Monoimine derived from trans-1,2-diaminocyclohexane and ethyl glyoxylate: An intermediate in aza-Diels-Alder and Mannich reactions

Article abstract of DOI:10.1021/jo302820m

Novel enantiopure policyclic nitrogen heterocycles have been obtained in the diastereoselective aza-Diels-Alder or Mannich reaction of dienes with imine formed in situ from ethyl glyoxylate and (1R,2R)-diaminocyclohexane.

Full text of DOI:10.1021/jo302820m

Note
pubs.acs.org/joc
Monoimine Derived from trans-1,2-Diaminocyclohexane and Ethyl
Glyoxylate: An Intermediate in Aza-Diels−Alder and Mannich
Reactions
Elzbieta Wojaczynska,* Julia Bąkowicz, Mateusz Dorsz, and Jacek Skarzewski
́
̇
̇
Department of Organic Chemistry, Faculty of Chemistry, Wrocław University of Technology, Wybrzeze Wyspian
Wrocław, Poland
skiego 27, 50-370
̇
S
* Supporting Information
ABSTRACT: Novel enantiopure policyclic nitrogen hetero-
cycles have been obtained in the diastereoselective aza-Diels−
Alder or Mannich reaction of dienes with imine formed in situ
from ethyl glyoxylate and (1R,2R)-diaminocyclohexane.
he stereoselective aza-Diels−Alder reaction serves as an
and stereoselectivity was observed, and despite the lower yield,
Teffective method for the preparation of chiral heterocyclic the major isomer 5 was obtained in 90:10 dr, which is
compounds.1 The exo-ester (1S,3R,4R)-1 containing a 2-
comparable with the diastereomeric composition of the starting
diene (Z:E = ca. 92:8).
azanorbornene (2-azabicyclo[2.2.1]heptene) skeleton was
easily obtained as the main product of the cycloaddition of
cyclopentadiene to iminium ion formed in situ from ethyl
glyoxylate and (S)-1-phenylethylamine (Scheme 1).2 This
bicyclic system has proved to be an attractive precursor of
chiral ligands useful in asymmetric synthesis.3−5
Chiral tetracyclic nitrogen heterocycles can be found among
biologically active molecules, including alkaloids (e.g., sparteine,
asperlicin, benzo[a]quinolizidine derivatives7), azasteroids8
(e.g., finasteride, chandonium), and various drugs (e.g.,
antidepressants mianserin and mirtazapine). Compounds
from this class, sparteine and Troger’s base, are also widely
̈
used in organic synthesis and as chiral discrimination
Scheme 1
compounds.9
A structure of the obtained cycloadducts was determined by
NMR (1H, 13C) spectroscopy and high resolution mass
spectrometry. In particular, 2D NMR spectra (1H−1H COSY
1
and NOESY, H−13C HMQC/HSQC and HMBC) made it
possible to assign spectral resonances and revealed signal
correlations that further confirmed formation of tetracyclic
(tricyclic in the case of 5) products and the assigned
configurations of the newly created stereogenic centers
((1S,11R,12R) for compounds 3 and 4, (10R,14R) for adduct
5). For example, the observed connectivities in the NOESY
map of compound 3 are in a good agreement with the expected
interproton contacts (H3 and H14; H11 and H15 of -CH2-bridge)
found in the DFT optimized structure of 3 (Figure 1). Also the
configuration ascribed to the remaining aza-Diels−Alder
adducts corroborated their 2D 1H and 13C NMR spectra.
Moreover, the product structures are in agreement with the
previously observed general stereochemical outcome of the
cycloaddition, i.e., formation of mainly exo-2-azanorbornyl
derivatives.2
In our quest for versatile ligands for asymmetric catalysis
based on the 2-azanorbornane framework, we focused on the
possibility of introducing an additional donor atom to the
molecule. The endocyclic nitrogen donor as a tertiary amine is
already present in the structure of 2-azanorbornyl derivatives.
Another one, of different character, can be introduced via an
appropriate modification of the exocyclic group as described by
Andersson et al.6
One can also imagine an alternative synthetic pathway
comprising the use of chiral diamine as a starting material for
the preparation of the dienophile for aza-Diels−Alder reaction.
