Pd-catalyzed chemoselective carbonylation of aminophenols with iodoarenes: Alkoxycarbonylation vs aminocarbonylation

Article abstract of DOI:10.1021/ja508588b

Palladium-catalyzed chemoselective carbonylation of aminophenols with iodoarenes was realized by changing ligand and base. 3- or 4-Aminophenols afforded esters in high yields and selectivities using 1,3-bis(diphenylphosphino)propane as the ligand and K₂CO₃ as the base, and gave amides in high yields and selectivities using 1,3-bis(diisobutylphosphino)propane as the ligand and DBU as the base. 2-Aminophenol only gave amides in high yields under both conditions.

Full text of DOI:10.1021/ja508588b

Communication
pubs.acs.org/JACS
Pd-Catalyzed Chemoselective Carbonylation of Aminophenols with
Iodoarenes: Alkoxycarbonylation vs Aminocarbonylation
Tongyu Xu and Howard Alper*
Centre for Catalysis Research and Innovation, Department of Chemistry, University of Ottawa, 10 Marie Curie, Ottawa, Ontario K1N
6N5, Canada
S
* Supporting Information
Scheme 1. Conventional Mechanism for the Carbonylation of
Aryl Halides
ABSTRACT: Palladium-catalyzed chemoselective carbon-
ylation of aminophenols with iodoarenes was realized by
changing ligand and base. 3- or 4-Aminophenols afforded
esters in high yields and selectivities using 1,3-bis-
(diphenylphosphino)propane as the ligand and K2CO3 as
the base, and gave amides in high yields and selectivities
using 1,3-bis(diisobutylphosphino)propane as the ligand
and DBU as the base. 2-Aminophenol only gave amides in
high yields under both conditions.
ransition metal-catalyzed carbonylation reactions are of
1,2
Tvalue for a variety of organic syntheses.
As a relatively
inexpensive and readily available C1 source, carbon monoxide
can be used to prepare various carbonyl containing products
from a broad scope of substrates.3,4 Esters and amides are
important motifs in natural products, agrochemicals, materials,
and pharmaceutical agents.5 Coupling reagents (e.g., EDC,
HOBt, and CDI) or activated carboxylic acids (e.g., acid
chlorides, esters, and anhydrides) are usually used for the
synthesis of esters and amides.6 However, the routes can produce
stoichiometric amounts of waste, which increases the cost of
commercial processes. In this respect, the atom-efficient
palladium-catalyzed carbonylation of aromatic halides has been
investigated extensively for the synthesis of esters and amides.7
The carbonylation of aniline and phenol derivatives has also
been investigated extensively for the preparation of the
corresponding amides and esters.1,4 These reactions may
proceed via (i) catalyst generation, (ii) oxidative addition, (iii)
CO coordination, (iv) carbonyl insertion through ligand
migration, (v) nucleophilic attack, and (vi) product release
(Scheme 1).8 Molecules containing both hydroxyl and amino
functionalities are common in drug intermediates and natural
products.9 The question arises as to the pathway for the
palladium-catalyzed carbonylation of aminophenols (eq 1). It is
conceivable that the selectivity for amides would be high given
that the amino group is a better nucleophile than the hydroxyl
function. However, other pathways may take precedence. Herein
we report useful methodology for the selective carbonylation of
aminophenols with iodoarenes, leading to esters or amides as the
principal reaction products.
80% isolated yield. The double carbonylation product 5a was
obtained in 2% yield, and no amide (4a) was formed (entry 1).
Bases and solvents were investigated using PPh3 as the ligand
(see Supporting Information). Using KF gave 3a in 82% yield,
with 4a and 5a obtained in only 2% and 4% yields, respectively
(entry 2). When the organic base, Et3N, was used, 3a was the
major product (75%) together with a small amount of 4a and 5a
(entry 3). Similar results were obtained using DMSO instead of
acetonitrile (entry 4). When DMF was used as the solvent, 3a
and 4a were obtained in 61% and 23% yields, respectively (entry
5). The yield of 4a increased when DBU was used in MeCN or
DMSO (entries 6 and 7). The ester 3a was the major product
when Et3N was used in DMSO (entry 8). The effect of ligands on
the carbonylation reaction was then investigated (see Supporting
Information). Under conditions favoring ester formation (entry
1), the bidentate ligand 1,3-bis(diphenylphosphino)propane
(DPPP) afforded 3a as the major product in 85% yield (entry 9).
