Preparation of a New Spirobi[thieno[2,3- c ]pyran] and Its Selective Mono- and Dimetalation: Application for the Preparation of Soluble Conjugated Oligothiophenes and Pyrene Derivatives

Article abstract of DOI:10.1055/s-0035-1560187

3-Thienylacetic acid was converted in six steps into a new spirobi[thieno[2,3-c]pyran] (overall yield: 52%). The spirobi[thieno[2,3-c]pyran] was selectively mono- or dimetalated with butyllithium and then transmetalated with zinc chloride; cross-coupling reaction with various aryl or heteroaryl bromides, including bromo-oligothiophenes, acid chlorides, and 1-bromopyrene, produced the corresponding spiro derivatives in high yields.

Full text of DOI:10.1055/s-0035-1560187

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2015, 47, 3972–3982
paper
3972
V. Dhayalan et al.
Paper
Synthesis
Preparation of a New Spirobi[thieno[2,3-c]pyran] and Its Selective
Mono- and Dimetalation: Application for the Preparation of Soluble
Conjugated Oligothiophenes and Pyrene Derivatives
1) i. n-BuLi, then ZnCl2
E1
Vasudevan Dhayalan
ii. E1-X, Pd(PPh3)4 (5 mol%)
O
O
S
S
S
S
Fernando Rabasa Alcañiz
Veronika Werner
O
O
E2
2) i. n-BuLi, then ZnCl2
ii. E2-X, Pd(PPh3)4 (5 mol%)
Konstantin Karaghiosoff
Paul Knochel*
SMe
SMe
O
O
S
S
S
S
O
O
NC
S
Department of Chemistry, Ludwig-Maximilians-Universität
München, Butenandtstr. 5-13, 81377 Munich, Germany
paul.knochel@cup.uni-muenchen.de
80%
68%
Received: 15.07.2015
Accepted after revision: 24.07.2015
Published online: 02.09.2015
CO2H
n
n
6 steps
X
S
52% overall yield
X
S
S
DOI: 10.1055/s-0035-1560187; Art ID: ss-2015-t0435-op
3
1: n = 1; X = O
2: n = 0; X = S
Abstract 3-Thienylacetic acid was converted in six steps into a new
spirobi[thieno[2,3-c]pyran] (overall yield: 52%). The spirobi[thieno[2,3-
c]pyran] was selectively mono- or dimetalated with butyllithium and
then transmetalated with zinc chloride; cross-coupling reaction with
various aryl or heteroaryl bromides, including bromo-oligothiophenes,
acid chlorides, and 1-bromopyrene, produced the corresponding spiro
derivatives in high yields.
Scheme 1 Retrosynthetic analysis for spiro compound 1
N-bromosuccinimide produced the 2,3-disubstituted thio-
phene 6 in 96% yield; Br/Li-exchange11 on the thiophene 6
using butyllithium followed by the addition of ethyl for-
mate afforded the symmetrical alcohol 7 in 73% yield. Oxi-
dation12 of this benzyl alcohol 7 with manganese dioxide
gave ketone 8 in 98% yield. Desilylation of compound 8 with
tetrabutylammonium fluoride13 in tetrahydrofuran led, af-
ter workup, to an intermediate diol that was refluxed in tol-
uene in the presence of 1 mol% 4-toluenesulfonic acid to
give the desired new and stable spiro compound 1 in 89%
yield and 52% overall yield (Scheme 2).
We first examined the selective metalation and func-
tionalization of the spiro molecule 1. The lithiation of 1
with butyllithium (1.1 equiv) at –78 °C in tetrahydrofuran
led to selective monolithiation. The resulting thienyllithium
9 reacted directly with 1,2-dibromo-1,1,2,2-tetrachloro-
ethane, dimethyl disulfide, or N,N-dimethylformamide fur-
nishing the expected products 11a–c in 64–97% yield
(Scheme 3). Alternatively, the treatment of spiro compound
1 with butyllithium (2.5 equiv) at –78 °C in tetrahydrofuran
for one hour allowed dilithiation leading to the dilithiospiro
compound 12, which after bromination or methylthiolation
furnished the desired difunctionalized spiro molecules
13a,b in 74–95% yield.
Key words lithiation, Negishi cross coupling, oligothiophene, or-
ganozinc reagent, spiro compound
The preparation of molecules bearing a quaternary cen-
ter common to two ring systems (spiro compounds) has at-
tracted much attention, since spiro compounds1 are im-
portant products in various fields of organic chemistry such
as drug discovery,2 medicinal chemistry,3 asymmetric syn-
thesis,4 natural product synthesis,5 and material science.6
Due to our interest in the synthesis of soluble oligothio-
phenes,7 we envisioned the preparation of new spiro scaf-
folds containing two thiophene units such as 1 or 2. Where-
as preliminary experiments showed that the spiro com-
pound 2 (n = 0, X = S) is not stable, the synthesis of 1 (n = 1,
X = O) could be readily performed. Herein, we wish to re-
port a straightforward synthesis of the new spirobi[thie-
no[2,3-c]pyran] 1 in six steps starting from 3-thienylacetic
acid (3) in an overall yield of 52%, as well as its use as a con-
junctive reagent8 to link thiophene or pyrenyl units togeth-
er (Scheme 1).
Thus, the reduction of commercially available 3-thienyl-
acetic acid (3) with lithium aluminum hydride,9 afforded
quantitatively the corresponding alcohol 4, which was si-
lylated with triisopropylsilyl chloride10 leading to thio-
phene 5 in 86% yield. Regioselective bromination of 5 using
Moreover, selective monolithiation of 1 with butyllithi-
um followed by transmetalation with zinc chloride14 afford-
ed thienylzinc reagent 14 (Scheme 4). This organozinc re-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 3972–3982

3973
V. Dhayalan et al.
Paper
Synthesis
OH
OTIPS
butyllithium (1.1 equiv) at –78 °C in tetrahydrofuran fol-
lowed by transmetalation with zinc chloride and palladi-
um-catalyzed cross-coupling with 4-bromobenzonitrile
(10g) gave the expected product 15a in 75% yield. Under
similar reaction conditions, the metalation of 11i (Table 1)
followed by cross-coupling reaction with 4-bromobenzoni-
trile (10g) or 3-bromobenzothiophene (10k) afforded the
TIPS-Cl (1.1 equiv)
DMAP (10 mol%)
CO2H
LiAlH4 (1.5 equiv)
THF, 0 °C, 3 h
Et3N, DMF, r.t.
S
S
S
2 h
3
4: 98%
5: 86%
TIPSO
OTIPS
1) n-BuLi (1.1 equiv)
THF, –78 °C, 1 h
OTIPS
NBS (1 equiv)
AcOH, r.t., 2 h
2) HCO2Et (0.5 equiv)
Br
S
S
–78 °C to r.t., 20 h
S
OH
6: 96%
7: 73%
Table 1 Palladium-Catalyzed Negishi Cross-Coupling Reaction of Or-
ganozinc Reagent 14 with Various Electrophiles 10d–o
TIPSO
OTIPS
1) TBAF (4 equiv)
r.t., 30 h
O
S
S
MnO2 (20 equiv)
O
1,2-DCE, r.t.
5 h
2) p-TsOH (1 mol%)
toluene, reflux
2 h
S
S
Entry
Electrophile (E-X)
Product: yielda,b
O
8: 98%
1: 89%
FG
Br
6 steps: 52% overall yield
O
S
S
O
Scheme 2 Synthesis of new stable spirobi[thieno[2,3-c]pyran] 1
FG
1
2
3
4
5
6
10d: FG = CO2Et
10e: FG = COCH3
10f: FG = CHO
10g: FG = CN
11d: 77%
11e: 92%
11f: 96%
11g: 97%
11h: 87%
11i: 73%
E-X (10a–c)
(1.5 equiv)
Li
E
n-BuLi (1.1 equiv)
O
O
O
S
S
S
S
S
S
O
O
O
THF, –78 °C, 1 h
–78 °C to r.t., 20 h
10a: C2Cl4Br2
10b: S2Me2
10c: DMF
11a: E = Br; 96%
1 (1.0 equiv)
9
11b: E = SMe; 97%
11c: E = CHO; 64%
10h: FG = NO2
10i: FG = SCH3
E
Li
E-X (10a,b)
(2.8 equiv)
O
S
O
N
N
O
S
S
n-BuLi (2.5 equiv)
S
S
S
O
N
Br
O
O
O
S
E
Li
–78 °C to r.t., 20 h
THF, –78 °C, 1 h
S
7
O
N
13a: E = Br; 95%
13b: E = SMe; 74%
1
12
10j
11j: 96%
Scheme 3 Mono- and dilithiation of spirobi[thieno[2,3-c]pyran] 1 fol-
lowed by the addition of electrophiles 10a–c
Br
S
O
S
8
S
S
O
10k
agent 1415 underwent smooth cross coupling with various
11k: 87%
aryl bromides 10d–i in the presence of
5
mol%
N
tetrakis(triphenylphosphine)palladium(0) [Pd(PPh3)4] at
50 °C for 3–6 hours furnishing the arylated spiro products
11d–i in 73–97% yield (Table 1, entries 1–6). Similarly,
Negishi cross coupling16 with various heteroaryl bromides
10j–m gave the corresponding monocoupling products
11j–m in 85–96% yield (entries 7–10). Finally, palladium-
catalyzed acylation17 reaction with the unsaturated acid
chlorides 10n,o under similar reaction conditions produced
the corresponding spiro ketones 11n,o in 89–94% yield (en-
tries 11 and 12).
O
Br
S
9
S
O
N
10l
11l: 85%
N
Br
S
N
S
O
S
S
10
O
10m
10n
11m: 86%
COCl
Notably, the introduction of two different electrophiles
was also achieved. The metalation of 11b (Scheme 3) with
O
S
11
12
S
O
O
11n: 94%
E-X (10)
(0.8 equiv)
1) n-BuLi (1.1 equiv)
THF, –78 °C, 1 h
ZnCl
E
O
O
O
S
S
S
S
S
S
O
O
O
2) ZnCl2 (1.2 equiv)
–78 to 0 °C, 1 h
Pd(PPh3)4 (5 mol%)
50 °C, 3–6 h
O
S
COCl
S
O
S
S
1 (1.0 equiv)
14
11d–o: 73–97%
10o
O
11o: 89%
Scheme 4 Monolithiation of spirobi[thieno[2,3-c]pyran] 1 followed by
a transmetalation with zinc chloride and cross-coupling reaction with
electrophiles 10d–o
a General reaction conditions: Pd(PPh3)4 (5 mol%), ArBr or ArCOCl (0.8
equiv), organozinc reagent (1.0 equiv), THF, 50 °C.
b Yield after purification by flash column chromatography.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 3972–3982

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Synthesis
corresponding difunctionalized products 15b,c in 68–80%
yield (Scheme 5).
ladium-catalyzed cross coupling with 17 gave the expected
bis-pyrenyl product 19 in 46% yield. The solubility of 19 in
organic solvents such as chloroform (3.7 g/L) and tetrahy-
drofuran (2.6 g/L) is acceptable.
