Microwave-assisted synthesis of guanidine organocatalysts bearing a tetrahydroisoquinoline framework and their evaluation in Michael addition reactions

Article abstract of DOI:10.1002/ejoc.201200303

The simple and practical syntheses of chiral guanidine organocatalysts and their evaluation in the asymmetric Michael addition reaction of malonates and β-keto esters with nitro-olefins is reported. These organocatalysts are the first of their kind based on a tetrahydroisoquinoline framework. In addition, a microwave-assisted procedure for introducing the guanidine unit onto amino amide derivatives is reported. The chiral products were obtained with quantitative chemical efficiency (up to 99 % yield) and excellent enantioselectivity (up to 97 % ee). Copyright

Full text of DOI:10.1002/ejoc.201200303

Job/Unit: O20303
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Date: 02-05-12 18:35:59
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FULL PAPER
DOI: 10.1002/ejoc.201200303
Microwave-Assisted Synthesis of Guanidine Organocatalysts Bearing a
Tetrahydroisoquinoline Framework and Their Evaluation in Michael Addition
Reactions
Tricia Naicker,[a] Per I. Arvidsson,[a,b,c] Hendrik G. Kruger,[d] Glenn E. M. Maguire,[d] and
Thavendran Govender*[a]
Keywords: Organocatalysis / Michael addition / Microwave chemistry
The simple and practical syntheses of chiral guanidine or-
ganocatalysts and their evaluation in the asymmetric
Michael addition reaction of malonates and β-keto esters
with nitro-olefins is reported. These organocatalysts are the
work. In addition, a microwave-assisted procedure for intro-
ducing the guanidine unit onto amino amide derivatives is
reported. The chiral products were obtained with quantita-
tive chemical efficiency (up to 99% yield) and excellent
first of their kind based on a tetrahydroisoquinoline frame- enantioselectivity (up to 97%ee).
widely investigated.[9] As illustrated in Figure 1, only a few
organocatalysts have taken advantage of including guanid-
ines into readily available amino acids.
Introduction
The guanidine moiety has become well known in both
chemistry and biology for its characteristic high pKa value
and its ability to form dual hydrogen bonds.[1] Therefore,
this functional group has been an attractive target that has
been incorporated into several chiral catalysts used for both
metal–ligand[2] and organocatalysis.[3] It has been success-
fully employed as both Brønsted base/acid and phase-trans-
fer catalysts for several important asymmetric reactions
such as the Henry,[4] Strecker,[5] Mannich, Diels–Alder, and
Michael reaction and Claisen rearrangement.[6] As a result,
the roles of guanidine-based catalysts are steadily increasing
in asymmetric synthesis. Some excellent reviews on guanid-
ine chemistry have emerged during the last dec-
ade.[1b,1c,2b,3,6,7]
Amino acid based organocatalysts have arisen as versa-
tile and efficient candidates that promote a wide range of
enantioselective transformations.[8] The incorporation of
naturally occurring α-amino acids as a source for chirality
into guanidine organocatalysts, however, has not been
[a] School of Pharmacy and Pharmacology, University of
KwaZulu-Natal,
Figure 1. Examples of chiral guanidine organocatalysts derived
from α-amino acids (I and II,[9a] IV,[9b] and V–VII[9c]).
Durban Private Bag 4000, South Africa
Fax: +27-72603091
E-mail: govenderthav@ukzn.ac.za
Furthermore, the amino acid based guanidine catalysts
developed thus far are molecules that are prepared through
nontrivial syntheses. Hence the development of a simple
route to prepare other chiral guanidines is still of great
interest. We have set out to introduce a new class of easily
accessible amino acid based guanidine organocatalysts
bearing a tetrahydroisoquinoline (TIQ) backbone (Fig-
ure 2).
[b] Organic Pharmaceutical Chemistry, Department of Medicinal
Chemistry, Uppsala Biomedical Centre, Uppsala University,
Box 574, 75123 Uppsala, Sweden
[c] Innovative Medicines, CNSP iMed, AstraZeneca R&D
Sodertalje,
15185 Sodertalje, Sweden
[d] School of Chemistry, University of KwaZulu-Natal,
Westville, Durban, South Africa
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201200303.
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T. Naicker, P. I. Arvidsson, H. G. Kruger, G. E. M. Maguire, T. Govender
FULL PAPER
Scheme 1. Synthetic route to catalysts 1. Reagents and conditions:
(i) KHCO3, CbzCl, dioxane/water in situ solvent evaporation,
DIPEA, ethyl chloroformate, 2,6-diisopropylphenylamine, dichlo-
romethane, 0 °C to r.t, 12 h; (ii) Pd/C (10 wt.-%), H2 (1 atm), meth-
anol, r.t, 1 h; (iii) Yb(OTf)3, DCC, microwave irradiation, toluene,
120 °C, 3 h; (iv) Lawesson’s reagent, toluene, reflux, 12 h.
Secondary amine 5 was protected by performing an in
situ reaction with benzyl chloroformate (Cbz)[12] followed
by amide bond formation with diisopropylphenylamine to
Figure 2. TIQ guanidine organocatalysts evaluated in this study.
This initiative was also partly encouraged by the observa-
tion that chiral pipecolic and pyrrole acid derived guanid-
ines (Figure 1) with an amide functional group (i.e., V–VII)
have been shown to promote synthetically useful transfor-
mations such as the Michael addition[9c] and domino reac-
tions.[10] The TIQ molecule and its derivatives have been
extensively studied due to their biological and pharmaceuti-
cal properties.[11] However, it has been sparsely used a
source for chirality in asymmetric catalysis. Recently, we
have made much progress with TIQ-based ligands for cata-
lytic asymmetric reactions, including the transfer hydrogen-
ation of prochiral ketones,[12] Henry reaction,[13] hydrogena-
tion of olefins,[14] and we have expanded the potential of
these TIQ derivatives as organocatalysts for the Diels–Alder
reaction[15] and allylation of aldehydes.[16]
Herein, we report the microwave-assisted synthesis and
catalytic activity of TIQ-based guanidines that promote the
asymmetric 1,4-addition of β-keto esters or malonates to
nitro-olefins in up to 97%ee. The catalysts are insensitive
to moisture and oxygen and are easily prepared from com-
mercially available starting materials in three straightfor-
ward steps with isolated yields of 90–95%.
yield compound 6. Thereafter, the amide was deprotected
through hydrogenation. Upon filtration of Pd/C and evapo-
ration of the solvent, the product was used directly for the
next step. To synthesize the guanidine unit, we applied the
lithiation and subsequent addition of DCC procedure as
done with pipecolic and pyrrole acid derivatives.[9c] How-
ever, even after several attempts, the reaction resulted in
many side products and the crude mixture proved difficult
to purify. Next, we attempted the one-pot procedure by
Shen et al., who reported the catalytic use of Yb(OTf)3 for
the addition of carbodiimides to non-chiral amines under
solvent-free conditions utilizing conventional heating.[17]
However, low product yields (40% isolated) and long reac-
tion times (Ͼ24 h) led us to modify this procedure by using
microwave irradiation. Initially, the reaction was carried out
under neat conditions in the microwave (Table 1, Entries 1–
3). An increase in temperature resulted in higher yields of
the product; however, for reactions performed at tempera-
tures greater than 100 °C charring of the reagents occurred.
