Microwave-enhanced carbonylative generation of indanones and 3-acylaminoindanones

Article abstract of DOI:10.1021/jo048375g

(Chemical Equation Presented). The development of microwave-accelerated protocols for palladium(0)-catalyzed carbonylative cyclization of unsaturated aryl bromides and chlorides is described. By employing o-bromostyryl derivatives lacking substituents on the vinylic bond, molybdenum hexacarbonyl-mediated in situ carbonylation delivered a set of indan-1-one products in high yield after only 20 min of heating. Without the addition of the tri-tert-butylphosphine releasing Fu-salt ((t-Bu)₃PHBF₄), only incomplete conversions of sluggish o-styryl bromides and chlorides were realized. Internal and chemoselective palladium(0)-catalyzed Heck arylations of enamides afforded suitable starting materials for subsequent rapid ring-closing reactions. Microwave-heated intramolecular in situ carbonylation of these electron-rich and sterically congested olefins conveniently afforded eight functionalized 3-acylaminoindanone derivatives in a novel synthetic process. Attempted carbonylative annulation of electron-poor o-bromocinnamic acid derivatives furnished only the corresponding lactones via a competing hydroxycarbonylation- Michael addition reaction sequence.

Full text of DOI:10.1021/jo048375g

only monosubstituted olefins but also two examples of
internally alkylated o-iodostyrenes. Inspired by this
elegant approach, we decided to further investigate the
scope of the methodology starting from the more readily
available o-styryl bromides (1) and chlorides (4). Utilizing
presynthesized 1-acylamino-o-bromostyrenes (7), we aimed
to develop a novel route to 3-acylaminoindan-1-ones (8).
Over the past few years, the applications of controlled
microwave heating6-8 and solid-phase reagents9 have
been two areas of rapid growth, and their importance in
today’s chemistry is now beyond question. Despite the
power these tools offer, there is still a considerable degree
of effort required in setting up and performing high-speed
reactions with gases. To address this issue in carbony-
lation chemistry, we previously identified molybdenum
hexacarbonyl as an easily handled solid reagent for in
situ release of carbon monoxide upon heating in sealed
vessels.10-13
Microwave-Enhanced Carbonylative
Generation of Indanones and
3-Acylaminoindanones
Xiongyu Wu, Peter Nilsson, and Mats Larhed*
Organic Pharmaceutical Chemistry,
Department of Medicinal Chemistry, Uppsala University,
BMC, Box-574, SE-751 23 Uppsala, Sweden
mats@orgfarm.uu.se
Received September 14, 2004
As a part of our interest in developing new, rapid, and
robust chemistry suitable for medicinal chemistry ap-
plications,7,14 we now wish to report a microwave method
to prepare indan-1-ones (2) and 3-amidoindan-1-ones (8)
by carbonylative cyclizations, using molybdenum hexa-
carbonyl as a solid source of carbon monoxide.
In our initial cyclization experiments we focused our
attempts on o-bromostyrenes (1) as starting precursors
(eq 1). For the preparation of styrenes 1b-f, we started
The development of microwave-accelerated protocols for
palladium(0)-catalyzed carbonylative cyclization of unsatur-
ated aryl bromides and chlorides is described. By employing
o-bromostyryl derivatives lacking substituents on the vinylic
bond, molybdenum hexacarbonyl-mediated in situ carbony-
lation delivered a set of indan-1-one products in high yield
after only 20 min of heating. Without the addition of the
tri-tert-butylphosphine releasing Fu-salt ((t-Bu)3PHBF4),
only incomplete conversions of sluggish o-styryl bromides
and chlorides were realized. Internal and chemoselective
palladium(0)-catalyzed Heck arylations of enamides afforded
suitable starting materials for subsequent rapid ring-closing
reactions. Microwave-heated intramolecular in situ carbo-
nylation of these electron-rich and sterically congested
olefins conveniently afforded eight functionalized 3-acylami-
noindanone derivatives in a novel synthetic process. At-
tempted carbonylative annulation of electron-poor o-bromo-
cinnamic acid derivatives furnished only the corresponding
lactones via a competing hydroxycarbonylation-Michael
addition reaction sequence.
