Competitive, substrate-dependent reductive debromination/dehydrobromination of 1,2-dibromides with triethylamine

Article abstract of DOI:10.1016/j.tetlet.2017.04.024

The interaction of various 1,2-dibromides with NEt₃ under various conditions (THF and DMF, respectively) at different temperatures was investigated. Our results from these reactions show that substrate dependent dehydrobrominations compete with reductive debrominations. A comprehensive discussion of these competitive pathways is offered.

Full text of DOI:10.1016/j.tetlet.2017.04.024

Accepted Manuscript
Competitive, substrate-dependent reductive debromination/dehydrobromina-
tion of 1,2-dibromides with triethylamine
Kristen M. McGraw, Greggory T. Kent, Joseph R. Gonzalez, Ihsan Erden,
Weiming Wu
PII:
S0040-4039(17)30439-2
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.04.024
TETL 48816
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
7 March 2017
27 March 2017
4 April 2017
Please cite this article as: McGraw, K.M., Kent, G.T., Gonzalez, J.R., Erden, I., Wu, W., Competitive, substrate-
dependent reductive debromination/dehydrobromination of 1,2-dibromides with triethylamine, Tetrahedron
Letters (2017), doi: http://dx.doi.org/10.1016/j.tetlet.2017.04.024
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Competitive, substrate-dependent
debromination/dehydrobromination of 1,2-
dibromides by triethylamine
Leave this area blank for abstract info.
Kristen M. McGraw, Greggory T. Kent, Joseph R. Gonzalez, Ihsan Erden*, and Weiming Wu*
Department of Chemistry and Biochemistry, San Francisco State University, San Francisco, CA 94132, USA
Br
Br
CO2Me
NEt3
DMF
O
Ar
Ar
+
CO2Me
Br
CO2Me
+
Br OMe
Ar
Ar
90 o
C

1
Tetrahedron Letters
journal homepage: www.els evier.com
Competitive, substrate-dependent reductive debromination/dehydrobromination of
1,2-dibromides with triethylamine
Kristen M. McGraw‡, Greggory T. Kent‡, Joseph R. Gonzalez, Ihsan Erden∗, and Weiming Wu*
Department of Chemistry and Biochemistry, San Francisco State University, 1600 Holloway Avenue, San Francisco, CA 94132, USA
ARTICLE INFO
ABSTRACT
Article history:
Received
The interaction of various 1,2-dibromides with NEt3 under various conditions (THF and DMF,
respectively) at different temperatures was investigated. Our results from these reactions show
Received in revised form
Accepted
that substrate dependent dehydrobrominations compete with reductive debrominations.
comprehensive discussion of these competitive pathways is offered.
A
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
Debromination
Dehydrobromination
E1cB
α-CH acidity
Basicity
1. Introduction
results from this study. Our findings point to a substrate-
dependent competition between reductive debrominations and
dehydrobrominations.
We recently uncovered a new reductive debromination of
vicinal dibromides derived from either α,β-unsaturated carbonyl
compounds, or aryl substituted alkenes (e.g., stilbene, indene)
using o- or m-anisidine in a trans-stereoselective manner.1 We
postulated that these easily oxidizable aromatic compounds affect
the elimination via electron transfer to the dibromide, with
concomitant double bond formation in a concerted fashion
(Scheme 1).
2. Results and Discussion
The 1,2-dibromides used in this study were prepared from the
corresponding alkenes by bromine addition and purified by
column chromatography on silica gel. The results from the
debrominations/dehydrobrominations are presented in Table 1.
Two different solvents, THF and DMF were used for most
reactions with similar results except for entries 3 and 5. To our
surprise, meso-stilbene dibromide
4 (entry 1) underwent
exclusively reductive debromination with NEt3, mimicking the
reaction with the o- or m-anisidines. The dibromide 6, derived
from ethyl acrylate, on the other hand, suffered regioselective
Scheme 1. Reductive debromination with o- or m-anisidine
°
dehydrobromination under much milder conditions (~20 C) in
THF to give 7, presumably by an E1cB mechanism. The
mildness of the elimination conditions can be traced to the
increased acidity of the α-H in 6. Placement of an aryl group (p-
tolyl) at the β-carbon, as in 8, likewise resulted in
dehydrobromination leading to the isomeric vinyl bromides 9 and
10 in refluxing THF; however, switching to DMF and raising the
temperature to 90 °C also gave significant amounts of the
reductive debromination product 11 in addition to 9 and 10 in
similar proportions. The corresponding N,N-dimethyl amide 12
gave exclusively the reductive debromination product 13 in either
We rationalized the anti-stereospecifity of the reductive
elimination by invoking a concerted mechanism via a one-
electron transfer to the bromine atom. We were curious as to
whether the use of triethylamine (NEt3) instead of the easily
oxidizable arenes o- and m-anisidines would also result in
reductive elimination or E2 and/or E1cB reactions with aryl or
carboxyl substituted vic-dibromides. In addition, we included
“activated” 1,2-dibromides derived from α,β-unsaturated
carboxylic acid derivatives (esters and amides, respectively) to
assess the role of the adjacent carbonyl group in the mechanism
of elimination or debromination. We report in this Letter our
———
‡ Equal contributions by these two authors
∗ Corresponding author. Tel.: +0-415-338-1627; fax: +0-415-338-2384; e-mail: ierden@sfsu.edu.
* Corresponding author. Tel.: +0-415-338-1436; fax: +0-415-338-2384; e-mail: wuw@sfsu.edu.

