Silylformylation-desilylation of propargyl amides: Synthesis of α,β-unsaturated aldehydes

Article abstract of DOI:10.1016/j.tetlet.2005.11.054

α,β-Unsaturated aldehydes are prepared from easily available propargyl amides through a two-step sequence of silylformylation-desilylation reactions. The substituent on the nitrogen atom markedly influences both reactions, β-silylalkenals being formed in

Full text of DOI:10.1016/j.tetlet.2005.11.054

Tetrahedron
Letters
Tetrahedron Letters 47 (2006) 527–530
Silylformylation–desilylation of propargyl amides: synthesis
of a,b-unsaturated aldehydes
Laura Antonella Aronica, Patrizio Raffa, Giulia Valentini,
Anna Maria Caporusso* and Piero Salvadori
`
Dipartimento di Chimica e Chimica Industriale, Universita di Pisa, Via Risorgimento, 35–56126 Pisa, Italy
Received 20 October 2005; accepted 9 November 2005
Available online 28 November 2005
Abstract—a,b-Unsaturated aldehydes are prepared from easily available propargyl amides through a two-step sequence of silyl-
formylation–desilylation reactions. The substituent on the nitrogen atom markedly influences both reactions, b-silylalkenals being
formed in the presence of tosyl or tert-butoxycarbonyl protected amines. TBAF is employed to induce the desilylation process that is
performed under very mild experimental conditions. A contemporary elimination step occurs when tosylamido aldehydes are
reacted affording 2-methylaryl-2-alkenals, while this process can be suppressed changing the functional group to NBOC, thus allow-
ing the formation of b-amino carbonyl compounds.
ꢀ 2005 Elsevier Ltd. All rights reserved.
Transition metal catalyzed carbonylation of unsaturated
compounds with carbon monoxide is one of the most
important reactions in synthetic organic chemistry.1 In
particular treatment of terminal acetylenes with CO
and a hydrosilane (silylformylation process) usually
results in the formylation of the internal sp carbon of
the triple bond affording (Z)-b-silylalkenals in high
yields and with high degree of regio and stereochemical
control. The silylformylation reaction has been studied
extensively in the past few years2 due to its wide applica-
bility to unsaturated compounds bearing several func-
tional groups such as alcohols, ethers, esters, ketones,
aldehydes, halogens and double bonds. In 1992,3 Mat-
suda et al. reported that propargyl amine derivatives
reacted under CO pressure with two equivalents of
hydrosilane to generate 2-silylmethyl-2-alkenals 5, while
the expected b-silylalkenals (Z)-3 could not be isolated
in good yields (Scheme 1).
R1 R2
R1 R2
NR3R4
CO
RMe2Si
1
CHO
5
+
2 RMe2SiH
2
R3R4NSiMe2R
NR3R4
1 R2
R
NR3R4
R2
R1
RMe2Si
CHO
OSiMe2R
(Z)-3
SiMe2R
4
Scheme 1.
nature of the substituents on the nitrogen atom highly
affected the reaction, the benzyl groups providing clear
results with high yields.
A following deep analysis of the mechanistic aspects4 of
this process revealed that the b-silylalkenal 3 was prob-
ably the unstable intermediate that was converted into
the double silylated product 4, susceptible to an elimina-
tion step to form 5 in the presence of heat or acid. The
In this letter, we report that suitable propargyl amides
react with one equivalent of ArMe2SiH affording the
corresponding b-silylalkenals (Z)-3 that are stable and
can be isolated in good yields (Scheme 2, step 1). The
protection of nitrogen atom is a fundamental step, since
free amino moieties are responsible for the formation
of uncharacterized material. Aldehydes (Z)-3 can be
submitted to a desilylation process by treatment with
tetrabutylammonium fluoride (TBAF)5 that is able to
induce a 1,2-migration of the aryl group of the silyl
Keywords: Rhodium-catalysed silylformylation; Desilylation; a,b-
Unsaturated aldehydes.
*
Corresponding author. Tel.: +39 0502219298; fax: +39
0502219260; e-mail: capored@dcci.unipi.it
0040-4039/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.11.054

