A novel approach to functionalized (E)-1,4-diaryl-1-butenes by Heck reaction and their applications for the construction of dibenzylbutyrolactone lignan skeletons by radical cyclization

Article abstract of DOI:10.1016/j.tetlet.2005.05.050

A highly regio- and stereoselective [Pd(allyl)Cl]₂ catalyzed Heck reaction of aryl iodides and electronically neutral terminal olefins generated in situ by fluoride induced protiodesilylation of alkenylsilanol derivatives under mild conditions

Full text of DOI:10.1016/j.tetlet.2005.05.050

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 4719–4722
A novel approach to functionalized (E)-1,4-diaryl-1-butenes
by Heck reaction and their applications for the construction of
dibenzylbutyrolactone lignan skeletons by radical cyclization
Rekha Singh, Gobind C. Singh and Sunil K. Ghosh*
Bio-Organic Division, Bhabha Atomic Research Centre, Mumbai 400 085, India
Received 1 April 2005; revised 3 May 2005; accepted 12 May 2005
Available online 31 May 2005
Abstract—A highly regio- and stereoselective [Pd(allyl)Cl]2 catalyzed Heck reaction of aryl iodides and electronically neutral termi-
nal olefins generated in situ by fluoride induced protiodesilylation of alkenylsilanol derivatives under mild conditions has been devel-
oped. The products, viz. terminally substituted styrenes and (E)-1,4-diaryl-1-butenes were obtained in very good yields. The
dibenzylbutyrolactone lignan skeletons have been prepared employing two regio- and stereoselective Bu3SnH-mediated radical cycli-
zation routes.
Ó 2005 Elsevier Ltd. All rights reserved.
Lignans1 constitute a class of natural products with a
great diversity of structures and significant pharmaco-
logical activities. The classification of lignans is based
on their carbon skeleton as shown in Figure 1. The most
common feature in these molecules is two aryl groups
separated by a C-4 unit (Fig. 1). Due to their unique
structures and biological activities, they are the targets
of extensive synthetic research.2
(OH)
(OH)
1
Ar
1
1
4
1
4
O
O
O
O
4
O
2
O
Ar
Ar
Ar
tetralins
naphthalenes
furofurans
Ar2
Ar1
4
Ar2
4
FG
FG
4
O
1
O
2
We envisage a functionalized 1,4-diaryl-1-butene 1 as a
potent precursor for the synthesis of all the different
types of lignans (Fig. 1). Herein, we report a general
and convenient synthetic protocol for functionalized
1,4-diaryl-1-butenes and the application of one such
functionalized 1,4-diaryl-1-butene for the construction
of dibenzylbutyrolactone lignan skeletons.
1
Ar
1
1
Ar
Ar1
O
tetrahydrofurans
dibenzyl-
butyrolactones
1
(OR)
Ar2
4
1
CH (OH)
3
1
4
1
O
O
Ar
CH (OH)
3
dibenzylbutan(diol)es
We have recently developed3 a general method for the
preparation of 1-substituted alkenylsilanols 2/disilox-
anes 3 from the corresponding alkenyl(phenyl)silanes
44 (Scheme 1) and used them in Hiyama–Denmark5–7
type cross-coupling reactions with aryl iodides. Our
exploratory studies3 on this cross-coupling reaction of
dibenzocyclooctadienes
Figure 1.
a mixture of 2a and 3a with iodobenzene using [Pd-
(allyl)Cl]2 as the catalyst and tetrabutylammonium
fluoride (TBAF) or a combination of TBAF and tetra-
butylammonium hydroxide (TBAOH)8 as the promoter
in various solvents gave a mixture of 1-substituted sty-
rene 5a, protiodesilylated olefin 6a and the cine-coupled
styrene derivative 7a (Scheme 2).
Keywords: Heck reaction; Stereoselective synthesis; Styrene derivatives;
Radical cyclization; Dibenzylbutyrolactones.
*
Corresponding author. Tel.: +91 22 5592299/5590265; fax: +91 22
5505151; e-mail: ghsunil@magnum.barc.ernet.in
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.05.050