Next, we investigated adding a solvent to the reaction mix-
ture (Table 1, Entries 4–6). Toluene proved to be optimal in
the microwave at 120 °C for 3 h (Table 1, Entry 8) with a
95% isolated yield. This is one of only few procedures em-
ploying microwave irradiation for guanidine attachment to
chiral auxiliaries.[18]
Results and Discussion
A similar synthetic route (as that of catalyst 1) was fol-
lowed for 2 except that the triflate salt of final product 1
Catalyst Synthesis
As a preliminary study we chose the 2,6-diisoprop- was treated with Lawesson’s reagent to yield the TIQ
ylphenylamine (dipp) amide and dicyclohexylcarbodiimide thioamide guanidine organocatalyst. We have previously re-
(DCC) functional groups to be used on the TIQ skeleton. ported the synthesis of both cis-/trans-substituted TIQ acids
These moieties proved to be optimal when used by Feng et 7a/7b.[13,16] The N-Cbz protected acid was treated with 2,6-
al. on pipecolic acid for application as an organocatalyst diisopropylphenylamine to furnish amides 8a/8b. The pro-
for Michael addition reactions.[9c] Catalyst 1 (Scheme 1) tecting group was then removed, and the guanidine moiety
was synthesized in 95% overall yield from commercially was attached following the same microwave procedure as
available tetrahydroisoquinoline amino acid 5 (phenyl- that for the unsubstituted organocatalysts to furnish com-
alanine derived).
pounds 3 and 4.
2
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Guanidine Organocatalysts Bearing a Tetrahydroisoquinoline Framework
Table 1. Optimization of microwave conditions for guanidine for-
mation on TIQ derivatives.
Table 2. Michael addition between dimethyl malonate (9) and ni-
trostyrene (10) with catalyst 1 at 0 °C.
Entry
Solvent
Time
[h]
Temperature
[°C]
Yield
[%]
1
2
3
4
5
6
7
8
neat
neat
neat
3
6
1
1
1
1
1
3
80
80
100
80
80
80
20
34
41
35
32
40
55
95
THF
CH3CN
toluene
toluene
toluene
Entry
Solvent[a]
Yield [%][b]
ee [%][c,d]
100
120
1
2
3
4
5
6
7
Et2O
EtOAc
THF
93
90
92
90
99
99
95
21 (S)
22 (S)
23 (S)
5 (S)
2 (S)
45 (S)
3 (S)
DCM
Notably, all compounds in Scheme 2 have a second chiral
center and could not be synthesized from a phenylalanine
derivative, as it was essential to employ activated aromatic
groups 7a/7b (derived from l-DOPA) to facilitate the cycli-
zation and to introduce the additional chiral group. More-
over, for catalysts 3 and 4, a single diastereomer was ob-
served by 1H NMR spectroscopy after both coupling of the
amide and carbodiimide groups.
MeOH
Toluene
CH3CN
[a] Reactions were carried out by using 10 mol-% of organocatalyst
1 for 12 h. [b] Isolated yield after column chromatography. [c] De-
termined by chiral HPLC. [d] The configuration of the chiral prod-
uct was established by comparison of its HPLC retention time with
that obtained from the literature.
creased both the selectivity and yield of the reaction prod-
uct (Table 3, Entry 2). This result indicated that the amide
hydrogen was also important in our system for conversion
and asymmetric induction.
Table 3. Michael addition between dimethyl malonate (9) and ni-
trostyrene (10) with catalysts 1–4 in toluene at 0 °C.
Entry
Catalyst[a]
Yield [%][b]
ee [%][c,d]
Scheme 2. Synthetic route to catalyst 3 and 4. Reagents and condi-
tions: (i) KHCO3, CbzCl, dioxane/water in situ solvent evapora-
tion, DIPEA, ethylchloroformate, 2,6-diisopropylphenylamine
dichloromethane, 0 °C to r.t, 12 h; (ii) Pd/C (10 wt.-%), H2 (1 atm),
methanol, r.t, 1 h; (iii) Yb(OTf)3, DCC, microwave irradiation, tol-
uene, 120 °C, 3 h.
1
2
3
4
1
2
3
4
99
90
91
95
45
20
2
31
[a] Reactions were carried out by using 10 mol-% of the organocat-
alyst for 12 h. [b] Isolated yield after column chromatography.
[c] Determined by chiral HPLC. [d] The configuration of the chiral
product was established by comparison of its HPLC retention time
with that obtained from the literature.
Catalyst Evaluation
The TIQ guanidine organocatalysts was evaluated on the
Next, we looked at the X-ray crystal structure of catalyst
asymmetric 1,4-addition reaction between dimethyl malon- 1 for further information on how the catalyst could be
ate (9) and nitrostyrene (10). It has been shown in the litera- modified to enhance the enantiomeric excess as illustrated
ture that the appropriate choice of solvent was crucial for from OLEX2-generated Figure 3.
asymmetric induction.[7h,9c,19] Therefore, catalyst 1 was
It is evident from the crystal structures that the N-con-
tested in the most common solvents used for this type of taining six-membered ring assumes a half-boat conforma-
asymmetric reaction (Table 2). The change in solvent had tion with the guanidine moiety tilted downwards. It is syn-
a noteworthy effect on the enantiomeric excess of reaction thetically possible to introduce a phenyl ring at the C1 atom
product 11 (Table 2, Entry 6).
in either the cis or trans position in hope that this would
Although moderate selectivity was observed, there was have an effect on the chiral induction of the catalyst. Deriv-
excellent reactivity to Michael addition product 11. Encour- atives 3 and 4 were synthesized and tested; however, a mar-
aged by these results we set out to modify our catalyst in ginal difference in enantiomeric excess was observed
the hope of increasing the enantiomeric excess. Feng and (Table 3, Entries 3 and 4). It was optimal to proceed with
co-workers have reported that the amide hydrogen was im- catalyst 1 and toluene as the solvent of choice.
