Use of aryl chlorides as electrophiles in Pd-catalyzed alkene difunctionalization reactions

Article abstract of DOI:10.1021/jo100344k

The development of conditions that allow use of inexpensive aryl chlorides as electrophiles in Pd-catalyzed alkene carboamination and carboetherification reactions is described. A catalyst composed of Pd(OAc)₂ and S-Phos minimizes N-arylation of the substrate and prevents formation of mixtures of regioisomeric products. A number of heterocycles, including pyrrolidines, isoxazolidines, tetrahydrofurans, and pyrazolidines, are efficiently generated with this method.

Full text of DOI:10.1021/jo100344k

pubs.acs.org/joc
substituted N-aryl-, N-acetyl-, or N-Boc-pyrrolidines with a
Use of Aryl Chlorides as Electrophiles in
Pd-Catalyzed Alkene Difunctionalization Reactions
high degree of stereocontrol.1,2 This strategy has also been
employed for the generation of several other oxygen- or
nitrogen-containing heterocycles.3-5
Brandon R. Rosen, Joshua E. Ney, and John P. Wolfe*
To further expand the scope and utility of these transfor-
mations, we sought to employ inexpensive aryl chlorides as
electrophilic coupling partners in these reactions.6 In our
prior studies, we had found that chelating phosphine ligands
with wide bite angles, such as Dpe-phos, Xantphos, or dppb,
provided optimal results in many transformations of aryl
bromides.2 However, Pd catalysts supported by these ligands
are not sufficiently active to facilitate transformations of
aryl chlorides, which are considerably less reactive than
the corresponding aryl bromides. Thus, to achieve our goal,
we would need to discover catalysts that both activate
aryl chlorides and also promote the alkene carboamination
process.
Department of Chemistry, University of Michigan, 930 North
University Avenue, Ann Arbor, Michigan, 48109-1055
jpwolfe@umich.edu
Received February 23, 2010
Due to the significant economic advantages associated
with using aryl chlorides in place of aryl bromides, consider-
able research effort has been expended on the development
of ligands for Pd-catalyzed cross-coupling reactions of these
relatively unreactive electrophiles.7 Many of these ligands
are highly effective in Suzuki couplings, N-arylations, and
other carbon-carbon or carbon-heteroatom bond-forming
processes.7-9 However, our initial efforts to employ
these ligands in Pd-catalyzed carboamination reactions of
γ-(N-arylamino)alkenes (e.g., 1a) provided unsatisfactory
results. Use of Buchwald’s biphenyl(dialkyl)phosphines8
led to competing N-arylation of these substrates, and many
other electron-rich ligands led to mixtures of regioisomeric
products. For example, the Pd/P(tBu)2Me-catalyzed reac-
tion of 1a with 2-chloronaphthalene afforded an 11:1:1:3
mixture of 2a:3:4:5 (eq 1).
The development of conditions that allow use of inexpen-
sive aryl chlorides as electrophiles in Pd-catalyzed alkene
carboamination and carboetherification reactions is
described. A catalyst composed of Pd(OAc)2 and S-Phos
minimizes N-arylation of the substrate and prevents
formation of mixtures of regioisomeric products. A number
of heterocycles, including pyrrolidines, isoxazolidines,
tetrahydrofurans, and pyrazolidines, are efficiently gener-
ated with this method.
Over the past several years, our group has developed a new
type of cross-coupling reaction in which alkenes bearing
pendant aminopropyl groups are transformed to substituted
pyrrolidines via Pd-catalyzed carboamination reactions
with aryl bromides. These alkene difunctionalization reac-
tions provide a convergent and efficient means to access
(1) (a) Ney, J. E.; Wolfe, J. P. Angew. Chem., Int. Ed. 2004, 43, 3605.
