A neighbouring group effect leading to enhanced nucleophilic substitution of amines at the hindered α-carbon atom of an α-hydroxyphosphonate

Article abstract of DOI:10.1016/j.tetlet.2011.11.026

Diethyl α-hydroxy-benzylphosphonate undergoes nucleophilic substitution with primary amines of sufficient reactivity at around 100 °C to afford the corresponding α-aminophosphonates. The substitution can be enhanced by microwave irradiation. The reaction

Full text of DOI:10.1016/j.tetlet.2011.11.026

Tetrahedron Letters 53 (2012) 207–209
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Tetrahedron Letters
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A neighbouring group effect leading to enhanced nucleophilic substitution
of amines at the hindered a-carbon atom of an a-hydroxyphosphonate
Nóra Zsuzsa Kiss a, Anna Kaszás a, László Drahos b, Zoltán Mucsi a, György Keglevich a,
⇑
a Department of Organic Chemistry and Technology, Budapest University of Technology and Economics, 1521 Budapest, Hungary
b Hungarian Academy of Sciences, Chemical Research Center, 1525 Budapest, Hungary
a r t i c l e i n f o
a b s t r a c t
Article history:
Diethyl
a
-hydroxy-benzylphosphonate undergoes nucleophilic substitution with primary amines of suf-
-aminophosphonates. The substitution
Received 30 September 2011
Revised 14 October 2011
Accepted 4 November 2011
Available online 10 November 2011
ficient reactivity at around 100 °C to afford the corresponding
a
can be enhanced by microwave irradiation. The reaction takes place with surprising ease due to the
neighbouring group effect of the P@O moiety as was justified by DFT calculations carried out to evaluate
the mechanism of the substitution under discussion.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
a
a
-Hydroxyphosphonate
-Aminophosphonate
Nucleophilic substitution
Microwave
Neighbouring group effect
a
-Aminophosphonates, structural analogues of
a
-aminocarbox-
lyst. It is problematic that the procedure of Kaboudin30 could not
be reproduced, as the syntheses were carried out in a domestic
MW oven and no temperatures were provided. Hence, it was a
ylates, have attracted significant attention because of their role in
the development of inhibitors of GABA-receptors, enzyme inhibi-
tors, antibiotics, antihypertensives and antitumour agents.1–5
The Kabachnik–Fields (or phospha-Mannich) reaction involving
the condensation of a dialkyl phosphite, an aldehyde or ketone and
a primary/secondary amine or ammonia is an important method
challenge for us to revisit the
ophosphonate transformation.
a-hydroxyphosphonate ? a-amin-
Diethyl
a-hydroxy-benzylphosphonate (1) was chosen as the
starting material which was reacted with primary amines under
for the synthesis of
a
-aminophosphonates.6–8 Although solvent-
microwave
MW and solventless conditions (Scheme 1 and Table 1).31
and catalyst-free variations9 and subsequently,
a
(MW)-assisted method have been elaborated,10–12 a number of
procedures were described that apply a variety of catalysts, such
as metal triflates,13,14 lanthanides,15 lanthanide triflates,16,17 other
metal halides or salts,18–23 or other species.24–27 Our research
showed that under MW and solventless conditions, there was no
need for a catalyst.28
OH
NHY
P(OEt)2
MW
T, t
P(OEt)2
O
+ YNH2
no solvent
O
1
2
i
i
a
e
b
c
d
Y = Pr ( ), Bu ( ), Pr ( ), Bu ( ),
Another possibility for the preparation of
nates involves nucleophilic substitution at the secondary carbon
atom of -hydroxyphosphonates by amines. Due to the hindered
hydroxy function,
a-aminophospho-
c
f
g
Bn ( ), PhCH2CH2 ( ), Hex ( )
a
Scheme 1. Nucleophilic substitution of diethyl a-hydroxy-benzyl-phosphonate by
a
-hydroxyphosphonates were not expected to
amines.
undergo substitution by amines29 and it was not a surprise that
this reaction could only be accomplished in the presence of an
acidic alumina catalyst on MW irradiation without the use of any
solvent. The yields were 50–65%.30
Using propylamine at 100 °C, the outcome depended on the mo-
lar quantity of the amine. If only one equivalent of n-propylamine
was used, the conversion of
a-hydroxyphosphonate 1 into the cor-
However, our earlier experiments showed that this reaction
may also take place on simple heating in the absence of any cata-
responding -aminophosphonate 2a was 57% after 45 min (Table
a
1, entry 1). However, by using 3 equiv of the amine, the substitu-
tion took place quantitatively after 10 min, and the preparative
yield of aminophosphonate 2a was 78% (Table 1, entry 2). The reac-
tion took place similarly with n-butylamine giving product 2b in a
⇑
Corresponding author. Tel.: +36 1 463 1111/5883; fax: +36 1 463 3648.
