One-pot catalytic asymmetric borylation of unsaturated aldehyde-derived imines; Functionalisation to homoallylic boronate carboxylate ester derivatives

Article abstract of DOI:10.1039/c4ob02657h

The β-borylation reaction of α,β-unsaturated aldehyde-derived imines, formed in situ, has been studied using a one-pot methodology, as a route to β-boryl aldehydes. The instability of the β-boryl aldehydes meant that derivatisation was required and routes

Full text of DOI:10.1039/c4ob02657h

Organic &
Biomolecular Chemistry
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One-pot catalytic asymmetric borylation of
unsaturated aldehyde-derived imines;
functionalisation to homoallylic boronate
carboxylate ester derivatives†
Cite this: Org. Biomol. Chem., 2015,
13, 5122
Alba Pujol, Adam D. J. Calow, Andrei S. Batsanov and Andrew Whiting*
The β-borylation reaction of α,β-unsaturated aldehyde-derived imines, formed in situ, has been studied
using a one-pot methodology, as a route to β-boryl aldehydes. The instability of the β-boryl aldehydes
meant that derivatisation was required and routes to both acetal derivatives and homoallylic boronates
were examined. β-Boryl acetals were also found to be unstable, however, the formation of homoallylic
boronate derivatives using an in situ imine hydrolysis-Wittig olefination protocol was found to be suitable,
resulting in an efficient synthesis with high enantiomeric excesses.
Received 23rd December 2014,
Accepted 24th March 2015
DOI: 10.1039/c4ob02657h
www.rsc.org/obc
egy, Scheme 1).6 Also, β-boryl aldehydes are known to be
Introduction
unstable6 making them problematic for further synthetic
Organoboron compounds have achieved many applications in applications. In addition, current procedures for the catalytic
several areas of organic chemistry, specifically as intermediates asymmetric synthesis of β-boryl aldehydes suffer from a
in asymmetric synthesis.1 Consequently, much research has number of further problems, including variable enantiomeric
focused on the preparation of key chiral compounds, through excesses (generally low to moderate), and reactions require
the addition of boryl units to CvC bonds; i.e. borylation strat- high catalyst and base loadings to produce even moderate
egies. Within the scope of the various borylation strategies, a yields.
novel approach consisting of a conjugate addition of a boryl
Over the last five years, we have been developing β-boryla-
unit, from a diboron reagent, into an α,β-unsaturated system tion methodologies which have been applied to the β-boryla-
has been developed, i.e. the β-borylation reaction.2 The dibory- tion of α,β-unsaturated imines.7 We envisaged that one major
lation (1,4-) of enones was first reported in the late 1990s by advantage of this methodology should be that one could
Marder et al.,3 and subsequent hydrolysis led to β-boryl potentially overcome the major issue of regiocontrol in the
ketones. Since then, many organometallic and organocatalytic borylation reaction α,β-unsaturated aldehydes 1 through the
systems have been developed to prepare β-functionalised com- in situ formation of the corresponding α,β-unsaturated imine.
pounds4 and the reaction has been developed into an enantio- Indeed, the formation of N-sterically hindered α,β-unsaturated
selective protocol through the use of chiral phosphines and aldimines can be used to promote a completely regioselective
N-heterocyclic carbenes, for example.4c,d Despite the major Cβ-boryl-addition, resulting in the formation of β-boryl imines,
successes in this area, introduction of boryl moiety into α,β-un- which can be readily transformed into γ-amino alcohols 2 (i.e.
saturated aldehydes still represents a substantial challenge see previous work, Scheme 1)8 and γ-diols.9 However, it is also
because the desired 1,4-boryl addition can be competitive with apparent that this effective methodology might be useful for
1,2-addition5 and even under two component or organocataly-
tic conditions, regiocontrol is variable (i.e. see Alternative strat-
Centre for Sustainable Chemical Processes, Department of Chemistry, Durham
University, South Road, Durham, DH1 3LE, UK.
E-mail: andy.whiting@durham.ac.uk
†Electronic supplementary information (ESI) available: Further experimental
details, ReactIR spectra, all 1H, 13C and 11B NMRs, and X-ray crystallographic
details. CCDC 1040392 (2a), 1040393 (2b), 1040394 (2e), 1040395 (2h) and
1040594 (2j). For ESI and crystallographic data in CIF or other electronic format
Scheme 1 Overall conversion of α,β-unsaturated aldehydes 1 to either
chiral γ-amino alcohols 2 or homoallylic boronates 3.
see DOI: 10.1039/c4ob02657h
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solving the problems of regioselectivity of the borylation of Cu(I)-phosphine mediated β-borylation reaction of
α,β-unsaturated aldehydes compared with the alternative strat- α,β-unsaturated aldehydes via β-boryl aldimines
egy6 (Scheme 1) and the instability of the resulting β-boryl
aldehydes. In addition, the development of a reliable, general,
In order to explore the conjugate addition of B2pin2 to enals
via the corresponding imine, cinnamaldehyde 1a was chosen
as the model substrate for developing optimal reaction con-
ditions for the overall process outlined in Scheme 2, using the
one-pot conditions outlined in Scheme 3.
Hence, after imine formation (to give 4a), catalytic boryla-
tion (via 5a) and hydrolysis using aqueous HCl, compound 6a
efficient, low catalyst loading [typically 3 mol% copper(I)-chiral
bis-phosphine8 compared with 20 mol% chiral secondary
amine and 5 mol% copper(I) catalyst for the alternative strate-
gy6a] and highly enantioselective synthesis of β-boryl aldehydes
would make such species more amenable for use in synthesis.
In this work, we report such a new process for the one-pot,
was obtained in a crude form with high mass recovery and a
in situ formation of β-boryl aldehydes, confirm their instability
notable absence of any starting aldehyde 1a. However, after
and hence, demonstrate their efficient synthesis by trapping
attempts to purify the crude product 6a, a considerable
amount of the starting aldehyde 1a was obtained, graphically
demonstrating the instability of β-boryl aldehydes of this type
through a Wittig reaction,6 resulting in chiral homoallylic
boronates 3 (see this work, Scheme 1).
and their facile capability to re-eliminate the boryl unit,
leading back to the starting unsaturated aldehyde 1a. At
present, the mechanism by which this de-borylation occurs is
Results and discussion
not clear; however, more importantly, this result highlighted
that this approach was incapable of providing clean β-boryl
aldehdye 6a on which to perform further studies.
