Synthesis of 2-(3-(3,5-bis(trifluoromethyl)phenyl)thioureido)-3- ((dimethylamino)methyl)camphor organocatalysts

Article abstract of DOI:10.1002/chir.22035

In a stereo-divergent synthesis, three novel camphor-derived bifunctional thiourea organocatalysts 7-9 have been prepared in five steps starting from (+)-camphor. In addition, borneol-derived bifunctional thiourea organocatalysts 19/19' have been prepared

Full text of DOI:10.1002/chir.22035

CHIRALITY 24:412–419 (2012)
Synthesis of 2-(3-(3,5-Bis(trifluoromethyl)phenyl)thioureido)-
3-((dimethylamino)methyl)camphor Organocatalysts
1
1
1,2
UROŠ GROŠELJ, SEBASTJAN RIČKO, JURIJ SVETE, AND BRANKO STANOVNIK1,2
*
1Organic chemistry, University of Ljubljana, Faculty of Chemistry and Chemical Technology, Ljubljana, Slovenia
2EN-FIST Centre of Excellence, Ljubljana, Slovenia
ABSTRACT
In a stereo-divergent synthesis, three novel camphor-derived bifunctional thiourea
organocatalysts 7–9 have been prepared in five steps starting from (+)-camphor. In addition,
borneol-derived bifunctional thiourea organocatalysts 19/19’ have been prepared in three steps
from (1S)-(+)-camphorquinone. Novel organocatalysts 7–9, 19/19’ have been evaluated in a
model reaction of Michael addition of dimethyl malonate to trans-b-nitrostyrene with low to
moderate enantioselectivities (20%–60% ee). Configuration of all novel compounds has been
meticulously determined using nuclear magnetic resonance (NMR) techniques. Chirality
24:412–419, 2012. © 2012 Wiley Periodicals, Inc.
KEY WORDS: enaminone methodology; enaminone reduction; oxime reduction; camphor-
derived amines; 2,3-functionalized camphor derivatives
6224 Accurate Mass TOF LC/MS (Agilent Technologies, Santa Clara, CA,
INTRODUCTION
USA) and infrared (IR) spectra on a Perkin-Elmer Spectrum BX FTIR spec-
trophotometer (Waltham, MA, USA). Microanalyses were performed on a
Perkin-Elmer CHN Analyzer 2400 II (PerkinElmer, Waltham, MA, USA).
Catalytic hydrogenation was performed on a Parr Pressure Reaction Hydro-
genation Apparatus (Moline, IL, USA). Column chromatography was per-
formed on silica gel (Silica gel 60 (Sigma-Aldrich, St. Louis, MO, USA),
particle size: 0.035–0.070mm). Medium-pressure liquid chromatography
(MPLC) was performed with Büchi Flash Chromatography System
(BUCHI Labortechnik AG, Flawil, Switzerland) (Büchi Fraction Collector
C-660, Büchi Pump Module C-605, Büchi Control Unit C-620) on silica
gel (LiChrosphereW Si 60 (12 mm) and/or LiChroprepW Si 60 (15–25 mm)
(Merck, KGaA, Darmstadt, Germany)); column dimensions (wet filled):
22Â 460 mm, 36Â 460 mm, and 40Â 460 mm; backpressure: 10–20Bar; de-
tection: UV 254 nm. High-performance liquid chromatography (HPLC) anal-
yses were performed on an Agilent 1260 Infinity LC (Agilent Technologies,
Santa Clara, CA, USA) by using CHIRALPAK AD-H (0.46cm øÂ 25 cm) as
chiral column. Low temperatures were maintained using Julabo FT902
immersion cooler (JULABO Labortechnik GmbH, Seelbach, Germany).
(+)-Camphor (1), tert-butoxy bis(dimethylamino)methane, anhydrous
DMF, 1-isothiocyanato-3,5-bis(trifluoromethyl)benzene (6), p-toluidine
hydrochloride (10), (1S)-(+)-camphorquinone (16), dimethyl malo-
nate (20),trans-b-nitrostyrene (21), and 10% palladium on charcoal are
commercially available (Sigma-Aldrich, St. Louis, MO, USA). (1S,4S,3E)-3-
((Dimethylamino)methylene)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-one
(2),37 (1S,4R,3E)-3-(hydroxyimino)-1,7,7-trimethylbicyclo-[2.2.1]heptan-2-one
(17),38 and (1S,2R,3R,4R)-3-amino-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ol
(18)39 were prepared following the literature procedure.
Camphor is one of nature’s privileged scaffolds, which is
readily available in both enantiomeric forms. It undergoes a
wide variety of chemical transformations that functionalize, at
first glance, inactivated positions.1,2 All of the aforementioned
makes camphor a very desirable starting material for the
preparation of a wide variety of compounds ranging from
natural products1,2 to chiral auxiliaries,3,4 ligands in asymmetric
synthesis,5–9 NMR shift reagents,10 and so on.
Bifunctional (thio)urea derivatives comprise the bulk of
noncovalent organocatalysts, which can achieve electrophile
and nucleophile binding and activation through hydrogen-
bonding interactions. The preferred substituent is the electron-
poor 3,5-bis(trifluoromethyl)phenyl-group attached through
thiourea functionality to a suitable chiral scaffold.11–26 Concerning
the camphor-derived noncovalent organocatalysts, the vast ma-
jority represent the pyrrolidinyl–camphor-derived bifunctional
organocatalysts, where both camphor and pyrrolidine chiral
frameworks, connected with an appropriate linker, act in
synergy (Fig. 1).27–36
To the best of our knowledge, we could not find any 3,5-
bis(trifluoromethyl)phenyl thiourea-derived bifunctional orga-
nocatalysts with camphor as the exclusive chiral framework.
