Hydroxylamines as oxygen atom nucleophiles in transition-metal-catalyzed allylic substitution

Article abstract of DOI:10.1021/jo047897t

(Chemical Equation Presented) The viability of hydroxylamines as nucleophiles in transition-metal-catalyzed allylic substitutions was examined. We have found that the oxygen atom of hydroxylamines having an N-electron-withdrawing substituent (also known a

Full text of DOI:10.1021/jo047897t

Hydroxylamines as Oxygen Atom Nucleophiles in
Transition-Metal-Catalyzed Allylic Substitution
Hideto Miyabe,† Kazumasa Yoshida,† Masashige Yamauchi,‡ and Yoshiji Takemoto*,†
Graduate School of Pharmaceutical Sciences, Kyoto University, Yoshida, Sakyo-ku,
Kyoto 606-8501, Japan, and Faculty of Pharmaceutical sciences, Josai University, Keyakidai,
Sakado, Saitama 350-0295, Japan
takemoto@pharm.kyoto-u.ac.jp
Received November 26, 2004
The viability of hydroxylamines as nucleophiles in transition-metal-catalyzed allylic substitutions
was examined. We have found that the oxygen atom of hydroxylamines having an N-electron-
withdrawing substituent (also known as hydroxamic acids) acts as a reactive nucleophile. The
palladium-catalyzed O-allylic substitution of hydroxylamines with allylic carbonate afforded the
linear hydroxylamines. The selective formation of the branched hydroxylamines was observed in
iridium-catalyzed reaction. Regio- and enantioselective allylic substitution of the unsymmetrical
phosphates with hydroxylamines was studied by using the iridium complex of chiral pybox ligand.
The aqueous-medium reaction with hydroxylamines proceeded smoothly in the presence of Ba-
(OH)2‚H2O to give the branched products with good enantioselectivities.
Introduction
interested in developing the effective oxygen nucleophiles
for the synthesis of functionalized allylic compounds
(Figure 1). For this purpose, we have focused our efforts
toward allylic substitution with the oxygen nucleophiles
directly connected with heteroatoms. As our first suc-
cessful results, we have recently reported the utility of
oximes and hydroxylamines having an N-electron-
withdrawing substituent as oxygen nucleophiles in tran-
sition-metal-catalyzed allylic substitution.4,5 These re-
sults indicate that oxime and hydroxylamine act as soft
Transition-metal-catalyzed allylic substitutions have
been developed as fundamentally important cross-
coupling reactions.1 In comparison with allylic amination
and alkylation, the corresponding reaction with oxygen
nucleophiles has received much less attention due to the
poor nucleophilic property of the oxygen atom and also
low regioselectivity attained in the reaction.2 Therefore,
O-allylic substitution had been largely limited to car-
boxylate and phenolic nucleophiles, except for the in-
tramoleclar reactions.2 Recently, synthetically useful
studies have been directed toward allylic substitution
with alcohols under basic conditions.3 Our laboratory is
(2) For some selected examples, see: (a) Stork, G.; Poirier, J. M. J.
Am. Chem. Soc. 1983, 105, 1073. (b) Stanton, S. A.; Felman, S. W.;
Parkhurst, C. S.; Godleski, S. A. J. Am. Chem. Soc. 1983, 105, 1964.
(c) Keinan, E.; Sahai, M.; Roth, Z. J. Org. Chem. 1985, 50, 3558. (d)
Trost, B. M.; Tenaglia, A. Tetrahedron Lett. 1988, 29, 2931. (e) Goux,
C.; Massacret, M.; Lhoste, P.; Sinou, D. Organometallics 1995, 14, 4585.
(f) Satoh, T.; Ikeda, M.; Miura, M.; Nomura, M. J. Org. Chem. 1997,
62, 4877. (g) Trost, B. M.; Tang, W.; Schulte, J. L. Org. Lett. 2000, 2,
4013. (h) Evans, P. A.; Leahy, D. K. J. Am. Chem. Soc. 2000, 122, 5012.
