A direct arylation-oxidation route to 3-arylisoindolinone inhibitors of MDM2-p53 interaction

Article abstract of DOI:10.1016/j.tetlet.2011.07.076

A route to the MDM2-p53 inhibitor isoindolinone pharmacophore from a pre-formed phthalimide is detailed. The route involves treatment of 3-hydroxy-2-(n-propyl)isoindolinone with a substituted benzene in the presence of triflic acid. The resulting 3-aryl-2-(n-propyl)isoindolinones are then oxidized to the corresponding 3-hydroxy-3-aryl-2-(n-propyl) isoindolinones by treatment with 2,2'-bipyridinium chlorochromate. The benzylic oxidation represents a rather rare oxochromium (VI)-mediated reaction in which a selective C-H to C-OH transformation occurs.

Full text of DOI:10.1016/j.tetlet.2011.07.076

Tetrahedron Letters 52 (2011) 4992–4995
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Tetrahedron Letters
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A direct arylation-oxidation route to 3-arylisoindolinone inhibitors
of MDM2-p53 interaction q
⇑
Richard K. Dempster, Frederick A. Luzzio
Department of Chemistry, University of Louisville, 2320 South Brook Street, Louisville, Kentucky 40292, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A route to the MDM2-p53 inhibitor isoindolinone pharmacophore from a pre-formed phthalimide is
detailed. The route involves treatment of 3-hydroxy-2-(n-propyl)isoindolinone with a substituted ben-
zene in the presence of triflic acid. The resulting 3-aryl-2-(n-propyl)isoindolinones are then oxidized to
the corresponding 3-hydroxy-3-aryl-2-(n-propyl) isoindolinones by treatment with 2,2’-bipyridinium
chlorochromate. The benzylic oxidation represents a rather rare oxochromium (VI)-mediated reaction
in which a selective C–H to C–OH transformation occurs.
Received 25 June 2011
Revised 18 July 2011
Accepted 18 July 2011
Available online 27 July 2011
Keywords:
MDM2-p53
Ó 2011 Elsevier Ltd. All rights reserved.
Isoindolinone
Acyliminium
Oxochromium (VI)
Benzylic oxidation
1. Introduction
and coworkers introduced the 2-alkyl-3-arylisoindolinone core as
the scaffold central to their development of MDM2-p53 inhibitors.
Substituted isoindolinones form the structural core of a variety
of natural products and medicinally important compounds. The
isoindolinone core structure is found in natural products such as
vitedoamine A, chilenine, lennoxamine, magallanesine and nuev-
amine, all of which have gained considerable synthetic attention.2
Within the realm of medicinal chemistry, compounds with such di-
Their synthesis entailed an interesting chlorination/amination/alk-
oxylation sequence of an o-carboxybenzophenone precursor
(Scheme 1).7a,b While the synthesis allows for the preparation of
isoindolinones of diverse substitution, its versatility would be lim-
ited to only those o-carboxybenzophenones which are conve-
niently prepared. We now detail herein an alternate route to the
2-substituted-3-aryl-3-oxygenated isoindolinone core in which
additional diversity in the target compounds will be introduced.
The scheme utilizes a direct iminium ion-type intermolecular ary-
lation, giving the isoindolinone core, followed by a rare oxochromi-
um (VI)-mediated oxidation of a benzylic methine to a hydroxyl
group.
verse activities such as anxiolytic/anticonvulsant, TNFa-inhibitory,
antiangiogenic, 5-HT antagonistic/antidepressant and urotensin-II
antagonistic encompass many derivatives of the 2,3-disubstituted
isoindolinone pharmacophore.3 More recently the 2-substituted-
3-aryl-3-alkoxyisoindolinone frame-work has been central to a
group of compounds which have significant inhibitory activity to-
ward the MDM2-p53 interaction.4 The tumor suppressor p53 is an
established cancer therapeutic target due to its properties in elim-
inating tumors on activation. In many human cancers the gene
encoding p53 is mutated or deleted thereby blocking the suppres-
sor activity. In other cancers, the wild-type p53 is effectively inhib-
ited by its interaction with MDM2 (murine double minute)
oncoprotein. Therefore, inhibiting the MDM2-p53 interaction to
reactivate the p53 function is a promising cancer therapeutic strat-
egy.5 Along with the isoindolinone inhibitors, several types of
small-molecule MDM2-p53 inhibitors have undergone study, and
include Nutlins, benzodiazepines and spirooxindoles.6 Hardcastle
O
Cl
HO
NH2
SOCl2
O
N
COOH
O
O
SOCl2
R1=n-pr, Bn
Cl
R2
R1O
R-OH
R2=H, Cl,
OSEM
N
O
N
q
O
See Ref. 1.
