Protected indanones by a Heck-Aldol annulation reaction

Article abstract of DOI:10.1021/jo025756q

Monoprotected 3-hydroxyindan-1-ones have been prepared in moderate to good yields by a new tandem reaction involving salicylaldehyde triflates and commercially available 2-hydroxyethyl vinyl ether. This one-pot annulation reaction proceeds in the presence of a palladium bidentate catalyst and results in the formation of two new ring systems.

Full text of DOI:10.1021/jo025756q

P r otected In d a n on es by a Heck -Ald ol
An n u la tion Rea ction
Anna Bengtson, Mats Larhed, and Anders Hallberg*
Department of Organic Pharmaceutical Chemistry, Uppsala
University, BMC, Box-574, SE-751 23 Uppsala, Sweden
Anders.Hallberg@farmkemi.uu.se
Received March 25, 2002
Abstr a ct: Monoprotected 3-hydroxyindan-1-ones have been
prepared in moderate to good yields by a new tandem
reaction involving salicylaldehyde triflates and commercially
available 2-hydroxyethyl vinyl ether. This one-pot annula-
tion reaction proceeds in the presence of a palladium
bidentate catalyst and results in the formation of two new
ring systems.
Indan structures are important components in many
bioactive compounds. Two examples of protease inhibitors
that contain the indan fragment are the aspartyl protease
inhibitor indinavir,1 an anti-HIV agent in clinic, and the
orally available matrix metalloprotease (MMP) inhibitor2
in Figure 1. In a medicinal chemistry program, where
carbohydrates are used as precursors for C2-symmetric
HIV-1 protease inhibitors,3 we require access to acetals
of 3-hydroxyindan-1-ones (3). These 1,3-difunctionalized
indan derivates should serve as suitable starting struc-
tures for further modification into a diverse array of
P2/P2′ residues.
F IGURE 1. Bioactive compounds containing indan structures.
of the commercially available 2-hydroxyethyl vinyl ether
(2) and subsequent ring-closure (eq 1). This one-pot
annulation offers a new route to monoprotected hydroxy
indanones.
Derivatives of 3-hydroxyindan-1-one have previously
been prepared by a more elaborate procedure involving
an intramolecular Friedel-Craft-type cyclization,4
a
reaction sequence that was not applicable for our pur-
poses. Aldol reactions with strong bases have been
employed to generate the 3-hydroxyindan-1-one system
in some complex molecules,5 but examples that lack
substituents in the 2-position are rare. The synthesis of
the parent 3-hydroxyindan-1-ones from the correspond-
ning o-formyl acetophenones by an aldol reaction has, to
the best of our knowledge, not been reported.
Initially we attempted to prepare 3a (R ) H) via an
aldol reaction of o-formyl acetophenone, followed by a
ketalization reaction (Scheme 1). Thus, the triflate 1a
was reacted with butyl vinyl ether in the presence of a
palladium-dppp catalyst.7 According to LC/MS the inter-
nal arylation smoothly produced the enol ether 4, but the
acid-mediated generation of the o-formyl acetophenone
was not successful. Only 3-hydroxyindanone (5) could be
isolated in low yield from the complex product mixture.
In fact, no o-formyl acetophenone was traced as deduced
from LC-MS.
We herein report that triflates (1) of salicylic alde-
hydes6 can be conveniently converted to 1,1-(ethylene-
dioxy)-3-hydroxyindans (3) by an internal Heck arylation
Fortunately, by using 2-hydroxyethyl vinyl ether8,9 as
the olefin instead of butyl vinyl ether, the outcome of the
reaction was significantly improved. Following this modi-
fication not only was the annulation accomplished, but
also the protection of the ketone was achieved concomi-
tantly (Scheme 2).
A mixture of the salicylic triflate (1) (1.0 equiv), the
hydroxyethyl vinyl ether (2) (3.0 equiv), and palladium
acetate/dppp (1,3-bis(diphenylphosphino)propane) (0.01/
0.02 equiv) with triethylamine or 1,2,2,6,6-pentameth-
ylpiperidine (PMP) (2.2 equiv) as base and DMF as
(1) Vacca, J . P.; Dorsey, B. D.; Schleif, W. A.; Levin, R. B.; McDaniel,
S. L.; Darke, P. L.; Zugay, J .; Quintero, J . C.; Blahy, O. M.; Roth, E.;
Sardana, V. V.; Schlabach, A. J .; Graham, P. I.; Condra, J . H.; Gotlib,
L.; Holloway, M. K.; Lin, J .; Chen, I.; Vastag, K.; Ostovic, D.; Anderson,
P. S.; Emini, E. A.; Huff, J . R. Proc. Natl. Acad. Sci. U.S.A. 1994, 91,
4096-4100.
