Copper-Catalyzed One-Pot Borylative Aldolisation β-Fluoride Elimination for the Formal Addition of Acrylates to Carbonyl Moieties

Article abstract of DOI:10.1002/chem.201802023

Herein, we report the copper-catalyzed domino borylation/aldolisation of methyl 2-fluoroacrylate with carbonyl compounds followed by an elimination to give Morita–Baylis–Hillman (MBH) analogues. The optimal conditions described were shown to be compatible

Full text of DOI:10.1002/chem.201802023

A Journal of
Accepted Article
Title: Copper-Catalyzed One-Pot Borylative Aldolisation beta-Fluoride
Elimination for the Formal Addition of Acrylates to Carbonyl
Moieties
Authors: Corentin Rasson, Adrien Stouse, Arnaud Boreux, Virginie
Cirriez, and Olivier Riant
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To be cited as: Chem. Eur. J. 10.1002/chem.201802023
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Copper-Catalyzed One-Pot Borylative Aldolisation β-Fluoride
Elimination for the Formal Addition of Acrylates to Carbonyl
Moieties
Corentin Rasson, Adrien Stouse, Arnaud Boreux, Virginie Cirriez and Olivier Riant*[a]
Abstract: Herein, we report the copper-catalyzed domino
borylation/aldolisation of methyl 2-fluoroacrylate with carbonyl
compounds followed by an elimination to afford Morita-Baylis-Hillman
(MBH) analogs. The optimal conditions described were shown to be
borylation with an aldolisation on carbonyl 1 followed by a
subsequent elimination would yield MBH adduct 4 (Scheme 1b).
a. MBH Reaction
amine or
compatible with
a wide range of aldehydes and ketones.
XH
X
phosphine
EWG
Unprecedented MBH adducts derived from ketones were efficiently
synthesized.
+
EWG
R
R
H
X = O or N(EWG)
b. This work
Recently domino reactions have emerged as highly efficient tools
for the synthesis of complex structures.[1] The most prominent
categories are the cationic[2], anionic[3], radical[4], pericyclic[5],
photochemically induced[6] and transition metal-catalyzed[7]
domino reactions. This last category relies mostly on expensive
palladium[8], ruthenium[9] and rhodium[10] catalysts. More recently,
copper-mediated conjugate additions have been exploited in the
initiating step of the domino process. Several nucleophilic
copper(I) species such as Cu-B[11], Cu-C[12], Cu-H[13] and Cu-Si[14]
have been successfully employed in this strategy.
1. [Cu]
B2pin2 3
R2 OH
O
F
COOMe
+
COOMe
R1
R1 R2
2. Elimination
1
2
4
R1= Ar, Alkyl
R2= Alkyl, H
Compatible with ketones
R2 OH
COOMe
R1
F
Bpin
Scheme 1. a. Classical MBH reaction. b. Synthesis of MBH analogs via a
copper catalyzed one-pot 1,4-addition/aldolisation/elimination.
The Morita-Baylis-Hillman (MBH) reaction[15] , a well-known
domino reaction that allows the formal condensation of a Michael
acceptor and an aldehyde or an aldimine (Scheme 1a), is now
recognized as one of the powerful synthetic tool of organic
synthesis. However, this reaction still suffers from certain
limitations such as high catalyst loading, low reaction rates, and,
notably, its poor applicability to ketones. Numerous studies
focused on modifying different parameters of the reaction have
been realized[16] to try to overcome those drawbacks. Other
synthetic routes have also been designed such as a nickel-
catalyzed hydroxycarboxylation of allenes,[17] hydroalumination of
acetylenic esters[18] or aldol reactions using sulfurated or
selenated substrates followed by oxidation/elimination.[19]
In order to develop this new approach we first focused on the
domino borylation/aldolisation step using 4-t-Bu-benzaldehyde as
a model substrate (Table 1). As a starting point, we applied the
conditions we previously described[14b] for catakytic alkyne
borocupration using
2
mol% of the copper catalyst
CuF(PPh3)3·2MeOH (5), 2 mol% of (rac)-BINAP (L1), 1.2
equivalent of diboron 3 in THF or toluene at room temperature
(entries 1 and 2).
