Pinacolborane as the boron source in nitrogen-directed borylations of aromatic N, N -dimethylhydrazones

Article abstract of DOI:10.1021/jo301965v

A mild procedure for the Ir(III)-catalyzed nitrogen-directed ortho borylation of aromatic N,N-dialkylhydrazones using pinacolborane as the boron source has been developed. The methodology relies on a modified, hemilabile N,N ligand built on a 4-N,N-dimethylaminopyridine unit that provides high reactivity while maintaining exclusive ortho-selectivity. This procedure can be combined with Suzuki-Miyaura cross-couplings in a 'one-pot' fashion to afford functionalized biaryl derivatives that, upon subsequent 'one-pot', high yielding transformations, provide a convenient entry for the preparation of advanced benzonitrile intermediates for the synthesis of Sartan-type drugs.

Full text of DOI:10.1021/jo301965v

Note
pubs.acs.org/joc
Pinacolborane as the Boron Source in Nitrogen-Directed Borylations
of Aromatic N,N‑Dimethylhydrazones
Rocío Lopez-Rodríguez,†,‡ Abel Ros,*,† Rosario Fernandez,*,‡ and Jose M. Lassaletta*,†
́
́
́
†Instituto de Investigaciones Químicas (IIQ), CSIC/US, Amer
‡Departamento de Química Organ
ica, Universidad de Sevilla, C/Profesor García Gonzal
́
ico Vespucio 49, 41092 Sevilla, Spain
ez 1, 41012, Sevilla, Spain
́
́
S
* Supporting Information
ABSTRACT: A mild procedure for the Ir(III)-catalyzed nitrogen-directed ortho borylation of aromatic N,N-dialkylhydrazones
using pinacolborane as the boron source has been developed. The methodology relies on a modified, hemilabile N,N ligand built
on a 4-N,N-dimethylaminopyridine unit that provides high reactivity while maintaining exclusive ortho-selectivity. This procedure
can be combined with Suzuki−Miyaura cross-couplings in a ‘one-pot’ fashion to afford functionalized biaryl derivatives that, upon
subsequent ‘one-pot’, high yielding transformations, provide a convenient entry for the preparation of advanced benzonitrile
intermediates for the synthesis of Sartan-type drugs.
he Ir-catalyzed borylation of arenes combined with cross-
coupling methodologies has emerged as a powerful tool for
Scheme 1. Nitrogen-Directed Arene Borylations Mediated by
N,N-Hemilabile Ligand L1
T
the direct functionalization of aromatic compounds.1 After the
seminal work by Smith, Hartwig, and Miyaura groups, the
catalytic system made by the combination of [Ir(μ-OMe)(cod)]2
(COD = cyclooctadiene) and 4,4′-di-tert-butylbipyridine
(dtbpy) has enabled reactions to proceed at low temperatures
with high turnover numbers.2 Unfortunately, the reaction usually
requires the use of expensive bis(pinacolate)diboron (B2pin2) as
the borylating agent to take place efficiently, while the use of
pinacolborane (HBPin), a cheaper and more 'atom-economic'
boron source,3 requires, with a few exceptions,4 elevated
temperatures and a higher excess of arene to give satisfactory
results.2b,c,5 This reaction is typically controlled by steric factors,
but recently, new methodologies for the ortho-directed
borylation of arenes employing modified Ir,6 Rh,7 or Pd8 based
catalysts have been developed. With no exceptions, these
methods have made use of B2pin2 as the borylating agent. We
wish to report herein the development of a catalytic system for
the nitrogen-directed borylation of arenes using HBpin as the
borylating reagent under mild conditions.
hydrazone ligand allows an increase of catalytic activity up to the
level required to perform these directed borylations using HBpin
as the boron source. Toward this goal, we reasoned that the
introduction of electron-donating groups11 at the para position
of the pyridine fragment should help stabilize the proposed Ir(V)
intermediates, an effect that was also observed in the classic
dtbpy-based catalyst. Moreover, increasing the basicity of the
pyridine ligand should facilitate the temporary decoordination of
the hydrazone terminus, thus enhancing the hemilabile character
Our approach for the nitrogen-directed iridium-catalyzed
ortho-borylation of 2-aryl pyridines(isoquinolines) and aromatic
́
hydrazones,9 and for the ortho,ortho′-diborylation of the latter,10
relies on the use of a hemilabile pyridine-hydrazone N,N ligand
L1 (Scheme 1) as the central strategy to generate a coordination
vacancy, thereby facilitating the formation of a preorganized
catalyst−substrate complex prior to the C−H activation step. In
this paper, we show that structural modifications of this pyridine-
Received: September 10, 2012
Published: October 16, 2012
© 2012 American Chemical Society
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Note
of the ligand presumably required to achieve an exclusive ortho-
selectivity. According to this idea, we decided to incorporate tert-
butyl (L6) and dimethylamino (L7) groups in the para position
of the pyridine ring of ligand L1. The synthesis was readily
accomplished from pyridines 2 and 3 by selective formylation at
the 2-position (→4 and 5) according to a known procedure,12
followed by condensation with N,N-dibenzylhydrazine to afford
L6 and L7 in 67 and 70% yield respectively (Scheme 2).
result in any improvement. Thus, similar conversions were
obtained when 1−1.2 equiv of HBPin were used (entries 6 and
7), whereas considerable amounts (12−20%) of diborylation
product 10a were observed for reactions carried out with 1.4−1.6
equiv (entries 8−9). All these preliminary results showed that the
best conditions in terms of activity and mono- versus
diborylation selectivity are achieved with 1 mol % of the Ir
precatalyst, 2 mol % of the ligand L7, and 1.4 equiv of HBpin.
The method was then extended to a variety of aromatic N,N-
dialkylhydrazones 8b−j (Scheme 3). The selected examples
demonstrate that the reaction has a broad substrate scope,
affording the desired ortho borylation products 9b−j in good to
excellent conversions. Due to their relative instability, a partial
decomposition of these products was regularly observed during
chromatographic purification.13 However, given the high degree
of purity of the crude reaction mixtures and considering that the
main application of these products is their use as coupling
partners in metal-catalyzed cross-coupling reactions, the crude
borylation products 9a−j were used in Suzuki-Miyaura couplings
without any further purification. In this manner, the desired ortho
arylation products 11 and 12 were obtained in moderate to
excellent yields (56−99%) in a two-step, ‘one-pot’ reaction. The
overall procedure tolerates both electron-donating (8b,e,f,h,j)
and -withdrawing (8c,d,g,i) groups in ortho, meta, and para
positions of the phenyl ring, as well as disubstituted derivatives.
