Reductive debromination of 1,2-dibromides with anisidines

Article abstract of DOI:10.1016/j.tetlet.2015.11.106

vic-Dibromides containing the α-bromocarbonyl or α-bromoaromatic moieties were reductively debrominated to furnish alkenes in high yields. o- and m-anisidines but not p-anisidine were found to be effective debrominating agents. The reductive debrominations were found to be trans-stereospecific.

Full text of DOI:10.1016/j.tetlet.2015.11.106

Tetrahedron Letters 57 (2016) 285–287
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Tetrahedron Letters
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Reductive debromination of 1,2-dibromides with anisidines
⇑
⇑
Kristen M. McGraw, Jeannette T. Bowler, Vy T. Ly, Ihsan Erden , Weiming Wu
Department of Chemistry and Biochemistry, San Francisco State University, San Francisco, CA 94132, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
vic-Dibromides containing the
a
-bromocarbonyl or
a
-bromoaromatic moieties were reductively
Received 26 October 2015
Revised 24 November 2015
Accepted 30 November 2015
Available online 1 December 2015
debrominated to furnish alkenes in high yields. o- and m-anisidines but not p-anisidine were found to
be effective debrominating agents. The reductive debrominations were found to be trans-stereospecific.
Ó 2015 Elsevier Ltd. All rights reserved.
Keywords:
Debromination
vic-Dibromides
Anisidine
Reduction
Introduction
attack by the base leading to 5. The fact that o-anisidine (3) indeed
gave 5 as the major product when reacted with authentic 4 was in
Reductive debromination of 1,2-dibromides is an important
synthetic transformation in organic chemistry, and a number of
methods have previously been reported, with Zn1 being the tradi-
tional reducing agent, also with Na in liquid ammonia,2 and a vari-
ety of other metals, (Mg,3 Sm,4 In5, Ni6), sodium naphthalene
radical anion,7 Cr(II) salts,8 and FeCl3/In.9 In the course of our stud-
ies toward developing an efficient synthesis of orotic acid, we
uncovered an unusual stereoselective 1,2-debromination method
without the use of metals, and herein we disclose our results from
this study.
support of our hypothesis (Scheme 2).
We decided to explore the scope and limitations of this unusual
1,2-debromination reaction and developed it into a convenient
synthetic method for converting vic-dibromides into trans-alkenes.
Reactions of o-anisidine with different vic-dibromides were
examined. As expected, debromination was observed with ethyl
2,3-dibromopropionate (6). The resulting acrylate 7 also reacted
with the amine to produce the 3-arylaminopropionate in the same
manner as discussed above for maleimide 4. In both reactions the
products were a,b-unsaturated carbonyl compounds formed from
2,3-dibromocarbonyl compounds.
Reactants with the bromine atom at the benzylic position were
subsequently examined. When meso-1,2-dibromo-1,2-dipheny-
lethane (8) was reacted in refluxing THF with o-anisidine, trans-
stilbene (9) was isolated in excellent yield (Table 1), even though
the starting material did not initially dissolve well in THF. Using
DMF as the reaction solvent at 80 °C showed no difference in reac-
tion rate and yields. The formation of cis-stilbene was not
observed.
The debromination reaction of 8 was further examined with
m- and p-anisidines. m-Anisidine was found to be very effective
and the reaction was somewhat more facile than with o-anisidine.
However, reaction with p-anisidine did not yield any product.
We have further tested the debromination reaction of more vic-
dibromides with m-anisidine as the debrominating agent in THF.
The results are summarized in Table 1. As expected, dibromides
Results and discussion
We recently developed an efficient synthetic method for
N1-substituted orotic acids.10 The method starts with the reaction
of an amine (e.g., aniline, benzyl amine, or cyclohexyl amine) with
a mixture of cis- and trans-2,3-dibromosuccinimide (1) in THF at
room temperature to yield 2-arylaminoaminomaleimide (2) via a
tandem dehydrobromination-conjugate addition–elimination
mechanism, as shown in Scheme 1.
However, when o-anisidine (3) was used, the reaction followed
a different course yielding 2-aminosuccinimide 5 instead of the
expected 2-aminomaleimide as shown in Scheme 2. This result
suggested that in the latter case a 1,2-debromination must have
taken place producing maleimide 4 first, followed by conjugate
containing the
a-bromocarbonyl or a-bromoaromatic moieties
⇑
Corresponding authors. Tel.: +1 415 338 1436; fax: +1 415 338 2384 (W.W.);
tel.: +1 415 338 1627; fax: +1 415 338 2384 (I.E.).
were reactive and 1,2-debromination occurred smoothly in high
yields. The reaction of dibromoindane 12 did not go to completion
E-mail addresses: ierden@sfsu.edu (I. Erden), wuw@sfsu.edu (W. Wu).
http://dx.doi.org/10.1016/j.tetlet.2015.11.106
0040-4039/Ó 2015 Elsevier Ltd. All rights reserved.

