Pyrrolidine-based organocatalysts for enantioselective Michael addition of cyclohexanone to trans-β-nitrostyrene

Article abstract of DOI:10.1055/s-0029-1216885

A series of readily prepared bifunctional catalysts promote the Michael addition of cyclohexanone to trans-β-nitrostyrene with excellent asymmetric induction. The enantioselection (up to 97%) and diastereoselection (up to 95:5) is comparable to other pyrr

Full text of DOI:10.1055/s-0029-1216885

PAPER
2509
Pyrrolidine-Based Organocatalysts for Enantioselective Michael Addition of
Cyclohexanone to trans-b-Nitrostyrene
Enantioselective
M
l
ichae
l
l
A
dditi
i
School of Chemistry, University of Southampton, Southampton, SO17 1BJ, UK
Fax +44(23)80594182; E-mail: jdk1@soton.ac.uk
Received 11 March 2009; revised 27 April 2009
subsequent N-deprotection furnished 6, whilst thiourea
methylation/N-deprotection steps gave 7 (Scheme 1).
Abstract: A series of readily prepared bifunctional catalysts pro-
mote the Michael addition of cyclohexanone to trans-b-nitrostyrene
with excellent asymmetric induction. The enantioselection (up to
97%) and diastereoselection (up to 95:5) is comparable to other
pyrrolidine-thiourea organocatalysts recently reported, however,
reaction times are often shorter.
OH
N
Boc
1
Key words: addition reactions, asymmetric catalysis, Michael
additions, bifunctional catalysis, nitroolefin
a, b
N
N
BocN NHBoc
Enantioselective organocatalysis of the Michael addition
of ketones to nitroalkenes1,2 has been the focus of exten-
sive recent effort, since synthetically valuable nitroalkane
products bearing contiguous stereocentres are generated.
Several chiral pyrrolidine-based catalysts have been de-
veloped and effective stereocontrol demonstrated via fa-
cial shielding of the expected enamine intermediate.3 In
particular, however, synergistic activation of both Michael
donor and acceptor sites has been achieved with many el-
egant chiral diamine4,5 and thiourea-amine6,7 bifunctional
catalyst systems. Bifunctional catalysis is believed to in-
volve proline-catalysed formation of an enamine
nucleophile8 and activation of the nitroalkene via hydro-
gen bond formation with the thiourea motif,9 and subse-
quent nitronate anion stabilisation in the same manner.
3
O
O
N
Boc
N
H
c, d
H
N
NH2
NH2
NH
⋅ 2 CF3CO2H
4
2
e
O
f
N
H
H
NPh
H
N
O
N
Boc
S
6
PhHN
NH
O
N
H
S
g
H
NPh
H
N
5
Although impressive progress towards improved stereo-
selectivity and substrate generality has been made, devel-
opment of simple bifunctional systems of ready
accessibility and improved catalytic activity remains of
interest. Herein we wish to report the activity and stereo-
control exercised by L-proline-based organocatalysts,
bearing tethered thiourea, thiouronium, or guanidinium
functionality for dual catalysis of the conjugate addition
of cyclohexanone to trans-b-nitrostyrene.
I–
Me
S+
7
Scheme 1 Reagents and conditions: (a) acrylonitrile, TBAI, aq 50%
NaOH, toluene, r.t., 99% (17); (b) NiCl2, NaBH4, MeOH, r.t., 82%
(2); (c) N,N¢-bis-Boc-1-guanylpyrazole (3), THF, r.t., 31% (18); (d)
20% v/v TFA–CH2Cl2, r.t., 97% (4); (e) PhNCS, CHCl3, MeOH, aq
NaHCO3, r.t., 82% (5); (f) 10% v/v TFA–CH2Cl2, r.t., then aq K2CO3,
r.t., 98% (6); (g) MeI, acetone, r.t. 5 h, then 10% v/v TFA–CH2Cl2,
r.t., then aq K2CO3, r.t., 88% (7).
Candidate catalysts incorporating guanidinium 4, thiourea
6, or thiouronium 7 functionality, tethered to a proline-de-
rived chiral pyrrolidine via an ether linkage, were readily
prepared. Michael addition of N-Boc-L-prolinol (1) with
acrylonitrile under phase-transfer conditions,10 followed
by nitrile reduction,11 furnished 2. Preparation of 4 was
accomplished upon treatment of 2 with N,N¢-bis-Boc-1-
guanylpyrazole derivative 3.12 Coupling of primary amine
2 with phenyl isothiocyanate13 was straightforward and
We wished to investigate the nature and length of spacer
separating the catalytic moieties and alternatively tethered
organocatalysts 10a/b, 12, and 13 were also prepared.14
Coupling of N-Boc-L-proline (8) with mono Cbz (benzyl-
oxycarbonyl) protected diamines,15 derived from 1,2-
ethanediamine or 1,3-propanediamine, gave, after reduc-
tion, secondary amines 9a and 9b, respectively. Hydro-
genolysis of 9a/b, followed by coupling of each resulting
bis-amine with 2 equivalents of PhNCS and removal of
pyrrolidine N-Boc protection, gave bis-thioureas 10a/b.
N-Boc protection of 9a, Cbz cleavage and coupling with
PhNCS proved straightforward and 11 was obtained in
good yield. Trifluoroacetic acid (TFA)-mediated N-Boc
SYNTHESIS 2009, No. 15, pp 2509–2516
x
x.
x
x
.
2
0
0
9
Advanced online publication: 07.07.2009
DOI: 10.1055/s-0029-1216885; Art ID: P03809SS
© Georg Thieme Verlag Stuttgart · New York

2510
A. P. Carley et al.
PAPER
Table 1 Enantioselective Addition of Cyclohexanone to trans-b-
Nitrostyrenea
deprotection of 11 gave a thiourea functionalised chiral
pyrrolidine 13 following basic workup. Further utility of
11 was also made; methylation to a thiouronium salt and
global N-deprotection resulted in cyclisation upon basic
workup and guanidinium 12 was isolated in excellent
yield (Scheme 2).
O
Ph
O
NO2
catalyst (15 mol%)
NO2
+
Ph
additive
toluene, r.t.
16
Entry Cata- Additiveb
lyst
Time Conver- dr
ee (%)e
(h)
720 23
AcOH–H2O 720 10
sion (%)c (syn/anti)d syn
CO2H
N
Boc
1
2
3f
4
5
6
7
8
9
15
15
4
–
91:9
91:9
92:8
94:6
94:6
94:6
94:6
94:6
95:5
94:6
91:9
92:8
89:11
91:9
90:10
92:8
94
93
71
86
78
86
80
91
90
87
87
85
91
97
85
92
8
a, b
S
NHPh
–
96
24
7
>90
>90
>90
>90
>90
H
N
d, e, f
N
N
Boc
6
–
S
N
H
n
CbzHN
n N
H
NHPh
6
AcOH–H2O
9a n = 1
9b n = 2
7
–
24
4
10a n = 1
10b n = 2
7
AcOH–H2O
–
n = 2 c, d, e
14
14
12
13
13
10a
120 >90
g
N
N+
I–
AcOH–H2O 48
AcOH–H2O 12
>90
>90
>90
>90
N
H
Boc
N
NHPh
10
N
Boc
12
11
12
13
14
15
16
–
20
7
H
N
f
PhHN
NH
N
H
AcOH–H2O
–
S
120 >90
>90
144 >90
>90
11
PhHN
NH
10a AcOH–H2O
10b
10b AcOH–H2O
9
S
–
13
4
Scheme 2 Reagents and conditions: (a) benzyl (2-aminoethyl)carb-
amate (n = 1, HCl salt) or benzyl (3-aminopropyl)carbamate (n = 2,
TFA salt), EDC, HOBt, i-Pr2NEt, DMF–THF, 0 °C to r.t., 79% (19,
n = 1), 71% (20, n = 2); (b) BH3, THF, 0 °C to r.t., 69% (9a), 60%
(9b); (c) (Boc)2O, Et3N, CH2Cl2, r.t., 69% (25); (d) Pd/C (10 mol%),
H2, MeOH, r.t., 96–ca. 100% (21, 23, 26); (e) PhNCS, CHCl3, MeOH,
aq NaHCO3, r.t., 47–73% (22, 24, 11); (f) 10% v/v TFA–CH2Cl2, r.t.,
then aq K2CO3, r.t., 88% (10a), ca. 100% (10b), 85% (13); (g) MeI,
acetone, r.t. 5 h, then 10% v/v TFA–CH2Cl2, r.t., then aq K2CO3, r.t.,
98% (12).
