Synthesis, resolution, and absolute configuration of chiral 4,4′-bipyridines

Article abstract of DOI:10.1021/jo300286z

A chiral polyhalogenated 4,4′-bipyridine derivative is described allowing an easy access to a new family of chiral 4,4′-bipyridines by site-selective cross-coupling reactions. The absolute configurations of all the HPLC separated enantiomers were determined by X-ray diffraction and electronic circular dichroism coupled with time-dependent density functional theory calculations.

Full text of DOI:10.1021/jo300286z

Brief Communication
pubs.acs.org/joc
Synthesis, Resolution, and Absolute Configuration of Chiral
4,4′-Bipyridines
Victor Mamane,*,† Emmanuel Aubert,‡ Paola Peluso,§ and Sergio Cossu∥
‡
†Laboratoire SRSMC UMR CNRS 7565 and Laboratoire CRM2 UMR CNRS 7036, Nancy Universite,
54506 Vandoeuvre-les-Nancy, France
́
§Istituto di Chimica Biomolecolare ICB CNR, UOS di Sassari, 07100 Sassari, Italy
∥Dipartimento di Scienze Molecolari e Nanosistemi, Universita
̀
Ca’ Foscari di Venezia, 30123 Venezia, Italy
S
* Supporting Information
ABSTRACT: A chiral polyhalogenated 4,4′-bipyridine derivative is
described allowing an easy access to a new family of chiral 4,4′-
bipyridines by site-selective cross-coupling reactions. The absolute
configurations of all the HPLC separated enantiomers were
determined by X-ray diffraction and electronic circular dichroism
coupled with time-dependent density functional theory calculations.
4,4′-Bipyridine is one of the most famous ligands used in
supramolecular chemistry due to the presence of two donor
atoms along a rigid structure.1 Moreover, it is an excellent
building block for the preparation of viologens2 and liquid
crystals.3,4 Considering the importance of chiral supramolecular
networks in many applications such as asymmetric catalysis,5 it
was surprising to find limited examples of chiral 4,4′-bipyridines
in the literature.6−8
Scheme 1. Cross-Coupling Reactions of 3
We have recently described a simple method to access to the
4,4′-bipyridine scaffold possessing several halogen groups.9
Herein, we described a new chiral polyhalogenated 4,4′-bipyridine
easily functionalized by cross-coupling reactions. The configura-
tionally stable enantiomers were separated on chiral HPLC
columns and their absolute configuration was assigned on the
basis of X-ray diffraction (XRD) and electronic circular dichroism
(ECD) analyses coupled with time-dependent density functional
theory calculations (TD-DFT).
With the aim to prepare atropisomeric 3,3′,5,5′-tetrasub-
stituted 4,4′-bipyridines, the reactivity of 3,3′,5,5′-tetrabromo-
4,4′-bipyridine 1 and 3,3′-dibromo-5,5′-diiodo-4,4′-bipyridine 3
was investigated under the Suzuki reaction conditions.10
Starting from 1, it was observed the formation of the 3,5-
disubstituted-3′,5′-dibromo-4,4′-bipyridine 2, as main product.11
This result suggested an electronic effect induced onto the
mono phenyl substituted pyridine ring by the first introduced
phenyl moiety which makes the position 5 more reactive than
the positions 3′ and 5′. Differently, in 3, the iodine onto the 3,3′
position acts as a regioselective modulator of reactivity pivoting
the substitution onto the iodine substituted C atoms of the 4,4′-
bipyridine system and, consequently, leading to the formation
of novel chiral 4,4′-bipyridines 4a−f (Scheme 1).12 Similarly,
alkynyl-substituted derivatives 5 were obtained through a
Sonogashira reaction.13 All prepared compounds bear on the
ortho-ortho′ positions of the heterocyclic scaffold two π-electron
groups.
