Synthesis of chromanes and 4H-chromenes: Exploring the oxidation of 2H-chromenes and dihydro-1-benzoxepines by hypervalent iodine(III)

Article abstract of DOI:10.1055/s-0032-1317497

The reaction of various oxygen-containing benzo-fused cycloalkenes were studied with the hypervalent iodine reagent hydroxy(tosyloxy)iodo]benzene [PhI(OH)OTs, HTIB]. 2H-Chromene and 4-methyl-2H-chromene resulted in substituted 4H-chromene and cis-3,4-dial

Full text of DOI:10.1055/s-0032-1317497

PAPER
▌3671
paper
Synthesis of Chromanes and 4H-Chromenes: Exploring the Oxidation of
2H-Chromenes and Dihydro-1-benzoxepines by Hypervalent Iodine(III)
Synthesis of Chromanes and 4H-Chromenes
Anees Ahmad, Luiz F. Silva, Jr.*
Instituto de Química - Universidade de São Paulo, Av. Prof. Lineu Prestes, 748, CP 26077, CEP 05513-970 São Paulo SP, Brazil
Fax +55(113)8155579; E-mail: luizfsjr@iq.usp.br
Received: 09.08.2012; Accepted: 02.10.2012
and (±)-indatraline.12,15 This encouraged us to examine
the behavior of 2H-chromenes and related cyclic alkenes
with hydroxy(tosyloxy)iodo]benzene, resulting in new
methods for the synthesis of different oxygen-containing
Abstract: The reaction of various oxygen-containing benzo-fused
cycloalkenes were studied with the hypervalent iodine reagent
hydroxy(tosyloxy)iodo]benzene [PhI(OH)OTs, HTIB]. 2H-
Chromene and 4-methyl-2H-chromene resulted in substituted
4H-chromene and cis-3,4-dialkoxy-4-methyl-3,4-dihydro-2H- heterocycles, such as 4H-chromenes, chromanes, and
chromenes, respectively. Ring contraction to chromanes and benzo-
furans was observed for dihydrobenzoxepines and 2,2-dimethyl-
2H-chromenes, respectively.
benzofurans. These reactions proceed under mild condi-
tions, they are easily performed, and they do not pose ma-
jor toxicity problems.
Key words: chromenes, chromanes, Koser’s reagent, ring contrac-
tion, hypervalent iodine
We focused our initial efforts on 2H-chromene (5a) which
was easily prepared in high yield from commercially
available chroman-4-one.11,16 Based on our previous ex-
perience,11,12,14,15,17 hydroxy(tosyloxy)iodo]benzene was
Benzopyrans, such as chromanes1 and chromenes,2 occur
selected from among several available hypervalent io-
in many biologically active compounds, and are key inter-
dine(III) reagents. The reactions of 5a were carried out
mediates in the construction of numerous natural products
with varying solvents, methanol, trimethyl orthoformate
and biologically active agents. Thus, several strategies
(TMOF), triethyl orthoformate (TEOF), acetonitrile,
have been developed for their synthesis.3
2,2,2-trifluoroethanol (TFE), hexafluoropropan-2-ol
(HFIP), and dichloromethane, and temperatures.18 The
most significant tests are shown in Table 1. The reaction
in methanol or trimethyl orthoformate gave methoxy-sub-
stituted 4H-chromene 6a as the main product, together
with the trans-addition product 7a (entries 1 and 2). The
reaction in triethyl orthoformate gave a similar result (en-
try 3). The reaction carried out in 2,2,2-trifluoroethanol
led to 2,2,2-trifluoroethoxy-substituted 4H-chromene 10a
in 24% yield; conversely, the addition product was not
isolated (entry 4).
In recent years, owing to their ecofriendly nature and
unique reactivity, hypervalent iodine compounds have
emerged as versatile and attractive reagents for a number
of noteworthy metal-free transformations.4 [Hydroxy(to-
syloxy)iodo]benzene or Koser’s reagent [PhI(OH)OTs,
HTIB]5 is a significant member of the family of hyperva-
lent iodine reagents, because of its extensive synthetic ap-
plications that cover areas such as tosyloxylation,6
intramolecular oxygenations,7 hydroxylation,8 oxidative
rearrangements9 and oxidative biaryl coupling.10 We have
developed the hydroxy(tosyloxy)iodo]benzene-mediated
ring contraction of 1,2-dihydronaphthalenes into indanes
(Scheme 1).11–13 This rearrangement was applied in the
diastereoselective total synthesis of (+)-mutisianthol14
The formation of 6a can be explained by the mechanism
shown in Scheme 2.9,11,19 The first step is electrophilic at-
tack by iodine(III) on the double bond, forming the cyclic
organoiodine 20. This intermediate is then attacked by the
F3CH2CO
OCH2CF3
1. HTIB, H2O
CH2Cl2, HFIP
2. NaBH4
OH
HTIB, TFE
73%
74%
2
1
3
58%
HTIB, HFIP
O
4
Scheme 1 Iodine(III)-mediated ring contraction of 1,2-dihydronaphthalene
SYNTHESIS 2012, 44, 3671–3677
Advanced online publication: 17.10.2012
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0032-1317497; Art ID: SS-2012-M0654-OP
© Georg Thieme Verlag Stuttgart · New York

3672
A. Ahmad, L. F. Silva, Jr.
PAPER
TsO
I
Ph
MeOH
OH
OMe
OH
OMe
O
OH2
I
Ph
δ+
I
δ+
+ H
– H
Ph
– H2O
– PhI
– OTs
O
H
O
O
5a
20
21
6a
MeOH
Scheme 2 Mechanism for the formation 4H-chromene
nucleophilic solvent at the benzylic carbon to form 21. 5d was treated with hydroxy(tosyloxy)iodo]benzene in
The final step is the β-elimination, displacing PhI and 2,2,2-trifluoroethanol, the ring contraction product 13d
water to give substituted 4H-chromene 6a.