(2) Yao, W.; Wasserman, Z. R.; Chao, M.; Reddy, G.; Shi, E.; Liu,
R.-Q.; Covington, M. B.; Arner, E. C.; Pratta, M. A.; Tortorella, M.;
Magolda, R. L.; Newton, R.; Qian, M.; Ribadeneira, M. D.; Christ, D.;
Wexler, R. R.; Decicco, C. P. J . Med. Chem. 2001, 44, 3347-3350.
(3) Alterman, M.; Andersson, H. O.; Garg, N.; Ahlsen, G.; Lo¨vgren,
S.; Classon, B.; Danielson, U. H.; Kvarnstro¨m, I.; Vrang, L.; Unge, T.;
Samuelsson, B.; Hallberg, A. J . Med. Chem. 1999, 42, 3835-3844.
(4) Dallemagne, P.; Pilo, J . C.; Rault, S.; Robba, M. Bull. Soc. Chim.
Fr. 1993, 130, 121-124.
(5) Boger, D. L.; J acobson, I. C. Tetrahedron Lett. 1989, 30, 2037-
2040.
(6) Bengtson, A.; Hallberg, A.; Larhed, M. Org. Lett. 2002, 4, 1231-
1233.
(7) Cabri, W.; Candiani, I. Acc. Chem. Res. 1995, 28, 2-7.
(8) Larhed, M.; Hallberg, A. J . Org. Chem. 1997, 62, 7858-7862.
(9) Vallin, K. S. A.; Larhed, M.; J ohansson, K.; Hallberg, A. J . Org.
Chem. 2000, 65, 4537-4542.
10.1021/jo025756q CCC: $22.00 © 2002 American Chemical Society
Published on Web 07/04/2002
5854
J . Org. Chem. 2002, 67, 5854-5856

SCHEME 1. r-Ar yla tion of Bu tyl Vin yl Eth er
F ollow ed by Cycliza tion
which triethylamine was used. Analysis of the reaction
mixture revealed that the reaction was more selective
when PMP was used. No ring closure occurred with the
inorganic base potassium carbonate.
Overall, moderate to good yields were encountered
except in cases where very electron-deficient aryl triflates
were subjected to the reaction conditions. For example,
the triflate of 4-nitrosalicylic aldehyde (entry 6) com-
pletely failed to deliver indans of type 3. A low conversion
of the aryl triflate to the internally arylated vinyl ether
in the Heck reaction accounts for this result.10 In the two
examples in which methoxy groups were meta to the
formyl group (entries 2 and 3), most of the cyclization
occurred prior to the addition of acetic acid with both
amine bases. For the preparation of 3d , where the
electron-releasing methoxy group is located in the para
position to the formyl group, the acetic acid addition was
absolutely essential to promote cyclization/ketalization
(entry 4). To achieve a reasonable reaction rate, an extra
amount of acetic acid (4.3 equiv) and a higher tempera-
ture (100 °C) were employed. In fact, when triethylamine
was used as the base no tricyclic 3d was obtained at all.
SCHEME 2. Rea ction Sequ en ce for th e
Heck -Ald ol Rea ction
TABLE 1. On e-P ot Syn th esis of Mon op r otected
3-h yd r oxyin d a n on es (3)a
The Heck arylation of vinyl ethers with aryl triflates
and bidentate ligands is proposed to proceed via charged
aryl palladium species.7,11,12 The insertion process is
electronically controlled leading to R-arylation of the
electron-rich olefin. We believe that 3 is formed by a
reaction sequence similar to that shown in Scheme 2.
Despite the fact that the 2-hydroxyethyl vinyl ether has
previously been used successfully for preparation of
ketals of acetophenones,8 no monocyclic 2-aryl-2-methyl-
1,3-dioxolane was detected after the Heck reaction in the
annulation reaction.8,9,13 In attempts to better understand
factors of importance for the annulation step, the inter-
mediate 6a was isolated and used as the starting mate-
rial for a series of model experiments. The experiments
demonstrated that catalytic amounts of palladium ac-
etate promote cyclization under acidic conditions. In
addition, a slow ring-closure was observed when acetic
acid was used and the palladium catalyst was omitted.