When the isobutyl replaced the phenyl group in DPPP,
trialkylphosphine ligands 1,3-bis(diisobutylphosphino)propane
(DIBPP) gave 3a and 4a in 33% and 50% yields, respectively
(entry 10). When DBU was used as the base, the amide 4a was
obtained in 81% yield, while 3a was formed in only 8% yield
(entry 11). The reactions were also carried out in the absence of
ligand under the conditions of entries 9 and 11. K2CO3 gave the
ester as the major product, and DBU gave the amide 4a as the
major product (entries 12 and 13), indicating that base also plays
an important role in the selectivity.
Initially, 4-aminophenol (1a) was used as the model substrate
to optimize the conditions for the reaction (Table 1). The
carbonylation of 4-aminophenol (1a) and 4-iodotoluene (2a)
was initially carried out in MeCN, using PPh3 as the ligand and
K2CO3 as the base, affording ester 3a in high selectivity and in
Received: August 31, 2014
© XXXX American Chemical Society
A
dx.doi.org/10.1021/ja508588b | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
Table 1. Screening of the Reaction Conditions for the
Carbonylation of 4-Aminophenol
Table 2. Selective Carbonylation of 4-Aminophenol
a
a
Derivatives
b
yield (%)
entry
ligand (mol %)
solvent
base
3a
4a
5a
1
PPh3
MeCN
MeCN
MeCN
DMSO
DMF
K2CO3
KF
80
82
75
80
61
30
13
70
85
33
8
2
4
3
4
2
5
3
3
1
5
4
5
3
2
PPh3
2
3
PPh3
Et3N
3
4
PPh3
K2CO3
K2CO3
DBU
2
5
PPh3
23
43
60
5
6
PPh3
MeCN
DMSO
DMSO
MeCN
MeCN
MeCN
MeCN
MeCN
7
PPh3
DBU
8
PPh3
Et3N
9
DPPP
DIBPP
DIBPP
K2CO3
K2CO3
DBU
10
11
12
13
50
81
9
K2CO3
DBU
58
10
62
a
Conditions: 0.5 mmol of 4-iodotoluene, 0.6 mmol of 4-aminophenol,
2 mol % Pd(OAc)2, Pd/P = 1:2, 1 mmol of base, 5 mL of solvent, 200
b
psi CO, 100 °C, 15 h. Isolated yield. DPPP = 1,3-bis-
(diphenylphosphino)propane. DIBPP = 1,3-bis(diisobutylphosphino)-
propane.
The selective carbonylation of 4-aminophenols was then
applied under conditions A and B (Table 2). After completion,
the reaction mixtures were analyzed by GC, and the product
ratios were used to indicate the ester/amide selectivity. The
results showed that the electronic property of substituents on the
iodoarenes had no effect on the selectivity for the ester or amide.
Iodoarene with electron-donating (Me and OMe, entries 1−4)
or electron-withdrawing (F and CO2Me, entries 4−8)
substituents successfully afforded esters under conditions A or
amides under conditions B in high yields and fine selectivities.
Steric hindrance on the iodoarene did not affect the selectivity
(entries 7−8). When methyl 2-iodobenzoate was reacted under
conditions B, subsequent reaction between the amide and
methoxycarbonyl substituent occurred to form isoindole-1,3-
dione derivative 4d in 67% yield (entry 8). Substituents on the 4-
aminophenol influence the selectivity and yield (entries 9−12). A
methyl substituent at the ortho position of the amino group had
no effect on the selectivity and yield of ester 3e under A
conditions (entry 9), but steric hindrance decreased the
selectivity of amide under B conditions (entry 10). The fluoride
at the ortho position of the hydroxyl group did not influence the
selectivity of the ester (3f) formation under conditions A, but the
yield decreased (entry 11).
