Influence of biaryl phosphine structure on C-N and C-C bond formation

Article abstract of DOI:10.1021/ja902679b

In order to understand how electronic and other structural characteristics of biphenyl phosphine ligands affect Pd-catalyzed C-N and C-C bond-forming reactions, a new ligand, 2-(dicyclohexylphosphino)-4′-(N,N-dimethylamino)- 1,1′-biphenyl, was synthesized. This compound is isomeric with the commercially available 2-(dicyclohexylphosphino)-2′-(N,N-dimethylamino)-1, 1′-biphenyl that has been useful in C-N bondforming reactions of nucleosides. The new p-dimethylamino biphenyl ligand bears electronic similarities to the o-dimethylamino isomer, but it also possesses structural similarities to 2-(dicyclohexylphosphino)biphenyl, such as the unsubstituted ortho positions in the non-phosphine ring. Whereas 2-(dicyclohexylphosphino)- biphenyl can support catalysts for C-C bond formation, it was not effective in promoting aryl amination of a nucleoside substrate. However, the new ligand proved to be effective in promoting both aryl amination and C-C bond-forming reactions of nucleoside substrates, with some reactions even occurring at room temperature. Thus, the composite structural elements of this new ligand are thought to be criteria for reactivity of the catalytic system derived from it. We have probed the structures of the isomeric N,N-dimethylamino biphenyl ligands by X-ray crystallographic analysis. Interactions of the two ligands with Pd(OAc)₂ have been investigated by ³¹P NMR, and they show substantial stoichiometry-dependent differences. These results have been compared to the interactions of Pd(OAc)₂ with 2- (dicyclohexylphosphino)biphenyl as well as 2-(di-tert-butylphosphino)biphenyl, and they reveal marked differences as well. In this process, three cyclopalladated biaryl derivatives have been isolated and characterized by X-ray analysis.

Full text of DOI:10.1021/ja902679b

Published on Web 08/05/2009
Influence of Biaryl Phosphine Structure on C-N and C-C
Bond Formation
Ramendra Pratap,† Damon Parrish,‡ Padmaja Gunda,† D. Venkataraman,§ and
Mahesh K. Lakshman*,†
Department of Chemistry, The City College and The City UniVersity of New York, 160 ConVent
AVenue, New York, New York 10031, NaVal Research Laboratory, Code 6030, 4555 OVerlook
AVenue, Washington, D.C. 20375, and Department of Chemistry, UniVersity of Massachusetts
Amherst, 710 North Pleasant Street, Amherst, Massachusetts 01003
Received April 3, 2009; E-mail: lakshman@sci.ccny.cuny.edu
Abstract: In order to understand how electronic and other structural characteristics of biphenyl phosphine
ligands affect Pd-catalyzed C-N and C-C bond-forming reactions, a new ligand, 2-(dicyclohexylphosphino)-
4′-(N,N-dimethylamino)-1,1′-biphenyl, was synthesized. This compound is isomeric with the commercially
available 2-(dicyclohexylphosphino)-2′-(N,N-dimethylamino)-1,1′-biphenyl that has been useful in C-N bond-
forming reactions of nucleosides. The new p-dimethylamino biphenyl ligand bears electronic similarities to
the o-dimethylamino isomer, but it also possesses structural similarities to 2-(dicyclohexylphosphino)biphenyl,
such as the unsubstituted ortho positions in the non-phosphine ring. Whereas 2-(dicyclohexylphosphino)-
biphenyl can support catalysts for C-C bond formation, it was not effective in promoting aryl amination of
a nucleoside substrate. However, the new ligand proved to be effective in promoting both aryl amination
and C-C bond-forming reactions of nucleoside substrates, with some reactions even occurring at room
temperature. Thus, the composite structural elements of this new ligand are thought to be criteria for reactivity
of the catalytic system derived from it. We have probed the structures of the isomeric N,N-dimethylamino
biphenyl ligands by X-ray crystallographic analysis. Interactions of the two ligands with Pd(OAc)2 have
been investigated by 31P NMR, and they show substantial stoichiometry-dependent differences. These
results have been compared to the interactions of Pd(OAc)2 with 2-(dicyclohexylphosphino)biphenyl
as well as 2-(di-tert-butylphosphino)biphenyl, and they reveal marked differences as well. In this pro-
cess, three cyclopalladated biaryl derivatives have been isolated and characterized by X-ray anal-
ysis.
Introduction
develop applications of Pd catalysis for modifying the biologi-
cally venerable nucleosides via C-N (aryl amination)3-10 and
Methodological advances in Pd-catalyzed amination1 and
cross-coupling with boronic acids2 have contributed significantly
to contemporary organic synthesis. In the context of generating
biomolecular diversity, we have sought to understand and
C-C (Suzuki-Miyaura)3,6,9,11-13 bond-forming reactions. In
(3) For reviews see: (a) Lakshman, M. K. Curr. Org. Synth. 2005, 2,
83–112. (b) Lakshman, M. K. J. Organomet. Chem. 2002, 653, 234–
251.
† The City College and The City University of New York.
‡ Naval Research Laboratory.
(4) Champeil, E.; Pradhan, P.; Lakshman, M. K. J. Org. Chem. 2007, 72,
5035–5045.
§ University of Massachusetts Amherst.
(1) For some reviews on amination, see: (a) Surry, D.; Buchwald, S. L.
Angew. Chem., Int. Ed. 2008, 47, 6338–6361. (b) Schlummer, B.;
Scholz, U. AdV. Synth. Catal. 2004, 346, 1599–1626. (c) Muci, A. R.;
Buchwald, S. L. Top. Curr. Chem. 2002, 219, 131–209. (d) Prim, D.;
Campagne, J.-M.; Joseph, D.; Andrioletti, B. Tetrahedron 2002, 58,
2041–2075. (e) Hartwig, J. F. Palladium-Catalyzed Amination of Aryl
Halides and Sulfonates. In Modern Amination Methods; Ricci, A., Ed.;
Wiley-VCH: New York, 2000; pp195-262. (f) Hartwig, J. F. Acc.
Chem. Res. 1998, 31, 852–860. (g) Wolfe, J. P.; Wagaw, S.; Marcoux,
J.-F.; Buchwald, S. L. Acc. Chem. Res. 1999, 31, 805–818. (h) Yang,
B. H.; Buchwald, S. L. J. Organomet. Chem. 1999, 576, 125–146. (i)
Frost, C. G.; Mendonc¸a, P. J. Chem. Soc., Perkin Trans. 1 1998, 2615–
2623.
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Ed. 2006, 45, 3660–3663.
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12240 J. AM. CHEM. SOC. 2009, 131, 12240–12249
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Biaryl Phosphine Structure and C-N as Well as C-C Reactions
A R T I C L E S
Scheme 1. Synthesis of 2-(Dicyclohexylphosphino)-4′-
(N,N-dimethylamino)-1,1′-biphenyl (L4)
Figure 1. Biaryl phosphine ligands that have been studied for nucleoside
modification.
our work3-13 as well as those of other groups,14-16 finding
effective catalysts for transformations of complex nucleoside
substrates has been an important consideration. From our studies,
among the cyclohexyl and tert-butyl biaryl phosphine ligands
L1-L3, unsubstituted L1 (Figure 1) was observed to yield a
highly efficient catalyst for C-C bond formation in conjunction
with a Pd source.6,9,11-13 On the other hand, combinations of
L3 and Pd provided effective amination catalysts.6,8-10 How-
ever, in some preliminary experiments, L1 had not produced
an effective amination catalyst, and L2 has thus far not been
effective for reactions involving nucleosides.
