Palladium/NHC (NHC = N-Heterocyclic Carbene)-Catalyzed B-Alkyl Suzuki Cross-Coupling of Amides by Selective N-C Bond Cleavage

Article abstract of DOI:10.1021/acs.orglett.8b02911

A highly chemoselective, palladium-NHC (NHC = N-heterocyclic carbene)-catalyzed, direct cross-coupling between B-sp³-alkyl reagents and activated amides by N-C(O) cleavage is reported. Palladium-NHC precatalysts promote chemoselective alkylations of amides that are inaccessible by applying strong organometallic reagents. Various amides, including challenging primary amides after direct and site-selective N,N-di-Boc activation, are compatible with this method. The potential of this mild protocol is demonstrated in sequential C(sp²)-C(sp²)/C(sp²)-C(sp³) cross-couplings deploying a di-Boc amide derived from a common primary amide bond. The method provides a rare example of air- and moisture-stable, well-defined, and highly reactive Pd-NHC precatalysts in B-alkyl-Suzuki cross-couplings.

Full text of DOI:10.1021/acs.orglett.8b02911

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Palladium/NHC (NHC = N‑Heterocyclic Carbene)-Catalyzed B‑Alkyl
Suzuki Cross-Coupling of Amides by Selective N−C Bond Cleavage
Guangrong Meng and Michal Szostak*
Department of Chemistry, Rutgers University, 73 Warren Street, Newark, New Jersey 07102, United States
S
* Supporting Information
ABSTRACT: A highly chemoselective, palladium-NHC
(NHC = N-heterocyclic carbene)-catalyzed, direct cross-
coupling between B-sp3-alkyl reagents and activated amides by
N−C(O) cleavage is reported. Palladium-NHC precatalysts
promote chemoselective alkylations of amides that are
inaccessible by applying strong organometallic reagents.
Various amides, including challenging primary amides after
direct and site-selective N,N-di-Boc activation, are compatible
with this method. The potential of this mild protocol is demonstrated in sequential C(sp2)−C(sp2)/C(sp2)−C(sp3) cross-
couplings deploying a di-Boc amide derived from a common primary amide bond. The method provides a rare example of air-
and moisture-stable, well-defined, and highly reactive Pd-NHC precatalysts in B-alkyl-Suzuki cross-couplings.
he cross-coupling of amides represents a powerful route
to carbon−carbon and carbon−heteroatom bond for-
T
mation by engaging traditionally inert amide bonds (amidic
resonance, 15−20 kcal/mol, nN → π*C=O conjugation).1−3
Direct functionalization of amides has recently become an
important goal in organic synthesis4−8 especially due to the
potential to unlock the Weinreb amide-type reactivity of
amides9 by catalytic metal insertion with much improved
functional group tolerance, chemoselectivity,10 and operational
convenience by avoiding strong organometallic reagents.
Furthermore, the direct activation of amides by N−Boc or
N−Ts protection offers significant advantages to manipulate
common primary (1°) and secondary (2°) amide bonds,11
providing a new synthetic disconnection for the construction
of functionalized molecules from ubiquitous amides.12 Despite
recent progress in C(acyl)−aryl cross-couplings of
amides,3,4,6−8 alkylation of amide bonds by transition-metal
catalysis remains a significant challenge due to competing β-
hydride elimination/protodemetalation decomposing the
organometallic and slower transmetalation.13 In previous
work, Ni-catalyzed alkylation of N-Ts activated amides using
alkylzinc reagents and Ni-catalyzed alkylation of N-Ph/Me
activated amides using alkylborane reagents has been
reported.14 Furthermore, a Ni-catalyzed reductive C(acyl)−
alkyl cross-coupling of N-acyl-succinimide amides has been
reported.4e We turned our attention to the B-alkyl Suzuki
cross-coupling15 of amides using Pd-catalysis to promote
selective formation of acyl-metal from more challenging N-Boc
and N-cyclic amides that are inaccessible by Ni-catalysis.
Herein, we report a highly chemoselective, palladium-NHC
(NHC = N-heterocyclic carbene)-catalyzed, direct cross-
coupling between B-sp3-alkyl reagents and activated amides
by N−C(O) cleavage (Figure 1). Various amides, including
challenging primary amides after direct and site-selective N,N-
di-Boc activation and sensitive N-glutarimide amides,3a,b are
Figure 1. Palladium/NHC-catalyzed B-alkyl Suzuki−Miyaura cross-
coupling of amides by selective N−C cleavage (previous and this
work).
