Synthesis and Characterization of Carboxylic Acids Bearing Poly(ethylene glycol) Chains

Article abstract of DOI:10.1055/s-0036-1591840

Carboxylic acids 1a and 1b bearing three poly(ethylene glycol) (PEG) chains and carboxylic acid 1c bearing one PEG chain were designed and synthesized. The carboxylic acids 1a - c were fully characterized by NMR and ESI-HRMS analyses. In a Pd-catalyzed ae

Full text of DOI:10.1055/s-0036-1591840

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Georg Thieme Verlag Stuttgart · New York
2017, 28, A–D
letter
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Synlett
M. Satou et al.
Letter
Synthesis and Characterization of Carboxylic Acids Bearing
Poly(ethylene glycol) Chains
Motoi Satoua
Tetsuaki Fujihara*a
Jun Teraob
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Yasushi Tsuji*a
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a
Department of Energy and Hydrocarbon Chemistry,
Graduate School of Engineering, Kyoto University, Kyoto
615-8510, Japan
tfuji@scl.kyoto-u.ac.jp
ytsuji@scl.kyoto-u.ac.jp
b
Department of Basic Science, Graduate School of Arts
and Sciences, The University of Tokyo, Tokyo 153-8902,
Japan
Received: 29.09.2017
Accepted after revision: 30.10.2017
Published online: 04.12.2017
Me
O
DOI: 10.1055/s-0036-1591840; Art ID: st-2017-u0725-l
Me
Me
n
O
n
O
O
Abstract Carboxylic acids 1a and 1b bearing three poly(ethylene gly-
col) (PEG) chains and carboxylic acid 1c bearing one PEG chain were de-
signed and synthesized. The carboxylic acids 1a–c were fully character-
ized by NMR and ESI-HRMS analyses. In a Pd-catalyzed aerobic
oxidation of 1-phenylethanol, 1a and 1b worked well as carboxylate li-
gands.
O
O
(a)
n
O
Me
n
P
O
O
Me
Me
Key words carboxylic acids, poly(ethylene) glycol, oxidation, alcohol,
palladium
O
O
O
O
O
O
O
n
O
O
n
1
O
Me
Poly(ethylene glycol) (PEG) derivatives are widely used
n
(
n = 4, ca.12)
owing to their low toxicity, high conformational flexibility,
and ease of availability. Various PEG materials with differ-
ent molecular weights and various terminal functionalities
are readily and commercially available.
O
n
O
Me
n
Me
(b)
We have been interested in the nature of PEG and devel-
oped novel ligands bearing PEGs as modification motifs
Me
O
O
O
O
O
O
O
Me
n
n
n
N
N
2,3
Me
O
n
(Figure 1). Triarylphosphines bearing PEG chains on the
O
O Me
n
periphery enhanced the catalytic activity in a Pd-catalyzed
Suzuki–Miyaura coupling reaction using less reactive aryl
Me
O
O
Me
n
(
n = 4, ca.12, ca.17)
2
chlorides as substrates (Figure 1, a). Furthermore, we syn-
Figure 1 (a) Phosphine ligands bearing PEG chains; (b) N-heterocyclic
carbene ligands bearing PEG chains.
thesized a series of N-heterocyclic carbene (NHC) ligands
3
bearing PEG chains (Figure 1, b). These ligands increased
3a
the catalytic activity of Pd-catalyzed Miyaura borylation
and Suzuki–Miyaura coupling reactions.3a,b
Herein, we report on the design and synthesis of a series
of carboxylic acids 1a–c bearing PEG chains (Figure 2), be-
cause carboxylates are known as common ligands for tran-
O
OH
O
Me
O
O
O
O Me
n
n
O
O Me
n
HO
4
5
O
O Me
n
sition-metal complexes, metalloproteins, and coordina-
6
tion polymers. We found that the carboxylic acids 1a and
1
a: (n = 3)
b: (n = ca.17)
d: (n = 0)
1c: (n = ca.16)
1
1b bearing three PEG chains worked well in the Pd-cata-
1
lyzed aerobic oxidation of 1-phenylethanol.
