Photoinduced Multicomponent Synthesis of α-Silyloxy Acrylamides, an Unexplored Class of Silyl Enol Ethers

Article abstract of DOI:10.1021/acs.orglett.8b00009

The photoinduced, multicomponent reaction of α-diazoketones, silanols, and isocyanides affords α-silyloxy acrylamides, formally derived from α-keto amides. The presence of a secondary amido group makes classic preparative methods for silyl enol ethers unfeasible in this case, while the mild conditions required by this photochemical approach allow their synthesis in good yields; moreover, the general structure can be easily modified by varying each component of the multicomponent reaction. Fine-tuning of the reaction conditions (i.e., solvents, radiation, additives) can be exploited to obtain complete Z selectivity. The reactivity of this overlooked class of silyl enol ethers has been investigated, and features that could pave the way to new applications have been found.

Full text of DOI:10.1021/acs.orglett.8b00009

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Photoinduced Multicomponent Synthesis of α‑Silyloxy Acrylamides,
an Unexplored Class of Silyl Enol Ethers
Francesco Ibba,‡,† Pietro Capurro,‡ Silvia Garbarino, Manuel Anselmo, Lisa Moni, and Andrea Basso*
̀
Department of Chemistry and Industrial Chemistry, Universita degli Studi di Genova, Via Dodecaneso 31, 16146 Genova, Italy
S
* Supporting Information
ABSTRACT: The photoinduced, multicomponent reaction of
α-diazoketones, silanols, and isocyanides affords α-silyloxy
acrylamides, formally derived from α-keto amides. The
presence of a secondary amido group makes classic preparative
methods for silyl enol ethers unfeasible in this case, while the
mild conditions required by this photochemical approach
allow their synthesis in good yields; moreover, the general
structure can be easily modified by varying each component of
the multicomponent reaction. Fine-tuning of the reaction
conditions (i.e., solvents, radiation, additives) can be exploited
to obtain complete Z selectivity. The reactivity of this
overlooked class of silyl enol ethers has been investigated, and features that could pave the way to new applications have
been found.
he chemistry of silyl enol ethers is now solid, and their use
has grown tremendously over the years as they are
Scheme 1. Retrosynthetic Scheme to α-Silyloxy Acrylamides
1
T
valuable intermediates in a wide variety of reactions.1 Many
preparative syntheses have been developed to improve both
yield and stereoselectivity; silyl enol ethers can now be
prepared from a wide range of starting compounds: not only
aldehydes and ketones, but also enones, esters, thioesters, and
ketoesters can be conveniently transformed into this class of
molecules.2 Despite great advances in the field, preparation of
these compounds from α-ketoamides remains a challenge,
especially considering secondary amides bearing an acidic
hydrogen. In this case, no general preparative methods are
available, and a very limited number of specific preparations
includes the synthesis from stable heterocyclic enol derivatives3
and from α-phosphono-α-silyloxy amides through an olefina-
tion reaction.4 On the contrary, α-silyloxy acrylic esters have
been extensively used for the preparation of biomolecules,5 in
radical reactions,6 or for the synthesis of α,β-unsaturated
ketoesters.7
A general synthesis of α-silyloxy acrylamides is therefore
highly desirable, and the possibility of obtaining them through a
multicomponent approach attracted our interest. Based on our
recent experience with photoinduced multicomponent reac-
tions,8 we reasoned that compounds of general formula 1 could
be assembled in one pot by a combination of a ketene, an
isocyanide, and a silanol (Scheme 1).
mark.10 From a structural point of view, they are comparable to
carboxylic acids, showing a dual reactivity: nucleophilic, thanks
to the hydroxyl group, and electrophilic, through the silicon
atom. Some silanols are commercially available, but they can be
also conveniently prepared from the corresponding chlorides.11
Our initial investigation began by reacting benzyldiazoketone
2a with cyclohexyl isocyanide 3a and triphenylsilanol 4a under
UV irradiation. Product 1a was isolated as a mixture of
geometric isomers. The choice for silanol 4a was dictated by
the mechanism postulated for the reaction: according to what is
depicted in Scheme 2, substituents able to enhance the
electrophilicity of the silicon atom should favor its migration
(through a pentacoordinate intermediate), allowing conversion
of 5 into 6 and subsequent stabilization of the product via
tautomerization.
Ketenes are generally unstable compounds; nevertheless, we
have recently shown that they can be efficiently generated in
situ through the Wolff rearrangement of diazoketones.9
Silanols, on the other hand, are easily manipulated and
stored, and although they are not widely used organosilicon
compounds, one of the few examples of real synthetic
applicability is the cross-coupling reaction of Hiyama−Den-
Optimization of the reaction conditions involved lamps with
three different emission maxima, two different reactors, acetone
or toluene as solvent, and trans-stilbene as additive. The results
Received: January 2, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b00009
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Toluene generally performed better than acetone (by
comparison of entry 4 with 5 or entry 8 with 10), although,
with more energetic radiation, results were comparable both in
terms of yield and selectivity (comparison of entry 1 with 2).
When the quartz test tube (A) was replaced with a reactor
made of borosilicate glass (B), Z selectivity was complete (entry
11). Under the latter conditions, the reaction could be also
scaled up without loss of selectivity and with improvement of
the overall yield (entry 12). Although use of an excess of one of
the three components could slightly improve the overall yield,
all reactions were always performed with equimolar amounts of
the reagents for a better process economy.
Scheme 2. Postulated Mechanism for the Three-Component
Reaction of Benzyldiazoketone, Cyclohexylisocyanide, and
Triphenylsilanol
During further optimization studies, we also observed that
when aromatic diazoketones were employed better results were
obtained working at 352 nm with 0.2 equiv of trans-stilbene.
With these results in hand, we proceeded to investigate the
scope of the reaction, employing the building blocks illustrated
in Figure 1; the results are reported in Table 2.
are summarized in Table 1. In accordance with our previous
experience,9b the addition of trans-stilbene was beneficial for
a
Table 1. Investigation of the Reaction Conditions
c
λmax
entry (nm)
additive
(equiv)
time
(h)
yield (%)
d
b
solvent reactor
(Z/E)
1
254
254
254
352
352
352
300
300
300
300
300
300
toluene
acetone
acetone
acetone
toluene
toluene
toluene
toluene
toluene
acetone
toluene
toluene
A
A
A
A
A
A
A
A
A
A
B
B
1.0
1.0
0.0
0.0
0.0
1.0
0.0
1.0
0.1
1.0
0.1
0.1
6
6
67 (83:17)
73 (80:20)
75 (53:47)
22 (88:12)
47 (96:4)
60 (97:3)
38 (96:4)
55 (96:4)
72 (96:4)
40 (90:10)
56 (100:0)
2
3
6
Figure 1. Building blocks employed to investigate the scope of the
multicomponent reaction.
4
24
16
24
5
5
6
Compounds 1b−k were obtained with yields ranging from
moderate to good, usually with good or complete Z/E
selectivities (except for entry 4). Yields were affected by partial
decomposition of the products during silica-gel purification,
7
8
22
6
9
10
11
12
28
9
e
a
14
66 (100:0)
Table 2. Investigation of the Reaction Scope
a
Reactions were performed in a Rayonet apparatus; a degassed 1:1:1
b
c
entry diazoketone isocyanide silanol product yield (%) (Z/E)
mixture of 2a, 3a, and 4a (0.3 mmol each) in the solvent (3 mL) was
e
b
1
2
2b
2a
2b
3a
3a
3a
3a
3b
3d
3c
3e
3a
3a
4b
4b
4a
4a
4a
4a
4a
4a
4c
4d
1b
1c
1d
1e
1f
27 (98:2)
49 (100:0)
80 (98:2)
75 (67:33)
35 (100:0)
69 (93:7)
68 (100:0)
irradiated until consumption of 2a. A = quartz; B = borosilicate glass.
c
d
Isolated yield after column chromatography. Diastereomeric ratio
e
e
3
determined by NMR on the crude material. Reaction was scaled up to
2 mmol of diazoketone.
e
4
2c
5
2d
2a
2a
2a
2a
2a
6
1g
1h
1i
7
the stereoselective outcome of the reaction, as this triplet
quencher molecule could inhibit Z/E isomerization occurring
during irradiation. This was evident by comparing entries 2 and
3, where the presence/absence of the additive strongly
influenced the stereochemical ratio. The effect of trans-stilbene,
on the other hand, was less evident when the reaction was
performed at 300 or 352 nm. At 300 nm, however, its presence
dramatically increased the reaction time (by comparison of
entries 7 and 8), an observation that can be explained by the
fact that trans-stilbene displays an absorption maximum at ca.
300 nm.
d
8
80 (100:0)
9
1j
30 (100:0)
50 (91:9)
10
1k
a
Reactions were performed in a Rayonet apparatus; a degassed 1:1:1
mixture of 2, 3, and 4 (0.3 mmol each) in toluene (3 mL) was
irradiated with 300 nm lamps until consumption of 2. Isolated yield
after column chromatography. Z/E ratio determined by NMR on the
crude material. Yield determined by NMR with an internal standard.
Reaction performed with 352 nm lamps with 0.2 equiv of trans-
b
c
d
e
stilbene.
B
DOI: 10.1021/acs.orglett.8b00009
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Organic Letters
Letter
although NMRs of crude materials were usually very clean
(entry 8). Triphenylsilanol 4a usually performed better than
others.
Scheme 5. One-Pot Michael/Aldol Condensation with
Butenone and Concomitant Formation of Dimerization
Product 10
The applicability of our method was tested by subjecting
compounds 1 to various reaction conditions typical of silyl enol
ethers. Not surprisingly, these compounds were found to be
less stable in acidic and basic conditions, compared to the
corresponding α-silyloxy acrylesters. In fact, the higher
nucleophilic character of the amidic carbonyl, compared to
esters, could destabilize the neighboring silicon atom and
facilitate its premature cleavage, through a transient migration
to the carbonyl itself.
For this reason, reactions with aldehydes under Mukayama
conditions failed to afford the desired products, and employ-
ment of organocatalysis afforded the aldol products in
unsatisfactory yields. Nevertheless, generation of the enolate
in situ with addition of TBAF was successful: Mannich reaction
of 1a with Eschenmoser’s salt gave the desired elimination
product 7 in 83% yield (Scheme 3); α,β-unsaturated ketoesters
Scheme 3. Mannich Reaction with Eschenmoser’s Salt
Very recently, Wu reported the decarboxylative cyclization of
α-amino acids and α-ketoamides.19 Intrigued by the possibility
that compounds 1 could also undergo a similar transformation,
we reacted compounds 1a and 1e with proline in 2-propanol at
110 °C. Tetrahydro-1H-pyrrolo[1,2-a]imidazole-2-ones 11 and
12 were isolated with 69% and 66% yield, respectively (Scheme
6). The nature of the R group had no influence on the outcome
have been efficiently employed in asymmetrical conjugate
additions12 and cycloadditions;13 therefore, our method offers
new substrates to assemble isoxazolines,14 carbazoles,13
dihydropyrans,15 or cyclic nitrones16 with an additional amide
functional group.
Moreover, Saegusa oxidation of 1c with Pd(OAc)2 resulted
in the formation of α,β-unsaturated ketoamide 8 in 60% yield
(Scheme 4). Therefore, unsaturated ketoamides 7 and 8 could
be alternatively obtained by simply varying the reaction
conditions.
Scheme 6. Decarboxylative Cyclization of Proline with
Compounds 1a and 1e
Scheme 4. Saegusa Oxidation of Silyl Enol Ether 1c
of the reaction, and moreover, the final compounds were
obtained in a completely stereoselective fashion. Noteworthy,
Wu reported only one example with an aliphatic substituent in
position 3 of the imidazolone ring, and in that case a dr of 10:1
was obtained. When the reactions with proline were performed
directly with the α-ketoamide derived from 1a, compound 11
was isolated, but in lower yield (53%). Apparently, the in situ
cleavage of the silyl group was beneficial for the outcome of the
reaction, possibly through a slow release of the reacting
ketoamide.
In addition, conjugate addition of 1a with butenone gave
interesting results, affording the Michael−aldol product 9 in
moderate yield as the trans diastereoisomer (Scheme 5). Under
the mild conditions developed, a competitive formation of 10
was observed, presumably derived from an aldol dimerization
followed by cyclization. When butenone was not added to the
reaction mixture, compound 10 was isolated as the sole product
in 69% yield. Compound 10 is a simplified analogue of
anchinopeptolides17 (peptide alkaloids isolated from Medi-
terranean sponges), and the stereochemistry was assigned in
accordance with NMR similarities with known compounds.18
This is the first example of aldol dimerization and hemiaminal
formation performed on silyl enol ethers; moreover, the
complete stereoselectivity observed opens up the route to the
total synthesis of these natural products and analogues.
Finally, we investigated the reactivity of compounds 1 in
cycloaddition reactions. Silyl enol ethers have been used as
substrates in [2 + 2] cycloaddition with carbonyl derivatives as
a modification of the classic Paterno−
̀
Buchi reaction.20 When
̈
compound 1a was irradiated at 300 nm in the presence of
benzaldehyde, oxetane 13 was isolated in a modest 15% yield.
Notably, the resulting cycloadduct bears three stereogenic
centers, an amide functional group, and a silyl protected tertiary
alcohol. Moreover, by performing the reaction under
C
DOI: 10.1021/acs.orglett.8b00009
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Author Contributions
continuous flow conditions, the yield was improved to 40%
‡F.I. and P.C. contributed equally.
Notes
(Scheme 7). Regioselectivity of the reaction was complete and
Scheme 7. Paterno−Buchi Reaction of Compounds 1a with
̀
̈
The authors declare no competing financial interest.
Benzaldehyde under Continuous Flow Conditions
ACKNOWLEDGMENTS
A.B. thanks Mr. Daniele Di Stefano and Mr. Francesco Negri
(University of Genova) for their contributions to this work.
■
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ASSOCIATED CONTENT
* Supporting Information
■
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glett.8b00009.
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Experimental procedures, full characterization of new
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AUTHOR INFORMATION
■
Corresponding Author
*E-mail: andrea.basso@unige.it.
ORCID
Lisa Moni: 0000-0001-5149-2963
Andrea Basso: 0000-0002-4700-1823
Present Address
†(F.I.) University of Oxford, Chemistry Research Laboratory,
12 Mansfield Road, OX1 3TA, U.K.
D
DOI: 10.1021/acs.orglett.8b00009
Org. Lett. XXXX, XXX, XXX−XXX