Synthesis of atropisomeric 1,8-bis(4′,4′-dipyridyl)naphthalenes from 4-trimethylstannylpyridines

Article abstract of DOI:10.1055/s-2002-25769

Two synthetic strategies towards atropisomeric 2′,2′-disubstituted 1,8-bis(4′,4′-dipyridyl)naphthalenes using Stille crosscoupling of trimethylstannylpyridine derivatives and 1,8-di-iodonaphthalene have been investigated. Introduction of substituents into the pyridyl moieties prior to the cross-coupling step provides higher overall yields than derivatization of 1,8-bis(4′,4′-dipyridyl)naphthalene under Ziegler reaction conditions.

Full text of DOI:10.1055/s-2002-25769

PAPER
749
Synthesis of Atropisomeric 1,8-Bis(4 ,4 -dipyridyl)naphthalenes from
4-Trimethylstannylpyridines
Synthesis of
Atro
h
pisomeric 1,
r
8-Bis(4
,
4-dipy
s
ridyl)naph
t
thalen
i
es an Wolf,* Bereket T. Ghebremariam
Department of Chemistry, Georgetown University, Washington, DC 20057, USA
Fax +1(202)6876209; E-mail: cw27@georgetown.edu
Received 11 December 2001; revised 13 February 2002
2 ,2 -disubstituted 1,8-bis(4 ,4 -dipyridyl)naphthalenes by
Ziegler reaction.6 Synthesis of 4-trimethylstannylpyridine
(3)7 from commercially available 4-bromopyridine hydro-
chloride was followed by Stille cross-coupling of 3 with
Abstract: Two synthetic strategies towards atropisomeric 2 ,2 -di-
substituted 1,8-bis(4 ,4 -dipyridyl)naphthalenes using Stille cross-
coupling of trimethylstannylpyridine derivatives and 1,8-di-
iodonaphthalene have been investigated. Introduction of substitu-
ents into the pyridyl moieties prior to the cross-coupling step 1,8-diiodonaphthalene8 to afford dipyridyl 1. Unfortu-
provides higher overall yields than derivatization of 1,8-bis(4 ,4 -
dipyridyl)naphthalene under Ziegler reaction conditions.
nately, Ziegler arylation of 1 using phenyllithium provid-
ed 1,8-bis(2 ,2 -diphenyl-4 ,4 -dipyridyl)naphthalene (2)
Key words: Stille coupling, 1,8-dipyridylnaphthalenes, 2,4-disub-
stituted pyridines, Ziegler reaction, atropisomers
in only moderate yields. Noteworthy, attempts to synthe-
size 1,8-bis(2 ,2 -dialkyl-4 ,4 -dipyridyl)naphthalenes by
Ziegler alkylation of dipyridyl 1 were not successful.
Due to the low overall yield and synthetic limitations in-
herent to route A, we attempted to introduce alkyl and aryl
groups, respectively, into the pyridyl moieties prior to the
formation of the 1,8-bis(4 ,4 -dipyridyl)naphthalene
framework (route B). Subsequent treatment of 4-bro-
mopyridine hydrochloride with a Grignard reagent and
phenyl chloroformate provided 2-substituted 1-phenoxy-
carbonyl-4-bromodihydropyridines that were readily oxi-
dized to 4-bromo-2-methylpyridine (4) and 4-bromo-2-
phenylpyridine (5), respectively.9 Lithiation of bromopy-
ridines 4 and 5 followed by treatment with trimethylstan-
nyl chloride afforded 2-methyl-4-trimethylstannyl-
pyridine (6) and 2-phenyl-4-trimethylstannylpyridine (7)
in good yields (Scheme 2).2,10 Use of diethyl ether as the
solvent proved to be crucial. No formation of the desired
product was observed in THF.
1,8-Diarylnaphthalenes afford a unique structure that
greatly facilitates the study of noncovalent interactions
between stacked aryl rings.1 In the ground state, both aryl
groups attached to the naphthalene moiety are cofacial
and almost perpendicular to the naphthalene framework.
