J. Org. Chem.

2000, 65, 5043-5047 5043

Free-Radical Reaction of Imine Derivatives Scheme 1

in Water

Hideto Miyabe, Masafumi Ueda, and Takeaki Naito*

Kobe Pharmaceutical University, Motoyamakita,
Higashinada, Kobe 658-8558, Japan

E-mail: taknaito@kobepharma-u.ac.jp

Received March 6, 2000

The use of water as a solvent has generated consider-
able interest from both economical and environmental
points of view.1 Particularly, the carbon-carbon bond
formation in aqueous media is a challenging problem.2
The carbon-nitrogen double bond of imine derivatives
has emerged as a radical acceptor, and thus numerous,
synthetically useful carbon-carbon bond-forming reac-
tions are available.3 However, the reactions of water-
sensitive imines have generally been performed in or-
ganic solvents under anhydrous reaction conditions.4,5 In glyoxylic oxime ether 1 because it had shown good
principle, the reactions of a strictly neutral species such reactivity in organic solvents (Scheme 1).8,9 To a solution
as uncharged free radicals are not affected by the of oxime ether 1 in water/methanol (1:1, v/v) were added
presence of water.6 We now report the results of experi- isopropyl iodide (30 equiv) and a commercially available
ments to prove the utility of imine derivatives in the 1.0 M solution of triethylborane in hexane (5 equiv),3 and
aqueous-medium radical reactions. As shown below, the then the biphasic reaction mixture was stirred vigorously
screening of several imines shows that oxime ethers, at 20 °C for 2 h. 1H NMR measurement of the crude
oximes, hydrazones, and nitrones may participate in the product showed almost quantitative conversion of 1 to
aqueous-medium radical reactions involving the con- the adduct 2. The R-amino acid derivative 2 was obtained
struction of the carbon-carbon bond. Another remark- in 99% yield after purification by preparative TLC. It is
able feature of this reaction is that employment of a noteworthy that triethylborane worked well as a radical
water-resistant radical species successfully integrated a initiator and a terminator to trap the intermediate
multistep chemical reaction into a one-pot reaction, thus aminyl radical even in the biphasic reaction to give a
providing a convenient method for preparing R-amino chain-propagating ethyl radical.
acid derivatives in water. We next chose the imine derivatives 3-6 as a model
substrate and investigated several reaction conditions for
Results and Disscusion an ethyl radical addition (Figure 1, Table 1). Oxime ether
3 having a free carboxyl group showed high solubility in
Among the different types of imines, the oxime ethers water, and the biphasic reaction using a solution of
are well-known to be excellent radical acceptors.7 We first triethylborane in hexane proceeded within 10 min. After
investigated the aqueous-medium radical addition to concentration of the reaction mixture at reduced pres-
sure,1H NMR measurement of the crude product showed
(1) Garner, P. P.; Parker, D. T.; Gajewski, J. J.; Lubineau, A.; Angé, almost quantitative formation of the ethylated product
J.; Queneau, Y.; Beletskaya, I. P.; Cheprakov, A. V.; Fringuelli, F.;
Piermatti, O.; Pizzo, F.; Kobayashi, S. Organic Synthesis in Water;
Grieco, P. A., Ed.; Blackie Academic & Professional: London, 1998. (7) For some examples of the radical reaction of oxime ethers, see:
(2) For reviews, see: (a) Li, C. J. Chem. Rev. 1993, 93, 2023. (b) (a) Miyabe, H.; Torieda, M.; Inoue, K.; Tajiri, K.; Kiguchi, T.; Naito, T.
Lubineau, A.; Angé, J.; Queneau, Y. Synthesis 1994, 741. (c) Li, C. J. J. Org. Chem. 1998, 63, 4397. (b) Iserloh, U.; Curran, D. P. J. Org.
Tetrahedron 1996, 52, 5643. Chem. 1998, 63, 4711. (c) Boiron, A.; Zillig, P.; Faber, D.; Giese, B. J.
(3) For reviews, see: (a) Naito, T. Heterocycles 1999, 50, 505. (b) Org. Chem. 1998, 63, 5877. (d) Marco-Contelles, J.; Balme, G.; Bouyssi,
Fallis, A. G.; Brinza, I. M. Tetrahedron 1997, 53, 17543. D.; Destabel, C.; Henriet-Bernard, C. D.; Grimaldi, J.; Hatem, J. M.
(4) (a) Bloch, R. Chem. Rev. 1998, 98, 1407. (b) Enders, D.; Reinhold, J. Org. Chem. 1997, 62, 1202.
U. Tetrahedron Asymmetry 1997, 8, 1895. (c) Denmark, S. E.; Nicaise, (8) Because the glyoxylic oxime ether is activated by an electron-
O. J.-C. Chem. Commun. 1996, 999. withdrawing substituent, it has high reactivity toward nucleophilic
(5) For some examples of reactions of imines in water, see: (a) carbon radicals. See: (a) Miyabe, H.; Ushiro, C.; Naito, T. Chem.
Petasis, N. A.; Zavialov, I. A. J. Am. Chem. Soc. 1998, 120, 11798. (b) Commun. 1997, 1789. (b) Miyabe, H.; Fujishima, Y.; Naito, T. J. Org.
Petasis, N. A.; Zavialov, I. A. J. Am. Chem. Soc. 1997, 119, 445. (c) Chem. 1999, 64, 2174. (c) Miyabe, H.; Yoshioka, N.; Ueda, M.; Naito,
Petasis, N. A.; Goodman, A.; Zavialov, I. A. Tetrahedron 1997, 53, T. J. Chem. Soc., Perkin Trans. 1 1998, 3659. (d) Miyabe, H.; Ueda,
16463. (d) Kobayashi, S.; Busujima, T.; Nagayama, S. Chem. Commun. M.; Yoshioka, N.; Naito, T. Synlett 1999, 465. (e) Miyabe, H.; Ushiro,
1998, 19. C.; Ueda, M.; Yamakawa, K.; Naito, T. J. Org. Chem. 2000, 65, 176.
(6) Triethylborane can be applied to the radical reactions in water. For the complete reaction and selective alkylation, the excesses of
For discussion of triethylborane-mediated radical reactions in aqueous reagents were employed. For example, treatment of oxime ether 1 with
media, see: (a) Yamazaki, O.; Togo, H.; Nogami, G.; Yokoyama, M. isopropyl iodide (1 equiv) and a commercially available 1.0 M solution
Bull. Chem. Soc. Jpn. 1997, 70, 2519. (b) Yorimitsu, H.; Nakamura, of triethylborane in hexane (1 equiv) in water gave the isopropylated
T.; Shinokubo, H.; Oshima, K. J. Org. Chem. 1998, 63, 8604. (c) adduct 2 (13%) accompanied by the ethylated adduct (13%) and the
Nakamura, T.; Yorimitsu, H.: Shinokubo, H.: Oshima, K. Synlett 1998, recovered oxime ether 1 (70%).
1351. Alkyl radical can be generated via sonication of alkyl iodide in (9) Bertrand’s group recently reported their studies on the radical
the presence of Zn/CuI in water. See: (d) Petrier, C.; Dupuy, C.; Luche, addition to glyoxylic imines. See: (a) Bertrand, M. P.; Feray, L.;
J. L. Tetrahedron Lett. 1986, 27, 3149. (e) Giese, B.; Damm, W.; Roth, Nouguier, R.; Stella, L. Synlett 1998, 780. (b) Bertrand, M. P.; Feray,
M.; Zehnder, M. Synlett 1992, 441. (f) Erdmann, P.; Schäfer, J.; L.; Nouguier, R.; Perfetti, P. Synlett 1999, 1148. (c) Bertrand, M. P.;
Springer, R.; Zeitz, H.-G.; Giese, B. Helv. Chim. Acta 1992, 75, 638. Feray, L.; Nouguier, R.; Perfetti, P. J. Org. Chem. 1999, 64, 9189.

