Metal-Free Asymmetric Synthesis of Indanes through Chiral Hypervalent Iodine(III)-Mediated Ring Contraction

Article abstract of DOI:10.1021/acs.joc.5b02803

The iodine(III)-mediated asymmetric oxidative rearrangement of 1,2-dihydronaphthalenes was investigated to prepare optically active 1-substituted indanes. The chiral hypervalent iodine species is generated in situ from a chiral aryl iodide, prepared in 94% yield in one step. This metal-free protocol was applied to different cyclic alkenes, substituted with oxygen, with nitrogen, or at position 1 with aryl or methyl. Indanes can be isolated as an acetal or alcohol in up to 78% ee.

Full text of DOI:10.1021/acs.joc.5b02803

Note
pubs.acs.org/joc
Metal-Free Asymmetric Synthesis of Indanes through Chiral
Hypervalent Iodine(III)-Mediated Ring Contraction
Anees Ahmad and Luiz F. Silva, Jr.*
̃ ̃
Instituto de Química, Universidade de Sao Paulo, CP 26077, CEP 05513-970, Sao Paulo − SP, Brazil
*
S Supporting Information
ABSTRACT: The iodine(III)-mediated asymmetric oxidative rearrangement of 1,2-dihydronaphthalenes was investigated to
prepare optically active 1-substituted indanes. The chiral hypervalent iodine species is generated in situ from a chiral aryl iodide,
prepared in 94% yield in one step. This metal-free protocol was applied to different cyclic alkenes, substituted with oxygen, with
nitrogen, or at position 1 with aryl or methyl. Indanes can be isolated as an acetal or alcohol in up to 78% ee.
he Indane skeleton occurs in many biologically active
natural products and in pharmaceuticals compounds,
Scheme 1. Ring Contraction of 1,2-Dihydronaphthalenes
1
T
constituting an important target in organic synthesis and in
2
medicinal chemistry. Indanes are also used as ligands in
3
catalysis. Particularly relevant are efficient methods toward
chiral nonracemic 1-substituted indanes, such as ramelteon,
rasagiline, and jimscaline.
4
5
6
Hypervalent iodine reagents play a pivotal role in chemical
2
3,24
synthesis, including carbon−carbon bond formation, rearrange-
aryl iodide.
Thus, iodides 4a−g were prepared in an
7
ments, and many functional group transformations. Using chiral
expedited manner from 2-iodophenol or 2-iodoresorcinol using
7
,8
hypervalent iodine compounds, several organic transforma-
as chiral sources the inexpensive natural compounds (−)-men-
12,25,26
tions can be accomplished in enantioselective fashion, such as α-
thol and (−)-ethyl lactate (Figure 1).
9
10
arylation of carbonyl compounds, alkynylation, dearomatiza-
The screening was performed by investigating the behavior of
1
1,12
tion of napthols,
oxidative cycloetherification and lactoniza-
tion, diamination of styrenes, and oxyamination. Oxidative
1a under different conditions. Based on our previous
1
3
14
15
23
experience, m-chloroperoxybenzoic acid (mCPBA) in the
16
rearrangements have been less explored. During the develop-
ment of our work, Wirth and co-workers reported the
asymmetric ring contraction for two substrates using a chiral
iodine(III). An acetal of Indane was obtained in 59%
enantiomeric excess (ee) from 1,2-dihydronaphthalene using
the chiral hypervalent iodine, prepared in 5 steps and 62% yield
from 2-iodoresorcinol, including an oxidation using Selectfluor.
Similarly, the 1,3-disubstituted trans-Indane was isolated in 9%
presence of p-toluenesulfonic acid monohydrate (TsOH·H O)
2
was selected for the in situ oxidation of iodobenzenes 4a−g into
the corresponding chiral iodine(III), which would promote the
desired oxidative rearrangement. After generation of iodine(III)
species, substrate 1a and water were added. To facilitate
purification and analysis, aldehyde 5a was reduced in situ by
1
7
NaBH . Two solvent mixtures (1:4 trifluoroethanol/dichloro-
4
methane (TFE/DCM) and 1:4 hexafluoroisopropanol/dichloro-
methane (HFIP/DCM)) were used for testing the iodobenzene
derivatives 4a−g, because either the oxidation of iodobenzene or
1
7
ee.
Our group developed the ring contraction of 1,2-dihydro-
18,27
18−20
the ring contraction has been reported in those solvents.
naphthalenes synthesizing a variety of indanes.
Further-
Chiral aryl iodide 4a afforded alcohol 6a in 6−7% ee. (Table 1,
entries 1 and 2). With menthol based aryl iodides 4b−c nearly a
racemic mixture was obtained (entries 3−6). New amide based
more, new possibilities in total synthesis can be envisioned using
a ring contraction approach, as exemplified for (+)-mutisian-
2
1
19
22
thol, (±)-indatraline, and (+)-trans-trikentrin A. Motivated
by the importance of indanes, we decide to investigate the
oxidative rearrangement of nonfunctionalized alkenes in an
asymmetric fashion (Scheme 1).
“
one-arm” 4d−e proved ineffective (entries 7−10). The desired
Indane 6a was isolated in 49−53% and in 14−15% ee with “two-
We planned a protocol where the required hypervalent iodine
species would be prepared in situ from a readily available chiral
Received: December 17, 2015
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.5b02803
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
Figure 1. Structures of chiral aryl iodide 4a−g.
Table 1. Screening of Aryl Iodides 4a−g
Table 2. Screening of Reaction Conditions
a
entry
Ar*I
solvent
6a (yield, ee)
product a
1
2
3
4
5
6
7
8
9
4a
4a
4b
4b
4c
4c
4d
4d
4e
4e
4f
HFIP/DCM (1:4)
TFE/DCM (1:4)
HFIP/DCM (1:4)
TFE/DCM (1:4)
HFIP/DCM (1:4)
TFE/DCM (1:4)
HFIP/DCM (1:4)
TFE/DCM (1:4)
HFIP/DCM (1:4)
TFE/DCM (1:4)
HFIP/DCM (1:4)
TFE/DCM (1:4)
HFIP/DCM (1:4)
TFE/DCM (1:4)
(43, 7)
(41, 6)
(−, 4)
(8, 5)
(37, 6)
(32, 8)
−
−
−
−
entry
1
solvent
acid
T, °C
(yield, ee)
TFE/DCM (1:1)
TsOH·
0
6a (51, 6)
H O
2
2
HFIP/DCM (1:1)
TsOH·
0
6a (53, 8)
H O
2
b
3
4
5
6
7
8
9
TFE/DCM (1:1)
HFIP/DCM (1:4)
HFIP/DCM (1:10)
HFIP/DCM (1:20)
HFIP/DCM (1:40)
DCM
−
0
0
0
0
0
0
6a (−, 4)
(+)-CSA
(+)-CSA
(+)-CSA
(+)-CSA
(+)-CSA
(+)-CSA
(+)-CSA
6a (54, 25)
6a (47, 31)
6a (44, 38)
6a (36, 42)
1
1
1
1
1
0
1
2
3
4
b
−
(49, 15)
(53, 14)
(30, 15)
(33, 13)
HFIP/DCM (1:40)
TFE/DCM (1:40)
−78 6a (34, 60)
4f
1
0
−78 2a (34, 57), 6a
4g
4g
c
(
20, 58)
c
c
c
,
,
,
d
d
d
,
e
e
1
1
1
1
2
3
TFE/DCM (1:40 then 1:4) (+)-CSA
TFE/DCM (1:40 then 1:1) (+)-CSA
−78 2a (60, 58)
−78 2a (62, 46)
−78 6a (42, 38)
a
ee determined by GC using chiral column.
,
TFE/DCM (1:40) then
HFIP/DCM (1:10)
(+)-CSA
arm” aryl iodide (R,R)-4f (entries 11−12). A similar ee, but lower
yield, was observed when the two-arm amide 4g was used
a
ee determined for 2a by HPLC and for 6a by GC using chiral
b
c
d
columns. Complex mixture. No addition of H O. Solvent of step i
2
e
(
entries 13−14). Based on the above results, 4f was selected for
(TFE/DCM,1:40) was removed under reduced pressure. No addition
additional screening.
of NaBH4.
Increasing the ratio of the fluorinated solvent (TFE or HFIP)
resulted in a lower ee (Table 2, entries 1 and 2). Without acid, the
ring contraction product was not isolated in pure form (entry 3).