On the basis of our prior results, we wanted to investigate
the structure-reactivity properties of these ligands, and we
queried whether combining the structural features of L1 and
L3 would produce a more general ligand useful for both C-N
and C-C bond-forming reactions of nucleosides. In this event,
comparison of the new ligand to commercially available L3
would also be possible. We reasoned that L4, with the
p-dimethylamino group, would have the electronic components
of L3 needed for C-N bond formation (e.g., the increased
electron density in the aromatic ring) while incorporating other
structural features of L1 that may be needed for C-C cross-
coupling, such as the unsubstituted ortho positions in the non-
phosphine ring. This paper reports the synthesis and evaluation
of this new ligand L4 for C-N and C-C cross-coupling
reactions. In addition, we compare the interactions of these
ligands with Pd(OAc)2 and report the X-ray crystal structures
of L3 and L4 as well as palladated complexes of L1, L2, and
L4.
Results and Dicussion
From a synthetic standpoint, L4 can be readily prepared in
two steps from commercially available p-(dimethylamino)phe-
nylboronic acid (Scheme 1) by methods that parallel the
synthesis of L3.17 With L4 in hand, initial studies were directed
at first ascertaining whether it was capable of enabling C-N
and C-C bond formation among simpler substrates and second
comparing the efficiency of catalysts derived from L4 to those
derived from L3. For this, we chose to primarily evaluate aryl
chlorides that are typically difficult substrates. The results from
these reactions are shown in Table 1 (in each case, the conditions
used parallel those reported,17 except that L4 was used in place
of L3).
From these experiments, it became clear that L4-supported
catalysts were active and that their productivity was generally
comparable to those derived from L3 for the reactions of the
aryl halides assessed. We next chose to examine the efficiency
of catalysts supported by L4 in comparison to L3 with
nucleoside substrates that generally possess more complex
reactivities. For this we selected the O6-(4-methylphenyl)sulfonyl
derivative of 2′-deoxyguanosine (2),18 a system we have
previously studied.6,12 The results from the aryl amination of 2
are shown in Table 2.
(14) For reviews, see: (a) Agrofoglio, L. A.; Gillaizeau, I.; Saito, Y. Chem.
ReV. 2003, 103, 1875–1916. (b) Hocek, M. Eur. J. Org. Chem. 2003,
245–254.
We first ascertained that, in these reactions, SNAr displace-
ment was not competitive with a catalyzed reaction, and as
anticipated no product formation was observed in the absence
of Pd(OAc)2. In the reaction involving L1 (devoid of the
dimethylamino group), no product formation was observed
(entries 1 and 8), consistent with our preliminary observations.
However, in each case L3 and L4 yielded catalysts that led to
successful amination. From these results it appears that, for an
effective amination catalyst, the electronic influence of the
dimethylamino group on the ligand is important but its location
is less critical. Under these reaction conditions and in side-by-
side comparisons, L4 emerged as at least comparable to, and
in some instances superior to L3. Thus, subtle differences in
the reactivities of catalysts derived from L1, L3, and L4 become
clearer in the reactions of the more complex substrate 2.
We then became interested in studying the effectiveness of
L3 and L4 in C-C bond-forming reactions with arylboronic
acids. For this two substrates were selected, the 6-bromo
nucleoside 4 and the O6-(2,4,6-trimethylphenyl)sulfonyl deriva-
tive of 2′-deoxyguanosine 5. We have previously shown that
L1/Pd(OAc)2 yields a highly effective catalytic complex, capable
of C-C bond-forming reactions with 5 under mild conditions
(15) For examples on Pd-catalyzed amination reactions of nucleosides, see:
(a) Bo¨ge, N.; Jacobsen, M. I.; Szombati, Z.; Baerns, S.; Di Pasquale,
F.; Marx, A.; Meier, C. Chem.sEur. J. 2008, 14, 11194–11208. (b)
Takamura-Enya, T.; Enomoto, S.; Wakabayashi, K. J. Org. Chem.
2006, 71, 5599–5606. (c) Bonala, R. R.; Torres, M. C.; Attaluri, S.;
Iden, C. R.; Johnson, F. Chem. Res. Toxicol. 2005, 18, 457–465. (d)
Stover, J. S.; Rizzo, C. J. Org. Lett. 2004, 6, 4985–4988. (e) Elmquist,
C. E.; Stover, J. S.; Wang, Z.; Rizzo, C. J. J. Am. Chem. Soc. 2004,
126, 11189–11201. (f) Chakraborti, D.; Colis, L.; Schneider, R.; Basu,
A. K. Org. Lett. 2003, 5, 2861–2864. (g) Gillet, L. C. J.; Sha¨rer, O. D.
Org. Lett. 2002, 4, 4205–4208. (h) Schoffers, E.; Olsen, P. D.; Means,
J. C. Org. Lett. 2001, 3, 4221–4223. (i) De Riccardis, F.; Johnson, F.
Org. Lett. 2000, 2, 293–295. (j) Harwood, E. A.; Hopkins, P. B.;
Sigurdsson, S. T. J. Org. Chem. 2000, 65, 2959–2964.
(16) For examples on Pd-catalyzed Suzuki-Miyaura reactions of nucleo-
sides, see: (a) Jacobsen, M. F.; Ferapontova, E. E.; Gothelf, K. V.
Org. Biomol. Chem. 2009, 7, 905–908. (b) Hobley, G.; Gubala, V.;
Del, C.; Rivera-Sa´nchez, M.; Rivera, J. M. Synlett 2008, 1510–1514.
ˇ
(c) Capek, P.; Hocek, M. Synlett 2005, 3005–3007. (d) Hocek, M.;
Nausˇ, P.; Pohl, R.; Votruba, I.; Furman, P. A.; Tharnish, P. M.; Otto,
M. J. J. Med. Chem. 2005, 48, 5869–5873. (e) Ferna´ndez, F.; Garc´ıa-
Mera, X.; Morales, M.; Vilarin˜o, L.; Caaman˜o, O.; De Clercq, E.
Tetrahedron 2004, 60, 9245–9253. (f) Western, E. C.; Daft, J. R.;
Johnson, E. M., II; Gannett, P. M.; Shaughnessy, K. H. J. Org. Chem.
2003, 68, 6767–6774. (g) Amann, N.; Wagenknecht, H.-A. Synlett
2002, 687–691. (h) Hocek, M.; Holy´, A.; Votruba, I.; Dvorˇa´kova´, H.
J. Med. Chem. 2000, 43, 1817–1825. (i) Havelkova´, M.; Hocek, M.;
ˇ
Cesnek, M.; Dvorˇa´k, D. Synlett 1999, 1145–1147.