In order to examine this possibility we reacted enantiopure
trans-1,2-diaminocyclohexane (DACH) with 1 equiv of ethyl
glyoxylate. The dienophile intermediate 2 was treated with
freshly distilled cyclopentadiene or 1,3-cyclohexadiene. In both
cases the reaction proceeded smoothly, leading to the single
aza-Diels−Alder adducts 3 and 4, respectively, in very high
yields (Scheme 2). The reaction generating three new
stereogenic centers furnished one diastereomer only. Even in
the case of unsymmetrical 1-methoxy-1,3-butadiene, high regio-
The described aza-Diels−Alder procedure offers an easy
access to enantiopure tri- or tetracyclic systems possessing up
to five stereogenic carbon centers. Chiral imine 2 (Scheme 2)
Received: December 30, 2012
© XXXX American Chemical Society
A
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The Journal of Organic Chemistry
Note
Scheme 2
bond effectively, while the lactam functionality in structure 6
does not.
When pyrrole or furan and 2 were used in the attempted
Diels−Alder reaction, only the ring-alkylation product was
isolated as a single diastereomer in 15% and 80% yield,
respectively (Scheme 2). The structures of pyrrole 7a and furan
8a adducts were deduced from 1D and 2D NMR spectra and,
in the case of 7a, confirmed by X-ray measurement, which
showed S configuration of the newly created stereogenic center
(Figure S1, Supporting Information). The pyrrole ring is almost
perpendicular to the mean plane of 10 atoms of the bicyclic
system (interplane angle equals 84.8°). Pyrrolic NH fragment is
engaged in a hydrogen bond with carbonyl oxygen atom of the
neighboring molecule with O−N distance of 2.96 Å.
Since under Diels−Alder conditions a product of nucleo-
philic addition of pyrrole to imine was obtained, we decided to
carry out the reaction using conditions applied by Minakawa et
al. to the addition of racemic 6 to phenols (phosphate buffer,
pH = 8).11 This time the conversion of chiral 6 was
quantitative, and the two diastereomeric adducts 7a and 7b
were isolated in 1.4:1 ratio (Scheme 3). After chromatographic
separation, diastereomers were identified by comparison with
compound 7a obtained in the course of the attempted Diels−
Alder reaction. As can be seen, a significant increase of reaction
yield under modified conditions was accompanied by the loss of
stereoselectivity.
With an enantiopure compound 6 in hand, we decided to
explore the possibility of chiral induction in its reaction with
phenols. Addition of p-cresol or p-(tert-butyl)phenol to 6
performed in phosphate buffer at pH = 8 resulted in a mixture
of diastereomers (9a/9b and 10a/10b, respectively). Identity of
products was confirmed by high resolution mass spectrometry
(see Experimental Section).
The overall yield of adducts and reaction diastereoselectivity
were rather modest (40% yield, dr 1.7:1 for 9a/9b, and 29%
yield, dr 1.6:1 for 10a/10b) and comparable with values
obtained for preparation of racemic compounds 9a and 9b.11
We were able to isolate the enantiomerically pure major isomer
(1R,4S,6R)-9a by column chromatography.
Figure 1. Part of NOESY map of compound 3 showing cross-peaks
derived from interproton contacts indicated in the DFT optimized
structure.
was prepared in situ in a one-pot procedure, starting from the
easily available starting materials. Furthermore, other chiral 1,2-
diamines may be also used, and glyoxylate can be replaced with
pyruvate derivatives;10 these possibilities together with the
diversity of available dienes show the potential of the proposed
synthetic route. The presence of several functional groups in
the resulting cycloadducts opens the possibility of their further
modification.
Moreover, when the initial imine intermediate 2 formed in
the reaction of glyoxylate and DACH was left without the
usually added diene, it converted into a bicyclic chiral imine 6
in >90% yield (Scheme 2). Racemic compound 6 has already
been prepared and applied as a phenol-alkylating agent by
Minakawa et al.11 Similar bicyclic imines were also obtained in
the reaction of pyruvate derivatives with various 1,2-diamines.10
Since compound 6 remains an activated chiral imine, we
decided to test it as a dienophile in aza-Diels−Alder reaction
with CF3COOH, BF3·Et2O, and freshly distilled cyclo-
pentadiene. Surprisingly, there was no reaction, and the
substrate was recovered. Thus clearly iminoglyoxylate 2 is an
active dienophile and its internal cyclization halts the Diels−
Alder reaction. It seems that an ester activates the imine double
B
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The Journal of Organic Chemistry
Note
(KBr): 747, 1294, 1370, 1670, 2858, 2935, 2978, 3195 cm−1. HRMS
(ESI-TOF): m/z [M + H]+ calcd for (C13H19N2O)+ 219.1497; found
219.1514.