Received: February 9, 2012
Published: February 28, 2012
© 2012 American Chemical Society
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Brief Communication
All of the atropisomeric 3,3′,5,5′-tetrasubstituted bipyridines
were enantioseparated by chiral HPLC. The use of this
technique was previously reported by Schalley and co-workers
for the separation of three chiral bis-amide substituted
bipyridines on an immobilized Chiralcel OD column.6 For
our compounds, polysaccharide-based columns proved also to
be versatile. For instance, bipyridines 3 and 4b were separated
on Lux Cellulose-2 and Chiralcel OD-H columns, respec-
tively.14 After multimilligram recovery of the enantiomers,15
assignment of absolute configurations for 3 and 4b were
achieved by single crystal XRD analysis, using anomalous
dispersion due to the presence of heavy atoms in the structures
(Figure 1).
Figure 2. Experimental ECD spectra for compounds (M)-4 and
(M)-5a (298K, MeOH, 0.1 mM, 1 cm cells).
Figure 1. ORTEP plots of one of the four molecules within the
asymmetric units of (a) 3 and (b) 4b. Thermal ellipsoids set at 50%
probability and hydrogen atoms shown as sticks. The absolute
configurations are P for 3 and M for 4b.
For 3 (2nd eluted peak) enantiomer, the Flack parameter
refined to 0.124(5); this small value identifies the configuration
of 3 as P, but also shows that a minor amount of M enantio-
mer is also present in the investigated sample as an enantio-
morphous crystal phase (see the Supporting Information for
full refinement details). It has to be noted that the enantiomeric
excess after the chiral HPLC separation was 97.8%, already
evidencing a small enantiomeric contamination. In the case of
4b (1st eluted peak) and 5b (second eluted peak) enantiomers,
the low value of the Flack parameters (respectively −0.005(5)
and −0.021(6)) and of their standard uncertainties unambigously
identify the absolute configurations of 4b (1st eluted peak)
as M and of 5b (second eluted peak) as P (see the Supporting
Information for ORTEP view of (P)-5b).
Figure 3. Comparison of experimental (black triangles) and
theoretical (squares) ECD spectra for the (M)-4b enantiomer.
Table 1. Absolute Configurations of All Bipyridine
Atropisomers
absolute configuration (ee%)
Because all compounds could not be crystallized (e.g., 5a
forms an oil at room temperature), ECD spectroscopy was then
used in order to determine the absolute configuration of all
enantiomers of bipyridines 4−5 (Figure 2). The ECD signal for
compound 5b was weak and is therefore omitted in Figure 3
for clarity (see the Supporting Information for ECD spectrum
of 5b).
Assignment of absolute configurations was then performed
by comparing the experimental spectra to the data calculated at
the TD-DFT level of theory (CAM − B3LYP/6-311+G(d,p))
using the Gaussian09 program package16 (Figure 3 and Supporting
Information).
bipyridine
HPLC column
first eluted peak
second eluted peak
3
Lux Cellulose-2
Lux Cellulose-4
Chiralcel OD-H
Lux Cellulose-4
Lux Cellulose-1
Lux Cellulose-4
Lux Cellulose-4
Lux Cellulose-2
Lux Cellulose-2
M (>99)
M (>99)
M (>99)
M (>99)
P (97.7)
M (>99)
M (>99)
M (92.0)
M (95.0)
P (97.8)
P (96.0)
P (>99)
P (>99)
M (96.2)
P (>99)
P (>99)
P (94.0)
P (95.0)
4a
4b
4c
4d
4e
4f
5a
5b
From Figure 2 it could be noticed that for all enantiomers of
the same absolute configuration M (respectively P), the ECD
spectrum presents first a negative (respectively positive)
Cotton effect at high wavelengths then a positive (respectively
negative) Cotton effect at lower wavelengths. This is even the
case for 5b for which no reasonable ECD spectra could be
calculated and for which the absolute configuration was
assessed through XRD only.
Except for the ferrocenyl compound 5b for which no
reasonable ECD spectra could be calculated, the agreement
between experimental and theoretical ECD spectra were good.
The main discrepancy is a systematic shift of the calculated
spectra to shorter wavelengths, as evidenced in previous studies
using the same DFT functional.17 These comparisons thus
allow a clear identification of the absolute configurations for all
the recovered enantiomers, as collected in Table 1. In partic-
ular, the absolute configuration found by ECD for 4b is
coherent with the one assessed through the XRD analysis.
