Solid-supported copper catalysts for atom-transfer radical cyclizations: Assessment of support type and ligand structure on catalyst performance in the synthesis of nitrogen heterocycles

Article abstract of DOI:10.1021/jo0521605

A range of solid supported pyridinemethanimine 9-11 and polyamine 12-15 ligands have been prepared on silica, polystyrene, and JandaJel supports. The CuCl and CuBr complexes of these supported ligands have been used to assess both the effect of the ligand type and the nature of the support upon a representative range of copper-mediated atom transfer 5-exo-trig 6, 24-25, 5-exo-dig 26, 4-exo-trig 28, and 5-endo-trig 27, 38 radical cyclizations to give nitrogen heterocycles. In addition, the effect of the nature of the support on the stereochemical outcome of the 5-exo cyclization of 25 has been probed. Generally, it was found that the type of support (e.g., polystyrene, silica, or JandaJel) had very little effect upon the efficiency and selectivity of the processes but that the nature of the ligand type immobilized was the important factor. Thus, the 5-exo cyclization of 6 and 24-26 proceeded more rapidly with the PMI ligands 9-11, whereas 4-exo cyclizations 28 and 5-endo radical polar crossover reactions 27 and 38 proceeded more efficiently with the JJ-TEDETA ligand 15. The efficiency of the supported ligands was also compared to their solution counterparts 4 and 5. The reusability of P-PMDETA ligand system 13 was assessed in the cyclization of 6.

Full text of DOI:10.1021/jo0521605

Solid-Supported Copper Catalysts for Atom-Transfer Radical
Cyclizations: Assessment of Support Type and Ligand Structure on
Catalyst Performance in the Synthesis of Nitrogen Heterocycles
Andrew J. Clark,*,† Joanna V. Geden,† and Stephen Thom‡
Department of Chemistry, UniVersity of Warwick, CoVentry, West Midlands CV4 7AL, U.K., and
AstraZeneca Research and DeVelopment, Charnwood, Bakewell Road, Loughborough,
Leicestershire LE11 5RH, U.K.
msrir@csV.warwick.ac.uk
ReceiVed October 17, 2005
A range of solid supported pyridinemethanimine 9-11 and polyamine 12-15 ligands have been prepared
on silica, polystyrene, and JandaJel supports. The CuCl and CuBr complexes of these supported ligands
have been used to assess both the effect of the ligand type and the nature of the support upon a
representative range of copper-mediated atom transfer 5-exo-trig 6, 24-25, 5-exo-dig 26, 4-exo-trig 28,
and 5-endo-trig 27, 38 radical cyclizations to give nitrogen heterocycles. In addition, the effect of the
nature of the support on the stereochemical outcome of the 5-exo cyclization of 25 has been probed.
Generally, it was found that the type of support (e.g., polystyrene, silica, or JandaJel) had very little
effect upon the efficiency and selectivity of the processes but that the nature of the ligand type immobilized
was the important factor. Thus, the 5-exo cyclization of 6 and 24-26 proceeded more rapidly with the
PMI ligands 9-11, whereas 4-exo cyclizations 28 and 5-endo radical polar crossover reactions 27 and
38 proceeded more efficiently with the JJ-TEDETA ligand 15. The efficiency of the supported ligands
was also compared to their solution counterparts 4 and 5. The reusability of P-PMDETA ligand system
13 was assessed in the cyclization of 6.
Introduction
materials applications. Active catalysts for both cyclization and
polymerization processes are derived mainly from ruthenium,3
iron,4 or copper1a complexes with those based upon the
coordination chemistry of copper being the most popular. A
whole range of copper catalysts based upon the coordination
Transition-metal-catalyzed atom transfer radical cyclization
(ATRC)1 and polymerization (ATRP)2 reactions have been
extensively studied over the past few years. The driving force
for this research has been the desire to find nonreductive
catalytic alternatives to organotin hydrides in mediating radical
cyclization reactions in organic synthesis, and the need to
prepare living polymers with a high degree of control for novel
(3) For ATRC (a) Pirrung, F. O. H.; Hiemstra, H.; Speckamp, W. N.
Tetrahedron 1994, 50, 12415. (b) Rachita, M. A.; Slough, G. A. Tetrahedron
Lett. 1993, 43, 6821. (c) Slough, G. A. Tetrahedron Lett. 1993, 43, 6825.
(d) Nagashima, H.; Gondo, M.; Masuda, S.; Kondo, H.; Yamaguchi, Y.;
Matsubara, K. J. Chem. Soc., Chem. Commun. 2003, 442. For ATRP (e)
Kato, M.; Kamigaito, M.; Sawamoto, M.; Higashimura, T. Macromolecules
1995, 28, 1721.
(4) For ATRC: (a) Lee, G. M.; Parvez, M.; Weinreb, S. M. Tetrahedron
1988, 44, 4671. For ATRP: (b) O’Reilly, R. K.; Gibson, V. C.; White, A.
J. P.; Williams, D. J. Polyhedron 2004, 23, 2921. (c) Zhang, H.; Schubert,
U. S. J. Polym. Sci., Part A: Polym Chem. 2004, 42, 4882.
† University of Warwick.
‡ AstraZeneca R & D Charnwood.
(1) (a) Clark, A. J. Chem. Soc. ReV. 2002, 31, 1. (b) Iqbal, J.; Bhatia,
B.; Nayyar, N. K. Chem. ReV. 1994, 94, 519. (c) Martin, P.; Steiner, E.;
Bellus, D. HelV. Chim. Acta 1980, 63, 1947.
(2) (a) Matyjaszewski, K. Current Org. Chem. 2002, 6, 67. (b) Wang,
J.; Matyjaszewski, K. Chem. ReV. 2001, 101, 2921.
10.1021/jo0521605 CCC: $33.50 © 2006 American Chemical Society
Published on Web 01/12/2006
J. Org. Chem. 2006, 71, 1471-1479
1471

Clark et al.
SCHEME 1. ATRC Using Silica-Supported PMI Ligand
perfluorous catalysts10 and solid-supported reagents11 have been
explored to overcome this. However, the use of a perfluorous
reagent can be costly, and solid-supported reagents tend not to
be as selective or as efficient in living polymerizations compared
to their solution counterparts.12 The reason for this is the
requirement for both the large living polymer to interact with
the active catalyst which is itself attached to a macromolecular
assembly. On the other hand, in organic synthetic applications,
ATRC reactions often involve relatively small molecular weight
substrates, and consequently mass transport, selectivity, and
efficiency should be less compromised. One of the drivers for
the development of copper-mediated ATRC catalysts was their
potential replacement of tin hydrides in industrial radical
applications. In light of the proven ability of ATRC reactions
to generate a range of medicinally active heterocyclic scaffolds,1
it is surprising that only one type of solid-supported reagent
(e.g., 8) has been evaluated in ATRC reactions (Scheme 1).13
In this paper, we wish to report our studies into the effect of
the nature of the support (cross-linked polystyrene (P), silica
(Si), or JandaJel (JJ)), along with the type of ligand conjugated
to the support (PMI 2, PMEDTA 4, or Me6-Tren 5 analogues)
on the radical cyclization of a range of substrates to furnish
nitrogen heterocycles.
