Phosphomolybdic acid-catalyzed efficient three-component reaction: A facile synthesis of protected homoallylic amines

Article abstract of DOI:10.1055/s-2005-863723

A new and efficient phosphomolybdic acid (H₃PMo ₁₂O₄₀)-catalyzed three-component reaction of aldehydes, carbamate and allyltrimethylsilane to yield the corresponding protected homoallylic amines in good yields is described.

Full text of DOI:10.1055/s-2005-863723

LETTER
839
Phosphomolybdic Acid-Catalyzed Efficient Three-Component Reaction:
A Facile Synthesis of Protected Homoallylic Amines
P
hosphomolybdic
.
A
cid-Cataly
S
zedEfficient
T
m
hree-Component
R
i
eactiontha, Bruhaspathy Miriyala, John S. Williamson*
Department of Medicinal Chemistry, School of Pharmacy, University of Mississippi, MS 38677, USA
Fax +1(662)9155638; E-mail: mcjsw@olemiss.edu
Received 10 December 2004
available catalysts that has not been utilized for the syn-
thesis of protected homoallylic amines.9
Abstract: A new and efficient phosphomolybdic acid
(H3PMo12O40)-catalyzed three-component reaction of aldehydes,
carbamate and allyltrimethylsilane to yield the corresponding
protected homoallylic amines in good yields is described.
In continuation of our interest in one-pot synthesis of
amines from carbonyl compounds,10 here we wish to re-
Key words: phosphomolybdic acid, three-component reaction, port a facile and efficient synthesis of protected homo-
homoallylic amines, heteropolyacid
allylic amines using phosphomolybdic acid (PMA) as a
catalyst. Accordingly, a three-component reaction of
aldehydes, carbamate and allyltrimethylsilane in the
presence of PMA (H3PMo12O40) resulted in the formation
of corresponding homoallylic amines in good yields
(Scheme 1).
Homoallylamines are useful synthetic intermediates in
natural product synthesis and also precursors to b-amino
acids and b-lactams.1 They are commonly prepared by the
allylation of aldimines prepared from aldehydes and
amines in advance using allylic nucleophiles such as allyl
silanes, allyl stannanes, and allylic organometallics.2,3 To
avoid the prior synthesis of aldimines a direct three-com-
ponent reaction has been reported for the preparation of
homoallylamines.4,5 These three-component reactions are
useful, not only because two bonds are formed in one step,
but also because the methods are useful for preparing a
broad variety of compound libraries. The catalysts em-
ployed for these three-component reactions are
BF3·OEt2,4a triphenyl methyl perchlorate,4b Bi(OTf3),4d
I2,4e etc.4c However, these methods while offering some
advantages, also suffer from drawbacks such as the re-
quirement of stoichiometric amounts of Lewis acid
(BF3·OEt2), prior silylation of the carbamate, use of a pre-
synthesized organometallic agent, use of expensive cata-
lysts and long reaction times. Furthermore, the protected
homoallyl amines can easily undergo further conversions
using well-established protective group chemistry without
effecting the double bond.6 Therefore, there is an impor-
tant need to develop new methods for the synthesis of pro-
tected homoallylic amines using commercially available,
pollution preventing green catalysts.
NHCbz
PMA (1 mol%)
SiMe3
R CHO
Cbz NH2
+
+
R
MeCN, r.t.
R = aryl, alkyl
Scheme 1
First we examined the reaction of benzaldehyde and allyl-
trimethylsilane with benzyl, tert-butyl carbamate and ben-
zene sulfonamide in the presence of 1 mol% PMA
catalyst. The results are summarized in Table 1. The
reaction with benzyl carbamate went to completion in ten
minutes to provide the Cbz-protected homoallyl amine in
92% yield. Whereas, tert-butyl carbamate and benzene
sulfonamide reactions are slower with relatively lower
yields.
Based on the above results, we next examined the reaction
of various aldehydes with benzyl carbamate and allyltri-
methylsilane using 1 mol% of PMA catalyst in aceto-
nitrile. The results are summarized in Table 2. Various
Table 1 Synthesis of N-Protected Homoallyl Amines from Benz-
aldehydea
The application of solid acids as efficient heterogeneous
catalysts continues to gain importance in organic synthe-
sis.7 Heteropolyacids (HPAs) are environment-friendly
and economically feasible solid acids owing to their high
catalytic activities and reactivities, ease of handling, allow
cleaner reactions in comparison to conventional catalysts
(less waste production), non toxicity and experimental
simplicity.8 Among the heteropolyacids, phosphomolyb-
dic acid (PMA) is one of the less expensive commercially
Entry Amide
Time (min) Amine
Yield (%)b
92
1
2
3
Cbz-NH2
10
45
30
NHCbz
Boc-NH2
64
81
NHBoc
PhSO2NH2
NHSO2Ph
SYNLETT 2005, No. 5, pp 0839–0841
Advanced online publication: 09.03.2005
DOI: 10.1055/s-2005-863723; Art ID: S11304ST
© Georg Thieme Verlag Stuttgart · New York
2
1.
0
3.
2
0
0
5
a Reaction condition: PMA (1 mol%), MeCN, r.t.
b Isolated yield after purification.