a The reaction was conducted with 0.5 mmol trans-b-nitrostyrene, 5.0
mmol cyclohexanone, and 15 mol% added catalyst in 0.75 mL tolu-
ene at r.t.
b Additive stoichiometry (entries 2, 5, 7, 9, 10, 12, 14, 16): 0.15 equiv
AcOH and 1 equiv H2O.
c Determined by HPLC analysis with naphthalene as internal stan-
dard. We chose to monitor the requisite reaction time for 90% conver-
sion; unless this threshold had not been reached within 30 days, in
which case the % conversion at that time is reported.
d Determined by reverse phase HPLC analysis of the diastereomeric
mixture (MeCN–H2O, 6:4).
As bis-secondary amine dual catalysis of the Michael ad-
dition between cyclic ketones and nitroalkenes has been
described,5c we also prepared (S)-benzyl(pyrrolidin-2-yl-
methyl)amine (14),16 alongside (S)-2-(benzyloxymeth-
yl)pyrrolidine (15),17 in order to assess the influence of
tethering amine/ether groups (Figure 1). Catalysis of the
asymmetric Michael reaction of cyclohexanone with
trans-b-nitrostyrene was now examined in the presence of
added acetic acid and water6c,7e (Table 1).
e Determined by chiral HPLC analysis (Daicel Chiralpak AI, hexane–
i-PrOH, 97:3).
f Carried out in the presence of 15 mol% added Et3N.
Simple pyrrolidine 15 demonstrated good diastereo- and
enantiocontrol of the Michael addition, however, conver-
sion was low (Table 1, entries 1 and 2) and is indicative of
the expected monofunctional activation of the cyclohex-
anone component only. Reaction time was improved in
the presence of guanidinium-functionalised pyrrolidine 4,
however, to the detriment of enantioselectivity in compar-
ison with 15 (entry 3). Ether tethered thiourea-pyrrolidine
catalyst 6 demonstrated better activity and excellent dia-
stereoselectivity both in the absence and presence of add-
ed acetic acid for catalysis of enamine formation,
H
N
O
Ph
Ph
N
H
N
H
15
14
Figure 1 Simple pyrrolidine organocatalysts
Synthesis 2009, No. 15, 2509–2516 © Thieme Stuttgart · New York

PAPER
Enantioselective Michael Addition
2511
although some loss of enantiocontrol was observed in the
latter case (compare entries 4 and 5). Some enhancement
of enantiocontrol was achieved with thiouronium-substi-
tuted catalyst 7, the syn/anti diastereomeric ratio remained
high and, pleasingly, significant rate enhancement was
observed with complete reaction in just four hours with
added acid (entry 7).
Table 2 Enantioselective Addition of Cyclohexanone to trans-b-
Nitrostyrenea
O
Ph
O
catalyst
NO2
AcOH–H2O
NO2
+
Ph
toluene, r.t.
16
Entry Catalyst Cyclohexanone Time Conver- dr (syn/ ee (%)d
(mol%) (equiv)
(h) sion (%)b anti)c
Simple diamine 14 promoted the Michael addition with
excellent diastereo- and enantioselectivity, comparable to
that reported by Pansare and Pandya for bis-secondary
amine catalysis with p-TsOH as additive5c (entries 8 and
9). Diamine-thiourea catalyst 13 demonstrated rate en-
hancement, but without improved stereocontrol (entries
11 and 12). Bifunctional guanidinium 12 displayed simi-
lar activity to 13 (entry 10), and improved enantiocontrol
in comparison with catalyst 4 in which guanidinium func-
tionality is incorporated more remotely from the chiral
pyrrolidine (compare entries 10 and 3). Alteration of the
nature of the tether had a substantial effect; bis-thioureas
10a and 10b each displayed only moderate activity, re-
sulting in long reaction times in toluene (entries 13 and
15) but a dramatic improvement in reaction time was ob-
served in the presence of added acid, 10a catalysing the
Michael addition in nine hours (entry 14) and 10b in only
four hours (entry 16). Additionally, catalysis by bis-thio-
urea 10a demonstrates excellent enantiocontrol (97% ee).
syn
92
84
80
87
86
81
90
90
85
85
86
84
1
2
10b (15) 10
4
>90
92:8
92:8
91:9
94:6
94:6
94:6
94:6
92:8
91:9
92:8
92:8
92:8
10b (15)
10b (5)
6 (15)
6 (15)
6 (15)
7 (15)
7 (15)
7 (15)
7 (5)
1
504 >90
720 28
3
1
4
10
5
11
24
>90
>90
5
6
1
336 >90
7
10
5
5
>90
>90
>90
>90
>90
8
8
9
1
30
24
48
10
11
12
10
5
7 (5)
7 (5)
1
120 >90
Reaction rates for catalysis by 7, 10a/b, and 13 are among
the highest reported for this thiourea-promoted Michael
addition,18 and prompted us to examine catalyst loading
and a reduction in the required amount of cyclohexanone.
Known organocatalysts for the asymmetric Michael addi-
tion typically require catalyst loading of between 10–20
mol%, and are also usually performed with 10–20 equiv-
alents of ketone. In several reported systems, reduced
loading of catalyst and Michael donor results in substan-
tial loss of yield and lower enantioselectivities.19 We
chose to use bis-thiourea 10b and ether-linked catalysts 6
and 7 (Table 2).
a The reaction was conducted with 0.5 mmol trans-b-nitrostyrene in
0.75 mL toluene at r.t. with 0.15 equiv AcOH and 1 equiv H2O.
b Determined by HPLC analysis in comparison with naphthalene inter
nal standard. We chose to monitor the requisite reaction time for 90%
conversion; unless this threshold had not been reached within 30 days
in which case the % conversion at that time is reported.
c Determined by reverse phase HPLC analysis of the diastereomeric
mixture (MeCN–H2O, 6:4).
d Determined by chiral HPLC analysis (Daicel Chiralpak AI, hexane–
i-PrOH, 97:3).
required and mixed single addition products were pro-
duced with poor diastereoselectivity.20
Reduced cyclohexanone equivalents and catalyst loading
appeared to be detrimental to both the reaction rate and the
enantioselectivity, when the reaction was catalysed by
bis-thiourea 10b (Table 2, entries 1–3). Considering thio-
urea/uronium catalysts 6 and 7, fewer equivalents of
cyclohexanone resulted generally in slower Michael addi-
tion and also some loss of enantiocontrol, nonetheless it is
pleasing that 7, in particular, remains a highly effective
catalyst; displaying high conversion, diastereo- and enan-
tioselectivity with only a single equivalent of the Michael
donor (entry 9). We were also successfully able to lower
catalyst loading of 7 to 5 mol% without significant detri-
ment to the enantiocontrol (entries 10–12).
The observed (2S,1R) absolute configuration of the major
syn Michael adduct 1621 is consistent with a synclinical
transition state for bifunctional catalysis22 in which the
hydrogen bond donor, thiourea, guanidinium or thiouroni-
um, directs the nitrostyrene to attack the re-face of the
enamine (Figure 2).
O
N
H
O–
S
N
+N
N
H
O
Ph
Use of acyclic ketones in the Michael addition with trans-
b-nitrostyrene was deleterious to catalyst performance in
all cases. The use of acetone resulted in single addition
products in an enantiomeric excess of only 5–30%, typi-
cally after 1–10 days. With butan-2-one, 5–30 days were
Ph
Figure 2 Proposed transition state for conjugate addition catalysis
by thiourea-functionalised pyrrolidine 6
Synthesis 2009, No. 15, 2509–2516 © Thieme Stuttgart · New York

2512
A. P. Carley et al.
PAPER
extracted with CH2Cl2 (3 ꢀ 200 mL). The combined organic phases
were dried (MgSO4) and concentrated in vacuo. Purification by col-
umn chromatography (SiO2 eluted with 4:1 CH2Cl2–MeOH) gave
the title compound 2 as an orange oil (167 mg, 82%); [a]D29.5 +20.5
(c 1.00, CHCl3).
In summary, we have developed a series of readily pre-
pared catalysts, which promote the Michael addition of
cyclohexanone to trans-b-nitrostyrene with excellent
asymmetric induction. Reduced catalyst loading is tolerat-
ed for thiouronium-pyrrolidine organocatalyst 7 and de-
velopment of related systems for catalysis of conjugate
addition is underway, alongside further investigation of
the mechanistic role of secondary amine and thiourea
functionality within the tethering group of catalysts 13
and 10. Combined short reaction time and high enantioin-
duction places 10a amongst the most useful of amine-
thiourea organocatalysts reported for this Michael addi-
tion.
IR (film): 3420 (w), 2970 (m), 2874 (m), 1689 (s), 1390 (m), 1167
(s), 1101 cm–1 (s).
1H NMR (400 MHz, DMSO-d6, 90 °C): d = 3.81 (m, 1 H, CHCH2),
3.52–3.42 (m, 3 H, CHCHH¢O and CH2O), 3.33 (dd, J = 9.5, 7.2
Hz, 1 H, CHCHH¢O), 3.30 (m, 1 H, NCHH¢), 3.20 (m, 1 H,
NCHH¢), 2.66 (t, J = 6.6 Hz, 2 H, CH2NH2), 2.20 (br s, 2 H, NH2),
1.90–1.81 (m, 3 H, CH2CHH¢), 1.74 (m, 1 H, CHCHH¢), 1.59 (qn,
J = 6.6 Hz, 2 H, CH2CH2CH2), 1.43 [s, 9 H, C(CH3)3].
13C NMR (75 MHz, DMSO-d6): d = 153.4 (C), 78.2 (C),
71.0 (CH2), 68.6 (CH2), 56.0 (CH), 46.1 (CH2), 38.7 (CH2), 33.4
(CH2), 28.0 (CH3), 23.1 (CH2), 22.3 (CH2).
Reagents and solvents were obtained from commercial suppliers
and if necessary dried and distilled before use. THF was freshly dis-
tilled from sodium benzophenone ketal under argon. CH2Cl2 and
Et3N were freshly distilled from CaH2. Petroleum ether (PE) used
refers to the fraction boiling in the range 40–60 °C. Reactions re-
quiring a dry atmosphere were conducted in oven dried glassware
under N2.
MS (ES+): m/z (%) = 259 (100, [M + H]+).
+
HRMS (ES+): m/z [M + H] calcd for C13H27N2O3: 259.2016;
found: 259.2021.
2-(3-{[(S)-Pyrrolidin-2-yl]methoxy}propyl)guanidininium
Trifluoroacetate (4)
1H and 13C NMR spectra were recorded on Bruker 300 or 400 MHz
spectrometers. 1H chemical shifts are reported as values in parts per
million, referenced to residual solvent. The following abbreviations
are used to denote multiplicity and may be compounded: s = singlet,
br s = broad singlet, d = doublet, t = triplet, q = quartet,
qn = quintuplet, sext = sextet. Coupling constants, J, are measured
in hertz (Hz). 13C NMR spectra were proton decoupled and refer-
enced to solvent. The number of adjacent protons was determined
by DEPT experiments. IR spectra were recorded either as neat sol-
ids or as oils on a Thermo Nicolet 380 FT IR spectrometer fitted
with an ATR accessory. Absorptions are given in wavenumbers
(cm–1) and the following abbreviations used to denote peak intensi-
ties: s = strong, m = medium, w = weak and/or br (broad). Low-res-
olution mass spectra were recorded on a Micromass platform single
quadrupole mass spectrometer in MeOH or MeCN. Accurate mass
spectra were recorded on a double focusing mass spectrometer.
Melting points were determined in open capillary tubes using a Gal-
lenkamp Electrothermal melting point apparatus and are uncorrect-
ed. HPLC chromatograms were recorded on a LaChrom D 7000
instrument using a Phenomenex 150 mm ꢀ 4.6 mm reverse phase
column (flow rate 1 mL min–1). Chiral HPLC was performed with a
Chiralpak AI 250 mm ꢀ 4.6 mm column (flow rate 0.5 mL min–1).
Microanalysis was performed by MEDAC Ltd., Surrey, UK.
To a solution of amine 2 (200 mg, 0.774 mmol) in THF (1 mL) was
added pyrazole 312 (240 mg, 0.774 mmol) and the mixture stirred at
r.t. for 8 h before concentration in vacuo. Purification by column
chromatography (SiO2 eluted with 97:3 CH2Cl2–MeOH) gave (S)-
2-(tert-butoxycarbonylimino-3-guanidinopropoxymethyl)pyrroli-
dine-1-carboxylic acid tert-butyl ester (18) as a colourless oil (120
mg, 31%). tert-Butyl ester 18 (48 mg, 0.0959 mmol) was treated
with TFA (5 mL of a 20% v/v solution in CH2Cl2) and stirred at r.t.
for 4 h before concentration in vacuo. Excess TFA was removed as
the toluene azeotrope in vacuo. The title compound 4 was isolated
as a cloudy white oil without further purification (40 mg, 97%);
[a]D31 +7.2 (c 0.90, CHCl3).
IR (film): 3374 (w), 3202 (w), 2964 (w), 1642 (s), 1589 (s), 1477
(m), 1397 (m), 1241 (s), 1142 cm–1 (s).
1H NMR (400 MHz, CD3OD): d = 7.78 (br s, 1 H, NH), 6.45 (br s,
1 H, NH), 3.79 (ddd, J = 15.8, 7.9, 3.6 Hz, 1 H, CHCH2), 3.67 (dd,
J = 10.6, 3.6 Hz, 1 H, CHCHH¢O), 3.54–3.44 (m, 3 H, CHH¢OCH2),
3.22–3.19 (m, 4 H, 2 NCH2), 2.09 (ddd, J = 15.8, 7.8, 4.8 Hz, 1 H,
CHCHH¢CH2), 2.00–1.89 (m, 2 H, CH2CH2CH2), 1.77 (qn, J = 6.7
Hz, 2 H, CH2CH2CH2), 1.68 (ddd, J = 16.3, 12.4, 7.9 Hz, 1 H,
CHCHH¢CH2).
13C NMR (100 MHz, CD3OD): d = 158.8 (C), 70.6 (CH2), 69.3
(CH2), 60.8 (CH), 46.7 (CH2), 39.4 (CH2), 29.8 (CH2), 27.4 (CH2),
24.8 (CH2).
(S)-2-(3-Aminopropoxymethyl)pyrrolidine-1-carboxylic Acid
tert-Butyl Ester (2)
MS (ES+): m/z (%) = 239 (100, [M + K]+).
N-Boc-L-Prolinol (1; 2.00 g, 9.94 mmol) was taken into a biphasic
mixture of toluene (4 mL) and aq NaOH (40 mL of a 40% w/v aque-
ous solution). TBAI (260 mg, 0.703 mmol) and acrylonitrile (3.2
mL, 50.0 mmol) were added and the mixture stirred vigorously for
20 h. The phases were separated and the aqueous phase extracted
with EtOAc (4 ꢀ 500 mL). The combined organic phases were dried
(MgSO4) and concentrated in vacuo. Purification by column chro-
matography (SiO2 eluted with 4:1 PE–EtOAc) gave (S)-2-(2-cyano-
ethoxymethyl)pyrrolidine-1-carboxylic acid tert-butyl ester (17) as
a pale yellow oil (2.50 g, 99%). To a solution of 17 (200 mg, 0.786
mmol) in MeOH (6 mL) was added NiCl2 (204 mg, 1.57 mmol) fol-
lowed by H2O (1 mL), the solution turned from colourless to pale
green. NaBH4 (179 mg, 4.70 mmol) was added portionwise, upon
which the solution became black and effervescent. The mixture was
stirred at room temperature for 3 h, MeOH (10 mL) was added and
the mixture filtered through Celite and washed with MeOH (20
mL). H2O (50 mL) was added to the pale green filtrate and this was
(S)-2-[3-(3-Phenylthioureido)propoxymethyl]pyrrolidine-1-
carboxylic Acid tert-Butyl Ester (5)
Amine 2 (800 mg, 3.10 mmol) and PHNCS (370 mL, 3.10 mmol)
were taken into a biphasic mixture of CHCl3 (95 mL), MeOH (30
mL) and aq sat. NaHCO3 (30 mL). The reaction mixture was stirred
vigorously at r.t. for 18 h before separation of the organic phase and
washing with H2O (2 ꢀ 100 mL). The aqueous phase was extracted
with CH2Cl2 (3 ꢀ 100 mL), the combined organic phases were dried
(MgSO4), and concentrated in vacuo. Purification by column chro-
matography (SiO2 eluted with 95:5 CH2Cl2–MeOH) gave the title
compound 5 as a white foam (1.00 g, 82%); [a]D30.5 +15.5 (c 1.00,
CHCl3).
IR (neat): 3312 (w), 2975 (w), 1675 (m), 1398 (m), 1168 (m), 1108
(m), 726 cm–1 (s).
Synthesis 2009, No. 15, 2509–2516 © Thieme Stuttgart · New York

PAPER
Enantioselective Michael Addition
2513
1H NMR (400 MHz, DMSO-d6, 90 °C): d = 9.14 (br s, 1 H, NH),
7.44 (dd, J = 8.3, 1.1 Hz, 2 H, 2CCHCH), 7.31 (tt, J = 7.3, 1.9 Hz,
2 H, 2CHCHCH), 7.10 (tt, J = 7.3, 1.1 Hz, 1 H, CHCHCH), 3.81
(m, 1 H, CHCH2), 3.56 (q, J = 6.8 Hz, 2 H, CH2NH), 3.59–3.49 (m,
3 H, CHCHH¢O and CH2O), 3.33 (dd, J = 9.6, 7.2 Hz, 1 H,
1H NMR (300 MHz, CDCl3): d = 7.27 (t, J = 7.3 Hz, 2 H, 2
CHCHCH), 7.02 (tt, J = 7.4, 1.2 Hz, 1 H, CHCHCH), 6.90 (dd,
J = 8.3, 1.2 Hz, 2 H, 2CCHCH), 3.81 (ddd, J = 15.1, 7.6, 3.8 Hz, 1
H, CHCH2), 3.68 (dd, J = 10.2, 3.8 Hz, 1 H, CHCHH¢O), 3.63–3.55
(m, 3 H, CH2O and CHCHH¢O), 3.49 (dt, J = 6.4, 4.1 Hz, 2 H,
NHCH2), 3.23 (t, J = 7.2 Hz, 2 H, NHCH2), 2.28 (s, 3 H, CH3),
2.12–1.84 (m, 5 H, CHH¢CH2 and CH2CH2CH2), 1.75 (m, 1 H,
CHCHH¢).
CHCHH¢O), 3.29 (m,
1 H, NCHH¢CH2), 3.22 (m, 1 H,
NCHH¢CH2), 1.91–1.78 (m, 5 H, CHCHH¢ and 2 CH2CH2CH2),
1.75 (m, 1 H, CHCHH¢), 1.42 [s, 9 H, C(CH3)3].
13C NMR (75 MHz, DMSO-d6): d = 180.4 (C), 153.5 (C), 139.2
(C), 128.6 (CH), 124.0 (CH), 123.1 (CH), 78.3 (C), 71.1 (CH2),
68.5 (CH2), 55.9 (CH), 46.2 (CH2), 41.5 (CH2), 28.7 (CH2), 28.1
(CH3), 23.2 (CH2), 22.3 (CH2).
13C NMR (75 MHz, CDCl3): d = 162.6 (C), 149.1 (C), 129.1 (CH),
123.2 (CH), 122.8 (CH), 69.7 (CH2), 69.1 (CH2), 59.1 (CH),
45.7 (CH2), 40.6 (CH2), 29.4 (CH2), 27.0 (CH2), 24.2 (CH2), 14.2
(CH3).
MS (ES+): m/z (%) = 416 (100, [M + Na]+).
MS (ES+): m/z (%) = 308 (100, [M]+).
HRMS (ES+): m/z [M]+ calcd for C16H26N3OS: 308.1791; found:
308.1789.
+
HRMS (ES+): m/z [M + Na] calcd for C20H31N3O3S + Na:
416.1978; found: 416.1969.
Anal. Calcd for C16H26IN3OS: C, 44.14; H, 6.02; N, 9.65; S, 7.36.
Found: C, 44.60; H, 6.31; N, 9.30; S, 7.18.
1-Phenyl-3-{3-[(S)-1-pyrrolidin-2-ylmethoxy]propyl}thiourea
(6)
Thiourea 5 (412 mg, 1.05 mmol) was treated with TFA (10 mL of a
20% v/v solution in CH2Cl2) and the mixture stirred at r.t. for 2 h
before concentration in vacuo. The resulting ammonium salt was
taken into CH2Cl2 (15 mL), treated with aq sat. K2CO3 (1 mL) and
stirred vigorously at r.t. for 30 min. The phases were separated and
the aqueous phase extracted with CH2Cl2 (3 ꢀ 50 mL). The com-
bined organic phases were dried (MgSO4) and concentrated in vac-
uo to give the title compound 6 as a colourless oil (302 mg, 98%);
[a]D21 +6.2 (c 1.00, CHCl3).
