Convenient and inexpensive synthesis of (1R,2R)-trans-1-amino-6-nitroindan- 2-ol

Article abstract of DOI:10.1002/adsc.200404296

Racemic trans-1-amino-6-nitroindam-2-ol (rac-1) has been prepared in five steps from inexpensive indene (7) in 96% overall yield. The key step was a direct nitration of the known trans-1-aminoindan-2-ol (rac-9) which gave sulfuric acid mono-(rac-trans-1-amino-6-nitroindan-2-yl) ester (rac-10) in quantitative yield. The latter was quantitatively converted into rac-1 by treatment with aqueous 6 N HCl and then ammonia solutions. The same transformations of (1R,2R)-9 [prepared by deracemization of rac-9 with (-)-dibenzoyl-L-tartaric acid (DBT)] proceeded without loss of the optical activity. Deracemization of rac-1 applying (+)-(5)-L-mandelic acid (MA) furnished (1R,2R)-1 and (1s,2s)-1 in 34 and 17% yield, respectively, with e.e. ≥ 98 and 97.6%, respectively. Procedures for recycling of the chiral auxiliaries DBT and MA are also described. The structures of key intermediates were confirmed by X-ray crystal structure analysis.

Full text of DOI:10.1002/adsc.200404296

FULL PAPERS
Convenient and Inexpensive Synthesis of (1R,2R)-
trans-1-Amino-6-nitroindan-2-ol
Sergei I. Kozhushkov,a Dmitrii S. Yufit,b Armin de Meijerea,*
a
Institut fꢀr Organische und Biomolekulare Chemie der Georg-August-Universitꢁt Gçttingen, Tammannstrasse 2,
37077 Gçttingen, Germany
Fax: (þ49)-551-399-475, phone (þ49)-551-393-232; e-mail: Armin.deMeijere@chemie.uni-goettingen.de
b
Department of Chemistry, University of Durham, Durham, South Rd., DH1 3LE, UK
E-mail: d.s.yufit@durham.ac.uk
Received: September 21, 2004; Accepted: November 24, 2004
Abstract: Racemic trans-1-amino-6-nitroindan-2-ol out loss of the optical activity. Deracemization of rac-
(rac-1) has been prepared in five steps from inexpen- 1 applying (þ)-(S)-l-mandelic acid (MA) furnished
sive indene (7) in 96% overall yield. The key step was (1R,2R)-1 and (1S,2S)-1 in 34 and 17% yield, respec-
a direct nitration of the known trans-1-aminoindan-2- tively, with e.e. ꢁ 98 and 97.6%, respectively. Proce-
ol (rac-9) which gave sulfuric acid mono-(rac-trans-1- dures for recycling of the chiral auxiliaries DBT and
amino-6-nitroindan-2-yl) ester (rac-10) in quantitative MA are also described. The structures of key inter-
yield. The latter was quantitatively converted into mediates were confirmed by X-ray crystal structure
rac-1 by treatment with aqueous 6 N HCl and then analysis.
ammonia solutions. The same transformations of
(1R,2R)-9 [prepared by deracemization of rac-9 with Keywords: amino alcohols; aromatic substitution; chi-
(ꢀ)-dibenzoyl-l-tartaric acid (DBT)] proceeded with- ral resolution; indene; nitration; structure elucidation
Introduction
During the last decade, (1R,2R)-trans-1-amino-6-nitro-
indan-2-ol [(1R,2R)-1] has been found to be a very im-
portant intermediate in medicinal chemistry for the
preparation of muscarinic agonists,[1] bronchodilators
and antihypertensives,[2] potassium channel regula-
tors,[3] multidrug resistance protein inhibitors,[4] and an-
tipsychotics[5] as well as in combinatorial chemistry to
build small-molecule libraries consisting of substituted
indanes.[6] Very recently this compound was also found
to be an excellent auxiliary for deracemization of un-
functionalized, a-epimerizable non-racemic ketones
and aldehydes.[7] In its racemic form, the title compound
Scheme 1. Known preparations of racemic (1R*,2R*)-trans-1-
amino-6-nitroindan-2-ol (rac-1).[1c, d,3a,8]
rac-1 had first been prepared (but reported without de-
tailed characterization) in three steps with 17% overall
yield[3a] starting from 6-nitroindene 5 and applying a perimental details. This compound and its preparation
general synthetic approach to trans-1-aminoindan-2- also are the subject of several patents filed mainly by
ols, i.e., epoxidation with mCPBA, ring opening of the Eli Lilly and Company, USA (see, for example,[1–6]);
epoxide 6 with azide anion and finally reduction of the however, their synthetic approach[1c, d] was essentially
azido to an amino group (Scheme 1).
the same as reported before,[3a,8] i.e., starting from in-
However, 6-nitroindene (5) is not commercially avail- dan-1-one (2), but more efficient, as the epoxide 6 was
able, and must be prepared in three steps[8] from the directly converted into rac-1 via ring opening with am-
rather expensive indan-1-one (2) (the lowest posted monia (Scheme 1). The resolution of the racemate[1]
price is currently US $ 666.00 for 500 g). The synthesis (see also ref.[5] cited in ref.[7a]) can be achieved using
of enantiomerically pure (1R,2R)-1 has also been re- (S)-(þ)-mandelic acid (lowest posted price US $
ported, but the original paper[7a] does not contain any ex- 583.00 for 1 kg).[9]
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Results and Discussion
heating of rac-10 in 6 N aqueous hydrochloric acid for
1 h (cf.[16e]), beautiful crystals of the hydrochloride mon-
A more efficient access to rac-1 would be by direct nitra- ohydrate rac-1·HCl·H2O precipitated upon cooling the
tion of trans-1-aminoindan-2-ol (rac-9). Two synthetic reaction mixture. Upon drying under vacuum over
approaches to rac-9 have been reported. The first one P4O10, rac-1·HCl was obtained and converted into the
starts with the transformation of indene (7) to the bro- free base rac-1 by treatment with aqueous ammonia in
mohydrin rac-8[10] with subsequent ring closure forming quantitative yield over both steps (Scheme 2). This cor-
the corresponding epoxide 11,[10d, e,11] ring opening of the responds to an overall yield of 96% over the whole se-
epoxide 11 with azide anion[10d, e,11] and finally reduction quence starting from inexpensive indene.
