Platinum-catalyzed direct amination of allylic alcohols with aqueous ammonia: Selective synthesis of primary allylamines

Article abstract of DOI:10.1002/anie.201106737

Direct amination of unactivated allylic alcohols with aqueous ammonia was catalyzed by a Pt/phosphine complex to give the corresponding allylamines along with water as the sole by-product. Under optimized reaction conditions, primary allylamines were obtained as major products with excellent monoallylation selectivity. cod=1,5-cyclooctadiene.

Full text of DOI:10.1002/anie.201106737

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DOI: 10.1002/anie.201106737
Synthetic Methods
Platinum-Catalyzed Direct Amination of Allylic Alcohols with
Aqueous Ammonia: Selective Synthesis of Primary Allylamines**
Kalpataru Das, Ryozo Shibuya, Yasuhito Nakahara, Nicolas Germain, Takashi Ohshima,* and
Kazushi Mashima*
Ammonia has been one of the most important chemical
feedstocks for the chemical industry since the discovery of the
Harber–Bosch process.[1] Direct synthesis of nitrogen-con-
taining compounds from ammonia is the most desirable
synthetic route, and recent achievements regarding the direct
use of ammonia have been reported.[2,3] Among nitrogen-
containing chemicals, allylamines are ubiquitous and preva-
lent in various biologically active compounds,[4,5] and are
valuable synthetic intermediates for a wide range of organic
compounds.[5,6] The direct catalytic substitution of allylic
alcohols with ammonia (Scheme 1, 1!2, R = H) is considered
allylic carbonates using a chiral iridium catalyst as reported by
Hartwig et al.[9] Recently, Carreira et al. reported that opti-
cally active allylamines were prepared by the iridium-
catalyzed stereospecific substitution reaction of optically
active branched allylic alcohols with sulfamic acid as an
ammonia equivalent.[10] To the best of our knowledge,
ammonia has never been used for the direct transformation
of allylic alcohols into primary allylamines (1!2, R = H)
because the nucleophilicity of ammonia is much lower than
that of alkylamines.
Direct amination of allylic alcohols is difficult to achieve
even when alkylamines (R = alkyl) and related nitrogen
nucleophiles are used, because of the poor leaving ability of
the hydroxy group. Thus, in the earliest stages of develop-
ment, transition-metal-catalyzed amination of allylic alcohols
exploited activated allylic alcohols,[11] and stoichiometric or
catalytic amounts of an activator were required for the direct
aminations of allylic alcohols.[12,13] Since the pioneering work
by Ozawa and Yoshifuji,[14a] some palladium[14] catalyst
systems without an activator were reported to facilitate the
direct amination of allylic alcohols 1 with alkyl- and aryl-
amines. We also demonstrated that a platinum catalyst
system, [Pt(cod)Cl2] (cod = 1,5-cyclooctadiene), and a large
bite-angle ligand, DPEphos or Xantphos, under microwave
irradiation conditions promotes the direct catalytic amination
of allylic alcohols with alkyl- and arylamines with high
monoallylation selectivity.[15] We report herein the first direct
amination of allylic alcohols with ammonia via a p-allylmetal
intermediate without the use of an activator.
In our search for efficient catalytic conditions, we chose
the allylic amination reaction of cinnamyl alcohol (1a) with
degassed aqueous ammonia[16] as a test reaction, and the
results are summarized in Table 1. Under the optimized
reaction conditions for alkylamine,[15a] we performed the
reaction using 28% aqueous ammonia[16] (ca. 20 equiv, 1:5 (v/
v) mixture of aq. ammonia and 1,4-dioxane) at 1008C for 24 h,
and the corresponding linear monoallylated amine 2a was
obtained in 60% yield along with bisallylated amine 4a (2a/
4a = 82:18) with water as the sole by-product (entry 1). The
formation of branched allylamines was not detected in the
1H NMR spectrum of the crude reaction mixture. Because
product 2a has much higher nucleophilicity than ammonia
and thus over-reaction of 2a with 1a to give 4a proceeds more
readily, the monoallylation selectivity was lower than that
when alkylamine was used as the nucleophile.[15a] This
moderate monoallylation selectivity was improved to 90:10
by increasing the amount of ammonia (60 equiv) to afford the
desired product 2a in 74% yield (entry 3). Unexpectedly, the
reaction with excess amounts of ammonia resulted in a lower
Scheme 1. Direct (1!2) and two-step (1!3!2) syntheses of allyl-
amines 2 from allylic alcohols 1.
