Suppressed β-hydride elimination in palladium-catalyzed cascade cyclization-coupling reactions: An efficient synthesis of 3-arylmethylpyrrolidines

Article abstract of DOI:10.1021/ol0056426

(formula presented) A novel type of palladium-catalyzed cascade cyclization-coupling reaction that proceeds with suppressed β-hydride elimination has been found. One of the N-sulfonyl oxygens is suggested to coordinatively stabilize an alkylpalladium inte

Full text of DOI:10.1021/ol0056426

ORGANIC
LETTERS
2000
Vol. 2, No. 9
1213-1216
Suppressed â-Hydride Elimination in
Palladium-Catalyzed Cascade
Cyclization−Coupling Reactions: An
Efficient Synthesis of
3-Arylmethylpyrrolidines
,†
Chi-Wan Lee, Kyung Seok Oh, Kwang S. Kim,* and Kyo Han Ahn*
Department of Chemistry and Center for Superfunctional Materials, Pohang UniVersity
of Science and Technology, San 31 Hyoja-dong, Pohang 790-784, Republic of Korea
ahn@postech.ac.kr
Received February 9, 2000
ABSTRACT
A novel type of palladium-catalyzed cascade cyclization−coupling reaction that proceeds with suppressed â-hydride elimination has been
found. One of the N-sulfonyl oxygens is suggested to coordinatively stabilize an alkylpalladium intermediate, thus preventing the intermediate
from the usual â-elimination. This is the first sequential palladium-catalyzed coupling reaction where the Suzuki and Heck reactions can
compete. The reaction provides an efficient synthetic route to 4-methylene-3-arylmethylpyrrolidines, which are not readily available by other
routes.
Transition metal catalyzed cross-coupling reactions have
emerged as powerful and versatile coupling methods avail-
able to us.1 Thanks to the recent developments of the
coupling reactions, traditionally difficult C-C bond-forming
reactions now become possible in many cases. The transition
metal catalyzed reactions, mostly palladium- or nickel-
catalyzed reactions, usually proceed under mild reaction
conditions and are tolerant of most functional groups. A
general mechanism of the metal catalyzed cross-coupling
reactions involves three stages: oxidative addition, trans-
metalation, and reductive elimination. One severe limitation
of the process is that the oxidative addition intermediate from
an alkyl halide that has â-hydrogen(s) is prone to undergo
â-hydride elimination. Therefore, the corresponding cou-
plings are limited to those substrates in which the elimination
is unfavorable owing to stereoelectronic reasons. Several
exceptions to this category have been recently overviewed.2
Negishi3 reported a palladium-catalyzed carbonylative cy-
clization in which the â-elimination is suppressed. It was
suggested that an adjacent carbonyl oxygen atom coordina-
tively stabilizes an alkylpalladium intermediate. Fast CO
insertion is also considered to be a contributing factor to the
success of the process, which proceeds prior to the decom-
position of the alkylpalladium intermediate. Oh4 and Meijere5
reported palladium-catalyzed cyclization reactions in which
cyclizations are preferred over the â-hydride elimination
routes. In both cases, explanations for the exceptions are left
(3) (a) Negishi, E.; Ma, S.; Amanfu, J.; Cope´ret, C.; Miller, J. A.; Tour,
J. M. J. Am. Chem. Soc. 1996, 118, 5919-5931. (b) Tour, J. M.; Negishi,
E. J. Am. Chem. Soc. 1985, 107, 8289-8291. (c) Cope´ret, C.; Negishi,
E.-i. Org. Lett. 1999, 1, 165-167.
(4) Oh, C. H.; Rhim, C. Y.; Kang, J. H.; Kim, A.; Park, B. S.; Seo, Y.
Tetrahedron Lett. 1996, 37, 8875-8878;
(5) Schweizer, S.; Song, Z.-Z.; Meyer, F. E.; Parsons, P. J.; de Meijere,
A. Angew. Chem., Int. Ed. 1999, 38, 1452-1454.
(6) Ishiyama, T.; Abe, S.; Miyaura, N.; Suzuki, A. Chem. Lett. 1992,
691-694.
† kim@postech.ac.kr.
(1) Metal-catalyzed Cross-coupling Reactions; Diederich, F., Stang, P.
J., Eds; Wiley-VCH: Weinheim, 1998.
(7) (a) Sole´, D.; Cancho, Y.; Llebaria, A.; Moreto´, J. M.; Delgado, A. J.
Am. Chem. Soc. 1994, 116, 12133-12134. (b) Sole´, D.; Cancho, Y.;
Llebaria, A.; Moreto´, J. M.; Delgado, A. J. Org. Chem. 1996, 61, 5895-
5904.
(2) Ca´rdenas, D. J. Angew. Chem., Int. Ed. 1999, 38, 3018-3020.
10.1021/ol0056426 CCC: $19.00 © 2000 American Chemical Society
Published on Web 04/14/2000

