Synthesis of 1-aryl-tetralins and 4-aryl-benzopyrans by sulfoxide-mediated benzylic carbocation cyclizations

Article abstract of DOI:10.1016/j.tetlet.2005.10.044

An alkylation/cyclization sequence, with both steps mediated by the ortho-N-methylformamido-phenylsulfinyl function, provided two new C-C bonds and an efficient entry to 1-aryl-tetralins and 4-aryl-benzopyrans. Scope and limits of the process have been studied in detail.

Full text of DOI:10.1016/j.tetlet.2005.10.044

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 8723–8726
Synthesis of 1-aryl-tetralins and 4-aryl-benzopyrans by
sulfoxide-mediated benzylic carbocation cyclizations
Alessandro Volonterio* and Matteo Zanda*
C.N.R.-I.C.R.M., section ‘A. Quilico’ and Department C.M.I.C. ‘G. Natta’, Politecnico di Milano, via Mancinelli 7, 20131 Milan, Italy
Received 12 August 2005; revised 11 October 2005; accepted 12 October 2005
Abstract—An alkylation/cyclization sequence, with both steps mediated by the ortho-N-methylformamido-phenylsulfinyl function,
provided two new C–C bonds and an efficient entry to 1-aryl-tetralins and 4-aryl-benzopyrans. Scope and limits of the process have
been studied in detail.
Ó 2005 Elsevier Ltdv. All rights reserved.
Both aryl-tetralin1 and benzopyran2 structural frame-
works are widespread in bioactive and natural mole-
cules, such as aryltetralin lignanes, thus representing
important synthetic targets. A major challenge is repre-
sented by the development of methods suitable for
the synthesis of a wide range of differently substituted
tetralin and benzopyran skeletons, in order to make
available libraries of compounds.3 We now describe a
versatile two-step approach to the title structures, in
which a properly functionalized sulfoxide 3 (Scheme
1), obtained by a-carbon alkylation of a benzyl sulfoxide
1, is used for the generation of a benzyl carbocation
intermediate, undergoing cyclization to form a new
six-membered ring 4.
A search in the literature revealed a surprising lack
of precedents on the use of similar sulfoxide-based
approaches to the target structures.4
Recently,5 we have demonstrated the usefulness of an
arylsulfoxide reagent 1a (Scheme 2) bearing an ortho-
N-methylformamide function for the two-step synthesis
(alkylation/Pummerer reaction) of secondary benzyl car-
binols and chlorides. We therefore decided to investigate
R1
alkylation
O
H
O
R3
R2
S
X
S
O
CONHCH3
NH
R4
1
3
R1
R3
R2
X
cyclization
R4
4
R1
Scheme 1. Planned synthetic strategy.
Keywords: Sulfoxides; Carbocations; Cyclizations; Alkylations.
*
Corresponding authors. Tel.: +39 02 2399 3084; fax: +39 02 2399 3080; e-mail: matteo.zanda@polimi.it
0040-4039/$ - see front matter Ó 2005 Elsevier Ltdv. All rights reserved.
doi:10.1016/j.tetlet.2005.10.044

