Hydroxy-1-aminoindans and derivatives: Preparation, stability, and reactivity

Article abstract of DOI:10.1021/jo052621m

The chemical stability and reactivity of hydroxy-1-aminoindans and their N-propargyl derivatives are strongly affected by the position of the OH group and its orientation relative to that of the amino moiety. Thus, the 4- and 6-OH regioisomers were found to be stable, while the 5-OH analogues were found to be inherently unstable as the free bases. The latter, having a para orientation between the OH and the amino moieties, could be isolated only as their hydrochloride salts. 7-Hydroxy-1-aminoindans and 7-hydroxy-1- propargylaminoindans represent an intermediate case; while sufficiently stable even as free bases, they exhibit, under certain experimental conditions, unexpected reactivity. The instability of the 5- and 7-hydroxy-aminoindans is attributed to their facile conversion to the corresponding, reactive quinone methide (QM) intermediates. The o-QM obtained from 7-hydroxy-aminoindans was successfully trapped with ethyl vinyl ether via a Diels-Alder reaction to give tricyclic acetals 32a,b.

Full text of DOI:10.1021/jo052621m

Hydroxy-1-aminoindans and Derivatives: Preparation, Stability,
and Reactivity
Yaacov Herzig,*,† Lena Lerman,‡ Willy Goldenberg,† David Lerner,† Hugo E. Gottlieb,‡ and
Abraham Nudelman*,‡
Global InnoVatiVe Research and DeVelopment, TeVa Pharmaceutical Industries Limited, Netanya 42504
and Jerusalem 91010, and Chemistry Department, Bar Ilan UniVersity, Ramat Gan 52900, Israel
nudelman@mail.biu.ac.il
ReceiVed December 21, 2005
The chemical stability and reactivity of hydroxy-1-aminoindans and their N-propargyl derivatives are
strongly affected by the position of the OH group and its orientation relative to that of the amino moiety.
Thus, the 4- and 6-OH regioisomers were found to be stable, while the 5-OH analogues were found to
be inherently unstable as the free bases. The latter, having a para orientation between the OH and the
amino moieties, could be isolated only as their hydrochloride salts. 7-Hydroxy-1-aminoindans and
7-hydroxy-1-propargylaminoindans represent an intermediate case; while sufficiently stable even as free
bases, they exhibit, under certain experimental conditions, unexpected reactivity. The instability of the
5- and 7-hydroxy-aminoindans is attributed to their facile conversion to the corresponding, reactive quinone
methide (QM) intermediates. The o-QM obtained from 7-hydroxy-aminoindans was successfully trapped
with ethyl vinyl ether via a Diels-Alder reaction to give tricyclic acetals 32a,b.
Introduction
and 7-hydroxy-1-amino-indan (4-, 6-, and 7-OHAI) isomers are
synthetically readily accessible,3 while the 5-OHAI analogue
defied our early synthetic attempts. (R)-6-Hydroxy-1-aminoindan
(R-3b) is a key intermediate in the synthesis of ladostigil.
Derivatives of 7-OHAI such as OPC-14117 were reported to
be cerebro-protective and central nervous system stimulants.4a,b
With the exception of 16, described herein, a literature search
has not revealed any other unsubstituted 5-OHAIs. Several
5-hydroxyaminoindan amides are known,5 and a tricyclic
5-OH-N-Me derivative has been reported.6 In the framework
of our structure activity relationship (SAR) studies on carbam-
Ladostigil ((N-propargyl-1R-aminoindan-6-yl)-ethylmethyl-
carbamate hemi-tartrate) is a novel derivative of the selective
irreversible MAO-B inhibitor rasagiline, possessing both cho-
linesterase- and MAO-inhibitory activity.1a,b It is currently under
development as an anti-Alzheimer’s and neuroprotective drug.
(R)-6-Hydroxy-N-propargyl-1-amimoindan (R-6-OHPAI) is a
major metabolite of ladostigil, responsible for the MAO-B
inhibitory activity of the parent drug (Figure 1).2 The 4-, 6-,
† Teva Pharmaceutical Industries Ltd.
‡ Bar Ilan University.
(1) (a) Youdim, M. B.; Weinstock, M. Mech. Ageing DeV. 2002, 123,
1081-1086. (b) Maruyama, W.; Weinstock, M.; Youdim, M. B.; Nagai,
M.; Naoi, M. Neurosci. Lett. 2003, 341, 233-236.
(2) Weinstock, M.; Gorodetsky, E.; Gross, A.; Sagi, Y.; Youdim, M. B.
Prog. Neuro-Psychopharmacol. Biol. Psychiatry 2003, 27, 555-561.
(3) Reference 5 and references therein.
(4) (a) Oshiro, Y.; Sakurai, Y.; Tanaka, T.; Kikuchi, T.; Hirose, T.;
Tottori, K. J. Med. Chem. 1991, 34, 2014-2023. (b) Oshiro, Y.; Sakurai,
Y.; Tanaka, T.; Ueda, H.; Kikuchi, T.; Tottori, K. J. Med. Chem. 1991, 34,
2004-2013.
10.1021/jo052621m CCC: $33.50 © 2006 American Chemical Society
Published on Web 05/04/2006
4130
J. Org. Chem. 2006, 71, 4130-4140

Hydroxy-1-aminoindans and DeriVatiVes
FIGURE 1. Aminoindan derivatives.
SCHEME 1. Synthetic Routes for OHAIs, OHPAIs, and Their N-Methyl Analoguesa
a Reaction conditions: (a) NaCNBH3, NH4OAc; (b) HNH2OH; (c) H2; (d) PgBr; (e) HBr; (f) NaCNBH3, (CH2O)n; (g) (1) HCO2Et, (2) LiAlH4.
oyl-N-propargyl-1-aminoindans, we have investigated the chem-
istry of the various regioisomers of both OHAIs and their
propargyl derivatives OHPAIs.7 Herein we report on the first
synthesis of 5-OHAI and on the stability and reactivity of some
OHAIs and OHPAIs. The instability of 5- and 7-OHAIs is
attributed to the facile formation of the corresponding quinone
methides (QMs). ortho-QMs are widely known as reactive and
unstable intermediates in organic chemistry. QMs are frequently
prepared by pyrolytic or photochemical elimination methods.
Different types of o-benzyl-substituted systems undergo this kind
of elimination under heating or irradiation conditions, most
commonly by thermal dehydration of 2-hydroxybenzyl phenols.8
In the thermal degradation, the temperature range required for
the elimination is about 100-600 °C, depending on the structure
of the starting material. The addition of metal complexes or
various Lewis acids enables the formation of the desired QMs
under milder conditions, increasing product stability.9 Other
systems that yield QMs are 2-alkoxymethyl phenols10 and
2-aminomethyl phenolic Mannich bases, where the amino
moiety is tertiary11 or quaternary12 12. The intermediacy of the
QM derived from 7-OHAI 2b was established by us by a Diels-
Alder reaction with ethyl vinyl ether (EVE) to give the tricyclic
acetals 32a,b.
Results and Discussion
(5) (a) Preparation of N-acyltetralinamines and analogues as cholesterol
biosynthesis inhibitors. Woitun, E.; Maier, R.; Mueller, P.; Hurnaus, R.;
Mark, M.; Eisele, B.; Budzinski, R. M.; Hallermayer, G. Ger. Offen. DE
4438029 A1, 1966. (b) Preparation of N-indanylacetamides and related
compounds as cholesterol acyltransferase inhibitors. Clader, J. W.; Fevig,
T.; Vaccaro, W.; Berger, J. G. Eur. Pat. Appl. EP 508425 A1, 1992. (c)
Bicyclic compounds and their use. Oka, Y.; Nishikawa, K.; Miyake, A.
Eur. Pat. Appl. EP 51391 A1, 1982. (d) Synthesis and angiotensin converting
enzyme inhibitory activity of N-benzocycloalkylglycine derivatives. Miyake,
A.; Itoh, K.; Inada, Y.; Nishikawa, K.; Oka, Y. Takeda Kenkyushoho 1985,
44 (3/4), 171-185. (e) Chromanyl glycines. Oka, Y.; Nishikawa, K.;
Miyake, A. US 4521607 A, 1985.
(6) Hays, S. J.; Novak, P. M.; Ortwine, D. F.; Bigge, C. F.; Colbry, N.
L.; Johnson, C. G.; Lescosky, L. J.; Malone, T. C.; Michael, A.; Reily, M.
D.; Coughenour, L. L.; Brahce, L. J.; Shillis, J. L.; Prober, A., Jr. J. Med.
Chem. 1993, 36, 654-670.
(7) Sterling, J.; Herzig, Y.; Goren, T.; Finkelstein, N.; Lerner, D.;
Goldenberg, W.; Miskolczi, I.; Molnar, S.; Rantal, F.; Tamas, T.; Toth, G.;
Zagyva, A.; Zekany, A.; Lavian, G.; Gross, A.; Friedman, R.; Razin, M.;
Huang, W.; Krais, B.; Chorev, M.; Youdim, M. B.; Weinstock, M. J. Med.
