Regioselective Rh(I)-catalyzed sequential hydrosilylation toward the assembly of silicon-based peptidomimetic analogues

Article abstract of DOI:10.1021/jo300904z

A highly regioselective Rh(I)-catalyzed hydrosilylation of enamides is presented. This mild protocol allows access to a wide variety of different arylsilanes with substitution at the β-position of the enamide and functionalization on the alkyl chain tethered to the silane. This protocol is extended to include a sequential one-pot hydrosilylation. Using diphenylsilane as the appendage point, hydrosilylation of a protected allyl alcohol followed by hydrosilylation of an enamide generates a complex organosilane in one step. This highly convergent strategy to synthesize these functionalized systems now provides a way for the rapid assembly of a diverse collection of silane-based peptidomimetic analogues.

Full text of DOI:10.1021/jo300904z

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pubs.acs.org/joc
Regioselective Rh(I)-Catalyzed Sequential Hydrosilylation toward the
Assembly of Silicon-Based Peptidomimetic Analogues
Geanna K. Min and Troels Skrydstrup*
Center for Insoluble Protein Structures, Department of Chemistry and Interdisciplinary Nanoscience Center, Aarhus University,
Langelandsgade 140, 8000 Aarhus C, Denmark
S
* Supporting Information
ABSTRACT: A highly regioselective Rh(I)-catalyzed hydro-
silylation of enamides is presented. This mild protocol allows
access to a wide variety of different arylsilanes with substitution
at the β-position of the enamide and functionalization on the
alkyl chain tethered to the silane. This protocol is extended to
include a sequential one-pot hydrosilylation. Using diphenylsilane as the appendage point, hydrosilylation of a protected allyl
alcohol followed by hydrosilylation of an enamide generates a complex organosilane in one step. This highly convergent strategy
to synthesize these functionalized systems now provides a way for the rapid assembly of a diverse collection of silane-based
peptidomimetic analogues.
INTRODUCTION
■
Silicon is the second most abundant element in the earth’s
crust. Despite its prevalence, its utility in medicinal chemistry is
still limited, possibly because of the limited number of methods
for incorporating silicon into organic molecules. Nevertheless,
the introduction of silicon into bioactive molecules can produce
interesting biological effects, such as increased binding to the
Figure 1. ACE inhibitor vs silicon-based ACE inhibitor.
target, improved pharmacokinetic properties, as well as
providing new intellectual property.1
inhibitor.8 This demonstrated silicon’s ability to act successfully
as an active tetrahedral intermediate mimic.
One of the emerging applications for silicon is its
incorporation into amino acids.1d,2,3 Although silicon-based
amino acids are not naturally occurring, introducing these
building blocks into peptide chains can provide the desired
modifications to the physical properties that are typically
exhibited by the original peptide structure.1b In 1998, Sieburth
and co-workers introduced the interesting concept of silicon
diols representing potent inhibitors of proteases such as the
ACE inhibitor 2, which can mimic the active tetrahedral
intermediate of a peptide cleavage.1a,4,5 Silicon has most of the
characteristics of the carbon element but with some slight
differences. It possesses a larger radius than carbon, and hence
the Si−OH bond in comparison to C−OH bond is
approximately 25% longer.1b In contrast to carbon, silicon
prefers to exist as the silanediol rather than as the silanone.
Thus, replacing carbon for silicon at the peptide cleavage site
becomes a viable choice.
Previously, simple silanediols were tested for bioactivity. In
these cases, the silanediols showed no activity for enzyme
inhibition.1b,6 However, upon testing a silicon replica of an
already known ketomethylene-based ACE inhibitor depicted as
its unstable hydrate 1 (Figure 1), the silicon analogue exhibited
similar inhibitory effect as the parent compound.7 Since then,
Sieburth and co-workers have reported other examples of
silicon-based peptidomimetic analogues that possess a high
inhibitory effect comparable to its parent carbon-based
Incorporating silicon into peptides whether to mimic an
active tetrahedral intermediate of a protease inhibitor or to
change the peptide’s lipophilicity or conformation has become
a growing field in drug design. As the interest into this
developing area grows, the demand for a wider variety of
organosilanes rises. Further exploration into alternative ways to
synthesize highly functionalized organosilanes is therefore
needed.
Previous Syntheses. Sieburth and co-workers reported the
first synthesis incorporating silanediols into a peptide.5 Since
then, a few modications to streamline the synthesis have been
reported. The modified strategy involves the formation of the
first C−Si bond by deprotonation of dithiane 3 followed by
attack onto Ph2SiF2 (Scheme 1). An organolithium reagent
then attacks the silyl fluoride 4 forming the second C−Si
bond.7 After several functional group manipulations, a highly
functionalized organosilane intermediate was synthesized. The
silane phenyls are carried throughout the synthesis and act as
masked silanediols. The silicon phenyl substituents can then be
converted to the diol form by using TfOH to promote the
initial C−Si bond cleavage.5
Received: May 3, 2012
Published: June 5, 2012
© 2012 American Chemical Society
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Scheme 1. Sieburth’s Modified Protocol To Access ACE Inhibitor Intermediate
A more concise route was reported by the same group in
2007 (Scheme 2) involving a magnesium-mediated addition of
Our group presented a further exploration into synthesizing
these peptidomimetics, whereby we demonstrated that the
more stable diphenylsilane, Ph2SiH2, could be introduced in the
hydrosilylation step using various olefins without any observed
double hydrosilated products (Scheme 3). In order to
introduce 1,1-disubstituted olefins, a radical-catalyzed strategy
was employed. The silyllithium species were generated from
these alkylhydridosilanes followed by attack onto a chiral
sufinimine producing functionalized silanes with high diaster-
eoselectivity.12 The Scheidt and Skrydstrup strategies provided
the compound in five steps using mild conditions starting from
a protected allyl alcohol.
Scheme 2. Sieburth’s Alternative Approach Using
Dihydrosilole
More recently, Sieburth and co-workers were able to extend
this methodology in an elegant fashion as depicted in Scheme
4. An enantioselective intramolecular hydrosilylation was
Scheme 4. Asymmetric Intramolecular Hydrosilylation on
1,1-Disubstituted Olefins To Access Silicon-Based ACE
Inhibitor
dichlorodiphenylsilane to diene 7.9 Hydroboration of the olefin
8 followed by ring-opening via cleavage of the Si−C bond using
HF furnished an olefin tethered to a silyl fluoride as the
organosilane 9. This silyl fluoride was further manipulated in
order to achieve the silanediol peptide isosteres.
Organ and Combs provided an alternative approach toward
the synthesis of these isosteres by a platinum-catalyzed
hydrosilylation using alkene 11 and chlorodiphenylsilane
(Scheme 3).10 The resulting chlorosilane 12 was reduced to a
silyl lithium reagent, which then attacks an imine. The Scheidt
group published afterward that using the Ellman auxiliary-
attached imines can undergo nucleophilic attack using silyl
lithium species without observing any aza-Brook rearrangement
and achieving high diastereoselectivity.11
Scheme 3. Organ/Combs (Top) and Skrydstrup (Bottom) Strategy toward ACE Protease Inhibitors via Hydrosilylation/
Lithiation/Nucleophilic Attack of Imine
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presented to allow for substitution on the olefin.13 Using
alkyldiphenylsilyl ether 17 and a chiral Rh(I) catalyst, the
terminal end of the alkene underwent asymmetric hydro-
silylation forming oxasilolane 18. The oxasilolane 18 was
subjected to HF to cleave the carbon−silicon bond followed by
MOM protection of the generated free alcohol. The silyl
lithium species was formed using Li metal and was used to
attack a chiral sulfinimine to afford the desired sulfinamide
product in good yields.
Scheme 6. Proposed Catalytic Cycle of Metal-Catalyzed
Enamide Hydrosilylation
Although alternative strategies to achieve α-alkyl-α-amino-
silane have been reported,2a,14 the lithiation strategy to attack a
chiral sulfinimine has become the common strategy employed
to form C−Si bonds.15 However, the two limitations to this
Organ and Combs/Skrydstrup protocol is the generation of the
silyl lithium species in order to attack the chiral sulfinimine.
These conditions do not tolerate a variety of different
functionalities attached on the arylsilane (furyl, thiophenyl,
etc.)16 or tethered to the terminal olefin (OBn, OAc, etc.).
Also, another downside to this protocol is that the method
requires the use of an auxiliary in order to induce stereo-
chemical control in the nucleophilic attack of the imine, which
will be removed subsequently. In order to access a wider variety
of silyl-containing substrates in an efficient and atom-
economical fashion, an asymmetric metal-catalyzed alternative
would be preferred.
In their paper, the substrate scope was moderate to high
yielding but was limited to nonbulky silanes, dimethylphenylsi-
lane, triethylsilane, and simple enamides, many lacking
complexity at the β-position. Sieburth and co-workers surmised
that N-alkenyl carbamates could also undergo hydrosilylation at
the α-position with more bulky silanes (Scheme 7)20 because
Hydrosilylations. The hydrosilylation of enamides provides
direct access to the α-alkyl-α-aminosilanes. However, the
process should optimally be high yielding, regioselective, and
stereoselective. Not many reports have been published
previously on the hydrosilylation of enamides. Most catalytic
hydrosilylations have been reported on simple olefins with
Scheme 7. Hydrosilylation of N-Alkenyl Carbamates
unfunctionalized hydrocarbon chains.17 Skoda-Foldes was the
̈
first to discover that hydrosilylations can occur with high
regioselectivity depending on the catalyst (Scheme 5).17j When
Scheme 5. Catalyst Governed Regioselectivity of
Hydrosilylation
Murai and Kato demonstrated that this reaction could also
proceed with N-alkenyl ureas.18a Although this strategy would
have provided a more expedient and straightforward synthesis
of the desired compounds, the approach was not used since
then due to the low reactivity of Rh2(OAc)4 with
diphenylmethylsilane and Boc-protected enamides. The low
reactivity was attributed to the silane’s electronic and steric
effects achieving yields around 0−46% with various N-alkenyl
carbamates. Despite the modest yields, the reaction was still
regioselective as observed previously by Murai and Kato.