perative for both selectivity and conversion with their pipec-
TIQ-based organocatalyst 1 was extended by applying it
olic organocatalysts.[9c] It has been shown in the literature, to other malonates or β-keto esters and nitrostyrene
for some organocatalysts in which the amide group played (Table 4, Entries 1–6).
a significant role, that replacement of this group with a
All of the reactions proceeded with quantitative yields
more acidic thioamide functionality could be beneficial.[20] and reasonable increases in selectivities were observed. This
Hence, catalyst 2 was synthesized; however, this change de- illustrated that catalyst 1 could be applied to both linear
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T. Naicker, P. I. Arvidsson, H. G. Kruger, G. E. M. Maguire, T. Govender
FULL PAPER
Table 5. Michael addition between diisopropyl malonate or tert-
butyl 2-oxocyclopentanecarboxylate ester and different nitrostyrene
derivatives with catalyst 1 at –15 °C in toluene.
Figure 3. OLEX2-generated[21] drawing of the X-ray structure of
catalyst 1 as the triflate salt.
Table 4. Michael addition between different malonates or β-keto
esters and nitrostyrene (10) with catalyst 1 at 0 °C in toluene.
[a] Reactions were carried out by using 10 mol-% of the organocat-
alyst after 20 h. [b] Isolated yield after column chromatography.
[c] Determined by chiral HPLC. [d] The configuration of the chiral
product was established by comparison of its HPLC retention time
with that obtained from the literature. [e] The absolute configura-
tion was arbitrarily assigned based on the sign of the optical rota-
tion for known diisopropyl 2-(2-nitro-1-phenylethyl)malonate (En-
try 1).
tivity. For the linear diisopropyl malonate substrate, in ge-
neral, an increase in electron density from the 4-position of
the aryl ring on the nitro-olefin resulted in an increase in
stereoselectivity. However, this effect appears less pro-
nounced when tert-butyl 2-oxocyclopentanecarboxylate es-
ter was employed. The best result observed from all of the
substrates screened was with diisopropyl malonate and 4-
methoxynitrosytrene (85% yield, 97%ee). These results
compare well with those reported for other catalytic sys-
tems for the same Michael addition, with cyclic and linear
esters and nitro-olefins,[9c,19a,19c,22] demonstrating the utility
of these readily available and modular TIQ-based catalysts.
[a] Reactions were carried out by using 10 mol-% of the organocat-
alyst for 12 h. [b] Isolated yield after column chromatography.
[c] Determined by chiral HPLC. [d] The configuration of the chiral
product was established by comparison of its HPLC retention time
with that obtained from the literature. [e] Reaction was carried out
at –15 °C after 20 h (further decrease in the temperature did not
increase the selectivity).
Conclusions
We have identified a novel class of TIQ-based guanidine
organocatalysts that promotes the enantioselective Michael
addition of malonates and β-keto esters with nitro-olefins.
The catalysts are easily prepared from commercially avail-
able substrates and are insensitive to moisture and oxygen.
Furthermore, a new microwave-assisted procedure of intro-
ducing the guanidine unit onto amino amide derivatives is
reported. The chiral products were obtained with quantita-
tive chemical efficiency (up to 99% yield) and excellent
enantioselectivity (up to 97%ee). Further studies of this
class of organocatalysts are ongoing in our laboratory.
and cyclic esters. The cyclic esters gave rise to chiral prod-
ucts containing an additional stereogenic center with excel-
lent diastereomeric ratios (Table 4, Entries 4–6). tert-Butyl
2-oxocyclopentanecarboxylate ester gave the highest selec-
tivity (Table 4, Entry 6) at –15 °C. It was then decided to
vary the nitro-olefin for both diisopropyl malonate and tert-
butyl 2-oxocyclopentanecarboxyl7ate ester (Table 5).
Nitro-olefins including electron-withdrawing and elec-
tron-donating group substituents on the aryl ring of nitro-
styrene were employed with both linear and cyclic esters
(Table 5). All substrates displayed very good conversions. A
decrease in activity for both ester systems was observed
when 4-OMe was used as the substituent on the nitro-ole-
Experimental Section
General Methods: Reagents and solvents were purchased from Ald-
fin, suggesting electronics play a role in this substrate’s reac- rich, Merck, or Fluka suppliers. All solvents were dried prior to
4
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Guanidine Organocatalysts Bearing a Tetrahydroisoquinoline Framework
use according to standard procedures. All NMR spectra were re-
corded with a Bruker Avance III 400 MHz instrument. Chemical
shifts are expressed in ppm relative to CDCl3. NMR spectra were
obtained at room temperature. Thin-layer chromatography (TLC)
was performed by using Merck Kieselgel 60 F254. Crude com-
pounds were purified by column chromatography by using silica
gel 60 mesh. All IR spectra were recorded with a Perkin–Elmer
spectrum 100 instrument with a universal ATR attachment. Optical
rotations were recorded with a Perkin–Elmer Polarimeter. Micro-
wave-assisted reactions were carried out with a CEM Discover SP
system. High-resolution mass spectrometric data was obtained by
using a Bruker microTOF-Q II instrument. The enantiomeric ex-
cess values of the chiral products were determined with a Shimadzu
Prominence HPLC with either a Chiralpak IA or IB column.
to afford the product (51%) as a yellow solid. M.p. 60–62 °C.
[α]2D0 = –11.32 (c = 0.53, CHCl3). NMR spectra are reported for a
mixture of two rotamers due to the Cbz group.[12,23] 1H NMR
(400 MHz, CDCl3): δ = 7.52–6.93 (m, 12 H), 5.58–5.00 (m, 3 H),
4.93–4.52 (m, 2 H), 3.53 (m, 1 H), 3.12 (m, 1 H), 1.22 (m, 2 H),
0.88 (m, 12 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 170.6,
146.1, 132.6, 128.7, 128.4, 127.9, 123.2, 68.2, 56.6, 45.9, 32.2, 28.2,
23.6 ppm. IR (ATR): ν = 3280, 1643, 1547, 1453, 1222, 1029, 963,
˜
755, 694 cm–1. HRMS: calcd. for C30H35N2O3 [M + H]+ 471.2642;
found 471.2639.