Figure 2 A series of carboxylic acids bearing PEG chains in this study
©
Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–D

B
Synlett
M. Satou et al.
Letter
First, we synthesized 1a bearing three PEG chains (n = 3)
in the α-position (Scheme 1, a). To synthesize the desired
carboxylic acids, inexpensive and easy-to-access pen-
taerythritol (2) was used as a starting material. The mono-
trityl (CPh )-protected compound 3 is a key intermediate
3
for successful introduction of three PEG chains, and it
was synthesized according to a published procedure.7
MsO(CH CH O) Me (4a) was prepared from the corresponding
2
2
3
commercially available PEG mono-ether, HO(CH CH O) Me.
2
2
3
The reaction of 3 with 4a produced 5a. Without thor-
oughly purifying 5a, deprotection with trifluoroacetic acid
afforded the corresponding alcohol 6a in 68% yield from 3.
As for oxidation of 6a to 1a, Jones oxidation conditions con-
siderably cleaved the PEG chains of 6a. After several trials,
Figure 3 ESI-HRMS spectrum of 1b (positive mode)
Each carboxylic acid was identified by NMR analysis and
1
13
1
a was successfully obtained in a two-step reaction: Swern
mass spectrometry. H NMR and C NMR spectra of 1a–d
confirmed the structures (see Supporting Information for
details). The ESI-HRMS spectrum of 1a exhibited a peak at
m/z 611.3237, which was assigned as a sodium adduct of 1a
(m/z 611.3249 calcd for C H O Na). In contrast, the mass
8
9
oxidation, which afforded 7a, and Pinnick oxidation,
which afforded 1a, in a high total yield (63% yield from 3).10
With regard to 1b bearing three longer PEG chains (n = ca.
17), a method similar to that used for 1a was adopted,
26
52 14
which employed MsO(CH CH O) Me (4b, n = ca. 17). The
spectrum of 1b showed molecular-weight distributions
comprising two sets of molecular ion peaks (Figure 3). The
former set of peaks was observed with m/z 14.7 intervals,
which corresponds to the one-third of 44 (–CH CH O–
2
2
n
corresponding carboxylic acid 1b was isolated in a total
11
yield of 27% (from 3) via 5b, 6b, and 7b. Here, these three
intermediates (5b, 6b, and 7b) were not purified and used
in the following reactions. Furthermore, 1c with one PEG
2
2
monomer unit). Therefore, these peaks were attributed to
the trivalent ion. A peak at m/z 835.4658, as indicated in
Figure 3, was in good agreement with the calculated value
for the trisodium adduct of 1b whose n = 17 (m/z 835.4681
12
chain (n = ca. 16) was synthesized by the known oxidation
of a commercially available PEG monoether, HO(CH CH O) Me
2
2
n
(n = ca. 17) (Scheme 1, b). For comparison, carboxylic acid
3+
1d bearing only three methoxy groups (n = 0, Figure 2) was
calcd for [C110H222O Na ] ). In the latter set, the peaks ap-
55 3
afforded by the Jones oxidation of 6d, which was synthe-
sized by trimethylation reaction of 2 (Scheme 1, c).
peared with m/z 22 intervals (i.e., half of 44) and were
therefore determined as divalent ions. The m/z value of the
peak indicated in Figure 3 (m/z 1241.7048) is assigned to a
MsO(CH2CH2O)nMe
OCPh3 4a (n = 3)
OH
OH
Et N
DMAP
OCPh3
O
3
4b (n = ca.17)
(
a) Ph CCl
+
O
3
HO
HO
OH
Me
O
O Me
n
DMF, rt, 19 h
NaH, THF, reflux
n
OH
OH
O
O
Me
n
2
3: 63%
5
a (n = 3)
5b (n = ca.17)
DMSO
(COCl)2
Et3N
H2O2
NaClO2
NaH2PO4•2H2O
TFA for 5a
HCl aq. for 5b
OH
H
O
HO
O
Me
O
O
O
O
Me
n
Me
O
O
O
O
Me
n
Me
O
O
O
O Me
n
n
n
MeCN/H2O (3:1), rt
n
CH2Cl2, –92 °C then rt
O
O
Me
n
O
O
Me
n
O
O Me
n
6
6
a (n = 3): 68% (from 3)
b (n = ca.17)
7
7
a (n = 3): 97%
b (n = ca.17)
1a (n = 3): 96% (63% from 3)
1b (n = ca.17): (27% from 3)
TEMPO
KBr
NaClO 5% aq.
