Stereoselective synthesis of 2H-chromans by reductive deoxygenation of differently substituted 2-sulfinylmethylchroman-2-ols

Article abstract of DOI:10.1002/ejoc.201100436

Good-to-excellent diastereoselectivies have been achieved in the synthesis of 2H-chromans by Et₃SiH/TMSOTf reductive deoxygenation of differently substituted 2-sulfinylmethylchroman-2-ols and their methyl ketals. The influence of both electron-

Full text of DOI:10.1002/ejoc.201100436

FULL PAPER
DOI: 10.1002/ejoc.201100436
Stereoselective Synthesis of 2H-Chromans by Reductive Deoxygenation of
Differently Substituted 2-Sulfinylmethylchroman-2-ols
Gloria Hernández-Torres,[a,b] M. Carmen Carreño,*[a] Antonio Urbano,*[a] and
Françoise Colobert*[b]
Keywords: Sulfoxides / Oxygen heterocycles / Diastereoselectivity / Reduction / Substituent effects
Good-to-excellent diastereoselectivies have been achieved
which the sulfoxide was reduced, thus lowering the yield of
in the synthesis of 2H-chromans by Et3SiH/TMSOTf re- the sulfinyl 2H-chromans. The method allows the presence
ductive deoxygenation of differently substituted 2-sulfinyl-
methylchroman-2-ols and their methyl ketals. The influence
of both electron-donating and -withdrawing substituents on
the sulfoxide and on the aromatic dihydobenzopyran core
of different groups on the aromatic dihydrobenzopyran unit.
The best results in terms of yield and diastereoselectivity
were obtained with 2-[(p-tolylsulfinyl)methyl]chroman-2-ols.
All the results are explained on mechanistic grounds. Syn-
has been studied. SOR1 electron-donating groups (R1 = pMe- thetic transformations of the enantiopure 2H-chroman (S,RS)-
OPh and 2-MeO-1-naphthyl) led to a competitive reaction in
21 are reported.
ries[13] and from the chiral pool.[14] Although some of the
procedures gave good results, there is no asymmetric route
applicable to a wide range of substrates. Among the strate-
gies available nowadays for the stereoselective synthesis of
cyclic ethers,[15] the Et3SiH/TMSOTf-promoted synthesis of
ethers by reductive condensation of carbonyl compounds
and alkoxysilanes[16] or alcohols[17] has been applied by us
to the asymmetric synthesis of a number of different sized
systems. Thus, the Et3SiH/TMSOTf-promoted reductive cy-
clization of enantiopure β-hydroxy sulfinyl ketones I
(Scheme 1), in turn accessible by the well-established dia-
Introduction
Stereoselective approaches to 2-substituted and 2,2-di-
substituted tetrahydrobenzopyran derivatives (chromans)
continue to attract considerable attention due to the wide-
spread appearance of these structural motifs in a number
of natural products that exhibit important biological prop-
erties.[1] Apart from the antioxidant and radical scavenging
properties of the vitamin E family and its analogues, some
of them play an important role in various therapeutic areas,
including cardiovascular diseases, diabetes, obesity, hyper-
tension, cancer, the central nerve system and endocrine dis-
orders as well as infectious diseases. The 2H-chroman skel-
eton appears, for example, in the important shikimate-de-
rived group of flavanoids[2] and in some antibiotics[3] and
enzyme inhibitors.[4] Synthetic chromans are also valuable
targets as several derivatives have been shown to possess
important biological activities, acting as hypoglycemic
agents,[5] potent in vitro inhibitors of rhinovirus replica-
tion[6] and anti-hypertensive agents.[7]
stereoselective reduction of
a suitably functionalized
enantiopure β-keto sulfoxide,[18] allowed the synthesis of
five-,[19] six-,[19–21] seven-[22] and eight-membered[23] cyclic
ethers with 2,ω-cis-disubstitution (II) in a highly diastereo-
selective manner. We tested the validity of our asymmetric
These diverse biological activities have stimulated many
synthetic studies. The stereoselective construction of the
chroman core[8] has been achieved by asymmetric cataly-
sis,[9–11] enzymatic resolution,[12] the use of chiral auxilia-
[a] Departamento de Química Orgánica (Módulo 01), Universidad
Autónoma de Madrid,
c/ Francisco Tomás y Valiente n° 7, 28049 Madrid, Spain
Fax: +34-91-4973966
E-mail: carmen.carrenno@uam.es
antonio.urbano@uam.es
[b] Laboratoire de Stéréochimie associé au CNRS, Université de
Strasbourg, E.C.P.M.,
Scheme 1. Asymmetric induction in the formation of cyclic ethers
by reductive cyclization/deoxygenation of ω-keto β-hydroxy sulf-
oxides in equilibrium with δ-(o-hydroxyphenyl)-substituted β-keto
sulfoxides.
25 rue Becquerel, 67087 Strasbourg Cedex 2, France
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Stereoselective Synthesis of 2H-Chromans
approach by completing the total enantioselective synthesis
of several structurally simple natural products[19,23] and
more densely functionalized derivatives such as (+)-goni-
othalesdiol.[24] In these syntheses the sulfoxide controlled
the absolute configuration of the β-hydroxylic centre, which
in turn directed the stereochemical course of the reductive
cyclization step. The essential role of the exocyclic sulfoxide
in stabilizing the reactive conformation of the intermediate
cyclic oxocarbenium ion suffering the attack of Et3SiH has
only recently been pointed out.[24a]
Scheme 2. Synthesis of 4-(o-hydroxyphenyl)-1-sulfinyl-substituted
2-butanones 4a–e in equilibrium with 2-sulfinylmethyl-substituted
chroman-2-ols 3.
Although our asymmetric strategy to cyclic ethers moni-
tored by sulfoxides could be used to construct the 3,4-dihy-
dro-2H-1-benzopyran (2H-chroman) core, to the best of
our knowledge, prior to our work, sulfoxides have never
been used as asymmetric inductors to directly generate this
moiety from a phenol in a single step. In a previous com-
munication,[25] we reported the asymmetric synthesis of the
S,R,R,R enantiomer of Nebivolol, an antihypertensive
drug, employing the new sulfoxide-directed reductive deox-
ygenation of a 2-[(p-tolylsulfinyl)methyl]chroman-2-ol of
type IV (Scheme 1) to generate the 2H-chroman moieties.
We thus showed that the sulfoxide as the sole chiral element
was able to produce a high asymmetric induction in the
synthesis of dihydrobenzopyrans. To know the generality of
this stereoselective 2H-chroman ring-forming step, we de-
cided to study the reaction of differently substituted sulfinyl
derivatives both on the aromatic ring and on the sulf-
oxide.[26] In this paper, we present our results showing that
the Et3SiH/TMSOTf-promoted reductive deoxygenation of
2-sulfinylmethyl-substituted chroman-2-ols IV, in equilib-
rium with the δ-(o-hydroxyphenyl)-substituted β-keto sulf-
oxides III (Scheme 1), is a short, efficient and stereoselective
protocol to 2H-chroman derivatives that can be applied to
a wide range of differently substituted structures. We in-
clude full details of the methodology used for the prepara-
tion of all the synthetic intermediates as well as our conclu-
sions on the relative influence of steric and electronic effects
both in the reactivity and diastereoselectivity of the ionic
cleavage process. Further synthetic applications to some de-
rivatives lacking the sulfoxide are reported.
the cyclic hemiketal (RS)-3a and the keto sulfoxide 4a. The
mixture was isolated in 90% yield and compound 3a was
characterized as a mixture of C-2 anomers. The tBu, p-
methoxyphenyl-, p-nitrophenyl- and 2-naphthyl-substituted
methyl sulfoxides 2b,[28] 2c,[29] 2d[29b] and 2e[30] were used
in the racemic form. They were synthesized by controlled
oxidation of the corresponding commercially available thio-
ethers with MCPBA in 67, 90, 81 and 81% yields, respec-
tively. Their treatment with LDA in THF at –78 °C fol-
lowed by the addition of the resulting mixture to a THF
solution of dihydrocoumarin 1 gave rise to the desired de-
rivatives 3 and 4 as mixtures of cyclic hemiketals 3 and
open-chain ketones 4 (3/4 ≈ 90:10) in the yields indicated in
Table 1 (entries 2–5). The lower yield of p-nitrophenylsulf-
inyl derivatives 3d and 4d (21% yield) could be due to the
low solubility of the starting methyl p-nitrophenyl sulfoxide
(2d) in THF, making difficult the quantitative formation of
the lithium anion, because part of the starting sulfoxide 2d
was recovered unchanged. The (RS)-2-[(2-methoxynaphth-
ylsulfinyl)methyl]chroman-2-ol (3f) could not be isolated
from the crude mixture resulting from the enantiopure sulf-
oxide (RS)-2f[31] following the same procedure due to its in-
stability. We thus transformed the hemiketal into the mixed
methyl ketal 5 (50:50 mixture of anomers) by treating the
crude mixture immediately with trimethyl orthoformate and
a catalytic amount of p-toluenesulfonic acid in methanol
(Table 1, entry 6; 26% isolated yield for the two steps).
Table 1. Reactions between the lithium anion derived from
MeSOR1 2 and hydrocoumarin (1).
Results and Discussion
Entry R1
3/4 (90:10)
Yield [%]
The synthesis of δ-(o-hydroxyphenyl)-substituted alkyl β-
keto sulfoxides 4, required for our study, is shown in
Scheme 2. We initially chose differently substituted sulf-
oxides having pTol, tBu, pMeOPh, pNO2Ph, 2-naphthyl
and 2-MeO-1-naphthyl substituents at the sulfur function
(R1) to evaluate the relative influence of steric and elec-
tronic factors of the sulfoxide on the diastereoselectivity of
the process.[26]
1
2
3
4
5
6
pTol (RS)-2a
3a[a]/4a
3b[a]/4b
3c[a]/4c
3d[a]/4d
3e[a]/4e
5[b]
90
77
76
21
89
tBu (Ϯ)-2b
pMeOPh (Ϯ)-2c
pNO2Ph (Ϯ)-2d
2-naphthyl (Ϯ)-2e
2-MeO-1-naphthyl (RS)-2f
26 (2 steps)[c]
[a] Mixture of anomers, ca. 85:15. [b] Mixture of anomers, ca.
50:50. [c] Second step: treatment with HC(OMe)3, cat. pTsOH in
MeOH.
The β-keto sulfoxides 4a–f were synthesized by reaction
of the lithium anion derived from methyl R1-substituted
From our methodological study, we also wanted to know
sulfoxides 2a–f with dihydrocoumarin (1; Scheme 2, if the electronic density of the aromatic ring of the 2-sulfin-
Table 1). Thus, the reaction of 1 with the LDA-generated ylmethyl-substituted chroman-2-ol could influence the re-
lithium anion of (RS)-methyl p-tolyl sulfoxide[27] (2a; ductive deoxygenation process. With this aim, we decided
Table 1, entry 1) afforded a 90:10 equilibrium mixture of to prepare derivatives 14, 15 and 19, having different sub-
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FULL PAPER
stituents on the aromatic ring, such as a MeO electron-do- ketal forms, and the open β-keto sulfoxides 16 and 17 in the
nating group, an electron-withdrawing F and the trimethyl yields indicated in Scheme 5. The chromanol (SS)-15 was
and OH substituents found in the vitamin E core. The F- obtained in a similar way from (SS)-2a.[25]
substituted core had been previously synthesized by us to
complete the synthesis of Nebivolol.[25] The enantiopure p-
tolylsulfinylmethyl substituent was chosen as a model of the
substituent at C-2 of the chroman-2-ol. The MeO- and F-
substituted hydrocoumarins 8 and 9 (Scheme 3), required
to access the sulfinyl chromanols 14 and 15, were obtained
from the corresponding 5-substituted 1-indanones 6 and 7,
respectively, by Baeyer–Villiger oxidation with MCPBA and
catalytic trifluoromethanesulfonic acid in CH2Cl2 at
0 °C.[32] A 50:50 mixture of two isomeric lactones 8 and 10
resulted from the 5-methoxy-substituted indanone 6 from
which 8 could be isolated pure by chromatography in 35%
yield. The fluoro-substituted hydrocoumarin 9 was regiose-
lectively formed and isolated in 87% yield.
Scheme 5. Synthesis of methoxy- and fluoro-substituted 2-[(p-tolyl-
sulfinyl)methyl]chroman-2-ols 14 and 15.
Previous to the reaction with the lithium anion of methyl
p-tolyl sulfoxide, the trimethylhydroxy-substituted dihy-
drocoumarin 12 was protected as the benzyl ether (BnBr,
K2CO3, acetone, 83%, Scheme 6). Reaction of the benzyl-
protected derivative 18 with the lithium anion resulting
from (RS)-2a (1.2 equiv.) led to the sulfinyl-substituted
chromanol (RS)-19, which was characterized as a mixture
of C-2 epimers in an 85:15 diastereomeric ratio and was
isolated in 81% yield. The byproduct 20, which results from
the double addition of the intermediate sulfinyl carbanion
to the lactone, was also isolated from the crude mixture by
chromatography in 3% yield.