of the azido to an amino group.[10d, e,11,12] In the second
The enantiomerically pure target compound (1R,2R)-
synthesis, formation of the epoxide 11 and its ring open- 1 can be prepared either by deracemization of rac-1 or
ing to directly yield rac-9 are performed as a one-pot op- by nitration of the enantiomerically pure aminoindanol
eration by working up the bromohydrin 8 with concen- (1R,2R)-9 as well. Initially, we turned our attention to
trated aqueous ammonia solution.[11,13]
the latter route. Over the last two decades, different syn-
Using the short second approach and, compiling the thetic approaches to enantiomerically pure materials of
best published protocols and optimizing the procedures types 8, 9, 11, and 12 have been investigated in great de-
for isolation, trans-1-aminoindan-2-ol (rac-9) could tail. The most elegant and, possibly, the most economi-
be prepared from indene (7) in 96% overall yield cal approach would be an enantioselective chemical
(Scheme 2).
transformation of an achiral precursor in the presence
The nitration of an aromatic compound containing hy- of a chiral catalyst, and this method has been exhaustive-
droxy and/or amino substituents on an aliphatic side ly investigated applying the Jacobsen asymmetric epox-
chain usually requires these functionalities to be pro- idation of indene (7) in the presence of different chiral
tected (cf.[14a]). Otherwise the nitration gives low Mn(III)-salen complexes. Indeed, when performing
yields,[14b] is accompanied by dehydration[8] and charac- the epoxidation at low temperature with expensive re-
terized by the formation of complex reaction mixtur- agents such as m-chloroperbenzoic acid (mCPBA) or
es.[14c] However, 1-aminoindane can be transformed N-methylmorpholine N-oxide (NMO), the epoxide
into its 6-nitro derivative in high yield by initially form-
ing its salt with nitric acid and slowly adding this salt to
concentrated sulfuric acid at ꢀ5 to ꢀ108C.[15] Adopting
this protocol, the nitration of rac-9 could be performed
in quantitative yield, however, the product was obtained
as the betain-type monosulfate ester rac-10 (Scheme 2).
The zwitterionic nature of rac-10 caused its low solubil-
ity in most organic solvents, and this probably is the rea-
son, why the hydroxy group in rac-10 could not be depro-
tected applying established methods[16] such as heating
in a pyridine/dioxane mixture,[16a] stirring in dioxane in
the presence of p-TsOH[16b] or stirring in THF in the
presence of sulfuric acid.[16c] Fortunately, after simple
Scheme 2. Synthesis of racemic (1R*,2R*)-trans-1-amino-6-nitroindan-2-ol (rac-1) by direct nitration of 1-aminoindan-2-ol
rac-9.
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FULL PAPERS
(1S,2R)-11 was obtained with enantiomeric excesses (1S,2S)-9 applying (þ)-dibenzoyl-d-tartaric acid report-
(e.e.) of 91–96%,[10d,17] and the amino alcohol (1S,2S)-9 ed by Lehr et al.[24] appeared to be the most promising.
prepared from this material had an e.e. of 93%. How- As was expected, with the less expensive (ꢀ)-dibenzo-
ever, the enantiomeric excess in the epoxide 11 varied yl-l-tartaric acid (DBT)[25] the corresponding (1R,2R)-
from 41 to 88%, when less expensive oxidizing reagents 9 was isolated in 35% yield (Scheme 3), while DBT
were applied.[18]
could be recovered in almost quantitative yield and
Enzymatic epoxidation of 7 applying E. coli JM 109 used again. However, this preparation takes more time
(pTaB19) gave better results, as e.e. values were better than that reported by Lehr et al.[24] (see Experimental
than 98% on a 10-g scale,[19] but enzymatic deracemiza- Section).
tion of the epoxide rac-11 was less successful in that it
The salt 13 exhibited very similar values of melting
provided lower yields.[20] At first glance, the enzymati- point and specific rotation as the reported values,[24]
cally obtained epoxide (1S,2R)-11 appears to be the however, the enantiomeric excess (e.e.) for the isolated
most convenient starting material for the preparation free base (1R,2R)-9, which was determined by HPLC
of (1R,2R)-9, as it can be isolated by simple distillation analysis of its N-Boc derivative, was only 77.6% (see Ex-
without chromatography. However, apart from the ne- perimental Section; in ref.[24] the e.e. was not determined
cessity of having special experience and equipment, by an independent method). Nevertheless, the synthetic
the superiority of this approach is limited by the low sta- sequence was completed with this material, and enantio-
bility of the epoxide (1S,2R)-11 itself.
merically enriched (1R,2R)-1 with [a]2D0: þ15.7 (c 1.16,
Also successful were lipase-mediated resolutions of THF) was obtained. This material was used to prepare
the bromohydrin 8[21] and the azido alcohol 12.[10e,22] seeding crystals of the salt with mandelic acid (see be-
However, these preparations require column chroma- low). The structure and the absolute configuration of
tography for the isolation of enantiomerically pure ma- (1R,2R)-10 and of (1R,2R)-1·HCl·H2O obtained along
terials.
this route were confirmed by X-ray crystal structure
Summarizing the results discussed above, it appeared analysis (Figure 1), which indicates that no racemization
that the most convenient large-scale preparation would occurred upon nitration and cleavage of the sulfuric acid
be the deracemization of rac-9 using an appropriate chi- monoester.
ral auxiliary. Such resolutions have been known for al-
Both trans-1,2-disubstituted 6-nitroindanes (1R,2R)-
most a century,[13b,23] and the procedure of isolation of 1·HCl·H2O and (1R,2R)-10 possess similar molecular
Scheme 3. Deracemization of rac-9 with (ꢀ)-dibenzoyl-l-tartaric acid (DBT) and conversion of (1R,2R)-9 into (1R,2R)-1 by
nitration.
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The enantiomeric excesses for the thus obtained
(1R,2R)-1 and (1S,2S)-1 were determined by HPLC
analysis of their N-Boc derivatives to be ꢁ98 and
97.6%, respectively. These compounds appear to be per-
fectly stable in the solid phase, but not very stable in sol-
ution, as diluted solutions in both MeOH and THFafter
measurements of the specific rotations slowly turned
dark after standing for two weeks at ambient tempera-
ture.
