Highly Modular Synthesis of 1,2-Diketones via Multicomponent Coupling Reactions of Isocyanides as CO Equivalents

Article abstract of DOI:10.1021/acscatal.9b00581

A one-pot, four-component Pd-catalyzed coupling has been developed for the synthesis of unsymmetrical 1,2-diketones from aryl halides and alkyl zincs employing tert-butyl isocyanide as a CO source. The intermediate 1,2-diketones have been elaborated to quinoxalines. Mechanistic studies help to rationalize the high selectivity for the bis- vs monoinsertion product.

Full text of DOI:10.1021/acscatal.9b00581

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Article
Highly Modular Synthesis of 1,2-Diketones via Multicomponent
Coupling Reactions of Isocyanides as CO Equivalents
Anne-Marie Dechert-Schmitt, Michelle Garnsey, Hanna Wisniewska, James
Murray, Taegyo Lee, Daniel W. Kung, Neal Sach, and Donna G Blackmond
ACS Catal., Just Accepted Manuscript • Publication Date (Web): 11 Apr 2019
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Page 1 of 10
ACS Catalysis
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Highly Modular Synthesis of 1,2-Diketones via Multicomponent
Coupling Reactions of Isocyanides as CO Equivalents
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Anne-Marie Dechert-Schmitt,1* Michelle R. Garnsey,1 Hanna M. Wisniewska,1 James I. Murray,2
Taegyo Lee,1 Daniel W. Kung,1 Neal Sach,1 Donna G. Blackmond2*
1Pfizer Worldwide Research and Development, Groton CT, 06340 USA; 2Department of Chemistry, Scripps Research,
La Jolla, CA 92037 USA
ABSTRACT: A one pot four-component Pd-catalyzed coupling has been developed for the synthesis of unsymmetrical 1,2-
diketones from aryl halides and alkyl zincs employing t-butyl isocyanide as a CO source. The intermediate 1,2-diketones have
been elaborated to quinoxalines. Mechanistic studies help to rationalize the high selectivity for the bis- vs. mono-insertion
product.
Keywords: isocyanides, Pd catalysis, reaction progress kinetics, multicomponent reactions, heterocycles
INTRODUCTION
pharmaceutical manufacturing. While the development of
stable CO-releasing molecules has addressed safety
challenges and present an attractive approach to isotope
labeling studies,33 their use in large scale manufacturing
would be problematic from cost and environmental
perspectives. The use of isocyanide as a stoichiometric CO
equivalent33,34 has emerged as a powerful alternative to
other CO sources,35 as demonstrated in a variety of
reactions, including carbonylative Sonogashira coupling
and aryl halide formylation36,37. Herein, we report a novel
method for the preparation of unsymmetrical 1,2-
diketones utilizing (heteroaryl) aryl halides, organozinc
reagents and t-butyl isocyanide as a CO equivalent. This
work is the first example of a modular approach allowing
formation of three new C-C bonds from three independent
compounds in a one-pot protocol. Detailed kinetic and
mechanistic studies help to rationalize both the high
selectivity to double cyanide addition and the success of
the final intramolecular C-C bond formation. In addition to
providing a modular approach and broad scope in a
straightforward synthesis of diketones using isocyanides
as CO surrogates, the reaction can also provide 1,2-
diimines or be further elaborated without purification to
other molecules important in medicinal chemistry
including heterocycles, such as quinoxaline derivatives.
Multicomponent one-pot reactions offer efficiency and
sustainability in organic synthesis and are increasingly