(18) (a) Nagatsugi, F.; Uemura, K.; Nakashima, S.; Maeda, M.; Sasaki, S.
Tetrahedron 1997, 53, 3035–3044. (b) Hayakawa, Y.; Hirose, M.;
Noyori, R. J. Org. Chem. 1993, 58, 5551–5555.
(17) Old, D. W.; Wolfe, J. P.; Buchwald, S. L. J. Am. Chem. Soc. 1998,
120, 9722–9723.
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A R T I C L E S
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Table 1. Comparison of C-N as well as C-C Bond Formation Using Catalysts Derived from L3 and L4a
a Reactions were conducted under conditions previously reported,17 except that L4 was used in place of L3. b Yields reported are of isolated and
purified products. c Yield reported in ref 17 using L3. d A comparable result was obtained at 100 °C.
and at room temperature.11,12 On the other hand, reactions of 4
at room temperature have not been evaluated. The results from
the experiments on these two substrates are shown in Table 3.
As can be seen from Table 3, in reactions of bromo nucleoside
4, catalysts derived from both L3 and L4 perform well at
elevated temperatures. However, L4 performs admirably in
room-temperature reactions (entries 2, 7, and 11). In comparison
to bromo nucleoside 4, the nucleoside aryl sulfonate 5 appears
to be a more difficult substrate for C-C bond formation,
requiring elevated temperature for complete reactions (incom-
plete reactions of PhB(OH)2 were observed with L3 and L4
over 24 h at room temperature). We have previously shown
that 2:1 L1/Pd(OAc)2 is excellent for reactions of 5 at room
temperature.12 In the current analysis, the presence of the
dimethylamino group, even at the para position, was found to
diminish catalytic efficiency. Nevertheless, in every reaction
involving substrate 5, L4, which bears two vacant ortho positions
like L1, was superior to L3 under the conditions utilized, and
these reactions include the electron-deficient (entry 17) as well
as the ortho-substituted arylboronic acids (entry 19).
lographic data (Figure 2).20 In the solid state, the angle between
the two aryl rings is about 66° in L3, whereas in L4 this angle
is smaller, about 55°. In both cases the phosphorus lone pair is
directed toward the amino group-substituted aromatic ring, as
reported for other biaryl phosphines.21 A planarization at the
nitrogen atom in L4 is observed, indicating conjugation of its
electron pair with the aromatic ring. If greater electron density
is important for the catalytic efficiency in amination reactions,
then L4 has this advantage over L3.
31P{1H} NMR Experiments with the Ligands. In comparing
the 31P chemical shifts of the four ligands shown in Figure 1,
in toluene-d8 the resonance of L1 appears at -13.4 ppm, L2 at
18.0 ppm, L3 at -8.5 ppm, and L4 at -12.6 ppm.22 In this
comparison, L4 is more similar to L1 than to L3. We next
undertook 31P{1H} NMR experiments to evaluate the interac-
tions of Pd(OAc)2 with L3 and L4.
Within 15 min of combining L3/Pd(OAc)2 in a 2:1 molar
ratio in toluene-d8 at room temperature, five new resonances [δ
ppm: 48.9, 43.9, 43.7, 31.0, and 29.3] were observed (see
X-ray Crystal Structures of L3 and L4. In order to compare
the structures of L3 and L4, we have obtained X-ray crystal-
(20) CCDC depositions 689629 and 689630 contain the supplementary
crystallographic data for this paper. These data can be obtained free
of charge from The Cambridge Crystallographic Data Center via
www.ccdc.cam.ac.uk/data_request/cif.
(19) A similar type of reaction has been observed in the cross-coupling of
Grignard reagents with an O6-aryl sulfonate of 2′-deoxyguanosine:
Nagatsugi, F.; Ogata, Y.; Imoto, S.; Sasaki, S. Heterocycles 2007,
73, 493–501.
(21) Barder, T. E.; Buchwald, S. L. J. Am. Chem. Soc. 2007, 129, 5096–
5101.
(22) 31P resonances (202 MHz, C6D6): L1 ) -14.1 ppm, L2 ) 17.9 ppm,
L3 ) -9.7 ppm, and L4 ) -13.7 ppm.
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Biaryl Phosphine Structure and C-N as Well as C-C Reactions
A R T I C L E S
Table 2. Aryl Amination Reactions of 3′,5′-Di-O-(tert-butyldimethylsilyl)-O6-[(4-methylphenyl)sulfonyl]-2′-deoxyguanosine (2) Using Biaryl
Phosphines L1, L3, and L4a
a Reactions were conducted at 0.1 M concentration of 2 in the solvent mixture (5:1 1,4-dioxane/t-BuOH) using 10 mol % Pd(OAc)2, 20 mol %
ligand, 2 molar equiv K3PO4, and 2 molar equiv amine. b Reactions were monitored by TLC for completion. c Yields reported are of isolated and
purified products. d Average of two reactions.
Figure 1 in the Supporting Information). Rapid appearance of
a broad singlet at 48.9 ppm was observed, even at 15 min, that
persisted and increased with time, and a substantial amount of
unligated L3 was observed after 1 h (Figure 3A). Upon changing
this stoichiometry to 1:1 L3/Pd(OAc)2, no major difference was
observed in the pattern of resonances, although some differences
emerged at 24 h (Figure 3B and Figure 2 in the Supporting
Information). These data indicate largely similar interactions
of L3 with Pd(OAc)2 under 2:1 or 1:1 stoichiometry.
In marked contrast to the behavior of L3, a 2:1 combination
of L4 and Pd(OAc)2 in toluene-d8 at room temperature produced
a major ABquartet pattern within 15 min, centered at 27.9 ppm
(doublets at 29.8 and 26.0 ppm, JA,B ∼ 370 Hz; Figure 3 in the
Supporting Information), with some residual L4. The species
producing the ABquartet pattern was stable to storage in solution
for 4 weeks at -5 °C. On the basis of the J value, it may be
inferred that the two phosphines are trans ligated to the metal
and are nonequivalent in the predominant species produced here.
There is broadening of the ligand resonance at -13.6 ppm that
may indicate a dynamic exchange process with the species
than for the ABquartet, the remaining resonances appear similar
to those produced in interaction between L3 and Pd(OAc)2
described above. Thus, the interaction of L4 with Pd(OAc)2
varies substantially with stoichiometry (Figure 3C,D). The broad
resonance at 47.3 ppm persisted and increased with time
(Figure 4 in the Supporting Information).
The broad resonances produced at 47-49 ppm in the
interactions of L3 with Pd(OAc)2 as well as in the 1:1
complex of L4 and Pd(OAc)2 are reminiscent of the interac-
tion of L1 and Pd(OAc)2 at a 1:1 stoichiometry.12 Since both
L1 and L4 have similar stoichiometry-dependent behavior,
we were curious to compare the influence of additional ligand
subsequent to formation of the major species under the 1:1
stoichiometry. For this reason, 1:1 complexes of L1 and L4
with Pd(OAc)2 were prepared in toluene-d8 and allowed to
age for 24 h (Figure 5 in the Supporting Information). After
24 h, in the case of L1 there was clear formation of a broad
resonance as the major species at 47.4 ppm (ca. 75%), and
in the case of L4 the broad resonance at 47.3 ppm was formed
almost exclusively. At that time an additional equivalent of
the appropriate ligand was added to each solution, and in
each case rapid formation of an ABquartet was observed. This
indicates that association of a second ligand occurs to an
producing the ABquartet
.
