Improved functional group compatibility in the palladium-catalyzed synthesis of aryl amines

Article abstract of DOI:10.1021/ol0262688

(figure presented) The use of Pd₂dba₃ with bulky, electron-rich ligands 1 or 2 and LiN(TMS)₂ as the base for the coupling of amines with aryl halides containing hydroxyl, amide, or enolizable keto groups is described. This protocol expands the utility of palladium-catalyzed C-N bond formation by allowing for the use of aryl halides containing these functional groups, obviating the need for protecting group manipulations.

Full text of DOI:10.1021/ol0262688

ORGANIC
LETTERS
2002
Vol. 4, No. 17
2885-2888
Improved Functional Group
Compatibility in the Palladium-Catalyzed
Synthesis of Aryl Amines
Michele C. Harris, Xiaohua Huang, and Stephen L. Buchwald*
Department of Chemistry, Massachusetts Institute of Technology,
Cambridge, Massachusetts 02139
sbuchwal@mit.edu
Received May 30, 2002
ABSTRACT
The use of Pd2dba3 with bulky, electron-rich ligands 1 or 2 and LiN(TMS)2 as the base for the coupling of amines with aryl halides containing
hydroxyl, amide, or enolizable keto groups is described. This protocol expands the utility of palladium-catalyzed C−N bond formation by
allowing for the use of aryl halides containing these functional groups, obviating the need for protecting group manipulations.
In recent years the palladium-catalyzed coupling of amines
with aryl halides or sulfonates has been widely investigated.1-3
Despite the improvements to the substrate scope of the
palladium-catalyzed C-N bond-forming reactions that utilize
triisopropylsilyl (TIPS),6 tert-butyldimethylsilyl (TBDMS),7
and benzyl protecting groups.8 Likewise, amides have been
protected with benzyl9 or methoxy methyl (MOM)10 groups.
Obviously, the use of protecting groups is inconvenient and
inefficient.
4
weak bases such as K3PO4 or Cs2CO3,5 limitations still exist.
A few exceptions to the limitations noted above have been
reported. For example, workers at Novartis used the Pd/
BINAP catalyst system, with NaOMe as the base, to couple
benzophenone imine with an aryl bromide containing a
carbamate.11 Link used Pd2(dba)3/BINAP in combination
with NaOt-Bu as the base to couple an amine with an aryl
bromide containing an amide that was distal to the aryl ring.12
Although the use of weak bases allows for the use of
substrates containing ester, cyano, nitro and keto groups in
the reaction, reactions of aryl substrates containing alcohol,
phenol, or amide functional groups have often been prob-
lematic. One hypothesis for the incompatibility of these
groups is that under the reaction conditions the deprotonated
alcohol, amide, or phenol binds to palladium and prevents
the desired reaction from occurring.
(6) Coleman, R. S.; Chen, W. Org. Lett. 2001, 3, 1141.
(7) Lakshman, M. K.; Keeler, J. C.; Hilmer, J. H.; Martin, J. Q. J. Am.
Chem. Soc. 1999, 121, 6090.
(8) Plante, O. J.; Buchwald, S. L.; Seeberger, P. H. J. Am. Chem. Soc.
2000, 1222, 7148.
(9) De Riccardis, F.; Bonala, R. R.; Johnson, F. J. Am. Chem. Soc. 1999,
121, 10453.
To synthesize aryl amines containing alcohol, phenol, or
amide groups, protecting group strategies have been em-
ployed. For example, alcohols have been masked with
(1) Muci, A. R.; Buchwald, S. L. Top. Curr. Chem. 2002, 219, 131.
(2) Yang, B. H.; Buchwald, S. L. J. Organomet. Chem. 1999, 576, 125.
(3) Hartwig, J. F. Angew. Chem., Int. Ed. 1998, 37, 2047.
(4) Old, D. W.; Wolfe, J. P.; Buchwald, S. L. J. Am. Chem. Soc. 1998,
120, 9722.
(10) Harayama, T.; Akamatsu, H.; Okamura, K.; Miyagoe, T.; Akiyama,
T.; Abe, H.; Takeuchi, Y. J. Chem. Soc., Perkin Trans. 1 2001, 523.
(11) Prashad, M.; Hu, B.; Lu, Y.; Draper, R.; Har, D.; Repicˇ, O.;
Blacklock, T. J. J. Org. Chem. 2000, 65, 2612.
(12) Link, J. T.; Sorensen, B.; Liu, G.; Pei, Z.; Reilly, E. B.; Leitza, S.;
Okasinski, G. Bioorg. Med. Chem. Lett. 2001, 11, 973.
(5) Wolfe, J. P.; Buchwald, S. L. Tetrahedron Lett. 1997, 38, 6359.
10.1021/ol0262688 CCC: $22.00 © 2002 American Chemical Society
Published on Web 07/30/2002

