Solid phase approaches to N-heterocycles using a sulfur linker cleaved by SmI2

Article abstract of DOI:10.1021/jo060940n

A sulfur HASC (α-hetero-atom substituted carbonyl) linker has been utilized in solid-phase approaches to oxindoles and tetrahydroquinolones. The route to oxindoles employs the first Pummerer cyclizations on solid phase, whereas the route to tetrahydroquinolones involves a microwave-assisted Heck reaction followed by a Michael cyclization. In both cases, the linker is cleaved in a traceless fashion by electron transfer from samarium(II) iodide. The routes illustrate the compatibility of the linker system with a number of reaction types and its utility for library synthesis.

Full text of DOI:10.1021/jo060940n

Solid Phase Approaches to N-Heterocycles Using a Sulfur Linker
Cleaved by SmI2
Laura A. McAllister,† Kristy L. Turner,‡ Stephen Brand,§ Mark Stefaniak,| and
David J. Procter*,‡
Department of Chemistry, The Joseph Black Building, UniVersity of Glasgow, Glasgow, G12 8QQ, U.K.,
The School of Chemistry, UniVersity of Manchester, Oxford Road, Manchester, M13 9PL, U.K.,
UCB Celltech R&D Ltd, 216 Bath Road, Slough, Berkshire, SL1 4EN, U.K., and
Pfizer Global Research & DeVelopment, Sandwich, Kent, CT13 9NJ, U.K.
daVid.j.procter@manchester.ac.uk
ReceiVed May 5, 2006
A sulfur HASC (R-hetero-atom substituted carbonyl) linker has been utilized in solid-phase approaches
to oxindoles and tetrahydroquinolones. The route to oxindoles employs the first Pummerer cyclizations
on solid phase, whereas the route to tetrahydroquinolones involves a microwave-assisted Heck reaction
followed by a Michael cyclization. In both cases, the linker is cleaved in a traceless fashion by electron
transfer from samarium(II) iodide. The routes illustrate the compatibility of the linker system with a
number of reaction types and its utility for library synthesis.
Introduction
Solid-phase synthesis remains an important tool for synthetic
organic chemists. The development of versatile linker designs
is important for continued advancements in the area.1 We have
previously described a traceless linker strategy for solid-phase
organic synthesis where the link to resin is cleaved using
samarium(II) iodide (SmI2).2 We refer to this family of linkers
as HASC (R-hetero-atom substituted carbonyl) linkers (Fig-
ure 1). We originally focused on an ether-based HASC linker3
but have begun to explore the considerable potential of sulfur-
FIGURE 1. A sulfur HASC (R-hetero-atom substituted carbonyl)
linker.
based HASC linkers. Sulfur linkers are finding increasing use
in phase tag-assisted synthesis,1c and we have recently applied
a sulfur linker of this type in fluorous phase synthesis.4 Adjusting
the oxidation state of the linking sulfur atom in our solid-phase
system allows the use of “classical” organosulfur chemistry to
functionalize substrates immobilized using the linker. Here, we
describe in full our studies on the solid-phase synthesis of
N-heterocycles using a sulfur linker cleaved by SmI2.5
† University of Glasgow.
‡ University of Manchester.
§ UCB Celltech R&D Ltd.
| Pfizer Global Research & Development.
(1) For recent reviews on linkers and cleavage strategies for solid-phase
organic synthesis: (a) James, I. W. Tetrahedron 1999, 55, 4855. (b) Guillier,
F.; Orain, D.; Bradley, M. Chem. ReV. 2000, 100, 2091. (c) McAllister, L.
A.; McCormick, R. A.; Procter, D. J. Tetrahedron 2005, 61, 11527.
(2) For reviews on the use of samarium(II) iodide in organic synthesis:
(a) Soderquist, J. A. Aldrichimica Acta 1991, 24, 15. (b) Molander, G. A.
Chem. ReV. 1992, 92, 29. (c) Molander, G. A. Org. React. 1994, 46, 211.
(d) Molander, G. A.; Harris, C. R. Chem. ReV. 1996, 96, 307. (e) Molander,
G. A.; Harris C. R. Tetrahedron 1998, 54, 3321. (f) Kagan, H.; Namy, J.
L. Lanthanides: Chemistry and Use in Organic Synthesis; Kobayashi, S.,
Ed.; Springer: Berlin, 1999; p 155. (g) Krief, A.; Laval, A.-M. Chem. ReV.
1999, 99, 745. (h) Steel, P. G. J. Chem. Soc., Perkin Trans. 1 2001, 2727.
(i) Kagan, H. B. Tetrahedron 2003, 59, 10351. (j) Edmonds, D. J.; Johnston,
D.; Procter, D. J. Chem. ReV. 2004, 104, 3371.
(3) (a) McKerlie, F.; Procter, D. J.; Wynne, G. Chem. Commun. 2002,
584. (b) McKerlie, F.; Rudkin, I. M.; Wynne, G.; Procter, D. J. Org. Biomol.
Chem. 2005, 3, 2805.
(4) McAllister, L. A.; McCormick, R. A.; Brand, S.; Procter, D. J. Angew.
Chem., Int. Ed. 2005, 44, 452.
(5) For preliminary accounts of this work, see (a) McAllister, L. A.;
Brand, S.; de Gentile, R.; Procter, D. J. Chem. Commun. 2003, 2380. (b)
Turner, K. L.; Baker, T. M.; Islam, S.; Procter, D. J.; Stefaniak, M. Org.
Lett. 2006, 8, 329.
10.1021/jo060940n CCC: $33.50 © 2006 American Chemical Society
Published on Web 07/18/2006
J. Org. Chem. 2006, 71, 6497-6507
6497

McAllister et al.
FIGURE 2. The oxindole and tetrahydroquinolone framework.
Our aim was to assess the feasibility of our sulfur linker sys-
tem and investigate its compatibility with a range of important
transformations and reagent systems. We chose to develop a
route to oxindoles6 and tetrahydroquinolones7 using our linker
system. These heterocyclic frameworks can be found in many
natural and nonnatural biologically active compounds and are
therefore attractive scaffolds for synthesis (Figure 2).6,7
Results and Discussion
FIGURE 3. Pummerer cyclizations mediated by a sulfur linker.
A Solid-Phase Approach to Oxindoles: Pummerer Cycli-
zations on Solid Phase. The Pummerer reaction of sulfoxides
is a powerful strategy for the efficient synthesis of carbocycles
and heterocycles.8 The R-sulfanyl carbonyl compounds bearing
tethered nucleophilic groups undergo cyclization via the forma-
tion of reactive sulfonium ions and are of particular synthetic
utility.8 We envisaged that oxidation of the sulfur in R-sulfanyl
amides bearing nucleophilic groups, attached to resin via a sulfur
atom, followed by sulfonium ion9 formation would trigger
Pummerer cyclization (Figure 3). Crucially, the sulfur link
remains intact thus allowing further solid-phase modification
steps to be carried out before traceless cleavage of the link using
samarium(II) iodide.
Applying this approach, we envisaged that simple R-sulfanyl
N-aryl acetamides 1, immobilized using our sulfur linker system,
could be converted to oxindoles. We chose to establish the sulfur
linkage through the reaction of a benzyl thiol resin with R-bromo
acetamides. This simple approach would allow access to
Pummerer cyclization substrates in a straightforward manner.
Benzyl thiol resin 210 was prepared from Merrifield resin by
two routes (Scheme 1). Routes via the thiourea11 and via the
thioacetate10 were found to give similar loadings of free “SH”
sites.12
(6) Jossang, A.; Jossang, P.; Hadi, H. A.; Se´venet, T.; Bodo, B. J. Org.
Chem. 1991, 56, 6527. (b) Shibata, N.; Ishimaru, T.; Suzuki, E.; Kirk, K.
L. J. Org. Chem. 2003, 68, 2494. (c) Kawasaki, T.; Nagaoka, M.; Satoh,
T.; Okamoto, A.; Ukon, R.; Ogawa, A. Tetrahedron, 2004, 60, 3493. (d)
Tokunaga, T.; Hume, W. E.; Nagamine, J.; Kawamura, T.; Taiji, M.; Nagata,
R. Biorg. Med. Chem. Lett. 2005, 15, 1789. (e) Li, X.; Huang, P.; Cui, J.
J.; Zhang, J.; Tang, C. Biorg. Med. Chem. Lett. 2003, 13, 1939.
(7) (a) Patel, M.; McHugh, R. J., Jr.; Cordova, B. C.; Klabe, R. M.;
Bacheler, L. T.; Ericksen-Viitanen, S.; Rodgers, J. D. Biorg. Med. Chem.
Lett. 2001, 11, 1943. (b) Hayashi, H.; Miwa, Y.; Miki, I.; Ichikawa, S.;
Yoda, N.; Ishii, A.; Kono, M.; Suzuki, F. J. Med. Chem. 1992, 35, 4893.
(c) Carling, R. W.; Leeson, P. D.; Moore, K. W.; Smith, J. D.; Moyes, C.
R.; Mawer, I. M.; Thomas, S.; Chan, T.; Baker, R.; Foster, A. C.; Grimwood,
S.; Kemp, J. A.; Marshall, G. R.; Tricklebank, M. D.; Saywell, K. L. J.
Med. Chem. 1993, 36, 3397. (d) Christopher, E.; Bedir, E.; Dunbar, C.;
Khan, I. A.; Okunji, C. O.; Schuster, B. M.; Iwu, M. M. HelV. Chim. Acta
2003, 86, 2914. (e) Ito, C.; Itoigawa, M.; Otsuka, T.; Tokuda, H.; Nishino,
H.; Furukawa, H. J. Nat. Prod. 2000, 63, 1344.
The feasibility of our solid phase Pummerer approach to
oxindoles was initially investigated in solution using benzyl thiol
(9) Sulfonium ions have begun to find application in solid-phase
chemistry. (a) In Pd-catalysed cross-coupling reactions see Vanier, C.; Lorge´,
F.; Wagner A.; Mioskowski, C. Angew. Chem., Int. Ed. 2000, 39, 1679.
(b) In cyclopropanations and epoxidations see La Porta, E.; Piarulli, U.;
Cardullo, F.; Paio, A.; Provera, S.; Seneci, P.; Gennari, C. Tetrahedron
Lett. 2002, 43, 761. (c) In the Pummerer cleavage of sulfoxide linkers see
Rolland, C.; Hanquet, G.; Ducep, J.-B.; Solladie´, G. Tetrahedron Lett. 2001,
42, 7563. (d) Tai, C.-H.; Wu, H.-C.; Li, W.-R. Org. Lett. 2004, 6, 2905.
(10) Kobayashi, S.; Hachiya, I.; Suzuki, S.; Moriwaki, M. Tetrahedron
Lett. 1996, 37, 2809.
(11) For the preparation of a different thiol resin via a thiourea, see ref
9a.
(12) The loading of free SH sites was determined by the immobilization
of N-methyl-N-phenyl R-bromoacetamide, followed by SmI2 cleavage and
isolation/quantification of N-methyl-N-phenyl acetamide. The discrepancy
between the loading obtained by this method and that obtained by sulfur
microanalysis (∼1 mmol g-1) is presumably due to oxidative cross-linking
of the thiol functional groups (See Experimental Section).
(8) For recent reviews on the Pummerer reaction see (a) Bur, S. K.;
Padwa, A. Chem. ReV. 2004, 104, 2401. (b) Padwa, A.; Danca, D. M.;
Ginn, J. D.; Lynch, S. M. J. Braz. Chem. Soc. 2001, 12, 571. (c) Padwa,
A.; Waterson, A. G. Curr. Org. Chem. 2000, 4, 175. (d) Padwa, A.; Gunn
D. E., Jr.; Osterhout, M. H. Synthesis, 1997, 1353.
6498 J. Org. Chem., Vol. 71, No. 17, 2006

Solid Phase Approaches to N-Heterocycles
FIGURE 4. Starting materials and oxindole products: (a) isolated, overall yields after four steps; (b) cyclized using TFAA and BF3‚OEt2; (c) cyclized
using TFAA.
