Selected reactions of diethyl (E)-1-(bromomethyl)-2-cyanovinylphosphonate with secondary and tertiary amines

Article abstract of DOI:10.1002/hc.21112

An easy regio- and stereoselective synthesis of new nitrogenous molecules 2a-e was successfully realized via an effective coupling reaction of diethyl (E)-1-(bromomethyl)-2-cyanovinylphosphonate 1 with various secondary amines in methanol. Hence, the use

Full text of DOI:10.1002/hc.21112

Heteroatom Chemistry
Volume 24, Number 6, 2013
Selected Reactions of Diethyl (E)-1-
(bromomethyl)-2-cyanovinylphosphonate with
Secondary and Tertiary Amines
Asma Fray, Jihe`ne Ben Kra¨ıem, and Hassen Amri
Selective Organic Synthesis & Biological Activity, Faculty of Science, El Manar University, 2092
Tunis, Tunisia
Received 22 January 2013; revised 13 July 2013
harsh reaction conditions and long reaction times.
ABSTRACT: An easy regio- and stereoselec-
On the other hand, displacement reaction of allyl
tive synthesis of new nitrogenous molecules 2a–
halides using amines as nucleophilic reagents seems
e was successfully realized via an effective cou-
to be the most effective one due to its atom econ-
pling reaction of diethyl (E)-1-(bromomethyl)-2-
omy and operational simplicity. It was considered as
cyanovinylphosphonate 1 with various secondary
the most successful pathway for carbon–heteroatom
amines in methanol. Hence, the use of less and more
bond formation [11–14]. Considering the impor-
bulky secondary amines gives rise, respectively, to
tance of C N bonding creation in organic synthesis
the successive (SN2ꢀ) substitution–isomerization and
and in connection with our research projects aimed
(SN2) substitution derivatives 2a–c and 2d–e. More-
to develop new routes to α-functional allylamines
over, the addition of tertiary amines to 1 in the same
[15–20], we report herein the behavior of diethyl
reaction conditions, leads exclusively to the rearranged
(E)-1-(bromomethyl)-2-cyanovinylphosphonate 1 as
ꢁC
vinyl ether 3 in good yields.
2013 Wiley Periodi-
a powerful Michael acceptor [21], toward secondary
and tertiary amines as a source of N-nucleophilic
reagents.
cals, Inc. Heteroatom Chem. 24:460–465, 2013; View
this article online at wileyonlinelibrary.com. DOI
10.1002/hc.21112
RESULTS AND DISCUSSION
We have recently reported a highly stereoselec-
tive synthesis of diethyl (E)-1-(bromomethyl)-
INTRODUCTION
The addition of amines to C C multiple bonds is one
of the most convenient procedures for the generation
of carbon–nitrogen ones [1]. This approach provides
an attractive route to a variety of biologically impor-
tant natural products [2], antibiotics [3], β-amino
alcohols [4], chiral auxiliaries [5] and other nitrogen-
containing molecules [6–9]. That is why different
protocols [10] have been developed in this context,
but much of them have many constraints such as
2-cyanovinylphosphonate
1
[21], using an
unusual successive SN2ꢀ-SN2ꢀ reaction of 1,4-
diazabicyclo[2.2.2]octane (DABCO) then KCN on
available diethyl 1-(acethoxymethyl) vinylphospho-
nate, followed by a radical brominating reaction of
the resulting β-cyanophosphonate E as shown in
Scheme 1.
We have also demonstrated that allylic halide
E-1 could be used efficiently in the one-step synthe-
sis of a new family of functionalized allylamines in
good yields, through its exclusive (SN2ꢀ) substitution
reaction with primary amines in methanol at low
temperature (Scheme 2).
Correspondence to: Hassen Amri; E-mail: hassen.amri@
fst.rnu.tn.
ꢁC
2013 Wiley Periodicals, Inc.
460

Selected Reactions of Diethyl (E)-1-(bromomethyl)-2-cyanovinylphosphonate with Secondary and Tertiary Amines 461
1) DABCO (1.2 equiv.)
