Asymmetric Organocatalytic Michael Addition-Cyclisation Cascade of Cyclopentane-1,2-dione with Alkylidene Malononitriles

Article abstract of DOI:10.1055/s-0039-1690484

An asymmetric organocatalytic cascade reaction between cyclopentane-1,2-diones and alkylidene malononitriles affords highly substituted 4 H-pyrans in moderate to high enantiomeric excess. The selective reduction of a bridged double bond leads to the forma

Full text of DOI:10.1055/s-0039-1690484

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2019, 51, A–G
paper
A
en
E. Silm et al.
Paper
Synthesis
Asymmetric Organocatalytic Michael Addition–Cyclisation Cas-
cade of Cyclopentane-1,2-dione with Alkylidene Malononitriles
R
Estelle Silm
Sandra Kaabel1
O
CN
N
*
H
H
CN
catalyst (10 mol%)
N
N
CF3
R
+
Ivar Järving
OH
S
CN
O
–20 °C
toluene
NH2
O
Tõnis Kanger*
0
0
0
0-
0
0
0
1-5
3
3
9-9
6
8
2
CF3
O
N
catalyst
12 examples
up to 87% yield
up to 88% ee
Department of Chemistry and Biotechnology, Tallinn University
of Technology, Akadeemia tee 15, 12618 Tallinn, Estonia
tonis.kanger@taltech.ee
Received: 15.05.2019
Accepted after revision: 27.06.2019
Published online: 11.07.2019
tions with unsaturated aldehydes,8–10 acetates of ni-
troalkenes,11 cyanoacrylates and alkylidene malononitrile
derivatives.12 Cyclic 1,2-dicarbonyl compounds have been
investigated less in cascade reactions. It has been previously
shown that cyclohexane-1,2-diones undergo a cascade with
nitroolefins,13 benzylidenemalononitriles14 and ,-unsatu-
rated aldehydes.15 However, cyclopentane-1,2-diones are
less reactive and do not afford the cascade reactions with
Michael acceptors characteristic of cascades involving cy-
clohexane-1,2-diones. Only single-bond-forming organo-
catalytic enantioselective reactions with nitroolefins16 and
cascade reactions with ,-unsaturated aldehydes17 were
described by our group recently. Highly reactive (E)-2-
oxobut-3-enoates18 were needed to run the cascade reac-
tion.19 Considering the previous research that our group has
conducted on cyclopentane-1,2-dione and the reported
cascade reactions using diketones, we assumed that the cy-
clopentane-1,2-dione 1 would undergo a Michael reaction
with alkylidene malononitriles 2, followed by the intramo-
lecular cyclisation of the adduct to afford multifunction-
alised bicycles 3 with one stereocentre (Scheme 1).
DOI: 10.1055/s-0039-1690484; Art ID: ss-2019-t0274-op
Abstract An asymmetric organocatalytic cascade reaction between
cyclopentane-1,2-diones and alkylidene malononitriles affords highly
substituted 4H-pyrans in moderate to high enantiomeric excess. The se-
lective reduction of a bridged double bond leads to the formation of cis-
substituted cyclopentanone with three contiguous stereogenic centres.