compatible with this method. The potential of this mild
protocol is demonstrated in sequential C(sp2)−C(sp2)/
C(sp2)−C(sp3) cross-couplings deploying a common primary
amide bond. Most importantly, the method expands the well-
developed manifold of Pd-catalyzed Suzuki−Miyaura aryl
cross-coupling of amides to the B-alkyl cross-coupling using
versatile organoboron reagents.15 Furthermore, the method
provides a rare example of air- and moisture-stable, well-
defined, and highly reactive Pd-NHC precatalysts in B-alkyl-
Suzuki cross-couplings.16
Received: September 11, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b02911
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 1 presents key results obtained during the
optimization of the reaction conditions. To test the B-alky-
Table 1. Optimization of Palladium-NHC-Catalyzed Cross-
a
Coupling by N−C Cleavage
entry
catalyst
base
solvent t (°C) yield (%)
1
2
(IPr)Pd(cin)Cl
(IPr)Pd(cin)Cl
(IPr)Pd(cin)Cl
(IPr)Pd(cin)Cl
(IPr)Pd(cin)Cl
(IPr)Pd(cin)Cl
(IPr)Pd(cin)Cl
(IPr)Pd(cin)Cl
(IPr)Pd(cin)Cl
(IPr)Pd(cin)Cl
(IPr)Pd(cin)Cl
(IPr)Pd(allyl)Cl
(IMes)Pd(cin)Cl
(SIPr)Pd(cin)Cl
Pd-PEPPSI-IPr
(IPr)Pd(1-t-Bu-ind)Cl
−
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Cs2CO3
K3PO4
K2CO3
K2CO3
K3PO4
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Cs2CO3
THF
THF
THF
THF
THF
THF
THF
THF
THF
toluene
Et2O
THF
THF
THF
THF
THF
THF
THF
23
65
65
23
23
23
65
23
23
23
23
23
23
23
23
23
23
110
56
67
48
70
53
84
91
<5
27
28
21
5
b
3
c
4
d
5
6
7
8
9
10
11
12
13
14
15
16
17
Figure 2. Structures of palladium-NHC precatalysts.
16). Of note, changes in the throw-away ligand ([(IPr)Pd-
(allyl)Cl], [Pd-PEPPSI-IPr]) and in the NHC scaffold
([(IMes)Pd(cin)Cl], [(SIPr)Pd(cin)Cl]) resulted in signifi-
cantly diminished yields.18 However, we identified the
[(IPr)Pd(1-t-Bu-ind)Cl] precatalyst as a promising Pd(II)-
NHC precatalyst19 for the B-alkyl-Suzuki cross-coupling of
amides. In line with previous studies and the high reactivity of
the preformed Pd(II)-NHC precatalysts, control experiments
in the absence of the catalyst and using representative Pd-PR3
conditions14e revealed the requirement for a strong σ-donating
Pd−NHC in this cross-coupling protocol.
7
21
15
57
<5
<5
e
18
Pd(PPh3)4
a
Conditions: 1 (1.0 equiv), n-C10H21-9-BBN (2.0 equiv), catalyst (3−
6 mol %), base (3.0 equiv), solvent (0.25 M), 23−110 °C, 15 h.
With the optimized conditions in hand, we tested the
preparative scope of the reaction using N,N-di-Boc amide as a
standard electrophile (Table 2). Pleasingly, this challenging
alkylation reaction tolerates a range of B-alkyl-9-BBN reagents,
including those with simple (entries 1−2) and sensitive
functional groups such as ether (entry 3), imide (entry 4),
indole (entry 5), and ester (entry 6). While in some cases the
yield is modest, the reaction provides a proof-of-concept and a
simple method for selectively installing functionalized alkyl
groups from amides derived from common primary
benzamides in a catalytic manner. Furthermore, we were
pleased to find that a variety of amides are tolerated in this B-
alkyl-Suzuki cross-coupling. Most interestingly, N-acyl-gluta-
rimides that feature two activated carbonyl groups20 were
selectively cross-coupled at the exocyclic N-acyl bond, attesting
that this catalytic system is selective for cleavage of activated
N−C(O) bonds (entries 7−12). Furthermore, N-Ph/Boc and
atom-economical N-Ph/Ms amides that can be prepared
directly from common secondary amides readily participated in
this coupling (entries 13−14).3a,b Finally, we found that even
sensitive N-benzoyl-saccharin that typically undergoes CO
addition to the saccharine ring and SO2 cleavage with strong
organometallics3a,b delivered the desired coupling product,
albeit in a modest yield (entry 15). At present, ortho-methyl
benzoic acid derived amides have not been tested. At this
stage, α-branched alkyl boron reagents are not tolerated. The
reaction can be routinely set up under open air conditions.
Future studies will be focused on further optimization of
reaction conditions and application to multicomponent
reactions.
b
Entries 1−5: [Pd] (3 mol %). Entries 6−16: [Pd] (6 mol %). K2CO3
(4.5 equiv). H2O (10 equiv). Et3N (30 mol %). [Pd] (5 mol %).