528
L. A. Aronica et al. / Tetrahedron Letters 47 (2006) 527–530
played an important role since at 25 ꢁC the formation
R1
R2
XHN
1
Rh4(CO)12
NHX
rate of (Z)-3 was too low and the generated b-silylalke-
nals were smoothly converted into the elimination prod-
uct 7 (Table 1, entry 4). In order to reach a good to
complete conversion of the reagents, 24 h was necessary
(Table 1, entries 6–9).
R1
R2
CO
step 1
+
OHC
SiMe2Ar
(Z)-3
ArMe2SiH 2
R1
R2
CH2 Ar
CHO
TBAF
step 2
The silylformylation of propargyl amides was appreci-
ably affected by the structure of the acetylenic reagents,
in agreement with the results we previously observed
studying the reaction of nonfunctionalized 1-alkynes.7
Indeed, the less hindered tosyl amides reacted rapidly
with almost total selectivity towards the corresponding
b-silylalkenals (Z)-3 (Table 1, entries 3, 8 and 9). On
the other hand, decreases on both the reaction rate
and selectivity were detected when the silylformylation
was carried out with acetylenes characterized by a bulky
propargyl carbon (Table 1, entries 6 and 7). In particu-
lar, in the case of propargyl amide 1e, the conversion
after 24 h was 53% and the hydrosilylation reaction
resulted highly competitive with the formylation one.
6
Scheme 2.
moiety with a contemporary elimination step that yields
2-methylaryl-2-alkenals 6 (Scheme 2, step 2). This result
is particularly interesting since only a few methods of
preparation of such molecules are described.6
Initially the silylformylation reaction of propargyl
amides 1 was investigated and the principal results are
summarized in Table 1. The reactions were performed
in a stainless steel autoclave, under 30 atm of CO, in
the presence of catalytic amounts of Rh4(CO)12 (0.1–
0.5 mol % respect to the acetylene). In agreement with
the data reported by Matsuda and co-workers,3,4
monobenzylamine 1a reacted with two equivalents of
Me2PhSiH to generate the allylsilylalkenal 7aa exclu-
sively. Under the same experimental conditions, the
para-tosyl derivative 1b yielded (Z)-3ba as major prod-
uct with concomitant formation of considerable quanti-
ties of 7ba (Table 1, entry 2). These preliminary data
confirmed that the nature of the substituent on the nitro-
gen atom was a key element of the reaction. Indeed, the
chemoselectivity towards the b-silylalkenals could be
improved by reacting the tosyl amides 1 with 1 equiv
of hydrosilane at 100 ꢁC. The reaction temperature
An analogous reaction trend was observed when substi-
tuted arylsilanes were employed: the use of ortho-tolyldi-
methylsilane involved a significant lowering of the
reaction rate with respect to Me2PhSiH (Table 1, entry
10 vs 9). In any cases, the chemoselectivity of the process
resulted quite good if not complete, thus allowing the
extension of the silylformylation of propargyl amides
to functionalized hydrosilanes.
With the easy access to tosylamido aldehydes (Z)-3 in
hand, we turned to the desilylation step promoted by
tetrabutylammonium fluoride (Table 2).6 The reactions
Table 1. Silylformylation of propargyl amides 1 with aryldimethylsilanesa
R1
R2
R1
R2
NHX
CO, 30atm
Rh4(CO)12
SiMe2Ar
CHO
TsHN
R1
R2
+
+ ArMe2SiH
2
1
OHC
SiMe2Ar
7
(Z)-3
Entry
1
X
R1/R2
t (h)
2
Ar
Conv.b (%)
Yieldb (%)
(Z)-3
7c
1d
2d
3
a
b
c
d
d
d
e
f
CH2Ph
p-Ts
p-Ts
p-Ts
p-Ts
p-Ts
p-Ts
p-Ts
p-Ts
p-Ts
p-Ts
p-Ts
Et/Me
Me/Me
Me/Me
Me/Et
Me/Et
Me/Et
Me/t-Bu
H/t-Bu
H/Me
4
4
24
24
6
24
24
24
24
24
24
24
a
a
a
a
a
a
a
a
a
b
c
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
76
100
100
32
54
79
53
73
100
65
82
/
/
aa
ba
ca
da
da
da
/
/
/
/
cc
cd
100
33
13
53
18
ba
ca
da
da
da
ea
fa
ga
gb
cc
cd
67
87 (42)
47
82
80 (44)
38
4e
5
6
7
20
f
8g
9g
10
11
12
95 (49)
91 (71)
100 (38)
86 (51)
87
/
/
/
14
13
g
g
c
c
H/Me
Me/Me
Me/Me
o-MePh
p-MePh
p-OMePh
d
68
a Reactions were performed with 2 mmol of silane, 2 mmol of amide, 2 · 10À3–10À2 mmol of Rh4(CO)12, 3 mL of CH2Cl2, in a stainless steel
autoclave, under 30 atm of CO, at 100 ꢁC, unless otherwise specified.
b Determined by GLC of the reaction mixture after work up. All new compounds were identified and characterized by FT-IR, NMR (1H and 13C),
GC–MS and elemental analysis. In parentheses the isolated yields of pure compounds are reported.
c A E/Z mixture was always observed.
d Reactions run with 2 equiv of Me2PhSiH.
e The reaction was performed at room temperature.
f 62% of hydrosilylated products were detected by 1H NMR analysis.
g Small amounts of isomerisation byproducts were observed.