⇑
Corresponding author. Tel./fax: +1 502 852 7323.
E-mail address: faluzz01@gwise.louisville.edu (F.A. Luzzio).
Scheme 1. Hardcastle isoindolinone synthesis.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.07.076

R. K. Dempster, F. A. Luzzio / Tetrahedron Letters 52 (2011) 4992–4995
4993
Table 1
2. Results and discussion
Arylation of hydroxylactam 2 followed by BPCC oxidation
Our synthesis starts with the readily-available N-propylphthal-
imide 1 which is conveniently prepared in high yield by the treat-
OH
H
Ar
HO Ar
N
Ar-H
BPCC
ment
of
potassium phthalimide with
freshly-distilled
N
N
1-iodopropane in warm DMF (Scheme 2).8 Extractive workup and
silica gel flash column chromatography gave the pure imide in
yields of 82–87%. We selected the n-propyl group as the 2-substi-
tuent since some of the more MDM2-p53-active analogues
described by the Hardcastle group possessed this appendage.7b
The phthalimide was then reduced with freshly-prepared alumi-
num amalgam in aqueous THF (rt) thereby affording the crystalline
hydroxylactam 2 in consistent yields of 82–87% after silica gel
flash-column chromatography.9,10 We have found the Al(Hg) pro-
cedure to be the most effective in terms of time, cost, scale and
simplicity as compared to the more commonly-utilized sodium
borohydride11a or diisobutylaluminum hydride.11b Next, we con-
centrated our efforts toward defining the optimal set of conditions
for the intermolecular arylation reaction. The utilization of acyli-
minium ions in carbon-carbon bond formation at the 3-position
of isoindolinones is a complementary method to that of carbanion
formation/alkylation at the same position.12 Moreover, a great deal
of synthetic studies which utilize the generation and intramolecu-
lar arylation of acyliminium ions have been directed toward the
assembly of polycyclic natural products and bioactive compounds
as reported by Daich, Decroix and co-workers.13 The intermolecu-
lar arylation reaction, in which the acyliminium ion is generated in
the presence of substituted benzene, has been less-studied and
appears to be relegated toward highly-activated aryl reactant part-
ners.14 Our refinements of the intramolecular arylation entail the
addition of triflic acid to a solution of hydroxylactam and the ary-
lation partner at an elevated temperature (Scheme 2). After the
addition of triflic acid, the reaction duration is anywhere from 2
to 16 h during which time there is complete consumption of the
starting hydroxylactam and the formation of products (3a–d, Ta-
ble 1).15 We also note that no water-scavenging components need
to be added to the reaction mixture. The workup of the reaction
mixture simply involves dilution with dichloromethane, neutral-
ization of the residual triflic acid, concentration and flash-column
chromatography. Interestingly, the arylations which utilized tolu-
ene and anisole gave exclusively the para-substitution products
while the arylation with chlorobenzene gave a chromatographi-
cally separable mixture of ortho and para products in a range from
50/50 to 45/55 (ortho:para).
CF3SO3H
O
O
O
2
3a-d
4a-d
Ar-H
Product (3a–d)a
Product (4a–d)a
H
N
HO
N
O
O
3a (91)
4a (67)
CH3
CH3
CH3
H
N
HO
N
O
O
3b (97)
4b (65)
OCH3
OCH3
OCH3
H
N
HO
N
O
O
4c (55)3
3c (87)
Cl
Cl
Cl
H
N
HO
N
O
O
4d (46)
3d (36)2
Yields of the para product from 72% yeild of an ortho, para mixture.
