Imide arylation with aryl(TMP)iodonium tosylates

Article abstract of DOI:10.3762/BJOC.14.90

Herein, we describe the synthesis of N-aryl phthalimides by metal-free coupling of potassium phthalimide with unsymmetrical aryl(TMP)iodonium tosylate salts. The aryl transfer from the iodonium moiety occurs under electronic control with the electron-rich trimethoxyphenyl group acting as a competent dummy ligand. The yields of N-aryl phthalimides are moderate to high and the coupling reaction is compatible with electron-deficient and sterically encumbered aryl groups.

Full text of DOI:10.3762/BJOC.14.90

Imide arylation with aryl(TMP)iodonium tosylates
Souradeep Basu, Alexander H. Sandtorv and David R. Stuart*
Letter
Open Access
Address:
Beilstein J. Org. Chem. 2018, 14, 1034–1038.
Department of Chemistry, Portland State University, Portland OR
97201, United States
doi:10.3762/bjoc.14.90
Received: 23 February 2018
Accepted: 27 April 2018
Published: 11 May 2018
Email:
David R. Stuart* - dstuart@pdx.edu
* Corresponding author
This article is part of the Thematic Series "Hypervalent iodine chemistry in
organic synthesis".
Keywords:
arylation; C–N coupling; diaryliodonium; hypercoordinate iodine;
metal-free
Guest Editor: T. Wirth
© 2018 Basu et al.; licensee Beilstein-Institut.
License and terms: see end of document.
Abstract
Herein, we describe the synthesis of N-aryl phthalimides by metal-free coupling of potassium phthalimide with unsymmetrical
aryl(TMP)iodonium tosylate salts. The aryl transfer from the iodonium moiety occurs under electronic control with the electron-
rich trimethoxyphenyl group acting as a competent dummy ligand. The yields of N-aryl phthalimides are moderate to high and the
coupling reaction is compatible with electron-deficient and sterically encumbered aryl groups.
Introduction
Imides are important structural units in a range of approved substrates [5]. Diaryliodonium salts are useful reagents for
pharmaceuticals and agrochemicals (Scheme 1a) [1]. Despite metal-free aryl transfer [6-10] and Muñiz and co-workers have
the general prevalence of imides, N-aryl imide derivatives are recently reported an elegant study on sterically controlled C–N
relatively rare in such compounds. We were surprised by this coupling of 2,6-disubstituted aryl(phenyl)iodonium salts and
disparity, but found that a lack of methods to synthesize N-aryl imides [11]. We have been investigating the generality of elec-
imides may explain their scarcity; this is particularly true rela- tronically controlled aryl transfer from aryl(trimethoxy-
tive to other N-aryl compounds. The survey of methods phenyl)iodonium salts [12-14] and describe here the develop-
revealed that the dominant approach to N-aryl imides is to ment of a C–N coupling of a phthalimide anion with non-steri-
employ aniline starting materials (Scheme 1b, left), as was done cally biased aryl groups. The protocol is compatible with
in the synthesis of pentoxazone and related herbicides [2]. The ortho-, meta-, and para-substitution on the aryl group and the
alternative aromatic substitution approach with imide anions phthalimide moiety may also provide access to anilines.
(Scheme 1b, right) is hampered by their low nucleophilicity [3].
Therefore, transition metals feature prominently in such Results and Discussion
methods, but even recent examples employ stoichiometric metal We initiated our optimization of the arylation of the potassium
mediators [4]. Metal-free methods by classic SNAr are also phthalimide nucleophile with diaryliodonium electrophiles by
attractive, but only possible on very electron-deficient arene surveying several reaction conditions: dummy ligand (Aux),
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Beilstein J. Org. Chem. 2018, 14, 1034–1038.
Scheme 1: Imides as an important scaffold.
counter anion, solvent and volume, reaction temperature, and superior to mesityl (Mes), phenyl (Ph), and anisyl (An) auxil-
stoichiometry (Table 1). Consistent with an electronically con- iaries under several different reaction conditions (Table 1,
trolled aryl transfer, the trimethoxyphenyl (TMP) auxiliary was entries 1–3; 11 and 12; 16 and 17). While the counter anion did
Table 1: Discovery and optimization of reaction conditions.a
Entry
X group
Aux group
Phth. equiv
Solvent
Temp. (°C)
1H NMR yield
1
TFA
TFA
TFA
TFA
OTs
TFA
OTf
Mes
Ph
2
DCE (1 mL)
70
27%
50%
52%
54%
62%
50%
56%
68%
64%
70%
23%
62%
39%
28%
16%
46%
75%
2
2
DCE (1 mL)
70
3
TMP
TMP
TMP
TMP
TMP
TMP
TMP
TMP
Ph
2
DCE (1 mL)
70
4
3
DCE (1 mL)
80
5
3
DCE (1 mL)
80
6
3
toluene (0.42 mL)
toluene (0.42 mL)
toluene (0.42 mL)
toluene (0.5 mL)
toluene (0.5 mL)
toluene (0.5 mL)
toluene (0.5 mL)
toluene (0.5 mL)
toluene (1 mL)
toluene (1.5 mL)
toluene (0.5 mL)