With the coupling products in hand, we decided to explore
their synthetic utility for the obtention of advanced intermediates
toward the synthesis of Sartan type drugs, well established
modulators of the renin-angiotensin system (RAS).14 The
efficient aza-Cope type oxidative cleavage of the hydrazone
moiety by magnesium monoperoxyphthalate (MMPP)15 was
applied for the high yielding transformation of compounds 11a−
j into the corresponding nitriles 13a−j (Scheme 4). While the
transformation of 11b,e,f,h−j into nitriles 13b,e,f,h−j was
accomplished with excellent (70−99%) yields, the high purity of
the crude products 13 (see crude spectra in the Supporting
Information) was exploited to combine this transformation with
a radical bromination of the benzylic position16 to afford
bromomethyl derivatives 14 without purification of the former.
In this manner, representative hydrazones 11a,c,d,g were
transformed into products 14a,c,d,g in good 78−84% overall
yields after a two-step reaction sequence. These compounds have
been used as intermediates in the synthesis of angiotensin II
antagonist compounds (Sartan drugs).14a Alternatively hydra-
zones 12a,b,j can be used for a ‘one-pot’ quantitative aldehyde
reduction/hydrazone-to-nitrile transformation to afford benzyl
alcohols 15a,b,j, which are also suitable precursors for modified
Sartan drugs.
Scheme 2. Synthesis of Modified Ligands L6 and L7 (DMAE:
2-(N,N-Dimethylamino)ethanol)
With these new ligands in hand, the relative activity of the
catalysts formed in situ from [Ir(μ-OMe)(cod)]2, the N,N ligand
(L1, L6, or L7), and HBpin was investigated using the borylation
of benzaldehyde N,N-dimethylhydrazone 8a as a model reaction
(Table 1). Preliminary experiments were carried out in THF at
Table 1. Screening of Ligands in the Borylation of 8a with
a
HBpin
[Ir]
L
HBpin
(equiv)
yield 9a
b
yield of 10a
b
entry
L
(mol %) (mol %)
(%)
(%)
1
2
3
4
5
6
7
8
9
L1
L6
L7
L7
L7
L7
L7
L7
L7
1
2
2
2
2
2
3
3
3
3
1
20
30
75
75
85
75
78
80
−
−
∼5%
∼5%
∼5%
8
1
1
1
1
1
1.2
1.4
1
1
1.5
1.5
1.5
1.5
1.2
1.4
1.6
8
12
74
20
a
b
1
Reactions were performed at 0.25 mmol scale. Estimated by H
NMR.
80 °C using initially stoichiometric amounts of HBpin. Under
these conditions, the unmodified catalytic system based on ligand
L1 showed a poor performance, leading to only a 20% yield of 9a
1
after 24 h (estimated by H NMR, entry 1). The tert-butyl-
CONCLUSIONS
■
substituted derivative L6 provided a slightly better 30% yield
(entry 2) and maintained exclusive ortho selectivity, in line with
the expectations but still unsatisfactory. Finally, the more basic
DMAP-derived ligand L7 afforded a much higher activity, leading
to a much higher yield of 9a (ca. 75%, entry 3), along with a
minor amount (ca. 5%) of the 2,6-diborylated product 10a.
However, no trace of regioisomers was detected in the crude
mixtures. Further experiments aimed to optimize the reactions
conditions (entries 4−9) were therefore conducted with ligand
L7. No significant improvement was observed when 1.2 equiv of
HBPin were used (entry 4), but increasing the amount of reagent
up to 1.4 equiv provided a higher 85% yield (entry 5). On the
other hand, increasing the catalyst loading to 1.5 mol % did not
In summary, it has been shown that the activity of the Ir(III)
borylation catalysts based on pyridine-hydrazone ligands can be
substantially increased without compromising the ortho
selectivity. Using modified ligand L7, the nitrogen-directed
borylation reaction can be achieved using cheap and readily
available pinacolborane with a broad reaction scope, excellent
conversions, and complete regioselectivity in all cases. This
reaction, combined with Suzuki−Miyaura cross-couplings in a
‘one-pot’ fashion, afforded functionalized biphenyl derivatives
that have been transformed into valuable intermediates for the
synthesis of modified Sartan type drugs upon high yielding, ‘one-
pot’ functional group transformations in a very efficient manner.
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Note
Scheme 3. One-Pot Directed Borylation/S-M Cross-Coupling Reaction
performed on silica gel (Merck Kieselgel 60). Analytical TLC was
performed on aluminum backed plates (1.5 cm × 5 cm) precoated (0.25
mm) with silica gel (Merck, Silica Gel 60 F254). Compounds were
visualized by exposure to UV light or by dipping the plates in a solution
of 5% (NH4)2Mo7O24·4H2O in 95% EtOH (w/v) or Mostain reagent
[ceric sulfate (1% (w/v) and ammonium molybdate (2.5% (w/v) in 10%
(v/v) aqueous sulfuric acid] followed by heating. Borylation reactions
were carried out in oven-dried Schlenk tubes under an argon
atmosphere employing standard manifold techniques. Anhydrous
THF was obtained using Grubbs-type solvent drying columns.
Pinacolborane (HBpin), [Ir(μ-OMe)(cod)]2, [PdCl2(dppf)], pyridines
2 and 3, aryl bromides, and N,N-dibenzylhydrazine were purchased from
commercial suppliers and used without further purification. Hydrazones
8 were synthesized according to a previously reported procedure.9,10,17
General Procedure for the Synthesis of Aldehydes 4 and 5.
Following a described methodology,12 n-BuLi (1.7 M in n-hexane, 28
mL, 48 mmol) was added dropwise to a cooled (−10 °C) solution of 2-
dimethylaminoethanol (2.4 mL, 24 mmol) in dry n-hexane (30 mL).