At a 1:1 L4/Pd(OAc)2 stoichiometry, three major resonances
were observed within 15 min [δ ppm: 47.3, 42.8, and an ABquartet
centered at 27.8; Figure 4 in the Supporting Information]. Other
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A R T I C L E S
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Table 3. C-C Bond-Forming Reactions of Bromo Nucleoside 4 and Nucleoside Aryl Sulfonate 5 Using Biaryl Ligands L3 and L4a
a Reactions with 4 and 5 were conducted at 0.1 M nucleoside concentration, using 2 molar equiv K3PO4 and 2 molar equiv of ArB(OH)2, with
Pd(OAc)2 and ligand stoichiometry as indicated. b Reactions were monitored by TLC for completion. c Yields reported are of isolated and purified
products. d Reaction using 10 mol % Pd(OAc)2/20 mol % ligand. e Reaction using 5 mol % Pd(OAc)2/10 mol % ligand. f In these cases, formation of an
unsymmetrical dimer was observed; see ref 19. g This reaction was incomplete at room temperature as well as at 35 °C. h Average of two reactions.
initially formed 1:1 ligand-Pd species. This experiment again
shows similar solution behavior of L1 and L4.
dimeric species with two bridging acetates, whereas that from
L2 (complex 2) is monomeric with a single ligated acetate. A
plausible basis for these differences resides in the relative steric
congestion at the phosphorus atoms in each ligand. Consistent
with this notion, two L1’s can be accommodated at the Pd center
under the 2:1 ligand/Pd(OAc)2 stoichiometry, which can then
lead to the observed ABquartet if the two phosphorus atoms are
nonequivalent. On the other hand, the lack of such a pattern
with L2 could be due to the increased steric demand at the
phosphine.
In order to evaluate the effect of additional ligand on the
cyclopalladated complexes 1 and 2, we conducted several
more 31P{1H} NMR experiments (Figure 5, also see Figures
8 and 9 in the Supporting Information). To complex 1 was
added a stoichiometric amount of L1. The resonance at 47.6
ppm corresponding to complex 1 disappeared almost im-
mediately upon addition of L1 and resulted in a broad signal
at about 28 ppm. This resonance remained unchanged at room
In order to compare this entire set of ligands, we also
conducted 31P{1H} experiments with L2 (Figures 6 and 7 in
the Supporting Information). Interestingly, at either a 2:1 or a
1:1 L2/Pd(OAc)2 stoichiometry, no ABquartet pattern is observed
with this ligand. Instead, in each case only the same species
that produced a resonance at δ 70.0 ppm was seen to form.
A cyclopalladated species resulting from L2 has been
reported,23 indicating cyclopalladation to be a facile process with
the biaryl phosphine ligands when appropriate unsubstituted
carbons are present on the non-phosphine ring. Thus, we
attempted crystallization of the various 1:1 and 2:1 Pd-ligand
complexes. So far we have not been successful at isolating any
2:1 complex or a 1:1 complex of L3. However, crystals of 1:1
complexes from the unsubstituted biphenyls L124 and L223,25
were obtained, yielding the X-ray structures shown in Figure
4. The cyclopalladated complex from L1 (complex 1) is a
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Biaryl Phosphine Structure and C-N as Well as C-C Reactions
A R T I C L E S
Figure 2. X-ray crystal structures of L3 (left) and L4 (right).
Figure 3. 31P{1H} NMR spectra of solutions of L3 or L4 and Pd(OAc)2 in toluene-d8 after 1 h at room temperature: (A) 2:1 L3/Pd(OAc)2; (B) 1:1 L3/
Pd(OAc)2; (C) 2:1 L4/Pd(OAc)2; and (D) 1:1 L4/Pd(OAc)2.
Figure 4. X-ray crystal structures of cyclopalladated complexes derived from L1 (complex 1) and L2 (complex 2).
temperature over 24 h (Figure 5A and Figure 8 in the
Supporting Information). Upon cooling this NMR sample to
0 °C, the broad resonance resolved into a sharp ABquartet (JA,B
∼ 370 Hz, Figure 5B). Notably, the resonance of unligated
L1, which was also broadened at room temperature, sharp-
ened upon cooling, indicating a possible dynamic exchange
process. Warming this sample back to room temperature again
produced the broad resonance. However, upon addition of 1
molar equiv of acetic acid to this sample, the ABquartet pattern
was restored at room temperature almost immediately (Figure
5C).
From these experiments the following inferences may be
drawn. As shown to the left in Scheme 2, addition of L1 to
complex 1 (R ) H) most likely produces a 2:1 ligand-Pd
9
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A R T I C L E S
Pratap et al.
Figure 5. 31P{1H} NMR experiments with complexes 1 and 2 in toluene-d8: (A) 24 h after addition of a molar equiv of L1 to complex 1; (B) same sample
as in panel A but data acquired at 0 °C; (C) data acquired at room temperature immediately after addition of 1 molar equiv of acetic acid to the sample; (D)
24 h after addition of a molar equiv of L2 to complex 2.
Scheme 2. Possible Interaction of Additional Ligand with the Cyclopalladated Complexes
species. In this case, the two phosphorus atoms are nonequiva-
lent and can result in an ABquartet in the 31P{1H} NMR. On the
basis of the foregoing, at the 1:1 ligand/Pd(OAc)2 stoichiometry,
cyclopallation appears to be predominant, but when this
stoichiometry is changed to 2:1, it is likely that the cyclopal-
ladated species undergoes ligation with a second L1, resulting
in the observed ABquartet. However, in this case, the presence of
acetic acid resulting from the cyclopalladation yields the ABquartet
at room temperature (for reasons not known currently). When
complex 1 is isolated, free of acetic acid, and exposed to
additional L1, the ABquartet is observable only at low temperature.
Addition of acetic acid then produces the ABquartet at room
temperature, comparable to the solution results. In marked
departure from the behavior of complex 1, addition of a
stoichiometric amount of L2 to complex 2 produced no
observable change in the resonance at 69.7 ppm (Figure 9 in
the Supporting Information), and this did not alter even after
24 h (Figure 5D). Thus, in the case of L2, it appears that the
cyclopalladated species, which is also formed quite readily, does
not undergo ligation with a second L2.
We have obtained the crystal structure of a 1:1 complex of
L4 and Pd(OAc)2 (complex 3, Figure 6). This structure shares
similarities to complex 1 obtained from L1, in that it is dimeric
with two bridging acetates. The nitrogen atom is quite planarized
due to conjugation with the aromatic ring. Overall, L1 and L4
share common features in the solid state. On the basis of the
previously described NMR experiments, L4 demonstrates solu-
tion behavior quite similar to that of L1, and Scheme 2 (R )
NMe2) illustrates this. However, the position of the dimethy-
lamino group in the non-phosphine ring seems to be responsible
for the different interactions of L3 and L4 with the metal.
