Efficient cyclodehydration of dicarboxylic acids with oxalyl chloride

Article abstract of DOI:10.1016/j.tetlet.2017.06.089

Literature examples illustrating the use of oxalyl chloride to prepare dicarboxylic acid anhydrides are surprisingly limited. At the same time, we have discovered a method involving the use of this readily available reagent which allowed the preparation of novel cyclic anhydrides where other, more conventional, methods had failed. Herein, we demonstrate that the method is applicable to a wide diversity of substrates, delivers good to excellent yields of cyclic anhydrides without chromatographic purification and can be considered a synthetic tool of choice whenever dicarboxylic acid cyclodehydration is required.

Full text of DOI:10.1016/j.tetlet.2017.06.089

Accepted Manuscript
Efficient cyclodehydration of dicarboxylic acids with oxalyl chloride
Grigory Kantin, Evgeny Chupakhin, Dmitry Dar'in, Mikhail Krasavin
PII:
S0040-4039(17)30834-1
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.06.089
TETL 49081
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
12 June 2017
26 June 2017
30 June 2017
Please cite this article as: Kantin, G., Chupakhin, E., Dar'in, D., Krasavin, M., Efficient cyclodehydration of
dicarboxylic acids with oxalyl chloride, Tetrahedron Letters (2017), doi: http://dx.doi.org/10.1016/j.tetlet.
2017.06.089
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Efficient cyclodehydration of dicarboxylic acids with oxalyl chloride
Grigory Kantin,a Evgeny Chupakhin,b Dmitry Dar’ina and Mikhail Krasavin a, b ,*
a Saint Petersburg State University, Saint Petersburg, 199034 Russian Federation
b Immanuel Kant Baltic Federal University, Kaliningrad, 236016 Russian Federation
* Corresponding author; phone: + 7 931 3617872, fax: +7 812 428 6939.
E-mail: m.krasavin@spbu.ru
Abstract
Literature examples illustrating the use of oxalyl chloride to prepare dicarboxylic acid
anhydrides are surprisingly limited. At the same time, we have discovered a method involving
the use of this readily available reagent which allowed the preparation of novel cyclic anhydrides
where other, more conventional, methods had failed. Herein, we demonstrate that the method is
applicable to a wide diversity of substrates, delivers good to excellent yields of cyclic anhydrides
without chromatographic purification and can be considered a synthetic tool of choice whenever
dicarboxylic acid cyclodehydration is required.
Keywords
Dicarboxylic acid cyclodehydration, cyclic anhydride, oxalyl chloride, oligomerization side-
reaction, N,N-dimethyl formamide catalyst.
One in need of transforming dicarboxylic acids into the corresponding cyclic anhydrides has a
vast arsenal of dehydrating agents whose use is amply exemplified in the literature. These
include acetic anhydride,1 trifluoroacetic anhydride,2 Boc2O,3 carbodiimides (e. g. EDC4 or
DCC5), 1,1ʹ-carbonyldiimidazole (CDI),6 thionyl chloride,7 phosphorus (V) oxide,8 cyanuric
chloride9 and many others. However, when these reagents fail to trigger the desired
cyclodehydration event, which usually results in the formation of oligomeric product mixtures,10
a workable alternative must be found among less popular dehydrating agents.
As part of our research program directed towards the design of novel cyclic anhydrides
employable in the Castagnoli-Cushman reaction (CCR),11 particularly after it was reported by
Ryabukhin and co-workers10 and ourselves12 that the CCR is capable of delivering ε-lactams

from seven-membered cyclic anhydrides, we required hitherto unknown 2H-
benzo[e][1,4]dioxepine-3,5-dione (1a) which we hoped to prepare via the cyclodehydration of
the known13 dicarboxylic acid 2a (Fig. 1). However, when the above-mentioned
cyclodehydration protocols were attempted and failed (delivering predominantly linear,
dehydrative homo-oligomerization products), we sought to screen other, less explored
dehydrating agents. Herein, we report the convenient application of oxalyl chloride to prepare
chemically diverse cyclic anhydrides from dicarboxylic acids.
Upon reviewing the literature, we were surprised to find that the employment of oxalyl chloride
to dehydrate mono- or dicarboxylic acids was rather limited. Following an example used to
dehydrate benzoic acids published nearly 100 years ago,14 we identified only two other
examples: cyclodehydration of fumaric acid (with intermittent addition of hydrochloric acid to
form the chlorosuccinic acid motif)15 and preparation of N-benzyliminodiacetic anhydride from
the respective dicarboxylic acid.16 The latter example prompted us to test the applicability of
oxalyl chloride as a dehydrating agent for the preparation of 1a from 2a.
Figure 1. Cyclic anhydride 1a that failed to form upon cyclodehydration of 2a using most
common protocols.
To our delight, treatment of 2a with oxalyl chloride (1.2 equiv.) in dry toluene for 10 h (with
1
periodic H NMR analysis of reaction mixture aliquots) led to the complete conversion to 1a.
Since we expected the conversion of 2aꢀ1a to involve the formation of monoacyl chloride 3,
we tested the same reaction in presence of catalytic DMF and found that it led to reaction
completion in only 3 h, likely due to the known17 acceleration mechanism involving formation of
the Vilsmeier-Haack reagent (4) which is the acting catalytic species (Fig. 2).
Figure 2. Likely mechanism of 2aꢀ1a conversion.