toluene (0.5 mL)
100
100
100
90
7
3
8
OTs
OTs
OTs
OTs
OTs
OTs
OTs
OTs
OTs
OTs
3
9
3
10
11
12
13
14
15
16
17
3
100
100
110
100
100
100
100
100
3
TMP
TMP
TMP
TMP
An
3
1.1
1.1
1.1
5
TMP
5
aConditions: 1 (0.1 mmol, 1 equiv), potassium phthalimide (see table for equivalents), solvent (see table), temperature (see table), 24 hours.
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Beilstein J. Org. Chem. 2018, 14, 1034–1038.
not exert a dramatic influence on the reaction yield, using tosyl- strong electron-withdrawing groups on the aryl ring lead to high
ate (OTs) produced the highest yield in both DCE and toluene yield of N-aryl phthalimide products (Scheme 2, 2a–d, 66–90%
as solvent (Table 1, entries 4–8). Given our ability to readily yield). However, the TMP auxiliary also enables the coupling of
access aryl(TMP)iodonium tosylate salts [12] we continued our phthalimide with moderately electron-deficient aryl groups. For
optimization with these reagents. We observed a very narrow instance the p-chlorophenyl moiety (2e) is coupled to phthal-
operating temperature with a maximum yield at 100 °C when imide in moderate yield (42%). Additionally, we have observed
toluene was used as solvent (Table 1, entries 9, 10, and 12). We that electronic and steric effects operate in concert to couple an
also observed that the reaction yield decreases with dilution o-tolyl (2f) moiety to phthalimide in high yield (67%). In this
(Table 1, entries 13–15). Finally, the yield increases with in- case, 2,6-disubstituted aryl groups are not required for a steri-
creasing stoichiometry of phthalimide (Table 1, entries 10, 13, cally controlled coupling. Finally, as an example two polysub-
and 17). It is also important to note that under “optimal” condi- stituted aryl groups are introduced in this coupling reaction,
tions (Table 1, entry 17) we did not observe a Phth–TMP which are specifically enabled by the use of an unsymmetrical
adduct. Moreover, we did observe essentially quantitative for- aryl(TMP)iodonium electrophile (Scheme 2, 2g and 2h, 42 and
mation of TMP–I and therefore complete consumption of 1a 99% yield, respectively).
and high fidelity for aryl transfer selectivity. At this time we are
unable to account for the remaining mass balance (≈25%) of the The phthalimide moiety is well-recognized as an “NH3” surro-
methyl benzoate moiety of 1a. We have employed the condi- gate, and the products depicted in Scheme 2 may be depro-
tions of entry 17 (Table 1) as our standard conditions to eval- tected to yield aniline derivatives. In a specific example, 1a is
uate the scope of this reaction.
reacted under modified conditions to yield 2a. In this one-pot
procedure, hydrazine in aqueous ethanol is added directly to the
We have assessed the scope of compatible aryl groups under reaction mixture and aniline 3 is isolated in 63% yield from 1a
our optimal conditions (Scheme 2). Under electronic control, (Scheme 3).
Scheme 2: Scope of compatible aryl groups. Conditions: 1 (0.5 mmol, 1 equiv), potassium phthalimide (2.5 mmol, 5 equiv), toluene (2.5 mL), 100 °C,
24 hours. Isolated yields are reported.
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Beilstein J. Org. Chem. 2018, 14, 1034–1038.
Scheme 3: One-pot synthesis of anilines.
We have previously described the coupling of aryl(TMP)iodo-
nium tosylates with azide nucleophiles [14]. Azide is a notably
stronger nucleophile than phthalimide and it is interesting to
compare the reaction of these two nucleophiles with 1a under
similar conditions (Table 2). The Mayr nucleophilicity constant
of azide [15] is 20.5 and high yield (95%) is observed in a reac-
tion with 1a under relatively mild temperature (65 °C) and short
reaction time (2 hours, Table 2, entry 1). The Mayr nucleophi-
licity constant for phthalimide is five-orders of magnitude lower
(15.5) [3] and under similar conditions leads to trace product
(Table 2, entry 2). In order to obtain a high yield of 2a, albeit
lower than given in entry 1, a higher temperature (100 °C) and a
longer reaction time (24 hours) are required (Table 2, entry 3).
This suggests that the contribution of nucleophilicity (via Mayr
nucleophilicity constants) [16] may be useful in developing
other coupling reactions with diaryliodonium electrophiles.
Supporting Information
Supporting Information File 1
General experimental details, procedures, tabulated
spectroscopic data, and 1H, 13C{1H}, and 19F NMR spectra
of compounds 1g, 2a–i, and 3.
[https://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-14-90-S1.pdf]
Acknowledgements
We acknowledge Portland State University for financial support
of this research.
ORCID® iDs
David R. Stuart - https://orcid.org/0000-0003-3519-9067
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