Atom-Economic Synthesis of Functionalized Octahydroacridines from Citronellal or 3-(Phenylthio)-citronellal

Article abstract of DOI:10.1080/00397910802663469

Here we present a simple, solvent-free, one-pot, hetero-Diels-Alder reaction of (R)-citronellal or 3-(phenylthio)-citronellal with arylamines using solid-supported catalyst (SiO₂/ZnCl₂). This general, efficient, and improved method i

Full text of DOI:10.1080/00397910802663469

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Atom-Economic Synthesis
of Functionalized
Octahydroacridines from
Citronellal or 3-(Phenylthio)-
citronellal
Raquel G. Jacob a , Márcio S. Silva a , Samuel R.
Mendes a , Elton L. Borges a , Eder J. Lenardão a &
Gelson Perin a
a Institute of Chemistry and Geosciences, Laboratory
of Clean Organic Synthesis (LASOL), Federal
University of Pelotas, Pelotas, Brazil
Published online: 26 Jun 2009.
To cite this article: Raquel G. Jacob , Márcio S. Silva , Samuel R. Mendes , Elton
L. Borges , Eder J. Lenardão & Gelson Perin (2009): Atom-Economic Synthesis of
Functionalized Octahydroacridines from Citronellal or 3-(Phenylthio)-citronellal,
Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 39:15, 2747-2762
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Synthetic Communications1, 39: 2747–2762, 2009
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910802663469
Atom-Economic Synthesis of Functionalized
Octahydroacridines from Citronellal
or 3-(Phenylthio)-citronellal
ꢀ
Raquel G. Jacob, Marcio S. Silva, Samuel R. Mendes,
Elton L. Borges, Eder J. Lenardao, and Gelson Perin
˜
Institute of Chemistry and Geosciences, Laboratory of Clean Organic
Synthesis (LASOL), Federal University of Pelotas, Pelotas, Brazil
Abstract: Here we present a simple, solvent-free, one-pot, hetero-Diels–Alder
reaction of (R)-citronellal or 3-(phenylthio)-citronellal with arylamines using
solid-supported catalyst (SiO2=ZnCl2). This general, efficient, and improved
method is selective, affording preferentially new trans-fused 3-(phenylthio)-
octahydroacridines (S-OHAs) in good yields. The use of microwave irradiation
facilitates the procedure and accelerates the reaction.
Keywords: Citronellal, octahydroacridines, solvent-free, supported catalysis
INTRODUCTION
Lewis-acid–catalyzed intramolecular reactions of N-arylimines with
nonactivated alkenes, formally a hetero-Diels–Alder (HDA) reaction of
a 2-azadiene, is a powerful synthetic tool for the preparation of
nitrogen-containing six-membered heterocycles.[1] This efficient protocol
has been used in the synthesis of several substituted tetrahydroquino-
line[2] and octahydroacridine (OHA) derivatives.[3] Among the OHA deri-
vatives, 1,2,3,4,4a,9,9a,10-octahydroacridines are of interest because of
Received November 11, 2008.
´
ˆ
Address correspondence to Gelson Perin, Instituto de Quımica e Geociencias,
LASOL, Universidade Federal de Pelotas, UFPel, P. O. Box 354, 96010-900,
Pelotas, RS, Brazil. E-mail: gelson_perin@ufpel.edu.br
2747

2748
R. G. Jacob et al.
Scheme 1. Synthesis of 3-(phenylthio)-octahydroacridines.
their pharmacological properties, acting as gastric acid secretion
inhibitors and antimalarial agents.[4]
There are a number of different methods for constructing the OHA
skeleton, such as acid-catalyzed isophorone-aniline condensation,[5]
Beckmann rearrangement of oxime sulfonate,[6] and catalytic hydrogena-
tion of acridine.[7] The imine-Diels–Alder reaction catalyzed by a Lewis-
acid is the most atom-economical method, furnishing OHAs in good
yields and, in some cases, with 100% of stereoselectivity.[3e] When trifluor-
oethanol[3f] or an ionic liquid[3g,h] is present, a Lewis acid is not necessary.
On the other hand, despite the increasing number of studies showing the
useful pharmacological and biological activities of organochalcogenium
compounds,[8] the synthesis of phenylthio-octahydroacridines (S-OHAs)
had not been described.
Our major research goal is the synthesis[3h,9] and application of
organochalcogenium compounds, including the development of
new, cleaner protocols for classical reactions.[3i,9] In continuation of
these studies, we report herein the full results on the imine-Diels–
Alder reaction of (R)-citronellal 1 or 3-(phenylthio)-citronellals 2
with anilines 3 in the presence of a solid-supported catalyst, under
solvent-free conditions, to afford new functionalized OHAs 4 and 5
and 3-(phenylthio)-octahydroacridines 6 and 7 (S-OHAs, Scheme 1,
Table 1).
RESULTS AND DISCUSSION
The partial results of the reaction of (R)-citronellal 1 and anilines 3 for the
synthesis of 1,2,3,4,4a,9,9a,10-octahydroacridines 4 and 5 by a hetero--
Diels–Alder reaction were described by us a few years ago.[3i] The method
involved the use of solid-supported catalyst (SiO2=ZnCl2) and afforded
selectively a series of OHAs after few minutes of irradiation with
microwaves (MW).[10]