At this time, it is intriguing as to how the ligand-metal
interactions of L4 influence amination reactions of nucleosides
that do not otherwise proceed with L1. This may be related to
the higher electron density of the non-phosphine aryl ring in
L4, but independent of the location of the dimethyl amino group.
One important consideration related to this moiety could be the
(23) Zim, D.; Buchwald, S. L. Org. Lett. 2003, 5, 2413–2415.
1
(24) Complex 1: H NMR (500 MHz, C6D6): δ 8.48 (d, 1H, Ar-H, J )
7.8), 7.52 (d, 1H, Ar-H, J ) 4.9), 7.32 (d, 1H, Ar-H, J ) 7.3),
7.13-6.98 (m, 4H, Ar-H), 6.94 (app t, 1H, Ar-H, J ) 7.8), 2.07 (s,
3H, OAc), 1.87-1.71 (m, 4H), 1.63-1.60 (m, 2H), 1.50-1.47 (m,
4H), 1.42-1.38 (m, 4H), 1.26-1.17 (m, 1H), 1.03-0.84 (m, 6H),
0.67-0.63 (m, 1H). 31P NMR (202 MHz, toluene-d8): δ 47.6. This
complex appears to be somewhat more labile compared to complex 3
during routine operations.
1
(25) Complex 2: H NMR (500 MHz, C6D6): δ 8.30 (d, 1H, Ar-H, J )
6.3), 7.67 (app t, 1H, Ar-H, J ) 7.8), 7.54 (dd, 1H, Ar-H, J ) 3.4,
7.8), 7.16-7.11 (m, 2H, Ar-H), 6.99-6.92 (m, 3H, Ar-H), 1.96 (s,
3H, OAc), 1.16 (s, 9H, t-Bu), 1.13 (s, 9H, t-Bu). 31P NMR (202 MHz,
toluene-d8): δ 69.7.
(27) (a) Christmann, U.; Pantazis, D A.; Benet-Buchholz, J.; McGrady,
J. E.; Maseras, F.; Vilar, R. J. Am. Chem. Soc. 2006, 128, 6376–
6390. (b) Faller, J. W.; Sarantopoulos, N. Organometallics 2004, 23,
2008–2014. (c) Walker, S. D.; Barder, T. E.; Martinelli, J. R.;
Buchwald, S. L. Angew, Chem., Int. Ed. 2004, 43, 1871–1876. (d)
Christmann, U.; Vilar, R.; White, A. J. P.; Williams, D. J. J. Chem.
Soc., Chem. Commun. 2004, 1294–1295. (e) Yin, J.; Rainka, M. P.;
Zhang, X.-X.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 1162–
1163.
(26) Complex 3: 1H NMR (500 MHz, C6D6): δ 7.87 (s, 1H, Ar-H), 7.67-
7.65 (m, 1H, Ar-H), 7.44 (d, 1H, Ar-H, J ) 8.3), 7.21-7.16 (m,
2H, Ar-H), 6.96-6.94 (m, 1H, Ar-H), 6.47 (d, 1H, Ar-H, J ) 9.3),
2.61 (s, 6H, NCH3), 2.06 (s, 3H, OAc), 1.98-1.92 (m, 2H), 1.83-
1.79 (m, 2H), 1.70-1.68 (m, 2H), 1.59-1.48 (m, 6H), 1.40-1.37 (m,
2H), 1.24-1.20 (m, 1H), 1.09-1.04 (m, 2H), 0.97-0.83 (m, 4H),
0.46-0.43 (m, 1H). 31P NMR (202 MHz, toluene-d8): δ 47.4.
9
12246 J. AM. CHEM. SOC. VOL. 131, NO. 34, 2009

Biaryl Phosphine Structure and C-N as Well as C-C Reactions
A R T I C L E S
Figure 6. X-ray structure of complex 3 obtained from L4 and Pd(OAc)2.
increased electron density in the non-phosphine ring. In this
context, some unusual coordination modes of biaryl ligands with
Pd are known. For example, Pd complexes with biphenyl
phosphines,27 MAP,28 and MeO-MOP29 have all been shown
to display arene-Pd interactions with the non-phosphine ring.
Thus, it is plausible that L4 with the para dimethylamino group
could yield similar arene-Pd interactions as well, and this may
be assisted by the greater conjugation of the amino group with
the aryl ring. If, on the other hand, formation of biaryl
palladacycles is a relatively facile process in these ligand-
Pd(OAc)2 interactions, then the efficiency with which the
palladacycles catalyze reactions could be dependent on how
easily they are converted to active catalyst.30,31 In this context,
it is noteworthy that a C-C bond-forming reaction between 4
and PhB(OH)2 using 20 mol % L2/10 mol % Pd(OAc)2 at room
temperature resulted in only 50% product formation after 24 h,
with no additional progress beyond that time. Thus, subtle
factors in structures of these ligands play a critical role in the
formation of active catalyst and the catalytic efficiency of each.
We were curious to evaluate whether another Pd(II) source
would yield similar interactions with L1. However, solutions
of (CH3CN)2PdCl2 and L1 did not display any of the NMR
characteristics observed with Pd(OAc)2 (see Figure 10 in the
Supporting Information). Nevertheless, unusual arene-Pd in-
teractions have been reported between Pd halide salts and L2
as well as related ligands.27a,d
Finally, we were interested in qualitatively assessing the
relative efficiencies of Pd complexes derived from L3 and L4
in the room-temperature C-C bond-forming reactions. Since
the anomeric H-1′ resonances of 4 and 6a are well separated,
they can be used for monitoring reactions by NMR. Four
separate cross-coupling experiments of 4 and PhB(OH)2 were
performed using 1:1 as well as 2:1 ligand (L3 and L4)/Pd(OAc)2
stoichiometry. After mixing all components at room temperature,
the reactions were monitored every 15 min, with the first
sampling at 2 min after mixing (Figure 7). Notably, all three
reactions had commenced within 2 min with noticeable product
formation. The absence of any induction period indicated that
Figure 7. Monitoring the amount of product (6a) formed as a function of
time: ([) reaction catalyzed by 2:1 L4/Pd(OAc)2; (2) reaction catalyzed
by 1:1 L4/Pd(OAc)2; (9) reaction catalyzed by 2:1 L3/Pd(OAc)2; and (b)
reaction catalyzed by 1:1 L3/Pd(OAc)2.
active catalyst was generated rapidly in each case.32 Continued
sampling showed that the L4-based catalysts tended to yield
product faster than those from L3 ([ and 2 compared to 9
and b in Figure 7). However, the 1:1 L4/Pd(OAc)2 reaction,
which was initiated quite rapidly, appeared to be retarded as
time progressed (2). Thus, from this experiment as well as the
31P NMR results, a plausible conclusion that emerges is that
the second equivalent of L4 may not be a bystander but appears
to have a role in the reaction. In contrast, the 31P NMR results
with L3 indicate that the interaction of the metal with the ligand
is quite independent of stoichiometry, and the reactions appear
comparable in the initial hour of observation.
