The first reaction of dimethoxycarbene with an imine moiety

Article abstract of DOI:10.1002/hlca.200790185

The nucleophilic dimethoxycarbene (DMC; 2) generated by thermal decomposition of 2,5-dihydro-1,3,4-oxadiazole derivative 1 in boiling toluene reacts smoothly with N-(9H-fluoren-9-ylidene)-4-methylbenzenesulfonamide (7b) to yield carbonimidoate derivative

Full text of DOI:10.1002/hlca.200790185

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The First Reaction of Dimethoxycarbene with an Imine Moiety
by Grzegorz Mloston´
´
´
´
´
University of Łodz, Department of Organic and Applied Chemistry, Narutowicza 68, PL-90-136 Łodz
(phone: þ 48426355761; fax: þ 48426355380; e-mail: gmloston@uni.lodz.pl)
and Heinz Heimgartner
Organisch-chemisches Institut der Universität Zürich, Winterthurerstrasse 190, CH-8057 Zürich
(phone: þ 41446354282; fax: þ 41446356812; e-mail: heimgart@oci.uzh.ch)
The nucleophilic dimethoxycarbene (DMC; 2) generated by thermal decomposition of 2,5-dihydro-
1,3,4-oxadiazole derivative 1 in boiling toluene reacts smoothly with N-(9H-fluoren-9-ylidene)-4-
methylbenzenesulfonamide (7b) to yield carbonimidoate derivative 10. A multi-step reaction pathway,
initiated by the attack of DMC onto the C¼N bond and followed by the migration of the sulfonyl group
(or via a sulfinate anion) is proposed to explain the formation of the final product. In contrast to the
formal ketimine 7b, N-benzylidene-4-methylbenzenesulfonamide (7a), a formal aldimine, does not react
with DMC under comparable conditions.
1. Introduction. – Dimethoxycarbene (¼dimethoxymethylene; 2; DMC) belongs to
the class of nucleophilic carbenes. The first method for its generation, based on the
thermal decomposition of a 7,7-dimethoxy-8,9,10-trinorbornadiene derivative at 1408,
was reported by Hoffmann et al. [1]. Another method, used by Moss and co-workers, is
the thermal or photochemical decomposition of 3,3-dimethoxy-3H-diazirine, but it has
not been used for preparative purposes [2]. The thermal decomposition of 2,5-dihydro-
2,2-dimethoxy-5,5-dimethyl-1,3,4-oxadiazole (1), elaborated by Warkentin and co-
workers [3][4], opened new perspectives for numerous synthetic applications of DMC
as a versatile building block. In a recent paper, 1 was used for the generation of DMC in
the gas-phase under flash vacuum pyrolysis (FVP) conditions, and subsequent analysis
of the pyrolysate at 10 K enabled the conformational analysis of the carbene [5]. For
practical applications of DMC, the introduction of the modified precursor, in which one
Me group is replaced by a 4-methoxyphenyl residue, is of significant practical
importance, because the decomposition can be carried out already at 508 [6].
In the chemistry of carbenes, the reactions with multiple bonds are of special
importance [7]. The addition to C¼C bonds, known as cyclopropanation reactions, are
widely applied in the synthesis of complex molecules [8]. Reactions with hetero-p-
systems are also extensively elaborated to prepare three-membered heterocycles
(oxiranes, thiiranes, aziridines) or products resulting from the interception of the
initially formed ylide species [7].
In the case of the nucleophilic dimethoxycarbene, the most extensively studied
reactions with relevant practical applications (two- or multi-component reactions) are
ꢀ 2007 Verlag Helvetica Chimica Acta AG, Zürich