Actual yields. 40% starting material was recovered.
a
Yields are for isolated, purified products.
transformation of alcohols to carbonyl compounds.16 In contrast,
there are relatively fewer selective oxidations of methylene or
methines which are mediated by oxochromium (VI) or any other
oxometal species. We have developed the use of 2, 2’-bipyridinium
chlorochromate (BPCC) in conjunction with peroxides (MCPBA) for
both cleavage of benzylidene acetals to hydroxyesters and methy-
lene oxidation of 2-substituted isoindolinones to imides.17,3b In the
former case, the hydroxyl group of the product survives the oxida-
tion and in both cases, the method is proven to be compatible with
amides. On treatment of the ‘parent’ 3-phenylisoindolinone 3a
with BPCC/MCPBA in dichloromethane (rt) complete consumption
of the starting material ensued and only a complex mixture of
products was detected by TLC analysis. However, deletion of the
peroxide co-oxidant and employing only BPCC in CH2Cl2 gave a sin-
gle, less mobile product which was determined to be the desired
hydroxylated product 4a (Table 1).18,19 While BPCC is commer-
cially available, some decomposition (as with most oxochromium
(VI)-amine reagents) does occur over prolonged storage as evi-
denced by a color change from bright yellow–orange to dark
brown. For the present application, we found that freshly-prepared
BPCC is superior to the commercial reagent in terms of activity and
yield of products. Any deviation from the published protocol, espe-
cially with regard to the equivalents of chlorochromic acid used as
well as the filtration steps, may result in the isolation of the less-
reactive dichromate. A proposed stepwise mechanism for the oxi-
dation is detailed in Scheme 3 and is based on previous studies on
the kinetics and mechanism of BPCC-mediated oxidations.20a,b
Intermolecular hydride abstraction by chlorochromate ion results
With the arylation now developed as a reliable and reproduc-
ible method, our attention was then turned to the benzylic
oxidation of the 3-arylisoindolines 3a–d. In general, oxidations
which utilize oxochromium (VI)-amine reagents are confined to
O
OH
N
Al(Hg)
N
THF/H2O
O
O
1
2
CF3SO3H
R
R
R
H
HO
BPCC
N
N
CH2Cl2
O
3a-d
O
4a-d
Scheme 2. Route to arylisoindoline inhibitors of MDM2-p53.

4994
R. K. Dempster, F. A. Luzzio / Tetrahedron Letters 52 (2011) 4992–4995
(c) Hardcastle, I. R.; Ahmed, S. U.; Atkins, H.; Calvert, A. H.; Curtin, N. J.; Farnie,
H
Ar
J.; Golding, B. T.; Griffin, R. J.; Guyenne, S.; Hutton, C.; Kallblad, P.; Kemp, S. J.;
Kitching, M. S.; Newell, D. R.; Norbedo, S.; Northen, J. S.; Reid, R. J.; Saravanan,
K.; Willems, H. M. G.; Lunec, J. Bioorg. Med. Chem. Lett. 2005, 15, 1515–1520.
5. Shangary, S.; Wang, S. Clin. Cancer. Res. 2008, 14, 5318–5324; Shangary, S.;
Wang, S. Ann. Rev. Pharmacol. Toxicol. 2009, 49, 223–241.
CrO3Cl-bipyH+
+
N
O
6. (a) Vassilev, L. T.; Vu, B. T.; Graves, B.; Carvajal, D.; Podlaski, F.; Filipovic, Z.;
Kong, N.; Kammlott, U.; Lukacs, C.; Klein, C.; Fotouhi, N.; Liu, E. A. Science 2004,
303, 844–848; (b) Grasberger, B. L.; Lu, T.; Schubert, C.; Parks, D. J.; Carver, T. E.;
Koblish, H. K.; Cummings, M. D.; LaFrance, L. V.; Milkiewicz, K. L.; Calvo, R. R.;
Maguire, D.; Lattanze, J.; Franks, C. F.; Zhao, S.; Ramachandren, K.; Bylebyl, G.
R.; Zhang, M.; Manthey, C. L.; Petrella, E. C.; Pantoliano, M. W.; Deckman, I. C.;
Spurlino, J. C.; Maroney, A. C.; Tomczuk, B. E.; Molloy, C. J.; Bone, R. F. J. Med.