Our reaction conditions were next applied to the carbon-
ylation of 3-aminophenol derivatives (Table 3). High selectivity
for esters and amides was realized using conditions A or B. 3-
Aminophenol reacted with 3-iodoanisole to selectively afford
ester 3g (conditions A) in 77% yield and amide 4g (conditions
B) in 84% yield (entries 1 and 2). With the methyl substituent at
the 2-position, the selectivity for the amide decreased (entries 3
and 4). Steric hindrance apparently has greater influence on
amide, rather than ester formation. When 6-methyl- and 6-
methoxy-substrates 1f and 1g were reacted with 4-iodotoluene
(entries 5−8), there was no noticeable influence on the extent of
formation of amides under conditions B. A significant decrease in
a
Conditions A: 0.6 mmol of 1, 0.5 mmol of 2, 2 mol % Pd(OAc)2, 2−
3 mmol % DPPP, 1 mmol of K2CO3, 5 mL of MeCN, 200 psi CO, 100
°C, 15 h. Conditions B: 0.6 mmol of 1, 0.5 mmol of 2, 2 mol %
Pd(OAc)2, 2−3 mmol % DIBPP, 1 mmol of DBU, 5 mL of MeCN,
b
c
200 psi CO, 100 °C, 15 h. GC area ratio of 3/4. Isolated yield.
Table 3. Selective Carbonylation of 3-Aminophenol
Derivatives
a
c
yield (%)
b
entry
1
2
3/4
3
4
5
1
2
1d
1d
1e
1e
1f
2f
A
B
A
B
A
B
A
B
A
B
>99/1
4/96
3g (77)
2f
4g (84)
4h (75)
3
2b
2b
2a
2a
2a
2a
2e
2e
99/1
3h (92)
3h (6)
3i (70)
4
11/89
97/3
5
5i (10)
5j (10)
6
1f
3/97
4i (85)
4j (10)
4j (80)
7
1g
1g
1h
1h
73/27
1/99
3j (41)
8
9
97/3
3k (95)
3k (8)
10
12/88
4k (73)
a
Conditions A: 0.6 mmol of 1, 0.5 mmol of 2, 2 mol % Pd(OAc)2, 2−
3 mmol % DPPP, 1 mmol of K2CO3, 5 mL of MeCN, 200 psi CO, 100
°C, 15 h. Conditions B: 0.6 mmol of 1, 0.5 mmol of 2, 2 mol %
Pd(OAc)2, 2−3 mmol % DIBPP, 1 mmol of DBU, 5 mL of MeCN,
b
c
200 psi CO, 100 °C, 15 h. GC area ratio of 3/4. Isolated yield.
the selectivity for ester under conditions A was observed (entries
5 and 7), and 2a was not consumed, indicating that the electronic
effect was greater than the steric effect, and the electron-donating
B
dx.doi.org/10.1021/ja508588b | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
substituent disfavored the formation of the ester under
conditions A. Substrate 1h with the fluoride substituent on the
para position of the hydroxyl group (entry 9) afforded the ester
under conditions A in high yield and high selectivity,
demonstrating that the electronic-withdrawing group favors
ester formation.
When 2-aminophenol (1i) was carbonylated with 4-
iodotoluene, only the amide (4l) was obtained in high yield
under A or B conditions (see Supporting Information). The
coordination at both nitrogen and oxygen might lead to this
result.10
isolated yield under A conditions. Ester 3m was also the major
product (70% yield) under B conditions, indicating the potential
importance of the steric factors for this reaction. Also, the
coordination of nitrogen to the palladium intermediate may be
critical to the catalytic process. 3-Aminopropanol gave the amide
(4n) in 75% yield under B conditions, but poor selectivity
resulted using A conditions. The method was also applied to the
carbonylation of 4-methylphenol with 4-iodoaniline and 4-
methylaniline with 4-iodophenol. The ester 13 was obtained in
75% yield under A conditions, and the amide 16 was obtained in
61% yield under B conditions.