OH
OH
OH
O
OH
OMe
O
MeI
NaH
Jones reagent
OMe MeO
O
O
Me
n
HO
(c)
MeO
(
b) HO(CH CH O) Me
HO
2
2
n
water, rt, overnight
THF, reflux, 19 h
acetone, rt, 18 h
OH
OMe
OMe
(
n = ca.17)
1c (n = ca.16): 89%
2
6d
1d
49%
67%
Scheme 1 Synthesis of carboxylic acids 1a–d
©
Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–D

C
Synlett
M. Satou et al.
Letter
disodium adduct of 1b whose n = 17 (m/z 1241.7076 calcd
1d without any PEG chains was not effective (27% yield, Ta-
ble 1, entry 4). When acetic acid was added, the product
was obtained in moderate yield (Table 1, entry 5). In the ab-
sence of carboxylic acid, acetophenone was obtained in low
yield (21% yield, Table 1, entry 6). In place of 1a, a simple
mixture of MeO(CH CH O) Me (8) and 1d (12 mol% and 4.0
2+
for [C110H222O Na ] ).
55
2
To gain insight into the structures of carboxylic acids
bearing PEG chains, conformational analysis of 1b was per-
13
14
formed using CONFLEX (MMFF94s force field ). Figure 4
a) shows the most stable structure of 1b (n = 17), wherein
(
2
2
3
long PEG chains have a folded structure and wrap-up the
carboxylic acid center. The folded structure in Figure 4 (a) is
much more stable by 80.6 kcal/mol (energy calculations by
B3LYP/6-31g(d)) than the all-trans and extended structures
shown in Figure 4 (b). From a conformational calculation,
multiple conformers with small energy differences were
found around the most stable structure. Thus, PEG chains
are considerably flexible due to C–C and C–O bond rotation.
We envisioned that such flexible and bulky structures of 1b
might function well as ligands in transition-metal-cata-
lyzed reactions.
mol%, respectively, 8/1d = 3) as a ligand afforded the prod-
uct in only 8% yield (Table 1, entry 7). Therefore, these re-
sults clearly indicate that PEG chains must be connected to
the carboxylic acid moiety in order to expedite the catalytic
activity. As a Pd precursor, PdCl (py) was also applicable
2
2
(Table 1, entry 8). When the reaction using 1a as the car-
boxylic acid was carried out in mesitylene, DMSO, 4-meth-
yltetrahydropyran, water, n-octane, and 1,2-dichlo-
roethane, the product was obtained in 45%, 30%, 18%, 9%, 8%
and 4% yields, respectively. The bulky and wrapped-up
structure as shown Figure 4 (a) might suppress the aggrega-
19
tion of the Pd center and prevent Pd black formation.
Table 1 Effect of Carboxylic Acids on Pd-Catalyzed Aerobic Oxidation
of 1-Phenylethanola
OH
O
Pd(OAc)2(py)2 (1 mol%)
ligand (4 mol%)
K2CO3 (10 mol%)
toluene, 80 °C, air, 14 h
0.5 mmol
Entry
Ligand system
Yield (%)b
1
2
3
4
5
6
7
1a
68
67
20
27
46
21
8
1b
1c
1d
Figure 4 Structures of 1b (n = 17). (a) The most stable structure by
CONFLEX (MMFF94s) and (b) all-trans-extended structure. The carboxy
group is represented by the ball and stick model, and the other parts
are indicated by the stick model.
AcOH
none
1d + 8c
1a
8d
66
a
Reaction conditions: 1-phenylethanol (0.50 mmol), Pd(OAc)
2 2
(py) (1.0
Previously, we reported that a pyridine ligand bearing a
rigid and bulky dendrimer moiety was highly effective in
mol%), carboxylic acid (4.0 mol%), K
0 °C for 14 h.
Determined by GC analysis using tridecane as an internal standard. The
yields were the average of 2 runs.