1) metalation
E1
E1-X
O
O
S
S
S
2) metalation
E2-X
S
O
O
E2
1) n-BuLi, THF, –78 °C, 1 h
then ZnCl2 (1.2 equiv)
O
O
S
S
S
1
15a–c: 68–80%
S
2) 1-bromopyrene 17 (0.8 equiv)
O
O
Pd(PPh3)4 (5 mol%), 50 °C, 3 h
SMe
SMe
O
S
O
S
S
1 (1.0 equiv)
18: 73%
O
S
O
NC
NC
O
15b: 80%
15a: 75%
S
1) n-BuLi, THF, –78 °C, 1 h
S
then ZnCl2 (1.2 equiv)
O
18
2) 17, Pd(PPh3)4 (5 mol%)
SMe
O
50 °C, 3 h
S
S
O
S
19: 46%
15c: 68%
Scheme 7 Synthesis of symmetrical pyrenyl-spiro molecule 19
Scheme 5 Synthesis of unsymmetrically difunctionalized spiro com-
pounds 15a–c
In summary, we have prepared a new conjunctive spiro
molecule 1 in six steps from commercially available 3-thie-
nylacetic acid with an overall yield of 52%. We have demon-
strated the selective metalation of 1 and trapping with one
or two electrophiles. Palladium-catalyzed cross coupling of
organozinc reagents with oligothiophene units or 1-pyrenyl
units provided soluble building blocks such as 16 and 19
that are of interest to materials science.
Remarkably, we anticipated that the cross coupling with
oligothiophenes moieties should provide materials that are
soluble in organic solvents. This could be confirmed, and
selective mono-cross-coupling reaction of 1 with various
bromothiophenes 10p–s18 [5 mol% Pd(PPh3)4, THF, 50 °C, 3
h] gave the desired oligothiophenes 11p–s in 57–68% yield.
Interestingly, further treatment of 11p with butyllithium
and subsequent transmetalation with zinc chloride fur-
nished, after palladium-catalyzed cross coupling with bro-
mothiophene 10p, the symmetrical disubstituted spiro
molecule 16 in 63% yield (Scheme 6). The solubility of prod-
ucts 11p–s and 16 is excellent in tetrahydrofuran and chlo-
roform.
All reactions were carried out under an argon atmosphere in flame-
dried glassware. Syringes, which were used to transfer anhydrous sol-
vents or reagents, were purged with argon prior to use. THF was con-
tinuously refluxed and freshly distilled from Na benzophenone ketyl
under N2. Yields refer to isolated yields of compounds estimated to be
>95% pure as determined by 1H NMR (25 °C) and capillary GC. NMR
spectra were recorded in a solution of CDCl3 (residual CHCl3: δ = 7.25
for 1H NMR and δ = 77.0 for 13C NMR). Column chromatographic puri-
fication was performed using silica gel (0.040–0.063 mm, 230–400
mesh ASTM) from Merck. All reagents were obtained from commer-
cial sources.
1) n-BuLi, THF, –78 °C, 1 h
then ZnCl2 (1.2 equiv)
O
O
S
S
S
S
S
S
2) E-X (10p–s) (0.8 equiv)
O
O
R
Pd(PPh3)4 (5 mol%), 50 °C, 3 h
11p: R = Me; 64%
11q: R = 1-adamantyl; 68%
11r: R = 2-thienyl; 57%
1 (1.0 equiv)
S
R
Br
S
10p: R = Me
10q: R = 1-adamantyl
10r: R = 2-thienyl
11s: R = 5-methylthienyl; 60%
10p–s
1 M Zinc Chloride in Tetrahydrofuran Solution
10s: R = 5-methylthienyl
A dry and argon-flushed 250-mL Schlenk flask equipped with a mag-
netic stirring bar and a septum was charged with ZnCl2 (13.6 g,
100 mmol). The salt was heated to 140 °C under high vacuum for
10 h. After cooling to 25 °C, anhyd THF (100 mL) was added and stir-
ring was continued until the salt was dissolved completely (4 h).
1) n-BuLi, THF, –78 °C, 1 h
then ZnCl2 (1.2 equiv)
O
S
S
S
11p
S
O
S
2) E-X (10p) (0.8 equiv)
Pd(PPh3)4 (5 mol%), 50 °C, 3 h
S
16: 63%
Scheme 6 Synthesis of soluble oligothiophenes 11p–s and 16
2-(Thiophen-3-yl)ethan-1-ol (4)9
In a flame-dried Schlenk flask, equipped with a magnetic stirring bar,
an argon inlet, and a septum, LiAlH4 (5.7 g, 150 mmol, 1.5 equiv) was
dissolved in THF (100 mL) at 0 °C. A solution of 3-thienylacetic acid (3,
14.2 g, 100 mmol, 1.0 equiv) in THF (50 mL) at 0 °C was added drop-
wise. The mixture was stirred for 3 h at 0 °C and then it was carefully
quenched with EtOAc and EtOH. Subsequently, 1–2% NaOH (20 mL)
was added and the mixture was stirred for 1 h, allowing aluminum
hydroxide to precipitate as a granular solid. Finally, the mixture was
filtered over Celite. The collected organic layers were dried (MgSO4),
and the solvent was evaporated in vacuo to give the pure alcohol 4
(12.5 g, 98%) as a pale yellow oil.
Furthermore, we have attached 1-pyrenyl moieties to
the conjunctive reagent 1. The pyrenyl group has found
many applications in material science as organic electron-
ics19 and the planar pyrenyl group often leads to products
of low solubility in organic solvents. Thus, metalation of 1
(1. n-BuLi; 2. ZnCl2) followed by standard Negishi cross cou-
pling with 1-bromopyrene (17) provided the well-soluble
mono-pyrenyl coupling product 18 in 73% yield (Scheme 7).
Successfully, further metalation of 18 and subsequent pal-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 3972–3982

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Synthesis
Triisopropyl[2-(thiophen-3-yl)ethoxy]silane (5)
column chromatography (silica gel pre-neutralized with Et3N, isohex-
ane–EtOAc, 90:10) to give the pure alcohol product 7 (1.8 g, 73%) as a
pale yellow solid; mp 40.0–41.3 °C.
A dry, argon-flushed Schlenk flask equipped with a magnetic stirring
bar and a septum was charged with 2-(thiophen-3-yl)ethan-1-ol (4,
12.3 g, 96 mmol, 1.0 equiv) and DMF (100 mL) at r.t. Subsequently,
Et3N (10.7 g, 105 mmol, 1.1 equiv), DMAP (1.17 g, 9.6 mmol), and
TIPSCl (20.3 g, 105 mmol, 1.1 equiv) were added. The resulting mix-
ture was stirred for 2 h at r.t. and then it was quenched with water
and extracted with Et2O (5 × 60 mL). The combined organic layers
were dried (MgSO4) and the solvent was evaporated in vacuo. The
crude residue was purified by flash column chromatography (silica
gel pre-neutralized with Et3N, isohexane–EtOAc, 99:1) and gave the
pure silylated compound 5 (23.4 g, 86%) as a pale yellow oil.
IR (ATR): 3432, 2940, 2865, 1462, 1084, 1032, 882, 740, 684 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 7.15 (d, J = 5.0 Hz, 2 H), 6.87 (d, J = 5.0
Hz, 2 H), 6.34 (s, 1 H), 4.41 (s, 1 H), 3.64–3.97 (m, 4 H), 2.70–3.04 (m, 4
H), 0.61–1.46 (m, 6 H), 1.00 (d, J = 4.7 Hz, 36 H).
13C NMR (75 MHz, CDCl3): δ = 143.0, 135.4, 128.9, 123.8, 64.5, 63.6,
32.0, 17.8, 11.9.
MS (ESI): m/z (%) = 579 ([M – OH]+, 100), 295 (4).
HRMS (ESI): m/z [M – OH] calcd for C31H55O2S2Si2: 579.3182; found:
579.3173.
IR (ATR): 2941, 2864, 1462, 1100, 881, 769, 677 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 7.18–7.27 (m, 1 H), 6.93–7.04 (m, 2 H),
3.88 (t, J = 6.9 Hz, 2 H), 2.88 (t, J = 6.9 Hz, 2 H), 0.77–1.35 (m, 3 H),
1.04 (d, J = 4.2 Hz, 18 H).
13C NMR (75 MHz, CDCl3): δ = 139.5, 128.7, 124.9, 121.1, 64.0, 34.0,
18.0, 12.0.
Bis{3-[2-(triisopropylsiloxy)ethyl]thiophen-2-yl}methanone (8)
Activated MnO2 (34.1 g, 392.3 mmol, 20 equiv) was added to a solu-
tion of alcohol 7 (11.7 g, 19.59 mmol, 1.0 equiv) in anhyd 1,2-dichlo-
roethane (400 mL); the mixture was stirred at r.t. for 5 h. The result-
ing solution was passed through Celite pad and washed with CHCl3 (5
× 50 mL). The removal of solvent gave the analytically pure product 8
(11.4 g, 98%) as a pale yellow oil.
MS (EI): m/z (%) = 241 ([M – C3H7]+, 100), 213 (15), 171 (13), 111 (28),
75 (9), 43 (31).
HRMS (EI): m/z [M – C3H7] calcd for C12H21OSSi: 241.1082; found:
241.1061.
IR (ATR): 2941, 2864, 1619, 1408, 1096, 880, 677 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.43 (d, J = 4.8 Hz, 2 H), 7.14 (d, J = 4.8
Hz, 2 H), 3.96 (t, J = 6.4 Hz, 4 H), 3.16 (t, J = 6.4 Hz, 4 H), 0.81–1.21 (m,
6 H), 1.04 (d, J = 5.4 Hz, 36 H).
[2-(2-Bromothiophen-3-yl)ethoxy]triisopropylsilane (6)
To a solution of thiophene 5 (15.6 g, 54.8 mmol. 1.0 equiv) in AcOH
(27 mL), NBS (9.76 g, 54.8 mmol, 1.0 equiv) was added at 0 °C and the
mixture was stirred at r.t. for 2 h. The mixture was quenched with
water (100 mL) and then it was neutralized with sat. aq NaHCO3 solu-
tion. The resulting solution was extracted with Et2O (4 × 50 mL). The
combined organic phases were dried (Na2SO4) and concentrated in
vacuo. The crude residue obtained was purified by flash column chro-
matography (silica gel pre-neutralized with Et3N, isohexane–EtOAc,
99:1) to give bromo compound 6 (19.1 g, 96%) as a pale yellow oil.
13C NMR (100 MHz, CDCl3): δ = 181.8, 147.2, 136.4, 132.0, 129.3, 63.6,
33.7, 18.0, 12.0.
