M. J. Mul6ihill et al. / Tetrahedron Letters 42 (2001) 7751–7754
7753
afford stable, isolable intermediates 4a–c which then
were reacted with various carboxylic acids to afford
novel methoxyfenozide-N-[(acyloxy)benzyloxy]carbonyl
derivatives 5–7.
2.34 (s, 3H), 3.74 (s, 3H), 6.70–7.10 (m, 11H); 13C NMR
(75 MHz, CDCl3) l (ppm): 13.2, 21.9, 22.2, 28.5, 56.3,
63.8, 86.8, 112.4, 117.6, 123.7, 125.2, 126.9, 130.0, 131.7,
133.7, 137.3, 138.1, 139.0, 141.2, 152.4, 158.6, 170.3,
173.5; Anal. calcd for C31H35ClN2O5: C, 67.57; H, 6.40;
N, 5.08. Found: C, 67.65; H, 6.11; N, 5.36.
Acknowledgements
10. A typical reaction sequence in the synthesis of chlorofor-
mates 2a–c, compounds 4a–c, and compounds 5–7 is
represented by 2b, 4b, and 6a: Synthesis of compound 2b:
A 1000 mL diethyl ether solution of 2-methylbenzalde-
hyde (75.0 g, 620.0 mmol), cooled to −20°C, was charged
with triphosgene (205.0 g, 690.0 mmol) followed by pyri-
dine (6.0 mL, 62.0 mmol). The reaction was allowed to
warm to room temperature (rt) and stir for 2 h, after
which time the reaction mixture was filtered through
Celite®. The filtrate was concentrated in vacuo to afford
103 g of chloroformate 2b in 75% yield (95% purity by 1H
and 13C NMR). Chloroformate 2b (1.36 g, 6.20 mmol)
then was added in one portion to a 0°C THF solution of
the potassium salt of methoxyfenozide (3b), prepared by
treating methoxyfenozide 3a (1.92 g, 5.20 mmol) with
potassium tert-butoxide (0.58 g, 5.20 mmol) in 50 mL of
THF at rt. The reaction was allowed to warm to rt and
stir for 4 h, after which time the solvent was removed in
vacuo and the crude mixture subjected to silica gel
column chromatography (90:10 hexanes/EtOAc) to
afford 2.0 g (70%) of the desired compound 4b. Prepara-
tion of compounds 5–7 via parallel synthesis: Synthesis of
compound 6a: Cs2CO3 (70 mg, 0.22 mmol) in 500 mL
DMF was delivered to a 96 well reaction block (496
MBS, Advanced Chemtech) followed by acetic acid (13
mg, 0.22 mmol). The block was stirred at rt for 30 min,
at which time a solution of 4b (100 mg, 0.18 mmol in 500
mL DMF) was delivered. Stirring was continued at rt for
up to 48 h. The reaction was filtered into the cleavage
block, the solvent was removed in a Genevac HT-12 and
the residue was taken up in CH2Cl2 and chro-
matographed on a preconditioned (hexanes) 2 g silica
solid phase extraction cartridge (gradient of hexanes to
1:1 hexanes/EtOAc) yielding 65 mg (65%) of compound
6a as a white solid; mp=70–72°C; IR w (cm−1): 2945,
We thank Drs. Dennis Patterson and Harvey Scribner
for many fruitful discussions and support of the project
and Kristen M. Mulvihill for her help in preparation of
the manuscript.
References
1. Thomson, W. T. Agricultural Chemicals, Book 1, Insecti-
cides, 14th ed.; Thomson Publications: Fresno, CA, 1998;
pp. 142–144.
2. Lidert, Z.; Le, D. P.; Hormann, R. E.; Opie, T. R. US
5530028, Chem. Abstr. 1996, 125, 161132.
3. Tomlin, C. D. S. The Pesticide Manual, 11th ed.; British
Crop Protection Council: Farnham, Surrey GU9 7PH,
UK, 1997; pp. 388–389.
4. Mulvihill, M. J.; MacDougall, B. S.; Ajello, C.; Martinez-
Teipel, B.; Joseph, R.; Weaver, D. G.; Nguyen, D. V.;
Gusev, A.; Weirenga, J. M.; Mathis, W. D. Synthesis
2001, submitted for publication.
5. Silverman, R. B. The Organic Chemistry of Drug Design
and Drug Action; Academic Press: San Diego, CA, 1992;
pp. 361–363.