open. Suzuki reported palladium-catalyzed coupling reactions
between alkyl iodides and alkylboranes, although yields were
moderate.6 Delgado7 reported an interesting nickel-promoted
cascade cyclization-capture reaction in which the â-elimina-
tion was suppressed. They suggested that an N-benzyl
nitrogen atom coordinatively stabilizes an alkylnickel inter-
mediate. Recently, Knochel8 reported a more general nickel-
catalyzed cross-coupling reaction between alkyl halides and
diorganozincs. In this case, all the alkyl halides contain a
carbonyl, sulfide, or ethylene group that facilitates the
reductive elimination. In addition, a cocatalyst such as
m-(trifluoromethyl)styrene is suggested to promote the
reductive elimination. Also, nickel complexes generally react
faster with alkyl iodides than palladium species do. It would
be beneficial in utilizing the powerful coupling methods in
organic synthesis if we understood those factors that suppress
the undesired â-hydride elimination. Herein, we wish to
report a novel palladium-catalyzed cascade cyclization-
coupling reaction in which a possible â-hydride elimination
is suppressed. This finding has led to an efficient synthesis
of 3-arylmethylpyrrolidines.
two compounds were barely separable on TLC. One of the
compounds was identified as six-membered cyclic compound
3, which was confirmed later by an authentic sample. The
other was assigned to be pyrrole derivative 4, which was an
expected Heck product resulting from double bond migra-
tion.12 When the N-tosyl group in 1 was changed to the
N-benzyl (1b) or N-acetyl group (1c), poor results were
obtained. The results are summarized in Table 1.
Table 1. Pd-Catalyzed Cascade Cyclization-Coupling
Reactions
In the course of our study to synthesize pyrrolidine
analogues that might have serotonin 1A ligand activity,9 we
had a chance to treat N-allyl-N-(2-bromoallyl)-4-methylben-
zenesulfonate (1a)10 with 4-fluorophenylboronic acid in the
presence of a catalytic amount of Pd(PPh3)4 and aqueous
Na2CO3 in THF at 80 °C. The reaction mixture provided a
major compound, which was isolated and characterized to
be 3-(4-fluorobenzyl)-4-methylene-1-(p-toluenesulfonyl)pyr-
rolidine (2, R ) Ts). Apparently, the â-hydride elimination
is suppressed during the reaction. To confirm the generality
of this reaction, we used other phenylboronic acid derivatives
and could obtain the same type of reaction products, though
the yields were varied. Side products were diaryl compounds
of the arylboronic acids and a trace amount of an unknown
compound in all cases, except for 3-nitrophenylboronic acid
which showed a complex pattern on TLC.11 Notably, possible
intramolecular Heck reaction products were not observed.
A plausible reaction mechanism for the formation of
compounds 2-4 is depicted in Scheme 1. The first step
should involve an oxidative addition of Pd(0) to vinyl
bromide 1, giving Pd(II) intermediate 5. From vinylpalladium
5, two reaction pathways are expected: (1) a carbopalladation
route to give alkylpalladium intermediate 6; (2) a direct
Suzuki coupling process with an added arylboronic acid (5
f 7). The former route is apparently preferred over the latter
one in the case of substrate 1a because the direct Suzuki
coupling product 7 was not observed. For the success of the
cascade reaction, alkylpalladium intermediate 6 should
favorably undergo transmetalation with an arylboronic acid,
rather than undergo â-elimination, to produce intermediate
8, from which a fast reductive elimination ensures the
cascade reaction. We found that the cascade cyclization-
When n-butylboronic acid or a heteroarylboronic acid such
as 2-furanboronic acid was used, however, the cascade
cyclization-coupling product was not observed. Instead, a
mixture of cyclization products was obtained, along with
starting material 1a. A careful analysis of the cyclization
mixture by NMR spectroscopy indicated that it was com-
posed of two compounds that have no aryl moieties. The
(8) (a) Giovannini, R.; Stu¨demann, T.; Dussin, G.; Knochel, P. Angew.
Chem., Int. Ed. 1998, 37, 2387-2390. (b) Giovannini, R.; Knochel, P. J.
Am. Chem. Soc. 1998, 120, 11186-11187.
(9) Ahn, K. H.; Lee, S. J.; Lee, C.-H.; Hong, C. Y.; Park, T. K. Bioorg.
Med. Chem. Lett. 1999, 9, 1379-1384.
(10) Prepared from allylamine in two steps: (1) TsCl, Et3N, CH2Cl2, 25
°C, 100%; (2) 2,3-dibromo-1-propene, K2CO3, toluene, reflux, 91%.
(11) General procedure: To a stirred solution of vinyl bromide 1a (165
mg, 0.5 mmol) and Pd(PPh3)4 (29 mg, 0.025 mmol) in dry THF (6 mL)
was added 4-fluorophenylboronic acid (140 mg, 1.0 mmol) under N2,
followed by aqueous Na2CO3 (2 M, 1 mL), and the resulting mixture was
heated at 80 °C overnight. The mixture was cooled and poured into water
(30 mL); then it was extracted with CH2Cl2. The organic layer was dried
over MgSO4 and concentrated. Purification of the crude product by
chromatography on SiO2 (ethyl acetate-hexane as eluant) gave 3-(4-
fluorophenylmethyl)-4-methylene-N-(p-toluenesulfonyl)pyrrolidine in 92%
yield (159 mg).
1
coupling reaction is slow below 80 °C by VT H NMR
studies at temperature ranging from 20 to 80 °C. When we
carried out the same reaction with substrate 1a (R′ ) H) in
the absence of an arylboronic acid at 90 °C under otherwise
(12) Notably, the combined yield of the two compounds is significantly
different depending on the boronic acid used.
1214
Org. Lett., Vol. 2, No. 9, 2000

