P(MeNCH2CH2)3N: An efficient silylation catalyst

Full text of DOI:10.1021/ja961010w

12832
J. Am. Chem. Soc. 1996, 118, 12832-12833
and triflate (with 2,6-lutidine),7n have also been employed. The
foregoing methods have two general disadvantages, however.
Thus, p-toluenesulfonic acid (PTSA) and potassium carbonate
cannot be used for acid and base sensitive alcohols, respectively.
Secondly, the use of DMF as a solvent, the relatively high base
concentrations, long reaction times, and high reaction temper-
atures required for obtaining high yields of secondary silyl ethers
when TBDMSCl is used as a silylating reagent incur procedural
inconveniences. A particular problem with TBDMS protection
has been the difficulty of silylating tertiary or hindered second-
ary alcohols and hindered phenols. This problem became acute
during the total synthesis of maytansine8 and of 1,4-bis (tert-
butyldimethylsiloxy)-2,5-di-tert-butylbenzene for electrochemi-
cal oxidation studies.9 Hence, more reactive silylating agents,
namely TBDMS perchlorate7m and TBDMS triflate,7n were
developed, which were found to be capable of silylating tertiary
and hindered secondary alcohols in high yield.7m,n The per-
chlorate derivative, however, is explosive, must be handled with
great care, and is not commercially available.
P(MeNCH2CH2)3N: An Efficient Silylation Catalyst
Bosco A. D’Sa and John G. Verkade*
Department of Chemistry, Iowa State UniVersity
Ames, Iowa 50011
ReceiVed March 27, 1996
In our continuing quest1 for new synthetic applications of
our recently synthesized and commercially available proaza-
phosphatrane 1b, we have discovered that 1b is an efficient
and mild catalyst for the silylation of tertiary alcohols and
hindered phenols that are difficult to silylate using the reagent
tert-butyldimethylsilyl chloride (TBDMSCl). The influence of
solvent on the yield of silylated benzyl alcohol is discussed,
and evidence for the first example of a P-silylating intermediate,
namely 2a, is given that stems from the detection of its analogue
3a. Of the functional groups amenable to silylation (e.g., -SH,
We report here a very effective and mild procedure for the
preparation of TBDMS ethers of tertiary alcohols and hindered
phenols. To this end, the commercially available and relatively
inexpensive TBDMSCl is employed in the presence of the
commercially available nonionic superbase 1b, first reported
from our laboratories,10 as a catalyst under a nitrogen atmosphere
in CH3CN or in DMF. The analogue 3a of the proposed
P-silylating intermediate 2a was detected by NMR spectroscopy.
Table 1 outlines the efficacy and the scope of this procedure
using alcohols 4-7. The silylated products were purified by
silica gel chromatography using hexanes as the eluent.
-COOH, -NH2, and -OH), the hydroxy group has thus far
received the most attention because of its presence in many
natural products. Among the many trialkylsilyl derivatives used
to protect hydroxyl groups, the TBDMS (tert-butyldimethylsilyl)
group has proven to be invaluable in synthetic organic chemistry,
ever since its introduction in 1972 by Corey and Venkateswarlu.2
This is primarily due to the comparative ease with which
TBDMSCl transforms an alcohol to the corresponding TBDMS
ether, the facile specific removal of the TBDMS group by either
fluoride ion or aqueous acid, and its stability to hydrogenation,
saponification, and to Jones, Grignard, and Wittig reagents.
