Synthesis and structural elucidation of novel camphor-derived thioureas

Article abstract of DOI:10.1002/chir.21999

Nine novel (+)-camphor-derived thioureas have been prepared. 3-((Dimethylamino)methylene)camphor (2) served as the common precursor for the preparation of both, 2-thiourea 15-20 and 3-thiourea functionalized camphor derivatives 6, 7/7′, respectively. Starting from 2, the latter were prepared in two or three steps whereas the former in five steps, respectively. Configuration of all novel compounds has been meticulously determined using NMR techniques and/or single crystal X-ray crystallography. Copyright

Full text of DOI:10.1002/chir.21999

CHIRALITY 24:307–317 (2012)
Synthesis and Structural Elucidation of Novel
Camphor-Derived Thioureas
ˇ
ˇ
ˇ
*
UROS GROSELJ, AMALIJA GOLOBIC, KATARINA STARE, JURIJ SVETE, AND BRANKO STANOVNIK
ˇ
Faculty of Chemistry and Chemical Technology, University of Ljubljana, Aˇskerceva 5, 1000 Ljubljana, Slovenia
ABSTRACT Nine novel (1)-camphor-derived thioureas have been prepared. 3-((Dimethyla-
mino)methylene)camphor (2) served as the common precursor for the preparation of both, 2-
thiourea 15–20 and 3-thiourea functionalized camphor derivatives 6, 7/70, respectively. Start-
ing from 2, the latter were prepared in two or three steps whereas the former in five steps,
respectively. Configuration of all novel compounds has been meticulously determined using
NMR techniques and/or single crystal X-ray crystallography. Chirality 24:307–317,
C
VV
2012.
2012 Wiley Periodicals, Inc.
KEY WORDS: camphor-derived oxime; camphor-derived amines; oxime reduction; enaminone
reduction; enaminone methodology; X-ray analysis; 2,3-functionalized camphor
derivatives
INTRODUCTION
gate the possibility to prepare some mono-functional 2- and
3-thiourea camphor derivatives, preferably in a stereo diver-
gent synthesis. Thus, herein, we report our preliminary
results on the synthesis and structural characterization of
novel 2-thiourea 15–20 and 3-thiourea 6, 7/70 functional-
ized camphor derivatives.
Camphor is one of nature’s privileged scaffolds, which is
readily available in both enantiomeric forms. It undergoes a
wide variety of chemical transformations which functionalize,
at first glance, inactivated positions.1,2 All of the above makes
camphor a very desirable starting material for the prepara-
tion of a wide variety of compounds ranging from natural
products1,2 to chiral auxiliaries,3,4 ligands in asymmetric syn-
thesis,5–9 NMR shift reagents,10 etc.
EXPERIMENTAL
Considering camphor’s vast potential for chemical manipu-
lation, it is fair to say it has not yet been fully exploited in the
relatively immature field of organocatalysis. In the subfield
of covalent organocatalysis, there are only a few reports of
camphor-derived catalysts. Those are mainly five- and six-
membered cyclic sulfonyl hydrazine derivatives prepared
from camphor sulfonic acid.11–14 However, there are also
more noncovalent camphor-derived organocatalysts, the bulk
of them comprised of pyrrolidinyl–camphor–derived bifunc-
tional organocatalysts, where both camphor and pyrrolidine
chiral frameworks, connected with an appropriate linker, act
in synergy.15–24 All the above mentioned camphor-derived
organocatalysts have been prepared via derivatization of cam-
phor i.e., camphorsulfonic acid at positions 2 and/or 10
(Fig. 1) in most cases in combination with ‘‘external chiral
fragments’’ like pyrrolidine.
On the other hand, position 3 in camphor displays the
reactivity of an active methylene group, which resulted in the
preparation of a large number of C(3)-substituted camphor
derivatives.1,2 This, in turn, has not yet been translated into
the preparation of the corresponding organocatalysts.
Thiourea derivatives are the workhorses of noncovalent
organocatalysis working through double hydrogen-bonding
interactions with a suitable substrate. The preferred substitu-
ent is the electron-poor 3,5-bis(trifluoromethyl)phenyl-group
attached through thiourea functionality to a suitable chiral
scaffold. Of special interest are the thiourea organocatalysts
with bi-functionality which can achieve electrophile and
nucleophile binding and activation (Fig. 2).25–40
Melting points were determined on a Kofler micro hot stage and on
SRS OptiMelt MPA100 - Automated Melting Point System. The NMR
spectra were obtained on a Bruker Avance DPX 300 at 300 MHz for 1H
and 75.5 MHz for 13C nucleus, and Bruker UltraShield 500 plus at 500
MHz for 1H and 126 MHz for 13C nucleus, using DMSO-d6 and CDCl3
with TMS as the internal standard, as solvents. Mass spectra were
recorded on an AutoSpecQ spectrometer and Agilent 6224 Accurate
Mass TOF LC/MS, IR spectra on a Perkin-Elmer Spectrum BX FTIR
spectrophotometer. Microanalyses were performed on a Perkin-Elmer
CHN Analyser 2400 II. Catalytic hydrogenations were performed in a
Parr Pressure Reaction Hydrogenation Apparatus and in Berghof type
RHS 175 autoclave. Column chromatography (CC) was performed on
silica gel (Fluka, Silica gel 60, particle size: 0.035–0.070 mm). Medium-
pressure liquid chromatography (MPLC) was performed with Bu¨chi
Flash Chromatography System (Bu¨chi Fraction Collector C-660, Bu¨chi
Pump Module C-605, Bu¨chi Control Unit C-620) on silica gel (LiChro-
sphere1 Si 60 (12 lm) and/or LiChroprep1 Si 60 (15–25 lm)); column
dimensions (wet filled): 22 3 460 mm, 36 3 460 mm and 40 3 460 mm;
backpressure: 10–20 Bar; detection: UV 254 nm.
(1)-Camphor, tert-butoxy bis(dimethylamino)methane, anhydrous
DMF, 1-isothiocyanato-3,5-bis(trifluoromethyl)benzene (5) and 10% pal-
ladium on charcoal are commercially available (Sigma-Aldrich).
(1S,4S,3E)-3-Benzylidene-1,7,7-trimethylbicyclo[2.2.1]heptan-2-one (8)
was prepared following the literature procedure.41
Contract grant sponsor: Slovenian Research Agency (financial support);
Contract grant numbers: P1-0179 and J1-0972.
Contract grant sponsor: Ministry of Science and Technology, Republic of
Slovenia (financial contribution for the purchase of Kappa CCD Nonius dif-
fractometer); Contract grant numbers: Packet X-2000 and PS-511-102.
*Correspondence to: Urosˇ Grosˇelj, University of Ljubljana, Faculty of Chem-
ˇ
istry and Chemical Technology, Asˇkerceva cesta 5, P.O. Box 537, 1000 Ljubl-
jana, Slovenia. E-mail: uros.groselj@fkkt.uni-lj.si
Received for publication 8 September 2011; Accepted 14 December 2011
DOI: 10.1002/chir.21999
Published online 17 February 2012 in Wiley Online Library
(wileyonlinelibrary.com).
To the best of our ability, we could not find any 3,5-bis(tri-
fluoromethyl)phenyl thiourea derivatives with camphor as
the exclusive chiral framework. This prompted us to investi-
C
VV
2012 Wiley Periodicals, Inc.

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308
GROSELJ ET AL.
(five drops, 37%, ca. 2 mmol) were added. The reaction vessel was
flushed with H2 and the reaction mixture was hydrogenated in Paar hy-
drogenator (P 5 4 Bar) at room temperature for 3 h. The reaction mix-
ture was filtered through a plug of Celite1 and washed with EtOH (100
ml). Volatile components were evaporated in vacuo, the residue was dis-
solved in CH2Cl2 (200 ml) and washed with NaOH (aq., 0.2 M, 50 ml).
