Synthesis and cycloaddition reactions of strained alkynes derived from 2,2′-dihydroxy-1,1′-biaryls

Article abstract of DOI:10.1039/c8ob01768a

A series of strained alkynes, based on the 2,2′-dihydroxy-1,1′-biaryl structure, were prepared in a short sequence from readily-available starting materials. These compounds can be readily converted into further derivatives including examples containing fluorescent groups with potential for use as labelling reagents. The alkynes are able to react in cycloadditions with a range of azides without the requirement for a copper catalyst, in clean reactions with no observable side reactions.

Full text of DOI:10.1039/c8ob01768a

Organic &
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Synthesis and cycloaddition reactions of strained
alkynes derived from 2,2’-dihydroxy-1,1’-biaryls†
Cite this: Org. Biomol. Chem., 2018,
16, 8965
Anish Mistry,a Richard C. Knighton, a Sam Forshaw, a Zakaria Dualeh,a
a
Jeremy S. Parker b and Martin Wills
*
A series of strained alkynes, based on the 2,2’-dihydroxy-1,1’-biaryl structure, were prepared in a short
sequence from readily-available starting materials. These compounds can be readily converted into
further derivatives including examples containing fluorescent groups with potential for use as labelling
reagents. The alkynes are able to react in cycloadditions with a range of azides without the requirement
for a copper catalyst, in clean reactions with no observable side reactions.
Received 23rd July 2018,
Accepted 5th October 2018
DOI: 10.1039/c8ob01768a
rsc.li/obc
In a recent paper, we reported the synthesis and appli-
cations of a class of strained alkyne based on the 10-mem-
Introduction
The use of highly reactive strained alkynes, typically within bered structure 4, derived from 2,2′-dihydroxy-1,1′-biaryl com-
eight-membered rings,1 in cycloaddition reactions with azides pounds.9 The unfunctionalised compound, 8,13-dioxatricyclo
is now a well-established reaction with numerous applications [12.4.0.02,7]octadeca-1(14),2,4,6,15,17-hexaen-10-yne
(dioxa-
in materials chemistry and in bioconjugation applications.2 biaryldecyne) 4 and its close derivatives are readily prepared in
Such reagents are ideal for these applications because the one step through the reaction of 2,2′-biphenol with but-2-yne-
cycloaddition reactions take place spontaneously and without 1,4-diyl bis(4-methylbenzene)sulfonate in the presence of pot-
the need for a catalyst to be added – in contrast to the reac- assium carbonate.9 Before our studies, the reactions of alkynes
tions of unstrained terminal alkynes with azides in which case such as 4 with azides had not been reported, and just three
a copper-based catalyst is generally required.3
papers could be identified which reported the synthesis of the
Widely adopted cyclooctyne reagents such as 1–3 and their same heterocyclic structure.10 In addition, we demonstrated
derivatives (Fig. 1),4–6 are highly reactive, and can be used at the that reagents such as 4 and its derivatives react with azides,
low concentrations which are often required in bioconjugation without the need for a Cu catalyst, at rates similar to unfunc-
applications, particularly for in vivo reactions.7 In applications tionalised cyclooctyne, although lower than the most reactive
where the concentration of reagents is more typical of synthetic and recently reported strained alkynes. Significantly, although
reactions e.g. 0.01–0.5 M, and on larger scales, less reactive longer reaction times are required than would be the case for
larger-ring molecules, which can be prepared through a short reagents such as 1–3, our alkynes reacted with azides in clean
synthetic sequence, have also proven to be synthetically valuable reactions with no visible decomposition when followed by
reagents.8 Earlier and less reactive cyclooctynes remain syn- 1H-NMR. We also reported the synthesis of acid 5 and the acti-
thetically important, for example (2-cyclooctyn-1-yloxy)acetic vated ester 6 derivatives and demonstrated applicability to bio-
acid (a derivative of ‘OCT’) was the subject of a successful multi-
gram scale up optimisation study reported in 2018.5d Some
highly strained derivatives are also prone to addition of thiols.5e
aDepartment of Chemistry, The University of Warwick, Coventry, CV4 7AL, UK.