When (+)-camphorsulfonic acid (CSA) was used instead of
Table 3. Asymmetric Ring Contraction of 1a Using (S,S)-4f
TsOH·H O, Indane 6a was isolated in 54% and 25% ee (compare
2
Table 1, entry 11 with Table 2, entry 4). This might be due to the
bulky structure of (+)-CSA when compared to TsOH·H O. An
2
increasing trend in ee was observed by decreasing the ratio of
HFIP to DCM from 1:10 to 1:40 (entries 5−7). Using only
DCM, ring contraction product was not isolated (entry 8). The
desired alcohol 6a was isolated in 34% yield and 60% ee when the
temperature was lowered to −78 °C (entry 9). However, using
TFE/DCM in a 1:40 ratio, the desired alcohol 6a was obtained
together with acetal 2a in 58% ee and 57% ee, respectively (entry
a
entry
acid
yield, ee
1
2
3
(+)-CSA
57, 56
56, 55
56, 55
(S,S)-4f recovered and reused, (+)-CSA
(−)-CSA
a
ee determined by HPLC using chiral column.
1
0). Using a higher ratio of TFE to favor the exclusive formation
of the acetal, only the acetal 2a was isolated in 60% yield and 58%
ee (entry 11). A lower ee was observed when a 1:1 mixture of
TFE/DCM was used (entry 12). Increasing the ratio of HFIP
resulted in a lower ee of the product 6a (entry 13).
After the above-mentioned experiments, we selected the
conditions of entry 11 for further investigation. When (S,S)-4f
in 84% yield. A similar result was obtained using recovered 4f
(entry 2). CSA could be acting as an acid or could also have an
influence in the chiral environment. Changes in yield or ee were
not observed when (−)-CSA was used as an acid (entry 3). These
results clearly show that the observed stereoinduction is
regulated only by chiral aryl iodide 4f; i.e., there is no
matched/mismatched case.
(
prepared from (+)-ethyl lactate) was used, (−)-2a was isolated
in similar yield and ee (compare entry 1, Table 3 to entry 11,
Table 2). After ring contraction, iodide 4f can be easily recovered
The scope of the reaction was investigated as shown in Table 4.
The ring contraction of the N-acetyl alkene 1b was performed in
B
DOI: 10.1021/acs.joc.5b02803
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
Table 4. Scope of Asymmetric Ring Contraction
71% and 75% yield, respectively, and 58% ee (entries 2 and 3).
Asymmetric ring contraction was also explored in oxygenated
substrates. By generating the iodine(III) species in TFE/DCM
(
1:40) and performing the ring contraction in TFE/DCM (1:1),
Indane 2e was isolated in 58% yield and 64% ee (entry 4). These
conditions were extended to other oxygen-containing substrates.
Acetal product 2f was obtained in 61% yield and 56% ee when 8-
benzoyl alkene 1f was subjected to oxidative rearrangement
conditions (entry 5). The treatment of 7-acetoxy alkene 1g with
4f resulted in Indane 2g in 41% yield and 78% ee (entry 6).
Similarly, alkene 1h gave the desired acetal 2h in good yield and
ee (entry 7). The reaction of racemic 1-substituted 1,2-
dihydronaphthalenes 1i and 1j were also investigated. Using
TFE/DCM (1:1), the acetal 2i was isolated together with alcohol
6
i in 88% combined yield and in 34−40% ee (entry 8). A very
good combined yield of 2j and 6j and 34−38% ee were also
obtained for alkene 1j at −78 °C (entry 9).
The absolute configuration of indanes was assigned by analogy
to that of 6a, which was determined to be (R) by comparison
28
with literature data. A plausible mechanism for asymmetric ring
contraction reaction is shown in Scheme 2.
18,19,29,30
Based on the
Scheme 2. A Plausible Mechanism
28
absolute configuration of 6a, the electrophilic attack of
iodine(III) species occurs selectively on the Re-face of double-
29
bond-forming benzylic carbocation 7. Nucleophilic attack of
CF CH OH into 7 gives intermediate 8. The necessary
3
2
antiperiplanarity for the rearrangement is achieved via
equilibration to its more stable conformational isomer 9.
Migration of the aryl group on 10 gives oxonium 11. Finally,
addition of CF CH OH leads to acetal 2a.
3
2
In conclusion, the asymmetric synthesis of indanes can be
accomplished through the ring contraction of 1,2-dihydronaph-
thalenes mediated by chiral iodine(III) in up to 78% ee, which is
the highest ee for this type of transformation. The rearrangement
step occurs in a very short time when compared to the previous
17
protocol (5 min vs 14 h ). Ring contraction products are
obtained as masked aldehydes, which can be converted into a
a
b
ee determined by HPLC using chiral column. Solvent of step i
c
19−22
(
TFE/DCM, 1:40) was removed under reduced pressure. (ii) DCM,
variety of compounds.
The hypervalent iodine species is
d e
5
0 equiv MeOH, −78 °C. (ii) TFE/DCM (1:1), −40 °C. (ii) TFE/
generated in situ using readily available MCPBA from chiral aryl
f
DCM (1:1), −40 °C; (iii) NaBH . (ii) TFE/DCM (1:1), −78 °C;
4
iodine 4f, which is prepared in 94% yield in one step from
(
iii) NaBH .
17
4
(
−)-ethyl lactate. In the previous work, iodine(III) was
prepared in 5 steps using as oxidant the expensive Selectfluor.
Furthermore, 4f can be recovered and reused in an efficient
manner. The metal-free oxidative rearrangement of non-
functionalized olefins herein reported will be certainly useful in
the development of a more efficient version of this reaction.
DCM in the presence of 50 equiv of MeOH to give the desired
Indane 3b in 60% yield and 64% ee (entry 1). Under similar
reaction conditions, N-benzoyl and Fmoc alkenes 1c and 1d
smoothly undergo ring contraction giving indanes 3c and 3d in
C
DOI: 10.1021/acs.joc.5b02803
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
+
HRMS [ESI(+)-TOF] calcd for [C H NO + H] 368.1651; found
EXPERIMENTAL SECTION
25 21
2
■
3
1
68.1648. IR (film): 3307, 3030, 2931, 2882, 2826, 1703, 1612, 1585,
527, 1478, 1465, 1450, 1425, 1326, 1308, 1278, 1219, 1170, 1104 cm .
,8-Dihydronaphthalen-1-yl benzoate (1f). The reaction was
performed using 7,8-dihydronaphthalen-1-ol (0.248 g, 1.70 mmol),
BzCl (0.22 mL, 0.267 g, 1.90 mmol), and Et N (0.51 mL, 0.374 g, 3.70
mmol) in DCM (10 mL). Purification by flash column chromatog-
All commercially available reagents were used without further
purification unless otherwise noted. All solvents used for reactions
and chromatography were dried and purified by standard methods.
−1
7
3
1
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 solutions followed by charring
at ∼150 °C for visualization. Flash column chromatography was
performed using silica gel 200−400 Mesh. All NMR analyses were
recorded using CDCl , acetone-d , and DMSO-d as solvents and TMS
3
38
raphy (3−4% EtOAc in hexane) gave benzoyl protected alkene 1f (0.398
g, 1.60 mmol, 94%) as a white solid (mp: 58.1−58.7 °C). 7,8-
1
Dihydronaphthalen-1-yl Benzoate (1f): H NMR (300 MHz, CDCl )
3
3
6
6
δ: 2.24−2.32 (m, 2H), 2.71 (t, J = 8.4 Hz, 2H), 6.04 (dt, J = 9.6, 4.5 Hz,
H), 6.49 (dt, J = 9.6, 1.8 Hz, 1H), 6.96 (d, J = 7.5 Hz, 1H), 7.00 (dd, J =
as internal standard. Chemical shifts are reported in ppm downfield from
TMS with reference to internal solvent. High-performance liquid
chromatography (HPLC) analysis was carried out using chiral columns
of Daicel CHIRALCEL OD-H (4.6 mm × 25 cm), AS-H (4.6 mm × 25
cm), and chiral Astec Cellulose DMP column (4.6 mm × 25 cm). Gas
chromatography analysis (GC) was conducted using a chiral ALPHA
DEX 120 fused silica capillary column (30 m × 0.25 mm × 0.25 μm).