2
CO (10 mol%) in toluene (1.25 mL) at
3
8
b
15
the Pd-catalyzed aerobic oxidation of alcohols. The bulki-
ness of the pyridine ligand successfully suppressed Pd black
formation. On the other hand, carboxylate ligands also play
c
MeO(CH
2
CH
(py) (1.0 mol%) was used as a Pd precursor instead of
Pd(OAc) (py)
2 3
O) Me (8) (12 mol%, 0.060 mmol) was added.
d
PdCl
2
2
16
2
2
.
an important role in oxidation reactions. Therefore, we
used 1a–d as ligands in the Pd-catalyzed aerobic oxidation
1
7
of 1-phenylethanol.
In summary, we designed carboxylic acids with PEG
chains, and the desired carboxylic acids 1a and 1b were ef-
ficiently synthesized using pentaerythritol as a starting
material. In the Pd-catalyzed aerobic oxidation of 1-phenyl-
ethanol, 1a and 1b functioned as ligands to prevent catalyst
deactivation. Further research on the application of these
carboxylic acids in other catalytic reactions is under way.
The reaction was performed in the presence of a catalyt-
ic amount of Pd(OAc) (py) , 1a–d, and K CO in toluene at
2
2
2
3
8
0 °C under air (Table 1).18 Employing 1a bearing three PEG
chains (n = 3) as the ligand, acetophenone was obtained in
8% yield (Table 1, entry 1). In addition, 1b with three lon-
ger PEG chains (n = ca. 17) afforded the product in 67% yield
Table 1, entry 2). In contrast, 1c bearing one PEG chain (n =
ca. 16) did not work well (Table 1, entry 3). An addition of
6
(
©
Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–D

D
Synlett
M. Satou et al.
Letter
Funding Information
3.39 (s, 9 H). 13C NMR (126 MHz, DMSO-d ): δ = 173.5, 71.3,
6
7
0.5, 69.82, 69.78, 69.6, 69.5, 68.2, 58.0, 52.5. ESI-HRMS: m/z
This work was supported by JSPS KAKENHI Grant Number
JP16H01020 in Precisely Designed Catalysts with Customized Scaf-
+
[
M+Na] calcd for C26H52O14Na: 611.3249; found: 611.3237.
(
11) 1b was obtained as colorless oil (0.36 g, 27% yield from 3).
folding.
S
JP
S
K
A
K
E
N
H
I
Grant
P
J(1
6
H
0
1
0
2
0)
Spectroscopic Data of 1b
1
H NMR (400 MHz, CDCl ): δ = 3.73–3.58 (m, 211 H, signals of
3
CH protons were overlapped), 3.57–3.53 (m, 6 H), 3.38 (s, 9 H).
2
Supporting Information
13
C NMR (126 MHz, CDCl ): δ = 173.3, 71.9, 71.0, 70.6 (signals of
3
CH carbons were overlapped), 70.0, 69.1, 59.0, 53.1. ESI-HRMS:
2
Supporting information for this article is available online at
2+
m/z [M + 2Na] calcd for C110H220O56Na : 1241.7076; found:
2
https://doi.org/10.1055/s-0036-1591840.
S
u
p
p
ortioIgnfrm oaitn
S
u
p
p
ortioIgnfrm oaitn
1241.7048.
(12) Araki, J.; Zhao, C.; Ito, K. Macromolecules 2005, 38, 7524.
(
13) (a) Goto, H.; Osawa, E. J. Am. Chem. Soc. 1989, 111, 8950.
References and Notes
(b) Goto, H.; Osawa, E. J. Chem. Soc., Perkin Trans. 2 1993, 187.
(
(
(
14) (a) Halgren, T. A. J. Comput. Chem. 1999, 20, 720. (b) Halgren, T.
A. J. Comput. Chem. 1996, 17, 490.
15) Iwasawa, T.; Tokunaga, M.; Obora, Y.; Tsuji, Y. J. Am. Chem. Soc.
(
1) (a) Poly(Ethylene Oxide); Bailey, F. E. Jr.; Koleske, J. V., Eds.; Aca-
demic Press: New York, San Fransisco, 1976. (b) Poly(ethylene
glycol) Chemistry and Biological Applications; Harris, J. M.;
Zalipsky, S., Eds.; American Chemical Society: Washington, D.C.,
2
004, 126, 6554.
