Controlling mode selectivity in palladium-catalyzed bisdiene carbocyclizations: Optimizing for cyclization-trapping over cycloisomerization

Article abstract of DOI:10.1021/ol035253m

[Equation presented] Screening combinations of five catalyst precursors with 13 phosphorus ligands identified cyclization catalysts that favor carbocyclization-trapping with N-hydroxyphthalimide over a competing cycloisomerization mode.

Full text of DOI:10.1021/ol035253m

ORGANIC
LETTERS
2003
Vol. 5, No. 20
3595-3598
Controlling Mode Selectivity in
Palladium-Catalyzed Bisdiene
Carbocyclizations: Optimizing for
Cyclization-Trapping over
Cycloisomerization
James M. Takacs,* Scott D. Schroeder, Jianxin Han, Meg Gifford, Xun-tian Jiang,
Twana Saleh, Suresh Vayalakkada, and Amy H. Yap
Department of Chemistry, UniVersity of Nebraska-Lincoln,
Lincoln, Nebraska 68588-0304
jtakacs1@unl.edu
Received July 7, 2003
ABSTRACT
Screening combinations of five catalyst precursors with 13 phosphorus ligands identified cyclization catalysts that favor carbocyclization-
trapping with N-hydroxyphthalimide over a competing cycloisomerization mode.
Efficient palladium-mediated carbocyclizations define a
variety of novel strategies for assembling structurally com-
plex ring systems.1 We are interested in palladium-catalyzed
reactions of 1,3-dienes,2,3 specifically, the intramolecular
reactions of acyclic substrates containing two 1,3-diene
moieties within their structure (i.e., bisdienes). Two of the
reaction modes exhibited by such substrates, (i) cyclization
with trapping by a pronucleophile4 and (ii) cycloisomerization
to a cyclized enediene,5 are particularly relevant to the present
study.
The cyclization-trapping and cycloisomerization modes
often compete, particularly in the case of substituted bis-
dienes. In the cyclization of 1, for example, the ratio of
cyclization-trapping product 2 to cycloisomerization product
3 varies widely (Table 1). The cyclization-trapping mode
can be favored by high concentration of trapping reagent or
by rendering the trapping agent intramolecular,6 and of
course, the cycloisomerization mode is favored in the absence
of trapping reagent. The goal of the present study is to find
a combination of a trapping reagent, catalyst precursor,
ligand, and reaction conditions that favors cyclization-
trapping with a synthetic equivalent to “OH” over bisdiene
cycloisomerization.
(1) Link, J. T. In Handbook of Organopalladium Chemistry for Organic
Synthesis; Negishi, E.-i., Ed.; Wiley Interscience: New York, 2002; Vol.
1, pp 1523-1559.
(2) Takacs, J. M. In Handbook of Organopalladium Chemistry for
Organic Synthesis; Negishi, E.-i., Ed.; Wiley Interscience: New York, 2002;
Vol. 1, pp 1579-1633.
A working model for the mechanism of the palladium-
catalyzed cyclization, one consistent with that proposed for
the related intermolecular 1,3-diene linear dimerization-
(3) Takacs, J. M.; Jiang, X.; Vayalakkada, S. Sci. Synth. 2002, 1, 63-
112.
(4) Takacs, J. M.; Zhu, J. J. Org. Chem. 1989, 54, 5193-5195.
(5) Takacs, J. M.; Clement, F.; Zhu, J.; Chandramouli, S. V.; Gong, X.
J. Am. Chem. Soc. 1997, 119, 5804-5817.
(6) Takacs, J. M.; Chandramouli, S. V. Tetrahedron Lett. 1994, 35,
9165-9168.
10.1021/ol035253m CCC: $25.00
© 2003 American Chemical Society
Published on Web 09/03/2003