1
8
(
(
1
.1, 1.2 Hz, 1H), 7.17−7.22 (m, 1H), 7.48−7.54 (m, 2H), 7.61−7.66
13
m, 1H), 8.21−8.25 (m, 2H). C NMR (75 MHz, CDCl ) δ: 20.6
3
CH ), 22.3 (CH ), 120.8 (CH), 123.8 (CH), 126.8 (CH), 127.2 (C),
2
2
27.3 (CH), 128.6 (CH), 129.0 (CH), 129.4 (C), 130.1 (CH), 133.5
CH), 135.7 (C), 148.0 (C), 164.8 (C). LRMS m/z (rel. int.): 250
, 9), 144 (3), 128 (11), 115 (10), 105 (100), 91 (2), 77 (36), 63
(3), 51 (10), 39 (2). HRMS [ESI(+)-TOF] calcd for [C H O + Na]
73.0891; found 273.0890. IR (film): 3035, 2935, 2887, 2834, 2127,
735, 1651, 1601, 1583, 1569, 1491, 1451, 1395, 1342, 1314, 1296,
(
+●
(M
Specific rotation was measured in CH Cl and THF (589 nm, T = 20 °C,
+
3
17 14 2
1
0 mm × 100 mm) with a digital polarimeter. Preparations of substrates
2
1
1
18,32 18 18,33 34 35 19,36 19
1a,
1b, 1c,
1e, 1g, 1i,
and 1j were performed as
reported in literature.
9H-Fluoren-9-yl)methyl (7,8-Dihydronaphthalen-2-yl)carba-
mate (1d). To a stirred solution of 6-amino-3,4-dihydronaphthalen-
(2H)-one (0.484 g, 3.00 mmol) and pyridine (0.29 mL, 3.60 mmol) in
anydrous DCM (25 mL) at 0 °C was added a solution of Fmoc-Cl
0.854 g, 3.30 mmol) in anhydrous DCM, and the resulting reaction
mixture was allowed to stir at rt. After 1 h the solution was acidified with
mol/L HCl. The product was extracted with DCM (3 × 10 mL) and
−1
266, 1247, 1229, 1212 cm .
5
(
,6-Dihydronaphthalen-2-yl Acetate (1h). The reaction was
18,39
performed using 6-methoxy-1,2-dihydronaphthalene
mmol), NaH (3.12 g, 130 mmol, 60% in mineral oil), and EtSH (6.5 mL,
0 mmol, 30 equiv based on olefin substrate) in DMF (35 mL) at 140
(0.481 g, 3.00
1
9
(
°
(
(
C. The crude product was purified by flash column chromatography
10−15% ethyl acetate in hexane) giving 5,6-dihydronaphthalen-2-ol
1
0.351 g, 2.40 mmol, 80%) as a white solid. Mp: 98−99 °C. 5,6-
37
dried over anhydrous Mg SO . After workup solvent was removed
1
2
4
Dihydronaphthalen-2-ol: H NMR (300 MHz, CDCl ) δ: 2.25−2.32
3
under reduced pressure. The crude product was purified by flash column
chromatography (15−25% EtOAc in hexane) giving (9H-Fluoren-9-
yl)methyl (5-oxo-5,6,7,8-tetrahydronaphthalen-2-yl)carbamate (1.13 g,
.95 mmol, 98%) as a white solid. Mp: 160.6−161.5. (9H-Fluoren-9-
yl)methyl (5-Oxo-5,6,7,8-tetrahydronaphthalen-2-yl)carbamate: H
(
m, 2H), 2.71 (t, J = 8.1 Hz, 2H), 4.59 (s, 1H), 6.04 (dt, J = 9.6, 4.4 Hz,
1
7
H), 6.38 (dt, J = 9.6, 1.8 Hz, 1H), 6.52 (d, J = 2.7 Hz, 1H), 6.59 (dd, J =
.8, 2.7 Hz, 1H), 6.96 (d, J = 8.1, Hz, 1H). C NMR (75 MHz, CDCl3)
δ: 23.5 (CH ), 26.6 (CH ), 112.9 (CH), 113.1 (CH), 127.5 (CH), 127.7
C), 128.3 (CH), 129.5 (CH), 135.3 (C), 154.0 (C). LRMS m/z (rel.
int.): 146 (M , 100), 145 (71), 131 (45), 127 (43), 117 (36), 115 (55),
03 (5), 91 (12), 77 (7), 63 (14), 51 (13), 39 (10). HRMS [ESI(+)-
TOF]: calcd for [C H O + K] 185.0369; found 185.0361. IR (film):
247, 3027, 2936, 2880, 2851, 2818, 1629, 1614, 1574, 1492, 1477,
1465, 1435, 1426, 1395, 1349, 1327, 1282, 1265, 1215 cm .
13
2
2
2
1
(
NMR (300 MHz, CDCl ) δ: 2.06−2.15 (m, 2H), 2.62 (t, J = 6.3 Hz,
+●
3
2
2
H), 2.91 (t, J = 6.0 Hz, 2H), 4.27 (t, J = 6.4 Hz, 1H), 4.57 (d, J = 6.6 Hz,
H), 6.95 (bs, 1H), 7.14 (dd, J = 8.4, 1.5 Hz, 1H), 7.32 (td, J = 7.6, 1.2
1
10
10
Hz, 1H), 7.37−7.44 (m, 3H), 7.56−7.62 (m, 2H), 7.78 (dt, J = 7.5, 0.9
3
Hz, 2H), 7.98 (d, J = 8.7 Hz, 1H). 13C NMR (75 MHz, CDCl ) δ: 23.2
−1
3
(
1
(
(
3
1
1
CH ), 30.0 (CH ), 38.9 (CH ), 47.0 (CH), 67.0 (CH ), 116.4 (CH),
2 2 2 2
The reaction was performed using 5,6-dihydronaphthalen-2-ol
0.351 g, 2.40 mmol), DMAP (0.08 g, 0.065 mmol), and Ac O (0.9
mL, 9.0 mmol) in Et N (10 mL). Purification by flash column
17.0 (CH), 120.1 (CH), 124.8 (CH), 127.1 (CH), 127.8 (CH), 128.1
C), 128.7 (CH), 141.3 (C), 142.2 (C), 143.5 (C), 146.3 (C), 152.9
C), 197.3 (C). HRMS [ESI(+)-TOF] calcd for [C H NO + H]
84.1600; found 384.1600. IR (film): 3305, 3065, 2946, 2890, 1737,
665, 1602, 1585, 1537, 1495, 1478, 1450, 1427, 1412, 1350, 1336,
323, 1287, 1219, 1185, 1164, 1129, 1105 cm .
The reaction was performed using (9H-fluoren-9-yl)methyl (5-oxo-
,6,7,8-tetrahydronaphthalen-2-yl)carbamate (1.15 g, 3.00 mmol),
(
2
3
+
25
21
3
chromatography (3−5% EtOAc in hexane) gave 5,6-dihydronaph-
thalen-2-yl acetate (1h) (0.359 g, 1.90 mmol, 85%) as a colorless liquid.
,6-Dihydronaphthalen-2-yl Acetate (1h): 1H NMR (300 MHz,
5
−1
CDCl ) δ: 2.27−2.36 (m, 2H), 2.28 (s, 3H), 2.77 (t, J = 8.0 Hz, 2H),
.06 (m, 1H), 6.41 (dt, J = 9.6, 1.8 Hz, 1H), 6.74 (d, J = 2.4 Hz, 1H), 6.81
dd, J = 8.1, 2.4 Hz, 1H), 7.08 (d, J = 8.1 Hz, 1H). C NMR (75 MHz,
CDCl ) δ: 21.1 (CH ), 23.2 (CH ), 26.8 (CH ), 118.8 (CH), 119.4
3
6
(
5
13
MeOH (50 mL), and NaBH (0.227 g, 6.00 mmol). After workup,
4
3
3
2
2
solvent was removed under reduced pressure and (9H-fluoren-9-
yl)methyl (5-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl)carbamate
1.12 g, 2.91 mmol, 97.0%) was obtained as a white solid and used in
the next step without purification. The reaction was performed using
9H-fluoren-9-yl)methyl (5-hydroxy-5,6,7,8-tetrahydronaphthalen-2-
yl)carbamate (1.12 g, 2.91 mmol), toluene (50 mL), and TsOH·H O
cat. few crystals) at 130 °C. The crude product was purified by flash
column chromatography (10−30% EtOAc in hexane) giving (9H-
fluoren-9-yl)methyl (7,8-dihydronaphthalen-2-yl)carbamate (1d)
(
1
1
CH), 127.3 (CH), 128.2 (CH), 129.6 (CH), 132.9 (C), 135.3 (C),
+●
49.2 (C), 169.7 (C). LRMS m/z (rel. int.): 188 (M , 20), 146 (100),
(
45 (52), 131 (30), 127 (19), 117 (24), 115 (42), 91 (15), 77 (5), 63
9), 43 (30), 39 (10). HRMS [ESI(+)-TOF]: calcd for [C H O +
(
12 12 2
(
Na] 211.0735; found 211.0724. IR (film): 3034, 2935, 2885, 2831, 1761,
−
1
2
1609, 1575, 1491, 1432, 1369, 1328, 1271, 1210 cm .