being employed to build complexity in pharmaceutical
and fine chemical synthesis.1–3 Of particular value are
highly modular unions of widely available building blocks
to access novel structural motifs. 1,2-Diketones are useful
intermediates in synthetic organic chemistry; often used
in the synthesis of medicinally relevant heterocycles, such
as imidazoles, pyrazines, and quinoxalines as well as
natural products.4-12 They are also used in materials
chemistry13-14 and as ligands for various metal
complexes.15-18 Despite their widespread synthetic utility,
1,2-diketone synthesis is typically achieved via lengthy
linear sequences and oxidative protocols.19-32 These
approaches are often limited to (symmetrical) dibenzylic
1,2-diketones and suffer poor compatibility with
heteroaryl substrates; preventing efficient access to large
libraries of these highly versatile derivatives (Scheme 1).
Scheme 1. 1,2-Diketone Syntheses
Previous Strategies:
O
R2
HO
OH
R2
R2
R1
R1
R2
R1
[O]
[O]
[O]
R1
alkene
O
alkyne
synthesis
synthesis
1,2-diketone
BACKGROUND
linear
synthesis
limited
substrate scope
poor functional group
tolerance
typically
dibenzylic products
Isocyanides have emerged as an advantageous building
block in synthetic organic chemistry, utilized extensively
in the multicomponent Passerini and Ugi reactions.38 t-
Butyl isocyanide has been utilized as a C1 reactant in
transition metal catalyzed carbonylation-type reactions to
form aryl aldehydes,39 diaryl ketones,40 carboxylic acids,41
amides,42 amidines,43 (thio)imidates,44 thiocarbamates,45
as well as various heterocycles.46 Interestingly, most
transition metal catalyzed isocyanide coupling
methodologies produce mono insertion products. The
first notable example of double isocyanide insertion
utilized in the context of synthesis was reported by
This Work:
NtBu
R1
O
Pd2(dba)3
dppf
R1
X
C
N-tBu
R1 ZnX
1 M HCl
R
R
R
NtBu
O
NaOtBu
PhCH3, 95 °C
3 new C-C bonds!
highly modular synthesis - excellent functional group compatibility
efficient access to heterocycles
Carbonylation of aryl halides in the formation of
ketones is well established; however, such reactions
however, such reactions typically require high pressure
CO, which can pose a safety risk in typical batch
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Yamamoto and coworkers47 in the Co-mediated formation
further improved the yield to 90% (83% isolated). The
of diiminofuran derivatives. Whitby and coworkers48
demonstrated the Pd-catalyzed synthesis of -
iminoimidates via double insertion of isocyanides into
aryl halides followed by trapping with metal alkoxides, a
multi-component reaction that forms two C-C and one C-
O bond. Kobiki and coworkers developed a Pd-catalyzed
double insertion of isocyanides with BiAr3 reagents,
generating a third new C-C bond in an intramolecular step,
to produce symmetrical -diimines, with good scope with
respect to the isocyanide but limited to formation of
symmetrical diimine systems from the few Bi reagents
commercially available.49 Shen and coworkers50
demonstrated further substrate scope in the double
cyanide insertion and suggested the versatility of the -
iminonitriles formed for conversion to a variety of
products. However, such conversions generally require
strong nucleophilic bases and are limited in scope.
reaction could also be performed on a gram scale, albeit in
diminished yield of 52%. We found that while both aryl
bromide and iodide were competent electrophiles in the