(1S,3S)-Benzyl 3-(2,6–2,6-Diisopropylphenylamine carbamoyl)-6,7-
dimethoxy-1-phenyl-3,4-dihydroisoquinoline-2-(1H)-carboxylate (8a):
The crude product was purified by column chromatography
(EtOAc/hexane, 50:50; Rf = 0.55) to afford the product (55%) as a
yellow oil. [α]2D0 = –5.26 (c = 0.19, CHCl3). NMR spectra are re-
ported for a mixture of two rotamers. 1H NMR (400 MHz,
CDCl3): δ = 7.39–6.69 (m, 16), 6.63 (s, 1 H), 6.30–6.11 (s, 0.5 H),
5.49 (m, 0.5 H), 5.26–4.85 (m, 2.3 H), 4.52–4.28 (m, 0.5 H), 3.92–
3.68 (m, 8 H), 3.32–2.75 (m, 2 H), 1.35–1.01 (m, 12 H) ppm. 13C
NMR (101 MHz, CDCl3): δ = 171.36, 156.13, 148.98, 148.90,
146.40, 141.01, 135.71, 129.46, 128.72, 128.65, 128.58, 127.85,
127.82, 126.95, 125.71, 125.37, 125.21, 123.45, 123.34, 123.26,
110.87,110.01, 110.46, 68.35, 68.02, 60.11, 59.55, 58.45, 57.88,
56.15, 56.09, 55.77, 53.65, 31.00, 27.99, 23.93, 23.58, 22.95 ppm.
Representative Procedure for Cbz Protection and Synthesis of TIQ-
Based Amides:[12] To a solution of TIQ carboxylic acid (1.0 g) in
dioxane (20 mL) and water (10 mL) at 0 °C was added a solution
of potassium hydrogen carbonate (5.0 equiv.) dropwise over 15 min
followed by the addition of CbzCl (1.1 equiv.). The solution was
stirred for 1.5 h at 0 °C and then at ambient temperature for 1.5 h.
The reaction was monitored with LC–MS (by neutralizing the reac-
tion mixture with 10% HCl and extraction with ethyl acetate). The
solvent was evaporated under reduced pressure, and the crude was
dried under high vacuum. To the solid N-Cbz-TIQ acid product
(2.0 g) dissolved in dichloromethane (20 mL) was added N,N-diiso-
propylethylamine (DIPEA, 1.5 equiv.) and ethyl chloroformate
(1.5 equiv.) at 0 °C. After 1 h, diisopropylamine (1.1 equiv.) was
added, and the mixture was stirred at ambient temperature for 18 h.
Completion of the reaction was monitored by TLC. The reaction
mixture was washed with saturated sodium hydrogen carbonate
(20 mL) followed by brine (10 mL). The organic layer was sepa-
rated, dried with anhydrous magnesium sulfate, and purified by
silica gel column chromatography (hexane/ethyl acetate).
IR (ATR): ν = 3298, 2962, 1688, 1513, 1224, 698 cm–1. HRMS:
˜
calcd. for C24H25N2O [M + H]+ 607.3166; found 607.3215.
(1R,3S)-Benzyl 3-(2,6–2,6-Diisopropylphenylamine carbamoyl)-6,7-
dimethoxy-1-phenyl-3,4-dihydroisoquinoline-2-(1H)-carboxylate (8b):
The crude product was purified by column chromatography
(EtOAc/hexane, 50:50; Rf = 0.55) to afford the product (58%) as a
yellow oil. [α]2D0 = +5.26 (c = 0.19, CHCl3). NMR spectra are re-
ported for a mixture of two rotamers. 1H NMR (400 MHz,
CDCl3): δ = 7.39–6.69 (m, 16), 6.63 (s, 1 H), 6.30–6.11 (s, 0.5 H),
5.49 (m, 0.5 H), 5.26–4.85 (m, 2.3 H), 4.52–4.28 (m, 0.5 H), 3.92–
3.68 (m, 8 H), 3.32–2.75 (m, 2 H), 1.35–1.01 (m, 12 H) ppm. 13C
NMR (101 MHz, CDCl3): δ = 171.36, 156.13, 148.98, 148.90,
146.40, 141.01, 135.71, 129.46, 128.72, 128.65, 128.58, 127.85,
127.82, 126.95, 125.71, 125.37, 125.21, 123.45, 123.34, 123.26,
110.87,110.01, 110.46, 68.35, 68.02, 60.11, 59.55, 58.45, 57.88,
56.15, 56.09, 55.77, 53.65, 31.00, 27.99, 23.93, 23.58, 22.95 ppm.
Representative Procedure for Deprotection of the Cbz Group and
Guanidine Formation: A solution of the N-Cbz protected TIQ
amide (1.0 g) in MeOH (20 mL) was added to a suspension of acti-
vated Pd/C (10 wt.-%, 250 mg) in MeOH (5 mL). The mixture was
supplied with H2 under atmospheric pressure and stirred at room
temperature for 1 h. The reaction was monitored by TLC. The Pd/
C was filtered through a Celite pad and washed with methanol
(20 mL). The filtrate was then evaporated under reduced pressure
to afford the deprotected TIQ amide derivatives. In a 10-mL micro-
wave vessel containing the TIQ amide (300 mg) dissolved in toluene
(5 mL) was added Yb(OTf)3 (0.4 equiv.) and DCC (1.1 equiv.). The
vessel was then placed in the microwave reactor and heated to
120 °C for 3 h. Toluene was then evaporated under reduced pres-
sure, and the residue was passed through a short plug of silica
(hexane/ethyl acetate, 50:50; 100 mL). The solvent was then evapo-
rated under reduced pressure, and the crude material was dissolved
in a minimum amount of ethyl acetate and left in the refrigerator
overnight. This mixture was then filtered, and the filtrate was evap-
orated under reduced pressure to yield a residue that was purified
by silica gel column chromatography (hexane/ethyl acetate). The
white foam product (triflate salt) was dissolved in dichloromethane
and an equal amount of saturated aqueous NaOH was added in a
separation flask, which was shaken for 2 min. The organic phase
was dried with anhydrous MgSO4, and the solvent was evaporated
under reduced pressure to yield solids for all TIQ guanidine
organocatalysts.
