An anomalous addition of chlorosulfonyl isocyanate to a carbonyl group: The synthesis of ((3aS,7aR,E)-2-ethyl-3-oxo-2,3,3a,4,7,7a-hexahydro-1H-isoindol-1-ylidene)sulfamoyl chloride

Article abstract of DOI:10.3762/bjoc.15.89

In this study, we developed a new addition reaction of chlorosulfonyl isocyanate (CSI), starting from 2-ethyl-3a,4,7,7a-tetrahydro-1H-isoindole-1,3(2H)-dione. The addition reaction of CSI with 2-ethyl-3a,4,7,7a-tetrahydro-1H-isoindole-1,3(2H)-dione resulted in the formation of ylidenesulfamoyl chloride, whose exact configuration was determined by X-ray crystal analysis. We explain the mechanism of product formation supported by theoretical calculations.

Full text of DOI:10.3762/bjoc.15.89

An anomalous addition of chlorosulfonyl isocyanate to a
carbonyl group: the synthesis of ((3aS,7aR,E)-2-ethyl-
3-oxo-2,3,3a,4,7,7a-hexahydro-1H-isoindol-
1-ylidene)sulfamoyl chloride
Aytekin Köse*1, Aslı Ünal2, Ertan Şahin3, Uğur Bozkaya2 and Yunus Kara*3
Letter
Open Access
Address:
Beilstein J. Org. Chem. 2019, 15, 931–936.
1Department of Chemistry, Aksaray University, 68100 Aksaray,
Turkey, 2Department of Chemistry, Hacettepe University, 06800
Ankara, Turkey and 3Department of Chemistry, Atatürk University,
25240 Erzurum, Turkey
doi:10.3762/bjoc.15.89
Received: 25 December 2018
Accepted: 15 March 2019
Published: 16 April 2019
Email:
Aytekin Köse* - aytekinkose@atauni.edu.tr; Yunus Kara* -
yukara@atauni.edu.tr
Associate Editor: P. Schreiner
© 2019 Köse et al.; licensee Beilstein-Institut.
License and terms: see end of document.
* Corresponding author
Keywords:
addition reaction; chlorosulfonyl isocyanate; sulfamoyl chloride;
theoretical calculations
Abstract
In this study, we developed a new addition reaction of chlorosulfonyl isocyanate (CSI), starting from 2-ethyl-3a,4,7,7a-tetrahydro-
1H-isoindole-1,3(2H)-dione. The addition reaction of CSI with 2-ethyl-3a,4,7,7a-tetrahydro-1H-isoindole-1,3(2H)-dione resulted in
the formation of ylidenesulfamoyl chloride, whose exact configuration was determined by X-ray crystal analysis. We explain the
mechanism of product formation supported by theoretical calculations.
Introduction
Since its identification in 1959 [1], chlorosulfonyl isocyanate β-Lactams 3 generally predominate and in many cases are the
(CSI, 1) continues to be the most reactive isocyanate to date. exclusive products and they serve as key substances in a variety
CSI is relatively more reactive than alkylsulfonyl isocyanate in of chemical transformations. When chlorosulfonyl amides 4 are
olefin additions [2]. Its highly reactive nature is due to the po- produced, they may be converted to other compounds. Graf [1]
larization of the allene double bond by the highly electronega- proposed that the reaction of CSI with unsaturated systems
tive chlorosulfonyl group. CSI reacts with unsaturated systems proceeds via the direct formation of dipolar intermediate 5
to yield either N-chlorosulfonyl-β-lactams 3 or unsaturated which may undergo a ring closure to form 3 or a hydrogen
N-chlorosulfonyl amides 4 (Scheme 1).
transfer to afford 4 (Figure 1).
931