Preparations of known chiral iodoarene compounds 4a, 4b, 4c,
12
26
25
(
1
2
12
4
f, and 4g were performed as reported in literature.
R)-2-(2-Iodophenoxy)-N-phenylpropanamide (4d). The reac-
tion was performed using (R)-2-(2-iodophenoxy)propanoic acid (0.584
g, 2.00 mmol), DCM (50 mL), aniline (0.233 g, 2.5 mmol), DCC (0.515
g, 2.5 mmol), and DMAP (0.037 g, 0.300 mmol). Purification by silica
gel flash column chromatography (10% EtOAc in hexane) gave
compound 4d (0.589 g, 1.87 mmol, 80%) as a white solid. Mp:
= −99.3 (c = 0.17, CHCl ). (R)-2-(2-
Iodophenoxy)-N-phenylpropanamide (4d): H NMR (300 MHz,
(
(
0.890 g, 2.42 mmol, 83%) as a white solid. Mp: 141−142 °C. (9H-
Fluoren-9-yl)methyl (7,8-Dihydronaphthalen-2-yl)carbamate (1d):
1
40
H NMR (300 MHz, CDCl ) δ: 2.25−2.33 (m 2H), 2.77 (t, J = 8.2 Hz,
3
2
4
H), 4.27 (t, J = 6.6 Hz, 2H), 4.53 (d, J = 6.9 Hz, 2H), 5.95 (dt, J = 9.6,
.4 Hz, 1H), 6.41 (dt, J = 9.6, 1.6 Hz, 1H), 6.57 (bs, 1H), 6.94 (d, J = 8.1
20
Hz, 1H), 7.08−7.18 (m, 2H), 7.32 (td, J = 7.4, 1.2 Hz, 2H), 7.38−7.44
128.6−129.3 °C, [α]
D
3
1
(
7
m, 2H), 7.61 (d, J = 7.2 Hz, 2H), 7.61 (d, J = 7.2 Hz, 2H), 7.78 (d, J =
.5 Hz, 2H). 13C NMR (75 MHz, CDCl ) δ: 23.0 (CH ), 27.7 (CH ),
CDCl ) δ: 1.73 (d, J = 6.6 Hz, 3H), 4.91 (q, J = 6.6 Hz, 1H), 6.81 (td, J =
3
2
2
3
4
7.1 (CH), 66.8 (CH ), 116.5 (CH), 118.2 (CH), 120.0 (CH), 124.9
7.5, 1.2 Hz, 1H), 6.87 (dd, J = 8.4, 1.2 Hz, 1H), 7.11−717 (m, 1H),
7.31−7.38 (m, 3H), 7.63−7.67 (m, 2H), 7.82 (dd, J = 7.8, 1,5 Hz, 1H),
8.02 (bs, 1H). 13C NMR (75 MHz, CDCl ) δ: 18.3 (CH ), 75.9 (CH),
2
(
CH), 126.4 (CH), 127.0 (CH), 127.1 (CH), 127.5 (CH), 127.7 (CH),
130.0 (C), 136.1 (C), 136.6 (C), 141.3 (C), 143.7 (C), 153.3 (C).
3
3
D
DOI: 10.1021/acs.joc.5b02803
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
8
7.5 (C), 113.3 (CH), 119.8 (CH), 124.0 (CH), 124.7 (CH), 129.1
The crude product was purified by flash column chromatography (10−
20%, EtOAc in hexane), giving alcohol 6a (0.050 g, 0.34 mmol, 34%) in
60% ee as a colorless oil (chiral ALPHA DEX 120 fused silica capillary
column (30 m × 0.25 mm × 0.25 μm), tr (major) = 25.7 min, tr (minor)
(CH), 129.9 (CH), 137.3 (C), 139.9 (CH), 155.0 (C), 169.1 (C).
+
HRMS [ESI(+)-TOF]: calcd for [C H INO + H] 368.0147; found
3
15
14
2
68.0149. IR (film): 3248, 3134, 3059, 2981, 2918, 2850, 1669, 1598,
−1
20
1
582, 1570, 1544, 1498, 1470, 1439, 1376, 1287, 1277, 1246, 1204 cm .
R)-2-(2-Iodophenoxy)-N-(2,6-dimethylphenyl)propanamide
4e). The reaction was performed using (R)-2-(2-iodophenoxy)-
= 26.3 min), [α]D = +8.8 (c = 1, CHCl3).
(R)-(2,3-Dihydro-1H-inden-1-yl)methanol (6a). 1H NMR
18
(
(
(200 MHz, CDCl ) δ: 1.56 (bs, 1H), 1.85−2.02 (m, 1H), 2.18−2.36
3
propanoic acid (0.876 g, 3.00 mmol), dimethylaniline (0.462 mL, 3.75
mmol), DCC (0.768 g, 3.75 mmol), and DMAP (0.055 g, 0.45 mmol) in
DCM (50 mL). Purification by silica gel flash column chromatography
(m, 1H), 2.80−3.10 (m, 2H), 3.30−3.42 (m, 1H), 3.80 (d, J = 6.2 Hz,
1
3
2H), 7.15−7.30 (m, 4H). C NMR (50 MHz, CDCl ) δ: 28.4, 31.4,
3
40
47.5, 66.0, 124.1, 124.7, 126.2, 127.0, 143.8, 144.7.
(
8
5−20% EtOAc in hexane) gave compound 4e in (0.970 g, 2.45 mmol,
(R)-N-(1-(Dimethoxymethyl)-2,3-dihydro-1H-inden-5-yl)-
acetamide (3b). To a stirred solution of Ar*I 4f (0.872 g, 2.00 mmol)
in TFE/DCM (1:40) (17 mL) was added mCPBA (77%) (0.448 g, 2.00
mmol) followed by (+)-CSA (0.464 g, 2.00 mmol). The resulting
solution was stirred at rt for 30 min. Solvent was removed under reduced
pressure. To this reaction mixture DCM (15 mL) and MeOH (1.7 mL)
were added, and the temperature was lowered to −78 °C, followed by
addition of alkene 1b (0.187 g, 1.00 mmol) (dissolved in 3 mL DCM/
MeOH (10:1)). After 5 min the reaction was quenched with a saturated
20
D
2%) as white solid. Mp: 171.8−173.2 °C, [α] = −52.7 (c = 0.16,
CHCl ). (R)-2-(2-Iodophenoxy)-N-(2,6-dimethylphenyl)-
3
1
propanamide (4e): H NMR (300 MHz, CDCl ) δ: 1.78 (d, J = 6.6
Hz, 3H), 2.19 (s, 6H), 4.99 (qd, J = 6.6, 0.6 Hz, 1 H), 6.81 (dd, J = 7.5,
3
1
8
.6 Hz, 1H), 6.92 (dd, J = 8.7, 1.5 Hz, 1H), 7.10 (m, 3H), 7.35 (ddd, J =
.2, 7.4, 1.6 Hz, 1H), 7.83 (dd, J = 7.8, 1.5 Hz, 1H), 8.07 (bs, 1H). 13
C
NMR (75 MHz, CDCl ) δ: 18.4 (CH ), 18.7 (CH ), 75.8 (CH), 87.3
3
3
3
(
1
C), 113.2 (CH), 123.9 (CH), 127.5 (CH), 128.3 (CH), 129.8 (CH),
32.8 (C), 135.4 (C), 139.7 (CH), 155.1 (C), 169.6 (C). HRMS
solution of NaHCO , extracted with DCM, washed with brine, and dried
3
+
[
ESI(+)-TOF]: calcd for [C H INO +H] 396.0460; found 396.0461.
over anhydrous MgSO . The solvent was evaporated under reduced
17
18
2
4
IR (film): 3234, 3025, 2990, 2919, 1667, 1593, 1582, 1569, 1538, 1471,
pressure. The crude product was purified by flash column chromatog-
raphy (30−60%, EtOAc in hexane), giving acetal 3b (0.149 g, 0.600
mmol, 60%) as a viscous colorless liquid in 64% ee (Daicel chiral ASH
column (25 cm), hexanes/EtOH:MeOH (1:1) = 95/5, 1.0 mL/min,
−1
1
438, 1372, 1278, 1250, 1231 cm .