Chem. 2005, 48, 090–912; (c) Shangary, S.; Ding, K.; Qiu, S.; Nikolovska-Coleska,
Z.; Bauer, J. A.; Liu, M.; Wang, G.; Lu, Y.; McEachern, D.; Bernard, D.; Bradford, C.
R.; Carey, T. E.; Wang, S. Mol. Cancer Ther. 2008, 7, 1533–1542.
7. (a) Kitching, M. S.; Clegg, W.; Elsegood, M. R. J.; Griffin, R. J.; Golding, B. T.
Synlett 1999, 997–999; (b) Willems, H. M. G.; Kallblad, P. ; Hardcastle, I. R.;
Griffin, R. K.; Golding, B. T.; Lunec, J.; Noble, M. E. M. Newell, D. R.; Calvert, A. H.
US0261917A1, 2008.
8. (a) Luzzio, F. A. In Science of Synthesis Compounds with Four and Three Carbon
Heteroatom Bonds; Weinreb, S. M., Ed.; Thieme: Stuttgart, 2005; pp 259–324.
Vol. 21; (b) Jeong, I. Y.; Lee, W. S.; Goto, S.; Sano, S.; Shiro, M.; Nagao, Y.
Tetrahedron 1998, 54, 14437–14454.
Ar
N
+
+
HOCrO2Cl=bpyH+
O
O
HCrO3Cl
Cl
O+
Cr
O
H
HO
Ar
N
Ar
N
O
O
Scheme 3. Proposed benzylic oxidation mechanism.
9. Luzzio, F. A.; O’Hara, L. C. Synthetic Commun. 1990, 20, 3223–3234.
10. 3-Hydroxy-2-propylisoindolin-1-one 2. To a magnetically-stirred solution of n-
propylphthalimide 1 (1.36 g, 7.18 mmol) dissolved in THF/water (9:1, 130 mL)
was added freshly-prepared aluminum amalgam. The amalgam was prepared
by cutting food-grade aluminum foil (429 mg) into 8 Â 50 mm strips, winding
in the formation of the benzylic iminium/carbonium ion and re-
duced oxochromium (IV) species.20c,d Interception of the interme-
diate cationic species with excess chlorochromate (VI) ion then
affords the unstable chromate ester. Hydrolysis or otherwise cleav-
age of the chromate ester during workup and isolation then results
in hydroxylated products. In summary, we have detailed an effec-
tive and straightforward route to a set of core structures represen-
tative of isoindolinone-based MDM2-p53 inhibitors. Within our
synthetic route, we both introduced an intermolecular iminium
ion-mediated arylation of a pre-formed phthalimide and enlisted
the reactivity of oxochromium (VI) in a rare benzylic oxidation.
The arylation employed substituted benzene co-reactants having
typical electron-donating or electron withdrawing substitution
thereby allowing for a range in the diversity of the intermediates.
The BPCC-mediated oxidation was selective for the benzylic
methine which resulted in hydroxylated products suitable for fur-
ther elaboration and submission as candidates for MDM2-p53
inhibitory evaluation.
the strips about
a glass rod to make coils, then degreasing the coils by
immersing in diethyl ether. Using tweezers, each aluminum coil was then
immersed for exactly 20 s in 2% aqueous mercuric chloride, washed quickly by
dipping into diethyl ether, then added to the reaction flask containing the
solution of 1. Stirring was continued for 2 h during which time the shiny
aluminum coils became macerated with evolution of hydrogen and the
reaction mixture changed to a gray suspension. The reaction mixture was
then vacuum-filtered through a Celite-packed filter funnel (60 mm) while
washing with ethyl acetate. The solvents were then removed by rotary
evaporation followed by removal of the aqueous component under high
vacuum. The white residue was flash-column chromatographed (hexane/
EtOAc, 4:1) which provided 1.13 g (82%) of hydroxylactam
2 as a white
crystalline solid: mp 93–95 °C; Rf 0.28 (hexane/EtOAc, 1:1); FTIR: 3256, 2961,
1664, 1406, 1062 cmÀ1 1H NMR (400 MHz, CDCl3) d: 7.58 (m, 3H), 7.44 (dd,
;
1H), 5.75 (s, 1H), 3.44 (m, 1H), 3.25 (s, 1H), 1.64 (m, 2H), 0.91 (t, 3H); 13C NMR
(100 MHz, CDCl3) d: 167.6, 144.0, 131.97, 131.34, 129.42, 123.22, 122.92,
81.50, 40.58, 21.39, 11.34; HRMS calcd for C11H14NO2 (M+H)+ 192.1024, Found
192.1020.