Figure 1. Molecular structures of (1R,2R)-trans-1-amino-6-ni-
troindan-2-ol hydrochloride monohydrate [(1R,2R)-1·HCl·
H2O] (top) and of sulfuric acid mono-[(1R,2R)-trans-1-ami-
no-6-nitroindan-2-yl] ester [(1R,2R)-10] (bottom) in the crys-
tal.[26]
Scheme 4. Preparation of (1R,2R)-trans-1-amino-6-nitroin-
dan-2-ol [(1R,2R)-1] by deracemization of rac-1 with (þ)-
(S)-l-mandelic acid (MA).
geometries with a C(2)-envelope conformation of the 5-
membered ring and a nitro group slightly rotated out of
the plane of the aromatic ring [torsional angles around
ꢀ
C(6) N(1) bonds are 17.7 and 11.78 for (1R,2R)-1·
HCl·H2O and (1R,2R)-10, respectively]. No abnormal Conclusion
bond lengths and angles were found. The crystal pack-
ings of molecules (1R,2R)-1·HCl·H2O (Figure 2, A) A new efficient approach to the target compound
and (1R,2R)-10 (Figure 2, B) are also remarkably simi- (1R,2R)-1 from inexpensive starting materials – indene
lar to each other in spite of the differing number of hy- (US $ 38.50/kg) and NBS (US $ 43.60/kg; most solvents
drogen bond donors and acceptors in the two structures. and the chiral auxiliary MA can be recovered) – using
A detailed scheme of the hydrogen bonding motifs is the nitration of rac-trans-1-aminoindan-2-ol (rac-9) as
shown in Figure 2 (C and D). In both cases the molecules a key step, has been elaborated. To the best of our
form two-dimensional H-bonded sheets, perpendicular knowledge, this ought to be the most efficient and least
to the c-axis of the unit cell, and a number of weak expensive of all the methods known up to now, at least
C(aryl)–H· · ·O(NO2) interactions connect the sheets for the preparation of 1 in racemic form. Of course, in
[29]
with each other. Such packing is quite different from terms of “atom economy”
the final deracemization
those observed in the crystals of similar compounds – is not perfect. However, this can easily be improved by
the salts of cis-1-aminoindan-2-ol with 2-arylalkanoic employing the previously published ring opening with
acids which form H-bonded columns, and a derivative ammonia of enantiomerically pure (prepared by enzy-
of trans-1-amino-6-nitroindan-2-ol which forms H- matic epoxidation[19]) or at least enantiomerically en-
bonded chains.[27]
riched (prepared by Jacobsen asymmetric epoxidation
Eventually, the target compound (1R,2R)-1 was pre- with NaOCl[18k]) epoxide (1S,2R)-11, followed by nitra-
pared by deracemization of rac-1 (cf.[1,7a]) applying tion and, if necessary, final purification via the salt
(þ)-(S)-l-mandelic acid (MA)[28] for the resolution with MA.
(Scheme 4, for details see Experimental Section). MA
can be recovered in almost quantitative yield and used
again and again.
Experimental Section
The (1R,2R)-1, obtained by this method, had mp 147–
148.58C (dec.) and [a]2D0: þ7.35 (c 1.146, MeOH) or
General
[a]2D0: þ19.9 (c 0.453, THF). As a bonus, (1S,2S)-1 which
had mp 146.5–148.58C (dec.) and [a]2D0: ꢀ6.90 (c 0.60,
All chemicals were used as commercially available. Indene (7)
MeOH) or [a]2D0: ꢀ19.3 (c 0.450, THF) was also isolated. was freshly distilled under reduced pressure, bp 70–728C/
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Figure 2. Crystal packing of (1R,2R)-trans-1-amino-6-nitroindan-2-ol hydrochloride monohydrate [(1R,2R)-1·HCl·H2O] (A),
of sulfuric acid mono-[(1R,2R)-trans-1-amino-6-nitroindan-2-yl] ester [(1R,2R)-10] (B) and detailed scheme of the hydrogen
bonding motifs (C and D, respectively) in the crystal.
25 mbar. Anhydrous dichloromethane and THF for the prepa-
ration of N-Boc derivatives were obtained by distillation from
P4O10 and sodium benzophenone ketyl, respectively. THF for
extractions was distilled from KOH using a rotary evaporator.
Organic extracts were dried over MgSO4. The 1H and 13C NMR
spectra were recorded at 250 (1H), and 62.9 MHz [13C, addi-
tional DEPT (distortionless enhancement by polarization
transfer)] on a Bruker AM 250 instrument in CDCl3, D2O
and DMSO-d6 solutions, CHCl3/CDCl3, DHO and
CD3SOCD2H as internal reference. Chiral HPLC analyses
were performed with a Chiracel OD column, hexane/2-propa-
nol, 98:2 [for N-Boc-(1R,2R)-9] or 90:10 [for N-Boc-(1R,2R)-
1], 0.9 mL/min. Melting points were determined on a Bꢀchi 510
capillary melting point apparatus, values are uncorrected. TLC
analyses were performed on precoated sheets (0.25 mm Sil G/
UV254, Macherey-Nagel).
ing amino and nitro groups is often hazardous, no safety data
for these substances are as yet available.
rac-trans-2-Bromoindan-1-ol (rac-8)
This protocol was essentially adopted from published proce-
dures[10d, e] taking the best details from each. A 2-L, four-
necked, round-bottomed flask equipped with a mechanical
stirrer, a reflux condenser and a thermometer was charged
with a solution of indene (7)[30] (99.6 g, 100 mL, 0.857 mol) in
a mixture of THF (700 mL) and water (700 mL). Under vigo-
rous stirring and external cooling with ice-cold water, N-bro-
mosuccinimide[31] (126,2 g, 0.709 mol) was added in small por-
tions over a period of 2 h, maintaining the internal temperature
around 208C, and the resulting mixture was stirred for an addi-
tional 22 h at ambient temperature. Brine (400 mL) was added,
the two layers were separated in a 4-L separating funnel, and
Caution: The operations with compounds 1, 9 and 10 should
be performed carefully, as the handling of compounds contain-
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the inorganic phase was extracted with ethyl acetate (2ꢂ
600 mL). The combined organic phases were washed with
10% aqueous Na2S2O3 solution (400 mL) and concentrated un-
der reduced pressure. The residue was taken up in diethyl ether
(1.2 L),[32] the solution was washed with water (500 mL), brine
(400 mL), dried and concentrated under reduced pressure to
give rac-8 as a colorless solid; yield: 182.0 g (99.6%); mp 124–
Sulfuric Acid Mono-(rac-trans-1-amino-6-nitroindan-
2-yl) Ester (rac-10)
This protocol for nitration was essentially adopted from a pub-
lished procedure.[15] A 500-mL, four-necked, round-bottomed
flask equipped with a mechanical stirrer, a nitrogen inlet and
a thermometer, was charged with concentrated sulfuric acid
(300 mL) and cooled to ꢀ108C under an atmosphere of nitro-
gen.[34] Under vigorous stirring and external cooling with ace-
tone/dry ice, thoroughly powdered rac-9·HNO3 (84.80 g,
0.4 mol) was added in small portions over a period of 2 h, main-
taining the internal temperature in the range of ꢀ5 to ꢀ108C.