4720
R. Singh et al. / Tetrahedron Letters 46 (2005) 4719–4722
suitable conditions for regio- and stereoselective Heck
EtO C
2
Me
EtO C
reactions of iodoarenes with electronically neutral func-
tionalized terminal olefins such as 6a generated in situ
from the reaction of the corresponding silanol/disilox-
ane 2a/3a with TBAF.
2
Si OH
R
Me
R=Me; 2a 25%
1.CF SO H
3
3
R=Bn; 2b 50%
2. aq. NH
3
R = 3-MeO-Bn; 2c 45%
CO Et
PhMe Si
2
2
+
In our initial cross-coupling studies, reaction of silanes
2a/3a, iodobenzene (1.5 equiv), a combination of TBAF
(1.5 equiv) and TBAOH (1 equiv) and [Pd(allyl)Cl]2 at
room temperature for 40 h gave the desired terminally
substituted styryl product 7a in 42% isolated yield.12
At this stage we introduced tetrabutylammonium chlo-
ride (TBACl)13 and replaced TBAOH with Et3N. After
a large number of variations of the proportions of
reagents, optimized coupling conditions were found.
The reaction could be carried out efficiently in the
presence of TBACl (1 equiv), Et3N (0.75 equiv), TBAF
CO Et
2
R
100%
EtO C
2
Me
Si
Me
EtO C
R=Me; 4a
2
O
R
R=Bn; 4b
R = 3-MeO-Bn; 4c
2
R=Me; 3a 75%
R=Bn; 3b 50%
R = 3-MeO-Bn; 3c 55%
Scheme 1.
14
PhI, TBAF,
TBAOH
[Pd(allyl)Cl]
(1.5 equiv) and [Pd(allyl)Cl]2 (0.05 equiv) with heating
of the mixture at 80 °C for 40 h. The desired product 7a
was obtained in 75% isolated yield exclusively as the (E)-
isomer without a trace of the regioisomer 5a. The scope
of this coupling reaction was first generalized with
silanol 2a/disiloxane 3a with a few functionalized
iodo-arenes (Table 1, entries 1–5). The styryl derivatives,
7a–e were formed in very good yields and with excellent
regio- and stereoselectivities. When benzyl substituted
silanols 2b,c/disiloxanes 3b,c were examined under the
optimized conditions using various aryl iodides, (E)-
1,4-diaryl-1-butenes 1a–h were obtained in very good
yields again, with complete regio- and stereocontrol.
The results are summarized in Table 1.
CO Et
CO Et
2
R
2
2
+
2a + 3a
Ph
CO Et
CO Et
2
2
Me
Me
7a
5a; R = Ph
6a; R = H
Scheme 2.
The ratio of the products varied depending on the reac-
tion conditions. We probed3 the formation of the cine-
coupled product and confirmed that it did not form by
the direct cross-coupling9 of the silanol 2a or disiloxane
3a. Under the coupling conditions, the silanes first un-
dergo a rapid fluoride induced protiodesilylation to ter-
minal olefin 6a, which then undergoes a Heck reaction
with iodobenzene in the presence of [Pd(allyl)Cl]2 to give
7a.
We successfully prepared the dibenzylbutyrolactone lig-
nan skeletons from 1,4-diaryl-1-butene 1a following two
routes as depicted in Scheme 3.17 The diester 1a was first
hydrolyzed to the racemic acid 8 (mp 117 °C). In the first
route, the acid was converted to its phenylselenomethyl
ester 918 and then a tin hydride-mediated radical cycliza-
tion provided the trans-dibenzylbutyrolactone 1019 as
the major product (trans/cis = 78/22). The trans-disub-
stituted lactone was expected to be the dominant
In general, traditional Heck reaction of aryl iodides pro-
ceeds smoothly with terminal alkenes substituted with
electron-withdrawing groups.10 However, electronically
neutral or electron-rich alkenes were less common as
substrates.11 Therefore, it was a challenge to establish
Table 1. Coupling of silanols/siloxanes with various aryl iodides15,16
ArI, [Pd(allyl)Cl] , TBAF
TBACl, Et N
3
2
CO Et
2
2a + 3a
or
Ar
CO Et
2
2b + 3b
or
R
°
80 C, 40 h
2c + 3c
1; R = CH Ar
2
7; R = Me
Entry
Ar
R
Product
% Yield
1
Ph–
4-MeO–C6H4–
Me
Me
Me
Me
Me
Bn
Bn
Bn
Bn
Bn
7a
7b
7c
7d
7e
1a
1b
1c
1d
1e
1f
75
75
80
68
72
75
75
65
76
73
71
80
75
2
3
2-MeO–4-Me–C6H3–
1-Naphth–
4
5
4-AcNH–C6H4–
4-MeO–C6H4–
4-AcNH–C6H4–
1-Naphth–
6
7
8
9
4-Me–C6H4–
2-MeO–4-Me–C6H3–
Ph–
10
11
12
13
3-MeO–C6H4–CH2–
3-MeO–C6H4–CH2–
3-MeO–C6H4–CH2–
4-MeO–C6H4–
4-AcNH–C6H4–
1g
1h

