An improved protocol for the Pd-catalyzed α-arylation of aldehydes with aryl halides

Article abstract of DOI:10.1021/ol8017775

(Chemical Equation Presented) An improved protocol for the Pd-catalyzed α-arylation of aldehydes with aryl halides has been developed. The new catalytic system allows for the coupling of an array of substrates including challenging electron-rich aryl bromides and less reactive aryl chlorides. The utility of this method has been demonstrated in a new total synthesis of (±)-sporochnol.

Full text of DOI:10.1021/ol8017775

ORGANIC
LETTERS
2008
Vol. 10, No. 20
4561-4564
An Improved Protocol for the
Pd-Catalyzed r-Arylation of Aldehydes
with Aryl Halides
Rube´n Mart´ın and Stephen L. Buchwald*
Department of Chemistry, Massachusetts Institute of Technology,
Cambridge, Massachusetts 02139
sbuchwal@mit.edu
Received July 31, 2008
ABSTRACT
An improved protocol for the Pd-catalyzed r-arylation of aldehydes with aryl halides has been developed. The new catalytic system allows
for the coupling of an array of substrates including challenging electron-rich aryl bromides and less reactive aryl chlorides. The utility of this
method has been demonstrated in a new total synthesis of (()-sporochnol.
The potential utility of R-aryl carbonyl compounds has
prompted organic chemists to look for alternatives to their
Scheme 1. R-Arylation of Aldehydes with Aryl Halides
classical syntheses.1 In recent years, the metal-catalyzed
R-arylation of carbonyl compounds has gained considerable
attention due to the ready availability of the starting materials
and the mild reaction conditions that are needed.2 Despite
the advances realized, the high sensitivity of aldehydes and
their propensity to undergo aldol condensation in basic media
make them particularly challenging substrates for R-arylation
reactions (Scheme 1).3,4
chlorides under mild reaction conditions.5 More recently, a
similar R-arylation reaction has been described with aryl
bromides and a limited set of activated aryl chlorides using
dppf and QPhos as the ligands, respectively.6,7 Despite these
improvements, however, the coupling of electron-rich aryl
bromides or their less reactive counterparts, aryl chlorides,
with linear aldehydes still remains a challenge.
In 2007, our research group reported a protocol for the
R-arylation of aldehydes with both aryl bromides and aryl
(1) (a) Yokoshima, S.; Uedo, T.; Kobayashi, S.; Sato, A.; Kuboyama,
T.; Tokuyama, H.; Fukuyama, T. J. Am. Chem. Soc. 2002, 124, 2137. (b)
Venkatesan, H.; Davis, M. C.; Altas, Y.; Snyder, J. P.; Liotta, D. C. J.
Org. Chem. 2001, 66, 3653. (c) Edmondson, S.; Danishefsky, S. J.; Sepp-
Lorenzino, L.; Rosen, N. J. Am. Chem. Soc. 1999, 121, 2147.
(2) For a recent review, see: Culkin, D. A.; Hartwig, J. F. Acc. Chem.
Res. 2003, 36, 234.
Although we previously suggested that water content may
be important in these R-arylation reactions,5 our early
(4) For an organocatalytic approach: Alema´n, J.; Cabrera, S.; Maerten,
E.; Overgaard, J.; Jørgensen, K. A. Angew. Chem., Int. Ed. 2007, 46, 5520.
(5) Mart´ın, R.; Buchwald, S. L. Angew. Chem., Int. Ed. 2007, 46, 7236.
(3) (a) First intermolecular R-arylation of aldehydes: Terao, Y.; Fukuoka,
Y.; Satoh, T.; Miura, M.; Nomura, M Tetrahedron Lett. 2002, 43, 101. (b)
Intramolecular version: Muratake, H.; Natsume, M.; Nakai, H. Tetrahedron
2004, 60, 11783. (c) For an example using 2-chlorotoluene, see: Lavallo,
V.; Canac, Y.; Prasang, C.; Donnadieu, B.; Bertrand, G. Angew. Chem.,
(6) Vo, G. D.; Hartwig, J. F. Angew. Chem., Int. Ed. 2008, 47, 2127
.
(7) According to the known -I effect of a methoxy group in the meta
position (σmeta ) +0.12), 3-chloroanisole cannot be considered electron-
Int. Ed. 2005, 44, 5705
.
neutral: Hansch, C.; Leo, A.; Taft, R. W. Chem. ReV. 1991, 97, 165.
10.1021/ol8017775 CCC: $40.75
Published on Web 09/23/2008
2008 American Chemical Society

