Thermal [2+3]-cycloadditions of trans-1-methyl-2,3-diphenylaziridine with C=S and C=C dipolarophiles: An unexpected course with dimethyl dicyanofumarate

Article abstract of DOI:10.1002/hlca.200900236

The thermal reaction of trans-1-methyl-2,3-diphenylaziridine (trans-1a) with aromatic and cycloaliphatic thioketones 2 in boiling toluene yielded the corresponding cis-2,4-diphenyl-1,3-thiazolidines cis-4 via conrotatory ring opening of trans-1a and a con

Full text of DOI:10.1002/hlca.200900236

Helvetica Chimica Acta – Vol. 92 (2009)
2631
Thermal [2 þ 3]-Cycloadditions of trans-1-Methyl-2,3-diphenylaziridine with
C¼S and C¼C Dipolarophiles: An Unexpected Course with Dimethyl
Dicyanofumarate
by Grzegorz Mloston´*, Katarzyna Urbaniak, and Małgorzata Domagała
´
´
´
´
University of Łodz, Faculty of Chemistry, Narutowicza 68, PL-90-136 Łodz
(phone: þ 48-42-6355761; fax: þ 48-42-6355380; e-mail: gmloston@uni-lodz.pl)
and Arno Pfitzner and Manfred Zabel
Institut fꢀr Anorganische Chemie, Universitꢁt Regensburg, Universitꢁtsstrasse 31, D-93040 Regensburg
and Heinz Heimgartner*
Organisch-Chemisches Institut der Universitꢁt Zꢀrich, Winterthurerstrasse 190, CH-8057 Zꢀrich
(phone: þ 41-44-6354282; fax: þ 41-44-6356812; e-mail: heimgart@oci.uzh.ch)
The thermal reaction of trans-1-methyl-2,3-diphenylaziridine (trans-1a) with aromatic and cyclo-
aliphatic thioketones 2 in boiling toluene yielded the corresponding cis-2,4-diphenyl-1,3-thiazolidines cis-
4 via conrotatory ring opening of trans-1a and a concerted [2 þ 3]-cycloaddition of the intermediate
(E,E)-configured azomethine ylide 3a (Scheme 1). The analogous reaction of cis-1a with dimethyl
acetylenedicarboxylate (5) gave dimethyl trans-2,5-dihydro-1-methyl-2,5-diphenylpyrrole-3,4-dicarbox-
ylate (trans-6) in accord with orbital-symmetry-controlled reactions (Scheme 2). On the other hand, the
reactions of cis-1a and trans-1a with dimethyl dicyanofumarate (7a), as well as that of cis-1a and dimethyl
dicyanomaleate (7b), led to mixtures of the same two stereoisomeric dimethyl 3,4-dicyano-1-methyl-2,5-
diphenylpyrrolidine-3,4-dicarboxylates 8a and 8b (Scheme 3). This result has to be explained via a
stepwise reaction mechanism, in which the intermediate zwitterions 11a and 11b equilibrate (Scheme 6).
In contrast, cis-1,2,3-triphenylaziridine (cis-1b) and 7a gave only one stereoisomeric pyrrolidine-3,4-
dicarboxylate 10, with the configuration expected on the basis of orbital-symmetry control, i.e., via
concerted reaction steps (Scheme 10). The configuration of 8a and 10, as well as that of a derivative of
8b, were established by X-ray crystallography.
1. Introduction. – Azomethine ylides, generated by different methods, were
extensively explored in 1,3-dipolar cycloadditions aimed at the preparation of five-
membered heterocycles. In many instances, the cycloadducts are important final
products or building blocks for the synthesis of biologically active substances as well as
in materials science [1 – 5]. Furthermore, the cycloadditions of azomethine ylides
belong to the most frequently studied reactions used to test new catalysts for the
stereocontrolled synthesis [6 – 8].
The oldest method for the generation of azomethine ylides consists in the thermal
ring opening of properly substituted aziridines. The fundamental experiments by
Huisgen evidenced the orbital control of this process [9]. Irrespective of the
development of new methods, the thermal, conrotatory ring opening of aziridines is
ꢂ 2009 Verlag Helvetica Chimica Acta AG, Zꢀrich