Scheme 3. Synthesis of substituted dihydrocoumarins 8 and 9.
The synthesis of the dihydrocoumarin 12, with the sub-
stitution present in the dihydrobenzopyran core of vitamin
E, was based on the reported Friedel–Crafts alkylation/lac-
tonization of an activated phenol.[33,34] We tried the one-
pot alkylation and lactonization of trimethylhydroquinone
11 using different acrylic acid derivatives such as methyl
acrylate, acryloyl chloride and acrylic acid in the presence
of different catalysts and we observed only the formation
of 12 when the reaction was effected with acrylic acid in
the presence of Amberlyst 15. Compound 12 was finally
obtained following a modification of a previously described
procedure[35] using 1.1 equiv. of acrylic acid and 400 mg/
mmol of Amberlyst 15 in toluene at reflux (Scheme 4). Un-
der these conditions, a mixture of 12 and the trimethyl-
benzoquinone 13 resulted, from which the hydrocoumarin
12 could be isolated pure in 53% yield.
Scheme 6. Synthesis of 6-benzyloxy-5,7,8-trimethyl-2-[(p-tolylsulf-
inyl)methyl]chroman-2-ol [(RS)-19].
With the sulfinylchromanols in hand, we initially exam-
ined the reaction of hemiketal (RS)-3a, chosen as a model,
with Et3SiH in the presence of different Lewis acids such
as ZnBr2, Yb(OTf)3, Me2AlCl, TiCl4 and TMSOTf. Sur-
prisingly, 3a did not react in the presence of Yb(OTf)3 or
Me2AlCl. Treatment of the mixture of the sulfoxide-bearing
chromanol (RS)-3a and the open β-keto sulfoxide (RS)-4a
with BF3·OEt2, followed by an excess of Et3SiH (3 equiv.)
Scheme 4. Synthesis of 6-hydroxy-5,7,8-trimethyl-3,4-dihydrocou-
marin (12).
The reactions of dihydrocoumarins 8 and 9 with the in CH2Cl2 at 0 °C led to the formation of 2H-chroman 21,
LDA-generated lithium anion derived from methyl p-tolyl although in a low yield of 17% (Scheme 7). A secondary
sulfoxide [(RS)-2a] allowed the synthesis of 2-(p-tolylsulfin- product, characterized as 2-(p-tolylsulfinylmethyl)-4H-
ylmethyl)-substituted chroman-2-ols (RS)-14 and (RS)-15, chromene (22) was isolated in 33% yield. The reaction with
which were isolated as mixtures of C-2 epimers in the hemi- Et3SiH in the presence of TiCl4 occurred in 2 h at 0 °C in
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Stereoselective Synthesis of 2H-Chromans
CH2Cl2 to give 2-[3-hydroxy-4-(p-tolylsulfinyl)butyl]phenol strong acid can coordinate both to the hemiketal OH or to
(23) in a non-stereoselective manner (dr 50:50, 75% yield). the less basic oxygen linked to the aromatic ring. The spe-
Similar results were obtained by using ZnBr2 as the Lewis cies C could suffer hemiketal ring-opening, leading to the
acid, although without complete conversion of the starting intermediate acyclic oxocarbenium ion E, the reduction of
material in the same reaction time.
which with Et3SiH justifies the formation of a mixture of
diastereomeric sulfinyl carbinols 23 observed in the pres-
ence of TiCl4. The activated species in the presence of
BF3·OEt2 B, would also form the intermediate D, the evol-
ution of which through a β-elimination explains the forma-
tion of chromene 22 (Scheme 9).
Scheme 7. Use of different Lewis acids in the reductive deoxygen-
ation reaction of (RS)-3a/(RS)-4a with Et3SiH.
Treatment of the mixture of (RS)-3a and (RS)-4a with
Et3SiH (3 equiv.) followed by addition of TMSOTf
(2 equiv.) in CH2Cl2 at 0 °C led to the rapid formation of
2H-chroman (S,RS)-21 in an excellent 95:5 diastereomeric
ratio and 75% yield (Scheme 8). The absolute S,RS configu-
ration of 21 was established by X-ray diffraction.[25] When
acetonitrile was used as the solvent, the formation of race-
mic 2-(p-tolylthiomethyl)chroman 24 was observed (54%
yield). This result indicates that acetonitrile first promotes
the reduction of the sulfoxide to the thioether and is fol-
lowed by reductive deoxygenation.
Scheme 9. Mechanistic pathway explaining the results obtained in
the reaction of 3a and Et3SiH in the presence of different Lewis
acids.
Taking this mechanistic proposal into account, we
thought of avoiding the formation of the undesired ring-
opened product 23 by performing the reaction on a mixed
methyl ketal derivative such as 25, with a slightly more basic
MeO group, which would favour the activation through a
species similar to A or B. Thus, product 25 was synthesized
by treatment of the hemiketal 3a with trimethyl orthofor-
mate and catalytic p-toluenesulfonic acid in methanol in
good yield as a mixture of C-2 epimers (50:50; Scheme 10).
Scheme 8. SO-directed reductive deoxygenation of (RS)-3a/(RS)-4a
with Et3SiH/TMSOTf.
A possible mechanistic pathway explaining these results
is shown in Scheme 9. Activation of the hemiketal OH must
occur with TMSOTf acting as a Lewis acid (or BF3·OEt2)
to give a species such as A which evolves into the cyclic
oxocarbenium intermediate D. The nucleophilic attack of
Et3SiH on this intermediate explains the formation of the
Scheme 10. Synthesis of mixed methyl ketal (RS)-25 and reaction
with Et3SiH in the presence of different Lewis acids.
The reaction of sulfinyl ketal (RS)-25 with Et3SiH in the
expected 2H-chroman 21. When TiCl4 is the Lewis acid, the presence of TMSOTf, BF3·OEt2 or TiCl4 as Lewis acid in
activated species could be B (similar to A) or C as this CH2Cl2 gave rise to the 2H-chroman 21. Working with
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FULL PAPER
Et3SiH and TMSOTf at 0 °C in CH2Cl2 solution, the sulf-
inyl ketal 25 was transformed into the sulfinyl chroman
mixture of diastereomers (S,RS)-21 and (R,RS)-21 in a ratio
of 89:11 (Table 2, entry 1). The reaction of 25 with Et3SiH
and BF3·OEt2 required 5 equiv. of the Lewis acid for com-
plete conversion of the starting 25 and a low temperature
(–20 °C) to avoid the formation of the elimination product
22. Under these conditions, chroman (S,RS)-21 was ob-
tained in 70% yield and with good diastereoselectivity
(94:6; Table 2, entry 2). In the presence of TiCl4, the re-
ductive deoxygenation of 25 was faster, even at lower tem-
peratures (Table 2, entries 3 and 4), but the diastereoselec-
tivity decreased dramatically. Although the diastereoselec-
tivity was highly dependent on the nature of the Lewis acid,
we never observed the inversion of the configuration at the
C-2 stereogenic centre created during the process. The
major diastereomer obtained from the mixed ketal (RS)-25
was always the (S,RS)-21 epimer, the same as that resulting
Scheme 11. Reductive deoxygenation of methyl ketal 25 with
iPr3SiH and PhSiH3 in the presence of TMSOTf.
from the hemiketal analogue (RS)-3a. These observations conditions shown (Et3SiH, TMSOTf, CH2Cl2, 0 °C). After
suggest that both reactions proceed through a similar mech- 24 h and 80% conversion, the reaction was quenched. The
anistic pathway.
NMR spectrum of the crude mixture evidences the presence
of a 75:25 mixture of epimeric chromans (2S*,R*S)-26 and
(2R*,R*S)-26 and the methylenechroman 30 resulting from
the exocyclic dehydration of hemiketal 3b. Chromato-
graphic separation allowed the isolation of pure dia-
stereomers (2S*,R*S)-26 and (2R*,R*S)-26 in 45 and 13%
yields, respectively, as well as a 20% yield of 2-(tert-butyl-
sulfinylmethylene)chroman (30; Table 3, entry 1). When the
reacting sulfoxide was 3c, having the electron-rich p-meth-
oxyphenyl substituent, the 2H-chroman 31 with a thioether
group, which results from sulfoxide reduction followed by
Table 2. Diastereomeric ratio in the reactions of (RS)-25 with Et3-
SiH in the presence of Lewis acids.
Entry Lewis acid (equiv.)
T [°C]
t [h] (S,RS)-21/(R,RS)-21
1
2
3
4
TMSOTf (2)
BF3·OEt2 (5)
TiCl4 (1.6)
0
10
18
89:11
94:6
75:25
68:32
–20 to r.t.
–40 to r.t.
–78
1.5
1.5
TiCl4 (1.6)
The influence of the reducing agent on the reductive de- reductive deoxygenation of 3c, was the major product (65%
oxygenation of mixed ketal (RS)-25 was also evaluated. Dif- isolated yield; Table 3, entry 2). A 23% yield of the dia-
ferent silicon hydrides such as triisopropylsilane (iPr3SiH), stereomers 27, which result from the expected deoxygen-
bulkier than Et3SiH, and phenylsilane (PhSiH3),[36] less ation, was also isolated with a 69:31 dr. In a similar way,
bulky, were tested in the reaction carried out in the presence the electron-rich (RS)-2-MeO-1-naphthylsulfinyl-substi-
of TMSOTf. Both reducing agents (3 equiv.) reacted with tuted chroman ketal 5 evolved into a complex mixture in
2-methoxy-2-(p-tolylsulfinylmethyl)-2-chroman [(RS)-25] in which the over-reduced product 32 was the only identified
the presence of TMSOTf (CH2Cl2, 0 °C) leading to the product, which was isolated in a poor yield of 15% (Table 3,
chromene 22 with a low conversion of the starting material. entry 5). Compound 32 was shown to be racemic, which
This indicates a lower reactivity of both hydrides in this again indicates that the starting sulfinylchroman derivative
process. When iPr3SiH was used at a lower temperature, 5 was first reduced to the thioether and later deoxygenated.
–20 °C, a mixture of epimeric 2-[(p-tolylsulfinyl)methyl]- In contrast, the electron-poor p-nitrophenyl-substituted
chromans (S,RS)-21 and (R,RS)-21 (dr 88:12) and chromene sulfoxide 28 favoured the reductive deoxygenation process,
22 was formed in a ratio of 60:40 (Scheme 11), but again giving rise to the 2H-chroman 28 in good yield (80%) and
with a low conversion.
diastereoselectivity: an 84:16 mixture of (2S*,R*S)-28 and
In the study carried out up to now, both the hemiketal (2R*,R*S)-28 (Table 3, entry 3). Good results were also ob-
(RS)-3a and the mixed methyl ketal (RS)-25 have shown very tained with the chromanol 3e bearing the 2-naphthyl-substi-
similar behaviour in the reductive deoxygenation reaction, tuted sulfoxide. The reductive deoxygenation products 29
with the best diastereoselectivities and yields of chroman were obtained in 76% yield and 87:13 dr (Table 3, entry 4).
derivative (S,RS)-21 obtained by using Et3SiH and In all cases, both diastereomers could be separated. A com-
TMSOTf in CH2Cl2 solution at 0 °C.
parison of the results depicted in Table 3 evidenced that the
We then decided to evaluate the role played by the nature efficiency of the reaction is highly dependent on the steric
of the sulfinyl substituent in the process. The results of the hindrance and electronic properties of the sulfoxide substit-
reactions of tBu-, p-methoxyphenyl-, p-nitrophenyl- and 2- uent. The tert-butyl sulfoxide was poorly reactive and made
naphthyl-substituted 2-sulfinylmethyl-2-chromanols 3b–e difficult the substitution of the OH by the hydride, the β-
are indicated in Scheme 12 and Table 3. The chromanol 3b, elimination product 30 being formed in 20% yield. The elec-
with a bulky tert-butyl sulfoxide, reacted slowly under the tron-rich p-MeOPh- and 2-MeO-naphthyl-substituted sulf-
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Stereoselective Synthesis of 2H-Chromans
Table 3. Reactions of 2-[(sulfinyl)methyl]chroman-2-ols (Ϯ)-3b–e and ketal 5 with Et3SiH in the presence of TMSOTf.
Entry
R1
Product yield [%]
26–29
(2S*,R*S):(2R*,R*S)/(yield [%])
1
2
3
4
5
6
tBu, 3b
26 (58),[a] 30 (20)
27 (23), 31(65)
28 (80)
75:25/(45:13)
69:31/(19:4)
84:16/(65:15)
87:13/(63:13)
–
pMeOPh, 3c
pNO2Ph, 3d
2-naphthyl, 3e
(RS)-2-MeO-1-naphthyl, 5
pTol, (RS)-3a
29 (76)
32 (15)
21 (86)
95:5/(75:3)
[a] 80% conversion.
oxides favoured the reduction of the sulfoxide and the β-
elimination compared with the substitution of the OH or
MeO group of the chromanol derivative by the hydride.
