Pyridinium ion catalysis of carbonyl protection reactions

Article abstract of DOI:10.1055/s-0029-1217022

Aprotic pyridinium ions incorporating electron-withdrawing substituents on the aromatic ring are powerful catalysts for the acetalization of aldehydes and the formation of dithianes, dithiolanes, dioxanes, and dioxolanes. Under optimum conditions the best catalyst can be used at a loading as low as 0.1 mol% and can outperform a Bronsted acid catalyst with a _pk_a of 2.2. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0029-1217022

4082
PRACTICAL SYNTHETIC PROCEDURES
Pyridinium Ion Catalysis of Carbonyl Protection Reactions
P
yridinium Ion
C
a
atalysts rbara Procuranti,a Lauren Myles,a Nicholas Gathergood,b Stephen J. Connon*a
a
Centre for Synthesis and Chemical Biology, School of Chemistry, University of Dublin, Trinity College, Dublin 2, Ireland
Fax +353(1)6712826; E-mail: connons@tcd.ie
School of Chemical Sciences, Dublin City University, Dublin 9, Ireland
b
PSP
Received 9 July 2009
No173
Abstract: Aprotic pyridinium ions incorporating electron-withdrawing substituents on the aromatic ring are powerful catalysts for the
acetalization of aldehydes and the formation of dithianes, dithiolanes, dioxanes, and dioxolanes. Under optimum conditions the best catalyst
can be used at a loading as low as 0.1 mol% and can outperform a Brønsted acid catalyst with a pKa of 2.2.
Key words: organocatalysis, catalysis, aldehydes, acetals, dithianes
HS
SH
S
(1.1 equiv)
4 (5 mol%)
S
THF, r.t., 24 h
20 70%
Me
O
O
O
O
4 (1 mol%)
EtO
OEt
Br–
O
MeOH (0.38 M)
r.t., 24 h
Me
N+
Bn
HO
OH
4
3 92%
2
(1.1 equiv)
4 (5 mol%)
O
O
THF, r.t., 40 h
22 88%
Scheme 1 Procedures 1–3
catalyzed process is assumed, and e) in all likelihood the
addition of methanol to the pyridinium ion (thereby gen-
Introduction
In the course of a research program aimed at the develop- erating a Brønsted acid in situ) is a key step in the catalytic
ment of an artificial ketoreductase catalyst1 designed to cycle. This allowed the design of a highly active catalyst
mimic enzyme-catalyzed reduction in the presence of 4 capable of the efficient, room temperature acetalization
NADH, we observed unambiguous catalysis of the forma- of benzaldehyde at 0.1 mol% levels (Scheme 3). It is note-
tion of benzaldehyde dimethyl acetal from a methanolic worthy that this material, devoid of any identifiable acidic
solution of benzaldehyde at room temperature groups, is capable of promoting the reaction between 2
(Scheme 2).2 This was surprising in view of the fact that and methanol faster than the rate obtained using o-nitro-
the pyridinium ion in question (i.e., 1, Scheme 2) is apro- benzoic acid (pKa = 2.2).2
tic and thus Brønsted acid catalysis initially seemed un-
likely to occur.3–5
O
Further investigation of the influence of the steric and
NH2
Br–
Me
O
O
electronic characteristics on the catalytic behavior of re-
lated pyridinium ions resulted in the following findings: a)
catalysts with electron-withdrawing groups at the 3- and
5-positions of the pyridinium ring proved most active, b)
catalysts possessing electron-donating groups (any posi-
tion) proved inactive, c) steric hindrance of the C-4 posi-
tion detracts from catalytic efficacy, d) the reaction does
not proceed in the presence of amine bases – thus an acid-
N+
Bn
O
1
Me
MeOH (0.38 M)
r.t.
2
3
20 mol% 1: 23% yield
0 mol% 1: 0% yield
Scheme 2 Unexpected catalysis by the aprotic pyridinium ion 1
In this paper, we wish to report practical procedures for
the facile formation of acetals, ketals, dioxanes, diox-
olanes, dithiolanes, and dithianes under mild conditions
SYNTHESIS 2009, No. 23, pp 4082–4086
Advanced online publication: 22.10.2009
DOI: 10.1055/s-0029-1217022; Art ID: Z15209SS
x
x.
x
x
.