2632
Helvetica Chimica Acta – Vol. 92 (2009)
still frequently applied for stereoselective syntheses of highly functionalized hetero-
cyclic systems.
In our earlier reports, reactions of N-substituted aziridines with acetylenes [10],
alkenes [10][11], carbonyl [11][12], and thiocarbonyl groups [10][13 – 15] were
described. All of the reported reactions yielded [2 þ 3]-cycloadducts with the expected
configuration, i.e., cis-2,3-disubstituted aziridines led to trans-disubstituted products,
and trans-2,3-disubstituted aziridines gave cis-disubstituted cycloadducts. Unexpect-
edly, the attempted [2 þ 3]-cycloaddition of cis-1-methyl-2,3-diphenylaziridine (cis-1a;
cf. Scheme 1) with the electron-deficient dimethyl dicyanofumarate (DCFM) [16]
afforded two stereoisomeric products. The same mixture of products was formed in the
reaction of trans-1-methyl-2,3-diphenylaziridine (trans-1a) with DCFM. This surprising
result prompted us to reinvestigate some [2 þ 3]-cycloadditions of thioketones with the
thermally generated azomethine ylide from trans-1a. Furthermore, the reactions of cis-
1a and trans-1a with DCFM will be described in order to elucidate the unexpected
course of the reaction.
2. Results and Discussion. – As shown in a competitive study with thiobenzophe-
none S-methanide, thioketones, and especially aromatic thioketones, exceed typical
C ꢀ C and C¼C dipolarophiles in their reactivity [17]. The [2 þ 3]-cycloadditions of
azomethine ylides with C¼S dipolarophiles are less well-known. In extension of the
earlier studies, performed with 1-substituted cis-2,3-diphenylaziridines [10][13 – 15],
thermal [2 þ 3]-cycloadditions of trans-1a with thiobenzophenone (2a), 2,2,4,4-
tetramethyl-3-thioxocyclobutane (2b), and adamantanethione (2c) were carried out
in boiling toluene. In the case of 2a, the blue color of the mixture disappeared already
after 45 min, and according to the 1H-NMR spectrum of the mixture, only one product
was formed. The characteristic singlets of HꢁC(2) and HꢁC(4) of a 1,3-thiazolidine of
type 4, appeared at 5.00 and 4.80 ppm, respectively1). These absorptions differed
significantly from those reported for trans-4a, the product obtained from the reaction of
cis-1a and 2a (5.40 and 5.13 ppm) [13] (see also [15]). This comparison and the
stereoselective course of both reactions led to the conclusion that the obtained 1,3-
thiazolidine derivative was cis-4a (Scheme 1). Thus, the intermediate azomethine ylide
3a possesses the (E,E)-configuration predicted by the symmetry rules, and the
cycloaddition step occurs as a concerted process. The cis-configuration was established
by X-ray crystallography in the case of the N-benzyl derivative [18].
In analogy to the experiment with 2a, reactions of trans-1a with the cycloaliphatic
thioketones 2b and 2c were carried out. However, in these cases, the reactions were
completed only after ca. 6 h, confirming the lower reactivity of 2b and 2c compared to
that of 2a. In each case, only a single cycloadduct was formed, and the structures of cis-
4b and cis-4c, respectively, were attributed to these products.
The stereoselective reaction of trans-1a with dimethyl acetylenedicarboxylate (5)
leading to dimethyl cis-2,5-dihydro-1-methyl-2,5-diphenylpyrrole-3,4-dicarboxylate
(cis-6) was already reported [19]. In our earlier publication, the reaction of cis-1-
isopropyl-2,3-diphenylaziridine with 5 in refluxing toluene was described to give a
mixture of the corresponding trans-2,5-dihydropyrrole-3,4-dicarboxylate and the
1
)
All chiral products described in this article are racemic.

Helvetica Chimica Acta – Vol. 92 (2009)
2633
Scheme 1
aromatized pyrrole derivative in a 85 :15 ratio [10]. In the present study, a 1:1 mixture
of cis-1a and 5 in toluene was heated to reflux for 10 h, and the progress of the reaction
1
was monitored by H-NMR spectroscopy, which indicated that only one product was
formed. After chromatographic workup and recrystallization, dimethyl trans-2,5-
dihydro-1-methyl-2,5-diphenylpyrrole-3,4-dicarboxylate (trans-6) was obtained in 77%
yield (Scheme 2).
Scheme 2
It is well-documented that dimethyl dicyanofumarate (DCFM; 7) is an excellent
dienophile and dipolarophile for reactions with electron-rich dienes or 1,3-dipoles.
Especially important are reactions with 1,1-dimethoxybuta-1,3-diene [20] and sterically
crowded thiocarbonyl ylides [21], which were established to occur stepwise via
intermediate zwitterions. To the best of our knowledge, apart from thiocarbonyl ylides,
the only other 1,3-dipoles used in reactions with 7 were diazo compounds [22], and the
addition with di(tert-butyl)diazomethane was also shown to occur stepwise [23]. For
our study aimed at reactions of 7 with thermally generated azomethine ylides, cis-1a
and trans-1a as well as cis-1,2,3-triphenylaziridine (cis-1b) were selected. The
conditions of the reactions were analogous to those described above for the reactions
with thioketones 2 and acetylene dicarboxylate 5. Whereas the reaction with cis-1a was
completed after 13 h, the isomeric trans-1a was consumed already after 4 h.
Unexpectedly, it turned out that the reaction mixtures obtained with cis-1a and

2634
Helvetica Chimica Acta – Vol. 92 (2009)
trans-1a contained the same two stereoisomeric cycloadducts in a ratio of ca. 2 :1 and
1:1, respectively (Scheme 3). Moreover, an additional experiment with cis-1a and
dimethyl dicyanomaleate (7b) afforded also the same products in comparable amounts.
Both products were separated chromatographically, and from the less polar fraction the
pyrrolidine-dicarboxylate 8b was obtained as an oily material. The more polar fraction,
however, gave the isomer 8a as colorless crystals, which were subjected to the X-ray
crystal-structure determination (Fig. 1).
Scheme 3
Fig. 1. ORTEP Plot [24] of the molecular structure of 8a (arbitrary numbering of the atoms, 50%
probability ellipsoids).
The crystal structure of 8a shows that the Ph rings at C(2) and C(5) are cis-oriented,
as well as the CN groups and the ester moieties at C(3) and C(4). Thus, the orientation
of the substituents does not correspond to the structure predicted on the basis of the
expected conrotatory ring opening of the aziridine, followed by the concerted [2s þ 3s]-
cycloaddition.

Helvetica Chimica Acta – Vol. 92 (2009)
2635
1
The symmetric structure of 8a is reflected in the H- and 13C-NMR spectra. For
instance, the absorptions of HꢁC(2) and HꢁC(5) appear as a singlet at 4.99 ppm, and
the two MeO groups absorb as a singlet at 3.84 ppm. The 1H-NMR spectrum of the oily
product 8b revealed two singlets for HꢁC(2) and HꢁC(5) at 4.48 and 4.59 ppm, and
two MeO singlets at 3.40 and 3.96 ppm. This pattern must be attributed to a non-
symmetrical structure presented tentatively as 8b. The attempted crystallization of 8b
1
from MeOH afforded a crystalline product, of which the H-NMR spectrum differed
fundamentally from that of 8b, as only one MeO group was present! Other relevant
signals were an AB system at 3.85 and 4.03 ppm (JAB ¼ 11.0 Hz) for two H-atoms and a
singlet at 4.25 ppm for one H-atom. Finally, the structure was established by X-ray
crystallography (Fig. 2), which disclosed that compound 9 was formed (Scheme 4). It is
likely that, during the crystallization, the hydrolysis (with traces of H2O?) of one ester
group took place, followed by a spontaneous decarboxylation. With respect to the
determined structure 9, the decarboxylation with subsequent inversion of the
configuration occurred at C(4). On the other hand, we propose that the configurations
at C(2), C(3), and C(5) are retained during the decarboxylation. Therefore, the cis-
orientation of the Ph groups in 9 reflects their orientation in the precursor 8b.
Scheme 4
Fig. 2. ORTEP Plot [24] of the molecular structure of 9 (arbitrary numbering of the atoms, 50%
probability ellipsoids).
In a series of independent experiments, the isomerization 8b ! 8a was studied. A
very fast and complete conversion was observed, when a solution of 8b in MeOH, after
addition of a drop of aq. HCl, was warmed to reflux for 15 min (Scheme 4). The same
effect was achieved using Et3N in MeOH, but also in pure MeOH after boiling for 3 h.

