Palladium-catalyzed allylic amination using aqueous ammonia for the synthesis of primary amines

Full text of DOI:10.1021/ja900328x

Published on Web 03/05/2009
Palladium-Catalyzed Allylic Amination Using Aqueous Ammonia for the
Synthesis of Primary Amines
Takashi Nagano and Shuj Kobayashi*
Department of Chemistry, School of Science and Graduate School of Pharmaceutical Sciences, The UniVersity of
Tokyo, The HFRE DiVision, ERATO, Japan Science Technology Agency (JST), Hongo, Bunkyo-ku,
Tokyo 113-0033, Japan
Received January 15, 2009; E-mail: shu_kobayashi@chem.s.u-tokyo.ac.jp
Scheme 1
Palladium-catalyzed allylic amination is a well-established
method for the synthesis of allyl amines. During the past three
decades, a variety of nitrogen nucleophiles have been applied for
this useful transformation.1 Surprisingly, however, there are no
reports on the use of ammonia for metal-catalyzed allylic amination
to give primary amines, even though ammonia is one of the most
attractive nitrogen sources from a cost and atom-economy point of
view.2 Authoritative review articles dealing with allylic aminations
have mentioned that “Ammonia does not react”1b and “Ammonia
fails to act as an effective nucleophile for π-allylpalladium.”1a In
iridium-catalyzed allylic amination, Hartwig and co-workers3 have
recently reported the reaction of methyl cinnamyl carbonate with
a dioxane solution of ammonia, although exclusive formation of
the corresponding secondary amine instead of the primary amine
was observed. Because of “the failure of ammonia,”4 a variety of
ammonia surrogates, such as p-toluenesulfonamide,5 phthalimide,6
di-tert-butyl iminodicarbonate,7 and sodium azide,8 for use in allylic
amination to synthesize primary amines have been reported.9 In
general, difficulty in the use of ammonia for metal-catalyzed
processes seems to originate from the fact that (i) many kinds of
transition metals are deactivated by ammonia to give stable amine
complexes and (ii) when a reaction forms a primary amine, this
product is more reactive than ammonia and causes problematic
overreactions. Although Overmann rearrangement instead of metal-
catalyzed allylic amination is an alternative approach to various
allylic amines from allylic acetimidates, direct access to unprotected
primary allylic amines using ammonia seems to be desirable.10 In
the course of our continuing studies of the use of ammonia as a
nitrogen source for organic synthesis,11 we decided to revisit
palladium-catalyzed allylic amination with ammonia and gratify-
ingly found that the reaction of 1,3-diphenylallyl acetate (1) with
aqueous ammonia in the presence of a catalytic amount of Pd(PPh3)4
proceeded with full conversion at room temperature to give 14%
of the primary amine 2a along with 71% of the corresponding
secondary amine 3. It is noted that (1) these results are contrary to
the common knowledge described in review articles and (2) we
also found that ammonia gas did not give the product at all under
these conditions (Scheme 1). These results prompted us to continue
further investigation of this chemistry.
Table 1. Optimization of Reaction Conditions
yield (%)b
2a 3
NH3(aq)/ conc.
(M)
cat.
(mol%) (h)
time selectivity
(2a/3)a
entry
solvent
THF
THF
THF
THF
solvent
1
2
3
1:6
1:2
1:2
1:2
1:2
1:2
1:2
1:2
1:2
1:2
1:2
1:2
1:2
0.33
0.33
0.17
0.11
0.11
0.11
0.11
0.11
0.11
0.06
0.04
0.03
0.03
5
5
16
6
26:74
28:72
47:53
59:41
62:36
-
14
20
34
40
44
71
66
55
42
39
5
5
10
23
12
12
12
12
12
18
18
18
18
c
4
5
THF
10
10
10
10
10
10
10
10
10
6
toluene
trace trace
7
DMF
68:32
58:42
77:23
83:17
89:11
-
48
39
61
66
71
0
37
46
29
22
16
0
8
9
10
11
12
acetonitrile
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
d
91:9
73
13
13
a The 2a/3 molar ratio was determined by 1H NMR spectroscopic
analysis of the crude material. b Isolated yield after chromatography (2a
and 3 were separated). Yield of 3 was based on half the amount of 1.
c 12% of 1 was recovered. d 13 mol % of external PPh3 was added.
1,4-dioxane gave the best result. We tried further dilution in the
dioxane/NH3(aq) system and found 0.04 M to be the critical
concentration for this reaction (entries 9-11). At 0.03 M, the
reaction did not proceed at all, probably because of deactivation
of Pd(0) (entry 12). We assumed that under such high dilution
conditions, liberated PPh3 could not stabilize catalytically active
Pd(0). Indeed, by addition of 13 mol % of external PPh3, which
made the total concentration of PPh3 the same as that in the reaction
at 0.04 M, the catalyst completely recovered its catalytic activity,
giving the products in good yields (entry 13).
With the optimized conditions in hand, we then investigated the
substrate generality of the present reaction system (Table 2). Not
only a 1,3-diaryl- but also a 1,3-dialkyl allyl acetate could be applied
to the present reaction, giving the primary amine 2b in 79% yield
(entry 2). The reaction of cyclic allyl carbonates possessing a variety
of substituents at the vinylic position, such as aryl substituents with
either electron-donating or electron-withdrawing groups as well as
alkyl substituents, proceeded with excellent selectivities to afford
Initially, we examined several reaction conditions using acetate
1 as a model substrate to improve primary/secondary amine
selectivity. Changing the NH3(aq)/THF ratio from 1:6 to 1:2 at 0.33
M in order to increase the quantity of ammonia resulted in a slight
improvement of the selectivity (Table 1, entries 1 and 2).
