2
082
K. J. Wallace et al.
PRACTICAL SYNTHETIC PROCEDURES
nation of the azide to the free amine 5. The inclusion of the ica gel (100 g) was added to the flask. The suspension was shaken,
and the CH Cl was removed using a rotary evaporator. This solid
other routes is to highlight the ease of the synthetic route
over the last couple of decades.
2
2
mixture was loaded on a fritted filter, and washed repeatedly with
:1 hexanes–CH Cl until no more product was observed by TLC
9
2
2
(
cf. Note 12). The combined washes were evaporated in vacuo. The
1
,3,5-Triethylbenzene (1)
1
13
product was obtained as a white solid with H and C NMR spectra
consistent with the desired compound; mp 144 °C. Further purifi-
AlCl (45.3 g, 340 mmol) was placed into an oven-dried, 250 mL
3
10
three-necked round bottom flask equipped with a magnetic stir bar
that was fitted with a reflux condenser and addition funnel. A N2
balloon was attached to exclude atmospheric water. The water con-
denser was fitted with a tube that is submerged into an aq sat. solu-
tion of NaHCO to quench the evolved HBr/HCl gas (Note 1). The
reaction flask was cooled to 0 °C in an ice water bath. EtBr (50 mL,
cation has been accomplished through recrystallization from hot
MeOH. Typical yields ranged from 80–90%. High temperature was
not necessary for this reaction (Note 13).
1H NMR (CDCl
Hzz), 4.69 (s, 6 H).
): d = 1.31 (t, 9 H, J = 7.6 Hz), 2.93 (q, 6 H, J = 7.6
3
3
5
90 mmol) was poured into the addition funnel and slowly added to
13
1
C{ H} NMR (CDCl , 75 MHz): d = 16.0, 22.6, 40.6, 132.6,
3
the AlCl with continuous stirring (Note 2). Once the addition of
10
3
1
45.0.
EtBr was complete, benzene (28.6 mL, 320 mmol) was added slow-
ly over 20 min (Note 3). Once the addition of benzene had been
completed, and the effervescence had ceased, EtBr (32.5 mL, 390
mmol) was then added dropwise whilst maintaining a reaction tem-
perature of 0 °C. The reaction was stirred for 12 h allowing the mix-
ture to warm to r.t. On completion, the mixture was decanted into a
1
,3,5-Tris(bromomethyl)-2,4,6-triethylbenzene (3)
A water condenser was connected to a 250 mL oven-dried round-
bottomed flask. Zn powder (5 g, 76 mmol) and AcOH (50 mL, 873
mmol) were added to the flask. HBr in AcOH (33% wt, 50 mL) was
added slowly through the condenser over a 0.5 h period into the re-
action vessel that was continuously stirred (Note 14). Once the HBr
was added, the reaction mixture was stirred until the Zn had com-
pletely dissolved, and the solution turned into a clear tan/orange col-
or. Triethylbenzene (1; 10 g, 62 mmol), paraformaldehyde (20 g),
and HBr in AcOH (33% wt, 148 mL) were then added and the solu-
tion was heated to 90 °C for 48 h resulting in a dark brown solution
1
L beaker containing ice, and once the ice had melted the pH of the
aqueous layer was measured (Note 4). The mixture was extracted
with Et O (250 mL) in a 1 L separating funnel (Note 5). The organic
layer was separated, and the aqueous phase was extracted with Et O
2
2
(
2 × 100 mL). The organic phases were combined and washed as
follows: H O (1 × 100 mL), aq 1 N NaOH (1 × 100 mL), and H O
(
2
2
1 × 100 mL). The organic phase was dried (MgSO ), and filtered
4
(
Note 15). The solution was allowed to cool slowly with continuous
through Celite into a one-necked round bottom flask. The solvent
was removed under reduced pressure, yielding a yellow oil. Upon
vacuum distillation, a colorless oil was produced (Note 6); typical
yields ranged from 80–90%. 1,3,5-Triethylbenzene (1) is a com-
mercially available compound, and the spectral data were in agree-
ment with those of the commercial source.
stirring, whence a white precipitate was formed over 2 h. The solid
was filtered, washed with H O (3 × 100 mL), and allowed to dry un-
der vacuum for 24 h (Note 16). Typical yields ranged from 60 to
2
7
0%; mp >150 °C (dec.).
1
H NMR (CDCl ): d = 1.34 (t, 9 H, J = 7.6 Hz), 2.94 (q, 6 H, J = 7.6
3
Hz), 4.58 (s, 6 H).