10.1021/jo000318+ CCC: $19.00 © 2000 American Chemical Society

Published on Web 07/08/2000
5044 J. Org. Chem., Vol. 65, No. 16, 2000 Notes

Scheme 2

Figure 1. Imine derivatives 3-6 and ethylated products

7-10.

Table 1. Ethyl Radical Addition to Glyoxylic Imines 3-6

sub- time yield
entry strate solvent product (min) (%)
1a 3 H2O 7 10 99d
2a 3 H2O/MeOH, 1:1 7 30 99d
3b 3 H2O 7 10 99d
4a 4 H2O 8 10 17 (82)d
5a 4 H2O 8 120 36 (63)d
6a 4 H2O 8 1200 44 (54)d
7a 5 H2O 9 120 71 (28)d
8c 5 H2O/MeOH, 1:5 9 50 52e
9a 6 H2O/MeOH, 1:1 10a/10b, 0.8:1 10 16 (83)d
Subsequently, the aqueous-medium radical reactions
10a 6 H2O/MeOH, 1:1 10a/10b, 3.7:1 1200 80 (2)e
of a variety of nonglyoxylic imine derivatives were tested
a Reaction was carried out with Et B in hexane (5 equiv) at 20
3 (Scheme 2). The ethyl radical addition to formaldoxime
°C. b Reaction was carried out with Et3B in THF (5 equiv) at 20
°C. c Reaction was carried out with Et3B in hexane (10 equiv) at
ether 1113 proceeded smoothly at 20 °C by using a
20 °C. d Yields based on 1H NMR. Yields in parentheses are for solution of triethylborane in MeOH to give a good yield
the recovered starting material. e Isolated yields. of alkylated product 12a. In the case of isopropyl radical
addition using isopropyl iodide, the product 12b was also
7 (Table 1, entry 1). The biphasic reaction also proceeded obtained with excellent chemical efficiency. In our recent
in aqueous methanol without any problem (entry 2). The studies, the activation of an oxime ether group with BF3‚
monophasic reaction using a commercially available OEt2 was found to be essential to achieve the intermo-
solution of triethylborane in THF gave a similar good lecular radical reaction of unactivated aldoxime ethers
result (entry 3). Although oxime 4, hydrazone 5, and such as benzaldehyde O-benzyloxime 13 in an organic
nitrone 6 also acted as radical acceptors in water, their solvent.14 It is important to note that the aqueous-
reactivities were quite different from those of oxime medium radical addition to 13 proceeded with the activa-
ethers 1 and 3.10 Reactions of water-soluble oxime 4 were tion of 1 N NH4Cl to give alkylated product 14 in 67%
run in water by using the solution of triethylborane in yield, whereas the reaction of 13 in H2O/MeOH (1:3, v/v)
hexane (entries 4 and 5), and more than half of the did not take place. To test the intramolecular reactivity
starting material remained even after being stirred for of the oxime ether group, we next investigated the
20 h. In the case of hydrazone 5,11 the diethylated product tandem radical cyclization of oxime ether 15. Treatment
9 was obtained as a result of the additional N-ethylation. of oxime ether 15 with triethylborane and isopropyl
Although hydrazone 5 was insoluble in water, good iodide in water at 80 °C gave the cyclized product 16 in
conversion was observed in the reaction using a stirred 62% yield via two carbon-carbon bond-forming steps.15
suspension of 5 in water alone (entry 7). The reaction of The radical alkylation of a heteroaromatic compound
hydrazone 5 in a mixed-solvent system such as aqueous having a nitrogen atom was also studied in acidic
methanol proceeded to give the diethylated product 9 in aqueous solution. Treatment of a solution of lepidine 17
52% yield within 50 min accompanied with unidentified in 3 N HCl with a solution of triethylborane in THF gave
complex products (entry 8). Although the aqueous- the ethylated product 18 in 62% yield.
medium radical reaction of nitrone 612 took long reaction In the field of combinatorial chemistry, integration of
time, a 3.7:1 mixture of the diethylated product 10a and a multistep chemical reaction into a one-pot reaction has
monoethylated product 10b was obtained in 80% com- (13) The radical addition to formaldoxime ether 11 in organic
bined yield (entry 10). solvents, see: (a) Hart, D. J.; Seely, F. L. J. Am. Chem. Soc. 1988,
110, 1631. (b) Bhat, B.; Swayze, E. E.; Wheeler, P.; Dimock, S.; Perbost,
M.; Sanghvi, Y. S. J. Org. Chem. 1996, 61, 8186.
(10) Oxime ether 3 and oxime 4 showed high solubility in water; (14) (a) Miyabe, H.; Shibata, R.; Ushiro, C.; Naito, T. Tetrahedron
however, hydrazone 5 and nitrone 6 were insoluble in water. Lett. 1998, 39, 631. (b) Miyabe, H.; Fujii, K.; Naito, T. Org. Lett. 1999,
(11) For some examples of the radical reaction of hydrazones, see: 1, 569. (c) Miyabe, H.; Shibata, R.; Sangawa, M.; Ushiro, C.; Naito, T.
(a) Grissom, J. W.; Klingberg, D.; Huang, D.; Slattery, B. J. J. Org. Tetrahedron 1998, 54, 11431. (d) Russell, G. A.; Lijuan, W.; Rajarat-
Chem. 1997, 62, 603. (b) Tauh, P.; Fallis, A. G. J. Org. Chem. 1999, nam, R. J. Org. Chem. 1996, 61, 8988.
64, 6960. (15) The radical alkylation was generally performed in the presence
(12) Nitrones have evolved as a useful trap for short-lived reactive of TFA or BF3‚OEt2 in an organic solvent. See: Togo, H.; He, W.; Waki,
free radicals. See: Becker, D. A. D. J. Am. Chem. Soc. 1996, 118, 905. Y.; Yokoyama, M. Synlett 1998, 700.
Notes J. Org. Chem., Vol. 65, No. 16, 2000 5045