L. A. Aronica et al. / Tetrahedron Letters 47 (2006) 527–530
Table 2. TBAF induced desilylation of b-silylalkenals (Z)-3a
529
Me
Et
OHC
NHBOC
NHBOC Me2PhSiH 2a
63%
SiMe2Ph
(Z)-3ha
Me
Et
R1
R2
NHTs
R1
R2
CH2 Ar
CHO
TBAF
CO, Rh4(CO)12
1h
OHC
SiMe2Ar
Me
6
NHBOC
(Z)-3
TBAF, H2O
Et
Entry (Z)-3 Ar
R1
R2
6
Yieldb (%) (E/Z)c
54%
OHC
Ph
1
2
3
4
5
6
ga
fa
Ph
Ph
Ph
Ph
H
H
Me
t-Bu fa
ga 52 (100/0)
45 (100/0)
ca 75
da 59 (65/35)
gb 67 (100/0)
cd 55
8
Scheme 3.
ca
da
gb
cd
Me Me
Me Et
Me
R1
R2
R1
R2
o-Tol
p-MeO Me Me
H
NHX
NHX
TBAF
Ar
Me
Me
a Reactions were performed adding 1 mmol of b-silylalkenals to a THF
solution (10 mL) of TBAF (2.5 mmol) at room temperature.
b Yields of pure compounds (not optimized). All new molecules were
identified and characterized by FT-IR, NMR (1H and 13C), GC–MS
and elemental analysis.
c Diasteromeric ratio was obtained by 1H NMR analysis. E and Z
configurations of the products were determined by NOE experiments.
Si
F
OHC
SiMe2Ar
(Z)-3
O
9
R1
R2
NHX
R1
Ar
NHX
Ar
R2
Brook
Me
Si
F
O
Me
Me
Me
O
Si
F
10
11
were performed under very mild experimental condi-
tions, adding 1 mmol of aldehydes to a THF solution
of TBAF (2.5 mmol) and hydrolyzing immediately after-
wards with water. A complete consumption of the
reagents was observed and the obtained products were
recovered in good yields (not optimized). The fluoride
source induced a 1,2-anionotropic rearrangement of the
aryl substituent from silicon to carbon with subsequent
desilylation.5 Unexpectedly, a contemporary elimination
of the tosyl amide moiety was detected and 2-methylaryl-
2-alkenals 6 were generated. The reaction resulted totally
stereoselective when a secondary allylic carbon was
present on the (Z)-3 precursors, the more stable isomer
(E) being formed exclusively (Table 2, entries 1 and 2).
The 1,2-rearrangement of the aromatic ring occurred
with complete retention of the original configuration of
the Ar, as observed in the cases of ortho- and para-func-
tionalized groups (Table 2, entries 5 and 6).
X = BOC
H2O
X = p-Ts
CH2 Ar
H2O
R1
R2
Me
Et
OHC
NHBOC
Ph
8
CHO
6
Scheme 4.
addition of fluoride to silicon yielding a pentacoordinate
Si atom 9, aryl-1,2-anionotropic migration to the adja-
cent carbon atom with the formation of enolate 10
and its possible Brook rearrangement. Hydrolysis of
11 generates the Boc protected amide 8, while contem-
porary elimination of the tosyl group affords the
observed 2-methylaryl-2-alkenals 6.
In conclusion, we have shown that it is possible to per-
form the silylformylation of acetylenes functionalized by
a propargyl amide group with aryldimethylsilanes, pro-
viding that the reaction is carried out with equivalent