experiments did not completely establish its significance. We
began our new investigation by studying the effects of water
in our Pd(OAc)2/BINAP catalytic system. As shown in Table
1, the addition of molecular sieves resulted in the complete
Pd-catalyzed R-arylation of linear aldehydes.6 Indeed, while
the coupling of linear aldehydes with 2-bromoanisole using
dppf as the ligand proceeded efficiently, the reaction of the
less sterically encumbered, electron-rich 4-bromoanisole
resulted in very low yields.6 In light of these precedents, we
present herein an improved protocol for the direct Pd-
catalyzed R-arylation of linear and R-branched aldehydes
with challenging electron-rich aryl bromides and the less
reactive aryl chlorides under mild conditions.
Table 1. Role of Water in Aldehyde R-Arylation Reactions
We initially studied the reaction of octanal with 4-bro-
moanisole using various palladium sources, ligands, bases,
and solvents (Table 2). Although several bases and solvents
H2O in
dioxanea (ppm)
yieldb
(%)
entry
R
additive
1
2
3
4
5
n-hexyl
n-hexyl
n-hexyl
n-hexyl
n-hexyl
+ 4 Å sieves
none
none
none
none
24
24
2
24
51
0
33c
24
64
67
Table 2. R-Arylation of Octanal with Electron-Rich Aryl
Halidesa
+ H2O
6
7
8
n-hexyl
n-hexyl
n-hexyl
(5 mol %)
+ H2O
(10 mol %)
+ H2O
(20 mol %)
+ H2O
(4 mol %)
none
24
24
24
67d
66d
51d
entry
X
Pd source
Pd(OAc)2
[Pd(allyl)Cl]2
[Pd(allyl)Cl]2
Pd(OAc)2
L
yieldb (%)
1
2
3
4
5
6
7
8
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Cl
Cl
Cl
Cl
Cl
Cl
Cl
rac-BINAP
QPhos
dppf
XantPhos
XantPhos
XantPhos
XantPhos
DPEPhos
L1
32
19c
39
9
10
n-hexyl
ethyl
24
24
66e
55
70, 0d
71e
73
Pd(OAc)2
a Determined by Karl Fisher titration. b GC yields using dodecane as
internal standard. c Freshly flame-dried Cs2CO3 was used. d After 8 h reaction
time. e Water-mediated preactivation, according to ref 10a.
[Pd(cinnamyl)Cl]2
[Pd(allyl)Cl]2
[Pd(allyl)Cl]2
[Pd(allyl)Cl]2
[Pd(allyl)Cl]2
[Pd(allyl)Cl]2
Pd(OAc)2
[Pd(allyl)Cl]2
[Pd(allyl)Cl]2
Pd(OAc)2
76
21
68
34
9
10
11
12
13
14
15
16
17
18
L2
loss of catalytic activity (entry 1). Additionally, the use of
flame-dried Cs2CO3 (entry 2)8 and/or a rigorously anhydrous
solvent (entry 3)8,9 resulted in very low conversions of
octanal to the desired R-aryl aldehyde. The yields of these
reactions are comparable with those recently reported in the
literature in which poor catalytic performance was found
when using the Pd(OAc)2/BINAP system.6 In contrast, yields
could substantially be improved by using regular “anhydrous”
solvents with higher water content (entries 4 and 5). These
results indicate that water might be promoting the reduction
of Pd(OAc)2 to the active LnPd(0) species.10 In accordance
with this hypothesis, a faster reaction rate was observed either
by adding water (entries 6-8) or by using our recently
developed water-mediated preactivation protocol (entry 9).10a
Next, we set out to explore the reaction of electron-rich
aryl halides in the R-arylation of linear aldehydes. Because
the elementary steps, oxidative addition, transmetalation, and
reductive elimination are relatively slow, such substrates are
more challenging than electron-neutral ones in cross-coupling
reactions.11 Recently, it has been demonstrated that both
electronic and steric effects might play a crucial role in the
dppb
21
L3
L3
34f
33f
0f,g
55f
41f
69f,h
58f,h
QPhos
XPhos
SPhos
Pd(OAc)2
1
2
a Reaction conditions: aryl bromide (1.0 mmol), aldehyde (1.20 mmol),
Pd precatalyst (2 mol %, 1 mol % if dimer was used), ligand (3 mol %),
Cs2CO3 (1.20 mmol), and dioxane (0.25 M) at 80 °C for 6 h. b GC yields
using dodecane as internal standard. c According to ref 6: [Pd(allyl)Cl]2
(0.50 mol %), QPhos (1 mol %), Cs2CO3 (2.0 mmol), and THF (0.50 M).
d With 4 Å molecular sieves. e Water-mediated preactivation, according to
ref 10a. f Reaction conducted at 100 °C. g According to ref 6: [Pd(allyl)Cl]2
(1 mol %), QPhos (2 mol %), Cs2CO3 (2.0 mmol), and THF (0.25 M) at
90 °C. h Pd precatalyst (2 mol %) was used.
(8) The reaction was set up in the glovebox.
were examined, the combination of Cs2CO3 and dioxane (24
ppm water content) gave the best results. Entries 1-3 show
that the previously reported best ligands, rac-BINAP5 (entry
1), dppf6 (entry 3), and QPhos6 (entry 2), afforded low yields
of the desired product. It is well recognized that the bite
(9) Dioxane was freshly distilled and dried over 4 Å molecular sieves
.
(10) (a) Fors, B. P.; Krattiger, P.; Strieter, E.; Buchwald, S. L. Org.
Lett. 2008, 10, 3505. (b) Amatore, C.; Jutand, A.; Khalil, F. ArkiVoc 2006,
4, 38. (c) Ozawa, F.; Kubo, A.; Hayashi, T. Chem. Lett. 1992, 2177.
(11) Cross-Coupling Reactions. A Practical Guide; Miyaura, N., Ed.;
Topics in Current Chemistry; Springer: Berlin, 2002.
4562
Org. Lett., Vol. 10, No. 20, 2008