Scheme 3 2-(Benzyloxyimino)ethanoic Acid (3). To a solution of

glyoxylic acid monohydrate (5.0 g, 54 mmol) in MeOH (250 mL)
were added benzyloxyamine hydrochloride (13.0 g, 82 mmol) and
AcONa (8.9 g, 109 mmol) under a nitrogen atmosphere at 20
°C. After the mixture was stirred at the same temperature for
12 h, the solvent was evaporated at reduced pressure, and the
resulting residue was added to water and CH2Cl2. The layers
were separated, and the aqueous phase was extracted with
CH2Cl2. The combined organic phase was dried over MgSO4 and
concentrated at reduced pressure. Purification of the residue by
recrystallization (AcOEt/hexane) afforded oxime ether (6.88 g,
71%) as a 2:1 mixture of E/Z-oxime. 1H NMR (CDCl3): δ 7.50
(2/3H, s), 7.29 (5H, s), 7.27 (1/3H, s), 5.18 (4/3, s), 4.89 (2/3, s).
13C NMR (CDCl ): δ 165.6, 142.5, 136.0, 135.5, 128.6, 128.43,
3
128.41, 128.29, 128.25, 77.6, 77.5. HRMS: calcd for C9H9NO3
attracted significant attention as a rapid synthetic (M+), 179.0582; found, 179.0569.
method of creating a compound library from simple Methyl 2-(Hydroxyimino)ethanoate (4). To a solution of
building blocks.16 Finally, the tolerance of the aqueous methyl 2-hydroxy-2-methoxyacetate (5.0 g, 41.6 mmol) in MeOH
media prompted us to examine a one-pot radical reaction (50 mL) were added hydroxylamine hydrochloride (4.3 g, 62.4
for the synthesis of R-amino acids in water (Scheme 3). mmol) and AcONa (6.8 g, 83.3 mmol) under nitrogen atmosphere
at 20 °C. After being stirred at the same temperature for 2 h,
Conventional condensation of glyoxylic acid hydrate 19 the reaction mixture was filtered and evaporated at reduced
with benzyloxyamine hydrochloride proceeded smoothly pressure. Purification of the residue by a combination of flash
in water. Subsequently, alkyl iodide (RI) and triethyl- column chromatography (hexane/AcOEt, 1:1) and recrystalliza-
borane were added to the reaction vessel to afford tion from hexane afforded 4 (3.7 g, 86%) as a white solid. IR
excellent yields of R-amino acid derivatives 20a-d after (CHCl3): 3268, 1740 cm-1. 1H NMR (CDCl3): δ 7.59 (1H, s), 3.87
the purification. It should be noted that the one-pot (3H, s). 13C NMR (CDCl3): δ 162.6, 141.7, 52.5. HRMS: calcd
for C3H5NO3 (M+), 103.0269; found, 103.0265.
reactions in water were much more effective compared N-Benzyl-R-Methoxycarbonylnitrone (6). To a solution of
to the reactions in an organic solvent such as toluene and methyl 2-hydroxy-2-methoxyacetate (0.94 g, 7.8 mmol) in Et2O
CH2Cl2.8c,d Moreover, the present method is more conve- (80 mL) were added N-benzylhydroxylamine (0.96 g, 7.8 mmol)
nient and milder than methods employing other multi- and calcium chloride (0.87 g, 7.8 mmol) under nitrogen atmo-
component routes to R-amino acids such as the Strecker sphere at 20 °C. After being stirred at the same temperature
and Ugi syntheses. for 3 h, the reaction mixture was filtered through a pad of Celite
diatomaceous earth, and then the filtrate was concentrated at
In conclusion, we have demonstrated that imine de- reduced pressure. Purification of the residue by recrystallization
rivatives such as oxime ethers, hydrazones, and nitrones from petroleum ether afforded an E/Z mixture of 6 (0.65 g, 43%)
are excellent radical acceptors for the aqueous-medium as a white solid. IR (CHCl3): 3014, 1731, 1698, 1558, 1456 cm-1.
radical reactions. Furthermore, the carbon radical addi- 1H NMR (CDCl ): δ 7.55-7.33 (5H, m), 7.22 (8/13H, s), 7.06 (5/
3
tion to imine derivatives presents new opportunities for 13H, s), 5.71 (16/13H, s), 5.00 (10/13H, s), 3.81 (24/13H, s), 3.78
the carbon-carbon bond formation in water. Employment (15/13H, s). 13C NMR (CDCl3): δ 161.3, 160.4, 133.2, 131.5,
129.53, 129.49, 129.2, 129.1, 128.8, 128.6, 126.5, 124.8, 73.3, 66.4,