OAc
NC
NBS / (PhCO)2 cat.
CCl4, reflux
NC
Br
THF/H2O, 25°C
2) KCN (1.2 equiv.)
P(OEt)2
O
P(OEt)2
P(OEt)2
O
-1
E
E
O
SCHEME 1 Synthesis of diethyl (E)-1-(bromomethyl)-2-cyanovinylphosphonate 1.
TABLE 1 Synthesis of Enamines 2a–c
NC
NC
Br
RNH2, MeOH, 0°C
SN2'
NHR
Product
R
Time (min)
Yield (%)
(E/Z)a
P(OEt)2
O
P(OEt)2
O
2a
2b
2c
Me
Et
15
30
30
78
72
74
100/0
65/35
60/40
E-1
nPr
SCHEME 2 Preparation of a new family of plurifunctional-
ized allylamines.
aStereochemical assignements and isomeric purities were based on
the difference in chemical shifts and integration ratios of protons of
vinyl methyl group in 1H NMR analysis and in correlation between
protons in NOESY and HMBC spectra.
nPr, unbranched or linear propyl.
To extend our research program aimed to elu-
cidate the factors that influence the reactivity of al-
lyl systems with different amines to access newly
functionalized nitrogenous molecules [22], we first
studied the reactivity of excess of some secondary
amines on allyl bromide E-1 in methanol at room
temperature. In fact, under the conditions described
above, the starting material E-1 was consumed
within 15 to 30 min providing enamines 2a–c in
good yields. Thus, the reaction of the electrophile E-
1 with dimethylamine exclusively gives compound
E-2a with the retention of configuration, while di-
ethylamine and dipropylamine lead to a mixture
of stereoisomeric enamines Z/E-2a–c. As shown be-
low, the formation of enamines can be explained
by proposing a two-step mechanism, which involves
first conjugate addition of amine (two equivalents)
to E-1, followed by a spontaneous isomerization
(Scheme 3, Table 1).
Notice that the coupling reaction of dimethy-
lamine, diethylamine, and dipropylamine with allyl
bromide E-1 provides a class of enamines 2a–c, not
well known, that belongs to an important class of
reactive intermediates in organic synthesis [23–33]
and may also be classified as synthons for the con-
struction of heterocyclic skeletons of various bio-
logically active analogues, including anticonvulsant
[34], anti-inflammatory [35], and antitumor agents
[36]. At this stage, an original task was satisfac-
torily accomplished; however the observed results
may raise a question: Could the conjugated addi-
NC
NC
Br
R2NH (2 equiv.)
MeOH, reflux
NR2
P(OEt)2
O
P(OEt)2
O
E-1
E-2 (d-e)
SCHEME 4 Preparation of new allylamines E-2d–e.
TABLE 2 Synthesis of New Allylamines E-2d–e
Product
R
Time (day)
Yield (%)
2d
2e
Ph
C6H11
10
12
64
58
tion of secondary amines to the allylic halide E-1 be
governed by the steric factor of secondary amines?
To answer this question, reactions described above
were carried out with more bulky amines like di-
cyclohexylamine and diphenylamine. Indeed, it was
found that the coupling reaction of allyl bromide E-
1 with these bulky secondary amines in methanol
at reflux provide unexpected allylamines 2d–e, re-
sulting from a predictable nucleophilic substitution
(SN2) (Scheme 4, Table 2).
For both compounds E-2d and E-2e, the pre-
ferred configuration is E, as confirmed by Nu-
clear Overhauser Effect SpectroscopY (NOESY).
H NR2
R2N
NC
CN
NC
Br
R2NH (2 equiv.)
MeOH, 25°C
Isomerization
P(OEt)2
O
P(OEt)2
O
P(OEt)2
O
E-1
-2a-c
E/Z
SCHEME 3 Stereoselective synthesis of enamines 2a–c.