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K. M. McGraw et al. / Tetrahedron Letters 57 (2016) 285–287
O
O
Br
Br
RNH2
NH
NH
RNH
O
O
1
2
Scheme 3.
Scheme 1.
Conclusion
In conclusion, we have uncovered an unusual and useful
method for trans-stereospecific debromination of vic-dibromides
that avoids the use of metals and drastic conditions and should
nicely complement the existing methodologies in this area.
Acknowledgments
Scheme 2.
W.W. acknowledges financial support of this study by the
National Institutes of Health – United States (Grant No. SC1
GM095419). I.E. acknowledges support of this work by the
National Institutes of Health – United States (Grant No. SC1
GM082340). J.T.B. was supported by a Beckman Scholarship. K.M.
in THF, but the reaction went smoothly in DMF. In cases where
both cis- or trans-alkenes are possible, only the trans-alkenes were
obtained. Unactivated vic-dibromides such as trans-1,2-dibromo-
cyclohexane (14) did not react.
The mechanism for the reductive 1,2-debromination has not
been elucidated at this time. However, it is quite likely that easily
oxidizable aromatic compounds of the type o- and m-anisidine
transfer an electron to the bromide. It has been reported that o-
and m-anisidines are more readily oxidized than p-anisidine.12
The anti-stereospecificity can be traced to a concerted reductive
elimination. Consistent with the postulated mechanism is the fact
that adding one equivalent of 2,6-di-tert-butylphenol or TEMPO,
radical scavengers, had no effect on the reaction.
We postulate that along with the o- or m-anisidine radical
cation, a Br atom is formed since the secondary products derived
from the anisidines had Br ring substitution (as shown in
Scheme 3). A mechanistic study centered on a careful analysis
and structure elucidation of secondary products from these reac-
tions is underway and will be reported in due course.
M. was supported by
a Departmental Summer Research
Fellowship. The NMR facility was funded by the National Science
Foundation (DUE-9451624 and DBI 0521342). We thank Thomas
Ituarte, Peter Ngoi, Carter Ly, and Cindy Wen for technical
assistance.
References and notes
1. Sauer, J. C. Org Syn. Coll. 1963, 4, 268–270.
2. Allred, E. L.; Beck, B. R.; Voorhees, K. J. J. Org. Chem. 1974, 39, 1426–1427.
3. Crieege, R.; Louis, G. Chem. Ber. 1957, 90, 417–424.
4. Yanada, R.; Negoro, N.; Yanada, K.; Fujita, T. Tetrahedron Lett. 1996, 37, 9313–
9316.
5. Ranu, B. C.; Sangar, K. G.; Sarkar, A. Chem. Commun. 1998, 2113–2114.
6. Yoo, B. W.; Choi, J. W.; Kim, Y. S. Bull. Korean Chem. Soc. 2008, 29, 1655–1656.
7. Scouten, C. G.; Barton, F. E., Jr.; Burgess, J. R.; Story, P. R.; Garst, J. F. Chem.
Commun. 1969, 78–79.
Table 1
Reductive debromination of vic-dibromides by anisidines11
Entry
Substrate
Product
Solvent
THF
Temperature
rt
Time (h)
Yield (isolated) (%)
NDa
1
2 (o-anisidine)
2
3
THF
rt
24 (o-anisidine)
NDb
THF
THF
THF
DMF
DMF
66
66
66
80
80
72 (o-anisidine)
24 (o-anisidine)
24 (m-anisidine)
48 (o-anisidine)
24 (m-anisidine)
92
65
79
89
78
4
5
6
THF
66
24 (m-anisidine)
71
THF
DMF
66
80
48 (m-anisidine)
48 (m-anisidine)
90c
85
THF
66
48 (m-anisidine)
No reaction
a
b
c
Yield not determined due to conjugate addition of amine to product.
Yield not determined due to conjugate addition of amine and partial polymerization of product.
Based on 51% conversion.

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8. (a) Singleton, D. M.; Kochi, K. K. J. Am. Chem. Soc. 1967, 89, 6547–6555; (b)
Singleton, D. M.; Kochi, K. K. J. Am. Chem. Soc. 1968, 90, 1582–1589; (c) Barton,
D. H. R.; Basu, N. K.; Hesse, R. H.; Morehouse, F. S.; Pechet, M. M. J. Am. Chem.
Soc. 1966, 88, 3016–3021.
9. Yoo, B. W.; Choi, J. W.; Yang, M. H. Synth. Commun. 2009, 39, 1488–1493.
10. Bowler, J. T.; Clausen, C. R.; Blackburn, D. J.; Wu, W. Tetrahedron Lett. 2014, 55,
6465–6466.
11. Experimental details: All reagents were obtained from commercial sources and
used without further purification. Typical experimental procedures are
described below using meso-1,2-dibromo-1,2-diphenylethane as an example.
o-Anisidine (123 mg, 1.0 mmol) was added to a mixture of meso-1,2-dibromo-
1,2-diphenylethane ((340 mg, 1.0 mmol) in 4 mL THF. The heterogeneous
mixture was refluxed for 72 hours and a homogeneous solution was obtained.
The reaction was acidified and extracted with hexanes three times. The
combined organic layer was dried with sodium sulfate and concentrated to
give
a yellow solid as crude product, which was purified by column
chromatography to give trans-stilbene (165 mg, 92%) as a white crystal. The
1H NMR spectrum was identical with that found in the Aldrich library.
12. Sharma, L. R.; Kalia, R. K. Electrochim. Acta 1976, 21, 1085–1087.