Ortho-substituted iodobenzenes as novel organocatalysts for bromination of alkenes

Article abstract of DOI:10.1039/b604130b

Suitably ortho-substituted iodobenzenes act as organocatalysts for the transfer of electrophilic bromine from N-bromosuccinimide to alkenes via the intermediacy of bromoiodinanes. The Royal Society of Chemistry 2006.

Full text of DOI:10.1039/b604130b

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Ortho-substituted iodobenzenes as novel organocatalysts for
bromination of alkenes{
D. Christopher Braddock,*a Gemma Cansella and Stephen A. Hermitageb
Received (in Cambridge, UK) 21st March 2006, Accepted 20th April 2006
First published as an Advance Article on the web 3rd May 2006
DOI: 10.1039/b604130b
3 and 4 may be attributed to the more nucleophilic oxygen atom
Suitably ortho-substituted iodobenzenes act as organocatalysts
for the transfer of electrophilic bromine from N-bromosuccin-
imide to alkenes via the intermediacy of bromoiodinanes.
of 3. A catalytic cycle invoking the intermediacy of the
bromoiodinane 1 is shown below (Scheme 1).
Recently we demonstrated that bromoiodinanes 1 and 2 are
readily prepared in a single step by reaction of N-bromosuccin-
imide (NBS) with carbinols 3 and 4 respectively.1 Subsequently,
bromoiodinane 1 proved to be an efficient electrophilic bromine
source for transfer to arenes or alkenes. A significant observation
of these bromination reactions is that the only by-product
observed is carbinol 3. Since carbinol 3 is converted directly into
1 by the action of NBS, and given that carbinol 3 is the sole by-
product of the subsequent bromination event, the bromination
reaction should be able to be rendered catalytic in carbinol 3. In
this communication we demonstrate that the reaction can indeed
be rendered catalytic in carbinol 3 with bromoiodinane 1 acting as
the actual catalytic brominating agent. We also show that superior
catalysts are available by increasing the nucleophilicity of the
ortho-substituent. This is a rare example of a system which has a
catalytic cycle with iodine in the I(I) and I(III) oxidation states.2,3
To the best of our knowledge it also constitutes the first
organocatalytic transfer of electrophilic bromine to alkenes.
Scheme 1 Catalytic cycle involving bromoiodinane 1.
On the basis of the above results, it is to be expected that other
ortho-substituted iodobenzenes with pendant nucleophilic groups
should function as catalysts by formation of bromoiodinane
intermediates.
We chose to examine the bromolactonisation of 4-pentenoic acid
5 into bromolactone 64 for the purpose of developing a catalytic
bromination of alkenes (Table 1). In the control experiments
without any catalyst (entry 1) the extent of bromolactonisation
after 0.5 h is insignificant. After 15 h, 20% bromolactonisation of 5
into 6 has occurred. Thus the background bromination rate using
NBS only is slow. The use of ditrifluoromethylcarbinol 4as catalyst
(25 mol%) resulted in a modest increase in conversion of 5 into 6 to
32%. At the same catalyst loading carbinol 3 catalysed the reaction
to quantitative conversion in the same time period. The cyclisation
is extremely clean and, apart from resonances for the catalyst and
1
succinimide, only the desired product 6 could be detected by H
and 13C NMR. The difference between the catalytic activities of
Accordingly, a series of iodobenzoic acids and derivatives were
screened (Table 1, entries 4–12). 2-Iodobenzoic acid 7a{ proved to
be superior as a catalyst (10 mol%) giving quantitative conversion
to 6 in 6 h at room temperature. Amino derivative 7b,5 which
should boost the nucleophilicity of the carboxylic acid group by
resonance proved still more superior. 3-Iodobenzoic acid (7c),
where the carboxylic acid group is now meta to the iodine gave no
increase in conversion relative to the control experiment, consistent
with the need to form a bromoiodinane with an O–I–Br
aDepartment of Chemistry, Imperial College London, London, UK
SW7 2AZ. E-mail: c.braddock@imperial.ac.uk;
Fax: +44(0)2075945805; Tel: +44(0)2075945772
bGlaxoSmithKline Ltd, Medicines Research Centre, Gunnels Wood
Road, Stevenage, UK SG1 2NY
{ Electronic supplementary information (ESI) available: Preparation and
full characterising details of catalysts 7g and 7i, and substrates 10–14. See
DOI: 10.1039/b604130b
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Table 1 Catalytic bromolactonisation of 5 into 6a
iodobenzene acts as a catalyst but the conversion relative to
2-iodobenzoic acid is much reduced.
