Titanium-catalyzed stereoselective synthesis of spirooxindole oxazolines

Article abstract of DOI:10.1021/ol1027305

A regio-and stereoselective cyclization between isatins and 5-methoxyoxazoles has been developed using catalytic titanium (IV) chloride (10 or 20 mol %) to afford spiro[3,3'-oxindoleoxazolines] in excellent yield (up to 99%) and diastereoselectivity (dr >

Full text of DOI:10.1021/ol1027305

ORGANIC
LETTERS
2011
Vol. 13, No. 3
418-421
Titanium-Catalyzed Stereoselective
Synthesis of Spirooxindole Oxazolines
Joseph J. Badillo, Gary E. Arevalo, James C. Fettinger, and Annaliese K. Franz*
Department of Chemistry, UniVersity of California, One Shields AVenue, DaVis,
California 95616, United States
akfranz@ucdaVis.edu
Received November 11, 2010
ABSTRACT
A regio- and stereoselective cyclization between isatins and 5-methoxyoxazoles has been developed using catalytic titanium(IV) chloride (10
or 20 mol %) to afford spiro[3,3′-oxindoleoxazolines] in excellent yield (up to 99%) and diastereoselectivity (dr >99:1). Substitution at the
4-position of the oxazole controls nucleophilic attack to provide either the 2-oxazoline or 3-oxazoline spirocycle with excellent (>99:1) regiocontrol.
The efficient and selective construction of complex hetero-
cycles is a continuing challenge for synthetic chemistry.
Spirocyclic oxindoles in particular have emerged as attractive
synthetic targets because of their prevalence in numerous
natural products and important biological activity.1,2 Fur-
thermore, the three-dimensional shape of spirooxindoles is
an attractive target to complement the flat heterocyclic
compounds encountered in many drug discovery programs.
The synthetic challenge of the spiro motif continues to
encourage the development of creative methods to access
these important structures. Recent synthetic methods to
access spirocyclic oxindoles include formal cycloaddition,3
organocascade,4 Prins cyclization,5 and other cyclization
reactions.6 Each of the aforementioned methods results in a
different class of spirocycle that may show promise as
biologically active compounds. Here we report a tita-
nium(IV)-catalyzed method for the selective synthesis of a
new class of spiro[3,3′oxindoleoxazolines] upon addition of
5-methoxy-2-aryloxazoles7 to isatins.
We initiated our investigations for the nucleophilic addition
and cyclization of oxazoles by screening various Lewis acids
for activation of chelating isatin 1a (Table 1). Initial screening
for spirocyclization was performed at 50 mol % of Lewis
(4) (a) Westermann, B.; Ayaz, M.; van Berkel, S. S. Angew. Chem.,
Int. Ed. 2009, 49, 846. (b) Bencivenni, G.; Wu, L.-Y.; Mazzanti, A.;
Giannichi, B.; Pesciaioli, F.; Song, M.-P.; Bartoli, G.; Melchiorre, P. Angew.
Chem., Int. Ed. 2009, 48, 7200. (c) Hari Babu, T.; Abragam Joseph, A.;
Muralidharan, D.; Perumal, P. T. Tetrahedron Lett. 2010, 51, 994. (d) Jiang,
K.; Jia, Z.-J.; Yin, X.; Wu, L.; Chen, Y.-C. Org. Lett. 2010, 12, 2766.
(5) Castaldi, M. P.; Troast, D. M.; Porco, J. A. Org. Lett. 2009, 11,
3362.
(1) For recent reviews, see: (a) Badillo, J. J.; Hanhan, N. V.; Franz,
A. K. Curr. Opin. Drug DiscoVery DeV. 2010, 13, 758. (b) Trost, B. M.;
Brennan, M. K. Synthesis 2009, 3003. (c) Galliford, C. V.; Scheidt, K. A.
Angew. Chem., Int. Ed. 2007, 46, 8748
.