Following simple evaporation of toluene, analytically pure 1a was obtained in 99% yield.
Notably, the same reaction attempted at reflux in dichloromethane, chlorobenzene or 1,2-
dichloroethane led to much poorer (<50%) conversions as evidenced by 1H NMR analysis of the
reaction mixture aliquots.
Encouraged by these findings, we applied the same protocol (Scheme 1)18 to a range of diverse
dicarboxylic acids 2b-v and found it to deliver good to excellent yields of the respective cyclic
1
anhydrides 1b-v (Table 1).19 The identity of all known anhydrides 1 was established using H
NMR spectroscopy and high-resolution mass-spectrometry (HRMS). All newly described
13
anhydrides 1 were fully characterized, including C NMR spectroscopy (ESI). In some cases,
electrospray ionization used in obtaining HRMS data did not allow detection of the molecular
ion of poorly ionizable compounds 1. In these cases, HRMS was run in methanol and the exact
molecular weight was reported for the respective methyl monoester, i. e. the ring-opening
product of anhydride 1 with methanol (ESI).
Scheme 1. Cyclodehydration of dicarboxylic acids 2a-v-.
Table 1. Results of cyclodehydration of dicarboxylic acids 2a-v.a
Isolated yield
1 (%)
Starting material (2)
Product (1)
99
62

81
96
96
93
88
88
91
93

91
85
88
44
80
81
70
72

85
83
79
OH
O
OH
2u
O
68
a Reagents and conditions: Dicarboxylic acid 2 (1.0 mmol), oxalyl chloride (1.2 mmol), DMF (1
drop), toluene, reflux, 3 h.
The data shown in Table 1 clearly demonstrate the general applicability of the new
cyclodehydration protocol to a wide range of structurally diverse substrates. In most cases,
particularly when the product yield was substantially lower than quantitative (e. g. 1b, 1n, 1u),
substantial tar formation was noted and attributed to the concomitant formation of oligomeric
products from intermolecular dehydration of the starting material. In case of 1n, the increased
acidity of the methylene group could possibly be responsible for degradation of the product due
to self-condensation.
In summary, we have identified a workable cyclodehydration protocol for dicarboxylic acids and
applied it toward the synthesis of a set of structurally diverse cyclic anhydrides. The method
provides high yields of the target products and clearly complements other, more established
protocols, particularly when those fail to provide the desired reaction outcome (as was
demonstrated for the conversion of 2aꢀ1a at the onset of this study).
Acknowledgement
This research was supported by the Russian Scientific Fund (project grant 14-50-00069). We are
grateful to the Research Centre for Magnetic Resonance and the Centre for Chemical Analysis

and Materials Research of Saint Petersburg State University Research Park for the analytical
data.
Supporting Information
Supporting information for this article is available online at http://dx.doi.org/xxx.
References and Notes
1. Sakai, M.; Ishikawa, Y.; Takamizawa, S.; Oikawa, M. Tetrahedron Lett. 2013, 54, 5911-
5912.
2. Chizhova, M.; Bakulina, O.; Dar'in, D.; Krasavin, M. ChemistrySelect 2016, 1, 5487-5492.
3. Robert, C.; de Montigny, F.; Thomas, C. M. ACS Catal. 2014, 4, 3586-3589.
4. Chen, H.; Jinadasa, R. G. W.; Jiao, L.; Fronczek, F. R.; Nguyen, A. L.; Smith, K. M. Eur. J.
Org. Chem. 2015, 3661-3665.
5. Riebeseel, K.; Biedermann, E.; Loeser, R.; Breiter, N.; Hanselmann, R.; Muelhaupt, R.;
Unger, C.; Kratz, F. Bioconjugate Chem. 2002, 13, 773-785.
6. Morton, R. C.; Mangroo, D.; Gerber, G. E. Can. J. Chem. 1988, 66, 1701-1705.
7. Kazemi, F.; Kiasat, A. R.; Mombani, B. Synth. Commun. 2007, 37, 3219-3223.
8. Burton, S. G.; Kaye, P. T. Synth. Commun. 1989, 19, 3331-3335.
9. Cochrane, J. R.; Yoon, D. H.; McErlean, C. S. P.; Joliffe, K. A. Beilstein J. Org. Chem.
2012, 8, 1344-1351.
10. Adamovskyi, M. I.; Ryabukhin, S. V.; Sibgatulin, D. A.; Rusanov, E.; Grygorenko, O. O.
Org. Lett. 2017, 19, 130–133.
11. Krasavin, M.; Dariin, D. Tetrahedron Lett. 2016, 57, 1635-1640.
12. Bakulina, O.; Dariin, D.; Krasavin, M. Synlett 2017, 28, 1165-1169.
13. Venkatesan, A. M.; Dos Santos, O.; Ellingboe, J.; Evrard, D. A.; Harrison, B. L.; Smith, D.
L.; Scerni, R.; Hornby, G. A.; Schechter, L. E.; Andree, T. H. Bioorg. Med. Chem. Lett.
2010, 20, 824-827.
14. Adams, R.; Wirth, W. V.; French, H. E. J. Am. Chem. Soc. 1981, 40, 424-431.
15. Dymicky, M. Org. Prep. Proc. Int. 1983, 15, 233-238.
16. Santos, M. A.; Marques, S. M.; Tuccinardi, T.; Carelli, P.; Paelli, L.; Rosello, A. Bioorg.
Med. Chem. 2006, 14, 7539-7550.
17. Clayden, J.; Greeves, N.; Warren, S. Organic Chemistry. Oxford: Oxford University Press,
2001. pp. 276–296.
18. General procedure for the preparation of cyclic anhydrides 1a-v: Dicarboxylic acid 2 (1
mmol) and oxalyl chloride (1.2 mmol) were combined in dry toluene (5 mL) and a drop of

