Palladium-catalyzed intramolecular iodine-transfer reactions in the presence of β-hydrogen atoms

Article abstract of DOI:10.1002/anie.201308534

Atom economy: A palladium-catalyzed atom-transfer reaction of secondary alkyl iodides is described. An intramolecular double insertion of an alkyne and olefin provides access to primary iodides possessing β-hydrogen atoms. The process delivers these complex bicyclic homoallylic iodides with tetrasubstituted olefins from easily accessible aliphatic iodides. Different functional groups, including common heterocycles, are tolerated. Copyright

Full text of DOI:10.1002/anie.201308534

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Angewandte
Communications
DOI: 10.1002/anie.201308534
Atom Transfer
Palladium-Catalyzed Intramolecular Iodine-Transfer Reactions in the
Presence of b-Hydrogen Atoms**
Brendan M. Monks and Silas P. Cook*
The ideal chemical transformation is one where all atoms in
the starting materials are present in the product with all other
reagents used catalytically.[1] Atom-economical reactions
strive to achieve this ideal and are essential for the continued
maturation of organic chemistry and the mitigation of its
negative effects on the environment.[2] The search for atom-
economical processes has advanced the field of catalysis and
broadened the study of environmental chemistry. The impres-
sive industrial synthesis of sitagliptin highlights the impor-
tance of atom economy in the chemical industry.[3] Therefore,
the identification of reactions that achieve high atom
economy is a worthwhile endeavor.
Palladium-catalyzed transformations are one of the most
important carbon–carbon bond forming reactions in medic-
inal chemistry[4] and total synthesis.[5] Recent interest in
Scheme 1. a) Previous palladium-catalyzed iodine-transfer reactions in
the absence of b-hydrogen atoms. b) Tandem insertion/Suzuki reaction
of primary iodides. c) An attempted alkyne insertion/Heck reaction
leads to a facile palladium-catalyzed iodine-transfer reaction in the
presence of b-hydrogen atoms.
palladium-catalyzed atom-transfer reactions has grown from
the work of Lautens et al.[6] and Tong et al.[7] They have
demonstrated the ability of aryl, vinyl, and alkynyl halides to
undergo intra- and intermolecular insertion events and
subsequently reductive elimination to form alkyl iodides in
the absence of b-hydrogen atoms (Scheme 1a). A useful
extension of this atom-transfer chemistry would be the
application of alkyl halides and olefin insertion in the
presence of b-hydrogen atoms.
We recently reported a tandem alkyne insertion/Suzuki
reaction of primary iodides (Scheme 1b).[8] Since a secondary
iodide also worked in the alkyne insertion/Suzuki reaction, we
sought to extend this methodology to a tandem alkyne
insertion/Heck reaction to produce bicyclic exo olefin prod-
ucts of type 1 (Scheme 1c). However, preliminary reactions
did not yield Heck products 1, but rather the iodine-transfer
product 3. The unexpected formation of the diquinane 3
bearing a primary iodide in high yield with few side products
was deemed worthy of investigation, especially given the need
to develop direct syntheses of complex compounds containing
tetrasubstituted olefins.[9] The transformation allows the use
of easy-to-access compounds of type 2 (two to three steps
from commercial materials) for the synthesis of functional-
ized diquinanes, which are important structural motifs found
in numerous natural products,[10] and provides substitution
patterns complementary to the current state-of-the-art
approach, the Pauson–Khand reaction.[11] Consequently, we
set out to determine the scope and reactivity of this important
iodine-transfer reaction.
The palladium-catalyzed iodine-transfer reaction was
optimized through the systematic evaluation of all relevant
reaction parameters. Interestingly, the addition of base was
essential to achieve full conversion. Without the inclusion of
base, the catalyst did not turn over and precipitated as
[Pd(PPh3)2I2], thereby suggesting a role for the base in the
reduction of PdII species. Interestingly, the addition of super-
stoichiometric amounts of iodine (sodium iodide or tetrabu-
tylammonium iodide) relative to palladium shut down the
reaction completely and allowed for the quantitative recovery
of starting material.
Utilizing optimal reaction conditions (Cs2CO3, [Pd-
(PPh3)4], PhMe, 508C, 20 h), a variety of substrates were
evaluated (Table 1). The iodine-transfer reaction proved
general, providing cis bicyclic ring systems with moderate-
to-good d.r. values. Varying the electronic properties of the
internal alkyne with electron-rich and electron-deficient
[*] B. M. Monks, Prof. S. P. Cook
Department of Chemistry, Indiana University
800 East Kirkwood Avenue, Bloomington, IN 47405 (USA)
E-mail: sicook@indiana.edu
Homepage: http://www.indiana.edu/~cooklab/
[**] We acknowledge funding from Indiana University in support of this
work. We also gratefully acknowledge the American Chemical
Society Petroleum Research Fund (PRF52233-DNI1) and NSF-
CAREER (CHE-1254783) for partial support of this work. We thank
Dr. Chun-Hsing Chen for collecting crystallographic data for
compound 21. ChemMatCARS Sector 15 is principally supported by
the National Science Foundation/Department of Energy under
grant number NSF/CHE-0822838. Use of the Advanced Photon
Source was supported by the U. S. Department of Energy, Office of
Science, Office of Basic Energy Sciences, under Contract No. DE-
AC02-06CH11357.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201308534.