(2) For recent examples, see: (a) Yong, S. R.; Ung, A. T.; Pyne, S. G.;
Skelton, B. W.; White, A. H. Tetrahedron 2007, 63, 5579. (b) Yeung,
B. K. S.; Zou, B.; Rottmann, M.; Lakshminarayana, S. B.; Ang, S. H.;
Leong, S. Y.; Tan, J.; Wong, J.; Keller-Maerki, S.; Fischli, C.; Goh, A.;
Schmitt, E. K.; Krastel, P.; Francotte, E.; Kuhen, K.; Plouffe, D.; Henson,
K.; Wagner, T.; Winzeler, E. A.; Petersen, F.; Brun, R.; Dartois, V.; Diagana,
T. T.; Keller, T. H. J. Med. Chem. 2010, 53, 5155. (c) Vintonyak, V.;
Warburg, K.; Kruse, H.; Grimme, S.; Hu¨bel, K.; Rauh, D.; Waldmann, H.
(6) (a) Shintani, R.; Hayashi, S.-y.; Murakami, M.; Takeda, M.; Hayashi,
T. Org. Lett. 2009, 11, 3754. (b) Lu, C.; Xiao, Q.; Floreancig, P. E. Org.
Lett. 2010, 12, 5112. (c) Jiang, X.; Cao, Y.; Wang, Y.; Liu, L.; Shen, F.;
Wang, R. J. Am. Chem. Soc. 2010, 132, 15328. (d) Nair, V.; Sethumadhavan,
D.; Nair, S. M.; Viji, S.; Rath, N. P. Tetrahedron 2002, 58, 3003.
(7) (a) Suga, H.; Fujieda, H.; Hirotsu, Y.; Ibata, T. J. Org. Chem. 1994,
59, 3359. (b) Suga, H.; Shi, X.; Ibata, T. J. Org. Chem. 1993, 58, 7397. (c)
Evans, D. A.; Janey, J. M.; Magomedov, N.; Tedrow, J. S. Angew. Chem.,
Int. Ed. 2001, 40, 1884. (d) Mitchell, J. M.; Shaw, J. T. Angew. Chem., Int.
Ed. 2006, 45, 1722.
Angew. Chem., Int. Ed. 2010, 49, 5902
(3) (a) Wei, Q.; Gong, L.-Z. Org. Lett. 2010, 12, 1008. (b) Zhang, Y.;
Panek, J. S. Org. Lett. 2009, 11, 3366.
.
10.1021/ol1027305  2011 American Chemical Society
Published on Web 12/27/2010

decreased yield with no improvement in diastereoselectivity
(entry 7). Reducing the reaction temperature required longer
reaction times and still provided no selectivity improvement
(entries 9, 10). A control experiment was performed with
2,6-di-tert-butyl-4-methylpyridine (DTBMP) to confirm that
the reaction is indeed catalyzed by a Lewis acid mechanism
and not by HCl potentially generated during the reaction
(entry 11). Furthermore, Bro¨nsted acids such as triflic and
phosphinic acid did not catalyze spirocycle formation. Tin(II)
chloride was also investigated and showed no improvement
in diastereoselectivity (entry 12).
Evaluation of titanium(IV) chloride showed excellent
promise, providing spirocycle cis-3a with excellent 92:8
diastereoselectivity. However, poor yields were observed as
a result of significant decomposition of the oxazole starting
material (entry 14). Upon further optimization it was
determined that removing molecular sieves increased the rate
of the reaction and also prevented oxazole decomposition,
with no effect on the diastereoselectivity (entry 15). The
structure of the major diastereomer was confirmed to be the
cis-oxazoline by X-ray analysis. Notably, both SnCl4- and
TiCl4-promoted reactions proceed efficiently at 20 mol %
(entries 5, 15). Additional Lewis acids such as In(OTf)3,
Zn(OTf)2, ZnBr2, CuCl2, Cu(OTf)2, MgF2, and BF3·OEt2
showed no reaction or poor conversion (<20%). Overall,
titanium(IV) chloride was identified as the optimal catalyst
on the basis of conversion and diastereoselectivity.