MS (EI): m/z (%) = 576 ([M – H2O]+, 6), 551 (100), 365 (85), 131 (60),
103 (86), 74 (65), 43 (87).
HRMS (EI): m/z [M – H2O] calcd for C31H52O2S2Si2: 576.2947; found:
576.2954.
4,4′,5,5′-Tetrahydro-7,7′-spirobi[thieno[2,3-c]pyran (1)
IR (ATR): 2941, 2864, 1462, 1103, 881, 679 cm–1
.
A dry, argon-flushed Schlenk flask equipped with a magnetic stirring
bar and a septum was charged with ketone 8 (5.0 g, 8.4 mmol. 1.0
equiv) in anhyd THF (80 mL) and cooled to 0 °C. Then 1 M TBAF in THF
(30.54 mL, 33.6 mmol, 4.0 equiv) was added and the mixture was
stirred at 0 to 25 °C for 30 h. Removal of the solvent afforded the
crude mixture which was quenched with sat. aq NH4Cl solution (20
mL) and extracted with EtOAc (4 × 30 mL). The combined organic
phases were dried (Na2SO4) and concentrated in vacuo. The obtained
crude diol was treated with p-TsOH (15.9 mg, 0.084 mmol, 0.01
equiv) in toluene (200 ml) and refluxed for 2 h; the mixture was
cooled to r.t. After removal of the solvent, the crude residue obtained
was purified by flash column chromatography (silica gel pre-neutral-
ized with Et3N, isohexane–EtOAc, 85:15) to give the pure spiro prod-
uct 1 (1.97 g, 89%) as a pale yellow solid; mp 156.7–157.6 °C.
1H NMR (300 MHz, CDCl3): δ = 7.17 (d, J = 5.5 Hz, 1 H), 6.88 (d, J = 5.5
Hz, 1 H), 3.85 (t, J = 6.9 Hz, 2 H), 2.84 (t, J = 6.9 Hz, 2 H), 0.73–1.35 (m,
3 H), 1.04 (d, J = 4.2 Hz, 18 H).
13C NMR (75 MHz, CDCl3): δ = 138.7, 129.1, 125.0, 109.8, 62.7, 33.1,
17.9, 11.9.
MS (EI): m/z (%) = 321 ([M – C3H7]+, 100), 319 ([M – C3H7]+, 85), 290
(19), 190 (15), 169 (24), 132 (11), 110 (22), 43 (10).
HRMS (EI): m/z [M – C3H7] calcd for C12H20BrOSSi: 319.0188; found:
319.0167.
Bis{3-[2-(triisopropylsiloxy)ethyl]thiophen-2-yl}methanol (7)
A dry, argon-flushed Schlenk flask equipped with a magnetic stirring
bar and a septum was charged with bromothiophene 6 (3.0 g, 8.25
mmol, 1.0 equiv) dissolved in THF (40 mL). 2.48 M n-BuLi in hexane
(3.66 mL, 9.08 mmol, 1.1 equiv) was added dropwise to this solution
at –78 °C and the resulting mixture was stirred for 1 h; ethyl formate
(0.30 g, 4.12 mmol, 0.5 equiv) was added and the mixture was al-
lowed to warm up to r.t. and stirred overnight. The resulting mixture
was quenched with sat. aq NH4Cl (30 mL) and extracted with Et2O (3 ×
50 mL). The combined organic phases were dried (Na2SO4) and con-
centrated in vacuo. The crude residue obtained was purified by flash
IR (ATR): 2934, 2876, 1554, 1277, 1244, 1158, 1041, 963, 932, 730,
715 cm–1
.
1H NMR (600 MHz, CDCl3): δ = 7.24 (d, J = 5.2 Hz, 2 H), 6.80 (d, J = 5.2
Hz, 2 H), 4.27 (td, J = 11.8, 3.0 Hz, 2 H), 4.06 (dd, J = 11.3, 5.7 Hz, 2 H),
2.95–3.06 (m, 2 H), 2.63 (dd, J = 16.2, 3.0 Hz, 2 H).
13C NMR (150 MHz, CDCl3): δ = 137.5, 136.3, 125.8, 125.7, 94.7, 60.0,
25.8.
MS (EI): m/z (%) = 264 (M+, 10), 235 (17), 234 (100), 201 (23), 109 (6),
97 (6).
HRMS (EI): m/z [M]+ calcd for C13H12O2S2: 264.0279; found: 264.0268.
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Reaction of Organolithium Reagent 9 with Various Electrophiles
10a–c; Typical Procedure 1 (TP1)
4,4′,5,5′-Tetrahydro-7,7′-spirobi[thieno[2,3-c]pyran]-2-carbalde-
hyde (11c)
A dry, argon-flushed Schlenk flask equipped with a magnetic stirring
bar and a septum was charged with spiro compound 1 (0.38 mmol.
1.0 equiv) in anhyd THF (3 mL) and cooled to –78 °C for 10 min. 2.48
M n-BuLi in hexane (0.42 mmol, 1.1 equiv) was added and the mix-
ture was stirred at –78 °C for 1 h until GC analysis of reaction aliquots
showed full consumption of the starting material. Then the electro-
phile 10a–c (0.6 mmol, 1.5 equiv) was added and the mixture was al-
lowed to warm up to r.t. and stirred overnight. The mixture was
quenched with sat. aq NH4Cl solution (5 mL) and extracted with EtO-
Ac (4 × 15 mL). The combined organic phases were dried (Na2SO4) and
concentrated in vacuo. The crude residue obtained was purified by
flash column chromatography (silica gel pre-neutralized with Et3N,
isohexane–EtOAc) to give the analytically pure spiro product 11a–c.
The reaction of spiro compound 1 (100 mg, 0.38 mmol, 1.0 equiv) in
anhyd THF (3 mL) with 2.48 M n-BuLi in hexane (0.17 mL, 0.42 mmol,
1.1 equiv) and DMF 10c (42 mg, 0.57 mmol, 1.5 equiv) was performed
according to TP1 overnight. Flash column chromatographic purifica-
tion (silica gel pre-neutralized with Et3N, isohexane–EtOAc, 50:50)
furnished 11c (71 mg, 64%) as a pale yellow solid; mp 171.6–172.8 °C.
IR (ATR): 2925, 2852, 1666, 1272, 1233, 1137, 1023, 969, 937, 714 cm–1
.
1H NMR (400 MHz, DMSO-d6): δ = 9.90 (s, 1 H), 7.81 (s, 1 H), 7.53 (d,
J = 5.1 Hz, 1 H), 6.92 (d, J = 5.1 Hz, 1 H), 3.91–4.22 (m, 4 H), 2.62–2.96
(m, 4 H).
13C NMR (100 MHz, DMSO-d6): δ = 185.1, 147.1, 142.8, 138.3, 137.3,
136.9, 136.4, 127.0, 126.6, 94.4, 60.0, 59.7, 25.7, 25.5.
MS (EI): m/z (%) = 292 (M+, 6), 262 (100), 229 (17), 190 (7), 109 (5), 65
2-Bromo-4,4′,5,5′-tetrahydro-7,7′-spirobi[thieno[2,3-c]pyran]
(4).
(11a)
HRMS (EI): m/z [M]+ calcd for C14H12O3S2: 292.0228; found: 292.0219.
The reaction of spiro compound 1 (100 mg, 0.38 mmol, 1.0 equiv) in
anhyd THF (3 mL) with 2.48 M n-BuLi in hexane (0.17 mL, 0.42 mmol,
1.1 equiv) and 1,2-dibromo-1,1,2,2-tetrachloroethane (10a, 185 mg,
0.57 mmol, 1.5 equiv) was performed according to TP1 overnight.
Flash column chromatographic purification (silica gel pre-neutralized
with Et3N, isohexane–EtOAc, 85:15) furnished 11a (125 mg, 96%) as a
pale yellow solid; mp 153.9–155.0 °C.
2,2′-Dibromo-4,4′,5,5′-tetrahydro-7,7′-spirobi[thieno[2,3-c]pyran]
(13a)
A dry, argon-flushed Schlenk flask equipped with a magnetic stirring
bar and a septum was charged with spiro compound 1 (200 mg, 0.76
mmol. 1.0 equiv) in anhyd THF (6 mL) and cooled to –78 °C for 10
min. 2.48 M n-BuLi in hexane (0.76 mL, 1.89 mmol, 2.5 equiv) was
added and the mixture was stirred at –78 °C for 1 h until GC analysis
of reaction aliquots showed full consumption of the starting material.
Then 1,2-dibromo-1,1,2,2-tetrachloroethane (10a, 691 mg, 2.12
mmol, 2.8 equiv) was added and the mixture was allowed to warm up
to r.t. and stirred overnight. The mixture was quenched with sat. aq
NH4Cl solution (5 mL) and extracted with EtOAc (4 × 15 mL). The com-
bined organic phases were dried (Na2SO4) and concentrated in vacuo.
The crude residue obtained was purified by flash column chromatog-
raphy (silica gel pre-neutralized with Et3N), isohexane–EtOAc, 90:10)
to furnish 13a (302 mg, 95%) as a pale yellow solid; mp 197.0–
197.4 °C.
IR (ATR): 2924, 2885, 1441, 1242, 1035, 974, 929, 816, 714 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.19 (d, J = 4.7 Hz, 1 H), 6.73 (d, J = 4.7
Hz, 1 H), 6.70 (s, 1 H), 4.09–4.26 (m, 2 H), 3.96 (td, J = 12.4, 5.7 Hz, 2
H), 2.80–2.97 (m, 2 H), 2.40–2.60 (m, 2 H).
13C NMR (100 MHz, CDCl3): δ = 139.3, 137.1, 136.8, 136.6, 128.8,
126.0, 126.0, 114.0, 94.1, 60.1, 59.9, 25.9, 25.4.
MS (EI): m/z (%) = 344 (M+, 12), 342 (M+, 14), 314 (100), 312 (97), 234
(20), 109 (25), 69 (28), 43 (38).
HRMS (EI): m/z [M]+ calcd for C13H11BrO2S2: 341.9384; found:
341.9386.
IR (ATR): 2991, 2952, 1558, 1440, 1240, 1146, 1033, 977, 928, 815 cm–1
.
2-(Methylthio)-4,4′5,5′-tetrahydro-7,7′-spirobi[thieno[2,3-
c]pyran] (11b)
1H NMR (400 MHz, CDCl3): δ = 6.77 (s, 2 H), 4.22 (td, J = 11.7, 3.0 Hz, 2
H), 4.01 (dd, J = 11.2, 5.6 Hz, 2 H), 2.82–2.99 (m, 2 H), 2.53 (dd,
J = 16.4, 3.0 Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 138.5, 137.1, 128.8, 114.3, 93.5, 60.0,
25.4.
MS (EI): m/z (%) = 422 (M+, 16), 420 (M+, 8), 394 (55), 392 (100), 390
(45), 313 (63), 311 (55), 232 (12), 109 (9).
