A new protocol for the preparation of aminals from aromatic aldehydes and their facile conversion to phosphonates

Article abstract of DOI:10.1080/10426500490257078

A new and fast method for the preparation of aminals is reported from the reaction of aromatic aldehydes and secondary amines in the presence of potassium carbonate in high yields. The aminal can be converted to the corresponding iminum salt in reaction with acetyl chloride very easily and in very short time with high yield. Addition of trialkylphosphite, as one possible nucleophile, to the prepared iminium salt produces the α-amino phosphonate in very high yield.

Full text of DOI:10.1080/10426500490257078

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Phosphorus, Sulfur, and Silicon and the Related
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A NEW PROTOCOL FOR THE PREPARATION OF AMINALS
FROM AROMATIC ALDEHYDES AND THEIR FACILE
CONVERSION TO PHOSPHONATES
Mohammad Karimi Dezfuli a & Mohammad Reza Saidi a
a Department of Chemistry, Sharif University of Technology, Tehran, Iran
Published online: 11 Aug 2010.
To cite this article: Mohammad Karimi Dezfuli & Mohammad Reza Saidi (2004) A NEW PROTOCOL FOR THE PREPARATION OF
AMINALS FROM AROMATIC ALDEHYDES AND THEIR FACILE CONVERSION TO PHOSPHONATES, Phosphorus, Sulfur, and Silicon and
the Related Elements, 179:1, 89-96, DOI: 10.1080/10426500490257078
To link to this article: http://dx.doi.org/10.1080/10426500490257078
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Phosphorus, Sulfur, and Silicon, 179:89–96, 2004
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Copyright Taylor & Francis Inc.
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500490257078
A NEW PROTOCOL FOR THE PREPARATION OF
AMINALS FROM AROMATIC ALDEHYDES AND
THEIR FACILE CONVERSION TO PHOSPHONATES
Mohammad Karimi Dezfuli and Mohammad Reza Saidi
Department of Chemistry, Sharif University of Technology,
Tehran, Iran
(Received July 3, 2003; accepted July 24, 2003)
A new and fast method for the preparation of aminals is reported from
the reaction of aromatic aldehydes and secondary amines in the pres-
ence of potassium carbonate in high yields. The aminal can be con-
verted to the corresponding iminum salt in reaction with acetyl chlo-
ride very easily and in very short time with high yield. Addition of
trialkylphosphite, as one possible nucleophile, to the prepared iminium
salt produces the α-amino phosphonate in very high yield.
Keywords: Aminal; iminium salt; phosphonate; trialkylphosphite
Preparation of Eschenmoser salts and other iminium salts are of great
interest due to their increased and varied usage, and their functions in
organic chemistry have been well documented.1 However, due to the hy-
groscopicity of iminium salts and their susceptibility to hydrolysis (with
the exception of Eschenmoser’s salt), these salts have been prepared
with different methods in situ.2−4 The direct methods for the prepara-
tion of iminium ions were also reported which can be useful in some
aspects.5−7 Iminium salts were also prepared from aminals, derived
from the aliphatic aldehydes.8,9 According to the Mannich-Davidsen
procedure,10 aliphatic aminals can be easily prepared from aliphatic
aldehyde and secondary amine in the presence of a dehydrating agent.
Although aromatic aminals can be transferred to iminium salts, the
procedure for the preparation of aromatic aminal is more difficult and
is carried out under azeotropical removal of water with 83–98% yield
or by dehydration with boric anhydride with 64–92% yield.11 For ex-
ample, according to one reported procedure, when benzaldehyde and
piperidine were refluxed in benzene for 24 h with a Dean-Stark trap,
the corresponding aminal was produced in 72% yield.11b
Address correspondence to Mohammad Reza Saidi, Department of Chemistry, Sharif
University of Technology, PO Box 11345-9516, Tehran, Iran. E-mail: saidi@sharif.edu
89

