Transition-metal free reactions of boronic acids: Cascade addition - Ring-opening of furans towards functionalized γ-ketoaldehydes

Article abstract of DOI:10.1039/c5cc08809g

We describe the first ring-opening of furfuryl alcohols with boronic acids to afford functionalized γ-ketoaldehydes. The transformation builds a new C-C bond at the original C-4 of the starting furan, and tolerates ring-substitution at C-3 and C-4 positions. The reaction takes place under metal-free conditions by promotion with tartaric acid.

Full text of DOI:10.1039/c5cc08809g

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Transition-metal Free reactions of boronic acids: Cascade addition
– ring-opening of furans towards functionalized γ-Ketoaldehydes†
Received 00th January 20xx,
Accepted 00th January 20xx
S. Roscales and A. G. Csákÿ*
DOI: 10.1039/x0xx00000x
www.rsc.org/
We describe the first ring-opening of furfuryl alcohols with
boronic acids to afford functionalized γ-ketoaldehydes. The
transformation builds a new C-C bond at the original C-4 of the
starting furan, and tolerates ring-substitution at C-3 and C-4
positions. The reaction takes place under metal-free conditions by
promotion with tartaric acid.
a) Reactions of furfuryl cations (ref 4):
R2
O
R1
OH
R2
R2
O
R2
H2O
HO
R1
H+
OH
R1
O
+
R1
[4+3]
R2
R3OH
Furans constitute a useful bridge between the chemistry of
aromatic heterocycles and the chemistry of aliphatic or
alicyclic compounds. Due to their relatively low aromaticity,1
they participate in reactions typical of aromatics and also in
reactions which are characteristic of alkenes or dienes, such as
cycloadditions or ring-opening reactions. These processes
constitute smart transformations from the standpoint of
synthetic strategy: The carbon backbone of a furan can be
decorated making use of classical aromatic reactions, and then
transformed into an aliphatic or alicyclic compound which may
be difficult to prepare otherwise.
R2
O
R1
R1
R3
O
b) Reactions of furans with boronic acid derivatives (ref 8):
-
-
+
R-B(pin)
Li
B(pin)
X
B(pin)
O
O
+
O
X+
R
R
pin = pinacol
X = I, Br, Cl
Nu-
B(pin)
R
R
O
X
O
c) Ring-opening of furfuryl alcohols with boronic acids (this work):
Furfuryl alcohols constitute a special class of furans which
have shown particular relevance in the context of ring-opening
reactions.2 The ability of their hydroxyl to act as leaving group
furnishes stabilized furfuryl cations (Scheme 1a) which may act
as intermediates in the formation of valuable targets such as 2-
cyclopentenones (the Piancatelli reaction),3 furan ring-fused
cycloheptenes, or dihydrofuran-based exo enol ether / cyclic
ketal natural products.4
R2
R2
R1
R2
R1
R1
4
R2
B(OH)2
OH
2
or
H
H
H
tartaric acid
CH2Cl2
O
O
O
O O
Scheme
1 Reactions of furfuryl cations, reactions of furans with boronic acid
derivatives, and ring-opening of furfuryl alcohols with boronic acids.
In this paper we report a new reaction of furfuryl alcohols
with boronic acids promoted by tartaric acid. The reaction
builds a new C-C bond at the original C-4 of the starting furan
simultaneously with the ring-opening process (Scheme 1).
Based on our previous results on metal-free additions of
boronic acids to various kinds of substrates using different
types of promoters, we began our studies by exploring the
On the other hand, boronic acids and their derivatives are
bench-stable reagents useful in C-C bond-forming processes.5
Under suitable activation, generally under transition-metal
catalysis, they are able to transfer their carbon moiety to
electrophilic centres under mild conditions. However, due to
the low intrinsic reactivity of boronic acids,6 transformations in
which they act as carbon nucleophiles under metal-free
conditions remain relatively scarce.7,8
reaction between 2-furylcarbinol
(
1a)
and (E)-2-
phenylvinylboronic acid (2a) or potassium (E)-2-
phenylvinyltrifluoroborate (3a). These optimization results are
gathered in Table 1.