The organic phase was dried owed anhydrous Na2SO4, filtered, and vola-
tile components evaporated in vacuo to give a crude mixture of amines
4/40 (100% conversion). The amine mixture could not be separated
using preparative chromatographic techniques and was used in the fol-
lowing transformation without further purification/separation. Yield: 213
mg (87%, 4:40 5 68:32) of yellow oil. EI-HRMS: m/z 5 182.1541 (MH1);
Fig. 1. The numbering system used in this article.2
C
11H20NO requires: m/z 5 182.1539 (MH1). 1H-NMR (500 MHz,
CDCl3) for 4: d 0.88 (s, Me); 0.90 (s, Me); 1.00 (s, Me); 1.27–1.34 (m, 1H
of CH2); 1.44–1.54 (m, 1H of CH2, NH2); 1.62–1.73 (m, 1H of CH2); 1.75–
1.84 (m, 1H of CH2); 2.14 (t, J 5 4.3 Hz, HꢀꢀC(4)); 2.50 (br dd, J 5 6.6;
12.2 Hz, HꢀꢀC(3)); 2.68 (dd, J 5 7.8; 12.6 Hz, Ha-C(30)); 3.02 (dd, J 5 7.2;
Source of chirality: (1)-Camphor (1) (Fluka AG), product number
20
21300, purum, natural, =97.0% (GC, sum of enantiomers), [a]D
142.5 6 2.5 (c 5 10, EtOH), mp 176–1808C, ee not specified.
5
1
12.6 Hz, Hb-C(30)). H-NMR (500 MHz, CDCl3) for 40: d 0.83 (s, Me);
0.90 (s, Me); 0.94 (s, Me); 1.38–1.43 (m, 1H of CH2); 1.95–2.00 (m,
HꢀꢀC(3), HꢀꢀC(4)); 2.00–2.07 (m, 1H of CH2); 2.72 (dd, J 5 7.3; 12.7 Hz,
Ha-C(30)); 3.11 (dd, J 5 6.8; 12.7 Hz, Hb-C(30)). 13C-NMR (126 MHz,
CDCl3) for 4: d 9.6, 19.2, 19.6, 20.5, 31.3, 40.8, 45.8, 53.0, 58.9, 59.0,
Syntheses
(1S,4S,3E)-3-((Dimethylamino)methylene)-1,7,7-trimethylbicyclo-
[2.2.1]heptan-2-one (2).42 To a solution of (1)-camphor (1) (456 g, 30
mmol) in anhydrous DMF (60 ml) under Argon tert-butoxy bis(dimethy-
lamino)methane (12 ml, 58 mmol) was added, and the resulting mixture
was heated under reflux for 24 h. The reaction mixture was cooled to
room temperature and volatile components were evaporated in vacuo.
The residue (100% conversion was achieved according to the 1H-NMR of
the raw reaction mixture) was purified by CC (Silica gel 60, EtOAc/pe-
troleum ether 5 1:1). Fractions containing the product were combined
and volatile components evaporated in vacuo to give 2. Yield: 4.79 g
(77%) of yellowish-brown solid; mp 57–618C (lit. 42: 59–628C). 1H-NMR
(300 MHz, CDCl3): d 0.85 (s, Me); 0.89 (s, Me); 0.94 (s, Me); 1.29–1.46
(m, 2H of CH2); 1.54–1.63 (m, 1H of CH2); 1.94–2.04 (m, 1H of CH2);
2.90 (d, J 5 3.8 Hz, HꢀꢀC(4)); 2.98 (s, NMe2); 7.00 (s, HꢀꢀC(30)).
13
221.0. C-NMR (126 MHz, CDCl3) for 40: d 9.4, 20.6, 21.8, 29.4, 29.5,
44.6, 46.0, 46.8, 58.0, 221.2.
1-(3,5-Bis(trifluoromethyl)phenyl)-3-((Z )-((1S,4S )-4,7,7-trimethyl-
3-oxobicyclo[2.2.1]heptan-2-ylidene)methyl)thiourea (6). To a sus-
pension of 3 (184 mg, 1.03 mmol) in Et2O (10 ml) under Argon 1-isothio-
cyanato-3,5-bis(trifluoromethyl)benzene (5) (195 lL, 1.03 mmol) was
added and the resulting mixture was stirred at room temperature for 24
h. Volatile components were evaporated in vacuo and the residue was
purified by CC (Silica gel 60; 1) EtOAc/petroleum ether 5 1:40 to elute
the unreacted 5; 2) EtOAc/petroleum ether 5 1:15 to elute the product
6). Fractions containing the product were combined and volatile compo-
nents evaporated in vacuo to give 6. Yield: 130 mg (28%) of light yellow
solid; mp 169–1718C. [a]D20 5 1178.3 (c 5 0.07, CH2Cl2). 1H-NMR (500
MHz, CDCl3): d 0.80 (s, Me); 0.90 (s, Me); 0.95 (s, Me); 1.32–1.39 (m,
1H of CH2); 1.41–1.47 (m, 1H of CH2); 1.67–1.76 (m, 1H of CH2); 2.04–
2.11 (m, 1H of CH2); 2.59 (d, J 5 3.7 Hz, HꢀꢀC(4)); 7.73 (d, J 5 9.7 Hz,
HꢀꢀC(30)); 7.77 (s, 1H of Arl); 7.96 (s, 2H of Arl), 8.65 (s, NH); 11.28 (d, J
5 9.6 Hz, HꢀꢀN(4’)). 13C-NMR (126 MHz, CDCl3): d 9.0, 18.7, 20.6, 27.6,
30.2, 48.9, 49.1, 59.3, 119.7–119.9 (m), 123.0 (q, J 5 273.0 Hz), 123.4,
123.8–124.0 (m), 130.0, 132.8 (q, J 5 33.8 Hz), 139.0, 178.6, 211.6.
(C20H20F6N2OS requires: C, 53.33; H, 4.48; N, 6.22. found C, 53.60; H,
(1S,4S,3E)-3-(Aminomethylene)-1,7,7-trimethylbicyclo[2.2.1]-
heptan-2-one (3).43 A mixture of NH4OAc (156 g, 20 mmol) and 2
(0.5 g, 2.41 mmol) in EtOH (25 ml) was stirred at room temperature for
48 h. Volatile components were evaporated in vacuo, the residue dis-
solved/suspended in CH2Cl2 (150 ml), and washed with NaHCO3 (aq.
sat,) and brine. The organic phase was dried over anhydrous Na2SO4, fil-
tered, and volatile components were evaporated in vacuo. The residue
was purified by CC (Silica gel 60, EtOAc/petroleum ether 5 2:1). Frac-
tions containing the product were combined and volatile components
evaporated in vacuo to give 3. Yield: 300 mg (69%); mp 147–1518C (lit.
43: mp 1568C). [a]D20 5 1275.0 (c 5 0.09, CH2Cl2). 1H-NMR (500 MHz,
CDCl3): d 0.82 (s, Me); 0.92 (s, Me); 0.94 (s, Me); 1.31–1.43 (m, 2H of
CH2); 1.60–1.68 (m, 1H of CH2); 1.91–1.98 (m, 1H of CH2); 2.50 (d, J 5
3.7 Hz, HꢀꢀC(4)); 4.24 (br d, J 5 7.8 Hz, NH2); 7.09 (t, J 5 10.7 Hz, CH).
13C-NMR (126 MHz, CDCl3): d 9.6, 19.0, 20.4, 26.7, 31.6, 45.6, 48.0, 57.9,
115.9, 133.8, 207.4. (Found C, 73.89; H, 9.85; N, 7.89. C11H17NO
requires: C, 73.70; H, 9.56; N, 7.81.); EI-HRMS: m/z 5 179.13156 (M1);
C11H17NO requires: m/z 5 179.13101 (M1); mmax (KBr) 3389, 3207,
4.33; N, 6.16); EI-HRMS: m/z
5 449.1126 (M-H); C20H19F6N2OS
2952, 2360, 1684, 1645, 1575, 1389, 1304, 1071, 949 cm21
.
Isomerization of (1S,4S,3E)-3-(aminomethylene)-1,7,7-trime-
thylbicyclo[2.2.1]heptan-2-one (3). A solution of 3-(E) (25 mg) in
CDCl3 (0.7 ml) was left standing at room temperature for 5 days. Partial
isomerization of the exocyclic double bond of 3-(E) took place to give a
1
mixture of E- and Z-isomers, 3-(E)/3-(Z) 5 83:17, respectively. H-NMR
(500 MHz, CDCl3) for 3-(Z): d 0.88 (s, Me); 0.93 (s, Me); 2.31 (d, J 5 3.6
Hz, HꢀꢀC(4)); 6.44 (t, J 5 10.3 Hz, HꢀꢀC(30)). 13C-NMR (126 MHz,
CDCl3) for 3-(Z): d 9.3, 19.3, 20.5, 28.6, 30.4, 49.1, 49.9, 58.8, 113.5,
138.5, 208.9.
