Reactive ketimino radical acceptors: Intermolecular alkyl radical addition to imines with a phenolic hydroxyl group

Article abstract of DOI:10.1021/jo052518x

Intermolecular carbon radical addition to the carbon-nitrogen double bond of ketimines was studied. In the study on the reactivity of various aldimines, we found that the aldimine 7 having a phenolic hydroxyl group shows an excellent reactivity toward nuc

Full text of DOI:10.1021/jo052518x

Reactive Ketimino Radical Acceptors: Intermolecular Alkyl Radical
Addition to Imines with a Phenolic Hydroxyl Group
Hideto Miyabe, Yousuke Yamaoka, and Yoshiji Takemoto*
Graduate School of Pharmaceutical Sciences, Kyoto UniVersity,
Yoshida, Sakyo-ku, Kyoto 606-8501, Japan
takemoto@pharm.kyoto-u.ac.jp
ReceiVed December 7, 2005
Intermolecular carbon radical addition to the carbon-nitrogen double bond of ketimines was studied. In
the study on the reactivity of various aldimines, we found that the aldimine 7 having a phenolic hydroxyl
group shows an excellent reactivity toward nucleophilic carbon radicals. A remarkable effect of phenolic
hydroxyl group is assumed to be the stabilization of intermediate aminyl radical provided by a hydroxyl
group. The screening of reactive ketimino acceptors showed that ketimines 15, 17, and 19 having a
phenolic hydroxyl group exhibit excellent reactivities. The radical addition to ketimines 15, 17, and 19
took place regioselectively at the imino carbon to give the C-alkylated products without the formation of
N-alkylated products. Enantioselective ethyl radical addition to ketimine 15 using chiral box ligand and
Zn(OTf)2 gave the diethylated product 30 in 80% ee.
Introduction
formation of reductive coupling products. The addition of a
strictly neutral species such as an uncharged free radical would
provide a highly general solution to the fundamental problems
that are associated with the strong basicity of organometallic
reagents.
Hart’s group reported the first study on intermolecular radical
addition to formaldoxime ether.5 Recently, the intermolecular
radical reactions of R-sulfonyl oxime ethers, aldoxime ethers,
hydrazones, glyoxylic imine derivatives, nitrones, and N-
sulfonylimines have been investigated mainly by the groups of
Kim,6 Bertrand,7 Friestad,8 and ourselves.9,10 However, these
studies on the intermolecular radical addition to the carbon atom
of imines have concentrated on the reaction of aldimines. The
difficulty in achieving the construction of an all-substituted sp3-
Free radical reactions have been developed as a powerful
method for constructing the carbon-carbon bond, providing
many advantages over ionic chemistry.1,2 Although the use of
radical reaction in organic synthesis has continued to increase,
the intermolecular radical addition to the carbon atom of imine
derivatives has received much less attention until recently.3 Most
synthetically useful carbon-carbon bond-forming reactions of
imines are restricted to the use of organometallic reagents.4
However, the addition of organometallic reagents is frequently
plagued by the enolization of the substrates with acidic
R-hydrogens, poor electrophilicity of the imino group, and the
(1) (a) Ryu, I.; Sonoda, N.; Curran, D. P. Chem. ReV. 1996, 96, 177. (b)
Renaud, P.; Gerster, M. Angew. Chem., Int. Ed. 1998, 37, 2562. (c) Giese,
B.; Kopping, B.; Go¨bel, T.; Dickhaut, J.; Thoma, G.; Kulicke, K. J.; Trach,
F. Org. React. 1996, 48, 301. (d) Sibi, M. P.; Porter, N. A. Acc. Chem.
Res. 1999, 32, 163. (e) Sibi, M. P.; Manyam, S. Tetrahedron 2000, 56,
8033. (f) In Radicals in Organic Synthesis; Renaud, P., Sibi, M. P., Eds.;
Wiley-VCH: New York, 2001; Vols. 1 and 2. (g) Bar, G.; Parsons, A. F.
Chem. Soc. ReV. 2003, 32, 251. (h) Sibi, M. P.; Manyam, S.; Zimmerman,
J. Chem. ReV. 2003, 103, 3263.
(4) For some reviews, see: (a) Enders, D.; Reinhold: U. Tetrahedron:
Asymmetry 1997, 8, 1895. (b) Denmark, S. E.; Nicaise, O. J.-C. J. Chem.
Soc., Chem. Commun. 1996, 999. (c) Risch, N.; Arend, N. In StereoselectiVe
Synthesis; Helmchen, G., Hoffmann, R. W., Mulzer, J., Schaumann, E.,
Eds.; Thieme: Stuttugart, New York, 1996; Vol. 3; pp 1833-2009.
(5) (a) Hart, D. J.; Seely, F. L. J. Am. Chem. Soc. 1988, 110, 1633. (b)
Bhat, B.; Swayze, E. E.; Wheeler, P.; Dimock, S.; Perbost, M.; Sanghvi,
Y. S. J. Org. Chem. 1996, 61, 8186.
(6) (a) Kim, S.; Lee, I. Y.; Yoon, J.-Y.; Oh, D. H. J. Am. Chem. Soc.
1996, 118, 5138. (b) Kim, S.; Yoon, J.-Y. J. Am. Chem. Soc. 1997, 119,
5982. (c) Ryu, I.; Kuriyama, H.; Minakata, S.; Komatsu, M.; Yoon, J.-Y.;
Kim, S. J. Am. Chem. Soc. 1999, 121, 12190. (d) Kim, S.; Song, H.-J.;
Choi, T.-L.; Yoon, J.-Y. Angew. Chem., Int. Ed. 2001, 40, 2524.
(2) For reviews on the radical cyclization of imines, see: (a) Fallis, A.
G.; Brinza, I. M. Tetrahedron 1997, 53, 17543. (b) Naito, T. Heterocycles
1999, 50, 505.
(3) For reviews, see: (a) Friestad, G. K. Tetrahedron 2001, 57, 5461.
(b) Miyabe, H.; Naito, T. J. Synth. Org. Chem. Jpn. 2001, 59, 35. (c) Miyabe,
H.; Ueda, M.; Naito, T. Synlett 2004, 1140.
10.1021/jo052518x CCC: $33.50 © 2006 American Chemical Society
Published on Web 01/31/2006
J. Org. Chem. 2006, 71, 2099-2106
2099

Miyabe et al.
FIGURE 1. Regiochemical course of radical addition to ketimines.