11. (a) Horii, Z.-I.; Iwata, C.; Tamura, Y. J. Org. Chem. 1961, 26, 2273–2276; (b)
Bennett, D. J.; Blake, A. J.; Cooke, P. A.; Godfrey, C. R. A.; Pickering, P. L.;
Simpkins, N. S.; Walker, M. D.; Wilson, C. Tetrahedron 2004, 60, 4491–4511.
12. For example, see: Luzzio, F. A.; Zacherl, D. P. Tetrahedron Lett. 1998, 39, 2285–
2288; Deniau, E.; Enders, D. Tetrahedron Lett. 2000, 41, 2347–2350; Comins, D.
L. Tetrahedron Lett. 2005, 46, 5639–5642.
13. Decroix, B.; Netchitaïlo, P. J. Heterocyclic Chem. 2000, 37, 827–830; Hucher, N.;
Decroix, B.; Daïch, A. J. Org. Chem. 2001, 66, 4695–4703.
14. Barili, P. G.; Scartoni, V. J. Heterocyclic Chem. 1985, 22, 1199–1202.
Acknowledgments
We acknowledge the support of this work through a University
of Louisville Summer Research Fellowship to RKD. Support of the
high resolution mass spectral facility at the University of Louisville
through a NSF-EPSCOR grant is gratefully acknowledged. The use of
the Texas A&M University/Laboratory for Biological Mass Spec-
trometry and Dr. Vanessa Santiago are acknowledged.
15. General
Procedure.
3-Aryl-2-n-propylisoindolinones
3a–d,
Table
1:
Hydroxylactam
2
(0.5 mmol) was dissolved in benzene (for 3a) or the
appropriate substituted benzene (for 3b–d) (7–9 mmol) co-reactant while
warming (52–55 °C, oil bath) under a nitrogen atmosphere while stirring. To
the clear solution was added trifluoromethanesulfonic acid (2.0 mmol) by
syringe which produced a light-yellow to orange-yellow color depending on
the aryl co-reactant. After 2–8 h, the color was somewhat discharged and
stirring and heating under N2 was continued. The co-reactant/solvent was then
removed under high vacuum and the oily residue was then flash-column
chromatographed (hexane/ethyl acetate, 4:1) to provide the aryl-substituted
isoindolinones 3a–d. 3-Phenyl-2-propylisoindolin-1-one 3a. Rf 0.36 (hexane/
References and notes
1. Presented by R.K.D. at the 141st National Meeting of the American Chemical
Society, Anaheim, California, March 29, 2011; ORGN 557.
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2664–2669; Daïch, A.; Marchalin, S.; Pigeon, P.; Decroix, B. Tetrahedron Lett.
1998, 39, 9187–9190; Taniguchi, T.; Iwasaki, K.; Uchiyama, M.; Tamura, O.;
Ishibashi, H. Org. Lett. 2005, 7, 4389–4390; Fang, F. G.; Feigelson, G. B.;
Danishefsky, S. J. Tetrahedron Lett. 1989, 30, 2743–2746; Alonso, R.; Castedo, L.;
Dominguez, D. Tetrahedron Lett. 1985, 26, 2925–2928; Kim, G.; Jung, P.; Tuan, L.
A. Tetrahedron Lett. 2008, 49, 2391–2392.
3. (a) Stuk, T. L.; Assink, B. K.; Bates, R. C.; Erdman, D. T.; Fedij, V.; Jennings, S. M.;
Lassig, J. A.; Smith, R. J.; Smith, T. L. Org. Proc. Res. Dev. 2003, 7, 851–855; (b)
Luzzio, F. A.; Zacherl, D. P. Tetrahedron Lett. 1999, 40, 2087–2090; (c) Luzzio, F.