A separate experiment was conducted in which the reactions
catalyzed by 2:1 L3/Pd(OAc)2 and L4/Pd(OAc)2 were monitored
until no starting material was detectable by NMR. Although
both reactions appeared complete at 20 h by NMR, the L4-
derived catalyst showed faster product formation (see Figure 11
in the Supporting Information) and an overall better product
yield (Table 3, entries 1 and 2). In this context, it should be
recognized that the behavior of nucleosides can be markedly
different from that of simpler systems, and often data obtained
from the reactions of simpler systems are not always directly
applicable to these more complex substrates. The reactivity
properties of nucleosides have offered the possibility to probe
ligand-based differences of catalytic activities.
(28) (a) Wang, Y.; Li, X.; Sun, J.; Ding, K. Organometallics 2003, 22,
ˇ
ˇ
1856–1862. (b) Kocovsky´, P.; Vyskocˇil, S.; C´ısaˇrova´, I.; Sejbal, J.;
Tisˇlerova´, I.; Smrcˇina, M.; Lloyd-Jones, G. C.; Stephen, S. C.; Butts,
C. P.; Murray, M.; Langer, V. J. Am. Chem. Soc. 1999, 121, 7714–
7715.
(29) (a) Dotta, P.; Kumar, P. G. A.; Pregosin, P. S.; Albinati, A.; Rizzato,
S. Organometallics 2004, 23, 4247–4254. (b) Dotta, P.; Kumar,
P. G. A.; Pregosin, P. S. HelV. Chim. Acta 2004, 87, 272–278. (c)
Dotta, P.; Kumar, P. G. A.; Pregosin, P. S.; Albinati, A.; Rizzato, S.
Organometallics 2003, 22, 5345–5349.
Conclusions
We have studied the utility of a new ligand, 2-(dicyclohexyl-
phosphino)-4′-(N,N-dimethylamino)-1,1′-biphenyl, for C-C and
(30) Dupont, J.; Consorti, C. S.; Spencer, J. Chem. ReV. 2005, 105, 2527–
2571.
(31) Strieter, E. R.; Buchwald, S. L. Angew. Chem., Int. Ed. 2006, 45, 925–
928.
(32) Inhibition of catalytic activity by nucleosides has been reported: Western,
E. C.; Shaughnessy, K. H. J. Org. Chem. 2005, 70, 6378–6388.
9
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A R T I C L E S
Pratap et al.
with Et2O (2 × 100 mL). The aqueous layer was discarded, and
the combined organic layer was then extracted with 1 M aqueous
NaOH (100 mL). Subsequently, the organic layer was extracted
with 1 M aqueous HCl (4 × 100 mL) and discarded. The aqueous
acid layer was basified to pH 14 with 6 M aqueous NaOH and
then extracted with Et2O (4 × 100 mL). The organic layer was
dried over anhydrous Na2SO4, filtered, and concentrated under
reduced pressure. The crude material thus obtained was purified
by flash chromatography on silica gel using 20% CH2Cl2 in hexanes
to yield 0.91 g (74%) of the bromo biphenyl 1 as a white, crystalline
C-N bond formation. This ligand, which is readily synthesized
from commercially available compounds, catalyzes both aryl
amination and Suzuki-Miyaura cross-coupling of nucleosides.
In contrast, L1, which lacks the dimethylamino moiety, catalyzes
the latter but not the former. Therefore, it appears that, by
balancing the structure and electronic properties of the biaryl
phosphines, more generally applicable ligands can be obtained.
We have also compared the interactions of these ligands with
Pd(OAc)2, and there are substantial differences. Whereas L3
demonstrates a generally stoichiometry-independent behavior,
L4 produces stoichiometry-dependent intermediates, and this
appears to be borne out in the relative efficiencies of the
reactions. The behavior of L4 parallels that of L1, but L2, which
has bulkier substituents on the phosphorus atom, demonstrates
only a single type of interaction with Pd(OAc)2, namely
cyclopalladation. During the course of these investigations, we
have obtained X-ray crystallographic structures of cyclopalla-
dated complexes derived from L1, L2, and L4. In comparing
these, the complex obtained from L1 exhibits a dimeric structure,
whereas that from L2 is monomeric. The cyclopalladated species
derived from L1 likely forms a bis-ligated Pd complex upon
exposure to additional L1, but the formation of such a species
in solution by mixing L1 and Pd(OAc)2 in a 2:1 molar ratio
appears to be quite facile. On the basis of data obtained in
solution as well as in the solid state, the behavior of L4 is similar
to that of L1. By contrast, the cyclopalladated compound derived
from L2 seems to remain a monoligated complex upon exposure
to additional L2. It is conceivable that the effectiveness of these
ligands in catalyzing transformations is dependent upon the
ability of the various cyclopalladated species produced to yield
active catalyst in a reaction medium, and this is tuned by subtle
structural features of the various biaryl ligands.
1
solid, Rf (1:1 CH2Cl2 in hexanes) ) 0.66. H NMR (500 MHz,
CDCl3): δ 7.67 (d, 1H, Ar-H, J ) 7.8), 7.36-7.32 (m, 4H, Ar-H),
7.17-7.14 (m, 1H, Ar-H), 6.80 (d, 2H, Ar-H, J ) 8.7), 3.02 (s,
6H, N(CH3)2). 13C NMR (125 MHz, CDCl3): δ 150.1, 142.9, 133.4,
131.6, 130.4, 129.3, 128.1, 127.6, 123.3, 111.9, 40.7. HRMS: calcd
for C14H15BrN [M + H]+ 276.0382, found 276.0388.
Step 2: Synthesis of 2-(Dicyclohexylphosphino)-4′-N,N-(dim-
ethylamino)-1,1′-biphenyl (L4). An oven-dried, three-neck round-
bottomed flask, equipped with a stirring bar, was charged with
2-bromo-N,N-(dimethylamino)-1,1′-biphenyl (552 mg, 2 mmol)
under a nitrogen atmosphere. The flask was then evacuated, held
under vacuum, and filled with nitrogen gas. Anhydrous Et2O (15
mL) was transferred via syringe, and the solution was cooled to 0
°C. n-BuLi (1.87 mL of 1.6 M solution in hexanes, 3 mmol) was
added dropwise to this stirred mixture, and the mixture was warmed
to room temperature and allowed to stir for 1 h. The reaction
mixture was then cooled to 0 °C, and Cl-PCy2 (788 mg, 3.4 mmol)
was added dropwise. The reaction mixture was again warmed to
room temperature and allowed to stir for 16 h. The mixture was
filtered through Celite, and the residue was washed with Et2O. The
solvent was evaporated under reduced pressure, and crude product
was purified by recrystallization from hot, degassed ethanol under
a nitrogen atmosphere to afford 526 mg (67%) of L4 as a white
1
solid, Rf (CH2Cl2) ) 0.47. H NMR (500 MHz, C6D6): δ 7.57 (d,
1H, Ar-H, J ) 7.1), 7.48 (d, 2H, Ar-H, J ) 8.1), 7.46-7.45 (m,
1H, Ar-H), 7.22-7.17 (m, 2H, Ar-H), 6.69 (d, 2H, Ar-H, J )
8.5), 2.53 (s, 6H, N(CH3)2), 1.88-1.81 (m, 4H), 1.72-1.53 (m,
8H), 1.26-1.13 (m, 8H), 1.11-1.03 (m, 2H). 13C NMR (125 MHz,
C6D6): δ 151.3 (d, J ) 28.6), 149.4, 134.7 (d, J ) 22.3), 132.8 (d,
J ) 2.7), 131.8 (d, J ) 4.8), 131.3 (d, J ) 6.0), 130.7 (d, J ) 5.0),
128.2, 125.8, 111.6, 39.9, 35.1 (d, J ) 16.9), 30.8 (d, J ) 18.5),
29.6 (d, J ) 9.6), 27.2, 27.1 (d, J ) 4.8), 26.5. 31P NMR (202
MHz, C6D6): δ -13.7. HRMS: calcd for C26H37NP [M + H]+
394.2658, found 394.2661.
