Palladium-Catalyzed Regiodivergent Substitution of Propargylic Carbonates

Article abstract of DOI:10.1002/chem.201603481

The palladium(0)-catalyzed, ligand-controlled, regioselective addition of diaryl acetonitrile pronucleophiles to propargylic carbonates is reported. Selective formation of either terminal 1,3-dienyl or propargylated products is proposed to arise from a change in reaction mechanism controlled by the denticity of the coordinating ligand.

Full text of DOI:10.1002/chem.201603481

DOI: 10.1002/chem.201603481
Full Paper
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Palladium Catalysis
Palladium-Catalyzed Regiodivergent Substitution of Propargylic
Carbonates
Theresa M. Locascio and Jon A. Tunge*[a]
Abstract: The palladium(0)-catalyzed, ligand-controlled, re-
gioselective addition of diaryl acetonitrile pronucleophiles to
propargylic carbonates is reported. Selective formation of
either terminal 1,3-dienyl or propargylated products is pro-
posed to arise from a change in reaction mechanism con-
trolled by the denticity of the coordinating ligand.
Introduction
Transition metal-catalyzed cross-coupling reactions with prop-
argyl electrophiles offer the potential to develop regiodiver-
gent strategies to access functionally diverse products from
a single class of starting materials (Scheme 1).[1,2] However,
compared to allylic analogues,[3–4] palladium-catalyzed cou-
plings of propargyl electrophiles have received much less at-
tention. One potential reason for the lesser development of
these couplings is the greater complexity in achieving regiose-
lective and chemoselective substitution (Scheme 1). Typically
palladium-catalyzed propargylic substitutions using relatively
non-stabilized carbon nucleophiles (pKa >20) yield allene prod-
ucts.[5] In contrast, the use of stabilized nucleophiles, such as
malonates, commonly leads to bis-addition products,[6] where-
as selectivity for propargylic substitution is much more rare.[7,8]
Furthermore, only under select circumstances, primarily con-
trolled through cyclization, have diene products arisen from
the substitution of propargyl electrophiles.[9] Therefore, devel-
opment of new methods that selectively arrive at propargyl
and/or terminal dienyl functionalities from propargylic carbo-
nates would be a significant step in overcoming current limita-
tions in catalytic propargylic substitution chemistry.[10–12] Here,
we report the palladium-catalyzed, ligand-controlled cross-cou-
pling of propargylic carbonates with diaryl acetonitrile pronu-
cleophiles to yield either terminal 1,3-dienyl or propargylated
quaternary diarylmethane products (Scheme 2).[13]
Scheme 1. Potential substitution products.
Scheme 2. Regiodivergent substitution of propargylic carbonates.
methods to cross-couple 1,3-dienyl motifs by reaction of readi-
ly available starting materials under mild reaction conditions,
while minimizing overall byproduct formation. To address this
need, we hypothesized that propargyl carbonates could serve
as diene electrophiles if, after mono-substitution to generate
a palladium p-allyl intermediate,[2b,5m,18a] elimination occurred
instead of the more common attack by a second nucleophile
(Scheme 3).[6] This method would provide facile access to 1,3-
dienes in an atom- and step-economic fashion through the
formal coupling of an electrophilic 1,3-diene synthon. To the
Current synthetic methods that achieve the direct cross-cou-
pling of butadiene synthons rely heavily on pre-formed organ-
[14,15]
ometallic or organoborane reagents.
Consequently, these
methods lack step-economy and produce a significant amount
of waste. Therefore, it would be useful to develop alternative
[a] T. M. Locascio, Prof. Dr. J. A. Tunge
Department of Chemistry, The University of Kansas
2010 Malott Hall, 1251 Wescoe Hall Drive, Lawrence, KS, 66045 (USA)
E-mail: tunge@ku.edu
Supporting information, including synthesis and characterization of starting
materials, screening of conditions, experimental procedure and NMR spec-
tra, as well as the ORCID number(s) for the author(s) of this article are
available under http://dx.doi.org/10.1002/chem.201603481.
Scheme 3. Proposed synthetic route to 1,3-dienes.