Table 1. Competing Reaction Modes: Cyclization-Trapping
versus Cycloisomerization with ROH Trapping Reagents
trapping agent (conditions)
2:3
yield (%)
MeOH (as solvent)
90:10
70:30
30:70
0:100
90
68
72
92
H2O (Na2CO3, CO2, THF)
(p-MeOC6H4)CH2OH (THF)
TBDMSiOH (THF)
Figure 1. A mechanistic model, showing potential roles for the
counterion (X, catalyst precursor), ligand (L), and trapping agent
(R2OH).
trapping (telomerization) reactions,7,8 is shown in Figure 1.
Palladium(0)-mediated oxidative coupling of the bisdiene 4
to palladacycle 5 is followed by protonation. The proton is
presumably supplied by the trapping reagent to generate
intermediates such as 6 and/or 7. The two differ in that 6 is
cationic and complexed with ligand (L), whereas 7 is neutral
and associated with counterion X, not L. We reported that
cycloisomerization products likely arise via deprotonation
of 6 or 7,5,9 and thus, the tendencies of 6 and 7 to
preferentially add nucleophile or deprotonate is potentially
a key to controlling the cyclization mode.
Several reaction variables are likely to be particularly
important in partitioning between the two cyclization modes.
Cationic and neutral catalysts show significant differences
in the linear dimerization-trapping of butadiene.10,11 Thus,
the nature of the counterion and, by extension, the choice of
catalyst precursor (e.g., PdX2 or Pd(0)Ln) are important
variables. The nature and quantity of the ligand are equally
important in diene dimerizations.2,12 The trapping reagent
serves both as a proton donor and, afterward, either as a
nucleophile adding to the η3-allyl to afford the cyclization-
trapping product 8 or alternatively as a base, deprotonating
the η3-allyl to afford the cycloisomerization product 9.
The trapping reagent should possess a relatively low pKa
as the pronucleophile and be strongly nucleophilic as the
conjugate base. Once having added, it should not readily
revert to a π-allylpalladium(II) intermediate via oxidative
addition, and it must be easily deprotected to afford the
desired allylic alcohol. A number of trapping reagents were
screened under the (then) standard reaction conditions (0.1
[Pd(OAc)2/2PPh3], THF, 65 °C, 12 h). N-Hydroxyphthal-
imide (10, NHP) emerged as a promising candidate. Its
reaction with bisdiene 11 gives the cyclized-trapped product
12 in about 50% yield in several solvents (65 °C, 4 h). At
the time of our studies, the use of NHP had not been reported
in diene dimerization-trapping reactions or in palladium-
catalyzed allylic substitution reactions. Takemoto recently
reported palladium-catalyzed O-allylic substitutions of other
hydroxylamine derivatives bearing an N-electron-withdraw-
ing substituent.13
Using 11 (bisdiene substrate), NHP (trapping reagent), and
1:1 THF/acetonitrile (solvent), the catalyst precursor and
ligand were varied in a parallel optimization mode (Figure
2). Five catalyst precursors were selected, (Pd(OAc)2, Pd-
(TFA)2, Pd(acac)2, Pd(hfa)2 (hfa ) hexafluoroacetyl aceto-
nate), and Pd2(dba)3. With the exception of Pd(hfa)2, each
had frequently been used in bisdiene carbocyclizations or
diene linear dimerizations. Thirteen phosphorus ligands,
spanning a wide range of steric and electronic characteristics,
were selected for screening (Figure 2, A-M).
Many of the ligands selected had previously been used to
effect bisdiene carbocyclizations or diene dimerizations (e.g.,
tricyclohexylphosphine (A),14 triphenylphosphine (B), tri(o-
tolyl)phosphine (C), tris(2,4,6-trimethoxy-phenyl) phosphine
(D),15 tri(o-tolyl) phosphite (G),16 2′-(diphenylphosphino)-
N,N-dimethyl-[1,1′-biphenyl]-2-amine (K)10). Others are
included for various reasons. In the absence of trapping
reagent, tri(2-furanyl)phosphine (F) does not efficiently
(7) Jolly, P. W.; Mynott, R.; Raspel, B.; Schick, K. P. Organometallics
1986, 5, 473-481.
(8) Vollmuller, F.; Krause, J.; Klein, S.; Magerlein, W.; Beller, M. Eur.
J. Inorg. Chem. 2000, 1825-1832.
(13) Miyabe, H.; Yoshida, K.; Matsumura, A.; Yamauchi, M.; Takemoto,
Y. Synlett 2003, 567-569.
(9) Takacs, J. M.; Lawson, E. C.; Clement, F. J. Am. Chem. Soc. 1997,
119, 5956-5957.
(14) Benvenuti, F.; Carlini, C.; Lami, M.; Marchionna, M.; Patrini, R.;
Raspolli Galletti, A. M.; Sbrana, G. J. Mol. Catal. A: Chem. 1999, 144,
27-40.
(10) Basato, M.; Crociani, L.; Benvenuti, F.; Galletti, A. M. R.; Sbrana,
G. J. Mol. Catal. A: Chem. 1999, 145, 313-316.
(11) Bouachir, F.; Grenouillet, P.; Neibecker, D.; Poirier, J.; Tkatchenko,
I. J. Organomet. Chem. 1998, 569, 203-215.
(15) Maddock, S. M.; Finn, M. G. Organometallics 2000, 19, 2684-
2689.
(12) For example, see: Vollmuller, F.; Magerlein, W.; Klein, S.; Krause,
J.; Beller, M. AdV. Synth. Catal. 2001, 343, 29-33 and references therein.
(16) Rodriguez, A.; Nomen, M.; Spur, B. W.; Godfroid, J.-J.; Lee, T.
H. Eur. J. Org. Chem. 2000, 2991-3000.
3596
Org. Lett., Vol. 5, No. 20, 2003