(S,E)-2-(N,NЈ-Dicyclohexylcarbamimidoyl)-N-(2,6–2,6-diisopropyl-
phenylamine)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide (1): The
crude product was purified by column chromatography (EtOAc/
hexane, 50:50; Rf = 0.20) to afford the product (95%) as a white
solid. M.p. 82–83 °C. [α]2D0 = –70.71 (c = 0.66, CHCl3). H NMR
1
(400 MHz, CDCl3): δ = 10.53 (s, 1 H), 7.32–6.72 (m, 8 H), 4.98 (s,
1 H), 4.43 (q, J = 16.5 Hz, 2 H), 3.42 (t, J = 13.3 Hz, 1 H), 2.88
(m, 5 H), 1.92–1.32 (m, 12 H), 1.32–0.55 (m, 20 H) ppm. 13C NMR
(101 MHz, CDCl3): δ = 170.25, 158.55, 145.84, 131.69, 131.31,
130.08, 128.48, 128.36, 127.98, 127.48, 126.04, 123.37, 122.01,
118.83, 77.36, 77.04, 76.72, 57.54, 55.56, 48.89, 33.52, 33.20, 32.43,
29.70, 28.75, 28.49, 25.08, 24.81, 23.62 ppm. IR (ATR): ν = 2926,
˜
2853, 1613, 799 cm–1. HRMS: calcd. for C35H51N4O [M + H]+
543.4059; found 543.4057.
CCDC-860511 (for 1) contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge from
The Cambridge Crystallographic Data Centre via www.ccdc.cam.
ac.uk/data_request/cif.
(S,E)-2-(N,NЈ-Dicyclohexylcarbamimidoyl)-N-(2,6–2,6-diisopropyl-
phenylamine)-1,2,3,4-tetrahydroisoquinoline-3-carbothioamide (2):
To a solution of the triflate salt (white foam) of compound 1 (0.1 g,
0.3 mmol) dissolved in dry toluene (20 mL) was added Lawesson’s
(S)-Benzyl 3-(2,6–2,6-Diisopropylphenylamine carbamoyl)-3,4-dihy-
droisoquinoline-2(1H)-carboxylate (6): The crude product was puri-
fied by column chromatography (EtOAc/hexane, 30:70; Rf = 0.40)
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5

Job/Unit: O20303
/KAP1
Date: 02-05-12 18:35:59
Pages: 8
T. Naicker, P. I. Arvidsson, H. G. Kruger, G. E. M. Maguire, T. Govender
FULL PAPER
reagent (0.5 equiv., 0.06 g) under a nitrogen atmosphere. The mix-
ture was heated gently at reflux under an atmosphere of nitrogen
for 12 h. Thereafter, the solvent was evaporated under reduced
pressure to yield a residue that was purified by silica gel column
chromatography (EtOAc/hexane, 50:50; Rf = 0.15) to afford the
product (92%) as a yellow solid. M.p. 100–102 °C. [α]2D0 = –100.00
(c = 0.20, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 7.44–6.67 (m,
8 H), 5.15 (s, 1 H), 4.37 (s, 2 H), 4.00 (d, J = 16.2 Hz, 1 H), 3.18–
2.67 (m, 6 H), 2.32–1.95 (m, 4 H), 1.61 (t, J = 42.6 Hz, 10 H),
1.36–0.84 (m, 18 H) ppm. 13C NMR (101 MHz, CDCl3): δ =
143.91, 132.77, 128.96, 127.25, 126.92, 125.36, 125.14, 123.40,
123.12, 77.33, 59.73, 54.73, 46.85, 35.35, 34.17, 31.93, 30.93, 28.73,
28.52, 25.42, 25.06, 24.88, 24.43, 24.34, 23.57, 23.13 ppm. IR
rate
(minor) min.
= 0.9 mL/min, λ = 210 nm): tR = 15.2 (major), 20.0
(S)-Diethyl 2-(2-Nitro-1-phenylethyl)malonate:[12,23] 1H NMR
(400 MHz, CDCl3): δ = 7.21–7.36 (m, 5 H), 4.95 (dd, J = 13.1,
5.3 Hz, 1 H), 4.87 (dd, J = 13.1, 8.1 Hz, 2 H), 4.17–4.34 (m, 3 H),
4.01 (q, J = 7.2 Hz, 2 H), 3.83 (d, J = 9.5 Hz, 1 H), 1.27 (t, J =
1.2 1.05 Hz, 3 H), (t, J = 72 Hz, 3 H) ppm. HPLC (Chiralpak IA,
hexane/2-propanol = 90:10, flow rate = 0.9 mL/min, λ = 210 nm):
tR = 12.8 (major), 16.8 (minor) min.
(S)-Diisopropyl 2-(2-Nitro-1-phenylethyl)malonate:[12,23] 1H NMR
(400 MHz, CDCl3): δ = 7.21–7.35 (m, 5 H), 5.09 (sept., J = 6.2 Hz,
1 H), 4.93 (dd, J = 12.7, 9.5 Hz, 1 H), 4.84 (dd, J = 12.7, 9.5 Hz,
1 H), 4.82 (sept., J = 6.2 Hz, 1 H), 4.21 (td, J = 9.5, 4.9 Hz, 1 H),
3.76 (d, J = 9.5 Hz, 1 H), 1.24 (d, J = 6.2 Hz, 6 H), 1.07 (d, J =
6.2 Hz, 3 H), 1.02 (d, J = 6.2 Hz, 3 H) ppm. HPLC (Chiralpak IA,
hexane/2-propanol = 90:10, flow rate = 0.9 mL/min, λ = 210 nm):
tR = 11.4 (major), 24.0 (minor) min.
(ATR): ν = 3302, 2924, 1651, 1651, 1494, 743, 698 cm–1. HRMS:
˜
calcd. for C35H51N4S [M + H]+ 559.3829; found 559.3840.
