Domino Heck/borylation sequence towards indolinone-3-methyl boronic esters: trapping of the σ-alkylpalladium intermediate with boron

Article abstract of DOI:10.1039/c5cc05193b

Pd-catalyzed domino Heck/borylation of acrylamides with B₂pin₂ is reported to generate synthetically useful indolinone-3-methyl boronic esters, via capturing σ-alkyl palladium with boron. Further functionalization of the obtained boronic ester qualify it as a new starting point for the functionalization of specific C(sp³)-H bond. Moreover, the application of an Ugi-adduct as starting material or B₂nep₂ as an alternative boron source works equally well, making this a broadly applicable and robust method for the formation of a C-C and C-B bond in a single operation.

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Domino Heck/borylation sequence towards indolinone-3-methyl
boronic esters: trapping of the σ-alkylpalladium intermediate
with boron†
Received 00th January 20xx,
Accepted 00th January 20xx
Dipak D. Vachhani,*[a] Himanshu H. Butani,[a],[b] Nandini Sharma,[a] Umed C. Bhoya,[b] Anamik K.
Shah,[b] and Erik V. Van der Eycken*[a]
DOI: 10.1039/x0xx00000x
www.rsc.org/
Pd-catalyzed domino Heck/borylation of acrylamides with B2pin2 is organometallic nucleophiles, such as Grignard or organolithium
reported to generate synthetically useful indolinone-3-methyl reagents, which react with boron electrophiles to deliver alkyl
boronic esters, via capturing σ-alkyl palladium with boron. Further boranes.[7] On the other hand, the groups of Cárdenas and Bäckvall
functionalization of the obtained boronic ester qualify it as a new have made very interesting reports in recent years on borylating
starting point for the functionalization of specific C(sp3)-H bond. carbocyclization of polyunsaturated compounds.[8] Inspired by these
Moreover, the application of an Ugi-adduct as starting material or findings, we envisioned to develop a novel Pd-catalyzed domino
B2nep2 as an alternative boron source works equally well, making Heck/borylation approach for the synthesis of indolinone-3-methyl
this a broadly applicable and robust method for the formation of a boronic esters (Scheme 1, eq 3). Such transformation could provide
C-C and C-B bond in a single operation.
a new starting point for the further functionalization of specific
C(sp3)-H bonds and could have great impact in the field of medicinal
chemistry and natural product synthesis. To develop this domino
protocol, the conditions must be fine-tuned to avoid two main
hurdles, i.e. direct Miyaura-type borylation and hydroarylation of
the alkene (Scheme 2).[6,9] Furthermore, the generated alkyl boronic
ester, may easily undergo transmetallation to a Pd(II)-species,
leading to the undesired Suzuki cross-coupling product. These
hurdles may explain why, to the best of our knowledge, no report
has appeared so far about the Pd-catalyzed Heck/borylation of
haloalkenes.
The insitu trapping of alkyl metal species, generated by the
cyclization of a halogenated alkene, with different nucleophiles, has
proven to be highly valuable for the performance of transition
metal-catalyzed domino reactions.[1] The high bond forming
efficiency of such domino processes is ideally suited for generating
molecular complexity in a single step.[2] For instance, Heck/anionic-
capture sequences have been extensively developed for the
synthesis of biologically useful 3-substituted indolines employing a
variety of nucleophiles to trap the σ-alkylpalladium intermediate
(Scheme 1, eq 1).[3] However, to the best of our knowledge, no
report has appeared using boron as a nucleophile in Heck/anion-
capture sequences for the synthesis of 3-substituted indolones.
Furthermore, organoboronates are convenient and versatile
reagents owing to their high functional group compatibility, good
stability and low toxicity.[4] Moreover, these compounds can easily
be oxidized to alcohols, or can be used to construct new C-C bonds
via Suzuki-Miyaura cross-coupling.[5] The most common way of
preparing a C-B bond is the Miyaura borylation of aryl or alkenyl
(pseudo)halides (Scheme 1, eq 2).[5g,6] However, the methodology
has severe limitations for the formation of the corresponding alkyl
halides. Therefore, alkyl halides are initially converted into the
Scheme 1.
To begin our study, we choose readily synthesized acrylamide 1a as
standard substrate and bis(pinacolato)diborane (B2pin2) as
borylation reagent under various reaction conditions (Table 1).