Additionally, Lemie`re successfully used Pd/BINAP with Cs2-
CO3 as the base to couple benzophenone imine with the
triflate of a 5-hydroxyflavone.13 Although these examples
are notable, they remain the exception. Herein, we describe
a significantly more general method for the direct coupling
of amines with aryl halide substrates containing alcohol,
phenol, and amide functional groups.
Silylamide bases have been used previously in Pd-catalyzed
C-N bond-forming processes15,16 but not, however, with
substrates containing alcohol, amide, phenol, or enolizable
keto groups.
In a typical protocol, 1 mol % Pd2(dba)3, 2.4 mol % of
the air-stable, commercially available ligands 1 or 2 (Figure
1), and 2.2 equiv of LiN(TMS)2 (1 M solution in THF)17
are employed.18,19 Using this system, aryl halides containing
alcohol (entries 1-5), phenol (entries 6-8), amide (entries
11-16), and keto (entries 17-19) groups may be coupled
with amines in good to excellent yields. Although the Pd-
catalyzed coupling of amines with aryl halides containing
an enolizable ketone group has previously been demonstrated
using Cs2CO3 and K3PO4 as base,20 the method described
herein allows for the use of lower temperatures (65 vs 100
°C) to provide products in comparable yields.
Scheme 1. LiN(TMS)2 as an Ammonia Surrogate
Amino alcohols were also investigated as substrates. No
reaction was observed when amino alcohols that may chelate
to the Pd center (e.g., 1,2- and 1,3-amino alcohols) were
employed as substrates. However, reactions of 4-hydroxypi-
peridine proceeded smoothly, as shown in entries 9 and 10.
Since 4-hydroxypiperidine was efficiently coupled with
unfunctionalized aryl bromides, we were interested in testing
how the presence of multiple functional groups affects this
chemistry. We were pleased to find that the reaction of
4-hydroxypiperidine with 3-chloroacetanilide using 3 equiv
of LiN(TMS)2 gave product in acceptable yield (entry 16).
While investigating the use of lithium bis(trimethylsilyl)-
amide as an ammonia equivalent,14 we observed that the
reaction of 4-bromoacetanilide with 2.2 equiv of LiN(TMS)2,
followed by acidic hydrolysis, gave 4-aminoacetanilide in
71% isolated yield (Scheme 1). C-N bond-forming reactions
with aryl bromides containing an amide group, particularly
with a N(H) moiety directly attached to the aromatic ring,
had been problematic. The results of this experiment thus
prompted us to follow up on our initial study.
Although this method is useful for a variety of substrates,
as expected, it is not without its limitations. This transforma-
tion works well with secondary amines and anilines;
however, primary aliphatic amines afford products in low
yields (ca. 30-40%). The reaction of 3-chlorophenethanol
with di-n-butylamine (entry 1) yields a large amount of
3-(trimethylsilyl)-phenethanol when the reaction is performed
at 65 °C.21 However, by conducting the reaction at room
Figure 1. Ligands used for the palladium-catalyzed amination
reaction with LiN(TMS)2 as the base.
(13) Deng, B.-L.; Lepoivre, J. A.; Lemie`re, G. Eur. J. Org. Chem. 1999,
2683.
(14) Huang, X.; Buchwald, S. L. Org. Lett. 2001, 3, 3417.
Expanding on our initial results, we found that LiN(TMS)2
could be used as the base, in many instances, in the coupling
reaction of amines with aryl halides containing alcohol,
phenol, amide, or keto groups (Scheme 2). Presumably, 1
(15) Louie, J.; Hartwig, J. F. Tetrahedron Lett. 1995, 36, 3609.
(16) Lee, S.; Jørgensen, M.; Hartwig, J. F. Org. Lett. 2001, 3, 2729.
(17) Solid LiN(TMS)2 in dioxane or THF may also be used with
comparable results; however, use of the solid is less desirable since the
setup requires use of a glovebox.
(18) General Procedure A. An oven-dried Schlenk tube was charged
with Pd2(dba)3 (4.6 mg, 0.005 mmol, 2 mol % Pd), ligand 1 (4.2 mg, 0.012
mmol, 2.4 mol %), aryl halide (0.50 mmol), and amine (0.60 mmol). The
Schlenk tube was evacuated and back-filled with argon, and the Teflon
screwcap was replaced with a rubber septa. The LiN(TMS)2 solution (1 M
in THF, 1.1 mL) was added via syringe (substrates that are liquids at room
temperature were added at this point). The rubber septum was replaced
with the Teflon screwcap, and the reaction vessel was sealed. The reaction
mixture was heated at 65 °C with stirring until the aryl halide had been
consumed as judged by GC analysis. The reaction mixture was then allowed
to cool to room temperature. To the reaction mixture was added 1 M HCl
(0.5-1.0 mL), and the mixture was stirred at room temperature for 5 min,
followed by neutralization with a saturated NaHCO3 solution (0.5-1.0 mL).
Dodecane (113 µL, 0.50 mmol) was added as an internal standard for GC
analysis, and the reaction mixture was diluted with ethyl acetate. The organic
layer was dried with MgSO4, filtered through a pad of Celite, and
concentrated in vacuo. The crude residue was purified by flash chroma-
tography on silica gel using mixtures of ethyl acetate/hexanes or methanol/
dichloromethane (for very polar compounds) as the eluent.
Scheme 2. General Reaction Scheme for Coupling of Amines
with Functionalized Aryl Halides
(19) General Procedure B. Same as general procedure A, but with
ligand 2 (4.6 mg, 0.012 mmol, 2.4 mol %).
(20) Wolfe, J. P.; Tomori, H.; Sadighi, J. P.; Yin, J.; Buchwald, S. L. J.
Org. Chem. 2000, 65, 1158.
equiv of the LiN(TMS)2 removes the most acidic proton of
the functional group, while the second equivalent is used as
the base (or as the nucleophile) in the coupling reaction.
2886
Org. Lett., Vol. 4, No. 17, 2002