was obtained in good yield (entry 9). Using the mixed sol-
vent system hexafluoropropan-2-ol–dichloromethane fol-
lowed by in situ reduction with sodium borohydride led to
the hydroxy functionalized chromane 14d in excellent
yield (entry 10). In this case the addition of small amount
of water is necessary to decrease the formation of unde-
sired acetal product 15d. The methyloxepine 5e also un-
dergoes ring contraction providing the keto-substituted
chromane 16e in good yield (entry 11).
Considering that the less electronegative sulfur atom
could have a less pronounced effect on the course of reac-
tion in comparison to the oxygen atom, the behavior of
2H-thiochromene (5b) was investigated. However, the re-
action of 5b with hydroxy(tosyloxy)iodo]benzene in tri-
ethyl orthoformate led to 4H-thiochromene 8b, similarly
to chromene 5a (entry 5).20
Taking into account that alkyl-substituted alkenes have
different behavior when compared to unsubstituted al-
kenes,12,21 the reaction of chromene 5c was also per-
formed under several conditions. The treatment of 5c with
hydroxy(tosyloxy)iodo]benzene in methanol or trimethyl
orthoformate gave cis-dimethoxychromane 11c in a dia-
stereoselective fashion and in good yield (entries 6 and 7).
The relative configuration was assigned by NMR includ-
ing NOESY experiments. Analogously, the reaction of 5c
in triethyl orthoformate gave 12c (entry 8). The fluorinat-
ed solvent 2,2,2-trifluoroethanol was also tested without
Several reaction conditions were tested for 2,2-dimethyl-
2H-chromene (5f). In this case, we expected the ring con-
traction product as there is no hydrogen atom at the car-
binolic carbon, which is responsible for the formation of
substituted 4H-chromene, such as 6a. Ring-contraction
products, such as the benzofurans 17f and 18f, were in-
deed isolated, however, in low yield (entries 12 and 13).
Intense efforts were made to improve these yields, but
without success.22 Analogues results were observed for
2,2,4-trimethyl-2H-chromene (5g) (entries 14 and 15).23
success. The diastereoselective synthesis of cis-dimeth- The mechanism for the ring contraction of 5d in hexa-
oxychromanes presumably follows a mechanism similar fluoropropan-2-ol–dichloromethane is shown in Scheme
to the formation of cis-addition product from 1,2-dihydro- 3.11–13 The electrophilic attack of hydroxy(tosyloxy)io-
naphthalenes.11,12
do]benzene on the double bond gave carbocation 22. The
oxygen lone pair attacks at the benzylic carbon resulting
in the cyclic oxonium ion 23. Ring opening of the four-
membered ring gives iodonium intermediate 24. The mi-
gration of an aryl bond on 24 leads to the ring-contraction
intermediate 25. After proton transfer, aldehyde 26 is re-
duced to the isolated alcohol 14d. The ring-contraction re-
actions under other conditions (entries 9, 11–15) take
place by similar mechanisms.
Based on the facilitating effect of the oxygen atom in the
β-elimination (Scheme 2), the oxidation of the substrates
5d–g, on which this effect would be less significant, was
investigated.
In the seven-membered-ring substrates 5d and 5e, the pos-
sibility of β-elimination could be avoid due to the pres-
ence of an additional methylene carbon. When the alkene
H
H
TsO
Ph
O
I
O
Ph
I
I
Ph
OH
– OTs
O
O
H
O
5d
22
HO
23
H
H
HO
O
O
I
Ph
NaBH4
– H
+ H
– PhI
O
O
O
O
24
25
26
14d
Scheme 3 Mechanism for the ring contraction in hexafluoropropan-2-ol–dichloromethane
Synthesis 2012, 44, 3671–3677
© Georg Thieme Verlag Stuttgart · New York

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Synthesis of Chromanes and 4H-Chromenes
3673
Table 1 Reaction of Oxygen-Containing Benzo-Fused Cyclic Alkenes 5a–g with [Hydroxy(tosyloxy)iodo]benzene (1.1 equiv)18,20,22,23
Entry
1
Substrate
Condition
Product (yielda)
OMe
OMe
O
OMe
MeOH, 0 °C, 3 h
O
O
5a
5a
6a
6a
8a
(66%)
7a
7a
9a
(15%)
OMe
OMe
OMe
2
3
4
5
6
TMOF, 0 °C, 2 h
TEOF, r.t., 4 h
O
O
(36%)
(13%)
OEt
O
OEt
OEt
5a
5a
O
(42%)
(8%)
OCH2CF3
TFE, 0 °C, 2 h
10aO (24%)
OEt
TEOF, 0 °C, 30 min
MeOH, 0 °C, 1 h
S
S
5b
8b
(60%)
MeO
OMe
O
O
11c
(64%)
5c
5c
MeO
OMe
7
8
TMOF, 0 °C, 2 h
TEOF, r.t., 4 h
11c O (44%)
EtO
OEt
5c
O
12c
(58%)
F3CH2CO
OCH2CF3
9
TFE, 0 °C, 30 min
O
O
5d
5d
13d
(50%)