HRMS (EI): m/z [M]+ calcd for C13H10Br2O2S2: 419.8489; found:
The reaction of spiro compound 1 (100 mg, 0.38 mmol, 1.0 equiv) in
anhyd THF (3 mL) with 2.48 M n-BuLi in hexane (0.17 mL, 0.42 mmol,
1.1 equiv) and dimethyl disulfide (10b, 53 mg, 0.57 mmol, 1.5 equiv)
was performed according to TP1 overnight. Flash column chromato-
graphic purification (silica gel pre-neutralized with Et3N, isohexane–
EtOAc, 80:20) furnished 11b (114 mg, 97%) as a pale yellow solid; mp
103.3–105.3 °C.
IR (ATR): 2967, 2914, 1556, 1424, 1273, 1151, 1034, 976, 932, 718 cm–1
.
419.8485.
1H NMR (400 MHz, CDCl3): δ = 7.18 (d, J = 5.0 Hz, 1 H), 6.73 (d, J = 5.0
Hz, 1 H), 6.68 (s, 1 H), 4.12–4.25 (m, 2 H), 3.97 (td, J = 10.5, 6.1 Hz, 2
H), 2.79–2.97 (m, 2 H), 2.42–2.60 (m, 2 H), 2.36 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 139.3, 138.6, 137.1, 136.6, 136.5,
129.0, 125.9, 125.8, 94.4, 60.1, 60.0, 25.9, 25.6, 21.6.
MS (EI): m/z (%) = 310 (M+, 27), 282 (18), 281 (27), 280 (100), 265
(19). 171 (10), 97 (14).
HRMS (EI): m/z [M]+ calcd for C14H14O2S3: 310.0156; found: 310.0165.
2,2′-Bis(methylthio)-4,4′,5,5′-tetrahydro-7,7′-spirobi[thieno[2,3-
c]pyran] (13b)
A dry, argon-flushed Schlenk flask equipped with a magnetic stirring
bar and a septum was charged with spiro compound 1 (100 mg, 0.38
mmol. 1.0 equiv) in anhyd THF (4 mL) and cooled to –78 °C for 10
min. 2.48 M n-BuLi in hexane (0.38 mL, 0.95 mmol, 2.5 equiv) was
added and the mixture was stirred at –78 °C for 1 h until GC analysis
of reaction aliquots showed full consumption of the starting material.
Then dimethyl disulfide (10b, 100 mg, 1.1 mmol, 2.8 equiv) was add-
ed and the mixture was allowed to warm up to r.t. and stirred over-
night. The mixture was quenched with sat. aq NH4Cl solution (5 mL)
and extracted with EtOAc (4 × 15 mL). The combined organic phases
were dried (Na2SO4) and concentrated in vacuo. The crude residue ob-
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Synthesis
tained was purified by flash column chromatography(silica gel pre-
neutralized with Et3N, isohexane–EtOAc, 80:20) to furnish 13b as a
white solid (100 mg, 74%); mp 114.6–116.7 °C.
1-[4-(4,4′,5,5′-Tetrahydro-7,7′-spirobi[thieno[2,3-c]pyran]-2-
yl)phenyl]ethan-1-one (11e)
Cross coupling of spiro compound 1 (100 mg, 0.38 mmol, 1.0 equiv)
was performed according to TP2. The intermediate zinc reagent was
prepared using 2.48 M n-BuLi in hexane (0.17 mL, 0.42 mmol, 1.1
equiv) and 1 M ZnCl2 in THF solution (0.46 mL, 0.46 mmol, 1.2 equiv)
and cross coupling was performed using the aryl bromide 10e (60 mg,
0.30 mmol, 0.8 equiv) and Pd(PPh3)4 (17 mg, 0.015 mmol, 0.05 equiv)
at 50 °C for 4 h. Flash column chromatographic purification (silica gel
pre-neutralized with Et3N, isohexane–EtOAc, 50:50) furnished 11e as
a yellow solid (105 mg, 92%); mp 155.6–158.2 °C.
IR (ATR): 2965, 2920, 2854, 1562, 1446, 1271, 1031, 930, 794 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 6.76 (s, 2 H), 4.25 (td, J = 11.7, 3.0 Hz, 2
H), 4.04 (dd, J = 11.3, 5.9 Hz, 2 H), 2.86–2.99 (m, 2 H), 2.54 (dd,
J = 16.1, 3.0 Hz, 2 H), 2.46 (s, 6 H).
13C NMR (100 MHz, CDCl3): δ = 138.8, 138.7, 136.7, 129.0, 94.0, 60.0,
25.6, 21.6.
MS (EI): m/z (%) = 356 (M+, 32), 326 (100), 311 (15), 279 (70), 97 (9),
69 (8).
IR (ATR): 3104, 3010, 2909, 1682, 1602, 1272, 1158, 1034, 968, 824,
HRMS (EI): m/z [M]+ calcd for C15H16O2S4: 356.0033; found: 356.0029.
718 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.94 (d, J = 8.4 Hz, 2 H), 7.62 (d, J = 8.4
Hz, 2 H), 7.30 (d, J = 5.1 Hz, 1 H), 7.17 (s, 1 H). 6.86 (d, J = 5.1 Hz, 1 H),
4.25–4.41 (m, 2 H), 4.12 (dd, J = 11.3, 5.8 Hz, 2 H), 2.98–3.12 (m, 2 H),
2.68 (dt, J = 16.2, 4.0 Hz, 2 H), 2.61 (s, 3 H).
Palladium-Catalyzed Cross-Coupling Reactions of Organozinc Re-
agent 14 with Various Electrophiles 10d–o; Typical Procedure 2
(TP2)
13C NMR (100 MHz, CDCl3): δ = 197.3, 143.0, 138.8, 138.6, 137.6,
137.0, 136.6, 135.9, 129.1, 126.0, 125.9, 125.6, 123.5, 94.6, 60.2, 60.0,
26.6, 25.9, 25.8.
MS (EI): m/z (%) = 382 (M+, 14), 354 (14), 353 (22), 352 (100), 319
(30), 154 (8), 43 (37).
A dry, argon-flushed Schlenk flask equipped with a magnetic stirring
bar and a septum was charged with spiro compound 1 (0.38 mmol.
1.0 equiv) in anhyd THF (3 mL) and cooled to –78 °C for 10 min. 2.48
M n-BuLi in hexane (0.42 mmol, 1.1 equiv) was added and the mix-
ture was stirred at –78 °C for 1 h until GC analysis of reaction aliquots
showed full consumption of the starting material. 1 M ZnCl2 in THF
solution (0.46 mmol, 1.2 equiv) was added and the mixture was
stirred at –78 to 0 °C for 1 h. An aryl bromide or acid chloride 10d–o
(0.30 mmol, 0.8 equiv) and Pd(PPh3)4 (0.015 mmol, 0.05 equiv, 5
mol%) were added and the mixture was stirred at 50 °C for 3–6 h. The
mixture was quenched with sat. aq NH4Cl solution (5 mL) and ex-
tracted with EtOAc (4 × 15 mL). The combined organic phases were
dried (Na2SO4) and concentrated in vacuo. The crude residue obtained
was purified by flash column chromatography (silica gel pre-neutral-
ized with Et3N, isohexane–EtOAc) to give the analytically pure spiro
product 11d–o.
HRMS (EI): m/z [M]+ calcd for C21H18O3S2: 382.0697; found: 382.0690.
4-(4,4′,5,5′-Tetrahydro-7,7′-spirobi[thieno[2,3-c]pyran]-2-yl)benz-
aldehyde (11f)
Cross coupling of spiro compound 1 (100 mg, 0.38 mmol, 1.0 equiv)
was performed according to TP2. The intermediate zinc reagent was
prepared using 2.48 M n-BuLi in hexane (0.17 mL, 0.42 mmol, 1.1
equiv) and 1 M ZnCl2 in THF solution (0.46 mL, 0.46 mmol, 1.2 equiv)
and cross coupling was performed using the aryl bromide 10f (56 mg,
0.30 mmol, 0.8 equiv) and Pd(PPh3)4 (17 mg, 0.015 mmol, 0.05 equiv)
at 50 °C for 4 h. Flash column chromatographic purification (silica gel
pre-neutralized with Et3N, isohexane–EtOAc, 50:50) furnished 11f as
a yellow solid (106 mg, 96%); mp 129.0–130.8 °C.
Ethyl 4-(4,4′,5,5′-Tetrahydro-7,7′-spirobi[thieno[2,3-c]pyran]-2-
yl)benzoate (11d)
Cross coupling of spiro compound 1 (100 mg, 0.38 mmol, 1.0 equiv)
was performed according to TP2. The intermediate zinc reagent was
prepared using 2.48 M n-BuLi in hexane (0.17 mL, 0.42 mmol, 1.1
equiv) and 1 M ZnCl2 in THF solution (0.46 mL, 0.46 mmol, 1.2 equiv)
and cross coupling was performed using the aryl bromide 10d (69
mg, 0.30 mmol, 0.8 equiv) and Pd(PPh3)4 (17 mg, 0.015 mmol, 0.05
equiv) at 50 °C for 3 h. Flash column chromatographic purification
(silica gel pre-neutralized with Et3N, isohexane–EtOAc, 70:30) fur-
nished 11d (95 mg, 77%) as a pale yellow solid; mp 183.6–184.7 °C.
IR (ATR): 3113, 2909, 2833, 2734, 1696, 1601, 1558, 1277, 1159, 1036,
968, 821, 717 cm–1
.
1H NMR (400 MHz, DMSO-d6): δ = 9.97 (s, 1 H), 7.89 (d, J = 8.2 Hz, 2
H), 7.81 (d, J = 8.2 Hz, 2 H), 7.49–7.54 (m, 2 H), 6.91 (d, J = 5.1 Hz, 1 H),
3.99–4.13 (m, 4 H), 2.80–2.94 (m, 2 H), 2.62–2.72 (m, 2 H).
13C NMR (100 MHz, DMSO-d6): δ = 192.7, 141.9, 139.5, 139.3, 138.4,
137.2, 137.1, 135.6, 130.8, 126.8, 126.6, 126.1, 125.3, 94.4, 59.9, 59.8,
25.8, 25.7.
MS (EI): m/z (%) = 368 (M+, 14), 338 (100), 310 (9), 305 (27), 171 (6).
HRMS (EI): m/z [M]+ calcd for C20H16O3S2: 368.0541; found: 368.0538.