FIGURE 1. Ligands for atom-transfer radical cyclization.
of the ligands bipyridine5 (Bipy) 1, pyridylmethanimines6 (PMIs)
2, tetramethylethylenediamine7 (TMEDA) 3, N,N,N′,N′,N′′-
pentamethyldiethylenetriamine8 (PMDETA) 4, and tris(N,N-2-
dimethylamino)ethylamine8b,9 5 (Me6-Tren) have been explored
for ATRC applications, Figure 1. Different ligands often show
different reactivities and selectivities.
In ATRP, the removal of the copper catalysts from the
synthesized polymer can be problematic. For industrial polymer
applications, where the removal of copper residues is necessary,
(5) (a) Nagashima, H.; Ozaki, N.; Ishii, M.; Seki, K.; Washiyama, M.;
Itoh, K. J. Org. Chem. 1993, 58, 464. (b) Iwamatsu, S.; Matsubara, K.;
Nagashima, H. J. Org. Chem. 1999, 64, 9625. (c) Iwamatsu, S.; Kondo,
H.; Matsubara, K.; H. Nagashima, N. Tetrahedron 1999, 55, 1687. (d)
Nagashima, H.; isonon, Y.; Iwamatsu, S. J. Org. Chem. 2001, 66, 315. (e)
Pirrung, F. O. H.; Steeman, W. J. M.; Hiemstra, H.; Speckamp, W. N.;
Kaptein, B.; Boesten, W. H. J.; Schoemaker, H. E.; Kamphius, J.
Tetrahedron Lett. 1992, 33, 5141. (f) Pirrung, F. O. H.; Hiemstra, H.;
Kaptein, B.; Sobrino, M. L. M.; Petra, D. G. I.; Schoemaker, H. E.;
Speckamp, W. N. Synlett 1993, 50, 735. (g) Pirrung, F. O. H.; Hiemstra,
H.; Speckamp, W. N.; Kaptein, B.; Schoemaker, H. E.; Tetrahedron 1994,
50, 12415. (h) Udding, J. H.; Tuijp, C. J. M.; Hiemstra, H.; Speckamp, W.
N. Tetrahedron 1994, 50, 1907. (i) Udding, J. H.; Tuijp, C. J. M.; van
Zanden, M. N. A.; Hiemstra, H.; Speckamp, J. Org. Chem. 1994, 59, 1993.
(j) Ram, R. N.; Charles, I. J. Chem. Soc., Chem. Commun. 1999, 2267. (k)
Baldovini, N.; Bertand, M.-P.; Carriere, A.; Nouguier, R.; Plancher, J.-M.
J. Org. Chem. 1996, 61, 3205. (l) Davies, D. T.; Kapur, N.; Parsons, A. F.
Tetrahedron Lett. 1999, 40, 8615. (m) Davies, D. T.; Kapur, N.; Parsons,
A. F Tetrahedron 2000, 56, 3941. (n) Bryans, J. S.; Chessum, N. E. A.;
Huther, N.; Parsons, A. F.; Ghelfi, F. Tetrahedron 2003, 59 6221. For ATRP
(o) Wang, J.; Matyjaszewski, K. J. Am. Chem. Soc. 1995, 117, 5614. (p)
Wang, J.; Matyjaszewski, K. Macromolecules. 1995, 28, 7572.
Results and Discussion
We decided to investigate how the nature of the polymeric
support and the type of ligand effected the rate and selectivity
of a range of simple cyclization reactions. We chose to prepare
solid-supported ligands that could be synthesized in only a few
steps from commercial sources. By far the most studied solid-
supported ligands in ATRP reactions are those derived from
(6) (a) Haddleton, D. M.; Clark, A. J.; Duncalf, D. J.; Hemming, A. M.;
Kukulj, D.; Shooter, A. J. J. Chem. Soc., Dalton Trans. 1998, 381. (b) Clark,
A. J.; Duncalf, D. J.; Filik, R. P.; Haddleton, D. M.; Thomas, G. H.; H.
Wongtap, H. Tetrahedron Lett. 1999, 40, 3807. (c) Clark, A. J.; Battle, G.
M.; Heming, A. M.; Haddleton D. M.; Bridge, A. Tetrahedron Lett. 2001,
42, 2003. (d) Clark, A. J.; Battle, G. M.; Bridge, A.; Tetrahedron Lett.
2001, 42, 1999.
(10) De Campo, F.; Laste´coue`res, D.; Vincent, J.-M.; Verlac, J.-B. J.
Org. Chem. 1999, 64, 4969.
(11) (a) Shen, Y.; Tang, H.; Ding, S. Prog. Polym. Sci. 2004, 29, 1053.
(b) Kickelbick, G.; Paik, H.-J.; Matyjaszewski, K. Macromolecules 1999,
32, 2941. (c) Haddleton, D. M.; Kukulj, D.; Radigue, A. P. Macromolecules
1999, 32, 4769. (d) Shen, Y.; Zhu, S.; Zeng, F.; Pelton, R. J. Polym. Sci.
Part A: Polym. Chem. 2001, 39, 1051. (e) Shen, Y.; Zhu, S.; Pelton, R.
Macromolecules 2001, 34, 3182. (f) Shen, Y.; Zhu, S. Macromolecules 2001,
34, 8603. (g) Nguyen, J. V.; Jones, C. W. Macromolecules 2004, 37, 1190.
(h) Nguyen, J. V.; Jones, C. W. J. Polym. Sci. Part A: Polym. Chem. 2004,
42, 1384. (i) Honigfort, M. E.; Brittain, W. J. Macromolecules 2003, 36,
3111.
(12) (a) Haddleton, D. M.; Duncalf, D.; Kukulj, D.; Radigue, A. P.
Macromolecules 1999, 32, 4769. (b) Haddleton, D. M.; Kukulj, D.; Radigue,
A. P. J. Chem. Soc., Chem. Commun. 1999, 99. (c) Kickelbick, G.; Paik,
H.; Matyjaszewski, K. Macromolecules 1999, 32, 2941. (d) Shen, Y.; Zhu,
S.; Pelton, R. Macromolecules 2000, 33, 5427. (e) Shen, Y.; Zhu, S.; Pelton,
R. Macromolecules 2001, 34, 5812. (f) Hong, S. C.; Matyjaszewski, K.
Macromolecules 2002, 35, 7592. (g) Shen, Y.; Tang, H.; Ding, S. Prog.
Polym. Sci. 2004, 29, 1053.
(7) (a) Benedetti, M.; Forti, L.; Ghelfi, F.; Pagnoni, U. M.; Ronzoni, R.
Tetrahedron 1997, 41, 14031. (b) Ghelfi, F.; Bellesia, F.; Forti, L.;
Ghirardini, G.; Grandi, R.; Libertini, E.; Montemaggi, M. C.; Pagnoni, U.
M.; Pinetti, A.; De Buyck, L.; A. F. Parsons, A. F. Tetrahedron 1999, 55,
5839. (c) Ghelfi, F.; Ghirardini, G.; Libertini, E.; Forti L.; Pagnoni, U. M.