Scheme 13. Mechanism of the formation of the thioethers 31 and
32 from 3c and 5.
could conclude that the p-tolyl sulfoxide, easily available in
enantiopure form, is the best choice for this enantioselective
synthesis of 2H-chroman derivatives.
Scheme 12. Reactions of chromanols 3 and 5, with differently sub-
stituted sulfoxides, with Et3SiH and TMSOTf.
These observations can be explained by taking into ac-
The final aim of our study was to determine the influence
count the fact that electron-donating aromatic groups must of the electronic density of the aromatic ring of the 2-sulfin-
increase the basicity of the sulfinyl oxygen. Coordination of ylmethyl-substituted chroman-2-ol in the reductive deoxy-
this oxygen to the TMSOTf, acting as a Lewis acid, would genation. Thus, 2-hydroxy-6-methoxy-2-[(p-tolylsulfinyl)-
be then favoured to give a species such as F, which evolves methyl]chroman-2-ol (14), both enantiomers of the 6-
into an intermediate thiocarbenium ion G, similar to the fluoro-substituted analogue 15[25] and the 6-benzyloxy-
one generated in the Pummerer reaction,[37] after hydrogen 5,7,8-trimethyl derivative 19 were submitted to the reductive
loss from the methylene at the α position. The excess of deoxygenation conditions by treatment with Et3SiH and
Et3SiH in the medium would attack the thiocarbenium ion TMSOTf in CH2Cl2 solution at 0 °C. The results are sum-
to generate the (methylthio)chromanol H (Scheme 13). Fur- marized in Scheme 14 and Table 4. In all cases, the final
ther evolution of H by reductive deoxygenation of the chro- diastereomers of the 2H-chromans could be separated dia-
manol fragment promoted by Et3SiH and TMSOTf ex- stereomerically pure.
plains the formation of 31 and 32.
As can be seen, the reductive deoxygenation occurred in
Better results in terms of yield of the substitution prod- all cases in moderate-to-good yields. The most significant
uct and stereoselectivity were obtained with sulfoxides bear- differences correspond to the lower yields and diastereo-
ing the electron-withdrawing pNO2Ph group 3d and the 2- selectivities observed when electron-donating substituents
naphthyl sulfoxide 3e, but the best result was obtained from are present (Table 4, entries 1 and 4). Thus, the MeO-substi-
the reaction of p-tolyl sulfoxide 3a (Table 3, entry 6), which tuted chromanol 14 led to a 67:33 mixture of (S,RS)-33 and
led to the enantiopure 2H-chroman (S,RS)-21.[25] Thus, we (R,RS)-33, which could be isolated diastereomerically pure
Table 4. Reactions of 2-[(p-tolylsulfinyl)methyl]chroman-2-ols 14, 15 and 19 with Et3SiH in the presence of TMSOTf.
Entry
Starting material
R1
R2
Yield [%]
Product/(S,RS):(R,RS)/(yield [%])
1
2
3
4
14
H
H
H
MeO
F[a]
40
88
91
61
33/67:33/(30:10)
34/87:13/(75:11)
34/89:11/(70:10)[c]
35/75:25/(46:14)
15
15[b]
19
F[a]
Me
BnO
[a] 10 equiv. of Et3SiH were required. Taken from ref.[25]. [b] (SS-15 enantiomer. [c] Diastereomers: (R,SS)-34/(S,SS)-34.
Eur. J. Org. Chem. 2011, 3864–3877
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3869

G. Hernández-Torres, M. C. Carreño, A. Urbano, F. Colobert
FULL PAPER
Scheme 15. Transformations of 2-(p-tolylsulfinylmethyl)-2H-chro-
man [(S,RS)-21].
Mechanistic and Stereochemical Course of the Reductive
Deoxygenation
Scheme 14. Reactions of 2-[(p-tolylsulfinyl)methyl]chroman-2-ols
14, 15 and 19 with Et3SiH and TMSOTf.
Several conclusions could be drawn from the results ob-
tained in the reductive deoxygenation of both sulfinyl-chro-
in 30 and 10% yields, respectively (Table 4, entry 1). The manols 3 and the mixed methyl ketal 5. The best system to
BnO,trimethyl-substituted chromanol 19 gave a 75:25 mix- effect this reaction is TMSOTf/Et3SiH. The increase in the
ture of epimers from which the major (S,RS)-35 was isolated electronic density on the sulfoxide by the presence of elec-
in a 46% yield and the minor (R,RS)-35 in 14% yield tron-donating substituents on the aromatic group directly
(Table 4, entry 4). 2-[(p-Tolylsulfinyl)methyl]chromanols 15, linked to the sulfur, such as pMeOPh (3c) or 2-MeO-1-
having a F substituent at C-6, were less reactive. Thus, (RS)- naphthyl (5; Scheme 12 and Table 3), produced an unde-
15 evolved only partially after 24 h under the conditions sired reaction leading to thioethers 31 and 32 in which the
shown in Scheme 14. Complete conversion of the starting sulfoxide had been reduced. This was probably due to the
material (RS)-15 could be achieved by using an excess of competitive activation of the more basic sulfinyl oxygen by
the reducing agent. Thus, the treatment of (RS)-6-fluoro- the Lewis acid, as shown in Scheme 13, which favoured the
substituted chromanol 15 with 10 equiv. of Et3SiH at 0 °C Pummerer-like reaction leading to the reduction of the sulf-
gave rise to an 87:13 mixture of the C-2 epimers (S,RS)-34 oxide to the thioether. The bulky tert-butylsulfinyl group
and (R,RS)-34 from which the major epimer was isolated in decreased the reactivity of the system, the reaction being
75% yield (Table 4, entry 2). A similar result was obtained slower. Moreover, the stereoselectivity of the reaction is
with the enantiomer (SS-15 (Table 4, entry 3), which gave an only moderate (75:25; Table 3, entry 1), which shows that
89:11 mixture of (R,SS)-34 and (S,SS)-34, the former being steric effects do not play an essential role in controlling the
isolated in 70% yield.[25] Thus, we could access both stereochemical course of the hydride attack. Better yields
enantiomers of the 2H-chroman unit by simply changing and diastereoselectivities were obtained with the less elec-
the absolute configuration at the sulfur of the starting sulf- tron-rich p-tolylsulfinyl (3a) and 2-naphthylsulfinyl (3e) de-
inyl lactol.
rivatives, as well as with the electron-poor pNO2-substituted
Once the methodology to efficiently generate the C-2 sulfoxide (3d). In agreement with the mechanistic pathways
stereocentre of the 2H-chromans had been established, we shown in Scheme 9 for the ionic cleavage of the C2–O bond
wanted to take advantage of the synthetic versatility of the of the chromanols, these results must be a consequence of
sulfoxide and employ it in further reactions. We thus could the higher electrophilicity of the intermediate cyclic oxo-
obtain compounds 37 and 38, lacking the sulfoxide, with carbenium ion D. The presence of substituents on the aro-
complete retention of the C-2 S configuration (Scheme 15). matic moiety of the dihydrobenzopyran 14 (6-MeO), 15 (6-
The carbaldehyde (S)-36 was formed starting from F) and 19 (6-BnO-5,7,8-trimethyl) mainly influenced the
(S,RS)-21 by the Pummerer reaction after treatment with yields, which are better in the case of the electron-with-
TFAA and 2,4,6-collidine followed by basic hydrolysis. The drawing F-substituted derivative.
aldehyde (2S)-36 was not stable and thus, without purifica-
With respect to the configuration of the C-2 stereogenic
tion, the final crude mixture was treated with NaBH4 to centre of the major (2S)-2H-chroman always obtained, this
give 2-hydroxymethyl-2H-chromanol (S)-37[38] in excellent must be defined in the attack of the hydride on the interme-
yield with total retention of the configuration (97% ee).[39] diate oxocarbenium ion D shown in Scheme 16. Extensive
The success of the overall sequence required the addition studies carried out by Smith and Woerpel[40] on the mecha-
of 2,4,6-collidine prior to TFAA to avoid the formation of nism of nucleophilic substitutions of tetrahydrofuran and
the thioether 24, which reduced significantly the yield of 36. pyran acetals allowed them to conclude that these reactions
Finally, we tested the reactivity of carbaldehyde (S)-36 with occur through intermediate formation of cyclic oxocarb-
TBDMSCN in CH2Cl2 at –78 °C. Although no selectivity enium ions. In such cases, the reactive conformation is de-
was observed, cyanohydrin (S)-38 was synthesized as a mix- fined by the electrostatic effects of the substituents of the
ture of epimers at the newly generated stereocentre.
cyclic intermediates. These reactive conformations undergo
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Stereoselective Synthesis of 2H-Chromans
a stereoelectronically governed[41] face-selective attack of 2H-chroman formation. Electron-withdrawing substituents
the nucleophile. Our previous studies of the Et3SiH/ on the sulfoxide (pNO2Ph) or on the aromatic moiety of
TMSOTf reductive cyclization of enantiopure hydroxysulf- the dihydrobenzopyran (6-F) are compatible and lead to
inyl ketones, en route to 2,5-cis-disubstituted tetra- good diastereoselectivities. The latter is very interesting be-
hydrofurans, also illustrate the importance of electrostatic cause the synthesis of enantiomerically enriched fluorine-
effects of an exocyclic sulfinyl oxygen and the positively containing molecules is of importance in drug discovery
charged carbon centre in the stabilization of the reactive and development.[42] The results are justified on the basis
intermediate oxocarbenium conformations.[24] In the case of of mechanistic proposals and a stereochemical model in
the bicyclic oxocarbenium ions D, which lead to 2H-chro- which it is proposed that the sulfoxide assists the axial
mans, the stereoelectronic effects of the sulfoxide must not transfer of the hydride in the reactive conformation.
be responsible for the stabilization of the reactive confor-
mation because the most electron-rich sulfoxides gave po-
Experimental Section
orer diastereoselectivities. We thus propose that, once the
bicyclic oxocarbenium ion is formed, after ionic cleavage of
the C2–O bond of (RS)-3a by activation with the Lewis
acid, the hydride of Et3SiH is transferred with the assistance
of the sulfinyl oxygen through a species such as I, which
adopts the chair-like geometry represented in Scheme 16.
This is a stable conformation because the bulky p-tolyl
group of the sulfoxide is in a favourable equatorial position.
The approach of the hydride from the lower face, in the
axial direction, is favoured by stereoelectronic effects.
1
General: Melting points were obtained in open capillary tubes. H
and 13C NMR spectra were recorded in CDCl3 at 300 and 75 MHz,
respectively. Integration of well-resolved signals in the 1H NMR
spectrum allowed the diastereomers ratio to be established. All re-
actions were monitored by thin-layer chromatography, which was
performed on precoated sheets of silica gel 60, and flash column
chromatography was performed with silica gel 60 (230–400 mesh)
from Merck. Eluting solvents are indicated in the text. The appara-
tus for experiments performed in an inert atmosphere was flame-
dried in a stream of dry argon. Diisopropylamine was used freshly
distilled from KOH. CH2Cl2 was predried with CaCl2, distilled
from P2O5 and carefully kept under argon. Dry THF was distilled
from sodium/benzophenone ketyl. All other reagent quality sol-
vents were predried with activated molecular sieves and kept under
argon. For routine work-up, hydrolysis was carried out with water,
extractions with CH2Cl2, and solvent drying with MgSO4.
Method A: Synthesis of 2-[(Arylsulfinyl)methyl]chroman-2-ols: A
solution of 2.5 m nBuLi in hexanes (2.15 equiv.) was added to a
solution of dry diisopropylamine (2.2 equiv.) in THF (1.8 m) at 0 °C
under N2. The mixture was stirred for 30 min, cooled to –78 °C
and a solution of methyl aryl sulfoxide (1.1–1.4 equiv.) in THF
(1.4 m) was added dropwise. The reaction was allowed to reach
–40 °C and stirred for 1 h. After cooling to –78 °C, a solution of
the corresponding dihydrocoumarin (1 equiv.) in THF (2 m) was
added. After stirring for 1 h, the reaction was hydrolyzed with a
saturated aqueous ammonium chloride solution and extracted with
ethyl acetate. After work-up and purification as indicated in each
case, the corresponding pure sulfinylmethyl-chromanols were ob-
tained.
Scheme 16. Stereochemical model explaining the diastereoselective
formation of (S,RS)-21.