For both P,M enantiomers of 4b, no racemization was
observed after heating in methanol at 70 °C for 72 h, suggesting
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The Journal of Organic Chemistry
Brief Communication
were performed in isocratic mode. n-Hexane/2-propanol =9/1 was
used as mobile phase, at flow rate 0.8 mL/min and 22 °C. CD spectra
were recorded at room temperature using 0.1 mM samples in
methanol and a 1 cm quartz cell, with the following conditions:
60 nm/min scanning speed, 1 nm data pitch, 4.0 nm bandwidth, 1 s
response time.
a high barrier for racemization. Indeed, activation energy
barriers calculated at the DFT level of theory (using the B97D
functional including dispersion corrections) for bipyridines 3,
4a−e, and 5a are all over 160 kJ/mol. In other words, the
lowest racemisation temperature (Tr, temperature at which the
half-life time of the atropisomer is 1000 s) is 383 °C, obtained
for 4c (for details, see the Supporting Information). It is then
expected that all these new chiral bipyridines can retain their
chiral configurations over a long period of time, in particular
the tetrahalogenated bipyridine 3 (Tr = 536 °C).
The use of bipyridine 3 as an enantiomerically pure precursor
was then considered by studying the transfer of the stereo-
chemical information after cross-coupling reactions. Such study
on binaphthyl derivatives have shown stereoconservation or
racemization depending on the organometallic counterpart
(Mg, Zn, Sn, B, Al) and the reaction conditions.18−23 In our
case, complete stereoconservativity was observed after Suzuki
and Sonogashira couplings with bipyridine (M)-3 demon-
trasting that bipyridine 3 is configurationally stable under
palladium catalysis (Scheme 2). This result indicates that both
3,5-Dibromo-3′,5′-diphenyl[4,4′]bipyridinyl (2). An oven-
dried resealable 10-mL tube equipped with a magnetic stir bar was
charged with Pd2(dba)3 (3.9 mg, 4.24.10−3 mmol), SPhos (7 mg,
0.017 mmol), bipyridine 1 (100 mg, 0.212 mmol), phenylboronic acid
(78 mg, 0.636 mmol), and powdered anhydrous K3PO4 (180 mg,
0.848 mmol). The tube was caped, evacuated, and backfilled with
argon (with a needle). Dry and degassed toluene (1.5 mL) was added,
and the mixture was heated at 100 °C with vigorous stirring for 12 h.
The reaction mixture was then allowed to cool to room temperature,
concentrated, and purified by column chromatography on silica gel
(cyclohexane/ethyl acetate 9/1) to give bipyridine 2 as a white solid
1
(30 mg, 30%): mp 190 °C; H NMR (200 MHz, CDCl3) δ 7.25 (s,
10H, HPh), 8.41 (s, 2H), 8.70 (s, 2H); 13C NMR (50 MHz, CDCl3) δ
122.8, 128.1, 128.2, 129.0, 135.6, 136.3, 141.9, 147.2, 149.95, 150.0.
MS (ESI) m/z 466 (M, 50), 385 (M − Br, 35), 305 (M − Br2, 100);
HRMS calcd for C22H15Br2N2 (M + H) 464.9581, found 466.9590.
3,5′-Dibromo-5,3′-diiodo[4,4′]bipyridinyl (3). Freshly distilled
diisopropylamine (1 mL, 6.6 mmol) was added to dry THF (70 mL),
and the solution was cooled to −40 °C. A solution of n-butyllitihium
(1.66 M in hexanes, 4 mL, 6.6 mmol) was added dropwise under argon
atmosphere. After the solution was stirred for 5 min at −40 °C,
3-bromo-5-iodopyridine (3.4 g, 12 mmol) solubilized in dry THF
(50 mL) was added dropwise via a syringe pump (rate: 30 mL/h). The
mixture was then stirred at −40 °C for 1 h and cooled to −78 °C, and
I2 (1.68 g, 6.6 mmol) in THF (15 mL) was added dropwise. After the
solution was warmed to rt, the reaction was quenched with a aqueous
Na2S2O3 and the mixture was extracted with ethyl acetate, dried over
MgSO4 and concentrated. The crude product was purified by
chromatography on silica gel to give 3 as a white powder (1.4 g,
41%): mp 180 °C; 1H NMR (200 MHz, CDCl3) δ 8.80 (s, 2H), 8.99
(s, 2H); 13C NMR (50 MHz, CDCl3) δ 96.6, 120.2, 151.4, 152.5,
156.2. MS (ESI) m/z 566 (M, 80), 439 (M − I, 35), 98 (100); HRMS
calcd for C10H5Br2I2N2 (M + H) 564.6903, found 564.6927.
