Pd(0)-catalyzed iodoalkynation of norbornene scaffolds: The remarkable solvent effect on reaction pathway

Article abstract of DOI:10.1021/ol2022388

A palladium-catalyzed iodoalkynation of norbornene has been realized with the use of alkynyl iodides 1, which is found to be strongly solventdependent. MeCN favors 1,7-iodoalkylation product 3 while CCl₄ leads to 1,2-iodoalkylation product 4.

Full text of DOI:10.1021/ol2022388

ORGANIC
LETTERS
2
011
Vol. 13, No. 19
072–5075
Pd(0)-Catalyzed Iodoalkynation of
Norbornene Scaffolds: The Remarkable
Solvent Effect on Reaction Pathway
5
Hui Liu, Chen Chen, Limin Wang, and Xiaofeng Tong*
Shanghai Key Laboratory of Functional Materials Chemistry, East China University of
Science and Technology, Shanghai 200237, P. R. China
tongxf@ecust.edu.cn
Received July 16, 2011
ABSTRACT
A palladium-catalyzed iodoalkynation of norbornene has been realized with the use of alkynyl iodides 1, which is found to be strongly solvent-
dependent. MeCN favors 1,7-iodoalkylation product 3 while CCl leads to 1,2-iodoalkylation product 4.
4
Alkyl halides are versatile intermediates in organic
1
synthesis. In the field of transition-metal catalysis, they
For the intermolecular variant, we immediately recognized
that it would encounter the following dilemma: the poly-
substituted alkenes are mandatory to prevent a Heck-type
side reaction while their large steric hindrance might hamper
the insertion of the related CÀPd bond (Scheme 1b, upper).
Norbornene may offer an attractive solution as the corre-
sponding β-H elimination can be completely prohibited
due to its rigid structure. On the other hand, we chose
iodoalkynes as organic halides with the consideration that
they are feasible to undergo oxidative addition to a Pd(0)
5
catalyst. Herein, we report the Pd(0)-catalyzed iodoalkyna-
are basic starting materials for various organic transfor-
mations. However, their halide atoms are always discarded,
rendering these transformations nonatom economic. Very
recently, we and Lautens et al. independently reported the
palladium-catalyzed intramolecular carboiodination of al-
kenes, which provides a new carbonÀcarbon bond while
4
retaining the reactive halide of the starting material (Scheme
2
a). These results represent a conceptually novel process in
1
palladium catalysis, especially the reductive elimination of
alkyl iodide in the involved catalytic cycle.
As part of our ongoing efforts on the metal-catalyzed
tion of norbornene with iodoalkynes, which features highly
selective formation of two different iodoalkylation products
depending on the reaction solvent (Scheme 1b, bottom).
3
formation of organic halides, we were devoted to devel-
oping the intermolecular carboiodination of alkenes.
2
b
First, we used the same conditions as those for intra-
molecular carboiodination to investigate the reaction
(
1) (a) Chambers, R. D.; James, S. R. In Comprehensive Organic
Chemistry; Barton, D. H. R., Ollis, W. D., Eds.; Pergamon Press: Oxford,
979; Vol. 1. (b) Bohlmann, R. In Comprehensive Organic Synthesis;
Trost, B. M., Fleming, I., Eds.; Pergamon Press: Oxford, 1991; Vol. 6. (c)
Hudlicky, M.; Hudlicky, T. In Chemistry of Functional Groups; Patai, S.,
Rappoport, Z., Eds.; Supplement D; Wiley: New York, 1983.
(4) For recent reviews, see: (a) Catellani, M.; Motti, E.; Ca’, N. D.
Acc. Chem. Res. 2008, 41, 1512. (b) Catellani, M.; Motti, E.; Faccini, F.;
Ferraccioli, R. Pure Appl. Chem. 2005, 77, 1243. (c) Catellani, M. Novel
Methods of Aromatic Functionalization Using Palladium and Norbor-
nene as a Unique Catalytic System. In Palladium in Organic Synthesis;
Tsuji, J., Ed.; Springer: Berlin, 2005; pp 21À53. (d) Alberico, D.; Scott,
M. E.; Lautens, M. Chem. Rev. 2007, 107, 174.
1
(
2) (a) Newman, S. G.; Lautens, M. J. Am. Chem. Soc. 2011, 133,
1778. (b) Liu, H.; Li, C.; Qiu, D.; Tong, X. J. Am. Chem. Soc. 2011, 133,
6
187.
(
(5) For recent examples, see: (a) Damle, S. V.; Seomoon, D.; Lee,
P. H. J. Org. Chem. 2003, 68, 7085. (b) Shi, Y.; Li, X.; Liu, J.; Jiang, W.;
Sun, L. Tetrahedron Lett. 2010, 51, 3626. (c) Kim, S. H.; Chang, S. Org.
Lett. 2010, 12, 1868.
3) (a) Wang, J.; Tong, X.; Xie, X.; Zhang, Z. Org. Lett. 2010, 12,
5370. (b) Tong, X.; Zhang, G.; Zhang, X. J. Am. Chem. Soc. 2003, 125,
6
370.
1
0.1021/ol2022388 r 2011 American Chemical Society
Published on Web 09/12/2011

