Regioselectivities in deprotonation of 2-(4-chloro-2-pyridyl)benzoic acid and corresponding ester and amide

Article abstract of DOI:10.1016/j.tet.2004.01.050

Upon treatment of ethyl 2-(4-chloro-2-pyridyl)benzoic acid, 2-(4-chloro-2-pyridyl)benzoate, and N,N-diisopropyl-2-(4-chloro-2-pyridyl) benzamide with LTMP at -75°C in THF, the lithio derivatives at C5′ are generated regiospecifically, as demonstrated by subsequent quenching with electrophiles. The lithio derivative at C3′ is only evidenced from the benzamide at higher temperature (-50°C), when treated with LTMP in THF; it instantly cyclizes to 1-chloro-4-azafluorenone. The latter is converted to onychine, an alkaloid endowed with anticandidal activity.

Full text of DOI:10.1016/j.tet.2004.01.050

Tetrahedron 60 (2004) 2181–2186
Regioselectivities in deprotonation of 2-(4-chloro-2-
pyridyl)benzoic acid and corresponding ester and amide
*
Anne-Sophie Rebstock, Florence Mongin, Franc¸ois Trecourt and Guy Queguiner
´
´
´ ´
Laboratoire de Chimie Organique Fine et Heterocyclique, UMR 6014, IRCOF, Place E. Blondel, BP 08, 76131 Mont-Saint-Aignan
Cedex, France
Received 20 November 2003; revised 19 January 2004; accepted 21 January 2004
Abstract—Upon treatment of ethyl 2-(4-chloro-2-pyridyl)benzoic acid, 2-(4-chloro-2-pyridyl)benzoate, and N,N-diisopropyl-2-(4-chloro-2-
pyridyl)benzamide with LTMP at 275 8C in THF, the lithio derivatives at C50 are generated regiospecifically, as demonstrated by subsequent
quenching with electrophiles. The lithio derivative at C30 is only evidenced from the benzamide at higher temperature (250 8C), when
treated with LTMP in THF; it instantly cyclizes to 1-chloro-4-azafluorenone. The latter is converted to onychine, an alkaloid endowed with
anticandidal activity.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
4-chloro-2-iodopyridine6 or 2-bromo-4-methylpyridine,
respectively, using previously reported conditions.5
Hydrolyses of the esters allowed the acids 3 and 4 to be
obtained (Scheme 2).
Directed ortho-metallation (DoM) plays an important role
in the modern organic synthesis.1,2 Despite the maturity
long since gained by the method, the way a substituent acts
in its vicinity remains incompletely understood.
The N,N-diisopropyl-2-(2-pyridyl)benzamides 5 and 6 were
synthesized from 2-(diisopropylaminocarbonyl)phenyl-
boronic acid7 and 4-chloro-2-iodopyridine6 or 2-chloro-4-
methylpyridine, respectively, under Suzuki’s conditions8
(Scheme 3).
From all the directing groups, the carboxylic acid and
derived functions stand out as particularly useful for
subsequent elaborations. In the p-deficient aza-aromatic
series, lithium pyridinecarboxylates, pyridineoxazolines
and pyridinecarboxamides have been deprotonated at ring
positions adjacent to the DMG.2 Moreover, studies concern
the deprotonation of a pyridine ring followed by in situ
condensation with remote N,N-dialkylcarboxamide,3 ester4
or lithium carboxylate groups.4b
Deprotonation of the substrates 1, 3 and 5 was then
considered.
A survey of the literature revealed that LTMP was capable
of deprotonate ethyl benzoate at the ortho position while
LDA was found to react with the function.5 We thus decided
to examine the behavior of ethyl 2-(4-chloro-2-pyridyl)-
benzoate (1), carrying out the reaction with LTMP.
We here describe the unprecedented behavior of 2-(4-
chloro-2-pyridyl)benzoic acid, its corresponding ethyl ester
and N,N-diisopropyl amide, when compared to their non-
chlorinated analogues (Scheme 1).
The ester 1 could be easily deprotonated at C50 using
2 equiv. of LTMP in THF at 275 8C, and the lithio
intermediate trapped with D2O, ortho-tolualdehyde or
chlorotrimethylsilane to give the compounds 7a–c in
good yields (Scheme 4). Note that the lithio derivative
thus obtained does not react intermolecularly with the ester
function under the conditions used.
2. Results and discussion
The starting biaryl substrates were synthesized by cross-
coupling reactions. The substituted ethyl 2-(2-pyridyl)-
benzoates 1 and 2 were prepared by reactions between ethyl
2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)benzoate5 and
Interestingly, the position 50 is regioselectively deproto-
nated.9 The deprotonation is directed by the0chloro group,
which acidifies the hydrogens at C30 and C5 , and exerts a
stabilizing effect on the lithio derivative. Studies have
shown that coordination of a lithium dialkylamide by an
Keywords: Metallation; Pyridines; Mechanism; Onychine.
*
Corresponding author. Tel.: þ33-2-35-52-24-82; fax: þ33-2-35-52-29-
62; e-mail address: florence.mongin@insa-rouen.fr
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.01.050

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A.-S. Rebstock et al. / Tetrahedron 60 (2004) 2181–2186
Scheme 1.
Scheme 2.
Scheme 3.
ester function was unlikely.10 Moreover, one can hardly
expect the ester function to stabilize a lithio derivative at C300
through chelation. A more acidic hydrogen at C5
(determined by molecular simulations) or/and the steric
hindrance encountered by the base to deprotonate at C30
could be invoked to justify this result.
the most stable (less basic) carbanion (chelation to the
carboxylate)13 could be put forward to explain the results
observed in the reported examples. Attempts to detect
complexation between the lithium carboxylate of 3 and
LTMP in THF using the in situ infrared spectroscopy14 only
suggested that equilibria15 between different aggregation
states (monomers, dimers, tetramers…) were not affected by
the addition of the base.
We recently described pyridine rings metallation examples
and subsequent cyclization using a remote lithium carboxyl-
ate unit.4b 2-(4-Chloro-2-pyridyl)benzoic acid (3) was
involved in the reaction with LTMP, under the conditions
used for the de0protonation of the ester 1. The reaction also
occurred at C5 , as demonstrated by deuteriolysis (Scheme
5). Conducting the reaction at higher temperatures only led
to degradation compounds.
Since various examples11 demonstrate dominance of a CIPE
process in the lithiation reactions with alkyllithiums, the
deprotonation of 3 was attempted using BuLi in THF at low
temperature (275 8C): under these metallation non-revers-
ible conditions, butylated products formed were
accompanied by a significant amount of 8, showing the
CIPE is not strong enough to counterbalance steric and/or
hydrogens acidity-based effects.
A complex-induced proximity effect (CIPE)11 is rarely cited
to rationalize the regioselectivities of deprotonation reac-
tions using LTMP;12 a thermodynamic control leading to
We then turned to the metallation of the benzamide 5.
Studies concern the deprotonation of phenylpyridines on the
nitrogenous ring, followed by in situ intramolecular
condensation with N,N-dialkylcarboxamide functions
Scheme 4.
Scheme 5.

A.-S. Rebstock et al. / Tetrahedron 60 (2004) 2181–2186
2183
borne by the phenyl group.3 We wondered whether N,N-
diisopropyl-2-(4-chloro-2-pyridyl)benzamide (5) could be
submitted to such a reaction.
The ester 1 and the acid 3 either remained unchanged or
underwent degradation reactions on exposure to LTMP at
higher temperatures. Attempts to shorten the synthesis of
onychine (11) using the methylated substrates 2, 4 and 6 in
the reaction with LTMP only evidenced deprotonation of
the methyl group.22
Attempts to detect complexation between the amide
function of free N,N-diisopropylbenzamide and LTMP in
THF using the in situ infrared spectroscopy14 only
evidenced a quick deprotonation of the substrate at
275 8C.16 When the amide 5 was submitted to 4 equiv.17
of LTMP in THF at 275 8C, deprotonation occurred once
again at C50, as demonstrated by deuteriolysis. Attempts to
trap lithio derivatives in other positions, e.g. using in situ
quenching with chlorotrimethylsilane,18 0failed: the first
lithio derivative formed seems to be at C5 (Scheme 6).
3. Conclusion
At low temperature (275 8C), LTMP in THF promotes an
exclusive regioselective metallation of 2-(4-chloro-2-pyr-
idyl)benzoic acid (3), ethyl 2-(4-chloro-2-pyridyl)benzoate
(1), and 0N,N-diisopropyl-2-(4-chloro-2-pyridyl)benzamide
(5) at C5 , a position close to the chloro group but far from
the carbonyl function. This demonstrates that the CIPE, if
exists in this case, is not strong enough to counterbalance
steric and/or hydrogens acidity-based effects. At higher
temperatures, in the case of the amide 5 but also in the
previously reported syntheses of azafluorenones,3 the N,N-
dialkylcarboxamide functions behave like an in situ trap for
the remote lithio derivative. The methodology here led to
onychine in three steps and 30% overall yield from 4-
chloro-2-iodopyridine.6 Several approaches have been
previously developed.23 As in the Parham cyclization
strategy through bromine-lithium exchange,24 the lithio
derivative formed reacts with a remote carbonyl group.
Nevertheless, even if the yields are comparable, the lithio
derivative results in our case from deprotonation, avoiding
the presence of a bromine atom. This short and regioselec-
tive method is attractive, when compared with the
previously reported syntheses.23
Scheme 6.
On the other hand, when the amide 5 was added to a solution
of LTMP (2 equiv.) in THF at higher temperature (250 8C),
the ketone 10 was obtained in 66% yield, the rest being
deuterated compound 9a.
4. Experimental
4.1. General
Cross-coupling19 of the chloride 10 with methylboronic acid
under palladium catalysis further allowed a new synthesis of
onychine (11), an alkaloid endowed with anticandidal
activity20 (Scheme 7).
1
The H NMR and 13C NMR spectra were recorded with a
300 MHz spectrometer. THF and dioxane were distilled
from benzophenone/Na. The water content of the solvents
Scheme 7.
Thus, at a higher temperature, the remote N,N-diisopropyl-
carboxamide group behaves like an in situ trap for the
3-lithiopyridine formed21 through the following equilibrium
(Scheme 8):
was estimated to be lower than 45 ppm by the modified Karl
Fischer method.25 Metallation and cross-coupling reactions
were carried out under dry argon. Deuterium incorporation
was determined from the 1H NMR integration values. After
Scheme 8.

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A.-S. Rebstock et al. / Tetrahedron 60 (2004) 2181–2186
the reaction, hydrolysis, and neutralization, the aqueous
solution was extracted several times with CH2Cl2. The
organic layer was dried over Na2SO4, the solvents were
evaporated under reduced pressure, and unless otherwise
noted, the crude compound was chromatographed on a
silica gel column (the eluent is given in the product
description).
4.5. 2-(4-Methyl-2-pyridyl)benzoic acid (4)
The procedure described above, using the ester 2 (0.24 g,
1.0 mmol) instead of the ester 1, gave 48% of 4: mp 170–
171 8C (dec.); 1H NMR (DMSO-d6) d 2.58 (s, 3H), 7.61 (d,
1H, J¼7.5 Hz), 7.71 (d, 1H, J¼7.5 Hz), 7.8 (m, 2H), 7.87 (s,
1H), 8.06 (d, 1H, J¼7.1 Hz), 8.71 (d, 1H, J¼5.6 Hz); 13C
NMR (DMSO-d6) d 21.8, 125.9, 127.3, 130.8, 131.1, 131.2,
131.5, 132.6, 134.4, 134.5, 142.0, 153.8, 167.4; IR (KBr) n
3386, 3061, 2449, 1954, 1702, 1612, 1315, 1278, 1142,
1048, 1017, 773, 747, 545. Anal. calcd for C13H11NO2
(213.24): C, 73.23; H, 5.20; N, 6.57. Found: C, 72.92; H,
4.90; N, 6.29%.
Starting materials. Pd(PPh3)4 was synthesized by a
literature method.26 4-Chloro-2-iodopyridine,6 2-(diisopro-
pylaminocarbonyl)phenylboronic acid7 and ethyl 2-(5,5-
dimethyl-1,3,2-dioxaborinan-2-yl)benzoate5 were prepared
according to literature procedures.
4.2. Ethyl 2-(4-chloro-2-pyridyl)benzoate (1)
4.6. N,N-Diisopropyl-2-(4-chloro-2-pyridyl)benzamide
(5)
A degassed mixture of 4-chloro-2-iodopyridine (0.29 g,
1.2 mmol), Pd(PPh3)4 (35 mg, 30 mmol), dioxane (10 mL),
ethyl 2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)benzoate
(0.26 g, 1.0 mmol), and K3PO4·3H2O (0.53 g, 2.0 mmol)
was heated at 100 8C for 18 h. The solvents were removed
under reduced pressure and water (10 mL) was added to
afford 76% of 1 (eluent: petrol/AcOEt 80:20): pale yellow
oil; 1H NMR (CDCl3) d 1.03 (t, 3H, J¼7.2 Hz), 4.09 (q, 2H,
J¼7.2 Hz), 7.20 (dd, 1H, J¼4.9, 1.6 Hz), 7.5 (m, 4H), 7.79
(d, 1H, J¼7.5 Hz), 8.46 (d, 1H, J¼5.6 Hz); 13C NMR
(CDCl3) d 14.3, 61.5, 122.7, 123.6, 129.2, 130.1, 130.4,
131.6, 132.0, 140.2, 144.5, 150.2, 160.8, 168.7; IR (KBr) n
3059, 2981, 2936, 1721, 1571, 1549. Anal. calcd for
C14H12ClNO2 (261.71): C, 64.25; H, 4.62; N, 5.35. Found:
C, 63.95; H, 4.49; N, 5.07%.
A degassed mixture of 4-chloro-2-iodopyridine (0.48 g,
2.0 mmol), K2CO3 (0.56 g, 4.0 mmol), water (2.0 mL),
EtOH (1.0 mL), toluene (20 mL), 2-(diisopropylamino-
carbonyl)phenylboronic acid (0.50 g, 2.0 mmol) and
Pd(PPh3)4 (70 mg, 60 mmol) was heated at reflux for 18 h
to afford 50% of 5 (eluent: CH2Cl2/Et2O 95:5): mp 100–
101 8C; 1H NMR (CDCl3) d 0.53 (d, 3H, J¼6.8 Hz), 0.88 (d,
3H, J¼6.8 Hz), 1.38 (d, 3H, J¼6.8 Hz), 1.46 (d, 3H,
J¼6.8 Hz), 3.26 (sept, 1H, J¼6.8 Hz), 3.51 (sept, 1H,
J¼6.8 Hz), 7.16 (dd, 1H, J¼5.3, 1.5 Hz), 7.22 (dd, 1H,
J¼4.9, 3.8 Hz), 7.3 (m, 2H), 7.63 (dd, 1H, J¼5.8, 2.8 Hz),
7.70 (d, 1H, J¼1.5 Hz), 8.45 (d, 1H, J¼5.3 Hz); 13C NMR
(CDCl3) d 19.9, 20.0, 20.9, 21.1, 46.0, 51.2, 122.5, 124.4,
126.7, 129.0, 129.6, 129.7, 135.9, 138.5, 144.7, 150.5,
159.0, 170.5; IR (KBr) n 2965, 2931, 1619, 1571, 1547,
1452, 1435, 1371, 1340, 783, 710. Anal. calcd for
C18H21ClN2O (316.83): C, 68.24; H, 6.68; N, 8.84.
Found: C, 67.93; H, 6.79; N, 8.78%.
4.3. Ethyl 2-(4-methyl-2-pyridyl)benzoate (2)
The procedure described above, using 2-bromo-4-methyl-
pyridine (0.31 g, 1.2 mmol) instead of 4-chloro-2-iodo-
pyridine, gave 66% of 2 (eluent: CH2Cl2/Et2O 90:10):
4.7. N,N-Diisopropyl-2-(4-methyl-2-pyridyl)benzamide
(6)
1
colorless oil; H NMR (CDCl3) d 0.97 (t, 3H, J¼7.2 Hz),
2.30 (s, 3H), 4.05 (q, 2H, J¼7.2 Hz), 6.98 (d,
1H, J¼4.9 Hz), 7.20 (s, 1H), 7.4 (m, 3H), 7.72 (d,
1H, J¼7.5 Hz), 8.39 (d, 1H, J¼5.2 Hz); 13C NMR
(CDCl3) d 14.2, 21.5, 61.3, 123.4, 124.0, 128.5, 130.0,
130.1, 131.3, 132.3, 141.4, 147.6, 149.2, 159.0, 169.3;
IR (KBr) n 3054, 2981, 2927, 1722, 1604, 1286, 1250,
775, 747, 450. Anal. calcd for C15H15NO2 (241.29): C,
74.67; H, 6.27; N, 5.80. Found: C, 74.37; H, 6.33; N,
6.08%.
The procedure described above, using 2-chloro-4-methyl-
pyridine (0.17 mL, 2.0 mmol) instead of 4-chloro-2-iodo-
pyridine, gave 42% of 6 (eluent: CH2Cl2/Et2O 85:15): mp
98–99 8C; 1H NMR (CDCl3) d 0.40 (d, 3H, J¼6.8 Hz), 0.84
(d, 3H, J¼6.8 Hz), 1.27 (d, 3H, J¼6.8 Hz), 1.46 (d, 3H,
J¼6.8 Hz), 2.27 (s, 3H), 3.22 (sept, 1H, J¼6.8 Hz), 3.50
(sept, 1H, J¼6.8 Hz), 6.98 (d, 1H, J¼4.5 Hz), 7.22 (d, 1H,
J¼6.8 Hz), 7.4 (m, 2H), 7.51 (s, 1H), 7.64 (d, 1H,
J¼7.5 Hz), 8.44 (d, 1H, J¼5.3 Hz); 13C NMR (CDCl3) d
19.3, 19.5, 20.5, 20.7, 45.3, 50.6, 123.3, 124.6, 126.2, 128.4,
128.6, 129.3, 136.9, 138.0, 147.1, 149.1, 156.9, 170.4; IR
(KBr) n 2968, 2931, 1628, 1604, 1436, 1370, 1339, 1212,
1033, 774, 742. Anal. calcd for C19H24N2O (296.42): C,
76.99; H, 8.16; N, 9.45. Found: C, 76.70; H, 8.24; N, 9.31%.
4.4. 2-(4-Chloro-2-pyridyl)benzoic acid (3)
A mixture of the ester 1 (0.26 g, 1.0 mmol) and NaOH
(0.10 g, 2.5 mmol) in water (1.0 mL) was heated under
reflux for 2 h. A 20% aqueous hydrochloric acid solution
was added until complete precipitation. The precipitate thus
obtained was recovered by filtration and dried under
vacuum to give 77% of 3: mp 134–135 8C (dec.); 1H
NMR (DMSO-d6) d 7.5 (m, 4H), 7.7 (m, 2H), 8.55 (d, 1H,
J¼5.3 Hz); 13C NMR (DMSO-d6) d 124.2, 124.7, 130.5,
130.7, 131.0, 131.8, 132.7, 139.5, 140.8, 141.0, 143.8,
152.0; IR (KBr) n 3071, 2777, 2455, 1699, 1581, 1552,
1386, 1275, 1142, 1010, 788, 770, 712. Anal. calcd for
C12H8ClNO2 (233.66): C, 61.69; H, 3.45; N, 5.99. Found: C,
61.38; H, 3.23; N, 5.69%.
4.8. Ethyl 2-(4-chloro-2-(5-D)pyridyl)benzoate (7a)
A solution of the ester 1 (0.10 g, 0.38 mmol) in THF (3 mL)
was added to a solution of LTMP (obtained by adding BuLi
(0.76 mmol) to a solution of 2,2,6,6-tetramethylpiperidine
(0.14 mL, 0.84 mmol) in THF (5 mL) at 0 8C( at 278 8C.
The mixture was stirred at 278 8C for 1 h before
deuteriolysis with D2O (0.5 mL) to afford 95% (100% d)
1
of 7a (eluent: petrol/AcOEt 80:20). The H and 13C NMR

A.-S. Rebstock et al. / Tetrahedron 60 (2004) 2181–2186
2185
data of this product showed the replacements of 50-H by 50-D,
and 50-CH by 50-CD, respectively.
adding BuLi (1.1 mmol) to a solution of 2,2,6,6-tetra-
methylpiperidine (0.20 mL, 1.2 mmol) in THF (5 mL) at
0 8C( at 278 8C. The mixture was stirred at 278 8C for 1.5 h
before deuteriolysis with D2O (0.5 mL) to afford 95%
4.9. Ethyl 2-(4-chloro-5-(hydroxy(2-methylphenyl)-
methyl)-2-pyridyl)benzoate (7b)
(100% d) of 9a (eluent: CH2Cl2/Et2O 95:5). The 1H and 13
C
NMR data of t0his product showed the replacements of 50-H
A solution of the ester 1 (0.30 g, 1.1 mmol) in THF (15 mL)
was added to a solution of LTMP (obtained by adding BuLi
(2.3 mmol) to a solution of 2,2,6,6-tetramethylpiperidine
(0.43 mL, 2.4 mmol) in THF (20 mL) at 0 8C (at 278 8C.
The mixture was stirred at 278 8C for 1 h before trapping
with 2-tolualdehyde (0.28 mL, 2.4 mmol), and hydrolysis
18 h later with H2O (5 mL) to afford 73% of 7b (eluent:
by 50-D, and 5 -CH by 50-CD, respectively.
4.13. N,N-Diisopropyl-2-(4-chloro-5-trimethylsilyl-2-
pyridyl)benzamide (9b)
To a mixture of the amide 5 (0.10 g, 0.28 mmol) and
ClSiMe3 (70 mL, 0.56 mmol) in THF (3 mL) at 278 8C was
added a solution of LTMP (obtained by adding BuLi
(0.56 mmol) to a solution of 2,2,6,6-tetramethylpiperidine
(98 mL, 0.59 mmol) in THF (5 mL) at 0 8C(. The mixture
was stirred at 278 8C for 1.5 h before hydrolysis with water
(5 mL) to afford 50% of 9b (eluent: CH2Cl2/Et2O 95:5): mp
105–106 8C; 1H NMR (CDCl3) d 0.34 (s, 9H), 0.58 (d, 3H,
J¼6.4 Hz), 0.91 (d, 3H, J¼6.4 Hz), 1.35 (d, 3H, J¼6.4 Hz),
1.47 (d, 3H, J¼6.4 Hz), 3.29 (sept, 1H, J¼6.4 Hz), 3.54
(sept, 1H, J¼6.4 Hz), 7.23 (m, 1H), 7.38 (m, 2H), 7.66 (m,
2H), 8.51 (s, 1H); 13C NMR (CDCl3) d 0.0, 20.5, 20.8, 21.7,
21.8, 46.7, 51.9, 125.1, 127.5, 129.7, 130.3, 130.4, 132.9,
136.6, 139.2, 152.3, 155.8, 160.0, 171.3; IR (KBr) n 2968,
2927, 1620, 1571, 1341, 1248, 861, 844, 758. Anal. calcd
for C21H29ClN2OSi (389.02): C, 64.84; H, 7.51; N, 7.20.
Found: C, 64.56; H, 7.57; N, 7.24%.
1
CH2Cl2/Et2O 90:10): yellow oil; H NMR (CDCl3) d 0.86
(t, 3H, J¼7.2 Hz), 2.11 (s, 3H), 3.54 (broad s, 1H), 1.94 (q,
2H, J¼7.2 Hz), 6.04 (s, 1H), 7.0 (m, 4H), 7.3 (m, 4H), 7.62
(d, 1H, J¼7.1 Hz), 8.42 (s, 1H); 13C NMR (CDCl3) d 14.2,
19.5, 61.5, 68.7, 123.8, 126.6, 127.0, 128.4, 129.2, 130.2,
130.4, 131.0, 131.7, 131.9, 135.2, 136.3, 139.6, 139.6,
143.2, 149.5, 159.1, 168.8; IR (KBr) n 3377, 2981, 1720,
1584, 1286, 1261, 756. Anal. calcd for C22H20ClNO3
(381.86): C, 69.20; H, 5.28; N, 3.67. Found: C, 68.89; H,
5.27; N, 3.58%.
4.10. Ethyl 2-(4-chloro-5-trimethylsilyl-2-pyridyl)-
benzoate (7c)
A solution of the ester 1 (0.10 g, 0.38 mmol) in THF (3 mL)
was added to a solution of LTMP (obtained by adding BuLi
(0.76 mmol) to a solution of 2,2,6,6-tetramethylpiperidine
(0.14 mL, 0.80 mmol) in THF (5 mL) at 0 8C( at 278 8C.