In order to examine possible means by which to avoid the
instability problem associated with 6a upon purification, the
sequence shown in Scheme 3 was repeated with the p-methoxy-
cinnamaldehyde-derived starting material 1b to see if the elec-
Homoallylic boronates 3 are attractive synthetic targets since
there are a number of possibilities, such as the introduction of
a second boryl unit, which can in turn be transformed into
other functionalities leading to key building blocks for the syn-
thesis of multifunctional, chiral compounds.10 Hence, we
initiated the development of a synthesis of such compounds
through examining whether it was possible to convert α,β-
unsaturated aldehydes 1 to the corresponding β-boryl aldehyde 6
tron donating group on the benzene might reduce the
instability of the benzylic boryl product, i.e. 6b. However, the
via a one-pot, copper-catalysed, asymmetric 1,4-addition of
β-boryl aldehyde 6b was again isolated in high mass recovery
B2pin2 to α,β-unsaturated aldehydes 1 via the corresponding
in a crude form, yet during the purification process using flash
imine 4 and β-boryl imine 5 (both formed in situ), followed by
chromatography on alumina or silica gel, only starting unsatu-
imine hydrolysis. The major question to be addressed was
rated aldehyde 1b was obtained. Additionally, attempting to
whether the β-boryl aldehyde 6 could be isolated and/or
apply this methodology to a non-benzylic, and more substi-
handled, and hence converted to subsequent derivatives, as
outlined in Scheme 2.
tuted system such as tiglic aldehyde 1c, surprisingly prevented
the borylation reaction completely under the conditions out-
lined in Scheme 3. The use of a more reactive catalytic system
(i.e. CuCl/PnBu3 as described previously4) gave the target
β-boryl aldehyde 6c (starting from 1c). However, it was not
possible to isolate the product in a pure form without
decomposition back to the starting tiglic aldehyde 1c. These
Scheme 2 Proposed synthetic pathway for the conversion of α,β-unsa-
turated aldehydes 1 to β-boryl aldehydes 6 via β-boryl imines 5.
Scheme 3 Synthetic pathway for the Cu(I)–phosphine catalysed β-bor-
ylation reaction of cinnamaldehyde 1a to derive the β-boryl aldehyde 6a.
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The conditions reported in entry 3 (Table 1) for the syn-
thesis of acetal 7b could be reproduced on a larger scale;
however, it was not possible to purify the product, as with the
β-boryl aldehydes 6. All chromatographic purification attempts
caused decomposition (presumably via facile acetal deprotec-
tion) resulting in sole re-isolation of the starting material 1b.
The challenge of isolating either β-boryl aldehydes 6 or
acetal derivatives 7 meant that alternative methods for direct
derivatisation of the β-boryl imines 5 (e.g. via in situ generation
of the corresponding β-boryl aldehydes 6) was still required.
Synthesis of chiral homoallylboronates via β-boryl aldimines
A potential solution to the problematic isolation of β-boryl
aldehydes 6 could entail direct Wittig olefination to the corres-
ponding and synthetically versatile homoallylic boronates 3,
i.e. as outlined in Scheme 5.
Scheme 4 Synthetic pathway for the Cu(I)–phosphine catalysed β-bor-
ylation reaction of an unsaturated aldehydes 1 to derive the β-boryl
acetals 7 (see Table 1).
Initially, Wittig reactions were attempted using β-boryl alde-
hydes 4a, 4b and 4d (all formed via the acid hydrolysis con-
ditions shown in Scheme 4), starting with the corresponding
substrates unsaturated aldehydes 1a, 1b and 1d. However, the
subsequent Wittig did not cleanly convert the crude β-boryl
aldehydes 6 to the corresponding homoallylic boronates 3 and
only complex mixtures of products resulted. Seemingly, the
instability of the β-boryl aldehydes 6 precludes the direct deri-
vatisation of these systems under the Wittig reaction con-
ditions. Hence, an alternative in situ, one-pot methodology was
examined to see if it was possible to generate the β-boryl alde-
hyde and immediately trap through the Wittig reaction, which
requires the use of a stabilised phosphorane to withstand the
conditions required to hydrolyse the imine function of systems
5. To that end and to test if that was feasible, unsaturated alde-
hyde 1a was initially chosen, as outlined in Scheme 6, for
examination of the in situ imine hydrolysis-olefination reaction
without isolation of the β-boryl aldehyde 6 intermediate.
results clearly corroborated literature reports that use of such
β-boryl aldehydes are unstable relative to β-boryl ketones and
esters.3,11 However, in exceptional circumstances, β-boryl alde-
hydes containing highly hindered boronate esters can be
isolated.12
In order to circumvent the instability of β-boryl aldehyde
products 6, the prolonged presence of the aldehyde functional-
ity needed to be avoided. We therefore examined alternative
solutions including deprotection of the β-boryl imine 5 fol-
lowed by the formation of the corresponding acetal 7 directly
in one-pot, as outlined in Scheme 4.
Hence, unsaturated aldehydes 1b and d were converted
through to the corresponding β-boryl imines 5b and d respect-
ively, and then reacted with 1,3-propanodiol in the presence of
an equivalent of TFA which efficiently gave the corresponding
β-boryl acetals 7b and d respectively (Table 1).
From the results presented in Table 1, it was concluded
that the presence of 3 Å molecular sieves was necessary for the
effective conversion, in one-pot, of the protonated imine
directly to the corresponding acetals 7, whereas the solvent
polarity had little influence.
Table 1 Reaction conditions screened for the synthesis of compounds
7, as in Scheme 3a
Additive
3 Å MS
Conversion
Conversion
Entry
Solvent
7bb (%)
7db (%)
1
2
3
4
5
6
THF
THF
Toluene
Toluene
MTBE
MTBE
Yes
No
Yes
No
Yes
No
93
68
97
87
91
81
93
96
94
96
95
97
a Reaction conditions: see Experimental. b Determined by 1H NMR on
the crude reaction mixture.
