Organocatalytic asymmetric allylic carbon-carbon bond formation

Article abstract of DOI:10.1039/b514564c

Organocatalytic allylic C-C bond-forming addition of activated alkylidenes to alkyl and aryl nitroalkenes has been achieved with high diastereo- and enantioselectivity. Chiral tertiary amine catalysts are used to give allyl intermediates which exhibit γ-s

Full text of DOI:10.1039/b514564c

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www.rsc.org/obc | Organic & Biomolecular Chemistry
Organocatalytic asymmetric allylic carbon–carbon bond formation†
Thomas B. Poulsen, Mark Bell and Karl Anker Jørgensen*
Received 14th October 2005, Accepted 31st October 2005
First published as an Advance Article on the web 23rd November 2005
DOI: 10.1039/b514564c
Organocatalytic allylic C–C bond-forming addition of activated alkylidenes to alkyl and aryl
nitroalkenes has been achieved with high diastereo- and enantioselectivity. Chiral tertiary amine
catalysts are used to give allyl intermediates which exhibit c-selectivity in the C–C bond forming step.
The reactions proceed with up to >99 : 1 syn : anti ratio for both the alkyl- and aryl nitroalkenes with
up 96% and 98% ee, respectively. The products of this conjugate addition are transformed into a range
of intermediates, such as optically active conjugated dienes and 1-substituted tetralones, which are
difficult to access via alternative methods.
The organocatalyzed asymmetric C–C bond formation by
Introduction
addition of carbon-electrophiles to the allylic position of acti-
vated alkylidenes has not yet been investigated in great detail.
A recent letter10 presenting the asymmetric direct vinylogues
Michael reaction of activated alkenes with aromatic nitroalkenes
prompted us to present a full account of our contribution towards
organocatalyzed asymmetric C–C bond formation by addition of
carbon-electrophiles to the allylic position of activated alkylidenes.
One of the fundamental reactions in organic chemistry is that
between active methylene compounds and carbonyl compounds
to give unsaturated (Knoevenagel) condensation products.1 Since
the first reports by Knoevenagel2 and the classic papers on the
efficient synthesis and reactivity of such systems3 (e.g. alkylidene
malonates, cyanoacetates, and malononitriles), attention from
the synthetic community has been continuous.4 Activated alkyli-
dene structures are common intermediates in complex molecule
synthesis, where their electrophilic character has been especially
exploited.5
As part of our recent research on organocatalyzed asymmetric
reactions,6 we have introduced a new concept exploiting the latent
nucleophilic reactivity of activated alkylidenes for performing
allylic aminations with excellent regio- and stereocontrol.7 This
concept relies on the deprotonation of an allylic hydrogen by a
chiral base.
Results and discussion
Our studies commenced by examining the feasibility of the
reaction between the alkylidene malononitrile 3a derived from
1-tetralone and Michael-acceptor trans-b-nitrostyrene 4a in the
presence of different cinchona alkaloid derivatives under various
reaction conditions [eqn (1), Table 1].11 The reaction was found
to take place smoothly, with near quantitative conversion to the
c−substituted product as well as traces of side products. To our
1
surprise, the H NMR spectrum of the reaction mixture showed
Scheme 1 shows the activated alkylidene systems (1), which
undergo a stereoselective electrophilic addition leading to a
substitution of the allylic C–H bond with the electrophile (E) via
a chiral ion-pair intermediate.
only one diastereoisomer. This turned out to be the case for all
screening experiments.
A screening of reaction conditions in CH2Cl2 showed that
(DHQD)2PYR was the most effective catalyst at −15 ◦C giving
95% conversion with 86% ee (entry 4). The quasienantiomer
(DHQ)2PYR gave the opposite configuration as expected with
76% ee (compare entries 3 and 4). Lower temperatures slightly
improved the enantiocontrol (86% ee at −15 ◦C and 92% ee at
−40 ◦C, entries 4 and 7). Poor conversion in the case of TBME as
the solvent is attributed to low solubility of the starting materials.
Surprisingly, acetone was identified as the best solvent for this
reaction (95% conversion, >99:1 dr and 95% ee, entry 12), which
is unusual for chiral ion-pair based reactions, and improves
the enantioselectivity of the reaction compared to CH2Cl2. It
should be noted that the reaction also proceeds in EtOAc with
excellent enantioselectivity (entry 11). The use of 1.5 equiv. of the
nitroalkene was found to be beneficial to the reaction rate.
The scope of the asymmetric allylic C–C bond-forming
reaction was probed using a range of nitroalkenes 4 reacting with
alkylidene malononitriles 3a [eqn (2), Table 2].
Scheme 1 Organocatalytic asymmetric electrophilic addition to allylic
C–H bonds.
Asymmetric functionalization of the allylic position plays an
important role in organic chemistry due to the great utility of the
optically active allylic compounds formed e.g. as intermediates in
total synthesis.8 Catalysis using chiral metal complexes, to give p-
allyl-metal intermediates, which undergo nucleophilic addition, is
a well developed method for asymmetric allylic functionalization.9
Danish National Research Foundation: Center for Catalysis, Department of
Chemistry, Aarhus University, DK-8000, Aarhus C, Denmark. E-mail: kaj@
chem.au.dk; Fax: +45 8619 6199; Tel: +45 8942 3910
† CCDC reference numbers [285436 and 285437]. For crystallographic
data in CIF or other electronic format see DOI: 10.1039/b514564c
Aryl and heteroaryl nitroalkenes reacted cleanly to give the
desired products in 92–99% yield with 92–98% ee (Table 2, entries
1–7, 9) with the exception of 2-Cl-trans-b-nitrostyrene (97% yield
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(1)
Table 1 Initial Screeninga
Entry
Cat./mol%
Temp./◦C
Solvent (0.25 M)
Time/h
Conv. (%)b
dr (syn/anti)b
ee (%)c
1
2
3
4
5
6
7
8
9
(DHQ)2AQN (10)
(DHQ)2PHAL (10)
(DHQ)2PYR (10)
(DHQD)2PYR (10)
(DHQD)2PYR (10)
(DHQD)2PYR (10)
(DHQD)2PYR (10)
(DHQD)2PYR (10)
(DHQD)2PYR (10)
(DHQD)2PYR (10)
(DHQD)2PYR (10)
(DHQD)2PYR (10)
−15
−15
−15
−15
−15
−15
−40
−40
−40
−40
−40
−40
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
Toluene
1,2-DCE
CH2Cl2
THF
16
24
16
14
14
20
40
20
20
20
20
25
>95
95
>95
>95
95
>95
>95
95
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
+50
+61
+76
−86
−88
−88
−92
−86
−90
−90
−95
−95
THF/Tol 1:4
TBME
EtOAc
68
10
11
12
11d
70
acetone
>95
a Reaction performed at a 0.15 mmol scale (3a) with 1.5 eq. of 4a. b Determined by 1H NMR analysis of the crude mixture. c Of the syn-isomer,
determined by CSP-HPLC analysis (see Experimental section for details). d Reaction mixture is heterogenous. TBME = tert-butyl methyl ether.
1,2-DCE = 1,2-dichloroethane.
and 53% ee, entry 8). This lower selectivity is possibly due to the
closeness of the ortho-substituent to the new C–C bond. Aromatic
substrates with a para- or meta-substituent reacted in a comparable
way to the benchmark reaction regardless of the electron density
of the aryl ring. The alkyl substituted nitroalkenes also reacted
smoothly to give high yields and enantioselectivities (82 and 99%
yield, 96 and 94% ee, entries 10 and 11). Only in two cases did we
Table 2 Reaction scope with respect to the electrophile (4)a
observe the formation of the anti-diastereomer, although in very
small amounts (entry 4, 13:1 and entry 11, 19:1). Our experiments
so far indicate, that the excellent diastereomeric ratios observed
are due to kinetic control and, therefore, not due to base-mediated
equilibration of the c-stereocenter.