The mixture was stirred at this temperature for 30 min, and then the
corresponding pyridine 2 or 3 (12 mmol) was added at once as a solid.
After stirring at 0 °C for 1 h, the reaction was cooled to −40 °C and a
solution of dry DMF (1.39 mL, 18 mmol) in dry THF (45 mL) was
added. After 30 min at −40 °C, the mixture was quenched with 60 mL of
1 M HCl, the organic layer was separated, and the aqueous phase was
extracted with Et2O (3 × 30 mL). The combined organic phases were
dried (MgSO4) and concentrated to dryness, and the resulting residue
was purified by flash chromatography. Methods used for purification,
yields, and characterization data for products 4 and 5 are as follows:
4-(tert-Butyl)picolinaldehyde (4). Following the general procedure,
flash chromatography (n-10:1 hexane/EtOAc) afforded 4 as a yellow
viscous oil. Product was obtained contaminated with an impurity, and
the yield was estimated by NMR (∼28%); aldehyde was used in the next
reaction step. A pure sample for the characterization of 4 was obtained
Scheme 4. One-Pot Hydrazone Transformation: Application
to the Sartan Type Drugs Synthesis
EXPERIMENTAL SECTION
■
General Experimental Methods. 1H NMR spectra were recorded
at 300, 400, or 500 MHz; 13C NMR spectra were recorded at 75, 100, or
125 MHz with the solvent peak used as the internal reference (7.26 and
1
1
77.0 ppm for H and 13C respectively). Column chromatography was
by purification on preparative TLC (20:1 toluene/EtOAc). H NMR
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Note
(400 MHz, CDCl3): δ 10.07 (s, 1H), 8.67 (d, 1H, J = 5.2 Hz), 7.96 (d,
1H, J = 2.2 Hz), 7.49 (dd, 1H, J = 5.2, 2.2 Hz), 1.34 (s, 9H). 13C NMR
(100 MHz, CDCl3): δ 193.8, 161.6, 152.8, 150.1, 125.0, 118.7, 35.0,
30.4. HRMS(EI) calcd for C10H13NO (M+) 163.0997. Found 163.0999.
4-(Dimethylamino)picolinaldehyde (5). Following the general
procedure, flash chromatography (EtOAc) afforded 5 (594 mg, 33%)
as a yellow viscous oil. 1H NMR (500 MHz, CDCl3): δ 9.97 (s, 1H), 8.37
(d, 1H, J = 6.0 Hz), 7.17 (d, 1H, J = 2.5 Hz), 6.64 (dd, 1H, J = 6.0, 3.0
Hz), 3.06 (s, 6H). 13C NMR (125 MHz, CDCl3): δ 194.6, 154.8, 153.1,
150.1, 109.9, 104.4, 39.3. HRMS(EI) calcd for C8H10N2O (M+)
150.0793. Found 150.0795.
General Procedure for the Synthesis of Ligands L6 and L7.
N,N-Dibenzylhydrazine (2.2 mmol) was added to a solution of aldehyde
4 or 5 (2 mmol) in MeOH (4 mL), and the mixture was stirred
overnight at rt. The solvent was removed under reduced pressure, and
the resulting residue was purified by column chromatography. Methods
used for purification, yields, and characterization data for products L6
and L7 are as follows:
4-(tert-Butyl)picolinaldehyde N,N-dibenzylhydrazone L6. Follow-
ing the general procedure, flash chromatography (8:1 n-hexane/EtOAc)
afforded L6 (480 mg, 67%) as a light yellow solid. Mp 102−104 °C. 1H
NMR (500 MHz, CDCl3): δ 8.35 (d, 1H, J = 5.0 Hz), 7.82 (d, 1H, J = 1.2
Hz), 7.33−7.25 (m, 11H), 7.08 (dd, 1H, J = 5.0, 1.5 Hz), 4.61 (s, 4H),
1.33 (s, 9H). 13C NMR (125 MHz, CDCl3): δ 159.9, 155.7, 148.6, 137.0,
131.6, 128.5, 127.5, 127.2, 118.9, 115.4, 57.7, 34.8, 30.5. HRMS(EI)
calcd for C24H27N3 (M+) 357.2205. Found 357.2205.
4-(Dimethylamino)picolinaldehyde N,N-dibenzylhydrazone L7.
Following the general procedure, flash chromatography (8:1 CH2Cl2/
MeOH) afforded L7 (482 mg, 70%) as a light yellow solid. Mp 98−100
°C. 1H NMR (300 MHz, CDCl3): δ 8.10 (d, 1H, J = 6.0 Hz), 7.29−7.22
(m, 11H), 7.02 (d, 1H, J = 2.7 Hz), 6.35 (dd, 1H, J = 6.0, 2.7 Hz.), 4.57
(s, 4H), 3.00 (s, 6H). 13C NMR (75 MHz, CDCl3): δ 155.4, 154.7,
148.6, 137.1, 131.9, 128.5, 127.6, 127.2, 105.5, 100.8, 57.6, 39.2.
HRMS(EI) calcd for C22H24N4 (M+) 344.2001. Found 344.1990.
General Procedure for Sequential ortho-Borylation/Suzuki−
Miyaura Coupling Reactions. 0.5 mL of the catalyst stock solution18
and HBPin (51 μL, 0.35 mmol) were added to a dried Schlenk tube
charged with the substrate 8a−j (0.25 mmol). The reaction mixture was
stirred at 80 °C until consumption of the starting material (1H NMR
monitoring), then cooled to rt, and concentrated to dryness.
[PdCl2(dppf)] (7.5 μmol, 6.2 mg), K3PO4 (0.375 mmol, 79.6 mg), 4-
bromotoluene (0.375 mmol, 65.5 mg) or 4-bromobenzaldehyde (0.375
mmol, 70.1 mg), and dry DMF (2 mL) were added under Ar. The
reaction mixture was stirred at 80 °C overnight, cooled to rt, diluted with
Et2O (20 mL), washed with H2O (2 × 10 mL), dried (MgSO4), and
concentrated to dryness. The resulting residue was purified by flash
chromatography using n-hexane/Et2O or acetone/toluene mixtures as
solvents. Methods used for purification, yields, and characterization data
for products 10a−j and 11a,b,j are as follows:
7.27 (d, 2H, J = 7.8 Hz), 7.24 (s, 1H), 7.21 (d, 2H, J = 7.5 Hz), 6.89 (dd,
1H, J = 8.6, 2.1 Hz), 6.77 (d, 1H, J = 2.2 Hz), 3.81 (s, 3H), 2.81 (s, 6H),
2.40 (s, 3H, Me). 13C NMR (125 MHz, CDCl3): δ 158.9, 141.7, 137.5,
136.9, 133.6, 129.5, 128.8, 127.0, 126.5, 114.6, 113.7, 55.4, 43.1, 21.2.
