Aminocarbonylation of Aryl Tosylates to Carboxamides

Article abstract of DOI:10.1021/acs.orglett.5b01283

The palladium - catalyzed aminocarbonylation of aryl tosylates with amines is reported. Suitable conditions were identified by high throughput reaction screening and then further optimized. The substrate scope of the reaction with respect to the aryl tosylate component and the amine component are reported. Competitive aminolysis of the aryl tosylates to afford the amine toluenesulfonamides and the phenol was not observed.

Full text of DOI:10.1021/acs.orglett.5b01283

Letter
pubs.acs.org/OrgLett
Aminocarbonylation of Aryl Tosylates to Carboxamides
Seungwon Chung,*,† Neal Sach,‡ Chulho Choi,† Xiaojing Yang,† Susan E. Drozda,† Robert A. Singer,§
and Stephen W. Wright*,†
§
†Biotherapeutics Chemistry and Chemical Research and Development, Pfizer Global Research and Development, Pfizer Global
Research and Development, 445 Eastern Point Road, Groton, Connecticut 06340, United States
‡Oncology Chemistry, Pfizer Global Research and Development, 10770 Science Center Drive, La Jolla, California 92121, United
States
S
* Supporting Information
ABSTRACT: The palladium - catalyzed aminocarbonylation
of aryl tosylates with amines is reported. Suitable conditions
were identified by high throughput reaction screening and
then further optimized. The substrate scope of the reaction
with respect to the aryl tosylate component and the amine
component are reported. Competitive aminolysis of the aryl tosylates to afford the amine toluenesulfonamides and the phenol
was not observed.
amine toluenesulfonamide had to be considered as a potentially
he synthesis of aryl and heteroaryl esters and amides from
Tthe corresponding aryl halides or triflates via palladium serious side reaction.5
We were encouraged by the recent successful development of
catalyzed carbonylation with carbon monoxide is a useful
procedure that is widely employed in organic synthesis, and
particularly in the synthesis of compounds pharmaceutical and
agricultural importance.1 The carbonylation of aryl and
heteroaryl triflates provides a synthetic transformation of
phenols and hydroxy-heteroaryl compounds into carboxylic
acid derivatives that makes use of a readily available and well-
populated starting material set, and frequently provides reliable
access to product regioisomers that are orthogonal to those
derived from readily available aryl and heteroaryl halides.2
During the course of a recent synthetic program, we found an
opportunity to convert readily available phenol starting materials
to carboxamide products by palladium catalyzed carbonylation.
While the use of the aryl triflates worked well, we considered the
eventual need to conduct this chemistry on significantly larger
scales and therefore the need to reduce the costs and
environmental impact of this transformation. While triflates are
useful, the trifluoromethanesulfonic anhydride from which they
are prepared is relatively expensive, and the triflate ion may not
necessarily be benign.3 We therefore considered the possibility of
palladium catalyzed carbonylation of aryl tosylates to provide the
desired amide products. Tosylates are often crystalline, excep-
tionally inexpensive, reasonably stable and simple to isolate, and
the tosylate ion has long been recognized as nontoxic. Aryl and
heteroaryl tosylates would also be desirable starting materials as
they would be expected to be less sensitive to moisture and
nucleophiles than the corresponding triflates. However, we
recognized that the carbonylation of tosylates to amides could
also be quite difficult. The tosylates would be expected to
undergo oxidative addition to palladium(0) much less easily than
the similar triflates,4 and the rapid aminolysis of the aryl tosylate
in the reaction mixture to provide the starting phenol and the
conditions to effect the alkoxycarbonylation of aryl and
heteroaryl tosylates to afford esters.6 Recently, the palladium
catalyzed alkoxy- and aminocarbonylation of vinyl tosylates
under high pressure (100 psig) was reported; these reactions
performed best with the Skewphos ligand.7 There is only one
literature example of aminocarbonylation with an aryl tosylate.8
This reaction was performed under rather forcing conditions of
temperature and pressure (dioxane at 180 °C) using microwave
heating and molybdenum hexacarbonyl as the source of carbon
monoxide. Nevertheless, this single example offered encourage-
ment that more generally useful conditions for the amino-
carbonylation of aryl and heteroaryl tosylates might be identified.
