Synthesis of 13-acylamino-huprines: Different behavior of diastereomeric 13-methanesulfonamido-huprines on PPA-mediated hydrolysis

Article abstract of DOI:10.1016/j.tet.2004.04.054

Two diastereomeric pairs of rationally designed huprines additionally substituted at position 13 with a formamido or an acetamido group have been synthesized as potential high affinity acetylcholinesterase inhibitors. The synthetic sequence involves hydrolysis of two diastereomeric 13-methanesulfonamido-huprines, followed by acylation of the resulting diastereomeric amines. In the hydrolysis reaction, carried out with PPA under harsh conditions, significant amounts of cyclized or rearranged by-products were also formed, depending on the stereochemistry of the starting compound.

Full text of DOI:10.1016/j.tet.2004.04.054

Tetrahedron 60 (2004) 5423–5431
Synthesis of 13-acylamino-huprines: different behavior of
diastereomeric 13-methanesulfonamido-huprines on
PPA-mediated hydrolysis
*
Pelayo Camps, Elena Gomez and Diego Mun˜oz-Torrero
*
´
´ ` `
Laboratori de Quımica Farmaceutica (Unitat Associada al CSIC), Facultat de Farmacia, Universitat de Barcelona, Av. Diagonal, 643,
E-08028 Barcelona, Spain
Received 5 December 2003; revised 23 March 2004; accepted 22 April 2004
Abstract—Two diastereomeric pairs of rationally designed huprines additionally substituted at position 13 with a formamido or an
acetamido group have been synthesized as potential high affinity acetylcholinesterase inhibitors. The synthetic sequence involves hydrolysis
of two diastereomeric 13-methanesulfonamido-huprines, followed by acylation of the resulting diastereomeric amines. In the hydrolysis
reaction, carried out with PPA under harsh conditions, significant amounts of cyclized or rearranged by-products were also formed,
depending on the stereochemistry of the starting compound.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
of huprines, functionalized at position 13 with a formamido
or acetamido group as new AChE inhibitors. These
compounds, with more extended binding near the active
site of AChE are expected to have higher AChE affinities.
We recently described the synthesis of compounds 2a,b
(Fig. 1) as advanced intermediates for the synthesis of these
new 13-acylamino-huprines,8 which requires cleavage of
the methanesulfonamido group of 2a,b followed by
acylation of the resulting primary amines 3a,b.
Huprines have recently emerged as a novel class of high
affinity central acetylcholinesterase (AChE) inhibitors of
interest for the treatment of Alzheimer’s disease, which
have shown to be superior in terms of affinity, potency and
selectivity to most of the currently approved drugs for this
disorder. This is probably due to their extended binding near
the active site of AChE.1–5 By the moment, the most
powerful huprines are the so-called huprine Y [(2)-1, Fig. 1]
and its 9-ethyl analogue, huprine X. The last one binds to the
human enzyme with one of the highest affinities yet reported
for a reversible AChE inhibitor (inhibition constant KI
26 pM).
Although arene- and alkane-sulfonyl groups have been used
to protect amines, removal of these protective groups is not
an easy task, and usually requires drastic conditions that
may not be compatible with other functional groups present
in the substrate. To solve this problem, many alternative
deprotection procedures have been developed. However,
most of them are not general, strongly depending on the
nature of the aryl or alkyl rest bound to the sulfur atom and
on the degree of substitution of the nitrogen atom.9–26 Thus,
most methods allow the cleavage of arenesulfonamides,
mainly p-toluenesulfonamides, while very few methods
have been reported for the cleavage of methanesulfona-
mides. Regarding the degree of substitution at the nitrogen
atom, most methods allow the deprotection of sulfonamides
of secondary amines (usually aromatic), while they
completely fail to cleave sulfonamides of primary amines
(especially aliphatic). To the best of our knowledge, only
three examples of cleavage of methane- or alkane-
sulfonamides derived from aliphatic primary amines (the
substitution pattern of compounds 2a,b) have been
reported, involving acidic conditions (Zn/HOAc at room
temperature12 or MeSO3H/H2O at 135 8C11) or photolytic
Figure 1. Structures of huprine Y, 13-methanesulfonamido-huprines 2a,b
and 13-amino-huprines 3a,b.
On the basis of molecular modeling studies1–3,6 and the 3D
X-ray diffraction analysis of a complex of Torpedo
californica AChE-huprine X,7 we designed a new series
Keywords: Huprines; Cleavage of primary aliphatic methanesulfonamides;
PPA; Rearrangement; Cyclization reaction.
*
Corresponding authors. Tel.: þ34-93-4024536; fax: þ34-93-4035941;
e-mail addresses: camps@farmacia.far.ub.es; dmunoztorrero@ub.edu
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.04.054

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P. Camps et al. / Tetrahedron 60 (2004) 5423–5431
cleavage,26 the amines being always obtained in low to
moderate yields (20–66%).
In this paper, we report the unprecedented hydrolysis of the
N-monosubstituted methanesulfonamides 2a and 2b using
PPA to the corresponding amines 3a and 3b, as well as the
formation of important amounts of cyclized or rearranged
by-products, depending on the configuration at position 13
of the starting methanesulfonamides, and the conversion of
the amines 3a and 3b into the rationally designed new
huprines 18a, 18b, 19a and 19b.
2. Results and discussion
Initial attempts to hydrolyze 2b, on reaction with MeSO3H/
H2O at 135 8C or with Zn/HOAc under different reaction
conditions, left the starting material unchanged. In view of
these disappointing results and the low yield of the above
mentioned photolytic deprotection method, we tried other
methodologies. HBr has proved to be efficient in the
deprotection of methanesulfonamides derived from primary
aromatic amines.9 Unfortunately, reaction of 2b with 48%
aq. HBr under reflux led to a complex mixture of products.
Sulfuric acid has been commonly used to cleave many
methanesulfonamides of primary aromatic amines.9 How-
ever, reaction of a 1:1 diastereomeric mixture of 2a and 2b
with a 1:1 mixture H2SO4/H2O for 30 min under reflux left
the starting material unchanged. Fortunately, the use of
polyphosphoric acid (PPA) for the hydrolysis of 2a afforded
better results. Under the best reaction conditions (2a and
PPA, 160 8C, 45 min), amine 3a was obtained in 28% yield
together with the pentacyclic amine 4 (68% yield) (entry 5,
Table 1), which were separated by column chromatography
(Scheme 1).
Scheme 1. Reaction of methanesulfonamides 2a and 5 with PPA.
200 8C for 20 min, 3a and 4 were obtained in 23 and 57%
yield, respectively (entry 6, Table 1).
When methanesulfonamide 5 was reacted with PPA at
160 8C for 45 min, the amines 3a and 4 were obtained in 19
and 57% yield, respectively, after column chromatography,
together with a small amount of unreacted 5 (entry 7,
Table 1) (Scheme 1). However, 4 could not be converted
into the desired amine 3a under similar reaction conditions.
From these results, we can conclude that methanesulfona-
mide 5 is formed from 2a in a reversible process under the
reaction conditions. The conversion of 2a to 5 can take place
by protonation of the CvC double bond at the less
substituted carbon atom to give a tertiary carbocation
followed by intramolecular addition of the sulfonamido
nitrogen atom and deprotonation (Scheme 2).