90
M. K. Dezfuli and M. R. Saidi
In this article, we describe a very simple, fast, and solvent-free
method for the preparation of aromatic aminals. We also report the
reaction of aromatic aminal with acetyl chloride, which produced the
corresponding iminium salts in high yields.
α-Amino phosphonates are an important class of compounds since
they are considered as structural analogues of the corresponding α-
amino acids, and their utilities as enzyme inhibitors, antibiotics, phar-
macological agents and many other applications are well documented.12
The prepared iminium salt was reacted with trialkylphosphite, as one
possible nucleophile for reaction with iminium salt, to give high yields
of α-amino phosphonates at ambient temperature.
RESULTS AND DISCUSSION
Addition of benzaldehyde 1 to the mixture of secondary amine 2 and
anhydrous potassium carbonate produced the aminal 3 after 2.5 h at
room temperature. High yields are observed from the reaction of an
aldehyde with a secondary cyclic amine by simply stirring at room tem-
perature without using any solvent at the initial step. The reactions
are run neat, there are no by-products, and the work-up procedure is
easy. Recrystallization in the proper solvent (Table I) gave the pure
aminal in high yield (Scheme 1). Other dehydrating agents such as an-
hydrous magnesium sulfate and zinc chloride also can be used. But in
these cases, in the absence of a solvent, the mixture coagulates and the
yield is low. Addition of a solvent at the initial step lowers the yield
too. Our study shows that the best secondary amine for the prepara-
tion of aminal is morpholine. In this case the corresponding aminal
can be crystallized very easily. Also, in contrast with the secondary
cyclic amine the acyclic amines did not produce any aminal with this
procedure.
SCHEME 1
In the past few years we have shown that iminium ions can be pre-
pared from aldehydes and secondary amines in situ in the concentrated
ethereal solution of lithium perchlorate, and they can be trapped by dif-
ferent nucleophiles.2 In the present work we report that the reaction

α-Aminophosphonates
91
TABLE I Synthesis of Aminals Using K2CO3 as Dehydrating Agent
Solvent used for
crystallization
Conv.
yield (%) yield (%)
Isolated
Aldehyde
Product
of the aminals with acetyl chloride in THF produced the iminium salt
in less than 1 min. The iminium salt, which is detected by 13C-NMR
spectroscopy in the solution,13 can be used for addition reaction.
The reported procedures for the preparation of α-amino phospho-
nates are a three-component reaction between an aldehyde, a sec-
ondary amine, and dialkylphosphite,12 or trialkylphosphite,14 or ad-
dition of triethylphosphite to preformed vinylogous iminium salt.12h In
the present work, addition of nucleophiles such as trimethylphosphite
to the prepared iminium salt gave a high yield of α-amino phosphonate
4 at ambient temperature and in a very short time (Scheme 2). The
results are summarized in Table II.

92
M. K. Dezfuli and M. R. Saidi
SCHEME 2
Solvent Effect
As mentioned above, an aldehyde and a cyclic secondary amine
were mixed without using any solvent at the initial step. Using
dichloromethane or acetonitrile at the initial step, lowers the reaction
TABLE II Synthesis of α Amino Phosphonate from Aminal
Isolated
yield (%)
Isolated
Aminal Solvent Product
Aminal Solvent Product yield (%)

