Synthesis and cross-coupling reactions of imidomethyltrifluoroborates with aryl chlorides

Article abstract of DOI:10.1016/j.tetlet.2011.12.062

Potassium imidomethyltrifluoroborate salts were efficiently synthesized. Potassium phthalimidomethyltrifluoroborate was successfully used in Suzuki-Miyaura-like cross-coupling reactions with a variety of aryl chlorides.

Full text of DOI:10.1016/j.tetlet.2011.12.062

Tetrahedron Letters 53 (2012) 1051–1055
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis and cross-coupling reactions of imidomethyltrifluoroborates
with aryl chlorides
Rammohan Devulapally a, Nicolas Fleury-Brégeot b, Gary A. Molander b, , Dave G. Seapy a,
⇑
⇑
a Department of Chemistry, Texas A&M University at Qatar, PO Box 23874, Doha, Qatar
b Roy and Diana Vagelos Laboratories, Department of Chemistry, University of Pennsylvania, Philadelphia, PA 19104-6323, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Potassium imidomethyltrifluoroborate salts were efficiently synthesized. Potassium phthalimidomethyl-
trifluoroborate was successfully used in Suzuki–Miyaura-like cross-coupling reactions with a variety of
aryl chlorides.
Received 23 October 2011
Revised 8 December 2011
Accepted 16 December 2011
Available online 23 December 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Potassium imidomethyltrifluoroborates
Suzuki–Miyaura cross-coupling reaction
N-Benzylphthalimides
Certain imides, particularly phthalimide derivatives, are biologi-
cally active as TXA2 receptor antagonists,1a analgesics,1b anti-inflam-
matory agents,1c,d anticonvulsants,1e herbicides,1f insecticides,1g, and
antipsychotics.1h N-Benzylphthalimides have been found to exhibit
non-nucleoside HIV-1 reverse transcriptase inhibitor activities2 and
boronate esters, organotrifluoroborate salts have proven to be
stable and efficient coupling partners in Suzuki–Miyaura coupling
reactions.8 We have previously reported the synthesis and use of
various organotrifluoroborates in cross-coupling reactions.8b,c,9
Most recently, the synthesis and cross-coupling reactions of various
functionalized organomethyltrifluoroborates such as sulfonami-
domethyl, amidomethyl, ammoniomethyl, and alkoxymethyltriflu-
oroborates have been reported.10 Coupling reactions with these
organotrifluoroborates have proven to be tolerant of a variety of
embedded functional groups. A second advantage is that a much lar-
ger library of aryl chlorides (compared to benzyl chlorides) is com-
mercially available, thus adding increased scope and diversity to
potential applications of this new synthetic approach (Scheme 1, b).
Herein, we report the efficient synthesis11 of potassium phtha-
limidomethyltrifluoroborate (3a) and potassium succinimidom-
ethyltrifluoroborate (3b) and a new imidomethylation procedure
resulting from cross-coupling reactions of potassium phthalimi-
domethyltrifluoroborate with a variety of aryl chlorides.
After numerous attempts under various reaction conditions,
the imidomethyltrifluoroborates 3a and 3b were optimally pre-
pared using a synthetic route based on Mattesson’s chemistry.12
Treatment of phthalimide (1a) and succinimide (1b), respectively,
with potassium hydride in the presence of bromomethylpinacolbor-
onate (2) in THF/DMF at room temperature for 24 h gave the corre-
sponding crude boronate esters, which were directly treated with
potassium hydrogen fluoride for 1 h to afford, after isolation and
purification,13 the desired potassium phthalimidomethyltrifluorob-
orate (3a, 60%) and potassium succinimidomethyltrifluoroborate
(3b, 80%) (Scheme 2).
TPA induced TNF-a-production enhancing activity by human leuke-
mia HL-60 cells.3 This large array of biological activities makes imido
derivatives desirable target molecules for synthesis. In addition,
N-benzylphthalimides are well known for the aminomethylation of
aromatic substrates4 and have been used for the synthesis of anti
HIV compounds.4a Traditional synthetic approaches to these imides
have involved formation of the carbon–nitrogen bond via N-benzyla-
tion of phthalimides proceeding via SN2 reactions of benzyl halides
with phthalimide (or potassium phthalimide),1a,5or the Mitsunobu
reaction6 of phthalimide and benzyl alcohols (Scheme 1, a).
A complementary synthetic approach can be envisaged by form-
ing the carbon–carbon bond via a Suzuki–Miyaura cross-coupling
(Scheme 1, b). This new disconnection would provide several
advantages. The first is that the Suzuki–Miyaura cross-coupling
reaction is an extremely versatile C–C bond forming reaction in or-
ganic synthesis.7 Traditionally, boronic acids or boronate esters are
used in Suzuki–Miyaura coupling reactions. However, both suffer
from limitations owing to the difficulty in purification, air and
moisture sensitivity, and in particular the sensitivities of boronic
acids to protodeboronation. As an alternative to boronic acids and
⇑
Corresponding authors. Tel.: +974 44230272; fax: +974 44230060 (D.G.S.).
E-mail addresses: gmolandr@sas.upenn.edu (G.A. Molander), dave.seapy@qatar.
tamu.edu (D.G. Seapy).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.12.062

