Aqueous medium radical addition to ketimines with a phenolic hydroxyl group

Article abstract of DOI:10.1055/s-2004-834803

Intermolecular alkyl radical addition to ketimines having 2-phenolic hydroxyl group proceeded effectively in aqueous media, providing the novel method for construction of all-substituted sp³-hybridized carbon center.

Full text of DOI:10.1055/s-2004-834803

LETTER
2597
Aqueous Medium Radical Addition to Ketimines with a Phenolic Hydroxyl
Group
A
queous Medium
i
R
adica
d
l
A
ddition to
e
K
etiminesto Miyabe, Yousuke Yamaoka, Yoshiji Takemoto*
Graduate School of Pharmaceutical Sciences, Kyoto University, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan
Fax +81(75)7534569; E-mail: takemoto@pharm.kyoto-u.ac.jp
Received 2 September 2004
To confirm the effect of phenolic hydroxyl group, we first
Abstract: Intermolecular alkyl radical addition to ketimines having
2-phenolic hydroxyl group proceeded effectively in aqueous media,
providing the novel method for construction of all-substituted sp3-
hybridized carbon center.
investigated the radical addition to aldimines 1 and 2 in
aqueous media (Scheme 1). As expected, aldimine 2 hav-
ing a hydroxyl group exhibits a good reactivity, compara-
ble to that of N-sulfonyl imines having a strong electron-
withdrawing substituent reported in our previous stud-
ies.11 The reaction of 2 was conducted in H2O–MeOH
(1:4, v/v) at 20 °C under tin-free iodine atom-transfer con-
ditions using i-PrI and 1.0 M Et3B in MeOH as a radical
initiator. The reaction proceeded within five minutes to
give the desired isopropylated product 3b in 68% yield,
along with an 8% yield of the ethylated product 3a as a re-
sult of competitive addition of ethyl radical generated
from Et3B. In this reaction, Et3B worked not only as a rad-
ical initiator but also as a radical chain terminator to trap
the intermediate radical to give a chain-propagating ethyl
radical.12 In contrast, aldimine 1 did not give the desired
adduct under the aqueous-medium conditions, because of
the competitive hydrolysis of the C=N bond. These results
show that the aldimines having phenolic hydroxyl group
are highly promising water-resistant radical acceptors.
Key words: radical, imine, ketimine, water, aqueous media
The carbon-nitrogen double bond of imines has emerged
as a radical acceptor.1 However, studies on the intermo-
lecular reaction of imines have concentrated on reaction
of aldimines.2–5 The difficulty in achieving the construc-
tion of all-substituted sp3-hybridized carbon center based
on the intermolecular radical addition to ketimines has re-
mained unresolved.6 Nothing has been known about the
radical addition to ketimines using a conventional radical
initiator such as Et3B or AIBN. Therefore, the screening
of reactive and stable ketimino radical acceptors is the
new focus of our efforts. In this paper, we report the inter-
molecular radical reaction of ketimines with a 2-phenolic
hydroxyl group, which exhibit the excellent reactivity
even under the mild aqueous medium reaction conditions.
R1
R1
N
O
N
O
N
O
N
i-PrI, 1 M Et3B in MeOH
[1,4]-shift
H
H
H
R
HN
H2O–MeOH
20 °C, 5 min
Ph
R2
Ph
R
R
3a: R1 = OH, R2 = Et (8%)
1: R1 = H
3b: R1 = OH, R2 = i-Pr (68%)
2: R1 = OH
Figure 1 Effect of phenolic hydroxyl group on the stability and
reactivity of imine derivatives in radical reaction
i-PrI
EtI
+
i-Pr
+
O2
Et
Et3B
The use of water in radical reactions has generated consid-
erable interest from both economical and environmental
points of view.7 As part of our program directed toward
the development of radical reactions of imines in aqueous
media,8,9 the aqueous-medium radical addition to imines
having a hydroxyl group has been newly investigated
(Figure 1). As a simple effect of phenolic hydroxyl group,
the activation and stabilization of C=N bond in aqueous
media would be provided by an intramolecular hydrogen
bond. Particularly, we expected that the extra stabilization
of intermediate aminyl radical, provided by the [1,4]-hy-
drogen shift from the hydroxyl group and the delocaliza-
tion on aromatic ring,10 would give the accelerated
addition rates.
