Introducing efficient palladium catalyzed cross coupling reaction of tertiary alcohols and aroyl chlorides for the synthesis of highly substituted esters

Article abstract of DOI:10.1016/j.tetlet.2019.07.027

Esters are chemical compounds with many practical uses. The common type of esterification is called the Fischer esterification. Another one is by the action of acid chlorides on alcohols but not with tertiary alcohols. The stable carbenium ions formed fro

Full text of DOI:10.1016/j.tetlet.2019.07.027

Accepted Manuscript
Introducing efficient palladium catalyzed cross coupling reaction of tertiary al-
cohols and aroyl chlorides for the synthesis of highly substituted esters
Mohammad Al-Masum, Arpona Hira, Sara Chrisman, Ngan T. Nguyen
PII:
S0040-4039(19)30685-9
https://doi.org/10.1016/j.tetlet.2019.07.027
TETL 50936
DOI:
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
7 May 2019
10 July 2019
12 July 2019
Please cite this article as: Al-Masum, M., Hira, A., Chrisman, S., Nguyen, N.T., Introducing efficient palladium
catalyzed cross coupling reaction of tertiary alcohols and aroyl chlorides for the synthesis of highly substituted
esters, Tetrahedron Letters (2019), doi: https://doi.org/10.1016/j.tetlet.2019.07.027
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Introducing efficient palladium catalyzed cross coupling reaction of tertiary
alcohols and aroyl chlorides for the synthesis of highly substituted esters
Mohammad Al-Masum*, Arpona Hira, Sara Chrisman, Ngan T. Nguyen
Department of Chemistry, Tennessee State University, 3500 John A Merritt Blvd. Nashville, TN
37209
malmasum@tnstate.edu
Abstract: Esters are chemical compounds with many practical uses. The common type of
esterification is called the Fischer esterification. Another one is by the action of acid chlorides on
alcohols but not with tertiary alcohols. The stable carbenium ions formed from tertiary alcohols
favor elimination and the byproduct, hydrogen chloride prevents ester formation. In this new
report, palladium inserted ArCOPdCl species reacts with tertiary alcohols and cross-coupling
under microwave heating, minimizes the formation of probable carbenium ion, and promotes
successful production of highly substituted esters in good to high yields.
Keywords Tertiary alcohols, ArCOPdCl, Solvent free, Microwave
Over the years there have been many studies done on the formation of esters. Many of these
studies have shown how readily primary alcohols react to form such esters. However, few
reactions have effectively used secondary or tertiary alcohols. The purpose of this research
project was to find a more efficient and economical way to synthesize esters that are more
complex by using the secondary and tertiary alcohols. Esters have many applications in
industries such as medicine.1,2 Esters are not only a source for the flavor of fruits but also for the
smell of everyday products. Industries where esters have an application are in agriculture
chemistry,3,4,5 polymer chemistry,6 petro chemistry.7 There are many applications of esters in the

