2,4,6-Tri-tert-butylpyrimidine (TTBP): A cost effective, readily available alternative to the hindered base 2,6-di-tert-butylpyridine and its 4-substituted derivatives in glycosylation and other reactions

Article abstract of DOI:10.1055/s-2001-10798

It is reported that 2,4,6-tri-tert-butylpyrimidine (TTBP), a highly sterically hindered base available through an efficient, cost-effective one pot sequence, is a replacement for 2,6-di-tert-butylpyridine and its 4-substituted analogs in glycosylation rea

Full text of DOI:10.1055/s-2001-10798

SPECIAL TOPIC
323
2,4,6-Tri-tert-butylpyrimidine (TTBP): A Cost Effective, Readily Available
Alternative to the Hindered Base 2,6-Di-tert-butylpyridine and its
4-Substituted Derivatives in Glycosylation and Other Reactions
David Crich,* Mark Smith, Qingjia Yao, John Picione
Department of Chemistry, University of Illinois at Chicago, 845 West Taylor Street, Chicago, Il 60607-7061, USA
Fax +1(312)9960431; E-mail: dcrich@uic.edu
Received 4 October 2000
sylations, and in the formation of enol triflates, and, more-
over, that it can be produced in 90 g batches in a one-pot
process that brings the cost down to approximately $4.3/g.
Abstract: It is reported that 2,4,6-tri-tert-butylpyrimidine (TTBP),
a highly sterically hindered base available through an efficient,
cost-effective one pot sequence, is a replacement for 2,6-di-tert-bu-
tylpyridine and its 4-substituted analogs in glycosylation reactions
and in the formation of vinyl triflates.
R
Key words: glycosylations, carbohydrates, non-nucleophilic base,
pyrimidines, triflates
N
N
N
2,6-Di-tert-butylpyridine (1) was introduced by Brown
and Kanner1 as a mild base capable of distinguishing be-
tween Brønsted and Lewis acids.1 Subsequently 2,4,6-tri-
tert-butylpyridine (2) and 2,6-di-tert-butyl-4-methylpyri-
dine (3) have also been described, and all three bases and
polymer-bound versions thereof,2 have been extensively
employed as non-nucleophilic bases in a broad variety of
contexts3 including glycosylation reactions,4,5 and the for-
mation of vinyl triflates.6-9 Kahne and coworkers exploit-
ed the inability of these bases to form amine-borane
complexes, as noted originally by Brown,1 by conducting
glycosylations in the presence of 3 and BF3, so avoiding
the formation of orthoesters seen in the absence of the
Lewis acid.10 In this laboratory we have made extensive
use of 3 in our various b-mannosylation sequences,11-14
but, in applying this chemistry to the synthesis of higher
oligosaccharides on larger scales have been confronted by
the irksome but real issue of cost. In effect 1, 2 and 3 as
purchased from the usual chemical supply houses are ex-
pensive (>$12/g in the year 2000) even when purchased in
25g lots. Syntheses of these bases making use of multiple,
one-pot or sequential additions of tert-butylmetal reagents
to pyridine or substituted pyridines, with rearomatization,
necessitate the use of large excesses of the nucleophile so
rendering them less than optimal for scale up as well as in-
efficient.1,15-18 The various syntheses involving the for-
mation of the corresponding tert-butylated pyrylium ions
followed by treatment with ammonia are attractive but
nevertheless require multiple steps or give only moderate
yields.19,20 The most direct of these approaches is
Stang’s21 but even this only allows for the production of
~65 g batches of 3 and only reduces the cost to an estimat-
ed $9.4/g. Bates’ synthesis of 3,22 the condensation of di-
lithio isobutylene with two equivalents of pivalonitrile, is
low yielding and does not appear to be scalable. We now
report that 2,4,6-tri-tert-butylpyrimidine (TTBP, 4) serves
as an admirable replacement for 1-3 in a range of glyco-
1: R = H
2: R = tert-Bu
3: R = Me
4
TTBP (4) was first prepared in modest yield by van der
Plas and Koudijs, by Minisci-type homolytic alkylation of
pyrimidine.23 A much improved synthesis was later de-
scribed by García Martínez, Hanack and coworkers in-
volving the condensation of pinacolone with two
equivalents of pivalonitrile, mediated by triflic anhy-
dride.24 We have found that this sequence may be readily
scaled to provide 90g batches in a one-pot, chromatogra-
phy-free sequence. The poor nucleophilicity of 4 was ap-
parent to van der Plas and Koudijs who noted that no
reaction took place on exposure to bromine and to perac-
ids.23 These authors also determined a pKa of 1.02 for 4 in
50% aqueous ethanol,23 which is considerably smaller
than those of 3.58, 4.02 and 4.41 for 1, 2 and 3, respective-
ly, in the same solvent.1,25 Although 4 is thus a very mild
base, it was thought that it would still be more than suffi-
cient to neutralize triflic acid, the byproduct in the type of
glycosylations studied here, in enol triflate formation, and
in the whole multitude of reactions for which triflic
anhydride26 is used as reagent.
In the event, a series of glycosidic couplings (Table) were
conducted by the sulfoxide method5,12 and the results
found to be in every way comparable to identical reactions
previously carried out with 3 as base in our laboratory.12,27
These include b-selective mannosylations,12 a-selective
glucosylations,27 standard b-selective glucosylations with
neighboring group participation,5,12 and high yielding
couplings to tert-alcohols.12
Although we have not carried out extensive investiga-
tions, it is obvious that the replacement of 1-3 by the new
base 4 is not limited to the sulfoxide glycosylation meth-
Synthesis 2001, No. 2, 323–326 ISSN 0039-7881 © Thieme Stuttgart · New York

