Palladium catalyzed carbonylations of alkenyl halides with formic acid to get corresponding Α,Β-unsaturated carboxylic acids and esters

Article abstract of DOI:10.1016/j.mcat.2018.12.026

Palladium-catalysed carbonylation reactions have been developed in the presence of formic acid as carbon monoxide source. α,β-Unsaturated carboxylic acids and esters were synthesized by the transformation of alkenyl halides in moderate to good yields. The selection of the base proved to be crucial regarding the reaction outcome. A set of various substrates were proven under optimised reaction conditions. Compared to aliphatic alcohols, phenols showed excellent reactivity as O-nucleophiles.

Full text of DOI:10.1016/j.mcat.2018.12.026

MolecularCatalysis467(2019)143–149
Contents lists available at ScienceDirect
Molecular Catalysis
journal homepage: www.elsevier.com/locate/mcat
Palladium catalyzed carbonylations of alkenyl halides with formic acid to
get corresponding α,β-unsaturated carboxylic acids and esters
Brigitta Bartal, Gábor Mikle, László Kollár, Péter Pongrácz⁎
Department of Inorganic Chemistry, University of Pécs and János Szentágothai Science Center, MTA-TKI Research Group for Selective Chemical Syntheses, H-7624, Pécs,
Hungary
A R T I C L E I N F O
A B S T R A C T
Keywords:
Palladium-catalysed carbonylation reactions have been developed in the presence of formic acid as carbon
monoxide source. α,β-Unsaturated carboxylic acids and esters were synthesized by the transformation of alkenyl
halides in moderate to good yields. The selection of the base proved to be crucial regarding the reaction out-
come. A set of various substrates were proven under optimised reaction conditions. Compared to aliphatic al-
cohols, phenols showed excellent reactivity as O-nucleophiles.
Palladium
Hydroxycarbonylation
Alkoxycarbonylation
Formic acid
1. Introduction
Aryl halides or triflates are likewise suitable substrates of carbo-
nylation reactions performed with formic acid or formates.
Palladium-catalysed carboxylation and alkoxycarbonylation reac-
tions are widely used approaches for preparing carboxylic acid and
ester derivatives, respectively. Beside olefins and alkynes, which un-
derwent hydrocarboxylation and hydroalkoxycarbonylation via ‘formal
addition’ of the H-COOH and H-COOR, respectively, aromatic bromides
and iodides are frequently used starting materials in such carbonylation
reactions [1–5] (Scheme 1).
Hydroxycarbonylation reactions run under mild conditions tolerate
various functional groups and compare well with carbon monoxide
based procedures [21,22]. The process requires the stoichiometric
amounts of acetic anhydride as activator, forming formic acetic anhy-
dride (generated in situ by the reaction of formic acid and acetic an-
hydride). The formation of mixed anhydride can be responsible for the
generation of carbon monoxide due to its thermal instability. The re-
action can be also initiated by the application of catalytic amount of
DCC (dicyclohexylcarbodiimide) as activator [23]. Wu et al. demon-
strated that the outcome of the reaction can be controlled by ligand
exchange, that is, the reaction can be switched to the production of
aldehydes in the presence of monodentate alkylphosphines, while wide
bite-angle diphosphines promote the formation of acids [24,25].
The palladium catalysed hydroalkoxycarbonylation of alkenes and
alkynes were described as well, using alkyl or phenyl formates [26]. In
the reaction of various vinyl arenes, either linear or branched phenyl
arylpropanoates can be obtained in good yields depending on the ligand
structure [27]. In addition, excellent enantioselectivity can be achieved
with (R)-DTBM-SEGPHOS ligand with high branched/linear ratios [28].
A serious drawback of these reactions is the inevitable synthesis of the
corresponding formates. Wide range of halogenated substrates (aryl,
alkenyl and allyl halides) can be transformed to phenyl esters under
similarly mild conditions with phenyl formate [29]. The reaction pro-
ceeds without the use of cocatalyst with 2 equivalents of formate re-
agent. Furthermore, palladium catalysed alkoxycarbonylations of aryl
iodides and bromides have been developed in the presence of phenols
All these reactions require the use of toxic carbon monoxide gas
often under harsh conditions (high pressure and temperature) with
special equipment, which set the limit of their applications. Many ef-
forts have been proposed, especially in the last decade to substitute the
carbon monoxide gas with cheaper, ‘greener’ and easily accessible al-
ternatives [6–8]. Beside many promising surrogates e.g. carbon dioxide
[9], formaldehyde [10] or chloroform [11], formates and formic acid
[12] proved to be particularly suitable for carbonylation reactions.
The hydrocarboxylation of alkynes with formic acid provided an
attractive and economic process for the synthesis of unsaturated car-
boxylic acids [13,14]. Beside the palladium-based systems, Zhou and
co-workers described the highly efficient hydrocarboxylation of acet-
ylene to acrylic acid with a TON of up to 7700 in the presence of Ni-
catalyst [15]. Olefins can be also transformed to the corresponding
carboxylic acids by using a similar process, thus far, there are only few
reports with Ir [16], Rh [17] or Pd [18,19] catalysts. Also good results
were achieved in the presence of palladium catalyst using HCOOLi as
carbonyl source, under mild and less acidic conditions compared to
previous examples [20].