to be the most rational synthetic protocol for primary
allylamines because of the ready availability of allylic alcohols
and the low cost of ammonia, and it is attractive in terms of its
environmental benefit because water is the sole by-product.[7]
The synthetic strategy to directly use ammonia as a nucleo-
phile has been applied for the amination of allylic esters and
carbonates (3!2) using a palladium catalyst as reported by
Kobayashi et al.,[8] and the enantioselective amination of
[*] Dr. K. Das, Y. Nakahara, N. Germain, Prof. Dr. K. Mashima
Department of Chemistry, Graduate School of Engineering Science
Osaka University, CREST
Toyonaka, Osaka 560-8531 (Japan)
E-mail: mashima@chem.es.osaka-u.ac.jp
R. Shibuya, Prof. Dr. T. Ohshima
Graduate School of Pharmaceutical Sciences
Kyushu University, CREST
Maidashi Higashi-ku, Fukuoka 812-8582 (Japan)
E-mail: ohshima@phar.kyushu-u.ac.jp
[**] This work was supported by The Core Research for Evolutional
Science and Technology (CREST) program of the Japan Science and
Technology Agency (JST) and The Grand-in-Aid for Scientific
Research on Innovative Area “Reaction Integration”, and the Uehara
Memorial Foundation. K.D. and Y.N. are grateful to the Global COE
Program of Osaka University for their research fellowship.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201106737.
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Table 1: Optimization of the reaction conditions.
in a 3:2:1 (v/v/v) ratio provided the best yield (79%) with high
monoallylation selectivity (2a/4a = 91:9; entry 16); these
reaction conditions were finally selected as the best set of
reaction conditions.[18] The reaction using only 0.5 mol% of
catalyst also proceeded smoothly, though the yield of 2a was
slightly lower (entry 17).
With the optimized conditions in hand, we examined the
scope of the allylic alcohols 1, and the results are summarized
in Table 2.[18] Direct amination of a series of cinnamyl alcohol
derivatives (1b–f) with aqueous ammonia afforded the
corresponding primary monoallylamines 2b–f with high
yield and high selectivity (entries 1–5). Notably, the branched
allylic alcohol 1g was efficiently converted into primary
allylamine 2a with the same 2/4 distribution (entry 6) as
observed for the reaction of 1a (entry 16, Table 1).[18] Other
branched allylic alcohols (1h–j) also gave comparable results
(entries 7–9). Sterically congested 1,3-disubstituted allylic
alcohols 1k–p were good substrates for the present catalysis.
(E)-1,3-Diphenylprop-2-en-1-ol (1k) was readily converted
into 1,3-diphenylallylamine (2k) in excellent yield, and,
notably, the corresponding bisallylated product 4k was not
detected by 1H NMR or CI-MS analysis of the crude reaction
mixture (entry 10). The excellent high monoallylation selec-
tivity observed for 1k originated from the selective attack of
the smaller nucleophile ammonia on the 1,3-diphenyl p-
allylplatinum intermediate, where the large bite angle of the
diphosphine ligand DPEphos produced a congested environ-
ment around the Pt center, compared with the corresponding
monoallylated amine 2k. Similarly, the amination of (E)-3-(4-
methoxyphenyl)-1-phenylprop-2-en-1-ol (1l) and (E)-1-(4-
methoxyphenyl)-3-phenylprop-2-en-1-ol (1m) produced
identical monoallylated amines 2l as a regioisomeric mixture
with the same ratio (53:47; entries 11 and 12).
Entry[a] Solvent
aq. NH3/solvent 2a
2a/4a[b]
(equiv of NH3)[16] Yield [%][b]
1
1,4-dioxane
1:5 (20)
1:2 (40)
1:1 (60)
2:1 (80)
1:1 (60)
1:1 (60)
1:1 (60)
1:1 (60)
1:1 (60)
1:1 (60)
1:1 (60)
1:1 (60)
1:1 (60)
1:1 (60)
– (120)
60
71
74
51
82:18
89:11
90:10
94:6
–
94:6
97:3
91:9
92:8
–
96:4
94:6
80:20
93:7
93:7
91:9
92:8
2
3
4
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
THF
5[c]
6[e]
7[e]
8
n.d.[d]
34
29
52
59
9
DME
10
11
12
13
14
15
16
17[h]
toluene
CH3CN
DMSO
DMF
MeOH
n.d.[d]
27
30
4
71
–
7[f]
1,4-dioxane/MeOH 3:2:1 (60)
1,4-dioxane/MeOH 3:2:1 (60)
79 (72)[g]
69
[a] Reaction conditions: 1a (0.5 mmol), [Pt(cod)Cl2] (1 mol%), DPEphos
(2 mol%), 28% aq. NH3[16] and solvent (total volume 6.0 mL), 1008C in
sealed tube. [b] Determined by 1H NMR spectrum of the crude reaction
mixture. [c] Reaction temperature was 808C. [d] Not detected. [e] Xant-
phos was used instead of DPEphos. Pt/L=1:2 (entry 6) and 1:1
(entry 7). [f] 1a was recovered in 92% yield. [g] Yield of isolated product
after Boc protection.[18] [h] 0.5 mol% of catalyst was used. DME=ethy-
leneglycol dimethyl ether, DMF=N,N’-dimethylformamide, DMSO=
dimethylsulfoxide, THF=tetrahydrofuran.