SCHEME 1a
SCHEME 2a
a Reagents and conditions: (i) BnSH, NEt3, DMF, rt, 47%. (ii) HFIP-
CH2Cl2 (2:1), H2O2, rt, 92%. (iii) TFAA, 1,2-dichloroethane, rt, 63%. (iv)
SmI2, DMPU, THF, rt, 48% (unoptimized).
a Reagents and conditions: (i) KSC(O)CH3, DMF, rt. (ii) LiBH4, THF,
rt. (iii) thiourea, DMF, 60 °C. (iv) n-BuNH2, DMF, 60 °C.
oxindole 12 was isolated in high purity and 47% yield after
four steps (Scheme 3).
as a model for thiol resin 2. Thus reaction of R-bromoamide 3,
readily accessible from the corresponding secondary amine and
bromoacetyl bromide, with benzyl thiol gave sulfide 4, which
was then oxidized selectively to the sulfoxide 5 using Be´gue´’s
H2O2 and hexafluoro-2-propanol (HFIP) reagent system.13
Pummerer cyclization of the electronically activated sulfoxide
5 was readily achieved using trifluoroacetic anhydride.14 After
chromatographic removal of the minor oxindole regioisomer
(Figure 4), cleavage of the benzylsulfanyl group from oxindole
6 was carried out using SmI2 and DMPU (Scheme 2).3-5
We next adapted the sequence to solid phase while also
assessing the feasibility of carrying out solid-phase Pummerer
cyclizations on unactiVated aromatic substrates. Immobilization
of N-methyl-N-phenyl R-bromoacetamide 8 was achieved by
stirring the amide with resin 2 in DMF. The sulfur link in
immobilized amide 9 was then oxidized to give sulfoxide 10.
In this electronically unactivated substrate, Pummerer cyclization
was found to be most efficiently carried out using stronger
activation with TFAA and BF3‚Et2O.14 Cleavage of the sulfur
link to resin was then carried out using SmI2 and DMPU
according to our previously reported conditions.3-5 Pleasingly,
By varying the R-bromoamide used in the sequence, a range
of oxindoles has been prepared (Figure 4). As can be seen from
the table, neutral, electron rich, and electron-deficient aromatic
amide substrates have been employed in the sequence. Interest-
ingly, in the solid-phase synthesis of 5-iodo-1-propyl-1,3-
dihydro-indol-2-one 23, cleavage of the sulfur link to resin can
be achieved chemoselectively in the presence of the aryl iodide
although the use of excess SmI2 leads to lower yields through
over-reduction. It is known that aryl and alkyl halides can be
readily reduced using SmI2 with additives.15 Crucially, no
aqueous work up is needed after cleavage of the product from
resin. In the majority of cases, the products could be separated
from DMPU and inorganic byproducts by simple filtration
through a short pad of silica after which they were found to
1
give satisfactory H and 13C NMR spectra. Routine chroma-
tography was used for the few examples where minor unchar-
acterized byproducts were obtained. The structure of the major
regioisomer of 7 was confirmed by X-ray crystallography.16
As the sulfur link to resin remains intact after the Pummerer
cyclization, further modification on resin can allow access to
elaborated heterocyclic frameworks. By way of illustration,
(13) Ravikumar, K. S.; Be´gue´, J-P.; Bonnet-Delpon, D. Tetrahedron
Lett. 1998, 39, 3141.
(14) It has been noted that BF3‚OEt2 is not required for the cyclization
of electronically activated systems: (a) Shinohara, T.; Takeda, A.; Toda,
J.; Ueda, Y.; Kohno, M.; Sano, T. Chem. Pharm. Bull. 1998, 46, 6, 918.
(b) Saitoh, T.; Ichikawa, T.; Horiguchi, Y.; Toda, J.; Sano, T. Chem. Pharm.
Bull. 2001, 49, 8, 979.
(15) Aryl and alkyl halides can be readily reduced using SmI2 with
additives such as HMPA: Inanaga, J.; Ishikawa, M.; Yamaguchi, M. Chem.
Lett. 1987, 1485.
(16) See Supporting Information for the X-ray structure of the major
isomer of 7 (CCDC 601447).
J. Org. Chem, Vol. 71, No. 17, 2006 6499

McAllister et al.
SCHEME 3a
a Reagents and conditions: (i) NEt3, DMF, rt. (ii) HFIP-CH2Cl2 (2:1), H2O2, rt. (iii) TFAA, BF3‚OEt2, 1,2-dichloroethane, rt. (iv) SmI2, DMPU, THF,
rt, 47% isolated yield after four steps on resin.
SCHEME 4a
a Reagents and conditions: (i) oxone, DMF:H2O (4:1), rt. (ii) K2CO3, KI, allyl bromide, DMF, 60 °C. (iii) SmI2, DMPU, THF, rt, 30% overall yield for
six steps on resin (9:1 mixture of regioisomers, major shown).
SCHEME 5a
crystallography.5b The cleavage reaction was next investigated
in the model system. Treatment of 37 and 38 with SmI2 using
LiCl as a promotor18 gave the expected products in moderate,
unoptimized yields. The use of LiCl as a promotor, rather than
DMPU, simplifies the purification procedure even further.
Further modification of 37 was readily achieved by alkylation
to give 41, the relative stereochemistry of which was confirmed
by X-ray crystallography.5b Cleavage using SmI2/LiCl gave 42
as a ∼1:1 mixture of diastereoisomers. Interestingly, the use of
t-BuOH as a proton source in the reduction gave syn-42 as the
major product (5:1 dr) (Scheme 3). The relative stereochemistry
of the major diastereoisomer was confirmed by X-ray crystallog-
raphy.5b
Satisfied that our approach was feasible we moved on to the
solid phase. An early reaction sequence on resin is shown in
Scheme 7.
a EWG ) electron-withdrawing group.
oxidation of resin-bound oxindole 25 gave sulfone 26, and
alkylation then gave allylated sulfone 27. Thus the approach
proceeds with assistance from the sulfur link in two different
oxidation states. Cleavage of the link with SmI2 and DMPU
gave the expected product 28 as a 9:1 mixture of regioisomers
in 30% overall yield (Scheme 4). As expected, cleavage of the
sulfur linker at the sulfone oxidation state was found to proceed
more rapidly than cleavage of the analogous sulfide linkages
although yields were found to be similar.
A Solid-Phase Approach to Tetrahydroquinolones. Our
proposed, solid-phase approach to tetrahydroquinolones using
the sulfur linker is outlined in Scheme 5. Heck reactions of
immobilized aryl halides 32 with electron-deficient alkenes
should allow access to key intermediates 31. Base-mediated
cyclization will then furnish the tetrahydroquinolone core 30
which can be modified before cleavage from the support.
We began our studies by evaluating the route using a solution
phase model system. R-Sulfanyl amides 33 and 34, in which
the benzyl sulfanyl group mimics a benzylic sulfur resin, were
prepared. Although few Heck reactions of N-R-halophenyl-
amides and carbamates have been reported,17 both 33 and 34
underwent efficient Heck coupling in o-xylene with tert-butyl
acrylate under microwave conditions. Oxidation of 35 and 36
to the corresponding sulfones and treatment with K2CO3 gave
the anti-tetrahydroquinolones 37 and 38 in good yield. The
relative stereochemistry of 37 and 38 was confirmed by X-ray
Immobilization of R-bromoamide 43 gave amide 44.
Microwave-assisted Heck reaction with tert-butyl acrylate was
unsatisfactory using o-xylene because of poor swelling of the
resin and because it gave low conversion as indicated by FTIR.
The use of a DMF/o-xylene solvent mixture in the Heck reaction
appeared to solve this issue and gave 45. Cyclization then gave
supported tetrahydroquinolone 46. As expected, treatment of
46 with SmI2/LiCl gave 39 although in a disappointing overall
yield of 15% (for 5 steps). The isolation of amide byproducts
47 and 48 indicated that the Heck reaction was not proceeding
efficiently on the solid phase. The debrominated product 48 most
likely results from SmI2 reduction during the cleavage step
although it is possible that reduction of the aryl bromide occurs
under the conditions of the Heck reaction. Although o-xylene
was an excellent solvent for the Heck reaction in solution, it
was clearly unsuitable for use on solid phase. The use of
JandaGel, a support more suitable for use with nonpolar solvents
such as o-xylene, also gave 39 in low yield. A more detailed
solution phase study on the pivotal Heck reaction was therefore
carried out to provide improved conditions for use on solid phase
(Table 1). The use of a combination of DMF and o-xylene (3:7)
gave lower conversion (entry 3). In neat DMF, a more suitable
(18) (a) Fuchs, J. R.; Mitchell, M. L.; Shabangi, M.; Flowers, R. A. II
Tetrahedron Lett. 1997, 38, 8157. (b) Miller, R. S.; Sealy, J. M.; Shabangi,
M.; Kuhlman, M. L.; Fuchs, J. R.; Flowers, R. A., II. J. Am. Chem. Soc.
2000, 122, 7718. (c) Hughes, A. D.; Price, D. A.; Simpkins, N. S. J. Chem.
Soc., Perkin Trans. 1 1999, 1295.
(17) For an example, see Arnold, L. A.; Luo, W.; Guy, R. K. Org. Lett.
2004, 6, 3005.
6500 J. Org. Chem., Vol. 71, No. 17, 2006

Solid Phase Approaches to N-Heterocycles
SCHEME 6a
TABLE 1. Optimizing the Heck Reaction
a Pd(OAc)2 (5 mol %), P(o-Tol)3 (5 mol %), NEt3. b Isolated yields.
a Reagents and conditions: (i) tert-butyl acrylate, Pd(OAc)2 (5 mol %),
P(o-Tol)3 (5 mol %), NEt3 o-xylene, MW 100 °C, 7 h, 88% 35, 99% 36.
(ii) 1. Oxone, DMF/H2O (4:1), rt. 2. K2CO3, DMF, for two steps 99% 37,
92% 38. (iii) SmI2, THF, LiCl, rt, unoptimized, 57% 39, 45% 40. (iv)
K2CO3, allyl bromide, DMF, rt, 76%. (v) SmI2, THF, LiCl, t-BuOH, rt,
79% (5:1, syn/anti).
SCHEME 7a
FIGURE 5. Starting materials and tetrahydroquinolone products for
(a) 5 and (b) 6 steps and (c) 2:1 to 1:1 diastereoisomeric ratio.
a Reagents and conditions: (i) 2, NEt3, DMF, rt. (ii) tert-butyl acrylate,
Pd(OAc)2 (10 mol %), P(o-Tol)3 (10 mol %), NEt3, DMF-o-xylene, MW
100 °C. (iii) 1. Oxone, DMF/H2O, rt. 2. K2CO3, DMF, rt. (iv) SmI2, THF,
LiCl, rt, 15% overall 39.
materials 43, 49-52. Additional diversity was introduced by
Heck reaction with a different olefin and by the alkylation of
an intermediate sulfone.
solvent for solid phase reactions, conversion was acceptable
particularly after a retreatment (entries 4 and 5).
The expected products were obtained in satisfactory overall
yields in five and six steps on solid phase. Aryl iodide 49 gave
improved yields owing to more efficient Heck reactions.
Alkylations of intermediate sulfones proved to be more difficult
than solution models had predicted and more forcing conditions
were necessary (50 °C, KI). Products 54 and 55 were obtained
with little diastereoselectivity possibly because of residual
moisture in the resin acting as an alternative proton source to
the added t-BuOH. Finally, we have investigated the feasibility
of a cyclative cleavage strategy using the HASC linker.
Pleasingly, treatment of sulfone 58 with SmI2 resulted in
cleavage of the sulfur linkage and cyclization to give 53 in good
overall yield. The cyclization may be either a radical or anionic
process (Scheme 8).
The improved Heck coupling conditions were applied in the
solid-phase sequence previously described with the additional
modification that m-CPBA was used for oxidation to the sulfone.
(The use of oxone for the oxidation caused problems with
inorganic byproducts contaminating the resin after washing.