This model also justifies the lack of reaction observed
with PhSiH3, which is less prone to associate to the sulfinyl
oxygen. Although the bulkier iPr3SiH gave the 2H-chroman
(S,RS)-21 with good diastereoselectivity (88:22 dr), a signifi-
cant amount of chromene 22 was formed, probably due to
the lower stability of the transition state I, having an iPr
group in the axial position.
Method B: Synthesis of 2-(Arylsulfinylmethyl)-2H-chromans: Trieth-
ylsilyl hydride (3 equiv.) was added dropwise to a solution of the
2-[(arylsulfinyl)methyl]chroman-2-ol (1 equiv.) in CH2Cl2 (0.07 m)
at 0 °C followed by trimethylsilyl triflate (2 equiv.) under argon.
The reaction was stirred for the time indicated in each case at 0 °C.
After work-up and flash chromatography 2-[(arylsulfinyl)methyl]-
2H-chromans were obtained.
Conclusions
We have reported herein a methodological study of the
diastereoselective synthesis of 2H-chromans in two steps: (RS)-2-[(p-Tolylsulfinyl)methyl]chroman-2-ol (3a): Starting from
commercially available dihydrocoumarin (1; 818 μL, 6.5 mmol) and
enantiopure (RS)-methyl p-tolyl sulfoxide,[27] a crude mixture con-
taining compound 3a and the open-chain keto sulfoxide 4a (3a/4a:
90:10) was obtained following Method A. After work-up, diethyl
ether was added until a precipitate appeared. The solid was filtered
and washed with several portions of dry diethyl ether/hexane to
obtain lactol (RS)-3a as a white solid in 90% yield (1.8 g) as an
85:15 mixture of C-2 epimers.. When the reaction was performed
on a smaller scale, the precipitation of the product was not ob-
served and the final mixture was purified by flash chromatography
the reaction of a dihydrocoumarin with the lithium anion
derived from a methyl sulfoxide and ionic cleavage of the
C2–O bond of the resulting lactol with Et3SiH, promoted
by a Lewis acid. Among the different Lewis acids tested,
TMSOTf gave the best results in terms of yield and dia-
stereoselectivity. The influence of electron-donating and
-withdrawing substituents on the sulfoxide in the reductive
deoxygenation allowed us to establish that strong electron
donors are not suitable for this reaction because other com-
petitive processes occur that decrease the overall yield of (eluent: hexane/EtOAc, 1:1); m.p. 115–116 °C; Rf = 0.37 (hexane/
Eur. J. Org. Chem. 2011, 3864–3877
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3871

G. Hernández-Torres, M. C. Carreño, A. Urbano, F. Colobert
FULL PAPER
EtOAc, 1:1). [α]2D0 = +196.5 (c = 1, CHCl3). 1H NMR: δ = 1.71
(tdd, J = 12.6, 5.8, 1.5 Hz, 1 H), 2.03 (ddd, J = 12.9, 6.0, 2.8 Hz,
1 H), 2.30 (s, 3 H), 2.59 (ddd, J = 16.4, 5.6, 2.4 Hz, 1 H), 2.91 and
3.09 (AB system, J = 12.8 Hz, 2 H), 2.99–3.07 (m, 1 H), 6.17 (d, J
= 1.7 Hz, 1 H), 6.80–7.09 (m, 4 H), 7.27 and 7.52 (AAЈBBЈ system,
J = 8.2 Hz, 4 H) ppm. 13C NMR: δ = 20.7, 21.4, 32.1, 63.5, 96.7,
117.3, 121.1, 121.8, 124.1 (2 C), 127.4, 129.1, 130.3 (2 C), 140.2,
142.3, 152.0 ppm. MS (EI): m/z (%) = 77 (46), 91 (77), 107 (82),
124 (26), 140 (100), 145 (36), 149 (30), 163 (43), 302 (5) [M]+.
HRMS (EI): calcd. for C17H18O3S [M]+ 302.09766; found
302.09897.
151.6 ppm. MS (EI): m/z (%) = 65 (44), 84 (100), 91 (46), 107 (88),
125 (37), 145 (83), 155 (49), 171 (12), 299 (9), 333 (1) [M]+. HRMS
(EI): calcd. for C16H15NO5S [M]+ 333.06709; found 333.06830.
(؎)-2-[(2-Naphthylsulfinyl)methyl]chroman-2-ol (3e): Starting from
dihydrocoumarin (1; 482 μL, 3.80 mmol) and (Ϯ)-methyl 2-naphth-
yl sulfoxide (860 mg, 4.5 mmol), a crude mixture containing com-
pound 3e and the open-chain keto sulfoxide 4e (3e/4e: 90:10) was
obtained following Method A. After purification by flash
chromatography (eluent: hexane/EtOAc, 1:2), lactol (Ϯ)-3e was ob-
tained as a white solid in 89% yield (1.14 g) as a mixture of epimers
at C-2 in an 85:15 ratio; m.p. 119–121 °C. Rf = 0.37 (hexane/
1
(؎)-2-[(tert-Butylsulfinyl)methyl]chroman-2-ol (3b): Starting from
dihydrocoumarin (1; 365 μL, 2.9 mmol) and (Ϯ)-tert-butyl methyl
sulfoxide (520 mg, 4.3 mmol), a crude mixture containing com-
pound 3b and the open-chain keto sulfoxide 4b (3b/4b: 90:10) was
obtained following Method A. After purification by flash
chromatography (eluent: hexane/EtOAc, 1:2), lactol (rac)-3b was
obtained in 77% yield (596 mg) as an 85:15 mixture of epimers. Rf
= 0.25 (hexane/EtOAc, 1:2). 1H NMR: δ = 1.32 (s, 9 H), 1.85 (tdd,
J = 12.8, 5.8, 2.3 Hz, 1 H), 2.18 (ddd, J = 13.0, 6.0, 2.6 Hz, 1 H),
2.70 (ddd, J = 16.2, 5.8, 2.6 Hz, 1 H), 2.83 and 2.96 (AB system,
J = 12.3 Hz, Δν = 71.4 Hz, 2 H), 3.16 (ddd, J = 16.2, 12.5, 5.8 Hz,
1 H), 6.53 (d, J = 2.3 Hz, 1 H), 6.88–6.95 (m, 2 H), 7.08–7.16 (m,
2 H) ppm. 13C NMR: δ = 20.7, 22.5 (3 C), 32.7, 49.6, 53.4, 97.0,
117.3, 121.0, 121.7, 127.4, 129.0, 152.0 ppm. MS (FAB+): m/z (%)
=77 (15), 107 (35), 177 (10), 195 (100), 251 (90), 269 (19) [M +
1]+. HRMS (FAB+): calcd. for C14H21O3S [M]+ 269.1211; found
269.1212.
EtOAc, 1:2). H NMR: δ = 1.81 (tdd, J = 12.6, 5.8, 2.1 Hz, 1 H),
2.13 (ddd, J = 12.8, 5.8, 2.6 Hz, 1 H), 2.69 (ddd, J = 16.4, 5.7,
2.6 Hz), 3.27 and 3.11 (AB system, J = 12.8 Hz, Δν = 47.8 Hz, 2
H), 3.10–3.21 (m, 1 H), 6.24 (d, J = 2.2 Hz, 1 H), 6.91–7.03 (m, 2
H), 7.10–7.21 (m, 2 H), 7.61–7.65 (m, 2 H), 7.70 (dd, J = 1.7 Hz,
1 H), 7.91–7.99 (m, δ = 20.7, 32.1, 63.3, 96.8, 117.4, 119.5, 121.2,
121.7, 124.8, 127.5, 127.6, 128.2 (2 C), 128.6, 129.2, 130.0, 132.9,
134.7, 140.4, 151.9 ppm. MS (FAB+): m/z (%) = 77 (21), 89 (21),
145 (14), 175 (71), 321 (39), 338 (17), 339 (25) [M + H]+, 677 (11)
[2M + H]+. HRMS (FAB+): calcd. for C20H18O3S [M + H]+
338.09766; found 338.09930.
(RS)-2-Methoxy-2-[(2-methoxy-1-naphthylsulfinyl)methyl]chroman
(5): Starting from dihydrocoumarin (1; 7.45 mmol, 1 equiv.) and
(+)-methyl 2-methoxy-1-naphthyl sulfoxide (9.68 mmol, 1.3 equiv.),
a crude mixture containing compound 3f and the open-chain keto
sulfoxide 4f (3f/4f: 90:10) was obtained following Method A. This
mixture was dissolved in dry MeOH (0.05 m) and trimethyl ortho-
(؎)-2-[(p-Methoxyphenylsulfinyl)methyl]chroman-2-ol (3c): Starting formate [CH(OCH3)3, 0.4 m] and a catalytic amount of p-tolu-
from dihydrocoumarin (1; 692 μL, 5.4 mmol) and (Ϯ)-methyl p-
methoxyphenyl sulfoxide (1.3 g, 7.6 mmol), a crude mixture con-
taining compound 3c and the open-chain keto sulfoxide 4c (3c/4c:
90:10) was obtained following Method A. After purification by
flash chromatography (eluent: hexane/EtOAc, 1:3), lactol (rac)-3c
was isolated as a white solid in 76% yield (1.3 g), as a mixture of
epimers at C-2 in an 86:14 ratio; m.p. 102–103 °C. Rf = 0.31 (hex-
enesulfonic acid (0.1 equiv.) were added. After stirring for 3 d at
room temperature (ca. 20 °C), the mixture was treated with a satu-
rated aqueous NaHCO3 solution and extracted with EtOAc. After
work-up and flash chromatography (eluent: hexane/EtOAc, 2:1),
compound (RS)-5 was obtained as a 50:50 mixture of C-2 dia-
stereomers in 26% yield. A small amount of each one could be
separated pure for characterization. Diastereoisomer A: [α]2D0
=
1
1
ane/EtOAc, 1:2). H NMR: δ = 1.80 (tdd, J = 12.6, 5.8, 2.1 Hz, 1
+123 (c = 0.13, CHCl3). H NMR: δ = 2.05–2.17 (m, 1 H), 2.64–
2.76 (m, 2 H), 3.01–3.13 (m, 1 H), 3.28 (s, 3 H), 3.76 and 4.01 (AB
system, J = 14.2 Hz, Δν = 76.7 Hz, 2 H), 4.04 (s, 3 H), 6.77 (dd, J
= 1.3, 8.4 Hz, 1 H), 6.9 (dt, J = 7.3, 1.1 Hz, 1 H), 7.06–7.11 (m, 2
H), 7.28 (d, J = 9.1 Hz, 1 H), 7.42 (td, J = 8.0, 1.4 Hz, 1 H), 7.56
(td, J = 6.8, 1.4 Hz, 1 H), 7.8 (d, J = 8.0 Hz, 1 H), 7.9 (d, J =
9.1 Hz, 1 H), 9.03 (dd, J = 9.1, 0.7 Hz, 1 H) ppm. 13C NMR: δ =
H), 2.13 (ddd, J = 12.8, 5.8, 2.8 Hz, 1 H), 2.98 and 3.19 (AB sys-
tem, J = 12.8 Hz, Δν = 60.9 Hz, 2 H), 3.09–3.19 (m, 1 H), 6.27 (d,
J = 2.1 Hz, 1 H), 6.89–7.00 (m, 2 H), 7.12–7.19 (m, 2 H), 7.07 and
7.68 (AAЈBBЈ system, J = 8.9 Hz, Δν = 160.3 Hz, 4 H) ppm. 13C
NMR: δ = 20.9, 32.4, 55.8, 63.7, 96.9, 115.4 (2 C), 117.5, 121.3,
121.9, 126.3 (2 C), 127.6, 129.3, 134.6, 152.2, 162.8 ppm. MS (EI):
m/z (%) = 65 (21), 84 (75), 91 (30), 107 (100), 121 (29), 125 (51), 21.1, 30.4, 49.4, 56.9, 59.0, 98.3, 112.9, 116.8, 121.2, 122.5, 122.6,
140 (93), 155 (92), 164 (28), 318 (3) [M]+. HRMS (EI): calcd. for
C17H18O4S [M]+ 318.09258; found 318.09250.
122.7, 124.5, 127.2, 128.0, 128.8, 129.2, 129.5, 132.3, 134.2, 151.8,
155.9 ppm. Diastereoisomer B: [α]2D0 = +114 (c = 0.18, CHCl3). 1H
NMR: δ = 2.15–2.28 (m, 1 H), 2.38 (dd, J = 6.2, 2.2 Hz, 1 H), 2.66
(dd, J = 5. 8, 2.1 Hz, 1 H), 3.02–3.13 (m, 1 H), 3.32 (s, 3 H), 3.75
and 4.09 (AB system, J = 13.7 Hz, Δν = 101.7 Hz, 2 H), 3.99 (s, 3
H), 6.66 (d, J = 8.2 Hz, 1 H), 6.88 (dt, J = 7.6, 1.2 Hz, 1 H), 7.07
(m, 2 H), 7.28 (d, J = 9.3 Hz, 1 H), 7.42 (td, J = 7.9, 1.2 Hz, 1 H),
7.56 (td, J = 7.6, 1.2 Hz, 1 H), 7.83 (d, J = 8.0 Hz, 1 H), 7.98 (d,
J = 9.0 Hz, 1 H), 8.93 (d, J = 8.6 Hz, 1 H) ppm. 13C NMR: δ =
21.0, 29.8, 49.5, 56.8, 59.7, 97.9, 113.0, 116.8, 121.2, 122.4, 122.8,
122.9, 124.5, 127.2, 128.1, 128.8, 129.2, 129.4, 132.1, 134.2, 151.7,
156.2 ppm.