Key words organocatalysis, asymmetric catalysis, diketone, pyran,
cascade reaction
Cascade reactions have been an interesting topic for
many researchers over the years.2 Such transformations are
atom- and step-economical and proceed in a one-pot man-
ner; thus, there is no need for additional protection/depro-
tection steps or purification of intermediates. These syn-
thetic and operational advantages make this approach
more sustainable and environmentally friendly than classi-
cal syntheses. Forming several bonds in one step is very ap-
pealing for the development of new strategies for the con-
struction of complex molecules, even more so if high stere-
oselectivity is achieved in the presence of a chiral catalyst
or auxiliary. In the last two decades organocatalysis3 has
proven to be competitive with metal2c,4 and enzymatic ca-
talysis,5 so asymmetric organocatalytic cascade reactions
are now a valuable approach for synthetic chemists.3b,3c
Starting with the pioneering work by Barbas6 of a consecu-
tive Michael addition and aldol condensation (i.e., Robinson
annulation), synthetic chemists have proceeded to quadru-
ple asymmetric cascades, where several chemical bonds
and stereogenic centres are formed in complex structures
in controlled ways.7
R
O
CN
CN
*
R
+
OH
CN
NH2
O
O
1
3
2
Scheme 1 General scheme for the cascade reaction
Derived compounds are highly substituted 4H-pyrans
with a comprehensive list of biological and pharmacologi-
cal properties, such as kinase inhibition,20 IKCA channel
blocker behaviour21 and antitumor properties.22
Among the different starting materials suitable for cas-
cade reactions, cyclic diketones are widely used. Various cy-
clic 1,3-diketones have been investigated in one-pot reac-
Chiral thioureas23 and squaramides24 are widely used as
catalysts in asymmetric Michael additions. We assumed
that H-bonds could activate alkylidene malononitrile suffi-
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–G
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
E. Silm et al.
Paper
Synthesis
F3C
CF3
CF3
N
N
HN
H
N
H
H
N
N
CF3
S
C
O
O
S
O
N
N
CF3
O
H
H
A
N
CF3
B
N
N
N
F3C
F3C
O
N
O
HN
CF3
N
H
N
S
N
HN
H
H
H
N
O
N
D
E
S
O
S
N
N
H
H
N
N
N
H
N
H
N
N
H
H
N
N
CF3
CF3
S
O
O
F
G
CF3
CF3
N
N
Figure 1 Catalysts screened in the model reaction
ciently to trigger the cascade. Therefore, various H-bond
catalysts (Figure 1) were screened in the model reaction be-
tween cyclopentane-1,2-dione and benzylidene malonitrile
(Table 1).
place. Finally, to minimise that effect, the reaction mixture
was diluted 10 times and an increase in enantioselectivity
was achieved (entry 11), even more so at lower tempera-
ture (entry 14). The overall best result was attained using
alkaloid-derived thiourea A and toluene at –20 °C (entry
14).
First, different catalysts were screened at room tem-
perature. The model reaction in the presence of 10 mol%
thiourea A afforded the product within two hours in 74%
yield (Table 1, entry 1). Soos’s bifunctional catalysts F (entry
6) gave the same stereoselectivity (54% ee), eliminating the
influence of the double bond and the methoxy substituent.
With Takemoto’s catalyst B and squaramide C (entries 2 and
3) the product was obtained with low enantioselectivity.
The enantioselectivity found with double-activated Pihko’s
catalyst25 D (entry 4) was similar to that obtained with
thiourea A. Double thiourea E afforded the product in low
enantiomeric purity (13% ee). Since the synthetic pathway
for catalyst A is less time- and resource-consuming than for
catalyst D, the former was seen as the most reasonable cat-
alyst. Next, we looked into solvent effects on the reaction.
The stereoselectivity was very dependent on the solvent
used (entries 1 and 7–9). Compared to toluene, the enantio-
meric excess was slightly lower in THF. Its greener alterna-
tive, 2-MeTHF, gave a racemic product and in CH2Cl2 the
product obtained was almost racemic. In addition, the reac-
tion was run at various temperatures (entries 1 and 10).
The results indicated that catalyst aggregation26 might take
Using these optimal conditions, the scope of the reac-
tion was investigated. Both electron-withdrawing (3d–j;
Scheme 2) and electron-donating groups (3b, 3c; Scheme 2)
were tolerated. The electronic properties of the aromatic
ring and also the position of the substituent did not seem to
have a significant influence on the yield; however, the en-
antioselectivity was more influenced when nitro-substitut-
ed benzylidene malononitriles were used. It is supposed
that the nitro group competes with the H-bonding acceptor
to influence the enantioselectivity. In addition, heteroaro-
matic malononitrile derivative 2k afforded the product in
slightly lower yield but with good ee. Furthermore, al-
kylidene malononitrile could also be used in this cascade,
although it affords the product in much lower yield and
lower enantioselectivity. Pyrrole derived malononitrile 2m
is probably too electron-rich and therefore did not react
with cyclopentane-1,2-dione 1. It is assumed that the prod-
uct 3n did not form because the substrate 2n was too steri-
cally hindered for the first addition to take place.
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–G

C
E. Silm et al.
Paper
Synthesis
Table 1 Screening Conditions for the Reaction
To eliminate racemisation from consideration, the enan-
tiomeric purity of the product was checked throughout the
reaction for a period of 47 hours (Scheme 3). The ee was
constant and varied only within the detection error. Two
additional experiments with the product were also carried
out. The product 3a was stirred for 24 hours in toluene ei-
ther with 10 mol% of catalyst A or without it (Scheme 3).
The results showed that no racemisation was observed un-
der either of these conditions.
