One-Pot Asymmetric Synthesis of Alkylidene 1-Alkylindan-1-ols Using Br?nsted Acid and Palladium Catalysis

Article abstract of DOI:10.1021/acs.joc.7b02287

A one-pot catalytic enantioselective allylboration/Mizoroki-Heck reaction of 2-bromoaryl ketones has been developed for the asymmetric synthesis of 3-methyleneindanes bearing a tertiary alcohol center. Br?nsted acid-catalyzed allylboration with a chiral BINOL derivative was followed by a palladium-catalyzed Mizoroki-Heck cyclization, resulting in selective formation of the exo-alkene. This novel protocol provides a concise and scalable approach to 1-alkyl-3-methyleneindan-1-ols in high enantiomeric ratios (up to 96:4 er). The potential of these compounds as chiral building blocks was demonstrated with efficient transformation to optically active diol and amino alcohol scaffolds.

Full text of DOI:10.1021/acs.joc.7b02287

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Article
One-Pot Asymmetric Synthesis of Alkylidene 1-Alkylindan-1-
ols using Brønsted Acid and Palladium Catalysis
Reka J. Faggyas, Ewen D. D. Calder, Claire Wilson, and Andrew Sutherland
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b02287 • Publication Date (Web): 06 Oct 2017
Downloaded from http://pubs.acs.org on October 7, 2017
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Page 1 of 33
The Journal of Organic Chemistry
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OneꢀPot Asymmetric Synthesis of Alkylidene 1ꢀ
Alkylindanꢀ1ꢀols using Brønsted Acid and Palladium
Catalysis
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Réka J. Faggyas, Ewen D. D. Calder, Claire Wilson and Andrew Sutherland*
WestCHEM, School of Chemistry, The Joseph Black Building, University of Glasgow,
Glasgow G12 8QQ, United Kingdom.
Andrew.Sutherland@glasgow.ac.uk
RECEIVED DATE (to be automatically inserted after your manuscript is accepted if required
according to the journal that you are submitting your paper to)
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Table of Contents Graphic:
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O
B
O
Br
Br
O
(S)-3,3’-Br -BINOL
2
R1
(7.5 mol %)
OH
OH
R2
R1
then PdCl (PPh )
7.5 mol %), K CO3
2
3 2
(
OH
2
R2
up to 96:4 er
N H .H O
Br
2
4
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• selective formation of two C-C bonds • tertiary alcohol stereocenters
•
•
commercially available catalysts
scalable and practical procedure
• access to either enantiomer
• alkene for product elaboration
Abstract: A oneꢀpot catalytic enantioselective allylboration/MizorokiꢀHeck reaction of 2ꢀbromoaryl
ketones has been developed for the asymmetric synthesis of 3ꢀmethyleneindanes bearing a tertiary
alcohol center. Brønsted acid catalyzed allylboration with a chiral BINOL derivative was followed by a
palladiumꢀcatalyzed MizorokiꢀHeck cyclization, resulting in selective formation of the exoꢀalkene. This
novel protocol provides a concise and scalable approach to 1ꢀalkylꢀ3ꢀmethyleneindanꢀ1ꢀols in high
enantiomeric ratios (up to 96:4 er). The potential of these compounds as chiral building blocks was
demonstrated with efficient transformation to optically active diol and amino alcohol scaffolds.
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The Journal of Organic Chemistry
INTRODUCTION
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1
Chiral indanꢀ1ꢀols are an important structural motif, used as key intermediates for the synthesis of
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biologically active substances, including anistatin (1, Figure 1), a sesquiterpene toxin from the seeds of
3
the Japanese star anise and, dopamine reuptake blockers for the treatment of cocaine abuse. Chiral
indanꢀ1ꢀols are also found as core components of natural products, such as tripartin (2), a demethylase
0
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inhibitor, isolated from a Streptomyces species associated with dung beetle larva.
Figure 1. Structures of anistatin (1) and tripartin (2).
Due to their importance, a number of approaches have been developed for the preparation of chiral
1
indanꢀ1ꢀol derivatives. Recent efforts have focused on the synthesis of optically active alkylidene
indanꢀ1ꢀols bearing a secondary alcohol center. These have been prepared from benzaldehyde
derivatives using asymmetric allylation reactions followed by a metalꢀcatalyzed C–C bond forming
5
6
reaction. Oneꢀpot methods have also been reported. For example, the groups of Schmalz and
7
Fukuzawa described a oneꢀpot asymmetric synthesis of 3ꢀmethyleneindanꢀ1ꢀols from oꢀformylaryl
iodides and triflates by sequential Sakuraiꢀtype allylstannylation and MizorokiꢀHeck reaction in the
presence of chiral P,Pꢀligands (e.g. Scheme 1a). More recently, we reported the oneꢀpot synthesis of
optically active 3ꢀmethyleneindanꢀ1ꢀols from benzaldehydes using allyboration, catalyzed by a chiral
8
binaphthylꢀderived phosphoric acid, followed by a MizorokiꢀHeck reaction (Scheme 1b). This process
was found to be general for both electronꢀdeficient and electronꢀrich benzaldehydes, giving 3ꢀ
methyleneindanꢀ1ꢀols in excellent yields and high enantioselectivity.
While there are numerous methods for the synthesis of 3ꢀmethyleneindanꢀ1ꢀols from benzaldehydes,
the more challenging analogous synthesis of 3ꢀmethyleneindanꢀ1ꢀols with a tertiary alcohol center is
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lessꢀwell known. Only two general methods for the racemic synthesis of these compounds have been
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reported. A multistep approach has been described involving the preparation of allyl substituted tertiary
1
0
bromobenzyl alcohols, followed by a MizorokiꢀHeck reaction, while Grigg and coꢀworkers developed
a oneꢀpot synthesis of tertiaryꢀsubstituted 3ꢀmethyleneindanꢀ1ꢀols by the palladiumꢀcatalyzed reaction
1
1
of 2ꢀbromoaryl ketones with allene. There is only one example of an asymmetric synthesis of a 1ꢀ
alkylꢀ3ꢀmethyleneindanꢀ1ꢀol, described by Oestreich and coꢀworkers, who used a desymmetrizing
intramolecular MizorokiꢀHeck reaction of an orthoꢀtriflate derived diallylated benzyl alcohol (Scheme
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2,13
1c).
This gave the tertiaryꢀsubstituted 3ꢀmethyleneindanꢀ1ꢀol in 35% yield and 46% ee.
Scheme 1. Methods for the Asymmetric Synthesis of 3-Methyleneindan-1-ols
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Due to a lack of methods to access optically active 1ꢀalkylꢀ3ꢀmethyleneindanꢀ1ꢀols, we were
1
2
interested in developing a general and concise approach for the synthesis of these compounds from
readily available 2ꢀbromoaryl ketones. Herein, we now report the oneꢀpot synthesis of 1ꢀalkylꢀ3ꢀ
methyleneindanꢀ1ꢀols from 2ꢀbromoaryl ketones using a combination of an asymmetric allylboration,
followed by a MizorokiꢀHeck reaction (Scheme 1d). The ease of synthesis has also allowed the
investigation of these compounds as synthetic intermediates for the preparation of more functionalized
diol and amino alcoholꢀderived indane scaffolds.
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RESULTS AND DISCUSSION
1
4–19
There are relatively few methods for the efficient catalytic asymmetric allylation of aryl ketones
and thus, our initial studies began by screening various allylboronic esters and chiral Brønsted acids that
would allow the effective allylation of 2ꢀbromoaryl ketones. Crucially, conditions were required that
would be compatible with a MizorokiꢀHeck reaction. As we had previously shown that chiral
8
binaphthylꢀderived phosphoric acids could promote asymmetric allylation of 2ꢀbromobenzaldehydes,
these were initially investigated for the catalytic allylation of 2ꢀbromoacetophenone (3a) using
allylboronic acid pinacol ester (5) (Table 1). However, neither unsubstituted phosphoric acid 7 or
2
0
sterically congested (R)ꢀTRIPꢀPA 8 promoted allylation (entries 1 and 2). The 3,3’ꢀdibrominated (S)ꢀ
BINOL catalyst 9, developed by Schaus and coꢀworkers for asymmetric allylation of aryl ketones was
1
5b,c
next investigated.
using allyldioxaborinane 6 and tꢀBuOH as the solvent (entry 4). To achieve the same result in toluene
required for the oneꢀpot process), an increase in catalyst loading of 9 to 7.5 mol % was required (entry
While allylation with 5 showed no reaction (entry 3), a 21% yield was obtained
(
5). Further optimization, involving longer reaction times and an increase in temperature eventually
yielded the allylated product in quantitative yield (entry 7). Analysis of 4 by chiral HPLC indicated an
enantiomeric ratio (er) of 98:2.
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Table 1.
Asymmetric Allylation of 2-Bromoacetophenone (3a)
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
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7
8
9
0
1
2
3
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8
9
0
1
2
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4
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9
0
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5
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9
0
a
entry allylborane chiral ligand time (h) yield (%)
1
2
3
5
5
5
6
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6
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9
9
9
9
9
20
20
0
0
24
0
b
4
5
6
24
21
25
67
100
c
c
24
72
c,d
7
120
a
b
c
d
Isolated yield of 4. tꢀBuOH was used as the solvent. 7.5 mol % of 9 was used. Reaction temperature
was raised to 35 °C.
Conditions were then investigated for the oneꢀpot, twoꢀstep synthesis of (1S)ꢀ2,3ꢀdihydroꢀ1ꢀmethylꢀ3ꢀ
(methylene)indanꢀ1ꢀol (Sꢀ10a) from 2ꢀbromoacetophenone (3a) using the (S)ꢀ3,3’ꢀBr ꢀBINOL
2
catalyzed allylation, followed by a MizorokiꢀHeck reaction (Table 2). The first attempt involved the use
of Pd(PPh ) to catalyze the MizorokiꢀHeck reaction. While this gave indanol S-10a as the major
3 4
2
1
product, endoꢀalkene isomer S-11a was also formed (entry 1). An improvement in the overall yield of
the oneꢀpot, twoꢀstep process was achieved using PdCl (dppf), however, this resulted in a lower ratio of
2
S-10a and S-11a (entry 2). The most selective catalyst was found to be PdCl (PPh ) (entry 3). In
2
3 2
combination with the reductant hydrazine hydrate, this led to a 5:1 ratio of S-10a and S-11a,
respectively, in 90% overall yield. Analysis of the products by chiral HPLC showed a 96:4 er.
Purification by column chromatography allowed the isolation of S-10a in 75% overall yield.