OH
TsO
OTs
1. HFIP–CH2Cl2 (1:4), H2O (22 equiv).
2. NaBH4, 2 h
10
O
O
14d
(87%)
15d
(9%)
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 3671–3677

3674
A. Ahmad, L. F. Silva, Jr.
PAPER
Table 1 Reaction of Oxygen-Containing Benzo-Fused Cyclic Alkenes 5a–g with [Hydroxy(tosyloxy)iodo]benzene (1.1 equiv)18,20,22,23
(continued)
Entry
Substrate
Condition
Product (yielda)
O
11
TFE, 0 °C, 30 min
O
O
16e
(58%)
5e
HO
1. HFIP–CH2Cl2 (1:4), H2O (22 equiv)
2. NaBH4, 2 h
12
13
14
O
O
5f
5f
17f (31%)
MeO
OMe
MeOH, 0 °C, 2 h
MeOH, 0 °C, 1 h
O
18f (30%)
O
O
O
19g (24%)
5g
5g
O
15
MeOH–Et2O, 0 °C, 1 h
O
19g (24%)
a Isolated yield after purification by column chromatography.
with EtOAc (3 × 10 mL), and the combined organic extracts were
washed with brine (2 × 15 mL) and dried (anhyd MgSO4). The
crude product was purified by flash column chromatography (2%
EtOAc–hexane) giving 6a (0.106 g, 0.654 mmol, 66%) as a color-
less oil and 7a (0.029 g, 0.15 mmol, 15%) as a light yellowish oil.
In conclusion, the behavior of 2H-chromenes and 2,3-di-
hydro-1-benzoxepine with hydroxy(tosyloxy)iodo]ben-
zene was explored. This study provides new approaches
to give a variety of different O-heterocycles in moderate
to good yield. This methodology is mild and environmen-
tally friendly.
4-Methoxy-4H-chromene (6a)
IR (film): 3052, 2956, 2927, 2829, 1729, 1643, 1607, 1575, 1489,
1458, 1087, 1034 cm–1.
All commercially available reagents were used without further pu-
rification unless otherwise noted. All solvents used for reactions
and chromatography were dried and purified by standard methods.
TLC analyses were performed using silica gel 60F 254 precoated
plates, with detection by UV absorption (254 nm) and by spraying
with p-anisaldehyde and phosphomolybdic acid solns followed by
charring at ~150 °C for visualization. Flash column chromatogra-
phy was performed using silica gel 200–400 mesh. All NMR anal-
yses were recorded using CDCl3 as solvent and TMS as internal
standard with reference to internal solvent. Preparation of substrates
5a,16 5b,11 5c,11 5d,16,24 5e,11,24 5f,16,25 and 5g11,25 was performed as
described in the literature.
1H NMR (200 MHz, CDCl3): δ = 3.49 (s, 3 H), 5.58 (d, J = 3.6 Hz,
1 H), 5.86 (dd, J = 9.6, 3.6 Hz, 1 H), 6.73 (d, J = 9.8 Hz, 1 H), 6.91–
7.01 (m, 2 H), 7.10–7.25 (m, 2 H).
13C NMR (50 MHz, CDCl3): δ = 55.0, 95.8, 116.5, 119.6, 120.7,
121.5, 126.6, 127.0, 129.3, 151.3.
LRMS: m/z (%) = 162 (M+•, 23), 161 (21), 146 (4), 131 (100), 118
(5), 103 (11). 91 (15), 77 (21), 65 (8), 51 (13), 32 (20).
HRMS [ESI(+)]: m/z [M + Na]+ calcd for C10H10O2Na: 185.0573;
found: 185.0583.
trans-3,4-Dimethoxy-3,4-dihydro-2H-chromene (7a)
IR (film): 3074, 3042, 2983, 2931, 2892, 2825, 1698, 1609, 1585,
1489, 1463 cm–1.
1H NMR (300 MHz, CDCl3): δ = 3.46 (s, 3 H), 3.47 (s, 3 H), 3.66
(td, J = 3.3, 1.8 Hz, 1 H), 4.18 (dd, J = 12, 1.8 Hz, 1 H), 4.19 (dd,
J = 3.6, 1.5 Hz, 1 H), 4.33 (ddd, J = 11.7, 3.3, 1.5 Hz, 1 H), 6.85–
6.89 (m, 1 H), 6.92 (dd, J = 7.5, 1.2 Hz, 1 H), 7.18–7.25 (m, 2 H).
4-Methoxy-4H-chromene (6a) and trans-3,4-Dimethoxy-3,4-di-
hydro-2H-chromene (7a); Typical Procedure 1
To a stirred soln of 2H-chromene (5a; 0.135 g, 1.02 mmol) in
MeOH (5 mL) was added HTIB (0.450 g, 1.15 mmol) at 0 °C. This
mixture was stirred for 3 h (TLC monitoring) and the reaction was
quenched with sat. NaHCO3 soln. The aqueous phase was extracted
Synthesis 2012, 44, 3671–3677
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Synthesis of Chromanes and 4H-Chromenes
3675
13C NMR (50 MHz, CDCl3): δ = 56.5, 56.9, 62.8, 73.9 (2 C), 116.8,
119.4, 120.3, 129.8, 131.4, 154.1.
