P(i-PrNCH2CH2)3N: an efficient catalyst for TMS-1,3-dithiane addition to aldehydes

Article abstract of DOI:10.1016/j.tetlet.2009.05.010

Herein we report the use of commercially available P(i-PrNCH₂CH₂)₃N (1a) as an efficient catalyst for 2-trimethylsilyl-1,3-dithiane (TMS-dithiane) addition to aldehydes at room temperature. The catalyst loading required fo

Full text of DOI:10.1016/j.tetlet.2009.05.010

Tetrahedron Letters 50 (2009) 4307–4309
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Tetrahedron Letters
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P(i-PrNCH2CH2)3N: an efficient catalyst for TMS-1,3-dithiane addition
to aldehydes
*
Kuldeep Wadhwa, John G. Verkade
Department of Chemistry, Gilman Hall, Iowa State University, Ames, IA 50011, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Herein we report the use of commercially available P(i-PrNCH2CH2)3N (1a) as an efficient catalyst for 2-
trimethylsilyl-1,3-dithiane (TMS–dithiane) addition to aldehydes at room temperature. The catalyst load-
ing required for these reactions (5 mol %) is the lowest recorded in the literature, and the majority of the
reaction times for this transformation are the shortest thus far reported. A variety of functional groups are
tolerated on the aryl aldehyde substrates.
Received 1 April 2009
Revised 1 May 2009
Accepted 6 May 2009
Available online 10 May 2009
Ó 2009 Elsevier Ltd. All rights reserved.
R
1. Introduction
R
P
N
N
1a
: R = i-Pr (pKa = 33.63)
R
N
1b : R = Bn
The addition of 1,3-dithiane (a masked acylcarbanion) to vari-
ous electrophiles (e.g., aldehydes, ketones, and alkyl halides) is
one of the most practiced methodologies in synthetic organic
chemistry for the formation of C–C bonds.1–6 Also known as an
‘umpolung’, ‘dipole inversion’, or ‘inversion of reactivity’ reaction,
this process at the SCS carbon of the dithiane allows facile genera-
tion of a carbonyl functionality under mild oxidation conditions
using reagents such as Hg(ClO4)2, CuCl2/CuO, AgNO3, Tl(NO3)3
,and [bis(trifluoroacetoxy)iodo]benzene.6–10 The most common
deprotonating agent for converting a 1,3-dithiane to a nucleophile
for addition to an electrophilic carbon center is the use of a stoichi-
ometric amount of BuLi.1–6
Umpolung of a dithiane for its addition to ketones and alde-
hydes has also been accomplished via catalytic activation of a silyl
group in a 2-silyl-1,3-dithiane.11–14 Thus Pollicino and co-workers
reported the use of a stoichiometric amount of cesium fluoride as a
base in DMF solvent using 2-trimethylsilyl-4,6-dimethyl-1,3-dithi-
ane and benzaldehyde to obtain a product yield of 72%, but the
substrate scope was limited to benzaldehyde.11 Corey and co-
workers utilized an equivalent of CsF in a 1:1 mixture with CsOH
at 0 °C for 2 h for the reaction of p-methoxybenzaldehyde with
TMS–dithiane, which achieved a product yield of 85%.12 A catalytic
amount (10 mol %) of the fluoride ion source [n-Bu4N][Ph3SiF2] was
reported by DeShong and co-workers to achieve a 96% yield of
product from the reaction of benzaldehyde (the only substrate
tested) with TMS–dithiane.13 Very recently, Mukaiyama and Mich-
ida reported that the use of 30 mol % of [n-Bu4N][OPh] as a general
catalyst for promoting the addition of TMS–dithiane at 0 °C in DMF
1c
1d
: R = i-Bu (pKa = 33.53)
: R = Me (pKa = 32.90)
N
1
Figure 1. Proazaphosphatrane 1.
