Halogen-lithium exchange between substituted dihalobenzenes and butyllithium: Application to the regioselective synthesis of functionalized bromobenzaldehydes

Article abstract of DOI:10.1016/j.tet.2005.04.051

Halogen-lithium interconversion reactions between unsymmetrically substituted mono- and bifunctional dihalobenzenes C₆H ₃XHal₂ and C₆H₂XYHal₂ (Hal=Br, I; X, Y=F, OR, CF₃, CH(OMe)₂) and butyllithium were investigated. The resultant organolithium intermediates were converted into the corresponding benzaldehydes in moderate to good yields. As a rule, bromine atoms in the position ortho to the functional group were replaced preferentially with lithium. Intramolecular competition experiments with bifunctional systems revealed that fluorine is capable of activating the neighboring bromine atom more strongly than methoxy and dimethoxymethyl groups. On the replacement of the non-activated bromine with iodine a complete reversal of this reactivity pattern can be accomplished due to the preferred iodine-lithium exchange.

Full text of DOI:10.1016/j.tet.2005.04.051

Tetrahedron 61 (2005) 6590–6595
Halogen–lithium exchange between substituted dihalobenzenes
and butyllithium: application to the regioselective synthesis of
functionalized bromobenzaldehydes
*
´
Marek Da˛browski, Joanna Kubicka, Sergiusz Lulinski and Janusz Serwatowski
Warsaw University of Technology, Faculty of Chemistry, Noakowskiego 3, 00-664 Warsaw, Poland
Received 13 January 2005; revised 4 April 2005; accepted 21 April 2005
Available online 23 May 2005
Abstract—Halogen–lithium interconversion reactions between unsymmetrically substituted mono- and bifunctional dihalobenzenes
C6H3XHal2 and C6H2XYHal2 (HalZBr, I; X, YZF, OR, CF3, CH(OMe)2) and butyllithium were investigated. The resultant organolithium
intermediates were converted into the corresponding benzaldehydes in moderate to good yields. As a rule, bromine atoms in the position
ortho to the functional group were replaced preferentially with lithium. Intramolecular competition experiments with bifunctional systems
revealed that fluorine is capable of activating the neighboring bromine atom more strongly than methoxy and dimethoxymethyl groups. On
the replacement of the non-activated bromine with iodine a complete reversal of this reactivity pattern can be accomplished due to the
preferred iodine–lithium exchange.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
the treatment of appropriate polyhalobenzenes with the
most common alkyllithium reagent, i.e. BuLi, which cannot
be overestimated from the viewpoint of any synthetic
organic process.
Halogen–lithium exchange (HLE) is one of the funda-
mental, and perhaps, most versatile methods used to
generate organolithium compounds. Its important advantage
is that it is extremely rapid even at very low temperatures
providing a direct access to many unstable organolithium
intermediates. Furthermore, this method offers a convenient
route to compounds that are not readily prepared by directed
metalation reactions.1 Nevertheless, there are drawbacks to
HLE including the availability of halogen-containing
starting materials. The HLE reaction between polyhalo-
benzenes and BuLi has been investigated with special
emphasis on regiospecifity in halolithiobenzene formation.
It was found initially that the methoxy group increases the
reactivity of neighboring bromine atoms in the HLE
reaction.2 This observation facilitated valuable synthetic
applications.3 More recently, similar effects with nitrogen
functionalities such as amino and nitro groups have been
described.4 This study probes directing effects on HLE with
other dibromo- and bromoiodobenzene derivatives contain-
ing functionalities based on oxygen and/or fluorine. More-
over, it is demonstrated that isomeric halogenated
aryllithium intermediates may be selectively generated by
2. Results and discussion
The regioselective ortho-directed bromine–lithium
exchange between 2,4-dibromoanisole as well as 2,4,6-
tribromoanisole and BuLi has been known since 1940.1,5
Accordingly, this reaction is suitable for the synthesis of the
corresponding benzaldehydes as shown in Table 1 (entries 1
and 2). Similarly, ortho-directed bromine–magnesium
exchange for these and related systems has been developed.6
It was interesting to determine how and to what extent the
regioselectivity of the HLE is tuned by the steric effect of a
bulky alkoxy group since it has been reported that the
protection of chlorophenols with TBDMS groups prevents
oxygen ortho-directed metalation.7 For this purpose,
TBDMS ethers of 2,5-dibromophenol and 2,4-dibromo-
phenol were subjected to the HLE reactions (entries 3 and
4). We found that the steric hindrance provided by the
TBDMS group was not reflected by any change of
selectivity as the bromine atom in the position ortho to
the oxygen atom was exclusively replaced with lithium.