O
catalyst (10 mol%)
CN
CN
*
+
OH
CN
2a
1
NH2
O
3a
O
Entrya Catalyst Solvent
Time (h) Temp (°C) ee (%)b Yield (%)c
1
A
B
C
D
E
toluene
2
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
–20
r.t.
r.t.
–20
–20
60
54
31
27
56
13
54
5
74
nd
nd
nd
nd
74
nd
77
nd
nd
82
79
78
78
74
nd
2
toluene
toluene
toluene
toluene
toluene
CH2Cl2
1
catalyst
(10 mol%)
O
3
1
CN
CN
+
4
3
A)
OH
CN
toluene
–20 °C
2a
NH2
O
5
1
1
3a
O
6
F
3
7
A
A
A
A
A
A
G
A
A
A
3
8
THF
2.5
2.5
4.5
2
47
rac
53
70
70
65
75
31
53
9
2-MeTHF
toluene
toluened
cat. A
(10 mol%)
3a
3a
3a
10
11
12
13
14
15
16
CN
CN
CN
B)
toluene
rt
toluene
rt
mesitylened
toluened
toluened
toluened
toluened
15
20
3
O
O
70% ee
O
NH2
NH2
NH2
O
O
O
70% ee
70% ee
Scheme 3 Racemisation studies: (A) throughout the reaction, (B) with
the product 3a
2
13 days –78
a Reaction conditions: 0.2 M solution of 1 (1 equiv), 2a (1.1 equiv), catalyst
The R-absolute configuration of compound 3a was de-
termined by single-crystal X-ray diffraction (Figure 2) and
the absolute configurations of the products 3 were assigned
by analogy.
(0.1 equiv).
b ee determined by chiral HPLC analysis either from isolated product or pre-
parative TLC.
c Isolated yield after column chromatography; nd = not determined.
d 0.02 M solution of 1.
R
N
O
H
N
H
N
catalyst A
CN
CN
CF3
R
+
– 20 °C
toluene
S
O
OH
CN
2
NH2
O
1
CF3
A
N
3
O
Br
CF3
Br
O
3d
3e
3f
3c
3g
Br
3b
3a
CN
CN
CN
CN
CN
CN
CN
O
O
NH2
NH2
O
O
O
NH2
NH2
NH2
O
O
NH2
NH2
O
O
O
O
O
O
O
78%, 78% ee
74%, 63% ee
68%, 78% ee
81%, 79% ee
82%, 66% ee
72%, 77% ee
81%, 74% ee
NO2
O2N
S
3k
HN
3h
3i
3j
O2N
3m
3n
3l
CN
CN
CN
CN
CN
CN
CN
O
NH2
O
O
O
NH2
NH2
NH2
O
O
O
O
NH2
NH2
NH2
O
O
O
O
O
O
58%, 74% ee
rt: 46%, 88% ee
76%, 49% ee
79%, 59% ee
87%, 40% ee
35%, 40% ee
0%
0%
Scheme 2 Scope of the reaction. Reagents and conditions: 0.02 M solution 1 (1 equiv), 2 (1.1 equiv), catalyst A (0.1 equiv), toluene, –20 °C; isolated
yields after column chromatography; ee determined by chiral HPLC.
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–G

D
E. Silm et al.
Paper
Synthesis
H-Cube
Pd/C (10%)
50 bar, 50 °C
0.8 mL/min
acetone
H
CN
CN
O
O
NH2
NH2
H
O
O
3a
4a
59% yield
Scheme 5 The reduction of 3a
In summary, we have developed a new, efficient organo-
catalytic cascade for the synthesis of substituted 4H-pyrans.
The cascade is efficiently catalysed by chiral bifunctional
thiourea A to provide bicyclic 4H-pyrans 3a–l in moderate
to high yields and enantioselectivities. The selective reduc-
tion of the bridged double bond leads to cyclopentanone
derivatives with three contiguous stereogenic centres.
Figure 2 X-ray crystal structure of compound 3a
A plausible reaction pathway is shown in Scheme 4. It is
believed that both reactants are activated by the catalyst:
alkylidene malononitrile via hydrogen bonds with thiourea
moiety and diketone via hydrogen bond with a tertiary
amino group of quinuclidine moiety. The stereodetermin-
ing step is the first Michael addition step. According to the
geometry of 3a, the attack of the cyclopentane-1,2-dione
on alkylidene malononitrile occurs from the Si-face, afford-
ing intermediate I with R-configuration of the stereogenic
centre. An O-nucleophile attack of the enol form II on the
cyano group leads to the cyclisation. The target compound
3a is isolated as an enamine tautomer of imine III.
