Harnessing reversible oxidative addition: Application of diiodinated aromatic compounds in the carboiodination process

Article abstract of DOI:10.1002/anie.201304923

An I for an I: Conditions for the intramolecular carboiodination and the simultaneous convergent intramolecular carboiodination/intermolecular Heck reaction of various diiodoarenes were developed. The ability of the Pd ⁰/QPhos catalyst/ligand combination to undergo reversible oxidative addition allows these reactions to proceed well, thus increasing both the appeal and utility of this class of substrates in site-selective cross-coupling reactions. Copyright

Full text of DOI:10.1002/anie.201304923

Angewandte
Chemie
DOI: 10.1002/anie.201304923
Simultaneous Catalysis
Harnessing Reversible Oxidative Addition: Application of Diiodinated
Aromatic Compounds in the Carboiodination Process**
David A. Petrone, Matthias Lischka, and Mark Lautens*
Transition-metal-mediated couplings of halogenated aromat-
ics have been extensively studied since the 1960s.[1] Notwith-
standing the success of recent aromatic functionalization
strategies such as directed ortho metalation[2] and C H
ꢀ
functionalization,[3–5] Pd-catalyzed aromatic carbon–halogen
bond functionalization remains a central strategy. In this
regard, the application of polyhalogenated aromatic com-
pounds in site-selective transformations is one of the remain-
ing challenges in this field,[6] due to overcoupling[6h] and
chemoselectivity issues.[7] Methods that take advantage of the
intrinsic steric and electronic differences between different
carbon–halogen bonds have been developed.[6a,i] However,
most of these strategies remain limited, requiring difficult
substrate prefunctionalization to enforce the desired selec-
tivity. Under traditional catalytic conditions, irreversible
oxidative addition to a carbon–halogen bond of A occurs to
give B (Scheme 1a), which lacks a productive reaction
pathway. The presence of intermolecular Heck acceptors, or
the addition of nucleophiles, is a strategy used to promote
a catalytic cycle, as it allows catalytic dead ends to be avoided
while increasing product complexity.[6b,f]
A more general and attractive solution would be to use
Scheme 1. a) Catalyst deactivation by irreversible oxidative addition;
catalysts capable of undergoing reversible oxidative addi-
b) Strategy to overcome catalyst deactivation (when R¼H).
tion.[8] Building on the stoichiometric experiments on reduc-
tive elimination from ArPdIIX complexes conducted by
QPhos=1,2,3,4,5-pentaphenyl-1’-(di-tert-butylphosphino)ferrocene.
Hartwig et al.,[9] and the contributions of Buchwald et al.,
[10a]
ꢀ
ꢀ
which afford aromatic C F
and C Br bonds;[10b] our group
the carboiodination, and the sequential intramolecular car-
boiodination/intermolecular Heck reaction of diiodinated
aromatic substrates (Scheme 1b).
has developed Pd0-catalyzed transformations exhibiting
reversible oxidative addition as a key to catalysis.[8,11] To this
end, the application of our carboiodination method to
diiodinated substrates would highlight the unique capabilities
of the Pd/QPhos combination: the ability to oxidatively add
reversibly to carbon–halogen bonds, and to promote sp3
carbon–iodine reductive elimination. Herein, we report both
We began by optimizing the intramolecular carboiodina-
tion of 1a (Table 1). Although 5 mol% of [Pd(PtBu3)2] in
toluene at 1008C led to full conversion, the desired product
(2a) was obtained in only 30% isolated yield after 18 h.[12]
The yield of 2a depended on the Pd0 precatalyst used, as well
as the presence of both additional QPhos and base.[13] Based
on previous synthetic reports[8,11] and computational eviden-
ce,[14a] we believe that the steric bulk of QPhos make it ideal
for promoting carbon-iodine reductive elimination.[14b] The
optimized conditions were found to be [Pd(QPhos)2] (Pd-1;
5 mol%), additional QPhos (10 mol%), and 1,2,2,6,6-pen-
tamethylpiperidine (PMP; 2 equiv) in toluene at 1108C.[15]
Under these conditions, 2a was isolated in 74% yield. With
the optimized reaction conditions in hand, we examined
a series of diiodinated compounds, 1b–1 f.