A.; Mayorov, A. V.; Ng, S. S. W.; Kruger, E. A.; Figg, W. D. J. Med. Chem. 2003, 46,
3793–3799; (d) Norman, M.; Minick, D. J.; Rigdon, G. C. J. Med. Chem. 1996, 39,
149–157; (e) Luci, D. K.; Lawson, E. C.; Ghosh, S.; Kinney, W. A.; Smith, C. E.; Qi,
J.; Wang, Y.; Minor, L. K.; Marynoff, B. E. Tetrahedron Lett. 2009, 50, 4958–4961.
4. (a) Riedinger, C.; Endicott, J. A.; Kemp, S. J.; Smyth, L. A.; Watson, A.; Valeur, E.;
Golding, B. T.; Griffin, R. J.; Hardcastle, I. R.; Noble, M. E.; McDonnell, J. M. J. Am.
Chem. Soc. 2008, 130, 16038–16044; (b) Hardcastle, I. R.; Ahmed, S. U.; Atkins,
H.; Farnie, G.; Golding, B. T.; Grifin, R. J.; Guyenne, S.; Hutton, C.; Kallblad, C.;
Kemp, S. J.; Kitching, M. S.; Newell, D. R.; Norbedo, S.; Norhten, J. S.; Reid, R. J.;
Saravanan, K.; Willems, H. M. G.; Lunec, J. J. Med. Chem. 2006, 49, 6209–6221;
EtOAc, 4:1); mp 92–93 °C; FTIR: 2963, 2869, 1690, 1468, 1404 cmÀ1 1H NMR
;
(400 MHz, CDCl3) d: 7.87 (dd, 1H, J = 3.6, 5.6 Hz), 7.42 (m, 2H), 7.32 (m, 3H),
7.12 (m. 3H), 5.42 (s, 1H), 3.86 (m, 1H), 2.83 (m, 1H), 1.56 (m, 2H), 0.85 (t, 1H,
J = 7.2 Hz); 13C NMR (100 MHz, CDCl3) d: 168.62, 146.23, 137.13, 131.69,
131.59, 129.06, 128.59, 128.23, 127.51, 123.51, 122.97, 64.37, 41.81, 21.52,
11.34; HRMS calcd for C17H18NO (M+H)+ 252.1388, Found: 252.1380. 2-Propyl-
3-p-tolylisoindolin-1-one 3b. Mp 118–120 °C; Rf 0.30 (hexane/EtOAc, 2:1); FTIR
2963, 2873, 1693, 1467, 1402, 1092 cmÀ1 1H NMR (400 MHz, CDCl3) d: 7.87
;
(m, 1H), 7.42 (m, 2H), 7.14 (m, 1H, overlap), 7.13 (d, 2H, J = 7.2 Hz), 7.00 (d, 2H,
J = 8 Hz), 5.4 (s, 1H), 3.85 (m, 1H), 2.82 (m, 1H), 2.32 (s, 3H), 1.55 (m, 2H), 0.87
(t, 3H, J = 7.2 Hz); 13C NMR (100 MHz, CDCl3) d: 168.57, 146.4, 138.44, 134.02,
131.72, 131.54. 129.73, 128.15, 127.45, 123.46, 122.94, 64.15, 41.73, 21.51,
21.14, 11.33; HRMS calcd for C18H20NO (M+H)+ 266.1545, Found: 266.1550. 3-
(4-Methoxyphenyl)-2-propylisoindolin-1-one 3c. (syrup) Rf 0.48 (hexane/EtOAc,
1:1); FTIR: 2963, 1693, 1612, 1512, 1404, 1246 cmÀ1 1H NMR (400 MHz,
;
CDCl3) d: 7.87 (m, 1H), 7.41 (m, 2H), 7.14 (m, 1H), 7.02 (d, 2H, J = 8.6 Hz), 6.84
(d, 2H, J = 8.6 Hz), 5.38 (s, 1H), 3.83 (m, 1H), 3.78 (s, 3H), 2.81 (m, 1H), 1.55 (m,
1H), 0.86 (t, 3H, J = 7.6 Hz); 13C NMR (100 MHz, CDCl3) d: 168.42, 159.78,
