. K. Angew. Chem., Int. Ed.
2013, 52, 2593. (e) Reference 1c.
(13) 1H-Imidazo[1,5-a]indol-3(2H)-ones are rare: Katritzky, A. R.;
Singh, S. K.; Bobrov, S. J. Org. Chem. 2004, 69, 9313.
B
Org. Lett., Vol. XX, No. XX, XXXX

products proved to be the 1H-imidazo[1,5-a]indol-3(2H)-
ones 42 and 43 although the former product was accom-
panied by quantities (22%) of the isomeric 2-phenyl-
pyrimido[1,6-a]indol-1(2H)-one 40. In contrast, subjection
of the diphenyl-substituted system 28 to the same condi-
tions afforded the pyrimido[1,6-a]indol-1(2H)-one 41 ex-
clusively (and in 68% yield).
Once again, the stepwise nature of the cyclization of
these substrates is supported by the observation that when
compound 22 was treated with 5 mol % of catalyst 11 at
18 °C for 24 h, then a chromatographically separable
mixture of compound 38 (21%) and the isomeric indole
44 (72%) was obtained. Resubjection of the latter product
to reaction with catalyst 11 under the usual conditions (1 h
at 100 °C) then gave pyrimido[1,6-a]indol-1(2H)-one 38 in
93% yield.
Efforts to deploy the cyclization processes detailed
above in the assembly of the ABC-ring system of variolin
B are outlined in Scheme 2. A substrate of the general form
2 suitable for examination of the proposed Au(I)-catalyzed
tandem cyclization process was prepared by first treating
commercially available 4-methoxypyridine N-oxide (45)
with tosic anhydride in the presence of tert-butylamine14
and thereby generating the 2-aminopyridine 46 in 61%
yield. Cleavage of the tert-butyl group within this product
was readily accomplished using trifluoroacetic acid, and
the primary amine 47 so-formed (73%) was reacted with
2.5 mol equiv of N-iodosuccinimide (NIS) in the presence
of triflic acid to give the di-iodinated derivative 48 in 70%
yield.15 Treatment of this last compound with n-butyl-
lithium in THF at ꢀ78 to 18 °C followed by quenching
with water resulted in selective removal of the C5-iodine
and formation of the monoiodide 49 which was obtained
as a white, crystalline solid in 74% yield. Sonogashira
cross-coupling of compound 49 with the acetylide anion
derived from the reaction of compound 6 with MeLi•LiBr
gave diyne 50 (63%) that, upon successive treatment with
trichloroacetyl isocyanate and then methanolic sodium
bicarbonate at 18 °C for 2 h, afforded the TMS-capped
compound 51 in 24% yield. In contrast, extended exposure
(24 h) of the product from the first step to sodium
bicarbonate gave the terminal diyne 52 in 75% yield.
Treatment of the former product (viz. 51) with catalyst
11 in THF at 60 °C for 5 h afforded the monocyclized
product 53 in 40% yield. However, all attempts to engage
this compound in a second cyclization reaction so as to
generate the target tricyclic system 54, failed. In particular,
subjection of compound 53 to the more forcing cyclization
conditions used to effect the various forms of the conver-
sion 1 f 3 detailed above (Table 1) only resulted in loss of
the carboxamide group16 in this case. On the basis that the
TMS-capping group in compounds 51 and 53 may be
Figure 2. Substrates and products associated with the title process.
Table 1. Outcomes of the Au(I)-Catalyzed Cyclization
Reactions of Compounds 13ꢀ27a
entry
substrate
product(s)
yield (%)
1
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
56
2
30
40
3
31
39
4
32
70
5
33
62
6
34
49
7
35
59
8
36
61
9
37
67
10
11
12
13
14
15
16b
38
60
3
75
30
56
39
65
40 þ 42
43
28 (of 42)
56
41
68
a Reactions carried out under microwave irradiation in THF at
100 °C for 1 h using 5 mol % of 11 as catalyst. b This conversion was
effected using 10 mol % of catalyst 11 at 100 °C for 2 h.
(entries11and 12), butatsomepointtheassociatedsilicon-
based group is lost and so compounds 3 and 30, respec-
tively, are the observed products. Additional substituents
on the ureamoiety appear capable of changing the mode of
the second cyclization step. Thus, when the readily ob-
tained N,N0-disubstituted ureas 26 and 27 were subjected
tothe normalconditions (entries 14and 15), thenthemajor
(14) Yin, J.; Xiang, B.; Huffman, M. A.; Raab, C. E.; Davies, I. W.
J. Org. Chem. 2007, 72, 4554.
(15) Monoiodination of compound 47 under various conditions (see
the SI) gave the 5-iodo-derivative, the structure of which was established
by single-crystal X-ray analysis.
(16) The structure of the product indole was confirmed by single-
crystal X-ray analysis (see the SI).
Org. Lett., Vol. XX, No. XX, XXXX
C

catalyst 11 only gave the Au(I)ꢀacetylide complex 58
(90% based on 11), the structure of which was confirmed
bysingle-crystalX-ray analysis.9 Inotherattemptstoeffect
the desired twofold cyclization of compounds such as 51,
52, 56, and 57, efforts were made to convert them into their
corresponding N-oxides and/or to complex them with
various acids prior to their exposure to catalyst 11. How-
ever, none of these resulted in the formation of the target
tricyclic ring system.
Scheme 2
Scheme 3
The origins of the divergent behaviors of compound 1
and its aza-analogues 52 and 57 are the subject of ongoing
investigations, the results of which will be reported in due
course.
inhibiting the second cyclization process, the terminal
alkyne 52 was treated with the catalyst 11, but in this
instance the only isolable product of reaction was the gold
acetylide 55 (62% based on 11).
Acknowledgment. We thank the Institute of Advanced
Studies and the Australian Research Council for financial
support.
We speculated that the conversion 53 f 54 may be
failing because of the chelating capacities of the 7-azaindole
nitrogen and the adjacent N-1 carboxamide residues
within the former compound. Accordingly, the behavior
of a 4-aminopyridine-derived system was investigated. The
substrate required for such an investigation was prepared
by the simple means shown in Scheme 3 and which
included treatment of the readily obtained (see the SI)
TMS-capped diyne 56 with trichloroacetyl isocyanate and
then methanolic sodium bicarbonate and so giving target
57(95%). However, treatmentof the lattercompound with
Supporting Information Available. Full experimental
procedures; data derived from the single-crystal X-ray
analyses of compounds 3, 10, 36, 43, the 5-iodo derivative
of compound 47, the indole from 53 (form 1), the indole
from 53 (form 2) and 58 (CCDC numbers 876496ꢀ
876503, respectively); 1H and 13C NMR spectra of com-
pounds 1, 3, 10, 12ꢀ44, 47ꢀ53, and 55ꢀ58. This material is
available free of charge via the Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX