Organocatalytic conjugate addition promoted by multi-hydrogen-bond cooperation: Access to chiral 2-amino-3-nitrile-chromenes

Article abstract of DOI:10.1039/c2ob27102h

A new efficient enantioselective conjugate addition strategy has been disclosed to rapidly construct 2-amino-3-nitrile-chromene complexes via a multi-hydrogen-bond cooperative activation model. The Royal Society of Chemistry 2013.

Full text of DOI:10.1039/c2ob27102h

Organic &
Biomolecular
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Organocatalytic conjugate addition promoted by
multi-hydrogen-bond cooperation: access to chiral
Cite this: Org. Biomol. Chem., 2013, 11,
400
2-amino-3-nitrile-chromenes†
Received 28th October 2012,
Accepted 20th November 2012
Wenjun Li, Jiayao Huang and Jian Wang*
DOI: 10.1039/c2ob27102h
www.rsc.org/obc
A new efficient enantioselective conjugate addition strategy has carbonitrile and its derivatives synthesis via
a cascade
been disclosed to rapidly construct 2-amino-3-nitrile-chromene Michael-cyclization sequence.5b,c More recently, our group
complexes via
a
multi-hydrogen-bond cooperative activation described a new example of an indane amine–thiourea organo-
catalyst catalyzed asymmetric reaction of tertbutyl(2-hydroxy-
phenyl)-
model.
(phenylsulfonyl)methylcarbamate with malononitrile to afford
similar 2-amino-3-nitrile-chromenes with good to excellent
enantioselectivities.5d However, limited substrate scope and
Introduction
The importance of heterocycles has been fully demonstrated
in medicinal chemistry. For example, a very large number of
drug molecules contain heterocycles.1 Therefore, the develop-
ment of efficient methods for rapid construction of hetero-
cycles has received great attention. In recent elegant reports,
2-amino-3-nitrile-chromenes have been proved to be an impor-
tant class of heterocyclic compounds and indicated as
common structural motifs in a diverse set of biologically
important molecules,2 such as mitogen-activated protein
kinase inhibitors,2e tumor antagonists2f and anticancer
drugs.2g–i Although a number of methods have been reported,
these are mostly focused on racemic synthesis of 2-amino-3-
nitrile-chromenes.3 Given the fact that enantiomers often indi-
cate distinct biological activity, the efficient access to optically
pure 2-amino-3-nitrile-chromenes would be extremely desir-
able to further study the correlation between the chirality and
their propensities for biological activities to acquire more
potent and appropriate pharmaceutical candidates.4 To date,
examples on the enantioselective assembly of 2-amino-3-
nitrile-chromene structures are still rather scarce.5 Recently,
Xie and co-workers reported an asymmetric reaction of α,β-un-
saturated ketones with malononitrile to give chiral 2-amino-3-
nitrile-chromenes with high enantioselectivities (up to 96%
ee).5a Later, the Zhao group described 4H-chromene-3-
inconvenient starting materials preparation in the
above examples largely reduce the synthetic attractiveness.
Therefore, advantageous methodology in terms of enantio-
selectivity, starting materials availability, operational simplicity
and high levels of functional group tolerance is still in high
demand.
As part of our efforts toward the efficient synthesis of
2-amino-3-nitrile-chromenes, we decided to seek a new class of
readily available starting materials.
A designed Michael
addition triggered cascade reaction of malononitrile with
diethyl benzylidenemalonate was tested (Scheme 1). Neverthe-
less, none of the desired product was afforded (Scheme 1, no
reaction). In this communication, we describe a new develop-
ment of a valuable catalytic process to construct enantiomeric
2-amino-3-nitrile-chromenes through 2-iminochromenes and
malonates (Scheme 1). Some noteworthy attributes of the
system include reaction mildness (room temperature), easy-
preparation of starting materials (note: one-step synthesis of
Department of Chemistry, National University of Singapore, Block S15, Level 5,
3 Science Drive 3, Singapore 11754, Singapore. E-mail: chmwangj@nus.edu.sg;
Fax: +(65) 6779 169; Tel: +(65) 6516 1760
†Electronic supplementary information (ESI) available. CCDC 903822. For ESI
and crystallographic data in CIF or other electronic format see DOI: 10.1039/
c2ob27102h
Scheme 1 Controlled experiments.
400 | Org. Biomol. Chem., 2013, 11, 400–406
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Scheme 2 Reaction feasibility investigation.
Fig. 1 Screened organocatalysts.
Table 1 Optimization of reaction conditionsa
Scheme 3 Proposed catalytic model.
Entry
Cat.
Solvent
R
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
I
II
III
IV
V
VI
VI
VI
VI
VI
VI
VI
VI
VI
VI
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
Toluene
Anisole
THF
Et (2a)
Et (2a)
Et (2a)
Et (2a)
Et (2a)
Et (2a)
Et (2a)
Et (2a)
Et (2a)
Et (2a)
Et (2a)
Me (2b)
i-Pr (2c)
t-Bu (2d)
Bn (2e)
54
74
52
62
82
85
85
88
90
82
83
81
85
<10
83
0
31
0
pure 2-iminochromenes with no flash chromatography), and
high levels of stereo-control.
