Synthesis of N-acyl-N,O-acetals from N-aryl amides and acetals in the presence of TMSOTf

Article abstract of DOI:10.1016/j.tetlet.2011.07.023

Secondary amides undergo in situ silyl imidate formation mediated by TMSOTf and an amine base, followed by addition to acetal acceptors to provide N-acyl-N,O-acetals in good yields. An analogous, high-yielding reaction is observed with 2-mercaptothiazolin

Full text of DOI:10.1016/j.tetlet.2011.07.023

Tetrahedron Letters 52 (2011) 4756–4759
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Tetrahedron Letters
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Synthesis of N-acyl-N,O-acetals from N-aryl amides and acetals in the presence
of TMSOTf
C. Wade Downey a, , Alan S. Fleisher a, James T. Rague a, Chelsea L. Safran a, Megan E. Venable a,
⇑
Robert D. Pike b
a Department of Chemistry, University of Richmond, Richmond, VA 23173, USA
b Department of Chemistry, The College of William & Mary, Williamsburg, VA 23187, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Secondary amides undergo in situ silyl imidate formation mediated by TMSOTf and an amine base,
followed by addition to acetal acceptors to provide N-acyl-N,O-acetals in good yields. An analogous,
high-yielding reaction is observed with 2-mercaptothiazoline as the silyl imidate precursor. Competing
reduction of the acetal to the corresponding methyl ether via transfer hydrogenation can be circum-
vented by the replacement of CY2NMe with 2,6-lutidine under otherwise identical reaction conditions.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 26 May 2011
Revised 20 June 2011
Accepted 6 July 2011
Available online 19 July 2011
Keywords:
N,O-Acetal
Silyl triflate
Silyl trifluoromethanesulfonate
Silyl imidate
TMSOTf
Addition of nucleophiles to N-acyliminium ions is a proven
method for the construction of substituted amines.1 Iminium ions
derived in situ from N,O-acetals are popular electrophiles, and are
often used in conjunction with Mannich reactions to yield b-amino
carbonyl compounds2 and organometallic additions to yield substi-
tuted alkyl amines,3 among other reactions.4 The N-acyl-N,O-acetal
functionality is also a key component of important natural prod-
ucts like zampanolide5 and psymberin.6 Accordingly, a convenient
synthesis of N-acyl-N,O-acetals from readily available starting
materials would provide access to a class of compounds that may
easily act as acyliminium ion precursors.7 We now report that
N-aryl amides can be N-alkoxyalkylated with acetals in the pres-
ence of trimethylsilyl trifluoromethanesulfonate (TMSOTf) and a
trialkylamine base, providing N-acyl-N,O-acetals in good yield.
In the course of our study of the Mukaiyama aldol reaction,8 we
examined the addition of in situ-generated silyl ketene acetals to
dimethyl acetals, including nucleophiles derived from tertiary
amides (Eq. 1).9 When the tertiary amide was replaced with a sec-
ondary amide, however, methoxyalkylation was observed at the
O
O
OMe
Ph
MeO OMe
Ph
i-Pr2NEt
ð1Þ
ð2Þ
Ph2N
Me
H
Ph2N
CH2Cl2
80% yield
O
O
TMSOTf
i-Pr2NEt
MeO OMe
PhN
MeO
77% conv
Me
PhN
H
Me
H
Me
CH2Cl2
Me
Given the importance of N-acyliminium ions, we chose to pur-
sue optimization of this N,O-acetal formation reaction. Replace-
ment of i-Pr2NEt with Cy2NMe provided improved and more
reproducible product yields. A slight excess of TMSOTf (1.45 equiv)
relative to acetal (1.4 equiv) was used to ensure that a catalytic
amount of silylating agent remained in solution even after full con-
version of the acetal to the oxocarbenium ion. After conversion to
products was complete, the unpurified reaction mixture was
quenched with pyridine in order to sequester any remaining
TMSOTf, which otherwise facilitated product decomposition dur-
ing purification on silica gel.
