Convenient Deuteration of Bromo Aromatic Compounds by Reductive Debromination with Sodium Amalgam in CH3OD

Full text of DOI:10.1021/jo9619037

1188
J . Org. Chem. 1997, 62, 1188-1190
Ch a r t 1
Con ven ien t Deu ter a tion of Br om o
Ar om a tic Com p ou n d s by Red u ctive
Debr om in a tion w ith Sod iu m Am a lga m in
CH3OD
Yozo Miura,* Hiroyuki Oka, Eiji Yamano, and
Masanori Morita†
Department of Applied Chemistry, Faculty of Engineering,
Osaka City University, Sumiyoshi-ku, Osaka 558, J apan,
and J oint Research Center, Kinki University, Kowakae,
Higashi-Osaka 577, J apan
Received October 8, 1996
Deuterated compounds provide conclusive information
on the proton assignments of 1H NMR and ESR spectra
and play important roles in kinetic and mechanism
studies and in the biochemical field.1 However, the
desired deuterated compounds, particularly partly deu-
terated compounds, with high isotopic purities are still
difficult to prepare and require many steps in their
preparation, starting from commercially available, but
expensive deuterated compounds.2 Deuteration by re-
ductive dehalogenation of halo compounds is one of the
most useful methods. For examples, hydrolysis of Grig-
nard or organolithium reagents obtained from halo
compounds in D2O or CH3COOD,3 treatment of trialkyl-
stannane compounds obtained from halo compounds in
CH3COOD-D2O,4 photolysis of halo compounds in
CD3OD,5 and Raney alloy reduction of halo compounds
in alkaline deuterium oxide solution6 have served for the
preparation of a variety of partly deuterated compounds.
However, these methods have still severe problems in the
isotopic purities or yields of the products, the easiness
of the procedures, or the prices of the deuterated solvents
used.
We have recently found that reductive debromination
of bromo aromatic compounds with sodium amalgam in
refluxing CH3OD gives the corresponding deuterated
compounds with high isotopic purities in high yields.7
Since CH3OD is commercially available at a relatively
inexpensive price and the procedure is quite simple, this
reductive debromination would provide a useful method
for the preparation of partly deuterated compounds.
Herein we report the preparation of deuterated aromatic
compounds shown in Chart 1 by this method.
MeOD over 4.8 wt % sodium amalgam for 2-24 h. The
reaction mixtures were then poured into a large excess
of water and the products were extracted with ether or
benzene. In the case of 17a , the reaction mixture was
first evaporated and then acidified, and the product was
extracted with ether. Upon removal of the solvent pure
or almost pure products were obtained in high yields in
most cases. The results of this deuteration reaction are
Resu lts a n d Discu ssion
Reductive debromination of bromo aromatic com-
pounds was carried out by heating them in refluxing
† Kinki University.
(1) For example: Miura, Y.; Momoki, M.; Fuchikami, T.; Teki, Y.;
Itoh, K; Mizutani, K. J . Org. Chem. 1996, 61, 4300.
(2) Murray, A., III; Williams, D. L. Organic Syntheses with Isotopes;
Interscience: New York, 1958; Part II, Chaper 16.
1
summarized in Table 1, and the H and 13C NMR data
shown in Table 2.
In the present reductive deuteration 10 mL (238 mmol)
of MeOD was used to keep the reaction system in high
isotopic purity. This amount corresponds to 33 times the
molar amount for one bromine atom of the bromo
compounds. Furthermore, aniline compounds were treated
with MeOD prior to the reductive deuteration. Since
some bromo compounds (7a , 10a , 11a , 16a , and 17a ) are
insoluble in such a small amount of MeOD even at the
reflux temperature, 10-20 mL of dry benzene (7a , 10a ,
11a , and 16a ) or 5 mL of D2O (17a ) was further added
to dissolve the bromo compounds completely in CH3OD
solution. The purities of the separated products were
evaluated by HPLC or TLC. For most products HPLC
or TLC analyses showed only a single peak or one spot.8
(3) For example: (a) Weldon, L. H. P.; Wilson, C. L. J . Chem. Soc.