from readily available o-bromobenzaldehydes and em-
ployed classical Wittig reactions following high-yielding
literature procedures.5 Parent compound 1a was instead
purchased from a commercial supplier. Palladium-
catalyzed intramolecular carbocyclizations of 1a-f were
thereafter carried out with a catalytic system composed
of 5% palladium acetate and 10% of the tri-tert-bu-
In a lead-optimization program toward the identifica-
tion of improved linear HIV-1 protease1 and plasmepsin
I and II inhibitors2 we required access to novel 1,3-
difunctionalized indan structures. These structures should
ideally have the potential to serve as both unique P2/P2′
residues and as precursors for further modifications.
Derivatives of indanones have previously been prepared
via various types of palladium-catalyzed carbonylative
cyclizations.3,4 Recently, Larock and co-workers managed
to use o-iodostyrenes as starting materials, synthesizing
five different indan-1-ones under a carbon monoxide
atmosphere in modest to excellent yields.5 Under these
reaction conditions they were able to carboannulate not
15
tylphosphine precursor (t-Bu)3PHBF4 in 2 mL of diox-
ane or DMF. Microwave heating at 150 °C for 20 min
with 0.5 equiv of molybdenum hexacarbonyl, 1.0 equiv
of Bu4NCl, and 2.0 of equiv pyridine generally afforded
good yields of cyclized indan-1-ones 2a-e (59-82%), with
the exception of the methylated 2f (34%, entry 6, Table
(5) Gagnier, S. V.; Larock, R. C. J. Am. Chem. Soc. 2003, 125, 4804-
4807.
(6) Lidstro¨m, P.; Tierney, J.; Wathey, B.; Westman, J. Tetrahedron
2001, 57, 9225-9283.
(7) Larhed, M.; Hallberg, A. Drug Discov. Today 2001, 6, 406-416.
(8) Kappe, C. O. Curr. Opin. Chem. Biol. 2002, 6, 314-320.
(9) Ley, S. V.; Baxendale, I. R. Nat. Rev. Drug Discov. 2002, 1, 573-
586.
(1) Alterman, M.; Bjo¨rsne, M.; Mu¨hlman, A.; Classon, B.; Kvarn-
stro¨m, I.; Danielson, H.; Markgren, P. O.; Nillroth, U.; Unge, T.;
Hallberg, A.; Samuelsson, B. J. Med. Chem. 1998, 41, 3782-3792.
(2) Ersmark, K.; Feierberg, I.; Bjelic, S.; Hamelink, E.; Hackett, F.;
Blackman, M. J.; Hulte´n, J.; Samuelsson, B.; A° qvist, J.; Hallberg, A.
J. Med. Chem. 2004, 47, 110-122.
(3) Negishi, E.-i.; Cope´ret, C.; Ma, S.; Liou, S.-Y.; Liu, F. Chem. Rev.
1996, 96, 365-93.
(4) Gevorgyan, V.; Quan, L. G.; Yamamoto, Y. Tetrahedron Lett.
1999, 40, 4089-4092.
(10) Kaiser, N. F. K.; Hallberg, A.; Larhed, M. J. Comb. Chem. 2002,
4, 109-111.
(11) Georgsson, J.; Hallberg, A.; Larhed, M. J. Comb. Chem. 2003,
5, 350-352.
(12) Wannberg, J.; Larhed, M. J. Org. Chem. 2003, 68, 5750-5753.
(13) Wu, X. Y.; Mahalingam, A. K.; Wan, Y. Q.; Alterman, M.
Tetrahedron Lett. 2004, 45, 4635-4638.
(14) Larhed, M.; Moberg, C.; Hallberg, A. Acc. Chem. Res. 2002, 35,
717-727.
(15) Netherton, M. R.; Fu, G. C. Org. Lett. 2001, 3, 4295-4298.