Table 1. Conditions and products in the reaction of methanesulfonamides
2a and 5 with PPA
Entry
Compound
Conditions
Reaction products (%)
T (8C)
t (h)
2a
3a
4
5
1
2
3
4
5
6
7
2a
2a
2a
2a
2a
2a
5
100
115
140
140
160
200
160
1
2
30
47
56
72
61
68
57
57
17
6
13
22
1.5
15
0.75
0.33
0.75
28
23
19
5
Scheme 2. Possible mechanistic pathway for the formation of 4 and 5 from
2a.
Hydrolysis of methanesulfonamides 2a and 5 would lead to
amines 3a and 4, respectively. The interconversion of 5 and
2a under the reaction conditions explains the formation of
both amines 3a and 4 in the reactions of sulfonamides 2a or
5 with PPA at 160 8C. The failure of amine 4 to give amine
3a on reaction with PPA supports the intermediacy of
sulfonamide 2a in the formation of amine 3a from
sulfonamide 5.
Interestingly, when this reaction was carried out at 100 8C
for 1 h, 4 was again the main product (47% yield), and no
amine 3a was obtained, pentacyclic methanesulfonamide 5
(17% yield) and starting 2a (30%) being isolated instead
(entry 1, Table 1). The increase in temperature (115 8C) and
reaction time (2 h) led to a total consumption of 2a and to
the formation of the desired amine 3a (13% yield), while the
yield of amine 4 increased and that of 5 greatly decreased
(entry 2, Table 1). When the reaction was carried out at
140 8C for 1.5 h, 3a and 4 were obtained in 22 and 72%
yield, respectively, while increasing the reaction time to
15 h, 4 was the only isolated product (entries 3 and 4,
Table 1). Finally, when the reaction was carried out at
The conversion of 2a to 5 seems to be faster than
its hydrolysis to 3a, since 5 is formed from 2a at
temperatures around 100 8C, while formation of 3a from
2a requires higher temperatures (around 115 8C). Also, not

P. Camps et al. / Tetrahedron 60 (2004) 5423–5431
5425
unexpectedly, hydrolysis of the N,N-disubstituted methane-
sulfonamide 5 to 4 (47% yield from 2a and PPA at 100 8C)
appears to be faster than hydrolysis of the N-mono-
substituted methanesulfonamide 2a to 3a (not formed
under the same reaction conditions, entry 1, Table 1).
departure of the protonated sulfonamido group. Deprotona-
tion of the resulting carbocation 8 and CvC double bond
isomerization would give the more stable compound 7,
containing a more extended aromatic system (Scheme 4).
Contrary to 2b, the reaction of 2a with 48% aq. HBr (using
phenol as solvent under reflux for 7 h)27 afforded the amines
3a and 4 in 24 and 53% yield, after column chromatography.
A completely different behavior towards PPA was exhibited
by the diastereomeric methanesulfonamide 2b. Thus,
treatment of 2b with PPA at 100 8C for 1–4 h left the
starting material unchanged, but the increase in the reaction
time to 15 h led to the formation of the desired amine 3b in
46% yield, together with a by-product, which was
characterized as aminocyclopentaacridine 7 (Scheme 3,
entries 1 and 2, Table 2).
Scheme 4. Possible mechanistic pathway for the formation of 7 from 2b or
3b.
In sharp contrast with the results obtained in the a series, in
this case, the hydrolysis product 3b was always the main
reaction product, thus indicating that hydrolysis is easier
than rearrangement to 7.
The increase in the yield of 7 together with the decrease in
the yield of 3b when this reaction was carried out at 150 8C
(compare entries 5 and 6, Table 2) may be indicative of the
alternative formation of 7 from 3b, a transformation that
could take place through the mechanism shown in Scheme 4,
being R¼H.
Scheme 3. Reaction of methanesulfonamide 2b with PPA.
To assess the scope of this procedure of hydrolysis of
methanesulfonamides derived from aliphatic primary
amines, three known methanesulfonamides with different
degree of substitution at the a-nitrogen position were
submitted to the PPA hydrolysis conditions: N-dodecyl-,28
N-(1-adamantyl)-,29 and N-(2-adamantyl)-methanesulfona-
mide,29 10, 12, and 13, respectively. Reaction of 10 with
PPA at 160 8C for 1 h proceeded efficiently, affording the
expected amine in 74% yield (Scheme 5). Lower reaction
temperatures (110 or 140 8C) left significant amounts of
starting material unchanged (89 and 30%, respectively). In
sharp contrast, reaction of adamantylmethanesulfonamides
12 and 13 with PPA at 110 8C for 1 h gave similar
mixtures not containing the expected amines. Thus,
GC–MS and 13C NMR analysis of the mixtures obtained
from 12 and 13 revealed the presence of adamantane,
Table 2. Conditions and products in the reaction of methanesulfonamide 2b
with PPA
Entry
Conditions
T (8C)
Reaction products
t (h)
2b
3b
7
1
2
3
4
5
6
100
100
130
130
140
150
1 (4)
15
3.75
4.5
3.5
1.75
100 (84)
7
46
37
57
59
50
12
21
26
27
33
Increasing the reaction temperature to 130–140 8C with
reaction times of 3.5–4.5 h higher yields of both 3b and 7
were obtained (entries 3–5, Table 2). Under the best
reaction conditions (2b and PPA, 140 8C, 3.5 h), 3b and 7
were obtained in 59 and 27% yield, respectively (Scheme 3
and entry 5, Table 2). When the reaction was carried out at
150 8C, a slightly lower yield of 3b and a slightly higher
yield of 7 were obtained (entry 6, Table 2).
In this case, the anti-arrangement of the 13-methane-
sulfonamido group and the propeno bridge of 2b prevents
any transannular reaction. However, the antiperiplanar
arrangement of the C10–C11 sigma bond and the
methanesulfonamido group favors the formation of by-
product 7, which can be rationalized on the basis of a
concerted 1,2-migration of C10 from C11 to the vicinal
position 13 of 2b, which becomes electron poor by the
Scheme 5. Reaction of methanesulfonamides 10, 12, and 13 with PPA.

5426
P. Camps et al. / Tetrahedron 60 (2004) 5423–5431
1-adamantanol, 2-adamantanone, 12, and 13 (the area ratios
by GC–MS are shown in Table 3) (Scheme 5). The presence
of sulfonamides 12 and 13 in both mixtures indicates that
these compounds may be interconverting under the reaction
conditions, probably through the intermediacy of 1- and
2-adamantyl carbocations (Scheme 6). Formation of
adamantane could be explained from 1- or 2-adamantyl
cations by hydride abstraction, while 2-adamantanone could
be formed from 13 by transfer of a hydride from position 2
to an adamantyl carbocation, followed by hydrolysis of the
resulting imino derivative (Scheme 6). The ratio
adamantane/2-adamantanone in these reactions is not
significant since part of the volatile adamantane could
have been lost during the isolation step. 1-Adamantanol
could arise from 1-adamantyl carbocation on reaction with
PPA followed by hydrolysis during the basic aqueous work-
up (Scheme 6).
Scheme 7. Synthesis of 13-formamido and 13-acetamido-huprines 18a,
18b, 19a and 19b from the diastereomeric amines 3a and 3b.
Consequently, the formamido derivatives were character-
ized as the free base instead of the corresponding
hydrochlorides as usual for other huprines.