transformation, aryl chlorides were unreactive (Table 1,
entries 6-7).
1
2
3
4
5
6
7
8
Table 1. Optimization of the 1,2-Diketone Synthesis.
O
i. C
N
tBu
9
Ph
Pd source
X
ligand (10 mol %)
base (1.3 equiv.)
95 °C, 18 h
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11
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tBu
3a
Ph
BrZn
tBu
O
Ph
1a
2a
ii.
1M HCl
1.5 equiv
1.0 equiv.
0.2 M
O
tBu
4a
Equiv.
tBuNC
Yielda,f
X
Base
Solvent
DMF
%4a (%3a)
15 (13)b
25 (0)c
61 (0)c
83 (0)c
90 (0)c,e
82 (0)c
0 (0)c
These and most approaches to double isocyanide
insertion involve intramolecular formation of the final C-
C bond. Several recent reports take advantage of the
transition metal catalyzed double isocyanide insertion to
form various heterocycles such as pyrrolo[2,3-b]indoles,
5-iminopyrrolones, 3-Iminoindol-2-amines, maleimides,
pyrrole derivatives, phthalimides, benzofurans, and
thiazolidines.51 In addition, the selectivity for double
insertion is not well understood and has not been probed
mechanistically. The work we report here offers a
modular approach to the intermolecular formation of
three carbon-carbon bonds via double isocyanide
insertion into aryl halides and alkyl zinc reagents to
produce 1,2- diketones, as well as a mechanistic study to
rationalize the formation of the bis isocyanide insertion
product relative to the mono isocyanide insertion product.
1
2
3
4
5
6
7
Br Na2CO3
Br Na2CO3
1.1
1.1
2.1
2.1
2.1
2.1
2.1
DMF
Br
Et3N
Toluene
Br NaOtBu
Br NaOtBu Toluened
Toluene
I
NaOtBu Toluened
NaOtBu Toluened
Cl
aNMR yield relative to 2,6-dimethoxytoluene internal
b
c
standard. Pd(OAc)2 (5 mol%), Johnphos. Pd2(dba)3 (5 mol%),
dppf. d1a at 0.086 M. e83% isolated yield. fAll reactions
performed on a 0.5 mmol scale with respect to reactant 1a. See
Table S1 in the supporting information.
We next sought to investigate substrate scope with
respect to aryl halide (Table 2). The diketone products
showed traces of decomposition upon standing at room
temperature, but could be stored for long periods of time
RESULTS AND DISCUSSION
Table 1 shows initial studies of the reaction coupling
aryl halides with isocyanides and alkylzinc reagents.
Initial studies of the coupling of 1-bromo-4-(tert-
butyl)benzene with t-butyl isocyanide and phenethyl zinc
bromide were undertaken with a desire to produce the
monoketone 3a. Analysis of the reaction mixture
indicated that ketone 3a was formed along with
byproduct diketone 4a in a 1:1 ratio (Table 1, entry 1).
Notably, the use of other isocyanides resulted in little to
no conversion to either the mono or bis ketone (see SI for
more details).
in the freezer.
Isolated yields were obtained by
conversion to quinoxaline derivatives. A wide variety of
functional groups were well tolerated, including tert-Bu
esters, amides and nitriles, as well as electron deficient
and electron rich aryl halides. Importantly, heteroaryl
derivatives were efficient coupling partners in the
process, demonstrating a significant advantage over
oxidative 1,2-diketone synthesis.19,26,30,31,52,53
Next we turned our attention to reaction scope
determination with respect to the organozinc coupling
partner (Table 3). Primary zinc reagents, including
methyl zinc chloride and n-Pr zinc bromide coupled
efficiently to form the desired product, while phenethyl
magnesium bromide gave no desired product. Various
secondary zinc reagents, including cycloalkyl derivatives
were also competent coupling partners in this process.
Attempts to couple aryl zinc halides were unsuccessful,