2
Tetrahedron
Table 1. Competitive dehydrobromination-reductive debromination of selected trans-1.2-dibromides with NEt3
Yield, %a
Entry
Substrate
Conditions
Product(s)
1
THF, RT, 1.5h
No reaction
0
2
3
DMF, 90 oC, 36h
88
92
THF, RT oC, 1.5h
CO2Et
7
Br
4
5
DMF, RT, 1.5h
THF,66 oC, 36h
7
91
84
6
7
DMF, 90 oC, 36h
61
65
THF, 66 oC, 24h
8
9
DMF, 90 oC, 36h
THF, 66 oC, 24h
13
92
75
Br
15
9%
16
66%
10
DMF, 90 oC, 24h
74
aIsolated yields
solvent, the reaction in DMF at higher temperature being more
efficient.
at higher temperature with the relatively weak base6 NEt3 is
competing, initially leading to 19. The latter undergoes a base-
catalyzed double bond isomerization to 17. Scheme 2 depicts the
pathways whereby bromoindenes 16 and 17 are formed in these
reactions. Stilbene dibromide 4 (Entry 1) does not undergo E2,
and reductive elimination is observed only in DMF. By replacing
one of the aryl groups with a carboxyl group, as in 6 and 8, the
extent of reductive debromination was minimized. In fact, ester 6
solely underwent elimination in either solvent at room
temperature, presumably by an E1cB mechanism.
The dibromide 14 derived from indene gave mixed results.
The reaction of 142 in THF (Entry 9) at reflux gave the
debromination product indene (15) in only 9% yield, with the
dehydrobromination pathway dominating (66%) furnishing 2-
bromo-1-indene 163 as the exclusive elimination product. On the
o
other hand, reaction in DMF at 90 C (Entry 10) furnished a
nearly equimolar mixture of both possible dehydrobromination
products 16 and 17.4 The latter two results from Entries 9 and 10
deserve immediate comment. The exclusive formation of the ‘2-
isomer’ of bromoindene, 16, is surprising at first glance, since an
E2 elimination with NEt3 would require an anti arrangement of
the β-proton and the α-halogen. However, due to the trans
configuration of bromine atoms in 14 the β-proton is cis to the
bromine atom on C2, and the proton on C1 is also cis to the
bromine atom on C2. In fact, if an E2 type elimination is to be
expected, then the more acidic proton on C1 would be abstracted
preferentially, leading to 17, rather than 16. Since the E2 is
impeded here due to stereoelectronic reasons, we postulate that
the only pathway leading to 16 is an E1 elimination via a stable
carbocation on C1. It is also conceivable that the cis-elimination
to give 16 might proceed via an E1cB pathway5 but we consider
this pathway less tenable since the less acidic proton at C2 would
have to be abstracted to give 16. In Entry 10, on the other hand,
in addition to the E1 component, a less favorable E2 elimination
NEt3
THF
-Br-
Br
Br
Br
E1
14
18
16
Br
E2 NEt3, DMF
NEt3
17
19
Br
Br
Scheme 2. Mechanistic pathways leading to 16 and 17
The results from the interaction of amide 12 in THF or DMF
with NEt3 (Entry 7) were unexpected since exclusive reductive
debromination was observed here and no E1cB product was
isolated. This result is not entirely surprising since the amide