15
−50
61
60
64
81
84
85
77
94
Results and discussion
9
10
11
12
13e
14
15
CPMEd
Et2O
In the course of our initial study, we made an interesting
finding (Scheme 2): the use of coumarin (1a, X = O, Y = H) as
an electrophile resulted in no formation of the desired product
3aa in the presence of diethyl malonate 2a and 10 mol%
quinine as the catalyst. We envision that the electrophilicity of
C4 may be the critical factor in this transformation. Then two
Et2O
Et2O
Et2O
Et2O
f
—
55
a Reaction condition: a mixture of 1d (0.10 mmol), 2a–e (0.30 mmol),
Cat. (10 mol%) in DCM (0.5 mL) was stirred at room temperature for
other controlled experiments were examined via the introduc- 12 h. b Isolated yield. c Determined by HPLC. d CPME refers to
cyclopentyl methyl ether. e 24 h. f Not determined.
tion of more electron-withdrawing groups to the C3 of the cou-
marin skeleton. However, two designed substrates (1b (X = O,
Next, we turned to explore an asymmetric version of
2-amino-3-nitrile-chromenes synthesis via chiral catalysts pro-
moted Michael addition of malonates to 2-iminochromenes.
Our initial investigation commenced with evaluating various
organocatalysts (Fig. 1). Recently, our group reported a new
indane amine–thiourea catalytic system (Fig. 1).5d,6 Thereafter,
we firstly sought to expand its usage to this new asymmetric
transformation. As shown in Table 1, 2-iminochromene 1d
reacted with diethyl malonate 2a in the presence of indane
amine–thiourea catalysts I–II, but achieved low levels of
enantioselectivity (entries 1–2, 0% ee and 31% ee, respect-
ively). To enhance the enantiocontrol, some other bifunctional
amine–thiourea catalysts III–VI (Fig. 1) were evaluated continu-
ously. To our delight, the use of quinine–thiourea catalyst VI7
resulted in a significantly improved enantioselectivity (Table 1,
Y = CO2Et) and 1c (X = O, Y = CN)) both indicated no enhanced
reactivity (Scheme 2, <5% yield). Surprisingly, if we use “NH”
to replace “O” (1c vs. 1d), the corresponding product 3da was
obtained with an 82% yield (Scheme 2). On the basis of struc-
ture difference of 1c and 1d, we envision that the “NH” group
may provide an additional binding force to allow compound
1d to react with nucleophile 2a more efficiently. Based on the
above assumption, we proposed a catalytic model (Scheme 3).
In general, the compound 1c can work as a hydrogen bond
acceptor. However, the compound 1d can work as not only a
hydrogen bond acceptor, but also a hydrogen bond donor. As
highlighted in Scheme 3, the tertiary amine functional group, a
Brønsted base of the catalyst, can activate 1d through two poten-
tial H-bondings. This multiple H-bondings cooperated catalytic
model may lead ultimately to higher activity in the reaction.
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Table 2 Substrate scopea
Entry
R1
R2
R3
Product
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
H
4-Br
4-Cl
4-F
4-NO2
4-Me
4-OMe
3-OMe
2-Allyl
2-Br-4-Cl
2,4-Br2
2,4-Cl2
4-Br
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
Et
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
F
3dc
3ec
3fc
3gc
3hc
3ic
3jc
3kc
3lc
3mc
3nc
3oc
3ea
3na
3eb
3df
85
87
93
91
92
89
80
91
81
94
88
81
90
92
85
91
94
95
96
96
96
91
91
84
89
84
84
82
86
95
96
95
Fig. 2 X-ray crystal structure of 3na.
Conclusions
In summary, we have developed a new efficient enantioselec-
tive conjugate addition of malonates to 2-iminochromenes
mediated by a thiourea catalyst VI. The method generates
2-amino-3-nitrile-chromenes in good to excellent yields
(80–94%) and with high levels of enantioselectivities (82–96%
ee). It is worth noting that our method provides a rapid entry
to 2-amino-3-nitrile-chromene complex structures from simple
starting materials in a highly enantioselective manner. Further
studies with respect to additional molecular complexity and
mechanistic insights are in progress in our laboratory.
9
10
11
12
13
14
15
16
2,4-Br2
4-Br
H
Et
Me
i-Pr
a Reaction conditions: 1 (0.10 mmol), 2c (0.30 mmol), VI (10 mol%),
Et2O (0.5 mL), room temperature, 24 h. b Isolated yield. c Determined
by chiral HPLC.
entry 6, 61% ee). Further optimization of other reaction para-
meters revealed that the solvent is one of the crucial factors for
enantioselectivity. When the reaction was carried out in THF,
cyclopentyl methyl ether (CPME) or Et2O, the results were
positively influenced, leading to the corresponding product
3da in high yields and high ee values (Table 1, entries 9–11,
82–90% yield, 81–95% ee). After a comprehensive evaluation,
Et2O was finally selected as the ideal reaction medium for
further optimization. In the process of further enhancing enantio-
control, we found that the size of dialkyl malonates largely
affected the results (entries 12–14). As highlighted in Table 1, a
suitable size based diisopropyl malonate 2c eventually supported
the highest enantioselectivity (entry 13, 85% yield, 94% ee, 24 h).
