Cross-Coupling of Primary Amides to Aryl and Heteroaryl Partners Using (DiMeIHeptCl)Pd Promoted by Trialkylboranes or B(C6F5)3

Article abstract of DOI:10.1021/jacs.7b09488

Boron-derived Lewis acids have been shown to effectively promote the coupling of amide nucleophiles to a wide variety of oxidative addition partners using Pd-NHC catalysts. Through a combination of NMR spectroscopy and control studies with and without oxygen and radical scavengers, we propose that boron-imidates form under the basic reaction conditions that aid coordination of nitrogen to Pd(II), which is rate limiting, and directly delivers the intermediate for reductive elimination.

Full text of DOI:10.1021/jacs.7b09488

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Communication
Cross-coupling of primary amides to aryl- and heteroaryl-partners
using (DiMeIHeptCl)Pd promoted by trialkylboranes or BCF.
Sepideh Sharif, Jonathan Day, Howard N. Hunter, Yu Lu,
David Mitchell, Michael J. Rodriguez, and Michael G. Organ
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.7b09488 • Publication Date (Web): 16 Oct 2017
Downloaded from http://pubs.acs.org on October 16, 2017
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Journal of the American Chemical Society
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Cross-coupling of primary amides to aryl- and heteroaryl-partners
using (DiMeIHeptCl)Pd promoted by trialkylboranes or BCF.
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Sepideh Sharif,[a] Jonathan Day,[a] Howard N. Hunter,[a] Yu Lu,[b] David Mitchell,[b] Michael J. Rodriꢀ
guez,[b] and Michael G. Organ*[a,c]
[a] Department of Chemistry, York University 4700 Keele Street, Toronto, M3J 1P3 (Canada). [b] Lilly Research Laboratoꢀ
ries, A Division of Eli Lilly and Company, Indianapolis, IN 46285 (USA). [c] Centre for Catalysis Research and Innovation
(CCRI) and Department of Chemistry and Biomolecular Sciences, University of Ottawa, Ottawa, K1N6N5 (Canada).
KEYWORDS (Pd, PEPPSI, cross-couple, amide, BCF, triethylborane, trisecbutylborane).
ABSTRACT: Boronꢀderived Lewis acids have been shown to effectively promote the coupling of amide nucleophiles to a wide
variety of oxidative addition partners using PdꢀNHC catalysts. Through a combination of NMR spectroscopy and control studies
with and without oxygen and radical scavengers, we propose that boronꢀimidates form under the basic reaction conditions that aid
coordination of nitrogen to Pd(II), which is rate limiting, and directly delivers the intermediate for reductive elimination.
The amide linkage forms the backbone of all peptides/proteins
and is prevalent in the structure of numerous biologically imꢀ
portant compounds, such as therapeutics.1 Consequently, exꢀ
tensive effort has gone into the development of efficient and
robust methods to form amide bonds.2 Within this area of synꢀ
thesis, Pd catalysis has been developed over the last 30 years
to establish the bond between the carbonyl carbon and the
nitrogen (i.e., carbonylative amine coupling)3 or between the
amide nitrogen and its substituents (i.e., crossꢀcoupling of
primary and secondary amides).4
that amine coordination precedes deprotonation, the ease of
proton removal to create the metalꢀamido intermediate (6)
necessary for reductive elimination will improve in this same
direction. However, assuming that the general crossꢀcoupling
mechanism in Figure 1 is operative in amide coupling, this
ease of deprotonation can only be realized if the amide first
coordinates. Herein we report the use of Lewis acids to ease
the crossꢀcoupling of amides to a selection of diverse partners
using mild base (CO32ꢀ) at moderate temperature (80ꢀ90 °C).
Based on experience we have had with couplings involvꢀ
ing the 2ꢀaminopyridine motif,8 we recognized that a successꢀ
ful catalyst for amide coupling would have to resist κ2 coordiꢀ
nation (8, Figure 1) to Pd.9 To this end, we examined three of
our bulkiest Nꢀheterocyclic carbene (NHC) ligands10 and repꢀ
resentative results are summarized in Table 1. As anticipated,
the bulkiest catalyst (14) had the best initial results (entries 1ꢀ
3). Inspired by earlier work by Hartwig,11 we examined the
impact of Lewis acids on this reaction. Trialkylboranes (enꢀ
tries 4 and 5) and B(C6F5) (BCF, entry 6) all led to a clean
conversion to the coupled product, while others (entries 7ꢀ9)
were less effective. Catalyst 13, inactive on its own (entry 2),
now saw conversion of 55% with Et3B (entry 10). A similar
pattern of results was obtained when 2ꢀchloropyridine was
used as the oxidative addition partner (see Table S1 in the SI).
