Synthesis of para-substituted 3-formyl arylboronic esters

Article abstract of DOI:10.1055/s-2002-35229

The synthesis of novel para-substituted amino- and phenoxy-3-formylarylboronic acids is described. These compounds are formed by the hitherto unreported nucleophilic aromatic substitution of fluorine with a range of phenols and amines in the presence of a boronic acid moiety. These reactions proceed in moderate to good yields (37-92%) and provide a useful regioselective synthetic route to trisubstituted arylboronates. These compounds are important both as intermediates in organic synthesis and as end products in their own right.

Full text of DOI:10.1055/s-2002-35229

PAPER
2379
Synthesis of para-Substituted 3-Formyl Arylboronic Esters
S
ynthesis of para
i
-Substi
c
tuted 3-For
h
myl
A
rylbor
a
onic Estersrd Holland,* John Spencer,1 John J. Deadman
Trigen Ltd, Emmanuel Kaye Building, Manresa Road, London, SW3 6LR, UK
Fax +44(207)3518324; E-mail: rholland@tri-london.ac.uk
Received 7 August 2002
O
Abstract: The synthesis of novel para-substituted amino- and phe-
noxy-3-formylarylboronic acids is described. These compounds are
formed by the hitherto unreported nucleophilic aromatic substitu-
tion of fluorine with a range of phenols and amines in the presence
of a boronic acid moiety. These reactions proceed in moderate to
good yields (37–92%) and provide a useful regioselective synthetic
OH
OH
F
B
1
route to trisubstituted arylboronates. These compounds are impor-
tant both as intermediates in organic synthesis and as end products
in their own right.
Figure 1
Nucleophilic aromatic substitution reactions are widely
used in synthetic methodology.8 These reactions are en-
hanced when the leaving group is ortho or para to an elec-
tron withdrawing species such as formyl9 or boronate, and
in addition fluorine is a particularly good leaving group
due to its substantial negative inductive effect.10 Nijhuis
and co-workers have previously reported a similar reac-
tion where a fluorine ortho to a formyl group was replaced
by a number of N-mono-substituted piperazines.11a A re-
lated procedure was reported whereby diaryl ethers were
formed starting from a fluorobenzaldehyde precursor and
various phenols.11b We reasoned that this reaction would
be useful for the introduction of diverse nucleophiles to
the template 1 in the position para to the boronic acid. In
addition the presence of the formyl group opens the pos-
sibility of further functional manipulations. The aromatic
nucleophilic substitution of fluorine in the presence of a
boronic ester is hitherto unreported.
Keywords: boron, nucleophilic aromatic substitutions, cross-cou-
pling, fluorine
The use of boronic acids, and their corresponding esters
has been widely reported in recent years. In biological and
medicinal applications they have found use in such di-
verse fields as carbohydrate recognition,2 protease en-
zyme inhibition3 and neutron capture therapy (NCT)
employed in the treatment of cancer.4 In addition they are
important synthetic precursors, notably in the synthesis of
biaryl derivatives by Suzuki–Miyaura type reactions
achieved by the cross-coupling of an arylboronic ester and
an aryl halide in the presence of a palladium catalyst.5
Arylboronic acids and esters can be prepared by a variety
of synthetic strategies e.g. via cross-coupling reactions
between boron–boron compounds and aryl halides or tri-
flates in the presence of a base and a palladium catalyst6
or by reaction of an aryl Grignard reagent with a trialkyl
borate.7 These transformations have been shown to toler-
ate a variety of functional groups and often provide effi-
cient routes for the synthesis of aryl boronates. However
given the importance of these compounds new synthetic
strategies are always welcome and in particular methods
that avoid catalysis by metals, which are expensive and
potential environmental risk hazards.
Boronic acids are highly soluble in water and also tend to
be slow moving on silica gel leading to problems with iso-
lation and purification.12 To minimise these problems, 1
was protected as its pinacol ester 2, synthesised in good
yield from pinacol in THF.
The nucleophilic aromatic substitution was conducted by
the reaction of stoichiometric amounts of 2 with nucleo-
philes 3a–f in N,N-dimethylacetamide (DMA) at 110 °C
in the presence of K2CO3 for 16 hours (Scheme 1). This
afforded the desired products 4a–f in good purities
(>90%) by 1H NMR examination, which were purified by
flash column chromatography (Table 1). Although the re-
actions were seen to proceed in an almost quantitative
manner as determined by 1H NMR of the crude product,
in some cases (4b,c,e) decomposition during purification
was observed which accounted for lower than expected
yields.