324
D. Crich et al.
SPECIAL TOPIC
Table Sulfoxide Glycosylations in the Presence of 4
Entry
1
Donor
Acceptor
Product
Yield
(%)
Ratio
(a/b)
OBn
O
OBn
O
Ph
O
Ph
O
O
O
O
BnO
82
b only
BnO
O
HO
S
Ph
5
5
7
6
O
O
OBn
O
OBn
O
2
3
OBn
O
76
~1/5
Ph
O
O
O
BnO
HO
N3
N3
8
9
O
O
O
O
O
HO
O
OBn
O
Ph
O
5
90
78
b only
O
O
BnO
O
O
O
O
10
6
11
Ph
O
Ph
O
O
S
O
O
O
O
BnO
4
a only
BnO
BnO
BnO
O
Ph
12
13
O
Ph
O
O
O
O
O
BnO
BnO
5
6
12
10
79
73
a only
O
O
O
14
PivO
PivO
PivO
PivO
PivO
PivO
O
S
O
O
b only
O
PivO
PivO
Ph
HO
15
6
16
od. By way of a further example we have, nevertheless, comparable and even superior to those reported in the
applied 4 in Gin’s28,29 dehydrative glycosylation sequence original papers.
(Scheme 1), when the yield and selectivity were again
comparable to the original.
In closing we return to the synthesis of 4 and also to sev-
eral of its features, aside from cost, which render it a very
Finally, as an illustration that 4 will find application as a attractive replacement for 1-3. The synthesis of 4 that we
replacement for 1-3 outside the field of carbohydrate have employed here is developed from a literature proce-
chemistry, we have employed it as base in the synthesis of dure,24 which recommended stirring of pivalonitrile, pina-
two vinyl triflates previously prepared by Stang30 and colone, and triflic anhydride at room temperature for 18 h,
others31 using 3 (Scheme 2). Yet again the yields were after which extractive work up and chromatography was
reported to give a 92% yield. In our hands, retaining the
Synthesis 2001, No. 2, 323–326 ISSN 0039-7881 © Thieme Stuttgart · New York

