Palladium-catalyzed atom transfer radical cyclization of unactivated alkyl iodide

Article abstract of DOI:10.1039/c2ob25990g

A palladium-catalyzed atom transfer cyclization of unactivated alkyl iodide has been developed. A radical chain mechanism has been proposed for this transformation, which might not involve an alkylpalladium intermediate.

Full text of DOI:10.1039/c2ob25990g

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Palladium-catalyzed atom transfer radical cyclization of unactivated alkyl
iodide†
Hui Liu, Zongjun Qiao and Xuefeng Jiang*
Received 22nd May 2012, Accepted 26th July 2012
DOI: 10.1039/c2ob25990g
A palladium-catalyzed atom transfer cyclization of unacti-
vated alkyl iodide has been developed. A radical chain
mechanism has been proposed for this transformation, which
might not involve an alkylpalladium intermediate.
Alkyl halides, especially those with β hydrogen atoms, are a
class of challenging substrates for palladium-catalyzed trans-
formations. The challenges mainly stem from the reluctant oxi-
dative addition1 of aliphatic C–X bond to Pd(0) species and the
Scheme 1 Pd(0)-catalyzed transformations of alkenyl iodides.
facile β-H elimination2 for alkylpalladium intermediate.
Despite the formidable challenges, several new catalyst
systems have been established to enable the use of alkyl halides
as the starting material.3 Among those elegant developments, the
palladium-catalyzed reactions of alkenyl iodide 1 have received
increasing attention (Scheme 1). In 1996, Knochel and co-
workers demonstrated that 5-hexenyl iodide can be readily con-
verted into cyclopentylmethylzinc iodide 2 in the presence of
catalytic Pd(0) species and a dialkylzinc reagent.4 For 4-pentenyl
iodide, two different protocols have been developed. Ryu and
co-workers established a Pd/light system to promote multiple
carbonylative cyclization with the assistance of alcohol, resulting
Scheme 2 Design plan for Pd(0)-catalyzed ATRC of alkenyl iodide.
in the formation of keto ester 3.5 Later, Alexanian and co-
workers realized a carbonylative Heck-type reaction of 4-pente-
Recently, both the Tong10 and Lautens11 groups have described
the carboiodination of alkenes and the Houk group reported the
nyl iodide to yield α,β-unsaturated ketone 4 when the above
mentioned light condition and alcohol additive are removed.6
Interestingly, when almost identical reaction conditions were
employed to 5-hexenyl iodide, an intramolecular Heck-type
product 5 was steadily isolated.7 It should be emphasized that a
common hybrid organometallic-radical mechanism has been pro-
posed for the above mentioned transformations. Some metal-
catalyzed atom transfer radical cyclization (ATRC) reactions
have been reported in the past,8 including the radical formation
mechanism.9 However, as shown above, subtle changes in reac-
tion conditions may result in very different outcomes, indicating
there might be many possible pathways in palladium-catalyzed
transformations of unactivated alkyl iodide.
theoretical study of Pd(0)-catalyzed carbohalogenation of
alkenes.12 During Tong’s study on Pd(0)-catalyzed iodide atom
transfer cyclization of (Z)-1-iodo-1,6-diene, they have found that
the Pd(0) catalyst (10 mol% Pd(OAc)2 and 30 mol% DPPF) may
transfer single electron to alkyl iodide 6 to form alkyl carbon-
centered radical A and LnPdI species, responsible for the obser-
vation of stereochemistry loss in 6 (Scheme 2a). These findings
lead us to envision that this palladium catalyst system might be
also workable toward 5-hexenyl iodide to form radical inter-
mediate B which would be followed by 5-exo addition and
iodide transfer to yield cyclic product 7 (Scheme 2b). Herein we
report a Pd(0)-catalyzed iodide atom transfer radical cyclization
(ATRC) of alkenyl iodide (Scheme 2b). To the best of our
knowledge, this is the first example related to Pd(0)-catalyzed
ATRC of unactivated alkyl iodide.13
Shanghai Key Laboratory of Green Chemistry and Chemical Process,
Department of Chemistry, East China Normal University, 3663 North
Zhongshan Lu, Shanhai 200062, P.R. China.
