Enantioselective N-heterocyclic carbene-catalysed intermolecular crossed benzoin condensations: Improved catalyst design and the role of in situ racemisation

Article abstract of DOI:10.1039/d0ob02017f

The enantioselective intermolecular crossed-benzoin condensation mediated by novel chiral N-heterocyclic carbenes derived from pyroglutamic acid has been investigated. A small library of chiral triazolium ions were synthesised. Each possessed a tertiary alcohol H-bond donor and a variable N-aryl substituent. It was found that increasing both the steric requirement and the electron-withdrawing characteristics of the N-aryl ring led to more chemoselective, efficient and enantioselective chemistry, however both quenching the reaction at different times and deuterium incorporation experiments involving the product revealed that this is complicated by product racemisation in situ (except in the case of benzoin itself), which explains the dependence of enantioselectivity on the electrophilicity of the reacting aldehydes common in the literature. Subsequent protocol optimisation, where one reacting partner was an o-substituted benzaldehyde, allowed a range of crossed-benzoins to be synthesised in moderate-good yields with moderate to excellent enantioselectivity.

Full text of DOI:10.1039/d0ob02017f

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Enantioselective N-heterocyclic carbene-catalysed
intermolecular crossed benzoin condensations:
improved catalyst design and the role of in situ
racemisation†
Cite this: DOI: 10.1039/d0ob02017f
Eoghan G. Delany and Stephen J. Connon
*
The enantioselective intermolecular crossed-benzoin condensation mediated by novel chiral
N-heterocyclic carbenes derived from pyroglutamic acid has been investigated. A small library of chiral
triazolium ions were synthesised. Each possessed a tertiary alcohol H-bond donor and a variable N-aryl
substituent. It was found that increasing both the steric requirement and the electron-withdrawing
characteristics of the N-aryl ring led to more chemoselective, efficient and enantioselective chemistry,
however both quenching the reaction at different times and deuterium incorporation experiments invol-
ving the product revealed that this is complicated by product racemisation in situ (except in the case of
benzoin itself), which explains the dependence of enantioselectivity on the electrophilicity of the reacting
aldehydes common in the literature. Subsequent protocol optimisation, where one reacting partner was
an o-substituted benzaldehyde, allowed a range of crossed-benzoins to be synthesised in moderate-
good yields with moderate to excellent enantioselectivity.
Received 2nd October 2020,
Accepted 17th November 2020
DOI: 10.1039/d0ob02017f
rsc.li/obc
In the intervening years, the use of N-heterocyclic carbenes
derived from the deprotonation of thiazolium and triazolium
Introduction
Since its discovery in 1832,1 the benzoin condensation ion precatalysts in homobenzoin/acyloin reactions conden-
between two molecules of benzaldehyde is acknowledged as sations has been explored extensively.6 These reactions
one of the oldest carbon–carbon bond forming reactions in produce synthetically malleable7,8 chiral α-hydroxy ketone pro-
organic synthesis. Initially catalysed by the cyanide anion,2 ducts. Consequently, many attempts have been made to design
over 100 years later Ukai and co-workers successfully employed chiral precatalysts capable of bringing about highly enantio-
thiamine (vitamin B1) and base to mediate the reaction.3 It selective benzoin condensations. In 1966, seminal work from
was through this work that the thiazolium ring came to be Sheehan and Hunnemann detailed the synthesis of the chiral
recognised as the catalytically relevant unit, which led to thiazolium salt 7 (Fig. 1).9 The carbene derived from this
Breslow’s subsequent elucidation of the associated mechanism material could promote the formation of 6 with 21% ee.
in 1958 (Scheme 1).4,5
Subsequent design of 8 10 several years later allowed the gene-
He proposed that initial deprotonation of 1 leads to in situ ration of 6 with 52% ee but in just 6% yield.11 Although thiazo-
production of 1a, which may also be formally considered a lium-derived NHCs of various design were utilised by other
carbene. Attack upon a molecule of benzaldehyde (2) forms
adduct 3 and, following a proton exchange, generates the key
nucleophilic enolamine intermediate 4 (often referred to as
the Breslow intermediate). This attacks a second molecule of
benzaldehyde to furnish adduct 5. A final proton exchange
allows the elimination of 1a, which re-enters the catalytic
cycle, with concurrent formation of benzoin (6).
Centre for Synthesis and Chemical Biology, Trinity Biomedical Sciences Institute,
School of Chemistry, The University of Dublin, Trinity College, Dublin 2, Ireland.
E-mail: delanye@tcd.ie, e.delany@latrobe.edu.au; Fax: +353 16712826
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
Scheme 1 Mechanism of the thiazolium ion-derived carbene-catalysed
d0ob02017f
benzoin condensation.
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chiral analogues capable of representing a reliable and repro-
ducible solution to this problem.
Results and discussion
Fig. 1 Early chiral precatalysts employed in the benzoin condensation.
