P(i-BuNCH2CH2)3N: an efficient promoter for the microwave synthesis of diaryl ethers

Article abstract of DOI:10.1016/j.tetlet.2008.03.089

With the title proazaphosphatrane as a promoter, the coupling of aryl fluorides with aryl TBDMS ethers under microwave conditions gave moderate to high yields of the desired products at low catalyst loadings and in short times. In this methodology, electron deficient aryl fluorides possessing substituents, such as nitro, cyano, and ester, were coupled with sterically demanding aryl TBDMS ethers as well as with aryl TBDMS ethers bearing a variety of functionalities such as methoxy, halo, and cyano groups.

Full text of DOI:10.1016/j.tetlet.2008.03.089

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 3507–3511
P(i-BuNCH2CH2)3N: an efficient promoter
for the microwave synthesis of diaryl ethers
Steven M. Raders, John G. Verkade *
Department of Chemistry, Iowa State University, Ames, IA 50011, United States
Received 7 February 2008; revised 17 March 2008; accepted 18 March 2008
Available online 23 March 2008
Abstract
With the title proazaphosphatrane as a promoter, the coupling of aryl fluorides with aryl TBDMS ethers under microwave conditions
gave moderate to high yields of the desired products at low catalyst loadings and in short times. In this methodology, electron deficient
aryl fluorides possessing substituents, such as nitro, cyano, and ester, were coupled with sterically demanding aryl TBDMS ethers as well
as with aryl TBDMS ethers bearing a variety of functionalities such as methoxy, halo, and cyano groups.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Proazaphosphatrane; Microwave; Diaryl ethers; TBDMS aryl ethers
The synthesis of diaryl ethers has been intensely studied
owing primarily to the presence of diaryl ether moieties in
many biologically active natural products such as Piperaz-
inomycin, Bouvardin, Vancomycin, Ristocetin A, and the
anti-HIV agent Chloropeptin I.1 Three general methods
developed for the synthesis of diaryl ethers are (1) SNAr
reactions between aryl halides (order of reactivity
F > Cl > Br > I)2 and phenols,3 (2) copper-catalyzed Ull-
mann reactions between aryl halides and phenols,4 and
(3) palladium-catalyzed reactions of aryl halides with
phenols.5
Disadvantages of the Ullmann coupling are its require-
ments for harsh reaction conditions and environmentally
unfriendly copper. Palladium-mediated syntheses suffer
from the expense of the metal. Because of these issues,
investigators have focused on seeking superior SNAr routes
owing to their generally milder reaction conditions. Ways
have also been sought to employ the nucleophilic phenolic
coupling partner more efficiently by, for example, deprotec-
tion of a trimethylsilyl- (TMS)-protected or a tert-butyldi-
methylsilyl- (TBDMS)-protected phenol in the presence of
a strong base. Thus, Kondo and co-workers found that by
using the phosphazene base P4-t-Bu, diaryl ethers could be
synthesized in a highly polar solvent such as DMSO or
DMF using electron deficient aryl fluorides and electron
rich TBDMS-protected phenols.6
About the time Kondo’s work was published, our group
reported that proazaphosphatrane 3 in Figure 1 also effi-
ciently promoted such diaryl ether syntheses;7 a finding
that was based on our earlier report of the first observation
of the efficient deprotection of TBDMS-protected alcohols
and phenols with 1.8 Proazaphosphatranes are strong non-
ionic bases (pKa 32–349), although these are much weaker
than P4-t-Bu (pKa 41.410). However, the former may be
more nucleophilic, perhaps in part because of the possible
transannulation of the basal nitrogen to the phosphorus
during the reaction.
R
R
P
N
R
N
1
: R = Me
N
2 : R =
3 : R =
i
i
-Pr
-Bu
4
: R = Bn
N
*
Corresponding author. Tel.: +1 515 294 5023; fax: +1 515 294 0105.
Fig. 1. Proazaphosphatranes.
E-mail address: jverkade@iastate.edu (J. G. Verkade).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.03.089