of a water-resistant radical species would eliminate the 52.1, 51.8. HRMS: calcd for C10H11NO3 (M+), 193.0738; found,
cumbersome operations and protection-deprotection step 193.0721.
involved in conventional ionic reactions. 2-(Benzyloxyamino)butanoic Acid (7). To a solution of
2-(benzyloxyimino)ethanoic acid 3 (50 mg, 0.28 mmol) in H2O
Experimental Section (10 mL) was added Et3B (1.0 M in hexane, 1.4 mL, 1.4 mmol) at
20 °C. After being stirred at the same temperature for 10 min,
General Methods. Melting points are uncorrected. 1H and the reaction mixture was concentrated at reduced pressure. 1H
13C NMR spectra were recorded at 200 or 300 MHz and at 50 or NMR measurement of the resulting residue showed almost
125 MHz, respectively. IR spectra were recorded using FTIR quantitative formation of the ethylated product 7 (Table 1, entry
apparatus. Mass spectra were obtained by EI, CI, or SIMS 1). 1H NMR (CD3OD): δ 7.34-7.26 (5H, m), 4.68 (2H, s), 3.50
methods. Preparative TLC separations were carried out on (1H, br t, J ) 10.2 Hz), 1.58 (2H, m), 0.95 (3H, t, J ) 7.4 Hz).
13C NMR (CD OD): δ 177.2, 138.9, 129.4, 129.1, 128.7, 76.9, 66.1,
precoated silica gel plates (E. Merck 60F254). Flash column 3
chromatography was performed using E. Merck Kieselgel 60 23.6, 10.7. HRMS: calcd for C11H15NO3 (M+), 209.1051; found,
(230-400 mesh). Integrative fractions of 1H NMR of the com- 209.1064.
pounds obtained as an a:b mixture of E/Z isomers and/or Methyl 2-(Hydroxylamino)butanoate (8). To a solution of
rotamers were described as a/bH. The NMR yields were calcu- methyl 2-(hydroxyimino)ethanoate 4 (50 mg, 0.49 mmol) in H2O
lated from the peak ratio due to both the products and starting (10 mL) was added Et3B (1.0 M in hexane, 2.4 mL, 2.4 mmol) at
material in the 1H NMR of almost pure crude product obtained 20 °C. After being stirred at the same temperature for 10, 120,
by concentration of the reaction mixture. or 1200 min, the reaction mixture was concentrated at reduced
Isopropyl Radical Addition to Oxime Ether 1. To a pressure. Yield was determined by 1H NMR measurement of the
solution of oxime ether 114c (50 mg, 0.26 mmol) in H2O/MeOH resulting residue without purification (Table 1, entries 4-6). IR
(1:1, 10 mL) were added i-PrI (0.78 mL, 7.8 mmol) and Et3B (CHCl3): 3583, 2955, 1736, 1461 cm-1. 1H NMR (CDCl3): δ 3.78
(1.0 M in hexane, 1.3 mL, 1.3 mmol) at 20 °C. After the mixture (3H, s), 3.60 (1H, t, J ) 6.8 Hz), 1.73-1.58 (2H, m), 0.97 (3H, t,
was stirred at the same temperature for 2 h, the solvent was J ) 7.5 Hz). 13C NMR (CDCl3): δ 174.2, 66.4, 51.9, 22.5, 10.2.
evaporated at reduced pressure. The resulting residue was HRMS: calcd for C5H11NO3 (M+), 133.0738; found, 133.0725.
diluted with saturated aqueous NaHCO3 and then extracted Carboxylic acid 8 was purified by preparative TLC (hexane/
with CH2Cl2. The organic phase was dried over MgSO4 and AcOEt, 2:1, 2-fold development).
concentrated at reduced pressure. Purification of the residue by Methyl 2-(N′-Ethyl-N,N-diphenylhydrazino)butanoate
preparative TLC (hexane/AcOEt, 12:1) afforded 214c (61 mg, 99%) (9). To a solution of methyl 2-(diphenylaminoimino)ethanoate
as a colorless oil. 514c (50 mg, 0.20 mmol) in H2O/MeOH (1:5, 10 mL) was added
Et3B (1.0 M in hexane, 2.0 mL, 2.0 mmol) at 20 °C. After being
(16) For reviews, see: (a) Brown, R. C. D. J. Chem. Soc., Perkin
stirred at the same temperature for 50 min, the reaction mixture
Trans. 1 1998, 3293. (b) Chem. Rev. 1997, 97, 347-510 (Special Issue). was concentrated at reduced pressure. Purification of the residue
(c) Hermkens, P. H. H.; Ottenheijm, H. C. J.; Rees, D. C. Tetrahedron by preparative TLC (hexane/AcOEt, 5:1, 2-fold development)
1997, 53, 5643. afforded 914c (29 mg, 52%) as a colorless oil (Table 1, entry 8).
5046 J. Org. Chem., Vol. 65, No. 16, 2000 Notes