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best of our knowledge, the use of a propargyl carbonate as
a source of a butadiene electrophile for cross-coupling has not
been reported.[9]
Table 1. Optimization of reaction conditions.[a]
Results and Discussion
Entry Catalyst Ligand
Solvent
1a Allene Diene Propargyl
1,3-Dienylation
1
2
3
4
5
6
7
8
9
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd2(dba)3 dppm
Pd2(dba)3 dppe
Pd2(dba)3 dppp
Pd2(dba)3 dppb
Pd2(dba)3 dppf
–
–
–
DMSO
THF
DMF
26
62
3
28
3
5
2
1
1
3
1
0
4
0
0
0.2
0.5
11
0.5
40
15
55
42
94
87
85
74
7
70
2
2
15
19
9
7
0.3
1
6
95
6
91
95
98
6
31
22
39
27
3
Given our experience with allylic alkylations of acetonitriles,[16]
our optimization studies began by examining the effects of
palladium catalyst, ligand, and solvent on the cross-coupling of
methyl propargyl carbonate with commercially available di-
phenyl acetonitrile (Table 1). Initially, reaction conditions that
previously provided high yields for allylation of tertiary acetoni-
triles with allylic alcohols were employed (entry 1).[16b] Under
these conditions, GC/MS analysis revealed the formation of
three isomeric products. Upon isolation and characterization of
each product, it was confirmed that the major products were
the 1,3-dienyl and propargyl isomers, with only minor forma-
tion of the allene. To optimize reaction conversion, we next
conducted a solvent screen, which revealed that polar aprotic
solvents provided optimal conversion (entries 1, 3) compared
to non-polar solvents (entries 2, 17, 18). In an attempt to deter-
mine the ligand effect on product ratios, several bidentate li-
gands were examined (entries 4–9). Excitingly, 1,2-bis(diphenyl-
phosphino)ethane (dppe) displayed optimal selectivity for the
1,3-diene product (entry 5). This result is in contrast with most
previous accounts that report cyclization,[9] bis-addition,[6] or al-
lenylation[5] as the major products arising from palladium-cata-
lyzed substitution of propargylic carbonates using bidentate li-
gands.[1a,5m]
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CD3CN
8
13
24
31
24
33
47
25
67
35
47
6
8
81
2
81
0
2
Pd2(dba)3 XantPhos
Pd2(dba)3 rac-BINAP
10
4
11[b] Pd2(dba)3 JohnPhos
45 20
22 29
56
11
12[b] Pd2(dba)3 tBu-MePhos CD3CN
13[b] Pd2(dba)3 Cy-JohnPhos CD3CN
4
3
5
3
6
5
3
0
3
0
0
0
3
14[b] Pd2(dba)3 MePhos
15[c] Pd2(dba)3 MePhos
16[b] Pd2(dba)3 MePhos
17[b] Pd2(dba)3 MePhos
18[b] Pd2(dba)3 MePhos
CD3CN
[D6]DMSO 51
[D7]DMF 43
[D8]toluene 87
dioxane
DMF
DMF
DMF
DMF
87
10
3
10
9
3
1
1
19
20
21
Pd2(dba)3 MePhos
Pd2(dba)3 dppe
Pd2(dba)3 MePhos
22[c] Pd2(dba)3 dppe
23[d] Pd2(dba)3 dppe
24[e] Pd2(dba)3 dppe
25[f] Pd2(dba)3 MePhos
CH3CN
CH3CN
DMF
1
90
[a] Reaction condtions: diphenylacetonitrile (0.3 mmol), carbonate
(0.3 mmol), catalyst (2.5 mol%), ligand (5 mol%), 0.15m, 908C, 14 h; con-
version (%) determined by GC/MS. [b] Diphenylacetonitrile (0.1 mmol),
carbonate (0.1 mmol), reaction monitored by 1H NMR spectroscopy.
[c] Isolated yield 24%. [d] 0.3m [e] 808C [f] 0.6 mmol carbonate.