Entry Catalyst Loading (mol%) Time/h
Conversionc (%)
Incorporating a more nucleophilic oxygen atom as part of an
amide group ortho to the iodo group gives even more superior
catalysts. The inductive effect of added alkyl groups on moving
along the 1u (7e),6 2u (7f)7 and 3u (7g)§ amide series is also clearly
evident. Dicarboxylic acid 7h8—a catalyst with a pendant
nucleophilic group at both ortho positions of the iodobenzene—
was found to be a superior catalyst compared to 2-iodobenzoic
acid 7a. Finally, amidine 7i" proved to be an excellent catalyst too,
as expected on the basis of nucleophilicity. The above experiments
demonstrate that (i) the pendant functional group is required to be
positioned ortho to the iodine atom on the benzene ring, (ii) for a
given ortho-positioned functional group increasing its nucleophi-
licity results in superior catalysts and (iii) substitution of an sp3-
hybridised group at the other ortho position retards the catalytic
ability. All these effects are consistent with the intermediacy of a
bromoiodinane which is the electrophilic bromine source. Further,
catalysts of higher activity are available by introduction of two
pendant nucleophilic groups at both ortho positions of the
iodobenzene cf. 7h vs. 7a.
1
2
3
4
5
6
7
8
—
4
3
—
25
25
10
10
10
10
10
10
10
10
10
0.5 (15)
15
15
6
2 (20)
32
100
100
100
25
7a
7b
7c
7d
7e
7f
7g
7h
7i
3
24
19
2
0.5
0.33
,1.5
,0.5
53
72
9b
10
11
12
a
100
100
100
100
b
All reactions performed with 1.0 eq NBS in CDCl3 at rt. 1.2 eq
NBS. Conversion determined by 1H NMR.
c
three-centre four-electron bond. Control experiments with just
iodobenzene or benzoic acid as potential catalysts (not shown in
Table 1) gave no increase in conversion. Further evidence for the
intermediacy of a bromoiodinane comes from the use of 3-methyl-
2-iodobenzoic acid 7d as catalyst, where the sp3-hybridised carbon
atom of the methyl group at the 3-position would engender a steric
clash with the bromine atom in the putative bromoiodinane. This
A series of other bromolactonisation substrates 8–14I were
screened using highly active catalyst 7i (Table 2). All the substrates
cyclised smoothly to give bromolactone products 15–22.** The
Table 2 Catalytic bromolactonisation of substrates 8–14 with catalyst 7ia
Entry
1
Substrate
Time/h
1
Product(s)
Conversionb (%)
Isolated yieldc (%)
89
100 (,5)
2
3
0.5
0.5
100 (0)
91
93
100 (14)
4
0.5
100 (100)
98
5
6
7
a
1.5
1
100 (13)d
100 (12)f
100 (0)
83e
81g
90
0.25
All reactions performed with 10 mol% 7i and 1.0 eq NBS in CDCl3 at rt. Conversion determined by 1H NMR. The percentage conversion
b
c
in the control experiment without catalyst is given in parentheses. Isolated yield after chromatography. The ratio of 19 : 20 was 1 : 1 in the
d
e
catalysed reaction and 8 : 2 in the uncatalysed reaction. Combined yield: 43% of 19; 40% of 20. A minor isomer (,10%) was observed in
f
g
both the catalysed and uncatalysed reaction. A 6-ring lactone was isolated in 6% yield. It was identified by the characteristic IR stretch at
1719 cm21
.
