Tetrahedron Letters 56 (2015) 2704–2706

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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet

RuO4 catalyzed dihydroxylation for the synthesis of mixed

medium-chain triacylglycerols
K. Nandini, P. Srinivas, B. K. Bettadaiah ⇑
Department of Spice and Flavour Science, CSIR-Central Food Technological Research Institute, Mysuru 570 020, India

a r t i c l e i n f o a b s t r a c t

Article history: RuO4 catalyzed dihydroxylation of allyl acylates (C5 to C12) to glyceryl acylates is reported. The dihydrox-
Received 19 February 2015 ylation was a major product (61–85%) with C5–C7 whereas carbonyl compounds by double bond fission
Revised 30 March 2015 were major with C8–C12 systems. 1-Hexanoylglycerol, obtained in high yields (85%), was further acylated
Accepted 2 April 2015
with medium chain fatty acid chlorides to prepare mixed medium chain triglycerides (85–90%). Hence, a
Available online 7 April 2015
facile preparation of triacylglycerols such as C6–C6–C6, C6–C8–C8, C6–C10–C10, and C6–C12–C12 is
accomplished.
Keywords:
Ó 2015 Elsevier Ltd. All rights reserved.
RuCl3
NaIO4
Dihydroxylation
Medium-chain triacylglycerols
Allyl hexanoate

The triacylglycerols of saturated fatty acids having 6–10 car-
bons such as hexanoic acid, octanoic acid, decanoic acid and some-
times dodecanoic acid are called medium-chain triacylglycerols
(MCT). They are of prime requirement in the parenteral nutrition
used for a person requiring supplemental nutrition and are also
commonly used in foods, drugs, and cosmetics.1 MCT are also used
as emulsifiers in various human and veterinary pharmaceutical
preparations. They form an alternate non-carbohydrate food
source, as they provide high energy and are rapidly digestible.2
They are obtained by esterification of medium chain fatty acids
resulting from hydrolysis of coconut or palm kernel oil.3 These
are a mixture of medium chain triacylglycerols with no selectivity
of particular fatty acid and its positioning on the glycerol back-
bone. RuCl3 catalyzed double bond dihydroxylations are milder
and promising reaction conditions for a wide range of activated
substrates.4,5 There are few reports on the catalytic dihydrox-
ylation of terminal olefins by ruthenium compared to olefins,
which are part of cyclic system.5–9 Ruthenium nanoparticles sup-
ported on hydroxypatite provide efficient dihydroxylation of term-
inal olefins.10 We report here ruthenium catalyzed efficient
dihydroxylation of allyl hexanoate to 1-hexanoylglycerol and fur-
ther its application in the synthesis of MCT.
In a typical reaction, allyl hexanoate (2) with NaIO4 in the pres-
ence of RuCl3 in ethyl acetate/acetonitrile/water (3:3:1) resulted in
the formation of 1-hexanoyl glycerol and only small amount of
⇑ Corresponding author. Tel.: +91 821 2512352; fax: +91 821 2517233.
E-mail address: bettadaiah@cftri.res.in (B.K. Bettadaiah).
over-oxidized aldehyde product was obtained (Scheme 1). This
result of dihydroxylation of terminal double bond interested us
to explore the reaction in detail.
The reaction conditions were similar to the earlier Letter but
devoid the use of H2SO4, which was found not necessary in our sys-
tem.11 Under this condition the dihydroxylated 1-hexanoylglycerol
product was obtained in a high yield (85–90%).
The reaction of allyl hexanoate with NaIO4 and RuCl3 with the
solvent system ethyl acetate/acetonitrile/water (3:3:1) in ten min-
utes resulted in the formation of dihydroxylated product (30%)
along with un-reacted starting material. The reaction progressed
without any over-oxidized aldehyde product for up to 75 min. At
this stage, the reaction mixture had diol and very small amount
of unreacted allyl hexanoate (10–15%) was obtained.
Continuation of reaction further led to the formation of aldehyde
product in >10%. The reaction was completed in 2 h at less than
0 °C. Isolation of the product after complete conversion of the start-
ing compound afforded small amount of aldehyde (10–15%) and
major amount of 1-hexanoylglycerol (85–90%). The reaction
afforded same amount of 1-hexanoylglycerol both after 75 min
and 2 h. The variations in solvent system did not help in any better
conversion of allyl hexanoate to dihydroxylated product. The best
condition to afford the highest yield of 1-hexanoylglycerol with
one equivalent allyl hexanoate was found to be NaIO4 (1.5 equiv),
RuCl3 (0.1 mol %) in acetate/acetonitrile/water (3:3:1) at <0 °C for
75 min. Reaction was repeated on one gram scale thrice and yield
of 1-hexanoylglycerol was in the range of 85–90%.

