Efficient synthesis of N-oxysulfonyl formamidines through thionyl chloride-promoted reaction of sulfamates with formamides

Article abstract of DOI:10.1080/00397911.2017.1361999

N-Oxysulfonyl formamidine derivatives have been efficiently synthesized under mild conditions through direct condensation of various sulfamates and formamides in the presence of thionyl chloride. The scope of this reaction was investigated, and a plausible mechanism was proposed. The resulting N-oxysulfonyl formamidines can be converted to sulfamates through appropriate deprotection.

Full text of DOI:10.1080/00397911.2017.1361999

Synthetic Communications
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Efficient synthesis of N-oxysulfonyl formamidines
via thionyl chloride-promoted reaction of
sulfamates with formamides
Abudureheman Wusiman & Ruzeahong Hudabaierdi
To cite this article: Abudureheman Wusiman & Ruzeahong Hudabaierdi (2017): Efficient
synthesis of N-oxysulfonyl formamidines via thionyl chloride-promoted reaction of sulfamates with
formamides, Synthetic Communications, DOI: 10.1080/00397911.2017.1361999
To link to this article: http://dx.doi.org/10.1080/00397911.2017.1361999
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Date: 03 August 2017, At: 08:11

Efficient synthesis of N-oxysulfonyl formamidines via
thionyl chloride-promoted reaction of sulfamates with
formamides
Abudureheman Wusiman*
School of Chemistry and Chemical Engineering, Xinjiang Normal University, Urumqi, People’s
Republic of China
Ruzeahong Hudabaierdi
School of Chemistry and Chemical Engineering, Xinjiang Normal University, Urumqi, People’s
Republic of China
Address correspondence to Abudureheman Wusiman. E-mail: arahman@xjnu.edu.cn
Supporting Information: Experimental synthetic details, 1H and 13Cꢀ NMR spectra for all new
compounds. This material can be found via the “Supplementary Content” section of this article’s
webpage.”
ABSTRACT
N-oxysulfonyl formamidine derivatives have been efficiently synthesized under mild
conditions through direct condensation of various sulfamates and formamides in the presence of
thionyl chloride. The scope of this reaction was investigated, and a plausible mechanism was
1

proposed. The resulting N-oxysulfonyl formamidines can be converted to sulfamates via
appropriate deprotection.
GRAPHICAL ABSTRACT
KEYWORDS: deprotection, formamidine, sulfamate, thionyl chloride
Introduction
Amidines are important intermediates in diverse functional group transformations,[1]
including as auxiliaries in asymmetric synthesis,[2] as protecting groups for primary amines,[3] and
as nitrogen-based nucleophiles.[4] Amidines have been used widely in medicinal chemistry,[5]
coordination chemistry,[6] and supramolecular chemistry[7] because of their structural
characteristics. They also occur in many bioactive natural products,[8] and N-sulfonyl
formamidines in particular are attractive because of their wide range of pharmaceutical and
biological properties.[9] Traditional methods for preparing N-sulfonylformamidines have been
supplemented[10] and recent efforts have led to the updating and improvement of traditional
processes as well as construction of the structurally diverse group of amidines.[11]
In contrast to the extensive literature on N-sulfonyl amidine synthesis, the preparation of
N-oxysulfonyl amidines has been largely ignored.[12] In continuation of our previous work on
2