Full assignment of 1H and 13C chemical shifts were based on the 1D
and 2D FT NMR spectra measured with a Bruker Avance III 400 MHz
instrument. Residual solvent signals were used (CDCl3:  = 7.26 1H
NMR,  = 77.2 13C NMR; (CD3)2CO:  = 2.05 1H NMR,  = 29.84/206.26
13C NMR) as internal standards. High-resolution mass spectra were
recorded with an Agilent Technologies 6540 UHD Accurate-Mass Q-
TOF LC/MS spectrometer by using AJ-ESI ionisation. Optical rotations
were obtained with an Anton Paar GWB Polarimeter MCP 500. Chiral
HPLC was performed by using Chiralpak AD-H, Chiralcel OJ-H, Chiral-
cel OD-H columns. Precoated silica gel 60 F254 plates were used for
TLC. Commercial reagents and solvents were generally used as re-
ceived. Toluene was distilled over sodium and CH2Cl2 was distilled
over phosphorus pentoxide.
CN
NC
OH
O
N
Racemic compounds were prepared by following the general proce-
dure using DABCO as catalyst. Cyclopentane-1,2-dione (1) was pre-
pared according to a reported procedure27 from commercially avail-
able cyclopentanone. Alkylidene malononitriles were prepared via
Knoevenagel condensation from commercially available malononi-
trile and commercially available aldehydes. Catalysts A, E, F,28 C,29 B,30
H
H
CN
CN
N
N
CF3
CN
CN
O
S
O
O
O
O
H
CF3
I
N
D
25 and G31 were prepared according to reported procedures.
a
Synthesis of 3; General Procedure
To a solution of cyclopentane-1,2-dione (0.07 mmol) and catalyst
(0.007 mmol) in toluene (3.5 mL) was added substituted malononi-
trile (0.08 mmol). The mixture was stirred until the reaction was
complete (TLC and/or NMR monitoring). The mixture was purified by
column chromatography (CH2Cl2/EtOAc, 19:1) to afford the product.
b
CN
CN
CN
C
O
NH2
O
NH
OH
N
O
3a
O
O
II
III
(R)-2-Amino-7-oxo-4-phenyl-4,5,6,7-tetrahydrocyclopen-
ta[b]pyran-3-carbonitrile (3a)
Scheme 4 Proposed transition state and reaction pathway: a) keto–
enol tautomerisation; b) imine–enamine tautomerisation
By following the general procedure (1.5 mmol scale), compound 3a
(78% yield, 301 mg) was obtained as an off-white solid; mp 215 °C
(decomp); 78% ee [HPLC (Chiralcel OJ-H; hexane/i-PrOH, 7:3; 35 °C;
0.9 mL/min; 254 nm): tr = 21.2 (minor), 30.8 (major) min]; []D20 –117.5
(c 0.14, acetone).
To show the synthetic utility of the obtained substituted
pyrans, compound 3a was reduced using an H-Cube Pro
continuous-flow reactor in the presence of a Pd catalyst
(Scheme 5). The reduction was cis-selective, affording only
cis-substituted cyclopentanone. The configuration of the
main diastereomer 4a was confirmed by NOE experiments
(see Supporting Information for details).
IR: 3339, 2191, 1713, 1679, 1621, 1593, 1491, 1404, 1111, 752, 698
cm–1
.
1H NMR (400 MHz, (CD3)2CO):  = 7.43–7.35 (m, 2 H), 7.35–7.28 (m,
3 H), 6.28 (s, 2 H), 4.5 (s, 1 H), 2.55–2.28 (m, 3 H), 2.20–2.09 (m, 1 H).
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–G

E
E. Silm et al.
Paper
Synthesis
13C NMR (101 MHz, (CD3)2CO):  = 197.1, 161.4, 148.5, 146.1, 142.3,
129.7, 129.0, 128.5, 119.8, 58.3, 43.1, 33.4, 23.6.
(R)-2-Amino-4-(3-bromophenyl)-7-oxo-4,5,6,7-tetrahydrocyclo-
penta[b]pyran-3-carbonitrile (3e)
HRMS (ESI): m/z [M + H]+ calcd for [C15H13N2O2]+: 253.0972; found:
253.0960.
By following the general procedure, compound 3e (82% yield, 19.1
mg) was obtained as a yellowish solid; mp 162 °C (decomp); 65% ee
[HPLC (Chiralcel OJ-H; hexane/i-PrOH, 7:3; 35 °C; 0.9 mL/min; 254
nm): tr = 18.4 (minor), 21.3 (major) min]; []D –67.4 (c 0.07, ace-
tone).
