Herrmann-Beller phosphapalladacycle-catalyzed addition of alkynes to norbornadienes

Article abstract of DOI:10.1021/ol061667e

(Chemical Equation Presented) Herrmann-Beller (H-B) phosphapalladacycle selectively catalyzed the addition of terminal alkynes across one double bond of norbornadiene to afford exo5-alkynyl-bicyclo[2.2.1]hept-2-enes. The reaction shows general applicabili

Full text of DOI:10.1021/ol061667e

ORGANIC
LETTERS
2006
Vol. 8, No. 19
4315-4318
Herrmann−Beller
Phosphapalladacycle-Catalyzed Addition
of Alkynes to Norbornadienes
Alphonse Tenaglia,* Laurent Giordano, and Ge´rard Buono
Laboratoire de Synthe`se Asyme´trique, UMR 6180 CNRS, UniVersite´ d’Aix-Marseille P.
Ce´zanne, Faculte´ des Sciences et Techniques de St Je´roˆme, EGIM, Case A62, AVenue
Escadrille Normandie Niemen, 13397 Marseille Cedex 20, France
alphonse.tenaglia@uniV-cezanne.fr
Received July 7, 2006
ABSTRACT
Herrmann−Beller (H−B) phosphapalladacycle selectively catalyzed the addition of terminal alkynes across one double bond of norbornadiene
to afford exo-5-alkynyl-bicyclo[2.2.1]hept-2-enes. The reaction shows general applicability to various functionalized alkynes and bicyclo[2.2.1]-
hepta-2,5-dienes. Insights into the mechanism of this reaction are discussed.
Palladacycles are recognized as important key intermediates
in numerous carbon-carbon (or carbon-heteroatom) bond-
forming processes1 and, as such, have been extensively
utilized as catalysts.2 Among these, phosphapalladacycles
have emerged as powerful catalysts, allowing the reactions
to proceed at low catalyst loading and high turnover numbers
(TON). For instance, Herrmann-Beller (H-B) phosphapal-
ladacycle 1 (Figure 1), readily available from tri-o-tolylphos-
phine and palladium acetate,3a is able to catalyze the Heck
or Suzuki couplings with TON up to 1,000,000.3 Generally,
these reactions are performed at high temperatures (>100
°C) and are believed to occur with decomposition of the
palladacycle, giving rise to highly reactive, coordinatively
unsaturated zerovalent palladium4 or ligand-free palladium
species.5 In contrast, carbon-carbon bond-forming reactions
under mild conditions are less common with palladacycles.
Herein, we describe the first palladium-catalyzed addition
of terminal acetylenes 3 across one double bond of norbor-
nadiene (NBD)6 2 (and related compounds) achieved under
mild conditions in the presence of 1 to afford 5-exo-alkynyl-
2-norbornenes 4 in fair to good yields.
Initial experiments, focused on the coupling of phenyl-
ethyne (3a) and alkenes (2 equiv) such as 1-hexene,
cyclopentene, or norbornene in the presence of Pd(OAc)2/
P(o-Tol)3 (5/10 mol %) in 1,2-dichloroethane (DCE) at 50
°C, proved disappointing, leading to a mixture of the known
linear and branched enynes resulting from the dimerization
of 3a.7 Since the coordination of an alkene to a metal center
in the presence of the alkyne is kinetically disfavored,8 the
coordination of more strained double bonds such as in
* To whom correspondence should be addressed. Fax: +33-491-282742.
(1) (a) Dyker, G.; Ko¨rning J.; Nerenz, F.; Siemsen, P.; Sostman, S.;
Wiegand, A. Pure Appl. Chem. 1996, 68, 323-326. (b) Dyker, G. Chem.
Ber./Recl. 1997, 130, 1967-1578. (c) Catellani, M. Synlett 2003, 298-
313.
(2) (a) Herrmann, W. A.; Bo¨hm, V. P. W.; Reisinger, C. P. J. Organomet.
