A Convenient Preparation of Muconaldehyde Using a One-Pot Acid-to-Aldehyde Reduction Protocol

Full text of DOI:10.1080/00304948.2021.1953889

Organic Preparations and Procedures International
The New Journal for Organic Synthesis
ISSN: (Print) (Online) Journal homepage: https://www.tandfonline.com/loi/uopp20
A Convenient Preparation of Muconaldehyde
Using a One-Pot Acid-to-Aldehyde Reduction
Protocol
Saurin R. Sutaria & Michael H. Nantz
To cite this article: Saurin R. Sutaria & Michael H. Nantz (2021): A Convenient Preparation of
Muconaldehyde Using a One-Pot Acid-to-Aldehyde Reduction Protocol, Organic Preparations and
Procedures International, DOI: 10.1080/00304948.2021.1953889
To link to this article: https://doi.org/10.1080/00304948.2021.1953889
Published online: 26 Jul 2021.
Submit your article to this journal
Article views: 7
View related articles
View Crossmark data
Full Terms & Conditions of access and use can be found at
https://www.tandfonline.com/action/journalInformation?journalCode=uopp20

ORGANIC PREPARATIONS AND PROCEDURES INTERNATIONAL
https://doi.org/10.1080/00304948.2021.1953889
OPPI BRIEF
A Convenient Preparation of Muconaldehyde Using
a One-Pot Acid-to-Aldehyde Reduction Protocol
Saurin R. Sutaria and Michael H. Nantz
Department of Chemistry, University of Louisville, Louisville, Kentucky, USA
ARTICLE HISTORY Received 4 February 2021; Accepted 11 May 2021
(E, E)-Muconaldehyde (1, Figure 1) (muconic dialdehyde, (2E,4E)-hexa-2,4-dienedial),
an open-ring metabolite of benzene,1 has become the subject of numerous investigations
into the toxic effects of exposure to benzene.2–4 The presumed formation of muconalde-
hyde as a result of tropospheric oxidation of benzene in photochemical smog also has
stimulated investigations on its formation in the atmosphere and resultant effects on
pollution.5–7 Finally, muconaldehyde is of interest to synthetic chemists, particularly as
a linking substrate for polyene synthesis8–10 and as a diene reactant for inverse electron-
demand Diels-Alder reactions.11 Our interest in the toxicological studies of this widely
investigated dialdehyde has led us to examine its synthesis from the corresponding
diacid, muconic acid (2).
Several syntheses of muconaldehyde have been reported (Figure 2),12–17 spanning a
wide variety of approaches from the first synthesis in 1949 by Karrer et al.12 (3 steps,
32% overall yield) to the more recent reports in 2005 by Kurteva and Afonso16 (4 steps,
27%) and in 2016 by Chen and coworkers17 (2 steps, 24%). The double Wittig-Horner
approach to the title compound by Kossmehl and Bohn13 appears most expeditious;
however, a recent application of this route reports formation of muconaldehyde in only
22% yield.18
Given that (E,E)-muconic acid is commercially available and that there are multiple
options for the reduction of carboxylic acid derivatives to aldehydes,19 such as the
mono-reduction of acid chlorides,20 derived carboxymethyleniminium salts,21 or corre-
sponding Weinreb amides,22 we postulated that the conversion of muconic acid to a
bis-activated intermediate might provide an efficient route to 1. Motivated by the
reported selective mono-reduction of acyl imidazole intermediates derived from Boc-
protected a-amino acids to aldehydes,23 we opted to prepare analogous bis-acylurea
derivatives of muconic acid for selective reduction studies. We found that when diacid
2 was reacted with N,N’-diisopropylcarbodiimide (DIC, Scheme 1), the initially-formed
bis-(O-acyl-N, N’-diisopropyl isourea) (3) underwent acyl O⟶N migration to produce
bis-acylurea 4.24,25 Subsequent slow addition of diisobutylaluminum hydride (Dibal) at
low temperature followed by quenching the putative bis(mono-reduced) aluminum che-
late [5] by addition of acetic acid afforded muconaldehyde in 71% yield after chroma-
tography. The use of N,N’-dicyclohexyl-carbodiimide or sodium bis(2-
CONTACT Michael H. Nantz
michael.nantz@louisville.edu
Department of Chemistry, University of Louisville,
Louisville, KY 40208, USA.
ß 2021 Taylor & Francis Group, LLC