2636
Helvetica Chimica Acta – Vol. 92 (2009)
All these results point out that 8a is the thermodynamically favored product. This
isomerization deserves a comment. All experimental evidences support a mechanism
via a zwitterion formed by cleavage of the C(4)ꢁC(5) bond. The subsequent rotation
about the C(3)ꢁC(4) bond, followed by ring closure, leads to the thermodynamically
favored diastereoisomer.
In an additional experiment, the reaction of cis-1b [25] with 7a afforded
stereoselectively a crystalline product, the structure of which was unambiguously
established as 10 by X-ray crystallography (Scheme 5 and Fig. 3). In this case, the
orientation of all substituents in accordance with the prediction based on a conrotatory
ring opening of cis-1b and a concerted [2s þ 3s]-cycloaddition of the intermediate
(E,Z)-configured azomethine ylide.
Scheme 5
Fig. 3. ORTEP Plot [24] of the molecular structure of 10 (arbitrary numbering of the atoms, 50%
probability ellipsoids).
The formation of the same products 8a and 8b in the reactions of cis-1a with 7a and
7b as well as of trans-1a with 7a is a strong evidence for a stepwise cycloaddition of 7
with other 1,3-dipols, i.e., the isomeric N-methylazomethine ylides 3a. A plausible
intermediate in these reactions with the strongly electron-deficient dipolarophiles 7 is

Helvetica Chimica Acta – Vol. 92 (2009)
2637
the zwitterion 11 (Scheme 6). The rotation about the indicated C,N and C,C bonds
results in the loss of the stereochemical integrity of the reactants. Apparently, the same
zwitterion 11 is formed in the key-step of the isomerization 8b ! 8a. It seems likely
that, in the presence of Hþ, the ring opening is facilitated as well as in polar solvents.
Scheme 6
Remarkably, the replacement of the NꢁMe group in cis-1a and, therefore, in (E,Z)-
3a, by a NꢁPh group results in the expected stereoselective formation of the
cycloadduct 10. The change of the reaction mechanism may be caused by steric and/or
electronic factors.
3. Conclusions. – The presented [2 þ 3]-cycloadditions of trans-1a with thioketones
2a – 2c supplement the earlier published results with the isomeric cis-1a. In all these
examples, the reactions occur stereoselectively, and the configuration of the products is
an accordance with the prediction for concerted processes.
The reaction of 1a with the strongly electron-deficient DCFM (7a) with a low-lying
LUMO [17][20] occurs stepwise via the intermediate zwitterion 11. To the best of our
knowledge, this is the first case reported in which a HOMOdipole/LUMOdipolarophile
-
controlled reaction of an azomethine ylide occurs in a non-stereospecific manner. The
formation of an intermediate zwitterion 11 and its isomerization depend on the
substituent attached to the N-atom. It is worth mentioning that some examples of non-
stereospecific [2 þ 3]-cycloadditions of azomethine ylides were reported by Sauer and
co-workers [26]. In these cases, however, the reactions are LUMOdipole/HOMOdipolar-
ophile-controlled processes. Moreover, photochemically induced [2 þ 3]-cycloadditions
of cis-1-butyl-2,3-diphenylaziridine with electron-deficient alkenes and alkines occur in
a non-stereospecific manner. These reactions, however, proceed via an initially formed
azomethine radical cation (PET mechanism) and not an azomethine ylide [27].