2
BEt3
O
O
H2O
Et2B
Ph
H
3b
HN
N
Pri
Ph
Pri
Scheme 1
The development of reactive ketimino radical acceptors is
a challenging problem. The next substrates of choice were
ketimines 4–7 prepared from methyl pyruvate, since
electron-deficient glyoxylic aldimines have shown an
excellent reactivity toward nucleophilic carbon radicals in
our previous work (Scheme 2).3 All reactions were carried
out by using 2.5 equivalents of Et3B. The reaction of
SYNLETT 2004, No. 14, pp 2597–2599
2
2
.1
1
.2
0
0
4
Advanced online publication: 20.10.2004
DOI: 10.1055/s-2004-834803; Art ID: U24704ST
© Georg Thieme Verlag Stuttgart · New York

2598
H. Miyabe et al.
LETTER
ketimines 4–6 proceeded slowly to give the low yields of ated reaction of 7 proceeded slowly to give the product
desired ethylated products 8–10, along with the recovered 11b in 60% yield, along with a small amount of reduced
starting materials 4–6 (Table 1, entries 1–3). As expected, product (entry 2). Although a significant amount of the re-
ketimine 7 exhibited an excellent reactivity in aqueous duced product was formed by using Zn in aqueous
media. The ethyl radical addition to 7 afforded the ethylat- NH4Cl–MeOH, a good yield of the product 11b was ob-
ed product 11a in 94% yield within five minutes without tained by using Zn–CuI in H2O–MeOH (entries 3 and 4).13
formation of other by-products (entry 4). To identify the
reactivity of ketimine 7, the reaction was tested in organic
solvent at lower reaction temperature. High chemical
yields were also observed in MeOH or toluene even at
–78 °C (entries 5 and 6). Additionally, the lower reactivity
of ketimines 4–6 was observed in non-H-bonding solvent
such as CH2Cl2 or toluene. Among the different types of
imino radical acceptors, the oxime ethers and hydrazones
are well known to be excellent radical acceptors, because
of the stabilization of the intermediate aminyl radical pro-
vided by the lone pair on the adjacent heteroatoms.1 How-
ever, the reaction of ketoxime ethers did not proceed even
in the presence of BF3·OEt2. Thus, these results indicated
that 2-phenolic hydroxyl group is important for the
reactivity of ketimine 7.
OH
OH
i-PrI, initiator
N
NH
20 °C
O
O
Me
Me
i-Pr
O
O
7
11b
Scheme 3
Table 2 Isopropyl Radical Addition to 7 in Aqueous Media
Entry Initiator
Solvent
Time (min) Yield (%)a
1b
2c
3c
4d
Et3B
In
H2O–MeOH
H2O–MeOH
aq NH4Cl–MeOH
H2O–MeOH
5
30
5
87 (> 30:1)e
60f
17f
83
R1
N
R1
Zn
1 M Et3B in MeOH or hexane
NH
Zn, CuI
5
O
O
a Isolated yields.
Me
Me
Et
b Reaction was carried out using i-PrI (30 equiv) and Et3B in MeOH
(2.5 equiv).
O
O
8: R1 = H
4: R1 = H
c Reactions were carried out using i-PrI (7 equiv) and In or Zn (7
equiv).
9: R1 = Me
5: R1 = Me
10: R1 = OMe
11a: R1 = OH
6: R1 = OMe
7: R1 = OH
d Reaction was carried out using i-PrI (7 equiv), Zn (7 equiv), CuI (1
equiv).
Scheme 2
e Ratio for 11b:11a is determined by 1H NMR analysis.
f The reduced product was formed as a by-product.
Table 1 Ethyl Radical Addition to Ketimines 4–7
Entry
Imine
Solvent
Temp
(°C)
Time
(min)
Yield
(%)a
OH
N
OH
NH
OH
R2
R2I, initiator
20 °C
N
1b
2b
3b
4b
5b
6c
4
5
6
7
7
7
H2O–MeOH
H2O–MeOH
H2O–MeOH
H2O–MeOH
MeOH
20
20
60
60
60
5
35 (30)
19 (41)
48 (10)
94
O
O
O
R1
R1
R1
R2
O
O
O
11c: R1 = Me, R2 = c-Hexyl
11d: R1 = Me, R2 = t-Bu
14b: R1 = Ph, R2 = i-Pr
14d: R1 = Ph, R2 = t-Bu
15d: R1 = CO2Et, R2 = t-Bu
7: R1 = Me
12: R1 = Ph
16 (No detection)
20
13: R1 = CO2Et
20
–78
–78
30
60
92
Scheme 4
Toluene
84
a Isolated yields. Yield in parentheses is for the recovered starting
material.
