Room Temperature Catalytic Animation of Aryl Iodides

Full text of DOI:10.1021/jo970876x

6066
J . Org. Chem. 1997, 62, 6066-6068
Ta ble 1. Solven t/Ad d itive Effects on th e Rea ction
Sh ow n in Eq 1
Room Tem p er a tu r e Ca ta lytic Am in a tion of
Ar yl Iod id es
solvent/additive
% conversion
THF
13
DMF
55a,b
J ohn P. Wolfe and Stephen L. Buchwald*
THF/18-C-6d
100 (85% isolated yield)
THF/TMEDA
THF/Bu4NCl (1.0 eq)
13
18
0
Department of Chemistry, Massachusetts Institute of
Technology, Cambridge, Massachusetts 02139
THF/poly(ethylene glycol), Mn ) 200
THF/poly(ethylene glycol), Mn ) 3400
46
THF/poly(ethylene oxide), Mn ) 200 000 44
Received May 13, 1997
THF/tetraglyme
24
tetraglymec
85 (57% isolated yield)
96 (77% isolated yield)
tetraglyme/cat. 18-C-6c
The palladium-catalyzed amination of aryl halides has
been shown to be a general method for the formation of
aromatic carbon-nitrogen bonds.1 However, current
versions of this method still suffer from the need for
relatively high reaction temperatures (65-100 °C) which
may pose problems for reactions involving thermally
sensitive molecules or in situations where it is inconve-
nient to heat reactions (e.g., combinatorial chemistry
applications).2 Herein, we report a general procedure for
palladium-catalyzed intermolecular carbon-nitrogen bond
formation which proceeds at room temperature and
affords the desired products in good to excellent yields.
Initial attempts to effect the intermolecular coupling
of aryl iodides with amines at room temperature by
employing conditions developed for the palladium-
catalyzed inter-1h or intramolecular1b,c amination of aryl
iodides were unsuccessful. During the course of kinet-
ics studies on the Pd2(dba)3/P(o-tolyl)3 catalyzed amina-
tion of aryl bromides, we observed a rate enhancement
when 18-crown-6 was added to the reaction mixture.3,4
This led us to develop the conditions shown in eq 1, which
allows for the successful coupling of aryl iodides with
amines at ambient temperature. For example, the reac-
tion of p-iodotoluene with piperidine in the presence of
stoichiometric quantities of NaO-t-Bu and 18-crown-6
and a catalytic amount of Pd2(dba)3/BINAP proceeds to
completion in ∼6 h at room temperature; the product
N-(4-methylphenyl)piperidine is isolated in 85% yield (eq
1).5
a
This reaction gave a mixture of N-(4-methylphenyl)piperidine
and N,N-dimethyl-p-toluidine. An amide product resulting from
b
amine exchange with DMF was also observed. A control reaction
run in DMF in the presence of 18-C-6 without a palladium catalyst
afforded a mixture of the two products mentioned above, as well
as their meta regioisomers. c Tol-BINAP was used in place of
BINAP. Analogous reactions run with BINAP as the supporting
ligand resulted in similar conversions. A control reaction run in
THF in the presence of 18-C-6 without a palladium catalyst gave
no reaction after 24 h at room temperature.
d
Studies to optimize this process were undertaken, and
the coupling of p-iodotoluene and piperidine catalyzed by
Pd2(dba)3/BINAP (1 mol % of Pd) at room temperature
was examined using a variety of solvent/additive combi-
nations. As shown in Table 1, the use of THF with added
18-crown-6 was found to be the most effective system.
Reactions with THF, triethylamine, toluene, TMEDA,
NMP, DMSO, or DME as solvent without additives
proceeded to low conversion.6 Reactions employing 18-
crown-6 as an additive in toluene, dioxane, or triethyl-
amine were slower than those conducted in THF with
added 18-crown-6. Tetraglyme (tetra(ethylene glycol)
dimethyl ether) was the most effective solvent in the
absence of 18-crown-6, although these reactions failed to
proceed to completion (up to 85% conversion). Addition
of catalytic amounts (10 mol %) of 18-crown-6 to reactions
run in tetraglyme gave improved results, but these
conditions did not prove to be effective with a wide range
of substrates.