synthesis of N-sulfonyl amidines,[13] we undertook studies to develop a simple, efficient synthesis
of N-oxysulfonyl formamidines (3) under mild conditions. To the best of our knowledge, this is
the first report of the direct transformation of sulfamates into N-oxysulfonyl amidines.
Results and Discussion
We initially selected phenyl sulfamate 1a and DMF 2a as model substrates in order to
investigate reaction conditions (Table 1). Treatment of 1a with 2a in the presence of 1.0 equiv of
phosphoryl chloride in chloroform at 60C afforded the desired oxysulfonyl formamidine 3a in
54% isolated yield (entry 1). Screening of acid chlorides showed that SOCl2 gave 3a in 58% yield
(entry 2), while oxalyl chloride gave lower yield (entry 3). The desired amidine product was
obtained in chloroform in highest yield, as well as in 1, 2-dichloroethane (DCE), dichloromethane
(DCM) and chlorobenzene at lower yields (entries 4–6). Increasing the reaction temperature to
70C reduced yield slightly (entry 7), which we attributed to sulfamate decomposition. Therefore,
we repeated the reaction at 40C, but were surprised to obtain even lower yield of 46% (entry 8).
Using DMF in slight excess improved the yield of 3a (entry 9), with 1.5 equiv DMF giving the
desired amidine in 85% yield (entry 10). There is no further influence on reaction yield when the
amount of DMF was increased to 2.0 equiv (entry 11). In contrast, when DMF was used as the
solvent, only a trace amount of desired product was obtained (entry 12). Therefore, 1.5 equiv was
found to be the ideal amount of 2a. Exposure to air did not affect the reaction (entry 13), while
removal of the chlorinating agent blocked the reaction completely (entry 14).
With the optimized conditions in hand (Table 1, entry 10), we examined reactions between
various types of sulfamate 1 and formamide 2. Aryl sulfamate derivatives bearing electron-
donating or -withdrawing groups such as methyl, tert-butyl, methoxy, chloro, bromo or fluoro
3

groups reacted smoothly with DMF to give the corresponding products 3a-3e in 85-90% yield
(Table 2, entries 1-5). The sulfamate ester derived from 4-hydroxyazobenzene was transformed
into the corresponding amidine 3f in 92% yield (entry 6). To our satisfaction, an array of
formamides proved to be suitable reaction partners, including N,N-diethylformamide, N,N-
diisopropylformamide,
N-methyl-N-phenylformamide,
N-formyl-piperidine,
and
4-
formylmorpholine. These substrates furnished the corresponding sulfonylamidines 3gꢀ-3l in good
yield (entries 7-12). In contrast, sulfamate esters derived from benzyl or pentyl alcohol generated
the desired N-oxysulfonyl amidines in low respective yields of 22% and 30% (entries 13 and 14);
in addition, the product mixture contained [(dimethylamino)methylene]sulfamic acid[14] in nearly
50% yield. IR spectroscopy showed very strong C = N and S = O vibrations, and 1H NMR revealed
(CH3)2Nꢀ signals and two downfield-shifted singlet peaks corresponding to -N = CH proton and
H-N + proton (see Supporting Information). We attribute this result to hydrolysis of the electron-
rich N-alkoxy sulfonyl formamidine under these acidic conditions. Consistent with this idea, the
electron-deficient substrate 2,2,2-trichloroethyl sulfamate (TcesNH2) generated amidine 3o in
92% yield (entry 15). These results suggest that the electronic properties of the alkyl significantly
affect reaction outcomes. Notably, no reaction occurred between 1a and N-phenyl formamide 2g
under the conditions we tested (entry 16).
Based on these synthetic studies, we attempted to react some biologically active
sulfamates[15] with DMF under standard conditions (Scheme 1). Chiral topiramate (1k) and estrone
sulfamate (1l) reacted smoothly, generating the desired products in good yield
To gain insight into the reaction mechanism, we performed several control experiments
(Scheme 2). We treated 1a with the commercially available Vilsmeier reagent (VR)
chloromethylenedimethyliminium chloride and obtained 60% of the desired 3a under standard
4