amounts of the reagents. The obtained b-silylalkenals
are stable and can be submitted to a desilylation process
by treatment with TBAF. Different functionalized alde-
The obtained data indicated that it was not possible to
maintain the amide moiety in the TBAF promoted desil-
ylation process, probably due to the good leaving group
properties of para-toluenesulfonamide. This result was
achieved by the two-step sequence of silylformylation–
desilylation of the BOC protected substrate 1h (Scheme
3).
2-Benzyl-3-methyl-2-pentenal (representative procedure): 2 mmol of
Me2PhSiH, 2 mmol of (R)(S)-N-(1-methyl-1-ethyl-2-propinyl)-p-tol-
uenesulfonamide 1d, 0.0016 g (2 · 10À3 mmol) of Rh4(CO)12 and
3 mL of CH2Cl2 were put, in a Pyrex ÔSchlenkÕ tube, under CO
atmosphere. This solution was introduced in a 25 mL stainless steel
autoclave fitted with a Teflon inner crucible and a stirring bar,
previously placed under vacuum (0.1 mmHg), by a steel siphon. The
reactor was pressurized with 30 atm of carbon monoxide and the
mixture was stirred at 100 ꢁC for 24 h. After removal of excess CO
(fume hood), the reaction mixture was diluted with CH2Cl2, filtered
(Celite) and concentrated under vacuum. The residue was purified by
column chromatography on silica gel using CH2Cl2 as eluent
affording 0.37 g (44%) of the pure aldehyde (Z)-3da. To a solution
of 2.5 mmol of TBAF in 10 mL of THF was added, at room
temperature, 1 mmol of (Z)-3d. The reaction mixture was hydrolyzed
with water, extracted with Et2O and the organic layers were dried
over Na2SO4. After concentration under vacuum, the crude product
was purified by column chromatography on silica gel using CH2Cl2 as
eluent affording 0.11 g (59%) of a (E/Z) mixture of 2-benzyl-3-methyl-
2-pentenal 6.
Both reactions afforded the corresponding products in
good yield. The silylformylation of the tert-butoxycarbon-
yl protected amine 1h with Me2PhSiH generated the
expected b-silylalkenal (Z)-3ha exclusively. The TBAF
promoted phenyl migration resulted in being totally
chemoselective towards the formation of the b-amino
aldehyde 8. It is noteworthy that b-amino carbonyl moi-
eties are found not only as structural units of natural
products,8 but are potentially useful building blocks for
Wittig type condensations9 and for the synthesis of natu-
ral molecules,10 b-amino acids and 1,3-amino alcohols.11
All the reported data were in agreement with the mech-
anism hypothesized for the TBAF induced rearrange-
ment of non functionalized b-silylalkenals6 as depicted
in Scheme 4. The proposed mechanism involves the

530
L. A. Aronica et al. / Tetrahedron Letters 47 (2006) 527–530
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