(؎)-2-[(p-Nitrophenylsulfinyl)methyl]chroman-2-ol (3d): Starting
from dihydrocoumarin (1; 489 μL, 3.86 mmol) and (Ϯ)-methyl p-
nitrophenyl sulfoxide (1.0 g, 5.4 mmol), compound 3d was obtained
following Method A. The methyl p-nitrophenyl sulfoxide was
hardly soluble in THF and the reaction proceeded with only 60%
of conversion. After work-up and purification by flash chromatog-
raphy (eluent: hexane/EtOAc, 1:2), lactol (Ϯ)-3d was obtained as
an orange oil in 21% yield (270 mg) as a mixture of epimers at C-
2 and the open-chain keto sulfoxide 4d in 62:18:20 ratio. Rf = 0.42
(hexane/EtOAc, 1:2). 1H NMR: δ = 1.83 (td, J = 12.7, 5.8 Hz, 1
H), 2.15 (ddd, J = 12.9, 5.9, 2.9 Hz, 1 H), 2.69 (ddd, J = 16.3, 5.6,
(RS)-6-Methoxy-2-[(p-tolylsulfinyl)methyl]chroman-2-ol (14): Start-
2.8 Hz), 3.04–3.15 (m, 1 H), 3.14 and 3.22 (AB system, J = 12.8 Hz, ing from 6-methoxychroman-2-one[12f] (8; 295 mg, 1.6 mmol) and
Δν = 21.2 Hz, 2 H), 5.74 (br. s, 1 H), 6.89–6.94 (m, 2 H), 7.08–7.16
(m, 2 H), 7.87 and 8.37 (AAЈBBЈ system, J = 8.4 Hz, Δν = ing compound 14 and the open-chain keto sulfoxide 16 (14/16:
149.6 Hz, 4 H) ppm. 13C NMR: δ = 20.6, 32.0, 63.9, 96.5, 117.2,
85:15) was obtained following Method A. After purification by
121.4, 121.6, 124.7 (2 C), 125.0 (2 C), 127.7, 129.2, 149.8, 151.1, flash chromatography (eluent: hexane/EtOAc, 2:3), lactol (RS)-14
enantiopure (RS)-methyl p-tolyl sulfoxide, a crude mixture contain-
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Stereoselective Synthesis of 2H-Chromans
was obtained as a white solid in 30% yield (165 mg) as a 77:23
mixture of C-2 epimers; m.p. 122 °C. H NMR: δ = 1.77 (tdd, J =
12.4, 5.6, 2.6 Hz, 1 H), 2.08 (ddd, J = 12.9, 6.0, 2.6 Hz, 1 H), 2.43
(s, 3 H), 2.65 (ddd, J = 16.5, 5.7, 2.6 Hz, 1 H), 2.97 and 3.16 (AB
system, J = 12.7 Hz, 2 H), 3.08–3.18 (m, 1 H), 3.76 (s, 3 H), 6.16
lowing Method B for 6 h at 0 °C, a 95:5 mixture of epimers (2S,RS)-
21 and (2R,RS)-21 was obtained (determined from the 1H NMR
spectrum of the crude reaction mixture). After purification by flash
chromatography (eluent: hexane/EtOAc, 3:2), compound (2S,RS)-
21 was isolated in 75% yield as a white solid. The C-2 epimer
1
(d, J = 2.1 Hz, 1 H), 6.64 (d, J = 2.5 Hz, 1 H), 6.73 (dd, J = 8.7, (2R,RS)-21 was obtained in 3% yield.
2.5 Hz, 1 H), 6.92 (d, J = 8.7 Hz, 1 H), 7.36 and 7.60 (AAЈBBЈ
(2S,RS)-21: M.p. 103–104 °C; Rf = 0.37 (hexane/EtOAc, 1:3). [α]2D0
system, J = 7.9 Hz, 4 H) ppm. 13C NMR: δ = 21.1, 21.4, 31.9, 55.6,
63.8, 96.6, 113.4, 113.6, 117.8, 122.3, 124.2, 130.1, 140.1, 142.2,
145.9, 153.8 ppm.
= +235.8 (c = 0.77, CHCl3). 1H NMR: δ = 1.89 (tdd, J = 13.5,
10.3, 5.6 Hz, 1 H), 2.01–2.10 (m, 1 H), 2.42 (s, 3 H), 2.76 (ddd, J
= 16.6, 5.3, 3.7 Hz, 1 H), 2.87–3.05 (m, 3 H), 4.61–4.69 (m, 1 H),
6.84–6.89 (m, 2 H), 7.03–7.14 (m, 2 H), 7.34 and 7.59 (AAЈBBЈ
system, J = 8.3 Hz, 4 H) ppm. 13C NMR: δ = 21.4, 24.3, 27.5, 64.3,
69.7, 117.0, 120.7, 121.4, 123.9 (2 C), 127.4, 129.5, 130.1 (2 C),
141.4, 141.6, 154.0 ppm. MS (EI): m/z (%) = 91 (35), 107 (12), 133
(13), 139 (37), 147 (100), 269 (15), 286 (1) [M]+. HRMS (EI): calcd.
for C17H18O2S [M]+ 286.10275; found 286.10312.
6-Fluoro-2-[(p-tolylsulfinyl)methyl]chroman-2-ol (15): Starting from
6-fluorochroman-2-one (9; 2.5 g, 15.0 mmol, 1 equiv.) and (RS)-
methyl p-tolyl sulfoxide (2.5 g, 16.5 mmol, 1.1 equiv.), a crude mix-
ture containing compound 15 and the open-chain keto sulfoxide 17
(14/17: 90:10) was obtained following Method A. After work-up,
diethyl ether was added until a precipitate appeared. The solid was
filtered and washed with several portions of dry diethyl ether/hex-
ane to obtain lactol (RS)-15 (87:13 C-2 epimers) as a white solid in
83% yield (3.99 g). When the reaction was performed on a smaller
scale, the precipitation of the product was not possible and the final
mixture was purified by flash chromatography (eluent: hexane/
(2R,RS)-21: Rf = 0.26 (hexane/AcOEt, 1:2). [α]2D0 = –88.3 (c = 0.77,
CHCl3). 1H NMR: δ = 1.89–2.04 (m, 1 H), 2.08–2.18 (m, 1 H),
2.42 (s, 3 H), 2.77–2.84 (m, 2 H), 2.99 and 3.36 (AB part of ABX
system, J = 13.3, 7.0, 5.4 Hz, Δν = 115.5 Hz, 2 H), 4.20 (dtd, J =
7.2, 5.4, 2.4 Hz, 1 H), 6.69 (dd, J = 8.1, 1.0 Hz, 1 H), 6.85 (td, J =
7.5, 1.2 Hz, 1 H), 7.02–7.08 (m, 2 H), 7.33 and 7.59 (AAЈBBЈ sys-
tem, J = 8.2 Hz, 4 H) ppm. 13C NMR: δ = 21.4, 24.1, 26.9, 62.0,
70.3, 116.8, 120.7, 121.3, 124.4 (2 C), 127.3, 129.5, 130.0 (2 C),
140.2, 141.7, 153.9 ppm. MS (EI): m/z (%) = 77 (16), 91 (41), 107
(15), 119 (8), 131 (12), 133 (11), 138 (47), 147 (100), 269 (20), 286
(2) [M]+. HRMS (EI): calcd. for C17H18O2S [M]+ 286.10275; found
286.10333.
EtOAc, 1:1); m.p. 125 °C; Rf = 0.43 (hexane/EtOAc, 1:2). [α]2D0
=
+179.7 (c = 1, CHCl3). 1H NMR: δ = 1.75 (tdd, J = 12.7, 6.1,
2.3 Hz, 1 H), 2.09 (ddd, J = 12.7, 6.1, 2.4 Hz, 1 H), 2.44 (s, 3 H),
2.65 (ddd, J = 16.7, 5.7, 2.4 Hz, 1 H), 2.97 and 3.16 (AB system,
J = 12.7 Hz, 2 H), 3.07–3.17 (m, 1 H), 6.25 (d, J = 2.3 Hz, 1 H),
6.67–6.95 (m, 3 H), 7.37 and 7.61 (AAЈBBЈ system, J = 8.0 Hz, 4
H) ppm. 13C NMR: δ = 20.8, 21.4, 31.8, 63.2, 96.7, 114.1 (d, J =
22.7 Hz), 115.0 (d, J = 23.4 Hz), 118.2 (d, J = 8.2 Hz), 123.0 (d, J
= 7.6 Hz), 124.0 (2 C), 130.3 (2 C), 140.1, 142.4, 147.9 (d, J =
2.2 Hz), 157.2 (d, J = 237 Hz) ppm. MS (EI): m/z (%) = 91 (65),
109 (31), 125 (64), 140 (100), 163 (46), 302 (7), 320 (11) [M]+.
HRMS (EI): calcd. for C17H17FO3S [M]+ 320.08814; found
320.08710.
(RS)-2-(p-Tolylsulfinylmethyl)-4H-chromene (22): Starting from
(RS)-2-[(p-tolylsulfinyl)methyl]chroman-2-ol (3a) following Method
B using BF3·OEt2 (2 equiv.) as the Lewis acid at 0 °C, a crude mix-
ture containing 21 (mixture of C-2 epimers) and 22 was obtained.
After purification by flash chromatography (eluent: hexane/EtOAc,
1:2), compounds 21 (17% yield) and (RS)-22 (33% yield) were iso-
lated. (RS)-22: Rf = 0.39 (hexane/AcOEt, 1:2). [α]2D0 = +59 (c = 0.59,
The enantiomer (SS)-15 was obtained in a similar way from (SS)-
methyl p-tolyl sulfoxide in a crude mixture containing compound
(SS)-15 and the open-chain keto sulfoxide 17 (14/17: 90:10). The
solid resulting from the precipitation was characterized as a 89:11
mixture of C-2 epimers of (SS)-15. White solid, 85% yield.
1
CHCl3). H NMR: δ = 2.39 (s, 3 H), 3.37–3.40 (m, 2 H), 3.44 and
3.62 (AB system, J = 12.8 Hz, Δν = 53.7 Hz, 2 H), 4.88 (t, J =
3.6 Hz, 1 H), 6.72 (d, J = 7.9 Hz, 1 H), 6.95–6.99 (m, 2 H), 7.06–
7.11 (m, 1 H), 7.27 and 7.52 (AAЈBBЈ system, J = 8.1 Hz, Δν =
75.0 Hz, 4 H) ppm. 13C NMR: δ = 21.4, 24.2, 62.6, 103.0, 116.3,
118.9, 123.5, 124.2 (2 C), 127.4, 129.0, 129.7 (2 C), 140.1, 141.6,
141.7, 151.3 ppm. MS (EI): m/z (%) = 65 (10), 77 (13), 91 (26), 115
(32), 117 (16), 139 (33), 145 (100), 172 (14), 268 (1), 284 (1) [M]+.
HRMS (EI): calcd. for C17H16O2S [M]+ 284.08710; found
284.08774.
(RS)-6-(Benzyloxy)-5,7,8-trimethyl-2-[(p-tolylsulfinyl)methyl]-
chroman-2-ol (19): Starting from 6-(benzyloxy)-5,7,8-trimethylchro-
man-2-one (18; 796 mg, 2.7 mmol), a crude mixture containing
compound 19 and the double addition product 20 was obtained
following Method A. Diethyl ether was added to the crude mixture
until a precipitate appeared. The solid was filtered and washed with
several portions of dry diethyl ether/hexane to obtain lactol (RS)-
19 as a white solid in 81% yield (983 mg) as an 85:15 mixture of
epimers at C-2. From the mother liquor, compound 20 was isolated
in 3% yield (see the Supporting Information for characterization
data). Chromanol 19: M.p. 168–169 °C (Et2O); [α]2D0 = +279 (c =
2-[3-Hydroxy-4-(p-tolylsulfinyl)butyl]phenol (23): Starting from
(RS)-2-[(p-tolylsulfinyl)methyl]chroman-2-ol (3a; 35 mg, 0.12 mmol
1 equiv.) following Method B using TiCl4 (25 μL, 0.23 mmol,
2 equiv.) as Lewis acid for 2 h at 0 °C, the reaction was completed.