2638
Helvetica Chimica Acta – Vol. 92 (2009)
´
´
The authors thank Ms. Katarzyna Wesołowska, University of Łodz, for her skillful help in the
´
´
refinement of structure 8a. Financial support by the Rector of the University of Łodz (Grant # 505/0712)
and F. Hoffmann-La Roche AG, Basel, is gratefully acknowledged.
Experimental Part
1. General. TLC: Merck 5554 aluminum-backed SiO2 plates; spots were visualized by UV light.
Column chromatography (CC): silica gel (SiO2; Merck 60, 0.063 – 0.200 mm). M.p.: Mel-Temp. II
apparatus (Aldrich) in capillaries; uncorrected. IR Spectra: Nexus FT-IR spectrometer; in KBr or as
1
films, ˜n in cmꢁ1. H- and 13C-NMR spectra: Bruker AC-300 (1H: 300.1 MHz, 13C: 75.5 MHz) or Varian
Gemini 200 (1H: 200 MHz, 13C: 50 MHz) or Tesla BS-687 (1H: 80 MHz) spectrometer with CDCl3 as
solvent; d in ppm rel. to Me4Si as internal standard, J in Hz. The majority of the 13C signals were assigned
with the aid of DEPT spectra. MS: LKB-2091, Finnigan MAT-95, or Finnigan TSQ-700 instruments; in
m/z (rel. %). HR-MS: Finnigan MAT-95; in m/z (rel. %). Elemental analyses were performed in the
Analytical Laboratory of the University of Zꢀrich.
2. Starting Materials. Thiobenzophenone (2a) [28], 2,2,4,4-tetramethyl-3-thioxocyclobutanone (2b)
[29], and adamantanethione (2c) [30] were obtained according to published procedures. trans-1-Methyl-
2,3-diphenylaziridine (trans-1a) was prepared from erythro-2-(methylamino)-1,2-diphenylethanol by
treatment with Ph3P/CCl4/Et3N, according to a known procedure [19], as well as cis-1a [31] and cis-1,2,3-
triphenylaziridine (cis-1b) [32]. Dimethyl dicyanofumarate (DCFM; 7a) was synthesized from methyl
cyanoacetate and SOCl2 [16].
3. Reactions of trans-1a with Thiones 2a – 2c. 3.1. Reaction of trans-1a with 2a. A soln. of 2a (198 mg,
1 mmol) and trans-1a (209 mg, 1 mmol) in toluene (5 ml) was heated under reflux for 45 min. After
evaporation of the solvent, the crude mixture was purified by CC (SiO2; CH2Cl2/petroleum ether (PE)
2 :3). Anal. pure product was obtained by recrystallization from PE in the refrigerator.
cis-3-Methyl-2,4,5,5-tetraphenyl-1,3-thiazolidine (cis-4a). Yield 270 mg (66%). Pale yellow crystals.
M.p. 132 – 1348 (PE). IR: 3027m, 3035m, 2790m, 1598m, 1491s, 1443s, 749s, 736s, 695vs. 1H-NMR: 7.70 –
6.90 (m, 20 arom. H); 4.99, 4.82 (2s, HꢁC(2), HꢁC(4)); 2.02 (s, MeN). 13C-NMR: 146.8, 143.2, 139.5,
138.5 (4s, 4 arom. C); 131.8, 130.2, 128.8, 128.2, 128.1, 127.9, 127.7, 127.4, 127.3, 126.6, 126.4, 126.2 (12d, 20
arom. CH); 79.5, 73.3 (2d, C(2), C(4)); 69.2 (s, C(5)); 39.2 (q, MeN). EI-MS: 407 (<0.5, Mþ), 406 (<1),
405 (<1), 356 (1), 332 (1), 328 (3), 288 (6), 287 (8), 256 (8), 210 (16), 209 (100), 208 (88), 198 (16), 194
(24), 179 (10), 178 (13), 166 (10), 165 (36), 121 (22), 118 (15), 77 (11). ESI-MS (MeOH): 431 (25), 430
(90, [M þ Na]þ), 408 (33, [M þ 1]þ), 309 (15), 301 (12), 287 (23), 286 (100), 232 (43). HR-ESI-MS
(MeOH): 430.16023 ([M þ Na]þ, C28H25NNaSþ; calc. 430.15999).
3.2. Reaction of trans-1a with 2b. A soln. of 2b (156 mg, 1 mmol) and trans-1a (209 mg, 1 mmol) in
toluene (5 ml) was heated under reflux for 6 h. After evaporation of the solvent, the crude mixture was
dissolved in hexane and crystallized in the refrigerator. The crystalline product was filtered and dried in
vacuum.
cis-1,1,3,3,7-Pentamethyl-6,8-diphenyl-5-thia-7-azaspiro[4.5]octan-2-one (cis-4b). Yield 230 mg
(63%). Pale yellow crystals. M.p. 156 – 1588 (hexane). IR (KBr): 3065w, 3022w, 2972m, 2962m, 1768vs
1
(C¼O), 1464s, 1456s, 1188m, 1022m, 742s, 703s. H-NMR: 7.85 – 7.75 (m, 2 arom. H); 7.55 – 7.47 (m, 2
arom. H); 7.40 – 7.25 (m, 6 arom. H); 4.68, 4.20 (2s, HꢁC(6), HꢁC(8)); 2.31 (s, MeN); 1.61, 1.59, 0.99,
0.57 (4s, 4 Me). 13C-NMR: 220.0 (s, C¼O); 144.2, 138.5 (2s, 2 arom. C); 129.0, 128.4, 128.3, 128.1, 127.7,
127.5 (6d, 10 arom. CH); 74.1, 73.9 (2d, C(6), C(8)); 68.7, 67.2, 61.8 (3s, C(4), 2 Me2C); 37.7 (q, MeN);
25.1, 24.1, 22.2, 19.6 (4q, 4 Me). EI-MS: 365 (2, Mþ), 350 (2), 295 (8), 294 (9), 278 (7), 248 (7), 247 (18),
246 (100), 176 (25), 161 (56), 144 (36), 143 (12), 129 (20), 128 (16), 120 (22), 118 (20), 91 (13). ESI-MS
(MeOH): 388 (100, [M þ 1]þ), 366 (10, [M þ 1]þ), 318 (33). HR-ESI-MS (MeOH): 388.17039 ([M þ
Na]þ, C23H27NNaOSþ; calc. 388.17056).
3.3. Reaction of trans-1a with 2c. A soln. of 2c (166 mg, 1 mmol) and trans-1a (209 mg, 1 mmol) in
toluene (5 ml) was heated under reflux for 6 h. After evaporation of the solvent, the crude mixture was
purified by CC (SiO2; CH2Cl2/hexane 2 :3). Anal. pure product was obtained by recrystallization from
hexane in the refrigerator.