Tetrahedron Lett. 1999, 40, 8595. (d) Ghelfi, F.; Parsons, A. F. J. Org.
Chem. 2000, 65, 6249. (e) De Buyck, L.; Cagnoli, R.; Ghelfi, F.; Merighi,
G.; Mucci, A.; Pagnoni, U. M.; Parsons, A. F. Synthesis 2004, 10, 1680.
(8) (a) De Campo, F.; Laste´coue`res, D.; Verlac, J.-B. Chem. Commun.
1998, 2117. (b) Clark, A. J.; De Campo, F.; Deeth, R. J.; Filik, R. P.; Gatard,
S.; Hunt, N. A.; Laste´coue`res, D.; Thomas, G. H.; Verlac J.-B.; Wongtap
H. J. Chem. Soc., Perkin Trans. 1 2000, 671 (c) De Campo, F.; Laste´coue`res,
D.; Verlac, J.-B. J. Chem. Soc., Perkin Trans. 1 2000, 575.
(9) (a) Clark, A. J.; Dell, C. P.; Ellard, J. M.; Hunt, N. A.; McDonagh,
J. P.; Tetrahedron Lett. 1999, 40, 8619. (b) Clark, A. J.; Filik, R. P.; Thomas,
G. H. Tetrahedron Lett. 1999, 40, 4885.
(13) Clark, A. J.; Filik, R. P.; Haddleton, D. M.; Radigue, A.; Sanders,
C. J.; Thomas, G. H.; Smith, M. E. J. Org. Chem. 1999, 64, 8954.
1472 J. Org. Chem., Vol. 71, No. 4, 2006

Solid-Supported Cu Catalysts for Atom-Transfer Radical Cyclizations
FIGURE 2. Solid-supported ligands 9-15.
SCHEME 2. Preparation and Functionalization of Resins 13 and 14
PMI ligands 2.11g-i,12a,b Thus, we chose to investigate the effect
of three different supports (9-11) on the ATRC reactions of
this ligand. The incorporation of 9 into the study would allow
us to compare our results with those previously published. As
conventional solution cyclization reactions can be influenced
by the nature of the ligand (with rate enhancements generally
following the order Me6-Tren 5 > PMEDTA 4 > PMI 2), we
chose to prepare a range of supported analogues of these ligands,
namely 12-15, Figure 2.8b
Preparation of Solid-Supported Ligands 9-15. We pre-
pared the silica-PMI 9, the 1% divinylbenzene cross-linked
polystyrene-PMI 10, and the JandaJel-PMI 11 using previously
published procedures from aminopropylated silica gel (1.26
mmol of -NH2/g),13 aminopolystyrene (70-90 mesh, 1.66
mmol of -NH2/g),12b and JandaJel-NH2 (0.635 mmol of -NH2/
g),11i respectively. The latter has been reported to have increased
solvent compatibility and site accessibility compared to divi-
nylbenzene cross-linked polystyrene resins in ATRP.11i Ligand
loadings were calculated for each resin using elemental analy-
sis,14 and all three polymers exhibited infrared spectra similar
to those already reported.
Polystyrene PMDETA 13 and Me6-tren 14 analogues were
prepared by Eschweiler-Clarke15 permethylation of com-
mercially available 16 (2.72 mmol of ligand/g) or 17 (1.18 mmol
of ligand/g) respectively, Scheme 2. Heating 16 or 17 with a
10-fold excess of formic acid and formaldehyde at 120 °C
furnished the desired permethylated supported ligands 13 or 14,
respectively. The novel supports were washed with Et3N, DCM,
and MeOH and dried to constant weight.
(14) All numerical values obtained were the average of duplicate
microanalysis results.
(15) (a) Ciampolini, M.; Nardi, N. Inorg. Chem. 1996, 41, 42. (b)
Thomas, E. W.; Cudahy, M. M.; Spilman, C. H.; Dinh, D. M.; Watkins, T.
L.; Vidmar, T. J. J. Med. Chem. 1992, 35, 1233.
J. Org. Chem, Vol. 71, No. 4, 2006 1473

Clark et al.
TABLE 1. Ligand and Copper Loadings
SCHEME 3. Preparation of Resins 12 and 15
liganda loading
(mmol/g)
loadinga copper
(mmol/g)
resin
Si-PMI 9:CuCl
Si-PMI 9:CuBr
P-PMI 10:CuCl
P-PMI 10:CuBr
JJ-PMI 11:CuCl
JJ-PMI 11:CuBr
P-PMDETA 13:CuCl
P-PMDETA 13:CuBr
P-Me6-Tren 14:CuCl
P-Me6-Tren 14:CuBr
JJ-TEDETA 15:CuCl
JJ-TEDETA 15:CuBr
Si-DETA 22:CuCl
Si-DETA 22:CuBr
0.87
1.16
1.19
1.16
0.53
0.52
1.81
1.57
0.86
0.84
0.45
0.45
1.10
1.07
0.81
0.69
0.51b
0.53b
0.26b
0.46
1.98c
1.78c
1.27c
1.07c
0.43
0.43
1.09
0.97
To determine qualitatively the degree of methylation, both
resins 13 and 14 were reacted with a 15-fold excess of the highly
reactive electrophile 3,4-dichlorophenyl isocyanate in anhydrous
DCM for 16 h to give 20 and 21.16 This allowed any remaining
NH groups to be functionalized as ureas. As a control, the
unmethylated starting resins 16 and 17 also were reacted in this
way to give 18 and 19. The resins produced were then analyzed
for chlorine content by elemental analysis. Comparison of their
chlorine content indicated that on average 0.7 of the 4 possible
methylation sites of 16 and 0.7 of the 5 methylation sites of 17
remained unmethylated. As expected from this analysis, both
resins gave a negative Kaiser test (indicating that no primary
amines were left unreacted) but did show positive p-chloroanil
tests indicative of some free secondary amines.17 Infrared
analysis also confirmed these conclusions.18
a All numerical values are the average of duplicate microanalysis results.
b Ratio of Cu:ligand approximately 1:2. c Copper loading is greater than
ligand loading.
Attempts at preparing the analogous silica supported resin
12 from commercially available 22 (1.28 mmol/g) using the
same Eschweiler-Clarke procedure furnished a product resin
with a very low nitrogen content, indicating that significant
quantities of ligand were cleaved from the silica support under
the reaction conditions (Scheme 3). As an alternative approach,
unmethylated resin 22 was reacted with 4 equiv of MeI in DCM
at room temperature overnight. After being washed with Et3N,
the product resin was found to contain iodine (6.59%) indicating
the presence of quaternary ammonium salts. Reaction of 12 with
3,4-dichlorophenyl isocyanate indicated a significant level of
unfunctionalized secondary amines in 12. Finally, the JandaJel
analogue 15 was prepared from 23 using an established literature
procedure.11i
FIGURE 3. IR of solution PMDETA 4 and 4:CuBr.