(i) Labrosse, J.-R.; Lhoste, P.; Sinou, D. J. Org. Chem. 2001, 66, 6634.
(j) Konno, T.; Nagata, K.; Ishihara, T.; Yamanaka, H. J. Org. Chem.
2002, 67, 1768.
(3) For some selected examples, see: (a) Keinan, E.; Sahai, M.; Roth,
Z. J. Org. Chem. 1985, 50, 3558. (b) Trost, B. M.; McEachern, E. J.;
Toste, F. D. J. Am. Chem. Soc. 1998, 120, 12702. (c) Trost, B. M.; Tang,
W.; Schulte, J. L. Org. Lett. 2000, 2, 4013. (d) Evans, P. A.; Leahy, D.
K. J. Am. Chem. Soc. 2002, 124, 7882. (e) Kim, H.; Lee, C. Org. Lett.
2002, 4, 4369. (f) Evans, P. A.; Leahy, D. K.; Slieker, L. M. Tetrahe-
dron: Asymmetry 2003, 14, 3613.
* To whom correspondence should be addressed. Fax: +81-75-753-
4569.
† Kyoto University.
‡ Josai University.
(1) For some reviews, see: (a) Frost, C. G.; Howarth, J.; Williams,
J. M. J. Tetrahedron: Asymmetry 1992, 3, 1089. (b) Trost, B. M. Chem.
Rev. 1996, 96, 395. (c) Johannsen, M.; Jorgensen, K. A. Chem. Rev.
1998, 98, 1689. (d) Pfaltz, A.; Lautens, M. In Comprehensive Asym-
metric Catalysis; Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.;
Springer: Berlin, Germany, 1999; Vol. 2, pp 833-884. (e) Trost, B.
M.; Lee, C. B. In Catalytic Asymmetric Synthesis II; Ojima, I. Ed.;
Wiley-VCH: Weinheim, Germany, 2000; pp 593-650. (f) Trost, B. M.
Chem. Pharm. Bull. 2002, 50, 1. (g) Trost, B. M.; Crawley, M. L. Chem.
Rev. 2003, 103, 2921.
10.1021/jo047897t CCC: $30.25 © 2005 American Chemical Society
Published on Web 02/08/2005
2148
J. Org. Chem. 2005, 70, 2148-2153

Hydroxylamines as Oxygen Atom Nucleophiles
SCHEME 1
FIGURE 1. Hydroxylamines and oximes as oxygen atom
nucleophiles.
nucleophiles due to their equilibrium acidities being
enhanced by a CdN bond or electron-withdrawing sub-
stituent. In this paper, we describe the in detail study of
hydroxylamines as oxygen nucleophiles in palladium or
iridium-catalyzed allylic substitutions. We also report the
iridium-catalyzed asymmetric reaction.
Hydroxylamine derivatives are the attractive synthetic
reagents for allylic substitution because they have ni-
trogen and oxygen atoms as nucleophiles. However,
allylic substitution using hydroxylamines has been lim-
ited to palladium-catalyzed amination, as a result of the
reaction of an electrophilic π-allyl palladium complex
with the nucleophilic nitrogen atom of hydroxylamines.6
Additionally, procedures for preparing the allylated hy-
droxylamines often require lengthy linear manipulation.7
As shown below, this reaction is extremely facile and give
allylated hydroxylamines in good yield under mild reac-
tion conditions.
TABLE 1. Iridium-Catalyzed Reaction of
Hydroxylamine Derivatives 4A-Ea
product (% yield)b
hydroxyl-
entry reagent solvent amine
time
5
6
1
2
1a
1a
1a
1a
1a
1a
1a
1a
2
MeCN
MeCN
MeCN
MeCN
MeCN
THF
CH2Cl2
toluene
MeCN
MeCN
4A
4B
4C
4D
4E
4D
4D
4D
4D
4D
10 min 5Aa (92)
none
3 h
6 h
5Ba (53)
5Ca (34)
6Ba (37)
6Ca (21)
6Da (98)
3
4
10 min none
5
3 h
no reaction
6
3.5 h
3.5 h
3.5 h
24 h
24 h
none
6Da (92)
6Da (86)
6Da (74)
7
none
none
no reaction
8
9
Results and Discussion
10
3a
6Da (5)
a Reactions were carried out using allylic reagents (1 equiv) and
hydroxylamine derivatives 4A-E (1 equiv) in the presence of
[IrCl(cod)]2 (4 mol %). b Isolated yields.