angle of bidentate phosphines may play a crucial role in the
reaction outcome of catalytic reactions,12 with wider bite
angles facilitating reductive elimination.13 In line with this
notion, we found that the use of XantPhos, which has a wider
bite angle than BINAP or dppf, afforded the desired R-aryl
aldehyde in 70% yield after 6 h (entry 4).14 Consistent with
the previous results shown in Table 1, while no conversion
was observed in the presence of molecular sieves (entry 4)
similar yields were obtained when using a water-mediated
preactivation protocol (entry 5).10a It is worth mentioning,
however, that ligands with wider bite angles than XantPhos,
such as L215 (entry 9) or dppb (entry 10), resulted in lower
yields, thus illustrating the subtleties of the system. Finally,
Table 3. Pd-Catalyzed R-Arylation of Linear Aldehydes
6
catalysts generated from [Pd(allyl)Cl]2 or [Pd(cinnamyl)-
Cl]216 turned out to be slightly more efficient than Pd(OAc)2
(entry 4 vs entries 6 and 7).
Encouraged by these results, we turned our attention to
the R-arylation of 4-chloroanisole since there are no previous
reports on the effective coupling of electron-rich aryl
chlorides with linear aldehydes. We found, however, that
low yields could be achieved when using our previous
catalytic system based on L35 (Table 2, entry 12). After
optimization, we found that our recently developed one-
component XPhos precatalyst (1)17 afforded the correspond-
ing R-aryl aldehyde in 69% yield (Table 2, entry 17). These
differences might be due to the ability of 1 to generate the
active LnPd(0) species efficiently within the catalytic cycle.
The scope of the Pd-catalyzed R-arylation of linear
aldehydes with electron-rich aryl bromides and chlorides is
shown in Table 3. The more challenging electron-rich
chloroarenes could all be successfully coupled albeit in
moderate yields. The process is compatible with several
functional groups in both coupling counterparts, including
those bearing ethers, amines, sulfides, alkenes, esters, car-
bamates, or acetals. In line with our previous findings, the
coupling of isovaleraldehyde required a longer reaction time
(entries 3, 6, 7, and 9). Particularly significant is the
compatibility of the new protocol toward labile substrates
such as epoxides (entry 7),18 which have not been thoroughly
investigated in the context of cross-coupling methods,19 and
N-Boc-protected groups (entry 12). Furthermore, the method
exhibited an excellent chemoselectivity for aldehyde R-ary-
lation over ester R-arylation (entry 8).
a X ) Br: aryl bromide (1.0 mmol), Pd precatalyst (1-2 mol %),
XantPhos (3 mol %), Cs2CO3 (1.20 mmol) in dioxane (0.25 M) at 80 °C
under argon; X ) Cl: Aryl chloride (1.0 mmol), 1 (2 mol %), Cs2CO3
(1.20 mmol) in dioxane (0.25 M) at 100 °C under argon. b Yields of isolated
products are an average of two runs. c [Pd(allyl)Cl]2 (1 mol %). d Pd(OAc)2
(2 mol %). e [Pd(cinnamyl)Cl]2.
Next, we set out to probe whether electron-rich aryl halides
were amenable to couple with R-branched aldehydes (Table
4). While the coupling of electron-rich aryl bromides was
(12) Van Leeuwen, P. W. N. M.; Kramer, P. C. J.; Reek, J. N. H.;
Dierkes, P. Chem. ReV. 2000, 100, 2741.
better performed with SPhos and Pd(OAc)2 as the palladium
precursor,20 the Xphos precatalyst 1 was found to be optimal
for electron-rich aryl chlorides under reaction conditions
identical to those using unbranched aldehydes. The results
(13) Brown, J. M.; Guiry, P. J. Inorg. Chem. Acta 1994, 220, 249.
(14) Similar results were obtained when the Pd/L ratio was 1:2 or 1:3.
(15) Kranenburg, M.; van der Burgt, Y. E. M.; Kamer, P. C. J.; van
Leeuwen, P. W. N. M. Organometallics 1995, 128, 4101.
(16) Marion, N.; Navarro, O.; Mei, J.; Stevens, E. D.; Scott, N. M.;
Nolan, S. P. J. Am. Chem. Soc. 2006, 128, 4101.
(17) Biscoe, M. R.; Fors, B. P.; Buchwald, S. L. J. Am. Chem. Soc.
2008, 130, 6686.
(20) The use of QPhos as the ligand gave comparable results.
(21) Selected total synthesis of (()-sporochnol: (a) Alibe´s, R.; Busque´,
F.; Bardaj´ı, G. G.; de March, P.; Figueredo, M.; Font, J. Tetrahedron:
(18) In any case, products derived from the ring-opening of the epoxide
could not be detected by NMR of the crude reaction mixtures.
(19) For recent cross-coupling reactions in the presence of epoxides:
(a) Fu¨rstner, A.; Mart´ın, R.; Krause, H.; Seidel, G.; Goddard, R.; Lehmann,
C. W. J. Am. Chem. Soc. 2008, 130, 8773. (b) Cattoe¨n, X.; Perica`s, M. A.
J. Org. Chem. 2007, 72, 3253.
´
Asymmetry 2006, 17, 2632. (b) Avila-Za´rraga, J. G.; Barroso, M.; Covarru-
bias-Zu´n˜iga, A.; Romero-Ortega, M. Synth. Commun. 2005, 35, 389. (c)
Shan, S.; Ha, C. Synth. Commun. 2005, 34, 4005. (d) Ohira, S.; Kuboki,
A.; Hasegawa, T.; Kikuchi, T.; Kutsukake, T.; Nomura, M. Tetrahedron
Lett. 2002, 43, 4641.
Org. Lett., Vol. 10, No. 20, 2008
4563