Preparation of Copper Complexes. To prepare the active
copper catalysts, each solid-supported ligand 9-15 was added
to a stirred acetonitrile solution of an excess of either CuCl or
CuBr. After addition, the resins were filtered, washed with
acetonitrile, dried, and stored under nitrogen. In light of our
difficulty in preparing the silica PMDETA analogue 12 we
prepared the copper chloride complexes of the unmethylated
commercially available silica triamine ligand 22 instead.
Analysis of the polymers by infrared spectroscopy, elemental
analysis, and ICP was undertaken to determine the copper
loading and the ligand-to-copper ratio and to provide evidence
for copper complexation by the supported ligand, Table 1. While
the copper complexes of ligands 9-11 and 15 have been
prepared before, evidence for copper complexation of the
supported ligands 12-14 was obtained by comparison of their
infrared spectra. In solution, the main changes upon complex-
ation of the free ligand 4 with either CuCl or CuBr are shown
in Figure 3. A shift to higher wavenumbers of the C-H
stretching frequencies is observed in the 2700-3000 cm-1
FIGURE 4. IR of P-PMDETA 13 and 13:CuBr.
range. The shift is accompanied by the merging of the two main
sets of absorbances into a broader single set. This change was
also observed for the supported ligands 12-14, Figure 4. In
this case, the C-H stretch region of the spectrum is more
complicated as it is made up of the absorbances from both the
ligand as well as the polystyrene backbone, but the broadening
and merging of bands is still observable.
Reactions of Solid-Supported Copper Catalysts. Our initial
experiments focused upon the cyclization of the trichloroaceta-
mide substrate 6.5a Thus, reacting 6 with 30 mol % of the
supported reagents 9-15 and 22 at room temperature in DCE
produced the expected atom-transfer product 7 with varying
levels of efficiency, Table 2. The reactions were repeated at
(16) Booth, R. J.; Hodges, J. C. J. Am. Chem. Soc. 1997, 119, 4882.
(17) Kaiser, E.; Colescott, R. L.; Bossinger, C. D.; Cook, P. I. Anal.
Biochem. 1969, 34, 595.
(18) Yan, B.; Kumaravel, G. Tetrahedron 1996, 52, 843.
1474 J. Org. Chem., Vol. 71, No. 4, 2006

Solid-Supported Cu Catalysts for Atom-Transfer Radical Cyclizations
TABLE 2. Cyclization of 6 with Resins
resin
time
yield of 7a (%)
Si-PMI 9
P-PMI 10
3 h
3 h
92b
98
JJ-PMI 11
3 h
120 h
5 min
40 h
80 h
80 h
100
80c
93d
93c
61c
0e
P-PMEDTA 13
Me6-Tren 5
P-Me6-Tren 14
JJ-TEDETA 15
Si-DETA 22
FIGURE 5. Rate Plots for P-PMDETA 13:CuCl.
a Conducted at room temperature in DCE. b Reference 13. c 100% after
30 min at reflux. d Solution ligand. e Starting material recovered.
reflux using the same supported reagents 9-15. This time, all
of the reactions went to completion in quantitative yields after
30 min.
There was some concern that the activity of complex
P-PMEDTA 13 may have been due to significant uncomplexed
Cu(I) since the loading of the copper on the support exceeded
that of the ligand. However, when the reaction was repeated
using the equivalent of “free” Cu(I)Cl, no cyclization was
observed. Interestingly, the polyamine-functionalized supports
13-15 were less efficient in cyclizing the test substrate than
the immobilized PMI ligands 9-11. This is the reverse behavior
to that observed in solution.8b In light of the inability of the
silica-functionalized support to mediate the reaction of 6, this
catalyst was not evaluated further. We next investigated the
reusability of the polyamine supports P-PMDETA 13:CuCl and
P-Me6-Tren 14:CuCl. Reactions were performed using a 0.12
M concentration of 6 in DCE with 30 mol % (Cu) of catalysts
at reflux under nitrogen. The reactions were monitored by the
removal of aliquots from the reaction mixture at regular
intervals. Once each reaction had reached completion the
catalysts were filtered, washed well with DCE, dried to constant
weight, and then reused with a fresh batch of substrate 6. The
reactions were repeated a total of seven times for each catalyst.
Both catalysts retained their activity even after seven runs with
the P-Me6-Tren 14:CuCl support requiring 4.5 h to reach
completion and the P-PMDETA 13:CuCl support requiring 9 h
after the final run (the initial reaction was over in less than 30
min for both catalysts). A pseudo-first-order rate plot for the
reaction mediated by P-PMDETA 13:CuCl is shown in Figure
5. For both catalysts P-PMDETA 13:CuCl and P-Me6-Tren 14:
CuCl, the copper content was determined after the seventh run.
Analysis indicated a leeching of 34% and 27% of Cu,
respectively.
FIGURE 6. Cyclization substrates 24-28.
TABLE 3. Cyclization of 24
ligand
T (°C)
time (h)
yield (%)
PMDETA 4
P-PMDETA 13
P-PMDETA 13
Me6-Tren 5
P-Me6-Tren 14
P-Me6-Tren 14
JJ-TEDETA 15
Si-PMI 9
18
18
83
18
18
83
83
22
22
22
0.5
48
0.5
<0.1
92
99
0
95
97
95
95
92
31
30
27
0.5
3
24
24
24
P-PMI 10
JJ-PMI 11
Cyclization of Substrates 24-25. Cyclizations of both
substrates 24 and 25 were undertaken using PMI 9-11 and
polyamine 13-15 catalysts (Table 3). In addition, the solution
ligand counterparts PMDETA 4 and Me6-Tren 5 of the solid-
supported reagents P-PMDETA 13 and P-Me6-Tren 14 were
also investigated in order to compare homogeneous versus
heterogeneous catalyst rates and selectivities. The homogeneous
catalysts PMDETA 4 and Me6-Tren 5 were found to effect
cyclization of substrates 24 and 25 at room temperature in less
than 5 min and in 1 h, respectively (with catalyst 4 providing
a de of 73% and catalyst 5 a de 75% for the cyclization of 25).
On the other hand, the solid-supported analogues P-PMDETA
13 and P-Me6-Tren 14 failed to mediate any cyclization of either
substrate even after 1 h. More detailed studies carried out at
room temperature indicated the cyclization of 24 with P-Me6-
Tren 14:CuBr was more efficient than with P-PMDETA 13:
CuBr paralleling the homogeneous reactivities of these ligands.
We next investigated the reactions of a variety of other
substrates to probe the efficiency of the catalysts. Test substrates
were picked in order to investigate 5-exo-trig cyclization of less
activated substrates 2413 and 253b (the latter being chosen in
order to determine if the stereochemical outcome of the reaction
would be effected by the nature of the supported catalyst), as
well as probing 5-exo-dig 26,8b 5-endo-trig 27,13 and 4-exo-
trig 28 cyclizations, Figure 6.
J. Org. Chem, Vol. 71, No. 4, 2006 1475

Clark et al.