E-mail: m.wills@warwick.ac.uk
bEarly Chemical Development, Pharmaceutical Sciences, IMED Biotech Unit,
AstraZeneca, Macclesfield, SK10 2NA, UK
†Electronic supplementary information (ESI) available: General experimental
details, synthesis of intermediates 7,13 11,12 12,12 13,19 34,20 and compounds
29–31 and 41–45, 1H and 13C NMR spectra, graphs of conversion/time, fluo-
rescence spectra, functionalisation of amino-loaded beads and X-ray crystallo-
graphic data. CCDC 1852221, 1852222 and 1852224. For ESI and crystallographic
data in CIF or other electronic format see DOI: 10.1039/c8ob01768a. The research
data supporting this publication can be accessed at http://wrap.warwick.ac.uk/.
Fig. 1 Strained alkynes 1–3, dioxabiaryldecyne 4 and its derivatives 5
and 6.
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conjugation through its attachment to a number of peptides ESI† for HPLC details and graph of conversion over time). The
and one protein in in vitro studies.9 Following our report, X-ray crystallographic structures of aldehyde 16 (Fig. 2) and
another group reported the preparation of some of the same ketone 17 (Fig. 3) revealed the strained nature of the alkyne
derivatives, as well as N-containing heterocyclic variants, within the constrained ring.
together with a comprehensive molecular modelling study to
Alkyne 16 could also be reduced to the alcohol 19 using
explain the enhanced reactivity of the reagents.11 This group sodium borohydride, which gave a clean product, however
also demonstrated that the dioxabiaryldecynes do not rapidly attempts to reduce substrate 15, lacking the methoxy group, to
undergo reactions with thiols.11
18 gave a complex mixture of products, for reasons that are not
In this paper we report the synthesis of a series of functio- clear.14
nalised analogues of the strained alkyne structure 4, in as little
The strained alkynes prepared in this project are stable
as two steps, from readily available and inexpensive starting solids at rt which can be stored for months without significant
materials, their subsequent functionalisation and representa- decomposition. However a thermal gravimetric analysis (TGA)
tive applications to a number of cycloaddition reactions with was carried out in order to examine their stability at higher
several azides.
temperatures. Aldehyde 16 exhibited a drop of ca. 10% mass
around 180 °C which may be associated with the loss of CvO
from the aldehyde, followed by a gradual mass loss of just over
20% as the temperature was raised to 600 °C. The TGA analysis
of the previously reported methyl ester of acid 5 was stable to
ca. 300 °C then gradually lost ca. 40% of its mass as the temp-
erature was increased to 600 °C (see ESI†).
Results and discussion
In order to develop an extended synthesis of dioxabiaryldecyne
reagents, we employed the reported coupling reactions of iodo-
benzaldehyde reagents 7 and 8 (iodovanillin) and 4-hydroxy-3′-
iodoacetophenone 9 with 2-(hydroxyphenyl)boronic acid 10,12
to give diols 11–13 respectively. This was followed by the
cyclisation reactions with ditosylate 14 using our previously-
reported procedure (Scheme 1).9 Strained alkynes 15, 16 and
17 were isolated respectively (Scheme 1). 3-Iodo-4-hydroxybenz-
aldehyde was prepared from 4-hydroxybenzaldehyde through
careful iodination using ICl/acetic acid.13 Iodovanillin can be
prepared by the same method but is readily commercially
available.
Both the Pd-catalysed coupling and the cyclisation to form
aldehydes 15 and 16 worked more efficiently for the product
containing a methoxy group adjacent to the strained alkyne,
giving a product in unoptimised but acceptable yield in each
case. In the case of the transformation of aldehyde 12 to 16,
we followed the reaction over time using chiral HPLC, which
resolved the two non-interconverting enantiomers of product
and allowed the conversion to be monitored over time (see
Fig. 2 Single crystal X-ray crystallographic structure of 16 (two views;
ellipsoids are plotted at the 50% probability level). The bond angles at
the sp atoms are 165.2° and 165.3° and the biphenyl torsion angle is
72.2°.
Fig. 3 Single crystal X-ray crystallographic structure of 17 (two views:
ellipsoids are plotted at the 50% probability level). The bond angles at
the sp atoms are 165.1° and 168.6° and the biphenyl torsion angle is
66.4°.
Scheme 1 Synthesis of aldehyde-functionalised CBD strained alkynes
15–17 and alcohol 19.