Chem. 2002, 45, 5260-5279.
The preparation of 4-, 6-, and 7-OHAIs and their N-methyl
and N-propargyl derivatives (OHPAIs and OHMPAIs) has been
reported.5 In short, OHAIs were prepared from the correspond-
ing indanones either by conversion of the latter to oximes and
subsequent reduction or via a one-step reductive amination
(NaCNBH3/NH4OAc). Propargylation with propargyl bromide
(either neat or as an 80% solution in toluene) in acetonitrile or
dimethylacetamide afforded the corresponding OHPAIs. N-
Methyl-OHAIs were obtained either by reductive alkylation
(9) Hogeveen, H.; Heldeweg, R. F. J. Am. Chem. Soc. 1976, 98, 6040-
6042.
(10) Eck, V.; Schweig, A.; Vermeer, H. Tetrahedron Lett. 1978, 27,
2433-2436.
(11) (a) Katada, T.; Eguchi, S.; Esaki, T.; Sasaki, T. J. Chem. Soc.,
Perkin Trans. 1 1984, 11, 2649-2653. (b) Katritzky, A. R.; Lan, X.
Synthesis 1992, 761-764. (c) Nakatani, K.; Higashida, N.; Saito, I.
Tetrahedron Lett. 1997, 38, 5005-5008.
(12) (a) Breuer, E.; Melumad, D. Tetrahedron Lett. 1969, 23, 3595-
3596. (b) Gardner, P. D.; Rafsanjani, H. S.; Rand, L. J. Am. Chem. Soc.
1959, 81, 3364-3367.
(8) (a) Talley, J. J. J. Org. Chem. 1985, 50, 1695-1699. (b) Arduini,
A.; Bosi, A.; Pochini, A.; Ungaro, R. Tetrahedron 1985, 41, 3095-3103.
(c) Letulle, M.; Guenot, P.; Ripoll, J. L. Tetrahedron Lett. 1991, 32, 2013-
2016. (d) Yato, M.; Ohwada, T.; Shudo, K. J. Am. Chem. Soc. 1990, 112,
5341-5342.
J. Org. Chem, Vol. 71, No. 11, 2006 4131

Herzig et al.
SCHEME 2. Degradation of 7-OHAIs and 7-OHPAIsa
a Reaction conditions: (a) NaCNBH3/(CH2O)n in MeOH; (b) NaCNBH3, CH3CN; (c) R'OH (R' ) Me/Et).
TABLE 1. Proton NMR Shifts of Isomeric Hydroxy-aminoindan
Derivatives
H-C1
H,H′-C3
Rdpropargyl
HO-position
RdH
Rdpropargyl
RdH
4-
6-
7-
4.19
4.14
4.39
2.59,2.77
2.59,2.74
2.68,2.85
4.07
4.39
2.52,2.68
2.68,2.80
FIGURE 2. Three-dimensional structure of 2b.
(NaCNBH3/paraformaldehyde) or by formylation followed by
LiAlH4 reduction. N-Methyl-OHPAIs (OHMPAIs) were pre-
pared either by propargylating N-methyl-OHAIs or by reductive
alkylation of OHPAIs (Scheme 1).
7-OHAI and its derivatives have been reported as neuroprotec-
tives4a,b and as 5-HT-1A receptor ligands.13
FIGURE 3. Bicyclic analogues of 7-hydroxy-1-aminoindan 2b.
We have found 7-OHAI (2b), 7-OHPAI (2c), and 7-OHMPAI
(2f) to differ from their 4- and 6-analogues in (i) their polarity,
as manifested by TLC, where the former are remarkably less
polar than the latter; and (ii) behavior of the amino group, as
exhibited during reductive alkylation.
proton and the N, which is consistent with the minimum H-bond
length (2.5 Å).
The free base OH absorption in DMSO was not always clearly
1
discernible in the H NMR spectra of all OHAI regioisomers.
Notably, in the spectrum of 2b, a peak was observed at a
nontypical 4.66 ppm, accounting for a H2O + NH2 + OH signal.
However, the presence of H-bonding in 2b and 2c is substanti-
ated by their H-C1 chemical shifts (Table 1), which are shifted
downfield by 0.25 and 0.32 ppm, respectively, relative to the
6-isomers. This is due to the deshielding effect resulting from
the lower electron density on C1, which in turn results from a
decrease in electron density on the nitrogen due to the H-bonding
of its lone pair to the OH proton. The chemical shifts of H,H′-
C3 are apparently not affected by the proximity of the OH group,
as evidenced by the practically identical δ values of H,H′-C3
for the 4- and 6-isomers.
The only report on H-bonding in 2b is that of Breslow and
McClure,15 who have shown assistance by the phenolic group
in the cleavage of an amide in a carboxypeptidase A model.
To the best of our knowledge, H-bonding in 8-hydroxy-1-
aminotetralin has not been reported. However, this phenomenon
has been investigated in 1-amino-8-hydroxy-naphthalenes 6 and
7 (OH and amine in the peri position in the fully aromatic
analogues; Figure 3) by Musso,16 who has shown, using IR
spectroscopy, a strong intramolecular interaction between the
OH and NH2 groups. The unusual acidity of N,N-dimethyl-
Reductive alkylation of the 7-analogues (successfully applied
to the 4- and 6-compounds) did not afford the desired N-
methylated products. Instead, 4-indanol (4a)14a and the novel
3-methoxy-4-indanol (4b) were isolated in about a 1:4.5 ratio
when either 2b or 2c5 was subjected to NaCNBH3/(CH2O)n in
MeOH. The refluxing of 2b in MeOH also led to 4b, and 4a
was isolated as the sole product upon attempted reductive
methylation in acetonitrile (Scheme 2).
To gain some insight into the mechanism(s) leading to the
formation of 4a and 4b, the acetonitrile was substituted for
methanol in the reductive alkylation. In this case, only 4a was
obtained. More intriguing was the observation that mere
refluxing of 2b or 2c in methanol resulted in a mixture of 4b
and dimer 4c (Scheme 2). This is in contrast to the 6-analogues,
which were found to be stable in this solvent.
In the TLC of the hydroxy-aminoindans, the 7-OH isomer
(2b) appeared to be the least polar. This behavior of 2b may be
ascribed to appreciable intramolecular H-bonding (O-H- -N)
present only in this isomer. Molecular modeling (ChemBats3D
2005) showed a distance of 2.15 Å (Figure 2) between the OH
(13) Landsiedel-Maier, D.; Frahm, A. W. Arch. Pharm. (Weinheim, Ger.)
1998, 331, 59-71.
(14) (a) Kraus, M.; Bazant, V. Collect. Czech. Chem. Commun. 1963,
28, 1877-1884. (b) Matlin, A. R.; Inglin, T. A.; Berson, J. A. J. Am. Chem.
Soc. 1982, 104, 4954-4955.
(15) Breslow, R.; McClure, D. E. J. Am. Chem. Soc. 1976, 98, 258-
259.
(16) Musso, H. Chem. Ber. 1971, 104, 1017-1024.
4132 J. Org. Chem., Vol. 71, No. 11, 2006

Hydroxy-1-aminoindans and DeriVatiVes
SCHEME 3. Preparation of N-Methyl Derivatives of 7-OHMPAI 2f and Carbamate 8a
a Reaction conditions: (a) propargyl bromide, MeCN, or dimethylacetamide; (b) NaCNBH3, (CH2O)n, MeOH; (c) MeI, MeOH; (d) HCO2Et, reflux; (e)
LiAlH4.
amino-8-hydroxy naphthalene 7, six pKa units stronger than
1-naphthol, was attributed by Awwal and Hibbert17 to the
presence of the intramolecular O- -H- -N bonds.
In fact, preparation of the few N-alkyl-7-OHAIs reported in
the literature invariably involved reductive amination of in-
danones4,13 and not reductive alkylation of aminoindans.
Moreover, the authors specifically noted that 7-hydroxy-N,N-
dipropyl-aminoindan was not “directly accessible from the
amine”, in contrast to non-OH analogues.13
As the synthesis of 2f by the usual sequence involving the
methylation of 2c proved unsuccessful, the order of the
alkylations was reversed, namely, 2b was first N-methylated
by formylation with ethyl formate, followed by LiAlH4 reduc-
tion, to provide 2d. No problem was found in this sequence, as
the reaction took place in neat ethyl formate in the absence of
either MeOH or a basic species. The final product 2f was
obtained by propargylation of 2d. This mode of introducing a
Me group was not applicable to 2c because the subsequent
LiAlH4 reduction step was not compatible with the propargyl
moiety. In contrast, N-methylation of the 7-carbamoyl-PAI 8
with NaCNBH3/(CH2O)n proceeded smoothly to afford 9.3 Also,
the N-H group in 8 may be H-bonded to the carbamate oxygen,
thus rendering the nitrogen more nucleophilic (Scheme 3).