Beilstein J. Org. Chem. 2019, 15, 931–936.
Scheme 1: The reaction of CSI with olefins.
amine with anhydride 8 in the presence of a toluene/triethyl-
amine mixture (3:1) produced imide 9 in 80% yield (Scheme 2).
To synthesize a new lactam derivative of isoindole-1,3-dione,
we investigated the reaction of imide 9 with CSI in toluene at
room temperature. Nevertheless, the starting imide 9 did not
react with CSI, and we could not obtain the expected products
lactam 11 and amide 12. Next, we studied the reaction of 9 with
CSI by heating without solvent, which produced a very interest-
Figure 1: The dipolar intermediate formed in the reaction of CSI with
olefins.
A wide variety of reactions has been reported for CSI, among ing product 10 that contained a N-chlorosulfonylimine group
which its addition to unsaturated systems has proven to be the (Scheme 3).
most interesting and synthetically useful [3]. The addition of
CSI to unsaturated systems and its further reactions have been Upon examination, the most conspicuous features in the 1H and
examined by various groups [4-11]. On the other hand, exam- 13C NMR spectra of 10 were the change in the molecular
ples for the reaction of carbonyl group containing compounds symmetry and the chemical shifts of the carbonyl groups in the
with CSI are limited in the literature. In particular, compounds molecule. If the amide compound 12 had formed, there would
containing an amide or pyrone skeletal structure were used in be a change in the symmetry of the molecule, but the 1H and
these studies. These reactions were reported by the research 13C NMR spectra do not support the structure of amide 12. The
groups of Reynolds [12], Sattur [13], Jiménez [14] and Schwarz results of double resonance experiments clearly indicated that
[15]. In our continuing studies on the synthesis of isoindole de- the HC=CH double bond was located between two CH2 groups
rivatives, we have included the addition of CSI to unsaturated (C-4 and C-7), similar to those present in the starting com-
systems and obtained unexpected results. When the reactions pound. Additionally, there was no signal of the three different
were performed by heating without any solvent, the condensa- carbonyl carbons in the 13C NMR spectrum of 10. On the other
tion product imine was the sole product. In this paper, we hand, the presence of double bond protons, three (CH2) groups,
present for the first time a unique example describing the addi- two CH protons, and one methyl (CH3) group, such as those in
tion of CSI to a system comprising both independent double the starting compound, reveal that the reaction takes place on
bonds and imide functional groups. The mechanism for the ad- the carbonyl groups in the imide ring. While the 1H and
dition of CSI to a carbonyl group is explained by theoretical 13C NMR spectra support a structure, we were not sure what
computations.
kind of structure was indicated based on the spectral data. We
determined the exact structure of 10 by X-ray crystal analysis
(Figure 2) [18].
Results and Discussion
Our starting material was 2-ethyl-3a,4,7,7a-tetrahydro-1H-
isoindole-1,3(2H)-dione (9), which we have synthesized in In addition to determining its structure, we performed X-ray
previous studies [16,17]. Imide 9 was synthesized via the cyclo- crystal analysis of molecule 10 to identify the possible interac-
addition of 3-sulfone to maleic anhydride. The reaction of ethyl- tions. The structure has a racemic form, with the atoms of race-
Scheme 2: The synthesis of imide 9.
932