6. Folkmann, M.; Lund, F. J. Synthesis 1990, 1159–1166.
7. Coghlan, M. J.; Caley, B. A. Tetrahedron Lett. 1989, 30,
2033–2036 and references cited therein.
8. Compounds 2a–c: Chloroformate 2a was synthesized via
the carbon tetrachloride route while chloroformates 2b,c
were synthesized via the diethyl ether route. All chloro-
formates 2a–c were directly carried on to the next reac-
tion (due to thermal stability issues) with the potassium
salt of methoxyfenozide to afford stable, isolable com-
pounds 4a–c which were fully characterized as described
below in Ref. 9.
1
1767, 1711, 1675; H NMR (300 MHz, CDCl3) l (ppm):
1.64 (s, 9H), 1.95 (bs, 3H), 2.05 (s, 3H), 2.08 (s, 6H), 2.35
(s, 3H), 3.74 (s, 3H), 6.68–7.32 (m, 10H), 7.64 (bs, 1H);
13C NMR (75 MHz, CDCl3) l (ppm): 12.7, 18.9, 20.7,
21.0, 27.5, 55.4, 62.7, 91.0, 111.2, 116.7, 122.7, 124.1,
125.8, 126.2, 127.5, 130.2, 130.6, 131.0, 131.9, 136.3,
136.7, 137.3, 138.0, 151.3, 157.5, 168.3, 169.6, 172.6;
Anal. calcd for C33H38N2O7: C, 68.97; H, 6.67; N, 4.87.
Found: C, 69.08; H, 6.72; N, 4.90.
9. Compounds 4a–c: Compound 4a: mp=103–105°C; IR w
1
(cm−1): 1766, 1712, 1676; H NMR (300 MHz, CDCl3) l
(ppm): 1.62 (s, 9H), 1.95 (bs, 3H), 2.20 (s, 6H), 3.77 (s,
3H), 6.70–7.30 (m, 12H); 13C NMR (75 MHz, CDCl3): l
(ppm): 14.5, 23.3, 29.8, 57.6, 65.1, 88.0, 113.7, 118.9,
125.0, 126.5, 128.3, 130.7, 132.4, 133.0, 137.8, 138.5,
139.4, 140.3, 153.7, 159.9, 171.6, 174.9; Anal. calcd for
C30H33ClN2O5: C, 67.09; H, 6.19; N, 5.22. Found: C,
66.88; H, 6.09; N, 5.15. Compound 4b: mp=111–113°C;
11. Compound 6a was fully characterized as a representative
example of this class of chemistry as described in Ref. 10.
Compounds 5a–l, 6b–h, and 7a–m were prepared via
parallel synthesis and analyzed by LC/UV/MS as pre-
sented in Table 1.
12. For liquid chromatography (LC)/ultraviolet (UV) mass
spectrometry (MS) analysis, the samples were dissolved in
CH3CN:H2O (1:1) at concentrations of 100 mg/mL to
1000 mg/mL. The LC/UV/MS analysis was performed
using the HPLC 1100-VG Platform. The UV and MS
instruments were connected in sequence, and the analysis
was carried out in one injection where LC/UV afforded
the purity (%) and MS confirmed the molecular weight.
1
IR w (cm−1): 2949, 1765, 1712, 1677; H NMR (300 MHz,
CDCl3) l (ppm): 1.61 (s, 9H), 1.95 (bs, 3H), 2.16 (bs,
6H), 2.24 (s, 3H), 3.72 (s, 3H), 6.62–7.27 (m, 11H); 13C
NMR (75 MHz, CDCl3) l (ppm): 12.4, 18.6, 21.0, 27.6,
55.3, 62.9, 83.5, 111.5, 116.8, 122.8, 124.2, 126.1, 126.2,
126.3, 129.9, 130.6, 130.7, 133.6, 134.4, 136.2, 137.2,
138.1, 151.7, 157.6, 169.3, 172.6; Anal. calcd for
C31H35ClN2O5: C, 67.57; H, 6.40; N, 5.08. Found: C,
67.69; H, 6.15; N, 5.05. Compound 4c: mp=123–125°C;
IR w (cm−1): 1766, 1713, 1676; 1H NMR (300 MHz,
CDCl3) l (ppm): 1.58 (s, 9H), 1.95 (bs, 3H), 2.18 (s, 6H),