No cyclization occurred without addition of acid. The fact
that the corresponding R-arylated butyl vinyl ether (4)
undergoes slower and less selective cyclization than 6a
under identical conditions suggests that the terminal
hydroxyl group plays an active role in the carbon-carbon
bond formation by stabilization of the partial positive
charge that builds up on the R-carbon as ring closure
occurs. Related neighboring group participations have
been proposed in other aldol-type condensation-like reac-
tions involving vinyl ethers and aldehydes.14 We therefore
postulate that the formation of 3 proceeds via a tandem
reaction in which the two ring systems are formed after
a highly regioselective palladium(0)-catalyzed arylation
a
b
Reaction scale: 200 µmol 1a -f. With PMP as base. c With
d
Et3N as base. Slow ring closure; 50 µL (4.3 equiv) acetic acid and
100 °C for 24 h. e No product was detected.
(10) It is known that electron-poor aryl triflates react sluggishly in
internal Heck arylations. Larhed, M.; Andersson, C. M.; Hallberg, A.
Tetrahedron 1994, 50, 285-304.
solvent was heated for 1-2 h at 120 °C. Following the
complete consumption of 1, acetic acid (2.6 equiv) was
routinely added and the reaction was stirred overnight
at 80 °C. The results of the preparative reactions with a
small series of salicylic triflates are outlined in Table 1.
As is apparent, the isolated yields of the tricyclic products
were higher after employing the sterically hindered base
PMP, compared to the more classical Heck conditions in
(11) Beletskaya, I. P.; Cheprakov, A. V. Chem. Rev. 2000, 100, 3009-
3066.
(12) Larhed, M.; Hallberg, A. In Handbook of Organo-Palladium
Chemistry for Organic Synthesis; Negishi, E.-i., Ed.; J ohn Wiley &
Sons: New York, 2002: Chapter IV.2.1.1.
(13) McClelland, R. A.; Watada, B.; Lew, C. S. Q. J . Chem. Soc.,
Perkin Trans. 2 1993, 1723-1727.
(14) Faunce, J . A.; Grisso, B. A.; Mackenzie, P. B. J . Am. Chem.
Soc. 1991, 113, 3418-3426.
J . Org. Chem, Vol. 67, No. 16, 2002 5855

161.7. MS (EI, 70 eV) m/z 222 (M+, 31), 205 (31), 179 (100), 161
(28). IR (neat) 3435 cm-1. Anal. Calcd for C12H14O4: C 64.9, H
6.4. Found: C 64.9, H 6.1.
of 2 and a protonation (or palladium(II) activation) of the
formyl group.15
In summary an efficient tandem annulation reaction
that delivers monoblocked 1,3-difunctionalized indans
from electron-rich or neutral salicylic aldehydes has been
developed. The synthetic method merits special attention
as for the simplicity of the one-pot experimental proce-
dure and the use of readily accessible starting materials.
1,1-(Eth ylen edioxy)-3-h ydr oxy-7-m eth oxyin dan (3c). The
title compound was obtained in 52% yield (23.1 mg) as an orange
1
syrup. H NMR (400 MHz, CDCl3) δ 2.18 (dd, J ) 4.6, 13.9 Hz,
1H), 2.26 (br s, 1H), 2.67 (dd, J ) 6.8, 13.9 Hz, 1H), 3.85 (s, 3H),
3.97-4.06 (m, 2H), 4.19-4.26 (m, 2H), 5.09 (dd, J ) 4.6, 6.8 Hz,
1H), 6.82 (d, J ) 8.2 Hz, 1H), 7.02 (d, J ) 7.5 Hz, 1H), 7.35 (dd,
J ) 7.5, 8.2 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ 49.0, 55.5,
66.07, 66.13, 71.4, 110.9, 115.2, 116.7, 128.4, 131.9, 147.8, 155.8.
MS (EI, 70 eV) m/z 222 (M+, 24), 205 (20), 179 (100), 161 (33).
IR (neat) 3427 cm-1. Anal. Calcd for C12H14O4: C 64.9, H 6.4.