Table 3. Conditions and products in the reaction of methanesulfonamides
12 and 13 with PPA
Entry Compound Conditions
Reaction products
(relative areas by GC–MS)
All of the new compounds have been fully characterized on
1
the basis of IR, H NMR, 13C NMR and MS spectra, and
elemental analysis and/or HRMS. Assignment of the NMR
T (8C)
12
13
14
15
16
17
1
spectra was performed with the aid of COSY H/1H and
1
2
3
4
12
13
12
13
110
110
160
160
36.0 10.8 8.5 15.8 28.8
13.4 3.9 12.2 17.8 52.7
HETCOR 1H/13C experiments and by comparison with
related compounds.1,2,8
2.2
11.8
43.7 19.4
49.6 11.4
3. Conclusion
In conclusion, we have carried out for the first time a PPA-
mediated hydrolysis of N-alkyl methanesulfonamides (2a
and 2b to amines 3a and 3b) in low to moderate yields.
Under the strong acidic reaction conditions, competitive
side-reactions involving the sulfonamido group at position
13 occur, whose course depends on the stereochemistry of
the starting sulfonamides 2a,b. Also, hydrolysis of the N,N-
dialkylmethanesulfonamide 5 took place in medium yield.
The method was successfully applied to the hydrolysis of
N-dodecylmethanesulfonamide, while it failed with N-(1-
adamantyl)- and N-(2-adamantyl)-methanesulfonamide.
Thus, the scope of the PPA hydrolysis of methanesulfona-
mides derived from aliphatic amines seems to be limited by
the tendency of the starting sulfonamides to give carbo-
cationic intermediates, from which by-products may be
easily derived.
Scheme 6. Possible mechanistic pathways for the formation of compounds
12–17 from 12 or 13.
Under more forcing conditions (160 8C), 12 and 13 were
fully transformed to give as before similar mixtures
containing adamantane and 2-adamantanone, as well as
1-adamantylamine (Scheme 5 and Table 3). In these cases,
the formation of 1-adamantanol was not detected, although
other unidentified minor by-products were also formed.
Although the formation of 1-adamantylamine from 13 is in
accord with the previously mentioned interconversion
between 12 and 13, it is not clear why formation of
2-adamantylamine is not observed.
Also, we have prepared the 13-formamido-huprines 18a and
18b and the 13-acetamido-huprines 19a and 19b, the first
examples of a new class of rationally designed huprines
with a potentially increased binding near the active site of
the enzyme AChE relative to the parent 13-unsubstituted
huprines. The AChE inhibitory activity of these compounds,
together with that of huprines 2a and 2b will be evaluated
and reported elsewhere.
With the diastereomeric amines 3a and 3b in hand, we
carried out their conversion in good yields into the
corresponding 13-formamido (18a and 18b) and 13-
acetamido (19a and 19b) derivatives on reaction with
HCO2H/Ac2O or AcOH/Ac2O mixtures, respectively
(Scheme 7). While the acetamido derivatives were routinely
transformed into the corresponding hydrochlorides by
treating them with a methanolic solution of HCl, partial
hydrolysis of the formamido derivatives was observed when
they were submitted to the same reaction conditions.
4. Experimental
4.1. General
Melting points were determined in open capillary tubes with

P. Camps et al. / Tetrahedron 60 (2004) 5423–5431
5427
a MFB 595010M Gallenkamp melting point apparatus.
1
alkalinized with NaOH pellets (pH¼12) and extracted with
AcOEt (4£50 mL). The combined organic extracts were
dried over anhydrous Na2SO4, and evaporated at reduced
pressure, to give a yellowish solid residue (194 mg) which
was submitted to flash column chromatography (SiO2, 8.0 g,
hexane/AcOEt/MeOH mixtures, containing 0.3% of Et3N).
On elution with AcOEt/MeOH 96:4, 94:6 and 90:10, pure
amine 3a (33 mg) and mixture of amine 3a/amine 4 in an
approximate ratio of 6:4 (1H NMR, 13 mg), a mixture of
3a/4 in an approximate ratio of 15:85 (82 mg, 28% total
yield of 3a), and pure amine 4 (55 mg, 68% total yield of 4),
were successively isolated.
500 MHz H NMR spectra, and 75.4 and 100.6 MHz 13C
NMR spectra were recorded on Varian Inova 500, Varian
Gemini 300 and Varian Mercury 400 spectrometers,
respectively. The chemical shifts are reported in ppm (d
scale) relative to internal TMS, and coupling constants are
reported in Hertz (Hz). Assignments given for the NMR
spectra of the new compounds are based on the following
experiments: DEPT and COSY 1H/1H (standard pro-
1
cedures), COSY H/13C (HMQC sequence with an indirect
1
detection probe). In the case of 7, also a COSY H/13C
(gHMBC sequence) was performed. The syn (anti) notation
of the amino or acylamino group at position 13 of
compounds 3b (3a), 18b (18a) and 19b (19a) means that
the substituent at position 13 is on the same (different) side
of the quinoline moiety with respect to the cyclohexene
ring. Routine MS spectra were taken on ThermoQuest Trace
MS and Hewlett–Packard 5988A spectrometers using the
chemical ionization (CH4) or the electron impact techniques
(70 eV, for 7), respectively: only significant ions are given.
HRMS were performed on a Micromass Autospec spec-
trometer. GC–MS spectra of the crude products of the
hydrolyses of compounds 12 and 13 were performed on a
Hewlett–Packard 5988A spectrometer, introducing the
samples through a gas chromatograph Hewlett–Packard
model 5890 Series II, equipped with a 30-meter HP-5 (5%
diphenyl-95% dimethyl-polysiloxane) column [10 psi,
initial temperature: 50 8C (2 min), then heating at a rate of
10 8C/min till 320 8C, then isothermic for 5 min], and using
the electron impact technique (70 eV). IR spectra were run
on a FT/IR Perkin–Elmer model 1600 spectrophotometer.
Absorption values are expressed as wave-numbers (cm21);
only the most intense absorption bands are given. Flash
column chromatography was performed on silica gel 60
AC.C (35–70 mesh, SDS, ref 2000027). Thin-layer
chromatography (TLC) was performed with aluminum-
backed sheets with silica gel 60 F254 (Merck, ref 1.05554),
and spots were visualized with UV light and 1% aqueous
solution of KMnO4. PPA (H3PO4 equivalent approx. 115%)
was purchased from Aldrich. Analytical grade solvents were
used for crystallization, while pure for synthesis solvents
were used in the reactions, extractions and column
chromatography. NMR spectra of all of the new
compounds and routine mass spectra of 7 were performed
Dihydrochloride of 3a. A solution of pure 3a (18 mg,
60 mmol) in MeOH (3 mL) was treated with a solution of
HCl in MeOH (0.48 M, 0.8 mL, 0.38 mmol), heated at
70 8C for 30 min and evaporated at reduced pressure, to give
3a·2HCl (22 mg) as a yellowish solid: mp.300 8C (dec.)