Beilstein J. Org. Chem. 2019, 15, 931–936.
Scheme 3: The synthesis of ylidene sulfamoyl chloride 10.
mate 10 labeled and the polymeric H-bonding geometries diffuse functions, 6-311++G(d,p) [23-25]. All the computations
shown in Figure 2a. We provide crystallographic data and struc- were performed using the Gaussian 09 program package [26].
tural refinement details in the experimental section. Compound The energies of all the structures are on the B3LYP/6-
10 crystallizes in the monoclinic space group C2/c. The C–C 311G++(d,p) level, and the zero-point vibrational energy
(cyclohexene) distances are in the typical single bond range (ZPVE) corrections are all at the DFT level. Throughout this
[1.491(3)–1.356(3) Å]. The C=C double bonds are in the cyclo- study, all the relative energies refer to the ZPVE-corrected ener-
hexene units range between 1.307–1.316(3) Å and the S=O gies. For the transition state (TS) between species A and B, we
bonds are between 1.417–1.414(3) Å. The conformation is use the notation A/B throughout the article.
defined by steric effects, which force a fold of the cyclohexene
rings relative to the mean plane through the pyrrolidine group. Figure 3 shows the relative energy profile for the reaction
For both enantiomers, the cyclohexene ring has a twist-boat mechanism shown in Scheme 4. The rate-determining steps for
conformation and the pyrrolidine rings are in half-chair confor- the formation of 10, 11, and 12 are the transition states 9/14,
mation. The structures contain four asymmetric carbon atoms 9/11, and 9/12, respectively. The difference between the reac-
and the stereogenic centers are as follows: C1(R), C6(S), tion barriers for the formations of 10 and 11 is 3.6 kcal/mol,
C11(R), and C16(S), where the N-chlorosulfonyl group at- whereas that for the formations of 10 and 12 is 14.1 kcal/mol.
tached to the carbonyl atom changes the stoichiometry. In Hence, the formation of 10 is kinetically more favorable. This
the solid state, compound 10 is stabilized via effective intramo- computational result is consistent with the experimental obser-
lecular H-bonds. Interactions between C9–H∙∙∙O5 [D∙∙∙A = vations.
3.331(3) Å], C5–H∙∙∙O6 [D∙∙∙A = 3.529(3) Å], C19–H∙∙∙O3
[D∙∙∙A = 3.316(3) Å], C16–H∙∙∙O5 [D∙∙∙A = 3.315(3) Å], and Conclusion
C9–H∙∙∙O4 [D∙∙∙A = 3.313(3) Å] contribute to the formation of a For the first time, we have demonstrated the addition of chloro-
stable structure (Figure 2a and Figure 2b).
sulfonyl isocyanate to the system comprising both independent
double bonds and imide functional groups. The mechanism for
Based on the structure of the product, we propose the reaction the addition of CSI to a carbonyl group is explained by theoreti-
mechanism shown in Scheme 4. First, CSI reacts with the car- cal computations. Supported by theoretical calculations, we de-
bonyl carbon in the imide ring to form a four-membered termined the reaction mechanism of the addition product. Such
urethane ring. Afterwards the imine is formed by the release of an addition reaction is one of the unique examples that define
carbon dioxide from the molecule.
the addition of CSI. Furthermore, the chemical transformation
of chlorosulfonyl isocyanate to the related compounds is cur-
We performed theoretical computations to better understand the rently under investigation.
reaction mechanism shown in Scheme 4 (Figure 3). For this
Experimental
purpose, we employed density functional theory (DFT) calcula-
tions and performed geometric optimizations using the B3LYP General
functional [19-22]. We computed the vibrational frequencies to All reagents and substrates were purchased from commercial
characterize each stationary structure. In all the computations, sources and used without further purification. Solvents were
we utilized Pople’s polarized triple-ζ split valence basis set with purified and dried by standard procedures before use. 1H and
933

Beilstein J. Org. Chem. 2019, 15, 931–936.
Figure 2: (a) Molecular structure of racemic molecule 10 (asymmetric unit). Thermal ellipsoids are drawn at the 30% probability level. (b) Geometric
parameter with H-bonded geometry. Hydrogen bonds are drawn as dashed lines. (c) Stacking motif with the unit cell viewed downward along the
c-axis. Dashed lines indicate C–H∙∙∙O interactions.
934