2749

2750

2751

2752
R. G. Jacob et al.
SiO2=ZnCl2, 10%: Silica gel (9.0 g of silica gel 60, 230–240 mesh,
Merck), ZnCl2 (1.0 g) and water (3.0 mL) were mixed in a 50-mL beaker,
and the suspension was stirred for 15 min at room temperature, dried at
80ꢀC for 3 h and subsequently 15 h at 150ꢀC in an oven, and finally
cooled to room temperature in a desiccator.
In view of the good results using the solid-supported catalyst system
in HDA reactions with citronellal and anilines,[3i] we decided to study the
preparation of thio-octahydroacridines using our solvent-free approach
(Scheme 1, Table 1).
Initially, we performed a study to establish the best conditions for the
HDA reaction of 3-(phenylthio)-citronellal (2a, R3 ¼ C6H5) and aniline
(3a, R1 ¼ R2 ¼ H), and we observed that the reaction occurs satisfactorily
even at room temperature. Thus, the best results were obtained when a
mixture of 2a (1.0 mmol) and 3a (1.2 mmol) was stirred in the presence
of 0.120 g of SiO2=ZnCl2 (10%) at room temperature, affording the
desired products 6a and 7a in good yield (74%) after 3 h (entry 1,
Table 1, method A). When the same protocol was performed under irra-
diation with MW, incomplete consumption of 2a and 3a was observed at
280 W, making it necessary to irradiate with 548 W (entry 2, Table 1,
method B).
Using the optimized conditions at room temperature, the protocol
was extended to other anilines 3 and to 3-(p-methoxyphenylthio)-
citronellal (2b, Table 1). Concerning the stereochemistry of the ring
fusion: for all the studied examples, the formation of a cis and trans mix-
1
ture of S-OHAs (determined by H NMR), with good selectivity to the
trans-S-OHAs in most of the examples (entries 1–2, 6–9 and 12–17),
was observed. Thus, under our optimized solvent-free conditions, trans-
6a was obtained preferentially in relation to cis-7a (6a:7a ratio ¼ 96:4,
entry 1, Table 1). This diastereoselectivity is probably due to steric bulk
at carbon-3, similar to that described for the intramolecular HDA of
3-methyl-citronellal with N-arylimines.[3a] When the reaction was per-
formed in the presence of benzene (5 mL=mmol, method C), the selectiv-
ity decreased significantly and the trans-6a:cis-7a ratio was 70:30 (entry 3,
Table 1). On the other hand, o-toluidine 3e and a-naphtylamine 3b
reacted with aldehydes 2a and 2b to afford the respective cis-S-OHA 7
as the principal diastereomer (entries 4, 5, 10, 11, 18, and 19, Table 1).
We observed almost exclusive formation of one of the two possible
trans-diastereomeric S-OHAs (6 and 60) in all the studied examples. Thus,
the diastereomeric ratio of trans-S-OHAs obtained varied from 75:25 for
trans-fused 7-chloro-1,2,3,4,4a,9a,10-octahydro-3,9,9-trimethyl-3-(phenylthio)-
acridinez (6d, method A, entry 8, Table 1) to >99:1 for trans-fused
1,2,3,4,4a,9a,10-octahydro-3,5,9,9-tetramethyl-3-(phenylthio)-acridine
(6e, method A, entry 10, Table 1).

Solvent-Free Synthesis of Octahydroacridines
2753
Figure 1. X-ray diagram of the major component of trans-6d.[11]
These diastereomers were unambiguously characterized by 1H NMR
and HRMS, with the relative configuration of the carbon bearing the
organosulfur group being determined by x-ray crystal analysis, similar
to that described by Laschat and coworkers for OHAs.[11] Figure 1 pre-
sents the x-ray diagram of trans-6d [(3Sꢁ,4aRꢁ,9aSꢁ)-7-chloro-1,2,3,4,
4a,9a,10-octahydro-3,9,9-trimethyl-3-(phenylthio)-acridine], the major
diastereomer derived from 3-(phenylthio)-citronellal 2a and p-
chloroaniline 3d.
Crystallographic data for 6d have been deposited with the
Cambridge Crystallographic Data Centre as supplementary publication
number CCDC 663282. Copies of the data can be obtained, free of
charge, on application to CCDC. E-mail: deposit@ccdc.ca.ac.uk.
We also performed the HDA reaction using (R)-citronellal 1 and
thio-functionalized anilines 3g and 3h. The reaction occurred satisfactorily
at room temperature after stirring a mixture of 1 with 3g or 3h in the pre-
sence of SiO2=ZnCl2 (10%) for 5–6 h. In contrast to the observed reaction
involving 3-(phenylthio)-citronellal 2 and anilines 3a–c, the S-OHAs 4a–b
and 5a–b were obtained with poor selectivity (entries 20 and 21, Table 1).
In conclusion, several 3-(phenylthio)-octahydroacridines were directly
and stereoselectively prepared by the reaction of 3-(phenylthio)-citronellals
with arylamines using solid-supported acid catalyst and solvent-free condi-
tions. This method has low consumption of solvent, short reaction time,
mild reaction conditions, and good yields and simplicity, with nonaqueous
workup. The reaction time can be reduced under irradiation with MW.
EXPERIMENTAL
General Remarks
1
The H and 13C NMR spectra of CDCl3 solutions were recorded with a
200-MHz or 400-MHz spectrometer (Bruker DPX), as noted. Chemical