2484 | Chem. Commun., 2006, 2483–2485
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(270 MHz, CDCl3) d 7.40–7.35 (m, 5H, ArH), 3.72 (d, J = 11.3 Hz, 1H,
HHCBr), 3.67 (d, J = 11.3, 1H, HHCBr), 2.85–2.73 (m, 2H, CH2), 2.60–
2.44 (m, 2H, CH2); 13C NMR (68 MHz, CDCl3) d 175.6, 140.8, 128.9,
128.8, 125.0, 86.5, 41.2, 32.5, 29.2; MS (CI+) 274, 272 (M + NH4+); HRMS
calcd for (M + NH4) C11H1579BrNO2 272.0286, found 272.0274; Anal.
calcd for C11H11BrO2 C, 51.79; H, 4.35; found: C, 51.86; H, 4.39.
5-(Bromomethyl)-5-methyl-c-butyrolactone (18): Rf 0.26 (3 : 7, petro-
leum ether : CH2Cl2); FT IR (NaCl) nmax 1776 cm21; 1H NMR (270 MHz,
CDCl3) d 3.52 (d, J = 10.8 Hz, 1H, CHHBr), 3.44 (d, J = 10.8 Hz, 1H,
CHHBr), 2.61–2.68 (m, 2H, CH2), 2.41–2.29 (m, 1H, CHH), 2.13–1.97 (m,
1H, CHH2), 1.54 (s, 3H, CH3); 13C NMR (68 MHz, CDCl3) d 175.9, 84.2,
39.6, 31.6, 29.3, 25.5; MS (CI+) 212, 210 (M + NH4+); HRMS calcd for
(M + NH4) C6H1379BrNO2 210.0130, found 210.0125.
5-Bromo-6,6-dimethyltetrahydropyran-2-one (19): mp 45–47 uC; Rf 0.30
(3 : 7, petroleum ether : CH2Cl2); FT IR (NaCl) nmax 1724 cm21; 1H NMR
(270 MHz, CDCl3) d 4.19 (dd, J = 8.0, 4.0 Hz, 1H, CHBr), 2.80 (ddd, J =
18.4, 7.9, 6.3 Hz, 1H, CHH), 2.60 (ddd, J = 18.5, 7.5, 6.3 Hz, 1H, CHH);
2.52–2.24 (m, 2H, CH2), 1.53 (s, 6H, C(CH3)2); 13C NMR (68 MHz,
CDCl3) d 169.2, 83.3, 52.5, 28.2, 27.8, 27.4, 26.1; MS (CI+) 226, 224 (M +
NH4+); HRMS calcd for (M + NH4) C7H1579BrNO2 224.0286, found
224.0279.
products are all consistent with the intermediacy of bromonium
ions followed by intramolecular attack of the nucleophilic
carboxylate. Two factors are at play in determining the ring-size
of the bromolactone product. The nucleophile prefers to attack the
bromonium ion at its most substituted carbon, consistent with the
stabilisation of partial positive charge there. Secondly, the exo ring-
closing process is preferredto the endo mode. With the exception of
substrate 12, both these factors are reinforcing and a single
bromolactone product is observed. For substrate 12, a ‘‘mis-
matched’’ substrate, both the 5 and 6-ring lactones are observed. It
is interesting to note that the product distribution changes
markedly in the catalysed versus uncatalysed reaction for this
substrate. Finally, the isomeric E and Z unsaturated acids 13 and
14 give two different diastereoisomers, consistent with the
stereospecific ring-opening of a bromonium ion. For all the
bromolactonisation products, the ring sizes were readily identified
by inspection of the lactone stretching frequency in the IR spectra.
For example 5-ring lactone 20 displays a stretching frequency of
1780 cm21, whereas 6-ring lactone 19 shows a characteristic stretch
5-(1-Bromo-1-methylethyl)-c-butyrolactone (20): mp 43–45 uC; Rf 0.40
(3 : 7, petroleum ether : CH2Cl2); FT IR (NaCl) nmax 1780 cm21; 1H NMR
(270 MHz, CDCl3) d 4.30 (t, J = 7.2 Hz, 1H, OCH), 2.72–2.48 (m, 2H,
CH2), 2.43–2.16 (m, 2H, CH2); 1.76 (s, 3H, CH3), 1.74 (s, 3H, CH3); 13C
NMR (68 MHz, CDCl3) d 176.5, 85.9, 65.6, 30.5, 29.5, 28.7, 24.6; MS (CI+)
226, 224 (M + NH4+); HRMS calcd for (M + NH4) C7H1579BrNO2
224.0286, found 224.0280; Anal. calcd for C7H11BrO2: C, 40.60; H, 5.35;
found: C, 40.74 H, 5.46.
at 1724 cm21
.