Allylic Substitution of Hydroxylamines Having
an N-Electron-Withdrawing Substituent. Controlling
the regioselectivities has been of great importance in
allylic substitution of simple acyclic substrates.8 The
iridium-catalyzed regioselective allylic amination giving
the branched products was achieved by Takeuchi’s
group.9 Therefore, the iridium-catalyzed allylic substitu-
tion has been a subject of current interest. The effective
iridium-catalyzed etherification of alcohols with allyl
acetate was also reported by Ishii’s group.10 The highly
regio- and enantioselective allylic substitutions have been
recently disclosed by using an iridium-phosphoramidite
complex.11
As a part of our studies on the iridium-catalyzed
reactions,12 we investigated the iridium-catalyzed allylic
substitution of several hydroxylamines 4A-E (Scheme
1). In the presence of [IrCl(cod)]2 (4 mol %), the reactions
of hydroxylamines 4A-E with allylic carbonate 1a were
run in MeCN at 20 °C (Table 1, entries 1-5). The
N-benzylhydroxylamine 4A worked as a nitrogen nucleo-
phile to give the branched N-allylated product 5Aa in
92% yield without formation of O-allylated product 6Aa
(entry 1). In contrast, both nitrogen and oxygen atoms
on N-Boc-hydroxylamine 4B and N-Cbz-hydroxylamine
4C acted as nucleophiles to give the N-allylated products
5Ba-Ca and O-allylated products 6Ba-Ca (entries 2
(4) Miyabe, H.; Yoshida, K.; Matsumura, A.; Yamauchi, M.; Take-
moto, Y. Synlett 2003, 567.
(5) (a) Miyabe, H.; Matsumura, A.; Yoshida, K.; Yamauchi, M.;
Takemoto, Y. Synlett 2004, 2123. (b) Miyabe, H.; Matsumura, A.;
Moriyama, K.; Takemoto, Y. Org. Lett. 2004, 6, 4631.
(6) (a) Murahashi, S.; Imada, Y.; Taniguchi, Y.; Kodera, Y. Tetra-
hedron Lett. 1988, 29, 2973. (b) Genet, J.-P.; Thorimbert, S.; Touzin,
A.-M. Tetrahedron Lett. 1993, 34, 1159.
(7) (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.
(8) For some selected examples, see: (a) Hayashi, T.; Kishi, K.;
Yamamoto, A.; Ito, Y. Tetrahedron Lett. 1990, 31, 1743. (b) Trost, B.
M.; Hachiya, I. J. Am. Chem. Soc. 1998, 120, 1104. (c) Glorius, F.;
Pfaltz, A. Org. Lett. 1999, 1, 141. (d) Bartels, B.; Helmchen, G. Chem.
Commun. 1999, 741. (d) You, S.-L.; Zhu, X.-Z.; Luo, Y.-M.; Hou, X.-L.;
Dai, L.-X. J. Am. Chem. Soc. 2001, 123, 7471. (e) Trost, B. M.; Dogra,
K. J. Am. Chem. Soc. 2002, 124, 7256. (f) Bartels, B.; G.-Yebra, C.;
Helmchen, G. Eur. J. Org. Chem. 2003, 1097.