2
S. R. SUTARIA AND M. H. NANTZ
Figure 1. Muconaldehyde and muconic acid.
Figure 2. Reported syntheses of muconaldehyde.
methoxyethoxy)aluminum hydride failed to deliver 1 as effectively as the one-pot DIC/
Dibal procedure. The selective mono-reduction of in-situ generated DIC adducts using
Dibal may find general utility in the synthesis of other highly reactive
a,b-unsaturated aldehydes.
Experimental section
All chemicals were purchased from VWR Chemicals BDH, Beantown Chemical, and
MilliporeSigma. The melting point was determined on a SRS MPA160 apparatus and is

ORGANIC PREPARATIONS AND PROCEDURES INTERNATIONAL
3
Scheme 1. Hydride reduction of the bis-acylurea derivative of muconic acid. DIC ¼ N,N’-
diisopropylcarbodiimide.
1
uncorrected. H and 13C NMR spectra were recorded using a Varian 400-MR spectrom-
eter using DMSO-d6 solvent as an internal reference. Thin-layer chromatography (TLC)
was performed using glass plates coated with Merck Silica Gel 60G F254. TLC spots
were examined using UV light, then visualized by a p-anisaldehyde stain. Column chro-
matography was conducted using RediSep Silica 40-60l, 60Å.
(E, E)-Muconaldehyde (1)
To a stirred suspension of trans, trans-muconic acid (2) (0.285 g, 2.01 mmol) in dry
CH2Cl2 (10 mL) at 0 ꢀC was added diisopropylcarbodiimide (0.519 g, 4.11 mmol) drop-
wise. The reaction mixture was gradually warmed to room temperature and stirred
overnight. The resulting clear brown solution was diluted by addition of CH2Cl2
(10 mL) and then cooled to ca. –80 ꢀC. Diisobutylaluminum hydride (8.14 mL of a 1 M
solution in CH2Cl2, 8.14 mmol) was added dropwise over 10 minutes via syringe. The
reaction was stirred 1 hour while maintaining the temperature near –80 ꢀC. The reaction
was quenched by slow addition of acetic acid (0.505 mL, 0.530 g, 8.83 mmol) via syringe.
The solution was diluted with Et2O (60 mL) and added to a stirred solution of saturated
potassium sodium tartrate tetrahydrate (30 mL) and water (30 mL). After vigorous stir-
ring for 30 min., the organic layer was separated and the aqueous layer was extracted
with Et2O (45 mL x 3). The combined organic extract was dried (MgSO4), filtered and
concentrated by rotary evaporation. The crude product was purified by silica gel column
chromatography, eluting with 3:7 v/v ethyl acetate:hexane, to afford the title compound
(0.157 g, 71%) as a pale yellow solid. Melting point and spectral characterization data
agree with the published values; mp. 120–121 ꢀC (lit.15 120–121 ꢀC), 1H NMR
(400 MHz, DMSO-d6): d 9.68 (2H, d, J ¼ 7.6 Hz), 7.56 (2H, m), 6.62 (2H, m) ppm; 13C
NMR (100 MHz, DMSO-d6): d 194.19, 147.82, 137.80 ppm.
1
The intermediacy of bis-acylurea 4 is supported by H and 13C NMR and IR data,
which agree closely with spectral characterization data reported for analogous unsatur-
1
ated N-acylurea derivatives;26,27 IR (neat) 3266, 1705, 1635 cmꢁ1; H NMR (400 MHz,