After hydrolysis with a saturated solution of NaHCO3 and extrac-
tion with CH2Cl2, the organic layer was dried with MgSO4. After
purification by flash chromatography, compound 23 was isolated
in 75% yield as a diastereomeric mixture at C-3. Rf = 0.08 (hexane/
EtOAc, 1:3). 1H NMR (2 diastereoisomers): δ = 1.63–1.70 (m, 1
H), 1.78–1.91 (m, 3 H), 2.26 (1 H), 2.39 (s, 6 H), 2.61–3.09 (m, 8
H), 4.11–4.19 (m, 2 H), 4.96 (br. s, 1 H), 5.06 (br. s, 1 H), 6.75–
6.87 (m, 4 H), 6.99–7.10 (m, 4 H), 7.30 (d, J = 7.9 Hz, 4 H), 7.47–
7.52 (m, 4 H), 7.92 (br. s, 1 H), 8.17 (br. s, 1 H) ppm. 13C NMR (2
diastereoisomers): δ = 21.4, 21.5, 25.2, 25.3, 37.5, 37.7, 62.5, 62.6,
64.8, 67.3, 116.0, 116.4, 120.3, 120.4, 124.1 (2 C), 127.0, 127.1,
1
0.36, CHCl3). H NMR: δ = 1.74–1.83 (m, 1 H), 2.12–2.19 (m, 1
H), 2.20 (s, 3 H), 2.26 (s, 3 H), 2.29 (s, 3 H), 2.44 (s, 3 H), 2.64
(ddd, J = 17.5, 6.7, 2.6 Hz, 1 H), 2.83–2.94 (m, 1 H), 3.01 and 3.20
(AB system, J = 12.7 Hz, 2 H), 4.71 (s, 2 H), 6.17 (d, J = 2.1 Hz,
1 H), 7.34–7.43 (m, 5 H), 7.63 and 7.51 (AAЈBBЈ system, J =
8.2 Hz, 4 H) ppm. 13C NMR: δ = 11.9, 12.0, 12.8, 19.2, 32.0, 63.7,
74.7, 95.9, 118.1, 124.0, 126.0, 127.7, 127.7, 128.4, 130.0, 137.9,
140.4, 141.5, 142.2, 142.5, 145.8, 149.4 ppm. MS (FAB+): m/z (%)
= 55 (100), 91 (65), 139 (40), 203 (33), 359 (37), 433 (10), 450 (9)
[M]+. HRMS (FAB+): calcd. for C27H30O4S [M]+ 450.1865; found
450.1858.
(2S,RS)-2-[(p-Tolylsulfinyl)methyl]chroman (21): Starting from (RS)- 127.5, 127.7, 130.1, 130.2 (4 C), 130.4, 130.5, 139.1, 129.8, 141.8,
2-[(p-tolylsulfinyl)methyl]chroman-2-ol (3a; 40 mg, 0.13 mmol) fol- 142.2, 154.6, 154.8 ppm. MS (EI): m/z (%) = 65 (16), 77 (37), 92
Eur. J. Org. Chem. 2011, 3864–3877
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3873

G. Hernández-Torres, M. C. Carreño, A. Urbano, F. Colobert
FULL PAPER
(54), 107 (96), 121 (16), 140 (100), 147 (70), 269 (15), 287 (82), 304
(32) [M]+. HRMS (EI): calcd. for C17H20O3S [M]+ 304.11332;
found 304.11301.
57 (100), 91 (9), 107 (30), 133 (65), 146 (18), 196 (58), 252 (1).
HRMS (EI): calcd. for C14H20O2S [M]+ 252.11840; found
252.117740.
1
(Ϯ)-(2R,RS)-26: Rf = 0.35 (hexane/EtOAc, 1:2). H NMR: δ = 1.3
2-(p-Tolylthiomethyl)chroman (24): Starting from (RS)-2-[(p-tolyl-
sulfinyl)methyl]chroman-2-ol (3a; 20 mg, 0.07 mmol, 1 equiv.) and
following Method B using MeCN (1 mL) as solvent for 15 h at
0 °C, after the usual work-up and purification by flash chromatog-
raphy, compound (rac)-24 was isolated in 54% yield. Rf = 0.77
(s, 9 H), 1.98 (tdd, J = 13.6, 10.6, 5.6 Hz, 1 H), 2.32–2.40 (m, 1 H),
2.74–2.99 (m, 2 H), 2.81 and 2.94 (ddd, J = 12.9, 8.9, 4.0 Hz, 2 H),
4.52 (tdd, J = 12.4, 3.7, 2.1 Hz, 1 H), 6.79–6.88 (m, 2 H), 7.05–
7.11 (m, 2 H) ppm. 13C NMR: δ = 22.8 (3 C), 24.2, 26.4, 51.3, 53.4,
71.4, 116.8, 120.6, 121.5, 127.3, 129.5, 154.3 ppm. MS (EI): m/z
(%) = 57 (100), 77 (10), 107 (30), 133 (61), 147 (18), 196 (54), 252
(1). HRMS (EI): calcd. for C14H20O2S [M]+ 252.11840; found
252.11720.
1
(hexane/EtOAc, 1:2). H NMR: δ = 1.75–1.88 (m, 1 H), 2.16–2.25
(m, 1 H), 2.33 (s, 3 H), 2.71–2.83 (m, 2 H), 3.04 and 3.31 (dd, J =
13.4, 7.2, 5.6 Hz, 2 H), 4.09–4.18 (m, 1 H), 6.73–6.85 (m, 2 H),
7.02–7.15 (m, 4 H), 7.33 (d, J = 8.3 Hz, 2 H) ppm. 13C NMR: δ =
21.0, 24.3, 26.2, 39.1, 74.6, 116.8, 120.3, 121.8, 127.2, 129.4, 129.8
(2 C), 130.4 (2 C), 132.2, 136.5, 154.5 ppm. MS (EI): m/z (%) = 65
(5), 77 (14), 91 (18), 105 (22), 133 (100), 138 (25), 147 (22), 270
(80) [M]+. HRMS (EI): calcd. for C17H18OS [M]+ 270.10784; found
270.10779.
(؎)-2-(tert-Butylsulfinylmethylene)chroman (30): M.p. 93–94 °C. Rf
= 0.13 (hexane/EtOAc, 1:2). 1H NMR: δ = 1.21 (s, 9 H), 2.59–2.64
(m, 2 H), 2.69–2.84 (m, 2 H), 5.12 (s, 1 H), 6.89–6.93 (m, 2 H),
7.01–7.03 (m, 1 H), 7.09–7.12 (m, 1 H) ppm. 13C NMR: δ = 22.7 (3
C), 23.8, 27.3, 54.6, 105.2, 116.4, 122.5, 122.8, 128.1, 128.6, 151.6,
159.1 ppm. MS (EI): m/z (%) = 57 (26), 107 (12), 131 (17), 146 (30),
178 (14), 194 (100), 234 (1.6) [M – 16]+. HRMS (EI): calcd. for
C14H18OS [M]+ 234.10784; found 234.10780.
(RS)-2-Methoxy-2-[(p-tolylsulfinyl)methyl]chroman (25): To a solu-
tion of (RS)-2-[(p-tolylsulfinyl)methyl]chroman-2-ol [(RS)-3a;
1.81 g, 6.0 mmol, 1 equiv.] in dry MeOH (0.05 m), trimethyl ortho-
formate [CH(OCH3)3, 0.4 m] and a catalytic amount of p-tolu-
enesulfonic acid (0.1 equiv.) were added. After stirring for 3 h at
room temperature (ca. 20 °C), the mixture was treated with a satu-
rated aqueous NaHCO3 solution and extracted with EtOAc. After
work-up and flash chromatography (eluent: hexane/EtOAc, 1:1),
compound (RS)-25 was obtained as white solid in 89% yield
(1.68 g) as a 50:50 mixture of C-2 diastereomers; m.p. 79 °C; Rf =
0.43 (hexane/EtOAc, 1:3). [α]2D0 = +122 (c = 3.6, CHCl3). 1H NMR
(diastereomer A): δ = 1.97–2.07 (m, 1 H), 2.42 (s, 3 H), 2.61 (ddd,
J = 13.7, 6.1, 3.3 Hz, 1 H), 2.71 (ddd, J = 16.2, 5.7, 3.3 Hz, 1 H),
2.98–3.10 (m, 1 H), 3.23 and 3.32 (AB system, J = 14.2 Hz, Δν =
23.2 Hz, 2 H), 3.34 (s, 3 H), 6.80 (d, J = 8.1 Hz, 1 H), 6.90 (td, J
= 7.4, 1.2 Hz, 1 H), 7.07–7.13 (m, 2 H), 7.33 and 7.58 (AAЈBBЈ
system, J = 8.0 Hz, Δν = 72.6 Hz, 4 H) ppm; diastereomer B: δ =
2.26–2.33 (m, 2 H), 2.43 (s, 3 H), 2.67–2.72 (ddd, J = 16.1, 5.2,
2.5 Hz, 1 H), 2.98–3.13 (m, 1 H), 3.22–3.34 (m, 5 H), 6.78 (d, J =
8.2 Hz, 1 H), 6.85 (td, J = 7.3, 1.1 Hz, 1 H), 7.08–7.15 (m, 2 H),
7.28 and 7.54 (AAЈBBЈ system, J = 8.1 Hz, Δν = 76.2 Hz, 4
H) ppm. 13C NMR (diastereomer A): δ = 21.1, 21.4, 30.2, 49.5,
64.7, 97.5, 116.8, 121.3, 122.0, 124.0 (2 C), 127.3, 129.3, 130.1 (2
C), 140.8, 141.2, 151.2 ppm; diastereomer B: δ = 20.9, 21.4, 30.0,
49.4, 65.1, 97.6, 116.9, 121.4, 122.4, 124.1 (2 C), 127.4, 129.3, 130.1
(2 C), 141.3, 141.7, 151.6 ppm. MS (EI): m/z (%) = 59 (21), 91 (18),
140 (40), 145 (100), 163 (17), 177 (34), 316 (0.3) [M]+. HRMS (EI):
calcd. for C18H20O3S [M]+ 316.11332; found 316.11432. C18H20O3S
(316.11): C 68.33, H 6.37, O 15.17, S 10.13; found C 68.31, H 6.44,
S 10.02.
(؎)-(2S,RS)-2-[(p-Methoxyphenylsulfinyl)methyl]chroman
(27):
Starting from (Ϯ)-2-[(p-methoxyphenylsulfinyl)methyl]chroman-2-
ol (3c; 50 mg, 0.16 mmol) following Method B for 6 h at 0 °C and
12 h at room temp., a mixture containing compound 27 (69:31 mix-
ture of C-2 epimers) and compound 31 was obtained. After flash
chromatography (eluent: hexane/EtOAc, 1:2), compound (Ϯ)-
(2S,RS)-27 was obtained in 19% yield (9 mg) and the C-2 isomer
(Ϯ)-(2R,RS)-27 in 4% yield along with 2-(p-methoxyphenylthio-
methyl)chroman 31 in 65% yield (29 mg); m.p. 117–118 °C. Rf =
0.32 (hexane/EtOAc, 1:2).
1
(Ϯ)-(2S,RS)-27: H NMR: δ = 1.83 (tdd, J = 13.6, 10.6, 5.6 Hz, 1
H), 2.03–2.11 (m, 1 H), 2.77 (ddd, J = 3.8, 5.2, 16.6 Hz, 1 H), 2.87–
3.05 (m, 3 H), 4.60–4.68 (m, 1 H), 6.84–6.89 (m, 2 H), 7.02–7.13 (m,
2 H), 7.04 and 7.64 (AAЈBBЈ system, J = 8.9 Hz, Δν = 178.3 Hz, 4
H) ppm. 13C NMR: δ = 24.3, 27.5, 55.5, 64.3, 69.8, 114.9 (2 C),
116.9, 120.7, 121.4, 125.8 (2 C), 127.4, 129.5, 135.5, 153.9,
162.1 ppm. MS (FAB+): m/z (%) = 57 (40), 73 (32), 83 (13), 107
(11), 136 (12), 147 (35), 155 (38), 303 (100) [M + H]+, 605 (5) [2M
+ H]+. HRMS (FAB+): calcd. for C17H19O3S [M + H]+ 303.105491;
found 303.10420.