(11) For some selected examples, see: (a) Bartels, B.; Helmchen,
G. Chem. Commun. 1999, 741. (b) Fuji, K.; Kinoshita, N.; Tanaka, K.;
Kawabata, T. Chem. Commun. 1999, 2289. (c) Ohmura, T.; Hartwig,
J. F. J. Am. Chem. Soc. 2002, 124, 15164. (d) Lo´pez, F.; Ohmura, T.;
Hartwig, J. F. J. Am. Chem. Soc. 2003, 125, 3426. (e) Lipowsky, G.;
Helmchen G. Chem. Commun. 2004, 116. (f) Welter, C.; Koch, O.;
Lipowsky, G.; Helmchen, G. Chem. Commun. 2004, 896. (g) Fisher,
C.; Defieber, C.; Suzuki, T.; Carreira, E. M. J. Am. Chem. Soc. 2004,
126, 1629. (h) Tissot-Croset, K.; Polet, D.; Alexakis, A. Angew. Chem.,
Int. Ed. 2004, 43, 2426. (i) Alexakis, A.; Polet, D. Org. Lett. 2004, 6,
3529. (j) Shu, C.; Hartwig, J. F. Angew. Chem., Int. Ed. 2004, 43, 4794.
(k) Shu, C.; Leitner, A.; Hartwig, J. F. Angew. Chem., Int. Ed. 2004,
43, 4797.
(9) For some selected examples, see: (a) Kezuka, S.; Kanemoto, K.;
Takeuchi, R. Tetrahedron Lett. 2004, 45, 6403. (b) Takeuchi, R.; Ue,
N.; Tanabe, K.; Yamashita, K.; Shiga, N. J. Am. Chem. Soc. 2001, 123,
9525. (c) Takeuchi, R.; Ue, N.; Tanabe, K. Angew. Chem., Int. Ed. 2000,
39, 1975. (d) Takeuchi, R.; Shiga, N. Org. Lett. 1999, 1, 265. (e)
Takeuchi, R.; Kashio, M. J. Am. Chem. Soc. 1998, 120, 8647. (f)
Takeuchi, R.; Kashio, M. Angew. Chem., Int. Ed. 1997, 36, 263. For a
review, see: (g) Takeuchi, R. Synlett 2002, 1954.
(12) Our studies on the iridium-catalyzed reaction, see: (a) Kanaya-
ma, T.; Yoshida, K.; Miyabe, H.; Takemoto, Y. Angew. Chem., Int. Ed.
2003, 42, 2054. (b) Kanayama, T.; Yoshida, K.; Miyabe, H.; Kimachi,
Y.; Takemoto, Y. J. Org. Chem. 2003, 68, 6197. (c) Miyabe, H.; Yoshida,
K.; Kobayashi, Y.; Matsumura, A.; Takemoto, Y. Synlett 2003, 1031.
(10) For some selected examples, see: (a) Nakagawa, H.; Hiraba-
yashi, T.; Sakaguchi, S.; Ishii, Y. J. Org. Chem. 2004, 69, 3474. (b)
Okimoto, Y.; Sakaguchi, S.; Ishii, Y. J. Am. Chem. Soc. 2002, 124, 1590.
J. Org. Chem, Vol. 70, No. 6, 2005 2149

Miyabe et al.
SCHEME 2
SCHEME 3
TABLE 2. Palladium-Catalyzed Reaction of
Hydroxylamine Derivatives 4B-D
SCHEME 4
product (% yield)a
reagent hydroxyl-
entry (equiv)
amine
time
7
8
9
1b 1a (1.0)
2b 1a (1.0)
3b 1a (1.0)
4D
4B
4C
4B
4C
10 min
8Da (93)
30 min 7Ba (10) 8Ba (67) 9Ba (6)
1.5 h
1 h
1 h
8Ca (59) 9Ca (12)
9Ba (76)
4c
5c
1a (2.5)
1a (2.5)
9Ca (79)
a Isolated yields. b Reactions were carried out using 1a (1 equiv)
and hydroxylamine derivatives 4B-D (1 equiv) in the presence
of Pd(PPh3)4 (4 mol %). c Reactions were carried out using 1a (2.5
equiv) and hydroxylamine derivatives 4B,C (1 equiv) in the
presence of Pd(PPh3)4 (4 mol %).