Methyl 2-(N-Benzyl-N-ethoxyamino)butanoate (10a) and hexane). IR (CHCl3): 3600-3300 cm-1. 1H NMR (CDCl3): δ 7.49
Methyl 2-(N-Benzyl-N-hydroxylamino)butanoate (10b). To (3/5H, t, J ) 5.2 Hz), 7.38-7.25 (5H, m), 6.79 (2/5H, t, J ) 4.4
a solution of N-benzyl-R-methoxycarbonylnitrone 6 (50 mg, 0.26 Hz), 5.10 (4/5H, s), 5.07 (6/5H, s), 3.65-3.57 (2H, m), 3.56 (4/
mmol) in H2O/MeOH (1:1, 10 mL) was added Et3B (1.0 M in 5H, d, J ) 4.4 Hz), 3.38 (6/5H, d, J ) 5.2 Hz), 2.78-2.70 (2H,
hexane, 1.3 mL, 1.3 mmol) at 20 °C. After being stirred at the m). 13C NMR (CDCl3): δ 151.3, 149.0, 137.6, 137.4, 128.3, 128.2,
same temperature for 10 or 1200 min, the reaction mixture was 128.0, 127.8, 76.1, 75.8, 60.8, 60.7, 51.0, 50.6, 47.7, 44.4.
concentrated at reduced pressure. Purification of the residue by HRMS: calcd for C11H17N2O2 (M + H+), 209.1289; found,
preparative TLC (hexane/AcOEt, 5:1, 2-fold development) af- 209.1271. Anal. Calcd for C11H16N2O2: C, 63.44; H, 7.74; N, 13.45.
forded 10a and 10b as a colorless oil (Table 1, entries 9 and Found: C, 63.43; H, 7.76; N, 13.50.
10). To a solution of N-(2-hydroxyethyl)aminoethanal O-benzyl-
10a. IR (CHCl3): 2976, 1604, 1495, 1455 cm-1. 1H NMR oxime (6.15 g, 29.6 mmol) in acetone (100 mL) was added a
(CDCl3): δ 7.40-7.22 (5H, m), 3.99 (1H, d, J ) 13.3 Hz), 3.91 solution of Na2CO3 (6.28 g, 59.2 mmol) in H2O (25 mL) at 20 °C.
(1H, d, J ) 13.3 Hz), 3.75 (3H, s), 3.52-3.35 (3H, m), 1.89-1.74 After acryloyl chloride (4.83 mL, 59.2 mmol) was added dropwise
(2H, m), 0.95 (3H, t, J ) 7.4 Hz), 0.91 (3H, t, J ) 7.1 Hz). 13C at 0 °C, the reaction mixture was stirred at the same temper-
NMR (CDCl3): δ 172.1, 137.6, 129.8, 127.9, 127.1, 70.2, 69.1, ature for 30 min. After the solvent was evaporated at reduced
59.3, 51.3, 22.9, 13.6, 10.4. HRMS: calcd for C14H21NO3 (M+), pressure, the resulting residue was diluted with water and then
251.1520; found, 251.1517. extracted with AcOEt. The organic phase was dried over MgSO4
10b. IR (CHCl3): 3572, 2954, 1737, 1496, 1455 cm-1. 1H NMR and concentrated at reduced pressure. Purification of the residue
(CDCl3): δ 7.38-7.23 (5H, m), 5.56 (1H, br s), 3.96 (2H, s), 3.76 by flash column chromatography (CHCl3/MeOH, 30:1) afforded
(3H, s), 3.40 (1H, t, J ) 7.0 Hz), 1.94-1.79 (2H, m), 0.98 (3H, t, 15 (6.72 g, 87%) as an oil. The presence of rotamers and E/Z
J ) 7.5 Hz). 13C NMR (CDCl3): δ 173.0, 137.2, 129.2, 128.3, isomers precluded a comprehensive assignment of all protons.
127.3, 70.0, 61.1, 51.5, 22.9, 10.3. HRMS: calcd for C12H17NO3 IR (CHCl3): 2936, 1647, 1611 cm-1. 1H NMR (CDCl3): 7.50 (1/
(M+), 223.1207; found, 223.1201. 4H, t, J ) 5.1 Hz), 7.43 (1/4H, t, J ) 4.8 Hz), 7.40-7.25 (5H,
O-Benzyl-N-propylhydroxylamine (12a). To a solution of m), 6.80-6.25 (5/2H, m), 5.72-5.64 (1H, m), 5.13 (1/2H, s), 5.11
oxime ether 1113 (50 mg, 0.37 mmol) in H2O/MeOH (1:1, 10 mL) (1/2H, s), 5.06 (1/2H, s), 5.04 (1/2H, s), 4.31 (1H, 2d, J ) 6.0, 4.2
was added Et3B (1.0 M in MeOH, 1.85 mL, 1.85 mmol) at 20 °C. Hz), 4.12 (1H, br d, J ) 4.8 Hz), 3.80-3.40 (5H, m). 13C NMR