With the optimized reaction conditions in hand, we then
investigated the generality of 2-iminochromenes 1. As presented
in Table 2, the substitution pattern of 2-iminochromenes could
be varied successfully: C4-substituted electron-withdrawing,
neutral and electron-donating substituents were tolerated and
demonstrated remarkably high yields and ees in all cases
(entries 1–7, 3dc–jc, 85–93% yield, 91–96% ee). In addition, sub-
strates with electron-withdrawing and/or electron-donating sub-
stituents at the 2- or 3-position also showed high degrees of
reactivities and enantioselectivities in generating the desired pro-
ducts (entries 8–12, 3kc–oc). Notably, variation of dialkyl malo-
nates 2 can also be tolerated in the reaction and gave a
corresponding good result (entries 13–15, 85–92% yield, 86–96%
ee). Moreover, 2-fluorated diisopropyl malonate 2f also showed
high activity and provided excellent enantiocontrol (entry 16,
91% yield, 95% ee). The absolute configuration of the products
was determined by single-crystal X-ray analysis of 3na (Fig. 2).8
Experimental
General methods
Chemicals and solvents were purchased from commercial sup-
pliers and used as received. 1H and 13C NMR spectra were
recorded on a Bruker ACF300 (300 MHz) or AMX500 (500 MHz)
spectrometer. Chemical shifts were reported in parts per
million (ppm), and the residual solvent peak was used as an
internal reference: proton (chloroform δ 7.26), carbon (chloro-
form δ 77.0) or tetramethylsilane (TMS δ 0.00) was used as a
reference. Multiplicity was indicated as follows: s (singlet), d
(doublet), t (triplet), q (quartet), m (multiplet), dd (doublet of
doublets), bs (broad singlet). Coupling constants were reported
in Hertz (Hz). Low resolution mass spectra were obtained on a
Finnigan/MAT LCQ spectrometer in ESI mode, and a Finni-
gan/MAT 95XL-T mass spectrometer in EI mode. All high
resolution mass spectra were obtained on a Finnigan/MAT
95XL-T mass spectrometer. For thin layer chromatography
(TLC), Merck pre-coated TLC plates (Merck 60 F254) were used,
and compounds were visualized with a UV light at 254 nm.
Further visualization was achieved by staining with KMnO4
solution, or ninhydrin followed by heating using a heat gun.
Flash chromatography separations were performed on Merck
60 (0.040–0.063 mm) mesh silica gel. The enantiomeric
excesses of products were determined by chiral phase HPLC
analysis. Optical rotations were recorded on a Jasco DIP-1000
polarimeter.
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General procedure
35.7. MS (ESI) m/z [M + Na+]: 476.91. HRMS (ESI): exact mass
calculatd for [M + Na+] (C27H22N2O5Na) 477.1422, found m/z
477.1421. The enantiomeric excess was determined to be 55%
by HPLC. [IC column, 254 nm, n-hexane : IPA = 9 : 1, 1.0 mL
min−1]: 47.6 min (minor), 54.0 min (major).
To a solution of Et2O (0.5 mL) were added chromene deriva-
tives 1 (0.10 mmol), malonate 2 (0.30 mmol) and catalyst VI
(0.01 mmol). The reaction mixture was stirred at room temp-
erature for the time given and then the solvent was removed
under vacuum. The residue was purified by column chromato-
graphy on silica gel, eluting with hexane–EtOAc (10 : 1 to 5 : 1),
to afford the desired product.
(R)-DIETHYL 2-(2-AMINO-3-CYANO-4H-CHROMEN-4-YL)MALONATE (3DA).
Yellow oil. [α]D25 = −1.5 (c = 0.50, CH2Cl2); 1H NMR (CDCl3,
500 MHz): δ (ppm) 7.29–7.28 (m, 1H), 7.25–7.21 (m, 1H),
7.11–7.10 (m, 1H), 7.00–6.97 (m, 1H), 4.73–4.72 (br, 2H), 4.39
(d, J = 9.0 MHz, 1H), 4.20–4.15 (m, 2H), 4.12–4.08 (m, 2H), 3.63
(d, J = 9.0 MHz, 1H), 1.26–1.14 (m, 6H). 13C NMR (CDCl3,
125 MHz): δ (ppm) 167.1, 167.0, 162.3, 150.0, 128.7, 128.4,
124.9, 120.8, 119.4, 116.3, 61.7, 61.6, 58.9, 55.9, 35.5, 13.8,
13.7. MS (ESI) m/z [M + Na+]: 352.91. HRMS (ESI): exact mass
calculated for [M + Na+] (C17H18N2O5Na) 353.1121, found m/z
353.1108. The enantiomeric excess was determined to be 85%
by HPLC. [ID column, 254 nm, n-hexane : IPA = 9 : 1, 1.0 mL
min−1]: 38.8 min (major), 43.2 min (minor).
(R)-DIMETHYL 2-(2-AMINO-3-CYANO-4H-CHROMEN-4-YL)MALONATE (3DB).
Yellow oil. [α]D25 = +4.1 (c = 0.50, CH2Cl2); 1H NMR (CDCl3,
500 MHz): δ (ppm) 7.24–7.23 (m, 2H), 7.13–7.10 (m, 1H),
7.01–6.99 (m, 1H), 4.78–4.77 (br, 2H), 4.39–4.37 (m, 1H), 3.73
(s, 3H), 3.66–3.64 (m, 4H). 13C NMR (CDCl3, 125 MHz):
δ (ppm) 167.4, 162.4, 150.0, 128.8, 128.2, 125.0, 120.7, 119.3,
116.4, 58.6, 55.7, 52.6, 52.5, 35.8. MS (ESI) m/z [M + Na+]:
324.92. HRMS (ESI): exact mass calculated for [M + Na+]
(C15H14N2O5Na) 325.0801, found m/z 325.0795. The enantio-
meric excess was determined to be 77% by HPLC. [OJ-H
column, 254 nm, n-hexane : IPA = 4 : 1, 1.0 mL min−1]:
18.9 min (minor), 24.5 min (major).