⁎ Corresponding author.
E-mail address: pongracz@gamma.ttk.pte.hu (P. Pongrácz).
https://doi.org/10.1016/j.mcat.2018.12.026
Received 3 December 2018; Received in revised form 19 December 2018; Accepted 29 December 2018
2468-8231/©2019ElsevierB.V.Allrightsreserved.

B. Bartal et al.
MolecularCatalysis467(2019)143–149
Scheme 1. Schematic representation of carbonylation reactions carried out with alkene or alkenyl halide substrates.
and aliphatic alcohols employing formic acid as the CO source [30].
Aryl halides are widely used substrates in carbonylation reactions,
while only sporadic results can be found with alkenyl halides. These
compounds can be interesting starting materials of the above men-
tioned carbonylation reactions, namely, their transformation leads to
valuable α,β-unsaturated carboxylic acids. In our efforts to explore the
reactions of these substrates, we describe the palladium-catalysed car-
boxylation and alkoxycarbonylation of alkenyl halides using formic
acid as CO source to provide a series of unsaturated acid and ester
derivatives.
(100), 67 (12), 53 (23).
4-terc-butyl-1-cyclohexene-1-carboxylic acid (2b)
δH (500 MHz, CDCl3) 7.16 (1H, t, CHCCOOH, 3.0 Hz), 2.55-2.51
(1H, m, CHaHbCCOOH), 2.34-2.28 (1H, m, CHaHbCCOOH), 2.19-2.12
(1H, m, C = CHCHaHb), 2.04-1.98 (1H, m, C = CHCHaHb), 1.97-1.93
(1H, m, CHaHbCH2CCOOH), 1.34-1.28 (1H, m, CHaHbCH2CCOOH),
1.21-1.19 (1H, m, tBuCH), 0.92 (9H, s, CH3). δC (125.7 MHz, CDCl3):
173.0, 143.0, 129.6, 43.2, 32.1, 27.7, 27.1, 25.2, 23.5. IR (KBr (cm−1)):
2956, 2865, 1676, 1643, 1424, 1315, 1277, 1088, 955, 731, 694, 534.
MS m/z (rel int.): 182 (5, M+), 167 (4), 154 (2), 139 (34), 126 (74), 11
(18), 95 (6), 79 (27), 57 (100).
2-carboxyl-1,7,7-trimethyl-bicyclo [2,2,1]-hept-2-ene (3b)
2. Experimental
δH (500 MHz, CDCl3): 7.12 (1H, d, 3.4 Hz, C = CH), 2.51-2.49 (1H,
m, CH2CH), 2.00-1.94 (1H, m, CHCHaHb), 1.68-1.63 (1H, m,
CHCHaHb), 1.28 (3H, s, CH2CCH3), 1.20-1.15 (1H, m, CCHaHb), 1.04-
1.00 (1H, m, CCHaHb), 0.83 (3H, s, CHCCH3), 0.82 (3H, s, CHCCH3). δC
(125.7 MHz, CDCl3): 171.1, 150.3, 140.3, 57.2, 53.8, 52.3, 31.0, 24.4,
19.2, 11.8. IR (KBr (cm−1)): 2958, 2879, 1673, 1582, 1421, 1249,
1074, 944, 763, 699. MS m/z (rel int.): 180 (47, M+), 165 (98), 135
(37), 118 (34), 93 (100), 65 (20).
2.1. General Information
All reactions were carried out under argon using standard Schlenk
techniques. All chemicals (precursor, ligands, solvents, etc.) were pur-
chased from commercial sources (Sigma-Aldrich) and used as received
without further purification. The 1H and 13C NMR spectra were re-
corded on a Bruker Avance III 500 spectrometer. Chemical shifts are
reported in ppm relative to TMS (downfield) for 1H and 13C NMR
spectroscopy. Conversions were determined using GC and GC–MS. The
products were purified by column chromatography on silica gel or
aluminium oxide using chloroform, hexane and ethyl acetate as sol-
vents.
17-carboxyl-3-hydroxyestra-1,3.5(10),16-tetraene (4b)
δH (500 MHz, CDCl3): 7.25 (1H, d, 8.6 Hz, 1-H), 7.02-7.01 (1H, dd,
3.0 Hz, 1.5 Hz, 16-H), 6.77-6.75 (1H, m, 2-H), 6.69-6.68 (1H, m, 4-H),
3.82 (3H, s, O-CH3), 2.94-1.51 (13H, m), 1.01 (3H, s, 18-H3). δC
(125.7 MHz, CDCl3): 170.4, 157.5, 146.6, 146.4, 137.8, 132.7, 126.1,
113.9, 111.5, 55.8, 55.2, 46.0, 44.2, 37.1, 34.8, 31.9, 29.7, 27.7, 26.5,
16.0. IR (KBr (cm−1)): 2931, 1676, 1680, 1500, 1430, 1282, 1254,
1053, 1034, 807. MS m/z (rel int.): 396 (100), 312 (1, M+), 269 (12),
213 (3), 173 (92), 147 (45), 128 (9), 95 (13), 55 (7).