Table 1. Selected experiments from the optimization of copper-catalyzed 1,4-
borylation/aldolisation between 1a and 2.
Inspired by a report from the group of Ogoshi[20] on the
concomitant β-elimination of boron and fluoride from
a
trifluoromethyl moiety, we realized that an analogous method
could lead to the generation of an acrylate from an α-fluoro-β-
borylester. Such patterns can be obtained by the addition of Cu-
B species onto an α-fluoro-acrylate 2. The combination of this β-
[*]
M. Sc. C. Rasson, M. Sc. A. Stouse, M. Sc. A. Boreux, Dr. V.
Cirriez, Prof. Dr. O. Riant
Institute of Condensed Matter and Nanosciences, Molecules, Solids
and Reactivity (IMCN/MOST) – Université catholique de Louvain
Place Louis Pasteur 1, bte L4.01.02
1348 Louvain-la-Neuve (Belgium)
E-mail: olivier.riant@uclouvain.be
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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5 L4
(2 mol%)
B2pin2 (1.5 equiv)
toluene, r.t.
Entry
Ligand
B2pin2 (equiv)
Solvent
THF
Yield [%][a]
1.
/
OH
O
F
COOMe
1
2
3
4
5
6
7
8
9
L1
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.0
1.5
70
78
0
COOMe
+
R
2. MeONa (3.5 equiv)
MeOH
R
L1
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
1a-p
2
4a-p
L1[b]
-
OH
OH
OH
Me
COOMe
COOMe
COOMe
48
36
68
87
58
89
R1
L2
Me
S
R1=
t-Bu
H
4a 87%
4b 90%
4j
4l
85%
4k 83%
L3
OH
OH
OH
COOMe
COOMe
L4
4c
4d
Me
87%
87%
92%
COOMe
L4
OMe
NMe2 4e 73%
L4
N
4m
73%
4f
Ph
F
94%
83%
[a] Yield determined by 1H NMR with 3,4,5-trimethoxybenzaldehyde as
internal standard. [b] With no copper source.
Tr
4n 64%
4g
OH
OH
Cl
Br
4h 75%
4i 69%
COOMe
COOMe
4o
4p
82%
99%
PPh2
PPh2
PPh2
PPh2
PPh2
PPh2
PPh2
Scheme 2. Scope for aldehydes. Reaction conditions: 1 (0.75 mmol, 1.5 equiv),
2 (0.5 mmol, 1 equiv), B2pin2 (0.75 mmol, 1.5 equiv), CuF(PPh3)3·2MeOH 5
(0.01 mmol, 2 mol%), 1,1’-bis(diphenylphosphino)ferrocene L4 (0.01 mmol, 2
mol%) in 2,5 mL toluene, room temperature, 18 h. NaOMe (1.75 mmol, 3.5
equiv) in 2.5 mL MeOH, room temperature, 24h. Yields of isolated products are
given.
Fe
O
PPh2
L1
L2
L3
L4
Toluene proved to be a more suitable solvent than THF,
affording 6a in 78% yield by NMR. We then studied the influence
of the metal and ligand. The metal is essential for this reaction.
When no copper was used (entry 3) no product was observed.
Similarly, in the absence of a ligand (entry 4) we observed a
significant drop in the yield. Several other phosphine ligands were
screened: dppbz (L2) or DPEphos (L3) gave lower yield than (L1)
(entry 5-6) while dppf (L4) gave a very good result with 87% yield
(entry 6). To further improve this transformation we modified the
stoichiometry of B2pin2 3. Notably, using 1.5 equivalents of 3
affords slightly better yield (entry 9).