Fortunately, the dilution method was found to be effective for
improvement of the selectivity (entries 2-4). Although combination
of NH3(aq) and nonpolar toluene resulted in no reaction, polar
aprotic solvents such as DMF and acetonitrile showed similar
efficiencies (entries 5-8). Among the solvents tested at 0.11 M,
9
4200 J. AM. CHEM. SOC. 2009, 131, 4200–4201
10.1021/ja900328x CCC: $40.75
2009 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Allylic Amination Using Aqueous Ammonia
tion of primary amines. It is noteworthy that the use of aqueous
ammonia is essential and that ammonia gas did not react at all.
We have also demonstrated the first catalytic asymmetric synthesis
using aqueous ammonia as a nitrogen source. Further investigations
to clarify the role of water provided by the aqueous ammonia and
of regioselective amination using unsymmetric allyl compounds and
an asymmetric variant are now in progress in our laboratory.
Acknowledgment. This work was partially supported by a
Grant-in-Aid for Science Research from the Japan Society for the
Promotion of Science (JSPS).
Note Added after ASAP Publication. After this paper was
published ASAP March 5, 2009, additional corrections were received
from the author. The fully corrected version was published March 6,
2009.
Supporting Information Available: Experimental procedures and
characterization data. This material is available free of charge via the
Internet at http://pubs.acs.org.
References
(1) For a general overview of allylic amination, see: (a) Godleski, S. A. In
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a A: Table 1, entry 11. B: Table 1, entry 9. b The primary/secondary
1
amine molar ratio was determined by H NMR spectroscopic analysis of
the crude material. c Isolated yield of
d Calculated on the basis of isolated products.
2 after chromatography.
(2) Recently, increasing attention has been paid to the direct use of ammonia
as a nitrogen source for organic synthesis. See: (a) Zimmermann, B.;
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Scheme 2. Preliminary Investigation of Asymmetric Allylic
Amination Using Aqueous Ammonia
the corresponding primary amines in yields of ∼80% (entries
3-7).12 It should be noted that the presence of a substituent at the
vinylic position is not the reason for the high primary amine
selectivity. Moreover, the reaction of the less sterically hindered,
simple nitrogen-containing cyclic allyl carbonate gave the desired
primary amine 2h in high yield with high selectivity (entry 8). Five-
and seven-membered cyclic allyl carbonates also reacted smoothly
to afford the primary amines in high yields with high selectivities
(entries 9-11).
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We then performed a preliminary investigation on an asymmetric
variant of this reaction. In the presence of catalytic amounts of
[PdCl(η3-allyl)]2 and (R)-BINAP, asymmetric allylic amination
using aqueous ammonia proceeded to give the corresponding allyl
amine in 71% yield with 87% ee (Scheme 2). The effective chiral
induction observed here suggests that no replacement of the
bisphosphine ligand by ammonia occurred under the present
conditions. To the best of our knowledge, this is the first example
of catalytic asymmetric synthesis using aqueous ammonia as a
nitrogen source, although a rather large amount of chiral ligand is
needed.13 The absolute configuration of the product amine was
assigned to be R by transformation of the product into the literature-
known tosyl amine.14 The sense of the stereochemistry in the chiral
induction was the same as that in the allylic substitution reaction
catalyzed by Pd/BINAP complexes.15
(9) For recent examples, see: (a) Weihofen, R.; Tverskoy, O.; Helmchen, G.
Angew. Chem., Int. Ed. 2006, 45, 5546. (b) Defieber, C.; Ariger, M. A.;
Moriel, P.; Carreira, E. M. Angew. Chem., Int. Ed. 2007, 46, 3139. Also
see ref 1b.
(10) (a) Overman, L. E. J. Am. Chem. Soc. 1976, 98, 2901. (b) Clizbe, L. A.;
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104. (c) Sugiura, M.; Hirano, K.; Kobayashi, S. Org. Synth. 2005, 83, 170.
(12) The corresponding allyl acetate was found to be unreactive. Under the same
conditions as in entry 3, the reaction of 2-phenylcyclohexenylallyl acetate
proceeded with 38% conversion to give 2c in 29% yield.
(13) At present, 20 mol % BINAP is required. With 12 mol % BINAP, the
reaction did not proceed at all, probably for the same reason as discussed
for Table 1, entry 12. Excess ligand may play a role in the stabilization of
catalytically active Pd(0).
(14) Smyth, D.; Tye, H.; Eldred, C.; Alcock, N. W.; Wills, M. J. Chem. Soc.,
Perkin Trans. 1 2001, 2840.
(15) (a) Yamaguchi, M.; Yabuki, M.; Yamagishi, T.; Sakai, K.; Tsubomura, T.
Chem. Lett. 1996, 241. (b) Kodama, H.; Taiji, T.; Ohta, T.; Furukawa, I.
Synlett 2001, 385.
In summary, we have developed for the first time palladium-
catalyzed allylic amination using aqueous ammonia for the prepara-
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