The resulting mixture was vigorously stirred for an additional
1 h at ꢀ108C and for 0.5 h at 08C until a clear solution had
formed, and was then poured onto cracked ice (700 g). The re-
sulting very fine precipitate was filtered off, washed with ice-
cold water (500 mL) and dried under vacuum over P4O10 for
24 h to give rac-10 as a colorless powder, decomposing slowly
above 2508C without melting; yield: 109.7 g (100%); 1H
NMR (DMSO-d6): d¼3.09 (dd, J¼6.6, 17.5 Hz, 1H, CH2),
3.48 (dd, J¼7.4, 17.5 Hz, 1H, CH2), 4.86–4.89 (m, 1H, CH),
4.98 (q, J¼6.5 Hz, 1H, CH), 7.59 (d, J¼8.3 Hz, 1H, Ar-H),
8.23 (d, J¼8.3 Hz, 1H, Ar-H), 8.48 (s, 1H, Ar-H), 8.57 (br. s,
3H, NH3þ); 13C NMR (DMSO-d6): d¼36.9 (CH2), 59.4 (CH),
79.1 (CH), 120.2 (br., CH), 124.8 (br, CH), 126.5 (br, CH),
138.4 (C), 147.1 (C), 148.4 (C); (aromatic CH signals are close
to coalescing); anal. calcd. for C9H10N2O6S (274.3): C 39.41, H
3.67; found: C 39.17, H 3.52.
1
1268C (lit. 127–1288C,[10b] 130–1318C[10e]). Its H[10d] and 13C
NMR spectra[21] were identical to the published ones. Accord-
ing to its 1H NMR spectrum, compound rac-8 was pure enough
to be used without further purification.
rac-trans-1-Aminoindan-2-ol (rac-9)
This protocol was essentially adopted from the published
one.[13c] A 4-L, three-necked, round-bottomed flask, equipped
with a mechanical stirrer and a thermometer, was charged with
25% aqueous ammonia solution (2 L). Under vigorous stirring
and external cooling with ice-cold water, rac-trans-2-bromoin-
dan-1-ol (rac-8) (170.5 g, 0.8 mol) was added in small portions
over a period of 2 h, maintaining the internal temperature
around þ58C, and the resulting mixture was vigorously stirred
for an additional 34 h at ambient temperature. Excess ammo-
nia and some water were evaporated directly from the reaction
flask under reduced pressure (Caution! Evaporation of am-
monia should be done carefully by only slowly decreasing the
pressure) to a volume of ca. 800 mL, then sodium hydroxide
[(32.0 g, 0.8 mol, as a solution in 128 mL of water (20%)] was
added, and the product was isolated by filtration. The mother
liquor was percolated with tert-butyl methyl ether (2 L) over
a period of 24 h.[33] The solvent was evaporated, and the residue
was dried under vacuum over P4O10 overnight to give rac-9 as a
colorless or light beige solid; yield: 114.6 g (96%); mp 1238C
(dec.) (lit.[13c] 128–1298C), which was used without further pu-
rification. Its 1H NMR spectrum was identical to the published
Sodium salt of rac-10: slow decomposition above 2508C
without melting; 1H NMR (DMSO-d6): d¼2.16 (s, 2H, NH2),
2.91 (dd, J¼4.1, 16.8 Hz, 1H, CH2), 3.32 (dd, J¼6.2, 16.8 Hz,
1H, CH2), 4.22 (br.s, 1H, CH), 4.54 (q, J¼6.0 Hz, 1H, CH),
7.45 (d, J¼8.1 Hz, 1H, Ar-H), 8.06 (d, J¼8.1 Hz, 1H, Ar-H),
8.11 (s, 1H, Ar-H); 13C NMR (DMSO-d6): d¼37.0 (CH2),
61.7 (CH), 85.1 (CH), 119.1 (br., CH), 121.8 (br., CH), 125.7
(br, CH), 146.6 (C), 147.0 (C), 147.8 (C); (aromatic CH signals
are close to their coalescence temperature); anal. calcd. for
C9H9N2O6SNa (296.2): C 36.48, H 3.06; found: C 36.36, H 3.06.
one[13c]
;
13C NMR (CDCl3): d¼38.1 (CH2), 64.0 (CH), 82.3
(CH), 123.2 (CH), 124.8 (CH), 127.1 (CH), 127.8 (CH), 138.9
(C), 144.0 (C).