A reasonable mechanism for this one-pot silyl imidate forma-
tion-N,O-acetal formation reaction appears in Figure 1. Deprotona-
tion of the TMSOTf-activated secondary amide with a trialkylamine
rapidly generates a silyl imidate, a process that appears to be rapid
and quantitative by 1H NMR spectroscopy. Reaction of the acetal
substrate with TMSOTf provides the oxocarbenium electrophile,
which is attacked by the silyl imidate through a Mukaiyama
amide nitrogen rather than at the
a carbon (Eq. 2). High conversion
to the N,O-acetal occurred with only a trace of aldol-type adduct
formation.
⇑
Corresponding author. Fax: +1 804 287 1897.
E-mail address: wdowney@richmond.edu (C.W. Downey).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.07.023

C. W. Downey et al. / Tetrahedron Letters 52 (2011) 4756–4759
4757
Whereas the oxocarbenium ion derived in situ from acetaldehyde
dimethyl acetal was potentially susceptible to deprotonation to
yield an enol ether, potentially instigating byproduct formation
and loss in yield, the benzaldehyde derivative is not acidic. This
observation may explain why acetaldehyde dimethyl acetal was
an inferior reaction partner with acetanilide (Table 1, entry 1),
but benzaldehyde dimethyl acetal reacted quite efficiently, provid-
ing an isolated yield of 74% (Table 2, entry 1). Propionanilide dis-
played a similar increase in yield with benzaldehyde dimethyl
acetal (89% vs 65%, entry 2). The other anilides investigated reacted
similarly well (entries 3–6).
O
MeO OMe
Me
NAr
H
H
R
TMSOTf
R3N
TMSOTf
TMSOMe
Me
H
OTMS
NAr
O
OMe
R
O
R3NH
TfO
Me
R
Me
N
Ar
TMSOMe
The representative N-aryl amide p-methoxyacetanilide was
chosen for a survey of various acetals under our optimized reaction
conditions (Table 3). For some substrates, the use of Cy2NMe re-
sulted in the competitive reduction of the acetals to the corre-
sponding aryl methyl ethers (vide infra), so 2,6-lutidine was
employed as a surrogate. Under the appropriate reaction condi-
tions, acetals derived from aromatic or heteroaromatic aldehydes
generally performed well (entries 3–7). Yields were lower for ali-
phatic acceptors (entries 1 and 2), presumably because of compet-
ing enol ether formation via deprotonation of the oxocarbenium
ion.
MeO OMe
H
R
TMS
OMe
R
O
Me
N
Ar
Figure 1. Proposed mechanistic scheme.
aldol-like addition. Silyl transfer to another acetal provides the fi-
nal product and generates another oxocarbenium ion, completing
the reaction cycle.
Despite attempts at re-optimization, however, some other ace-
tals were inferior substrates. For example, 2-thiophene carboxalde-
hyde dimethyl acetal appeared to react cleanly but the product was
unstable to chromatography. Initial conversion for formaldehyde
dimethyl acetal (dimethoxymethane) appeared to be 80–90%, but
the preliminary product quickly decomposed under the reaction
conditions. Glycosidation-like reactions with 2-methoxytetrahyd-
ropyran provided intractable mixtures. The reaction was effective,
however, for the diethyl acetal of acetaldehyde, which reacted to
afford desired product 17 in 78% yield (Eq. 3).
The scope of the secondary amide reaction partner was deter-
mined through reaction with two representative acetals. A survey
of condensations with acetaldehyde dimethyl acetal is summa-
rized in Table 1. Various anilides performed well, including both
electron-rich and -poor secondary amides. The poor reactivity dis-
played by acetanilide itself (entry 1) remains unexplained, but
replacement of the acetyl group with other acyl groups (propionyl,
benzoyl, and cinnamoyl) provided good yields of the N,O-acetal. To
date, amide nucleophiles appear to be limited to N-aryl secondary
amides. Other silyl imidate precursors displayed no reactivity
(N-alkyl) or provided complex mixtures of unidentified products
(N-allyl and -benzyl).
OMe
OEt
Me
17
TMSOTf (1.45 equiv)
EtO OEt
Ar
N
H
Me Cy2NMe (1.4 equiv)
CH2Cl2, 0 °C
ð3Þ
Ac
N(H)Ac
Similar or better reactivity was observed when benzaldehyde
dimethyl acetal was employed as the electrophile (Table 2).