Scheme 5 Proposed conversion of β-boryl imines 5 to the corres-
ponding homoallylic boronates 3.
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Table 3 Reaction conditions screened for the hydrolysis of imine 5a
and Wittig reaction to give 3aa
Time
(h)
Temp.
(°C)
Entry
CuSO4 equiv.
Ylide (equiv.)
1aa
1
2
3
4
5
6
0.5
1.0
1.0
Ph3PCHCO2Et (1.3)
Ph3PCHCO2Et (1.3)
Ph3PCHCO2Et (1.5)
Ph3PCHCO2Me (1.1)
Ph3PCHCO2Me (1.5)
Ph3PCHCO2Me (1.5)
3
4
8
4
5
5
RT
40
RT
RT
RT
40
Yes
Yes
Yes
Yes
No
Excess (sat.)
2.0
2.0
Yes
a Residual 1a was observed by 1H NMR on the reaction crude mixture.
Table 3, entry 5 shows that using 2 equivalents of copper(II)
sulfate gave complete β-boryl imine 5a hydrolysis and efficient
Wittig trapping occurred with 1.5 equivalents of ylide, and
hence transformation into 3a. In this case, there was no start-
ing unsaturated aldehyde 1a remaining in the crude reaction
mixture. Hence, with these reaction conditions defined, the
next targets were to apply these reaction sequences for the
asymmetric borylation reaction7,8 using (R)-DM-BINAP L1 for
the conversion of unsaturated imines 4 to the corresponding
β-boryl imines 5 to give the absolute stereochemistry shown
in Scheme 6.8 This would then be followed by the in situ
hydrolysis, Wittig trapping process on a range of different
unsaturated aldehydes. Scheme 7 shows the general pathway
employed for transformation of the unsaturated aldehydes 1,
with the respective yields and ees summarized in Table 4.
Table 4, entry 1 exemplifies the successful synthesis of com-
pound 3aii from cinnamaldehyde 1a using the sequence out-
lined in Scheme 7. Hence, homoallylic boronate 3aii was
obtained in a 54% isolated yield over the four-step sequence,
with an ee of 98% when using (R)-DM-BINAP L1 in place of tri-
phenylphosphine in the copper(I)-mediated borylation step.
This methodology also worked well on a wider range of α,β-un-
saturated aldehydes 1 to derive for the corresponding homo-
Scheme 6 One-pot, four-step methodology proposed for the syn-
thesis of homoallylic boronate 3a from cinnamaldehyde 1a.
Table 2 Optimisation of the conditions for the flash-column chrom-
atography for the isolation of homoallylic boronate 3ai
Column
support
Ratio, petroleum
ether–EtOAc
Yield
(%)
Entry
1
2
3
4
5
6
7
8
Silica gel
Silica gel
Silica gel
Silica gel
Alumina
Alumina
Florisil
20 : 1
35
60
64
55
77
36
88
71
2 : 1 (cold)
3 : 2 (cold)
13 : 1 (cold)
1 : 1 (cold)
2 : 1 (cold)
2 : 1 (cold)
Gradient (cold)
Florisil
The overall conversion for the sequence shown in Scheme 5
was high, however, conditions needed to be optimised for
chromatographic purification of the homoallylic boronate 3a
in order to provide matching isolated yields, as outlined
in Table 2.
As shown in Table 2, the first attempts to purify compound
3a (obtained in over 95% conversion in all cases) provided
only a low yield (35%) using silica gel under standard room
temperature conditions, along with a considerable proportion
of starting unsaturated aldehyde 1a (entry 1, Table 2). Cooling
the solvent and changing its polarity gave increased isolated
yields (entries 2–4, Table 2), again using silica gel, however,
the highest yield was still only 64%. It was noted though that
using either alumina or Florisil (entries 5–8, Table 2) gave no
decomposition of the homoallylic boronate 3a, and high yields
could be obtained, i.e. up to 88%. Based on these results, it
was clear that purification of the homoallylic boronates 3 was
possible, however, it was felt that the yields obtained needed
to be optimised further to reduce the presence of starting
unsaturated aldehyde 1a, i.e. by ensuring the complete hydro-
lysis of the intermediate imine 4 and a fast, efficient Wittig
reaction to trap the intermediate β-boryl aldehyde 6. Each of
these steps was further screened for different conditions, as
reported in Table 3.
Scheme 7 Enantioselective synthetic pathway proposed for the syn-
thesis of homoallylic boronates 3 from the corresponding unsaturated
aldehydes 1.
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The impact of the different unsaturated aldehyde substitu-
ents on the overall process is interesting to note. Highest ees
are obtained with R = aryl functions, such as in entries 1, 2
and 5 (Table 4). With alkyl substituents, there was evidence of
steric effects operating, and hence, a R = propyl function (entry
4, Table 1) gave higher ee than the corresponding ethyl or
methyl groups (entries 6 and 7, Table 4 respectively). The influ-
ence of a substituent R′ in the starting unsaturated aldehyde 1
was also interesting and gave mixed results. Hence, tiglic alde-
hyde 1c Table 4, entry 3) and α-methyl-cinnamaldehyde 1h
(Table 4, entry 8) provided the corresponding imines 4
smoothly. However, there was a significant effect of the R
methyl groups in both cases, with the boryl conjugate addition
step being slower, and especially when the chiral diphosphine
ligand was used. This was reflected in slower reactions and low
yields in both cases and in fact, for the α-methyl-cinnamalde-
hyde substrate 1h, the β-borylation did not take place at room
temperature and the reaction needed to be performed at 50 °C.
Because of this, the efficiency of the asymmetric step was not
determined, however, the diastereocontrol was the same for
both the achiral and chiral phosphines, i.e. a 1 : 4 mixture of
syn : anti diastereoisomers (Table 4, entry 8). For the tiglic alde-
hyde 1c (Table 4, entry 3), homoallylic boronate 3c was
obtained in 20% isolated yield as a mixture of diastereoiso-
mers which was not readily separable by chiral HPLC using
several different columns (including OD, OJ-H, AS and AD and
a range solvent elution systems). However, the relative stereo-
chemistry from the racemic reaction (PPh3 as ligand) was
assigned, and was in agreement with previous reports, i.e. as a
1 : 4 mixture of syn : anti diastereoisomers.