rac-trans-1-Amino-6-nitroindan-2-ol (rac-1)
A 1-L, one-necked, round-bottomed flask equipped with a
magnetic stirrer and a reflux condenser, was charged with
rac-10 (53.5 g, 0.195 mol) and 6 N aqueous HCl (600 mL; by in-
creasing this quantity one can accelerate the reaction, but the
yield drops to 67–74%, as the product is rather well soluble
in water at ambient temperature). The reaction mixture was
stirred at 1008C until rac-10 had completely dissolved and a
clear solution had formed (ca. 1 h), it was then stored in ice
for 15 h. Still cold, the mixture was quickly filtered to give
48.47 g (100%) of rac-trans-1-amino-6-nitroindan-2-ol hydro-
chloride monohydrate (rac-1·HCl·H2O) as beautiful slightly
yellow crystals which easily loose water upon drying under vac-
uum over P4O10 (12 h) to give rac-trans-1-amino-6-nitroindan-
2-ol hydrochloride (rac-1·HCl) (44.95 g, 100%) as a colorless
powder, slowly decomposing above 2418C without melting;
1H NMR (D2O): d¼2.90 (dd, J¼3.8, 17.2 Hz, 1H, CH2), 3.38
(dd, J¼5.7, 17.2 Hz, 1 H, CH2), 4.52–4.57 (m, 2H, 2 CH),
7.41 (d, J¼8.4 Hz, 1H, Ar-H), 8.12 (d, J¼8.4 Hz, 1H, Ar-H),
8.17 (s, 1H, Ar-H); 13C NMR (D2O): d¼41.0 (CH2), 63.4
(CH), 77.9 (CH), 122.5 (br, CH), 127.9 (br, CH), 129.1 (br,
CH), 139.3 (C), 149.7 (C), 151.5 (C); (aromatic CH signals
rac-trans-1-Aminoindan-2-ol Nitrate (rac-9·HNO3)
To a stirred suspension of rac-trans-1-aminoindan-2-ol (rac-9)
(6.88 g, 46.1 mmol) in water in a 500-mL one-necked round-
bottomed flask was added 65% aqueous nitric acid (2.5 mL,
1 equiv.). The mixture was stirred until a clear solution had
formed (ca. 15 min), then water was evaporated under reduced
pressure (408C bath temperature), and the residue was dried
under vacuum over P4O10 for 24 h to give rac-9·HNO3 as a col-
orless or light yellow powder which is very well soluble in wa-
ter; yield: 9.78 g (100%); mp 160–1628C (dec.) (lit.:[13b] not re-
1
ported); H NMR (D2O): d¼2.73 (dd, J¼4.9, 16.4 Hz, 1H,
CH2), 3.21 (dd, J¼6.0, 16.4 Hz, 1H, CH2), 4.42 (m, 2H, 2
CH), 7.11–7.28 (m, 4H, Ar-H); 13C NMR (D2O): d¼40.8
(CH2), 64.0 (CH), 77.9 (CH), 126.9 (CH), 128.0 (CH), 130.0
(CH), 132.4 (CH), 137.5 (C), 143.2 (C). If the solution is col-
ored (this was observed when beige rac-9 was used), it was stir-
red for 1 h with several spoons of charcoal and then filtered
through a pad of Celite before evaporation.
260
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Synthesis of (1R,2R)-trans-1-Amino-6-nitroindan-2-ol
FULL PAPERS
are close to coalescing); anal. calcd. for C9H11ClN2O3 (230.7): C
46.86, H 4.81; found: C 46.54, H 4.59.
(1R,2R)-trans-1-Aminoindan-2-ol [(1R,2R)-9]
The salt (ꢀ)-13 (45.85 g, 90.34 mmol) was suspended in diethyl
ether (150 mL), and the mixture was vigorously stirred for
30 min. Under cooling with ice-cold water 1 N aqueous HCl
solution (226 mL) was added, and the mixture was stirred until
two clear phases had formed (ca. 30 min) which were separat-
ed. The organic phase was dried, filtered and concentrated un-
der reduced pressure to give DBT·H2O as a colorless solid;
yield: 33.66 g (99%); mp 95–988C; [a]2D0: ꢀ119.4 (c 1.055,
MeOH). This corresponds to the data for the pure compound
as commercially available.
This compound (44.2 g, 191.6 mmol) was magnetically stir-
red in a 2-L beaker with water (300 mL) for 10 min. Then
THF (300 mL) was added, the mixture was stirred for an addi-
tional 10 min before 25% aqueous ammonia solution (ca.
65 mL) was added in one portion. After stirring for an addition-
al 5 min, the aqueous layer was saturated with sodium chloride,
the layers were separated, and the aqueous phase was extract-
ed with THF (2ꢂ300 mL). The combined organic phases were
dried, filtered and concentrated under reduced pressure. The
residue was stirred with diethyl ether/hexane mixture (1:1)
and filtered again to give rac-1; yield: 37.0 g (100%); mp 150–
The aqueous layer was transferred to a percolator and
cooled to 58C. Sodium hydroxide (14.46 g, 0.362 mol) was add-
ed, the mixture was stirred with cooling (ice-cold water) until
all of the sodium hydroxide had dissolved, and then was perco-
lated with tert-butyl methyl ether (0.5 L) over a period of 24 h.
The solvent was evaporated, and the residue was dried under
vacuum over P4O10 overnight to give (1R,2R)-9 as colorless
crystals; yield: 13.442 g (99.7%); mp 133–1358C (dec.); [a]2D0:
ꢀ21.5 (c 0.58, MeOH) [lit. for (1S,2S)-9:[10d,24] [a]D20: þ25.0 (c
0.14, CHCl3); [a]2D0: þ22.8 (c 1.112, MeOH)]. The enantiomeric
excesses in (1R,2R)-9 were determined according to the litera-
ture procedure.[10d] Both rac-9 and (1R,2R)-9 were converted
into their N-tert-butoxycarbonyl derivatives adopting a pub-
lished protocol.[10d] 1H and 13C NMR data of N-Boc-rac-9 and
N-Boc-(1R,2R)-9 were identical to the published ones.[3e]
N-Boc-rac-9: mp 114–1158C (lit.[10d] 113–1148C).
1
1528C (EtOAc, dec.) (lit:[3a] 136–1378C). Its H-NMR spec-
trum (DMSO-d6) was identical to the published one (support-
ing information in ref.[7a]); 13C NMR (DMSO-d6): d¼38.7
(CH2), 63.5 (CH), 81.3 (CH), 119.1 (br, CH), 122.9 (br, CH),
125.8 (br, CH), 147.0 (C), 147.7 (C), 148.3 (C); (aromatic CH
signals are close to coalescing). This product can also be puri-
fied by recrystallization from ethyl acetate, but this is less prac-
tical, as the precipitate from EtOAc is rather voluminous.
P-Salt of (1R,2R)-1-Aminoindan-2-ol and (–)-
Dibenzoyl l-Tartrate [(ꢀ)-13]
N-Boc-(1R,2R)-9: mp 130–1328C, [a]2D0: þ55.7 (c 1.376,
CHCl3) [lit.[10d] for N-Boc-(1S,2R)-9: mp not reported, [a]2D0:
ꢀ51.3 (c 0.15, CHCl3)]. These two samples were analyzed by
HPLC, tR ¼22.13 min for (1R,2R)-9 and 28.28 min for
(1S,2S)-9. The analysis disclosed an e.e. of 77.6%.
This protocol was adopted from the published one.[24] A 2-L
beaker equipped with a mechanical stirrer was charged with
a solution of (ꢀ)-dibenzoyl l-tartrate monohydrate (DBT)
(100.0 g, 0.266 mol) in 95% ethanol (350 mL), and the solution
was warmed to ca. 358C. In another 1-L beaker, rac-trans-1-
aminoindan-2-ol (rac-9) (39.69 g, 0.266 mol) was dissolved in
warm (ca. 458C) 95% EtOH, and this solution was added to
the solution of DBT under vigorous stirring. The mixture was
stirred for an additional 30 min. After 12 h, the voluminous
precipitate was filtered off and washed with EtOH (200 mL),
transferred into a 2-L, one-necked round-bottom flask and
heated under reflux for 3 h with 1450 mL of EtOH. After
this, the solution was partially evaporated to a volume of ca.