TABLE 4. Cyclization of 25
TABLE 5. Cyclization of 26
ligand
T (°C)
time (h)
yield (%) (de, %)
PMDETA 4
P-PMDETA 13
Me6-Tren 5
P-Me6-Tren 14
JJ-TEDETA15
Si-PMI 9
18
83
20
83
83
83
83
83
1
1
1
24
24
18
18
18
98 (73)
91 (65)
88 (75)
93 (63)
58 (31)
94 (64)
92 (62)
93 (60)
yield of 32/33 (%),
ratio E/Z
ligand
time (h)
yield of 34 (%)
PMDETA 4
P-PMDETA 13
Me6-Tren 5
P-Me6-Tren 14
JJ-TEDETA 15
Si-PMI 9
0.5
48
0.5
48
24
24
70, 3.7:1.0
88, 2.4:1.0
70, 3.8:1.0
93, 2.4:1.0
90, 2.4:1.0
98, 2.2:1.0
93, 2.2:1.0
29
11
29
6
8
0
P-PMI 10
JJ-PMI 11
JJ-PMI 11
24
6
Yet again, however, the most reactive catalysts were those
derived from PMI ligands 9-11 (all providing >95% yield in
only 30 min at reflux). Comparing the effect of the support type
(polystyrene versus JandaJel) on the rate of cyclization of 24
with PMI ligands at room temperature (Table 3) indicated that
the JandaJel resin with its flexible cross-linker provided no
advantage over the analogous polystyrene or silica catalyst.
Upon reflux, all of the catalysts mediated the cyclization of 24
to completion in 30 min with the exception of the JJ-TEDETA‚
CuBr complex, which took 3 h.
TABLE 6. Cyclization of 27
Cyclization of the dichloroamide 25 indicated a different order
of reactivity (Table 4). While cyclization of 25 with PMDETA
13:CuCl and PS-Me6-Tren 14:CuCl again paralleled their
solution reactivities, catalyst 14 was particularly active. As
before, the PMI ligands 9-11 all performed similarly. All
reagents showed a decrease in diastereoselectivity compared to
their solution counterparts. The JJ-TEDETA 15:CuBr complex
was again one of the least efficient, giving a relatively low yield
of product (58%) with an extremely low diastereoselectivity (de
31%).
ligand
ratio of 35:36
yield of 35 + 36 (%)
P-PMEDTA 13
P-Me6-Tren 14
JJ-TEDETA 15
Si-PMI 9
1.2:1.0
1.0:1.0
1.1:1.0
1.0:1.0
42
50
100
78
JJ-PMI 11
15a
a Yield of 37.
Effect of Reduction versus Atom Transfer in the Cycliza-
tion of Alkyne 26. Copper-mediated atom transfer 5-exo-dig
cyclizations onto alkynes have been reported to be difficult with
the nature of the ligand being crucial to the success of the
reaction.7d Previous work has shown that PMI ligands 2 mediate
the reaction of 26 to give an inseparable mixture of the vinyl
bromides 32/33 as well as the reduced alkene 34. The reduced
alkene 34 is thought to arise via reduction of the intermediate
vinyl radical by H abstraction from either the ligand or the
solvent or from both.7d That the nature of the ligand used in
this homogeneous catalyzed reaction can affect both the amount
of 34 obtained as well as the E/Z ratio of the vinyl bromides
32/33 was ascertained by reacting 26 with the solution catalysts
obtained by mixing 30 mol % of CuBr and 30 mol % of PMI
2, PMDETA 4, or Me6-Tren 5 as ligand in DCE. Substantial
amounts of reduced product 34 (29%) was obtained when the
PMDETA 4 or Me6-Tren 5 ligands were used (29% for both)
but only a trace was obtained with the PMI ligand 2 (4%). To
a certain degree, this reflects the relative ease of H atom donor
ability of the respective ligands with the polyamine ligands being
better donors. The E/Z ratio of the vinyl bromides 32/33 obtained
were also somewhat different for the polyamine ligands 4 and
5 (3.7:1.0) compared to the pyridine-based ligand system 2 (2.5:
1.0). The solid-supported catalysts followed the same reactivity
trends as those observed in the other supported 5-exo cycliza-
tions with the PMI catalysts being more reactive than the
polyamine ones. However, in all cases, the E/Z selectivity was
eroded compared to the reactions with the solution catalysts.
This may be due to the greater steric bulk of the polymer-
supported reagents which led to a significantly retarded rate of
atom transfer at the most hindered site (giving rise to 32) in
the intermediate vinyl radical.
While all supported ligands showed reduced stereoselectivity
they also provided significantly lower amounts of the undesired
reduced alkene 34. Presumably, the supported ligands are less
sterically accessible for H atom donation compared to their
solution analogues (Table 5). Thus, higher overall yields of
atom-transfer products could be obtained when using the
heterogeneous Si-PMI 9 ligand system compared to the homo-
geneous catalysts.
Mediation of 4-exo and 5-endo Radical Polar Crossover
Reactions. Efficient 5-endo radical polar crossover reactions
of tertiary bromide precursors have been reported to be mediated
in solution by Me6-Tren 5:CuX complexes.9a Hence, precursor
27 has been shown to furnish a 1:1 mixture of 35 and 36 in an
overall yield of 82% after 20 min at room temperature (Table
6). This reaction has also been reported to be mediated by the
Si-PMI 9:CuBr complex13 at reflux giving the same 1:1 mixture
of isomers albeit in an extended reaction time (24 h) and reduced
yield (78%).
Interestingly, attempts to mediate the cyclization of 27 with
the analogue JJ-PMI 11 only furnished the oxindole 37 in 15%
1476 J. Org. Chem., Vol. 71, No. 4, 2006

Solid-Supported Cu Catalysts for Atom-Transfer Radical Cyclizations
SCHEME 4. Cyclization of 28 and 38a
onto alkynes (e.g., 26) was indicated by the fact that cyclization
of 26 led to significantly less of the undesired reduced product
34 compared to the corresponding homogeneous catalyzed
processes.8b The reusability of the ligands was briefly probed
with the P-PMDETA ligand system 13. This indicated that in
the cyclization of 6 the catalyst system was capable of reuse
up to the seven runs investigated. The decrease in reactivity
observed in each consecutive run is likely to arise from both
leaching of the copper from the support as well as oxidative
deactivation to unreactive copper(II) complexes. Generally, it
was found that the type of support (e.g., polystyrene, silica, or
JandaJel) had very little effect upon the efficiency and selectivity
of the processes but that the nature of the ligand type
immobilized was the important factor.
a Key: (i) 30 mol % of JJ-TEDETA 15:CuBr, DCE, reflux.
yield19 (the remaining mass balance being unreacted starting
material). Both P-PMDETA 13 and P-Me6-Tren 14 did facilitate
the reaction, but neither went to completion even after 48 h.
Most surprising, however, was that the JJ-TEDETA 15 complex
was now the most efficient, providing a quantitative yield of
both regioisomers 35 and 36 in 48 h. Encouraged by this result,
we wondered whether it would be possible to mediate the 5-endo
cyclization of secondary halides, such as 38, using this reagent.