HRMS(EI) calcd for C17H20N2O (M+) 268.1576. Found 268.1571.
(E)-2′-[(2,2-Dimethylhydrazono)methyl]-5′-methoxy-[1,1′-bi-
phenyl]-4-carbaldehyde (12b). Following the general procedure, flash
chromatography (1:2 Et2O/n-hexane) afforded 12b (55 mg, 78%) as a
yellow solid. Mp 81−83 °C. 1H NMR (500 MHz, CDCl3): δ 10.07 (s,
1H), 7.94−7.92 (m, 3H), 7.55 (d, 2H, J = 8.0 Hz), 7.11 (s, 1H), 6.95 (dd,
1H, J = 8.8, 2.5 Hz), 6.76 (d, 1H, J = 2.6 Hz), 3.83 (s, 3H), 2.81 (s, 6H).
13C NMR (125 MHz, CDCl3): δ 191.9, 158.9, 147.0, 140.1, 135.2, 131.7,
130.3, 129.5, 127.0, 126.8, 114.6, 114.5, 55.4, 42.9. HRMS(EI) calcd for
C17H18N2O2 (M+) 282.1368. Found 282.1373.
5-Fluoro-4′-methyl-[1,1′-biphenyl]-2-carbaldehyde N,N-Dime-
thylhydrazone (11c). Following the general procedure, flash
chromatography (170:1 toluene/acetone) afforded 11c (45 mg, 70%)
as a yellow oil. 1H NMR (500 MHz, CDCl3): δ 7.92 (dd, 1H, J = 8.6, 6.2
Hz), 7.24−7.17 (m, 4H), 7.17 (s, 1H), 6.98 (td, 1H, J = 8.6, 2.5 Hz), 6.93
(dd, 1H, J = 9.5, 2.4 Hz), 2.82 (s, 6H), 2.39 (s, 3H). 13C NMR (125
MHz, CDCl3): δ 162.0 (d, 1JC,F = 245 Hz), 142.0 (d, 3JC,F = 8 Hz), 137.3,
136.5, 132.1, 130.4, 129.4, 129.0, 126.9 (d, 3JC,F = 8 Hz), 116.4 (d, 2JC,F
=
2
21 Hz), 114.5 (d, JC,F = 21 Hz), 42.9, 21.1. HRMS(EI) calcd for
C16H17FN2(M+) 256.1376. Found 256.1373.
5-Chloro-4′-methyl-[1,1′-biphenyl]-2-carbaldehyde N,N-Dime-
thylhydrazone (11d). Following the general procedure, flash
chromatography (1:8 Et2O/n-hexane) afforded 11d (54 mg, 80%) as
a pale solid. Mp 70−72 °C. 1H NMR (500 MHz, CDCl3): δ 7.90 (d, 1H,
J = 8.5 Hz), 7.26−7.19 (m, 6H), 7.14 (s, 1H), 2.84 (s, 6H), 2.39 (s, 3H).
13C NMR (125 MHz, CDCl3): δ 141.6, 137.3, 136.4, 132.7,132.6, 131.1,
129.9, 129.4, 129.0, 127.4, 126.3, 42.8, 21.2. HRMS(EI) calcd for
C16H17ClN2 (M+) 272.1080. Found 272.1078.
4,4′-Dimethyl-[1,1′-biphenyl]-2-carbaldehyde N,N-Dimethylhy-
drazone (11e). Following the general procedure, flash chromatography
(110:1 toluene/acetone) afforded 11e (63 mg, 99%) as a yellow oil. 1H
NMR (500 MHz, CDCl3): δ 7.78 (s, 1H), 7.25−7.24 (m, 3H), 7.19 (d,
2H, J = 7.5 Hz), 7.14 (d, 1H, J = 7.5 Hz), 7.09 (d, 1H, J = 7.5 Hz), 2.84 (s,
6H), 2.38 (s, 6H). 13C NMR (125 MHz, CDCl3): δ 137.8, 137.6, 136.9,
136.5, 133.6, 133.2, 130.1, 129.6, 128.7, 128.3, 125.3, 42.9, 21.2, 21.1.
HRMS(EI) calcd. for C17H20N2 (M+) 252.1626. Found 252.1620.
4-Methoxy-4′-methyl-[1,1′-biphenyl]-2-carbaldehyde N,N-Dime-
thylhydrazone (11f). Following the general procedure, flash
chromatography (130:1 toluene/acetone) afforded 11f (54 mg, 80%)
as a pale solid. 1H NMR (500 MHz, CDCl3): δ 7.52 (s, 1H), 7.24−7.22
(m, 2H), 7.19 (d, 2H, J = 8.0 Hz), 7.15 (d, 2H, J = 8.5 Hz), 6.85 (dd, 1H,
J = 8.0, 2.0 Hz), 3.87 (s, 3H), 2.86 (s, 6H), 2.39 (s, 3H). 13C NMR (125
MHz, CDCl3): δ 158.9, 137.4, 136.3, 134.9, 133.4, 131.3, 131.3, 129.7,
128.8, 114.5, 108.3, 55.4, 42.9, 21.1. HRMS(EI) calcd for C17H20N2O
(M+) 268.1576. Found 268.1575.
4-Chloro-4′-methyl-[1,1′-biphenyl]-2-carbaldehyde N,N-Dime-
thylhydrazone (11g). Following the general procedure, flash
chromatography (1:15 Et2O/n-hexane) afforded 11g (56 mg, 83%) as
a yellow oil. 1H NMR (500 MHz, CDCl3): δ 7.94 (d, 1H, J = 1.9 Hz),
7.23−7.21 (m, 5H), 7.15 (d, 2H, J = 8.0 Hz), 2.88 (s, 6H), 2.41 (s, 3H).
