Palladium-catalyzed cross-coupling reactions of potassium n-methyltrifluoroborate isoindolin-1-one with aryl and heteroaryl chlorides

Article abstract of DOI:10.1080/00397911.2014.884591

Potassium N-methyltrifluoroborate isoindolin-1-one was synthesized and used in Suzuki-Miyaura palladium-catalyzed cross-coupling reactions with aryl and heteroaryl chlorides to prepare 29 examples of substituted N-benzyl isoindolin-1-ones. The new approach benefits from mild reaction conditions that tolerate a variety of functional groups. In addition, because of the large number of commercially available aryl and heteroaryl chlorides that can serve as coupling partners, the approach readily provides access to libraries of substituted N-benzyl isoindolin-1-ones. Copyright

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Palladium-Catalyzed Cross-
Coupling Reactions of Potassium N-
Methyltrifluoroborate Isoindolin-1-one
with Aryl and Heteroaryl Chlorides
Rashid N. Nadaf a & Dave G. Seapy a
a Department of Chemistry , Texas A&M University at Qatar , Doha ,
Qatar
Accepted author version posted online: 03 Apr 2014.Published
online: 09 Jun 2014.
To cite this article: Rashid N. Nadaf & Dave G. Seapy (2014) Palladium-Catalyzed Cross-Coupling
Reactions of Potassium N-Methyltrifluoroborate Isoindolin-1-one with Aryl and Heteroaryl Chlorides,
Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic
Chemistry, 44:14, 2012-2020, DOI: 10.1080/00397911.2014.884591
To link to this article: http://dx.doi.org/10.1080/00397911.2014.884591
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Synthetic Communications1, 44: 2012–2020, 2014
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2014.884591
PALLADIUM-CATALYZED CROSS-COUPLING
REACTIONS OF POTASSIUM
N-METHYLTRIFLUOROBORATE ISOINDOLIN-1-ONE
WITH ARYL AND HETEROARYL CHLORIDES
Rashid N. Nadaf and Dave G. Seapy
Department of Chemistry, Texas A&M University at Qatar, Doha, Qatar
GRAPHICAL ABSTRACT
Abstract Potassium N-methyltrifluoroborate isoindolin-1-one was synthesized and used in
Suzuki–Miyaura palladium-catalyzed cross-coupling reactions with aryl and heteroaryl
chlorides to prepare 29 examples of substituted N-benzyl isoindolin-1-ones. The new
approach benefits from mild reaction conditions that tolerate a variety of functional groups.
In addition, because of the large number of commercially available aryl and heteroaryl
chlorides that can serve as coupling partners, the approach readily provides access to
libraries of substituted N-benzyl isoindolin-1-ones.
Keywords Isoindolinone; methylaminotrifluoroborates; organotrifluoroborates; palladium-
catalyzed cross-coupling; potassium N-methyltrifluoroborate isoindolin-1-one; Suzuki–
Miyaura cross-coupling
INTRODUCTION
Synthesis of isoindolin-1-one derivatives (1) (Fig. 1) is important because
the isoindolin-1-one substructure is common in a number of natural products
and pharmaceuticals.[1–5] The isoindolin-1-one scaffold is of particular interest
to medicinal chemistry because of its centrality in a variety of biologically active
compounds and pharmaceutical target molecules. In particular, the N-benzyl
substitution motif is a common structural variation (Fig. 2).[6–10]
Numerous synthetic approaches exist to access isoindolin-1-one target mole-
cules containing N-benzyl or substituted N-benzyl substructures. These include
Received December 29, 2013.
Address correspondence to Dave G. Seapy, Department of Chemistry, Texas A&M University at
Qatar, P.O. Box 23874, Doha, Qatar. E-mail: dave.seapy@qatar.tamu.edu
Color versions of one or more of the figures in the article can be found online at www.tandfonline.
com/lsyc.
2012