Synthesis of chiral triazolium salts (12, 21–26)
Having previously designed precatalyst 12, capable of mediat-
ing a high-yielding and enantioselective homobenzoin conden-
sation under basic conditions, we set about the synthesis of a
family of chiral triazolium salts (21–26, Scheme 2) possessing
the same general structure but also incorporating the struc-
tural elements previously discerned29 to be sine qua non for
promoting chemoselective intermolecular crossed-benzoin
chemistry. Precatalysts 12 and 22–26 were prepared according
to a general procedure: esterification of (L)-pyroglutamic acid
13 provides 14, which was reacted with excess phenylmagne-
sium bromide to afford alcohol 15. Subsequent silylation pro-
vided the TMS-protected lactam 16 which, when treated with
Meerwein salt overnight followed by addition of the relevant
aryl hydrazine, yielded the crude hydrazone intermediate 18
via 17. Ring closure with triethyl orthoformate at elevated
temperature and deprotection of the silylated triazolium salt
19 with HBr (generated catalytically through use of bromotri-
methylsilane in MeOH) provides the desired triazolium salt of
general structure 20. The relevant hydrazine precursors, if not
commercially available, were derived from the parent aniline
through diazotisation and subsequent reduction in situ using
SnCl2·H2O. An important note is that the 19F NMR spectra of
groups in later years, no efforts succeeded in substantially
improving enantiocontrol.12
Enders reported the use of the first chiral triazolium ion
precatalyst in 1996.13 Under basic conditions, use of 9 allowed
the production of 6 in 66% yield and 75% ee, although both
product yields and optical purities varied considerably when
employing other aromatic aldehydes; the use of activated ben-
zaldehydes tended to negatively impact the enantioselectivity
of the reaction, while electron-rich benzaldehydes induced the
opposite effect, albeit at the expense of reaction rates. Similar
observations were reported by Leeper et al. in 1998 using pre-
catalyst 10,14 which produced (R)-benzoin in 80% ee. Enders’
later developed 11, which allowed the isolation of benzoin in
90% ee,15,16 while You and co-workers showed that bis-triazoly-
lidene carbenes could also mediate various homobenzoin con-
densations with high-excellent enantioselectivity (84–95%
ee).17,18 In 2009 – as part of a programme aimed as using
hydrogen-bond donation as a control element in acyloin con-
densations19 – we devised the NHC precatalyst 12 which, in
the presence of Rb2CO3, could catalyse the benzoin conden-
sation in 90% yield with almost perfect enantioselectivity
(>99%).20 Again, however, significant variations in both yield
and ee were observed depending upon the identity of the aro-
matic aldehyde employed – with trends paralleling those out-
lined above.21
Despite the advances made in recent years in the homoben-
zoin condensation (which has dominated the field until
recently), the lack of an efficient protocol for the NHC-cata-
lysed intermolecular cross-condensation22–26 between two non-
identical aromatic aldehydes has hampered the synthetic
utility of the reaction.
To the best of our knowledge, there exists in the literature
no study dedicated exclusively to the development of an
efficient protocol for the chemoselective and asymmetric inter-
molecular crossed-benzoin condensation between two aryl
aldehydes catalysed by an NHC. As part of a programme aimed
at the development of highly efficient crossed acyloin
reactions,23c,27,28 we recently reported the synthesis of a novel
triazolium precatalyst capable of directing the racemic inter-
molecular crossed-benzoin condensation with excellent
chemoselectivity if one of the partners incorporated an o-halo
substituent.29 The steric and electronic characteristics of the
catalyst’s N-aryl substituent proved to be key: steric bulk near
the carbene centre is required to attain high selectivity, yet the
aryl unit needs to incorporate electron-withdrawing functional-
ity to allow useful efficacy. Given the dearth of NHC-mediated
systems for the asymmetric synthesis of crossed-benzoins, we
sought to extend this methodology through the design of Scheme 2 General synthesis of chiral triazolium salts.
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catalysts of general type 20 are silent, so full or partial anion 15% ee (entry 4). Concerned that this irreproducibility could
exchange (most likely with bromide derived from the last step) be due to the poor solubility of K2CO3 in THF, we screened
may occur.
a series of soluble nitrogenous bases of varying basicities
to evaluate their effect upon the stereochemical outcome.
Use of 1,4-diazabicyclo[2.2.2]octane (DABCO, pKaH conj. acid
Preliminary studies
With the necessary precatalysts in hand, we set about estab- at 25 °C = 8.8) afforded 30 in low yield after just 1 h in 67% ee
lishing a set of conditions amenable to an asymmetric (entry 5).
crossed-benzoin condensation between two non-identical aro-
Gratifyingly, we observed no change in the ee of the isolated
matic aldehydes. Previous studies have shown that, in crossed product over the course of a 2–4 h reaction time when DABCO
acyloin condensations where one coupling partner is an ortho- was employed as the base, while yields increase in an approxi-
substituted benzaldehyde, use of an NHC catalyst typically mately time-dependent linear fashion; with 1H NMR spectro-
results in higher yields of crossed acyloins derived from initial scopic analysis indicating a 65% yield of 30 after 4 hours
attack of the NHC upon the non-ortho-substituted coupling (entries 6–8). Similar results were obtained employing N,N-
partner.27,29–32 With this in mind, we focused upon the poten- diisopropylethylamine (pKaH 10.8, (entries 9–12). Surprisingly,
tial cross-condensation between benzaldehyde 2 and 2-bromo- employing N,N-dimethylaminopyridine (DMAP, pKaH 9.7)
benzaldehyde 27 and the effect of various precatalysts on resulted in a slower reaction rate, despite its increased basicity
selectivity under basic conditions (Table 1).