(R)-DIISOPROPYL 2-(2-AMINO-6-BROMO-3-CYANO-4H-CHROMEN-4-YL)MAL-
1
ONATE (3EC). Yellow oil. [α]D25 = +4.6 (c = 0.50, CH2Cl2); H NMR
(CDCl3, 500 MHz): δ (ppm) 7.46–7.45 (m, 1H), 7.36–7.32 (m,
1H), 6.86 (d, J = 14.5 MHz, 1H), 5.12–5.03 (m, 1H), 4.98–4.90
(m, 1H), 4.79–4.78 (br, 2H), 4.33 (d, J = 8.5 MHz, 1H), 3.59 (d,
J = 8.5 MHz, 1H), 1.25–1.21 (m, 6H), 1.15–1.12 (m, 6H). 13C
NMR (CDCl3, 125 MHz): δ (ppm) 166.7, 166.4, 161.7, 149.2,
131.6, 131.3, 122.8, 119.0, 117.9, 117.2, 69.7, 69.4, 59.0, 56.2,
35.0, 21.6, 21.5, 21.4, 21.3. MS (ESI) m/z [M
+
Na+]:
460.89. HRMS (ESI): exact mass calculated for [M + Na+]
(C19H21BrN2O5Na) 459.0536, found m/z 459.0526. The enantio-
meric excess was determined to be 95% by HPLC. [ID column,
254 nm, n-hexane : IPA = 4 : 1, 1.0 mL min−1]: 9.1 min (major),
10.3 min (minor).
(R)-DIISOPROPYL
2-(2-AMINO-6-CHLORO-3-CYANO-4H-CHROMEN-4-YL)-
MALONATE (3FC). Yellow oil. [α]2D5 = +2.5 (c = 0.50, CH2Cl2);
1H NMR (CDCl3, 500 MHz): δ (ppm) 7.31–7.30 (m, 1H),
7.20–7.17 (m, 1H), 6.91 (d, J = 14.5 MHz, 1H), 5.11–5.03 (m,
1H), 4.97–4.89 (m, 1H), 4.85–4.84 (br, 2H), 4.32 (d, J =
8.5 MHz, 1H), 3.58 (d, J = 8.5 MHz, 1H), 1.24–1.22 (m, 6H),
1.15–1.12 (m, 6H). 13C NMR (CDCl3, 125 MHz): δ (ppm) 166.7,
166.4, 161.8, 148.6, 129.7, 128.6, 128.3, 122.3, 117.5, 69.7, 69.4,
58.9, 55.9, 35.0, 21.5, 21.4, 21.3, 21.2. MS (ESI) m/z [M + Na+]:
414.97. HRMS (ESI): exact mass calculated for [M + Na+]
(C19H21ClN2O5Na) 415.1030, found m/z 415.1031. The enantio-
meric excess was determined to be 96% by HPLC. [ID column,
254 nm, n-hexane : IPA = 4 : 1, 1.0 mL min−1]: 8.7 min (major),
10.0 min (minor).
(R)-DIISOPROPYL
2-(2-AMINO-3-CYANO-6-FLUORO-4H-CHROMEN-4-YL)-
(R)-DIISOPROPYL
2-(2-AMINO-3-CYANO-4H-CHROMEN-4-YL)MALONATE
MALONATE (3GC). Yellow oil. [α]2D3 = +21.4 (c = 1.0, CH2Cl2); 1H
NMR (CDCl3, 500 MHz): δ (ppm) 7.08 (d, J = 8.5 MHz, 1H),
6.93 (d, J = 5.5 MHz, 2H), 5.09–5.04 (m, 1H), 4.95–4.90 (m, 1H),
4.81–4.80 (br, 2H), 4.34 (d, J = 4.5 MHz, 1H), 3.58 (d, J =
4.5 MHz, 1H), 1.24–1.22 (m, 6H), 1.13–1.11 (m, 6H). 13C NMR
(CDCl3, 125 MHz): δ (ppm) 166.8, 166.5, 162.0, 160.0, 158.1,
146.2, 122.4, 122.3, 119.3, 117.6, 117.5, 115.3 (q, J = 45.0 MHz,
1H), 69.7, 69.4, 59.0, 55.8, 35.3, 21.6, 21.5, 21.4, 21.3. MS (ESI)
m/z [M + Na+]: 398.98. HRMS (ESI): exact mass calculated for
[M + Na+] (C19H21FN2O5Na) 399.1333, found m/z 399.1327. The
enantiomeric excess was determined to be 96% by HPLC.
[ID column, 254 nm, n-hexane : IPA = 4 : 1, 1.0 mL min−1]:
8.7 min (major), 9.7 min (minor).
(3DC). Yellow oil. [α]2D5 = +11.8 (c = 0.50, CH2Cl2); 1H NMR
(CDCl3, 500 MHz): δ (ppm) 7.33–7.32 (m, 1H), 7.25–7.22 (m,
1H), 7.11–7.09 (m, 1H), 6.97–6.96 (m, 1H), 5.06–5.04 (m, 1H),
4.94–4.92 (m, 1H), 4.73–4.72 (br, 2H), 4.38 (d, J = 5.0 MHz,
1H), 3.59 (d, J = 5.0 MHz, 1H), 1.22–1.20 (m, 6H), 1.13–1.11 (m,
6H). 13C NMR (CDCl3, 125 MHz): δ (ppm) 166.9, 166.5, 161.9,
150.0, 128.6, 128.5, 124.8, 120.7, 116.2, 69.3, 69.2, 59.2, 56.4,
35.1, 21.5, 21.4, 21.3, 21.2. MS (ESI) m/z [M
+
Na+]:
381.01. HRMS (ESI): exact mass calculated for [M + Na+]
(C19H22N2O5Na) 381.1437, found m/z 381.1421. The enantio-
meric excess was determined to be 94% by HPLC. [ID column,
254 nm, n-hexane : IPA = 4 : 1, 1.0 mL min−1]: 11.3 min
(major), 14.3 min (minor).