Helvetica Chimica Acta – Vol. 90 (2007)
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focused on the use of ketones [4][9] or mixtures of acetylene dicarboxylate (¼ but-2-
ynedioate) and an aldehyde [10] as substrates. Recently, DMC was shown to react
smoothly with cycloaliphatic thioketones [11] and carbodithioates [12]. Cyclopropa-
nones, cyclobutanones, and cyclopentanone react with DMC to give ring-enlarged
products [9], whereas 9H-fluoren-9-one and cyclohexanone yield methyl a-hydroxy-
carboxylates via the initially formed oxiranes [13][14]. Analogous reactions with
ꢁcageꢂ ketones lead to the corresponding a-hydroxy esters [15]. The reactions of DMC
with C¼N bonds are limited to isocyanates, which occur via a zwitterionic intermediate
3. In the case of unsaturated isocyanates with R ¼ CR1¼CHR2, subsequent 1,5-
cyclization leads to pyrrolones 4 (Scheme 1). This methodology has been widely
applied for the preparation of a variety of natural products [16]. In addition,
decomposition of 1 in the presence of aryl isocyanates in chlorobenzene was shown to
yield tetramethoxy-b-lactams 5 in competition with the formation of isatin derivatives 6
[17].
Scheme 1
To the best of our knowledge, no reports on the reactions of DMC with aldimines or
ketimines have been published to date. In a recent paper, we described that electron-
deficient imines derived from hexafluoroacetone failed to react with DMC [18]. The
present study is aimed at the examination of the reactivity of formal imines, which are
activated by a sulfonyl group attached to the N-atom, toward DMC.
2. Results and Discussion. – For the study presented in this paper, N-tosylimines of
benzaldehyde and 9H-fluoren-9-one, i.e., N-substituted 4-methylbenzenesulfonamides
7a and 7b, were selected. Both substrates were easily available by condensation of 4-
methylbenzenesulfonamide with the corresponding carbonyl compound in the
presence of Et3N and TiCl4 [19].
The decomposition of 1 was carried out in the presence of 7 in boiling toluene
under Ar. In both cases, the reaction was finished after 7 h, and the crude products were
analyzed by 1H-NMR spectroscopy. The formal imine 7a failed to react with DMC, and
the dimer of the latter was the main product containing MeO groups. It was identified
by the chemical shift of four equal MeO groups (d 3.53), which fits well with the

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reported data [20]. Other minor products formed in this reaction underwent
decomposition during the attempted chromatographic separation on silica gel.
The TLC analysis of the reaction mixture obtained with 7b showed the absence of
the starting 7b, and the 1H-NMR analysis revealed the presence of two equally intense
MeO signals located at d 3.10 and 4.00, and one Me signal at d 2.33 for the p-tolyl
residue. These data suggested the formation of a new product corresponding to a 1:1
stoichiometry of DMC and 7b. After crystallization from hexane, yellowish crystals
with an intense absorption at 1663 cmꢀ1 in the IR spectra (KBr) were obtained, and the
presence of a C¼N bond was confirmed by the 13C-NMR spectrum (d 161.8). The
spectroscopic evidence excluded the structure of an aziridine for the isolated product.
The result obtained with 7b should be compared with those described by Pole and
Warkentin in the case of the reaction of DMC with 9H-fluoren-9-one, where the oxirane
8 was observed in the reaction mixture along with the rearranged product 9 [13]
(Scheme 2). In the light of the data of the product isolated from the reaction with 7b,
the structure corresponding to 9 with X ¼ p-MeC6H4SO2N could be proposed.
However, the X-ray crystal-structure determination solved the problem, unambigu-
ously disclosing the unexpected structure 10 (Fig.).
Scheme 2
A mechanistic interpretation of the formation of 10 is presented in Scheme 3.
Under the assumption that the nucleophilic DMC attacks the imino C-atom to form the
zwitterion 11 in analogy to the reactions with carbonyl groups, ring closure to give the
aziridine 12 is necessary to explain the further reaction pathway via the intermediate
azomethine ylide (¼ iminium ylide) 13. The appearance of the latter is conclusive as the
C¼N bond attached to the fluorene moiety is preserved in the product 10. However,
this interpretation is not compatible with the observed lack of reactivity in the case of
7a, which is believed to be more reactive toward nucleophilic reagents. Therefore, the
attack of DMC at the N-atom of 7b, leading directly to 13, is a plausible alternative.
Finally, a 1,2-sulfonyl migration leads to the isolated product 10, but the release of
sulfinate to form an ion pair, which recombines to yield 10, cannot be excluded.

