March 1998
SYNLETT
311
References and Notes
(1) Fuson, R.C.; Keever, C.H. Org. React. 1942, 1, 63.
(2) Olah, G.A.; Tolgyesi, W.S. Friedel-Crafts and Related Reactions;
Wiley: New York, 1964, Vol. II, pp. 659-784.
(3) Mitchell, R.H.; Iyer, V.S. Synlett 1989, 55.
(4) van der Made, A.W.; van der Made, R.H. J. Org. Chem. 1993, 58,
1262.
(5) Compounds 3a and 3b were commercially available from Aldrich;
compounds 2c-f and 3c-f were synthesized using typical
procedures described here for 2f and 3f, respectively.
1,2-Di(1'-hydroxypentadecyl)benzene (2f). A dropping funnel
was capped with a rubber septum, and attached to a 200 mL
Schlenk flask equipped with a magnetic stirring bar. The assembly
was flame dried under Ar. In a separate dry 200 mL round-
bottomed flask, 4.23 g (31.5 mmol) of phthalaldehyde was
introduced. The flask was capped with a rubber septum, and
purged with Ar. Dry and degassed toluene (60 mL) was added,
and the solution was transferred to the Schlenk flask via cannula.
The flask was placed in
a -20 °C salt/ice bath, and n-
pentadecylmagnesium bromide (0.090 mol in Et O) was added
2
dropwise via the dropping funnel. The stirred solution was
allowed to warm to rt over a period of 20 h. After addition of satd
NH Cl, the mixture was filtered through a medium glass frit, and
4
the filtrate was concentrated by rotary evaporation, and
chromatographed on silica gel using hexanes. A fast eluting
fraction (R = 0.5 in hexanes) was separated, and the eluant was
Tables 1 and 2 show a progressive decrease in the rate of formation of
bis-bromomethylated products as the length of the substituent R
increases. Substantially slower rates of reaction were observed for the
substrates 3e and 3f when compared to the derivatives having shorter
alkyl chains. In preparative scale reactions conducted at 110 °C, the
bromomethylation of 3d for 6 days yielded a product ratio of 30:70 of
mono:bis-bromomethyl with a 45% overall yield of bromomethylated
products. In contrast, the bromomethylation of 3e and 3f for 19 and 24
days, respectively, yielded product ratios of 25:75 and 29:71 with
overall yields of 51% and 38%, respectively.
f
adjusted to a 3:1 ratio of hexanes/Et O. A fraction (R = 0.65
2
f
using the solvent mixture as eluant) was then collected. Removal
1
of the solvent in vacuo gave 16.7 g (31.5 mmol, 76%) of 2f. H
NMR (300 MHz, CDCl ): δ 0.88 (t, 6 H, J = 8 Hz, CH ), 1.25-
3
3
1.50 (m, 52 H), 4.97 (t, 2 H, J = 5.7 Hz, CHOH), 7.27 (d of “d”, 2
H, J = 7.5 Hz, J = 2.8 Hz, Ar-H), 7.43 (d of “d”, 2 H, J
=
1,2
1,2
1,3
13
7.5 Hz, J = 2.8 Hz, Ar-H). C NMR (75 MHz, CDCl ): δ 14.1,
1,3
3
22.7, 26.4, 29.4, 29.7, 31.9, 38.6, 71.1, 126.2, 127.7, 141.6.
1,2-Dipentadecylbenzene (3f). A dry 250 mL round-bottomed
flask equipped with a magnetic stirring bar was charged with 10%
palladium on carbon (100 mg) and p-toluenesulfonic acid (100
mg). The flask was capped with a rubber septum, and purged with
Ar. Degassed methanol (40 mL) was added via cannula, and the
Increasing the temperature from 80 to 110 °C increased the rate of
bromomethylation for all substrates. For longer chain derivatives, a
brief study exploring the use of the co-solvents carbon tetrachloride,
chloroform and 1,4-dioxane found no substantial increase in the rate of
the reaction. Also, the addition of a phase transfer catalyst (hexadecyl-
suspension was stirred under H for 25-30 min. Separately, a 250
2
mL round-bottomed flask was charged with 2.00 g (37.8 mmol) of
2f and methanol (40 mL). The flask was capped with a rubber
septum and purged with Ar. The methanolic solution was then
added via cannula to the catalyst. The mixture was stirred under
trimethylammonium bromide) or a Lewis acid catalyst (ZnBr ) showed
2
no increase in the rate of the reaction. We found, however, that the
reaction was highly sensitive to the experimental conditions (e.g.,
freshness of the HBr solution; rate of stirring). These latter observations
are consistent with the results of halomethylation reactions reported by
H
for 24 h at rt, after which no olefinic peaks of the starting
2
1
3,8
material could be observed by H NMR spectroscopy. The
solution was concentrated under vacuum, and passed through a
plug of silica gel using hexanes. The filtrate was concentrated by
other researchers.
As a synthetic tool, the bromomethylation of 1,2-dialkylbenzenes shows
great promise for its regioselectivity. Relatively long reaction times,
however, are required to generate the desired products in high yields.
We are currently attempting to optimize the yields of bis-
bromomethylated products as a function of the reaction time.
rotary evaporation to give 1.85 g (39.2 mmol, 98%) of 3f as a
1
colorless liquid. H NMR (300 MHz, CDCl ): δ 0.88 (t, 6 H, J = 8
3
Hz, CH ), 1.25-1.50 (m, 52 H), 2.58 (t, 4 H, J = 8 Hz, CH Ar),
3
2
13
7.09-7.11 (m, 4 H, Ar-H). C NMR (75 MHz, CDCl ): δ 14.1,
3
22.7, 29.4, 29.6, 29.7, 29.8, 31.4, 31.9, 32.7, 125.6, 129.1, 140.6.
Acknowledgments. The National Science Foundation (CAREER
Award to TRL; CHE-9625003), the Robert A. Welch Foundation (Grant
No. E-1320) and the Camille and Henry Dreyfus Foundation (New
Faculty Award to TRL; NF-93-040) provided generous support for this
research. We thank our colleagues Jonathan Friedman and Randy
Thummel for helpful advice.
(6) The synthesis of 5d from 3d illustrates
a
typical
bromomethylation procedure: A 100 mL cylindrical high pressure
glass vessel equipped with a magnetic stirring bar was charged
with 0.50 g (2.3 mmol) of 3d, 10 mL of acetic acid, 0.25 g (8.3
mmol) of paraformaldehyde and 1 mL of 33 wt% hydrobromic
4
acid in acetic acid. The resulting mixture was heated with stirring
at 110 °C for 6 days. Hydrobromic acid solution (~1 mL) and
paraformaldehyde (~0.25 g) were added twice during the course
Garg, Nupur