TABLE 3. Reaction of 1a with Hydroxylamine
Derivatives 4F-I
and 3). The N-benzoyl-N-phenylhydroxylamine 4D worked
well as an oxygen nucleophile to give the branched
O-allylated product 6Da in 98% yield after being stirred
for 10 min (entry 4). In contrast to hydroxylamines 4B-D
having an N-electron-withdrawing substituent, the reac-
tion of N,N-dibenzylhydroxylamine 4E did not occur after
being stirred at 20 °C for 3 h (entry 5). In our recent
studies, the nitrogen atom of guanidine derivatives
having two N-electron-withdrawing substituents acted
as a reactive nucleophile in allylic substitution.13 On the
basis of these observations, it is noted that the stability
of conjugate base of hydroxylamines would be an impor-
tant criteria for the nucleophilic property of an oxygen
atom of hydroxylamines. Thus, a rational hypothesis of
this reaction is that hydroxylamine 4D would be ef-
fectively activated by methoxide generated from the
carbonate 1a as shown in Scheme 1. Considering the
solvent effect, polar solvent such as MeCN gave the best
result. The reaction in other solvents such as THF, CH2-
Cl2, and toluene proceeded slowly (entries 6-8). In
contrast to allylic carbonate 1a, a linear carbonate 2 and
phosphate 3a did not work well under the similar
reaction conditions (entries 9 and 10).
We next investigated the palladium-catalyzed allylic
substitution of several hydroxylamines 4B-D (Scheme
2). The palladium-catalyzed reaction of N-benzoyl-N-
phenylhydroxylamine 4D with carbonate 1a afforded the
linear O-allylated product 8Da in 93% yield after being
stirred for 10 min (Table 2, entry 1). In the case of N-Boc-
hydroxylamine 4B, the O-allylation was dominant to give
the O-allylated product 8Ba in 67% yield, accompanied
with a small amount of N-allylated product 7Ba and
diallylated product 9Ba (entry 2). The similar trend was
observed in the reaction of N-Cbz-hydroxylamine 4C
(entry 3). Since hydroxylamines having an N-electron-
withdrawing substituent have shown excellent reactivity
toward π-allyl palladium complexs, the palladium-
entry
hydroxylamine
catalyst
product
yield (%)a
1b
2b
3b
4b
5c
6c
7c
8c
4F
4G
4H
4I
4F
4G
4H
4I
[IrCl(cod)]2
[IrCl(cod)]2
[IrCl(cod)]2
[IrCl(cod)]2
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
6Fa
6Ga
6Ha
6Ia
8Fa
8Ga
8Ha
8Ia
82
87
86
85
96
98
95
93
a Isolated yields. b Reactions were carried out using 1a (1 equiv)
and hydroxylamine derivatives 4F-I (1 equiv) in MeCN in the
presence of [IrCl(cod)]2 (4 mol %). c Reactions were carried out
using 1a (1 equiv) and hydroxylamine derivatives 4F-I (1 equiv)
in MeCN in the presence of Pd(PPh3)4 (4 mol %).
catalyzed N,O-diallylation of hydroxylamines was exam-
ined in latter cases. As expected, the selective formation
of N,O-diallylated products 9Ba and 9Ca was observed
in the reaction of N-Boc-hydroxylamine 4B or N-Cbz-
hydroxylamine 4C with 2.5 equiv of 1a (entries 4 and
5).
We also investigated the additional allylation of the
branched hydroxylamines 5Ba and 6Ba prepared from
the iridium-catalyzed reaction (Scheme 3). Although the
iridium-catalyzed allylation of 5Ba and 6Ba did not
proceed probably as a result of the low activity of iridium
catalyst, the palladium-catalyzed allylation gave the N,O-
diallylated products 10 and 11. In the presence of Pd-
(PPh3)4, the O-allylation of 5Ba proceeded smoothly to
give the diallylated product 10, which has the O-linear
and N-branched substituents. The palladium-catalyzed
N-allylation of 6Ba also proceeded smoothly to give the
N-linear and O-branched product 11 in 81% yield.