In conclusion, the palladium-catalyzed selective carbonylation
of 3- and 4-aminophenols was realized, affording esters in high
yields and selectivities using 1,3-bis(diphenylphosphino)-
propane as the ligand and K2CO3 as the base, while producing
amides in high yields and selectivities using 1,3-bis-
(diisobutylphosphino)propane as the ligand and DBU as the
base. 2-Aminophenol only gave the amide in high yields under
both conditions. These results demonstrate that the nature of the
phosphine ligand is key to the selectivity of the catalytic reactions.
These chemoselective reactions have considerable potential for
organic synthesis.
According to the conventional mechanism outlined in Scheme
1, the amide should be favored over the ester because the amino
group is a better nucleophile than the hydroxyl group. However,
in our case, the selectivity was dependent on the ligand and the
base. Both are important in the process (Table 1, entries 9−13).
To determine the selectivity, p-toluoyl chloride (6) was reacted
with 4-aminophenol in MeCN using K2CO3 and DBU as the
base, respectively (see Supporting Information). Surprisingly,
the selectivity of 3a/4a was the reverse of the palladium-catalyzed
carbonylation of 4-aminophenol.
We then carried out two reactions using a mixture of 4-
methylphenol (7) and 4-methylaniline (8) instead of 4-
aminophenol under conditions A and B, respectively (see
Supporting Information). The selectivity for ester (9) or amide
(10) was consistent with the result of 4-aminophenol. Buchwald
and co-workers observed that the ester was formed as an
intermediate in the palladium-catalyzed aminocarbonylation of
aryl chlorides using sodium phenoxide as the base.11 However, in
our work, we used excess aminophenol and base, and ester 3 did
not convert to the amide even using 3 equiv of aminophenol.
Prolonging the reaction time or raising the reaction temperature
to 120 °C did not alter the selectivity, suggesting a different
mechanism here. Lei and co-workers reported a base-induced
mechanistic variation for the palladium-catalyzed alkoxycarbo-
nylation of aryl iodides.12 Sodium alkoxide was used instead of
tertiary amines in their work, affording high yields of ester while
tertiary amine gave low product yields. They proposed that
transmetalation with sodium alkoxide led to the key
intermediate. The ligand effect was not mentioned in their work.
Treatment of aroyl chlorides with Pd(0) catalysts can form
ArCOPdCl.13 Unfortunately, preparation of the complex
ArCOPdCl bearing DPPP or DIBPP was fruitless. We prepared
(p-TolCO)Pd(PPh3)2Cl from Pd(PPh3)4 and p-toluoyl chloride.
Then (p-TolCO)Pd(PPh3)2Cl was used to react with 4-
aminophenol quantitatively or to catalyze the carbonylation
using K2CO3 or DBU as base (see Supporting Information),
affording ester or amide selectively consistent to the palladium-
catalyzed carbonylation of 4-aminophenol. The results indicate
that ArCOPdX may be an intermediate, and coordination of NH2
or OH to the palladium intermediate occurred in the process,
affording products after reductive elimination. On the basis of the
experimental results and literature reports, it is reasonable to
conclude that the nature of ligand is key to the selectivity.14 An
electron-rich ligand favors the coordination of the amino group
rather than the hydroxyl group. The base assists the selectivity.
Inorganic base can react with phenol to form phenoxide, which
facilitates transmetalation with the palladium intermediate to
form ester.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures and spectral data. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
* howard.alper@uottawa.ca
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful to Cytec Canada and to the Natural Sciences and
Engineering Research Council of Canada for support of this
research.