Scheme 3
(1S,3R,8R,11R,12R)-10-Oxo-2,9-diazatetracyclo-
[10.2.2.02,11.03,8]hexadec-13-ene (4). Yield 2.7 g (95%), mp 152−
153 °C. [α]20D −21.4 (c 0.55, CH2Cl2). 1H NMR (300 MHz, CDCl3):
δ 1.22−1.39 (m, 6H), 1.64−1.90 (m, 5H), 2.15−2.20 (m, 2H), 3.00−
3.14 (m, 1H), 3.34−3.36 (m, 1H), 3.69−3.71 (m, 2H), 6.15 (bs, 1H,
NH), 6.36−6.43 (m, 2H). 13C NMR (75 MHz, CDCl3): δ 22.5, 23.9,
24.4, 26.4, 30.4, 31.5, 32,5, 48.6, 52.8, 62.4, 62.9, 134.0, 134.4, 172.0.
IR (KBr): 705, 1373, 1668, 2856, 2929, 3066, 3185 cm−1. HRMS
(ESI-TOF): m/z [M + H]+ calcd for (C14H21N2O)+ 233.1654; found
233.1645.
(2R,7R,10R,14R)-14-Methoxy-9-oxo-1,8-diazatricyclo-
[8.4.0.02,7]tetradec-12-ene (5). Yield 0.92 g (32%), de 80%. 1H
NMR (500 MHz, CDCl3): δ 1.20−1.36 (m, 4H), 1.73−1.80 (m, 4H),
2.46−2.55 (m, 2H), 2.64−2.68 (m, 1H), 2.97−3.02 (m, 1H), 3.0 (s,
3H, OMe), 3.55 (dd, 1H, J1 = 10.3 Hz, J2 = 3.4 Hz), 4.81 (d, 1H, J =
5.2 Hz), 5.55 (dd, 1H, J1 = 15.6 Hz, J2 = 5.2 Hz), 5.80−5.85 (m, 1H),
6.18 (bs, 1H, NH). 13C NMR (125 MHz, CDCl3): δ 23.8, 24.7, 30.7,
31.3, 35.5, 52.6, 53.2, 57.5, 58.4, 102.0, 130.9, 131.4, 172.2. IR (film):
838, 995, 1055, 1128, 1355, 1448, 1657, 2859, 2932, 3183, 3303 cm−1.
HRMS (ESI-TOF): m/z [M + H]+ calcd for (C13H21N2O2)+
237.1603; found 237.1591.
Among rare reports on 2-furyl-substituted bicyclic diaza-
compounds, racemic hexa- and decahydroquinoxaline deriva-
tives have been described.12 Quinoxalinones, imines containing
a lactam functionality closely related to 6, were applied in the
Friedel−Crafts reaction to yield indolyl derivatives.13 Asym-
metric induction was observed in the reaction of various
azinones with nucleophiles.14 Diastereoselective Barbier
allylation of dihydropyrazinones followed by cyclization
afforded chiral bicyclic and tricyclic piperazinones.15 In
conclusion, the stereoselective addition of pyrrole and furan
to bicyclic imine under Diels−Alder conditions described
herein (see Scheme 2) provides an interesting route to new
chiral heterocyclic compounds, which will be tested as (N,X)-
donating ligands for asymmetric catalysis.
(1R,6R)-3-Oxo-2,5-diazabicyclo[4.4.0]decane (6). [α]20
D
−234.7 (c 1.11, CH2Cl2), spectral characteristics of this compound
was in agreement with literature data for racemic imine.11
(1R,4S,6R)-3-Oxo-4-(2-pyrrolyl)-2,5-diazabicyclo[4.4.0]-
decane (7a). Yield 0.40 g (15%, de 100%, attempted Diels−Alder
reaction)/0.25 g (55%, de 58%, Mannich conditions), mp 193−194
1
°C. [α]20 +35.3 (c 0.39, CH2Cl2). H NMR (300 MHz, CDCl3): δ
D
1.30−1.40 (m, 4H), 1.63−1.97 (m, 5H), 2.66 (td, 1H, J1 = 10.1 Hz, J2
= 3,5 Hz), 3.05−3.09 (m, 1H), 4.76 (s, 1H), 5.93 (bs, 1H, NH), 6.16−
6.20 (m, 2H), 6.75−6.77 (m, 1H), 9.38 (bs, 1H, NH). 13C NMR (75
MHz, CDCl3): δ 23.8, 24.7, 30.7, 31.6, 57.3, 58.2, 58.4, 105.5, 108.1,
117.5, 128.3, 170.4. IR (film): 717, 1083, 1451, 1648, 1746, 2925, 3362
cm−1. HRMS (ESI-TOF): m/z [M + H]+ calcd for (C12H18N3O)+
220.1450; found 220.1457. Rf (ethyl acetate) 0.18.