Table 1. Optimization of Spirocyclization of 5-Methoxyoxazole
with N-Methylisatina
temp time
yield
(%)c
entry
Lewis acid
solvent
(°C)
(h)
drb
1
2
3
4
5
6
7
8
Sc(OTf)3
ScCl3
InCl3
SnCl4
SnCl4
SnCl4
SnCl4
SnCl4
SnCl4
SnCl4
DCM
DCM
DCM
DCM
DCM
MeCN
THF
CH3Ph
DCM
DCM
rt
rt
rt
rt
rt
rt
rt
rt
-20
-40
rt
rt
rt
rt
rt
rt
24
48
24
1
24
4
48
4
4
48
4
24
72
4
58:42
53:47
52:48
73:27
74:26
72:28
57:43
66:34
75:25
79:21
63:37
54:46
66:33
92:8
39
53
92
99
80d
86
17
99
99
99
96
88
15
9
10
11
12
13
14
15
16
SnCl4/DTMP DCM
SnCl2
SnCl2
TiCl4
TiCl4
TiCl4
DCM
MeCN
DCM
DCM
MeCN
45d e
,
,
1
1
94:6
83d f
82:18 <10d
f
-
a All reactions performed at 0.12 M with 1.5 equiv of isatin under argon.
b cis:trans ratio determined by analysis of unpurified reaction mixture using
1H NMR spectroscopy. c Isolated yield. d Using 20 mol % of Lewis acid.
e Significant oxazole decomposition was observed. f Reaction performed
without 4 Å molecular sieves.
Using the optimal conditions with titanium(IV) chloride
(without molecular sieves), the scope of the isatin electrophile
was examined (Table 2). The titanium(IV) chloride catalyst
acid. Previously in our group, scandium(III) and indium(III)
triflates have been shown to catalyze the nucleophilic addition
of heteroaromatics to isatins.8 In this reaction, scandium(III)
triflate afforded spirocycle 3a in 39% yield as a 58:42
inseparable mixture of cis- and trans-isomers (entry 1), as
Table 2. Scope of Isatins for 2-Oxazoline Spirocyclesa
1
determined by H NMR analysis of the unpurified reaction
mixture. Although scandium(III) and indium(III) chlorides
afforded 3a in moderate to excellent yield (entries 2, 3), the
diastereoselectivity observed was still negligible.
Additional Lewis acids were investigated to improve
diastereoselectivity for the cis-oxazoline product. Tin(IV)
chloride showed exceptional reactivity (99% yield in <1 h),
with an improved diastereomeric ratio of 73:27 (entry 4) in
favor of the cis-oxazoline product.9 The effect of solvent
and temperature were examined for the tin(IV)-promoted
reactions in order to improve the diastereoselectivity (entries
6-10). Changing the solvent from dichloromethane (DCM)
to acetonitrile gave comparable reactivity and diastereose-
lectivity (entry 6), whereas THF resulted in a dramatically
entry
R
R1
product time (h)
drb
% yieldc
1
2
3
4
5
6
7
8
CH3
PMB
Ph
H
H
H
H
3a
3b
3c
3d
3e
3f
1
3
1.5
3
1
94:6d
91:9
91:9
91:9
91:9
93:7
90:10
86:14
92:8
99:1
99:1
83:17
81:9
83
82
88
83
72
85
55
65
85
99
81
81
77
Bn
PMB
CH3
CH2CCH 5-F
CH3
CH3
CH3
H
5-Br
5-Br
1
3g
3h
3i
1
3
1
5-OCH3
9
5-Cl
4-Cl
4-Cl
H
10
11
12
13
3j
15
3k
3l
3m
23
23
19
(8) Hanhan, N. V.; Sahin, A. H.; Chang, T. W.; Fettinger, J. C.; Franz,
A. K. Angew. Chem., Int. Ed. 2010, 49, 744.
H
H
(9) For reports of aldehyde cyclizations, diastereoselectivity is
dependent on selection of metal, with cis-selectivity observed for Sn(IV)
and trans-selectivity observed for Ti(IV) and Al(III) Lewis acids, see
reference: Suga, H.; Hirotsu, Y; Fujieda, H.; Ibata, T. Tetrahedron Lett.
1991, 32, 6911. The trans-oxazoline is proposed to result from epimer-
ization of the initial cis-adduct under the reaction conditions. Also see
ref 7 for additional details.
Br
a Reactions performed with 1.5 equiv of isatin under argon. b Determined
by 1H NMR analysis of unpurified reaction mixture. Diasteromers are
inseparable by column chromatography. c Isolated yield. d Diasteroselectivity
for purified product.