10.1021/jo048375g CCC: $30.25 © 2005 American Chemical Society
Published on Web 11/26/2004
346
J. Org. Chem. 2005, 70, 346-349

TABLE 1. Palladium-Catalyzed and Microwave-Heated
TABLE 2. Palladium-Catalyzed and Microwave Heated
Carbonylative Cyclization of o-Bromostyrenes
Carbonylative Cyclization of o-Chlorostyrenes
a Reaction conditions: 1.0 mmol of 4, 5 mol % of palladacycle,
10 mol % of (t-Bu)3PHBF4, 0.5 equiv of Mo(CO)6, 1.0 equiv of
n-Bu4NCl, 2.0 equiv of pyridine, and 2.0 mL of dioxane at 170 °C;
microwave heating for 30 min in a sealed vessel. b DMF as solvent.
of sluggish aryl chlorides in related, but non-carbonyla-
tive, palladium(0)-catalyzed coupling reactions.15 To in-
crease the thermal stability of the catalytic system, the
palladium source was switched to Herrmann’s pallada-
cycle,17 and it was discovered that this small modification
was sufficiently general to afford complete conversion of
4a-e after 30 min at 170 °C in dioxane. The yields of
the isolated products 2 were unfortunately low (25-51%,
Table 2). GC-MS and 1H NMR analysis on the reaction
mixtures proved that dehalogenated starting materials
were always formed, but only in small amounts. We
therefore suspect that the moderate yields obtained were
a consequence of competing polymerization of the starting
styrenes 4 at the high reaction temperature (170 °C).18
Having established the principle of carbonylative ring
closing with Mo(CO)6 and o-halostyrenes under high
temperature we turned our attention to prepare the
desired 3-acylaminoindan-1-ones (8). Regarding the prepa-
ration of the o-haloaryl enamide starting materials, it has
been known for some time that enamides can be regi-
oselectively arylated at the internal R-carbon using
bidentate ligands and aryl triflates following a cationic
reaction route.19 In addition, Cabri has demonstrated the
high reactivity of the triflate leaving group under these
cationic Heck conditions.20 Prompted by these literature
preferences, we decided to investigate o-bromoaryl tri-
flates (5) as starting materials for the preparation of
electron-rich carboannulation precursors 7a-h. Using in
principle the reported standard method for dppp (1,3-
bis(diphenylphosphino)propane)-controlled R-arylations,20
sluggish but very chemo- and regioselective reactions
a Reaction conditions: 1.0 mmol of 1, 5 mol % of Pd(OAc)2, 10
mol % of (t-Bu)3PHBF4, 0.5 equiv of Mo(CO)6, 1.0 equiv of
n-Bu4NCl, 2.0 equiv of pyridine, and 2.0 mL of dioxane at 150 °C;
microwave heating for 20 min in a sealed vessel. b Reaction
conditions: 2.0 mL of DMF as solvent at 130 °C for 20 min.
c Reaction conditions: 0.7 equiv of Mo(CO)6 and 1.5 equiv of
n-Bu4NCl without pyridine at 150 °C for 40 min.
1). In the latter case, a short series of optimization
reactions provided improved conditions using 40 min of
microwave heating. The highest yield of 2f (62%, Table
1) was surprisingly experienced employing an increased
amount of Mo(CO)6 and Bu4NCl, but in complete absence
of the pyridine base. The pyridine-free protocol furnished
only inferior yields with monosubstituted olefins 1a-e,
as did reactions with the alternative bases diisopropyl-
ethylamine and 4-(dimethylamino)pyridine. In all inves-
tigated cases, the use of (t-Bu)3PHBF4 was essential for
reaching full consumption of 1. Thus, the released
(t-Bu)3P ligand produced a much superior carbonylation
catalyst compared to all investigated arylphosphine
ligands. With styryl derivatives that were substituted in
the terminal vinylic position with electron-withdrawing
groups the anticipated acylpalladium intermediate did
not insert into the C-C double bond. Instead, 1g and 1h
underwent hydroxycarbonylation and subsequent 1,4-
addition to deliver the corresponding lactones 3g,h16 in
relatively low yields (30-31%).
(16) Larock, R. C.; Varaprath, S.; Lau, H. H.; Fellows, C. A. J. Am.
Chem. Soc. 1984, 106, 5274-5284.