Metal-catalyzed hydrosilylation of enamides would provide
the most direct route toward obtaining a widely diverse
collection of highly functionalized organosilanes. The only
deterrence from utilizing this strategy is the low yields obtained
when using methyldiphenylsilane. Given new knowledge gained
from similar protocols such as metal-catalyzed hydroborations21
and hydrogenations,22 as well as having new strategies to access
a wider variety of enamides, our group surmised that
hydrosilylations would be a possibility using a more reactive
catalyst species. We envisioned that using one catalyst in a one
pot, highly regioselective and stereoselective sequential hydro-
silylation would provide the most optimal strategy toward
achieving diversity in these substrates (Scheme 8). This would
afford highly complex organosilanes in the most atom
economical fashion. Herein, we report on our initial efforts to
develop a Rh-catalyzed highly regioselective sequential hydro-
silylation and its possible extension into a one-pot protocol
using one catalyst. Both binuclear and mononuclear rhodium
switching the catalyst from Pt(PhCN)2Cl2 to Wilkinson’s
catalyst in the presence of N-pyrrolidinone 21 and
triethylsilane, the regioselectivity reverses from preferring the
β-position of the enamide to the α-position.
Murai and Kato, in 1998, reported a similar regioselectivity
using Rh2(OAc)4 in toluene at 110 °C.18 Different Rh catalysts
were investigated including Wilkinson’s catalyst. Rh2(OAc)4
proved to be the superior catalyst in the hydrosilylations giving
the product in high regioselectivity for the α-position of the
enamide. Murai and Kato postulated that the mechanism
proceeds via a hydrometalation step with the adjoining
carbonyl group directing the reaction to obtain high
regioselectivity for the α-position of the enamide as depicted
in Scheme 6.18b With the use of the Pt catalyst in the case of
Skoda-Foldes, the regioselectivity changes. This can be
̈
explained by a silylmetalation mechanism in which the
regioselectivity is still directed by the carbonyl group (Scheme
6). However, Murai and Kato do not exclude the possibility of
the Rh-catalyzed reaction occurring through a silylmetalation
mechanism.19
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Scheme 8. Proposal for Stereoselective and Regioselective Metal-Catalyzed Sequential Hydrosilylation
catalysts are investigated in this work. This method provides a
straightforward entry to the silanediol class of peptide isosteres.
Because of the results obtained in our initial studies, the
discrepancies in yields between Murai/Kato and Sieburth and
co-workers indicated that the N-substituent plays an important
role in the hydrosilylation. Different representative N-
substituents were therefore screened as shown in Table 2. In
RESULTS AND DISCUSSION
■
Since Murai and Kato achieved good to excellent yields using
N-vinylacetamide and methyldiphenylsilane, preliminary studies
were conducted on the same enamide but using a bulkier silane,
methyldiphenylsilane, as depicted in Table 1. Rhodium sources
Table 2. Effect of Varying N-Substituents
Table 1. Optimization of Hydrosilylations Using N-
Vinylacetamide 26 and Diphenylmethylsilane
entry
Rh+ cat.
ligand
none
solvent
temp (οC) yield (%)
a
1
2
Rh2OAc4
DCE
DCE
DCE
DCE
DCE
THF
PhMe
DCE
DCE
DCE
65
65
65
65
65
65
65
40
65
65
87
50
0
a
[Rh(cod)Cl]2
Rh(PPh)3Cl
Rh(cod)2BF4
Rh(cod)2BF4
Rh(cod)2BF4
Rh(cod)2BF4
Rh(cod)2BF4
none
none
3
none
4
none
73
78
0
5
P(OPh)3
P(OPh)3
P(OPh)3
P(OPh)3
none
6
7
0
8
78
0
9
10
none
P(OPh)3
0
a
0.005 mol % of Rh catalyst was used.
were screened as shown in entries 1−4. The dimer rhodium
species, Rh2(OAc)4 (entry 1) achieved higher yield of the
hydrosilylated product 27 than the [Rh(cod)Cl]2. This
demonstrated that the increased steric bulk of the silane from
dimethylphenylsilane to diphenylmethylsilane using rhodium-
(II) acetate dimer did not result in significantly lower yields.
However, when taking a chiral rhodium dimer species, Rh2(S-
DOSP)4, complete conversion to the product was observed, but
no enantiomeric excess was obtained.
Because there were more opportunities in developing a
stereoselective reaction using a rhodium monomer catalyst,
Wilkinson’s catalyst and Rh(cod)2BF4 were screened. Interest-
ingly, Wilkinson’s catalyst which was originally reported by
all cases, only one regioisomer was observed. N-Alkenylaceta-
mide achieved 100% conversion to product and 97% isolated
yield (entry 1). The carbamate provided a similar conversion;
however, the yield significantly drops to 54%. Adding another
N-substituent (entries 3 and 4) lowers the yield in comparison
to the monosubstituted nitrogen counterpart (entries 1 and 2).
As expected, the cyclic carbamate 31 furnished the lowest yield
of the four screened. Starting material was still observed in
entry 4 and proved to be inseparable from the product during
flash chromatography. The marked difference in yields obtained
between acetamide versus carbamate particularly in entries 3
and 4 suggests that the acetamide possesses a better donating
ability to sufficiently chelate to the rhodium complex over the
carbamate. This could explain the differences observed in
Sieburth’s results versus those of Murai and Kato.
Skodes-Foldes’ case to give complete regioselectivity for the α-
̈
position of N-pyrrolidinone,17j achieved none of the desired
product in these conditions. However, using the Rh(I) catalyst,
Rh(cod)2BF4 gave the hydrosilylated product 27 in good yields
(entry 4).
Addition of a phosphite ligand, P(OPh)3, improved the yield
giving 95% consumption of N-vinylacetamide 26 and a 78%
isolated yield. With this rhodium complex, different solvents
were screened (entries 5−7) with dichloroethane providing the
Having optimized the necessary components for the
hydrosilylation to occur in good yields, different aryl
substituents on the silicon were investigated (Table 3). As
indicated in a previous paper from our group, the electron-rich
aromatic groups are highly desired for their ability to cleave
ο
highest yields. Even at lower temperatures, 40 C, the reaction
was complete in 30 min. However, it is important to note that
once the enamide is substituted at the β-position, increased
temperatures and reaction times are necessary.
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reactivity of the silane (entry 5). However, by placing a methyl
in the ortho position of the aryl group (entry 4), the
hydrosilylation is greatly impeded. Switching the methyl
group with an electron-withdrawing group such as trifluor-
omethyl on the aryl ring (entry 6) provides comparable yields
to silanes containing methyl substitution in the m- or p-
position. If the aryl group is switched to furan (entry 7) or
thiophene (entry 8), the reaction furnishes the desired products
in 69% and 75% isolated yields, respectively. These two entries
are important because lithiation of either one of these two
silanes (42 or 43) followed by attack on a sulfinimine did not
result in the formation of the desired product as seen in
previous studies done in the group. However, applying this
mild approach, access to these types of silanes is now possible.
Different silyl alkyl chains were also investigated (Table 4).
Benzyl (entry 1) and THP (entry 2) protecting group on the 3-
hydroxypropyl chain generated the hydrosilylated products in
good yields. Acetyl (entry 3) and tert-butyldiphenylsilyl (entry
4) groups were also tolerated in the reaction. Having a
hydrocarbon chain without any functionality on the silane
provided the compound in good yields (entry 6). Using a
Table 3. Effect of Varying the Silane Aryl Groups on
Hydrosilylation
Table 4. Variation of the Functional Group on Silyl Alkyl
Group
under milder acidic conditions to furnish the silanediol more
readily.15c Having a methyl substituent in the meta (entry 2) or
para (entry 3) positions of the aryl group gave the desired
products in good yields, 86% and 74%, respectively. Carrying
two methyl groups at the meta positions does not change the
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Table 5. Effect of Varying the Substituents on the Enamide Olefin
typically unreactive trialkylsilane under these reaction con-
ditions still afforded the desired product 64 (entry 7). If the
alkyl chain is one carbon shorter than in entry 2, the product 62
is obtained in a 70% isolated yield (entry 5). Although it seems
rather trivial to shorten the chain by one carbon, it is enough to
cause problems in the lithiation of these silanes. Upon lithiation
and attack on the imine, the reaction gives a mixture of
undetermined compounds that are inseparable from each other.
However, when the hydrosilylation strategy is used, only the
desired product is observed in a 70% isolated yield.
product is observed with complete regioselectivity for the α-
position as for the enamide (entry 1). However, if a THP-
protected enol is reacted with the Rh(I) catalyst and Ph2SiH2,
complete reversal of the regioselectivity is observed providing
the β-product in a 78% isolated yield (results not depicted).
This gives further proof that the carbonyl adjoining the
heteroatom (N or O) controls the regioselectivity. However, if
the enamide is 1,1-substituted as in entry 7, sterics overrule the
directing effect of the carbonyl, and the silicon ends up again at
the terminal position in excellent yields.
After investigating the effect of varying the enamide’s N-
substituents and the silane’s aryl and alkyl groups, variations of
the substituents on the enamide were explored as depicted in
Table 5. If instead of reacting methyldiphenylsilane with an
enamide it is reacted with enol acetate (entry 2), the desired
When the β-position of the enamide is substituted with a
methyl group, the cis- or trans-configuration of this particular
substrate does not demonstrate a difference in isolated yield of
the hydrosilylated product giving yields of 97% and 95%,
respectively (entries 3 and 4). However, if the methyl
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substituent is switched with an aromatic group, the
configuration of the enamide becomes very important. With
the trans-geometry, the reaction does not proceed. In order to
drive the reaction forward, a cis-stereoisomer was tested, which
resulted in complete consumption of the starting material and
an isolated yield of the product of 78% was obtained.
Table 6. Hydrosilylation of Enamides Using Silane 51
With a methyl group in the para position, a 73% yield of 81 is
achieved. However, if the aromatic group becomes more
electron rich with a OMe group as in entry 9, the reaction
affords only trace amounts of the desired product. These
hydrosilylation conditions do tolerate aryl halides such as Cl
(entry 10) and F (entry 11), providing the product in 64% and
61% yield, respectively. A cyclic enamide works as well, giving,
as depicted in entry 12, silane 85 even despite the presence of a
Boc-protecting group on the nitrogen. However, when the
enamide double bond is trisubstituted, the reaction gave no
desired product (entry 13). Having a more electron-rich
trisubstituted enamide does not facilitate the reaction either
(entry 14). The hydrosilylation also does not occur with esters
on the β-carbon (entry 15).
Interestingly, when this methodology was applied to a highly
functionalized enamide, compound 89 (Scheme 9), the
Scheme 9. Hydrosilylation of a Highly Functionalized
Enamide
hydrosilylation occurred in excellent yield providing an
approximately 1:1 diastereomeric mixture of products. Epime-
rization of the α-center of the phenylalanine unit was also not
observed.23 This result is interesting for two reasons. First,
there is no chirality transfer from the adjacent amino acid,
which suggests that with a suitable asymmetric ligand control at
the new stereogenic carbon center should be possible. Second,
it implies that the hydrosilylation step could be performed on
an intact peptide with a C-terminal enamide functionality.