FIGURE 2. Aldimine derivatives prepared from benzaldehyde.
carbon center based on the intermolecular radical addition to
the carbon atom of ketimines has remained unresolved (path
a), due to the low reactivity of ketimines and the regiochemical
course of carbon radical addition to ketimines (Figure 1). In
fact, the regioisomeric carbon-nitrogen bond formation based
on intramolecular radical addition to the nitrogen atom of
ketimines has been investigated, although there are no inter-
molecular examples of this process (path b).11
SCHEME 1
For an example of intermolecular radical addition to the
carbon atom of ketimines, Shono’s group reported the elec-
troreductive intermolecular coupling of ketoxime ethers with
ketones.12 More recently, the photoinduced intermolecular
reaction of ketoxime ethers with R-alkoxy carbon radical was
achieved by the group of Alonso.13 However, nothing is known
about the radical addition to ketimines using a conventional
radical initiator such as Et3B or AIBN.14 Therefore, the screening
of reactive ketimino acceptors is the new focus of our efforts.
Our recent studies showed that ketimines having a 2-phenolic
hydroxyl group have excellent reactivities toward nucleophilic
alkyl radicals under mild aqueous-medium reaction conditions
using Et3B.15a We also reported the results of experiments to
test the viability of several ketimines in Et3B-induced intermo-
lecular radical reactions.15b In this paper, we report, in detail,
the Et3B-induced reaction of imines having a 2-phenolic
hydroxyl group in organic solvent. This reaction was applied
to the first reported example of intermolecular enantioselective
radical addition to ketimine.16
(7) (a) Bertrand, M. P.; Feray, L.; Nouguier, R.; Stella, L. Synlett 1998,
780. (b) Bertrand, M. P.; Feray, L.; Nouguier, R.; Perfetti, P. Synlett 1999,
1148. (c) Bertrand, M. P.; Feray, L.; Nouguier, R.; Perfetti, P. J. Org. Chem.
1999, 64, 9189. (d) Bertrand, M. P.; Coantic, S.; Feray, L.; Nouguier, R.;
Perfetti, P. Tetrahedron 2000, 56, 3951. (e) Bertrand, M.; Feray, L.; Gastaldi,
S. C. R. Acad. Sci. Paris, Chim. 2002, 5, 623.
(8) (a) Friestad, G. K.; Qin, J. J. Am. Chem. Soc. 2000, 122, 8329. (b)
Friestad, G. K.; Qin, J. J. Am. Chem. Soc. 2001, 123, 9922. (c) Friestad, G.
K.; Shen, Y.; Ruggles, E. L. Angew. Chem., Int. Ed. 2003, 42, 5061. (d)
Friestad, G. K.; Draghici, C.; Soukri, M.; Qin, J. J. Org. Chem. 2005, 70,
6330.
(9) (a) Miyabe, H.; Ushiro, C.; Naito, T. Chem. Commun. 1997, 1789.
(b) Miyabe, H.; Shibata, R.; Ushiro, C.; Naito, T. Tetrahedron Lett. 1998,
39, 631. (c) Miyabe, H.; Ueda, M.; Yoshioka, N.; Naito, T. Synlett 1999,
465. (d) Miyabe, H.; Fujii, K.; Naito, T. Org. Lett. 1999, 1, 569. (e) Miyabe,
H.; Yamakawa, K.; Yoshioka, N.; Naito, T. Tetrahedron 1999, 55, 11209.
(f) Miyabe, H.; Ushiro, C.; Ueda, M.; Yamakawa, K.; Naito, T. J. Org.
Chem. 2000, 65, 176. (g) Miyabe, H.; Ueda, M.; Naito, T. J. Org. Chem.
2000, 65, 5043. (h) Miyabe, H.; Ueda, M.; Naito, T. Chem. Commun. 2000,
2059. (i) Miyabe, H.; Ueda, M.; Nishimura, A.; Naito, T. Org. Lett. 2002,
4, 131. (j) Miyabe, H.; Nishimura, A.; Ueda, M.; Naito, T. Chem. Commun.
2002, 1454. (k) Ueda, M.; Miyabe, H.; Teramachi, M.; Miyata, O.; Naito,
T. Chem. Commun. 2003, 426. (l) Ueda, M.; Miyabe, H.; Nishimura, A.;
Sugino, H.; Naito, T. Tetrahedron: Asymmetry 2003, 14, 2857. (m) Miyabe,
H.; Naito, T. Org. Biomol. Chem. 2004, 2, 1267. (n) Miyabe, H.; Ueda,
M.; Nishimura, A.; Naito, T. Tetrahedron 2004, 60, 4227. (o) Miyabe, H.;
Ueda, M.; Sugino, H.; Naito, T. Org. Biomol. Chem. 2005, 3, 1124. (p)
Ueda, M.; Miyabe, H.; Teramachi, M.; Miyata, O.; Naito, T. J. Org. Chem.
2005, 70, 6653.
(10) For related examples, see: (a) Singh, N.; Anand, R. D.; Trehan, S.
Thetrahedron Lett. 2004, 45, 2911. (b) Risberg, E.; Fischer, A.; Somfai, P.
Chem. Commun. 2004, 2088. (c) Yamada, K.; Yamamoto, Y.; Maekawa,
M.; Tomioka, K. J. Org. Chem. 2004, 69, 1531. (d) Liu, X.; Zhu, S.; Wang,
S. Synthesis 2004, 683. (e) Yamada, K.; Yamamoto, Y.; Tomioka, K. Org.
Lett. 2003, 5, 1797. (f) Ferna´ndez, M.; Alonso, R. Org. Lett. 2003, 5, 2461.
(g) Alves, M. J.; Fortes, G.; Guimara˜es, E.; Lemos, A. Synlett 2003, 1403.
(h) Yamada, K.; Fujihara, H.; Yamamoto, Y.; Miwa, Y.; Taga, T.; Tomioka,
K. Org. Lett. 2002, 4, 3509. (i) Masson, G.; Py, S.; Valle´e, Y. Angew.
Chem., Int. Ed. 2002, 41, 1772. (j) Russell, G. A.; Wang, L.; Rajaratnam,
R. J. Org. Chem. 1996, 61, 8988.
(11) For some examples, see: (a) Viswanathan, R.; Prabhakaran, E. N.;
Plotkin, M. A.; Johnston, J. N. J. Am. Chem. Soc. 2003, 125, 163. (b) Orito,
K.; Uchiito, S.; Satoh, Y.; Tatsuzawa, T.; Harada, R.; Tokuda, M. Org.