Typical Procedure for Synthesis of 4. To a degassed toluene
solution (1 mL) containing Pd(PPh3)4 (5.8 mg, 0.005 mmol) and
bipyridine 3 (56.6 mg, 0.1 mmol) were successively added degassed
solutions of arylboronic acid (0.3 mmol, 3 equiv) in methanol
(0.5 mL) and Na2CO3 (64 mg, 0.6 mmol) in water (0.5 mL). After
being heated for 12 h at 100 °C, the reaction mixture was cooled to
room temperature, extracted with ethyl acetate, and dried over MgSO4.
After concentration, the residue was purified by chromatography on
silica gel to give bipyridine 4.
Scheme 2. Stereoconservative Couplings of (M)-3
enantiomers of 3 can be used for the direct preparation of
enantiomerically pure 4,4′-bipyridines.
In summary, we have presented a novel family of chiral
configurationally stable 4,4′-bipyridines. For all compounds, the
absolute configurations of the enantiomers were assigned on
the basis of XRD and ECD analyses. The ease of introduction
of different substituents on the parent 3,3′-dibromo-5,5′-diiodo-
4,4′-bipyridine 3 makes this compound an essential precursor
toward enantiomerically pure 4,4′-bipyridine ligands for
incorporation in metal−organic frameworks (MOFs).
EXPERIMENTAL SECTION
3,5′-Dibromo-5,3′-diphenyl[4,4′]bipyridinyl (4a): mp 188 °C;
1H NMR (250 MHz, CDCl3) δ 6.61 (d, J = 7.3 Hz, 4H), 7.12 (t, J =
7.3 Hz, 4H), 7.23 (t, J = 7.3 Hz, 2H), 8.33 (s, 2H), 8.82 (s, 2H); 13C
NMR (66 MHz, CDCl3) δ 123.3, 128.0, 128.2, 128.8, 135.3, 137.5,
144.4, 149.2, 150.4; MS (ESI) m/z 466 (M, 35), 387 (M − Br, 30),
305 (M − Br2, 100); HRMS calcd for C22H15Br2N2 (M + H)
464.9597, found 464.9587.
■
General Experimental Methods. All reactions were performed
under an atmosphere of argon in oven-dried glassware. Diisopropyl-
amine was distilled over CaH2. Tetrahydrofuran (THF) and toluene
were distilled over sodium/benzophenone and stored over sodium. All
other solvents and reagents were used as received. TLC was performed
on silica gel plates and visualized with a UV lamp (254 nm).
Chromatography was performed on silica gel (70−230 mesh). All
3,5′-Dibromo-5,3′-bis(4-methoxyphenyl)[4,4′]bipyridinyl
1
melting points were uncorrected. The H and 13C NMR spectra were
1
(4b): mp 167 °C; H NMR (200 MHz, CDCl3) δ 3.76 (s, 6H), 6.57
(d, J = 8.8 Hz, 4H), 6.66 (d, J = 8.8 Hz), 8.32 (s, 2H), 8.78 (s, 2H);
13C NMR (66 MHz, CDCl3) δ 55.2, 113.4, 123.2, 127.7, 130.1, 137.3,
144.5, 149.3, 150.0, 159.5; MS (ESI) m/z 526 (M, 100), 447 (M − Br,
30), 365 (M − Br2, 45); HRMS calcd for C24H19Br2N2O2 (M + H)
524.9808, found 524.9796.
recorded at 200 and 50 MHz or at 250 and 66 MHz, respectively.