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The Journal of Organic Chemistry
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Table 2.
Optimization of the One-Pot Procedure
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a
b
entry palladium catalyst time (h) yield (%) S-10a:S-11a
1
2
Pd(PPh3)4
24
24
18
57
77
90
2:1
1.5:1
5:1
PdCl (dppf)
2
c
3
PdCl (PPh )
2
3 2
a
b
1
Combined yield of S-10a and S-11a. Ratio determined by analysis of H NMR spectrum of crude
c
reaction mixture. N H .H O (0.4 equiv) was added with Pd cat.
2
4
2
Following optimization of the oneꢀpot process for the preparation of indanol S-10a, we wanted to
explore the scope of the oneꢀpot method with a range of 2ꢀbromoaryl ketones. These were prepared in a
straightforward manner from commercially available 2ꢀbromobenzaldehydes (Scheme 2). Addition of a
Grignard reagent gave the corresponding secondary alcohols that were then oxidized to the 2ꢀbromoaryl
ketones using either manganese oxide or a PDC/silica mixture. This allowed the scalable synthesis of a
wide range of 2ꢀbromoaryl ketones in good yields over the two steps. An additional substrate bearing a
22
5
ꢀnitro group (3g) was prepared in 54% yield by direct nitration of 2ꢀbromoacetophenone (3a).
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a
Scheme 2. Synthesis of 2-Bromoaryl Ketones
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9
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Isolated yields are shown. PDC was used to prepare ketone 3h.
Having produced a series of 2ꢀbromoaryl ketones, these were then applied to the oneꢀpot allylboration
and MizorokiꢀHeck process (Scheme 3). Initially, we wanted to demonstrate that either indanol
enantiomer could be prepared using either (S)ꢀ or (R)ꢀ3,3’ꢀBr ꢀBINOL. Therefore, the oneꢀpot process
2
with 2ꢀbromoacetophenone (3a) was repeated using (R)ꢀ3,3’ꢀBr ꢀBINOL. As expected, this gave similar
2
results, with indanol R-10a produced with a 96:4 er and isolated in 70% overall yield. 2ꢀBromoaryl
methyl ketones with various aryl substituents were then subjected to the oneꢀpot process using (S)ꢀ3,3’ꢀ
Br ꢀBINOL. Substrates with electronꢀrich aryl substituents gave the two isomeric indanols in high yields
2
over the twoꢀsteps, with the major (1S)ꢀ3ꢀmethyleneindanols 10a–10c produced with high er (from
89.5:10.5 to 96:4) and easily isolated in good yields (61–75%). The exception to these general results
was observed for methoxyꢀderived indanols 10d/11d. While the (1S)ꢀ3ꢀmethyleneindanol 10d was
formed with high er and isolated in a reasonable 47% overall yield, a modest 2:1 ratio of alkene isomers
was generated from the oneꢀpot process. In this case, we believe the methoxy substituent facilitates
isomerization in the presence of the Pd(0)ꢀcatalyst following completion of the MizorokiꢀHeck reaction.
It should be noted that other studies which have prepared electronꢀrich, racemic 1ꢀalkylꢀ3ꢀ
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methyleneindanꢀ1ꢀols by a single step MizorokiꢀHeck reactions have been complicated by the formation
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9
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of an indene byꢀproduct, formed via dehydration. In this study, using the asymmetric oneꢀpot process,
no dehydration was observed with analogous substrates (e.g. 3c). Electronꢀdeficient 2ꢀbromoaryl
ketones were then investigated and also found to be substrates for this process. While halogenated
analogues 10e and 10f were formed with high er and isolated in good overall yields, the nitroꢀ
substituted (1S)ꢀ3ꢀmethyleneindanol 10g was formed in only 19% yield, demonstrating a limitation of
this approach. Interestingly, pyridine analogue 11h was isolated solely as the endoꢀalkene isomer, in
63% yield. In this case, isomerization of the exoꢀalkene is likely facilitated by coordination of the Pd(0)ꢀ
catalyst with the adjacent nitrogen atom. This study also briefly investigated the scope of the ketone
sideꢀchain. Use of the oneꢀpot process with 2ꢀbromoaryl ethyl ketone 3i gave a high overall yield of the
indanol products with (1S)ꢀ3ꢀmethyleneindanol 10i produced with 94:6 er and isolated in 59% yield.
However, increasing the bulk of the sideꢀchain with an isopropyl group (3j) completely inhibited the
0
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allylation step. While (S)ꢀ3,3’ꢀBr ꢀBINOLꢀcatalyzed allylations have been performed with a range of
2
1
5b,c
alkylꢀsubstituted aryl ketones,
compounds with both a bulky alkyl group and a 2ꢀbromoaryl
substituent are not substrates for this reaction.
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a
Scheme 3. Scope of the One-Pot Two-Step Process
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9
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a
1
Ratio of isomers 10 and 11 determined by analysis of H NMR spectrum of crude reaction mixture.
b
Enantiomeric ratio determined by chiral HPLC. The oneꢀpot process was performed using (R)ꢀ3,3’ꢀBr ꢀ
2
BINOL.
In the next stage of this project, we wanted to demonstrate that the optically active 1ꢀalkylꢀ3ꢀ
methyleneindanols that can now be accessed using our concise oneꢀpot approach, could be further
functionalized to generate chiral synthetic building blocks. In a preliminary study, we have shown that
the methylene unit of the indanols can be used to incorporate a second stereogenic center through an
oxidation and reduction sequence (Scheme 4). Initially, multigram quantities of S-10a were produced
by scaleꢀup of the oneꢀpot process. During these reactions it was found that the catalyst loading of both
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(
S)ꢀ3,3’ꢀBr ꢀBINOL 9 and PdCl (PPh ) could be lowered to 5 mol %, while still maintaining er (96:4)
2 2 3 2
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
and high yield (72%) of S-10a. Ozonolysis of S-10a under standard conditions gave indanone 14 in
81% yield. Indanone 14 is a structural analogue of tripartin (2, Figure 1), a natural product from bacteria
4
associated with the dung beetle Copris tripartitus. Various borohydride reagents were next investigated
for reduction of 14. The most selective was sodium triacetoxyborohydride and while the use of this
required a prolonged reaction time, diol 15 was isolated as a single diastereomer in 75% yield. The
highly selective nature of sodium triacetoxyborohydride was used for reductive amination of indanone
14. With various amines this gave the corresponding 3ꢀaminoindanols 16a–d as single diastereomers in
high yields (78–84%). It was proposed that reduction of indanone 14 and the corresponding imines was
achieved via a directed mechanism, involving coordination of the reducing agent to the 1ꢀhydroxyl
group, followed by reduction of the same face of the ketone/imine. This was confirmed by Xꢀray
crystallographic analysis of diol 15 and morpholine derivative 16d, which clearly show the antiꢀ
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
3
relationship of the Cꢀ1 hydroxyl and Cꢀ3 hydroxyl/amine groups.
a
Scheme 4. Synthesis of 3-Hydroxy and 3-Aminoindanols
a
Isolated yields are shown.
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CONCLUSIONS
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
In summary, a oneꢀpot asymmetric allylboration and MizorokiꢀHeck reaction of 2ꢀbromoaryl ketones
has been developed for the concise synthesis of optically active 1ꢀalkylꢀ3ꢀmethyleneindanes bearing a
tertiary alcohol center. As well as generating these compounds with high enantiomeric ratios, the
method is scalable and can be used to access either enantiomer. Now that a general procedure for the
preparation of these compounds has been established, the synthetic utility of these highly functional
scaffolds can be realized. We have shown that these compounds can be readily converted to hydroxyl
and amine chiral building blocks in a highly diastereoselective manner. Investigation of further
applications of these chiral 3ꢀmethyleneindanes is currently underway.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
EXPERIMENTAL SECTION
All reagents and starting materials were obtained from commercial sources and used as received. All
dry solvents were purified using a solvent purification system. All reactions were performed in ovenꢀ
dried glassware under an atmosphere of argon unless otherwise stated. Brine refers to a saturated
solution of sodium chloride. Flash column chromatography was performed using silica gel 60 (40–63
ꢀm). Aluminiumꢀbacked plates preꢀcoated with silica gel 60F254 were used for thin layer
1
chromatography and were visualized with a UV lamp or by staining with potassium permanganate. H
NMR spectra were recorded on a NMR spectrometer at either 400 or 500 MHz and data are reported as
follows: chemical shift in ppm relative to tetramethylsilane or the solvent as the internal standard
(
CDCl , δ 7.26 ppm or CD OD, δ 3.31 ppm), multiplicity (s = singlet, d = doublet, t = triplet, q =
3
3
1
3
quartet, m = multiplet or overlap of nonequivalent resonances, integration). C NMR spectra were
recorded on a NMR spectrometer at either 101 or 126 MHz and data are reported as follows: chemical
shift in ppm relative to tetramethylsilane or the solvent as internal standard (CDCl , δ 77.0 ppm or
3
CD OD, δ 49.0 ppm), multiplicity with respect to hydrogen (deduced from DEPT experiments, C, CH,
3
–
1
CH or CH ). IR spectra were recorded on a FTIR spectrometer; wavenumbers are indicated in cm .
2
3
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Mass spectra were recorded using electron impact, chemical ionization or electrospray techniques.
HRMS spectra were recorded using a dualꢀfocusing magnetic analyzer mass spectrometer. Melting
points are uncorrected. Optical rotations were determined as solutions irradiating with the sodium D line
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
−1
2
−1
(
λ = 589 nm) using a polarimeter. [α] values are given in units 10 deg cm g . Chiral HPLC methods
D
were calibrated with the corresponding racemic mixtures.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
General procedure for the synthesis of secondary alcohols (13). To a stirred solution of a 2ꢀ
bromobenzaldehyde (1 equiv.) in dry diethyl ether (2 mL/mmol) at ‒78 °C, under an argon atmosphere
was added dropwise, a solution of methylmagnesium bromide (1 M in dibutyl ether, 2 equiv.),
ethylmagnesium bromide (1 M in THF, 2 equiv.) or isopropylmagnesium bromide (1 M in THF, 2
equiv.). After addition, the reaction mixture was allowed to warm to 0 °C and stirred for 3 h. The
reaction mixture was then quenched with a saturated solution of aqueous ammonium chloride (10‒15
mL/mmol). The product was extracted using diethyl ether (3 × 20 mL/mmol). The combined organic
layers were washed with brine (2 × 20 mL/mmol), dried over MgSO , filtered and concentrated in
4
vacuo. Purification of the crude material using silica gel flash column chromatography, eluting with
diethyl ether in petroleum ether gave the secondary alcohols.
