Novel pyrrolidine-thiohydantoins/thioxotetrahydropyrimidinones as highly effective catalysts for the asymmetric Michael addition

Article abstract of DOI:10.1039/c0ob01083a

The synthesis of novel organocatalysts consisting of a pyrrolidine moiety and a thiohydantoin or a thioxotetrahydropyrimidinone ring is described. The compound combining the pyrrolidine with the thioxotetrahydropyrimidinone was found to be a highly effect

Full text of DOI:10.1039/c0ob01083a

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PAPER
Novel pyrrolidine-thiohydantoins/thioxotetrahydropyrimidinones as highly
effective catalysts for the asymmetric Michael addition†
Christoforos G. Kokotos, Dimitris Limnios, Despoina Triggidou, Maria Trifonidou and George Kokotos*
Received 25th November 2010, Accepted 11th February 2011
DOI: 10.1039/c0ob01083a
The synthesis of novel organocatalysts consisting of a pyrrolidine moiety and a thiohydantoin or a
thioxotetrahydropyrimidinone ring is described. The compound combining the pyrrolidine with the
thioxotetrahydropyrimidinone was found to be a highly effective catalyst for the Michael reaction. Low
catalyst loadings (1–2.5%) can be employed leading to quantitative yields and excellent
stereoselectivities in the reaction between cyclic ketones and nitroolefins.
a primary amino group,11 like the alanine derivative 6 (Fig. 1),12
Introduction
may also catalyse asymmetric reactions, including the Michael
At the end of the first decade of the 21st century, organocatalysis
reaction. In the last few years, our group proposed 4-substituted
prolines13a,b and proline sulfonamides,13c homoproline and dipep-
tide sulfonamides,13d heterocyclic analogues of homoproline13e as
well as chiral primary amine-thioureas13f as improved catalysts
for the aldol and Michael reactions. In an effort to search for
new and improved catalytic motives, we focused on developing
new bifunctional catalysts combining the secondary amine of the
pyrrolidine ring with a new chiral template. To this end, we thought
of the thiohydantoin ring or the corresponding six-membered
ring as the appropriate scaffold. In the present work, we present
the synthesis of novel pyrrolidine-based bifunctional molecules
incorporating a thiohydantoin or a 2-thioxotetrahydropyrimidin-
4-one ring and the evaluation of these catalysts in the Michael
reaction.
now constitutes a well recognized methodology complementing
transition metal complex-mediated catalysis and biocatalysis in
the armoury of asymmetric synthesis.1 Over the last decade, a
wide variety of organocatalysts have been developed presenting
distinct mechanisms of action.2 Among the existing organocat-
alysts, proline3 and related aminocatalysts, chiral thioureas ini-
tially proposed by Jacobsen4 and imidazolidinones developed
by MacMillan5 represent the major organocatalyst categories.6
The five-membered secondary amine structure of pyrrolidine is
considered to be a “privileged” structure able to activate carbonyl
compounds through the formation of enamine intermediates. In
combination with other functional groups, it provides bifunctional
molecules such as chiral diamines 1 and 2,7 sulfonamide 3,8 diaryl-
prolinols 4 and the corresponding TMS ethers,9 amides like 5,10
(Fig. 1) able to catalyze a variety of asymmetric transformations.
In addition, it has been demonstrated that compounds containing
Results and discussion
The rationale for the design of the new catalysts is illustrated
in Fig. 2. For the construction of the catalyst, apart from the
pyrrolidine ring, a chiral template capable of creating either
hydrogen bonds or a bulky environment is required. Bearing
in mind the amino acid chemistry and the ease of thioureas
Fig. 1 Some pyrrolidine-based organocatalysts.
Laboratory of Organic Chemistry, Department of Chemistry, University
of Athens, Panepistimiopolis, 15771, Athens, Greece. E-mail: gkokotos@
chem.uoa.gr; Fax: (+ 30) 210 7274761; Tel: (+ 30) 210 7274462
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c0ob01083a
Fig. 2 Design of the new catalysts.
3386 | Org. Biomol. Chem., 2011, 9, 3386–3395
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to participate in hydrogen bonding, the thiohydantoin ring or
the corresponding six-membered ring of thioxotetrahydropy-
rimidinone may be formed from thioureas involving a- or b-
amino acids (Fig. 2). The commercially available methyl ester
of (S)-b-phenylalanine (7) was converted to the correspond-
ing isothiocyanate by treatment with thiophosgene and reacted
with (S)-tert-butyl-2-(aminomethyl)pyrrolidine-1-carboxylate (8)
to afford thiourea 9 (Scheme 1). In order to elucidate whether
a primary or a secondary amine moiety is optimal for high
catalytic activity, the isothiocyanate from 7 also reacted with
tert-butyl (1S, 2S)-2-amino-1,2-diphenylethylcarbamate (10) and
thiourea 11 was obtained. It is known that (thio)ureas con-
taining amino acid esters may be cyclized to (thio)hydantoins
or 2-(thio)oxotetrahydropyrimidin-4-ones under acidic or basic
conditions.14 Treatment of 9 and 11 with 6 N HCl/MeOH upon
heating resulted in the formation of the heterocyclic ring with
simultaneous removal of the Boc group providing compounds 12
and 13. The synthesis of the corresponding five-membered thiohy-
dantoin ring was necessary because five and six-membered rings
are known to adopt different conformations, that may result in
different reactivities. The synthesis of pyrrolidine/thiohydantoins
started from commercially available methyl esters of glycine (14a),
(S)-tert-leucine (14b), (S)-phenylalanine (14c), (S)-phenylglycine
(14e) and (R)-phenylglycine (14e) and is illustrated in Scheme 2, in
a similar fashion as in Scheme 1. Altering the reaction conditions
in the cyclization step can lead to the Boc-protected compound 17
(Scheme 3) that can be used for studies of the reaction mechanism.
Scheme 2 Synthesis of new catalysts 16a–e.
Scheme 3 Synthesis of compound 17.
trans-b-nitrostyrene was chosen as the model reaction to evaluate
the effectiveness of the new catalysts.
At the beginning, catalyst 12 was tested at catalyst loadings from
15% to 2.5% using toluene as the solvent and acetic acid and water
as the additives. A catalyst loading of 2.5% was enough to achieve
high yield and enantioselectivity (entry 3, Table 1), indicating the
high reactivity of the catalysts and their potential use at even lower
catalyst loadings. In the absence of additives, only traces of the
product were obtained (entry 4, Table 1). Both an acidic additive
and H2O are necessary for the catalytic activity (entry 4 vs. 5 and 6,
Table 1). The acidic counterpart facilitates the enamine formation
which is key for the catalytic cycle, while water should be involved
in the hydrolysis of the catalyst from the addition product helping
the catalyst turnover. The effect of the reaction solvent was next
examined (entries 7–16, Table 1) and it was found that although
high enantioselectivities were observed in most cases, the yield
varied from low to satisfactory. Polar and chlorinated solvents led
to decreased yields while non-polar solvents seem to favour the
reaction. Using tetrahydrofuran as the solvent, the product was
obtained in a yield comparable to that obtained by using toluene,
but the enantiomeric excess was higher (entry 13, Table 1).
An extensive study of various acids instead of acetic acid,
highlighted the importance of the nature of the acidic coun-
terpart. Brønsted acids have been reported to facilitate the
action of aminocatalysts, improving both the yield and the
stereoselectivity.16 Strong acids like trifluoroacetic acid, citric acid
or 2,4-dinitrobenzoic acid did not work leading to traces of the
product (entries 2–4, Table 2). Benzoic acid provided low yield,
however the introduction of a nitro group, with simultaneous alter-
ation of the acidity of the additive, drastically improved the activity
(entries 5–7, Table 2). 4-Nitrobenzoic acid gave excellent results in
particular when tetrahydrofuran was used as a solvent (entry 8,
Table 2). When the reaction was performed at 0 ◦C, a decrease in
the yield was observed using either acetic acid or 4-nitrobenzoic
acid (entries 9 and 10, Table 2), without any improvement in the
enantiocontrol of the reaction. It was gratifying to see that under
Scheme 1 Synthesis of new catalysts 12 and 13.
The asymmetric Michael addition is one of the most useful
processes for the synthesis of new C–C and C–X bonds. Thus,
much effort has been devoted to exploring various organocatalysts
for this key transformation.15 The reaction of cyclohexanone with
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Table 1 Michael reaction between cyclohexanone and trans-b-
nitrostyrene using catalyst 12a
Table 3 Michael reaction between cyclohexanone and trans-b-
nitrostyrene using catalyst 12, 13, 16a–e and 17a
Catalyst
Entry loading (%) Solvent
Entry Catalyst
Solvent
Yield (%)b
dr (syn : anti)c
ee (%)d
Additives
Yield (%)b
ee (%)c
1
2
3
4
5
6
7
8
12
toluene
THF
toluene
THF
toluene
THF
toluene
THF
toluene
THF
toluene
THF
THF
THF
96
100
19
24
72
100
92
94
92
96
81
91
20
—
99 : 1
99 : 1
96 : 4
96 : 4
99 : 1
99 : 1
98 : 2
98 : 2
99 : 1
99 : 1
99 : 1
99 : 1
60 : 40
—
97
96
91
92
95
96
92
92
95
95
94
95
50
—
1
2
3
4
5
6
7
8
15
5
toluene
toluene
toluene
toluene
toluene
toluene
neat
brine
Et2O
MeCN
DMSO
H2O
AcOH, H2O 99
AcOH, H2O 99
AcOH, H2O 95
92
92
92
—
90
88
93
94
94
93
90
88
96
94
95
93
12
16a
16a
16b
16b
16c
16c
16d
16d
16e
16e
13e
17e
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
—
AcOH
H2O
traces
62
8
AcOH, H2O 41
AcOH, H2O 22
AcOH, H2O 22
AcOH, H2O 69
AcOH, H2O 17
9
9
10
11
12
13
14
10
11
12
13
14
15
16
AcOH, H2O
8
THF
AcOH, H2O 92
AcOH, H2O 78
AcOH, H2O 47
CH2Cl2
CHCl3
CHCl3
a Reactions were performed using 0.2 mmol nitroolefin, ketone (10 equiv.),
4-NBA (15 mol%) and H2O (2 equiv.) for 18 h. b Isolated yield. c The
diastereomeric ratio (dr) was determined by 1H NMR spectroscopy
(600 MHz). d The enantiomeric excess (ee) was determined by chiral HPLC.
e 10% mol catalyst was used.
AcOH,
MeOH
42
a Reactions were performed using 0.2 mmol nitroolefin, ketone (10 equiv.),
acid (15 mol%) and H2O (2 equiv.) for 18 h. b Isolated yield. c The enan-
tiomeric excess (ee) was determined by chiral HPLC. The diastereomeric
ratio (dr) was determined by 1H NMR spectroscopy (600 MHz) and found
to be 99 : 1 (syn : anti).
the optimized conditions (tetrahydrofuran, p-nitrobenzoic acid
and water), the product was obtained in 86% yield and 97% ee
using even as little as 1% catalyst loading of 12 (entry 11, Table
2). Furthermore, catalyst 12 efficiently catalyzed the reaction even
when a slight excess amount of ketone (1.2 to 2 equiv.) was used
(entries 12 and 13, Table 2). To fully elucidate the importance of the
acid additive, 4-cyanobenzoic acid and 4-trifluoromethylbenzoic
acid were tested (entries, 14 and 15, Table 2). In both cases, high
yields and stereoselectivities were observed. Comparing the pKa
values (in H2O) of 4-nitrobenzoic acid (3.44), 4-cyanobenzoic acid
(3.55) and 4- trifluoromethylbenzoic acid (3.60), all of which led to
excellent results, it seems that an optimum pKa value of the additive
is needed in order to maximise the yield and the enantioselectivity.
In order to shed more light on the required building aspects
of a favorable catalyst, we evaluated catalysts 16a–e, 13 and 17
with different structural features (Table 3). For this study, p-
nitrobenzoic acid and water, 2.5% catalyst loading and tetrahy-
drofuran or toluene as solvents were used. When the thioxote-
trahydropyrimidinone ring was replaced by the thiohydantoin
ring (entry 1 vs. 9 and entry 2 vs. 10, Table 3) similar results
were obtained showing that the two different-sized rings adopted
similar conformations in the transition state. The absence of a
substituent in the thiohydantoin ring (entry 3 vs. 9 and entry
4 vs. 10, Table 1) led to decreased selectivities and low yields
highlighting the necessity of a substituent on the ring in order
to lock its conformation to a much more efficient one for the
catalytic activity. Using various substituents such as tert-butyl
(catalyst 16b), benzyl (catalyst 16c) and phenyl (catalyst 16c),
similar results were obtained (entries 5–10, Table 3). Thus, it can be
postulated that the nature of the substituent does not seem to be so
important for high selectivities, but the conformation of the ring
adopted due to the substituent is the important factor. This point
is also supported by the fact that catalysts 16d and 16e, which have
Table 2 Michael reaction between cyclohexanone and trans-b-
nitrostyrene using catalyst 12a
Catalyst
Entry loading (%)
Additive and
H2O
Solvent
Yield (%)b ee (%)c
1
2
3
4
5
6
7
8
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
1
toluene
toluene
toluene
toluene
toluene
toluene
toluene
THF
toluene
toluene
THF
THF
THF
AcOH
TFA
95
92
—
—
—
89
95
97
97
97
97
97
96
96
97
97
traces
traces
traces
16
61
96
100
71
67
86
98
citric acid
2,4-diNBA
PhCO2H
2-NBA
4-NBA
4-NBA
AcOH
4-NBA
4-NBA
4-NBA
4-NBA
4-CBA
4-TBA
9d
10d
11
12e
13f
14
15
2.5
1
2.5
2.5
71
95
97
THF
THF
a Reactions were performed using 0.2 mmol nitroolefin, ketone (10 equiv.),
acid (15 mol%) and H2O (2 equiv.) for 18 h. b Isolated yield. c The enan-
tiomeric excess (ee) was determined by chiral HPLC. The diastereomeric
ratio (dr) was determined by 1H NMR spectroscopy (600 MHz) and found
to be 99 : 1 (syn : anti). d The reaction was performed at 0 ◦C. e 2 equiv.
of ketone were used, reaction time 48 h, dr 98 : 2. f 1.2 equiv. of ketone
were used, reaction time 48 h, dr 98 : 2. 2,4-diNBA: 2,4-dinitrobenzoic
acid, 2-NBA: 2-nitrobenzoic acid, 4-NBA: 4-nitrobenzoic acid, 4-CBA:
4-cyanobenzoic acid, 4-TBA: 4-trifluoromethylbenzoic acid.
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the phenyl substituent of the thiohydantoin ring in the opposite
configuration, furnished the same product enantiomer in similar
diastereomeric ratios and ees. Derivative 13 led to poor results
regarding both the yield and the stereoselectivities (entry 13, Table
3), while the protected derivative 17 failed to catalyse the Michael
reaction (entry 14, Table 3). Both these data indicate that a free
secondary amino group is a requirement for the catalytic activity.
In conclusion, both the thioxotetrahydropyrimidinone ring and
the thiohydantoin ring carrying a phenyl or a bulky substituent
work as excellent catalysts for the reaction between cyclohexanone
and trans-b-nitrostyrene.
To explore the scope and the limitations of the Michael reaction,
various nitroolefins and ketones were studied using the pyrroli-
dine/thioxopyrimidinone 12 and the pyrrolidine/thiohydantoin
16b as a catalyst and the results are presented in Table 4. Using
catalyst 12, the products of the reaction between cyclohexanone
and various nitroolefins were isolated in excellent yields (88–100%)
(entries 1, 3, 5, 7, 9, Table 4). In all cases high diastereoselectivities
(94 : 6 to 99 : 1) and enantioselectivities (95–97% ee) were observed.
When other ketones were used, all the products were isolated in
high to quantitative yields, high diastereoselectivities (87 : 13 to
98 : 2) and enantioselectivities (95 to 96% ee), although elongation
of the reaction time was needed to reach reaction completion
(entries 11, 13, 15, 17, 19, Table 4). Slight variations were observed
when catalyst 16b was used.
To account for the stereochemical outcome of the Michael
reaction, a plausible transition-state model is proposed in Fig. 3.
The secondary amine of the pyrrolidine ring activates the ketone
through the formation of an enamine intermediate. The approach
of the electrophile is controlled by the heterocyclic ring through
stabilizing interactions, such as hydrogen bonding. Thus, the high
enantiocontrol observed can be accounted for by a postulated
stabilizing interaction of the heterocyclic ring with the nitroolefin
which controls the face of the nucleophilic attack. Thus, the
approach occurs in the same way irrespective of the configuration
of the stereogenic center of the thiohydantoin ring, leading to the
same product enantiomer in both cases (see ESI†). In the absence
of the substituent, the front face is not blocked that efficiently.
Fig. 3 Proposed transition state.