In conclusion we have developed the first organocatalytic
method for the transfer of electrophilic bromine to alkenes. We
invoke a catalytic cycle involving I(I) and I(III) oxidation states.
These results should provide a platform for the development of a
highly efficient asymmetric bromination reaction of prochiral
alkenes.
(1R*,2S*)-5-(1-Bromobutyl)-c-butyrolactone (21): Rf 0.34 (4 : 6,
petroleum ether : CH2Cl2); FT IR (NaCl) nmax 1781 cm21 1H NMR
;
(270 MHz, CDCl3) d 4.50 (q, J = 7.0, 1H, HCO), 4.04 (ddd, J = 10.0, 6.9,
3.4 Hz, 1H, HCBr), 2.67–2.35 (m, 3H, CH2), 2.21–2.05 (m, 1H, CHH),
1.98–1.85 (m, 1H, CHH), 1.81–1.54 (m, 2H, CH2), 1.52–1.33 (m, 1H,
CHH), 0.92 (t, J = 7.3 Hz, 3H, CH3); 13C NMR (68 MHz, CDCl3) d 176.4,
81.4, 57.6, 36.7, 28.6, 26.0, 20.4, 13.4; MS (CI+) 240, 238 (M + NH4+);
HRMS calcd for (M + NH4) C8H1779BrNO2 238.0443, found 238.0442.
(1S*,2S*)-5-(1-Bromobutyl)-c-butyrolactone (22): Rf 0.32 (4 : 6,
We thank the EPSRC and GlaxoSmithKline Ltd. for an
Industrial CASE award to G.C.
Notes and references
petroleum ether : Et2O); FT IR (NaCl) nmax 1782 cm21 1H NMR
;
{ 7a, 7c and 7d are all commercially available iodobenzoic acids.
§ 7g was prepared by N,N-alkylation of benzamide 7e with bromobutane.
Full details are given in the ESI.{
(270 MHz, CDCl3) d 4.61 (ddd, J = 7.0, 6.0, 3.0 Hz, 1H, OCH), 4.03 (ddd,
J = 8.0, 5.0, 3.0 Hz, 1H, HCBr), 2.66 (ddd, 17.5, 11.0, 6.0 Hz, 1H, CHH),
2.53 (dd, J = 10, 7.5 Hz, 1H, CHH), 2.47–2.31 (m, 1H, CHH), 2.22–2.09
(m, 1H, CHH), 1.94–1.75 (m, 2H, CH2), 1.70–1.54 (m, 1H, CHH), 1.51–
1.32 (m, 1H, CHH), 0.91 (t, J = 7.0 Hz, 3H, CH3): 13C NMR (68 MHz,
CDCl3) d 176.6, 81.0, 57.8, 36.6, 28.4, 25.5, 20.9, 13.4; MS (CI+) 240, 238
(M + NH4+); HRMS calcd for (M + NH4) C8H1779BrNO2 238.0443, found
238.0433; Anal. calcd for C8H13BrO2: C, 43.36; H, 5.93; found: C, 43.53; H,
5.93.
" Amidine 7i was prepared by the method of Daoust and Lessard for
amidine preparation from amides [ref. 9] starting from 2-iodo-
N-phenylbenzamide [ref. 10]. Full details are given in the ESI.{
I Acids 8–14 are all known compounds. 5-Hexenoic acid 8 and
2-cyclopentene-1-acetic acid
9 are commercially available. c,d-
Unsaturated acids 11, 12 and 13 are prepared by Johnson–Claisen
rearrangement [ref. 11] of the appropriately substituted prop-2-en-1-ol with
triethylorthoformate, followed by hydrolysis of the resulting ethyl ester.