2754
R. G. Jacob et al.
shifts are expressed as parts per million (ppm) downfield from
tetramethylsilane (TMS) as an internal standard. Low-resolution mass
spectra (LRMS, EI) were obtained at 70 eV with a Hewlett Packard
EM=CG HP-5988A spectrometer. High-resolution mass spectra
(HR-ESI-MS) were obtained in the positive mode (UltrOTOF-Q system,
version 1.10, Bruker Daltonics, MA, USA). The MW-irradiated
reactions were performed using a Panasonic model Piccolo NN-S42BK
operating at 2.45 MHz. Merck’s silica gel (230–400 mesh) was used for
flash chromatography.
General Procedure for the Synthesis of 3-(Phenylthio)-
octahydroacridines 6 and 7
Method A
A mixture of 3-(arylthio)-citronellal[9c] (2, 1 mmol) and aniline (3,
1 mmol) was added to SiO2=ZnCl2 (10%) (0.120 g). The mixture was
stirred at room temperature. The reaction progress was followed by
thin-layer chromatography (TLC), and after consumption of starting
materials (see Table 1), ethyl acetate (10 mL) was added, and the organic
solution was separated from the SiO2 by filtration. The solvent was
evaporated under reduced pressure, and the residue was purified by
column chromatography over silica gel (SiO2), eluting with hexane=ethyl
acetate (90:10) and yielding the diastereomers trans-6 and cis-7, according
Table 1.
Method B
The aforementioned whole mixture was previously stirred for 1 min and
then irradiated with MW (a domestic Panasonic model Piccolo
NN-S42BK, operating at 2.45 MHz) at 548 W[11] for 0.5–1.5 min
(Table 1), and the product was extracted and purified according to
method A.
Method C
To a mixture of 3-(phenylthio)-citronellal (2a, 0.262 g, 1 mmol) and
aniline (3a, 0.093 g, 1 mmol) in benzene (5 mL), SiO2=ZnCl2 (10%)
(0.120 g) was added at room temperature. The mixture was stirred at
room temperature, and the reaction progress was followed by TLC. After

Solvent-Free Synthesis of Octahydroacridines
2755
stirring for 6 h (entry 3, Table 1), ethyl acetate (10 mL) was added, and
the organic solution was separated from the SiO2 by filtration. The sol-
vent was evaporated under reduced pressure and the residue was purified
according to method A. Spectral data of 6a–i and 7a–i are listed. Except
when mentioned, the spectral data are related to the major trans-isomer
6, and the relative stereochemistry was assigned only for trans-fused
OHAs 6 and 60 (monocrystal x-ray analysis). The minor trans-60 and
1
cis-7 isomers were characterized by analysis of the H NMR spectra of
the isomeric mixture and by GC-MS analysis.
Data
(3Sꢁ,4aRꢁ,9aSꢁ)-1,2,3,4,4a,9a,10-Octahydro-3,9,9-trimethyl-3-
(phenylthio)-acridines, trans-6a and cis-7a
cis-7a (first eluted fraction): 1H NMR (400 MHz, CDCl3) d 7.40–7.44 (m,
2H), 7.19–7.35 (m, 3H), 7.14 (dd, J ¼ 7.6 and 1.2 Hz, 1H), 6.99 (td, J ¼ 7.2
and 1.6 Hz, 1H), 6.62 (td, J ¼ 7.6 and 1.2 Hz, 1H), 6.50 (dd, J ¼ 8.0 and
1.2 Hz, 1H), 4.11 (br s, 1H), 3.90–3.93 (m, 1H), 1.50–2.20 (m, 4H), 1.38
(s, 3H), 1.22 (s, 3H), 1.20–1.35 (m, 3H), 1.13 (s, 3H); 13C NMR
(100 MHz, CDCl3) d 142.2, 137.3, 132.7, 128.5, 128.4, 127.6, 126.6,
125.5, 116.3, 113.6, 47.8, 46.8, 44.7, 44.2, 37.8, 35.4, 32.9, 32.6, 26.0,
1
19.5. trans-6a (second eluted fraction): H NMR (400 MHz, CDCl3) d
7.49–7.52 (m, 2H), 7.32–7.37 (m, 3H), 7.24 (dd, J ¼ 7.6 and 1.6 Hz, 1H),
6.95 (td, J ¼ 7.2 and 1.6 Hz, 1H), 6.66 (td, J ¼ 7.2 and 1.2 Hz, 1H), 6.43
(dd, J ¼ 7.8 and 1.2 Hz, 1H), 3.70 (td, J ¼ 10.8 and 4.0 Hz, 1H; major dia-
stereomer (3Sꢁ, 4aRꢁ, 9aSꢁ)-6a), 3.58 (br s, 1H), 3.19 (td, J ¼ 10.6 and
4.2 Hz, 1H; minor diastereomer, (3Sꢁ, 4aSꢁ, 9aRꢁ)-6a0), 1.60–2.00 (m,
4H), 1.35 (s, 3H), 1.26 (s, 3H), 1.25 (s, 3H), 1.30–1.45 (m, 3H); 13C
NMR (100 MHz, CDCl3) d 142.9, 137.5, 131.7, 131.2, 128.7, 128.6,
126.6, 126.5, 117.2, 113.8, 49.7, 47.6, 46.8, 45.5, 37.8, 34.9, 31.8, 27.4,
26.8, 21.0. MS m=z (rel. int.) 337 (Mþ ꢂ1, 52.8), 226 (23.4), 212
(100.0), 77 (27.7). HRMS (ESI): m=z calcd. for C22H28NS [M þ H]þ:
338.1937; found: 338.1965.
(7aSꢁ,10Sꢁ,11aRꢁ)-7,7a,8,9,10,11,11a,12-Octahydro-7,7,10-trimethyl-
10-(phenylthio)-benz[c]acridines, trans-6b and cis-7b
1
cis-7b and trans-6b: H NMR (400 MHz, CDCl3) d 7.15–7.93 (m, 22H),
5.17 (br s, 1H), 4.11 (br s, 1H), 3.86–3.90 (m, 1H; cis-7b), 3.77 (td,
J ¼ 11.0 and 4.4 Hz, 1H; trans-6b), 1.20–2.40 (m, 14H), 1.40 (s, 3H),