R. Singh et al. / Tetrahedron Letters 46 (2005) 4719–4722
4721
via both routes if the starting acid 8 was homochiral.23
Lignans containing tetrahydrofuan, dibenzylbutane
and dibenzylbutane diol skeletons (Fig. 1) could also
be easily available from the lactones 10, 13 and alcohol
11 by simple chemical manipulations. The syntheses of
other members of the lignan family could also be pre-
dicted from suitably substituted diaryl butanes of type 1.
C H -p-OMe
6
4
CO Et
2
Ph
CO Et
2
1a
88%
KOH
C H -p-OMe
6
4
References and notes
Ph
CO H
2
1. (a) Ayres, D. C.; Loike, J. D. Lignans: Chemical,
Biological and Clinical Properties; Cambridge University
Press: Cambridge, 1990; (b) Lewis, N. G.; Davis, L. B. In
Lignans: Biosynthesis and Function; Sankura, U., Ed.;
Comprehensive Natural Product Chemistry; Elsevier:
Amsterdam, 1999; Vol. 1, pp 639–712.
2. Ward, R. S. Recent Advances in the Chemistry of
Lignans. In Studies in Natural Products Chemistry;
Rahman, A. U., Ed.; Bioactive Natural Products, Part
E; Elsevier: Amsterdam, 2000; Vol. 24, pp 739–798, and
references cited therein.
8
PhSeCH Cl
LAH,
2
i
THF-Et O
Pr NEt, DME
2
2
87%
96%
C H -p-OMe
C H -p-OMe
6
4
6
4
SePh
O
Ph
Ph
CH OH
2
O
11
9
3. Ghosh, S. K.; Singh, R.; Singh, G. C. Eur. J. Org. Chem.
2004, 4141–4147.
(i) triphosgene, Py
(ii) PhSeH, Et N
4. Ghosh, S. K.; Singh, R.; Date, S. M. Chem. Commun.
2003, 636–637.
Bu SnH, AIBN
3
91%
92%
3
C H , reflux
6
6
5. (a) Diederich, F.; Stang, P. J. Metal-Catalyzed
Cross-Coupling Reactions; Wiley-VCH: Weinheim,
Germany, 1998; (b) Negishi, E. Handbook of Organo-
palladium Chemistry for Organic Synthesis; John Wiley &
Sons: NY, 2002; Vol. 1, Part-III.
C H -p-OMe
C H -p-OMe
6
4
6
4
SePh
O
O
O
Ph
6. Hiyama, T.; Shirakawa, E. Top. Curr. Chem. 2002, 219,
61–88.
O
Ph
12
7. Denmark, S. E.; Sweis, R. F. Acc. Chem. Res. 2002, 35,
835–846.
10
Bu SnH, AIBN
3
90%
trans/cis = 78/22
C H , reflux
8. Denmark, S. E.; Wehrli, D. Org. Lett. 2000, 2, 565–568.
9. The direct cross-coupling of alkenyl(phenyl)silane via an
alkenylsilanol with iodobenzene to produce a cine-coupled
product has been reported. See: Anderson, J. C.; Anguille,
S.; Bailey, R. Chem. Commun. 2002, 2018–2019.
10. (a) Heck, R. F. Org. React. 1982, 27, 345–390; (b) Negishi,
E. Handbook of Organopalladium Chemistry for Organic
Synthesis; John Wiley & Sons: New York, 2002; Vol. 1,
Part-IV.
6
6
Ar
O
O
Ph
13
trans/cis = 78/22
11. (a) Daves, G. D., Jr.; Hallberg, A. Chem. Rev. 1989, 89,
1433–1445; (b) Cabri, W.; Candiani, I. Acc. Chem. Res.
1995, 28, 2–7.
Scheme 3.
12. Increasing the reaction temperature in the range of 40–
80 °C did not improve the yield; instead, by products were
formed.
13. Jeffery, T. Tetrahedron 1996, 52, 10113–10130.
14. Coupling of 6a (pure/generated in situ) with iodobenzene
was carried out under the traditional Heck conditions
using Pd(OAc)2/(Tol)3P in the presence and absence of
TBAF at 80 °C, but the conversion was <5% in both the
cases.
15. In a typical experiment, a 1 M solution of TBAF in DMF
(4 mL, 4 mmol) was added to a mixture of silanes 2b+3b
(930 mg, 2.66 mmol with respect to the silanol) at 80 °C.
After 5 min, a 1 M solution of TBACl in DMF (2.6 mL,
2.6 mmol), 4-iodoanisole (933 mg, 4 mmol), Et3N
(0.28 mL, 2 mmol) and [Pd(allyl)Cl]2 (48 mg, 0.13 mmol)
were added and the mixture was heated at 80 °C under a
blanket of nitrogen in a Schlenk flask for 40 h. The
reaction mixture was cooled, diluted with hexane–EtOAc
(8/2) and washed with water. The organic extract was
concentrated and purified by column chromatography to
give 1a (760 mg, 75%) as a colourless oil.
product on the basis of BeckwithÕs model20 for stereose-
lectivity in 5-exo radical cyclizations.
The two racemic, and stereoisomeric lactones, trans-10
(mp 77 °C) and cis-10 (mp 57 °C) were separated nearly
quantitatively by fractional crystallization. The cis-
stereochemistry of the minor isomer was confirmed by
recording NOE spectra and about a 5% NOE enhance-
ment was observed between the a- and b-protons in the
lactone ring. In the second route, the acid 8 was reduced
to alcohol 11 (mp 65 °C) and converted to phenylseleno-
carbonate 12.21 Tin hydride induced radical cyclization
then provided the trans-dibenzylbutyrolactone trans-
1322 with good selectivity (trans/cis = 78/22). The regio-
isomeric relationship of trans-10 and trans-13 bestowed
additional advantages. In the case of lignan natural
products where the two aryl groups are the same, the
present strategy would produce enantiomeric products