α-Aminophosphonates
93
yield. After stirring the reaction mixture for 1 h, dichloromethane was
added.
Addition of acetyl chloride to the aminal in a solvent gives the
iminium salt. Using THF as a solvent for all aminals gave the iminium
salt in less than one min. Although aminals derived from morpholine
gave the corresponding iminium salt in dichloromethane or acetoni-
trile in 10 min, aminals derived from piperidine gave no product af-
ter stirring for 24 h at room temperature. The best solvent for the
reaction of each iminium ion with trialkylphosphite is indicated in
Table II.
Table I shows the prepared aminals and the best solvent system
for their recrystallization. The conversion yields for the prepared am-
inals are between 84%–100%. The structures of the known and the
new compounds have been unambiguously characterized on the ba-
sis of their IR, NMR (1H, 13C), MS spectra and by comparison with
those reported in the literature.11 The 1H and 13C NMR spectra
display the characteristic signals of protons and carbons of all the
constituents.
CONCLUSION
In summary, aromatic aminals have been prepared with secondary
cyclic amine in good yields and in short time. The aminals can be con-
verted to the iminium salts almost immediately by reaction with acetyl
chloride. The iminium ions were reacted with trimethylphosphite as
one possible nucleophile to produce the corresponding α-amino phos-
phonates.
EXPERIMENTAL
Preparation of (Dimorpholinomethyl)benzene 3a. Typical
Procedure
Benzaldehyde (10 mmol, 1.06 g) was added drop wise to the mixture
of morpholine (30 mmol, 2.6 g) and anhydrous potassium carbonate
(1.3 g) during 1 h. Then dichloromethane (1.5 mL) was added and the
mixture was stirred at room temperature for 1.5 h. Dichloromethane
(20 mL) was added and the potassium carbonate filtered off. The solvent
was removed to give the crude product. Recrystallization in petroleum
ether gave the pure aminal 3a. Proper recrystallization solvent for each
aminal is given in Table I.

94
M. K. Dezfuli and M. R. Saidi
General Procedure for the Preparation of α-Amino
Phosphonates 4
The aminal (2.7 mmol) was dissolved in THF or CH2Cl2 (5 mL) and
acetyl chloride (2.8 mmol) was added. The iminium salt was precipitated
immediately. Then trimethylphosphite (3.5 mmol) was added and the
mixture was stirred at room temperature until all the iminium salt
was used. Dichloromethane (10 mL) and 2 M aqueous HCl (10 mL)
were added. The aqueous phase was separated, neutralized with 5 M
NaOH solution, extracted with dichloromethane, dried over MgSO4,
and the solvent was removed. Almost pure crude product was obtained.
The structures of the products were determined by comparison of the
spectroscopic data with those reported in the literature.12
(Dimorpholinomethyl)benzene (3a)
Known,11a,11c m.p. 104–105.5◦C (pet. ether, lit. 105◦C), 85% (isolated
1
yield); IR (KBr), 1113.7 (s, CH N) cm−1; HNMR (CDCl3), δ, 2.44 (m,
8H), 3.66 (s.1H), 3.70 (t, J = 10.53 Hz, 8H), 7.20–7.38 (m, 5H); 13CNMR
(CDCl3), 49.9 (CH2 N), 68.2 (CH2 O), 89.5 (N CH N), 128.2 (CH),
129.2 (CH), 129.3 (CH), 134.45 (C).
1-Bromo-4-(dimorpholinomethyl)benzene (3d)
M.p. 138.6–140◦C (ethyl acetate), 90% (isolated yield); IR (KBr),
1
1111.9 (s, CH N) cm−1; HNMR (CDCl3), δ, 2.39–2.45 (m, 8H), 3.64
(s, 1H), 3.68 (t, J = 4.65 Hz, 8H), 7.11 (d, J = 8.55 Hz, 2H), 7.5 (d,
J = 8.25 Hz, 2H); 13CNMR (CDCl3), 49.9 (CH2 N), 67.5 (CH2 O), 88.8
(N CH N), 122.1 (C), 130.7 (CH), 131.4 (CH), 133.5 (C).
(Dipiperidinomethyl)benzene (3f)
Known,11a m.p. 82.5–84.0◦C (pet. ether), 80% (isolated yield); IR
1
(KBr), 1111.8 (s, CH N) cm−1; HNMR (CDCl3), δ, 1.38 (m, 4H), 1.55
(m, 8H), 3.58 (s, 1H), 7.21–7.90 (m, 5H).
3-(Dimorpholinomethyl)-1-nitrobenzene (3h)
Known,11c m.p. 143–144.5◦C (pet. ether, lit. 140–142◦C), 87% (iso-
lated yield); IR (KBr), 1110.1 (s, CH N) cm−1; 1HNMR (CDCl3), δ, 2.40-
2.47 (m, 8H), 3.70–3.75 (m, 8H), 3.81 (s, 1H), 7.58–8.20 (m, 4H).
1-(Dipiperidinomethyl)-3-nitro benzene (3i)
M.p. 89–90.3◦C (pet. ether), 80% (isolated yield); IR (KBr), 1104.0 (s,
1
CH N), 1344, 1525 (s, NO2) cm−1; HNMR (CDCl3), δ, 1.40 (m, 4H),
1.52–1.57 (m, 8H), 2.30–2.35 (m, 8H), 3.75 (s, 1H), 7.51-7.57 (m, 2H),
8.07 (s, 1H), 8.15 (m, 1H); 13C-NMR (CDCl3), δ, 25.4 (CH2) , 26.5 (CH2),