To increase the substrate scope of this in situ carbo-
nylation, we decided to investigate challenging o-chlo-
rostyrenes (4) as starting materials. In fact, the catalytic
system employed in Table 1 with o-bromostyrenes (1) was
originally developed by Fu’s research group for activation
(17) trans-Di(µ-acetato)bis[o-(di-o-tolylphosphino)benzyl]dipalladium-
(II); CAS registry no. 172418-32-5.
(18) Kacker, S.; Sissano, J. A.; Schulz, D. N. J. Polym. Sci. Part
A-Polymer Chem. 2000, 38, 752-757.
(19) Cabri, W.; Candiani, I. Acc. Chem. Res. 1995, 28, 2-7.
J. Org. Chem, Vol. 70, No. 1, 2005 347

TABLE 3. Two-Step Synthesis of 3-Acylamino-1-indanones by Internal Heck Arylation and Subsequent
Microwave-Heated in Situ Carboannulation
a Reaction conditions: 3.0 mmol of 5, 7.5 mol % of Pd(OAc)2, 15 mol % of dppp, 3.0 equiv of enamide 6a or 6b, 1.1 equiv of NEt3, and
12.0 mL of DMF at 110 °C; classical heating for 16 h. b Reaction conditions: 0.50-0.82 mmol of 7, 5 mol % of Pd(OAc)2, 10 mol % of
(t-Bu)3PHBF4, 0.5 equiv of Mo(CO)6, 1.0 equiv of n-Bu4NCl, 2.0 equiv of pyridine, and 2.0 mL of dioxane at 160 °C; microwave heating for
30 min. c Reaction conditions: 0.75 equiv of Mo(CO)6. d Reaction conditions: 0.8 equiv of Mo(CO)6 and without pyridine. e Cyclization
according to condition b but product mixture subsequently reduced with Pd/C and HCO2NH4.21
were realized with both enamides 6a and 6b. Although
detriflatation of starting materials 5a-d were always
detected, the fact that no substitution of the bromine
atoms occurred simplified the purification such that this
shortcoming did not compromise the viability of the
reaction, except for the low yields of electron-poor 7c,d
(eq 2, Table 3, entries 3 and 4). Thus, the o-bromoaryl
substituted enamides 7a-h were isolated in 26-78%
yield after standard silica column purification (Table 3).
Higher reaction temperature furnished reduced regiose-
lectivity and lower yields.
To produce the target compounds 8a-h, electron-rich
denones were formed as side products, while debromi-
nation was the most pronounced side reaction with the
remaining caprolactams 8b,d,f,h. Different modifications
of the reaction protocol were therefore investigated to
improve the outcome of entry 1. However, it was expe-
rienced that the original protocol remained the best,
delivering 58% of parent 8a (Table 3). Subsequent
transfer hydrogenation21 of 8a/3-acylamino-2-indenone
reaction mixtures did not result in an improved final
yield of purified 8a. Notably no traces of acetophenones,
7a-h were microwave heated for 30 min on a 0.5-0.8
mmol scale using identical in situ carbonylation condi-
tions as in the syntesis of 2a-e in Table 1 except at a
slightly higher reaction temperature (160 °C). Hence,
products 8a-h could be isolated in 47-88% yield (Table
3). In the synthesis of vinylpyrrolidinones 8a,c,e,g,
5-20% of the corresponding unsaturated 3-acylaminoin-
(20) Cabri, W.; Candiani, I.; Bedeschi, A.; Santi, R. J. Org. Chem.
1992, 57, 3558-3563.
348 J. Org. Chem., Vol. 70, No. 1, 2005

trated and dissolved in 3 mL of dichloromethane. The crude
product was thereafter purified on silica gel using diethyl ether
and pentane to give pure indanones 2a,g-j.
the hydrolysis products from R-arylated enamides 7, were
detected in any of the annulations reactions despite the
high reaction temperature (160 °C).22
General Procedure for Internal Arylation and Isolation
of Enamides 7a-h from 5a-d,20 Table 3. A mixture of Pd-
(OAc)2 (51 mg, 0.23 mmol), dppp (186 mg, 0.45 mmol), aryl
triflate 5 (3.0 mmol),23 NEt3 (334 mg, 3.3 mmol), N-vinylpyrro-
lidinone 6a (1.000 g, 9.0 mmol), or N-vinylcaprolactam 6b (1.253
g, 9.0 mmol) and 12 mL of DMF was stirred at 110 °C under
nitrogen for 16 h using a heating block. The crude product was
concentrated with bulb-to-bulb distillation at 65 °C/1-2 mmHg.
