P(i-BuNCH2CH2)3N: An efficient promoter for the nucleophilic aromatic substitution reaction of aryl fluorides with aryl TBDMS (or TMS) ethers

Article abstract of DOI:10.1021/ol051108s

(Chemical Equation Presented) The nucleophilic aromatic substitution reaction between electron-deficient aryl fluorides and aryl TBDMS (or TMS) ethers has been shown to be efficiently promoted by proazaphosphatranes such as P(i-BuNCH₂CH₂)₃N (3). Excellent yields of diaryl ether products were obtained under unusually mild conditions.

Full text of DOI:10.1021/ol051108s

ORGANIC
LETTERS
2005
Vol. 7, No. 15
3319-3322
P(i-BuNCH2CH2)3N: An Efficient
Promoter for the Nucleophilic Aromatic
Substitution Reaction of Aryl Fluorides
with Aryl TBDMS (or TMS) Ethers
Sameer Urgaonkar† and John G. Verkade*
Department of Chemistry, Iowa State UniVersity, Ames, Iowa 50011
jVerkade@iastate.edu
Received May 12, 2005
ABSTRACT
The nucleophilic aromatic substitution reaction between electron-deficient aryl fluorides and aryl TBDMS (or TMS) ethers has been shown to
be efficiently promoted by proazaphosphatranes such as P(i-BuNCH2CH2)3N (3). Excellent yields of diaryl ether products were obtained under
unusually mild conditions.
The synthesis of diaryl ethers has attracted significant interest
because of the frequent occurrence of these structural units
in biologically active natural products such as vancomycin,
riccardin C, ristocetin aglycon, and chloropeptin I.1 Further-
more, poly(aryl ethers) find applications as engineering
thermoplastic materials.2 Three general routes to diaryl ethers
are (1) nucleophilic aromatic substitution (SNAr) reactions
between activated aryl halides (of general reactivity order F
> Cl > Br > I) and phenols,3 (2) classical copper-catalyzed
Ullmann reactions of aryl halides with phenols,4 and (3) more
recently developed palladium-catalyzed arylations of phe-
nols.5
Of these three methods, the SNAr reaction is relatively
milder and more environmentally benign. In addition to
identifying suitable reaction conditions for the standard SN-
Ar reaction, research in this field has also focused on
modifying the nucleophilic phenol coupling partner. For
example, in 1988, Saunders found that activated aryl fluorides
react directly with TBDMS (tert-butyl dimethyl silyl) aryl
ethers in the presence of tetrabutylammonium fluoride in
THF to give diaryl ethers.6 However, this novel method was
(2) Cotter, R. J. Engineering Plastics: A Handbook of Polyarylethers;
Gordon and Breach: Langhorne, PA, 1995.
(3) (a) Bunnett, J. F.; Zahler, R. E. Chem. ReV. 1951, 49, 273. (b) Parker,
A. J. Chem. ReV. 1969, 69, 1. (c) Sawyer, J. S. Tetrahedron 2000, 56, 5045.
(d) Sawyer, J. S.; Schmittling, E. A.; Palkowitz, J. A.; Smith, W. J., III J.
Org. Chem. 1998, 63, 6338.
(4) (a) Ullmann, F. Chem. Ber. 1904, 37, 853. (b) Lindley, J. Tetrahedron
1984, 40, 1433. (c) Thomas, A. W.; Ley, S. V. Angew. Chem., Int. Ed.
2003, 42, 5400.
(5) (a) Aranyos, A.; Old, D. W.; Kiyomori, A.; Wolfe, J. P.; Sadighi, J.
P.; Buchwald, S. L. J. Am. Chem. Soc. 1999, 121, 4369. (b) Mann, G.;
Hartwig, J. F. Tetrahedron Lett. 1997, 38, 8005.
† Present address: Chemical Biology Program, Broad Institute of Harvard
and MIT, 320 Bent Street, Cambridge, MA 02141.
(1) (a) Nicolaou, K. C.; Boddy, C. N. C. J. Am. Chem. Soc. 2002, 124,
10451. (b) Zhu, J. Synlett 1997, 133. (c) Boger, D. L.; Patane, M. A.; Zhou,
J. J. Am. Chem. Soc. 1994, 116, 8544. (d) Gottsegen, A.; Vermes, B.;
Kajtarperedy, M.; Bihatsikarasai, E.; Nogradi, M. Tetrahedron Lett. 1988,
29, 5039. (e) Crowley, B. M.; Mori, Y.; McComas, C. C.; Tang, D.; Boger,
D. L. J. Am. Chem. Soc. 2004, 126, 4310. (f) Deng, H.; Jung, J.-K.; Liu,
T.; Kuntz, K. W.; Snapper, M. L.; Hoveyda, A. H. J. Am. Chem. Soc. 2003,
125, 9032.
(6) Saunders, D. G. Synthesis 1988, 377.
10.1021/ol051108s CCC: $30.25
© 2005 American Chemical Society
Published on Web 06/22/2005