Benzaldehyde and simple alkyl substituted aromatic
aldehydes were readily converted into the corresponding MBH
adduct 4a-c and 4j-k (83 to 90% yield). For non-bulky groups
such as methyl, the substitution in ortho, meta or para position
seems to have no significant influence on the yield of the reaction
(4c,j,k). Additionally, the presence of halogens is well tolerated
with only a minor decline in efficiency observed with larger
halogens (4g-i). Even deactivated aldehydes (1d-e) gave good
yields of the desired products. This result is noteworthy, especially
for 4-dimethylaminobenzaldehyde 1e which typically does not
react at all in the MBH reaction. Heteroatoms are well tolerated
with 2-thiophene carboxaldehyde 1l giving 92% yield of 4l and N-
trityl prolinal yielding 4n in 64% and only one diastereosiomer. α-
β-unsaturated aldehyde 1m and alkyl aldehyde 1o-p also readily
react under the reaction conditions to give 4o-p in 82% and 99%
yield, respectively.
Following
the
successful
optimization
of
the
borylation/aldolisation step, we moved to the elimination step
using several nucleophiles known to interact with borylated
compounds (See supporting information). After extensive tests
we found that using 3.5 equivalents of sodium methoxide in
methanol afforded the MBH adduct in 81% yield. This yield was
further improved by using 1.5 equivalent of aldehyde 1a to obtain
4a in 87% isolated yield.
Based on the high reactivity observed for the unactivated
aldehydes, we postulated that these conditions might allow
extending the scope of the reaction to substrates where the MBH
reaction is usually poorly applicable, notably ketones. To test this,
we applied the optimized conditions to acetophenone 7a as a
model substrate (Table 3).
With the optimized conditions in hand we started to investigate
the scope of the reaction by testing different aldehydes (Scheme
2).
Table 3. Selected experiments from the optimization reactions using ketones.
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OH
1. IPrCuDBM (7 mol%)
COOMe
B2pin2 (1.5 equiv)
toluene, r.t.
R2 OH
1. [Cu]/L
B2pin2 (1.5 equiv)
toluene, r.t.
O
F
COOMe
COOMe
O
+
R1
R1 R2
7a-u
2. MeONa (3.5 equiv)
MeOH
F
COOMe
+
8a
2
8a-u
HO
2. MeONa (3.5 equiv)
MeOH
COOMe
OH
7a
2
OH
COOMe
COOMe
COOMe
Bpin
9
R3
3
8a
H
84%
8h
8i
HO
89%
OH
53%
R =
Entry
[Cu]
L
7a
2
Yield [%][a]
OMe 8b 91%
86%[a]
NMe2 8c 50%
COOMe
(mol %)
(mol%)
(equiv)
(equiv)
COOMe
8a
49
48
29
23
57
70
79
83
9
Fe
1
2
3
4
5
6
7
8
5 (2)
5 (2)
5 (2)
L4 (2)
L4 (2)
L1 (2)
1.5
1
1
1
28
33
45
32
27
4
8j
8k
OH
50%
OH
73%
F
8d 87%
8e
8f
Br
98%
89%
COOMe t-Bu
COOMe
1
1
CF3
63%[a]
63%
OH
IMesCuDBM (2)
IPrCuDBM (2)
IPrCuDBM (5)
IPrCuDBM (7)
IPrCuDBM (7)
1
1
8l
8m
NO2
8g 30%
1
1
OH
OH
COOMe
TsN
COOMe
BocN
COOMe
COOMe
1
1
8o 72%
8p 38%
1
1
4
8n 38%
1
1.2
11
OH
OH
OH
COOMe
COOMe
[a] Yield determined by 1H NMR with 3,4,5-trimethoxybenzaldehyde as
internal standard.