Crossꢀcoupling of (hetero)aryl oxidative addition partners
with primary and secondary alkylꢀ and arylꢀamines5 is now
well developed with catalysts capable of coupling together
electronically and/or sterically challenged partners with mild
base at low temperature.6 Conversely, crossꢀcoupling involvꢀ
ing amide nucleophiles is less well developed as it poses new
difficulties.5 When considering nitrogen nucleophiles, the amꢀ
ide nitrogen is one of the least nucleophilic, which can be esꢀ
timated by considering pKa values. Whereas an alkyl amine
has a pKa of ~43 and an aniline ~30, an amide is ~23 (all valꢀ
ues in DMSO). So when considering the general catalytic cyꢀ
cle for arylation of amines (Figure 1),7 nitrogen (4) coordinaꢀ
tion to Pd of intermediate 3 (to create 5) is dramatically reꢀ
duced in this same order. Conversely, presuming for now
R2
Ar-Cl
Pd(0)Ln
It is interesting to note that the results using Et3B are in
stark contrast to what Hartwig’s group observed. Using bidenꢀ
tate phosphine ligands they reported that intermediate 6 reꢀ
quired a heteroatom in the oxidative addition partner to comꢀ
plex the Lewis acid in order to lower the barrier for reductive
elimination.11 It should be noted that the intermediates Hartꢀ
wig studied were not derived from amides, but diarylamines
with an assumption, presumably, that the same trends would
hold for amide nucleophiles; this appears not to be the case.
While methoxy groups can push electron density into the
metal amido intermediate (e.g., 6), presumably disfavoring
Ar
N
2
1
Reductive
Elimination
Oxidative
Addition
R1
7
Ar
Cl
Ar
O
PdLn
Ln-Pd(II)
R1
Ln-Pd(II)
R3
N
R4
N
3
8
R2
6
Amine
Coordination
R2
N
R1
Deprotonation
R2
R1
Cl
HN
Ln-Pd(II)
Ar
4
H
5
Figure 1. Catalytic cycle for Pdꢀcatalyzed arylation of amines.
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Table 3. Scope of amide coupling using 14 and (secBu)3B.a
Page 2 of 5
Table 1. Optimization of amide coupling using PdꢀNHCs.
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2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
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Entry Base
equiv.
Additive
(20 mol %)
ꢀ
Temp.
(°C)
Cat.
Conv.a
(Yield)b
1
2
3
80
80
80
90
90
90
90
90
90
90
12
13
14
14
14
14
14
14
14
13
0
3
ꢀ
0
21
3
3
ꢀ
4
1.5
1.5
1.5
1.5
1.5
1.5
1.5
Et3B
100 (86)
100 (92)
100 (70)
0
5
(secBu)3B
B(C6F5)3
(MeO)3B
ZnCl2
Et2AlCl
Et3B
6
7
8
20
9
26
10
55
aPercent conversion is the conversion of 9 to 11 as determined
by 1H NMR spectroscopy of the crude reaction mixture. Perꢀ
b
aPercent yield is determined after purification on silica gel.
cent yield is determined after purification on silica gel.
bReaction run at 90°C. cReaction run with 1 equiv. (secBu)3B.
reductive elimination, it is also possible that coordination of
the Lewis acid to oxygen could pull electron density out of 6,
actually driving reductive elimination. Replacing the methoxy
group on 9 with a tertꢀbutyl moiety (i.e., 15) did not change
the reaction outcome (Table 2).
coupling by the same mechanism. However, a closer look will
reveal three very different species. We have shown in alkyne
hydrostannylation that while BCF14 and Et3B15 gave products
with identical regioꢀ and stereoselectivity, the mechanisms
could not be more unrelated. BCF is by far the most Lewis
acidic of the three,15 while the alkylboranes are prone to autoxꢀ
idation leading to the formation of radicals under even the
most careful attempts to exclude oxygen.15,17 It is therefore
possible that a redox shuttle might be operative with the alkylꢀ
boranes. It has been shown recently by Buchwald and Macꢀ
Millan that photoredox is effective for Niꢀcatalyzed aminaꢀ
tion.18 To explore this possibility, we performed the coupling
in the presence of radical scavengers (Table 4) and there do
appear to be some differences between (secBu)3B and Et3B.