1946, 235. (b) Turkevich, J .; McKenzie, H. A.; Friedman, L.; Spurr, R.
J . Am. Chem. Soc. 1949, 71, 4045. (c) Goubeau, J .; Luther, H.;
Feldmann, K.; Brandes, G. Chem. Ber. 1953, 86, 214. (d) Hall, G. E.;
Piccolini, R.; Roberts, J . D. J . Am. Chem. Soc. 1955, 77, 4540. (e) Lauer,
W. M.; Day, J . T. J . Am. Chem. Soc. 1955, 77, 1904.
(4) Asomaning, W. A.; Eaborn, C.; Walton, R. M. J . Chem. Soc.,
Perkin Trans. 2 1973, 137.
(5) Mu¨ller, J . P. H.; Parlar, H.; Korte, F. Synthesis 1976, 524.
(6) (a) Tashiro, M.; Iwasaki, A.; Fukata, G. J . Org. Chem. 1978, 43,
196. (b) Tashiro, M.; Nakayama, K.; Fukata, G. J . Chem. Soc., Perkin
Trans. 1 1983, 2315. (c) Tashiro, M.; Tsuzuki, H.; Tsukinoki, T.;
Mataka, S.; Nakayama, K.; Yonemitsu, T. J . Labelled Compd. Ra-
diopharm. 1990, 28, 703. (d) Tsuzuki, H.; Iyama, H.; Tsukinoki, T.;
Mukumoto, M.; Yonemitsu, T.; Nagano, Y.; Thiemann, T.; Mataka, S.;
Tashiro, M. J . Chem. Res. (S) 1994, (S) 302 and references cited
therein.
(7) Miura, Y.; Yamano, E. J . Org. Chem. 1995, 60, 1070.
S0022-3263(96)01903-2 CCC: $14.00 © 1997 American Chemical Society

Notes
J . Org. Chem., Vol. 62, No. 4, 1997 1189
The only two exceptions were 11b and 16b which
contained some byproducts in small amounts. However,
pure 11b and 16b were easily obtained by column
chromatography.
As found in Table 1, the product yields are high (74-
99%), and the isotopic purities, determined by mass
spectra, are satisfactorily high in any case (89-99%).
Deuteration of 11a was previously undertaken using
similar reaction conditions (11a , 1.59 mmol; 4.2 wt %
sodium amalgam, 33 g; CH3OD, 10 mL; benzene, 20 mL;
reflux time, 4 h),7 giving similar results to the current
work (the previous yield and isotopic purity, 80 and 87%,
the current yield and isotopic purity, 74 and 89%).
1
The structures of the products were confirmed by H
and 13C NMR spectra. In the 13C NMR spectra the
deuterium-bounded carbons were recorded as a 1:1:1
triplet with J ) 24.8 or 23.2 Hz, with a ∼0.3 ppm upfield
chemical shift relative to the corresponding nonlabeled
compounds. On the basis of the 1H and 13C NMR results,
it was confirmed that the deuteration occurred at the
expected positions, and no migration of bromine atoms
or deuterium atoms during the reductive debromination
was observed.
As found in Table 1, reductive deuteration of 4a and
5a gave interesting results. Although the bromo atoms
were rapidly subjected to this reductive deuteration, the
chloro atoms were inert for this reduction. This selective
dehaloganation was further examined in more detail.
Compound 4a was treated for 6 h in refluxing MeOD over
4.8% sodium amalgam, and the reaction mixture was
analyzed by HPLC. After 1 h, 4a disappeared completely
and only a peak due to 4b appeared. After 6 h, the
reaction mixture was again inspected, and the situation
was observed to be entirely the same.9 Since 4b and 5b
can be converted to a variety of deuterated compounds
via the Grignard reagent, they will be useful intermedi-
ates for the syntheses of deuterated compounds.
