Chemoselective deprotonative lithiation of azobenzenes: Reactions and mechanisms

Article abstract of DOI:10.1021/jo500230q

Whereas standard strong bases (n-BuLi, s-BuLi/TMEDA, n-BuLi/t-BuOK, TMPMgCl·LiCl, and LDA) reduce the N=N bond of the parent azobenzene (Y = H), aromatic H→Li permutation occurs with LTMP when a suitable director of lithiation (Y = OMe, CONEt₂, F) is present in the benzene residue of the azo compound. The method allows direct access to new substituted azobenzenes.

Full text of DOI:10.1021/jo500230q

Note
pubs.acs.org/joc
Chemoselective Deprotonative Lithiation of Azobenzenes: Reactions
and Mechanisms
Thi Thanh Thuy Nguyen,† Anne Boussonniere,† Estelle Banaszak,† Anne-Sophie Castanet,†
̀
Kim Phi Phung Nguyen,‡ and Jacques Mortier*,†
†Institut des Molec
Avenue Olivier Messiaen, 72085 Le Mans Cedex 9, France
́
ules et Mater
́
iaux du Mans, Faculte
́
des Sciences et Techniques, Universite
́
du Maine and CNRS UMR 6283,
‡
́
Ecole des Sciences Naturelles, Laboratoire de Chimie Organique, Universite
́
Nationale de Ho-Chi-Minh-Ville, 283/2 Nguyen Van
Cu. Arrondissement 5, Ho Chi Minh Ville, Vietnam
S
* Supporting Information
ABSTRACT: Whereas standard strong bases (n-BuLi, s-BuLi/
TMEDA, n-BuLi/t-BuOK, TMPMgCl·LiCl, and LDA) reduce
the NN bond of the parent azobenzene (Y = H), aromatic
H→Li permutation occurs with LTMP when a suitable director
of lithiation (Y = OMe, CONEt2, F) is present in the benzene
residue of the azo compound. The method allows direct access
to new substituted azobenzenes.
Table 1. Reactions of Azobenzene (1) with Strong Bases
hemistry of aromatic azobenzenes is well studied because
C
of the ease of the NN bond E/Z photoisomerization.1,2
Azobenzene exists mainly as the E isomer but upon
photoexcitation converts to the Z isomer. Azobenzenes are
widely and commercially used as dyes and, more recently, have
been applied to photoresponsive molecular switches and
materials by taking advantage of this photoisomerization.3
The synthesis of lithiated azobenzene derivatives represents a
difficult challenge resulting from the high electrophilicity of the
azo functionality.1 The only approach to these carbanions is the
halogen−lithium exchange at very low temperature.4 In this
note, we wish to report conditions for chemoselective
deprotonative lithiation of substituted azobenzenes.
Efforts were initially directed toward interacting alkyllithium
and sterically hindered lithium amide bases with the parent
azobenzene 1 under the conditions depicted in Table 1. In
agreement with the previous work of Katritzky5 among others,6
n-BuLi does not work as a base and only has the strength to
react with the NN bond of 1 to afford a mixture of tri and
tetrasubstituted hydrazines 2 and 3a after the addition of
TMSCl (entry 1).
It is well-known that the use of s-BuLi/TMEDA (1:1
complex) provides optimal and highly reliable conditions for
ortholithiation of many aromatic compounds.7 Treatment of 1
with 3 equiv of s-BuLi/TMEDA followed by quench with
TMSCl afforded hydrazine 3b in high yield (entry 2). Both the
1H and 13C NMR spectra showed two sets of signals indicating
the existence of two stable conformers resulting from the slow
flipping of the N-atom to which the chiral C-atom of the s-butyl
group is attached (See Supporting Information).
Lithium diisopropyl amide (LDA) equally acts as a reductor
(entry 3);8 however, the reaction proceeds only sluggishly as
evidenced by a meager 32% yield of 4. The probable
mechanism is given in Scheme 1. In the initial (reversible)
a
b
c
entry
base
n-BuLi
2−5 (%)
1
2
3
4
5
6
2 (40) + 3a (46)
d
s-BuLi/TMEDA
LDA
3b (89)
4 (32)
LTMP
e
LICKOR
4 (14) + 5 (36)
4 (22) + 5 (50)
TMPMgCl·LiCl
a
b
Lithiation attempts at −78 °C failed. Azobenzene (1) in THF was
allowed to react with the base at −40 °C, and the electrophile was
added (external quench conditions). Purified yields. Two stable
conformers (1:1 ratio) in CDCl3 or DMSO-d6 at rt. Complex mixture
c
d
e
of products.
step, azobenzene (1) interacts with LDA and forms a complex
A*.8 Transfer of a hydride ion within the complex results in the
reduction of the NN bond leading to lithium 1,2-
diphenylhydrazin-1-ide (6) and oxidation of the amide to the
corresponding imine. Compound 6 can react further with the
excess of base to give 4 via the dilithio compound 7 (path a).9
Received: January 29, 2014
Published: February 26, 2014
© 2014 American Chemical Society
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Note
be interposed between the first and the second H→Li
permutation (path b). As a result, lithio compound 6 could
be the stable species prior to the addition of TMSCl. The
reaction of 8 with LDA giving monolithio compound 9 could
be faster than the expected rapid degradation of LDA by
TMSCl. Since the reaction of hydrazobenzene (5) with LDA (3
equiv) at −40 °C followed by quench with MeI provided a
mixture of 10 (27%) and 11 (62%), it is likely that the reaction
proceeds via 7.
Scheme 1. Mechanism of Reduction of Azobenzene by LDA
Treatment of 1 with lithium 2,2,6,6-tetramethylpiperidide
(LTMP) followed by quench with TMSCl led to a complex
mixture of products (Table 1, entry 4). In these reactions,
hydrazines 2 and 5 could result, at least partially, from the
protodesilylation of 3 and 4 during aqueous workup.
The Lochmann-Schlosser superbase n-BuLi/t-BuOK (LICK-
OR)12 and the Hauser base TMPMgCl·LiCl13 are strong
metalating agents of poor nucleophilicity13,14 which never-
theless also reduced the NN bond of 1 to give mixtures of
1,2-diphenyl-1,2-bis(trimethylsilyl)hydrazine (4) and 1,2-diphe-
nylhydrazine (5) (entries 5 and 6).
It was found that introduction of a director of lithiation
(OMe, F, and CONEt2)7,15 in the phenyl group of the azo
compound changed radically the pattern of the reaction (Table
TMSCl is a treacherous electrophile since it reacts slowly
with bulky bases such as LDA and LTMP, coexisting with them
at low temperatures over hours.10,11 A silylation step could then
Table 2. Lithiation of Substituted Azobenzenes 14−20 with LTMP
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Note
from tetramethylsilane) and are referenced to the residual solvent peak
2). In the literature, Kauffmann showed that methyllithium
reacts with electron-rich azobenzene derivatives (4-NMe2, 4-
NH2, and 4-OMe) by nucleophilic addition to the electron-rich
phenyl group, while Me3FeLi ortho-methylates the less
electron-rich phenyl group.16 Less reactive organometallic
compounds (M = Zn and Mn) give reduction products when
applied at higher temperatures.17
Metalation conditions were initially explored with a methoxy
group in para position. This directing metalation group (DMG)
is moderately powerful with regard to directing ability but of
high synthetic value.7 To our delight, treatment of (E)-1-(4-
methoxyphenyl)-2-phenyldiazene (14) with LTMP (5 equiv) at
−78 °C followed by trapping with dry ice and aqueous
quenching provided the acids 21 and 22 in good yields (entry
1).18 The azo bond was not affected, and lithiation occurred
preferentially ortho to the methoxy.19
1
of CDCl3 at δ 7.26 and δ 77.00 in H and 13C NMR, respectively.
Coupling constants are reported in Hz with multiplicities denoted as s
(singlet), d (doublet), t (triplet), q (quartet), p (pentet), m
(multiplet), and br (broad). IR spectra were acquired by an FT-IR
spectrometer and are reported in wave numbers (cm−1).
All experiments were carried out under argon with anhydrous
solvents in dried glassware, using syringe−septum cap techniques. For
standard working practice, see ref 23. THF was dried using the drying
station. n-BuLi (1.6 M in hexanes) and s-BuLi (1.3 M in a mixture of
cyclohexane and hexanes) were titrated periodically against N-
benzylbenzamide.24 2,2,6,6-Tetramethylpiperidine (TMP) was pre-
pared from 2,2,6,6-tetramethyl-4-piperidinone by Wolff−Kishner−
Huang reduction.25 The Hauser base TMPMgCl·LiCl was prepared
according to a literature procedure.13 N,N,N′,N′-Tetramethyl-1,2-
ethylenediamine (TMEDA), TMP, and chlorotrimethylsilane
(TMSCl) were distilled from CaH2 and stored under argon. Potassium
tert-butoxide (t-BuOK) was sublimated prior to use.
Aside from some polysilylated products (<10%), the reaction
of 14 with a 1:1 mixture of LTMP/TMSCl (5 equiv) at −45 °C
under in situ quench (ISQ) conditions10 followed by warming
to rt gave the substituted azobenzene 23 arising from silylation
in the position adjacent to the methoxy. This experiment
strongly suggests that 23-formation is a kinetically controlled
process (CIPE effect).20 The diethyl carboxamide is a strong
DMG which has the requirements for good coordination to the
lithium reagent and the electron-withdrawing properties to
cause the ortho-protons to become acidic enough for efficient
and rapid deprotonation.7,15 Halogens direct by an inductive,
acidifying effect alone. Deprotonation of 1-(4-fluorophenyl)-2-
phenyldiazene (15) and N,N-diethyl-4-(phenyldiazenyl)-benza-
mide (16) occurred exclusively in C3 providing carboxylic acid
derivatives 24 (89%) and 25 (81%) after quenching with CO2.
In principle, 1,3-interrelated DMGs promote metalation at
the common ortho site. This was indeed the case with a
methoxy located meta with respect to the azo group (entry 5)
but not with a diethylamido group where lithiation occurred
exclusively in position C4 (entry 7). With a fluorine atom
occupying a meta position to the azo group, a 3:1 mixture of 2-
and 4-substituted azobenzenes 27 and 28 was obtained.
It was also desirable to ascertain whether the reaction of 1-
(2-fluorophenyl)-2-phenyldiazene (20) with LTMP would
proceed with lithiation ortho to the azo group or the fluorine
atom. Exposing 20 to LTMP followed by quench with dry ice
led to carboxylation exclusively ortho to the fluorine
functionality. The dicarboxylated azobenzene 31 was isolated
in a yield of 70% when 5 equiv of LTMP was used.
Suitable conditions have indeed been found under which
substituted azobenzenes can undergo effective and regioselec-
tive lithiation, as evidenced by several trapping experiments.
Despite the modest strength of NN-Ph group as an ortho-
lithiation director, the synthetic potential of this new reaction
which allows a late-stage functionnalization of the azobenzene
scaffold is clearly enormous. Conceptually, this methodology
complements palladium-catalyzed regioselective functionaliza-
tion reactions of aromatic azo compounds which only lead to
ortho-substituted azobenzenes.21 This reaction could play a
crucial role particularly in tuning the functional features of
azobenzene-containing monolayers with photoswitchable wett-
ability.3,22
Reactions of Parent Azobenzene (1) and Hydrazobenzene
(5) with Strong Bases (Table 1 and Scheme 1). 1-n-Butyl-1,2-
diphenylhydrazine (2) and 1-n-Butyl-1,2-diphenyl-2-(trimethylsilyl)-
hydrazine (3a) (Entry 1). To a stirred solution of azobenzene (1) (364
mg, 2 mmol) in THF (20 mL) at −40 °C was added dropwise n-
butyllithium (3.8 mL, 1.6 M in hexanes, 6 mmol). The reaction
mixture was stirred for 2 h, after which TMSCl (0.8 mL, 6 mmol) was
added. Stirring was maintained for 2 additional hours. The reaction
mixture was then allowed to warm to room temperature and
hydrolyzed with water (20 mL). The aqueous layer was extracted
with ethylacetate (3 × 10 mL), the combined organic layers were dried
(MgSO4), and concentrated in vaccuo. Purification by chromatog-
raphy (cyclohexane/ethylacetate 10:0 → 8:2) afforded a mixture of 2
(190 mg, 40%, yellow oil) and 3a (286 mg, 46%, orange oil).
1-n-Butyl-1,2-diphenylhydrazine (2). 1H NMR (400 MHz, CDCl3,
Litt.5) δ: 7.26−7.20 (m, 4H), 6.93−6.90 (m, 2H), 6.85−6.77 (m, 4H),
5.60 (br s, 1H), 3.51 (t, J = 7.5 Hz, 2H), 1.67 (p, J = 7.5 Hz, 2H), 1.67
(sext, J = 7.5 Hz, 2H), 0.96 (t, J = 7.5 Hz, 3H).
1
1-n-Butyl-1,2-diphenyl-2-(trimethylsilyl)hydrazine (3a). H NMR
(400 MHz, CDCl3) δ: 7.21−7.15 (m, 4H), 6.84−6.77 (m, 3H), 6.72−
6.64 (m, 3H), 3.51−3.43 (m, 2H), 1.76−1.65 (m, 2H), 1.40−1.30 (m,
2H), 0.94 (t, J = 7.2 Hz, 3H), 0.34 (s, 9H). 13C NMR (100 MHz,
CDCl3) δ: 150.0 (C), 148.0 (C), 129.4 (2CH), 129.0 (2CH), 118.9
(CH), 116.9 (CH), 115.1 (2CH), 111.0 (2CH), 53.4 (CH2), 30.6
(CH2), 20.6 (CH2), 14.1 (CH3), 1.0 (3CH3). IR (neat): 2959, 2855,
1594, 1497, 1255, 838, 693 cm−1. HRMS (TOF MS FI) calcd for
C19H28N2Si, [M]+ 312.2022; found, 312.2029.
1-(sec-Butyl)-1,2-diphenyl-2-(trimethylsilyl)hydrazine (3b) (entry
2). Following the procedure described above for entry 1, azobenzene
(1) (182 mg, 1 mmol) was allowed to react with s-BuLi/TMEDA (1:1
complex). Standard workup followed by chromatography (cyclo-
hexane/ethylacetate 10:0 → 8:2) afforded 1-(sec-butyl)-1,2-diphenyl-2-
(trimethylsilyl)hydrazine (3b) (277 mg, 89%, yellow oil). The 1H and
13C NMR spectra of 3b in CDCl3 at room temperature consist in two
sets of signals, indicating an equilibrium of two invertomers (isomers
stemming from slow nitrogen inversion) in a 1:1 ratio. 1H NMR (400
MHz, CDCl3) δ: 7.22−7.13 (m, 8H), 6.90 (d, J = 8.1 Hz, 2H), 6.85−
6.77 (m, 4H), 6.70 (t, J = 7.2 Hz, 2H), 6.64 (d, J = 7.9 Hz, 4H), 3.84−
3.72 (m, 2H), 2.01−1.91 (m, 2H), 1.49−1.33 (m, 2H), 1.29 (d, J = 6.6
Hz, 3H), 1.17 (d, J = 6.5 Hz, 3H), 1.00 (t, J = 7.5 Hz, 3H), 0.92 (t, J =
7.5 Hz, 3H), 0.35 (s, 9H), 0.35 (s, 9H). 13C NMR (100 MHz, CDCl3)
δ: 150.5 (C), 150.3 (C), 149.1 (C), 149.1 (C), 129.4 (2CH), 129.3
(2CH), 129.0 (2CH), 128.8 (2CH), 128.7 (2CH), 119.1 (CH), 119.0
(CH), 118.4 (CH), 116.6 (CH), 116.5 (CH), 115.7 (CH), 115.4
(CH), 114.4 (CH), 112.1 (CH), 111.7 (CH), 58.3 (CH), 58.2 (CH),
28.2 (CH2), 28.1 (CH2), 17.3 (CH3), 16.9 (CH3), 11.9 (CH3), 11.4
(CH3), 1.2 (3 CH3), 1.1 (3 CH3). IR (neat): 2959, 2900, 1592, 1497,
1488, 1255, 924, 838, 694 cm−1. HRMS (TOF MS ESI) calcd for
C19H28N2NaSi, [M+Na+]+ 335.1914; found, 335.1919.
EXPERIMENTAL SECTION
■
General Experimental Methods. 1H and 13C NMR spectra were
obtained on a 200 MHz or a 400 MHz spectrometer in CDCl3 unless
otherwise indicated. Chemical shifts are reported in δ (ppm downfield
The presence of invertomers was confirmed by variable-temperature
1H NMR spectra in DMSO-d6. The CH3c and CH3d signals at
ambient temperature appear, respectively, as two doublets (δH = 1.29
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Note
and 1.17) and two triplets (δH = 1.00 and 0.92) that coalesce on
warning the sample to 90 °C. Degradation products were observed
above 60 °C. See Supporting Information.
2-Methoxy-5-(phenyldiazenyl)benzoic Acid (21) and 5-methoxy-
2-(phenyldiazenyl)benzoic Acid (22) (Entry 1). According to the
general procedure, a solution of 1-(4-methoxyphenyl)-2-phenyldiazene
(14) (212 mg, 1 mmol) in THF (10 mL) was added to a THF
solution of LTMP (5 mmol) at −78 °C. The resulting mixture was
stirred at this temperature for 2 h and poured onto dry ice. Standard
workup followed by chromatography (cyclohexane/ethylacetate 9:1 →
0:10) afforded 21 (200 mg, 78%) and 22 (20 mg, 8%) as yellow solids.
2-Methoxy-5-(phenyldiazenyl)benzoic acid (21). Mp 168−169
°C. 1H NMR (400 MHz) δ: 8.76 (d, J = 2.6 Hz, 1H), 8.15 (dd, J = 8.9
Hz, J = 2.6 Hz, 1H), 7.92−7.89 (m, 2H), 7.54−7.46 (m, 3H), 7.19 (d,
J = 8.9 Hz, 1H), 4.15 (s, 3H). 13C NMR (100 MHz) δ: 165.3 (C),
159.8 (C), 152.5 (C), 147.3 (C), 131.4 (CH), 129.3 (2CH), 129.0
(CH), 128.9 (CH), 123.0 (2CH), 118.5 (C), 112.3 (CH), 57.3 (CH3).
IR (neat): 3000−2400 (br), 2920, 1688, 1663, 1608, 1571, 1496, 1418,
1254, 768, 689 cm−1. HRMS (TOF MS CI) calcd for C14H13N2O3, [M
+H]+ 257.0926; found, 257.0927.
5-Methoxy-2-(phenyldiazenyl)benzoic Acid (22). Mp 141−142
°C. 1H NMR (400 MHz) δ: 8.06 (d, J = 9.0 Hz, 1H), 7.90 (d, J = 2.9
Hz, 1H), 7.83−7.80 (m, 2H), 7.59−7.55 (m, 3H), 7.20 (dd, J = 9.0
Hz, J = 2.9 Hz, 1H), 3.97 (s, 3H). 13C NMR (100 MHz) δ: 166.2 (C),
163.4 (C), 151.7 (C), 144.1 (C), 132.8 (CH), 129.9 (2CH), 129.2
(C), 123.4 (2CH), 121.5 (CH), 118.1 (CH), 115.4 (CH), 56.2 (CH3).
IR (neat): 3000−2500 (br), 2970, 1738, 1593, 1490, 1438, 1337, 1232,
1068, 1019, 779, 679 cm−1. HRMS (TOF MS CI) calcd for
C14H13N2O3, [M+H]+ 257.0926; found, 257.0918.
