Direct use of allylic alcohols for platinum-catalyzed monoallylation of amines

Article abstract of DOI:10.1021/ol071365s

A new direct catalytic amination of allylic alcohols promoted by the combination of platinum and a large bite-angle ligand DPEphos was developed in which the allylic alcohol was effectively converted to a π-allylplatinum intermediate without the use of an activating reagent. The use of the DPEphos ligand was essential for obtaining high catalyst activity and high monoallylation selectivity of primary amines, allowing the formation of a variety of monoallylation products in good to excellent yield.

Full text of DOI:10.1021/ol071365s

ORGANIC
LETTERS
2007
Vol. 9, No. 17
3371-3374
Direct Use of Allylic Alcohols for
Platinum-Catalyzed Monoallylation of
Amines
Masaru Utsunomiya, Yoshiki Miyamoto, Junji Ipposhi, Takashi Ohshima,* and
Kazushi Mashima*
Department of Chemistry, Graduate School of Engineering Science, Osaka UniVersity,
Toyonaka, Osaka 560-8531, Japan
ohshima@chem.es.osaka-u.ac.jp; mashima@chem.es.osaka-u.ac.jp
Received June 8, 2007
ABSTRACT
A new direct catalytic amination of allylic alcohols promoted by the combination of platinum and a large bite-angle ligand DPEphos was
developed in which the allylic alcohol was effectively converted to a -allylplatinum intermediate without the use of an activating reagent. The
π
use of the DPEphos ligand was essential for obtaining high catalyst activity and high monoallylation selectivity of primary amines, allowing
the formation of a variety of monoallylation products in good to excellent yield.
Allylamines are ubiquitous in various biologically active
compounds and are highly useful substrates for many types
of reactions,1 such as asymmetric isomerization2 and ring-
closing metathesis.3 For the synthesis of allylamines, a
transition metal-catalyzed substitution reaction of activated
allylic alcohol derivatives with nitrogen nucleophiles is one
of the most powerful and reliable methods.4 The reaction
proceeds through π-allylmetal intermediates, generated by
the oxidative addition of allylic substrates to a low-valence
metal center, and following nucleophilic addition gives
allylamines as a consequence of new C-N bond formation
with high regio-, stereo-, and enantioselectivities. Since the
pioneering work of π-allylpalladium chemistry by Tsuji and
Trost,4 various efficient catalyst systems have been developed
and applied to the syntheses of natural and unnatural
compounds.1c In terms of atom-economy5 and environmental
concerns, however, these catalyses still have much room for
improvement. They usually require preactiVation of the
parent allylic alcohol to the corresponding allylic halides,
carboxylates, carbonates, phosphates, and related compounds
(Scheme 1, 1 f 2 f 4). The activated substrates 2 cause
the formation of more than stoichiometric amounts of
unwanted salt waste both in the preactivation and amination
steps. Thus, the development of a direct catalytic substitution
(1) For reviews, see: (a) Cheikh, R. B.; Chaabouni, R.; Laurent, A.;
Mison, P.; Nafti, A. Synthesis 1983, 685. (b) Johannsen, M.; Jørgensen, K.
A. Chem. ReV. 1998, 98, 1689. (c) Trost, B. M.; Crawley, M. L. Chem.
ReV. 2003, 103, 2921.
(2) For reviews, see: (a) Akutagawa, S.; Tani, K. In Catalytic Asymmetric
Synthesis, 2nd ed.; Ojima, I., Ed.; Wiley-VCH: New York, 2000. (b) Noyori,
R. In Asymmetric Catalysis in Organic Synthesis; Wiley-VCH: New York,
1994; Chapter 3, p 95.
(3) For reviews, see: (a) Handbook of Metathesis; Grubbs, R. H., Ed.;
Wiley-VCH: Weinheim, Germany, 2003; Vols 1-3. (b) Nicolaou, K. C.;
Bulger, P. G.; Sarlar, D. Angew. Chem., Int. Ed. 2005, 44, 4490.