A great variety of pyrrolidine-based catalysts have been studied
for this model Michael addition.8,13d,17 Although some of the
existing catalysts provide the product in high yield and stereos-
electivity, two major drawbacks exist. A high catalyst loading (10–
30%) as well as a large excess amount of Michael donor (up to
20 equiv. of ketone) has to be applied. Our novel pyrrolidine–
thioxopyrimidinone system has as a major advantage in that it
works efficiently even at as little as 1–2.5% catalyst loading. In
addition, the use of a slight excess of ketones (1.2 to 2 equiv.)
may be successfully applied. Recently, a small number of very
efficient organocatalysts (1% to 2% catalyst loading) for the
Michael reaction of aldehydes to nitroolefins, like tripeptides or
diarylprolinol silyl ethers, have appeared in the literature.16c,18
To further study the scope of the new catalyst 12 in Michael
additions, acyclic ketones and aldehydes were tested under the
optimised conditions for cyclic ketones (Scheme 4). Using 5%
catalyst loading, only acetone afforded the desired product in high
yield and good enantioselectivity. A more “difficult” substrate
like butan-2-one led to high enantioselectivity but low yield after
extended reaction time. The use of linear aldehydes was amenable,
although good yields and unsatisfactory enantioselectivities were
observed. The introduction of geminal substitution in the a-
position of the aldehyde led to decreased yields but high ee.
Conclusions
In conclusion, we have developed novel organocatalysts combin-
ing the “privileged” pyrrolidine ring with the thioxotetrahydropy-
rimidinone or the thiohydantoin rings. These novel catalysts are
highly effective for the asymmetric Michael addition of cyclic
ketones to nitroolefins providing the product in high yields and
stereoselectivities. The advantages of the new catalysts are that: (a)
they are easily synthesized, and (b) the reaction can be conducted
in the presence of as little as 1% catalyst loading. Further studies
on exploring the catalytic activity of the novel organocatalysts on
other asymmetric transformations are under way.
Experimental section
General information
Organic solutions were concentrated under reduced pressure
on a Bu¨chi rotary evaporator. Chromatographic purification of
products was accomplished using forced-flow chromatography on
Merck Kieselgel 60 F254 230–400 mesh. Thin-layer chromatog-
raphy (TLC) was performed on aluminium backed silica plates
(0.2 mm, 60 F254). Visualization of the developed chromatogram
Scheme 4 Michael reaction between acyclic ketones and aldehydes with
nitrostyrene using catalyst 12.
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Table 4 Michael reaction between cyclic ketones and nitroolefins using catalyst 12 and 16ba
Entry
Product
Catalyst
Time (h)
Yield (%)b
dr (syn : anti)c
ee (%)d
1
2
12
16b
18
18
89
90
94 : 6
92 : 8
95
96
3
4
12
16b
18
18
92
91
99 : 1
98 : 2
97
96
5
6
12
16b
18
18
100
99
97 : 3
98 : 2
97
96
7
8
12
16b
46
46
96
96
98 : 2
98 : 2
96
98
9
10
12
16b
18
18
88
85
99 : 1
96 : 4
96
96
11
12
12
16b
46
46
98
94
93 : 7
95 : 5
95
96
13
14
12
16b
46
46
99
96
97 : 3
97 : 3
95
96
15
16
12
16b
46
46
96
98
98 : 2
98 : 2
96
95
17
18
12
16b
46
46
92
90
87 : 13
87 : 13
96
96
19
20
12
16b
46
46
93
91
98 : 2
98 : 2
95
96
a Reactions were performed using 0.2 mmol nitroolefin, ketone (10 equiv.), 4-NBA (15 mol%) and H2O (2 equiv.) for 18 h. b Isolated yield. c The
diastereomeric ratio (dr) was determined by 1H NMR spectroscopy (600 MHz). d The enantiomeric excess (ee) was determined by chiral HPLC.
was performed by fluorescence quenching using phosphomolybdic
acid, anisaldehyde or ninhydrin stains. Melting points were deter-
mined on a Buchi 530 hot stage apparatus and are uncorrected.
1H and 13C NMR spectra were recorded on Varian Mercury
(200 MHz or 50 MHz) or Bruker (600 MHz and 150 MHz
respectively) as noted, and are internally referenced to residual
as follows: chemical shift (d ppm), integration, multiplicity (s =
singlet, d = doublet, t = triplet, q = quadruplet, m = multiplet, bs =
broad signal, bs m = broad signal multiplet), coupling constant
and assignment. Wherever rotamers exist, these are presented
in brackets. Diastereomeric ratios were determined by H NMR
(600 MHz). Data for 13C NMR are reported in terms of chemical
1
1
protio solvent signals (CDCl3). Data for H NMR are reported
shift (d ppm). IR spectra were recorded on a Nicolet 6700 FT-IR
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spectrometer and are reported in terms of frequency of absorption
(cm-1). Mass spectra were recorded on a Finnigan Surveyor
MSQ Plus, with only molecular ions and major peaks being
reported with intensities quoted as percentages of the base peak.
High Performance Liquid Chromatography (HPLC) was used to
determine enantiomeric excesses and was performed on a Agilent
58.2 (NCH), 52.2 (OCH3), 37.9 (CH2), 28.2 [C(CH3)]; IR (film)
3345, 1743, 1682, 1532, 1452 cm-1; MS (ESI) 534 (M + H+, 100%);
HRMS exact mass calculated for [M + Na]+ (C30H35N3O4SNa)
requires m/z 556.2246, found m/z 556.2239; [a]D = +79.6 (c = 1.0,
CHCl3).
(S) - tert - Butyl - 2 - {[3 - (2 - methoxy - 2 - oxoethyl)thioureido] -
methyl}pyrrolidine-1-carboxylate (15a). Light yellow oil, 85%
yield; 1H NMR (200 MHz, CDCl3) d 7.86 (1H, br H, NH), 7.12
(0.6H, br s, NH), 6.77 (0.4H, br s, NH), 4.39–4.11 (2H, m, NCH
and NCHH), 3.96–3.62 (2H, m, 2 ¥ NCHH), 3.63 (3H, s, OCH3),
3.52–3.30 (1H, m, NCHH), 3.30–3.08 (2H, m, 2 ¥ NCHH), 1.95–
1.61 (4H, m, 4 ¥ CHH), 1.33 [9H, s, C(CH3)3]; 13C NMR (50 MHz,
CDCl3) d 182.0 (C S), 170.1 (C O), 156.4 (OCONH), 79.9
[C(CH3)3], 56.0 (NCH), 51.9 (OCH3), 46.8 (NCH2), 46.6 (NCH2),
45.7 (NCH2), 29.2 (CH2), 28.1 [C(CH3)], 23.4 (CH2); IR (film)
2974, 1749, 1667, 1553, 1407 cm-1; MS (ESI) 332 (M + H+, 100%);
HRMS exact mass calculated for [M + Na]+ (C14H25N3O4SNa)
requires m/z 354.1464, found m/z 354.1456; [a]D = -1.8 (c = 1.0,
CH2Cl2).
R
1100 Series apparatus using a ChiralpakꢀAD-H column. Optical
rotations were measured on a Perkin Elmer 343 polarimeter.
General procedure for the synthesis of thioureas 9, 11 and 15a–e
To a stirring solution of amino acid methyl ester hydrochloride
(1.00 mmol) in dichloromethane (5 mL), a ◦saturated aqueous
solution of NaHCO3 (5 mL) was added at 0 C and left stirring
vigorously for 10 min. The stirring was stopped and thiophosgene
(0.10 mL, 1.05 mmol) was added to the organic layer (bottom
layer) via syringe. The reaction mixture was stirred vigorously at
room temperature for 1 h. The two layers were separated and the
aqueous layer was extracted with dichloromethane (3 ¥ 5 mL). The
combined organic layers were dried over Na2SO4 and the solvent
was evaporated to afford the isothiocyanate with enough purity to
be used in the subsequent step. A solution of the isothiocyanate
in dichloromethane (15 mL) was added to a stirring solution of
the amine (1.00 mmol) in dichloromethane (10 mL) over a period
of 5 min at room temperature and the reaction mixture was left
stirring until the consumption of the isothiocyanate (0.5–5 h). The
solvent was evaporated and the crude product was purified using
flash column chromatography eluting with various mixtures of
CHCl3 : MeOH or CH2Cl2 : MeOH.