Lett. 2000, 2, 307. (c) McClure, C. K.; Kiessling, A. J.; Link, J. S.
Tetrahedron 1998, 54, 7121. (d) Tomaszewski, M. J.; Warkentin, J.;
Werstiuk, N. H. Aust. J. Chem. 1995, 48, 291. (e) Bowman, W. R.;
Stephenson, P. T.; Terrett, N. K.; Young, A. R. Tetrahedron Lett. 1994,
35, 6369. (f) Takano, S.; Suzuki, M.; Ogasawara, K. Heterocycles 1994,
37, 149. (g) Tomaszewski, M. J.; Warkentin, J. Tetrahedron Lett. 1992,
2123. (h) Han, O.; Frey, P. A. J. Am. Chem. Soc. 1990, 112, 8982. (i)
Takano, S.; Suzuki, M.; Kijima, A.; Ogasawara, K. Chem. Lett. 1990, 315.
(12) Shono, T.; Kise, N.; Fujimoto, T. Tetrahedron Lett. 1991, 32, 525.
Results and Discussion
Reactivity of N-Aromatic Aldimine Having a Phenolic
Hydroxyl Group. To compare the effect of substituent of
nitrogen atom of CdN bond, our experiments began with the
investigation of intermolecular radical addition to several
aldimines (Figure 2). In our previous studies, we reported that
the Et3B-induced radical addition to oxime ether 1 and hydra-
zone 2 did not proceed in the absence of Lewis acid and the
activation of CdN bond with BF3‚OEt2 was essential to achieve
the intermolecular radical addition to 1.9b,d,e More recently, we
reported that electron-deficient N-sulfonyl imine 3 exhibits an
excellent reactivity and the radical addition to 3 proceeded
smoothly even in the absence of Lewis acid.9h
The substrates of choice were different types of aldimines
4-7 prepared from benzaldehyde to identify the reactivity of
aldimine 7 having a phenolic hydroxyl group. The reactions
were run in undegassed CH2Cl2 at 20 °C for 5 min by using
Et3B as an ethyl radical source (Scheme 1). In contrast to
N-sulfonyl imine 3,9h the reaction of similar electron-deficient
imines 4 and 5 gave not only the inferior yields of products 8a
(13) Torrente, S.; Alonso, R. Org. Lett. 2001, 3, 1985.
(14) Utimoto and Oshima were the first to apply the reaction of Et3B
with oxygen to initiate radical reactions. See: (a) Miura, K.; Ichinose, Y.;
Nozaki, K.; Fugami, K.; Oshima, K.; Utimoto, K. Bull. Chem. Soc. Jpn.
1989, 62, 143. (b) Kabalka, G. W.; Brown, H. C.; Suzuki, A.; Honma, S.;
Arase, A.; Itoh, M. J. Am. Chem. Soc. 1970, 92, 710. For reviews of radical
reaction with organoborane, see: (c) Yorimitsu, H.; Shinokubo, H.; Oshima,
K. Synlett 2002, 674. (d) Olliver, C.; Renaud, P. Chem. ReV. 2001, 101,
3415.
(15) (a) Miyabe, H.; Yamaoka, Y.; Takemoto, Y. Synlett 2004, 2597.
(b) Miyabe, H.; Yamaoka, Y.; Takemoto, Y. J. Org. Chem. 2005, 70, 3324.
(16) For the intermolecular enantioselective radical addition to aldimines,
see refs 8b,c and 9f.
2100 J. Org. Chem., Vol. 71, No. 5, 2006

ReactiVe Ketimino Radical Acceptors
TABLE 1. Radical Addition to Aldimines 4-7
entry
imine
RI
initiator
product
yield (%)a
1b
2b
3b
4b
5b
6c
4
5
6
7
7
7
none
none
none
none
none
i-PrI
Et3B
Et3B
Et3B
Et3B
Et2Zn
Et3B
8a
9a
10a
11a
23
21
40
85
no reaction
90
11b
a Isolated yields. b Reactions were carried out using 1 M Et3B or Et2Zn
in hexane (2.5 equiv). c Reaction was carried out using i-PrI (30 equiv)
and 1 M Et3B in hexane (2.5 equiv).
FIGURE 4. Cyclic N-aromatic ketimine derivatives.
SCHEME 2
FIGURE 3. Effect of 2-hydroxyl group and reaction pathway.
and 9a but also significant amounts of starting materials and
hydrolysis products due to the unstable CdN bond (Table 1,
entries 1 and 2). Although moderate chemical yield was
observed in the reaction of N-aromatic imine 6, it is important
to note that the reaction of N-aromatic imine 6 proceeded even
in the absence of Lewis acid under mild reaction conditions
using Et3B (entry 3). These results suggested that the CdN
bonds of both 6 and its intermediate aminyl radical were
stabilized by the conjugation with N-aromatic ring. We then
examined the N-aromatic aldimine 7 capable of forming an
intramolecular hydrogen bond. The aldimine 7 having a phenolic
hydroxyl group was extremely reactive, and the radical reaction
proceeded within 5 min to give the desired product 11a in 85%
yield, because of the effective activation of the CdN bond and
extra stabilization of the intermediate aminyl radical provided
by the intramolecular hydrogen bond (entry 4). The role of a
phenolic hydroxyl group has not yet been completely clear;
however, the stabilization of intermediate aminyl radical A
would be provided by a hydroxyl group, giving the accelerated
addition rates (Figure 3). In this reaction, Et3B worked as not
only a radical initiator but also a radical chain terminator to
trap the intermediate radical A or B to give a chain-propagating
ethyl radical. In the case of the reaction using Et2Zn as an ethyl
radical source,17 no reaction occurred (entry 5). This result
suggests that a hydroxyl group of 7 was reacted with Et2Zn to
give zinc alkoxide,18 which did not have a good reactivity. The
reaction of 7 with isopropyl radical was conducted under tin-
free iodine atom-transfer conditions using i-PrI and Et3B.
Isopropyl radical addition reaction was also facile, and the
desired isopropylated product 11b was isolated in 90% yield
(entry 6). Results from these studies show that aldimine 7 having
a hydroxyl group is a highly promising imino radical acceptor,
comparable to N-sulfonyl imine 3 having a strong N-electron-
withdrawing substituent reported in our previous studies.9h
Reactivity of N-Aromatic Ketimines. The development of
reactive ketimino acceptors is a challenging problem. On the
basis of the above results of aldimines, we hoped that N-aromatic
ketimines would serve as radical acceptors, as a result of the
stabilization of intermediate aminyl radical by the delocalization
on adjacent N-aromatic ring. Therefore, we decided to explore
the reactivity of N-aromatic ketimines 12-19 (Figure 4).19 We
also expected that the electron-withdrawing carbonyl moiety
of the ketimines 12-19 activates the CdN bond, and cyclic
structure of 12-19 enhances the stabilization of CdN bond
toward hydrolysis. Moreover, the intermolecular radical addition
to ketimines 12-19 provides a new method for the synthesis
of R,R-disubstituted amino acids.
All reactions of ketimines 12-14 were carried out in
undegassed solvent under a nitrogen atmosphere (Scheme 2).20
Several trends in Table 2 are noteworthy. The ethyl radical
addition to N-aromatic ketimine 12 proceeded effectively to give
a 77% yield of the desired C-ethylated product 20a even in the
absence of Lewis acids, although a large amount of Et3B (2.5
equiv × 3) was required (entry 1). In contrast, the isopropyl
radical addition reaction using isopropyl iodide gave the mixture
of products, and a careful product analysis showed that the
diisopropylated products 23b and 24b were also formed (entries
(17) Ryu and Komatsu reported that Et2Zn can serve as a radical initiator.
See: Ryu, I.; Araki, F.; Minakata, S.; Komatsu, M. Tetrahedron Lett. 1998,
39, 6335.
(18) (a) Kim, H.; Lee, C. Org. Lett. 2002, 4, 4369. (b) Miyabe, H.;
Yoshida, K.; Reddy, V. K.; Matsumura, A.; Takemoto, Y. J. Org. Chem.
2005, 70, 5630.
(19) The preparation method of required starting materials 12-19 is
reported in Supporting Information.
(20) The [2 + 2] photocycloaddition of ketimine 12 was reported. See:
Nishio, T.; Omote, Y. J. Org. Chem. 1985, 50, 1370.
J. Org. Chem, Vol. 71, No. 5, 2006 2101

Miyabe et al.
TABLE 2. Alkyl Radical Addition to Ketimines 12-14
entry
imine
R2I (equiv)
solvent
CH2Cl2
CH2Cl2
CH2Cl2
Lewis acid
time (min)
product (% yield)a
1b
12
12
12
12
12
12
12
12
12
12
13
13
13
13
14
14
none
none
none
none
60
60
60
15
15
15
15
15
15
15
60
20
20
20
60
20
20a (77)
2c
i-PrI (10)
i-PrI (15)
i-PrI (10)
i-PrI (10)
i-PrI (15)
c-Hexyl I (10)
c-Hexyl I (15)
t-BuI (10)
t-BuI (15)
none
20b (24), 20a (10) f
20b (26), 20a (3)g
20b (54), 20a (5)h
20b (64), 20a (20)
20b (75), 20a (trace)
20c (60), 20a (21)
20c (66), 20a (19)
20d (89), 20a (7)
20d (96)
3c
4d
CH2Cl2
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
none
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
none
5d
THF-CH2Cl2
THF-CH2Cl2
THF-CH2Cl2
THF-CH2Cl2
THF-CH2Cl2
THF-CH2Cl2
CH2Cl2
THF-CH2Cl2
THF-CH2Cl2
THF-CH2Cl2
CH2Cl2
6d
7d
8d
9d
10d
11b
12e
13d
14d
15b
16e
21a (32)
21a (73)
21b (76), 21a (trace)
21d (84)
22a (13)
none
i-PrI (15)
t-BuI (15)
none
none
THF-CH2Cl2
Yb(OTf)3
22a (63)
a Isolated yields. b Reactions were carried out using 1 M Et3B in hexane (2.5 equiv × 3). c Reactions were carried out using RI and 1 M Et3B in hexane
(2.5 equiv × 3). d Reactions were carried out using RI and 1 M Et3B in hexane (2.5 equiv × 3) in the presence of Yb(OTf)3 (1.0 equiv). e Reactions were
f
carried out using 1 M Et3B in hexane (2.5 equiv × 3) in the presence of Yb(OTf)3 (1.0 equiv). Products 23b (9%) and 24b (10%) were also obtained.
g Products 23b (13%) and 24b (14%) were also obtained. h Products 23b (4%) and 24b (4%) were also obtained.
SCHEME 3
desired alkyl radical addition products, especially when second-
ary alkyl radicals were used (entries 7-9). The reaction with
an isopropyl radical gave a significant amount of the ethylated
product 25a, as a result of competitive addition of an ethyl
radical generated from Et3B (entry 7). Under identical condi-
tions, the addition of more nucleophilic and stable tert-butyl
radical gave the desired product 25d with higher selectivity,
due to the efficient iodine atom-transfer from tert-butyl iodide
to ethyl radical (entry 10). We have previously reported that a
highly reactive imino radical acceptor, such as glyoxylic oxime
ether or BF3-activated aldoxime ether, gives the ethylated
product as a byproduct, whereas a less reactive imino radical
acceptor gives the desired alkylated product selectively.9b-f
Thus, these observations strongly indicate that ketimine 15
having a hydroxyl group has an excellent reactivity. Low
selectivity with Yb(OTf)3 lends support to this conclusion (entry
8). To suppress the formation of the undesired ethylated product
25a, Bu3SnH was employed as a radical mediator (entries 11-
16). The effect of temperature on selectivity was also examined,
and it was found that outstanding levels of selectivity can be
obtained at 20 °C (entries 14-16). In the case of the reaction
using isopropyl iodide and Bu3SnH, the formation of 25a
diminished remarkably, leading to an excellent yield of the
isopropylated product 25b after being stirred in CH2Cl2 at 20
°C for 5 min (entry 14). Other radical precursors such as
cyclohexyl iodide and t-BuI worked well under similar reaction
conditions to give the desired products 25c and 25d selectively
(entries 15 and 16).
To gain further insight into the effect of a phenolic hydroxyl
group, the next radical acceptors of choice were ketimines 16-
19 (Scheme 4). All reactions were carried out by using 2.5 equiv
of Et3B. The influence of the substituent R2 on reactivity is
shown in Table 4, and several entries are noteworthy. Since
ketimines 16 and 17 (R2 ) CO2Et) have two electrophilic centers
(carbon and nitrogen atoms of the CdN bond), we are interested
in regiochemical course of radical addition to 16 and 17.
