Synthesis of chiral ferrocenylazines. Negishi cross-coupling or S N H reactions?

Article abstract of DOI:10.1134/S1070428013080150

Preparation of new hetaryl-containing planar chiral ferrocene by a nucleophilic substitution of hydrogen in azines was performed using a lithium derivative of (S)-ferrocenyl-p-tolylsulfoxide as s nucleophilic reagent

Full text of DOI:10.1134/S1070428013080150

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2013, Vol. 49, No. 8, pp. 1191−1194. © Pleiades Publishing, Ltd., 2013.
Original English Text © A.A. Musikhina, I.A. Utepova, P.O. Serebrennikova, O.N. Chupakhin, V.N. Charushin, 2013, published in Zhurnal Organicheskoi
Khimii, 2013, Vol. 49, No. 8, pp. 1207−1210.
Synthesis of Chiral Ferrocenylazines.
Negishi Cross-Coupling or SNH Reactions?
A. A. Musikhinaa,b, I. A. Utepovaa,b, P. O. Serebrennikovaa,b,
O. N. Chupakhina,b, and V. N. Charushina,b
aUral Federal University, Yekaterinburg, 620002 Russia
e-mail: chupakhin@ios.uran.ru
bInstitute of Organic Synthesis, Ural Branch of Russian Academy of Sciences, Yekaterinburg, Russia
Received April 10, 2013
Abstract—Preparation of new hetaryl-containing planar chiral ferrocene by a nucleophilic substitution of hydrogen
in azines was performed using a lithium derivative of (S)-ferrocenyl-p-tolylsulfoxide as s nucleophilic reagent
DOI: 10.1134/S1070428013080150
Planar chiral ferrocene derivatives are extensively
used as ligands in versatile reactions of asymmetric
synthesis [1–10]. An important place among the ligands
of the ferroce series belongs to heterocyclic derivatives
capable of forming complexes with metals and also with
charged and neutral molecules [1, 11].
lone electron pair in the directing group, and to the spatial
orientation of the substituent at the asymmetric center
of the side chain of the ferrocene scaffold (compound
B, Scheme 2).
In most cases hetarylferrocenes, also the optically ac-
tive ones, are prepared by cross-coupling catalyzed with
transition metals [1, 11, 16]. At the same time the direct
С–С and C–X couplings (X = N, O, S, P) are known of
nucleophilic reagents with azines, the reactions of direct
nucleophilic aromatic substitution of hydrogen (SNH reac-
tion) providing the possibility to functionalize the bonds
Quite a number [12–17] of compounds is known con-
taining chiral groups, among them sulfoxide I (Scheme 1)
[18]. The presence in the ferrocene structure of directing
the 1,2-lithiation chiral moieties plays a decisive role in
attaining both regio- and diastereoselectivity owing to the
formation of cyclic structures in the intermediate metal
derivatives (Complex Induced Proximity Effect, CIPE)
[19, 20] due to the coordination of the lithium atom by the
2
Csp –Н in (hetero)arenes [21, 22]. We formerly showed
the efficiency of the SNH reaction in the direct coupling
of lithium derivatives of ferrocene and cymantrene with
Scheme 1.
N
Br
II
O
O
Br
O
S
N
Zn
5 mol% Pd(dba)2,
10 mol% P(Ph)3
S
S
i
Fe
Fe
Fe
ii
THF, 60oC, 20 h
CH3
CH3
CH3
III
А
I
(i) LDA, THF, –78°С, 30 min; (ii) ZnBr2, THF, –78°С, 60 min.
1191