successful only with highly active 2,4-dinitrofluorobenzene.
In a related process, Oriyama and co-workers described the
direct conversion of TBDMS aryl ethers to aryl alkyl ethers
by their reaction with an alkyl halide in DMF using CsF as
the source of silyl group activation.7
and basicity of proazaphosphatranes stem in part from
transannular bond formation between the bridgehead phos-
phorus and nitrogen atoms. It is also interesting to note that,
unlike P4-t-Bu, proazaphosphatranes can become protonated
on the phosphorus atom whereas the imino nitrogen is the
basic site in P4-t-Bu (Figure 1).
We began our study by screening the proazaphosphatrane
catalysts 1-3 owing to their commercial availability12 and
the demonstrated ability of 1 and 2 to activate the silyl
group.9,10 The SNAr reaction of 2,4-dinitrofluorobenzene with
TMS aryl ether 4 was chosen as a representative reaction.
Pleasingly, almost quantitative yields of the corresponding
diaryl ether were obtained in the presence of 10 mol % of
1, 2, or 3 in toluene within 1 h at room temperature (Table
1, entries 1-3). In a control experiment, no reaction was
Very recently, Kondo and co-workers coupled aryl fluo-
rides with aryl TBDMS or TMS (trimethylsilyl) ethers using
the phosphazene base P4-t-Bu.8 In that study, it was
interesting to note that weaker bases such as DBU and BEMP
were totally ineffective.8 This significantly improved method
does, however, require a highly polar aprotic solvent (DMF
or DMSO) even with active fluoronitrobenzenes. Because
the TBDMS group is a common protecting group for OH
groups in organic synthesis, the aforementioned direct
coupling by in situ activation of the silyl group not only
eliminates the unmasking step of a TBDMS-protected OH
group but it also opens new avenues for synthetic chemists
to exploit. Related to this intriguing chemistry is the report
from our group of a few years ago in which the first
observation of the desilylation of TBDMS ethers by a
nonionic base, namely, proazaphosphatrane 1, was described
(Figure 1).9 This reaction takes place efficiently in DMSO
Table 1. Optimization Study
entry
proazaphosphatrane
yield (%)a
98
1
2
3
4
1
2
3
none
98
>98
no reactionb
a Isolated yields (average of two runs). b Reaction time: 16 h.
observed in the absence of a proazaphosphatrane even after
16 h at room temperature (Table 1, entry 4). The SNAr
reaction is usually performed in a highly polar aprotic solvent
such as DMF or DMSO in order to stabilize the charged
intermediate Meisenheimer complex formed during the
reaction.13 Thus, it is remarkable that in the presence of
proazaphosphatranes, the reaction proceeded smoothly even
in the apolar solvent toluene.
Encouraged by these initial successes, we next focused
on expanding the scope of the methodology using the most
basic of the three proazaphosphatranes,10 namely, 3, as the
promoter. Table 2 contains the results of SNAr reactions of
various nitro-substituted aryl fluorides. The coupling of the
more active 2,4-dinitrofluorobenzene with 3-chlorophenyl
TBDMS ether and 2-methoxy-4-methylphenyl TBDMS ether
occurred in excellent yields (Table 2, entries 1 and 3). It
should be noted that SNAr reactions of aryl fluorides
generally proceed readily with electron-rich phenols and
sluggishly with electron-poor phenols. However, in the
presence of 3, even a TBDMS aryl ether bearing an electron-
withdrawing group served as an efficient coupling partner,
Figure 1. Nonnucleophilic superbases.
at 80 °C under catalytic conditions. These findings prompted
us to determine whether proazaphosphatranes, which we have
demonstrated to activate silyl groups, can also be used for
coupling aryl fluorides with TBDMS ethers in a synthesis
of diaryl ethers. In the present report, we illustrate the
usefulness of proazaphosphatranes as an activator for such
couplings and further expand the method developed by
Saunders.
Proazaphosphatranes are powerful nonionic bases with pKa
values in the range of 32-3410 in CH3CN. However, their
basicities are 7-9 pKa units less basic than the phosphazene
base P4-t-Bu (pKa: 41.4 in CH3CN11). The nucleophilicity
(7) Oriyama, T.; Noda, K.; Yatabe, K. Synlett 1997, 701.
(8) Ueno, M.; Hori, C.; Suzawa, K.; Ebisawa, M.; Kondo, Y. Eur. J.
Org. Chem. 2005, 1965.
(9) Yu, Z.; Verkade, J. G. J. Org. Chem. 2000, 65, 2065.
(10) For recent reviews, see: (a) Verkade, J. G. Top. Curr. Chem. 2002,
233, 1. (b) Kisanga, P. B.; Verkade, J. G. Tetrahedron 2003, 59, 7819.
(c) Verkade, J. G.; Kisanga, P. B. Aldrichimica Acta 2004, 37, 3.
(11) Schwesinger, R.; Schlemper, H.; Hasenfratz, C.; Willaredt, J.;
Dambacher, T.; Breuer, T.; Ottaway, C.; Fletschinger, M.; Boele, J.; Fritz,
H.; Putzas, D.; Rotter, H. W.; Bordwell, F. G.; Satish, A. V.; Ji, G.-Z.;
Peters, E.-M.; Peters, K.; von Schnering, H. G.; Walz, L. Liebigs Ann. 1996,
1055.
(12) Proazaphosphatranes 1, 2, and 3 are commercially available from
Aldrich, and 1 and 2 can also be obtained from Strem Chemicals.
(13) (a) Acevedo, O.; Jorgensen, W. L. Org. Lett. 2004, 6, 2881.
(b) Carey, F. A.; Sundberg, R. J. AdVanced Organic Chemistry, 4th ed.;
Plenum Publishing: New York, 2001.
3320
Org. Lett., Vol. 7, No. 15, 2005