8724
A. Volonterio, M. Zanda / Tetrahedron Letters 46 (2005) 8723–8726
R1
Br
SH
R1
S
5
COOH
TEA, dioxane
COOH
R1
1) CH3NH2
O
S
R1 = H
1a (82%)
BOP-DIPEA
DMF
R1 = OCH3 1b (78%)
R1 = CF3 1c (68%)
R1 = NO2 1d (75%)
NH
2) MCPBA, CHCl3
O
Scheme 2. Synthesis of sulfoxides 1a–d (in brackets the overall isolated yields).
the suitability of reagents 1a–d for the synthesis of the
target structures.
ing amides by coupling with CH3NH2, and oxi-
dized with MCPBA to 1a–d in good overall isolated
yields.
The preparation of racemic sulfoxides 1 (Scheme
2) started with S-alkylation of thiosalicylic acid by
benzyl bromides, affording the ortho-carboxy sulfides
5, which were transformed into the correspond-
The 1-Br-3-arylpropyl substrates 2 (see Scheme 3 and
Table 1) were either commercially available (2a,b,h) or
prepared according to known methodologies.6,7
R1
O
O
S
H
R4
R2
1) BuLi, HMPA,
THF
X
R3
R2
S
Br
O
2) 2
CONHCH3
NH
R3
2
R4
1
3
R1
Scheme 3. Alkylation of racemic 1.
Table 1. Alkylation of lithiated racemic 1a–d with 2a–h
Entry
Substrate
1-Br-3-Aryl derivatives
Product
R1
R2
R3
R4
X
dr
Yield (%)
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1a
1a
1a
1a
1b
1b
1b
1b
1b
1c
1c
1c
1c
1c
1c
1d
1a
2a
2a
2b
2c
2d
2e
2f
3a
3a
3b
3c
3d
3e
3f
H
H
H
H
H
H
H
H
OCH3
OCH3
OCH3
OCH3
OCH3
CF3
CF3
CF3
CF3
CF3
CF3
NO2
H
H
H
H
OCH3
OCH3
OCH3
H
CN
H
H
H
H
H
H
H
Cl
OCH3
Br
H
H
H
H
H
H
H
H
OCH3
H
H
H
H
H
H
OCH3
H
H
H
H
H
CH2
CH2
O
93:7
93:7
88:12
97:3
99:1
>98:2
—
>98:2
93:7
89:11
85:15
90:10
98:2
89:11
29:71
98:2
42:58
95:5
64:46
—
74
88a
60
CH2
CH2
CH2
CH2
CH2
CH2
CH2
O
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
85
94
65
n.d.b
95
2g3g
2a
2a
2b
2d
2e
2a
2a
2c
2c
2c
2d
2a
2h
9
3h
3h
3i
78
10
11
12
13
14
15
16
17
18
19
20
21
83a
85
H
3j
OCH3
OCH3
H
Cl
OCH3
H
H
H
H
H
Cl
H
H
90
88
3l
3m
3m
3n
3n
3n
3o
3p
3q
51c
65d
45c
77d
51c
79d
n.d.b
n.r.e
H
OCH3
OCH3
OCH3
OCH3
H
H
H
H
H
C@O
—
a Reactions performed at ꢀ30 °C.
b Not determined: a complex mixture of products and starting material was obtained.
c Reactions stopped after 2 h (ꢀ70 °C ! ꢀ20 °C).
d Reactions stopped after 330 min (ꢀ70 °C ! rt).
e No reaction: deprotonation in a to the carbonyl is faster than substitution.