reaction conditions (Scheme 2, eq. 1). Repeating the reaction with 1.0 equiv of VR and 0.5 equiv
of DMF increased yield to 83% (Scheme 2, eq. 2). These results indicate that efficient reaction
depends on the presence of a small amount of DMF, which may participate in the mechanism.
Performing the reaction at room temperature led to 3a in 46% yield (Scheme 2, eq. 3).
On the basis of our synthetic and mechanistic studies as well as the literature,[16], [17] we
propose a possible mechanism for the dehydroxylation reaction (Scheme 3). Initially, thionyl
chloride generates highly electrophilic active complex I from DMF, and removal of sulfur dioxide
reversibly converts I to Velsmeier reagent II, which acts as a Lewis acid to attack DMF and form
more stable complex III. (A chlorotropic tautomerization can occur via carbocation
rearrangement.) Then, sulfamate 1 reacts via kinetically controlled path A with highly active
complex I, via path B with Velsmeier reagent II, or via thermodynamically controlled path C with
complex III to generate the final product 3.
Sulfamates are important functional groups in medicinal chemistry and drug
development,[18] and sulfamates are targets normally the amido (NH2) group must be protected
during drug discovery.[19] Therefore we wanted to know whether we could recover sulfamates
efficiently from our N-oxysulfonyl amidines. When we reacted N-oxysulfonyl amidines with
hydrazine hydrate in ethanol under mild reaction conditions, we selectively removed the
formamidine functionality, recovering the sulfamates in good to excellent yields (Table 3).
Experimental
General procedure for preparing N-oxysulfonylformamidine
A mixture of phenyl sulfamate 1 (2.0 mmol, 1.0 equiv), formamide 2 (3.0 mmol, 1.5 equiv)
and thionyl chloride (2.0 mmol, 1.0 equiv) in CHCl3 (2.0mlꢀ) was stirred at 60 oC for the indicated
5

reaction time (see Table 2). The reaction mixture was cooled down to room temperature and
evaporated under vacuum. The resulting residue was purified by silica gel column chromatography
to give the desired product 3.
(E)-phenyl((dimethylamino)methylene)sulfamate (3a):[12a] White solid, m.p.: 67–68°C; 1H
NMR (400MHzꢀ, CDCl3): δ 7.93 (s, 1H), 7.33-7.18 (m, 5H), 3.06 (s, 3H), 3.02 (s, 3H); 13Cꢀ NMR
(100MHzꢀ, CDCl3): δ 160.7, 150.6, 129.4, 126.4, 122.2, 41.5, 35.6; HRMS calcd. for
C9H12N2NaO3Sꢀ [M + Na] +; 251.0466; found 251.0464.
General procedure for the deprotection of N-Oxysulfonyl formamidines
Hydrazine monohydrate (500mg, 10 mmol) was added at room temperature to a stirred
mixture of the appropriate N-oxysulfonyl formamidine 3 (1.0 mmol) in ethanol (5 mLꢀ). The
reaction mixture was stirred for 1~2 h and the solvents were removed. Water and ethyl acetate
(20mLꢀ) were then added, the phases were separated, and the water phase was additionally
extracted with ethyl acetate (2 x 10mLꢀ). The organic phases were combined, dried with anhydrous
Na2SO4 and filtered, the solvents were removed and purified by silica gel column chromatography
to give the product 1inꢀ good to excellent yield (see Table 3).
Conclusion
In conclusion, we have developed an efficient procedure for synthesizing N-oxysulfonyl
formamidines under mild conditions. The reaction tolerates aromatic and electron-withdrawing
aliphatic sulfamates, as well as biologically active sulfamates, and the desired products are
generated in good to high yield. The resulting N-oxysulfonyl formamidines are easily converted
into sulfamates by selectively removing the formamidine functionality using hydrazine hydrate in
ethanol.
6