20
(R)-2-Amino-4-(3-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydrocy-
clopenta[b]pyran-3-carbonitrile (3b)
IR: 3317, 2191, 1720, 1678, 1638, 1607, 1471, 1415, 1110, 1071, 749
By following the general procedure, compound 3b (74% yield, 14.9
mg) was obtained as a yellow solid; mp 143 °C (decomp); 63% ee
[HPLC (Chiralcel OJ-H; hexane/i-PrOH, 7:3; 35 °C; 0.9 mL/min; 254
cm–1
.
1H NMR (400 MHz, (CD3)2CO):  = 7.56–7.47 (m, 2 H), 7.39–7.33 (m,
2 H), 6.37 (s, 2 H), 4.56 (s, 1 H), 2.56–2.28 (m, 3 H), 2.25–2.11 (m, 1 H).
20
nm): tr = 24.2 (minor), 40.0 (major) min]; []D –78.8 (c 0.07, ace-
tone).
13C NMR (101 MHz, (CD3)2CO):  = 197.1, 161.5, 147.4, 146.4, 145.0,
IR: 3323, 2194, 1714, 1678, 1639, 1593, 1492, 1412, 1284, 1113,
131.9, 131.8, 131.7, 128.1, 123.4, 119.6, 57.7, 42.7, 33.4, 23.6.
HRMS (ESI): m/z [M + Na]+ calcd for [C15H11BrN2O2Na]+: 352.9896;
found: 352.9887.
1048, 750 cm–1
.
1H NMR (400 MHz, (CD3)2CO):  = 7.35–7.27 (m, 1 H), 6.91–6.86 (m,
3 H), 6.28 (s, 2 H), 4.47 (s, 1 H), 3.8 (s, 3 H), 2.52–2.30 (m, 3 H), 2.23–
2.14 (m, 1 H).
(R)-2-Amino-4-(2-bromophenyl)-7-oxo-4,5,6,7-tetrahydrocyclo-
penta[b]pyran-3-carbonitrile (3f)
13C NMR (101 MHz, (CD3)2CO):  = 197.1, 161.4, 161.2, 148.4, 146.1,
143.9, 130.8, 121.1, 119.8, 114.8, 113.7, 58.2, 55.5, 45.1, 33.4, 23.6.
HRMS (ESI): m/z [M + H]+ calcd for [C16H15N2O3]+: 283.1077; found:
283.1074.
By following the general procedure, compound 3f (72% yield, 17 mg)
was obtained as a dark-yellow solid; mp 144 °C (decomp); 77% ee
[HPLC (Chiralcel OJ-H; hexane/i-PrOH, 7:3; 35 °C; 0.9 mL/min; 254
20
nm): tr = 20.9 (minor), 24.0 (major) min]; []D –77.5 (c 0.08, ace-
tone).
(R)-2-Amino-4-(3,4-dimethylphenyl)-7-oxo-4,5,6,7-tetrahydrocy-
clopenta[b]pyran-3-carbonitrile (3c)
IR: 3381, 2197, 1718, 1677, 1645, 1594, 1463, 1417, 1109, 1051, 767,
749 cm–1
.
By following the general procedure, compound 3c (68% yield, 13.6
mg) was obtained as a yellow-brown solid; mp 144 °C (decomp); 78%
ee [HPLC (Chiralcel OJ-H; hexane/i-PrOH, 7:3; 35 °C; 0.9 mL/min; 254
1H NMR (400 MHz, (CD3)2CO):  = 7.65 (dd, J = 8.0, 1.1 Hz, 1 H), 7.49–
7.37 (m, 2 H), 7.27 (ddd, J = 8.0, 7.2, 1.9 Hz, 1 H), 6.38 (br s, 2 H), 5.10
(s, 1 H), 2.63–2.51 (m, 1 H), 2.39 (qdd, J = 18.8, 6.5, 1.5 Hz, 2 H), 2.22–
2.11 (m, 1 H).
20
nm): tr = 12.0 (minor), 13.9 (major) min]; []D –51.3 (c 0.03, ace-
tone).
13C NMR (101 MHz, (CD3)2CO):  = 196.9, 161.8, 147.3, 134.0, 131.8,
130.5, 129.5, 124.2, 119.4, 100.9, 57.2, 33.4, 23.6.