(b) Bertrand, M. B.; Wolfe, J. P. Tetrahedron 2005, 61, 6447. (c) Ney, J. E.;
Wolfe, J. P. J. Am. Chem. Soc. 2005, 127, 8644. (d) Bertrand, M. B.; Wolfe,
J. P. Org. Lett. 2006, 8, 2353. (e) Bertrand, M. B.; Neukom, J. D.; Wolfe, J. P.
J. Org. Chem. 2008, 73, 8851. (f ) Rossiter, L. M.; Slater, M. L.; Giessert,
R. E.; Sakwa, S. A.; Herr, R. J. J. Org. Chem. 2009, 74, 9554.
After considerable optimization, we discovered that PCy2Ph
provided acceptable results in many Pd-catalyzed carboami-
nation reactions of aryl chlorides with γ-N-(arylamino)-
alkenes. As shown in Table 1, both electron-donating and
(2) For reviews on Pd-catalyzed carboamination reactions, see: (a) Wolfe,
J. P. Eur. J. Org. Chem. 2007, 571. (b) Wolfe, J. P. Synlett 2008, 2913.
(3) For related syntheses of imidazolidin-2-ones, isoxazolidines, pyrazo-
lidines, piperazines, and morpholines via Pd-catalyzed carboamination
reactions, see: (a) Fritz, J. A.; Wolfe, J. P. Tetrahedron 2008, 64, 6838. (b)
Lemen, G. S.; Giampietro, N. C.; Hay, M. B.; Wolfe, J. P. J. Org. Chem.
2009, 74, 2533. (c) Giampietro, N. C.; Wolfe, J. P. J. Am. Chem. Soc. 2008,
130, 12907. (d) Nakhla, J. S.; Schultz, D. M.; Wolfe, J. P. Tetrahedron 2009,
65, 6549. (e) Leathen, M. L.; Rosen, B. R.; Wolfe, J. P. J. Org. Chem. 2009,
74, 5107. (f ) Peng, J.; Jiang, D.; Lin, W.; Chen, Y. Org. Biomol. Chem. 2007,
5, 1391. (g) Peng, J.; Lin, W.; Yuan, S.; Chen, Y. J. Org. Chem. 2007, 72, 3145.
(4) For Cu- or Au-catalyzed carboamination reactions, see: (a) Fuller,
P. H.; Chemler, S. R. Org. Lett. 2007, 9, 5477. (b) Zeng, W.; Chemler, S. R.
J. Am. Chem. Soc. 2007, 129, 12948 and references cited therein. (c) Zhang, G.;
Cui, L.; Wang, Y.; Zhang, L. J. Am. Chem. Soc. 2010, 132, 1474.
(6) The use of aryl chlorides as electrophiles in Pd-catalyzed carboamina-
tion reactions that afford aziridines or pyrrolizidin-2-ones has recently been
reported. See: (a) Hayashi, S.; Yorimitsu, H.; Oshima, K. Angew. Chem., Int.
Ed. 2009, 48, 7224. (b) Bagnoli, L.; Cacchi, S.; Fabrizi, G.; Goggiamani, A.;
Scarponi, C.; Tiecco, M. J. Org. Chem. 2010, 75, 2134.
(7) Reviews: (a) Littke, A. In Modern Arylation Methods; Ackermann, L.,
Ed.; Wiley-VCH: Weinheim, 2009; p 25. (b) Bedford, R. B.; Cazin, C. S. J.;
Holder, D. Coord. Chem. Rev. 2004, 248, 2283. (c) Littke, A. F.; Fu, G. C. Angew.
Chem., Int. Ed. 2002, 41, 4176.
(5) For alkene carboamination reactions involving solvent C-H bond
functionalization, see: (a) Rosewall, C. F.; Sibbald, P. A.; Liskin, D. V.;
Michael, F. E. J. Am. Chem. Soc. 2009, 131, 9488. (b) Sibbald, P. A.;
Rosewall, C. F.; Swartz, R. D.; Michael, F. E. J. Am. Chem. Soc. 2009,
131, 15945.
(8) Surry, D. S.; Buchwald, S. L. Angew. Chem., Int. Ed. 2008, 47, 6338.
(9) (a) Stambuli, J. P.; Kuwano, R.; Hartwig, J. F. Angew. Chem., Int. Ed.
2002, 41, 4746. (b) Navarro, O.; Kelly, R. A. III; Nolan, S. P. J. Am. Chem.
Soc. 2003, 125, 16194. (c) Reddy, C. V.; Kingston, J. V.; Verkade, J. G. J. Org.
Chem. 2008, 73, 3047 and references cited therein.
2756 J. Org. Chem. 2010, 75, 2756–2759
Published on Web 03/18/2010
DOI: 10.1021/jo100344k
r
2010 American Chemical Society

Rosen et al.
JOCNote
TABLE 1. Carboamination of γ-(N-Arylamino)alkenes with Aryl
SCHEME 1. Mechanism and Side Reactions
Chloridesa
of II, followed by a series of hydridopalladation/β-hydride
elimination steps.1,2 In light of this mechanism, the difficulties
we encountered during our studies on carboamination reac-
tions between aryl chlorides and γ-(N-arylamino)alkenes can
be ascribed to two factors: (a) use of electron-rich ligands slows
reductive elimination from II, leading to increased amounts of
regioisomers, and (b) use of bulky, electron-rich ligands that
facilitate C-C bond forming reductive elimination leads to
competing N-arylation via C-N bond-forming reductive
elimination from I.
This mechanistic analysis suggests that transformations of
the analogous N-Boc-protected substrates may be less pro-
blematic. The electron-withdrawing Boc-group is known to
slow the rate of C-N bond-forming reductive elimination
that leads to N-arylation.1b,12 Thus, bulky electron-rich
ligands could be used to facilitate the C-C bond-forming
reductive elimination from intermediates analogous to II
with less concern about competing N-arylation. In addition,
the electron-withdrawing Boc-group also disfavors β-hy-
dride elimination pathways that provide regioisomers,1b
which should further aid in the selective formation of a single
product.
We have recently illustrated that the electron-rich ligand
S-Phos14,15 provides excellent results in Pd-catalyzed car-
boetherification reactions between unsaturated alcohols and
aryl bromides,16 and this ligand appeared to be a good
candidate for use in alkene difunctionalization reactions
between aryl chlorides and substrates containing relatively
non-nucleophilic heteroatoms. As such, we examined the
Pd-catalyzed coupling of 6a with 4-chlorotoluene and were
gratified to find this transformation afforded the desired
product 7a in 74% yield (eq 2).
aConditions: amine (1.0 equiv), aryl chloride (1.1-1.4 equiv), NaOtBu
(1.2 equiv), Pd2(dba)3 (1 mol %), PCy2Ph (4 mol %), toluene (0.25 M),
110 °C. bDetermined by 1H NMR analysis. The minor regioisomers
formed are analogous to 3-5 shown in eq 1. cIsolated yield (average of
d
two or more experiments). PCy3 HBF4 was used in place of PCy2Ph.
3
f
eThe minor regioisomer was arylated at C4 rather than C5. P(tBu)2-
Me HBF4 was used in place of PCy2Ph.
3
electron-withdrawing groups are tolerated on the aryl chloride,
and in all cases the major products were formed with g90%
regioselectivity. Transformations involving acyclic internal
alkene substrates were unsuccessful, affording complex mix-
tures of products.10 However, cyclopentene-derived substrate
1d was converted to bicyclic heterocycles 2f-g in good yields
and with high diastereoselectivities.11
The mechanism of the carboamination reactions involves
the syn-aminopalladation of intermediate I, followed by
C-C bond-forming reductive elimination from intermediate
II to afford the desired products (Scheme 1).1,2 Diarylamine
side products (III) result from competing C-N bond form-
ing reductive elimination of intermediate I.12,13 Undesired
regioisomers 3-5 are generated through β-hydride elimination
In order to explore the scope of this method, we examined
the coupling of a range of N-Boc-protected γ-aminoalkene
derivatives. As shown in Table 2, the transformations are
effective with a variety of aryl chlorides, including electron-
rich, electron-poor, and ortho-substituted compounds.
In addition, satisfactory results were also obtained with
the heteroaromatic electrophiles N-benzyl-5-chloroindole,
2-chloropyridine, and 2-chloropyrazine (entries 2, 6, and 8).