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Figure. ORTEP Representation [21] of the molecular structure of one of the three symmetry-independent
molecules of 10 (50% probability ellipsoids, arbitrary atom numbering)
3. Conclusions. – The formation of 10 as the sole product of the reaction of the
formal imine 7b with DMC suggests that the transient azomethine ylide 13 isomerizes
via migration of the sulfonyl group (or via a sulfinate anion). The reaction pathway
leading to 13 is not clear, but the intermediacy of aziridine 12 formed via 11 is doubtful.
One of the arguments of this interpretation is that aziridines bearing electron-donating
substituents at a C-atom and/or electron-withdrawing substituents at the N-atom are
not suitable precursors for the thermal generation of azomethine ylides [22]. Despite
the mechanistic consideration, the presented results show that DMC can in principal
react with an electron-deficient C¼N moiety. In contrast to the analogous reaction with
an electron-deficient ethene derivative [23], the expected [2 þ 1] cycloadduct has not
been detected. Instead, isomeric products, resulting from further conversion of the
intermediate aziridine or its precursor, are formed.
We thank PD Dr. A. Linden, University of Zürich, for performing the crystal structure analysis and
´
´
Mrs. M. Celeda, University of Łodz, for technical assistance. G. M. thanks the Polish Ministry of Science
and Higher Education for a Grant (No. PBZ-KBN-126/T09/12), and H. H. acknowledges financial
support by F. Hoffmann-La Roche AG, Basel.
Experimental Part
1. General. M.p.: Meltemp 2 apparatus, in capillary; uncorrected. IR Spectra: Nexus-FT-IR
spectrophotometer, in KBr. 1H- and 13C-NMR Spectra: Bruker 200 and 400 spectrometer (200 and
100 MHz, resp.); d in ppm rel. to SiMe4 (¼0 ppm) as an internal standard, J in Hz. CI-MS: Finnigan Mat-

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Scheme 3
90 spectrometer; in m/z (rel. %). Elemental analyses were performed in the Analytical Laboratory of the
University of Zürich.
2. Starting Materials. The 2,5-dihydro-2,2-dimethoxy-5,5-dimethyl-1,3,4-oxadiazole (1) was prepared
according to [3]. The formal imines 7a and 7b were synthesized from 4-methylbenzenesulfonamide and
benzaldehyde (08, CH2Cl2) or 9H-fluoren-9-one (boiling CH2Cl2, Et3N), respectively, in the presence of
TiCl4 and Et3N: N-benzylidene-4-methylbenzenesulfonamide (7a), pale yellow crystals, m.p. 109 – 1118
([24]: 1078); N-(9H-fluoren-9-ylidene)-4-methylbenzenesulfonamide (7b), orange-yellow crystals, m.p.
184 – 1868 ([19]: 182 – 1848).
3. Reaction of DMCwith Formal Imine 7b. Under Ar, 1,3,4-oxadiazole 1 (240 mg, 1.5 mmol) and 7b
(333 mg, 1.5 mmol) were dissolved in abs. toluene (3 ml). The mixture was heated under reflux, and the
progress of the reaction was monitored by TLC (SiO2, CH2Cl2/hexane). After 4 h, 7b was completely
consumed, heating was stopped, and the solvent was evaporated. The residual viscous oil was triturated
with Et2O, and after several min at r.t., pale yellow crystals were separated by filtration. An anal. pure
sample of dimethyl N-{9-[(4-methylphenyl)sulfonyl]-9H-fluoren-9-yl]carbonimidoate (10) was obtained
by crystallization from hexane: 289 mg (71%). Colorless crystals. M.p. 178 – 1808 (hexane). IR (KBr):
1664vs (C¼N), 1463m, 1451m, 1300s, 1143s, 1090m, 752m, 6 70m, 580m. 1H-NMR (200 MHz): 7.49, 7.01
(AA’BB’, J ¼ 8, 4 arom. H); 7.43 – 7.15 (m, 8 arom. H); 3.99, 3.11 (2s, 2 MeO); 2.33 (s, Me). 13C-NMR
(100 MHz): 153.2 (s, C¼N); 143.7, 141.5, 132.4 (3s, 6arom. C); 131.1, 129.8, 127.7, 127.1, 125.6, 119.6(6 d,
12 arom. CH); 90.1 (s, (MeO)2C); 56.5, 54.9 (2q, 2 MeO); 21.6( q, Me). CI-MS (NH3): 257 (22), 254 (18),
240 (18), 238 (100, [M ꢀ C7H7NO2S]þ). Anal. calc. for C23H21NO4S (407.49): C 67.79, H 5.19, N 3.44, S
7.87; found C 67.88, H 5.08, N 3.26, S 7.60.
4. Attempted Reaction of DMCwith Formal Imine 7a. Under Ar, 1,3,4-oxadiazole 1 (240 mg,
1.5 mmol) and 7a (389 mg, 1.5 mmol) were dissolved in abs. toluene (3 ml). The mixture was heated
under reflux as in Exper. 3. After 4 h, the evolution of N2 was finished indicating complete decomposition