2
0
0
9
© Georg Thieme Verlag Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
Pyridinium Ion Catalysts
4083
using this readily prepared catalyst, together with a short
study on the influence of the counter-anion on catalyst ef-
Scope and Limitations
ficacy, which identifies further potential for the fine-tun- A range of aldehydes – both aromatic and aliphatic – can
ing of both catalyst activity and properties (Scheme 1).
be protected as the dimethyl acetal at ambient tempera-
tures with low catalyst loadings (Table 1). The methodol-
Table 1 Preliminary Evaluation of Substrate Scope
Me
O
O
(cat.)
4
MeOH (0.38 M), r.t.
R
R
O
Me
Entry
1
Substrate
Product
Time (h)
24
Loading (mol%)
Yield (%)a
Me
O
O
1
92
O
Me
2
5
6
3
Me
O
O
2
3
4
24
24
24
1
5
5
99
92
82
O
Me
12
13
Me
O
O
O
Me
Me
O
O
O
Me
Me
Me
O
O
7
14
Me
O
O
O
O
O
O
O
O
5
6
7
24
5
1
1
81
O
Me
8
15
16
17
Me
Me
1 min
25 min
98c
O
Me
9
97c
O
Me
10
Me
O
8b
48
10
52
Me
O2N
O2N
11
18
a Isolated yield.
b At 35 °C.
c Determined by 1H NMR spectroscopy using an internal standard due to product decomposition on isolation.
Synthesis 2009, No. 23, 4082–4086 © Thieme Stuttgart · New York

4084
B. Procuranti et al.
PRACTICAL SYNTHETIC PROCEDURES
Table 2 Aldehyde Protection with Diols and Dithiols
O
O
n
O
MeO
OMe
4 (cat.)
X
X
Ph
(1.1 equiv)
THF, r.t.
N+
Bn
Me
Br–
n
Ph
O
O
2
HX
XH
4
X = O or S
n = 1 or 2
O
(0.1 mol%)
Me
Entry
1
Product
Time
(h)
Loading
(mol%)
Yield
(%)a
MeOH (0.38 M)
r.t.
2
3 92%
Scheme 3 Acetalization with the highly active catalyst 4
S
S
24
24
24
40
5
96
ogy is particularly effective using electron-neutral or
electron-deficient aromatic aldehydes, although increas-
ing the catalyst loading to 5% brings electron-rich, hin-
dered, and a,b-unsaturated analogues into the orbit of the
methodology without difficulty (entries 1–5). Aliphatic
aldehydes are particularly suitable substrates in these re-
actions, complete conversion to the protected products
was observed in minutes. It should be noted, however, that
isolation of these materials proved difficult due to decom-
position (entries 6,7). The methodology is less effective
for ketalization reactions – in our hands only highly acti-
vated ketones such as p-nitroacetophenone (11) could be
converted in moderate yield (entry 8). Practically speak-
ing, these reactions are straightforward to carry out – the
only precaution we would mention is that care should be
taken to ensure that both the catalyst and alcohol solvent
are dry – in all cases lower yields and irreproducible re-
sults were obtained if materials were not rigorously dried
before use.
19
S
2
3
4
5
10
5
70
S
20
21
O
O
O
41
88 (91)b
O
22
a Isolated yield.
b Value in parentheses refers to the yield obtained using 10 mol% 4
We also found catalyst 4 to be useful in the formation of
thiolanes, dithianes, and dioxolanes at ambient tempera-
ture in the presence of a small excess of dithiol/diol
(Table 2). While these products were formed with ease,
the corresponding dioxanes proved difficult to synthesize
in good yield using this methodology (entry 4). Given that
we propose that the alcohol/thiol nucleophile first adds to
the pyridinium ion in order to generate the acid which pro-
motes the reaction, the relative difficulty encountered us-
ing ethylene glycol as the nucleophile is not surprising as
the inductive effect of the two proximal electronegative
oxygen atoms would reduce each other’s nucleophilicity.
Thus, we would suggest that potential nucleophiles be
chosen carefully with this in mind.
for 24 h.
O
S
1. 4 (5 mol%)
THF, r.t., 24 h
SH
SH
S
+
2. catalyst
precipitation
(hexane)
19
2
cycle 1: 89% (quant conversion)
cycle 2: 96% (quant conversion)
Scheme 4 Recycling of catalyst 4
fluoroborate salt 24 proved a considerably (and reproduc-
ibly) more active catalyst than 23 (entries 1,2). This
allows the efficient catalysis of the acetalization process
using 24 (which is derived from nicotinic acid, a consid-
erably less expensive raw material than that required to
prepare 4) at only 0.5 mol% loading.