E-mail address: gkeglevich@mail.bme.hu (G. Keglevich).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.11.026

208
N. Zsuzsa Kiss et al. / Tetrahedron Letters 53 (2012) 207–209
Table 1
The reaction of
HO
Ph
OEt
O
HO
Ph
OEt
O
a
-hydroxyphosphonates with primary amines under MW conditions
OEt
O
HO
Ph
YNH2
Ψ (C)
P
δ
P
P
H
Entry
Y
Amine
(equiv)
T
(°C)
t
1 ? 2
Yield of 2
(%)
N
OEt
δ
OEt
(min) Conversiona
OEt
YNH2
H
Y
1
b
3
4
1
2
3
4
5
6
7
8
9
Pr
Pr
1
3
3
3
3
1
3
3
1
3
3
3
100
45
57 (2a)
100 (2a)
100 (2b)
100 (2c)
100 (2d)
82 (2e)
100 (2e)
100 (2f)
100 (2g)
100 (2g)
0
100c 10
78 (2a)
86 (2b)
63 (2c)
Bu
iPr
iBu
Bn
Bn
100
100
100
110
15
40
40
60d
EtO
Ph
EtO
Ph
OEt
Ph
N
O
H
OEt
O
OEt
OH
−
P
H
P
P
O
+
54 (2d)
H
H
b
− H2O
H
OEt
N
O
N
H
110e 15
60 (2e)
58 (2f)
72 (2g)
H
Y
Y
Y
PhCH2CH2
cHex
cHex
Ph
110
110
110
130
160
30
40
10
120
120
6
7
2
Y = alkyl, aralkyl
10
11
12
84 (2g)
b
Scheme 2. Mechanism for the substitution of diethyl
a
-hydroxy-benzylphospho-
b
Ph
0
nate by amines supported by B3LYP/6-31G(d,p) calculations.
a
b
c
On the basis of relative 31P NMR spectroscopic intensities.
No yields were determined.
In the comparative thermal experiment, complete conversion required 45 min
and the yield was 48%.
d
No change on further irradiation.
In the comparative thermal experiment, complete conversion required 1 h and
e
the yield was 41%.
yield of 86% (Table 1, entry 3). Applying i-propylamine and i-butyl-
amine, the reactions took somewhat longer (40 min) at 100 °C and
products 2c and 2d were isolated in 63% and 54% yields, respec-
tively (Table 1, entries 4 and 5). A similar tendency was experi-
enced with benzylamine as that with n-propylamine. Carrying
out the reaction at 110 °C with 1 equiv of the amine, the conver-
sion was 82% after 1 h (and the substitution did not proceed on fur-
ther irradiation), while using three equivalents of the reagent, the
Figure 1. The enthalpy (H) pathway for the transformation 1 ? 2. PR1 = pseudo-
rotation 1.
conversion was complete after 15 min affording the
a-amin-
ophosphonate 2e in a yield of 60% (Table 1, entries 6 and 7). The
situation was similar with phenylethylamine affording amin-
ophosphonate 2f in a yield of 58% (Table 1, entry 8). Cyclohexyl-
amine was so reactive such that only one equivalent was
sufficient at 110 °C to ensure quantitative conversion; on using
three equivalents the substitution was much faster (Table 1, en-
the OHꢀ group with the phosphorus atom of the adjacent P@O
function and is accompanied by attack of the amine on the carbon
atom with a partial positive charge to afford intermediate 4 via the
transition state (TS) 3. The amine enters from the opposite side, as
in an SN2 mechanism. The activation enthalpy of 170.9 kJ molꢀ1
belonging to TS 3 can be overcome, especially under MW condi-
tions, due to the beneficial effect of the statistically appearing local
tries 9 and 10). The
a-aminophosphonate 2g was obtained in
72% and 84% yields. Aniline was unreactive and there was no reac-
tion at 130 °C or even at 160 °C (Table 1, entries 11 and 12).
In comparative thermal experiments the substitutions were
slower and the yields lower (Table 1, entries 2 and 7). It is notewor-
thy that the reaction also takes place under thermal conditions.
overheating. In the next step, pseudorotation [w(C)] in species 4
leads to an almost equally stable intermediate 6 via a low energy
TS (5) that is not shown in Scheme 2. Finally, intramolecular proton
transfer from P–OH to the other P–OH brings about elimination of
H2O to provide a-aminophosphonate 2 through TS 7 with an acti-
Kaboudin claimed that the substitution of a-hydroxyphosphonate
vation enthalpy of 125.1 kJ molꢀ1. Overall, the process is slightly
exothermic.