IR: 3345, 2923, 2198, 1718, 1680, 1644, 1608, 1503, 1412, 1383,
1357, 1109, 773 cm–1
.
1H NMR (400 MHz, (CD3)2CO):  = 7.14 (d, J = 7.7 Hz, 1 H), 7.07 (s, 1 H),
7.02 (dd, J = 7.7, 1.6 Hz, 1 H), 6.23 (s, 1 H), 4.40 (s, 1 H), 2.50–2.41 (m,
1 H), 2.40–2.33 (m, 2 H), 2.24 (d, J = 5.3 Hz, 6 H), 2.18–2.11 (m, 1 H).
HRMS (ESI): m/z [M – H]– calcd for [C15H8BrN2O2]–: 326.9775; found:
326.9757.
13C NMR (101 MHz, (CD3)2CO):  = 197.1, 161.2, 148.9, 139.8, 137.8,
136.7, 130.8, 130.0, 126.4, 119.9, 58.5, 42.7, 23.6, 19.8, 19.4.
(R)-2-Amino-7-oxo-4-(4-(trifluoromethyl)phenyl)-4,5,6,7-tetra-
hydrocyclopenta[b]pyran-3-carbonitrile (3g)
HRMS (ESI): m/z [M + H]+ calcd for [C17H17N2O2]+: 281.1285; found:
281.1283.
By following the general procedure, compound 3g (81% yield, 18.4
mg) was obtained as a yellow solid; mp 167 °C (decomp); 74% ee
[HPLC (Chiralcel OJ-H; hexane/i-PrOH, 8:2; 1 mL/min; 254 nm): tr =
24.9 (major), 30.0 (minor) min]; []D20 –72.6 (c 0.09, acetone).
(R)-2-Amino-4-(4-bromophenyl)-7-oxo-4,5,6,7-tetrahydrocyclo-
penta[b]pyran-3-carbonitrile (3d)
IR: 3328, 2190, 1720, 1682, 1638, 1589, 1420, 1331, 1123, 764 cm–1
.
1H NMR (400 MHz, (CD3)2CO):  = 7.76 (d, J = 8.1 Hz, 2 H), 7.59 (d, J =
8.1 Hz, 2 H), 6.41 (s, 2 H), 4.67 (s, 1 H), 2.57–2.30 (m, 3 H), 2.23–2.11
(m, 1 H).
13C NMR (101 MHz, (CD3)2CO):  = 197.1, 161.5, 147.2, 146.8, 146.5,
129.9, 126.7, 126.6, 119.6, 57.4, 42.8, 33.4, 23.5.
By following the general procedure, compound 3d (81% yield, 19.1
mg) was obtained as a brownish solid; mp 184 °C (decomp); 79% ee
[HPLC (Chiralcel OD-H; hexane/i-PrOH, 9:1; 25 °C; 1 mL/min; 254
nm): tr = 26.5 (minor), 34.2 (major) min]; []D –13.6 (c 0.05, ace-
tone).
20
IR: 3325, 2191, 1716, 1681, 1633, 1590, 1486, 1402, 1111, 1010, 754
HRMS (ESI): m/z [M – H]– calcd for [C16H10F3N2O2]–: 319.0700; found:
319.0691.
cm–1
.
1H NMR (400 MHz, (CD3)2CO):  = 7.61–7.55 (m, 2 H), 7.34–7.27 (m,
2 H), 6.34 (s, 2 H), 4.54 (s, 1 H), 2.53–2.30 (m, 3 H), 2.24–2.12 (m, 1 H).
13C NMR (101 MHz, (CD3)2CO):  = 197.1, 161.4, 147.6, 146.3, 147.7,
(R)-2-Amino-4-(2-nitrophenyl)-7-oxo-4,5,6,7-tetrahydrocyclo-
penta[b]pyran-3-carbonitrile (3h)
122.0, 119.7, 57.8, 42.5, 33.4, 23.5.
HRMS (ESI): m/z [M – H]– calcd for [C15H8BrN2O2]–: 326.9775; found:
326.9757.
By following the general procedure, compound 3h (76% yield, 16.1
mg) was obtained as an orange solid; mp 157 °C (decomp); 49% ee
[HPLC (Chiralcel OD-H; hexane/i-PrOH, 8:2; 25 °C; 1 mL/min; 254
20
nm): tr = 21.6 (major), 26.8 (minor) min]; []D –21.5 (c 0.05, ace-
tone).