Table 1. Synthesis of Aryl Amines Using LiN(TMS)2 as Basea
a Reaction conditions: (1) 1.2 equiv of amine, 1.0 equiv of aryl halide, 2.2 equiv of LiN(TMS)2 (1 M in THF), 0.5-1.5 mol % Pd2(dba)3 (1-3 mol %
Pd), 1.2-3.6 mol % ligand 1, 65 °C, 14-25 h. (2) H+. b Yields represent isolated yields of compounds estimated to be g95% pure as judged by 1H NMR,
GC, and combustion analysis (average of two runs). c Reaction performed at room temperature with a reaction time of 4 d. d Reaction proceeded to ∼95%
conversion. e Reaction performed with 2 as the supporting ligand. f Yield represents an average of three runs. g 3 equiv of LiN(TMS)2 used.
temperature, we were able to minimize the formation of this
silylated material, and the product was obtained in 64%
yield.22 We also observed that the coupling of aryl halides
containing functional groups (phenols, alcohols, and amides)
ortho to the halide is unsuccessful. However, use of non-
functionalized ortho-substituted aryl halides affords the
desired product in good yield (entry 10). Surprisingly, aryl
halides containing a N-BOC moiety are not compatible with
this method as cleavage of the BOC group is observed.
We were puzzled as to why this transformation works
using LiN(TMS)2, but is unsuccessful when other bases, such
as NaOt-Bu, LiOt-Bu, or K3PO4 (except in the case of
substrates containing a ketone) are employed. We considered
the possibility that formation of an in situ protected substrate
prevents the amide, alcohol, phenol, or ketone from binding
to the palladium (preventing catalyst deactivation). We
postulated that because Si-O bonds are significantly stronger
than a N-Si bond,23 perhaps a trimethylsilyl group is
(21) At this elevated temperature the 3-silated product may result from
lithium-halogen exchange, followed by a silyl group transfer.
(22) The reaction only proceeded to ca. 95% conversion.
(23) ComprehensiVe Organometallic Chemistry. The Synthesis, Reactions,
and Structures of Organometallic Compounds, 1st ed.; Pergamon Press:
New York, 1982; Vol. 2.
Org. Lett., Vol. 4, No. 17, 2002
2887