Previous work has shown that polyamine ligands such as Me6-
Tren 5 will not mediate this cyclization in solution, and instead,
more active multidentate pyridine ligands such as tripyridy-
lamine are necessary for successful reaction.20 Thus, it came as
no surprise that neither the P-PMDETA 13 or P-Me6-Tren 14
ligands facilitated the cyclization of 38. In both cases, only
starting material was recovered from the reactions. However,
heating 38 with JJ-TEDETA 15:CuBr for 48 h at reflux did
provide the cyclized diene 39 in low yield (21%) along with
recovered starting material. It remains unclear why the JJ-
TEDETA 15 ligand should be so effective at mediating these
5-endo cyclizations but is one of the least efficient resins in
mediating 5-exo cyclizations. In addition, we determined that
the JJ-TEDETA 15 was the only resin to mediate the 4-exo
cyclization of 28 to give 40 (all the other resins providing only
recovered starting material) (Scheme 4).
Experimental Section
General Procedures. N-Allyl-N-4-toluenesulfonyl-2,2,2-trichlo-
roacetamide 6,5a N-allyl-N-4-toluenesulfonyl-2-bromo-2-methyl-
propionamide 24,13 N-allyl-N-4-toluenesulfonyl-2,2-dichloropropi-
onamide 25,3b N-propargyl-N-4-toluenesulfonyl-2-bromo-2-methyl-
propionamide 26,8b and N-benzyl-2-methyl-2-bromo-N-cyclohexyl-
1-enylpropionamide 2713 were prepared by literature procedures.
4-Chloromethyl-3,3-dichloro-1-toluene-4-sulfonylpyrrolidin-2-
one 7,5a 4-bromomethyl-3,3-dimethyl-1-toluene-4-sulfonylpyrroli-
din-2-one 29,13 (3S*,4R*)-4-chloromethyl-3-chloro-3-methyl-1-
toluene-4-sulfonylpyrrolidin-2-one 30,3b (3S*,4S*)-4-chloromethyl-
3-chloro-3-methyl-1-toluene-4-sulfonylpyrrolidin-2-one 31,3b (E)-
4-bromomethylene-3,3-dimethyl-1-toluene-4-sulfonylpyrrolidin-2-
one 32,8b (Z)-4-bromomethylene-3,3-dimethyl-1-toluene-4-sulfonyl-
pyrrolidin-2-one 33,8b 3,3-dimethyl-4-methylene-1-toluene-4-sul-
fonylpyrrolidin-2-one 34,8b 1-benzyl-3,3-dimethyl-1,3,4,5,6,7-
hexahydroindol-2-one 35,13 1-benzyl-3,3-dimethyl-1,3,3a,4,5,6-
hexahydroindol-2-one 36,13 and 1-benzyl-3,3-dimethyl-1,3-dihydro-
indol-2-one 3719 exhibited spectroscopic details identical to those
already reported. Nuclear magnetic resonance, 1H NMR, were
recorded at 300 or 400 MHz and 13C NMR recorded at 75.5 or
100.6 MHz with residual solvent as internal standard; infrared
spectra (IR) were recorded as solutions or neat; and mass spectra
were recorded using either electron impact or chemical ionization
(NH3). All reactions were carried out under nitrogen unless
otherwise stated.
Conclusions
Synthesis of Supported Ligands. Si-PMI 9. A mixture of
aminopropylated silica gel (1.26 mmol of -NH2/g) (4.00 g, 5.04
mmol) and pyridine-2-carboxaldehyde (4.26 mL, 45.0 mmol) in
dry toluene (100 mL) was heated to reflux for 24 h with a Soxhlet
containing crushed 4 Å molecular sieves (10.0 g). The orange solid
was filtered, washed with toluene (3 × 50 mL), DCM (3 × 20
mL), and ethanol (10 mL), and dried in vacuo to give (Si-NPMI)
9 as an orange solid (4.35 g): νmax (solid)/cm-1 1045, 796. Found:
C, 15.25; H, 1.78; N, 3.54; 1.26 mmol of ligand/g.
P-PMI 10. A mixture of (aminomethyl)polystyrene (1% cross
linked; 1.66 mmol of -NH2/g) (4.50 g, 7.47 mmol) and pyridine-
2-carboxaldehyde (6.41 mL, 67.5 mmol) in dry toluene (100 mL)
was heated to reflux for 24 h with a Soxhlet containing crushed 4
Å molecular sieves (10.0 g). The resin was filtered, washed with
anhydrous toluene (10 × 25 mL), and dried in vacuo to give P-PMI
10 as an orange solid (4.97 g): νmax (solid)/cm-1 3057, 3025, 2919,
2850, 2320, 1700, 1646, 1594, 1492, 1452, 1361, 1152, 1072, 1025,
994, 755, 697. Found: C, 88.13; H, 7.29; N, 3.30; 1.18 mmol of
ligand/g.
We have shown that a range of supported pyridinemetha-
nimine 9-11 and polyamine 13-15 ligand/copper complexes
will mediate 4-exo-trig, 5-exo-trig, 5-exo-dig, and 5-endo-trig
radical cyclizations of a representative set of substrates. The
rates of reaction of all the supported reagents were significantly
slower than for their corresponding solution analogues. In
addition, the effect of the nature of the supported ligand upon
the cyclization of 6 indicated that the pyridinemethanimine
ligands 9-11 were more effective than the polyamine ligands
12-15. This was unexpected in light of the reverse result for
their behavior in solution.8b In general, the PMI catalysts 9-11
were more efficient in 5-exo cyclizations with the JJ-TEDETA
catalyst being the least efficient. This situation was reversed,
however, when examining the 4-exo and 5-endo cyclizations
of 28, 27, and 38. In fact, the JJ-TEDETA catalyst was the only
system to mediate the cyclization of 28 and 38. The reason for
this difference in reactivity is unclear at this stage. A potential
advantage in using solid-supported reagents in the cyclization
JJ-PMI 11. A mixture of JandaJel-NH2 (0.635 mmol of -NH2/
g) (5.08 g, 3.22 mmol) and pyridine-2-carboxaldehyde (613 µL,
6.45 mmol) in dry toluene (100 mL) was heated to reflux for 16 h
with a Soxhlet containing crushed 4 Å molecular sieves (5.0 g).
The resin was filtered, washed with anhydrous toluene (10 × 25
mL), and dried in vacuo to give JJ-NPMI 11 as a yellow solid
(19) Trifonov, L. S.; Orahovats, A. S. HelV. Chim. Acta 1987, 70, 1732.
(20) Clark, A. J.; Dell, C. P.; McDonagh, J. P. C. R. Acad. Sci. Ser IIc:
Chim. 2001, 4, 575.
J. Org. Chem, Vol. 71, No. 4, 2006 1477

Clark et al.
(5.02 g): νmax (solid)/cm-1 3058, 3025, 2917, 2850, 1645, 1601,
1510, 1493, 1452, 1368, 1239, 1178, 1111, 1024, 906, 825, 754,
695. Found: C, 89.10; H, 7.64; N, 1.46; 0.521 mmol of ligand/g.
Attempted Synthesis of Si-PMDETA 12, Method A. 3-Pro-
pyldiethylenetriamine-functionalized silica gel (1.28 mmol of
triamine/g) (4.50 g, 5.76 mmol) was cooled to 0 °C in an ice bath.