IR (ATR): 3111, 2981, 2922, 2884, 1712, 1606, 1273, 1027, 971, 766,
696 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.92 (d, J = 8.2 Hz, 2 H), 7.50 (d, J = 8.4
Hz, 2 H), 7.19 (d, J = 5.1 Hz, 1 H), 7.05 (s, 1 H), 6.76 (d, J = 5.1 Hz, 1 H),
4.14–4.34 (m, 4 H), 4.02 (dd, J = 11.0, 5.7 Hz, 2 H), 2.87–3.03 (m, 2 H),
2.57 (dt, J = 16.3, 3.8 Hz, 2 H), 1.31 (t, J = 7.1 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 166.2, 143.2, 138.6, 138.3, 137.5,
137.0, 136.6, 130.2, 129.4, 126.0, 125.9, 125.4, 123.3, 94.6, 61.0, 60.1,
60.0, 25.9, 25.8, 14.4.
MS (EI): m/z (%) = 412 (M+, 11), 383 (23), 382 (100), 349 (22), 171 (6),
147 (6).
HRMS (EI): m/z [M]+ calcd for C22H20O4S2: 412.0803; found: 412.0798.
4-(4,4′,5,5′-Tetrahydro-7,7′-spirobi[thieno[2,3-c]pyran]-2-yl)ben-
zonitrile (11g)
Cross coupling of spiro compound 1 (100 mg, 0.38 mmol, 1.0 equiv)
was performed according to TP2. The intermediate zinc reagent was
prepared using 2.48 M n-BuLi in hexane (0.17 mL, 0.42 mmol, 1.1
equiv) and 1 M ZnCl2 in THF solution (0.46 mL, 0.46 mmol, 1.2 equiv)
and cross coupling was performed using the aryl bromide 10g (55
mg, 0.30 mmol, 0.8 equiv) and Pd(PPh3)4 (17 mg, 0.015 mmol, 0.05
equiv) at 50 °C for 5 h. Flash column chromatographic purification
(silica gel pre-neutralized with Et3N, isohexane–EtOAc, 67:33) fur-
nished 11g (106 mg, 97%) as a pale yellow solid; mp 152.2–153.2 °C.
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IR (ATR): 3112, 2939, 2906, 2832, 2226, 1604, 1276, 1158, 1034, 968,
930, 818, 718 cm–1
HRMS (EI): m/z [M]+ calcd for C20H18O2S3: 386.0469; found: 386.0463.
.
1H NMR (400 MHz, CDCl3): δ = 7.54–7.64 (m, 4 H), 7.28 (d, J = 5.1 Hz, 1
H), 7.13 (s, 1 H), 6.84 (d, J = 5.1 Hz, 1 H), 4.22–4.37 (m, 2 H), 4.10 (dd,
J = 11.1, 5.7 Hz, 2 H), 2.95–3.10 (m, 2 H), 2.66 (ddd, J = 16.2, 5.7, 3.2
Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 142.1, 139.5, 138.5, 137.8, 136.8,
136.7, 132.7, 126.0, 126.0, 126.0, 124.0, 118.8, 110.8, 94.5, 60.2, 60.0,
25.9, 25.8.
2-(4,4′,5,5′-Tetrahydro-7,7′-spirobi[thieno[2,3-c]pyran]-2-yl)py-
rimidine (11j)
Cross coupling of spiro compound 1 (100 mg, 0.38 mmol, 1.0 equiv)
was performed according to TP2. The intermediate zinc reagent was
prepared using 2.48 M n-BuLi in hexane (0.17 mL, 0.42 mmol, 1.1
equiv) and 1 M ZnCl2 in THF solution (0.46 mL, 0.46 mmol, 1.2 equiv)
and cross coupling was performed using heteroaryl bromide 10j (48
mg, 0.30 mmol, 0.8 equiv) and Pd(PPh3)4 (17 mg, 0.015 mmol, 0.05
equiv) at 50 °C for 4 h. Flash column chromatographic purification
(silica gel pre-neutralized with Et3N, isohexane–EtOAc, 75:25) fur-
nished 11j (99 mg, 96%) as a pale yellow solid; mp 196.0–197.8 °C.
MS (EI): m/z (%) = 365 (M+, 11), 335 (100), 302 (24), 146 (5).
HRMS (EI): m/z [M]+ calcd for C20H15NO2S2: 365.0544; found:
365.0533.
IR (ATR): 2975, 2925, 2874, 1554, 1414, 1391, 1276, 1154, 1034, 973,
2-(4-Nitrophenyl)-4,4′,5,5′-tetrahydro-7,7′-spirobi[thieno[2,3-
c]pyran] (11h)
933, 803 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 8.65 (d, J = 4.9 Hz, 2 H), 7.73 (s, 1 H),
7.26 (d, J = 5.1 Hz, 1 H), 7.07 (t, J = 4.9 Hz, 1 H), 6.82 (d, J = 5.1 Hz, 1 H),
4.31 (dddd, J = 13.4, 12.3, 11.7, 3.0 Hz, 2 H), 4.11 (dd, J = 11.1, 5.8 Hz, 2
H), 2.95–3.15 (m, 2 H), 2.67 (ddd, J = 16.2, 6.5, 3.0 Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 161.4, 157.2, 143.0, 142.4, 137.3,
137.0, 136.6, 127.6, 126.0, 125.8, 118.7, 94.6, 60.2, 60.1, 26.0, 25.8.
MS (EI): m/z (%) = 342 (M+, 10), 313 (21), 312 (100), 283 (12), 279
(20), 141 (5).
HRMS (EI): m/z [M]+ calcd for C17H14N2O2S2: 342.0497; found:
Cross coupling of spiro compound 1 (100 mg, 0.38 mmol, 1.0 equiv)
was performed according to TP2. The intermediate zinc reagent was
prepared using 2.48 M n-BuLi in hexane (0.17 mL, 0.42 mmol, 1.1
equiv) and 1 M ZnCl2 in THF solution (0.46 mL, 0.46 mmol, 1.2 equiv)
and cross coupling was performed using the aryl bromide 10h (61
mg, 0.30 mmol, 0.8 equiv) and Pd(PPh3)4 (17 mg, 0.015 mmol, 0.05
equiv) at 50 °C for 4 h. Flash column chromatographic purification
(silica gel pre-neutralized with Et3N, isohexane–EtOAc, 65:35) fur-
nished 11h as a yellow solid (100 mg, 87%); mp 223.4–225.2 °C.
IR (ATR): 3109, 2970, 2876, 1593, 1506, 1335, 1274, 1160, 1108, 1036,
342.0490.
971, 932, 850, 750, 722, 687 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 8.19 (d, J = 8.8 Hz, 2 H), 7.64 (d, J = 8.8
Hz, 2 H), 7.28 (d, J = 5.1 Hz, 1 H), 7.19 (s, 1 H), 6.85 (d, J = 5.1 Hz, 1 H),
4.30 (dddd, J = 14.8, 11.9, 11.3, 3.1 Hz, 2 H), 4.10 (dd, J = 11.2, 5.7 Hz, 2
H), 2.95–3.12 (m, 2 H), 2.61–2.74 (m, 2 H).
13C NMR (100 MHz, CDCl3): δ = 146.8, 141.6, 140.4, 140.2, 137.9,
136.7, 126.1, 126.0, 125.9, 124.6, 124.4, 94.5, 60.2, 60.0, 25.9, 25.8.
2-(Benzo[b]thiophen-3-yl)-4,4′,5,5′-tetrahydro-7,7′-spirobi[thie-
no[2,3-c]pyran] (11k)
Cross coupling of spiro compound 1 (100 mg, 0.38 mmol, 1.0 equiv)
was performed according to TP2. The intermediate zinc reagent was
prepared using 2.48 M n-BuLi in hexane (0.17 mL, 0.42 mmol, 1.1
equiv) and 1 M ZnCl2 in THF solution (0.46 mL, 0.46 mmol, 1.2 equiv)
and cross coupling was performed using heteroaryl bromide 10k (64
mg, 0.30 mmol, 0.8 equiv) and Pd(PPh3)4 (17 mg, 0.015 mmol, 0.05
equiv) at 50 °C for 4 h. Flash column chromatographic purification
(silica gel pre-neutralized with Et3N, isohexane–EtOAc, 75:25) fur-
nished 11k (103 mg, 87%) as a pale yellow solid; mp 158.4–160.3 °C.
MS (EI): m/z (%) = 385 (M+, 11), 327 (6), 322 (22), 276 (7), 137 (5).
HRMS (EI): m/z [M]+ calcd for C19H15NO4S2: 385.0442; found:
385.0436.
2-[4-(Methylthio)phenyl]-4,4′,5,5′-tetrahydro-7,7′-spirobi[thie-
no[2,3-c]pyran] (11i)
IR (ATR): 3071, 2966, 2903, 1557, 1458, 1422, 1278, 1243, 1157, 1044,
758, 720 cm–1
.
Cross coupling of spiro compound 1 (100 mg, 0.38 mmol, 1.0 equiv)
was performed according to TP2. The intermediate zinc reagent was
prepared using 2.48 M n-BuLi in hexane (0.17 mL, 0.42 mmol, 1.1
equiv) and 1 M ZnCl2 in THF solution (0.46 mL, 0.46 mmol, 1.2 equiv)
and cross coupling was performed using the aryl bromide 10i (61 mg,
0.30 mmol, 0.8 equiv) and Pd(PPh3)4 (17 mg, 0.015 mmol, 0.05 equiv)
at 50 °C for 6 h. Flash column chromatographic purification (silica gel
pre-neutralized with Et3N, isohexane–EtOAc, 70:30) furnished 11i
(85 mg, 73%) as a pale yellow solid; mp 173.4–174.2 °C.
1H NMR (400 MHz, CDCl3): δ = 8.03 (d, J = 7.6 Hz, 1 H), 7.79 (d, J = 7.4
Hz, 1 H), 7.26–7.40 (m, 3 H), 7.19 (t, J = 5.0 Hz, 1 H), 6.97 (s, 1 H), 6.75
(d, J = 5.1 Hz, 1 H), 4.26 (dddd, J = 13.5, 11.9, 11.7, 3.0 Hz, 2 H), 4.04
(dd, J = 10.6, 5.9 Hz, 2 H), 2.88–3.08 (m, 2 H), 2.59 (ddd, J = 16.0, 9.8,
3.0 Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 140.6, 137.7, 137.3, 137.1, 136.9,
136.5, 130.4, 126.0, 125.9, 124.7, 124.6, 124.1, 123.9, 123.1, 122.9,
94.6, 60.1, 60.1, 25.9, 25.9.
MS (EI): m/z (%) = 396 (M+, 45), 366 (100), 333 (33), 290 (6), 184 (5),
158 (5).
HRMS (EI): m/z [M]+ calcd for C21H16O2S3: 396.0312; found: 396.0301.
IR (ATR): 3101, 2982, 2955, 2881, 1559, 1502, 1462, 1278, 1162, 1037,
973, 926, 812, 729 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.46 (d, J = 8.2 Hz, 2 H), 7.29 (d, J = 5.1
Hz, 1 H), 7.23 (d, J = 8.20 Hz, 2 H), 7.01 (s, 1 H), 6.85 (d, J = 5.1 Hz, 1 H),
4.33 (dddd, J = 15.2, 12.0, 11.8, 3.0 Hz, 2 H), 4.04–4.18 (m, 2 H), 2.97–
3.13 (m, 2 H), 2.66 (td, J = 11.5, 3.0 Hz, 2 H), 2.50 (s, 3 H).