a fish deterrent, by using the R-arylation of an R-branched
aldehyde as the key step (Scheme 2). Subsequent Wittig
Table 4. Pd-catalyzed R-Arylation of R-Branched Aldehydes
Scheme 2. Total Synthesis of (()-Sporochnol
reaction followed by deprotection of the aryl ether provided
(()-sporochnol in 54% overall yield over three steps from
commercially available starting materials.
In summary, we have shown that subtle ligand changes
can lead to a dramatic increase in the catalytic activity of
aldehyde R-arylation reactions. The transformation is dis-
tinguised by its scope, including the coupling of challenging
electron-rich aryl bromides and aryl chlorides under mild
reaction conditions. The combination of these results with
those previously reported in the literature5,6 provide a fairly
general means for the R-arylation of aldehydes. Further
studies on this transformation as well as the development of
enantioselective protocols are currently underway.
Acknowledgment. We thank the National Institutes of
Health (GM 46059) for support of this work. Chemetall and
BASF are acknowledged for a generous gift of Cs2CO3 and
Pd(OAc)2, respectively. We are also indebted to Merck,
Amgen, and Boehringer-Ingelheim for unrestricted support.
The Varian 300 MHz used in this work was purchased with
funding from the National Institutes of Health (GM 1S10RR-
13886-01).
a X ) Br, as in Table 2, but using Pd(OAc) (2 mol %) and SPhos (3
mol %); X ) Cl, as in Table 2. b Yields of isolated products are an average
of two runs.
summarized in Table 4 indicate that the coupling of non-
sterically biased 4-oxygen-, 4-sulfur-, as well as 4-nitrogen-
substituted aryl halides behaved similarly well. Notably,
epoxides could again be tolerated under these reaction
conditions, thus affording the corresponding R-aryl aldehyde
in moderate yield (entry 2).
Supporting Information Available: Experimental pro-
cedures and spectral data for all compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
The utility of this method is further illustrated in the short
total synthesis of (()-sporochnol,21 a natural product that is
OL8017775
4564
Org. Lett., Vol. 10, No. 20, 2008