a
Scheme 1. Design Plan for Intermolecular Iodoalkynation
Table 1. Optimization of Reaction Conditions
b
temp
yield (%)
entry
[Pd]
ligand (x)
Solvent
(°C)
(3a:4a)
1
2
3
4
5
6
7
8
9
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
2
2
2
2
2
2
2
DPPF (30)
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhH
120
50
rt
10 (60:40)
28 (72:28)
NR
DPPF (30)
DPPF (30)
DPPF (20)
50
50
50
50
50
50
50
50
50
50
50
36 (66:34)
53 (69:31)
69 (89:11)
61 (89:11)
78 (96:4)
68 (26:74)
82 (3:97)
31 (1:99)
48 (1:99)
69 (1:99)
25 (1:99)
DPPF (10)
--
--
--
--
--
--
--
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)2
Pd(OAc)
Pd(PPh
2
CCl
4
2
THF
of phenylethynyl iodide 1a and norbornene 2 (1.2 equiv)
Table 1, entry 1). To our delight, both 1,7-iodoalkylation
10
2
MeCN
DMSO
DMF
(
11
2
6
7
product 3a and 1,2-iodoalkylation product 4a were iso-
lated in a ratio of 60:40, albeit in 10% yield (Table 1, entry 1).
The reaction temperature was found to be essential for
product yield; the reaction conducted at 50 °C afforded
a combined 28% yield of 3a and 4a in a ratio of 72:28,
while no reaction occurred at room temperature (Table 1,
entries 2À3). The ligand effect was further investigated.
The reaction was improved in the presence of 20 or 10 mol %
DPPF, leading to a combined yield of 36% (Table 1,
entry 4) and 53% (Table 1, entry 5), respectively, implying
that the additional ligand would impose a negative effect
on the overall yield. Indeed, when the reaction was con-
ducted in the absence of ligand, a 69% isolated yield was
obtained and the product distribution was also improved
to 89:11 (Table 1, entry 6). Afterward, we decided to per-
12
13
2
PPh
--
3
(20)
MeCN
MeCN
14
3
)
4
a
Reaction conditions: 1a (68.4 mg, 0.3 mmol), 2 (33.8 mg, 0.36
b
2
mmol), Pd(OAc) (6.8 mg, 0.03 mmol). Isolated yield. The ratio was
1
determined according to H NMR analysis.
With the optimized conditions in hand, we then inves-
tigated the reaction scope with various iodoalkynes, and
the results are summarized in Table 2. In general, the
reactions of (iodoethynyl)aromatics smoothly proceeded
in either CCl or MeCN, affording 1,2- and 1,7-iodoalk-
4
ynation products, respectively, in good to excellent yields
(Table 2, entries 1À9). In contrast, only a moderate yield
was obtained in the case of (iodoethynyl)alkyl substrates,
regardless of whether CCl or MeCN was used (Table 2,
4
form further optimizations with 10 mol % Pd(OAc) as
2
entries 10 and 11). With respective to selectivity, good to
excellent results were obtained for (iodoethynyl)aromatic
substrates in either CCl or MeCN solvent. Again, for
catalyst. It was found that the solvent CCl was an optimal
4
one, affording 4a in 78% yield with a selectivity as high as
9
6% (Table 1, entry 8). Surprisingly, when a polar solvent
was used instead, such as THF, MeCN, DMSO, and
DMF, an opposite selectivity was observed, resulting in
4
(iodoethynyl)alkyl substrates, a much lower 1,7-selectivity
was obtained in the solvent MeCN. The stereochemistry of
other products was tentatively assignedby comparing their
1
CHI peak from H NMR to that of 3a and 4a, respectively.
1
,7-iodoalkynation product 3a as the majority (Table 1,
entries 9À12). MeCN was found to be suitable for practic-
able synthesis in terms of yield and stereoselectivity. It
should be noted that the selectivity of 3a could be further
To extend the scope of this transformation, (bromo-
ethynyl)benzene 5 was employed as the substrate. To our
delight, it was also active enough for Pd-catalyzed 1,7-
bromoalkynation in MeCN to give compound 6 in 80%
yield with 98% selectivity (Scheme 2a). It should be noted
that bromoalkyne 5 was found to be inert in solvent CCl4.
When the reaction of 1a and norbornene derivative 7 was
conducted in solvent MeCN, to our surprise, 1,2-iodoalk-
improved to be 99% in the presence of 20 mol % PPh or
3
with the use of Pd(PPh ) as catalyst (Table 1, entries
3
4
1
3À14). On the basis of these results, we can conclude that
the iodoalkynation is strongly affected by the reaction
media, with a nonpolar solvent favoring 1,2-selectivity
and a polar solvent favoring 1,7-selectivity.
ynation product 8 was instead obtained in 72% yield with
9
8
7% selectivity (Scheme 2b). This result implied that 1,2-
(
6) The structure of 3a was determined by comparision of the
authentic samples according to the following paper: Li, Y; Liu, X; Jiang,
and 1,7-iodoalkynation probably involved a common
intermediate and the latter could be diminished due to
H; Liu, B; Chen, Z; Zhou, P. Angew. Chem., Int. Ed. 2011, 50, 6341.
(7) The structure of 4a was determined according to the authentic
sample: Allen, A.; Villeneuve, K.; Cockburn, N.; Fatila, E.; Riddell, N.;
Tam, W. Eur. J. Org. Chem. 2008, 4178. The molecular structure of 4a
was further established by X-ray crystallography.
(8) Compound 7 is not dissolved in CCl
possible reason for the failure of the reaction of 7 in CCl
4
even at 50 °C, which is a
4
.
Org. Lett., Vol. 13, No. 19, 2011
5073