On the other hand, the conversion into corresponding
benzaldehydes was not quantitative as substantial amounts
Keywords: Dihalobenzenes; Halogen–lithium exchange; Arylithium com-
pounds; Benzaldehydes.
Corresponding author. Tel.: C48 22 660 7575; fax: C48 22 628 2741;
e-mail: serwat@ch.pw.edu.pl
*
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.04.051

M. Da˛browski et al. / Tetrahedron 61 (2005) 6590–6595
6591
Table 1. Preparation of functionalized bromobenzaldehydes via halogen–lithium exchange and subsequent DMF quench
Entry
Aryl halide
Solvent, temperature
Product
Yield (%)
1
Et2O, K78 8C
84
2
3
4
5
Et2O, K78 8C
Et2O, K78 8C
Et2O, K78 8C
Et2O, K78 8C
90
32
36
69
6
Et2O, K78 8C
52
82
72
48
13a
46
70
73
7
THF/Et2O (1:1), K78 8C
THF/Et2O (1:1), K78 8C
THF/Et2O (1:1), K78 8C
THF/Et2O (4:1), K100 8C
Et2O, K100 8C
8
9
10
11
12
13
Et2O, K78 8C
Et2O, K78 8C
a The major product isolated from the mixture with the regioisomeric by-product 2-bromo-4-fluoro-3-methoxybenzaldehyde and 2,3-dibromo-5-fluoro-6-
methoxybenzaldehyde.

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M. Da˛browski et al. / Tetrahedron 61 (2005) 6590–6595
of unreacted TBDMS ethers were recovered (ca. 30% of and
40% for entries 3 and 4, respectively) which indicates
that the lithiation proceeds quite sluggishly in Et2O at about
K70 8C. Interestingly, 3-bromobenzaldehyde is derived
from 1,3-dibromobenzene by the HLE rapidly under these
conditions. We also investigated the competitive metala-
tions with 2-bromo-5-iodoanisole and in this case a selective
replacement of iodine was observed. Thus, bromine
kinetically activated by adjacent methoxy group is less
reactive than iodine. Furthermore, the HLE product, i.e.
4-bromo-3-methoxyphenyllithium does not undergo
rearrangement to the thermodynamically more stable
2-methoxyphenyllithium system at low temperature in
ether solution. Hence, it can be converted cleanly into
the corresponding 4-bromo-3-methoxybenzaldehyde8
(entry 5) which is not available by the direct bromination
of 3-methoxybenzaldehyde. It should be noted that a
more recent attempt to prepare this compound was
reported9 but comparison of the NMR spectroscopic data
suggests clearly that the spectra were interpreted
erroneously.10
the distinct influence of fluorine was observed again as
2-bromo-5-fluoro-4-methoxybenzaldehyde (entry 10) was
formed as a major product (according to GC/MS analysis,
ca. 70% in the crude reaction mixture containing ca. 20%
of 2-bromo-4-fluoro-5-methoxybenzaldehyde and 10% of
2,3-dibromo-6-fluoro-5-methoxybenzaldehyde) resulting
from the preferred exchange of the bromine atom in the
position meta to fluorine.