Considering camphor’s vast potential for chemical manipula-
tion and our previous experiences with monofunctional
camphor-derived thioureas prompted us to investigate the
possibility to prepare novel bifunctional thiourea camphor
derivatives, preferably in a stereo-divergent synthesis. Thus,
herein, we report our results on the synthesis, structural
characterization, and catalyst evaluation of novel camphor-
thiourea-derived bifunctional organocatalysts.
The source of chirality is as follows: (+)-camphor (1) (Sigma-Aldrich),
product number 21300, purum, natural, 97.0% (GC, sum of enantiomers),
[a]2D0 = +42.5 Æ 2.5 (c= 10, EtOH), mp 176–180 ꢀC, ee not specified and
Additional Supporting Information may be found in the online version of this
article.
Contract grant sponsor: Slovenian Research Agency (financial support); Con-
tract grant number: P1-0179 and J1-0972.
EXPERIMENTAL
Materials and Methods
Contract grant sponsor: Ministry of Science and Technology, Republic of
Slovenia (financial contribution for the purchase of Kappa CCD Nonius
diffractometer); Contract grant number: Packet X-2000 and PS-511-102.
Correspondence to: U. Grošelj, Organic chemistry, University of Ljubljana,
Faculty of Chemistry and Chemical Technology, Aškerčeva cesta 5, P.O.
Box 537, 1000 Ljubljana, Slovenia. E-mail: uros.groselj@fkkt.uni-lj.si
Received for publication 28 December 2011; Accepted 13 February 2012
DOI: 10.1002/chir.22035
Melting points were determined on a Kofler micro hot stage and on SRS
OptiMelt MPA100—Automated Melting Point System (Stanford Research
Systems, Sunnyvale, CA, USA). The NMR spectra were obtained on a
Bruker UltraShield 500 plus (Bruker, Billerica, MA, USA) 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 Agilent
Published online 19 April 2012 in Wiley Online Library
(wileyonlinelibrary.com).
© 2012 Wiley Periodicals, Inc.

SYNTHESIS OF CAMPHOR ORGANOCATALYSTS
413
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 EtOAc
(3Â 70ml). Combined organic phase was dried over anhydrous Na2SO4,
filtered, and volatile components evaporated in vacuo to give the crude
amine 5, as a mixture of stereoisomers in a ratio of 54:29:17 and in 100%
conversion. The amine mixture was used in the following transforma-
tion without further purification/separation. Yield: 1 g (89%) of yellowish
brown oil. EI-HRMS: m/z = 211.2170 (MH+); C13H27F6N2 requires:
m/z = 211.2169 (MH+).
Preparation of 2-(3-(3,5-Bis(trifluoromethyl)phenyl)
thioureido)-3-((dimethylamino)methyl)-camphor
Stereoisomers 7, 8, and 9
To a solution of crude mixture of amines 5 (632 mg, 3 mmol) in
anhydrous Et2O (20 ml) at 0ꢀC, 1-isothiocyanato-3,5-bis(trifluoromethyl)
benzene (6) (418ml, 2.2 mmol) was added, and the resulting mixture was
stirred for 30min at 0ꢀC and further 24h at room temperature. The reaction
mixture was passed through a plug of Silica gel 60 (length of 5 cm) and
washed with EtOAc/Et3N/MeOH = 100:2:1 to elute all the products. Volatile
components were evaporated in vacuo, and the residue was separated by
MPLC (EtOAc/Et3N/MeOH = 100:2:1). Fractions containing the separated
products were combined and volatile components evaporated in vacuo to give
7, 8, and 9, respectively. Fractions containing mixtures of products or not
fully separated products were discarded.
Fig. 1. General outline and an example of a bifunctional thiourea organocatalyst
and selected examples of camphor-derived bifunctional organocatalysts.
(1S)-(+)-camphorquinone (16) (Sigma-Aldrich), product number 272078,
20
99%, [a]D = +100 (c= 1.9, PhMe); mp 197–201 ꢀC, ee not specified.
Syntheses
N,N-Dimethyl-1-((1R,2R,4S)-4,7,7-trimethyl-3-oxobicyclo[2.2.1]
heptan-2-yl)methanaminium chloride (3)40 and N,N-dimethyl-1-
((1R,2S,4S)-4,7,7-trimethyl-3-oxobicyclo[2.2.1]heptan-2-yl)metha-
1-(3,5-Bis(trifluoromethyl)phenyl)-3-((1S,2R,3R,4R)-3-((dimethy-
lamino)methyl)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl) thiourea
naminium chloride (3’)40
.
To a solution of (1S,4S,3E)-3-((dimethyla-
mino)methylene)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-one (2)37 (1.5 g,
7.24 mmol) in anhydrous EtOH (40 ml) under Argon, Pd–C (10%, 450 mg)
and HCl (5ml, 2 M in EtOAc, 10mmol) were added. The reaction vessel
was flushed with H2, and the reaction mixture was hydrogenated in a Paar
hydrogenator (P= 4 Bar) at room temperature for 3 h. The reaction mixture
was filtered through a plug of CeliteW and washed with EtOH (100ml).