3508
S. M. Raders, J. G. Verkade / Tetrahedron Letters 49 (2008) 3507–3511
Table 2
To obtain diaryl ethers in high yields using our reported
Optimization study for proazaphosphatranes using 1 mol % catalyst
thermal protocol with 3, high mole percentages of this base
were needed (10–50 mol %) even with highly electron defi-
cient aryl fluorides.7 To avoid using large molar percent-
ages of promoters for a variety of SNAr reactions, several
groups have resorted to microwave techniques.11 For
example, Wang and co-workers used a microwave for the
SNAr reaction involving 2 equiv of K2CO3 in the highly
polar solvent DMSO in the absence of catalyst.12
In this report, we describe the utility of 3 at low loading
in the synthesis of diaryl ethers under microwave condi-
tions. Since we previously reported using 3 under thermal
conditions for such syntheses,7 we began our study by
determining the lowest loading of 3 which can be usefully
employed for this reaction under microwave conditions
to achieve high product yields. Using the same model reac-
tion given in our previous report, we found that only
1 mol % of 3 was necessary to obtain a 99% isolated yield
of the desired product under microwave conditions in the
nonpolar solvent toluene (Table 1).
In determining the best proazaphosphatrane for diaryl
ether synthesis using the present protocol, we standardized
on employing 1 mol % each of 1–4 (Table 2). As shown in
entry 1 of this table, 90% of the desired product was
achieved using 1. Earlier we showed that proazaphospha-
trane basicity rises with the steric bulk of the substituent
on its P–N nitrogens.9 Herein, a parallel trend is seen for
the product yield in Table 2. Because 4 is apparently less
basic than 3,13 it was surprising to observe that proaza-
phosphatrane 4 (as well as 3) gave a quantitative yield of
the desired product (Table 2, entry 4).
It was previously shown by our group that the reaction
in Table 1 fails under thermal conditions in the absence of a
proazaphosphatrane.8 However, in the same experiment
carried out under microwave conditions, 45% of desired
product was obtained (Table 2, entry 5). When the same
model compounds were used with no catalyst in DMF at
180 °C for 5 h, the yields of the desired products did not
increase.
1 mol %
proazaphosphatrane
NO2
NO2
F
TBDMSO
O
toluene
microwave
130 ºC
+
O2N
Br
O2N
Br
30 min
Entry
Proazaphosphatrane
Yielda,b (%)
1
2
3
4
5
a
1
90 (98)
91 (98)
99 (98)
99
2
3
4
None
45 (0)
Average of two runs.
Yields in parentheses are under thermal conditions with 10 mol % 3
b
(Ref. 7).
TBDMS aryl ethers (Table 3) using 3 because of its ease of
handling and its commercial availability. Two solvents (tol-
uene and DMF) were used for the SNAr reactions in this
table. Nitro-substituted aryl fluorides functioned better in
the relatively non-polar solvent toluene, while other aryl
fluorides required highly polar DMF, apparently to stabi-
lize the Meisenheimer complex.14 Thus, the coupling of
highly activated 2,4-dinitrofluorobenzene with 4-methoxy-
phenyl and 3-chlorophenyl TBDMS ethers proceeded well
with only 1 mol % of 3 in toluene (Table 3, entries 1 and 3).
SNAr reactions have been observed to proceed smoothly
with electron rich phenols but are sluggish with electron
deficient analogues.7 Even coupling between 2,4-dinitro-
fluorobenzene and electron deficient 4-cyanophenyl
TBDMS ether proceeded in 45 min with a 93% isolated
yield in the presence of 1 mol % 3 in toluene (Table 3, entry
2).
For 4-nitrofluorobenzene in toluene, the catalyst loading
required for 3 for timely completion of the reaction was
2 mol % and the temperature needs to be increased to
180 °C for complete conversion of the starting material.
Under these conditions, 4-nitrofluorobenzene reacted read-
ily with 4-methoxyphenyl and 3-chlorophenyl TBDMS
ethers affording product yields of 97% and 95%, respec-
tively (Table 3, entries 4 and 6). With this increased catalyst
loading, 4-cyanophenyl TBDMS ether as a coupling part-
ner provided an excellent product yield of 96% (Table 3,
entry 5). Under thermal conditions, we obtained only a
moderate yield of this product (73%) using 20 mol % of
3.7 Although Wang and co-workers reported a 95% yield
of the same product in 5 min using microwave conditions,
2 equiv of K2CO3 in DMSO was required.12
With these results in hand, the scope of our microwave
approach was explored with a variety of aryl fluorides and
Table 1
Optimization study on amount of proazaphoshpatrane
NO2
NO2
F
TBDMSO
O
3
X mol %
toluene
+
O2N
Br
O2N
Br
microwave
130 ºC
30 min
We then screened aryl fluorides bearing a nitrile or an
ester functional group (Table 3, entries 7–12). These sub-
strates required DMF as a solvent to avoid the sluggishness
we observed for their reactions in toluene. Although longer
reaction times were needed, the reactions in Table 3, entries
7–12 were amenable to lower loadings of 3 than we had
reported under thermal conditions,7 particularly for the
reaction of 4-cyanofluorobenzene with 3-chlorophenyl
Entry
mol % 3
Yielda (%)
1
2
3
4
a
10
5
1
99b
99
99
76
0.5
Average of two runs.
b
Thermal reaction required 1 h (Ref. 7).