(S)-2-[(2-Benzyloxycarbonylaminoethylamino)methyl]pyrroli-
dine-1-carboxylic Acid tert-Butyl Ester (9a)
A solution of N-Boc-L-proline (8; 4.85 g, 22.5 mmol) in DMF–THF
(220 mL of a 1:1 v/v solution) was cooled to 0 °C before the addi-
tion of 2-benzyloxycarbonylaminoethylammonium chloride15 (4.81
g, 24.8 mmol), HOBt (4.57 g, 33.8 mmol), EDC (4.76 g, 24.8 mmol)
and i-Pr2NEt (19.6 mL, 113 mmol). The reaction mixture was
warmed to r.t. and stirred for 17 h before concentration in vacuo.
The resulting oil was taken into CH2Cl2 (200 mL) and washed with
aq 1 M KHSO4 (3 ꢀ 150 mL), aq sat. NaHCO3 (2 ꢀ 150 mL) and
brine (150 mL). The organic phase was separated and dried
(MgSO4) before concentration in vacuo. Crystallisation (EtOAc–
hexane) gave (S)-2-(3-benzyloxycarbonylaminoethylcarbam-
oyl)pyrrolidine-1-carboxylic acid tert-butyl ester (19), as an off-
white crystalline solid (6.92 g, 79%). A solution of amide 19 (7.29
g, 18.6 mmol) in THF (22 mL) was cooled to –5 °C and BH3·THF
complex (37.2 mL of a 1 M solution, 37.2 mmol) was added drop-
wise over 10 min. The mixture was stirred between –5 and 0 °C for
2 h, then warmed to r.t., and stirred for 7 days. The mixture was then
cooled to –5 °C and cold H2O (40 mL) added dropwise over 30 min.
The mixture was extracted with EtOAc (3 ꢀ 250 mL) and the com-
bined EtOAc layers were washed with brine (100 mL), aq sat.
NaHCO3 (100 mL), and H2O (2 ꢀ 100 mL) before drying (MgSO4)
and concentration in vacuo. Purification by column chromatogra-
phy (SiO2 eluted with 4:1 CH2Cl2–MeOH) gave the title compound
9a as a colourless oil (4.87 g, 69%); [a]D31 –24.9 (c 1.00, CHCl3).
IR (film): 2974 (w), 2875 (w), 1684 (s), 1392 (s), 1102 (s), 732
cm–1 (s).
1H NMR (300 MHz, CDCl3): d = 7.38–7.28 (m, 5 H, 4 CH and NH),
7.18 (tt, J = 6.7, 1.9 Hz, 1 H, CHCHCH), 3.80–3.65 (m, 2 H,
CH2O), 3.54 (q, J = 5.6 Hz, 2 H, NHCH2), 3.38 (dd, J = 9.5, 3.9 Hz,
1 H, CHCHH¢O), 3.25 (dd, J = 9.5, 7.9 Hz, 1 H, CHCHH¢O), 3.15
(m, 1 H, CHCH2), 2.96–2.80 (m, 2 H, NHCH2), 1.86 (qn, J = 5.7
Hz, 2 H, CH2CH2CH2), 1.78–1.60 (m, 3 H, CHHH¢CH2), 1.30 (m, 1
H, CHCHH¢).
13C NMR (75 MHz, CDCl3): d = 180.9 (C), 137.8 (C), 129.5 (CH),
126.1 (CH), 124.8 (CH), 73.5 (CH2), 70.2 (CH2), 58.1 (CH),
46.3 (CH2), 44.1 (CH2), 28.4 (CH2), 27.7 (CH2), 25.2 (CH2).
MS (ES+): m/z (%) = 294 (100, [M + H] +).
HRMS (ES+): m/z [M]+ calcd for C15H24N3OS: 294.1635; found:
294.1640.
Anal. Calcd for C15H23N3OS: C, 61.40; H, 7.90; N, 14.31; S, 10.93.
Found: C, 61.21; H, 7.23; N, 14.53; S, 10.50.
IR (film): 3326 (w), 2973 (w), 2880 (w), 1675 (s), 1533 (m), 1392
(s), 1247 cm–1 (m).
1H NMR (400 MHz, DMSO-d6, 80 °C): d = 7.37–7.34 (m, 4 H, 4
CH), 7.28 (m, 1 H, CHCHCH), 6.71 (br s, 1 H, NH), 5.03 (s, 2 H,
CH2Ph), 3.71 (ddd, J = 10.8, 7.0, 3.6 Hz, 1 H, CHCH2), 3.26 (m, 1
H, NCHH¢), 3.17 (m, 1 H, NCHH¢), 3.15–3.09 (m, 3 H, NHCH2),
2.70 (dd, J = 11.8, 4.1 Hz, 1 H, CHCHH¢), 2.64 (dt, J = 6.6, 1.3 Hz,
2 H, NHCH2), 2.50 (dd, J = 11.9, 7.9 Hz, 1 H, CHCHH¢), 1.87–1.67
(m, 4 H, 2 CH2), 1.40 [s, 9 H, C(CH3)3].
Methyl(1-phenylamino-1-{3-[(S)-1-pyrrolidin-2-yl-
methoxy]propylamino}methylidene)sulfonium Iodide (7)
To a solution of thiourea 5 (682 mg, 1.73 mmol) in acetone (10 mL)
was added MeI (1.08 mL, 17.3 mmol) and the reaction mixture
stirred at r.t. for 5 h before concentration in vacuo to give a thiouro-
nium iodide as a yellow foam (926 mg, ca. 100%). A solution of this
thiouronium iodide (439 mg, 0.82 mmol) was treated with TFA (10
mL of a 20% v/v solution in CH2Cl2) and stirred at r.t. for 3 h before
concentration in vacuo. The resulting ammonium salt was taken
into CH2Cl2 (10 mL), treated with aq sat. K2CO3 (1 mL), and stirred
vigorously at r.t. for 30 min. The phases were separated and the
aqueous phase extracted with CH2Cl2 (5 ꢀ 50 mL). The combined
organic phases were dried (MgSO4) and concentrated in vacuo to
13C NMR (75 MHz, DMSO-d6): d = 155.9 (C), 153.3 (C), 136.9
(C), 128.3 (CH), 128.1 (CH), 127.7 (CH), 77.8 (C), 64.8 (CH2),
56.4 (CH), 51.1 (CH2), 48.6 (CH2), 45.9 (CH2), 40.3 (CH2), 28.4
(CH2), 27.8 (CH3), 22.9 (CH2).
MS (ES+): m/z (%) = 378 (100, [M + H]+).
21
give the title compound 7 as a pale yellow oil (314 mg, 88%); [a]D
+6.3 (c 1.00, CHCl3).
HRMS (ES+): m/z [M + H]+ calcd for C20H32N3O4: 378.2387;
found: 378.2381.
IR (film): 3315 (w), 3051 (w), 2870 (w), 1581 (s), 1484 (m), 1118
(s), 696 cm–1 (s).
Synthesis 2009, No. 15, 2509–2516 © Thieme Stuttgart · New York

2514
A. P. Carley et al.
PAPER
(S)-2-[(3-Benzyloxycarbonylaminopropylamino)methyl]pyrro-
lidine-1-carboxylic Acid tert-Butyl Ester (9b)
CH2Cl2 (10 mL), treated with aq sat. K2CO3 (1 mL) and stirred vig-
orously for 30 min. The phases were separated and the aqueous
phase was extracted with CH2Cl2 (5 ꢀ 20 mL). The combined or-
ganic phase was dried (MgSO4) and concentrated in vacuo to give
to give the title compound 10a as a white foam (251 mg, 88%);
[a]D27 –64.0 (c 1.00, CHCl3).
A solution of N-Boc-L-proline (8; 0.95 g, 4.43 mmol) in DMF–THF
(60 mL of a 1:1 v/v solution) was cooled to 0 °C before addition of
3-benzyloxycarbonylaminopropylammonium
trifluoroacetate15
(1.57 g, 4.87 mmol), HOBt (898 mg, 6.65 mmol), EDC (934 mg,
4.87 mmol), and i-Pr2NEt (3.39 mL, 19.5 mmol). The reaction mix-
ture was warmed to r.t. and stirred for 17 h before concentration in
vacuo. The resulting oil was taken into CH2Cl2 (50 mL) and washed
with aq 1 M KHSO4 (2 ꢀ 30 mL), aq sat. NaHCO3 (2 ꢀ 30 mL), and
brine (30 mL). The organic phase was separated and dried (MgSO4)
before concentration in vacuo. Crystallisation (EtOAc–hexane)
gave (S)-2-(3-benzyloxycarbonylaminopropylcarbamoyl)pyrroli-
dine-1-carboxylic acid tert-butyl ester (20) as an off-white crystal-
line solid (1.28 g, 71%). A solution of amide 20 (3.67 g, 9.05 mmol)
in THF (11 mL) was cooled to –5 °C and BH3·THF complex (18.1
mL of a 1 M solution, 18.1 mmol) was added dropwise over 10 min.
The mixture was stirred between –5 and 0 °C for 2 h, then warmed
to r.t., and stirred for a further 7 days. The mixture was then cooled
to –5 °C and cold H2O (40 mL) added dropwise over 20 min. The
mixture was extracted with EtOAc (200 mL), the EtOAc layer
washed with aq sat. NaHCO3 (200 mL) and brine (200 mL) before
drying (MgSO4) and concentration in vacuo. Purification by column
chromatography (SiO2 eluted with 9:1 CH2Cl2–MeOH) gave the ti-
tle compound 9b as a colourless oil (2.13 g, 60%); [a]D30 –25.6 (c
1.00, CHCl3).
IR (neat): 3243 (w), 2926 (w), 1538 (s), 1496 (s), 1347 (s), 1311 (s),
1255 (s) 695 cm–1 (s).
1H NMR (400 MHz, DMSO-d6): d = 9.71 (br s, 1 H, NH), 8.06 (br
s, 1 H, NH), 7.41–7.34 (m, 4 H, 4 CCH), 7.33 (t, J = 7.7 Hz, 2 H,
CHCHCH), 7.28 (t, J = 7.6 Hz, 2 H, CHCHCH), 7.13 (t, J = 7.3 Hz,
1 H, CHCHCH), 7.05 (t, J = 7.3 Hz, 1 H, CHCHCH), 4.42–3.59 (m,
6 H, CH2NCH2 and NHCH2), 3.41 (m, 1 H, CHCH2), 3.00 (m, 1 H,
NHCHH¢CH2), 2.75 (m, 1 H, NHCHH¢CH2), 1.92 (m, 1 H,
CH2CHH¢), 1.79 (m, 1 H, CH2CHH¢), 1.61 (dt, J = 15.8, 7.9 Hz, 1
H, CHCHH¢), 1.40 (dt, J = 14.6, 7.5 Hz, 1 H, CHCHH¢).
13C NMR (100 MHz, DMSO-d6): d = 182.6 (C), 180.7 (C), 141.5
(C), 138.9 (C), 128.6 (CH), 128.0 (CH), 124.4 (CH), 123.5 (CH),
123.3 (CH), 123.2 (CH), 57.8 (CH), 56.3 (CH2), 50.3 (CH2),
45.2 (CH2), 41.3 (CH2), 28.8 (CH2), 26.1 (CH2).
MS (ES+): m/z (%) = 414 (100, [M + H]+).
+
HRMS (ES+): m/z [M + H] calcd for C21H28N5S2: 414.1781;
found: 414.1785.
Anal. Calcd for C21H27N5S2: C, 60.98; H, 6.58; N, 16.92; S, 15.52.
Found: C, 60.37; H, 6.56; N, 16.89; S, 15.99.
IR (film): 3305 (w), 2973 (w), 1678 (s), 1530 (w), 1392 (s), 1165
(m), 749 cm–1 (s).
(S)-2-{3-Phenyl-1-[2-(3-phenylthioureido)propyl]thioureido-
methyl}pyrrolidine (10b)
1H NMR (400 MHz, DMSO-d6, 80 °C): d = 7.38–7.29 (m, 5 H, 5
CH), 6.96 (br s, 1 H, NH), 5.04 (s, 2 H, CH2Ph), 3.89 (m, 1 H,
CHCH2), 3.32 (m, 1 H, NCHH¢), 3.24 (m, 1 H, NCHH¢), 3.10 (q,
J = 6.7 Hz, 2 H, NHCH2), 3.05 (br s, 1 H, NH), 2.85 (dd, J = 12.2,
4.9 Hz, 1 H, CHCHH¢N), 2.75 (t, J = 7.1 Hz, 2 H, NHCH2), 2.70
(dd, J = 12.2, 7.3 Hz, 1 H, CHCHH¢N), 1.92 (m, 1 H, CHCHH¢),
1.86–1.79 (m, 3 H, CHH¢CH2), 1.70 (qn, J = 7.2 Hz, 2 H,
CH2CH2CH2), 1.43 [s, 9 H, C(CH3)3].
A solution of carbamate 9b (539 mg, 1.38 mmol) in MeOH (30 mL)
was treated with 10% Pd/C (147 mg, 1.4 mmol) and stirred under
H2 (1 atm) at r.t. for 18 h before filtration through Celite. The filtrate
was concentrated in vacuo to give diamine (S)-2-[(3-aminopropyl-
amino)methyl]pyrrolidine-1-carboxylic acid tert-butyl ester (23) as
a pale yellow oil (343 mg, 96%). Diamine 23 (300 mg, 1.17 mmol)
was taken into a biphasic solution of CHCl3 (65 mL), MeOH (20
mL), and aq sat. NaHCO3 (20 mL) and treated with phenyl isothio-
cyanate (349 mL, 2.91 mmol). The reaction mixture was stirred vig-
orously at r.t. for 3 days before separation of the organic phase and
washing with H2O (2 ꢀ 50 mL). The aqueous phase was extracted
with CH2Cl2 (3 ꢀ 100 mL), and the combined organic phases dried
(MgSO4) and concentrated in vacuo. Purification by column chro-
matography (SiO2 eluted with 3:1 PE–EtOAc) gave (S)-2-{3-phe-
nyl-1-[2-(3-
13C NMR (75 MHz, CDCl3): d = 23.9 (CH2), 25.7 (CH2), 28.6
(CH3), 29.7 (CH2), 40.7 (CH2), 46.8 (CH2), 48.6 (CH2), 53.1 (CH2),
56.9 (CH), 66.7 (CH2), 79.7 (C), 128.1 (CH), 128.2 (CH), 128.6
(CH), 136.8 (C), 156.7 (C), 158.3 (C).