146.51, 131.55, 131.4, 128.78, 128.11, 127.85, 123.32, 122.99, 121.05, 114.40,

R. K. Dempster, F. A. Luzzio / Tetrahedron Letters 52 (2011) 4992–4995
4995
63.86, 55.20, 41.67, 21.49, 11.32; HRMS calcd for C18H20NO2 (M+H)+ 282.1494,
1H), 1.27 (m, 1H), 0.69 (t, 3H, J = 7.6 Hz); 13C NMR (100 MHz, CDCl3) d: 167.83,
Found: 282.1488. 3-(4-Chlorophenyl)-2-propylisoindolin-1-one 3d. (syrup) Rf
148.98, 138.67, 132.49, 130.52, 129.38, 128.42, 128.38, 126.14, 123.17, 122.59,
0.18 (hexane/EtOAc, 4:1); FTIR: 2964, 1693, 1467, 1401, 1089 cmÀ1
;
1H NMR
91.36, 41.30, 21.98, 11.64; HRMS calcd for
Found: 268.1331. 3-Hydroxy-2-propyl-3-p-tolylisoindolin-1-one 4b. Mp 167–
C
17H18NO2 (M+H)+ 268.1338,
(400 MHz, CDCl3) d: 7.88 (m, 1H), 7.45 (m, 2H), 7.31 (d, 2H, J = 8.4 Hz), 7.12 (m,
1H), 7.12 (m, 1H), 7.06 (d, 2H, J = 7.6 Hz), 5.40 (s, 1H), 3.86 (m, 1H), 2.81 (m,
1H), 1.53 (m, 2H), 0.87 (t, 1H, J = 7.6 Hz); 13C NMR (100 MHz, CDCl3) d: 168.54,
145.77, 135.74, 134.51, 131.76, 131.58, 129.34, 128.87, 128.48, 123.65, 122.90,
63.67, 41.84, 21.52, 11.32; HRMS calcd for C17H17ClNO (M+H)+ 286.0999,
Found: 286.0992.
168 °C; Rf 0.14 (hexane/EtOAc, 4:1); FTIR 3289, 2924, 1682, 1405, 1063 cmÀ1
;
1H NMR (400 MHz, CDCl3) d: 7.77 (dd, 1H, J = 2, 8.4 Hz), 7.45 (m, 2H), 7.26 (m,
1H), 7.25 (d, 2H, J = 8.4 Hz), 7.12 (d, 2H, J = 8 Hz), 3.45 (m, 1H), 2.93 (m, 1H),
2.32 (s, 3H), 1.46 (m, 2H), 0.81 (t, 3H, J = 7.6 Hz); 13C NMR (100 MHz, CDCl3) d:
167.78, 149.10, 138.20, 135.64, 132.75, 130.52, 129.32, 129.14, 126.05, 123.17,
122.52, 91.42, 41.32, 22.05, 21.10, 11.67; HRMS calcd for C18H20NO2 (M+H)+
16. Luzzio, F. A. In Organic Reactions, vol. 53; Paquette, L. A., Ed.; Wiley: New York,
1999; pp 1–221; Luzzio, F. A.; Guziec, F. S., Jr. Org. Prep. Proc. Int. 1988, 20, 533–
584.
17. Luzzio, F. A.; Bobb, R. A. Tetrahedron Lett. 1997, 38, 1733–1736; See also the use
of BPCC as a benzylic oxidant in the synthesis of the preussomerins: Barrett, A.
G. M.; Blaney, F.; Campbell, A. D.; Hamprecht, D.; Meyer, T.; White, A. J. P.;
Witty, D.; Williams, D. J. J. Org. Chem. 2002, 67, 2735–2750.
282.1494,
propylisoindolin-1-one 4c. Mp 163–165 °C; Rf 0.38 (hexane/EtOAc, 1:1); FTIR
3253, 2963, 2930, 1680, 1508, 1251 cmÀ1 1H NMR (400 MHz, CDCl3) d: 7.71 (d,
Found:
282.1487.