Solution phase oxidation of sulfide 35 with m-CPBA gave the
corresponding sulfone in 71% yield (m-CPBA, K2CO3, CH2-
Cl2, 2 h, rt). Longer reaction times led to some epoxidation of
the electron-deficient alkene). Pleasingly, employing these con-
ditions gave 39 in an improved 27% overall yield after puri-
fication (Figure 5). We have utilized the approach to prepare a
collection of tetrahydroquinolones using R-bromoamide starting
J. Org. Chem, Vol. 71, No. 17, 2006 6501

McAllister et al.
SCHEME 8a
1450, 1065. Loading was determined using the procedure outlined
in the general methods section.
N-Benzyl-2-bromo-N-(3-methoxy-phenyl) Acetamide 3. To
a solution of N-benzyl-3-methoxyaniline (878 mg, 4.12 mmol,
1 equiv) and NEt3 (0.87 mL, 6.20 mmol, 1.5 equiv) in CH2Cl2 (30
mL) at 0 °C was added bromoacetyl bromide (0.54 mL, 6.20 mmol,
1.5 equiv). The reaction was allowed to stir at room temperature
for 7 h. The reaction mixture was then washed with 0.5 M HCl
(3 × 20 mL) and aqueous saturated NaCl (3 × 20 mL). The organic
layer was dried (MgSO4) and concentrated in vacuo to give
N-benzyl-2-bromo-N-(3-methoxy-phenyl) acetamide 3 (1.34 g, 4.09
mmol, 99%) as a brown oil which was used without further
a Reagents and conditions: (i) SmI2, THF, LiCl, rt, 25% for four steps.
Conclusions
1
purification. H NMR (400 MHz, CDCl3): δ 3.64 (2H, s, CH2-
CO), 3.65 (3H, s, CH3O), 4.81 (2H, s, PhCH2), 6.49 (1H, apparent
triplet, J ) 2.1 Hz, ArH), 6.57 (1H, d, J ) 7.8 Hz, ArH), 6.81
(1H, dd, J ) 8.3, 2.2 Hz, ArH), 7.12-7.23 (6H, m, ArH). 13C NMR
(100 MHz, CDCl3): δ 27.7 (CH2CO), 54.0 (PhCH2), 55.7 (CH3O),
114.1 (ArCH), 114.8 (ArCH), 120.6 (ArCH), 128.1 (ArCH), 128.8
(2 × ArCH), 129.3 (2 × ArCH), 130.8 (ArCH), 137.1 (ArC), 142.6
(ArC), 160.7 (ArCO), 166.8 (C)O). υmax (neat)/cm-1: 3029, 1662
(CdO), 1600, 148, 1286. m/z (EI+ mode): 333 (M+, 5%), 254
(82), 212 (12), 150 (80), 91 (100), 65 (12). C16H16NO2Br requires
333.0364; found, 333.0361.
We have developed a solid-phase approach to N-heterocycles
using a sulfur linker cleaved using SmI2. The route to oxindoles
employs the first Pummerer cyclizations on solid phase, while
the route to tetrahydroquinolones involves a microwave-assisted
Heck reaction followed by a Michael cyclization. In both cases,
the linker is cleaved in a traceless fashion by reduction with
samarium(II) iodide. We have also shown the feasibility of
cyclative-cleavage processes using the linker. The routes illus-
trate the compatibility of the linker system with a number of
important reaction types and its utility for library synthesis.
N-Benzyl-2-benzylsulfanyl-N-(3-methoxy-phenyl)-acetamide
4. To a solution of N-benzyl-2-bromo-N-(3-methoxyphenyl) ac-
etamide 3 (300 mg, 0.90 mmol, 1 equiv) in DMF (4 mL) was added
NEt3 (0.13 mL, 0.90 mmol, 1 equiv) and benzyl thiol 2 (0.11 mL,
0.90 mmol, 1 equiv). The reaction was allowed to stir at room
temperature for 4.5 h. CH2Cl2 (10 mL) was added, and the organic
layer was washed with water (3 × 10 mL) and aqueous saturated
NaHCO3 (3 × 10 mL). The organic layer was dried (MgSO4) and
concentrated in vacuo. The crude product was purified by column
chromatography on silica gel (30% ethyl acetate in petroleum ether
as eluant) to give N-benzyl-2-benzyl sulfanyl-N-(3-methoxyphenyl)-
Experimental Section
Preparation of SmI2. Samarium (II) iodide was prepared by
the method of Imamoto19 with the modification that the samarium-
iodine solution was heated at 60 °C rather than at reflux.
General Washing and Drying Procedure. The resin was
washed with THF (30 mL), THF/H2O (3:1) (3 × 30 mL), THF/
H2O (1:1) (3 × 30 mL), THF/H2O (1:3) (3 × 30 mL), THF (2 ×
30 mL), then alternate washings with CH2Cl2 (3 × 30 mL) and
MeOH (3 × 30 mL), finishing with THF (2 × 30 mL). The resin
was then left to dry for 10 min under water pump pressure before
being dried for approximately 6 h under high vacuum.
(i) Thioacetate Route to Thiol Resin 2. Merrifield Thioacetate
Resin10.
Merrifield resin (5.00 g, 6.00 mmol) was swollen in DMF (50
mL) for 15 min. Potassium thioacetate (1.88 g, 16.5 mmol) in DMF
(10 mL) was added, and the reaction mixture was stirred slowly at
room temperature for 24 h before washing according to the standard
procedure. υmax (ATR)/cm-1: 2917, 2023, 1687 (CdO), 1493, 1450,
1130.
1
acetamide 4 (160 mg, 0.44 mmol, 49%) as a yellow oil. H NMR
(400 MHz, CDCl3): δ 2.86 (2H, s, CH2CO), 3.60 (3H, s, CH3O),
3.82 (2H, s, PhCH2S), 4.80 (2H, s, PhCH2), 6.43 (1H, d, J ) 2.3
Hz, ArH), 6.49 (1H, d, J ) 7.8 Hz, ArH), 6.73 (1H, dd, J ) 8.3,
2.3 Hz, ArH), 7.09-7.25 (11H, m, 11 × ArH). 13C NMR (100
MHz, CDCl3): δ 32.5 (CH2), 36.7 (CH2), 53.5 (PhCH2), 55.7
(CH3O), 114.4 (ArCH), 120.9 (ArCH), 127.4 (ArCH), 127.8
(ArCH), 128.8 (4 × ArCH), 129.1 (2 × ArCH), 129.6 (2 × ArCH),
130.5 (ArCH), 137.7 (ArC), 138.1 (ArC), 143.3 (ArC), 160.6
(ArCO), 169.7 (C)O). υmax (neat)/cm-1: 3060, 3027, 2937, 1650
(CdO), 1600, 1488, 1390. m/z (EI+ mode): 377 (M+, 8%), 255
(62), 213 (16), 164 (5), 122 (10), 91 (100), 65 (10). C23H23NO2S
requires 377.1449; found, 377.1451.
(()-N-Benzyl-2-benzylsulfinyl-N-(3-methoxyphenyl) Acet-
amide 5. To a solution of N-benzyl-2-benzylsulfanyl-N-(3-methoxy-
phenyl) acetamide 4 (126 mg, 0.34 mmol, 1 equiv) in HFIP/CH2-
Cl2 (4 mL: 2 mL) was added 30% aqueous H2O2 (0.15 mL, 1.36
mmol, 4 equiv), and the reaction was allowed to stir at room
temperature for 1 h. The reaction was then quenched with aqueous
saturated Na2SO3 solution. The aqueous and organic layers were
separated, and the aqueous layer was extracted with CH2Cl2. The
combined organic layers were dried (MgSO4) and concentrated in
vacuo to give (()-N-benzyl-2-benzylsulfinyl-N-(3-methoxyphenyl)
acetamide 5 as a yellow oil (122 mg, 0.31 mmol, 92%) which was
used without further purification. 1H NMR (400 MHz, CDCl3): δ
3.26 (1H, d, AB system, J ) 14.6 Hz, 1H from PhCH2S), 3.35
(1H, d, AB system, J ) 14.6 Hz, 1H from PhCH2S), 3.59 (3H, s,
OCH3), 4.05 (1H, d, AB system, J ) 13.0 Hz, 1H from CH2CO),
4.24 (1H, d, AB system, 13.0 Hz, 1H from CH2CO), 4.75 (1H, d,
AB system, J ) 14.2 Hz, 1H from PhCH2N), 4.85 (1H, d, AB
system, J ) 14.2 Hz, 1H from PhCH2N), 6.33 (1H, apparent triplet,
J ) 2.2 Hz, ArH), 6.43 (1H, dd, J ) 7.8, 1.0 Hz, ArH), 6.73-6.76
(1H, multiplet, ArH), 7.08 - 7.30 (11H, m, 11 × ArH). 13C NMR
(100 MHz, CDCl3): δ 52.0 (PhCH2S), 52.7 (CH2CO), 54.4 (OCH3),
56.4 (PhCH2N), 112.9 (ArCH), 113.5 (ArCH), 119.3 (ArCH), 126.7
Thiol Resin 210. Thioacetate resin (5.15 g, 6.13 mmol) was
swollen in THF for 15 min. LiBH4 (0.66 g, 30.6 mmol) was added,
and the reaction mixture was stirred slowly at room temperature
for 48 h. The reaction was then quenched by dropwise addition of
MeOH, and the resin 2 was washed according to the standard
procedure. υmax (ATR)/cm-1: 3024, 2918, 1601, 1493, 1450, 1065.
Loading was determined using the procedure outlined in the general
methods section.
(i) Thiourea Route to Thiol Resin 2. S-Merrifield Bound
Isothiouronium Chloride. Merrifield resin (1.00 g, 1.1 mmol/g,
1.1 mmol, 1 equiv) was swollen in DMF (10 mL) for 15 min.
Thiourea (419 mg, 5.5 mmol, 5 equiv) was added, and the reaction
was heated at 60 °C for 24 h. The resin was then washed using the
standard washing protocol. The product resin was then dried in
vacuo. υmax (ATR)/cm-1: 1648 (CdN).
Benzyl Thiol Resin 210. S-Merrifield bound isothiouronium
chloride (1.07 g, 1.02 mmol/g, 1.09 mmol, 1 equiv) was swollen
in DMF (10 mL). n-Butylamine (0.28 mL, 5.45 mmol, 5 equiv)
was added, and the reaction was heated at 60 °C for 18 h. The
resin was then washed using our standard washing protocol. Thiol
resin 2 was then dried in vacuo. IR analysis showed disappearance
of the CdN stretch. υmax (ATR)/cm-1: 3024, 2918, 1601, 1493,
(19) Imamoto, T.; Ono, M. Chem. Lett. 1987, 501.
6502 J. Org. Chem., Vol. 71, No. 17, 2006

Solid Phase Approaches to N-Heterocycles
(ArCH), 127.3 (ArCH), 127.5 (2 × ArCH), 127.7 (2 × ArCH),
127.9 (2 × ArCH), 128.5 (ArC), 129.5 (3 × ArCH), 135.5 (ArC),
140.8 (ArC), 159.5 (ArCO), 163.4 (CdO). υmax (neat)/cm-1: 3060,
3029, 2919, 1644 (CdO), 1587, 1488, 1402, 1164. m/z (EI+
at room temperature for 16 h. CH2Cl2 (10 mL) was added to the
reaction, and the organic layer was washed with 0.5 M HCl (3 ×
20 mL) and brine (3 × 20 mL). The organic layer was dried
(MgSO4) and concentrated in vacuo. The crude product was purified
by recrystallization from petroleum ether/methanol to give 2-bromo-
N,N-diphenylacetamide 13 (0.49 g, 1.68 mmol, 42%) as a white
solid. 1H NMR (400 MHz, CDCl3): δ 3.87 (2H, s, CH2CO), 7.18-
7.59 (10H, broad signal, ArH). 13C NMR (100 MHz, CDCl3): δ
28.3 (CH2Br), 125-131 (10 × ArCH). m/z (EI+ mode): 289 (M+,
32%), 222 (4), 196 (14)), 169 (100), 167 (53), 86 (30), 84 (48), 49
(25). C14H12BrNO requires 289.0102; found, 289.0103.
mode): 393 (M+ 10%), 255 (16), 212 (6), 91 (100), 83 (24), 65
,
(7). C23H23NO3S requires 393.1399; found, 393.1400.