Chem. 1999, 576, 23-41. (b) Poli, G.; Scolastico, C. Chemtracts 1999,
12, 643-655. (c) Speicher, A.; Shulz, T.; Eicher, T. J. Prakt. Chem. 1999,
341, 605-608. (d) Dupont, J.; Pfeffer, M.; Spencer, J. Eur. J. Inorg. Chem.
2001, 1917-1927. (e) Herrmann, W. A.; O¨ fele, K.; von Preysing, D.;
Schneider, S. K. J. Organomet. Chem. 2003, 687, 229-248. (f) Beller, M.;
Zapf, A.; Riemer, T. H. In Transition Metals for Organic Synthesis; Beller,
M., Bolm, C., Eds.; Wiley-VCH: Weinheim, 2004; Vol. 1, pp 274-281.
(g) Beletskaya, I. P.; Cheprakhov, A. V. J. Organomet. Chem. 2004, 689,
4055-4082. (h) Dupont, J.; Consorti, C. S.; Spencer, J. Chem. ReV. 2005,
105, 2527-2571.
Figure 1. Structure of Herrmann-Beller phosphapalladacycle
10.1021/ol061667e CCC: $33.50
© 2006 American Chemical Society
Published on Web 08/16/2006

norbornadiene 2, able to form η2 and/or η4 complexes without
increasing steric hindrance, was expected to compete favor-
ably. Effectively, transition metal-catalyzed cycloadditions
between alkynes and NBD are well-documented.9,10 Much
to our delight, the reaction of norbornadiene 2 and phenyl-
ethyne (3a) under similar conditions afforded a new adduct
4a (77%) as a single diastereomer and the self-coupling
products of 3a (e5-10%), which were easily removed by
chromatography (Scheme 1).11
catalyst after addition of petroleum ether and filtration from
the crude reaction mixture. The recovered complex proved
to be active without loss of efficiency.
The structure of the cycloadduct 4a was established by
1H and 13C NMR, and the exo stereochemistry of the alkynyl
group was assigned on the basis of the coupling patterns of
H-5 and H-6 protons (Figure 2) and the lowfield shielding
Scheme 1. Temperature Dependence of the Reaction of
Norbornadiene 2 and Phenylethyne (3a) Catalyzed with
Pd(OAc)2/P(o-Tol)3
Figure 2. 1H NMR (CDCl3, 500 MHz) Data of 4a and D-4a
of H-6ex with respect to H-6en as a result of the anisotropy
effect of the triple bond.
The NMR spectra reveal that addition of the terminal
alkyne occurred across one double bond of NBD and the
exo stereochemistry of the carbon-carbon bond formed was
deduced from NOESY experiments. One striking feature
supporting the stereochemical outcome of the reaction
becomes apparent after labeling the alkyne. exo-6-D-exo-5-
phenylethynyl-bicyclo[2.2.1]hept-2-ene D-(4a) (see Figure
2) was obtained in 92% yield from an excess of NBD and
2-D-phenylethyne D-(3a) under strictly anhydrous solvent-
free conditions (Supporting Information).
In contrast, the reaction performed at room temperature
led to only 25% of a 3:1 mixture of linear (L) and branched
(B) enynes in agreement with Trost’s observations.7 The
major feature of this new hydroalkynylation reaction rests
upon the nature of the catalyst. On performing the reaction
at 50 °C, phosphapalladacycle 1 generated in situ was the
key catalyst. More interestingly, the reaction carried out
without solvent with phosphapalladacycle 1 (2.5 mol %) and
a 10-fold molar excess of NBD allowed a quantitative
formation of 4a and the recovery of 60% of the loaded
The hydroalkynylation of NBD 2 with Herrmann-Beller
phosphapalladacycle 1 appears to be generally applicable to
a variety of alkynes, and the wide tolerance of the reaction
to functional groups is illustrated in Table 1. In these
(3) (a) Herrmann, W. A.; Brossmer, C.; O¨ fele, K.; Reisinger, C.-P.;
Priermeier, T.; Beller, M.; Fischer, H. Angew. Chem., Int. Ed. Engl. 1995,
34, 4, 1844-1848. (b) Beller, M.; Fischer, H.; Herrmann, W. A.; O¨ fele,
K.; Brossmer, C. Angew. Chem., Int. Ed. Engl. 1995, 34, 1848-1849.