(1S,3R,4R )-3-(Aminomethyl)-1,7,7-trimethylbicyclo[2.2.1]heptan-
2-one (4)44 and (1S,3S,4R )-3-(aminomethyl)-1,7,7-trimethylbicy-
clo[2.2.1]heptan-2-one (40).44 To a solution of 3 (240 mg, 1.34 mmol)
in anhydrous EtOH (100 ml) under Argon, Pd–C (10%, 100 mg) and HCl
Fig. 2. General outline and an example of a bi-functional thiourea organo-
catalyst. [Color figure can be viewed in the online issue, which is available at
wileyonlinelibrary.com.]
Chirality DOI 10.1002/chir

SYNTHESIS OF NOVEL CAMPHOR-DERIVED THIOUREAS
309
requires: m/z 5 449.1128 (M-H); mmax (KBr) 3418, 2962, 1703, 1647,
24 h, and recrystallized from EtOH to give the product as a mixture of
1619, 1549, 1516, 1471, 1453, 1381, 1337, 1281, 1249, 1180, 1127, 1107,
epimers 10/100. Yield: 750 mg (54%, 10:100 5 66:34) of white solid;
1070, 1025, 959, 888 cm21
.
mp 141.2–143.08C. [a]D 5 128.4 (c 5 0.08, CH2Cl2). (C17H23NO
20
requires: C, 79.33; H, 9.01; N 5.44. found C, 79.47; H, 9.17; N, 5.51); EI-
HRMS: m/z 5 258.1858 (MH1); C17H24NO requires: m/z 5 258.1855
(MH1); mmax (KBr) 3264, 3148, 3028, 2966, 2945, 2873, 2366, 2357, 2337,
1601, 1497, 1472, 1454, 1445, 1389, 1375, 1317, 1072, 1021, 934, 834, 740,
699, 513 cm21. 1H-NMR (500 MHz, CDCl3) of 10: d 0.90 (s, Me); 1.03 (s,
Me); 1.06 (s, Me); 1.10–1.17 (m, 1H of CH2); 1.41–1.47 (m, 1H of CH2);
1.61–1.81 (m, HꢀꢀC(4), 2H of CH2); 2.57 (dd, J 5 10.0; 13.8 Hz, Ha-
C(30)); 2.69 (dd, J 5 3.2; 10.0 Hz, HꢀꢀC(3)); 3.81 (dd, J 5 3.2; 13.8 Hz,
Hb-C(30)); 7.16–7.22 (m, 1H of Ph); 7.23–7.33 (m, 4H of Ph); 7.53 (br s,
1-(3,5-Bis(trifluoromethyl)phenyl)-3-(((1R,2R,4S)-4,7,7-trimethyl-
3-oxobicyclo[2.2.1]heptan-2-yl)methyl)thiourea (7) and 1-(3,5-bis
(trifluoromethyl)phenyl)-3-(((1R,2S,4S)-4,7,7-trimethyl-3-oxobicyclo-
[2.2.1]heptan-2-yl)methyl)thiourea (70). To a solution of 4 (4:40 ꢁ
68:32, 183 mg, 1.01 mmol) in Et2O (10 ml) under Argon 1-isothiocya-
nato-3,5-bis(trifluoromethyl)benzene (5) (192 lL, 1.01 mmol) was added,
and the resulting mixture was stirred at room temperature for 24 h. Vola-
tile components were evaporated in vacuo and the residue (7/70
5
1
OH). H-NMR (500 MHz, CDCl3) of 100: d 0.81 (s, Me); 0.89 (s, Me);
69:31) was purified by CC (Silica gel 60; CHCl3/MeOH 5 150:1). No
separation of diastereoisomers took place. Fractions containing the prod-
uct were combined and volatile components evaporated in vacuo to give
7/70. The residue was dissolved in Et2O (7 ml), n-heptane (50 ml) was
added and the resulting solution was left open overnight for the Et2O to
evaporate. The precipitate was collected by filtration, washed with petro-
leum ether (10 ml) and dried on high vacuum. Yield: 300 mg (65%, 7/70
0.97 (s, Me); 1.48–1.54 (m, 1H of CH2); 2.50 (dd, J 5 11.9; 14.3 Hz, Ha-
C(30)); 3.21–3.27 (m, HꢀꢀC(3)); 3.92 (dd, J 5 4.3; 14.4 Hz, Hb-C(30)). 13C-
NMR (75 MHz, CDCl3) of 10 and 100: d 11.6, 12.1, 19.1, 19.3, 20.1, 20.9,
22.6, 29.2, 32.26, 32.30, 33.4, 37.0, 43.1, 46.5, 47.5, 48.2, 48.3, 50.6, 53.1,
53.3, 125.9, 126.0, 128.4, 128.5, 129.0, 129.1, 141.1, 142.8, 170.0, 172.1.
20
5 70:30) of white solid; mp 150–1528C. [a]D 5 14.8 (c 5 0.19,
Catalytic hydrogenation of (1S,3RS,4R,2E)-3-benzyl-1,7,7-
trimethylbicyclo[2.2.1]heptan-2-one 10/100 at 608C
CH2Cl2). (C20H22F6N2OS requires: C, 53.09; H, 4.90; N, 6.19. found C,
53.12; H, 4.78; N, 6.13); EI-HRMS: m/z
20H22F6N2OS requires: m/z 5 453.1435 (MH1); mmax (KBr) 3420, 1730,
1636, 1618, 1558, 1532, 1472, 1386, 1337, 1279, 1185, 1129, 959, 886,
cm21 1H-NMR (500 MHz, DMSO-d6) for 7: d 0.82 (s, 2xMe); 0.98 (s,
5
453.1421 (MH1);
To a suspension of oxime 10/100 (10/100 ꢁ 66:34, 1.36 g, 5.3 mmol)
in anhydrous EtOH (30 ml) under Argon Pd–C (10%, 400 mg) was
added. The reaction vessel was flushed with H2 and the reaction mixture
was hydrogenated in an autoclave (P 5 50–55 Bar) at 608C for 4 days.
The reaction mixture was filtered through a plug of Celite1, washed
with CH2Cl2 (200 ml), and volatile components were evaporated in
vacuo. The residue (ca. 90% conversion according to 1H-NMR; 11/12/
13 ꢁ 1:1:0.3) was separated by MPLC (EtOAc/Et3N 5 100:1). Fractions
containing the partially separated products were combined and volatile
components evaporated in vacuo to give crude amines 11, 12, and 13,
respectively.
C
.
Me); 1.20–1.28 (m, 1H of CH2); 1.56–1.81 (m, 3H of CH2); 2.13 (s,
HꢀꢀC(4)); 2.91–2.97 (m, HꢀꢀC(3)); 3.53 (br s, Ha-C(30)); 3.66–3.81 (m,
Hb-C(30)); 7.75 (s, 1H of Arl); 8.22 (s, 2H of Arl); 8.28 (br s, NH); 10.13
1
(br s, NH). H-NMR (500 MHz, DMSO-d6) for 70: d 0.85 (s, Me); 0.92 (s,
Me); 1.31–1.39 (m, 1H of CH2); 1.40–1.46 (m, 1H of CH2); 1.92–2.00 (m,
1H of CH2); 2.33–2.38 (m, HꢀꢀC(3)); 8.41 (br s NH). 13C NMR (126
MHz, DMSO-d6) for 7 and 70: d 9.3, 9.4, 18.9, 19.2, 20.1, 21.1, 28.4, 28.6,
30.4, 41.9, 45.1, 45.2, 45.4, 45.5, 46.4, 48.4, 53.4, 57.1, 58.2, 116.1 (br s),
121.8 (br s), 122.0 (br s), 123.2 (q, J 5 272.7 Hz), 130 (q, J 5 32.3 Hz),
141.8, 180.3, 218.2, 218.3.