Direct catalytic amination of alkyl-substituted allylic
alcohol remains a challenging task because of its low
reactivity and the potential risk of b-hydride elimination. In
our previous platinum catalysis using alkyl- and arylamines as
a nucleophile, such undesired side reactions were prevented
by changing the solvent from 1,4-dioxane to DMF and
lowering the reaction temperature to 508C. As shown in
Table 1, however, the present platinum-catalyzed amination
with ammonia could not employ either DMF or low temper-
ature conditions. Fortunately, under the optimized reaction
conditions shown in Table 2, reactions of (E)-4-phenylbut-3-
en-2-ol (1n) and (E)-1-phenylbut-2-en-1-ol (1o) resulted in
the good conversion into the same monoallylated amine 2n
with the same high 2/4 selectivity (> 99:1; entries 13 and
14).[17] The reaction of (E)-4-(4-methoxyphenyl)but-3-en-2-ol
(1p) with ammonia also proceeded efficiently to give the
corresponding monoallylated amine 2p in 70% yield without
the formation of the bisallylated amine 4p. Although the
cyclic allylic alcohols 1q (entry 16) and the b-substituted 1r
(entry 17) were less reactive substrates, good yields were
obtained when using 3 mol% of the catalyst.
yield because of the partial deactivation of the platinum
catalyst at a higher concentration of ammonia (entry 4). At a
lower reaction temperature (808C), no reaction occurred
(entry 5). Under the same reaction conditions as those used
for entry 3, the Pt/Xantphos catalyst systems (Pt/L = 1:2 and
1:1) were less efficient and gave 2a in poor yield (entries 6 and
7). We then examined the solvent effects relative to a 1:1 (v/v)
ratio of aqueous ammonia and solvents. In THFand DME, 2a
was obtained in moderate yields; 52% and 59%, respectively
(entries 8 and 9). In toluene, no reaction proceeded because
of the biphasic reaction mixture (entry 10). Coordinative
solvents such as acetonitrile and DMSO afforded the
products in lower yields (entries 11 and 12). In DMF, N,N-
dimethyl-3-phenylprop-2-en-1-amine was formed as the
major product through transamidation of DMF with ammo-
nia, and a trace amount of the desired primary allylamine was
detected in the crude reaction mixture (entry 13).[15b] In protic
methanol media, the results were similar (entry 14) to those
obtained in 1,4-dioxane. Other alcohols were less effective
than MeOH in terms of the yield of 2a.[17] The reaction in
aqueous ammonia without organic solvent resulted in a very
low yield of 2a along with recovered starting material (92%;
entry 15). It is intriguing that the Pt/DPEphos in the mixed
solvent system of aqueous ammonia, 1,4-dioxane, and MeOH
Furthermore, highly unstable thiophene- and furan-sub-
stituted allylic alcohols 1s and 1t, respectively (entries 18 and
19), were also successfully converted into the corresponding
primary amines without decomposition. Overall, this plati-
num catalytic system provides a new protocol for the direct
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Table 2: Platinum-catalyzed direct amination of various allylic alcohols with aqueous ammonia.
Entry[a]
1
2
t [h]
2
2/4[b]
Yield [%][b]
1
2
3
4
5
6
1b
1c
1d
1e
1 f
1g
2b
2c
2d
2e
2 f
2a
24
48
48
48
48
24
76 (68)
78 (70)
73 (68)
77 (70)
75 (69)
77 (66)
93:7
91:9
91:9
94:6
91:9
91:9
7
1h
1i
2h
2i
24
24
24
48
65
65
48
48
48
77 (66)
81 (71)
71 (69)
88 (78)
84 (72)
84
93:7
91:9
8
9
1j
2j
91:9
10
11[d]
12[d]
13
14
15
1k
1l
2k
2l[e]
2l[e]
2n
2n
2p
>99:1[c]
>99:1[c]
>99:1[c]
>99:1[c]
>99:1[c]
>99:1[c]
1m
1n
1o
1p
80 (65)
71 (61)
70 (62)
16[f]
1q
2q
64
78 (66)
>99:1[c]
>99:1[c]
92:8
17[f]
18[f]
1r
2r[g]
2s
48
48
76 (70)
72 (67)
1s
19
1t
2t[h]
13
(64)
94:6
[a] Reaction conditions: 1 (0.5 mmol), [Pt(cod)Cl2] (1 mol%), DPEphos (2 mol%), 28% aq. NH3,[16] 1,4-dioxane and MeOH (3:2:1, total volume
6.0 mL), 1008C in sealed tube. Starting material 1 was consumed except for those reaction in entries 5 and 17. [b] Determined by 1H NMR spectrum of
the crude reaction mixture. The number in parenthesis is the yield of the isolated product after Boc protection.[18] [c] 4 was not detected by either
1H NMR or CI-MS analysis of the crude reaction mixture. [d] 2.5 mol% of catalyst was used. [e] A mixture of regioisomers (53:47) was obtained.