2.2. General procedure
In a typical experiment, catalyst precursor [Pd(OAc)2] (2 mol %)
and ligand (4 mol %) were placed in a three-necked flask and refilled
with argon gas three times. DMF (10 mL), substrate (0.5 mmol), Et3N
(0.5 mmol), HCOOH (1 mmol) and Ac2O (1 mmol) was transferred to
the flask. The mixture was placed in oil bath (100 °C) and stirred with
magnetic stirrer for 24 h. After the reaction was completed, the mixture
was cooled, filtered and immediately analyzed by GC and GC–MS. GC
yields were determined by using undecane as internal standard. The
reaction mixture was concentrated under vacuum and the crude pro-
duct was purified by column chromatography on silica gel using
chloroform to afford the corresponding product. The esters were pur-
ified by flash chromatography on neutral aluminium oxide using
chloroform hexane 1:1 as eluent. Steroids were dissolved in DMF and
after the addition of water the precipitates were filtered and dried
under vacuum.
17-carboxylandrost-16-ene (5b)
δ
H (500 MHz, CDCl3): 6.88–6.89 (1H, m, 16-H), 2.30-0.76 (22H, m),
0.93 (3H, s, 18-H3), 0.83 (3H, s, 19-H3). δC (125.7 MHz, CDCl3): 169.8,
146.8, 145.9, 56.7. 55.2, 47.3, 45.8, 38.5, 36.6, 34.8, 33.9, 32.0, 31.9,
29.0, 28.9, 26.8, 22.2, 20.6, 16.0, 12.2. IR (KBr (cm−1)): 2918, 2853,
1680, 1599, 1433, 1262, 1246, 960. MS m/z (rel int.): 302 (29, M+),
287 (100), 269 (31), 257 (51), 241 (13), 192 (12, 163 (18), 123 (10),
91 (30), 55 (25).
20-carboxyl-3β-hydroxypregn-5,20-diene (6b)
δH (500 MHz, CDCl3): 6.25 (1H, s, 21-Ha), 5.60 (1H, s, 21-Hb), 5.39-
5.38 (1H, m, 6-H), 3.46-3.39 (1H, m, 3-H) 2.85-2.81 (1H, m, 17-H),
2.30-1.01 (19H, m), 1.05 (3H, s, 19-H3) 0.61 (3H, s, 18-H3). δC
(125.7 MHz, CDCl3): 170.7, 141.0, 140.9, 122.6, 120.9, 71.0, 56.5,
50.5, 50.1, 42.8, 41.6, 37.8, 37.2, 36.4, 32.3, 31.5, 30.9, 25.3, 23.8,
20.7, 18.5, 11.6. IR (KBr (cm−1)): 2934, 2903, 2649, 1695, 1622, 1436,
1378, 1256, 1190 1163, 1052, 953, 824. MS m/z (rel int.): 300 (83),
267 (89), 225 (15), 197 (19), 159 (41), 146 (49), 119 (52), 91 (100), 55
(44).
2.3. Characterisation of the products
1-cyclohexene-1-carboxylic acid (1b)
1,4-diphenyl-buta-1,3-diin (7b)
δH (500 MHz, CDCl3): 7.16 (1H, s, CH), 2.28-2.25 (4H, m,
CH2CHCCH2), 1.71-1.63 (4H, m, CH2CH2CH2CH2). δC (125.7 MHz,
CDCl3): 173.2, 142.5, 129.8, 26.0, 23.7, 22.0, 21.3. IR (KBr (cm−1)):
2940, 2862, 1684, 1652, 6140, 1457, 1423, 1307, 1284, 1262, 1241,
924, 738, 551. MS m/z (rel int.): 126 (34, M+), 108 (20), 93 (2), 81
δH (500 MHz, CDCl3): 7.58-7.36 (10H, m, Ph). δC (125.7 MHz,
CDCl3): 132.5, 129.2, 128.5, 121.8, 81.6, 73.9. IR (KBr (cm−1)): 1764,
1485, 1440, 915, 755, 687, 527, 434. MS m/z (rel int.): 202 (100, M+),
174 (3), 150 (6), 126, (2), 101 (8), 75 (2), 51 (1).
144

B. Bartal et al.
MolecularCatalysis467(2019)143–149
Cis-cinnamic acid (8b)
(61), 91 (100), 55 (72).
δH (500 MHz, CDCl3): 7.67-7.40 (5H, m, Ph), 7.12 (1H, d, 12.6 Hz,
PhCHCH), 6.03 (1H, d, 12.6 Hz, PhCH). δC (125.7 MHz, CDCl3) 13C
NMR characterisation is missing due to low yield). IR (KBr (cm−1)):
(mixture of cis and trans isomers) 3061, 3017, 2963, 1689, 1630, 1449,
1421, 1312, 1286, 1263, 1223, 980, 769, 711, 697. MS m/z (rel int.):
148 (70, M+), 147 (100), 103 (44), 77 (44), 51 (31).