to aldehydes and ketones, providing product yields of 60–97% and
63–93%, respectively.14 This significantly improved methodology
does, however, require a highly polar aprotic solvent and a high
mol % of catalyst.14
We have found15 that proazaphosphatranes such as those
shown in Figure 1 are strongly basic, possessing pKa values in the
range 32–34 in MeCN for their P-protonated Nbasal?P transannu-
lated conjugate acids.16 To the extent that Nbasal?P transannula-
tion may be occurring during reactions catalyzed by 1, the
nucleophilicity of the phosphorus may be enhanced.15b We previ-
ously reported reactions in which proazaphosphatranes can acti-
vate silicon functionalities,17–23 as for example in the silylation of
alcohols using tert-butyldimethylsilyl chloride,17,18 the synthesis
of cyanohydrins via the addition of a trialkylsilylcyanide to car-
bonyl compounds,19,20 the desilylation of TBDMS ethers,21 and
the nucleophilic aromatic substitution of aryl fluorides with aryl
silylethers.22,23
Because proazaphosphatranes can activate silicon functional
groups17–23 in addition to functioning as strong Lewis bases,15,16
it occurred to us that in view of the paucity of reports in which
the catalytic activation of TMS–dithiane for carbonyl umpo-
lung13,14 has been utilized, proazaphosphatranes might function
well in such reactions. Here we report the use of a proazaphospha-
trane as an efficient catalyst for 1,3-dithiane addition to the
carbonyl of aldehydes as shown in Scheme 1.
* Corresponding author. Tel.: +1 515 294 5023; fax: +1 515 294 0105.
E-mail address: jverkade@iastate.edu (J.G. Verkade).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.05.010

4308
K. Wadhwa, J. G. Verkade / Tetrahedron Letters 50 (2009) 4307–4309
Table 2
i-Pr
i-Pr
Reaction scope of aldehydes with 2-trimethylsilyl-1,3-dithiane catalyzed by 1aa
i-Pr
P
N
N
N
OH
O
N
TMS
S
Yieldb (%)
+
S
Entry
1
Aldehyde
Product
H
S
OH
S
CHO
FG
S
FG
95 Lit.: 85c,95d
1. 5 mol %, THF, rt
2. H3O+
MeO
S
MeO
OH
CHO
S
Scheme 1. General reaction scheme.
2
3
4
5
6
7
98 Lit.: 97d
Me
S
Me
OH
2. Results and discussion
CHO
S
93
S
For optimization studies (Table 1) we chose the reaction of an
electron-neutral aldehyde (2) with TMS–dithiane (3). Using
2 mol % of 1a, the isolated yield of product 4 was only 52% (entry
1). Increasing the catalyst loading to 5 mol %, however, augmented
that yield to 98% (entry 2) over the same time period. Gratifyingly,
this reaction time could be shortened to 30 min without compro-
mising yield (entry 3). The conditions of entry 3 for proazaphos-
phatranes 1b–d also gave excellent yields of product 4 (Table 1,
entries 4–6). Proazaphosphatrane 1a was our catalyst of choice,
however, because of the combination of its superior performance,
commercial availability,24 and ease in handling owing to its crys-
talline nature when purified by sublimation.25 It is noteworthy that
our catalyst loading of 5 mol % is the lowest recorded in the litera-
ture for this methodology. According to NMR spectroscopy, no
reaction was observed in the absence of catalyst (entry 7).
With the conditions in entry 3 of Table 1, a variety of aldehydes
were screened to generalize the scope of catalyst 1a (Table 2).
Electron-donating groups such as methoxy (entry 1) and methyl
(entry 2) resulted in excellent isolated product yields. Electron-
withdrawing and acid-sensitive groups such as ester (entry 3)
and cyano (entry 4) gave excellent and good yields, respectively.
A halogen-containing aryl aldehyde (entry 5) and an enolizable ali-
phatic aldehyde (entry 6) provided excellent product yields. With
the sterically congested aldehyde 2-biphenyl carboxaldehyde (Ta-
ble 2, entry 7) a good isolated yield of product (81%) was realized.