Volatile components were evaporated in vacuo to give a crude mixture of
ammonium salts 3/3’ (100% conversion), which was used in the
following transformation without further purification/separation. Yield:
100% conversion (3/3’ = 78:22) of dirty white solid. Electron ionization
high-resolution mass spectrometry (EI-HRMS): m/z = 210.1851 (M+);
C13H24NO+ requires: m/z = 210.1852 (M+). 1H-NMR (500 MHz, DMSO-d6)
for 3: d 0.83 (s, Me); 0.86 (s, Me); 0.98 (s, Me); 1.12–1.18 (m, 1H of CH2);
1.51–1.58 (m, 1H of CH2); 1.63–1.81 (m, 2H of CH2); 2.33 (t, J= 4.1Hz, H-C
(4)); 2.77 (s, NMe2H+); 2.93–2.98 (m, H-C(3)); 3.22 (d, J= 7.6Hz, H2-C(3’));
10.31 (s, NMe2H+). 1H-NMR (500 MHz, DMSO-d6) for 3’: d 0.68 (s, Me);
0.82 (s, Me); 0.91 (s, Me); 1.43–1.49 (m, 1H of CH2); 1.92–1.98 (m, 1H
of CH2); 2.24 (d, J= 4.0Hz, H-C(4)); 2.41 (dd, J = 3.5; 6.3 Hz, H-C(3)); 2.76
(s, NMe2H+);10.51 (s, NMe2H+).
(7).
7 elutes first from the column. Yield: 439 mg (41%) of white
solid; mp 50–58 ꢀC. [a]Dr.t. = –121.4 (c = 0.12, CH2Cl2) (C22H29F6N3S
requires: C, 54.87; H, 6.07; N, 8.73 and found: C, 55.22; H, 6.24; N,
8.65); EI-HRMS: m/z = 480.1917 (M-H-); C22H28F6N3S requires:
m/z = 480.1914 (M-H-); nmax (KBr) 3438, 2956, 1636, 1496, 1472,
1382, 1278, 1204, 1174, 1134, 1107, 1002, 884, 701, 681 cmÀ1 1H-NMR
.
(500 MHz, DMSO-d6): d 0.84 (s, 2ÂMe); 0.99 (s, Me); 1.16–1.22 (m, 1H
of CH2); 1.42–1.59 (m, 3H of CH2); 1.70 (br s, H-C(4)); 2.11
(s, NMe2); 2.18–2.26 (m, H-C(3), Ha-C(3’)); 2.43 (t, J= 12.5 Hz, Hb-C
(3’)); 4.11 (dd, J = 6.0; 7.8Hz, H-C(2)); 7.71 (s, 1H of Arl); 7.78
(d, J= 8.7Hz, H-N(2’)); 8.32 (s, 2H of Arl); 10.16 (br s, NH). 13C-NMR
(126 MHz, DMSO-d6): d 11.9, 19.6, 19.7, 20.6, 36.0, 44.7, 45.4, 46.6,
47.4, 50.1, 60.2, 65.4, 115.7 (br s), 121.1 (br s), 123.3 (q, J= 272.7 Hz),
130.1, (q, J= 32.8 Hz), 142.0, 180.7.
1-(3,5-Bis(trifluoromethyl)phenyl)-3-((1S,2S,3S,4R)-3-((dimethy-
lamino)methyl)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl) thiourea
(8).
8 elutes second from the column. Yield: 64mg (6%) of white solid;
mp 50–57 ꢀC. [a]Dr.t. = +108.7 (c= 0.12, CH2Cl2) (C22H29F6N3S requires: C,
54.87; H, 6.07; N, 8.73 and found: C, 55.83; H, 6.11; N, 8.69); EI-HRMS:
m/z = 480.1914 (M-H-); C22H28F6N3S requires: m/z = 480.1914 (M-H-); nmax
(KBr) 3416, 2958, 1635, 1541, 1502, 1473, 1383, 1278, 1178, 1133, 1107,
(1S,3R,4R,2E)-3-((Dimethylamino)methyl)-1,7,7-trimethylbicy-
clo[2.2.1]heptan-2-one oxime (4)41 and (1S,3S,4R,2E)-3-
((dimethylamino)methyl)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-one
1025, 1002, 883, 700, 682 cmÀ1 1H-NMR (500 MHz, DMSO-d6): d 0.80
.
oxime (4’)4 1
.
To a solution of 3/3’ (3:3’ = 78:22, 7.2mmol) in EtOH
(s, Me); 0.84 (s, Me); 0.97 (s, Me); 1.16–1.25 (m, 1H of CH2); 1.26–1.35
(m, 1H of CH2); 1.37–1.43 (m, H-C(4)); 1.60–1.68 (m, H-C(3), 1H of
CH2); 1.73–1.81 (m, 1H of CH2); 2.09 (s, NMe2); 2.31 (dd, J = 3.3; 11.9 Hz,
Ha-C(4’)); 2.46 (dd, J = 9.4; 12.3 Hz, Hb-C(4’)); 4.81 (t, J = 6.9 Hz, H-C(2));
7.72 (s, 1H of Arl); 8.27 (s, 2H of Arl); 8.29 (d, J = 9.5 Hz, H-N(2’)); 9.92
(s, NH). 13C-NMR (126 MHz, DMSO-d6): d 13.7, 19.7, 21.1, 27.7, 29.9,
45.3, 47.4, 48.4, 49.6, 50.4, 63.9, 64.6, 115.7 (br s), 121.3 (br s), 123.3
(q, J = 272.8 Hz), 130.2, (q, J = 33.0 Hz), 142.0, 181.1.