In addition to these efforts, we studied the competition
between iodine and ortho-activated bromine in 5-bromo-4-
fluoro-2-iodotoluene. It was plausible that the strong
activating effect of fluorine (which should be stronger than
that of the methoxy group in 2-bromo-5-iodoanisole)
together with some deactivating effect of methyl group19
may significantly change the reaction course. However,
iodine-lithium exchange was preferred again, and the
corresponding lithiated compound was relatively stable as
demonstrated by the isolation of 4-bromo-5-fluoro-2-
methylbenzaldehyde (entry 11) in moderate yield.
The trifluoromethyl group is known as a strong electron-
withdrawing substituent,20 and has also been found
as effective ortho-director for HLE. 1,4-Dibromo-2-
(trifluoromethyl)benzene was converted into 4-bromo-2-
trifluoromethylbenzaldehyde (entry 12). On the other hand,
1-bromo-4-iodo-2-(trifluoromethyl)benzene produces
4-bromo-3-(trifluoromethyl)phenyllithium by the treatment
with BuLi via the selective iodine–lithium exchange and the
corresponding benzaldehyde21 in subsequent steps (entry
13). This last example confirms the general reactivity
pattern observed for bromoiodobenzenes with activating
substituent adjacent to bromine. The thermal stability of
4-bromo-3-(trifluoromethyl)phenyllithium in Et2O was
investigated. A solution of this compound was warmed up
to 0 8C prior to DMF quench and aqueous workup. GC/MS
analysis of the isolated material revealed that 4-bromo-2-
trifluoromethylbenzaldehyde (27%) and 4-iodo-2-trifluoro-
methylbenzaldehyde (45%) together with some amount of
the starting material (18%) and 1,4-diiodo-2-trifluoro-
methylbenzene (8%) were formed. Hence, the isomerization
of the primary aryllithium species leading to the formation
of more stable 2-CF3 substituted phenyllithium derivatives
was accompanied by extensive halogen redistribution
processes.
The reaction of 2,5-dibromo-1-(dimethoxymethyl)benzene
with BuLi followed by DMF quench and aqueous workup
with deprotection of the dimethoxymethyl group afforded
4-bromophtalaldehyde11 (entry 6). The ortho-directing
ability of the methoxy group can be explained in terms of
the inductive effect but for the dimethoxymethyl group this
is not so obvious as its electronegative character is weak.
Hence, it can be assumed that in the case of 2,5-dibromo-1-
(dimethoxymethyl)benzene the initial precoordination of
lithium by the acetal oxygen atoms may be important. To
support this view, it should be noted, that the lithiation of
3-(dimethoxymethyl)thiophene proceeds selectively in the
2-position12,13 which suggests a significant ortho-directing
ability by the dimethoxymethyl group.
It is well-documented that fluorine possesses a strong ortho-
directing ability in the metalation reaction14 and this
property should also be reflected in the HLE between
ortho-bromofluoro- or ortho-iodofluorobenzenes and BuLi.
Indeed, the high-yield preparation of 2-fluoro-4-bromo-
benzaldehyde starting with 1,4-dibromo-2-fluorobenzene
and Li[MgBu3] ate complex as the metalating agent was
reported recently.15 We were interested to compare the
relative directing potential of fluorine with respect to
oxygen-based functionalities such as methoxy and
dimethoxymethyl groups. The results are shown in
Table 1 (entries 7–9). THF was used as a solvent as it is
more suitable for the stabilization of ortho-halogenated
aryllithium species.16 Based on these internal directing
group competition experiments, it is clear that fluorine is a
more powerful ortho-directing group than methoxy (entries
7 and 8),17 or dimethoxymethyl group (entry 9). It should
be noted that BuLi/THF slowly deprotonates ortho to the
methoxy group, whereas the selective metalation (deproto-
nation) of 2- and 4-fluoroanisole in the position ortho to
fluorine requires superbasic mixture of BuLi with PMDTA
or KOBut.18 The competition of long-range inductive
interactions of fluorine and methoxy groups was probed
by the reaction of 4,5-dibromo-2-fluoroanisole with BuLi.