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–G

F
E. Silm et al.
Paper
Synthesis
IR: 3321, 2197, 1721, 1679, 1643, 1590, 1526, 1420, 1402, 1113, 765
cm–1
13C NMR (101 MHz, CDCl3):  = 197.0, 159.5, 147.2, 145.0, 143.9,
127.3, 126.1, 126.13, 126.07, 118.8, 59.9, 37.1, 32.9, 23.1.
.
1H NMR (400 MHz, (CD3)2CO):  = 7.99–7.95 (m, 1 H), 7.84–7.75 (m,
1 H), 7.67–7.56 (m, 2 H), 6.54 (s, 2 H), 5.19 (s, 1 H), 2.65–2.31 (m, 3 H),
2.24–2.14 (m, 1 H).
HRMS (ESI): m/z [M + H]+ calcd for [C13H11N2O2S]+: 259.0536; found:
259.0517.
13C NMR (101 MHz, (CD3)2CO):  = 197.0, 161.8, 150.6, 146.8, 146.6,
136.3, 134.6, 132.5, 129.9, 125.1, 119.3, 57.3, 38.0, 33.4, 23.7.
(R)-2-Amino-4-hexyl-7-oxo-4,5,6,7-tetrahydrocyclopen-
ta[b]pyran-3-carbonitrile (3l)
HRMS (ESI): m/z [M – H]– calcd for [C15H10N3O4]–: 296.0677; found:
296.0657.
By following the general procedure, compound 3l (62% yield, 24.5 mg)
was obtained as an off-white solid; mp 106–111 °C; 40% ee [HPLC
(Chiralpak AD-H; hexane/i-PrOH, 9:1; 25 °C; 1 mL/min; 254 nm): tr =
10.9 (major), 18.9 (major) min]; []D20 –60.4 (c 0.08, acetone).
1H NMR (400 MHz, CDCl3):  = 4.68 (br s), 3.44 (t, J = 4.6 Hz, 1 H),
2.63–2.38 (m, 4 H), 1.85–1.61 (m, 2 H), 1.43–1.23 (m, 7 H), 1.18–1.04
(m, 1 H), 0.91–0.83 (m, 3 H).
(R)-2-Amino-4-(4-nitrophenyl)-7-oxo-4,5,6,7-tetrahydrocyclo-
penta[b]pyran-3-carbonitrile (3i)
By following the general procedure, compound 3i (79% yield, 16.7 mg)
was obtained as an orange solid; mp 214 °C (decomp); 59% ee [HPLC
(Chiralpak AD-H; hexane/i-PrOH, 8:2; 25 °C; 1 mL/min; 254 nm): tr =
21.6 (major), 30.0 (minor) min]; []D20 –65.8 (c 0.14, acetone).
13C NMR (101 MHz, CDCl3):  = 197.0, 160.6, 149.8, 146.9, 119.5, 58.0,
35.5, 33.0, 32.8, 31.8, 29.4, 25.1, 23.3, 22.7, 14.2.
IR: 3330, 2193, 1716, 1679, 1610, 1519, 1491, 1458, 1425, 1107, 746
HRMS (ESI): m/z [M + H]+ calcd for [C15H21N2O2]+: 261.1598; found:
261.1575.
cm–1
.
1H NMR (400 MHz, (CD3)2CO):  = 8.33–8.22 (m, 2 H), 7.71–7.62 (m,
2 H), 6.46 (br s, 2 H), 4.75 (s, 1 H), 2.53 (ddt, J = 17.2, 6.4, 1.8 Hz, 1 H),
2.45–2.30 (m, 2 H), 2.20 (ddt, J = 17.2, 6.2, 1.3 Hz, 1 H).
(4S,4aS,7aR)-2-Amino-7-oxo-4-phenyl-4,4a,5,6,7,7a-hexahydrocy-
clopenta[b]pyran-3-carbonitrile (4a)
13C NMR (101 MHz, (CD3)2CO):  = 197.0, 161.2, 149.5, 148.5, 146.6,
130.3, 124.8, 119.5, 57.1, 42.7, 33.4, 23.5.
HRMS (ESI): m/z [M – H]– calcd for [C15H10N3O4]–: 296.0677; found:
296.0520.
Compound 3a (35 mg, 0.14 mmol) was dissolved in acetone (14 mL,
0.01 M). The reaction parameters were set on the H-Cube Pro: full H2,
50 bar, 50 °C and 0.8 mL/min flow rate. The instrument was fitted
with 10% Pd/C CatCart and the process was started. After evaporation
the mixture was purified by column chromatography (CH2Cl2/EtOAc,
12:1→5:1) to afford the product 4a (58% yield, 20.5 mg) as a light-or-
ange solid; mp 148–150 °C.