1100 mL at ambient pressure, and a few seed crystals (prepared
by repeated crystallization) were added. After the mixture had
been left standing for 1 week at ambient temperature, the pre-
cipitate was filtered off, washed with EtOH (200 mL) and dried
under vacuum over P4O10 overnight to give the P-salt (ꢀ)-13 as
colorless crystals; yield: 47.26 g (35%); mp 199–2008C (dec.),
[a]D20: ꢀ100.8 (c 1.18, MeOH) [lit. for (þ)-13:[24] [a]2D0: þ100.7
(c 1.11, MeOH)]. After repeated crystallizations, neither the
Recovery of (ꢀ)-Dibenzoyl L-Tartrate[35]
This procedure is partially described in the previous experi-
ment. The combined mother liquors from the preparation of
(1R,2R)-9 were evaporated in a 1-L, one-necked, round-bot-
tomed flask. The residue was vigorously stirred (mechanical
stirrer) with diethyl ether (500 mL) overnight, filtered off
and washed with diethyl ether (200 mL).[36] The salt was sus-
pended in a mixture of diethyl ether (500 mL) and water
(700 mL) in a 2-L beaker and vigorously stirred for 30 min (me-
chanical stirrer). With cooling in ice-cold water 12 N aqueous
HCl solution (29 mL) was added, and the mixture was stirred
until two clear phases had formed (ca. 1 h), which were separat-
ed. The inorganic phase[37] was extracted with Et2O (250 mL),
the combined organic phases were dried, filtered and concen-
trated under reduced pressure to give DBT·H2O as a light yel-
low foam; yield: 64.41 g (99%); [a]2D0: ꢀ119.2 (c 1.160, MeOH).
1
mp nor [a]2D0: had changed; H NMR (DMSO-d6): d¼2.69
(dd, J¼6.9, 16.5 Hz, 1H, CH2), 3.17 (dd, J¼6.8, 16.5 Hz, 1H,
CH2), 4.31–4.36 (m, 2H, 2 CH), 5.16 (s, 2H, 2 CH), 7.15–7.26
(m, 3H, Ar-H), 7.41–7.44 (m, 1H, Ar-H), 7.49–7.55 (m, 4H,
Ar-H), 7.55–7.68 (m, 2H, Ar-H), 7.96–7.99 (m, 4H, Ar-H),
9.0 (br s, 5H, OHþNH). All the mother liquors from this prep-
aration were collected for the recovery of DBT (see below).
In the second experiment, from rac-9 (20.42 g, 0.137 mol)
and regenerated DBT·H2O (51.48 g, 0.137 mmol) using the
corresponding quantity of regenerated EtOH, (ꢀ)-13 (23.6 g,
34%) was obtained as described above. This sample had
[a]2D0: ꢀ100.5 (c 1.065, MeOH).
(1R,2R)-trans-1-Aminoindan-2-ol Nitrate [(1R,2R)-9·
HNO3]
From (1R,2R)-9 (13.28 g, 89.03 mmol) and 65% aqueous nitric
acid (2.5 mL, 1 equiv.) in water (500 mL), (1R,2R)-9·HNO3
was obtained under the conditions described above as a color-
lesspowder; yield:18.89 g(100%);mp162–1648C(dec.);[a]2D0:
ꢀ24.3 (c 1.149, H2O) [lit.[13b] [a]D20: ꢀ27.8 (c 0.7, H2O)].
Adv. Synth. Catal. 2005, 347, 255–265
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261

Sergei I. Kozhushkov et al.
FULL PAPERS
(1R,2R)-trans-1-Amino-6-nitroindan-2-ol [(1R,2R)-1]
(1R,2R)-trans-1-Amino-6-nitroindan-2-ol [(1R,2R)-1]
and (1S,2S)-trans-1-Amino-6-nitroindan-2-ol [(1S,2S)-1]
From (1R,2R)-9·HNO3 (18.25 g, 85.98 mmol) and H2SO4
(60 mL), sulfuric acid mono-[(1R,2R)-trans-1-amino-6-nitro-
indan-2-yl] ester [(1R,2R)-10] under the conditions described
above, was obtained as a colorless powder, slowly decomposing
above 2508C; yield: 23.57 g (100%). Its 1H and 13C NMR data
were identical to those of rac-10.
The salt (þ)-14 (24.590 g, 71.0 mmol) was suspended in a mix-
ture of diethyl ether (200 mL) and water (200 mL), and the
mixture was vigorously stirred for 15 min. Under cooling
with ice-cold water 1 N aqueous HCl (118 mL) was added,
and the mixture was stirred at ambient temperature until two
clear phases had formed (ca. 15 min) which were separated.
The aqueous layer was extracted with diethyl ether (3ꢂ
150 mL), the combined organic phases were dried, filtered
and concentrated under reduced pressure to give MA as a col-
orless solid; yield: 10.69 g (99%); mp 129–1318C; [a]2D0: þ156.9
(c 3.318, H2O). This corresponds to the data for the pure com-
pound as commercially available [mp 130–1328C and [a]2D0:
þ155.0ꢃ5 (c 5.0, H2O)]. The aqueous layer was magnetically
stirred in a 1-L beaker with THF (200 mL) for 10 min before
25% aqueous ammonia (ca. 30 mL) was added in one portion.
After stirring for an additional 5 min, the aqueous layer was sa-
turated with sodium chloride, the layers were separated, and
the aqueous phase was extracted with THF (3ꢂ150 mL).
The combined organic phases were dried, filtered and concen-
trated under reduced pressure. The residue was stirred with di-
ethyl ether/hexane mixture (1:1, 100 mL), filtered off and
dried under vacuum over P4O10 overnight to give (1R,2R)-1;
yield: 13.64 g (99%); mp 147–148.58C (dec.), [a]2D0: þ7.35 (c
1.146, MeOH), þ19.9 (c¼0.453, THF).