(Ϯ)-(2R,RS)-27: Rf = 0.26 (hexane/EtOAc, 1:2). 1H NMR: δ = 1.95
(tdd, J = 13.2, 10.0, 6.1 Hz, 1 H), 2.07–2.16 (m, 1 H), 2.76–2.83
(m, 2 H), 2.97 and 3.38 (ddd, J = 13.1, 7.2, 5.0 Hz, 2 H), 3.86 (s,
3 H), 4.11–4.19 (m, 1 H), 6.72 (d, J = 8.0 Hz, 1 H), 6.85 (t, J =
7.4 Hz, 1 H), 7.05–7.10 (m, 2 H), 7.03 and 7.64 (AAЈBBЈ system,
J = 8.7 Hz, Δν = 183.5 Hz, 4 H) ppm. 13C NMR: δ = 24.1, 27.0,
55.6, 62.1, 70.4, 114.9 (2 C), 116.8, 120.7, 121.4, 126.3 (2 C), 127.4,
129.6, 134.2, 153.9, 162.2 ppm.
(؎)-(2S,RS)-2-[(tert-Butylsulfinyl)methyl]chroman (26): Starting
from (Ϯ)-2-[(tert-butylsulfinyl)methyl]chroman-2-ol (3b; 50 mg,
0.18 mmol) following Method B for 18 h at 0 °C and 6 h at room
temp., a crude mixture containing epimers (Ϯ)-(2S,RS)-26 and (Ϯ)-
(2R,RS)-26 (75:25) and (Ϯ)-2-(tert-butylsulfinylmethylene)chroman
(30) was obtained. After flash chromatography (eluent: hexane/
EtOAc, 1:2), (Ϯ)-(2S,RS)-26 was obtained in 45% yield (22 mg) and
the C-2 isomer (Ϯ)-(2R,RS)-26 in 13% yield along with compound
30 in 20% yield.
2-[(p-Methoxyphenylthio)methyl]chroman (31): Colourless oil. Rf =
0.72 (hexane/EtOAc, 1:2). 1H NMR: δ = 1.75–1.88 (m, 1 H), 2.15–
2.24 (m, 1 H), 2.71–2.85 (m, 2 H), 2.99 and 3.24 (ddd, J = 13.6,
7.2, 5.7 Hz, 2 H), 3.80 (s, 3 H), 4.06–4.15 (m, 1 H), 6.77–6.86 (m,
4 H), 7.05 (t, J = 8.7 Hz, 2 H), 7.40 (d, J = 8.7 Hz, 2 H) ppm. 13C
NMR: δ = 24.3, 26.2, 40.5, 55.3, 74.7, 116.8, 120.3, 121.8, 127.2,
128.4, 129.4, 132.6 (2 C), 133.5 (2 C), 154.5, 159.1 ppm. MS (EI):
m/z (%) = 77 (15), 84 (15), 105 (22), 124 (12), 133 (61), 139 (100),
147 (13), 154 (15), 278 (34), 286 (64) [M]+. HRMS (EI): calcd. for
C17H18O2S [M]+ 286.10275; found 286.10214.
(Ϯ)-(2S,RS)-26: Rf = 0.29 (hexane/AcOEt, 1:2). 1H NMR: δ = 1.29
(s, 9 H), 1.88 (tdd, J = 13.4, 10.9, 5.7 Hz, 1 H), 2.11–2.19 (m, 1 H),
2.61 and 2.85 (ddd, J = 12.8, 9.2, 3.2 Hz, 2 H), 2.75–3.00 (m, 2 H),
4.59 (tt, J = 9.8, 2.8 Hz, 1 H), 6.82–6.87 (m, 2 H), 7.04–7.11 (m, 2 (؎)-(2S,RS)-2-[(p-Nitrophenylsulfinyl)methyl]chroman (28): Starting
H) ppm. 13C NMR: δ = 22.8 (3 C), 24.5, 27.9, 51.9, 52.9, 70.2,
116.9, 120.6, 121.5, 127.3, 129.5, 154.0 ppm. MS (EI): m/z (%) =
from
(Ϯ)-2-[(p-nitrophenylsulfinyl)methyl]chroman-2-ol
(3d;
56 mg, 0.16 mmol) following Method B for 4 h at 0 °C and 12 h at
3874
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 3864–3877

Stereoselective Synthesis of 2H-Chromans
room temp., an 84:16 mixture of (Ϯ)-(2S,RS)-28 and (Ϯ)-(2R,RS)- 2.31 (m, 1 H), 2.71–2.75 (m, 2 H), 3.00 and 3.28 (ddd, J = 13.4,
28 epimers was obtained. After flash chromatography (eluent: hex-
ane/EtOAc, 1:2), (Ϯ)-(2S,RS)-28 was obtained in 65% yield (33 mg)
7.7, 5.6 Hz, 2 H), 3.94–4.05 (m and s, 4 H), 6.65 (dd, J = 8.2,
1.2 Hz, 1 H), 6.78 (dd, J = 7.5, 1.3 Hz, 1 H), 6.97–7.05 (m, 2 H),
as a yellow solid and the C-2 isomer of (Ϯ)-(2R,RS)-28 in 15% 7.30–7.39 (m, 2 H), 7.51–7.57 (m, 1 H), 7.72–7.88 (m, 2 H), 8.67
yield (8 mg).
(d, J = 8.6 Hz, 1 H) ppm. 13C NMR: δ = 24.3, 26.3, 39.2, 56.7,
75.3, 112.9, 116.7, 120.1, 121.9, 123.6, 125.5, 127.1, 127.6, 128.2,
128.9, 129.4, 130.7, 130.9, 132.3, 136.3, 154.6 ppm. MS (FAB+):
m/z (%) = 77 (96), 89 (63), 91 (79), 115 (92), 149 (51), 158 (56), 189
(53), 336, (34) [M]+, 337 (5) [M + 1]+. HRMS (FAB+): calcd. for
C21H20O2S [M]+ 336.11840; found 336.11760.
(Ϯ)-(2S,RS)-28: M.p. 153–154 °C. Rf = 0.42 (hexane/EtOAc, 1:2).
1H NMR: δ = 1.85 (tdd, J = 13.4, 10.7, 5.6 Hz, 1 H), 2.03–2.12
(m, 1 H), 2.79 (ddd, J = 16.6, 5.2, 3.6 Hz, 1 H), 2.92 (dd, J = 10.7,
6.0 Hz, 1 H), 3.00 and 3.10 (ddd, J = 13.1, 9.8, 3.0 Hz, 2 H), 4.69
(tt, J = 9.8, 2.6 Hz), 6.86 (t, J = 8.4 Hz, 2 H), 7.06–7.15 (m, 2 H),
7.89 and 8.40 (AAЈBBЈ system, J = 8.8 Hz, Δν = 151.9 Hz, 4
H) ppm. 13C NMR: δ = 24.2, 27.4, 64.3, 69.4, 116.9, 121.0, 121.2,
124.4 (2 C), 124.9 (2 C), 127.5, 129.6, 149.6, 152.4, 153.6 ppm. MS
(EI): m/z (%) = 57 (6), 65 (8), 77 (22), 91 (41), 107 (25), 119 (11),
131 (20), 133 (21), 146 (100), 317 (2) [M]+. HRMS (EI): calcd. for
C16H15NO4S [M]+ 317.07218; found 317.07150.
(2S,RS)-6-Methoxy-2-[(p-tolylsulfinyl)methyl]chroman (33): Starting
from (RS)-6-methoxy-2-[(p-tolylsulfinyl)methyl]chroman-2-ol (14;
40 mg, 0.12 mmol) following Method B for 6 h at 0 °C and 16 h at
room temp., a 67:33 mixture of epimers (2S,RS)-33 and (2R,RS)-33
was obtained. After work-up and flash chromatography (eluent:
hexane/EtOAc, 1:1), compound (2S,RS)-33 was isolated in 30%
yield and the C-2 isomer (2R,RS)-33 in 10% yield as colourless oils.
1
(Ϯ)-(2R,RS)-28: Colourless oil, Rf = 0.28 (hexane/EtOAc, 1:2). H
1
(2S,RS)-33: H NMR: δ = 1.77–1.83 (m, 1 H), 1.98–2.05 (m, 1 H),
NMR: δ = 1.93–2.17 (m, 2 H), 2.74–2.93 (m, 2 H), 3.19 and 3.34
(ddd, J = 13.6, 7.4, 4.1 Hz, 2 H), 4.35–4.43 (m, 1 H), 6.45 (d, J =
8.2 Hz, 1 H), 6.85 (td, J = 8.2, 1.0 Hz, 1 H), 7.02–7.07 (m, 2 H),
7.88 and 8.39 (AAЈBBЈ system, J = 8.9 Hz, Δν = 151.7 Hz, 4
H) ppm. 13C NMR: δ = 24.1, 27.1, 61.1, 69.1, 116.5, 121.0, 121.1,
124.1 (2 C), 125.5 (2 C), 127.5, 129.6, 149.5, 151.2, 153.4 ppm. MS
(EI): m/z (%) = 65 (6), 77 (16), 91 (34), 107 (22), 131 (17), 133 (18),
146 (100), 300 (15), 317 (1) [M]+. HRMS (EI): calcd. for
C16H15NO4S [M]+ 317.07218; found 317.07180.
2.42 (s, 3 H), 2.70–2.78 (m, 1 H), 2.85–2.99 (m, 3 H), 3.75 (s, 3 H),
4.55–4.60 (m, 1 H), 6.58 (d, J = 2.3 Hz, 1 H), 6.69 (dd, J = 9.0,
2.3 Hz, 1 H), 6.80 (d, J = 9.0 Hz, 1 H), 7.33 and 7.57 (AAЈBBЈ
system, J = 8.4 Hz, 4H) ppm. 13C NMR: δ = 21.4, 24.6, 27.5, 55.7,
64.7, 69.6, 113.4, 113.9, 117.5, 121.9, 123.8, 130.0, 141.4, 141.5,
148.0, 153.6 ppm.
1
(2R,RS)-33: H NMR: δ = 1.90–2.00 (m, 1 H), 2.06–2.12 (m, 1 H),
2.41 (s, 3 H), 2.69–2.82 (m, 2 H), 2.97 and 3.34 (ddd, J = 13.2, 7.1,
5.3 Hz, 2 H), 3.75 (s, 3 H), 4.09–4.18 (m, 1 H), 6.56 (d, J = 2.7 Hz, 1
H), 6.63–6.65 (m, 2 H), 7.32 and 7.58 (AAЈBBЈ system, J = 8.4 Hz,
4H) ppm.
(؎)-(2S,RS)-2-[(2-Naphthylsulfinyl)methyl]chroman (29): Starting
from (Ϯ)-2-[(2-naphthylsulfinyl)methyl]chroman-2-ol (3e; 50 mg,
0.15 mmol) following Method B for 8 h at 0 °C and 12 h at room
temp., an 87:13 mixture of epimers (Ϯ)-(2S,RS)-29 and (Ϯ)-
(2R,RS)-29 was obtained. After flash chromatography (eluent: hex-
ane/EtOAc, 3:2), compound (Ϯ)-(2S,RS)-29 was obtained in 63%
yield (30 mg) as a beige solid and the C-2 isomer (Ϯ)-(2R,RS)-29
in 13% yield (6 mg).
(2S,RS)-6-Fluoro-2-[(p-tolylsulfinyl)methyl]chroman (34):[25] Starting
from (RS)-6-fluoro-6-methoxy-2-[(p-tolylsulfinyl)methyl]chroman-
2-ol (15; 3.0 g, 9.37 mmol, 1 equiv.) following Method B for 5 h at
0 °C and 2 h at room temp., an 87:13 mixture of epimers (2S,RS)-34
and (2R,RS)-34 was obtained. After flash chromatography (eluent:
hexane/EtOAc, 3:2), compound (2S,RS)-34 was obtained in 75%
yield (2.14 g) as a white solid; m.p. 115–117 °C; Rf = 0.36 (hexane/
EtOAc, 1:2). [α]2D0 = +232.0 (c = 0.64, CHCl3). 1H NMR: δ = 1.74–
1.87 (m, 1 H), 1.99–2.08 (m, 1 H), 2.42 (s, 3 H), 2.74 (ddd, J =
16.7, 5.6, 3.4 Hz, 1 H), 2.84–3.03 (m, 3 H), 4.60 (ddt, J = 12.5, 7.4,
2.4 Hz, 1 H), 6.73–6.81 (m, 3 H), 7.33 and 7.57 (AAЈBBЈ system,
J = 7.8 Hz, 4 H) ppm. 13C NMR: δ = 21.4, 24.5, 27.1, 64.1, 69.8,
114.1 (d, J = 23 Hz), 115.2 (d, J = 23 Hz), 117.8 (d, J = 7.7 Hz),
122.5 (d, J = 7.5· Hz), 123.8 (2 C), 130.1 (2 C), 141.3, 141.7, 149.9
(d, J = 1.9 Hz), 157.0 (d, J = 239 Hz) ppm. MS (EI): m/z (%) = 91
(25), 109 (40), 125 (21), 139 (74), 149 (21), 165 (100), 288 (11), 304
(2) [M]+. HRMS (EI): calcd. for C17H17FO2S [M]+ 304.09333;
found 304.09270.