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Given the improved synthesis of the methoxy-substituted
aldehyde 16 over 15, we focussed our studies on the former
reagent. Its reaction with a range of functionalised azides was
studied (Scheme 2) and in each case the reactions were fol-
1
lowed over time, using H NMR to monitor the cyclisations of
a 1 : 1 mixture of reagents in solution; the spectra are in the
ESI.† The reaction of 16 with benzylazide 20 was also carried
out in MeCN, the product 21 being isolated in 84% yield. In all
cases, the cycloadditions proceeded smoothly, with no obvious
accompanying decomposition of reagents. Conversions (by
NMR) and yields (isolated products) are given in Scheme 2. In
all cases the products were formed as inseparable regioiso-
meric mixtures in ca. 1 : 1–3 : 2 ratios. Benzylazide gave a clean
product 21 of addition, in analogy with previous reactions.9,11
An azide attached to a red dye, disperse red, 2215a gave a red
product 23 from the cycloaddition, which was carried out at
0.128 M, 9 days at rt (95% conversion, 76% isolated yield). An
azide containing a PEG-2000 chain, 24, also added cleanly to
the strained alkyne 16, and the product in this case (25) was
characterised by GPC as well as by NMR, revealing the
expected increase to the molar mass of the polymeric product
(ESI†). This was gratifying as the reagent concentration (0.025
M) in this example was lower than for other cycloadditions.
The cycloaddition of coumarin azide 26 gave a highly fluo-
rescent product 27 (see ESI†) as has been reported previously
for this class of reagent.15b,c For improved solubility, deuterated
acetonitrile was used as the solvent, and the reaction at 0.11 M
proceeded to ca. 80% conversion to 27. Although long reaction
times are required relative to the more reactive strained alkynes
such as 1–3, the benefits of the catalyst-free conditions and
clean cycloadditions make these reagents potentially valuable
for the preparation of materials for biological applications.
The addition of benzyl azide to alcohol 19 to give adduct 28
as a 3 : 2 regioisomeric mixture of products (Fig. 4) proceeded
at a similar rate (0.17 M, 5 d at rt, 97% yield, ESI†) indicating
that the functional group has minimal influence on the rate of
Fig. 4 Derivatives of 15–17.
the cycloaddition, probably because of the separation from the
alkyne.
The aldehyde group on 15 and 16 permits their functionali-
sation with other reagents. The reaction of 15 with benzylhy-
droxylamine in MeOH overnight at 45 °C gave oxime ether 29
in 66% isolated yield. The formation of oxime ethers rep-
resents a valuable method for functionalisation due to their
high stability and ease of preparation.16 Also, notably, reduc-
tive amination with benzylamine led to the synthesis of amine-
containing derivatives 30 and 31. The reaction of methoxy-sub-
stituted 30 with benzylazide was found to proceed at a similar
rate to aldehyde-containing reagents 16 (ESI†). It was gratifying
that these functionalisations could be completed without
damaging the strained alkyne group.
The treatment of amine-functionalised polystyrene beads
with 16 and sodium cyanoborohydride was followed by reac-
tion of the functionalised beads 32 with disperse red azide 22.
After washing, the strong red colour of the dye remained on
the beads 33 (Scheme 3). As a control reaction, stirring the
solution of red dye-azide 22 with unfunctionalised beads gave
only lightly coloured beads after washing, indicating that the
cycloaddition had taken place on the dioxabiaryldecyne
reagent on the beads (ESI†).
Other reagents were prepared through reactions of the
aldehyde, notably fluorescent groups. The reductive amination
of 16 with the amine-functionalised dansyl reagent 34 resulted
in formation of 35 (Scheme 4A), which showed strong fluo-
rescent behaviour upon irradiation. A number of BoDIPY
derivatives 36–38 were also prepared through the direct reac-
tion of pyrroles with the aldehyde and BF3 in good yield
(Scheme 4B).17 Again, the ability to functionalise aldehyde 16
with a variety of reagents, without damaging the strained
alkyne, is noteworthy.
Scheme 2 Use of aldehyde alkyne 16 in addition reactions with a range
of azides.
Scheme 3 Functionalisation of beads with disperse red dye.
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Scheme 4 Synthesis of fluorescent derivatives of 16.