2756
R. G. Jacob et al.
1.38 (s, 3H), 1.32 (s, 3H), 1.29 (s, 3H), 1.26 (s, 3H), 1.11 (s, 3H); (cis-7b
and trans-6b) 13C NMR (100 MHz, CDCl3) d 137.4, 137.3, 137.1, 136.7,
132.8, 132.3, 131.7, 128.7, 128.6, 128.5, 128.4, 128.2, 128.0, 125.4, 125.0,
124.8, 124.7, 124.5, 123.4, 122.0, 120.6, 119.7, 117.0, 116.6, 49.8, 47.8,
47.5, 47.2, 46.9, 45.4, 44.7, 43.3, 38.1, 37.7, 35.4, 35.1, 34.0, 32.7, 31.8,
27.3, 27.2, 27.0, 26.6, 21.0, 19.2. cis-7b: MS m=z (rel. int.) 387 (Mþ ꢂ 1,
100.0), 372 (19.3), 262 (77.1), 194.0 (60.1), 110 (73.9). HRMS (ESI):
m=z calcd for C26H29NS [M þ H]þ: 388.2093; found: 388.2125. trans-
6b: MS m=z (rel. int.) 387 (Mþ ꢂ 1, 85.8), 372 (28.6), 262 (36.3), 194.0
(100.0), 110 (72.1). (7aRꢁ,10Sꢁ,11aSꢁ)-6b0: MS m=z (rel. int.) 387
(Mþ ꢂ1, 54.5), 262 (41.4), 194.0 (34.5), 110 (100.0).
(3Sꢁ,4aRꢁ,9aSꢁ)-1,2,3,4,4a,9a,10-Octahydro-3,7,9,9-tetramethyl-3-
(phenylthio)-acridines, trans-6c and cis-7c
trans-6c (second eluted fraction): 1H NMR (400 MHz, CDCl3) d
7.49–7.52 (m, 2H), 7.29–7.36 (m, 3H), 7.04 (d, J ¼ 1.2 Hz, 1H), 6.77
(dd, J ¼ 8.0 and 1.2 Hz, 1H), 6.37 (d, J ¼ 8.0 Hz, 1H), 3.88–3.91 (m,
1H; cis-7c), 3.66 (td, J ¼ 10.8 and 4.0 Hz, 1H; major diastereomer
(3Sꢁ,4aRꢁ,9aSꢁ)-6c), 3.45 (br s, 1H), 3.15 (td, J ¼ 10.7 and 4.0 Hz, 1H;
minor diastereomer, (3Sꢁ,4aSꢁ,9aRꢁ)-6c0), 2.23 (s, 3H), 1.60–2.0 (m,
4H), 1.30–1.46 (m, 3H), 1.34 (s, 3H), 1.25 (s, 3H), 1.24 (s, 3H); 13C
NMR (100 MHz, CDCl3) d 140.6, 137.5, 131.8, 131.3, 128.7, 128.6,
127.9, 127.2, 126.1, 114.0, 49.8, 47.9, 46.9, 45.6, 37.8, 34.9, 31.9, 27.5,
26.9, 21.0, 20.7. MS m=z (rel. int.) 351 (Mþ ꢂ1, 74.4), 240 (26.7), 226
(100.0), 186.0 (71.8), 77 (21.1). HRMS (ESI): m=z calcd. for C23H29NS
[M þ H]þ: 352.2093; found: 352.2115. (3Sꢁ,4aSꢁ,9aRꢁ)-6c0 MS m=z (rel.
int.) 351 (Mþ ꢂ1, 54.1), 240 (17.7), 226 (31.9), 186.0 (100.0), 77 (26.2).
(3Sꢁ,4aRꢁ,9aSꢁ)-7-Chloro-1,2,3,4,4a,9a,10-octahydro-3,9,9-trimethyl-
3-(phenylthio)-acridines, trans-6d and cis-7d
trans-6d (second eluted fraction): 1H NMR (200 MHz, CDCl3) d
7.48–7.50 (m, 2H), 7.32–7.35 (m, 3H), 7.17 (d, J ¼ 2.4 Hz, 1H), 6.88
(dd, J¼ 8.4 and 2.4 Hz, 1H), 6.35 (d, J¼ 8.4 Hz, 1H), 3.90 (m, 1H; cis-7d),
3.67 (td, J¼ 10.8 and 4.0 Hz, 1H; major diastereomer (3Sꢁ,4aRꢁ,9aSꢁ)-6d),
3.60 (br s, 1H), 3.15 (td, J ¼ 10.6 and 4.2 Hz, 1H; minor diastereomer
(3Sꢁ,4aSꢁ,9aRꢁ)-6d0), 1.70–1.93 (m, 4H), 1.33 (s, 3H), 1.25 (s, 3H), 1.22
(s, 3H), 1.30–1.50 (m, 3H); 13C NMR (100 MHz, CDCl3) d 141.3,
137.4, 132.7, 131.6, 128.8, 128.6, 126.4, 126.3, 121.4, 114.9, 49.6, 47.1,
46.8, 45.4, 37.6, 35.1, 31.7, 27.1, 26.5, 20.9. MS m=z (rel. int.) 371