(4) For reviews, see: (a) Tsuji, J. Transition Metal Reagents and
Catalysis; Wiley-VCH: Weinheim, Germany, 2000. (b) Trost, B. M.; Lee,
C. In Catalytic Asymmetric Synthesis, 2nd ed.; Ojima, I., Ed.; Wiley-VCH:
New York, 2000.
(5) Trost, B. M. Science 1991, 254, 1471.
10.1021/ol071365s CCC: $37.00
© 2007 American Chemical Society
Published on Web 07/21/2007

generality of those reactions is, however, still limited. In
particular, the reaction with primary alkylamines resulted
only in the formation of the diallylation product18,19 because
of the higher nucleophilicity of the monoallylation product
compared to that of the substrate. Herein, we report a direct
conversion of allylic alcohols to allylamines catalyzed by 1
mol % of Pt-DPEphos complex with broad substrate general-
ity. The use of the large bite-angle ligand DPEphos is
essential for obtaining high catalyst activity. Moreover, a
sterically congested active site created by the large bite-angle
ligand led to the selective monoallylation of primary alkyl-
amines.
Scheme 1
A rate-determining step of the above-mentioned Pd-
catalyzed substitution reactions of allylic alcohol is the
activation of the hydroxyl group to form a π-allyl complex.
Based on the fact that the Pt-O bond is stronger than the
Pd-O bond,23 we anticipated that the platinum complex
would be a good candidate for a direct amination catalyst
for allylic alcohols. Thus, using Pt(cod)Cl2 as a metal source,
we first examined various phosphine ligands in the reaction
of allyl alcohol (1a) and aniline (2a). No reaction proceeded
in the absence of a phosphine ligand (Table 1, entry 1) and
of allylic alcohols with amines, which produces the desired
allylamines together with water as the sole coproduct, is
highly desired (1 f 4).6
Due to the poor leaving ability of the hydroxyl group, the
precedented direct aminations of allylic alcohols require
stoichiometric or catalytic amounts of an activator, such as
PPh3-DEAD,7 As2O3,8 B2O3,9 BF3‚Et2O,10 BEt3,11 BPh3,12,13
SnCl2,13 Ti(O-i-Pr)4,14 and CO2,15 including an efficient
enantioselective variant.16 Recently, palladium- and gold-
catalyzed direct aminations of allylic alcohols without the
use of an activator were developed by the research groups
of Ozawa and Yoshifuji,17 Ikariya,18 Shinokubo and Oshi-
ma,19 Le Floch,20 and Liu,21 realizing a highly atom
economical synthetic process for allylamines.22 The substrate
Table 1. Ligand Effects on Pt-Catalyzed Direct Amination of
Allyl Alcohol (1a)a
(6) For a review, see: Muzart, J. Eur. J. Org. Chem. 2007, 3077 and
references cited therein.
(7) Lumin, S.; Falck, J. R.; Capdevila, J.; Karara, A. Tetrahedron Lett.
1992, 33, 2091.
(8) Lu, X.; Lu, L.; Sun, J. J. Mol. Catal. 1987, 41, 245.
(9) Lu, X.; Jiang, X.; Tao, X. J. Organomet. Chem. 1988, 344, 109.
(10) Tsay, S.; Lin, L. C.; Furth, P. A.; Shum, C. C.; King, D. B.; Yu, S.
F.; Chen, B.; Hwu, J. R. Synthesis 1993, 329.
(11) (a) Kimura, M.; Tomizawa, T.; Horino, Y.; Tanaka, S.; Tamaru, Y.
Tetrahedron Lett. 2000, 41, 3627. (b) Kimura, M.; Horino, Y.; Mukai, R.;
Tanaka, S.; Tamaru, Y. J. Am. Chem. Soc. 2001, 123, 10401. (c) Kimura,
M.; Futamata, M.; Shibata, K.; Tamaru, Y. Chem. Commun. 2003, 234.
(12) Stary, I.; Stara´, I. G.; Kocovsky, P. Tetrahedron Lett. 1993, 34,
179.