Asymmetric Ring Contraction Reactions Mediated by Chiral
I(III) (R)-1-(Bis(2,2,2-trifluoroethoxy)methyl)-2,3-dihydro-1H-in-
dene (2a). To a stirred solution of Ar*I 4f (0.872 g, 2.00 mmol) in
TFE/DCM (1:40) (17 mL) was added mCPBA (77%) (0.448 g, 2.00
mmol) followed by (+)-CSA (0.464 g, 2.00 mmol). The resulting
solution was stirred at rt for 30 min. Solvent was removed under reduced
pressure. To this reaction mixture TFE/DCM (1:4) (17 mL) was added,
and the temperature was lowered to −78 °C, followed by addition of
alkene 1a (0.130 g, 1.00 mmol) (dissolved in 3 mL of TFE/DCM
temp 28 °C, 215 nm; tr (minor) = 15.7 min, tr (major) = 16.7 min),
20
[
α]D = +13.1 (c = 0.59, CHCl3).
(
R)-N-(1-(Dimethoxymethyl)-2,3-dihydro-1H-inden-5-yl)-
1
8
1
acetamide (3b). H NMR (300 MHz, CDCl ) δ: 1.93−2.02 (m,
3
1H), 2.15 (s, 3H), 2.17−2.23 (m, 1H), 2.77−2.97 (m, 2H), 3.37 (s, 3H),
3.39 (m, 1H), 3.42 (s, 3H), 4.27 (d, J = 7.5 Hz, 1H), 7.14 (dd, J = 8.4, 1.8
Hz, 1H), 7.31 (bs, 1H), 7.33 (d, J = 8.1 Hz, 1H), 7.46 (s, 1H). C NMR
1
3
(1:4)). After 5 min the reaction was quenched with saturated solution of
(75 MHz, CDCl ) δ: 24.5, 27.5, 31.4, 47.0, 52.9, 54.2, 107.2, 116.3,
3
NaHCO , extracted with DCM, washed with brine, and dried over
118.1, 125.7, 136.7, 138.9, 145.8, 168.3.
3
anhydrous MgSO . The solvent was evaporated under reduced pressure.
(R)-N-(1-(Dimethoxymethyl)-2,3-dihydro-1H-inden-5-yl)-
benzamide (3c). The reaction was performed using Ar*I 4f (0.872 g,
2.00 mmol), mCPBA (77%) (0.448 g, 2.00 mmol), and (+)-CSA (0.464
g, 2.00 mmol) in TFE/DCM (1:40) (17 mL). After evaporation of the
solvent, DCM (15 mL) and MeOH (1.7 mL) were added, followed by
addition of alkene 1c (0.249 g, 1.00 mmol) (dissolved in 3 mL of DCM/
MeOH (10:1)) at −78 °C. After workup solvent was removed under
reduced pressure. The crude product was purified by flash column
chromatography (30−40% EtOAc in hexane) giving acetal 3c (0.221 g,
0.710 mmol, 71%) as a white solid (mp: 91.5−93 °C) in 58% ee (Daicel
chiral ASH column (25 cm), hexanes/EtOH:MeOH (1:1) = 92/8, 1.0
mL/min, temp 28 °C, 220 nm; tr (minor) = 25.1 min, tr (major) = 27.5
min) [α]20 = +11.2 (c = 0.28, CHCl )).
4
The crude product was purified by flash column chromatography (2−
3%, EtOAc in hexane), giving acetal 2a (0.196 g, 0.110 mmol, 60%) as a
colorless oil in 58% ee (Daicel chiral ODH column (25 cm), hexanes/i-
PrOH = 99.7/0.3, 0.3 mL/min, temp 28 °C, 215 nm; tr (major) = 40.3
min, tr (minor) = 46.4 min), [α]D20 = +6.5 (c = 0.35, CHCl )).
3
(
R)-1-(Bis(2,2,2-trifluoroethoxy)methyl)-2,3-dihydro-1H-in-
18
1
dene (2a).
2
4
(
H NMR (300 MHz, CDCl ) δ: 1.96−2.08 (m, 1H),
3
.19−2.31 (m, 1H), 2.83−3.03 (m, 2H), 3.47 (q, J = 9.0 Hz, 1H), 3.86−
.05 (m, 4H), 4.70 (d, J = 8.1 Hz, 1H), 7.15−7.24 (m, 3H), 7.38−7.41
m, 1H). 13C NMR (75 MHz, CDCl ) δ: 27.1, 31.1, 47.1, 61.8 (q, J =
3
3
4.8 Hz), 63.3 (q, J = 34.8 Hz), 105.3, 123.7 (q, J = 276.07 Hz), 123.8 (q,
J = 276.0 Hz), 124.6, 125.4, 126.4, 127.5, 140.7, 144.5.
S)-1-(Bis(2,2,2-trifluoroethoxy)methyl)-2,3-dihydro-1H-in-
D
3
(
(R)-N-(1-(Dimethoxymethyl)-2,3-dihydro-1H-inden-5-yl)-
1
dene (2a). The reaction was performed using Ar*I 4f (Ar*I derived
from (+)-ethyl-D-lactate) (0.872 g, 2.00 mmol), mCPBA (77%) (0.448
g, 2.00 mmol), and (+)-CSA (0.464 g, 2.00 mmol) in TFE/DCM (1:40)
benzamide (3c). H NMR (300 MHz, CDCl ) δ: 1.92−2.04 (m, 1H),
3
2.15−2.27 (m, 1H), 2.78−2.99 (m, 2H), 3.37−3.47 (m, 1H), 3.38 (s,
3H), 3.42 (s, 3H), 4.29 (d, J = 7.5 Hz, 1H), 7.29 (dd, 8.1, 2.1 Hz, 1H),
7.38 (d, J = 8.4 Hz, 1H), 7.42−7.55 (m, 3H), 7.61 (s, 1H), 7.83−7.86
(m, 2H), 7.93 (bs, 1H). 13C NMR (75 MHz, CDCl ) δ: 27.5 (CH ),
(
17 mL). After evaporation of the solvent, TFE/DCM (17 mL) (1:4)
was added, followed by addition of alkene 1a (0.130 g, 1.00 mmol)
3
2
(
dissolved in 3 mL TFE/DCM (1:4)) at −78 °C. After workup solvent
31.4 (CH ), 46.9 (CH), 52.8 (CH ), 54.2 (CH ), 107.1 (CH), 116.6
2
3
3
was removed under reduced pressure. The crude product was purified
by flash column chromatography (3−5% EtOAc in hexane) giving acetal
2
(CH), 118.5 (CH), 125.6 (CH), 126.9 (CH), 128.5 (CH), 131.5 (CH),
134.9 (C), 136.8 (C), 139.1 (C), 145.7 (C), 165.8 (C). HRMS [ESI(+)-
18
+
a
(0.188 g, 0.57 mmol, 57%) as a colorless oil in 56% ee (Sigma-
TOF] calcd for [C H NO + Na] 334.1419; found 334.1408. IR
19
21
3
Aldrich chiral Astec Cellulose DMP column (25 cm), hexanes/i-PrOH
(film): 3307, 3060, 2937, 2830, 1737, 1650, 1601, 1580, 1532, 1493,
−1
=
(
99.0/1.0, 0.3 mL/min, temp 28 °C, 215 nm; tr (minor) = 19.7 min, tr
1447, 1424, 1374, 1328, 1283, 1248, 1210, 1187, 1154, 1116 cm .
(9H-Fluoren-9-yl)methyl (R)-(1-(Dimethoxymethyl)-2,3-dihy-
dro-1H-inden-5-yl)carbamate (3d). The reaction was performed
using Ar*I 4f (0.872 g, 2.00 mmol), mCPBA (77%) (0.448 g, 2.00
mmol), and (+)-CSA (0.464 g, 2.00 mmol) in TFE/DCM (1:40) (17
mL). After evaporation of the solvent, DCM (15 mL) and MeOH (1.7
mL) was added, followed by addition of alkene 1d (0.367 g, 1.00 mmol)
(dissolved in 3 mL DCM/MeOH (10:1)) at −78 °C. After workup
solvent was removed under reduced pressure. The crude product was
purified by flash column chromatography (20−30% EtOAc in hexane)
giving acetal 3d (0.321 g, 0.750 mmol, 75%) as a white solid (mp: 111−
major) = 21.1 min), [α]D20 = −6.3 (c = 0.4, CHCl )).