Additionally, we expected that the reactivity of 16 and 17 is
enhanced by the electron-withdrawing substituent R2, which
would lower the LUMO energy of a radical acceptor. However,
increasing the size of R2 affected the reactivity of acceptor
toward radical additions, and the reaction of ketimine 16 did
not proceed effectively (entries 1-5). In contrast, ketimine 17
having a hydroxyl group had shown reactivity higher than that
2-4). A Lewis acid such as Yb(OTf)3, which is sufficiently
mild to be compatible with the other reactants, greatly increased
the chemical yield of the reaction. THF serves to dissolve the
Yb(OTf)3. When a stoichiometric amount of Yb(OTf)3 was
employed in THF-CH2Cl2, the formation of 23b and 24b was
remarkably diminished, leading to a 75% yield of the desired
product 20b (entry 6). Under the analogous reaction conditions,
cyclohexyl iodide and t-BuI worked well (entries 8 and 10).
The similar trends were observed in the reaction of ketimine
13 having a methyl group and ketimine 14 having a methoxyl
group (entries 11-16). The use of Yb(OTf)3 was found to be
optimal for good chemical yields, although substrates 13 and
14 with increased steric size at the 2-position showed slightly
lower reactivity. In these reactions, radical addition to the
nitrogen atom of ketimines 12-14 was not observed. Results
were consistent with the fact that simple alkyl radicals are
relatively nucleophilic and their additions are uncomplicated
by electronic effects or chelation with Lewis acid.
The reaction of ketimine 15 having a hydroxyl group was
faster than those of other ketimines 12-14 (Scheme 3).
Treatment of 15 with only 2.5 equiv of Et3B furnished the
ethylated product 25a without the formation of any other
byproducts (Table 3, entries 1-6). In the absence of Lewis acid
additive, the reaction of 15 in CH2Cl2 afforded the ethylated
product 25a in 89% yield within 5 min (entry 1). It is important
to note that high chemical yields were observed even at -78
°C, although the reaction took a longer time for completion
(entries 2, 4, and 6). The replacement of CH2Cl2 with a nonpolar
aromatic solvent such as toluene was also effective for the
reaction of 15 (entries 3 and 4). The use of Yb(OTf)3 led to a
small enhancement in chemical yields (entries 5 and 6). We
next explored the alkyl radical addition to ketimine 15. At first,
the tin-free reaction of 15 was tested under iodine atom-transfer
reaction conditions (entries 7-10). As a result of the enhanced
reactivity of 15, the ethylated product 25a contaminated the
2102 J. Org. Chem., Vol. 71, No. 5, 2006

ReactiVe Ketimino Radical Acceptors
TABLE 3. Alkyl Radical Addition to Ketimine 15a
entry
RI
solvent
additive
T (°C)
time (min)
productb
% yieldc (selectivity)d
1
2
3
none
none
none
none
none
none
i-PrI
i-PrI
c-Hexyl I
t-BuI
i-PrI
c-Hexyl I
t-BuI
i-PrI
CH2Cl2
CH2Cl2
toluene
toluene
THF-CH2Cl2
THF-CH2Cl2
CH2Cl2
THF-CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
none
none
none
none
Yb(OTf)3
Yb(OTf)3
none
Yb(OTf)3
none
20
-78
20
-78
20
-78
20
20
20
20
-78
-78
-78
20
20
20
5
60
5
60
5
60
5
5
5
5
60
60
60
5
25a
25a
25a
25a
25a
25a
25b
25b
25c
25d
25b
25c
25d
25b
25c
25d
89
82
93
84
95
90
4
5e
6e
7
87 (4:1)
86 (1:1)
76 (3.5:1)
89 (16:1)
95 (1.8:1)
95 (1.6:1)
92 (10:1)
96 (>30:1)
95 (13:1)
97 (>30:1)
8e
9
10
11f
12f
13f
14f
15f
16f
none
Bu3SnH
Bu3SnH
Bu3SnH
Bu3SnH
Bu3SnH
Bu3SnH
c-Hexyl I
t-BuI
5
5
a
Reactions were carried out using RI (30 equiv) and 1 M Et3B in hexane (2.5 equiv). b Major products. c Isolated yields. d Selectivity for 25b-d:25a is
determined by 1H NMR analysis. e Reactions were carried out in the presence of Yb(OTf)3 (1.0 equiv). f Reactions were carried out in the presence of
Bu3SnH (3 equiv).
SCHEME 4
addition, the highly reactive acceptor 17 gave the reduced
selectivity as a result of the competitive addition of an ethyl
radical (compare entry 7 in Table 4 with entry 7 in Table 3).
Past results on optimizing selectivity indicated that Bu3SnH was
good chain carrier for the alkyl radical addition to ketimine 15
(entries 14-16 in Table 3). It was again found that Bu3SnH
gave the high selectivity when ketimine 17 was used (entry 8).
It is important to note that the regioselective radical addition
took place at the carbon atom of CdN bond, and the formation
of N-alkylated Michael-type adducts was not observed. We next
investigated the bulky ketimines 18 and 19, highly stabilized
by conjugation with phenyl group (R2 ) Ph). The radical
addition to 18 was extremely slow, and ethyl radical did not
add in the absence of Lewis acid (entry 10). In contrast to 18,
the reaction of 19 having a hydroxyl group took place even in
the absence of Lewis acid (entry 13). Use of zinc Lewis acid
led to high yields (entries 14-17), and the ethyl radical addition
to 19 proceeded even at -78 °C (entry 15). It was observed
that the substrate reactivity followed the order R2 ) CO2Et (17)
> Me (15) > Ph (19).
SCHEME 5
Enantioselective Reaction of Ketimines. In recent years,
studies on enantioselective radical reactions have achieved some
remarkable success, particularly in radical additions to CdC
bonds.1 Direct asymmetric synthesis of amines by enantiose-
lective addition to the CdN bond of imines provides an efficient
method for introducing the stereogenic center and carbon-
carbon bond in one step.4,21 We previously reported the first
enantioselective radical addition to aldimino acceptor mediated
by chiral Lewis acid.9f Similar study was carried out using a
chiral Lewis acid derived from Cu(I) and Tol-BINAP with less
success.22 Recently, highly enantioselective radical addition to
aldimine was achieved by Friestad’s group.8c However, nothing
has been known about the enantioselective radical addition to
ketimines. Therefore, the stereocontrol in the intermolecular
reaction of ketimines has been a subject of current interest.