presumably dye to the decreased ability of these species
to undergo transmetallation. Similarly the more reactive
diarlyzinc reagents gave no desired product.
Recognizing the value of such a modular approach to
1,2-diketones, we shifted our efforts to optimize for the
diketone 4a. Switching from the ligand Johnphos to dppf
resulted in the formation of diketone 4a in 25% yield, with
no detected monoketone 3a (entry 2, Table 1). Addition
of an extra equivalent of the t-butyl isocyanide with
triethylamine as a more soluble base in toluene afforded
the diketone product 4a in 61% yield (entry 3, Table 1).
Encouraged by these results, a high-throughput screen of
76 bases was conducted to find improved conditions (See
SI for full details). NaOtBu was selected as the optimal
base. Scaling the conditions identified in high-throughput
reaction optimization afforded the desired product in
83% (Entry 4, Table 1). Reduction in concentration
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Table 2. Substrate Scope for 1,2-diketone synthesis.
Table 3. Zinc Scope for 1,2-diketone synthesis.
1
2
3
4
5
ArBr
4-tBu-PhBr
+
Pd2(dba)3 (5 mol%)
dppf (10 mol%)
+
Pd2(dba)3 (5 mol%)
dppf (10 mol%)
t-Bu
o-phenylene-
diamine
O
tBu
o-phenylene-
diamine
O
N
N
R1
R1
N
N
Ar
(2.1 equiv)
+
N
N
(2.1 equiv)
+
R1 ZnX
Ar
NaOtBu (1.3 equiv)
PhCH3, 95 °C, 18 h
then 1 M HCl
NaOtBu (1.3 equiv)
PhCH3, 95 °C, 18 h
then 1 M HCl
MeOH, NH4Cl
Ph
MeOH, NH4Cl
O
R1
O
ZnX
Ar
R1
Ar
R1
=
Ph
5
6
Ar = 4-t-Bu-PhBr
(1.5 equiv)
(1.5 equiv)
6
7
8
9
isolated yielda
R2 = tBu
5a 69%
R2 = 4-Cl
5b 66%
R2 = 4-OMe 5c 71%
R2 = 4-NMe2 5d 55%
R2 = 4-CN 5e 76%
R2 = 3-CF3 5f 67%
R2 = 2-Me 5g 83%
1,2-dicarbonyl product quinoxaline product
isolated yielda
1,2-dicarbonyl product
quinoxaline product
R1
Ar
N
N
R1 = Me
R1 = n-Pr
R1 = i-Pr
6a
6b
6c
56%
78%
38%
R1
N
N
O
O
O
R1
R1
10
11
12
13
14
15
16
17
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22
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Ar
Ar
R2
R2
O
O
O
n = 1
n = 2
n = 3
61%
83%
36%
6d
6e
6f
n
n
R1
N
N
N
N
N
O
R2 = OtBu 5h 76%
R2 = NHMe 5i 44%
R2 = NMe2 5j 75%
R1
Ar
R2
O
R2
3
2
O
3
O
O
NC
6g 68%
6h 79%
Ar
CN
R1
N
5k 70%
Ar
Ar
Ar
N
N
O
O
F3C
R1
F3C
O
N
2
t-BuO2C
O
Ar
CO2t-Bu
N
N
N
N
O
R1
R1
R1
N
O
R1
N
6i
6j
54%
70%
O
69%
5l
O
N
tBu
tBu
tBu
tBu
N
N
Ar
N
N
O
O
O
O
R1
R1
R1
N
N
O
51%
62%
5m
5n
O
O
N
N
O
O
O
O
Ar
N
N
O
Ar
BnN
BnN
O
N
N
a Reactions conducted on 0.5 mmol Ar-Br. Isolated yield is of the quinoxaline.
R1
N
N
70%
5o
To investigate the mechanism of this reaction, with
particular focus on the high selectivity for bis vs. mono
addition, methods of monitoring reaction progress for use
of the Reaction Progress Kinetic Analysis methodology54
were investigated. Reaction monitoring using ReactIR
N
Me
N
Me
R1
N
N
N
N
O
O
R1
5p 54%
O
O
spectroscopy
combined
with
sample
analysis
R1
N
N
demonstrated that the isocyanide stretching vibration at
2134 cm-1 provides an accurate measure of reaction
progress. The temporal concentration profiles (Figure 1)
for the aryl halide 1a and product 4a may be calculated
from that of isocyanide using the reaction stoichiometry
and the concept of “excess” ([xs]) as shown in eqs. 1–3.
Figure 1 shows excellent agreement between analytical
measurement of [1a], [isocyanide], and [4a] and the
ReactIR profile measured for [isocyanide] and calculated
for [1a] and [4a]. This ensures that further studies may be
carried out by monitoring the profile of isocyanide.
R1
78%
5q
N
N
a Reactions conducted on 0.5 mmol Ar-Br. Isolated yield is of the quinoxaline.