relative to DABCO (entry 13); the cause of this observation was
In the presence of 6 mol% of 21 and an equimolar loading not elucidated but may relate to the less hindered (and thus
of K2CO3, we observed no conversion to any of the four more nucleophilic) nature of DMAP.
benzoin products 6, 28, 29 or 30 (entry 1) after 48 h; which
Use of the considerably less basic N-methylimidazole (NMI,
underscores the need for the N-aryl substituent to be electron pKaH 7.1) led to slower product formation – with just 6% of 30
deficient in these systems.33 Subsequent use of the N-2,4,6-tri- observed after 20 h (entry 14). Finally, 1,8-diazabicyclo[5.4.0]
chlorophenyl analogue 22 under identical conditions pro- undec-7-ene (DBU, pKaH ca. 13) mediated significantly faster
duced benzoin (6) in 15% yield (via 1H NMR spectroscopic coupling than observed using other bases. Quenching the reac-
analysis of the crude reaction mixture) and allowed isolation of tion after only 2 h allowed the isolation of 36 in 55% yield but
30 in 71% yield, albeit with very poor enantiocontrol (entry 2). with reduced ee (entry 15).
Conscious of potential racemisation through base-mediated
It is noteworthy that in these reactions, none of either the
enolisation, the reaction time was reduced to 17 h; resulting in homodimer of 27 (i.e. 28) or the product 29 (derived from for-
improved enantioselectivity of 64% ee (entry 3). However, rep- mation of the Breslow intermediate from 27 followed by attack
etition of the same experiment on threefold scale for 2 h on 2) were formed. Significant (albeit as a minor product)
resulted in the generation of 30 in high yield but with just levels of 6 were usually observed.
Table 1 Asymmetric crossed-benzoin condensation: preliminary studies
Entry
Precatalyst
Base
Time (h)
Yield 28 (%)
Yield 6a (%)
Yield 29a (%)
Yield 30a,b (%)
ee 30c (%)
1
2
21
22
22
22
22
22
22
22
22
22
22
22
22
22
22
22
K2CO3
K2CO3
K2CO3
K2CO3
DABCO
DABCO
DABCO
DABCO
DIPEA
DIPEA
DIPEA
DIPEA
DMAP
NMI
48
48
17
2
1
2
3
4
1
2
3
4
4
20
1
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
8
9
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
n/a
7
79 (71)
65 (60)
87 (85)
30 (25)
49 (45)
59 (55)
60 (57)
20 (14)
34 (30)
48 (45)
65 (63)
16 (9)
3
64
15
67
67
67
67
67
67
67
67
67
n/d
n/d
57
4d
5
4
14
19
20
20
7
6
7
8
9
10
11
12
13
14
15
16
9
11
14
1
0
17
18
6 (n/d)
48 (n/d)
59 (55)
DBU
DBU
2
a Determined via 1H NMR spectroscopic analysis of the crude reaction mixture using styrene (0.25 equiv.) as an internal standard. b Value in
parentheses represents isolated yield. c Determined via CSP-HPLC analysis. d Reaction carried out on a 3.3 mmol scale as opposed to 1.1 mmol
scale.
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Catalyst screening
but greater steric bulk of iodine relative to bromine resulted in
sluggish coupling and moderate product ee (entry 6).
Confident that – although the enantio- and chemoselectivity of
the reaction remained suboptimal – we had established a reac-
tion timeframe and suitable base (DIPEA) amenable to the
generation of reproducible data, we then set about evaluating
the other members of the triazolium precatalyst library in the
coupling between 2 and 27 (Table 2). As previously detailed, in
the presence of DIPEA, 6 mol% of the carbene derived from 22
promotes the reaction in 63% yield and 67% ee after 4 h in
THF (entry 1). To our surprise, reducing the nucleophilicity of
the carbene through the use of precatalyst 12 under the same
conditions provided 30 in just 26% isolated yield in racemic
form (entry 2). In addition, benzoin (6) was isolated as the
major product in 74% yield and >99% ee. Use of triazolium
salt 23 – possessing a bulkier N-aryl ring but a more electron-
rich carbene centre – led to an improvement in the ee of 30
albeit stemming from slow, inefficient reaction (entry 3).
Intrigued by this observation, we postulated that the presence
of a sterically demanding substituent in the ortho-positions of
the N-aryl ring may serve to improve the catalyst’s ability to dis-
tinguish between different faces of the aromatic aldehydes.
However, an increase in the pKa of the triazolium precatalyst
may consequently impact upon the levels of carbene generated
in situ and thus, the isolated yields of the desired cross-
product.