1
-(2’-Bromo-4’-methylphenyl)ethan-1-ol (13b). The reaction was performed according to the
general procedure using 2ꢀbromoꢀ4ꢀmethylbenzaldehyde (12b) (0.40 g, 2.0 mmol) and
methylmagnesium bromide solution (4.0 mL, 4.0 mmol). Purification by flash column chromatography,
eluting with 10% diethyl ether in petroleum ether (40–60) gave 1ꢀ(2’ꢀbromoꢀ4’ꢀmethylphenyl)ethanꢀ1ꢀ
−
1 1
ol (13b) (0.42 g, 98%) as a colorless oil. IR (neat) 3335, 2974, 1609, 1488 cm ; H NMR (400 MHz,
CDCl3) 1.47 (d, J = 6.5 Hz, 3H), 1.95 (d, J = 3.5 Hz, 1H), 2.31 (s, 3H), 5.21 (qd, J = 6.5, 3.5 Hz, 1H),
δ
13
7
.15 (br d, J = 8.0 Hz, 1H), 7.35 (br d, J = 0.9 Hz, 1H), 7.46 (d, J = 8.0 Hz, 1H); C NMR (101 MHz,
CDCl3)
δ 20.7 (CH ), 23.6 (CH ), 69.0 (CH), 121.6 (C), 126.4 (CH), 128.7 (CH), 133.1 (CH), 138.9
3 3
+
79
11
+
(C), 141.5 (C); MS (ESI) m/z 237 (MNa , 100); HRMS (ESI) calcd for C H BrNaO (MNa ),
9
2
36.9885, found 236.9882.
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2
4
1
-(2’-Bromo-4’,5’-methylenedioxyphenyl)ethan-1-ol (13c). The reaction was performed according
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
to the general procedure using 2ꢀbromoꢀ4,5ꢀmethylenedioxybenzaldehyde (12c) (0.69 g, 3.0 mmol) and
methylmagnesium bromide solution (6.0 mL, 6.0 mmol). Purification by flash column chromatography,
eluting with 10% diethyl ether in petroleum ether (40–60) gave 1ꢀ(2’ꢀbromoꢀ4’,5’ꢀ
methylenedioxyphenyl)ethanꢀ1ꢀol (13c) (0.63 g, 86%) as a colorless oil which solidified upon standing
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
4
1
to give a white solid. Mp 51–53 °C (lit. 52–53 °C); H NMR (400 MHz, CDCl )
δ
1.43 (d, J = 6.4 Hz,
3
3
H), 1.87 (d, J = 3.3 Hz, 1H), 5.18 (qd, J = 6.4, 3.3 Hz, 1H), 5.97 (d, J = 1.6 Hz, 1H), 5.98 (d, J = 1.6
1
3
Hz, 1H), 6.96 (s, 1H), 7.09 (s, 1H); C NMR (101 MHz, CDCl ) δ 23.6 (CH ), 69.1 (CH), 101.7 (CH ),
3 2
3
+
1
06.6 (CH), 111.8 (C), 112.4 (CH), 138.1 (C), 147.4 (C), 147.8 (C); MS (ESI) m/z 269 (MNa , 100),
267 (98).
1
0
1
-(2’-Bromo-5’-methoxyphenyl)ethan-1-ol (13d). The reaction was performed according to the
general procedure using 2ꢀbromoꢀ5ꢀmethoxybenzaldehyde (12d) (0.44 g, 3.0 mmol) and
methylmagnesium bromide solution (6.0 mL, 6.0 mmol). Purification by flash column chromatography,
eluting with 10% diethyl ether in petroleum ether (40–60) gave 1ꢀ(2’ꢀbromoꢀ5’ꢀmethoxyphenyl)ethanꢀ1ꢀ
1
0 1
ol (13d) (0.63 g, 90%) as a colorless oil. Spectroscopic data were consistent with the literature.
H
NMR (400 MHz, CDCl3)
δ
1.47 (d, J = 6.4 Hz, 3H), 1.96 (d, J = 3.4 Hz, 1H), 3.81 (s, 3H), 5.19 (qd, J =
13
6
.4, 3.4 Hz, 1H), 6.69 (dd, J = 8.8, 3.1 Hz, 1H), 7.16 (d, J = 3.1 Hz, 1H), 7.39 (d, J = 8.8 Hz, 1H); C
NMR (101 MHz, CDCl3)
δ 23.6 (CH ), 55.5 (CH ), 69.2 (CH), 111.8 (C), 112.0 (CH), 114.7 (CH),
3 3
+
1
33.2 (CH), 145.8 (C), 159.4 (C); MS (EI) m/z 232 (M , 39), 230 (40).
1
-(2’-Bromo-5’-fluorophenyl)ethan-1-ol (13e). The reaction was performed according to the
general procedure using 2ꢀbromoꢀ5ꢀfluorobenzaldehyde (12e) (0.61 g, 3.0 mmol) and methylmagnesium
bromide solution (6.0 mL, 6.0 mmol). Purification by flash column chromatography, eluting with 10%
diethyl ether in petroleum ether (40–60) gave 1ꢀ(2’ꢀbromoꢀ5’ꢀfluorophenyl)ethanꢀ1ꢀol (13e) (0.58 g,
−
1 1
8
8%) as a colorless oil. IR (neat) 3323, 2974, 1580, 1465 cm ; H NMR (400 MHz, CDCl )
δ
1.47 (d, J
3
=
6.4 Hz, 3H), 2.05 (d, J = 3.5 Hz, 1H), 5.14–5.23 (m, 1H), 6.86 (ddd, J = 8.6, 8.0, 3.2 Hz, 1H), 7.34
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1
3
(
dd, J = 9.8, 3.2 Hz, 1H), 7.46 (dd, J = 8.6, 5.2 Hz, 1H); C NMR (101 MHz, CDCl )
δ
23.5 (CH3),
3
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
2
2
3
69.1 (CH), 114.0 (d, J = 24.0 Hz, CH), 115.3 (C), 115.9 (d, J = 22.8 Hz, CH), 133.8 (d, J = 7.8
CꢀF
CꢀF
CꢀF
3
1
+
Hz, CH), 147.0 (d, J = 6.7 Hz, C), 162.5 (d, J = 247.2 Hz, C); MS (EI) m/z 218 (M , 38), 205
CꢀF
CꢀF
79
+
(
82), 203 (100), 175 (16), 152 (38), 123 (11), 96 (60); HRMS (EI) calcd for C H BrFO (M ),
8 8
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
217.9743, found 217.9731.
1
-(2’-Bromo-5’-chlorophenyl)ethan-1-ol (13f). The reaction was performed according to the
general procedure using 2ꢀbromoꢀ5ꢀchlorobenzaldehyde (12f) (0.66 g, 3.0 mmol) and methylmagnesium
bromide solution (6.0 mL, 6.0 mmol). Purification by flash column chromatography, eluting with 10%
diethyl ether in petroleum ether (40–60) gave 1ꢀ(2’ꢀbromoꢀ5’ꢀchlorophenyl)ethanꢀ1ꢀol (13f) (0.68 g,
−
1 1
9
6%) as a colorless oil. IR (neat) 3336, 2976, 1449 cm ; H NMR (400 MHz, CDCl )
δ
1.47 (d, J = 6.4
3
Hz, 3H), 2.01 (d, J = 3.7 Hz, 1H), 5.18 (qd, J = 6.4, 3.7 Hz, 1H), 7.11 (dd, J = 8.4, 2.6 Hz, 1H), 7.43 (d,
13
J = 8.4 Hz, 1H), 7.60 (d, J = 2.6 Hz, 1H); C NMR (101 MHz, CDCl )
δ
23.6 (CH ), 69.0 (CH), 119.2
3
3
+
(C), 127.0 (CH), 128.8 (CH), 133.7 (CH), 134.1 (C), 146.5 (C); MS (EI) m/z 236 (M , 38), 234 (29),
81 35
+
2
23 (24), 221 (100), 219 (81), 112 (56), 75 (27); HRMS (EI) calcd for C H Br ClO (M ), 235.9425,
8 8
found 235.9430.
1-(2’-Bromo-3’-pyridyl)ethan-1-ol (13h). The reaction was performed according to the general
procedure using 2ꢀbromopyridineꢀ3ꢀcarboxaldehyde (12h) (1.00 g, 5.40 mmol) and methylmagnesium
bromide solution (11.0 mL, 10.8 mmol). Purification by flash column chromatography, eluting with
10% diethyl ether in petroleum ether (40–60) gave 1ꢀ(2’ꢀbromoꢀ3’ꢀpyridyl)ethanꢀ1ꢀol (13h) (0.94 g,
−1
1
8
7%) as a yellow oil. IR (neat) 3410, 2932, 1651, 1389 cm ; H NMR (400 MHz, CDCl ) δ 1.47 (d, J =
3
6.4 Hz, 3H), 3.76 (br s, 1H), 5.12–5.20 (m, 1H), 7.28 (dd, J = 7.6, 4.8 Hz, 1H), 7.93 (dd, J = 7.6, 2.0 Hz,
13
1
H), 8.16 (dd, J = 4.8, 2.0 Hz, 1H); C NMR (101 MHz, CDCl )
δ
23.7 (CH ), 67.9 (CH), 123.4 (CH),
3
3
+
135.8 (CH), 140.9 (C), 142.6 (C), 148.4 (CH); MS (ESI) m/z 224 (MNa , 98); HRMS (ESI) calcd for
79
8
+
C H BrNNaO (MNa ), 223.9681, found 223.9674.
7
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25
1
-(2’-Bromophenyl)propan-1-ol (13i). The reaction was performed according to the general
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
procedure using 2ꢀbromobenzaldehyde (12a) (1.0 mL, 8.0 mmol) and ethylmagnesium bromide solution
(16 mL, 16 mmol). Purification by flash column chromatography, eluting with 10% diethyl ether in
petroleum ether (40–60) gave 1ꢀ(2’ꢀbromophenyl)propanꢀ1ꢀol (13i) (1.40 g, 81%) as a colorless oil.
2
5 1
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Spectroscopic data were consistent with the literature. H NMR (400 MHz, CDCl3)
δ
1.01 (td, J = 7.4,
0
1
.8 Hz, 3H), 1.65–1.90 (m, 2H), 1.95–2.05 (m, 1H), 5.01 (dt, J = 8.0, 4.0 Hz, 1H), 7.12 (br t, J = 7.5 Hz,
1
3
H), 7.33 (br t, J = 7.5 Hz, 1H), 7.49–7.56 (m, 1H); C NMR (101 MHz, CDCl )
δ 10.1 (CH ), 30.6
3
3
(
CH ), 74.2 (CH), 122.2 (C), 127.4 (CH), 127.6 (CH), 128.7 (CH), 132.6 (CH), 143.6 (C); MS (ESI) m/z
2
+
2
39 (MNa , 95), 237 (100).