4-terc-butyl-1-cyclohexene-1-carboxylic acid methyl ester (2d)
δH (500 MHz, CDCl3): 7.01-6.96 (1H, m, C = CH), 3.73 (3H, s,
OCH3), 2.55-2.46 (1H, m, CHaHbCCOOH), 2.29-2.06 (2H, m,
CHaHbCCOOH, C = CHCHaHb), 1.99-1.87 (2H, m, C = CHCHaHb,
CHaHbCH2CCOOH), 1.32-1.22 (1H, m, CHaHbCH2CCOOH), 1.15-1.11
(1H, m, tBuCH), 0.88 (9H, s, tBu). 13C NMR characterisation of the
analytically pure sample was failed due to low yield. MS m/z (rel. int.):
196 (15, M+), 165 (16), 140 (84), 108 (22), 79 (54), 57 (100).
4-terc-butyl-1-cyclohexene-1-carboxylic acid ethyl ester (2e)
NMR characterisation of the analytically pure sample was failed due
to low yield. MS m/z (rel int.): 210 (22, M+), 182 (5), 165 (28), 154
(48), 136 (29), 126 (54), 79 (53), 57 (100).
Trans-cinnamic acid (8b’)
δH (500 MHz, CDCl3): 7.84 (1H, d, 15.5 Hz, PhCHCH), 7.61-7.44
(5H, m, Ph), 6.50 (1H, d, 15.5 Hz, PhCH). δC (125.7 MHz, CDCl3):
172.6, 147.1, 134.1, 130.8, 129.0, 128.4, 117.4. IR (KBr (cm−1)):
(mixture of cis and trans isomers) 3061, 3017, 2963, 1689, 1630, 1449,
1421, 1312, 1286, 1263, 1223, 980, 769, 711, 697. MS m/z (rel int.):
148 (69, M+), 147 (100), 103 (43), 77 (37), 51 (26).
4-terc-butyl-1-cyclohexene-1-carboxylic acid 4-chlorophenyl ester
(2f)
Trans-methyl-2-butenoic acid (9b)
δ
H (500 MHz, CDCl3): 7.07-6.97 (1H, m, C = CH), 1.88-1.81 (6H, m,
δH (500 MHz, CDCl3) 7.38-7.29 (4H, m, Ph), 7.07 (1H, t, C = CH,
3 Hz), 2.65-2.61 (1H, m, CHaHbCCOOH), 2.38-2.26 (2H, m,
CHaHbCCOOH; C = CHCHaHb), 2.08-1.99 (2H, m, C = CHCHaHb,
CHaHbCH2CCOOH), 1.36-1.34 (1H, m, CHaHbCH2CCOOH), 1.24-1.21
(1H, m, tBuCH), 0.94 (9H, s, tBu). δC (125.7 MHz, CDCl3): 166.3, 157.1,
142.2, 130.2, 129.8, 128.6, 122.5, 43.3, 32.2, 27.8, 27.1, 25.7, 23.6. IR
(KBr (cm−1)): 2964, 1736, 1712, 1649, 1485, 1261, 1201, 1094, 1034,
856, 802, 726, 508. MS m/z (rel int.): 165 (100), 137 (4), 107 (7), 95
(22), 81 (26), 57 (38).
CH3). δC (125.7 MHz, CDCl3): 173.9, 140.0, 128.1, 14.6, 11.6. IR (KBr
(cm−1)): 2959, 2923, 1726, 1699, 1677, 1653, 1559, 1261, 1096,
1019, 802. MS m/z (rel int.): 100 (100, M+), 82 (24), 55 (99).
4-terc-butyl-1-cyclohexene-1-carboxylic acid phenyl ester (2c)
δH (500 MHz, CDCl3) 7.41-7.13 (6H, m, Ph, CCH), 2.68-2.64 (1H, m,
CHaHbCCOOH), 2.39-2.28 (2H, m, CHaHbCCOOH; C = CHCHaHb),
2.09-1.99 (2H, m, C = CHCHaHb, CHaHbCH2CCOOH), 1.37-1.35 (1H,
m, CHaHbCH2CCOOH), 1.25-1.23 (1H, m, tBuCH), 0.95 (9H, s, tBu). δC
(125.7 MHz, CDCl3): 166.1, 151.2, 142.4, 129.8, 129.3, 125.5, 121.8,
43.3, 32.2, 27.8, 27.7, 25.7, 23.6. IR (KBr (cm−1)): 3043, 2954, 2932,
1662, 1653, 1594, 1473, 1237, 756. MS m/z (rel int.): 165 (100), 137
(4), 107 (6), 95 (15), 81 (22), 57 (31).
4-terc-butyl-1-cyclohexene-1-carboxylic acid 4-methoxyphenyl
ester (2g)
δH (500 MHz, CDCl3) 7.16-6.92 (5H, m, Ph, C = CH), 3.83 (3H, s,
OMe), 2.66-2.63 (1H, m, CHaHbCCOOH), 2.38-2.27 (2H, m,
CHaHbCCOOH; C = CHCHaHb), 2.07-1.98 (2H, m, C = CHCHaHb,
CHaHbCH2CCOOH), 1.34-1.21 (1H, m, CHaHbCH2CCOOH), 1.24-1.21
(1H, m, tBuCH), 0.94 (9H, s, tBu). δC (125.7 MHz, CDCl3): 166.3, 157.1,
142.2, 130.2, 129.8, 128.6, 122.5, 43.3, 32.2, 27.8, 27.1, 25.7, 23.6. IR
(KBr (cm−1)): 2951, 1724, 1508, 1401, 1366, 1248, 1196, 1062, 1037,
865, 725, 709, 520. MS m/z (rel int.): 288 (11, M+), 165 (100), 123
(13), 107 (24), 95 (33), 82 (33), 57 (51).