13C NMR (125 MHz, CDCl3): δ 138.4, 137.0, 136.5, 135.6, 133.4, 131.4,
4′-Methyl-[1,1′-biphenyl]-2-carbaldehyde N,N-dimethylhydra-
zone (11a). Following the general procedure, flash chromatography
(160:1→50:1 toluene/acetone) afforded 11a (47 mg, 79%) as a yellow
oil. 1H NMR (500 MHz, CDCl3): δ 7.97 (d, 1H, J = 7.6 Hz), 7.30 (dt,
1H, J = 8.0, 1.0 Hz), 7.29−7.22 (m, 7H), 2.85 (s, 6H), 2.40 (s, 3H).13C
NMR (125 MHz, CDCl3): δ 140.3,137.6, 136.7, 134.0, 132.8, 130.1,
129.6, 128.8, 127.3, 127.2, 124.9, 42.9, 21.2. HRMS(EI) calcd for
C16H18N2 (M+) 238.1470. Found 238.1473.
130.3, 129.4, 128.9, 126.9, 124.5, 42.7, 21.2. HRMS(EI) calcd for
C16H17ClN2 (M+) 272.1080. Found 272.1087.
4,5-Dimethoxy-4′-methyl-[1,1′-biphenyl]-2-carbaldehyde N,N-Di-
methylhydrazone (11h). Following the general procedure, flash
chromatography (1:15 Et2O/n-hexane) afforded 11h (57 mg, 77%) as
a yellow oil. 1H NMR (500 MHz, CDCl3): δ 7.52 (s, 1H), 7.25−7.24 (m,
3H), 7.22 (s, 2H, J = 7.5 Hz), 6.73 (s, 1H), 3.96 (s, 3H), 3.87 (s, 3H),
2.82 (s, 6H), 2.39 (s, 3H). 13C NMR (125 MHz, CDCl3): δ 148.5, 148.4,
137.3, 136.5, 133.6, 129.6, 128.8, 128.1, 126.6, 112.7, 107.1, 55.8, 55.8,
43.1, 21.1. HRMS(EI) calcd for C18H22N2O2 (M+) 298.1681. Found
298.1674.
4,5-Dichloro-4′-methyl-[1,1′-biphenyl]-2-carbaldehyde N,N-Di-
methylhydrazone (11i). Following the general procedure, flash
chromatography (1:15 Et2O/n-hexane) afforded 11i (61 mg, 80%) as
a pale solid. Mp 95−97 °C. 1H NMR (500 MHz, CDCl3): δ 8.06 (s, 1H),
(E)-2′-[(2,2-Dimethylhydrazono)methyl]-[1,1′-biphenyl]-4-carbal-
dehyde (12a). Following the general procedure, flash chromatography
(1:6→1:5 Et2O/n-hexane) afforded 12a (45 mg, 70%) as a yellow solid.
Mp 95−97 °C. 1H NMR (500 MHz, CDCl3): δ 10.08 (s, 1H), 8.01 (d,
1H, J = 7.7 Hz), 7.94 (d, 2H, J = 7.7 Hz), 7.57 (d, 2H, J = 7.6 Hz), 7.39 (t,
1H, J = 7.3 Hz), 7.31 (t, 1H, J = 7.2 Hz), 7.27−7.24 (m, 1H), 7.14 (s,
1H), 2.87 (s, 6H). 13C NMR (125 MHz, CDCl3): δ 191.9, 147.3, 138.7,
135.1, 134.1, 130.7, 130.4, 129.8, 129.6, 128.3, 127.2, 125.2, 42.7.
HRMS(EI) calcd for C16H16N2O (M+) 252.1263. Found 252.1259.
5-Methoxy-4′-methyl-[1,1′-biphenyl]-2-carbaldehyde N,N-Dime-
thylhydrazone (11b). Following the general procedure, flash
chromatography (60:1 toluene/acetone) afforded 11b (52 mg, 77%)
as a yellow oil. 1H NMR (500 MHz, CDCl3): δ 7.91 (d, 1H, J = 8.7 Hz),
9918
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The Journal of Organic Chemistry
Note
7.31 (s, 1H), 7.22 (s, 4H), 7.04 (s, 1H), 2.89 (s, 6H), 2.40 (s, 3H). 13
NMR (125 MHz, CDCl3): δ 139.5, 137.5, 135.4, 134.2, 131.6, 131.5,
130.2, 129.3, 129.1, 128.9, 126.3, 42.7, 21.2. HRMS(EI) calcd for
C16H16Cl2N2 (M+) 306.0691. Found 306.0692.
C
= 8.0 Hz), 7.31 (d, 2H, J = 7.5 Hz), 2.42 (s, 3H). 13C NMR (125 MHz,
CDCl3): δ 145.1, 139.7, 137.8, 134.8, 133.1, 131.9, 131.8, 129.7, 128.4,
117.0, 110.7, 21.3. HRMS(EI) calcd for C14H9Cl2N (M+) 261.0112.
Found 261.0113.
3-Methoxy-4′-methyl-[1,1′-biphenyl]-2-carbaldehyde N,N-Dime-
thylhydrazone (11j). Following the general procedure, flash chroma-
tography (70:1 toluene/acetone) afforded 11j (37 mg, 56%) as a yellow
oil. 1H NMR (500 MHz, CDCl3): δ 7.24−7.17 (m, 4H), 7.13 (d, 2H, J =
7.8 Hz), 6.88 (d, 2H, J = 8.0 Hz), 3.86 (s, 3H), 2.71 (s, 6H), 2.36 (s, 3H).
13C NMR (125 MHz, CDCl3): δ 157.6, 142.7, 138.8, 136.1, 131.3, 129.7,
3-Methoxy-4′-methyl-[1,1′-biphenyl]-2-carbonitrile (13j). Follow-
ing the general procedure, flash chromatography (1:10 EtOAc/n-
hexane) afforded 13j (32 mg, 96%) as a yellow solid. Mp 118−120 °C.