Chemical shifts are quoted in parts per million (ppm) downfield of
tetramethylsilane. Coupling constants J are quoted in Hz. Mass spectra
were recorded using EI at 70 eV and high resolution mass spectra were
recorded using APCI. For chiral HPLC analyses, a high-pressure
binary gradient system equipped with a diode-array detector operating
at 254 (220, 280) nm and a 20 μL sample loop was employed.
Chiralcel OD-H and Lux Cellulose-1 (250 × 4.6 mm) (5 μm)
(cellulose tris-3,5-dimethylphenylcarbamate), Lux Cellulose-2 (250 ×
4.6 mm) (5 μm) (cellulose tris-3-chloro-4-methylphenylcarbamate)
and Lux Cellulose-4 (250 × 4.6 mm) (5 μm) (cellulose tris-4-chloro-
3-methylphenylcarbamate) were used as chiral columns. HPLC-grade
hexane and 2-propanol were purchased and used as received. Analyses
3,5′-Dibromo-5,3′-bis(2-methoxyphenyl)[4,4′]bipyridinyl
1
(4c): mp 190 °C; H NMR (200 MHz, CDCl3) δ 3.41 (s, 6H), 6.32
(br s, 2H), 6.63 (d, J = 7.8 Hz, 2H), 6.65 (dd, J = 7.8, 6.8 Hz, 2H),
7.18 (dt, J = 7.8, 1.6 Hz, 2H), 8.31 (s, 2H), 8.78 (s, 2H); 13C NMR
(50 MHz, CDCl3) δ 54.4, 110.0, 120.1, 123.9, 129.7, 131.4, 145.0,
149.9, 150.9, 156.2; MS (ESI) m/z 526 (M, 100), 447 (M − Br, 50),
366 (M − Br2, 25); HRMS calcd for C24H19Br2N2O2 (M + H)
524.9808, found 524.9800.
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3,5′-Dibromo-5,3′-bis(4-chlorophenyl)[4,4′]bipyridinyl (4d):
mp 248 °C; 1H NMR (200 MHz, CDCl3) δ 6.58 (d, J = 8.4 Hz, 4H),
7.14 (d, J = 8.4 Hz, 4H), 8.33 (s, 2H), 8.85 (s, 2H); 13C NMR
(50 MHz, CDCl3) δ 128.4, 130.1, 133.7, 134.8, 136.3, 144.2, 149.1,
149.2, 150.9; MS (ESI) m/z 535 (M, 100), 455 (M − Br, 35), 373
(M − Br2, 65); HRMS calcd for C22H13Br2Cl2N2 (M + H) 532.8817,
found 532.8825.
(all data). The goodness of fit on F2 was 1.071. CCDC no. CCDC
859201.
Crystal data for 4b: C24H18Br2N2O2, M = 526.22, monoclinic, a =
8.2955(2) Å, b = 14.6494(3) Å, c = 35.3289(7) Å, α = 90.00°, β =
94.144(2)°, γ = 90.00°, V = 4282.09(16) Å3, T = 110(2) K, space
group P21, Z = 8, μ(Mo Kα) = 3.832 mm−1, 76167 reflections
measured, 19684 independent reflections (Rint = 0.0560). Flack
parameter = −0.005(5). The final R1 values were 0.0450 (I > 2σ(I))
and 0.0594 (all data). The final wR(F2) values were 0.0673 (I > 2σ(I))
and 0.0711 (all data). The goodness of fit on F2 was 1.095. CCDC no.
CCDC 859202.
Crystal data for 5b: C34H22Br2Fe2N2, M = 730.06, orthorhombic,
a = 11.8083(2) Å, b = 11.9540(2) Å, c = 19.8145(3) Å, α = 90.00°, β =
90.00°, γ = 90.00°, V = 2796.94(8) Å3, T = 110(2) K, space group
P212121, Z = 4, μ(Mo Kα) = 3.923 mm−1, 40732 reflections measured,
8046 independent reflections (Rint = 0.0351). Flack parameter =
−0.021(6). The final R1 values were 0.0350 (I > 2σ(I)) and 0.0435 (all
data). The final wR(F2) values were 0.0639 (I > 2σ(I)) and 0.0666 (all
data). The goodness of fit on F2 was 1.097. CCDC no. CCDC 859203.