Only rapid degradation of the starting materials was
observed
(TCL-monitoring)
under
promotion
with
trifluoroacetic anhydride (TFAA) either when using 2a or 3a
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(Table 1, entries 1, 2). On the other hand, we were pleased to substituted alkenylboronic acid was used, we were pleased to
observe the formation of the -ketoaldehyde 4a upon find that the primary reaction product (racemic) was stable
γ
treatment of 1a with 2a when tartaric acid was used as the enough to chromatographic purification (4g). This was also the
promoter (Table 1, entry 3). However, all attempts to isolate case with a heteroarylboronic acid (4h). However, no reaction
this compound completely pure were unsuccessful. Partial occurred with phenylboronic acid (4i).
isomerization to 5a was experienced upon chromatography on
silica-gel or alumina stationary phases. Thus, we isomerized
crude 4a directly to 5a with Et3N prior to product isolation.
Compound 5a was obtained as a single E isomer, as confirmed
by NOE measurements. Further improvement of the reaction
conditions led to an increase in the molar ratio of tartaric acid
(Table 1, entries 4 - 6) in DCM as solvent. We found that the
addition of water was beneficial for the process (Table 1,
entries 7 - 9). The reaction also worked using the trifluroborate
3a instead of the boronic acid 2a (Table 1, entry 10). The
process could also be promoted with lactic acid (Table 1, entry
11), but not with diethyl tartrate (Table 1, entry 12). Under
optimum conditions (Table 1, entry 8) the cascade ring-
opening reaction / C-C bond formation was best performed
with 1.0 equiv of tartaric acid and 3 equiv of H2O in DCM for 18
h at rt.
Table 1 Selected optimization conditionsa
Ph
Ph
[B]
OH
Et3N
DCM
1 h, rt
O
O
Ph
conditions
O
OHC
OHC
1a
2a, [B] = B(OH)2
3a, [B] = BF3K
4a
5a
Entry
Conditions
5a
Yield (%)b
1
2
3
4
5
6
7
2a, TFAA (0.5 equiv), DCM, rt, 1 h
3a, TFAA (0.5 equiv), DCM, rt, 1 h
---
---
2a, tartaric acid (0.3 equiv), DCM, rt, 18 h
2a, tartaric acid (0.5 equiv), DCM, rt, 18 h
2a, tartaric acid (1.0 equiv), DCM, rt, 18 h
2a, tartaric acid (1.0 equiv), Tol, rt, 18 h
36
53
62
51
70
2a, tartaric acid (1.0 equiv), DCM, H2O (1.0
equiv), rt, 18 h
8
2a, tartaric acid (1.0 equiv), DCM, H2O (3.0
equiv), rt, 18 h
89
88
83
78
---
9
2a, tartaric acid (1.0 equiv), DCM, H2O (5.0
equiv), rt, 18 h
10
11
12
3a, tartaric acid (1.0 equiv), DCM, H2O (3.0
equiv), rt, 18 h
2a, lactic acid (1.0 equiv), DCM, H2O (3.0 equiv),
rt, 18 h
2a, diethyl tartrate (1.0 equiv), DCM, H2O (3.0
equiv), rt, 18 h
a
b
Reaction scale: 1.2 equiv of 2a or 3a. Yield of product isolated after flash
column chromatography.
Scheme 2 Ring-opening reactions of furans with boronic acids: scope and limitations.
Under the optimized conditions, firstly we extended the
Next, we investigated the scope and limitations of the
reaction with regard to the substitution of the furan ring.
Substitution at 3-position led to attack of the boronic acid at C-
reaction of 1a to other boronic acids towards the synthesis of a
variety of
γ
-ketopentanals.9 The results are gathered in
Scheme 2. We began by considering other (E)-2-
4 of the furan ring, affording 2,3-disubstituted-
5j ). When 4-substituted furfuryl alcohols where used, the
formation of the new C-C bond again took place at C-4 of the
furan ring, giving rise to 2,2-disubstituted- -ketopentanals (4p
γ-ketopentanals
arylvinylboronic acids endowed with electron-accepting and
(
-o
electron-donating groups at the aryl ring (5b, 5c). In addition,
we were satisfied to see that the reaction could also be
γ
-
extended to non-styryl alkenylboronic acids (5d-f). When a 1-
2 | Chem. Commun., 2016, 52, 1-3
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s
). However, no reaction was observed between 5-methyl-2- protonation, and the formation of compound
8
(R2, R3 = Ph) by
at C-5
furylmethanol (1g) and (E)-2-phenylvinylboronic acid (2a). rapid direct attack to the corresponding intermediate
Instead, treatment of 1g with potassium (E)-2- position.
A
phenylvinyltrifluoroborate (3a) led to benzylic substitution
without ring-opening (6). Also, no reaction was observed when
starting from 3-furylmethanol.
