Communication
Organic & Biomolecular Chemistry
3
4
(a) W. Markownikoff, Ann. der Chemie und Pharm., 1870,
53, 228; (b) V. V. Markovnieoff, C. R. Hebd. Seances Acad.
Sci., 1875, 81, 668.
It has been suggested that Markovnikov’s “rule” was the
result of inspired guess-work rather than significant experi-
mental evidence. For an interesting account see:
P. Hughes, J. Chem. Educ., 2006, 83, 1152.
components present. However, we found this led to
poor reproducibility, presumably due to poor control
over the concentration of HBr. Pre-saturation of the
solvent with HBr prior to addition of the substrate
removed this limitation. Furthermore, the solution of
HBr in toluene could be stored for up to one month
in the freezer.
1
5
(a) R. J. Bordoli and S. M. Goldup, J. Am. Chem. Soc., 2014, 17 Kharasch and co-workers reported the hydrobromina-
1
36, 4817; (b) J. Winn, A. Pinczewska and S. M. Goldup,
tion of styrene in dilute pentane solution with deben-
zoyl peroxide to give an 80 : 20 ratio in favour of the
primary bromide. Unfortunately, detailed conditions
were not provided: (a) C. Walling, M. S. Kharasch and
F. R. Mayo, J. Am. Chem. Soc., 1939, 61, 2693. The
only other reliable report of the direct hydrobromina-
J. Am. Chem. Soc., 2013, 135, 13318; (c) M. Galli,
J. E. M. Lewis and S. M. Goldup, Angew. Chem., Int. Ed.,
2
015, 54, 13545; (d) J. E. M. Lewis, R. J. Bordoli, M. Denis,
E. A. Neal, C. Fletcher, M. Galli, E. Rochette and
S. M. Goldup, Chem. Sci., 2016, 7, 3154.
6
7
S. Huo, Org. Lett., 2003, 5, 423.
tion of
a
styrene derivative to give the primary
V. Aucagne, J. Berná, J. D. Crowley, S. M. Goldup,
K. D. Hänni, D. A. Leigh, P. J. Lusby, V. E. Ronaldson,
A. M. Z. Slawin, A. Viterisi and D. B. Walker, J. Am. Chem.
Soc., 2007, 129, 11950.
bromide involved pentachloro or tetrachloro-benzenes
which have significant electronic bias towards to the
primary product.
1
9c
18 Instead of direct hydrobromination, hydrometallation fol-
lowed by oxidative bromination or oxidation to the alcohol
with subsequent conversion to bromide is commonly
employed in the synthesis of primary homo-benzyl bromides
from styrenes. For selected examples see: (a) E. M. Zippi,
H. Andres, H. Morimoto and P. G. Williams, Synth.
Commun., 1994, 24, 1037; (b) P. L. Ornstein, M. B. Arnold,
N. K. Allen, T. Bleisch, P. S. Borromeo, C. W. Lugar,
J. D. Leander, D. Lodge and D. D. Schoepp, J. Med. Chem.,
1996, 39, 2219; (c) M. D. Erion, S. R. Kasibhatla,
B. C. Bookser, P. D. Van Poelje, M. R. Reddy, H. E. Gruber
and J. R. Appleman, J. Am. Chem. Soc., 1999, 121, 308;
(d) S. R. Kasibhatla, B. C. Bookser, G. Probst, J. R. Appleman
and M. D. Erion, J. Med. Chem., 2000, 43, 1508;
(e) S. R. Kasibhatla, B. C. Bookser, W. Xiao and M. D. Erion,
J. Med. Chem., 2001, 44, 613; (f) J. Lee, S. Y. Kim, S. Park,
J.-O. Lim, J.-M. Kim, M. Kang, J. Lee, S.-U. Kang, H.-K. Choi,
M.-K. Jin, J. D. Welter, T. Szabo, R. Tran, L. V. Pearce, A. Toth
and P. M. Blumberg, Bioorg. Med. Chem., 2004, 12, 10559;
(g) G. Médard, Tetrahedron, 2014, 70, 186; (h) T. Miyazaki,
M. Shibahara, J. Fujishige, M. Watanabe, K. Goto and
T. Shinmyozu, J. Org. Chem., 2014, 79, 11440.
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9
For example see: J. Clayden, N. Greeves and S. Warren,
Organic Chemistry, Oxford University Press, Oxford, 2nd
edn, 2012, p. 433.
M. S. Kharasch, C. Hannum and M. Gladstone, J. Am.
Chem. Soc., 1934, 56, 244.
1
0 W. E. Vaughan, F. F. Rust and T. W. Evans, J. Org. Chem.,
942, 7, 477.
1
1
1 For an excellent contemporary review of the early work on
the addition of hydrohalous acids to alkenes and the per-
oxide effect, including the observation of anti-Markovnikov
addition in the absence of added initiators, see: F. R. Mayo
and C. Walling, Chem. Rev., 1940, 27, 351.
1
2 Pseudo-hydrobromination by hydrometallation followed by
oxidative bromination has also been demonstrated. See:
(a) G. W. Kabalka, K. A. R. Sastry, H. C. Hsu and
M. D. Hylarides, J. Org. Chem., 1981, 46, 3113;
(
(
b) H. C. Brown and C. F. Lane, Tetrahedron, 1988, 44, 2763;
c) J. Schwartz and J. A. Labinger, Angew. Chem., Int. Ed.
Engl., 1976, 15, 333–340.
13 A search using the Reaxys database with the criteria below
provides 330 reactions when limited to those that use HBr as
a reactant. By comparison, a search for primary bromides of 19 When the alkene substituent is strongly electron withdraw-
this form suggest >46 000 such compounds are known.
ing, such as in the case of conjugated carbonyl com-
pounds, anti-Markovnikov addition is the expected
outcome. For selected examples see: (a) J. B. Christensen
and A. Schluter, Org. Prep. Proced. Int., 1994, 26, 355–357;
(b) T. Kaku, T. Hitaka, A. Ojida, N. Matsunaga, M. Adachi,
T. Tanaka, T. Hara, M. Yamaoka, M. Kusaka, T. Okuda,
S. Asahi, S. Furuya and A. Tasaka, Bioorg. Med. Chem.,
2011, 19, 6383–6399; (c) S. D. Ross, M. Markarian,
H. H. Young and M. Nazzewski, J. Am. Chem. Soc., 1950, 72,
1133.
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1
4 We selected as our starting point the procedure reported by
Bloodworth and Mitchel: A. J. Bloodworth, T. Melvin and
J. C. Mitchell, J. Org. Chem., 1988, 53, 1078.
5 Unfortunately, although the desired conversion of estragole
to 3a has previously been reported, detailed experimental
conditions were not provided: J. Delobelle, M. Fetizon,
P. Baranger, J. Schalbar and M. J. Trefouel, C. R. Hebd. 20 (a) M. L. Sherrill, K. E. Mayer and G. F. Walter, J. Am. Chem.
Seances Acad. Sci., 1957, 244, 2402.
6 The majority of literature procedures call for HBr gas,
readily produced by reaction of Br
be passed through the reaction mixture with all other
Soc., 1934, 56, 926; M. L. Sherrill, K. E. Mayer and
G. F. Walter. Sherrill and Kharasch publicly disagreed on
the origin of the unexpected selectivity see:
(b) M. S. Kharasch, J. A. Hinckley and M. M. Gladstone,
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with tetraline, to
Org. Biomol. Chem.
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