The observation that the carbene derived from precatalyst
– containing the smaller but more electronegative
12
N-pentafluorophenyl ring (relative to 23–26) – exhibits a
marked preference for promoting the formation of benzoin 6
in good yields and excellent enantioselectivity (see Table 2,
entry 2) with concurrent production of crossed-benzoin 30 in
racemic form in the same pot is remarkable. Catalyst 22 pro-
motes the formation of 30 as the major reaction product with
modest enantiocontrol (see Table 2, entry 1) via attack on 27
from the opposite face to that attacked on benzaldehyde
during the formation of 6.
After crossed-benzoin reactions between 2 and 27 in the
presence of either 12, 22 or 23, hydrogenolysis of 27 using a
palladium catalyst under a hydrogen atmosphere and sub-
sequent CSP-HPLC analysis revealed that the benzoin is
formed as the (R)-enantiomer, whereas crossed-benzoin 30 is
produced in enantioenriched (S)-form (Table 3).
As previously noted, precatalyst 12 catalyses the formation
of 6 in >99% ee while 30 is concurrently synthesised as a race-
mate (entry 1). However, in addition to promoting the pro-
duction of (S)-30 in 63% yield and 67% ee, precatalyst 22
allows the formation of (R)-6 in 12% yield and 80% ee
(entry 2). Similar results were observed using the bromo-substi-
tuted 23 (entry 3).
The precatalyst 24 (in which the p-bromo atom of the N-aryl
substituent has been replaced with the more electron with-
drawing CF3 unit) mediated the formation of 29 with an ee of
75% ee but just 28% isolated yield (entry 4). We have pre-
viously shown28 that under basic conditions an achiral ana-
logue of 25 has been shown to catalyse the crossed-benzoin
condensation between benzaldehyde and 2-bromobenzalde-
hyde with unprecedented levels of chemoselectivity. It was
therefore disappointing that under our reaction conditions,
utilisation of precatalyst 25 led to isolation of 30 in 38% yield
and 68% ee; although accelerated reaction rates relative to 24
were observed, (entry 5). The iodo-substituted salt 26 offered
no improvement: the influence of the reduced electronegativity
We next endeavoured to determine whether this trend was
reliant solely on the steric characteristics of the catalyst or if
the identity of the ortho-substituted aldehyde also influenced
the enantioselectivity of the reaction. We therefore evaluated
the effect selected precatalysts had on both the chemo- and
enantioselectivity of the crossed-condensation between 2 and
2-chlorobenzaldehyde (31) and 2-iodobenzaldehyde (32,
Table 4). In the presence of 6 mol% of precatalyst 12 and
Table 3 Crossed-benzoin
condensation
and
subsequent
hydrogenolysis
Table 2 Crossed-benzoin condensation: catalyst evaluation
Entry
Precatalyst
Yielda (%)
eeb (%)
Yield 6a
(%)
ee 6b
(%)
Yield 30a
(%)
ee 30c,d
(%)
Entry
Precatalyst
1
2
3
4
5
6
22
12
23
24
25
26
63
26c
23
28
38
3
67
0
72
75
68
60
1
2
3
12
22
23
74
12
2
>99
80 (R)
78 (R)
36
63
23
0
67 (S)
72 (S)
a Isolated yields. b Determined via CSP-HPLC analysis. c Determined
through hydrogenolysis of the brominated crossed-benzoin adduct
a Isolated yields. b Determined via CSP-HPLC analysis. c In the same and subjection to CSP-HPLC analysis. d No racemisation of 30 is
reaction pot, benzoin was also produced in 74% yield with >99% ee.
assumed.
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Table 4 Asymmetric crossed-benzoin condensation: effect of a substrate ortho-substituent upon enantioselectivity
Entry
Precatalyst
R
Yield 33/34a (%)
Yield 6b,c (%)
Yield 35/36a (%)
Yield 37/38b (%)
ee 37/38d (%)
1
2
3
4
5
6
12
22
23
12
22
23
Cl
Cl
Cl
I
I
I
8
5
2
0
0
0
52 (>99)
32 (80)
24 (78)
65 (n/d)
42 (n/d)
32 (n/d)
2
1
1
0
0
0
44
49
28
35
43
27
44 (R)
40 (S)
53 (S)
58 (S)
72 (S)
74 (S)
a Determined via 1H NMR spectroscopic analysis of the crude reaction mixture using styrene (0.25 equiv.) as an internal standard. b Isolated
yields. c Value in parentheses represents enantiomeric excess of isolated product, for (R)-benzoin, as determined via CSP-HPLC analysis.
d Determined via CSP-HPLC analysis.
DIPEA, the cross-coupling between 2 and 31 proceeds with outcome of cross-benzoins with 2 mediated by the novel chiral
adduct (R)-33 formed in moderate yield and ee. However, once triazolium ion-based precatalysts under basic conditions. In
again, (R)-6 represented the major reaction product (entry 1). general, the bigger the halogen, the higher the crossed
Use of 22 as the carbene precursor results in a change in the product ee. Furthermore, as the steric bulk of the ortho-
absolute configuration of the crossed-benzoin product, with halogen atoms on the carbene’s N-aryl ring increase, the enan-
(S)-37 produced also in moderate yield and ee. Formation of tiomeric excess of the crossed adducts also improves.