Suitably substituted 1,8-dihetarylnaphthalene derivatives
exist as a mixture of syn- and anti-isomers that rapidly in-
terconvert at room temperature.2 Since 1,8-dipyridylnaph-
thalenes exhibit cofacial heterocycles, they can be used as
model compounds to mimic - interactions in pyridin-
ophanes, proteins, nucleic acids, and inclusion complex-
es. 1,8-Dihetarylnaphthalenes bearing unsubstituted 2 -
pyridyl and 3 -pyridyl moieties, respectively, have been
synthesized to investigate their conformational stability,
intramolecular - interactions, and syn/anti population.3
Herein, we describe two alternative routes towards atrop-
isomeric 1,8-bis(4 ,4 -dipyridyl)naphthalene derivatives
exhibiting substituents in position 2 of the pyridyl moi-
eties. Both synthetic strategies involve Stille cross-cou-
pling as well as the preparation of substituted pyridines,
which has remained an important topic in heterocyclic
chemistry over the past years.4 Interestingly, only a small
number of 2-substituted 4-trimethyl- or 4-tributylstan-
nylpyridines that can be utilized for cross-coupling reac-
tions has been reported in the literature.5 We found 4-
trimethylstannylpyridines to be highly useful for the syn-
thesis of constrained naphthalenes bearing 2,4-disubsti-
tuted pyridyl rings in peri positions.
Following route B, atropisomeric 1,8-bis(2 ,2 -diphenyl-
4 ,4 -dipyridyl)naphthalene (2) and 1,8-bis(2 ,2 -dimeth-
yl-4 ,4 -dipyridyl)naphthalene (8) were synthesized by
Stille cross-coupling of trimethylstannylpyridines 6 and 7,
respectively, with 1,8-diiodonaphthalene (Scheme 1).
Stille coupling using 5 mol% Pd(PPh3)4 as the catalyst
proceeded in good yields. Use of other palladium cata-
lysts, such as (PPh3)2PdCl2 or (dppf)PdCl2, and LiCl as an
additive did not improve the yields. Interestingly, consid-
erable formation of the homo-coupling product 2 ,2 -
diphenyl-4 ,4 -bipyridyl (9) was observed.11
Comparison of the two routes investigated herein reveals
that incorporation of substituents in position 2 of the
pyridyl rings prior to the cross-coupling step affords supe-
rior yields. Route A affords atropisomer 2 in only 14%
yield, whereas route B allows the synthesis of 2 from 4-
bromopyridine hydrochloride in 3 steps with 34% overall
yield. The usefulness of route A is limited to the synthesis
of 2 ,2 -diaryl derivatives of 1. By contrast, route B can
also be applied to the synthesis of 1,8-bis(2 ,2 -dialkyl-
4 ,4 -dipyridyl)naphthalenes.
First, we envisioned a straightforward synthetic strategy
(route A) utilizing 1,8-bis(4 ,4 -dipyridyl)naphthalene (1)
as a key intermediate (Scheme 1). This route would allow
the convenient synthesis of a variety of atropisomeric
Synthesis 2002, No. 6, 29 04 2002. Article Identifier:
1437-210X,E;2002,0,06,0749,0752,ftx,en;M06501SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

750
C. Wolf, B. T. Ghebremariam
PAPER
Route A
Br
N
HCl
Route B
1. BuLi
66 %
2. Me3SnCl
SnMe3
SnMe3
N
R
6, R = Me
7, R = Ph
N
3
R = Ph, 64 %
R = Me, 80 %
67 %
I
I
I
I
Pd(PPh3)4
Pd(PPh3)4
PhLi
+
N
R
N
R
R = Ph, 31%
N
N
R
N
N
R
9, R = Ph, 28 %
1
2, R = Ph
8, R = Me
Scheme 1 Synthesis of 2 ,2 -disubstituted 1,8-bis(4 ,4 -dipyridyl)naphthalenes
It should be noted that the synthesis of atropisomers 2 and In summary, two routes towards 2 ,2 -disubstituted 1,8-
8 affords a mixture of syn- and anti-isomers. Both isomers bis(4 ,4 -dipyridyl)naphthalene derivatives have been ex-
are not conformationally stable since rotation of a pyridyl amined. Derivatization of pyridyl rings prior to Stille
ring about the naphthalene–pyridyl bond proceeds fast at cross-coupling of the corresponding trimethylstannylpyr-
room temperature. Our semiempirical computations idines with 1,8-diiodonaphthalene provides 2 ,2 -dialkyl
(PM3) suggest a slight preference of less than 0.5 kJ/mol as well as 2 ,2 -diaryl derivatives of 1,8-bis(4 ,4 -dipyr-
for the anti- over the syn-diastereoisomer. The calculated idyl)naphthalene in good overall yield.