During the course of our research efforts, we have had
cause to investigate a number of differentially tri-substi-
tuted arylboronic esters. Initially, we looked at introduc-
ing structural diversity around an aryl bromide template
followed by formation of the boronic acid moiety as a fi-
nal step, although this was found to be unsatisfactory.
Consequently we turned our attention to the commercially
available aromatic template 4-fluoro-3-formylbenzenebo-
ronic acid (1) (Figure 1), which already contains the re-
quired functionality.
Having successfully exploited the SNAr reaction of phe-
nolic and amino nucleophiles with arylboronic ester 2, we
tested the synthetic utility of the products as precursors in
the Suzuki–Miyaura coupling reaction to form biaryl
compounds with high levels of regiocontrol.
Synthesis 2002, No. 16, Print: 14 11 2002.
Art Id.1437-210X,E;2002,0,16,2379,2382,ftx,en;P04302SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

2380
R. Holland et al.
PAPER
Scheme 1
Table 1 Phenoxy- and Amino-Substituted 3-Formyl Arylboronic
Esters
Unexpectedly, Method A furnished the reduced product 6
(Figure 2) as the major isolated reaction component
(61%). Method B gave no evidence of reaction as deter-
mined by TLC, however, Method C furnished the required
product 5 as a colourless oil (83%).
Product No.
RH
3a
Yield (%)
64
OH
4a
O
4b
46
OH
O
O
3b
6
4c
4d
4e
44
62
37
O
OH
Figure 2
3c
In conclusion, we have successfully applied an SNAr reac-
tion to form a number of amino and phenoxy para-subti-
tuted-3-formylbenzene boronic esters. The synthetic
utility of these compounds has been illustrated by the for-
mation of biaryl derivative 5 using the Suzuki–Miyaura
cross-coupling reaction to give compounds exhibiting
high levels of regiocontrol. The formation of arylbor-
onates by such SNAr reactions represents a complementa-
ry process to the recently disclosed SN2 substitutions of
methylphenylboronic acid derivatives by thiols and
amines.16
NC
OH
3d
NH
NH
O
N
N
O
3e
3f
4f
92
All reagents and solvents were purchased from Aldrich and Lan-
caster and were used without purification. Product 2 was used in
subsequent substitution reactions without further purifications. All
reactions involving air-sensitive reagents were conducted under ar-
gon. Silica gel pre-coated plates (aluminium sheets) were used for
TLC and silica gel 60 was used for flash column chromatography.
As an illustrative example, arylboronic ester derivative 4a
was reacted with bromobenzene using three general pro-
cedures (Table 2) with the intention of forming the de-
sired biaryl 5 (Scheme 2).
O
O
Br
O
O
B
O
Method A -C
O
5
4a
Scheme 2
Table 2 Reaction Conditions Investigated for the Suzuki–Miyaura Cross-Coupling
Method
A13
Solvent
Base
Catalyst
Temp (°C)
Time (h)
Yield (%)
o-xylene
THF
K2CO3
Herrmann’s a
Pd(PPh3)4
Pd(PPh3)4
130
60
16
16
2
0
0
B14
KOH (1 M, aq)
Na2CO3 (2 M, aq)
C15
toluene–EtOH
80
83
a Hermann’s Catalyst = trans-Di-µ-acetobis[2-(di-o-tolylphosphino)benzyl]dipalladium(II)
Synthesis 2002, No. 16, 2379–2382 ISSN 0039-7881 © Thieme Stuttgart · New York

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Synthesis of para-Substituted 3-Formyl Arylboronic Esters
2381
1H NMR and 13C NMR spectra were recorded at 400 MHz, chemi-
cal shifts are given in ppm from TMS, coupling constants are given
in Hertz. HRMS were obtained from the School of Pharmacy
(Univeristy of London), and elemental analysis were obtained from
the University of North London. Mps are uncorrected and were de-
termined with a Stuart Scientific SMP1 apparatus.
HRMS: m/z calcd for C25H25BO5 (M + H): 417.1855; found:
417.1873.
2-(3 -Methoxy)phenoxy-5-(4,4,5,5-tetramethyl[1,3,2]dioxa-
borolan-2-yl)benzaldehyde (4c)
Yield: 622 mg (37%); white solid; mp 103–105 °C.