other than nitro such as ester, nitrile, and aldehyde (Table
3). Thus, for 4-fluorobenzonitrile, ethyl-4-fluorobenzoate, and
Table 2. SNAr of Nitro-Substituted Aryl Fluorides with Aryl
TBDMS (or TMS) Ethers
Table 3. SNAr of Cyano-, Ester-, and Aldehyde-Substituted
Aryl Fluorides with Aryl TBDMS Ethers
a Isolated yields (average of two runs). b Conditions: 50 mol % 3, 4 h.
c Conditions: 20 mol % 3, 9 h. d Conditions: 10 mol % 3, 3 h. e Conditions:
50 mol % 3, 12 h. f Conditions: 20 mol % 3, 17 h. g Conditions: 20 mol
% 1, 17 h. h Conditions: 20 mol % 3, 8 h. i Conditions: 10 mol % 3, 2 h.
j Conditions: 20 mol % 3, 10 h.
a Isolated yields (average of two runs). b Conditions: rt, 45 min.
c Conditions: 80 °C, 3 h. d Conditions: rt, 1 h. e Conditions: rt, 75 min.
f Conditions: 80 °C, 105 min. g Conditions: 20 mol % 3. h Conditions: rt,
5 h.
2-fluorobenzaldehyde, DMF was the solvent of choice owing
to the sluggishness of these reactions in toluene. While longer
reaction times, a higher temperature (80 °C), and an increased
loading of 3 (20-50 mol %) were necessary for these
reactions, it is noteworthy that reasonable to excellent yields
of the desired diaryl ethers were obtained (Table 3, entries
1-9). Not surprisingly, the electronically favored reaction
of ethyl-4-fluorobenzoate with 4-methoxyphenyl TBDMS
ether afforded a 97% isolated yield of the corresponding
diaryl ether (Table 3, entry 8), and the electronically
disfavored reaction of ethyl-4-fluorobenzoate with 4-cy-
anophenyl TBDMS ether gave a significantly lower yield
(39%, Table 3, entry 7). An aldehyde functional group on
an aryl fluoride was also compatible under these conditions,
although a slightly lower yield was obtained in the reaction
of 2-fluorobenzaldehyde with 3-chlorophenyl TBDMS ether
(59%, Table 3, entry 9).
although a higher temperature was required (Table 2, entry
2). 4-Fluoronitrobenzene also reacted efficiently with elec-
tronically diverse TBDMS as well as TMS aryl ethers. Since
TMS groups are more labile than TBDMS moieties, only
one aryl TMS ether was employed in this study in order to
demonstrate the versatility of our method. Again most
striking is the electronically disfavored reaction of 4-fluoro-
nitrobenzene with 4-cyanophenyl TBDMS ether (Table 2,
entries 6 and 7). The yield obtained in the traditional SNAr
reaction of 4-fluoronitrobenzene with 4-cyanophenol using
KOH/DMSO/55 °C14 was significantly higher (98% isolated
yield) compared with ours (73% isolated yield, entry 7 in
Table 2). On the other hand, the isolated yield (93%) we
obtained for the reaction detailed in entry 8 demonstrates
the somewhat greater efficacy of the proazaphosphatrane
catalyst 3 than the similar reaction performed with 4-meth-
oxyphenol in the presence of KF-Al2O3/Aliquat 336
(MeOct3N+Cl-)15 in a microwave oven (92%).
Finally, we probed the SNAr reaction of aryl fluorides with
a sterically hindered TBDMS aryl ether. Sterically encum-
bered nucleophiles such as 2-tert-butylphenol, have been
quite problematic as coupling partners in SNAr reactions.3d
As illustrated in Table 4, 4-cyanofluorobenzene (entry 1) with
3 (50 mol %) as the promoter was efficiently coupled with
the sterically hindered TBDMS aryl ether 5 in DMF at
The scope of this novel SNAr reaction was also explored
with respect to the aryl fluorides containing functional groups
(14) Wilcox, C. S. Tetrahedron Lett. 1985, 26, 5749.
(15) Lee, J. C.; Choi, J.-H.; Lee, J. S. Bull. Korean Chem. Soc. 2004,
25, 1117.
Org. Lett., Vol. 7, No. 15, 2005
3321

coupling of 4-fluoronitrobenzene with 2-tert-butylphenol
provided the diaryl ether product in 90% yield in 10 min.15
It is important to emphasize, however, that the SNAr method
using microwave conditions was limited to nitroaryl fluo-
rides.
Table 4. SNAr of Aryl Fluorides with a Sterically Hindered
Aryl TBDMS Ether
In summary, we have successfully demonstrated the scope
and generality of a novel nucleophilic aromatic substitution
reaction of electron-poor aryl fluorides with TBDMS (or
TMS) aryl silyl ethers. Proazaphosphatrane 3 was shown to
be a highly efficient promoter for this reaction, and excellent
yields of diaryl ethers were obtained under particularly mild
conditions. Most significantly, it was observed that SNAr
reactions of fluoronitrobenzenes can be efficiently performed
even in an apolar solvent (toluene), thus circumventing the
need of the more tedious workup procedure required when
employing DMF or DMSO. Further studies are underway
to elucidate mechanistic details of our protocol. In this
context, it is worth mentioning the following observations:
(a) a silyl (TBDMS or TMS)-protected phenol is required
since the reaction of 4-fluoronitrobenzene with 3-chlorophe-
nol failed, and (b) the presence of an electron-poor aryl
fluoride is also important, because no reaction occurred
between 4-chloronitrobenzene and 4-methoxyphenyl TB-
DMS ether (both reactions performed in the presence of 3
under typical conditions).
a Isolated yields (average of two runs). b Reaction time: 5 h. c Toluene
was used as the solvent, 9 h. d Conditions: 40 mol % 3, 10 h.
80 °C to provide the corresponding diaryl ether product in
excellent yield. Although fluoronitrobenzenes react efficiently
with silyl ethers in toluene at room temperature, we were
disappointed to observe that the SNAr reaction of 4-fluoro-
nitrobenzene with 5 proceeded slowly at room temperature.
To our delight, however, efficient coupling occurred in
toluene at 80 °C, affording the diaryl ether product in almost
quantitative yield (entry 2). Steric hindrance on an aryl
fluoride was also well accommodated. Thus, the reaction of
ortho-substituted aryl fluoride (2-fluorobenzaldehyde) with
5 produced the corresponding diaryl product in 70% isolated
yield (entry 3). It is worth noting that the conventional SN-
Ar reactions of 4-fluorobenzonitrile and 4-fluoronitrobenzene
with 2-tert-butylphenol, promoted by KF-Al2O3/18-crown-
6, required 120 and 84 h, respectively, to proceed to
completion in refluxing CH3CN, and the corresponding
coupling products were obtained in 83 and 98% yields,
respectively.3d However, under more forcing conditions
(KF-Al2O3/Aliquat 336, microwave, no solvent), the SNAr
Acknowledgment. We heartily thank Professor Yoshinori
Kondo for a copy of the manuscript cited in reference 8 in
advance of its publication. We are grateful to the Aldrich
Chemical Co. for their generous support of this study by
supplying research samples. The National Science Founda-
tion is acknowledged for financial support of this work in
the form of a grant.
Supporting Information Available: Experimental pro-
cedures and characterization data for all compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
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