1052
R. Devulapally et al. / Tetrahedron Letters 53 (2012) 1051–1055
O
O
Traditional
O
a
This work
b
approach
Cl
X
b
N
NY
N
a
BF3K
R
O
R
O
O
Y = H, K
X = Br, Cl, OH
R
Scheme 1. Retrosynthetic analysis.
O
O
1. KH, 0 °C, THF/DMF (5/1)
0 °C to rt, 24 h.
2. KHF2, MeOH, H2O
rt, 1 h, 60%.
O
Br
B
O
NH
N
BF3K
O
O
O
1a
2
3a
O
1. KH, 0°C, THF/DMF (5/1)
0 °C to rt, 24 h.
2. KHF2, MeOH, H2O
2
N
NH
BF3K
rt, 1 h, 80%.
O
3b
O
1b
Scheme 2. Synthesis of potassium imidomethyltrifluoroborates.
After successful synthesis of potassium phthalimidomethyltri-
fluoroborate (3a), cross-coupling reaction conditions were screened
and optimized using 4-chloroanisole (4a) as the electrophilic part-
ner. These optimization studies involved using different catalysts,
ligands (Fig. 1), bases, and solvent systems at different temperatures
(Table 1). The coupling product was first observed at 100 °C using
PdCl2(MeCN)2 or PdCl2(PhCN)2 as the palladium source in 40–43%
conversion (Table 1, entries 5 and 6). By replacing Cs2CO3 base with
K2CO3 the percent conversion increased from 40–43% to 85% (56%
yield) (Table 1, entry 7). Even for a proven catalyst–ligand system,
the ratio of t-BuOH/H2O in the solvent system had a profound effect
on product formation (Table 1, entries 7–9). Similarly, for a proven
catalyst–ligand system, changes in base (Table 1, entries 10 and
11) and/or solvent systems (Table 1, entries 12–16) had dramatic ef-
fects on the coupling reaction. For a 20 h reaction time, increasing
the catalyst/ligand loading from 2.5 mol %/5 mol % to 10 mol %/
20 mol % increased the conversion from 32% to 100% (Table 1,
entries 17–19). Adequate amounts (3 equiv) of base were also
essential for efficient coupling (Table 1, entry 20). Entries 21–28
demonstrate the significant role of ligand selection in that by
varying only the ligand (Fig. 1), the percent conversions range from
a trace to 77%. Ultimately, the optimized conditions resulted in 100%
conversion and a 64% isolated yield (Table 1, entry 29) when using
PdCl2(MeCN)2 (7.5 mol %), X-Phos (15 mol %), K2CO3, in t-BuOH/
H2O (4:1) for 13 h at 100 °C. To our surprise, when trifluoroborate
3a was treated with 4-chloroanisole (4a) under these optimized
reaction conditions, but substituting microwave heating for con-
ventional heating, only a trace amount of cross-coupled product
was observed. Also, the succinimidomethyltrifluoroborate (3b)
when treated with 4-chloroanisole (4a) did not afford any cross-
coupled product under these reaction conditions.
These optimal conditions were then used with an array of
diversely substituted aryl chlorides to explore the scope of the
reaction (Table 2). The coupling products 5b–5j were formed in
36–77% yields. Functional group tolerance included methoxy,
ester, ketone, and pyrrole units. In contrast, 4-chloroaniline and
2-chloro-5-methylphenol were not tolerated and yielded no
cross-coupling product, presumably due to the role of the free
hydroxy and amino functional groups. The yields in Table 2 indi-
cate no clear structure-reactivity correlation with the aryl chloride
variables of steric hindrance or electrophilicity. Reaction times be-
yond the minimum reaction time required for 100% conversion
PCy2
i-Pr
PCy2
O-iPr
Me
N
PCy2
PCy2
P(t-Bu)2
i-Pr
Me
iPr-O
Me
i-Pr
XPhos
RuPhos
DavePhos
MePhos
JohnPhos
OMe
P(t-Bu)2
PPh2
PPh2
MeO
i-Pr
PCy2
i-Pr
PCy2
OMe
O
i-Pr
i-Pr
MeO
i-Pr
t-Bu-XPhos
i-Pr
BrettPhos
SPhos
DPEPhos
Figure 1. Structures of the various phosphine ligands.

