Aza-Morita-Baylis-Hillman reactions catalyzed by a cyclopropenylidene

Article abstract of DOI:10.1039/c6cc06201f

Catalysis using a bis(dialkylamino)cyclopropenylidene (BAC) has been developed, which relies on a formal umpolung activation of Michael acceptor pro-nucleophiles. Various aza-Morita-Baylis-Hillman reactions between aromatic, heteroaromatic, or aliphatic imines and acyclic or cyclic α,β-unsaturated ketones and carboxylic acid derivatives have been catalyzed by a BAC under mild conditions. Functionalities such as unprotected amino and hydroxy groups have been tolerated. The catalyst loading was decreased to 1 mol% without loss of activity. The BAC catalyst was shown to be substantially more active than a cyclic (alkyl)(amino) carbene (CAAC), N-heterocyclic carbenes (NHCs), and P- or N-centered Lewis bases.

Full text of DOI:10.1039/c6cc06201f

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Aza-Morita–Baylis–Hillman reactions catalyzed by
a cyclopropenylidene†
Cite this:DOI: 10.1039/c6cc06201f
Xun Lu and Uwe Schneider*
Received 27th July 2016,
Accepted 30th September 2016
DOI: 10.1039/c6cc06201f
www.rsc.org/chemcomm
Catalysis using a bis(dialkylamino)cyclopropenylidene (BAC) has
been developed, which relies on a formal umpolung activation of
Michael acceptor pro-nucleophiles. Various aza-Morita–Baylis–Hillman
reactions between aromatic, heteroaromatic, or aliphatic imines and
acyclic or cyclic a,b-unsaturated ketones and carboxylic acid derivatives
have been catalyzed by a BAC under mild conditions. Functionalities
such as unprotected amino and hydroxy groups have been tolerated.
The catalyst loading was decreased to 1 mol% without loss of activity.
The BAC catalyst was shown to be substantially more active than
a cyclic (alkyl)(amino) carbene (CAAC), N-heterocyclic carbenes
(NHCs), and P- or N-centered Lewis bases.
Scheme 1 Properties of NHC, CAAC, and BAC – proposed BAC catalysis.
Since the isolation of the first carbene species over 25 years
ago,1 N-heterocyclic carbenes [NHCs (1)] have proved to be
extremely versatile in both inorganic and organic chemistry stable than NHCs.9a In addition, CAACs have been shown to display
(Scheme 1). Due to their unique electronic and steric properties both stronger s donor9a and p acceptor11 abilities than NHCs.8a,12b
as well as structural flexibility,2 s donors 1 have been shown to While CAACs have been used as ligands in stoichiometric12 and
stabilize elements in their low-oxidation state,3 and to act as catalytic9a,13 metal complex applications, CAAC organocatalysis has
ligands in metal catalysis.4 In addition, NHCs have proved to be not been reported yet. BACs (3) bear a carbocyclic core; these
unique Lewis bases for catalytic umpolung of aldehydes and unique and stable carbenes can be synthesized in a straightforward
Michael acceptors,5 as well as Lewis acidic pro-nucleophiles.6 two-step protocol.10a Due to the distance of the bulky dialkylamino
Moreover, NHCs have been critical components in dual catalysis groups to the carbene centre, BACs have been considered the least
with acid or Pd redox co-catalysts.7
sterically hindered carbenes.12b,14b Moreover, BACs have been shown
In order to further develop the field of carbene catalysis, it is to be stronger s donors14b than NHCs, whereas the p acceptor
important to increasingly explore the potential of non-NHC ability11 has been described as comparable to NHCs. BACs have
carbenes.8 In this context, Bertrand et al. have recently discovered been sporadically used as ligands in stoichiometric metal
distinct species that can be isolated, cyclic (alkyl)(amino)carbenes complexes,14 as well as in Ni catalysis.15
[CAACs (2)]9 and bis(dialkylamino)cyclopropenylidenes [BACs (3);10
In our program exploiting low-oxidation main group elements
Scheme 1]. CAACs (2) have to be synthesized in a multi-step in catalysis, we have become interested in examining BACs (3) as
sequence;9 the N–C–N motif of 1 has been replaced by an N–C–C we anticipated a distinct reactivity profile due to their strong s
unit bearing a quaternary carbon atom adjacent to the carbene donor ability and unique non-sterically demanding shape com-
centre, which renders CAACs both more sterically demanding and pared to carbene types 1 and 2.8 To date, sporadic BAC organo-
catalysis has been reported for the umpolung of aldehydes.16
Inspired by a recently published NHC catalysis,17 we have examined
The University of Edinburgh, EaStCHEM School of Chemistry, The King’s Buildings,
aza-Morita–Baylis–Hillman (aza-MBH) reactions18 between various
David Brewster Road, Edinburgh EH9 3FJ, UK. E-mail: uwe.schneider@ed.ac.uk;
imines and acyclic or cyclic Michael acceptors (PG = N-protecting
Tel: +44 (0)131-650-4718
group; EWG = electron-withdrawing group; Scheme 1). The aza-
MBH reaction is one of the most important C–C bond formations
† Electronic supplementary information (ESI) available: Analytical data of all
novel compounds and copies of NMR spectra. See DOI: 10.1039/c6cc06201f
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Table 1 Screening of bases and carbene saltsa
due to its atom economy and high synthetic value.18 Typically,
amine or phosphine catalysts18,19 form a zwitterionic enolate
through conjugate addition to a Michael acceptor; the in situ
generated nucleophile undergoes subsequent addition to an
imine, followed by proton transfer and regeneration of the Lewis
base catalyst.18c In certain cases, an acid co-catalyst has been
shown to facilitate C–C bond formation, which has proved to
be critical for asymmetric catalysis; the acid may be included in
the Lewis base catalyst,20 or may act as a separate co-catalyst.21
Although various catalyst systems have been developed, a general
aza-MBH reaction with low catalyst loading and mild conditions
for a broad variety of electrophiles and pro-nucleophiles has
remained a challenge.18–21 We report here rare BAC-catalyzed
C–C bond formations, which rely on a formal umpolung activa-
tion of Michael acceptor pro-nucleophiles.
In an initial experiment, cyclopropenylidene 3a was generated
in situ from its bench-stable salt 3aÁHBF4 and a potassium
amide10a (Scheme 2). In order to confirm the formation of Lewis
base 3a, the latter was reacted with a Lewis acid, triethyl borane,
to form a donor–acceptor complex, 3aÁBEt3 (Scheme 2). This
reaction was monitored by 11B NMR spectroscopy (see ESI†):
the signal at 87 ppm (BEt3) was cleanly converted to a peak at
À13 ppm, which is consistent with the formation of a boron–ate
complex involving a carbene.22 In this context, KN(SiMe3)2 was
reacted in a control experiment with BEt3 to form a boron–ate
complex that displays a distinct chemical shift (d = À1.7 ppm). To
the best of our knowledge, 3aÁBEt3 represents the first example of
a boron–ate complex involving a BAC. Next, the in situ generated
carbene 3a (10 mol%) was used to trigger an aza-MBH reaction
between benzaldehyde-derived N-tosyl imine 4a (1.1 equiv.) and
cyclopentenone (5a) in THF (Scheme 2). Adduct 6a was obtained
in 26% yield, which confirmed that a catalyst turnover was possible
although the reaction conditions had to be optimized.
Entry
Carbene salt [mol%]
Base [mol%]
Yielda [%]
1
2
3
4
5
6
7
8
3aÁHBF4 [10]
—
KN(SiMe3)2 [10]
KN(SiMe3)2 [10]
NaN(SiMe3)2 [10]
LiN(SiMe3)2 [10]
LiNiPr2 [10]
LiTMP [10]
NaOtBu [10]
KOtBu [10]
Li2CO3 [10]
Na2CO3 [10]
K2CO3 [10]
Cs2CO3 [10]
Proton sponge [10]
TMG [10]
DBU [10]
DBU [10]
DBU [5]
DBU [5]
DBU [5]
DBU [5]
DBU [1]
26
NRb
17
3aÁHBF4 [10]
3aÁHBF4 [10]
3aÁHBF4 [10]
3aÁHBF4 [10]
3aÁHBF4 [10]
3aÁHBF4 [10]
3aÁHBF4 [10]
3aÁHBF4 [10]
3aÁHBF4 [10]
3aÁHBF4 [10]
3aÁHBF4 [10]
3aÁHBF4 [10]
3aÁHBF4 [10]
—
10
12
33
NRb
24
9
NRb
26
10
11
12
13
14
15
16
17c
18c
19c
20c
21d
36
57
NRb
60
79
NRb
94
3aÁHBF4 [5]
3bÁHBPh4 [5]
3cÁHBPh4 [5]
2Á(HCl)2 [5]
3aÁHBF4 [1]
34
26
NRb
90
Hence, a base screening14a was carried out (Table 1). In contrast
to the initial carbene catalysis (entry 1), the control reaction with
KN(SiMe3)2 alone failed to give product 6a (entry 2). The use of
other alkali metal amides or alkoxides did not improve the initial
result (entries 3–8). Among alkali metal carbonates, the use of the
cesium base gave 6a in the highest yield (57%; entry 12). The use of
metal-free organobases revealed that DBU was the best co-catalyst
(79% yield; entry 15); a control experiment with DBU alone failed
a
Yields have been determined by 1H NMR analysis of a reaction aliquot vs.