(Ϯ)-(2S,RS)-29: M.p. 123–124 °C. Rf = 0.34 (hexane/EtOAc, 1:1).
1H NMR: δ = 1.84 (tdd, J = 13.5, 10.1, 5.5 Hz, 1 H), 2.03–2.11
(m, 1 H), 2.77 (ddd, J = 16.5, 5.3, 3.5 Hz, 1 H), 2.94 (ddd, J =
16.8, 10.9, 6.0 Hz, 1 H), 3.04 and 3.14 (ddd, J = 13.2, 9.5, 3.2 Hz,
2 H), 4.72 (tt, J = 9.7, 2.5 Hz, 1 H), 6.86–6.91 (m, 2 H), 7.05–7.15
(m, 2 H), 7.57–7.63 (m, 2 H), 7.66 (dd, J = 8.6, 1.8 Hz, 1 H), 7.90–
8.01 (m, 3 H), 8.26 (d, J = 1.5 Hz, 1 H) ppm. 13C NMR: δ = 24.3,
27.5, 64.1, 69.7, 117.0, 119.7, 120.8, 121.4, 124.4, 127.4, 127.5,
127.8, 128.1, 128.5, 129.5, 129.6, 132.9, 134.5, 141.6, 153.9 ppm.
MS (FAB+): m/z (%) = 88 (17), 109 (25), 177 (15), 323 (77) [M +
H]+, 645 (2M+ + H). HRMS (FAB+): calcd. for C20H19O2S [M]+
323.11057; found 323.11210.
(2R,SS)-6-Fluoro-2-[(p-tolylsulfinyl)methyl]chroman (34):[25] Com-
pound 34 was obtained in a similar way from (SS)-6-fluoro-6-meth-
oxy-2-[(p-tolylsulfinyl)methyl]chroman-2-ol (15) as an 89:11 mix-
ture of C-2 epimers from which diastereomers (2R,SS)-34 and
(2S,SS)-34 were isolated pure in 70 and 10% yields, respectively.
(Ϯ)-(2R,RS)-29: Rf = 0.26 (hexane/EtOAc, 1:1). 1H NMR: δ =
1.93–2.06 (m, 1 H), 2.11–2.19 (m, 1 H), 2.71–2.89 (m, 2 H), 3.13
and 3.43 (ddd, J = 13.4, 7.0, 5.1 Hz, 2 H), 4.24–4.32 (m, 1 H), 6.61
(d, J = 8.1 Hz, 1 H), 6.84–6.91 (m, 2 H), 7.56–7.63 (m, 2 H), 7.68
(dd, J = 8.7, 1.7 Hz, 1 H), 7.92 (dd, J = 9.4, 6.0 Hz, 2 H), 7.99 (d,
J = 8.5 Hz, 1 H), 8.26 (s, 1 H) ppm. 13C NMR: δ = 24.1, 27.0, 61.8,
70.2, 116.8, 120.2, 120.7, 121.3, 125.1, 127.3, 127.4, 127.9, 128.1,
128.6, 129.5, 129.6, 132.9, 134.6, 140.5, 153.8 ppm. MS (FAB+):
m/z (%) = 109 (54), 263 (16), 305 (10), 323 (36) [M + H]+. HMRS
(FAB+): calcd. for C20H19O2S [M]+ 323.11058; found 323.10930.
(2S,RS)-6-Benzyloxy-5,7,8-trimethyl-2-[(p-tolylsulfinyl)methyl]-
chroman (35): Starting from (RS)-6-(benzyloxy)-5,7,8-trimethyl-2-
[(p-tolylsulfinyl)methyl]chroman-2-ol (19; 40 mg, 0.09 mmol) fol-
lowing Method B for 4 h at 0 °C, a 75:25 mixture of epimers
(2S,RS)-35 and (2R,RS)-35 was obtained. After work-up and flash
chromatography (eluent: hexane/EtOAc, 3:2), compound (2S,RS)-
35 was isolated in 46% yield and the C-2 isomer (2R,RS)-35 in 14%
yield.
2-(2-Methoxy-1-naphthylthiomethyl)chroman (32): Starting from
(RS)-2-methoxy-2-[(2-methoxy-1-naphthylsulfinyl)methyl]chroman
(5; 47 mg, 0.13 mmol) following Method B for 1 h at 0 °C, after
flash chromatography (eluent: hexane/EtOAc, 3:2) compound 32
was obtained in 15% yield. 1H NMR: δ = 1.75–1.89 (m, 1 H), 2.22–
(2S,RS)-35: Rf = 0.37 (hexane/EtOAc, 1:2). [α]2D0 = +398 (c = 0.05,
CHCl3). 1H NMR: δ = 1.74–1.88 (m, 1 H), 2.04–2.10 (m, 1 H),
Eur. J. Org. Chem. 2011, 3864–3877
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3875

G. Hernández-Torres, M. C. Carreño, A. Urbano, F. Colobert
FULL PAPER
2.17 (s, 3 H), 2.18 (s, 3 H), 2.23 (s, 3 H), 2.43 (s, 3 H), 2.67–2.72
the cyanohydrin (2S)-38 as a mixture of two diastereoisomers at
(m, 2 H), 2.98–3.00 (m, 2 H), 4.52–4.60 (m, 1 H), 4.70 (s, 2 H), the hydroxy centre in a 60:40 ratio and in 52% yield for the two
1
7.33–7.43 (m, 5 H), 7.50 and 7.59 (AAЈBBЈ system, J = 8.3 Hz, Δν
= 25.2 Hz, 4 H) ppm. 13C NMR: δ = 11.9, 12.0, 12.8, 21.4, 22.7,
27.6, 64.5, 68.9, 74.7, 118.0, 123.1, 123.8 (2 C), 126.4, 127.7 (2 C),
127.8, 128.4, 128.5 (2 C), 130.0 (2 C), 137.8, 141.5, 148.2,
149.0 ppm. MS (FAB+): m/z (%) = 55 (12), 77 (26), 91 (22), 107
steps, starting from 21. Rf = 0.48 (hexane/AcOEt, 1:2). H NMR:
δ = 1.93–2.21 (m, 2 H), 2.77–2.95 (m, 2 H), 4.25 (ddd, J = 11.0,
4.3, 2.6 Hz, 1 H), 4.64 (dd, J = 4.0, 2.8 Hz, 1 H), 6.86–6.93 (m, 2
H), 7.05–7.15 (m, 2 H) ppm. 13C NMR (2 diastereoisomers): δ =
23.0, 23.3, 23.9, 23.9, 64.1, 64.6, 75.6, 75.7, 116.8, 116.9, 117.4,
(25), 120 (12), 343 (53), 435 (100) [M + 1]+. HRMS (FAB+): calcd. 117.7, 121.1, 121.4, 127.6 (2 C), 129.5 (2 C), 153.4 (2 C) ppm.
for C27H31O3S [M + 1]+ 435.1994; found 435.2001.
Supporting Information (see footnote on the first page of this arti-
cle): Experimental procedures for the synthesis and characteriza-
(2S,RS)-35: Rf = 0.25 (hexane/EtOAc, 1:2). [α]2D0 = –172 (c = 0.04,
CHCl3). 1H NMR: δ = 1.85–1.88 (m, 1 H), 1.95–2.03 (m, 1 H),
2.07 (s, 3 H), 2.13 (s, 3 H), 2.22 (s, 3 H), 2.41 (s, 3 H), 2.57–2.68
(m, 2 H), 2.99 and 3.44 (ddd, J = 12.8, 7.7, 4.9 Hz, 2 H), 3.98–4.07
(m, 1 H), 4.61 (s, 2 H), 7.30–7.43 (m, 5 H), 7.49 and 7.59 (AAЈBBЈ
system, J = 8.2 Hz, Δν = 32 Hz, 4 H) ppm. 13C NMR: δ = 11.7,
11.9, 12.8, 21.4, 22.4, 27.2, 62.6, 69.8, 74.7, 117.8, 124.4 (2 C),
126.4, 126.7, 127.7 (2 C), 127.8, 128.4 (2 C), 130.0 (2 C), 132.9,
140.3, 141.7, 148.1, 149.0, 151.3 ppm.
tion data of compounds 8–10, 12, 18 and 20.
Acknowledgments
We thank the Spanish Ministerio de Ciencia e Innovación (MIC-
INN) (grant number CTQ2008-04691), the Comunidad de Madrid,
the European Social Fund (grant number SOLGEMAC-S2009/
ENE-1617) and the French Ministère de la Recherche and the Cen-
tre National de la Recherche Scientifique (CNRS) for financial sup-
port.
(2S)-Chroman-2-carbaldehyde (36): Trifluoroacetic anhydride
(296 μL, 2.1 mmol, 3.05 equiv.) was added to a solution of sulfoxide
(2S,RS)-21 (198 mg, 0.69 mmol, 1 equiv.) and 2,4,6-collidine
(291 μL, 2.2 mmol, 3.2 equiv.) in CH3CN (12 mL) at 0 °C under
nitrogen. After stirring at 0 °C for 15 min, an aqueous solution
(7 mL) of NaHCO3 (526 mg, 6.2 mmol, 9 equiv.) was added. The
mixture was stirred at room temperature for 4 h, extracted with
Et2O and the organic layer washed with brine and dried with
MgSO4. After work-up, compound (2S)-36 was obtained and used
without further purification. 1H NMR: δ = 1.94–2.32 (m, 2 H),
2.67–2.92 (m, 2 H), 4.49 (ddd, J = 8.7, 3.5, 0.7 Hz, 1 H), 6.80–6.96
(m, 2 H), 7.04–7.18 (m, 2 H) ppm. 13C NMR: δ = 22.5, 23.3, 79.4,
116.9, 121.1, 121.5, 127.7, 129.7, 153.4, 201.5 ppm.
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(150 μL, 1.05 mmol, 5.0 equiv.) was added to a solution of (2S,RS)-
21 (60 mg, 0.21 mmol, 1 equiv.) and 2,4,6-collidine (83 μL,
0.63 mmol, 3.0 equiv.) in CH3CN (2 mL) at 0 °C under nitrogen.
After stirring at 0 °C for 15 min, an aqueous solution of K2CO3
was added until pH 7. The mixture was stirred at room temperature
for 15 min and then NaBH4 (0.42 mmol, 2 equiv.) was added and
the resulting mixture was stirred for 1 h at room temp. The reaction
was carefully quenched at 0 °C with a saturated NH4Cl solution
and extracted with EtOAc. The organic layers were washed with
1 m HCl, NaHCO3 and brine. Compound (2S)-37 was isolated pure
by flash chromatography (eluent: hexane/EtOAc, 1:1) as a colour-
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1
less oil in 80% yield. [α]2D0 = +90.4 (c = 0.56, CH3OH). H NMR:
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see: H. C. Shen, Tetrahedron 2009, 65, 3931–3952.
δ = 1.78–1.99 (m, 2 H), 2.13 (t, J = 5.9 Hz, 1 H), 2.78 (ddd, J =
16.3, 5.7, 3.3 Hz, 1 H), 2.89 (ddd, J = 16.5, 11.5, 5.7 Hz, 1 H), 3.74
(dd, J = 11.8, 6.0 Hz, 1 H), 3.83 (ddd, J = 15.1, 6.6, 3.3 Hz, 1 H),
4.12 (ddd, J = 12.5, 6.3, 3.0 Hz, 1 H), 6.84–6.90 (m, 2 H), 7.07–
7.10 (m, 2 H) ppm. 13C NMR: δ = 23.7, 24.5, 65.6, 76.4, 116.7,
120.4, 122.1, 127.3, 129.5, 154.8 ppm. MS (EI): m/z (%) = 77 (22),
105 (43), 133 (100), 164 (57) [M]+. HRMS (EI): calcd. for C10H12O2
[M]+ 164.08373; found 164.08385. 97% ee (HPLC; 90:10 hexane/
isopropanol, 0.5 mL/min, 210 nm, tr = 18.21 min, T = 25 °C).
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(2S)-(Chroman-2-yl)-2-hydroxyacetonitrile (38): (2S)-Chroman-2-
carbaldehyde (36), synthesized as reported above starting from sulf-
inylcroman (2S,RS)-21 (50 mg, 0.17 mmol, 1 equiv.), was dissolved
in CH2Cl2 (2 mL) and the solution was cooled to –78 °C.
TBDMSCN (30 mg, 0.21 mmol, 1.2 equiv.) was then added and the
resulting mixture was stirred for 6 h at –78 °C and left to reach
room temp. with stirring for an additional 10 h. After hydrolysis
with H2O and extraction with CH2Cl2, standard work-up and puri-
fication by flash chromatography (eluent: hexane/EtOAc, 2:1) gave
3876
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Eur. J. Org. Chem. 2011, 3864–3877

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Received: March 29, 2011
Published Online: June 17, 2011
Eur. J. Org. Chem. 2011, 3864–3877
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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