(S)-tert-Butyl-2-{[3-((S)-1-methoxy-3,3-dimethyl-1-oxobutan-
2-yl)thioureido]methyl} pyrrolidine-1-carboxylate (15b). Light
1
yellow oil, 84% yield; H NMR (200 MHz, CDCl3) d 8.04 (1H,
br H, NH), 7.13 (0.5H, br s, NH), 6.37 (0.5H, m, NH), 4.97–
4.55 (1H, m, NCH), 4.01–3.64 (2H, m, NCH and NCHH), 3.60
(3H, s, OCH3), 3.51–3.32 (1H, m, NCHH), 3.31–3.08 (2H, m, 2 ¥
NCHH), 1.92–1.57 (4H, m, 4 ¥ CHH), 1.35 [9H, s, C(CH3)3],
0.93 [9H, s, C(CH3)3]; 13C NMR (50 MHz, CDCl3) d 181.9
(182.1) (C S), 171.4 (171.6) (C O), 156.8 (OCONH), 80.1 (80.0)
[C(CH3)3], 65.7 (NCH), 56.0 (NCH), 51.5 (OCH3), 46.7 (NCH2),
46.6 (NCH2), 34.8 [C(CH3)3], 29.2 (CH2), 28.2 [C(CH3)], 26.5
[C(CH3)], 23.6 (CH2); IR (film) 2967, 1739, 1664, 1544, 1406 cm-1;
MS (ESI) 388 (M + H+, 100%); HRMS exact mass calculated for
[M + Na]+ (C18H33N3O4SNa) requires m/z 410.2090, found m/z
410.2083; [a]D = -8.9 (c = 1.0, CH2Cl2).
(S)-tert-Butyl-2-{[3-((S)-3-methoxy-3-oxo-1-phenylpropyl)-
thioureido]methyl}pyrrolidine-1-carboxylate (9). Light yellow
◦
1
solid, mp 64–66 C, 88% yield; H NMR (200 MHz, CDCl3) d
8.93 (1H, br d, J = 8.2 Hz, NH), 7.43–7.17 (5H, m, ArH), 6.39
(1H, br s, NH), 5.56 (1H, ddd, J = 11.3, 8.2 and 6.1 Hz, NCH),
4.15–3.99 (1H, m, NCH), 3.72 (3H, s, OCH3), 3.62–3.21 (4H, m,
4 ¥ NCHH), 3.19–3.01 (2H, m, COCH2), 2.01–1.71 (4H, m, 4 ¥
CHH), 1.52 [9H, s, C(CH3)3]; 13C NMR (50 MHz, CDCl3) d 181.5
(181.3) (C S), 173.6 (172.4) (C O), 154.6 (154.2) (OCONH),
135.5 (134.7) (Ar), 129.0 (Ar), 128.1 (Ar), 126.6 (127.0) (Ar), 80.0
[C(CH3)3], 60.3 (60.2) (NCH), 55.9 (NCH), 52.0 (OCH3), 46.5
(46.4) (NCH2), 46.1 (45.9) (NCH2), 36.5 (37.7) (CH2CO), 29.7
(29.6) (CH2), 28.2 [C(CH3)], 23.5 (23.2) (CH2); IR (film) 2973,
1744, 1663, 1543, 1508, 1405 cm-1; MS (ESI) 422 (M + H+, 100%);
HRMS exact mass calculated for [M + Na]+ (C21H31N3O4SNa)
requires m/z 444.1933, found m/z 444.1926; [a]D = -1.5 (c = 1.0,
CH2Cl2).
(S)-tert-Butyl-2-{[3-((S)-1-methoxy-1-oxo-3-phenylpropan-2-
yl)thioureido]methyl}pyrrolidine-1-carboxylate (15c). Light yel-
low oil, 89% yield; 1H NMR (200 MHz, CDCl3) d 7.44–7.09 (5H,
m, ArH), 5.21 (1H, br s, NCH), 4.11–3.91 (1H, m, NCH), 3.70
(3H, s, OCH3), 3.57–3.05 (6H, m, 4 ¥ NCHH and 2 ¥ CHHPh),
2.13–1.56 (4H, m, 4 ¥ CHH), 1.47 [9H, s, C(CH3)3]; 13C NMR
(50 MHz, CDCl3) d 181.5 (181.3) (C S), 172.5 (172.9) (C O),
155.4 (OCONH), 136.0 (Ar), 129.1 (Ar), 128.2 (Ar), 126.6 (Ar),
80.1 [C(CH3)3], 60.1 (NCH), 56.0 (56.3) (NCH), 52.0 (OCH3), 46.6
(46.6) (NCH2), 46.5 (46.5) (NCH2), 37.5 (37.4) (CH2), 29.4 (29.4)
(CH2), 28.2 [C(CH3)], 23.5 (CH2); IR (film) 2973, 1746, 1662, 1543,
1405 cm-1; MS (ESI) 444 (M + Na+, 53%), 422 (M + H+, 100%);
HRMS exact mass calculated for [M + Na]+ (C21H31N3O4SNa)
requires m/z 444.1933, found m/z 444.1925; [a]D = +2.8 (c = 1.0,
CHCl3).
(6S, 7S, 11S)-Methyl 2,2-dimethyl-4-oxo-6,7,11-triphenyl-9-
thioxo-3-oxa-5,8,10-triazatridecan-13-oate (11)
◦
1
White solid, mp 189–191 C, 82% yield; H NMR (200 MHz,
CDCl3) d 7.58–7.49 (1H, br m, NH), 7.38–6.82 (16H, m, NH
and ArH), 6.58–6.42 (1H, m, NCH), 5.80–5.48 (1H, br m, NH),
5.38–5.22 (1H, m, NCH), 4.97–4.79 (1H, m, NCH), 3.61 (3H, s,
OCH3), 3.24–2.90 (2H, m, CH2CO), 1.34 [9H, s, C(CH3)3]; 13C
NMR (50 MHz, CDCl3) d 181.8 (C S), 172.3 (C O), 156.7
(OCONH), 138.1 (Ar), 137.9 (Ar), 135.7 (Ar), 129.0 (Ar), 128.6
(Ar), 128.5 (Ar), 128.4 (Ar), 128.3 (Ar), 127.8 (Ar), 127.4 (Ar),
127.3 (Ar), 126.7 (Ar), 80.4 [C(CH3)3], 63.5 (NCH), 60.3 (NCH),
(S)-tert-Butyl-2-{[3-((S)-2-methoxy-2-oxo-1-phenylethyl)thio-
ureido]methyl}pyrrolidine-1-carboxylate (15d). Light yellow oil,
83% yield; 1H NMR (200 MHz, CDCl3) d 7.62–7.21 (7H, m, ArH
and 2 ¥ NH), 5.29–5.02 (1H, m, NCH), 4.11–3.86 (1H, m, NCH),
3.84–3.64 (3H, s, OCH3), 3.57–3.17 (4H, m, 4 ¥ NCHH), 2.05–
1.61 (4H, m, 4 ¥ CHH), 1.43 [9H, s, C(CH3)3]; 13C NMR (50 MHz,
CDCl3) d 184.5 (181.5) (C S), 171.3 (172.7) (C O), 156.9 (155.0)
(OCONH), 135.8 (133.1) (Ar), 128.7 (128.8) (Ar), 128.5 (Ar),
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126.7 (127. 6) (Ar), 80.3 (80.4) [C(CH3)3], 62.3 (60.4) (NCH),
56.0 (56.4) (NCH), 52.7 (52.7) (OCH3), 46.8 (46.9) (NCH2), 46.0
(46.1) (NCH2), 29.6 (CH2), 28.3 [C(CH3)], 23.7 (CH2); IR (film)
2973, 1744, 1661, 1551, 1406 cm-1; MS (ESI) 408 (M + H+, 100%);
HRMS exact mass calculated for [M + Na]+ (C20H29N3O4SNa)
requires m/z 430.1777, found m/z 430.1769; [a]D = -4.8 (c = 1.0,
CH2Cl2).
37.7 (CH2); IR (film) 3412, 1741, 1683, 1497, 1453 cm-1; MS (ESI)
402 (M + H+, 100%); HRMS exact mass calculated for [M + H]+
(C24H24N3OS) requires m/z 402.1640, found m/z 402.1647; [a]D =
-0.6 (c = 1.0, CHCl3).
(S)-3-(Pyrrolidin-2-ylmethyl)-2-thioxoimidazolidin-4-one (16a).
Light yellow oil, 76% yield; 1H NMR (200 MHz, CDCl3) d 4.43–
4.02 (2H, m, NCH and NCHH), 3.84–3.78 (1H, m, NCHH), 3.69–
3.51 (3H, m, 3 ¥ NCHH), 3.35–3.27 (1H, m, NCHH), 2.31–1.90
(4H, m, 4 ¥ CHH); 13C NMR (50 MHz, CDCl3) d 181.2 (C S),
176.3 (C O), 67.4 (NCH), 53.4 (NCH2CO), 46.4 (NCH2), 42.5
(NCH2), 29.7 (CH2), 26.4 (CH2); IR (film) 2962, 1742, 1655, 1431
cm-1; MS (ESI) 200 (M + H+, 11%), 184 (M + H-O+, 100%), 166
(M + H-H2S+, 92%); HRMS exact mass calculated for [2M +
H]+ (C16H27N6O2S2) requires m/z 399.1636, found m/z 399.1636;
[a]D = -44.4 (c = 0.25, CH2Cl2).