After the mixture was stirred at the same temperature for 5 (CDCl3): δ 168.1, 167.7, 167.4, 167.2, 149.1, 148.4, 147.1, 145.7,
min, the solvent was evaporated at reduced pressure. The 137.5, 137.1, 129.7, 129.3, 128.7, 128.6, 128.5, 128.43, 128.36,
resulting residue was diluted with saturated aqueous NaHCO3 128.33, 128.25, 128.1, 128.0, 127.7, 127.5, 127.3, 126.9, 76.7, 76.3,
and then extracted with CH2Cl2. The organic phase was dried 76.2, 76.0, 61.2, 61.1, 60.2, 60.0, 51.0, 50.8, 50.5, 50.4, 48.4, 45.6,
over MgSO4 and concentrated at reduced pressure. Purification 45.4, 43.3. HRMS: calcd for C14H18N2O2 (M+), 262.1317; found,
of the residue by flash column chromatography (hexane/AcOEt, 262.1318.
8:1) afforded 12a14c (50 mg, 82%) as a colorless oil. Radical Cyclization of Oxime Ether (15). To a suspension
O-Benzyl-N-(2-methylpropyl)hydroxylamine (12b). To a of oxime ether 15 (100 mg, 0.382 mmol) in H2O (3 mL) were
solution of oxime ether 11 (50 mg, 0.37 mmol) in H2O/MeOH added iPrI (1.14 mL, 11.5 mmol) and Et3B (1.0 M in hexane,
(1:1, 10 mL) were added i-PrI (1.1 mL, 11.1 mmol) and Et3B 1.15 mL, 1.15 mmol) at 80 °C. After being stirred at the same
(1.0 M in MeOH, 1.85 mL, 1.85 mmol) at 20 °C. After the mixture temperature for 20 min, the reaction mixture was diluted with
was stirred at the same temperature for 5 min, the solvent was saturated aqueous NaHCO3 and then extracted with CH2Cl2.
evaporated at reduced pressure. The resulting residue was The organic phase was dried over MgSO4 and concentrated at
diluted with saturated aqueous NaHCO3 and then extracted reduced pressure. Purification of the residue by preparative TLC
with CH2Cl2. The organic phase was dried over MgSO4 and (AcOEt) afforded a trans/cis mixture of 16 (74 mg, 63%) as a
concentrated at reduced pressure. Purification of the residue by colorless oil. IR (CHCl3): 2959, 1674, 1670, 1489, 1467, 1455
flash column chromatography (hexane/AcOEt, 8:1) afforded 12b cm-1. 1H NMR (CDCl3): δ 7.40-7.25 (5H, m), 4.70 (4/3H, s), 4.69
(66 mg, 99%) as a colorless oil. IR (CHCl3): 3011, 2959, 1496, (1/3H, d, J ) 11.8 Hz), 4.66 (1/3H, d, J ) 11.8 Hz), 3.79-3.23
1469, 1454 cm-1. 1H NMR (CDCl3): δ 7.38-7.25 (5H, m), 4.70 (7H, m), 2.57 (1/3H, m), 2.34 (2/3H, m), 1.82-1.21 (3H, m), 0.928
(2H, s), 2.74 (2H, d, J ) 6.8 Hz), 1.88 (1H, m), 0.91 (6H, d, J ) (6/3H, d, J ) 6.2 Hz), 0.926 (3/3H, d, J ) 6.2 Hz), 0.911 (3/3H,
6.6 Hz). 13C NMR (CDCl3): δ 137.9, 128.3, 127.6, 75.9, 59.8, 25.8, d, J ) 6.2 Hz), 0.908 (6/3H, d, J ) 6.2 Hz). 13C NMR (CDCl3):
20.5. HRMS: calcd for C11H17NO (M+), 179.1309; found, 179.1328. δ 176.7, 176.3, 137.3, 137.0, 128.64, 128.61, 128.4, 128.3, 128.1,
O-Benzyl-N-(2-methyl-1-phenylpropyl)hydroxylamine 128.0, 76.7, 76.4, 60.5, 60.4, 59.6, 56.2, 51.24, 51.19, 46.0, 45.9,
(14). To a solution of oxime ether 1314c (50 mg, 0.24 mmol) and 44.1 42.8, 39.1, 32.5, 26.0, 25.8, 23.13, 23.09, 21.8, 21.7. HRMS:
i-PrI (0.72 mL, 7.2 mmol) in 1 N NH4Cl/MeOH (1:3, 10 mL) was calcd for C17H26N2O2 (M+), 306.1941; found, 306.1941.
added Et3B (1.0 M in hexane, 1.2 mL, 1.2 mmol) three times at 2-Ethyl-4-methylquinoline (18). To a solution of lepidine