840
G. Smitha et al.
LETTER
aromatic aldehydes having methyl, nitro, halo, cyano and reaction was demonstrated by the conversion of the alde-
trifluoro methyl groups at the para-position were em- hyde to the homoallylamines in the presence of a keto
ployed for the production of the corresponding protected group for the first time, as shown in entry 12.
homoallylic amines in good yields (entries 2–6, Table 2).
In conclusion, an efficient and selective three-component
Application of the present methodology was also exam-
reaction has been developed to produce the protected
ined using aldehydes processing acid sensitive ethers
homoallylic amines in the presence of a catalytic amount
(protecting groups) such as methyl, tert-butyl dimethyl-
(1 mol%) of PMA. The advantages of this protocol in-
silyl (TBS) and methoxy methyl (MOM). These corre-
clude mild reaction conditions, cleaner reaction profiles,
spond to entries 7–9 in Table 2. Similarly, the present
and simple experimental procedure that all together make
protocol also behaved well with cinnamaldehyde and
this method efficient.
octanaldehyde to yield the corresponding Cbz-protected
General Experimental Procedure
homoallylamines. The chemoselectivity of the present
To a stirred solution of aldehyde (1 mmol) in MeCN (10 mL), ben-
zyl carbamate (0.151 g, 1 mmol) and allyltrimethylsilane (0.125 g,
1.1 mmol), PMA (18 mg, 1 mol% and commercially available) was
added and the reaction mixture was stirred at r.t. for the given time
(see Table 2). The solvent was evaporated in vacuo and the crude
product was purified by column chromatography to yield the corre-
sponding homoallylic amine.11
Table 2 Synthesis of Cbz-Protected Homoallyl Amines
Entry Aldehyde
Time Aminea
(min)
Yield
(%)b
1
2
10
92
CHO
NHCbz
Acknowledgment
10
90
NHCbz
CHO
CHO
Authors wish to thank the Center for Disease Control for the finan-
cial assistance (CDC U50-CCU418839 and CDC UR3-
CCU418652).
H3C
O2N
H3C
O2N
3
20
82
NHCbz
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12
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Synlett 2005, No. 5, 839–841 © Thieme Stuttgart · New York

LETTER
Phosphomolybdic Acid-Catalyzed Efficient Three-Component Reaction
841
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d = 140.6, 140.3, 133.2, 132.2, 128.7 (2 C), 128.3 (2 C),
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3276, 2949, 2331, 1319, 1161, 753 cm–1. HRMS (ESI): m/z
calcd for C16H17NO2S: 310.0877 [M + Na]+; found:
310.0870.
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Table 2, Entry 8: 1H NMR (500 MHz, CDCl3): d = 7.35–
7.26 (m, 5 H), 7.18 (d, J = 7.5 Hz, 2 H), 6.85 (d, J = 8.5 Hz,
2 H), 5.67–5.61 (m, 1 H), 5.30–5.10 (m, 5 H), 4.85 (br s, 1
H), 2.56 (br s, 1 H), 1.05 (s, 9 H), 0.26 (s, 6 H). 13C NMR
(125 MHz, CDCl3): d = 155.6, 154.6, 136.5, 134.7, 133.9,
128.4 (2 C), 128.0 (2 C), 127.3 (2 C), 119.9 (3 C), 118.1,
66.9, 54.5, 41.3, 26.1 (3 C), 18.6, –3.8 (2 C). IR (neat): 3325,
2929, 1698, 1509, 1256, 914 cm–1. HRMS (ESI): m/z calcd
for C24H33NO3Si: 434.2127 [M + Na]+; found: 434.2120.
Table 2, Entry 9: 1H NMR (500 MHz, CDCl3): d = 7.41–
7.34 (m, 5 H), 7.24 (dd, J = 2.0, 6.0 Hz, 2 H), 7.16 (d, J = 8.0
Hz, 1 H), 7.01 (t, J = 7.5 Hz, 1 H), 5.80–5.70 (m, 2 H), 5.30
(s, 2 H), 5.17–5.08 (m, 5 H), 3.52 (s, 3 H), 2.64 (t, J = 6.0 Hz,
2 H). 13C NMR (125 MHz, CDCl3): d = 155.5, 154.2, 136.6,
134.5, 130.2, 128.4, 128.3, 128.1, 128.0, 127.9, 121.7 (3 C),
117.7, 114.2, 94.3, 66.8, 56.4, 52.2, 40.3. IR (neat): 3342,
2954, 1716, 1492, 1233, 995 cm–1. HRMS (ESI): m/z calcd
for C20H23NO4: 364.1524 [M + Na]+; found: 364.1517.
Table 2, Entry 12: 1H NMR (400 MHz, CDCl3): d = 7.92
(d, J = 8.0 Hz, 2 H,), 7.43–7.34 (m, 7 H), 5.66–5.58 (m, 1 H),
5.14–5.02 (m, 4 H), 4.85 (br s, 1 H), 2.58 (s, 5 H). 13C NMR
(100 MHz, CDCl3): d = 197.8, 155.9, 136.2, 133.4, 128.7 (3
C), 128.5 (2 C), 128.1 (2 C), 128.0 (2 C), 126.5 (2 C), 118.7,
116.5, 66.8, 40.8, 26.5. IR (neat): 3329, 3065, 1708, 1681,
1530, 1219, 698 cm–1. HRMS (ESI): m/z calcd for
(11) Spectroscopic data for the selected products:
Table 1, Entry 3: 1H NMR (400 MHz, CDCl3): d = 7.65 (d,
J = 7.6 Hz, 2 H), 7.45 (t, J = 7.6 Hz, 1 H), 7.34 (t, J = 7.6 Hz,
2 H), 7.18–7.14 (m, 3 H), 7.07–7.04 (m, 2 H), 5.55–5.47 (m,
1 H), 5.08–5.04 (m, 2 H), 4.93 (br s, 1 H), 4.42–4.40 (m, 1
H), 2.46 (t, J = 5.2 Hz, 2 H). 13C NMR (100 MHz, CDCl3):
C20H21NO3: 346.1417 [M + Na]+; found: 346.1409.
Synlett 2005, No. 5, 839–841 © Thieme Stuttgart · New York