Formic acid (11.0 mL, 294 mmol) was added by syringe over 10
min, followed by aqueous formaldehyde (19.4 mL, 36% aqueous
solution, 259 mmol). The reaction mixture was heated to reflux
for 16 h. The mixture was cooled and the resin filtered through a
pre-tared filter funnel. The resin was washed repeatedly with 19:1
DCM/MeOH and was dried in vacuo at room temperature to give
a white solid (3.75 g): νmax (solid)/cm-1 3245, 1591, 1044, 795.
Found: C, 7.45; H, 1.90; N, 1.79. Kaiser test (solid initially
colorless, stains pale black after 30 s); p-chloranil test (silica stained
dark green). Method B. Methyl iodide (1.27 mL, 20.4 mmol) was
added to a suspension of 3-propyldiethylenetriamine-functionalized
silica gel (4.00 g, 5.10 mmol) in anhydrous DCM (40 mL) at room
temperature under nitrogen. After 16 h, the solid was filtered
through a pretared filter funnel, washed repeatedly with 19:1:0.5
DCM/MeOH/Et3N, and dried in vacuo at room temperature to give
a white solid (4.43 g). Found: C, 12.26; H, 2.72; N, 4.80; I, 6.59.
P-PMDETA 13. Stratospheres PL-DETA (diethylenetriamine)
resin (2.72 mmol of triamine/g) (4.50 g, 12.2 mmol) was cooled to
0 °C in an ice bath. Formic acid (23.4 mL, 622 mmol) was added
by syringe over 10 min, followed by aqueous formaldehyde (41.2
mL, 36% aqueous solution, 549 mmol). The reaction mixture was
heated to reflux for 16 h. The mixture was cooled and the resin
filtered through a pretared filter funnel. The resin was washed well
with Et3N (3 × 5 mL), water (3 × 5 mL), DCM (3 × 5 mL),
MeOH (3 × 5 mL), DMF (3 × 5 mL), and MeOH (3 × 5 mL) and
was dried in vacuo at room temperature to give P-PMDETA 13
(5.07 g) as a white solid: νmax (solid)/cm-1 3024, 2924, 2764, 1673,
1602, 1489, 1448, 1361, 1285, 1119, 1025, 788, 760, 699. Found:
C, 78.90; H, 9.24; N, 9.88; 2.35 mmol of triamine/g; Kaiser test
(resin colorless); p-chloranil test (resin stained orange brown then
green).
P-Me6-tren 14. Tris(2-aminoethyl)amine polystyrene (1.18 mmol
tetramine/g) (3.00 g, 3.53 mmol) was cooled to 0 °C in an ice bath.
Formic acid (6.79 mL, 180 mmol) was added by syringe over 10
min, followed by aqueous formaldehyde (11.9 mL, 36% aqueous
solution, 154 mmol). The reaction mixture was heated to reflux
for 16 h. The mixture was cooled and the resin filtered through a
pretared filter funnel. The resin was washed well with Et3N (3 ×
5 mL), water (3 × 5 mL), DCM (3 × 5 mL), MeOH (3 × 5 mL),
DMF (3 × 5 mL), and MeOH (3 × 5 mL) and was dried in vacuo
to give 14 (2.99 g) as a white solid: νmax (solid)/cm-1 3057, 3023,
2920, 2847, 2766, 1679, 1599, 1491, 1448, 1361, 1113, 1025, 754,
695. Found: C, 84.34; H, 8.54; N, 5.69; Cl, 0.14; 1.02 mmol of
tetramine/g; Kaiser test (resin colorless); p-chloranil test (resin
stained blue).
JJ-TEDETA 15. N,N,N,N′,N′-Tetraethyldiethylenetriamine (5.00
mL, 19.4 mmol) was added to a suspension of JandaJel-supported
acrylate (JJ-Acrylate)11i (4.50 g, 8.69 mmol) in anhydrous THF (100
mL) at room temperature under nitrogen. After 48 h, the solids
were filtered, washed several times with THF, and dried in vacuo
to give JJ-TEDETA 15 (4.42 g) as an orange solid: νmax (solid)/
cm-1 3296, 3060, 3025, 2920, 2848, 1724, 1602, 1493, 1448, 1374,
1244, 1175, 1065, 1027, 908, 815, 753, 696. Found: C, 83.97; H,
8.02; N, 2.09; 0.497 mmol of ligand/g.
to 1-2 mg of solid: (i) 2% acetaldehyde in DMF, (ii) 2%
p-chloranil (tetrachloro-1,4-benzoquinone) in DMF, and (iii) 2 mL
0.001 M KCN (aq) and 98 mL of pyridine. The mixture was allowed
to stand for 5 min at room temperature. Coloration of the solid
indicates the presence of secondary amines on the solid support.
Determination of Free Amine Content and Reaction of Resins
with 3,4-Dichlorophenyl Isocyanate. To the resin was added to a
solution of 3,4-dichlorophenyl isocyanate (15 equiv) in anhydrous
DCM (10 mL) under nitrogen. After 16 h at room termperature,
the reaction mixture was filtered through a pretared filter funnel.
The resin was washed well with with Et3N (3 × 5 mL), water (3
× 5 mL), DCM (3 × 5 mL), MeOH (3 × 5 mL), DMF (3 × 5
mL), and MeOH (3 × 5 mL) and was dried in vacuo at room
temperature to give the functionalized resin.
General Synthesis of CuCl- and CuBr-Supported Catalysts.
To the supported ligand was added a stirred solution of CuCl or
CuBr (1.2 equiv) in dry acetonitrile (10 mL) at room temperature
under nitrogen. After 30 min, the dark resin was filtered, washed
with acetonitrile (3 × 20 mL), and dried in vacuo.
N-Benzyl-2-bromo-N-cyclohexylidenemethyl-2-methylpropi-
onamide 28. A stirred solution of cyclohexanecarboxaldehyde (7.27
mL, 60.0 mmol) and benzylamine (6.55 mL, 60.0 mmol) in toluene
(40 mL) was heated to reflux in a Dean-Stark apparatus for 24 h.
The reaction mixture was concentrated in vacuo (12.1 g, 100%).
The crude product (3.22 g, 16 mmol) was dissolved in anhydrous
toluene (90 mL), and N,N-diethylaniline (2.55 mL, 16.0 mmol) was
added. To this mixture was added 2-bromoisobutyryl bromide (1.98
mL, 16.0 mmol) dropwise over 10 min at 0 °C. After being stirred
for 16 h at room temperature, the reaction mixture was washed
with water (40 mL) and then 1 M HCl (40 mL). The organic layer
was dried over MgSO4, filtered, and concentrated in vacuo. The
residue was purified by flash column chromatography (SiO2, 9:1,
petroleum ether/ethyl acetate) to give 28 as a colorless oil (4.86 g,
87%): Rf (5:1 petroleum ether/ethyl acetate) 0.44; IR (film) (film)
1
2928, 2853, 1636 cm-1; H NMR (300 MHz, CDCl3) 7.33-7.20
(5H, m), 6.30 (1H, s), 4.67 (2H, s), 2.13-2.06 (4H, m), 1.98 (6H,
s), 1.58-1.46 (6H, m); 13C NMR (75.5 MHz, CDCl3) δ 171.0,
141.5, 137.7, 128.8 (×2), 128.3 (×2), 127.5, 123.2, 58.9, 55.5, 33.2,
32.7, 29.0, 27.9, 26.6, 26.5; HRMS (EI) calcd for C18H24Br81NO
352.1099, found 352.1111; CI-MS m/z 350 (M)+, 270, 200, 91.