The reaction was not as selective as found in previous
examples and a mixture of products was formed. However,
In conclusion, the halogen–lithium exchange of substituted
dibromobenzenes and BuLi is strongly controlled by the
electronegative substituent adjacent to bromine. Fluorine
competes effectively with methoxy and dimethoxymethyl
groups to provide high regioselectivity. On the other
hand, the replacement of the non-activated bromine with
iodine gives access to thermodynamically less stable but
still relatively inert organolithium species that under
appropriate conditions do not rearrange spontaneously to
their more stable isomers via halogren migration (‘halogen
dance’) processes.22 Hence, the synthesis of multiple
isomeric halogenated benzaldehydes can be readily
accomplished by means of this modification. Obviously,
the synthetic potential of all described HLE experiments
is not limited to benzaldehydes and promises broad
applicability.

M. Da˛browski et al. / Tetrahedron 61 (2005) 6590–6595
6593
3. Experimental
(from methanol); (Found: C, 49.43; H, 6.31. C13H19BrO2Si
requires C, 49.52; H, 6.07%); nmax(KBr) 2938, 2855, 1684,
1588, 1470, 1265 cmK1; dH (400 MHz, CDCl3) 10.39 (1H,
d, JZ1.0 Hz, CHO), 7.67 (1H d, JZ8.0 Hz, Ph), 7.19 (1H,
ddd, JZ8.0, 1.5, 1.0 Hz, Ph), 7.06 (1H, d, JZ1.0 Hz, Ph),
1.02 (9H, s, ButMe2Si), 0.30 (6H, s, ButMe2Si); dC
(100.6 MHz, CDCl3) 189.3, 159.3, 130.1, 129.7, 126.4,
125.3, 123.7, 25.8, 18.5, K4.2. m/z (EI, 70 kV) molecular
ion not found, 259 (100), 257 (100, MK(CH3)3C), 241(36),
239 (35%).
3.1. General
All reactions were carried out under an argon atmosphere.
Solvents were stored over sodium wire before use.
Butyllithium (10 M solution in hexanes) and anhydrous
N,N-dimethylformamide (Aldrich) were used as received.
2,4-Dibromoanisole, 2,5-dibromoanisole and 1,4-dibromo-
2-(trifluoromethyl)benzene were received from Aldrich,
whereas 1-bromo-4-iodo-2-(trifluoromethyl)benzene was
prepared according to the published procedure from
3-bromo-4-(trifluoromethyl)aniline (Aldrich).23 Remaining
functionalized dihalobenzenes are novel compounds.
2-(tert-Butyldimethylsilyloxy)-1,4-dibromobenzene and
1-(tert-butyldimethylsilyloxy)-2,4-dibromobenzene were
obtained by treatment of corresponding sodium dibromo-
phenolates with tert-butyldimethylsilyl chloride. 2,4-
Dibromo-5-fluoroanisole and 4,5-dibromo-2-fluoroanisole
were prepared by multistep procedures involving regio-
selective bromination of appropriate bromofluorophenols
as a key step.24 The synthesis of 3,6-diiodo-2-fluoroanisole
and 1,4-dibromo-2-(dimethoxymethyl)-3-fluorobenzene
involved regioselective metalation of 2-fluoro-6-iodo-
anisole25 and 1,4-dibromo-2-fluorobenzene,26 respectively.
Detailed procedures for these novel dihalobenzenes are
provided in the Supplementary Material.
