Microwave-accelerated spiro-cyclizations of o-halobenzyl cyclohexenyl ethers by palladium(0) catalysis

Article abstract of DOI:10.1021/jo0708487

(Chemical Equation Presented) A number of new spiro[cyclohexane-1,1′- isobenzofuran]-based compounds was synthesized by palladium(0)-catalyzed 5-exo cyclization of a series of cyclohexenyl o-halobenzyl ethers. Controlled microwave heating was found to pro

Full text of DOI:10.1021/jo0708487

Intramolecular Heck arylations proceed, when possible, with
a preference for 5- and 6-exo cyclizations, except in a few cases
where endo cyclizations have been reported.7,10 As revealed by
a large number of prominent chemists,11-13 when operating
under optimized conditions, this class of cyclization reactions
has a remarkable ability to form congested quaternary centers.14
This report is part of an ongoing project toward the develop-
ment of novel and robust metal-catalyzed transformations of
fundamental importance with a special focus on microwave-
enhanced protocols. Construction of rare spiro-compounds from
o-halobenzyl cyclohexenyl ethers 1-8 was envisioned via 5-exo
cyclization. Herein we report the discovery and examination of
a series of microwave-accelerated intramolecular Heck reactions
with controlled regioselectivity. The developed methodology
allowed facile formation of new and restricted spiro[cyclohex-
ane-1,1′-isobenzofuran] derivatives 9-12.
Microwave-Accelerated Spiro-Cyclizations of
o-Halobenzyl Cyclohexenyl Ethers by
Palladium(0) Catalysis
Andreas Svennebring, Peter Nilsson, and Mats Larhed*
Organic Pharmaceutical Chemistry, Department of Medicinal
Chemistry, Uppsala Biomedical Centre, Uppsala UniVersity,
Box 574, SE-751 23 Uppsala, Sweden
mats@orgfarm.uu.se
ReceiVed May 2, 2007
SCHEME 1. Preparation of Heck Cyclizations Substrates
1-6
A number of new spiro[cyclohexane-1,1′-isobenzofuran]-
based compounds was synthesized by palladium(0)-catalyzed
5-exo cyclization of a series of cyclohexenyl o-halobenzyl
ethers. Controlled microwave heating was found to promote
both product yield and reaction rate without compromising
the selectivity. Heck cyclization of aryl iodide 6, 2-(2-
iodobenzyloxy)cyclohex-2-enyl acetate, proceeded selectively
without involvement of the allylic acetate functionality.
New methods in preparation of constrained products are of
importance in both natural product synthesis and in medicinal
chemistry applications. In drug discovery, the use of restricted
analogues serves as an important method to allow determination
of bioactive conformations.1 Palladium(0)-catalyzed Heck cou-
pling reactions have emerged as one of the most versatile
carbon-carbon bond forming processes.2-6 The reaction is
attractive for the synthetic chemist since (a) it provides a unique
method for arylation or vinylation of double bonds, (b) it
proceeds under mild conditions, and c) it tolerates the presence
of a wide variety of functional groups. Although the traditional
intermolecular Heck coupling has found wide utility, the
intramolecular version of the Heck arylation constitutes perhaps
the most important development of the Heck arylation reaction
in recent times.7,8 Unfortunately, the optimization of Heck
reaction conditions is typically demanding and reaction times
are generally long.9
Preparation of Cyclization Precursors. The required ethers
1-6 were all prepared from commercially available 1,2-
cyclohexanedione (Scheme 1). Ketones 1 and 2 were prepared
by treating the appropriate o-halobenzyl alcohol with an excess
of 1,2-cyclohexanedione and a catalytic amount of p-toluene-
sulfonic acid (PTSA). The condensation reaction was carried
out in dry benzene, and the produced water was continuously
removed via azeotropic distillation. This process afforded 1 and
2 in good yields (83% and 77%, respectively). Alcohols 3 and
4, were smoothly synthesized by the sodium borohydride
reduction of 1 and 2, respectively. Finally, allylic esters 5 and
6 were prepared in 90% and 89% yield by acetylation of 3 and
4, using acetic anhydride and 4-dimethylaminopyridine (DMAP).