(70ml), pyridine (6.3ml, 78.8 mmol) and NH2OHÁHCl (6.95g, 100mmol)
were added, and the resulting mixture was refluxed for 24 h. Volatile compo-
nents were thoroughly evaporated in vacuo, and to the residue, NaHCO3
(aq. sat. 100 ml) was added followed by extraction with CH2Cl2
(3 Â 100 ml). The combined organic phase was dried over anhydrous
Na2SO4, filtered, and volatile components evaporated in vacuo. The residue
was dried on high vacuum to give a crude mixture of oximes 4/4’, which
was used in the following transformation without further purification/
separation. Yield: 1.4 g (86%, 4:4’= 84:16) of dirty white solid. EI-HRMS:
m/z = 225.1949 (MH+); C13H25N2O requires: m/z = 225.1961 (MH+); 1H-NMR
(500 MHz, CDCl3) for 4: d 0.85 (s, Me); 0.93 (s, Me); 1.02 (s, Me); 1.34
(t, J=9.4Hz, 1H of CH2); 1.42–1.47 (m, 1H of CH2); 1.63–1.75 (m, 2H of
CH2); 1.86 (t, J= 4.0 Hz, 1H-C(4)); 2.26 (dd, J= 2.4; 12.5 Hz, Ha-C(3’)); 2.37
(s, NMe2); 2.55 (dd, J= 11.3; 12.4 Hz, Hb-C(3’)); 2.82–2.87 (m, H-C(3)); 12.54
1-(3,5-Bis(trifluoromethyl)phenyl)-3-((1S,2S,3R,4R)-3-((dimethy-
lamino)methyl)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl) thiourea
(9).
9 elutes third from the column. Yield: 341 mg (32%) of white solid;
mp 48–56 ꢀC. [a]Dr.t. = +141.7 (c= 0.16, CH2Cl2) (C22H29F6N3S requires: C,
54.87; H, 6.07; N, 8.73 and found: C, 54.88; H, 6.37; N, 8.60); EI-HRMS:
m/z = 480.1913 (M-H-); C22H28F6N3S requires: m/z = 480.1914 (M-H-); nmax
(KBr) 3422, 2961, 1625, 1541, 1474, 1385, 1278, 1225, 1177, 1133, 1108,
1
(br s, OH). H-NMR (500 MHz, CDCl3) for 4’: d 0.89 (s, Me); 0.89 (s, Me);
1.04 (s, Me); 2.35 (s, NMe2). 13C-NMR (126 MHz, CDCl3) for 4: d 12.3, 18.8,
1
1001, 883, 700, 682 cmÀ1. H-NMR (500 MHz, DMSO-d6): d 0.76 (s, Me);
19.1, 21.0, 32.3, 40.7, 45.3, 47.2, 48.3, 53.2, 59.9, 167.3.
0.90 (s, Me); 0.99 (s, Me); 1.30–1.58 (m, 4H of CH2); 1.68 (br s, H-C(4));
1.95 (dd, J = 5.5; 12.0 Hz, Ha-C(3’)); 2.09 (s, NMe2); 2.32 (t, J = 11.7 Hz,
Hb-C(3’)); 2.43–2.50 (m, H-C(3)); 4.76 (t, J = 9.9 Hz, H-C(2)); 7.72 (s, 1H
of Arl); 7.94 (d, J = 9.2 Hz, H-N(2’)); 8.39 (s, 2H of Arl); 10.13 (br s, NH).
13C-NMR (126 MHz, DMSO-d6): d 14.1, 18.2, 19.7, 19.9, 27.6, 35.2, 45.3,
46.2, 47.0, 49.5, 56.0, 58.4, 115.7 (br s), 121.0 (br s), 123.3 (q, J= 272.7 Hz),
130.1, (q, J = 32.7 Hz), 142.0, 181.3.
(1S,4R)-3-((Dimethylamino)methyl)-1,7,7-trimethylbicyclo[2.2.1]
heptan-2-amine (5)41
.
To a solution of oxime 4/4’ (4:4’ = 84:16, 1.2 g,
5.35 mmol) in anhydrous nPrOH (25ml) under Argon under reflux, sodium
(ca. 200 mg) was added. Before all the added sodium reacted, another
chunk of sodium (ca. 200 mg) was added, followed by addition of further
Chirality DOI 10.1002/chir

414
GROŠELJ ET AL.
1389, 1366, 1349, 1293, 1242, 1211, 1182, 1129, 1112, 1090, 1056, 982, 909,
872, 824, 816 cmÀ1 1H-NMR (500 MHz, CDCl3): d 0.82 (s, Me); 0.94
(1S,4S,3Z)-1,7,7-Trimethyl-3-((p-tolylamino)methylene)bicyclo
[2.2.1]heptan-2-one (11) and (1S,4S,3E)-1,7,7-trimethyl-3-
((p-tolylamino)methylene)bicyclo[2.2.1]heptan-2-one (11’). To
.