With the optimized reaction conditions established for the
1,3-dienylation of diphenylacetonitrile, we next evaluated the
scope of a,a-diaryl acetonitrile derivatives in the substitution
of methyl propargyl carbonate to synthesize 1,3-dienyl motifs
(Scheme 4).[17] A variety of unsymmetric diarylacetonitrile reac-
tants with electron-donating or -withdrawing substituents pro-
vided product in good to excellent yield (3b,c,h,m). Further,
meta-chloro- and para-bromo-substituted arenes, which can
be prone to other coupling reactions, were well tolerated
(3g,e). Notably, a variety of substitution patterns were tolerat-
ed and even increased steric bulk at the ortho-position did not
hinder product formation (3c,f,h). Basic heteroaryl moieties re-
quired reduced reaction time and, unfortunately, lead to poor
isolated yields (3i,j). In contrast, the non-basic heteroaromatic
1,5-dimethyl pyrrole reactant provided product in good yield
as did arene substituents that contained extended conjugation
(3d,f,k). Lastly, styrene and benzoxazole derivatives were un-
successful and only degradation of the starting material was
observed (3n,o).
With the functional group tolerance evaluated for the aceto-
nitrile reaction component, other propargylic carbonates were
examined to see if they could be used to form substituted
diene products (Table 2). It was found that nucleophilic substi-
tution of a terminally substituted ethyl or heptyl propargylic
carbonate resulted in decreased isolated yields (4b,c) com-
pared to the model substrate 3a. However, terminally substi-
Scheme 4. Acetonitrile scope in 1,3-diene synthesis. a) nitrile (0.3 mmol), car-
bonate (0.6 mmol), palladium (5 mol%), dppe (10 mol%), DMF (2 mL), 808C,
1 h. Isolated yields are reported.
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tuted benzyl propargylic carbonate produced the substituted
1,3-diene product in moderate yield (4d). To access more intri-
cate triene functionalities, an allyl substituent was utilized at
the terminus of the propargylic carbonate, and the resulting
triene was isolated in good yield (4e). Unfortunately, both ter-
minal carbocyclic substituents along with internal alkyl sub-
stituents on the propargylic carbonate significantly hindered
product formation (4 f,g).
Table 2. Scope of substituted 1,3-dienes.
Entry
4b
Carbonate
Product
Yield
[%][b]
Diene:Propargyl[c]
Figure 1. Potential pathways for 1,3-dienylation.
42
41
70
>20:1
9:1
path a, protonation could occur from either methanol or ni-
trile, leading to p-allyl palladium intermediate C. Base-induced
elimination would regenerate the palladium(0) catalyst and
yield the 1,3-diene product.[2a,21] Alternatively, b-hydride elimi-
nation from the palladacycle B could produce intermediate E,
followed by reductive elimination of the 1,3-diene product.
To determine which pathway is more likely, two isotopic la-
beling experiments were performed (Scheme 5). The terminally
deuterated propargylic carbonate produced product with an
8.1:1.0 H/D ratio at the internal carbon of the diene as deter-
4c
4d
>20:1
4e
74
9:1
[d]
1
4 f
–
nd
mined by H NMR spectroscopy (Scheme 5a). A similar reaction
coupling deuterated diphenyl acetonitrile with protio methyl
propargyl carbonate resulted in an H/D ratio of 1.2:1.0
(Scheme 5b).[22] These results are inconsistent with a mecha-
nism involving b-hydride elimination/reductive elimination.
Thus, we favor path a involving protonation of the pallada-cy-
clobutene to form p-allyl palladium intermediate C. To trap
a putative p-allyl intermediate, the palladium-catalyzed aceto-
nitrile cross-coupling was performed with a propargylic car-
bonate that was unable to undergo elimination (Scheme 6).
The observation of bis-substituted 1,3-diene product in 93%
yield supports the kinetic feasibility of the formation of a p-
allyl palladium intermediate required for path a.
4g
51
1:1.2
[a] Reaction conditions: nitrile (0.3 mmol), carbonate (0.6 mmol), palladi-
um (5 mol%), dppe (10 mol%), DMF (2 mL), 808C, 1 h, isolated yields are
reported. [b] Isolated yield. [c] Determined by H NMR spectroscopy; nd=
not determined. [d] 14% conversion determined by GC/MS.