2
6
1
-(2’-Bromophenyl)-2-methylpropan-1-ol (13j). The reaction was performed according to the
general procedure using 2ꢀbromobenzaldehyde (12a) (1.0 mL, 8.0 mmol) and isopropylmagnesium
bromide solution (16 mL, 16 mmol). Purification by flash column chromatography, eluting with 10%
diethyl ether in petroleum ether (40–60) gave 1ꢀ(2’ꢀbromophenyl)ꢀ2ꢀmethylpropanꢀ1ꢀol (13j) (0.91 g,
2
6 1
5
7%) as a colorless oil. Spectroscopic data were consistent with the literature. H NMR (400 MHz,
CDCl3) 0.95 (d, J = 6.8 Hz, 3H), 0.97 (d, J = 6.8 Hz, 3H), 1.85 (br s, 1H), 2.00–2.14 (m, 1H), 4.86 (d,
J = 6.0 Hz, 1H), 7.09–7.15 (m, 1H), 7.29–7.36 (m, 1H), 7.50 (td, J = 7.6, 1.6 Hz, 2H); C NMR (101
MHz, CDCl3) 16.8 (CH ), 19.5 (CH ), 34.0 (CH), 77.6 (CH), 122.7 (C), 127.4 (CH), 128.3 (CH),
128.6 (CH), 132.6 (CH), 142.9 (C); MS (EI) m/z 230 (M , 8), 228 (10), 187 (81), 185 (100), 172 (17),
δ
1
3
δ
3
3
+
1
57 (9), 105 (9), 84 (23), 77 (43).
General procedure A for oxidation to 2-bromoaryl ketones (3). To a stirred solution of a
secondary alcohol (1 equiv.) in chloroform (3 mL/mmol) at room temperature was added
manganese(IV) oxide (10 equiv.). The reaction mixture was stirred for 18 h under reflux. After cooling
to room temperature, the mixture was filtered through a pad of Celite®, which was washed with diethyl
ether (2 × 15 mL/mmol). The filtrate was then concentrated. The crude product was purified using silica
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gel flash column chromatography, eluting with diethyl ether in petroleum ether to give the
corresponding ketone derivatives.
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
General procedure B for oxidation to 2-bromoaryl ketones (3). To a stirred solution of a
secondary alcohol (1 equiv.) in dichloromethane (5 mL/mmol) at room temperature was added a
homogeneous mixture of PCC and silica gel (1:1 by mass) (3 equiv.). The resulting suspension was
stirred for 2 h. The mixture was filtered through a pad of silica gel, which was washed with
dichloromethane (2 × 30 mL/mmol). The filtrate was then concentrated. The crude product was purified
using silica gel flash column chromatography, eluting with diethyl ether in petroleum ether to give the
corresponding ketone derivatives.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
27
1
-(2’-Bromo-4’-methylphenyl)ethan-1-one (3b). The reaction was performed according to
general procedure A using 1ꢀ(2’ꢀbromoꢀ4’ꢀmethylphenyl)ethanꢀ1ꢀol (13b) (0.42 g, 2.0 mmol).
Purification by flash column chromatography, eluting with 10% diethyl ether in petroleum ether (40–60)
gave 1ꢀ(2’ꢀbromoꢀ4’ꢀmethylphenyl)ethanꢀ1ꢀone (3b) (0.33 g, 79%) as a yellow oil. Spectroscopic data
2
7 1
were consistent with the literature. H NMR (400 MHz, CDCl3)
δ
2.36 (s, 3H), 2.62 (s, 3H), 7.17 (dd,
13
J = 8.0, 0.8 Hz, 1H), 7.43 (d, J = 8.0 Hz, 1H), 7.45 (d, J = 0.8 Hz, 1H); C NMR (101 MHz, CDCl )
δ
3
2
1.0 (CH ), 30.2 (CH ), 119.3 (C), 128.2 (CH), 129.4 (CH), 134.5 (CH), 138.1 (C), 142.9 (C), 200.7
3 3
+
(
C); MS (CI) m/z 215 (MH , 48), 213 (51), 136 (100), 71 (33), 69 (35).
28
1
-(2’-Bromo-4’,5’-methylenedioxyphenyl)ethan-1-one (3c).
The reaction was performed
according to general procedure B using 1ꢀ(2’ꢀbromoꢀ4’,5’ꢀmethylenedioxyphenyl)ethanꢀ1ꢀol (13c) (0.50
g, 2.0 mmol). Purification by flash column chromatography, eluting with 10% diethyl ether in petroleum
ether (40–60) gave 1ꢀ(2’ꢀbromoꢀ4’,5’ꢀmethylenedioxyphenyl)ethanꢀ1ꢀone (3c) (0.39 g, 79%) as a
2
8 1
colorless oil. Spectroscopic data were consistent with the literature. H NMR (400 MHz, CDCl3)
δ
13
2
.61 (s, 3H), 6.04 (s, 2H), 7.03 (s, 1H), 7.05 (s, 1H); C NMR (101 MHz, CDCl )
δ
30.3 (CH ), 102.5
3
3
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(
CH ), 109.3 (CH), 112.0 (C), 113.9 (CH), 134.3 (C), 147.4 (C), 150.4 (C), 199.5 (C); MS (ESI) m/z
2
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
+
2
67 (MNa , 100), 265 (99).
1
0
1-(2’-Bromo-5’-methoxyphenyl)ethan-1-one (3d). The reaction was performed according to
general procedure A using 1ꢀ(2’ꢀbromoꢀ5’ꢀmethoxyphenyl)ethanꢀ1ꢀol (13d) (0.62 g, 2.7 mmol).
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Purification by flash column chromatography, eluting with 10% diethyl ether in petroleum ether (40–60)
gave 1ꢀ(2’ꢀbromoꢀ5’ꢀmethoxyphenyl)ethanꢀ1ꢀone (3d) (0.46 g, 74%) as a colorless oil. Spectroscopic
10 1
data were consistent with the literature. H NMR (400 MHz, CDCl3)
δ 2.63 (s, 3H), 3.81 (s, 3H), 6.85
1
3
(dd, J = 8.8, 3.1 Hz, 1H), 6.98 (d, J = 3.1 Hz, 1H), 7.48 (d, J = 8.8 Hz, 1H); C NMR (101 MHz,
CDCl3) 30.3 (CH ), 55.6 (CH ), 109.1 (C), 114.2 (CH), 117.9 (CH), 134.6 (CH), 142.3 (C), 158.9 (C),
01.3 (C); MS (EI) m/z 230 (M , 54), 228 (55), 215 (99), 213 (100), 187 (17), 185 (17), 172 (14), 157
15), 78 (18), 63 (35).
δ
3
3
+
2
(
10
1
-(2’-Bromo-5’-fluorophenyl)ethan-1-one (3e). The reaction was performed according to general
procedure A using 1ꢀ(2’ꢀbromoꢀ5’ꢀfluorophenyl)ethanꢀ1ꢀol (13e) (0.55 g, 2.5 mmol). Purification by
flash column chromatography, eluting with 10% diethyl ether in petroleum ether (40–60) gave 1ꢀ(2’ꢀ
bromoꢀ5’ꢀfluorophenyl)ethanꢀ1ꢀone (3e) (0.40 g, 74%) as a colorless oil. Spectroscopic data were
1
0 1
consistent with the literature. H NMR (400 MHz, CDCl3)
δ
2.64 (s, 3H), 7.04 (ddd, J = 8.8, 7.6, 3.1
13
Hz, 1H), 7.18 (dd, J = 8.4, 3.1 Hz, 1H), 7.58 (dd, J = 8.8, 4.9 Hz, 1H); C NMR (101 MHz, CDCl )
δ
3
4
2
2
30.1 (CH ), 113.1 (d, J = 3.2 Hz, C), 116.1 (d, J = 24.1 Hz, CH), 119.1 (d, J = 22.5 Hz, CH),
3
CꢀF
CꢀF
CꢀF
3
3
1
1
35.4 (d, J = 7.8 Hz, CH), 142.9 (d, J = 5.8 Hz, C), 161.4 (d, J = 250.3 Hz, C), 199.9 (C); MS
CꢀF CꢀF CꢀF
+
(EI) m/z 218 (M , 35), 216 (36), 203 (98), 201 (100), 175 (33), 173 (34), 94 (58), 86 (38), 84 (60).
2
4
1
-(2’-Bromo-5’-chlorophenyl)ethan-1-one (3f). The reaction was performed according to general
procedure A using 1ꢀ(2’ꢀbromoꢀ5’ꢀchlorophenyl)ethanꢀ1ꢀol (13f) (0.43 g, 1.8 mmol). Purification by
flash column chromatography, eluting with 10% diethyl ether in petroleum ether (40–60) gave 1ꢀ(2’ꢀ
bromoꢀ5’ꢀchlorophenyl)ethanꢀ1ꢀone (3f) (0.33 g, 78%) as a yellow oil. Spectroscopic data were
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2
4 1
consistent with the literature. H NMR (400 MHz, CDCl3)
δ 2.63 (s, 3H), 7.28 (dd, J = 8.5, 2.5 Hz,
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
3
1H), 7.43 (d, J = 2.5 Hz, 1H), 7.55 (d, J = 8.5 Hz, 1H); C NMR (101 MHz, CDCl )
δ
30.2 (CH3),
3
+
1
16.8 (C), 128.9 (CH), 131.8 (CH), 133.8 (C), 135.0 (CH), 142.7 (C), 199.9 (C); MS (EI) m/z 234 (M ,
4
5), 232 (33), 219 (100), 217 (77), 191 (39), 189 (24), 110 (16), 84 (12), 75 (33).