To study the effect of a N-electron-withdrawing sub-
stituent, several hydroxylamines 4F-I were employed
(Scheme 4). As expected, hydroxylamines 4F-I having
a N-electron-withdrawing substituent worked well as
oxygen atom nucleophiles (Table 3). In the presence of
[IrCl(cod)]2, the reactions of 4F-I proceeded smoothly to
give the branched product 6Fa-Ia with excellent regi-
(13) Miyabe, H.; Matsumura, A.; Yoshida, K.; Yamauchi, M.; Take-
moto, Y. Lett. Org. Chem. 2004, 1, 119.
2150 J. Org. Chem., Vol. 70, No. 6, 2005

Hydroxylamines as Oxygen Atom Nucleophiles
SCHEME 5
SCHEME 7
SCHEME 8
SCHEME 6
employed. However, the utility of C2-symmetric pybox
ligand in transition-metal-catalyzed allylic substitution
has not been widely invesitigated.14 We have recently
demonstrated that an iridium-pybox complex has the
potential to control regio- and enantiostereochemistry in
allylic substitution with oximes and amines.5b As a part
of our program directed toward the development of
reactions catalyzed by the iridium-pybox complex, we
next investigated the enantioselective allylic substitution
with the oxygen atom of hydroxylamines. Recently, the
iridium-idane-pybox catalyst was also used in a reduc-
tive aldol reaction.15
The use of water as a solvent has many advantages in
organic synthesis from both economical and environmen-
tal points of view.16 In our recent study,5b the iridium-
pybox complex catalyzed reaction in organic solvent.
Therefore, utility of the iridium-pybox complex in aque-
ous media has been the new focus of our efforts. We
investigated the aqueous-medium reaction of 3a with 4D
under several reaction conditions (Scheme 8). As ex-
pected, the chiral iridium complex of pybox ligand
exhibited a good activity even in aqueous media. Ad-
ditionally, the water-resistant phosphate 3a participated
in the present aqueous-medium reaction even under basic
reaction conditions, although the reaction of phosphate
3a did not proceed effectively in the absence of the base.
To a solution of hydroxylamine 4D and Ba(OH)2‚H2O in
THF-H2O was added a solution of the phosphate 3a,
oselectivities (entries 1-4). The palladium-catalyzed
reactions afforded the linear O-allylated product 8Fa-
Ia in good yields (entries 5-8).
As hydroxylamines having two N-electron-withdrawing
substituents, N-hydroxyphthalimide 4J and N-hydroxy-
succinimide 4K were employed (Scheme 5). These hy-
droxylamine derivatives worked well. The iridium- and
palladium-catalyzed reactions afforded the branched and
linear products, respectively.
Recently, a mild and efficient method for allylic etheri-
fication using zinc alkoxides was reported by Lee’s
group.3e To test the viability of zinc alkoxide generated
from hydroxylamine, the reaction of N,N-dibenzylhy-
droxylamine 4E was investigated in the presence of
Et2Zn as shown in Scheme 6. Although the reaction of
4E did not proceed without base (Table 1, entry 5), the
iridium-catalyzed O-allylation of 4E afforded the branched
product 6Ea by using Et2Zn as a base. In the presence
of Pd(PPh3)4 and Et2Zn, a 75% yield of the linear product
8Ea was obtained.
Finally, we examined the O-allylation of hydroxy-
lamine 4D with allylic carbonates 1b-d bearing a variety
of substituents (Scheme 7). Allylic reagents having an
electron-withdrawing substituent or bulky 1-naphthyl
groups worked well. The iridium- and palladium-cata-
lyzed reactions proceeded with excellent regioselectivities
to afford the branched products 6Db-Dd and linear
products 8Db-Dd, respectively.