energy differences for diastereoisomers of 2 and 8, re-
spectively, can be considered negligible. 1H NMR spectra
of 2 and 8 are in good agreement with almost equimolar
mixtures of anti- and syn-isomers.
All chemicals were of reagent grade and were purchased from Ald-
rich. All reactions were carried out under N2 under anhydrous con-
ditions. Flash chromatography was carried out on SiO2 (Merck
Kieselgel 60, particle size 0.032–0.063 mm). GC-MS was per-
formed using a Fison Instrument MD800 capillary GC-Mass spec-
trometer. NMR spectra were obtained at 300 MHz (1H NMR) and
75 MHz (13C NMR) on a Varian FT-NMR spectrometer using
CDCl3 as the solvent. Chemical shifts are reported in ppm relative
to TMS. Elemental analyses were performed by Oneida Research
Services, NY.
Br
Br
1. RMgCl, 2eq.
2. PhOCOCl
o-chloranil
R
N
N
HCl
H
Ph
O
O
1,8-Bis(4 ,4 -dipyridyl)naphthalene (1)
A solution of 1,8-diiodonaphthalene (0.6 g, 1.58 mmol), 4-trime-
thylstannylpyridine (3, 1.0 g, 4.14 mmol) and Pd(PPh3)4 (90 mg, 4.9
mol%) in anhyd DMF (3 mL) was refluxed for 5 h. The reaction
mixture was allowed to cool to r.t., poured into 10% NH4OH, and
extracted with CH2Cl2. The combined organic layers were washed
with water, dried (MgSO4), and the filtrate was concentrated under
reduced pressure. Recrystallization from EtOAc afforded 1 (300
mg, 67%) as light yellow crystals; mp 279–280 °C.
Br
SnMe3
1. BuLi
2. Me3SnCl
R
N
N
R
4, R = Me, 57 %
5, R = Ph, 69 %
6, R = Me, 67%
7, R = Ph, 77%
Scheme 2 Synthesis of 2-substituted 4-trimethylstannylpyridines
1H NMR: = 6.93 (dd, J = 1.7, 4.4 Hz, 4 H), 7.43 (dd, J = 1.1, 7.2
Hz, 2 H), 7.62 (dd, J = 1.1, 8.2 Hz, 2 H), 8.04 (dd, J = 7.2, 8.2 Hz,
2 H), 8.23 (dd, J = 1.7, 4.4 Hz, 4 H).
Synthesis 2002, No. 6, 749–752 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Synthesis of Atropisomeric 1,8-Bis(4 ,4 -dipyridyl)naphthalenes
751
13C NMR: = 14.44, 125.49, 128.02, 129.74, 131.10, 135.19,
136.96, 148.79, 150.31.
EI-MS (70 eV): m/z (%) = 282 (100, M+), 254 (25, M+ – CH2N),
226 (19, M+ – 2 CH2N), 202 (26, M+ – H, – Py), 127 (25, M+ – H, –
2Py).
MeMgCl in THF (21 mL) was added dropwise while the tempera-
ture was kept below –50 °C. The reaction mixture was stirred at
–78 °C for another 15 min. Phenyl chloroformate (3.8 mL, 30
mmol) in THF (10 mL) was added slowly and the mixture was al-
lowed to warm to r.t. Quenching of the mixture with 20% NH4Cl at
0 °C was followed by extraction with Et2O. The combined organic
layers were washed successively with H2O, aq 10% HCl, and H2O.