1-(4-Methoxy-3-(trimethylsilyl)phenyl)-2-phenyldiazene (23)
(Entry 2). According to the general procedure, a stirred solution of
LTMP (5 mmol) in THF (10 mL) was added dropwise to a solution
of 1-(4-methoxyphenyl)-2-phenyldiazene (14) (212 mg, 1 mmol) and
TMSCl (0.63 mL, 5 mmol) in THF (10 mL) at −45 °C. The resulting
mixture was stirred for 2 h at this temperature and then hydrolyzed
with water (10 mL). The aqueous phase was extracted with diethyl
ether (3 × 10 mL), and the combined organic layers were dried
(MgSO4) and concentrated in vaccuo. Purification by chromatography
(cyclohexane/ethylacetate 10:0 → 8:2) afforded 23 (148 mg, 52%) as
a red solid. Mp 61−65 °C. 1H NMR (400 MHz) δ: 8.05 (d, J = 2.4 Hz,
1H), 7.98 (dd, J = 8.8 Hz, J = 2.4 Hz, 1H), 7.93−7.90 (m, 2H), 7.54−
7.50 (m, 2H), 7.45 (m, 1H), 6.96 (d, J = 8.8 Hz, 1H), 3.90 (s, 3H),
0.37 (s, 9H). 13C NMR (100 MHz) δ: 166.9 (C), 153.1 (C), 146.8
(C), 130.6 (CH), 130.3 (CH), 129.1 (2CH), 129.0 (C), 125.7 (CH),
122.6 (2CH), 109.8 (CH), 55.6 (CH3), −0.9 (3CH3). IR (neat):
2953, 2898, 1578, 1462, 1386, 1238, 1067, 833, 762, 687 cm−1. HRMS
(TOF MS CI) calcd for C16H21N2OSi, [M+H]+ 285.1422; found,
285.1423.
2-Fluoro-5-(phenyldiazenyl)benzoic Acid (24) (Entry 3). Accord-
ing to the general procedure, 4-fluoroazobenzene (15) (200 mg, 1
mmol) in THF (10 mL) was added dropwise to LTMP (3 mmol) at
−78 °C. The resulting mixture was stirred for 2 h and poured onto dry
ice. Standard workup followed by chromatography (cyclohexane/
ethylacetate 8:2 → 0:10) gave 24 (217 mg, 89%) as an orange solid.
Mp 172−175 °C. 1H NMR (400 MHz) δ: 8.64 (dd, JH−F = 6.8 Hz, J =
2.6 Hz, 1H), 8.16 (ddd, J = 8.8 Hz, JH−F= 4.4 Hz, J = 2.6 Hz, 1H),
7.96−7.92 (m, 2H), 7.56−7.48 (m, 3H), 7.33 (dd, JH−F = 10.0 Hz, J =
8.8 Hz, 1H). 13C NMR (100 MHz) δ: 168.5 (d, JC−F = 3.3 Hz, C),
163.9 (d, JC−F = 265.7 Hz, C), 152.6 (C), 148.9 (d, JC−F = 3.4 Hz, C),
131.7 (CH), 129.3 (2CH), 129.1 (d, JC−F = 9.7 Hz, CH), 128.2 (CH),
123.2 (2CH), 118.5 (d, JC−F = 10.5 Hz, C), 118.2 (d, JC−F = 23.8 Hz,
CH). 19F (376 MHz) δ: −105.7 (ddd, JH−F = 10.0 Hz, JH−F = 6.8 Hz,
JH−F = 4.4 Hz). IR (neat) 2800−2600 (br), 1687, 1618, 1444, 1283,
1237, 924, 843, 766, 679 cm−1. HRMS (TOF MS FI) C13H9FN2O2,
[M]+ calcd 244.0648; found, 244.0653.
1,2-Diphenyl-1,2-bis(trimethylsilyl)hydrazine (4) and 1,2-Diphe-
nylhydrazine (5) (Entries 3, 5, and 6). Following the procedure
described above for entry 1, azobenzene (1) (182 mg, 1 mmol) was
allowed to react with LDA (entry 3), LICKOR (entry 5),26 or
TMPMgCl·LiCl (entry 6). With LDA, 1,2-diphenyl-1,2-bis-
(trimethylsilyl)hydrazine (4) (103 mg, 32%, white solid) was the
only product isolated. With the Schlosser-Lochmann superbase
(LICKOR), standard workup followed by chromatography (cyclo-
hexane/ethylacetate 10:0 → 8:2) gave a mixture of 4 (45 mg, 14%)
and 5 (66 mg, 36%, yellow solid). With TMPMgCl·LiCl, a literature
procedure13 led to compounds 4 (22%) and 5 (50%), which were
separated and purified by column chromatography.
1
1,2-Diphenyl-1,2-bis(trimethylsilyl)hydrazine (4). H NMR (400
MHz, CDCl3, Litt.27) δ: 7.19−7.14 (m, 4H), 6.84−6.74 (m, 6H), 0.32
(s, 18H).
1,2-Diphenylhydrazine (5). 1H NMR (400 MHz, CDCl3) δ: 7.25−
7.20 (m, 4H), 6.87−6.83 (m, 6H), 5.63 (s, 2H).