Solvent-Free Synthesis of Octahydroacridines
2757
(Mþ ꢂ1, 48.6), 261 (21.6), 246 (100.0), 206 (67.6), 77 (21.7). HRMS (ESI):
m=z calcd. for C22H27ClNS [M þ H]þ: 372.1547; found: 372.1555.
(3Sꢁ,4aSꢁ,9aRꢁ)-6d0 MS m=z (rel. int.) 371 (Mþ ꢂ1, 38.8), 261 (14.7),
246 (21.7), 206 (100.0), 77 (23.6).
(3Sꢁ,4aRꢁ,9aSꢁ)-1,2,3,4,4a,9a,10-Octahydro-3,5,9,9-tetramethyl-3-
(phenylthio)-acridines, trans-6e and cis-7e
cis-7e (first eluted fraction): 1H NMR (400 MHz, CDCl3) d 7.43–7.49 (m,
2H), 7.22–7.35 (m, 3H), 7.08 (dd, J ¼ 7.6 e 1.2 Hz, 1H), 6.91 (br d,
J ¼ 7.4 Hz, 1H), 6.62 (t, J ¼ 7.4 Hz, 1H), 3.95–4.05 (m, 1H), 3.40 (br s,
1H), 2.20 (s, 3H), 1.36 (s, 3H), 1.26 (s, 3H), 1.12 (s, 3H), 1.20–2.40 (m,
7H). MS m=z (rel. int.) 351 (Mþ ꢂ1, 77.5), 241 (30.8), 226 (100.0),
186.0 (74.3), 77 (30.3). HRMS (ESI): m=z calcd for C23H29NS [M þH]þ:
1
352.2093; found: 352.2117. trans-6e (second eluted fraction): H NMR
(400 MHz, CDCl3) d 7.50–7.53 (m, 2H), 7.25–7.36 (m, 3H), 7.16 (dd,
J ¼ 8.0 and 1.6 Hz, 1H), 6.88 (br d, J ¼ 7.2 Hz, 1H), 6.58 (t, J ¼ 7.6 Hz,
1H), 3.71 (td, J ¼ 10.8 and 4.0 Hz, 1H; major diastereomer 6e), 3.40 (br
s, 1H), 2.07 (s, 3H), 1.38 (s, 3H), 1.27 (s, 3H), 1.24 (s, 3H), 1.20–2.30
(m, 7H); (cis-7e and trans-6e) 13C NMR (100 MHz, CDCl3) d 140.9,
140.4, 137.8, 137.5, 132.5, 131.8, 130.7, 128.8, 128.6, 128.4, 127.7,
127.1, 124.5, 123.5, 120.9, 120.3, 116.4, 115.7, 49.9, 47.9, 47.4, 46.9,
46.8, 45.9, 44.8, 44.2, 37.9, 37.8, 35.4, 35.0, 33.3, 32.5, 31.9, 27.4, 27.0,
26.4, 21.0, 19.4, 17.7, 17.5. MS m=z (rel. int.) 351 (Mþ ꢂ1, 98.3), 242
(42.3), 226 (39.2), 186.0 (100.0), 77 (30.5). (3Sꢁ,4aSꢁ,9aRꢁ)-6e0 MS m=z
(rel. int.) 351 (Mþ ꢂ1, 53.4), 242 (23.0), 226 (30.0), 186.0 (100.0), 77
(19.7).
(3Sꢁ,4aRꢁ,9aSꢁ)-7-Fluoro-1,2,3,4,4a,9a,10-octahydro-3,9,9-
trimethyl-3-(phenylthio)-acridines, trans-6f and cis-7f
trans-6f (second eluted fraction): 1H NMR (400 MHz, CDCl3) d
7.48–7.52 (m, 2H), 7.29–7.36 (m, 3H), 6.94 (dd, J ¼ 10.6, 2.8 Hz, 1H),
6.66 (ddd, J ¼ 9.0, 8.0 and 2.8 Hz, 1H), 3.88–3.90 (m, 1H; cis-7f), 6.36
(dd, J ¼ 8.6 e 5.0 Hz, 1H), 3.65 (td, J ¼ 10.8 and 4.4 Hz, 1H; major dia-
stereomer (3Sꢁ,4aRꢁ,9aSꢁ)-6f), 3.46 (br s, 1H); 3.14 (td, J ¼ 10.8 and
4.0 Hz, 1H; minor diastereomer (3Sꢁ,4aSꢁ,9aRꢁ)-6f0), 1.60–2.00 (m,
4H), 1.28–1.44 (m, 3H), 1.32 (s, 3H), 1.25 (s, 3H), 1.23 (s, 3H); 13C
NMR (100 MHz, CDCl3) d 155.7 (d, JC-F ¼ 233.1 Hz), 139.1 (d, JC-F ¼1.4 Hz),
137.4, 132.6 (d, JC-F ¼ 5.6 Hz), 131.7, 128.7, 128.6, 114.5 (d, JC-F ¼ 7.1 Hz), 113.1
(d, JC-F ¼ 22.6 Hz), 113.0 (d, JC-F ¼ 22.6 Hz), 49.7, 47.3, 46.9, 45.5, 37.7, 35.2,