(S)-tert-Butyl-2-{[3-((R)-2-methoxy-2-oxo-1-phenylethyl)thio-
ureido]methyl}pyrrolidine-1-carboxylate (15e). Light yellow
◦
1
solid, mp 67–69 C, 82% yield H NMR (200 MHz, CDCl3) d
7.99 (1H, br H, NH), 7.51–7.21 (6H, m, ArH and NH), 6.21–5.93
(1H, br m, NCHPh), 4.03–3.77 (1H, m, NCH), 3.68–3.59 (1H,
m, NCHH), 3.66 (3H, s, OCH3), 3.51–3.39 (1H, m, NCHH),
3.33–3.14 (2H, m, 2 ¥ NCHH), 1.99–1.61 (4H, m, 4 ¥ CHH), 1.38
[9H, s, C(CH3)3]; 13C NMR (50 MHz, CDCl3) d 181.0 (180.9)
(C S), 171.2 (171.0) (C O), 156.3 (156.0) (OCONH), 135.9
(135.7) (Ar), 128.6 (Ar), 128.3 (Ar), 127.5 (127.4) (Ar), 80.1
[C(CH3)3], 60.2 (60.7) (NCH), 56.4 (55.9) (NCH), 52.5 (52.5)
(OCH3), 46.7 (46.7) (NCH2), 46.6 (NCH2), 29.4 (CH2), 28.2
[C(CH3)], 23.6 (CH2); IR (film) 2973, 1744, 1662, 1550, 1406 cm-1;
MS (ESI) 408 (M + H+, 100%); HRMS exact mass calculated for
[M + Na]+ (C20H29N3O4SNa) requires m/z 430.1777, found m/z
430.1769;; [a]D = -15.3 (c = 1.0, CH2Cl2).
(S)-5-tert-Butyl-3-[(S)-pyrrolidin-2-ylmethyl)-2-thioxoimida-
zolidin-4-one (16b). Light yellow oil, 72% yield; 1H NMR
(200 MHz, CDCl3) d 5.30 (2H, br s, 2 ¥ NH), 3.90–3.67 (3H,
m, 2 ¥ NCH and NCHH), 3.64–3.40 (1H, m, NCHH), 3.08–2.94
(1H, m, NCHH), 2.91–2.76 (1H, m, NCHH), 1.95–1.58 (3H, m,
3 ¥ CHH), 1.52–1.32 (1H, m, CHH), 1.00 [9H, s, C(CH3)3]; 13C
NMR (50 MHz, CDCl3) d 184.0 (184.2) (C S), 174.0 (173.5)
(C O), 67.8 (67.9) (NCH), 56.9 (NCH), 46.2 (46.1) (NCH2), 45.0
(45.1) (NCH2), 35.4 [C(CH3)3], 29.6 (29.5) (CH2), 25.5 [C(CH3)],
25.2 (25.1) (CH2); IR (film) 2962, 1741, 1658, 1508, 1431 cm-1; MS
(ESI) 256 (M + H+, 100%); HRMS exact mass calculated for [M +
H]+ (C12H22N3OS) requires m/z 256.1483, found m/z 256.1479;
[a]D = -8.8 (c = 1, CH2Cl2).
General procedure for the ring closing step
Thiourea (0.5 mmol) was put in a pressure vessel and HCl 6 N
in methanol (3 mL) and AcOH (5 mL) were added. The reaction
mixture was heated to 100 ◦C and left stirring at that temperature
for 3 h. It was then cooled to room temperature and the pH of
the mixture was adjusted to 8 with a solution of NaHCO3 (10%).
The resulting mixture was extracted with CH2Cl2 (3 ¥ 10 mL). The
combined organic layers were dried over Na2SO4 and the solvent
was evaporated to afford the desired product.
(S)-5-Benzyl-3-[(S)-pyrrolidin-2-ylmethyl)-◦2-thioxoimidazo-
lidin-4-one (16c). Light yellow solid, mp 96–98 C, 80% yield; 1H
NMR (200 MHz, CDCl3) d 7.49–6.99 (5H, m, ArH), 6.17–5.50
(2H, br m, 2 ¥ NH), 4.56–4.32 (1H, m, NCH), 3.93–3.57 (2H,
m, NCH and NCHH), 3.56–3.35 (1H, m, NCHH), 3.26 (1H, dd,
J = 14.0 and 4.0 Hz, CHHPh), 3.11–2.59 (3H, m, CHHPh and
2 ¥ NCHH), 2.05–1.52 (4H, m, 4 ¥ CHH); 13C NMR (50 MHz,
CDCl3) d 183.9 (183.6) (C S), 173.9 (174.5) (C O), 134.9 (Ar),
129.3 (Ar), 128.8 (Ar), 127.4 (Ar), 60.9 (60.6) (NCH), 57.2 (NCH),
45.8 (45.9) (NCH2), 44.6 (NCH2), 37.3 (CH2), 29.2 (CH2), 24.8
(24.7) (CH2); IR (film) 2962, 1741, 1656, 1508, 1431 cm-1; MS
(ESI) 290 (M + H+, 100%); HRMS exact mass calculated for [M +
H]+ (C15H20N3OS) requires m/z 290.1319, found m/z 290.1327;
[a]D = -16.8 (c = 0.5, CHCl3).
(S)-6-Phenyl-3-[(S)-pyrrolidin-2-ylmethyl]-2-thioxotetrahydro-
pyrimidin-4(1H)-one (12). Light yellow solid, mp 88–90 ◦C, 88%
yield; 1H NMR (200 MHz, CDCl3) d 7.33–7.14 (5H, m, ArH), 5.21
(2H, br m, 2 ¥ NH), 4.43 (1H, ddd, J = 14.9, 8.3 and 3.7 Hz, NCH),
3.81–3.59 (2H, m, NCH and NCHH), 3.49–3.34 (1H, m, NCHH),
3.24 (1H, dd, J = 14.0 and 3.6 Hz, NCHH), 2.97–2.58 (3H, m,
NCHH and COCH2), 1.79–1.54 (3H, m, 3 ¥ CHH), 1.37–1.20 (1H,
m, CHH); 13C NMR (50 MHz, CDCl3) d 184.0 (183.7) (C S),
174.0 (174.6) (C O), 135.0 (135.0) (Ar), 129.3 (129.2) (Ar), 128.7
(Ar), 127.4 (Ar), 60.8 (60.5) (NCH), 57.0 (57.0) (NCH), 46.0 (45.8)
(NCH2), 44.9 (NCH2), 37.3 (COCH2), 29.4 (29.5) (CH2), 25.0
(24.9) (CH2); IR (film) 2927, 1742, 1707, 1658, 1511, 1453 cm-1;
MS (ESI) 290 (M + H+, 100%); HRMS exact mass calculated
for [M + H]+ (C15H20N3OS) requires m/z 290.1319, found m/z
290.1327; [a]D = -35.7 (c = 1.0, CH2Cl2).
(S)-5-Phenyl-3-[(S)-pyrrolidin-2-ylmethyl)-2-thioxoimidazo-
lidin-4-one (16d). Light yellow solid, mp 166–168 ◦C, 85% yield;
1H NMR (200 MHz, CDCl3) d 7.51–7.07 (5H, m, ArH), 6.78 (2H,
br s, 2 ¥ NH), 5.29–5.08 (1H, m, NCH), 4.21–3.44 (3H, m, NCH
and 2 ¥ NCHH), 3.35–3.04 (1H, m, NCHH), 2.99–2.50 (1H, m,
NCHH), 2.07–1.59 (3H, m, 3 ¥ CHH), 1.51–1.27 (1H, m, CHH);
13C NMR (50 MHz, CDCl3) d 182.4 (C S), 172.0 (C O), 136.4
(Ar), 129.0 (Ar), 128.6 (Ar), 126.9 (Ar), 73.5 (NCH), 58.1 (NCH),
45.2 (NCH2), 43.0 (NCH2), 28.9 (CH2), 25.5 (CH2); IR (film) 2927,
1742, 1707, 1658, 1511, 1453 cm-1; MS (ESI) 276 (M + H+, 100%);
HRMS exact mass calculated for [M + H]+ (C14H18N3OS) requires
m/z 276.1170, found m/z 276.1165; [a]D = +36.8 (c = 1, CH2Cl2).