Anal. Calcd for C18H24BrNO: C, 61.7; H, 6.9; N, 4.0; Br, 22.8.
Found: C, 61.7; H, 6.9; N, 4.0; Br, 22.7.
N-Benzyl-2-bromo-N-cyclohex-1-enylpropionamide 38. 2-Bro-
mopropionyl bromide (1.68 mL, 16.0 mmol) was added dropwise
over 10 min to a solution of benzylcyclohexylideneamine20 (3.00
g, 16.0 mmol) and N,N-diethylaniline (2.55 mL, 16.0 mmol) in
anhydrous toluene (90 mL) at 0 °C. After stirring for 16 h at room
temperature, the reaction mixture was washed with water (40 mL)
and then 1M HCl (40 mL). The organic layer was dried over
MgSO4, filtered, and concentrated in vacuo. The residue was
purified by flash column chromatography (SiO2, 9:1, petroleum
ether/ethyl acetate) to give 38 as an off-white solid (3.59 g, 70%):
mp 87-88 °C; Rf (5:1 petroleum ether/ethyl acetate) 0.29; IR (film)
ν
max 2931, 1656 cm-1; 1Η ΝΜR (300 MHz, CDCl3) δ 7.28-7.18
(5H, m), 5.48 (1H, br s), 4.70-4.45 (3H, m), 2.22-1.84 (4H, m),
1.78 (3H, d, J ) 8.0 Hz), 1.70-1.58 (2H, m), 1.56-1.47 (2H, m);
13Η ΝΜR (75.5 MHz, CDCl3) δ 169.7, 138.0, 137.8, 129.4, 129.0
(×2), 128.7 (×2), 127.7, 50.4, 39.9, 28.4, 25.1, 23.1, 21.7, 22.6;
HRMS (EI) calcd for C16H20Br79NO 321.0728, found 321.0734;
CI-MS m/z 322 (MH)+, 242, 152, 91. Anal. Calcd for C16H20-
BrNO: C, 59.6; H, 6.3; N, 4.35; Br, 24.8. Found: C, 59.6; H, 6.2;
N, 4.4; Br, 24.8.
Kaiser Test for Determining Primary Amines on Solid
Supports. One drop of each of the following solutions was added
to 1-2 mg of solid: (i) 5 g of ninhydrin in 100 mL of ethanol, (ii)
80 g of phenol in 20 mL of ethanol, and (iii) 2 mL of 0.001 M
KCN (aq) mixed with 98 mL of pyridine. The mixture was heated
for a few seconds. Coloration of the solid indicates the presence of
primary amines on the solid support.
General Procedure for Homogeneous Cyclization Reactions.
To a solution of the cyclization substrate (0.120 mmol) and ligands
4 and 5 (0.036 mmol) in anhydrous dichloroethane (1 mL) under
nitrogen was added copper(I) chloride or copper(I) bromide (0.0360
mmol). The mixture was stirred at an appropriate temperature and
was monitored by TLC or NMR until no further change in reaction
composition was observed. The crude reaction mixture was filtered
p-Chloranil Test for Determining Secondary Amines on Solid
Supports. One drop of each of the following solutions was added
1478 J. Org. Chem., Vol. 71, No. 4, 2006

Solid-Supported Cu Catalysts for Atom-Transfer Radical Cyclizations
through a short plug of silica, which was washed with CH2Cl2 and
then EtOAc. The filtrate was concentrated in vacuo and the crude
residue purified by flash column chromatography.
1-Benzyl-4-cyclohex-1-enyl-3,3-dimethylazetidine-2-one 40:
clear oil; Rf (3:1 petroleum ether/ethyl acetate) 0.31; IR (film) νmax
2927, 1751, 1642 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.37-7.21
(5H, m), 5.57 (1H, m), 4.83 (1H, d, J ) 14.9 Hz), 3.86 (1H, d, J
) 14.9 Hz), 3.36 (1H, s), 2.14-2.05 (2H, m), 1.85-1.45 (6H, m),
1.26 (3H, s), 1.06 (3H, s); 13C NMR (75.5 MHz, CDCl3) δ 174.8,
136.6, 133.2, 129.1 (×2), 128.8 (×2), 127.9, 123.7, 66.7, 44.8, 33.2,
27.7, 25.2, 22.9, 22.7, 17.1; HRMS (FAB) calcd for C18H24NO
270.1858, found 270.1859; m/z (EI) 270 (MH)+, 200, 136, 121,
91.
General Procedure for Solid-Supported Cyclization Reac-
tions. The polymer-supported copper chloride or copper bromide
complex (0.0360 mmol of Cu) was added to a solution of the
cyclization substrate (0.120 mmol) in anhydrous dichloroethane (1
mL) under nitrogen. The mixture was stirred at an appropriate
temperature and was monitored by TLC or 1H NMR until no further
change in reaction composition was observed. The crude reaction
mixture was filtered, and the resin was washed well with CH2Cl2
and then EtOAc. The filtrate was concentrated in vacuo and was
characterized by 1H NMR. Reaction products were purified by flash
column chromatography where necessary.
Acknowledgment. We acknowledge AstraZeneca for a
studentship (J.V.G).
1-Benzyl-3-methyl-1,4,5,6-tetrahydroindol-2-one 39: pale yel-
low oil; yield 21%; Rf (5:1 petroleum ether/ethyl acetate) 0.26; IR
1
(film) νmax 2922, 2856, 1682, 1653 cm-1; H NMR (300 MHz,
Supporting Information Available: Microanalysis data for
supported ligands 9-15 and 18-21, and CuCl and CuBr complexes
of 9-15 and 22 as well as representative 1H NMR data for 28 and
38-40. Data for the re-usability of catalyst 13:CuCl in the
cyclization of 6. This material is available free of charge via the
Internet at http://pubs.acs.org.
CDCl3) δ 7.32-7.18 (5H, m), 5.42 (1H, t, J ) 4.5 Hz), 4.76 (2H,
s), 2.53 (2H, m), 2.24 (2H, m), 1.89 (3H, s), 1.78 (2H, m); 13C
NMR (125.8 MHz, CDCl3) δ 171.5, 140.4, 139.4, 138.3, 123.8,
128.9 (×2), 127.6 (×2), 127.5, 108.9, 43.2, 24.7, 23.7, 22.9, 8.8;
m/z (EI) 239 (M)+, 216, 122, 105, 91, 77, 65; HRMS (EI) calcd
for C16H17NO 239.1310, found 239.1310; EI-MS m/z 239 (M)+,
216, 122, 105, 91.
JO0521605
J. Org. Chem, Vol. 71, No. 4, 2006 1479