Preliminary attempts to prepare the elusive 5-OHAI (11) and
its propargyl derivative proved unsuccessful (Scheme 4). Thus,
attempts to demethylate 10d18 under mild conditions (BBr3, -5
°C) led to its degradation (large number of unidentified products)
and did not afford the OH product. Likewise, demethylation of
10e (AlCl3, toluene, 60 °C) resulted in a compound lacking the
familiar aminoindan NMR characteristics.
the nonnucleophilic acetonitrile in the presence of K2CO3
afforded the 5-hydroxy-indene 18,20 whereas in the absence of
base, no reaction took place. Attempted base-catalyzed prop-
argylation failed (Scheme 7).
The formation of 4a, 4b, and 4c during the attempted
reductive methylation of 2b or 2c (Scheme 2); the inability to
prepare 2f from 2c by reductive alkylation and the successful
methylation of 8 (Scheme 3); all the unsuccessful reactions
described in Scheme 4; as well as the formation of compounds
17 and 18 and the stability of 10c and 11 in the absence of
base (Scheme 8) may stem from the intrinsic instability of the
5- and 7-OHAIs, attributed to facile formation of the corre-
sponding QMs 19 and 20 obtained upon the elimination of
ammonia or an amine in the 5- and 7-hydroxy aminoindans
(Scheme 8). The base-catalyzed formation of compound 18 is
attributed to the formation of the para-QM, followed by
deprotonation and aromatization.
This putative mechanism resembles the well-documented self-
immolative connector concept in prodrugs, which undergo
spontaneous fragmentation to afford the parent drugs and QMs
22 and 24. This approach was used, inter alia, for the synthesis
of two doxorubicin prodrugs (Scheme 9).21
Although the 5-hydroxy-propargylated aminoindan (10f) was
not accessible (Scheme 4), we succeeded in preparing carbamoyl
derivatives of 5-OHAI (Scheme 10). Thus, the OH group of
10a22 was first carbamoylated to give 25a, followed by reductive
amination of the ketone under conditions compatible with the
carbamoyl moiety to give 25d. The carbamoyl functionality
cannot donate electrons to the aromatic ring system, and, thus,
no QM is formed. Propargylation of 25d afforded 25, a
regioisomer of ladostigil. In contrast, attempts to prepare the
analogous ester 25c proved unsuccessful due to the instability
of 25b under the reaction conditions, where the ester, unlike
the carbamate, underwent facile methanolysis to the 5-OH
Compound 11, reported by Oshiro et al.4b to be unstable, and
its N-Me derivative 10c, as well as the 5,6-dihydroxy-N-Me
aminoindan 16,19 were eventually synthesized and isolated as
their HCl salts, which, unlike the free bases, were found to be
stable (Schemes 5 and 6).
When the hydrochlorides of compounds 10c and 11, which
are unstable as free bases, were heated in the presence of MeOH/
K2CO3, the methoxy derivative 17 was obtained. Heating in
(20) (a) 1-Aryloxy-4-amino-2-butanols and the pharmaceutical use
thereof. Lunsford, C. D.; Chen, Y. H. US Patent 4,379,167, 1983. (b)
Scharden, G. J. Anal. Appl. Pyrolysis 1979, 1, 159-64.
(21) (a) Michel, S.; Desbene, S.; Gesson, J. P.; Monneret, C.; Tillequin,
F. Stud. Nat. Prod. Chem. 2000, 21, 157-180. (b) Leenders, R. G. G.;
Gerrits, K. A. A.; Ruijtenbeek, R.; Scheeren, H. W.; Haisma, H. J.; Boven,
E. Tetrahedron Lett. 1995, 36, 1701-1704. (c) Leenders, R. G. G.; Damen,
E. W. P.; Bijsterveld, E. J. A.; Scheeren, H. W.; Houba, P. H. J.; Van der
Meulen-Muileman, I. H.; Boven, E.; Haisma, H. J. Bioorg. Med. Chem.
1999, 7, 1597-1610.
(17) Awwal, A.; Hibbert, F. J. Chem. Soc., Perkin Trans. 2 1977, 1,
152-156.
(18) Borne, R. F.; Forrester, M. L.; Waters, I. W. J. Med. Chem. 1977,
20, 771-776.
(19) Propargylamino indan derivatives and propargylamino tetralin
derivatives as brain-selective MAO inhibitors. Blaugrund, E.; Herzig, Y.;
Sterling, J. PCT Int Appl 2003072055, Sept. 4, 2003.
(22) Chakraborti, A. K.; Sharma, L.; Nayak, M. K. J. Org. Chem. 2002,
67, 6406-6414.
J. Org. Chem, Vol. 71, No. 11, 2006 4133

Herzig et al.
SCHEME 4. Unsuccessful Attempts to Prepare 10fa
a Reaction conditions: (a) AlCl3, toluene; (b) NaCNBH3, NH4OAc; (c) NH2OH, HCl; (d) HBr, HOAc; (e) propargyl bromide; (f) BBr3; (g) H2SO4; (h)
propargyl amine, Na(OAc)3BH, rt, 5 days; (i) propargyl amine, Na(OAc)3BH, HOAc, 55 °C, 24 h; (j) propargyl amine, NaCNBH3, MeOH, rt; (k) MeNH2;
(l) H2, Pd/C; (m) BnCl, K2CO3.
SCHEME 5. Preparation of the 5-OHAI Hydrochloride 11a
a Reaction conditions: (a) BnCl, K2CO3; (b) BnNH2, TsOH; (c) (1) NaBH4, MeOH, (2) HCl; (d) H2, 10% Pd/C, MeOH, 24 h, rt; (e) MeNH2, NaCNBH3;
(f) H2, 10% Pd/C.
SCHEME 6. Preparation of the
indanone (10a), which in turn was converted into 5-OHAI (11),
stable only as its hydrochloride salt.
5,6-Dihydroxy-N-methyl-1-aminoindan Hydrochloride 16a
To evaluate whether the instability of the 5- and 7-OHAIs
stems from their facile conversion into reactive QM intermedi-
ates, the presence of which usually can only be deduced from
trapping studies, the following experiments were conducted.
2-Aminomethyl phenol 26, as a monocyclic model of 2b,
was used in our initial studies on the formation and trapping of
the QM intermediates (Scheme 11).
The products obtained in these experiments (Scheme 11)
showed that 26 underwent thermal elimination to give the ortho-
QM, which subsequently reacted as a Michael acceptor in the
presence of a nucleophile. Although the reactions described were
carried out in a nucleophilic solvent, the QM intermediate that
formed preferentially reacted with another molecule of 26, the
best nucleophile present in the reaction mixture, leading to the
formation of 27, labeled as “symmetrical addition product”
a Reaction conditions: (a) AlCl3, toluene; (b) BnCl, K2CO3, DMF; (c)
MeNH3Cl, NaCNBH3, THF/MeOH; (d) H2, Pd/C, MeOH.
(SAP). When the reaction was carried out at 120 °C in a sealed
pressure tube, the intermediate reacted with the solvent (ethanol)
4134 J. Org. Chem., Vol. 71, No. 11, 2006

Hydroxy-1-aminoindans and DeriVatiVes
SCHEME 7. Degradation of 5-OHAIsa
Compound 30 is a bicyclic acetal possessing an asymmetric
carbon center, and the cyclohexene ring was expected to be in
equilibrium of two possible conformers (Scheme 13).25 How-
ever, its 1H NMR spectrum, based on acetal-proton multiplicity,
showed the presence of A as a sole conformer, where the ethoxy
group is found at an axial position with no evidence for the
presence of conformer E. The spectrum showed the acetal proton
as a triplet with a coupling constant of 3.9 Hz, which is possible
only when the proton is found in an equatorial position (JHHa
) JHHb ) 3.9 Hz). The prevalence of conformer A may be due
to the anomeric effect, which contributes to the relative stability
of this regioisomer.
a Reaction conditions: (a) propargyl amine, K2CO3; (b) MeOH, K2CO3,
heat; (c) MeCN, K2CO3, heat; (d) MeCN, heat.
After succeeding in trapping the intermediate obtained from
the 2-aminomethyl phenol (26) model compound, the analogous
reaction was repeated with 7-hydroxy-1-aminoindan (2b).4b
Unlike the benzylic amine 26, aminoindan 2b, when refluxed
in nucleophilic solvents (MeOH or EtOH), gave primarily ethers
4b and 4b′14b and a minor amount of the SAP product 4c
(Scheme 2). In the nonnucleophilic acetonitrile, the SAP product
4c formed as a 2:1 mixture of a major (M) and a minor (m)
diastereomers, which were not separated. The difference in the
products obtained from 26 and 2b may be attributed to the
relative reactivity of their respective ortho-QM intermediates.