A. Volonterio, M. Zanda / Tetrahedron Letters 46 (2005) 8723–8726
8725
The C–C bond-forming reaction of lithiated sulfoxides
1a–d with bromides 2a–g took place in good to excellent
yields (Scheme 3 and Table 1), with few exceptions. In
the optimized protocol, treatment of benzyl sulfoxide
1a with 2.1 equiv of n-BuLi, in the presence of 5 equiv
of HMPA (THF, ꢀ78 °C), followed by addition of alkyl
bromides 2a–g afforded the products 3a–g with good to
excellent yields and high diastereoselectivity.8
with the electron poor p-CF3-benzyl sulfoxide 1c (entries
14–19), whereas the nitro sulfoxide 1d (entry 20) pro-
duced a complex reaction mixture. It is worth noting
that performance of the reactions at higher temperatures
(ꢀ30 to ꢀ20 °C) led to higher yields (entries 10, 14, 16,
and 18), but also to partial epimerization of the
products, which became very relevant with the p-CF3
substrate 1c at rt (entries 15, 17, and 19).9
All the reactions occurred with nearly complete site-
selectivity in favor of the C-alkylation. The stereochem-
istry of the main diastereomers was confidentially
assigned on the basis of a previous study on the C-alkyl-
ation of 1a.4 Benzyl sulfoxide 1a afforded very good
yields of the a-alkyl products 3a–g (entries 1–8), except
for the m-Br-derivative 3f (entry 7), owing to the unex-
pected formation of complex reaction mixtures. Fur-
thermore, no reaction was observed with the b-Br
ketone 2h (entry 21), because a-deprotonation of the
carbonyl group was faster than the C–C bond forming.
Excellent results, both in terms of yields and diastereose-
lectivity, were obtained with the electron rich, and there-
fore highly nucleophilic, a-lithiated p-MeO-Bn sulfoxide
1b (entries 9–13), and good results were achieved even
The cyclization step (Scheme 4 and Table 2) was per-
formed by treatment of sulfoxides 3a–o with triflic anhy-
dride in DCM, in the presence of a base, preferably
3 equiv of TMP or 1.5 equiv of 2,6-di-tert-butyl-4-meth-
ylpyridine (DTBMP), at ꢀ78 °C for less than 5 min.
DTBMP was preferentially used with p-methoxy sulf-
oxides 3h–l (entries 10–17), since it allowed to suppress
the b-elimination of the sulfinyl group observed with
TMP.10 Five and 3 equiv of Tf2O were used with TMP
and DTBMP, respectively.11 The reactions took place
in very good yields with a wide range of substrates,
affording the corresponding 4-aryl-benzopyrans 4b and
4h (entries 4 and 15) and 1-aryl-tetralins (all of the other
entries in Table 2), failing only in the case of 3g
(R2 = CN, entries 8–9), which is deactivated toward
R3
R2
X
O
R3
R2
H
X
X
R3
R2
S
Tf2O, base
CH2Cl2
O
+
+
S
R4
O
N
R4
NH
R4
3
4
R1
Alkene by product
R1
9
R1
Scheme 4. Synthesis of 1-aryltetralines and 4-arylbenzopyrans 4.
Table 2. Synthesis of 1-aryltetralines and 4-arylbenzopyrans 4
Entry
Substrate
Product
R1
R2
R3
R4
X
T (°C)
Base (equiv)
Yield (%)
1
2
3
4
5
6
7
8
3a
3a
3a
3b
3c
4a
4a
4a
4b
4c
4d
4e
H
H
H
H
H
H
H
H
H
H
H
H
OCH3
OCH3
OCH3
CN
CN
H
H
H
H
H
H
Cl
OCH3
H
H
H
H
H
H
H
H
Cl
OCH3
H
H
Cl
Cl
H
H
H
H
H
H
OCH3
H
H
H
H
H
H
H
H
H
OCH3
H
H
H
H
CH2
CH2
CH2
O
0
ꢀ78
ꢀ78 ! rt
ꢀ78
ꢀ78
ꢀ78
ꢀ78
ꢀ78
ꢀ78
0
ꢀ20
ꢀ78
ꢀ78
ꢀ78
ꢀ78
ꢀ78
ꢀ78
0
TMP (3)
TMP (3)
TMP (1.5)
TMP (3)
TMP (3)
TMP (3)
TMP (3)
TMP (3)
DTBMP (3)
TMP (3)
78
75
37a
63
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
O
CH2
CH2
CH2
CH2
CH2
CH2
95
3d
3e
85b
70
d
3g4f
3g4f
3h
3h
3h
3h
3h
3i
—
—
n.d.a,c
n.d.a,c
n.d.a,c
41
d
9
H
10
11
12
13
14
15
16
17
18
19
20
21
4g
4g
4g
4g
4g
4h
4i
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
CF3
CF3
CF3
CF3
H
H
H
H
TMP (3)
TMP (3)
DTBMP (3)
DTBMP (1.5)
DTBMP (1.5)
DTBMP (1.5)
DTBMP (1.5)
TMP (3)
TMP (3)
TMP (3)
TMP (3)
70
H
85
3j
OCH3
OCH3
H
OCH3
OCH3
OCH3
88b
89
3l
4j
3m
3n
3o
3o
4l
80
4m
4n
4n
0
77
ꢀ78
45b
85b
0
a Mixture with the olefin by-product formed by b-elimination of the sulfinyl group.
b As a single regioisomer.
c Not determined.
d Only the formation of alkene by-products via elimination of the sulfinyl group was obtained, in 76% (entry 7) and 37% yield (entry 8).