2
real world and there are also many ways to make esters. One commonly used synthetic process
for ester synthesis is Fischer esterification.8 Transition metal catalysis and cross-coupling
reactions is believed to be one of the most important advancement in the field of organic
chemistry.9 In our report, we focus on palladium inserted ArCOPdCl10 species and making
functional groups labile aromatic ester via treatment with tertiary alcohols (Scheme 1).
New result
0.5 mole % PdCl2(dtbpf)
R'
O
R'
R2
O
Ar
OH
R3
R2
+
R3
60 - 80 %
O
NaOtBu
Ar
Cl
Neat, 100 0C, 1 h
Scheme 1. Cross-coupling of tertiary alcohols and aroyl chlorides
This not only makes a more efficient way of synthesizing highly substituted aromatic esters, but
also cuts down on the production of unwanted or unsafe by-products. We also have observed
that this kind of reaction succeeds under microwave heating without any catalyst or base for
primary alcohols and in some cases for secondary alcohols as well. The complication lies with
tertiary alcohols (Table 1). Cross coupling reactions of tertiary alcohols and aroyl chlorides are
largely unknown.11,12 Use of an ArCOPdCl species, a new source of ArCO moiety, to react with
tertiary alcohols and form bulky esters has yielded interesting findings. Reactions of tertiary
alcohols successfully ran with aroyl chlorides containing several varieties of functional groups.
These substituents classify as either electron-withdrawing group (EWG) or electron-donating
group (EDG) depending on their effectiveness at attracting or giving away an electron. Among
several other available palladium complexes, a minimum load of PdCl2(dtbpf) proved to offer an
effective catalytic effect for esterification. PdCl2(dtbpf) complex has been successfully employed
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3
as a catalyst in various organic transformations.13 The higher cone angle of P-Pd-P in
PdCl2(dtbpf) improves its effectiveness as a catalyst.14 To extend further application of this Pd-
complex in esterification, we scanned it along with many bases and found best results with
NaOtBu.
Table 1. Solvent free ester synthesis from aroyl chlorides and tertiary alcohols
O
O
+
R OH
R
mw
Ar
Cl
Ar
O
PdCl2(dtbpf)
No catalyst
No catalyst
No catalyst
NaOtBu
No base
No base
No base
No base
NaOtBu
Temp
Time
Ester
100 %
Alcohols
100 °C
100 °C
100 °C
100 °C
100 °C
100 °C
100 °C
30 min
30 min
30 min
30 min
30 min
OH
62 %
OH
OH
OH
OH
OH
OH
No product
No product
No product
PdCl2(dtbpf)
No catalyst
PdCl2(dtbpf)
NaOtBu
30 min
ester formed
1 h
ester formed
PdCl2(dtbpf)
NaOtBu
better result good yields
Best results are displayed in Table 2, Table 3, and Table 4. We utilized microwave irradiation to
cut down the time and energy necessary for esterification. Another significant point of this
process is
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Table 2. Esters from tertiary butanol and aroyl chloridesa
O
O
Cl
O
1a
1a
2a
2b
3a, 68 %
3b, 60 %
NO2
Cl
NO2
Cl
OH
OH
O
O
Cl
Cl
O
Cl
Cl
O
Cl
Cl
O
O
O
1a
1a
2c
2d
3c, 66 %
3d, 58 %
F3CO
F3CO
OH
OH
F
O
F
F
O
F
Cl
Cl
F
F
O
F
F
O
O
F
F
1a
1a
2e
2f
3e, 53 %
3f, 55 %
OH
OH
F3CO
O
O
F3CO
O
O
Cl
Cl
O
O
1a
2g
3g, 64 %
OH
F
F
a All reactions microwaved for 1 h at 100 °C. Isolated and confirmed by NMR.
4

5
that it is a solvent free reaction. In addition, limitations of this new esterification process were
noted when aliphatic acid chlorides instead of aromatic acid chlorides were used. Further studies
are underway to overcome this limitation. The probable catalytic cycle of the reaction is
displayed in Scheme 2. The ArCOPdCl species is also proposed in Stille’s direct cross-coupling
reaction of organotin compounds and aroyl chlorides for ketone synthesis.15 Several others have
also reported similar cross-coupling reaction by using arylboronic acids and acid chlorides as
starting reagents.16
Table 3. Esters from 2-methyl-2 butanol and aroyl chloridesa
F
O
F
O
F
Cl
O
1b
1b
2d
3h, 78 %
3i, 64 %
OH
OH
F
O
O
Cl
O
2c
F3CO
F3CO
F3CO
O
F3CO
O
Cl
O
1b
2h
OH
3j, 60 %
O
O
Cl
O
1b
2g
3k, 65 %
3l, 70 %
OH
F
F
O
O
Cl
O
1b
2i
OH
Br
Br
a All reactions microwaved for 1 h at 100 °C. Isolated and confirmed by NMR.
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6
Table 4. Esters from tertiary alcohols 1c, 1d, and cholesterol 1e.a
O
O
O
O
Cl
Cl
O
O
OH
OH
1c
1c
2g
2g
3m, 90 %
3n, 55 %
F
F
MeO
MeO
O
O
F3C
O
CF3
CF3
F3C
F3C
CF3
1d
Cl
2g
3o, 70 %
OH
F
F
(CH2)3CH(CH3)2
(CH2)3CH(CH3)2
O
H
Cl
H
H
H
3p, 76 %b
2c
F3CO
H
H
HO
O
1e
F3CO
O
(CH2)3CH(CH3)2
(CH2)3CH(CH3)2
O
H
Cl
2g
H
H
H
3q, 60 %b
F
H
H
HO
O
1e
F
O
aAll are isolated products. bCholesterol esters formed. Products still contain
some impurities.
The reaction methods used for all the reactions shown in Table 2, Table 3, and Table 4 are the
same except for cholesterol, 1e where 1.0 mL of 1,4-dioxane was added. An oven dry clean
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7
microwave vial is loaded with 1.0 mmol of NaOtBu (100.0 mg), 0.0025 mmol of PdCl2(dtbpf)
(2.0 mg), capped with air-tight silicon septa and flushed with argon.
PdCl2(dtbpf)
Base
Pd(0)
Cl
Ar
OA
L
O
Ar
R3C
O
O
O
Ar
RE
Pd
Cl
L
Inorganic
byproducts
H OCR3
NaOtBu
O
L
Ar
OCR3
Pd
L
Scheme 2
. Plausible reaction mechanism
Then 0.5 mmol of aroyl chloride was added as limiting reagent via micro syringe, and tertiary
alcohol (1.0 mL) was added via dry syringe. The resulting reaction mixture was then
microwaved (CEM Explorer 24, 300W) at 100 °C for 60 min. Crude reaction product in reaction
tube was diluted with dichloromethane and transferred into a separating funnel. Water was then
added to the funnel and, after standard extraction, excess alcohol was completely miscible with
water. The bottom organic layer was collected in a small Erlenmeyer flask over anhydrous
Na2SO4. The dichloromethane layer was filtered through sintered funnel and filtrate, collected in
a round bottom flask, and completely dried by rotary evaporator and under reduced pressure in
vacuo. In case of cholesterol 1e, 0.5 mmol of aroyl chloride, 1.0 mmol of cholesterol, and 1.0 mL
of 1,4-dioxane were used. The desired ester product was confirmed by 1H NMR, 13C NMR, and
7