(R)-6 under these conditions is less pronounced (entry 2).
Despite these findings, our efforts to develop an efficient
Consistent with previous observations; employment of the asymmetric variant of the intermolecular crossed-benzoin con-
N-2,4,6-tribromophenyl precatalyst 23 resulted in a further densation could not have been considered successful at this
improvement in enantioselectivity, alongside a diminution in point. While utilisation of o-iodobenzaldehyde (32) offered the
chemoselectivity and crossed-product yield (entry 3). The greatest potential for achieving a highly enantioselective
observation of the formation of 35 may be rationalised crossed-benzoin condensation, we were discouraged by the
through the reduced steric bulk of the ortho-chlorine substitu- lack of chemoselectivity observed using this substrate.
ent (relative to the bromine atom in 27), which results in a Conversely, use of 27 gave rise to a comparable process from
greater propensity of the catalyst to attack 31 initially relative an enantioselectivity standpoint (see Table 1, entry 12 vs.
to 27, which also produces a less hindered, less discerning Table 4, entry 6) but also provided the desired crossed-benzoin
Breslow intermediate. This is reflected in the production of adduct as the main reaction product (albeit with sub-optimal
both 33 and 35 in trace amounts (entries 1–3), a feature not chemoselectivity). The o-bromo aldehyde 27 was therefore
observed in the data detailed in Table 1.
chosen as the best substrate for further study.
Utilising 32 as the ortho-substituted coupling partner
In order to develop a truly enantioselective protocol, we first
results in similarly low levels of chemoselectivity; when the had to understand why, if the size of the catalyst N-aryl ring
reaction is mediated by the carbene derived from 12, (R)-6 is has a direct effect on facial selectivity, the design of precata-
again the primary reaction product, whereas the desired lysts 24–26 did not result in a significantly improved method-
crossed-benzoin adduct 38 is produced in 35% isolated yield ology. We reasoned that because – for instance – the steric
(entry 4). However, in contrast to the analogous use of 31 bulk around the carbene centre in precatalyst 23 relative to 24
under these conditions, (S)-38 was formed in 58% ee (compare and 25 were identical (owing to the presence of the N-aryl
with entry 1). Subsequent use of 22 resulted in improved ortho-bromine atoms), the answer must lie in the electronic
enantioselectivity (entry 5). Distinct chemoselectivity issues characteristics of the materials. The additional trifluoromethyl
arise here; 6 and 38 were generated with almost equal facility. moieties incorporated into salts 24 and 25 would allow for
Increasing the size of the precatalyst’s N-aryl ring negatively more facile deprotonation and thus a greater concentration of
impacts chemoselectivity further, to the extent that the carbene in solution relative to 23. We further posited that
carbene derived from 23 will preferentially induce the for- crossed-benzoin 30, possessing an electronegative o-bromine
mation of (R)-6 over the crossed-benzoin (S)-38 (entry 6), albeit atom in close proximity to the α-carbon chiral centre, would
with an increase in the cross-product ee to 74%.
have a pKa lower than benzoin and so, under our reaction con-
The results obtained in Tables 3 and 4 are indicative of a ditions, may therefore be subject to racemisation via either
clear trend – that, in general, the identity of the ortho-halo- base-mediated enolisation or a catalyst-mediated addition/
benzaldehyde substituent does influence the stereochemical elimination mechanism (Scheme 3).
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in the same pot (by the same catalyst) but with such contrast-
ing degrees of enantiocontrol.
We sought to further support this hypothesis by studying
the effect of exposure of enantioenriched 30 to various car-
benes (Table 6). After stirring 6 mol% of precatalyst 12 in the
presence of DIPEA in THF for 15 minutes; addition of (S)-30
(53% ee) leads to rapid onset of racemisation: just 15 min fol-
lowing exposure, the ee of the sample was depleted (entry 1);
similarly, but in a less pronounced manner, the use of pre-
catalyst 22 under identical conditions returned (S)-30 in 47%
ee after 15 minutes reaction time (entry 2). The use of the less
acidic and more hindered precatalyst 23 allowed the re-iso-
lation of (S)-30 without any observable loss of ee after
15 minutes (entry 3). Finally, the carbene derived from 24
Scheme 3 Potential racemisation pathways.
In order to investigate these possibilities, we initially
sought to expose an enantioenriched sample of 30 to a solu-
tion of pre-formed carbene in the presence of 5 equivalents of
CD3OD as solvent and monitor the corresponding deuterium
1
appears
to
represent
a
median
between
its
incorporation into 30 via H NMR spectroscopy. However, the
N-pentafluorophenyl and N-trichlorophenyl analogues; with
(S)-30 recovered in 43% ee. It appears that the size of the
N-aryl ring and the pKa of the triazolium ring (and thus the
concentration of carbene generated in solution) are the key
factors influencing the racemisation of 30 under these reaction
conditions.
In an attempt to ameliorate the racemisation problem, we
examined the effect of various mixed solvent systems (Table 7)
upon the chemo- and enantioselective outcome of the cross-
condensation between 2 and 27 in the presence of chiral tria-
zolium precatalysts and base. In a 4 : 1 THF : n-hexane solu-
tion, (S)-30 is produced in low isolated yield and 54% ee after
18 h employing 6 mol% of precatalyst 22.
Alternatively, conducting the reaction in a 4 : 1 THF : MTBE
solvent system increased the yield significantly but was
accompanied by a marked reduction in ee (entry 2). A
10 : 1 mixture of PhMe : CH2Cl2 allowed isolation of (S)-30 in
54% yield and higher ee (entry 3). While the solubility of 22 in
conjunction with DIPEA was too low in toluene alone to allow
the reaction to be carried out efficiently, a 7.5 : 1 PhMe : THF
mixture resulted in a moderate 63% isolated yield and 75% ee
after 20 h when 1.25 equivalents of 27 were employed (entry 4).
Gratifyingly, under these conditions, concurrent formation of
6 was suppressed to just 5% levels (determined via 1H NMR
spectroscopic analysis of the crude reaction mixture).
excess of CD3OD resulted in deactivation of the carbene in situ
and we failed to observe any reaction.
Therefore, we instead exposed both 30 and 6 to a 6 mol%
loading of the non-nucleophilic base DIPEA in THF in the
presence of 10 equivalents of CD3OD (but the absence of
carbene) and monitored the rate of deuterium incorporation
as a function of time (Table 5). For accuracy and reproducibil-
ity, it was necessary to operate at a lower concentration (0.45
M) to that which we had used previously – as benzoin exhibits
poor solubility in THF at 1.1 M concentration (which were the
previously typical reaction conditions).
As expected, at t0 there is no incorporation of deuterium
observed (entry 1). However, at t = 2 h we were able to detect
trace levels of deuteration (entry 2). This deuterium uptake
continued – with 12% incorporation after 44 h (entries 3–5). In
contrast, under identical conditions and sampling timepoints,
6 displays no inclination for D-uptake at all (entries 6–9). With
these results, we were confident that in parallel with inducing
a change in the cross-product’s absolute configuration, the
presence of the ortho-bromine atom also increases the acidity
of the α-proton of (S)-30, resulting in base-mediated racemisa-
tion to which 6 is not susceptible under the same conditions.
This provides an explanation for how 6 and 30 can be formed
Table 5 Base-mediated enolisation: deuterium labelling studies
Table 6 Carbene-mediated racemisation studies
Entry
Substrate
X
Time (h)
H%a
1
2
3
4
5
6
7
8
9
30
30
30
30
30
6
6
6
6
Br
Br
Br
Br
Br
H
H
H
H
0
2
5
20
44
0
2
5
20
100
96
95
91
88
100
100
100
100
Entry
Precatalyst
Time (h)
eea (%)
1
2
3
4
12
22
23
24
0.25
0.25
0.25
0.25
38
47
53
43
a Determined via 1H NMR spectroscopic analysis using protons 1 and
1′ as an internal reference.
a Determined via CSP-HPLC analysis.
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Table 7 Asymmetric crossed-benzoin condensation: solvent screening
Entry
Precat.
Base
Solvent
Time (h)
Yield 36a (%)
ee 36b (%)
1
2
22
22
22
22
22
23
23
22
23
22
22
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
KHMDS
KHMDS
KHMDS
KHMDS
KHMDS
KHMDS
THF : n-hex. (4 : 1)
THF : MTBE (4 : 1)
PhMe : CH2Cl2 (10 : 1)
PhMe : THF (7.5 : 1)
PhMe : THF (7.5 : 1)
PhMe : THF (7.5 : 1)
PhMe : THF (7.5 : 1)
PhMe : THF (7.5 : 1)
PhMe : THF (7.5 : 1)
PhMe : THF (7.5 : 1)
PhMe : THF (7.5 : 1)
18
18
18
20
4
18
20
72
72
24
18
19
56
54
63
40
27
52
2
54
33
66
75
75
85
57
72
80
79
0
3
4c
5
6
7d
8e
9e
10f
11g,h
5
6
94
a Isolated yield. b Determined via CSP-HPLC analysis. c 1.25 equiv. of 27 employed. d Reaction carried out using 12 mol% of both precatalyst and
base. e Reaction performed at −40 °C. f Reaction performed at 0 °C. g Reaction carried out using 12 mol% KHMDS. h 1.5 equiv. of 27 employed.