The generality of the allylic functionalization as demonstrated
in Table 2 prompted us to investigate the reaction for a series of
alkylidene malononitriles 3b–i with trans-b-nitrostyrene 4a. The
results are presented in Table 3.
Increasing the ring-size to seven carbon atoms (3b) afforded
similar results to the six-membered system with the enantios-
electivity remaining high at 92% ee and a small decrease in
diastereoselectivity (15:1, Table 3, entry 1). Many important
bioactive compounds contain a methoxy-substituted aromatic
ring fused with a cyclohexane ring. We were therefore pleased
that placing a methoxy group in the 5, 6, or 7 position gave high
enantioselectivity (93, 96 and 94% ee), yield (90, 96 and 99%)
Entry
R3
Yieldb(%)
drc (syn/anti)
eed(%)
1
2e
3
4
5
6
7
8
9
C6H5
2-naphthyl
2-thienyl
5a-98(95)
5b-98
>99:1( >99:1)
>99:1
>99:1
13:1
>99:1
>99:1( >99:1)
>99:1
>99:1
>99:1
>99:1
95(89)
92
97
94
98
95(90)
96
53
91
96
5c-93
2-furyl
5d-99
4-MeO–C6H4
4-NO2–C6H4
4-Br–C6H4
2-Cl–C6H4
3-NO2–C6H4
c-hexyl
5e-97
5f-99(92)
5g-96
5h-97
5i-92
10
11
5j-82
n-pentyl
5k-99
19:1
94
a Reaction carried out with 0.25 mmol of 3a and 1.5 eq. of 4, values
in parenthesis obtained with the quasienantiomer (DHQ)2PYR in ace-
tone/THF (3:1). b Isolated yield. c Determined by 1H NMR. d Of the syn-
isomer determined by CSP-HPLC (see Experimental section). e Reaction
carried out in acetone/EtOAc (1:1, 0.25 M).
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Table 3 Reaction scope with different activated alkylidenes 3b–ia
Entry
Substrate
Product
Yield (%)b
dr (syn/anti)c
ee (%)d
92
1e
3b
5l-96
15:1
2
7-MeO-3c
5m-96(94)
>99:1( >99:1)
96(86)
3
4
5
6
7
6-MeO-3d
5-MeO-3e
6,7-MeO-3f
5,7-Me-3g
7-NO2-3h
5n-99
5o-90
5p-99
5q-95
>99:1
>99:1
>99:1
>99:1
—
94
93
80
91
—
f
—
8
3i
5r-95
>99:1
74
a Reaction carried out with 0.25 mmol of 3 and 1.5 eq. of 4a at −40 ◦C in acetone (0.25 M) in the presence of 10 mol% (DHQD)2PYR, value in parenthesis
obtained with the quasienantiomer (DHQ)2PYR in acetone/THF (3:1). b Isolated yield. c Determined by 1H NMR. d Of the syn-isomer determined by
CSP-HPLC (see Experimental section). e Reaction carried out in EtOAc (0.25 M). f No conversion observed, even at higher temperatures.
and diastereocontrol (>99:1 in all cases) (Table 3, entries 2–4).
An alkylidene possessing the ubiquitous 6,7-dimethoxy motif (3f)
reacted cleanly to give good, if slightly lower enantiocontrol (99%
yield and 80% ee, entry 5). The 5,7-dimethyl substituted compound
(3g) reacted with high yield and stereocontrol (95%, 91% ee, entry
6). Surprisingly the introduction of a nitro-group in the 7-position
of the alkylidene (3h) completely retarded the reaction even at
higher temperatures. Finally the 4-chromanone derived alkylidene
(3i) gave 95% yield and 75% ee (entry 8).
The absolute configuration of the products was established to
be (2S,3R) by examination of an X-ray crystal structure obtained
from the 4-Br substituted nitrostyrene (5g) (Table 4, Fig. 1).12,13
To show the ease with which the present reaction allows access
to larger quantities of enantiopure material, we subjected 10 mmol
Fig. 1 X-ray crystal structure of (2S,3R)-5g (most hydrogen atoms have
been omitted for clarity).
of alkylidene 3a and 1.1 eq. nitroalkene 4a to the standard reaction
conditions in the presence of 3 mol% of (DHQD)2PYR [eqn (3)].
After the nucleophile had been consumed as judged by TLC-
analysis the product was filtered through a short pad of silica
to remove the catalyst. Recrystalization from EtOH afforded the
Michael adduct as a single stereoisomer in 84% yield.
Table 4 Crystallographic data for 5g and 6
5g
6
Formula, weight
Crystal system
C21H16BrN3O2
orthorhombic
6.7062 (5)
12.4969 (10)
22.780 (2)
90
C21H17N3O2
monoclinic
8.990 (1)
23.048 (2)
15.980 (1)
90
96.130 (3)
90
3292.1 (4)
100 (1)
P2(1)/c
8, 2
˚
a, A
During the course of our initial studies we sometimes noted
the formation of intensely coloured orange/red reaction mixtures,
especially when the catalytic reactions were carried out at higher
temperatures. The origin of this phenomenon was identified to
be the formation of an interesting, highly conjugated three ring
system. Optically active diene 6 (structure confirmed by X-ray
analysis,12 Scheme 2) arises from an intramolecular cyclisation
between the nitroalkane and one of the cyano groups followed
by tautomerization. Previous reports on similar ring-closures
performed under harsher conditions14 yielded the fully aromatized
compounds. Different bases were evaluated for this transformation
(Scheme 2) and quinidine was found to give the highest isolated
yield.15 A chiral base is obviously not necessary to effect this
transformation, however, the efficiency of quinidine compared to
˚
b, A
˚
c, A
a, deg
b, deg
c , deg
90
90
3
˚
Volume, A
1909.1 (3)
150 (1)
P2(1)2(1)2(1)
4, 4
Temperature
Space group
Z, Zꢀ
l
2.174
0.091
Nmeas
38312
5814
0.043
0.061
0.064
−0.01 (1)
65363
4696
0.081
0.107
0.148
N/A
Nunique
Rint
R(F), all
Rw(F2), all
Flack
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Scheme 2 Ring-closing reaction of 5a to afford optically active diene 6 under different conditions. To the right, X-ray crystal structure of 6 (most
hydrogen atoms have been omitted for clarity).
achiral bases tested combined with its low cost renders this the
best alternative. In fact, the high loadings necessary of e.g. Et3N
to afford even low isolated yields of diene 6 leads to an erosion of
the optical purity (>99.9% ee to 93% ee). This observation might
be ascribed to racemization through a retro-Michael mechanism,
being increasingly favored under high base concentrations.
As mentioned in the introduction, activated alkylidene systems
are related to their parent carbonyl compounds through Kno-
Conclusions
In conclusion, we have presented a direct organocatalytic enan-
tioselective C–C bond forming reaction in the allylic position
of activated alkylidene systems. The reaction is broad in scope
and takes place with excellent regio- and diastereoselectivity,
and with good to excellent enantioselectivity for both aryl
and alkyl nitroalkenes. Furthermore, we have demonstrated the
synthetic utility of the optically active products by performing
reactions exploiting the electron-deficient alkylidene double bond.