With (secBu)3B, there was a gradual decrease in conversion to
product (entries 1ꢀ5), whereas Et3B was less impacted (entries
6ꢀ10). That coupling went to 80% when one equivalent of
TEMPO was used with Et3B means that the scavenger is not
just otherwise interfering in the (secBu)3B runs. Substituting
galvinoxyl for TEMPO produced similar results (entry 11).
The protocol using (secBu)3B is easy to carry out operaꢀ
tionally and shows good generality (Table 3). Baseꢀsensitive
nitrile (29), ketone (18, 30) and ester (31) groups are well tolꢀ
erated and the procedure works equally well for alkyl12 or aryl
amides. Of note, hinderance on the amide (26, 27, 29, 30),
oxidative addition partner (32ꢀ34), or both (35) is acceptable
under the standard conditions. Temperatures up to 150 °C
have been required to make such couplings work.13
On the surface, it is tempting to suggest that all three boꢀ
ronꢀderived Lewis acids used in this study promote the
Table 2. Amide coupling to tertbutylꢀ4ꢀchlorobenzene (15).
Given the coupling is not fully suppressed when a scavenꢀ
ger is present with either alkylborane reagent suggests that a
redox pathway is not operating with respect to this coupling.
That said, it is known that alkylboranes react rapidly with the
trace levels of oxygen that would be present in our reactions,15
so there must be some impact of oxygen on these amide couꢀ
plings. To examine this, reactions with both alkylboranes were
set up in the glovebox using degassed (freezeꢀpumpꢀthaw)
solvents and glassware and syringes that had been first extenꢀ
Entry
Additive (20 mol%)
Conv.a (Yield)b
26
1
2
3
ꢀ
(secBu)3B
100 (87)
(C6F5)3B
100 (82)
aPercent conversion is the conversion of 15 to 16 as deterꢀ
mined by 1H NMR spectroscopy of the crude reaction mixture.
bPercent yield is determined after purification on silica gel.
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Table 4. Effect of radical scavengers TEMPO and galvinoxyl
on amide coupling using 14 and Et3B or (secBu)3B.
set up. Conversely, Et3B, which burns upon exposure to air,
1
2
3
4
5
6
7
8
can tolerate oxygen when air is introduced after Et3B first stirs
with the other reaction components (entry 2a). When Et3B was
exposed to air prior to adding the rest of the reaction mixture
(entry 3a), no turnover occurs at all. This would imply that
something in the reaction mixture acts to ‘protect’ the Et3B
from the effects of oxygen. The same trend was observed
when these couplings were performed using 2ꢀchloropyridine
as the oxidative addition partner (see Table S2 in the SI).
Entry
Additive
Radical Scavenger
(equiv.)