1a

xs  isocyanide  2 1a



(1)



0

0



1a

isocyanide  xs
(2)
(3)

0

1a 
0

2
4a  1a  1a
t 0 t



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further shift (Figures 3d, 3e). This demonstrates that
addition of base is necessary to enter the catalytic cycle.
160
140
120
100
80
1
2
3
4
5
6
7
8
C
N
tBu
e)
reaction mixture
1a
Pd + dppf + NaOtBu
60
d)
c)
b)
40
Pd + dppf + ArBr
Pd + dppf
dppf
4a
20
9
0
10
11
12
13
14
15
16
17
18
19
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21
22
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49
50
51
52
53
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55
56
57
58
59
60
0
20
40
60
80
100
time (min)
Figure 1. Concentration profiles for the reaction of Scheme 1
monitored by ReactIR spectroscopy (open circles) and HPLC
analysis of discrete samples (filled squares). The ReactIR
profile for isocyanide is used to calculate those for 1a and 4a
from eqs. 1–3. HPLC samples are obtained for 4a after
workup. Reaction conditions: [1a]0 = 70 mM; [2a]0 = 105 mM
(in THF); [isocyanide]0 = 150 mM; [NaOtBu]0 = 90 mM (in
THF); [Pd2(dba)3] = 3.5 mM; [dppf] = 7 mM; toluene 95 oC.
a)
Figure 3. 31P-NMR spectra of various reaction components in
toluene. a) dppf ligand (20 mM); b) Pd2(dba)3 (10 mM) plus
dppf ligand (20 mM); c) Pd2(dba)3 (10 mM) plus dppf ligand
(20 mM) plus 1a (70 mM); d) Pd2(dba)3 (10 mM) plus dppf
ligand (20 mM) plus NaOtBu (90 mM); e) under the standard
reaction conditions of Figure 1 at ca. 14% conversion of 1a.
The kinetic profile shows a slight sigmoidal shape
indicative of an induction period at the outset of the
reaction. In experiments varying the initial concentrations
of the various reaction components, we noted that higher
concentrations of NaOtBu helped to eliminate this
induction period, as shown in Figure 2, where a time shift
of the profile exhibiting an induction period gives
excellent overlay on that from the reaction carried out
under identical conditions except with higher [NaOtBu].
The results in Fig. 3 suggest that a palladium species
formed after interaction of the catalyst precursor with
base serves as the active entry into the catalytic cycle. This
proposal is supported by previous work by Amatore and
Jutand,55 who documented multiple roles for the base in
Suzuki-Miyaura reactions catalyzed by Pd phosphine
complexes. In the present case, the similarity of spectra d)
and e) in Figure 3 suggest that the role of the base appears
to occur prior to oxidative addition of the aryl halide and
may be related to accelerating removal of dba ligands to
produce the active catalytic species. Precatalyst activation
and inhibition processes have been investigated in detail
recently for other transition metal-catalyzed reactions.56
“Same excess” experiments54 showed that the reaction
system is robust, showing little if any catalyst
deactivation, as evidenced by the time and concentration
shift overlay in Figure 4, top. Carrying out Variable Time
Normalization Analysis (VTNA)57 for reactions at different
catalyst concentrations showed that the reaction is first
order in [Pd] (Figure 4, bottom). These data demonstrate
the robustness of the catalyst system.
Further “different excess” kinetic studies44 were carried
out varying the initial concentration of each of the
reactants in turn. Strikingly, Figure 5 shows that identical
profiles are observed in reactions higher [1a]0, [2a]0, or
[isocyanide]0, indicating that the reaction exhibits zero
order kinetics in all three substrate concentrations. These
results suggest the resting state within the cycle is a Pd
species containing all three substrates and that reductive
elimination is a likely candidate for the rate-determining
step.
70
time shift
gives overlay
60
50
40
30
t
90 mM NaOtBu
20
10
0
t
180 mM NaOtBu