(1S,3S)-2-[(E)-N,NЈ-Dicyclohexylcarbamimidoyl]-N-(2,6–2,6-diiso-
propylphenylamine)-6,7-dimethoxy-1-phenyl-1,2,3,4-tetrahydroiso-
quinoline-3-carboxamide (3): The crude product was purified by col-
umn chromatography (EtOAc/hexane, 50:50; Rf = 0.20) to afford
the product (90%) as a white solid. M.p. 100–103 °C. [α]2D0 = –44.09
(c = 0.93, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 8.92 (s, 1 H),
7.29–6.88 (m, 9 H), 6.60 (s, 1 H), 6.33 (s, 1 H), 6.16 (s, 1 H), 4.58
(s, 1 H), 3.85–3.46 (m, 7 H), 3.34 (d, J = 10.0 Hz, 2 H), 3.13 (s, 1
H), 2.80 (d, J = 32.8 Hz, 2 H), 1.70–0.86 (m, 16 H) ppm. 13C NMR
(101 MHz, CDCl3): δ = 173.08, 153.99, 147.87, 147.54, 146.29,
146.13, 145.70, 131.45, 129.59, 129.17, 127.81, 127.69, 126.66,
124.67, 123.12, 111.56, 110.76, 59.94, 58.93, 55.79, 55.68, 53.36,
49.10, 36.34, 34.50, 34.05, 33.96, 32.48, 28.67, 28.09, 25.98, 25.74,
Ethyl 1-(2-Nitro-1-phenylethyl)-2-oxocyclopentanecarboxylate: 1H
NMR (400 MHz, CDCl3): δ = 7.22–7.32 (m, 5 H), 4.75–4.87 (m, 2
H), 4.11–4.20 (m,3 H), 4.02 (q, J = 6.8 Hz, 1 H), 3.83 (d, J =
9.6 Hz, 1 H), 1.25 (t, J = 7.2 Hz, 3 H), 1.05 (t, J = 7.2 Hz,3 H) ppm.
HPLC (Chiralpak IB, hexane/2-propanol = 95:5, flow rate =
0.9 mL/min, λ = 210 nm): tR = 11.9 (syn, major), 24.5 (minor) min.
tert-Butyl
1-(2-Nitro-1-phenylethyl)-2-oxocyclopentanecarboxyl-
ate:[12,23] 1H NMR (400 MHz, CDCl3): δ = 7.31–7.24 (m, 5 H),
5.16 (dd, J = 13.44, 3.76 Hz, 1 H), 4.98 (dd, J = 13.28, 11.16 Hz,
1 H), 4.04 (dd, J = 11.12, 3.72 Hz, 1 H), 2.38–2.25 (m, 2 H), 2.02–
1.74 (m, 4 H), 1.44 (s, 9 H) ppm. HPLC (Chiralpak IA, hexane/2-
propanol = 99:1, flow rate = 0.9 mL/min, λ = 210 nm): tR = 12.8
(syn, major), 15.1 (minor) min.
25.63, 25.38, 24.95, 24.78, 24.07, 23.35, 22.74 ppm. IR (ATR): ν =
˜
3349, 2926, 2852, 1629, 1254, 699 cm–1. HRMS: calcd. for
C43H59N4O3 [M + H]+ 679.4582; found 679.4564.
(1R,3S)-2-[(E)-N,NЈ-Dicyclohexylcarbamimidoyl]-N-(2,6–2,6-diiso-
propylphenylamine)-6,7-dimethoxy-1-phenyl-1,2,3,4-tetrahydroiso-
quinoline-3-carboxamide (4): The crude product was purified by col-
umn chromatography (EtOAc/hexane, 50:50; Rf = 0.20) to afford
Diisopropyl 2-(2-Nitro-1-p-tolylethyl)malonate: [α]2D0 = +863 (c =
0.10, CH2Cl2). 1H NMR (400 MHz, CDCl3): δ = 7.19 (s, 1 H), 7.01
(m, 3 H), 5.01 (q, J = 6.64, 12.61 Hz, 1 H), 4.80 (m, 3 H), 4.09 (m,
1 H), 3.66 (d, J = 8.77 Hz, 1 H), 2.10 (s, 3 H), 1.17 (m, 6 H), 0.98
(m, 3 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 175.1, 133.2,
129.5, 127.9, 78.10, 69.8, 69.4, 55.3, 42.5, 21.6, 21.4, 21.3,
1
the product (95%) as a white solid. H NMR (400 MHz, CDCl3):
δ = 8.93 (s, 1 H), 7.34–6.82 (m, 9 H), 6.60 (s, 1 H), 6.33 (s, 1 H),
6.18 (s, 1 H), 4.59 (s, 1 H), 3.87–3.43 (m, 7 H), 3.29 (d, J = 63.6 Hz,
2 H), 3.13 (s, 1 H), 2.80 (d, J = 20.6 Hz, 2 H), 1.59–0.86 (m, 17
H) ppm. 13C NMR (101 MHz, CDCl3): δ = 173.01, 154.06, 147.90,
147.59, 146.30, 146.12, 145.65, 131.44, 129.53, 129.12, 128.23,
127.82, 127.75, 126.72, 124.62, 124.47, 123.98, 123.45, 123.13,
119.09, 111.55, 110.75, 59.99, 58.98, 55.80, 55.71, 53.39, 36.29,
34.47, 34.02, 32.50, 31.93, 31.44, 30.20, 28.66, 28.10, 25.95, 25.70,
25.36, 24.96, 24.75, 24.03, 23.40 ppm.
21.2 ppm. IR (ATR): ν = 2983, 1727, 1553, 1100 cm–1. HRMS:
˜
calcd. for C18H25NO6 [M + Na]+ 374.1580; found 374.1677. HPLC
(Chiralpak IA, hexane/2-propanol = 90:10, flow rate = 0.9 mL/min,
λ = 210 nm): tR = 24.9 (major), 23.5 (minor) min.
Diisopropyl 2-[2-Nitro-1-(4-nitrophenyl)ethyl]malonate: [α]2D0
=
1
+11.6 (c = 0.17, CH2Cl2). H NMR (400 MHz, CDCl3): δ = 8.75
(d, J = 8.75 Hz, 2 H), 7.48 (d, J = 8.75 Hz, 2 H), 5.10 (q, J = 6.06,
12.12 Hz, 1 H), 4.92 (m, 3 H), 4.35 (m, 1 H), 3.78 (d, J = 9.3 Hz,
1 H), 1.26 (m, 6 H), 1.10 (m, 6 H) ppm. 13C NMR (101 MHz,
CDCl3): δ = 166.0, 143.9, 137.4, 129.5, 124.2, 70.4, 70.2, 54.6, 42.5,
General Procedure for Michael Addition Reactions: To a 10-mL mi-
crowave vial was added the catalyst (0.02 mmol) followed by tolu-
ene(1.0 mL) and the nitro-olefin (0.20 mmol); thereafter, the mal-
onate (0.20 mmol) was added. The reaction was kept at the speci-
fied temperature while stirring for 12 h (or some cases 20 h). Tolu-
ene was directly evaporated under vacuum, and the resulting resi-
due was purified by silica gel chromatography (Et2O/hexane, 40:60)
and analyzed as described below. NMR spectroscopic data and re-
tention times for all chiral products were in agreement to the race-
mic samples or previously reported literature data. Chiral products
are listed in the order of presentation in Tables 2–5.
21.5, 21.4, 21.36, 21.33 ppm. IR (ATR): ν = 2975, 1718, 1522,
˜
1139 cm–1. HRMS: calcd. for C17H22N2O8 [M + Na]+ 405.1274;
found 4051352. HPLC (Chiralpak IA, hexane/2-propanol = 90:10,
flow rate = 0.9 mL/min, λ = 210 nm): tR = 18.6 (major), 17.4
(minor) min.