(R)-DIISOPROPYL 2-(2-AMINO-3-CYANO-6-NITRO-4H-CHROMEN-4-YL)MALO-
(R)-DIBENZYL 2-(2-AMINO-3-CYANO-4H-CHROMEN-4-YL)MALONATE (3DE).
Yellow oil. [α]D25 = −3.2 (c = 0.50, CH2Cl2); 1H NMR (CDCl3,
500 MHz): δ (ppm) 7.31–7.26 (m, 6H), 7.23–7.15 (m, 6H),
7.03–7.00 (m, 1H), 6.93–6.91 (m, 1H), 5.18–5.06 (m, 4H),
4.66–4.65 (br, 2H), 4.28 (d, J = 5.5 MHz, 1H), 3.60 (d, J =
5.0 MHz, 1H).13C NMR (CDCl3, 125 MHz): δ (ppm) 166.8,
166.7, 162.3, 149.9, 135.1, 135.0, 128.9, 128.8, 128.5, 128.4,
128.3, 125.0, 124.5, 120.4, 119.4, 116.4, 67.5, 67.4, 58.8, 55.7,
1
NATE (3HC). Yellow oil. [α]D25 = −4.6 (c = 0.50, CH2Cl2); H NMR
(CDCl3, 500 MHz): δ (ppm) 8.27–8.26 (m, 1H), 8.16–8.13 (m,
1H), 7.12 (d, J = 15.0 MHz, 1H), 5.12–5.08 (m, 1H), 4.97–4.92
(m, 3H), 4.45 (d, J = 7.5 MHz, 1H), 3.68 (d, J = 7.5 MHz, 1H),
1.28–1.22 (m, 6H), 1.17–1.13 (m, 6H). 13C NMR (CDCl3,
125 MHz): δ (ppm) 166.6, 166.3, 161.0, 154.3, 144.4, 124.7,
124.4, 121.9, 118.4, 117.2, 70.2, 69.7, 58.6, 56.2, 35.0, 21.6,
21.5, 21.4, 21.3. MS (ESI) m/z [M + Na+]: 426.01. HRMS (ESI):
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exact mass calculated for [M + Na+] (C19H21N3O7Na) 426.1275, exact mass calculated for [M + Na+] (C22H26N2O5Na) 421.1740,
found m/z 426.1272. The enantiomeric excess was determined found m/z 421.1734. The enantiomeric excess was determined
to be 96% by HPLC. [ID column, 254 nm, n-hexane : IPA = 4 : 1, to be 89% by HPLC. [ID column, 254 nm, n-hexane : IPA = 4 : 1,
1.0 mL min−1]: 13.4 min (minor), 15.7 min (major).
(R)-DIISOPROPYL
1.0 mL min−1]: 8.6 min (major), 10.9 min (minor).
(R)-DIISOPROPYL
2-(2-AMINO-3-CYANO-6-METHYL-4H-CHROMEN-4-YL)-
2-(2-AMINO-8-BROMO-6-CHLORO-3-CYANO-4H-
MALONATE (3IC). Yellow oil. [α]2D5 = +3.8 (c = 0.50, CH2Cl2); 1H CHROMEN-4-YL)MALONATE (3MC). Yellow oil. [α]D25 = +6.2 (c = 0.50,
NMR (CDCl3, 500 MHz): δ (ppm) 7.09–7.08 (m, 1H), 7.02–7.01 CH2Cl2); 1H NMR (CDCl3, 500 MHz): δ (ppm) 7.47 (d, J =
(m, 1H), 6.85 (d, J = 9.0 MHz, 1H), 5.08–5.03 (m, 1H), 4.97–4.92 4.0 MHz, 1H), 7.30 (d, J = 4.0 MHz, 1H), 5.12–5.04 (m, 1H),
(m, 1H), 4.87–4.86 (br, 2H), 4.33 (d, J = 5.0 MHz, 1H), 3.58 (d, 4.99–4.92 (m, 3H), 4.34 (d, J = 8.5 MHz, 1H), 3.58 (d, J =
J = 5.0 MHz, 1H), 2.28 (s, 3H), 1.23–1.22 (m, 6H), 1.15–1.12 (m, 8.5 MHz, 1H), 1.26–1.23 (m, 6H), 1.16–1.12 (m, 6H). 13C NMR
6H). 13C NMR (CDCl3, 125 MHz): δ (ppm) 166.9, 166.7, 162.2, (CDCl3, 125 MHz): δ (ppm) 166.6, 166.2, 161.6, 145.9, 131.9,
148.0, 134.4, 129.2, 128.7, 120.4, 119.6, 115.9, 69.4, 69.2, 59.3, 130.0, 127.7, 123.8, 118.5, 110.8, 69.9, 69.6, 59.0, 56.5, 35.6,
56.4, 35.3, 21.6, 21.5, 21.4, 20.7. MS (ESI) m/z [M + Na+]: 21.6, 21.5, 21.4, 21.3. MS (ESI) m/z [M + Na+]: 492.85. HRMS
395.00. HRMS (ESI): exact mass calculated for [M + Na+] (ESI): exact mass calculated for [M + Na+] (C19H20BrClN2O5Na)
(C20H24N2O5Na) 395.1581, found m/z 395.1577. The enantio- 493.0137, found m/z 493.0136. The enantiomeric excess was
meric excess was determined to be 91% by HPLC. [ID column, determined to be 84% by HPLC. [ID column, 254 nm,
254 nm, n-hexane : IPA = 4 : 1, 1.0 mL min−1]: 11.1 min n-hexane : IPA = 85 : 15, 1.0 mL min−1]: 9.5 min (major),
(major), 15.8 min (minor).