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Table 1: Atom transfer substrate scope.
aromatic groups had little effect on the reaction, providing
good yields of primary iodides 4b, 5b, 6b, and 7b (entries 1–4,
Table 1). Alkynes substituted with either an alkyl or vinyl
group proceeded cleanly in satisfactory yields, generating
diene 9b and all-alkyl tetrasubstituted olefin 10b, respectively
(entries 6 and 7, Table 1). Additionally, tertiary iodide 13a
provided iodine-transfer product 13b in 55% yield as a single
1
diastereomer as determined by H NMR analysis (entry 10,
Table 1). The reaction tolerated a variety of heterocycles,
allowing the formation of primary iodides in the presence of
pyridine, quinoline, isoquinoline, and thiofuran (entries 8–13,
15, and 16, Table 1). Functional groups such as ethers, esters,
and aldehydes were also compatible with the reaction
conditions (entries 1–4 and 13, Table 1). Unfortunately, sub-
strates capable of palladium sequestration, such as terminal
alkyne 8a and 2-pyridine 17a, suffered from a lack of
reactivity (entries 5 and 14, Table 1).
While the reaction conditions worked well for the
formation of diquinane ring systems, attempts to access
hydroindene ring systems 18b and 19b led to the recovery of
starting material under standard reaction conditions
(entries 15 and 16, Table 1). Higher reaction temperatures
(e.g., 808C) effected the cyclization but produced formal
Heck products of type 1, presumably through E2 elimination
by Cs2CO3 of 18b and 19b (see the Supporting Information).
Substitution of Cs2CO3 with a weaker base, NaHCO3, allowed
for the isolation of the primary iodides 18b and 19b in 63%
and 71% yield, respectively (entries 15 and 16, Table 1). Even
under elevated temperatures (1408C), all attempts to cyclize
secondary iodide 20a failed to produce the hydroazulene
system, despite signficant consumption of starting material
(entry 17, Table 1).
The primary iodide products can be elaborated into high-
value, drug-like molecules through standard chemistry. For
example, triazole 21 was synthesized in two steps and
crystallized for unambiguous assignment of relative stereo-
chemistry by using X-ray diffraction analysis (Scheme 2). The
cis relative stereochemistry would be expected from the
pseudo-equatorial orientation of the terminal olefin during
the second insertion.
While the iodine-transfer reaction reported here may
proceed through a radical mechanism, variation of the
phosphine ligands revealed a clear influence on conversion
(at 20 h) and d.r., thereby arguing against a purely free-
radical mechanism (Table 2). For example, minor modifica-
tions to the PPh3 ligand had significant effects. The addition of
[a] Reaction performed at 608C. [b] Standard conditions lead to NR
(recovered starting material). [c] 808C, NaHCO3 (1.0 equiv). [d] 1408C,
NaHCO3 (1.0 equiv) leads to starting material decomposition. NR=no
reaction, ND=not determined, N/A=not available.
Scheme 2. Derivatization of primary iodide 12b and confirmation of
relative stereochemistry.[17]
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Table 2: The dependence of conversion and d.r. on the ligand.
Finally, in the absence of any phosphine no reaction was
observed (entry 18, Table 2).
Oxidative addition of alkyl halides by palladium(0) most
commonly proceeds through either SN2[12] or radical mecha-
nisms.[13] To probe the nature of oxidative addition, enan-
tioenriched secondary iodide (R)-12a was prepared and
subjected to standard reaction conditions (Scheme 3a). The
Entry
Ligand
X
Conversion [%]
d.r.
1
2
3
4
5
6
7
8
PPh3
PPh3
PPh3
PPh3
10
20
30
40
40
40
40
20
40
20
20
20
40
40
40
20
20
–
0
29
53
95
100
33
100
80
66
13
7
9
4
0
0
0
0
0
N/A
N/A
N/A
13:1
14:1
13:1
10:1
>30:1[b]
>20:1
N/A
N/A
N/A
N/A
–
[a]
PPh3
P(4-CF3C6H4)3
P(4-OMeC6H4)3
rac-BINAP
XPhos
QPhos
DPEphos
DPPP
TFP
P(2-MeC6H4)3
AsPh3
DPPF
Xanphos
–
9
10
11
12
13
14
15
16
17
18
–
–
–
–
Scheme 3. a) Racemization of enantioenriched substrate (R)-12a;
b) recovery of enantioenriched substrate (R)-12a at low conversion.