Helvetica Chimica Acta – Vol. 92 (2009)
2639
cis-3-Methyl-2,4-diphenylspiro[1,3-thiazolidine-5,2’-tricyclo[3.3.1.13,7]decane] (cis-4c). Yield 225 mg
(60%). Pale yellow crystals. M.p. 138 – 1408 (hexane). IR (KBr): 3062m, 3027m, 2904s, 2848s, 1455m,
1445m, 1213m, 744s, 701s. 1H-NMR: 7.75 – 7.65 (d-like, 2 arom. H); 7.60 – 7.50 (d-like, 2 arom. H); 7.40 –
7.20 (m, 6 arom. H); 4.87, 3.82 (2s, HꢁC(2), HꢁC(4)); 2.90 – 2.75, 2.30 – 2.20 (2m, 2 H of adamantane);
2.14 (s, MeN); 2.10 – 1.00 (m, 12 H of adamantane). 13C-NMR: 142.7, 139.1 (2s, 2 arom. C); 130.1, 128.2,
127.9, 127.8, 127.5, 127.0 (6d, 10 arom. CH); 80.5, 71.6 (2d, C(2), C(4)); 67.6 (s, C(5)); 38.5 (q, MeN); 39.4,
35.0, 26.7, 26.6 (4d, 4 CH of adamantane); 38.5, 37.2, 35.6, 33.6, 33.1 (5t, 5 CH2 of adamantane). EI-MS:
374 (3, [M ꢁ 1]þ), 298 (3), 224 (4), 210 (16), 209 (100), 208 (70), 194 (15), 118 (12), 91 (13). ESI-MS
(MeOH): 398 (12, [M þ Na]þ), 377 (28), 376 (100, [M þ 1]þ), 309 (8), 120 (24). HR-ESI-MS (MeOH):
376.20860 ([M þ 1]þ, C25H30NSþ; calc. 376.20935).
4. Reaction of cis-1a with Dimethyl Acetylenedicarboxylate (5). A soln. of 5 (142 mg, 1 mmol) and
cis-1a (209 mg, 1 mmol) in toluene (5 ml) was heated under reflux for 10 h. After evaporation of the
solvent, the crude mixture was purified by CC (SiO2; CH2Cl2/PE 4 :1). Anal. pure product was obtained
by recrystallization from PE with a small amount of Et2O.
Dimethyl trans-2,5-dihydro-1-methyl-2,5-diphenylpyrrole-3,4-dicarboxylate (trans-6). Yield 270 mg
(77%). Pale yellow crystals. M.p. 90 – 938 (PE/Et2O). IR (KBr): 3027w, 2955w, 2785m, 1740vs and 1721vs
1
(C¼O), 1457m, 1442m, 1326s, 1295m, 1199s, 1172s, 1006s, 702s. H-NMR: 7.25 – 7.45 (m, 10 arom. H);
5.22 (s, HꢁC(2), HꢁC(5)); 3.60 (s, 2 MeO); 1.98 (s, MeN). 13C-NMR: 163.7 (s, C¼O); 140.3, 137.8 (2s, 2
arom. C, C(3), C(4)); 130.4, 128.4, 128.2 (3d, 10 arom. CH); 74.6 (q, 2 MeO); 52.0 (d, C(2), C(5)); 34.0
(q, MeN). EI-MS: 351 (17, Mþ), 320 (17), 319 (13), 318 (17), 292 (43), 275 (17), 274 (100), 261 (13), 260
(34), 243 (15), 242 (90), 230 (16), 215 (19), 198 (21), 184 (33), 171 (10), 118 (15), 115 (11). ESI-MS
(MeOH): 375 (20), 374 (100, [M þ Na]þ), 353 (10), 352 (44, [M þ 1]þ). HR-ESI-MS (MeOH): 374.13594
([M þ Na]þ, C21H21NNaO4þ ; calc. 374.13628); 352.15387 ([M þ 1]þ, C21H22NOþ4 ; calc. 352.15433).
5. Reaction of cis-1a with DCFM (7a). A soln. of 7a (194 mg, 1 mmol) and cis-1a (209 mg, 1 mmol) in
toluene (5 ml) was heated under reflux for 13 h. After evaporation of the solvent, the crude mixture was
separated by prep. TLC (SiO2; CH2Cl2/hexane 3 :2). Anal. pure 8a was obtained by recrystallization
from hexane with a small amount of CH2Cl2. The attempted isolation of the isomeric product 8b by
chromatography was in vain.
Dimethyl 2,3-trans,3,4-cis,4,5-trans-3,4-Dicyano-1-methyl-2,5-diphenylpyrrolidine-3,4-dicarboxylate
(8a). Yield 220 mg (55%). Colorless crystals. M.p. 124 – 1268 (hexane/CH2Cl2). IR (KBr): 3065w,
3035w, 2959m, 2250w (C ꢀ N); 1770vs and 1754vs (C¼O); 1494m, 1456m, 1436m, 1266vs, 1243s, 1172s,
1
1024m, 736m, 699s. H-NMR: 7.66 – 7.64 (m, 4 arom. H); 7.50 – 7.40 (m, 6 arom. H); 4.39 (s, HꢁC(2),
HꢁC(5)); 3.84 (s, 2 MeO); 2.14 (s, MeN). 13C-NMR: 165.0 (s, 2 C¼O); 134.5 (s, 2 arom. C); 129.7, 129.1,
128.8 (3d, 10 arom. CH); 114.0 (s, 2 CN); 73.9 (C(2), C(5)); 60.9 (s, C(3), C(4)); 54.7 (q, 2 MeO); 37.9 (q,
MeN). CI-MS (NH3): 406 (5), 405 (26), 404 [100, [M þ 1]þ), 209 (6). Anal. calc. for C23H21N3O4 (403.44):
C 68.48, H 5.25, N 10.42; found: C 68.44, H 5.25, N 10.42.
6. Reaction of trans-1a with DCFM (7a). A soln. of 7a (194 mg, 1 mmol) and trans-1a (209 mg,
1 mmol) in toluene (5 ml) was heated under reflux for 4 h. After evaporation of the solvent, the crude
mixture was separated by prep. TLC (SiO2; hexane/AcOEt 4.5 :0.5). The more-polar fraction contained
8a (120 mg, 30%). The less-polar fraction was the isomeric product 8b, which was isolated as a pale
yellow oil (115 mg, 29%). By chance, crystallization of this material from MeOH led to the unexpected
formation of crystalline 9. In spite of attempted repetitions of this crystallization, compound 9 could
neither be obtained again from MeOH nor from other solvents (CH2Cl2, hexane, Et2O). Crystals of 9
were additionally purified by recrystallization from PE/Et2O or from PE/CH2Cl2 (crystals for X-ray
measurement).
Dimethyl 2,3-cis,3,4-trans,4,5-trans-3,4-Dicyano-1-methyl-2,5-diphenylpyrrolidine-3,4-dicarboxylate
(8b). Yield 115 mg (29%). Pale yellow oil. IR (film): 3033m, 2957s, 2850m, 2253 (C ꢀ N), 1747s (br.,
C¼O), 1455s, 1436s, 1244s, 1181s, 1025s, 731s, 701s. 1H-NMR: 7.30 – 7.80 (m, 10 arom. H); 4.48, 4.59 (2s,
HꢁC(2), HꢁC(5)); 3.40, 3.96 (2s, 2 MeO); 2.20 (s, MeN). 13C-NMR: 162.2, 166.1 (2s, 2 C¼O); 133.2,
134.8 (2s, 2 arom. C); 128.4, 128.7, 128.8, 129.1, 129.5, 129.7 (6d, 10 arom. CH); 113.7, 115.5 (2s, 2 CN);
74.6, 76.5 (2d, C(2), C(5)); 59.1, 59.7 (2s, C(3), C(4)); 53.6, 55.1 (2q, 2 MeO); 38.2 (q, MeN). EI-MS: 403
(3, Mþ), 344 (4), 317 (4), 216 (28), 210 (14), 209 (89), 208 (100), 194 (23), 184 (10), 118 (18), 91 (21), 77