3.1.4. 5-Bromo-2-(tert-butyldimethylsilyloxy)benzalde-
hyde (entry 4). The title compound was prepared from
1-(tert-butyldimethylsilyloxy)-2,4-dibromobenzene (7.32 g,
20 mmol) as colorless crystals (2.0 g, 32%), mp 60–62 8C
(from methanol); (Found: C, 49.36; H, 6.09. C13H19BrO2Si
requires C, 49.52; H, 6.07%); nmax(KBr) 2936, 2858, 1685,
1590, 1478, 1271, 916 cmK1; dH (400 MHz, CDCl3) 10.38
(1H, s, CHO), 7.91 (1H, d, JZ2.5 Hz, Ph), 7.53 (1H, dd, JZ
9.0, 2.5 Hz, Ph), 6.80 (1H, d, JZ9.0 Hz, Ph), 1.02 (9H, s,
ButMe2Si), 0.29 (6H, s, ButMe2Si); dC (100.6 MHz, CDCl3)
188.8, 158.0, 138.4, 131.1, 128.6, 122.3, 114.3, 25.8, 18.5,
K4.2. m/z (EI, 70 kV) molecular ion not found, 259 (100),
257 (100, MK(CH3)3C), 241(24), 239 (24%).
3.1.5. 4-Bromo-3-methoxybenzaldehyde (entry 5). The
title compound was prepared from 2-bromo-5-iodoanisole
(4.0 g, 13 mmol) as colorless crystals (1.9 g, 69%), mp
74–76 8C (from hexane, Ref. 7 mp 74 8C); (Found: C, 44.65;
H, 3.16. C8H7BrO2 requires C, 44.68; H, 3.28%); dH
(400 MHz, CDCl3) 9.95 (1H, s, CHO), 7.74 (1H, d, JZ
8.0 Hz, Ph), 7.39 (1H, d, JZ2.0 Hz, Ph), 7.33 (1H, dd, JZ
8.0, 2.0 Hz, Ph); dC (100.6 MHz, CDCl3) 191.3, 156.8,
136.9, 134.1, 124.8, 119.8, 110.0, 56.6.
3.1.1. 4-Bromo-2-methoxybenzaldehyde (entry 1). The
method described here is representative for the preparation
of other benzaldehydes (modifications may concern the
choice of solvent and temperature as shown in Table 1): A
solution of 2,5-dibromoanisole (5.32 g, 20 mmol) in Et2O
(10 mL) was added to the solution of BuLi (10 M solution in
hexanes, 2.0 mL, 20 mmol) in Et2O (20 mL) at K78 8C.
After 15 min DMF (1.61 g, 22 mmol) was added slowly.
The mixture was stirred for 15 min and hydrolyzed with aq.
H2SO4 (1 M, 20 mL). The organic layer was separated and
solvents were removed in vacuo. The residue was washed
with water (20 mL) and recrystallized from hexane (10 mL)
to give the title compound (3.6 g, 84%) as colorless crystals,
mp 68–70 8C (Ref. 27 mp 66–68 8C); (Found: C, 44.60; H,
3.47. C8H7BrO2 requires C, 44.68; H, 3.28%); dH
(400 MHz, CDCl3) 10.39 (1H, d, JZ1.0 Hz, CHO), 7.68
(1H, d, JZ8.0 Hz, Ph), 7.17 (1H, ddd, JZ8.0, 1.5, 1.0 Hz,
Ph), 7.15 (1H, d, JZ1.5 Hz, Ph), 3.93 (3H, s, OMe); dC
(100.6 MHz, CDCl3): 188.9, 162.1, 130.7, 129.8, 124.3,
123.8, 115.5, 56.2.
3.1.6. 4-Bromophtalaldehyde (entry 6). The title com-
pound was prepared from 1,4-dibromo-2-(dimethoxy-
methyl)benzene (6.20 g, 20 mmol). The heating of the
crude product with boiling 1 M aq. HCl (20 mL) was
necessary to complete the cleavage of the acetal moiety and
deprotect the second formyl group. Colorless crystals (2.2 g,
52%), mp 98–100 8C (from hexane/toluene 3:1, Ref. 10 mp
99–100 8C); (Found: C, 44.91; H, 2.36. C8H5BrO2 requires
C, 45.11; H, 2.37%); dH (400 MHz, CDCl3) 10.52 (1H, s,
CHO), 10.45 (1H, s, CHO), 8.10 (1H, d, JZ2.0 Hz, Ph),
7.92 (1H, dd, JZ8.5, 2.0 Hz, Ph), 7.85 (1H, d, JZ8.5 Hz,
Ph); dC (100.6 MHz, CDCl3) 191.4, 190.9, 137.6, 136.9,
135.0, 133.8, 133.0, 129.3.