(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) An example of an intramo-
lecular carbon-nitrogen bond forming process which proceeds at room
temperature has been reported: 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. (k) Marcoux, J .-F.; Wagaw, S.; Buchwald, S. L. J . Org.
Chem. 1997, 62, 1568-1569.
(2) J effery has reported that Heck arylations may be run at lower
temperatures in the presence of stoichiometric amounts of tetraalkyl-
ammonium salts. We found that these reagents were not effective
promoters of the aryl amination process at room temperature. (a)
J effery, T. Tetrahedron 1996, 52, 10113-10130. Suzuki reactions
which proceed at room temperature in the presence of TlOH have also
been reported. (b) Uenishi, J .-I.; Beau, J .-M.; Armstrong, R. W.; Kishi,
Y. J . Am. Chem. Soc. 1987, 109, 4756-4758. (c) Anderson, J . C.;
Namli, H. Synlett 1995, 765-766.
BINAP and Tol-BINAP7 were the only phosphine
ligands tested which were found to be generally effective
in these reactions. In one case the use of DPPF8 gave
similar results (Table 2, entry 2), but for other substrates
examined its use as the supporting ligand led to slower
reactions and incomplete consumption of the starting aryl
halide.
(3) Widenhoefer, R. A.; Buchwald, S. L. Unpublished results.
(4) Use of 18-crown-6 to promote one example of the Ullmann aryl
ether synthesis (at 150 °C) has been reported. J ung, M. E.; J achiet,
D.; Rohloff, J . C. Tetrahedron Lett. 1989, 30, 4211-4214.
(6) It is interesting to note that the reaction of 4-bromoiodobenzene
with piperidine only proceeded to 79% conversion in THF at 65 °C in
the absence of 18-C-6 (1 mol % Pd catalyst). This coupling went to
completion and afforded the product in high yield (Table 2, entry 8)
when the room temperature/18-C-6 conditions were employed.
(7) (S)-BINAP ) 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl; (R)-
Tol-BINAP ) 2,2′-bis(di-p-tolylphosphino)-1,1′-binaphthyl. Racemic
BINAP is now commercially available from Strem Chemical Company.
(8) DPPF ) 1,1′-bis(diphenylphosphino)ferrocene.
(5) Our original amination protocol for iodides1h afforded this product
in only 59% isolated yield (Table 2, entry 9). The reaction of N,N-
diethyl-4-iodobenzamide with n-hexylamine also gave a higher yield
when the room temperature conditions were employed (Table 2, entry
1).
S0022-3263(97)00876-1 CCC: $14.00 © 1997 American Chemical Society

Notes
J . Org. Chem., Vol. 62, No. 17, 1997 6067
Ta ble 2. Room Tem p er a tu r e Ca ta lytic Am in a tion of Ar yl Iod id es
As shown in Table 2, the THF/18-crown-6 conditions
mixture of the desired product and a side product
resulting from the unexpected cleavage of the tert-butyl
group (Table 2, entry 6), although no products resulting
from a similar process were detected in the reaction of
4-tert-butyliodobenzene with morpholine (Table 2, entry
5). An additional benefit of this new procedure is that
the selective substitution of the iodide in o-, m-, or
p-bromo(iodo)benzene (Table 2, entries 7, 8, and 11) can
be achieved. Attempts to carry out this selective substi-
tution using our original conditions resulted in the
formation of a mixture of products.
While we have not conducted a detailed study, we
believe that the mechanism of this process likely is
analogous to that of the catalytic amination of aryl
bromides using BINAP as the supporting ligand.1d Our
current view is that the 18-crown-6 activates the NaO-
t-Bu by increasing solvation of the Na+.
are effective for the reactions of both electron-rich and
electron-deficient aryl iodides with primary and second-
ary aliphatic amines at room temperature using rela-
tively low catalyst loadings (1 mol % of Pd). This
procedure is most effective for cyclic secondary amines,
while attempted arylation of acyclic secondary amines
often resulted in low conversion to and/or poor ratios of
the desired products:reduced arene side products.9 Reac-
tions which used anilines as substrates required slightly
higher temperatures (40 °C) and catalyst levels (4-5 mol
% of Pd) to proceed to completion. The reaction of 4-tert-
butyliodobenzene with N-methylaniline afforded a 6.6:1
(9) In general, secondary acyclic amines are not good substrates in
reactions catalyzed by mixtures of Pd2(dba)3/BINAP. Wolfe, J . P.;
Marcoux, J . F.; Buchwald, S. L. Unpublished results. For a successful
method for the coupling of these amines, see ref 1k.

