TABLE 1. Temperature, Time, and Solvent Dependence of
TABLE 2. Palladium Source and Ligand Dependence of
a
a
N-Arylation Microwave Reactions
N-Arylation Microwave Reactions
b
b
c
entry
temp (°C)
time (min)
solvent
yield (%)
entry
Pd source
ligand (equiv)
yield (%)
1
2
3
4
5
6
7
8
100
100
80c
100
100
120
120
80
15
30
15
15
15
15
30
15
THF
THF
toluene
DMF
(neat)
THF
69 (54)
95 (89)
38
60
33-55
65
1
2
3
4
5
6
7
8
Pd(OAc)2
PdCl2
Pd(dba)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
DPEphos (1.1)
DPEphos (1.1)
DPEphos (1.1)
BINAP (1.1)
DPPF (1.1)
DPPE (1.1)
PPh3 (2.2)
DPEphos (1.5)
DPEphos (0.5)
DPEphos (1.1)
95 (89)
94
46
93
96
45
21
97
43
d
THF
THF
66
48
9
a
Reagents and typical conditions: 1.42 mmol 2,6-diisopropylaniline,
.45 mmol o-bromofluorobenzene, 1.71 mmol NaOt-Bu, 0.0071 mmol
Pd(OAc)2, 0.0078 mmol DPEphos, 4 mL of solvent. Yields are based
on quantities of product relative to starting materials and side products
quantified by gas chromatography. Where applicable, isolated yields are
e
1
0
90 (84)
1
b
a
Reagents and typical conditions: 1.51 mmol 2,6-diisopropylaniline,
1.52 mmol o-bromofluorobenzene, 1.75 mmol NaOt-Bu, 0.0072 mmol
Pd(OAc)2, 0.0090 mmol DPEphos, 4 mL of THF, 30 min heating at 100
c
b
given in parentheses. This was the highest temperature achieved by
this sample.
°C. DPEphos ) bis(2-phenylphosphinophenyl)ether, BINAP ) bis-2,
2′-bis(diphenylphosphino)-1,1′-binapthyl, DPPF ) bis(1,1′-diphenylphos-
c
phino)ferrocene, DPPE ) 1,2-bis(diphenylphosphino)ethane. Yields are
based on quantites of starting material, product, and unidentified side
products observed by gas chromatography. Where applicable, isolated
rylation reaction is also a good candidate for such acceleration,
as it involves polar reagents inherently suited to absorbing
d
yields are given in parentheses.
Reaction prepared on bench and flushed with nitrogen prior to heating.
dba ) dibenzylideneacetone.
e
1
8,20
microwaves.
microwave-accelerated N-arylation
The most relevant reported conditions for
2
2,25
proved ineffective in
1
8,20
coupling the sterically demanding substrates of interest, and we
are aware of no prior reports of microwave-accelerated aryl
fluoride phosphorylation, so we have developed conditions under
which both couplings occur efficiently. Herein we describe
microwave-assisted procedures by which these ligands may be
prepared in high yields in less than 3 h total reaction time.
N-Arylation. Literature reports describe microwave condi-
tions for the coupling of 4-aminobenzophenone with 2,4-
marginally polar enough for effective microwave heating,
the desired reaction temperature was typically achieved within
1 min at a maximum power of 1600 W. (After the initial heating,
the reaction temperature was usually maintained at powers of
approximately 500 W.) This efficiency may be a consequence
of the relatively high concentration of more polar substrates in
the reaction mixture (ca. 0.2 M each in aniline, haloarene, and
base), which likely absorb much of the incident microwave
radiation. However, the target temperature was not achieved in
a timely manner when benzene or toluene was used as the
solvent, and at comparable reaction times, syntheses in these
solvents yielded incomplete conversion (entry 3). DMF (entry
4) offered no obvious advantage relative to THF and gave a
greater proportion of unidentified side products than did other
solvents, which showed incomplete conversion of starting
materials rather than unwanted side products. Although the best
results were achieved at very high substrate concentrations,
solvent-free conditions yielded inconsistent and generally poor
results (entry 5). Higher reaction temperatures resulted in
incomplete conversion even at longer reaction times, suggesting
catalyst deactivation occurred. This sensitivity to higher tem-
peratures offers one possible explanation for the considerable
acceleration achieved by microwave irradiation in this system:
this method may avoid catalyst decomposition that would occur
under less homogeneous heating conditions, maintaining the
effective loading closer to the 0.5 mol % originally added.
Palladium acetate and palladium chloride showed very similar
activities, while Pd(dba)2 gave poorer yields (Table 2). The
chelating phosphine ligands BINAP, DPPF, and DPEphos all
gave relatively similar yields (entries 4-6), and even DPPE
and PPh3 gave significant, although dramatically lower, yields
of product (entries 6 and 7). This stands in marked contrast to
Skjaerbaek’s work, which identified DPE and DPPF as par-
ticularly ineffectiVe ligands in microwave-assisted N-arylation
2
5
difluorobromobenzene and for the amination of p-bromotol-
22
uene with aniline. Neither set of conditions achieved favorable
results using the more sterically demanding 2,6-diisopropyla-
niline substrate. New conditions for its coupling with o-
bromofluorobenzene were evaluated by screening conditions on
a small scale (ca. 0.25 g of o-bromofluorobenzene) and assessing
reaction outcomes by gas chromatography; most of these
reactions were intentionally run to less than full conversion in
order to best identify differences in yields among the various
conditions, and the key results are summarized in Tables 1–3.
Temperature, time, and solvent conditions were screened
using the same palladium source and ligand employed in the
conventional synthesis of the target compound 1a (Table 1).
Interestingly, conditions nearly identical to those reported for
the much slower oil-bath reaction could be used to effect >95%
conversion in 30 min under microwave conditions, the only
differences being a temperature increase of 5 °C and the
substitution of THF for toluene as solvent (entry 2). (We have
not rigorously mapped the differences between microwave and
oil-bath conditions in this system, but subjection of an identical
reaction mixture to conventional heating at 100 °C for 1 h
yielded a reaction mixture still dominated by starting materials.)
Although THF is generally considered to be a solvent only
(22) Wan, Y.; Alterman, M.; Hallberg, A. Synthesis 2002, 11, 1597–1600.
(23) Wang, T.; Magnin, D. R.; Hamann, L. G. Org. Lett. 2003, 5, 897–900.
(24) Maes, B. U. W.; Loones, K. T. J.; Hostyn, S.; Diels, G.; Rombouts, G.
25
of electron-poor anilines. Yields increased with ligand loading
up to a maximum L:Pd ratio of 1.5:1, although little advantage
was observed beyond 1 equiv of ligand relative to palladium.
Reactions were typically conducted under air-free conditions;
abandonment of these precautions led to marked drops in yield,
although sparging the reaction mixture with nitrogen prior to
heating produced results roughly comparable to those achieved
Tetrahedron 2004, 60, 11559–11564.
25) Jensen, T. A.; Liang, X.; Tanner, D.; Skjaerbaek, N. J. Org. Chem. 2004,
9, 4936–4947.
26) Bonnaterre, F.; Bois-Choussy, M.; Zhu, J. Org. Lett. 2006, 8, 4351–
354.
(
6
4
7
(
(
27) Tundel, R. E.; Anderson, K. W.; Buchwald, S. L. J. Org. Chem. 2006,
1, 430–433.
(
28) Li, S.; Miao, W.; Tang, T.; Cui, D.; Chen, X.; Jing, X. J. Organomet.
Chem. 2007, 692, 4943–4952.
4
292 J. Org. Chem. Vol. 73, No. 11, 2008