(14) (a) Bourguignon, J.; Bremberg, U.; Dupas, G.; Hallman, K.;
Hagberg, L.; Hortala, L.; Levacher, V.; Lutsenko, S.; Macedo, E.;
Moberg, C.; Que´guiner, C.; Rahm, F. Tetrahedron 2003, 59, 9583. (b)
Chelucci, G.; Deriu, S.; Pinna, G. A.; Saba, A.; Valenti, R. Tetrahe-
dron: Asymmetry 1999, 10, 3803.
(15) Zhao, C.-X.; Duffey, M. O.; Taylor, S. J.; Morken, J. P. Org. Lett.
2001, 3, 1829.
(16) Garner, P. P.; Parker, D. T.; Gajewski, J. J.; Lubineau, A.; Ange´,
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.
Enantioselective Allylic Substitution of Hydroxy-
lamines. The development of regio- and enantioselective
allylic substitution has attracted much recent atten-
tion,8,11 and thus, a variety of chiral ligands have been
J. Org. Chem, Vol. 70, No. 6, 2005 2151

Miyabe et al.
TABLE 4. Reaction of 3a with 4D in the Presence of
SCHEME 9
Ba(OH)2‚H2Oa
entry
solvent
time (h) % yieldb (ratioc) % eed
1
2
3
4
5
THF-H2O (10:1)
toluene-H2O (10:1)
CH2Cl2-H2O (10:1)
PhCF3-H2O (2:1)
PhCF3-H2O (1:2)
3
3
3
4
4
95 (37:63)
37 (45:55)
96 (65:35)
70 (80:20)
65 (77:23)
80
35
82
87
84
a Reactions were carried out in the presence of Ba(OH)2‚H2O
(1 equiv). b Combined yields. c Ratio for 6Da:8Da. d Enantioste-
reoselectivities were determined by HPLC analysis.
TABLE 5. Effect of Base on Reaction of 3a with 4D in
PhCF3-H2Oa
TABLE 6. Reaction of 3a-d with 4D-K in PhCF3-H2Oa
% yieldb (ratioc)
% eed
entry
nucleophile
reagent
% yieldb (ratioc)
% eed
entry
base
time (h)
1
2
3
4
5
6
7
none
BaCO3
CsOH‚H2O
Cs2CO3
NaOH
NaOH, TBAB
Ca(OH)2
20
15
15
15
15
5
trace
1
2
3
4
5
6
7
8
4E
4F
4G
4H
4I
4D
4D
4D
3a
3a
3a
3a
3a
3b
3c
3d
no reaction
75 (77:23)
63 (64:36)
70 (76:24)
68 (80:20)
61 (72:28)
67 (79:21)
60 (94:6)
10 (>95:5)
30 (82:18)
30 (85:15)
33 (82:18)
67 (71:29)
85 (50:50)
60
67
56
65
86
88
82
68
82
87
62
72
78
0.2
a Reactions were carried out in PhCF3-H2O (2:1, v/v). b Com-
bined yields. c Ratio for 6Da:8Da. d Enantiostereoselectivities were
determined by HPLC analysis.
a Reactions were carried out in PhCF3-H2O (2:1, v/v) in the
presence of Ba(OH)2‚H2O (1 equiv). b Combined yields. c Ratio for
6Db-Ia:8Db-Ia. d Enantiostereoselectivities were determined
by HPLC analysis.