Because only two heterocyclic aldehydes were previously
examined in this reaction,14 we examined five five- and two six-
membered ring examples with our protocol, in which the low cat-
alyst loading of 5 mol % was maintained. The oxygen-containing
benzofuran-2-carboxaldehyde participated well in its reaction
with dithiane (Table 2, entry 8) as did the halogenated nitrogen
heterocycle in entry 9 and the N- and S-containing heterocycle in
MeO2C
NC
MeO2C
NC
OH
CHO
S
80
S
OH
CHO
S
S
96 Lit.: 95d
94 Lit.: 83d
81
S
Cl
Cl
OH
CHO
S
OH
CHO
S
S
OH
8
9
CHO
95
92
94
67
O
S
O
S
S
OH
CHO
N
N
N
N
S
Br
Br
OH
CHO
S
10
11
S
S
S
OH
CHO
N
S
N
N
N
S
Table 1
Survey of proazaphosphatranes (1)a
OH
O
OH
CHO
CHO
S
12
13
97
98
94
S
TMS
S
+
1. catalyst, THF, rt
2.H3O+
H
S
S
S
S
S
OH
4
2
3
S
Entry
Catalyst
Mol %
Time
Yield of 4b (%)
N
N
S
1
2
3
4
5
6
7
1a
1a
1a
1b
1c
1d
None
2
5
5
5
5
5
—
24 h
24 h
52
98
Me
Me
30 min
30 min
30 min
30 min
24 h
98d (96)c
95d
97d
95d
0
OH
CHO
14
N
S
N
S
a
a
Reaction conditions: aldehyde (2 mmol), 3 (2.4 mmol), THF (2 mL), 1a (5 mol %),
Reaction conditions: catalyst (x mol %), benzaldehyde (2.0 mmol), 3 (2.4 mmol),
rt, 30 min followed by 1 N HCl (3 mL).
THF (2 mL), rt followed by 1 N HCl (3 ml).
b
b
Isolated yield after silica gel column chromatography.
See Ref. 12.
See Ref. 14.
Isolated yield after column chromatography.
Lit. yield see Refs. 13,14.
Averages of three runs.
c
C
d
d

K. Wadhwa, J. G. Verkade / Tetrahedron Letters 50 (2009) 4307–4309
4309
(2.0 mmol) at room temperature. The resulting solution was stirred
at room temperature for 15 min and then 2-trimethylsilyl-1,3-
dithiane 3 (2.4 mmol) was added over a period of two min. Pro-
gress of the reaction was monitored by proton NMR spectroscopy.
The reaction mixture was stirred for 30 min followed by quenching
with 3 mL of an aq solution of 1 N HCl. The mixture was stirred for
an additional 1 h and then it was neutralized with saturated aq
NaHCO3 solution followed by extraction with CH2Cl2 (3 Â 30 mL).
The combined organic extracts were dried over anhydrous MgSO4.
The crude product was purified by column chromatography using
30% EtOAc/hexane as eluent, whereas in the case of entry 11 of Ta-
ble 2, 20% (v/v) MeOH/CH2Cl2 was employed.
S
Si
P
S
N
R
R
R
R
R
P
N
N
R
Me
Si
Me
S
S
N
N
Me
N
+
N
N
OX
1a
A
S
R'
S
H3O+
E(Si)
X = H
E
(H)
X = TMS
Si
P
Si
P
R
R
R
R
R
R
Acknowledgments
N
O-
N
N
N
N
N
R'CHO
S
S
S
+
R'
The National Science Foundation is gratefully acknowledged for
financial support of this research through Grant 0750463. We also
thank Dr. Ch. Venkat Reddy for helpful discussions.
S
N
N
B
C
B
D
Scheme 2. Proposed mechanism for TMS-1,3-dithiane addition reactions of alde-
hydes catalyzed by 1a.
Supplementary data
Supplementary data (complete experimental details, references
to known compounds, copies of 1H and 13C NMR spectra for all
products, and HRMS reports for new compounds) associated with
this article can be found, in the online version, at doi:10.1016/
j.tetlet.2009.05.010.
entry 10; all giving excellent product yields. Although the hetero-
cycle containing two nitrogens shown in entry 11 gave a rather
moderate yield of product, excellent product yields were achieved
with thiophene-2-carboxaldehyde (entry 12), 6-methyl-2-pyri-
dinecarboxaldehyde (entry 13), and N-methylindole-2-carboxalde-
hyde (entry 14).
From the variety of aldehydes included in the scope of our pro-
tocol, it appears that our methodology is general for those possess-
ing electron-withdrawing or -donating groups and also for acid- or
base-labile functional groups. Heterocyclic and enolizable aliphatic
aldehydes are also amenable to our protocol.