(S)-3-[(1S,
2S)-2-Amino-1,2-diphenylethyl]-6-phenyl-2-thio-
tetrahydr◦opyrimidin-4-(1H)-one (13). Light yellow solid, mp
105–107 C, 93% yield; 1H NMR (200 MHz, CDCl3) d 7.50–7.42
(1H, m, NH), 7.41–7.02 (15H, m, ArH), 6.87–6.71 (1H, m, NCH),
5.42–5.12 (1H, m, NCH), 4.31–4.05 (1H, m, NCH), 3.28–2.91
(2H, m, CH2CO); 13C NMR (50 MHz, CDCl3) d 181.8 (C S),
172.3 (C O), 141.5 (Ar), 135.7 (Ar), 134.7 (Ar), 129.5 (Ar), 129.1
(Ar), 129.0 (Ar), 128.5 (Ar), 128.4 (Ar), 128.0 (Ar), 127.7 (Ar),
127.2 (Ar), 126.6 (Ar), 60.5 (NCH), 60.4 (NCH), 58.3 (NCH),
(R)-5-Phenyl-3-[(S)-pyrrolidin-2-ylmethyl)-2-thioxoimidazo-
lidin-4-one (16e). Light yellow solid, mp 145–147 ◦C, 82% yield;
3392 | Org. Biomol. Chem., 2011, 9, 3386–3395
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1H NMR (200 MHz, CDCl3) d 7.52–7.06 (5H, m, ArH), 6.17
(2H, br s, 2 ¥ NH), 5.27–5.17 (1H, m, NCH), 4.10–3.89 (1H, m,
NCH), 3.80–3.47 (2H, m, 2 ¥ NCHH), 3.35–3.04 (1H, m, NCHH),
3.04–2.65 (1H, m, NCHH), 2.07–1.54 (3H, m, 3 ¥ CHH), 1.52–
1.34 (1H, m, CHH); 13C NMR (50 MHz, CDCl3) d 182.3 (C S),
172.0 (C O), 133.4 (Ar), 129.0 (Ar), 128.7 (Ar), 126.9 (Ar), 73.5
(NCH), 58.1 (NCH), 45.2 (NCH2), 43.0 (NCH2), 28.9 (CH2), 25.4
(CH2); IR (film) 2960, 1740, 1602, 1490, 1431 cm-1; MS (ESI)
276 (M + H+, 100%); HRMS exact mass calculated for [M + H]+
(C14H18N3OS) requires m/z 276.1170, found m/z 276.1166; [a]D =
+23.8 (c = 0.5, CH2Cl2).
42.9 (CHPh), 33.4 (CH2), 28.8 (CH2), 25.2 (CH2); HPLC analysis:
Diacel Chiralpak AD-H, hexane/i-PrOH 95 : 5, flow rate 1 mL
min-1, retention time: 13.21 (minor) and 16.78 (major).
(S)-2-[(S)-1-(Furan-2-yl)-2-nitroethyl]cyclohexanone19. 90%
yield; 1H NMR (600 MHz, CDCl3) d 7.35 (1H, s, ArH), 6.31–6.29
(1H, m, ArH), 6.20–6.17 (1H, m, ArH), 4.80 (1H, dd, J = 12.5 and
4.8 Hz, CHHNO2), 4.68 (1H, dd, J = 12.5 and 9.4 Hz, CHHNO2),
3.98 (1H, td, J = 9.4 and 4.8 Hz, CHPh), 2.80–2.72 (1H, m,
CHCO), 2.51–2.32 (2H, m, CHH), 2.16–2.07 (1H, m, CHH), 1.88–
1.61 (4H, m, 4 ¥ CHH), 1.34–1.21 (1H, m, CHH); 13C NMR
(125 MHz, CDCl3) d 210.9 (C O), 151.1 (Ar), 142.3 (Ar), 110.4
(Ar), 109.0 (Ar), 75.2 (CH2NO2), 51.2 (CHCO), 42.5 (COCH2),
37.6 (CHAr), 32.5 (CH2), 28.2 (CH2), 25.1 (CH2); HPLC analysis:
Diacel Chiralpak AD-H, hexane/i-PrOH 95 : 5, flow rate 0.5 mL
min-1, retention time: 36.55 (minor) and 29.41 (major).
General procedure for the ring-closure step under basic conditions
Boc-protected thiourea 9 (0.14 g, 0.33 mmol) was dissolved in
methanol (7 mL) in a pressure vessel. Aqueous ammonia (2
drops, 25% NH3) was added. The reaction mixture was heated
at 65 ◦C and left stirring at that temperature for 1 h. It was then
cooled to room temperature and the solvents were evaporated
under vacuo. The crude product was purified using flash column
chromatography eluting with petroleum ether (40–60 ◦C) : EtOAc
80 : 20 to afford the desired product.
(S)-2-[(R)-1-(4-Fluorophenyl)-2-nitroethyl]cyclohexanone20.
1
92% yield; H NMR (600 MHz, CDCl3) d 7.18–7.15 (2H, m,
ArH), 7.02 (2H, t, J = 8.6 Hz, ArH), 4.95 (1H, dd, J = 12.5
and 4.5 Hz, CHHNO2), 4.61 (1H, dd, J = 12.5 and 10.1 Hz,
CHHNO2), 3.78 (1H, td, J = 10.1 and 4.5 Hz, CHPh), 2.70–2.63
(1H, m, CHCO), 2.51–2.45 (1H, m, CHH), 2.44–2.34 (1H, m,
CHH), 2.14–2.06 (1H, m, CHH), 1.84–1.52 (4H, m, 4 ¥ CHH),
1.29–1.17 (1H, m, CHH); 13C NMR (125 MHz, CDCl3) d 211.7
(C O), 162.1 (d, J = 240 Hz, Ar), 133.4 (Ar), 129.8 (d, J = 10 Hz,
Ar), 115.8 (d, J = 20 Hz, Ar), 78.8 (CH2NO2), 52.4 (CHCO),
43.2 (COCH2), 42.7 (CHPh), 33.2 (CH2), 28.4 (CH2), 25.0 (CH2);
HPLC analysis: Diacel Chiralpak AD-H, hexane/i-PrOH 75 : 25,
flow rate 0.7 mL min-1, retention time: 10.44 (minor) and 13.03
(major).
(S)-tert-Butyl
2-{[(S)-6-oxo-4-phenyl-2-thioxotetrahydro-
pyrimidin-1(2H)-yl]methyl}pyrrolidine-1-carboxylate (17). Light
yellow solid, mp 94–97 ◦C, 88% yield; 1H NMR (200 MHz,
CDCl3) d 8.02 (0.5H, br s, NH), 7.79 (0.5H, br s, NH), 7.52–7.23
(5H, m, ArH), 4.50–4.21 (2H, m, 2 ¥ NCH), 4.16–3.83 (1H,
m, NCHH), 3.80–3.49 (1H, m, NCHH), 3.47–3.15 (3H, m, 2 ¥
NCHH and COCHH), 3.14–2.89 (1H, m, COCHH), 2.09–1.58
(4H, m, 4 ¥ CHH), 1.41 [9H, s, C(CH3)3]; 13C NMR (50 MHz,
CDCl3) d 183.9 (184.0) (C S), 173.7 (173.6) (C O), 154.9
(154.5) (OCONH), 135.2 (135.9) (Ar), 129.1 (129.3) (Ar), 129.0
(128.9) (Ar), 127.4 (127.5) (Ar), 79.0 (79.8) [C(CH3)3], 60.2
(60.5) (NCH), 53.6 (53.7) (NCH), 46.0 (44.5) (NCH2), 44.0
(42.4) (NCH2), 37.0 (36.9) (COCH2), 28.5 (28.4) [C(CH3)3], 28.1
(28.0) (CH2), 23.3 (22.4) (CH2); IR (film) 2973, 2929, 1742, 1690,
1501, 1401, 1248 cm-1; MS (ESI) 390 (M + H+, 100%); HRMS
exact mass calculated for [M + H]+ (C20H28N3O3S) requires m/z
390.1851, found m/z 390.1846; [a]D = +10.5 (c = 1.0, CHCl3).
(S)-2-[(R)- 2-Nitro 1-(4-nitrophenyl)ethyl]cyclohexanone21.