Heteroatom Chemistry DOI 10.1002/hc

462 Fray, Kra¨ıem, and Amri
SCHEME 5 Regioselective substitution of allylbromide E-1 with bulky secondary amines.
TABLE 3 Preparation of Vinyl Ether Z-3
There is no correlation between the vinylic pro-
ton (6.31 ppm) and those of CH2NPh2 (4.79 ppm)
for 2d, then the ethylenic proton (6.31 ppm) and
those of CH2N(C6H11)2 (4.56 ppm) in the case
of 2e. This result may justify the geometry of
each synthetic intermediates E-2d-e. While the elec-
trophilic behavior of diethyl (E)-1-(bromomethyl)-
2-cyanovinylphosphonate 1 toward different sec-
ondary amines is summarized in Scheme 5. First, the
regioselective and the abnormal (SN2ꢀ) substitution
of bromide, observed with less bulky amines (cases
a–c), may be due to the increased electrophilic-
ity of βꢀ-carbon of compound 1. With more bulky
amines, reaction on sp2-hybridized βꢀ-carbon is not
possible. Thus the SN2 mechanism takes place oc-
casionally at an elevated temperature leading to
a geometrically pure allylamines 2d–e in 100% E
configuration.
Time Yield
Ethera
R1
R2
R3
(h)
(%)
3
3
3
Et
Et
Et
Et
1
4
3
83
69
76
iPr
iPr
CH2CH2OH CH2CH2OH CH2CH2OH
aConfigurational assignment of product 3 was established by 1H NMR
and HMBC spectroscopy.
iPr, isopropyl.
acceptor 1 in methanol. We also isolated a new vinyl
ether 3 which could be used as key synthetic interme-
diate for the generation of new polymeric materials
[37].
EXPERIMENTAL
To optimize our research in this area, we treated
allyl bromide E-1 with an excess of tertiary amines
(2 equivalents) like triethylamine, triethanolamine
and ethyldiisopropylamine at 25◦C in methanol as
the solvent. Initially, the result did not seem to be
satisfactory, because the reaction of tertiary amines
with Michael acceptor E-1 will not occur due to the
steric hindrance, thus providing the possibility of
addition of methanol, which yields to an allyl ether,
which rearranges to its vinylic isomer in Z configu-
ration and with good yields (Scheme 6, Table 3).
It should be noted that the reaction described
in Scheme 6 cannot take place in the absence of an
excess of tertiary amines which ensured permanent
activation of the methanol to obtain the new vinyl
ether’s family 3.
Starting materials and solvents were used with-
out further purification. 1H-NMR, 31P-NMR, and
13CNMR spectra were recorded on a Bruker AMX
300 spectrometer (El Manar University, Tunis,
Tunisia) working at 300 MHz, 121 MHz, and
75 MHz, respectively, for 1H, 31P, and 13C with CDCl3
as the solvent and tetramethylsilane (TMS) as the in-
ternal standard. The chemical shifts (δ) and coupling
constants (J) are, respectively, expressed in parts per
million (ppm) and Hertz (Hz). All NMR spectra were
acquired at room temperature. Assignments of pro-
ton (1H-NMR) and carbon (13C-NMR) signals were
secured by distortionless enhancement by polariza-
tion transfer (DEPT-135) and heteronuclear multiple
bond correlation (HMBC) experiments. Multiplicity
of peaks is indicated by the following: s, singlet; d,
doublet; t, triplet; q, quartet; dq, doublet of quartets;
and m, multiplet. Infrared spectra were recorded
on a Bruker Vertex 70 FT-IR spectrophotometer
(INRAP, Tunis, Tunisie). The elementary analyses
(C, H, and N) were performed on a Perkin–Elmer
Series II CHNS/O Analyzer 2400 (INRAP, Tunis,
CONCLUSIONS
A
synthesis of new functionalized nitrogen
molecules 2a–e was successfully completed by the
coupling reaction of secondary amines with Michael
H OMe
NC
R1R2R3N (2 equiv.)