Thus, oxidative cleavage of the alkylidene moiety allows for the
preparation of optically active substituted 1-tetralones.
evenagel condensation with malononitrile. Obviously, the reverse
transformation—i.e. the formation of the carbonyl compound
from the Knoevenagel condensation product—does not have
much synthetic relevance, unless the formation of the activated
alkylidene system allows for chemical transformations not possible
with the parent carbonyl compound. The similarity between the
=
CO and the C C(CN)2 functionality has been noted by several
groups.16 The similarity, however, is of course only qualitative,
and in fact very fundamental differences in reactivity do exist.
As we have demonstrated here and previously,7 the formation
of an activated alkylidene system permits deprotonation in the
a-position of the group (the c-position of the alkylidene system),
thereby enabling chiral base-catalyzed asymmetric reactions to be
performed. To the best of our knowledge, similar transformations
cannot be carried out on the parent carbonyl compound. Thus, the
C(CN)2 group can be regarded as a transient activating group in
a synthetic sequence towards the catalytic asymmetric functional-
ization of the carbonyl compound. In fact, the justification of this
indirect a-functionalization of carbonyl compounds is increased,
when efficient direct approaches to the same transformation are
not available—as is indeed currently the case for substituted 1-
tetralones (Scheme 3).17
Experimental
General Methods
NMR spectra were acquired on a Varian AS 400 spectrometer,
running at 400 and 100 MHz for 1H and 13C, respectively. Chemical
shifts (d) are reported in ppm relative to residual solvent signals. 13C
NMR spectra were acquired on a broad band decoupled mode.
Mass spectra were recorded on a micromass LCT spectrometer
using electrospray (ES+) ionization techniques. Flash column
chromatography (FC) was carried out using the FlashMaster II
from Jones Chromatography with columns containing silica gel.
Analytical thin layer chromatography (TLC) was performed using
pre-coated aluminium-backed plates (Merck Kieselgel 60 F254)
and visualized by ultraviolet irradiation or KMnO4 dip. Optical
rotations were measured on a Perkin-Elmer 241 polarimeter. The
enantiomeric excess (ee) of the products was determined by chiral
stationary phase HPLC (Daicel Chiralpak AS/AD or Daicel
Chiralcel OD columns).
Materials
Scheme 3 Indirect catalytic asymmetric functionalization of 1-tetralone,
via carbonyl activation, chiral base chemistry, and oxidative cleavage.
Analytical grade solvents were used as received. For flash
chromatography (FC) silica gel was purchased from Iatron
Laboratories Inc. (Iatrobeads 6RS-8060) or from Fluka (Silica
gel 60, 230–400 mesh). All catalysts are commercially available
and were used as received. Alkylidene malononitriles 3a and
3c-j were prepared from the corresponding commercially avail-
able ketone and malononitrile by Al2O3-mediated Knoevenagel
condensation.18 3b was prepared by condensing commercially
The desired oxidative cleavage could be carried out using
potassium permanganate in a mixture of acetone and water at
ambient temperature [eqn (4)]. After column chromatography,
optically active substituted 1-tetralone 7 was obtained as a single
stereoisomer in 77% yield.
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available 1-benzosuberone with malononitrile in the presence of
catalytic amounts of triethylamine.19 Nitroalkenes 4a,c-i were ob-
tained from commercial suppliers and used as received. Naphthyl-
substituted nitroalkene 4b was prepared by Henry-reaction,20
followed by elimination.21 Alkyl-substituted nitroalkenes 4j-k were
prepared according to a literature procedure.21
12.6, 5.2 Hz, 1H), 3.85 (dt, J 10.4, 5.2 Hz, 1H), 3.58 (td, J 11.0,
3.7 Hz, 1H), 3.04–3.07 (m, 1H), 2.91–2.94 (m, 1H), 1.99–2.08 (m,
2H). 13C NMR (CDCl3) d 174.0, 139.4, 138.1, 134.5, 129.9, 128.6,
127.8, 127.3, 127.0, 125.8, 113.0, 112.9, 81.3, 79.0, 45.8, 40.0, 25.5,
24.2. HRMS calc.: C19H15N3NaO2S 372.0783; found: 372.0791.
20
[a]D − 260 (c = 1.0, CH2Cl2, 93% ee). The ee was determined
by HPLC using a Chiralpak AD column [hexane/i-PrOH (90 :
10)]; flow rate 1.0 mL min−1; smajor = 15.4 min, sminor = 13.9 min
(97% ee).
Representive procedure for the enantioselective addition of
alkylidene malononitriles to conjugated nitroalkenes. Alkylidene
malononitrile 3a (0.25 mmol, 48.5 mg) and trans-b-nitrostyrene
(0.375 mmol, 56.1 mg) were mixed in a glass flask equipped with a
magnetic stirring bar. Solvent (1.0 mL) was added, and the mixture
was cooled to −78 ◦C. At this temperature (DHQD)2PYR (10
mol%, 0.025 mmol, 22 mg) was added, and the resulting mixture
was placed at −40 ◦C for the time specified below. The mixture was
then cooled to −78 ◦C and passed quickly through a short pad of
iatrobeads (elute Et2O) to remove the catalyst. The pure product
was obtained by FC on iatrobeads eluting with CH2Cl2/n-hexane
(50 : 50 to 100 : 0).
(S,R)-2-[2-(1-Furan-2-yl-2-nitro-ethyl)-3,4-dihydro-2H-naphthalen-
1-ylidene]-malononitrile (5d). The title compound was obtained
according to the general procedure (rea◦ction time 30 h) as a pale
yellow crystalline solid (mp = 165–167 C), yield 93%. 1H NMR
(CDCl3) d 7.99 (d, J 8.0 Hz, 1H), 7.56 (t, J 7.6 Hz, 1H), 7.36–7.40
(m, 2H), 7.31 (d, J 7.7 Hz, 1H), 6.32 (m, 1H), 6.26 (d, J 3.3 Hz,
1H), 4.73–4.78 (m, 1H), 4.39 (dd, J 12.7, 4.1 Hz, 1H), 3.68–3.70
(m, 2H), 3.00–3.04 (m, 1H), 2.90–2.92 (m, 2H), 2.06–2.08 (m,
1H), 1.80–1.85 (m, 1H). 13C NMR (CDCl3) d 174.1, 148.9, 143.5,
139.8, 134.6, 130.1, 128.8, 128.2, 127.5, 113.3, 113.1, 110.8, 110.0,
81.8, 76.5, 43.5, 39.0, 25.8, 24.7. HRMS calc.: C19H15N3NaO3
(S,R)-2-[2-(2-Nitro-1-phenyl-ethyl)-3,4-dihydro-2H-naphthalen-
1-ylidene]-malononitrile (5a). The title compound was obtained
according to the general procedure (reaction time 29 h, reaction
with (DHQ)2PYR 80 h) as a white crystalline solid (mp =
20
365.1011; found: 365.1006. [a]D − 321 (c = 1.0, CH2Cl2, 99%
ee). The ee was determined by HPLC using a Chiralpak AD
column [hexane/i-PrOH (90 : 10)]; flow rate 1.0 mL min−1; smajor
15.2 min, sminor = 13.7 min (95% ee).