LRMS: m/z (%) = 194 (M+•, 13), 162 (9), 136 (53), 121 (41), 107
(100), 91 (13), 77 (19), 65 (11), 51 (10).
13C NMR (75 MHz, CDCl3): δ = 64.0 (q, J = 138 Hz, CH2CF3),
95.16, 116.5, 118.4, 120.3, 122.1, 123.7 (q, J = 1106.4 Hz,
CH2CF3), 127.2, 127.6, 129.7, 150.6.
LRMS: m/z (%) = 230 (M+•, 9), 131 (100), 118 (3), 102 (7), 91 (7),
77 (14).
HRMS [ESI(+)]: m/z [M + Na]+ calcd for C11H14O3Na: 217.0835;
found: 217.0832.
HRMS [ESI(+)]: m/z [M + Na]+ calcd for C11H9F3O2Na: 253.0447;
found: 253.0549.
4-Ethoxy-4H-chromene (8a) and trans-3,4-Diethoxy-3,4-di-
hydro-2H-chromene (9a); Typical Procedure 2
4-Ethoxy-4H-thiochromene (8b)
HTIB (0.450 g, 1.14 mmol) was added at r.t. to a stirred soln of 2H-
chromene (5a; 0.135 g, 1.02 mmol) in TEOF (6 mL). The resulting
turbid soln became clear after 10 min. After 4 h, the reaction was
quenched with sat. NaHCO3 soln. The mixture was extracted with
EtOAc (3 × 10 mL), and the combined organic extracts were
washed with brine soln (2 × 20 mL) and dried (anhyd MgSO4). The
solvent was evaporated under reduced pressure. The crude product
was purified by flash column chromatography (5% EtOAc–hexane)
giving product 8a (0.075 g, 0.42 mmol, 42%) as a colorless oil and
9a (0.018 g, 0.081 mmol, 8%) as a light yellowish oil.
Following typical procedure 2 using 2H-thiochromene (5b; 0.120 g,
0.810 mmol), TEOF (6 mL), and HTIB (0.350 g, 0.891 mmol). Pu-
rification by column chromatography (silica gel) gave 8b (0.93 g,
0.48 mmol, 60%) as a light yellow oil.
IR (film): 3057, 3035, 2975, 2892, 2873, 1945, 1920, 1719, 1675,
1639, 1627, 1586, 1471, 1439 cm–1.
1H NMR (200 MHz, CDCl3): δ = 1.15 (t, J = 7.0 Hz, 3 H), 3.36 (dq,
J = 9.1, 7.0 Hz, 1 H), 3.75 (dq, J = 9.1, 7.0 Hz, 1 H), 5.29 (d, J = 6.4
Hz, 1 H), 6.14 (dd, J = 10.2, 6.4 Hz, 1 H), 6.84 (d, J = 10.2 Hz, 1
H), 7.10–7.35 (m, 4 H).
13C NMR (50 MHz, CDCl3): δ = 14.8, 61.5, 75.0, 119.7, 125.2,
127.1, 128.2, 129.2, 129.7, 129.9, 130.1.
HRMS [ESI(+)]: m/z [M + Na]+ calcd for C11H12OSNa: 215.0501;
found: 215.0498.
4-Ethoxy-4H-chromene (8a)
IR (film): 3046, 2976, 2927, 2880, 1718, 1644, 1607, 1576, 1497
cm–1.
1H NMR (200 MHz, CDCl3): δ = 1.20 (t, J = 7 Hz, 3 H), 3.65 (dq,
J = 9.7, 7 Hz, 1 H), 3.64 (dq, J = 9.7, 7 Hz, 1 H), 5.68 (d, J = 3.8 Hz,
1 H), 5.85 (dd, J = 9.6, 3.8 Hz, 1 H), 6.71 (d, J = 9.6 Hz, 1 H), 6.96
(d, J = 7.2 Hz, 2 H), 7.10–7.24 (m, 2 H).
Anal. Calcd for C11H12OS: C, 68.71; H, 6.29. Found: C, 68.65; H,
6.31,
13C NMR (50 MHz, CDCl3): δ = 15.2, 63.4, 94.8, 116.5, 119.9,
120.7, 121.4, 126.5, 127.0, 129.2, 151.4.
LRMS: m/z (%) = 176 (M+•, 42), 147 (35), 131 (100), 118 (5), 103
(25), 91 (36), 77 (32), 65 (18), 51 (23), 39 (22).
cis-3,4-Dimethoxy-4-methyl-3,4-dihydro-2H-chromene (11c)
Following typical procedure 1 using methylchromene 5c (0.202 g,
1.38 mmol), MeOH (6 mL), and HTIB (0.595 g, 1.51 mmol). Puri-
fication by column chromatography (silica gel) gave 11c (0.183 g,
0.878 mmol, 64%) as a colorless oil.
HRMS [ESI(+)]: m/z [M + Na]+ calcd for C11H12O2Na: 199.0725;
IR (film): 3069, 3036, 2981, 2938, 2896, 2826, 1628, 1608, 1582,
1488 cm–1.
found: 199.0715.
trans-3,4-Diethoxy-3,4-dihydro-2H-chromene (9a)
IR (film): 3042, 2976, 2926, 2882, 1624, 1610, 1586, 1489, 1464
cm–1.