The organic solution was dried (MgSO4) and the solvents were
evaporated under vacuum. The residue was dissolved in anhyd tol-
uene (100 mL) and a solution of o-chloranil (7.8 g, 32 mmol) in gla-
cial AcOH (60 mL) was added dropwise and the mixture was stirred
for 22 h. A red suspension was formed and was made basic using aq
10% NaOH until a black emulsion was obtained. The mixture was
filtered through Celite and washed with H2O. The organic layer was
extracted three times with aq 10% HCl. The aqueous layers were
made basic and extracted with CH2Cl2. The combined organic lay-
ers were dried (MgSO4) and the solvent was removed under vacuum
to give 4 (2.5 g, 57%) as a yellow oil.
Anal. Calcd for C20H14N2: C, 85.00; H, 5.00; N, 9.92. Found: C,
84.66; H, 5.08; N, 9.91.
1,8-Bis(2 ,2 -diphenyl-4 ,4 -dipyridyl)naphthalene (2)
Method A: To a solution of 1 (80 mg, 0.28 mmol) in anhyd THF (20
mL) was added PhLi (0.34 mL, 1.8 M solution in cyclohexane)
dropwise at –78 °C. The solution was stirred at r.t. for 2 h and then
refluxed for another 2 h. The mixture was poured into 10% NH4OH
and extracted with CH2Cl2. The combined organic layers were
washed with H2O, dried (MgSO4), and concentrated under reduced
pressure. Purification by flash chromatography (EtOAc–hexanes–
Et3N, 200:200:1) and recrystallization from 95% EtOH yielded 2
(38 mg, 31%) as white crystals; mp 188–190 °C.
1H NMR: = 2.54 (s, 3 H), 7.28 (dd, J = 1.4, 5.2 Hz, 1 H), 7.35 (d,
J = 1.4 Hz, 1 H), 8.31 (d, J = 5.2 Hz, 1 H).
13C NMR: = 24.26, 124.03, 126.44, 132.80, 149.66, 159.72.
Method B: The title compound 2 was prepared from 1,8-di-
iodonaphthalene (0.4 g, 1.05 mmol) and 2-phenyl-4-trimethylstan-
nylpyridine (7; 0.82 g, 2.6 mmol) according to the procedure
described above. Purification by flash chromatography and recrys-
tallization yielded 2 (292 mg, 64%) as white crystals.
EI-MS (70 eV): m/z (%) = 171 (100, M+), 156 (34, M+ – Me), 129
(24, M+ – Me, – HCN), 92 (97, M+ – Br), 77 (36, M+ – Br, – Me).
1H NMR (mixture of syn- and anti-isomers): = 6.81 (br s, 1 H),
6.82 (br s, 1 H), 6.86 (br s, 1 H), 6.88 (br s, 1 H), 7.05–7.18 (m, 8
H), 7.22 (br s, 2 H), 7.23–7.48 (m, 14 H), 7.55 (dd, J = 7.1, 8.3 Hz,
4 H), 7.67 (br s, 2 H), 7.70 (br s, 2 H), 7.97 (dd, J = 1.3, 7.1 Hz, 4
H), 8.05 (br s, 1 H), 8.06 (br s, 1 H), 8.22 (br s, 1 H), 8.24 (br s, 1 H).
13C NMR (mixture of syn- and anti-isomers): = 121.55, 121.97,
122.09, 122.64, 125.51, 126.54, 126.87, 128.15, 128.37, 128.46,
128.61, 129.78, 130.70, 130.86, 135.25, 138.54, 139.11, 148.70,
150.85, 151.00, 156.26, 156.47.
4-Bromo-2-phenylpyridine (5)
This compound was prepared from 4-bromopyridine hydrochloride
(4.8 g, 24.7 mmol) and PhMgCl (30 mL, 2.0 M in THF) following
the procedure described for 4. After workup, 5 (4.0 g, 69%) was ob-
tained as a brown oil.
1H NMR: = 7.38 (dd, J = 1.7, 5.2 Hz, 1 H), 7.42–7.50 (m, 3 H),
7.88 (d, J = 1.7 Hz, 1 H), 7.95 (m, 2 H), 8.48 (d, J = 5.2 Hz, 1 H).