Table 4 Overall isolated yields and ees for the conversion of unsatu-
rated aldehydes 1 to homoallylic boronates 3
Yield 3
(%)
ee 3a, f
(%)
Entry
Unsaturated aldehyde 1
Ligand
1
2
L1
PPh3
46
54
98
3
4
L1
PPh3
40
27
87
5
6
L1
PPh3
20
[—]c
60b
7
8
L1
PPh3
45
74
91
9
10
L1
PPh3
38
54
98
73
11
12
L1
PPh3
70
54
13
14
L1
PPh3
65
34
80
15
16
L1
PPh3
19d
29d
[—]c
17
18
PPh3
PPh3
36
—
—
e
—
This methodology represents an effective enantioselective
protocol providing good to excellent ees in the asymmetric
variant. However, the lower enantiomeric excesses obtained
from hexenal 1f and pentenal 1g (entries 6 and 7, Table 4)
prompted us to further examine possible methods of improv-
ing the asymmetric induction. Considering the key role of
methanol as the protonating additive in the catalytic cycle
corresponding of the β-borylation step as originally developed
by Yun et al.,13 we decided to examine the use of an alcohol as
both the reaction medium and protonating agent, wondering
if a more hindered alcohol might improve the enantio-
a Absolute stereochemistry as shown in Scheme 7 where relevant and
on the basis of previous reports (see ref. 8). b Obtained as an
1 : 4 mixture of syn : anti diastereoisomers. c Not determined.
d Conversion only and with a 50 °C reaction temperature. e β-Borylation
proved efficient (measured by NMR), but subsequent transformation
via Wittig chemistry failed to form the resulting compound 3j.
f Measured by chiral HPLC (see ESI).
allylic boronates 3 with ees varying from 73 to >98%. The iso- selectivity while maintaining a solvent polarity similar to THF
lated yields, considering the number of steps in this one-pot for solubility purposes. Hence, isopropanol was employed in
protocol, were moderate to good.
place of THF in Scheme 7, i.e. as sole solvent for the entire
Despite the successful application of this methodology to reaction sequence, from imine formation to imine hydrolysis-
a range of substrates, as outlined in Table 4, not all sub- Wittig trapping, with no methanol addition. The results are
strates were suitable for the borylation reaction, i.e. p-nitro- summarised in Tables 5 and 6.
cinnamaldehyde was found to be unsuitable for imine
The result of this solvent change (Tables 5 and 6) was con-
formation, resulting only in Michael addition products siderably beneficial in two aspects: (1) improved asymmetric
rather than imine formation. In addition, acrolein was also induction was observed when the homoallylic boronates 3
unsuitable, since attempts to use it as a starting material were isolated. In fact, both hexenal and pentenal-derived pro-
resulted only in polymerisation products. However, and ducts 3d and 3f showed ees of 96 and 83% respectively
perhaps surprisingly, methacrolein did undergo the imine (Table 5). Indeed, even crotonaldehyde 1g could be employed
formation to give 4i, borylation to give 5i, hydrolysis and effectively in this asymmetric process to give the corres-
Wittig trapping, as shown in Table 4, entry 9, to give homoallyic ponding homoallylic boronate 3g in 82% ee; (2) monitoring
boroate 3i.
the imine formation step (Scheme 7) by in situ IR spectroscopy
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trapping of the resulting aldehyde. Additionally, the use of
iPrOH as a reaction medium for all steps in the one-pot
sequence resulted in faster reactions and higher ees when
compared to previous attempts using THF.
The further exploitation of the chiral homoallylic boronates
as platforms in synthetic chemistry is under examination and
will be reported in due course.
Table 5 Enantioselective synthesis of homoallylic boronates 3 from
unsaturated aldehydes 1 in iPrOHa
Yield
(%)
ee
(%)
Entry
1
Substrate 1
Product 3 structure
a
66
99
2
d
50
96
Experimental
General experimental
All the reactions reported herein were performed under air
unless otherwise specified. The reagents were purchased
directly from standard chemical suppliers and used as received
from the supplier without further purification. All solvents
were used as received from the supplier, except THF and
MeOH which were stored over dehydrating reagents and were
deoxygenated before use. Molecular sieves, 3 Å 1–2 mm beads,
were supplied from Alfa Aesar, and stored at 220 °C (>48 h).
Deuterated chloroform (CDCl3) was used as solvent for
routine NMR measurements. 1H NMR spectra were recorded
on a Varian-Mercury 400 MHz spectrometer, operating at
ambient probe temperature unless specified elsewhere. Coup-
ling constants (J) are given in Hz, and the multiplicity of the
NMR signals is described as singlet (s), doublet (d), triplet (t),
quartet (q) and multiplet (m). 13C NMR spectra were recorded
on Varian Brüker Avance 400 MHz. 1H NMR and 13C NMR
chemical shifts are reported in ppm (δ) relative to tetramethyl-
silane, references to the chemical shifts of residual solvent
resonances. 11B NMR spectra were recorder on a Varian Brüker
Avance 400 MHz operating at a frequency of 128 MHz and the
chemical shifts are reported in ppm (δ) relative to BF3(CH3)2O.
Mass spectra for liquid chromatography mass spectrometry
(LCMS) were obtained using a Waters (UK) TQD mass spectro-
meter (low resolution ESI+, electrospray in positive ion mode,
ES+) unless stated elsewhere. Accurate mass spectrometry was
obtained on a Finnigan LTQ-FT. The purification of the reac-
tion crudes was performed using flash column chromato-
graphy, which was carried out using different supports; Silica
gel as supplied from Sigma-Aldrich (230–400 mesh, 40–63 μm,
60 Å); activated magnesium silicate Florisil® (100–200 mesh,
289 m2 g−1) and monitored in both cases using TLC analysis
using POLYGRAM® SIL G/UV254 (40 × 80 mm) TLC plates; and
3
4
f
65
37
83
82
g
a Reaction followed in situ by ReactIR (see ESI).