3
carboxyl group is considerably less electron-withdrawing owing
to the electron-donating resonance characteristics of the amide
nitrogen. The reductive debrominations observed in a few cases
are not discussed further here since in our previous report on
similar reactions with anisidines we had offered a reasonable
mechanism for these reactions.
of the α-hydrogen than with esters 6 or 8 (pKa values of α-CH
in ethyl acetate and N,N-dimethylacetamide are 25 and 30,
respectively).8
Acknowledgments
This investigation was partly supported by the National
Institutes of Health, United States [Grant No. SC1 GM095419
(W.W.) and Grant No. SC1 GM082340 (I.E.)]. The NMR
facility was funded by the National Science Foundation, United
States (DUE-9451624 and DBI 0521342).
3. Conclusions.
After having uncovered a new reductive debromination of
non-activated 1,2-dibromides with o- and m-anisidines, and in an
effort to shed light on the types of interaction of vicinal
dibromides with tertiary amines, we studied the corresponding
reactions of 1,2-dibromides derived from non-activated
arylalkenes as well their activated counterparts, α,β-unsaturated
carboxyl derivatives, with NEt3. The reactions were conducted in
two different solvents (THF and DMF, respectively) at different
temperatures, and based on the product distribution under the
conditions applied, the outcome of the NEt3 promoted reactions
turned out to be quite different from that achieved with o- and m-
anisidine, respectively. With the latter weak aromatic bases that
are easily oxidizable, exclusive reductive debromination was
observed in activated and non-activated 1,2-dibromides (pKa of
the conjugate acids, respectively, of o-anisidine 4.52, m-anisidine
4.23).7 On the other hand, with a much stronger base like NEt3
(pKa of conjugate acid 10.75), and in particular with activated
dibromides, the dehydrobromination by an E1cB dominates,
except for the N,N-dimethyl amide 12, where in either solvent
only the reductive debromination product 13 was isolated. With
the ester 8, the reductive debromination product 11 was absent in
References and Notes
1. McGraw, K. M.; Bowler, J. T.; Ly, V. T.; Erden, I.; Wu, W.
Tetrahedron Lett. 2016, 57, 2185-2187.
2. (a) Tutar, A.; Cakmak, O.; Balci, M. J. Chem. Res. 2006, 507-511.
(b) Heasley, G. E.; Bower, T. R.; Dougharty, K. W.; Easton, J. C.;
Heasley V. L.; Arnold, S.; Carter, T. L.; Yaeger, D. B.; Gipe, B.
T.; Shellhamer, D. F. J. Org. Chem. 1980, 45, 5150-5155.
3. (a) Halterman, R. L.; Fahey, D. R.; Bailly, E. F.; Dockter, D. W.;
Stenzel, O.; Shipman, J. L.; Khan, M. A.; Dechert, S.;
Schuhmann, H. Organometallics, 2000, 19, 5464-5470. (b)
Usanov, D. L.; Yamamoto, H. Org. Lett. 2012, 14, 414-417.
4. Von Braun, J.; Ostermayer, H. Chem. Ber. 1937, 70, 1006-1008.
5. Keeffe, J. R.; Jenks, W. P. J. Am. Chem. Soc. 1983, 105, 265-269,
and references cited therein.
6. E2 Eliminations require strong bases. Triethylamine is not a
common E2 base due to its relatively low basicity (pKa of the
conjugate acid 10.75) as compared to, e.g., 1,8-
diazabicyclo[5.4.0]undec-7-ene (DBU), a popular E2 base (pKa of
conjugate acid 12): Srivastava, R. J. Mol. Catal A: Chem. 2007,
264, 146-152.
o
THF at 66 C, but its proportion relative to the E1cB products
7. (a) Perrin, D. D., Dissociation Constants of Organic Bases
Aqueous Solution, Butterwoths, London, 1965; Supplement, 1972.
(b) Serjeant, E. P.; Dempsey, B., Ionization Constants of Organic
Acids in Aqueous Solution, Pergamon, Oxford, 1979.
9+10 was ca. 36%. Apparently, the reductive debromination
pathway requires higher temperatures than the E1cB reaction.
Thus, with the deactived dibromide 4, the E1cB pathway is
precluded, but the reductive debromination pathway still requires
8. These pKa values were taken from a Table in J. G. Smith Organic
Chemistry, 4th ed.; McGraw-Hill: New York, 2014; p A2.
°
90 C in DMF. The question why the debromination dominates
with the N,N-dimethyl amide 12 can be traced to the fact that the
E1cB in this case is much less preferred due the decreased acidity

Highlights
• Reductive debrominations compete with dehydrobrominations..
• C–H acidity of the substrates determines selectivity.
• Triethylamine is not an efficient base for reductive debromination.