Moreover, TBDMS ethers are approximately 104 times more
stable to solvolysis than the corresponding trimethylsilyl ether,3
thus facilitating hydroxy group protection during the synthesis
of a variety of structures including prostaglandins,4 paclitaxels,5
and vitamin D3.6
When 0.2 equiv of 1b, one equiv of benzyl alcohol, and 1.1
equiv each of Et3N and TBDMSCl in CH3CN at 24 °C were
mixed, the corresponding silyl ether was produced in quantitative
yield in 0.2 h (eq 1). A similar yield was obtained in 2.5 h
Conventional methods7 for the preparation of TBDMS ethers
include the reaction of an alcohol with TBDMSCl in the
presence of bases such as imidazole,2 Et3N/1,1,3,3-tetrameth-
ylguanidine (TMG),7a Et3N/DBU (1,8-diazabicyclo[5.4.0]undec-
7-ene),7b,c 18-crown-6/K2CO3,7d i-Pr2NEt,7e Et3N/DMAP (4-
(dimethylamino)pyridine),7f and Li2S7g in solvents such as DMF,
CH3CN, and CH2Cl2. TBDMS derivatives, such as its ketene
methyl acetyl,7h enol ether of pentane 2,4-dione (with catalytic
PTSA (p-toluenesulfonic acid)),7i allyl silane (with catalytic
PTSA),7j N-methyl-N-tert-butyldimethylsilyl amides,7k N,O-bis-
(tert-butyldimethylsilyl)acetamide,7l perchlorate (with pyridine),7m
employing only 0.04 equiv of 1b. The influences of different
solvents on the yield of the silyl benzyl ether at 24 °C using
0.04 equiv of 1b are pentane, 43%; ether, 46%; benzene, 78%;
THF, 92%; CH3CN, ∼100%; and DMF, ∼100%.
The favorable effect of polar solvents on the silylation of
alcohols under our conditions may be rationalized on the basis
of an ionic species such as 2a being formed as an active
intermediate in the reaction of 1b and TBDMSCl, even though
such an intermediate was not detectable by variable temperature
(7) (a) Kim, S.; Chang, H. Synth. Commun. 1984, 14 (10), 899. (b) Kim,
S.; Chang, H. Bull. Chem. Soc. Jpn. 1985, 58, 3669. (c) Aizpuraua, J. M.;
Palono, C. Tetrahedron Lett. 1985, 26, 475. (d) Lissel, M.; Weiffer, J. Synth.
Commun. 1981, 11 (7), 545. (e) Lombardo, L. Tetrahedron Lett. 1984, 25,
227. (f) Chaudhary, S. K.; Hernandez, O. Tetrahedron Lett. 1979, 2, 99.
(g) Olah, G. A.; Gupta, B. G.; Narang, S. C.; Malhotra, R. J. Org. Chem.
1979, 44, 4272. (h) Kita, Y.; Haruta, J.; Fuji, T.; Segawa, J.; Tamura, Y.
Synthesis 1981, 451. (i) Verysoglu, T.; Mitscher, L. A. Tetrahedron Lett.
1981, 22, 1299. (j) Morita, T.; Okamoto, Y.; Sakurai, H. Tetrahedron Lett.
1980, 21, 835. (k) Mawhinney, T. P.; Madson, M. A. J. Org. Chem. 1982,
47, 3336. (l) Johnson, D. A.; Taubner, L. M. Tetrahedron Lett. 1996, 37,
605. (m) Barton, T. J.; Tully, C. R. J. Org. Chem. 1978, 43, 3649. (n)
Corey, E. J.; Cho, H.; Rucker, C.; Hua, D. H. Tetrahedron Lett. 1981, 22,
3455.
(1) (a) D’Sa, B. A.; Verkade, J. G. J. Org. Chem. 1996, 61, 2963. (b)
Tang, J. S.; Verkade, J. G. Angew. Chem., Int. Ed. Engl. 1993, 32, 896. (c)
Tang, J. S.; Mohan, T.; Verkade, J. G. J. Org. Chem. 1994, 59, 4931. (d)
Tang, J. S.; Verkade, J. G. J. Org. Chem. 1994, 59, 7793. (e) Verkade, J.
G. Coord. Chem. ReV. 1994, 137, 233. (f) Laramay, M. A. H.; Verkade, J.
G. Z. Anorg. Allg. Chem. 1991, 605, 163. (g) Tang, J. S.; Verkade, J. G. J.
Org. Chem. 1996. In press.
(2) Corey, E. J.; Venkateswarlu, A. J. Am. Chem. Soc. 1972, 94, 6190.