(s, Me); 1.00 – 1.08 (m, 2H of CH2); 1.19 (s, Me); 1.45 – 1.51 (m, 1H of
CH2); 1.60 (d, J= 3.8Hz, H-C(4)); 1.70–1.78 (m, 1H of CH2); 1.94–2.01
(m, H-C(3)); 2.24 (s, Me); 3.03 (br s, NH, OH); 3.18 (dd, J = 5.3; 12.0 Hz,
Ha-C(3’)); 3.55 (t, J = 11.5Hz, Hb-C(3’)); 3.81 (d, J = 7.9 Hz, H-C(2)); 6.60
(d, J = 8.0 Hz, 2H of Arl); 6.99 (d, J = 8.0Hz, 2H of Arl). 13C-NMR (126 MHz,
CDCl3): d 11.7, 20.6, 21.8, 22.3, 30.0, 33.6, 45.8, 47.0, 49.2, 49.8, 50.1, 81.2,
114.3, 127.5, 129.9, 146.2.
a solution of (1S,4S,3E)-3-((dimethylamino)methylene)-1,7,7-trimethylbi-
cyclo[2.2.1]heptan-2-one (2) (196 mg, 0.947mmol) in anhydrous EtOH
(2 ml), p-toluidine hydrochloride (10) (136 mg, 0.947mmol) was added,
and the mixture was stirred at room temperature for 24h. The resulting pre-
cipitate was collected by filtration and washed with cold EtOH (1ml, 0ꢀC) to
give the product as a mixture of major (Z)-isomer 11 and minor (E)-isomer
11’. Yield: 140 mg (54%, 11/11’ = 92:8) of dirty white solid; mp 171–181 ꢀC.
[a]Dr.t. = +363.7 (c= 0.08, CH2Cl2) (C18H23NO requires: C, 80.26; H, 8.61; N,
5.20 and found: C, 80.22; H, 8.85; N, 5.20); EI-HRMS: m/z = 268.1708
(M-H-); C18H22NO requires: m/z = 268.1707 (M-H-); nmax (KBr) 3423, 3304,
2956, 2867, 1696, 1603, 1583, 1525, 1500, 1473, 1451, 1385, 1368, 1301,
1-(3,5-Bis(trifluoromethyl)phenyl)-3-((1R,2S,3R,4S)-3-hydroxy-
4,7,7-trimethylbicyclo[2.2.1]-heptan-2-yl)thiourea (19) and 1-(3,5-
bis(trifluoromethyl)phenyl)-3-((1R,2R,3S,4S)-3-hydroxy-4,7,7-tri-
methylbicyclo [2.2.1]heptan-2-yl)thiourea (19’).
To a solution of
1251, 1218, 1201, 1170, 1106, 1076, 1014, 947, 896, 827, 812, 793 cmÀ1
.
crude (1S,2R,3R,4R)-3-amino-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ol38,39 (18)
(88 mg, 0.52mmol) in anhydrous Et2O (10 ml) at 0ꢀC, 1-isothiocyanato-
3,5-bis(trifluoromethyl)benzene (6) (97 ml, 0.52 mmol) was added, and
the resulting mixture was stirred for 30min at 0ꢀC and further 24h at room
temperature. Volatile components were evaporated in vacuo, and the resi-
due was purified by column chromatography (Silica gel 60; (1) EtOAc/
petroleum ether = 1:9 to elute the nonpolar impurities and (2) EtOAc/
petroleum ether= 1:5 to elute the product). Fractions containing the product
were combined and volatile components evaporated in vacuo to give 19/
19’. Yield: 115 mg (50%; 19/19’ = 89:11) of white solid; mp 173–176 ꢀC.
[a]rD.t. = –74.3 (c= 0.07, CH2Cl2) (C19H22F6N2OS requires: C, 51.81; H, 5.03;
N, 6.36 and found: C, 52.02; H, 5.10; N, 6.39); EI-HRMS: m/z = 441.1425
(MH+); C19H23F6N2OS requires: m/z = 441.1430 (MH+); nmax (KBr) 3440,
2962, 1624, 1560, 1508, 1471, 1383, 1345, 1291, 1278, 1178, 1127, 1094,
1H-NMR (500MHz, CDCl3) for 11: d 0.85 (s, Me); 0.91 (s, Me); 0.97
(s, Me); 1.35–1.43 (m, 2H of CH2); 1.66 (t, J = 10.1Hz, 1H of CH2);
2.00–2.09 (m, 1H of CH2); 2.28 (s, Me); 2.44 (d, J = 3.6 Hz, H-C(4)); 6.83
(d, J = 8.4 Hz, 2H of Arl); 6.94 (d, J = 12.1 Hz, H-C(3’)); 7.07 (d, J = 8.2 Hz, 2H
of Arl); 9.71 (d, J = 11.9 Hz, NH). 1H-NMR (500 MHz, CDCl3) for 11’: d
0.86 (s, Me); 0.95 (s, Me); 2.62 (d, J = 3.5 Hz, H-C(4)); 6.13 (d, J = 13.3 Hz,
NH); 7.58 (d, J= 13.4 Hz, H-C(3’)). 13C-NMR (126MHz, CDCl3) for 11: d
9.3, 19.3, 20.7, 20.8, 28.6, 30.4, 49.2, 49.9, 58.8, 114.6, 114.7, 130.3, 131.4,
132.8, 138.9, 208.6.