In Table 3 the present reductive deuteration method
(method A) is compared with the Raney alloy method
(method B) developed by Tashiro et al.6 Method B has
many advantages over the other methods mentioned
above.3-5 That is, the procedure is quite convenient and
has a wide appreciation. The yields and isotopic purities
of the products are very high in most cases. However,
in the sodium amalgam method even better results are
observed in the yields and isotopic purities of the
products, as found in Table 3. Since our current method
is quite convenient and CH3OD is less expensive, this
method would be useful for the preparation of deuterated
compounds from bromo aromatic compounds.
Exp er im en ta l Section
1H and 13C NMR spectra were obtained with a J EOL R-400
NMR spectrometer (400 MHz), and mass spectra were recorded
on a J EOL J MS-HX 100 instrument at 70 eV by the GC mass
method. The isotopic purities of the products were determined
by comparison with the mass spectra of the deuterated com-
(8) In the cases of 4b and 5b, the products were obtained as a
mixture with the solvent MeOH (derived from MeOD) because the
solvents ether and MeOH were removed at atmospheric pressure to
avoid the loss of the low boiling point products. The yields were
determined by the integration ratio of the protons of 1H NMR spectra
of the mixtures weighed.
(9) We further investigated reductive dechlorination of some chloro
aromatic compounds in a similar manner. While 1,4-dichlorobenzene
was not subject to reductive dechlorination, 1,3-dichloro- and 1,3,5-
trichlorobenzenes underwent slow reductive dechlorination to give a
mixture of 1,3-dichloro- and chlorobenzenes and a mixture of 1,3,5-
trichloro-, 1,3-dichloro-, and chlorobenzenes, respectively.

1190 J . Org. Chem., Vol. 62, No. 4, 1997
Ta ble 2. 1H a n d 13C NMR Da ta for Deu ter a ted Com p ou n d s
Notes
compound
1H chemical shifts (ppm)a
13C chemical shifts (ppm)a
1b
2b
3b
4b
5b
6b
1.32 (s, 9 H), 7.30 (d, J ) 7.8 Hz, 2 H), 7.40 (d, J ) 7.8 Hz, 2 H)
1.32 (s, 9 H), 7.17 (s, 1 H), 7.39 (s, 2 H)
2.28 (s, 9 H), 6.80 (s, 2 H)
7.29 (d, J ) 8.3 Hz, 2 H), 7.34 (d, J ) 8.3 Hz, 2 H)
7.25 (s, 1 H), 7.34 (s, 2H)
7.34 (t, J ) 7.8 Hz, 1 H), 7.428 (d, J ) 7.8 Hz, 2 H), 7.430
(t, J ) 7.8 Hz, 2 H), 7.59 (d, J ) 7.8 Hz, 4 H)
7.42 (d, J ) 7.8 Hz, 4 H), 7.58 (d, J ) 7.8 Hz, 4 H)
7.44 - 7.47 (m, 4 H), 7.81 - 7.83 (m, 3 H)
7.45 - 7.47 (m, 3 H), 7.82 - 7.84 (m, 4 H)