3
(
R)-(2,3-Dihydro-1H-inden-1-yl)methanol (6a). To a stirred
solution of Ar*I 4f (0.872 g, 2.00 mmol) in HFIP/CH Cl (1:40) (17
2
2
mL) was added mCPBA (77%) (0.448 g, 2.00 mmol) followed by
+)-CSA (0.464 g, 2.0 mmol). The resulting solution was stirred at rt for
0 min. H O (0.4 mL) and alkene 1a (0.130 g, 1.0 mmol) (dissolved in 3
(
3
2
mL of HFIP/DCM (1:40)) were added at −78 °C. After 2 min, NaBH
4
(
0.190 g, 5.0 mmol) was added. The reaction stirred for 2 h at rt. The
reaction was quenched with a saturated solution of NaHCO , extracted
3
with DCM (3 × 10 mL), washed with brine (2 × 10 mL), and dried over
20
anhydrous MgSO . The solvent was evaporated under reduced pressure.
112 °C) in 58% ee, [α] = +7.9 (c = 0.29, CHCl ).
4
D
3
E
DOI: 10.1021/acs.joc.5b02803
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
(
9H-Fluoren-9-yl)methyl (R)-(1-(Dimethoxymethyl)-2,3-dihy-
2H), 7.64 (tt, J = 7.5, 1.5 Hz, 1H), 8.18−8.22 (m, 2H). 13C NMR (75
MHz, CDCl ) δ: 26.8 (CH ), 28.2 (CH ), 47.6 (CH), 61.9 (q, J = 34.8
1
dro-1H-inden-5-yl)carbamate (3d). H NMR (300 MHz, CDCl ) δ:
1
(
3
3
2
2
.89−2.01 (m, 1H), 2.12−2.24 (m, 1H), 2.73−2.94 (m, 2H), 3.34−3.43
m, 1H), 3.35 (s, 3H), 3.40 (s, 3H), 4.22−4.26 (m, 1H), 4.26 (d, J = 7.5
Hz, 1H), 4.51 (d, J = 6.6 Hz, 2H), 6.71 (bs, 1H), 7.04 (d, J = 7.2 Hz, 1H),
Hz) (CH ), 63.4 (q, J = 34.8 Hz) (CH ), 105.1 (CH), 120.7 (CH),
2
2
123.2 (CH), 123.69 (q, J = 276 Hz) (CF ), 123.74 (q, J = 276 Hz)
3
(CF ), 128.1 (CH), 128.6 (CH), 129.4 (C), 130.2 (CH), 133.6 (CH),
3
7
.27−7.32 (m, 4H), 7.36−7.41 (m, 2H), 7.59 (d, J = 7.5 Hz, 2H), 7.76
136.8 (C), 143.4 (C), 147.4 (C), 164.5 (C). HRMS [ESI(+)-TOF]
+
(
(
1
(
(
d, J = 7.5 Hz, 2H). 13C NMR (75 MHz, CDCl ) δ: 27.5 (CH ), 31.4
calcd for [C H F O +Na] 471.1007; found 471.1012. IR (film):
3
2
21 18
6
4
CH ), 46.8 (CH), 47.0 (CH), 52.8 (CH ), 54.1 (CH ), 66.6 (CH ),
07.1 (CH), 115.0 (CH), 117.0 (CH), 119.9 (CH), 124.8 (CH), 125.6
CH), 127.0 (CH), 127.6 (CH), 136.6 (C), 138.0 (C), 141.2 (C), 143.7
C), 145.7 (C), 153.5 (C). HRMS [ESI(+)-TOF] calcd for
3067, 2948, 1738, 1602, 1585, 1469, 1453, 1423, 1383, 1279, 1230,
2
3
3
2
−1
1168, 1134 cm .
(R)-1-(Bis(2,2,2-trifluoroethoxy)methyl)-2,3-dihydro-1H-
inden-4-yl Acetate (2e). To a stirred solution of acetal 2f (0.130 g,
0.29 mmol) in methanol (15 mL) was added a solution of K CO (0.040
+
[
C H NO +Na] 452.1832; found 452.1837. IR (film): 3307, 3066,
2
7
27
4
2
3
2
1
942, 2849, 2830, 1730, 1708, 1598, 1538, 1493, 1478, 1450, 1431,
g, 0.29 mmol) in H O (0.12 mL). The reaction mixutre was stirred for 3
2
−1
375, 1326, 1297, 1220 cm .
R)-N-(1-(Dimethoxymethyl)-2,3-dihydro-1H-inden-5-yl)-
h. The reaction was diluted with water (5 mL), neutralized with 10%
HCl, and extracted with DCM (3 × 5). The extract was then washed
with water (5 mL) and brine (2 × 5 mL) and dried over anhydrous
(
acetamide (3b). To a stirred solution of 3d (0.12 g, 0.28 mmol) in
dichloromethane (15 mL) was added piperidine (20% v/v) (3 mL). The
solution was stirred for 25 min, and the solvent was removed under
reduced pressure. The crude product was purified by flash column
chromatography (60−70% EtOAc in hexane) giving deprotected acetal
MgSO . The solvent was evaporated under reduced pressure. The crude
4
product was purified by flash column (10−15%, EtOAc in hexane)
43
giving phenolic acetal (0.10 g, 0.29 mmol, 96%) as a colorless oil. The
phenolic acetal was protected with an acetyl group. The reaction was
performed using deprotected acetal (0.10 g, 0.29 mmol), cat. DMAP,
41
(
0.050 g, 0.241 mmol, 86%) as a colorless liquid. As deprotected amine
1
8
acetal was unstable, it was protected with acetyl group. The reaction was
performed using deprotected acetal (0.050 g, 0.241 mmol), cat. DMAP,
and Ac O (0.08 mL, 0.82 mmol) in Et N (2 mL). Purification by flash
and Ac O (0.096 mL, 0.986 mmol) in Et N (2 mL). Purification by
2
3
flash column chromatography (3−4% EtOAc in hexane) gave acetyl
protected acetal 2e (0.105 g, 0.272 mmol, 94%) in 56% ee (Daicel chiral
ODH column (25 cm), hexanes/i-PrOH = 98.0/2.0, 0.4 mL/min, temp
26 °C, 215 nm; tr (major) = 18.3 min, tr (minor) = 21.6 min).
42
2
3
column chromatography (50−60% EtOAc in hexane) gave acetyl
18
protected acetal 3b (0.054 g, 0.217 mmol, 90%) in 58% ee (Daicel
chiral ASH column (25 cm), hexanes/EtOH:MeOH (1:1) = 95/5, 1.0
mL/min, temp 28 °C, 215 nm; tr (minor) = 15.7 min, tr (major) = 16.7
min).
(R)-1-(Bis(2,2,2-trifluoroethoxy)methyl)-2,3-dihydro-1H-
inden-5-yl Acetate (2g). The reaction was performed using Ar*I 4f
(0.872 g, 2.0 mmol), mCPBA (77%) (0.448 g, 2.00 mmol) and (+)-CSA
(0.464 g, 2.00 mmol) in TFE/DCM (1:40) (17 mL). After evaporation
of the solvent, TFE/DCM (17 mL) (1:1) was added, followed by
addition of alkene 1g (0.188 g, 1.00 mmol) (dissolved in 3 mL TFE/
DCM (1:1)) at −40 °C. After workup solvent was removed under
reduced pressure. The crude product was purified by flash column
chromatography (4−5% ethyl acetate in hexane) giving acetal 2g (0.158
g, 0.410 mmol, 41%) as colorless viscous liquid in 78% ee (Sigma-Aldrich
chiral Astec Cellulose DMP column (25 cm), hexanes/i-PrOH = 99.0/
1.0, 0.4 mL/min, temp 28 °C, 215 nm; tr (major) = 45.3 min, tr (minor)
(
R)-1-(Bis(2,2,2-trifluoroethoxy)methyl)-2,3-dihydro-1H-
inden-4-yl Acetate (2e). The reaction was performed using Ar*I 4f
(
0.872 g, 2.00 mmol), mCPBA (77%) (0.448 g, 2.00 mmol), and
(
+)-CSA (0.464 g, 2.00 mmol) in TFE/DCM (1:40) (17 mL). After
evaporation of the solvent, TFE/DCM (17 mL) (1:1) was added,
followed by addition of alkene 1e (0.188 g, 1.00 mmol) (dissolved in 3
mL of TFE/DCM (1:1)) at −40 °C. After workup solvent was removed
under reduced pressure. The crude product was purified by flash column
chromatography (4−5% EtOAc in hexane) giving acetal 2e (0.223 g,
= 49.8 min), [α]20 = +13.5 (c = 0.58, CHCl3).