1H NMR (500 MHz, CDCl3): δ 7.52 (t, 1H, J = 8.0 Hz),7.43 (d, 2H, J =
7.0 Hz), 7.26 (d, 2H, J = 7.5 Hz), 7.03 (d, 1H, J = 8.0 Hz), 6.91 (d, 1H, J
= 8.5 Hz), 3.95 (s, 3H), 2.39 (s, 3H). 13C NMR (125 MHz, CDCl3): δ
162.2, 147.3, 138.7, 135.2, 133.6, 129.3, 128.6, 121.8, 116.1, 109.3, 100.9,
56.2, 21.2. HRMS(EI) calcd for C15H13NO(M+) 223.0997. Found
223.0994.
General Procedure for Sequential Hydrazone-to-Nitrile
Transformation/Radical Bromination. A solution of magnesium
monoperoxyphthalate hexahydrate (MMPP·6H2O, 0.25 mmol, 124
mg) in methanol (0.5 mL) was added dropwise to a stirred suspension of
11a,c,d,g (0.1 mmol) in MeOH (0.5 mL). After consumption of the
starting material (∼20 min at rt, TLC monitoring), CH2Cl2 (15 mL)
and H2O (15 mL) were added. The organic layer was washed with brine
(2 × 10 mL), dried over MgSO4, and concentrated to dryness to give
crude 13a,c,d,g products in >95% yield (estimated by 1H NMR).
Reaction crudes were used directly in the next bromination reaction.16 A
solution of Na2S2O5 (0.15 mmol, 28.5 mg) in H2O (0.3 mL) was added
to a cooled (0 °C) biphasic mixture composed by a solution of NaBrO3
(0.15 mmol, 22.6 mg) in H2O (0.15 mL) and the reaction crude
containing 14a,c,d,g in EtOAc (0.2 mL). The reaction mixture was
stirred at rt until consumption of the starting material (4−10 h, TLC
monitoring). EtOAc (10 mL) and H2O (10 mL) were added, and the
organic layer was washed with brine (2 × 10 mL), dried over MgSO4,
and concentrated to dryness. Purification was carried out by flash
chromatography using Et2O/n-hexane or EtOAc/n-hexane mixtures as
solvents. Methods used for purification, yields, and characterization data
for products 14a,c,d,g are as follows:
128.3, 127.9, 123.7, 123.0, 110.2, 56.0, 42.7, 21.1. HRMS(EI) calcd for
C17H20N2O(M+) 268.1576. Found 268.1576.
(E)-2′-[(2,2-Dimethylhydrazono)methyl]-3′-methoxy-[1,1′-bi-
phenyl]-4-carbaldehyde (12j). Following the general procedure, flash
chromatography (1:2 Et2O/n-hexane) afforded 12j (42 mg, 60%) as a
yellow solid. Mp 88−90 °C. 1H NMR (500 MHz, CDCl3): δ 10.00 (s,
1H), 7.81 (d, 2H, J = 8.1 Hz), 7.42 (d, 2H, J = 8.0 Hz), 7.31 (s, 1H),
7.24−7.23 (m, 1H), 6.91 (d, 1H, J = 8.0 Hz), 6.84 (d, 1H, J = 8.2 Hz),
3.86 (s, 3H), 2.61 (s, 6H). 13C NMR (125 MHz, CDCl3): δ 192.2, 157.7,
149.8, 140.7, 134.3, 130.2, 129.1, 128.2, 127.9, 123.8, 122.9, 110.5, 55.8,
42.4. HRMS(EI) calcd for C17H18N2O2 (M+) 282.1368. Found
282.1367.
General Procedure for Hydrazone-to-Nitrile Transforma-
tion.15 A solution of magnesium monoperoxyphthalate hexahydrate
(MMPP·6H2O, 0.38 mmol, 186 mg) in MeOH (0.75 mL) was added
dropwise to a stirred suspension of 11b,e,f,h−j (0.15 mmol) in MeOH
(0.75 mL). After consumption of the starting material (∼20 min at rt,
TLC monitoring), CH2Cl2 (15 mL) and H2O (15 mL) were added. The
organic layer was washed with brine (2 × 10 mL), dried over MgSO4,
and concentrated to dryness. Purification was carried out by flash
chromatography using acetone/toluene or EtOAc/n-hexane mixtures as
solvents. Methods used for purification, yields, and characterization data
for products 13b,e,f,h-j are as follows:
5-Methoxy-4′-methyl-[1,1′-biphenyl]-2-carbonitrile (13b). Follow-
ing the general procedure, flash chromatography (1:10 EtOAc/n-
hexane) afforded 13b (34 mg, 99%) as a pale solid. Mp 116−118 °C. 1H
NMR (500 MHz, CDCl3): δ 7.67 (d, 1H, J = 9.0 Hz), 7.46 (d, 2H, J = 7.5
Hz), 7.29 (d, 2H, J = 8.0 Hz), 6.97 (d, 1H, J = 1.5 Hz), 6.92 (dd, 1H, J =
8.5, 2.0 Hz), 3.88 (s, 3H), 2.42 (s, 3H). 13C NMR (125 MHz, CDCl3): δ
162.6, 147.6, 138.7, 135.3, 135.3, 129.3, 128.4, 119.2, 115.3, 113.2, 103.0,
55.6, 21.2 . HRMS(EI) calcd for C15H13NO (M+) 223.0997. Found
223.0996.
4′-(Bromomethyl)-[1,1′-biphenyl]-2-carbonitrile (14a). Following
the general procedure, flash chromatography (Et2O/n-hexane 1:15)
afforded 14a (33 mg, 80%) as a white solid. Spectroscopic and physical
data matched those reported in the literature.19
4′-(Bromomethyl)-5-fluoro-[1,1′-biphenyl]-2-carbonitrile (14c).