1,7,7-trimethylbicyclo [2,2,1]-hept-2-en-2-carboxylic acid phenyl
ester (3c)
δH (500 MHz, CDCl3): 7.57-7.11 (6H, m, Ph, CCH), 2.57-2.55 (1H,
m, CH2CH), 2.05-1.99 (1H, m, CHCHaHb), 1.73-1.68 (1H, m,
CHCHaHb), 1.34 (3H, s, CH2CCH3), 1.28-1.24 (1H, m, CCHaHb), 1.13-
1.08 (1H, m, CCHaHb), 0.90 (3H, s, CHCCH3), 0.87 (3H, s, CHCCH3). δC
(125.7 MHz, CDCl3): 169.5, 150.8, 149.5, 140.1, 129.4, 125.8, 121.8,
57.3, 54.2, 52.4, 31.2, 24.5, 19.5, 19.2, 11.9. IR (KBr (cm−1)): 2963,
2927, 2852, 1734, 1700, 1539, 1507, 1263, 1019, 796, 667, 413. MS
m/z (rel int.): 256 (3, M+), 163 (100), 135 (24), 107 (18), 91 (18), 77
(13), 61 (11), 55 (5).
4-terc-butyl-1-cyclohexene-1-carboxylic acid 1-naphtyl ester (2h)
δH (500 MHz, CDCl3) 7.91-7.29 (8H, m, Ph, C = CH), 2.79-2.76 (1H,
m, CHaHbCCOOH), 2.45-2.40 (2H, m, CHaHbCCOOH; C = CHCHaHb),
2.16-2.05 (2H, m, C = CHCHaHb, CHaHbCH2CCOOH), 1.47-1.43 (1H,
m, CHaHbCH2CCOOH), 1.35-1.28 (1H, m, tBuCH), 0.98 (9H, s, tBu). δC
(125.7 MHz, CDCl3): 165.8, 146.6, 142.8, 134.7, 129.7, 128.1, 128.0,
126.5, 126.1, 125.7, 125.4, 121.2, 118.1, 43.4, 32.2, 27.9, 27.2, 25.9,
23.6. IR (KBr (cm−1)): 3066, 2955, 1772, 1768,1734, 1700, 1684,
1653, 1558, 1507, 1204, 774, 662, 417.MS m/z (rel int.): 308 (9, M+),
165 (100), 115 (14), 82 (21), 57 (30).
3-Hydroxyestra-1,3,5(10),16-tetraene-17-carboxylic acid phenyl
ester (4c)
δH (500 MHz, CDCl3): 7.41-6.63 (9H, m, Ph, 16-H), 3.70 (3H, s, O-
CH3), 2.91-1.38 (13H, m, skeleton protons), 0.84 (3H, s, 18-H3). δC
(125.7 MHz, CDCl3): 162.8, 157.5, 142.2, 137.8, 132.7, 129.8, 126.7,
126.3, 122.3, 119.2, 115.7, 114.0, 111.9, 55.8, 45.9, 44.2, 37.3, 36.2,
35.0, 31.2, 29.6, 27.7, 26.6, 16.4. IR (KBr (cm−1)): 3429, 2930, 1702,
1606, 1500, 1403, 1237, 1026, 999, 760, 541. MS m/z (rel int.): 284
(100), 256 (3), 227 (9), 199 (37), 187 (21), 160 (30), 115 (13), 77 (5),
50 (1).
4-terc-butyl-1-cyclohexene-1-carboxylic acid 2-naphtyl ester (2i)
δH (500 MHz, CDCl3) 7.88-7.30 (8H, m, Ph, C = CH), 2.72-2.69 (1H,
m, CHaHbCCOOH), 2.42-2.30 (2H, m, CHaHbCCOOH; C = CHCHaHb),
2.12-2.02 (2H, m, C = CHCHaHb, CHaHbCH2CCOOH), 1.43-1.38 (1H,
m, CHaHbCH2CCOOH), 1.28-1.26 (1H, m, tBuCH), 0.97 (9H, s, tBu). δC
(125.7 MHz, CDCl3): 166.1, 148.8, 142.6, 133.9, 131.4, 130.2, 129.3,
128.6, 127.8, 126.5, 125.5, 121.5, 118.6, 43.3, 32.2, 27.9, 27.2, 25.8,
23.6 IR (KBr (cm−1)): 3061, 2960, 1760, 1728, 1600, 1366, 1238,
1205, 806, 475. MS m/z (rel int.): 308 (9, M+), 165 (100), 115 (14), 82
(21), 57 (30).