Thus, the monocyclic intermediate 29, obtained from 26,
appeared to be less reactive and more selective than the
corresponding bicyclic intermediate 20, obtained from 2b.
Whereas in the former case of intermediate 29, the SAP product
was that derived from selective nucleophilic addition of 26 to
29, and in the latter case, intermediate 20 reacted rapidly with
the alcoholic solvent present in large excess to give 4b or 4b′.
The higher reactivity of the bicyclic ortho-QM intermediate 20
may stem from the cyclopentene ring strain, enabling it to react
with the alcoholic solvent.
SCHEME 8. Quinone Methides of 5- and 7-OHAIs
SCHEME 9. Self-Immolative Mode of Action of
Doxorubicin Prodrugs
The ortho-QM intermediate 20 was also trapped by a similar
Diels-Alder reaction, leading to a 1.5:1 mixture (1H NMR) of
novel tricyclic acetals 32a and 32b, obtained by exo and endo
additions, respectively (Scheme 14). The structural determination
of 32a and 32b was based on the multiplicity and coupling
constants of the protons attached to both of the asymmetric
carbons (Figure 4, models created with Symapps 6).
An analogous tetracyclic acetal 35, obtained by photolysis
of hydroxy-9-fluorenol (33) in the presence of EVE, has been
reported (Scheme 15).26
The acetal protons in the 1H NMR spectrum of 32a and 32b
appeared as two neighboring multiplets, one as a triplet and
the other as a double-doublet. The triplet multiplicity of the
hydrogen is possible when found at an equatorial position so
that it is gauche to both of its neighboring protons. According
to this observation, the hydrogen displaying a triplet multiplicity
belongs to the 32a stereoisomer. Moreover, the axial position
of the EtO group contributes to the relative stability of this
conformer by involving the anomeric effect. The proton
displaying a double-doublet multiplicity belongs to the stereo-
isomer 32b, where the acetal proton is at an axial position being
anti to one of its neighboring hydrogens and gauche to the other.
The H-C9 appears as a triplet of triplets in both regioisomers
32a and 32b. The coupling constants correspond to the hydrogen
located at a pseudoaxial position to both rings (Figure 4).
to provide 28 as the only product in a temperature-dependent
yield. When benzylamine was treated under the same conditions,
no products of displacement or condensation were observed,
and the benzylamine remained intact. This observation suggests
that the presence of the o-hydroxyl group plays a key role in
these reactions.
Because ortho-QMs behave as heterodienes, another possible
trapping course is the Diels-Alder reaction.23 A QM, being an
“inverse electron demand diene” in Diels-Alder reactions,
requires electron-rich dienophiles, such as EVE.24 Heating a neat
mixture of 26 and EVE in a pressure tube at 140 °C led to the
Diels-Alder adduct 30, while at 100 °C, it gave a mixture of
30 as a minor product together with the tertiary amine 31 as a
major component that was not isolated, but the structure of
1
which was established by H NMR (Scheme 12).
(23) Hall, H. K., Jr.; Rasoul, H. A. A.; Gillard, M.; Abdelkader, M.;
Nogues, P.; Sentman, R. C. Tetrahedron Lett. 1982, 23, 603-606.
(24) Goldschmidt, Z.; Levinger, S.; Gottlieb, H. E. Tetrahedron Lett.
1994, 35, 7273-7276.
(25) Descotes, G.; Martin, J. C.; Mathicolonis, N. Bull. Soc. Chim. Fr.
1972, 1077-1084.
(26) Fischer, M.; Shi, Y.; Zhao, B.; Snieckus, V.; Wan, P. Can. J. Chem.
1999, 77, 868-874.
J. Org. Chem, Vol. 71, No. 11, 2006 4135

Herzig et al.
SCHEME 10. Preparation of Carbamates 25 and 25da
a Reaction conditions: (a) PhCOCl; (b) NaCNBH3, NH4OAc, MeOH; (c) ethyl-methyl carbamoyl chloride, K2CO3, CH3CN; (d) propargyl bromide,
K2CO3, CH3CN.
SCHEME 11. Degradation of 2-Aminomethyl Phenol 26
chemical stability and reactivity. Thus, the 4- and 6-OH
regioisomers were found to be stable, while the 5-OH analogues
were found to be inherently unstable as the free bases, and they
could be isolated only as their HCl salts. 7-OHAI and 7-OHPAI
represent an intermediate case, while sufficiently stable even
as free bases, they exhibit, under certain experimental conditions,
unexpected reactivity. The instability of the 5- and 7-hydroxy-
aminoindans is attributed to their facile conversion to the
corresponding, reactive QM intermediates, which readily react
with nucleophiles to provide different types of addition products.
The presence of the QM obtained from 2b (7-OHAI) was
established upon its trapping with EVE to give the tricyclic
acetals 32a,b.
SCHEME 12. Trapping of QM 29 via a Diels-Alder
Reaction
Experimental Section
All commercial chemicals and solvents were reagent grade and
were used without further purification, unless otherwise specified.
Melting points are uncorrected. Silica gel 60 F254 plates were used
for analytical TLC (visualized with UV light and iodine vapors);
flash column chromatography was performed on silica gel 60 (70-
230 mesh). Chemical shifts are expressed in δ (ppm) relative to
TMS (in DMSO-d6 or CDCl3) as internal standard, or to HOD (4.80
ppm, in D2O), and coupling constants (J) are in Hz. Reaction
conditions were not optimized. The 4-, 6- and 7- OHAIs, OHPAIs
and OHMPAIs were prepared as previously reported.5 Spectroscopic
data for compounds 10,27 10a,22 10d,18 10i (Scheme 4),28 12,29 13,30
14,19 15,19 16 (Scheme 6)19 and 1820 (Scheme 7) have been
previously described in the literature.
7-Hydroxy-indan (4a).14a A mixture of 2b4b,5 free base (1.0 g),
paraformaldehyde (0.8 g), and NaCNBH3 (0.44 g) in MeCN (20
mL) was heated at reflux under Ar for 5 h. The solvent was
removed, and the yellow solid residue (2.4 g) was purified by flash
column chromatography (hexane/EtOAc, 4:1) to give 110 mg of
4a.
SCHEME 13. Equilibrium of 30 Conformers
1-Methoxy-7-hydroxy-indan (4b) and N,N-Bis-(7-hydroxy-
indan-1-yl)amine (4c). Method A: A solution of 2b free base
(1.5 g) in MeOH (40 mL) was heated at reflux under Ar for 20 h.
The solvent was removed, and the residue (brown oil, 1.25 g) was
purified by flash column chromatography (hexane/EtOAc, 3:1) to
When the 1.5:1 diastereomeric mixture of 32a and 32b,
obtained from 2b, was dissolved in CDCl3, it underwent
epimerization at the acetal carbon, shifting the ratio of 32a and
32b to 6:1. This observation supports the assumption that 32a
is the predominant product due to the anomeric effect.
(27) (a) Noureldin, N. A.; Zhao, D.; Lee, D. G. J. Org. Chem. 1997, 62,
8767-72. (b) Ohkata, K.; Akiyama, M.; Wada, K.; Sakaue, S.; Toda, Y.;
Hanafusa, T. J. Org. Chem. 1984, 49, 2517-2520.
(28) Miyake, A.; Itoh, K.; Tada, N.; Tanabe, M.; Hirata, M.; Oka, Y.
Chem. Pharm. Bull. 1983, 31, 2329-2348.
(29) (a) Garnier, S. V.; Larock, R. C. J. Am. Chem. Soc. 2003, 125,
4804-4807. (b) Haadsma-Svensson, S. R.; Cleek, K. A.; Dinh, D. M.;
Duncan, J. N.; Haber, C. L.; Huff, R. M.; Lajiness, M. E.; Nichols, N. F.;
Smith, M. W.; Svensson, K. A.; Zaya, M. J.; Carlsson, A.; Lin, C. H. J.
Med. Chem. 2001, 44, 4716-4732.
(30) Gazit, A.; Osherov, N.; Posner, I.; Yaish, P.; Poraduso, E.; Gilon,
C.; Levitzki, A. J. Med. Chem. 1991, 34, 1896-1907.
Conclusions
The position of the OH group and its orientation relative to
that of the amino moiety in hydroxy-aminoindans and their
N-propargyl analogues was found to strongly affect their
4136 J. Org. Chem., Vol. 71, No. 11, 2006

Hydroxy-1-aminoindans and DeriVatiVes
FIGURE 4. 1H NMR evaluation of 32a,b.