1-Methyl-1,2-diphenylhydrazine (10) and 1,2-dimethyl-1,2-di-
phenylhydrazine (11). 1,2-Diphenylhydrazine (5) (182 mg, 1
mmol) in THF (10 mL) was slowly added to a solution of LDA (3
mmol) in THF (10 mL) at −40 °C. The resulting mixture was stirred
for 2 h at this temperature, and iodomethane (0.18 mL, 3 mmol) in
THF (3 mL) was added. The mixture was allowed to warm to room
temperature and hydrolyzed with water (20 mL). The aqueous layer
was extracted with ethylacetate (3 × 10 mL), and the combined
organic layers were dried (MgSO4) and concentrated in vaccuo.
Purification by chromatography (cyclohexane/ethylacetate/Et3N
10:0:0 → 9:0.5:0.5) afforded 10 (53 mg, 27%) and 11 (131 mg,
62%) as yellow oils.
1-Methyl-1,2-diphenylhydrazine (10). 1H NMR (400 MHz,
CDCl3, Litt.28) δ: 7.28−7.22 (m, 4H), 6.98−6.95 (m, 2H), 6.87−
6.81 (m, 4H), 5.47 (s, 1H), 3.17 (s, 3H).
1,2-Dimethyl-1,2-diphenylhydrazine (11). 1H NMR (400 MHz,
CDCl3, Litt.28) δ: 7.28−7.23 (m, 4H), 6.86−6.80 (m, 6H), 3.00 (s,
6H).
-Deprotonative Lithiation of Azobenzenes 14−20 with
LTMP: Reactions and Structural Elucidation (Table 2). 1-(4-
Methoxyphenyl)-2-phenyldiazene (14) is commercially available from
a chemical supplier. 1-(4-Fluorophenyl)-2-phenyldiazene (15),29 1-(3-
fluorophenyl)-2-phenyldiazene (18),30 1-(2-fluorophenyl)-2-phenyl-
diazene (20),31 and 1-(3-methoxyphenyl)-2-phenyldiazene (17)32
were synthesized by condensation of nitrosobenzene with, respec-
tively, 4-fluoroaniline, 3-fluoroaniline, 2-fluoroaniline, and 3-methox-
yaniline. N,N-Diethyl-4-(phenyldiazenyl)benzamide (16) and the
meta isomer 19 were synthesized from the corresponding phenyl-
diazenylbenzoyl chlorides and diethylamine in dry dichloromethane
under nitrogen.33 Phenyldiazenylbenzoyl chlorides were themselves
prepared by reaction of the corresponding phenyldiazenylbenzoic
acids with thionyl chloride in the presence of anhydrous sodium
carbonate.34 (E)-4-(Phenyldiazenyl)benzoic acid and the correspond-
ing meta isomer were prepared by the reaction of 4-aminobenzoic acid
and 3-aminobenzoic acid with nitrosobenzene in glacial acetic acid.35
General Procedure. To a solution of TMP (3−5 mmol) in THF
(10 mL) at −20 °C under argon was added dropwise n-butyllithium in
hexanes (3−5 mmol). The resulting LTMP solution was stirred at 0
°C for 30 min and cooled to −78 °C, and a solution of the azo
compound (1 mmol) in THF (10 mL) was slowly added. Stirring was
maintained for 2 h at −78 °C, after which the mixture was poured into
an excess of freshly crushed carbon dioxide. The solution was then
allowed to warm up to 20 °C. Water (10 mL) was added, and the
resulting mixture was basified to pH 13 with a 1 M NaOH aq. solution.
The aqueous layer was separated, washed with diethyl ether (3 × 10
mL), acidified to pH 1 with 2 M HCl, and extracted with ethylacetate
(3 × 10 mL). The combined organic layers were dried (MgSO4) and
concentrated in vaccuo. The residue was purified by chromatography
or recrystallization.
2-(Diethylcarbamoyl)-5-(phenyldiazenyl)benzoic Acid (25) (Entry
4). According to the general procedure, N,N-diethyl-4-
(phenyldiazenyl)benzamide (16) (282 mg, 1 mmol) in THF (10
mL) was added dropwise to a THF solution of LTMP (5 mmol) at
−78 °C. The mixture was stirred at this temperature for 2 h and then
poured onto dry ice. Standard workup followed by recrystallization
(ethylacetate) afforded 25 as an orange solid (263 mg, 81%). Mp
1
159−161 °C. H NMR (400 MHz) δ: 8.62 (d, J = 2.0 Hz, 1H), 8.11
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Note
(dd, J = 8.0, J = 2.0 Hz, 1H), 7.96−7.93 (m, 2H), 7.56−7.49 (m, 3H),
7.45 (d, J = 8.0 Hz, 1H), 3.61 (br s, 2H), 3.16 (q, J = 7.4 Hz, 2H), 1.30
(t, J = 7.2 Hz, 3H), 1.07 (t, J = 7.4 Hz, 3H). 13C NMR (100 MHz) δ:
170.4 (C), 168.8 (C), 152.5 (C), 152.4 (C), 141.0 (C), 131.8 (CH),
129.3 (2CH), 128.9 (C, observed in HMBC spectrum, see below),
127.9 (CH), 126.5 (CH), 126.4 (CH), 123.3 (2CH), 43.1 (CH2), 39.2
(CH2), 13.7 (CH3), 12.2 (CH3). IR (neat): 3000−2600 (br), 2978,
2877, 1710 (2), 1588, 1443, 1240, 767, 689 cm−1. HRMS (TOF MS
FD) C18H19N3O3, [M]+calcd 325.1426; found, 325.1423.