1
100% yield; H NMR (600 MHz, CDCl3) d 8.20 (2H, d, J =
8.7 Hz, ArH), 7.41 (2H, d, J = 8.7 Hz, ArH), 5.00 (1H, dd, J =
13.0 and 4.4 Hz, CHHNO2), 4.71 (1H, dd, J = 13.0 and 10.0 Hz,
CHHNO2), 3.94 (1H, td, J = 10.0 and 4.4 Hz, CHPh), 2.78–2.69
(1H, m, CHCO), 2.52–2.45 (1H, m, CHH), 2.44–2.35 (1H, m,
CHH), 2.16–2.08 (1H, m, CHH), 1.85–1.79 (1H, m, CHH),
1.73–1.57 (3H, m, 3 ¥ CHH), 1.32–1.22 (1H, m, CHH); 13C NMR
(125 MHz, CDCl3) d 210.8 (C O), 147.5 (Ar), 145.5 (Ar), 129.3
(Ar), 124.1 (Ar), 78.0 (CH2NO2), 52.2 (CHCO), 43.7 (COCH2),
42.7 (CHPh), 33.2 (CH2), 28.3 (CH2), 25.1 (CH2); HPLC analysis:
Diacel Chiralpak AD-H, hexane/i-PrOH 80 : 20, flow rate 0.5 mL
min-1, retention time: 48.57 (minor) and 76.52 (major).
General procedure for the Michael reaction of cyclohexanones with
nitrostyrenes
To a stirring solution of catalyst 12 (0.005 mmol) in THF (1 mL),
4-nitrobenzoic acid (5 mg, 0.03 mmol) and H2O (8 mL, 0.40 mmol)
were added. Nitroolefin (0.20 mmol) was added followed by
cyclohexanone (2.00 mmol). The reaction mixture was left stirring
for 18 h to 60 h. The solvent was evaporated and the crude
product was purified using flash column chromatography eluting
(S)-2-[(R)-1-(4-Methoxyphenyl)-2-nitroethyl]cyclohexanone17c
.
96% yield; 1H NMR (600 MHz, CDCl3) d 7.09 (2H, d, J = 8.6 Hz,
ArH), 6.86 (2H, d, J = 8.6 Hz, ArH), 4.92 (1H, dd, J = 12.3
and 4.6 Hz, CHHNO2), 4.60 (1H, dd, J = 12.3 and 10.0 Hz,
CHHNO2), 3.79 (3H, s, OCH3), 3.73 (1H, td, J = 10.0 and 4.6 Hz,
CHPh), 2.66 (1H, td, J = 10.0 and 4.8 Hz, CHCO), 2.52–2.45
(1H, m, CHH), 2.40 (1H, ddd, J = 12.8, 12.5 and 5.7 Hz, CHH),
2.13–2.04 (1H, m, CHH), 1.82–1.52 (4H, m, 4 ¥ CHH), 1.30–1.18
(1H, m, CHH); 13C NMR (125 MHz, CDCl3) d 212.0 (C O),
158.9 (Ar), 129.5 (Ar), 129.1 (Ar), 114.2 (Ar), 79.0 (CH2NO2),
55.1 (OCH3), 52.6 (CHCO), 43.1 (COCH2), 42.6 (CHPh), 33.1
(CH2), 28.5 (CH2), 24.9 (CH2); HPLC analysis: Diacel Chiralpak
AD-H, hexane/i-PrOH 95 : 5, flow rate 1.0 mL min-1, retention
time: 22.66 (minor) and 27.77 (major).
◦
with various mixtures of petroleum ether (40–60 C) : EtOAc to
afford the desired product.
(S) - 2 - [(R) - 3 - Nitro - 1 - phenylethyl] cyclohexanone13d
.
100%
yield; 1H NMR (600 MHz, CDCl3) d 7.38–7.05 (5H, m, ArH), 4.93
(1H, dd, J = 12.5 and 4.5 Hz, CHHNO2), 4.59 (1H, dd, J = 12.5
and 9.9 Hz, CHHNO2), 3.86–3.68 (1H, m, CHPh), 2.75–2.64 (1H,
m, CHCO), 2.50–2.35 (2H, m, CHH), 2.16–2.05 (1H, m, CHH),
1.81–1.52 (4H, m, 4 ¥ CHH), 1.32–1.16 (1H, m, CHH); 13C NMR
(125 MHz, CDCl3) d 212.2 (C O), 138.0 (Ar), 129.1 (Ar), 128.4
(Ar), 127.9 (Ar), 79.1 (CH2NO2), 52.7 (CHCO), 44.2 (COCH2),
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(S)-2-[(R)-1-(Naphthaen-2-yl)-2-nitroethyl]cyclohexanone17c
.
m, ArH), 7.19–7.17 (2H, m, ArH), 4.96 (1H, dd, J = 12.5 and
4.7 Hz, CHHNO2), 4.63 (1H, dd, J = 12.5 and 9.8 Hz, CHHNO2),
4.01–3.82 (5H, m, CHPh and 4 ¥ OCHH), 3.08 (1H, ddd, J =
13.0, 10.1 and 5.5 Hz, CHCO), 2.76–2.68 (1H, m, CHH), 2.48
(1H, dd, J = 13.8, 5.1 and 3.5 Hz, CHH), 2.06 (1H, ddt, J = 13.0,
6.6 and 3.5 Hz, CHH), 1.97 (1H, td, J = 13.0 and 5.1 Hz, CHH),
1.70 (1H, ddd, J = 13.0, 5.5 and 3.5 Hz, CHH), 1.57 (1H, t, J =
13.4 Hz, CHH); 13C NMR (125 MHz, CDCl3) d 201.3 (C O),
137.2 (Ar), 128.9 (Ar), 128.2 (Ar), 127.8 (Ar), 107.0 [C(OCH2)2],
78.9 (CH2NO2), 64.7 (OCH2), 64.5 (OCH2), 48.1 (CHCO), 43.4
(CHPh), 39.2 (CH2), 38.5 (CH2), 35.0 (CH2); HPLC analysis:
Diacel Chiralpak AD-H, hexane/i-PrOH 80 : 20, flow rate 1 mL
min-1, retention time: 9.03 (minor) and 14.37 (major).
1
88% yield; H NMR (600 MHz, CDCl3) d 7.86–7.81 (3H, m,
ArH), 7.66 (1H, s, ArH), 7.53–7.48 (2H, m, ArH), 7.28 (1H, dd,
J = 8.5 and 1.6 Hz, ArH), 5.05 (1H, dd, J = 12.5 and 4.5 Hz,
CHHNO2), 4.76 (1H, dd, J = 12.5 and 10.1 Hz, CHHNO2), 3.98
(1H, td, J = 10.1 and 4.5 Hz, CHPh), 2.84–2.76 (1H, m, CHCO),
2.55–2.48 (1H, m, CHH), 2.42 (1H, td, J = 13.0 and 6.1 Hz,
CHH), 2.14–2.04 (1H, m, CHH), 1.78–1.52 (4H, m, 4 ¥ CHH),
1.34–1.23 (1H, m, CHH); 13C NMR (125 MHz, CDCl3) d 211.8
(C O), 135.1 (Ar), 133.3 (Ar), 132.8 (Ar), 128.8 (Ar), 127.7 (Ar),
127.6 (Ar), 126.4 (Ar), 126.1 (Ar), 125.2 (Ar), 78.8 (CH2NO2),
52.4 (CHCO), 44.0 (CH2CO), 42.7 (CHPh), 33.2 (CH2), 28.4
(CH2), 24.9 (CH2); HPLC analysis: Diacel Chiralpak AD-H,
hexane/i-PrOH 95 : 5, flow rate 1.0 mL min-1, retention time:
23.98 (minor) and 27.77 (major).
(R)-1-Acetyl-3-[(R)-2-nitro-1-phenylethyl]piperidin-4-one.
92% yield; light yellow oil; IR (film) 3012, 2924, 1714, 1648,
1552, 1431 cm-1; 1H NMR (200 MHz, CDCl3) d 7.44–7.19
(5H, m, ArH), 5.06–4.87 (1H, m, CHHNO2), 4.72–4.55 (1H, m,
CHHNO2), 4.33–4.24 (0.4H, m, NCHH), 4.03–3.72 (1.6H, m,
NCHH and CHPh), 3.58–3.40 (1H, m, NCHH), 3.28–3.10 (1H,
m, NCHH), 3.04–2.68 (2H, m, NCHH and CHCO), 2.67–2.43
(2H, m, CHHCO), 2.16 (2H, s, CH3), 1.82 (1H, s, CH3); 13C
NMR (50 MHz, CDCl3) d 207.5 (207.5) (C O), 169.2 (169.5)
(NCO), 136.4 (136.1) (Ar), 129.5 (129.2) (Ar), 128.7 (128.3) (Ar),
127.7 (128.1) (Ar), 78.6 (CH2NO2), 52.2 (51.4) (COCH), 49.5
(NCH2), 44.9 (45.7) (NCH2), 41.8 (41.7) (COCH2), 41.2 (41.6)
(CHPh), 20.8 (21.3) (CH3); MS (ESI) 291 (M + H+, 100%); [a]D =
+20.9 (c = 1, CH2Cl2); HPLC analysis: Diacel Chiralpak AD-H,
hexane/i-PrOH 95 : 5, flow rate 1.0 mL min-1, retention time:
75.37 (minor) and 81.15 (major).