We next investigated the reaction with other radical pre-
cursors (Scheme 4). In the reaction of 7, other radical pre-
cursors such as c-hexyl-I and tert-BuI worked well to give
the desired products 11c and 11d by using Et3B or Zn–CuI
as a radical initiator (Table 3, entries 1–4). The isopropyl
radical addition to ketimine 12, highly stabilized by con-
jugation with a phenyl substituent, proceeded smoothly to
give the adduct 14b in 95% yield (entry 5). The reaction
of 12 with a bulky tert-butyl radical also proceeded effec-
tively (entry 6). The reaction of ketimine 13 having an ad-
ditional ester group proceeded regioselectively to give the
desired product 15d without formation of Michael-type
product 16 (entry 7).
b Reactions were carried out using 1.0 M Et3B in MeOH.
c Reaction was carried out using 1.0 M Et3B in hexane.
We next investigated the aqueous medium addition of an
isopropyl radical to ketimine 7 by using several radical
initiators (Scheme 3). The isopropylated product 11b was
also obtained in 87% yield under iodine atom-transfer
conditions using i-PrI and Et3B without Bu3SnH (Table 2,
entry 1). We recently reported that indium has the poten-
tial to induce radical reactions as a single-electron transfer
radical initiator in aqueous media.8c–e,9 The indium-medi-
Synlett 2004, No. 14, 2597–2599 © Thieme Stuttgart · New York

LETTER
Aqueous Medium Radical Addition to Ketimines
2599
Table 3 Alkyl Radical Addition to 7–13 in Aqueous Media
Acknowledgment
This work was supported in part by The Japan Health Sciences
Foundation and Grant-in-Aid for Scientific Research (C) (Y.T.) and
for Young Scientists (B) (H.M.) from the Ministry of Education,
Culture, Sports, Science and Technology of Japan, and for Reseach
Grants, 21st Century COE Program ‘Knowledge Information Infra-
structure for Genome Science’.
Entry
1b
Imine
7
RI
Initiator
Et3B
Yield (%)a
89 (9:1)d
59 (>30:1)d
81
c-Hexyl-I
t-BuI
2b
7
Et3B
3c
7
c-Hexyl-I
t-BuI
Zn, CuI
Zn, CuI
Et3B
4c
7
90
References
5b
12
12
13
i-PrI
95 (>30:1)d
62 (>30:1)d
95 (>30:1)d
(1) For reviews, see: (a) In Radicals in Organic Synthesis, Vol.
1 and 2; Renaud, P.; Sibi, M. P., Eds.; Wiley-VCH: New
York, 2001. (b) Miyabe, H.; Naito, T. J. Synth. Org. Chem.
Jpn. 2001, 59, 35. (c) Friestad, G. K. Tetrahedron 2001, 57,
5461. (d) Miyabe, H.; Ueda, M.; Naito, T. Synlett 2004,
1140.
(2) (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.
(3) (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.; Fujii, K.;
Naito, T. Org. Lett. 1999, 1, 569. (d) Miyabe, H.; Ushiro,
C.; Ueda, M.; Yamakawa, K.; Naito, T. J. Org. Chem. 2000,
65, 176. (e) Ueda, M.; Miyabe, H.; Teramachi, M.; Miyata,
O.; Naito, T. Chem. Commun. 2003, 426.
(4) (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.
(5) (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.
6b
t-BuI
Et3B
7b
t-BuI
Et3B
a Isolated yields.
b Reactions were carried out using RI (30 equiv) and Et3B in MeOH
(2.5 equiv) in H2O–MeOH for 5 min.
c Reactions were carried out using RI (7 equiv), Zn (7 equiv), CuI (1
equiv) in H2O–MeOH for 5 min.
d Ratios are for the desired alkylated product to ethylated product de-
termined by 1H NMR analysis.
The product 11d was converted to a,a-disubstituted
amino acid derivative 17 (Scheme 5). The reaction of 11d
with benzylamine in the presence of 2-pyridinol gave
amide, which was converted to methyl ether. The methyl
ether was treated with CAN to afford 17.