MeOH, 25°C
NC
Br
CN
Isomerization
MeO
P(OEt)2
O
P(OEt)2
O
P(OEt)2
O
E-1
-
Z 3
SCHEME 6 Synthesis of diethyl (Z)-[2-(cyano)(methoxy)-1-methyl]vinylphosphonate 3.
Heteroatom Chemistry DOI 10.1002/hc

Selected Reactions of Diethyl (E)-1-(bromomethyl)-2-cyanovinylphosphonate with Secondary and Tertiary Amines 463
7.5 Hz), 17.6 (d, CH3-E, 2JCP = 8 Hz), 16.3 (d, 2CH3,
3JCP = 6 Hz), 13.3 (s, 2CH3); 31P-NMR (121 MHz,
CDCl3/TMS) δ: 15.90; Anal. calcd for C12H23N2O3P:
C, 52.54; H, 8.45; and N, 10.21. Found: C, 52.59; H,
8.46; and N, 10.23.
Tunisia). All reactions were monitored by thin layer
chromatography (TLC) on silica gel plates (Fluka
Kieselgel 60 F254, Merck) eluting with the solvents
indicated, visualized by a 254 nm UV lamp and aque-
ous potassium permanganate solution. For column
chromatography, Fluka Kieselgel 70–230 mesh was
used.
Diethyl (E, Z) 2-[(cyano)(dipropylamino)]-
1-methylvinylphosphonate (2c)
General Procedure for the Synthesis of
Enamines (2a–c)
Yield: 74 %; yellow liquid; IR (neat): 2222, 1721,
1244 cm−1. 1H-NMR (300 MHz, CDCl3/TMS) δ: 4.15
(dq, 4H, J = 7.5 Hz, J = 7.5 Hz, 2OCH2), 2.63 (t, 4H,
In a one-neck 25-mL round bottomed flask, was in-
troduced 0.7g of allyl bromide (E)-1 (2.25 mmol) di-
luted in 5 mL of absolute methanol then, secondary
amine (4.5 mmol) was added dropwise with vigorous
stirring. The reaction mixture was stirred at room
temperature until all starting allyl bromide was con-
sumed (TLC monitoring). The mixture was concen-
trated and the methanol was evaporated in vacuum.
The obtained liquid was purified by column chro-
matography (Hexane-AcOEt, 6:4). The Z/E- enam-
ine isomers 2b–c could not be separated by column
chromatography.
3
J = 7.3 Hz, 2CH2), 2.18 (d, JHP = 14 Hz, CH3-Z),
3
2.03 (d, JHP = 15 Hz, CH3-E), 1.64 (m, 4H, 2CH2),
1.36 (t, 6H, J = 7.3 Hz, 2CH3-Z), 0.84 (t, 6H, J =
7.5 Hz, 2CH3-E); 13C-NMR (75 MHz, CDCl3/TMS) δ:
151.2 (d, C, 1JCP = 174.5 Hz), 134.6 (d, = C, 2JCP
=
3
18.25 Hz), 113.3 (d, CN-Z, JCP = 22.8 Hz), 111.2
3
2
(d, CN-E, JCP = 30.2 Hz), 63.0 (d, 2OCH2, JCP
=
7.5 Hz), 51.8 (s, 2CH2), 22.6 (s, 2CH2), 16.9 (d, CH3-
2
2
Z, JCP = 7.5 Hz), 16.3 (d, CH3-E, JCP = 7.5 Hz),
3
15.8 (d, 2CH3, JCP = 6 Hz), 13.2 (s, 2CH3); 31P-
NMR (121 MHz, CDCl3/TMS) δ: 14.5; Anal. calcd for
C14H27N2O3P: C, 55.61; H, 9.00; and N, 9.27. Found:
C, 55.66; H, 9.03; and N, 9.23.