(R)-3-[(R)-2-Nitro-1-phenylethyl]dihydro-2H-pyran-4-one22.
1
98% yield; H NMR (600 MHz, CDCl3) d 7.35–7.17 (5H, m,
ArH), 4.93 (1H, dd, J = 12.4 and 4.0 Hz, CHHNO2), 4.63 (1H,
dd, J = 12.4 and 10.0 Hz, CHHNO2), 4.11–4.02 (1H, m, CHPh),
3.87–3.66 (3H, m, 3 ¥ OCHH), 3.26 (1H, dd, J = 11.4 and 9.4 Hz,
OCHH), 2.95–2.79 (1H, m, CHCO), 2.73–2.52 (2H, m, CHH);
13C NMR (125 MHz, CDCl3) d 207.3 (C O), 136.2 (Ar), 129.1
(Ar), 128.3 (Ar), 127.8 (Ar), 78.6 (CH2NO2), 71.5 (OCH2), 68.9
(OCH2), 53.2 (CHCO), 42.9 (COCH2), 41.2 (CHPh); HPLC
analysis: Diacel Chiralpak AD-H, hexane/i-PrOH 85 : 15, flow
rate 1 mL min-1, retention time: 13.82 (minor) and 25.75 (major).
(S)-3-[(R)-2-Nitro-1-phenylethyl]dihydro-2H -thiopyran-4-
one17d
.
99% yield; 1H NMR (600 MHz, CDCl3) d 7.37–7.17 (5H,
m, ArH), 4.75 (1H, dd, J = 12.4 and 4.4 Hz, CHHNO2), 4.62 (1H,
dd, J = 12.4 and 9.6 Hz, CHHNO2), 3.86 (1H, dt, J = 10.4 and
4.4 Hz, CHPh), 3.07–2.92 (3H, m, 3 ¥ SCHH), 2.88–2.75 (2H, m,
SCHH and CHCO), 2.63–2.56 (1H, m, CHH), 2.48–2.41 (1H, m,
CHH); 13C NMR (125 MHz, CDCl3) d 209.5 (C O), 136.5 (Ar),
129.3 (Ar), 128.3 (Ar), 128.1 (Ar), 78.6 (CH2NO2), 54.9 (CHCO),
44.5 (COCH2), 42.9 (CHPh), 35.1 (SCH2), 31.6 (SCH2); HPLC
analysis: Diacel Chiralpak AD-H, hexane/i-PrOH 85 : 15, flow
rate 1 mL min-1, retention time: 12.34 (minor) and 31.06 (major).
(R)-5-Nitro-4-phenylpentan-2-one (18)13f
.
95% yield; 1H NMR
(200 MHz, CDCl3) d 7.38–7.26 (3H, m, ArH), 7.19–7.14 (2H, m,
ArH), 4.69 (1H, dd, J = 12.3 and 7.0 Hz, CHHNO2), 4.59 (1H,
dd, J = 12.3 and 7.6 Hz, CHHNO2), 4.07–3.92 (1H, m, CHPh),
2.91 (2H, d, J = 7.0 Hz, CH2CO), 2.11 (3H, s, CH3); 13C NMR
(50 MHz, CDCl3) d 205.4 (C O), 138.8 (Ar), 129.0 (Ar), 127.8
(Ar), 127.3 (Ar), 79.4 (CH2NO2), 46.1 (CHPh), 39.0 (CH2), 30.3
(CH3); HPLC analysis: Diacel Chiralpak AD-H, hexane/i-PrOH
94 : 6, flow rate 1 mL min-1, retention time: 12.54 (minor) and
13.58 (major).
(S)-4,4-Dimethyl-2-[(R)-2-nitro-1-phenylethyl]cyclohexanone.
98% yield; white solid; mp 79–81 ◦C; IR (film) 2957, 1706, 1551,
1431, 1137 cm-1; 1H NMR (600 MHz, CDCl3) d 7.25 (2H, t, J =
7.3 Hz, ArH), 7.19 (1H, t, J = 7.3 Hz, ArH), 7.07 (2H, d, J =
7.3 Hz, ArH), 4.92 (1H, dd, J = 12.4 and 4.6 Hz, CHHNO2),
4.57 (1H, dd, J = 12.4 and 9.7 Hz, CHHNO2), 3.63 (1H, td, J =
9.7 and 4.6 Hz, CHPh), 2.82–2.78 (1H, m, CHCO), 2.48 (1H,
td, J = 13.8 and 6.2 Hz, CHHCO), 2.24 (1H, ddd, J = 13.8, 4.5
and 3.1 Hz, CHHCO), 1.68 (1H, dtd, J = 9.2, 6.2 and 3.1 Hz,
CHH), 1.56 (1H, td, J = 13.8 and 4.5 Hz, CHH), 1.32–1.29 (1H,
m, CHH), 1.15 (1H, t, J = 13.8 Hz, CHH), 1.06 (3H, s, CH3), 0.81
(3H, s, CH3); 13C NMR (125 MHz, CDCl3) d 212.5 (C O), 137.8
(Ar), 128.9 (Ar), 128.1 (Ar), 127.7 (Ar), 79.0 (CH2NO2), 47.7
(CHCO), 45.8 (COCH2), 43.9 (CHPh), 40.6 (CH2), 39.1 (CH2),
31.0 [C(CH3)2], 24.3 (CH3); MS (ESI) 276 (M + H+, 100%); [a]D =
-105.8 (c = 1, CH2Cl2); HPLC analysis: Diacel Chiralpak AD-H,
hexane/i-PrOH 95 : 5, flow rate 0.5 mL min-1, retention time:
17.81 (minor) and 21.99 (major).
(3R,4R)-3-Methyl-5-nitro-4-phenyl-pentan-2-one (19)24. 15%
yield; 1H NMR and 13C NMR were consistent with those
reported in the literature;24 HPLC analysis: Diacel Chiralpak AS-
H, hexane/i-PrOH 90 : 10, flow rate 1 mL min-1, retention time:
13.84 (major) and 15.98 (minor).
(S)-2,2-Dimethyl-4-nitro-3-phenylbutanal (20)25. 17% yield; 1H
NMR and 13C NMR were consistent with those reported in the
literature;25 HPLC analysis: Diacel Chiralpak AD-H, hexane/i-
PrOH 85 : 15, flow rate 0.8 mL min-1, retention time: 15.89 (minor)
and 20.15 (major).
(2S,3R)-2-Benzyl-4-nitro-3-phenylbutanal (21)18b
. 85% yield;
1H NMR (200 MHz, CDCl3) d 9.62 (1H, br s, CHO), 7.35–
7.07 (8H, m, ArH), 7.02–6.85 (2H, m, ArH), 4.79–4.51 (2H, m,
CHHNO2), 3.75 (1H, td, J = 8.7 and 6.0 Hz, CHPh), 3.11–2.91
(1H, m, CHCO), 2.75–62 (2H, m, CH2Ph); 13C NMR (50 MHz,
CDCl3) d 203.2 (C O), 137.5 (Ar), 136.5 (Ar), 129.4 (Ar),
128.9 (Ar), 128.7 (Ar), 128.5 (Ar), 128.0 (Ar), 127.1 (Ar), 78.4
(S)-7-[(R)-2-Nitro-1-phenylethyl]-1,4-dioxaspiro[4.5]decan-8-
one23. 93% yield; 1H NMR (600 MHz, CDCl3) d 7.36–7.26 (3H,
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(CH2NO2), 55.3 (CHPh), 43.5 (CH), 34.2 (CH2); HPLC analysis:
Diacel Chiralpak AD-H, hexane/i-PrOH 97.5 : 2.5, flow rate 1 mL
min-1, retention time: 23.86 (minor) and 27.13 (major).
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Acknowledgements
This project is co-funded by the European Social Fund and
National resources (EPEAK II). The authors would like to thank
Prof. A. Giannis for HR-MS analysis.
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The Royal Society of Chemistry 2011
Org. Biomol. Chem., 2011, 9, 3386–3395 | 3395
©