(MeOH); Rf (3a, free base) 0.09 (SiO2, CH2Cl2/MeOH, 9:1,
containing 0.5% of 25% aq. NH4OH); IR (KBr) n 3500–
2500 (max. at 3384, 3176 and 2910), 1654, 1630,
1
1587 cm21; H NMR (500 MHz, CD3OD) d 1.67 (s, 3H,
9-CH3), 2.12 (d, J¼19.5 Hz, 1H, 10-Hendo), 2.56 (broad dd,
J¼19.5 Hz, J0¼5.5 Hz, 1H, 10-Hexo), 2.92 (m, 1H, 7-H),
3.10 (dd, J¼18.0 Hz, J0¼1.5 Hz, 1H, 6-Hendo), 3.44 (dd,
J<18.0 Hz, J0¼5.5 Hz, 1H, 6-Hexo), 3.59 (m, 1H, 11-H),
3.79 (m, 1H, 13-H), 4.84 (s, NHþþNH2þNH3þ), 5.55 (broad
d, J¼4.5 Hz, 1H, 8-H), 7.64 (dd, J¼9.0 Hz, J0¼2.0 Hz, 1H,
2-H), 7.78 (d, J¼2.0 Hz, 1H, 4-H), 8.39 (d, J<9.0 Hz, 1H,
1-H); 13C NMR (75.4 MHz, CD3OD) d 23.3 (CH3, 9-CH3),
30.1 (CH, C11), 30.6 (CH2, C10), 31.6 (CH, C7), 35.7 (CH2,
C6), 49.2 (CH, C13), 113.0 (C, C11a), 115.3 (C, C12a),
119.2 (CH, C4), 120.1 (CH, C8), 126.5 (CH, C1), 128.0
(CH, C2), 135.9 (C, C9), 139.7 (C, C4a), 141.0 (C, C3),
151.0 (C) and 156.8 (C) (C5a and C12); m/z (CI) 328
[(MþC2H5)þ, 20], 302 (39) and 300 (100) [(MþH)þ], 301
(34), 299 (40), 285 (13) and 283 (32) [(M2NH2)þ], 264
[(M2Cl)þ, 64]. HRMS calcd for C17H19ClN3 [(MþH)þ]:
300.1268. Found: 300.1253.
Dihydrochloride of 4. A solution of pure 4 (200 mg,
0.67 mmol) in MeOH (10 mL) was treated with a solution
of HCl in MeOH (0.48 M, 8.4 mL, 4.03 mmol), heated at
70 8C for 30 min and evaporated at reduced pressure, to give
4·2HCl (229 mg) as a yellowish solid: mp.300 8C (dec.)
(MeOH); Rf (4, free base) 0.02 (SiO2, CH2Cl2/MeOH, 9:1,
containing 0.5% of 25% aq. NH4OH); IR (KBr) n 3500–
2500 (max. at 3360, 3190 and 2867), 1654, 1635,
´
`
at the Serveis Cientıfico-Tecnics of the University of
Barcelona, while routine and high resolution mass spectra
of the rest of new compounds were carried out at the Mass
Spectrometry Laboratory of the University of Santiago de
Compostela (Spain) and the elemental analyses of com-
pounds 7, 18a, 18b, 19a and 19b were carried out at the
Mycroanalysis Service of the IIQAB (CSIC, Barcelona,
Spain).
1594 cm21 1H NMR (500 MHz, CD3OD) d 1.54 (dd,
;
J<12.5 Hz, J0<3.0 Hz, 1H, 1-Hendo), 1.62 (s, 3H, 2-CH3),
superimposed in part 1.64 (dd, J¼13.5 Hz, J0¼6.0 Hz, 1H,
12-Hendo), 2.28 (ddd, J¼13.5 Hz, J0¼12.0 Hz, J00¼3.0 Hz,
1H, 12-Henx), 2.70 (ddd, J<J0<12.5 Hz, J00¼3.5 Hz, 1H,
1-Hexo), 3.09 (m, 1H, 4-H), 3.23 (broad dd, J<19.0 Hz,
J0<1.5 Hz, 1H, 5-Hexo), 3.41 (dd, J¼19.0 Hz, J0¼6.0 Hz,
1H, 5-H0endo), 3.72 (dm, J¼11.5 Hz, 1H, 11b-H), 4.36
(dd, J<J <5.0 Hz, 1H, 3a-H), 4.85 (s, NHþþNH2þNH2þ),
7.63 (dd, J¼9.0 Hz, J0¼2.0 Hz, 1H, 9-H), 7.82 (d, J¼
2.0 Hz, 1H, 7-H), 8.40 (d, J<9.0 Hz, 1H, 10-H); 13C NMR
(100.6 MHz, CD3OD) d 18.5 (CH3, 2-CH3), 29.6 (CH2,
C5), 32.0 (CH, C11b), 32.9 (CH, C4), 39.2 (CH2, C12),
42.9 (CH2, C1), 60.1 (CH, C3a), 70.6 (C, C2), 111.8 (C,
C11a), 115.3 (C, C10a), 119.3 (CH, C7), 126.5 (CH, C10),
4.1.1. 12,anti-13-Diamino-3-chloro-6,7,10,11-tetrahydro-
9-methyl-7,11-methanocycloocta[b]quinoline dihydro-
chloride (3a·2HCl) and 11-amino-8-chloro-2,3,3a,4,5,
11b-hexahydro-2-methyl-1H-2,4-methanopyrrolo[3,2-a]-
acridine dihydrochloride (4·2HCl). Methanesulfonamide
2a (240 mg, 0.64 mmol) was added in portions over a 5 min
period to stirred PPA (3.65 g) at 160 8C. The reaction
mixture was thoroughly stirred at this temperature for
45 min, cooled to room temperature and treated with ice up
to a total volume of 10 mL. The resulting suspension was

5428
P. Camps et al. / Tetrahedron 60 (2004) 5423–5431
128.1 (CH, C9), 139.9 (C, C6a), 141.1 (C, C8), 149.1
(C) and 157.5 (C) (C5a and C11); m/z (CI) 328
[(MþC2H5)þ, 18], 302 (34) and 300 (100) [(MþH)þ], 301
(30), 299 (35), 283 [(M2NH2)þ, 12], 264 [(M2Cl)þ, 56].
HRMS calcd for C17H19ClN3 [(MþH)þ]: 300.1268. Found:
300.1257.
hexane/AcOEt/MeOH mixtures containing 0.3% of Et3N).
On elution with hexane/AcOEt 60:40 and AcOEt/MeOH
95:5, compound 7 (58 mg, 27% yield) and amine 3b
(132 mg, 59% yield) were isolated, respectively, as
yellowish solids.
Dihydrochloride of 3b. A solution of pure 3b (206 mg,
0.69 mmol) in MeOH (10 mL) was treated with a solution of
HCl in MeOH (0.48 M, 8.6 mL, 4.13 mmol), and the solvent
was evaporated at reduced pressure, to give 3b·2HCl
(245 mg) as a yellowish solid. The analytical sample was
obtained by precipitation in AcOEt/MeOH 1:2.5 followed
by drying of the solid material at 80 8C/1 Torr for 2 days:
mp.300 8C (dec.) (AcOEt/MeOH 1:2.5); Rf (3b, free base)
0.08 (SiO2, CH2Cl2/MeOH, 9:1, containing 1% of 25% aq.
NH4OH); IR (KBr) n 3500–2500 (max. at 3379, 3190 and
4.1.2. 11-Amino-8-chloro-2,3,3a,4,5,11b-hexahydro-3-
methanesulfonyl-2-methyl-1H-2,4-methanopyrrolo[3,2-a]-
acridine hydrochloride (5·HCl). This reaction was carried
out as described for 3a, from methanesulfonamide 2a
(220 mg, 0.58 mmol) and PPA (3.50 g), heating at 120 8C
for 1 h. A yellowish solid (200 mg) was obtained, which
was submitted to flash column chromatography (SiO2, 6.4 g,
hexane/AcOEt/MeOH mixtures, containing 0.3% of Et3N).