[a] [Pd(PPh3)4] (10 mol%). [b] See the Supporting Information.
isolation of racemic 12b rules out an SN2 pathway for
oxidative addition. To test whether reversible, two-electron
oxidative addition is the source of racemization, enantioen-
riched secondary iodide (R)-12a (72% ee) was subjected to
the optimized reaction conditions at 308C (Scheme 3b). The
reaction produced low conversion at 20 h with 28% yield of
the racemic product 12b and 64% recovered starting material
(R)-12a without any observable erosion of ee. These results
strongly suggest that a poorly stereoselective, reversible, two-
electron oxidative addition is not responsible for the forma-
tion of racemic product.
Attempts to intercept any carbopalladium species in the
catalytic cycle with PhB(OH)2 under the optimized reaction
conditions were unsuccessful, returning only secondary iodide
starting material 12a. TEMPO (2,2,6,6-tetramethylpiperdine
1-oxyl)[13a,14] and galvinoxyl[15] are often used as radical traps
in free-radical chemistry. Conducting the reaction in the
presence of one equivalent of TEMPO or galvinoxyl led to no
reaction and quantitative recovery of starting material, an
outcome opposite to the primary iodides studied previously.[8]
Furthermore, the terminal olefin proved critical for the
overall efficiency of the transformation. For example, when
the allyl group was replaced with a methyl group, the reaction
produced vinyl iodide 22b in low yield with multiple
reduction products (42% conversion, 23% yield of E/Z
mixture, Scheme 4a). While products expected from a cyclo-
propylcarbinyl rearrangement were not observed for any of
the substrates in Table 2, replacing the terminal olefin with
a cyclopropyl ring provided ring-opened primary iodide 23b
(Scheme 4b). Since radical atom-transfer cyclizations are
known,[16] we subjected substrate 12a to a range of radical
conditions (see the Supporting Information). Under most
a para-methoxy group afforded faster reactions with lower
d.r. value (entry 7, Table 2), whereas a para-trifluoromethyl
group produced slower reactions with virtually unchanged d.r.
value (entry 6, Table 2). The sterically encumbered mono-
dentate phosphines XPhos and QPhos, which have been used
successfully in previous atom-transfer reactions,[6] proved
inferior to PPh3 in terms of conversion (entries 9 and 10,
Table 2). Note that the reactions described in entries 6, 8, and
9 all reached full conversion at later time points. More
electron-donating phosphines, such as P(tBu)3, P(Cy)3, and
MeP(tBu)2, led to complex reaction mixtures with no
observable product (data not shown). Weakly coordinating
ligands such as TFP or AsPh3 were ineffective for the reaction
(entries 13 and 15, Table 2). Although rac-BINAP provided
reasonable conversion with high d.r. value (entry 8, Table 2),
the other bidentate phosphines tested proved ineffective
(entries 11, 12, 16, and 17, Table 2). Furthermore, the use of
(S)-BINAP provided racemic product, unlike in previous
examples of palladium-catalyzed atom-transfer reactions.[7a]
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Chemie
hydroindene ring systems. Preliminary mechanistic studies
rule out an SN2 oxidative addition. Additionally, phosphine
ligands have a direct impact on the conversion and d.r. of the
reaction, thereby arguing against a purely free-radical reac-
tion. Further efforts will be directed towards a greater
understanding of reaction mechanism and expanding the
scope of this interesting transformation.
Experimental Section
General procedure for the atom transfer reaction:
An oven-dried Kimberly-Chase 8 mL screw thread culture tube
was purged with nitrogen, then charged with [Pd(PPh3)4] (0.10 equiv)
and Cs2CO3 (1.0 equiv). The flask was then purged with nitrogen. A
solution of the alkyl iodide (1.0 equiv) in PhMe (0.10m) was then
added all at once by using a gas-tight syringe, and the tube was sealed
with the screw top vial. The reaction was stirred for 20 h at 508C. The
reaction was returned to room temperature, quenched with a 10%
aqueous solution of N-acyl cysteine (5 mL), and extracted with Et2O
(3 ꢀ 10 mL). The combined organic extracts were then washed with
H2O (25 mL), dried (MgSO4), filtered, and concentrated to give
a residue. The residue was purified by silica flash chromatography
using hexanes and ethyl acetate in appropriate combination based on
the Rf value of the desired product.
Scheme 4. a) Removing the terminal olefin severely compromises the
efficiency of the iodine-transfer reaction; b) cyclopropylcarbinyl rear-
rangement leads to no reaction with the internal alkyne.
conditions, quantitative recovery of starting material was
observed. The iodine-transfer product could be observed in
low yield using conditions reported by Curran et al. (slow
addition of azobisisobutyronitrile (AIBN) and nBu3SnH in
benzene, 858C, 24 h).[16d] The results from the free-radical
experiments (see the Supporting Information) clearly dem-
onstrate the superiority of this method over traditional free-
radical methods. Taken together, the racemic product, ligand
influence on d.r., and compromised reactivity in the absence
of the terminal olefin suggest a role for palladium beyond
radical initiation. A possible explanation for these observa-
tions would be the coordination of a putative PdI intermediate
to the terminal olefin (Scheme 5).
Received: September 30, 2013
Revised: October 9, 2013
Published online: November 19, 2013
Keywords: atom transfer · diquinanes · iodine · palladium ·
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substituted olefins
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