2758
R. G. Jacob et al.
31.8, 27.3, 26.8, 20.9. MS m=z (rel. int.) 355 (Mþ ꢂ1, 56.4), 246 (26.0), 230
(100.0), 190.0 (80.5), 77 (18.9). HRMS (ESI): m=z calcd for C22H27FNS
[M þH]þ: 356.1842; found: 356.1865. (3Sꢁ,4aSꢁ,9aRꢁ)-6f0 MS m=z (rel. int.)
355 (Mþ ꢂ1, 33.6), 246 (15.7), 230 (21.0), 190.0 (100.0), 77 (11.5). cis-7f MS
m=z (rel. int.) 355 (Mþ ꢂ1, 65.0), 246 (32.0), 230 (100.0), 190.0 (95.5), 77 (21.8).
(3Sꢁ,4aRꢁ,9aSꢁ)-1,2,3,4,4a,9a,10-Octahydro-3-)
[(4-methoxyphenyl)thio]-3,7,9,9-tetramethyl-acridines, trans-6g
and cis-7g
cis-7g (first eluted fraction): 1H NMR (200 MHz, CDCl3) d 6.70–7.50 (m,
5H), 6.96 (d, J ¼ 1.6 Hz, 1H), 6.46 (d, J ¼ 8.0 Hz, 1H), 4.14 (br s, 1H),
3.88–3.90 (m, 1H), 3.78 (s, 3H), 0.70–2.40 (m, 7H), 2.24 (s, 3H), 1.37
(s, 3H), 1.22 (s, 3H), 1.11 (s, 3H). m=z (rel. int.) 381 (Mþ ꢂ1, 29.5),
242 (72.6), 186 (65.8), 118 (61.0), 91 (100.0), 77 (45.3). trans-6 g (second
eluted fraction): 1H NMR (400 MHz, CDCl3) d 7.41 (d, J ¼ 8.4 Hz,
2H), 7.04 (d, J ¼ 1.2 Hz, 1H), 6.85 (d, J ¼ 8.4 Hz, 2H), 6.76 (dd, J ¼ 8.0
and 1.2 Hz, 1H), 6.37 (d, J ¼ 8.0 Hz, 1H), 3.81 (s, 3H), 3.64 (td,
J ¼ 10.6 and 4.0 Hz, 1H), 3.45 (br s, 1H), 2.23 (s, 3H), 1.15–2.00 (m,
7H), 1.34 (s, 3H), 1.24 (s, 3H), 1.23 (s, 3H); 13C NMR (100 MHz, CDCl3)
d 160.2, 140.6, 138.8, 131.3, 127.2, 127.1, 126.1, 122.5, 114.1, 114.0, 55.2,
49.4, 47.8, 46.8, 45.4, 37.6, 35.0, 31.8, 27.5, 27.0, 21.0, 20.7. trans-6g: m=z
(rel. int.) 381 (Mþ ꢂ1, 60.6), 242 (41.7), 186 (100.0), 158 (74.3), 77 (15.2).
HRMS (ESI): m=z calcd for C24H31NOS [Mþ H]þ: 382.2199; found:
1
382.2209. (3Sꢁ,4aSꢁ,9aRꢁ)-6g0: H NMR (400 MHz, CDCl3) d 7.43 (d,
J ¼ 8.4 Hz, 2H), 6.98 (d, J ¼ 1.2 Hz, 1H), 6.84 (d, J ¼ 8.4 Hz, 2H), 6.72
(dd, J ¼ 8.0 and 1.2 Hz, 1H), 6.32 (d, J ¼ 8.0 Hz, 1H), 3.80 (s, 3H), 3.45
(br s, 1H), 3.14 (td, J ¼ 10.4 and 4.0 Hz, 1H), 2.21 (s, 3H), 1.15–2.00
(m, 7H), 1.31 (s, 3H), 1.27 (s, 3H), 1.08 (s, 3H); 13C NMR (100 MHz,
CDCl3) d 160.3, 140.4, 139.2, 131.0, 127.2, 127.0, 126.1, 121.8, 114.1,
114.0, 53.4, 48.0, 47.6, 47.4, 46.0, 38.0, 34.7, 27.3, 26.8, 24.4, 21.3, 20.7.
(3Sꢁ,4aRꢁ,9aSꢁ)-7-Chloro-1,2,3,4,4a,9a,10-octahydro-3-)
[(4-methoxyphenyl)thio]-3,9,9-trimethyl-acridines, trans-6h and cis-7h
cis-7h, trans-6h and (3Sꢁ,4aSꢁ,9aRꢁ)-6h0 (trans-6h0): 1H NMR (200 MHz,
CDCl3) d 7.27–7.43 (m, 2H), 7.06–7.17 (m, 1H), 6.80–6.89 (m, 3H),
6.26–6.42 (m, 1H), 4.11 (m, 1H; cis-7h), 3.73–3.85 (m, 4), 3.64 (td,
J ¼ 10.9 and 4.0 Hz, 1H; trans-6h), 3.11 (td, J ¼ 10.5 and 3.8 Hz, 1H;
trans-6h0), 1.0–2.0 (m, 16H), (cis-7h, trans-6h and trans-6h0); 13C NMR
(100 MHz, CDCl3) d 160.3, 160.2, 160.0, 141.5, 141.3, 140.8, 139.1,