Table 6 Comparison of the imine formation reaction time between
iPrOH and THF–MeOH
Imine formation time (h)
Entry
Substrate 1
iPrOH
THF
1
2
3
4
Cinnamaldehyde 1a
2-Hexenal 1d
2-Pentenal 1f
2.5
1
1
6
8
8
6
Crotonaldehyde 1g
1
(ReactIR)7d in IPA (Table 6) showed that it was considerably
faster that using the standard THF-based system. It is note-
worthy that not only were imine formations faster in IPA, and
ees higher, but in many cases, the imines crystallised and clean
crystalline compounds suitable for X-ray analysis were obtained.
Conclusions
In summary, an efficient one-pot methodology for the syn- activated neutral aluminium oxide Alumina and monitored
thesis of chiral homoallylic boronates has been developed (ees using TLC-PET foils of aluminium oxide with fluorescent indi-
up to 99%). During this work, the significant challenge of cator 254 nm (40 × 80 mm). In all cases the TLC plates were visu-
working with α,β-unsaturated aldehydes were met in terms of alised under a UV lamp operating at short (254 nm) and long
controlling the competitive 1,2- vs. 1,4-addition. Additionally (365 nm) wavelength ranges. Visualisation was aided by dipping
and more importantly, the even greater challenge of handling plates into an alkaline potassium permanganate solution.
β-boryl aldehydes has been circumvented. In particular, it was
For the imine formation studies reactions were monitored
confirmed that β-boryl aldehydes are indeed unstable and by in situ IR spectroscopy experiments (ReactIR), the instru-
especially under chromatographic purification conditions, ment which these experiments were carried out with is a
leading to de-borylation. The solution presented herein is a ReactIR 4000 equiped with MCT detector; ConcIRT window =
mild, efficient derivatisation process involving an in situ 1900–900 cm−1. Advance setting: Laser WN = 7901–415 cm−1
;
copper(II) sulfate-based imine hydrolysis followed by Wittig Apodization
= Happ General. Probe: Prob A DiComp
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(Diamond) connected via K6 Conduit (16 mm prob); Sampling saturated imine 4. To a Schlenk tube (under Ar) containing CuCl
4000–6500 at 8 cm−1 resolution; Scan option: auto select, gain 2×. (12.0 mg, 0.15 mmol, 3 mol%), PPh3 (63.0 mg, 0.3 mmol,
6 mol%) or DM-BINAP L1 (88.0 mg, 0.15 mmol, 3 mol%),
Copper(I)–phosphine mediated β-borylation reaction of
α,β-unsaturated aldehydes
NaOtBu (35.0 mg, 0.45 mmol, 9 mol%) and B2pin2 (1.02 g,
5 mmol, 1.0 equiv.), was added an aliquot of the solution con-
General procedure for the synthesis of β-boryl aldehydes 6a–c
taining unsaturated imine 4 (16.0 mL). Note that in the case of
α,β-Unsaturated imine 4 was formed in situ from the reac- the use of THF as solvent after 5 minutes stirring the mixture,
tion between enal (0.5 mmol) and amine (0.5 mmol) stirred in MeOH (2.5 equiv., 0.4 mL) was added. After 16 h, the resulting
THF (2.0 mL) and oven-dried 3 Å MS (0.5 g) for 6 h. After 6 h, β-boryl imine 5a–h was transferred into a round bottom flask
an aliquot of the solution containing the in situ-formed imine then methyl(triphenylphosphoranylidene)acetate (1.5 equiv.,
2 (2.0 mL, 0.5 mmol) was transferred to a Schlenk-tube (under 2.0 g) was added, after 5 minutes CuSO4 (2.0 equiv., 1.3 g) was
argon) containing CuCl (1.5 mg, 0.015 mmol, 3 mol%), PPh3 added along with H2O (10.0 equiv., 0.7 mL). The mixture was
(32.0 mg, 0.12 mmol, 6 mol%), NaOtBu (4.3 mg, 0.045 mmol, stirred for 5 h at room temperature. The resulting solution
9 mol%) and B2pin2 (104.0 mg, 0.55 mmol, 1.1 equiv.). After was partioned between EtOAc and brine. The aqueous layer was
5 min, MeOH (50.0 μL, 1.25 mmol, 2.5 equiv.) was added to extracted further with EtOAc (3 × EtOAc). The organic phase was
the solution and the reaction was stirred overnight. The solu- separated and washed with a CuSO4 saturated solution (3 ×
tion containing the β-boryl mine 5 was transferred into a CuSO4), dried over MgSO4. The crude reaction mixture was puri-
round bottom flask, then H2O (5.0 mL) were added into the fied by a silica gel chromatography (hexane–methanol, 20 : 1 and
solution. The reaction mixture was stirred during 1 h at room 10 : 1 as eluent) which gave the pure homoallylic boronates 3.
temperature. The resulting solution was partitioned with
Ethyl (E)-5-phenyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-
EtOAc (60.0 mL). The organic layer was washed with HCl 5% 2-yl)pent-2-enoate 3ai. Compound 3ai was obtained as a
(3 × HCl) and with H2O (3 × H2O) until the aqueous layer had yellow oil (906 mg, 55%): IR (neat) νmax 2978 (m), 1718 (m),
a neutral pH. The organic phase was separated and dried over 1653 (s), 1365 (m), 1326 (m), 1265 (m), 1167 (s), 1140 (m),
1
MgSO4. After filtration the organic phase removed under 1030 (s), 966 (s), 849 (s), 696 (m); H NMR (400 MHz, CDCl3)
reduced pressure to yield crude of the aldehyde 4a–c. Purifi- δ 7.42–7.12 (m, 5H), 6.96 (dt, J 15.7, 6.9 Hz, 1H), 5.82
cation by silica gel chromatography using a gradient of solvent (dt, J 15.6, 1.4 Hz, 1H), 4.15 (q, J 7.1 Hz, 2H), 2.73 (m, 1H), 2.53
mixture of petroleum ether–EtOAc in the ratios 9 : 1, 7 : 3, 2 : 1, (m, 1H), 2.46 (m, 1H), 1.26 (t, J 7.1 Hz, 3H), 1.21 (s, 6H), 1.18
1 : 1, 3 : 2, 2 : 3, 0 : 1.