(()-1-Benzyl-3-benzylsulfanyl-6-methoxy-1,3-dihydro-indol-
2-one 6. To a solution of (()-N-benzyl-2-benzylsulfinyl-N-(3-
methoxyphenyl) acetamide 5 (41.2 mg, 0.11 mmol, 1 equiv) in 1,2-
dichloroethane (4 mL) was added TFAA (93 µL, 0.66 mL, 6 equiv),
and the reaction was allowed to stir at room temperature for 2 h.
The reaction was quenched with 5% NaOH solution (5 mL), and
the aqueous and organic layers were separated. The aqueous layer
was extracted with CH2Cl2 (2 × 5 mL) and the combined organic
layers were dried (MgSO4) and concentrated in vacuo. The crude
product was purified by column chromatography on silica gel (20%
ethyl acetate in petroleum ether) to give (()-1-benzyl-3-benzyl-
sulfanyl-6-methoxy-1,3-dihydro-indol-2-one 6 (26 mg, 0.07 mmol,
63%) as a yellow oil. 1H NMR (400 MHz, CDCl3): δ 3.64 (3H, s,
CH3O), 3.68-3.72 (1H, m, 1H from PhCH2), 4.04-4.16 (2H, m,
1H from PhCH2 and CHS), 4.75 (2H, s, PhCH2N), 6.19 (1H, d, J
) 2.2 Hz, ArH), 6.42 (1H, dd, J ) 2.2, 8.2 Hz, ArH), 7.08 (1H, d,
J ) 8.2 Hz, ArH), 7.14-7.32 (10H, m, 10 × ArH). 13C NMR (100
MHz, CDCl3): δ 34.7 (PhCH2S), 43.2 (CHS), 44.3 (PhCH2N), 55.8
(CH3O), 97.7 (ArCH), 106.9 (ArCH), 117.5 (ArC), 126.2 (ArCH),
127.6 (ArCH), 127.7 (2 × ArCH), 128.1 (ArCH), 128.7 (2 ×
ArCH), 129.2 (2 × ArCH), 129.7 (2 × ArCH), 136.0 (ArC), 137.8
2-Bromo-N-allyl-N-phenylacetamide 14. To a solution of
N-allylaniline (1.0 g, 7.50 mmol, 1 equiv) and NEt3 (1.05 mL, 7.50
mmol, 1 equiv) in CH2Cl2 (15 mL) at 0 °C was added a solution
of bromoacetyl bromide (1.96 mL, 22.5 mmol, 3 equiv) in CH2Cl2
(5 mL), and the reaction was allowed to stir at room temperature
for 18 h. The reaction mixture was then washed with 0.5 M HCl
(3 × 20 mL) and brine (3 × 20 mL). The organic layer was dried
(MgSO4), and concentrated in vacuo. The crude reaction was puri-
fied by flash chromatography on alumina using 40% ethyl acetate
in petroleum ether as eluant to give 2-bromo-N-allyl-N-phenyl-
1
acetamide 14 (868 mg, 3.38 mmol, 45%) as a clear oil. H NMR
(400 MHz, CDCl3): δ 3.67 (2H, s, CH2Br), 4.32 (2H, d, J ) 6.1
Hz, CH2N), 5.15 (2H, apparent t, J ) 7.5 Hz, CH2dCH), 5.83-
5.93 (1H, m, CH)CH2), 7.22-7.28 (2H, m, ArH), 7.39-7.48 (3H,
m, ArH). 13C NMR (100 MHz, CDCl3): δ 27.6 (CH2Br), 53.3
(CH2N), 119.0 (CH2dCH), 128.5 (2 × ArCH), 129.1 (ArCH), 130.2
(2 × ArCH), 132.5 (CHdCH2), 141.8 (ArC), 166.5 (C)O).
(ArC), 144.9 (ArC), 161.0 (ArCO), 176.8 (C)O). υmax (neat)/cm-1
:
2915, 2838, 1720 (CdO), 1621, 1496, 1373, 1164. m/z (EI+
mode): 375 (M+, 5%), 253 (100), 252 (82), 162 (5), 91 (85), 65
(7). C23H21NO2S requires 375.1293; found, 375.1292.
υ
max(neat)/cm-1: 1666 (CdO), 1594, 1494, 1394, 1276. m/z (EI+
mode): 253 (M+, 8%), 212 (7), 174 (100), 132 (25), 106 (28), 83
(65), 77 (35), 41 (19). C11H12BrNO requires 253.0102; found,
253.0107.
Solution Phase Model Cleavage of (()-1-Benzyl-3-benzyl-
sulfanyl-6-methoxy-1,3-dihydro-indol-2-one 6. To a solution of
(()-1-benzyl-3-benzylsulfanyl-6-methoxy-1,3-dihydro-indol-2-
one 6 (19 mg, 0.05 mmol, 1 equiv) in THF (2 mL) and DMPU
(0.05 mL) was added SmI2 (0.15 mL of a 1 M solution in THF,
0.15 mmol, 3 equiv) at room temperature, and the reaction was
stirred for 18 h. The reaction mixture was then diluted with CH2Cl2
(4 mL) and the organic layer washed with aqueous saturated
NaHCO3 (2 mL) before being dried (MgSO4) and concentrated in
vacuo. The crude product was purified by column chromatography
on silica gel (40% ethyl acetate in petroleum ether) to give 1-benzyl-
6-methoxy-1,3-dihydro-indol-2-one 7-major (6 mg, 0.025 mmol,
48%) as a colorless oil.
2-Bromo-N-methyl-N-phenylacetamide 820. To a solution of
N-methyl aniline (0.33 mL, 3.00 mmol, 1 equiv) and NEt3 (0.42
mL, 3.00 mmol, 1 equiv) in CH2Cl2 (3.5 mL) at 0 °C was added
by cannula, a solution of bromoacetyl bromide (0.26 mL, 3.00
mmol, 1 equiv) in CH2Cl2 (5 mL). The reaction was allowed to
stir at room temperature for 16 h. CH2Cl2 (10 mL) was then added
to the reaction, the organic layer was washed with 0.5 M HCl (3 ×
20 mL) and aqueous saturated NaCl (3 × 20 mL). The combined
organic layers were dried (MgSO4) and concentrated in vacuo, to
give 2-bromo-N-methyl-N-phenylacetamide 8 (0.60 g, 2.63 mmol,
88%) as a brown solid which was used without further purification.
1H NMR (400 MHz, CDCl3): δ 3.24 (3H, s, NCH3), 3.65 (2H, s,
CH2Br), 7.22 (2H, d, J ) 7.3 Hz, 2 × ArH) and 7.31-7.41 (3H,
m, 3 × ArH). 13C NMR (100 MHz, CDCl3): δ 27.2 (CH2Br), 38.5
(NCH3), 127.4 (2 × ArCH), 128.9 (ArCH), 130.4 (2 × ArCH),
143.5 (ArC) and 166.9 (C)O). υmax (neat)/cm-1: 3060, 2969, 1662
(CdO), 1594, 1496, 1382, 1226, 1118 and 701 (C-Br). m/z (FAB
mode): 228 ((M + H)+, 100%), 227 (20), 199 (5), 148 (17), 106
(11), 92 (3) and 69 (3). C9H11NOBr requires 228.0024; found,
228.0023.
2-Bromo-N-methyl-N-(3-methylphenyl)-acetamide 15. To a
solution of N-methyl toluidine (1.00 mL, 7.80 mmol, 1 equiv) and
NEt3 (1.20 mL, 8.60 mmol, 1.1 equiv) in CH2Cl2 (30 mL) at 0 °C
was added bromoacetyl bromide (0.74 mL, 8.60 mmol, 1.1 equiv);
the reaction was allowed to stir at room temperature for 1.5 h. The
reaction mixture was then washed with 0.5 M HCl (3 × 20 mL)
and brine (3 × 20 mL). The organic layer was dried (MgSO4) and
concentrated in vacuo to give 2-bromo-N-methyl-N-(3-methyl-
phenyl) acetamide 15 (660 mg, 2.73 mmol, 35%) as a red/brown
1
solid which was used without further purification. H NMR (400
MHz, CDCl3): δ 2.33 (3H, s, CH3-Ar), 3.22 (3H, s, NCH3), 3.60
(2H, s, CH2Br), 7.00 (2H, overlapping singlet and doublet, 2 ×
ArH), 7.13 (1H, d, J ) 8.0 Hz, ArH), 7.25 (1H apparent t, J ) 7.6
Hz, ArH). 13C NMR (100 MHz, CDCl3): δ 21.7 (CH3Ar), 27.3
(CH2Br), 38.4 (CH3N), 124.3 (ArCH), 127.9 (ArCH), 129.7 (ArCH),
130.1 (ArCH), 140.6 (ArC), 143.4 (ArC), 166.9 (C)O). υmax
/
(cm-1): 3045, 2962, 1664 (CdO), 1376, 1114. m/z (EI+ mode):
241 (M+, 7%), 162 (9), 121 (13), 83 (100), 47 (17). C10H12BrNO
requires 241.0102; found, 241.0104.
N-Benzo[1,3]dioxol-5-yl-2-bromo-N-(3-cyclopentyl-propyl)-
acetamide 16. To a solution of 3,4-(methylenedioxy) aniline (1.72
g, 12.5 mmol, 1 equiv) in CH2Cl2 (20 mL) was added NEt3 (1.94
mL, 13.8 mmol, 1.1 equiv) and 3-cyclopentyl propionyl chloride
(1.94 mL, 13.8 mmol, 1.1 equiv). The reaction was allowed to stir
at room temperature for 3 h before EtOAc was added to the reaction
mixture. After separation, the organic layer was washed with
NaHCO3, dried (MgSO4) and concentrated to give a white solid.
To a solution of the crude amide (3.20 g, 12.2 mmol, 1 equiv) in
THF (45 mL) at 0 °C was added LiAlH4 (972 mg, 25.6 mmol, 2.1
equiv). The reaction was allowed to stir at room temperature for
18 h. The reaction was quenched with H2O. The aqueous and
organic layers were separate, and the aqueous layer was washed
with NaHCO3, dried (MgSO4), and concentrated in vacuo. The
crude reaction mixture was purified by flash chromatography using
50% petroleum ether in CH2Cl2 as eluant to give benzo[1,3]dioxol-
5-yl-(3-cyclopentyl-propyl)-amine (1.07 g, 4.38 mmol, 35%) as a
brown oil. 1H NMR (400 MHz, CDCl3): δ 1.07-1.12 (2H, m, 2H
2-Bromo-N,N-diphenylacetamide 1321. To a solution of N,N-
diphenylamine (0.68 g, 4.00 mmol, 1 equiv) and NEt3 (0.56 mL,
4.00 mmol, 1 equiv) in CH2Cl2 (10 mL) at 0 °C was added by
cannula, a solution of bromoacetyl bromide (1.05 mL, 12.0 mmol,
3.0 equiv) in CH2Cl2 (5 mL), and the reaction was allowed to stir
J. Org. Chem, Vol. 71, No. 17, 2006 6503

McAllister et al.
from 2 × CH2), 1.37-1.49 (2H, m, CH2), 1.50-1.67 (6H, m, 3 ×
CH2), 1.73-1.87 (3H, m, CH and 2H from 2 × CH2), 3.07 (2H, t,
J ) 7.3 Hz, CH2N), 5.89 (2H, s, CH2O2), 6.18 (1H, dd, J ) 2.3,
8.3 Hz, ArH), 6.36 (1H, d, J ) 2.3 Hz, ArH), 6.69 (1H, d, J ) 8.3
Hz, ArH). 13C NMR (100 MHz, CDCl3): δ 25.5 (2 × CH2), 28.7
(CH2), 33.1 (2 × CH2), 33.9 (CH2), 40.3 (CH), 46.6 (CH2), 97.2
(ArCH), 101.1 (CH2O2), 106.1 (ArCH), 109.0 (ArCH), 141.0
(ArCO), 143.0 (ArCO), 148.7 (C)O). υmax(neat)/cm-1: 3399 (NH),
2857, 1633, 1504, 1199. m/z (EI+ mode): 247 (M+, 68%), 150
(100), 137 (8), 65(5). C15H21NO2 requires 247.1572; found,
247.1572.
