O-allylic substitution of hydroxylamine derivatives having an N-electron-withdrawing substituent

Article abstract of DOI:10.1055/s-2003-37526

The O-allylic substitution of hydroxylamines having an N-electron-withdrawing substituent proceeded smoothly to afford O-allylated products by using [IrCl(cod)]₂ or Pd(PPh₃)₄.

Full text of DOI:10.1055/s-2003-37526

LETTER
567
O-Allylic Substitution of Hydroxylamine Derivatives Having an N-Electron-
Withdrawing Substituent
O
-Allylic Substitu
ition of
d
H
ydroxylam
e
ine
D
erivat
t
ives o Miyabe,a Kazumasa Yoshida,a Akira Matsumura,a Masashige Yamauchi,b Yoshiji Takemoto*a
a
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
b
Faculty of Pharmaceutical Sciences, Josai University, Keyakidai, Sakado, Saitama 350-0295, Japan
Received 27 January 2003
with N,N-dibenzylhydroxylamine 2b under similar reac-
tion conditions. However, practically no reaction of 1 with
N,N-dibenzylhydroxylamine (2b) occurred after being
stirred at 20 °C for 3 h. These observations suggest that
the N-electron-withdrawing substituent would be impor-
tant for the nucleophilic property of an oxygen atom on
hydroxylamine. A rational hypothesis of these reactions is
that hydroxylamine 2a would be effectively activated by
methoxide generated from 1.
Abstract: The O-allylic substitution of hydroxylamines having an
N-electron-withdrawing substituent proceeded smoothly to afford
O-allylated products by using [IrCl(cod)]2 or Pd(PPh3)4.
Key words: allylations, iridium, palladium, cyclizations, meta-
thesis
Transition metal-catalyzed allylic amination and alkyla-
tion have been developed as a fundamentally important
cross-coupling reaction.1 In contrast, the corresponding
reaction with oxygen nucleophiles has not been widely
studied due to the poor nucleophilic property of the oxy-
gen atom and poor regioselectivity attained in the reac-
tion.2 Therefore, O-allylic substitution is largely limited to
carboxylate and phenolic nucleophiles.2 Recently, a few
studies have been directed toward allylic substitution with
alcohols under basic conditions.3 Herein, we now report
the utility of hydroxylamines having an N-electron-with-
drawing substituent as an oxygen nucleophile in transition
metal-catalyzed allylic substitution. We also report the
N,O-diallylation of hydroxylamines and an application to
novel cyclization.4
PhBzN OH 2a
NBzPh
O
[IrCl(cod)]2
Ph
MeCN, 20 °C
10 min
OCO2Me
3a (98%)
Ph
PhBzN OH 2a
1
NBzPh
Pd(PPh3)4
Ph
O
MeCN, 20 °C
10 min
4a (93%)
Bn2N OH 2b
[IrCl(cod)]2 or Pd(PPh3)4
1
No reaction
Hydroxylamine derivatives would be an attractive syn-
thetic reagent for allylic substitution, since they have ni-
trogen and oxygen atoms as a nucleophile. However,
allylic substitution using hydroxylamines has been limit-
ed to palladium-catalyzed amination, as a result of the re-
MeCN, 20 °C
3 h
Scheme 1
action of an electrophilic π-allyl palladium complex with We next studied the reaction of 1 with N-Boc-hydroxyl-
the nucleophilic nitrogen atom of hydroxylamines.5 In the amine (2c) (Scheme 2). In the case of 2c, both nitrogen
presence of [IrCl(cod)]2 (4 mol%), a reaction of allylic and oxygen atoms on hydroxylamine acted as a nucleo-
carbonate 1 with N-benzoyl-N-phenylhydroxylamine (2a) phile. The iridium-catalyzed reaction afforded 37% yield
was run in MeCN at 20 °C for 10 min (Scheme 1). The N- of O-allylated product 3c and 53% yield of N-allylated
benzoyl-N-phenylhydroxylamine (2a) worked well as an product 5, after being stirred at 20 °C for 3 h. In the case
oxygen nucleophile to give the branched O-allylated of the palladium-catalyzed reaction, the O-allylation was
product 3a in 98% yield with excellent regioselectivity.6 mainly observed to give the O-allylated product 4c in 67%
In contrast, the palladium-catalyzed reaction afforded the yield, accompanied with a small amount of N-allylated
linear product 4a in 93% yield. In these reactions, the sol- product 6.
vent influenced the reactivity of N-benzoyl-N-phenylhy-
droxylamine (2a). A polar solvent such as MeCN gave the
best result, while nonpolar solvents such as benzene and
Since the π-allyl palladium complex has shown excellent
reactivity toward hydroxylamines, we next studied the
palladium-catalyzed N,O-diallylation of hydroxylamines
toluene gave poor yields of the products. We also investi-
(Scheme 3). As expected, the formation of N,O-diallylat-
gated the iridium and palladium-catalyzed reactions of 1
ed products 7c and 7d was observed in the reaction of 1
(2.5 equiv) with N-Boc-hydroxylamine (2c) or N-Cbz-hy-
droxylamine (2d). The additional allylation of the
branched hydroxylamines 3c and 5, prepared from the iri-
dium-catalyzed reaction, was also tested (Scheme 2). In
Synlett 2003, No. 4, Print: 12 03 2003.
Art Id.1437-2096,E;2003,0,04,0567,0569,ftx,en;U13503ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