8
1
19F NMR. Ester (Compound 3c) from tertiary alcohol, 1a; H NMR (CDCl3, 400 MHz) δ 7.95
13
(d, J = 8.64, 2H), 7.16 (d, J= 8.36 Hz, 2H), 1.51 (s, 9H). C NMR (CDCl3, 100 MHz) δ 164.5,
152.3, 130.5, 120.1, 81.5, 28.1. 19F NMR (CDCl3, 400 MHz) δ -57.7 (OCF3); Ester (Compound
3k) from tertiary alcohol, 1b; 1H NMR (CDCl3, 400 MHz) δ 8.00 (dd, J = 8.04, 1H), 7.08 (t, J=
13
8.52 Hz, 1H), 1.92 (q, J = 7.48, 2H), 1.56 (s, 6H), 0.97 (t, J = 7.44 3H). C NMR (CDCl3, 100
MHz) δ 166.7, 164.7, 131.8, 128.2, 115.3, 83.6, 33.7, 25.6, 8.3. 19F NMR (CDCl3, 400 MHz) δ -
106.9 (F); Ester (Compound 3m) from tertiary alcohol, 1c; 1H NMR (CDCl3, 400 MHz) δ 7.24
13
(dd, J=8.72, 2H), 7.16 (m, 5H), 6.99 (t, J = 8.64 Hz, 2H), 3.1 (s, 2H), 1.51 (s, 6H). C NMR
(CDCl3, 100 MHz) δ 166.8, 165.0, 137.1, 130.6, 128.0, 126.5, 115.4, 83.1, 46.6, 26.14; 19F NMR
(CDCl3, 400 MHz) δ -106.6 (F);
The cross-coupling reaction of tertiary alcohols and aroyl chlorides is significant because it
overcomes the limitation of tertiary alcohols in esterification. Since involvement of tertiary
alcohols allow for a more complex ester, this process could prove to be very useful in both the
chemical and biological fields of study.
Acknowledgement
Arpona Hira gratefully acknowledges the graduate fellowship award from Tennessee State
University; Nashville, TN.
References
1. Zhang J, Liu M, Jin H, Deng L, Xing J, Dong A. In vitro Enhancement of Lactate Esters
on the Percutaneous Penetration of Drugs with Different Lipophilicity. AAPS
PharmSciTech., 2010, 11 (2), 894-903.
8