[*] D. A. Petrone, M. Lischka, Prof. Dr. M. Lautens
Department of Chemistry, University of Toronto
80 St. George St. Toronto, Ontario (Canada)
E-mail: mlautens@chem.utoronto.ca
Homepage: http://www.chem.utoronto.ca/staff/ML/index.php
[**] We thank the Natural Sciences and Engineering Research Council of
Canada (NSERC) and the University of Toronto for financial
support. NSERC/Merck-Frosst Canada is thanked for an Industrial
Research Chair. D.A.P. thanks NSERC for a postgraduate scholar-
ship (CGS-D). The authors wish to acknowledge CFI project number
19119 for funding the CSICOMP NMR Facility. Dr. Timothy Burrow
is sincerely thanked for his dedicated assistance with NMR. We
thank Johnson Matthey for kind gifts of QPhos, [Pd(QPhos)2], and
[Pd(crotyl)QPhosCl].
Varying the location of the halogen substituent did not
affect the transformation as 1b could be efficiently cyclized to
2b in 76% yield (Table 1, entry 2). Six-membered rings could
be accessed, as 1c cyclized to afford chroman 2c in 74% yield
(entry 3). Dihydrobenzofuran 2d and oxindole 2 f were
isolated in 60% and 68% yield when the reaction times
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201304923.
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Table 1: Scope of the intramolecular carboiodination of diiodoarenes.[a]
Table 2: Optimization of the orthogonal intramolecular carboiodination/
intramolecular Heck reaction sequence.[a]
Entry
1
Substrate 1
Product 2
t [h]
Yield [%][b]
Entry
Pd Source
QPhos
(x mol%)
NR3
(y equiv)
Yield [%][b]
74
5
(67)[c]
2a
3a
4a
1
2
Pd-1
Pd-1
Pd-1
Pd-1
Pd-1
Pd-1
Pd-1
Pd-2
Pd-2
–
–
–
10
10
10
5
10
8
NEt3 (2)
NEt3 (4)
NEt3 (4)
NEt3 (2)
NEt3 (2)
PMP (2)
PMP (2)
PMP (2)
PMP (2)
16
18
8
10
14
4
5
–
–
16
18
5
7
8
–
16
–
40
21
55
57
57
86
62
86
3[c]
4
2
3
7
8
76
74
5[c]
6[c]
7[c]
8[c,d]
9[c–f]
–
88[g] (80)[h]
[a] 0.2 mmol scale, 0.1m in toluene. [b] Yields determined by 1H NMR
analysis of the crude reaction mixture using 1,3,5-trimethoxybenzene as
an internal standard. [c] TBA (1.5 equiv). [d] KOtBu (20 mol%) used.
[e] Pd-2 (4 mol%). [f] 1a (0.125m). [g] Yield of isolated product.
[h] Reaction run on a 2.5 mmol scale.
4
5
20
11
60
58
neopentyl PdII intermediate[16] D could undergo an intermo-
lecular Heck reaction (path b) instead of reductive elimina-
tion to form 4a (path c).
We began by optimizing the reaction between 1a and tert-
butyl acrylate (TBA; Table 2). With Pd-1 (5 mol%) and NEt3
(2 equiv) in toluene at 1008C for 24 h, 4a was obtained as the
major product in 40% yield along with 16% of both 2a and
3a (entry 1). The reaction was completely chemoselective, as
no undesired Heck products were observed. Increasing the
amount of NEt3 to 4 equiv led to a decrease in the yield of 4a
to 21% (entry 2). However, increasing the amount of olefin to
1.5 equiv, or adding an additional 10 mol% of QPhos
increased the yield of 4a to 55% and 57%, respectively,
while simultaneously decreasing the amount of 2a and 3a
(entries 3 and 4). When PMP was used, 4a was furnished in
86% yield, with only 4% of 2a and no trace of 3a (entry 6).