t
90 mM NaOtBu
time shift
0
20
40
60
80
100
120
140
time (min)
Figure 2. Concentration profiles for the reaction of Scheme 1
monitored by ReactIR spectroscopy. Reaction conditions:
[1a]0 = 70 mM; [2a]0 = 105 mM (in THF); [isocyanide]0 = 150
mM; [Pd2(dba)3] = 3.5 mM; [dppf] = 7 mM; toluene 95 oC.
[NaOtBu]0 as shown in legend. A time shift of 20 min for the
reaction profile at lower [NaOtBu]0 is shown.
The role of the base in catalyst activation was explored
further using 31P-NMR studies of the dppf ligand, as shown
in Figure 3. The species formed from Pd2(dba)3 addition to
dppf (Figure 3b) exhibits two peaks, as previously noted,
55
and is unaffected by addition of the aryl bromide
substrate 1a (Figure 3c). Addition of NaOtBu to
Pd2(dba)3/dppf results in a shift in the two peaks. Under
reaction conditions, the addition of substrates causes a
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Scheme 2, in accordance with precedent from previous
160
140
120
100
80
concentration
shift
standard conditions
same excess
literature on Pd-catalyzed carbonylation reactions. 59,60
1
2
3
4
5
6
7
8
time shifted
concentration shifted
175
dppe (82o)
time shift
150
125
60
40
100
75
50
25
0
dppp (91o)
20
9
0
dppf (96o)
0
20
40
60
80
100 120 140 160
10
11
12
13
14
15
16
17
18
19
20
21
22
time (min)
xantphos (111o)
35
standard conditions
2x [catalyst]
30
25
20
15
10
5
0
20
40
60
80
100
time (min)
Figure 6. Concentration profiles for the reaction of Table 1
monitored by ReactIR spectroscopy under the standard
conditions in Figure 1 using ligands with different bite angles
as shown.
n = 1
0
25 50 75 100 125 150 175 200 225 250
time * [cat]n
Scheme 2. Proposed Reaction Mechanism for the
Multicomponent Reaction of Scheme 1.
23
24
25
26
27
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29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 4. “Same excess” protocol (top) showing overlay for
time and concentration shifted profiles. Variable Time
Normalization Analysis57 (VTNA, bottom) for reaction
profiles of the reaction of Scheme 1 carried out under the
conditions of Figure 1 and at twice the Pd and ligand
concentrations.
Pd2(dba)3
tBu
O
+
N
dppf
Ph
HCl
Ph
Ar
Ar
O
N
4a'
NaOt-Bu
tBu
ArBr
1a
4a
LnPd(0)
tBu
N
N
r.d.s.
A
Ar
X
LnPdII
Ar
Alk
LnPdII
F
C
N
B
resting state
standard conditions
40
tBu
tBu
High [1a]o
ZnBrX
ZnBr
High [2a]o
30
tBu
High [[i3soac]oyanide]o
N
E
Ph
tBu
C
2a
Ar
X
20
tBu
Ar
N
LnPdII
C
N
X
C
10
0
tBu
Ar
LnPdII
N
X
D
LnPdII
0
10
20
30
40
50
60
C
X = Br or Ot-Bu
N
time (min)
tBu
Figure 5. Concentration profiles for the reaction of Scheme 1
monitored by ReactIR spectroscopy. Standard conditions are
those of the reaction in Figure 1. Only one component is
altered in each of the other experiments. High [1a]0 = 100
mM; High [2a]0 = 175 mM (in THF); High [isocyanide]0 = 210
mM. Curves are time-shifted to account for the induction
period at the outset of the reaction.
Kinetic studies of the induction behavior couple with
NMR studies of the catalyst interaction with various
reaction components suggests that NaOtBu assists in
converting Pd2(dba)3 and the dppf ligand into the active
catalyst A, which is likely to be a zerovalent Pd with the
chelating phosphine. In similar systems Pd-alkoxide
intermediates have been proposed as the active
catalyst61,62 and this remains a possibility in our case.
Oxidative addition of 1a to Pd/dppf only occurs after
formation of this active catalyst, giving species B.
Subsequent coordination of isocyanide and subsequent
migratory insertion to form D. Coordination of a second
equivalent of isocyanide affords complex E, which upon
transmetallation and subsequent migratory insertion of
Examining the influence of ligand bite angle on
reactivity for Pd catalysts with selected phosphine