(s, 6H); 13C NMR (101 MHz, CDCl3): δ 166.5 (COOR), 148.3,
141.6 (CHvCH–COOR), 128.6, 128.3, 125.4, 121.9 (CHvCH–
COOR), 83.6, 60.0 (O–CH2CH3), 35.1, 24.5 (C–CHvC), 21.4;
11B NMR (128 MHz, CDCl3) δ 32.7; LRMS (ESI+) m/z [M + H]
General procedure for the synthesis of β-boryl acetals 7 via
β-boryl imines
An aliquot containing the β-boryl aldimine
5 (2.0 mL, 354.1 (100%), 332.1 (35%), 329.9 (23%), 317 (21%), 313.9 (8%);
0.5 mmol) was transferred into a test tube containing the Chiral HPLC conditions OJ-H-CHIRALCEL column (250 ×
solvent followed by the addition of 1,3-propanediol (36.0 μL, 4.60 mm) fitted with guard cartridge (50 × 4.6 mm), 25 °C,
0.5 mmol, 1 equiv.) and TFA (38.0 μL, 0.5 mmol, 1 equiv.). The 0.2 mL min−1, 210 nm, hexane–iPrOH (99 : 1), tR (S) =
reaction mixture was stirred during 24 h at RT.
35.6 min, tR (R) = 39.7 min. All spectroscopic and analytical
data were identical to those reported in the literature.6
Methyl (E)-5-phenyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaboro-
Synthesis of chiral homoallylboronates via β-boryl imines
General procedure for the synthesis of homoallylic boronates 3 lan-2-yl)pent-3-enoate 3aii. Compound 3aii was obtained as a
from the β-boryl aldehyde 6. An aliquot containing the β-boryl yellow oil (680 mg, 54%) with a Rf = 0.25: IR (neat) νmax 2980
aldehyde 6a (0.94 g, 4 mmol) was transferred into a round (m), 1720 (l), 1656 (m), 1438 (m), 1370 (l), 1328 (l), 1270 (l),
bottom flask containing THF (40 mL) followed by the addition 1194 (m), 1140 (l), 1032 (s), 966 (m), 848 (l), 752 (l), 700 (l);
of (carbethoxymethylene)triphenylphosphorane (1.7 g, 1.3 equiv.). 1H NMR (400 MHz, CDCl3) δ 7.33–7.14 (m, 5H), 7.02–6.94 (m,
The reaction mixture was stirred for 3 h at room temperature. 1H), 5.86–5.82 (d, J 16 Hz, 1H), 3.71 (s, 3H), 2.82–2.72 (m, 1H),
The resulting solution was partitioned with EtOAc (60.0 mL) 2.62–2.54 (m, 1H), 2.51–2.47 (m, 1H), 1.23 (s, 6H), 1.20 (s, 6H);
and brine (15.0 mL). The organic phase was separated and dried 13C NMR (101 MHz, CDCl3) δ 167.0 (COOR), 148.2, 141.7
over MgSO4. After filtration the organic phase removed under (CHvCH–COOR), 128.8, 128.3, 125.7, 121.8 (CHvCH–COOR),
reduced pressure to yield crude of the homoallylboronate 3a.
83.6, 51.7, 35, 24.9 (C–CHvC); 11B NMR (128 MHz, CDCl3)
δ 32.7; LRMS (ESI+) m/z [M + H] 318.3 (100%), 317.7 (21%),
317.8 (33%); HRMS (ESI+) m/z calculated C18H26BO4 [M + H]
316.1960, found 316.1953; Chiral HPLC conditions OJ-H-CHIR-
ALCEL column (250 × 4.60 mm) fitted with guard cartridge
General procedure for the one-pot, four-step enantioselective
synthesis of homoallylic boronates 3 from α,β-unsaturated
aldehydes 1
Into a round bottom flask containing oven-dried 3 Å molecular (50 × 4.6 mm), 25 °C, 0.2 mL min−1, 210 nm, hexane–iPrOH
sieves (5.0 g), were added solvent (20.0 mL), enal (5.0 mmol) (99 : 1), tR = 41.9 min (S), tR = 45.8 min (R). All spectroscopic
and benzhydrylamine (1.0 equiv.). The reaction mixture was and analytical data were identical to those reported in the
stirred at room temperature leading to the imine-derived un- literature.2
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Methyl (E)-5-(4-methoxyphenyl)-5-(4,4,5,5-tetramethyl-1,3,2- 5.84–5.79 (dt, J 16, 1H), 3.71 (s, 3H), 2.79–2.68 (m, 1H),
dioxaborolan-2-yl)pent-2-enoate 3bii. Compound 3bii was 2.59–2.49 (m, 1H), 2.48–2.44 (m, 1H), 1.22 (s, 6H), 1.20 (s, 6H);
obtained as a yellow oil (367 mg, 53%): IR (neat) νmax 2984 (m), 13C NMR (101 MHz, CDCl3) δ 166.8, 148.1, 147.7, 140.1, 131.1,
2886 (s), 1722 (l), 1658 (m), 1650 (m), 1630 (s), 1510 (l), 1442 129.5, 128.4, 127.5, 121.7, 83.7, 51.1, 34.8, 33.6, 33.3, 30.2,
(m), 1368 (m), 1328 (m), 1248 (l), 1180 (m), 1140 (l), 1124 (s), 24.5; 11B NMR (128 MHz, CDCl3) δ 32.7; LRMS (ESI+) m/z
1042 (m), 1016 (s), 970 (m), 852 (m), 850 (m), 760 (m), 744 (m), [M + H] 373.5 (100%), 351.1 (91%), 372.6 (80%), 375.1 (75%);
710 (m); 1H NMR (400 MHz, CDCl3) δ 7.18–6.89 (m, 4H), HRMS (ESI+) m/z calculated C18H25BO4Cl [M] 350.1571 found
6.85–6.81 (dt, J 8, 1H), 5.82 (d, J 15, 1H), 3.80 (s, 3H), 3.71 350.1573; Chiral HPLC conditions OD-CHIRALCEL column
(s, 3H), 2.69 (m, 1H), 2.54 (m, 1H), 2.43 (m, 1H), 1.22 (s, 6H), (250 × 4.60 mm) fitted with guard cartridge (50 × 4.6 mm),
1.20 (s, 6H); 13C NMR (101 MHz, CDCl3): δ 167.0 (COOR), 25 °C, 0.8 mL min−1, 210 nm, hexane–iPrOH (99 : 1), tR
157.6, 148.9 (CHvCH–COOR), 133.5, 129.1, 121.4 (CHvCH– 10.7 min (S), tR = 13.0 min (R).