On elution with hexane/AcOEt 40:60, pure 5 (31 mg) and
mixture 5/2a in an approximate ratio of 3:7 (1H NMR,
21 mg, 17% total yield of 5) were successively isolated. On
elution with hexane/AcOEt 30:70, sulfonamide 2a (52 mg,
30% total yield) was isolated. Finally, on elution with
AcOEt/MeOH 90:10, pure amine 4 (82 mg, 47% yield) was
isolated.
2926), 1654, 1635, 1587 cm21 1H NMR (500 MHz,
;
CD3OD) d 1.63 (s, 3H, 9-CH3), 2.18 (broad d, J¼18.0 Hz,
1H, 10-Hendo), 2.75 (broad dd, J¼18.0 Hz, J0¼4.5 Hz, 1H,
10-Hexo), 3.01 (m, 1H, 7-H), 3.09 (d, J¼19.0 Hz, 1H,
6-Hendo), 3.23 (dd, J¼19.0 Hz, J0¼5.5 Hz, 1H, 6-Hexo), 3.57
(m, 1H, 11-H), 3.92 (dd, J¼3.5 Hz, J0¼2.5 Hz, 1H, 13-H),
4.85 (s, NHþþNH2þNHþ3 ), 5.62 (broad d, J¼6.0 Hz, 1H,
8-H), 7.64 (dd, J¼9.0 Hz, J0¼2.0 Hz, 1H, 2-H), 7.82 (d,
J¼2.0 Hz, 1H, 4-H), 8.40 (d, J<9.0 Hz, 1H, 1-H); 13C NMR
(75.4 MHz, CD3OD) d 22.7 (CH3, 9-CH3), 30.1 (CH2, C6),
30.8 (CH, C7), 31.2 (CH, C11), 36.7 (CH2, C10), 50.4 (CH,
C13), 109.7 (C, C11a), 115.5 (C, C12a), 119.3 (CH, C4),
123.4 (CH, C8), 126.5 (CH, C1), 128.0 (CH, C2), 135.4
(C, C9), 139.8 (C, C4a), 141.0 (C, C3), 150.7 (C) and
157.8 (C) (C5a and C12); m/z (CI) 328 [(MþC2H5)þ, 17],
302 (35) and 300 (100) [(MþH)þ], 301 (33), 299 (37), 285
(16) and 283 (38) [(M2NH2)þ], 264 [(M2Cl)þ, 60].
HRMS calcd for C17H19ClN3 [(MþH)þ]: 300.1268. Found:
300.1253.
Hydrochloride of 5. A solution of pure 5 (44 mg,
0.12 mmol) in MeOH (3 mL) was treated with a solution
of HCl in MeOH (0.48 M, 0.75 mL, 0.36 mmol), heated at
60 8C for 30 min and evaporated at reduced pressure, to give
5·HCl (45 mg) as a yellowish solid: mp.300 8C (dec.)
(MeOH); Rf (5, free base) 0.59 (SiO2, CH2Cl2/MeOH, 9:1,
containing 0.5% of 25% aq. NH4OH); IR (KBr) n 3500–
2500 (max. at 3373, 3227 and 2931), 1669, 1636, 1591,
1
1308, 1140, 1086 cm21; H NMR (500 MHz, CD3OD) d
1.28 (dd, J¼11.5 Hz, J0¼3.0 Hz, 1H, 1-Hendo), 1.36 (dd,
J¼12.5 Hz, J0¼6.0 Hz, 1H, 12-Hendo), 1.65 (s, 3H, 2-CH3),
2.28 (ddd, J<J0<12.5 Hz, J00¼3.0 Hz, 1H, 12-Henx), 2.66
(ddd, J¼J0¼11.5 Hz, J00¼3.0 Hz, 1H, 1-Hexo), 2.92 (m, 1H,
4-H), 3.12 (s, 3H, CH3SO2), 3.15 (broad d, J<19.0 Hz, 1H,
5-Hexo), 3.36 (dd, J<19.0 Hz, J0<6.0 Hz, 1H, 5-Hendo), 3.47
(dm, J¼11.5 Hz, 1H, 11b-H), 4.38 (dd, J<J0<5.0 Hz, 1H,
3a-H), 4.86 (s, NHþþNH2), 7.61 (dd, J¼9.0 Hz, J0¼2.0 Hz,
1H, 9-H), 7.77 (d, J¼2.0 Hz, 1H, 7-H), 8.36 (d, J¼9.0 Hz,
1H, 10-H); 13C NMR (75.4 MHz, CD3OD) d 19.2 (CH3,
2-CH3), 30.7 (CH2, C5), 33.4 (CH, C11b), 34.7 (CH, C4),
43.5 (CH2, C12), 44.1 (CH3, CH3SO2), 47.1 (CH2, C1), 62.8
(CH, C3a), 69.9 (C, C2), 114.2 (C, C11a), 115.0 (C, C10a),
119.1 (CH, C7), 126.3 (CH, C10), 127.7 (CH, C9), 139.6 (C,
C6a), 140.6 (C, C8), 149.4 (C) and 157.3 (C) (C5a and C11);
m/z (CI) 406 [(MþC2H5)þ, 15], 380 (35) and 378 (96)
[(MþH)þ], 379 (31), 377 (33), 344 (30) and 342 (47)
[(M2Cl)þ], 300 (17) and 298 (34) [(M2CH3SO2)þ], 285
(35) and 283 (100) [(M2CH3SO2NH)þ], 249
[(M2CH3SO2NH–ClþH)þ, 29]. HRMS calcd for
C18H21ClN3O2S [(MþH)þ]: 378.1043. Found: 378.1028.
Compound 7. Mp 248–250 8C (dec.) (isopropanol); Rf 0.38
(SiO2, CH2Cl2/MeOH, 9:1, containing 1% of 25% aq.
NH4OH); IR (KBr) n 3473, 2953, 2927, 1654, 1607, 1561,
1
1474, 1453, 1249 cm21; H NMR (500 MHz, CD3OD) d
1.18 (d, J¼7.0 Hz, 3H, 2-CH3), 2.60 (ddq, J¼J0¼J00¼7.0
Hz, 1H, 2-H), 2.66 (dd, J<16.0 Hz, J0<7.5 Hz, 1H, 1-Ha),
2.68 (dd, J<15.5 Hz, J0<7.5 Hz, 1H, 3-Ha), 3.19 (dd,
J<16.0 Hz, J0¼4.5 Hz, 1H, 1-Hb), 3.20 (dd, J<15.5 Hz,
J0<4.5 Hz, 1H, 3-Hb), 4.85 (s, NH2), 7.22 (dd, J<9.5 Hz,
J0<2.0 Hz, 1H, 8-H), 7.57 (s, 1H, 4-H), 7.75 (d, J<2.0 Hz,
1H, 6-H), 7.98 (s, 1H, 11-H), 8.19 (d, J¼9.5 Hz, 1H, 9-H);
13C NMR (75.4 MHz, CD3OD) d 20.6 (CH3, 2-CH3), 36.4
(CH, C2), 41.4 (CH2, C1), 42.0 (CH2, C3), 112.0 (C, C9a),
113.1 (C, C10a), 117.3 (CH, C11), 120.9 (CH, C4), 123.2
(CH, C8), 125.2 (CH, C6), 125.6 (CH, C9), 137.3 (C, C7),
141.4 (C, C11a), 147.9 (C, C5a), 148.6 (C, C4a), 151.1 (C,
C3a), 152.5 (C, C10); m/z (EI) 284 (34) and 282 (100)
(Mzþ), 283 (26), 281 (19), 269 (13) and 267 (39)