Org. Lett., Vol. 13, No. 3, 2011
419

continued to provide excellent diastereoselectivity with
N-alkylated isatins (entries 1-10), including the synthetically
useful N-protected p-methoxybenzyl (PMB) isatins. The
N-propargyl spirooxazolines can also be accessed in good
yield and diastereoselectivity, and are expected to be useful
for further diversification and incorporation of heterocycles
with alkyne cycloaddition reactions.10 Slightly reduced
diastereoselectivity (86:14) was observed with the 5-methoxy
electron donating substituent on isatin (entry 8). Notably,
4-chloroisatin provided excellent 99:1 diastereoselectivity for
both the NH and N-methyl derivatives (entries 9, 10). Unpro-
tected NH isatins could be successfully utilized with high
yield and up to 99:1 diastereoselectivity (entries 11-13).
The major product has been assigned to be the cis-
oxazoline, which is the kinetic product. Epimerization studies
demonstrate that the cis-oxazoline can be converted to the
trans-oxazoline upon treatment with catalytic 1,8-
diazabicyclo[5.4.0]undec-7-ene (DBU) (Scheme 1).11 X-ray
Table 3. Scope of Oxazole and Regiocontrol of Oxazoline
time yield
(h)
drb
of 3
drb
of 4
entry
R
Ar
product
(%)a
1
2
3
4
5
6
7g
8
9
H
4-OCH3 3a
1
24
9
14
24
4
20
1
1
83
94:6
H
H
H
H
H
3ab
3ac
3ad
88c
75
81:19
88:12
86:14
TMPd
4-Br
57e
no rxn
99
99
84
Scheme 1. Epimerization with DBU
2-OCH3 3ae
CH3 4-OCH3 3af/4aff
CH3 4-OCH3 3af/4afg
i-Pr 4-OCH3 4ag
84:16 55:45
83:17 54:46
89:11
i-Pr TMP
4ah
91
92:8
a Isolated yield. b Determined by 1H NMR analysis of unpurified reaction
c
mixture. 1H NMR spectra includes 12% of the amide decomposition
byproduct. d TMP ) 3,4,5-trimethoxyphenyl. e A 3-hydroxy ring-opened
product was also isolated in 8% yield; Yield is lower in order to ensure
separation. f Regioselectivity (3af:4af) is 49:51 with TiCl4. g Performed with
20 mol % SnCl4; regioselectivity is 87:13 (3af:4af).
crystal structure analysis of the epimerized product (trans-
3m) confirmed the trans stereochemistry. Computational
analysis revealed that trans-3m has a ground-state energy
that is 1.11 kcal/mol lower relative to the cis-isomer.12 This
supports our observation that the cis-product is the kinetic
product. Thus, the reduced diastereoselectivity observed for
other Lewis acids in Table 1 is likely due to conditions that
allow epimerization to occur upon complexation of the Lewis
acid to the oxazoline ring or ester substituent.9
When the oxazole scope was investigated, it was observed
that the substitution at the 4-position of the oxazole controls
the regioselectivity of the reaction, thus providing selective
access to either 2- or 3-oxazoline spirocycles (e.g., 3 or 4,
Table 3).13 Varying the electronic and steric effects of the
aryl ring on oxazole 2a still provided good, albeit reduced,
diastereoselectivity and did not influence the regioselectivity
(entries 1-5). Interestingly, with a more electron-withdraw-
ing aryl group (p-Br), a 3-hydroxy-2-oxindole ring-opened
product was also isolated in 8% yield.11 The (2-methoxy-
phenyl)oxazole 2e proceeds with poor conversion where the
attenuated reactivity is attributed to the steric hindrance and
disruption of conjugation between the aryl and oxazole rings.
Smaller substituents at the 4-position of the oxazole (i.e.,
H and CH3), favor formation of the 2-oxazoline (3) (Table
3, entries 1-4, 7). However, when 4-(isopropyl)oxazoles
were investigated, exclusive formation of the cis-adduct of
regioisomer 4 was observed in high yield (91%) and excellent
92:8 diastereoselectivity (entries 8, 9). The 4-methyloxazole
provides an intermediary case where the regioselectivity is
dependent on both the substituent and the selection of Lewis
acid. With titanium(IV) chloride, a 49:51 mixture of regioi-
somers was obtained, while tin(IV) chloride provided an
improved 87:13 regioselectivity for 2-oxazoline 3 with
similar diastereoselectivity. The structures and relative ster-
eochemistry for both regioisomers have been confirmed by
X-ray crystal structure analysis.