1) BnNH2, 2-Pyridinol, 98%
2) MeI, K2CO3, 98%
3) CAN, 67%
NH2
BnHN
Me
t-Bu
11d
O
(6) (a) Shono, T.; Kise, N.; Fujimoto, T. Tetrahedron Lett. 1991,
32, 525. (b) Torrente, S.; Alonso, R. Org. Lett. 2001, 3,
1985.
17
Scheme 5
(7) (a) Yamazaki, O.; Togo, H.; Nogami, G.; Yokoyama, M.
Bull. Chem. Soc. Jpn. 1997, 70, 2519. (b) Yorimitsu, H.;
Nakamura, T.; Shinokubo, H.; Oshima, K. J. Org. Chem.
1998, 63, 8604. (c) Nakamura, T.; Yorimitsu, H.;
Shinokubo, H.; Oshima, K. Synlett 1998, 1351. (d)Kita,Y.;
Nambu, H.; Ramesh, N. G.; Anikumar, G.; Matsugi, M. Org.
Lett. 2001, 3, 1157.
In conclusion, we have demonstrated the utility of imines
having 2-phenolic hydroxyl group in radical reactions.
These are the first examples of intermolecular reaction of
ketimines using Et3B or Zn as a conventional radical ini-
tiator.
(8) (a) Miyabe, H.; Ueda, M.; Naito, T. J. Org. Chem. 2000, 65,
5043. (b) Miyabe, H.; Fujii, K.; Goto, T.; Naito, T. Org. Lett.
2000, 2, 4071. (c) Miyabe, H.; Ueda, M.; Nishimura, A.;
Naito, T. Org. Lett. 2002, 4, 131. (d) Miyabe, H.;
Nishimura, A.; Ueda, M.; Naito, T. Chem. Commun. 2002,
1454. (e) Ueda, M.; Miyabe, H.; Nishimura, A.; Miyata, O.;
Takemoto, Y.; Naito, T. Org. Lett. 2003, 5, 3835. (f) Ueda,
M.; Miyabe, H.; Nishimura, A.; Sugino, H.; Naito, T.
Tetrahedron: Asymmetry 2003, 14, 2857.
(9) For a review, see: Miyabe, H.; Naito, T. Org. Biomol. Chem.
2004, 1267.
(10) Russell, G. A.; Wang, L.; Rajaratnam, R. J. Org. Chem.
1996, 61, 8988.
General Procedure for Radical Addition to Ketimines by Using
Et3B.
To a solution of ketimine 7, 12, or 13 (0.25 mmol) in H2O–MeOH
(1:4, v/v, 2.5 mL) were added RI (7.50 mmol) and Et3B (1.0 M in
MeOH, 0.63 mL, 0.63 mmol) at 20 °C. After being stirred at the
same temperature for 5 min, the reaction mixture was evaporated,
diluted with sat. NaHCO3 and then extracted with EtOAc. The or-
ganic phase was dried over MgSO4 and concentrated at reduced
pressure. Purification of the residue by preparative TLC (hexane–
EtOAc = 4:1, 2-fold development) afforded product.
(11) Miyabe, H.; Ueda, M.; Naito, T. Chem. Commun. 2000,
2059.
(12) Miyabe, H.; Ueda, M.; Yoshioka, N.; Naito, T. Synlett 1999,
465.
(13) Giese, B.; Damm, W.; Roth, M.; Zehnder, M. Synlett 1992,
441.
Representative Characterization Data of Product 11a.
Colorless oil; IR (CHCl3): 1762 cm–1. 1H NMR (CDCl3): d = 6.72
(1 H, br t, J = 8.3 Hz), 6.62 (1 H, br d, J = 8.3 Hz), 6.60 (1 H, br d,
J = 8.3 Hz), 3.86 (1 H, br s), 1.83 (1 H, m), 1.68 (1 H, m), 1.47 (3
H, s), 0.97 (3 H, t, J = 7.6 Hz). 13C NMR (CDCl3): d = 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 (40) [M+], 150 (100). HRMS (EI+): m/z calcd for
C11H13NO3 [M+]: 207.0895. Found: 207.0892.
Synlett 2004, No. 14, 2597–2599 © Thieme Stuttgart · New York