[(M2CH3)þ], 268 (13), 266 (21), 232 [(M2Cl–CH3)zþ,
13]; m/z (CI) 285 (37) and 283 (100) [(MþH)þ], 284 (37),
282 (56), 247 [(M2Cl)þ, 47]. Anal. calcd for
C17H15ClN2·3/5H2O: C, 69.55; H, 5.56; N, 9.54; Cl,
12.08. Found: C, 69.31; H, 5.34; N, 9.35; Cl, 12.37.
4.1.3. 12,syn-13-Diamino-3-chloro-6,7,10,11-tetrahydro-
9-methyl-7,11-methanocycloocta[b]quinoline dihydro-
chloride, (3b·2HCl) and 10-amino-7-chloro-2,3-dihydro-
2-methyl-1H-cyclopenta[b]acridine (7). This reaction
was carried out as described for 3a, from methanesulfona-
mide 2b (285 mg, 0.75 mmol), added over a 30 min
period and PPA (3.75 g), heating at 140 8C for 3.5 h. A
yellowish solid (234 mg) was obtained, which was sub-
mitted to flash column chromatography (SiO2, 7.5 g,
4.1.4. PPA hydrolysis of N-dodecylmethanesulfonamide.
This reaction was carried out as described for 3a, from
methanesulfonamide 10 (200 mg, 0.76 mmol) and PPA

P. Camps et al. / Tetrahedron 60 (2004) 5423–5431
5429
(3.80 g), heating at 160 8C for 1 h, obtaining pure
N-dodecylamine (105 mg, 74% yield) as a brown oil.
292 [(M2Cl)þ, 16]. HRMS calcd for C18H19ClN3O
[(MþH)þ]: 328.1217. Found: 328.1217. Anal. calcd for
C18H18ClN3O·1/2H2O·0.07CH2Cl2: C, 63.32; H, 5.63; N,
12.26; Cl, 11.79. Found: C, 63.34; H, 5.46; N, 12.10; Cl,
11.84.
4.1.5. PPA hydrolysis of N-(1-adamantyl)methane-
sulfonamide, 12, and N-(2-adamantyl)methanesulfona-
mide, 13. Conditions 1. This reaction was carried out as
described for 3a, from methanesulfonamide 12 or 13
(200 mg, 0.87 mmol) and PPA (4.47 g), heating at 110 8C
for 1 h. GC–MS and 13C NMR analysis of the crude
products obtained from 12 and 13 (80 and 74 mg,
respectively) revealed that they consisted of a mixture of
adamantane, 14 (tR¼8.3 min), 1-adamantanol, 15 (tR¼
11.1 min), 2-adamantanone, 16 (tR¼12.1 min), methane-
sulfonamide 12 (tR¼19.9 min), and methanesulfonamide 13
(tR¼20.1 min). For the GC–MS relative areas of these
compounds see Table 3.
4.1.7. 12-Amino-3-chloro-syn-13-formamido-6,7,10,11-
tetrahydro-9-methyl-7,11-methanocycloocta[b]quino-
line (18b). It was prepared as described for 18a. Starting
from a solution of amine 3b (121 mg, 0.40 mmol) in
HCO2H (1 mL, 1.22 g, 26.5 mmol) and Ac2O (756 mL,
818 mg, 8.01 mmol) with a reaction time of 1 h, formamide
18b (113 mg, 86% yield) was obtained as a yellowish solid:
mp 252–253 8C (dec.) (hexane/AcOEt 1:1); Rf 0.17 (SiO2,
CH2Cl2/MeOH 9:1, containing 1% of 25% aq. NH4OH); IR
(KBr) n 3351, 3246, 2903, 1637, 1560, 1489 cm21 1H
;
NMR (500 MHz, CDCl3) d 1.55 (s, 3H, 9-CH3), 2.08 (broad
d, J¼17.0 Hz, 1H, 10-Hendo), 2.70 (dm, J<17.0 Hz, 1H,
10-Hexo), 2.86 (m, 1H, 7-H), 2.96 (broad d, J<19.0 Hz, 1H,
6-Hendo), superimposed in part 3.14 (dd, J¼19.0 Hz,
J0¼6.0 Hz, 1H, 6-Hexo), 3.16 (m, 1H, 11-H), 4.58 (m, 1H,
13-H), 4.75 (broad s, 2H, NH2), 5.54 (dm, J¼4.0 Hz, 1H,
8-H), 5.7–6.0 (broad signal, 1H, HCONH), 7.34 (m, 1H,
2-H), 7.60 (m, 1H, 1-H), 7.83 (broad s, 1H, 4-H), 8.16 (s,
1H, HCONH), signals corresponding to AcOEt were also
observed; 13C NMR (75.4 MHz, CDCl3þCD3OD) d 22.7
(CH3, 9-CH3), 31.3 (CH, C7), 32.2 (CH, C11), 33.0 (CH2,
C6), 35.8 (CH2, C10), 46.5 (CH, C13), 111.0 (C, C11a),
115.1 (C, C12a), 122.2 (CH, C1), 124.2 (CH, C8), 124.9
(CH, C2), 125.0 (CH, C4), 132.5 (C, C9), 135.5 (C, C4a),
145.4 (C, C3), 149.4 (C) and 155.4 (C) (C5a and C12),
161.9 (C, HCONH); m/z (CI) 356 [(MþC2H5)þ, 16], 330
(35) and 328 (100) [(MþH)þ], 329 (25), 294 (55), 292
[(M2Cl)þ, 22]. HRMS calcd for C18H19ClN3O [(MþH)þ]:
Conditions 2. This reaction was carried out as described for
3a, from methanesulfonamide 12 (200 mg, 0.87 mmol) or
13 (179 mg, 0.78 mmol) and PPA (3.60 and 3.45 g,
respectively), heating at 160 8C for 1 h. GC–MS and 13C
NMR analysis of the crude products obtained from 12
and 13 (43 and 67 mg, respectively) revealed that they
consisted mainly of a mixture of adamantane, 14,
1-adamantylamine, 17 (tR¼10.7 min), and 2-adamantanone,
16. For the GC–MS relative areas of these compounds see
Table 3.