The complex [Pd(crotyl)QPhosCl] (Pd-2) was an equally
effective Pd0 precursor,[17] and employing 5 mol%, while
maintaining all established conditions, gave rise to 4a in 86%
yield (entry 8). Using this catalyst is ideal, as it is air stable and
allows the ligand loading to be decreased. The final optimized
conditions were TBA (1.5 equiv), Pd-2 (4 mol%), QPhos
(8 mol%), and PMP (2 equiv) in toluene at 1008C for 24 h,
where 4a was isolated in 88% yield with no observed 2a or 3a
(entry 9).
6
30
68
[a] Reactions conditions: diiodoarene (0.1–0.2 mmol), [Pd(QPhos)2],
(5 mol%), QPhos (10 mol%), PMP (2 equiv), PhMe, 1108C. [b] Yield of
isolated product. [c] Reaction run on 2.5 mmol scale.
were increased to 20 h and 30 h, respectively (entries 4 and 6).
Substrate 1e contains iodides on different aryl rings, but gave
2e in 58% yield after 11 h (entry 5).
We next sought to apply diiodinated compounds in an
orthogonal intramolecular carboiodination/intermolecular
Heck reaction sequence. Among the challenges are
(Scheme 2): 1) starting material homo-dimerization; 2) unde-
sired Heck reactions occurring either prior to or after the
desired intermolecular Heck reaction (path a); 3) reactive
Control experiments were then conducted to determine if
all proposed intermediate products could ultimately convert
into the desired adducts (Scheme 3). We found that both 2a
and 3a could be converted into 4a in 83% and 91% yield,
respectively. These experiments suggest that either inter-
mediate could proceed towards the desired product, and that
both pathways could be occurring simultaneously.
We tested this proposal using 1H NMR spectroscopy
to monitor the reaction between 1a and TBA in situ
Scheme 2. Challenges of the reaction sequence (R=CO2tBu).
2
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Table 3: Reaction scope.[a]
Entry Product
4
Yield [%][b]
Scheme 3. Control experiments concerning reaction intermediates.
Conditions: Pd-2 (4 mol%), QPhos (8 mol%), KOtBu (20 mol%),
PMP (2 equiv), toluene, 1008C, 12 h. R=CO2tBu.
1
2
R=CO2tBu
R=CO2Me
R=CONMe2
R=Ph
4a
4b
4c
4d
4e
(4:1 E/Z)
88 (79)[c]
83
73
3[c]
4
82
5
R=CN
90[d]
(Scheme 4).[18] We observed similar increases in the concen-
tration of both products 2a and 3a, from the intramolecular
carboiodination and the intermolecular Heck reaction,
respectively. In contrast to Table 1 where selective ortho
6
7
4 f (R=Me) 77
4 f’ (R=Ph) 25
8[e]
9
R=CO2tBu
R=2-py
4g
4h
86
84
10[e]
4i
87
86
4j[f]
(d.r.=87:13)
11
12
13
14
R=CO2tBu
R=CONMe2
R=2-py
4k
4l
4m
91
88
74
Scheme 4. In situ monitoring of the reaction of 1a and TBA. Condi-
tions: Pd-2 (0.04 equiv), QPhos (0.08 equiv), KOtBu (0.2 equiv), 1a
(0.087m), TBA (0.122m), PMP (0.216m), [D8]toluene, 373 K, 700 MHz.
15[e]
4n
70
coupling occurs, this experiment strongly suggests that the Pd0
catalyst can oxidatively add reversibly into both carbon–
iodine bonds of 1a, allowing both reactions to proceed
simultaneously. Additionally, there are similar decreases in
the concentrations of 2a and 3a, thus highlighting that both
intermediates can converge to 4a.
[a] 0.2 mmol scale. [b] Yield of isolated product. [c] 1a (2.5 mmol,
0.25m), Pd-2 (2 mol%), QPhos (4 mol%), KOtBu (10 mol%), toluene,
48 h. [d] Combined yield of both isomers. [e] Reaction heated for 48 h.