A high throughput screen was conducted in a CAT-96 gas
handling device to identify possible conditions that might be of
promise.9 This screen examined 60 possible combinations of five
solvents and 12 phosphine ligands in combination with carbon
monoxide, palladium acetate, tert-butylamine, and Hunig’s base
to effect the transformation of 1 to 2 (see Supporting
Information). The selection of tert-butylamine was motivated
by its compatibility with the high throughput screening
technique, as well as by our ability to transform the resulting
tert-butyl amide 2 efficiently to either a primary amide or a
nitrile.10,11 A large excess (25 equiv) of tert-butylamine was
selected for initial screening to maximize the potential for
product formation as well as the potential for unwanted tosylate
aminolysis in any particular screening reaction. The initial
reaction screen was performed at a low concentration of 1 (0.01
M) and relatively high temperature (120 °C) and pressure (130
psig). Product yields were estimated after an arbitrary 18 h
Received: April 30, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b01283
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Organic Letters
Letter
reaction time by the product UV area percent of a UPLC analysis
of each reaction. Three conditions were identified which showed
some promise; the remaining experiments failed to provide
significant amounts of the desired product 2. These conditions
are excerpted in Table 1. Full results of this screen are given in the
Supporting Information.
(entry 3), resulting in the complete consumption of the starting
material and a cleaner overall reaction profile. Further
simultaneous reduction of the reaction temperature and pressure
resulted in diminished conversion of the starting material (entry
4). Remarkably, no aminolysis of the phenol tosylate was
observed, indicating that this potentially serious side reaction
failed to proceed at a significant rate. The catalyst loading was
reduced to 3% without change in the reaction profile (entry 5).
Further reduction of the catalyst loading to 1% resulted in
diminished conversion of the starting material (entry 6). As
expected, a negative control experiment performed under a
nitrogen atmosphere returned only starting material. Following
this second round of reaction screening, we conducted a
preparative experiment on a 5 mmol scale at 0.2 M
concentration, keeping the other parameters (solvent, temper-
ature, pressure, catalyst loading) the same as entry 3 of Table 2.
Under these conditions, compound 2 was returned in 86%
purified yield. Having found efficient conditions for the
preparation of 2 from the readily available aryl tosylate 1, we
examined the extension of this method to other aryl tosylate
substrates (Table 3), including several that had previously been
included in reports dealing with palladium−catalyzed alkox-
ycarbonylation.13
a
Table 1. Summary of Screening of Ligands and Solvents
b
entry
solvent
ligand
yield (%)
c
11
21
22
DMF
dcyhpe·2HBF4
30
21
MeCN
MeCN
dcyppp·2HBF4
dcyppb·2HBF4
15
a
b
For experimental details, see the Supporting Information. As UV
c
area percent of UPLC analysis of the reaction mixture. dcyhpe·2HBF4
=
Notably, the successful ligands were from the recently
described, very electron rich bis(dicyclohexylphosphino)alkane
family.12 More well established bisphosphines such as dppp, dppf
and BINAP, as well as monophosphines such as triphenylphos-
phine and tri(tert-butyl)phosphine, failed to return significant
amounts of 2 under these conditions. Having identified the
dcyhpe·2HBF4/DMF conditions as the screening hit with the
highest apparent conversion, we studied this reaction further, in
particular to understand the effects of temperature and pressure
on the reaction, with the goals of improving the reaction profile
and yield of desired product, as well as of reducing the
temperature and pressure to levels readily accommodated by
the laboratory equipment most commonly available in organic
chemistry laboratories. For this second round of reaction
screening experiments, the reactions were conducted in an
Endeavor reactor at 0.1 M concentration. Catalyst loading was
maintained at 6 mol percent while tert-butylamine was reduced
to 20 equiv. As in the initial screen, product yields were estimated
after an arbitrary 18 h reaction time by the product area percent
of a GCMS analysis of each reaction (Table 2).
We found that aryl tosylates substituted with electron
withdrawing groups were converted to the corresponding
amides in good yields (entries 1−5). Heterobicyclic substrates
likewise worked well (entries 6, 7). An aldehyde was well
tolerated despite the use of a large excess of primary amine, and
a
Table 3. Evaluation of Aryl Tosylate Substrate Scope
This work showed that the carbon monoxide pressure could be
reduced to 60 psi without detriment, allowing the reaction to be
run without need for specialized autoclave equipment. Notably, a
reduction in the reaction temperature appeared to be beneficial
Table 2. Screen of Temperature and Pressure
a
entry
temp (°C)
pressure (psi)
yield (%)
1
2
3
4
120
120
100
80
100
60
60
15
60
60
74
65
>90
49
b
5
c
100
100
>90
47
6
a
All reactions were conducted with Pd(OAc)2 (6%), dcyhpe·2HBF4
a
b
As area percent of GCMS analysis of the reaction mixture. 3%
(6%), and 20 equiv of tert-BuNH2 in DMF at 100 °C under 60 psig of
CO. Isolated yields of purified products.
c
b
catalyst. 1% catalyst.
B
DOI: 10.1021/acs.orglett.5b01283
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Organic Letters
Letter
a
no byproducts resulting from imine formation were observed
(entry 8). Aryl tosylates lacking electron withdrawing groups or
an ortho-directing methoxy group were not fully converted to
corresponding amides (entries 9−11).14 In these cases the
reactions appeared to be stalled after 18 h and extension of the
reaction time up to 48 h did not result in further progression. In
no case were the products of aryl tosylate aminolysis (the parent
phenol or N-tert-butyl 4-toluenesulfonamide) observed. Further
work was carried out using 2-methoxyphenyl tosylate (13) to
understand why those substrates lacking electron withdrawing
groups failed to proceed to completion. The substitution of
DMA for DMF in the reaction mixture resulted in no substantial
improvement in yield of the carbonylation product, suggesting
that reduction of 13 to anisole was not the problem.15 However,
the substitution of 1-butanol for tert-butylamine resulted in a 71%
isolated yield of the expected butyl ester.16 (Scheme 1)
Table 4. Evaluation of Amine Substrate Scope
Scheme 1. Carbonylation of 2-Methoxyphenyl Tosylate to n-
Butyl Ester
This result showed that the catalyst was competent to undergo
oxidative addition to 2-methoxyphenyl tosylate (13), and the
subsequent carbonylation and reductive elimination steps
proceeded as expected. We postulate that the poor conversion
of substrates such as 13 is likely due to deactivation of the catalyst
by the amine present in the mixture, through formation of a
palladium(II) amine complex that is not catalytically competent.
For those substrates that undergo oxidative addition rapidly, such
as 1, significant formation of the amide product can occur before
the catalyst is consumed. To test this hypothesis, tosylate 13 was
subjected to carbonylation in the presence of aniline, which
would be expected to coordinate palladium at a slower rate than
tert-butylamine. The expected anilide was obtained in 40%
isolated yield, as opposed to the 20% yield obtained with tert-
butylamine. The addition of LiBr as a supporting ligand to
stabilize the palladium17 was deleterious and resulted in the
failure of 13 to afford any carbonylation product.
Additionally, we sought to modify the reactions conditions to
permit the use of more structurally diverse amines (Table 4). For
these transformations, we decreased the amine component to
two equivalents and incorporated one equivalent of potassium
carbonate. The addition of potassium carbonate increased
reaction yields relative to the same reactions conducted without
potassium carbonate, and the reaction temperature could be
reduced to 80 °C. The transformation under these conditions
worked well to provide good yields of the expected amide
products with a variety of amines, including relatively weakly
basic amines such as morpholine, aniline, and ethanolamine
(entries 1−6).
a
All reactions were conducted with Pd(OAc)2 (3%), dcyhpe·2HBF4
(4%) with 2 equiv of amine and 1 equiv of K2CO3 in DMF at 80 °C
b
under 60 psig of CO. Isolated yields of purified products.
Scheme 2. Intramolecular Aminocarbonylation
In this case, there was no additional free amine present in the
reaction mixture. This result also supports our postulate that the
catalyst is entirely competent to effect carbonylation of substrates
lacking electron withdrawing groups, and that the low conversion
observed with substrates such as 13 is likely due to deactivation of
the catalyst by the amine in the reaction mixture.