A proposed mechanism for the addition of TMS–dithiane to
aldehydes under our conditions is depicted in Scheme 2. Initially,
1 forms a pentacoordinated silicate TMS–dithiane adduct A which
enriches the electron density on the silicon, consequently weaken-
ing the bonds around this atom and thus favoring ionization to
species B and C. Thereafter, the dithiane anion C nucleophilically
attacks the aldehyde carbon giving D, which then nucleophilically
attacks cation B giving intermediate E(Si). This intermediate is sub-
sequently hydrolyzed in a second step to give the product E(H)
with regeneration of the catalyst 1a.
In summary, we find that the nonionic strongly Lewis basic pro-
azaphosphatrane 1a is an efficient catalyst for the addition of 2-tri-
methylsilyl-1,3-dithiane to aldehydes. To the best of our
knowledge, our catalyst loading for the synthesis of b-hydroxydi-
thianes using a TMS–dithiane reagent is the lowest reported in
the literature. Our protocol operates efficiently at room tempera-
ture in 30 min with a commercially available catalyst, and product
yields are generally excellent. Compared with literature reports of
the highest yields for five products shown in Tables 1 and 2, our
methodology gave a substantially higher yield in one instance
and equal yields (within 1%) in the remaining 4 cases.
References and notes
1. Smith, A. B., III; Adams, A. C. Acc. Chem. Res. 2004, 37, 365–377.
2. Corey, E. J.; Seebach, D. Angew. Chem., Int. Ed. Engl. 1965, 4, 1075–1077.
3. Corey, E. J.; Seebach, D. Angew. Chem., Int. Ed. Engl. 1965, 4, 1077–1078.
4. Corey, E. J.; Seebach, D.; Freedman, R. J. Am. Chem. Soc. 1967, 89, 434–436.
5. Seebach, D.; Corey, E. J. J. Org. Chem. 1975, 40, 231–237.
}
6. Grobel, B.-T.; Seebach, D. Synthesis 1977, 357–402.
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9. Stork, G.; Zhao, K. Tetrahedron Lett. 1989, 30, 287–290.
10. Greene, T. W.; Wuts, P. G. M. In Protective Groups in Organic Synthesis, 3rd ed.;
John Wiley & Sons: New York, 1999; pp 329–344.
11. Capperucci, A.; Cere, V.; Innocenti, A. D.; Nocentini, T.; Pollicino, S. Synlett 2002,
1447–1450.
12. Busch-Petersen, J.; Bo, Y.; Corey, E. J. Tetrahedron Lett. 1999, 40, 2065–
2068.
13. Pilcher, A. S.; DeShong, P. J. Org. Chem. 1996, 61, 6901–6905.
14. Michida, M.; Mukaiyama, T. Chem. Lett. 2008, 37, 26–27.
15. For reviews of proazaphosphatrane chemistry, see: (a) Verkade, J. G. New
Aspects of Phosphorus Chemistry II. In Top.Curr. Chem. Majoral, J. P.; Ed.; 2002,
Vol. 233, pp 1–44.; (b) Verkade, J. G.; Kisanga, P. B. Tetrahedron 2003, 59, 7819–
7858; (c) Verkade, J. G.; Kisanga, P. B. Aldrichimica Acta 2004, 37, 3–14; (d)
Urgaonkar, S.; Verkade, J. G. Specialty Chemicals 2006, 26, 36–39.
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17. D’Sa, B. A.; Verkade, J. G. J. Am. Chem. Soc. 1996, 118, 12832–12833.
18. D’Sa, B. A.; McLeod, D.; Verkade, J. G. J. Org. Chem. 1997, 62, 5057–5061.
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24. Proazaphosphatranes 1a, 1c, and 1d are commercially available from sources
such as aldrich and strem chemicals.
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3. Experimental
3.1. General reaction procedure
A round-bottomed flask was charged with 1 (0.1 mmol, 5 mol %)
in a nitrogen-filled glove-box. To this was added 2.0 mL of anhy-
drous tetrahydrofuran (THF) followed by the addition of aldehyde