Experimental Section
General Experimental Considerations. Thin-layer chromatog-
raphy was performed on 250 µm silica plates and column
chromatographic purifications were performed on 200-300 mesh
silica gel. The ligands and Pd(OAc)2 were purchased from com-
mercial suppliers. All other reagents were obtained from commercial
sources and used without further purification. 1,4-Dioxane was
distilled over LiAlH4 and was freshly distilled over Na prior to
use. Toluene and Et2O were distilled over Na. Nucleoside substrates
were prepared as described previously. 1H NMR spectra were
recorded at 500 MHz and 13C NMR spectra at 125 MHz in the
solvents indicated (when CDCl3 was used, it was deacidified by
percolating the solvent through a bed of solid NaHCO3 and basic
alumina). All proton spectra are referenced to residual protonated
solvent resonance, and carbon spectra are referenced to the solvent
resonance. 31P NMR spectra were recorded at 202 MHz in the
solvents indicated, using 85% H3PO4 as external standard. No
attempt has been made to ascertain the position of the aryl amino
proton (-NH-Ar) in the products. Therefore, this and the aromatic
protons are collectively assigned as Ar-H. The sugar protons are
numbered 1′-5′ beginning at the anomeric carbon and proceeding
via the carbon chain to the primary carbinol carbon.
Synthesis of Ligand L4. Step 1: Synthesis of 2-Bromo-N,N-
(dimethylamino)-1,1′-biphenyl (1). A solution of 4-(N,N-dimethy-
lamino)phenylboronic acid (736 mg, 4.46 mmol) in EtOH (5 mL)
was added to a round-bottomed flask containing a solution of
Pd(PPh3)4 (260 mg, 5 mol %) and 2-bromoiodobenzene (728 µL,
5.68 mmol) in DME (40 mL) under nitrogen gas. A solution of
Na2CO3 (2.00 g, 19.04 mmol) in degassed water (15 mL) was added
to the reaction mixture, and the mixture was heated at reflux for
24 h. The reaction mixture was then cooled to room temperature,
diluted with Et2O (100 mL), and transferred to a separatory funnel.
The layers were separated, and the aqueous layer was extracted
Cross-Coupling Reactions Shown in Table 1. In each case the
reaction was conducted using identical amounts of reagents, under
identical stoichiometry, solvent, and conditions as those reported
in ref 17, using L3 or L4.
Typical Procedure for C-N Bond-Forming Reactions of Nu-
cleoside Aryl Sulfonate 2. In an oven-dried screw-cap vial, equipped
with a stirring bar, were placed Pd(OAc)2 (1.4 mg, 6.2 µmol), L3
or L4 (4.8 mg, 12.3 µmol), K3PO4 (26.0 mg, 0.123 mmol),
nucleoside sulfonate 2 (40 mg, 0.615 mmol), and aryl amine (0.123
mmol). A mixture of 5:1 anhydrous 1,4-dioxane and t-BuOH (0.6
mL) was added, the vial was flushed with nitrogen gas and sealed
with a Teflon-lined cap, and the mixture was allowed to stir at 110
°C in a pre-equilibrated oil bath. Upon completion, the reaction
mixture was filtered through Celite, and the residue was washed
with CH2Cl2. Evaporation of the filtrate provided the crude mixture
that was purified by column chromatography on silica gel using
3% acetone in CH2Cl2 as eluent. Data for all compounds except
3b have been reported previously.6
2,6-Diamino-N6-(2-naphthyl)-9-[3,5-di-O-(tert-butyldimethylsil-
yl)-2-deoxy-ꢀ-D-ribofuranosyl]purine (3b). The eluting solvent for
chromatography was CH2Cl2, followed by 3% acetone in CH2Cl2.
1
Colorless oil, Rf (5% acetone in CH2Cl2) ) 0.25. H NMR (500
MHz, CDCl3): δ 8.37 (s, 1H, Ar-H), 7.89 (s superimposed on br
s, 2H, Ar-H), 7.79-7.77 (m, 3H, Ar-H), 7.74-7.72 (m, 1H,
Ar-H), 7.46-7.43 (m, 1H, Ar-H), 7.38-7.35 (m, 1H, Ar-H),
9
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Biaryl Phosphine Structure and C-N as Well as C-C Reactions
A R T I C L E S
6.34 (t, 1H, H-1′, J ) 6.6), 4.91 (br s, 2H, NH2), 4.62-4.60 (m,
1H, H-3′), 4.01 (app q, 1H, H-4′, J ∼ 3.4), 3.85 (dd, 1H, H-5′, J
) 4.1, 11.1), 3.77 (dd, 1H, H-5′, J ) 3.2, 11.1), 2.62 (app quint,
1H, H-2′, Japp ∼ 6.1), 2.38 (ddd, 1H, H-2′, J ) 3.8, 6.0, 13.0),
0.93 and 0.92 (2s, 18H, t-Bu), 0.11 and 0.10 (2s, 12H, Si-CH3).
13C NMR (125 MHz, CDCl3): δ 159.6, 152.4, 151.0, 136.5, 136.3,
134.0, 130.1, 128.5, 127.6, 127.4, 126.3, 124.5, 120.8, 116.2, 115.2,
87.7, 83.7, 71.9, 62.8, 41.0, 26.0, 25.8, 18.4, 18.0, -4.7, -4.8,
-5.4, -5.5. HRMS: calcd for C32H49N6O3Si2 [M + H]+ 621.3399,
found 621.3399.
General Procedure for C-C Bond-Forming Reactions of
Bromo Nucleoside 4 at Room Temperature. In an oven-dried,
screw-cap vial equipped with a stirring bar were placed Pd(OAc)2
(1.6 mg, 7.0 µmol), L3 or L4 (5.5 mg, 14.0 µmol), the boronic
acid (2 molar equiv), and K3PO4 (29.5 mg, 0.14 mmol). Finally,
bromo nucleoside 4 (38 mg, 0.070 mmol) was added, followed by
the addition of dry toluene (0.7 mL). The vial was flushed with
nitrogen gas and sealed with a Teflon-lined cap, and the mixture
was allowed to stir at room temperature. Reactions were monitored
by TLC. Upon completion, the mixtures were filtered through Celite,
the residue was washed with CH2Cl2, and the filtrate was evaporated
to dryness. The products were purified by column chromatography
on silica gel using appropriate solvents.
arylsulfonate 5 (40 mg, 0.059 mmol), and the arylboronic acid (2
molar equiv). PhMe or THP (0.6 mL) as appropriate was added,
the vial was flushed with nitrogen gas and sealed with a Teflon-
lined cap, and the mixture was allowed to stir at 80 °C in an oil
bath. Upon completion, the reaction mixture was filtered through
Celite, and the residue was washed with CH2Cl2. Evaporation of
the filtrate yielded the crude mixture that was purified by column
chromatography on silica gel using 3% acetone in CH2Cl2 as eluent.