Beilstein J. Org. Chem. 2019, 15, 931–936.
Scheme 4: Mechanism for the formation of ylidenesulfamoyl chloride 10.
Figure 3: Relative energy profile of the reaction mechanism shown in Scheme 4.
13C NMR spectra were recorded on Varian 400 and Bruker 400 ((3aS,7aR,E)-2-Ethyl-3-oxo-2,3,3a,4,7,7a-hexahydro-1H-
spectrometers. Elemental analyses were performed on a Leco isoindol-1-ylidene)sulfamoyl chloride (10): The synthesis of
CHNS-932 instrument. The melting points were measured with 2-ethyl-3-oxo-2,3,3a,4,7,7a-hexahydro-1H-isoindol-1-
Gallenkamp melting point devices. X-ray crystallography was ylidene)sulfamoyl chloride started from (3aR,7aS)-2-ethyl-
performed using a Rigaku R-AXIS RAPID IP diffractometer. 3a,4,7,7a-tetrahydro-1H-isoindole-1,3(2H)-dione (0.50 g,
HRMS: electron-spray technique (M+/M−) from the solution in 2.79 mmol). The starting material was put into a round
MeOH (Waters LCT PremierTM XE UPLC/MS TOF bottomed flask and N2 was passed throughout the flask. Chloro-
(Manchester, UK)). All the computations were performed using sulfonyl isocyanate (CSI, 0.73 mL, 8.37 mmol) was added and
the Gaussian 09 program package. The energies of all the struc- reaction mixture was stirred at 80 °C for 4 h. At the end of this
tures are on the B3LYP/6-311G++(d,p) level.
time, it was cooled to rt and diluted with EtOAc. Unreacted CSI
935