=
◦
1
157–160 C), yield 98%. H NMR (CDCl3) d 8.08 (d, J 7.9 Hz,
1H), 7.60 (dt, J 7.6, 1.1 Hz, 1H), 7.26–7.44 (m, 7H), 4.70 (dd,
J 12.6, 10.2 Hz, 1H), 4.42 (dd, J 12.6, 5.1 Hz, 1H), 3.64 (dt, J
11.4, 3.4 Hz, 1H), 3.46 (td, J 11.0, 4.9 Hz, 1H), 3.02 (ddd, J
18.5, 11.9, 6.3 Hz, 1H), 2.88 (dd, J 18.6, 7.3 Hz, 1H), 1.94–2.03
(m, 1H), 1.77–1.85 (m, 1H). 13C NMR (CDCl3) d 174.5, 139.5,
136.0, 134.5, 130.0, 129.4 (2C), 128.7, 128.6, 127.8, 127.7 (2C),
127.3, 113.1 (2C), 81.0, 78.6, 44.7, 44.5, 25.4, 24.0. HRMS calc.:
(S,R)-2-{2-[1-(4-Methoxy-phenyl)-2-nitro-ethyl]-3,4-dihydro-2H-
naphthalen-1-ylidene}-malononitrile (5e). The title compound
was obtained according to the general procedure (reaction time
30 h) as a pale yellow crystalline solid (mp = 163–166 ◦C), yield
97%. 1H NMR (CDCl3) d 8.07 (d, J 8.0 Hz, 1H), 7.59 (t, J 7.6 Hz,
1H), 7.40 (t, J 7.7 Hz, 2H), 7.33 (d, J 7.7 Hz, 1H), 7.18 (d, J 8.5 Hz,
1H), 6.90 (d, J 8.5 Hz, 1H) 4.65 (dd, J 12.4, 10.6 Hz, 1H), 4.39
(dd, J 12.5, 5.1 Hz, 1H), 3.79 (s, 3H), 3.58 (td, J 11.3, 3.4 Hz, 1H),
3.41 (dt, J 10.9, 5.0 Hz, 1H), 3.01 (m, 1H), 2.87 (dd, J 18.5, 6.4 Hz,
1H), 1.95–1.99 (m, 1H) 1.80–1.85 (m, 1H). 13C NMR (CDCl3) d
174.8, 159.6, 139.5, 134.5, 130.0, 128.8 (2C), 128.6, 127.8, 127.6,
20
C21H17N3NaO2 366.1218; found: 366.1224. [a]D − 214 (c =
1.0, CH2Cl2, 91% ee). The ee was determined by HPLC using
a Chiralpak AD column [hexane/i-PrOH (90:10)]; flow rate
1.0 mL min−1; smajor = 13.5 min, sminor = 11.8 min (95% ee).
(S,R)-2-[2-(1-Naphthalen-2-yl-2-nitro-ethyl)-3,4-dihydro-2H-
naphthalen-1-ylidene]-malononitrile (5b). The title compound
was obtained according to the general procedure (reaction time
29 h) as a pale yellow crystalline solid (mp = 184–186 ◦C), yield
98%. 1H NMR (CDCl3) d 8.11 (d, J 8.0 Hz, 1H), 7.91 (d, J
8.4 Hz, 1H), 7.84 (m, 2H), 7.70 (s, 1H), 7.62 (t, J 7.6 Hz, 1H),
7.53 (m, 2H), 7.36–7.46 (m, 3H), 4.81 (dd, J 12.5, 10.0 Hz, 1H),
4.50 (dd, J 12.5, 5.0 Hz, 1H), 3.76 (dt, J 11.8, 3.5 Hz, 1H), 3.64
(td, J 11.7, 4.9 Hz, 1H), 3.08 (ddd, J 18.0, 11.8, 6.0 Hz, 1H), 2.88
(dd, J 18.8, 7.7 Hz, 1H), 1.95–2.05 (m, 1H), 1.77–1.86 (m, 1H).
13C NMR (CDCl3) d 174.5, 139.4, 134.4, 133.2 (2C), 133.0, 130.0,
129.5, 128.6, 127.7 (4C), 127.2, 126.7, 126.6, 124.0, 113.1 (2C),
127.3, 114.7, 113.1 (2C), 78.8, 78.7, 55.2, 44.9, 43.8, 25.5, 24.0.
20
HRMS calc.: C22H19N3NaO3 396.1324; found: 396.1315 [a]D
−
204 (c = 1.0, CH2Cl2, 81% ee). The ee was determined by HPLC
using a Chiralcel OD column [hexane/i-PrOH (80 : 20)]; flow
rate 1.0 mL min−1; smajor = 28.2 min, sminor = 23.4 min (98% ee).
(S,R)-2-{2-[2-Nitro-1-(4-nitro-phenyl)-ethyl]-3,4-dihydro-2H-
naphthalen-1-ylidene}-malononitrile (5f). The title compound
was obtained according to the general procedure (reaction time
30 h, reaction with (DHQ)2PYR 80 h) as a pale yellow crystalline
◦
1
solid (mp = 196–199 C), yield 99%. H NMR (CDCl3) d 8.27
(d, J 8.6 Hz, 2H), 8.10 (d, J 8.0 Hz, 1H), 7.63 (t, J 7.6 Hz, 1H),
7.49 (d, J 8.6 Hz, 2H), 7.44 (t, J 7.7 Hz, 1H), 7.37 (d, J 7.8 Hz,
1H) 4.73 (dd, J 12.8, 10.1 Hz, 1H), 4.46 (dd, J 13.0, 4.5 Hz,
1H), 3.59–3.67 (m, 2H), 2.95–2.99 (m, 2H), 2.07–2.03 (m, 1H)
1.70–1.75 (m, 1H). 13C NMR (CDCl3) d 173.1, 148.1, 143.4,
139.0, 134.8, 130.2, 128.9, 128.7 (2C), 127.6, 127.5, 124.6 (2C),
20
80.9, 78.5, 44.6, 44.5, 25.5, 23.9. [a]D − 190 (c = 0.5, CH2Cl2,
92% ee). The ee was determined by HPLC using a Chiralpak AD
column [hexane/i-PrOH (80 : 20)]; flow rate 1.0 mL min−1; smajor
11.2 min, sminor = 12.4 min (92% ee).
=
(S,R)-2-[2-(2-Nitro-1-thiophen-2-yl-ethyl)-3,4-dihydro-2H-naph-
thalen-1-ylidene]-malononitrile (5c). The title compound was
obtained according to the general procedure (reaction time 30 h)
20
113.0, 112.8, 81.5, 77.9, 44.2, 44.1, 25.3, 24.0. [a]D − 223 (c =
1.0, CH2Cl2, 85% ee). The ee was determined by HPLC using
a Chiralpak AD column [hexane/i-PrOH (90 : 10)]; flow rate
1.0 mL min−1; smajor = 40.2 min, sminor = 35.1 min (95% ee).
◦
as a pale yellow crystalline solid (mp = 150–152 C), yield 93%.