EXPERIMENTAL SECTION
■
(1R,4S,6R)-3-Oxo-4-(2-furyl)-2,5-diazabicyclo[4.4.0]decane
Synthesis of Cycloadducts 3−5 and Adducts 7a, 8a. Aza-
Diels−Alder reaction of dienes and an iminium ion derived from ethyl
glyoxylate and (1R,2R)-trans-diaminocyclohexane (DACH) was
performed according to the modified literature procedure.2c In a
typical synthesis, 1.39 g (6.12 mmol) of HIO4·2H2O was added
stepwise to a stirred solution of 1.26 g (6.12 mmol) of diethyl tartrate
in 30 mL of diethyl ether at 0 °C during 0.5 h, and the stirring was
continued for 0.5 h at room temperature. The precipitate was filtered
off, and solvent was evaporated. The solid residue was dissolved in 40
mL of CH2Cl2, and 1.39 g (12.25 mmol, 1 equiv) of DACH was added
to the solution, which was stirred over molecular sieves 4Å for 2 h at
room temperature. CF3COOH (0.94 mL, 12.25 mmol), 1.50 mL of
BF3·Et2O (12.25 mmol), and freshly distilled diene (1.2 equiv) were
then introduced in 10 min intervals. The reaction mixture was stirred
for 20 h at room temperature. Reaction was quenched by stirring with
aqueous Na2CO3 for 2 h. The reaction mixture was filtered through a
bed of cellite, and extracted with CH2Cl2 (3 × 20 mL). The combined
organic phases were dried over Na2SO4, filtered, and evaporated.
Chromatography on silica column (5% CH3OH in CHCl3 was used as
eluent) was then performed, yielding cycloadducts (3−5) or adducts
(7a, 8a).
(8a). Yield 2.2 g (80%), mp 146−147 °C. [α]20 +61.8 (c 0.18,
D
CH2Cl2). 1H NMR (300 MHz, CDCl3): δ 1.19−1.33 (m, 5H), 1.60−
1.81 (m, 4H), 2.65−2.72 (m, 1H), 3.06−3.13 (m, 1H), 4.79 (s, 1H),
6.20 (bs, 1H, NH), 6.29−6.35 (m, 2H), 7.38 (s, 1H). 13C NMR (75
MHz, CDCl3): δ 23.8, 24.6, 30.6, 31.4, 53,1, 57.0, 58.5, 107.8, 110.5,
142.2, 153.5, 167.8. IR (KBr): 755, 808, 1050, 1352, 1671, 2933, 3184
cm−1. HRMS (ESI-TOF): m/z [M + H]+ calcd for (C12H17N2O2)+
221.1290; found 221.1296.
Mannich Reaction of Imine 6 with Nucleophiles. Addition of
pyrrole and phenols (p-cresol or p-(tert-butyl)phenol) to imine 7 (0.31
g, 2 mmol) was performed according to the literature procedure (24 h
at rt in pH = 8.0 phosphate buffer containing 5% of DMSO).11
Diastereomer ratio was assigned from 1H NMR measurement. Pyrrolic
adducts 7a,7b were separated by chromatography on silica using ethyl
acetate as eluent. Major diastereomer from cresol addition, 9a was
isolated in an enantiopure form using column chromatography with t-
BuOMe/CHCl3 (2:1 v/v).
(1R,4R,6R)-3-Oxo-4-(2-pyrrolyl)-2,5-diazabicyclo[4.4.0]-
decane (7b). Yield 0.18 g (40%), mp 175−177 °C. [α]20 +45.7 (c
D
1
0.14, CH2Cl2). H NMR (300 MHz, CDCl3): δ 1.26−1.42 (m, 4H),
1.61 (bs, 1H), 1.77−1.81 (m, 2H), 1.84−1.90 (m, 1H), 1.93−1.96 (m,
1H), 2.65−2.69 (m, 1H), 3.07−3.12 (m, 1H), 4.76 (s, 1H), 5.74 (bs,
1H, NH), 6.16 (dd, 1H, J1 = 6.0 Hz, J2 = 2.7 Hz), 6.18−6.20 (m, 1H),
6.76 (dd, 1H, J1 = 4.1 Hz, J2 = 2.5 Hz), 9.38 (bs, 1H, NH). 13C NMR
(75 MHz, CDCl3): δ 23.8, 24.7, 30.7, 31.6, 57.3, 58.2, 58.5, 105.5,
108.1, 117.6, 128.2, 170.3. IR (film): 717, 803, 1083, 1308, 1572, 1655,
2857, 2926, 3239, 3365 cm−1. HRMS (ESI-TOF): m/z [M + H]+
calcd for (C12H18N3O)+ 220.1450; found 220.1458. Rf (ethyl acetate)
0.24.