J ) 8.4 Hz, 2 × ArH). 13C NMR (100 MHz, CDCl3): δ 11.2 (CH3),
20.7 (CH2), 27.2 (CH2), 51.5 (CH2N), 94.1 (ArCI), 130.1 (2 ×
ArCH), 139.5 (2 × ArCH), 141.3 (ArC), 165.7 (C)O). υmax(neat)/
cm-1: 2961, 2930, 1655 (CdO), 1481, 1211. m/z (CI+ mode): 384
((M+H)+, 43%), 382 ((M+H)+, 43%), 302 (45), 256 (40), 218
(27), 176 (100), 136 (20). C11H14NOBrI requires 381.9304; found,
381.9305.
2-Bromo-N-(4-chlorophenyl)-N-propylacetamide 18. To a
solution of 4-chloroaniline (1.18 g, 14.2 mmol, 1 equiv) in CH2Cl2
(40 mL) was added NEt3 (4.00 mL, 28.4 mmol, 2 equiv) and
propionic anhydride (2.00 mL, 15.6 mmol, 1.1 equiv). The reaction
was allowed to stir at room temperature for 3 h. The reaction
mixture was washed with NaHCO3 and 1 M HCl, dried (MgSO4),
filtered, and concentrated in vacuo to give a white solid. THF
(100 mL) was added, and the solution was cooled to 0 °C before
the addition of LiAlH4 (1.02 g, 26.8 mmol, 2 equiv). The reaction
was then allowed to stir at room temperature for 18 h before being
quenched with H2O. The aqueous and organic layers were separated,
and the aqueous layer was washed with NaHCO3, dried (MgSO4),
and concentrated in vacuo to give 4-chloro-N-propyl aniline (2.12 g,
24.9 mmol, 93%) as a yellow oil which was used without further
To a solution of benzo[1,3]dioxol-5-yl-(3-cyclopentyl-propyl)-
amine (1.07 g, 4.30 mmol, 1 equiv) in CH2Cl2 (50 mL) at 0 °C
was added NEt3 (1.20 mL, 8.60 mmol, 2 equiv) and bromoacetyl
bromide (0.45 mL, 5.20 mmol, 1.2 equiv), and the reaction was
allowed to stir at room temperature for 14 h. The reaction mixture
was washed with 0.5 M HCl and NaHCO3, dried (MgSO4), and
concentrated to give N-benzo[1,3]dioxol-5-yl-2-bromo-N-(3-cyclo-
pentyl-propyl) acetamide 16 as a brown oil (1.53 g, 4.13 mmol,
1
96%) which was used without further purification. H NMR (400
MHz, CDCl3): δ 0.97-0.99 (2H, m, 2H from 2 × CH2), 1.19-
1.28 (2H, m, CH2), 1.35-1.52 (6H, m, 3 × CH2), 1.62-1.65 (3H,
m, CH and 2H from 2 × CH2), 3.56 (2H, t, J ) 7.7 Hz, CH2N),
3.60 (2H, s, CH2Br), 5.98 (2H, s, CH2O2), 6.65 (2H, m, 2 × ArH),
6.76 (1H, d, J ) 8.7 Hz, ArH). 13C NMR (100 MHz, CDCl3): δ
25.5 (CH2), 27.0 (CH2), 27.8 (CH2CO), 33.0 (2 × CH2), 33.4 (2 ×
CH2), 40.3 (CH), 50.6 (CH2N), 102.4 (CH2O2), 209.0 (ArCH), 109.1
(ArCH), 122.0 (ArCH), 135.64 (ArCN), 148.1 (ArCO), 148.9
(ArCO), 166.8 (C)O). υmax(neat)/cm-1: 1661 (CdO), 1623, 1504,
1484, 1228. m/z (EI+ mode): 367 (M+, 57%), 288 (23), 257 (25),
192 (14), 150 (100), 111(29), 69 (30), 41 (15). C17H22NO3Br
requires 367.0783; found, 367.0788.
1
purification. H NMR (400 MHz, CDCl3): δ 1.05 (3H, t, J ) 7.4
Hz, CH3CH2), 1.62-1.72 (2H, m, CH2), 3.08 (2H, t, J ) 7.1 Hz,
CH2N), 3.67 (1H, broad singlet, NH), 6.55 (2H, apparent doublet,
J ) 8.8 Hz, 2 × ArH), 7.14 (2H, apparent doublet, J ) 8.9 Hz,
2 × ArH). 13C NMR (100 MHz, CDCl3): δ 12.01 (CH3), 23.0
(CH2), 46.3 (CH2N), 114.1 (2 × ArCH), 121.9 (ArCCl), 129.6 (2 ×
ArCH), 147.5 (ArCN). υmax(neat)/cm-1: 3413 (NH), 1598, 1496,
1317, 1176. m/z (EI+ mode): 169 (M+, 70%), 143 (25), 140 (100),
111 (26), 82 (45), 77 (14), 46 (7). C9H12NCl requires 169.0658;
found, 169.0657.
To a solution of N-propyl-4-chloroaniline (1.18 g, 10.7 mmol,
1 equiv) and NEt3 (4.5 mL, 32.1 mmol, 3 equiv) in CH2Cl2 (40
mL) at 0 °C was added bromoacetyl bromide (1.23 mL, 13.9 mmol,
1.3 equiv) and the reaction allowed to stir at room temperature for
16 h. The reaction mixture was washed with 0.5 M HCl and 1 M
NaOH. The organic layer was dried (MgSO4) and concentrated in
vacuo to give 2-bromo-N-(4-chlorophenyl)-N-propylacetamide 18
(3.11 g, 10.7 mmol, 100%) as a brown oil which was used without
further purification. 1H NMR (400 MHz, CDCl3): δ 0.83 (3H, t, J
) 7.4 Hz, CH3), 1.36-1.51 (2H, m, CH2), 3.51-3.61 (4H, m, CH2N
and CH2CO), 7.16 (2H, apparent d, J ) 8.7 Hz, 2 × ArH), 7.39
(2H, apparent d, J ) 8.7 Hz, 2 × ArH). 13C NMR (100 MHz,
CDCl3): δ 11.5 (CH3), 21.1 (CH2), 27.4 (CH2CO), 51.9 (CH2N),
129.8 (2 × ArCH), 130.9 (2 × ArCH), 134.9 (ArC), 140.4 (ArC),
166.6 (C)O). υmax(neat)/cm-1: 2962, 2931, 1658 (CdO), 1488.
m/z (EI+ mode): 289 (M+, 7%), 249 (11), 140 (52), 84 (100), 47
(15). C11H13NOClBr requires 288.9869; found, 288.9875.
General Procedure A: The Immobilization of R-Bromo
Acetamides Using 2. S-Merrifield Bound N-Benzyl-2-mercapto-
N-(3-methoxyphenyl) Acetamide. Benzyl thiol resin 2 (617 mg,
0.56 mmol/g, 0.35 mmol, 1 equiv) was swollen in DMF (5 mL)
for 15 min, and NEt3 (0.22 mL, 1.56 mmol, 4.6 equiv) was added.
A solution of N-benzyl-2-bromo-N-(3-methoxyphenyl) acetamide
3 (520 mg, 1.56 mmol, 4.6 equiv) in DMF (3 mL) was then added
by cannula. The reaction was allowed to stir at room temperature
for 18 h. The resin was then washed using our standard washing
protocol. The product resin was then dried in vacuo. υmax (ATR)/
cm-1: 1650 (CdO).
2-Bromo-N-(4-iodophenyl)-N-propylacetamide 17. To a solu-
tion of 4-iodoaniline 389 (3.00 g, 13.7 mmol, 1 equiv) in CH2Cl2
(60 mL) was added NEt3 (5.78 mL, 41.1 mmol, 3 equiv) and
propionic anhydride (3.51 mL, 27.4 mmol, 3 equiv). The reaction
was allowed to stir at room temperature for 3 h. The reaction
mixture was washed with NaHCO3 and 1 M HCl, dried (MgSO4),
and concentrated in vacuo to give a white solid. THF (100 mL)
was added the solution cooled to 0 °C. LiAlH4 (1.09 g, 28.8 mmol,
2.1 equiv) was added slowly. The reaction was allowed to stir at
room temperature for 18 h. The reaction was quenched with H2O.
The aqueous and organic layers were separated, and the aqueous
layer was washed with NaHCO3, dried (MgSO4), and concentrated
in vacuo to give a yellow oil. The crude reaction mixture was
purified by flash chromatography using 50% petroleum ether in
CH2Cl2 as eluant to give 4-iodo-N-propyl aniline (1.31 g, 4.93
mmol, 36%) as a yellow oil. 1H NMR (400 MHz, CDCl3): δ 1.01
(3H, t, J ) 7.4 Hz, CH3), 1.60-1.69 (2H, m, CH2CH3), 3.07 (2H,
t, J ) 7.1 Hz, CH2N), 3.75 (1H, broad s, NH), 6.34-6.40 (2H,
apparent dt, J ) 3.0, 9.8 Hz, 2 × ArH), 7.41-7.45 (2H, apparent
dt, J ) 3.0, 9.8 Hz, 2 × ArH). 13C NMR (100 MHz, CDCl3): δ
11.9 (CH3), 22.9 (CH2), 46.1 (CH2N), 77.9 (ArCI), 115.3 (2 ×
ArCH), 138.1 (2 × ArCH), 148.3 (ArC). υmax(neat)/cm-1: 2962,
1604, 1506, 1321. m/z (EI+ mode): 261 (M+, 62%), 232 (92), 105
(36), 84 (100), 47 (17). C9H12NI requires 261.0015; found,
261.0014.
To a solution of 4-iodo-N-propyl aniline (813 mg, 3.11 mmol,
1 equiv) and NEt3 (0.87 mL, 6.22 mmol, 2 equiv) in CH2Cl2 (20
mL) at 0 °C was added bromoacetyl bromide (0.35 mL, 4.04 mmol,
1.3 equiv) and the reaction was allowed to stir at room temperature
for 1.5 h. The reaction mixture was then washed with 0.5 M HCl
(3 × 20 mL) and brine (3 × 20 mL). The organic layer was then
dried (MgSO4) and concentrated in vacuo to give 2-bromo-N-(4-
iodophenyl)-N-propylacetamide 17 (1.02 g, 2.67 mmol, 86%) as a
S-Merrifield Bound 2-Mercapto-N-methyl-N-(3-methyl-
phenyl)acetamide. As for general procedure A. Thiol resin 2, on
treatment with 2-bromo-N-methyl-N-(3-methylphenyl) acetamide
15 gave S-Merrifield bound 2-mercapto-N-methyl-N-(3-methyl-
phenyl)acetamide. υmax (ATR)/cm-1: 1650 (CdO).
S-Merrifield Bound 2-Mercapto-N,N-diphenylacetamide. As
for general procedure A. Thiol resin 2, on treatment with 2-bromo-
N,N-diphenyl acetamide 13 gave S-Merrifield bound 2-mercapto-
N,N-diphenylacetamide. υmax (ATR)/cm-1: 1664 (CdO).
1
brown oil which was used without further purification. H NMR
(400 MHz, CDCl3): δ 0.85 (3H, t, J ) 7.2 Hz, CH3), 1.41-1.51
(2H, m, CH2), 3.53 (2H, s, CH2CO), 3.57 (2H, t, J ) 7.6 Hz, CH2N),
6.95 (2H, apparent d, J ) 8.4 Hz, 2 × ArH), 7.71 (2H, apparent d,
6504 J. Org. Chem., Vol. 71, No. 17, 2006

Solid Phase Approaches to N-Heterocycles
S-Merrifield Bound 2-Mercapto-N-methyl-N-phenylacet-
amide. As for general procedure A. Thiol resin 2, on treatment
with 2-bromo-N-methyl-N-phenyl acetamide 8 gave S-Merrifield
gave S-Merrifield bound N-(4-iodophenyl)-N-propyl-2-sulfinyl
acetamide. υmax (ATR)/cm-1: 1648 (CdO).