11.9 min (minor).
(R)-DIISOPROPYL 2-(2-AMINO-3-CYANO-6-METHOXY-4H-CHROMEN-4-YL)-
(R)-DIISOPROPYL 2-(2-AMINO-6,8-DIBROMO-3-CYANO-4H-CHROMEN-4-YL)-
MALONATE (3JC). Yellow oil. [α]2D5 = +0.6 (c = 0.50, CH2Cl2); 1H MALONATE (3NC). Yellow oil. [α]2D5 = +5.8 (c = 0.50, CH2Cl2);
NMR (CDCl3, 500 MHz): δ (ppm) 7.03–7.00 (m, 1H), 6.87 (d, J = 1H NMR (CDCl3, 500 MHz): δ (ppm) 7.61 (d, J = 4.0 MHz, 1H),
7.5 MHz, 1H), 6.81 (d, J = 7.5 MHz, 1H), 5.05–5.03 (m, 1H), 7.44 (d, J = 4.0 MHz, 1H), 5.10–5.06 (m, 1H), 4.97–4.93 (m, 3H),
4.95–4.91 (m, 3H), 4.36 (d, J = 5.0 MHz, 1H), 3.84 (s, 3H), 3.55 4.34 (d, J = 8.5 MHz, 1H), 3.58 (d, J = 8.5 MHz, 1H), 1.26–1.23
(d, J = 5.0 MHz, 1H), 1.22–1.20 (m, 6H), 1.15–1.10 (m, 6H). 13C (m, 6H), 1.16–1.13 (m, 6H). 13C NMR (CDCl3, 125 MHz):
NMR (CDCl3, 125 MHz): δ (ppm) 166.8, 166.6, 162.2, 147.3, δ (ppm) 166.6, 166.2, 161.6, 146.4, 134.7, 130.6, 124.3,
139.6, 124.5, 122.0, 119.9, 119.5, 110.9, 69.3, 69.2, 59.4, 55.9, 118.5, 117.2, 111.1, 70.0, 69.6, 59.1, 56.6, 35.5, 21.6, 21.5,
35.3, 21.5, 21.4, 21.3. MS (ESI) m/z [M + Na+]: 410.93. HRMS 21.4, 21.3. MS (ESI) m/z [M + Na+]: 533.66. HRMS (ESI):
(ESI): exact mass calculated for [M + Na+] (C20H24N2O6Na) exact mass calculated for [M + Na+] (C19H20Br2N2O5Na)
411.1537, found m/z 411.1527. The enantiomeric excess was 536.9629, found m/z 536.9631. The enantiomeric excess
determined to be 91% by HPLC. [ID column, 254 nm, was determined to be 84% by HPLC. [ID column, 254 nm,
n-hexane : IPA = 4 : 1, 1.0 mL min−1]: 16.1 min (major), n-hexane : IPA = 4 : 1, 1.0 mL min−1]: 7.7 min (major), 9.6 min
20.2 min (minor).
(R)-DIISOPROPYL 2-(2-AMINO-3-CYANO-7-METHOXY-4H-CHROMEN-4-YL)-
(minor).
(R)-DIISOPROPYL
2-(2-AMINO-6,8-DICHLORO-3-CYANO-4H-CHROMEN-4-
MALONATE (3KC). Yellow oil. [α]2D5 = +1.6 (c = 0.50, CH2Cl2); 1H YL)MALONATE (3OC). Yellow oil. [α]2D5 = +1.6 (c = 0.50, CH2Cl2);
NMR (CDCl3, 500 MHz): δ (ppm) 7.24–7.22 (m, 1H), 6.67–6.63 1H NMR (CDCl3, 500 MHz): δ (ppm) 7.32–7.31 (m, 1H),
(m, 1H), 6.50 (d, J = 4.0 MHz, 1H), 5.07–5.03 (m, 1H), 4.95–4.91 7.27–7.26 (m, 1H), 5.10–5.08 (m, 1H), 4.97–4.94 (m, 1H),
(m, 1H), 4.71–4.70 (br, 2H), 4.32 (d, J = 8.0 MHz, 1H), 3.77 (s, 4.84–4.83 (br, 2H), 4.36 (d, J = 5.0 MHz, 1H), 3.59 (d, J =
3H), 3.57 (d, J = 8.0 MHz, 1H), 1.23–1.21 (m, 6H), 1.15–1.12 (m, 5.0 MHz, 1H), 1.26–1.21 (m, 6H), 1.16–1.14 (m, 6H). 13C NMR
6H). 13C NMR (CDCl3, 125 MHz): δ (ppm) 167.1, 166.7, 161.9, (CDCl3, 125 MHz): δ (ppm) 166.5, 166.1, 161.4, 144.8, 129.6,
159.8, 150.7, 129.3, 119.5, 112.6, 111.0, 101.6, 69.3, 69.1, 59.2, 129.0, 126.9, 123.8, 122.3, 118.4, 69.9, 69.5, 58.9, 56.4, 35.4,
56.9, 55.9, 55.4, 34.6, 21.6, 21.5, 21.4. MS (ESI) m/z [M + Na+]: 21.5, 21.4, 21.3, 21.2. MS (ESI) m/z [M + Na+]: 448.93. HRMS
410.94. HRMS (ESI): exact mass calculated for [M + Na+] (ESI): exact mass calculated for [M + Na+] (C19H20Cl2N2O5Na)
(C20H24N2O6Na) 411.1529, found m/z 411.1527. The enantio- 449.0649, found m/z 449.0641. The enantiomeric excess was
meric excess was determined to be 84% by HPLC. [ID column, determined to be 82%, 81% by HPLC. [ID column, 254 nm,
254 nm, n-hexane : IPA = 4 : 1, 1.0 mL min−1]: 14.2 min n-hexane : IPA = 4 : 1, 1.0 mL min−1]: 7.2 min (major), 8.9 min
(major), 19.5 min (minor).