POTASSIUM N-METHYLTRIFLUOROBORATE ISOINDOLIN-1-ONE
2013
Figure 1. N-Substituted isoindolin-1-one.
monoreduction of phthalimides before or after N-benzylation of the isoindolin-1-one
or phthalimide,[5,11,12] addition of benzylamines to phthalaldehyde followed by
dehydration,[5] condensation of phthalide or 2-(bromomethyl)benzoate with
benzylamines,[11] conversion of benzoylbenzoic acids into the corresponding w-acid
chlorides followed by condensation with benzylamines,[13] and copper-catalyzed
deamidative carbon–carbon coupling of iodoaryl amides.[14] While these and other
synthetic approaches have their merits, the increasing demand for high-throughput
screening of libraries of potential pharmaceutical molecules has encouraged contin-
ual improvements in synthetic efficiencies and diversity of strategies, including func-
tional group tolerance. For example, the isoindolin-1-one scaffold’s contribution to
potency in the inhibition of MDM2-p53 interaction was studied.[13] These structure–
activity relationship (SAR) studies involved the preparation of 33 N-substituted
3-hydroxy isoindolin-1-ones. Screening SAR studies such as this offer increasing
impetus for complementary synthetic strategies to be developed, strategies that
provide easy access to libraries of compounds built on a single scaffold.
Organotrifluoroborate chemistry has widespread utility in Suzuki–Miyaura
cross-coupling reactions.[15] In particular, a new and complementary synthetic strat-
egy for the preparation of substituted N-benzyl phthalimides (4) (Scheme 1) was
recently reported.[16] In this study, the authors prepared substituted N-benzyl
Figure 2. N-Substituted isoindolin-1-one drugs.

2014
R. N. NADAF AND D. G. SEAPY
Scheme 1. Preparation of substituted N-benzyl phthalimides 4.[16]
phthalimides by palladium-catalyzed Suzuki–Miyaura cross-coupling between
potassium phthalimidomethyltrifluoroborate (2) and aryl chlorides (3).[16] The
authors noted that a key difference is the dissonant carbon–carbon bond-forming
reaction that couples an N-methyl nucleophile with aryl chloride electrophiles, rather
than the traditional nitrogen–carbon bond formation between the nucleophilic nitro-
gen of deprotonated phthalimide and benzyl halide electrophiles. A significant benefit
of this approach is that there are many more commercially available aryl chlorides
than benzyl chlorides, thereby supporting easier access to large libraries of com-
pounds. A second advantage is that organotrifluoroborate salts are very stable in
air and water, tolerate a wide scope of functionality, and may be introduced early
in synthetic strategies. A third advantage is that organotrifluoroborate salts are
excellent coupling partners for Suzuki–Miyaura coupling reactions, in part because
their coupling reaction conditions are compatible with a variety of functional groups.
These methylaminotrifluoroborate nucleophiles have proven to be effective coupling
partners in variety of Suzuki–Miyaura coupling reactions.[16–24]
One drawback of methylaminotrifluoroborates is that coupling reaction
conditions are usually not general in nature and typically need to be developed for
each unique application. Because there are numerous reaction variables (e.g.,
substrate, solvent mixture, catalyst, ligand, base, temperature, time) screening for
reaction protocols often benefits from the use of high-throughput facilities.[25] In light
of these previous successes, we set out to determine if the N-benzyl isoindolin-1-one
scaffold could readily be accessed using organotrifluoroborate chemistry.
In this work, we describe the successful synthesis of potassium N-methyltri-
fluoroborate isoindolin-1-one and demonstrate the scope of its palladium-catalyzed
cross-coupling with a range of aryl and heteroaryl halides to prepare substituted
N-benzyl isoindolin-1-ones.
RESULTS AND DISCUSSION
Isoindolin-1-one (5) was prepared by a known procedure involving the
monoreduction of phthalimide.[11] Deprotonation of 5 (Scheme 2) with NaH and
refluxing in tetrahydrofuran (THF) with commercially available potassium
Scheme 2. Preparation of potassium N-methyltriflouro-borate isoindolin-1-one salt (6).