It should be noted that the corresponding 1,2-bromoalky-
nation product 9 was not detected at all. The presence of
compound 6 indicated that the exchange between iodide
and bromine ions would take place before the formation of
a
Table 2. Reaction Scope
1
,7-haliodoalkynation products. On the other hand, the
absence of compound 9 implied that the process of 1,
-iodoalkynation might not involve a similar exchange.
2
In CCI
4
In MeCN
Scheme 3. Proposed Mechanism
b
b
entry
R
4 (yield)
4:3
3 (yield)
3:4
1
2
3
4
5
6
7
8
9
Ph
4a (75%)
4b (73%)
4c (62%)
4d (58%)
4e (97%)
4f (65%)
4g (70%)
4h (52%)
4i (66%)
4j (31%)
4k (36%)
41 (58%)
98:2
99:1
3a (82%)
3b (75%)
3c (58%)
3d (61%)
3e (95%)
3f (64%)
3g (86%)
3h (58%)
3i (73%)
3j (41%)
3k (56%)
31 (64%)
97:3
99:1
96:4
92:8
99:1
96:4
98:2
97:3
96:4
80:20
81:19
98:2
4-Me-C
3-Me-C
6
H
H
4
6
4
88:12
89:11
94:6
4-MeO-C
6
H
4
2-Br-C
4-Br-C
6
H
4
6
H
4
91:9
4-Cl-C
4-F-C
6
H
4
97:3
6
H
4
97:3
2-thietyl
98:2
1
0
n-Bu
94:6
11
BnOCH
TMS
2
-
82:18
81:19
1
2
a
Reaction conditions: 1 (0.3 mmol), 2 (33.8 mg, 0.36 mmol), Pd(OAc)
6.8 mg, 0.03 mmol). Isolated yield. The ratio was determined according
2
b
(
to H NMR analysis (see Supporting Information).
1
Scheme 2. Extension of Reaction Scope
9
Recently, Jiang and co-workers reported a Pd(OAc) -
2
catalyzed iodoalkynation of alkyne, which is proposed to
be initiated by oxidative addition of Pd(OAc) to iodoalkyne,
2
1
0
leading to a key Pd(IV) intermediate. The present
iodoalkynation, however, is believed to be initiated by a
Pd(0) species based on the fact that the classic Pd(0)-
systems, such as the combination of Pd(OAc) and phos-
2
phine ligand as well as Pd(PPh ) , are proven to work well.
3
4
With the combination of the above-mentioned considera-
tions and observations, a proposed reaction mechanism is
present in Scheme 3. First, oxidative addition of the Pd(0)
species to iodoalkyne forms Pd(II)-acetylide intermediate A.
Then, the olefin of norbornene coordinates to the Pd(II)
center with its exo-face, which is followed by cis-insertion
to gerenate C with well-defined stereochemistry. The strong
effect of solvent on the reaction pathways inspired us to
postulate that intermediate C might be represented by an
equilibrium between inner form C1 and outer form C2
inhibited rearrangement imposed by the molecular struc-
ture, such as compound 7.
(Scheme 3). Inner form C1 is believed to have a neutral
palladium center while outer form C2 is a cationic palla-
dium species. Thus, C1 is overwhelming in a nonpolar
To obtain insight into the reaction mechanism, the
Pd(OAc) -catalyzed reaction of 1a and norbornene was
re-evaluated with LiBr (5 equiv) as an additive in MeCN
2
1
solvent (eq 1). The H NMR analysis of the reaction
(
9) Li, Y.; Liu, X.; Jiang, H.; Feng, Z. Angew. Chem., Int. Ed. 2010,
9, 3338.
10) Canty, A. J.; Rodemann, T.; Skelton, B. W.; White, A. H.
Organometallics 2006, 25, 3996.
4
mixture disclosed that 1,7-bromoalkylation product 6 was
yielded along with iodoalkylation products 4a and 3a.
(
5
074
Org. Lett., Vol. 13, No. 19, 2011