4
S. R. SUTARIA AND M. H. NANTZ
CDCl3): d 7.35 (2H, brs), 7.17 (2H, m), 6.42 (2H, m), 4.48 (2H, m), 4.02 (2H, m), 1.36
(12H, d, J ¼ 6.5 Hz), 1.27 (12H, d, J ¼ 6.5 Hz) ppm; 13C NMR (100 MHz, CDCl3): d
165.0, 153.4, 140.1, 129.2, 47.5, 43.5, 22.5, 20.8 ppm.
Acknowledgments
This research project was financially supported by NIH (P42 ES023716).
Funding
National Institutes of Health.
ORCID
Michael H. Nantz
http://orcid.org/0000-0003-1301-3399
References
1. L. Latriano, B. D. Goldstein and G. Witz, Proc. Natl. Acad. Sci. USA, 83, 8356 (1986). doi:10.
1073/pnas.83.21.8356
2. Y. Oshiro, P. S. Balwierz and G. Witz, Toxicol. Lett., 121, 159 (2001). doi:10.1016/S0378-
4274(01)00340-X
3. R. Snyder, Drug Metab. Rev., 36, 531 (2004). doi:10.1081/dmr-200033445
4. J. Whysner, M. V. Reddy, P. M. Ross, M. Mohan and E. A. Lax, Mutat. Res., 566, 99 (2004).
doi:10.1016/S1383-5742(03)00053-X
5. G. Ghigo and G. Tonachini, J. Am. Chem. Soc., 121, 8366 (1999). doi:10.1021/ja990552l
6. C. Liu, X. Zhang, Q. Wang and K. Shi, Environ. Pollution, 247, 447 (2019). doi:10.1016/j.env-
pol.2019.01.020
7. L. Wang, R. Wu and C. Xu, J. Phys. Chem. A, 117, 14163 (2013). doi:10.1021/jp4101762
8. D. A. Vosburg, S. Weiler and E. J. Sorensen, Chirality, 15, 156 (2003). doi:10.1002/chir.10181
€
9. G. Markl, N. Aschenbrenner, A. Baur, C. Rastorfer and P. Kreitmeier, Helv. Chim. Acta, 86,
2589 (2003). doi:10.1002/hlca.200390209
10. G. S. W. Craig, R. E. Cohen, R. R. Schrock, A. Esser and W. Schrof, Macromolecules, 28,
2512 (1995). doi:10.1021/ma00111a053
11. N. D. Epiotis and R. L. Yates, J. Org. Chem., 39, 3150 (1974). doi:10.1021/jo00935a025
12. P. Karrer, C. H. Eugster and S. Perl, Helv. Chim. Acta, 32, 1013 (1949). doi:10.1002/hlca.
19490320339
13. G. Kossmehl and B Bohn, Chem. Ber., 107, 710 (1974). doi:10.1002/cber.19741070244
14. S. G. Davies and G. H. Whitham, J. Chem. Soc. Perkin Trans. I, 1346 (1977). doi:10.1039/
P19770001346
15. B. T. Golding, G. Kennedy and W. P. Watson, Tetrahedron Lett., 29, 5991 (1988). doi:10.
1016/S0040-4039(00)82248-0
16. V. B. Kurteva and C. A. M. Afonso, J. Molec. Catal. A: Chem., 234, 159 (2005). doi:10.1016/j.
molcata.2005.02.028
17. X. Chen, Y. Zhang, H. Wan, W. Wang and S. Zhang, Chem. Commun., 52, 3532 (2016). doi:
10.1039/c5cc10093c
18. M. M. Murray, P. Kaszynski, D. A. Kaisaki, W. Chang and D. A. Dougherty, J. Am. Chem.
Soc., 116, 8152 (1994). doi:10.1021/ja00097a024
19. J. S. Cha, Org. Prep. Proc. Int., 21, 451 (1989). doi:10.1080/00304948909356413
20. J. S. Cha, and H. C. Brown, J. Org. Chem., 58, 4732 (1993). doi:10.1021/jo00069a043

ORGANIC PREPARATIONS AND PROCEDURES INTERNATIONAL
5
21. T. Fujisawa, T. Mori, S. Tsuge and T. Sato, Tetrahedron Lett., 24, 1543 (1983). doi:10.1016/
S0040-4039(00)81704-9
22. S. Nahm and S. M. Weinreb, Tetrahedron Lett., 22, 3815 (1981). doi:10.1016/S0040-
4039(01)91316-4
23. J. Ivkovic, C. Lembacher-Fadum and R. Breinbauer, Org. Biomol. Chem., 13, 10456 (2015).
doi:10.1039/c5ob01838b
24. J. Kuo, D. A. Swann and G. D. Prestwich, Bioconjugate Chem., 2, 232 (1991). doi:10.1021/
bc00010a007
25. We thank one of the reviewers for pointing out the ease of O-acylisourea to N-acylurea
rearrangement in the absence of an external nucleophile.
26. A. Ramazani, F. Z. Nasrabadi, A. Rezaei, M. Rouhani, H. Ahankar, P. A. Asiabi, S. W. Joo,
ꢀ
K. Slepokura and T. Lis, J. Chem. Sci., 127, 2269 (2015). doi:10.1007/s12039-015-0988-6
ꢀ
ꢁ
27. J. M. Anglada, T. Campos, F. Camps, J. M. Moreto and Ll. Pages, J. Heterocyclic Chem., 33,
1259 (1996). doi:10.1002/jhet.5570330444