We also found that the catalyst could be conveniently re-
cycled: protection of 2 as its dithiolane with 1,2-
ethanedithiol in the presence of 4 (5 mol%) proceeded
smoothly (Scheme 4). After the reaction, addition of hex-
ane precipitated the catalyst, which could be reused in an
identical second reaction without any loss of catalytic ac-
tivity being evident.
In conclusion we have demonstrated that aprotic pyridin-
ium ions can act as Brønsted acids in protic solvents such
as methanol. This property is accentuated by electron-
withdrawing substituents on the pyridinium ring – as ex-
emplified by the high activity of catalyst 4, which can pro-
mote the smooth acetalization of benzaldehyde (2) at
ambient temperature at 0.1 mol% loading and which out-
performs a strong Brønsted acid (pKa = 2.2) in this reac-
In order to determine if the pyridinium counteranion ex-
erts any influence on catalysis we synthesized the simple
catalysts 23 and 24 – which differ by the presence of a
bromide or tetrafluoroborate anion only – and evaluated
their performance as catalysts for the acetalization of 2 as
before (Table 3). The results were intriguing – the tetra-
Synthesis 2009, No. 23, 4082–4086 © Thieme Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
Pyridinium Ion Catalysts
4085
mL, 6.30 mmol) via syringe. The solution was then heated under re-
flux for 24 h. After cooling to r.t., the solvent was removed in vacuo
and the crude product was purified by dissolution in EtOAc–MeOH
(9:1, ca. 1–20 mL) in a conical flask fitted with a septum and a nee-
dle open to the air and left for 12 h. At this point, unreacted starting
material precipitated and was removed by filtration. The mother li-
quor was then cooled to 0 °C and the catalyst precipitated by the
slow addition of Et2O over 2–4 h. The catalyst was obtained as an
off-white solid (592 mg, 39%), was filtered, dried in vacuo, and
stored under a protective atmosphere of argon; mp 130–131 C.
Table 3 Influence of the Counteranion on Catalysis
O
Me
O
O
OEt
23 or 24 (cat.)
O
MeOH (0.38 M)
r.t., 24 h
N+
X–
Me
3
2
23 X = Br
24 X = BF4
IR (solid): 3007, 2955, 1732, 1635, 1605, 1493, 1434, 1258, 1161,
996, 878, 731, 674, 699 cm–1.
1H NMR (CDCl3): d = 4.07 (s, 6 H), 6.60 (s, 2 H), 7.47–7.48 (m, 3
H), 7.70–7.73 (m, 2 H), 9.37 (s, 1 H), 10.02 (s, 2 H).
13C NMR (CDCl3): d = 53.8, 65.6, 129.5, 129.8, 130.1, 130.3, 131.1,
145.0, 148.2, 160.4.
HRMS (ES): m/z [M+] calcd for C16H16NO4: 286.1079; found:
286.1084.
Entry
Catalyst
23
Loading (mol%) Yield (%)a
1
2
3
4
1
90
95
35
81
24
1
23
0.5
0.5
24
a Isolated yield.
Aldehyde Acetalization Catalyzed by 4; General Procedure
A 20 mL reaction vial containing a stirring bar was charged with 4
(0.05 mmol), fitted with a septum and flushed with argon. The ap-
propriate aldehyde (0.50 mmol) was added followed by anhyd
MeOH (1.25 mL, 0.38 M) via syringe. The solution was then stirred
at r.t. for 24 h. When conversion was judged to be either complete
tion. Subsequent studies revealed that 4 is of broad scope
and can promote the acetalization of a range of aromatic
and aliphatic aldehydes, in addition to being a useful cat-
alyst for thiolane-, dithiane- and dioxolane-formation re-
actions at ambient temperature. The catalyst can also be
recycled and reused without any apparent loss of activity
via a simple, chromatography-free protocol. A short study
concerning the influence of the counterion on catalysis
strongly indicates that catalyst activity can be tuned along
these lines and resulted in the identification of tetrafluo-
roborate salt 24 as an inexpensive alternative to catalyst 4
(which can also be used at loadings of lower than 1 mol%)
in these processes.
1
or >95% (by H NMR spectroscopic analysis) the reaction was
quenched with PhNHNH2 and the solvent was removed in vacuo.
The crude product was then purified by flash chromatography
(Table 1).