SCHEME 14. Diels-Alder Trapping Reaction of QM 20
2H, J ) 6.6 Hz, H-C1 of M), 4.45-4.43 (t, 2H, J ) 6.6 Hz, H-C1
of m), 2.95-2.91 (ddd, 2H, J ) 15, 8, 4 Hz, H-C3 of M), 2.92-
2.86 (m, 2H, H-C3 of m), 2.78-2.72 (ddd, 2H, J ) 15, 8, 8 Hz,
H-C3 of M), 2.68-2.63 (m, 2H, H-C3 of m), 2.52-2.46 (m, 2H,
H-C2 of M), 2.42-2.35 (m, 2H, H-C2 of m), 1.89-1.83 (m, 4H,
H-C2 of M/m). 13C NMR (DMSO-d6) δ 154.9 (C7 of m), 154.6
(C7 of M), 144.3 (C9 of M), 144.0 (C9 of m), 129.9 (C8 of m),
129.1 (C8 of M), 128.8 (C5 of M), 128.5 (C5 of m), 115.2 (C4 of
M), 115.0 (C4 of m), 112.7 (C6 of M), 112.6 (C6 of m), 61.4 (C1
of m), 59.4 (C1 of M), 34.5 (C2 of m), 33.2 (C2 of M), 30.3 (C3
of m), 30.2 (C3 of M). MS (ES-) m/z 280 ([M - H]-, 100).
Method B: A mixture of 2c free base (8.5 g), paraformaldehyde
(6 g), and NaCNBH3 (3.30 g) in anhydrous MeOH (150 mL) was
heated at reflux under Ar for 4 h. The solvent was removed, and
the yellow solid residue (16 g) was purified by flash column
chromatography (hexane/EtOAc, 7:3) to give 6.1 g of a yellow oil.
Of the latter, 3.3 g was further purified by flash column chroma-
tography (CH2Cl2) to give 4a (210 mg) and 4b (880 mg).
SCHEME 15. Diels-Alder Trapping Reaction of Fluorenol
33
1-Ethoxy-7-hydroxy-indan (4b′).14b A solution of 2b free base
(0.5 g) in EtOH (30 mL) was heated at 65 °C under Ar for 20 h.
The solvent was removed, and the yellow oil residue (640 mg)
was purified by flash column chromatography (hexane/EtOAc, 6:1)
1
to give 180 mg of 4b′. H NMR (DMSO-d6) δ 7.07-6.99 (t, 1H,
J ) 7.3 Hz), 6.69-6.61 (d, 1H, J ) 7.3 Hz), 6.59-6.52 (d, 1H, J
) 7.3 Hz), 4.93-4.9 (t, 1H, J ) 3.5 Hz), 3.54-3.46 (m, 2H), 2.98-
2.90 (dd, 1H, J ) 16, 8 Hz), 2.70-2.62 (dt, 1H, J ) 16, 5 Hz),
2.03-1.99 (m, 2H), 1.08-1.04 (t, 3H, J ) 7.2 Hz). 13C NMR
(DMSO-d6) δ 154.5, 146.7, 129.6, 129.0, 115.3, 113.0, 79.2, 63.3,
32.0, 30.4, 15.6. MS (CI/NH3) m/z 196 (MNH4+, 9), 178 (M, 29),
149 ([M - C2H5], 100), 131 ([M - C2H6O]+, 100).
2,3-Dihydro-5-methoxy-1H-inden-1-amine Hydrochloride
(10d).31 A mixture of dry (evaporated 3 times from MeOH)
ammonium acetate (54.3 g, 0.7 mol), 5-methoxy-1-indanone (10;27
10.0 g, 0.06 mol), and NaCNBH3 (6.54 g, 0.1 mol) in dry MeOH
(300 mL) was stirred and heated at reflux under nitrogen for 6 h.
The mixture was cooled to 5 °C and acidified with concentrated
HCl to pH of 1. The solvent was removed at reduced pressure to
give an off-white solid. Ether (150 mL) was added, and the mixture
was stirred for 20 min. The ether was decanted, and the process
was repeated with another portion (150 mL) of ether. The yellow
solid residue was dried under vacuum for 2 h and then dissolved
give 700 mg of 4b and 400 mg of dimer 4c (∼1:1 diastereomeric
mixture, peak assignment based on full analysis of two-dimensional
spectra). Spectroscopic Data for 4b: 1H NMR (DMSO-d6) δ 7.07-
6.99 (t, 1H, J ) 7.5 Hz, H-C5), 6.69-6.67 (d, 1H, J ) 7.5 Hz,
H-C4), 6.62-6.59 (d, 1H, J ) 7.5 Hz, H-C6), 4.85-4.82 (dd, 1H,
J ) 4.7, 3.5 Hz, H-C1), 3.2 (s, 3H, OCH3), 3.00-2.88 (dt, 1H, J
) 16.4, 8 Hz, H-C3), 2.77-2.62 (ddd, 1H, J ) 16.4, 8, 3.5 Hz,
H-C3), 2.09-2.00 (m, 2H, H-C2). 13C NMR (DMSO-d6) δ 154.6
(C7), 146.8 (C9), 129.8 (C5), 128.6 (C8), 115.2 (C4), 113.0 (C6),
80.8 (C1), 55.7 (OCH3), 31.4 (C2), 30.3 (C3). MS (CI/NH3) m/z
164 (M+., 19), 148 ([M - CH3]+, 17), 132 ([M - CH3OH], 86).
Spectroscopic Data for 4c: (mixture of diastereomers RR/RS [M
) major, m ) minor], peak assignment based on full analysis of
1
two-dimensional spectra). H NMR (DMSO-d6) δ 7.03-7.01 (t,
2H, J ) 7.2 Hz, H-C5 of M), 7.01-6.98 (t, 2H, J ) 7.2 Hz, H-C5
of m), 6.69-6.68 (d, 2H, J ) 7.2 Hz, H-C4 of M), 6.65-6.64 (d,
2H, J ) 7.2 Hz, H-C4 of m), 6.55-6.53 (d, 2H, J ) 7.2 Hz, H-C6
of M), 6.53-6.52 (d, 2H, J ) 7.2 Hz, H-C6 of m), 4.48-4.46 (t,
(31) Panetta, C. A.; Bunce, S. C. J. Org. Chem. 1961, 26, 4859-4866.
J. Org. Chem, Vol. 71, No. 11, 2006 4137

Herzig et al.
in a mixture of 25% aqueous NH4OH (200 mL), water (100 mL),
and CH2Cl2 (150 mL). The layers were separated, and the aqueous
layer was re-extracted with CH2Cl2 (6 × 70 mL). The combined
organic layer was dried over Na2SO4 and filtered, and the solvent
was evaporated. The residue was purified by flash column chro-
matography (CH2Cl2/MeOH 3:1) to give 4.08 g (40.6% yield) of
the free base as a tan oil. This oil (1.2 g, 7.35 mmol) was dissolved
in a mixture of dry ether (30 mL) and MeOH (50 mL), and ether
saturated with HCl gas (14 mL) was added. The mixture was stirred
at room temperature for 30 min, and the solvent was evaporated to
give a white solid. Dry ether (130 mL) was added, and the mixture
was stirred and filtered. Drying at 60 °C under vacuum for 60 h
gave the title product as a white solid (1.10 g, 75%), mp 229-230
°C. 1H NMR (D2O) δ 7.45-7.42 (d, 1H, J ) 8.4 Hz), 7.01 (d, 1H,
J ) 2.5 Hz), 6.96-6.92 (dd, 1H, J ) 8.4, 2.5 Hz), 4.8-4.79 (m,
1H), 3.85 (s, 3H), 3.14-3.09 (m, 1H), 3.01-2.98 (m, 1H), 2.63-
2.6 (m, 1H), 2.19-2.13 (m, 1H).
times to give 2.2 g of a light tan solid (57% from 10i), mp 186-
188 °C. 1H NMR (D2O) δ 7.59-7.57 (d, 1H, J ) 6 Hz), 7.52-7.5
(d, 2H, J ) 5.2 Hz), 7.29-7.19, 7.62 (m, 8H), 6.74-6.71 (m, 2H,
H-C4), 4.84 (d, 2H, J ) 1.4 Hz), 4.29-4.26 (dd, 1H, J ) 5.7, 2.2
Hz), 3.72 (s, 2H), 3.23-3.15 (dt, 1H, J ) 12.1, 5.9 Hz), 2.75-
2.67 (ddd, 1H, J ) 12.1, 6.6, 2.7 Hz), 2.34-2.28 (m, 1H), 2.27-
2.19 (m, 1H). MS (CI/NH3) m/z 224 ([M - PhCH2OH]+, 100),
330 (MH+, 52).