Last, we considered the possibility of using secondary
furfuryl alcohols (Scheme 3). No reaction was observed
between 1h and (E)-2-phenylvinylboronic acid (2a) under
standard reaction conditions. On the other hand, the reaction
of the 1-aryl-1-(2-furyl)methanol 1i with 2a or 2e led to
ketoaldehydes 7a . In the case of the diphenylfurylcarbinol 1j
the product of attack to position C-5 ( ) was obtained instead.
γ-
,
,
b
8
Scheme 4 Plausible reaction course for the ring-opening reactions.
Due to the dense functionalization present in the γ-
ketoaldehydes and which resulted from the ring-opening
4
5
reaction of furans with boronic acids, a variety of synthetically
useful transformations can be envisioned for this type of
compounds. This makes them them attractive as intermediates
in diversity oriented synthesis.14 For instance (Scheme 5), we
have considered the transformation of selected examples of
Scheme 3 Reactions of secondary and tertiary furfuryl alcohols.
A plausible reaction course that can explain the ring-opening
reaction of furans with boronic acids is proposed in Scheme 4.
We have observed that furfuryl alcohol 1a does not suffer
transformation when treated with tartaric acid and H2O in
DCM alone in the absence of a boronic acid, and we have also
checked that 4-oxopent-2-enal does not react with (E)-2-
phenylvinylboronic acid (2a) under these reaction conditions.
These observations rule out the possibility of the formation of
crude compounds
cascade cyclization / Friedel-Crafts acylation (Scheme 4a),
compounds 5a have been converted into the -alkylidene-
butyrolactones16 11 by a reduction / oxidation sequence
(Scheme 4b), and compounds 4p have been cyclized to the
cyclopentenone 12 (Scheme 4c) or subjected to base-induced
deformylation to the
-unsaturated ketones17 13 (Scheme
4d), which have been thus synthesized under transition-metal-
free conditions, or to ketone 14
4 9 by a
into the polysubstituted furans15
,
e
α
γ-
-
s
β,γ
compounds
4
via direct ring-opening (H2O, H+) of the furan ring
.
of the starting furfuryl alcohols
1
followed by conjugate
In conclusion, we have developed a new ring-opening
reaction of furans using boronic acids as reagents under metal-
free conditions. The transformation allows the generation of a
new C-C bond at the original C-4 of the starting furfuryl
addition.10 The reaction course gathered in Scheme 4 is based
on the well-known intermediates of the ring-opening reaction
of furfuryl alcohols in the Piancatelli3,4 reaction. Thus, addition
of H2O to the 5-position of the furanoxonium cation
rise to the key intermediate . Protonation would render a
oxo- -unsaturated oxonium cation (intermediate ), which
A will give
alcohol. This gives rise to γ-ketoaldehydes functionalized at
B
γ-
carbon C-2 or at carbons C-2 and C-3: Monofunctionalization
at C-2 has been achieved when starting from 2-furylmethanol,
difunctionalization at C-2 and C-3 has been achieved when
starting from 3-substituted-2-furylmethanols, and double
functionalization at C-2 has been achieved when starting from
4-substituted-2-furylmethanols. The potential usefulness of
these compounds in diversity oriented synthesis has been
highlighted by selected examples of their transformations into
α
,
β
C
after coordination to an in situ generated electron-deficient
trivalent boron species11 (RBX2) will transfer intramolecularly
the carbon backbone of the original boronic acid. The latter
step is similar to a conjugate Petasis reaction.12 Final hydrolysis
furnishes the
also explains the failure of the reaction with 2a when the 5-
position of intermediate is blocked by a substituent, due to
slow conversion to . However, under these circumstances,
intermediate can be attacked by potassium
trifluoroborate13
3a) to give benzylic substitution (compound
). The formation of compounds
(R2 = Ph, R3 = H) can be
understood following a similar pathway, by reaction of the key
γ-ketoaldehydes 4. The proposed reaction course
A
polysubstituted
furans,
α-alkylidene-γ-butyrolactones,
B
cyclopentenones or β,γ-unsaturated ketones.
A
a
We gratefully acknowledge the financial support provided by
the Spanish Ministerio de Economía Competitividad
(
y
6
7
(CTQ2014-52213-R) and Universidad Complutense de Madrid –
Banco Santander (GR3/14-910815).
enol intermediate
furanoxium cation
B
A
with
a second equivalent of the
at the benzylic position instead of
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