Hydrosilylation proved to be possible on a wide variety of
different enamides. Taking these enamides, the hydrosilylation
was further tested by using a slightly more functionalized and
bulkier silane 51 (Table 6). Using Rh(cod)2BF4 and P(OPh)3,
N-vinylacetamide (entry 1) and (Z)-N-(prop-1-en-1-yl)-
acetamide (entry 2) gave good yields of the hydrosilylated
product. However, when the β-substituent is switched to an
aromatic group, the reaction is low yielding when Rh-
(COD)2BF4 and triphenyl phosphite are used.
Because of its sluggish reactivity, the rhodium catalyst ends
up decomposing over time. Despite catalyst decay, isomer-
ization of the enamide configuration was not observed.
Rh2(OAc)4, which has not shown quick decomposition in our
studies, was used in these cases instead. The 4-fluoroaryl group
reveals an improved yield using the rhodium dimer compared
to the monomeric rhodium species (entry 4). However, with
the phenyl group (entry 3) and the 4-chlorophenyl group
(entry 5), low yields are obtained, even though in all three cases
complete consumption of the starting material had occurred.
The desired product and the trans-enamide were present in the
crude mixture. This result indicates that with the bulkier silane,
the reductive elimination occurs slower than the β-hydride
a
0.01 equiv of [Rh2(OAc)4] was used as catalyst for these entries.
elimination resulting in the preferred formation of the more
stable trans-enamide. However, despite the increased sterics
around the silane, functionalization of the enamide 89 does not
seem to be problematic (entry 6).
Since the two alkyl chains on the silicon could be introduced
via two Rh(I)-catalyzed hydrosilylations, exploring a sequential
sequence to form two C−Si bonds in a one-pot fashion became
a viable option, the results of which are depicted in Table 7.
The first hydrosilylation of the allylic alcohol derivative with
diphenylsilane takes place rapidly (15 min for 100% NMR
conversion). If Rh2OAc4 is used instead, NMR conversion is
52% after 24 h for the first hydrosilylation. If the reaction time
is longer than 15 min for the first step using Rh(COD)2BF4 and
P(OPh)3, the catalyst’s reactivity decreases for the second
hydrosilylation. Next, the enamide is added to the reaction
mixture and heated allowing the second hydrosilylation step to
proceed. The sequential hydrosilylation with vinyl acetamide
proceeds in an acceptable yield for the two-step process in one
pot (entry 1). Because the first step is not a quantitative
reaction, the yield drops when using a one to one ratio of the
protected allyl alcohol and diphenylsilane with the enamide.
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Table 7. One-Pot Sequential Hydrosilylation To Access
Highly Functionalized Organosilane
CONCLUSIONS
■
In summary, a highly regioselective Rh(I)-catalyzed hydro-
silylation of enamides is reported. This mild protocol is
amenable to different functionalization on the silicon and the
enamide. This protocol can be extended to a sequential one-pot
procedure in which hydrosilylation of a protected allyl alcohol
using diphenylsilane followed by hydrosilylation of the enamide
occurs using the same catalyst in order to generate a complex
organosilane in one step. This ability to hydrosilylate these type
of highly functionalized systems without altering the chemical
components of the molecule would allow for the facile
assembly of a wide variety of silicon-based peptidomimetic
analogues.
EXPERIMENTAL PROCEDURES
■
General Methods. 1H NMR and 13C NMR spectra were recorded
at 400 and 100 MHz, and the chemical shifts are reported in ppm
relative to solvent residual peak.24 HRMS spectra were recorded on
LC TOF (ES) apparatus. Flash chromatography was performed on
silica gel 60 (230−400 mesh). All solvents were dried according to
standard procedures.25 Enamides (26 65, 74) and silanes (36, 57)
were provided by commercially available sources. Aryl vinyl
bromides,26,27 enamides,28 diarylmethylsilanes,15c alkyldiphenylsilane-
29
s,12a and BocPheNH2 were synthesized by known procedures. The
commercial reagents were used without further purification. The
reagents used in the enamide synthesis were weighed out in the argon
glovebox using 8 mL vials sample vials with a Teflon-sealed screw cap.
Synthesis of Enamides 28−31, 66−77, and 89. General
Procedure A.28 CuI (0.05 equiv), amide/carbamate (1.2 equiv),
K2CO3, dimethylethylenediamine (0.10 equiv), vinyl bromide, and
PhMe were added to a round-bottom flask in glovebox. The reaction
was placed in a preheated oil bath at 110 οC for 24 h. The reaction was
cooled to room temperature and filtered through a pad of Celite using
EtOAc. The reaction was purified via flash chromatography using 40−
60% EtOAc/pentanes as eluent.
General Procedure B.28,30 CuI (0.05 equiv), amide/carbamate (1.2
equiv), K2CO3, dimethylethylenediamine (0.10 equiv), vinyl bromide,
and PhMe were added to a round-bottom flask in glovebox. The
a
1.0 equiv of enamide, 1.2 equiv of protected allyl alcohol, and 1.2
ο
reaction was placed in a preheated oil bath at 110 C for 24 h. The
equiv of Ph2SiH2 were used.
reaction was cooled to room temperature and filtered through a pad of
Celite using EtOAc. The reaction was purified via flash chromatog-
raphy using 40−60% EtOAc/pentanes as eluent. The trans-enamide
was suspended in benzene and isomerized using a UV lamp at 100 W
for 6−8 h. The reaction was purified via flash chromatography using
40−60% EtOAc/pentanes as eluent.
(Z)-N-(Prop-1-en-1-yl)acetamide (28). The product was obtained
using general procedure A yielding 28 (1.12 g, 56%) as a colorless
powder. Mp: 67−70 οC. 1H NMR (400 MHz, CD3CN): δ (ppm) 7.85
(bs, 1H), 6.59−6.62 (m, 1H), 4.66−4.74 (m, 1H), 1.94 (s, 3H), 1.61
(dd, J = 7.1, 1.8 Hz, 3H). 13C NMR (100 MHz, CD3CN): δ (ppm)
168.6, 123.1, 105.3, 23.1, 11.3 HRMS: C5H9NO [M + H+] calcd
100.0763, found 100.0754.
However, a higher yield of the product can be achieved if 1.2
equiv of the protected allyl alcohol and silane are used in
comparison to the enamide as shown in entry 2. It should be
pointed out that carrying out the sequential hydrosilylation
with both the allylic alcohol derivative and enamide in the
reaction flask was not fruitful, and neither was the attempt to
reverse the addition of the two olefins.
The one-pot procedure for (Z)-N-(prop-1-en-1-yl)acetamide
achieves good yields (entry 3). Entry 4 also demonstrates that
this strategy can be applied to a highly functionalized case as
well. Because not all the enamide is consumed in the reaction,
the cis enamide is still present and is inseparable from the
product using flash chromatography. However, one can resolve
this issue by applying 1.2 equiv of the silane in comparison to
the enamide. The desired product is achieved in good yields
with the functionalities still preserved. This result is important
because it demonstrates the potential of this methodology to be
used as an end strategy to assemble a variety of silicon-based
peptidomimetic analogues. Upon discovery of an asymmetric
version of this hydrosilylation, one could dictate the stereo-
chemical outcome of the resulting aminosilane end by the
choice of ligand. Investigations on an asymmetric version of
these hydrosilylations are currently undergoing.
(Z)-tert-Butyl Prop-1-en-1-ylcarbamate (29). The product was
obtained using general procedure A yielding 29 (480 mg, 24%) as a
ο
1
colorless powder. Mp: 74−75 C. H NMR (400 MHz, CD3CN): δ
(ppm) 6.90 (bs, 1H), 6.32 (t, J = 9.2 Hz, 1H (t, J = 8.0 Hz, 2H), 4.58
(t, J = 7.0 Hz, 1H), 1.54 (dd, J = 7.0, 1.8 Hz, 3H), 1.44 (s, 9H). 13C
NMR (100 MHz, CD3CN): δ (ppm) 154.0, 124.2, 103.2, 80.3, 28.5
(3C), 11.0. HRMS: C8H15NO2 [M + Na+] calcd 180.1001, found
180.1016.
(Z)-1-(Prop-1-en-1-yl)pyrrolidin-2-one (30).31 The product was
obtained using general procedure A yielding 30 (680 mg, 34%). The
spectra are in accord with the literature.31
(Z)-3-(Prop-1-en-1-yl)oxazolidin-2-one (31). The product was
obtained using general procedure A yielding 31 (720 mg, 36%) as a
viscous oil. 1H NMR (400 MHz, CD3CN): δ (ppm) 6.15 (dq, J = 9.4,
3.4, 1.7 Hz, 1H), 4.87−4.95 (m, 1H), 4.30−4.34 (m, 2H), 3.93−3.97
(m, 2H), 1.73 (dd, J = 7.3, 1.8 Hz, 3H). 13C NMR (100 MHz,
5901
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CD3CN): δ (ppm) 158.0, 124.9, 110.3, 63.5, 46.4, 12.2. HRMS:
C6H9NO2 [M + H+] calcd 128.0712, found 128.0721.
(E)-N-(Prop-1-en-1-yl)acetamide (66). The product was obtained
(S,Z)-tert-Butyl (1-Oxo-3-phenyl-1-(prop-1-en-1-ylamino)propan-
2-yl)carbamate (89). The product was obtained using general
1
procedure A yielding 89 (480 mg, 24%) as a viscous oil. H NMR
(400 MHz, CD3CN): δ (ppm) 8.20 (bs, 1H), 7.20−7.38 (m, 5H),
6.56−6.61 (m, 1H), 5.79 (bs, 1H), 4.78−4.85 (m, 1H), 4.45 (bs, 1H),
3.10 (dd, J = 12.0, 4.0 Hz, 1H), 2.89 (dd, J = 12.0, 8.0 Hz, 1H), 1.57
(dd, 7.2, 1.6 Hz, 3H), 1.36 (s, 9H). 13C NMR (100 MHz, CD3CN): δ
(ppm) 170.6, 156.7, 138.4, 130.3 (2C), 129.3 (2C), 127.6, 122.5,
107.3, 80.2, 56.7, 38.6, 28.5 (3C), 11.4. HRMS: C17H24N2O3 [M +
Na+] calcd 327.1685, found 327.1684.
using general procedure A yielding 66 (1.10 g, 54%) as a colorless
ο
1
solid. Mp: 72−74 C. H NMR (400 MHz, CD3CN): δ (ppm) 8.25
(bs, 1H), 6.60−6.67 (m, 1H), 5.11−5.20 (m, 1H), 1.88 (s, 3H), 1.62
(dd, J = 6.7, 1.7 Hz. 13C NMR (100 MHz, CD3CN): δ (ppm) 168.1,
124.6, 107.4, 22.9, 15.1. HRMS: C5H9NO [M + H+] calcd 100.0763,
found 100.0754.