Androst-16-ene-17-carboxylic acid phenyl-ester (5c)
δH (500 MHz, DMSO-d6): 7.42-6.84 (6H, m, Ph, 16-H), 2.30-0.73
(22H, m), 0.93 (3H, s, 18-H3), 0.84 (3H, s, 19-H3). δC (125.7 MHz,
CDCl3): 173.9, 161.0, 146.5, 145.7, 129.3, 125.5, 122.1, 55.1, 54.9,
47.3, 44.3, 38.7, 37.0, 35.1, 34.2, 32.0, 31.6, 29.1, 28.9, 26.8, 22.2,
20.5, 16.9, 12.2. IR (KBr (cm−1)): 2965, 2921, 2856, 2841, 1695, 1665,
1511, 1259, 1232. MS m/z (rel int.): 285 (100), 207 (4), 147 (3), 95 (7),
55 (6).
4-terc-butyl-1-cyclohexene-1-carboxylic
acid
4-ethox-
ycarbonylphenyl ester (2j)
3β-Hydroxypregn-20-ene-20-carboxylic acid phenyl ester (6c)
δH (500 MHz, CDCl3): 8.12-8.05 (2H, m, Ph), 7.31-7.21 (3H, m, Ph,
δ
H (500 MHz, DMSO-d6): 7.16-6.76 (5H, m, Ph), 5.60 (1H, s, 21-Ha),
C = CH), 4.41 (2H, q, 7.1 Hz, OCH2), 2.67-2.63 (1H, m,
CHaHbCCOOH), 2.39-2.28 (2H, m, CHaHbCCOOH; C = CHCHaHb),
2.09-1.99 (2H, m, C = CHCHaHb, CHaHbCH2CCOOH), 1.42-1.35 (4H,
m, CHaHbCH2CCOOH overlapping CH3), 1.29-1.22 (1H, m, tBuCH),
0.95 (9H, s, tBu). δC (125.7 MHz, CDCl3): 165.3, 154.8, 143.2, 131.1,
129.5, 127.7, 121.7, 61.0, 43.3, 32.2, 27.9, 27.1, 25.7, 23.5, 14.3. IR
(KBr (cm−1)): 2964, 1727, 1712, 1604, 1503, 1366, 1306, 1275, 1200,
1161, 1107, 762, 742, 706. MS m/z (rel int.): 315 (1), 285 (3), 165
5.23 (1H, s, 21-Hb), 4.86–4.88 (1H, m, 6=CH), 3.28-3.26 (1H, m, 3-
CH), 2.15-0.89 (20H, m, skeleton protons), 0.94 (3H, s, 19-H3) 0.48
(3H, s, 18-H3). δC (125.7 MHz, CDCl3): 166.3, 158.2, 141.8, 133.5,
129.7, 120.9, 119.1, 115.8, 114.0, 70.5, 56.7, 51.2, 50.5, 42.8, 38.0,
37.5, 36.6, 36.3, 32.6, 31.9, 31.3, 25.8, 24.4, 21.0, 19.7, 13.0. IR (KBr
(cm−1)): 3445, 2928, 1658, 1650, 1562, 1552, 1536, 1421. MS m/z (rel
int.): 354 (6), 300 (63), 282 (49), 267 (76), 207 (82), 159 (46), 119
145

B. Bartal et al.
MolecularCatalysis467(2019)143–149
Table 1
CDCl3): 165.7, 151.1, 143.0, 132.0, 129.3, 127.0, 126.7, 126.4, 122.9,
61.2, 43.3, 32.2, 27.9, 27.1, 25.7, 23.6, 14.3. IR (KBr (cm−1)): 2962,
1770, 1725, 1588, 1443, 1366, 1272, 1217, 1198, 1099, 1025, 752. MS
m/z (rel int.): 315 (1), 285 (8), 165 (100), 121 (8), 95 (8), 81 (14), 57
(19).
Optimization of 1-iodocyclohexene carboxylation.a
Entry
T
HCOOH
[eq.]
Ac2O
[eq.]
Conv.b
[%]
Yieldb (1b) [%]
3. Results
[oC]
1
2
100
100
100
100
100
100
100
80
1
2
4
1
1
2
2
2
2
2
2
2
1
1
85
97
59
93
The initial investigations were performed with 1-iodocyclohexene
(0.5 mmol) as the starting material to get the corresponding carboxylic
acid derivative. We chose Pd(OAc)2 precursor and dppb diphosphine
ligand as catalyst system in the presence of one equivalent formic acid
and acetic acid anhydride as activator in DMF as initial conditions
(Table 1). After 24 h, the carboxylation product cyclohexene-1-car-
boxylic acid was produced in 59% yield (entry 1), but significant
amount (26%) of dimerization side product was also detected. Results
can be improved by increasing the amount of formic acid, where 4
equivalents of reagent provide total conversion and excellent chemos-
electivity (entries 2 and 3). The amount of the anhydride has no such
remarkable influence on the carboxylation reaction (results are com-
parable to those obtained under standard condition), but in the pre-
sence of 2 equivalents of anhydride beside 2 equivalents of formic acid
exquisite yield can be achieved, which conditions were chosen for
further reactions (entry 6).