Catalytic Hydrogenation of a Mixture of 11 and 11’
To a solution of enaminones 11/11’ (11:11’= 92:8, 330 mg, 1.23 mmol) in
anhydrous EtOH (70 ml) under Ar, Pd–C (10%, 180 mg) and HCl (1.5 ml, 2 M
in EtOAc, 3 mmol) were added. The reaction vessel was flushed with H2, and
the reaction mixture was hydrogenated in Paar hydrogenator (P=4Bar) at
room temperature for 3 h. The reaction mixture was filtered through a plug
of CeliteW and washed with EtOH (100 ml). Volatile components were evapo-
rated in vacuo, and the residue was dissolved in EtOAc (200 ml) and washed
with NaHCO3 (aq. sat. 10 ml). The organic phase was dried over anhydrous
Na2SO4, filtered, and volatile components evaporated in vacuo to give a mix-
ture of p-toluidine 12, 12’, 13 and the corresponding saturated derivatives
14, 14’, 15 (all the starting material 11/11’ was consumed). The crude
reaction mixture was partially separated by column chromatography (Silica
gel 60; (1) EtOAc/petroleum ether = 1:2 to elute the p-toluidine derivatives
(200 mg, 12:12’:13 = 42:26:32) and (2) EtOAc/MeOH = 10:1 to elute the
cyclohexyl derivatives (45 mg, the ratio of 14:14’:15, their presence was
determined only by HRMS)). p-Toluidine derivatives were partially separated
by MPLC (EtOAc/petroleum ether = 1:2 ) to give a mixture ketone epimers
12 and 12’ in a 70:30 ratio and an amino alcohol 13. Mixture of compounds
14, 14’, and 15 has not been preparatively separated (LC–MS analysis).
1055, 968, 888, 710, 683 cmÀ1 1H-NMR (500 MHz, DMSO-d6) for 19: d
.
0.76 (s, Me); 0.88 (s, Me); 1.01 (s, Me); 1.03–1.14 (m, 2H of CH2);
1.42–1.49 (m, 1H of CH2); 1.60–1.67 (m, 1H of CH2); 1.99 (d, J= 5.3Hz,
H-C(4)); 3.70 (dd, J = 6.1; 7.6 Hz, H-C(2)); 4.02 (dd, J= 5.9; 7.7Hz, H-C(3));
5.81 (d, J = 5.8 Hz, OH); 7.70 (s, 1H of Arl); 7.94 (d, J = 5.7 Hz, H-N(2’)); 8.43
(s, 2H of Arl); 10.73 (s, NH). 1H-NMR (500 MHz, DMSO-d6) for 19’: d 0.82
(s, Me); 0.94 (s, Me); 1.25–1.32 (m, 1H of CH2); 1.35–1.40 (m, 1H of CH2);
1.79–1.85 (m, 1H of CH2); 2.18 (t, J = 4.1 Hz, H-C(4)); 3.90 (dd, J = 5.0;
10.1 Hz, H-C(2)); 4.41–4.46 (m, H-C(3)); 5.66 (d, J= 5.2 Hz, OH); 7.81
(d, J= 6.1 Hz, H-N(2’)); 10.74 (s, NH). 13C-NMR (126MHz, DMSO-d6) for
19: d 11.6, 21.0, 21.6, 25.6, 32.6, 45.9, 48.8, 49.8, 60.9, 77.4, 115.5 (br s),
120.7 (br s), 123.3 (q, J= 272.7 Hz), 130.2, (q, J = 32.7 Hz), 142.2, 178.8.
General Procedure for Organocatalytic Michael Addition
Reaction
Dimethyl malonate (20) (2.5 mmol, 292 ml) was added to a solution of
catalyst 7–9, 19/19’ (0.1 mmol, 10 mol%), and trans-b-nitrostyrene (21)
(149 mg, 1 mmol) in toluene (1.5 ml) at room temperature or at À30 ꢀC,
and the mixture was stirred for 1 day or 3 days. The reaction mixture
was passed through a plug of Silica gel 60 (7 Â 2 cm (ø); EtOAc/
petroleum ether = 1:1) to remove the catalyst. Volatile components were
evaporated in vacuo, and the residue was used for the determination of
conversion (1H-NMR(CDCl3)) and HPLC analysis. Characterization of
Michael addition product (22): HPLC analysis: CHIRALPAK AD-H,
n-Hexane/i-PrOH = 80:20, flow rate: 1.0 ml/min, 25 ꢀC, UV: l = 210 nm,
t (minor) = 11 min, t (major) = 13 min. Absolute configuration was deter-
mined by comparing the relative retention time of the HPLC analysis with
the reported data.24
(1S,3S,4R)-1,7,7-Trimethyl-3-((p-tolylamino)methyl)bicyclo[2.2.1]
heptan-2-one (12) and (1S,3R,4R)-1,7,7-trimethyl-3-((p-tolylamino)
methyl)bicyclo[2.2.1]heptan-2-one (12’).