20 °C. After the mixture was stirred at the same temperature (50 mg, 0.35 mmol) in 3 N HCl (10 mL) was added Et3B (1.0 M
for 30 h, the solvent was evaporated at reduced pressure. The in THF, 1.75 mL, 1.75 mmol) five times at 20 °C. After being
resulting residue was diluted with saturated aqueous NaHCO3 stirred at the same temperature for 40 h, the reaction mixture
and then extracted with CH2Cl2. The organic phase was dried was neutralized by NaHCO3 and then extracted with CH2Cl2.
over MgSO4 and concentrated at reduced pressure. Purification The organic phase was dried over MgSO4 and concentrated at
of the residue by preparative TLC (hexane/AcOEt, 15:1) afforded reduced pressure. Purification of the residue by preparative TLC
14 (41 mg, 67%) as a colorless oil. IR (CHCl3): 2964, 1495, 1454 (hexane/AcOEt, 2:1) afforded 18 (37 mg, 62%) as a colorless oil.
cm-1. 1H NMR (CDCl3): δ 7.32-7.16 (10H, m), 4.57 (1H, d, J ) IR (CHCl3): 3016, 2972, 1605, 1562, 1508 cm-1. 1H NMR
11.4 Hz), 4.52 (1H, d, J ) 11.4 Hz), 3.73 (1H, br d, J ) 7.3 Hz), (CDCl3): δ 8.04 (1H, br m), 7.94 (1H, dd, J ) 8.4, 1.2 Hz), 7.67
1.98 (1H, m), 0.96 (3H, d, J ) 6.8 Hz), 0.74 (3H, d, J ) 6.8 Hz). (1H, ddd, J ) 8.4, 7.0, 1.2 Hz), 7.49 (1H, ddd, J ) 8.4, 7.0, 1.5
13C NMR (CDCl ): δ 141.0, 137.7, 128.4, 128.2, 128.1, 127.8,
3 Hz), 7.15 (1H, br s), 2.95 (2H, q, J ) 7.8 Hz), 2.67 (3H, s), 1.39
127.6, 127.0, 76.4, 71.6, 30.8, 19.8, 18.9. HRMS: calcd for C17H21- (3H, t, J ) 7.8 Hz). 13C NMR (CDCl3): δ 163.6, 147.6, 144.2,
NO (M+), 255.1622; found, 255.1635. 129.2, 128.9, 126.7, 125.3, 123.4, 121.4, 32.1, 18.6, 19.9. HRMS:
Preparation of Oxime Ether (15). To 2-aminoethanol (10 calcd for C12H13N (M+), 171.1047; found, 171.1053.
mL, 166 mmol) was added chloroacetaldehyde O-benzyloxime General Procedure for the One-Pot Synthesis of r-Ami-
(10 g, 54.5 mmol) under a nitrogen atmosphere at 0 °C. After no Acid Derivatives. To a solution of glyoxylic acid monohy-
being stirred at room temperature for 12 h, the reaction mixture drate (50 mg, 0.54 mmol) in H2O (10 mL) was added O-benzyl-
was added to saturated aqueous NaHCO3 and CH2Cl2. The hydroxylamine hydrochloride (86 mg, 0.54 mmol) at 20 °C. After
layers were separated and the aqueous phase was extracted with the reaction mixture was stirred at the same temperature for 3
CH2Cl2. The combined organic phase was washed with brine, h, RI (16.2 mmol) and Et3B (1.0 M in hexane, 2.7 mL, 2.7 mmol)
dried over Na2SO4, and concentrated at reduced pressure. were added. After the reaction mixture was stirred at the same
Purification of the residue by flash column chromatography temperature for 1 h, the solvent was evaporated at reduced
(CHCl3/MeOH, 30:1 to CHCl3/MeOH, 15:1) afforded N-(2-hy- pressure. Purification of the residue by flash column chroma-
droxyethyl)aminoethanal O-benzyloxime (10 g, 88%) as colorless tography (CHCl3/MeOH, 10:1) afforded 20a-d as a white
crystals and a 3:2 mixture of E/Z-oxime. Mp 58.5-60 °C (AcOEt/ powder.
Notes J. Org. Chem., Vol. 65, No. 16, 2000 5047