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1-(2’-Bromo-3’-pyridyl)ethan-1-one (3h). To a stirred solution of 1ꢀ(2’ꢀbromoꢀ3’ꢀpyridyl)ethanꢀ1ꢀ
ol (13h) (0.940 g, 4.70 mmol) in DMF (5 mL) at room temperature was added a solution of PDC (2.65
g, 7.05 mmol) in DMF (5 mL). The resulting suspension was stirred for 18 h then filtered through a pad
of Celite®, washed with diethyl ether (2 × 30 mL) and concentrated in vacuo. The crude product was
then purified using silica gel flash column chromatography, eluting with 10% diethyl ether in petroleum
ether (40–60) to give 1ꢀ(2’ꢀbromoꢀ3’ꢀpyridyl)ethanꢀ1ꢀone (3h) (0.69 g, 74%) as a yellow oil. IR (neat)
−
1 1
1
697, 1566, 1389, 1273 cm ; H NMR (400 MHz, CDCl ) δ 2.68 (s, 3H), 7.36 (dd, J = 7.6, 4.7 Hz,
3
13
1
H), 7.75 (dd, J = 7.6, 2.0 Hz, 1H), 8.45 (dd, J = 4.7, 2.0 Hz, 1H); C NMR (101 MHz, CDCl )
δ
30.3
3
+
(
CH ), 122.7 (CH), 137.4 (CH), 138.1 (C), 138.5 (C), 151.4 (CH), 199.8 (C); MS (ESI) m/z 200 (MH ,
3
79
+
1
00); HRMS (ESI) calcd for C H BrNO (MH ), 199.9706, found 199.9710.
7 7
2
5
2
’-Bromopropiophenone (3i). The reaction was performed according to general procedure B using
1
ꢀ(2’ꢀbromophenyl)propanꢀ1ꢀol (13i) (1.30 g, 6.00 mmol). Purification by flash column
chromatography, eluting with 10% diethyl ether in petroleum ether (40–60) gave 2’ꢀ
bromopropiophenone (3i) (1.15 g, 90%) as a yellow oil. Spectroscopic data were consistent with the
25
literature. δ (400 MHz, CDCl )
δ 1.21 (t, J = 7.2 Hz, 3H), 2.93 (q, J = 7.2 Hz, 2H), 7.25–7.31 (m,
H
3
13
1H), 7.33–7.39 (m, 2H), 7.57–7.62 (m, 1H); C NMR (101 MHz, CDCl )
δ 8.1 (CH ), 36.1 (CH ),
3 2
3
1
18.5 (C), 127.4 (CH), 128.2 (CH), 131.3 (CH), 133.6 (CH), 142.0 (C), 205.1 (C); MS (ESI) m/z 237
+
(
MNa , 98) 235 (100).
2
6
1-(2’-Bromophenyl)-2-methylpropan-1-one (3j). The reaction was performed according to
general procedure B using 1ꢀ(2’ꢀbromophenyl)ꢀ2ꢀmethylpropanꢀ1ꢀol (13j) (0.90 g, 3.9 mmol).
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Purification by flash column chromatography, eluting with 10% diethyl ether in petroleum ether (40–60)
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
gave 1ꢀ(2’ꢀbromophenyl)ꢀ2ꢀmethylpropanꢀ1ꢀone (3j) (0.73 g, 83%) as a yellow oil. Spectroscopic data
2
6 1
were consistent with the literature. H NMR (400 MHz, CDCl3)
δ 1.20 (d, J = 7.0 Hz, 6H), 3.32 (sept,
1
3
J = 7.0 Hz, 1H), 7.25–7.31 (m, 2H), 7.33–7.39 (m, 1H), 7.57–7.62 (m, 1H); C NMR (101 MHz,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
CDCl3)
δ
18.1 (2 × CH ), 40.2 (CH), 118.7 (C), 127.2 (CH), 128.1 (CH), 131.0 (CH), 133.4 (CH), 142.1
3
+
(
C), 208.7 (C); MS (ESI) m/z 251 (MNa , 98) 249 (100).
2
2
1
-(2’-Bromo-5’-nitrophenyl)ethan-1-one (3g). 1ꢀ(2’ꢀBromophenyl)ethanꢀ1ꢀone (3a) (0.54 mL,
4.0 mmol) was added to a solution of potassium nitrate (0.50 g, 5.0 mmol) in concentrated sulfuric acid
4 mL) at 0 °C. The reaction mixture was then allowed to warm to room temperature and was stirred for
.5 h. The mixture was quenched with water (5 mL) and extracted with dichloromethane (2 × 15 mL),
(
1
dried over MgSO , filtered and concentrated in vacuo. Purification by silica gel flash chromatography,
4
eluting with 10% diethyl ether in petroleum ether (40–60) yielded 1ꢀ(2’ꢀbromoꢀ5’ꢀnitrophenyl)ethanꢀ1ꢀ
22
1
one (3g) (0.53 g, 54%) as a white powder. Mp 86–87 °C (lit. 85–87 °C); H NMR (400 MHz, CDCl )
3
13
δ
2.69 (s, 3H), 7.83 (d, J = 8.7 Hz, 1H), 8.15 (dd, J = 8.7, 2.7 Hz, 1H), 8.31 (d, J = 2.7 Hz, 1H); C
NMR (101 MHz, CDCl3)
δ
30.1 (CH ), 123.8 (CH), 125.9 (CH), 126.2 (C), 135.2 (CH), 142.4 (C),
3
+
1
47.1 (C), 198.7 (C); MS (EI) m/z 245 (M , 27), 243 (27), 230 (100), 182 (22), 151 (28), 105 (17), 75
(44).
1
5c
B-Allyl-1,3,2-dioxaborinane (6). Trimethylborate (5.6 mL, 50 mmol) was dissolved in dry diethyl
ether (50 mL) under an argon atmosphere and cooled to –78 °C. Allylmagnesium bromide solution (50
mL, 1 M in diethyl ether) was added dropwise over 0.5 h. After addition, the reaction mixture was
stirred for 2 h at –78 °C, then acidified at 0 °C with a 3 M aqueous solution of hydrochloric acid (60
mL). The organic phase was separated and the aqueous layer was extracted with diethyl ether (3 × 50
mL). The combined organic layers were dried over MgSO , filtered and concentrated in vacuo to
4
approximately 100 mL. To this solution was added 1,3ꢀpropanediol (3.6 mL, 50 mmol) as well as oven
dried 4Å molecular sieves (10 g) and the resulting mixture was stirred for 16 h at room temperature. The
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The Journal of Organic Chemistry
molecular sieves were filtered and washed with diethyl ether (2 × 50 mL). The solvent was removed in
vacuo, and the crude product was then dissolved in nꢀpentane (100 mL). The resulting cloudy
suspension was filtered through a pad of Celite®, washed and concentrated in vacuo. Purification by
silica gel flash chromatography, eluting with 35% diethyl ether in nꢀpentane gave a pale yellow oil.
Further purification by shortꢀpath Kugelrohr distillation gave Bꢀallylꢀ1,3,2ꢀdioxaborinane (6) (4.0 g,
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
5c 1
6
3%) as a colorless oil. Spectroscopic data were consistent with the literature.
H NMR (400 MHz,
CDCl3)
δ 1.63 (br d, J = 7.6 Hz, 2H), 1.93 (quin, J = 5.5 Hz, 2H), 3.98 (t, J = 5.5 Hz, 4H), 4.88 (ddt, J =
1
3
10.0, 2.4, 1.2 Hz, 1H), 4.92 (ddt, J = 15.2, 2.4, 1.2 Hz, 1H), 5.85 (ddt, J = 15.2, 10.0, 7.6 Hz, 1H); C
1
NMR (101 MHz, CDCl3)
δ
22.0 (d, J = 64.6 Hz, CH ), 27.3 (CH ), 61.9 (2 × CH ), 113.9 (CH )
CꢀB
2
2
2
2
+
135.5 (CH); MS (CI) m/z 127 (MH , 12), 113 (32), 103 (44), 97 (40), 85 (83), 71 (100), 69 (71).
1
0
(
2S)-2-(2’-Bromophenyl)pent-4-en-2-ol (4). BꢀAllylꢀ1,3,2ꢀdioxaborinane (6) (0.026 mL, 0.21
mmol) and (S)ꢀ(–)ꢀ3,3’ꢀdibromoꢀ1,1’ꢀbiꢀ2ꢀnaphthol (9) (0.0050 g, 0.011 mmol) was dissolved in toluene
(1 mL) and stirred for 0.1 h at 35 °C in an oven dried microwave vial. A solution of 1ꢀ(2’ꢀ
bromophenyl)ethanꢀ1ꢀone (3a) (0.020 mL, 0.15 mmol) in distilled toluene (0.75 mL) was added and the
reaction mixture was stirred for 5 days at 35 °C under an argon atmosphere. Purification by flash
column chromatography, eluting with 10% diethyl ether in petroleum ether (40–60) gave (2S)ꢀ2ꢀ(2’ꢀ
bromophenyl)pentꢀ4ꢀenꢀ2ꢀol (4) (0.036 g, 100%) as a colorless oil. Spectroscopic data were consistent
1
0
31
1
with the literature. [α]
–34.3 (c 1.2, CHCl ); H NMR (400 MHz, CDCl )
δ
1.72 (s, 3H), 2.62 (s,
H), 2.64 (br dd, J = 14.0, 8.4 Hz, 1H), 3.29 (ddt, J = 14.0, 6.3, 1.1 Hz, 1H), 5.06–5.19 (m, 2H), 5.55
dddd, J = 17.0, 10.1, 8.4, 6.3 Hz, 1H), 7.10 (td, J = 7.8, 1.7 Hz, 1H), 7.30 (td, J = 7.8, 1.3 Hz, 1H), 7.58
D
3
3
1
(
1
3
(dd, J = 7.8, 1.3 Hz, 1H), 7.70 (dd, J = 7.8, 1.7 Hz, 1H); C NMR (101 MHz, CDCl )
δ
27.3 (CH3),
3
4
5.1 (CH ), 74.7 (C), 119.4 (CH ), 120.0 (C), 127.4 (CH), 128.3 (CH), 128.6 (CH), 133.7 (CH), 135.1
2
2
+
(CH), 145.0 (C); MS (ESI) m/z 265 (MNa , 100), 263 (97). Enantiomeric excess was determined by
i
HPLC analysis with a chiralcel ODꢀH column (hexane: PrOH 95:5, flow rate 1.0 mL/min), t
min, tmajor = 1.96 min; er = 98:2.