Solvent-Free Synthesis of Octahydroacridines
2759
138.7, 138.6, 132.6, 132.5, 132.3, 129.1, 126.5, 126.3, 123.2, 126.1, 125.3,
123.1, 122.2, 121.6, 121.2, 121.1, 120.3, 114.8, 114.5, 114.4, 114.1, 114.0,
113.9, 55.1, 55.0, 49.2, 47.7, 47.4, 47.3, 47.0, 46.7, 46.6, 46.5, 45.7, 45.1,
43.9, 43.7, 37.9, 37.4, 37.1, 35.5, 35.0, 34.9, 32.3, 32.2, 31.6, 27.0, 26.9,
26.4, 26.3, 25.7, 24.3, 21.1, 20.8, 19.3. trans-6h: m=z (rel. int.) 263 (Mþ
ꢂp-CH3OC6H4S, 0.86), 143 (28.0), 107 (70.0), 93.0 (100.0), 77 (71.5).
HRMS (ESI): m=z calcd. for C23H28ClNOS [M þ H]þ: 402.1652; found:
402.1652.
(3Sꢁ,4aRꢁ,9aSꢁ)-1,2,3,4,4a,9a,10-Octahydro-3-)
[(4-methoxyphenyl)thio]-3,5,9,9-tetramethyl-acridines, trans-6i and cis-7i
cis-7i (first eluted fraction): 1H NMR (400 MHz, CDCl3) d 7.34 (d,
J ¼ 8.8 Hz, 2H), 7.06 (d, J ¼ 6.8 Hz, 1H), 6.90 (d, J ¼ 6.4 Hz, 1H), 6.79
(d, J ¼ 8.8 Hz, 2H), 6.58 (t, J ¼ 7.6 Hz, 1H), 4.15 (m, 1H), 3.95 (m, 1H),
3.76 (s, 3H), 2.20 (s, 3H), 1.20–1.83 (m, 7H), 1.38 (s, 3H), 1.23 (s, 3H),
1.10 (s, 3H). m=z (rel. int.) 381 (Mþ ꢂ1, 53.1), 226 (92.2), 186 (100.0),
1
158 (77.0), 77 (19.0). trans-6i: H NMR (400 MHz, CDCl3) d 7.42 (d,
J ¼ 8.8 Hz, 2H), 7.16 (d, J ¼ 7.6 Hz, 1H), 6.81–6.87 (m, 4H), 3.81 (s,
3H), (td, J ¼ 10.8 and 4.0 Hz, 1H), 2.07 (s, 3H), 1.20–2.30 (m, 7H), 1.35
(s, 3H), 1.25 (s, 3H), (cis-7i and trans-6i); 13C NMR (100 MHz, CDCl3)
d 160.1, 140.4, 138.9, 132.6, 127.6, 127.2, 123.5, 123.2, 121.0, 115.7,
114.6, 113.9, 55.2, 47.5, 46.9, 44.7, 43.8, 37.7, 35.4, 33.3, 32.5, 26.4,
19.3, 17.7. m=z (rel. int.) 381 (Mþ ꢂ1, 68.6), 242 (55.5), 186 (100.0),
158 (67.6), 77 (21.2). HRMS (ESI): m=z calcd. for C24H31NOS [M þ
H]þ: 382.2199; found: 382.2206.
General Procedure for the Synthesis of Octahydroacridines 4 and 5
Method A
A mixture of (R)-citronellal (1, 1.0 mmol) and aniline (3g, 1.0 mmol) was
added to SiO2=ZnCl2 (10%) (0.120 g).[10] The mixture was stirred at room
temperature, and the reaction progress was followed by TLC. After
consumption of the starting materials (see Table 1), ethyl acetate
(10 mL) was added, and the organic solution was separated from the
SiO2 by filtration. The solvent was evaporated under reduced pressure,
and the residue was purified by column chromatography over silica gel
(SiO2) eluting with hexane=ethyl acetate (90:10), yielding the diastereo-
mers trans-4 and cis-5, according to Table 1. Spectral data of 4a–b and
5a–b are listed below.