Diisopropyl 2-[1-(4-Methoxyphenyl)-2-nitroethyl]malonate: [α]2D0
=
+580 (c = 0.1, CH2Cl2). 1H NMR (400 MHz, CDCl3): δ = 7.08 (d,
J = 8.36 Hz, 2 H), 6.75 (d, J = 8.36 Hz, 2 H), 5.10 (q, J = 7.76,
13.5 Hz, 1 H), 4.77 (m, 3 H), 4.08 (m, 1 H), 3.69 (s, 3 H), 3.65 (d,
J = 9.52 Hz, 1 H), 1.16 (m, 6 H), 0.99 (m, 6 H) ppm. 13C NMR
(101 MHz, CDCl3): δ = 164.5, 142.1, 136.6, 129.3, 114.26, 78.2,
(S)-Dimethyl 2-(2-Nitro-1-phenylethyl)malonate:[22] 1H NMR
(400 MHz, CDCl3): δ = 7.19–7.38 (m, 5 H),4.92 (dd, J = 13.0,
5.7 Hz, 1 H), 4.89 (dd, J = 13.0, 8.6 Hz, 1 H), 4.25 (td, J = 8.6, 69.8, 69.5, 55.3, 55.2, 21.6, 21.4, 21.34, 21.32 ppm. IR (ATR): ν =
˜
5.7 Hz, 1 H), 3.87 (d, J = 8.6 Hz, 1 H), 3.77 (s, 3 H), 3.56 (s, 3
H) ppm. HPLC (Chiralpak IA, hexane/2-propanol = 90:10, flow
2984, 1718, 1555, 1099 cm–1. HRMS: calcd. for C18H25NO7 [M +
Na]+ 390.1529; found 390.1533. HPLC (Chiralpak IA, hexane/2-
6
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© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O20303
/KAP1
Date: 02-05-12 18:35:59
Pages: 8
Guanidine Organocatalysts Bearing a Tetrahydroisoquinoline Framework
13, 3627; e) K. A. Schug, W. Lindner, Chem. Rev. 2005, 105,
67; f) T. Suhs, B. Koenig, Chem. Eur. J. 2006, 12, 8150; g) T.
Suhs, B. Koenig, Mini Rev. Org. Chem. 2006, 3, 315; h) M.
Terada, J. Synth. Org. Chem. Jpn. 2010, 68, 1159.
[8] a) A. Berkessel, H. Gröger, Asymmetric Organocatalysis – From
Biomimetic Concepts to Applications in Asymmetric Synthesis,
Wiley-VCH, Weinheim, 2005; b) A. H. Hoveyda, A. W. Hird,
M. A. Kacprzynski, Chem. Commun. 2004, 1779; c) S. J. Miller,
Acc. Chem. Res. 2004, 37, 601; d) J. F. Traverse, Y. Zhao, A. H.
Hoveyda, M. L. Snapper, Org. Lett. 2005, 7, 3151.
[9] a) Q. B. Pan, D. W. Ma, Chin. J. Chem. 2003, 21, 793; b) Y.
Sohtome, Y. Hashimoto, K. Nagasawa, Adv. Synth. Catal.
2005, 347, 1643; c) Z. Yu, X. Liu, L. Zhou, L. Lin, X. Feng,
Angew. Chem. 2009, 121, 5297; Angew. Chem. Int. Ed. 2009,
48, 5195.
propanol = 90:10, flow rate = 0.9 mL/min, λ = 210 nm): tR = 11.1
(major), 9.7 (minor) min.
tert-Butyl
1-(2-Nitro-1-p-tolylethyl)-2-oxocyclopentanecarboxyl-
ate:[12,23] 1H NMR (400 MHz, CDCl3): δ = 7.18–7.16 (m, 2 H),
7.12–7.10 (m, 2 H), 5.16 (dd, J = 13.28, 3.76 Hz, 1 H), 4.97 (dd, J
= 13.32, 11.20 Hz, 1 H), 4.03 (dd, J = 11.16, 3.76 Hz, 1 H), 2.32
(s, 3 H), 2.38–2.29 (m, 3 H), 2.02–1.77 (m, 4 H), 1.47 (s, 9 H) ppm.
HPLC (Chiralpak IB, hexane/2-propanol = 98:2, flow rate =
1.0 mL/min, λ = 210 nm): tR = 12.0 (syn, major), 16.9 (minor) min.
tert-Butyl 1-[2-Nitro-1-(4-nitrophenyl)ethyl]-2-oxocyclopentanecarb-
oxylate:[12,23] 1H NMR (400 MHz, CDCl3): δ = 8.19–8.17 (m, 2 H),
7.59–7.55 (m, 2 H), 5.23 (dd, J = 13.84, 3.56 Hz, 1 H), 5.02 (dd, J
= 13.84, 11.20 Hz, 1 H), 4.09 (dd, J = 11.20, 3.56 Hz, 1 H), 2.49–
2.40 (m, 1 H), 2.34–2.25 (m, 1 H), 2.14–1.84 (m, 4 H), 1.44 (s, 9
H) ppm. HPLC (Chiralpak IB, hexane/2-propanol = 95:5, flow rate
[10] S. Dong, X. Liu, Y. Zhang, L. Lin, X. Feng, Org. Lett. 2011,
13, 5060.
[11] a) J. D. Scott, R. M. Williams, Chem. Rev. 2002, 102, 1669; b)
V. Sridharan, P. A. Suryavanshi, J. C. Menéndez, Chem. Rev.
2011, 111, 7157–7259; c) M. E. Zarranz De Ysern, L. A. Or-
doñez, Prog. Neuro-Psychopharmacol. 1981, 5, 343.
[12] B. K. Peters, S. K. Chakka, T. Naicker, G. E. M. Maguire,
H. G. Kruger, P. G. Andersson, T. Govender, Tetrahedron:
Asymmetry 2010, 21, 679.
[13] R. B. Kawthekar, S. K. Chakka, V. Francis, P. G. Andersson,
H. G. Kruger, G. E. M. Maguire, T. Govender, Tetrahedron:
Asymmetry 2010, 21, 846.
[14] S. K. Chakka, B. K. Peters, P. G. Andersson, G. E. M. Mag-
uire, H. G. Kruger, T. Govender, Tetrahedron: Asymmetry 2010,
21, 2295.