(minor).
(R)-DIISOPROPYL 2-(8-ALLYL-2-AMINO-3-CYANO-4H-CHROMEN-4-YL)MALO-
(R)-DIETHYL 2-(2-AMINO-3-CYANO-4H-CHROMEN-4-YL)-2-FLUOROMALO-
NATE (3LC). Yellow oil. [α]D25 = +6.2 (c = 0.50, CH2Cl2); H NMR NATE (3DF). Yellow oil. [α]2D5 = +10.8 (c = 0.50, CH2Cl2); H NMR
(CDCl3, 500 MHz): δ (ppm) 7.19–7.17 (m, 1H), 7.09–7.08 (m, (CDCl3, 500 MHz): δ (ppm) 7.33–7.30 (m, 1H), 7.24–7.21 (m,
1H), 7.05–7.03 (m, 1H), 5.94–5.89 (m, 1H), 5.08–5.00 (m, 3H), 1H), 7.15–7.10 (m, 1H), 7.06–7.03 (m, 1H), 4.93–4.92 (br, 2H),
4.94–4.91 (m, 1H), 4.75–4.74 (br, 2H), 4.37 (d, J = 5.5 MHz, 4.63 (d, J = 20.5 MHz, 1H), 4.42–4.35 (m, 2H), 4.27–4.19 (m,
1H), 3.55–3.51 (m, 1H), 3.45–3.35 (m, 2H), 1.23–1.21 (m, 6H), 2H), 1.36 (t, J = 12.0 MHz, 3H), 1.23 (t, J = 12.0 MHz, 3H). 13C
1.15–1.10 (m, 6H). 13C NMR (CDCl3, 125 MHz): δ (ppm) 166.9, NMR (CDCl3, 125 MHz): δ (ppm) 164.1, 151.2, 129.4, 128.4,
166.7, 162.2, 148.1, 135.8, 129.4, 127.3, 127.2, 126.8, 124.6, 125.0, 118.9, 117.6, 116.7, 97.5, 95.8, 63.2, 62.9, 60.4, 51.8,
121.0, 119.5, 117.1, 116.2, 69.4, 69.3, 59.5, 56.7, 35.5, 33.8, 41.6, 41.4, 21.0, 14.2, 13.8. MS (ESI) m/z [M + Na+]: 370.89.
1
1
33.1, 21.6, 21.4. MS (ESI) m/z [M + Na+]: 421.00. HRMS (ESI): HRMS (ESI): exact mass calculated for [M
+
Na+]
404 | Org. Biomol. Chem., 2013, 11, 400–406
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(C17H17FN2O5Na) 371.1021, found m/z 371.1014. The enantio-
meric excess was determined to be 86%, 95% by HPLC. [IC
column, 254 nm, n-hexane : IPA = 9 : 1, 1.0 mL min−1]:
44.2 min (minor), 48.9 min (major).
P. Taneja, A. Jha, O. D. Tyagi, A. K. Prasad, J. Wengel,
C. E. Olsen and P. M. Boll, Phytochemistry, 1997, 46, 597;
(c) J. Elguero, in Comprehensive Heterocyclic Chemistry, ed.
A. R. Katritzky, C. W. E. Rees and F. V. Scriven, Pergamon,
Oxford, 1996; (d) T. Eicher and S. Hauptmann, The Chemistry
(R)-DIETHYL
2-(2-AMINO-6-BROMO-3-CYANO-4H-CHROMEN-4-YL)MALO-
1
NATE (3EA). Yellow oil. [α]D25 = +7.0 (c = 0.50, CH2Cl2); H NMR
(CDCl3, 500 MHz): δ (ppm) 7.42–7.41 (m, 1H), 7.37–7.33 (m,
1H), 6.87 (d, J = 14.0 MHz, 1H), 4.83–4.82 (br, 2H), 4.33 (d, J =
of
Heterocycles,
Wiley-VCH,
Weinheim,
2003;
(e) A. R. Katrizky and A. F. Pozharskii, Handbook of Hetero-
cyclic Chemistry, Pergamon, Amsterdam, 2nd edn, 2000.
9.0 MHz, 1H), 4.24–4.10 (m, 4H), 3.62 (d, J = 9.0 MHz, 1H), 2 (a) M. M. Khafagy, A. H. F. A. El-Wahab, F. A. Eid and
1.25 (t, J = 12.0 MHz, 3H), 1.18 (t, J = 12.0 MHz, 3H). 13C NMR
(CDCl3, 125 MHz): δ (ppm) 166.9, 166.8, 161.9, 149.1, 131.6,
131.1, 122.8, 118.9, 117.9, 117.2, 61.8, 61.7, 58.6, 55.7, 35.2,
13.8, 13.7. MS (ESI) m/z [M + Na+]: 430.83. HRMS (ESI): exact
mass calculated for [M + Na+] (C17H17BrN2O5Na) 431.0220,
found m/z 431.0213. The enantiomeric excess was determined
to be 86% by HPLC. [IC column, 254 nm, n-hexane : IPA = 4 : 1,
1.0 mL min−1]: 12.3 min (major), 14.1 min (minor).