Acid 10 is prepared by the action of a Wittig reagent on ethyl 4-oxo-4-
phenylbutyrate, followed by ester hydrolysis. Z-Unsaturated acid 14, was
prepared by the Wittig reaction of the phosponium salt of ethyl
4-bromobutyrate with butyraldehyde followed by ester hydrolysis. Full
details are given in the ESI.{
1 D. C. Braddock, G. Cansell, S. A. Hermitage and A. J. P. White, Chem.
Commun., 2006, 1442–1444.
2 T. Dohi, A. Maruyama, M. Yoshimura, K. Morimoto, H. Tohma and
Y. Kita, Angew. Chem., Int. Ed., 2005, 44, 6193–6196.
3 M. Ochiai, Y. Takeuchi, T. Katayama, T. Sueda and K. Miyamoto,
J. Am. Chem. Soc., 2005, 127, 12244–12245.
4 D. C. Braddock, G. Cansell and S. A. Hermitage, Synlett, 2004,
461–464.
5 J. Protiva, V. Krecek, B. Maca, J. Urban, M. Budesinsky and
M. Prochazka, Collect. Czech. Chem. Commun., 1989, 54, 1012–1018.
6 A. Gescher, M. F. G. Stevens and C. P. Turnbull, J. Chem. Soc., Perkin
Trans. 1, 1977, 103–106.
** Data for bromolactones 15–22: 6-Bromomethyltetrahydropyran-2-one
(15): Rf 0.30 (2 : 8, EtOAc : petroleum ether); FT IR (NaCl) nmax 1738
cm21; 1H NMR (270 MHz, CDCl3) d 4.52–4.42 (m, 1H, OCH), 3.55–3.41
(m, 2H, CH2Br), 2.65–2.37 (m, 2H, CH2), 2.16–1.61 (m, 4H, CH2CH2); 13
C
NMR (68 MHz, CDCl3) d 170.4, 78.6, 33.8, 29.4, 26.3, 18.1; MS (CI+) 212,
210 (M + NH4+); HRMS calcd for (M + NH4) C6H1379BrNO2 210.0130,
found 210.0120.
7 C. S. Cho, X. Wu, L. H. Jiang, S. C. Shim, H.-J. Choi and T. J. Kim,
J. Heterocycl. Chem., 1998, 35, 265.
6-Bromohexahydrocyclopenta[b]furan-2-one (16): Rf 0.30 (1 : 9, EtOAc :
petroleum ether); FT IR (NaCl) nmax 1778 cm21 1H NMR (270 MHz,
;
8 K. P. Shelly, S. Venimadhavan, K. Nagarajan and R. Stewart, Can. J.
Chem., 1989, 67, 1274–1282.
CDCl3) d 5.04 (d, J = 6.2 Hz, 1H, OCH), 4.41 (d, J = 4.5 Hz, 1H, CHBr),
3.20–3.03 (m, 1H, CH), 2.85 (dd, J = 18.5, 10.2 Hz, 1H, C(O)CHH), 2.47–
2.00 (m, 4H, CH2), 1.62–1.49 (m, 1H, CHH); 13C NMR (68 MHz, CDCl3)
d 176.5, 90.5, 52.9, 36.0, 35.9, 33.1, 31.4; MS (CI+) 224, 222 (M + NH4+);
HRMS calcd for (M + NH4) C7H1379BrNO2 222.0130, found 222.0122.
5-Bromomethyl-5-phenyldihydrofuran-2-one (17): Rf 0.13 (4 : 6,
9 B. Daoust and J. Lessard, Can. J. Chem., 1995, 73, 362–374.
10 R. J. Perry and S. R. Turner, J. Org. Chem., 1991, 56, 6573–6579.
11 W. S. Johnson, L. Werthemann, W. R. Bartlett, T. J. Brocksom,
T.-T. Li, D. J. Faulkner and M. R. Petersen, J. Am. Chem. Soc., 1970,
92, 741–743.
petroleum ether : CH2Cl2); FT IR (NaCl) nmax 1783 cm21 1H NMR
;
This journal is ß The Royal Society of Chemistry 2006
Chem. Commun., 2006, 2483–2485 | 2485