1H NMR (CDCl3): δ = 1.27 (s, 12 H, 4 CH3), 3.73 (s, 3 H, OCH3),
6.58 (m, 2 H, 3,2 - CH), 6.68 (d, 1 H, J = 8.1 Hz, 4 -CH), 6.82 (d, 1
H, J = 8.3 Hz, 4 -CH), 7.22 (m, 1 H, 5 -CH), 7.84 (d, 1 H, J = 8.3
Hz, 4 -CH), 8.32 (s, 1 H, 6-CH), 10.44 (s, 1 H, CHO).
13C NMR (CDCl3): δ = 25.2, 55.9, 84.5, 106.1, 110.8, 112.2, 117.8,
126.4, 130.9, 136.3, 142.4, 157.4, 161.6, 162.5, 189.8.
2-Fluoro-5-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)ben-
zaldehyde (2)
4-Fluoro-3-formylphenylboronic acid (5 g, 29.8 mmol) and pinacol
(3.52 g, 29.8 mmol) were stirred under argon in anhyd THF (70 mL)
with activated 4 Å molecular sieves for 16 h at r.t. The reaction mix-
ture was filtered and the filtrate concentrated in vacuo to give 2.
Anal. Calcd for C20H23BO5: C, 67.82; H, 6.54. Found C, 67.74; H,
6.49.
Yield: 7.47 g (100%); white solid; mp 65–67 °C.
1H NMR (CDCl3): δ = 1.28 (s, 12 H, 4 CH3), 7.10 (m, 1 H, 3-CH),
7.97 (m, 1 H, 4-CH), 8.26 (d, 1 H, J = 8 Hz, 6-CH), 10.29 (s, 1 H,
CHO).
HRMS: m/z calcd for C20H23BO5 (M + H): 355.1704; found:
355.1717.
13C NMR (CDCl3): δ = 25.3, 84.7, 116.2, 116.4, 124.1, 136.7,
143.2, 168.1, 187.8.
3-[2-Formyl-4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)-
phenoxy]benzonitrile (4d)
Anal. Calcd for C13H16BFO3: C, 62.44; H, 6.45. Found: C, 62.50; H,
6.39.
Yield: 863 mg (62%); yellow solid; mp 185–187 °C.
1H NMR (CDCl3): δ = 1.28 (12 H, 4 CH3), 6.83 (d, 1 H, J = 8.2 Hz,
3-CH), 7.24 (m, 2 H, 2 ,4 -CH), 7.42 (m, 2 H, 3 ,6 -CH), 7.92 (d, 1
H, J = 8.3 Hz, 4-CH), 8.35 (s, 1 H, 6-CH), 10.35 (s, 1 H, CHO).
13C NMR (CDCl3): δ = 25.3, 84.7, 114.5, 118.2, 118.6, 122.6,
124.1, 124.6, 127.0, 128.3, 131.2, 142.7, 157.2, 160.6, 189.1.
Nucleophilic Aromatic Substitution Reaction of 2; General Pro-
cedures
2-Fluoro-5-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)benzalde-
hyde (2) (1 g, 4 mmol), K2CO3 (550 mg, 4 mmol) and the appropri-
ate nucleophile 3a–d (4 mmol) were heated in anhyd DMA (10 ml)
at 110 °C for 16 h. After cooling the reaction mixture was filtered
and the filtrate concentrated in vacuo. The residue was dissolved in
CHCl3 (20 mL), washed with H2O (2 4mL), dried (MgSO4) and
evaporated in vacuo. The crude products were purified by flash
chromatography (Et2O–hexane; 0:100 to 20:80) as appropriate.
Anal. Calcd for C20H20BNO4: C, 68.79; H, 5.77; N, 4.01. Found: C,
68.54; H, 5.56; N, 3.92.
HRMS: m/z calcd for C20H20BNO4 (M + H): 350.1567; found:
350.1564.
2-[4-(tert-Butoxycarbonyl)piperizin-1 -yl]-5-(4,4,5,5-tetrameth-
yl[1,3,2]dioxaborolan-2-yl)benzaldehyde (4e)
Yield: 495 mg (37%); yellow solid; 97–99 °C.
1H NMR (CDCl3): δ = 1.18 (s, 12 H, 4 CH3), 1.33 [s, 9 H, C(CH3)3],
2.9 (m, 4 H, 2 ,6 -CH2), 3.47 (m, 4 H, 3 ,5 -CH2), 6.88 (d, 1 H,
J = 8.2 Hz, 3-CH), 7.77 (d, 1 H, J = 8.1 Hz, 4-CH), 8.09 (s, 1 H, 6-
CH), 10.06 (s, 1 H, CHO).