Vinyl ethers 7 and 8 were synthesized via an acid-catalyzed
transetherification reaction from methyl 1-cyclohexenyl ether
and the appropriate o-halobenzyl alcohol (Scheme 2). The
* To whom correspondence should be addressed. E-mail: mats@orgfarm.uu.se.
Tel.: +46-18-4714667. Fax: +46-18-4714474.
(1) Ullrich, T.; Krich, S.; Binder, D.; Mereiter, K.; Anderson, D. J.;
Meyer, M. D.; Pyerin, M. J. Med. Chem. 2002, 45, 4047-4054.
(2) De Meijere, A.; Meyer, F. E. Angew. Chem., Int. Ed. Engl. 1994,
33, 2379-2411.
(7) Gibson, S. E.; Middleton, R. J. Contemp. Org. Synth. 1996, 3, 447-
471.
(8) Overman, L. E. Pure Appl. Chem. 1994, 66, 1423-1430.
(9) Larhed, M.; Moberg, C.; Hallberg, A. Acc. Chem. Res. 2002, 35,
717-727.
(3) Beletskaya, I. P.; Cheprakov, A. V. Chem. ReV. 2000, 100, 3009-
3066.
(10) Wannberg, J.; Dallinger, D.; Kappe, C. O.; Larhed, M. J. Comb.
Chem. 2005, 7, 574-583.
(4) Larhed, M.; Hallberg, A. In Handbook of Organopalladium Chemistry
for Organic Synthesis; Negishi, E.-i., Ed.; Wiley-Interscience: New York,
2002; Vol. 1, pp 1133-1178.
(11) Shibasaki, M.; Boden, C. D. J.; Kojima, A. Tetrahedron 1997, 53,
7371-7395.
(5) Phan, N. T. S.; Van Der Sluys, M.; Jones, C. W. AdV. Synth. Catal.
2006, 348, 609-679.
(12) Dounay, A. B.; Overman, L. E. Chem. ReV. 2003, 103, 2945-2963.
(13) Ripa, L.; Hallberg, A. J. Org. Chem. 1997, 62, 595-602.
(14) Corey, E. J.; Guzman-Perez, A. Angew. Chem., Int. Ed. 1998, 37,
388-401.
(6) Nilsson, P.; Olofsson, K.; Larhed, M. Top. Curr. Chem. 2006, 266,
103-144.
10.1021/jo0708487 CCC: $37.00 © 2007 American Chemical Society
Published on Web 06/28/2007
J. Org. Chem. 2007, 72, 5851-5854
5851

SCHEME 2. Preparation of Heck Cyclizations Substrates 7
and 8
generating o-bromotoluene as byproduct, together with other
decomposition products. Employing considerably less polar
toluene, as the solvent, furnished a significant improvement in
both product selectivity and yield (Table 1). The best results
with 1 were obtained after 10 min of microwave heating at
180 °C using sealed vessels (82% 9a, entry 1), while the
identical cyclization performed at 120 °C with classical heating
delivered 71% of conjugated vinyl ketone 9a after 18 h (entry
2). Addition of 5% v/v of water provided almost identical yields
of 9a (80% with microwave heating and 70% with oil-bath
heating). Changing the ammonium salt additive to the halide
free salts tetrabutylammonium hydrogen sulfate or tetra-
butylammonium acetate severely diminished the isolated yield
(22% and 9%, respectively). Regardless of the reaction system,
full exo-selectivity and complete double-bond migration to give
the R,â-unsaturated ketone was observed in all halide-containing
reactions.
CHART 1. Heck Cyclization Products
With the more exclusive aryl iodide substrate 2 in hand, we
first explored similar nonaqueous toluene based conditions as
developed for aryl bromide 1. However, it was quickly realized
that the ring-closure was promoted by the addition of 5% v/v
of water.3 With this aqueous solvent system, high yields of 9a
were smoothly obtained with both microwave and classical
heating (entries 3 and 4, Table 1). The enhanced reactivity of
2 encouraged us to investigate the use of silver additives to
inhibit double bond migration and thus the production of
conjugated ketone 9a.12,21 In fact, predominant formation of
regioisomer 9b (Table 1, entry 5, Chart 1) could be ac-
complished by the addition of Ag3PO4 (0.6 equiv) and replacing
TBAB and toluene with tetrabutylammonium hydrogen sulfate
and dioxane. In addition to 9a and 9b, the corresponding 6-endo-
arylation product (1,2-dihydrodibenzo[b,d]pyran-4(3H)-one) was
also isolated (14%). Despite extensive tuning of several reaction
equilibrium was driven toward the elimination products 7 and
8 by the continuous removal of methanol via azeotropic
distillation. The remaining o-halobenzyl ketal was consumed
by subjecting the crude product to 5 min of microwave
irradiation (220 °C) in dimethylacetamide (DMAc).