When 1a was treated with B2pin2 in the presence of catalytic
Pd(OAc)2 using PPh3 as ligand and Na2CO3 as base in toluene at 120
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Pd(PPh3)2Cl2
-
ACN/water
ACN/water
ACN/water
ACN/water
ACN/water
ACN/water
ACN/water
ACN/water
60
60
60
60
60
30
15
300
93
49
11
12
13
14
15
16
17
18
Pd(OAc)2
Pd(OAc)2
X-Phos
P(tBu)3
51
[f]
Pd(PPh3)4
-
-
-
-
-
92
[g]
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
95
[g]
[g]
[g]
93
83
Scheme 2. Possible hurdles for the domino Heck/borylation.
82[h]
0C under microwave irradiation for 60 min, no desired product
formation was observed (Table 1, entry 1). However, applying the
same conditions using a solvent mixture of toluene/water (9:1) gave
2a in 68% isolated yield (Table 1, entry 2). This result suggests that
the presence of water is crucial for this domino reaction, as it is
most probably needed for the formation of hydroxide ion, which
consequently promotes transmatallation and reduction elimination
steps.[10] While THF and EtOH gave similar results, dioxane gave a
somewhat lower yield. The reaction performance can be
substantially enhanced upon changing the solvent from toluene to
ACN (Table 1, entries 3-6). An attempt to make the protocol greener
by increasing the amount of water resulted in a poorer yield (Table
1, entry 7). Changing the base did not ameliorate the reaction yield
(Table 1, entries 8 and 9). Among the different catalytic systems
used, Pd(PPh3)4 gave the best result with a cleaner reaction profile
even at lower catalyst loading (Table 1 , entries 10-15). The reaction
time can be reduced to 30 min without compromising the yield,
although a further reduction led to incomplete reaction (Table 1,
entries 16 and 17). Upon carrying out the same reaction under
conventional heating for 5h gave a comparable result, showing the
compatibility of the reaction for both ways of heating (Table 1,
entry 18).
[a] Unless otherwise stated, all reactions were run with 1a (0.1 mmol),
B2pin2 (2 equiv), Pd-catalyst (10 mol%), ligand (20 mol%), Na2CO3(2 equiv) in
the indicated solvent (9:1) (1 mL) under N2 atmosphere at 120 0C for 1 h
under microwave irradiation using a maximum power of 100W; [b] yields
were determined by 1H NMR using 2,4,6-trimethoxy benzaldehyde as an
internal standard; yields between brackets are isolated yields; [c]
EtOH/water (1:1) was used; [d] K2CO3 was used as a base; [e] NaHCO3 was
used as base; [f] 5 mol% of Pd(PPh3)4 was used; [g] 2 mol% of Pd(PPh3)4 was
used; [h] conventional heating was used; nd = not detected.
Table 2. Substrate scope for the domino Heck/borylation approach.[a]
Table 1.Optimization of the domino Heck/borylation.[a]
time
entry
catalyst
ligand
solvent
yield[b](%)
(min)
60
60
60
60
60
60
60
60
60
60
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(PPh3)4
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
-
toluene
toluene/water
THF/water
nd
72 (68)
81
1
2
3
dioxane/water
EtOH/water
ACN/water
EtOH/water[c]
ACN/water
ACN/water
ACN/water
53
4
82
5
[a] Reactions were run with 1 (0.2 mmol), B2pin2 (2 equiv), Pd(PPh3)4 (2
mol%), Na2CO3 (2 equiv) in ACN/water (9:1) (1 mL) under N2 atmosphere at
120 oC for 40 min under microwave-irradiation using a maximum power of
100W; [b] N(2-bromophenyl)acrylamide was used as substrate; nd = not
detected.
94
6
52
7
90[d]
62[e]
98
8
Having optimized the domino Heck/borylation protocol (Table 1,
entry 16), we evaluated the scope and limitations. To our great
satisfaction, the optimized reaction conditions were found to be
generally applicable for substituents having different electronic
9
10
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properties, on either part of the acrylamides (Table 2). For instance, Replacement of B2pin2 with bis(neopentyl glycolato)diboron
different alkyl- or benzyl-substituents on nitrogen are well (B2nep2) was also found successful and compounds 5a,b were
tolerated. On the contrary an electron withdrawing tosyl group or a synthesized in good yields. To our surprise, employment of
free –NH are found to be incompatible with these conditions (Table conventional heating proved better than microwave-irradiation for
2, 2a-i). It is worth mentioning that highly electron withdrawing this transformation.
groups such as -CN and -CF3are also compatible with these
transformations (2m,n) Atropic acids bearing an electron donating
or electron withdrawing substituent also nominated themselves as
effective substrates (2q,r). Benzyl acrylamide undergoes this
domino Heck/borylation smoothly (2s). Finally, acrylamide bearing a
bromo instead of an iodo substituent, works equally well under the
optimized conditions (2a). Further attemp to expand the substrate
scope towards alkyne was found to be complete failure and
employment of N-(2-iodophenyl)-N-methylbut-2-ynamide instead
of 1a gave only reductive cyclization product.[11]
[a] The reaction was carried out under microwave-irradiation on 2a,b (0.2
mmol) with 2 equiv of (B2nep2) at 120 oC for 40 min using a maximum power
of 100W; [b] yield was determined by 1H NMR.