3
1
> 99
86
> 99
52
4
0.2
2
5
72
62
6
2
> 99
97
> 99
97
7c
8
2
2
> 99
81
> 99
66
9
60
2
10d
11e
12f
100
100
100
2
18
7
2
68
68
2
52
40
a
Reaction conditions (unless otherwise stated): Pd(OAc)2: 0.01 mmol, dppb:
0.02 mmol, substrate 0.5 mmol, Et3N: 0.5 mmol, solvent: 5 mL of DMF, reaction
time: 24 h.
b
c
d
e
Determined by GC.
Reaction time was 1 h.
HCOONa was used instead of HCOOH.
Under the selected reaction conditions close to total conversion can
be obtained even in 1 h, without side reactions (entry 7). Furthermore,
lower reaction temperature (80 °C) is still suitable for the proper car-
boxylation reaction, but at 60 °C side reaction becomes considerable
(entries 8 and 9). The experiment with sodium formate, contrary to the
literature [21], was unsuccessful under our standard conditions (entry
10). Two other solvents were also tested as reaction medium (entries
11, 12), which results obviously demonstrate that DMF is far the most
suitable solvent of the palladium catalysed carboxylation reaction.
Considering the satisfactory results, no other optimization reactions
seemed to be necessary, therefore our attention was turned to potential
aryloxycarbonylation reactions.
Toluene was used as solvent.
f
DCE was used as solvent.
(100), 137 (2), 95 (10), 82 (15), 57 (66).
4-terc-butyl-1-cyclohexene-1-carboxylic
acid
3-ethox-
ycarbonylphenyl ester (2k)
δH (500 MHz, CDCl3) 7.96-7.30 (5H, m, Ph, C = CH), 4.41 (2H, q,
7.1 Hz, OCH2), 2.67-2.64 (1H, m, CHaHbCCOOH), 2.40-2.28 (2H, m,
CHaHbCCOOH; C = CHCHaHb), 2.09-1.99 (2H, m, C = CHCHaHb,
CHaHbCH2CCOOH), 1.41-1.38 (4H, m, CHaHbCH2CCOOH overlapping
CH3), 1.25-1.23 (1H, m, tBuCH), 0.95 (9H, s, tBu). δC (125.7 MHz,
Table 2
Optimization of iodo cyclohexene aryloxycarbonylation.
Entry
Variation from the common conditions
Conv.b
[%]
Yieldb (1c) [%]
Yieldb (1b) [%]
1
2
common conditionsa
anhydrous DMF was used
mol. sieve was added
0.3 mmol of Ac2O
97
> 99
97
1
6
90
80
3
1
90
4
> 99
> 99
> 99
90
6
79
5
2.0 mmol of Ac2O
20
n.d.
1
80
6
4.0 mmol of HCOOH
toluene as solvent
> 99
23
7
8
THF as solvent (reflux temp.)
DCE as solvent (reflux temp.)
MEK as solvent (reflux temp.)
tpp as ligand
77
10
trace
10
trace
4
63
9
3
trace
82
10
11
12
13
14
15
16
17
18
> 99
80
80
dppp as ligand
77
73
dppe as ligand
76
5
71
Xantphos as ligand
> 99
> 99
> 99
30
12
6
77
2 mmol phenol
80
6 mmol phenol
12
4
77
MeOH instead of phenol (as solvent as well)
Na2CO3 as base
3
92
> 99
trace
a
Common conditions: Pd(OAc)2: 0.01 mmol, dppb: 0.02 mmol, substrate 0.5 mmol, phenol: 1.0 mmol Et3N: 2.5 mmol, HCOOH: 1.0 mmol, Ac2O: 1.0 mmol,
solvent: 5 mL of DMF, temperature: 100 °C, reaction time: 24 h.
b
Determined by GC.
146

B. Bartal et al.
MolecularCatalysis467(2019)143–149
As starting point, the conditions of the previously optimised car-
phenoxycarbonylation reactions as well (Table 3). tert-Butyl-substituted
1-iodocyclohexene and iodobornene proved to be proper substrates of
the reactions and provide the corresponding carboxylic acids and
phenyl esters in good or moderate yields (2b, 3b and 2c, 3c respec-
tively). Additionally, steroidal structures with biological relevance have
been also studied and tolerated well in the reactions. The transforma-
tion of iodoalkenyl functionalities as part of the steroidal ring system
(estrene (4b, 4c) and androstene (5b, 5c) derivatives) or in side chain
(pregnene derivative (6b, 6c)) are equally suitable for carbonylation,
but in some cases lower yields can be achieved.
boxylation reaction were chosen in the presence of 1 mmol phenol as
nucleophile to get the corresponding phenyl ester derivative. As it can
be seen (Table 2, entry 1), only 1% of target product was formed beside
large amount of carboxylic acid. Small amount of dimerization product
can be also identified. In the next runs always only one parameter was
varied (entries 2–18). The application of anhydrous solvent and mole-
cular sieve in order to decrease the carboxylic acid formation proved to
be unsuccessful (entries 2 and 3). Small increase of ester formation was
observed using double amount of acetic anhydride (entry 5), while no
ester was detected by increased formic acid concentration (entry 6).