1 with amines (e.g., with cyclohexylamine) failed on heating, but
no exact temperature was provided.30
Among the
a
-aminophosphonates, 2a,33 2e33 and 2g34 have
The reaction enthalpy (
DHR), reaction Gibbs free energy (DGR)
and reaction entropy ( SR) values obtained by the B3LYP/6-
31G(d,p) calculations for the species of the reaction sequence out-
lined in Scheme 2 are listed in Table 2.
D
been described and characterised. Compound 2b was characterised
only partially.29 Species 2c35 and 2f36 have been described, but no
spectral characterisation was provided. Aminophosphonate 2d is
new. Accordingly, compounds 2b–d and 2f have now been fully
characterised by 31P, 13C and 1H NMR spectroscopic and HRMS
data.
It should be noted that the simple inductive effect from the P@O
group may also contribute to the enhanced reactivity of
a-
hydroxyphosphonate 1 in nucleophilic substitution with amines.
The participation of a P@O group in a nucleophilic substitution
on the adjacent carbon atom is a novel example of a beneficial
neighbouring group effect. To the best of our knowledge, no similar
example has been reported.
In our case, the experimental results on the possibility of a
nucleophilic substitution at the hindered carbon atom of
As previously mentioned,
a-hydroxyphosphonates are consid-
ered as potential intermediates in the Kabachnik–Fields reaction.8
In this case, a substitution analogous with the cases discussed in
this paper is the last step. The energy gain of this substitution is
only around 2.4 kJ molꢀ1 37
The involvement of another kind of
.
intermediate that is an imine (or Schiff-base), may be of more gen-
eral importance.38
a-hydroxyphosphonates are in full agreement with the results of
the quantum chemical calculations justifying the substitution
due to a beneficial neighbouring group effect.
The reaction mechanism was evaluated using B3LYP/6-31G(d,p)
calculations.39 The first and, at the same time, rate determining
step of this multistep reaction sequence (Scheme 2 and Fig. 1)
In conclusion, the sterically hindered substitution reaction of
starts with the departure of the OHꢀ group from the
a-carbon
a-hydroxy-benzylphosphonate with primary amines could be
performed efficiently under solventless MW conditions applying
atom. This step is promoted by the simultaneous interaction of

N. Zsuzsa Kiss et al. / Tetrahedron Letters 53 (2012) 207–209
209
Table 2
a-aminophosphonates 2a–g as oils in purities of P99%. For details, see Table 1,
entries 2–5, 7, 8 and 10.
Summary of the reaction enthalpy (DHR), reaction Gibbs free energy (DGR) in
kJ molꢀ1, and reaction entropy (
Entropy was calculated at 400 K
D
SR) in J molꢀ1 Kꢀ1 of the transformation 1 ? 2.
31P NMR (CDCl3)
(M+H)found Formula
(M+H)calcd
Species
D
HR
D
GR
DSR
Measured Literature
1
3
4
5
6
7
2
0.00
170.9
73.3
85.0
73.6
125.1
ꢀ11.7
0.00
0.00
2a 23.7
2b 23.6
2c 24.1
2d 23.7
2e 23.7
2f 23.4
2g 24.3
23.833
286.1572 C14H25NO3P 286.1572
300.1731 C15H27NO3P 300.1729
225.3
131.5
145.4
130.1
176.3
ꢀ5.1
136.0
145.6
151.0
122.5
149.2
16.5
24.029
286.1571
300.1725
C
C
14H25NO3P 286.1572
15H27NO3P 300.1729
22.933
24.234
334.1572 C18H25NO3P 334.1572
348.1735 19H27NO3P 348.1729
326.1884 C17H29NO3P 326.1885
C
the amine in a twofold excess (that means three equivalents). The
substitution was enhanced by the neighbouring effect of the adja-
cent P@O group. This novel phenomenon was supported by high
level DFT calculations.