SPECIAL TOPIC
2,4,6-Tri-tert-butylpyrimidine (TTBP)
325
All glycosyl donors (5,12 12,27 15,32 and 1733) and acceptors (6, 8,34
10, and 1835) were prepared as previously described or were com-
mercially available. All glycosides (7,12 9,12 11,12 13,27 14,27 16,12
and 1929) gave spectral data fully consistent with those previously
reported in the literature.
BnO
BnO
O
O
BnO
HO
+
BnO
BnO
OH
BnO
BnO
OMe
17
18
CH2Cl2, -78 °C
Large Scale Synthesis of TTBP (4)
Ph2SO,
4, Tf2O
A solution of pinacolone (65.7 mL, 0.52 mol) in CH2Cl2 (100 mL)
was slowly added to a solution containing Tf2O (100.8 mL,
0.60 mol) and trimethylacetonitrile (125 mL, 1.10 mol) in CH2Cl2
(350 mL) at 20 °C under argon. After stirring for 5 d, additional tri-
methylacetonitrile (20 mL, 0.18 mol) was added. The reaction mix-
ture was stirred for a further 24 h then quenched by the addition of
sat aq NaHCO3 solution, washed with brine, dried (MgSO4) and
concentrated under reduced pressure. The residue was crystallized
from MeOH to give TTBP as a white solid (91.0 g, 70%); mp 77-
78 °C (Lit.24 mp 76-77 °C).
BnO
O
BnO
BnO
BnO
O
O
BnO
BnO
BnO
OMe
19, 81%, α/β = 60/40
Scheme 1
1H NMR (CDCl3): d = 1.33 (18 H, s, 6 î CH3), 1.39 (9 H, s,
3 î CH3), 7.03 (1 H, s, ArH).
13C NMR (CDCl3): d = 29.8 (6 î CH3), 29.9 (3 î CH3), 37.8 and
39.7 (3 î CCH3), 107.3 (ArCH), 175.1 and 176.6 (3 î ArC).
O
OTf
Tf2O, 4,
CH2Cl2, r.t.
Sulfoxide Coupling Using TTBP (4); General Procedure
(Table)
Tf2O (0.033 mL, 0.20 mmol) was added to a stirred solution of the
sulfoxide (0.18 mmol), TTBP (0.11 g, 0.44 mmol) and activated
powdered molecular sieves (3 Å) in CH2Cl2 (3 mL), at -60 °C un-
der argon. After stirring for 5 min at -60 °C, a solution of the ac-
ceptor (0.36 mmol) in CH2Cl2 (2 mL) was added. The reaction
mixture was stirred for a further 5 min at -60 °C, then quenched by
the addition of MeOH, filtered, washed with sat aq NaHCO3 solu-
tion, brine, dried (MgSO4) and concentrated under reduced pres-
sure. The glycosides were isolated by chromatography on silica gel.
20, 62%
O
OTf
Tf2O, 4,
CH2Cl2, r.t.
21, 54%
Scheme 2
Vinyl Triflates Using TTBP (4); General Procedure (Scheme 2)
To a stirred solution of the ketone (30 mmol) and TTBP (8.19 g,
33 mmol) in CH2Cl2 (150 mL) was added Tf2O (5.24 mL, 32 mmol).
The reaction mixture was left to stir at r.t. under argon (the progress
of the reaction was monitored by 1H NMR). Once complete, the sol-
vent was removed under reduced pressure, the residue diluted with
hexanes (100 mL) and filtered to remove the tri-tert-butylpyrimi-
same ratios of reactants and solvent, we find that the reac-
tion is far from complete after 18 hours with both the con-
version of pinacolone to its enol triflate and the reaction
of the enol triflate with the nitrile incomplete. Our obser- dine triflate. The filtrate was washed with cold 1 M HCl, brine,
dried (K2CO3) and concentrated under reduced pressure. The vinyl
triflate was isolated by distillation under reduced pressure.
vations are consistent with those of Hargrove and Stang
who found that pinacolone was only converted in approx-
imately 60% yield to its enol triflate after 60 h.30 It is en-
Methyl 2,3,6-Tri-O-benzyl-4-O-(2,3,4,6-tetra-O-benzyl-a/b-D-
tirely probable that the rate of reaction in the original
glucopyranosyl)-a-D-glucopyranoside (19) by Dehydrative Gly-
protocol was accelerated by an undetermined catalyst.
cosylation with TTBP as Base
To a stirred solution of 1733 (0.187 mmol), diphenyl sulfoxide
(0.525 mmol), and powdered molecular sieves (3 Å) in a mixture
of toluene and CH2Cl2 (3:1, 7.5 mL) at -78 ∞C was added Tf2O
(0.044 mL, 0.258 mmol). The reaction mixture was stirred at this
temperature for 10 min, and then at -40 ∞C for 1 h. TTBP (232 mg,
0.94 mmol) and a solution of 1835 (0.300 mmol) in toluene (2 mL)
were added sequentially at -40 ∞C. The solution was stirred at this
temperature for 30 min, then at 0 ∞C for 25 min, and finally at 25 ∞C
for 4 h before the addition of excess Et3N (0.19 mL, 1.34 mmol).
The reaction was diluted with CH2Cl2, washed with sat aq NaHCO3
solution, brine, dried (Na2SO4), and concentrated under reduced
pressure. The two anomers of 19 were isolated by chromatography
(5% THF in toluene) on silica gel with spectral data consistent with
that reported in the literature.29
Until such a time as this is verified we simply find it con-
venient, and recommend, that the reaction be monitored
by removal of aliquots and not quenched until complete.
The pyridines 1-3 are low melting solids and sublime
readily on attempted drying under only moderate vacuum
(~1 mm Hg) at room temperature. The pyrimidine 4 on the
other hand is nicely crystalline and, while certainly sus-
ceptible to sublimation, does so much less readily than
1-3. Pyridines 1-3 are hygroscopic and discolor rapidly
on exposure to air and light, whereas 4, in the several
months that we have had samples in the laboratory, does
not appear to suffer from these inconveniences. All in all,
the storage and handling of the crystalline 4 combine to
make it a very user-friendly alternative to the popular hin-
dered pyridines.
Synthesis 2001, No. 2, 323–326 ISSN 0039-7881 © Thieme Stuttgart · New York

326
D. Crich et al.
SPECIAL TOPIC
(20) Lin, Z.; Schuster, G. B. J. Org. Chem. 1994, 59, 1119.
(21) Anderson, A. G.; Stang, P. J. Org. Synth. 1990, Coll. Vol. 7,
144.
Acknowledgement
We thank the NIHGMS (GM 57335) for partial support of this
work.
(22) Bates, R. B.; Gordon, B.; Keller, P. C.; Rund, J. V.; Mills, N.
S. J. Org. Chem. 1980, 45, 168.
(23) van der Plas, H. C.; Koudijs, A. Rec. Trav. Chim. Pays Bas
References
1978, 97, 159.
(24) Garcia Martinez, A.; Herrera Fernandez, A.; Moreno Jimenez,
F.; Garcia Fraile, A.; Subramanian, L. R.; Hanack, M. J. Org.
Chem. 1992, 57, 1627.
(25) Deutsch, E.; Cheung, N. K. V. J. Org. Chem. 1973, 38, 1123.
(26) Baraznenok, I. L.; Nenajdenko, V. G.; Balenkova, E. S.
Tetrahedron 2000, 56, 3077.
(27) Crich, D.; Cai, W. J. Org. Chem. 1999, 64, 4926.
(28) Garcia, B. A.; Poole, J. L.; Gin, D. Y. J. Am. Chem. Soc. 1997,
119, 7597.
(29) Garcia, B. A.; Gin, D. Y. J. Am. Chem. Soc. 2000, 122, 4269.
(30) Hargrove, R. J.; Stang, P. J. J. Org. Chem. 1974, 39, 581.
(31) Adah, S. A.; Nair, V. Tetrahedron 1997, 53, 6747.
(32) Kakarla, R.; Dulina, R. G.; Hatzenbuhler, N. T.; Hui, Y. W.;
Sofia, M. J. J. Org. Chem. 1996, 61, 8347.
(33) Perrine, T. D.; Glaudemans, C. P. J.; Ness, R. K.; Kyle, J.;
Fletcher, H. J. Org. Chem. 1967, 32, 664.
(34) Tailler, D.; Jacquinet, J.-C.; Noirot, A.-M.; Beau, J.-M. J.
Chem. Soc., Perkin Trans. 1 1992, 3163.
(35) Garegg, P. J.; Hultberg, H.; Wallin, S. Carbohydr. Res. 1982,
108, 97.
(1) Brown, H. C.; Kanner, B. J. Am. Chem. Soc. 1953, 75, 3865.
(2) Wright, M. E.; Pulley, S. R. J. Org. Chem. 1987, 52, 1623.
(3) 2,6-Di-tert-butylpyridine In Encyclopedia of Reagents for
Organic Synthesis; Paquette, L. A., Ed.; Wiley: Chichester,
1995; Vol. 3, p 1623.
(4) Kahne, D.; Walker, S.; Cheng, Y.; Engen, D. V. J. Am. Chem.
Soc. 1989, 11, 6881.
(5) Yan, L.; Kahne, D. J. Am. Chem. Soc. 1996, 118, 9239.
(6) Stang, P. J.; Fisk, T. E. Synthesis 1979, 438.
(7) Stang, P. J.; Treptow, W. Synthesis 1980, 283.
(8) Wright, M. E.; Pulley, S. E. J. Org. Chem. 1989, 54, 2886.
(9) Wright, M. E.; Pulley, S. R. J. Org. Chem. 1987, 52, 5036.
(10) Thompson, C.; Ge, M.; Kahne, D. J. Am. Chem. Soc. 1999,
121, 1237.
(11) Crich, D.; Sun, S. J. Am. Chem. Soc. 1997, 119, 11217.
(12) Crich, D.; Sun, S. Tetrahedron 1998, 54, 8321.
(13) Crich, D.; Sun, S. J. Am. Chem. Soc. 1998, 120, 435.
(14) Crich, D.; Sun, S. J. Org. Chem. 1997, 62, 1198.
(15) Scalzi, F. V.; Golob, N. F. J. Org. Chem. 1971, 36, 2541.
(16) Francis, R. F.; Colling, E. L. J. Org. Chem. 1986, 51, 1889.
(17) Francis, R. F.; Davis, W.; Wisener, J. T. J. Org. Chem. 1974,
39, 59.
Article Identifier:
1437-210X,E;2001,0,02,0323,0326,ftx,en;C03000SS.pdf
(18) Francis, R. F.; Howell, H. M.; Fetzer, D. T. J. Org. Chem.
1981, 46, 2213.
(19) Balaban, A. T. Org. Prep. Proc. Intl. 1977, 9, 125.
Synthesis 2001, No. 2, 323–326 ISSN 0039-7881 © Thieme Stuttgart · New York