2-Methoxy-6-(phenyldiazenyl)benzoic Acid (26) (Entry 5). Ac-
cording to the general procedure, 1-(3-methoxyphenyl)-2-phenyl-
diazene (17) (212 mg, 1 mmol) in THF (10 mL) was added to a THF
solution of lithium LTMP (5 mmol) at −78 °C. Standard workup and
purification by chromatography (cyclohexane/ethylacetate 9:1 →
0:10) gave 26 as an orange solid (189 mg, 74%). Mp 171−173 °C. 1H
NMR (400 MHz, acetone-d6) δ: 7.90−7.87 (m, 2H), 7.61−7.55 (m,
3H), 7.54 (dd, J = 8.1 Hz, J = 8.2 Hz, 1H), 7.42 (br d, J = 8.1 Hz, 1H),
7.27 (br d, J = 8.2 Hz, 1H), 3.94 (s, 3H). 13C NMR (100 MHz,
acetone-d6) δ: 167.3 (C), 157.7 (C), 153.4 (C), 150.3 (C), 132.6
(CH), 131.2 (CH), 130.2 (2CH), 125.9 (C), 123.8 (2CH), 114.7
(CH), 109.8 (CH), 56.7 (CH3). IR (neat): 2800−2550 (br), 1687,
1469, 1270, 1093, 747, 687 cm−1. HRMS (TOF MS FD) calcd for
C14H12N2O3, [M]+ 256.0848; found, 256.0851.
2-Fluoro-6-(phenyldiazenyl)benzoic Acid (27) and 2-Fluoro-4-
(phenyldiazenyl)benzoic Acid (28) (Entry 6). According to the
general procedure, 1-(3-fluorophenyl)-2-phenyldiazene (18) (200 mg,
1 mmol) in THF (10 mL) was added dropwise to a THF solution of
LTMP (3 mmol) at −78 °C. The mixture was stirred at this
temperature for 2 h and poured onto dry ice. Standard workup
followed by chromatography (cyclohexane/ethylacetate 9:1 → 0:10)
gave 27 (149 mg, 61%) and 28 (49 mg, 20%) as orange-yellow solids.
2-Fluoro-6-(phenyldiazenyl)benzoic acid (27). Mp 116−118 °C.
1H NMR (400 MHz) δ: 7.91−7.89 (m, 2H), 7.72 (d, J = 8.1 Hz, 1H),
2-Fluoro-3-(phenyldiazenyl)benzoic Acid (30) and 3-((2-
Carboxyphenyl)diazenyl)-2-fluorobenzoic Acid (31) (Entry 8).
According to the general procedure, 1-(2-fluorophenyl)-2-phenyl-
diazene (20) (200 mg, 1 mmol) in THF (10 mL) was added to a THF
solution of LTMP (3 mmol) at −78 °C. Standard workup followed by
chromatography (cyclohexane/ethylacetate 9:1 → 0:10) afforded 30
(164 mg, 67%) as a red solid and 31 (46 mg, 16%) as an orange solid.
2-Fluoro-3-(phenyldiazenyl)benzoic Acid (30). Mp 178−179 °C.
1H NMR (400 MHz) δ: 8.16 (ddd, J = 7.9 Hz, JH−F = 6.7 Hz, J = 1.6
Hz, 1H), 8.02−7.98 (m, 3H), 7.57−7.51 (m, 3H), 7.34 (t, J = 7.9 Hz,
1H). 13C NMR (100 MHz) δ: 168.6 (d, JC−F = 2.6 Hz, C), 160.0 (d,
JC−F = 271.9 Hz, C), 152.8 (C), 141.8 (d, JC−F = 7.1 Hz, C), 135.0
(CH), 132.1 (CH), 129.4 (2CH), 124.0 (d, JC−F = 4.9 Hz, CH), 123.5
(2CH), 123.2 (CH), 119.3 (d, JC−F = 8.2 Hz, C). 19F (376 MHz) δ:
−121.51 (t, JF−H = 6.7 Hz). IR (neat): 3000−2500 (br), 2817, 1688,
1608, 1577, 1461, 1409, 1278, 1232, 768, 681 cm−1. HRMS (CI) calcd
for C13H10FN2O2, [M+H]+ 245.0726; found, 245.0729.