0
.580 mmol, 58%) as a white solid (mp: 59.3−60.5 °C) in 64% ee
D
(
Daicel chiral ODH column (25 cm), hexanes/i-PrOH = 98.0/2.0, 0.4
(R)-1-(Bis(2,2,2-trifluoroethoxy)methyl)-2,3-dihydro-1H-
1
mL/min, temp 26 °C, 215 nm; tr (major) = 18.3 min, tr (minor) = 21.6
inden-5-yl Acetate (2g). H NMR (300 MHz, CDCl
3
) δ: 1.97−2.09
min), [α]20 = +11.8 (c = 0.28, CHCl )).
(m, 1H), 2.21−2.33 (m, 1H), 2.28 (s, 3H), 2.82−3.01 (m, 2H), 3.43 (q,
J = 7.8 Hz, 1H), 3.86−4.08 (m, 4H), 4.68 (d, J = 8.4 Hz, 1H), 6.87 (dd, J
= 8.4, 2.2 Hz, 1H), 6.94 (s, 1H), 7.38 (d, J = 8.1 Hz, 1H). C NMR (75
D
3
(
R)-1-(Bis(2,2,2-trifluoroethoxy)methyl)-2,3-dihydro-1H-
1
13
inden-4-yl Acetate (2e). H NMR (300 MHz, CDCl ) δ: 1.98−2.10
3
(
3
m, 1H), 2.22−2.32 (m, 1H), 2.30 (s, 3H), 2.70−2.91 (m, 2H), 3.47−
.55 (m, J = Hz, 1H), 3.84−4.07 (m, 4H), 4.71 (d, J = 8.1 Hz, 1H), 6.94
MHz, CDCl ) δ: 21.0 (CH ), 27.4 (CH ), 31.1 (CH ), 46.4 (CH), 61.6
3
3
2
2
(q, J = 34.8 Hz) (CH ), 63.3 (q, J = 34.8 Hz) (CH ), 105.1 (CH), 117.8
2
2
13
(
dt, J = 7.8 Hz, 1H), 7.21 (t, J = 7.8 Hz, 1H), 7.28 (d, J = 7.5 Hz, 1H). C
(CH), 119.7 (CH), 123.6 (q, J = 276 Hz) (CF ), 123.7 (q, J = 276 Hz)
3
NMR (75 MHz, CDCl ) δ: 20.8 (CH ), 26.8 (CH ), 28.1 (CH ), 47.5
(CF ), 126.1 (CH), 138.3 (C), 146.1 (C), 150.3 (C), 169.7 (C). LRMS
m/z (rel. int.): 386 (M , 4), 344 (7), 245 (7), 211 (14), 175 (8), 145
3
3
2
2
3
+
●
(
CH), 61.8 (q, J = 34.8 Hz) (CH ), 63.3 (q, J = 34.8 Hz) (CH ), 105.0
2
2
(
=
(
CH), 120.6 (CH), 123.2 (CH), 123.6 (q, J = 276 Hz) (CF ), 123.7 (q, J
(6), 133 (100), 115 (7), 105 (11), 83 (11), 77 (6), 43 (19). HRMS
3
+
276 Hz) (CF ), 128.0 (CH), 136.6 (C), 143.3 (C), 147.1 (C), 168.9
[ESI(+)-TOF]: calcd for [C H F O +Na] 409.0850; found
3
16 16
6
4
+
C). HRMS [ESI(+)-TOF]: calcd for [C H F O +Na] 409.0850;
409.0851. IR (film): 2953, 1761, 1610, 1592, 1485, 1460, 1431, 1372,
16
16
6
4
−1
found 409.0849. IR (film): 2947, 1764, 1615, 1587, 1468, 1433, 1372,
1
1282, 1216, 1163, 1134, 1103 cm .
−
1
281, 1213 cm .
(R)-3-(Bis(2,2,2-trifluoroethoxy)methyl)-2,3-dihydro-1H-
inden-5-yl Acetate (2h). The reaction was performed using Ar*I 4f
(0.872 g, 2.00 mmol), mCPBA (77%) (0.448 g, 2.00 mmol) and
(+)-CSA (0.464 g, 2.00 mmol) in TFE/DCM (1:40) (17 mL). After
evaporation of the solvent, TFE/DCM (17 mL) (1:1) was added,
followed by addition of alkene 1h (0.188 g, 1.00 mmol) (dissolved in 3
mL TFE/DCM (1:1)) at −40 °C. After workup solvent was removed
under reduced pressure. The crude product was purified by flash column
chromatography (4−5% ethyl acetate in hexane) giving acetal 2h (0.204
g, 0.530 mmol, 53%) as white solid (MP: 61.2−62.1 °C) in 54% ee
(Sigma-Aldrich chiral Astec Cellulose DMP column (25 cm), hexanes/i-
PrOH = 99.0/1.0, 0.4 mL/min, temp 26 °C, 215 nm; tr (major) = 28.5
min, tr (minor) = 31.3 min) [α]20 = +4.7 (c = 0.48, CHCl )).
(
R)-1-(Bis(2,2,2-trifluoroethoxy)methyl)-2,3-dihydro-1H-
inden-4-yl Benzoate (2f). The reaction was performed using Ar*I 4f
(
0.872 g, 2.00 mmol), mCPBA (77%) (0.448 g, 2.00 mmol), and
(
+)-CSA (0.464 g, 2.00 mmol) in TFE/DCM (1:40) (17 mL). After
evaporation of the solvent, TFE/DCM (17 mL) (1:1) was added,
followed by addition of alkene 1f (0.250 g, 1.00 mmol) (dissolved in 3
mL TFE/DCM (1:1)) at −40 °C. After workup, solvent was removed
under reduced pressure. The crude product was purified by flash column
chromatography (3−4% ethyl acetate in hexane) giving acetal 2f (0.272
g, 0.610 mmol, 61%) as a white solid (mp: 77.5−77.9 °C) in 56% ee,
20
[α] = +19.4 (c = 0.33, CHCl ).
D
3
(
R)-1-(Bis(2,2,2-trifluoroethoxy)methyl)-2,3-dihydro-1H-
1
D
3
inden-4-yl Benzoate (2f). H NMR (300 MHz, CDCl ) δ: 1.99−2.11
(R)-3-(Bis(2,2,2-trifluoroethoxy)methyl)-2,3-dihydro-1H-
3
1
(
m, 1H), 2.20−2.32 (m, 1H), 2.76−2.97 (m, 2H), 3.54 (q, J = 8.1 Hz,
H), 3.85−4.09 (m, 4H), 4.74 (d, J = 8.1 Hz, 1H), 7.10 (dt, J = 7.8, 1.2
Hz, 1H), 7.26 (t, J = 7.8 Hz, 1H), 7.33 (d, J = 7.8 Hz, 1H), 7.48−7.54 (m,
inden-5-yl Acetate (2h). H NMR (300 MHz, CDCl ) δ: 1.98−2.09
3
1
(m, 1H), 2.21−2.33 (m, 1H), 2.28 (s, 3H), 2.79−2.99 (m, 2H), 3.46 (q,
J = 7.8 Hz, 1H), 3.85−4.06 (m, 2H), 4.69 (d, J = 8.4 Hz, 1H), 6.91 (ddd,
F
DOI: 10.1021/acs.joc.5b02803
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
J = 8.1, 2.1, 0.3 Hz, 1H), 7.10 (d, J = 1.8 Hz, 1H), 7.20 (d, J = 8.1 Hz,
Astec Cellulose DMP column (25 cm), hexanes/i-PrOH = 99.5/0.5, 0.5
mL/min, temp 28 °C, 220 nm; tr (major) = 11.3 min, tr (minor) = 15.7
1
H). 13C NMR (75 MHz, CDCl ) δ: 21.1 (CH ), 27.5 (CH ), 30.6
3 3 2
min) as a colorless oil, [α]D20 = +6.7 (c = 0.57, CHCl ), and alcohol 6j
(
CH ), 61.7 (q, J = 34.8 Hz) (CH ), 63.5 (q, J = 34.8 Hz) (CH ), 105.1
2
2
2
3
(
=
(
2
4
CH), 118.9 (CH), 120.9 (CH), 123.6 (q, J = 276 Hz) (CF ), 123.7 (q, J
(0.055 g, 0.34 mmol, 34%) in 34% ee (Daicel chiral ASH column (25
cm), hexanes/EtOH:MeOH (1:1) = 99.0/1.0, 0.5 mL/min, temp 28 °C,
220 nm; tr (major) = 25.3 min, tr (minor) = 33.7 min) as a colorless oil,
3
276 Hz) (CF ), 125.1 (CH), 142.0 (C), 142.2 (C), 149.5 (C), 169.8
3
+●
C). LRMS m/z (rel. int.): 386 (M , 2), 344 (25), 287 (7), 244 (8),
20
11 (100), 145 (17), 133 (92), 115 (15), 105 (17), 83 (29), 77 (12),
[α]
D
= +1.5 (c = 0.23, CHCl ).