MS (ES+): m/z (%) = 392 (100, [M + H]+).
HRMS (ES+): m/z [M + H]+ calcd for C21H34N3O4: 392.2544,
found: 392.2536.
phenylthioureido)propyl]thioureidomethyl}pyrrolidine-1-carboxy-
lic acid tert-butyl ester (24) as a white foam (290 mg, 47%). Car-
bamate 24 (201 mg, 0.381 mmol) was treated with TFA (10 mL of
a 20% v/v solution in CH2Cl2) and stirred at r.t. for 3 h before con-
centration in vacuo The resulting oil was taken into CH2Cl2 (10
mL), treated with aq sat. K2CO3 (1 mL) and stirred vigorously for
30 min. The phases were separated and the aqueous phase extracted
with CH2Cl2 (5 ꢀ 20 mL). The combined organic phases were dried
(MgSO4) and concentrated in vacuo to give the title compound 10b
as a white foam (163 mg, ca. 100%); [a]D27 –55.9 (c 1.00, CHCl3).
(S)-2-{3-Phenyl-1-[2-(3-phenylthioureido)ethyl]thioureido-
methyl}pyrrolidine (10a)
A solution of carbamate 9a (573 mg, 1.52 mmol) in MeOH (30 mL)
was treated with 10% Pd/C (162 mg, 1.52 mmol) and stirred under
H2 (1 atm) at r.t. for 5 h before filtration through Celite. The filtrate
was concentrated in vacuo to give (S)-2-[(2-aminoethylamino)me-
thyl]pyrrolidine-1-carboxylic acid tert-butyl ester (21) as a colour-
less oil (364 mg, 98%). Diamine 21 (324 mg, 1.33 mmol) was taken
into a biphasic solution of CHCl3 (65 mL), MeOH (20 mL), and aq
sat. NaHCO3 (20 mL) and treated with phenyl isothiocyanate (398
mL, 3.33 mmol). The reaction mixture was stirred vigorously at r.t.
for 3 days before separation of the organic phase and washing it
with H2O (2 ꢀ 50 mL). The combined aqueous phases were extract-
ed with CH2Cl2 (3 ꢀ 100 mL), and the combined organic phases
dried (MgSO4) and concentrated in vacuo. Purification by column
chromatography (SiO2 eluted with 3:1 PE–EtOAc) gave (S)-2-{3-
phenyl-1-[2-(3-phenylthioureido)ethyl]thioureidomethyl}pyrroli-
dine-1-carboxylic acid tert-butyl ester (22) as a white foam (462
mg, 68%). Carbamate 22 (355 mg, 0.691 mmol) was treated with
TFA (10 mL of a 20% v/v solution in CH2Cl2) and stirred at r.t. for
3 h before concentration in vacuo The resulting oil was taken into
IR (neat): 3247 (w), 2926 (w), 1538 (s), 1496 (s), 1347 (s), 1311 (s),
1255 (s), 695 cm–1 (s).
1H NMR (300 MHz, CDCl3): d = 12.48 (br s, 1 H, NH), 7.76 (br s,
1 H, NH), 7.51 (br s, 1 H, NH), 7.21–7.18 (m, 9 H, 9 CH), 7.07 (tt,
J = 7.0, 1.6 Hz, 1 H, CHCHCH), 4.00 (dd, J = 13.8, 6.8 Hz, 1 H,
CHCHH¢N), 3.82 (q, J = 6.5 Hz, 2 H, CH2NH), 3.72–3.63 (m, 3 H,
CH2N and CHCH2), 3.25 (d, J = 13.6 Hz, 1 H, CHCHH¢N), 3.09
(m, 1 H, NHCHH¢CH2), 2.84 (ddd, J = 11.0, 8.5, 6.2 Hz, 1 H, NH-
CHH¢CH2), 2.09–1.97 (m, 3 H, CH2CHH¢ and CH2CH2CH2), 1.89
(m, 1 H, CH2CHH¢), 1.70 (ddd, J = 19.9, 15.9, 7.4 Hz, 1 H,
CHCHH¢), 1.42 (dt, J = 14.0, 7.3 Hz, 1 H, CHCHH¢).
Synthesis 2009, No. 15, 2509–2516 © Thieme Stuttgart · New York

PAPER
Enantioselective Michael Addition
2515
13C NMR (75 MHz, CDCl3): d = 184.3 (C), 180.4 (C), 141.3 (C),
136.2 (C), 130.1 (CH), 128.5 (CH), 127.2 (CH), 125.3 (CH),
124.1 (CH), 123.4 (CH), 58.4 (CH), 56.4 (CH2), 49.4 (CH2),
46.3 (CH2), 42.2 (CH2), 29.7 (CH2), 27.1 (CH2), 26.7 (CH2).
stirred vigorously for 30 min. The phases were separated and the
aqueous phase extracted with CH2Cl2 (5 ꢀ 50 mL). The combined
organic phases were dried (MgSO4) and concentrated in vacuo to
give the title compound 12 as a colourless oil (205 mg, 98%); [a]D
+6.0 (c 1.00, CHCl3).
21
MS (ES+): m/z (%) = 428 (100, [M + H]+).
IR (film): 3432 (w), 2963 (w), 1579 (m), 1199 (m), 1125 (m), 752
cm–1 (s).
HRMS (ES+): m/z [M + H]+ calcd for C22H30N5S2: 428.1937; found:
428.1937.
1H NMR (400 MHz, CDCl3): d = 7.79 (br s, 2 H, 2 NH), 7.29 (t,
J = 7.6 Hz, 2 H, 2CHCHCH), 7.08 (tt, J = 7.4, 1.0 Hz, 1 H,
CHCHCH), 6.99 (dd, J = 8.5, 1.1 Hz, 2 H, 2CCHCH), 4.01 (appar-
ent dq, J = 7.6, 2.0 Hz, 1 H, CHCH2), 3.78 (dd, J = 15.1, 9.5 Hz, 1
H, CHCHH¢N), 3.66 (m, 1 H, NHCHH¢), 3.35–3.20 (m, 5 H, 2
NCH2 and CHCHH¢N), 2.88 (td, J = 11.0, 7.1 Hz, 1 H, NHCHH¢),
2.09–2.00 (m, 2 H, CH2CH2CH2), 1.97 (m, 1 H, CHHH¢), 1.95–1.87
(m, 2 H, CH2CH2CH2), 1.49 (td, J = 12.8, 7.7 Hz, 1 H, CHCHH¢).
Anal. Calcd for C22H29N5S2: C, 61.79; H, 6.84; N, 16.37; S, 15.00.
Found: C, 61.87; H, 6.46; N, 16.18; S, 15.15.