12/12’ elute first from
the column. Yield: 79 mg (23%, 12/12’ = 70:30) of dirty white solid; mp
60–64 ꢀC. [a]Dr.t. =+83.3 (c=0.11, CH2Cl2) (C18H25NO requires: C, 79.66; H,
9.28; N, 5.16 and found: C, 79.90; H, 9.46; N, 5.19); EI-HRMS:
m/z = 272.2025 (MH+); C18H26NO requires: m/z = 272.2009 (MH+); nmax
(KBr) 3376, 2964, 2870, 1732, 1620, 1583, 1522, 1466, 1407, 1390, 1374,
1318, 1304, 1270, 1250, 1211, 1182, 1124, 1092, 1044, 1023, 932, 850, 822,
1
806 cmÀ1. H-NMR (500 MHz, CDCl3) for 12: d 0.87 (s, Me); 0.91 (s, Me);
0.95 (s, Me); 1.34–1.40 (m, 1H of CH2); 1.44–1.52 (m, 1H of CH2); 1.61–1.67
(m, 1H of CH2); 1.97–2.05 (m, H-C(4), 1H of CH2); 2.19 (t, J=7.0Hz, H-C
(3)); 2.23 (s, Me); 3.24 (dd, J=7.0; 12.7Hz, Ha-C(3’)); 3.41 (dd, J=7.0;
12.7 Hz, Hb-C(3’)); 4.15 (br s, NH); 6.55–6.60 (m, 2H of Arl); 6.99
(d, J=8.0Hz, 2H of Arl). 1H-NMR (500 MHz, CDCl3) for 12’: d 1.00 (s, Me);
1.52 – 1.59 (m, 1H of CH2); 1.68–1.75 (m, 1H of CH2); 1.78–1.87 (m, 1H of
CH2); 2.14–2.17 (m, H-C(4)); 2.73 (dd, J= 7.1; 12.1 Hz, H-C(3)); 3.11
(dd, J=7.8; 12.2Hz, Ha-C(3’)); 3.33 (dd, J=7.4; 12.2Hz, Hb-C(3’)). 13C-NMR
(126 MHz, CDCl3) for 12: d 9.4, 20.5, 20.6, 21.9, 29.2, 29.4, 46.7, 47.0, 47.3,
53.9, 58.1, 113.5, 127.0, 129.9, 145.5, 221.1. 13C-NMR (126 MHz, CDCl3) for
12’: d 9.6, 19.3, 19.7, 20.7, 31.3, 43.1, 46.1, 46.2, 49.0, 59.1, 113.6, 127.2,
129.9, 145.9, 220.8.
RESULTS AND DISCUSSION
Syntheses
The title bifunctional camphor-derived organocatalysts 7–9
were prepared in five steps starting from (+)-camphor (1).
Following the literature procedure,37 (+)-camphor (1) was trans-
formed into 3-((dimethylamino)methylene)camphor (2). Next,
catalytic hydrogenation of enaminone 2 in EtOH in the presence
of 10% Pd–C and excess HCl gave the corresponding ammo-
nium salt as a mixture of the major endo-epimer 340 and the
minor exo-epimer 3’40 in a ratio of 78:22 and in 100% conversion.
The observed formation of the major endo-epimer for a closely
related transformation has been proposed previously.37 Treat-
ment of ammonium salts 3/3’ under conditions used by Page42
(NH2OHÁHCl, pyridine) gave the corresponding oximes 4/4’41
(1S,2R,3S,4R)-1,7,7-Trimethyl-3-((p-tolylamino)methyl)bicyclo
[2.2.1]heptan-2-ol (13).
13 elutes second from the column. Yield:
58 mg (17%) of dirty white solid; mp 69–72ꢀC. [a]Dr.t. = +102.2 (c= 0.09,
CH2Cl2) (C18H27NO requires: C, 79.07; H, 9.95; N, 5.12 and found: C,
79.19; H, 10.24; N, 5.11); EI-HRMS: m/z = 274.2162 (MH+); C18H28NO
requires: m/z = 274.2165 (MH+); nmax (KBr) 2947, 1616, 1516, 1483, 1459,
Chirality DOI 10.1002/chir

SYNTHESIS OF CAMPHOR ORGANOCATALYSTS
415
with a slight change of epimer composition (4/4’ = 84:16) in 86%
yield. Hine and coworkers reported the preparation of
(1R,2S,3R,4R)-diamine 5,41 via reduction of oximes 4/4’ with
excess LiAlH4 under reflux for 48 h. To obtain diamine 5 in a
stereo-divergent way in a short reaction time, the crude oximes
4/4’ were reduced with Na37 in nPrOH to give a mixture of dia-
mines 5 in full conversion and in 54:29:17 stereoisomer ratio.
of hydrogenation of 2, a complex mixture of products.
Partial chromatographic separation of the reaction
mixture gave products containing the p-toluidine group
intact (compounds 12/12’ and 13; the major products)
and the corresponding 4-methyl-cyclohexyl derivatives
(compounds 14/14’ and 15; the minor products). Further
chromatographic separation of compounds 12/12’/13
yielded ketone epimers 12/12’ in a 70:30 ratio as an
inseparable mixture in 23% yield and amino alcohol 13 in
17% yield. The mixture of compounds 14/14’ and 15
was preparatively not separated, and their identity was
confirmed only by mass spectroscopy (LC–MS). Changing
the conditions of hydrogenation (solvent, reaction time,
and acid used) consistently produced similarly complex
mixtures of products. Further transformation of ketones
12/12’ has not been pursued (Scheme 2).
Finally, a borneol-derived bifunctional thiourea organocatalyst
19 has been prepared in three steps from (1S)-(+)-
camphorquinone (16). Following the literature procedure,
(1S)-(+)-camphorquinone (16) was first transformed into the
corresponding keto oxime 17,38 followed by reduction with
LiAlH4 to give the amino alcohol 18.39 The crude 18 was
treated with 1-isothiocyanato-3,5-bis(trifluoromethyl)benzene
(6) to give borneol-derived thiourea stereoisomers
19 and 19’ in a 89:11 ratio and in 50% yield. Stereoisomers
19/19’ could not be separated neither by chromatography
nor by crystallization. The crude 18 must have contained
impurities of a minor stereoisomer, which eventually led to
19’ (Scheme 3).
1
Because of the overlap of the signals in H-NMR spectra, the
stereochemistry assignation was impossible. Finally, the mix-
ture of diamine stereoisomers 5 in anhydrous Et2O was reacted
with 1-isothiocyanato-3,5-bis(trifluoromethyl)benzene (6),
which, after chromatographic separation, gave 2-thiourea deriva-
tives 7, 8, and 9 in 41%, 6%, and 32% yield, respectively
(Scheme 1).