3.1.2. 5-Bromo-2-methoxybenzaldehyde (entry 2). The
title compound was prepared from 2,4-dibromoanisole
(5.32 g, 20 mmol) as colorless crystals (3.9 g, 90%), mp
115–118 8C (from hexane, Ref. 28 mp 116–119 8C); (Found:
C, 44.29; H, 3.48. C8H7BrO2 requires C, 44.68; H, 3.28%);
dH (400 MHz, CDCl3) 10.37 (1H, s, CHO), 7.90 (1H, d, JZ
2.5 Hz, Ph), 7.62 (1H, dd, JZ9.0, 2.5 Hz, Ph), 6.89 (1H, d,
JZ9.0 Hz, Ph), 3.92 (3H, s, OMe); dC (100.6 MHz, CDCl3)
188.5, 160.9, 138.4, 131.1, 125.2, 113.9, 113.6, 56.1.
3.1.7. 5-Bromo-2-fluoro-4-methoxybenzaldehyde (entry
7). The title compound was prepared from 2,4-dibromo-5-
fluoroanisole (5.68 g, 20 mmol) as colorless crystals (3.8 g,
82%), mp 98–100 8C (from hexane); (Found: C, 41.02; H,
2.65. C8H6BrFO2 requires C, 41.23; H, 2.60%); nmax(KBr)
3082, 2869, 1672, 1608, 1274, 1137, 1043, 852, 660 cmK1
;
dH (400 MHz, CDCl3) 10.16 (1H, s, CHO), 8.05 (1H, d, JZ
7.5 Hz, Ph), 6.69 (1H, d, JZ12.0 Hz, Ph), 3.98 (3H, s,
3
OMe); dC (100.6 MHz, CDCl3) 184.9 (d, JCFZ6.0 Hz),
165.5 (d, 1JCFZ260.0 Hz), 162.0 (d, 3JCFZ11.0 Hz), 132.7
3.1.3. 4-Bromo-2-(tert-butyldimethylsilyloxy)benzalde-
hyde (entry 3). The title compound was prepared from
2-(tert-butyldimethylsilyloxy)-1,4-dibromobenzene (7.32 g,
20 mmol) as colorless crystals (2.3 g, 36%), mp 34–36 8C
(d, 3JCFZ3.5 Hz), 118.4 (d, 2JCFZ9.5 Hz), 107.9 (d, 4JCF
Z
3.0 Hz), 100.3 (d, 2JCFZ26.0 Hz), 57.2; m/z (EI, 70 kV) 234
(74, MC2), 233 (100), 232 (74, MC), 231 (95), 163 (14),
161 (14), 81 (25%).

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M. Da˛browski et al. / Tetrahedron 61 (2005) 6590–6595
4
3.1.8. 2-Fluoro-4-iodo-3-methoxybenzaldehyde (entry 8).
The title compound was prepared from 2-fluoro-3,6-
diiodoanisole (7.56 g, 20 mmol) in a mixed solvent
(Et2O–THF 1:1) at K90 8C. In this case, lithiation was
carried out by the addition of the solution of BuLi (10 M,
2 mL, 20 mmol) in hexane (10 mL) to the solution of
2-fluoro-3,6-diiodoanisole. Pale yellow crystals (4.0 g,
72%), mp 97–99 8C (from hexane); (Found: C, 33.42; H,
2.35. C8H6FIO2 requires C, 34.31; H, 2.16%); nmax(KBr)
3080, 2866, 1682, 1423, 1262, 1031, 772 cmK1; dH
(400 MHz, CDCl3) 10.30 (1H, d, JZ0.5 Hz, CHO), 7.68
(1H, ddd, JZ8.5, 1.5, 0.5 Hz, Ph), 7.30 (1H, dd, JZ8.5,
6.5 Hz, Ph), 4.00 (3H, d, OMe); dC (100.6 MHz, CDCl3)
Me); dC (100.6 MHz, CDCl3) 190.3 (d, JCFZ1.5 Hz),
1 4
157.9 (d, JCFZ247 Hz), 137.5 (d, JCFZ4.0 Hz), 136.8,
134.6 (d, 3JCFZ5.5 Hz), 117.8 (d, 2JCFZ23.0 Hz), 115.8 (d,
2JCFZ20.5 Hz), 18.3. m/z (EI, 70 kV) 218 (85, MC2), 217
(100), 216 (87, MC), 215 (95), 189 (38), 187 (38), 108 (45),
107 (52%).