13C NMR: = 123.86, 125.17, 126.92, 128.77, 129.52, 133.40,
137.89, 150.18, 158.73.
EI-MS (70 eV): m/z (%) = 434 (83, M+), 357 (12, M+ – Ph), 330 (18,
M+ – Ph, – HCN), 280 (38, M+ – 2Ph), 202 (41, M+ – Ph, – PhPy),
155 (57, PhPy), 77 (100, Ph).
EI-MS (70 eV): m/z (%) = 233 (100, M+), 206 (20, M+ – HCN), 156
(23, M+ – Ph), 154 (98, M+ – Br), 127 (97, M+ – Br, – HCN).
Anal. Calcd for C32H22N2: C, 88.45; H, 5.10; N, 6.45. Found: C,
88.77; H, 5.08; N, 6.08.
2-Methyl-4-trimethylstannylpyridine (6)
4-Bromo-2-methylpyridine (4; 1.5 g, 8.72 mmol) was dissolved in
anhyd Et2O (22 mL) and cooled to –78 °C. A solution of BuLi (6.5
mL, 1.6 M in hexanes) was added dropwise and the suspension was
stirred for 30 min. To this solution, Me3SnCl (2.5 g, 12.5 mmol) in
anhyd Et2O (20 mL) was added dropwise. The reaction mixture was
allowed to stir at r.t. for 4 h and quenched with 10% NH4OH. Fol-
lowing the workup procedure described above gave a brown residue
that was purified by flash chromatography (EtOAc–hexanes–Et3N,
400:200:1) to afford 6 (1.5 g, 67%) as a light yellow oil.
1H NMR: = 0.32 (s, 9 H), 2.53 (s, 3 H), 7.18 (m, 1 H), 7.26 (m, 1
H), 8.40 (dd, J = 1.1, 4.7 Hz, 1 H).
13C NMR: = –9.54, 24.43, 127.86, 130.62, 147.60, 152.89, 156.68.
4-Trimethylstannylpyridine (3)
Commercially available 4-bromopyridine hydrochloride (3.1 g,
15.4 mmol) was partitioned between aq 2 N NaOH and CH2Cl2. The
organic layers were dried (MgSO4) and CH2Cl2 was removed under
reduced pressure. A yellow oil of 4-bromopyridine was obtained
and used without further purification. The crude 4-bromopyridine
was dissolved in anhyd Et2O (20 mL) and cooled to –78 °C. A 1.6
M solution of BuLi in hexanes (10.4 mL) was added and the mixture
was stirred for 1 h. A solution of Me3SnCl (3.8 g, 19 mmol) in an-
hyd Et2O (10 mL) was added dropwise. The mixture was allowed to
stir at r.t. for 5 h, quenched with 10% NH4OH, and extracted with
Et2O. The combined organic layers were washed with H2O, dried
(MgSO4), and concentrated under reduced pressure. Purification of
the brown residue by flash chromatography (EtOAc–hexanes–Et3N,
250:250:1) afforded 3 (2.41 g, 66%) as a light orange oil.
EI-MS (70 eV): m/z (%) = 253 (100, M+), 238 (98, M+ – Me), 223
(100, M+ – 2Me), 208 (97, M+ – 3Me), 161 (5, Me3Sn), 131 (88,
MeSn), 116 (38, Sn), 92 (44, M+ – SnMe3).
1H NMR: = 0.33 (s, 9 H), 7.39 (dd, J = 1.5, 4.2 Hz, 2 H), 8.51 (dd,
J = 1.5, 4.2 Hz, 2 H).
13C NMR: = –9.61, 131.04, 148.33, 152.80.
EI-MS (70 eV): m/z (%) = 239 (29, M+), 224 (100, M+ – Me), 209
(34, M+ – 2Me), 194 (68, M+ – 3Me), 161 (18, Me3Sn), 131 (50,
MeSn), 116 (30, Sn), 78 (17, C5H4N).