Thereafter, the residue was diluted with 5 mL of dichlo-
romethane and purified on silica gel with a mixture of diethyl
ether, hexane, and triethylamine as eluent to give pure bromo
arylenamides 7.
1-[1-(2-Bromo-4-methylphenyl)vinyl]pyrrolidin-2-one (7e).
The residue was purified over silica gel with 35:65:5 diethyl
ether/hexane/triethylamine as eluent to give 531 mg, yield
63%: 1H NMR (400 MHz, CDCl3) δ 1.96-2.08 (m, 2H), 2.13 (s,
3H), 2.47 (dd, J ) 8.2, 7.9 Hz, 2H), 3.48 (dd, J ) 7.1, 6.9 Hz,
2H), 4.84 (s, 1H), 5.30 (s, 1H), 7.07-7.12 (m, 1H), 7.20 (d, J )
7.7 Hz, 1H), 7.34 (br s, 1H); 13C NMR (100 MHz, CDCl3) δ 18.0,
20.8, 32.0, 48.6, 106.3, 121.5, 128.1, 130.8, 133.0, 135.5, 140.0,
143.0, 173.6; IR 1708 cm-1; MS (m/z, relative intensity) 282 ((M+
+ 2) + H), 25), 280 ((M+ + H), 25), 200 (100); HRMS (FAB+)
calcd for C13H15BrNO (M+ + H) 280.0337, found 280.0323. Anal.
Calcd for C13H14BrNO: C, 55.73; H, 5.04; N, 5.00. Found: C,
55.79; H, 5.09; N, 5.12.
Larock has rationalized the closely related carbonyla-
tive ring closure of unsaturated aryl iodides under
classical conditions in terms of a Pd(0)-catalyzed oxida-
tive addition-carbon monoxide insertion-acylpalladium-
protonation pathway.5 In this highly plausible scenario,
the released Pd(II) salt is subsequently reduced back to
Pd(0) under the reductive pressure of carbon monoxide.
We currently find no reason to question the validity of
this mechanistic hypothesis also for the presented
Mo(CO)6-mediated carboannulation of o-styryl bromides
and chlorides. Regarding the required proton/water
source, we suggest that hygroscopic Bu4NCl provides the
essential water.
We have demonstrated for the first time that the
combination of a thermostable catalytic system and
carbon monoxide releasing Mo(CO)6 with controlled
microwave heating can be utilized in high-speed annu-
lation chemistry for the production of novel indanones
from either o-bromostyrenes or o-chlorostyrenes. Both
neutral and electron-rich o-halostyrene derivatives un-
derwent rapid and robust carbonylative cyclization with-
out the need for an external carbon monoxide source. The
ability to conduct internal Heck arylations of enamides
with o-bromoaryl triflates without affecting the bromo
group enabled easy access to annulation precursors for
the rapid synthesis of valuable 3-amidoindan-1-ones.
Finally, we believe that the use of microwave-assisted
in situ carbonylation protocols will markedly increase the
preparative convenience of carbonylative transformations
in organic synthesis.
General Procedure for Formation and Isolation of
3-Acylaminoindanones 8a-h from o-Bromoaryl Enamides
(7a-h). A 5 mL process vial was flushed with N2 and then
charged with 7 (0.50-0.82 mmol, 1.0 equiv), Mo(CO)6 (0.5 equiv),
Pd(OAc)2 (0.05 equiv), (t-Bu)3PHBF4 (0.1 equiv), Bu4NCl (1.0
equiv), pyridine (2.0 equiv), and dioxane 2.0 mL. The reaction
mixture was flushed with nitrogen again, and the cap was
tightened thoroughly. The vessel was exposed to microwave
heating for 30 min at 160 °C. The reaction tube was thereafter
cooled to room temperature, and the mixture was diluted with
ethyl acetate and then filtered. The precipitate was washed with
ethyl acetate, and the crude product mixture was concentrated.