solvent, such as CCl , which undergoes reductive elimina-
4
mechanism lacks solid evidence, it does account for the
observed chemical outcome, especially the “abnormal”
1,7-iodoalkynation. Nevertheless, the exact catalytic me-
chanism still needs more investigation.
tion (RE) to form 1,2-alkynation product 4 with retention
1
1
of the stereochemistry (Scheme 3). In contrast, polar solvent,
such as MeCN, could stabilize the ionic species thus
rendering C2 as the majority. As a result, the correspond-
ing norbornene fragment becomes more positively charged
It should be mentioned that during our preparation of
this munascript, Jiang and co-workers have reported a
similar 1,7-bromoalkynation with the use of bromoalkyne
in MeCN at room temperature, which inspired us to
12
to initiate a nonclassical “norbornonium” rearrangement
via “bridging” palladium complex D, leading to intermedi-
ate E. Subsequently, the iodide ligand recoordinates to the
cation palladium center to form neutral palladium inter-
mediate F which undergoes a direct alkyl iodide RE to
yield 1,7-iodoalkynation product 3 and regenerates the
Pd(0) catalyst. It should be mentioned that no rearrange-
ment was observed in the case of Pd[P(t-Bu) ] -catalyzed
6
propose a similar mechanism depicted in Scheme 3. How-
ever, their selectivity is lower than ours, indicating that a
higher reaction temperature could promote “norborno-
nium” rearrangement.
In summary, we have reported the iodoalkynation of
norbornene with the use of iodoalkyne in the presence of a
simple palladium catalyst. This transformation is found to
be solvent-dependent. Nonpolar solvents favor 1,2-iodoalk-
ynation while polar solvents lead to unexpected 1,7-iodoalk-
ynation. The fact that the norbornene structure undergoes
facile “norbornonium” rearrangement might afford a reason-
able explanation for 1,7-iodoalkynation. Further investiga-
tions of the reaction mechanism and synthetic transforma-
tion are currently underway in our laboratory.
3
2
2
a
iodoaromatization of norbornene with aryl iodides. We
believed that the bulky ligand P(t-Bu) might enforce the
3
alkyl iodide RE to be more rapid, diminishing the possi-
bility of rearrangement. For the case of (iodoethynyl)alkyl
substrates, the coordination of an alkyne moiety to the
Pd(II) center may be present in intermediate C2. Thus, the
rearrangement might be partially inhibited, resulting in
lower selectivity (Table 2, entries 10 and 11). While the
(
11) The reductive elimination of organic halides from Pd(II) inter-
Acknowledgment. The financial support from NSFC
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Vigalok, A. Inorg. Chem. 2008, 47, 5. (d) Watson, D. A.; Su, M;
(
No. 21002025), the Fundamental Research Funds for
the Central Universities, Shanghai Rising-Star Program
11QA1401700), and Specialized Research Fund for the
(
Teverovskiy, G.; Zhang, Y.; Garcıa-Fortanet, J.; Kinzel, T.; Buchwald,
´
S. L. Science 2009, 325, 1661. (e) Shen, X.; Hyde, A. M.; Buchwald, S. L.
J. Am. Chem. Soc. 2010, 132, 14076. (f) Newman, S. G.; Lautens, M.
J. Am. Chem. Soc. 2010, 132, 11416.
Doctoral Program of Higher Education (20100074120014)
is highly appreciated.
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2, 1916. (b) Gultekin, D. D.; Taskesenligil, Y.; Dastan, A.; Balci, M.
Supporting Information Available. Experimental pro-
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pounds, as well as X-ray crystal data of compound 4a.
This material is available free of charge via the Internet at
http://pubs.acs.org.
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Org. Lett., Vol. 13, No. 19, 2011
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