1H NMR (300 MHz, CDCl3): δ = 1.20 (t, J = 6.9 Hz, 3 H), 1.24 (t,
J = 6.9 Hz, 3 H), 3.59–3.69 (m, 2 H), 3.69–3.76 (m, 3 H), 4.20 (dd,
J = 11.7, 2.4 Hz, 1 H), 4.23–4.29 (m, 2 H), 6.85 (dd, J = 8.1, 1.2 Hz,
1 H), 6.91 (td, J = 7.5, 1.2 Hz, 1 H), 7.19 (m, 1 H), 7.25 (dd, J = 7.5,
1.5 Hz, 1 H).
13C NMR (75 MHz, CDCl3): δ = 15.4, 15.6, 64.0, 64.7, 64.8, 73.0,
73.2, 116.7, 120.4, 120.5, 129.4, 131.0, 154.1.
LRMS: m/z (%) = 222 (M+•, 6), 176 (9), 150 (42), 131 (16), 122
(71), 121 (100), 107 (30), 91 (28), 71 (26), 65 (13), 51 (10), 43 (22),
32 (29).
1H NMR (200 MHz, CDCl3): δ = 1.56 (s, 3 H), 3.08 (s, 3 H), 3.50
(s, 3 H), 3.60 (dd, J = 6.0, 2.8 Hz, 1 H), 4.12 (dd, J = 11.4, 6.0 Hz,
1 H), 4.32 (dd, J = 11.4, 2.6 Hz, 1 H), 6.82 (dd, J = 8.1, 1.3 Hz, 1
H), 6.86–6.94 (m, 1 H), 7.12–7.21 (m, 1 H), 7.31 (dd, J = 7.6, 1.7
Hz, 1 H).
13C NMR (50 MHz, CDCl3): δ = 21.0, 49.8, 57.6, 62.8, 74.4, 76.1,
116.5, 120.1, 123.0, 127.8, 129.0, 154.1.
LRMS: m/z (%) = 208 (M+•, 3), 176 (13), 161 (13), 145 (49), 131
(79), 115 (52), 105 (49), 91 (34), 77 (48), 63 (44), 51 (53), 32 (100).
HRMS [ESI(+)]: m/z [M + Na]+ calcd for C12H16O3Na: 231.0992;
found: 231.0995.
cis-3,4-Diethoxy-4-methyl-3,4-dihydro-2H-chromene (12c)
Following typical procedure 2 using methylchromene 5c (0.160 g,
1.109 mmol), TEOF (6 mL), and HTIB (0.478 g, 1.22 mmol). Puri-
fication by column chromatography (silica gel) gave 12c (0.152 g,
0.643 mmol, 58%) as colorless oil.
HRMS [ESI(+)]: m/z [M + Na]+ calcd for C13H18O3Na: 245.1148;
found: 245.1152.
4-(2,2,2-Trifluoroethoxy)-4H-chromene (10a); Typical Proce-
dure 3
IR (film): 3069, 3036, 2976, 2932, 2880, 1608, 1583, 1486, 1446
cm–1.
To a soln of 2H-chromene (5a; 0.142 g, 1.07 mmol) in TFE (6 mL)
was added HTIB (0.462 g, 1.18 mmol) at 0 °C. Immediately after
the addition of HTIB, the mixture became dark in color. After 2 h,
the reaction was quenched with sat. NaHCO3 soln. The mixture was
extracted with EtOAc (3 × 10 mL), and the combined extracts were
washed with brine soln (2 × 20 mL) and dried (anhyd MgSO4). The
solvent was evaporated under reduced pressure. The crude product
was purified by flash column chromatography (2% EtOAc–
hexanes) giving 10a (0.590 g, 0.260 mmol, 24%) as a colorless oil.
1H NMR (200 MHz, CDCl3): δ = 1.10 (t, J = 7 Hz, 3 H), 1.22 (t, J =
7 Hz, 3 H), 1.59 (s, 3 H), 3.19–3.32 (m, 2 H), 3.67–3.81 (m, 3 H),
4.06 (dd, J = 11.2, 7.0 Hz, 1 H), 4.32 (dd, J = 11.2, 3.2 Hz, 1 H),
6.81 (dd, J = 8.2, 1.2 Hz, 1 H), 6.86–6.96 (m, 1 H), 7.17 (ddd, J =
8.1, 7.2, 1.7 Hz, 1 H), 7.34 (dd, J = 7.8, 1.6 Hz, 1 H).
13C NMR (50 MHz, CDCl3): δ = 15.5, 15.7, 22.4, 57.6, 64.4, 65.7,
74.2, 75.0, 116.5, 120.5, 124.5, 127.8, 129.0, 154.3.
LRMS: m/z (%) = 236 (M+•, 4), 164 (45), 147 (14), 136 (35), 121
(100), 105 (7), 91 (12), 77 (9), 65 (9), 43 (21).
HRMS [ESI(+)]: m/z [M + Na]+ calcd for C14H20O3Na: 259.1305;
found: 259.1306.
IR (film): 3048, 2927, 2855, 1644, 1610, 1584, 1489 cm–1.
1H NMR (300 MHz, CDCl3): δ = 4.02 (dq, J = 12.6, 3.9 Hz, 1 H),
4.08 (dq, J = 12.3, 3.9 Hz, 1 H), 5.81 (d, J = 3.9 Hz, 1 H), 5.88 (dd,
J = 9.6, 3.6 Hz, 1 H), 6.80 (d, J = 9.3 Hz, 1 H), 6.70–7.01 (m, 2 H),
7.14–7.17 (m, 1 H), 7.21–7.27 (m, 1 H).