= 1.78
minor
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General procedure for the one-pot asymmetric synthesis of 1-alkyl-1-indanols. BꢀAllylꢀ1,3,2ꢀ
dioxaborinane (6) (1.4 equiv.) and (S)ꢀ(–)ꢀ3,3’ꢀdibromoꢀ1,1’ꢀbiꢀ2ꢀnaphthol (9) (7.5 mol %) was
dissolved in distilled toluene (5 mL/mmol) and stirred for 0.1 h at 35 °C in an oven dried microwave
vial. A solution of 2’ꢀbromoaryl ketone (1.0 equiv.) in toluene (5 mL/mmol) was added and the reaction
mixture was stirred for 5 days at 35 °C. Bis(triphenylphosphine)palladium(II) dichloride (7.5 mol %),
potassium carbonate (2 equiv.) and hydrazine monohydrate (0.4 equiv.) were added to the reaction
mixture. The vial was sealed and heated to 135 °C for 18 h. The reaction mixture was cooled to room
temperature, diluted with diethyl ether (2 mL/mmol), filtered through a pad of Celite® and concentrated
in vacuo. Purification of the crude product using silica gel flash chromatography, eluting with diethyl
ether or ethyl acetate in petroleum ether or ethyl acetate in hexane gave the corresponding 1ꢀalkylꢀ1ꢀ
indenols.
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(1S)-1,3-Dimethylinden-1-ol [(S)-11a] and (1S)-2,3-dihydro-1-methyl-3-(methylene)indan-1-ol
1
0
[(S)-10a].
The reaction was performed according to the general procedure using 1ꢀ(2’ꢀ
bromophenyl)ethanꢀ1ꢀone (3a) (0.067 mL, 0.50 mmol). The crude mixture was purified by silica gel
flash chromatography, eluting with 10% diethyl ether in petroleum ether (40–60) to yield first (1S)ꢀ1,3ꢀ
dimethylindenꢀ1ꢀol [(S)-11a] (0.012 g, 15%), and then (1S)ꢀ2,3ꢀdihydroꢀ1ꢀmethylꢀ3ꢀ(methylene)indanꢀ
1ꢀol [(S)-10a] (0.060 g, 75%) as colorless oils, which solidified upon standing. Spectroscopic data were
10
31
consistent with the literature. Data for (1S)ꢀ1,3ꢀdimethylindenꢀ1ꢀol [(S)-11a]: Mp 95–97 °C; [α]D
1
+55.9 (c 1.0, CHCl ); H NMR (400 MHz, CDCl )
δ
1.58 (s, 3H), 1.67 (s, 1H), 2.06 (d, J = 1.6 Hz, 3H),
3
3
5
.99 (q, J = 1.6 Hz, 1H), 7.15 (br d, J = 7.3 Hz, 1H), 7.22 (td, J = 7.3, 1.0 Hz, 1H), 7.28 (td, J = 7.3, 1.0
1
3
Hz, 1H), 7.40 (br d, J = 7.3 Hz, 1H); C NMR (101 MHz, CDCl )
δ 12.7 (CH ), 23.8 (CH ), 81.1 (C),
3 3
3
1
19.3 (CH), 121.2 (CH), 126.3 (CH), 128.3 (CH), 137.7 (CH), 138.9 (C), 143.0 (C), 150.0 (C); MS
+
(
ESI) m/z 183 (MNa , 100). Enantiomeric excess was determined by HPLC analysis with a chiralcel
i
ODꢀH column (hexane: PrOH 95:5, flow rate 1.0 mL/min), t
= 2.43 min, tminor = 2.80 min; er = 96:4;
major
31
Data for (1S)ꢀ2,3ꢀdihydroꢀ1ꢀmethylꢀ3ꢀ(methylene)indanꢀ1ꢀol [(S)-10a]: Mp 79–81 °C; [α]D +10.9 (c
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1
1
.0, CHCl ); H NMR (400 MHz, CDCl )
δ
1.59 (s, 3H), 1.95 (s, 1H), 2.88 (dt, J = 16.5, 2.1 Hz, 1H),
3
3
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
2.95 (dt, J = 16.5, 2.1 Hz, 1H), 5.09 (t, J = 2.1 Hz, 1H), 5.52 (t, J = 2.1 Hz, 1H), 7.28–7.34 (m, 2H),
1
3
7
.39–7.44 (m, 1H), 7.46–7.52 (m, 1H); C NMR (101 MHz, CDCl ) δ 28.1 (CH ), 49.4 (CH ), 78.7
3 3 2
(
C), 104.5 (CH ), 120.6 (CH), 122.9 (CH), 128.6 (CH), 129.1 (CH), 139.4 (C), 145.9 (C), 150.4 (C);
2
+
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
MS (ESI) m/z 183 (MNa , 100). Enantiomeric excess was determined by HPLC analysis with a chiralcel
i
ODꢀH column (hexane: PrOH 95:5, flow rate 1.0 mL/min), t
= 2.58 min, tminor = 2.96 min; er = 96:4.
major
(1R)-1,3-Dimethylinden-1-ol [(R)-11a] and (1R)-2,3-dihydro-1-methyl-3-(methylene)indan-1-ol
[(R)-10a]. The reaction was performed according to the general procedure using 1ꢀ(2’ꢀ
bromophenyl)ethanꢀ1ꢀone (3a) (0.067 mL, 0.50 mmol) and (R)ꢀ(+)ꢀ3,3’ꢀdibromoꢀ1,1’ꢀbiꢀ2ꢀnaphthol
(0.016 g, 0.040 mmol). The crude mixture was purified by silica gel flash chromatography, eluting with
1
0% diethyl ether in petroleum ether (40–60) to yield first (1R)ꢀ1,3ꢀdimethylindenꢀ1ꢀol [(R)-11a] (0.014
g, 18%) and then (1R)ꢀ2,3ꢀdihydroꢀ1ꢀmethylꢀ3ꢀ(methylene)indanꢀ1ꢀol [(R)-10a] (0.056 g, 70%) as
colorless oils, which solidified upon standing. Melting point and spectroscopic data were as recorded for
31
[
(S)-11a] and [(S)-10a]. Additional data for [(R)-11a]: [α]D –56.2 (c 0.5, CHCl ); enantiomeric excess
3
i
was determined by HPLC analysis with a chiralcel ODꢀH column (hexane: PrOH 95:5, flow rate 1.0
3
1
mL/min), tminor = 2.38 min, tmajor = 2.75 min; er = 96:4; Additional data for [(R)-10a]: [α]D –13.0 (c
1
.0, CHCl ); enantiomeric excess was determined by HPLC analysis with a chiralcel ODꢀH column
3
i
(hexane: PrOH 95:5, flow rate 1.0 mL/min), t
= 2.53 min, tmajor = 2.94 min; er = 96:4.
minor
(1S)-2,3-Dihydro-1,5-dimethyl-3-(methylene)indan-1-ol (10b). The reaction was performed
according to the general procedure using 1ꢀ(2’ꢀbromoꢀ4’ꢀmethylphenyl)ethanꢀ1ꢀone (3b) (0.10 g, 0.47
mmol). The crude mixture was purified by silica gel flash chromatography, eluting with 8% ethyl
acetate in hexane to yield (1S)ꢀ2,3ꢀdihydroꢀ1,5ꢀdimethylꢀ3ꢀ(methylene)indanꢀ1ꢀol (10b) (0.050 g, 61%)
−
1
31
D
1
as a colorless oil. IR (neat) 3352, 2969, 1644 cm ; [α] +24.4 (c 1.2, CHCl ); H NMR (400 MHz,
3
CDCl3)
δ 1.56 (s, 3H), 1.90 (s, 1H), 2.37 (s, 3H), 2.87 (dt, J = 16.4, 2.1 Hz, 1H), 2.93 (dt, J = 16.4, 2.1
Hz, 1H), 5.05 (t, J = 2.1 Hz, 1H), 5.48 (t, J = 2.1 Hz, 1H), 7.13 (br d, J = 7.9 Hz, 1H), 7.28–7.32 (m,
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1
3
2
H); C NMR (101 MHz, CDCl ) δ 21.4 (CH ), 28.1 (CH ), 49.6 (CH ), 78.4 (C), 104.1 (CH ), 121.0
3 3 3 2 2
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
+
(CH), 122.7 (CH), 130.1 (CH), 138.5 (C), 139.6 (C), 146.0 (C), 147.8 (C); MS (ESI) m/z 197 (MNa ,
+
1
00); HRMS (ESI) calcd for C H NaO (MNa ), 197.0937, found 197.0933. Enantiomeric excess was
1
2
14
i
determined by HPLC analysis with a chiralcel ODꢀH column (hexane: PrOH 99:1, flow rate 1.0
mL/min), tminor = 12.88 min, tmajor = 13.57 min; er = 96:4.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(
1S)-2,3-Dihydro-5,6-(methylenedioxy)-1-methyl-3-(methylene)indan-1-ol (10c). The reaction
was
performed according to the general procedure using 1ꢀ(2’ꢀbromoꢀ4’,5’ꢀ
methylenedioxyphenyl)ethanꢀ1ꢀone (3c) (0.12 g, 0.50 mmol). The crude mixture was purified by silica
gel flash chromatography, eluting with 20% diethyl ether in petroleum ether (40–60) to yield (1S)ꢀ2,3ꢀ
dihydroꢀ5,6ꢀ(methylenedioxy)ꢀ1ꢀmethylꢀ3ꢀ(methylene)indanꢀ1ꢀol (10c) (0.071 g, 69%) as a colorless
−
1
30
D
1
oil. IR (neat) 3403, 2970, 1474 cm ; [α] +35.3 (c 1.0, MeOH); H NMR (400 MHz, CD OD)
δ
1.45
3
(
s, 3H), 2.86 (t, J = 2.0 Hz, 2H), 4.89 (t, J = 2.0 Hz, 1H), 5.29 (t, J = 2.0 Hz, 1H), 5.94 (d, J = 1.2 Hz,
1
3
1H), 5.95 (d, J = 1.2 Hz, 1H), 6.82 (s, 1H), 6.90 (s, 1H); C NMR (101 MHz, CD OD)
δ
27.6 (CH3),
3
4
1
2
9.0 (CH ), 77.4 (C), 99.6 (CH), 100.5 (CH ), 101.4 (CH ), 102.5 (CH), 133.4 (C), 145.3 (C), 146.0 (C),
2 2 2
+
+
48.7 (C), 149.0 (C); MS (ESI) m/z 227 (MNa , 100); HRMS (ESI) calcd for C H NaO (MNa ),
12 12
3
27.0679, found 227.0672. Enantiomeric excess was determined by HPLC analysis with a chiralcel ODꢀ
i
H column (hexane: PrOH 95:5, flow rate 1.0 mL/min), t
89.5:10.5.