=
COOR), 113.9, 83.5, 55.1, 51.3, 35.3, 24.6, 24.5; 11B (128 MHz,
(E)-Methyl
5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-
CDCl3) δ 32.6; LRMS (ESI+) m/z [M + H] 368.9 (100%), 364.0 hept-2-enoate 3fii. Compound 3fii was obtained as a yellow oil
(37%), 347.1 (35.5%), 363.5 (12%); HRMS (ESI+) m/z calculated (746 mg, 70%) with a Rf = 0.1: IR (neat) νmax 2980 (l), 2982 (l),
C19H27BO5 [M + H] 346.2066 found 346.2066; Chiral HPLC 2914 (m), 1726 (l), 1656 (m), 1440 (m), 1388 (l), 1322 (l), 1266 (l),
conditions OJ-H-CHIRALCEL column (250 × 4.60 mm) fitted 1200 (s), 1138 (l), 1048 (s), 974 (m), 846 (m), 760 (m), 744 (s);
with guard cartridge (50 × 4.6 mm), 25 °C, 0.8 mL min−1
,
1H NMR (400 MHz, CDCl3) δ 7.00–6.91 (dt, J 15.6, 7.2 Hz, 1H),
210 nm, hexane–iPrOH (97 : 3), tR = 12.6 min (R), tR = 14.7 min (S). 5.84–5.88 (dt, J 15.6, 1.5 Hz, 1H), 3.70 (s, 3H), 2.36–2.18
Methyl (E)-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaboro- (m, 2H), 1.50–1.36 (m, 2H), 1.26–1.18 (s, 12H), 1.12 (m, 1H),
lan-2-yl)hex-2-enoate 3cii. Compound 3cii was obtained as a 0.93–0.86 (t, J 7.4 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 167.5
yellow oil (161 mg, 60%): IR (neat) νmax 2986 (m), 2904 (s), (COOR), 150.1, 121.5 (CHvCH–COOR), 83.5, 51.7, 33.8,
2336 (l), 2370 (l), 1726 (l), 1704 (m), 1466 (m), 1464 (m), 1382 25.1 (C–CHvC), 24.0, 13.7; 11B NMR (128 MHz, CDCl3)
(l), 1380 (l), 1320 (l), 1308 (m), 1240 (m), 1144 (l), 1032 (m),
δ 34.1; LRMS (ESI+) m/z [M + H] 269.2 (74%), 290.8
1
1030 (m), 954 (s), 848 (m), 750 (s), 704 (m), 670 (m); H NMR (60%), 237.1 (54%); HRMS (ESI+) m/z calculated C14H26BO4
(400 MHz, CDCl3) δ 6.89–6.83 (m, 1H), 5.80 (d, J 16, 1H), 3.74 [M + H] 269.1924 found 269.1933; Chiral HPLC conditions
(s, 3H), 1.58 (s, 1H), 1. 26 (s, 6H), 1.25 (s, 6H), 1.09 (dd, J 6.8, OD-CHIRALCEL column (250 × 4.60 mm) fitted with guard
2.6 Hz, 3H), 0.93 (d, J 7.3 Hz, 3H); 13C NMR (101 MHz, CDCl3): cartridge (50 × 4.6 mm), 25 °C, 0.40 mL min−1, 210 nm, hexane–
δ 167.2 (COOR), 154.9 (CHvCH–COOR), 128.3, 127.2, 119.7 iPrOH (98 : 2), tR = 12.8 min (S), tR = 14.9 min (R).
(CHvCH–COOR), 83.1, 51.2, 39.2, 24.8 (C–CHvC), 19.0, 13.6;
Methyl (E)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hex-
11B NMR (128 MHz, CDCl3) δ 33.8; LRMS (ESI+) m/z 269.2 2-enoate 3gii. Compound 3g was obtained as a yellow oil
(100%), 237.1 (95%), 291.2 (66%); [M + H] HRMS (ESI+) m/z (662 mg, 65%) with a Rf = 0.1: IR (neat) νmax 2976 (s), 1720 (l),
calculated C14H25BO4 [M + H] 268.1960 found 268.1982.
1654 (s), 1458 (s), 1436 (s), 1368 (m), 1316 (m), 1266 (m), 1158
Methyl (E)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)oct- (s), 1142 (l), 1038 (s), 966 (m), 850 (m), 706 (m), 670 (m);
2-enoate 3dii. Compound 3dii was obtained as a yellow oil 1H NMR (400 MHz, CDCl3) δ 7.01–6.93 (dt, J 15.6, 7.2 Hz, 1H),
(832 mg, 74%) with a Rf = 0.33: IR (neat) νmax 2934 (m), 1722 5.85–5.79 (dt, J 15.6, 1.5 Hz, 1H), 3.72 (s, 3H), 2.40–2.31
(l), 1656 (s), 1434 (s), 1386 (m), 1316 (l), 1262 (m), 1140 (l), (m, 1H), 2.22–2.13 (m, 1H), 1.23 (s, 12H,), 1.01–0.95 (d, J 7.4,
1046 (s), 982 (m), 860 (m), 752 (l), 696 (m); 1H NMR (400 MHz, 3H); 13C NMR (101 MHz, CDCl3) δ 167.5(COOR), 150.0, 121.7
CDCl3) δ 7.03–6.95 (m, 1H), 5.86–5.82 (d, J 16 Hz, 1H), 3.73 (CHvCH–COOR), 83.6, 51.7, 35.9, 25.1 (C–CHvC), 15.5;
(s, 3H), 2.83–2.66 (m, 1H), 2.38–2.21 (m, 1H), 2.38–2.21 11B NMR (128 MHz, CDCl3) δ 33.9; LRMS (ESI+) m/z [M+] 236.2
(m, 1H), 1.61 (s, 6H), 1.35 (s, 6H), 0.92–0.89 (t, J 7.2, 3H); (58%), 235.6 (40%), 254.2 (25%); HRMS (ESI+) m/z calculated
13C NMR (101 MHz, CDCl3) δ 167.1 (COOR), 149.8, 121.2 C13H24BO4 [M
+ H] 254.1804 found 254.1817; Chiral
(CHvCH–COOR), 83.2, 51.3, 33.7, 33.0, 24.8 (C–CHvC), 22.0, HPLC conditions OD-CHIRALCEL column (250 × 4.60 mm)
14.30; 11B NMR (128 MHz, CDCl3) δ 33.9; LRMS (ESI+) m/z fitted with guard cartridge (50 × 4.6 mm), 25 °C, 1.0 mL
[M + H] 283.2 (100%), 282.1 (12%), 284.5 (10%); HRMS (ESI+) min−1, 210 nm, hexane–iPrOH (98 : 2), tR = 5.3 min (S), tR
m/z calculated C15H28BO4 [M + H] 282.2117, found 282.2130; 5.9 min (R).