R. Devulapally et al. / Tetrahedron Letters 53 (2012) 1051–1055
1053
Table 1
Cross-coupling of 3a with 4-chloroanisole (4a): optimization studies
O
O
Catalyst
Ligand
Base (3 equiv)
Solvent (0.25 M)
T °C.
Cl
N
N
BF3K
OMe
O
5a
O
OMe
Time (h)
3a
4a
Entry
Catalyst/mol %
Ligand/mol %
Base
Solvent/ratio
T (°C)
Conversion (yield %)a
1
2
3
4
5
6
7
8
Pd(OAc)2/5
Pd(dppf)2/5
Pd(PPh3)4/5
XPhos/10
XPhos/10
XPhos/10
XPhos/10
XPhos/10
XPhos/10
XPhos/10
XPhos/10
XPhos/10
XPhos/10
XPhos/10
XPhos/10
XPhos/10
XPhos/10
XPhos/10
XPhos/10
XPhos/5
XPhos/7.5
XPhos/20
XPhos/20
RuPhos/20
DavePhos/20
MePhos/20
t-Bu-XPhos/20
SPhos/20
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
Cs2CO3
Cs2CO3
K2CO3
K2CO3
K2CO3
t-BuONa
DIPEA
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
CPME:H2O/10:1
CPME:H2O/10:1
CPME:H2O/10:1
t-BuOH:H2O/4:1
t-BuOH:H2O/4:1
t-BuOH:H2O/4:1
t-BuOH:H2O/4:1
t-BuOH:H2O/8:1
t-BuOH:H2O/2:1
t-BuOH:H2O/4:1
t-BuOH:H2O/4:1
DMSO:H2O/4:1
DMF:H2O/4:1
CPME:H2O/4:1
Toluene:H2O/4:1
CH3CN:H2O/4:1
t-BuOH:H2O/4:1
t-BuOH:H2O/4:1
t-BuOH:H2O/4:1
t-BuOH:H2O/4:1
t-BuOH:H2O/4:1
t-BuOH:H2O/4:1
t-BuOH:H2O/4:1
t-BuOH:H2O/4:1
t-BuOH:H2O/4:1
t-BuOH:H2O/4:1
t-BuOH:H2O/4:1
t-BuOH:H2O/4:1
t-BuOH:H2O/4:1
85
85
85
80
24
24
24
24
20
20
16
16
16
20
25
16
16
16
16
16
20
20
20
20
24
24
24
24
24
24
24
24
13
0
0
0
0
PdCl2(MeCN)2/5
PdCl2(MeCN)2/5
PdCl2(PhCN)2/5
PdCl2(MeCN)2/5
PdCl2(MeCN)2/5
PdCl2(MeCN)2/5
PdCl2(MeCN)2/5
PdCl2(MeCN)2/5
PdCl2(MeCN)2/5
PdCl2(MeCN)2/5
PdCl2(MeCN)2/5
PdCl2(MeCN)2/5
PdCl2(MeCN)2/5
PdCl2(MeCN)2/2.5
PdCl2(MeCN)2/5
PdCl2(MeCN)2/10
PdCl2(MeCN)2/10
PdCl2(MeCN)2/10
PdCl2(MeCN)2/10
PdCl2(MeCN)2/10
PdCl2(MeCN)2/10
PdCl2(MeCN)2/10
PdCl2(MeCN)2/10
PdCl2(MeCN)2/10
PdCl2(MeCN)2/10
PdCl2(MeCN)2/7.5
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
43
40
85 (56)
0
20
5
Trace
0
0
2
0
0
32
46
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
100 (58)
60b
77
16
42
6
47
Trace
12
1
DPEPhos/20
JohnPhos/20
BrettPhos/20
XPhos/15
100 (64)
a
Reagents and conditions: 1.0 equiv of aryl chloride, 1.2 equiv of trifluoroborate 3a; conversion measured by GC/MS on the crude product mixture based on 4-chloro-
anisole; all reactions were carried out overnight (13–24 h); isolated yields after silica gel column chromatography; CPME = cyclopentyl methyl ether.
b
Two equivalents of base were used.
Table 2
Cross-coupling of 3a with aryl and heteroaryl chlorides
O
O
PdCl2(MeCN)2 (7.5 mol%)
X-Phos (15 mol%)
K2CO3 (3 equiv)
N
N
(Het)Ar-Cl
BF3K
Ar(Het)
t-BuOH/H2O (4/1; 0.25 M)
100 °C.
O
O
3a
4
5
Entry
1
(Het)Ar-Cl
Time/h
Product 5a (%)
5b (36)
MeO
Cl
42
4b
Cl
2
3
14
14
5c (58)
5d (77)
4c
Cl
Me
4d
Me
Cl
4
14
5e (71)
4e
(continued on next page)