The proposed mechanism is initiated by titanium(IV)
activation of the isatin dicarbonyl to accelerate nucleophilic
attack by the oxazole, proceeding in a stepwise mechanism
through zwitterionic intermediate 5 or 6 (Scheme 2).7,13 This
intermediate cyclizes through an intramolecular acyl transfer
to afford the cis-oxazoline selectively.14 The Lewis acid may
also accelerate the cyclization by coordination to the imino-
nitrogen. When the 4-substituent on the oxazole is a hydrogen
(or methyl) group, the reaction likely proceeds with initial
bond formation at the 4-position of the oxazole through
(10) Meldal, M.; Tornoe, C. W. Chem. ReV. 2008, 108, 2952.
(11) See Supporting Information for complete experimental details.
(12) The calculated ground-state energy difference is based on the
B3LYP/6-31+G(d) model of crystal structures for trans-3m and modified
cis-3af.
(13) (a) Suga, H.; Shi, X.; Ibata, T. Chem. Lett. 1994, 1673. (b) Suga,
H.; Shi, X.; Ibata, T.; Kakehi, A. Heterocycles 2001, 55, 1711.
420
Org. Lett., Vol. 13, No. 3, 2011

Scheme 2
.
Mechanism and Regiochemical Reversal
Table 4. Scope of 3-Oxazoline Spirocyclesa
yield of
major isomer (%)c
entry
R
R1
product
drb
1
2
3
4
5
6
CH3
CH3
PMB
CH3
H
H
4ah
4bh
4ch
4dh
4eh
4fh
92:8
93:7
98:2
91:9
85:15
78:22
91
90
90
88
82
72
Br
Br
Cl
F
H
H
intermediate 5. However, steric interactions with the 4-iso-
propyl group inhibit the attack from the 4-position and divert
the initial bond-formation to the 2-position of the oxazole,
proceeding through intermediate 6. Increasing the size of the
alkoxy group at the 5-position showed no effect on the
diastereo- or regioselectivity.
The scope of isatins for the synthesis of 3-oxazoline
spirocycles 4 was examined. In addition to providing a
dramatic reversal of regioselectivity, the 4-(isopropyl)ox-
azoles maintain excellent diastereoselectivity and generally
appear to be more reactive proceeding with 10 mol % catalyst
loading (Table 4). Although diastereoselectivity is somewhat
diminished for cyclization with the NH isatins, the isomers
are separable and products can be isolated as single diaster-
eomers.
a All reactions performed with 1.5 equiv of oxazole under argon.
b Determined by analysis of unpurified reaction mixture using 1H NMR
spectroscopy. c Isolated yield; Diastereomers are separable and isolated yield
is reported for major isomer.
excellent regiocontrol. Biological evaluation and efforts to
make the reaction enantioselective are ongoing.
Acknowledgment. This research is supported by funds
from the University of California, Davis, the donors of the
American Chemical Society Petroleum Research Fund, and
NIH/NIGMS (P41-GM0089153). A.K.F. acknowledges 3M
Corporation for a Nontenured Faculty Award, J.J.B. ac-
knowledges the NSF for a graduate research fellowship, and
G.E.A. acknowledges the McNair Scholars Program. Special
thanks to Dr. James Fettinger for solving X-ray structures
and Ngon Tran for assistance with calculations.
In conclusion, we have developed a method for the
synthesis of a new class of spirocyclic oxindole oxazolines
by the addition of 5-alkoxy-2-aryloxazoles to isatins. Utiliz-
ing the substitution at the 4-position of the oxazole, we are
able to access either the 2- or 3-oxazoline spirocycles with
Supporting Information Available: Detailed experimen-
tal procedures and characterization data for all new com-
pounds, including X-ray crystal structures for 3k, trans-3m,
3af, 4af, and 4eh. This material is available free of charge
via the Internet at http://pubs.acs.org.
(14) In an alternate mechanistic pathway, it is envisioned that intermedi-
ate 5 may first undergo ring opening to form a nitrilium ion, followed by
cyclization to give the observed product.
OL1027305
Org. Lett., Vol. 13, No. 3, 2011
421