Figure 2. The palladium-catalyzed cyclization of bisdiene 11 with NHP. HPLC yields of cyclization-trapping product 12 as a function of
ligand (ligands A-M; NL ) no added ligand) and catalyst precursor (Pd(OAc)2, Pd(TFA)2, Pd(acac)2, Pd(hfa)2, Pd2(dba)3).
promote (the undesired) bisdiene cycloisomerization.5 (2,4-
Di-tert-butylphenyl) phosphite (H, DTBPP), triisopropyl
phosphite (I), and 2-(di-tert-buylphosphino)biphenyl (J) form
catalysts exhibiting high turnover numbers in palladium-
catalyzed cross-coupling reactions.17,18 2-(Diphenylphosphi-
no)pyridine (L) is included because several P,N-ligands form
very active catalysts for the reaction of butadiene with
methanol.19 Diphosphines are occasionally used in diene
dimerizations,14 and one chelating diphosphine (M, dppe)
is included. Each catalyst precursor is also screened in
the absence of added ligand (Figure 2, NL ) no ligand
added).
are the least successful catalyst precursors. Eight ligands
in the screening set (those highlighted in red) give at least
one catalyst yielding 50% or greater. The combination
of Pd(acac)2 and Ph3P gives the overall highest yield
(80%).
The substituted bisdiene 14a was prepared. Its reaction
with NHP using the old standard catalyst system, i.e., [Pd-
(OAc)2/2 PPh3], gives the cyclized-trapped product 15a in
only 10% yield; the major product is 16. The cyclization-
trapping of bisdiene 14a with NHP was screened using all
combinations of the three best catalyst precursors (Pd(OAc)2,
Pd(acac)2, Pd2(dba)3) and six of the best ligands (A, B, F,
H, I, K). The results are shown graphically in Figure 3. The
yield of 15a varied widely. Nonetheless, four combinations
give HPLC yields greater than 60%; three of these employed
DTBPP (H), a ligand that had not been previously been used
in palladium-catalyzed bisdiene carbocyclizations.
The results of the parallel optimization study are sum-
marized graphically in Figure 2.20 The reaction is surprisingly
sensitive to the precise combination of catalyst precursor and
ligand. Few trends are apparent. Pd(hfa)2 and Pd(OTFA)2
(17) Zapf, A.; Beller, M. Chem. Eur. J. 2000, 6, 1830-1833.
(18) Vogl, E. M.; Buchwald, S. L. J. Org. Chem. 2002, 67, 106-111.
(19) Benvenuti, F.; Carlini, C.; Marchionna, M.; Patrini, R.; Raspolli
Galletti, A. M.; Sbrana, G. J. Mol. Catal. A: Chem. 1999, 140, 139-155.
(20) The series was carried out twice, first by two students working as
a team and then repeated (albeit with a few substitute ligands) by a third
student. Although the absolute yields varied (ca. (5%), the trends were
quite consistent between the runs. The second data set are shown in Figure
2.
The combination of Pd2(dba)3 and DTBPP was studied
further. In THF or acetonitrile alone the yield is lower than
in the 1:1 solvent mixture. A 2:1 L:Pd ratio was used the
screening experiments, but the [Pd2(dba)3/DTBPP] catalyst
is insensitive to L:Pd ratios ranging from 1:1 to 10:1.
Although the screening reactions were run at 65 °C (4 h),
Org. Lett., Vol. 5, No. 20, 2003
3597