Characterization data for 7a, 7b, 7d, and 7e have been described
previously.33
2-Amino-9-[3,5-di-O-(tert-butyldimethylsilyl)-2-deoxy-ꢀ-D-ribo-
furanosyl]-6-(4-phenoxyphenyl)purine (7c). The eluting solvent was
CH2Cl2 followed by 3% acetone in CH2Cl2. Colorless oil, Rf (5%
1
acetone in CH2Cl2) ) 0.25. H NMR (500 MHz, CDCl3): δ 8.69
(d, 2H, Ar-H, J ) 8.8), 8.08 (s, 1H, Ar-H), 7.39-7.36 (m, 2H,
Ar-H), 7.17-7.12 (m, 3H, Ar-H), 7.09-7.08 (m, 2H, Ar-H),
6.39 (t, 1H, H-1′, J ) 6.4), 5.12 (br s, 2H, NH2), 4.63-4.60 (m,
1H, H-3′), 4.01 (app q, 1H, H-4′, J ∼ 3.4), 3.82 (dd, 1H, H-5′, J
) 4.4, 11.2), 3.77 (dd, 1H, H-5′, J ) 3.4, 11.2), 2.62 (app quint,
1H, H-2′, Japp ∼ 6.1), 2.40 (ddd, 1H, H-2′, J ) 3.4, 6.7, 13.0),
0.93 and 0.91 (2s, 18H, t-Bu), 0.12, 0.09, and 0.08 (3s, 12H,
Si-CH3). 13C NMR (125 MHz, CDCl3): δ 159.7, 159.3, 156.5,
154.9, 153.9, 139.8, 131.4, 130.6, 129.8, 125.8, 123.7, 119.5, 118.3,
87.7, 83.6, 72.1, 62.9, 40.7, 25.9, 25.8, 18.4, 18.1, -4.7, -4.8,
-5.4, -5.5. HRMS: calcd for C34H50N5O4Si2 [M + H]+ 648.3396,
found 648.3395.
General Procedure for C-C Bond-Forming Reactions of
Bromo Nucleoside 4 at Elevated Temperature. These reactions
were carried out as described for the ones at room temperature with
some differences. Specifically, the reaction of p-methoxyphenyl-
boronic acid was conducted using a lower catalyst loading,
Pd(OAc)2 (0.8 mg, 3.5 µmol) and L3 or L4 (2.8 mg, 7.0 µmol),
and THP was used as solvent for the reaction of m-nitrophenyl-
boronic acid. The reactions were conducted in an oil bath that was
maintained at 100-102 °C.
Acknowledgment. This work was supported by NSF Grant
CHE-0640417 and a PSC CUNY-39 award (M.K.L.). Infrastructural
support at CCNY was provided by NIH RCMI Grant G12
RR03060. We thank Dr. Padmanava Pradhan (CCNY NMR
laboratory manager) for assistance with several NMR experiments.
Purification and characterization data for 6a, 6b, and 6d have
Supporting Information Available: 31P{1H} NMR analysis
of 2:1 and 1:1 ligand/Pd(OAc)2 combinations involving ligands
L2, L3, and L4; 31P{1H} NMR analysis of the effect of
additional L1 and L4 on initially formed 1:1 complexes in
solution; 31P{1H} NMR analysis of the effect of additional L1
and L2 on cylopalladated complexes derived from each; 31P{1H}
NMR analysis of L2/(MeCN)2PdCl2 at 2:1 and 1:1 stoichiom-
etry; analysis of a reaction between 4 and PhB(OH)2 over 20 h
been described previously.9
9-[3,5-Di-O-(tert-butyldimethylsilyl)-2-deoxy-ꢀ-D-ribofuranosyl]-
6-(4-phenoxyphenyl)purine (6c). The eluting solvent for chroma-
tography was CH2Cl2, followed by 3% acetone in CH2Cl2. Colorless
oil, Rf (5% acetone in CH2Cl2) ) 0.73. 1H NMR (500 MHz, CDCl3):
δ 8.98 (s, 1H, Ar-H), 8.80 (d, 2H, Ar-H, J ) 8.9), 8.42 (s, 1H,
Ar-H), 7.40-7.37 (m, 2H, Ar-H), 7.18-7.15 (m, 3H, Ar-H),
7.11-7.10 (m, 2H, Ar-H), 6.56 (t, 1H, H-1′, J ) 6.4), 4.66-4.64
(m, 1H, H-3′), 4.06 (app q, 1H, H-4′, J ∼ 3.5), 3.89 (dd, 1H, H-5′,
J ) 3.9, 11.2), 3.79 (dd, 1H, H-5′, J ) 3.0, 11.2), 2.70 (app quint,
1H, H-2′, Japp ∼ 6.6), 2.50 (ddd, 1H, H-2′, J ) 3.9, 5.9, 13.2),
0.93 and 0.91 (2s, 18H, t-Bu), 0.12, 0.09, and 0.08 (3s, 12H,
Si-CH3). 13C NMR (125 MHz, CDCl3): δ 160.3, 156.6, 154.4,
152.5, 152.1, 142.8, 131.9, 131.5, 130.6, 130.1, 124.2, 123.2, 119.9,
118.5, 88.3, 84.7, 72.3, 63.1, 41.5, 26.2, 26.0, 18.7, 18.3, -4.4,
-4,5, -5.1, -5.2. HRMS: calcd for C34H49N4O4Si2 [M + H]+
633.3287, found, 633.3285.
1
using catalytic complexes derived from L3 and L4; H NMR
spectra of 1, L4, all products in Table 1, 3a-f, 6a-d, and 7a-e;
13C NMR spectra of 1, L4, 3c, 6c, and 7c; 31P{1H} and HMQC
spectra of L4; 1H and 31P{1H} NMR spectra for complexes 1-3;
additional X-ray (ORTEP) structures of L3, L4, and complexes
1-3; and CIF files. This material is available free of charge
via the Internet at http://pubs.acs.org.
Typical Procedure for C-C Bond-Forming Reactions of Nu-
cleoside Aryl Sulfonate 5. In an oven-dried, screw-cap vial equipped
with a stirring bar were placed Pd(OAc)2 (1.3 mg, 5.9 µmol), L3
or L4 (4.6 mg, 11.8 µmol), K3PO4 (25 mg, 0.118 mmol), nucleoside
JA902679B
(33) Lakshman, M. K.; Thomson, P. F.; Nuqui, M. A.; Hilmer, J. H.;
Sevova, N.; Boggess, B. Org. Lett. 2002, 4, 1479–1482.
9
J. AM. CHEM. SOC. VOL. 131, NO. 34, 2009 12249