Selective oxidation of alcohol-d1 to aldehyde-d1 using MnO2

The selective oxidation of alcohol-d1 to prepare aldehyde-d1 was newly developed by means of NaBD4 reduction/activated MnO2 oxidation. Various aldehyde-d1 derivatives including aromatic and unsaturated aldehyde-d1 can be prepared with a high deuterium incorporation ratio (up to 98% D). Halogens (chloride, bromide, and iodide), alkene, alkyne, ester, nitro, and cyano groups in the substrates are tolerated under the mild conditions.


Introduction
Deuterium ( 2 H, d) is a stable, non-radioactive, and safe isotope of hydrogen ( 1 H). Since its discovery, 1 d has been widely utilized in organic chemistry, biochemistry, analytical chemistry, pharmaceutical science, and drug discovery. 2,3 Because of the high demand for d-labelled molecules in the scientic research elds, many efforts have been devoted to developing a new method for the synthesis of d-labelled molecules.
Aldehyde-d 1 2 has received signicant attention as a synthetic target due to the facts that aldehyde 1 is a useful feedstock in organic synthesis. Various methods have been performed in the synthesis of alkyl and aryl aldehyde-d 1 . For example, more than 40 syntheses (25 different reaction conditions) of benzaldehyde-d 1 (PhCDO) were conducted even since 2018 in the studies to develop new d-incorporation method or reaction mechanism using PhCDO. [4][5][6][7][8] The previous synthetic approaches to access d-labelled molecules are classied into 5 types; (A) addition of D À followed by oxidation, (B) carbonyl Umpolung approach, (C) radical reaction, (D) transition metal-catalysed reaction, and (E) others. Recently, mild, one-step, and catalytic syntheses of aldehyde-d 1 2 have been achieved by deuteration of the Breslow intermediates, 9 deuteration of acyl radicals, 6,10 and transition metal-catalysed deuterium incorporation. 11 However, the previous synthetic methods including the modern direct syntheses oen suffered from drawbacks such as overdeuteration, requirements of harsh conditions (high and low temperature, and strong base and acids), and the use of expensive catalysts. Moreover, the synthetic examples of substituted acrolein and propynal-d 1 are much less than those of alkyl and aryl aldehyde-d 1,12,13 though recently developed NHC-catalysed H-D exchange reactions allowed access to various substituted acrolein-d 1 derivatives. 9 In this context, development of a new d-incorporation method which allows exible synthesis of aromatic and unsaturated aldehyde-d 1 2 remains to be a challenging synthetic task (Scheme 1).
Method A using D À as a deuterium source has been recognized as a robust and conventional synthetic method to prepare aldehyde-d 1 2 (Scheme 2). The synthesis is typically performed in two steps; (i) reduction of carboxylic acid derivatives using LiAlD 4 to provide alcohol-d 2 3 and (ii) oxidation to aldehyde-d 1 2 (eqn (1)). 14 In this approach, the deuterium incorporation ratio (%D) of the commercially available D À sources such as LiAlD 4 (>98 atom) is reliably transferred into the product. On the other hand, the use of highly reactive LiAlD 4 oen limits the synthetic scope. Under the conditions, various functional groups such as nitro, nitrile, ester, and acid moieties, and alkene and alkyne with electron-withdrawing group(s) are not tolerated. To overcome the limitation, we emerged selective oxidation of alcohold 1 derivatives 4 (Scheme 2(eqn (2))). It is expected that various alcohol-d 1 4 can be prepared by the mild NaBD 4 reduction. The next selective oxidation of D (H/D selectivity) is the key to this approach. Recently, oxidation of benzyl alcohol-d 1 (PhCDHOH) with PCC or PDC was conducted to prepare PhCDO with $85% D. 4a,4e,4q On the other hand, further efforts to improve the selectivity (%D) in the selective oxidation have not been wellexamined. Herein, we would like to report that NaBD 4 reduction followed by activated MnO 2 oxidation (NaBD 4 /MnO 2 system). The simple and mild protocol allows expansion of the synthetic range of aldehyde-d 1 2 including not only aromatic aldehyde-d 1 derivatives but also substituted acrolein-d 1 and propynal-d 1 derivatives with high %D (up to 98%).

Results and discussion
In a similar manner to the previous synthetic examples of NaBH 4 reduction of aldehyde 1, the reduction with NaBD 4 gave the corresponding alcohol-d 1 derivatives 4 with excellent functional group compatibility and yields (Scheme 3). Chloride, bromide, iodide, methoxy, ethoxy, or methylene acetal, nitrile, ester, nitro, and alkyne groups on the aromatic ring of 4c-4q were tolerated under the conditions. Substituted acrolein and propynal 1r-1aa also underwent smooth NaBD 4 reduction to provide 4r-4aa without loss of the alkyne and alkene moieties, and tetrahydropyanyl (THP), benzoyl (Bz), and tert-butyldimethylsilyl (TBS) protecting groups.
Activated MnO 2 oxidation was successfully expanded to the synthesis of various aldehyde-d 1 2a-2aa with high %D (85-96% D) (Scheme 4A-C). Chloride, bromide, iodide, methoxy, ethoxy, or methylene acetal, nitrile, ester, nitro, and alkyne groups on the aromatic ring of 4c-4q are preserved under the mild oxidation conditions (Scheme 4A). Substituted acrolein 4r-4v and propynal 4w-4aa smoothly underwent MnO 2 oxidation to provide 2r-2aa without loss of the alkene and alkyne moieties (Scheme 4B and C). The synthetic utility was further demonstrated by the synthesis of 2v with a bromo group at the aposition of cinnamaldehyde. In addition, Bz, THP, and TBS protecting groups of 4y, 4z, and 4aa were also maintained under the conditions. These propargyl alcohols 4y, 4z, and 4aa were smoothly converted to the corresponding propynal derivatives 2y, 2z, and 2aa with high %D, respectively.
In conjunction with our recent efforts toward elucidation of biosynthetic reaction mechanisms of terpene synthases using dlabelled prenols, 15,16 we needed geranylgeraniol-d 2 (6) as an enzyme substrate. Previously, the synthesis of 6 (ref. 17) and other acyclic prenol-d 2 derivatives 18 was performed in four steps from 5 via reduction of ester 7 with LiAlD 4 . However, commercially available LiAlD 4 is almost out of stock in recently years. In addition, low temperature conditions (À20 C) is required for the LiAlD 4 reduction to avoid the undesired 1,4-reduction. We expected that NaBD 4 /MnO 2 system would be an alternative to the LiAlD 4 procedure to prepare 6, conveniently. According to the literature, 19 geranylgeraniol (5) was converted to aldehyde 8 by MnO 2 oxidation (Scheme 5). Aldehyde 8 was subjected to NaBD 4 /MnO 2 to deliver d-enriched aldehyde 9 which was subsequently reduced by NaBD 4 to provide geranylgeraniol-d 2 (6) in 70% yield over four steps with satisfactory deuterium incorporation ratio (94% D). Under the conditions, the undesired 1,4-addition reaction was not observed. Thus, an DMSO (10 eq.), SO 3 -pyridine (4 eq.), iPr 2 NEt (5 eq.), 1. operationally simple and mild deuteration of prenols-d 2 was achieved by application of NaBD 4 /MnO 2 system. Previously, Brecker et al. investigated 13 C kinetic isotope effects (KIEs) in the oxidation of cinnamyl alcohol using MnO 2 , Dess-Martin periodinane, and Swern oxidation (DMSO/(COCl) 2 / Et 3 N) to gain insight into the reaction mechanism. 20 Comparison of the kinetic isotope of effects revealed the following order MnO 2 > Dess-Martin oxidation z Swern oxidation. The higher 13 C KIE using MnO 2 displayed that the C-H bond breaking in the intermediate is irreversible and rate-determining, and the oxidation proceeded via energy rich transition state. On the other hand, the lower 13 C KIEs observed in Swern oxidation and Dess-Martin oxidation indicated that the intramolecular C-H bond cleavage in these oxidation reaction processes would not be slower to be rate-limiting.
Experimental results in Table 1 clearly shows that the degrees of %D are as follows MnO 2 > PDC > TEMPO z Dess-Martin > SO 3 -pyridine/DMSO. It is speculated that higher %D of MnO 2 oxidation and lower %D of SO 3 -pyridine/DMSO oxidation would correlate to the 13 C KIE data (MnO 2 > Swern oxidation). It is interesting to note that the %D value in Scheme 4 depended on the substrates. The oxidation of propargyl alcohols 4w-4aa resulted in higher %D than those of the other alcohols. The oxidation of 4w-4aa needed a longer reaction period to complete the reactions. As mentioned in the previous 13 C KIE studies, the rate limiting steps of the MnO 2 oxidation relies on the C-H cleavage step of the reaction intermediate. It is considered that the slower C-H cleavage would provide the higher %D.

Conclusions
We have established a facile synthesis of aldehyde-d 1 derivatives by NaBD 4 /MnO 2 system. The new method is characterized by a high degree of functional group compatibility and a wide range of substrate scope including the synthesis of d-containing unsaturated aldehydes. Aromatic aldehyde-d 1 derivatives such as 2c and 2g would be a useful synthetic intermediate for ole-nation, amination, hydride reduction, Suzuki cross coupling, and Sonogashira coupling reactions. 9e,10c Substituted acroleins and propynals can be used for Michael addition reaction, cycloaddition reaction, and transition metal catalysed transformations. In this context, NaBD 4 /MnO 2 system would offer vital opportunity to the synthesis of highly functionalized dlabelled molecules via facile preparation of aromatic and unsaturated aldehyde-d 1 2. Deuterium-labelled compounds are oen needed for the investigation of the mechanisms or determination of the rate-limiting step. The present synthetic method supports the studies from the viewpoint of the facile preparation of aldehyde-d 1 2 and its derivatives. Further application and mechanism studies are ongoing in our laboratory.

Conflicts of interest
There are no conicts to declare.