Scheme 4. Expanding the scope of the protocol to the application of B2nep2.
Next, we tried to expand the ring size (six- and seven-membered)
employing higher homologous of acrylamide 1 (table 3). Whereas
microwave irradiation completely failed to give the desired product
in either case, conventional heating gave 19% yield of the six-
membred product 2u (by 1H NMR) as a inseperable mixture of two
compounds. The probable reason for this failure might be the
difficulty to form a seven- or eight-membered palladacycle. In all
cases, along with the desired product, unreacted staring material
was isolated next to 7-38% of the direct Miyaura borylation
product.
The development of one-pot reaction is greatly desired in
contemporary organic synthesis. Since it is known that boronic
esters can be oxidized to alcohols by oxone,[13] we hypothesized
that a one pot Heck/borylation/oxidation strategy would constitute
a direct route to 3-hydroxymethyl indolinones. To our delight,
employing our Heck/borylation strategy followed by addition of
oxone, furnished 3-hydroxymethyl indolinone 6a in a one-pot
fashion with an overall yield of 82%. Further modification of 6a
following the literature procedure, would provide a concise route
for the synthesis of esermethole and physostigmine,[14] the last
being a reversible cholinesterase inhibitor.
Table 3. Exapanding the substrate scope to six- and seven-membered rings
for the domino Heck/borylation approach.[a]
O
O
Br
B
O
Conditions
B
O
N
n
O
n
O
N
N
n
O
1
Scheme 5. Onepot Heck/borylation/oxidation strategy giving access to the
formal synthesis of esermethole and physostigmine.
2'
2
% yield of 2’
(Miyaura borylation)
Substrate 1
n
% yield of 2
To test the applicability of this domino Heck/borylation reaction, we
successfully scaled up the reaction to 3.0 mmol, which afforded 2f
in 81% yield. Subsequently, we also demonstrated that 2f can easily
undergo Suzuki coupling,[15] or can be converted into different
synthons such as a boronic acid[16] or a trifluoroborate salt[17]
following known transformations (Scheme 6).
1
Traces[b]
(19)[c],[d]
Nd[b] (nd)[c]
1u
1v
7[b]
2
30[b] (38)[c]
Conditions: [a] Reactions were run with 1 (0.2 mmol), B2pin2 (2 equiv),
Pd(PPh3)4 (2 mol%), Na2CO3 (2 equiv) in ACN/water (9:1) (1 mL) under N2
atmosphere at 120 oC; [b] microwave-irradiation was used for 40 min using a
maximum power of 100W; [c] conventional heating was used for 6 h; [d]
obtained as a inseparable mixture of two product.
While performing this Pd-catalyzed domino Heck/borylation study,
in some cases, we observed the formation of hydroarylated product
(Scheme 2). Based on this observation and earlier reports,[3,6] we
can rationalyze that the reaction involves the formation of a σ-
alkylpalladium intermediate. Oxidative addition of Pd(0) to
Furthermore, to demonstrate the utility and the robustness of this
protocol, compounds 3a,b were synthesized via U-4CR (Ugi 4-
component reaction)[12] and subjected to the optimized protocol.
Gratifyingly, this strategy led to a facile synthesis of borylated
indolinones 4a,b in good yields as diastereomeric mixtures (Scheme
3).
acrylamide
1 followed by insertion to the alkene, leads to
intermediate II. This can react with base (most probably insitu
generated hydroxide)[10] to give a more reactive intermediate III,
which undergoes transmetallation with boron resulting in
intermediate IV. Finally, reductive elimination of IV delivers product
2 and Regenerates Pd(0).
Conclusions
In summary, we have developed
a domino Heck/borylation
approach for the construction of indolinone-3-methyl boronic
esters via trapping of the σ-alkylpalladium intermediate with a
Scheme 3. Expanding the scope to a post-Ugi domino Heck/borylaiton
protocol.
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Scheme 6. Versatile transformations of the alkyl borylated product.
boron reagent. The protocol shows remarkable selectivity for the
domino reaction over known hurdles, i.e. the direct Miyaura
borylation and the hydroarylation of the alkene. The addition of
water was found to be essential for this reaction. The robustness of
the methodology was further demonstrated by the application of
an Ugi-adduct as a starting material and by using B2nep2 as
borylating agent. Furthermore, the borylated product can easily be
converted into valuable synthons, applying known transformations.
6
7
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