MUSIKHINA et al.
1192
Scheme 2.
O
N
N
O
O
S
O
Li
Li
H
S
H
N
H
S
S
IV
H2O
THF, LDA
_78oC
CH3
Fe
Fe
Fe
Fe
_78oC
CH3
CH3
CH3
I
C
D
B
N
N
N
N
O
Air
S
PPh2
Li
PPh2
.
PhLi, THF_Et2O
_78oC
oxygen
PPh2Cl BH3
_78oC
BH3
NHEt2
50oC
Fe
Fe
Fe
Fe
_H2O
CH3
V
VI
VII
E
H
presumable that the formation of compound V proceeds
according to the scheme generally accepted for the SN
azines [23–25]. To the best of our knowledge the SN
H
reaction was not used as the key stage in the synthesis of
reaction [21, 22]: the addition of the lithium derivative
B to the azine with the formation of σН-adducts C, their
hydrolysis to dihydrocompounds D, and fast spontaneous
aromatization of dihydroazines D to the reaction products
V under the oxidative action of the air oxygen (Scheme 2).
chiral P,N-ligands.
In this report we show by an example of (quinolin-
2-yl)-containing ferrocene P,N-ligand that the SN pro-
cedure can be applied to the preparation of planar chiral
compounds.
H
Sulfoxide I we prepared by an improved method react-
ing ferrocenelithium with (S)-(–)-menthyl-p-tolylsulfinate
at –78°С. The process proceeds stereoselectively with the
formation of S-isomer in a good yield (80%).
In [18] (Scheme 1) a five-stage synthesis was de-
scribed of a ligand (SFc,S)-[2-(quinolin-8-yl)ferrocene-
1-yl]-p-tolylsulfoxide (III) using as the initial reagent
sulfoxide I [26] that was subjected to lithiation (i), then
to transmetallation into Zn-derivative А (ii), and to
palladium-catalyzed cross-coupling with 8-bromoquino-
line by Negishi reaction to obtain finally compound III,
whose p-tolyl sulfoxide group was replaced by a diphe-
nylphosphine residue.
We showed that the application of the SNH procedure
made it possible to introduce directly a quinoline residue
into compound B (Scheme 2). This approach has a number
of advantages: It permits avoiding the use of quinoline
haloderivatives, does not require the application of pal-
ladium salts and of the accompanying ligands, reduces
the number of stages. The overall yield with respect to
compound I along our protocol reached 50.4% (28.5%
[18]).
The exchange of the functional group sulfoxide–
lithium in hetarylsulfoxide V and the subsequent intro-
duction of the diphenylphosphine fragment afforded a
P,N-ligand, (SFс,S)-[2-(quinolin-2-yl)-ferrocene-1-yl]
diphenylphosphine (VII). Thus at –78°С in anhydrous
THF PhLi reacts with derivative V giving within 10 min
1-lithium-2-hetarylferrocene E that with PPh2Cl·BH3
furnishes a stable against the air and moisture borane
complex VI (Scheme 2). Complex VI was subjected to
column chromatography on SiO2. The removal of the
borane protection occurs readily at heating compound VI
in diethylamine in a quantative yield [27]. Compound VI
was isolated in 72% yield. The de value for compounds
V, VI was >99%.
The assumed structure of 1,2-disubstituted
hetarylferrocenes is in agreement with the data of H
and 13С NMR, IR, and mass spectra; the composition is
Compound B readily enters into the direct coupling
reaction with quinoline (IV) affording the corresponding
planar chiral derivative V at –78°С within 30 min. It is
1
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 49 No. 8 2013