General procedure C: Pummerer Cyclization of Electron Rich
Aromatic Systems
bound 2-mercapto-N-methyl-N-phenylacetamide. υmax (ATR)/cm-1
1654 (CdO).
:
S-Merrifield Bound 1-Benzyl-3-mercapto-6-methoxy-1,3-di-
hydro-indol-2-one 25-major and S-Merrifield Bound 1-Benzyl-
3-mercapto-4-methoxy-1,3-dihydro-indol-2-one 25-minor. S-
Merrifield bound N-benzyl-N-(3-methoxyphenyl)-2-sulfinyl acetamide
(671 mg, 0.49 mmol/g, 0.33 mmol, 1 equiv) was swollen in 1,2-
dichloroethane (6 mL) for 15 min. Trifluoroacetic anhydride (0.75
mL, 5.3 mmol, 16 equiv) was then added, and the reaction was
allowed to stir at room temperature for 18 h. The resin was then
washed using the standard washing protocol. The product resin 25
was then dried in vacuo. υmax (ATR)/cm-1: 1714 (CdO).
S-Merrifield Bound 5-(3-Cyclopentylpropyl)-7-mercapto-5H-
[1,3]dioxolo[4,5-f]indol-6(7H)-one. As for general procedure C.
Upon cyclization, S-Merrifield bound N-(benzo[d][1,3]dioxol-5-
yl)-N-(3-cyclopentylpropyl)-2-sulfinyl acetamide gave S-Merrifield
bound 5-(3-cyclopentylpropyl)-7-mercapto-5H-[1,3]dioxolo[4,5-f]-
indol-6(7H)-one. νmax (ATR)/cm-1: 1710 (CdO).
S-Merrifield Bound N-Allyl-2-mercapto-N-phenylacetamide.
As for general procedure A. Thiol resin 2, on treatment with
2-bromo-N-allyl-N-phenyl acetamide 14 gave S-Merrifield bound
N-allyl-2-mercapto-N-phenylacetamide. υmax (ATR)/cm-1: 1652
(CdO).
S-Merrifield Bound N-(benzo[d][1,3]dioxol-5-yl)-N-(3-cyclo-
pentylpropyl)-2- mercaptoacetamide. As for general procedure
A. Thiol resin 2, on treatment with N-benzo[1,3]dioxol-5-yl-2-
bromo-N-(3-cyclopentyl-propyl) acetamide 16 gave S-Merrifield
bound N-(benzo[d][1,3]dioxol-5-yl)-N-(3-cyclopentylpropyl)-2-
mercaptoacetamide. υmax (ATR)/cm-1: 1650 (CdO).
S-Merrifield Bound N-(4-chlorophenyl)-2-mercapto-N-propyl-
acetamide. As for general procedure A. Thiol resin 2, on treatment
with 2-bromo-N-(4-chlorophenyl)-N-propylacetamide 18 gave prod-
uct resin S-Merrifield bound N-(4-chlorophenyl)-2-mercapto-N-
propylacetamide. υmax (ATR)/cm-1: 1652 (CdO).
S-Merrifield Bound N-(4-iodophenyl)-2-mercapto-N-propyl-
acetamide. As for general procedure A. Thiol resin 2, on treatment
with 2-bromo-N-(4-iodophenyl)-N-propylacetamide 17 gave S-
Merrifield bound N-(4-iodophenyl)-2-mercapto-N-propylacetamide.
υmax (ATR)/cm-1: 1650 (CdO).
General Procedure B: Oxidation of Resin Bound Sulfides
to Sulfoxides. S-Merrifield Bound N-Benzyl-N-(3-methoxy-
phenyl)-2-sulfinyl Acetamide. S-Merrifield bound N-benzyl-2-
mercapto-N-(3-methoxyphenyl) acetamide (716 mg, 0.49 mmol/g,
0.35 mmol, 1 equiv) was swollen in HFIP (4 mL) and CH2Cl2
(2 mL). An amount of 30% aqueous H2O2 (0.26 mL, 2.28 mmol,
6.5 equiv) was then added, and the reaction was allowed to stir at
room temperature overnight. The resin was then washed using the
standard washing protocol. The product resin was then dried in
vacuo. υmax (ATR)/cm-1: 1670 (CdO).
S-Merrifield Bound N-Methyl-N-(3-methylphenyl)-2-(sulfinyl)
Acetamide. As for general procedure B. Upon oxidation, S-
Merrifield bound 2-mercapto-N-methyl-N-(3-methylphenyl)aceta-
mide gave S-Merrifield bound N-methyl-N-(3-methylphenyl)-2-
(sulfinyl) acetamide. υmax (ATR)/cm-1: 1650 (CdO).
General Procedure D: Pummerer Cyclization of Neutral and
Electron Deficient Aromatic Systems.
S-Merrifield Bound 3-Mercapto-1,6-dimethyl-1,3-dihydro-
indol-2-one and S-Merrifield Bound 3-Mercapto-1,4-dimethyl-
1,3-dihydro-indol-2-one. S-Merrifield bound N-methyl-N-(3-
methylphenyl)-2-(sulfinyl) acetamide and S-Merrifield bound
N-methyl-N-(5-methylphenyl)-2-(sulfinyl) acetamide (647 mg, 0.55
mmol/g, 0.36 mmol, 1 equiv) were swollen in 1,2-dichloroethane
(6 mL) for 15 min. Trifluoroacetic anhydride (0.85 mL, 0.60 mmol,
17 equiv) was added, and the reaction was allowed to stir at room
temperature for 3 h. BF3‚OEt2 (1.14 mL, 9 mmol, 25 equiv) was
added, and the reaction was allowed to stir at room temperature
for a further 18 h. The resin was then washed using the standard
washing protocol. The product resin was then dried in vacuo. υmax
(ATR)/cm-1: 1714 (CdO).
S-Merrifield Bound 3-Mercapto-1-phenyl-1,3-dihydro-indol-
2-one. As for general procedure D. Upon cyclization, S-Merrifield
N,N-diphenyl 2-(sulfinyl) acetamide gave S-Merrifield bound
3-mercapto-1-phenyl-1,3-dihydro-indol-2-one. υmax (ATR)/cm-1
1722 (CdO).
:
S-Merrifield Bound 3-Mercapto-1-methyl-1,2-dihydro-indol-
2-one. As for general procedure D. Upon cyclization, S-Merrifield
bound N-methyl-N-phenyl 2-(sulfinyl) acetamide gave S-Merrifield
bound 3-mercapto-1-methyl-1,2-dihydro-indol-2-one. υmax (ATR)/
cm-1: 1716 (CdO).
S-Merrifield Bound 1-Allyl-3-mercapto-1,3-dihydro-indol-2-
one. As for general procedure D. Upon cyclization, S-Merrifield
bound N-allyl-N-Phenyl-2-sulfinyl acetamide gave product resin
S-Merrifield bound 1-allyl-3-mercapto-1,3-dihydro-indol-2-one. υmax
(ATR)/cm-1: 1714 (CdO).
S-Merrifield Bound 5-Chloro-3-mercapto-1-propyl-1,3-
dihydro-indol-2-one. As for general procedure D. Upon cyclization,
S-Merrifield bound N-(4-chlorophenyl)-N-propyl-2-sulfinyl aceta-
mide gave S-Merrifield bound 5-chloro-3-mercapto-1-propyl-1,3-
dihydro-indol-2-one. υmax (ATR)/cm-1: 1716 (CdO).
S-Merrifield N,N-Diphenyl-2-(sulfinyl) Acetamide. As for gen-
eral procedure B. Upon oxidation, S-Merrifield bound 2-mercapto-
N,N-diphenylacetamide gave product resin S-Merrifield N,N-
diphenyl-2-(sulfinyl) acetamide. υmax (ATR)/cm-1: 1660 (CdO).
S-Merrifield Bound N-Methyl-N-phenyl-2-(sulfinyl) Acet-
amide. As for general procedure B. Upon oxidation, S-Merrifield
bound 2-mercapto-N-methyl-N-phenylacetamide gave S-Merrifield
bound N-methyl-N-phenyl 2-(sulfinyl) acetamide. υmax (ATR)/cm-1
1650 (CdO).
:
S-Merrifield Bound N-Allyl-N-phenyl-2-sulfinyl Acetamide.
As for general procedure B. Upon oxidation, S-Merrifield bound
N-allyl-2-mercapto-N-phenylacetamide gave S-Merrifield bound
N-allyl-N-phenyl-2-sulfinyl acetamide. υmax (ATR)/cm-1: 1648
(CdO).
S-Merrifield Bound N-(Benzo[d][1,3]dioxol-5-yl)-N-(3-cyclo-
pentylpropyl)-2-sulfinyl Acetamide. As for general procedure B.
Upon oxidation, S-Merrifield bound N-(benzo[d][1,3]dioxol-5-yl)-
N-(3-cyclopentylpropyl)-2-mercaptoacetamide gave S-Merrifield
bound N-(benzo[d][1,3]dioxol-5-yl)-N-(3-cyclopentylpropyl)-2-
sulfinyl acetamide. υmax (ATR)/cm-1: 1648 (CdO).
S-Merrifield Bound N-(4-chlorophenyl)-N-propyl-2-sulfinyl
Acetamide. As for general procedure B. Upon oxidation, S-
Merrifield bound N-(4-chlorophenyl)-2-mercapto-N-propylaceta-
mide gave S-Merrifield bound N-(4-chlorophenyl)-N-propyl-2-
sulfinyl acetamide. υmax (ATR)/cm-1: 1644 (CdO).
S-Merrifield Bound N-(4-Iodophenyl)-N-propyl-2-sulfinyl
Acetamide. As for general procedure B. Upon oxidation, S-
Merrifield bound N-(4-iodophenyl)-2-mercapto-N-propylacetamide
S-Merrifield Bound 5-Iodo-3-mercapto-1-propyl-1,3-dihydro-
indol-2-one. As for general procedure D. Upon cyclization,
S-Merrifield bound N-(4-iodophenyl)-N-propyl-2-sulfinyl acetamide
gave S-Merrifield bound 5-iodo-3-mercapto-1-propyl-1,3-dihydro-
indol-2-one. υmax (ATR)/cm-1: 1714 (CdO).
1-Methyl-1,3-dihydro-indole-2-one 12.22S-Merrifield bound
3-mercapto-1-methyl-1,2-dihydro-indol-2-one (315 mg, 0.52 mmol/
g, 0.16 mmol, 1 equiv) was swollen in THF (4 mL) for 15 min.
(20) Diehl, K.; Himbert, G.; Henn, L. Chem. Ber. 1986, 119, 2430.
(21) Kleiner, T.; Bongardt, F.; Voegtle, F.; Laeubli, M. W.; Dinten, O.;
Simon, W. Chem. Ber. 1985, 118, 1071.
(22) Tamura, Y.; Uneshi, J. I.; Maeda, H.; Choi, H. D.; Ishibashi, H.
Synthesis 1981, 534.
J. Org. Chem, Vol. 71, No. 17, 2006 6505

McAllister et al.
DMPU (0.30 mL, 2.48 mmol, 15.5 equiv), and a solution of SmI2
(6.20 mL, 0.1 M in THF, 0.62 mmol, 3.9 equiv) were added, and
the reaction was allowed to stir at room temperature for 18 h. The
resin was filtered, and the solution phase was collected and con-
centrated in vacuo. Filtration through a short plug of silica washing
with 50% ethyl acetate in petroleum ether gave 1-methyl-1,3-
dihydro-indole-2-one 12 (10 mg, 0.07 mmol, 43%) as a clear oil.
