4880 J. Am. Chem. Soc., Vol. 119, No. 21, 1997
Flynn et al.
16 h. The mixture was transferred to a fritted plastic cartridge
containing aminomethylpolystyrene (CMR/R resin 14: 0.577 g, 0.45
mmol, 0.78 mequiv/g) and diluted with 6.0 mL of dry CH2Cl2. The
resulting mixture was agitated at rt for 3 h and then filtered. The resin
was washed with CH2Cl2 (4 × 6 mL × 15 min). The combined filtrate
and washings were concentrated and transferred to a vial, and the
solvent was blown off by a stream of N2. The resulting product was
dried in a vacuum oven overnight. Each product was weighed and
analyzed by NMR (1H, 13C, APT), mass spectrometry, and HPLC.
Benzanilide (11a): 19.6 mg, 99.5%; 1H NMR (CDCl3, 400 MHz):
δ 7.90 (m, 3H), 7.65 (d, J ) 7.6 Hz, 2H), 7.55 (m, 1H), 7.48 (t, J )
7.4 Hz, 2H), 7.37 (t, J ) 8.0 Hz, 2H), 7.16 (t, J ) 7.4 Hz, 1H);16
HPLC purity (retention time): 97.8% (12.1 min).
General Procedure II (for compounds 12 and 13).16 This pro-
cedure was conducted in a parallel reaction format. To each 7 mL
scintillation vial containing 1.0 mL of dry CH2Cl2 and dry poly
4-vinylpyridine (CMR/R resin 20: 0.25 g), amine 5 (0.1 mmol) was
added (aniline, 9.2 µL; benzylamine, 11.0 µL; or dibenzylamine, 19.8
µL), followed by acylating reactant 8 or 9 (0.50 mmol). Each vial
was closed tightly, and the mixture was agitated at rt with an orbital
shaker for 16 h. The mixture was transferred to a fritted plastic cartridge
containing aminomethylpolystyrene (CMR/R resin 14: 1.125 g, 0.90
mmol, 0.80 mequiv/g) and diluted with 10.0 mL of dry CH2Cl2. The
resulting mixture was agitated at rt for 3 h and then filtered. The resin
was washed with CH2Cl2 (4 × 10 mL × 15 min). The combined filtrate
and washings were concentrated and transferred to a vial, and the
solvent was blown off by a stream of N2. The resulting product was
dried in a vacuum oven overnight to afford the desired sulfonamides
or carbamates. Each product was weighed and analyzed by NMR (1H,
13C, APT), mass spectrometry, and HPLC.
3.00 (dd, J ) 14,7 Hz, 1H), 2.95-2.80 (cb, 5H), 2.48 (dt, J ) 15,7
Hz, 1H), 2.45 (dt, J ) 15,7 Hz, 1H), 2.42 (s, 3H), 1.57 (m, 1H), 0.79
(d, J ) 7 Hz, 6H); 13C NMR (CDCl3, 75 MHz): δ 204.1, 172.5, 143.8,
140.9, 137.2, 136.21, 129.9, 129.7, 129.4, 129.1, 128.8, 128.0, 127.8,
126.8, 57.1, 56.5, 55.8, 38.4, 37.6, 31.8, 27.2, 22.1, 20.4; HRMS m/z
521.2456 (C30H37N2O4S1 requires 521.2474); HPLC Purity (retention
time): 92.7% (20.2 min).
Utilization of Workup and Reactant Sequestering CMR/R Res-
ins: Reaction of Grignard Reactants with Carbonyl Compounds.
Under conditions of parallel reaction synthesis, a solution of allylmag-
nesium chloride 35 (2.0 M solution in a tetrahydrofuran, 0.30 mL, 0.60
mmol) was added to each vial containing a solution of aldehyde 34
(0.50 mmol) in tetrahydrofuran (freshly distilled) at -78 °C (acetone/
CO2) and the resulting solution stirred at room temperature for 2.5 h.