4.1.6. 12-Amino-3-chloro-anti-13-formamido-6,7,10,11-
tetrahydro-9-methyl-7,11-methanocycloocta[b]quino-
line (18a). Ac2O (682 mL, 738 mg, 7.23 mmol) was added
to a solution of amine 3a (108 mg, 0.36 mmol) in HCO2H
(1 mL, 1.22 g, 26.5 mmol), and the reaction mixture was
heated under reflux for 45 min, allowed to reach room
temperature and concentrated in vacuo. The resulting
residue was taken in MeOH (5 mL) and treated with a
saturated aqueous solution of NaHCO3 (10 mL). The
organic solvent was evaporated at reduced pressure, and
the resulting aqueous suspension was extracted with CH2Cl2
(3£10 mL). The combined organic extracts were dried over
anhydrous Na2SO4 and evaporated at reduced pressure, to
give formamide 18a (98 mg, 83% yield) as a white solid: mp
254–256 8C (AcOEt); Rf 0.51 (SiO2, CH2Cl2/MeOH 85:15,
containing 1% of 25% aq. NH4OH); IR (KBr) n 3424, 3386,
3151, 2876, 1694, 1671, 1606, 1566, 1488 cm21; 1H NMR
(500 MHz, CDCl3) d 1.59 (s, 3H, 9-CH3), 1.97 (d,
J0¼18.0 Hz, 1H, 10-Hendo), 2.46 (ddm, J<18.0 Hz,
J ¼4.5 Hz, 1H, 10-Hexo), 2.64 (m, 1H, 7-H), 3.10 (dm,
J¼17.5 Hz, 1H, 6-Hendo), 3.32 (dd, J¼17.5 Hz, J0¼5.5 Hz,
1H, 6-Hexo), 3.42 (m, 1H, 11-H), 4.42 (m, 1H, 13-H), 4.76
(broad s, 2H, NH2), 5.48 (dm, J¼5.0 Hz, 1H, 8-H), 5.88
(broad d, J¼6.5 Hz, 1H, HCONH), 7.34 (dd, J¼9.0 Hz,
J0¼2.0 Hz, 1H, 2-H), 7.63 (d, J¼9.0 Hz, 1H, 1-H), 7.87
(broad s, 1H, 4-H), 8.28 (s, 1H, HCONH), a very small
signal at d 5.30 ppm corresponding to CH2Cl2 was also
observed; 13C NMR (75.4 MHz, CDCl3þCD3OD) d 23.0
(CH3, 9-CH3), 30.0 (CH, C11), 30.4 (CH2, C10), 32.9 (CH,
C7), 38.5 (CH2, C6), 46.2 (CH, C13), 113.1 (C, C11a),
115.0 (C, C12a), 121.1 (CH, C1), 122.4 (CH, C8), 124.8
(CH, C2), 125.2 (CH, C4), 133.7 (C, C9), 135.4 (C, C4a),
145.8 (C, C3), 148.3 (C) and 155.4 (C) (C5a and C12),
161.7 (C, HCONH); m/z (CI) 356 [(MþC2H5)þ, 17], 330
(37) and 328 (100) [(MþH)þ], 329 (28), 327 (20), 294 (17),
328.1217.
Found:
328.1215.
Anal.
calcd
for
C18H18ClN3O·2/5H2O·1/2AcOEt: C, 63.37; H, 6.06; N,
11.09; Cl, 9.35. Found: C, 63.66; H, 5.74; N, 11.40; Cl, 8.93.
4.1.8. anti-13-Acetamido-12-amino-3-chloro-6,7,10,11-
tetrahydro-9-methyl-7,11-methanocycloocta[b]quino-
line hydrochloride (19a·HCl). It was prepared as described
for 18a, but using AcOH instead of HCO2H. Thus, starting
from a solution of amine 3a (100 mg, 0.33 mmol) in AcOH
(1 mL, 1.05 g, 17.5 mmol) and Ac2O (62 mL, 67 mg,
0.66 mmol), acetamide 19a (96 mg, 85% yield) was
obtained as a brown solid.
Hydrochloride of 19a. A solution of pure 19a (96 mg,
0.28 mmol) in MeOH (2 mL) was treated with a solution of
HCl in MeOH (0.48 M, 1.95 mL, 0.94 mmol), stirred at
room temperature for 5 min and evaporated at reduced
pressure, to give the corresponding hydrochloride (110 mg)
as a yellowish solid: mp.300 8C (dec.) (AcOEt/MeOH
4:1); Rf (19a, free base) 0.37 (SiO2, CH2Cl2/MeOH 85:15,
containing 1% of 25% aq. NH4OH); IR (KBr) n 3500–2500
(max. at 3323, 3150 and 2923), 1675, 1589, 1541 cm21; 1H
NMR (500 MHz, CD3OD) d 1.63 (s, 3H, 9-CH3), 1.92
(broad d, J¼18.5 Hz, 1H, 10-Hendo), 2.02 (s, 3H, CH3-
CONH), 2.53 (broad dd, J¼18.5 Hz, J0¼5.0 Hz, 1H,
10-Hexo), 2.68 (m, 1H, 7-H), 2.98 (dd, J¼18.0 Hz,
J0¼1.5 Hz, 1H, 6-Hendo), 3.39 (dd, J¼18.0 Hz, J0¼5.5 Hz,
1H, 6-Hexo), 3.49 (m, 1H, 11-H), 4.16 (m, 1H, 13-H), 4.84
(s, NHþþNH2), 5.51 (dm, J¼4.5 Hz, 1H, 8-H), 7.60 (dd,

5430
P. Camps et al. / Tetrahedron 60 (2004) 5423–5431
J¼9.0 Hz, J0¼2.0 Hz, 1H, 2-H), 7.74 (d, J¼2.0 Hz, 1H,
4-H), 8.13 (d, J¼7.5 Hz, 1H, CH3CONH), 8.35 (d,
J¼9.0 Hz, 1H, 1-H); 13C NMR (75.4 MHz, CD3OD) d
22.6 (CH3, CH3CONH), 23.4 (CH3, 9-CH3), 30.6 (CH,
C11), 31.1 (CH2, C10), 32.8 (CH, C7), 36.5 (CH2, C6), 48.3
(CH, C13), 114.7 (C, C11a), 115.1 (C, C12a), 119.1 (CH,
C4), 121.9 (CH, C8), 126.3 (CH, C1), 127.7 (CH, C2), 135.4
(C, C9), 139.6 (C, C4a), 140.6 (C, C3), 151.8 (C) and 156.9
(C) (C5a and C12), 173.5 (C, CH3CONH); m/z (CI) 344 (13)
and 342 (32) [(MþH)þ], 306 [(M2Cl)þ, 9]. HRMS calcd
for C19H21ClN3O [(MþH)þ]: 342.1373. Found: 342.1361.
Anal. calcd for C19H20ClN3O·HCl·2.65H2O: C, 53.57; H,
6.22; N, 9.86; Cl, 16.64. Found: C, 53.18; H, 6.06; N, 9.48;
Cl, 17.03.
References and notes
¨
˜
1. Camps, P.; El Achab, R.; Gorbig, D. M.; Morral, J.; Munoz-
Torrero, D.; Badia, A.; Banos, J. E.; Vivas, N. M.; Barril,
X.; Orozco, M.; Luque, F. J. J. Med. Chem. 1999, 42,
3227–3242.
˜
2. Camps, P.; El Achab, R.; Morral, J.; Mun˜oz-Torrero, D.;
Badia, A.; Ban˜os, J. E.; Vivas, N. M.; Barril, X.; Orozco, M.;
Luque, F. J. J. Med. Chem. 2000, 43, 4657–4666.
3. Camps, P.; Cusack, B.; Mallender, W. D.; El Achab, R.;
Morral, J.; Mun˜oz-Torrero, D.; Rosenberry, T. L. Mol.
Pharmacol. 2000, 57, 409–417.
´
4. Camps, P.; Gomez, E.; Mun˜oz-Torrero, D.; Badia, A.; Vivas,
N. M.; Barril, X.; Orozco, M.; Luque, F. J. J. Med. Chem.
2001, 44, 4733–4736.
4.1.9. syn-13-Acetamido-12-amino-3-chloro-6,7,10,11-
tetrahydro-9-methyl-7,11-methanocycloocta[b]quino-
line hydrochloride (19b·HCl). It was prepared as described
for 18a, but using AcOH instead of HCO2H. Thus, starting
from a solution of amine 3b (101 mg, 0.34 mmol) in AcOH
(1 mL, 1.05 g, 17.5 mmol) and Ac2O (62 mL, 67 mg,
0.66 mmol) with a reaction time of 1.25 h, acetamide 19b
(101 mg, 88% yield) was obtained as a brown solid.