SYNTHESIS OF CHIRAL FERROCENYLAZINES.
1193
consistent with the elemental analysis data. The optical
purity of the derivatives was determined by HPLC on
a column with an optically active adsorbent Chiralcel
OD-Н.
Hence the SNH procedure that we applied for the first
time to the synthesis of chiral ensembles ferrocene–azine
made it possible to simplify their synthesis. We believe
that the above described metal noncatalyzed SNH cross-
coupling possesses a general character.
sulfoxide I in 5 ml of THF under an argon atmosphere
at –78°C was added 0.55 ml (1.1 mmol) of 2 M of LDA
solution in THF. After 40 min of vigorous stirring was
added a solution of 0.26 ml (2.0 mmol) of quinoline (IV)
in 7 ml of THF. The reaction mixture was stirred for
30 min at –78°C, then it was gradually warmed to room
temperature. The solution was concentrated at a reduced
pressure. The residue obtained was chromatographed
on SiO2, eluent hexane–ethyl acetate, 8:2 (Rf 0.2).
Yield 0.316 g (70%), dark red crystals, mp 104°С, [α]
EXPERIMENTAL
+188.08o (c 0.1 CHCl3). IR spectrum, ν, cm–1: 2920,
D
1
2850, 1597, 1041, 1004. Н NMR spectrum, δ, ppm:
1H (400 MHz), 13С (100 MHz), and 31P (162 MHz)
NMR spectra were registered on a spectrometer Bruker
Avance II (400 MHz) from solutions in CDCl3. Chemical
shifts are reported from internal reference SiMe4. The as-
signment of 1Н and 13С signals was performed with the
help of a combination of 2D heteronuclear experiments
1H–13C HSQC and 1H–13C HMBC. IR spectra were re-
corded on an IR Fourier spectrophotometer BrukerAlpha
equipped with a device for measuring incomplete internal
reflection. Mass spectra were taken on an instrument
MicrOTOF-Q II Bruker Daltonics. Elemental analysis
was carried out on an analyzer Perkin Elmer 2400-II,
HPLC analysis, on a chromatograph Merck Hitachi (col-
umn DIACELChiralcel OD-H). The rotation angles were
measured on a spectrophotopolarimeter Perkin Elmer 343
Plus. The solvents were purified and dried by standard
procedures. In the study were used commercial reagents
quinoline, (S)-(–)-menthyl p-tolylsulfinate, BuLi, LDA,
PhLi, THF purchased from Sigma-Aldrich, all other re-
agents and solvents were obtained from Khimreaktivsnab.
Bromoferrocene [28], Ph2PCl·BH3 [18] were synthesized
by published methods. The properties of compounds
coincide with the published data [18, 28].
(S)-Ferrocenyl-p-tolylsulfoxide (I). To a solution
of 0.265 g (1 mmol) of bromoferrocene in 6 ml of THF
under an argon atmosphere at room temperature was
added 0.63 ml (1 mmol) of 1.6 M solution of BuLi in
hexane, and the mixture was kept for 20 min. Then to
the reaction mixture was added 0.325 g (1.1 mmol) of
(1R,2S,5R)-(–)-menthyl-(S)-p-toluenesulfinate in 15 ml
THF, the mixture was cooled to –78°С and maintained for
30 min. The reaction products were isolated by column
chromatography, eluent hexane–ethyl acetate, 7:3 (Rf 0.3).
Yield 0.217 g (67%), yellow powder. The properties of
compound I are consistent with the published data [26].
(SFс,S)-[2-(Quinolin-2-yl)ferrocen-1-yl]-p-tolyl-
sulfoxide (V). To a solution of 0.324 g (1 mmol) of
2.37 s (3Н, CH3), 4.18 s (5Н, Cp), 4.39 br.s (1Н, C5H3),
4.57 br.s (1Н, C5H3), 5.25 br.s (1Н, C5H3), 7.26 t (2Н,
C6H4, J 7.4 Hz), 7.51 t (1Н, H4', J 7.0 Hz), 7.68 d (1Н,
H7', J 8.0 Hz), 7.71 d (2Н, C6H4, J 4.0 Hz), 7.78 d (1Н,
H6', J 7.8 Hz), 8.09 s (2Н, H5', H8'), 8.12 d (1Н, H3',
J 8.68 Hz). 13С NMR spectrum, δ, ppm: 21.50 (CH3),
70.38 (C5H3), 71.49 (Cp), 71.85 (C5H3), 72.62 (C5H3),
85.37 (C–Cp), 94.54 (C–Cp), 121.53 (C6H4), 125.62 (С8),
125.71 (C7), 126.99 (C4), 127.53 (C6), 129.33, 129.48
(C6H4), 129.53 (C5), 135.71 (C3), 140.95 (C8a), 141.42
(C6H4), 148.05 (C4a), 157.26 (C2). Mass spectrum, m/z
(Irel., %): 452.07 (100) [M + H]+. Found, %: C 68.52;
H 4.98; N 2.99. C26H21FeNOS. Calculated, %: С 69.18;
H 4.66; N 3.10. M 451.36.
(SFс,S)-[2-(Quinolin-2-yl)ferrocene-1-yl]
diphenylphosphine·BH3 (VI). To a solution of 0.451 g
(1 mmol) of quinolinylferrocenyl p-tolyl sulfoxide (V)
in 5 ml of THF under an argon atmosphere at –78°C was
added 1.1 ml (2.0 mmol) of 1.8 M solution of PhLi in
dibutyl ether. After 10 min of vigorous stirring at –78°C
was added 3.0 mmol of Ph2PCl·BH3. The reaction mix-
ture was kept for 5 min at –78°C, then it was gradually
warmed to room temperature. On the completion of the
reaction was added 0.5 ml of water and 0.15 ml of tri-
ethylamine, and the mixture was stirred for 5 min. The
solution was concentrated at a reduced pressure. The
residue obtained was chromatographed on SiO2, eluent
hexane–ethyl acetate, 8 : 2 (Rf 0.4). Yield 0.368 g (72%),
dark red crystals, mp 142°С, [α]D +305o (c 0.1 CHCl3).
IR spectrum, ν, cm–1: 2963, 2380, 2343, 1099, 1056,
1016, 797. 1Н NMR spectrum, δ, ppm: 1.25 s (3Н, ВH3),
3.93 s (1Н, C5H3), 4.49 s (5Н, CрН), 4.59 s (1Н, C5H3),
5.12 s (1Н, C5H3), 7.28–7.32 m (2Н, Ph), 7.38–7.53 m
(5Н, Ph), 7.56–7.65 m (3Н, Ph), 7.67 s (1Н, H4'), 7.70 d
(2Н, H6', H7', J 4.0 Hz), 7.72 s (1Н, H5'), 7.74 s (1Н, H8'),
7.94 d (1Н, H3', J 8.0 Hz). 13С NMR spectrum, δ, ppm:
71.42 (C5H3), 71.58 (C5H3), 73.78 (Cp), 76.84 (C5H3),
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 49 No. 8 2013