(3) Greene, T. W.; Wuts, P. G. M. ProtectiVe Groups in Organic
Synthesis, 2nd Ed.; John Wiley and Sons, Inc.: New York, 1991; pp 77-
80, 414.
(4) Hwang, S. W.; Adiyaman, M.; Khanapure, S.; Schio, L.; Rokach, J.
J. Am. Chem. Soc. 1994, 116, 10829.
(8) Corey, E. J.; Weigel, L. O.; Chamberlin, A. R.; Cho, H.; Hua, D. H.
J. Am. Chem. Soc. 1980, 102, 6613.
(9) Stewart, R. F.; Miller, L. L. J. Am. Chem. Soc. 1980, 102, 4999.
(10) Schmidt, H.; Lensink, C.; Xi, S. K.; Verkade, J. G. Z. Anorg. Allg.
Chem. 1989, 75, 578.
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1995, 36, 829.
S0002-7863(96)01010-4 CCC: $12.00 © 1996 American Chemical Society

Communications to the Editor
J. Am. Chem. Soc., Vol. 118, No. 50, 1996 12833
Table 1. Conditions for Alcohol Silylation with TBDMSCl Using
1b as a Catalysta
isolation of 3a from DMSO resulted in its decomposition. This
is not suprising, since 1a is stable only in solution.1f Apparently,
the augmented basicity and nucleophilicity of the phosphorus
in 1 stemming from transannular bond formation play important
roles in the rate of formation and stability, respectively, of the
cations of type 2 and 3. Under the present reaction conditions,
we believe that 1b forms the adduct 2a with TBDMSCl, which
subsequently reacts with alcohols to afford TBDMS ethers. That
triethylamine does not catalyze reaction 1 is well-known from
earlier alcohol silylation experiments.7f
We believe that the extensive positive charge delocalization
in cation 2a is facilitated by transannular bond formation,
permitting substantial separation of the ion pair, thereby making
the cation more reactive. The resonance structures for cation
2a shown and implied below indicate the possibility of positive
charge delocalization to all four nitrogens, whereas in 8 only
three nitrogens can be involved in such delocalization. This
reasoning finds support in the fact that the electron-donating
dimethylamino group in TMG facilitates formation of the
proposed charged intermediate 8.7b
equiv
of 1b
time
(h)
T
(°C)
yield
(%)
alcoholb
solventc
4
0.2
0.2
0.2
1.1
0.2
0.4
1.1
0.4
0.4
0.2
A
D
D
N
D
D
N
A
A
D
24
24
24
24
24
48
24
18
18
24
24
24
80
80
80
80
80
24
60
80
4
12
80
90
12
77
80
50
86
86
5
6
7
a No attempt was made to maximize yields by optimizing reaction
time and temperature and the concentration of 1b. b All the alcohols
are commercially available and were used as received. c A ) acetoni-
trile, D ) dimethylformamide, N ) no solvent.
31P NMR spectroscopy in an equimolar mixture of 1b and
TBDMSCl, TBDMS triflate, tert-butyldiphenylsilyl chloride
(TBDPSCl), or triphenylsilyl chloride (TPSCl) in CD3CN (-10
to +40 °C) or C6D6 (+10 to +40 °C). It may be noted in this
respect, however, that the P-acylated intermediate 2b in our
benzoylation of alcohols was found by NMR spectroscopy to
be in equilibrium with 1b at room temperature.1a We also have
substantial NMR spectroscopic evidence that the active catalytic
site in compounds of type 1 for the synthesis of isocyanurates
and carbodiimides is the phosphorus atom.1c Molecular struc-
tures determined by X-ray analysis for 1c11 as well as 3b12 and
3c12 show that the three R groups are attached to planar
nitrogens, thus orienting the R groups like a picket fence around
the phosphorus. Proceeding from the assumption that interme-
diate 2a is too sterically encumbered to form in concentrations
detectable by NMR spectroscopy, we sought to make the less
hindered 3a in which the 1a moiety is more basic than 1b.1e
Thus, we generated 1a (δ31P ) 89.0 ppm) in deuterated DMSO
at 20 °C under nitrogen1f and then added a 10% molar excess
of TBDPSCl at room temperature. The 31P NMR spectrum of
this solution then displayed a single peak at -0.4 ppm, with or
Kim et al.7a reported that the silylation of 5 using 0.2 equiv
of TMG in the presence of 1 equiv of TBDMSCl and Et3N
resulted in only 11% of the silylated product at room temperature
in DMF. Prolonged heating and the use of 1 equiv of TMG
did not significantly improve the yield. Alcohol 5 could not
be silylated using 1.1 equiv of DBU in DMF at room
temperature.7b However, silylation of 5 using only 0.4 equiv
of 1b as a catalyst at 80 °C gave a 77% yield of the silylated
product in 48 h. TBDMS perchlorate, although not com-
mercially available, rapidly silylates 7 in quantitative yield at
room temperature in acetonitrile, whereas the TBDMSCl/DMF/
imidazole cocktail produced only 10% of silylated product in 3
days.7m From Table 1 it is seen that this alcohol was silylated
in 86% yield using our method. Sterically hindered 1,4-bis-
(tert-butyldimethylsiloxy)-2,5-di-tert-butylbenzene was difficult
to prepare in reactions of TBDMSCl with 6, and hence, the
more reactive TBDMS triflate was employed.9 However only
a 53% yield of the pure disilylated product was reported,
whereas our method gave 86% of the disilylated product of 6
(Table 1). Recently, an efficient and mild palladium(II)-
catalyzed desilylation of phenolic TBDMS ethers was reported14
which should enhance the use of the TBDMS moiety as a
protecting group for phenols. Investigations of functional group
compatibilities, sterically hindered alcohol silylations using
solvents other than DMF, and catalyst recycling are underway.
1
without proton decoupling, which we assign to 3a. The H
NMR spectrum revealed the presence of unreacted TBDPSCl
and a doublet centered at 1.07 ppm with JHP ) 24 Hz, which
we assign to a two-bond PNH spin-spin interaction in 3a on
the basis of a 28 Hz value for this coupling in 3b.1f This
substantiates the assignment of the -0.4 ppm 31P NMR peak
to the cation of 3a rather than that of 3b (δ31P ) -42.0 ppm),
since the latter exhibits a 453 Hz doublet due to one-bond P-H
coupling without proton decoupling.1f Evidence for considerable
transannulation in 3a is its high-field 31P NMR chemical shift
(-0.4 ppm) which is indicative of phosphorus five-coordination.
This shift is consistent with the high-field 31P chemical shifts
observed for cations 2b, 2c, 3b, and 3c.1a,1f,13 Attempted
(11) Wroblewski, A. E.; Pinkas, J.; Verkade, J. G. Main Group Chem.
1995, 1, 69.
Acknowledgment. The authors thank the Center for Advanced
Technology Development of Iowa State University and the Donors of
the Petroleum Research Fund Administered by the American Chemical
Society for grant support of this research.
(12) Verkade, J. G. Acc. Chem. Res. 1993, 26, 483.
(13) P-Ethyl carboxylation of 1b to give the intermediate 2c is supported
1
by NMR spectroscopy. A H NMR spectrum of an equimolar mixture of
1b and ethyl chloroformate in CD3CN at 24 °C under N2 revealed a doublet
centered at 2.68 ppm with a P-H coupling constant JHP of 14.1 Hz which
we assign to a three-bond spin-spin interaction involving the methyl protons
in 2c on the basis of a 17.4 Hz value for this coupling in 3c.11 The 13C
NMR spectrum of this mixture shows a doublet for the carbonyl carbon
peak centered at 172.4 ppm with a coupling constant of 201.8 Hz, consistent
with a one-bond C-P interaction.1a The 31P NMR spectrum displays a single
peak at -1.5 ppm with or without proton decoupling which we assign to
2c rather than 3c (-9.9 ppm), since the latter resonance without proton
decoupling is a doublet owing to one-bond P-H coupling.1a,c
Supporting Information Available: Compound characterizational
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(14) Wilson, N. S.; Keay, B. A. Tetrahedron Lett. 1996, 37, 153.