3,5′-Dibromo-5,3′-dinaphthalen-1-yl-[4,4′]bipyridinyl (4e):
1
mp 202 °C; H NMR (200 MHz, CDCl3) δ 5.93 (d, J = 8.2 Hz,
2H), 6.43 (ddd, J = 8.2, 7.0, 1.2 Hz, 2H), 6.95 (ddd, J = 8.2, 7.0, 1.0 Hz,
2H), 7.21 (d, J = 2.8 Hz, 2H), 7.25 (d, J = 6.4 Hz, 2H), 7.40 (d,
J = 8.2 Hz, 2H), 7.61 (dd, J = 6.4, 2.8 Hz, 2H), 8.27 (s, 2H), 8.89 (s,
2H); 13C NMR (50 MHz, CDCl3) δ 123.4, 124.3, 125.6, 126.1, 127.3,
127.5, 128.8, 131.3, 132.3, 133.5, 135.4, 145.7, 150.2, 151.5; MS (ESI)
m/z 566 (M, 100), 487 (M − Br, 40), 365 (M − Br2, 90); HRMS
calcd for C30H19Br2N2 (M + H) 564.9910, found 564.9895.
3,5′-Dibromo-5,3′-bis(4-diphenylaminophenyl)[4,4′]-
bipyridinyl (4f): mp 213 °C; 1H NMR (200 MHz, CDCl3) δ 6.52 (d,
J = 8.6 Hz, 4H), 6.78 (d, J = 8.6 Hz, 4H), 6.95−7.05 (m, 12 H), 7.10−
7.25 (m, 8H), 8.44 (s, 2H), 8.76 (s, 2H); 13C NMR (50 MHz, CDCl3)
δ 121.9, 123.6, 124.8, 128.5, 129.4, 129.6, 144.4, 147.1, 148.0, 149.1,
150.1, 153.8; HRMS calcd for C46H33Br2N4 (M + H) 799.1066, found
799.1044.
ASSOCIATED CONTENT
■
S
* Supporting Information
1H and 13C spectra of all compounds; X-ray structures of 2, 4a,
and (P)-5b; ECD experimental and calculations details; details
on calculations of energy barriers of racemization. This material
is available free of charge via the Internet at http://pubs.acs.org.
Typical Procedure for the Synthesis of 5. An oven-dried
resealable 10-mL tube equipped with a magnetic stir bar was charged
with PdCl2(PPh3)2 (7 mg, 0.01 mmol), CuI (1.9 mg, 0.01 mmol), and
bipyridine 3 (56.6 mg, 0.1 mmol). The tube was caped, evacuated, and
backfilled with argon (with a needle). A degassed solution of phenyl-
or ferrocenylacetylene (0.3 mmol) in dry triethylamine (1 mL) was
added, and the mixture was heated at 70 °C for 12 h. The reaction
mixture was then allowed to cool to room temperature, extracted with
ethyl acetate, and concentrated. Purification by column chromato-
graphy on silica gel (cyclohexane/ethyl acetate 9/1) gave bipyridine 5.
3,5′-Dibromo-5,3′-bis-phenylethynyl[4,4′]bipyridinyl (5a):
1H NMR (250 MHz, CDCl3) δ 7.15 (dd, J = 7.5, 1.3 Hz, 4H),
AUTHOR INFORMATION
Corresponding Author
*E-mail: victor.mamane@srsmc.uhp-nancy.fr.
■
Notes
The authors declare no competing financial interest.
7.20−7.40 (m, 6H), 8.83 (s, 2H), 8.84 (s, 2H); 13C NMR (66 MHz,
CDCl3) δ 83.1, 97.4, 120.4, 121.2, 121.6, 128.4, 129.2, 131.6, 147.7,
150.7; MS (ESI) m/z 514 (M, 100), 433 (M − Br, 15), 353 (M − Br2,
70); HRMS calcd for C26H15Br2N2 (M + H) 512.9597, found
512.9622.