5. Camps, P.; Mun˜oz-Torrero, D. Mini Rev. Med. Chem. 2001, 1,
163–174.
6. Barril, X.; Orozco, M.; Luque, F. J. J. Med. Chem. 1999, 42,
5110–5119.
7. Dvir, H.; Wong, D. M.; Harel, M.; Barril, X.; Orozco, M.;
Luque, F. J.; Mun˜oz-Torrero, D.; Camps, P.; Rosenberry, T. L.;
Silman, I.; Sussman, J. L. Biochemistry 2002, 41, 2970–2981.
´
8. Camps, P.; Gomez, E.; Mun˜oz-Torrero, D.; Font-Bardia, M.;
Solans, X. Tetrahedron 2003, 59, 4143–4151.
9. Review article on the cleavage of sulfonamides: Searles, S.;
Nukina, S. Chem. Rev. 1959, 59, 1077–1103. For selected
examples of methods for cleavage of sulfonamides see Refs.
10–26.
Hydrochloride of 19b. A solution of pure 19b (101 mg,
0.30 mmol) in MeOH (2 mL) was treated with a solution of
HCl in MeOH (0.48 M, 2 mL, 0.96 mmol), stirred at room
temperature for 1 h and evaporated at reduced pressure, to
give the corresponding hydrochloride (121 mg) as a
yellowish solid: mp.300 8C (dec.) (isopropanol/AcOEt/
MeOH 3:2:0.5); Rf (19b, free base) 0.22 (SiO2, CH2Cl2/
MeOH 85:15, containing 1% of 25% aq. NH4OH); IR (KBr)
n 3500–2500 (max. at 3351, 3190 and 2922), 1654, 1646,
10. With H2SO4: Carpenter, P. D.; Lennon, M. J. Chem. Soc.,
Chem. Commun. 1973, 664–665.
11. With MeSO3H/H2O: Feit, P. W.; Nielsen, O. T. J. Med. Chem.
1970, 13, 447–452.
12. With Zn/HOAc: Hendrickson, J. B.; Bergeron, R. Tetrahedron
Lett. 1970, 345–348.
1
1587 cm21; H NMR (500 MHz, CD3OD) d 1.60 (s, 3H,
9-CH3), 1.91 (s, 3H, CH3CONH), 2.09 (broad d, J¼18.0 Hz,
1H, 10-Hendo), 2.69 (ddm, J¼18.0 Hz, J0¼4.5 Hz, 1H,
10-Hexo), 2.84 (broad d, J¼18.5 Hz, 1H, 6-Hendo), 2.88
(m, 1H, 7-H), 3.22 (dd, J¼18.5 Hz, J0¼5.0 Hz, 1H, 6-Hexo),
3.30 (m, 1H, 11-H), 4.31 (m, 1H, 13-H), 4.84 (s,
CH3CONHþNH2þNHþ), 5.57 (broad d, J¼6.0 Hz, 1H,
8-H), 7.61 (dd, J¼9.0 Hz, J0¼2.0 Hz, 1H, 2-H), 7.77 (d,
J¼2.0 Hz, 1H, 4-H), 8.37 (d, J¼9.0 Hz, 1H, 1-H); 13C NMR
(100.6 MHz, CD3OD) d 22.5 (CH3, CH3CONH), 22.9 (CH3,
9-CH3), 30.9 (CH2, C6), 31.7 (CH, C7), 32.5 (CH, C11),
36.9 (CH2, C10), 48.9 (CH, C13), 112.4 (C, C11a), 115.5
(C, C12a), 119.2 (CH, C4), 124.8 (CH, C8), 126.4 (CH, C1),
127.9 (CH, C2), 135.0 (C, C9), 139.7 (C, C4a), 140.8 (C,
C3), 152.1 (C) and 157.8 (C) (C5a and C12), 173.6 (C,
CH3CONH); m/z (CI) 344 (7) and 342 (19) [(MþH)þ], 306
[(M2Cl)þ, 6]. HRMS calcd for C19H21ClN3O [(MþH)þ]:
342.1373. Found: 342.1361. Anal. calcd for C19H20ClN3-
O·HCl·H2O: C, 57.58; H, 5.85; N, 10.60; Cl, 17.89. Found:
C, 57.88; H, 5.72; N, 10.15; Cl, 17.64.
13. With HBr/HOAc/phenol: Roemmele, R. C.; Rapoport, H.
J. Org. Chem. 1988, 53, 2367–2371.
14. With Mg/MeOH: Nyasse, B.; Grehn, L.; Maia, H. L. S.;
Monteiro, L. S.; Ragnarsson, U. J. Org. Chem. 1999, 64,
7135–7139.
´
15. With metal/naphthalene: Alonso, E.; Ramon, D. J.; Yus, M.
Tetrahedron 1997, 53, 14355–14368.
16. With Na/alcohol: Merlin, P.; Braekman, J. C.; Daloze, D.
Tetrahedron Lett. 1988, 29, 1691–1694.
17. With Na/NH3: see Ref. 13.
18. With SmI2: Goulaouic-Dubois, C.; Guggisberg, A.; Hesse, M.
Tetrahedron 1995, 51, 12573–12582.
19. With Bu3SnH/AIBN: Parsons, A. F.; Pettifer, R. M.
Tetrahedron Lett. 1996, 37, 1667–1670.
20. With LiAlH4 or Red-Al: Hendrickson, J. B.; Bergeron, R.
Tetrahedron Lett. 1973, 3839–3842.
21. With PhMe2SiLi: Fleming, I.; Frackenpohl, J.; Ila, H. J. Chem.
Soc., Perkin Trans. 1 1998, 1229–1235.
22. With KF/Al2O3/microwave: Sabitha, G.; Abraham, S.; Reddy,
B. V. S.; Yadav, J. S. Synlett 1999, 1745–1746.
23. With PhSH/DIPEA: Wuts, P. G. M.; Northuis, J. M.
Tetrahedron Lett. 1998, 39, 3889–3890.
Acknowledgements
24. With TMSCl/NaI: Sabitha, G.; Reddy, B. V. S.; Abraham, S.;
Yadav, J. S. Tetrahedron Lett. 1999, 40, 1569–1570.
25. With TBAF: Yasuhara, A.; Sakamoto, T. Tetrahedron Lett.
1998, 39, 595–596.
´
Financial support from the Direccion General de Investiga-
´
´
cion of Ministerio de Ciencia y Tecnologıa and
FEDER (project PPQ2002-01080) and Comissionat per a
Universitats i Recerca of the Generalitat de Catalunya
(project 2001-SGR-00085) are gratefully acknowledged.
26. By photolysis: D’Souza, L.; Day, R. A. Science 1968, 160,
882–883.

P. Camps et al. / Tetrahedron 60 (2004) 5423–5431
5431
27. Snyder, H. R.; Heckert, R. E. J. Am. Chem. Soc. 1952, 74,
2006–2009.
29. Satyamurthy, N.; Bida, G. T.; Phelps, M. E.; Barrio, J. R. Appl.
Radiat. Isot. 1990, 41, 733–738.
28. Vanden Heuvel, W. J. A.; Gardiner, W. L.; Horning, E. C.
Anal. Chem. 1964, 36, 1550–1560.