5-Hydroxy-1-aminoindan Hydrochloride (11). A mixture of
11b (1.20 g, 3.3 mmol) in MeOH (200 mL) and 10% Pd/C catalyst
(1.50 g) was hydrogenated at an initial pressure of 3.5 atm for 28
h. The mixture was then filtered through Celite, and the residue
was washed with MeOH. Evaporation of the solvent at 35 °C gave
1
520 mg (85% yield) of a light tan solid. H NMR (D2O) δ 7.35-
7.32 (d, 1H, J ) 8.3 Hz), 6.85-6.84 (d, 1H, J ) 2.2 Hz), 6.81-
6.77 (dd, 1H, J ) 8.3, 2.2 Hz), 4.72 (m, 1H), 3.33-2.95 (dt, 1H,
J ) 12.1, 8 Hz), 2.94-2.91 (ddd, 1H, J ) 12.1, 9, 5 Hz), 2.57-
2.51 (m, 1H), 2.14-2.08 (m, 1H). MS (CI/NH3) m/z 150 (MH+,
13), 132 ([M - NH2]+, 100). Anal. Calcd for C9H12NOCl‚
0.75H2O: C, 54.28; H, 6.83; N, 7.03. Found: C, 54.45; H, 6.38;
N, 7.26. HRMS (DCI/CH4) m/z calcd for C9H11NO (M+),
149.0841; found, 149.0815.
2,3-Dihydro-5-methoxy-N-(prop-2-ynyl)-1H-inden-1-amine Hy-
drochloride (10e).31 A mixture of 10d free base (2.02 g, 12.38
mmol) and K2CO3 (1.82 g, 13.17 mmol) in MeCN (50 mL) was
stirred at room temperature under nitrogen for 20 min. A solution
of propargyl bromide (1.33 g, 11.18 mmol) in MeCN (10 mL) was
added dropwise with stirring under nitrogen over 15 min. After
being stirred for 22 h, the mixture was filtered and the solvent was
evaporated. The residue was purified by flash column chromatog-
raphy (hexane/EtOAc, 1:1) to give 1.3 g (58% yield) of the free
base as a tan oil. This oil (0.75 g, 3.73 mmol) was dissolved in a
mixture of dry ether (50 mL), and ether saturated with HCl gas (6
mL) was added. A gummy solid formed, and the mixture was stirred
at room temperature for 20 min. The ether was decanted, a fresh
portion of ether (50 mL) was added, and stirring was continued
for 20 more minutes. The process was repeated with another portion
(50 mL) of ether. The precipitated white solid was filtered and dried
under vacuum at 60 °C for 48 h to give the title product as a white
O-Benzyl-N-methyl-5-hydroxy-1-aminoindan Hydrochloride
(10h). A mixture of 10i (3.45 g, 14.5 mmol), 8 M ethanolic
methylamine (15 mL, 120 mmol), MeNH2 hydrochloride (3.6 g,
53 mmol), NaCNBH3 (1.47 g, 23.4 mmol), dry THF (375 mL),
and MeOH (125 mL) was stirred and heated at reflux under N2 for
8 h. The mixture was cooled to 5 °C and acidified to pH 1 with
concentrated HCl. Evaporation at 45 °C gave a tan solid that was
treated with CH2Cl2 (250 mL) and water (250 mL). The resulting
mixture was separated, and the aqueous layer was re-extracted with
CH2Cl2 (10 × 60 mL). The combined organic layer was washed
with water (150 mL) and brine (150 mL) and dried (Na2SO4).
Evaporation of solvent at reduced pressure gave a light tan solid
that was purified by flash chromatography (CH2Cl2/MeOH, 4:1)
to give 3.0 g of a light yellow solid. The solid was further purified
by stirring it with hexane (50 mL) at 25 °C for 30 min and filtering.
The hexane washing was repeated one more time to give 2.70 g
(64%) of a yellowish solid, mp 174-176 °C. 1H NMR (CDCl3) δ
7.6-7.57 (d, 1H, J ) 9.1 Hz), 7.31-7.2 (m, 5H), 6.8-6.78 (m,
2H), 4.91 (s, 2H), 4.48-4.44 (dd, 1H, J ) 7.7, 3.2 Hz), 3.23-3.17
(m, 1H), 2.84-2.81 (m, 1H), 2.41-2.09 (m, 5H). MS (CI/NH3)
m/z 254 (MH+, 20), 222 ([M - NHCH3]+, 100), 132 (C9H10N,
98).
1
solid (650 mg, 73%), mp 122-124 °C. H NMR (D2O) δ 7.49-
7.46 (d, 1H, J ) 8.4 Hz), 7.03-7.02 (d, 1H, J ) 2.2 Hz), 6.96-
6.92 (dd, 1H, J ) 8.4, 2.2 Hz), 4.92-4.88 (dd, 1H, J ) 7.6, 2.5
Hz), 3.95-3.93 (t, 2H, J ) 2.4 Hz), 3.85 (s, 3H), 3.18-3.12 (m,
1H), 3.09-2.99 (m, 2H, H-C3), 2.62-2.54 (m, 1H), 2.33-2.28
(m, 1H).
Benzyl-(5-bezyloxy-indan-1-ylidene)-amine (11a).32 A mixture
of 10i28 (2.5 g, 10.5 mmol), benzylamine (1.26 g, 11.8 mmol),
p-toluenesulfonic acid monohydrate (0.60 g, 3.15 mmol), and dry
toluene (150 mL) was stirred and heated at reflux for 5 h while
removing the water formed by means of a Dean-Stark trap. The
mixture was cooled to 25 °C, and the insoluble material was filtered
off. The filtrate was evaporated at reduced pressure to give a residue
shown by TLC to consist of a mixture of unreacted 10i (∼40%)
and compound 11a (∼60%). The residue was used in the next step
without further purification.
N-Methyl-5-hydroxy-1-aminoindan Hydrochloride (10c). A
solution of 10h (1.75 g, 6 mmol) in MeOH (200 mL) was
hydrogenated in the presence of 10% Pd/C (550 mg) at 25 °C at
an initial pressure of 3.5 atm for 2 h. The mixture was then filtered
through filter-aid, and the residue was washed with MeOH.
Evaporation of the solvent at 35 °C gave 1.16 g (96%) of an off-
N,O-Dibenzyl-5-hydroxy-1-aminoindan Hydrochloride (11b).32
The residue from the previous step was dissolved in MeOH (150
mL), and NaBH4 (600 mg, 15.9 mmol) was added portionwise under
ice cooling. After stirring at 25 °C for 1 h under N2, the mixture
was poured into cold water (70 mL) and extracted with CH2Cl2 (6
× 70 mL). The combined organic phase was washed with water
(150 mL), dried (Na2SO4), and evaporated. The residue was
dissolved in a mixture of anhydrous ether (25 mL) and CH2Cl2 (5
mL), and ether saturated with HCl gas (10 mL) was added with
stirring. A dark solid precipitated, and the solvent was decanted.
Dry ether (100 mL) was added to the solid, and the mixture was
stirred for 30 min and filtered. The solid was again treated with
dry ether (100 mL) and stirred for 30 min, and the suspension was
filtered to give 2.5 g of a tan solid. This crude material was purified
by stirring it with EtOAc (30 mL) for 20 min and filtering under
vacuum. The above washings with EtOAc were repeated two more
1
white solid. H NMR (D2O) δ 7.38-7.36 (d, 1H, J ) 8.4 Hz),
6.85 (s, 1H), 6.82-6.79 (dd, 1H, J ) 8.4, 2.1 Hz), 4.66-4.62 (dd,
1H, J ) 7.8, 2.7 Hz), 3.15-3 (dt, 1H, J ) 12, 8 Hz), 2.96-2.85
(ddd, 1H, J ) 12, 6, 2.7 Hz), 2.67 (s, 3H), 2.58-2.4 (m, 1H), 2.3-
2.15 (m, 1H). MS (CI/NH3) m/z 164 (MH+, 28), 132 ([M - CH3-
NH2], 100). Anal. Calcd for C10H14NOCl‚H2O: C, 55.17; H, 7.41;
N, 6.44. Found: C, 55.62; H, 6.84; N, 6.31. HRMS (DCI/CH4)
m/z calcd for C10H13NO (M+), 163.0997; found, 163.0970.
1-Methoxy-5-hydroxy-indan (17). A mixture of 5-hydroxy-1-
aminoindan hydrochloride (11; 300 mg, 1.50 mmol), K2CO3 (500
mg, 3.62 mmol), and MeOH (50 mL) was stirred and heated at
reflux for 4.5 h. The mixture was cooled, silica gel (600 mg) was
added, and the mixture was evaporated to give silica gel impreg-
nated with the crude product, which was purified by flash column
chromatography (CH2Cl2/MeOH, 100:3) to give 150 mg (61%) of
1
a yellow oil. H NMR (DMSO-d6) δ 9.29 (s, 1H), 7.13-7.11 (d,
1H, J ) 8 Hz), 6.61 (s, 1H), 6.58-6.55 (dd, 1H, J ) 8, 2.3 Hz),
4.63-4.6 (dd, 1H, J ) 6.4, 3.2 Hz), 3.23 (s, 3H), 3.05-2.9 (m,
(32) Chromanyl Glycines. Oka, Y.; Nishikawa, K.; Miyake, A. US Patent
4,521,607, June 4, 1985.