1H NMR (CDCl3) d 8.01 (d, J 8.0 Hz, 1H), 7.58 (t, J 7.5 Hz,
1H), 7.39 (t, J 7.7 Hz, 1H), 7.33 (d, J 7.7 Hz, 1H), 7.29–7.30 (m,
1H), 6.98–6.99 (m, 2H), 4.66 (d, J 12.7, 9.9 Hz, 1H), 4.45 (dd, J
(S,R)-2-{2-[1-(4-Bromo-phenyl)-2-nitro-ethyl]-3,4-dihydro-2H-
naphthalen-1-ylidene}-malononitrile (5g). The title compound
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was obtained according to the general procedure (reaction time
30 h) as a pale yellow crystalline solid (mp = 195–197 ◦C), yield
96%. 1H NMR (CDCl3) d 8.07 (d, J 8.0 Hz, 1H), 7.60 (t, J 7.0 Hz,
1H), 7.53 (d, J 8.5 Hz, 1H), 7.42 (t, J 7.4 Hz, 1H), 7.34 (d, J
7.6 Hz, 1H), 7.15 (d, J 8.4 Hz, 2H) 4.66 (dd, J 12.8, 10.5 Hz,
1H), 4.40 (dd, J 12.8, 5.0 Hz, 1H), 3.58 (td, J 11.5, 3.5 Hz,
1H), 3.40–3.46 (m, 1H), 2.91–2.98 (m, 2H), 1.97–2.02 (m, 1H)
1.76–1.81 (m, 1H). 13C NMR (CDCl3) d 174.3, 139.6, 135.3, 134.9
(2C), 130.4, 129.7 (2C), 128.9, 127.9, 127.7, 123.1, 113.3, 113.2,
7.0 Hz, 1H), 3.43 (dt, J 11.0, 3.6 Hz, 1H), 2.96–3.00 (m, 2H),
2.31–2.36 (m, 2H), 2.06–2.14 (m, 1H) 1.70–1.84 (m, 5H) 1.54 (d, J
12.3 Hz, 1H) 1.10–1.31 (m, 5H), 0.92(dd, J 12.5, 3.3 Hz, 1H). 13
C
NMR (CDCl3) d 175.0, 138.6, 133.5, 129.0, 128.3, 128.1, 126.6,
112.7 (2C), 80.7, 77.1, 43.2, 38.0, 32.1, 28.6, 25.3, 24.9, 22.6, 14.2.
20
HRMS calc.: C21H23N3NaO2 372.1688; found: 372.1695. [a]D
−
353 (c = 1.0, CHCl3, 96% ee). The ee was determined by HPLC
using a Chiralpak AD column [hexane/i-PrOH (90 : 10)]; flow
rate 1.0 mL min−1; smajor = 12.2 min, sminor = 9.2 min (96% ee).
20
81.4, 78.6, 44.7, 44.3, 25.7, 24.2. [a]D − 185 (c = 1.0, CH2Cl2,
(S,R)-2-[2-(1-Nitromethyl-hexyl)-3,4-dihydro-2H-naphthalen-1-
ylidene]-malononitrile (5k). The title compound was obtained
according to the general procedure (reaction time 30 h) as a
yellow oil, yield 99%. 1H NMR (CDCl3) d 7.93 (d, J 8.0 Hz, 1H),
7.53 (t, J 7.6 Hz, 1H), 7.36 (t, J 7.7 Hz, 1H), 7.29 (d, J 7.7 Hz,
1H), 4.38 (dd, J 12.6, 7.3 Hz, 1H), 4.20 (dd, J 12.7, 6.1 Hz, 1H),
3.34 (dt, J 8.6, 4.3 Hz, 1H), 2.43–2.48 (m, 1H), 2.15–2.18 (m,
91% ee). The ee was determined by HPLC using a Chiralpak AD
column [hexane/i-PrOH (90 : 10)]; flow rate 1.0 mL min−1; smajor
10.1 min, sminor = 9.4 min (96% ee).
=
(S,R)-2-{2-[1-(2-Chloro-phenyl)-2-nitro-ethyl]-3,4-dihydro-2H-
naphthalen-1-ylidene}-malononitrile (5h). The title compound
was obtained according to the general procedure (reaction time
29 h) as a pale yellow crystalline solid (mp = 164–166 ◦C), Yield
97%. The compound was found to exist as a 1 : 4 mixture of
rotameric isomers at room temperature (at 60 ◦C in CDCl3 the
signals in the 1H NMR spectrum merge into one set of broadened
2H), 1.44–1.46 (m, 2H) 1.25–1.32 (m, 6H) 0.86–0.89 (m, 3H). 13
C
NMR (CDCl3) d 175.6, 139.9, 134.2, 129.7, 129.2, 128.5, 127.5,
113.4, 113.1, 81.8, 77.1, 43.2, 38.0, 32.1, 28.6, 25.3, 24.9, 22.6,
14.2. HRMS calc.: C20H23N3NaO2 360.1688; found: 360.1700.
◦
1
20
signals). H NMR (CD2Cl2, 0 C) d 8.04 (d, J 7.8 Hz, 1H), 7.61
(t, J 7.6 Hz, 1H), 7.14–7.46 (m, 6H), 4.65 (dd, J 12.7, 10.1 Hz,
0.8H), 4.44 (dd, J 12.7, 5.1 Hz, 1.2 H), 4.16 (td, J 10.9, 5.1 Hz,
1.0H), 3.66 (dt, J 11.2, 3.5 Hz, 0.8H), 3.52 (td, J 11.5, 5.3 Hz,
0.2H), 3.21 (ddd, J 18.4, 11.3, 6.2 Hz, 0.8H), 2.91 (dd, J 18.8,
7.0 Hz, 1.2 H), 1.94–2.11 (m, 1.0H), 1.70–1.82 (m, 1.0H). 13C
NMR (CD2Cl2, 0 ◦C)* d 174.5, 140.3, 135.2, 134.7, 134.8, 134.3,
134.2, 131.8, 130.6, 130.5, 130.3, 129.9, 129.0, 128.7, 128.4, 128.0,
127.8, 127.7, 127.2, 113.5, 113.4, 81.5, 78.4, 76.0, 46.8, 45.2,
40.8, 39.7, 26.0, 25.5, 24.6, 24.0. HRMS calc.: C21H16ClN3NaO2
[a]D − 391 (c = 1.0, CHCl3, 94% ee). The ee was determined
by HPLC using a Chiralcel OD column [hexane/i-PrOH (90 :
10)]; flow rate 1.0 mL min−1; smajor = 22.2 min, sminor = 13.8 min
(94% ee).
(S,R)-2-[6-(2-Nitro-1-phenyl-ethyl)-6,7,8,9-tetrahydro-benzocyclo-
hepten-5-ylidene]-malononitrile (5l). The title compound was
obtained according to the general procedure (reaction time 24 h)
as a white solid. The compound was obtained as a 1 : 15 mixture
of diastereomers (anti : syn), yield 96% (of both diastereomers).
20
400.0829; found: 400.0764. [a]D − 108 (c = 0.5, CH2Cl2, 53%
syn-diastereomer. 1H NMR (CDCl3) d 7.49 (t, J 6.5 Hz, 1H),
7.40 (t, J 7.6 Hz, 1H), 7.23–7.36 (m, 5H), 7.14 (d, J 6.3 Hz, 2H),
4.56 (dd, J 12.4, 10.8 Hz, 1H), 4.39 (dd, J 12.4, 8.6 Hz, 1H), 3.60
(dt, J 11.6, 4.1 Hz, 1H), 3.30 (td, J 10.8, 3.7 Hz, 1H), 2.71–2.87 (m,
2H), 1.61–1.83 (m, 4H). 13C NMR (CDCl3) d 183.6, 138.8, 135.5,
133.2, 132.0, 130.8, 129.4 (2C), 128.6, 128.4, 128.0 (2C), 127.4,
111.5 (2C), 88.2, 78.7, 46.5, 44.8, 35.8, 33.2, 21,7. HRMS calc.:
ee). The ee was determined by HPLC using a Chiralpak AD
column [hexane/i-PrOH (80 : 20)]; flow rate 1.0 mL min−1; smajor
=
9.0 min, sminor = 8.1 min (53% ee). *The 13C NMR spectrum
contains extra signals due to the presence of distinct rotameric
isomers.