Ar = 4-MeO-C6H4
78% yield
Table 2
Table 1
Addition of various anilides to benzaldehyde dimethyl acetala
Condensation of various anilides with acetaldehyde dimethyl acetala
R
R
R
R
TMSOTf (1.45 equiv)
MeO OMe
OMe
Ph
TMSOTf (1.45 equiv)
OMe
Me
MeO OMe
Me
N
N
R'
H
Ph
Cy2NMe (1.4 equiv)
CH2Cl2, 0 °C
H
Cy2NMe (1.4 equiv)
CH2Cl2, 0 °C
R'
N(H)R'
N(H)R'
Yield (%)b
Entry
Amide
Product
Yield (%)b
Entry
Amide
Product
1
2
3
X@H
X@OMe
X@NO2
1
2
3
41
68
65
X
1
2
3
X@H
X@OMe
X@NO2
7
8
9
74
73
69
X
O
O
N
H
Me
N
H
Me
O
O
Ph
N
4
5
6
4
5
6
65
88
93
Ph
N
4
5
6
10
11
12
89
76
93
Et
Et
H
H
O
O
O
O
Ph
N
Ph
N
Ph
Ph
H
H
Ph
N
Ph
N
Ph
Ph
H
H
a
a
Standard reaction conditions: amide (1.00 mmol), acetal (1.40 mmol), TMSOTf
Standard reaction conditions: amide (1.00 mmol), acetal (1.40 mmol), TMSOTf
(1.45 mmol), Cy2NMe (1.40 mmol), CH2Cl2 (5 mL), 0 °C, 2 h.
(1.45 mmol), Cy2NMe (1.40 mmol), CH2Cl2 (5 mL), 0 °C, 2 h.
b
b
Isolated yield after chromatography.
Isolated yield after chromatography.

4758
C. W. Downey et al. / Tetrahedron Letters 52 (2011) 4756–4759
Table 3
Table 4
Condensation of p-methoxyacetanilide with various dimethyl acetalsa
Reduction of dimethyl acetals to methyl ethersa
OMe
TMSOTf (1.45 equiv)
i-Pr2NEt (1.4 equiv)
MeO OMe
MeO
Ar
OMe
TMSOTf (1.45 equiv)
MeO OMe
OMe
Ar
H
N
Ac
R
H
R
Cy2NMe (1.4 equiv)
CH2Cl2, 0 °C
Entry
Solvent
Ar
Conv (%)b
Yield (%)c
N(H)Ac
1
2
3
4
5
CH2Cl2
Et2O
Et2O
Et2O
Et2O
X@OMe
X@OMe
X@H
X@Br
X@Cl
67
94
65
65
57
20
23
X
Entry
R
Product
Yield (%)b
NDd
27
1
2
Me
Et
2
13
68
52
NDd
3
4
5
X@H
X@Br
X@OMe
8
14
15
73
X
99c
6
Et2O
95
32
77c
a
Standard reaction conditions: acetal (2.00 mmol), TMSOTf (2.90 mmol),
O
6
16
61
i-Pr2NEt (2.80 mmol), solvent (10 mL), rt, 2 h.
b
Determined by 1H NMR spectroscopy of the unpurified reaction mixture.
Isolated yield after chromatography.
ND, not determined.
c
a
Standard reaction conditions: amide (1.00 mmol), acetal (1.40 mmol), TMSOTf
(1.45 mmol), Cy2NMe (1.40 mmol), CH2Cl2 (5 mL), 0 °C, 2 h.
d
b
Isolated yield after chromatography.
2,6-Lutidine was used instead of Cy2NMe.
c
Table 5
Condensation of 2-mercaptothiazoline with dimethyl acetalsa
As mentioned above, formation of aryl methyl ethers occurred as
a major side reaction during the attempted condensation reactions
with some aryl acetals. A number of further observations led us to
hypothesize that ether formation occurs via transfer of a hydride
from the trialkylamine base to the oxocarbenium ion, as illustrated
in Figure 2. First, the ether byproduct was observed in some reac-
tions when Cy2NMe or i-Pr2NEt was used as base, but never when
2,6-lutidine was employed as base, presumably because 2,6-lutidine
TMSOTf (1.45 equiv)
SH
S
OMe
MeO OMe
S
N
S
N
R
H
R
Cy2NMe (1.4 equiv)
CH2Cl2, 0 °C
Entry
R
Product
Yield (%)b
1
2
Me
Et
18
19
97
85
3
4
5
X@H
X@Br
20
21
88
98
X
bears no
a hydrogens that may be transferred to the oxocarbenium
X@OMe
22
89c
ion. Second, no reaction was observed when the dimethyl acetal was
stirred with TMSOTf in the absence of amine. Third, when the amine
base was replaced with cyclohexadiene, a known hydride donor,
similar reduction to the methyl ether was observed.