42% (83%)[b]
8q
8r
74%
8s 57%
H3C
H3C
CH3
CH3
N
O
N
O
N
O
N
O
H
O
OH
H
H3C
Cu
Cu
O
HO
H
8t
38%
50% (56%)[b]
1 dia
MeOOC
(E)/(Z)= 70:30
from 50:50
8u
Ph
Ph
Ph
Ph
IMesCuDBM
IPrCuDBM
Scheme 3. Scope for ketones. Reaction conditions: 7 (0. 5 mmol, 1 equiv), 2
(0.6 mmol, 1.2 equiv), B2pin2 (0.75 mmol, 1.5 equiv), IPrCuDBM (0.035 mmol,
7 mol%) in 2,5 mL toluene, room temperature, 18 h. NaOMe (1.75 mmol, 3.5
equiv) in 2.5 mL MeOH, room temperature, 24h. Yields of isolated products are
We were delighted to observe the formation of 8a. However,
the lower reactivity of ketones compared to aldehydes also lead
to byproduct 9. The use of 1 or 1.5 equivalents of 7a yielded
similar results (entries 1-2). To see if different ligands could
prevent the formation of 9 and improve the reaction, various
phosphine ligands and NHCs were tested. The phosphines and
IMes gave lower yields for 8a, while the use of IPrCuDBM gave a
better yield (57%) of the product but did not change the amount
of 9 formed. However, upon using a higher catalyst loading (entry
6-7) the yield of 8a increased and the formation of 9 could be
significantly supressed. The best result (83%) was obtained when
1.2 equivalent of 2 was used.
given. [a] On
a
5
mmol scale. [b] 1H NMR yield with 3,4,5-
trimethoxybenzaldehyde as internal standard.
Impressively, aromatic ketones bearing electron-withdrawing
or electron-donating groups (8a-h) were well-tolerated and gave
good to excellent yields with the exception of p-nitro-substituted
acetophenone (8g, 30%). Even modification of R2 from a methyl
to an ethyl or allyl (8i-j) gave acceptable yields. Alkyl ketones (8m-
q,u) gave in most cases moderate to good yields except for
azetidinone 7p (38%) and tetralone 7n (38%). Interestingly, the
use of 7r-s showed a better reactivity of (E)-enone (74%)
compared to the (Z) counterpart (57%). This difference in
reactivity is also seen with use of a 50:50 mixture of 7t to give a
70:30 ratio in the final product 8t.
Using these new optimized conditions we started to
investigate the scope of the reaction towards other ketones
(Scheme 3).
On the basis of in situ NMR analysis and precedent in the
literature, we can postulate a general mechanism for this
transformation. We previously described a mechanism for the
borylation/aldolisation leading to A.[11b] Upon treatment with
NaOMe in MeOH, A undergoes a nucleophilic attack from two
methoxide ions on both borons to give the bis-boronate B.
Following a cleavage of a B-O bond to give an alcohol, the other
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10.1002/chem.201802023
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boronate undergoes a concomitant elimination of the fluoride and
the boron moiety to give 4 (Scheme 4a). The formation of side
product 9 was also studied by NMR (see supporting information).
9 is obtained by the conjugate addition of Cu-Bpin on 2 to give the
enolate C which will trap a proton from the reaction media to give
D. Upon treatment with NaOMe in MeOH methyl acrylate E is
obtained and reacts with a Cu-Bpin species to give 9.
including ketones and deactivated aldehydes. Work is now in
progress to devise an enantioselective version and to further
study the potential of transformations of our adducts into
synthetically useful intermediates.
Acknowledgements
Financial support from the Université catholique de Louvain is
gratefully acknowledged. We warmly thank Professor Michael
Singleton for the valuable help during the preparation of this
manuscript.
a. Formation of 4
O
MeO
B
O
R2 OBpin
COOMe
R2
O
R2 OH
Na
NaOMe
MeOH
COOMe
COOMe
R1
R1
R1
F
F
O Na
B
Bpin
A
Keywords: copper • catalysis • borylation • Morita-Baylis-
MeO
4
O
Hillman • domino
B
b. Formation of 9
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OMe
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Et3N (5 equiv)
O
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importantly permits the use of normally unreactive substrates
,
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10.1002/chem.201802023
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Corentin Rasson, Adrien Stouse, Arnaud
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Copper-Catalyzed One-Pot Borylative
Aldolisation β-Fluoride Elimination
for the Formal Addition of Acrylates
to Carbonyl Moieties
Herein we report the copper-catalyzed domino borylation/aldolisation of methyl 2-
fluoroacrylate with carbonyl compounds followed by an elimination to afford Morita-
Baylis-Hillman (MBH) analogs. The optimal conditions described were shown to be
compatible with a wide range of aldehydes and ketones. Unprecedented MBH
adducts derived from ketones were efficiently synthesized.
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