Benzaldehyde Dimethyl Acetal (3)
The desired dimethyl acetal was obtained following the general pro-
cedure using catalyst 4 (12.5 mg, 0.03 mmol), MeOH (6.7 mL), and
benzaldehyde (340 mL, 3.34 mmol). After purification of the crude
material by flash chromatography, the product 3 was obtained as a
pale yellow liquid (466 mg, 92%). The NMR spectra of 3 were con-
sistent with those previously reported.7
1H NMR spectra were recorded on a 400 MHz spectrometer in
CDCl3 (unless otherwise stated) referenced relative to residual
CHCl3 (d = 7.26). Chemical shifts are reported in ppm and coupling
constants in Hertz. 13C NMR spectra were recorded on the same in-
strument (100 MHz) with total proton decoupling. All melting
points are uncorrected. Flash chromatography was carried out using
silica gel (0.04–0.063 mm). TLC analyses were performed on pre-
coated 60F254 slides, and visualized by UV irradiation, KMnO4 or
anisaldehyde staining. Aldehydes 2, and 5–11 were sourced com-
mercially and distilled under vacuum prior to use. Aldehyde 6 was
sourced commercially, immediately before use this was dissolved in
CH2Cl2 and washed with aq 2 M NaOH. Catalyst 4 was synthesized
via the benzylation of pyridine 3,5-dicarboxylic acid dimethyl ester6
(procedure below). MeOH was distilled over sodium and stored un-
der argon – best results were obtained using freshly distilled MeOH
in all cases. All reactions were carried out under a protective argon
atmosphere. Careful drying of catalysts 4, 23, and 24 is essential for
best results – a convenient procedure for this follows: the catalysts
were dissolved in anhyd toluene under argon. The solvent was re-
moved in vacuo and the procedure was repeated twice, taking care
that the compound was not exposed to air. The catalysts were then
dried under high vacuum for 2 h and used in the reaction.
1H NMR (CDCl3): d = 3.37 (s, 6 H), 5.42 (s, 1 H), 7.34–7.42 (m, 3
H), 7.47–7.49 (m, 2 H).
13C NMR (CDCl3): d = 52.3, 102.7, 126.2, 127.8, 128.0, 137.6.
2-Phenyl-1,3-dithiane (20)
The desired dithiane was obtained following the general procedure
using catalyst 4 (49.8 mg, 0.14 mmol), 1,3-propanethiol (300 mL,
2.98 mmol), THF (9.1 mL), and benzaldehyde (276 mL, 2.71
mmol). After completion of the reaction, the mixture was poured
onto aq sat. NaHCO3 (5 mL) and the product was extracted with
EtOAc (2 × 10 mL). The organic layer was separated, dried
(MgSO4), and concentrated in vacuo. Further purification was
achieved by flash chromatography. After chromatography, a small
1
amount of aldehyde starting material was detected by H NMR
spectroscopy. The crude mixture was then dissolved in cold MeOH,
and NaBH4 (17 mg, 0.45 mmol) was added to the solution, the mix-
ture was washed with H2O (5 mL) and the product was extracted
with EtOAc (2 × 5 mL). Concentration of the combined organic
layers in vacuo afforded spectroscopically pure 20 as a white solid
(370 mg, 70%); mp 60–62 °C (Lit.8 mp 71–72 °C). The NMR spec-
tra of 20 were consistent with those previously reported.9
1H NMR (CDCl3): d = 1.88–1.99 (m, 1 H), 2.14–2.21 (m, 1 H), 2.92
(ddd, J = 7.5, 4.3, 3.3 Hz, 2 H), 3.07 (ddd, J = 14.5, 12.3, 2.5 Hz, 2
H), 5.17 (s, 1 H), 7.28–7.36 (m, 3 H), 7.46–7.48 (m, 2 H).
13C NMR (CDCl3): d = 25.1, 32.1, 51.5, 127.8, 128.5, 128.8, 139.1.
Catalyst 4
A 25 mL round bottomed flask containing a stirring bar was charged
with the pyridine-3,5-dicarboxylic acid dimethyl ester (820 mg,
4.20 mmol), fitted with a septum and flushed with argon. Anhyd
MeOH (10 mL, 0.4 M) was added followed by benzyl bromide (750
Synthesis 2009, No. 23, 4082–4086 © Thieme Stuttgart · New York

4086
B. Procuranti et al.
PRACTICAL SYNTHETIC PROCEDURES
Catalyst 24
(3) Catalysts/ionic liquids, which incorporate N-alkylpyri-
dinium ions for which no specific catalytic role has been
identified for the pyridinium ring other than as a polar or
electron-deficient group have been reported; for
representative recent examples, see: (a) Maki, T.; Ishihara,
K.; Yamamoto, H. Org. Lett. 2005, 7, 5043. (b) Rix, D.;
Clavier, H.; Coutard, Y.; Gulajski, L.; Grela, K.; Mauduit,
M. J. Organomet. Chem. 2006, 691, 5397. (c) Ni, B.;
Zhang, Q.; Headley, A. D. J. Org. Chem. 2006, 71, 9857.