1054
R. Devulapally et al. / Tetrahedron Letters 53 (2012) 1051–1055
Table 2 (continued)
Entry
(Het)Ar-Cl
Time/h
14
Product 5a (%)
5f (46)
Me
Cl
Cl
5
Me
4f
CO2Me
6
7
6
5
5g (51)
5h (56)
4g
4h
O
Cl
Cl
Me
OMe
8
9
15
5i (74)
OMe
N
4i
Cl
Cl
18
15
5j (61)
5k (35)
4j
OMe
10
N
4k
a
Reagents and conditions: 1.0 equiv of aryl or heteroaryl chloride, 1.2 equiv of trifluoroborate 3a; isolated yields after silica gel column chromatography.
Table 3
Electrophile compatibility
O
O
PdCl2(MeCN)2 (7.5 mol%)
X-Phos (15 mol%)
K2CO3 (3 equiv)
X
N
N
BF3K
t-BuOH/H2O (4/1; 0.25 M)
100 °C.
O
O
3a
4
5c
Entry
X
Time/h
Yielda (%)
1
2
3
4
5
6
Cl
Br
I
OTf
OTs
OMs
14
18
17
17
18
17
58
43
7
36
31
48
a
Reagents and conditions: 1.0 equiv of ArX; 1.2 equiv of trifluoroborate 3a; isolated yields after silica gel column chromatography.
(based on TLC monitoring of the aryl chloride) often led to reduced
isolated yields. This observation is consistent with product decom-
position under the reaction conditions and highlights the need to
avoid excessive reaction times.
The heteroaryl chloride 4k afforded the cross-coupled product
5k in 35% yield (Table 2, entry 10). However, under the same reac-
tion conditions, a variety of substituted pyridine, quinoline, and
thiophene heteroaryl chlorides resulted in unwanted reduction of
the heteroaryl chlorides, while producing only traces of the desired
cross-coupling products.
31%, and 48% yields of cross-coupled products, respectively (Table
3, entries 4–6).
In summary, potassium succinimidomethyltrifluoroborate and
potassium phthalimidomethyltrifluoroborate salts were success-
fully synthesized from succinimide and phthalimide, respectively,
in moderate to good yields. As a new approach to aminomethylation
methods, potassium phthalimidomethyltrifluoroborate was suc-
cessfully used in Suzuki–Miyaura-like cross-coupling reactions
with a variety of aryl chlorides and one heteroaryl chloride.
Acknowledgments
Trifluoroborate 3a was shown to couple with a variety of elec-
trophiles (Table 3). Coupling with bromobenzene and iodobenzene
produced 43% and 7% yields, respectively (Table 3, entries 2 and 3).
Phenyl triflate, phenyl tosylate, and phenyl mesylate afforded 36%,
This research was supported by a National Priorities Research
Program (NPRP) grant from the Qatar National Research Fund

R. Devulapally et al. / Tetrahedron Letters 53 (2012) 1051–1055
1055
5. (a) Cho, S.-D.; Kim, H.-J.; Ahn, C.; Falck, J. R.; Shin, D.-S. Tetrahedron Lett. 1999,
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(Grant No. 08-035-1-008). G.A.M. thanks the National Institute of
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Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.12.062.
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