reaction results from a subtle balance between several
competing pathways.14 As in the above case, where the
intramolecular carbopalladation is slow, direct Suzuki cou-
pling can compete with it.
Scheme 1
As a possible origin of the suppressed â-elimination, we
propose a neighboring group coordination to the alkylpal-
ladium intermediate such as in 9, which is reminiscent of
Delgado’s nickel-catalyzed reaction.7 However, in our case,
N-sulfonyl oxygen(s), not the nitrogen, is believed to stabilize
the alkylpalladium intermediate. The nitrogen may coordinate
to the palladium in the case of N-benzyl analogue 1b, though
it seems less effective. A theoretical calculation on the
relative stability of the N- vs O-coordination in the case of
1a indicated that the latter mode leads to a more stable system
by 3.1 kcal/mol.15 When we changed the N-sulfonyl group
in 1 to the N-acetyl or N-Boc group, the cascade reaction
route became less favorable, as noted previously. Treatment
of vinyl bromide 1c with phenylboronic acid under the same
reaction conditions provided a rather complex reaction
mixture compared with the case of 1a.16 In the case of 1d,
an even more complex reaction pattern was observed. These
results suggest that, in both cases, the coordinative stabiliza-
tion is less favorable than that of the N-sulfonyl case, possibly
due to the strain that develops on the metal coordination.
We believe that this is one of the reasons why a similar
cascade reaction has not been observed in other related
cases.17
Apparently, ease of the transmetalation of an aryl group
from the boron to the palladium is also an important factor
that determines the product distribution. With arylboronic
acids that are comparatively reluctant to transmetalation,
alkylpalladium 6 can go back to the starting material, follow
the â-elimination route, or undergo the rearrangement route.
When the â-elimination route was blocked as in substrate
1a (R′ ) Me), the cascade cyclization-coupling reaction
with phenylboronic acid proceeded but with competition by
the rearrangement route in this case producing a mixture of
2 (R ) Ts, R′ ) Me) and 3 (R ) Ts, R′ ) Me) in a ratio of
7:3.18 Thus, the rearrangement route becomes favorable if
we introduce a substituent such as R′ that facilitates the
identical reaction conditions, the rearrangement product 3
(R ) Ts, R′ ) H) was produced in 20% yield, along with
36% of the starting material, and the expected Heck product
4 (R ) Ts) was only observable as a minor contaminant
(about 10%) of product 3 (R ) Ts, R′ ) H). Therefore, under
the reaction conditions, the rearrangement route is preferred
over the â-elimination route.
As noted previously, we could not observe the direct
Suzuki coupling product 7 in the case of vinyl bromide 1a.
When we extended the N-allyl group in 1a to an N-homoallyl
group as in N-(2-bromoallyl)-N-(but-3-enyl)-4-methylben-
zenesulfonate, however, the direct Suzuki coupling process
was observable. Thus, with 4-fluorophenylboronic acid under
the same reaction conditions, we could isolate the corre-
sponding Suzuki coupling product in 34% yield and a
mixture of intramolecular Heck reaction products in 58%
yield.13 In this case, the carbopalladation route is supposed
to be slower than the case of substrate 1a, probably because
it involves the formation of a six-membered ring rather than