(R)-2-Amino-4-(3-nitrophenyl)-7-oxo-4,5,6,7-tetrahydrocyclo-
penta[b]pyran-3-carbonitrile (3j)
IR: 3340, 2948, 2183, 1752, 1596, 1492, 1453, 1411, 1129, 752 cm–1
.
By following the general procedure, compound 3j (87% yield, 18.8 mg)
was obtained as a pale-yellow solid; mp 208 °C (decomp); 40% ee
[HPLC (Chiralpak AD-H; hexane/i-PrOH, 8:2; 25 °C; 1 mL/min; 254
1H NMR (400 MHz, CDCl3):  (major diastereomer) = 7.36–7.31 (m,
2 H), 7.31–7.27 (m, 1 H), 7.24–7.18 (m, 2 H), 4.61 (br s, 2 H), 4.35 (d,
J = 5.1 Hz, 1 H), 4.05 (d, J = 6.7 Hz, 1 H), 2.65 (dtd, J = 9.4, 6.7, 5.3 Hz,
1 H), 2.00 (dd, J = 8.7, 4.7 Hz, 2 H), 1.86 (dq, J = 13.3, 9.1 Hz, 1 H), 1.55
(ddt, J = 13.0, 7.7, 4.4 Hz, 1 H).
13C NMR (101 MHz, CDCl3):  (major diastereomer) = 209.7, 162.9,
138.7, 128.8, 128.5, 127.8, 120.4, 79.5, 57.5, 39.0, 38.0, 34.5, 21.4.
20
nm): tr = 20.0 (major), 27.5 (minor) min]; []D –48.8 (c 0.11, ace-
tone).
IR: 3318, 2192, 1722, 1683, 1648, 1590, 1526, 1413, 1112, 758 cm–1
.
1H NMR (400 MHz, (CD3)2CO):  = 8.24–8.19 (m, 2 H), 7.85 (dt, J = 7.6,
1.3 Hz, 1 H), 7.77–7.70 (m, 1 H), 6.47 (br s, 1 H), 4.80 (s, 1 H), 2.54
(ddt, J = 17.5, 6.4, 1.9 Hz, 1 H), 2.49–2.31 (m, 2 H), 2.20 (ddt, J = 17.5,
6.4, 1.8 Hz, 1 H).
HRMS (ESI): m/z [M + H]+ calcd for [C15H15N2O2]+: 255.1128; found:
255.1134.
13C NMR (101 MHz, (CD3)2CO):  = 197.1, 161.7, 149.7, 146.8, 146.6,
144.6, 135.5, 131.2, 123.7, 123.6, 119.5, 57.3, 42.7, 33.5, 23.5.
HRMS (ESI): m/z [M + H]+ calcd for [C15H12N3O4]+: 298.0822; found:
Funding Information
298.0804.
The authors thank the Estonian Ministry of Education and Research
(Haridus- ja Teadusministeerium grant nos. IUT 19-32, IUT 19-9, and
PUT 1468) and the Centre of Excellence in Molecular Cell Engineering
(R)-2-Amino-7-oxo-4-(thiophen-2-yl)-4,5,6,7-tetrahydrocyclo-
penta[b]pyran-3-carbonitrile (3k)
(2014-2020.4.01.15-0013) for financial support.
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By following the general procedure, compound 3k (58% yield, 10.7
mg) was obtained as a brown solid; mp 207 °C (decomp); 74% ee
[HPLC (Chiralpak AD-H; hexane/EtOH/IPA, 90:5:5; 25 °C; 1 mL/min;
254 nm): tr = 44.0 (major), 63.3 (minor) min]; []D20 –94.4 (c 0.06, ac-
etone).
Acknowledgment
The authors thank Dr Aleksander-Mati Müürisepp for IR spectra.
IR: 3323, 3108, 2921, 2195, 1715, 1678, 1637, 1590, 1402, 1111, 779,
728 cm–1
.
Supporting Information
1H NMR (400 MHz, CDCl3):  = 7.32–7.28 (m, 1 H), 7.02–6.7 (m, 2 H),
4.80 (br s, 1 H), 4.74 (s, 1 H), 2.57–2.39 (m, 4 H).
Supporting information for this article is available online at
https://doi.org/10.1055/s-0039-1690484.
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© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–G

G
E. Silm et al.
Paper
Synthesis
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© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–G