A simple and inexpensive procedure for low valent copper mediated benzylation of aldehydes in wet medium

An operationally simple, inexpensive and efficient procedure for benzylation of aldehydes in wet medium has been developed that was mediated with low valent copper, prepared in situ through spontaneous reduction of CuCl 2 -2H 2 O with magnesium in situ . Notably, copper mediated benzylation of 3h took place with good syn selectivity that was opposite to that for the corresponding Grignard addition. Finally, homobenzyl alcohol 5a was elegantly transformed into a known protease inhibitor synthon I .


Introduction
Carbon-carbon bond formation is the essence of organic synthesis.In this regard, metal mediated carbon-carbon bond forming reactions is always treated as a useful strategy in organic synthesis.Consequently, over the ages exploration of the potentials of various metals to promote various types of Barbier type addition of organic halides to electrophiles has become a topic of wide attention. 1It is well known that to mediate any C-C bond forming reaction, obtaining a metal in suitably active form under the reaction condition is of high importance.Furthermore, apart from its nature, the method of its activation plays a good role in directing the stereo-selectivity in the case of asymmetric additions.In this perspective, there is a scope for studying the potential of different metals in their various active forms to promote Barbier type additions to carbonyls.
Benzylation of aldehydes is an important type of Barbier type carbon-carbon bond forming reactions in organic synthesis.The homobenzylic alcohols produced from such reactions due to their functional richness are amenable for versatile applications in organic synthesis. 2A very common procedure traditionally practiced to prepare homobenzylic alcohols is via Grignard addition of benzylic bromides to carbonyls which can only be performed in anhydrous reaction media.In addition, some other strategies were reported in earlier days to prepare homobenzylic alcohols involving hydroboration of 1-aryl-alkenes, 3 solvolyses of sulfonates obtained from aromatic bridged hydrocarbons 4 and regio-selective hydrogenation of aromatic epoxides in recent years 5 etc.Recently, in view of current attention on performing many organic reactions in environmentally friendly aqueous media, 6 considerable attention has been focused on performing Barbier type additions of benzyl bromide to aldehydes mediated with metals viz Cd obtained from tri-metal system, 7a Zn in presence of Ag catalyst, 7b etc.In a recently reported approach, silver catalysed Mn mediated Barbier type benzylation can be performed in highly anhydrous THF. 8 We present here a very simple and practically viable procedure for benzylation of aldehydes in wet solvent.Our strategy was based on judicious application of bimetal redox strategy (Scheme 1) 9 to effect this reaction in wet condition. 9Earlier, this approach was applied to perform two C-C bond forming reactions successfully viz allylation 9a,b and Reformatsky reaction 9c in distilled THF.Interestingly, to carry out the afore-mentioned allylation and Reformatsky reaction through application of bimetal redox strategy, the low valent metal mediators needed to be prepared in situ by reduction of their salts with different reducing metals viz Zn 9a,b and Mg 9c respectively.From these two instances, it could be suggested that the choice of a suitable combination of reducing metal and reducible salt is of high importance regarding the efficacy of a C-C bond forming reaction in moist condition according to this bimetal redox strategy (Scheme 1).However, all the above mentioned C-C bond forming reactions 9a-c could be performed efficiently in distilled THF whose inherent moisture content 10 distinctly favored such organometallation (as shown in Scheme 1).We once again attempted to explore the scope of this strategy for benzylation of aldehydes in distilled THF.Based on our earlier success, 9a-c we decided to investigate on the efficacy of the present reaction using all four possible combinations between two reducible salts (M1X), viz FeCl3 (97%, Aldrich) and CuCl2-2H2O (Aldrich) and two reducing metals (M2) viz Zn dust (SRL India) and magnesium turning (SRL India).Three classes of aldehyde substrates were chosen, viz aliphatic (3a-c, Aldrich), aromatic (3d-g, Aldrich) and a chiral 3h 11 with a view to exploring the generality of this strategy.(Scheme 1) In all these heterogeneous reactions, an aldehyde was treated with excess amounts of reagents viz benzyl bromide (Aldrich), salt M1X and reducing metal M2 to ensure their smooth progress.The ratio was determined from 13 C NMR of the product (reference 13)

Results and Discussion
Using zinc as reducing metal in combination with either of the metal salts (Zn/ CuCl2-2H2O or Zn/FeCl3), was found to be ineffective for reactions with all the aldehydes 3a-h.Likewise, using the combination of Mg/ FeCl3 also did not give any encouraging sign of progress with any of these aldehydes.However, to our great delight the combination of Mg / CuCl2, 2H2O was found to be highly favorable for benzylation of all the aldehydes producing corresponding homobenzylic alcohols in good yields.(Table 1 and Scheme 1, 4a-g from 3a-g, 5 from 3h).Among the successful reactions, aromatic aldehydes reacted more efficiently at comparatively faster rates (entries d-g, Table 1) with respect to aliphatic ones.Benzylation with 3h (entry h, Table 1) took place to produce homobenzylic alcohol 5 in reasonably good yield (68.4%) and syn selectivity (syn-5a : anti-5b 80 : 20).Owing to the inseparability of the diastereomers 5a/5b by column chromatography, their ratio could be assayed from 13 C NMR spectrum 13 of this mixture.
The predominant formation of syn-5a for (entries s, Table 1) gave evidence of the fact that all the reactions took place via the addition of the corresponding organocopper reagents 2 (Scheme 1) through α-chelate cyclic model. 14It is worth mentioning that the corresponding benzyl-Grignard addition to 5a took place with lower yield (43.8 %) compared to the organo-copper addition done above and with anti selectivity (syn-5a : anti-5b : 35 : 65, vide 13 -C NMR supporting information) 13 .The proportion of syn-5a in this distereoisomeric mixture has been increased (Scheme 2) following a known oxidation-reduction protocol. 15Thus, PCC oxidation of the diastereoismeric mixture 5a,b to afford ketone 6 which on reduction with K-selectride yielded syn-5a with 99% stereo-selectivity. 13Tosylation of 5a, followed by deketalization of the resulting tosylate 7 in acidic condition afforded crude diol 8 which on treatment with NaN3 afforded 9 16b,d,e, 17 in good yield.Monotosylation of the primary hydroxyl of 9 and base treatment of the resulting tosylate 10 yielded azido epoxide I, a key synthon 16 of a HIV protease inhibitor.(Scheme 2) Our synthesized compound I were characterized from the conformity of its physical, spectral and optical data with the reported ones. 16hus, a very mild and efficient procedure for benzylation of aldehydes has been developed.The novelty of the approach was due to smooth exploitation of the spontaneous bimetal redox reaction in an environmentally benign wet condition between commercially available chemicals, Mg and CuCl2, 6H2O in THF to effect this important carbon-carbon bond formation.The inexpensiveness, practical viability and good yields with varied types of aldehyde substrates (3ah, Table 1) associated with this non hazardous procedure are of immense significance regarding its overall efficacy.Finally, as a representative application of the this work, benzylation product of 3h has been judiciously exploited in a simple and straight forward manner (Scheme 2) to prepare a key synthon I 16 of a protease inhibitor.

Experimental Section
General.Chemicals used as starting materials are commercially available and were used without further purification.All solvents used for chromatography and extraction were distilled twice at atmospheric pressure prior to use.Moist THF was distilled once prior to use in all bimetal redox reactions.For anhydrous reactions, THF was dried by heating over LiAlH4.IR spectra were recorded with a Perkin-Elmer 837 spectrophotometer. 1 H and 13 C NMR spectra were scanned with a Bruker Ac-200 (200 MHz) instrument in CDCl3.Chemical shifts are expressed in ppm downfield from TMS Optical rotations were measured with a JASCO DIP-360 polarimeter; []D values are given in units of 10 -1 deg cm -3 g -1 .

a
The compounds were characterized from their spectral data (reference 7b) b the compound was characterized from its spectral data (reference 12) c