568
H. Miyabe et al.
LETTER
BocHN OH 2c
NHBoc
Boc
Ph
OH
O
N
[IrCl(cod)]2
+
Ph
MeCN, 20 °C
3 h
OCO2Me
5 (53%)
3c (37%)
Ph
1 (1.0 equiv)
BocHN OH 2c
NHBoc
Boc
Pd(PPh3)4
Ph
O
Ph
N
+
OH
MeCN, 20 °C
30 min
4c (67%)
6 (10%)
Scheme 2
the presence of Pd(PPh3)4, the N-allylation of 3c proceed- The iridium-catalyzed allylation using hydroxylamines
ed smoothly to give the N,O-diallylated product 8, which was successfully applied to a novel tandem cyclization of
has the N-linear and O-branched substituents. The O- 13 (Scheme 4). In the presence of [IrCl(cod)]2, the reac-
allylation of 5 also proceeded smoothly to give the O-lin- tion of 13 with N-Boc-hydroxylamine (2c) proceeded
ear and N-branched product 9 in 72% yield. We next stud- smoothly to give the six-membered product 14c in 48
ied the utility of the O,N-disubstituted hydroxylamine for yield, after being stirred at 50 °C for 1.5 hours.9 The reac-
a temporary tether in the ring-closing metathesis.7 The tion of 13 with N-Cbz-hydroxylamine (2d) afforded the
N,O-disubstituted hydroxylamine 11 was prepared from cyclic product 14d in 53% yield. In contrast, the reaction
the reaction of 10 with 5. Treatment of 11 with Grubbs’ of 13 with N-benzylhydroxylamine did not give a cyclic
catalyst in toluene furnished the cyclic product 12 in 75% product. For comparison with hydroxylamines, the reac-
yield.8
tion of 13 with hydrazines was studied. In contrast to
hydroxylamines, the hydrazines having N-electron-with-
drawing substituents such as N,N′-di-Boc-hydrazine did
not work. The effective formation of cyclic product 14e
was observed when N,N′-diphenylhydrazine (2e) was em-
ployed.
BocHN OH 2c
Boc
N
Pd(PPh3)4
Ph
Ph
Ph
Ph
O
MeCN, 20 °C
1 h
7c (76%)
OCO2Me
BocHNOH 2c
BocN O
Ph
1 (2.5 equiv)
[IrCl(cod)]2
CbzHN OH 2d
Cbz
N
Pd(PPh3)4
MeCN, 50 °C
O
14c (48%)
1.5 h
MeCN, 20 °C
1 h
7d (79%)
CbzHNOH 2d
MeO2CO
OCO2Me
CbzN O
3c
[IrCl(cod)]2
Ph Boc
Pd(PPh3)4
N
Ph
MeCN, 50 °C
1.5 h
O
14d (53%)
PhN NPh
14e (49%)
MeCN, 20 °C
30 min
13
OCO2Me
8 (81%)
Boc
Ph
PhHNNHPh 2e
5
[IrCl(cod)]2
1 (1.0 equiv)
N
Pd(PPh3)4
Ph
O
MeCN, 20 °C
10 min
Ph
MeCN, 20 °C
30 min
9 (72%)
Scheme 4
5
Boc
OCO2Me
Pd(PPh3)4
In conclusion, the oxygen atom of hydroxylamines having
an N-electron-withdrawing substituent acted as a reactive
nucleophile in the iridium- or palladium-catalyzed allylic
substitution.
N
O
MeCN, 20 °C
30 min
Ph
11 (78%)
10
Grubbs' catalyst (10 mol%)
toluene, 100 °C, 12 h
A mixture of 13 (100 mg, 0.388 mmol), hydroxylamines 2c or 2d
(0.388 mmol), and [IrCl(cod)]2 (10 mg, 0.0155 mmol) in MeCN
(1.0 mL) was stirred under argon atmosphere at 50 °C for 1.5 h. The
reaction mixture was concentrated at reduced pressure. Purification
of the residue by preparative TLC (hexane–EtOAc, 10:1) afforded