Chiral imine 6 was isolated from the reaction mixture before the
acidification step.
(1S,3R,8R,11R,12R)-10-Oxo-2,9-diazatetracyclo-
[10.2.1.02,11.03,8] pentadec-13-ene (3). Yield 2.4 g (90%), mp
1
149−150 °C. [α]20 +24.2 (c 1.22, CH2Cl2). H NMR (300 MHz,
D
CDCl3): δ 1.20−1.30 (m, 4H), 1.53−1.57 (dt, 1H, J1 = 8.4 Hz, J2 = 1.5
Hz), 1.71−1.74 (m, 3H), 1.86−1.92 (m, 1H), 1.98−2.12 (m, 2H),
3.09−3.12 (m, 1H), 3.51 (d, 1H, J = 1.5 Hz), 3.95 (d, 1H, J = 6.0 Hz),
4.09 (d, 1H, J = 1.5 Hz), 6.08 (bs, 1H, NH), 6.31−6.34 (m, 1H),
6.42−6.50 (m, 1H). 13C NMR (75 MHz, CDCl3): δ 23.9, 24.2, 30.7,
31.1, 46.8, 48.0, 54.1, 61.3, 61.8, 62.4, 136.3, 137.7, 172.4 ppm. IR
(1R,4S,6R)-3-Oxo-4-(2-hydroxy-5-methylphenyl)-2,5-
diazabicyclo[4.4.0]decane (9a). Yield 0.2 g (25%), [α]20D +155.8 (c
C
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The Journal of Organic Chemistry
Note
0.2, CH2Cl2); spectral characteristics were in agreement with literature
data for the racemic adduct.11 Rf (ethyl acetate) 0.50; for 9b Rf (ethyl
acetate) 0.58.
(9) Wenzel, T. J. Discrimination of Chiral Compounds Using NMR
Spectroscopy; Wiley-Interscience: Hoboken, NJ, 2007.
(10) Murthy, S. N.; Madhav, B.; Nageswar, Y. V. D. Helv. Chim. Acta
2010, 93, 1216−1220.
9a/9b HRMS (ESI-TOF): m/z [M + H]+ calcd for (C15H21N2O2)+
261.1603; found 261.1590. 10a/10b HRMS (ESI-TOF): m/z [M +
H]+ calcd for (C18H27N2O2)+ 303.2072; found 303.2080.
(11) Minakawa, M.; Guo, H.-M.; Tanaka, F. J. Org. Chem. 2008, 73,
8669−8672.
(12) Raw, S. A.; Wilfred, C. D.; Taylor, R. J. K. Org. Biomol. Chem.
2004, 2, 788−796.
ASSOCIATED CONTENT
■
(13) Han, Y.-Y.; Wu, Z.-J.; Zhang, X.-M.; Yuan, W.-C. Tetrahedron
Lett. 2010, 51, 2023−2028.
S
* Supporting Information
1
Copies of H and 13C spectra and selected 2D NMR maps,
(14) Chupakhin, O. N.; Egorov, I. N.; Rusinov, V. R.; Slepukhin, P.
DFT optimized structure of compound 3, and ORTEP view of
compound 7a. This material is available free of charge via the
Internet at http://pubs.acs.org.
A. Russ. Chem. Bull., Int. Ed. 2010, 59, 991−1001.
́
(15) Viso, A.; Fernan
́
dez de la Pradilla, R.; Flores, A.; del Aguila, M.
A. Tetrahedron 2008, 64, 11580−11588.
AUTHOR INFORMATION
Corresponding Author
*E-mail: elzbieta.wojaczynska@pwr.wroc.pl.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The work was financed by a statutory activity subsidy from the
Polish Ministry of Science and Higher Education for the
Faculty of Chemistry of Wrocław University of Technology. Dr.
Robert Wieczorek from the University of Wrocław is gratefully
acknowledged for performing DFT calculations.
DEDICATION
■
Dedicated to Professor Jacek Gawron
seventieth birthday.
́
ski on the occasion of his
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