1
3
1
,3,5-Tris(chloromethyl)-2,4,6-triethylbenzene (2)
C NMR (CDCl ): d = 15.6, 22.7, 28.5, 132.6, 145.0.
3
CAUTION! Chloromethyl methyl ether is volatile and reported to
be a potent carcinogen.
1,3,5-Tris(azidomethyl)-2,4,6-triethylbenzene (4)
CAUTION! NaN has been found to be explosive under certain
conditions and is highly toxic.
To a three-necked round-bottomed flask fitted with a mechanical
stirrer, an efficient water condenser, and a pressure-equilibrating
3
addition funnel, was added CS (100 mL, 13 mmol) followed by
Method A: The conversion of the trihalo triethylbenzene
(halo = chloro or bromo) into the trisazide product was achieved by
dissolving either 2 or 3 in a mixture of DMF and CH Cl (50 mL and
2
1
,3,5-triethylbenzene (1; 13.4 mL, 123 mmol), which had been
freshly distilled with a Kugelrohr apparatus at 65 °C/1 Torr. The so-
2
2
lution was purged, by forcing dry N through a glass dispersion tube
20 mL respectively), and heating the reaction mixture to 80 °C. A
slurry of 6 mol equiv of NaN was made up in distilled H O (20
2
submerged beneath the surface of the solvent for 15 min. Removal
3
2
of dissolved O from the solvent and subsequent inert reaction con-
mL), and added through the top of the condenser, which was subse-
2
ditions are believed to minimize the color and impurities in the
quently rinsed with distilled H O and the reaction mixture was
2
product. Following this step, SnCl (43 mL, 652 mmol) (Note 7)
stirred gently for 22 h (Note 17). The condenser was removed from
the flask whilst behind a blast shield (Caution! Note 18). The DMF
4
was added resulting in the appearance of a bright yellow color. A
CaCl drying tube was also attached (Note 8). Chloromethyl methyl
was removed under reduced pressure, and distilled H O (100 mL)
2
2
ether (64 mL, 1.1 mol), measured volumetrically with an appropri-
ate-sized syringe, was added to the addition funnel, and the reaction
was stirred on the fastest setting of the mechanical stirrer (Note 9).
This reagent was added rapidly, allowing a controlled reflux result-
ing from the exothermicity of the reaction and the reaction was al-
lowed to stir overnight (Note 10). For an in situ TLC analysis, a
was added to the residue. The organic layer was separated and the
aqueous layer was washed with CH Cl (3 × 20 mL). The organic
2
2
layers were combined, dried (MgSO ), and filtered. The solvent was
4
removed by rotary evaporation to afford an oil. The oil was purified
by chromatography (Note 19) using EtOAc–n-hexane (25:75). The
solvent was removed under reduced pressure to give a white solid;
mp 61 °C.
small aliquot was removed and washed with NaHCO . The organic
3
layer was removed and dried (MgSO ) before the TLC experiment
4
IR (deposit from CDCl on NaCl): 2084 cm–1 (N=N=N).14
3
was performed (Note 11). On completion of the reaction, the solu-
tion was carefully decanted over 500 g of ice. The reaction vessel
was rinsed with CH Cl (100 mL), and this was added to the CS /
1H NMR (CDCl
Hz), 4.49 (s, 6 H).
): d = 1.23 (t, 9 H, J = 7.6 Hz), 2.85 (q, 6 H, J = 7.6
3
2
2
2
H O. Once all of the ice had melted, the aqueous and organic layers
13
2
C NMR (CDCl , 75 MHz): d = 15.7, 23.1, 47.9, 129.9, 145.0.
3
were separated, and the CS –CH Cl was removed under reduced
2
2
2
Method B: The conversation of trihalo triethylbenzene
pressure (Note 12). The residue was dissolved in CH Cl (250 mL)
2
2
(halo = chloro or bromo) into 1,3,5-tris(azidomethyl)-2,4,6-trieth-
to which H O (50 mL) had been added. The mixture was decanted
2
ylbenzene (4) has also been achieved by an alternative method
whereby no chromatography is required. To a previously oven dried
into a separating funnel, and the organic layer was separated, which
was then washed with aq 1 N NaOH (100 mL), H O (100 mL), and
2
5
00 mL round-bottomed flask, 1,3,5-tris(bromomethyl)-2,4,6-tri-
brine (100 mL), dried (MgSO ), and evaporated under reduced pres-
4
ethylbenzene (3; 10.8 g, 2.5 mmol) was added to DMF (250 mL) to
sure. The crude product was dissolved in CH Cl (200 mL), and sil-
2
2
Synthesis 2005, No. 12, 2080–2083 © Thieme Stuttgart · New York