1
Fueled by the selective formation of the terminal 1,3-diene
analogues, we next examined the potential pathways to dieny-
lation. It has been reported that palladium catalysts, in the
presence of bidentate ligands, favor oxidative addition to form
an h3-propargyl palladium intermediate.[18] Furthermore, outer-
sphere nucleophilic attack at h3-propargyl palladium species
often occurs exclusively at the center carbon.[19] Therefore, we
envisioned that 1,3-dienylation could arise through two poten-
tial mechanistic pathways (Figure 1). In both cases, initial oxi-
dative addition of the propargylic carbonate and subsequent
loss of CO2 would yield an h3-propargyl palladium intermediate
along with methoxide. Next, deprotonation of the pronucleo-
phile would promote nucleophilic attack at the center carbon
of the palladium intermediate to generate the corresponding
pallada-cyclobutene (B).[20] If the mechanism proceeds through
Propargylation
As discussed previously, palladium-catalyzed substitution of
methyl propargyl carbonate with a,a-diaryl acetonitrile pronu-
cleophiles selectively forms 1,3-dienyl products in the presence
of bidentate ligand dppe. During our reaction optimization
studies, a change from bidentate (dppe) to monodentate
(MePhos) ligand was accompanied by a switch in selectivity
from the 1,3-dienyl isomer to the propargyl isomer under oth-
erwise identical reaction conditions (Table 1). The development
of palladium-catalyzed substitution of propargylic carbonates
to selectively yield propargylated nucleophiles would not only
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yields (5i,j). However, when the heterocycle was changed to
a benzoxazole functionality, a dramatic decrease in yield was
observed (5o, Scheme 7). A styrene derivative proceeded
smoothly to the propargylated product albeit in slightly lower
yield when compared to the polycyclic and bicyclic analogues
(5n). Lastly, a para-morpholine-substituted acetonitrile failed to
undergo the reaction (5m).
Scheme 5. Deuterium labeling studies.
Scheme 6. Trapping of palladium p-allyl intermediate.
expand on the limited strategies known for catalytic propargy-
lation from internal propargylic electrophiles,[23] but also allow
for a regiodivergent synthesis of 1,3-dienyl and propargyl ace-
tonitrile derivatives solely by altering the denticity of the coor-
dinating ligand.[24]
Classically, the Nicholas reaction has been utilized as
a method for propargylation utilizing propargylic alcohol reac-
tants. Despite this, its utility has been limited by the require-
ment for stoichiometric organometallic reagents.[25] Recent
focus on propargylation has concentrated on the development
of alternative methods using catalytic transition metals. For ex-
ample, propargylic alkylation using propargylic carbonates was
only recently reported by Iazzetti in 2015.[7a] However, the reac-
tion is limited to highly stabilized Meldrum’s acid-like nucleo-
philes. Most other cases report palladium-catalyzed nucleophil-
ic substitution of propargylic carbonates that result in cycload-
dition or formation of allene derivatives.[26,5g] The method out-
lined here aims to expand the scope of palladium-catalyzed
propargylation to weakly acidic a,a-diaryl acetonitrile motifs
that give rise to functionalized quaternary diarylmethane prod-
ucts.
Scheme 7. Propargylation of acetonitrile derivatives. a) nitrile (0.3 mmol), car-
bonate (0.6 mmol), palladium (5 mol%), MePhos (10 mol%), DMF (2 mL),
808C, 1 h, isolated yields are reported. b) isolated with 10% allene and 7%
bis-addition product.
With the propargylation of various diaryl acetonitrile sub-
strates examined, we next sought to apply our propargylation
method to substituted propargylic carbonates (Table 3). Nucle-
ophilic substitution of terminally substituted ethyl or heptyl
propargylic carbonates was well tolerated (6b,c). However,
a decrease in isolated yield was observed by using a benzyl
propargylic carbonate (6d). Gratifyingly, excellent isolated
yields were obtained from propargylic carbonates that were
terminally substituted by carbocycles (6e–g). Further, allyl and
internally substituted methyl and ethyl propargylic carbonates
resulted in moderate to high isolated yields of the propargylat-
ed products (6h–k). Unfortunately, vinyl and phenyl propargyl-
ic carbonates were not well-tolerated under the standard reac-
tion conditions (6l,m).