POTASSIUM N-METHYLTRIFLUOROBORATE ISOINDOLIN-1-ONE
2015
bromomethyltrifluoroborate led to the desired potassium N-methyltriflouro-borate
isoindolin-1-one salt (6) as a white crystalline stable salt in 65% yield.
Cross-coupling reaction conditions for coupling 6 and aryl chlorides were first
optimized using 4-chloroanisole (7a) (Table 1, entry 1). These conditions were later
used without further optimization for all other coupling reactions. Successful coup-
ling conditions were found after 25 combinations of catalyst, ligand, base, and solvent
were attempted using a block reactor. PdCl2(CH3CN)2 was the best catalyst (93%
conversion) with Pd2(dba)2 nearly as effective (90% conversion). X-Phos proved to
be the best ligand (>90% conversion) with Ata-Phos providing modest conversions
(40%) as well. Screening for bases showed K2CO3 (93% conversion) was slightly better
than Na2CO3 (90% conversion). t-BuOH=H2O (4:1) was superior to other solvents
used. In contrast to our previous experiences with different coupling substrates,
and much to our surprise, the optimum conditions for this coupling reaction were
found to be the same as those published[16] for potassium phthalimidomethyltrifluor-
oborate coupling reactions. Potassium N-methyltrifluoroborate isoindolin-1-one (6)
and 7a were found to optimally couple with the use of PdCl2 (CH3CN)2 (7.5 mol%),
X-Phos (15 mol%), and K2CO3 (3 equiv.) in t-BuOH=H2O (4=1) as solvent at
100 ꢀC for 16 h (Table 1, entry 1). Table 1 shows the scope of the coupling potassium
N-methyltrifluoroborate isoindolin-1-one (6) with 17 aryl chlorides (7a–q). The
desired substituted N-benzyl isoindolin-1-ones (8a–q) were obtained in moderate
to excellent isolated yields (52–93%). The coupling reaction was compatible with
a variety of electron-donating (Table 1, entries 1–4), electron-neutral (Table 1, entries
5–9), and electron-withdrawing groups on aryl chlorides including carbonyl (ketone,
aldehyde, and ester), cyano, nitro, methoxy, pyrrolo, and fluoro substituents (Table 1,
entries 10–17). Ortho-substituted aryl chlorides (Table 1, entries 7, 9, and 12)
consistently gave lower yields, suggesting steric hindrance has an adverse effect.
The yields in Table 1 were uniformly generated from 0.25 mmol (Ar-Cl) reac-
tions with 7.5 mol% catalyst loadings and 15 mol% ligand. To make an initial probe
into the scalability of these reactions, a larger scale reaction was performed. This
scaled-up reaction was run without further optimization efforts and with a reduced
catalyst loading because larger scale reactions typically require a smaller percent cata-
lyst loading. When the chlorobenzene reaction (Table 1, entry 5) was run on a larger
4-mmol scale (ca. 1 g) with 1 mol% catalyst loading (2 mol% ligand) and for the same
length of time (16 h), the reaction did not go to completion and resulted in only a 57%
isolated yield. The comparable small-scale reaction yield was 93%. As only starting
materials and product were observed, the reduction in yield upon scaling was
attributed to the lack of reaction completion. because reaction rates of organotrifluor-
oborates are known[26] to depend on catalyst loading and variables such as vessel size
and shape or stirring rate, optimum scaled conditions will require additional effort.
Because heteroaryl rings are often desired in screening libraries of pharmaceuti-
cal compounds, we also studied the scope of heteroaryl chloride coupling with 6 using
the same reaction conditions as those optimized for 4-chloroanisole (7a) (Table 1,
entry 1). These results are given in Table 2. Relative to aryl chlorides, coupling of 6
with nitrogen-, sulfur-, and oxygen-containing heteroaryl chlorides gave more modest
yields (47–69%) of the desired substituted N-benzyl isoindolin-1-ones (Table 2, entries
1–7). Successful coupling was achieved with electron-rich and electron-poor chloro-
pyridines (Table 2, entries 1 and 2, respectively), four different chlorothiophenes