(c) Beller, M.; Riermeier, T. H.; Haber, S.; Kleiner, H.-J.; Herrmann, W.
A. Chem. Ber. 1996, 129, 1259-1264. (d) Beller, M.; Riermeier, T. H.
Tetrahedron Lett, 1996, 37, 6535-6538. (e) Beller, M.; Riermeier, T. H.;
Reisinger, C.-P.; Herrmann W. A. Tetrahedron Lett. 1997, 38, 2073-2074.
(f) Riermeier, T.;. Zapf, H. A.; Beller, M. Top. Catal. 1997, 4, 301-309.
(g) Herrmann, W. A.; Brossmer, C.; Reisinger, C.-P.; Riermeier, T. H.;
O¨ fele, K.; Beller, M. Chem. Eur. J. 1997, 3, 1357-1364. (h) Herrmann,
W. A.; Bo¨hm, V. P. W. J. Organomet. Chem. 1999, 572, 141-145.
(4) Louie, J.; Hartwig, J. F. Angew. Chem., Int. Ed. Engl. 1996, 35, 2359-
2361.
(5) de Vries, A. H. M.; Mulders, J. M. C. A.; Mommers, J. H. M.;
Henderickx, H. J. W.; de Vries, J. G. Org. Lett. 2003, 5, 3285-3288.
(6) Norbornadiene is used for bicyclo[2.2.1]hepta-2,5-diene as a matter
of convenience.
(7) (a) Trost, B. M.; Chan, C.; Ru¨hter, G. J. Am. Chem. Soc. 1987, 109,
3486-3487. (b) Trost, B. M.; Sorum, M. T.; Chan, C.; Harms, A. E.; Ru¨hter,
G. J. Am. Chem. Soc. 1997, 119, 698-708.
(8) However, coordination of an alkene is favored when the latter is
connected to the alkyne; see: (a) Collman, J. P.; Hegedus, L. S.; Norton,
J. R.; Finke, R. G. Principles and Applications of Organotransition Metal
Chemistry; University Science Books: Mill Valley, 1987; pp 149-151.
(b) L. S. Hegedus, Transition Metals in the Synthesis of Complex Organic
Molecules; University Science Books: Mill Valley, 1994.
(9) [2 + 2] Cycloaddition: Mitsudo, T.; Naruse, H.; Kondo, T.; Ozaki,
Y.; Watanabe, Y. Angew. Chem., Int. Ed. Engl. 1994, 33, 580-581.
(10) [2 + 2 + 2] Cycloaddition: Lautens, M.; Lautens, J. C.; Smith, A.
C. J. Am. Chem. Soc. 1990, 112, 5627-5628 and references therein.
(11) Other complexes such as [PdCl(η3-(C3H5)]2, PdCl2(MeCN)2, and
Pd2(dba)3‚CHCl3 with or without PPh3 were inefficient.
1
conditions, the H NMR of the crude reaction mixtures
reveals the formation of a single cross-coupling adduct and
the alkyne self-coupling byproducts are only observed in few
cases.
The presence of functional groups such as ether, including
TBDMS ether, ester, carbonate, ketone, sulfone, tertiary
alcohol or amine, in the alkyne have no deleterious effects
on the reaction. A thiophenyl group at the propargylic
position turned out to be moderately tolerable, but the
reaction fails to proceed to completion (Table 1, entry 15).
Cross-coupling adduct 4o was obtained in 37% yield along
with unreacted 3o as an unseparable mixture.12 Whatever
the conditions (55 °C, 24 h or room temperature, 3 d), the
reaction stopped at about 50% conversion. Alkynes 3q and
3r bearing a free hydroxyl group also participate in coupling
with moderate yields (Table 1, entry 17 and 18). With prop-
2-ynol (3q), the self-coupling process competes favorably
and hex-2E-en-4-yne-1,6-diol (5)13 was obtained in 43% yield
along with the expected adduct 4q (44%) (Table 1, entry
17).14,15 In contrast, sterically demanding tertiary propargylic
alcohols such as 3s behave similarly to other alkynes,
(12) Attempts to purify 4o by distillation resulted in decomposition.