Palladium-Catalyzed Spiro-Cyclizations. We have previ-
ously reported a number of very rapid microwave-accelerated
palladium-catalyzed intermolecular Heck reactions.15-17 How-
ever, this convenient superheating methodology has not been
generally applied to intramolecular Heck processes.18,19 There-
fore, we decided to utilize controlled microwave irradiation for
the fast spiro-cyclization of 1-8, although for comparison and
general usefulness we decided to also include examples with
traditional heating.
parameters, full conversion of 2 was never obtained in presence
12,21
of Ag3PO4.
We also investigated a number of additional
silver(I)22 and thallium(I)23 salts, but they proved even less
successful, typically affording yields below 10% of ring-closed
products.
Switching our attention toward allyl alcohols 3 and 4, as
cyclization precursors, proved straightforward. Even though the
allylic double bond is considered more electron-rich and thus
slightly less reactive under the established neutral Heck condi-
tions,24 spiro-cyclohexanone product 10a was directly obtained
as the dominating product, regardless of the heating method
(entries 6-8, Table 1). Double bond migration and subsequent
Pd-enolate tautomerism explain the formation of the saturated
ketone 10a.4,25 After chromatography, 51-59% of ketone 10a
and 7-15% of alcohols 10b,c (E/Z-mixture) were isolated. The
effect of solvent polarity was next studied with n-hexane-
toluene-water mixtures as an alternative to the above utilized
toluene-water system. In short, the selectivity for 10a improved
although the total yield diminished with increasing n-hexane
content (entries 9 and 10).
Among the available reported protocols for Heck reactions
with aryl bromides, we chose phosphine-free Jeffery type
conditions with the addition of 2 equiv of tetrabutylammonium
bromide (TBAB) for ring-closure of captodative olefin 1.20
Classical Pd(OAc)2 (1%) was used as the palladium source, and
pentamethylpiperidine (PMP)12 was chosen as the amine base,
since it was found to be superior to less hindered amines, e.g.,
triethylamine or diisopropylethylamine. In the initial microwave-
mediated cyclization experiments we employed DMF or PEG,
with or without addition of water, as reaction media in sealed
vessels at 150-180 °C. Under these conditions, spiro-compound
9a (Chart 1) was quickly formed although starting material 1
also underwent competing degradation by benzylic cleavage,
(15) Larhed, M.; Hallberg, A. J. Org. Chem. 1996, 61, 9582-9584.
(16) Olofsson, K.; Larhed, M. In MicrowaVe Assisted Organic Synthesis;
Tierney, J., Lindstro¨m, P., Eds.; Blackwell Publishing: Malden, MA, 2005;
pp 23-43.
(21) McDermott, M. C.; Stephenson, G. R.; Walkington, A. J. Synlett
2007, 51-54.
(17) Svennebring, A.; Nilsson, P.; Larhed, M. J. Org. Chem. 2004, 69,
3345-3349.
(22) Karabelas, K.; Westerlund, C.; Hallberg, A. J. Org. Chem. 1985,
50, 3896-3900.
(18) Larhed, M.; Hallberg, A. Drug DiscoVery Today 2001, 6, 406-
(23) Grigg, R.; Loganathan, V.; Santhakumar, V.; Sridharan, V.; Teasdale,
A. Tetrahedron Lett. 1991, 32, 687-690.
416.
(19) Lautens, M.; Tayama, E.; Herse, C. J. Am. Chem. Soc. 2005, 127,
72-73.
(20) Jeffery, T. Tetrahedron 1996, 52, 10113-10130.
(24) Cabri, W.; Candiani, I. Acc. Chem. Res. 1995, 28, 2-7.
(25) Larock, R. C.; Leung, W. Y.; Stolz-Dunn, S. Tetrahedron Lett. 1989,
30, 6629-6632.