Scheme 3. Use of LDA to Deprotonate the Acidic Hydrogen
and Subsequent Palladium-Catalyzed Coupling Reaction
Figure 2. Proposed silylated intermediates.
transferred from LiN(TMS)2 to the oxygen atom of the
amide, alcohol, or ketone (Figure 2).
To probe the veracity of this hypothesis, we devised a set
of experiments to test whether formation of a silylated
intermediate was necessary to account for the compatibility
of these functional groups. For example, we combined
4-bromoacetanilide with LDA in THF at room temperature.
After stirring for 5 min, the contents of this flask were added
to a flask containing Pd2(dba)3, 1, N-methylaniline, and
NaOt-Bu, and the reaction mixture was stirred at 65 °C
(Scheme 3). If formation of a silylated intermediate is
necessary for the reaction to proceed, then no product should
be observed.
that a silylated intermediate may be required and that in situ
silylation may be occurring when LiN(TMS)2 is used as the
base.
In summary, we have developed a method for the use of
LiN(TMS)2 as the base in Pd-catalyzed C-N bond-forming
reactions with substrates containing alcohol, phenol, ketone,
or amide groups. This method expands the utility of this
methodology by allowing for the use of substrates containing
these functional groups. Investigations to understand the
factors behind these results are underway.
In fact, under these conditions, the desired product was
formed in 60% yield (as determined by GC). An identical
protocol with 4-bromophenol as the substrate yielded the
desired product in 69% yield (GC analysis). However, when
3-bromoacetophenone was used as the substrate, no desired
product was formed. Further, coupling reactions with 4-bro-
moacetanilide or 4-bromophenol with N-methylaniline where
the LDA deprotonation step was omitted yielded none of
the desired product.
Acknowledgment. We are grateful to the National
Institutes of Health (GM58160) and the National Cancer
Institute (training grant NCI CI T32CA09112) for financial
support. We also thank Pfizer, Merck, and Bristol-Myers-
Squibb for additional unrestricted support.
The results of these experiments imply that in situ
silylation of the oxygen of the phenol or amide is not required
for the success of the reaction. Instead, we suggest that
perhaps the lithiate or a lithium-amide aggregate24 of the
deprotonated substrate functions as a protecting group, thus
inhibiting binding of the oxygen to the palladium center. The
experimental results of the reaction with 3-bromoacetophe-
none, while not conclusive, are consistent with the notion
Supporting Information Available: Experimental pro-
cedures and details of compound characterization. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(24) Lucht, B. L.; Collum, D. B. Acc. Chem. Res. 1999, 32, 1035.
OL0262688
2888
Org. Lett., Vol. 4, No. 17, 2002