= 6.04 min, tmajor = 6.59 min; er =
minor
1
0
(1S)-2,3-Dihydro-6-methoxy-1-methyl-3-(methylene)indan-1-ol (10d).
performed according to the general procedure using 1ꢀ(2’ꢀbromoꢀ5’ꢀmethoxyphenyl)ethanꢀ1ꢀone (3d)
0.12 g, 0.50 mmol). The crude mixture was purified by silica gel flash chromatography, eluting with
0% diethyl ether in petroleum ether (40–60) to yield (1S)ꢀ2,3ꢀdihydroꢀ6ꢀmethoxyꢀ1ꢀmethylꢀ3ꢀ
methylene)indanꢀ1ꢀol (10d) (0.044 g, 47%) as a yellow oil. Spectroscopic data were consistent with the
The reaction was
(
2
(
1
0
30
D
1
literature. [α] +30.8 (c 1.0, MeOH); H NMR (400 MHz, CD OD) δ 1.48 (s, 3H), 2.84 (dt, J = 16.4,
3
1
.6 Hz, 1H), 2.89 (dt, J = 16.4, 1.6 Hz, 1H), 3.80 (s, 3H), 4.90 (t, J = 1.6 Hz, 1H), 5.32 (t, J = 1.6 Hz,
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1
H), 6.85 (dd, J = 8.5, 2.3 Hz, 1H), 6.94 (d, J = 2.3 Hz, 1H), 7.39 (d, J = 8.5 Hz, 1H); C NMR (101
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
MHz, CD OD) 27.7 (CH ), 49.1 (CH ), 54.5 (CH ), 77.6 (C), 100.4 (CH ), 106.7 (CH), 115.2 (CH),
δ
3
3
2
3
2
+
1
1
21.2 (CH), 132.1 (C), 145.9 (C), 152.5 (C), 160.9 (C); MS (EI) m/z 190 (M , 84), 175 (100), 160 (10),
32 (11), 115 (14), 88 (12), 61 (17). Enantiomeric excess was determined by HPLC analysis with a
i
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
chiralcel ODꢀH column (hexane: PrOH 95:5, flow rate 1.0 mL/min), t
= 2.99 min, tminor = 3.67 min;
major
er = 93.5:6.5.
(1S)-2,3-Dihydro-6-fluoro-1-methyl-3-(methylene)indan-1-ol (10e). The reaction was performed
according to the general procedure using 1ꢀ(2’ꢀbromoꢀ5’ꢀfluorophenyl)ethanꢀ1ꢀone (3e) (0.054 g, 0.25
mmol). The crude mixture was purified by silica gel flash chromatography, eluting with 10% diethyl
ether in petroleum ether (40–60) to yield (1S)ꢀ2,3ꢀdihydroꢀ6ꢀfluoroꢀ1ꢀmethylꢀ3ꢀ(methylene)indanꢀ1ꢀol
−1
31
D
(10e) (0.020 g, 46%) as a colorless oil. IR (neat) 3356, 2970, 1643, 1605, 1481 cm ; [α]
+18.3 (c
1
0
.5, CHCl ); H NMR (400 MHz, CD OD)
δ
1.48 (s, 3H), 2.87 (dt, J = 16.4, 2.1 Hz, 1H), 2.92 (dt, J =
3
3
16.4, 2.1 Hz, 1H), 5.02 (t, J = 2.1 Hz, 1H), 5.45 (t, J = 2.1 Hz, 1H), 7.01 (ddd, J = 9.2, 8.6, 2.4 Hz, 1H),
13
7
.10 (dd, J = 8.8, 2.4 Hz, 1H), 7.51 (dd, J = 8.6, 5.2 Hz, 1H); C NMR (101 MHz, CD OD)
δ
27.5
3
4
2
2
(CH ), 48.9 (CH ), 77.3 (d, J = 2.2 Hz, C), 102.5 (CH ), 109.3 (d, J = 23.2 Hz, CH), 115.3 (d, J
3
2
CꢀF
2
CꢀF
Cꢀ
3
4
3
=
24.2 Hz, CH), 121.9 (d, J = 9.1 Hz, CH), 135.3 (d, J = 2.0 Hz, C), 145.3 (C), 153.3 (d, J
CꢀF
=
F
CꢀF
CꢀF
1
+
7
.1 Hz, C), 163.5 (d, JCꢀF = 247.5 Hz, C); MS (EI) m/z 178 (M , 37), 163 (100), 133 (33), 88 (12), 61
+
(17). HRMS (EI) calcd for C H FO (M ), 178.0794, found 178.0801. Enantiomeric excess was
11
11
i
determined by HPLC analysis with a chiralcel ODꢀH column (hexane: PrOH 95:5, flow rate 1.0
mL/min), tmajor = 10.50 min, tminor = 12.92 min; er = 94:6.
(1S)-2,3-Dihydro-6-chloro-1-methyl-3-(methylene)indan-1-ol (10f). The reaction was performed
according to the general procedure using 1ꢀ(2’ꢀbromoꢀ5’ꢀchlorophenyl)ethanꢀ1ꢀone (3f) (0.10 g, 0.43
mmol). The crude mixture was purified by silica gel flash chromatography, eluting with 10% diethyl
ether in petroleum ether (40–60) to yield (1S)ꢀ2,3ꢀdihydroꢀ6ꢀchloroꢀ1ꢀmethylꢀ3ꢀ(methylene)indanꢀ1ꢀol
−1
31
(
10f) (0.044 g, 52% yield) as a colorless oil. IR (neat) 3372, 2924, 1628, 1458 cm ; [α]D +19.5 (c 1.2,
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1
CHCl ); H NMR (400 MHz, CD OD)
δ
1.48 (s, 3H), 2.89 (t, J = 2.0 Hz, 1H), 5.08 (t, J = 2.0 Hz, 1H),
3
3
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
5.52 (t, J = 2.0 Hz, 1H), 7.27 (dd, J = 8.2, 1.9 Hz, 1H), 7.39 (d, J = 1.9 Hz, 1H), 7.48 (d, J = 8.2 Hz,
1
3
1
H); C NMR (101 MHz, CD OD) δ 27.5 (CH ), 48.7 (CH ), 77.4 (C), 103.7 (CH ), 121.6 (CH), 123.1
3 3 2 2
+
(
CH), 128.2 (CH), 134.0 (C), 137.9 (C), 145.3 (C), 152.8 (C); MS (EI) m/z 194 (M , 76), 179 (100), 159
35
11
+
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(
71), 144 (23), 115 (43), 84 (18); HRMS (EI) calcd for C H ClO (M ), 194.0498, found 194.0491.
1
1
i
Enantiomeric excess was determined by HPLC analysis with a chiralcel ODꢀH column (hexane: PrOH
95:5, flow rate 1.0 mL/min), tmajor = 5.33 min, tminor = 5.72 min; er = 95:5.
(1S)-2,3-Dihydro-6-nitro-1-methyl-3-(methylene)indan-1-ol (10g). The reaction was performed
according to the general procedure using 1ꢀ(2’ꢀbromoꢀ5’ꢀnitrophenyl)ethanꢀ1ꢀone (3g) (0.029 g, 0.10
mmol). The crude mixture was purified by silica gel flash chromatography, eluting with 30% diethyl
ether in petroleum ether (40–60) to yield (1S)ꢀ2,3ꢀdihydroꢀ6ꢀnitroꢀ1ꢀmethylꢀ3ꢀ(methylene)indanꢀ1ꢀol
−
1
30
D
(
10g) (0.0090 g, 19%) as a yellow oil. IR (neat) 3372, 2970, 1520, 1342 cm ; [α]
+45.0 (c 0.5,
1
CHCl ); H NMR (400 MHz, CD OD)
δ
1.55 (s, 3H), 2.92–3.04 (m, 2H), 5.32 (t, J = 2.2 Hz, 1H), 5.78
3
3
13
(
t, J = 2.2 Hz, 1H), 7.73 (d, J = 8.5 Hz, 1H), 8.18 (dd, J = 8.5, 2.2 Hz, 1H), 8.26 (d, J = 2.2 Hz, 1H); C
NMR (126 MHz, CD OD)
δ 27.5 (CH ), 48.5 (CH ), 77.2 (C), 108.0 (CH ), 118.5 (CH), 121.2 (CH),
3 2 2
3
+
1
23.5 (CH), 144.8 (C), 145.3 (C), 148.4 (C), 152.3 (C); MS (ESI) m/z 228 (MNa , 100); HRMS (ESI)
+
calcd for C H NNaO (MNa ), 228.0631, found 228.0625. Enantiomeric excess was determined by
11 11
3
i
HPLC analysis with a chiralcel ODꢀH column (hexane: PrOH 93:7, flow rate 2.0 mL/min), t
min, tminor = 4.18 min; er = 93.5:6.5.
= 3.84
major
(5S)-5,7-Dimethylcyclopenta[b]pyridin-5-ol (11h). The reaction was performed according to the
general procedure using 1ꢀ(2’ꢀbromoꢀ3’ꢀpyridyl)ethanꢀ1ꢀone (3h) (0.080 g, 0.40 mmol). The crude
mixture was purified by silica gel flash chromatography, eluting with 10% ethyl acetate in petroleum
ether (40–60) to yield (5S)ꢀ5,7ꢀdimethylcyclopenta[b]pyridinꢀ5ꢀol (11h) (0.040 g, 63%) as a yellow oil.
−
1
31
D
1
IR (neat) 3322, 2972, 1603, 1572, 1474 cm ; [α]
+24.2 (c 0.4, CHCl ); H NMR (400 MHz,
3
CD OD)
δ
1.53 (s, 3H), 2.10 (d, J = 1.6 Hz, 3H), 6.36 (q, J = 1.6 Hz, 1H), 7.19 (dd, J = 7.4, 5.3 Hz,
3
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1
3
1
H), 7.74 (dd, J = 7.4, 1.4 Hz, 1H), 8.30 (dd, J = 5.3, 1.4 Hz, 1H); C NMR (101 MHz, CD OD)
δ
10.4
3
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
(CH ), 22.8 (CH ), 77.7 (C), 120.7 (CH), 128.8 (CH), 138.8 (C), 143.1 (CH), 144.5 (C), 147.4 (CH),
3
3
+
1
61.9 (C); MS (EI) m/z 161 (M , 75), 146 (100), 132 (12), 117 (14); HRMS (EI) calcd for C H NO
10 11
+
(
M ), 161.0841, found 161.0835. Enantiomeric excess was determined by HPLC analysis with a
i
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
chiralcel ODꢀH column (hexane: PrOH 95:5, flow rate 1.0 mL/min), t
= 11.95 min, tminor = 18.05
major
min; er = 92.5:7.5.