Acknowledgements
This work was supported by the National Natural Science Foundation of China
(21362038), and the China Scholarship Council (CSC).
References
[1] Ishikawa, T. Superbases for Organic Synthesis: Guanidines, Amidines, Phosphazenes and
Related Organocatalysts; Wiley, Chippenham, 2009, pp 49–91. (b) Dineen, T. A.; Zajac,
M. A.; Myers, A. G. J. Am. Chem. Soc. 2006, 128, 16406–16409. (c) Streith, J.; Rudyk,
H.; Tschamber, T.; Tarnus, C.; Strehler, C.; Deredas, D.; Frankowski, A. Eur. J. Org.
Chem. 1999, 4, 893–898.
[2] (a) Meyers, A. I.; Hutchings, R. Heterocycles 1996, 42, 475–478. (b) Matulenko, M. A.;
Meyers, A. I. J. Org. Chem. 1996, 61, 573–580. (c) Meyers, A. I.; Santiago, B. Tetrahedron
Lett. 1995, 36, 5877–5580.
[3] (a) Wuts, P. G. M.; Greene, T. W. Greene’s Protective Groups in Organic Synthesis, 5th ed.;
Wiley-Interscience: Hoboken, NJ, 2014, pp 1064–1065. (b) Kumar, P.; Chandak, N.;
Nielsen P.; Sharma, P. K. Bioorg. Med. Chem. 2012, 20, 3843–3849. (c) Sharma, P. K.;
Chandak, N.; Kumar, P.; Sharma, C.; Aneja, K. R. Eur. J. Med. Chem. 2011, 46, 1425–
1432. (d) Andersen, N. K., Chandak, N., Kumar, P., Brulikova, L., Sharma, P. K., Jensen,
M. D., Jensen, F.; Nielsen, P. Bioorg. Med. Chem. 2010, 18, 4702–4710. (e) Vernier, W.;
Chong, W.; Rewolinski, D.; Greasley, S.; Pauly, T.; Shaw, M.; Dinh, D.; Ferre, R. A.;
Nukui, S.; Ornelas, M.; Reyner, E. Bioorg. Med. Chem. 2010, 18, 3307–3319.
[4] Monge, A.; Palop, J. A.; Gonzalez, M.; Martinezcrespo, F. J.; Decerain, A. L.; Sainz, Y.; Narro,
S.; Barker, A. J.; Hamilton, E. J. Heterocycl. Chem. 1995, 32, 1213–1217.
[5] (a) Arya, S.; Kumar, N.; Roy, P.; Sondhi, S. M. Eur. J. Med. Chem. 2013, 59, 7–14. (b) Bekhit,
A. A.; Ashour, H. M.; Ghany, Y. S. A.; Bekhit, A. E. D. A.; Baraka, A. Eur. J. Med. Chem.
2008, 43, 456–463. (c) Luca, L. D. Curr. Med. Chem. 2006, 13, 1–23.
[6] Collins, S. Coord. Chem. Rev. 2011, 255, 118–138.
[7] Katagiri, H.; Tanaka, Y.; Furusho, Y.; Yashima, E. Angew. Chem. Int. Ed. 2007, 46, 2435–
2491.
[8] Greenhill, J. V.; Lue, P. Prog. Med. Chem. 1993, 30, 203–326.
[9] (a) Lee, M. Y.; Kim, M. H.; Kim, J.; Kim, S. H.; Kim, B. T.; Jeong, I. H.; Chang, S.; Kim, S.
H.; Chang, S.-Y. Bioorg. Med. Chem. Lett. 2010, 20, 541–545. (b) Goubet, A., Chardon,
A., Kumar, P., Sharma, P. K., Veedu, R. N. Bioorg. Med. Chem. Lett. 2013, 23, 761–763.
[10] (a) King, C. J. Org. Chem. 1960, 25, 352–356; (b) Tosolini, G. Chem. Ber. 1961, 94, 2731–
2737; (c) Pettit, G. R.; Kadunce, R. E. J. Org. Chem.1962, 27, 4566–4570; (d) Jakobsen,
P.; Treppendah, S. Tetrahedron 1977, 33, 3137–3140; (e) Krasnov, V. L.; Vasyanina, G.
I.; Bodrikov, I. V. Zh. Org. Khim. 1990, 27, 1552–1556; (f) Arnswald, M.; Neumann, W.
P. J. Org. Chem. 1993, 58, 7022–7028; (g) Silva, A. L.; Covarrubias- Zuniga, A.;
Maldonado, L. A. Org. Prep. Proced. Int. 2002, 34, 545–549; (h) Vandenheuvel, W. J. A.;
Gruber, V. F. J. Chromatogr. A 1975, 112, 513–521; (i) Gazvoda, M.; Kocevar, M.; Polanc,
7