Nucleophiles 3e and 3f were reacted in an identical fashion on a 3.2
mmol and 10 mmol scale, respectively. The aq washing protocol
was omitted.
2-Phenoxy-5-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)-
benzaldehyde (4a)
Yield: 830 mg (64%); white solid; mp 102–104 °C.
1H NMR (CDCl3): δ = 1.31 (s, 12 H, 4 CH3), 6.77 (d, 1 H, 3-CH),
7.01 (d, 1 H, 2 ,6 -CH), 7.14 (t, 1 H, J = 8 Hz, 4 -CH), 7.34 (t, 1 H,
J = 8.2 Hz, 3 ,5 - CH), 7.82 (d, 1 H, J = 8.3 Hz, 4-CH), 8.33 (s, 1 H,
6-CH), 10.47 (s, 1 H, CHO).
13C NMR (CDCl3): δ = 25.2, 28.8, 80.4, 84.4, 118.2, 127.7, 139.8,
141.7, 139.8, 141.7, 155.1, 157.0, 191.3.
Anal. Calcd for C22H33BN2O5: C, 63.47; H, 7.99; N, 6.73. Found: C,
63.41; H, 8.09; N, 5.49.
13C NMR (CDCl3): δ = 25.2, 84.7, 116.4, 120.3, 125.1, 126.4,
HRMS: m/z calcd for C22H33BN2O5 (M + H): 416.2483; found:
416.2468.
130.5, 136.4, 142.4, 156.2, 162.7, 189.8.
Anal. Calcd for C19H21BO4: C, 70.39; H, 6.53. Found: C, 70.22; H,
6.43.
2-[4-(Benzyl)piperizin-1 -yl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxa-
borolan-2-yl)benzaldehyde (4f)
Yield: 3.74 g (92%); yellow oil.
1H NMR (CDCl3): δ = 1.26 (s, 12 H, 4 CH3), 2.60 (m, 4 H, 3 ,5 -
CH2), 3.10 (m, 4 H, 1 ,6 -CH2), 3.53 (s, 2 H, C6H5CH2) 6.97 (d, 1 H,
J = 8.2 Hz, 3-CH), 7.19 (m, 5 H, 5 ArH), 7.83 (m, 1 H, 4-CH), 8.16
(s, 1 H, 6-CH), 10.14 (s, 1 H, CHO).
HRMS: m/z calcd for C19H21BO4 (M + H): 325.1606; found:
325.1611.
2-(4 -Phenoxy)phenoxy-5-(4,4,5,5-tetramethyl[1,3,2]dioxaboro-
lan-2-yl)benzaldehyde (4b)
Yield: 759 mg (46%); beige oil.
1H NMR (CDCl3): δ = 1.27 (s, 12 H, 4 CH3), 6.77 (d, 1 H, 3-CH),
6.97 (m, 6 H, 2 ,3 ,5 ,6 ,2 ,6 -CH), 7.05 (t, 1 H, J = 7.8 Hz, 4 -CH),
7.28 (t, 2 H, J = 8.0 Hz, 3 ,5 -CH), 7.83 (d, 1 H, J = 10.0 Hz, 4-
CH), 8.32 (s, 1 H, 6-CH), 10.49 (s, 1 H, CHO).
13C NMR (CDCl3): δ = 25.2, 53.3, 53.8, 63.4, 84.3, 118.1, 127.6,
128.7, 129.6, 138.9, 141.6, 157.5, 191.6.
Anal. Calcd for C24H31BN2O3: C, 70.94; H, 7.69; N, 6.89. Found: C,
70.85; H, 7.63; N, 6.83.
13C NMR (CDCl3): δ = 25.2, 84.7, 116.8, 199.0, 120.8, 121.8,
HRMS: m/z calcd for C24H31BN2O3 (M + H): 407.2494; found:
407.2506.
123.8, 126.0, 130.2, 136.5, 142.4, 151.3, 154.4, 157.7, 163.0, 189.8.
Anal. Calcd for C25H25BO5: C, 72.13; H, 6.05. Found: C, 72.26; H,
5.89.