O
6
7
23
24
83
H
68c,d
Noyori has reported that TMSOTf catalyzes the reduction of di-
methyl acetals with silanes.10 We attempted to optimize a similar
reaction with i-Pr2NEt as the hydride source, as summarized in Table
4. In general, conversion for the electron-rich p-anisaldehyde (entry
2) was consistently higher than for other aromatic dimethyl acetals
(entries 3–5). More discouragingly, isolated yields for these reac-
tions did not approach the conversions observed by 1H NMR spec-
troscopy. Over reduction of the acetal carbon to the corresponding
methyl group was observed, but only in trace amounts that did
not account for the loss of yield. In order to rule out volatility of
the product as a problem, 2-naphthaldehyde dimethyl acetal was
subjected to the reaction conditions. Despite a 95% conversion to
the methyl ether, only 32% yield was isolated after chromatography.
Further attempts at optimization of the reduction were abandoned.
Upon completion of the anilide study, we expanded the
N,O-acetal formation reaction to include the thioamide equivalent
2-mercaptothiazoline. The products of these reactions are
N-(1-alkoxy)alkylated thiazolidinethiones, compounds that hold
promise as precursors to N-acyliminium ions equivalents.11 The
results of this survey are summarized in Table 5. The identity of
the products was confirmed by X-ray crystallographic analysis of
a single crystal of product 21.12 Yields were consistently high,
a
Standard reaction conditions: 2-mercaptothiazoline (1.00 mmol), acetal
(1.40 mmol), TMSOTf (1.45 mmol), Cy2NMe (1.40 mmol), CH2Cl2 (5 mL), 0 °C, 2 h.
b
Isolated yield after chromatography.
2,6-Lutidine was used instead of Cy2NMe.
Product was contaminated with approximately 5 mol % side product (see text).
c
d
although replacement of Cy2NMe with 2,6-lutidine was necessary
in some cases. Even formaldehyde dimethyl acetal, an inferior ace-
tal when reacted with p-methoxyacetanilide, provided a good yield
of the methoxymethylated thiazolidinethione. Interestingly, the
formaldehyde dimethyl acetal reaction suffered slightly from
byproduct formation even when 2,6-lutidine was employed as
the base. In this instance, however, the observed byproduct was
not the reduced acetal, but rather appeared to be a methylene-
bridged bis-thiazolidinethione. Future efforts will be directed to-
ward the synthesis and applications of chiral versions of these
thiazolidinethione species because of their prevalent position as
chiral auxiliaries in organic synthesis.13
Condensation of 2-mercaptothiazoline with the diethyl acetal of
acetaldehyde under typical reaction conditions was plagued by
competing enol ether formation. Substitution of Cy2NMe with the
less basic 2,6-lutidine alleviated this issue, allowing N,O-acetal 25
to be isolated in 85% yield (Eq. 4).
Me
O
SH
S
OEt
TMSOTf (1.45 equiv)
EtO OEt
S
N
2,6-lutidine (1.4 equiv)
CH2Cl2, 0 °C
S
N
Me
H
Me
Me
Me
H
H
R
ð4Þ
Me
H
O
25
85% yield
Et
N
Et
R
Me
Me
i-Pr
H
N
In conclusion, TMSOTf mediates the one-pot silyl imidate for-
mation-N,O-acetal formation reactions of secondary amides and
thioamide equivalents. The reaction is general to N-aryl amides
i-Pr
Figure 2. Reduction of oxocarbenium ion by i-Pr2NEt.