5852 J. Org. Chem., Vol. 72, No. 15, 2007

TABLE 1. Palladium Catalyzed Spiro-Cyclizations
a Conditions: 0.50 mmol starting olefin, 0.005-0.05 mmol Pd(OAc)2, 2.0 mmol PMP, 1.0 mmol TBAB, solvent added to provide a total volume of 3 mL.
Reaction vessels were sealed under air. Entries 12 and 14 required 10 mol% Pd(OAc)2 to give full conversion. b 95% purity by GC-MS and 1H NMR. c 0.3
mmol of Ag3PO4 was added to the reaction mixture and TBAB was replaced by an equimolar amount of tetrabutylammonium hydrogen sulfate. d 14% of
the corresponding product from arylation in the 3-position was isolated. e Combined isolated yield of 10b and 10c. Diastereomeric mixture 3:1.
In an attempt to inhibit the formation of the thermodynami-
cally favored ketone 10a via a repeated HPdX elimination-
insertion sequence, the free hydroxy group of 4 was modified
into the corresponding blocked O-acetyl compound 6 (Scheme
1). The hypothesis was first tested by subjecting 6 to the same
conditions used for the spiroannulation of 4. However, sub-
stantially higher yields were achieved when the reaction was
performed in DMF. Four compounds of a reminiscent mass
spectrometric fragmentation pattern were detected, although only
the most abundant, 11a, could be isolated in a pure state (54%,
entry 11). According to 1H NMR of the crude product mixture,
the diastereomeric ratio of 11a/11b was 2.5:1. Also, 11c and
11d were detected in minor amounts.
Starting from 5 or 6, no side products from competing allylic
substitutions were detected. Given the well-known reactivity
of allylic acetates toward palladium(0) and the presence of 2
equiv of potentially nucleophilic bromide ions (from TBAB),
we find the selective activation of the aryl-iodo bond at
140 °C noteworthy.26 This selectivity may be due to a Pd(0)-
vinyl group precoordination and subsequent presentation of the
metal center to the halogen-carbon bond. The addition of
dimethyl malonate to the reaction mixture did not give rise to
any new products, and the only impact was a significantly
reduced reaction rate. The attempted Heck cyclization starting
from bromide precursor 5 was too sluggish to be preparatively
useful, but GC-MS investigations revealed that the same product
mixture (11a-d) resulted as when starting from 6.
such as aqueous DMF significantly promoted the reaction and,
fortunately, electron-rich 7 and 8 did not decompose in this
solvent system despite microwave heating to 140-180 °C. The
highest yield of ring-closed allylic ether 12 (77%) was obtained
with 10 mol% Pd(OAc)2 (entry 14, Table 1). It is notable that
no double bond isomerization seems to occur.
In summary, new, fast, and highly efficient intramolecular
Heck methods for the generation of conformationally restricted
spiro[cyclohexane-1,1′-isobenzofuran] derivatives have been
established. The double bond position and oxidation state of
the hexacycle was controlled by a careful choice of starting
materials and reaction conditions. The presented reactions
constitute an alternative to free radical protocols for construction
of spirocyclic compounds.27-29 In all investigated reactions,
high-density microwave heating afforded shorter reaction times
(10 min) and higher yields compared with classical heating.
Experimental Section
General Procedure for Preparation of 2-(2-Halobenzyloxy)-
2-cyclohexenones (1 and 2). The following chemicals were added
to a dry 100 mL three-necked round-bottomed flask: either
o-bromobenzyl alcohol (4.68 g, 25 mmol) or o-iodobenzyl alcohol
(5.85 g, 25 mmol), 1,2-cyclohexandione (4.20 g, 37.5 mmol),
p-toluenesulfonic acid monohydrate (0.28 g, 1.25 mmol), and
benzene (50 mL). A Soxhlet device filled with K2CO3 (s) was
connected to the flask with a condenser on the top. Upon heating,
condensed vapors rinsed through the Soxhlet device, trapping the
released water. The contents of the flask were magnetically stirred
and heated using an oil bath (120 °C) until no further conversion
of the o-halobenzyl alcohol was detected. A second portion of 1,2-
cyclohexandione (1.40 g, 12.5 mmol) was added, and the reaction
Finally, we turned our attention to exploring the cyclization
of vinyl ethers 7 and 8. Trying the toluene conditions previously
found to be successful for the reaction of 1-4, cyclization of 7
and 8 proved sluggish. In contrast, the use of more polar solvents
(27) Zhang, W.; Pugh, G. Tetrahedron Lett. 1999, 40, 7595-7598.