3-Hydroxy-3-(4-methoxyphenyl)-2-
;
1H, J = 6.8 Hz), 7.45 (dd, 1H, J = 7.6, 5.6 Hz), 7.41 (dd, 1H, J = 5.6, 6.8 Hz), 7.29 (d,
2H, J = 8.8 Hz), 7.25 (d, 1H, J = 7.6 Hz), 6.83 (d, 2H, J = 8.8 Hz), 3.78 (s, 3H), 3.40
(m, 1H), 2.92 (m, 1H), 1.52 (m. 1H), 1.40 (m, 1H), 0.70 (t, 3H, J = 7.2 Hz); 13C
NMR (100 MHz, CDCl3) d: 167.62, 159.62, 149.04, 132.5, 130.54, 130.48,
129.42, 127.45 (overlap), 123.20, 122.47, 113.78 (overlap), 91.33, 55.25, 41.26,
22.13, 11.69. HRMS (TOF M ES+) m/z (M+H)+ calcd for C18H20NO3 298.1443,
Found: 298.1448. 3-(4-Chlorophenyl)-3-hydroxy-2-propylisoindolin-1-one 4d.
Mp 188–190 °C; Rf 0.41 (toluene/EtOAc, 2:1); FTIR 3191, 2970, 2932, 2874,
18. General Procedure. 3-Hydroxy-3-Aryl-2-n-propylisoindolin-ones 4a–d, Table 1:
To
a suspension of freshly-prepared 2, 2’-bipyridinium chlorochromate
(4 mmol, 4 eq) in CH2Cl2 (2.0 mL) were added the substrate 3-aryl-2-n-
propylisoindolinones 3a–d (1 mmol) while stirring. The reaction mixture was
then capped and stirring was continued at room temperature whereupon the
yellow oxidation reagent decomposed to a brown solid. After a reaction time of
3–4 h, TLC analysis (hexane/EtOAc, 4:1) indicated the formation of the UV-
active, lower-running hydroxylated product. Stirring for another 3–6 h
facilitated the complete consumption of starting material during which time
more brown chromium reduction products precipitated. The reaction was then
arrested by the addition of 2–3 mL of diethyl ether followed by filtration
through a silica gel pad while washing with ethyl acetate. Removal of the
solvents followed by flash-column chromatography (hexane/EtOAc, 4:1) of the
residue gave the hydroxylated isoindolinones 4a–d.
1670, 1404, 1059 cmÀ1 1H NMR (400 MHz, CDCl3) d: 7.75 (d, 1H, J = 7.2 Hz),
;
7.48 (dd, 1H, J = 7.6, 7.2 Hz), 7.45 (dd, 1H, J = 7.2, 7.6 Hz), 7.32 (d, 2H, J = 8.8 Hz),
7.29 (d, 2H, J = 8.8 Hz), 7.23 (d, 1H, J = 7.6 Hz), 3.41 (m, 1H), 2.92 (m, 1H), 1.53
(m, 1H), 1.44 (m, 1H), 0.81 (t, 1H, J = 7.2 Hz); 13C NMR (100 MHz, CDCl3) d:
167.74, 148.58, 137.35, 134.45, 132.69, 130.45, 129.69, 128.69 (overlap),
127.74 (overlap), 123.33, 122.54, 90.97, 41.30, 22.09, 11.67. HRMS (TOF M ES+)
m/z (M+H)+ calcd for C17H17ClNO2 302.0948, Found: 302.0952.
20. (a) Loonker, K.; Sharma, P.; Banerji, K. K. J. Chem. Res. 1998, 66–67; (b) Loonker,
K.; Sharma, P.; Banerji, K. K. J. Chem. Res. 1997, 242–243; The BPCC studies
reported by Banerji within this reference discount the occurrence of a one-
electron (hydrogen abstraction) mechanism (c) Wiberg, K. B.; Evans, R. J.
Tetrahedron 1960, 8, 313–335; (d) Al-Ajlouni, A.; Bakac, A.; Espenson, J. H. Inorg.
Chem. 1994, 33, 1011–1014.
19. 3-Hydroxy-3-phenyl-2-propylisoindolin-1-one 4a. Mp 176–177 °C; Rf 0.18
(hexane/EtOAc, 4:1); FTIR: 3265, 2956, 1678, 1406, 1057 cmÀ1 1H NMR
;
(400 MHz, CDCl3) d: 7.58 (d, 1H, J = 7.2 Hz), 7.37 (dd, 1H, J = 1.2, 7.6 Hz), 7.32
(m, 3H), 7.25 (m, 3H), 7.19 (d, 1H, J = Hz), 3.27 (m, 1H), 2.82 (m, 1H), 1.41 (m,