Following the general procedure, flash chromatography (EtOAc/n-
hexane 1:12) afforded 14c (34 mg, 78%) as a white solid. Mp 122−124
°C. 1H NMR (500 MHz, CDCl3): δ 7.78 (dd, 1H, J = 8.6, 5.5 Hz), 7.54
(s, 4H), 7.22 (dd, 1H, J = 9.0, 2.8 Hz), 7.17 (td, 1H, J = 7.6, 2.8 Hz), 4.55
4,4′-Dimethyl-[1,1′-biphenyl]-2-carbonitrile (13e). Following the
1
(s, 2H). 13C NMR (125 MHz, CDCl3): δ 164.8 (d, JC,F = 255 Hz),
general procedure, flash chromatography (1:20 EtOAc/n-hexane)
1
3
3
afforded 13e (28 mg, 89%) as a light yellow solid. Mp 53−55 °C. H
147.7 (d, JC,F = 9 Hz), 138.9, 136.9, 136.1 (d, JC,F = 10 Hz), 129.5,
129.0, 117.8, 117.3 (d, 2JC,F = 23 Hz), 115.4 (d, 2JC,F = 23 Hz), 107.3,
32.5. HRMS(EI) calcd for C14H9BrFN(M+) 288.9902. Found 288.9900.
4′-(Bromomethyl)-5-chloro-[1,1′-biphenyl]-2-carbonitrile (14d).
Following the general procedure, flash chromatography (Et2O/n-
pentane 1:10) afforded 14d (39 mg, 84%) as a white solid. Mp 95−97
°C. 1H NMR (500 MHz, CDCl3): δ 7.70 (d, 1H, J = 8.3 Hz), 7.53 (s,
4H), 7.52 (d, 1H, J = 1.9 Hz), 7.44 (dd, 1H, J = 8.3, 1.8 Hz), 4.54 (s, 2H).
13C NMR (125 MHz, CDCl3): δ 146.3, 139.5, 139.0, 136.8, 134.9, 130.3,
129.6, 129.1, 128.2, 117.8, 109.6, 32.5. HRMS(EI) calcd for
C14H9BrClN (M+) 304.9602. Found 304.9603.
NMR (500 MHz, CDCl3): δ 7.55 (s, 1H), 7.45−7.42 (m, 3H), 7.39 (d,
1H, J = 8.0 Hz), 7.28 (d, 2H, J = 8.0 Hz), 2.42 (s, 6H). 13C NMR (125
MHz, CDCl3): δ 142.7, 138.3, 137.3, 135.2, 133.9, 133.7, 129.8, 129.3,
128.5, 119.0, 110.9, 29.7, 21.2, 20.7. HRMS(EI) calcd for C15H13N (M+)
207.1048. Found 207.1046.
4-Methoxy-4′-methyl-[1,1′-biphenyl]-2-carbonitrile (13f). Follow-
ing the general procedure, flash chromatography (1:200 acetone/
toluene) afforded 13f (33 mg, 98%) as a white solid. Mp 108−110 °C.
1H NMR (500 MHz, CDCl3): δ 7.43−7.40 (m, 3H), 7.28 (d, 2H, J = 8.0
Hz), 7.23 (d, 1H, J = 3.0 Hz), 7.17 (dd, 1H, J = 8.5, 2.5 Hz), 3.86 (s, 3H),
2.41 (s, 3H). 13C NMR (125 MHz, CDCl3): δ 158.4, 138.1, 135.0, 131.2,
129.3, 128.7, 128.5, 119.6, 118.7, 117.7, 111.7, 55.6, 21.2. HRMS(EI)
calcd for C15H13NO (M+) 223.0997. Found 223.0995.
4,5-Dimethoxy-4′-methyl-[1,1′-biphenyl]-2-carbonitrile (13h).
Following the general procedure, flash chromatography (1:3 EtOAc/
n-hexane) afforded 13h (35 mg, 92%) as a yellow solid. Mp 87−89 °C.
1H NMR (500 MHz, CDCl3): δ 7.44 (d, 2H, J = 8.0 Hz), 7.28 (d, 2H, J =
8.0 Hz), 7.15 (s, 1H), 6.92 (s, 1H), 3.95 (s, 3H), 3.93 (s, 3H), 2.42 (s,
3H). 13C NMR (125 MHz, CDCl3): δ 152.5, 148.0, 140.2, 138.3, 135.3,
129.3, 128.4, 119.2, 114.9, 112.3, 102.2, 56.2, 56.0, 21.1. HRMS(EI)
calcd for C16H15NO2 (M+) 253.1103. Found 253.1102.
4′-(Bromomethyl)-4-chloro-[1,1′-biphenyl]-2-carbonitrile (14g).
Following the general procedure, flash chromatography (Et2O/n-
pentane 1:10) afforded 14g (38 mg, 82%) as a white solid. Mp 127−129
°C. 1H NMR (500 MHz, CDCl3): δ 7.74 (d, 1H, J = 2.0 Hz), 7.63 (dd,
1H, J = 8.4, 2.1 Hz), 7.56 (s, 4H), 7.45 (d, 1H, J = 8.4 Hz), 4.54 (s, 2H).
13C NMR (125 MHz, CDCl3): δ 143.2, 138.7, 137.0, 134.0, 133.3, 131.3,
129.6, 129.1, 117.3, 112.6, 32.6. HRMS(EI) calcd for C14H9BrClN (M+)
304.9602. Found 304.9598.
General Procedure for Sequential Formyl Reduction/Hydra-
zone-to-Nitrile Transformation. To a cooled (0 °C) suspension of
substrate 12a,b,j (0.15 mmol) in MeOH (0.5 mL), NaBH4 (0.15 mmol,
5.7 mg) was added, and the reaction mixture was stirred at this
temperature until consumption of the starting material (∼30 min, TLC
monitoring). Then, a solution of MMPP·6H2O (0.23 mmol, 111 mg) in
methanol (0.5 mL) was added dropwise at 0 °C, and reaction mixture
4,5-Dichloro-4′-methyl-[1,1′-biphenyl]-2-carbonitrile (13i). Fol-
lowing the general procedure, flash chromatography (1:10 EtOAc/n-
hexane) afforded 13i (28 mg, 70%) as a yellow solid. Mp 131−133 °C.
1H NMR (500 MHz, CDCl3): δ 7.81 (s, 1H), 7.60 (s, 1H), 7.43 (d, 2H, J
9919
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The Journal of Organic Chemistry
Note
was stirred at rt for 30 min. CH2Cl2 (20 mL) and H2O (20 mL) were
added, and the organic layer was washed with brine (2 × 10 mL), dried
over MgSO4, and concentrated to dryness. Purification was carried out
by flash chromatography using n-hexane/Et2O mixtures as solvents.
