M. B. Gazizov et al. / Tetrahedron Letters 57 (2016) 210–212
211
O
RN
H
O
R1
R2
O
Hal
Hal
Br
H
Br
H
MS
+
X
+
RNH2
P
X
-H2O
OMe
H
H
H
Br
Br
7
13a-d
14a-d
1a-b
2
3
13a R = iPr, 13b R = 4-MeOC6H4
13c R = CH2CH(OEt)2,
13d R = (CH2)3CH(OEt)2
,
14a R = Pr 77%, 14b R = 4-MeOC6H4 100%,
14c R = CH2CH(OEt)2 93%,
14d R = (CH2)3CH(OEt)2 92%
i
1a R1 = R2 = iPr,
2 X = H, MeO, NO2;
Hal = Cl, Br
3 X = H 90%, MeO 65%, NO2 54%
1b R1 = Me, R2 = MeO
R1
O
R1
O
O
P
P
O
O
O
R1
R1
Br
H
RO
H
Br
H+
-HCOOR
or
P
O
+
MeHal +
P
P
HC(OR)3
+
R2
O
R2
H
O
H
Br
OR
Br
O
7
12a-b
15a-b
15a R = Me 92%, 15b R = Et 93%
4
5
R1
4 R1 = R2
=
iPr; 5 R1= Me
12a R = Me, 12b R = Et
Scheme 3. Reactions of aldehyde
orthoformates 12a–b.
7
with primary amines 13a–d and trialkyl
Scheme 1. Aldehyde generation from (dihalomethyl)arenes.
MeO
O
Br
Br
H
R1O
Br
P
+
P
H
15a-b + PCl3
Cl
+
R1O
MeO
OMe
Br
Br
Br
Br
H
H
Cl
1c
6
9
Cl
Br
16a-b
15a R1= Me, 15b R1 = Et
16a R1 = Me, 16b R1 = Et
Br
H
O
MeO
O
-MeBr
P
R1O
H
Br
H
H
P
Me
R2
Br
+
R3O
+
R3Cl
16a-b
OMe
R2
P
Br
17a-c
R2
18a-d
O
O
Br
H
MeO
R2
18a R1 = Me, R2 = OEt 30%, 18b R1 = Me, R2 = Ph 77%,
18c R1 = Me, R2 = OMe 38%, 18d R1 = Et, R2 = OMe 81%
17a R2 = OR3, R3= Me,
17b R2 = OR3, R3 = Et,
17c R2 = Ph, R3 = Et
P
H
O
OMe
Br
Br
10
Scheme 4. Synthesis of 4-(dibromomethyl)-substituted benzenes 18a–d, contain-
ing a phosphorous functional group in the side-chain.
O
MeO
Br
Br
+
P
H
O
OMe
H
of the Michaelis–Arbuzov reaction. The formed bromine-substi-
tuted ether 10 is unstable and decomposes to give aldehyde 7
and bromophosphate 11. A multistep reaction of compound 11
with trimethyl phosphate and the intermediate compounds con-
taining a methoxy group at P(IV) possibly results in the formation
of the polymeric anhydride of phosphoric acid.
Br
11
7
42%
Scheme 2. Proposed mechanism for aldehyde generation from a dibromomethyl
group.
momethyl)benzene 6. Trimethyl phosphate 1c, which is the least
expensive commercially available methyl ester of P(IV) acid was
used and we expected that proper selection of the ratio of com-
pounds 1 and 6 would allow preservation of one of the dibro-
momethyl groups while terephthalic aldehyde 4-OCHC6H4CHO 8
could be obtained using excess trimethyl phosphate. The reactions
were monitored by dynamic 1H NMR spectroscopy. The reactants
1c and 6 were found to have the following optimal ratios: 1.5:1
and 2.1:1 leading to the formation of mixtures of 7 and 8 with
ratios of 4:1 and 1:19, respectively. Tetrabromide 6 was not
observed in the reaction mixture under these conditions. The 1H
NMR spectrum of a mixture of compounds 1c and 6, using the
above ratios and heated to 180 °C for 5.5 and 21 h, respectively,
showed no resonance signal at dP 3.79 ppm (d, 3JPH = 11 Hz) corre-
sponding to the P(IV)—OMe protons. The polymeric anhydride of
phosphoric acid was insoluble in conventional organic solvents
including isooctane; therefore, the mixture of compounds 7 and
8 was extracted by heating the reaction mixture in isooctane.
The target products 7 and 8 were individually obtained by column
chromatography using benzene as an eluent.
To synthesize new polyfunctional organic compounds, 4-(dibro-
momethyl)benzenecarbaldehyde
7 was reacted with trialkyl
orthoformates 12a–b and primary amines 13a–d. The reaction of
aldehyde 7 with amines 13a–d was carried out in benzene in the
presence of molecular sieves (MS). After solvent removal in vacuo,
imines 14a–d were obtained in high yields (Scheme 3).
Catalytic sulfuric acid was added to a mixture of aldehyde 7 and
trialkyl orthoformate 12a–b (1:4). The exothermic reaction pro-
ceeded over 24 h before excess orthoester was removed in vacuo
to give acetals 15a–b in high yields (Scheme 3).
Subsequent reaction of acetals 15a–b with phosphorous trichlo-
ride and P(III) acid esters 17a–c allowed the synthesis of 1-(dibro-
momethyl)-substituted benzenes containing
a
phosphorous
functional group in the side chain: O,O-dialkylalkoxy[4-(dibro-
momethyl)phenyl]methanephosphonates 18a,c–d and diphenyl
[4-(dibromomethyl)phenyl]methoxymethane-phosphinoxide 18b.
The formation of the intermediate
a-chloroether 16a–b was con-
firmed by 1H NMR spectroscopy (Scheme 4).
Thus, the reaction of trimethyl phosphate 1c with 1,4-bis(dibro-
momethyl)benzene 6 allowed the synthesis of 4-(dibromomethyl)
benzenecarbaldehyde 7, which was then transformed into acetals
15a–b and imines 14a–d, which included those containing an
acetal group 14c–d. Acetals 15a–b were converted into 4-(dibro-
momethyl)-substituted benzenes, containing phosphorous func-
tionality in the side chain 18a–d.
We propose the following mechanism for the generation of an
aldehyde from the dibromomethyl functionality (Scheme 2).
Nucleophilic attack of the methine carbon by the phosphoryl oxy-
gen results in the release of a bromide anion and the formation of
the quasi-phosphonium salt 9, which undergoes the second stage