This material (10.69 g, 38.98 mmol) was converted into
(1R,2R)-trans-1-amino-6-nitroindan-2-ol
hydrochloride
[(1R,2R)-1·HCl] as indicated above; yield: 8.80 g (98%);
[a]2D0: ꢀ6.2 (c 1.05, H2O). 1H and 13C NMR data were identical
to those of rac-1·HCl. Work-up of this salt with aqueous am-
monia furnished (1R,2R)-1 in 99% yield, mp 145–1478C
(dec.), [a]2D0: þ15.7 (c 1.16, THF).
Salt [(þ)-14] of (1R,2R)-trans-1-Amino-6-nitroindan-
2-ol [(1R,2R)-1] and (þ)-(S)-l-Mandelic Acid (MA)
A 2-L beaker equipped with a mechanical stirrer was charged
with a solution of MA (41.46 g, 272.5 mmol) in ethanol
(280 mL), and the solution was warmed to ca. 358C. In another
2-L beaker, rac-trans-1-amino-6-nitroindan-2-ol (rac-1)
(51.26 g, 264 mmol) was dissolved in warm (ca. 458C) EtOH
(800 mL), and this solution was added to the solution of MA
with vigorous stirring. The mixture was stirred for an additional
30 min at ca. 408C. After 12 h, the voluminous precipitate was
filtered off and washed with EtOH (240 mL) to give 72.54 g of
the salt mixture. This was transferred into a 2-L, one-necked
round-bottomed flask and heated under reflux for 1 h with
1500 mL of EtOH. After this, seeding crystals (prepared by re-
peated crystallization of the salt from enantiomerically en-
riched [(1R,2R)-1], the preparation of which is described in
the previous experiment) were added. After standing of this
mixture for 1 week at ambient temperature, the precipitate
was filtered off and washed with EtOH (200 mL) to give the
salt mixture; yield: 55.97 g (61%); mp 162–1708C (dec.).[38]
A small portion of this material was converted into (1R,2R)-
1 as described above and then into its N-Boc derivative (see be-
low). The HPLC analysis of the latter disclosed an e.e. of
61.8%. This salt was heated in THF (1100 mL) under reflux
for 30 min (the material dissolved only partially) and, after
standing for two days at ambient temperature, the precipitate
was filtered off and washed with THF (200 mL) to give the
salt; yield: 33.51 g (36.6%); mp 181–1828C (dec.).
This was recrystallized again from EtOH (670 mL, seeding
crystals were added) to give (þ)-14; yield: 31.10 g (34%); mp
183–1848C (dec.), which is essentially the same as the mp of
the seeding crystals (183.5–1848C, dec.); [a]2D0: þ45.3 (c
1.672, MeOH).
The mother liquor from the first crystallization from EtOH
was evaporated, and the residue was recrystallized from EtOH
three times (40 mL of EtOH for every 10 g of the salt; the ma-
terial which did not dissolve in this quantity was filtered off) to
give the salt of MA with (1S,2S)-1 [salt (þ)-14a]; yield: 15.53 g
(17%); mp 163–1648C; [a]2D0: þ47.0 (c 2.088, MeOH).[39]
Analogously, from the salt (þ)-14a (12.432 g, 35.9 mmol),
(þ)-mandelic acid (5.46 g, 100%) and (1S,2S)-1 (6.90 g, 99%)
were obtained according to the same protocol. The latter com-
pound had mp 146.5–148.58C (dec.) and [a]2D0: ꢀ6.90 (c 0.60,
MeOH), ꢀ19.3 (c 0.450, THF). The NMR spectra of both
enantiomers (DMSO-d6) were identical to those of the racemic
compound rac-1.
A sample each of rac-1 (411 mg, 2.12 mmol), (1R,2R)-1
(108 mg, 0.56 mmol) or (1S,2S)-1 (92 mg, 0.47 mmol), respec-
tively, was stirred in anhydrous THF (15 mL) with 1.1 equivs.
of di-tert-butyl pyrocarbonate (Boc2O) at ambient tempera-
ture for 1 h. The reaction mixture was concentrated under re-
duced pressure, and the residue was recrystallized from EtOAc
to give N-Boc-rac-1 (488 mg, 78%), N-Boc-(1R,2R)-1 (147 mg,
90%) and N-Boc-(1S,2S)-1 (125 mg, 90%) as colorless crystals
with mp 184–186 (dec.), 198–199 (dec.) and 199–2018C
(dec.), respectively. The latter two compounds had [a]2D0:
ꢀ73.1 (c 0.884, THF) and [a]2D0: þ70.0 (c 0.916, THF), respec-
1
tively. H NMR (CDCl3) of all three compounds: d¼1.51 (s,
9H, 3 CH3), 2.99 (dd, J¼8.2, 16.8 Hz, 1H, CH2), 3.39 (dd, J¼
7.7, 16.8 Hz, 1H, CH2), 4.10 (br. s, 1H, OH), 4.50 (q, J¼
7.4 Hz, 1H, CH), 4.98 (t, J¼6.0 Hz, 1H, CH), 5.06 (br. s, 1H,
NH), 7.38 (d, J¼8.3 Hz, 1H, Ar-H), 8.09 (s, 1H, Ar-H), 8.16
(dd, J¼2.0, 8.3 Hz, 1H, Ar-H). The HPLC analyses [injection
as a solution in THF, tR ¼12.5 min for (1R,2R)-1 and 14.3 min
for (1S,2S)-1] disclosed an e.e. of ꢁ98% for N-Boc-(1R,2R)-1
and an e.e. of 97.6% for N-Boc-(1S,2S)-1.
All the mother liquors from the different recrystallizations
were evaporated together, and (þ)-mandelic acid was recov-
ered in 98% yield under the conditions described above for
DBT, but with several extractions with diethyl ether, as MA
is rather well soluble in water.
262
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Synthesis of (1R,2R)-trans-1-Amino-6-nitroindan-2-ol
FULL PAPERS
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Acknowledgements
This work was supported by the State of Niedersachsen and the
Fonds der Chemischen Industrie (Germany) as well as EPSRC
(UK). The authors are grateful to the companies BASF AG,
Bayer AG, Chemetall GmbH, and Degussa AG for generous
gifts of chemicals, and particularly to Dr. B. Knieriem, Gçttin-
gen, for his careful proofreading of the final manuscript.
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[9] A financial award was also offered by InnoCentive for an
efficient route to this compound (challenge #861093). No
solution has yet been accepted. The reason for declining
the present one was the impossibility to perform nitra-
tion in concentrated sulfuric acid on a large scale.