(1S,2R,3R,4R)-3-Benzyl-1,7,7-trimethylbicyclo[2.2.1]heptan-2-
amine (11). 11 elutes first from the column. Yield: 324 mg (25%, ca.
75–85% pure) of yellowish oil. Part of the free amine was transformed
into the corresponding hydrochloride salt for NMR characterization.
Free amine 11 (70 mg) was dissolved in Et2O (5 ml) followed by addi-
tion of HCl (2 M in EtOAc, 0.2 ml). Volatile components were evaporated
in vacuo to give the corresponding 11-HCl salt for NMR characteriza-
tion. 1H-NMR (500 MHz, CDCl3): d 0.73 (s, Me); 0.83–0.90 (m, 1H of
CH2); 1.11 (s, Me); 1.16–1.23 (m, 1H of CH2); 1.22 (s, Me); 1.48–1.62 (m,
HꢀꢀC(4), 2H of CH2); 2.27 (ddd, J 5 4.1; 9.7, 13.5 Hz, HꢀꢀC(3)); 2.72 (t, J
5 13.2 Hz, Ha-C(30)); 3.40 (dd, J 5 4.0; 13.2 Hz, Hb-C(30)); 3.44 (dd, J 5
6.7; 9.2 Hz, HꢀꢀC(2)); 7.05 (d, J 5 7.1 Hz, 2H of Ph); 7.12–7.21 (m, 3H of
Ph); 8.45 (s, NH31). 13C-NMR (126 MHz, CDCl3): d 12.9, 22.1, 22.6,
29.7, 36.1, 36.5, 46.7, 47.5, 49.2, 49.6, 62.8, 125.9, 128.4, 129.4, 140.9.
(1S,3R,4R)-3-Benzyl-1,7,7-trimethylbicyclo[2.2.1]heptan-2-one
(9) and (1S,3S,4R)-3-benzyl-1,7,7-trimethylbicyclo[2.2.1]heptan-
2-one (90). To a solution of (E)-3-benzylidene-camphor (8)41 (5.34 g,
22.22 mmol) in anhydrous EtOH (150 ml) under Argon Pd–C (10%, 0.5
g) was added. The reaction vessel was flushed with H2 and the reaction
mixture was hydrogenated in Paar hydrogenator (P 5 4 Bar) at room
temperature for 10 min. The reaction mixture was filtered through a
plug of Celite1 and washed with CH2Cl2 (100 ml). Volatile components
were evaporated in vacuo to give a mixture of ketones 9/90 (100% con-
20
version). Yield: 5.12 g (95%, 9:90 5 66:34) of colorless oil. [a]D
5
152.7 (c 5 0.26, CH2Cl2, 9:90 5 62:38). EI-HRMS: m/z 5 243.1746
(MH1); C17H23O requires: m/z 5 243.1743 (MH1); mmax (NaCl) 2959,
1741, 1604, 1496, 1453, 1391, 1372, 1323, 1268, 1104, 1074, 1043, 1030,
1
1018, 757, 730 cm21. H-NMR (500 MHz, CDCl3) of 9: d 0.94 (s, 2xMe);
(1S,2R,3S,4R)-3-Benzyl-1,7,7-trimethylbicyclo[2.2.1]heptan-2-
amine (12). 12 elutes second from the column. Yield: 452 mg (35%,
ca. 90–95% pure) of colorless oil. The crude free amine 12 (452 mg,
1.857 mmol) was dissolved in anhydrous Et2O (25 ml) under argon,
cooled to 08C, followed by addition of HCl (2 M in EtOAc, 1 ml). The
resulting precipitate was collected by filtration and washed with anhy-
drous Et2O (50 ml) to give analytically pure amine hydrochloride 12-
HCl. Yield: 318 mg (21%, calculated from 10/100) of white solid; mp
0.97 (s, Me); 1.22–1.28 (m, 1H of CH2); 1.46–1.53 (m, 1H of CH2); 1.61–
1.67 (m, 1H of CH2); 1.89–1.96 (m, 1H of CH2); 1.97 (d, J 5 4.0 Hz,
HꢀꢀC(4)); 2.16 (dd, J 5 3.8; 10.6 Hz, HꢀꢀC(3)); 2.48–2.55 (m, Ha-C(30));
3.25 (dd, J 5 3.8; 14.2 Hz, Hb-C(30)); 7.18–7.22 (m, 3H of Ph); 7.27–7.32
1
(m, 2H of Ph). H-NMR (500 MHz, CDCl3) of 90: d 0.85 (s, Me); 0.93 (s,
Me); 1.33–1.39 (m, 1H of CH2); 1.68–1.81 (m, 3H of CH2); 2.68–2.73 (m,
HꢀꢀC(3)); 3.18 (dd, J 5 4.3; 14.3 Hz, Hb-C(30)). 13C-NMR (126 MHz,
CDCl3) of 9 and 90: d 9.7, 9.8, 19.5, 19.7, 20.5, 20.7, 22.2, 29.45, 29.48,
31.1, 32.9, 37.3, 45.9, 46.6, 47.0, 52.0, 56.9, 57.9, 58.9, 126.19, 126.23,
128.64, 128.67, 128.69, 128.8, 140.5, 141.5, 220.6, 220.8.
255–2628C. [a]D 5 –41.7 (c 5 0.06, CH2Cl2). 1H-NMR (500 MHz,
20
CDCl3):d 0.83 (s, Me); 1.10 (s, Me); 1.13 (s, Me); 1.19–1.28 (m, 1H of
CH2); 1.51 (br s, HꢀꢀC(4)); 1.58–1.76 (m, 3H of CH2); 2.54 (deg t, J 5
12.5 Hz, Ha-C(30)); 2.79 (br s, HꢀꢀC(2), HꢀꢀC(3)); 3.48 (dd, J 5 3.2; 13.0
Hz, Hb-C(30)); 7.11–7.21 (m, 3H of Ph); 7.29 (br d, J 5 7.0 Hz, 2H of Ph);
8.59 (br s, NH31). 13C-NMR (126 MHz, CDCl3): d 12.5, 20.1, 20.4, 20.8,
36.0, 36.7, 46.4, 47.8, 48.4, 49.1, 64.9, 126.1, 128.5, 129.1, 140.6. (Found
C, 72.84; H, 9.60; N, 4.96. C17H26ClN requires: C, 72.96; H, 9.36; N,
5.01.); EI-HRMS: m/z 5 244.2071 (M1); C17H26ClN requires: m/z 5
244.2065 (M1); mmax (KBr) 3473, 3414, 2954, 2894, 1636, 1617, 1605,
1521, 1510, 1496, 1485, 1400, 1388, 1183, 1134, 1053, 1030, 748, 700
(1S,3R,4R,2E )-3-Benzyl-1,7,7-trimethylbicyclo[2.2.1]-heptan-
2-one oxime (10) and (1S,3S,4R,2E )-3-benzyl-1,7,7-trimethyl-
bicyclo[2.2.1]heptan-2-one oxime (100). To a solution of 9/90
(9/90 ꢁ 66:34, 1.30 g, 5.36 mmol) in EtOH (100 ml) pyridine (3.27 ml,
40.5 mmol) and NH2OHꢂHCl (4.08 g, 58.7 mmol) were added and the
resulting mixture was refluxed for 48 h. Volatile components were evapo-
rated in vacuo and to the residue H2O (50 ml) was added. The resulting
precipitate was collected by filtration, dried over NaOH in a desicator for
cm21
.
Chirality DOI 10.1002/chir

ˇ
310
GROSELJ ET AL.
12-HCl was dissolved in CH2Cl2 (150 ml) and washed with NaHCO3
vacuo to give the desired product or products. Fractions containing mix-
tures of products or not fully separated products were discarded.
(aq. sat, 15 ml). The organic phase was dried over anhydrous Na2SO4,
filtered, and volatile components evaporated in vacuo to give pure free
amine 12 for further transformation and NMR characterization. 1H-NMR
(500 MHz, CDCl3):d 0.82 (s, Me); 0.82 (s, Me); 0.99 (s, Me); 1.01–1.06
(m, 1H of CH2); 1.50–1.62 (m, HꢀꢀC(4), 3H of CH2); 2.10–2.17 (m,
HꢀꢀC(3)); 2.30 (d, J 5 5.5 Hz, HꢀꢀC(2)); 2.62 (dd, J 5 8.8; 13.4 Hz, Ha-
C(30)); 2.84 (dd, J 5 7.0; 13.4 Hz, Hb-C(30)); 7.15–7.30 (m, 5H of Ph).