Conv.a
(20 mol %)
(Yield)b
To explore possible interactions between the trialkylꢀ
boranes and the amide, a series of NMR experiments were
performed (see Figure 2 for Et3B and Figures S1 and S2 in the
SI for (secBu)3B and BCF). The 11B resonance for trialkyl
boranes (R3B) typically comes around 85 PPM (panel d),
while the borinate (R2BꢀOR), boronate (RB(OR)2), and borate
species associated with autoxidation come at approximately
55, 35, and 20 PPM, respectively (panel f).15 When the amide
and boranes were mixed with careful exclusion of air, signifiꢀ
cant differences were seen in both the 11B and 13C NMR specꢀ
tra. With Et3B, the peak around 85 PPM in the 11B spectra
diminishes, and the peak at 55 PPM intensifies (panel e). At
the same time the peak for the amide in the 13C NMR spectrum
(168.6 PPM) gives rise to three new signals, the most promiꢀ
nent of which is a broad peak at 169.5 PPM (panel b). After
aqueous work up and extraction of this NMR sample, the sinꢀ
gle amide peak reemerges illustrating that nothing untoward
has happened to 10 stemming from Et3B (panel c). These data
suggest that the amide is coordinated to Et3B leading to the
formation of a boron amidonium complex (36), which preꢀ
sumably under the basic conditions of the coupling would be
deprotonated forming ceꢀ
1
2
(secBu)3B
(secBu)3B
(secBu)3B
(secBu)3B
(secBu)3B
(secBu)3B
Et3B
ꢀ
100 (92)
94 (88)
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
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TEMPO (0.1)
TEMPO (0.2)
TEMPO (0.3)
TEMPO (0.4)
TEMPO (1.0)
ꢀ
2
75 (68)
3
65 (52)
4
55 (52)
5
27 (24)
6
100 (86)
100 (88)
100 (92)
100 (92)
100 (90)
80 (71%)
100 (97)
7
Et3B
TEMPO (0.1)
TEMPO (0.2)
TEMPO (0.3)
TEMPO (0.4)
TEMPO (1.0)
galvinoxyl (1.0)
7
Et3B
8
Et3B
9
Et3B
10
Et3B
11
Et3B
aPercent conversion is the conversion of 9 to 11 as determined
by 1H NMR spectroscopy of the crude reaction mixture. Perꢀ
b
cent yield is determined after purification on silica gel.
sively scrubbed free of oxygen for 7 days (Table 5, entry 4).14
sium boron amidate salt 37.
Keeping in mind the results
where the reaction with Et3B
was initiated
The coupling proceeded well with the scrupulous removal
of oxygen, supporting the hypothesis that radicals are not inꢀ
volved in this Pdꢀcatalyzed process. Entries 2 and 3 are very
instructive. (secBu)3B seems to be completely insensitive to
oxygen, regardless of when it is introduced into the coupling
Figure 2. NMR spectra for Et3B and amide 10.
Table 5. Effect of oxygen on amide coupling using 14 and
Et3B or (secBu)3B.
d)
a)
e)
b)
Entry/Additive Reaction Conditions
Conv.
1a) Et3B
Standard Schlenk technique
a) 100
b) 100
1b) (secBu)3B
2a) Et3B
Premix reagents using standard a) 100
Schlenk technique, stir for 5 min.,
expose to air and heat for 24h
f)
c)
2b) (secBu)3B
b) 100
3a) Et3B
Dissolve borane in toluene and a) 0
stir open to air for 10 min., add all
other reagents, heat for 24h
3b) (secBu)3B
b) 100
Spectra are all run in benzene D6 at 75 °C. Panel a) 13C NMR
spectrum of amide 10. Panel b) 13C NMR spectrum of amide
10 plus Et3B (1:1). Panel c) 13C NMR spectrum of sample in
b) following aqueous extraction. Panel d) 11B NMR spectrum
of Et3B prepared with rigorous exclusion of air. Panel e) 11B
NMR spectrum amide 10 plus Et3B. Panel f) 11B NMR specꢀ
trum of Et3B sample from panel a) after brief exposure to air.
4a) Et3B
Set up reaction in glove box with a) 93
stringent removal of oxygen and
degassed solvents, heat for 24h
4b) (secBu)3B
b) 78
5) Et3B
Using std. Schlenk technique, 100
Et3B (1.0 equiv.) and 10 were
stirred together for 1h, add base, 9
and 14 and heat for 24h
and then exposed to air (Table 5, entry 2a), the species in panꢀ
els b and e maybe be a stable boron amidate that resists autoxꢀ
Percent conversion is the conversion of 9 to 11 as determined
by 1H NMR spectroscopy of the crude reaction mixture.
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Page 4 of 5
idation. Based on negligible changes to both the 11B and 13C
NMR spectra, it would appear that complexation with (sec-
Bu)3B is notably weaker than Et3B (Fig. S1 in SI).
Author Contributions
1
2
3
4
5
6
7
8
The manuscript was written through contributions of all authors
and all have given approval to the final version of the manuscript.