REFERENCES
■
(1) (a) Kollar
́
, L. Modern Carbonylation Methods; Wiley-VCH Verlag:
Weinheim, Germany, 2008. (b) Beller, M. Catalytic Carbonylation
Reactions; Springer: Berlin, Germany, 2006. (c) Gadge, S. T.; Bhanage,
B. M. RSC Adv. 2014, 4, 10367. (d) Sumino, S.; Fusano, A.; Fukuyama,
T.; Ryu, I. Acc. Chem. Res. 2014, 47, 1563. (e) Wu, X.-F.; Neumann, H.;
Beller, M. ChemCatChem 2013, 6, 229. (f) Wu, X.-F.; Neumann, H.;
Beller, M. Chem. Rev. 2013, 113, 1. (g) Wu, X.-F.; Neumann, H.; Beller,
M. ChemCatChem 2012, 4, 447. (h) El Ali, B.; Alper, H. Synlett 2000,
161. (i) Liu, Q.; Zhang, H.; Lei, A. Angew. Chem., Int. Ed. 2011, 50,
10788.
(2) For selected references, see: (a) Mulzer, M.; Tiegs, B. J.; Wang, Y.
P.; Coates, G. W.; O’Doherty, G. A. J. Am. Chem. Soc. 2014, 136, 10814.
(b) Li, S. H.; Chen, G.; Feng, C.-G.; Gong, W.; Yu, J.-Q. J. Am. Chem.
Soc. 2014, 136, 5267. (c) Volla, C. M. R.; Backvall, J.-E. Org. Lett. 2014,
̈
16, 4174. (d) Fang, X.; Li, H.; Jackstell, R.; Beller, M. Angew. Chem., Int.
Ed. 2014, 53, 9030. (e) Li, W.; Liu, C.; Zhang, H.; Ye, K.; Zhang, G.;
Zhang, W.; Duan, Z.; You, S.; Lei, A. Angew. Chem., Int. Ed. 2014, 53,
2443. (f) Chen, M.; Ren, Z.-H.; Wang, Y.-Y.; Guan, Z.-H. Angew. Chem.,
Int. Ed. 2013, 52, 14196.
(3) For selected references, see: (a) Bai, Y.; Davis, D. C.; Dai, M.
Angew. Chem., Int. Ed. 2014, 53, 6519. (b) Ferguson, J.; Zeng, F. Z.;
Alwis, N.; Alper, H. Org. Lett. 2013, 15, 1998. (c) Kippo, T.; Hamaoka,
K.; Ryu, I. J. Am. Chem. Soc. 2013, 135, 632. (d) Takahashi, K.;
Yamashita, M.; Nozaki, K. J. Am. Chem. Soc. 2012, 134, 18746.
A secondary aminophenol and an aliphatic aminoalcohol were
subjected to the carbonylation reaction with 4-iodotoluene (see
Supporting Information). We were pleased to observe that 4-
isopropylaminophenol (1j) afforded the ester (3m) in 93%
C
dx.doi.org/10.1021/ja508588b | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
(e) Chikkali, S. H.; Bellini, R.; de Bruin, B.; van der Vlugt, J. I.; Reek, J. N.
H. J. Am. Chem. Soc. 2012, 134, 6607. (f) Fleischer, I.; Dyballa, K. M.;
Jennerjahn, R.; Jackstell, R.; Franke, R.; Spannenberg, A.; Beller, M.
Angew. Chem., Int. Ed. 2013, 52, 2949. (g) Wang, L.; Wang, Y.; Liu, C.;
Lei, A. Angew. Chem., Int. Ed. 2014, 53, 5657. (h) Zhang, H.; Shi, R.;
Ding, A.; Lu, L.; Chen, B.; Lei, A. Angew. Chem., Int. Ed. 2012, 51, 12542.
(4) (a) Brennfuhrer, A.; Neumann, H.; Beller, M. Angew. Chem., Int. Ed.
̈
2009, 48, 4114. (b) Wu, X.-F.; Neumann, H.; Beller, M. Chem. Soc. Rev.
2011, 40, 4986. (c) Kiss, G. Chem. Rev. 2001, 101, 3435. (d) Driller, K.
M.; Prateeptongkum, S.; Jackstell, R.; Beller, M. Angew. Chem., Int. Ed.
2011, 50, 537. (e) Wu, X.-F.; Fang, X. J.; Wu, L. P.; Jackstell, R.;
Neumann, H.; Beller, M. Acc. Chem. Res. 2014, 47, 104. (f) Franke, R.;
Selent, D.; Borner, A. Chem. Rev. 2012, 112, 5675. (g) Chen, J.; Natte,
̈
K.; Spannenberg, A.; Neumann, H.; Langer, P.; Beller, M.; Wu, X.-F.