Amberlite IRC-50S (CMR/R resin 37: 0.80-1.0 g, 8-10 mmol, ∼10.0
mequiv/g) was added to each vial, and the mixture was stirred for an
additional 4 h. The mixture was filtered, and the polymer was rinsed
with tetrahydrofuran until no more UV activity was seen in the eluant.
The solvent was removed to afford essentially pure carbinol products
36 (R2 ) allyl). Isolated yields were in the range of 88-99% with
purity in the range of 95-99%. Products were characterized by GC/
MS, TLC, and proton NMR.
Upon observation of the GC/MS of product 36e, remaining starting
aldehyde, 6-methyl-2-pyridinecarboxaldehyde, was detected. To purify
this reaction mixture the following procedure was performed:
The residue was dissolved into dichloromethane, and the polyamine
CMR/R resin 40 (0.50 g, 1.49 mmol) was added. The slurry was stirred
at rt for 5 h. The mixture was filtered, and the polymer was rinsed
with dichloromethane until no more UV activity was seen in the eluant.
The solvent was removed to afford the carbinol 36e, demonstrated to
be >99% pure by GC/MS analysis.
N-Phenyl p-toluenesulfonamide (13e): 24.9 mg, 100%. 1H NMR
(CDCl3, 400 MHz): δ 7.68 (d, J ) 8.3 Hz, 2H), 7.22 (m, 4H), 7.09
(m, 3H), 6.97 (s, 1H), 2.37 (s, 3H);16 HPLC purity (retention time):
98.3% (13.5 min).
1-Phenyl-3-buten-1-ol (36a):16 90% mass yield; 1H NMR
(CDCl3): δ 2.06 (d,1H), 2.56 (m,2H), 4.78 (m,1H), 5.20 (m,2H), 5.85
(m,1H), 7.33 (m,5H); HRMS m/z 148.0866 (C10H12O1 requires 148.0888);
GC/MS purity (retention time): >99% (3.30 min).
Moffatt Oxidation. The oxidations of alcohols 26a-f to carbonyls
27a-f were performed in parallel. An example of the EDC-Moffatt
oxidation and the demonstration of tagged-reagent sequestration by
CMR/R polymers 30 and 31 is exemplified with the formation and
purification of 27d (Table 2, entry d). To N-[2-hydroxy-3-[[(4-
methylphenyl)sulfonyl](2-methylpropyl)amino]-1(S)-(phenylmethyl)pro-
pyl]benzenepropanamide (26d) (28.7 mg, 0.055 mmol) and EDC HCl
28 (53 mg, 0.275 mmol) in a 1:1 mixture of DMSO and CH2Cl2 (0.5
mL) in a 7 mL scintillation vial was added dichloroacetic acid (0.3 M
in DMSO, 0.9 mL). The mixture was agitated on an orbital shaker for
24 h. The mixture was transferred to a fritted plastic cartridge
containing Amberlyst 15 (585 mg, 2.75 mmol) and Amberlyst A-21
(59 mg, 0.275 mmol) and agitated for 20 h. The mixture was filtered,
and the resins were washed once with CH2Cl2. The combined filtrates
were concentrated under a stream of N2. The residue was retreated
with EDC HCl 28 (53 mg, 0.275 mmol) and dichloroacetic acid (0.3
M in DMSO, 0.9 mL) in 1:1 DMSO/CH2Cl2 (0.5 mL). After 24 h the
reaction was quenched into Amberlyst 15 (CMR/R resin 30: 585 mg,
2.75 mmol) and Amberlyst A-21 (CMR/R resin 31: 59 mg, 0.275
mmol) and agitated for 20 h. Filtration and concentration as before
yielded 27d as a yellow oil.
1-(6-Methyl-2-pyridyl)-3-buten-1-ol (36e): 99% mass yield; 1H
NMR (CDCl3): δ 2.55 (m,2H), 2.63 (s,3H), 4.85 (m,1H), 5.10 (m,-
2H), 5.88 (m,1H), 7.14 (m,2H), 7.66 (t,1H); HRMS m/z 163.0984
(C10H13N1O1 requires 163.0970); GC/MS purity (retention time): 99%
(5.53 min).