Having studied the synthetic scope of the dienylation and
propargylation reactions, we aimed to convert our observation
of denticity-dependent regioselectivity into a more formal
mechanistic hypothesis. Beginning with Pd0 and monodentate
MePhos, we propose that oxidative addition of the propargylic
carbonate would initially favor a cationic h3-propargyl palladi-
um intermediate E similar to intermediate A in the dienylation
pathway (Figure 2). Contrary to bidentate ligand dppe, which
Beginning with the same optimized reaction conditions de-
veloped for the 1,3-dienylation method, we merely changed
the coordinating ligand from bidentate dppe to monodentate
MePhos and evaluated the scope of diarylacetonitriles that un-
dergo propargylation (Scheme 7). Analogous to results of 1,3-
diene syntheses, the propargylation of acetonitriles containing
1-naphthyl, 2-naphthyl, and para-substituted biphenyl deriva-
tives provided very good yields without being influenced by
steric hindrance (5a,d,f,l). When para-methoxy-, ortho-fluoro-,
and meta-chloro-substituted phenyl rings were screened, all
corresponding products were obtained in moderate to good
isolated yields (5b,c,g). Altering the ortho-substituent to
a nitro moiety resulted in an excellent isolated yield of 94%
(5h). In contrast to their poor reactivity for dienylation, hetero-
cyclic pyridine and pyrimidine derivatives were tolerated under
the general reaction conditions and resulted in good isolated
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Figure 2. 1,3-Dienyl and propargyl mechanistic cycles.
Table 3. Propargylation with substituted carbonates.[a]
forces outer-sphere nucleophilic attack of the activated nitrile,
we propose that the mono-coordination of the MePhos ligand
provides an open coordination site for binding of the activated
nitrile.[16a,27] Binding of an anionic ligand has been observed to
typically favor the h1-allenyl species (in this case G).[2a,18,20] Sub-
sequent inner-sphere nucleophilic attack at the terminal allenyl
carbon could then occur to provide the propargylated produc-
t.[16a,27]
Carbonate
Product
Carbonate
Product
Conclusion
We have reported the regiodivergent synthesis of substituted
1,3-dienyl and propargyl quarternary diaryl methanes. We pro-
pose that regioselective nucleophilic substitution to palladium-
bound intermediates occurs through two distinct reaction
mechanisms that are controlled by the denticity of the ligand.
Bidentate ligands block coordination of the nitrile nucleophile,
favoring outer-sphere attack of the nucleophile, leading to di-
enylation. In contrast, a monodentate ligand allows coordina-
tion of the nucleophile to palladium, resulting in propargyla-
tion through an inner sphere nucleophilic attack.
Acknowledgements
We thank the National Science Foundation (CHE-1465172) and
the Kansas Bioscience Authority Rising Star program for finan-
cial support. Support for the NMR instrumentation was provid-
ed by NSF Academic Research Infrastructure Grant No.
9512331, NIH Shared Instrumentation Grant No. S10RR024664,
and NSF Major Research Instrumentation Grant No. 0320648.
Keywords: coupling · dienylation · palladium · propargylation
[a] Reaction conditions: diphenylacetonitrile (0.3 mmol), carbonate
(0.6 mmol), palladium (5 mol%), MePhos (10 mol%), DMF (2 mL), 808C,
1 h. Isolated yields are reported.
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Received: July 23, 2016
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Published online on && &&, 0000
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FULL PAPER
&
Palladium Catalysis
T. M. Locascio, J. A. Tunge*
&& – &&
Palladium-Catalyzed Regiodivergent
Substitution of Propargylic Carbonates
Regiodivergent coupling of propargyl
carbonates allows their use to form qua-
ternary diarylmethanes that are either
propargylated or dienylated. The latter
case represents the first example of the
use of propargyl carbonates as inexpen-
sive, readily available synthetic equiva-
lents of dienyl cations.
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ÝÝ These are not the final page numbers!