2-Phenyl-4-trimethylstannylpyridine (7)
To a solution of 4-bromo-2-phenylpyridine (5; 1.1 g, 4.7 mmol) in
anhyd Et2O (12) was added BuLi (3.5 mL, 1.6 M in hexanes) at –
78 °C. The reaction mixture was stirred for 30 min and Me3SnCl
(1.35 g, 6.8 mmol) in Et2O (10 mL) was added slowly. The mixture
was allowed to come to r.t. and stirred for 4 h. Following the workup
procedure described for 3 and purification by flash chromatography
(EtOAc–hexanes–Et3N, 500:125:1) afforded 7 (1.16 g, 77%) as a
colorless oil.
4-Bromo-2-methylpyridine (4)
A suspension of 4-bromopyridine hydrochloride (5.0 g, 25.7 mmol)
in anhyd THF (90 mL) was cooled to –78 °C. A 3 M solution of
Synthesis 2002, No. 6, 749–752 ISSN 0039-7881 © Thieme Stuttgart · New York

752
C. Wolf, B. T. Ghebremariam
PAPER
1H NMR: = 0.35 (s, 9 H), 7.34 (dd, J = 0.8, 4.7 Hz, 1 H), 7.40–
7.50 (m, 3 H), 7.82 (m, 1 H), 7.97 (m, 2 H), 8.60 (dd, J = 1.1, 4.7
Hz, 1 H).
13C NMR: = –9.47, 126.94, 127.95, 128.58, 128.61, 129.43,
139.76, 148.07, 153.58, 155.91.
EI-MS (70 eV): m/z (%) = 315 (32, M+), 300 (100, M+ – Me), 275
(26, M+ – 2Me), 270 (98, M+ – 3Me), 154 (92, M+ – Me3Sn), 127
(95, M+ – Me3Sn, – HCN), 116 (28, Sn).
(2) Katoh, T.; Ogawa, K.; Inagaki, Y.; Okazaki, R. Tetrahedron
1997, 53, 3557.
(3) (a) Bahl, A.; Grahn, W.; Stadler, S.; Feiner, F.; Bourhill, G.;
Bräuchle, C.; Reisner, A.; Jones, P. G. Angew. Chem., Int.
Ed. Engl. 1995, 34, 1485. (b) Zoltewicz, J. A.; Maier, N. M.;
Fabian, W. M. F. J. Org. Chem. 1996, 61, 7018.
(c) Zoltewicz, J. A.; Maier, N. M.; Fabian, W. M. F.
Tetrahedron 1996, 52, 8703. (d) Maier, N. M.; Zoltewicz, J.
A. Tetrahedron 1997, 53, 465. (e) Zoltewicz, J. A.; Maier,
N. M.; Fabian, W. M. F. J. Org. Chem. 1997, 62, 2763.
(f) Zoltewicz, J. A.; Maier, N. M.; Fabian, W. M. F. J. Org.
Chem. 1997, 62, 3215. (g) Zoltewicz, J. A.; Maier, N. M.;
Lavieri, S.; Ghiviriga, I.; Abboud, K. A. Tetrahedron 1997,
53, 5379. (h) Lavieri, S.; Zoltewicz, J. A. J. Org. Chem.
2001, 66, 7227.
1,8-Bis(2 ,2 -dimethyl-4 ,4 -dipyridyl)naphthalene (8)
This compound was synthesized from 1,8-diiodonaphthalene (0.4 g,
1.05 mmol) and 2-methyl-4-trimethylstannylpyridine (6; 0.68 g, 2.7
mmol) following the procedure for Stille coupling described for 1.
Purification by flash chromatography (EtOAc–hexanes–EtOH–
Et3N, 400:200:200:1) and recrystallization from 95% EtOH afford-
ed 8 (260 mg, 80%) as white crystals; mp 142–144 °C.
1H NMR (mixture of syn- and anti-isomers): = 2.6 (br s, 6 H), 2.39
(br s, 6 H), 6.54 (br s, 2 H), 6.71 (br s, 2 H), 6.78 (br s, 2 H), 6.94
(br s, 2 H), 7.39 (d, J = 7.1 Hz, 4 H), 7.57 (dd, J = 7.1, 8.0 Hz, 4 H),
7.99 (d, J = 8.0 Hz, 4 H), 8.10 (br s, 2 H), 8.28 (br s, 2 H).