Several combinations of chiral box ligands A-H and Lewis
acids were initially evaluated in the ethyl radical addition to
of ketimines 16 and 15 (entries 6-9). The ethyl radical addition
to ketimine 17 proceeded cleanly and efficiently even in the
absence of Lewis acid, giving the C-ethylated product 27a
uncontaminated by starting material and any other products
(entry 6). However, as observed with an isopropyl radical
(21) For reviews, see: (a) Alvaro, G.; Savoia, D. Synlett 2002, 651. (b)
Kobayashi, S.; Ishitani, H. Chem. ReV. 1999, 99, 1069. (c) Bloch, R. Chem.
ReV. 1998, 98, 1407. (d) Davis, F. A.; Zhou, P.; Chen, B.-C. Chem. Soc.
ReV. 1998, 27, 13.
(22) Halland, N.; Jørgensen, K. A. J. Chem. Soc., Perkin Trans. 1 2001,
1290.
J. Org. Chem, Vol. 71, No. 5, 2006 2103

Miyabe et al.
TABLE 4. Alkyl Radical Addition to Ketimines 16-19a
entry
imine
R3I
Lewis acid
additive
T (°C)
time (min)
productb
% yieldc (selectivity)d
1
16
16
16
16
16
17
17
17
17
18
18
18
19
19
19
19
19
19
none
none
none
i-PrI
i-PrI
none
i-PrI
i-PrI
t-BuI
none
none
none
none
none
none
i-PrI
i-PrI
t-BuI
none
none
none
none
none
Bu3SnH
none
none
Bu3SnH
none
none
none
none
none
none
none
none
Bu3SnH
none
20
20
-78
20
20
20
20
20
20
20
20
-78
20
20
60
60
900
60
60
5
5
5
5
60
60
900
20
5
60
5
5
26a
26a
26a
26b
26b
27a
27b
27b
27d
28a
28a
28a
29a
29a
29a
29b
29b
29d
12
56
35
2e
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
none
none
none
none
none
Zn(OTf)2
Zn(OTf)2
none
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
none
3e
4e
17 (>30:1)
35 (>30:1)
94
94 (1:1)
91 (11:1)
83 (8:1)
trace
24
13
88
91
5e,f
6
7
8f
9
10
11e
12e
13
14e
15e
16e
17e,f
18
-78
20
20
20
80
96 (7:1)
88 (>30:1)
96 (>30:1)
5
a Reactions were carried out using RI (30 equiv) and 1 M Et3B in hexane (2.5 equiv) in CH2Cl2. b Major products. c Isolated yields. d Selectivity for the
alkylated products 26b-29d:the ethylated products 26a-29a is determined by 1H NMR analysis. e Reactions were carried out in the presence of Zn(OTf)2
(1.0 equiv). f Reactions were carried out in the presence of Bu3SnH (3 equiv).
TABLE 5. Enantioselective Radical Addition to Ketimine 15a
SCHEME 6
25a
30
yield
(%) b
ee
yield
(%) b
ee
entry
ligand
Lewis acid
(%) c
(%) c
1
2
3
4
5
6
7
8
9
10
A
A
A
B
C
D
E
F
Mg(OTf)2
Zn(OTf)2
Cu(OTf)2
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
72
49
32
19
50
36
19
34
41
32
2
33
-72
23
6
trace
35
trace
63
38
31
34
19
10
16
78 (R)
80 (R)
22 (R)
racemic
racemic
racemic
33 (R)
3
2
8
7
G
H
3
14 (R)
a Reactions were carried out using 1 M Et3B in hexane (2.5 equiv), ligand
(1 equiv), and Lewis acid (1 equiv) in CH2Cl2 at -78 °C for 10 h. b Isolated
yields. c Enantioselectivity was determined by HPLC analysis.
two-point-binding ketimine 15 (Scheme 5). The reactions of
the highly reactive acceptor 15 were run in CH2Cl2 at -78 °C,
and then the enantiomeric purities of products were checked
by chiral HPLC analysis (Table 5). We expected that the
coordination of the Lewis acid would be activating the substrate
15 for radical addition step. However, the enantioselective
radical reaction of 15 was relatively slow as evidenced by low
conversions after a short time. Increasing the reaction time to
10 h improved the chemical yields, and the formation of
diethylated product 30 was newly observed in the presence of
chiral Lewis acid. Therefore, it is assumed that the trapping
step of the intermediate radical with Et3B is suppressed by a
bulky chiral Lewis acid. The formation of 30 may result from
the accumulation of intermediate radical and enough time to
couple with an ethyl radical. In general, the enantiomeric ratio
of diethylated product 30 was better than that of ethylated
product 25a. The best result was obtained with the zinc Lewis
acid and phenyl-substituted ligand B to afford the highest 80%
ee of the diethylated product 30 in 63% yield, accompanied by
a 19% yield of the ethylated product 25a (entry 4).23 The
absolute configuration at the stereocenter of 30 was determined
to be R by converting the adduct 30 into the amino acid
derivative 33, which was also synthesized from known chiral
compound 34 (Scheme 6).15b,24 A re face radical addition to
the zinc complex with octahedral geometry accounts for the
observed product configuration (Figure 5).25
Next, the ethyl radical addition to ketimine 14 having a
methoxy group was investigated under several reaction condi-
tions using chiral box ligands and Lewis acids (Scheme 7). The
reactions of the less reactive acceptor 14 were run at 20 °C for
15 h to give a mixture of ethylated product 22a and diethylated
product 37. The results obtained by using Cu(OTf)2 and box
ligand A having a benzyl group are shown in Table 6. The
(23) The similar trends were observed in other radical reactions. In
general, the phenyl-substituted box ligand B-zinc Lewis acid combination
gives high selectivity, whereas the aliphatic substituted box ligands give
high selectivity in combination with magnesium Lewis acid. See: (a) Sibi,
M. P.; Ji, J. J. Am. Chem. Soc. 1996, 118, 9200. (b) Porter, N. A.; Wu, J.
H. L.; Zhang, G. R.; Reed, A. D. J. Org. Chem. 1997, 62, 6702. (c) Sibi,
M. P.; Zimmerman, J.; Rheault, T. Angew. Chem., Int. Ed. 2003, 42, 4521.
(24) Harwood: L. M.; Vines, K. J.; Drew, M. G. B. Synlett 1996, 1051.