MUSIKHINA et al.
1194
89.88 (C–Cp), 89.96 (C–Cp), 120.71 (C4), 125.92,
126.69, 127.30, 128.01, 128.11, 128.21 (Ph), 128.30 (C8),
128.97 (C8а), 129.39 (C6), 131.40 (C5), 132.81, 132.90
(Ph) 133.40 (C7), 135.34 (C3), 147.18 (C4a), 156.17 (C2).
31PNMR spectrum, δ, ppm: 29.85 (PPh2). Mass spectrum,
m/z (Iоtн.,%): 512.13 (25) [M + H]+, 498.1 (100) [M + H –
BH3]+. Found, %: C 72.47; H 5.60; N 2.49. C31H27BFeNP.
Calculated, %: С 72.80; H 5.28; N 2.74. M 511.18.
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(SFс,S)-[2-(Quinolin-2-yl)ferrocene-1-yl]diphe-
nylphosphine (VII). In 2 ml of diethylamine was dis-
solved 0.01 g (0.02 mmol) of borane complex VI, and
the solution was heated at 50°С for 30 min. The solvent
was distilled off at a reduced pressure. The procedure was
repeated 4 times. Yield 0.010 g (99%), dark red crystals.
1Н NMR spectrum, δ, ppm: 3.83 s (1Н, C5H3), 4.10 s (5Н,
CрН), 4.53 s (1Н, C5H3), 5.20 s (1Н, C5H3), 7.23–7.41 m
(6Н, Ph), 7.51–7.71 m (7Н, H4', H5', H7', Ph), 7.80 d (1Н,
H6', J 8.0 Hz), 7.92 d (1Н, H8', J 8.0 Hz), 8.03 d (1Н,
H3', J 8.0 Hz). 31P NMR spectrum, δ, ppm: 17.59 (PPh2).
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ACKNOWLEDGMENTS
The study was carried out under the financial support
of the Council of grants at the President of the Russian
Federation (Program of State support of the leading
scientific schooles, grant NSh no. 5505.2012.3), Federal
targeted program of the Ministry of the Education and Sci-
ence of the Russian Federation “Scientific and scientific-
pedagogical staff of innovation Russia” (contracts nos.
14.A18.21.0830, 14.А18.21.0806 of August 31, 2012 ),
and of the Russian Foundation for Basic Research (grants
nos. 12-03-33144, 13-03-01271).
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