9
2. Loretta L., Monica D., Barbara R., Konstantin C., Elisabetta M.; Clara C., Antonella
D.S., Roberta F., Stefano B., Ennio O.,Alberto G. (Nitrooxyacyloxy) methyl Esters of
Aspirin as Novel Nitric Oxide Releasing Aspirins. Journal of Medicinal
Chemistry, 2009 52 (16), 5058-5068
3. Devappa, R.K., Angulo-Escalante, M.A., Makkar, H.P.S., Becker, K. Ind. Crops
Products, 2012, 38, 50-53.
4. Niu, L., Xu, Y., Xu, C., Yun, L., Liu, W. Environ. Pollut., 2014, 195, 16-23.
5. Chen, N., Shuai, W., Hao, X., Zhang, H., Zhou, D., Gao, J. Pedosphere, 2017, 27 (3),
439-451.
6. Zawada, K., Plichta, A., Jańczewski, D., Hajmowicz, H., Florjańczyk, Z., Stępień, M.,
Sobiecka, A., Synoradzki, L. ACS Sustainable Chemistry & Engineering 2017 5 (7),
5999-6007.
7. Vedaraman, N., Puhan, S., Nagarajan, G.,Ramabrahmam, B.V.,Velappan, K.C. Ind.
Crops Products, 2012, 36 (1), 282-288.
8. Fischer,E., Speier, A. Darstellung der Ester. Chem. Ber. 1895 28, 3252–3258
9. Meijere, A. D.; Diederich, F. Metal-Catalyzed Cross-Coupling Reactions 2nd Edition.
2004 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim ISBN 3-527-30518-1
10. Espinet, P.; Echavarren, A. M. Angew. Chem. Int. Ed., 2004, 43, 4704–4734.
11. Kaiser, E. M.; Woodruff, R. A. J. Org. Chem. 1970, 35, 1198-1199.
12. Muzart, J. Palladium-catalyzed reactions of alcohols. Tetrahedron, 2005, 61, 9423-9463.
13. (a) Grasa, G. A.; Colacot, T. J. Org. Lett. 2007, 9, 5489-5492. (b) Al-Masum, M.; Saleh,
N.; Islam, T. Tetrahedron Lett. 2013, 54, 1141-1144.
9

10
14. (a) Mann, G.; Shelby, Q.; Roy, A. H.; Hartwig, J. F. Organometallics 2003, 22, 2775-
2789. (b) Elsagir, A. R.; Gassner, F.; Gorls, H.; Dinjus, E. J. Organomet. Chem. 2000,
597, 139-145. (c) Bianchini, C.; Meli, A.; Overhauser, W.; Parisel, S.; Passaglia, E.;
Ciardelli, F.; Gusev, O. V.; Kal’sin, A. M.; Vologdin, N. V. Organometallics 2005, 24,
1018-1030.
15. (a) Labadie, J. W.; Stille, J. K. J. Am. Chem. Soc. 1983, 105, 6129-6137. (b) Milstein,
D.; Stille, J. K. J. Am. Chem. Soc. 1978, 100, 3636-3637.
16. (a) Urawa, Y.; Ogura, K. Tetrahedron lett. 2003, 44, 271. (b) Haddach, M.; McCarthy, J.
R. Tetrahedron Lett. 1999, 40, 3109-3112. (c) Bumagin, N.; Korolev, D. N. Tetrahedron
Lett. 1999, 40, 3057. (d) Xin, B.; Zhang, Y.; Cheng, K. Synthesis, 2007, 1970. (e)
Eddarir, S.; Cotelle, N.; Bakkour, Y.; Ronaldo, C. Tetrahedron Lett. 2003, 44, 5339. (f)
Al-Masum, M.; Liu, K-Y. Tetrahedron Lett. 2011, 52, 5090-5093.
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Introducing efficient palladium catalyzed cross coupling reaction of tertiary
alcohols and aroyl chlorides for the synthesis of highly substituted esters
Mohammad Al-Masum*, Arpona Hira, Sara Chrisman, Ngan T. Nguyen
Department of Chemistry, Tennessee State University, 3500 John A Merritt Blvd.
Nashville, TN 37209
0.5 mole % PdCl2(dtbpf)
R'
O
R'
R2
O
Ar
OH
R3
R2
+
R3
60 - 80 %
O
NaOtBu
Ar
Cl
Neat, 100 0C, 1 h
11

12
 Tertiary alcohols as cross-coupling partner
 Pd inserted ArCOPdCl species
 Cholesterol ester
 Microwave
 Solvent free reaction
17.
12