ACKNOWLEDGMENTS
■
The Service Commun de Diffraction des rayons X − Nancy-
Universite
́
is thanked for providing access to crystallographic
facilities. GENCI-CINES (Grant No. 2012-X2012085106)
and Institut Jean Barriol are thanked for providing access to
computing facilities. The Service Commun d’Analyse (S. Parant)
is thanked for ECD measurements.
3,5′-Dibromo-5,3′-bis-ferrocenylethynyl[4,4′]bipyridinyl
1
(5b): mp 210 °C; H NMR (200 MHz, CDCl3) δ 4.11 (s, 10H, Cp),
4.20 (s, 8H), 8.80 (s, 2H), 8.86 (s, 2H); 13C NMR (50 MHz, CDCl3)
δ 62.9, 69.5, 70.1, 71.5, 71.6, 77.2, 79.7, 98.2, 120.3, 121.9, 147.7,
149.8, 150.2; MS (ESI) m/z 730 (M, 100); HRMS calcd for
C34H23Br2Fe2N2 (M + H) 728.8928, found 728.8948.
REFERENCES
■
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16.61130(10) Å, b = 12.44370(10) Å, c = 17.7610(2) Å, α = 90.00°,
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0.0673 (I > 2σ(I)) and 0.0676 (all data). The goodness of fit on F2 was
1.101. CCDC no. CCDC 859199.
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8.07800(10) Å, b = 11.29930(10) Å, c = 15.5039(2) Å, α =
102.6890(10)°, β = 98.1530(10)°, γ = 90.8930(10)°, V = 1365.01(3) Å3,
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106245 reflections measured, 27062 independent reflections (Rint
=
(8) Jouaiti, A.; Hosseini, M. W.; Kyritsakas, N. Chem. Commun. 2002,
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0.0227). Flack parameter = 0.124(5). The final R1 values were 0.0317
(I > 2σ(I)) and 0.0361 (all data). The final wR(F2) values were 0.0685
(I > 2σ(I)) and 0.0707 (all data). The goodness of fit on F2 was 1.063.
CCDC no. CCDC 859200.
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Buchwald method was used: Barder, T. E.; Walker, S. D.; Martinelli,
J. R.; Buchwald, S. L. J. Am. Chem. Soc. 2005, 127, 4685.
(12) The phenyl group distribution on the pyridine rings in
compounds 2 and 4a was determined by XRD (see the Supporting
Information).
Crystal data for 4a: C22H14Br2N2, M = 466.17, orthorhombic, a =
7.7417(4) Å, b = 11.2941(6) Å, c = 10.3290(4) Å, α = 90.00°, β =
90.00°, γ = 90.00°, V = 903.12(8) Å3, T = 110(2) K, space group Pnc2,
Z = 2, μ(Mo Kα) = 4.530 mm−1, 6477 reflections measured, 2061
independent reflections (Rint = 0.0663). Flack parameter =
−0.012(17). The final R1 values were 0.0372 (I > 2σ(I)) and 0.0426
(all data). The final wR(F2) values were 0.0905 (I > 2σ(I)) and 0.0945
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The Journal of Organic Chemistry
Brief Communication
(13) Sonogashira, K. J. Organomet. Chem. 2002, 653, 46.
(14) Chromatographic parameters: hexane/2-propanol = 9/1 as
mobile phase, flow rate 0.8 mL/min, T = 22 °C. For 3: Lux Cellulose-2
(250 × 4.6 mm, 5 μm), α =1.07, Rs = 1.1; for 4b: Chiralcel OD-H
(250 × 4.6 mm, 5 μm), α =1.57, Rs = 2.9.
(15) Starting from 200 mg of rac-4b and 20 mg of rac-3, the HPLC
multimilligram recovery led to 60 mg of each atropisomer (M)-4b and
(P)-4b and to 8 mg and 5 mg of (M)-3 and (P)-3, respectively. In all
cases, to enhance throughput, the technique of overlapping injections
was used.
(16) Frisch et al. See the Supporting Information for the full
reference.
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