Found: C 64.3, H 6.2
Exp er im en ta l Section
Gen er a l. The triflates were prepared according to a fast
microwave procedure.6 All other chemicals used are com-
mercially available. The reactions were monitored with reversed
phase LC/MS utilizing electrospray ionization (ESI). 1H NMR
and 13C NMR were recorded with CDCl3 or DMSO-d6 as solvent
on a 400 MHz spectrometer. Mass spectra were recorded on a
GC-MS, equipped with a nonpolar capillary column, utilizing
electron impact (EI) at an ionizing energy of 70 eV. All
compounds 3 were pure according to NMR.
Gen er a l P r oced u r e for th e Syn th esis of 1,1-(Eth ylen e-
d ioxy)-3-h yd r oxyin d a n s (3). The aryl triflate (200 µmol) was
dissolved in DMF (1.0 mL) in a reaction tube. 2-Hydroxyeth-
ylvinyl ether (600 µmol, 54 µL), Pd(OAc)2 (2,0 µmol, 20 µL 1.0
M stock solution in DMF), and dppp (4,0 µmol, 40 µL 1.0 M stock
solution in DMF) were added. Either triethylamine (440 µmol,
58 µL) or PMP (440 µmol, 80 µL) was also added. The tube was
flushed with N2 and sealed with a screw cap. The reaction
mixture was stirred at 120 °C for 1-2 h. The temperature was
reduced to 80 °C and acetic acid (30 µL) was added. After 18 h
the reaction mixture was extracted with 10% K2CO3 (aq) and
EtOAc. The organic phases were combined and evaporated.
P u r ifica t ion P r oced u r e 1 (E t 3N a s Ba se). A prepacked
column with 5 g of silica gel was flushed with EtOAc/i-hexane
(1:1, 2% Et3N) (eluent A). The crude product was dissolved in
eluent A and applied to the column. The column was rinsed with
eluent A and EtOAc. The obtained product was left under
vacuum overnight.
1,1-(Eth ylen edioxy)-3-h ydr oxy-6-m eth oxyin dan (3d). The
synthesis was conducted according to the general method but
at 100 °C with 50 µL of acetic acid and for 24 h instead of at 80
°C, with 30 µL acetic acid, and for 18 h. The title compound was
obtained in 57% yield (25.1 mg) as an orange syrup. 1H NMR
(400 MHz, CDCl3) δ 2.18 (dd, J ) 3.9, 13.9 Hz, 1H), 2.22 (br s,
1H), 2.66 (dd, J ) 6.6, 13.9 Hz, 1H), 3.82 (s, 3H), 4.02-4.12 (m,
2H), 4.14-4.23 (m, 2H), 5.13 (dd, J ) 3.9, 6.6 Hz, 1H), 6.84 (d,
J ) 2.5 Hz,1H), 6.95 (dd, J ) 2.5, 8.3 Hz, 1H), 7.32 (d, J ) 8.3
Hz, 1H). 13C NMR (100 MHz, CDCl3) δ 48.3, 55.6, 65.4, 65.5,
71.4, 106.9, 114.6, 117.7, 125.7, 137.5, 143.0, 160.8. MS (EI, 70
eV) m/z 222 (M+, 10), 204 (17), 179 (100), 161 (16). IR (neat)
3418 cm-1. Anal. Calcd for C12H14O4: C 64.9, H 6.4. Found: C
64.5, H 6.5.
1,1-(Eth ylen ed ioxy)-3-h yd r oxy-5-ch lor oin d a n (3e). The
title compound was obtained in 47% yield (21.3 mg) as an orange
solid. 1H NMR (400 MHz, CDCl3) δ 2.45 (br s, 1H), 2.17 (dd, J
) 5.0, 13.9 Hz, 1H), 2.69 (dd, J ) 6.8, 13.9 Hz, 1H), 4.03-4.11
(m, 2H), 4.14-4.21 (m, 2H), 5.15 (dd, J ) 5.0, 6.8 Hz, 1H), 7.29
(d, J ) 8.1 Hz, 1H), 7.34 (dd, J ) 8.1, 1.8 Hz, 1H), 7.43 (d, J )
1.8 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ 48.1, 65.3, 65.6, 71.5,
113.9, 124.4, 124.9, 129.5, 136.2, 140.0, 146.9. MS (EI, 70 eV)
m/z 226 (M+, 5), 209 (11), 183 (100), 165 (20). IR (neat) 3311
cm-1. Anal. Calcd for C11H11ClO3: C 58.3, H 4.9. Found: C 58.2,
H 5.0.