[15] T. Naicker, K. Petzold, T. Singh, P. I. Arvidsson, H. G. Kruger,
G. E. M. Maguire, T. Govender, Tetrahedron: Asymmetry 2010,
21, 2859.
=
1.0 mL/min,
λ = 254 nm): tR = 22.9(syn, major), 49.5
(minor) min.
tert-Butyl 1-[1-(4-Methoxyphenyl)-2-nitroethyl]-2-oxocyclopentane-
carboxylate:[12,23] 1H NMR (400 MHz, CDCl3): δ = 7.23–7.21 (m,
2 H), 6.86–6.82 (m, 2 H), 5.14 (dd, J = 13.20, 3.80 Hz, 1 H), 4.95
(dd, J = 13.20, 11.28 Hz, 1 H), 3.93 (dd, J = 13.20, 3.80 Hz, 1 H),
3.79 (s, 3 H), 2.39–2.29 (m, 2 H), 2.02–1.77 (m, 4 H), 1.47 (s, 9
H) ppm. HPLC (Chiralpak IB, hexane/2-propanol = 95:5, flow rate
=
1.0 mL/min,
λ
=
210 nm): tR
=
9.2 (syn, major), 10.1
(minor) min.
Supporting Information (see footnote on the first page of this arti-
cle): NMR and high-resolution mass spectra of novel compounds,
and crystallographic details.
[16] T. Naicker, P. I. Arvidsson, H. G. Kruger, G. E. M. Maguire,
T. Govender, Eur. J. Org. Chem. 2011, 6923.
Acknowledgments
[17] X. Zhu, Z. Du, F. Xu, Q. Shen, J. Org. Chem. 2009, 74, 6347.
[18] a) H. Marquez, A. Loupy, O. Calderon, E. R. Perez, Tetrahe-
dron 2006, 62, 2616; b) H. Sandin, M. L. Swanstein, E. Wellner,
J. Org. Chem. 2004, 69, 1571; c) W. Solodenko, P. Broker, J.
Messinger, U. Schon, A. Kirschning, Synthesis 2006, 461.
[19] a) H. M. Li, Y. Wang, L. Tang, F. H. Wu, X. F. Liu, C. Y. Guo,
B. M. Foxman, L. Deng, Angew. Chem. 2005, 117, 107; Angew.
Chem. Int. Ed. 2005, 44, 105; b) S. B. Tsogoeva, Eur. J. Org.
Chem. 2007, 1701; c) Z.-H. Zhang, X.-Q. Dong, D. Chen, C.-
J. Wang, Chem. Eur. J. 2008, 14, 8780.
The authors wish to thank the National Research Foundation, the
SA/Swedish Research Links Programme Grant and Aspen Pharm-
acare, South Africa.
[1] a) X. Fu, C.-H. Tan, Chem. Commun. 2011, 47, 8210; b) T.
Ishikawa, T. Kumamoto, Synthesis 2006, 737; c) D. W. Oliver,
I. C. Dormehl, J. E. S. Wikberg, M. Dambrova, Med. Chem.
Res. 2004, 13, 427.
[2] a) D.-W. Lee, Y.-M. Park, K.-Y. Lee, Catal. Surv. Asia 2009,
13, 63; b) M. S. Taylor, E. N. Jacobsen, Angew. Chem. 2006,
118, 1550; Angew. Chem. Int. Ed. 2006, 45, 1520.
[3] a) M. K. Kiesewetter, M. D. Scholten, N. Kirn, R. L. Weber,
J. L. Hedrick, R. M. Waymouth, J. Org. Chem. 2009, 74, 9490;
b) D. Leow, C.-H. Tan, Synlett 2010, 1589.
[4] H. Ube, M. Terada, Bioorg. Med. Chem. Lett. 2009, 19, 3895.
[5] E. J. Corey, M. J. Grogan, Org. Lett. 1999, 1, 157.
[6] D. Leow, C.-H. Tan, Chem. Asian J. 2009, 4, 488.
[7] a) R. G. S. Berlinck, A. C. B. Burtoloso, M. H. Kossuga, Nat.
Prod. Rep. 2008, 25, 919; b) A. G. Doyle, E. N. Jacobsen,
Chem. Rev. 2007, 107, 5713; c) T. Ishikawa, T. Isobe, Chem.
Eur. J. 2002, 8, 552; d) L. P. Masic, Curr. Med. Chem. 2006,
[20] a) D. Almas¸i, D. A. Alonso, A.-N. Balaguer, C. Nájera, Adv.
Synth. Catal. 2009, 351, 1123; b) D. Almas¸i, D. A. Alonso, C.
Nájera, Adv. Synth. Catal. 2008, 350, 2467; c) D. Gryko, M.
Chrominski, D. J. Pielacinska, Symmetry 2011, 3, 265.
[21] O. V. Dolomanov, L. J. Bourhis, R. J. Gildea, J. A. K. Howard,
H. Puschmann, J. Appl. Crystallogr. 2009, 42, 339.
[22] a) Q. Zhu, H. Huang, D. Shi, Z. Shen, C. Xia, Org. Lett. 2009,
11, 4536; b) H. M. Li, Y. Wang, L. Tang, L. Deng, J. Am.
Chem. Soc. 2004, 126, 9906; c) H. M. Li, Y. Wang, L. Tang, L.
Deng, J. Am. Chem. Soc. 2004, 126, 9906.
[23] D. C. Craig, Z. M. A. Judeh, R. W. Read, Aust. J. Chem. 2002,
55, 733.
Received: March 12, 2012
Published Online: ᭿
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7

Job/Unit: O20303
/KAP1
Date: 02-05-12 18:35:59
Pages: 8
T. Naicker, P. I. Arvidsson, H. G. Kruger, G. E. M. Maguire, T. Govender
FULL PAPER
Organocatalysis
T. Naicker, P. I. Arvidsson, H. G. Kruger,
G. E. M. Maguire, T. Govender* ....... 1–8
Microwave-Assisted Synthesis of Guan-
idine Organocatalysts Bearing
a Tetra-
hydroisoquinoline Framework and Their
Evaluation in Michael Addition Reactions
The synthesis of chiral guanidine organo-
catalysts based on a tetrahydroisoquinoline
framework and their evaluation in asym-
metric Michael additions of malonates and
β-keto esters with nitro-olefins is reported.
A microwave-assisted procedure for intro-
ducing the guanidine unit onto
amino amide derivatives is also reported.
The chiral products were obtained in up to
99% yield with up to 97%ee.
Keywords: Organocatalysis / Michael ad-
dition / Microwave chemistry
8
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