Synthesis and use of chiral substituted benzenes containing 1,2-diols protected as cyclic acetals

Article abstract of DOI:10.1016/j.tetlet.2011.11.111

1,2-Dihydroxy benzenes have been protected as cyclic diacetals using 2,3-butane dione. These diacetals are extremely robust and can be further chemically diversified and resolved with chirality embedded in the 1,4-dioxane ring attached to the aromatic back bone as a result of the anomeric effect. These systems can serve as ligands, auxiliaries or organocatalysts for asymmetric synthesis.

Full text of DOI:10.1016/j.tetlet.2011.11.111

Tetrahedron Letters 53 (2012) 637–640
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis and use of chiral substituted benzenes containing 1,2-diols
protected as cyclic acetals
⇑
Chandrashekar Ramarao , Ramadevi Nandipati, Rajasekhar Navakoti, Ramanjaneyulu Kottamasu
Avra Laboratories Pvt. Ltd, Avra House, 54 Sai Enclave, Habsiguda, Hyderabad 500007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
1,2-Dihydroxy benzenes have been protected as cyclic diacetals using 2,3-butane dione. These diacetals
are extremely robust and can be further chemically diversified and resolved with chirality embedded in
the 1,4-dioxane ring attached to the aromatic back bone as a result of the anomeric effect. These systems
can serve as ligands, auxiliaries or organocatalysts for asymmetric synthesis.
Received 21 October 2011
Revised 18 November 2011
Accepted 22 November 2011
Available online 28 November 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Dedicated to Professor S. V. Ley, FRS, on the
occasion of his 65th birthday
Keywords:
Butane diacetals
Catechols
Asymmetric synthesis
Phosphine ligands
1,2-Diacetal motifs have been extensively used as selective 1,2-
diequatorial diol protecting groups1 and also for stereo-controlled
transformations2 by virtue of their ability towards retention and
transmission of chirality.3 Several applications have been reported
in the literature where the motif’s chiral memory protocol can lend
itself as a powerful synthetic tool for constructing asymmetric
building blocks.4 In all the reported studies on the use of 1,2-ace-
tals, especially 2,3-butane diacetals (BDAs)5 the diols that were
protected for further synthetic manipulation were always those
attached to at least one sp3 carbon atom.6 Until now no attempt
has been made to ascertain if 1,2-diols attached to sp2 carbon
atoms such as catechol or 1,2-dihydroxy substituted benzenes
can be protected as 1,2-diacetals. The present work was inspired
by the pioneering contributions of Ley’s group1–4 and relates to
the development of a synthetic protocol enabling the preparation
of substituted racemic and optically active benzenes containing
1,2-diols protected as diacetal groups.
Considering that 1,2-diacetals are normally used to protect anti
or diequatorial 1,2-diols it was envisaged that the protection of
1,2-diols attached to unsaturated sp2 carbon atoms and aromatic
species such as catechol or substituted 1,2-dihydroxy aromatic
compounds with 2,3-butane dione7 or any similar alkyl dione8
may be tedious and require a multi-step approach.9 However, we
found that catechol when treated with trimethyl orthoformate
and boron trifluoride diethyl etherate in methanol gave the re-
quired diacetal 1 which was isolated in good yield.
Having prepared the diacetal, we were keen to explore the possi-
bility of making substituted benzenes with varying functionality
and to obtain the compounds with this motif in its chiral form. We
envisaged that making a BDA protected 1,2-dihydroxy aniline or
benzoic acid would allow us to use such functional handles to facil-
itate resolution and isolate the enantiomerically enriched constitu-
ents. These compounds would now have a chiral framework in the
form of a substituted diacetal functionality attached directly to the
aromatic backbone allowing the molecule to possess chirality.
Accordingly, the BDA protected catechol 1 was subjected to a
series of conditions that allowed us to obtain aniline 3 in its solid
crystalline form as shown in Scheme 1. We now needed to find a
suitable way to resolve the aniline where chirality was embedded
in the 1,4-dioxane ring as a result of the favourable anomeric ef-
fects and equatorial placement of functionality. After several at-
tempts we succeeded in finding a scalable method that allowed
for the resolution of the BDA isomers. The procedure involved
treating the aniline 3 with phthalic anhydride10 and the resulting
amide 4 was stirred with either (R) or (S) homochiral methylben-
zylamine in isopropyl alcohol at room temperature overnight and
during this time a colourless solid separated out which was filtered
and dried.
This enriched diastereomeric salt which separated as colourless
solid was suspended in methanol and heated to 60–65 °C for
15 min and filtered under hot conditions.
⇑
Corresponding author. Tel.: +91 40 27178566/27178569; fax: +91 40 27179149.
E-mail address: chandra@avralab.com (C. Ramarao).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.11.111