(S)-2-({tert-Butoxycarbonyl-[2-(3-phenylthioureido)pro-
pyl]amino}methyl)pyrrolidine-1-carboxylic Acid tert-Butyl
Ester (11)
A solution of amine 9b (1.68 g, 4.29 mmol) in CH2Cl2 (200 mL)
was treated with di-tert-butyl dicarbonate (1.03 g, 4.72 mmol) and
Et3N (658 mL, 4.72 mmol) and then stirred at r.t. for 18 h before
washing with aq sat. K2CO3 (3 ꢀ 40 mL), drying (MgSO4), and con-
centration in vacuo. Purification by column chromatography (SiO2
eluted with CH2Cl2) gave (S)-2-{[(2-benzyloxycarbonylaminopro-
pyl)-tert-butoxycarbonylamino]methyl}pyrrolidine-1-carboxylic
acid tert-butyl ester (25) as a colourless oil (1.45 g, 69%). A solu-
tion of the bis-carbamate 25 (1.39 g, 2.82 mmol) in MeOH (40 mL)
was treated with 10% Pd/C (301 mg, 2.82 mmol) and stirred under
H2 (1 atm) at r.t. for 18 h before filtration through Celite. The filtrate
was concentrated in vacuo to give (S)-2-{[(2-aminopropyl)-tert-bu-
toxycarbonylamino]methyl}pyrrolidine-1-carboxylic acid tert-bu-
tyl ester (26), as a colourless oil (1.01 g, ca. 100%). Amine 26 (500
mg, 1.39 mmol) was taken into a biphasic mixture of CHCl3 (85
mL), MeOH (25 mL), and aq sat. NaHCO3 (25 mL) and treated with
phenyl isothiocyanate (167 mL, 1.39 mmol). The reaction mixture
was stirred vigorously at r.t. for 36 h before separation of the organ-
ic phase and washing it with H2O (2 ꢀ 55 mL). The aqueous phase
was extracted with CH2Cl2 (2 ꢀ 55 mL), the combined organic
phases were dried (MgSO4), and concentrated in vacuo. Purification
by column chromatography (SiO2 eluted with 3:1 PE–EtOAc) gave
13C NMR (100 MHz, CDCl3): d = 154.1 (C), 141.1 (C), 130.0 (CH),
124.8 (CH), 124.0 (CH), 58.2 (CH), 55.4 (CH2), 48.2 (CH2),
44.9 (CH2), 39.4 (CH2), 28.5 (CH2), 26.2 (CH2), 21.9 (CH2).
MS (ES+): m/z (%) = 293 (100, [M + H]+).
HRMS (ES+): m/z [M]+ calcd for C15H23N4: 259.1917; found:
259.1920.
Anal. Calcd for C15H23IN4: C, 46.64; H, 6.00; N, 14.50. Found: C,
46.95; H, 6.32; N, 14.84.
1-Phenyl-3-(3-{[(S)-1-pyrrolidin-2-ylmethyl]amino}pro-
pyl)thiourea (13)
Carbamate 11 (371 mg, 0.753 mmol) was treated with TFA (10 mL
of a 20% v/v solution in CH2Cl2) and stirred at r.t. for 3 h before
concentration in vacuo. The residual ammonium salt was taken into
CH2Cl2 (10 mL) and treated with aq sat. K2CO3 (1 mL), and stirred
vigorously at r.t. for 30 min. The phases were separated and the
aqueous phase extracted with CH2Cl2 (5 ꢀ 50 mL). The combined
organic phases were dried (MgSO4) and concentrated in vacuo to
give the title compound 13 as a pale yellow oil (186 mg, 85%);
[a]D28.5 –6.8 (c 0.90, CHCl3).
31
the title compound 11 as a pale yellow oil (500 mg, 73%); [a]D
–21.6 (c 1.00, CHCl3).
IR (film): 2956 (w), 1668 (m), 1200 (m), 1132 (m), 722 cm–1 (s).
IR (film): 3271 (w), 2974 (w), 2926 (w), 1675 (s), 1536 (m), 1158
(s), 728 cm–1 (s).
1H NMR (300 MHz, CDCl3): d = 7.87 (br s, 1 H, NH), 7.38–7.29
(m, 4 H, 4 CH), 7.16 (t, J = 7.0 Hz, 1 H, CHCHCH), 5.20 (br s, 2 H,
2 NH), 3.77–3.66 (m, 2 H, CH2NH), 3.30 (m, 1 H, CHCH2), 3.05–
3.00 (m, 2 H, NHCH2), 2.75–2.63 (m, 3 H, CHCHH¢NH and
NHCH2), 2.55 (dd, J = 12.6, 9.7 Hz, 1 H, CHCHH¢NH), 1.90–1.79
(m, 3 H, CHH¢CH2), 1.71 (qn, J = 6.0 Hz, 2 H, CH2CH2CH2), 1.42
(m, 1 H, CHCHH¢).
1H NMR (400 MHz, DMSO-d6, 80 °C): d = 9.33 (br s, 1 H, NH),
7.61 (br s, 1 H, NH), 7.45 (dd, J = 8.7, 1.3 Hz, 2 H, 2 CH), 7.30 (td,
J = 7.5, 2.0 Hz, 2 H, 2 CH), 7.09 (tt, J = 7.5, 1.1 Hz, 1 H,
CHCHCH), 3.94 (m, 1 H, CHCH2), 3.50 (q, J = 7.1 Hz, 2 H,
CH2NH), 3.30–3.25 (m, 4 H, 2 NCH2), 3.23 (dd, J = 14.5, 7.2 Hz, 2
H, CHCH2N), 1.88–1.75 (m, 6 H, 3 CH2), 1.43 [s, 9 H, C(CH3)3],
1.42 [s, 9 H, C(CH3)3].
13C NMR (100 MHz, CDCl3): d = 181.0 (C), 138.4 (C), 129.3 (CH),
125.8 (CH), 124.8 (CH), 58.6 (CH), 51.9 (CH2), 47.3 (CH2), 45.4
(CH2), 43.7 (CH2), 28.8 (CH2), 28.4 (CH2), 24.7 (CH2).
13C NMR (100 MHz, CDCl3): d = 180.4 (C), 159.4 (C), 156.5 (C),
136.4 (C), 129.8 (CH), 126.6 (CH), 125.3 (CH), 80.5 (C), 80.2 (C),
55.6 (CH), 47.7 (CH2), 46.2 (CH2), 42.6 (CH2), 41.6 (CH2), 29.7
(CH2), 28.6 (CH3), 28.3 (CH3), 23.4 (CH2), 22.5 (CH2).
MS (ES+): m/z (%) = 293 (100, [M + H]+).
Anal. Calcd for C15H24N4S: C, 61.61; H, 8.27; N, 19.15; S, 10.97.
Found: C, 61.91; H, 8.06; N, 19.41; S, 10.68.
MS (ES+): m/z (%) = 515 (100, [M + Na]+).
HRMS (ES+): m/z [M + Na]+ calcd for C25H40N4O4S + Na:
515.2662; found: 515.2658.
Acknowledgment
We thank GlaxoSmithKline for a CASE studentship (A.P.C.) and
EPSRC. We also thank Dr. Malcolm Berry and John Watson (GSK)
for their advice and assistance.
2-Phenylamino-3-(S)-1-pyrrolidin-2-ylmethyl-3,4,5,6-tetrahy-
dropyrimidinium Iodide (12)
To a solution of thiourea 11 (389 mg, 0.793 mmol) in acetone (5
mL) was added MeI (494 mL, 7.93 mmol) and the reaction mixture
stirred at r.t. for 5 h before concentration in vacuo to give a thiouro-
nium iodide as a yellow foam (503 mg, ca. 100%). A solution of this
thiouronium iodide (340 mg, 0.537 mmol) was treated with TFA
(10 mL of a 20% v/v solution in CH2Cl2) and stirred at r.t. for 4 h
before concentration in vacuo. The resulting ammonium salt was
taken into CH2Cl2 (10 mL), treated with aq sat. K2CO3 (1 mL) and
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Synthesis 2009, No. 15, 2509–2516 © Thieme Stuttgart · New York

2516
A. P. Carley et al.
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Synthesis 2009, No. 15, 2509–2516 © Thieme Stuttgart · New York