With other PdꢀNHC catalysts we have shown that nitrogen
coordination to Pd(II) is rate limiting for anilines,19 and we
believe that the same is the case here with more electron poor
amide nucleophiles. Indeed, both oxidative addition and reꢀ
ductive elimination with bulky NHCs is spontaneous at room
temperature.6 This amide coupling progresses very smoothly
in the absence of coordinating groups on either coupling partꢀ
ner, further shifting the focus away from reductive eliminaꢀ
tion7 as the source of the acceleration of this coupling, at least
with NHC ligands. It seems logical that the boron catalysts,
under basic reaction conditions, form the boronꢀamidate comꢀ
plex, thereby heightening the amide’s nucleophilicity. With
Et3B this appears to be rapid and complete, whereas (sec-
Bu)3B, with its additional steric bulk and lowered Lewis acidiꢀ
ty, may only form weak complexes. In support of this, preꢀ
forming the Et3Bꢀamidate complex (100 mol %) followed by
the addition of the remaining reaction components led to full
conversion (Table 5, entry 5). No one has reported successful
amide coupling using NaOtBu, presumably because it is not
strong enough to deprotonate the amide prior to binding to
Pd(II) and the base out competes the amide for the metal.
When we tried this coupling with NaOtBu alone there was no
conversion; with 20% Et3B, coupling proceeded fully to prodꢀ
uct because the amidate now preferentially coordinates to Pd.
Notes
Some of the catalysts in this manuscript are commercially availaꢀ
ble and the Principal Author receives royalties from their sales.
ACKNOWLEDGMENT
The work was supported by NSERC Canada in the form of a Disꢀ
covery Grant to MGO. This work was supported by the Eli Lilly
Research Assistance Program (LRAP).
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REFERENCES
(1) Simplicio, A. L.; Clancy, J. M.; Gilmer, J. F. Molecules 2008,
13, 519ꢀ547.
(2) Pattabiraman, Vijaya R.; Bode, Jeffrey W Nature, 2011,
480, 471ꢀ479.
(3) Earley, W. G.; Oh, T.; Overman, L. E. Tetrahedron Lett. 1988,
29, 3785ꢀ3788.
(4) Yin, J.; Buchwald, S. L. Org. Lett. 2000, 2, 1101−1104.
(5) For a recent review of amine arylation using Pd, see: Ruizꢀ
Castillo, P.; Buchwald, S. L. Chem. Rev. 2016, 116, 12564−12649.
For an example using Cu catalysis, see: Strieter, E. R.; Bhayana, B.;
Buchwald, S. L. J. Am. Chem. Soc., 2009, 131, 78–88.
(6) Pompeo, M.; Farmer, J. L.; Froese, R. D. J.; Organ, M. G. An-
gew. Chem. Int. Ed. 2014, 53, 3223ꢀ3226.
(7) Shekhar, S.; Hartwig, J. F. Organometallics 2007, 26, 340−351.
(8) Khadra, A.; Mayer, S.; Organ, M. G. Chem. Eur. J. 2017, 23,
3206ꢀ3212.
We have also considered that in the case of BCF that
something different could be happening, just as it did in our
hydrostannylation work.14 It is known that BCF can abstract
anion ligands from Pd(II) to generate cationic Pd,19 which
would more readily coordinate the amide nucleophile. During
the submission of this manuscript a very detailed mechanistic
study by Becica and Dobereiner appeared asap reporting on
the use of other Lewis acids to promote amide coupling, in
their case using phosphine ligands.21 Based on their data they
also postulated that the Lewis acid may abstract the halide
from the oxidative addition intermediate generating cationic
Pd. While we do not believe that this would be likely with the
trialkyboranes, this could support such the case with BCF,
which is a potent anion abtractor.15,19
(9) Fujita, K.ꢀI.; Yamashita, M.; Puschmann, F.; AlvarezꢀFalcon,
M. M.; Incarvito, C. D.; Hartwig, J. F. J. Am. Chem. Soc. 2006, 128,
9044−9045.
(10) (a) Lombardi, C.; Day, J.; Chandrasoma, N.; Mitchell, D.; Roꢀ
driguez, M. J.; Farmer, J. L.; Organ, M. G. Organometallics 2017,
36, 251ꢀ254; (b) Sharif, S.; Mitchell, D.; Rodriguez, M. J.; Farmer, J.