The synthesis of cis-2,5-disubstituted products was achieved
(10) Analysis by 1H NMR suggests that mixtures of pyrrolidine regioi-
somers are formed, and competing substrate N-arylation also occurs. This
outcome may be due to a combination of relatively slow aminopalladation of
the more hindered internal alkene combined with relatively slow reductive
elimination from a secondary alkylpalladium intermediate analogous to II.
(11) The installation of the aryl group at C5 rather than C6 in 2f-g results
from β-hydride elimination/hydridopalladation processes similar to those
illustrated in Scheme 1 (II f IV f 3-5). Selective formation of the 6-aryl
isomers has been ascribed to the relative stabilities of intermediates along this
pathway. For a detailed discussion of reaction mechanism and the origin of
these products, see ref 1c.
(12) (a) Muci, A. R.; Buchwald, S. L. Top. Curr. Chem. 2002, 219, 131. (b)
Hartwig, J. F. Inorg. Chem. 2007, 46, 1936.
(13) The reactivity of intermediates I and II is highly dependent on ligand
structure. For further discussion, see refs 1c and 2a.
(14) S-Phos = 2-dicyclohexylphosphino-20,60-dimethoxy-1,10-biphenyl.
(15) Walker, S. D.; Barder, T. E.; Martinelli, J. R.; Buchwald, S. L.
Angew. Chem., Int. Ed. 2004, 43, 1871.
(16) Ward, A. F.; Wolfe, J. P. Org. Lett. 2010, 12, 1268.
J. Org. Chem. Vol. 75, No. 8, 2010 2757

Rosen et al.
JOCNote
TABLE 2. Carboamination of γ-(N-Boc)aminoalkenes with Aryl
TABLE 3. Synthesis of Other Heterocycles Using Aryl Chlorides as
Electrophilesa
Chloridesa
aConditions: substrate (1 equiv), aryl chloride (1.2 equiv), NaOtBu
(1.2 equiv), Pd(OAc)2 (2 mol %), S-Phos (4 mol %), toluene (0.25 M), 90
c
or 110 °C. bIsolated yield (average of two or more experiments). This
material was obtained as a 13:1 mixture of regioisomers.
was tolerated (entries 9-11), efforts to employ substrates
bearing internal alkenes were unsuccessful due to competing
substrate decomposition.17
Following our success with N-Boc-aminopropylalkenes,
we proceeded to examine the utility of the Pd/S-Phos catalyst
in carboamination and carboetherification reactions of aryl
chlorides that generate other heterocycles. As shown in
Table 3, the conversion of urea 8, hydroxylamine 9, and
hydrazine 10 to the corresponding imidazolidin-2-one 14,
isoxazolidine 15, and pyrazolidine 16 proceeded smoothly.
The heterocyclic products were obtained in good chemical
yield, and 15 was formed with 20:1 dr. The coupling of
tertiary alcohol 11 with 1-chloronaphthalene afforded tetra-
hydrofuran 17 in 89% yield, although a 13:1 mixture of
regioisomers was generated. However, attempts to effect a
similar transformation between secondary alcohol 12 and
4-chloroanisole failed to yield the desired tetrahydrofuran
product.18 Instead, oxidation of the alcohol was observed,
which suggests that alkene oxypalladation from an intermedi-
ate analogous to I is relatively slow with S-Phos as ligand. As a
(17) Analysis of crude reaction mixtures by 1H NMR showed predomi-
nantly the desired product, with little or no evidence of side product
formation. Modest yields obtained in some transformations may be due to
base-mediated substrate decomposition. See: Tom, N. J.; Simon, W. M.;
Frost, H. N.; Ewing, M. Tetrahedron Lett. 2004, 45, 905.
aConditions: amine (1 equiv), aryl chloride (1.2 equiv), NaOtBu
(1.2 equiv), Pd(OAc)2 (2 mol %), S-Phos (4 mol %), toluene (0.25 M),
90 °C. bIsolated yield (average of two or more experiments).
(18) Both of these transformations are effective with the corresponding
aryl bromides when an appropriate phosphine ligand is used. For transfor-
mations that afford cis-3,5-disubstituted morpholines using P(2-furyl)3 as
ligand, see ref 3e. For transformations that generate trans-2,5-disubstituted
tetrahydrofurans using bis(2-diphenylphosphinophenyl)ether (dpe-phos) as
ligand, see: Hay, M. B.; Hardin, A. R.; Wolfe, J. P. J. Org. Chem. 2005, 70,
3099.
with excellent stereocontrol (entries 12 and 13), and good to
excellent selectivity was obtained in the synthesis of trans-2,
3-disubstituted products (entries 9-11). In all cases, the pro-
ducts were generated with complete regioselectivity.17 Although
substitution at the allylic position of the γ-aminoalkene derivative
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Rosen et al.
JOCNote
result, β-hydride elimination from this intermediate is the
predominant reaction pathway with substrate 12. The conver-
sion of amine 13 to morpholine 19 was also unsuccessful due to
competing N-arylation of the substrate.18,19
In conclusion, we have developed conditions that allow
use of inexpensive and readily available aryl chloride
electrophiles in many Pd-catalyzed carboamination and
carboetherification reactions. These studies significantly
expand the scope and utility of this method for heterocycle
synthesis and also illustrate several remaining challenges
for catalyst development in the field.
Schlenk tube via syringe. The mixture was heated in a 90 °C oil
bath with stirring until the starting material had been consumed
as judged by GC analysis (7 h). The reaction mixture was cooled
to room temperature, quenched with saturated aqueous NH4Cl
(2 mL), and diluted with EtOAc (2 mL). The layers were
separated, and the aqueous layer was extracted with EtOAc
(3 ꢀ 5 mL). The organic layers were concentrated in vacuo, and
the crude product was purified by flash chromatography on
silica gel to afford 95 mg (69%) of the title compound as a pale
yellow oil: 1H NMR (400 MHz, C6D5CD3, 100 °C) δ 7.03-6.89
(m, 4 H), 4.03-3.91 (m, 1 H), 3.33-3.23 (m, 1 H), 3.20-3.01 (m,
2 H), 2.51 (dd, J = 8.9, 13.0 Hz, 1 H), 2.13 (s, 3 H), 1.55-1.28
(m, 13 H); 13C NMR (100 MHz, C6D5CD3, 100 °C) δ 154.6,
137.1, 135.9, 130.0, 129.6, 78.9, 59.5, 59.4, 47.2, 30.3, 29.1, 23.7,
21.2; IR (film) 1693, 1394, 1172 cm-1; MS (ESI) 298.1779
(298.1783 calcd for C17H25NO2, M þ Naþ).
Experimental Section
Representative Procedure for Pd-Catalyzed Carboamination
Reactions of Aryl Chlorides. (()-tert-Butyl 2-(4-Methylbenzyl)-
pyrrolidine-1-carboxylate (7a). A Schlenk tube was evacuated,
flame-dried, and backfilled with nitrogen. The tube was charged
with Pd(OAc)2 (2.3 mg, 0.01 mmol), 2-dicyclohexylphosphino-
20,60-dimethoxy-1,10-biphenyl (S-Phos, 8.2 mg, 0.02 mmol), and
NaOtBu (57.7 mg, 0.60 mmol). The tube was evacuated and
backfilled with nitrogen three times. A solution of tert-butyl
pent-4-en-1-ylcarbamate (93 mg, 0.50 mmol) and 4-chloroto-
luene (71 μL, 0.60 mmol) in toluene (2 mL) was added to the
Acknowledgment. We thank the NIH-NIGMS (GM071650)
for financial support of this work. Additional support was
provided by the Camille and Henry Dreyfus Foundation
(Camille Dreyfus Teacher Scholar Award), GlaxoSmithKline,
Eli Lilly, and Amgen.
Supporting Information Available: Experimental proce-
dures, spectroscopic data, and copies of 1H and 13C NMR
spectra for all new compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
(19) Efforts to employ a Boc-protected analogue of 13 also failed to
provide a substituted morpholine product. Base-mediated decomposition of
the substrate was observed.
J. Org. Chem. Vol. 75, No. 8, 2010 2759