The X-ray crystallographic structure of 38 (Fig. 5) revealed
the strained nature of the alkyne but also that the BoDIPY
component was orientated almost perpendicular to the con-
nected arene ring, presumable with restricted rotation about
the connecting C–C bond. This accounts for the observed
differences in chemical shifts of the groups attached to the
heterocyclic rings of the BoDIPY unit in each of 36–38, which
will be in sharply different diastereotopic environments.
The fluorescence spectra for compounds 35–38 are given in
the ESI.† However the strong and contrasting fluorescence
behaviour of the BoDIPY dyes 36–38 is sharply illustrated by
their response to UV irradiation. Compound 36 and 37 both
show strong fluorescence upon irradiation whereas 38 gives a
weaker response (ESI†).
The addition of benzylazide to BoDIPY derivative 36 was
tested and worked efficiently to give two regiosiomers 39 and
40 in a 1 : 1 ratio (Fig. 6). In this case, we were able to separate
the isomers by flash chromatography and independently
characterise them. We have not unambiguously established
which regiosiomer is which, of the two possibilities, however
on the basis of the positions of the methylene groups in the
Fig. 6 Separated cycloaddition products 39 and 40.
13C-NMR spectra compared to previous examples, we have ten-
tatively assigned them as shown in Fig. 6 (see ESI†).
Further derivatives were also prepare from the corresponding
alcohol 19 using a variety of coupling methods (Fig. 7). These
included a biotin-containing reagent 41 which was formed
through formation of an ester bond to biotin in one step.
It was also possible to attach a group through a carbamate
i.e. 42, using N,N′-disuccinimidyl carbonate (DSC) as a coup-
ling agent to attach alcohol 19 to form the dansyl amine
derivative 34.7d,18 Finally, from the alcohol, the direct reaction
with an isocyanate could also be employed to create a derivative
Fig. 5 X-ray crystallographic structure of 38 (ellipsoids are plotted at the 50% probability level). The bond angles at the sp atoms are 165.7° and
168.1° and the biphenyl torsion angle is 68.6°.
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2′,6-Dihydroxybiphenyl-3-carbaldehyde
11
(3.20
g,
14.9 mmol), potassium carbonate (10.22 g, 73.95 mmol) and
but-2-yne-1,2-diyl bis(4-methylbenzenesulfonate) 14 (5.31 g,
13.5 mmol) were added to a clean dry schlenk. The schlenk
was then put under nitrogen and purged, thereafter dry aceto-
nitrile (747 mL) was added to the mixture and the reaction left
to stir at rt for 10 days. The organics were removed under
vacuum, water (500 mL) and DCM (500 mL) were added and
the product extracted with DCM (3 × 300 mL). The organic
extracts were washed with brine and dried over Na2SO4, filtered
and concentrated under vacuum. The crude product was puri-
fied by column chromatography (8 : 2 hexane : ethyl acetate) to
afford the product 15 as a white solid (1.50 g, 5.68 mmol,
38%). Mp 143–145 °C; (found (ESI-Q-TOF) [M + Na]+ 287.0675.
C17H12O3Na requires 287.0679); νmax 2910, 2863, 1686, 1568,
1495, 1473, 1415, 1345, 1305, 1288, 1188 cm−1; δH (500 MHz,
CDCl3) 9.98 (1H, s, CHO), 7.94 (1H, dd, J 8.4, 2.9, ArH), 7.75
(1H, d, J 2.0, ArH), 7.44–7.40 (1H, m, ArH), 7.32 (1H, d, J 8.3,
ArH), 7.22–7.19 (3H, m, ArH), 4.63–4.61 (1H, m, CH2),
4.54–4.50 (m, 1H, CH2), 4.41–4.32 (m, 2H, CH2); δC (125 MHz,
CDCl3) 191.2, 159.8, 154.4, 136.8, 134.9, 134.6, 132.6, 131.7,
129.7, 129.6, 124.3, 123.6, 122.6, 87.3, 86.0, 63.8, 63.5; m/z
(ESI) 287.1 ([M + Na]+).
Fig. 7 Functionalised derivatives of alcohol 19 and acid 5 strained
alkynes which were prepared in this project.
with a carbamate linkage i.e. 43. Formation of derivatives from
the acid 5 was also investigated; the in situ formation of isocya-
nate from acid 5 using diphenylphosphoryl azide and trapping
with MeOH gave carbamate derivative 44 through a method that
could be used for future functionalisation. Acid 5 was also
linked using EDC·HCl to create the disperse-red functionalised
45. These results (Fig. 7) illustrate the range of methods which
can be employed to functionalise the strained alkynes.