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 3671–3677

3676
A. Ahmad, L. F. Silva, Jr.
PAPER
4-[Bis(2,2,2–trifluoroethoxy)methyl]-3,4-dihydro-2H-
chromene (13d)
Following the typical procedure 3 using dihydro-1-benzoxepine 5d
(0.146 g, 1.00 mmol), TFE (6 mL), and HTIB (0.43 g, 1.1 mmol).
Purification by column chromatography (silica gel, 2% EtOAc–
hexanes) gave 13d (0.172 g, 0.500 mmol, 50%) as a colorless oil.
1-(3,4-Dihydro-2H-chromen-4-yl)ethanone (16e)
Following typical procedure 3 using methylbenzoxepine 5e (0.135
g, 0.843 mmol), HTIB (0.363 g, 0.930 mmol), and TFE (6 mL). Pu-
rification by column chromatography (silica gel, 10% EtOAc–
hexanes) gave 16e in (0.86 g, 0.49 mmol, 58%) as a colorless oil.
IR (film): 3067, 3070, 2967, 2930, 2885, 1708, 1607, 1581, 1490,
1453 cm–1.
1H NMR (300 MHz, CDCl3): δ = 2.05–2.15 (m, 1 H), 2.20 (d, J =
0.3 Hz, 3 H), 2.22–2.32 (m, 1 H), 3.80 (t, J = 6 Hz, 1 H), 4.12–4.24
(m, 2 H), 6.84–6.87 (m, 1 H), 6.90 (dd, J = 7.5, 1.5 Hz, 1 H), 7.06
(dddd, J = 7.5, 1.5, 0.9, 0.3 Hz, 1 H), 7.14–7.20 (m, 1 H).
13C NMR (75 MHz, CDCl3): δ = 24.5, 28.0, 48.5, 63.8, 117.4, 119.0,
120.5, 128.7, 130.0, 154.7, 208.8.
LRMS: m/z (%) = 176 (M+•, 58), 148 (9), 133 (42), 120 (100), 105
(8), 91 (94), 77 (23), 65 (18), 51 (19), 39 (34).
IR (film): 3073, 3040, 2948, 2899, 1716, 1622, 1608, 1582, 1569,
1491, 1454 cm–1.
1H NMR (300 MHz, CDCl3): δ = 2.00–2.2 (m, 2 H), 3.06–3.11 (m,
1 H), 3.78–4.01 (m, 4 H), 4.10–4.26 (m, 2 H), 4.85 (d, J = 7.2 Hz, 1
H), 6.81–6.84 (m, 1 H), 6.89 (dd, J = 7.5, 1.2 Hz, 1 H), 7.13–7.18
(m, 1 H), 7.26 (dd, J = 7.8, 1.5 Hz, 1 H).
13C NMR (75 MHz, CDCl3): δ = 22.7, 36.6, 62.6 (q, J = 139.5 Hz,
OCH2CF3), 63.1, 64.8 (q, J = 138.6 Hz, OCH2CF3), 105.8, 117.2,
119.0, 120.3, 123.1 (q, J = 1105.8 Hz, OCH2CF3), 123.6 (q, J =
1104.6 Hz, OCH2CF3), 128.7, 130.8, 155.0.
HRMS [ESI(+)]: m/z [M + Na]+ calcd for C11H12O2Na: 199.073;
found: 199.0743.
LRMS: m/z (%) = 344 (M+•, 7), 245 (6), 211 (76), 145 (18), 133
(100), 115 (13), 105 (73), 83 (63), 77 (44), 51 (25), 39 (14).
HRMS [ESI(+)]: m/z [M + Na]+ calcd for C14H14F6O3Na: 367.0739;
found: 367.0753.
(2,2-Dimethyl-2,3-dihydrobenzofuran-3-yl)methanol (17f)
Following typical procedure 4 using dimethylchromene 5f (0.192 g,
1.20 mmol), HTIB (0.517g, 1.32 mmol), HFIP–CH2Cl2 (1:4, 5 mL),
and H2O (22 equiv) at 0 °C. NaBH4 was added in excess (5 equiv).
Purification by column chromatography (silica gel, 15% EtOAc–
hexane), gave 17f (0.66 g, 0.37 mmol, 31%) as a colorless oil.
(3,4-Dihydro-2H-chromen-4-yl)methanol (14d) and 4-[Bis(tosyl-
oxy)methyl]-3,4-dihydro-2H-chromene (15d);
Typical Procedure 4
A mixture of 5d (0.155 g, 1.06 mmol) at 0 °C was stirred with HTIB
(0.431 g, 1.10 mmol) for 5 min in HFIP–CH2Cl2 (1:4, 5 mL) and
H2O (0.4 mL, 22 equiv) (TLC monitoring). When the starting ma-
terial had been consumed, NaBH4 (5 equiv) was added. This mix-
ture was stirred for 2 h at r.t. When the reaction was complete, H2O
was added, and the mixture was extracted with EtOAc. The com-
bined organic extracts were washed with brine and dried (anhyd
MgSO4), and the solvent was evaporated under reduced pressure.
The crude product was purified by flash column chromatography
(2–15%, EtOAc–hexane) giving alcohol 14d (0.152 g, 0.930 mmol,
87%) and 15d (0.46 g, 0.10 mmol, 9%).