Next, other solvents and various ligands were tested in the phe-
noxycarbonylation reaction, which unfortunately still did not lead to
success. It is worth mentioning that the application of methyl ethyl
ketone as solvent and the large bite angle ligand Xantphos gave slightly
better results (entries 10 and 14). Larger amount (4 or 12 equivalents)
of the nucleophile slightly but not satisfactory increases the ester for-
mation (entries 15, 16). Using methanol as solvent and nucleophile as
well gave poor results. Finally, using sodium carbonate base instead of
triethylamine, strikingly turn the reaction towards the formation of the
wished phenyl ester (entry 18). Simply changing the base, almost ex-
clusive ester formation can be achieved with acceptable conversions,
which opened the way for further phenoxycarbonylation reactions.
With the optimized reaction conditions in hand, we examined the
transformation of other model substrates in carboxylation and
In order to get a deeper insight into the limits of the reaction, io-
doalkyne, alkyl halides and bromo-substituted derivatives were also
tested. The carbonylation of the reactive 2′-iodophenylacetylene was
failed, since the homocoupling reaction dominated under both reaction
conditions providing 1,4-diphenyl-buta-1,3-diyne (7b) as product.
Alkenyl bromides worked well in carboxylation reactions, nevertheless
bromo-substituted derivatives usually perform poorer in catalytic trans-
formations. Cinnamic acid (8b) and tiglic acid (9b) can be synthesised in
moderate yields. It is worthwhile to mention, that the formation of trans
carboxylic acid isomers were significantly preferred. Accordingly, 97% of
trans-cinnamic acid and 100% of trans-tiglic acid were formed, i.e., no
formation of the cis isomer of tiglic acid was observed, though the sub-
strates have ca. 1/1 cis/trans composition. That is, the cis isomers (8a’
and 9a’) was (partially) isomerised to the corresponding trans isomer (8a
and 9a) and converted to the carbonylated product.
Table 3
Carboxylation and aryloxycarbonylation reactions of the tested substrates.
aReaction conditions (carboxylation): Pd(OAc)2: 0.01 mmol, dppb: 0.02 mmol, substrate
0.5 mmol, Et3N: 0.5 mmol, HCOOH: 1.0 mmol, Ac2O: 1.0 mmol, DMF: 5 mL, reaction time:
b
20 h.
Reaction conditions (phenoxycarbonylation): Pd(OAc)2: 0.01 mmol, Xantphos:
0.02 mmol, substrate 0.5 mmol, Phenol: 3.0 mmol, Na2CO3: 2.5 mmol, HCOOH: 1.0 mmol,
Ac2O: 1.0 mmol, DMF: 10 mL, reaction time: 20 h.c Isolated yields. d Yields determined by GC.
147

B. Bartal et al.
MolecularCatalysis467(2019)143–149
Scheme 2. Esterification reactions with al-
cohol and phenol nucleophilesa.
a Reaction conditions (unless otherwise stated):
Pd(OAc)2: 0.01 mmol, Xantphos: 0.02 mmol,
substrate: 0.5 mmol, Nucleophile: 3.0 mmol,
Na2CO3: 2.5 mmol, HCOOH: 1.0 mmol, Ac2O:
1.0 mmol, DMF: 10 mL, reaction time: 20 h.
b
Yields determined by GC. Alcohols (MeOH,
EtOH) were used as solvent.
Scheme 3. Proposed mechanism of hydroxy/alkoxy/aryloxycarbonylation of haloalkenes.
Unfortunately the syntheses of the corresponding phenyl esters (8c,
reacted readily and the corresponding aryl esters were produced in
moderate yields (47–61%). Ethyl carboxylate derived phenols are also
capable partners (2 j, 2k), but sterically more crowded ortho position
hinders the reaction.
9c) were not succeeded, not even under harsher conditions or longer
reaction times.
Beside phenol, different O-nucleophiles were also tested in the es-
terification reaction without additional optimization. It is turned out,
that aliphatic alcohols do not perform well compared to phenol (2d,
2e), therefore various phenol derivatives were chosen for further ex-
periments. Moderate yields of the corresponding products can be suc-
cessfully achieved using 4-tert-butyl-1-iodocyclohexene as substrate
(Scheme 2). para-Substituted phenols with electron withdrawing or
donating groups (2f, 2 g), as well both naphthol isomers (2h, 2i)
Based on the above experiments, we can state (as it is recommended
by cited authors [21,22,25]), that the reaction involves the inter-
mediacy of mixed anhydride formed in situ by the reaction of formic
acid and acetic anhydride, which releases carbon monoxide (Scheme 3).
First the oxidative addition of alkenyl halides on palladium(0)
complex to give the corresponding alkenylpalladium species (A). It is
followed by the coordination and insertion of the in situ generated
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B. Bartal et al.
MolecularCatalysis467(2019)143–149
carbon monoxide providing the terminal carbonyl complex (B) and the
acyl (C) complex. The nucleophilic attack of water (or alcohol or
phenol) resulted in the formation of the acyl-alkoxy/aryloxy palladium
(II) complex (D). The carboxylic acid or ester products are formed via
reductive elimination and the initial Pd(0) complex (E) for next cata-
lytic cycle is re-formed. The same species can be responsible for the
observed cis-trans isomerization of some derivatives mentioned above
(8a and 9a), by the assistance of the nucleophile in the course of alkyl
complex formation followed by β-hydride elimination.
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