In summary, we report for the first time the amino-
carbonylation of aryl tosylates to afford amides. Competitive
aminolysis of the aryl tosylates was not observed. The reaction
proceeded well with aryl tosylates bearing electron withdrawing
substituents, presumably due to rapid oxidative addition of Pd(0)
under the reaction conditions. Aryl tosylates lacking electron
withdrawing groups and/or an ortho-directing alkoxy group were
not fully converted to the corresponding amides. In these cases it
appears that the rate of oxidative addition of Pd(0) to the aryl
tosylate proceeded more slowly, permitting a competitive
pathway involving catalyst deactivation by the amine to become
more significant. A variety of amines were tolerated and
performed well, including less basic amines such as aniline and
morpholine.
The reaction with ethanolamine showed no evidence of
formation of the ester or bis-acylated products. A chiral amine
worked well, and the product was obtained without epimeriza-
tion (entry 7), showing that palladium(II) oxidation of the amine
to an imine was not a competing side reaction.
Lastly, an intramolecular reaction (Scheme 2) showed that the
expected cyclization occurred with concomitant cleavage of the
BOC group following cyclization.18,19
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental procedures and characterization data for all new
compounds. The Supporting Information is available free of
C
DOI: 10.1021/acs.orglett.5b01283
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(13) See ref 6a.
charge on the ACS Publications website at DOI: 10.1021/
acs.orglett.5b01283.
(14) The following substrates failed to afford significant amounts
(>10% by UPLC) of the desired carbonylation product under these
conditions: 4-methoxyphenyl tosylate, 2,4-dimethylphenyl tosylate, and
pyridin-3-yl tosylate.
AUTHOR INFORMATION
Corresponding Authors
■
(15) (a) Wan, Y.; Alterman, M.; Larhed, M.; Hallberg, A. J. Org. Chem.
2002, 67, 6232. (b) The only byproducts observed in these reactions,
besides unreacted starting aryl tosylates, were the products of reduction
of the aryl tosylates Ar-OTs to the hydrocarbons Ar-H. These reduction
products were not observed in every reaction, and were thought to likely
be due to reduction of the Pd(II) oxidative addition product by
dimethylamine, which was in turn derived by a competing side reaction
between tert-butylamine and DMF. This was confirmed by a blank
experiment, in which tert-butylamine and excess DMF were heated for
18 h at 100 °C under 60 psi of carbon monoxide pressure, that returned a
10% yield of tert-butylformamide, identified by comparison to an
authentic sample. The formation of reduction products could be largely
suppressed by substitution of DMA for DMF.
(16) Magerlein, W.; Indolese, A. F.; Beller, M. J. Organomet. Chem.
2002, 641, 30.
(17) For a review, see: Beletskaya, I. P.; Cheprakov, A. V. Chem. Rev.
2000, 100, 3009.
(18) This reaction was conducted without an added amine component.
(19) (a) Hermange, P.; Lindhardt, A. T.; Taanin, R. H.; Bjerglund, K.;
Lupp, D.; Skrydstrup, T. J. Am. Chem. Soc. 2011, 133, 6061.
(b) Marosvolgyi-Hasko, D.; Takacs, A.; Riedl, Z.; Kollar, L. Tetrahedron
2011, 67, 1036.
*E-mail: seungwon.chung@pfizer.com.
*E-mail: stephen.w.wright@pfizer.com.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge lively discussions with our colleagues
in the Pfizer “Palladium Club”.
REFERENCES
■
(1) For recent reviews, see: (a) Gadge, S. T.; Bhanage, B. M. RSC Adv.
2014, 4, 10367. (b) Fang, W.; Zhu, H.; Deng, Q.; Liu, S.; Liu, X.; Shen,
Y.; Tu, T. Synthesis 2014, 46, 1689. (c) Grigg, R.; Mutton, S. P.
Tetrahedron 2010, 66, 5515. (d) Brennfuhrer, A.; Neumann, H.; Beller,
M. Angew. Chem., Int. Ed. 2009, 48, 4114. (e) Skoda-Foldes, R.; Kollar, L.
Curr. Org. Chem. 2002, 6, 1097. (f) Wu, X.-F.; Neumann, H.; Beller, M.
Chem.Eur. J. 2010, 16, 9750.