Org. Lett., Vol. 8, No. 19, 2006
4316

Scheme 2. Hydroalkynylation of Benzonorbornadiene 6 and
7-Oxa-benzonorbornadiene 7 with Trimethylsilylethyne (3d)
Table 1. Palladium-Catalyzed Addition of Alkynes 3 to
Norbornadiene 2a
temp (°C),
entry
alkyne
time (h) adduct yield (%)
1
2
3
4
5
6
7
8
9
3a R ) Ph
3b R ) n-C4H9
3c R ) 1-cyclohexen-1-yl
3d R ) SiMe3
3e R ) CH2OPh
3f R ) CH2OBn
3g R ) CH2OTBDMS
3h R ) CH2OAc
3i R ) CH(Me)OAc
55, 20
50, 20
45, 16
55, 16
50, 16
50, 16
50, 16
50, 16
50, 16
50, 15
50, 16
55, 16
4ab
4b
4cc
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4qe
4r
4s
90
72
87
93
80
95
95
67
63
91
70
92
82
90
37 (64)d
52
room temperature affording the expected adducts 8 or 9 in
good yields (Scheme 2).
Although the mechanisms involving Pd(IV)/Pd(II) or Pd-
(II)/Pd(0) intermediates from palladacycles as precatalysts
are still under debate, recent investigations on Heck-type
coupling,2a,18 amination,4 and allylic alkylation19 reactions
focused on Pd(0) species generated in situ from palladacycles
as active catalysts. It is important to note that these reactions
are carried out at high temperatures and require the presence
of base which plays a crucial role in generating the active
species. In contrast, the hydroalkynylation was performed
under neutral and mild conditions (45-55 °C) and even at
room temperature (Table 1, entries 17 and 18 and Scheme
2). In addition, the recovery of the phosphapalladacycle from
reactions carried out under solvent-free conditions suggest
that a Pd(II)/Pd(0) pathway is unlikely for the present
reaction. To probe such a pathway, experiments were
conducted with bis-allylic dicarbonate 10 able to perform
both the hydroalkynylation and/or the allylic alkylation under
neutral conditions.20 First, in the presence of Pd(PPh3)4 an
equimolar mixture of 10 and methyl malonate 11 afforded a
87:13 mixture of vinylcyclopropanes 12a and 12b in 77%
yield (Scheme 3). Second, an equimolar mixture of dicar-
10 3j R ) CH2CH2OAc
11 3k R ) CH2OCO2Me
12 3l R ) CH2CH(CO2Me)2
13 3m R ) CH2C(CO2Me)2(allyl) 50, 14
14 3n R ) CH2C(Me)2CH2Ac
15 3o R ) CH2SPh
16 3p R ) CH2SO2Ph
17 3q R ) CH2OH
18 3r R ) CH2CH2OH
19 3s R ) 1-hydroxycyclohexyl
20 3t R ) -CH2Mpf
50, 16
55, 24
45, 22
22, 96
22, 96
45, 16
45, 16
44
52
97
69
4t
a Reactions were carried out with 2.5% of 1 in 1,2-dichloroethane (0.125
M) based on alkyne, molar ratio 2/3/H-B cat. ) 2/1/0.025). b See text.
c Enyne 4c slowly polymerizes on standing in refrigerator. d Number in the
parenthesis refer to the yield based on recovered starting material (57%
conversion of 2o). e Hex-2E-en-4-yne-1,6-diol was also formed in 43% yield.
No significant change in products ratio was observed at higher temperatures.
f Mp ) morpholinyl (C4H8NO).
providing enyne 4s in excellent yield (Table 1, entry 19).
Applying these conditions to tertiary amine 3t allowed the
formation of enyne 4t in a satisfactory 69% yield (Table 1,
entry 20).