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C. Ramarao et al. / Tetrahedron Letters 53 (2012) 637–640
OMe
OMe
OMe
OMe
OMe
OMe
2,3-butane
dione
OMe
OMe
O
O
OH
OH
O
O
O
O
Pd(OH)2
HNO3, AcOH
15 h, rt, 83%
CH(OMe)3
BF3..Et2O
MeOH, 5 h, rt,
78%
H2,MeOH
2 h, 84%
H2N
O2N
3
1
2
OMe
OMe
O
O
O
O
Phthalic
Resolution
22%
anhydride
(R)-1-phenylethylamine
N
H
O
N
H
O
DMF, 4 h, rt,
92%
IPA, 12 h, rt,
CO2H
CO2
H3N
5
4
OMe
OMe
OMe
OMe
O
O
O
O
O
5N NaOH, 18 h
100 oC, 85%
N
H2N
O
O
NH2
OMe
H
OMe
CO2
6b
6a
H3N
[S, S] optically active
[obtained from (S) - -
phenylethylamine
(ee=99.8%)]
[R, R] optically active
(ee=98.9%)
5a
enriched
diastereomeric salt
Scheme 1. Synthesis of chiral anilines.
Figure 1. ORTEP diagram of compound 5a, 6a and 6b.
O
O
O
O
(S)-1-phenylethyl
2,3-butane
dione
OMe
OMe
OMe
OMe
OH
OH
O
O
O
O
3 N NaOH
amine
HO
O
O
HO
CH(OMe)3
IPA, 12 h, rt, 95%
MeOH, 1 h,
rt, 95%
BF3 Et2O
.
MeOH, rt, 50%
Resolution
7
O
8
O
OMe
O
O
OMe
OMe
OMe
OMe
OH
O
O
O
O
O
O
1N HCl
rt, 96%
HO
O
NH3
NH3
O
OMe
OMe
11b
OMe
Ph
Ph
[S ,S] optically active
[obtained from (R)-1-
phenylethyl amine
(ee=99.8%)]
10a
9
11a
enriched
diastereomeric salt
Scheme 2. Synthesis of chiral benzoic acids.
This process was repeated to yield a highly enriched diastereo-
ylethylamine] gave the R,R isomer 5a. Resolution of the diastereo-
meric salt prepared by treating the amide
meric salt. The stereochemistry of the optically active butane diac-
etal moiety was confirmed from X-ray data of the diastereomeric
salt formed from the chiral methylbenzylamine11 (Fig. 1). As ex-
pected the 1,2-dimethyl groups were in a pseudo equatorial posi-
tion with the 1,2-dimethoxy groups in the pseudo axial positions.
The salt formed with (R)-(+)-methylbenzylamine [(R)-(+)-1-phen-
4
with (S)-(À)-
methylbenzylamine [(S)-(À)-1-phenylethylamine] gave the S,S
isomer. The chiral anilines 6a and 6b were easily obtained by treat-
ing the above diastereomeric salts with aqueous 5 N sodium
hydroxide. Having succeeded in resolving the anilines with the
BDA rings attached in optically active forms, we looked into the