(25) For zinc-box ligand complex, see: (a) Sibi, M. P.; Shay, J. J.; Ji, J.
Tetrahedron Lett. 1997, 38, 5955. (b) Sibi, M. P.; Zhang, R.; Manyem, S.
J. Am. Chem. Soc. 2003, 125, 9306.
2104 J. Org. Chem., Vol. 71, No. 5, 2006

ReactiVe Ketimino Radical Acceptors
SCHEME 8
conducted under tin-free iodine atom-transfer conditions using
i-PrI and Et3B (Scheme 8). Although the competitive reaction
with ethyl radical and isopropyl radical gave a complex mixture,
65% ee of diisopropylated product 38 was isolated in 28% yield.
FIGURE 5. Model to explain enantioselectivity and absolute stereo-
chemistry.
SCHEME 7
Conclusion
We have demonstrated the utility of aldimine and ketimines
having a 2-phenolic hydroxyl group in intermolecular radical
reactions. In addition to the radical reaction of aldimine
derivatives, the radical addition to ketimine derivatives disclosed
a broader aspect of the utility of imino radical acceptor for the
synthesis of various types of amines.
TABLE 6. Enantioselective Radical Addition to Ketimine 14a
37b
Experimental Section
entry
Lewis acid
solvent
yield (%) c
ee (%) d
General Procedure for Enantioselective Radical Addition to
Ketimines 15 and 14. A solution of ketimine 14 or 15 (0.5 mmol),
Lewis acid (0.5 mmol), and ligand (0.5 mmol) in benzene/CH2Cl2
(1:2, v/v, 3 mL, for 14) or CH2Cl2 (3 mL, for 15) was stirred for
30 min under nitrogen atmosphere at 20 °C. To the reaction mixture
was added Et3B (1.0 M in hexane, 1.25 mL, 1.25 mmol) at 20 °C
(for 14) or -78 °C (for 15). After being stirred at the same
temperature for 10-15 h, the reaction mixture was diluted with
saturated NaHCO3 and then extracted with AcOEt. The organic
phase was dried over MgSO4 and concentrated at reduced pressure.
Purification of the residue by column chromatography (hexane/
AcOEt 4:1) afforded 30 or 37 along with 25a or 22a. Under similar
reaction conditions, the isopropyl radical addition to ketimine 14
gave the diisopropylated product 38.
1
2
3
4
5
Zn(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
CH2Cl2
CH2Cl2
benzene
toluene
31
35
37
31
40
-28 (R)
54 (S)
57 (S)
56 (S)
65 (S)
benzene/CH2Cl2
a Reactions were carried out using 1 M Et3B in hexane (2.5 equiv), ligand
A (1 equiv), and Lewis acid (1 equiv) at 20 °C for 15 h. b The monoethylated
product 22a was also obtained in 21-34% yields. c Isolated yields.
d Enantioselectivity was determined by HPLC analysis.
combination of zinc Lewis acid and box ligand was less effective
for the reaction of 14 (entry 1). Copper Lewis acid, which is
generally unsuccessful under reductive radical conditions,26 was
quite efficient in radical addition to 14. The copper Lewis acid
mediated reaction of 14 proceeded slowly to give 65% ee of
the diethylated product 37 in 40% yield, accompanied by the
monoethylated product 22a, after being stirred in benzene-
CH2Cl2 (entry 5). The absolute configuration at the stereocenter
of 37 was determined to be S by comparison with the chiral
HPLC analysis and the optical rotation value of R-37, which
was prepared from the R-adduct 30 by methylation of a phenolic
hydroxyl group. Although the selectivity differs depending on
substrates, ligands, and Lewis acids, the most noteworthy
outcome of these experiments was that the opposite sense of
stereoinduction is found between the zinc- and copper-mediated
reactions (compare entries 2-5 in Table 6 with Table 5 and
entry 1 in Table 6).27 The reversal in enantioselectivity of
copper-mediated reaction remains unclear; however, the similar
reversal of stereochemistry was observed.26-28 The distortion
of square planar geometry of copper(II) center may be respon-
sible for the reversal in enantioselectivity.29 Finally, the chiral
copper-mediated reaction of 14 with isopropyl radical was
(R)-3,7-Diethyl-3,4-dihydro-5-hydroxy-3-methyl-2H-1,4-ben-
zoxazin-2-one (30). A colorless oil. IR (CHCl3) 3597, 1760 cm-1
.
1H NMR (CDCl3) δ 6.47 (1H, s), 6.46 (1H, s), 5.41 (1H, br s),
3.61 (1H, br s), 2.53 (2H, q, J ) 7.5 Hz), 1.79 (1H, m), 1.67 (1H,
m), 1.45 (3H, s), 1.19 (3H, t, J ) 7.5 Hz), 0.96 (3H, t, J ) 7.5
Hz). 13C NMR (CDCl3) δ 169.4, 145.3, 143.4, 137.8, 116.8, 110.5,
107.8, 57.7, 29.6, 28.3, 22.6, 15.4, 7.5. MS (EI+): m/z 235 (M+,
13), 178 (100). HRMS (EI+): calcd for C13H17NO3 (M+) 235.1208,
found 235.1217. HPLC (Chiralcel AD-H, hexane/2-propanol 90/
10, 0.5 mL/min, 254 nm) tR (major, R) ) 17.8 min, tR (minor, S)
) 25.9 min. A sample of 80% ee by HPLC analysis gave [R]22
-8.2 (c 1.1, CHCl3).
D
(R)-3-Ethyl-3,4-dihydro-5-hydroxy-3-methyl-2H-1,4-benzox-
azin-2-one (25a). A colorless oil. IR (CHCl3) 1762 cm-1. 1H NMR
(CDCl3) δ 6.72 (1H, br t, J ) 8.3 Hz), 6.62 (1H, br d, J ) 8.3 Hz),
6.60 (1H, br d, J ) 8.3 Hz), 5.53 (1H, br s), 3.86 (1H, br s), 1.83
(1H, m), 1.68 (1H, m), 1.47 (3H, s), 0.97 (3H, t, J ) 7.6 Hz). 13
C
NMR (CDCl3) δ 170.1, 144.5, 141.9, 120.4, 119.4, 111.3, 108.4,
57.7, 29.7, 22.7, 7.4. MS (EI+): m/z 207 (M+, 40), 150 (100).