freshly distilled DMF was added. The reaction vessel was purged with argon and the
reaction was heated at reflux with stirring for 3 h. The stirring was stopped and the toluene
solution was decanted from the oily residue and filtered. Evaporation of the volatiles
provided the analytically pure target product which, if necessary, was transformed into the
crystalline form by trituration with diethyl ether. In some cases (see ESI) additional
crystallization or trituration with a 1:2 v/v hexane-toluene mixture was used.
19. Characterization data of representative new cyclic anhydrides (for more comprehensive data
1
– see ESI): 1a - white crystalline solid, mp = 68.5 – 70.0 °C; H NMR (400 MHz CDCl3) δ
8.05 (dd, J = 7.9, 1.7 Hz, 1H, CH(Ar)), 7.70-7.57 (m, 1H, CH(Ar)), 7.34-7.25 (m, 1H,
13
CH(Ar)), 7.19 (dd, J = 8.4, 0.8 Hz, 1H, CH(Ar)), 4.84 (s, 2H, CH2); C NMR (101 MHz,
CDCl3) δ 162.4, 159.6, 158.8, 136.5, 134.5, 124.5, 120.5, 117.7, 71.1; HRMS (ESI), m/z
calcd for C10H10NaO5 [M+CH3OH+Na]+ 233.0420, found 233.0426; 1o - white crystals, mp
204.5 – 207.0 °C; 1H NMR (400 MHz CDCl3) δ 8.32 (d, J = 7.6 Hz, 1H, CH(Ar)), 7.73-7.65
(m, 2H, CH(Ar)), 7.63-7.56 (m, 1H, CH(Ar)), 7.51-7.44 (m, 2H, CH(Ar)), 7.03-6.96 (m, 2H,
CH(Ar)), 5.23 (d, J = 8.7 Hz, 1H, CH(CO2H)), 4.82 (d, J = 8.7 Hz, 1H, CH(CO2H)), 3.86 (s,
3H, CH3O); 13C NMR (101 MHz, CDCl3) δ 168.8, 166.6, 161.2, 159.3, 133.7, 133.6, 130.3,
130.1, 128.5, 127.9, 127.8, 126.4, 114.8, 61.5, 55.5, 43.8; HRMS (ESI), m/z calcd for
C19H17NNaO6 [M+CH3OH+Na]+ 378.0948, found 378.0953; calcd for C18H13NaO5
[M+Na]+ 346.0686, found 346.0701; 1r - light brown crystals, mp 218.0-222.0 °C melting
1
with decomposition; H NMR (400 MHz, d6-acetone) δ ppm 7.83 (d, J = 7.93 Hz, 1H,
CH(Ar)), 7.64 (d, J = 8.24 Hz, 1H, CH(Ar)), 7.57 (s, 1H, CH(Ar)), 7.49 (t, J = 7.63 Hz, 1H,
CH(Ar)), 7.27 (t, J = 7.48 Hz, 1H, CH(Ar)), 5.43 (s, 2H, CH2); 13C NMR (101 MHz, d6-
acetone) δ ppm 162.7, 153.9, 137.2, 127.3, 126.6, 123.1, 122.1, 120.1, 110.9, 110.1, 44.4;
HRMS (ESI), m/z calcd for C12H11NNaO4 [M+CH3OH+Na]+ 256.0580, found 256.0585.

•
•
•
Oxalyl chloride promotes cyclodehydration of dicarboxylic acids.
DMF accelerates the reaction, suggesting intermediacy of a monoacyl chloride.
The method can be applied to a wide range of structurally diverse carboxylic acids.

Efficient cyclodehydration of dicarboxylic acids with oxalyl chloride
Grigory Kantin, Evgeny Chupakhin, Dmitry Dar’in and Mikhail Krasavin*