E-mail: xfjiang@chem.ecnu.edu.cn; Tel: +86-21-52133654
†Electronic supplementary information (ESI) available. See DOI:
10.1039/c2ob25990g
To validate our hypothesis outlined in Scheme 2, alkenyl
iodide 1a was subjected to the conditions of Pd(OAc)2 (10 mol%),
DPPF (30 mol%) in toluene at 120 °C (Table 1). To our delight,
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Table 1 Optimization of reaction conditionsa
Table 2 Pd(0)-catalyzed IATCa
Entry
1
Substrate
Product
Yieldb
82%
2
3
4
5
6
7
70%
68%
35%
72%
58%
81%
Entry
[Pd]
Ligand-x
Solvent
T (°C)
Yieldb
1
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(PPh3)4
Pd2(dba)3
dppf-30
PtBu3-60
PPh3-60
binap-30
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
DMF
DCE
Xylene
MeCN
PhH
PhMe
PhMe
PhMe
PhMe
120
120
120
120
120
120
120
120
120
120
120
120
130
150
130
130
54%
Trace
13%
48%
49%
47%
ND f
ND f
ND f
36%
32%
Traceg
82%
62%
66%
78%
2c
3
4
5
6
7
8
9
10
11
12
13
14
15
16
d
—
dppf-30
dppf-30
dppf-30
dppf-30
dppf-30
dppf-30
dppf-30
dppf-30
dppf-30
dppf-20
dppf-40
e
—
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
a Reactions were carried out using 0.2 mmol 1a. b Isolated yield.
c PtBu3·HFB4
+
K2CO3 were used. d Without ligand. e Without
palladium. f ND = not detected. g 92% of 1a was recovered.
iodide atom transfer cyclization (IATC) product 7a was indeed
isolated in the yield of 54% (Table 1, entry 1). An extensive
screening of catalysts showed that other palladium catalyst
systems were also workable albeit with decreased efficiency
(Table 1, entries 2–6), no product was formed without palladium
source (Table 1, entry 7). The solvent screening proved that
toluene was the optimal one (Table 1, entries 8–11). To our
delight, the yield was improved to be 82% when the reaction
was conducted in a closed vessel at 130 °C (Table 1, entry 13).
Higher reaction temperature, for example 150 °C, was found to
be negative in terms of yield (Table 1, entry 14). It was found
that the quantity of DPPF was an important factor, but its
influence on the product yields is not monotonous (Table 1,
entries 15–16).
8
76%
9
NRc
NRc
ð1Þ
10
With the optimized conditions in hand, we then turned our
attention to the reaction scope and the results are summarized in
Table 2. In general, the palladium-catalyzed IATC can be
efficiently achieved with a wide range of 5-hexenyl iodides, deli-
vering alkyl iodide derivatives 7 in moderate to high yields. Sub-
stitution on C5-position shows wide tolerance; even the bulky
isobutyl group is compatible in terms of reaction rate and yield
(Table 2, entry 3). An oxygen-functionalized tether could also be
introduced into C5-position (Table 2, entries 5 and 6). However,
substrate 1d with benzylic substituent at C5-position exhibits
relative worse reactivity, leading to 35% isolated yield (Table 2,
a Reactions run 0.05 M in PhMe at 130 °C with the use of Pd(OAc)2
(0.02 mmol, 4.6 mg) and dppf (0.06 mmol, 34 mg) for 24 h. b Isolated
yield. c No reaction.
entry 4). The transformation is also tolerant with 2-substituted
substrate, such as 1g and 1h, delivering the corresponding IATC
products 7g and 7h in the yields of 81% and 76%, respectively
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(Table 2, entries 7 and 8). Unfortunately, the six- and seven-
member ring could not be obtained in this reaction (Table 2,
entries 9 and 10). Interestingly, the reaction of the substrate 1k
with no substituent at C5-position afforded not only IATC
product 7k in 68% yield, but also Heck-type byproduct 8 in 8%
yield (eqn (1)).