4722
R. Singh et al. / Tetrahedron Letters 46 (2005) 4719–4722
16. The products were fully characterized by physical and
spectroscopic data. Compounds 1a–1f and 7a–7e gave
satisfactory analytical (CHN) data. The compositions of
1g, 1h, 3c and 4c were confirmed by ESI-HRMS measure-
ments.
17. The products were fully characterized by physical and
spectroscopic data. Compounds 8, cis-10 and trans-10
gave satisfactory analytical (CH) data. The composition of
11 was confirmed by ESI-HRMS measurement.
18. The corresponding methylthiomethyl and phenylthio-
methyl esters did not undergo radical cyclization
smoothly; see: Beckwith, A. L. J.; Pigou, P. E. Aust. J.
Chem. 1986, 39, 77–87.
126.79, 128.61 (2C), 129.23 (2C), 129.49 (2C), 129.84,
137.69, 158.28, 178.50; Data for cis-10: 1H NMR
(500 MHz, CDCl3) d 2.33 (t, J = 14 Hz, 1H, ArCHAHB),
2.60–2.65 (m, 1H, CHCH2O–), 2.85 (dd, J = 11 and 15 Hz,
1H, PhCHAHB), 2.93 (dd, J = 3.5 and 15 Hz, 1H,
ArCHAHB), 3.09–3.14 (m, 1H, COCH), 3.33 (dd, J = 4.5
and 15 Hz, 1H, PhCHAHB), 3.78 (s, 3H, MeOAr), 4.00
(dd, J = 5 and 9.5 Hz, 1H, OCHAHB), 4.04 (d, J = 9.5 Hz,
1H, OCHAHB), 6.81 (d, J = 8.5 Hz, 2H, Ar), 6.95 (d,
J = 8.8 Hz, 2H, Ar), 7.25–7.31 (m, 3H, Ar), 7.36 (t,
J = 7 Hz, 2H, Ar); 13C NMR (50 MHz, CDCl3) d 30.76,
31.94, 39.95, 45.17, 55.20, 69.36, 114.06 (2C), 126.63,
128.33 (2C), 128.73 (2C), 129.84 (2C), 130.30, 138.58,
158.27, 177.93.
19. 1H and 13C NMR data for trans-10 and cis-10.
Data for trans-10: 1H NMR (500 MHz, CDCl3) d 2.46–
2.52 (m, 2H, CHCH2O–, ArCHAHB), 2.57–2.63 (m, 2H,
COCH, ArCHAHB), 2.95 (dd, J = 7.5 and 14 Hz, 1H,
PhCHAHB), 3.08 (dd, J = 5 and 14 Hz, 1H, PhCHAHB),
3.78 (s, 3H, MeOAr), 3.84 (dd, J = 8.5 and 8.5 Hz, 1H,
OCHAHB), 4.07 (dd, J = 8 and 8 Hz, 1H, OCHAHB), 6.80
(d, J = 8.5 Hz, 2H, Ar), 6.91 (d, J = 8.8 Hz, 2H, Ar), 7.18
(d, J = 7.5 Hz, 2H, Ar), 7.24 (t, J = 7.5 Hz, 1H, Ar), 7.30
(t, J = 7.5 Hz, 2H, Ar); 13C NMR (50 MHz, CDCl3) d
34.95, 37.46, 41.36, 46.24, 55.18, 71.07, 114.00 (2C),
20. Beckwith, A. L. J.; Schiesser, C. H. Tetrahedron 1985, 41,
3925–3941.
21. Bachi, M. D.; Bosch, E. Heterocycles 1989, 28, 579–582.
22. Obtained as inseparable mixture of isomers.
23. For reviews on chemical approaches, see: (a) Dalko, P. I.;
Moisan, L. Angew. Chem., Int. Ed. 2004, 43, 5138–5175;
(b) Eames, J.; Weerasooriya, N. Tetrahedron: Asymmetry
2001, 12, 1–24; For an enzymatic approach, see: Back, T.
G.; Wulff, J. E. Angew. Chem., Int. Ed. 2004, 43, 6493–
6496.