5-Methyl-2-(4,4′,5,5′-tetrahydro-7,7′-spirobi[thieno[2,3-c]pyran]-
2-yl)pyridine (11l)
13C NMR (100 MHz, CDCl3): δ = 144.1, 138.1, 137.3, 137.3, 136.6,
136.5, 131.1, 126.7, 126.1, 126.0, 125.8, 121.6, 94.6, 60.1, 60.1, 25.9,
25.9, 15.8.
MS (EI): m/z (%) = 386 (M+, 46), 357 (22), 356 (100), 328 (7), 323 (36),
69 (5).
Cross coupling of spiro compound 1 (100 mg, 0.38 mmol, 1.0 equiv)
was performed according to TP2. The intermediate zinc reagent was
prepared using 2.48 M n-BuLi in hexane (0.17 mL, 0.42 mmol, 1.1
equiv) and 1 M ZnCl2 in THF solution (0.46 mL, 0.46 mmol, 1.2 equiv)
and cross coupling was performed using heteroaryl bromide 10l (52
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mg, 0.30 mmol, 0.8 equiv) and Pd(PPh3)4 (17 mg, 0.015 mmol, 0.05
equiv) at 50 °C for 6 h. Flash column chromatographic purification
(silica gel pre-neutralized with Et3N, isohexane–EtOAc, 67:33) fur-
nished 11l (91 mg, 85%) as a pale yellow solid; mp 202.1–203.1 °C.
1H NMR (400 MHz, CDCl3): δ = 7.78 (d, J = 8.4 Hz, 2 H), 7.47 (d, J = 8.4
Hz, 2 H), 7.39 (s, 1 H), 7.24 (d, J = 2.7 Hz, 1 H), 6.81 (d, J = 5.1 Hz, 1 H),
4.27 (dddd, J = 13.4, 12.1, 11.3, 3.2 Hz, 2 H), 4.08 (dd, J = 11.2, 5.7 Hz, 2
H), 2.94–3.07 (m, 2 H), 2.57–2.69 (m, 2 H), 1.34 (s, 9 H).
IR (ATR): 2964, 2876, 1595, 1498, 1458, 1276, 1161, 1028, 973, 932,
13C NMR (100 MHz, CDCl3): δ = 187.9, 156.0, 146.3, 143.0, 136.9,
136.8, 136.4, 135.3, 133.1, 129.2, 126.2, 125.9, 125.4, 94.6, 60.3, 59.9,
35.1, 31.2, 25.9, 25.7.
MS (EI): m/z (%) = 424 (M+, 3), 394 (100), 189 (14), 161 (20), 145 (9),
91 (6).
828, 712 cm–1
.
1H NMR (400 MHz, DMSO-d6): δ = 8.28 (s, 1 H), 7.75 (d, J = 8.0 Hz, 1
H), 7.58–7.66 (m, 1 H), 7.44–7.53 (m, 2 H), 6.90 (d, J = 5.1 Hz, 1 H),
3.96–4.16 (m, 4 H), 2.78–2.93 (m, 2 H), 2.58–2.70 (m, 2 H), 2.27 (s, 3
H).
13C NMR (100 MHz, DMSO-d6): δ = 149.9, 149.4, 144.7, 139.2, 137.9,
137.5, 137.4, 136.9, 132.4, 126.5, 126.4, 123.6, 118.5, 94.4, 59.8, 59.7,
25.8, 25.7, 18.1.
MS (EI): m/z (%) = 355 (M+, 15), 325 (100), 296 (20), 292 (14), 264 (6),
148 (6).
HRMS (EI): m/z [M]+ calcd for C19H17NO2S2: 355.0701; found:
355.0697.
HRMS (EI): m/z [M]+ calcd for C24H24O3S2: 424.1167; found: 424.1160.
(4,4′,5,5′-Tetrahydro-7,7′-spirobi[thieno[2,3-c]pyran]-2-yl)(thio-
phen-2-yl)methanone (11o)
Cross coupling of spiro compound 1 (100 mg, 0.38 mmol, 1.0 equiv)
was performed according to TP2. The intermediate zinc reagent was
prepared using 2.48 M n-BuLi in hexane (0.17 mL, 0.42 mmol, 1.1
equiv) and 1 M ZnCl2 in THF solution (0.46 mL, 0.46 mmol, 1.2 equiv)
and cross coupling was performed using the acid chloride 10o (44
mg, 0.30 mmol, 0.8 equiv) and Pd(PPh3)4 (17 mg, 0.015 mmol, 0.05
equiv) at 50 °C for 4 h. Flash column chromatographic purification
(silica gel pre-neutralized with Et3N, isohexane–EtOAc, 67:33) fur-
nished 11o (100 mg, 89%) as a pale yellow solid; mp 155.4–157.7 °C.
2-Methyl-5-(4,4′,5,5′-tetrahydro-7,7′-spirobi[thieno[2,3-c]pyran]-
2-yl)benzothiazole (11m)
Cross coupling of spiro compound 1 (100 mg, 0.38 mmol, 1.0 equiv)
was performed according to TP2. The intermediate zinc reagent was
prepared using 2.48 M n-BuLi in hexane (0.17 mL, 0.42 mmol, 1.1
equiv) and 1 M ZnCl2 in THF solution (0.46 mL, 0.46 mmol, 1.2 equiv)
and cross coupling was performed using heteroaryl bromide 10m (69
mg, 0.30 mmol, 0.8 equiv) and Pd(PPh3)4 (17 mg, 0.015 mmol, 0.05
equiv) at 50 °C for 5 h. Flash column chromatographic purification
(silica gel pre-neutralized with Et3N, isohexane–EtOAc, 56:44) fur-
nished 11m (106 mg, 86%) as a pale yellow solid; mp 243.1–244.0 °C.
IR (ATR): 3093, 2931, 2874, 1623, 1552, 1514, 1412, 1274, 1160, 1049,
975, 775, 724 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.89 (d, J = 3.3 Hz, 1 H), 7.69 (d, J = 4.9
Hz, 1 H), 7.64 (s, 1 H), 7.25–7.34 (m, 1 H), 7.17 (t, J = 4.4 Hz, 1 H), 6.85
(d, J = 5.1 Hz, 1 H), 4.32 (dddd, J = 13.1, 12.0, 11.7, 3.0 Hz, 2 H), 4.13
(ddd, J = 11.2, 5.5, 0.8 Hz, 2 H), 2.96–3.17 (m, 2 H), 2.70 (ddd, J = 16.2,
8.4, 3.0 Hz, 2 H).
IR (ATR): 3096, 2969, 2875, 1518, 1422, 1276, 1159, 1033, 974, 903,
13C NMR (100 MHz, CDCl3): δ = 178.8, 146.0, 142.8, 142.0, 137.0,
136.8, 136.4, 133.6, 133.2, 131.9, 128.0, 126.2, 126.0, 94.6, 60.3, 59.9,
25.9, 25.7.
MS (EI): m/z (%) = 374 (M+, 4), 344 (100), 234 (5), 110 (43).
HRMS (EI): m/z [M]+ calcd for C18H14O3S3: 374.0105; found: 374.0108.
808, 745 cm–1
.
1H NMR (600 MHz, CDCl3): δ = 8.10 (s, 1 H), 7.73 (d, J = 8.2 Hz, 1 H),
7.50 (d, J = 8.2 Hz, 1 H), 7.25 (d, J = 1.9 Hz, 1 H), 7.07 (s, 1 H), 6.82 (d,
J = 4.9 Hz, 1 H), 4.30 (dddd, J = 14.8, 11.8, 11.5, 3.0 Hz, 2 H), 4.09 (dd,
J = 11.0, 5.2 Hz, 2 H), 2.96–3.10 (m, 2 H), 2.82 (s, 3 H), 2.57–2.71 (m, 2
H).
13C NMR (150 MHz, CDCl3): δ = 168.1, 153.6, 144.0, 137.4, 137.2,
137.1, 136.5, 134.7, 132.5, 125.9, 125.8, 123.0, 122.3, 121.6, 119.1,
94.5, 60.1, 60.0, 25.9, 25.8, 20.1.
MS (EI): m/z (%) = 411 (M+, 23), 381 (100), 353 (11), 348 (37), 277
(12), 181 (6).
HRMS (EI): m/z [M]+ calcd for C21H17NO2S3: 411.0421; found:
411.0411.
4-[2′-(Methylthio)-4,4′,5,5′-tetrahydro-7,7′-spirobi[thieno[2,3-
c]pyran]-2-yl]benzonitrile (15a)
Cross coupling of spiro compound 11b (60 mg, 0.19 mmol, 1.0 equiv)
was performed according to TP2. The intermediate zinc reagent was
prepared using 2.48 M n-BuLi in hexane (0.085 mL, 0.21 mmol, 1.1
equiv) and 1 M ZnCl2 in THF solution (0.23 mL, 0.23 mmol, 1.2 equiv)
and cross coupling was performed using the aryl bromide 10g (28
mg, 0.15 mmol, 0.8 equiv) and Pd(PPh3)4 (9 mg, 0.008 mmol, 0.05
equiv) at 50 °C for 3 h. Flash column chromatographic purification
(silica gel pre-neutralized with Et3N, isohexane–EtOAc, 67:33) fur-
nished 15a (46 mg, 75%) as a pale yellow solid; mp 158.4–159.6 °C.
(4-tert-Butylphenyl)(4,4′,5,5′-tetrahydro-7,7′-spirobi[thieno[2,3-
c]pyran]-2-yl)methanone (11n)
IR (ATR): 2973, 2954, 2881, 2227, 1602, 1558, 1511, 1268, 1153, 1040,
Cross coupling of spiro compound 1 (100 mg, 0.38 mmol, 1.0 equiv)
was performed according to TP2. The intermediate zinc reagent was
prepared using 2.48 M n-BuLi in hexane (0.17 mL, 0.42 mmol, 1.1
equiv) and 1 M ZnCl2 in THF solution (0.46 mL, 0.46 mmol, 1.2 equiv)
and cross coupling was performed using the acid chloride 10n (59
mg, 0.30 mmol, 0.8 equiv) and Pd(PPh3)4 (17 mg, 0.015 mmol, 0.05
equiv) at 50 °C for 3 h. Flash column chromatographic purification
(silica gel pre-neutralized with Et3N, isohexane–EtOAc, 65:35) fur-
nished 11n (120 mg, 94%) as a white solid; mp 139.1–143.3 °C.