(d) Zhang, L.; Luo, S.; Mi, X.; Liu, S.; Qiao, Y.; Xu, H.;
Cheng, J.-P. Org. Biomol. Chem. 2008, 6, 567. (e) Ni, B.;
Zhang, Q.; Headley, A. D. Tetrahedron: Asymmetry 2008,
49, 1249. (f) Kull, T.; Peters, R. Angew. Chem. Int. Ed.
2008, 47, 5461.
(4) For examples of the use of pyridinium ions in photoinduced
processes, see: (a) Elstner, E. F.; Fischer, H. P.; Osswald,
W.; Kwiatkowski, G. Z. Naturforsch. C 1980, 35, 770.
(b) Seshadri, G. Electrochem. Soc. Interface 1994, 3, 51.
(c) Yagci, Y.; Endo, T. Adv. Polym. Sci. 1997, 127, 59.
(d) Vieira, R. C.; Falvey, D. E. J. Am. Chem. Soc. 2008, 130,
1552.
A 50 mL round-bottomed flask was charged with 2310 (3.22 g, 10
mmol) in anhyd acetone (10 mL) under N2. To this solution was
added NaBF4 (1.32 g, 12 mmol). The mixture was then heated under
reflux for 4 days. A fine white precipitate was obtained and this was
then removed by filtration, and washed with anhyd acetone (3 × 5
mL). The filtrate and washings were combined and the solvent re-
moved in vacuo. The catalyst obtained was an off-white low-melt-
ing solid (3.13 g, 95%). The product was dried under high vacuum
and stored under argon; mp 46–48 °C.
IR (solid): 3088, 1731, 1637, 1456, 1371, 1298, 1010, 860, 747,
704, 678 cm–1.
1H NMR (DMSO-d6): d = 1.37–1.41 (t, J = 7.2 Hz, 3 H), 4.44–4.49
(q, J = 7.2 Hz, 2 H), 5.98 (s, 2 H), 7.44–7.50 (m, 3 H), 7.55–7.58
(m, 2 H), 8.28–8.32 (dd, J = 8.0, 6.0 Hz, 1 H), 9.01–9.03 (d, J = 8.0
Hz, 1 H), 9.33–9.35 (d, J = 6.0 Hz, 1 H), 9.78 (s, 1 H).
13C NMR (DMSO-d6): d = 14.5, 63.1, 64.0, 129.2, 129.4, 129.7,
129.9, 130.9, 134.5, 146.1, 146.5, 148.3, 162.1.
HRMS (ES): m/z [M+] calcd for C15H16NO2: 242.1181; found:
242.1173.
(5) For a representative example of the use of pyridinium ions as
stoichiometric reagents in redox processes, see: Xu, H.-J.;
Liu, Y.-C.; Fu, Y.; Wu, Y.-D. Org. Lett. 2006, 8, 3449.
(6) Kristiansen, M.; Eriksen, J.; Jørgensen, K. A. J. Chem. Soc.,
Perkin Trans. 1 1990, 101.
Acknowledgment
Financial support from the Irish Research Council for Science,
Engineering and Technology (IRCSET), and the Environmental
Protection Agency (EPA) is gratefully acknowledged.
(7) Hatano, B.; Nagahashi, K.; Habaue, S. Chem. Lett. 2007, 36,
1418.
(8) Campos, M. M.; Hauptmann, H. J. Am. Chem. Soc. 1952, 74,
2962.
(9) Drew, G. M.; Kitching, W. J. Org. Chem. 1981, 46, 558.
(10) MacTavish, J.; Proctor, G. R.; Redpath, J. J. Chem. Soc.,
Perkin Trans. 1 1996, 2545.
References
(1) Procuranti, B.; Connon, S. J. Chem. Commun. 2007, 1421.
(2) For a preliminary account, see: Procuranti, B.; Connon, S. J.
Org. Lett. 2008, 10, 4935.
Synthesis 2009, No. 23, 4082–4086 © Thieme Stuttgart · New York