b
Bn2O. NR = no reaction; product 6a was not detectable – only unreacted
4a and 5a were detected (1H NMR analysis of a reaction aliquot). THF
c
d
(0.3 M), 30 1C, 30 h. THF (0.3 M), 30 1C, 72 h. Solvent screening
(conditions in entry 15) – dioxane, dimethoxyethane, toluene, ethyl acetate:
50–65%; Et2O, BuOMe, C6H5CF3, MeCN: 24–46%; in our hands, chlori-
t
nated aliphatic solvents have not been tolerated.
to give 6a (entry 16). At 5 mol% loading using DBU as a base, the
activity of various carbene salts was examined; the use of BAC
precursor 3aÁHBF4 gave product 6a in 94% yield, and proved to
be substantially more active than its BAC analogues 3bÁHBPh4
and 3cÁHBPh4 as well as CAAC salt 2Á(HCl)2 (entries 17–20).14a
Remarkably, even at 1 mol% loading the combined use of 3aÁHBF4
and DBU gave product 6a in 90% yield (entry 21). This C–C bond
formation represents the first BAC catalysis with 3a.16 In addition,
this formal umpolung activation of a Michael acceptor is clearly
distinct from the reported BAC catalysis, which has triggered
umpolung of aldehydes.16 It is noted that NHCs and conventional
aza-MBH catalysts, such as N- or P-centered Lewis bases, proved to
Scheme 2 Initial experiments with in situ generated BAC 3a.
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be significantly less reactive (see ESI†). Preliminary stoichiometric effective (10 mol%; Table 3). Various Michael acceptors were
experiments using in situ formed carbene 3a and imine 4a or shown to be compatible with the in situ formed cyclopropenyl-
Michael acceptor 5a failed to give conclusive data regarding initial idene catalyst under mild conditions. Cyclic and acyclic
adduct formation; we assume a classic aza-Morita–Baylis–Hillman a,b-unsaturated ketones were converted to products 6ab–ae in
mechanism.18c
90–95% isolated yields. Various a,b-unsaturated carboxylic acid
Next, the imine scope was examined by using cyclopente- derivatives have reacted in an aza-MBH fashion as well: esters,
none (5a) as pro-nucleophile in the presence of in situ formed amides, and a nitrile were a-alkylated to give adducts 6af–aj
cyclopropenylidene 3a (5 mol%) at 30 1C (Table 2). The use in 74–96% isolated yields. This BAC-triggered regioselectivity
of various aromatic imines proved to be effective resulting contrasts NHC-induced b-alkylation23 of the same type of pro-
in the formation of products 6a–q in 70–95% isolated yields. nucleophiles in the absence23a,c,d or the presence23b of an imine.
It is noted that o-, m-, and p-substitution as well as electron- This distinct BAC catalysis has proved to go far beyond the reported
donation and -withdrawal were tolerated. Likewise, accessible NHC catalysis in terms of efficiency and scope.17
functionalities include amino, hydroxy, ester, cyano, and nitro
Finally, the potential for asymmetric BAC catalysis was
groups (h–j, n, p–q). In addition, various heterocyclic imines demonstrated by using Gravel’s enantiopure carbene precursor
16a
with distinct electron demand proved to be excellent substrates 3dÁHBPh4 (Scheme 3).
giving products 6r–w in 83–92% isolated yields. It is noted that
In summary, a rare BAC catalysis has been uncovered, which
primary, secondary, and tertiary aliphatic imines were converted is clearly distinct from related catalyses.16,17 Aza-MBH reactions
to products 6x–z in 78–92% isolated yields. between aromatic, heteroaromatic, or aliphatic imines and acyclic
Furthermore, the scope of Michael acceptors was examined or cyclic a,b-unsaturated ketones and carboxylic acid derivatives
by using imine 4a as electrophile; here, a catalyst system
composed of 3bÁHBPh4 and DBU at 40 1C proved to be most
Table 3 Scope of Michael acceptorsa
Table 2 Scope of iminesa
a
Yields refer to isolated products 6ab-aj, after purification by prepara-
tive thin-layer chromatography (PTLC) on silica gel.
a
Scheme 3 Asymmetric induction with the enantiopure BAC precursor
3dÁHBPh4.
Yields refer to isolated products 6a–z, after purification by preparative
thin-layer chromatography (PTLC) on silica gel.
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