Suzuki-Miyaura Coupling Reaction; Method C
A solution of aryl bromide (0.84 mmol) and Pd(PPh3)4 (0.026 mol)
in toluene (5 mL) was stirred with aq Na2CO3 (2.0 M; 2.5 mL) under
Synthesis 2002, No. 16, 2379–2382 ISSN 0039-7881 © Thieme Stuttgart · New York

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R. Holland et al.
PAPER
argon. Boronic ester (0.93 mmol) in EtOH (2.5 mL) was added and
the mixture was refluxed under argon at 80 °C for 2.5 h, when the
reaction was seen to be complete by TLC. After cooling, the mix-
ture was diluted with Et2O (20 mL), washed with H2O, dried
(MgSO4) and evaporated in vacuo. The crude products were puri-
fied by flash chromatography (Et2O–hexane; 0:100 to 20:80) as ap-
propriate.
References
(1) Current address: James Black Foundation, 68 Half Moon
Lane, Dulwich, SE24 9JE, UK.
(2) Shinkai, S. Angew. Chem., Int. Ed. Engl. 1996, 35, 1910.
(3) Jagannathan, S.; Forsyth, T. P.; Kettner, C. A. J. Org. Chem.
2001, 66, 6375.
(4) Kabalka, G. W.; Das, B. C.; Das, S. Tetrahedron. Lett. 2001,
42, 7145.
(5) (a) Suzuki, A. J. Organomet. Chem. 1999, 576, 147.
(b) Miyaura, N. Adv. Met. Org. Chem. 1998, 6, 187.
(6) Ishiyama, T.; Ishida, K.; Miyaura, N. Tetrahedron 2001, 57,
9813.
2-Phenoxy-5-phenylbenzaldehyde (5)
Yield: 230 mg (83%); colourless oil.
1H NMR (CDCl3): δ = 6.91 (d, 1 H, J = 8.6 Hz, 4-CH), 7.05 (d, 2
H, J = 8.2 Hz, 3 ,5 -CH), 7.14 (t, 1 H, J = 7.14 Hz, 4 -CH), 7.33 (m,
5 H, 1 ,2 ,3 ,4 ,5 -CH), 7.53 (d, 2 H, J = 7.8 Hz, 2 ,6 -CH), 7.67
(d, 1 H, J = 8.6 Hz), 8.10 (s, 1 H, 6-CH), 10.50 (s, 1 H, CHO).
(7) Cladingboel, D. E. Org. Process Res. Dev. 2000, 4, 153.
(8) March, J. Advanced Organic Chemistry; Wiley: New York,
1992, 641.
13C NMR (CDCl3): δ = 119.3, 119.9, 124.8, 127.1, 127.3, 128.0,
(9) Ross, S. D.; Finkelstein, M. J. Am. Chem. Soc. 1963, 70,
2778.
(10) Vlasov, V. M. J. Fluorine Chem. 1993, 61, 193.
(11) (a) Nijhuis, W. H. N.; Verboom, W.; Reinhoudt, D. N.
Synthesis 1987, 641. (b) Yeager, G. W.; Schissel, D. N.
Synthesis 1991, 63.
129.3, 130.5, 134.6, 136.8, 139.7, 156.8, 159.8, 189.8.
Anal. Calcd for C19H14O2: C, 83.19; H, 5.14. Found: C, 83.10; H,
5.21.
HRMS: m/z calcd for C19H14O2 (M + H): 274.1002; found:
274.0994.
(12) Gravel, M.; Thompson, K. A.; Zak, M.; Bérubé, C.; Hall, D.
G. J. Org. Chem 2002, 67, 3.
(13) Herrmann, W. A.; Bohm, V. P. W.; Reisinger, C.
J. Organomet. Chem. 1999, 576, 23.
(14) Organ, M. G.; Arvanitis, E. A.; Dixon, C. E.; Lavorato, D. J.
J. Comb. Chem. 2001, 3, 473.
Acknowledgement
This work was supported by The Thrombosis Research Institute and
Trigen Ltd (UK).
(15) Eicher, T.; Fey, S.; Puhl, W.; Büchel, E.; Speicher, A. Eur.
J. Org. Chem. 1998, 877.
(16) Spencer, J.; Burd, A. P.; Goodwin, C. A.; Mérette, S. A. M.;
Scully, M. F.; Adatia, T.; Deadman, J. J. Tetrahedron 2002,
58, 1551.
Synthesis 2002, No. 16, 2379–2382 ISSN 0039-7881 © Thieme Stuttgart · New York