13C-NMR (126 MHz, CDCl3): d 12.2, 20.0, 20.5, 21.4, 37.1, 37.8, 47.9,
48.1, 49.1, 51.9, 67.1, 125.9, 128.5, 129.0, 142.1.
1-((1S,2R,3R,4R)-3-Benzyl-1,7,7-trimethylbicyclo[2.2.1]heptan-
2-yl)-3-(3,5-bis(trifluoro-methyl)phenyl)thiourea (15). Prepared
from 11 (223 mg, 0.916 mmol) and 5 (174 lL, 0.916 mmol) in Et2O (10
ml) following GP1. Yield: 177 mg (37%) of white solid; mp 59–708C.
20
[a]D 5 –17.8 (c 5 0.17, CH2Cl2). 1H-NMR (500 MHz, DMSO-d6): d
0.82 (s, Me); 0.90 (s, Me); 0.96–1.04 (m, 1H of CH2); 1.16 (s, Me); 1.27–
1.34 (m, 1H of CH2); 1.54 (d, J 5 3.9 Hz, HꢀꢀC(4)); 1.55–1.68 (m, 2H of
CH2); 2.22 (td, J 5 4.8; 11.0 Hz, HꢀꢀC(3)); 2.53 (dd, J 5 11.5; 14.0 Hz,
Ha-C(30)); 2.84 (dd, J 5 4.6, 13.7 Hz, Hb-C(30)); 4.69 (t, J 5 9.0 Hz,
HꢀꢀC(2)); 7.12–7.21 (m, 3H of Ph); 7.23–7.28 (m, 2H of Ph); 7.72 (d, J 5
8.8 Hz, HꢀꢀN(20)); 7.74 (s, 1H of Arl); 8.41 (s, 2H of Arl); 10.49 (s, NH).
13C-NMR (126 MHz, DMSO-d6): d 12.2, 21.7, 21.9, 29.2, 36.1, 36.1, 47.3,
47.4, 49.1, 51.2, 64.6, 115.9, 121.3, 123.3 (q, J 5 272.7 Hz), 125.5, 128.3,
128.7, 130.1 (q, J 5 32.8 Hz), 141.9, 142.1, 180.9. (Found C, 60.63; H,
5.40; N, 5.39. C26H28F6N2S requires: C, 60.69; H, 5.48; N, 5.44.); EI-
HRMS: m/z 5 515.1952 (MH1); C26H29F6N2S requires: m/z 5 515.1950
(MH1); mmax (KBr) 3416, 2958, 1622, 1522, 1472, 1381, 1342, 1278, 1182,
(1S,2S,3S,4R)-3-Benzyl-1,7,7-trimethylbicyclo[2.2.1]heptan-2-
amine (13). 13 elutes third from the column. Yield: 133 mg (10%, ca.
75–85% pure) of yellowish oil. 1H-NMR (500 MHz, CDCl3): d 0.80 (s,
Me); 0.87 (s, Me); 0.90 (s, Me); 1.16–1.27 (m, 1H of CH2); 1.42 (t, J 5 3.9
Hz, HꢀꢀC(4)); 1.45–1.55 (m, 1H of CH2); 1.56–1.64 (m, 2H of CH2); 2.50–
2.57 (m, HꢀꢀC(3), Ha-C(30)); 2.81 (q, J 5 11.0 Hz, Hb-C(30)); 3.12 (dd, J
5 1.7; 10.0 Hz, HꢀꢀC(2)); 7.13–7.20 (m, 3H of Ph); 7.24–7.28 (m, 2H of
Ph). 13C-NMR (126 MHz, CDCl3): d 14.5, 18.5, 20.4, 20.4, 26.2, 32.7,
41.2, 46.5, 48.2, 50.4, 57.1, 125.7, 128.4, 128.9, 142.3.
1135, 1108, 960, 888, 700, 682 cm21
.
1-((1S,2R,3S,4R)-3-Benzyl-1,7,7-trimethylbicyclo[2.2.1]heptan-
Catalytic Hydrogenation of (1S,3RS,4R,2E)-3-benzyl-1,7,7-
trimethylbicyclo[2.2.1]heptan-2-one 10/100 at 908C
2-yl)-3-(3,5-bis(trifluoro-methyl)phenyl)thiourea (16). Prepared
from 12 (230 mg, 0.945 mmol) and 5 (179 lL, 0.945 mmol) in Et2O (10
ml) following GP1. Yield: 338 mg (69%) of white solid; mp 167–1688C.
[a]D20 5 –46.0 (c 5 0.13, CH2Cl2). 1H-NMR (500 MHz, DMSO-d6): d 0.81
(s, Me); 0.85 (s, Me); 0.93 (s, Me); 1.27–1.35 (m, 1H of CH2); 1.45 (br s,
HꢀꢀC(4)); 1.51–1.64 (m, 2H of CH2); 1.67–1.74 (m, 1H of CH2); 2.28–2.35
(m, HꢀꢀC(3)); 2.67 (dd, J 5 9.6; 13.5 Hz, Ha-C(30)); 2.86 (dd, J 5 6.0; 13.6
Hz, Hb-C(30)); 4.28 (dd, J 5 7.0; 7.9 Hz, HꢀꢀC(2)); 7.10–7.15 (m, 1H of
Ph); 7.19–7.26 (m, 4H of Ph); 7.72 (d, J 5 8.9 Hz, HꢀꢀN(20)); 7.73 (s, 1H of
Arl); 8.26 (s, 2H of Arl); 10.03 (s, NH). 13C-NMR (126 MHz, DMSO-d6): d
11.9, 19.7, 20.5, 36.1, 36.5, 46.9, 47.4, 48.7, 50.4, 66.6, 115.8, 121.4, 123.3
(q, J 5 272.7 Hz), 125.6, 128.1, 128.5, 130.1 (q, J 5 32.8 Hz), 141.0, 142.0,
181.0. (Found C, 60.75; H, 5.35; N, 5.42. C26H28F6N2S requires: C, 60.69;
H, 5.48; N, 5.44.); EI-HRMS: m/z 5 515.1953 (MH1); C26H29F6N2S
requires: m/z 5 515.1950 (MH1); mmax (KBr) 3407, 2958, 1618, 1527,
To a suspension of oxime 10/100 (10/100 ꢁ 66:34, 2.06 g, 8 mmol)
in anhydrous EtOH (40 ml) under Argon Pd–C (10%, 600 mg) was
added. The reaction vessel was flushed with H2 and the reaction mixture
was hydrogenated in an autoclave (P 5 50–55 Bar) at 908C for 48 h. The
reaction mixture was filtered through a plug of Celite1, washed with
CH2Cl2 (200 ml), and volatile components were evaporated in vacuo.
The residue (100% conversion according to 1H-NMR) was dissolved in
Et2O (200 ml) and washed with HCl (1 M in H2O, 40 ml). The aqueous
phase was extracted with addition Et2O (100 ml). Combined organic
phase was dried over anhydrous Na2SO4, filtered, and volatile compo-
nents evaporated in vacuo. The residue was dissolved in CH2Cl2 (200
ml) and washed with NaHCO3 (aq. sat., 30 ml). The organic phase was
dried over anhydrous Na2SO4, filtered, and volatile components evapo-
rated in vacuo to give the crude products, a complex mixture of 3-benzyl-
amines 11–13 and corresponding 3-cyclohexylmethyl-amines 110-130.
Product mixture was used in the following transformation without fur-
ther purification/separation. Yield: 1.3 g.
1496, 1471, 1384, 1344, 1279, 1176, 1135, 1108, 962, 889, 700, 682 cm21
.