[f] Stereochemistry assigned based on analogy to a previous report, see
Ref. [11c]. 2-py=2-pyridyl.
Finally, the optimized conditions were applied to a series
of Heck acceptors and diiodoarenes (Table 3). When the
reaction time was doubled to 48 h, the loadings of Pd-2 and
QPhos could be decreased to 2 mol% and 4 mol%, respec-
tively, when the reaction was run on a 2.5 mmol scale. This
combination allowed the isolation of 4a in 79% yield
(entry 1). Methyl acrylate and N,N-dimethyl acrylamide
were well tolerated as acceptors, and their adducts, 4b and
4c, were isolated in 83% and 73% yield, respectively
(entries 2 and 3). Subjecting styrene and acrylonitrile to the
standard conditions delivered the desired products 4d and 4e
in 82% and 90% yield, respectively (entries 4 and 5). Methyl
methacrylate reacted selectively to form 4 f in 77% yield
(entry 6) in the presence of 5 equiv of olefin. N-tosyl indolines
could also be obtained as 4g and 4h were afforded in 86%
and 84% (entries 8 and 9). Electron-deficient olefins were
tolerated in the intramolecular carboiodination component,
as N-methyl oxindole 4i could be synthesized in 87% yield
(entry 10). Switching to a para-iodo substitution pattern had
no effect (entries 12–14). A nitrogen-containing polycycle 4n
could also be obtained in 70% yield (entry 15).
In conclusion, we have shown the utility of diiodinated
aromatic compounds in a Pd0-catalyzed intramolecular car-
boiodination. These two complementary reactions allow
access to a diverse range of cross-coupling substrates and
olefin containing heterocycles. Commonly encountered prob-
lems associated with this important class of compounds are
effectively avoided by carefully selecting a ligand that allows
reductive elimination from unproductive catalytic intermedi-
ates.
Angew. Chem. Int. Ed. 2013, 52, 1 – 5
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Experimental Section
KOtBu (4.5 mg, 0.04 mmol, 20 mol%), [Pd(crotyl)QPhosCl] (7.3 mg,
0.008 mmol, 4 mol%), and QPhos (11.4 mg, 0.016 mmol, 8 mol%)
were added to a dry screw cap vial equipped with a stir bar, which was
purged with dry argon. The contents were taken up in toluene
(0.8 mL) and stirred at room temperature for 15 min. A toluene
solution (0.8 mL) of 1a (79.9 mg, 0.2 mmol, 1 equiv), tert-butyl
acrylate (44 mL, 0.3 mmol, 1.5 equiv), and PMP (72 mL, 0.4 mmol,
2 equiv) was then added to the pre-mixed catalyst solution. The vial
was sealed and placed into a preheated oil bath (1008C). After 24 h,
the reaction was filtered through silica, and concentrated. The crude
product was purified by column chromatography using hexanes/
EtOAc (100:0–100:3 v/v) to give a clear, colourless oil (70.4 mg,
0.176 mmol, 88%).
Received: June 7, 2013
Revised: July 11, 2013
Published online: && &&, &&&&
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Keywords: carboiodination · Heck reaction · heterocycles ·
oxidative addition · palladium
.
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4
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Angew. Chem. Int. Ed. 2013, 52, 1 – 5
These are not the final page numbers!

Angewandte
Chemie
Communications
Simultaneous Catalysis
D. A. Petrone, M. Lischka,
M. Lautens*
&&&& — &&&&
Harnessing Reversible Oxidative
Addition: Application of Diiodinated
Aromatic Compounds in the
Carboiodination Process
An I for an I: Conditions for the intra-
molecular carboiodination and the
simultaneous convergent intramolecular
carboiodination/intermolecular Heck
reaction of various diiodoarenes were
developed. The ability of the Pd0/QPhos
catalyst/ligand combination to undergo
reversible oxidative addition allows these
reactions to proceed well, thus increasing
both the appeal and utility of this class of
substrates in site-selective cross-coupling
reactions.
Angew. Chem. Int. Ed. 2013, 52, 1 – 5
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!