16) (a) Steinhoff, B. A.; Guzei, I. A.; Stahl, S. S. J. Am. Chem. Soc. 2004,
26, 11268. (b) John, L. C.; Gunay, A.; Wood, A. J.; Emmert, M. H.
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997.
2) (a) Fujihara, T.; Yoshida, S.; Terao, J.; Tsuji, Y. Org. Lett. 2009, 11,
121. (b) Fujihara, T.; Yoshida, S.; Ohta, H.; Tsuji, Y. Angew.
1
(
Tetrahedron 2013, 69, 5758.
2
(
17) (a) Blackburn, T. F.; Schwartz, J. J. Chem. Soc., Chem. Commun.
Chem. Int. Ed. 2008, 47, 8310.
1977, 157. (b) Nishimura, T.; Onoue, T.; Ohe, K.; Uemura, S. J. Org.
(
3) (a) Fujihara, T.; Yoshikawa, T.; Satou, M.; Ohta, H.; Terao, J.;
Tsuji, Y. Chem. Commun. 2015, 51, 17382. (b) Ohta, H.; Fujihara,
T.; Tsuji, Y. Dalton Trans. 2008, 379.
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Stahl S. S.; Chem. Rev.; 2017, 117: in press; DOI:
1
0.1021/acs.chemrev.7b00334
18) General Procedure for the Pd-Catalyzed Aerobic Oxidation of
-Phenylethanol
A 20 mL Schlenk flask was first charged with a CH Cl solution
(4) For selected reviews, see: (a) Ackermann, L. Chem. Rev. 2011,
(
111, 1315. (b) Ackermann, L. Acc. Chem. Res. 2014, 47, 281.
1
(5) (a) Tshuva, E. Y.; Lippard, S. J. Chem. Rev. 2004, 104, 987. (b) de
Boer, J. W.; Browne, W. R.; Feringa, B. L.; Hage, R. C. R. Chim.
2
2
(
ca. 1 mL) of carboxylic acid (in case it is liquid or sticky solid, 4
2
007, 10, 341.
6) (a) Ye, B. H.; Tong, M. L.; Chen, X. M. Coord. Chem. Rev. 2005, 249,
45. (b) Ahmad, N.; Chughtai, A. H.; Younus, H. A.; Verpoort, F.
mol%). Then, CH Cl was removed by gentle heating under
2
2
(
vacuum. The flask was further charged with a carboxylic acid
5
(
in case it is a solid, 4 mol%), Pd(OAc) (py) (1.9 mg, 5.0 μmol,
2
2
Coord. Chem. Rev. 2014, 280, 1.
1
.0 mol%), K CO (6.9 mg, 50 μmol, 10 mol%), toluene (1.25 mL),
2 3
(
(
(
7) Tanaka, K.; Tanaka, T.; Hasegawa, T.; Shionoya, M. Chem. Lett.
and Teflon-coated stirring bar under air. The resulting mixture
was stirred under air at room temperature for 1 min, and
further at 80 °C for 3 min. Next, 1-phenylethanol (61 mg, 0.50
mmol) was added at 80 °C, and the reaction was carried out at
the same temperature for 14 h under air. After the reaction, the
mixture was diluted with ethyl acetate (4 mL), and the solution
was passed through a pad of Celite. The yield of acetophenone
was determined by GC analysis relative to an internal standard
2
008, 37, 440.
8) Taillier, C.; Gille, B.; Bellosta, V.; Cossy, J. J. Org. Chem. 2005, 70,
097.
9) Vogt, H.; Baumann, T.; Nieger, M.; Bräse, S. Eur. J. Org. Chem.
006, 5315.
2
2
(
10) 1a was obtained as colorless oil (1.8 g, 63% yield from 3 ).
Spectroscopic Data of 1a
1
H NMR (500 MHz, CDCl ): δ = 3.68 (s, 6 H), 3.67–3.60 (m, 30 H,
3
(tridecane).
signals of CH2 protons were overlapped), 3.58–3.56 (m, 6 H)
(19) Komano, T.; Iwasawa, T.; Tokunaga, M.; Obora, Y.; Tsuji, Y. Org.
Lett. 2005, 7, 4677.
©
Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–D