4138 J. Org. Chem., Vol. 71, No. 11, 2006

Hydroxy-1-aminoindans and DeriVatiVes
1H), 2.78-2.64 (m, 1H), 2.31-2.26 (m, 1H), 2.16-2.11 (m, 1H).
MS (CI/i-butane) m/z 163 (M+, 17).
additional 20 min. This ether was also decanted, and the process
was repeated with another portion (50 mL) of ether. The precipitated
white solid was filtered and dried to give 25 (700 mg, 79%), mp
168-170 °C. 1H NMR (D2O) δ 7.58 (d, 1H, J ) 8.3 Hz), 7.16 (s,
1H), 7.11-7.08 (d, 1H, J ) 8.3 Hz), 5.0-4.96 (dd, 1H, J ) 7.65,
2.9 Hz), 3.99 (d, 2H, J ) 0.72 Hz), 3.55-3.37 (q, 2H, J ) 7.3
Hz), 3.19-2.99 (m, 6H), 2.65-2.6 (m, 1H), 2.37-2.29 (m, 1H),
1.27-1.15 (t, 3H, J ) 7.3 Hz). MS (CI/NH3) m/z 273 (MH+, 12),
218 ([M - C3H4N], 100). Anal. Calcd for C16H20N2O2‚HCl: C,
62.23; H, 6.86; N, 9.07; Cl, 11.48. Found: C, 61.83; H, 6.99; N,
9.09; Cl, 11.02.
2-Aminomethyl Phenol (26).33 A mixture of salicyloxime (3 g,
22 mmol) and 5% Pd/C (0.5 g) in MeOH (50 mL) was hydrogenated
at room temperature under 13 psi pressure, with vigorous stirring,
for 4 h. The catalyst was filtered through Celite, and the filtrate
was further purified by column chromatography (hexane/EtOAc,
1:1) to provide a colorless solid in 35% yield, mp 125-128 °C
[lit34 128 °C]. 1H NMR (DMSO-d6) δ 7.05 (m, 2H), 6.70 (m, 2H),
3.85 (s, 2H). 13C NMR (DMSO-d6) δ 157.0, 127.7, 127.3, 126.6,
118.0, 115.0, 43.0. MS (ES+) m/z 230 ([C7H7O]2NH, 100), 214
(MH+, 10). HRMS (DCI/CH4) m/z calcd for C7H9NO (M+),
123.068414; found, 123.06642.
5-Hydroxy-1-indene (18).20 A mixture of 5-hydroxy-1-aminoin-
dan hydrochloride (11; 170 mg, 0.92 mmol), K2CO3 (306 mg, 2.21
mmol), and MeCN (75 mL) was stirred and heated at reflux for
4.5 h. The mixture was cooled, silica gel (550 mg) was added, and
the mixture was evaporated to give silica gel impregnated with the
crude product. The residue was purified by flash column chroma-
tography (CH2Cl2/MeOH, 100:3) to give 70 mg (58%) of an off-
white solid.
Ethyl-methyl-carbamic Acid 1-Oxo-indan-5-yl Ester (25a).
A mixture of 10a22 (2.5 g, 16.7 mmol), dry MeCN (100 mL), K2-
CO3 (4.6 g, 33.4 mmol), and N-methyl-N-ethyl-carbamoyl chloride
(2.4 g, 20 mmol) was stirred and heated at reflux under N2 for 6 h.
The solvent was evaporated, and water (150 mL) and ether (150
mL) were added to the residue. The layers were separated, and the
aqueous layer was re-extracted with ether (7 × 70 mL). The
combined ether layer was washed with saturated NaHCO3 and dried
(Na2SO4). The solution was filtered, the solvent was evaporated,
and the residue was purified by flash column chromatography
(hexane/EtOAc, 4:6) to give 3.60 g (92.5%) of a white solid, mp
59-61 °C. 1H NMR (DMSO-d6) δ 7.64-7.61 (d, 1H, J ) 8.3 Hz),
7.32 (s, 1H), 7.16-7.13 (d, 1H, J ) 8.3 Hz), 3.45-3.29 (q, 2H, J
) 6.5 Hz), 3.09-3 (m, 2H), 2.9 (s, 3H), 2.65-2.61 (m, 2H), 1.2-
1.08 (m, 3H).
2-((2-Hydroxybenzylamino)methyl)phenol (27).35 A solution
of 26 (1 mmol) in EtOH (5 mL) was refluxed overnight and
concentrated under reduced pressure to give a yellowish solid. Upon
addition of MeOH, the residue precipitated as a white solid, which
was filtered and dried to give 27 in 80% yield, mp 173-174 °C.
Anal. Calcd for C14H15NO2 (229.11): C, 73.34; H, 6.59; N, 6.11.
Found: C, 73.12; H, 6.67; N, 5.93.
Ethyl-methyl-carbamic Acid 1-Amino-indan-5-yl Ester Hy-
drochloride (25d). A mixture of dry NH4OAc (13 g, 169 mmol;
evaporated 3 times from MeOH), 25a (2.83 g, 12 mmol), and
NaCNBH3 (1.3 g, 20.7 mmol) in dry MeOH (150 mL) was stirred
and heated at reflux under N2 for 9 h. The mixture was cooled to
5 °C and acidified to pH 1 with concentrated HCl. The solvent
was evaporated to give a white semisolid. Ether (150 mL) was
added, and the mixture was stirred for 20 min. The ether was
decanted, and the process was repeated with another 150 mL portion
of ether. The white semisolid was dried at room temperature under
vacuum for 2 h. The white residual solid was then dissolved in a
mixture of 25% aqueous NH4OH (200 mL), water (75 mL), and
CH2Cl2 (150 mL). The layers were separated, and the aqueous layer
was re-extracted with CH2Cl2 (6 × 70 mL). The combined organic
phase was dried (Na2SO4), filtered, and evaporated. The residue
was purified by flash column chromatography (CH2Cl2/MeOH, 3:1)
to give 1.45 g (51%) of 25d (free base) as a yellow oil. This oil
(0.30 g, 1.3 mmol) was dissolved in a mixture of dry ether (50
mL) and MeOH (35 mL), and ether saturated with HCl gas (3 mL)
was added. The mixture was stirred at room temperature for 30
min, and the solvent was evaporated to give a viscous oil. Dry
ether (50 mL) was added, the mixture was stirred, and the ether
was decanted. The process was repeated with another portion (50
mL) of ether. Drying of the residue at 50 °C under vacuum for 60
2-(Ethoxymethyl)phenol (28).36 A solution of 26 (1 mmol) in
EtOH (5 mL) was heated at 120 °C in a sealed pressure tube for 8
h. After cooling, the solvent was concentrated to give 28 as a
1
yellow-colored oil in quantitative yield. H NMR (DMSO-d6) δ
7.22-7.18 (dd, 1H, J ) 5.8, 1.6 Hz), 7.11-7.03 (td, 1H, J ) 8.2,
1.8 Hz), 6.81-6.72 (m, 2H), 4.40 (s, 2H), 3.53-3.42 (q, 2H, J )
7 Hz), 1.23-1.05 (t, 3H, J ) 7 Hz). 13C NMR (DMSO-d6) δ 154.8,
129.6, 128.1, 124.8, 118.7, 114.9, 66.7, 65.0, 15.2. MS (ES+) m/z
107 (C7H7O, 100), 153 (MH+, 20).