S. M. Raders, J. G. Verkade / Tetrahedron Letters 49 (2008) 3507–3511
3509
Table 3
SNAr reactions of aryl fluoride with TBDMS ethers
TBDMSO
F
O
1-10 mol % 3
R2
R1
R1
R2
+
toluene/DMF,
microwave, temp
Entry
1
Aryl fluoride
TBDMS ether
mol % time
Product
Yielda,b (%)
97 (88)c,d
NO2
NO2
NO2
NO2
TBDMSO
O
O
O
O
F
1/30 min
OMe
CN
O2N
O2N
O2N
O2N
O2N
OMe
CN
TBDMSO
TBDMSO
2
1/45 min
93 (88)c,e
3
4
1/30 min
2/1 h
95 (96)c,e
97 (92)f,g
96 (95)f,h
95 (90)e,f
94 (85)f,i
90 (95)e,f
92 (92)f,j
61 (84)f,k
73 (96)e,f
Cl
Cl
F
TBDMSO
O2N
OMe
CN
OMe
CN
O
O
TBDMSO
TBDMSO
5
2/3 h
O2N
O2N
6
2/90 min
1/3 h
Cl
Cl
F
TBDMSO
O
7
NC
OMe
NC
NC
OMe
TBDMSO
O
8
1/5 h
Cl
Cl
F
O
TBDMSO
9
2/5 h
EtO2C
EtO2C
OMe
OMe
CN
O
O
TBDMSO
10
10/5 h
5/5 h
EtO2C
EtO2C
CN
TBDMSO
11
Cl
Cl
a
Isolated yields (average of two runs).
b
c
d
e
f
Yields in parentheses are literature values.
Reaction temperature is 130 °C.
See Ref. 16.
See Ref. 7.
Reaction temperature is 180 °C.
See Ref. 17.
See Ref. 12.
See Ref. 11c.
See Ref. 6.
See Ref. 18.
g
h
i
j
k