1-((1S,2S,3S,4R)-3-Benzyl-1,7,7-trimethylbicyclo[2.2.1]heptan-
2-yl)-3-(3,5-bis(trifluoro-methyl)phenyl)thiourea (17). Prepared
from 13 (100 mg, 0.41 mmol) and 5 (78 lL, 0.41 mmol) in Et2O (5 ml)
20
following GP1. Yield: 60 mg (28%) of white solid; mp 151–1618C. [a]D
Reduction of (1S,3RS,4R,2E)-3-benzyl-1,7,7-
5 125.2 (c 5 0.10, CH2Cl2). 1H-NMR (500 MHz, DMSO-d6): d 0.79 (s,
Me); 0.87 (s, Me); 0.97 (s, Me); 1.35–1.43 (m, HꢀꢀC(4), 1H of CH2);
1.48–1.57 (m, 1H of CH2); 1.60–1.70 (m, 2H of CH2); 2.51–2.53 (Ha-
C(30)); 2.62–2.72 (m, HꢀꢀC(3), Hb-C(30)); 4.82 (t, J 5 9.6 Hz, HꢀꢀC(2));
7.10–7.18 (m, 3H of Ph); 7.20–7.25 (m, 2H of Ph); 7.73 (s, 1H of Arl); 8.09
(d, J 5 9.3 Hz, HꢀꢀN(20)); 8.34 (s, 2H of Arl); 10.14 (s, NH). 13C-NMR
(126 MHz, DMSO-d6): d 14.2, 18.3, 19.60, 19.65, 27.6, 32.0, 40.0, 46.5,
46.8, 49.7, 59.1, 115.8, 121.4, 123.3 (q, J 5 272.7 Hz), 125.5, 128.2, 128.4,
130.1 (q, J 5 32.8 Hz), 140.9, 142.0, 181.6. (Found C, 60.97; H, 5.74; N,
5.41. C26H28F6N2S requires: C, 60.69; H, 5.48; N, 5.44.); EI-HRMS: m/z
5 515.1960 (MH1); C26H29F6N2S requires: m/z 5 515.1950 (MH1);
mmax (KBr) 3298, 2958, 1622, 1602, 1538, 1493, 1473, 1384, 1346, 1278,
trimethylbicyclo[2.2.1]heptan-2-one 10/100 with sodium
To a solution of oxime 10/100 (10/100 ꢁ 66:34, 315 mg, 1.223
mmol) in anhydrous nPrOH (10 ml) under Argon under reflux sodium
(ca. 100 mg) was added. Before all the added sodium reacted, another
chunk of sodium (ca. 100 mg) was added, followed by addition of further
sodium to ensure a continuous evolution of hydrogen for 1 h. After all
the sodium reacted, volatile components were evaporated in vacuo and
to the residue H2O (100 ml) was added followed by extraction with
CHCl3 (3x70 ml). Combined organic phase was dried over anhydrous
Na2SO4, filtered, and volatile components evaporated in vacuo to give
the crude products, amines 12, 13, and 14 in a ratio of about ꢁ
0.45:0.45:1, respectively. The product mixture was used in the following
transformation without further purification/separation. Yield: 279 mg
(100% conversion according to 1H-NMR).
1223, 1180, 1136, 1108, 976, 961, 888, 720, 700, 682 cm21
.
Reaction of a Mixture of Amines 12, 13, and 14 with
1-isothiocyanato-3,5-bis(trifluoromethyl)benzene (5)
Prepared from a mixture of 12, 13, and 14 in a ratio of about
0.45:0.45:1 (279 mg, 1.146 mmol) and 5 (218 lL, 1.146 mmol) in Et2O
(10 ml) following GP1. Fractions containing the separated products were
combined and volatile components evaporated in vacuo to give 16, 18,
and 17, respectively.
General Procedure for the Formation of 2-thiourea-
camphor derivatives 15–20 (GP1)
To a solution of amine or mixture of amines (1 equivalent) in anhy-
drous Et2O (V1) 1-isothiocyanato-3,5-bis(trifluoromethyl)benzene (5) (1
equivalent) was added and the resulting mixture was stirred at room
temperature for 24 h. The reaction mixture was passed through a plug of
Silica gel 60 (length of 5 cm) and washed with Et2O (100 ml). Volatile
components were evaporated in vacuo, and the residue was separated by
MPLC (EtOAc/petroleum ether 5 1:15). Fractions containing the sepa-
rated products were combined and volatile components evaporated in
16 elutes first from the column. Yield: 102 mg (17%) of white solid
(for exp. details see above).
1-((1S,2S,3R,4R)-3-Benzyl-1,7,7-trimethylbicyclo[2.2.1]heptan-
2-yl)-3-(3,5-bis(trifluoromethyl)phenyl)thiourea (18). Elutes sec-
ond from the column. Yield: 216 mg (36%) of white solid; mp 162–1678C.
Chirality DOI 10.1002/chir

SYNTHESIS OF NOVEL CAMPHOR-DERIVED THIOUREAS
311
Scheme 1. Preparation of 3-thiourea functionalized camphor derivatives 6, 7/70.
[a]D 5 130.7 (c 5 0.11, CH2Cl2). 1H-NMR (500 MHz, DMSO-d6): d
H, 6.58; N, 5.38.); EI-HRMS: m/z 5 521.2438 (MH1); C26H35F6N2S
requires: m/z 5 521.2425 (MH1); mmax (KBr) 3416, 2927, 2852, 1618,
20
0.83 (s, Me); 0.84 (s, Me); 1.03–1.11 (m, 1H of CH2); 1.16 (s, Me); 1.25–
1.34 (m, 1H of CH2); 1.51 (d, J 5 3.4 Hz, HꢀꢀC(4)); 1.56–1.75 (m,
HꢀꢀC(3), 2H of CH2); 2.75 (dd, J 5 10.3; 13.5 Hz, Ha-C(30)); 2.92 (dd, J 5
5.2; 13.7 Hz, Hb-C(30)); 4.98 (t, J 5 7.0 Hz, HꢀꢀC(2)); 7.11–7.27 (m, 5H of
Ph); 7.73 (s, 1H of Arl); 8.22 (s, 2H of Arl); 8.25 (d, J 5 9.0 Hz, HꢀꢀN(20));
9.86 (s, NH). 13C-NMR (126 MHz, DMSO-d6): d 13.7, 20.0, 21.3, 27.7, 30.2,
40.3, 45.7, 47.5, 50.7, 53.1, 64.6, 115.7, 121.6, 123.3 (q, J 5 272.7 Hz),
125.6, 128.2, 128.6, 130.1 (q, J 5 32.8 Hz), 141.5, 142.0, 181.3. (Found C,
60.95; H, 5.69; N, 5.46. C26H28F6N2S requires: C, 60.69; H, 5.48; N, 5.44.);
EI-HRMS: m/z 5 515.1944 (MH1); C26H29F6N2S requires: m/z 5
515.1950 (MH1); mmax (KBr) 3410, 2958, 1617, 1538, 1472, 1384, 1351,
1528, 1472, 1384, 1349, 1278, 1182, 1138, 1108, 962, 888, 710, 682 cm21
.
1-(3,5-Bis(trifluoromethyl)phenyl)-3-((1S,2S,3S,4R)-3-(cyclohexyl-
methyl)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl)thiourea (20). Elutes
second from the column. Yield: 54 mg (5%) of white solid; mp 155–
1598C. [a]D 5 112.0 (c 5 0.05, CH2Cl2). 1H-NMR (500 MHz, DMSO-
20
d6): d 0.75 (s, Me); 0.76–0.88 (m, 2H of CH2); 0.90 (s, Me); 0.98 (s, Me);
1.05–1.21 (m, CH, 5H of CH2); 1.29–1.43 (m, 2H of CH2); 1.49–1.66 (m,
CH, 6H of CH2); 1.70 (d, J 5 12.5, 1H of CH2); 2.35–2.44 (m, HꢀꢀC(3));
4.76 (t, J 5 9.8 Hz, HꢀꢀC(2)); 7.73 (s, 1H of Arl); 7.95 (d, J 5 9.6 Hz,
HꢀꢀN(20)); 8.35 (s, 2H of Arl); 10.11 (s, NH). 13C-NMR (126 MHz,
DMSO-d6): d 14.2, 18.2, 19.5, 19.7, 25.8, 26.0, 26.2, 27.6, 32.1, 33.6, 34.1,
34.5, 35.0, 46.4, 47.4, 49.5, 58.9, 115.8 (br s), 121.3 (br s), 123.3 (q, J 5
272.8 Hz), 130.1 (q, J 5 32.8 Hz), 142.0, 181.3. (Found C, 60.16; H, 6.65;
N, 5.36. C26H34F6N2S requires: C, 59.98; H, 6.58; N, 5.38.); EI-HRMS: m/
z 5 521.2410 (MH1); C26H35F6N2S requires: m/z 5 521.2425 (MH1);
mmax (KBr) 3412, 2928, 2853, 1618, 1539, 1473, 1447, 1384, 1351, 1278,
1278, 1176, 1134, 966, 888, 700, 682 cm21
17 elutes third from the column. Yield: 73 mg (12%) of white solid
.