The mixture was stirred at 278 8C for 1 h before quenching
with ClSiMe3 (96 mL, 0.76 mmol) and, 1.5 h later,
hydrolysis with water (5 mL) to afford 78% of 7c (eluent:
4.14. 1-Chloro-4-azafluorenone (10)
A solution of the amide 5 (0.10 g, 0.28 mmol) in THF
(3 mL) was added to a solution of LTMP (obtained by
adding BuLi (0.56 mmol) to a solution of 2,2,6,6-tetra-
methylpiperidine (99 mL, 0.59 mmol) in THF (5 mL) at
0 8C( at 250 8C. The mixture was stirred at 250 8C for 1.5 h
before hydrolysis with water (5 mL) to afford 66% of 10
(eluent: CH2Cl2): mp 167–168 8C; 1H NMR (CDCl3) d 7.10
(d, 1H, J¼5.6 Hz), 7.42 (t, 1H, J¼7.3 Hz), 7.56 (t, 1H,
J¼7.5 Hz), 7.70 (d, 1H, J¼7.1 Hz), 7.80 (d, 1H, J¼7.5 Hz),
8.40 (d, 1H, J¼5.6 Hz); 13C NMR (CDCl3) d 106.6, 121.7,
124.8, 125.4, 132.0, 135.8, 139.2, 142.2, 154.4, 155.0,
159.5, 200.2; IR (KBr) n 2924, 1722, 1606, 1573, 1558,
1449, 1172, 919, 819, 746. Anal. calcd for C12H6ClNO
(215.64): C, 66.84; H, 2.80; N, 6.50. Found: C, 66.52; H,
2.94; N, 6.22%.
1
petrol/AcOEt 90:10): yellow oil; H NMR (CDCl3) d 0.37
(s, 9H), 1.07 (t, 3H, J¼7.2 Hz), 4.12 (q, 2H, J¼7.2 Hz), 7.38
(s, 1H), 7.5 (m, 3H), 7.79 (d, 1H, J¼7.5 Hz), 8.51 (s, 1H);
13C NMR (CDCl3) d 0.0, 14.8, 62.1, 124.5, 129.8, 130.7,
131.0, 132.3, 132.6, 140.8, 151.8, 155.6, 161.7, 169.4; IR
(KBr) n 2957, 2900, 1725, 1568, 1284, 1252, 1129, 1097,
1056, 844, 763. Anal. calcd for C17H20ClNO2Si (333.89): C,
61.15; H, 6.04; N, 4.19. Found: C, 61.16; H, 6.11; N, 4.21%.
4.11. 2-(4-Chloro-2-(5-D)pyridyl)benzoic acid (8)
A solution of the acid 3 (0.10 g, 0.43 mmol) in THF
(2 mL) was added to a solution of LTMP (obtained by
adding BuLi (1.1 mmol) to a solution of 2,2,6,6-
tetramethylpiperidine (0.20 mL, 1.2 mmol) in THF
(5 mL) at 0 8C (at 278 8C. The mixture was stirred at
278 8C for 1 h before deuteriolysis with D2O (0.5 mL).
After evaporation, a 20% aq. hydrochloric acid solution
was added until complete precipitation. The precipitate
thus obtained was recovered by filtration and dried under
4.15. 1-Methyl-4-azafluorenone (11)
A suspension of methylboronic acid (30 mg, 0.50 mmol),
K2CO3 (0.21 g, 1.5 mmol), Pd(PPh3)4 (58 mg, 50 mmol),
and the azafluorenone 10 (0.12 g, 0.55 mmol) in dioxane
(5 mL) was stirred at reflux temperature for 18 h to afford
96% of 11 (eluent: petrol/CH2Cl2 80:20): mp 128–129 8C
(lit.23j mp 127–129 8C). The spectral data of compound 11
are in agreement with those already described.23j
1
vacuum to afford 95% (100% d) of 8. The H and 13C
NMR data of this product showed the replacements of
50-H by 50-D, and 50-CH by 50-CD, respectively.
4.12. N,N-Diisopropyl-2-(4-chloro-2-(5-D)pyridyl)-
benzamide (9a)
References and notes
A solution of the amide 5 (0.10 g, 0.28 mmol) in THF
(3 mL) was added to a solution of LTMP (obtained by
1. The concept emerged from the systematic studies of Gilman,
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2186
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reversible initial complexation between the substrate and the
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17. In situ infrared spectroscopy showed incomplete deprotona-
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´
2. In the p-deficient azaaromatics series, see: (a) Queguiner, G.;
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