Figure 3. The palladium-catalyzed cyclization of bisdiene 14a with
NHP. HPLC yields as a function of ligand (A, B, F, H, I, K) and
catalyst precursor (Pd(OAc)2, Pd(acac)2, Pd2(dba)3).
Figure 4. The crystal structure of 15d and its conversion to allylic
alcohol 17 and the hydroxylamine derivative 18.
the [Pd2(dba)3/DTBPP] catalyst proceeds readily at room
temperature (3 h). With this modest refinement, bisdienes
14a-e give products 15a-e in 67-90% yield (Table 2).
trapping reagent; O-allyl hydroxylamines are themselves
useful functionalities22 and 18 is readily obtained by treatment
with N-methylamine.23,24
Palladium-catalyzed bisdiene carbocyclizations proved
very sensitive to the choice of catalyst precursor, ligand, and
reaction conditions. Using a parallel optimization strategy
we achieved our goal of obtaining good yields of cyclized-
trapped products from substituted bisdienes. The conditions
obtained from optimizing a simple substrate provided a useful
starting point for the more complicated one. The catalyst
system identified via screening gives good preparative yields
for five related bisdienes. Further studies into the reasons
for its success are in progress.
Table 2. Preparative Cyclization-Trapping of Bisdienes 14a-e
compound
R1
R2
yield (%)
15a
15b
15c
15d
15e
Me
i-Pr
i-Pr
Bn
n-C5H11
n-C5H11
Me
n-C5H11
Me
68
79
90
67
86
Acknowledgment. Support from the NIH (GM34927) is
gratefully acknowledged. We thank Dr. Joanna Clark for
obtaining the crystal structure of 15d, the NSF (CHE-
0091975) and the UNL Center for Materials Research and
Analysis for purchase of the diffractometer, and the NIH
(SIG-1-510-RR-06307) and NSF (CHE-0091975) for pur-
chase of NMR spectrometers used in this work.
Bn
Three new tetrahedral stereocenters and a disubstituted
alkene are formed in the cyclization of bisdiene 14. Thus,
16 diastereomers of 15 are possible, but essentially one is
formed. Compound 15d crystallized readily, and its crystal
structure is shown in Figure 4. A regioisomer, wherein the
NHP moiety is allylically transposed, is also formed (10 (
5%). The allylic alcohol 17 (78%) is obtained by cleavage
of the N-O bond with Mo(CO)6 using a modification of
the procedure by Goti.21 NHP has an added benefit as a
Supporting Information Available: Procedures and
spectral data for 14a-e, 15a-e, 17, and 18 and details for
the crystal structure of 15d. This material is available free
of charge via the Internet at http://pubs.acs.org.
OL035253M
(22) Bates, R. W.; Sa-Ei, K. Org. Lett. 2002, 4, 4225-4227.
(23) Karpeisky, A.; Gonzalez, C.; Burgin, A. B.; Beigelman, L.
Tetrahedron Lett. 1998, 39, 1131-1134.
(21) Cicchi, S.; Goti, A.; Brandi, A.; Guarna, A.; Desarlo, F. Tetrahedron
Lett. 1990, 31, 3351-3354.
(24) Fischer, E.; Zinner, G. Chem.-Z. 1979, 103, 371-372.
3598
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