[IrCl(cod)]2 (6 mol %), and chiral ligand (12 mol %) in
THF, and then the reaction mixture was stirred at 20
°C for 3 h (Table 4, entry 1). This monophasic reaction
proceeded smoothly to give good yields of the products
6Da and 8Da, although a low regioselectivity was
observed. Enantiomeric excess of 6Da was determined
to be 80% ee by high performance liquid chromatography
analysis using Chiralcel AD-H. In contrast, the pal-
ladium-catalyzed reaction using Ph-pybox gave the linear
product as major products. The replacement of THF-
H2O with toluene-H2O led to a decrease in the enantio-
selectivity (entry 2). The biphasic reaction in CH2Cl2-
H2O also proceeded smoothly to give 6Da in 82% ee
(entry 3). The use of PhCF3-H2O (2:1, v/v) as a biphasic
solvent led to an increase in regioselectivity to 80:20 and
enantioselectivity to 87% ee (entry 4). The similar result
was observed in PhCF3-H2O (1:2, v/v) (entry 5). Although
the reaction using anhydrous MeCN as solvent proceeded
smoothly to give the good yields of the products, a low
enantioselectivity was observed. The absolute configu-
ration of product 6Da was determined to be S by
converting 6Da into authentic alcohol (S)-12.17 The
reduction of CdC and N-O bonds of 6Da was achieved
by hydrogenolysis in the presence of Pd(OH)2.
The base dramatically influenced the reactivity, regi-
oselectivity and enantioselectivity (Table 5). In the
absence of base, the reaction did not proceeded (entry 1).
When BaCO3, CsOH‚H2O, Cs2CO3 and NaOH were
employed as a base, the reactions proceeded slowly to give
the low yields of 6Da with moderate enantioselectivities
(entries 2-5). In the presence of TBAB, the reaction using
NaOH gave the 86% ee of branched product 6Da with a
75:25 regioselectivity (entry 6). In the presence of Ca-
(OH)2, the branched product 6Da was obtained with 88%
ee within 0.2 h, although a significant amount of the
linear product 8Da was obtained (entry 7). Nevertheless,
good ee values were obtained at lower reaction times with
low regioselectivity, whereas the opposite effect had been
noticed at longer reaction times using the bases shown
in Table 5.
Next, several hydroxylamines 4D-I and phosphates
3a-d were employed under the optimized reaction condi-
tions using Ba(OH)2‚H2O (Scheme 9). The reaction of 3a
with hydroxylamines 4F-I containing an electron-
withdrawing substituent proceeded smoothly to give the
products 6Fa-Ia and 8Fa-Ia (entries 2-5). It is im-
portant to note that practically no reaction with N,N-
dibenzyl hydroxylamine 4E occurred under the similar
reaction conditions (entry 1). These results indicate that
the stabilization of conjugate base of hydroxylamines by
an electron-withdrawing substituent is important for the
iridium-pybox complex-catalyzed enantioselective allylic
substitution as well as racemic reactions. Phosphates
3b-d worked well, allowing facile incorporation of struc-
tural variety (entries 6-8).
Conclusions
We have clearly demonstrated that the oxygen atom
of hydroxylamines acts as a reactive nucleophile in
transition-metal-catalyzed allylic substitutions. The elec-
tron-withdrawing substituents on the nitrogen atom of
hydroxylamine increased the acidity of the proton on the
oxygen atom to generate an O-anion and decreased the
nucleophilicity of the nitrogen atom. The linear O-
allylated products were obtained in the palladium-
catalyzed allylic substitution of allylic carbonates. The
selective formation of the branched products was also
observed in iridium-catalyzed reaction. In addition to the
enantioselective allylic substitution with oximes,5b the
enantioselective reaction with hydroxylamines disclosed
a broader aspect of the utility of the iridium-pybox
complex in allylic substitutions.
(17) Yoshioka, M.: Kawakita, T.; Ohno, M. Tetrahedron Lett. 1989,
30, 1657.
2152 J. Org. Chem., Vol. 70, No. 6, 2005

Hydroxylamines as Oxygen Atom Nucleophiles
Supporting Information Available: Experimental pro-
cedures and characterization data for all obtained compounds
and 1H and 13C NMR spectra of all obtained compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Acknowledgment. This work was supported in part
by a Grant-in-Aid for Young Scientists (B) (H.M.) from
the Ministry of Education, Culture, Sports, Science and
Technology of Japan, and Foundation for Reseach
Grants, 21st Century COE Program “Knowledge Infor-
mation Infrastructure for Genome Science”.
JO047897T
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