http://dx.doi.org/10.1016/j.tetlet.2015.04.008
0040-4039/Ó 2015 Elsevier Ltd. All rights reserved.
 K. Nandini et al. / Tetrahedron Letters 56 (2015) 2704–2706 2705

compounds in better yields compared to the same with its higher

O O O
NaIO4 homologues (Table 1). It has been found that it was marginally
O
O O OH + O lower than allyl hexanoate.
RuCl 3 0oC
OH H Overall, the dihydroxylation of terminal olefins with RuO4 is
feasible for C5 to C7 whereas fission products are major with C8
Scheme 1. RuO4 catalyzed dihydroxylation of allyl hexanoate. to C12 systems. All the reactions were completed in about an hour.
RuO4 catalyzed dihydroxylation of allyl hexanoate in comparison
with its higher homologues is mechanistically not clear. We have
Table 1
proceeded further for the preparation of MCT using 1-hexanoyl-
RuO4 catalyzed dihydroxylation of allyl acylates
glycerol and acyl chlorides (Scheme 2). Though the dihydroxy com-
Allyl acylates % dihydroxy % aldehyde Time pounds like 1-pentanoylglycerol and 1-heptanoylglycerol were
Allyl valerate 61 20 65 obtained in very good yields, the MCT preparation using these
Allyl hexanoate 85 15 75 has been excluded in the present study as they are less-common.
Allyl heptanoate 75 10 60
Reaction of 1-hexanoylglycerol with fatty acid chlorides such as
Allyl octanoate 34 50 45
Allyl decanoate 40 40 60 hexanoyl, octanoyl, decanoyl and dodecanoyl chlorides in the pres-
Allyl dodecanoate 38 45 60 ence of DMAP in DCM afforded the desired mixed medium chain
glycerides (Table 2).13 The MCT like glycerol trihexanoate (2b) is
obtained in high yields by different protocols.14 These reactions
1-Hexanoylglycerol was purified by column chromatography are either performed using solvent like benzene14a or at high
and characterized by NMR and HRMS studies.12 temperature for long time.14b,c The preparation of mixed glycerol
We intended to expand the scope of ruthenium catalyzed triesters like C6–C8–C8, C6–C10–C10 and C6–C12–C12 has not been
dihydroxylation to range of allyl acylates such as allyl valerate tested under these conditions. We proceeded in preparing mixed
(1, Scheme 2), allyl heptanoate (3), allyl octanoate (4), allyl decan- medium chain glycerides such as 2c, 2d, and 2e using 1-
oate (5) and allyl dodecanoate (6). The reaction of allyl acylates hexanoylglycerol, a diol obtained by ruthenium catalyzed
such as allyl valerate and allyl heptanote afforded the dihydroxy dihydroxylation. The yields of MCT were in the range of 85–90%

NaIO4 (1.5eq), O R'

RuCl3 (0.1Mol %) O
O
EtOAc/CH 3CN/H2 O R1 COCl (2.2 eq)
(3/3/1) DMAP(3 eq)
O R HO O R O O O O
00 C, OH DCM, RT
85-90%
35-85% R' R
R = C 4H 9 (1), C 5H 11 (2), R = C 4H9 (1a), C5H 11 (2a)
C 6H13 (3), C 7H15 (4) C6H 13 (3a), C 7H15 (4a), 2b= R = C 5 H 11, R'= C5 H 11
C 9H19 (5), C11H 23 (6) C9H 19 (5a), C 11H 23 (6a) 2c= R = C5 H 11, R'= C 7 H15,
2d= R = C 5 H 11, R'= C9 H 19
2e= R = C5 H 11, R'= C 11H 23

Scheme 2. Synthesis of MCT.

Table 2
Synthesis of MCT from 1-hexanoyl glycerol and acyl chlorides

Acyl chloride MCT Time (h) Yielda (%)