14c or 14d.
Major isomer of 14c: IR (CHCl3) 1698 cm–1; 1H NMR (500 MHz ,
CDCl3) δ 6.06–5.90 (2 H, m), 5.29–5.12 (4 H, m), 4.48 (2 H, br s),
N
N
Ar
Ar
Cl
Ru
Cl
O NBoc
Ph
Ph
PCy3
Grubbs' catalyst
(Ar = 2,3,6-Trimethylbenzene)
12 (75%)
Scheme 3
Synlett 2003, No. 4, 567–569 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
O-Allylic Substitution of Hydroxylamine Derivatives
569
2.03 (2 H, m), 1.56 (2 H, m), 1.43 (9 H, s); 13C NMR (125 MHz ,
CDCl3) δ 154.8, 136.4, 135.6, 117.0, 115.9, 80.9, 79.1, 56.9, 28.3,
23.9, 23.6; HRMS: Calcd for C13H21NO3 (M+): 239.1521, Found:
239.1525.
(3) (a) Evans, P. A.; Leahy, D. K. J. Am. Chem. Soc. 2002, 124,
7882. (b) Kim, H.; Lee, C. Org. Lett. 2002, 4, 4369.
(4) Procedures for preparing the allylated hydroxylamines often
require lengthy linear manipulation. See: (a) Bull, S. D.;
Davies, S. G.; Domingez, S. H.; Jones, S.; Price, A. J.;
Sellers, T. G. R.; Smith, A. D. J. Chem. Soc., Perkin Trans.
1 2002, 2141. (b) Ishikawa, T.; Kawakami, M.; Fukui, M.;
Yamashita, A.; Urano, J.; Saito, S. J. Am. Chem. Soc. 2001,
123, 7734.
(5) (a) Murahashi, S.; Imada, Y.; Taniguchi, Y.; Kodera, Y.
Tetrahedron Lett. 1988, 29, 2973. (b) Genet, J.-P.;
Thorimbert, S.; Touzin, A.-M. Tetrahedron Lett. 1993, 34,
1159.
(6) The iridium-catalyzed regioselective allylic amination was
recently achieved by Takeuchi’s group. See: (a) Takeuchi,
R.; Ue, N.; Tanabe, K.; Yamashita, K.; Shiga, N. J. Am.
Chem. Soc. 2001, 123, 9525. (b) Takeuchi, R.; Shiga, N.
Org. Lett. 1999, 1, 265. (c) For a review, see: Takeuchi, R.
Synlett 2002, 1954.
Major isomer of 14d: IR (CHCl3) 1697 cm–1; 1H NMR (500 MHz ,
CDCl3) δ 7.37–7.30 (10 H, m), 5.95–6.08 (4 H, m), 5.12–5.33 (12
H, m), 4.63–4.64 (2 H, m), 4.55 (2 H, br s), 1.61–2.15 (8 H, s); 13
C
NMR (125 MHz , CDCl3) δ 155.3, 136.1, 135.9, 135.0, 128.3, 127.9
(2 C), 117.4, 116.4, 79.4, 67.2, 56.6, 23.6, 23.2; HRMS: Calcd for
C16H19NO3 (M+): 273.1365, Found: 273.1358.
Acknowledgement
This work was supported in part by The Japan Health Sciences
Foundation and Grant-in-Aid for Scientific Research (C) from the
Ministry of Education, Culture, Sports, Science and Technology of
Japan.
(7) Recently, the effect of a hydroxylamine tether on
intramolecular Diels-Alder reactions was reported. See:
Ishikawa, T.; Senzaki, M.; Kadoya, R.; Morimoto, T.;
Miyake, N.; Izawa, M.; Saito, S. J. Am. Chem. Soc. 2001,
123, 14607.
(8) For recent reviews on ring-closing methathesis, see:
(a) Grubbs, R. H. Tetrahedron 1998, 54, 4413. (b) Pandit,
U. K.; Overleeft, H. S.; Borer, B. C.; Bieraugel, H. Eur. J.
Org. Chem. 1999, 9.
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Synlett 2003, No. 4, 567–569 ISSN 0936-5214 © Thieme Stuttgart · New York