2640
Helvetica Chimica Acta – Vol. 92 (2009)
Table. Crystallographic Data for Compounds 8a, 9, and 10
8a
9
10
Crystallized from
Empirical formula
Formula weight
hexane/Et2O
C23H21N3O4
403.43
EtOH/CH2Cl2
C21H19N3O2
345.40
Et2O/petroleum ether
C28H23N3O4
465.49
Crystal color, habit
colorless block
translucent
colorless prism
colorless flat
parallelepiped
Crystal dimensions [mm]
Temp. [K]
Crystal system
Space group
0.40 ꢂ 0.30 ꢂ 0.30 0.14 ꢂ 0.10 ꢂ 0.06 0.28 ꢂ 0.06 ꢂ 0.02
173(2)
monoclinic
P21/c
123(1)
monoclinic
P21/c
123(1)
orthorhombic
P212121
2
Z
4
4
Reflections for cell determination
8000
8000
8000
2q Range for cell determination [8]
4.64 – 53.2
4.1 – 51.7
4.48 – 51.7
Unit cell parameters
a [ꢃ]
b [ꢃ]
c [ꢃ]
b [8]
15.781(5)
10.768(5)
12.891(5)
105.266(5)
2113.3(1)
1.268
0.088
rotation
53.2
20.427(4)
8.043(2)
22.772(6)
150.860(10)
1821.8(7)
1.259
0.083
rotation
51.7
6.471(1)
16.423(1)
10.939(1)
90.00
1162.5(2)
1.330
0.090
rotation
51.7
V [ꢃ3]
Dx [g cmꢁ3
Linear absorption coefficient [mmꢁ1
Scan type
]
]
2q(max) [8]
Total reflections measured
Symmetry-independent reflections
Reflections with I > 2s(I)
Reflections used in refinement
Parameters refined; restraints
Final R(F) (I > 2s(I) reflections)
wR(F2) (all data)
25895
4099
3323
4099
274; 0
0.0301
0.0729
0.0350; 0.2323
1.079
13210
3489
1749
3489
238; 0
0.0617
0.1423
0.0617; 0.0000
0.882
10286
2236
1748
2236
161; 0
0.0349
0.0736
0.0318; 0.0000
0.881
Weighting parameters [a; b]a)
Goodness-of-fit
Final Dmax/s
D1 (max; min) [e ꢃꢁ3
0.000
0.226; ꢁ 0.163
0.000
0.278; ꢁ 0.222
0.001
0.225; ꢁ 0.151
]
a) wꢁ1 ¼ s2(F2o ) þ (aP)2 þ bP, where P ¼ (Fo2 þ 2F2c )/3
(14). ESI-MS (MeOH): 427 (26), 426 (100, [M þ Na]þ). HR-ESI-MS (MeOH): 426.14190 ([M þ Na]þ,
C23H21N3NaOþ4 ; calc. 426.14243).
Methyl 2,3-cis,3,4-trans,4,5-trans-3,4-Dicyano-1-methyl-2,5-diphenylpyrrolidine-3-carboxylate (9).
Colorless crystals. M.p. 60 – 628 (PE/Et2O). IR (KBr): 3065w, 2956m, 2251w (C ꢀ N), 1759s (C¼O),
1
1497m, 1455s, 1232s, 1180s, 1022m, 751m, 701m. H-NMR: 7.61 – 7.57 (m, 2 arom. H); 7.50 – 7.38 (m, 8
arom. H); 4.24 (s, HꢁC(2)); 4.01, 3.82 (AB, 3J ¼ 10.1, HꢁC(4), HꢁC(5)); 3.22 (s, MeO); 2.07 (s, MeN).
13C-NMR: 164.7 (s, C¼O); 136.1, 134.3 (2s, 2 arom. C); 129.6, 129.5, 129.3, 128.8, 128.3, 127.7 (6d, 10
arom. CH); 116.4, 115.6 (2s, 2 CN); 79.3, 72.9 (2d, C(2), C(5)); 54.9 (s, C(3)); 53.9 (q, MeO); 44.0 (d,
C(4)); 37.7 (q, MeN). ESI-MS (MeOH): 368 (47, [M þ Na]þ), 346 (100, [M þ 1]þ). HR-ESI-MS
(MeOH): 368.13734 ([M þ Na]þ, C21H19N3NaO2þ ; calc. 368.13695); 346.15557 ([M þ 1]þ, C21H20N3Oþ2 ;
calc. 346.15500).
7. Reaction of cis-1b with DCFM (7a). A soln. of 7a (194 mg, 1 mmol) and cis-1b (271 mg, 1 mmol) in
toluene (5 ml) was heated under reflux for 4.5 h. After evaporation of the solvent, the crude mixture was