L.; Organ, M. G. Chem. Eur. J. 2016, 22. 14860ꢀ14863; (c) Atwater,
B.; Chandrasoma, N.; Mitchell, D.; Rodriguez, M. J.; Organ, M. G.
Chem. Eur. J. 2016, 22, 14531ꢀ14534; (d) Sharif, S.; Rucker; R. P.;
Chandrasoma, N.; Mitchell, D.; Rodriguez, M. J.; Pompeo, M.; Froꢀ
ese, R. D. J.; Organ, M. G. Angew. Chem. Int. Ed. 2015, 54, 9507ꢀ
9511; (e) Atwater, B.; Chandrasoma, N.; Mitchell, D.; Rodriguez, M.
J.; Pompeo, M.; Froese, R. D. J.; Organ, M. G. Angew. Chem. Int. Ed.
2015, 54, 9502 –9506; (f) Farmer, J. L.; Pompeo, M.; Lough, A. J.;
Organ, M. G. Chem. Eur. J. 2014, 20, 15790ꢀ15798; (g) McCann, L.
A.; Organ, M. G. Angew. Chem. Int. Ed. 2014, 53, 4386ꢀ4389.
(11) Shen, Q.; Hartwig, J. F. J. Am. Chem. Soc. 2007, 129, 7734ꢀ35.
(12) For additional coupling of n-alkyl and 2,2–dimethylꢀalkyl amꢀ
ides, see the Supporting Information.
(13) Falk F. C.; Frohlich, R.; Paradies, J. Chem. Commun., 2011,
47, 11095–11097.
(14) Oderinde, M. S.; Organ, M. G. Angew. Chem. Int. Ed. 2012,
51, 9834ꢀ9837
(15) Oderinde, M. S.; Froese, R. D. J.; Organ, M. G. Angew. Chem.
Int. Ed. 2013, 52, 11334ꢀ11338.
(16) Eisenberger, P.; Bailey, A. M.; Crudden, C. M. J. Am. Chem.
Soc., 2012, 134, 17384ꢀ17387; (b) Welch, G. C.; Stephan, D. W. J.
Am. Chem. Soc. 2007, 129, 1880ꢀ1881; (c) Parks, J. D.; Blackwell, M.
J.; Piers, E. W. J. Org. Chem. 2000, 65, 3090ꢀ3098.
(17) Grotewold, J.; Lissi, E. A.; Scaiano, J. C. J. Chem. Soc. (B),
1969, 475ꢀ480.
(18) Corcoran, E. B.; Pirnot, M. T.; Lin S.; Dreher S. D.; DiRocco
D. A.; Davies I. W.; Buchwald S. L.; MacMillan, D. W. Science
2016, 353, 279ꢀ283.
(19) Hoi, K. H.; Çalimsiz, S.; Froese, R. D. J.; Hopkinson; A. C.;
Organ, M. G. Chem. Eur. J. 2012, 18, 145ꢀ151.
(20) Contrella, N. D.; Jordan, R. F. Organometallics 2014, 33,
7199−7208.
In summary, we have shown that (secBu)3B, Et3B, and
BCF are all excellent promoters of Pdꢀcatalyzed amide couꢀ
pling. (secBu)3B demonstrates broadꢀspectrum reactivity and
was found to tolerate baseꢀsensitive functional groups and
steric congestion, which has proven difficult.5,13 The reactions
are simple to set up and require no careful exclusion of air. We
propose that a boronꢀamidate complex forms under the basic
reaction conditions that aids in transmetallation of the amide
moiety to Pd(II) and drives coupling under mild conditions.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website. General Experimental details, details
of synthesis, and characterization data (PDF).
AUTHOR INFORMATION
Corresponding Author
organ@uottawa.ca
ORCID
Michael G. Organ: 0000ꢀ0002ꢀ4625ꢀ5696
(21) Becica, J.; Dobereiner, G. E. ACS Catal. 2017, 7, 5862–5870.
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Ar
Ar
O
BEt3
L Pd
L Pd
O
O
BEt3
X
N
H
R
R
NH2
R
N
H
readily
X-BEt3
+ base
combusts air stable
in air
reductively
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complex
eliminates
with borane >90% conversion, without borane no conversion
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