=
Chiral HPLC conditions OD-CHIRALCEL column (250
×
Methyl
(E)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-
4.60 mm) fitted with guard cartridge (50 × 4.6 mm), 25 °C, pent-2-enoate 3iii. Compound 3i was obtained as a yellow oil
0.7 mL min−1, 210 nm, hexane–iPrOH (99.5 : 0.5), tR = 8.7 min (S), (181 mg, 36%): IR (neat) νmax 2980 (m), 2944 (s), 2910 (s), 1724
tR = 11.1 min (R).
(l), 1658 (m), 1440 (m), 1368 (l), 1324 (l), 1274 (l), 1202 (m),
Methyl (E)-5-(4-chlorophenyl)-5-(4,4,5,5-tetramethyl-1,3,2- 1200 (s), 1140 (l), 1014 (s), 986 (s), 970 (m), 940 (s), 888 (s),
dioxaborolan-2-yl)pent-2-enoate 3eii. Compound 3eii was 848 (l), 834 (s), 762 (s), 716 (s), 706 (s); 1H NMR (400 MHz,
obtained as a yellow oil (377 mg, 54%): IR (neat) νmax 2982 (m), CDCl3) δ 7.03–6.93 (m, 1H), 5.80 (m, 1H), 3.74 (s, 3H),
2970 (s), 1722 (l), 1658 (m), 1492 (l), 1438 (m), 1372 (m), 2.65–2.57 (m, 1H), 1.26 (s, 6H), 1.24 (s, 6H), 1.11–1.10 (m, 3H),
1332 (m), 1274 (m), 1202 (m), 1200 (m), 1142 (l), 1092 (m), 0.95 (d, J 6.7, 1H), 0.89 (m, 1H); 13C NMR (101 MHz, CDCl3)
1
1012 (m), 970 (m), 844 (m), 842 (m), 796 (s), 702 (m); H NMR δ 167.2 (COOR), 157.5, 156.1, 118.0 (CHvCH–COOR), 116.5,
(400 MHz, CDCl3) δ 7.27–7.11 (m, 4H), 7.03–6.89 (m, 1H), 83.2, 83.0, 51.3, 32.5, 29.0, 24.8 (C–CHvC), 22.3, 21.4;
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11B NMR (128 MHz, CDCl3) δ 33.1; LRMS (ESI+) m/z [M + H]
277.1 (100%), 255.1 (62%), 253.9 (10%); HRMS (ESI+) m/z
calculated C13H24BO4 [M + H] 254.1804 found 254.1814.
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10, 5485–5497.
Other procedures
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(2E)-3-(Thiophen-2-yl)prop-2-enal. (2E)-3-(Thiophen-2-yl)-
prop-2-enoic acid (3.0 g, 19.5 mmol) was dissolved in THF
(80 mL) and cooled to −78 °C under argon. DIBAL-H (58.5 mL,
1 M THF) was added slowly over 1 hour, and the resulting solu-
tion was allowed to react overnight, warming to room tempera-
ture. The resulting solution was quenched with saturated
potassium sodium tartrate solution (aqueous) and allowed to
stir for 1 h. After, the resulting solution was partitioned
between EtOAc and the aqueous layer was extracted with
EtOAc (3 × EtOAc). The organic phase was separated and dried
over MgSO4. After filtration the organic phase was removed
under reduced pressure to yield a crude allylic product [(2E)-
3(thiophen-2-yl)prop-2-en-1-ol)]. In a separate vessel, DMSO
(42.9 mmol, 3.0 mL) and DCM (40 mL) were combined under
argon and cooled to −78 °C). Oxalyl chloride (21.5 mmol,
1.8 mL) was added and the reaction mixture was stirred for
10 min. The crude allylic alcohol [(2E)-3(thiophen-2-yl)prop-2-
en-1-ol)] was added (in DCM, 12 mL) to the −78 °C solution,
and allowed to stir for 10 min. Triethylamine (97.5 mmol,
13.6 mL) was subsequently added, and the solution allowed to
warm to room temperature over 1.5 h. After, the resulting solu-
tion was partitioned quenched with water and partitioned
between EtOAc and the aqueous layer was extracted with
EtOAc (3 × EtOAc). The organic phase was separated and dried
over MgSO4. After filtration the organic phase was removed
under reduced pressure to yield a crude brown oil. Purification
by silica gel chromatography (hexane–EtAcO, 9 : 1) gave 1j as a
yellow oil (996 mg, 37%). 1H NMR (400 MHz, CDCl3): δ 9.63
(d, J = 7.7 Hz, 1H, CH), 7.58 (d, J = 15.6 Hz, 1H, CH), 7.51 (d,
J = 5.0 Hz, 1H, CH), 7.37 (d, J = 3.7 Hz, 1H, CH), 7.11 (dd, J =
5.1, 3.6 Hz, 1H, CH), 6.52 (dd, J = 15.6, 7.7 Hz, 1H, CH).
13C NMR (101 MHz, CDCl3): δ 192.9, 144.4, 139.3, 132.0, 130.4,
128.5, 127.4. LRMS (ESI+) [M + H]+, 138.8. HRMS (ESI+) calcu-
lated [C7H6OS + H]+ 139.0218, found 139.0246. All spectro-
scopic and analytical properties are identical with those
reported in the literature.14
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We thank the EPSRC for a Doctoral Training Award (to ADJC).
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Notes and references
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