Utilization of Workup and Reactant Sequestering CMR/R Res-
ins: Reaction of n-Butyllithium Reactions with Carbonyl Com-
pounds. Under conditions of parallel reaction synthesis, a solution of
n-butyllithium (1.6 M solution in hexanes, 0.36 mL, 0.57 mmol) was
added to a solution of aldehyde 34 (0.50 mmol) in tetrahydrofuran
(freshly distilled) at -78 °C (acetone/CO2) and the resulting solution
stirred at rt for 2.5 h. Amberlite IRC-50S (CMR/R resin 37: 0.80-
1.0 g, 8-10 mmol, ∼10.0 mequiv/g) was added and stirred for 4 h.
The mixture was filtered, and the polymer was rinsed with tetrahy-
drofuran until no more UV activity was seen in the eluant. The solvent
was removed to afford the essentially pure carbinol products 36 (R2 )
n-butyl). Yields were in the range 75-94% with purity in the range
of 72-99%. Products were characterized by GC/MS, TLC, and proton
NMR.
Upon observation of the GC/MS of examples 36i and 36k, remaining
starting material carboxaldehyde was detected. To purify this reaction
mixture the following procedure was performed:
The residue was dissolved into dichloromethane and the polyamine
CMR/R resin 40 (0.50 g, 1.49 mmol) was added. The slurry was stirred
at rt for 5 h. The mixture was filtered, and the polymer was rinsed
with dichloromethane until no more UV activity was seen in the eluant.
The solvent was removed to afford the pure carbinols 36i and 36k.
1-(1-Naphthyl)-1-pentanol (36i):16 94% mass yield; 1H NMR
(CDCl3): δ 0.96 (t,3H), 1.43 (m,4H), 1.97 (m,2H), 2.18 (bs,1H), 5.48
(t,1H), 7.56 (m,3H), 766 (d,1H), 7.70 (d,1H), 7.93 (d,1H), 8.15 (d,-
1H); HRMS m/z 214.1363 (C15H18O1 requires 214.1357); GC/MS purity
(retention time): 97% (7.09 min).
Preparation of the Polyamine CMR/R Resin (40). Merrifield’s
resin (2% cross-linked, 325 g, 0.549 mol, 1.69 mmol/g) was added to
diethylenetriamine (955 g, 9.25 mol) and the mixture heated at 100 °C
for 4 h. The polymer was filtered and successively rinsed two times
N-[3-[[(4-Methylphenyl)sulfonyl](2-methylpropyl)amino]-2-oxo-
1(S)-(phenylmethyl)propyl]benzenepropanamide (27d): 61% mass
yield; 1H NMR (CDCl3, 300 MHz): δ 7.63 (d, J ) 8.0 Hz, 2H), 7.33-
7.13 (cb, 10H), 7.09 (dd, J ) 8,2 Hz, 2H), 5.96 (d, J ) 7 Hz, 1H),
4.75 (q, J ) 7, 1H), 4.11 (d, J ) 19 Hz, 1H), 3.91 (d, J ) 19 Hz, 1H),
(16) Compounds 11a, 13e, and 36a are known compounds whose spectral
characterizations have been previously reported. The proton and/or carbon
NMR data obtained by us for these compounds agree with those reported.
Compound 11a: Itai, A.; Toriumi, Y.; Tomioka, N.; Kagechika, H.;
Azumaya, I.; Shudo, K. Tetrahedron Lett. 1989, 30, 6177-6180. Compound
13e: Chang, Y. H.; Chia, F-T.; Zon, G. J. Org. Chem. 1981, 46, 342-354.
Compound 36a: Smith, G. G.; Voorhees, K. J. J. Org. Chem. 1970, 35,
2182-2185. Compounds 36h and 36i have been previously reported but
not fully characterized. For these two compounds complete analytical data
are reported herein. Compound 36h: Roblin, R. O., Jr.; Davidson, D.;
Bogert, M. T. J. Am. Chem. Soc. 1935, 57, 151-159. Compound 36i:
Condon, F. E.; Mitchell, G. J. Org. Chem. 1980, 45, 2009-2010.