IR (film): 3452, 2973, 2930, 2874, 1611, 1596, 1482, 1461 cm–1.
1H NMR (200 MHz, CDCl3): δ = 1.47 (s, 3 H), 1.48 (s, 3 H), 1.84
(s, 1 H), 3.21 (t, J = 6.6 Hz, 1 H), 3.87 (d, J = 6.8 Hz, 2 H), 6.75 (d,
J = 7.8 Hz, 1 H), 6.84 (td, J = 7.4, 0.8 Hz, 1 H), 7.10–7.25 (m, 2 H).
13C NMR (75 MHz, CDCl3): δ = 22.0, 29.3, 53.0, 62.6, 88.4, 109.8,
120.0, 124.8, 128.1, 128.7, 158.5.
LRMS: m/z (%) = 178 (M+•, 33), 147 (100), 131 (17), 119 (47), 107
(13), 91 (49), 77 (18), 65 (7), 51 (8), 39 (14).
HRMS [ESI(+)]: m/z [M + Na]+ calcd for C11H14O2Na: 201.0886;
found: 201.0879.
(3,4-Dihydro-2H-chromen-4-yl)methanol (14d)
IR (film): 3437, 3071, 3036, 2928, 2878, 1607, 1580, 1490, 1453
cm–1.
3-(Dimethoxymethyl)-2,2-dimethyl-2,3-dihydrobenzofuran
(18f)
1H NMR (300 MHz, CDCl3): δ = 1.70 (s, 1 H), 2.04–2.11 (m, 2 H),
2.95–3.03 (m, 1 H), 3.80 (dd, J = 11.0, 8.0 Hz, 1 H), 3.89 (dd, J =
10.8, 5.1 Hz, 1 H), 4.17–4.21 (m, 2 H), 6.83 (dd, J = 8.1, 1.2 Hz, 1
H), 6.87 (td, J = 7.5, 1.2 Hz, 1 H), 7.09–7.18 (m, 2 H).
Following typical procedure 1 using dimethylchromene 5f (0.142 g,
0.890 mmol), HTIB (0.382 g, 0.980 mmol), and MeOH (6 mL). Pu-
rification by column chromatography (silica gel, 2–5% EtOAc–
hexanes) gave 18f (0.60 g, 0.27 mmol, 30%) as a colorless oil.
IR (film): 3045, 2974, 2934, 2831, 1610, 1594, 1478, 1460 cm–1.
13C NMR (75 MHz, CDCl3): δ = 24.4, 36.0, 63.3, 66.4, 117.1, 120.3,
1H NMR (300 MHz, CDCl3): δ = 1.35 (s, 3 H), 1.55 (s, 3 H), 3.41
(s, 3 H), 3.43 (s, 3 H), 3.44 (d, J = 5.1 Hz, 1 H), 4.52 (d, J = 5.1 Hz,
1 H), 6.72 (dt, J = 4.8, 0.3 Hz, 1 H), 6.83 (td, J = 4.5, 0.6 Hz, 1 H),
7.11–7.15 (m, 1 H), 7.34 (dtd, J = 4.5, 0.9, 0.3 Hz, 1 H).
13C NMR (75 MHz, CDCl3): δ = 22.2, 29.0, 52.2, 52.3, 53.8, 88.3,
103.9, 109.5, 120.1, 126.3, 128.5, 158.7.
122.0, 127.9, 129.1, 155.2.
LRMS: m/z (%) = 164 (M+•, 30), 133 (100), 131 (15), 105 (66), 103
(21), 77 (34), 63 (6), 51 (16), 39 (20).
HRMS [ESI(+)]: m/z [M + Na]+ calcd for C10H12O2Na: 187.0735;
found: 187.0741.
4-[Bis(tosyloxy)methyl]-3,4-dihydro-2H-chromene (15d)
IR (film): 3066, 3040, 2975, 2929, 2591, 1935, 1914, 1597, 1584,
1492 cm–1.
1H NMR (300 MHz, CDCl3): δ = 1.97–2.09 (m, 1 H), 2.21–2.30 (m,
1 H), 2.40 (s, 3 H), 2.45 (s, 3 H), 3.25–3.29 (m, 1 H), 4.01–4.13 (m,
2 H), 6.59 (d, J = 4.5Hz, 1 H), 6.66–6.71 (m, 2 H), 6.95 (ddd, J =
8.1, 1.5, 0.9 Hz, 1 H), 7.05–7.11 (m, 1 H), 7.12–7.16 (m, 2 H), 7.28–
7.33 (m, 2 H), 7.40 (t, J = 1.8 Hz, 1 H). 7.42 (t, J = 1.8 Hz, 1 H),
7.75 (t, J = 1.8 Hz, 1 H), 7.77 (t, J = 1.8 Hz, 1 H).
13C NMR (75 MHz, CDCl3): δ = 21.2, 21.6, 21.7, 38.5, 63.5, 100.3,
109.7, 117.1, 117.3, 120.4, 127.7 (2 C), 128.1 (2 C), 128.6, 129.6 (2
C), 129.8 (2 C), 132.7, 133.0, 145.1, 145.4, 155.3.
HRMS [ESI(+)]: m/z [M + Na]+ calcd for C24H24O7S2Na: 511.0856;
found: 511.0858.