(2) (a) Cacchi, S.; Ciattini, P. G.; Morera, E.; Ortar, G. Tetrahedron
Lett. 1986, 27, 3931. (b) Holt, D. A.; Levy, M. A.; Ladd, D. L.; Oh, H. J.;
Erb, J. M.; Heaslip, J. I.; Brandt, M.; Metcalf, B. W. J. Med. Chem. 1990,
33, 937. (c) Gerlach, U.; Wollmann, T. Tetrahedron Lett. 1992, 33, 5499.
(3) Key, B. D.; Howell, R. D.; Criddle, C. S. Environ. Sci. Technol. 1998,
32, 2283.
(4) (a) Kobayashi, Y.; Mizojiri, R. Tetrahedron Lett. 1996, 37, 8531.
(b) Ueda, M.; Saitoh, A.; Oh-tani, S.; Miyaura, N. Tetrahedron 1998, 54,
13079. (c) Percec, V.; Bae, J.-Y.; Hill, D. H. J. Org. Chem. 1995, 60, 1060.
(d) Percec, V.; Bae, J.-Y.; Zhao, M.; Hill, D. H. J. Org. Chem. 1995, 60,
1066.
(5) See, for example: Wilden, J. D.; Geldeard, L.; Lee, C. C.; Judd, D.
B.; Caddick, S. Chem. Commun. 2007, 1074.
(6) (a) Munday, R. H.; Martinelli, J. R.; Buchwald, S. L. J. Am. Chem.
Soc. 2008, 130, 2754. (b) Cai, C.; Rivera, N. R.; Balsells, J.; Sidler, R. R.;
McWilliams, J. C.; Schultz, C. S.; Sun, Y. Org. Lett. 2006, 8, 5161.
(c) Kubota, Y.; Nakada, S.; Sugi, Y. Synlett 1998, 183.
(7) Reeves, D. C.; Rodriguez, S.; Lee, H.; Haddad, N.; Krishnamurthy,
D.; Senanayake, C. H. Org. Lett. 2011, 13, 2495.
(8) (a) Odell, L. R.; Savmarker, J.; Larhed, M. Tetrahedron Lett. 2008,
̈
49, 6115. (b) For a nickel-catalyzed amidation of aryl tosylates by
isocyanates, see: Correa, A.; Martin, A. J. Am. Chem. Soc. 2014, 136,
7253. (c) For the synthesis of (2-alkoxy)aryl carboxamides from the
corresponding aryl iodides, see: Takac
́
s, A.; Abreu, A. R.; Peixoto, A. F.;
Pereira, M.; Kollar, L. Synth. Commun. 2009, 39, 1534.
́
(9) Sach, N. W. Abstracts of Papers, 244th ACS National Meeting &
Exposition, Philadelphia, PA, Aug 19−23, 2012; American Chemical
Society: Washington, DC, 2012.
(10) The conversion of tert-butyl amides to primary amides with TFA
has been reported; see, for example: (a) Wu, X.; Wan, Y.; Mahalingam,
́
A. K.; Murugaiah, A. M. S.; Plouffe, B.; Botros, M.; Karlen, A.; Hallberg,
M.; Gallo-Payet, N.; Alterman, M. J. Med. Chem. 2006, 49, 7160.
(b) Moree, W. J.; van der Marel, G. A.; Liskamp, R. J. J. Org. Chem. 1995,
60, 5157.
(11) The conversion of tert-butyl amides to nitriles has been reported;
see, for example: (a) With POCl3: Piwinski, J. J.; Wong, J. K.; Green, M.
J.; Ganguly, A. K.; Billah, M. M.; West, R. E., Jr.; Kreutner, W. J. Med.
Chem. 1991, 34, 457. (b) With PCl5: Carney, S. L.; Broadmore, R. J.;
Tomlinson, R.; Kingston, A.; Gallagher, P. T.; Owton, W. M.; Miles, M.
V.; Brunavs, M.; Smith, C. W.; Hicks, T. A.; Dobson, D. R.; Steggles, D.
J.; Ambler, S. J.; Halliday, K. A. Bioorg. Med. Chem. Lett. 1997, 7, 817.
(12) These ligands are commercially available as their HBF4 salts. We
found that these ligands purchased as the free phosphines were of
unreliable purity.
D
DOI: 10.1021/acs.orglett.5b01283
Org. Lett. XXXX, XXX, XXX−XXX