(4) (a) Comprehensive Heterocyclic Chemistry, Vol. 2; Boulton,
A. J.; McKillop, A., Eds.; Pergamon: Oxford, 1984.
(b) Karig, G.; Spencer, J. A.; Gallagher, T. Org. Lett. 2001,
3, 835; and references cited therein.
(5) (a) Yamamoto, Y.; Yanagi, A. Chem. Pharm. Bull. 1982, 30,
2003. (b) Yamamoto, Y.; Azuma, Y.; Mitoh, H. Synthesis
1986, 564. (c) Wentland, M. P.; Lesher, G. Y.; Reuman, M.;
Gruett, M. D.; Singh, B.; Aldous, S. C.; Dorff, P. H.; Rake,
J. B.; Coughlin, S. A. J. Med. Chem. 1993, 36, 2801.
(d) Yamamoto, Y.; Tanaka, T.; Ouchi, H.; Miyakawa, M.;
Morita, Y. Heterocycles 1995, 41, 817. (e) Reuman, M.;
Daum, S. J.; Singh, B.; Wentland, M. P.; Perni, R. B.;
Pennock, P.; Carabateas, P. M.; Gruett, M. D.; Saindane, M.
T.; Dorff, P. H.; Coughlin, S. A.; Sedlock, D. M.; Rake, J. B.;
Lesher, G. Y. J. Med. Chem. 1995, 38, 2531. (f) Sauer, J.;
Heldmann, D. K.; Pabst, G. R. Eur. J. Org. Chem. 1999, 313.
(6) Chupakhin, O. N.; Charushin, V. N.; van der Plas, H. C.
Tetrahedron 1988, 44, 1.
13C NMR (mixture of syn- and anti-isomers): = 24.05, 120.83,
121.28, 123.96, 124.13, 125.28, 128.01, 129.51, 130.63, 135.04,
137.12, 147.94, 148.02, 150.45, 156.78.
EI-MS (70 eV): m/z (%) = 310 (100, M+), 295 (8, M+ – Me), 268 (7,
M+ – Me, – HCN), 218 (6, M+ – C6H6N).
Anal. Calcd for C22H18N2: C, 85.13; H, 5.85; N, 9.03. Found: C,
84.90; H, 5.77; N, 9.33.
References and Notes
(1) (a) House, H. O.; Magin, R. W.; Thompson, H. W. J. Org.
Chem. 1963, 28, 2403. (b) House, H. O.; Bashe, R. W. J.
Org. Chem. 1965, 30, 2942. (c) House, H. O.; Bashe, R. W.
J. Org. Chem. 1967, 32, 784. (d) House, H. O.; Campbell,
W. J.; Gall, M. J. Org. Chem. 1970, 35, 1815. (e) House, H.
O.; Koepsell, D. G.; Campbell, W. J. J. Org. Chem. 1972, 37,
1003. (f) Clough, R. L.; Roberts, J. D. J. Am. Chem. Soc.
1976, 98, 1018. (g) Cozzi, F.; Cinquini, M.; Annunziata, R.;
Dwyer, T.; Siegel, J. S. J. Am. Chem. Soc. 1992, 114, 5729.
(h) Cozzi, F.; Cinquini, M.; Annunziata, R.; Siegel, J. S. J.
Am. Chem. Soc. 1993, 115, 5330. (i) Watkinson, M.;
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(11) Isolated by flash chromatography (EtOAc–hexanes–Et3N,
200:200:1). The yield is based on 7. 1H NMR: = 7.47–7.58
(m, 8 H), 8.00 (d, J = 1.5 Hz, 2 H), 8.07 (dd, J = 1.5, 5.1 Hz,
4 H), 8.84 (d, J = 5.1 Hz, 2 H). EI-MS (70 eV): m/z (%) =
308 (100, M+), 280 (12, M+ – CH2N), 231 (11, M+ – Ph), 204
(24, M+ – Ph, – HCN), 176 (13, M+ – Ph, – HCN, – CH2N),
154 (31, M+ – 2Ph).
Synthesis 2002, No. 6, 749–752 ISSN 0039-7881 © Thieme Stuttgart · New York