6068 J . Org. Chem., Vol. 62, No. 17, 1997
Notes
(lit.11 mp 89 °C): 1H NMR (CDCl3, 300 MHz) δ 2.30 (s, 3H), 5.60
(s, br, 1H), 6.88 (t, 1H, J ) 7.3 Hz), 6.90-7.10 (m, 6H), 7.21-
7.26 (m, 2H); 13C NMR (CDCl3, 300 MHz) δ 20.6, 116.8, 118.9,
120.2, 129.3, 129.8, 130.9, 140.2, 143.9; IR (KBr, cm-1) 3394,
1596, 1513, 1308, 746.
In conclusion, we have developed a general procedure
for the palladium-catalyzed intermolecular amination of
aryl iodides which proceeds at ambient temperatures.
Further studies are underway to devise mild, general
reaction conditions which allow for enhanced functional
group tolerance in palladium-catalyzed amination reac-
tions.
N-(2,5-Xylyl)p yr r olid in e.12 The general procedure gave 74
mg (84%) of a colorless oil: 1H NMR (CDCl3, 300 MHz) δ 1.84-
1.94 (m, 4H), 2.28 (s, 3H), 2,29 (s, 3H), 3.16-3.22 (m, 2H), 6.65
(d, 1H, J ) 7.8 Hz), 6.70 (s, 1H), 7.00 (d, 1H, J ) 7.5 Hz).
N,N-Dieth yl-p-(h exyla m in o)ben za m id e.1h The general
procedure gave 119 mg (86%) of a purple solid, mp 37-38 °C
(lit.1h oil):2 1H NMR (CDCl3, 300 MHz) δ 0.9 (m, 3H), 1.18 (t,
6H, J ) 6.9 Hz), 1.29-1.42 (m, 6H), 1.61 (p, 2H, J ) 6.9 Hz),
3.11 (t, 2H, J ) 7.2 Hz), 3.43 (q, 4H, J ) 6.9 Hz), 3.80 (s, br,
1H), 6.53-6.56 (m, 2H), 7.23-7.27 (m, 2H).
Exp er im en ta l Section
Gen er a l. All reactions were carried out under an argon
atmosphere in oven-dried glassware. Elemental analyses were
performed by E & R Microanalytical Laboratory Inc., Corona,
NY. THF was continuously refluxed and distilled from sodium
benzophenone ketyl under argon. Aryl iodides were purchased
from commercial sources and were used without further puri-
fication except for 3-bromoiodobenzene which was passed through
alumina before use. Amines were purchased from commercial
sources and were purified by being passed through alumina or
distilled from calcium hydride under argon or vacuum. Sodium
tert-butoxide was purchased from Aldrich Chemical Co. and
stored in a Vacuum Atmospheres glovebox under nitrogen or
argon. Small amounts of sodium tert-butoxide were removed
from the glovebox, stored in a desiccator for up to 1 week, and
weighed in the air. 18-Crown-6 was purchased from Lancaster
Synthesis and was stored under nitrogen in a Vacuum Atmo-
spheres glovebox. For reasons of convenience, the reaction
vessels were charged with 18-crown-6 in the glovebox. All other
reagents were weighed and loaded into the reaction vessels in
the air. A reaction employing 18-crown-6 which had been stored
and weighed in the air gave comparable results to the analogous
reaction run with 18-crown-6 from the glovebox. BINAP, Tol-
BINAP, DPPF, and Pd2(dba)3 were purchased from Strem
Chemical Co. and used without further purification. Preparative
flash chromatography was performed on ICN Biomedicals
Silitech 32-63d silica gel. Yields in Table 1 refer to isolated
yields (average of two runs) of compounds estimated to be g95%
pure as determined by 1H 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.
Gen er a l P r oced u r e. In a nitrogen-filled glovebox, an oven-
dried Schlenk tube was charged with 18-crown-6 (185 mg, 0.7
mmol), which was capped with a rubber septum and removed
from the glovebox. The Schlenk tube was then charged with
the aryl iodide (0.5 mmol), the amine (0.6 mmol), NaO-t-Bu (67
mg, 0.7 mmol), Pd2(dba)3 (2.3 mg, 0.0025 mmol, 1 mol % of Pd),
and BINAP (4.7 mg, 0.0075 mmol) and purged with argon. THF
(1 mL) was added, and the reaction mixture was stirred at room
temperature under argon until the reaction had proceeded to
completion as judged by GC or TLC analysis. The reaction
mixture was taken up in ether (20 mL), filtered, and concen-
trated in vacuo. The crude product was then purified by flash
chromatography on silica gel.
N-(4-Meth oxyp h en yl)p yr r olid in e.12,13 The general proce-
dure gave 76 mg (85%) of a white solid, mp 41-42 °C (lit.12 41
°C): 1H NMR (CDCl3, 300 MHz) δ 1.96-2.01 (m, 4H), 3.23-
3.26 (m, 2H), 3.76 (s, 3H), 6.53 (d, 2H, J ) 8.8 Hz), 6.84 (d, 2H,
J ) 9.1 Hz).
N-(2,5-Xylyl)-p-a n isid in e.12,14 The general procedure using
2 mol % of Pd2(dba)3, 6 mol % of BINAP, and a reaction
temperature of 40 °C gave 95 mg (83%) of a white solid, mp 37
°C (lit.14 mp 34-35 °C): 1H NMR (CDCl3, 300 MHz) δ 2.20 (s,
3H), 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).
N-(4-Meth ylp h en yl)p ip er id in e.14 The general procedure
gave 74 mg (84%) of a colorless oil: 1H NMR (CDCl3, 300 MHz)
δ 1.50-1.73 (m, 6H), 2.26 (s, 3H), 3.09 (t, 4H, J ) 5.4 Hz), 6.85
(d, 2H, J ) 8.4 Hz), 7.05 (d, 2H, J ) 8.4 Hz).
4-(2-Br om op h en yl)m or p h olin e.15 The general procedure
gave 100 mg (83%) of a colorless oil: 1H NMR (CDCl3, 300 MHz)
δ 3.05 (t, 4H, J ) 4.6 Hz), 3.88 (t, 4H, J ) 4.6 Hz), 6.93 (dt, 1H,
J ) 1.6 Hz, 7.3 Hz), 7.05 (dd, 1H, J ) 1.6 Hz, 7.9 Hz), 7.29 (dt,
1H, J ) 1.1 Hz, 7.3 Hz), 7.57 (dd, 1H, J ) 1.6 Hz, 8.0 Hz); 13C
NMR (CDCl3, 300 MHz) δ 52.1, 67.1, 119.8, 120.8, 124.6, 128.3,
133.9, 150.3; IR (neat, cm-1) 2853, 1475, 1115; GC/MS (m/ z)
241, 243. Anal. Calcd for C10H12BrON: C, 49.61; H, 5.00.
Found: C, 50.51; H, 5.20. The material was homogeneous by
GC, 1H NMR, and 13C NMR. A small amount of material was
Kugelrohr distilled and resubmitted for analysis. Found: C,
49.64; H, 5.00.
4-(4-ter t-Bu tylp h en yl)m or p h olin e.16 The general proce-
dure gave 104 mg (95%) of a white solid, mp 59 °C (lit.16 mp
50-52 °C): 1H NMR (CDCl3, 300 MHz) δ 1.30 (s, 9H), 3.14 (t,
4H, J ) 4.9 Hz), 3.86 (t, 4H, J ) 4.7 Hz), 6.87 (d, 2H, J ) 8.9
Hz), 7.30 (d, 2H, J ) 8.9 Hz); 13C NMR (CDCl3, 300 MHz) δ
31.4, 33.9, 49.5, 66.7, 115.3, 125.9, 142.7, 148.9; IR (KBr, cm-1
)
2961, 1521, 1238, 927, 820. Anal. Calcd for C14H21NO: C, 76.67;
H, 9.65. Found: C, 76.86; H, 9.87.