Scheme 3. H-B Palladacycle-Catalyzed Hydroalkynylation
versus Allylic Alkylation
Among the selectivity issues, the palladacycle 1 discrimi-
nates against unstrained cyclic or acyclic alkenes (see entries
3 and 13, Table 1), and most noteworthy, intramolecular
cyclization (cycloisomerization) of 1,6-enyne 3m is totally
precluded in contrast with Trost’s observations with electron-
deficient palladacycles.16 The fact that the hydroalkynylation
of norbornene fails under our conditions suggested that
through space interaction between the two double bonds of
norbornadiene is crucial for the coupling.17 Indeed, the
addition of trimethylsilylethyne (3d) to benzonorbornadiene
6 or 7-oxa-benzonorbornadiene 7 proceeded smoothly at
bonate 10, methyl malonate 11, and phenylethyne (3a) was
reacted at 50 °C for 18 h in the presence of 2.5 mol % of
(17) Mazzocchi, P. H.; Stahly, B.; Dodd, J.; Rondan, N. G.; Domelsmith,
L. N.; Rozeboom, M. D.; Caramella, P.; Houk, K. N. J. Am. Chem. Soc.
1980, 102, 6482-6490.
(13) Self-coupling of prop-2-ynol (3q) affording a mixture of linear and
branched conjugated enynes was reported using Wilkinson’s complex;
see: Schaefer, H.-A.; Marcy, R.; Rueping, T.; Singer, H. J. Organomet.
Chem. 1982, 240, 17-25.
(18) (a) Bo¨hm, P. V. W.; Herrmann, W. A. Chem. Eur. J. 2001, 7, 4191-
4197. (b) Whitcombe, N. J.; Hii, K. K.; Gibson, S. E. Tetrahedron 2001,
57, 7449-7476.
(14) No significant change in products ratio 4q/5 was observed at higher
temperatures.
(19) Poli, G.; Giambastiani, G.; Pacini, B. Tetrahedron Lett. 2001, 42,
5179-5182.
(20) (a) Tsuji, J. Tetrahedron 1986, 42, 4361-4401. See also: (b).
Brunel, J. M.; Maffei, M.; Muchow, G.; Buono, G. Eur. J. Org. Chem.
2000, 1799-1803. (c) Brunel, J. M.; Maffei, M.; Muchow, G.; Buono, G.
Eur. J. Org. Chem. 2001, 1009-1012.
(15) The homocoupling of propyn-2-ol (3q) needs the presence of NBD,
presumably as active ligand to stabilize reaction intermediates. In the absence
of NBD, no product was formed as a result of catalyst decomposition.
(16) Trost, B. M.; Tanoury, G. J. J. Am. Chem. Soc. 1987, 109, 4753-
4755.
Org. Lett., Vol. 8, No. 19, 2006
4317

phosphapalladacycle 1 in order to compete the hydroalky-
nylation with the allylic alkylation. In this experiment, the
hydoalkynylation adduct 13 was detected as the sole product
by 1H and 13C NMR analyses of the crude reaction mixture
and isolated in 88% yield (Scheme 3).
On the basis of these observations, Pd(0) species can be
ruled out under our conditions,21 and we propose a rationale
involving Pd(II) intermediates for the hydroalkynylation
(Scheme 4). The monomeric palladium(II) acetate A could
addition of a base such as DBU (1 molar equiv with respect
to 3a) or K2CO3 (as a 5 M aqueous solution; 1 molar equiv
with respect to 3a) to the reaction media shut down the
catalytic reaction.
To demonstrate the synthetic utility of alkynylnorbornenes,
compound 4a was transformed into 1,2,4-trisubstituted
cyclopentane 14 by catalytic dihydroxylation followed by
cleavage of the diol with NaIO4 in 63% overall yield (Scheme
5).