See Supporting Information (SI) for experimental details.
c
d
e
Suzuki cross-coupling, we selected N,N-di-Boc activated
benzamide. The site-selective N,N-diacylation of the 1°
amide bond allows a significant decrease in amidic resonance
(ER = 7.6 kcal/mol) and engages common benzamides in
general cross-coupling manifolds.11 However, the major
challenge is the propensity of the N-Boc group to undergo
scission, deactivating the acyl amide bond toward metal
insertion. To our delight, we observed the desired B-alkyl
Suzuki alkylation product using the [(IPr)Pd(cin)Cl]
precatalyst17 (3 mol %) in a promising 56% yield at room
temperature (Table 1, entry 1) using n-C10H21-9-BBN (2.0
equiv) in the presence of K2CO3 as a base. Improvement in the
reaction efficiency was realized by increasing the reaction
temperature to 65 °C (entry 2); however, the reaction was less
efficient using an excess of base (entry 3), consistent with facile
decomposition of the alkyl-organometallic.13 The addition of
water had a minor, but positive effect on the reaction efficiency
(entry 4); however, our attempts to generate the more reactive
acylammonium species in situ by using Lewis bases4c did not
result in noticeable improvements of the reaction efficiency
(entry 5). Further optimization revealed that yields could be
dramatically improved by employing 6 mol % of the Pd-NHC
precatalyst (entries 6−7), consistent with the difficulty of the
cross-coupling. Tuning of different bases and solvents
demonstrated that a combination of K2CO3 and THF is
preferred for this coupling (entries 8−11). An extensive screen
of various Pd-NHC precatalysts (Figure 2) identified [(IPr)-
Pd(cin)Cl] as essential for this coupling (Table 2, entries 12−
We speculated that the potential of this mild alkylation
protocol could be demonstrated in sequential C(sp2)−C(sp2)/
C(sp2)−C(sp3) cross-couplings employing amides derived
from common primary amide bonds. To this end, site-selective
B
DOI: 10.1021/acs.orglett.8b02911
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a b
,
Table 2. Palladium-NHC-Catalyzed Alkylation of Amides by N−C Cleavage
a
Conditions: (A) 1 (1.0 equiv), 2 (2.0 equiv), (IPr)Pd(cin)Cl (6 mol %), K2CO3 (3.0 equiv), THF (0.25 M), 23 °C, 15 h. (B) 65 °C. (C)
b
(IPr)Pd(1-t-Bu-ind)Cl (6 mol %), 65 °C. See SI for experimental details. Isolated yields.
N,N-di-Boc activation of 4-iodobenzamide, followed by aryl
Suzuki cross-coupling and C(acyl)−B-alkyl Suzuki cross-
coupling, has been accomplished with a high degree of
efficiency and excellent chemoselectivity (Scheme 1). Of note,
aryl Suzuki cross-coupling could be readily performed in the
presence of the electrophilic N,N-di-Boc amide, which
together with the B-alkyl regime allows for a strategically
valuable disconnection typical to Weinreb amides, but in a
catalytic manner.
C
DOI: 10.1021/acs.orglett.8b02911
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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Scheme 1. Sequential Cross-Coupling of 1° Amides
In conclusion, we have reported a new method for highly
chemoselective, palladium-NHC-catalyzed, direct cross-
coupling between B-sp3-alkyl reagents and activated amides
by N−C acyl cleavage. This protocol is compatible with
various amides, including challenging primary amides after
direct and site-selective N,N-di-Boc activation and sensitive N-
cyclic amides. The method delivers chemoselective alkylation
products of amides that are inaccessible by applying strong
organometallic reagents. We have further demonstrated the
utility of the method in sequential C(sp2)−C(sp2)/C(sp2)−
C(sp3) cross-couplings employing amides derived from
common primary amide bonds. Further studies will focus on
optimization of the catalyst system and reaction parameters to
expand the substrate scope and mechanistic investigations to
facilitate further reaction development.
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b02911.
Procedures and analytical data (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: michal.szostak@rutgers.edu.
ORCID
Guangrong Meng: 0000-0002-3023-0654
Michal Szostak: 0000-0002-9650-9690
Notes
The authors declare no competing financial interest.
(11) Meng, G.; Shi, S.; Lalancette, R.; Szostak, R.; Szostak, M. J. Am.
Chem. Soc. 2018, 140, 727.
(12) Trost, B. M.; Fleming, I. Comprehensive Organic Synthesis;
ACKNOWLEDGMENTS
■
Rutgers University and the NSF (CAREER CHE-1650766)
are gratefully acknowledged for support. G.M. thanks the
Graduate-School-Newark for a Dissertation Fellowship.
Pergamon Press: Oxford, 1991.
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1417. (b) Giri, R.; Thapa, S.; Kafle, A. Adv. Synth. Catal. 2014, 356,
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