Helvetica Chimica Acta – Vol. 90 (2007)
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of 1; heating was stopped, and the solvent was evaporated. The semi-solid residue was analyzed by
1H-NMR: tetramethoxyethene and significant amounts of 1a along with some unidentified products in
low yield.
5. X-Ray Crystal-Structure Determination of 10 (Fig.)1). All measurements were performed on a
Nonius KappaCCD area-detector diffractometer [25] by using graphite-monochromated MoKa radiation
(l 0.71073 Š) and an Oxford-Cryosystems Cryostream-700 cooler. The data collection and refinement
parameters are given below, and a view of the molecule is shown in the Figure. Data reduction was
performed with HKL Denzo and Scalepack [26]. The intensities were corrected for Lorentz and
polarization effects, and an absorption correction based on the multi-scan method [27] was applied. The
structure was solved by direct methods with SHELXS97 [28], which revealed the positions of all non-H-
atoms. There are three symmetry-independent molecules in the asymmetric unit. The atomic coordinates
of the three molecules were tested carefully for a relationship from a higher symmetry space group by
using the program PLATON [29], but none could be found. The non-H-atoms were refined
anisotropically. All of the H-atoms were placed in geometrically calculated positions and refined by
using 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 the Me groups). The refinement of the structure
was carried out on F2 by full-matrix least-squares procedures, which minimized the function
À
Á
Sw Fo2 ꢀ Fc2 2. A correction for secondary extinction was applied. Five reflections, whose intensities
were considered to be extreme outliers, were omitted from the final refinement. Neutral atom scattering
factors for non-H-atoms were taken from [30], and the scattering factors for H-atoms were taken from
[31]. Anomalous dispersion effects were included in Fc [32]; the values for f’ and f’’ were those of [33].
The values of the mass attenuation coefficients are those of [34]. All calculations were performed with
the SHELXL97 program [35].
Crystal Data for 10: C23H21NO4S, Mr 407.47, colorless, prism, crystal dimensions 0.25 ꢁ 0.25 ꢁ
0.30 mm, monoclinic, space group P21/n, Z ¼ 12, a ¼ 9.2447(2) Š, b ¼ 18.0563(4) Š, c ¼ 37.0577(8) Š,
b ¼ 90.7056(8)8, V ¼ 6185.4(2) Š3, DX ¼ 1.313 g · cmꢀ3, m(MoKa) ¼ 0.186mm ꢀ1, T 160 K, f and w scans,
transmission factors (min; max) 0.859; 0.958, 2qmax ¼ 608, total reflections measured 139999, symmetry
independent reflections 18076, reflections with I > 2s(I) 8878, reflections used in refinement 18071,
parameters refined 794, R (on F; I > 2s(I) reflections) ¼ 0.0596, wR(F2) (all reflections) ¼ 0.1653 (w ¼
(s2(Fo2) þ (0.0759P)2)ꢀ1, where P ¼ (Fo2 þ 2Fc2 )/3), goodness of fit 1.011, secondary extinction coefficient
ꢀ3
0.0037(4), final Dmax/s 0.001, D1 (max; min) ¼ 0.43; ꢀ 0.51 e Š
.
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Received May 4, 2007