(The yield is over four solid-phase steps based on a loading of
3-mercapto-1,6-dimethyl-1,3-dihydro-indol-2-one and S-Merrifield
bound 3-mercapto-1,4-dimethyl-1,3-dihydro-indol-2-one (584 mg,
0.55 mmol/g, 0.32 mmol, 1 equiv) was swollen in THF (7 mL) for
15 min. DMPU (0.51 mL, 4.20 mmol, 13 eq), and a solution of
SmI2 (10.4 mL, 0.1 M in THF, 1.04 mmol, 3.3 equiv) were then
added, and the reaction was allowed to stir at room temperature
for 18 h. The resin was filtered, and the solution phase was collected
and concentrated in vacuo. Filtration through a short plug of silica
washing with 30% ethyl acetate in petroleum ether to gave 1,6-
dimethyl-1,3-dihydro-indol-2-one 21-major and 1,4-dimethyl-1,3-
dihydro-indol-2-one 21-minor (32.4 mg, 0.20 mmol, 63%) as a
2:1 mixture and as a clear oil. (The yield is over four solid-phase
steps based on a loading of 0.61 mmol/g for 2). For 21-major 1H
NMR (400 MHz, CDCl3): δ 2.31 (3H, s, CH3Ar), 3.11 (3H, s,
NCH3), 3.40 (2H, s, CH2), 6.57 (1H, s, ArH), 6.77 (1H, d, J ) 8.2
Hz, ArH), 6.79 (1H, d, J ) 8.2 Hz, ArH). 13C NMR (100 MHz,
CDCl3): δ 20.7 (CH3Ar), 25.1 (NCH3), 34.5 (CH2CO), 108.0
(ArCH), 120.4 (ArC), 121.7 (ArCH), 123.0 (ArCH), 136.9 (ArC),
144.3 (ArC), 174.5 (C)O). υmax (neat)/cm-1: 3052, 2937, 1695
(CdO), 1619, 1606, 1467, 1097, 948. m/z (EI+ mode): 161 (M+,
100%), 132 (83), 117 (24), 91 (19), 83 (34), 57 (18), 55 (10).
C10H11NO requires 161.0841; found, 161.0840. For 21-minor 1H
NMR (400 MHz, CDCl3): δ 2.26 (3H, s, CH3Ar), 3.12 (3H, s,
NCH3), 3.33 (2H, s, CH2), 6.57 (1H, d, J ) 9.8 Hz, ArH), 7.03
(1H, d, J ) 7.5 Hz, ArH), 7.13 (1H, apparent t, J ) 7.8 Hz, ArH).
13C NMR (100 MHz, CDCl3): δ 17.5 (CH3Ar), 25.3 (NCH3), 33.7
(CH2CO), 104.6 (ArCH), 122.2 (ArC), 122.7 (ArCH), 126.8
(ArCH), 133.0 (ArC), 143.9 (ArC), 174.1 (C)O).
1
0.56 mmol/g for 2). H NMR (400 MHz, CDCl3): δ 3.14 (3H, s,
NCH3), 3.46 (2H, s, CH2CO), 6.75 (1H, d, J ) 7.8 Hz, ArH), 6.97
(1H, t, J ) 7.5 Hz, ArH) and 7.17-7.24 (2H, m, 2 × ArH). 13C
NMR (100 MHz, CDCl3): δ 25.1 (NCH3), 34.7 (CH2CO), 107.1
(ArCH), 121.3 (ArCH), 123.3 (ArCH), 123.5 (ArC), 126.9 (ArCH)
144.2 (ArC) and 174.0 (C)O). υmax(neat)/cm-1: 3058, 2942, 2919,
1700 (CdO), 1612, 1463, 1348 and 754. m/z (EI+ mode): 147
(M+, 90%), 132 (10), 118 (100), 104 (7), 91 (20), 85 (24), 82 (38),
78 (16), 57 (12) and 47(11). C9H9NO requires 147.0684; found,
147.0684.
1-Phenyl-1,3-dihydro-indol-2-one 19.22 S-Merrifield bound
3-mercapto-1-phenyl-1,3-dihydro-indol-2-one (577 mg, 0.50 mmol/
g, 0.29 mmol, 1 equiv) was swollen in THF (6 mL) for 15 min.
DMPU (0.51 mL, 4.2 mmol, 8.4 equiv), and a solution of SmI2
(10.6 mL, 0.1 M in THF, 1.06 mmol, 3.7 equiv) were added, and
the reaction was allowed to stir at room temperature for 18 h. The
resin was filtered, and the solution phase was collected and
concentrated in vacuo. Filtration through a short plug of silica
washing with 40% ethyl acetate in petroleum ether gave 1-phenyl-
1,3-dihydro-indol-2-one 19 (24 mg, 0.11 mmol, 39%) as a clear
oil. (The yield is over four solid-phase steps based on a loading of
1-Benzyl-6-methoxy-1,3-dihydro-indol-2-one 7-major and 1-
Benzyl-4-methoxy-1,3-dihydro-indol-2-one 7-minor. S-Merri-
field bound 1-benzyl-3-mercapto-6-methoxy-1,3-dihydro-indol-2-
one 25-major and S-Merrifield bound 1-benzyl-3-mercapto-4-
methoxy-1,3-dihydro-indol-2-one 25-minor (598 mg, 0.49 mmol/
g, 0.29 mmol, 1 equiv) were swollen in THF (5 mL) for 15 min.
DMPU (0.58 mL, 4.8 mmol, 16.5 equiv) and a solution of SmI2
(12.0 mL of 0.1 M, 1.20 mmol, 4.1 equiv) were added, and the
reaction was allowed to stir at room temperature for 15 h. The resin
was filtered, and the solution phase was collected and concentrated
before filtration through a short plug of silica washing with 30%
ethyl acetate in petroleum ether to give 1-benzyl-6-methoxy-1,3-
dihydro-indol-2-one 7-major and 1-benzyl-4-methoxy-1,3-dihydro-
indol-2-one 7-minor (27.7 mg, 0.11 mmol, 38% as a 9:1 mixture
of regioisomers) as a clear oil. (The yield is calculated over four
solid-phase steps based on a loading of 0.48 mmol/g for 2). The
regioisomers were separated by chromatography using 20% ethyl
acetate in petroleum ether as eluant. 7-major was obtained as a
white solid and was recrystallized from EtOH to give crystals
1
0.56 mmol/g for 2). H NMR (400 MHz, CDCl3): δ 3.65 (2H, s,
CH2), 6.71 (1H, d, J ) 7.9 Hz, ArH), 7.0 (1H, t, J ) 7.3 Hz, ArH),
7.13 (1H, t, J ) 7.5 Hz, ArH), 7.24 (1H, d, J ) 7.4 Hz, ArH),
7.32-7.36 (3H, m, 3 × ArH), 7.44-7.57 (2H, m, 2 × ArH). 13C
NMR (100 MHz, CDCl3): δ 36.5 (CH2CO), 109.8 (ArCH), 123.2
(ArCH), 124.7 (ArC), 125.0 (ArCH), 127.0 (2 × ArCH), 128.2
(ArCH), 128.5 (ArCH), 130.1 (2 × ArCH), 134.9 (ArC), 145.6
(ArC), 174.8 (C)O). υmax (neat)/cm-1: 3056, 2948, 2919, 1706
(CdO), 1610, 1590, 1500, 1479, 1365. m/z (EI+ mode): 209 (M+,
50%), 209 (54), 180 (100), 82 (25), 77 (11), 46 (8). C14H11NO
requires 209.0841; found, 209.0840.
1-Allyl-1,3-dihydro-indol-2-one 20.23S-Merrifield bound 1-allyl-
3-mercapto-1,3-dihydro-indol-2-one (641 mg, 0.55 mmol/g, 0.35
mmol, 1 equiv) was swollen in THF (6 mL) for 15 min. DMPU
(0.57 mL, 4.70 mmol, 13.4 equiv) and a solution of SmI2 (11.8
mL of 0.1 M solution in THF, 1.18 mmol, 3.4 equiv) were added
and the reaction allowed to stir at room temperature for 18 h. The
resin was filtered and the solution phase was collected and
concentrated. It was then filtered through a short plug of silica
washing with 40% ethyl acetate in petroleum ether to give 1-allyl-
1,3-dihydro-indol-2-one 20 (18 mg, 0.10 mmol, 30%) as a clear
oil. (The yield is over four solid-phase steps based on a loading of
1
suitable for X-ray analysis (mp 104 °C). For 7-major H NMR
(400 MHz, CDCl3): δ 3.48 (2H, s, CH2CO), 3.65 (3H, s, CH3O),
4.82 (2H, s, PhCH2) 6.25 (1H, d, J ) 2.3 Hz, ArH), 6.43 (1H, dd,
J ) 8.2, 2.3 Hz, ArH), 7.05 (1H, d, J ) 8.2 Hz, ArH), 7.16-7.26
(5H, m, 5 × ArH). 13C NMR (100 MHz, CDCl3): δ 35.5 (CH2-
CO) 44.2 (PhCH2), 55.8 (CH3O), 97.7 (ArCH), 106.4 (ArCH), 116.8
(ArC), 125.2 (ArCH), 127.8 (2 × ArCH), 128.0 (ArCH), 129.2 (2
× ArCH), 136.2 (ArC), 145.9 (ArC), 160.2 (ArCO), 176.3 (C)O).
1
0.61 mmol/g for 2). H NMR (400 MHz, CDCl3): δ 3.5 (2H, s,
CH2CO), 4.27-4.29 (2H, m, CH2N), 5.14-5.19 (2H, m, CH2d
CH), 5.73-5.82 (1H, m, CH)CH2), 6.75 (1H, d, J ) 7.8 Hz, ArH),
6.96 (1H, t, J ) 7.3 Hz, ArH), 7.15-7.19 (2H, m, 2 × ArH). 13C
NMR (100 MHz, CDCl3): δ 36.1 (CH2CO), 42.7 (CH2N), 109.3
(CHdCH2), 117.9 (CH2)), 122.7 (ArCH), 124.8 (ArCH), 124.9
(ArC), 128.2 (ArCH), 131.8 (ArCH), 144.8 (ArC), 175.2 (C)O).
υmax (neat)/cm-1: 3054, 2917, 1702 (CdO), 1612, 1486, 1465,
1349, 1197. m/z (EI+ mode): 173 (M+, 85%), 144 (31), 130 (51),
118 (26), 84 (100), 77 (17), 47 (20). C11H11NO requires 173.0841;
found, 173.0841.
υ
max (ATR)/cm-1: 3002, 2937, 1700 (CdO), 1623, 1594,1496. m/z
(EI+ mode): 253 (M+, 97%), 224 (8), 162 (144), 149 (13), 91 (100),
83 (18), 57 (10). C16H15NO2 requires 253.1103; found, 253.1103.
For 7-minor 1H NMR (400 MHz, CDCl3): δ 3.48 (2H, s, CH2-
CO), 3.78 (3H, s, CH3O), 4.82 (2H, s, PhCH2), 6.32 (1H, d, J )
7.8 Hz, ArH), 6.51 (1H, d, J ) 8.1 Hz, ArH), 7.07 (1H, apparent
t, J ) 8.1 Hz, ArH), 7.16-7.26 (5H, m, 5 × ArH). 13C NMR (100
MHz, CDCl3): δ 33.9 (CH2CO) 44.3 (PhCH2), 55.8 (CH3O), 102.9
(ArCH), 105.8 (ArCH), 111.4 (ArC), 127.8 (2 × ArCH), 127.9
(ArCH), 129.1 (2 × ArCH), 129.5 (ArCH) 136.5 (ArC), 145.9
(ArC), 155.8 (ArCO), 175.9 (C)O).
1,6-Dimethyl-1,3-dihydro-indol-2-one 21-major24 and 1,4-
Dimethyl-1,3-dihydro-indol-2-one 21-minor.24 S-Merrifield bound
(23) Ishikuru, M.; Terashima, M. Tetrahedron Lett. 1992, 33, 6849.
(24) (a) Redcastle, G. W.; Palmer, B. D.; Dobrusin, E. M.; Fry, D. W.;
Kraker, A. J.; Denny, W. A. J. Med. Chem. 1994, 37, 2033. (b) Goehring,
R. R.; Sachdeva, Y. P.; Pisipati, J. S.; Sleevi, M. C.; Wolfe, J. F. J. Am.
Chem. Soc. 1985, 107, 435.