3
+
3(43). HRMS [ESI(+)-TOF]: calcd for [C H F O +Na] 409.0850;
(1S,3S)-1-(Bis(2,2,2-trifluoroethoxy)methyl)-3-methyl-2,3-di-
hydro-1H-indene (2j). H NMR (300 MHz, CDCl ) δ: 1.26 (d, J =
16
16
6
4
18
1
found 409.0864. IR (film): 2919, 2850, 1760, 1610, 1591, 1540, 1484,
1
3
−1
6.9 Hz, 3H), 1.76−1.86 (m, 1H), 2.27−2.36 (m, 1H), 3.27 (sext, J = 7.2
Hz, 1H), 3.46 (sext, J = 4.2 Hz, 1H), 3.82−4.05 (m, 4H), 4.64 (d, J = 8.4
459, 1429, 1372, 1281, 1214 cm .
(
1S,3R)-1-(Bis(2,2,2-trifluoroethoxy)methyl)-3-(3,4-dichloro-
1
3
phenyl)-2,3-dihydro-1H-indene (2i) and ((1R,3R)-3-(3,4-Dichlor-
ophenyl)-2,3-dihydro-1H-inden-1-yl)methanol (6i). To a stirred
solution of Ar*I 4f (0.872 g, 2.00 mmol) in TFE/DCM (1:40) (17 mL)
was added mCPBA (77%) (0.448 g, 2.00 mmol) followed by (+)-CSA
Hz, 1H), 7.15−7.28 (m, 3H), 7.35 (d, J = 6.9 Hz, 1H). C NMR (75
MHz, CDCl
(q, J = 34.7 Hz) (CH
= 276 Hz) (CF ), 123.5 (CH), 123.8 (q, J = 276 Hz) (CF
126.6 (CH), 127.8 (CH), 140.3 (C), 149.2 (C).
((1R,3S)-3-Methyl-2,3-dihydro-1H-inden-1-yl)methanol (6j).
) δ: 20.5 (CH
), 35.9 (CH
), 37.6 (CH), 45.9 (CH), 61.5
), 105.0 (CH), 123.6 (q, J
), 125.8 (CH),
3
3 2
), 63.8 (q, J = 34.7) (CH
2
2
3
3
(
0.464 g, 2.00 mmol). The resulting solution was stirred at rt for 30 min.
Solvent was removed under reduced pressure. To this reaction mixture
TFE/DCM (1:1) (17 mL) was added, and the temperature was lowered
to −40 °C, followed by addition of alkene 1i (0.275 g, 1.00 mmol)
1
H NMR (300 MHz, CDCl
) δ: 1.27 (d, J = 6.9 Hz, 3H), 1.62 (bs,
3
1H), 1.77−1.87 (m, 1H), 2.16−2.24 (m, 1H), 3.22−3.38 (m, 2H), 3.71
1
3
(
(
dissolved in 3 mL of TFE/DCM (1:1)). After 5 min, NaBH (5 equiv)
(d, J = 6.6 Hz, 2H), 7.14−7.27 (m, 4H). C NMR (75 MHz, CDCl
20.4 (CH ), 37.5 (CH ), 37.7 (CH), 46.2 (CH), 66.1 (CH ), 123.6
(CH), 124.3(CH), 126.3 (CH), 127.2 (CH), 143.4 (C), 149.2 (C).
3
) δ:
4
0.189 g, 5.00 mmol) was added to this reaction mixture. The reaction
3
2
2
was stirred for 2 h at rt. The reaction was quenched with saturated
solution of NaHCO , extracted with DCM, washed with brine, and dried
over anhydrous MgSO . The solvent was evaporated under reduced
pressure. The crude product was purified by flash column chromatog-
raphy (2−20%, EtOAc in hexane), giving acetal 2i (0.21 g, 0.44 mmol,
4
+
HRMS [ESI(+)-TOF]: calcd for [C11H14O+Na] 185.0942; found
3
+●
185.0938. LRMS m/z (rel. int.): 162 (M , 12), 144 (11), 132 (11), 131
4
(100), 129 (30), 115 (24), 91 (29), 77 (7), 63 (5), 51 (6), 39 (4).
4%) in 40% ee (Sigma-Aldrich chiral Astec Cellulose DMP column (25
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.5b02803.
■
cm), hexanes/i-PrOH = 99.0/1.0, 0.5 mL/min, temp 28 °C, 220 nm; tr
*
S
20
(
major) = 10.8 min, tr (minor) = 15.2 min) as a colorless oil [α]D =
+
3
(
1.8 (c = 0.50, CHCl ) and alcohol 6i (0.128 g, 0.440 mmol, 44%) in
3
4% ee (Daicel chiral ASH column (25 cm), hexanes/EtOH:MeOH
1:1) = 98.0/2.0, 0.5 mL/min, temp 28 °C, 220 nm; tr (major) = 30.3
NMR spectra, HPLC and GC chromatograms (PDF)
20
min, tr (minor) = 32.9 min) as a colorless oil, [α]D = +1.6 (c = 0.33,
CHCl3).
AUTHOR INFORMATION
Corresponding Author
E-mail: luizfsjr@iq.usp.br.
Notes
■
(
1S,3R)-1-(Bis(2,2,2-trifluoroethoxy)methyl)-3-(3,4-dichloro-
1
phenyl)-2,3-dihydro-1H-indene (2i). H NMR (300 MHz, CDCl )
3
*
δ: 2.11−2.21 (m, 1H), 2.57−2.66 (m, 1H), 3.56−3.63 (m, 1H), 3.82−
4
6
9
.08 (m, 4H), 4.41 (t, J = 8.1 Hz, 1H), 4.73 (d, J = 7.8 Hz, 1H), 6.93−
.99 (m, 2H), 7.20 (d, J = 2.1 Hz, 1H), 7.24−7.29 (m, 2H), 7.35 (d, J =
The authors declare no competing financial interest.
1
3
.0 Hz, 1H), 7.43−7.45 (m, 1H). C NMR (75 MHz, CDCl ) δ: 37.5
3
(
CH ), 46.4 (CH), 49.0 (CH), 62.0 (q, J = 34.9 Hz) (CH ), 63.9 (q, J =
2
2
ACKNOWLEDGMENTS
CAPES, FAPESP, and CNPq for financial support. Aline Utaka
for initial experiments
■
34.7 Hz) (CH ), 105.1 (CH), 123.62 (q, J = 276 Hz) (CF ), 123.66 (q, J
2
3
=
276 Hz) (CF ), 125.2 (CH), 125.9 (CH), 127.3 (CH), 127.5 (CH),
3
1
1
5
1
28.3 (CH), 129.8 (CH), 130.5 (CH), 132.6 (C), 141.0 (C), 145.3 (C),
46.0 (C). Anal. Calcd for C H Cl F O : C, 50.76; H, 3.41. Found: C,
0.55; H, 3.43. IR (film): 3077, 2943, 1590, 1561, 1469, 1421, 1401,
2
0
16
2
6
2
DEDICATION
■
−
1
280, 1167, 1133 cm .
(1R,3R)-3-(3,4-Dichlorophenyl)-2,3-dihydro-1H-inden-1-yl)-
Dedicated with deep respect to Prof. R. A. Pilli on the occasion of
his 60th birthday.
(
1
methanol (6i). H NMR (300 MHz, CDCl ) δ: 1.66 (bs, 1H), 2.14−
3
2
.24 (m, 1H), 2.47−2.55 (m, 1H), 3.44−3.52 (m, 1H), 3.80 (d, J = 6.3
Hz, 2H), 4.42 (t, J = 7.8 Hz, 1H), 6.95−7.00 (m, 2H), 7.18−7.28 (m,
H), 7.35 (d, J = 8.4 Hz, 2H). 13C NMR (75 MHz, CDCl ) δ: 39.3
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6
14
2
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(
1S,3S)-1-(Bis(2,2,2-trifluoroethoxy)methyl)-3-methyl-2,3-di-
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DOI: 10.1021/acs.joc.5b02803
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H
DOI: 10.1021/acs.joc.5b02803
J. Org. Chem. XXXX, XXX, XXX−XXX