Scheme 5. Oxidative Cleavage of Adduct 4a to Trisubstituted
Cyclopentane 14
Scheme 4. Proposed Mechanism for the Herrmann-Beller
Phosphapalladacycle Catalyzed Hydroalkynylation of
Norbornadiene
In summary, the palladium-catalyzed addition of terminal
alkynes to one double bond of norbornadienes provides an
entry to exo-2-alkynyl-5-norbornenes using an operationally
simple procedure and a readily accessible catalyst.25 The
reaction exhibits extraordinary generality with respect to the
alkyne. This constitutes, to our knowledge, the first addition
of a C(sp)-H bond to a nonactivated isolated double bond
under neutral conditions.26 On the basis of the fact that
trimethylsilylethyne (3d) as well as alkynol 3s may be used
as ethyne equivalent, the opportunity to introduce any side
chain in 4 by further alkylation greatly enhances the scope
of such couplings. The interesting possibilities to develop
an enantioselective version of the hydroalkynylation with
chiral palladacycles is underway.
bind the alkyne 3 and undergo a concerted acetate assisted
deprotonation and palladium-carbon bond-forming reaction
to give alkynylpalladium(II) B. This will carbopalladate
norbornadiene 2 to form C, which undergoes protonolysis
to release the adduct 4 and the palladacycle A.22
The acetate ligand of the phosphapalladacycle 1 is crucial
to effect the coupling.23 Indeed, the chloropalladacycle
obtained by chlorine to acetate exchange3g showed no
catalytic activity under the usual conditions.24 We assume
that acetic acid plays an important role in the catalytic cycle
and this was demonstrated as follows. When D-3a and NBD
were reacted in the presence of AcOH (8 equiv with respect
to D-3a), no deuterium incorporation was detected in the
coupling product 4a, indicating an efficient intermolecular
scrambling. Conversely, when 3a and NBD were reacted in
the presence of AcOD (8 equiv with respect to D-3a), 4a
incorporated 50% of the deuterium. On the other hand, the
Acknowledgment. The authors would like to thank Dr.
I. De Riggi (EGIM, Universite´ P. Ce´zanne, Marseille) for
help with the NMR and the CNRS for financial support.
Supporting Information Available: Experimental pro-
cedures and characterization data of all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL061667E
(25) Typical Experimental Procedure. Norbornadiene 2 (184 mg, 2
mmol) and phenylethyne 3a (102 mg, 1 mmol) in DCE (6 mL) were added
to a solution of palladium catalyst 1 (23.5 mg, 0.025 mmol) in DCE (2
mL). The mixture was stirred at 55 °C for 20 h, cooled at room temperature,
and concentrated in vacuo. The crude product was purified by chromatog-
raphy on silica gel (hexanes) to yield 175 mg (90% yield) of exo-5-
(phenylethynyl)-2-norbornene (4a).
(26) To the best of our knowledge, the metal-catalyzed addition of the
Csp-H bond across the C-C double bond of allenes (a, b), 1, 3-butadiene
(c), or bicyclo[2.2.1]hepta-2, 5-diene (d) has been described. (a) Pd: Trost,
B. M.; Kottirsch, G. J. Am. Chem. Soc. 1990, 112, 2816-2818. (b) Rh:
Yamaguchi, M.; Omata, K.; Hirama, M. Tetrahedron Lett. 1994, 35, 5689-
5692. (c) Ru: Mitsudo, T.; Nakagawa, Y.; Watanabe, H.; Watanabe, K.;
Misawa, H.; Watanabe, Y. J. Chem. Soc., Chem. Commun. 1981, 496-
497. (d) Rh: Brunner, H.; Prester, F. Tetrahedron: Asymmetry 1990, 1,
587-588.
(21) The propensity to form η-1-allenylpalladium(II) complexes from
zerovalent palladium and propargyl acetate 3h or carbonate 3k also ruled
out Pd(0) species as active catalyst from 1.
(22) We thank one of the referees for useful comments regarding the
mechanism.
(23) Similar observations have been reported for the palladium-catalyzed
[2 + 1] cycloaddition of terminal alkynes with norbornenes. See: Bigeault,
J.; Giordano, L.; Buono, G. Angew. Chem., Int. Ed. 2005, 44, 4753-4757.
(24) For a pertinent review on the halide effects in transition-metal
catalysis, see: Fagnou, K,. Lautens, M. Angew. Chem., Int. Ed. 2002, 41,
26-47.
4318
Org. Lett., Vol. 8, No. 19, 2006