C. Ramarao et al. / Tetrahedron Letters 53 (2012) 637–640
639
protection of 3,4-dihydroxy benzoic acid as a butane diacetal and
again this was achieved using similar conditions that were applied
to catechol (Scheme 2). The diastereomeric salt 10a was prepared
Our proposed plan was to subject the aniline to conditions
required for diazotization to obtain a halide, preferably an aryl bro-
mide as depicted in 12. It was apparent that the aryl bromide 12
could then be converted into a phosphine oxide 1312 followed by
ortho-lithiation to obtain iodide 14. The subsequent homo coupling
under Ullmann conditions followed by reduction would yield the
bisphosphine ligand 17 with dual chirality resulting from the
BDA components and the atropisomeric biphenyl structure. The
BDA group proved to be extremely stable and no trace of any
deprotected diol was noticed while performing the synthetic se-
quence. As envisaged, the bisphosphonate was obtained but sur-
prisingly with a diastereomeric ratio of 84:16 for the resulting
atropisomeric biphenyls. It appears that the chiral BDA component
is having an effect in allowing for one diastereoisomer to form as
the major product in the Ullmann reaction13 (Scheme 3). The bis-
phosphines were further enriched to an optically pure form
(>99% ee) using O,O-dibenzoyltartaric acid. The (+)-bisphosphine
was enriched using (+)-O,O-dibenzoyltartaric acid14 and the (À)-
bisphosphine was enriched using (À)-O,O-dibenzoyltartaric acid.
by stirring the acid 8 with a chiral a-methylbenzylamine to resolve
the isomers. The salt formed with (R)-(+)-methylbenzylamine [(R)-
(+)-1-phenylethylamine] gave the S,S isomer 11b while the salt
from (S)-(À)-methylbenzylamine [(S)-(À)-1-phenylethylamine]
gave the R,R isomer 11a. We now had two ways to prepare enan-
tiomerically enriched 1,2-dihydroxy benzenes protected as butane
diacetals with suitable functionality that could be used for further
synthetic conversion and construction. The next objective was to
ascertain the stability of the acetal functionality and find suitable
applications for such systems. We set upon exploring the plausibil-
ity of using such compounds as ligands for asymmetric catalysis
and in this regard decided to construct atropisomeric bisphos-
phines having the chiral BDA motif. The preparation of such ligands
would allow us to subject the BDA functionality through a series of
chemically diverse conditions that would allow us to test the
stability of this group.
NaNO2
CuBr, ACN
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
1. n-BuLi, (Ph)2PCl
THF, 6 h, -75 o
O
O
O
O
O
O
O
O
2M LDA, I2
C
O
P
O
AcOH, 2.5 h
0-5 oC to 60 oC,
59%
THF, 5 h,
2. H2O2 MeOH
H2N
Br
P
-75 oC, 84%
Ph
Ph
2 h, 15-20 oC,
60%
Ph
Ph
I
6a
12
13
14
OMe
OMe
OMe
O
O
O
O
O
O
O
P
O
P
Ph
Ph
(-) -O, O-dibenzoyl
tartaric acid
P
1. 1 N KOH, DCM
Ph
OMe
Ph
Ph
Ph
OMe
Ph
OMe
Ph
CuI, DMF
Ph
30 min, rt, 83%
O
O
P
OMe
O
OMe
OMe
O
12 h, 150 o
C
2. HSiCl3, Bu3N
xylene, 5 h,
EtOAc, CHCl3
P
O
P
12 h, 20 oC, 58%
Ph
Ph
Ph
130 oC, 20%
O
O
O
HO2C
CO2H
OMe
OMe
OMe
15
17
O
O
*
*
16
O
O
Ph
Ph
Scheme 3. Synthesis of bisphosphine 17.
Table 1
Asymmetric hydrogenation—comparative study
Entry
Substrate
Conditionsc
Product
ee% (Reported)a,b
10 bar, 110 °C
18.86 (23) L1
53.82 (49) L2
78.04 L3
O
O
1a
OH
OH
O
1 h, EtOH
1
F3C
O
OC2H5
F3C
OC2H5
OC2H5
O
10 bar, 110 °C
1 h, EtOH
49.00 (44) L1
74.22 (63) L2
89.78 L3
O
2a
C2F5
2
3
C2F5
OC2H5
10 bar, 80 °C
26.80 (56) L1
29.86 (63) L2
74.80 L3
O
3a
O
24 h, EtOH
OC2H5
S
OC2H5
O
S
O
OH
F
O
O
10 bar, 80 °C
24 h, EtOH
43.38 (—) L1
57.82 (88) L2
81.50 L3
4a
F
OH
OC2H5
4
5
OC2H5
O
O
20 bar, 50 °C
24 h, MeOH
O
O
94.86 (90) L1
97.24 (93) L2
89.14 L3
5a
O
O
O
O
a
b
c
L1 = (R)-BINAP, L2 = (R)-SEGPHOS, L3 = (R)-17.
Enantiomeric excess measured by chiral HPLC and GC.
Reactions were conducted on a 1-mmol scale with 1 mol % of in situ prepared RuBr2[ligand] as catalyst. (—) = Not reported.

640
C. Ramarao et al. / Tetrahedron Letters 53 (2012) 637–640
Atropisomeric ligands such as BINAP and several other related
(854474), 6a (854475) and 6b (854476), HPLC and GC chromato-
grams.) associated with this article can be found, in the online
version, at doi:10.1016/j.tetlet.2011.11.111.
systems have proved to be excellent ligands for ruthenium cata-
lysed asymmetric hydrogenations.15 The aryl BDA ligand 17 was
tested and compared for catalytic activity in asymmetric hydroge-
nations along with the commercially available BINAP16 and SEG-
PHOS.17 To ascertain if there could be any added value or
enhancement of activity due to the presence of the BDA function-
ality, we only chose substrates that were reported in the litera-
ture18 where the use of these popular ligands did not provide a
high degree of selectivity resulting in low enantiomeric excess in
the isolated products. A selective comparative study was done
where BINAP19 or SEGPHOS gave poor stereo-induction in ruthe-
nium catalysed asymmetric hydrogenations. The results shown in
Table 1 are very encouraging and clearly show that (R)-17 can
serve as a stable and selective ligand in promoting asymmetric
catalysis.
In conclusion, we have described a method for protecting and
isolating enantiomerically enriched anilines or benzoic acids
containing 1,2-diols. These compounds can serve as precursors to
construct novel and diverse chiral scaffolds. Future work will focus
on the design of other aryl-BDA containing phosphines, amines,
N-heterocyclic carbenes and other chelating systems and gauge
their efficacy in asymmetric and organocatalytic reactions.
References and notes
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Supplementary data
Supplementary data (Complete experimental details, copies of
1H and 13C NMR for all new compounds. ORTEP diagrams of 5a