The residue was dissolved in 3 mL of dichloromethane and
purified over silica gel with petroleum ether-ethyl acetate or
CH2Cl2-MeOH as eluent to afford pure products 8a-h.
1-(5-Methyl-3-oxoindan-1-yl)pyrrolidin-2-one (8e). The
reaction was run at a 0.80 mmol scale and the residue was
purified on silica gel with ethyl acetate to give a colorless solid
(94 mg, yield 51%): 1H NMR (400 MHz, CDCl3) δ 1.85-2.10 (m,
2H), 2.40 (s, 3H), 2.46 (t, J ) 8.4 Hz, 2H), 2.51 (dd, J ) 19.2, 3.2
Hz, 1H), 2.81-2.90 (m, 1H), 3.00 (dd, J ) 19.2, 7.6 Hz, 1H),
3.05-3.14 (m, 1H), 5.94 (dd, J ) 7.6, 3.2 Hz, 1H), 7.31 (d, J )
7.8 Hz, 1H), 7.45 (d, J ) 7.8 Hz, 1H), 7.54 (s, 1H); 13C NMR
(100 MHz, CDCl3) δ 17.6, 20.8, 30.8, 40.3, 41.8, 48.3, 123.1, 125.2,
136.2, 137.0, 139.1, 149.0, 174.9, 202.6; IR 1716, 1686 cm-1; MS
Experimental Section
General Procedure for Carboannulation of o-Bromosty-
renes 1a-h and Isolation of Indanones 2a-2f and Lac-
tones 3 g,h, Table 1. A 5 mL process vial was flushed with N2
and then charged with 1 (1.0 mmol), Mo(CO)6 (132.0 mg, 0.5
mmol), Pd(OAc)2 (11.2 mg, 0.05 mmol), (t-Bu)3PHBF4 (29.0 mg,
0.10 mmol), n-Bu4NCl (277.9 mg, 1.0 mmol), pyridine (158 mg,
2.0 mmol), and dioxane 2.0 mL. The reaction mixture was
flushed with nitrogen again and the cap was tightened thor-
oughly. The vessel was exposed to microwave heating for 20 min
at 150 °C. The reaction tube was thereafter cooled to room
temperature, and the mixture was diluted with ethyl acetate
and then filtered. The precipitate was washed with ethyl acetate.
The organic layer was concentrated and dissolved in 3 mL of
dichloromethane. The crude product was thereafter purified on
silica gel using diethyl ether and pentane as eluents to give pure
indanones 2a-f or lactones 3g,h.
(m/z, relative intensity) 229 (M+, 100). Anal. Calcd for C14H15
-
NO2: C, 73.34; H, 6.59; N, 6.11. Found: C, 73.34; H, 6.56; N,
6.17.
Acknowledgment. We acknowledge financial sup-
port from the Swedish Research Council and the Knut
and Alice Wallenberg Foundation. We also thank Biotage
AB for providing us with the Smith Microwave synthe-
sizer. Finally, we thank Prof. Anders Hallberg, Dr.
Mathias Alterman, and Mr. Shane Peterson for intel-
lectual contributions to this project.
General Procedure for Formation and Isolation of
Indanones 2a,g-j from o-Chlorostyrenes 4a-e, Table 2. A
5 mL process vial was flushed with N2 and then charged with 4
(1.0 mmol), Mo(CO)6 (132 mg, 0.5 mmol), Herrmann’s pallada-
cycle (47 mg, 0.05 mmol), (t-Bu)3PHBF4 (29 mg, 0.10 mmol),
n-Bu4NCl (278 mg, 1.0 mmol), pyridine (158 mg, 2.0 mmol), and
dioxane 2.0 mL. The reaction mixture was flushed with nitrogen
again, and the cap was tightened thoroughly. The vessel was
exposed to microwave heating for 30 min at 170 °C. The reaction
tube was thereafter cooled to room temperature, and the mixture
was diluted with ethyl acetate and then filtered. The precipitate
was washed with ethyl acetate. The organic layer was concen-
Supporting Information Available: Experimental pro-
cedures and spectral data for all new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
JO048375G
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J. Org. Chem, Vol. 70, No. 1, 2005 349