O
O
Hexanoyl chloride O O O 5 90
O

O
O
O O O
Octanoyl chloride 8 85
O

O
O
O O O
Decanoyl chloride 8 85
O

O
O
O O O

Dodecanoyl chloride O 10 90

a
Isolated yield.
2706 K. Nandini et al. / Tetrahedron Letters 56 (2015) 2704–2706
and reactions were completed in reasonable time (5–10 h).
Products were isolated in pure form by column chromatography
over silica gel (100–200) using petroleum ether as eluent. Pure
products were characterized by NMR and HRMS spectral studies.
In conclusion, we report here a facile preparation of MCT using
1-hexanoylglycerol and acyl chlorides. An expedient synthesis of
1-hexanoylglycerol by dihydroxylation procedure is developed.
Allyl hexanoate, a flavor impact compound of pineapple is an
inexpensive and easily available, was explored for the synthesis
of MCT. RuO4 catalyzed dihydroxylation of allyl hexanoate in high
yield is identified and successfully applied for the synthesis of MCT,
which are useful in foods, drugs, and cosmetics. The feasibility of
dihydroxylation over fission products for the range of allyl acylates
(C5–C12) has been tested.
Acknowledgments
K.N. is grateful to the Department of Science and Technology,
New Delhi, India for the award of SRF-DST (INSPIRE) Fellowship.
The authors thank Prof. Ram Rajasekharan, Director, CSIR-CFTRI,
Mysuru, for his support and constant encouragement for the work.
Financial support to carry out this work from BSC-0202 project is
gratefully acknowledged. We thank Mr. J. R. Manjunatha,
Technical Officer, CSIR-CFTRI for NMR analysis.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2015.04.
008.
References and notes
1. Traul, K. A.; Driedger, A.; Ingle, D. L.; Nakhasi, D. Food Chem. Toxicol. 2000, 38,
79.
2. Babayan, V. Lipids 1987, 22, 417.
3. Bach, A. C.; Babayan, V. K. Am. J. Clin. Nutr. 1982, 36, 950.
4. Pagliaro, M.; Campestrini, S.; Ciriminna, R. Chem. Soc. Rev. 2005, 34, 837.
5. Shing, T. K. M.; Tam, E. K. W.; Tai, V. W. F.; Chung, I. H. F.; Jiang, Q. Chem. Eur. J.
1996, 2, 50.
6. Shing, T. K. M.; Tai, V. W. F.; Tam, E. K. W. Angew. Chem., Int. Ed. 1994, 33, 2312.
7. Plietker, B.; Niggemann, M. J. Org. Chem. 2005, 70, 2402.
8. Gore, E. S. Platinum Metals Rev. 1983, 27, 111.
9. Bataille, C. J.; Donohoe, T. J. Chem. Soc. Rev. 2011, 40, 114.
10. Ho, C. M.; Yu, W.-Y.; Che, C.-M. Angew. Chem., Int. Ed. 2004, 43, 3303.
11. Plietker, B.; Niggemann, M. Org. Lett. 2003, 5, 3353.
12. 1-Hexanoyl glycerol (2a): yield: 1.05 g (85%, 5.53 mmol, colorless oil); 1H NMR
(500 MHz, CDCl3) d: 0.84–0.87 (m, 3H), 1.22–1.32 (m, 4H), 1.55–1.61 (m, 2H),
2.28–2.32 (m, 2H), 3.51–3.55 (m, 1H), 3.62–3.65 (m, 1H), 3.86–3.89 (m, 1H),
4.02 (Bs, 2H), 4.07–4.09 ppm (m, 2H); 13C NMR (125 MHz, CDCl3) d: 13.47,
21.93, 27.17, 30.90, 33.73, 63.05, 64.14, 69.82, 174.05 ppm; IR (neat) 1176 (s),
1727 (s), 2940 (s), 2958 (s), 3409 (broad, s) cm 1; HRMS (ESI) m/z: [M+H]+
Calculated for C9H18O4, 191.1283, found 191.1249.
13. General procedure to prepare MCT: 1-hexanoyl glycerol (500 mg, 2.6 mmol) was
dissolved in 15 ml of anhydrous DCM and DMAP (1.2 equiv) was added
followed by acid chloride (2.2 equiv). The mixture was magnetically stirred
under nitrogen atmosphere. Progress of reaction was monitored by TLC for the
disappearance of 1-hexanoyl glycerol. After completion of reaction, the
mixture was partitioned between water (20 ml) and DCM. Subsequent
extraction with DCM (15 ml  2) followed by drying the combined organic
layer over Na2SO4 and concentration afforded crude product. It was purified by
column chromatography over silica gel (200–400) using petroleum ether (60–
80 °C) as eluent. MCT’s 2a, 2b, 2c and 2d were confirmed by NMR and HRMS
spectral data.
14. (a) Prager, R. H.; Zhang, Y. Aus. J. Chem. 1989, 42, 1003; (b) Zhan, S.; Tao, X.; Cai,
L.; Liu, X.; Liu, T. Green Chem. 2014, 16, 4649; (c) Boulos, Z.; Duceppe, J. S.;
Penney, C. Patent WO2013126990 A1, 2013.