Alkyne 16
In conclusion, we have prepared a selection of derivatives,
including fluorescently-labelled variants, of a new class of
strained alkyne, which benefit from ease of synthesis from
readily available and inexpensive starting materials through a
short sequence of reactions. We have demonstrated that this
class of alkyne undergoes uncatalysed cycloaddition reactions
with azides with minimal decomposition or side product for-
mation. Studies of the applications of these reagents are
ongoing and further results will be published in due course.
This compound is novel.
2′,6-Dihydroxy-5-methoxybiphenyl-3-carbaldehyde 12 (1.70 g,
6.96 mmol), potassium carbonate (4.76 g, 34.4 mmol) and
but-2-yne-1,2-diyl bis(4-methylbenzenesulfonate) 14 (2.47 g,
6.27 mmol) were added to a schlenk. The schlenk was then
put under nitrogen and purged, thereafter dry acetonitrile
(346 mL) was added to the mixture and the reaction was left to
stir at rt for 10–14 days. The organics were removed under
vacuum, water (400 mL) and DCM (400 mL) were added and
the product extracted with DCM (3 × 200 mL). The organics
were collected and washed with brine and dried over Na2SO4,
filtered and concentrated under vacuum. The crude product
was purified by column chromatography (8 : 2 hexane : ethyl
acetate) to afford 16 as a white solid (1.2 g, 4.08 mmol, 59%).
Mp 171–173 °C; (found (ESI-Q-TOF) [M + Na]+ 317.0787.
C18H14O4Na requires 317.0784); νmax 2951, 2923, 2852, 1687,
1601, 1580, 1491, 1459, 1426, 1384, 1334, 1290, 1240, 1180,
1163, 1127 cm−1; δH (500 MHz, CDCl3) 9.92 (1H, s, CHO), 7.49
(1H, s, ArH), 7.44–7.40 (1H, m, ArH), 7.33 (1H, s, ArH),
7.22–7.19 (3H, m, ArH), 4.69–4.66 (1H, m, CH2), 4.56–4.60 (2H,
m, CH2), 4.37–4.34 (1H, m, CH2) 3.98 (3H, s, OCH3); δC
(125 MHz, CDCl3) 191.5, 154.4, 154.2, 148.1, 137.6, 134.7,
Experimental section
General experimental details, synthesis of intermediates 7,13 11,12
12,12 13,19 3420 and compounds 29–31 and 41–45 are in the ESI.†
Alkyne 15
A series of strained alkynes, based on the 2,2′-dihydroxy-1,1′- 132.7, 131.7, 129.7, 129.0, 124.4, 122.6, 108.6, 86.9, 86.7, 63.6,
biaryl structure, were prepared in a short sequence from 60.5, 55.9; m/z (ESI) 317.1 ([M + Na]+). This reaction was also
readily-available starting materials. This compound is novel.
monitored by HPLC over 14 days, using 15 : 85 IPA : Hexane,
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1 ml min−1, IB column. Full details are in the ESI.† The X-ray (Found (ESI-Q-TOF) [M + Na]+ 301.0834. C18H14O3Na requires
crystallographic structure of this compound was obtained and 301.0835); νmax 2158, 1679, 1499, 1357, 1307, 1251, 1188, 1106,
is described in the ESI.†
963 cm−1; δH (500 MHz, CDCl3); 8.00 (1H, d, J 8.4, ArH), 7.82
(1H s, ArH), 7.42–7.39 (1H, m, ArH), 7.25–7.18 (4H, m, ArH),
4.60–4.50 (2H, m, CH2), 4.39–4.32 (2H, m, CH2), 2.57 (3H, s,
CH3); δC (125 MHz, CDCl3) 197.3 (CvO), 158.7 (C), 154.2 (C),
136.1 (C), 135.0 (C), 133.5 (C), 132.9 (CH), 131.8 (CH), 129.1
(CH), 129.0 (CH), 124.8 (CH), 123.2 (CH), 123.0 (CH), 87.5 (C),
86.5 (C), 64.0 (CH2). 63.7 (CH2), 26.8 (CH3); m/z (ESI) 278.08
([M]+), 301.08 ([M + Na]+).
Alkyne alcohol 19
This compound is novel.