Diethyl (E) 2-[(cyano)(dimethylamino)]-
1-methylvinylphosphonate (2a)
General Procedure for the synthesis of
allylamines (2d–e)
Yield: 78 %; yellow liquid; IR (neat): 2220, 1713,
1242 cm−1. 1H-NMR (300 MHz, CDCl3/TMS) δ: 4.15
(dq, 4H, J = 7.5 Hz, J = 7.5 Hz, 2OCH2), 2.73 (s, 6H,
2CH3N), 2.07 (d, 3H, 3JHP = 15 Hz, CH3),1.36 (t, 6H,
J = 7.5 Hz, 2CH3); 13C-NMR (75 MHz, CDCl3/TMS)
To a solution of allyl bromide (E)-1 (0.7g, 2.25 mmol)
in 5 mL of absolute methanol, secondary amine
(4.5 mmol) was dropwise added. The reaction mix-
ture was stirred at reflux for 10–12 days, then the
mixture was cooled and the methanol was removed
under reduced pressure. The obtained liquid was pu-
rified by column chromatography (Hexane-AcOEt,
3:7).
δ: 151.2 (d, C, 1JCP = 174.7 Hz), 133.6 (d, C, 2JCP
=
3
18.7 Hz), 111.0 (d, CN, JCP = 31.5 Hz), 63.0 (d,
2
2OCH2, JCP = 7.5 Hz), 38.6 (s, 2CH3N), 17.6 (d,
CH3, 2JCP = 7.5 Hz), 16.3 (d, 2CH3, 3JCP = 6 Hz); 31P-
NMR (121 MHz, CDCl3/TMS) δ: 13.95; Anal. calcd
for C10H19N2O3P: C, 48.78; H, 7.78; and N, 11.38.
Found: C, 48.71; H, 7.82; and N, 11.41.
Diethyl (E)-[2-cyano-1-(diphenylamino)
methyl]vinylphosphonate (2d)
Diethyl (E, Z) 2-[(cyano)(diethylamino)]-
1-methylvinylphosphonate (2b)
Yield: 64 %; brown liquid; IR (neat): 2221, 1610,
1
1241, 1451 cm−1. H-NMR (300 MHz, CDCl3/TMS)
Yield: 72 %; yellow liquid; IR (neat): 2222, 1728,
1245 cm−1. 1H-NMR (300 MHz, CDCl3/TMS) δ: 4.15
(dq, 4H, J = 7.5 Hz, J = 7.5 Hz, 2OCH2), 2.93 (q, 4H,
δ: 7.27 (t, 4H, J = 6 Hz, aromatic H), 7.09 (d, 4H,
J = 6 Hz, aromatic H), 7.00 (t, 2H, J = 6 Hz, aro-
3
matic H), 6.31 (d, 1H, JHP = 21 Hz, = CH), 4.79
3
3
J = 7.5 Hz, 2CH2N), 2.21 (d, JHP = 15 Hz, CH3-Z),
(d, 2H, JHP = 12 Hz, CH2N), 4.05 (dq, 4H, J =
2.05 (d, 3JHP = 16 Hz, CH3-E), 1.38 (t, 6H, J = 7.5 Hz,
2CH3-Z), 1.35 (t, 6H, J = 7.5 Hz, 2CH3-E), 1.07 (t, 6H,
J = 7.5 Hz, CH3); 13C-NMR (75 MHz, CDCl3/TMS)
7.5 Hz, J = 7.5 Hz, 2OCH2), 1.25 (t, 6H, J = 7.5 Hz,
2CH3); 13C-NMR (75 MHz, CDCl3/TMS) δ: 152.7 (d,
1
C, JCP = 171 Hz), 147.7 (s, aromatic C), 129.2 (s,
1
δ: 151.3 (d, C, JCP = 174.75 Hz), 131.4 (d, C,
aromatic CH), 121.4 (s, aromatic CH), 120.4 (s, aro-
3
3
2JCP = 17.4 Hz), 114.5 (d, CN-Z, JCP = 23.7 Hz),
matic CH), 114.4 (d, CN, JCP = 30.75 Hz), 111.8
3
2
2
112.7 (d, CN-E, JCP = 30.75 Hz), 62.7 (d, 2OCH2,
(d, CH, JCP = 18.75 Hz), 63.1 (d, 2OCH2, JCP =
2JCP = 7.5 Hz), 47.5 (s, 2CH2N), 18.3 (d, CH3-Z, 2JCP
Heteroatom Chemistry DOI 10.1002/hc
=
6 Hz), 53.8 (d, CH2N, 2JCP = 9.75 Hz), 16.2 (d, 2CH3,

464 Fray, Kra¨ıem, and Amri
3JCP = 6 Hz); 31P-NMR (121 MHz, CDCl3/TMS) δ:
13.29; Anal. calcd for C20H23N2O3P: C, 64.86; H,
6.26; and N, 7.56. Found: C, 64.78; H, 6.23; and N,
7.59.