Beilstein J. Org. Chem. 2019, 15, 931–936.
11.Moriconi, E. J.; Crawford, W. C. J. Org. Chem. 1968, 33, 370–378.
doi:10.1021/jo01265a075
and solvent were removed in vacuo and the residue was dis-
solved in CH2Cl2. It was filtered via a column and concen-
trated in vacuo. The residue was crystallized from CH2Cl2/
hexane to obtain ((3aS,7aR,E)-2-ethyl-3-oxo-2,3,3a,4,7,7a-
hexahydro-1H-isoindol-1-ylidene)sulfamoyl chloride (10,
0.233 g, colorless crystalline solid, 30% yield). 1H NMR
(400 MHz, CDCl3) δ 5.93–5.89 (m, 1H, A of AB system, H6),
5.86–5.81 (m, 1H B of AB system, H5), 4.09 (m, 1H, H7a) 3.68
(q, J = 7.2 Hz 2H, N-CH2-), 3.10 (m, 1H, H3a), 2.70–2.61 (m,
2H, 2 × H4), 2.47–2.40 (m, 1H, H7(axial)), 2.34–2.26 (m, 1H,
H7(equatorial)), 1.17 (t, 3H, -CH3, J = 7.2 Hz.); 13C NMR (100
MHz, CDCl3) δ 179.7 (C1), 178.1 (C3), 127.6 (C6), 126.0 (C5),
39.5 (C7a), 37.9 (C3a), 36.5 (N-CH2-), 25.5 (C7), 22.4 (C4),
12.6 (-CH3); mp 68–70 °C; HRMS (APCI): [M + H]+ calcd for
C10H13ClN2O3S, 276.7350; found, 277.0434.
12.Van Allan, J. A.; Chang, S. C.; Reynolds, G. A. J. Heterocycl. Chem.
1974, 11, 195–198. doi:10.1002/jhet.5570110216
13.Rao, K. R.; Nageswar, Y. V. D.; Srinivasan, T. N.; Sattur, P. B.
Synth. Commun. 1988, 18, 877–880. doi:10.1080/00397918808057857
14.Castellanos, L.; Duque, C.; Zea, S.; Espada, A.; Rodríguez, J.;
Jiménez, C. Org. Lett. 2006, 8, 4967–4970. doi:10.1021/ol062087k
15.Bartsch, H.; Schwarz, O. Arch. Pharm. (Weinheim, Ger.) 1982, 315,
545–551. doi:10.1002/ardp.19823150612
16.Tan, A.; Koc, B.; Şahin, E.; Kishali, N. H.; Kara, Y. Synthesis 2011,
1079–1084. doi:10.1055/s-0030-1258466
17.Tan, A.; Kazancıoğlu, M. Z.; Aktaş, D.; Gündoğdu, Ö.; Şahin, E.;
Kishali, N. H.; Kara, Y. Turk. J. Chem. 2014, 38, 629–637.
doi:10.3906/kim-1310-30
18.SHELXS-97, SHELXL-97 Program for Crystal Structure Solution and
Refinement; University of Göttingen: Göttingen, Germany, 1997.
19.Becke, A. D. J. Chem. Phys. 1993, 98, 5648–5652.
doi:10.1063/1.464913
20.Lee, C.; Yang, W.; Parr, R. G. Phys. Rev. B 1988, 37, 785–789.
doi:10.1103/physrevb.37.785
Supporting Information
21.Vosko, S. H.; Wilk, L.; Nusair, M. Can. J. Phys. 1980, 58, 1200–1211.
doi:10.1139/p80-159
Supporting Information File 1
Theoretical computations, experimental procedures, copies
of 1H and 13C NMR spectra, X-ray diffraction and HRMS
analysis.
22.Stephens, P. J.; Devlin, F. J.; Chabalowski, C. F.; Frisch, M. J.
J. Phys. Chem. 1994, 98, 11623–11627. doi:10.1021/j100096a001
23.Hariharan, P. C.; Pople, J. A. Theor. Chim. Acta 1973, 28, 213–222.
doi:10.1007/bf00533485
[https://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-15-89-S1.pdf]
24.McLean, A. D.; Chandler, G. S. J. Chem. Phys. 1980, 72, 5639–5648.
doi:10.1063/1.438980
25.Krishnan, R.; Binkley, J. S.; Seeger, R.; Pople, J. A. J. Chem. Phys.
1980, 72, 650–654. doi:10.1063/1.438955
Acknowledgements
26.Gaussian 09, Revision D.01; Gaussian, Inc.: Wallingford CT, 2013.
The authors are indebted to Department of Chemistry and
Atatürk University for financial support. This research was sup-
ported by the Scientific and Technological Research Council of
Turkey (TÜBİTAK-116Z506).
License and Terms
This is an Open Access article under the terms of the
Creative Commons Attribution License
References
1. Graf, R. Chem. Ber. 1959, 92, 509–513.
(http://creativecommons.org/licenses/by/4.0). Please note
that the reuse, redistribution and reproduction in particular
requires that the authors and source are credited.
doi:10.1002/cber.19590920237
2. Clauβ, K. Justus Liebigs Ann. Chem. 1969, 722, 110–121.
doi:10.1002/jlac.19697220111
3. Graf, R. Angew. Chem., Int. Ed. Engl. 1968, 7, 172–182.
doi:10.1002/anie.196801721
The license is subject to the Beilstein Journal of Organic
Chemistry terms and conditions:
4. Moriconi, E. J.; Jalandoni, C. C. J. Org. Chem. 1970, 35, 3796–3800.
doi:10.1021/jo00836a047
(https://www.beilstein-journals.org/bjoc)
5. Vorbrüggen, H. Tetrahedron Lett. 1968, 9, 1631–1634.
doi:10.1016/s0040-4039(01)99018-5
The definitive version of this article is the electronic one
which can be found at:
6. Hoffmann, R.; Woodward, R. B. J. Am. Chem. Soc. 1965, 87,
2046–2048. doi:10.1021/ja01087a034
7. Woodward, R. B.; Hoffmann, R. Angew. Chem., Int. Ed. Engl. 1969, 8,
781–853. doi:10.1002/anie.196907811
doi:10.3762/bjoc.15.89
8. Moriconi, E. J.; Kelly, J. F. Tetrahedron Lett. 1968, 9, 1435–1439.
doi:10.1016/s0040-4039(01)98973-7
9. Bestian, H.; Biener, H.; Clauss, K.; Heyn, H.
Justus Liebigs Ann. Chem. 1968, 718, 94–100.
doi:10.1002/jlac.19687180109
10.Paquette, L. A.; Wyvratt, M. J.; Allen, G. R., Jr. J. Am. Chem. Soc.
1970, 92, 1763–1765. doi:10.1021/ja00709a060
936