2016
R. N. NADAF AND D. G. SEAPY
Table 1. Scope of cross-coupling compound 6 with aryl chlorides
Entry
Ar-CI
Product 8 (%)a
1
2
3
4
8a (83)
8b (79)
8c (82)
8d (63)
7a,4-OMe
7b, 2-OMe
7c, 3-OMe
7d,3,5-OMe
5
7e
8e (93)
6
7
8
9
8f (93)
8 g (61)
8 h (80)
8i (63)
7f, 4-Me
7g, 2-Me
7h, 3-Me
7i,2,6-Me
10
11
12
7j, R ¼ 4-CO2Me
7k, R ¼ 4-COMe
71, R ¼ 2-COPh
8j (89)
8k (86)
81 (60)
7m
13
8 m (71)
7n, R0 ¼ ꢁCHO
7o, R0 ¼ ꢁCN
7p, R0 ¼ ꢁNO2
7q, R0 ¼ ꢁF
14
15
16
17
8n (56)
8o (63)
8p (52)
8q (75)
aReaction conditions: 1.0 equiv. of aryl chloride; 1.2 equiv. of trifluoroborate 6;
isolated yields after silica gel column chromatography or preparative TLC.
(Table 2, entries 3–6), and one furan ring (Table 2, entry 7). As was the case with aryl
chloride coupling, functional groups such as ketones and aldehydes (entries 3, 4, and
7) were tolerated during the coupling reactions. In comparison to aryl chlorides, the

POTASSIUM N-METHYLTRIFLUOROBORATE ISOINDOLIN-1-ONE
Table 2. Scope of cross-coupling compound 6 with heteroaryl chlorides
2017
Entry
Ar(Het)-CI
Product 10 (%)a
9a, R00 ¼ -OMe
9b, R00 ¼ -F
1
2
3
10a (59)
10b (53)
10c (66)
9c, R000 ¼ -COMe
9d, R000 ¼ -CHO
9e, R000 ¼ -H
4
5
10d (47)
10e (61)
9f
6
7
10f (69)
10g (53)
9 g
aReaction conditions: 1.0 equiv. of heteroaryl chloride; 1.2 equiv. of trifluoroborate 6;
isolated yields after silica gel column chromatography or preparative TLC.
scope of coupling with 6 was not as broadly successful because no reaction was
observed with 2- or 3-chloropyridine, 3-chloroisonicotinaldehyde, 2-chloro-5-methox-
ypyrimidine, or 5-chloro-1H-indole. No further attempt was made to find reaction
conditions to support the failed nitrogen heteroaryl coupling reactions.
These same cross-coupling reaction conditions were used to study the scope of
cross coupling between 6 and various aromatic electrophiles (Table 3). While the best
coupling yield (93%) was obtained with the phenyl chloride (Table 3, entry 1), good to
excellent yields (71–91%) were also obtained with phenyl mesylate, tosylate, triflate,
and bromide (Table 3, entries 2–5). Only phenyl iodide gave an unsatisfactory yield
(27%) (Table 3, entry 6). This demonstrates the versatility of 6 as a Suzuki–Miyaura
coupling partner.
In conclusion, potassium N-methyltrifluoroborate isoindolin-1-one (6) has
been synthesized and shown to undergo palladium-catalyzed Suzuki–Miyaura
cross-coupling with aryl and heteroaryl chlorides to produce a variety of substituted
N-benzyl isoindolin-1-ones in moderate to excellent yields. The mild reaction
conditions tolerate a wide range of functional groups. In addition, potassium
N-methyltrifluoroborate isoindolin-1-one was shown to couple with a range of aryl