Additional spectral characterisation:
Compound 2b: 13C NMR (CDCl3) d 13.8 (CH2CH2CH3), 16.3 (3J = 13.3, OCH2CH3), 16.4
(2J = 13.2, OCH2CH3), 20.2 (CH2CH3), 31.9 (CH2CH2CH3), 47.7 (J = 16.6, NCH2), 61.1
(J = 152.6, PCN), 6⁄2.7 (1J = 7.0, OCH2), ⁄62.9 (1J = 7.1, OCH2), 127.7 (J = 3.2, C40),
128.3 (J = 2.5, C20), 128.5 (J = 6.2, C30), 136.2 (J = 4.1, C10), ⁄may be reversed; 1H
NMR (CDCl3) d 0.86 (t, J = 7.2, 3H, CH2CH2CH3), 1.14 (t, J = 7.1, 3H, OCH2CH3), 1.28
(t, J = 7.1, OCH2CH3) and 1.23–1.36 (m, CH2) partially overlapped, total integra-
tion = 5, 1.38–1.51 (m, 2H, CH2), 1.75 (br s, 1H, NH), 2.39–2.57 (m, 2H, NCH2),
Acknowledgements
This project was supported by the Hungarian Scientific and Re-
search Fund (OTKA K83118). This work is connected to the scien-
tific programme of the ‘Development of quality-oriented and
harmonized R+D+I strategy and functional model at BME’. This
project is also supported by the New Széchenyi Plan (Project ID:
TÁMOP-4.2.1/B-09/1/KMR-2010-0002). The authors are indebted
to Professor Dr Harry R. Hudson (London Metropolitan University)
for his advice.
3.77–3.91 (m, 1H, NCHP), 3.91–4.14 (m, 4H, 2 ꢁ OCH2), 7.24–7.47 (m, 5H, Ar). d29
H
(CDCl3) 0.85 (t, J = 7.1, 3H), 1.14 (t, J = 7.2, 3H), 1.27 (t, J = 7.0, 3H), 1.30–1.40 (m,
2H), 1.40–1.50 (m, 2H), 2.05–2.25 (br s, 1H), 2.35–2.60 (m, 2H), 3.70–4.20 (m, 4H),
7.20–7.50 (m, 5H ArH).
Compound 2c: 13C NMR (CDCl3)
d
16.2 (3J = 17.2, OCH2CH3), 16.3 (2J = 17.2,
OCH2CH3), 21.3 (CH(CH3)2), 23.9 (CH(CH3)2), 45.7 (J = 16.0, CHMe2), 58.3 (J = 153.6,
PCN), 62.6 (1J = 7.0, OCH2), 63.0 (1J = 7.0, OCH2), 127.6 (J = 3.1, C40), 128.3 (J = 2.4,
C20),⁄ 128.4 (J = 6.3, C30),⁄ 136.6 (J = 2.9, C10), ⁄may be reversed; 1H NMR (CDCl3) d
0.99 (d, J = 6.3, 3H, CHCH3), 1.01 (d, J = 6.7, 3H, CHCH3), 1.11 (t, J = 7.1, 3H, CH2CH3),
1.30 (t, J = 7.1, 3H, CH2CH3), 1.88 (br s, 1H, NH), 2.65–2.73 (m, 1H, CHMe2), 3.70–3.83
(m, 1H, NCH), 3.88–4.20 (m, 4H, 2 ꢁ OCH2), 7.24–7.43 (m, 5H, Ar).
References and notes
Compound 2d: 13C NMR (CDCl3)
d
16.2 (3J = 14.4, OCH2CH3), 16.3 (2J = 14.4,
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OCH2CH3), 20.3 (CH(CH3)2), 20.5 (CH(CH3)2), 28.2 (CHMe2), 55.9 (J = 16.4, NCH2),
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d
16.2 (2J = 12.8, OCH2CH3), 16.3 (2J = 12.8,
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128.3 (C200),b 128.4 (J = 6.1, C30),a 128.7 (C300),b 135.9 (J = 4.3, C10), 139.8 (C100), a,bmay
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CH2CH3), 1.80 (br s, 1H, NH), 2.70–2.84 (m, 4H, 2 ꢁ CH2), 3.75–3.84 (m, 1H, NCH),
3.87–4.10 (m, 4H, 2 ꢁ OCH2), 7.10–7.40 (m, 10H, Ar).
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31. General procedure for the preparation of
of 0.10 g (4.1 mmol) of
-hydroxyphosphonate [1, dP (CDCl3) 21.5]32 and
12.3 mmol of amine [propylamine (0.10 mL), benzylamine (0.13 mL) or
cyclohexylamine (0.14 mL)] in sealed tube was irradiated in CEM
a-aminophosphonates 2a–g: A mixture
a
a
a
Microwave reactor equipped with a pressure controller at the temperatures
and for the times shown in Table 1. The volatile components were removed
under reduced pressure. The residue obtained was purified by flash column
chromatography using silica gel and 3% MeOH in CHCl3 as the eluent to afford
41. Becke, A. D. J. Chem. Phys. 1993, 98, 5648.