ligands.58 (Figure 6) showed that increasing ligand bite-
angle resulted in increased rates of reaction. Since larger
bite angles should increase the rate of reductive
elimination, these results are consistent with the
suggestion that this step is rate-determining. These
studies allow us to propose the mechanism shown in
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ACS Catalysis
the alkyl ligand into the metal isocyanide bond furnishes
Page 6 of 10
1
2
3
4
F. This complex is the resting state of the catalyst and
undergoes rate-determining reductive elimination to
produce diimine product 4a’ and regenerate the active
catalyst A.
Scheme 4. Reaction Coordinate from Species D to
a Putative Mono-Insertion Product, G, Compared
to the Observed Bis-Insertion Product, F.
5
6
7
8
The catalyst resting state F contains all four reactant
components. We carried out DFT calculations to probe the
nature of the species, as shown in Scheme 3. The lowest
energy conformation for two potential candidates F and F’
revealed that a Pd-iminoacyl species F similar to that
proposed by Whitby48 and analogous to the acyl species
proposed by Yamamoto47 is significantly lower in energy
than a putative bis-insertion intermediate F’. Reductive
elimination from a bis-iminoyl complex F as compared to
F’ has been shown experimentally in related
carbonylation studies.63,64
tBu
Ph
Gtoluene
(kcal/mol)
N
tBu
Ph
P
P
N
PdII
+ RZnBr(THF)2
P
P
R
9
PdII
G
+1.1
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Br
+ ZnBr2(THF)2
0.0
D
tBu
N
+ RZnBr(THF)2
+ tBuNC
P
P
Ph
R
PdII
R=CH2CH2Ph
-11.2
N
tBu
Scheme 3. Proposed Catalyst Resting States.
F
+ ZnBr2(THF)2
t-Bu
P
N
P
N
Ph
Ph
Pd
P
P
H
H
t-Bu
H
Pd
H
N
H
H
Ph
H
Ph
N
H
t-Bu
t-Bu
+4.3
F'
+0
Supporting Information. Reaction
procedures, compound characterization
data, and kinetic and spectroscopic
data. This material is available free
of charge via the Internet
F
Calculations also allow us to rationalize why double
insertion of isocyanide dominates over the possible mono-
insertion product in this system. Scheme 4 compares the
calculated reaction coordinate from species D in Scheme 2
to the resting state F to the analogous species G for a
mono-insertion product, which lies at significantly higher
energy. Strong and rapid coordination of the isocyanide to
the catalytic Pd center may rationalize preference for
double addition.59
at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
Anne-Marie.DechertSchmitt@pfizer.com,
Blackmond@scripps.edu
CONCLUSIONS
ACKNOWLEDGMENT
We report development of the first highly modular
synthesis of unsymmetrical 1,2-diketones employing Pd
catalysis and t-butyl isocyanide as CO equivalents. The
highly modular transformation forges three new C-C
bonds in one synthetic operation from readily available
building blocks. Kinetic and mechanistic studies have
revealed reductive elimination to be rate-determining,
which rationalized the high selectivity for bis vs. mono
isocyanide addition in this process. Further studies
investigating alternate nucleophilic coupling partners and
controlling for mono isocyanide addition are ongoing in
our laboratory.
DGB acknowledges funding from Scripps Research.
Jason Chen and the Scripps Automated Synthesis
Facility are acknowledged for helpful discussions.
AMDS acknowledges helpful discussions with Rob
Singer, Kevin Hesp and Daniel Schmitt.
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tBu
Ar
Pd2(dba)3
dppf
NaOtBu
Ar
X
N
R1
O
1M HCl
t
R1
8
C N Bu
N
Ar
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PhCH3, 95 °C
tBu
O
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R1ZnX
3 new C-C bonds!
diverse synthetic intermediate
27 examples
Ar = aromatic and
heteroaromatic
Isocyanide as non-
gaseous CO surrogate
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