N-Meth yl-N-(4-ter t-bu tylp h en yl)a n ilin e. The general pro-
cedure using 2.5 mol % of Pd2(dba)3, 7.5 mol % of BINAP, and a
reaction temperature of 40 °C gave a 6.6/1 mixture (1H NMR)
of the title compound and N-methyldiphenylamine (84 mg, 68%)
as a colorless oil: 1H NMR (CDCl3, 300 MHz) δ 1.32 (s, 9H),
3.30 (s, 3H), 3.32 (s, 0.45H), 6.86 (m, 5H), 7.20-7.31 (m, 4H);
13C NMR (CDCl3, 300 MHz) δ 19.5, 31.4, 34.2, 40.2, 119.0, 120.2,
120.4, 121.2, 126.1, 129.0, 129.2, 144.8; IR (neat, cm-1) 2960,
N-(3-Br om op h en yl)-o-tolu id in e. The general procedure
using 2.5 mol % of Pd2(dba)3, 7.5 mol % of BINAP, and a reaction
temperature of 40 °C gave 88 mg (67%) of a colorless oil: 1H
NMR (CDCl3, 300 MHz) δ 2.24 (s, 3H), 5.39 (s, br, 1H), 6.80 (dd,
1H, J ) 3.2 Hz, 8.9 Hz), 6.92-7.25 (m, 7H); 13C NMR (CDCl3,
300 MHz) δ 17.9, 114.9, 118.9, 120.9, 122.7, 126.9, 128.0, 130.0,
130.5, 131.1, 139.9, 146.0; IR (neat, cm-1) 3397, 3058, 1587, 1478,
1310, 1068; GC/MS m/ z 261, 263. Anal. Calcd for C13H12BrN:
C, 59.56; H, 4.61. Found: C, 59.74; H, 4.75.
1498, 1133; HRMS calcd for
239.16762.
C17H21N 239.167400, found
Ack n ow led gm en t. We thank the National Science
Foundation, Pfizer, and Eastman Kodak for their sup-
port of this work.
N-(4-Br om op h en yl)p ip er id in e.10 The general procedure
gave 110 mg (92%) of a white solid, mp 69-70 °C (lit.10 mp 77
°C). 1H NMR (CDCl3, 300 MHz) δ 1.53-1.60 (m, 2H), 1.65-
1.72 (m, 4H), 3.12 (t, 4H, J ) 5.2 Hz), 6.79 (d, 2H, J ) 8.6 Hz),
7.31 (d, 2H, J ) 8.6 Hz); 13C NMR (CDCl3, 300 MHz) δ 24.1,
25.6, 50.4, 111.0, 113.5, 118.0, 131.7; IR (KBr, cm-1) 2939, 1494,
1244, 807; GC/MS (m/ z) 238, 239, 240, 241. Anal. Calcd for
J O970876X
(11) Dictionary of Organic Compounds, 6th ed.; Cazoga, J . I. G., Ley,
S. V., Pattenden, G., Raphael, R. A., Rees, C. W., Eds; Chapman &
Hall; London, 1996.
(12) Wolfe, J . P.; Buchwald, S. L. J . Am. Chem. Soc. 1997, 119,
6054-6058.
(13) Shim, S. C.; Huh, K. T.; Park, W. H. Tetrahedron 1986, 42, 259-
263.
C
11H14BrN: C, 55.02; H, 5.88. Found: C, 55.23; H, 6.01.
N-P h en yl-p-tolu id in e.1g,11 The general procedure using 2
(14) 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.
mol % of Pd2(dba)3, 6 mol % of BINAP, and a reaction temper-
ature of 40 °C gave 74 mg (80%) of a white solid, mp 87-88 °C
(15) Verboom, W.; Reinhoudt, D. N.; Visser, R.; Harkeman, S. J .
Org. Chem. 1984, 49, 269-276.
(10) Verardo, G.; Giumanini, A. G.; Favret, G.; Strazzolini, P.
Synthesis 1991, 447-450.
(16) May, G. C.; Pinhey, J . T. Aust. J . Chem. 1982, 35, 1859-1871.