[f] 3.0 mol% of catalyst was used. [g] E/Z mixture (88:12) was obtained. [h] E/Z mixture (95:5) was obtained.
amination of allylic alcohols with aqueous ammonia with a
wide substrate scope, thus offering an efficient, direct access
to primary allylic amines in an atom-economical and environ-
mentally benign way.
As shown in Tables 1 and 2, reactions using the terminal
allylic alcohol 1a and internal allylic alcohol 1g, and reactions
using 1n and 1o, respectively, gave almost identical results.
These facts provide insight into the mechanism of the
platinum-catalyzed direct amination of allylic alcohols with
ammonia that proceeded via a p-allylplatinum intermediate.
In the platinumt-catalyzed direct amination, the use of
aqueous ammonia is essential for achieving the high yield of
2a and high monoallylation selectivity. The reaction of 1a
with gaseous ammonia dissolved in 1,4-dioxane afforded 2a in
poor yield (11%) along with a bisallylated amine 4a (11%)
and a tertiary amine 5a [8%; Eq. (1)]. In contrast to our
previous observation that amine salts (NH2R·HCl) activated
the hydroxy group of the allylic alcohols, the addition of
NH4Cl (2 equiv to substrate) to the present aqueous con-
152
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In summary, we developed the first direct catalytic
amination of allylic alcohols with aqueous ammonia using a
Pt/DPEphos catalyst system without the prior activation of
the allylic alcohol. In this new protocol under aqueous
conditions, a variety of primary allylamines were directly
synthesized from the corresponding allylic alcohols with high
monoallylation selectivity. Additional investigation of the
scope of the syntheses of highly functionalized bioactive
natural and unnatural compounds and application to enan-
tioselective variants, one-pot sequential reaction, and flow
system are ongoing in our group.
Experimental Section
Degassed aq. ammonia (3 mL) was added to a solution of allylic
alcohol 1k (105 mg, 0.500 mmol), [Pt(cod)Cl2] (1 mol%), and DPE-
phos (2 mol%) in a mixed solvent (3 mL) of 1,4-dioxane and MeOH
in 2:1 proportion. The reaction mixture was stirred in a stainless steel
autoclave at 1008C for 48 h. The reaction mixture was cooled and
then an excess of ammonia was released. The resulting reaction
mixture was diluted with a saturated aq. NaHCO3 solution (10 mL),
and then organic compounds were extracted with CH2Cl2 (4 ꢀ 15 mL).
The combined organic layers was dried over anhydrous Na2SO4,
filtered, and concentrated under vacuum (Caution: some primary
amines are too volatile to be evaporated under prolonged vacuum
condition) to give the crude reaction mixture, which was analyzed by
1H NMR spectroscopy (in C6D6) using phenanthrene as an internal
standard. The yield of the corresponding monoallylamine 2k was
determined to be 88% (selectivity > 99%) in the crude reaction
mixture. Then, the crude reaction mixture was dissolved in CH2Cl2
(4 mL), cooled to 08C, and added to a solution of Boc anhydride
(164 mg, 0.750 mmol) and Et3N (175 mL, 1.25 mmol) in CH2Cl2
(4 mL). After stirring for 24 h at room temperature, the reaction
mixture was diluted with NaHCO3 and extracted with CH2Cl2 (3 ꢀ
15 mL). The combined organic layers were dried over anhydrous
Na2SO4, filtered, and concentrated under reduced pressure. The crude
reaction mixture was purified by flash column chromatography on
silica gel (n-hexane/EtOAc = 19:1) to afford the corresponding N-
Boc-protected monoallylamine 6k in 78% yield (120 mg,
0.388 mmol) as a white solid.
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Received: September 22, 2011
Published online: November 15, 2011
Keywords: allylic compounds · amination ·
.
homogeneous catalysis · platinum · synthetic methods
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[17] See the Supporting Information for details.
[18] Primary amines are highly volatile and can be isolated in lower
yields. Because these free amines were obtained as crude
reaction mixtures under aqueous conditions, we isolated the
monoallylamines 2a–t as their N-Boc derivatives. In the case of
2a, 2k, and 2n, they were also isolated as their hydrochloride
salts.
[13] For another successful direct amination of allylic alcohols with
electron-deficient nitrogen nucleophiles via hydroamination or
carbocationic intermediacy, see: a) S. Guo, F. Song, Y. Liu,
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