980, 930, 820 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.47–7.57 (m, 4 H), 7.05 (s, 1 H), 6.70
(s, 1 H), 4.12–4.27 (m, 2 H), 4.00 (td, J = 10.6, 5.8 Hz, 2 H), 2.81–3.00
(m, 2 H), 2.53 (ddd, J = 16.2, 7.6, 2.5 Hz, 2 H), 2.37 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 142.2, 139.1, 139.0, 138.4, 137.8,
136.9, 132.7, 128.9, 126.0, 124.0, 118.8, 110.9, 94.1, 60.1, 60.0, 25.8,
25.7, 21.5.
MS (EI): m/z (%) = 411 (M+, 26), 382 (25), 381 (100), 366 (10), 348
(14), 334 (30), 291 (6).
HRMS (EI): m/z [M]+ calcd for C21H17NO2S3: 411.0421; found:
IR (ATR): 3092, 2963, 1628, 1604, 1555, 1456, 1274, 1244, 1162, 1028,
972, 935, 738, 704 cm–1
.
411.0417.
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2-(4-Cyanophenyl)-2′-[4-(methylthio)phenyl]-4,4′,5,5′-tetrahydro-
7,7′-spirobi[thieno[2,3-c]pyran (15b)
IR (ATR): 2968, 2921, 2853, 1558, 1484, 1432, 1275, 1223, 1152, 1032,
974, 901, 799, 711 cm–1
.
1H NMR (600 MHz, CDCl3): δ = 7.27 (d, J = 4.9 Hz, 1 H), 6.91–6.98 (m, 3
H), 6.87 (s, 1 H), 6.83 (d, J = 5.2 Hz, 1 H), 6.63–6.68 (m, 1 H), 4.29
(dddd, J = 14.8, 12.8, 11.5, 3.0 Hz, 2 H), 4.04–4.12 (m, 2 H), 2.95–3.06
(m, 2 H), 2.62 (ddd, J = 16.2, 7.1, 3.0 Hz, 2 H), 2.48 (s, 3 H).
13C NMR (150 MHz, CDCl3): δ = 139.4, 137.5, 137.1, 137.0, 136.5,
136.4, 135.3, 134.7, 126.0, 125.9, 125.9, 124.4, 123.6, 123.5, 122.2,
94.5, 60.1, 60.0, 25.9, 25.8, 15.4.
Cross coupling of spiro compound 11i (100 mg, 0.26 mmol, 1.0 equiv)
was performed according to TP2. The intermediate zinc reagent was
prepared using 2.48 M n-BuLi in hexane (0.11 mL, 0.28 mmol, 1.1
equiv) and 1 M ZnCl2 in THF solution (0.31 mL, 0.31 mmol, 1.2 equiv)
and cross coupling was performed using the aryl bromide 10g (38
mg, 0.208 mmol, 0.8 equiv) and Pd(PPh3)4 (12 mg, 0.01 mmol, 0.05
equiv) at 50 °C for 3 h. Flash column chromatographic purification
(silica gel pre-neutralized with Et3N, isohexane–EtOAc, 50:50) fur-
nished 15b (82 mg, 80%) as a pale yellow solid; mp 225.0–228.0 °C.
MS (EI): m/z (%) = 442 (M+, 77), 412 (100), 379 (45), 288 (6), 183 (8).
HRMS (EI): m/z [M]+ calcd for C22H18O2S4: 442.0190; found: 442.0186.
IR (ATR): 2955, 2895, 2222, 1602, 1567, 1465, 1313, 1264, 1162, 1032,
970, 926, 829, 814 cm–1
.
2-{5′-(Adamantan-1-yl)-[2,2′-bithiophen]-5-yl}-4,4′,5,5′-tetrahy-
dro-7,7′-spirobi[thieno[2,3-c]pyran (11q)
1H NMR (400 MHz, CDCl3): δ = 7.55–7.64 (m, 4 H), 7.44 (d, J = 8.2 Hz, 2
H), 7.20 (d, J = 8.2 Hz, 2 H), 7.14 (s, 1 H), 7.00 (s, 1 H), 4.25–4.40 (m, 2
H), 4.02–4.19 (m, 2 H), 2.94–3.13 (m, 2 H), 2.59–2.72 (m, 2 H), 2.48 (s,
3 H).
13C NMR (100 MHz, CDCl3): δ = 144.5, 142.2, 139.3, 138.4, 138.4,
137.9, 137.6, 135.9, 132.7, 130.9, 126.7, 126.1, 126.0, 124.0, 121.7,
118.8, 110.9, 94.3, 60.2, 60.0, 25.9, 25.8, 15.7.
Cross coupling of spiro compound 1 (100 mg, 0.38 mmol, 1.0 equiv)
was performed according to TP2. The intermediate zinc reagent was
prepared using 2.48 M n-BuLi in hexane (0.17 mL, 0.42 mmol, 1.1
equiv) and 1 M ZnCl2 in THF solution (0.46 mL, 0.46 mmol, 1.2 equiv)
and cross coupling was performed using heteroaryl bromide 10q (114
mg, 0.30 mmol, 0.8 equiv) and Pd(PPh3)4 (17 mg, 0.015 mmol, 0.05
equiv) at 50 °C for 3 h. Flash column chromatographic purification
(silica gel pre-neutralized with Et3N, isohexane–EtOAc, 70:30) fur-
nished 11q (115 mg, 68%) as a yellow solid; mp 109.1–113.7 °C.
MS (EI): m/z (%) = 487 (M+, 40), 457 (100), 424 (31), 367 (6), 171 (6).
HRMS (EI): m/z [M]+ calcd for C27H21NO2S3: 487.0734; found:
487.0726.
IR (ATR): 2899, 2846, 1555, 1443, 1314, 1277, 1154, 1043, 973, 903,
2-(Benzo[b]thiophen-3-yl)-2′-[4-(methylthio)phenyl]-4,4′,5,5′-tet-
rahydro-7,7′-spirobi[thieno[2,3-c]pyran (15c)
789, 713 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.21–7.29 (m, 1 H), 6.90–7.00 (m, 3 H),
6.76–6.89 (m, 2 H), 6.69 (d, J = 3.7 Hz, 1 H), 4.19–4.36 (m, 2 H), 4.06
(ddd, J = 11.0, 5.4, 0.7 Hz, 2 H), 2.90–3.07 (m, 2 H), 2.61 (td, J = 16.7,
2.6 Hz, 2 H), 2.02–2.12 (m, 3 H), 1.89–2.00 (m, 6 H), 1.67–1.82 (m, 6
H).
13C NMR (100 MHz, CDCl3): δ = 158.0, 137.6, 137.3, 137.1, 136.5,
136.3, 135.2, 133.5, 125.9, 125.9, 124.5, 123.5, 123.2, 122.2, 121.2,
94.5, 60.1, 60.0, 44.8, 36.6, 36.5, 28.9, 25.9, 25.8.
Cross coupling of spiro compound 11i (100 mg, 0.26 mmol, 1.0 equiv)
was performed according to TP2. The intermediate zinc reagent was
prepared using 2.48 M n-BuLi in hexane (0.11 mL, 0.28 mmol, 1.1
equiv) and 1 M ZnCl2 in THF solution (0.31 mL, 0.31 mmol, 1.2 equiv)
and cross coupling was performed using heteroaryl bromide 10k (44
mg, 0.208 mmol, 0.8 equiv) and Pd(PPh3)4 (12 mg, 0.01 mmol, 0.05
equiv) at 50 °C for 3 h. Flash column chromatographic purification
(silica gel pre-neutralized with Et3N, isohexane–EtOAc, 60:40) fur-
nished 15c (73 mg, 68%) as a pale yellow solid; mp 190.7–191.2 °C.
MS (EI): m/z (%) = 562 (M+, 91), 532 (100), 499 (34), 265 (6), 220 (8).
HRMS (EI): m/z [M]+ calcd for C31H30O2S4: 562.1129; found: 562.1124.
IR (ATR): 3067, 2966, 2918, 1566, 1502, 1462, 1277, 1154, 1050, 1032,
968, 902, 811, 758, 729 cm–1
.
2-([2,2′:5′,2′′-Terthiophen]-5-yl)-4,4′,5,5′-tetrahydro-7,7′-spiro-
bi[thieno[2,3-c]pyran (11r)
1H NMR (400 MHz, CDCl3): δ = 8.12 (d, J = 7.6 Hz, 1 H), 7.87 (d, J = 7.4
Hz, 1 H), 7.34–7.50 (m, 5 H), 7.21 (d, J = 8.2 Hz, 2 H), 7.07 (s, 1 H), 7.00
(s, 1 H), 4.26–4.44 (m, 2 H), 4.05–4.21 (m, 2 H), 2.95–3.18 (m, 2 H),
2.59–2.78 (m, 2 H), 2.48 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 144.3, 140.6, 138.2, 137.9, 137.5,
137.1, 137.0, 136.6, 136.4, 131.1, 130.4, 126.8, 126.2, 124.7, 124.6,
124.2, 124.0, 123.1, 122.9, 121.7, 94.5, 60.2 (2 C), 26.0, 25.9, 15.8.
Cross coupling of spiro compound 1 (100 mg, 0.38 mmol, 1.0 equiv)
was performed according to TP2. The intermediate zinc reagent was
prepared using 2.48 M n-BuLi in hexane (0.17 mL, 0.42 mmol, 1.1
equiv) and 1 M ZnCl2 in THF solution (0.46 mL, 0.46 mmol, 1.2 equiv)
and cross coupling was performed using heteroaryl bromide 10r (98
mg, 0.30 mmol, 0.8 equiv) and Pd(PPh3)4 (17 mg, 0.015 mmol, 0.05
equiv) at 50 °C for 3 h. Flash column chromatographic purification
(silica gel pre-neutralized with Et3N, isohexane–EtOAc, 70:30) fur-
nished 11r (87 mg, 57%) as a yellow solid; mp 221.3–224.9 °C.
MS (EI): m/z (%) = 518 (M+, 41), 488 (100), 455 (39), 259 (8), 184 (8).
HRMS (EI): m/z [M]+ calcd for C28H22O2S4: 518.0503; found: 518.0498.
2-(5′-Methyl-[2,2′-bithiophen]-5-yl)-4,4′,5,5′-tetrahydro-7,7′-
spirobi[thieno[2,3-c]pyran (11p)
IR (ATR): 3060, 2936, 2878, 1442, 1424, 1276, 1223, 1200, 1044, 1034,
975, 938, 910, 831, 821, 788, 703 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.16–7.34 (m, 3 H), 6.97–7.14 (m, 5 H),
6.79–6.96 (m, 2 H), 4.24–4.41 (m, 2 H), 4.02–4.20 (m, 2 H), 2.92–3.14
(m, 2 H), 2.56–2.76 (m, 2 H).
13C NMR (100 MHz, CDCl3): δ = 137.3, 137.2, 137.1, 136.7, 136.6,
136.4, 136.2, 136.1, 135.8, 127.9, 126.0, 125.9, 124.6, 124.4, 124.3,
124.3, 123.8, 122.5, 94.5, 60.1, 60.0, 25.9, 25.8.
