Nickel-catalyzed amination of aryl chlorides

Article abstract of DOI:10.1021/ja964391m

Aryl chlorides are converted to aniline derivatives using catalytic amounts of Ni(COD)₂ (COD = 1,5-cyclooctadiene) and DPPF (DPPF = 1,1'- bis(diphenylphosphino)ferrocene) or 1,10-phenanthroline in the presence of sodium tert-butoxide. This procedure has a broad substrate scope: electron- rich or electron-poor aryl chlorides, as well as chloropyridine derivatives, can be combined with primary and secondary amines to give the desired aryl amine products in moderate to excellent yields. Additionally, a procedure which utilizes the air-stable precatalysts (DPPF)NiCl₂ or (1,10- phenanthroline)NiCl₂ is also described.

Full text of DOI:10.1021/ja964391m

6054
J. Am. Chem. Soc. 1997, 119, 6054-6058
Nickel-Catalyzed Amination of Aryl Chlorides
John P. Wolfe and Stephen L. Buchwald*
Contribution from the Department of Chemistry, Massachusetts Institute of Technology,
Cambridge, Massachusetts 02139
ReceiVed December 23, 1996X
Abstract: Aryl chlorides are converted to aniline derivatives using catalytic amounts of Ni(COD)2 (COD )
1,5-cyclooctadiene) and DPPF (DPPF ) 1,1′-bis(diphenylphosphino)ferrocene) or 1,10-phenanthroline in the presence
of sodium tert-butoxide. This procedure has a broad substrate scope: electron-rich or electron-poor aryl chlorides,
as well as chloropyridine derivatives, can be combined with primary and secondary amines to give the desired aryl
amine products in moderate to excellent yields. Additionally, a procedure which utilizes the air-stable precatalysts
(DPPF)NiCl2 or (1,10-phenanthroline)NiCl2 is also described.
The palladium-catalyzed amination of aryl bromides,1a-g
Nickel complexes have been shown to catalyze carbon-
carbon bond-forming reactions which use aryl chlorides as
coupling partners.2 This prompted us to investigate their utility
in catalyzing carbon-nitrogen bond-forming reactions with aryl
chloride substrates, and herein, we report our initial results.6
This process, which proceeds at moderate temperatures (70-
100 °C), is capable of converting a wide variety of aryl chlorides
to substituted anilines.
iodides,1g,h and triflates1i,j with primary and secondary amines
and anilines has provided a new route to a wide variety of aryl
amines. Our desire to expand the aryl amination methodology
to include aryl chlorides stems from the fact that they are both
the least expensive and the most widely available aryl halides.
Many of the methods used to extend the scope of palladium-
catalyzed carbon-carbon bond-forming reactions to include aryl
chlorides are limited by the need for substrates that are activated
by electron-withdrawing groups or by complexed transition
metal fragments.2,3 While electron-rich phosphines have been
utilized,2,4 these do not appear to be viable ligands for palladium-
catalyzed aminations; increased electron density on the metal
center decreases the rate of reductive elimination relative to
â-hydride elimination, leading to lower yields of coupled
products and increased amounts of arene side products (see
below).5
After some initial experimentation, we found that mixtures
of Ni(COD)2 (COD ) cyclooctadiene) and DPPF7 effectively
promote the coupling of aryl chlorides with amines (eq 1). For
Ar-Cl + HN(R)R′ cat. Ni(COD) , ligand, NaOtBu8 Ar-N(R)R′ (1)
2
toluene, 70-100 °C
example, 4-chlorotoluene and N-methylaniline (Table 1, entry
1) give the desired tertiary amine in 80% yield by employing 2
mol % Ni(COD)2/4 mol % DPPF in the presence of a
stoichiometric amount of NaOtBu at 100 °C in toluene. This
method effectively couples both electron-rich (entries 1-10)
and electron-poor aryl chlorides (entries 11-12), as well as
chloropyridine derivatives (entries 13-14), with amines in
moderate to excellent yields (Table 1). The reaction conditions
are sufficiently mild to tolerate a variety of functional groups
including ethers, nitriles, acetals, and non-enolizable ketones,
Our initial attempts to utilize aryl chlorides as substrates with
palladium catalysts resulted in low conversion when P(o-tolyl)3
or BINAP-based7 catalyst systems were employed as ligands.
For example, the reaction of 4-chlorotoluene and N-methylben-
zylamine at 100 °C resulted in low conversion (<10%) when a
Pd2(dba)3/P(o-tolyl)3 catalyst system was employed (4 mol %
Pd). When P(cyclohexyl)3 was used as the phosphine ligand,
the reaction proceeded to completion, but the yield of desired
product was low (<30% by GC).
(5) (a) Hegedus, L. S. Transition Metals in the Synthesis of Complex
Organic Molecules; University Science Books: Mill Valley, CA, 1994; p
27. (b) Marcoux, J.-F.; Wagaw, S.; Buchwald, S. L. J. Org. Chem. 1997,
62, 1568-1569. (c) Hartwig, J. F.; Richards, S.; Baran˜ano, D.; Paul, F. J.
Am. Chem. Soc. 1996, 118, 3626-3633.
X Abstract published in AdVance ACS Abstracts, June 15, 1997.
(1) (a) Kosugi, M.; Kameyama, M.; Migita, T. Chem. Lett. 1983, 927-
928. (b) Guram, A. S.; Rennels, R. A.; Buchwald, S. L. Angew. Chem.,
Int. Ed. Engl. 1995, 34, 1348-1350. (c) Wolfe, J. P.; Rennels, R. A.;
Buchwald, S. L. Tetrahedron 1996, 52, 7525-7546. (d) Wolfe, J. P.;
Wagaw. S.; Buchwald, S. L. J. Am. Chem. Soc. 1996, 118, 7215-7216.
(e) Wagaw, S.; Buchwald, S. L. J. Org. Chem. 1996, 61, 7240-7241. (f)
Louie, J.; Hartwig, J. F. Tetrahedron Lett. 1995, 36, 3609-3612. (g) Driver,
M. S.; Hartwig, J. F. J. Am. Chem. Soc. 1996, 118, 7217-7218. (h) Wolfe,
J. P.; Buchwald, S. L. J. Org. Chem. 1996, 61, 1133-1135. (i) Wolfe, J.
P.; Buchwald, S. L. J. Org. Chem. 1997, 62, 1264-1267. (j) Louie, J.;
Driver, M. S.; Hamann, B. C.; Hartwig, J. F. J. Org. Chem. 1997, 62, 1268-
1273.
(2) Grushin, V. V.; Alper, H. Chem. ReV. 1994, 94, 1047-1062. Nickel-
catalyzed C-S bond formation has also been reported: (a) Takagi, K. Chem.
Lett. 1987, 2221-2224. (b) Cristau, H. J.; Chabaud, B.; Chene, A.; Christol,
H. Synthesis 1981, 892-894.
(3) Carpentier, J. F.; Petit, F.; Mortreux, A.; Dufaud, V.; Basset, J.-M.;
Thivolle-Cazat, J. J. Mol. Catal. 1993, 81, 1-15.
(6) Previous reports of nickel-catalyzed aryl carbon-nitrogen bond
formation consist of a few examples with no isolated yields of products
given. The only example of nickel-catalyzed amination of an aryl chloride
was the reaction of chlorobenzene with dimethylamine, which required 10
equiv of dimethylamine and only proceeded to 68% conversion after 6 h at
200 °C. (a) Cramer, R.; Coulson, D. R. J. Org. Chem. 1975, 40, 2267-
2273. (b) Christau, H. J.; Desmurs, J. R. Ind. Chem. Libr. 1995, 7, 240. (c)
In the report by Cristau and Desmurs, no specific aryl halides were referred
to. Instead, the generic example “Ar-Br” was used. Additionally, no
experimental details were given. (d) After the submission of this manuscript,
Beller reported the coupling of electron-deficient aryl chlorides with amines
in the presence of a palladacycle catalyst, potassium tert-butoxide, and
lithium bromide at 135-140 °C. The aniline products were obtained as
mixtures of regioisomers resulting from a competing benzyne pathway.
Beller, M.; Reirmeier, T. H.; Reisinger, C.-P.; Herrmann, W. A. Tetrahedron
Lett. 1997, 38, 2073-2074.
(4) (a) Portnoy, M.; Milstein, D. Organometallics 1993, 12, 1665-1673
and references therein. (b) The most effective ligands for Pd-catalyzed
reactions of aryl chlorides2 are chelating bis(diisopropylphosphine) com-
plexes such as 1,3-bis(diisopropylphosphino)propane (dippp). However,
these ligands are not commercially available and can be difficult to prepare
due to the air-sensitive nature of small, basic phosphines.
(7) Abbreviations used: dba ) dibenzylideneacetone, DPPF) 1,1′-bis-
(diphenylphosphino)ferrocene, BINAP ) 2,2′-bis(diphenylphosphino)-1,1′-
binaphthyl, PPFA ) N,N-dimethyl-1-[2-(diphenylphosphino)ferrocenyl]-
ethylamine, PPFE ) 1-[2-(diphenylphosphino)ferrocenyl]ethyl methyl ether,
DPPP ) 1,3-bis(diphenylphosphino)propane, and DPPE ) 1,2-bis(diphen-
ylphosphino)ethane.
S0002-7863(96)04391-0 CCC: $14.00 © 1997 American Chemical Society

Nickel-Catalyzed Amination of Aryl Chlorides
J. Am. Chem. Soc., Vol. 119, No. 26, 1997 6055
Table 1. Nickel-Catalyzed Amination of Aryl Chlorides
a Method A: 1 equiv of halide, 1.2 equiv of amine, 1.4 equiv of NaOtBu, 2-5 mol % Ni(COD)2, 4-10 mol % DPPF, toluene (0.25 M), 100
°C. Method B: 1 equiv of halide, 1.2 equiv of amine, 1.4 equiv of NaOtBu, 2-5 mol % Ni(COD)2, 4-10 mol % 1,10-phenanthroline, pyridine
(0.25 M), 100 °C. Method C: Same as method A, but (DPPF)NiCl2/MeMgBr used in place of Ni(COD)2. Method D: Same as method B, but
(Phen)NiCl2/MeMgBr used in place of Ni(COD)2. b 3.0 equiv of amine used.
and reactions may be run at temperatures as low as 70 °C. The
main side products of the reaction are arenes resulting from
reduction of the aryl halides, although in some cases small
amounts of homocoupled arenes were produced. Attempts to
couple 4-chlorobenzaldehyde with pyrrolidine resulted in
the formation of amide side products which may arise from
â-hydride elimination of a hemi-aminal intermediate as shown
in Scheme 1. Primary amines with â-hydrogens give large
amounts of reduced side products, unless electron-deficient
aryl chlorides are used as coupling partners. Additionally, when
primary amines with â-hydrogens are coupled with electroni-
cally-neutral aryl chlorides, imine side products resulting from
oxidation of the coupled amine were also detected. Formation
of these side products is significantly decreased when the
couplings were performed with an excess (3 equiv) of the amine.
reaction. However, the chelating nitrogen ligand 1,10-phenan-
throline (phen), which was not an effective ligand in palladium-
catalyzed aminations, proved quite useful for nickel-catalyzed
C-N bond-forming procedures (Table 1, entries 4, 6, 7, 9, and
12). With this ligand, substantially higher yields of desired
products could be obtained for some substrates than with the
Ni(COD)2/DPPF catalyst system. For example, the attempted
reaction of 2-chloro-p-xylene with pyrrolidine afforded a 1:2
ratio8 of the desired product/arene side product using the Ni-
(COD)2/DPPF combination. With the Ni(COD)2/1,10-phenan-
throline catalyst, a 12:1 ratio of desired product/arene was
obtained; N-(2,5-xylyl)pyrrolidine was isolated in 84%. In most
cases, reactions which employed 1,10-phenanthroline required
a larger catalyst loading than those using DPPF (5% vs 2%).
In addition, it was necessary to employ pyridine as a solvent to
obtain complete consumption of the starting aryl chloride.
However, 1,10-phenanthroline is much less expensive than either
Other phosphine ligands examined (BINAP, PPFA, PPFE,
DPPP, DPPE, PPh3, and P(o-tolyl)3)7 gave either low conversion
or poor product/reduced substrate ratios for the coupling
(8) Ratios are not corrected for GC response factors.

6056 J. Am. Chem. Soc., Vol. 119, No. 26, 1997
Wolfe and Buchwald
Scheme 1
Scheme 2
BINAP or DPPF, and its high polarity allows for its easy
chromatographic separation from the desired products.9 The
use of other 1,10-phenanthroline derivatives such as neocuproine
hydrate and 2,9-dimethyl-4,7-diphenyl-1,10-phenanthroline af-
forded little or no desired products. While 1,10-phenanthroline
proved to be a superior ligand for some coupling reactions,
attempts to use it in procedures to couple aryl chlorides with
anilines failed under these conditions, giving mainly homo-
coupled byproducts.
Due to the air sensitivity and thermal instability of Ni(COD)2,
we felt it would be desirable to develop conditions to carry out
this transformation with air stable (L-L)NiCl2 precatalysts.
Attempts to directly employ these complexes without additional
additives resulted in no reaction. Use of activated zinc2a,10 to
reduce the Ni(II) precatalysts in situ also failed, resulting in
low conversion of the aryl chloride to the desired aniline.
However, MeMgBr (2 equiv/Ni) proved to be an effective
reagent for the activation of these complexes (eq 2).11 Use of
We currently have little mechanistic information about this
transformation. The reaction sequence may be similar to the
one proposed for the palladium-catalyzed amination of aryl
halides,1d or it may proceed through Ni(I) and Ni(III) intermedi-
ates as proposed by Kochi for the nickel-catalyzed coupling of
aryl halides with Grignard reagents.12 A mechanism which
involves electron transfer from Ni to an aryl halide is consistent
with the fact that reaction of 2-bromo-p-xylene with pyrrolidine
afforded mainly xylene and only a small amount of the desired
product under conditions which gave excellent yields for the
coupling of the corresponding chloride (Scheme 2). These
results are consistent with the observations made by Kumada
on reactions of halobenzenes with n-butylmagnesium bromide,
although the differences between the results obtained with the
aryl chloride and aryl bromide are more dramatic in this case.11
In conclusion, we have demonstrated the first nickel-catalyzed
amination of aryl chlorides which allows for the coupling of a
wide variety of substrates under relatively mild conditions.
Studies are underway to further expand the scope of this
methodology, as well as to ascertain mechanistic details of the
nickel-catalyzed process.
Ar-Cl + HN(R)R′ cat. (L-L)NiCl , cat. MeMgBr, ligand8 Ar-N(R)R′ (2)
2
NaOtBu, toluene, 100 °C
the in situ generated catalyst provided yields which were
generally comparable to those obtained with Ni(COD)2, although
sometimes slightly higher catalyst levels were required. While
this method proved satisfactory for some coupling reactions
(Table 1, entries 4, 5, and 11), it did not provide reproducible
results for the attempted combination of 4-chloroanisole with
o-toluidine.
Experimental Section
General. All reactions were carried out under an argon atmosphere
in oven dried glassware. Reactions catalyzed by mixtures of Ni(COD)2
and DPPF or 1,10-phenanthroline were run in Schlenk tubes equipped
with a Teflon screwcap and were mixed and sealed in a Vacuum
Atmospheres glovebox prior to heating in an oil bath outside of the
glovebox. Reactions in which (L-L)NiCl2 complexes were employed
(9) DPPF is relatively nonpolar, and separation of the excess DPPF from
nonpolar aryl amines occasionally required an additional step in the workup
to oxidize the phosphine.
(10) (a) Kende, A. S.; Liebeskind, L. S.; Braitsch, D. M. Tetrahedron
Lett. 1975, 3375-3378. (b) Percec, V.; Bae, J.-Y.; Zhao, M.; Hill, D. H. J.
Org. Chem. 1995, 60, 176-185.
(11) Tamao, K.; Sumitani, K.; Kiso, Y.; Zembayashi, M.; Fujioka, A.;
Kodama, S.-I.; Nakajima, I.; Minato, A.; Kumada, M. Bull. Chem. Soc.
Jpn. 1976, 49, 1958-1969.
(12) (a) Kochi, J. K. Organometallic Mechanisms and Catalysis;
Academic Press: New York, 1978; pp 393-398. (b) Hillhouse has reported
examples of carbon-nitrogen bond-forming reductive eliminations from
Ni(II) amido complexes that are promoted either thermally or by oxidation
of the nickel complexes. Koo, K.; Hillhouse, G. L. Organometallics 1996,
15, 2669-2671 and references therein. (c) Tsou, T. T.; Kochi, J. K. J. Am.
Chem. Soc. 1979, 101, 6319-6332.

Nickel-Catalyzed Amination of Aryl Chlorides
J. Am. Chem. Soc., Vol. 119, No. 26, 1997 6057
as catalysts were run in Schlenk tubes equipped with rubber septa and
were assembled outside of the glovebox. Elemental analyses were
performed by E & R Microanalytical Laboratory Inc., Corona, NY.
Toluene was distilled under nitrogen from molten sodium, degassed
under vacuum, and stored under argon in a Vacuum Atmospheres
glovebox. Pyridine was distilled under argon from CaH2, degassed
under vacuum, and stored under argon in a Vacuum Atmospheres
glovebox. All amines were purchased from commercial sources.
Amines which were liquids at ambient temperature were distilled from
CaH2 under argon or vacuum, degassed under vacuum, and stored under
argon in a Vacuum Atmospheres glovebox. Amines which were solids
at ambient temperature were stored under argon in a Vacuum
Atmospheres glovebox and used without further purification. Sodium
tert-butoxide was purchased from Aldrich chemical company and stored
in a Vacuum Atmospheres glovebox under nitrogen or argon. For
reactions which employed (L-L)NiCl2 precatalysts, small amounts of
sodium tert-butoxide were removed from the glovebox, stored in a
dessicator for up to 1 week, and weighed in the air. Solvents for these
reactions were taken directly from solvent stills using standard syringe
techniques. Bis(1,5-cyclooctadiene)nickel was purchased from Strem
Chemical Company, stored in the freezer of a Vacuum Atmospheres
glovebox under argon, and used without further purification. DPPF
was purchased from Strem Chemical Company and used without further
purification. 1,10-Phenanthroline was purchased from Lancaster
Synthesis, Inc., and used without further purification. Aryl chlorides
were purchased from commercial sources, degassed under vacuum, and
stored under argon in a Vacuum Atmospheres glovebox. Methylmag-
nesium bromide (3 M solution in Et2O) was purchased from Aldrich.
was added to oxidize the phosphine. The mixture was stirred at room
temperature for 10 min and then poured into a separatory funnel. The
aqueous layer was drained, and the ether layer was washed with distilled
water (10 mL) and saturated aqueous FeSO4 (20 mL). (CAUTION:
The reaction between H2O2 and FeSO4 is vigorously exothermic, and
both the washing of the organic layer with aqueous FeSO4 and the
mixing of the aqueous washes should be done with care.) The aqueous
washes were combined, and the aqueous mixture was allowed to cool
to room temperature and then was extracted with ether (3 × 20 mL).
The combined organic extracts were washed with brine (20 mL), dried
over anhydrous magnesium sulfate, filtered, and concentrated. The
crude product was then purified by flash chromatography on silica gel.
(B) Method B. A sealable Schlenk tube was charged with bis(1,5-
cyclooctadiene)nickel (15 mg, 0.05 mmol, 5 mol %), 1,10-phenanthro-
line (18 mg, 0.10 mmol, 10 mol %), and sodium tert-butoxide (135
mg, 1.4 mmol) under argon in a Vacuum Atmospheres glovebox.
Pyridine (1 mL) was added, followed by the aryl chloride (1.0 mmol),
the amine (1.2 mmol), and additional pyridine (3 mL). The tube was
sealed, removed from the glovebox, and heated to 100 °C with stirring
until the starting halide had been consumed as judged by GC analysis.
The mixture was cooled to room temperature, taken up in ether (10
mL), filtered, and concentrated. The crude product was purified by
flash chromatography on silica gel.
(C) Method C. A Schlenk tube was charged with (DPPF)NiCl2
(14mg, 0.02 mmol, 2 mol %), DPPF (11mg, 0.02 mmol, 2 mol %),
and sodium tert-butoxide (135 mg, 1.4 mmol) and purged with argon.
Toluene (2 mL) was added, followed by methylmagnesium bromide
(13 µL, 3.0 M in diethyl ether, 0.04 mmol, 4 mol %), and additional
toluene (2 mL). The mixture was stirred at room temperature for 15
min, and then the aryl halide (1.0 mmol) and amine (1.2 mmol) were
added. The mixture was heated to 100 °C with stirring until the starting
aryl halide had been consumed as judged by GC analysis. The mixture
was cooled to room temperature, taken up in ether (10 mL), filtered,
and concentrated. The crude product was purified by flash chroma-
tography on silica gel.
13
14
The paramagnetic complexes (DPPF)NiCl2 and (phen)NiCl2 were
prepared by slightly modified literature procedures and characterized
by IR spectroscopy and elemental analysis. For example, the (phen)-
NiCl2 obtained from the literature procedure was found to contain large
amounts of alcohol by IR analysis. This compound was dried under
vacuum at 180 °C overnight. The preparation of (DPPF)NiCl2 was
carried out in a 1:1:1 mixture of ethanol/n-butanol/CH2Cl2 due to the
low solubility of the phosphine in ethanol. Preparative flash chroma-
tography was performed on ICN Biomedicals Silitech 32-63d silica
gel. Yields in Table 1 refer to isolated yields (average of two runs) of
(D) Method D. A Schlenk tube was charged with (phen)NiCl2 (22
mg, 0.07 mmol, 7 mol %), 1,10-phenanthroline (13 mg, 0.07 mmol, 7
mol %), and sodium tert-butoxide (135 mg, 1.4 mmol) and purged
with argon. Pyridine (2 mL) was added, followed by methylmagnesium
bromide (47 µL, 3.0 M in diethyl ether, 0.14 mmol, 14 mol %) and
additional pyridine (2 mL). The mixture was stirred at room temper-
ature for 15 min, and then the aryl halide (1.0 mmol) and amine (1.2
mmol) were added. The mixture was heated to 100 °C with stirring
until the starting aryl halide had been consumed as judged by GC
analysis. The mixture was cooled to room temperature, taken up in
ether (10 mL), filtered, and concentrated. The crude product was
purified by flash chromatography on silica gel.
1
compounds estimated to be g95% pure as determined by H NMR
and either capillary GC (known compounds) or combustion analysis
(new compounds). The procedures described below are representative;
thus, the yields may differ from those given in Table 1.
General Procedure for the Catalytic Amination of Aryl Chlo-
rides. (A) Method A. A sealable Schlenk tube was charged with
bis(1,5-cyclooctadiene)nickel (6 mg, 0.02 mmol, 2 mol %), DPPF (22
mg, 0.04 mmol, 4 mol %), and sodium tert-butoxide (135 mg, 1.4
mmol) under argon in a Vacuum Atmospheres glovebox. Toluene (1
mL) was added, followed by the aryl chloride (1.0 mmol), the amine
(1.2 mmol), and additional toluene (3 mL). The tube was sealed,
removed from the glovebox, and heated to 100 °C with stirring until
the starting halide had been consumed as judged by GC analysis.
Workup Method 1. The reaction mixture was cooled to room
temperature, diluted with ether (10 mL), filtered, and concentrated. The
crude product was purified by flash chromatography on silica gel.
Products which were inseparable from DPPF by silica gel chromatog-
raphy were purified according to one of the following workup
procedures.
Workup Method 2. The reaction mixture was cooled to room
temperature, diluted with ether (20 mL), and poured into a separatory
funnel. The mixture was extracted with 1 M HCl (3 × 10 mL). The
organic layer was discarded after confirming that no desired product
remained. The aqueous extracts were then combined and taken to pH
12 with 3 M NaOH. The aqueous solution was extracted with ether
(3 × 20 mL), and the combined ether extracts were washed with brine
(20 mL), dried over anhydrous magnesium sulfate, filtered, and
concentrated.
Di-p-tolylamine.15 The general procedure A using workup 1 gave
1
186 mg (94%) of a white solid: mp 77 °C (lit.15 mp 77-78 °C); H
NMR (CDCl3, 300 MHz) δ 2.29 (s, 6H), 5.54 (s, br, 1H), 6.93 (d, 4H,
J ) 8.5 Hz), 7.06 (d, 4H, J ) 8.6 Hz); 13C NMR (CDCl3, 300 MHz)
δ 20.6, 117.9, 129.7, 130.1, 141.1; IR (KBr, cm-1) 3418, 1610, 1518,
1320, 807.
N-Methyl-N-phenyl-p-toluidine.1h The general procedure A using
workup 1 gave 152 mg (77%) of a colorless oil: 1H NMR (CDCl3,
300 MHz) δ 2.32 (s, 3H), 3.28 (s, 3H), 6.86-7.25 (m, 9H).
N-(p-Methylphenyl)-1,4-dioxa-8-azaspiro[4.5]decane.1h The gen-
eral procedure A but using 5 mol % Ni(COD)2, 10 mol % DPPF, and
workup 1 gave 188 mg (88%) of a white solid: mp 65 °C (lit.1h mp
1
64.8-65.6 °C); H NMR (CDCl3, 300 MHz) δ 1.84 (t, 1H, J ) 5.7
Hz), 2.26 (s, 3H), 3.26 (t, 4H, J ) 5.9 Hz), 3.98 (s, 4H), 6.86 (d, 2H,
J ) 9.1 Hz), 7.05 (d, 2H, J ) 8.5 Hz).
N-p-Tolylpyrrolidine.16 The general procedure A using workup 2
1
gave 91 mg (57%) of a tan solid: mp 34-35 °C (lit.16 oil); H NMR
(CDCl3, 300 MHz) δ 1.95-2.05 (m, 4H), 2.25 (s, 3H), 3.22-3.29 (m,
4H), 6.50 (d, 2H, J ) 8.2 Hz), 7.03 (d, 2H, J ) 8.1 Hz); 13C NMR
(CDCl3, 300 MHz) δ 20.3, 25.4, 47.8, 111.7, 124.4, 129.6, 146.1; IR
(KBr, cm-1) 2964, 1624, 1523, 1370, 1187, 801.
Workup Method 3. The reaction mixture was cooled to room
temperature, diluted with ether (10 mL), filtered, and concentrated. The
product was then taken up in ether (20 mL), and 30% H2O2 (5 mL)
(13) Rudie, A. W.; Lichtenberg, D. W.; Katcher, M. L.; Davison, A.
Inorg. Chem. 1978, 17, 2859-2863.
(14) Allan, J. R.; McCloy, B. Thermochem. Acta 1993, 214, 219-225.
(15) Waters, W. L.; Marsh, P. G. J. Org. Chem. 1975, 40, 3349-3351.
(16) Shim, S. C.; Huh, K. T.; Park, W. H. Tetrahedron 1986, 42, 259-
263.

6058 J. Am. Chem. Soc., Vol. 119, No. 26, 1997
Wolfe and Buchwald
N-(2,5-Dimethylphenyl)-p-anisidine.17 The general procedure A
using workup 1 gave 216 mg (95%) of a pale yellow solid: mp 37 °C
NMR (CDCl3, 300 MHz) δ 3.17-3.21 (m, 4H), 3.86-3.90 (m, 4H),
7.17-7.19 (m, 2H), 8.13 (t, 1H, J ) 3.0 Hz), 8.30-8.32 (m, 1H).
1
(lit,17 mp 34-35 °C); H NMR (CDCl3, 300 MHz) δ 2.20 (s, 3H),
N-(4-Benzoylphenyl)hexylamine.1b The general procedure A using
1
2.23 (s, 3H), 3.80 (s, 3H), 5.17 (s, br, 1H), 6.63 (d, 1H, J ) 7.0 Hz),
6.82-6.89 (m, 3H), 7.02 (m, 3H); 13C NMR (CDCl3, 300 MHz) δ
17.3, 21.2, 55.5, 114.6, 115.9, 120.7, 122.0, 122.3, 130.5, 136.4, 143.1,
154.9; IR (KBr, cm-1) 3419, 2928, 1526, 1509, 1246, 826.
N-(2,5-Dimethylphenyl)hexylamine.1h The general procedure A
but using 3 mmol of amine, 5 mol % Ni(COD)2, 10 mol % DPPF, and
workup 3 gave 107 mg (52%) of a colorless oil: 1H NMR (CDCl3,
300 MHz) δ 0.91-0.93 (m, 3H), 1.32-1.69 (m 8H), 2.09 (s, 3H), 2.29
(s, 3H), 3.13 (t, 2H, J ) 7.2 Hz), 3.40 (s br, 1H), 6.44-6.47 (m, 2H),
6.92 (d, 12H, J ) 7.5 Hz).
workup 1 gave 262 mg (93%) of a yellow solid: mp 55-56 °C; H
NMR (CDCl3, 300 MHz) δ 0.91 (t, 3H, J ) 6.8 Hz), 1.30-1.69 (m,
8H), 3.19 (t, 2H, J ) 7.3 Hz), 4.22 (s, br, 1H), 6.57 (d, 2H, J ) 8.8
Hz), 7.42-7.52 (m, 3H), 7.71-7.79 (m, 4H); 13C NMR (CDCl3, 300
MHz) δ 14.0, 22.5, 26.7, 29.2, 31.5, 43.2, 111.1, 125.6, 127.9, 129.4,
131.1, 133.0, 139.2, 152.3, 195.0; IR (KBr, cm-1) 3354, 2924, 1635,
1586, 1321, 1285. Anal Calcd for C19H23NO: C, 81.10; H, 8.24.
Found: C, 81.35; H, 8.02.
N-(4-Cyanophenyl)morpholine.18 The general procedure A using
workup 1 gave 163 mg (87%) of a white solid: mp 77-78 °C (lit.18
mp 75-76.5 °C); 1H NMR (CDCl3, 300 MHz) δ 3.28 (t, 4H, J ) 5.2
Hz), 3.85 (t 4H, J ) 5.1 Hz), 6.86 (d, 2H, J ) 8.5 Hz), 7.51 (d, 2H,
J ) 8.2 Hz); 13C NMR (CDCl3, 300 MHz) δ 47.2, 66.4, 100.8, 114.0,
119.8, 133.4, 153.4; IR (KBr, cm-1) 2981, 2217, 1606, 1518, 1245.
N-(2-Methylphenyl)-p-anisidine. The general procedure A but
using 3 mol % Ni(COD)2, 6 mol % DPPF, and workup 1 gave 187 mg
1
(88%) of a white solid: mp 78 °C; H NMR (CDCl3, 300 MHz) δ
2.25 (s, 3H), 3.80 (s, 3H), 5.20 (s, br, 1H), 6.67-7.16 (m, 8H); 13C
NMR (CDCl3, 300 MHz) δ 17.7, 55.5, 114.6, 115.1, 119.9, 122.0,
125.2, 126.7, 130.7, 136.2, 143.3, 155.0; IR (KBr, cm-1) 3392, 2997,
1514, 1236. Anal Calcd for C14H15NO: C, 78.84; H, 7.09. Found:
C, 78.85; H, 6.83.
N-(4-Methoxyphenyl)pyrrolidine.16 The general procedure B gave
a white solid which was contaminated with the byproduct 4,4′-
dimethoxybiphenyl. This material was taken up in ether (20 mL) and
extracted with 1 M HCl (3 × 10 mL). The organic layer was discarded
after confirming that no desired product remained. The aqueous extracts
were then combined and taken to pH 12 with 3 M NaOH. The aqueous
solution was extracted with ether (3 × 20 mL), and the combined ether
extracts were washed with brine (20 mL), dried over anhydrous
magnesium sulfate, filtered, and concentrated to give 98 mg (55%) of
N-Methyl-N-phenyl-p-anisidine. The general procedure A but
using 3 mol % Ni(COD)2, 6 mol % DPPF, and workup 3 gave 120 mg
(56%) of a colorless oil: 1H NMR (CDCl3, 300 MHz) δ 3.26 (s, 3H),
3.81 (s, 3H), 6.76-7.20 (m, 9H); 13C NMR (CDCl3, 300 MHz) δ 40.4,
55.5, 114.7, 115.7, 118.3, 126.2, 128.9, 142.2, 149.7, 156.2; IR (neat,
cm-1) 2932, 1596, 1508, 1243. Anal Calcd for C14H15NO: C, 78.84;
H, 7.09. Found: C, 78.77; H, 7.22.
1
a white solid: mp 41 °C (lit.16 oil); H NMR (CDCl3, 300 MHz) δ
1.96-2.01 (m, 4H), 3,23-3.26 (m, 4H), 3.76 (s, 3H), 6.53 (d, 2H, J )
8.8 Hz), 6.84 (d, 2H, J ) 9.1 Hz); 13C NMR (CDCl3, 300 MHz) δ
25.3, 48.1, 55.9, 112.5, 114.9, 143.1, 150.7; IR (KBr, cm-1) 2960, 1516,
1238, 1044.
N-(2,5-Xylyl)pyrrolidine.19 The general procedure B gave 143 mg
(82%) of a colorless oil: 1H NMR (CDCl3, 300 MHz) δ 1.89-1.93
(m, 4H), 2.28 (s, 3H), 2.29 (s, 3H), 3.15-3.20 (m, 4H), 6.64 (d, 1H,
J ) 7.5 Hz), 6.69 (s, 1H), 6.99 (d, 2H, J ) 7.5 Hz); 13C NMR (CDCl3,
300 MHz) δ 20.1, 21.2, 24.9, 50.9, 116.5, 120.8, 125.5, 131.5, 135.6,
149.2; IR (neat, cm-1) 2964, 1505, 1312. Anal Calcd for C12H17N:
C, 82.23; H, 9.78. Found: C, 82.30; H, 9.71.
N-Methyl-N-(4-pyridyl)aniline. A sealable Schlenk tube was
charged with 4-chloropyridine hydrochloride (150 mg, 1.0 mmol),
NaOtBu (135 mg, 1.4 mmol), and toluene (1 mL) under argon in a
Vacuum Atmospheres glovebox. The mixture was stirred for 2 min at
ambient temperature, and then Ni(COD)2 (15 mg, 0.05 mmol, 5 mol
%), DPPF (55 mg, 0.10 mmol, 10 mol %), NaOtBu (96 mg, 1.0 mmol),
and toluene (3 mL) were added. The tube was sealed, removed from
the glovebox, and heated to 100 °C with stirring until the halide had
been consumed as judged by GC analysis. The product was isolated
using workup 1 to give 138 mg (75%) of a pale yellow oil: 1H NMR
(CDCl3, 300 MHz) δ 3.32 (s, 3H), 6.54 (d, 2H, J ) 5.2 Hz), 7.19-
7.26 (m, 3H), 7.40-7.45 (m, 2H), 8.21 (s br, 2H); 13C NMR (CDCl3,
300 MHz) δ 39.3, 108.2, 126.3, 126.6, 129.9, 146.1, 149.8, 153.6; IR
(neat, cm-1) 3030, 1587, 1504, 1363. Anal Calcd for C12H12N2: C,
78.23; H, 6.57. Found: C, 78.34; H, 6.54.
Acknowledgment. We thank the National Science Founda-
tion, Pfizer, and Eastman Kodak for their support of this work.
We thank Dr. Jens Åhman and Dr. Tricia Breen for preparing
(DPPF)NiCl2 and (phen)NiCl2 and Professor Gregory Fu for
helpful suggestions on the manuscript.
N-(3-Pyridyl)morpholine.1e The general procedure A but using 5
mol % Ni(COD)2, 10 mol % DPPF, and workup 1 gave a yellow oil
which contained slight impurities as judged by 1H NMR. The oil was
then Ku¨gelrohr distilled to give 141 mg (86%) of a colorless oil: 1H
JA964391M
(17) Hall, R. J.; Marchant, J.; Oliveira-Campos, A. M. F.; Queiroz, M.-
J. R. P.; Shannon, P. V. R.; J. Chem. Soc., Perkin Trans. 1 1992, 3439-
3450.
(18) Kotsuki, H.; Kobayashi, S.; Suenaga, H.; Nishizawa, H. Synthesis
1990, 1145-1147.
(19) Walkup, R. E.; Searles, S., Jr. Tetrahedron 1985, 41, 101-106.