(13) (a) Masuyama, Y.; Takahara, J. P.; Kurusu, Y. J. Am. Chem. Soc.
1988, 110, 4473. (b) Masuyama, Y.; Kagawa, M.; Kurusu, Y. Chem. Lett.
1995, 1121.
(14) (a) Itoh, K.; Hamaguchi, N.; Miura, M.; Nomura, M. J. Chem. Soc.,
Perkin Trans. 1 1992, 2833. (b) Satoh, T.; Ikeda, M.; Miura, M.; Nomura,
M. J. Org. Chem. 1997, 62, 4877. (c) Yang, S.-C.; Hung, C.-W. J. Org.
Chem. 1999, 64, 5000. (d) Yang, S.-C.; Tsai, Y.-C.; Shue, Y.-J. Organo-
metallics 2001, 20, 5326. (e) Shue, Y.-J.; Yang, S.-C.; Lai, H.-C.
Tetrahedron Lett. 2003, 44, 1481.
bite-angle
(deg)b
yield
(%)d
entry
ligand (x)
1
2
3
4
5
6
7
8
9
-
0
11
7
36
0
1
0
9
29
4
PPh3 (4.0)
P(OPh)3 (4.0)
P(2-furyl)3 (4.0)
DPPE (2.0)
(C6F5)2PCH2CH2P(C6H5)2 (2.0)
DPPP (2.0)
Ph2P(CH2)5PPh2 (2.0)
DPPF (2.0)
BINAP (2.0)
DPEphos (2.0)
Xantphos (2.0)
85
90
90
93
10
11
12
104 (106)c
108 (108)c
91
86
a 1.0 mmol scale, dioxane (0.5 mL). b Bite-angle of Pd complex.24 c Bite-
angle of (ligand)Pt(π-allyl)Cl complex optimized with the B3LYP function
(LANL2DZ for Pt and 6-31G** for others).25 d Determined by GC analysis.
(15) Sakamoto, M.; Shimizu, I.; Yamamoto, A. Bull. Chem. Soc. Jpn.
1996, 69, 1065.
(16) Yamashita, Y.; Gopalarathnam, A.; Hartwig, J. F. J. Am. Chem.
Soc. ASAP.
(17) (a) Ozawa, F.; Okamoto, H.; Kawagishi, S.; Yamamoto, S.; Minami,
T.; Yoshifuji, M. J. Am. Chem. Soc. 2002, 124, 10968. (b) Ozawa, F.;
Ishiyama, T.; Yamamoto, S.; Kawagishi, S.; Murakami, H.; Yoshifuji, M.
Organometallics 2004, 23, 1698.
(18) Kayaki, Y.; Koda, T.; Ikariya, T. J. Org. Chem. 2004, 69, 2595.
(19) Kinoshita, H.; Shinokubo, H.; Oshima, K. Org. Lett. 2004, 6, 4085.
(20) (a) Piechaczyk, O.; Doux, M.; Ricard, L.; Le Floch, P. Organome-
tallics 2005, 24, 124. (b) Piechaczyk, O.; Thoumazet, C.; Jean, Y.; Le Floch,
P. J. Am. Chem. Soc. 2006, 128, 14306. (c) Mora, G.; Deschamps, B.; van
Zutphen, S.; Le, Goff, X. F.; Ricard, L.; Le Floch, P. Organometallics 2007,
26, 1846.
the use of monodentate ligands gave unsatisfactory results
(entries 2-4), in contrast to the reports that Pd-monophos-
phine ligand complexes showed good catalyst activity.18,19
Commonly used diphosphine ligands such as DPPE, DPPP,
DPPF, and BINAP also led to low yields (entries 5-10).
(21) Guo, S.; Song, F.; Liu, Y. Synlett 2007, 964.
(22) Very recently, efficient bismuth-catalyzed direct substitution of
allylic alcohols with sulfonamides, carbamates, and carboxamides via
carbenium intermediate was reported, see: Qin, H.; Yamagiwa, N.;
Matsunaga, S.; Masakatsu, S. Angew. Chem., Int. Ed. 2007, 46, 409.