3.1.12. 4-Bromo-2-(trifluoromethyl)benzaldehyde (entry
12). The title compound was prepared from 1,4-dibromo-2-
trifluoromethyl)benzene (6.08 g, 20 mmol). Pale yellow
crystals (3.5 g, 69%), mp 48–50 8C (from hexane);
(Found: C, 37.51; H, 1.45. C8H4BrF3O requires C, 37.98;
H, 1.59); nmax(KBr) 1703, 1591, 1304, 1172, 1134,
840 cmK1; dH (400 MHz, CDCl3) 10.31 (1H, qd, JZ2.0,
1.0 Hz, CHO), 7.98 (1H, d, JZ8.5 Hz, Ph), 7.92 (1H, d, JZ
2.0 Hz, Ph), 7.86–7.83 (1H, m, Ph); dC (100.6 MHz, CDCl3)
3
1
186.4 (d, JCFZ7.5 Hz), 156.4 (d, JCFZ264.0 Hz), 148.5
2
3
(d, JCFZ10.5 Hz), 134.7 (d, JCFZ4.0 Hz), 126.0 (d,
2JCFZ7.0 Hz), 123.9 (d, JCFZ2.0 Hz), 101.0, 61.7 (d,
4
4JCFZ5.5 Hz); m/z (EI, 70 kV) 280 (100, MC), 279 (42),
265 (12), 137 (14, 30%).
4
2
187.9 (q, JCFZ3.5 Hz), 135.8, 132.50 (q, JCFZ32.5 Hz),
3
132.49, 130.8, 129.6 (q, JCFZ6.0 Hz), 129.0, 122.9 (q,
1JCFZ275 Hz). m/z (EI, 70 kV) 254 (66, MC2), 253 (100),
252 (66, MC), 251 (98), 225 (32), 223 (32), 145 (39), 144
(37), 125 (36%).
3.1.9. 4-Bromo-1,3-diformyl-2-fluorobenzene (entry 9).
The title compound was prepared from 1,4-dibromo-2-
(dimethoxymethyl)-3-fluorobenzene (6.56 g, 20 mmol).
The heating of the crude product with boiling dil. aq. HCl
was necessary to complete the cleavage of the acetal moiety
and deprotect the second formyl group. Colorless crystals
(2.2 g, 48%), mp 120–122 8C (from hexane/toluene 3:1);
(Found: C, 41.37; H, 1.82. C8H4BrFO2 requires: C, 41.59;
H, 1.75%); nmax(KBr) 3086, 2896, 1693, 1688, 1591, 1392,
1222, 955 cmK1; dH (400 MHz, CDCl3) 10.38 (1H, d, JZ
1.0 Hz, CHO), 10.37 (1H, s, CHO), 7.94 (1H, dd, JZ8.0,
7.0 Hz, Ph), 7.66 (1H, d, JZ8.0 Hz, Ph);. dC (100.6 MHz,
3.1.13. 4-Bromo-3-(trifluoromethyl)benzaldehyde (entry
13). The title compound was prepared from 1-bromo-4-
iodo-2-(trifluoromethyl)benzene (7.02 g, 20 mmol). Color-
less crystals 3.7 g (73%), mp 51–54 8C (from hexane,
Ref. 22 mp 52.5–53.5 8C); (Found: C, 37.35; H, 1.62.