Reduction of the reaction time still allowed us to obtain (S)-30 1.25 equivalents of 27: conditions which we felt enabled mod-
in 40% yield but no improvement in enantioselectivity was erate chemoselective production of the desired cross-product
detected (entry 5) – suggesting that while the use of non-polar without significantly impacting the enantioselectivity of the
solvents succeeds in partially alleviating the problems associ- reaction. Under these conditions, benzaldehyde (2) can be
ated with product racemisation, there is an inherent lack of coupled with 27 in 63% isolated yield and 75% ee (entry 1). A
facial selectivity displayed by the carbene derived from pre- lower concentration furnished 30 in 80% ee, although as
catalyst 22. Seeking to overcome the slow reaction rate, we expected, the yield was negatively impacted (entry 2).
decided to employ precatalyst 23 in toluene alone and utilised Interestingly, 2-naphthaldehyde (39) proved an exceptionally
KHMDS (6 mol%) as base – to generate a higher concentration active substrate: 40 precipitated from solution after just 1 h;
of carbene in situ while concurrently avoiding solubility issues. however, the product is present in racemic form after 20 h
Under these conditions (S)-30 was formed in 85% ee, albeit in (entry 3). Quenching the reaction after 2 h enabled the iso-
poor yield (entry 6).
lation of 40 in moderate yield and with good ee (entry 4).
Further modifications to this system proved unsuccessful – Electron-neutral benzaldehydes proved the most suitable coup-
doubling the catalyst and base loading was accompanied by a ling partners in our hands, with 3-tolualdehyde (41) under-
corresponding improvement in yield after 20 h but a reduction going asymmetric condensation with 27 to form 42 with high
in ee (entry 7). While lowering the reaction temperature caused ee (entry 5). Biphenyl-3-carbaldehyde (43) reacts more slowly,
the reaction rate to drop sharply (entry 8). Under these con- undoubtedly due to the increased steric requirement, but still
ditions, use of precatalyst 23 offered slight improvements: pro- allows access to 44 in 57% yield and appreciable enantiopurity
ducing (S)-30 in 5% yield and 80% ee (entry 9) at −40 °C. (77% ee, entry 6).
Increasing the temperature to 0 °C was not effective (entry 10).
Consistent with observations disclosed in previous
Conversely, doubling the loading of KHMDS and employing studies,19,20 enantioselectivity in the presence of electron-
1.5 equivalents of 27 enables chemoselective production of 30 deficient benzaldehydes 45, 47 and 49 is reduced (entries 7–9).
in 94% isolated yield but as a racemate (entry 11).
This may be attributable to increased acidity of the α-proton in
It seemed clear that in these systems the factors which products 46, 48 and 50. In addition, the chemoselectivity of
favour high efficiency are detrimental to achieving high the process is reduced when employing 45 and 47 due to a
enantioselectivity. For instance; the optimal reaction con- greater proclivity for the formation of the corresponding
ditions to maximise yields of (S)-30 also encourage racemisa- homobenzoin products derived from these aldehydes; result-
tion, while a system promoting a more enantioselective ing in diminished yields. Conversely, electron-rich benzal-
crossed-condensation relies on a non-polar environment and a dehydes tend to participate in highly chemoselective but
bulky, less active carbene catalyst, which reduces rate and slower reactions: 52 can be obtained in 48% yield through
yield. Acknowledging the above, we decided to strike a compro- cross-coupling between 3-anisaldehyde (51) and 27 with 83%
mise between the two extremes and screen a range of substi- ee after 20 hours (entry 10), while 3-isopropoxybenzaldehyde
tuted benzaldehydes in the intermolecular cross-condensation (53) participates in the condensation with isolation of 54 with
with 27 using the best conditions identified (Table 8).
marginally lower enantiocontrol (entry 11).
Precatalyst 22 was employed in the presence of DIPEA in a
The methoxy-substituted naphthaldehyde 55 proved less
7.5 : 1 PhMe : THF solvent system (see Table 7, entry 4) using adequate as a substrate, however 56 could still be obtained in
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Table 8 Substrate scope: non-ortho-substituted benzaldehydes
Since our efforts to marry both high yields and enantio-
selectivity had reached an impasse, we dedicated our efforts to
maximising enantiocontrol, irrespective of yield. Having
already extensively evaluated a range of reaction conditions, we
focused our attention instead on our choice of ortho-substi-
tuted benzaldehyde. Conscious of the fact that the increased
acidity of the crossed-benzoin α-proton was hindering our
efforts, we postulated that installation of an ortho-substituent
capable of deterring deprotonation might be a viable strategy
to overcome this obstacle. In this regard, we took inspiration
from the pKa values of the ortho-substituted phenol series
where, despite the superior electronegativity of fluorine, the
pKa of 2-fluorophenol (8.73) is actually greater than that of
2-chlorophenol (8.51) or 2-bromophenol (8.39). This is primar-
ily attributed to the fact that fluorine can favourably hydrogen-
bond with the acidic proton (O–H–F) to form a chelating intra-
molecular five-membered ring to a greater extent than chlor-
ine, while the larger atomic radius of bromine prevents it from
participating in this way (Fig. 2).34
Entry
1
Substrate
Product
Yielda (%)
63
eeb(%)
75 (S)
2c
3
40
76
62
66
57
47
48
79
48
42
56
80 (S)
0
4d
5
84e
83
We postulated that such an interaction would be potentially
achievable in a crossed-benzoin product and, in an analogous
manner, could lead to decrease in the acidity of the α-proton.