7.47 (d, J ) 7.8 Hz, 6 H), 7.70 (d, J ) 7.8 Hz, 6 H), 7.78 (s, 3 H)
1.57 (s, 18 H), 8.18 (s, 4 H)
3.81 (s, 3 H), 6.91 (d, J ) 7.8 Hz, 2 H), 7.29 (d, J ) 7.8 Hz, 2 H)
3.81 (s, 3 H), 6.91 (d, J ) 8.8 Hz, 1 H), ∼ 7.29 (br. m, 2 H)
31.3, 34.6, 125.1 (t, J ) 24.8 Hz), 125.3, 127.9, 151.1
31.4, 34.6, 125.1, 125.2, 127.7 (t, J ) 24.8 Hz), 151.1
21.1, 21.2, 126.6 (t, J ) 24.8 Hz), 126.9, 137.6, 137.7
126.1 (t, J ) 24.8 Hz), 128.6, 129.6, 134.2
126.2, 128.5, 129.4 (t, J ) 24.8 Hz), 134.2
126.9 (t, J ) 24.8 Hz), 127.15, 127.23, 128.6, 128.7, 141.2
7b
8b
9b
10b
11b
12b
13b
126.9 (t, J ) 24.8 Hz), 127.2, 128.6, 141.2
125.7, 125.8, 127.5 (t, J ) 23.2 Hz), 127.8, 127.9, 133.37, 133.44
125.5 (t, J ) 23.2 Hz), 125.7, 125.8, 127.7, 127.9, 133.4
125.2, 127.2 (t, J ) 24 Hz), 127.3, 128.7, 141.1, 142.3
32.0, 35.2, 121.9, 122.9, 127.0 (t, J ) 24.8 HZ), 130.7, 148.5
55.0, 113.8, 120.3 (t, J ) 24.8 Hz), 129.3, 159.5
55.1, 113.6 (t, J ) 24.8 Hz), 113.9, 120.3 (t, J ) 24.8 Hz),
129.2, 129.3, 159.5
14b
15b
16b
3.58 (br. s, 2 H), 6.68 (d, J ) 8.3 Hz, 2 H), 7.16 (d, J ) 8.3 Hz, 2 H) 114.9, 118.1 (t, J ) 24.8 Hz), 129.0, 146.3
3.63 (s, 2 H), 7.16 (s, 2 H)
114.8 (t, J ) 24.8 Hz), 118.2 (t, J ) 24.8 Hz), 129.0, 146.2
3.91 (s, 2 H), 7.38 (d, J ) 8.3 Hz, 2 H), 7.41 (s, 2 H),
7.47 (d, J ) 8.3 Hz, 4 H), 7.56 (d, J ) 8.3 Hz, 4 H),
7.59 (d, J ) 8.3 Hz, 2 H)
126.0 (t, J ) 24.8 Hz), 126.4, 127.1 (t, J ) 24.8 Hz), 128.25,
128.34, 128.53, 128.8, 129.3, 131.0, 139.6, 140.3, 140.8
17b
7.50 (d, J ) 8.3 Hz, 2 H), 8.13 (d, J ) 8.3 Hz, 2H)
128.4, 129.3, 130.2, 133.5 (t, J ) 24.8 Hz), 172.4
a
Solvent, CDCl3. Chemical shifts refer to tetramethylsilane.
Ta ble 3. Com p a r ison of th e Sod iu m Am a lga m Meth od (A) w ith th e Ra n ey Cu -Al Alloy Meth od (B)
method A method B
isotopic purity (%) isotopic purity (%)
entry
reaction
yield (%)
yield (%)
1
2
3
4
8a f 8b
95
88
87
94
99 (D1), 1 (D0)
97 (D2), 3 (D1)
1 (D4), 96 (D3), 2 (D2), 1 (D1)
97 (D1), 3 (D0)
37
56
71
86
99 (D1), 1 (D0)
13a f 13b
15a f 15b
17a f 17b
1 (D3), 95 (D2), 4 (D1)
3 (D4), 77 (D3), 20 (D2)
1.3 (D3), 1.4 (D2), 94.9 (D1), 2.4 (D0)
pounds of the corresponding nondeuterated compounds obtained
under the same instrument conditions. TLC analyses were
carried out on Merck Kieselgel 60 F254 plates. HPLC analyses
were performed with a Shimadzu LC-9A instrument equipped
with a Shimadzu SPD-6A UV spectrophotomeric detector using
MeOH as eluant.