a five-membered ring. These results indicate that the cascade
(15) The calculations were carried out at the HF/3-21G level using
Gaussian 94 (Frisch et al. Gaussian 94; Gaussian Inc.: Pittsburgh, PA,
1995).
(16) From the mixture, two major compounds were isolated and
characterized by NMR and mass analysis. One of the products was assigned
as the corresponding cascade reaction product (18% yield) and the other
was tentatively assigned as the direct Suzuki coupling product (9% yield).
In both products, an extensive double bond migration occurred probably
due to the acetyl group, which resulted in a mixture of isomeric products.
(17) For example, see: (a) de Meijere, A.; Bra¨se, S. J. Organomet. Chem.
1999, 576, 88-110. (b) Bra¨se, S.; de Meijere, A. Palladium-catalyzed
Coupling of Organyl Halides to AlkenessThe Heck Reaction. In Metal-
catalyzed Cross-coupling Reactions; Diederich, F., Stang, P. J., Eds.; Wiley-
VCH: Weinheim, 1998; pp 99-164. (c) Grotjahn, D. B.; Zhang, X. J. Mol.
Catal. A: Chem. 1997, 116, 99-107.
(18) Both products were barely separable on TLC; hence, the ratio was
1
(13) Because of the double bond isomerization, an isomeric mixture of
Heck products was observed, which were inseparable on TLC.
(14) The cascade cyclization-coupling reaction is different from the first
example of the tandem Heck-Suzuki reaction reported by Shibasaki and
co-workers (Kojuma, A.; Honzawa, S.; Boden, C. D. J.; Shibasaki, M.
Tetrahedron Lett. 1997, 38, 3455-3458). In our case, the first step is not
a complete Heck reaction but it involves a “Heck-type” carbopalladation
intermediate.
determined by H NMR analysis of the mixture. The isolated yield of the
mixture was 60% on the basis of the product ratio.
(19) For related rearrangements, see: (a) Owczarczyk, Z.; Lamaty, F.;
Vawter, E. J.; Negishi, E. J. Am. Chem. Soc. 1992, 114, 10091-10092. (b)
Grigg, R.; Sridharan, V. Tetrahedron Lett. 1992, 33, 7965-7968. (c) Grigg,
R.; Rasul, R.; Redpath, J.; Wilson, D. Tetrahedron Lett. 1996, 37, 4609-
4612. (d) Steinig, A. G.; de Meijere, A. Eur. J. Org. Chem. 1999, 1333-
1344.
Org. Lett., Vol. 2, No. 9, 2000
1215

elimination step from 11 to 3. In the absence of an
arylboronic acid, only product 3 (R ) Ts, R′ ) Me) was
obtained in 90% yield, starting from 1a (R′ ) Me) under
the same reaction conditions, as expected. Six-membered ring
compound 3 is presumably produced via cyclopropane-
methylpalladium 10.19
readily available by other routes in moderate to high yields.
Application to other substrates is under investigation.
Acknowledgment. K.H.A. thanks KOSEF for the inter-
disciplinary research program (1999-1-123-001-5). We thank
Professor A. de Meijere for kindly providing us reference
materials and helpful suggestions. This work was supported
by KISTEP (CRI).
In conclusion, we have presented a novel type of pal-
ladium-catalyzed cascade cyclization-coupling reaction that
proceeds with suppressed â-hydride elimination. The cascade
reaction has been found to be the result of a subtle balance
between various competing reaction pathways. The cascade
process provides 3-arylmethylpyrrolidines which are not
Supporting Information Available: Synthesis and char-
acterization of the vinyl substrates and the reaction products
mentioned including 2 and 3. This material is available free
of charge via the Internet at http://pubs.acs.org.
OL0056426
1216
Org. Lett., Vol. 2, No. 9, 2000