Helvetica Chimica Acta – Vol. 92 (2009)
2641
separated by prep. TLC (CH2Cl2/hexane 3.5 :1.5). An anal. pure sample of 10 was obtained by
recrystallization from PE with a small amount of CH2Cl2.
Dimethyl 2,3-trans,3,4-trans,4,5-trans-3,4-Dicyano-1,2,5-triphenylpyrrolidine-3,4-dicarboxylate (10).
Yield 290 mg (62%). Colorless crystals. M.p. 247 – 2518 (hexane/CH2Cl2). IR (KBr): 3064w, 3036w,
1748vs (C¼O), 1597m, 1500s, 1455m, 1330m, 1248s, 1223s, 703s. 1H-NMR: 7.38 – 6.20 (m, 15 arom. H);
6.45 (s, HꢁC(2), HꢁC(5)); 3.35 (s, 2 MeO). 13C-NMR: 163.4 (s, 2 C¼O); 133.6, 141.9 (2s, 3 arom. C);
119.1, 119.3, 128.0, 128.4, 128.5, 129.1 (6d, 15 arom. CH); 114.6 (s, 2 CN); 71.4 (2d, C(2), C(5)); 59.3 (s,
C(3), C(4)); 54.1 (q, 2 MeO). EI-MS: 465 (17, Mþ), 272 (21), 271 (100), 270 (95), 219 (14), 218 (13), 181
(17), 180 (31), 167 (35), 165 (10), 104 (13), 77 (27). ESI-MS (MeOH): 489 (33), 488 (100, [M þ Na]þ),
466 (5, [M þ 1]þ). HR-ESI-MS (MeOH): 488.15737 ([M þ Na]þ, C28H23N3NaOþ4 ; calc. 488.15808);
466.17574 ([M þ 1]þ, C28H24N3Oþ4 ; calc. 466.17613).
8. X-Ray Crystal-Structure Determination of 8a, 9, and 10 (Table and Figs. 1 – 3)2). All measurements
were made on a Stoe IPDS diffractometer [33] with graphite monochromated MoKa radiation (l
0.71073 ꢃ) and an Oxford Cryosystems Cryostream 700 cooler. The data collection and refinement
parameters are given in the Table, views of the molecules are shown in Figs. 1 – 3. For all compounds, the
data reduction was performed with Stoe IPDS [33]. The intensities were corrected for Lorentz and
polarization effects. No absorption correction was applied. Each structure was solved by direct methods
[34], which revealed the positions of all non-H-atoms. The non-H-atoms were refined anisotropically. All
of the H-atoms were placed in geometrically calculated positions and refined with a riding model where
each H-atom was assigned a fixed isotropic displacement parameter with a value equal to 1.2 Ueq of its
parent C-atom (1.5 Ueq for Me groups). Refinement of each structure was carried out on F2 by full-matrix
least-squares procedures, which minimized the function Sw(F2o ꢁ Fc2 )2. Refinement of the absolute
structure parameter [35] of 10 yielded a value of ꢁ 1.0(13), which suggests that the absolute structure
parameter is meaningless because the compound is a weak anomalous scatterer, which emphases the
large s.u. of the Flack parameter. Neutral atom scattering factors for non-H-atoms were taken from
[36a], and the scattering factors for H-atoms were taken from [37]. Anomalous dispersion effects were
included in Fc [38]; the values for f’ and f’’ were those of [36b]. The values of the mass attenuation
coefficients are those of [36c]. All calculations were performed using SHELXL97 [39].
REFERENCES
[1] L. M. Harwood, R. J. Vickers, in ꢄThe Chemistry of Heterocyclic Compounds, Vol. 59: Synthetic
Application of 1,3-Dipolar Cycloaddition Chemistry Toward Heterocycles and Natural Productsꢅ,
Eds. A. Padwa, W. H. Pearson, J. Wiley & Sons, New York, 2002, p. 169.
´
[2] C. Najera, J. M. Sansano, Curr. Org. Chem. 2003, 7, 1105.
[3] A. F. Khlebnikov, M. S. Novikov, A. A. Bespokoev, R. R. Kostikov, J. Kopf, Z. A. Starikova, M. Yu.
Antipin, Russ. J. Org. Chem. 2005, 41, 922.
[4] L. M. Stanley, M. P. Sibi, Chem. Rev. 2008, 108, 2887.
[5] X. Wang, D. Jiang, S. Dai, Chem. Mater. 2008, 20, 4800.
´
´
[6] C. Najera, M. de Garcia Retamosa, J. M. Sansano, A. de Cozar, F. P. Cossio, Tetrahedron:
´
Asymmetry 2008, 10, 2913; C. Najera, M. de Garcia Retamosa, J. M. Sansano, Angew. Chem., Int.
Ed. 2008, 47, 6055.
˜
[7] M. Alvarez-Corral, M. Munoz-Dorado, I. Rodriguez-Garcia, Chem. Rev. 2008, 108, 3174.
[8] S.-I. Fukuzawa, H. Oki, Org. Lett. 2008, 10, 3174.
[9] R. Huisgen, W. Scheer, H. Huber, J. Am. Chem. Soc. 1967, 89, 1753; R. Huisgen, Angew. Chem., Int.
Ed. 1963, 2, 633.
´
´
´
[10] K. Urbaniak, R. Szymanski, J. Romanski, G. Mloston, M. Domagała, A. Linden, H. Heimgartner,
Helv. Chim. Acta 2004, 87, 496.
2
)
CCDC-729141 – 729143 contain the supplementary crystallographic data for this article. These data
can be obtained free of charge from the Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.