8726
A. Volonterio, M. Zanda / Tetrahedron Letters 46 (2005) 8723–8726
Kobayashi, R.; Nabeshima, T.; Furukawa, N. Tetrahe-
dron Lett. 1996, 37, 667–670; (f) Naka, H.; Sato, S.; Horn,
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Satoh, T.; Hanaki, N.; Yamada, N.; Asano, T. Tetra-
hedron 2000, 56, 6223–6234; For a review on the synthesis
of heterocycles via Pummerer-type reactions: (h) Bur, S.
K.; Padwa, A. Chem. Rev. 2004, 104, 2401–2432; For
studies on benzyl cation initiated cyclization reactions: (i)
Angle, S. R.; Louie, M. S. J. Org. Chem. 1991, 56, 2853–
2866; (j) Angle, S. R.; Arnaiz, D. O. J. Org. Chem. 1992,
57, 5937–5947.
intramolecular electrophilic substitution. In that case,
elimination of the sulfinyl group became competitive
and was the only observed outcome. Satisfactorily, both
electron-donating (such as OMe, entries 10–17) and
-withdrawing substituents R1 (such as CF3, entries 18–
21) appear to be compatible with the reaction, although
in the latter case the optimized reaction temperature was
higher (0 °C).
Concerning the mechanism, it is very likely that the
cyclization takes place through a benzyl carbocation
formed by action of Tf2O on the sulfinyl moiety of 3,
which undergoes a fast electrophilic cyclization with
the aromatic ring originally belonging to the 1-Br-3-
arylpropyl derivatives 2, affording the title compounds
4.12
5. Volonterio, A.; Bravo, P.; Zanda, M. Tetrahedron Lett.
2002, 43, 6537–6540.
6. Nystrom, R. F.; Brown, W. G. J. Am. Chem. Soc. 1947,
69, 2548–2549.
7. Hamilton, G. S.; Wu, Y.-Q.; Limburg, D. C.; Wilkinson,
D. E.; Vaal, M. J.; Li, J.-H.; Thomas, C.; Huang, W.;
Sauer, H.; Ross, D. T.; Soni, R.; Chen, Y.; Guo, H.;
Howorth, P.; Valentine, H.; Liang, S.; Spicer, D.; Fuller,
M.; Steiner, J. P. J. Med. Chem. 2002, 45, 3549–3557.
8. Synthesis of compounds 3. To a cooled solution of 1
(1.83 mmol, 500 mg) and dry HMPA (9.15 mmol,
1.60 mL) in dry THF (29 mL), a 2.5 M solution of n-BuLi
(3.85 mmol, 1.54 mL) was added drop-wise at ꢀ70 °C and
under Ar atmosphere. After 10 min, at ꢀ78 °C bromide 2
(2.01 mmol) was added. After the reaction was complete
(TLC monitoring), saturated aqueous NH4Cl was added,
the temperature raised to rt, and the solution extracted
with AcOEt. The collected organic layers were dried on
anhydrous Na2SO4, filtered, and the solvent evaporated in
vacuo. The residue was purified by flash-chromatography
to give 3.
In summary, we have developed a very effective two-step
approach to a large array of structurally diverse 1-aryl-
tetralins and 4-aryl-benzopyrans, exploiting the synthetic
potential of ortho-N-methylformamido-phenylsulfox-
ides 1. We are currently investigating an enantioselective
version of the process starting from enantiopure 1,
which could be feasible thanks to the high diastereo-
selectivity of the a-carbon alkylation step, as well as
its application to the synthesis of more complex, biolog-
ically important structures.
9. In fact, diastereomerically pure 3n, obtained according to
entry 16 (Table 1), epimerized quantitatively when treated
with n-BuLi/HMPA in THF at 0 °C.
10. (a) When p-MeO sulfoxides 3h–l were kept in CDCl3
solution at 305 K, a 1:1:2 mixture of the corresponding
cyclized product 4, olefin by-product arising by b-elimi-
nation of the sulfinyl group, and 2-methyl-benzo[d]iso-
Acknowledgment
Politecnico di Milano and CNR are gratefully acknow-
ledged for economic support.
References and notes
thiazol-3-one co-product
9 (Scheme 4) was formed
spontaneously in few hours, as detected by NMR analy-
sis.; (b) Synthesis of compounds 4. To a cooled solution of
3 (1 equiv) and a base (TMP or DTBMP, 3 equiv or
1.5 equiv, see Table 2) in dry DCM (0.1 M solution), neat
Tf2O (5 or 3 equiv, respectively) was added under nitrogen
at ꢀ78 or 0 °C (see Table 2). After less than 5 min, the
reaction was diluted with a 1 N HCl aqueous solution, the
temperature raised to rt, and the mixture extracted with
DCM. The collected organic layers were washed with a
NaHCO3 saturated aqueous solution, dried on anhydrous
Na2SO4, filtered, and the solvent evaporated in vacuo. The
crude was purified by flash chromatography affording
pure 4.
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Shoemaker, R. K. Org. Lett. 2000, 2, 1149–1152; For
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E.; Eggers, M. D. J. Am. Chem. Soc. 1987, 109, 2435–
2442; (d) Furukawa, N.; Kobayashi, K.; Sato, S. J.
Organomet. Chem. 2000, 611, 116–126; (e) Shima, H.;
11. Less equivalent of TMP (Table 2, entry 3) or more
equivalent of DTBMP (entry 13) led to a drop of yields.
12. Although we failed to isolate sulfur-containing reaction
co-products sufficiently pure for allowing a reliable struc-
ture assignment, we believe that in analogy with previously
studied Pummerer-type reactions involving ortho-N-methyl-
formamido-phenylsulfoxides 1 (Ref. 5), 2-methyl-benzo-
[d]isothiazol-3-one 9 (Scheme 4) is formed in the reaction.
In order to learn more about this issue, a CDCl3 solution
of pure 9 was treated, in an NMR tube, with an excess
of Tf2O, which resulted in a complete and immediate
conversion of the substrate to a complex mixture of
products. This suggests that the same event occurs in the
cyclization process.