(for exp. details see above).
Reaction of a mixture of amines 11–13 and 110-130 with
1-isothiocyanato-3,5-bis(trifluoromethyl)benzene (5)
Prepared from a complex mixture of 11–13 and 110-130 (500 mg, ca.
2 mmol) and 5 (373 lL, 2 mmol) in Et2O (10 ml) following GP1. Fractions
containing the separated products were combined and volatile compo-
nents evaporated in vacuo to give 19, 20, 16, 17, and 15, respectively.
1181, 1137, 1108, 974, 959, 888 cm21
.
16 elutes third from the column. Yield: 210 mg (20%) of white solid
(for exp. details see above). 17 elutes fourth from the column. Yield: 59
mg (5%) of white solid (for exp. details see above). 15 elutes fifth from
the column. Yield: 51 mg (5%) of white solid (for exp. details see above).
1-(3,5-Bis(trifluoromethyl)phenyl)-3-((1S,2R,3S,4R)-3-(cyclohexyl-
methyl)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl)thiourea (19). Elutes
first from the column. Yield: 112 mg (10%) of white solid; mp 177–1808C.
Single crystal X-Ray structure analysis for compounds
10/100, 12-HCl, 16, and 19
[a]D 5 –25.4 (c 5 0.11, CH2Cl2). 1H-NMR (500 MHz, DMSO-d6): d
20
0.82 (s, Me); 0.84 (s, Me); 0.80–0.89 (m, 2H of CH2); 0.98 (s, Me); 1.07–
1.30 (m, CH, 5H of CH2); 1.32–1.39 (m, 1H of CH2); 1.41–1.76 (m, CH,
8H of CH2); 2.13 (br s, HꢀꢀC(3)); 4.10 (dd, J 5 6.4; 8.6 Hz, HꢀꢀC(2)); 7.72
(s, 1H of Arl); 7.72 (d, J 5 9.0 Hz, HꢀꢀN(20)); 8.31 (s, 2H of Arl); 10.12 (s,
NH). 13C-NMR (126 MHz, DMSO-d6): d 11.9, 19.5, 19.7, 20.6, 25.89,
25.95, 26.2, 32.7, 33.5, 35.4, 36.1, 38.5, 43.1, 47.2, 47.6, 50.1, 67.2, 115.7
(br s), 121.2 (br s), 123.3 (q, J 5 272.7 Hz), 130.1 (q, J 5 32.8 Hz), 142.1,
180.7. (Found C, 60.19; H, 6.28; N, 5.32. C26H34F6N2S requires: C, 59.98;
Single crystal X-ray diffraction data of compounds 10/100, 12-HCl,
16, and 19 were collected at room temperature on a Nonius Kappa
CCD diffractometer using the Nonius Collect Software.45 DENZO and
SCALEPACK46 were used for indexing and scaling of the data and the
structures were solved by direct methods using SIR97.47 Refinement
was done by means of Xtal3.448 for compound 10 and SHELXL-9749 for
12-HCl, 16, and 19. Hydrogen atoms positions for all four compounds
were placed at ideal positions. Their parameters were not refined. Fig-
Chirality DOI 10.1002/chir

ˇ
312
GROSELJ ET AL.
Scheme 2. Preparation of 2-amino camphor derivatives 11–14, 110–140.
ures 4–7 of molecules were prepared with the aid of ORTEP-350 pro-
gram.
gave the corresponding aminomethyl compound as a mix-
ture of the major endo- 444 and the minor exo-epimer 40 in
44
Crystallographic data for compounds 10/100, 12-HCl, 16 and 19
have been deposited with the Cambridge Crystallographic Data Centre
as supplementary publication number 835835–835838. These data can be
obtained free of charge via http://www.ccdc.cam.ac.uk/conts/retrie-
ving.html, or from the Cambridge Crystallographic Data Centre, 12
Union Road, Cambridge CB2 1EZ, UK; fax: (144) 1223-336-033; or e-
mail: deposit@ccdc.cam.ac.uk.
about 2:1 ratio and in 87% yield, respectively. Formation of
the major endo-isomer 4 could be explained by the initial
isomerization of enamine 3 in the presence of acid into the
thermodynamically more stable endo-iminium salt 400, which
upon reduction yields the corresponding major endo-product
4. Chromatographic separation of 4/40 failed. Finally, reac-
tion of 3 and 4/40 with 1-isothiocyanato-3,5-bis(trifluorome-
thyl)benzene (5) in anhydrous Et2O gave (Z)-3-methylene-
thiourea 6 and an inseparable 3-methylthiourea mixture 7/
70 (endo-7/exo-70 5 70:30) in 28 and 65% yield, respectively.
Low yield of 6 could be explained by diminished nucleophi-
licity of the vinylogous amide 3 compared to the amine 4/40.
Base-assisted reactions of 3 with 5 gave complex mixtures
of products (Scheme 1).
RESULTS AND DISCUSSION
Syntheses
First, 3-methylene- 6 and 3-methyl-thiourea camphor deriv-
atives 7/70 were prepared. Starting from (1)-camphor (1),
our second common precursor, 3-((dimethylamino)-
methylene)-camphor (2) was prepared following a modified
literature procedure42 using enaminone methodology.51
Accordingly, reaction of 1 with tert-butoxy bis(dimethylami-
no)methane under reflux in anhydrous DMF for 24 h gave 2
in 100% conversion and in 77% isolated yield. Treatment of 2
with excess NH4OAc gave aminomethylene compound 343
in 69% yield. In CDCl3 solution compound 3 exists as (E)-iso-
mer, which upon prolonged standing isomerizes52 into a mix-
ture of (E)- and (Z)-isomers (ca. 20% of (Z)-isomer is formed
after 5 days in CDCl3 solution). Next, catalytic hydrogenation
of 3 in the presence of 10% Pd–C and a slight excess of HCl
Next, the 2-thiourea camphor derivatives 15–20 were pre-
pared in five steps from enaminone 2. Treatment of the
crude 2 with PhMgBr following the literature procedure
gave (E)-3-benzylidene-camphor (8).41 Catalytic hydrogena-
tion of 8 in the presence of 10% Pd–C gave a 2:1 mixture of
the major exo-3-benzyl-camphor 953,54 and its minor endo-iso-
53,54
mer 90
in quantitative yields. Major exo-epimer 9 is the
kinetic product of the reaction due to the approach of the rea-
gent from the sterically less hindered endo-face of the double
bond in an irreversible transformation—epimerization of 9/
TABLE 1. Reduction of oxime 10 (d.e. 5 32%) under different reaction conditions
Reduction conditions Ratio of products and conversion Separated amines and yield
Entry
1
2
3
4
10% Pd–C, H2 (50–55 Bar), 408C, 7 days
10% Pd–C, H2 (50–55 Bar), 608C, 4 days
10% Pd–C, H2 (50–55 Bar), 908C, 2 days
Na, nPrOH, reflux, 1 h
11/12/13 ꢁ 1:1:0.3; 60%
11/12/13 ꢁ 0.6:1:0.3; 90%
No separation attempted
11b (25%); 12c (35%); 13 (10%)
Separation unsuccessful
No separation attempted
a
11–13, 110-130 ; 100%
12/13/14 ꢁ 0.45:0.45:1; 100%
aUnable to determine the product ratio.
bFor NMR characterization transformed into 11-HCl salt.
cObtained in analytically pure form as 12-HCl salt (yield 21%).
Chirality DOI 10.1002/chir

SYNTHESIS OF NOVEL CAMPHOR-DERIVED THIOUREAS
313
Scheme 3. Preparation of 2-thiourea functionalized camphor derivatives 15–20.