2018
R. N. NADAF AND D. G. SEAPY
Table 3. Scope of cross-coupling compound 6 with aromatic electrophiles
Entry
Ph-X
Product 8e (%)a
1
2
3
4
5
6
Ph-CI (7e)
Ph-Br(11a)
Ph-OTf(11b)
Ph-OMs(11c)
Ph-OTs(11d)
Ph-I(11e)
(93)
(71)
(83)
(91)
(86)
(27)
aReaction conditions: 1.0 equiv. of aryl chloride; 1.2 equiv. of trifluoroborate 6;
isolated yields after silica gel column chromatography or preparative TLC.
electrophiles. This new and complementary approach to synthesizing the N-benzyl
isoindolin-1-one substructure has the advantage over existing methods in that there
is an abundance of commercially available aryl and heteroaryl chloride coupling
partners, thereby providing easy access to libraries of substituted N-benzyl
isoindolin-1-ones.
EXPERIMENTAL
Potassium N-Methyltrifluoroborate Isoindolin-1-one (6)
Sodium hydride 60% in mineral oil (0.750 mg, 30.0 mmol) and dry THF (150 ml)
were added to a two-necked round-bottomed flask. Isoindolin-1-one (5) (2.50 g,
18.8 mmol) was added to the suspension at 0 ꢀC under N2. The reaction mixture was
stirred for 30 min at 0 ꢀC, and then potassium bromomethyl trifluoroborate (3.00 g,
15.0 mmol) was added to the reaction mixture in one portion and stirred for 30 min
at 0 ꢀC. The reaction mixture was warmed to room temperature and refluxed for
48 h. The reaction mixture was cooled to 0 ꢀC and quenched by KHF2 (3.0 M) in
H2O (14 mL). The reaction mixture was stirred at room temperature for 2 h. The sol-
vents were removed under vacuum, and residue was dissolved in ethyl acetate (100 mL)
and filtered. The solid obtained was triturated with boiling acetone (3 ꢂ 50 mL) and the
resulting white powder was washed with cold ether (3 ꢂ 20 mL) and dried to give the
potassium N-methyltrifluoroborate isoindolin-1-one (6) as white solid (2.54 g, 65%):
mp: 229–234 ꢀC; IR (KBr, neat): 3032, 2936, 2897, 2879, 1658, 1590, 1473, 1455,
1
1426, 1415, 1306, 1228, 1210, 1099, 1069, 1011, 996, 760, 726, 538 cmꢁ1; H NMR
(DMSO-d6, 400 MHz) d ¼ 7.59 (d, J ¼ 8.0 Hz, 1H), 7.53–7.46 (m, 2H), 7.42–7.39 (m,
1H), 4.38 (s, 2H), 2.47 (s, 2H); 13C NMR (DMSO-d6, 100 MHz) d ¼ 169.9, 144.0,
131.5, 131.2, 127.5, 123.7, 122.7, 44.8; 11B NMR (DMSO-d6, 128.37 MHz) d ¼ 3.46
(br s); 19F NMR (DMSO-d6, 376.49 MHz): d ¼ ꢁ138.67. HRMS (ESI-TOF) m=z
calcd. for C9H8BNOFꢁ3 (M – K) 214.0651; found 214.0661.

POTASSIUM N-METHYLTRIFLUOROBORATE ISOINDOLIN-1-ONE
2019
General Procedure for the Cross-Coupling Reaction of Potassium
N-Methyltrifluoroborate Isoindolin-1-one (6) with Aryl and
Heteroaryl Electrophiles (7a–q, 9a–l, 11a–e)
In a microwave vial equipped with a stirring bar, potassium N-methyltrifluor-
oborate isoindolin-1-one (6) (80.1 mg, 0.316 mmol), potassium carbonate (104 mg,
0.752 mmol), Pd(MeCN)2Cl2 (4.9 mg, 7.5 mol%), and XPhos (17.9 mg, 15.0 mol%)
were successively introduced. The vial was capped and put under inert atmosphere
(3 ꢂ vacuum=N2 cycles). The electrophile was then introduced using a microsyringe
(0.25 mmol, 1.0 equiv.) followed by 0.8 mL of degassed t-BuOH and 0.2 mL of
degassed distilled water. The resulting mixture was then placed in an oil bath or
a hotplate-magnetic stirrer system preheated at 100 ꢀC and stirred at this tempera-
ture overnight (reactions followed by thin-layer chromatography, TLC). After cool-
ing to room temperature, the vial was uncapped and the reaction mixture was diluted
with dichloromethane (DCM) (5 mL) and water (5 mL). The aqueous layer was
extracted with dichloromethane (3 ꢂ 15 mL). Organic layers were combined, washed
with brine solution, and dried over Na2SO4, and the solvent was removed under
vacuum to yield the crude product. The crude product was purified by flash column
chromatography on silica gel using 30% ethyl acetate=hexane as the eluent.
FUNDING
This research was supported with funding from Texas A & M University at
Qatar and the Qatar Foundation.
SUPPLEMENTARY MATERIAL
Supplementary material (i.e., full experimental details and copies of 1H,
13C, 19F, and 11B spectra for all compounds synthesized) associated with this article
can be accessed on the publisher’s website.
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