Cycloadduct 21
NaBH4 (15 mg, 0.41 mmol, 1.0 eq.) was added carefully at
0 °C to a stirring solution of 16 (0.12 g, 0.41 mmol, 1.0 eq.) in
methanol (10 mL) under a nitrogen atmosphere and the reac-
tion was left for 1 hour to react at rt. The methanol was
removed under vacuum and the residue was redissolved in
ethyl acetate (15 mL). The organic extracts were washed with
sat. NH4Cl (15 mL) and then brine (15 mL). The organics col-
lected, dried over Na2SO4, filtered and concentrated under
vacuum to afford a white solid. This was purified by column
chromatography (1 : 1 hexane : ethyl acetate) to afford the
product 19 as a white solid (0.12 g, 0.40 mmol, 99%).
Mp 165–168 °C; (found (ESI-Q-TOF) [M + Na]+ 319.0940.
C18H16O4Na requires 319.0941); νmax 3522, 2927, 2866, 2835,
1587, 1494, 1446, 1421, 1338, 1264, 1246, 1192, 1165, 1133,
1122 cm−1; δH (400 MHz, CDCl3) 7.39–7.34 (1H, m, ArH),
7.19–7.17 (2H, m, ArH), 7.14 (1H, d, J 7.9, ArH), 7.01 (1H, d,
J 1.7, ArH), 6.74 (1H, d, J 1.8, ArH), 4.65 (2H, s, CH2OH),
4.63–4.57 (1H, m, CH2), 4.53–4.47 (1H, m, CH2), 4.41–4.36 (1H,
m, CH2), 4.34–4.28 (1H, m, CH2), 3.91 (3H, s, OCH3); δC
(100 MHz, CDCl3) 154.2, 153.3, 141.7, 137.0, 136.8, 135.8,
131.9, 129.1, 124.2, 122.4, 122.2, 109.9, 87.5, 85.9, 65.0, 63.5,
60.2, 55.7; m/z (ESI) 319.1 ([M + Na]+).
This compound is novel.
Alkyne 16 (30 mg, 0.102 mmol) and benzyl azide 20
(13.8 mg, 13 μL, 0.102 mmol) were stirred in MeCN (0.6 mL)
for 6 days at rt (ca. 0.17 M), monitoring each day by TLC. At
the end of this time the solvent was removed under vacuum
and the product purified by flash chromatography on silica gel
(hexane : EtOAc, 7 : 3) to yield the product 21 as a white solid
(40 mg, 0.94 mmol, 84%). TLC (hexane : EtOAc, 7 : 3), silica,
Rf 0.15; M.p. 181–184 °C; (found (ESI+): [M + Na]+ 450.1426.
C25H21N3NaO4 requires 450.1424); νmax 1684, 1575, 1493, 1155,
722 cm−1; δH (500 MHz, CHCl3, two regioisomers 3 : 2); 9.94
(0.6H, s, CHO, major regiosomer). 9.91 (0.4H, s, CHO, minor
regiosomer), 7.52 (1H, s, ArH), 7.47–7.43 (2H, m, ArH),
7.35–7.30 (3H, m, ArH), 7.20–7.05 (2.6H, m, ArH, 3 × major
and 2 × minor regiosiomer), 7.01 (0.6H, t, J 7.0, ArH, major
regiosomer), 6.96 (0.4H, t, J 7.5, ArH, minor regiosomer), 6.90
(0.4H, t, J 7.5, ArH, minor regiosomer), 6.09 (0.4H, d, J 8.0, CH,
minor regiosomer), 5.87 (0.4H, d, J 11.0, CH, minor regio-
somer), 5.80–5.72 (1.2H, m, CH, 2 × major regiosomer), 5.57
(0.6H, d, J 13.0, CH, minor regiosomer), 5.52–5.45 (1.4H, m,
CH, 1 × major and 2 × minor regioisomer), 5.20 (0.6H, d,
J 15.0, CH, major regiosomer), 5.04 (0.4H, d, J 14.0, CH, minor
regiosomer), 4.96 (0.4H, d, J 11.0, CH, minor regiosomer), 4.83
(0.6H, d, J 13.0, CH, major regiosomer), 4.02 (3H, s, OCH3),
Ketoalkyne 17
This compound is novel.