2-Ethoxy-3,4-dihydro-2H-chromene (30)37 and 2-((2-Methyl-
2H-benzo[e][1.3]oxazin-3(4H)-yl)methyl)phenol (31). A solution
of 26 (1 mmol) and EVE (5 mL) was heated in a sealed pressure
tube at 140 °C overnight. After cooling, traces of EVE were
evaporated to provide a yellow-colored residue, which consisted
mainly of polymerized EVE. To this residue was added CH2Cl2,
and the mixture was filtered through a short silica gel column. The
filtrate was evaporated to dryness to give 30 as a colorless oil in
1
10% yield. H NMR (CDCl3) δ 7.20-7.08 (t, 1H, J ) 8.1 Hz,
H-C5), 7.08-7.00 (d, 1H, J ) 7.4 Hz, H-C3), 6.90-6.70 (m, 2H,
H-C6, H-C4), 5.20 (t, 2H, J ) 3.9 Hz, H-C7), 3.90-3.80 (dq, 1H,
J ) 9.7, 7.1 Hz, OCH2CH3), 3.65-3.55 (dq, 1H, J ) 9.7, 7.1 Hz,
OCH2CH3), 3.05-2.90 (td, 1H, J ) 12.7, 4.2 Hz, Hax-C9), 2.60-
2.50 (dt, 1H, J ) 12.7, 5.6 Hz, Heq-C9), 2.10-1.90 (m, 2H, H-C8),
1.20-1.10 (t, 3H, J ) 7.1 Hz, OCH2CH3). 13C NMR (CDCl3) δ
156.1 (C1), 129.4 (C3), 127.4 (C5), 124.8 (C2), 120.7 (C4), 117.1
(C6), 99.0 (C7), 63.8 (OCH2CH3), 26.7 (C8), 20.7 (C9), 15.8
(OCH2CH3). MS (CI+) m/z 107.03 (C7H7O, 100), 178.097 (MH+,
100). HRMS (DCI/CH4) m/z calcd for C11H14O2 (MH+), 178.099380;
found, 178.097403. When the reaction was carried out at 100 °C,
1
h gave 25d as a white solid (260 mg, 75%), mp 97-103 °C. H
NMR (D2O) δ 7.53-7.5 (d, 1H, J ) 8.3 Hz), 7.13 (s, 1H), 7.09-
7.06 (d, 1H, J ) 8.3 Hz), 4.89-4.85 (dd, 1H, J ) 7.9, 4.7 Hz),
3.56-3.35 (q, 2H, J ) 6.4 Hz), 3.22-2.96 (m, 5H), 2.72-2.6 (m,
1H), 2.22-2.13 (m, 1H), 1.28-1.15 (m, 3H, J ) 6.4 Hz). MS (CI/
NH3) m/z 235 (MH+, 10), 218 ([M - NH3], 100).
Ethyl-methyl-carbamic Acid 1-Prop-2-ynylamino-indan-5-yl
Ester Hydrochloride (25). A mixture of 25d free base (1.2 g, 5
mmol), K2CO3 (0.68 g, 4.95 mmol), and MeCN (100 mL) was
stirred at room temperature under N2 for 20 min. A solution of
propargyl bromide (0.53 g, 4.5 mmol) dissolved in MeCN (12 mL)
was added dropwise with stirring under N2 over 15 min. After being
stirred for 22 h, the mixture was filtered and the solvent was
evaporated. The residue was purified by flash column chromatog-
raphy (elution with EtOAc) to give 780 mg (65%) of 25 (free base)
as a viscous yellow oil. This oil (0.78 g, 2.9 mmol) was dissolved
in dry ether (50 mL), and ether saturated with HCl gas (7 mL) was
added. A gummy solid formed, and the mixture was stirred at room
temperature for 20 min. The ether was decanted, a fresh portion of
ether (50 mL) was added, and stirring was continued for an
1
a mixture of 30 and 31 in a ratio of 1:2.5, as determined by H
(33) (a) Sakata, K.; Tachifuji, Y.; Hashimoto, M. Synth. React. Inorg.
Met.-Org. Chem. 1990, 20, 901-908. (b) Kanatomi, H.; Murase, I. Bull.
Chem. Soc. Jpn. 1970, 43, 226-231.
(34) Calvo, K. C. J. Org. Chem. 1987, 52, 3654-358.
(35) Searcey, M.; Grewal, S. S.; Madeo, F.; Tsoungas, P. G. Tetrahedron
Lett. 2003, 44, 6745-6747.
(36) Lau, C. K.; Williams, H. W. R.; Tardiff, S.; Dufresne, C.; Scheigetz,
J.; Belanger, P. C. Can. J. Chem. 1989, 67, 1384-1387.
(37) Tsutomu, I.; Seiichi, I.; Kikumasa, S. Bull. Chem. Soc. Jpn. 1990,
63, 1062-1068.
J. Org. Chem, Vol. 71, No. 11, 2006 4139

Herzig et al.
1
NMR, was obtained. H NMR of compound 31, which was not
5.5, 2 Hz, Heq-C8 of 32a), 1.63-1.56 (qd, 1H, J ) 11.7, 8 Hz,
Hax-C10 of 32a and 32b), 1.48-1.43 (td, 1H, J ) 11.7, 2 Hz, Hax-
C8 of 32a and 32b), 1.31-1.29 (t, 3H, J ) 7.2 Hz, OCH2CH3 of
32b), 1.21-1.19 (t, 3H, J ) 7.2 Hz, OCH2CH3 of 32a). 13C NMR
(CDCl3) δ 150.4 (C1 of 32a/32b), 144.7 (C3 of 32a/32b), 130.1
(C2 of 32a/32b), 128.5 (C5 of 32b), 128.1 (C5 of 32a), 116.4 (C4
of 32a), 116.2 (C4 of 32b), 112.0 (C6 of 32a), 111.9 (C6 of 32b),
102.0 (C7 of 32b), 98.2 (C7 of 32a), 64.9 (OCH2CH3 of 32b),
63.8 (OCH2CH3 of 32a), 37.2 (C10 of 32b), 35.2 (C10 of 32a),
35.1 (C8 of 32b), 33.2 (C8 of 32a), 32.9 (C11 of 32b), 32.4 (C11
of 32a), 31.8 (C9 of 32a), 29.7 (C9 of 32b), 15.2 (OCH2CH3 of
32b), 15.1 (OCH2CH3 of 32a). No molecular peak was observed
in the MS spectrum of compounds 32a,b.
1
isolated. H NMR (CDCl3) δ 7.25-7.15 (m, 2H), 6.93-6.8 (m,
6H), 5.15-5.11 (q, 1H, J ) 6 Hz), 4.2-4.15 (d, 1H, J ) 14.4 Hz),
4.02 (s, 2H), 3.88-3.85 (d, 1H, J ) 14.4 Hz), 1.6-1.57 (d, 3H, J
) 6 Hz).
2-Ethoxy-3,3a,4,5-tetrahydro-2H-cyclopenta(de)chromene
(32a,b). A solution of 2b (0.25 mmol) and EVE (3 mL) was heated
in a sealed pressure tube at 120 °C overnight. After cooling, traces
of EVE were evaporated to provide a yellow-colored residue, which
consisted mainly of polymerized EVE. To the residue was added
CH2Cl2, and the mixture was filtered through a short silica gel
column. The filtrate was evaporated to dryness to give the desired
1
product as colorless oil in 7% yield. H NMR (CDCl3) δ 7.08-
7.05 (t, 1H, J ) 7.8 Hz, H-C5 of 32a), 7.05-7.03 (t, 1H, J ) 7.8
Hz, H-C5 of 32b), 6.83-6.82 (d, 1H, J ) 7.8 Hz, H-C4 of 32a),
6.77-6.76 (d, 1H, J ) 7.8 Hz, H-C4 of 32b), 6.63-6.62 (d, 1H,
J ) 7.8 Hz, H-C6 of 32a), 6.61-6.59 (d, 1H, J ) 7.8 Hz, H-C6 of
32b), 5.36-5.34 (t, 1H, J ) 2 Hz, Heq-C7 of 32a), 5.27-5.25 (dd,
1H, J ) 7.3, 2.4 Hz, Hax-C7 of 32b), 4.14-4.08 (dq, 1H, J ) 9.5,
7.2 Hz, OCH2CH3 of 32b), 3.97-3.92 (dq, 1H, J ) 9.5, 7.2 Hz,
OCH2CH3 of 32a), 3.68-3.63 (dq, 1H, J ) 9.5, 7.2 Hz, OCH2-
CH3 of 32a and 32b), 3.28-3.23 (tt, 1H, J ) 11.7, 5.5 Hz, H-C9
of 32a), 3.19-3.12 (tt, 1H, J ) 11.7, 5.5 Hz, H-C9 of 32b), 2.98-
2.92 (ddd, 1H, J ) 15, 11.7, 5.5 Hz, Hax-C11 of 32a and 32b),
2.79-2.75 (dd, 1H, J ) 15, 8 Hz, Heq-C11 of 32b), 2.78-2.74
(dd, 1H, J ) 15, 8 Hz, Heq-C11 of 32a), 2.41-2.37 (dt, 1H, J )
11.7, 5.5 Hz, Heq-C10 of 32a and 32b), 2.36-2.33 (ddd, 1H, J )
11.7, 5.5, 2 Hz, Heq-C8 of 32b), 2.33-2.30 (ddd, 1H, J ) 11.7,
Acknowledgment. We gratefully acknowledge Dr. Laszlo
Tamas (Biogal, Hungary) for his stimulating suggestions for
the mechanisms accounting for the reactivity of 7-OHAIs,
generous support for this work by the David Sauber Foundation,
the Marcus Center for Pharmaceutical and Medicinal Chemistry,
and the Bronia and Samuel Hacker Fund for Scientific Instru-
mentation at Bar Ilan University.
Supporting Information Available: 1H or 13C NMR spectra
for 4a, 4b, 4b′, 4c, 10d, 10e, 10h, 11b, 17, 18, 25a, 25d, and 31.
This material is available free of charge via the Internet at
http://pubs.acs.org.
JO052621M
4140 J. Org. Chem., Vol. 71, No. 11, 2006