(Z)-N-Styrylacetamide (67). The product was obtained using
Synthesis of Methyldiarylsilanes 37−43. General Procedure
C.15c Magnesium turnings (2.1 equiv) were suspended in THF under
an atmosphere of argon. Iodine crystals were added to initiate the
reaction. ArBr (2.1 equiv) was added slowly dropwise and the mixture
refluxed for 3 h. In a separate flask, dichloromethylsilane (3.3 mmol,
1.0 equiv) was dissolved in THF and cooled to 0 °C under atmosphere
of argon. The generated ArMgBr was added to the silane and allowed
to warm to room tempertaure with stirring overnight. The reaction
was diluted with Et2O and washed with water (2×) and brine (1×).
The organic layer was dried using MgSO4, filtered, and concentrated in
vacuo. The product was purified via flash chromatography using
pentane as the eluent.
general procedure B yielding 67 (540 mg, 27%) as a colorless solid.
ο
1
Mp: 65−67 C. H NMR (400 MHz, CD3CN): δ (ppm) 8.21 (bs,
1H), 7.35−7.40 (m, 4H), 7.22−7.28 (m, 1H), 6.85 (dd, J = 12.0, 8.0
Hz), 5.66 (d, J = 8.0 Hz, 1H), 1.99 (s, 3H). 13C NMR (100 MHz,
CD3CN): δ (ppm) 169.3, 136.8, 129.7 (2C), 129.2 (2C), 127.6, 123.1,
110.0, 23.3. HRMS: C10H11NO [M + Na+] calcd 184.0738, found
184.0737.
(E)-N-Styrylacetamide (68). The product was obtained using
general procedure A yielding 68 (1.10 g, 54%) as a white solid. Mp:
106−108 οC. 1H NMR (400 MHz, CD3CN): δ (ppm) 8.50 (bs, 1H),
7.46 (dd, J = 16.0, 12.0 Hz, 1H), 7.25−7.35 (m, 4H), 7.16 (tt, J = 8.0,
4.0 Hz, 1H), 6.15 (d, J = 16.0 Hz, 1H). 13C NMR (100 MHz,
CD3CN): δ (ppm) 168.6, 137.8, 129.6 (2C), 127.2, 126.3 (2C), 124.3,
112.2, 23.1. HRMS: C10H11NO [M + H+] calcd 162.0920, found
162.0913.
Methyldi-m-tolylsilane (37).15c The product was obtained using a
known literature procedure. The spectra are in accord with the
literature.15c
Methyldi-p-tolylsilane (38).15c The product was obtained using a
known literature procedure. The spectra are in accord with the
literature.15c
N-(1-Phenylvinyl)acetamide (69).32 The product was obtained
using a known literature procedure. The spectra are in accord with the
literature.32
Methyldi-o-tolylsilane (39).15c The product was obtained using a
known literature procedure. The spectra are in accord with the
literature.15c
(Z)-N-(4-Methylstyryl)acetamide (70). The product was obtained
using general procedure B yielding 70 (560 mg, 28%) as an
1
amorphous solid. H NMR (400 MHz, CD3CN): δ (ppm) 8.12 (bs,
Bis(3,5-dimethylphenyl)(methyl)silane (40).15c The product was
obtained using a known literature procedure. The spectra are in accord
with the literature.15c
1H), 7.25 (d, J = 8.2 Hz, 2H), 7.19 (d, J = 8.0 Hz, 2H), 6.80 (dd, J =
11.0, 9.8 Hz), 5.62 (d, J = 9.8 Hz, 1H), 2.33 (s, 3H), 1.99 (s, 3H). 13C
NMR (100 MHz, CD3CN): δ (ppm) 169.2, 137.4, 133.9, 130.3 (2C),
129.1 (2C), 122.5, 110.0, 23.3, 21.2. HRMS: C11H13NO [M + H+]
calcd 176.1076, found 176.1078.
Methylbis(4-(trifluoromethyl)phenyl)silane (41).36 The product
was obtained using general procedure C yielding 41 (916 mg, 83%) as
a viscous oil. 1H NMR (400 MHz, CDCl3): δ (ppm) 7.70 (J = 8.3 Hz,
4H), 7.63 (d, J = 8.3 Hz, 4H), 5.03 (q, J = 7.7, 3.8 Hz), 0.71 (s, 3H).
13C NMR (100 MHz, CDCl3): δ (ppm) 139.3 (2C), 135.1 (4C),
(Z)-N-(4-Methoxystyryl)acetamide (71). The product was obtained
using general procedure B yielding 71 (540 mg, 27%) as an
1
amorphous solid. H NMR (400 MHz, CD3CN): δ (ppm) 8.09 (bs,
131.9 (q, J = 7.5, 3.7 Hz, 4C), 124.7 (q, J = 64.3, 32.0 Hz, 2C), 124.1
(d, J = 170.0 Hz, 2C), 5.5. GCMS temp ramp: 40 °C (5 min), 40−230
°C (15 °C/min); τ = 13.2 min; GCMS m/z (rel intensity) 108 (84),
127 (64), 173 (45), 188 (28), 207 (100), 319 (84), 333 (38).
Di(furan-2-yl)(methyl)silane (42).36 The product was obtained
using general procedure C yielding 52 (182 mg, 31%) as a viscous oil.
1H NMR (400 MHz, CDCl3): δ (ppm) 7.73 (d, J = 1.6 Hz, 2H), 6.85
(d, J = 3.3 Hz, 2H), 6.45 (dd, J = 3.3, 1.7 Hz, 2H), 4.97 (q, J = 7.7, 3.9
Hz, 1H), 0.65 (d, J = 3.8 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ
(ppm) 153.3 (2C), 147.7 (2C), 122.8 (2C), 109,7 (2C), 6.4. GCMS
temp ramp: 40 °C (5 min), 40−230 °C (15 °C/min); τ = 13.2 min;
GCMS m/z (rel intensity) 111 (35), 126 (15), 195 (100), 210 (48).
Methyldi(thiophene-2-yl)silane (43).36 The product was obtained
using general procedure C yielding 43 (354 mg, 51%) as a viscous oil.
1H NMR (400 MHz, CDCl3): δ (ppm) 7.73 (d, J = 4.0 Hz, 2H),
1H), 7.29 (d, J = 8.5, 2H), 6.93 (d, J = 6.7 Hz, 2H), 6.76 (dd, J = 10.9,
9.8 Hz, 1H), 5.61 (d, J = 9.8 Hz, 1H), 3.79 (s, 3H), 1.99 (s, 3H) . 13C
NMR (100 MHz, CD3CN): δ (ppm) 169.2, 159.3, 130.5 (2C), 129.2,
121.8, 115.1 (2C), 109.9, 55.9, 23.3. HRMS: C11H13NO2 [M + H+]
calcd 192.1025, found 192.1021.
(Z)-N-(4-Chlorostyryl)acetamide (72). The product was obtained
using general procedure B yielding 72 (580 mg, 29%) as an
1
amorphous solid. H NMR (400 MHz, CD3CN): δ (ppm) 8.25 (bs,
1H), 7.35 (d, J = 5.9, 2H), 7.31 (d, J = 6.6 Hz, 2H), 6.84 (dd, J = 10.7,
9.8 Hz, 1H), 5.67 (d, J = 9.8 Hz, 1H), 1.98 (s, 3H). 13C NMR (100
MHz, CD3CN): δ (ppm) 169.4, 135.6, 132.5, 130.8 (2C), 129.6 (2C),
123.7, 108.7, 23.2. HRMS: C10H10ClNO [M + H+] calcd 196.0530,
found 196.0521.
(Z)-N-(4-Fluorostyryl)acetamide (73). The product was obtained
using general procedure B yielding 73 (520 mg, 26%) as an
1
amorphous solid. H NMR (400 MHz, CD3CN): δ (ppm) 8.17 (bs,
7.46−7.47 (m, 2H), 7.26−7.29 (m, 2H), 5.30−5.33 (m, 1H), 0.78−
0.80 (m, 3H). 13C NMR (100 MHz, CDCl3): δ (ppm) 136.5 (2C),
133.5 (2C), 132.0 (2C), 128.4 (2C), 2.8. GCMS temp ramp: 40 °C (5
min), 40−230 °C (15 °C/min); τ = 10.1 min; GCMS m/z (rel
intensity) 95 (53), 137 (89), 149 (28), 163 (68), 178 (100).
Synthesis of Alkyldiphenylsilane 51−56. General Procedure
D.12a Rh(PPh3)3Cl (0.01 equiv) was dissolved in THF in the glovebox.
Alkene (1.0 equiv) was added and stirred overnight. The reaction was
concentrated and purified via flash chromatography with 0−2%
EtOAc/pentanes as eluent.
1H), 7.37 (q, J = 8.0, 4.0 Hz, 2H), 7.11 (t, J = 12.0 Hz, 2H), 6.83 (t, J
= 10.0 Hz, 1H), 5.64 (d, J = 9.6 Hz, 1H), 1.98 (s, 3H). 13C NMR (100
MHz, CD3CN): δ (ppm) 169.4, 165.5 (d, J = 242.0), 133.2 (d, J = 3.3
Hz), 131.1 (d, J = 8.0 Hz, 2C), 123.1, 116.4 (d, J = 21.4 Hz, 2C),
109.0, 23.2. HRMS: C10H10FNO [M + H+] calcd 180.0825, found
180.0820.
N-(2-Methylprop-1-en-1-yl)acetamide (75).33 The product was
obtained using a known literature procedure. The spectra are in accord
with the literature.33
(E)-tert-Butyl (2-(Benzyloxy)prop-1-en-1-yl)carbamate (76).34
The product was obtained using a known literature procedure. The
spectra are in accord with the literature.34
(3-(Benzyloxy)propyl)diphenylsilane (51).12a The product was
obtained using a known literature procedure. The spectra are in
accord with the literature.12a
(Z)-Ethyl 3-Acetamidoacrylate (77).35 The product was obtained
using a known literature procedure. The spectra are in accord with the
literature.36
Diphenyl(3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)silane (52).12a
The product was obtained using a known literature procedure. The
spectra are in accord with the literature.12a
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Featured Article
3-(Diphenylsilyl)propyl Acetate (53). The product was obtained
using general procedure D yielding 53 (427 mg, 75%) as a viscous oil.
1H NMR (400 MHz, CDCl3): δ (ppm) 7.55−7.58 (m, 4H), 7.35−
2.05 (m, 1H), 1.65−1.74 (m, 1H), 1.54−1.64 (m, 1H), 0.85 (t, J = 7.2,
3H), 0.66 (s, 3H). 13C NMR (100 MHz, CD3CN): δ (ppm) 175.2,
136.7, 136.3, 135.5 (2C), 135.4 (2C), 130.6, 130.5, 129.0 (2C), 128.9
(2C), 46.3, 44.1, 31.3, 21.9, 18.9, 12.8, 5.1. HRMS: C20H25NOSi [M +
H+] calcd 324.1784, found 324.1782.
7.43 (m, 6H), 4.88−4.90 (m, 1H), 4.07 (t, J = 6.7 Hz, 2H), 2.04 (s,
3H), 1.75−1.82 (m, 2H), 1.15−1.20 (m, 2H). 13C NMR (100 MHz,
CDCl3): δ (ppm) 171.1, 135.1 (4C), 133.8 (2C), 129.7 (2C), 128.0
(4C), 66.5, 23.7, 21.0, 8.4. HRMS: C17H20O2Si [M + H+] calcd
285.1130, found 285.1131.
3-(1-(Methyldiphenylsilyl)propyl)oxazolidin-2-one (35). The prod-
uct was obtained using general procedure F yielding 35 in (36.3 mg,
1
37%) as a viscous oil mixture with the trans enamide. H NMR (400
tert-Butyl(3-(diphenylsilyl)propoxy)diphenylsilane (54).12a The
product was obtained using a known literature procedure. The spectra
are in accord with the literature.12a
MHz, CD3CN): δ (ppm) 7.61−7.63 (m, 2H), 7.55−7.59 (m, 2H),
7.36−7.44 (m, 6H), 4.32−4.36 (m, 1H), 4.06−4.12 (m, 1H), 3.93−
4.00 (m, 1H), 3.34−3.41 (m, 1H), 3.15−3.22 (m, 1H), 1.72−1.80 (m,
1H), 1.57−1.67 (m, 1H), 0.88 (t, J = 7.2 Hz, 3H), 0.69 (s, 3H). 13C
NMR (100 MHz, CD3CN): δ (ppm) 159.6, 136.1, 135.9, 135.6 (2C),
135.5 (2C), 130.7 (2C), 129.1 (2C), 129.0 (2C), 62.6, 46.0, 43.7, 21.9,
12.7, 5.3. HRMS: C19H23NO2Si [M + Na+] calcd 348.1395, found
348.1392.
N-(1-(Methyldi-m-tolylsilyl)propyl)acetamide (44). The product
was obtained using general procedure E yielding 44 (84.1 mg, 86%) as
a viscous oil. 1H NMR (400 MHz, CD3CN): δ (ppm) 7.33−7.41 (m,
4H), 7.19−7.28 (m, 4H), 6.18 (d, J = 9.7, 1H), 4.02 (ddd, J = 16.3,
10.1, 3.5 Hz), 2.32 (s, 3H), 2.30 (s, 3H), 1.53−1.64 (m, 1H), 1.34−
1.46 (m 1H), 0.87 (t, J = 11.2 Hz, 3H), 0.60 (s, 3H). 13C NMR (100
MHz, CD3CN): δ (ppm) 170.2, 138.3, 138.1, 136.5, 136.4, 136.2
(2C), 132.7, 132.6, 131.1, 131.0, 128.8, 128.7, 40.5, 25.3, 23.0, 21.6
(2C), 12.6, 6.0. HRMS: C20H27NOSi [M + H+] calcd 326.1941, found
326.1944.
N-(1-(Methyldi-p-tolylsilyl)propyl)acetamide (45). The product
was obtained using general procedure E yielding 45 (72.6 mg, 74%)
as a viscous oil. 1H NMR (400 MHz, CD3CN): δ (ppm) 7.44 (dt, J =
10.1, 7.9 Hz, 4H), 7.19 (dd, J = 10.1, 7.9, 4H), 6.13 (d, J = 9.7 Hz,
1H), 3.99 (ddd, J = 14.8, 11.4, 3.5 Hz, 1H), 2.33 (s, 3H), 2.32 (s, 3H),
1.78 (s, 3H), 1.52−1.62 (m, 1H), 1.32−1.44 (m, 1H), 0.85 (t, J = 7.2
Hz, 3H), 0.57 (s, 3H). 13C NMR (100 MHz, CD3CN): δ (ppm)
170.2, 140.4, 140.3, 135.8 (2C), 135.7 (2C), 133.0, 132.9, 129.6 (2C),
129.5(2C), 40.5, 25.3, 23.0, 21.5 (2C), 12.6, 5.9. HRMS: C20H27NOSi
[M + Na+] calcd 348.1760, found 348.1754.
Diphenyl(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)silane (55). The
product was obtained using general procedure C yielding 55 (495 mg,
79%) as a viscous oil. 1H NMR (400 MHz, CDCl3): δ (ppm) 7.57 (d,
J = 7.8 Hz, 4H), 7.34−7.42, (m, 6H), 4.92 (t, J = 3.6 Hz, 1H), 4.54 (t,
J = 3.8 Hz, 1H), 3.96 (q, J = 17.2, 9.3 Hz, 1H), 3.77 (t, J = 8.6 Hz,
1H), 3.56 (q, J = 18.9, 8.7 Hz, 1H), 3.40−3.44 (m, 1H), 1.47−1.77
(m, 8H). 13C NMR (100 MHz, CDCl3): δ (ppm) 135.1 (4C), 133.9
(2C), 129.6 (2C), 128.0 (4C), 98.4, 64.2, 62.1, 30.7, 25.4, 19.5, 14.1.
HRMS: C19H24O2Si [M + Na+] calcd 335.1444, found 335.1448.
Hexyldiphenylsilane (56).12a The product was obtained using a
known literature procedure. The spectra are in accord with the
literature.12a
Hydrosilylation of Enamides 27, 32−35, 44−50, 58−64, 78−
88, and 90. General Procedure E. Rh(cod)2BF4 (0.003 mmol) and
P(OPh)3 (0.006 mmol) were dissolved in DCE (0.15 mL), and the
mixture was stirred for 5 min. Enamide (0.30 mmol) and silane (0.30
mmol) in DCE (0.10 mL) were added in that order in the glovebox.
The mixture was placed in preheated oil bath at 65 °C for 18 h. The
reaction was cooled to room temperature and concentrated. The crude
mixture was purified via flash chromatography using 40−60% EtOAc/
pentanes as eluent.
General Procedure F. Rh2OAc4 (0.003 mmol) were dissolved in
DCE (0.25 mL). Enamide (0.30 mmol) and silane (0.30 mmol) were
added in that order in the glovebox. The mixture was placed in a
ο
preheated oil bath at 65 C and stirred for 18 h. The reaction was
cooled to room temperature and concentrated. The crude mixture was
purified via flash chromatography using 40−60% EtOAc/pentanes as
eluent.
N-(1-(Methyldi-o-tolylsilyl)propyl)acetamide (46). The product
was obtained using general procedure E yielding 46 (8.0 mg, 8%) as
a viscous oil. 1H NMR (400 MHz, CD3CN): δ (ppm) 7.62 (dt, J = 7.4,
1.4 Hz, 2H), 7.08−7.33 (m, 6H), 5.99 (d, J = 9.5 Hz, 1H), 4.27 (ddd, J
= 13.5, 10.3, 3.2 Hz, 1H), 2.15 (s, 3H), 2.09 (s, 3H), 2.07 (s, 3H),
1.50−1.56 (m, 1H), 1.28−1.38 (m, 1H), 0.87 (t, J = 7.2 Hz, 3H), 0.65
(s, 3H). 13C NMR (100 MHz, CD3CN): δ (ppm) 170.4, 145.0, 144.8,
136.0 (2C), 135.7 (2C), 131.0, 130.9, 130.7, 130.6, 126.2, 126.0, 39.9,
30.8, 25.7, 23.2, 23.1, 12.4, 4.3. HRMS: C20H27NOSi [M + Na+] calcd
348.1759, found 348.1759.
N-(1-(Methyldiphenylsilyl)ethyl)acetamide (27). The product was
obtained using general procedure E yielding 32 (66.0 mg, 78%) as a
1
viscous oil. H NMR (400 MHz, CD3CN): δ (ppm) 7.59−7.63 (m,
4H), 7.36−7.42 (m, 6H), 6.48 (d, J = 8.8 Hz, 1H), 4.17−4.26 (m,
1H), 1.80 (s, 3H), 1.18 (d, J = 7.6 Hz, 3H), 0.68 (s, 3H). 13C NMR
(100 MHz, CD3CN): δ (ppm) 169.9, 136.3, 136.2, 135.7 (2C), 135.6
(2C), 130.5, 130.4, 128.9 (2C), 128.8 (2C), 33.5, 23.1, 17.4, 6.3.
HRMS: C17H21NOSi [M + H+] calcd 284.1471, found 284.1473.
N-(1-(Methyldiphenylsilyl)propyl)acetamide (32). The product
was obtained using general procedure E yielding 32 (89.2 mg, 97%)
N-(1-(Bis(3,5-dimethylphenyl)(methyl)silyl)propyl)acetamide
(47). The product was obtained using general procedure E yielding 47
1
(91.0 mg, 86%) as a viscous oil. H NMR (400 MHz, CD3CN): δ
1
as a viscous oil. H NMR (400 MHz, CD3CN): δ (ppm) 7.54−7.60
(ppm) 7.15 (d, J = 11.68 Hz, 4H), 7.04 (d, J = 9.2 Hz, 2H), 6.02 (d, J
= 9.8 Hz, 1H), 3.97 (ddd, J = 13.3, 10.2, 3.4, 1H), 2.28 (s, 3H), 2.26
(s, 3H), 1.78 (s, 3H), 1.52−1.58 (m, 1H), 1.32−1.40 (m, 1H), 0.85 (t,
J = 7.3 Hz, 3H), 0.55 (s, 3H). 13C NMR (100 MHz, CD3CN): δ
(ppm) 170.2, 138.2 (2C), 138.0 (2C), 136.5, 136.4, 133.3(4C), 132.0,
131.9, 40.5, 25.4, 23.1, 21.5 (4C), 12.6, 6.0. HRMS: C22H31NOSi [M +
Na+] calcd 376.2073, found 376.2088.
(m, 4H), 7.33−7.43 (m, 6H), 6.18 (d, J = 9.2 Hz, 1H), 4.03, (ddd, J =
13.6, 10.0, 3.6 Hz, 1H), 1.78 (s, 3H), 1.55−1.64 (m, 1H), 1.35−1.47
(m, 1H), 0.86 (t, J = 7.2 Hz, 3H), 0.62 (s, 3H). 13C NMR (100 MHz,
CD3CN): δ (ppm) 170.3, 136.6, 136.5, 135.7 (2C), 135.6 (2C), 130.5,
130.4, 128.9 (2C), 128.8 (2C), 40.4, 25.2, 23.0, 12.5, 6.0. HRMS:
C18H23NOSi [M + H+] calcd 298.1628, found 298.1625.
tert-Butyl (1-(Methyldiphenylsilyl)propyl)carbamate (33). The
N-(1-(Methylbis(4-(trifluoromethyl)phenyl)silyl)propyl)acetamide
(48). The product was obtained using general procedure E yielding 47
product was obtained using general procedure E yielding 33 (107
1
1
(107.8 mg, 83%) as a viscous oil. H NMR (400 MHz, CD3CN): δ
mg, 54%) as a viscous oil. H NMR (400 MHz, CD3CN): δ (ppm)
(ppm) 7.73−7.77 (m, 4H), 7.64−7.68 (m, 4H), 6.36 (d, J = 9.2 Hz,
1H), 3.99 (dd, J = 15.0, 9.5, 3.6 Hz, 1H), 1.76 (s, 3H), 1.53−1.61 (m,
1H), 1.41−1.50 (m, 1H), 0.87 (t, J = 7.2 Hz, 3H), 0.71 (s, 3H). 13C
NMR (100 MHz, CD3CN): δ (ppm) 170.5, 141.9, 141.7, 136.4 (2C),
136.2 (2C), 131.7 (dd, J = 63.1, 7.7 Hz, 2C), 125.4 (d, J = 269.6 Hz),
125.4 (d, J = 269.4 Hz), 125.3 (q, J = 7.6, 3.8 Hz, 2C), 125.2 (q, J =
7.7, 3.9 Hz, 2C), 40.3, 25.0, 22.8, 12.5, 6.1. HRMS: C20H21F6NOSi [M
+ H+] calcd 434.1376, found 434.1373.
7.54−7.58 (m, 4H), 7.33−7.43 (m, 6H), 4.97 (d, 9.8 Hz, 1H), 3.64
(dt, J = 11.1, 3.6 Hz, 1H), 1.51−1.61 (m, 1H), 1.33−1.41 (m, 10H),
0.88 (t, J = 7.3 Hz, 3H), 0.61 (s, 3H). 13C NMR (100 MHz, CD3CN):
δ (ppm) 157.3, 136.6, 136.5, 135.6 (4C), 130.5, 130.4, 128.9 (2C),
128.8 (2C), 78.8, 41.6, 28.6, 25.5, 12.4, 6.2. HRMS: C21H29NO2Si [M
+ Na+] calcd 378.1865, found 378.1862.
1-(1-(Methyldiphenylsilyl)propyl)pyrrolidin-2-one (34). The prod-
uct was obtained using general procedure E yielding 34 (75.4 mg,
78%) as a viscous oil. 1H NMR (400 MHz, CD3CN): δ (ppm) 7.53−
7.62 (m, 2H), 7.33−7.40 (m, 2H), 4.10 (dd, J = 12.2, 3.7 Hz, 1H),
3.18−3.21 (m, 1H), 2.95−3.00 (m, 1H), 2.11−2.19 (m, 1H), 1.93−
N-(1-(Di(furan-2-yl)(methyl)silyl)propyl)acetamide (49). The
product was obtained using general procedure E yielding 49 (57.1
1
mg, 69%) as a viscous oil. H NMR (400 MHz, CD3CN): δ (ppm)
5903
dx.doi.org/10.1021/jo300904z | J. Org. Chem. 2012, 77, 5894−5906

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Featured Article
7.76 (ddd, J = 5.6, 1.6, 0.5 Hz, 2H), 6.84 (ddd, J = 11.5, 3.3, 0.5 Hz,
2H), 6.45−6.47 (m, 2H), 6.33 (d, J = 7.8 Hz, 1H), 3.69 (ddd, 13.1,
9.2, 3.9 Hz, 1H), 1.84 (s, 3H), 1.58−1.68 (m, 1H), 1.40−1.51 (m,
1H), 0.87 (t, J = 7.3 Hz, 3H), 0.55 (s, 3H). 13C NMR (100 MHz,
CD3CN): δ (ppm) 170.5, 155.8, 155.7, 148.7 (2C), 123.7, 123.5,
110.8 (2C), 40.9, 24.8, 22.8, 12.3, 6.0. HRMS: C14H19NO3Si [M +
Na+] calcd 300.1031, found 300.1037.
64.5, 63.0, 32.8, 31.5, 26.2, 20.5, 17.4, 13.0. Since it was a mixture the
last 3 carbons and 12 hydrogens were not assigned HRMS:
C23H31NO3Si [M + H+] calcd 398.2152, found 398.2145.
N-(1-(Hexyldiphenylsilyl)ethyl)acetamide (63). The product was
obtained using general procedure F yielding 63 (77.5 mg, 73%) as a
1
viscous oil. H NMR (400 MHz, CDCl3): δ (ppm) 7.51−7.57 (m,
4H), 7.37−7.45 (m, 6H), 5.17 (d, J = 9.9 Hz, 1H), 4.29−4.37 (m,
1H), 1.86 (s, 3H), 1.18−1.30 (m, 11H), 1.08−1.12 (m, 2H), 0.83 (t, J
= 12.4 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ (ppm) 169.3, 135.4
(2C), 135.3 (2C), 133.1, 132.6, 129.8, 129.7, 128.1 (2C), 128.0 (2C),
33.2, 31.6, 31.3, 23.5, 23.2, 22.5, 17.2, 14.0, 11.4. HRMS: C22H31NOSi
[M + Na+] calcd 376.2072, found 376.2066.
N-(1-(Methyldi(thiophene-2-yl)silyl)propyl)acetamide (50). The
product was obtained using general procedure E yielding 50 (69.5
1
mg, 75%) as a viscous oil: H NMR (400 MHz, CD3CN): δ (ppm)
7.75 (ddd, J = 10.5, 4.6, 3.8 Hz, 2H), 7.43 (ddd, J = 25.6, 3.4, 0.9 Hz,
2H), 7.22−7.27 (m, 2H), 6.27 (d, J = 8.6 Hz, 1H), 3.77 (ddd, J = 13.0,
9.6, 3.5 Hz, 1H), 1.84 (s, 3H), 1.61−1.71 (m, 1H), 1.39−1.51 (m,
1H), 0.88 (t, J = 7.2 Hz, 3H), 0.69 (s, 3H). 13C NMR (100 MHz,
CD3CN): δ (ppm) 170.5, 137.7, 137.6, 135.2, 135.0, 133.2, 133.1,
129.4 (2C), 42.3, 25.0, 22.7, 12.5, 3.1. HRMS: C14H19NOS2Si [M +
Na+] calcd 332.0575, found 332.0573.
N-(1-(Triethylsilyl)ethyl)acetamide (64). The product was obtained
using general procedure F yielding 64 (45.0 mg, 75%) as a viscous oil.
1H NMR (400 MHz, CD3CN): δ (ppm) 6.07 (bs, 1H), 3.55−3.64 (m,
1H), 1.83 (s, 3H), 1.10 (d, J = 7.7 Hz, 3H), 0.96 (t, J = 8.1 Hz, 9 H),
0.59 (q, J = 8.5, 4.6 Hz, 6H). 13C NMR (100 MHz, CD3CN): δ (ppm)
169.6, 33.1, 23.2, 17.3, 7.8 (3C), 2.6 (3C). HRMS: C10H23NOSi [M +
H+] calcd 202.1628, found 202.1624.
N-(1-((3-(Benzyloxy)propyl)diphenylsilyl)ethyl)acetamide (58).
The product was obtained using general procedure E yielding 58
1
(93.0 mg, 74%) as a viscous oil. H NMR (400 MHz, CD3CN): δ
1-(Methyldiphenylsilyl)ethyl Acetate (78). The product was
obtained using general procedure F yielding 78 (47.2 mg, 55%) as a
viscous oil. H NMR (400 MHz, CD3CN): δ (ppm) 7.54−7.63 (m,
4H), 7.37−7.46 (m, 6H), 5.27 (q, J = 14.9, 7.5 Hz, 1H), 1.91 (s, 3H),
1.27 (d, J = 10.2 Hz, 3H), 0.62 (s, 3H). 13C NMR (100 MHz,
CD3CN): δ (ppm) 171.5, 135.8 (2C), 135.7 (2C), 135.4, 135.2, 130.7
(2C), 129.0 (4C), 63.3, 21.3, 16.8, 6.5. HRMS: C17H20O2Si [M + Na+]
calcd 307.1131, found 307.1121.
(ppm) 7.55 (m, 4H), 7.25−7.46 (m, 11H), 6.12 (d, J = 6.9 Hz, 1H),
4.41 (s, 2H), 4.17−4.26 (m, 1H), 3.41 (t, J = 6.5 Hz, 2H), 1.76 (s,
3H), 1.55−1.63 (m, 2H), 1.17−1.21 (m, 2H), 1.13 (dd, J = 7.6 Hz,
3H). 13C NMR (100 MHz, CD3CN): δ (ppm) 169.8, 140.0, 136.4
(2C), 136.2 (2C), 134.8, 134.5, 130.6 (2C), 129.2 (2C), 128.9 (4C),
128.5 (2C), 128.3, 73.5, 73.1, 32.9, 24.8, 23.2, 17.7, 8.1. HRMS:
C26H31NO2Si [M + H+] calcd 418.2203, found 418.2199.
1
N-(1-(Methyldiphenylsilyl)-2-phenylethyl)acetamide (79). The
N-(1-(Diphenyl(3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)silyl)-
ethyl)acetamide (59). The product was obtained using general
product was obtained using general procedure F yielding 79 (84.3
1
1
procedure E yielding 59 (96.2 mg, 78%) as a viscous oil. H NMR
mg, 78%) as a viscous oil. H NMR (400 MHz, CDCl3): δ (ppm)
(400 MHz, CDCl3): δ (ppm) 7.51−7.57 (m, 4H), 7.37−7.42 (m, 6H),
5.19 (d, J = 10.0, 1H), 4.48−4.51 (m, 1H), 4.30−4.39 (m, 1H), 3.66−
3.85 (m, 1H), 3.66−3.69 (m, 1H), 3.43−3.49 (m, 1H), 3.33−3.36 (m,
1H), 1.87 (d, J = 1.6 Hz, 3H), 1.76−1.83 (m, 1H), 1.48−1.71 (8H),
1.14−1.20 (m, 5H). 13C NMR (100 MHz, CDCl3): δ (ppm) 169.3,
135.3 (4C), 132.8, 132.7, 129.8 (2C), 128.1 (4C), 98.8, 69.8, 62.4,
31.6, 30.7, 25.4, 23.6, 23.4, 19.7, 17.1, 7.5. HRMS: C24H33NO3Si [M +
Na+] calcd 434.2127, found 434.2122.
7.60−7.66 (m, 4H), 7.36−7.48 (m, 6H), 7.09−7.27 (m, 5H), 5.20 (d, J
= 9.3, 1H), 4.48 (ddd, J = 14.2, 9.8, 4.4 Hz, 1H), 3.01 (dd, J = 14.5, 4.4
Hz, 1H), 2.69 (dd, J = 14.4, 11.1 Hz, 1H), 1.74 (s, 3H), 0.61 (s, 3H).
13C NMR (100 MHz, CDCl3): 169.2, 139.3, 134.9 (2C), 134.8 (2C),
134.5, 134.3, 129.7 (2C), 128.8 (2C), 128.2 (2C), 128.1 (2C), 128.0
(2C), 126.2, 39.5, 37.3, 23.1, 5.2. δ (ppm) HRMS: C23H25NOSi [M +
H+] calcd 360.1784, found 360.1781.
N-(2-(Methyldiphenylsilyl)-1-phenylethyl)acetamide (80). The
3-((1-Acetamidoethyl)diphenylsilyl)propyl Acetate (60). The
product was obtained using general procedure F yielding 80 (96.7
1
product was obtained using general procedure E yielding 60 (67.8
mg, 90%) as a viscous oil. H NMR (400 MHz, CD3CN): δ (ppm)
1
mg, 61%) as a viscous oil. H NMR (400 MHz, CDCl3): δ (ppm)
7.54−7.57 (m, 2H), 7.47−7.50 (m, 2H), 7.31−7.41 (m, 6H), 7.18−
7.27 (m, 5H), 6.75 (d, J = 8.2 Hz, 1H), 5.01−5.07 (m, 1H), 1.78 (dd, J
= 14.8, 9.6 Hz, 1H), 1.64 (dd, J = 14.9, 5.9 Hz, 1H), 1.60 (s, 3H), 0.46
(s, 3H). 13C NMR (100 MHz, CD3CN): δ (ppm) 169.3, 146.7, 138.1,
137.8, 135.4 (2C), 135.2 (2C), 130.3, 130.2, 129.3 (2C), 128.9 (4C),
127.8, 127.2 (2C), 51.0, 23.6, 22.9, 4.3. HRMS: C23H25NOSi [M +
H+] calcd 360.1784, found 360.1783.
7.50−7.56 (m, 4H), 7.37−7.47 (m, 6H), 5.20 (d, J = 9.8 Hz, 1H),
4.30−4.38 (m, 1H), 3.98 (dt, J = 6.8, 1.0 Hz, 2H), 1.99 (s, 3H), 1.87
(s, 3H), 1.59−1.67 (m, 2H), 1.19 (d, J = 7.5 Hz, 3H), 1.09−1.14 (m,
2H). 13C NMR (100 MHz, CDCl3): δ (ppm) 171.0, 169.3, 135.3
(4C), 132.3, 131.9, 129.98 (2C), 128.2 (4C), 66.6, 31.5, 23.4, 22.7,
20.9, 17.1, 7.5. HRMS: C21H27NO3Si [M + H+] calcd 370.1839, found
370.1838.
N-(1-(Methyldiphenylsilyl)-2-(p-tolyl)ethyl)acetamide (81). The
N-(1-((3-((tert-Butyldiphenylsilyl)oxy)propyl)diphenylsilyl)ethyl)-
product was obtained using general procedure F yielding 81 (81.9
mg, 73%) as an amorphous solid. H NMR (400 MHz, CDCl3): δ
1
acetamide (61). The product was obtained using general procedure E
1
yielding 61 (105 mg, 62%) as a viscous oil. H NMR (400 MHz,
(ppm) 7.57−7.63 (m, 4H), 7.37−7.44 (m, 6H), 7.00−7.06 (m, 4H),
5.26 (bs, 1H), 4.43−4.50 (m, 1H), 2.98 (dd, J = 14.4, 4.3 Hz, 1H),
2.65 (dd, J = 14.4, 11.1, 1H), 2.30 (s, 3H), 1.74 (s, 3H), 0.62 (s, 3H).
13C NMR (100 MHz, CDCl3): δ (ppm) 169.2, 136.1, 135.6, 134.9
(2C), 134.8 (2C), 134.5, 134.4, 129.6 (2C), 128.9 (2C), 128.6 (2C),
128.0 (4C), 39.6, 36.9, 23.1, 21.0, 5.2. HRMS: C24H27NOSi [M +
Na+] calcd 396.1760, found 396.1754.
N-(2-(4-Chlorophenyl)-1-(methyldiphenylsilyl)ethyl)acetamide
(83). The product was obtained using general procedure F yielding 83
(75.9 mg, 64%) as an amorphous solid. 1H NMR (400 MHz, CDCl3):
δ (ppm) 7.55−7.61 (m, 4H), 7.37−7.47 (m, 6H), 7.17 (d, J = 8.4 Hz,
2H), 7.04 (d, J = 8.4 Hz, 2H), 5.28 (d, J = 9.8 Hz, 1H), 4.43−4.49 (m,
1H), 2.95 (dd, J = 14.5, 4.4 Hz, 1H), 2.64 (dd, J = 14.4, 11.2 Hz, 1H),
1.73 (s, 3H), 0.62 (s, 3H). 13C NMR (100 MHz, CDCl3): δ (ppm)
169.2, 137.8, 134.9 (2C), 134.7 (2C), 134.1, 133.9, 131.9, 130.1 (2C),
129.8, 129.7, 128.2 (2C), 128.1 (4C), 39.3, 36.8, 23.0, 5.4. HRMS:
C23H24ClNOSi [M + Na+] calcd 416.1213, found 416.1217.
CDCl3): δ (ppm) 7.65 (m, 4H), 7.55 (m, 4H), 7.34−7.48 (12H), 5.17
(d, J = 9.9 Hz, 1H), 4.31−4.39 (m, 1H), 3.59−3.68 (m, 2H), 1.87 (s,
3H), 1.55−1.63 (m, 2H), 1.11−1.24 (m, 5H), 1.06 (s, 9H). 13C NMR
(100 MHz, CDCl3): δ (ppm) 169.4, 135.5 (4C), 135.4 (4C), 134.0
(2C), 132.9, 132.4, 129.9 (2C), 129.5 (2C), 128.2 (2C), 128.1 (2C),
127.6 (4C), 66.2, 31.7, 26.9 (3C), 26.5, 23.5, 19.2, 17.2, 7.2. HRMS:
C35H43NO2Si2 [M + Na+] calcd 588.2729, found 588.2720.
N-(1-(Diphenyl(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)silyl)-
ethyl)acetamide (62). The product was obtained using general
procedure E yielding the viscous oil of 62 (83.7 mg, 70%) as
1
diastereomeric mixture. Compound A: H NMR (400 MHz, CDCl3):
δ (ppm) inter alia, 6.50 (d, J = 9.2 Hz, 1H), 3.80−3.87 (m, 2H), 3.64−
3.74 (m, 2H), 1.80 (s, 3H), 1.16 (d, J = 2.0 Hz, 3H). 13C NMR (100
MHz, CDCl3): δ (ppm) inter alia, 169.8, 136.2 (2C), 136.1 (2C),
135.0, 134.8, 128.9 (4C), 100.2, 64.7, 63.7, 33.0, 31.5, 26.2, 21.0, 17.5,
13.3. Compound B: 1H NMR (400 MHz, CDCl3): δ (ppm) inter alia,
6.36 (d, J = 9.2 Hz, 1H), 3.48−3.54 (m, 2H), 3.32−3.40 (m, 2H), 1.79
(s, 3H), 1.14 (d, J = 1.9 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ
(ppm) inter alia, 169.8, 136.1 (4C), 134.8, 134.7, 128.9 (4C), 99.6,
N-(2-(4-Fluorophenyl)-1-(methyldiphenylsilyl)ethyl)acetamide
(84). The product was obtained using general procedure F yielding 84
(68.7 mg, 61%) as an amorphous solid. 1H NMR (400 MHz,
5904
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Featured Article
CD3CN): δ (ppm) 7.62−7.65 (m, 2H), 7.57−7.60 (m, 2H), 7.34−
7.46 (m, 6H), 7.10−7.15 (m, 2H), 6.91−6.97 (m, 2H), 6.28 (d, J = 9.8
Hz, 1H), 4.33 (ddd, J = 15.5, 10.0, 3.4 Hz, 1H), 2.84 (dd, J = 14.3, 3.4
Hz, 1H), 2.61 (dd, J = 14.2, 12.1 Hz, 1H), 1.60 (s, 3H), 0.65 (s, 3H).
13C NMR (100 MHz, CD3CN): δ (ppm) 169.7, 162.3 (d, J = 239.7
Hz), 137.4 (d, J = 3.2 Hz), 136.2, 136.1, 135.8 (2C), 135.7 (2C), 131.5
(d, J = 7.9 Hz, 2C), 130.6, 130.5, 129.0 (2C), 128.8 (2C), 115.5 (d, J =
21.1, 2C), 40.7, 36.9, 22.8, 6.0. HRMS: C23H24FNOSi [M + H+] calcd
378.1690, found 378.1693.
CDCl3): δ (ppm) 169.0, 138.4, 137.6, 135.4 (2C), 135.3 (2C), 132.8,
132.4, 132.0, 130.1 (2C), 129.9 (2C), 129.2 (2C), 128.3 (2C), 128.2
(2C), 128.1 (2C), 127.6 (2C), 127.5, 72.7, 72.6, 37.9, 37.0, 23.6, 23.1,
7.7. HRMS: C32H34ClNO2Si [M + Na+] calcd 550.1945, found
550.1955.
tert-Butyl ((2S)-1-((1-((3-(Benzyloxy)propyl)diphenylsilyl)propyl)-
amino)-1-oxo-3-phenylpropan-2-yl)carbamate (95). The product
was obtained using general procedure F yielding 95 (143 mg, 75%) as
1
a viscous oil. Compound A: H NMR (400 MHz, CDCl3): δ (ppm)
inter alia, 5.47 (d, J = 9.9 Hz, 1H), 5.03 (bs, 1H), 0.75 (m, 2H). 13C
NMR (100 MHz, CDCl3): δ (ppm) inter alia, 170.9, 155.2, 136.8
(2C), 132.8, 132.7, 24.6, 23.5, 7.6. Compound B: 1H NMR (400 MHz,
CDCl3): δ (ppm) inter alia, 5.54 (d, J = 7.0 Hz, 1H), 4.82 (bs, 1H),
0.83 (t, J = 7.2 Hz, 2H). 13C NMR (100 MHz, CDCl3): δ (ppm) inter
alia, 170.5, 154.9, 136.6 (2C), 132.5, 132.4, 24.5, 23.5, 7.4. Since it was
a mixture of epimers, the last 30 carbons and 44 hydrogens were not
assigned. HRMS: C39H48N2O4Si [M + Na+] calcd 659.3281, found
659.3276.
tert-Butyl 2-(Methyldiphenylsilyl)pyrrolidine-1-carboxylate
(85).15a The product was obtained using general procedure F yielding
85 (63.8 mg, 58%) as a viscous oil.
tert-Butyl ((2S)-1-((1-(Methyldiphenylsilyl)propyl)amino)-1-oxo-
3-phenylpropan-2-yl)carbamate (90). The product was obtained
using general procedure F yielding 90 (136 mg, 90%) as a viscous oil.
Compound A: 1H NMR (400 MHz, CD3CN): inter alia, δ (ppm) 6.37
(d, J = 9.9 Hz, 1H), 5.51 (d, J = 7.9 Hz, 1H), 2.98 (dd, J = 14.0, 5.4
Hz, 1H), 2.79 (dd, J = 14.1, 4.8 Hz, 1H), 0.86 (t, J = 7.2 Hz, 3H), 0.60
(s, 3H). 13C NMR (100 MHz, CD3CN): δ (ppm) inter alia, 172.4,
156.4, 57.1, 25.3, −5.7. Compound B: 1H NMR (400 MHz, CD3CN):
δ (ppm) inter alia, 6.31 (d, J = 9.6 Hz, 1H), 5.44 (d, J = 7.4 Hz, 1H),
2.59−2.71 (m, 2H), 0.77 (t, J = 7.1 Hz, 3H), 0.61 (s, 3H), 13C NMR
(100 MHz, CD3CN): δ (ppm) inter alia, 172.1, 156.2, 56.9, 25.1, −5.9.
Since it contained a mixture of epimers, the last 25 carbons and 28
hydrogens were not assigned. HRMS: C30H38N2O3Si [M + Na+] calcd
525.2549, found 525.2552.
Sequential Hydrosilylation (58 and 91−95). General Proce-
dure G. Rh(cod)2BF4 (0.003 mmol) and P(OPh)3 (0.006 mmol) were
dissolved in DCE (0.15 mL), and the mixture was stirred for 5 min.
((Allyloxy)methyl)benzene (0.30 mmol) and Ph2SiH2 (0.30 mmol)
were added in that respective order and stirred for 15 min in the
glovebox. Enamide (0.30 mmol) in DCE (0.10 mL) was added, placed
in a preheated oil bath at 65 οC, and stirred for 18 h. The reaction was
cooled to room temperature and concentrated. The crude mixture was
purified via flash chromatography.
N-(1-((3-(Benzyloxy)propyl)diphenylsilyl)propyl)acetamide (91).
General Procedure H. Rh(cod)2BF4 (0.003 mmol) and P(OPh)3
(0.006 mmol) were dissolved in DCE (0.15 mL), and the mixture was
stirred for 5 min. ((Allyloxy)methyl)benzene (0.36 mmol) and
Ph2SiH2 (0.36 mmol) were added in that order and the mixture
stirred for 15 min in the glovebox. Enamide (0.30 mmol) in DCE
The product was obtained using general procedure F yielding 91
1
(110 mg, 85%) as a viscous oil. H NMR (400 MHz, CD3CN): δ
(ppm) 7.52−7.57 (m, 4H), 7.25−7.45 (m, 11H), 5.96 (d, J = 10.1 Hz,
1H), 4.41 (s, 2H), 4.08 (ddd, J = 13.4, 10.2, 3.3 Hz, 1H), 3.40 (t, J =
6.5 Hz, 2H), 1.79 (s, 3H), 1.51−1.67 (m, 3H), 1.26−1.37 (m, 1H),
1.3−1.6 (m, 2H), 0.84 (t, J = 7.2 Hz, 3H). 13C NMR (100 MHz,
CD3CN): δ (ppm) 170.3, 140.1, 136.4 (2C), 136.2 (2C), 135.1, 134.8,
130.6, 130.5, 129.2 (2C), 128.9 (4C), 128.5 (2C), 128.3, 73.5, 73.0,
39.9, 25.4, 24.8, 23.0, 12.5, 8.1. HRMS: C27H33NO2Si [M + Na+] calcd
454.2179, found 454.2174.
ο
(0.10 mL) was added, placed in a preheated oil bath at 65 C, and
stirred for 18 h. The reaction was cooled to room temperature and
concentrated. The crude mixture was purified via flash chromatog-
raphy.
N-(1-(Diphenyl(3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)silyl)-
ethyl)acetamide (59). The product was obtained using general
procedure G yielding 59 (53.0 mg, 43%). When general procedure H
was used, silylated product 59 was achieved in 79.1 mg, 64% isolated
yield. Characterization is reported above.
N-(1-((3-(Benzyloxy)propyl)diphenylsilyl)propyl)acetamide (91).
The product was obtained using general procedure G yielding 59
(95.8 mg, 74%). Characterization is reported above.
tert-Butyl ((2S)-1-((1-((3-(Benzyloxy)propyl)diphenylsilyl)propyl)-
amino)-1-oxo-3-phenylpropan-2-yl)carbamate (95). The product
was obtained using general procedure G yielding 94 (133.9 mg, 70%).
When using general procedure H, silylated product 94 was achieved in
134.1 mg, 70% isolated yield. Characterization is reported above.
N-(1-((3-(Benzyloxy)propyl)diphenylsilyl)-2-phenylethyl)-
acetamide (92). The product was obtained using general procedure F
1
yielding 92 (55.9 mg, 38%) as a viscous oil. H NMR (400 MHz,
CD3CN): δ (ppm) 7.59−7.64 (m, 4H), 7.12−7.45 (m, 16H), 6.11 (d,
J = 10.0 Hz, 1H), 4.39−4.45 (m, 3H), 3.41 (t, J = 6.5 Hz, 2H), 2.90
(dd, J = 14.2, 3.1 Hz, 1H), 2.52 (dd, J = 14.2, 12.4 Hz, 1H), 1.55−1.63
(m, 5H), 1.21 (t, J = 8.7 Hz, 2H). 13C NMR (100 MHz, CD3CN): δ
(ppm) 169.6, 141.4, 140.1, 136.5 (2C), 136.3 (2C), 134.8, 134.4,
130.7 (2C), 129.8 (2C), 129.2 (2C), 129.0 (6C), 128.5 (2C), 128.3,
126.9, 73.5, 73.1, 40.2, 38.0, 24.8, 22.8, 8.2. HRMS: C32H35NO2Si [M
+ Na+] calcd 516.2335, found 516.2340.
N-(1-((3-(Benzyloxy)propyl)diphenylsilyl)-2-(4-fluorophenyl)-
ethyl)acetamide (93). The product was obtained using general
1
ASSOCIATED CONTENT
procedure F yielding 93 (106 mg, 69%) as an amorphous solid. H
■
NMR (400 MHz, CDCl3): δ (ppm) 7.54−7.58 (m, 4H), 7.37−7.43
(m, 6H), 7.23−7.29 (m, 5H), 7.03−7.09 (m, 2H), 6.86−6.90 (m, 2H),
5.21 (d, J = 10.2 Hz, 1H), 4.53−4.60 (m, 1H), 4.42 (s, 2H), 3.40 (t, J
= 6.4 Hz, 2H), 2.95 (dd, J = 14.5, 4.2 Hz, 1H), 2.52 (dd, J = 14.5, 11.3
Hz, 1H), 1.71, (s, 3H), 1.59−1.66 (m, 2H), 1.15−1.19 (m, 2H). 13C
NMR (100 MHz, CDCl3): δ (ppm) 169.1, 161.4 (d, J = 242.3 Hz),
138.4 (2C), 135.4 (2C), 135.2 (2C), 134.8 (d, J = 3.1 Hz), 132.8,
132.5, 130.1 (d, J = 7.8 Hz, 2C), 129.8, 128.3 (2C), 128.1 (4C), 127.6
(2C), 127.4, 114.8 (d, J = 21.0 Hz, 2C), 72.6 (2C), 38.2, 36.8, 23.6,
23.0, 7.7. HRMS: C32H34FNO2Si [M + H+] calcd 512.2377, found
512.2378.
S
* Supporting Information
1H and 13C NMR of enamides and hydrosilylated products.
This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: ts@chem.au.dk.
ACKNOWLEDGMENTS
N-(1-((3-(Benzyloxy)propyl)diphenylsilyl)-2-(4-chlorophenyl)-
■
ethyl)acetamide (94). The product was obtained using general
We thank Dr. Dac
́
il Hernan
́
dez for helpful discussions on the
1
procedure F yielding 94 (44.8 mg, 28%) as a viscous oil. H NMR
project and contribution of silanes used in this project. We are
also deeply appreciative for financial support from the Danish
National Research Foundation, the Danish Council for
Independent Research/Natural Sciences, and Aarhus Univer-
sity.
(400 MHz, CDCl3): δ (ppm) 7.54−7.58 (4H), 7.27−7.47 (11H), 7.17
(d, J = 8.3 Hz, 2H), 7.03 (d, J = 8.3 Hz, 2H), 5.16 (d, J = 10.1 Hz,
1H), 4.55−4.61 (m, 1H), 4.43 (s, 2H), 3.40 (t, J = 6.4 Hz, 2H), 2.96
(dd, J = 14.5, 4.3 Hz, 1H), 2.53 (dd, J = 14.5, 11.3, 1H), 1.72 (s, 3H),
1.59−1.68 (m, 2H), 1.18 (t, J = 3.8 Hz, 2H). 13C NMR (100 MHz,
5905
dx.doi.org/10.1021/jo300904z | J. Org. Chem. 2012, 77, 5894−5906

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