S. Eur. J. Org. Chem. 2013, 5381–5386; (j) Chandna, N.; Chandak, N.; Kumar, P.;
Kapoorb, J. K.; Sharma, P. K. Green Chem. 2013, 15, 2294–2301.
[11] (a) Liu, N.; Tang, B. Y.; Chen, Y.; He, L. Eur. J. Org. Chem. 2009, 2059–2062; (b) Xu, X.
L.; Ge, Z. C.; Cheng, D. P.; Ma, L.; Lu, C. S.; Zhang, Q. F.; Yao, N.; Li, X. N. Org. Lett.
2010, 12, 897–899. (b) Xu, X. L.; Li, X. N.; Ma, L.; Ye, N.; Weng, B. J. J. Am. Chem. Soc.
2008, 130, 14048–14049. (c) Chen, J.; Guo, Y. P.; Sun,M. H.; Fan, G. T.; Zhou, L. Chem.
Commun. 2014, 50, 12367–123. (d) Chen, S.; Xu, Y.; Wan, X. Org. Lett. 2011, 13, 6152–
6155. (e) Zheng, Y.; Mao, J. C.; Chen, J.; Rong, G. W.; Liu, D. F.; Yan, H.; Chia, Y. J.;
Xu, X. F. RSC Adv. 2015, 5, 50113–50117. (f) Niu, Z. H.; Lin, S. X.; Dong, Z. Y.; Sun,
H.; Liang, F. S.; Zhang, J. P. Org. Biomol. Chem. 2013, 11, 2460–2465.
[12] (a) Rmedi, H.; Beji, M.; Baklouti, A. Journal de la Société Chimique de Tunisie. 2009, 11,
163–166. (b) Yang, T.; Cui, H.; Zhang, C. H.; Zhang, L.; Su, C. Y. Chem. Cat. Chem.
2013, 5, 3131–3138.
[13] (a) Mulati, A.; Wusiman, A. Heterocycles 2015, 91, 2163–2171. (b) Hudabaierdi, R.;
Wusiman, A.; Mulati, A. Phosphorus, Sulfur Silicon Relat. Elem. 2017, 192, 485–489.
[14] Schwarz, S.; Thieme, I.; Richter, M.; Undeutsch, B.; Henkel, H.; Elger, W. Steroids 1996, 61,
710–717.
[15] Sabers, A.; Gram, L. Drugs 2000, 60, 23–33.
[16] Martin, J.; Poignant, S.; Filleux, M. L.; Querneneur, M. T. Tetrahedron Lett. 1970, 58, 5061–
5064.
[17] (a)Vinogradova, S. V.; Pankratov, V. A.; Korshak, L. V. V.; Komarova, I. Russ Chem Bull.
1971, 20, 450–455. (b) Kikugawa, K.; Kawashima, T. Chem Pharm Bull. 1971, 19, 2629–
2630. (c) Kikugawa, K.; Ichino, M.; Kawashima, T. Chem Pharm Bull. 1971, 19, 2466–
2471.
[18] Winum, J. Y.; Scozzafava, A.; Montero, J. L.; Supuran, C. T. Med. Res. Rev. 2005, 25, 186–
228.
[19] Reuillon, T.; Alhasan S. F.; Beale, G. S.; Bertoli, A.; Brennan, A.; Cano, C.; Reeves, H. L.;
Newell, D. R.; Golding, B. T.; Miller, D. C.; Griffin, R. J. Chem. Sci. 2016, 7, 2821–2826.
8

Table 1. Optimization of reaction conditionsa.
Entry
Acid chloride
Solvent
Time (h)
Yield (%)b
Temp. (C)
1
POCl3
SOCl2
(COCl)2
SOCl2
SOCl2
SOCl2
SOCl2
SOCl2
SOCl2
SOCl2
SOCl2
SOCl2
SOCl2
CHCl3
CHCl3
CHCl3
DCM
60
60
60
40
60
60
70
40
60
60
60
60
60
3
3
54
60
2
3
3
56
4
3
44
5
DCE
3
50
6
PhCl
3
21
7
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
DMF
2.5
6
53
8
46
9c
10d
11e
12
13cf
2
72
2
85
2
87
5
trace
86
CHCl3
2
9

14c
–
CHCl3
60
6
NR
aReactions were performed with 2.0 mmol of phenyl sulfamate 1a (1.0 equiv.) and 2.0 mmol acid
chloride (1.0 equiv) in 2 mL of solvent, unless otherwise noted. bIsolated yield after column
chromatography. c1.2 equiv of DMF was used. d1.5 equiv of DMF was used. e2.0 equiv of DMF
was used. fThe reaction was performed with the drying tube on top of the condenser.
10

Table 2. Preparation of N-oxysulfonyl formamidinesa.
Entry
R1
R2, R3
Me, Me
Me, Me
Time (h)
Yield (%)b
1
2
3
1
2
C6H5
2
2
85
87
1a
1b
2a
2a
3a
3b
4-
MeOC6H5
3
4
5
6
4-tBuC6H5
4-ClC6H5
4-FC6H5
Me, Me
Me, Me
Me, Me
Me, Me
2
2
3
3
90
85
90
92
1c
1d
1e
1f
2a
2a
2a
2a
3c
3d
3e
3f
4-
azobenzene
7
C6H5
Et, Et
Et, Et
3
2
3
5
4
5
77
76
88
60
85
63
1a
1gꢀ
1a
1a
1a
1a
2b
2b
2c
2d
2e
2f
3gꢀ
3hꢀ
3i
8
4-BrC6H5
C6H5
9
i-Pr, i-Pr
Me, Ph
(CH2)5
10
11
12
C6H5
3j
C6H5
3k
3l
C6H5
(C2H4)2O
11

13
14
15
16
C6H5CH2
n-C5H9
Cl3CCH2
C6H5
Me, Me
Me, Me
Me, Me
H, Ph
3
3
2
5
22c
30c
92
0
1hꢀ
1i
2a
2a
2a
2gꢀ
33mmꢀꢀ
3n
1j
3o
1a
3p
aReactions were performed with 2.0 mmol of sulfamate 1 (1.0 equiv) and 3.0 mmol formamide 2 (1.5 equiv) in 2.0 mL of
chloroform, unless otherwise noted. bIsolated yield after column chromatography. c(Dimethylamino)methylene sulfamic acid was
isolated in nearly 50% yield.
12

Table 3 Deprotection of N-oxysulfonyl formamidinesa.
Entry
Formamidine (3)
Amidine (1)
Time (h)
Yield (%)b
1
2
3
4
5
6
7
8
9
1
1
89
91
93
85
96
83
89
90
85
3a
3c
3gꢀ
3i
1a
1c
1a
1a
1a
1a
1j
1.5
2
2
3k
3l
2
1
3o
3qꢀ
3r
1
1k
1l
1
aN-Sulfonylformamidine 3 (1.0 mmol), N2H4·H2O (10.0 mmol), EtOH (5mLꢀ). bIsolated yield.
13

Scheme 1. Reactions of topiramate and estrone sulfamate with DMF.
14

Scheme 2. Control experiments.
15

Scheme 3. Proposed reaction mechanism.
16