(1S)-2,3-Dihydro-1-ethyl-3-(methylene)indan-1-ol (10i). The reaction was performed according to
the general procedure using 2’ꢀbromopropiophenone (3i) (0.10 g, 0.47 mmol). The crude mixture was
purified by silica gel flash chromatography, eluting with 10% diethyl ether in petroleum ether (40–60)
to yield (1S)ꢀ2,3ꢀdihydroꢀ1ꢀethylꢀ3ꢀ(methylene)indanꢀ1ꢀol (10i) (0.048 g, 59%) as a yellow oil. IR (neat)
−
1
31
D
1
3348, 2932, 1628, 1458 cm ; [α] +8.3 (c 1.0, CHCl ); H NMR (400 MHz, CD OD)
δ
0.81 (t, J =
3
3
7
.5 Hz, 3H), 1.76 (dq, J = 13.3, 7.5 Hz, 1H), 1.88 (dq, J = 13.3, 7.5 Hz, 1H), 2.77 (dt, J = 16.4, 2.1 Hz,
1H), 2.96 (dt, J = 16.4, 2.1 Hz, 1H), 5.04 (t, J = 2.1 Hz, 1H), 5.49 (t, J = 2.1 Hz, 1H), 7.25–7.32 (m,
13
2
H), 7.35–7.40 (m, 1H), 7.48–7.53 (m, 1H); C NMR (126 MHz, CD OD)
δ
7.5 (CH ), 33.9 (CH ),
3
3
2
4
5.7 (CH ), 80.7 (C), 102.3 (CH ), 120.0 (CH), 123.3 (CH), 128.0 (CH), 128.3 (CH), 140.0 (C), 146.8
2
2
+
+
(
C), 149.6 (C); MS (ESI) m/z 197 (MNa , 100); HRMS (ESI) calcd for C H NaO (MNa ), 197.0937,
12 14
found 197.0932. Enantiomeric excess was determined by HPLC analysis with a chiralcel ODꢀH column
i
(hexane: PrOH 95:5, flow rate 1.0 mL/min), t
= 2.38 min, tminor = 2.80 min; er = 94:6.
major
(3S)-2,3-Dihydro-3-hydroxy-3-methyl-1-indanone
(14).
(3S)ꢀ2,3ꢀDihydroꢀ1ꢀmethylꢀ3ꢀ
(methylene)indanꢀ1ꢀol [(S)-10a] (0.300 g, 1.87 mmol) was dissolved in a mixture of dichloromethane
(60 mL) and methanol (60 mL) and cooled to −78 °C. The reaction mixture was purged with oxygen
and then ozone was bubbled through until the clear solution turned to blue. The excess ozone was
purged with oxygen and then with argon. Triphenylphosphine (1.47 g, 5.61 mmol) was added
portionwise to the mixture with vigorous stirring. The reaction mixture was allowed to return to room
temperature over 2 h. The reaction mixture was concentrated in vacuo. The resulting residue was
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The Journal of Organic Chemistry
Page 28 of 33
purified by silica gel flash column chromatography, eluting with 20% diethyl ether in petroleum ether
40–60) to give (3S)ꢀ2,3ꢀdihydroꢀ3ꢀhydroxyꢀ3ꢀmethylꢀ1ꢀindanone (14) (0.250 g, 81%) as a yellow oil.
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
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3
3
3
3
3
3
3
3
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4
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4
4
4
4
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5
5
5
5
5
5
5
6
(
−
1
31
D
1
IR (neat) 3393, 2972, 1701, 1603 cm ; [α] +96.9 (c 1.0, CHCl ); H NMR (400 MHz, CDCl )
δ
1.73
3
3
1
3
(
s, 3H), 2.15 (s, 1H), 2.91 (s, 2H), 7.44–7.53 (m, 1H), 7.68–7.75 (m, 3H); C NMR (101 MHz, CDCl )
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
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9
0
1
2
3
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9
0
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7
8
9
0
δ 29.3 (CH ), 53.8 (CH ), 74.5 (C), 123.2 (CH), 123.6 (CH), 129.4 (CH), 135.4 (C), 135.6 (CH), 158.6
3 2
+
(
C), 203.2 (C); MS (EI) m/z 162 (M , 88), 147 (100), 129 (53), 115 (43), 91 (22), 84 (38), 77 (19);
+
HRMS (EI) calcd for C H O (M ), 162.0681, found 162.0680.
1
0
10
2
(1S,3S)-2,3-Dihydro-1-(methyl)indan-1,3-diol (15). To a stirred solution of (3S)ꢀ2,3ꢀdihydroꢀ3ꢀ
hydroxyꢀ3ꢀmethylꢀ1ꢀindanone (14) (0.020 g, 0.12 mmol) in 1,2ꢀdichloroethane (2 mL) was added
sodium triacetoxyborohydride (0.038 g, 0.18 mmol) and acetic acid (0.0070 mL, 0.12 mmol) at room
temperature under an argon atmosphere. Sodium triacetoxyborohydride (0.038 g, 0.18 mmol) and acetic
acid (0.0070 mL, 0.12 mmol) were then added after two days. The reaction mixture was stirred at room
temperature for a total of 6 days and then quenched with 1 M sodium hydroxide solution (2 mL). After
phase separation, the aqueous layer was extracted with dichloromethane (2 × 5 mL), dried over MgSO4,
filtered and concentrated in vacuo. Purification of the crude material using silica gel flash column
chromatography, eluting with 5% methanol in dichloromethane gave (1S,3S)ꢀ2,3ꢀdihydroꢀ1ꢀ
(methyl)indanꢀ1,3ꢀdiol (15) (0.015 g, 75% yield) as a white solid. Mp 97–99 °C; IR (neat) 3331, 2967,
−
1
31
D
1
1
092 cm ; [α] +48.5 (c 0.6, CHCl ); H NMR (500 MHz, CDCl ) δ 1.70 (s, 3H), 1.76 (s, 1H), 1.90
3
3
(s, 1H), 2.10 (dd, J = 13.5, 5.0 Hz, 1H), 2.63 (dd, J = 13.5, 6.5 Hz, 1H), 5.41 (br t, J = 6.0 Hz, 1H),
13
7
.33–7.45 (m, 4H); C NMR (126 MHz, CDCl ) δ 28.7 (CH ), 52.6 (CH ), 73.6 (CH), 79.4 (C), 122.3
3 3 2
+
(
CH), 124.5 (CH), 129.1 (CH), 129.1 (CH), 144.3 (C), 147.4 (C); MS (ESI) m/z 187 (MNa , 98); HRMS
+
(
ESI) calcd for C H NaO (MNa ), 187.0730, found 187.0730.
1
0
12
2
General procedure for the reductive amination reactions. To a solution of (3S)ꢀ2,3ꢀdihydroꢀ3ꢀ
hydroxyꢀ3ꢀmethylꢀ1ꢀindanone (14) (1 equiv.) in 1,2ꢀdichloroethane (2 mL/mmol) was added the amine
(1.1–1.5 equiv.) and sodium triacetoxyborohydride (1.4–1.5 equiv) at room temperature under an argon
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Page 29 of 33
The Journal of Organic Chemistry
atmosphere. The same amounts of amine and hydride source were added after 2 days. The reaction
mixture was stirred at room temperature up to 6 days and then quenched with 1 M sodium hydroxide
solution (2 mL/mmol). After phase separation, the aqueous layer was extracted with dichloromethane (2
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
×
5 mL/mmol), dried (MgSO ), filtered and concentrated in vacuo. Purification using silica gel flash
4
column chromatography, eluting with methanol in dichloromethane gave the 3ꢀaminoꢀsubstituted 2,3ꢀ
dihydroꢀ1ꢀ(methyl)indanꢀ1ꢀols.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
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8
9
0
1
2
3
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7
8
9
0
1
2
3
4
5
6
7
8
9
0
(1S,3S)-3-Benzylamino-2,3-dihydro-1-(methyl)indan-1-ol (16a). The reaction was performed
according to the general procedure using (3S)ꢀ2,3ꢀdihydroꢀ3ꢀhydroxyꢀ3ꢀmethylꢀ1ꢀindanone (14) (0.032
g, 0.20 mmol) and benzylamine (0.024 mL, 0.22 mmol). The reaction mixture was stirred at room
temperature for 3 days. Purification of the crude material using silica gel flash column chromatography,
eluting with 5% methanol in dichloromethane gave (1S,3S)ꢀ3ꢀbenzylaminoꢀ2,3ꢀdihydroꢀ1ꢀ
−
1
31
D
(
methyl)indanꢀ1ꢀol (16a) (0.042 g, 84%) as a yellow oil. IR (neat) 3312, 2965, 1452 cm ; [α] +22.9
1
(
c 1.0, CHCl ); H NMR (500 MHz, CDCl )
δ
1.60–1.77 (m, 5H), 1.98 (dd, J = 13.2, 6.5 Hz, 1H), 2.59
3
3
(dd, J = 13.2, 6.5 Hz, 1H), 3.88 (d, J = 13.0 Hz, 1H), 3.93 (d, J = 13.0 Hz, 1H), 4.48 (t, J = 6.5 Hz, 1H),
1
3
7
.22–7.44 (m, 9H); C NMR (126 MHz, CDCl ) δ 28.1 (CH ), 50.4 (CH ), 51.7 (CH ), 59.8 (CH), 79.4
3 3 2 2
(C), 122.3 (CH), 124.5 (CH), 127.0 (CH), 128.2 (2 × CH), 128.2 (CH), 128.5 (2 × CH), 128.7 (CH),
+
1
40.5 (C), 145.0 (C), 147.4 (C); MS (ESI) m/z 254 (MH , 100); HRMS (ESI) calcd for C H NO
1
7
20
+
(MH ), 254.1539, found 254.1534.
(1S,3S)-2,3-Dihydro-3-(4’-methoxybenzyl)amino-1-(methyl)indan-1-ol (16b). The reaction was
performed according to the general procedure using (3S)ꢀ2,3ꢀdihydroꢀ3ꢀhydroxyꢀ3ꢀmethylꢀ1ꢀindanone
(14) (0.020 g, 0.12 mmol) and 4ꢀmethoxybenzylamine (0.018 mL, 0.014 mmol). The reaction mixture
was stirred at room temperature for 6 days. Purification of the crude material using silica gel flash
column chromatography, eluting with 5% methanol in dichloromethane gave (1S,3S)ꢀ2,3ꢀdihydroꢀ3ꢀ(4’ꢀ
methoxybenzyl)aminoꢀ1ꢀ(methyl)indanꢀ1ꢀol (16b) (0.029 g, 84%) as a yellow oil. IR (neat) 3360, 2961,
−1
31
1
1
611, 1512 cm ; [α]D +19.1 (c 1.0, CHCl ); H NMR (400 MHz, CDCl )
δ
1.50–1.77 (m, 5H), 1.99
3
3
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