3-((2-Carboxyphenyl)diazenyl)-2-fluorobenzoic Acid (31). Mp
1
237−239 °C (degradation). H NMR (400 MHz, CD3OD) δ: 8.10
(ddd, J = 8.0 Hz, JH−F = 6.6 Hz, J = 1.8 Hz, 1H), 7.92 (ddd, J = 8.2 Hz,
JH−F = 6.6 Hz, J = 1.8 Hz, 1H), 7.88 (d, J = 8.0 Hz, 1H), 7.69−7.65
(m, 2H), 7.62−7.58 (m, 1H), 7.36 (td, J = 8.0 Hz, J = 1.0 Hz, 1H). 13C
NMR (100 MHz, CD3OD) δ: 170.5 (C), 166.6 (d, JC−F = 2.5 Hz, C),
160.7 (d, JC−F = 276.2 Hz, C), 152.8 (C), 142.7 (d, JC−F = 7.4 Hz, C),
136.2 (CH), 133.1 (CH), 132.0 (CH), 131.6 (C), 130.9 (CH), 125.2
(d, JC−F = 5.0 Hz, CH), 123.4 (CH), 122.4 (d, JC−F = 8.9 Hz, C), 119.2
(CH). 19F (376 MHz, CD3OD) δ: −123.57 (t, JF−H = 6.6 Hz). IR
(neat): 3100−2500 (br), 2817, 1712, 1692, 1607, 1578, 1457, 1413,
1285, 1230, 757, 682 cm−1. HRMS (FI) calcd for C14H9FN2O4, [M]+
288.0546; found, 288.0559.
ASSOCIATED CONTENT
■
S
* Supporting Information
7.59 (td, J = 8.1 Hz, JH−F = 5.6 Hz, 1H), 7.52−7.48 (m, 3H), 7.31
(ddd, JH−F = 9.2 Hz, J = 8.1 Hz, J = 0.8 Hz, 1H). 13C NMR (100
MHz) δ: 168.1 (C), 160.8 (d, JC−F = 253.8 Hz, C), 152.0 (C), 150.8
(d, JC−F = 2.1 Hz, C), 132.6 (CH), 132.4 (d, JC−F = 9.2 Hz, CH), 129.5
Details of compound characterization. This material is available
free of charge via the Internet at http://pubs.acs.org.
(2CH), 123.6 (2CH), 118.7 (d, JC−F = 22.0 Hz, CH), 117.8 (d, JC−F
=
AUTHOR INFORMATION
15.4 Hz, C), 115.6 (d, JC−F = 3.3 Hz, CH). 19F (376 MHz) δ: −123.57
(bs). IR (neat): 3000−2500 (br), 2802, 1687, 1615, 1575, 1460, 1294,
1244, 797, 683 cm−1. HRMS (TOF MS CI) calcd for C13H10FN2O2,
[M+H]+ 245.0726; found, 245.0718.
■
Corresponding Author
*Fax: +33 243 83 39 02. E-mail: jacques.mortier@univ-lemans.
fr.
2-Fluoro-4-(phenyldiazenyl)benzoic acid (28). Mp 216−218 °C.
Notes
1H NMR (400 MHz, acetone-d6) δ: 8.19 (dd, J = 8.1 Hz, JH−F = 8.0
The authors declare no competing financial interest.
Hz, 1H), 8.02−7.94 (m, 2H) 7.87 (ddd, J = 8.1 Hz, J = 1.7 Hz, JH−F
=
0.4 Hz, 1H), 7.72 (dd, JH−F = 11.6 Hz, J = 1.7 Hz, 1H), 7.65−7.62 (m,
3H). 13C NMR (100 MHz, acetone-d6) δ: 164.7 (d, JC−F = 3.5 Hz, C),
163.3 (d, JC−F = 258.4 Hz, C), 157.2 (d, JC−F = 7.6 Hz, C), 153.2 (C),
134.2 (d, JC−F = 1.6 Hz, CH), 133.3 (CH), 130.4 (2CH), 124.1
(2CH), 121.6 (d, JC−F = 11.3 Hz, C), 120.2 (d, JC−F = 3.6 Hz, CH),
110.4 (d, JC−F = 24.3 Hz, CH). 19F (376 MHz, acetone-d6) δ: −109.78
(dd, JF−H = 11.6 Hz, JF−H = 8.0 Hz). IR (neat): 3000−2500 (br), 2817,
1682, 1613, 1575, 1447, 1295, 1280, 778, 688 cm−1. HRMS (TOF MS
CI) calcd for C13H10FN2O2, [M+H]+ 245.0726; found, 245.0729.
2-(Diethylcarbamoyl)-4-(phenyldiazenyl)benzoic Acid (29) (Entry
7). According to the general procedure, N,N-diethyl-3-
(phenyldiazenyl)benzamide (19) (282 mg, 1 mmol) in THF (10
mL) was added dropwise to a THF solution of LTMP (5 mmol) at
−78 °C. The resulting mixture was stirred at this temperature for 2 h
and poured onto dry ice. Standard workup and purification by
recrystallization (ethylacetate) gave 29 as a red solid (214 mg, 66%).
ACKNOWLEDGMENTS
■
This research was supported by CNRS and Universite
Maine. E.B. would like to thank CNRS for a postdoctoral
fellowship and T.T.T.N. a grant from the Ministry of Education
́
du
and Training of the Socialist Republic of Viet
express appreciation to Amelie Durand, Patricia Gangnery, and
Frederic Legros (Universite du Maine) for technical assistance.
̂
Nam. We also
́
́
́
́
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