The dimethylamino group in enaminone 2 and in
other enaminones and related 3-(dimethylamino)propeno-
ates undergoes
a
facile acid-catalyzed substitution
with various amines, especially amines less basic
than dimethylamine (i.e., aromatic and heteroaromatic
amines) as well as with other N-nucleophile, C-nucleophile,
and O-nucleophile.43–45 Following the synthetic route
in Scheme 1 might lead to a significant increase in the
number of potential bifunctional organocatalysts. Thus,
enaminone 2 was treated with p-toluidine hydrochloride
(10), which yielded the expected dimethylamino substitu-
tion product as a mixture of the major (Z)-product 11 and
the minor (E)-product 11’ in a 92:8 ratio and in 54%
yield as a filterable precipitate. As shown previously, the
(E)-enaminone and the (Z)-enaminone readily interconvert
(the equilibrium is especially solvent dependent).44 Next,
catalytic hydrogenation of 11/11’ in EtOH in the pres-
ence of 10% Pd–C and excess HCl gave, unlike in the case
Structure Determination
The structures of compounds 3/3’,40 4/4’,41 and 541
were determined by 1H-NMR, and/or 13C-NMR, and/or
Scheme 1. Preparation of camphor-derived bifunctional thiourea organocatalysts 7–9.
Chirality DOI 10.1002/chir

416
GROŠELJ ET AL.
Scheme 2. Catalytic hydrogenation of dimethylamino substitution product 11/11’.
Scheme 3. Preparation of borneol—thiourea derivatives 19/19’.
MS-HRMS. They were prepared following procedures dif-
ferent from the literature procedures and used as crude
compounds in the following transformations. The struc-
tures of novel compounds 7–9, 11/11’, 12/12’, 13 and
19/19’ were determined by spectroscopic methods (IR,
NMR spectroscopy (1H-NMR and 13C-NMR, DEPT 90
and 135, COSY, HSQC, HMBC, and NOESY experiments)
and MS-HRMS) and by elemental analyses for C, H, and
N. Identities of compounds 14/14’ and 15 were con-
firmed by MS-HRMS.
The (2E)-configuration of oximes 4/4’ was ascribed on
the basis of the configuration of closely related oximes.37
The (Z)-configuration around the C = C bond in the enami-
none 11 was determined on the basis of NOE between
H-C(3’) and H-C(4) in the NOESY spectra. Accordingly, the
(E)-configuration around the C= C bond in the enaminone 11’
was determined on the basis of the NOE between NH and
H-C(4). Similarly, the configuration(s) at position(s) 2 and/or
Chirality DOI 10.1002/chir
3 of compounds 4, 7–9 12/12’, 13, and 19/19’ was/were
determined on the basis of NOE observed in NOESY spectra
between the corresponding key proton signals. See also the
Supporting information for 1H-NMR, 13C-NMR data, and
selected parts of NOESY spectra (Fig. 2).
Organocatalyst Performance
Compounds 7–9, 19/19’ have been evaluated as
organocatalysts in a model reaction of Michael addition of
dimethyl malonate to trans-b-nitrostyrene (Table 1). An
equivalent of trans-b-nitrostyrene (21), 2 equivalents of
dimethyl malonate (20), and 10% of catalyst in toluene were
used.24 Borneol derivatives 19/19’ gave no traces of the
corresponding product 22 because of the lack of the basic
functionality in the catalyst (Entry 1). All three catalysts 7–9
gave the addition product 22 of the same (R)-configuration24
with low to moderate enantioselectivities (20.0%–60.1% ee).

SYNTHESIS OF CAMPHOR ORGANOCATALYSTS
417
Fig. 2. Key NOE observed in NOESY spectra of compounds 4, 7–9, 11/11’, 12/12’, 13, and 19/19’ for the determination of configuration.
TABLE 1. Organocatalytic enantioselective addition of dimethyl malonate to trans-b-nitrostyrene
Entry
Catalyst
T (ꢀC)
t (days)
Conversion (%)a
ee (%)b
1
2
3
4
5
6
7
19/19’
r.t.
r.t.
r.t.
3
1
1
1
3
3
3
–
–
7
8
9
7
8
9
98
99
99
58
85
86
49.0; (R)
20.0; (R)
60.1; (R)
53.7; (R)
21.7; (R)
45.0; (R)
r.t.
À30
À30
À30
aConversion was determined using 1H-NMR.
bee was determined using CHIRALPAK AD-H.
CONCLUSIONS
Lowering the reaction temperature in the case of catalyst 7
slightly increased the selectivity (Entries 2 and 5), whereas
in the case of catalyst 9, lowering of the temperature actually
decreased the selectivity (Entries 4 and 7). The selectivity
of catalyst 8 stayed equally low regardless of the reaction
temperature (Entries 4 and 6). In all cases, lowering of the
reaction temperature led to incomplete conversions albeit the
prolonged reaction times.
Starting from (+)-camphor (1), three novel bifunctional
thiourea organocatalysts 7–9 have been prepared using
stereo-divergent straightforward transformations. Borneol
derivatives 19/19’ have been prepared in three steps from
(1S)-(+)-camphorquinone (16). Acid-catalyzed substitution
of the dimethylamino group of enaminone 2 with various
nucleophiles could potentially lead to a diversity-oriented
Chirality DOI 10.1002/chir

418
GROŠELJ ET AL.
configuration at C9 dramatically improves catalyst performance.
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