(23) Pedley, J. B.; Marshall, E. M. J. Phys. Chem. Ref. Data 1983, 12,
967.
3372
Org. Lett., Vol. 9, No. 17, 2007

The use of the large bite-angle ligands24,25 DPEphos and
Xantphos, however, dramatically improved catalyst activity
of this reaction to afford the desired product 3aa in 91%
yield (entry 11) and 86% yield (entry 12), respectively. It
was reported that the nucleophilic attack on the π-allylpal-
ladium complexes with larger P-Pd-P bite-angles was faster
than that with smaller bite-angles.26 The results shown in
Table 1 indicated that large bite-angle ligands are also quite
effective for platinum-catalyzed direct conversion of allylic
alcohol to the π-allylplatinum complex. To the best of our
knowledge, this is the first example of a platinum catalyzed
direct amination of allylic alcohols without the use of
activators.14d,27
Table 2. Direct Amination of Allylic Alcohol with Aromatic
Amines Catalyzed by Pt-DPEphos Complexa
We next examined the effects of a platinum source together
with palladium and nickel complexes using DPEphos as a
ligand.25 Although other PtII complexes such as Pt(cod)(OTf)2
gave only moderate yield (up to 64%), the Pt0 complex Pt-
(PPh3)4 showed comparable reactivity (89%). The combina-
tion of palladium with DPEphos gave only a low yield (up
to 11%) and nickel complexes did not promote the reaction
at all. Thus, in the presence of 1 mol % of Pt(cod)Cl2 and 2
mol % of DPEphos, substrate generality was investigated.
All reactions were performed in 4 mmol scale and the
isolated yields of the products are summarized in Table 2.
The reaction of various aniline derivatives with electron-
donating (entries 2-4) and electron-withdrawing (entry 5)
substituents proceeded smoothly to afford the corresponding
monoallylation product 4aa-ae in good yield along with a
small amount of the corresponding diallylation product 5aa-
ae (4:5 ) >10:1). When ortho-substituted aniline derivatives
were used as a substrate, the formation of diallylation
products 5 was effectively prevented and monoallylation
products 4 were obtained as the sole detectable products in
good yield (entries 6 and 7). Secondary amine 3h was also
applicable to the present catalysis (entry 8). The reaction of
trans-cinnamyl alcohol (1b) with aniline derivatives resulted
in comparable yield and selectivity (entries 9-11), in which
the corresponding trans-cinnamyl amine compounds were
obtained predominantly and neither cis-cinnamyl amine
compounds nor regioisomers were detected.
We then examined the use of alkylamines as nucleophiles.
In the precedented direct aminations of allylic alcohols
without the use of an activator, only monoallylation of the
secondary alkylamines and diallylation of primary alkyl-
amines were reported, and monoallylation of the primary
alkylamine has not yet been achieVed.6,17-21 In view of the
usefulness of the monoallylation products,1 we first focused
on the monoallylation of primary alkylamines. When ben-
zylamine (3i) was used, the reaction proceeded smoothly,
and all of substrate 1b was consumed in 18 h, affording
monoallylation product 4bi in 59% yield and diallylation
product 5bi in 20% yield (Table 3, entry 1). This moderate
a 4.0 mmol scale, dioxane (2.0 mL for 1a and 0.8 mL for 1b). b Isolated
yield. c Not detected in the reaction mixture.
selectivity, caused by the strong nucleophilicity of the
alkylamine, was improved by increasing the amine amount
from 1.5 to 3.0 equiv, and the desired product 4bi was
obtained in 79% yield (entry 2). Under these reaction
conditions, monoallylation of 1-naphthylamine (3j) and
n-hexylamine (3k) proceeded in the same efficiency to afford
4bj and 4bk, respectively, in 78% yield (entries 3 and 4).