C8H4BrF3O: C, 37.98; H, 1.59); dH (400 MHz, CDCl3)
10.04 (1H, s, CHO), 8.20–8.18 (1H, m, Ph), 7.94–7.89 (2H,
m, Ph); dC 2(100.6 MHz, CDCl3) 189.9, 136.3, 135.3, 133.2,
3
131.6 (q, JCFZ33 Hz), 129.0 (q, JCFZ5.5 Hz), 127.3,
3
3
1
CDCl3) 187.5 (d, JCFZ2.5 Hz), 185.3 (d, JCFZ7.5 Hz),
122.1 (q, JCFZ272 Hz).
1
4
164.6 (d, JCFZ276.0 Hz), 133.3 (d, JCFZ4.0 Hz), 132.4
(d, 3JCFZ4.0 Hz), 130.9 (d, 3JCFZ4.5 Hz), 124.4 (d, 2JCF
Z
8.5 Hz), 123.7 (d, 2JCFZ10.0 Hz); m/z (EI, 70 kV) 232 (79,
MC2), 231 (100), 230 (81, MC), 229 (93), 203 (15), 201
(15), 175 (21), 173 (22), 121 (25), 94 (40%).
Acknowledgements
This work was supported by the Warsaw University of
Technology. The support by Aldrich Chemical Co., Inc.,
Milwaukee, WI, through continuous donation of chemicals
and equipment is gratefully acknowledged.
3.1.10. 2-Bromo-5-fluoro-4-methoxybenzaldehyde (entry
10). The title compound was identified as the main product
of the reaction of 4,5-dibromo-2-fluoroanisole (5.68 g,
20 mmol) with BuLi and DMF at K100 8C in THF–Et2O
(4:1) and isolated by two-fold fractional recrystallization of
the crude product from hexane/toluene (1:1, 10 mL). Pale
yellow crystals (0.60 g, 13%), mp 99–102 8C; (Found: C,
41.00; H, 2.58. C8H6BrFO2 requires C, 41.23; H, 2.60%);
nmax(KBr) 3079, 2881, 1678, 1608, 1495, 1278, 1138, 1021,
804 cmK1; dH (400 MHz, CDCl3) 10.14 (1H, d, JZ3.5 Hz,
CHO), 7.62 (1H, d, JZ11.0 Hz, Ph), 7.17 (1H, d, JZ7.0 Hz,
Ph), 3.98 (3H, d, JZ1.0 Hz, OMe); dC (100.6 MHz, CDCl3)
189.9, 153.2 (d, 2JCFZ12.0 Hz), 151.8 (d, 1JCFZ250.0 Hz),
126.8 (3JCFZ4.5 Hz), 122.9 (3JCFZ3.0 Hz), 117.6, 116.3
(2JCFZ20.0 Hz), 56.8; m/z (EI, 70 kV) 234 (62, MC2), 233
(100), 232 (62, MC), 231 (96), 163 (10), 161 (10), 81 (30%).
Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tet.2005.04.
051
Synthetic procedures and analytical data for all new
compounds prepared in the course of this work including
copies of the 13C NMR spectra of all new compounds and all
isolated benzaldehydes.
3.1.11. 4-Bromo-5-fluoro-2-methylbenzaldehyde (entry
11). The title compound was prepared from 3-bromo-4-
fluoro-2-iodotoluene (4.1 g, 13 mmol). Pale yellow crystals
(1.3 g, 46%), mp 68–70 8C (from hexane); (Found: C,
44.26; H, 2.77. C8H6BrFO requires: C, 44.27; H, 2.79);
References and notes
nmax(KBr) 3039, 2888, 1683, 1597, 1387, 1259, 732 cmK1
;
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(1H, d, JZ8.5 Hz, Ph), 7.51–7.48 (1H, m, Ph), 2.63 (3H, m,

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