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ARKIVOC, 2009, 13, 363; (d) N. M. Sabry, H. M. Mohamed,
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Eur. J. Med. Chem., 2011, 46, 765; (e) D. R. Anderson,
S. Hegde, E. Reinhard, L. Gomez, W. F. Vernier, L. Lee,
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Med. Chem. Lett., 2005, 15, 1587; (f) J. L. Wang, D. Liu,
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2000, 97, 7124; (g) P. Vachal and E. N. Jacobsen, J. Am.
Chem. Soc., 2002, 124, 10012; (h) T. Okino, Y. Hoashi and
Y. Takemoto, J. Am. Chem. Soc., 2003, 125, 12672;
(i) T. Okino, Y. Hoashi, T. Furukawa and Y. T. X. Xu, J. Am.
Chem. Soc., 2005, 127, 119.
(R)-DIETHYL 2-(2-AMINO-6,8-DIBROMO-3-CYANO-4H-CHROMEN-4-YL)MAL-
1
ONATE (3NA). Yellow oil. [α]D25 = +7.8 (c = 0.50, CH2Cl2); H NMR
(CDCl3, 500 MHz): δ (ppm) 7.61 (d, J = 3.5 MHz, 1H), 7.37 (d,
J = 3.5 MHz, 1H), 5.05–5.04 (br, 2H), 4.30 (d, J = 9.0 MHz, 1H),
4.25–4.08 (m, 4H), 3.60 (d, J = 9.0 MHz, 1H), 1.26 (t, J =
12.0 MHz, 3H), 1.18 (t, J = 12.0 MHz, 3H). 13C NMR (CDCl3,
125 MHz): δ (ppm) 166.7, 166.6, 161.8, 146.4, 134.7, 130.4,
124.2, 117.2, 111.1, 62.0, 61.8, 58.6, 55.9, 35.7, 13.8, 13.7. MS
(ESI) m/z [M − H]−: 485.96. HRMS (ESI): exact mass calculated 3 For selected examples, see: (a) S. N. Murthy, B. Madhav,
for [M
+
Na+] (C17H16Br2N2O5Na) 508.9333, found m/z
V. P. Reddy and Y. V. D. Nageswar, Tetrahedron Lett., 2010,
51, 3649; (b) D. Grée, S. Vorin, V. L. Manthati, F. Caijo,
G. Viault, F. Manero, P. Juin and R. Grée, Tetrahedron Lett.,
2008, 49, 3276; (c) M. N. Elinson, A. S. Dorofeev,
F. M. Miloserdov, A. I. Ilovaisky, S. K. Feducovich,
P. A. Belyakov and G. I. Nikishina, Adv. Synth. Catal., 2008,
350, 591; (d) M. N. Elinson, A. I. Ilovaisky, V. M. Merkulova,
P. A. Belyakov, A. O. Chizhov and G. I. Nikishin, Tetrahedron,
2010, 66, 4043; (e) L. Moafi, S. Ahadi and A. Bazgir, Tetra-
hedron Lett., 2010, 51, 6270; (f) K. Kumaravel and G. Vasuki,
Green Chem., 2009, 1945; (g) N. Vidhya Lakshmi,
S. E. Kiruthika and P. T. Perumal, Synlett, 2011, 1389;
(h) Z.-H. Dong, X.-H. Liu, J.-H. Feng, M. Wang, L.-L. Lin and
X.-M. Feng, Eur. J. Org. Chem., 2011, 137; (i) W.-L. Chen,
Y.-F. Cai, X. Fu, X.-H. Liu, L.-L. Lin and X.-M. Feng, Org.
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508.9318. The enantiomeric excess was determined to be 95%
by HPLC. [ID column, 254 nm, n-hexane : IPA = 4 : 1, 1.0 mL
min−1]: 9.5 min (major), 10.9 min (minor).
(R)-DIMETHYL 2-(2-AMINO-6-BROMO-3-CYANO-4H-CHROMEN-4-YL)MALO-
1
NATE (3EB). Yellow oil. [α]D25 = +9.0 (c = 0.50, CH2Cl2); H NMR
(CDCl3, 500 MHz): δ (ppm) 7.36–7.34 (m, 2H), 6.90–6.87 (m,
1H), 4.91–4.90 (br, 2H), 4.31 (d, J = 10.0 MHz, 1H), 3.74 (s, 3H),
3.68 (s, 3H), 3.63 (d, J = 10.0 MHz, 1H). 13C NMR (CDCl3,
125 MHz): δ (ppm) 167.2, 167.1, 162.1, 149.1, 131.7, 130.9,
122.7, 118.0, 117.3, 58.2, 55.1, 52.7, 52.6, 35.5. MS (ESI) m/z
[M + Na+]: 404.73. HRMS (ESI): exact mass calculated for
[M + Na+] (C15H13BrN2O5Na) 402.9894, found m/z 402.9900.
The enantiomeric excess was determined to be 96% by HPLC.
[ID column, 254 nm, n-hexane : IPA = 9 : 1, 1.0 mL min−1]:
32.2 min (major), 33.4 min (minor).
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2001.
Acknowledgements
The authors acknowledge the Ministry of Education and
National Research Foundation (Singapore) for financial
support (MOE R143000480112 and NRF-CRP7-2010-03).
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Notes and references
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406 | Org. Biomol. Chem., 2013, 11, 400–406
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