2760
R. G. Jacob et al.
Data
7-[(4-Chlorobenzyl)thio]-1,2,3,4,4a,9,9a,10-octahydro-
3,9,9-trimethyl-acridines, trans-4a and cis-5a
cis-5a (first eluted fraction): 1H NMR (200 MHz, CDCl3) d 7.18–7.23 (m,
2H), 6.86–6.98 (m, 4H), 6.18 (d, J ¼ 8.4 Hz, 1H), 3.81 (s, 2H), 3.70–3.73
(m, 1H), 3.71 (br s, 1H), 1.0–1.90 (m, 8H), 1.14 (s, 3H), 1.09 (s, 3H),
0.87 (d, J ¼ 6.2 Hz, 3H). trans-4a: 1H NMR (200 MHz, CDCl3) d
7.13–7.16 (m, 2H), 6.17–7.04 (m, 4H), 6.30 (d, J ¼ 8.2 Hz, 1H), 3.81 (s,
2H), 3.70 (br s, 1H), 2.98–3.06 (m, 1H), 1.90–2.0 (m, 8H), 1.17 (s, 3H),
0.97 (s, 3H), 0.93 (d, J ¼ 6.6 Hz, 3H). (cis-5a and trans-4a) 13C NMR
(100 MHz, CDCl3) d 143.3, 143.1, 137.4, 137.3, 135.0, 133.3, 133.1,
132.9, 132.7, 132.3, 132.2, 131.4, 130.3, 130.2, 128.2, 128.1, 119.1,
118.2, 113.9, 113.1, 53.4, 50.5, 46.7, 46.5, 43.9, 43.2, 41.6, 41.5, 40.9,
35.4, 35.0, 34.7, 34.5, 33.5, 30.8, 26.7, 26.2, 25.7, 25.4, 24.5, 22.8, 22.1.
HRMS (ESI): m=z calcd. for C23H28ClNS [M þ H]þ: 385.1631; found:
385.1625.
7-(Dodecylthio)-1,2,3,4,4a,9,9a,10-octahydro-3,9,9-trimethyl-acridines,
trans-4b and cis-5b
1
cis-5b and trans-4b: H NMR (400 MHz, CDCl3) d 7.21 and 7.31 (2d,
J ¼ 2.0 Hz, 1H), 7.03 (dd, J ¼ 8.0 and 2.0 Hz, 1H), 6.34 and 6.35 (2d,
J ¼ 8.0 Hz, 1H), 3.81 (m, 1H; cis-5b), 3.66 (br s, 1H), 1.10–3.00 (m,
1H; trans-4b), 2.72 (t, J ¼ 7.2 Hz, 2H), 0.86–1.88 (m, 40H). 13C
NMR (100 MHz, CDCl3) d 142.6, 142.5, 131.8, 131.6, 131.5, 131.4,
128.5, 121.0, 120.3, 113.9, 113.2, 50.6, 46.8, 44.2, 43.2, 41.0, 37.0,
36.9, 35.6, 35.0, 34.8, 34.6, 33.9, 31.9, 30.8, 29.7, 29.6, 29.5, 29.4,
29.3, 29.2, 29.1, 28.6, 26.8, 26.4, 26.0, 24.6, 22.9, 22.6, 22.1, 22.0.
trans-4b: m=z (rel. int.) 429 (Mþ, 100.0), 414 (15.8), 260 (22.8), 246
(5.0). HRMS (ESI): m=z calcd. for C28H47NS [M þ H]þ: 430.3508;
found: 430.3500.
ACKNOWLEDGMENTS
This project was funded by FAPERGS, CNPq, and CAPES. Prof. E. S.
Lang (x-ray) from UFSM, Prof. N. P. Lopes (HRMS) from
FCFRP-USP, and J. P. Pinto (LRMS) from UEL are thanked for the
analyses.

Solvent-Free Synthesis of Octahydroacridines
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