(S,R)-2-{2-[2-Nitro-1-(3-nitro-phenyl)-ethyl]-3,4-dihydro-2H-
naphthalen-1-ylidene}-malononitrile (5i). The title compound
was obtained according to the general procedure (reaction time
29 h) as a pale yellow crystalline solid (mp = 214–216 ◦C22), yield
20
C22H19N3NaO2 380.1375; found: 380.1376. [a]D − 202 (c = 0.25,
CH2Cl2, 92% ee). After separation of the diastereomers by FC
(Et2O/hexane 0 : 100 to 50 : 50), the ee of the syn-diastereomer was
determined by HPLC using a Chiralpak AS column [hexane/i-
1
92%. H NMR (CDCl3) d 8.25 (dt, J 7.3, 2.1 Hz, 1H), 8.14 (t, J
PrOH (85 : 15)]; flow rate 1.0 mL min−1; smajor = 14.9 min, sminor
=
2.0 Hz, 1H), 8.10 (d, J 7.7 Hz, 1H), 7.62–7.70 (m, 3H), 7.45 (t,
J 7.9 Hz, 1H), 7.39 (d, J 8.0 Hz, 1H), 4.75 (dd, J 13.3, 10.4 Hz,
1H), 4.46 (dd, J 13.0, 4.5 Hz, 1H), 3.58–3.76 (m, 2H), 2.96–3.08
(m, 2H), 2.07 (m, 1H), 1.75 (m, 1H). 13C NMR (CD2Cl2) d 173.7,
148.9, 139.9, 138.7, 134.9, 134.1, 130.9, 130.6, 128.9, 128.0, 127.5,
124.0, 123.5, 113.4 (2C), 82.0, 78.3, 44.5, 44.4, 25.5, 24.3. HRMS
13.8 min (92% ee).
(S,R)-2-[7-Methoxy-2-(2-nitro-1-phenyl-ethyl)-3,4-dihydro-2H-
naphthalen-1-ylidene]-malononitrile (5m). The title compound
was obtained according to the general procedure (reaction time
27 h, reaction with (DHQ)2PYR 80 h) as a a pale yellow crystalline
20
calc.: C21H16N4NaO4 411.1069; found: 411.1015 [a]D − 209 (c =
◦
1
solid (mp = 163–166 C), yield 96%. H NMR (CDCl3) d 7.54
(d, J 2.5 Hz, 1H), 7.34–7.40 (m, 3H), 7.27 (m, 3H), 7.23 (d, J
8.5 Hz, 1H), 4.71 (dd, J 12.7, 10.3 Hz, 1H), 4.44 (dd, J 12.7,
4.9 Hz, 1H), 3.87 (s, 3H), 3.60 (td, J 11.4, 3.3 Hz, 1H), 3.49 (td,
J 10.8, 5.0 Hz, 1H), 2.95 (m, 1H), 2.79 (dd, J 18.0, 6.2 Hz, 1H),
1.96 (m, 1H) 1.78 (m, 1H). 13C NMR (CDCl3) d 174.6, 158.1,
136.0, 131.6, 131.0 (2C), 129.3 (2C), 128.6, 128.2, 127.6, 122.6,
113.2, 113.1, 111.4, 80.8, 78.6, 55.6, 44.6, 44.5, 25.8, 23.2. HRMS
0.5, CH2Cl2, 91% ee). The ee was determined by HPLC using
a Chiralpak AD column [hexane/i-PrOH (75 : 25)]; flow rate
1.0 mL min−1; smajor = 11.8 min, sminor = 9.6 min (91% ee).
(S,R)-2-[2-(1-Cyclohexyl-2-nitro-ethyl)-3,4-dihydro-2H-naph-
thalen-1-ylidene]-malononitrile (5j). The title compound was
obtained according to the general procedure (reaction time 30 h)
as a yellow oil, yield 82%. 1H NMR (CDCl3) d7.91 (d, J 8.0 Hz,
1H), 7.50 (t, J 7.5 Hz, 1H), 7.32 (t, J 7.7 Hz, 1H), 7.26 (d, J
7.7 Hz, 1H), 4.40 (dd, J 13.6, 4.4 Hz, 1H), 4.18 (dd, J 13.6,
20
calc.: C22H19N3O3Na 396.1324; found: 396.1324. [a]D − 165 (c =
1.0, CH2Cl2, 86% ee). The ee was determined by HPLC using
6 8 | Org. Biomol. Chem., 2006, 4, 63–70
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a Chiralpak AD column [hexane/i-PrOH (90 : 10)]; flow rate
1.0 mL min−1; smajor = 11.7 min, sminor = 8.7 min (96% ee).
137.0, 136.3, 134.9, 129.6 (2C), 129.0 (2C), 128.0, 127.9, 127.0,
20
113.6 (2C), 80.4, 78.8, 44.8, 44.6, 25.8, 22.2, 21.1, 19.8. [a]D
−
191 (c = 1, CH2Cl2, 91% ee). The ee was determined by HPLC
using a Chiralpak AD column [hexane/i-PrOH (98 : 2)]; flow rate
1.0 mL min−1; smajor = 21.6 min, sminor = 14.0 min (91% ee).
(S,R)-2-[6-Methoxy-2-(2-nitro-1-phenyl-ethyl)-3,4-dihydro-2H-
naphthalen-1-ylidene]-malononitrile (5n). The title compound
was obtained according to the general procedure (reaction time
27 h) as a a pale yellow crystalline solid (mp = 157–159 ◦C), yield
(S,R)-2-[3-(2-Nitro-1-phenyl-ethyl)-chroman-4-ylidene]-malono-
nitrile (5r). The title compound was obtained according to the
general procedure◦ (reaction time 29 h) as a yellow crystalline solid
1
99%. H NMR (CDCl3) d 8.13 (d, J 8.9 Hz, 1H), 7.34–7.40 (m,
3H), 7.27 (d, J 7.7 Hz, 2H), 6.80 (d, J 2.0 Hz, 1H), 4.72 (dd, J
12.6, 10.5 Hz, 1H), 4.42 (dd, J 12.7, 4.9 Hz, 1H), 3.91 (s, 3H),
3.58 (td, J 11.5, 3.3 Hz, 1H), 3.46 (dt, J 10.9, 4.8 Hz, 1H), 3.02
(ddd, J 18.3, 12.0, 6.1 Hz, 1H), 2.83 (dd, J 18.5, 6.5 Hz, 1H),
1.95 (m, 1H) 1.74 (m, 1H). 13C NMR (CDCl3) d 173.4, 164.5,
142.2, 136.2, 130.9, 129.4 (2C), 128.7, 127.7 (2C), 120.6, 114.8,
113.8, 113.7, 113.5, 78.6, 77.8, 55.7, 44.6, 44.5, 25.2, 24.3. HRMS
1
(mp = 150–152 C), yield 95%. H NMR (CDCl3) d 8.25 (d, J
8.2 Hz, 1H), 7.61 (t, J 7.2 Hz, 1H), 7.29–7.45 (m, 5H), 7.15 (t, J
7.3 Hz, 1H), 7.06 (d, J 8.4 Hz, 1H), 4.85 (dd, J 12.9, 10.6 Hz, 1H),
4.50 (dd, J 12.9, 5.3 Hz, 1H), 4.04–4.15 (m, 2H), 3.73 (td, J 10.9,
5.4 Hz, 1H), 3.31 (d, J 11.4 Hz, 1H). 13C NMR (CDCl3) d 165.2,
156.0, 137.7, 135.3, 129.6 (2C), 129.0, 128.0 (2C), 127.8, 122.3,
20
20
calc.: C22H19N3NaO3 396.1324; found: 396.1302. [a]D − 430 (c =
118.5, 114.8, 113.0, 112.8, 78.9, 77.4, 66.5, 43.4, 42.8. [a]D
−
1.0, CH2Cl2, 89% ee). The ee was determined by HPLC using
a Chiralpak AD column [hexane/i-PrOH (90 : 10)]; flow rate
1.0 mL min−1; smajor = 15.3 min, sminor = 13.1 min (94% ee).