Thus, under our previously established conditions, we
attempted to cross-couple 2 and 2-fluorobenzaldehyde (59)
(Table 9, entry 1). All four possible benzoin products were
6
77
7
66
1
observed at approximately 20% levels each via H NMR spec-
troscopic analysis of the crude material. Attempts to separate
these using flash chromatography were unsuccessful. It seems
obvious, a posteriori, that the fluorine atom is not of sufficient
steric bulk to control both the formation and reactivity of the
required Breslow intermediate. However, we noted how a
similar trend in pKa emerges when one considers the pKa of
both 2-fluoromphenol and 2-(trifluoromethyl)phenol (8.95 and
8.68 respectively). Thus, we repeated the attempted cross-con-
densation with 2 as before, employing 2-trifluoromethyl-
benzaldehyde (61).
Despite the slow reaction rate, we were able to isolate 62 in
34% yield and 92% ee after 20 hours (entry 2), which, to the
best of our knowledge, represents the first ever highly enantio-
selective intermolecular crossed-benzoin condensation
between two non-identical aromatic aldehydes as catalysed by
a chiral NHC catalyst. Aldehyde 62 participates in the reaction
quite slowly: reaction with the methoxybenzalehyde 51 in the
presence of the carbene provided 63 in very low yield but
again, with excellent enantiocontrol (entry 3). Use of the more
activated aromatic aldehyde 47 allowed the preparation of 64
in marginally improved yield and 88% ee after 20 hours (entry
4). In a final attempt to improve efficacy, we synthesised alde-
8
45
9
52
10
11
12
83
76
67
13
76
71
a Isolated yield. b Determined via CSP-HPLC analysis. c Reaction carried
out at 0.5 M. d Reaction time reduced to 2 h. e Subsequent recrystallisa-
tion returned the product in racemic form.
67% ee (entry 12). Finally, we were pleased to find that hetero-
cyclic aldehyde 2-thiophenecarbaldehyde (57) was also a ser-
viceable substrate (entry 13). We attempted to recrystallise
enantioenriched 40 (84% ee) from hexane: however, it appears
that enol formation in these adducts is so facile that even the
mild heating required to dissolve the material promotes com-
plete racemisation.
Fig. 2 2-Fluorophenol and a potential strategy for reducing product
acidity in a crossed-benzoin product using an o-fluoro substituent.
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Table 9 Substrate scope: fluorine-containing benzaldehydes
selective version of the reaction met with failure: deuterium
exchange experiments revealed how – in the presence of
carbene and base – these crossed-benzoin adducts are enolisa-
ble and can undergo racemisation via deprotonation at the
aryloin α-carbon atom (or possibly an addition–elimination
process involving the carbene). Susceptibility to enolisation is
enhanced in the presence of electron-withdrawing substitu-
ents; which could rationalise in part why previous studies
investigating homobenzoin condensations have observed fluc-
tuating enantioselectivity when employing activated benzal-
dehydes. Benzoin itself appears resistant to such racemisation
in the presence of catalyst and base (and sometimes precipi-
tates from solution at higher concentrations) and so we
propose that the archetypal benzoin condensation can no
longer be considered a suitable model reaction for the mean-
ingful evaluation of the potential catalytic utility of a chiral
carbene in mediating crossed acyloin condensations.
After investigation of these pathways, reaction conditions
could be modified to minimise the impact of racemisation,
thus allowing the synthesis of a range of crossed-benzoins in
moderate-good yields with moderate-high enantioselectivities
for the first time. Furthermore, careful planning and choice of
the substrate aldehyde coupling partners employed allowed
the first highly enantioselective intermolecular crossed-
benzoin condensation using an NHC. It was also shown that
the enantioselectivity of the reaction is heavily dependent
upon the identity of the ortho-substituted benzaldehyde, with
general trends suggesting that the larger the substituent, the
greater the enantiocontrol. A similar trend was observed when
considering the size of the precatalyst N-aryl ring.
Entry
1
S1
2
S2
59
Product
Yielda (%)
eeb (%)
n/d
∼20c
2
3
4
5
2
51
47
2
61
61
61
65
34
6
92
90
88
4
12
58
6d
2
65
10
50
a Isolated yield. b Determined via CSP-HPLC analysis. c Determined via
1H NMR spectroscopic analysis using styrene as an internal standard.
d Reaction time reduced to 4 h.
Conflicts of interest
hyde 65 – this retains the CF3 unit which contributes to high
chemoselectivity and enantiocontrol, yet also possesses a
(removable) p-bromo moiety to increase the activity of the elec-
trophile. Use of 65 in conjunction with 2 was unsuccessful: the
product 66 was obtained in 58% yield, but as a near racemate.
Shortening the reaction time to 4 h produced just 10% yield of
66 – albeit with improved enantiocontrol (entry 6). Evidently,
the installation of the para-bromine atom again lowers the pKa
of the α-proton to the extent that our proposed H-bonding pro-
tective effect to alleviate product racemisation is obviated
under these conditions.
There are no conflicts to declare.
Acknowledgements
We are grateful to the Irish Research Council for financial
support.
Notes and references
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Conclusions
In conclusion, we have carried out the first extensive study into
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22 For an approach involving a chiral metallophosphite cata-
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