3510
S. M. Raders, J. G. Verkade / Tetrahedron Letters 49 (2008) 3507–3511
TBDMS ether (Table 3, entry 8). The 90% product yield
for this reaction was obtained with only 1 mol % of 3, in
contrast to the 50 mol % of this catalyst that was necessary
to obtain a 95% product yield thermally.7 For the fluoro-
aryl ester (Table 3, entries 8–11) higher loadings of 3 were
required to obtain reasonable to high product yields.
Although the reaction between ethyl-4-fluorobenzoate
and 4-cyanophenyl TBDMS ether required 10 mol % of 3
to obtain a 61% product yield, 20 mol % of this catalyst
was required to obtain only a 39% product yield
thermally.7
Finally, we examined two sterically hindered aryl
TBDMS ethers in our protocol (Table 4). Under the ther-
mal conditions used in our previous work,7 50 mol % of 3
was needed to obtain high yields, whereas under micro-
wave conditions, the same products were made in excellent
yields by employing only 10 mol % of 3 (Table 4, entries 1–
6). However, the new compound made from 2-nitro-4-fluo-
rotoluene generated only a moderate product yield of 56%
(Table 4, entry 3). With 4-fluorobenzonitrile, the reaction
failed in toluene, but when DMF was used as the solvent,
a 95% yield of the desired product was achieved (Table 4,
entry 4). Surprisingly, 4-nitrofluorobenzene also reacted
with the sterically demanding 2,6-di-isopropylphenyl
TBDMS ether to give a 92% product yield using
10 mol % of 3 (Table 4, entry 5). A previous method for
making this compound involved the use of a 4-nitrophen-
oxide anion and 1,4-dinitrobenzene in DMSO to obtain a
76% product yield.15 4-Fluorobenzonitrile reacted with
2,6-di-isopropylphenyl TBDMS ether to afford a 98% yield
of the new compound in Table 4, entry 6.
In summary, we have demonstrated the utility of pro-
azaphosphatrane 3 under the microwave conditions for
synthesizing diaryl ethers from electron poor aryl fluorides
and a variety of TBDMS-protected phenols, including ste-
rically hindered ones. As in our previous work under the
thermal conditions,7 the reaction of 2,4-dinitrofluoroben-
zene with 4-methoxyphenol also failed in our microwave
Table 4
SNAr reactions of aryl fluoride with sterically hindered TBDMS ethers
R2
R2
TBDMSO
F
O
R3
3
10 mol %
R1
R1
+
toluene or DMF
microwave, 180 ºC
R3
Entry
1
Aryl fluoride
TBDMS ether
mol % time
Product
NO2
Yielda,b (%)
NO2
F
O
O
TBDMSO
10/3 h
92
O2N
O2N
O2N
O2N
F
F
2
3
4
5
10/3 h
10/3 h
10/3 h
10/3 h
95 (90)c
O
56
O2N
O2N
F
O
95 (77)d
92 (76)e
NC
NC
F
TBDMSO
O
O2N
O2N
F
O
6
10/3 h
98
NC
NC
a
Isolated yields (average of two runs).
Yields in parentheses are literature values.
See Ref. 17.
See Ref. 11c.
See Ref. 15.
b
c
d
e

S. M. Raders, J. G. Verkade / Tetrahedron Letters 49 (2008) 3507–3511
3511
2. Parker, A. J. Chem. Rev. 1969, 69, 1.
protocol. This result is consistent with our earlier finding
that the phosphorus of 3 can activate the silicon atom by
weakening the Si–O bond.8 Thermal7 as well as microwave
conditions require the use of an electron deficient aryl fluo-
ride with a TBDMS aryl ether. Thus, the reaction of 4-flu-
oroanisole with 3-chlorophenyl TBDMS ether failed in
both protocols.
3. (a) Sawyer, J. S. Tetrahedron 2000, 56, 5045; (b) Wipf, P.; Lynch, S.
M. Org. Lett. 2003, 5, 1155; (c) Saitoh, T.; Ichikawa, J. J. Am. Chem.
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General procedure: To a 10 mL microwave tube was
charged 1.2 mmol of aryl TBDMS ether to which was
added 1 mmol of aryl fluoride. Proazaphosphatrane 3
(from a stock solution prepared in the appropriate solvent)
was then added to the tube under inert atmosphere. The
tube was capped and placed in the microwave for the times
given in Tables 1–3 and in entries 1–3 in Table 4, after
which the solvent was removed in vacuo to produce the
crude product that was purified by column chromatogra-
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Acknowledgment
We thank the SQM Corporation for support of this
work.
Supplementary data
Supplementary data (complete experimental procedures
and characterizational data for all compounds.) associated
with this article can be found, in the online version, at
doi:10.1016/j.tetlet.2008.03.089.
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