90 under basic conditions leads to the thermodynamically
tion mixture was used in the next step. Finally, catalytic hy-
drogenation at 608C for 4 days gave amines 11, 12, and 13
in a ratio of 2:3.3:1, respectively, in about 90% conversion.
Amines 11–13 were partially separated using CC to obtain
the corresponding crude amines. Only amine 12 could be
prepared in analytically pure form as the corresponding
hydrochloride (12-HCl salt). Reduction of epimers 10/100
with Na in nPrOH gave a mixture of amines 12, 13, and 14
in a ratio of about 0.45:0.45:1, respectively, in full conversion.
No separations attempts were undertaken—the crude mix-
ture was used in the following transformation (Scheme 2, Ta-
ble 1).
Finally, reaction of crude amines 11 and 13, and free
amine 12 (obtained from 12-HCl salt) with 1-isothiocyanato-
3,5-bis(trifluoromethyl)benzene (5) in anhydrous Et2O gave
the corresponding 2-thiourea derivatives 15, 17, and 16 in
37, 28, and 69% yield, respectively. Reaction of a mixture of
41,53,54
favored endo-product 90
Next, treatment of epimers 9/
90 under conditions used by Page55 (NH2OHꢂHCl, pyridine)
gave the corresponding oximes 10/100 with retention of epi-
mer composition in 54% yield. Reduction of epimers 10/100
with complex hydrides (LiAlH4, NaBH4, NaCNBH3) as well
as catalytic hydrogenation in the presence of 10% Pd–C
under mild condition (4 Bar, room temperature) failed to
give the corresponding amines. On the other hand, catalytic
hydrogenation in EtOH under 50–55 Bar of H2 in an auto-
clave at 408C for 7 days gave three out of four amines, com-
pounds 11, 12, and 13, in a ratio of 1:1:0.3, respectively, in
about 60% conversion. Hydrogenation under harsher condi-
tions (908C for 2 days) gave a complex mixture of 3-benzyl
amines 11–13 and the corresponding fully saturated 3-cyclo-
hexylmethyl amines 110–130. All attempts to separate this
mixture into its constituents failed—therefore the crude reac-
TABLE 2. Reaction of amine/amine mixture with 5—formation of 2-thiourea camphor derivativesa
Entry
Amine or amine mixture
Isolated thiourea product(s) and yield
15 (37%)
16 (69%)
17 (28%)
16 (17%), 17 (12%), 18 (36%)
15 (5%), 16 (20%), 17 (5%), 19 (10%), 20 (5%)
Absolute configuration
1
2
3
4
5
11b
12c
(1S,2R,3R,4R)
(1S,2R,3S,4R)
(1S,2S,3S,4R)
13b
12, 13, 14
18-(1S,2R,3R,4R)
19-(1S,2R,3S,4R); 20-(1S,2S,3S,4R)
11–13, 110-130
aFractions containing mixtures of products after chromatographic separation were discarded.
bCrude amine after chromatographic separation used.
cAnalytically pure amine used.
Chirality DOI 10.1002/chir

ˇ
GROSELJ ET AL.
314
Fig. 3. Key NOEs observed in NOESY spectra of compounds 3, 4/40, 6, 7/70, 9/90, 10/100, 11-HCl, 12, 13, and 15–20 for the determination of configura-
tion. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
amines 12, 13, and 14 with 5 gave, after chromatographic
separation, 2-thiourea derivatives 16, 17, and 18 in 17, 12,
and 36% yield, respectively. Treatment of the complex mix-
ture of amines 11–13, 110–130 (after the hydrogenation of
10/100 at 908C) with 5 furnished, after chromatographic
separation, 3-benzyl-thiourea derivatives 15, 16, and 17 in
5, 20, and 5% yield, respectively, and 3-cyclohexylmethyl-thio-
urea derivatives 19 and 20 in 10 and 5%, respectively. Thus,
all four possible 3-benzyl-thiourea stereoisomers 15–18
have been obtained in analytically pure form (Scheme 3,
Table 2).
Fig. 5. Ortep drawing of the compound 12-HCl. The asymmetric unit con-
tains four chloride anions and four protonated molecules of 12 with the
same structural formula and absolute configuration. [Color figure can be
viewed in the online issue, which is available at wileyonlinelibrary.com.]
Fig. 4. Ortep drawing of the asymmetric unit consisting of two C-3 epi-
mers, compound 10 (top) and 100 (bottom), respectively. [Color figure can
be viewed in the online issue, which is available at wileyonlinelibrary.com.]
Chirality DOI 10.1002/chir

SYNTHESIS OF NOVEL CAMPHOR-DERIVED THIOUREAS
315
Structure Determination
The structures of compounds 343 and 9/90
53,54
and novel
compounds 6, 7/70, 11–13 and 15–20 were determined
by spectroscopic methods (IR, NMR spectroscopy (1H- and
13C-NMR, DEPT 90 and 135, COSY, HSQC, HMBC, and
NOESY experiments), and MS) and by elemental analyses
for C, H, and N. Compounds 9/90, 11, 13, 19, and 20 were
not obtained in analytically pure form. Their identities were
confirmed by 13C-NMR and/or EI-HRMS. The structure of
amine 14 was established on the basis of the structure of its
thiourea derivative 18. Physical and spectral data for known
compounds 2,42 3,43 8,41 were in agreement with the litera-
ture data.
The (Z)-configuration around the C¼¼C bond in the enami-
none 3-(Z) and methylene-thiourea 6 was determined on the
basis of NOE between HꢀꢀC(30) and HꢀꢀC(4) in the NOESY
spectra. Accordingly, the (E)-configuration around the C¼¼C
bond in the enaminone 3-(E) was determined on the basis of
the NOE between NH2 and HꢀꢀC(4). Similarly, the configu-
ration(s) in 2- and/or 3-position(s) of compounds 4/40, 7/70,
9/90, 10/100, 11-HCl, 12, 13, and 15–20 was/were deter-
mined on the basis of NOEs observed in NOESY spectra
between the corresponding key proton signals (Fig. 3).
The structures of compounds 10/100, 12-HCl, 16, and
19 have been confirmed by single crystal X-ray analysis
(Figs. 4–7). The configuration of C5N double bond in the
Fig. 7. Ortep drawing of the compound 19. The asymmetric unit contains
three molecules with the same structural formula and absolute configuration.
[Color figure can be viewed in the online issue, which is available at wiley
onlinelibrary.com.]
solid state in both exo- 10 and endo-oxime 100 is (E). In the
(E)-configuration in the solid state, the OH group is accom-
modated between the two substituents in the 3 position,
whereas in the (Z)-configuration, the OH group would be
near planar with the Me group in position 10 (torsion angle
N¼¼C(2)-C(1)-C(10) is ca. 168 in endo-isomer 100 and ca. 25
in exo-isomer 10), which would cause massive 1,5-repul-
sion56 (Fig. 4).
CONCLUSIONS
In this preliminary report, new 3-thiourea 6, 7/70 and six
new 2-thiourea functionalized camphor derivatives 15–20
have been prepared starting from commercially available
(1)-camphor (1) in three or four and six straightforward
steps, respectively, using manipulations at positions 2 and/or
3 of camphor. In a stereo-divergent synthesis all four possi-
ble stereoisomers of 3-benzyl-2-thiourea camphor derivatives,
compounds 15–18, have been prepared along with the two
corresponding 3-cyclohexylmethyl derivatives 19 and 20.
Structure/configuration of all novel compounds has been
carefully characterized using NMR techniques, especially
NOESY spectroscopy, and single crystal X-ray crystallogra-
phy. 3-Thiourea derivatives 6, 7/70 are set for further func-
tionalizations. Preparation and testing of these and other
potential novel (bi)functional camphor-derived thiourea orga-
nocatalysts is an ongoing project results of which will be
reported in due time.
Fig. 6. Ortep drawing of the compound 16. The asymmetric unit contains
two molecules with the same structural formula and absolute configuration.
[Color figure can be viewed in the online issue, which is available at wiley
onlinelibrary.com.]
Chirality DOI 10.1002/chir

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316
GROSELJ ET AL.
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