The use of sterically more congested amines 3l improved
the selectivity of the monoallylation with better yield of the
desired products 4bl (entry 5, 86%). Moreover, in the case
of cyclohexylamine (3m), 1-phenethylamine (3n), and 1-ada-
mantylamine (3o), even less amine (1.5 equiv) realized
sufficient selectivity to produce the desired monoallylation
products in up to 90% yield (entries 6-8). Furthermore,
direct amination with secondary alkylamines proceeded quite
efficiently to afford the desired products 4bp-br in excellent
yields (entries 9-11, up to 96% yield).
Catalytic direct amination of allylic alcohols 1 provides
efficient access to various allylamines 4. Having established
this new process, the utility was demonstrated by one-step
synthesis of the antifungal drug naftifine (4bs).28 In the
presence of 1 mol % of the catalyst, the substitution reaction
of 1b with 1 equiv of N-methyl-1-naphthylamine (3s) was
(24) Due to the lack of information about bite angles of platinum
complexes, those of palladium complexes are shown in Table 1.
(25) See the Supporting Information for details.
(26) Johns, A. M.; Utsunomiya, M.; Incarvito, C. D.; Hartwig, J. F. J.
Am. Chem. Soc. 2006, 128, 1828.
(27) Pt-catalyzed direct amination of allylic alcohols with ammonia to
provide a mixture of mono-, di-, and triallylation products was reported,
see: Ishimura, Y.; Nagato, N. Jpn. Kokai Tokkyo Koho JP 63002958, 1988.
(28) Petranyi, G.; Ryder, N. S.; Stu¨tz, A. Science 1984, 224, 1239.
Org. Lett., Vol. 9, No. 17, 2007
3373

is the same product obtained by using terminal allylic alcohol
1b (Table 2, entry 9). Moreover, reactions of both a terminal
Table 3. Direct Amination of Allylic Alcohol with
Alkylamines Catalyzed by Pt-DPEphos Complexa
Scheme 3
allylic alcohol 1c and an internal allylic alcohol 6c gave a
mixture of products in almost the same distribution. These
results strongly suggest that the platinum-catalyzed direct
amination proceeds through a π-allylplatinum intermediate
9 and selective attack of the amine to the less hindered allyl
carbon. Sterically congested electrophile 9 created by the
large bite-angle ligand allows a selective reaction with
substrate 3 in preference to monoallylation compound 4.
In conclusion, we developed a new direct catalytic
amination of allylic alcohols promoted by the combination
of platinum and the large bite-angle ligand DPEphos without
the use of an activating reagent. The DPEphos ligand was
essential for obtaining high catalyst activity and high
monoallylation selectivity of primary amines, allowing the
formation of a variety of monoallylation products in good
to excellent yield. Moreover, we demonstrated the synthetic
utility of this catalysis by the one-step synthesis of the
antifungal drug naftifine. Further mechanistic studies and
application to enantioselective variants are ongoing in our
group.
a 4.0 mmol scale, dioxane (0.8 mL). b Isolated yield.
1
completed in 12 h, and H NMR analysis of the crude
mixture revealed the formation of almost pure naftifine (4bs)
where water was the sole coproduct (Scheme 2). Purification
Scheme 2
Acknowledgment. This work was supported by Encour-
agement of Young Scientists (A) from the Japan Society for
the Promotion of Science and the Uehara Memorial Founda-
tion.
by simple silica gel column chromatography gave 4bs in 98%
yield. Alternatively, treatment of the crude mixture with 1
M HCl in EtOH and recrystallization from EtOH/Et2O
provided pure naftifine hydrochloride (4bs‚HCl) in 83% yield
without chromatographic purification.
To gain insight into the mechanism of this platinum
catalysis, we performed the following reactions. Direct
amination of internal allylic alcohol 1-phenyl-2-propen-1-
ol (6b) exclusively provided terminal allylamine 4ba, which
Supporting Information Available: Experimental pro-
cedures, characterization of the products, and other detailed
results. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL071365S
3374
Org. Lett., Vol. 9, No. 17, 2007