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Diethyl (E)-[2-cyano-1-(dicyclohexylamino)
methyl]vinylphosphonate (2e)
Yield: 58 %; yellow liquid; IR (neat): 2220, 1689,
1245 cm−1. 1H-NMR (300 MHz, CDCl3/TMS) δ: 6.31
3
3
(d, JHP = 21 Hz, CH), 4.56 (d, JHP = 12 Hz,
CH2N), 4.15 (dq, 4H, J = 7.5 Hz, J = 7.5 Hz, 2OCH2),
2.74–2.69 (m, 2H, 2CH), 1.42–1.33 (m, 20H, 10CH2),
1.26 (t, 6H, J = 6 Hz, 2CH3); 13C-NMR (75 MHz,
CDCl3/TMS) δ: 151.3 (d, C, 1JCP = 174.75 Hz), 114.5
3
2
(d, CN, JCP = 30.75 Hz), 112.3 (d, CH, JCP
=
=
2
14.25 Hz), 55.3 (s, 2CHN), 53.8 (d, CH2N, JCP
9.75 Hz), 52.6 (s, 2CH), 31.2 (s, 4CH2), 26.9 (s, 2CH2),
22.8 (s, 4CH2), 16.3 (d, 2CH3, JCP = 6 Hz); 31P-
3
NMR (121 MHz, CDCl3/TMS) δ: 13.53; Anal. calcd for
C20H35N2O3P: C, 62.80; H, 9.22; and N, 7.32. Found:
C, 62.73; H, 9.23; and N, 7.35.
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Diethyl (Z)-[2-(cyano)(methoxy)-
1-methyl]vinylphosphonate (3)
Compound 3 was similarly prepared as 2a–c from
1. The compound 3 was purified by column chro-
matography (CH2Cl2-AcOEt, 7:3). Yellow liquid; IR
(neat): 2224, 1713, 1244, 1171, 1014 cm−1. 1H-NMR
(300 MHz, CDCl3/TMS) δ: 4.15 (dq, 4H, J = 7.5 Hz,
J = 7.5 Hz, 2OCH2), 3.92 (s, 3H, CH3), 1.90 (d, 3H,
3JHP = 15 Hz, CH3), 1.37 (t, 6H, J = 6 Hz, 2CH3); 13C-
2
NMR (75 MHz, CDCl3/TMS) δ: 136.5 (d, C, JCP
=
1
21 Hz), 119.6 (d, C, JCP = 189 Hz), 111.1 (d, CN,
3JCP = 5.25 Hz), 62.6 (d, 2OCH2, 2JCP = 5.25 Hz), 58.6
(s, OCH3), 16.2 (d, 2CH3, 3JCP = 6 Hz), 12.8 (d, CH3,
2JCP = 4.5 Hz); 31P-NMR (121 MHz, CDCl3/TMS) δ:
14.85; Anal. calcd for C9H16NO4P: C, 46.35; H, 6.92;
and N, 6.01. Found: C, 46.22; H, 6.95; and N, 6.05.
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