Methods used for purification, yields, and characterization data for
products 15a,b,j are as follows:
4′-(Hydroxymethyl)-[1,1′-biphenyl]-2-carbonitrile (15a). Follow-
ing the general procedure, flash chromatography (Et2O/n-hexane 2:1)
afforded 15a (31 mg, 99%) as a pale solid. Spectroscopic and physical
data matched those reported in the literature.20
4′-(Hydroxymethyl)-5-methoxy-[1,1′-biphenyl]-2-carbonitrile
(15b). Following the general procedure, flash chromatography (Et2O/n-
hexane 3:1) afforded 15b (36 mg, 99%) as a pale solid. Mp 128−130 °C.
1H NMR (500 MHz, CDCl3): δ 7.68 (d, 1H, J = 8.5 Hz), 7.55 (d, 2H, J =
8.0 Hz), 7.49 (d, 2H, J = 8.5 Hz), 6.98 (d, 1H, J = 2.0 Hz), 6.94 (dd, 1H, J
= 9.0, 2.5 Hz), 4.76 (s, 2H), 3.89 (s, 3H), 1.89 (s, 1H). 13C NMR (125
MHz, CDCl3): δ 162.7, 147.3, 141.6, 137.5, 135.4, 128.8, 127.2, 119.1,
115.5, 113.4, 103.1, 64.9, 55.6. HRMS(EI) calcd for C15H13NO2 (M+)
239.0946. Found 239.0939.
4′-(Hydroxymethyl)-3-methoxy-[1,1′-biphenyl]-2-carbonitrile
(15j). Following the general procedure, flash chromatography (Et2O/n-
hexane 3:1) afforded 15j (35 mg, 99%) as a pale solid. Mp 124−126 °C.
1H NMR (500 MHz, CDCl3): δ 7.57−7.54 (m, 3H), 7.47 (d, 2H, J = 7.5
Hz), 7.05 (d, 1H, J = 7.5 Hz), 6.96 (d, 1H, J = 8.5 Hz), 4.74 (s, 2H), 3.97
(s, 3H), 1.96 (s, 1H). 13C NMR (125 MHz, CDCl3): δ 162.2, 147.0,
141.5, 137.4, 133.8, 129.0, 127.1, 121.9, 116.1, 109.6, 101.0, 64.9, 56.3.
HRMS(EI) calcd for C15H13NO2 (M+) 239.0946. Found 239.0940.
R. C.; Maleczka, R. E., Jr.; Smith, M. R., III. J. Am. Chem. Soc. 2006, 128,
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(9) Ros, A.; Estepa, B.; Lop
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́
́ ́
ez-Rodríguez, R.; Estepa, B.; Alvarez, E.; Fernan
(10) Ros, A.; Lop
R.; Lassaletta, J. M. J. Am. Chem. Soc. 2012, 134, 4573.
dez,
(11) The effect of introduction of donating- and electron-withdrawing
groups in ligands for nondirected borylation has been studied. See:
Ishiyama, T.; Takagi, J.; Hartwig, J. F; Miyaura, N. Angew. Chem., Int. Ed.
2002, 41, 3056.
́
(12) (a) Gros, P.; Fort, Y.; Caubere, P. J. Chem. Soc., Perkin Trans. 1
ASSOCIATED CONTENT
■
1997, 3597. (b) Cuperly, D.; Gros, P.; Fort, Y. J. Org. Chem. 2002, 67,
238.
S
* Supporting Information
1H and 13C NMR spectra for new compounds. This information
is available free of charge via the Internet at http://pubs.acs.org.
(13) Compounds 9 can be purified by flash chromatography on neutral
alumina, although a partial decomposition is observed. See ref 9 for
details and characterization.
(14) (a) Wexler, R. R.; Greenlee, W. J.; Irvin, J. D.; Goldberg, M. R.;
Prendergast, K.; Smith, R. D.; Timmermans, P. B. M. W. M. J. Med.
Chem. 1996, 39, 625. (b) Blakeney, J. S.; Reid, R. C.; Le, G. T.; Fairlie, D.
P. Chem. Rev. 2007, 107, 2960. (c) Naik, P.; Murumkar, P.; Giridhar, R.;
Yadav, M. R. Bioorg. Med. Chem. 2010, 18, 8418 and references cited
therein.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: abel.ros@iiq.csic.es; ffernan@us.es; jmlassa@iiq.csic.es.
Notes
The authors declare no competing financial interest.
(15) Hydrazone to nitrile tranformation was carried out following a
known procedure: Fernan
́
dez, R.; Gasch, C.; Lassaletta, J. M.; Llera, J.
ACKNOWLEDGMENTS
M.; Vazquez, J. Tetrahedron Lett. 1993, 34, 141.
́
■
́
(16) Bromination reaction was carried out following: Huszar, C.; Arvai,
G.; Hegedus, A. WO/2011/073703.
We thank the Spanish ‘Ministerio de Ciencia e Innovacion
(Grants CTQ2010-15297, CTQ2010-14974 and fellowship to
R.L-R.), the European FEDER funds, and the Junta de Andalucia
(Grants 2008/FQM-3833 and 2009/FQM-4537) for financial
support. A.R. thanks the European Union for a Marie Curie
Reintegration Grant (FP7-PEOPLE-2009-RG-256461) and the
CSIC for a JAE Postdoctoral Fellowship. R.L.-R. thanks the
CSIC for a JAE Predoctoral Fellowship.
́
’
(17) (a) Barret, I. C.; Langille, J. D.; Kerr, M. A. J. Org. Chem. 2000, 65,
6268. (b) Petroski, R. J. Synth. Commun. 2006, 12, 1727. (c) Hwu, J. R.;
Wang, N. Tetrahedron 1988, 44, 4181.
(18) A catalyst stock solution was prepared dissolving L7 (86 mg, 0.25
mmol) and [Ir(μ-OMe)(cod)]2 (83 mg, 0.125 mmol) in dry THF with a
total volume of 25 mL (sonication for 1h was used to accelerate
dissolution). The stock yellow-orange solution was kept under argon.
(19) Goossen, L. J.; Melzer, B. J. Org. Chem. 2007, 72, 7473.
́
(20) Kristensen, J.; Lysen
1435.
́
, M.; Vedsø, P.; Begtrup, M. Org. Lett. 2001, 3,
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9920
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