(28) Zhang, W.; Pugh, G. Tetrahedron Lett. 2001, 42, 5617-5620.
(29) Zhang, W.; Pugh, G. Tetrahedron 2003, 59, 4237-4247.
(26) Mariampillai, B.; Herse, C.; Lautens, M. Org. Lett. 2005, 7, 4745-
4747.
J. Org. Chem, Vol. 72, No. 15, 2007 5853

was continued until not more than traces of o-halobenzyl alcohol
remained in the reaction mixture. The reaction mixture was cooled
to 0 °C, 0.5 M Na2CO3 (100 mL) was added, and the layers were
separated. The organic phase was washed with additional portions
of 0.5 M Na2CO3 until no trace of 1,2-cyclohexandione was left.
The organic phase was dried (MgSO4) and concentrated under
reduced pressure. The crude product was purified by silica
chromatography (ether/toluene) to give the title products.
2-(2-Bromobenzyloxy)-cyclohex-2-enone (1). The compound
was prepared according to the General Procedure for Preparation
of 2-(2-Halobenzyloxy)-2-cyclohexenones. White crystalline solid,
83% yield (5.83 g, 20.7 mmol, >95% by GC-MS), mp ) 51 °C.
1H NMR (400 MHz, CDCl3) δ 7.54-7.48 (m, 2H), 7.33-7.28 (m,
1H), 7.17-7.12 (m, 1H), 5.91 (t, J ) 4.6 Hz, 1H), 4.90 (s, 2H),
2.53 (t, J ) 6.7 Hz, 2H), 2.39 (td, J ) 6.0, 4.6 Hz, 2H), 1.96 (tt,
J ) 6.7, 6.0 Hz, 2H). 13C NMR (100 MHz, CDCl3) δ 194.2, 150.3,
136.0, 132.6, 129.4, 128.9, 127.8, 122.1, 119.8, 69.0, 39.1, 24.7,
23.1. IR (KBr) 1692 cm-1. MS m/z (relative intensity 70 eV) 253
(10), 251 (10), 202 (16), 201 (100), 173 (19), 171 (98), 170 (13),
169 (94), 90 (38), 89 (37), 63 (23), 55 (24). Anal. Calcd for C13H13-
BrO2: C, 55.54; H, 4.66. Found: C, 55.40; H, 4.56.
General Procedure for Preparation of 2-(2-Halobenzyloxy)-
cyclohex-2-enol (3 and 4). 1 (7.03 g, 25 mmol) or 2 (8.20 g, 25
mmol) was dissolved in a mixture of THF (50 mL) and methanol
(50 mL) in a 250 mL round bottomed flask and cooled to 0 °C.
NaBH4 (0.95 g, 25 mmol) was added in portions under continuous
cooling and stirring. The mixture was allowed to stir for another
10 min before 0.5 M citric acid (50 mL) was added, and finally
the mixture was concentrated to <20 mL under reduced pressure.
The remaining mixture was extracted with diethyl ether, the
combined ethereal phases were dried (MgSO4) and concentrated,
and the residue was purified by chromatography (aluminum oxide
with 6% (w/w) water added, ether/toluene eluent) to furnish the
title products.