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4936 (2qmax ¼57.988), independent: 2743 (Rint ¼0.0381),
197 parameters refined, R1 ¼0.0322 for 2743 reflections
with I>2s(I), wR2 (all data)¼0.0836, GoF¼1.123, max-
imum and minimum residual electron density 0.373 and
ꢀ0.256 e·ꢃꢀ3. (1R,2R)-10: C9H10N2O6S (M 274.25), crys-
tal size 0.14ꢂ0.06ꢂ0.02 mm3, monoclinic, a¼5.2119(2),
b¼7.6336(3), c¼13.4631(5) ꢃ, a¼g¼90, b¼100.79(2)8,
V¼526.17(3) ꢃ3, Z¼2, space group P 21, 1¼1.731 g·
cm–3, m¼0.333 mmꢀ1
,
intensities measured: 5140
(2qmax ¼58.948), independent: 2818 (Rint ¼0.0250), 203
parameters refined, R1 ¼0.0310 for 2818 reflections
with I>2s(I), wR2 (all data)¼0.0618, GoF¼1.020, max-
imum and minimum residual electron density 0.271 and
ꢀ0.338 e·ꢃꢀ3. Crystallographic data (excluding struc-
ture factors) for the structures reported in this paper
have been deposited as supplementary publication no.
CCDC-250618 [(1R,2R)-1·HCl·H2O] and CCDC-
250617 [(1R,2R)-10] with the Cambridge Crystallograph-
ic Data Centre. Copies of the data can be obtained free
of charge on application to The Director, CCDC, 12 Un-
ion Road, Cambridge CB2 1EZ, UK [Fax: (þ44)1223-
336-033; E-mail: deposit@ccdc.cam.ac.uk].
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1 kg; c) City Chemical LLC, US $ 38.50 for 1 kg.
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[31] Cheapest commercial sources: a) Oakwood Products,
Inc., US $ 62.00 for 1 kg; b) City Chemical LLC, US $
109.00 for 2.5 kg; c) Fluorochem Ltd., £ 95.00 for 5 kg.
[32] According to the original procedures,[10d, e] after work-up
with aqueous 10% Na2S2O3 solution, the organic layer
was washed with brine, dried, concentrated and recrys-
tallized from EtOAc[10d] or EtOH,[10e] respectively. How-
ever, this decreases the yield to 85 and 82.5%, respec-
tively, as rac-8 is rather well soluble in both solvents.
Moreover, the main impurity – succinimide – remains
even after recrystallization (from traces and up to 5%).
As this impurity is very poorly soluble in diethyl ether,
we have slightly modified the procedure in this point.
[33] According to the original protocol,[13c] the product was
only filtered off and dried; however, this decreased the
yield to 69%. Another procedure[24] recommends to per-
form an extraction with EtOAc in a percolator for 4 h.
However, we have found that rac-9 is not completely in-
ert towards this solvent under the conditions of continu-
ous extraction, and thus the N-acetyl derivative of rac-9
was found in the resulting product as an impurity (1–
8%, depending on the extraction time, 4–16 h) according
to the 1H NMR spectrum. Unlike this, the extraction
with tert-butyl methyl ether proceeds at a lower temper-
ature and without undesirable side reactions.
[25] Cheapest commercial source: Alfa Aesar, US $ 370.00
for 2.5 kg.
[26] Crystals of the compounds were obtained by recrystalli-
zation from water [(1R,2R)-1·HCl·H2O] and by slow
evaporation of
a solution in THF/aqueous NH3
[(1R,2R)-10]. The X-ray single crystal data were collect-
ed at 120(2) K on Bruker Proteum-M CCD (for 1),
equipped with Bede Microsource X-ray generator, and
Bruker SMART CCD 6000 (for 10) diffractometers us-
ing graphite monochromated Mo-Ka radiation. The
structure solutions and refinements on F2 were per-
formed with the Bruker SHELXTL program suite.
(1R,2R)-1·HCl·H2O:
C9H11N2O3þ ꢂCl– ꢂH2O
(M
248.66), crystal size 0.24ꢂ0.20ꢂ0.12 mm3, monoclinic,
a¼5.2952(2), b¼8.0441(3), c¼12.7859(4) ꢃ, a¼g¼90,
b¼90.90(1)8, V¼544.55(3) ꢃ3, Z¼2, space group P 21,
1¼1.517 g·cmꢀ3, m¼0.352 mmꢀ1, intensities measured:
[34] The role of nitrogen in this reaction is to prevent the di-
lution of H2SO4 by atmospheric moisture only.
264
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Synthesis of (1R,2R)-trans-1-Amino-6-nitroindan-2-ol
FULL PAPERS
[35] The recovery of (–)-dibenzoyl l-tartrate has been describ-
ed in the patents: a) S. Martin, D. Piergentili, UK Pat.
Appl. GB 2382074 A1, 2003; Chem. Abstr. 2003, 138,
385169; b) J. Jendrichovsky, L. Stibranyi, Recovery of
(þ)- and (–)-dibenzoyltartaric acid monohydrate after
resolution of optically active forms of a-methyl-b-dime-
thylaminopropiophenone. Czech. Patent, 1975; Chem.
Abstr. 1975, 83, 78879. However, these patents do not
cover our method, as in both patents the substituted tar-
taric acid derivatives from the resolution process were
firstly neutralized by adding a base (for example, aque-
ous sodium bicarbonate), extracted into an aqueous
phase, and secondly crystallized from the aqueous phase
by addition of a mineral acid.
stirring and washing with Et2O, the salt is colorless again.
Without this operation, the recovered DBT·H2O can
have a dark color.
[37] The aqueous layer can be used for the preparation of
(1S,2S)-9 by isolation of enriched 9 and applying the es-
tablished procedure.[24]
[38] As the specific rotations of the two salts of MA with
(1R,2R)-1 [salt (þ)-14] and (1S,2S)-1 [salt (þ)-14a] are
very close to one another ([a]2D0: þ45.3 (c 1.672,
MeOH) and þ47.0 (c 2.088, MeOH), respectively), the
progress of purification can better be monitored by
measuring the melting points. The second salt is better
soluble in EtOH and in THF than the first one.
[39] Alternatively, the salts (þ)-14 and (þ)-14a can be sepa-
rated by low temperature crystallization from water/
MeOH, 100:1.[1]
[36] This procedure is necessary to purify the salt, which after
evaporation of EtOH has a yellow to green color. After
Adv. Synth. Catal. 2005, 347, 255–265
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ꢂ 2005 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
265