2-[1-(2-Hyd r oxyeth oxy)vin yl]ben za ld eh yd e (6a ). The aryl
triflate 1a (1.0 mmol, 254 mg) was dissolved in DMF (4.0 mL)
in a reaction tube. 2-Hydroxyethylvinyl ether (3.0 mmol, 269
µL), Pd(OAc)2 (10 µmol, 100 µL 1.0 M stock solution in DMF),
dppp (20 µmol, 200 µL 1.0 M stock solution in DMF), and
K2CO3 (2.2 mmol, 304 mg) were added. The tube was flushed
with N2 and sealed with a screw cap. The reaction mixture was
stirred at 120 °C for 1 h and then extracted with 10% K2CO3
(aq) and EtOAc. The organic phases were combined and evapo-
rated. Purification on silica gel according to purification proce-
dure 1 gave the acid- and air-sensitive compound 6a (24.1 mg)
with around 90% purity. The instability of 6a prevented further
P u r ifica tion P r oced u r e 2 (P MP a s Ba se). The crude
product, dissolved in H2O/MeOH (1:1, 3 mL), was added to a
20-g C18 column and washed through with pure MeOH.
Compounds 3a ,d -e were purified further according to purifica-
tion procedure 1.
Only the yields from the reactions that were carried out with
PMP as base are reported below.
1,1-(Eth ylen ed ioxy)-3-h yd r oxyin d a n (3a ). The title com-
pound was obtained in 51% yield (19.6 mg) as an orange syrup.
1H NMR (400 MHz, CDCl3) δ 2.03 (br s, 1H), 2.19 (dd, J ) 4.4,
13.8 Hz, 1H), 2.70 (dd, J ) 6.7, 13.8 Hz, 1H), 4.05-4.12 (m, 2H),
4.16-4.22 (m, 2H), 5.20 (dd, J ) 4.4, 6.7 Hz, 1H), 7.36-7.46 (m,
4H); 13C NMR (100 MHz, CDCl3) δ 47.9, 65.3, 65.5, 72.0, 114.6,
123.1, 124.6, 129.2, 130.3, 141.6, 145.1. MS (EI, 70 eV) m/z 192
(M+, 1), 175 (13), 149 (100), 131 (16). IR (neat) 3413 cm-1. Anal.
Calcd for C11H12O3: C 68.7, H 6.3. Found: C 68.7, H 6.4.
1,1-(Eth ylen edioxy)-3-h ydr oxy-5-m eth oxyin dan (3b). The
title compound was obtained in 78% yield (35.5 mg) as an orange
1
purification.16 The structure was verified with H NMR and high-
resolution MS. 1H NMR (400 MHz, CDCl3) δ 3.91-3.95 (m, 2H),
4.01-4.03 (m, 2H), 4.39 (d, 1H), 4.53 (d, 1H), 7.46-7.59 (m, 3H),
7.89-7.91 (m, 1H), 10.22 (s, 1H). HRMS calcd for C11H12O3
192.0786, found 192.0785.
1
syrup. H NMR (400 MHz, CDCl3) δ 2.15 (dd, J ) 4.7, 13.7 Hz,
Ack n ow led gm en t. The authors acknowledge the
financial support from the Swedish Research Council
and from Knut and Alice Wallenberg’s Foundation. We
also thank professor Torbjo¨rn Lundstedt for assistance
with the initial optimization studies.
1H), 2.38 (br s, 1H), 2.67 (dd, J ) 6.7, 13.7 Hz, 1H), 3.81 (s, 3H),
3.99-4.10 (m, 2H), 4.13-4.21 (m, 2H), 5.13 (dd, J ) 4.7, 6.7 Hz,
1H), 6.89 (dd, J ) 2.2, 8.3 Hz, 1H), 6.93 (d, J ) 2.2 Hz, 1H),
7.26 (d, J ) 8.3 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ 48.4,
55.6, 65.1, 65.4, 71.8, 108.3, 114.3, 116.5, 124.2, 133.4, 147.0,
J O025756Q
(15) An alternative mechanism, as pointed out by a referee, might
be that initially a Wacker-type dioxolane formation takes place leading
to a σ-Pd intermediate, which then intramolecularly reacts in an
insertion reaction with the carbonyl group to give the product 3.
(16) Andersson, C. M.; Hallberg, A. J . Org. Chem. 1987, 52, 3529-
3536.
5856 J . Org. Chem., Vol. 67, No. 16, 2002