Cross coupling of spiro compound 1 (200 mg, 0.76 mmol, 1.0 equiv)
was performed according to TP2. The intermediate zinc reagent was
prepared using 2.48 M n-BuLi in hexane (0.34 mL, 0.83 mmol, 1.1
equiv) and 1 M ZnCl2 in THF solution (0.91 mL, 0.91 mmol, 1.2 equiv)
and cross coupling was performed using heteroaryl bromide 10p (155
mg, 0.60 mmol, 0.8 equiv) and Pd(PPh3)4 (35 mg, 0.03 mmol, 0.05
equiv) at 50 °C for 3 h. Flash column chromatographic purification
(silica gel pre-neutralized with Et3N, isohexane–EtOAc, 70:30) fur-
nished 11p (170 mg, 64%) as a yellow solid; mp 191.1–192.1 °C.
MS (EI): m/z (%) = 509 (M+, 97), 480 (100), 446 (41), 223 (8), 126 (5).
HRMS (EI): m/z [M]+ calcd for C25H18O2S5: 509.9910; found: 509.9904.
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Synthesis
2-(5′′-Methyl-[2,2′:5′,2′′-terthiophen]-5-yl)-4,4′,5,5′-tetrahydro-
7,7′-spirobi[thieno[2,3-c]pyran (11s)
at 50 °C for 3 h. Flash column chromatographic purification (silica gel
pre-neutralized with Et3N, isohexane–EtOAc, 60:40) furnished 18
(101 mg, 73%) as a yellow solid; mp 216.7–217.4 °C.
Cross coupling of spiro compound 1 (200 mg, 0.76 mmol, 1.0 equiv)
was performed according to TP2. The intermediate zinc reagent was
prepared using 2.48 M n-BuLi in hexane (0.34 mL, 0.83 mmol, 1.1
equiv) and 1 M ZnCl2 in THF solution (0.91 mL, 0.91 mmol, 1.2 equiv)
and cross coupling was performed using heteroaryl bromide 10s (205
mg, 0.60 mmol, 0.8 equiv) and Pd(PPh3)4 (35 mg, 0.03 mmol, 0.05
equiv) at 50 °C for 3 h. Flash column chromatographic purification
(silica gel pre-neutralized with Et3N, isohexane–EtOAc, 67:33) fur-
nished 11s (188 mg, 60%) as a yellow solid; mp 208.6–210.9 °C.
IR (ATR): 3038, 2974, 2940, 1600, 1560, 1428, 1274, 1248, 1031, 977,
904, 842, 760, 723, 701 cm–1
.
1H NMR (600 MHz, CDCl3): δ = 8.54 (d, J = 9.3 Hz, 1 H), 8.15–8.22 (m, 2
H), 8.13 (d, J = 8.0 Hz, 1 H), 7.96–8.10 (m, 5 H), 7.31 (d, J = 5.1 Hz, 1 H),
7.09 (s, 1 H), 6.85 (d, J = 5.1 Hz, 1 H), 4.46 (td, J = 11.6, 2.7 Hz, 1 H),
4.36 (td, J = 11.6, 2.7 Hz, 1 H), 4.12–4.25 (m, 2 H), 3.17 (ddd, J = 15.8,
12.4, 5.9 Hz, 1 H), 3.07 (ddd, J = 15.8, 12.4, 5.9 Hz, 1 H), 2.76 (dd,
J = 16.0, 2.7 Hz, 1 H), 2.69 (dd,, J = 16.0, 2.7 Hz, 1 H).
IR (ATR): 3057, 2939, 2910, 2881, 1553, 1519, 1441, 1276, 1224, 1151,
13C NMR (150 MHz, CDCl3): δ = 142.9, 138.3, 137.4, 136.7, 136.5,
131.4, 131.0, 130.9, 129.5, 128.9, 128.2, 127.9, 127.8, 127.3, 126.8,
126.1, 125.9, 125.8, 125.3, 125.0, 125.0, 124.9, 124.7, 124.5, 94.7, 60.1
(2 C), 26.0, 25.9.
MS (EI): m/z (%) = 464 (M+, 67), 434 (100), 401 (28), 294 (10), 226
(21), 43 (11).
1068, 1031, 972, 937, 911, 793, 714 cm–1
.
1H NMR (600 MHz, CDCl3): δ = 7.28 (d, J = 4.9 Hz, 1 H), 6.93–7.04 (m, 5
H), 6.88 (s, 1 H), 6.83 (d, J = 5.2 Hz, 1 H), 6.64–6.69 (m, 1 H), 4.29
(dddd, J = 14.2, 12.0, 11.2, 2.7 Hz, 2 H), 4.09 (ddd, J = 11.0, 6.0, 0.6 Hz,
2 H), 2.94–3.07 (m, 2 H), 2.64 (ddd, J = 16.4, 7.9, 2.7 Hz, 2 H), 2.48 (s, 3
H).
13C NMR (150 MHz, CDCl3): δ = 139.5, 137.3, 137.1, 137.0, 136.9,
136.6, 136.5, 136.3, 135.8, 135.1, 134.7, 126.0, 125.9, 125.9, 124.5,
124.2, 124.0, 123.7, 123.6, 122.4, 94.5, 60.1, 60.0, 25.9, 25.8, 15.4.
HRMS (EI): m/z [M]+ calcd for C29H20O2S2: 464.0905; found: 464.0905.
2,2′-Di(pyren-1-yl)-4,4′,5,5′-tetrahydro-7,7′-spirobi[thieno[2,3-
c]pyran (19)
MS (EI): m/z (%) = 524 (M+, 100), 495 (21), 493 (80), 461 (29), 247
Cross coupling of spiro compound 18 (135 mg, 0.29 mmol, 1.0 equiv)
was performed according to TP2. The intermediate zinc reagent was
prepared using 2.48 M n-BuLi in hexane (0.13 mL, 0.32 mmol, 1.1
equiv) and 1 M ZnCl2 in THF solution (0.35 mL, 0.35 mmol, 1.2 equiv)
and cross coupling was performed using the aryl bromide 17 (65 mg,
0.23 mmol, 0.8 equiv) and Pd(PPh3)4 (13 mg, 0.011 mmol, 0.05 equiv)
at 50 °C for 6 h. Flash column chromatographic purification (silica gel
pre-neutralized with Et3N, isohexane–EtOAc, 67:33) furnished 19 (70
mg, 46%) as a yellow solid; mp 257.1–258.5 °C.
(12).
HRMS (EI): m/z [M]+ calcd for C26H20O2S5: 524.0067; found: 524.0071.
2,2′-Bis(5′-methyl-[2,2′-bithiophen]-5-yl)-4,4′,5,5′-tetrahydro-7,7′-
spirobi[thieno[2,3-c]pyran (16)
Cross coupling of spiro compound 11p (80 mg, 0.18 mmol, 1.0 equiv)
was performed according to TP2. The intermediate zinc reagent was
prepared using 2.48 M n-BuLi in hexane (0.08 mL, 0.2 mmol, 1.1
equiv) and 1 M ZnCl2 in THF solution (0.22 mL, 0.22 mmol, 1.2 equiv)
and cross coupling was performed using heteroaryl bromide 10p (36
mg, 0.14 mmol, 0.8 equiv) and Pd(PPh3)4 (8.4 mg, 0.007 mmol, 0.05
equiv) at 50 °C for 5 h. Flash column chromatographic purification
(silica gel pre-neutralized with Et3N, isohexane–EtOAc, 60:40) fur-
nished 16 (55 mg, 63%) as a yellow solid; mp 223.0–224.5 °C.
IR (ATR): 3041, 2926, 1601, 1566, 1456, 1428, 1271, 1150, 1027, 968,
930, 845, 838, 720, 695 cm–1
.
1H NMR (200 MHz, DMSO-d6): δ = 7.82–8.65 (m, 18 H), 7.30 (s, 2 H),
3.95–4.48 (m, 4 H), 2.65–3.21 (m, 4 H).
13C NMR (100 MHz, CDCl3): δ = 143.0, 138.4, 136.7, 131.4, 131.1,
130.9, 129.6, 129.0, 128.2, 127.9, 127.7, 127.2, 126.7, 126.0, 125.2,
125.0, 125.0, 124.8, 124.4, 94.7, 60.2, 26.0.
MS (EI): m/z (%) = 664 (M+, 76), 634 (100), 590 (44), 295 (43), 226
(29).
HRMS (EI): m/z [M]+ calcd for C45H28O2S2: 664.1531; found: 664.1538.
IR (ATR): 3062, 2913, 2852, 1568, 1527, 1444, 1274, 1207, 1151, 1044,
1032, 971, 912, 798, 785 cm–1
.
1H NMR (600 MHz, CDCl3): δ = 6.97 (d, J = 3.6 Hz, 2 H), 6.94 (d, J = 3.0
Hz, 4 H), 6.87 (s, 2 H), 6.61–6.68 (m, 2 H), 4.29 (td, J = 11.3, 2.5 Hz, 2
H), 4.09 (dd, J = 11.0, 5.7 Hz, 2 H), 2.95–3.04 (m, 2 H), 2.61 (dd,
J = 16.0, 2.5 Hz, 2 H), 2.47 (s, 6 H).
13C NMR (150 MHz, CDCl3): δ = 139.4, 137.7, 137.2, 137.0, 135.9,
135.2, 134.7, 126.0, 124.5, 123.6, 123.5, 122.1, 94.2, 60.0, 25.8, 15.4.
Acknowledgment
MS (EI): m/z (%) = 620 (M+, 90), 590 (100), 560 (26), 557 (69), 272 (8).
HRMS (EI): m/z [M]+ calcd for C31H24O2S6: 620.0101; found: 620.0091.
The research leading to these results has received funding from the
European Research Council under the European Community’s Sev-
enth Framework Programme (FP7/2007–2014) ERC grant agreement
No. 227763. We thank the Fonds der Chemischen Industrie for finan-
cial support. We also thank Heraeus Holding GmbH (Hanau), Rock-
wood Lithium (Frankfurt), and BASF SE (Ludwigshafen) for the
generous gift of chemicals.
2-(Pyren-1-yl)-4,4′,5,5′-tetrahydro-7,7′-spirobi[thieno[2,3-c]pyran
(18)
Cross coupling of spiro compound 1 (100 mg, 0.38 mmol, 1.0 equiv)
was performed according to TP2. The intermediate zinc reagent was
prepared using 2.48 M n-BuLi in hexane (0.17 mL, 0.42 mmol, 1.1
equiv) and 1 M ZnCl2 in THF solution (0.46 mL, 0.46 mmol, 1.2 equiv)
and cross coupling was performed using the aryl bromide 17 (84 mg,
0.30 mmol, 0.8 equiv) and Pd(PPh3)4 (17 mg, 0.015 mmol, 0.05 equiv)
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1560187.
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 3972–3982

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V. Dhayalan et al.
Paper
Synthesis
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 3972–3982