HRMS (EI+): calcd for C11H13NO3 (M+) 207.0895, found 207.0892.
HPLC (Chiralcel AD-H, hexane/2-propanol 90/10, 0.5 mL/min, 254
(26) For few examples of chiral copper Lewis acid catalyzed radical
reaction, see: Sibi, M. P.; Chen, J. J. Am. Chem. Soc. 2001, 123, 9472.
Also see ref 8c.
(27) For discussion on the reversal of stereochemistry, see: (a) Sibi, M.
P.; Liu, M. Curr. Org. Chem. 2001, 5, 719. (b) Evans, D. A.; Johnson, J.
S.; Burgey, C. S.; Campos, K. R. Tetrahedron Lett. 1999, 40, 2879. (c)
Sibi, M. P.; Ji, J.; Wu, J. H.; Gu¨rtler, S.; Porter, N. A. J. Am. Chem. Soc.
1996, 118, 9200.
(28) For a discussion of a square planar geometry model relative to
copper, see: (a) Sibi, M. P.; Ma, Z.; Jasperse, C. P. J. Am. Chem. Soc.
2004, 126, 718. (b) Sibi, M. P.; Venkatraman, L.; Liu, M.; Jasperse, C. P.
J. Am. Chem. Soc. 2001, 123, 8444. (c) Evans, D. A.; Miller, S. J.; Lectka,
T.; von Matt, P. J. Am. Chem. Soc. 1999, 121, 7559.
(29) A working hypothesis for the reversed sense of stereoinduction is
shown in Supporting Information.
J. Org. Chem, Vol. 71, No. 5, 2006 2105

Miyabe et al.
nm) tR (major, R) ) 15.2 min, tR (minor, S) ) 19.9 min. A sample
cm-1. 1H NMR (CDCl3) δ 6.51 (1H, s), 6.49 (1H, s), 4.10 (1H, br
s), 3.87 (3H, s), 2.82 (1H, m), 2.10 (1H, m), 1.39 (3H, s), 1.22
(6H, d, J ) 6.7 Hz), 0.95 (3H, d, J ) 6.8 Hz), 0.90 (3H, d, J ) 6.7
Hz). 13C NMR (CDCl3) δ 168.7, 147.1, 141.0, 140.1, 119.1, 106.4,
104.9, 60.4, 55.9, 33.9, 31.4, 24.1, 19.2, 17.0, 15.9. MS (EI+): m/z
277 (M+, 37), 234 (100). HRMS (EI+): calcd for C16H23NO3 (M+)
277.1678, found 277.1681. HPLC (Chiralcel AD-H, hexane/2-
propanol 98/2, 0.5 mL/min, 254 nm) tR (minor, R) ) 11.1 min, tR
(major, S) ) 13.5 min. A sample of 65% ee by HPLC analysis
of 33% ee by HPLC analysis gave [R]24 -13.4 (c 1.3, CHCl3).
D
(S)-3,7-Diethyl-3,4-dihydro-5-methoxy-3-methyl-2H-1,4-ben-
zoxazin-2-one (37). A colorless oil. IR (CHCl3) 3390, 1763 cm-1
.
1H NMR (CDCl3) δ 6.50 (1H, s), 6.47 (1H, s), 3.96 (1H, br s),
3.86 (3H, s), 2.57 (2H, q, J ) 7.3 Hz), 1.83 (1H, m), 1.65 (1H, m),
1.44 (3H, s), 1.21 (3H, t, J ) 7.3 Hz), 0.94 (3H, t, J ) 7.3 Hz).
13C NMR (CDCl3) δ 168.9, 147.3, 140.9, 135.3, 119.2, 107.8, 106.2,
57.7, 55.7, 30.0, 28.5, 23.0, 15.5, 7.5. MS (EI+): m/z 249 (M+,
29), 220 (100). HRMS (EI+): calcd for C14H19NO3 (M+): 249.1365.
Found: 249.1362. HPLC (Chiralcel AD-H, hexane/2-propanol 98/
2, 0.5 mL/min, 254 nm) tR (minor, R) ) 13.5min, tR (major, S) )
15.1 min. A sample of 65% ee by HPLC analysis gave [R]24D +9.6
(c 1.1, CHCl3).
gave [R]20 +8.9 (c 1.3, CHCl3).
D
Acknowledgment. This work was supported in part by
Grant-in-Aid for Young Scientists (B) (H.M.) and Scientific
Research on Priority Areas 17035043 (Y.T. and H.M.) from
the Ministry of Education, Culture, Sports, Science and Tech-
nology of Japan, 21st Century COE Program “Knowledge
Information Infrastructure for Genome Science”.
(S)-3-Ethyl-3,4-dihydro-5-methoxy-3-methyl-2H-1,4-benzox-
azin-2-one (22a). A colorless oil. IR (CHCl3) 1764 cm-1. 1H NMR
(CDCl3) δ 6.75 (1H, t, J ) 7.9 Hz), 6.66 (1H, d, J ) 7.9 Hz), 6.62
(1H, d, J ) 7.9 Hz), 4.08 (1H, br s), 3.87 (3H, s), 1.84 (1H, m),
1.66 (1H, m), 1.45 (3H, s), 0.95 (3H, t, J ) 7.3 Hz). 13C NMR
(CDCl3) δ 168.7, 147.5, 140.9, 121.7, 118.5, 108.9, 106.3, 57.6,
55.9, 30.2, 23.1, 7.6. MS (EI+): m/z 221 (M+, 23), 192 (100).
HRMS (EI+): calcd for C12H15NO3 (M+) 221.1052, found 221.1059.
HPLC (Chiralcel AD-H, hexane/2-propanol 98/2, 0.5 mL/min, 254
nm) tR (minor, R) ) 17.3 min, tR (major, S) ) 18.8 min. A sample
Supporting Information Available: Experimental procedure
and characterization data for other compounds 8a-21d, 23b, 24b,
25b-29d, and 31-36, and 1H and 13C NMR spectrum of all
obtained compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
of 21% ee by HPLC analysis gave [R]22 +4.2 (c 1.2, CHCl3).
D
(S)-3,4-Dihydro-3,7-diisoproyl-5-methoxy-3-methyl-2H-1,4-
benzoxazin-2-one (38). A colorless oil. IR (CHCl3) 3403, 1762
JO052518X
2106 J. Org. Chem., Vol. 71, No. 5, 2006