To investigate the mechanism of the Pd(0)-catalyzed IATC,
two deuterium-labeled substrates (Z)-1k-D and (E)-1k-D were
tested under the optimized conditions. The same product 7k-D14
was obtained from either (Z)-1a-D or (E)-1a-D, with similar
yields.
(2)
Scheme 3 Proposed mechanism.
intermediate C by the LnPdI species might lead to the formation
of alkylpalladium intermediate D. Given the fact that the alkyl-
palladium complex rapidly undergoes β-H elimination, inter-
mediate D barely has a chance to reductively eliminate alkyl
iodide to generate 7k, indicating that the Pd(0)-catalyzed ATRC
might not proceed via the hybrid organometallic-radical mechan-
ism, i.e. path c is unlikely. Alternatively, intermediate D could be
generated via oxidative addition of 7k to Pd(0) species, which
undergoes β-H elimination to yield the Heck-type17 byproduct 8
and IPdH species. Without the assistance of base additive, IPdH
species can not regenerate Pd(0) catalyst, rendering compound 8
being isolated only in 8% yield.18
In summary, we have found that the combination of 10 mol%
Pd(OAc)2 and 30 mol% DPPF is an efficient catalyst system to
promote ATRC of unactivated alkyl iodide. A radical chain
mechanism has been proposed for this transformation on the
basis of the fact that TEMPO additive can readily trap the
involved carbon-centered radicals. A proposal has also been
suggested to account for the isolation of Heck-type byproduct 8,
which might provide a complementary understanding for hybrid
organometallic-radical mechanism. Further studies of the reac-
tion mechanism and employment of this catalyst system to other
types of unactivated alkyl iodides are currently underway and
will be reported in due course.
These outcomes strongly indicated that the IATC might
involve radical intermediate(s). Thus, TEMPO (2,2,6,6-tetra-
methylpiperidine 1-oxyl) was added into the optimized con-
ditions to probe the potential intermediacy of carbon-centered
radicals. Indeed, the reaction of substrate 1a with 2 equiv of
TEMPO yielded adducts 9a and 10a in the yields of 8% and
3%, respectively (eqn (2)). While substrate 1k was tested under
the same conditions, only 10k was isolated in the yield of 5%
(eqn (2)). No detection of compound 9k implied that the corres-
ponding 5-exo radical addition might be a fast step due to less
steric hindrance.
ð3Þ
If this process is a radical mechanism, we expect this reaction
should be promoted by the normal radical cyclization conditions.
So we tested the substrate 1k in the presence of AIBN (20 mol%)
and n-Bu3SnH (2.0 equiv.), and compound 11 was obtained
in 48% yield (eqn (3)). This result implied that this kind of cycli-
zations could be realized by radical process.
On the basis of these observations, our proposed mechanism
is depicted in Scheme 3, although the detailed mechanism for
this process remains uncertain at this stage. Single-electron trans-
fer between Pd(0) catalyst and substrate 1k produces LnPdI
species and a carbon-centered free radical B. The latter under-
goes intramolecular radical addition to form a second carbon-
centered free radical C. According to the related findings on
metal-catalyzed atom transfer radical cyclization,15 intermediate
C is believed to abstract iodide atom from LnPdI species to
deliver the IATC product 7k with concomitant regeneration of
the catalyst (Scheme 3, path a). Alternatively, intermediate C
might abstract iodide atom from substrate 1k, resulting in the
formation of product 7k and intermediate B (Scheme 3, path b).
For path b, Pd(0) catalyst just serves as a radical initiator.16
Besides these two possible reaction pathways, a hybrid orga-
nometallic-radical mechanism should be considered (Scheme 3,
path c), as has been reported in previous work.4–7 Interception of
Notes and references
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14 Unfortunately, the deuterium scrambling can not be determined according
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