2-(Benzyloxyamino)-3-methylbutanoic Acid (20a). 1H 177.3, 138.4, 129.2, 128.8, 128.4, 76.5, 69.0, 40.5, 30.6, 29.9, 25.6,
NMR (CD3OD): δ 7.38-7.26 (5H, m), 4.67 (2H, s), 3.30 (1H, br 25.5. HRMS: calcd for C14H19NO3 (M+), 249.1364; found,
m), 1.90-1.70 (1H, m), 0.94 (6H, d, J ) 10.1 Hz). 13C NMR 249.1355.
(CD3OD): δ 177.2, 139.0, 129.5, 129.1, 128.6, 76.7, 70.6, 29.9,
19.7. HRMS: calcd for C12H17NO3 (M+), 223.1207; found, Acknowledgment. This work was supported by
223.1221. research grants from the Ministry of Education, Science,
2-(Benzyloxyamino)-2-cyclohexylethanoic Acid (20b). 1H Sports and Culture of Japan and the Science Research
NMR (CD3OD): δ 7.34-7.26 (5H, m), 4.65 (2H, s), 3.31 (1H, m), Promotion Fund of the Japan Private School Promotion
1.35-0.78 (11H, m). 13C NMR (CD3OD): δ 177.2, 139.0, 129.5,
129.1, 128.6, 76.7, 70.1, 39.5, 30.72, 30.66, 27.1, 27.0. HRMS: Foundation. Partial support for this work was also
calcd for C15H21NO3 (M+), 263.1520; found, 263.1505. provided (to H.M.) by the Nissan Chemical Industries
2-(Benzyloxyamino)-3-methylpentanoic Acid (20c) as a Award in Synthetic Organic Chemistry, Japan. H.M.
Diastereomeric Mixture. 1H NMR (CD3OD): δ 7.38-7.26 (5H, gratefully acknowledges the financial support from
m), 4.65 (2H, s), 3.42 (1H, br m), 1.68-1.38 (2H, m), 1.26-1.11 Takeda Science Foundation and Fujisawa Foundation
(1H, m), 0.87 (6H, m). 13C NMR (CD3OD): δ 177.4, 177.1, 139.0, in Japan.
129.5, 129.1, 128.6, 76.1, 69.1, 68.6, 36.8, 36.2, 27.3, 26.9, 16.0,
15.7, 11.8, 11.5. HRMS: calcd for C13H19NO3 (M+), 237.1364; Supporting Information Available: Spectra for com-
found, 237.1354. pounds 1-20e. This material is available free of charge via
2-(Benzyloxyamino)-2-cyclopentylethanoic Acid (20d). the internet at http://pubs.acs.org.
1H NMR (CD OD): δ 7.38-7.20 (5H, br m), 4.68 (2H, s), 3.40-
3
3.32 (2H, br m), 1.99-1.18 (8H, br m). 13C NMR (CD3OD): δ JO000318+