5-(3-Cyclopentylpropyl)-5H-[1,3]dioxolo[4,5-f]indol-6(7H)-
one 22. S-Merrifield bound 5-(3-cyclopentylpropyl)-7-mercapto-
6506 J. Org. Chem., Vol. 71, No. 17, 2006

Solid Phase Approaches to N-Heterocycles
5H-[1,3]dioxolo[4,5-f]indol-6(7H)-one (620 mg, 0.48 mmol/g, 0.30
mmol, 1 equiv) was swollen in THF (5 mL) for 15 min. DMPU
(0.46 mL, 3.8 mmol, 12.7 equiv) and a solution of SmI2 (9.6 mL,
0.1 M in THF, 0.96 mmol, 3.2 equiv) were added, and the reaction
was allowed to stir at room temperature for 18 h. The resin was
filtered, and the solution phase was collected and concentrated in
vacuo. Filtration through a short plug of silica washing with 30%
ethyl acetate in petroleum ether to give 5-(3-cyclopentylpropyl)-
5H-[1,3]dioxolo[4,5-f]indol-6(7H)-one 22 (31 mg, 0.11 mmol, 36%)
as a clear oil. (The yield is over four solid-phase steps based on a
S-Merrifield Bound 1-Benzyl-6-methoxy-3-sulfonyl-1,3-di-
hydro-indol-2-one 26. S-Merrifield bound 1-benzyl-3-mercapto-
6-methoxy-1,3-dihydro-indol-2-one 25 (2.51 g, 0.49 mmol/g, 1.23
mmol, 1 equiv) was swollen in DMF/H2O (20 mL:5 mL) for 15
min. Oxone (11.4 g, 18.6 mmol, 15.1 equiv) was then added, and
the reaction was allowed to stir at room temperature for 18 h. The
resin was then washed using the standard washing protocol, and
the product resin, S- Merrifield bound 1-benzyl-6-methoxy-3-
sulfonyl-1,3-dihydro-indol-2-one 26 was then dried in vacuo. υmax
(ATR)/cm-1: 1712 (CdO), 1166 (SdO).
S-Merrifield Bound 3-Allyl-1-benzyl-6-methoxy-3-sulfonyl-
1,3-dihydro-indol-2-one 27. S-Merrifield bound 1-benzyl-6-
methoxy-3-sulfonyl-1,2-dihydro-indol-2-one 26 (2.06 g, 0.48 mmol/
g, 0.98 mmol, 1 equiv) was swollen in DMF (20 mL) for 15 min.
K2CO3 (2.56 g, 18.5 mmol, 18.9 equiv), KI (123 mg, 0.74 mmol,
0.76 equiv) and allyl bromide (1.28 mL, 14.8 mmol, 15.1 equiv)
were then added, and the reaction was heated at 60 °C for 16 h.
The resin was then washed using the standard washing protocol,
and the product resin, S-Merrifield bound 3-allyl-1-benzyl-6-
methoxy-3-sulfonyl-1,3-dihydro-indol-2-one 27, was then dried in
vacuo. υmax (ATR)/cm-1: 1714 (CdO), 1180 (SdO).
1
loading of 0.56 mmol/g for 2). H NMR (400 MHz, CDCl3): δ
0.98-1.02 (2H, m, 2H from 2 × CH2), 1.26-1.32 (2H, m, CH2),
1.42-1.60 (6H, m, 3 × CH2), 1.65-1.70 (3H, m, CH and 2H from
2 × CH2), 3.37 (2H, s, CH2CO), 3.56 (2H, t, J ) 7.5 Hz, CH2N),
5.86 (2H, s, CH2O2), 6.37 (1H, s, ArH), 6.7 (1H, s, ArH). 13C NMR
(100 MHz, CDCl3): δ 25.5 (2 × CH2), 27.1 (CH2), 33.0 (2 × CH2),
33.7 (CH2), 36.5 (CH2CO), 40.2 (CH), 40.7 (CH2N), 92.7 (ArCH),
101.4 (CH2O2), 106.5 (ArCH), 116.5 (ArC), 139.2 (ArCN), 143.2
(ArCO), 147.5 (ArCO), 175.6 (C)O). υmax (neat)/cm-1: 1687 (Cd
O), 1616, 1500, 1473,1328. m/z (EI+ mode): 287(M+, 100%), 177
(20), 162 (45), 132 (28), 104 (5), 77 (7), 41 (14). C17H21NO3
requires 287.1521; found, 287.1520.
3-Allyl-1-benzyl-6-methoxy-1,3-dihydro-indol-2-one 28. S-
Merrifield bound 3-allyl-1-benzyl-6-methoxy-3-sulfonyl-1,3-di-
hydro-indol-2-one 27 (1.00 g, 0.47 mmol/g, 0.47 mmol, 1 equiv)
was swollen in THF (10 mL) for 15 min. DMPU (1.68 mL, 13.9
mmol, 30 equiv) and a solution of SmI2 (34.7 mL, 0.1 M in THF,
3.47 mmol, 7.4 equiv) were added, and the reaction was allowed
to stir at room temperature for 18 h. The resin was filtered and the
solution phase was collected and concentrated in vacuo. Filtration
through a short plug of silica washing with 20% ethyl acetate in
petroleum ether gave 3-allyl-1-benzyl-6-methoxy-1,3-dihydro-indol-
2-one 28 (38.7 mg, 0.13 mmol, 28%) as a clear oil. (The yield is
over six solid phase-steps based on a loading of 0.56 mmol/g for
5-Iodo-1-propyl-1,3-dihydro-indol-2-one 23. S-Merrifield bound
5-iodo-3-mercapto-1-propyl-1,3-dihydro-indol-2-one (845 mg, 0.48
mmol/g, 0.41 mmol, 1 equiv) was swollen in THF (7 mL) for 15
min. DMPU (0.44 mL, 3.65 mmol, 8.9 equiv) and a solution of
SmI2 (9.10 mL, 0.1 M in THF, 0.91 mmol, 2.2 equiv) were added,
and the reaction was allowed to stir at room temperature for 18 h.
The resin was filtered, and the solution phase was collected and
concentrated in vacuo. Filtration through a short plug of silica
washing with 30% ethyl acetate in petroleum ether gave 5-iodo-
1-propyl-1,3-dihydro-indol-2-one 23 (24 mg, 0.08 mmol, 20%) as
a clear oil. (The yield is over four solid-phase steps based on a
1
1
2). H NMR (400 MHz, CDCl3): δ 2.48-2.56 (1H, m, 1H from
loading of 0.56 mmol/g for 2). H NMR (400 MHz, CDCl3): δ
CH2CHdCH2), 2.71-2.81 (1H, m, 1H from CH2CHdCH2), 3.47
(1H, t, J ) 6.1 Hz, CH), 3.65 (3H, s, CH3O), 4.72 (1H, d, J )
15.6 Hz, 1H from CH2N), 4.88 (1H, d, J ) 15.6 Hz, 1H from
CH2N), 4.98 (1H, d, J ) 10.1 Hz, 1H from CH2dCH), 5.05 (1H,
dd, J ) 17.0 Hz, 1.1 Hz, 1H from CH2dCH), 5.62-5.72 (1H, m,
CH)CH2), 6.22 (1H, d, J ) 2.2 Hz, ArH), 6.44 (1H, dd, J ) 8.1,
2.2 Hz, ArH), 7.10 (1H, d, J ) 8.1 Hz, ArH), 7.16-7.27 (5H, m,
5 × ArH). 13C NMR (100 MHz, CDCl3): δ 35.3 (CH2CHdCH2),
43.8 (NCH2Ph), 44.7 (CH), 55.4 (CH3O), 97.2 (ArCH), 105.9
(ArCH), 118.1 (CH2dCH), 120.5 (ArC), 124.7 (ArCH), 127.3 (2
× ArCH), 127.6 (ArCH), 128.6 (2 × ArCH), 134.1 (CHdCH2),
135.9 (ArC), 144.7 (ArC), 159.9 (ArC), 178.0 (CdO). υmax (neat)/
cm-1: 1710 (CdO), 1624, 1503, 1382, 1165. m/z (EI+ mode): 293
(M+, 28%), 252 (100), 91 (75), 83 (39), 47 (8). C19H19NO2 requires
293.1416; found, 293.1415.
0.88 (3H, t, J ) 7.4 Hz, CH3), 1.56-1.66 (2H, m, CH2), 3.43 (2H,
s, CH2CO), 3.57 (2H, t, J ) 7.3 Hz, CH2N), 6.44 (1H, d, J ) 8.2
Hz, ArH), 7.47 (1H, s, ArH), 7.52 (1H, d, J ) 8.2 Hz, ArH). 13C
NMR (100 MHz, CDCl3): δ 10.3 (CH3), 19.6 (CH2), 34.3 (CH2-
CO), 40.6 (CH2N), 83.4 (ArCI), 109.3 (ArCH), 126.0 (ArC), 132.2
(ArCH), 135.6 (ArCH), 143.5(ArC), 173.1 (C)O). υmax (neat)/cm-1
:
2960, 2917, 2848, 1698 (CdO), 1600, 1481. m/z (EI+ mode):
301 (M+, 100%), 272 (36), 259 (19), 244 (19), 177 (70), 83 (29).
C11H12NOI requires 300.9964; found, 300.9964.
5-Chloro-1-propyl-1,3-dihydro-indol-2-one 24.25S-Merrifield
bound 5-chloro-3-mercapto-1-propyl-1,3-dihydro-indol-2-one (0.99
g, 0.50 mmol/g, 0.50 mmol, 1 equiv) was swollen in THF (10 mL)
for 15 min. DMPU (0.99 mL, 8.20 mmol, 16.4 equiv) and a solution
of SmI2 (20.5 mL, 0.1 M in THF, 2.05 mmol, 4.1 equiv) were
added, and the reaction was allowed to stir at room temperature
for 18 h. The resin was filtered, and the solution phase was collected
and concentrated in vacuo. Filtration through a short plug of silica
washing with 30% ethyl acetate in petroleum ether gave 5-chloro-
1-propyl-1,3-dihydro-indol-2-one 24 (39.7 mg, 0.19 mmol, 38%)
as a clear oil. (The yield is over four solid phase-steps based on a
Acknowledgment. We thank The Carnegie Trust for the
Universities of Scotland (Postgraduate Research Scholarship to
L.A.M.), Celltech R&D (CASE award, L. A. M.), the EPSRC,
and Pfizer for an Industrial CASE award (K. L. T). We also
thank AstraZeneca and Pfizer for additional untied funding. We
also thank undergraduate project students Re´my de Gentile,
Thomas Baker, and Saidul Islam for their contributions. We
acknowledge Dr D. Apperley at the EPSRC Solid State NMR
facility for MAS NMR, Dr Ken Muir (Glasgow), Prof. M.
Helliwell (Manchester), and Dr N. Feeder (Pfizer) for X-ray
crystallographic studies.
1
loading of 0.56 mmol/g for 2). H NMR (400 MHz, CDCl3): δ
0.89 (3H, t, J ) 7.4 Hz, CH3), 1.57-1.67 (2H, m, CH2), 3.45 (2H,
s, CH2CO), 3.59 (2H, t, J ) 7.4 Hz, CH2N), 6.76 (1H, d, J ) 7.9
Hz, ArH), 7.15-7.18 (2H, m, 2 × ArH). 13C NMR (100 MHz,
CDCl3): δ 10.4 (CH3), 19.7 (CH2), 34.6 (CH2CO), 40.7 (CH2N),
108.1 (ArCH), 123.9 (ArCH), 125.2 (ArC), 126.4 (ArC), 126.7
(ArCH), 142.3 (ArC), 173.4 (CdO). υmax (neat)/cm-1: 1695 (Cd
O), 1610, 1486, 1342. m/z (EI+ mode): 209 (M+, 64%), 180 (36),
152 (58), 117 (32), 85 (65), 84 (100), 47 (17). C11H12NOCl requires
209.0607; found, 209.0605.
Supporting Information Available: General methods, further
experimental, selected IR and MAS 1H NMR and 1H NMR spectra
of all new compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
(25) Wiseman, E. H.; Chiani, J.; McManus, J. M. J. Med. Chem. 1973,
16, 131.
JO060940N
J. Org. Chem, Vol. 71, No. 17, 2006 6507