289 (c = 0.5, CH2Cl2, 74% ee). The ee was determined by HPLC
using a Chiralpak AD column [hexane/i-PrOH (75 : 25)]; flow
rate 1.0 mL min−1; major = 7.2 min, sminor = 6.6 min (75% ee).
(S,R)-2-[5-Methoxy-2-(2-nitro-1-phenyl-ethyl)-3,4-dihydro-2H-
naphthalen-1-ylidene]-malononitrile (5o). The title compound
was obtained according to the general procedure (reaction time
30 h) as a yellow crystalline solid (mp = 189–192 ◦C), yield 90%.
1H NMR (CDCl3) d 7.67 (d, J 8.0 Hz, 1H), 7.34–7.42 (m, 4H),
7.27 (d, J 6.9 Hz, 2H), 7.14 (d, J 8.3 Hz, 1H), 4.70 (dd, J 12.6,
10.5 Hz, 1H), 4.38 (dd, J 12.6, 4.9 Hz, 1H), 3.92 (s, 3H), 3.58 (td, J
11.5, 3.2 Hz, 1H), 3.44 (td J 10.9, 4.9 Hz, 1H), 2.74–2.81 (m, 2H),
1.83–1.90 (m, 2H). 13C NMR (CDCl3) d 175.2, 157.6, 136.4, 129.6
(2C), 129.0, 128.7 (2C), 128.5, 128.3, 128.0, 120.5, 115.5, 113.4,
Procedure for large scale preparation of 5a. Alkylidene mal-
ononitrile 3a (10.0 mmol, 1.94 g) and trans-b-nitrostyrene 4a
(11.0 mmol, 1.64 g) were mixed in a glass flask equipped with
a magnetic stirring bar. Acetone (40.0 mL) was added, and the
mixture was cooled to −78 ◦C. At this temperature (DHQD)2PYR
(3 mol%, 0.3 mmol, 260 mg) was added, and the resulting mixture
was placed at −40 ◦C for 37 h (until 3a had be consumed, as
observed on TLC). The mixture was then cooled to −78 ◦C
and passed quickly through a short pad of silica (elute Et2O)
to remove the catalyst. The solvent was then removed in vacuo.
The pure product was obtained in 84% yield and >99% ee after
recrystalization in EtOH (725 mL).
20
81.3, 78.7, 55.9, 44.9, 44.5, 25.2, 19.2. [a]D − 201 (c = 1, CH2Cl2,
93% ee). The ee was determined by HPLC using a Chiralpak AD
column [hexane/i-PrOH (95 : 5)]; flow rate 1.0 mL min−1; smajor
15.3 min, sminor = 13.7 min (93% ee).
=
Procedure for cyclization of 5a to 6. 5a (103.2 mg, 0.30 mmol,
>99.9% ee) was added to a screw capped plastic vial equipped with
a magnetic stirring bar. Then quinidine (10 mol%, 9.8 mg, 0.03
mmol) was added, followed by addition of CH2Cl2 (1.5 mL). The
mixture was stirred at ambient temperature for 15 h, at which time
the colour of the mixture is intensely red. The solution was then
quickly passed through a short pad of SiO2 to remove the catalyst.
The pure compound 6 was obtained by FC on SiO2 eluting with
CH2Cl2/Et2O (100:0 to 95:5) in 81% yield.
(S,R)-2-[6,7-Dimethoxy-2-(2-nitro-1-phenyl-ethyl)-3,4-dihydro-
2H-naphthalen-1-ylidene]-malononitrile (5p). The title com-
pound was obtained according to the general procedure (but
at a temperature of −25 ◦C, reaction time 29 h) as a yellow
crystalline solid (mp = 191–193 ◦C), yield 99%. 1H NMR
(CDCl3) d 7.62 (s, 1H), 7.26–7.41 (m, 5H), 6.73 (s, 1H), 4.74
(dd, J 12.8, 10.2 Hz, 1H), 4.45 (dd, J 12.7, 4.6 Hz, 1H), 3.98
(s, 3H), 3.96 (s, 3H), 3.45–3.60 (m, 2H), 3.02 (m, 1H), 2.79 (dd,
J 17.6, 7.2 Hz, 1H), 1.92–2.01 (m, 1H), 1.73–1.79 (m, 1H). 13C
NMR (CDCl3) d 173.2, 154.5, 147.7, 136.3, 134.7, 129.3 (2C),
128.6, 127.6 (2C), 120.0, 114.0, 113.8, 111.5, 110.1, 78.7, 77.6,
56.1 (2C), 44.7, 44.3, 25.5, 24.0. HRMS calc.: C23H21N3NaO4
3-Amino-2-nitro-1-phenyl-1,9,10,10a-tetrahydro-phenanthrene-4-
carbonitrile (6). The title compound was obtained according to
the procedure above as a brightly yellow crystalline solid (mp =
116–118 ◦C). 1H NMR (CDCl3) d 9.41–10.38 (br s, 1H), 7.9 (d, J
7.9 Hz, 1H), 7.46 (t, J 7.5 Hz, 1H), 7.22–7.37 (m, 7H), 6.00–6.79
(br s, 1H), 4.44 (d, J 2.2 Hz, 1H), 3.03–3.21 (m, 3H), 2.30–2.38
(m, 1H), 2.11–2.22 (m, 1H). 13C NMR (CDCl3) d 167.5, 144.7,
143.4, 139.3, 133.2, 132.2, 129.4, 128.9 (2C), 127.3, 126.5, 126.3
(2C), 126.2, 117.1, 115.0, 99.8, 47.6, 43.9, 32.7, 29.1. HRMS
20
426.1430; found: 426.1440 [a]D − 381 (c = 0.5, CH2Cl2, 80%
ee). The ee was determined by HPLC using a Chiralpak AD
column [hexane/i-PrOH (75 : 25)]; flow rate 1.0 mL min−1; smajor
9.8 min, sminor = 7.8 min (80% ee).
=
(S,R)-2-[5,7-Dimethyl-2-(2-nitro-1-phenyl-ethyl)-3,4-dihydro-2H-
naphthalen-1-ylidene]-malononitrile (5q). The title compound
was obtained according to the general procedure (reaction time
30 h) as a yellow crystalline solid (mp = 150–152 ◦C), yield 95%.
1H NMR (CDCl3) d 7.72 (s, 1H), 7.34–7.41 (m, 3H), 7.31 (s, 1H),
7.26 (d, J 6.3 Hz, 1H), 4.71 (dd, J 12.6, 10.8 Hz, 1H), 4.38 (dd,
J 12.6, 4.8 Hz, 1H), 3.58 (td, J 11.5, 3.3 Hz, 1H), 3.41 (td J 1.1,
4.8 Hz, 1H), 2.70 (dd, J 8.8, 3.9 Hz, 2H), 2.39 (s, 3H), 2.27 (s
3H), 1.83–1.97 (m, 2H). 13C NMR (CDCl3) d 176.0, 138.0, 137.6,
20
calc.: C21H17N3NaO2 366.1218; found: 366.1224. [a]D − 347
(c = 0.5, CH2Cl2, 98% ee). The ee was determined by HPLC
using a Chiralcel OD column [hexane/i-PrOH (80 : 20)]; flow rate
1.0 mL min−1; smajor = 19.1 min, sminor = 29.0 min (98% ee).