LRMS: m/z (%) = 222 (M+•, 2), 159 (8), 131 (4), 91 (5), 75 (100),
45 (7).
HRMS [ESI(+)]: m/z [M + Na]+ calcd for C13H18O3Na: 245.1148;
found: 245.1140.
1-(2,2-Dimethyl-2,3-dihydrobenzofuran-3-yl)ethanone (19g)
Following typical procedure 1 using trimethylchromene 5g (0.120
g, 0.690 mmol), HTIB (0.297 g, 0.760 mmol), and MeOH (6 mL).
Purification by column chromatography (silica gel, 2–4% EtOAc–
hexane) gave 19g in (0.031 g, 0.16 mmol, 24%) as a colorless oil.
IR (film): 3050, 2979, 2934, 2873, 1704, 1610, 1596, 1480, 1460
cm–1.
1H NMR (200 MHz, CDCl3): δ = 1.43 (s, 3 H), 1.52 (s, 3 H), 2.05
(s, 3 H), 3.88 (s, 1 H), 6.83 (d, J = 8 Hz, 1 H), 6.91 (dd, J = 7.4, 1
Hz, 1 H), 7.14 (d, J = 7.4 Hz, 1 H), 7.18–7.27 (m, 1 H).
Synthesis 2012, 44, 3671–3677
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of Chromanes and 4H-Chromenes
3677
13C NMR (50 MHz, CDCl3): δ = 23.3, 29.4, 65.4, 88.4, 11.4, 120.8,
125.9, 126.1, 129.5, 159.2, 207.4.
LRMS: m/z (%) = 190 (M+•, 15), 147 (100), 131 (20), 119 (55), 103
(7), 91 (50), 77 (18), 63 (6), 51 (10), 43 (61).
HRMS [ESI(+)]: m/z [M + Na]+ calcd for C12H14O2Na: 213.0886;
found: 213.0877.
(Washington, DC, U. S.) 2010, 328, 1376. (i) Ochiai, M.;
Miyamoto, K.; Kaneaki, T.; Hayashi, S.; Nakanishi, W.
Science (Washington, DC, U. S.) 2011, 332, 448. (j) Skucas,
E.; MacMillan, D. W. C. J. Am. Chem. Soc. 2012, 134, 9090.
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(b) Koser, G. F.; Relenyi, A. G.; Kalos, A. N.; Rebrovic, L.;
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Acknowledgment
(7) Farooq, U.; Schaefer, S.; Shah, A.-u.-H. A.; Freudendahl, D.
M.; Wirth, T. Synthesis 2010, 1023.
This work was financially supported by Capes, Fapesp and CNPQ.
(8) Xie, Y. Y.; Chen, Z. C. Synth. Commun. 2002, 32, 1875.
(9) (a) Justik, M. W.; Koser, G. F. Tetrahedron Lett. 2004, 45,
6159. (b) Justik, M. W.; Koser, G. F. Molecules 2005, 10,
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Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnuIomprifgtooatrinSugpIoi
n
nfomartit
(10) Morimoto, K.; Nakae, T.; Yamaoka, N.; Dohi, T.; Kita, Y.
Eur. J. Org. Chem. 2011, 6326.
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(18) Some additional tests for 5a: (a) MeOH, BF3·OEt2, r.t., 2.5
h; 6a (27%) and 7a (23%). (b) TFE, BF3·OEt2, r.t., 30 min;
10a (23%). (c) MeCN, 0 °C; complex mixture. (d) HFIP–
CH2Cl2 (1:4), 0 °C; complex mixture. (e) HFIP, 0 °C;
unstable product. (f) HFIP, BF3·OEt2, 0 °C; no prominent
spot on TLC. (g) CH2Cl2, 0 °C; complex mixture.
(h) HFIP–CH2Cl2 (1:4), H2O (22 equiv) 0 °C, NaBH4;
starting material recovered.
(19) Rebrovic, L.; Koser, G. F. J. Org. Chem. 1984, 49, 2462.
(20) Some additional tests for 5b: (a) MeOH, 0 °C, 40 min; 4-
methoxy-4H-thiochromene (6b) (29%). (b) TMOF, 0 °C, 30
min; 4-methoxy-4H-thiochromene (6b) (38%). (c) TFE 0
°C; complex mixture. (d) HTIB, HFIP–CH2Cl2 (1:4), H2O
(22 equiv) 0 °C, NaBH4; starting material recovered.
(21) Ferraz, H. M. C.; Carneiro, V. M. T.; Silva, L. F. Jr.
Synthesis 2009, 385.
(22) Some additional tests for 5f: (a) TFE, 0 °C; complex
mixture. (b) MeCN, 0 °C; no prominent spot on TLC.
(c) DMF, 0 °C; starting material recovered. (d) HFIP, 0 °C;
no prominent spot on TLC. (e) PhI(OAc)2 (1.1 equiv),
MeOH, 0 °C; starting material recovered. (f) PhI(OAc)2 (1.1
equiv), MeOH, BF3·OEt2, 0 °C; 18f (12%). (g) TMOF, 0 °C;
18f (13%).
(23) Some additional tests for 5g: (a) TFE, 0 °C; complex
mixture. (b) MeCN, 0 °C; complex mixture. (c) HFIP–
CH2Cl2 (1:4), 0 °C; complex mixture.
(24) Barrett, I.; Meegan, M. J.; Hughes, R. B.; Carr, M.; Knox, A.
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© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 3671–3677