CH3OD (99.5% isotopic purity) and D2O (99.9% isotopic purity)
were purchased from Aldrich and used without any further
purification. Sodium amalgam (4.8 wt %) was prepared accord-
ing to the usual method:10 20 g of mercury was placed in a 100
mL flask; 1.0 g of sodium was cut to small pieces and added
directly to the mercury under a nitrogen stream. After comple-
tion of the addition, it was cooled under a nitrogen stream and
used in the following reaction.
amalgam was rinsed twice with CH3OH, ether, or benzene. The
organic products were extracted twice with ether or benzene,
and the combined extracts were washed with brine and dried
(MgSO4). Evaporation of the solvent under reduced pressure
gave a deuterated compound as an oil or crystals. HPLC
analyses showed a single peak for the deuterated compounds
except 2,7-di-tert-butylpyrene-4,5,9,10-d4 (11b) and 2,4,6-tri-
(phenyl-4-d)aniline (16b). Compounds 11b and 16b were sepa-
rated by column chromatography on silica gel (Wako gel, C200)
with hexane (11b) or 1:1 benzene-hexane (16b) as eluant.
Deu ter a tion of Br om oa n ilin es. 4-Bromoaniline (2.4-7.2
mmol) was dissolved in 5 mL of CH3OD on warming. For 2,4,6-
tribromoaniline (2.4 mmol) 5 mL of dry benzene was further
added to dissolve the bromo compound. The solvent was then
completely removed in vacuum, and this cycle was again
repeated. The resulting amino proton deuterated aniline was
refluxed in CH3OD (10 mL) over 4.8% sodium amalgam (21 g)
for 2 h under dry nitrogen. After cooling, the methanol solution
was poured into a large amount of water, and the sodium
amalgam was rinsed twice with CH3OH. The organic products
were extracted with ether, and the combined ether extracts were
washed with brine and dried (MgSO4). Evaporation of the
solvent under reduced pressure gave a deuterated aniline.
HPLC analyses gave a single peak for the deuterated anilines.
Compounds 2a ,11 5a ,12 10a ,13 and 11a 7 were obtained by the
reported method. Compound 16a 14 was prepared by the analo-
gous procedure as for 2,4,6-triphenylaniline. Other bromo
compounds were commercially available.
Gen er a l P r oced u r e for Deu ter a tion of Br om oa r en es,
Br om oa n isoles, a n d Br om on itr oben zen es. Onto 21 g of
4.8% sodium amalgam were put 2.4-7.2 mmol of a bromo
compound and 10 mL of CH3OD. The mixture was then refluxed
for 2-24 h under dry nitrogen. If the bromo compounds were
not completely dissolved in the refluxing methanol, 5-20 mL of
dry benzene was added. After cooling, the methanol solution
was poured into a large amount of water, and the sodium
Deu ter a tion of 4-Br om oben zoic Acid . 4-Bromobenzoic
acid (7.2 mmol) was refluxed in 10 mL of MeOD and 5 mL of
D2O over 4.8% sodium amalgam (21 g) for 3 h under dry
nitrogen. After cooling, the reaction mixture was decanted and
the sodium amalgam was rinsed twice with MeOH. The
combined methanol solutions were evaporated and the residue
was acidified with 10% HCl. The colorless crystals deposited
were extracted with ether, and the ether extract was washed
with brine and dried (MgSO4). Evaporation of the solvent gave
pure benzoic-4-d acid.
(10) Holleman, A. F. Organic Syntheses, Wiley: New York, 1941;
Collective Vol. 1, p 554. Fieser, L. F.; Fieser, M. Reagents for Organic
Syntheses; Wiley: New York, 1967; Vol. 1, p 1033.
(11) Ishida, T.; Iwamura, H. J . Am. Chem. Soc. 1991, 113, 4238.
Miura, Y; Matsumoto, M.; Ushitani, Y. Macromolecules 1993, 26, 2628.
Miura, Y.; Oka, H.; Momoki, M. Synthesis 1995, 1419.
(12) Hurtley, W. H. J . Chem. Soc. 1901, 79, 1293.
(13) Elmorsy, S. S.; Pelter, A.; Smith, K. Tetrahedron Lett. 1991,
32, 4175.
(14) Dimroth, K.; Berndt, A.; Reichardt, C. Organic Syntheses;
Wiley: New York, 1969; Vol. 49, p 114.
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