α-Aminophosphonates
95
50.5 (CH2 N) , 89.2 (N CH N), 122.6 (CH), 123.3 (CH), 128.7 (CH),
134.8 (CH), 139.0 (CH), 148.3 (C).
2-(Dimorpholinomethyl)-1-methoxybenzene (3k)
Known,11c m.p. 75.5–77◦C (pet. ether, lit. 70–74◦C), 90% (isolated
1
yield); HNMR (CDCl3), δ, 2.40–2.44 (m, 8H), 3.65–3.70 (m, 8H), 3.80
(s, 3H), 4.41(s, 1H), 6.92–6.98 (m, 2H), 7.25–7.36 (m, 2H); 13C-NMR
(CDCl3), 50.0 (CH2 N), 55.7 (OCH3), 67.7 (CH2 O), 79.5 (N CH N),
111.2 (CH), 120.1 (CH), 123.1 (CH), 128.8 (CH), 129.8 (C), 158.8 (C).
2-(Dimorpholinomethyl) Pyridine (3n)
M.p. 102.2–103.7◦C (pet. ether), 92% (isolated yield); IR (KBr), 1114.3
(s, CH N) cm−1; 1HNMR (acetone-d6), δ, 2.39–2.42 (m, 8H), 3.58–3.64
(m, 8H), 3.88 (s, 1H), 7.31 (m, 1H), 7.39 (m, 1H), 7.8 (d, J = 1.8 Hz, 1H),
8.6 (m, 1H); 13C-NMR (acetone-d6) 49.9 (CH2 N), 67.5 (CH2 O), 90.0
(N CH N) , 123.0 (CH), 123.2 (CH), 135.86 (CH), 149.4 (C), 155.5 (C).
α-Morpholino Phosphonates (4a)
Known,12 1H NMR (500 MHz, CDCl3): δ 2.58 (t, J = 6.3 Hz, 2H), 2.79
(t, J = 6.1 Hz, 2H), 3.51 (m, 3H), 3.67–3.74 (m, 4H), 3.81–3.88 (m, 4H),
7.187–7.43 (m, 5H), 13C NMR: 125 MHz, CDCl3): δ 24.3 (CH2), 26.5
(CH2), 52.3 (CH2), 54.8 (d, J = 6.8 Hz, CH3), 54.9 (d, J = 7.8 Hz, CH3),
63.9 (d, J = 161.3 Hz, CH), 128.1 (CH), 128.8 (CH), 131.2 (d, J = 5.6 Hz,
CH), 134.8 (d, J = 3.4 Hz, C).
α-Piperidino Phosphonates (4g)
Known,12 1H NMR (500 MHz, CDCl3): 1.34 (t, J = 6.2 Hz, 2H), 1.56–
1.64 (m, 4H), 2.41 (m, 2H), 2.78 (m, 2H), 3.54 (d, J = 8.6 Hz, 3H), 3.92
(d, J = 8.7 Hz, 3H), 4.01 (d, J = 22.8 Hz, 1H), 7.67 (d, J = 8.0, 2H),
8.22 (d, J = 8.4, 2H).
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