C. W. Downey et al. / Tetrahedron Letters 52 (2011) 4756–4759
4759
3. For recent examples, see (a) Hirner, S.; Somfai, P. J. Org. Chem. 2009, 74, 7798–
7803; (b) Sakai, N.; Asano, J.; Kawada, Y.; Konkahara, T. Eur. J. Org. Chem. 2009,
917–922.
and performs competently with acetals derived from both aryl
and aliphatic aldehydes. It appears that TMSOTf plays two roles
in this reaction, silylating an alkoxy group on the acetal and acti-
vating the amide toward deprotonation. Further investigations of
these N-acyliminium ion precursors will be reported in due
course.
4. For recent examples, see: (a) Yamaguchi, Y.; Hashimoto, M.; Tohyama, K.;
Kimura, M. Tetrahedron Lett. 2011, 52, 913–915; (b) Kim, C.; Bae, J. J.; Lee, J. H.;
Jeong, W.; Kim, H.; Sampath, V.; Rhee, Y. H. J. Am. Chem. Soc. 2009, 131, 14660–
14661; (c) Yian, Y.-G.; Wang, X.-W.; Zheng, X.; Ruan, Y.-P.; Huang, P.-Q. Chem.
Commun. 2009, 7045–7047; (d) Note added in proof: Very recently, researchers
in the Mary Watson group applied our conditions, which were reportedly
briefly in 2008 (ref 9) and are fully described in the current manuscript, to
generate certain N,O-acetal substrates for the nickel-catalyzed synthesis of
isoindolinones. See: Shacklady-McAtee, D. M.; Dasgupta, S.; Watson, M. P. Org.
Lett. 2011, 13, 3490–3493.
Acknowledgments
We gratefully acknowledge Research Corporation and the
American Chemical Society-Petroleum Research Fund for fund-
ing. A.S.F. acknowledges the University of Richmond Department
of Chemistry for a Puryear-Topham fellowship. We thank Dr.
Diane Kellogg for assistance with mass spectral data. We are in-
debted to NSF (CHE-0443345) and the College of William and
Mary for the purchase of the X-ray equipment, and to NSF
(CHE-0541848) and the University of California-Riverside for
mass spectral data.
5. Konishi, M.; Saito, K.; Numata, K.; Tsuno, T.; Asama, K.; Tsukiura, H.; Naito, T.;
Kawaguchi, H. J. Antibiot. 1977, 30, 789–805.
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Hooper, J. N. A.; Schmidt, J. M. J. Med. Chem. 2004, 47, 1149–1152; (b)
Cichewicz, R. J.; Valeriote, F. A.; Crews, P. Org. Lett. 2004, 6, 1951–1954.
7. For previous syntheses of N-acyl-N,O-acetals, see (a) Wan, S.; Green, M. E.; Park,
J.-H.; Floreancig, P. E. Org. Lett. 2007, 5385–5388; (b) Li, G.; Fronczek, F. R.;
Antilla, J. C. J. Am. Chem. Soc. 2008, 130, 12216–12217; (c) Kiren, S.; Shangguan,
N.; Williams, L. J. Tetrahedron Lett. 2007, 47, 7456–7459; (d) Venkov, A. P.;
Minkov, M. M.; Lukanov, L. K. Synth. Commun. 1989, 19, 2133–2139; For a
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Downey, C. W.; Johnson, M. W.; Lawrence, D. H.; Fleisher, A. S.; Tracy, K. J. J. Org.
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Supplementary data
Supplementary data (experimental procedures and spectral
data, tables of crystal data, atomic coordinates, bond lengths and
angles, and anisotropic displacement parameters) associated with
this article can be found, in the online version, at doi:10.1016/
j.tetlet.2011.07.023.
9. Downey, C. W.; Johnson, M. W.; Tracy, K. J. J. Org. Chem. 2008, 73, 3299–3302.
10. Silyl trifluoromethanesulfonate-catalyzed reductions of acetals with silanes:
Tsunoda, T.; Suzuki, M.; Noyori, R. Tetrahedron Lett. 1979, 20, 4679–4680.
11. For recent examples of related oxazolidinones as acyliminium ion precursors,
see: (a) Le Corre, L.; Kizirian, J.-C.; Levraud, C.; Boucher, J.-L.; Bonnet, V.;
Dhimane, H. Org. Biomol. Chem. 2008, 6, 3388–3398; (b) Nishikawa, Y.;
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