2-(2-Bromobenzyloxy)-cyclohex-2-enol (3). The compound was
prepared according to the General Procedure for Preparation of 2-(2-
Halobenzyloxy)-2-cyclohexenol. White solid, 92% yield (6.51 g,
23.0 mmol, >95% by GC-MS), mp ) 54 °C. 1H NMR (400 MHz,
CDCl3) δ 7.56 (dd, J ) 8.0, 1.3 Hz, 1H), 7.46 (dd, J ) 7.7, 1.8
Hz, 1H), 7.32 (ddd, J ) 7.7, 7.5, 1.3 Hz, 1H), 7.17 (ddd, J ) 8.0,
7.5, 1.8 Hz, 1H), 4.86-4.84 (m, 1H), 4.81 (s, 2H), 4.26-4.24 (m,
1H), 2.42 (s, 1H), 2.20-2.10 (m, 1H), 2.08-1.99 (m, 1H), 1.92-
1.77 (m, 2H), 1.76-1.66 (m, 1H), 1.61-1.52 (m, 1H). 13C NMR
(100 MHz, CDCl3) δ 154.6, 136.7, 133.0, 129.6, 129.5, 127.8,
123.1, 98.4, 68.7, 66.7, 31.3, 24.2, 19.0. IR (thin film) 3422, 3364
cm-1. MS m/z (relative intensity 70 eV) 266 (12), 264 (12), 186
(11), 185 (18), 172 (11), 171 (100), 170 (12), 169 (93), 90 (30), 89
(34), 67 (11), 63 (14). Anal. Calcd for C13H15BrO2: C, 55.14; H,
5.34. Found: C, 55.01; H, 5.21. Compound unstable in solution.
General Procedure for Spiro-Cyclizations (Table 1). The
following chemicals were added to a thick-walled tube: Pd(OAc)2,
either as a 0.1 M stock solution (50 µL of solution containing 22.5
mg/mL Pd(OAc)2 in acetonitrile, 0.005 mmol) or as solid (11.2
mg, 0.05 mmol); tetrabutylammonium bromide (322 mg, 1 mmol)
or tetrabutylammonium hydrogen sulfate (340 mg, 1 mmol); either
of the substrates: 1 (141 mg, 0.5 mmol), 2 (164 mg, 0.5 mmol), 3
(142 mg, 0.5 mmol), 4 (165 mg, 0.5 mmol), 5 (163 mg, 0.5 mmol),
6 (186 mg, 0.5 mmol), 7 (134 mg, 0.5 mmol), or 8 (157 mg, 0.5
mmol); in entry 5 only, Ag3PO4 (84 mg, 0.2 mmol); 3 mL of solvent
and PMP (0.362 mL, 2 mmol). The reaction mixture was septum
sealed in air and magnetically stirred and heated according to
specifications. The reaction mixture was cooled, diluted (diethyl
ether) and washed with water, dried (K2CO3), and concentrated
under vacuum, and the residue was purified by chromatography
(silica, ether/isohexane mobile phase) to yield products 9-12.
3′H-Spiro[cyclohex-3-ene-1,1′-isobenzofuran]-2-one (9a). Col-
orless oil, 91% yield (91.1 mg, 0.455 mmol, Table 1, entry 3, >95%
1
by GC-MS). H NMR (400 MHz, CDCl3) δ 7.27-7.21 (m, 1H),
7.20-7.15 (m, 2H), 7.11-7.08 (m, 1H), 7.01 (dtd, J ) 10.1, 4.0,
0.7 Hz, 1H), 6.07 (dt, J ) 10.1, 2.0 Hz, 1H), 5.19 (d, J ) 12.2 Hz,
1H), 5.09 (d, J ) 12.2 Hz, 1H), 2.58 (dddd, J ) 6.7, 5.5, 4.0, 2.0
Hz, 2H), 2.31 (ddd, J ) 13.6, 5.5, 0.7 Hz, 1H), 2.25 (dtd, J )
13.6, 6.7, 5.5 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ 196.2, 150.7,
140.1, 139.6, 129.0, 128.7, 127.6, 121.9, 121.7, 89.5, 73.2, 34.4,
24.5. IR (thin film) 1682 cm-1. MS m/z (relative intensity 70 eV)
200 (67), 182 (11), 133 (23), 132 (100), 131 (41), 115 (13), 104
(49), 103 (19), 90 (12), 89 (22), 78 (17), 77 (11), 63 (13), 50 (10).
Anal. Calcd for C13H12O2: C, 77.98; H, 6.04. Found: C, 77.75; H,
5.94.
Acknowledgment. We acknowledge the Swedish Research
Council, Knut and Alice Wallenberg’s Foundation, Prof. Anders
Hallberg, and Dr. Luke Odell.
Supporting Information Available: Text giving full details of
experimental procedures and spectroscopic data. This material is
available free of charge via the Internet at http://pubs.acs.org.
JO0708487
5854 J. Org. Chem., Vol. 72, No. 15, 2007