Angew. Chem., Int. Ed. 2014, 53, 757.
(5) (a) Pattabiraman, V. R.; Bode, J. W. Nature 2011, 480, 471.
(b) Cupido, T.; Tulla-Puche, J.; Spengler, J.; Albericio, F. Curr. Opin.
Drug Discovery Dev. 2007, 10, 768. (c) Locatelli, C.; Filippin-Monteiro,
F. B.; Creczynski-Pasa, T. B. Eur. J. Med. Chem. 2013, 60, 233.
(d) Fonseca, A. C.; Gil, M. H.; Simoes, P. N. Prog. Polym. Sci. 2014, 39,
1291.
(6) (a) Valeur, E.; Bradley, M. Chem. Soc. Rev. 2009, 38, 606.
(b) Montalbetti, C.; Falque, V. Tetrahedron 2005, 61, 10827.
(7) (a) Friis, S. D.; Skrydstrup, T.; Buchwald, S. L. Org. Lett. 2014, 16,
4296. (b) Skogh, A.; Fransson, R.; Skold, C.; Larhed, M.; Sandstrom, A.
̈
̈
J. Org. Chem. 2013, 78, 12251. (c) Watson, D. A.; Fan, X. X.; Buchwald,
S. L. J. Org. Chem. 2008, 73, 7096. (d) Schranck, J.; Tlili, A.; Neumann,
H.; Alsabeh, P. G.; Stradiotto, M.; Beller, M. Chem.Eur. J. 2012, 18,
15592. (e) Chen, J.; Natte, K.; Spannenberg, A.; Neumann, H.; Langer,
P.; Beller, M.; Wu, X.-F. Angew. Chem., Int. Ed. 2014, 53, 7579.
(8) (a) Barnard, C. F. J. Organometallics 2008, 27, 5402. (b) Barnard,
C. F. J. Org. Process Res. Dev. 2008, 12, 566.
(9) (a) Niemann, G. J.; Liem, J.; van der Kerk-van Hoof, A.; Niessen,
W. M. A. Phytochemistry 1992, 31, 3761. (b) Caldarelli, A.; Minazzi, P.;
Canonico, P. L.; Genazzani, A. A.; Giovenzana, G. B. J. Enzyme Inhib.
Med. Chem. 2013, 28, 148. (c) Marrone, T. J.; Luty, B. A.; Rose, P. W.
Perspect. Drug Discovery 2000, 20, 209.
(10) Perry, R. J.; Wilson, B. D.; Miller, R. J. J. Org. Chem. 1992, 57,
2883.
(11) Martinelli, J. R.; Clark, T. P.; Watson, D. A.; Munday, R. H.;
Buchwald, S. L. Angew. Chem., Int. Ed. 2007, 46, 8460.
(12) Hu, Y. H.; Liu, J.; Lu, Z. X.; Luo, X. C.; Zhang, H.; Lan, Y.; Lei, A.
̈
W. J. Am. Chem. Soc. 2010, 132, 3153.
(13) (a) Quesnel, J. S.; Arndtsen, B. A. J. Am. Chem. Soc. 2013, 135,
16841. (b) Korsager, S.; Taaning, R. H.; Skrydstrup, T. J. Am. Chem. Soc.
2013, 135, 2891. (c) Fitton, P.; Johnson, M. P.; McKean, J. E. Chem.
Commun. 1968, 6.
(14) (a) Maiti, D.; Buchwald, S. L. J. Am. Chem. Soc. 2009, 131, 17423.
(b) Jones, G. O.; Liu, P.; Houk, K. N.; Buchwald, S. L. J. Am. Chem. Soc.
2010, 132, 6205. (c) Shafir, A.; Lichtor, P. A.; Buchwald, S. L. J. Am.
Chem. Soc. 2007, 129, 3490.
D
dx.doi.org/10.1021/ja508588b | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX