Surprises in the Study of Ruthenium-catalyzed Stereo- and Chemoselective Aldolizations

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 Typical procedure for ruthenium-catalyzed aldol reaction
A mixture of aldehyde (1 mmol), ketone (3 mmol), RuCl₃.nH₂O(0.02 mmol) and KOH (28 mg, 0.5 mmol) was stirred at 15 °C and monitored by TLC. After the indicated reaction time, the reaction mixture was purified by thin layer chromatography (silica gel, EtOAc-petroleum ether, 4:12) providing the aldol adduct.

Selected Spectral Data of the Products
Product (3aa)
Yellow oil; FT-IR (neat) (υ_max/cm^-1): 1666, 3415. Only syn isomer was isolated. ¹H NMR (500 MHz, CDCl₃): δ_H(ppm) 1.69-2.65 (m, 7H), 2.52 (s, 3H), 3.03 (d, J = 3.2 Hz, OH), 5.39 (m, 1H), 7.28 (m, 4H). ¹³C NMR (125 MHz, CDCl₃): δ_C(ppm) 12.2, 14.0, 14.9, 41.1, 58.1, 72.2, 126.5, 128.5, 133.5, 135.2, 218.4. Anal Calcd for C₁₃H₁₆O₂S (236): C, 66.10; H, 6.77; S, 13.55. Found: C, 66.10; H, 6.79; S, 13.56.


Table 1: Ruthenium-catalyzed cross aldol reactions of aldehydes with cycloalkanones 3aa-ec.

Entrya	R	Aldol	Yield (%)b	Time (h)
1	1a 4-MeSC6H4	3aa	81	5
2	1b 3-Methylthiophen-2-yl	3ba	86	1.5
3	1c 5-Methylthiophen-2-yl	3ca	83	1
4	1d Thiophen-2-yl	3da	91	3
5	1a 4-MeSC6H4	3ab	79	4.5
6	1b 3-Methylthiophen-2-yl	3bb	76	2.5
7	1c 5-Methylthiophen-2-yl	3cb	77	3
8	1a 4-MeSC6H4	3ac	72	4.5
9	1b 3-Methylthiophen-2-yl	3bc	80	2.5
10	1c 5-Methylthiophen-2-yl	3cc	78	2.5
11 12c	1d Thiophen-2-yl 1e  4-NO2C6H4	3dc 3ec	73 55	2 5

^aAll products were characterized by ¹H NMR, ¹³C NMR and IR. ^b Yields after purification by chromatography. ^c Identified by comparison with authentic sample.³⁸





 

I t is a well understood phenomenon that the lower values of the ¹H NMR coupling constants of the carbinol protons than 1 Hz, for example 3cc, along with very weak correlation between the 1-H and 2-H (Figure 1) in the NOESY spectrum clearly indicate the relative stereochemistry of the aldol adduct in favor of the syn geometry. Also, in the IR spectrum of 3cc, the broad band of OH was observed with a maximum at 3500 cm^-1, which indicates the existence of hydrogen bonding of aldol adduct (Figure 2). In fact, the structure has been fixed in a special stereochemistry which dominated by hydrogen   bonding observed in IR spectra and the tendency to minimize the steric crowding between the 5-Methylthiophen-2-yl and cycloheptanone rings. These results illuminate that 1-C, 2-C, 1-H and 2-H has the same chemical environment, that is to say 3cc is exclusively of syn stereochemistry.


Product (3cc)
Yellow oil; FT-IR (neat) (υ_max/cm^-1): 1674, 3465. Only syn isomer was isolated. ¹H NMR (500 MHz, CDCl₃): δ_H(ppm) 2.92-1.54 (m, 11H), 2.44 (s, 3H), 3.37 (d, J = 3.9 Hz, OH), 5.25 (s, 1H), 6.60 (d, J = 2.4 Hz, 1H), 6.72 (d, J = 3.2 Hz, 1H). ¹³C NMR (125 MHz, CDCl₃): δ_C(ppm) 15.2, 23.6, 25.3, 28.4, 28.6, 44.0, 57.8, 71.5, 124.5, 124.6, 138.6, 143.3, 217.2. Anal Calcd for C₁₃H₁₈O₂S (238): C, 65.54; H, 7.56; S, 13.44. Found: C, 65.53; H, 7.56; S, 13.44.

Keshavarz E, Tabatabaeian K, Mamaghani M, Mahmoodi N. O. Surprises in the Study of Ruthenium-catalyzed Stereo- and Chemoselective Aldolizations. Orient J Chem 2015;31(4).

Volume 31, Number 4

Elahe Keshavarz,^1,* Khalil Tabatabaeian², Manouchehr Mamaghani² and Nosrat O. Mahmoodi²

¹Department of Sciences, Farhangian University, P.O. Box 1998963341, Rasht, Iran.

²Department of Chemistry, Faculty of Sciences, Guilan University, P.O. Box 41335-1914, Rasht, Iran.

Corresponding Author E-Mail: keshavarz@guilan.ac.ir

ABSTRACT: A convenient and diastereoselective method was developed for the synthesis of aldol derivatives in the presence of a catalytic amount of RuCl₃.nH₂O under solvent-free conditions. Aldol adducts were obtained in good yields and with high chemoselectivity  in short reaction times. In this protocol, aromatic and heteroaromatic aldehydes readily participate as electrophilic cross-aldol partners with a range of cycloalkanones as ketone donors.
KEYWORDS: catalytic aldol reaction; diastereoselective aldolization; green synthesis

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