Procedure for the oxidative cleavage of 5a to 7. A flask equipped
with a magnetic stirring bar was charged with 5a (113.3 mg,
0.33 mmol, >99.9% ee), KMnO4 (130.4 mg, 0.83 mmol), and anh.
MgSO4 (44.0 mg). Then acetone (2 mL) and water (3 mL) was
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added, and the mixture was stirred at ambient temperature for 1 h.
At this time the mixture was passed through a short pad of SiO2
with EtOAc/CH2Cl2 (1 : 1) to remove residual KMnO4 and MnO2.
More water was added and the organic phase separated, and the
aqueous phase was extracted twice with CH2Cl2. The combined
organic phases were concentrated under reduced pressure to afford
the crude product (by 1H found to be consisting of the ketone along
with traces of starting material and unidentified by-products).
The pure product was obtained after FC on SiO2 eluting with
Et2O/pentane (1 : 1) in 77% yield.
L. Moisan, Angew. Chem., Int. Ed., 2001, 40, 3726–3748; For recent
examples of cinchona alkaloid catalyzed asymmetric reactions see e.g.:
(e) M. A. Calter, R. M. Phillips and C. Flaschenriem, J. Am. Chem.
Soc., 2005, 127, 14566–14567; (f) G. Bartoli, M. Bosco, A. Carlone, M.
Locatelli, P. Melchiorre and L. Sambri, Angew. Chem., Int. Ed., 2005,
44, 6219–6222; (g) T. B. Poulsen, C. Alemparte, S. Saaby, M. Bella
and K. A. Jørgensen, Angew. Chem., Int. Ed., 2005, 44, 2896–2899; (h)
S. Lou, B. M. Taoka, A. Ting and S. E. Schaus, J. Am. Chem. Soc.,
2005, 127, 11256; (i) S. Saaby, M. Bella and K. A. Jørgensen, J. Am.
Chem. Soc., 2004, 126, 8120–8121; (j) M. Bella and K. A. Jørgensen,
J. Am. Chem. Soc., 2004, 126, 5672–5673; see also refs 11d–e,j–k.
7 T. B. Poulsen, C. Alemparte and K. A. Jørgensen, J. Am. Chem. Soc.,
2005, 127, 6964–6965.
8 (a) B. M. Trost, J. Org. Chem., 2004, 69, 5813–5837; (b) B. M. Trost and
M. L. Crawley, Chem. Rev., 2003, 103, 2921–2944.
9 B. M. Trost and D. L. Van Vranken, Chem. Rev., 1996, 96, 395–422.
10 D. Xue, Y.-C. Chen, Q.-W. Wang, L.-F. Cun, J. Zhu and J.-G. Deng,
Org. Lett., 2005, 7, 5293–5296.
2-(2-Nitro-1-phenyl-ethyl)-3,4-dihydro-2H-naphthalen-1-one (7).
The title compound was obtained according to the procedure
◦
1
above as a white crystalline solid (mp = 112–114 C). H NMR
d 8.03 (d, J 7.8 Hz, 1H), 7.49 (t, J 7.5 Hz, 1H), 7.21–7.37 (m,
7H), 5.11 (dd, J 12.9, 5.5 Hz, 1H), 4.77 (dd, J 12.9, 9.8 Hz, 1H),
4.06 (td, J 9.5, 5.6 Hz, 1H), 2.79–3.02 (m, 3H), 1.97–2.04 (m, 1H),
1.66–1.75 (m, 1H). 13C NMR d 198.3, 143.4, 137.4, 133.8, 132.0,
128.9 (2C), 128.7, 128.2 (2C), 127.8, 127.6, 126.8, 79.0, 49.3, 43.0,
27.6, 26.3. HRMS calc.: C18H17NNaO3 318.1106; found: 318.1008.
11 For recent examples of catalytic asymmetric additions to conjugated
nitroalkenes, see: (a) R. P. Herrera, V. Sgarzani, L. Bernadi and A.
Ricci, Angew. Chem., Int. Ed., 2005, 44, 6576–6579; (b) D. A. Evans
and D. Seidel, J. Am. Chem. Soc., 2005, 127, 9958–9959; (c) Y. Hayashi,
H. Gotoh, T. Hayashi and M. Shoji, Angew. Chem., Int. Ed., 2005, 44,
4212–4215; (d) H. Li, Y. Wang, L. Tang, F. Wu, X. Liu, C. Guo, B. M.
Foxman and L. Deng, Angew. Chem., Int. Ed., 2005, 44, 105–108; (e)
H. Li, Y. Wang, L. Tang and L. Deng, J. Am. Chem. Soc., 2004,
126, 9906–9907; (f) T. Ishii, S. Fujioka, Y. Sekiguchi and H. Kotsuki,
J. Am. Chem. Soc., 2004, 126, 9558–9559; (g) T. Okino, Y. Hoashi, T.
Furukawa, X. Xu and Y. Takemoto, J. Am. Chem. Soc., 2005, 127, 119–
125; (h) T. Okino, Y. Hoashi and Y. Takemoto, J. Am. Chem. Soc., 2003,
125, 12672–12673; (i) A. J. A. Cobb, D. A. D. Lonbottom, M. Shaw and
S. Ley, Chem. Commun., 2004, 1808; (j) J. Wang, H. Li, W. Duan, L. Zu
and W. Wang, Org. Lett., 2005, 7, 4713–4716; (k) S. H. McCooey and
S. J. Connon, Angew. Chem., Int. Ed., 2005, 44, 6367–6370; for reviews
see:; (l) O. M. Berner, L. Tedeschi and D. Enders, Eur. J. Org. Chem.,
2002, 1877–1894; (m) N. Kranse and A. Hoffmann-Ro¨der, Synthesis,
2001, 171.
12 CCDC 285437 and 285436 contains the supplementary crystallo-
graphic data for this paper.† These data can be obtained free of charge
via http://www.ccdc.cam.ac.uk/conts/retrieving.html (or from the
Cambridge Crystallographic Data Centre, 12, Union Road, Cambridge
CB2 1EZ, UK; fax: (+44) 1223-336-033; or deposit@ccdc.cam.ac.uk).
13 By analogy with HPLC traces, NMR spectra, and optical rotations the
same configuration for the Michael adducts 5a–f,h–s could be inferred.
14 F. M. A. El-Taweel, M. A. Sofan, T. M. Abu El-Maati and A. A.
Elagamey, Boll. Chim. Farm., 2001, 140, 306–310.
20
[a]D − 15 (c = 0.5, CH2Cl2, >99.9% ee). The ee was determined
by HPLC using a Chiralcel OD column [hexane/i-PrOH (90 :
10)]; flow rate 1.0 mL min−1; smajor = 18.2 min, sminor = 25.3 min
(>99.9% ee).
Acknowledgements
This work was made possible by a grant from The Danish National
Research Foundation and EU-HMPT-CT-2001-00317. We are
grateful to Dr. Jacob Overgaard for X-ray crystallographic analysis
and to Karen Skov for performing HRMS-analysis.
References
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22 At this temperature the compound had changed colour from pale
yellow to red/brown which might indicate some decomposition.
7 0 | Org. Biomol. Chem., 2006, 4, 63–70
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