2642
Helvetica Chimica Acta – Vol. 92 (2009)
´
[11] R. Bartnik, G. Mloston, Tetrahedron 1984, 40, 2569.
´
´
[12] T. Skarz˙ynski, A. M. Brzozowski, Z. Derewenda, G. Mloston, Acta Crystallogr., Sect. C 1983, 39,
1051.
´
[13] G. Mloston, Z. Skrzypek, Bull. Soc. Chim. Belg. 1990, 99, 167.
´
[14] G. Mloston, K. Urbaniak, H. Heimgartner, Helv. Chim. Acta 2002, 85, 2056.
´
[15] G. Mloston, K. Urbaniak, A. Linden, H. Heimgartner, Helv. Chim. Acta 2002, 85, 2644.
[16] C. J. Ireland, J. S. Pizey, J. Chem. Soc., Chem. Commun. 1972, 4.
ˇ
´
[17] L. Fisera, R. Huisgen, I. Kalwinsch, E. Langhals, X. Li, G. Mloston, K. Polborn, J. Rapp, W. Sicking,
R. Sustmann, Pure Appl. Chem. 1996, 68, 789.
´
[18] M. Domagała, S. J. Grabowski, K. Urbaniak, G. Mloston, J. Mol. Struct. 2004, 690, 69.
[19] W. K. Anderson, A. S. Milowsky, J. Med. Chem. 1986, 29, 2241.
[20] R. Sustmann, S. Tappanchai, H. Bandmann, J. Am. Chem. Soc. 1996, 118, 12555; see also C. S. Kniep,
R. Boese, R. Sustmann, Tetrahedron 2000, 56, 4157; M. Rese, M. Dern, K. Luecking, R. Sustmann,
Liebigs Ann. Chem. 1995, 1139; R. Sustmann, M. Rogge, U. Nuechter, H. Bandmann, Chem. Ber.
1992, 125, 1657.
´
´
[21] R. Huisgen, G. Mloston, E. Langhals, J. Am. Chem. Soc. 1986, 108, 6401; R. Huisgen, G. Mloston, E.
´
Langhals, Helv. Chim. Acta 2001, 84, 1805; R. Huisgen, G. Mloston, H. Giera, E. Langhals,
´
´
Tetrahedron 2002, 58, 507; M. Woznicka, M. Rutkowska, G. Mloston, A. Majchrzak, H.
Heimgartner, Pol. J. Chem. 2006, 80, 1683.
[22] R. Huisgen, H. Giera, K. Polborn, Tetrahedron 2005, 61, 6143.
´
[23] R. Huisgen, P. Pçchlauer, G. Mloston, K. Polborn, Helv. Chim. Acta 2007, 90, 983.
[24] A. L. Spek, ꢄPLATONꢅ, Program for the Analysis of Molecular Geometry, University of Utrecht,
The Netherlands, 2003.
[25] J. H. Hall, R. Huisgen, J. Chem. Soc., Chem. Commun. 1971, 1187; J. H. Hall, R. Huisgen, C. H. Ross,
W. Scheer, J. Chem. Soc., Chem. Commun. 1971, 1188; A. C. Oehlschlager, A. S. Yim, M. H. Akhtar,
Can. J. Chem. 1978, 56, 273.
[26] T. Bçhm, A. Weber, J. Sauer, Tetrahedron 1999, 55, 9535; K. Elender, H. Nçth, P. Riebel, A. Weber,
J. Sauer, Tetrahedron 2000, 56, 5443.
¨
[27] V. Caer, A. Laurent, E. Laurent, R. Tardivel, Z. Cebulska, R. Bartnik, Nouv. J. Chim. 1987, 11, 351.
[28] B. S. Pedersen, S. Scheibye, N. H. Nilsson, S.-O. Lawesson, Bull. Soc. Chim. Belg. 1978, 87, 223.
[29] J. W. Greidanus, Can. J. Chem. 1970, 48, 3530.
[30] E. W. Elam, H. E. Davis, J. Org. Chem. 1967, 32, 1563.
´
´
[31] R. Bartnik, G. Mloston, S. Lesniak, Pol. J. Chem. 1979, 53, 537.
[32] T. W. J. Taylor, J. S. Owen, D. Whittaker, J. Chem. Soc. 1938, 206.
[33] STOE IPDS-Software, Version 2.89, STOE & CIE GmbH, Darmstadt, Germany, 1998.
[34] G. M. Sheldrick, Acta Crysallogr., Sect. A 1990, 46, 467.
[35] H. D. Flack, G. Bernardinelli, Acta Crystallogr., Sect. A 1999, 55, 908; H. D. Flack, G. Bernardinelli,
J. Appl. Crystallogr. 2000, 33, 1143.
[36] a) E. N. Maslen, A. G. Fox, M. A. OꢅKeefe, in ꢄInternational Tables for Crystallographyꢅ, Ed. A. J. C.
Wilson, Kluwer Academic Publishers, Dordrecht, 1992, Vol. C, Table 6.1.1.1, p. 477; b) D. C. Creagh,
W. J. McAuley, in ꢄInternational Tables for Crystallographyꢅ, Ed. A. J. C. Wilson, Kluwer Academic
Publishers, Dordrecht, 1992, Vol. C, Table 4.2.6.8, p. 219; c) D. C. Creagh, J. H. Hubbell, in
ꢄInternational Tables for Crystallographyꢅ, Ed. A. J. C. Wilson, Kluwer Academic Publishers,
Dordrecht, 1992, Vol. C, Table 4.2.4.3, p. 200.
[37] R. F. Stewart, E. R. Davidson, W. T. Simpson, J. Chem. Phys. 1965, 42, 3175.
[38] J. A. Ibers, W. C. Hamilton, Acta Crystallogr. 1964, 17, 781.
[39] G. M. Sheldrick, ꢄSHELXL97ꢅ, Program for the Refinement of Crystal Structures, University of
Gçttingen, Germany, 1997.
Received June 16, 2009