In a round bottom flask under nitrogen atmosphere 13 3.95 (3H, s, OCH3); δC (125 MHz, CDCl3) 191.0 (CH), 191.0
(550 mg, 2.41 mmol, 1.2 equiv.) and but-2-yne-1,4-diyl-bis (CH), 153.8 (C), 153.6 (C), 152.7 (C), 152.6 (C), 151.7 (C), 145.0
(4-methylbenzenesulfonate) (792 mg, 2.01 mmol) were (C), 144.2 (C), 134.9 (C), 134.1 (C), 133.6 (C), 133.1 (C), 133.0
dissolved in anhydrous acetonitrile (111 mL). K2CO3 (1.39 g, (C), 132.6 (C), 132.4 (C), 131.4 (CH), 130.7 (CH), 129.5, (CH),
10.0 mmol) was added and the mixture was stirred at RT for 14 129.3 (CH), 129.0 (CH), 128.5 (C), 128.0 (C), 127.7 (CH), 127.1
days. The volatiles were removed in vacuum and H2O (50 mL) (CH), 126.7 (CH), 122.3 (CH), 121.9 (CH), 113.2 (CH), 111.2
was added. The product was extracted with DCM (3 × 50 mL). (CH), 110.6 (CH), 109.9 (CH), 67.5 (CH2), 62.6 (CH2), 61.0
The combined organic layers were washed with brine (30 mL), (CH2), 57.7 (CH2), 56.2 (CH3), 56.1 (CH3), 53.0 (CH2), 52.0
dried over MgSO4, filtered and solvent removed via rotary (CH2). m/z (ES-API+) 450.0 ([M + Na]+). The reaction was also
1
evaporation. The product was purified by column chromato- followed over time by H NMR and full details are in the ESI.†
graphy on silica (hexane/EtOAc = 4 : 1) to give 17 (252 mg, Alkyne 16 (15 mg, 51.0 µmol) and benzyl azide 20 (6.4 mg,
0.906 mmol, 45%) as a crystalline white solid. Crystals suitable 51.0 µmol) were added together in deuterated chloroform
for X-ray spectroscopy were grown by vapour diffusion of hexane (0.4 mL) (0.128 M in both reagents) and the reaction was fol-
into a CHCl3 solution of the compound. Mp 137–139 °C. lowed at rt by 1H NMR.
8970 | Org. Biomol. Chem., 2018, 16, 8965–8975
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Disperse red cycloadduct 23
7.80–6.80 (6H, m, ArHs), 5.80–4.50 (6H, m, 2 × OCH2, NCH2
of addition product), 3.98 (3H, s, OCH3), 3.90 (3H, s, PEG
OCH3), 3.60–3.30 (ca. 190H, m, PEG OCH2 groups). Due to its
heterogeneous nature, only the 1H NMR and GPC data was
recorded for this complex, and the product was not purified
further.
Fluorescent coumarin dye cycloadduct 27
This compound is novel.
Aldehyde 16 (15 mg, 51.0 µmol) and azide 22 (19 mg,
51.0 µmol) were combined in deuterated chloroform (0.4 mL)
and the reaction (ca. 0.128 M in both reagents) was left at rt.
The progression of the reaction was monitored daily. The pro-
gression of the reaction was monitored daily by 1H NMR
(ESI†). Upon completion, the reaction was worked up and the
product purified by column chromatography (DCM→85 : 15
DCM : EtOAc) to give 23 as a red solid (26 mg, 0.039 mmol,
76%). TLC DCM, silica, Rf 0.05; M.p. 155–158 °C; (found
This compound is novel.
Compound 16 (13 mg, 44.2 µmol) and coumarin azide 26
(9.0 mg, 44.2 µmol) were added together in deuterated aceto-
nitrile (0.4 mL) and the reaction left at r.t. (ca. 0.11 M in
both reagents). The progression of the reaction was moni-
tored daily. Stacked NMR spectra and the conversion/time
graph are in the ESI.† At the end of this time (80% conver-
sion after 12 d) the solvent was removed and the product 27
was purified by column chromatography using a gradient of
EtOAc in hexane (14 mg, 28 µmol, 64%,). TLC hexane : EtOAc
3 : 7, silica, Rf 0.60; M.p. 222–228 °C; (found (ESI+):
[M + Na]+ 520.1119. C27H19N3NaO5 requires 520.1115); νmax
(ESI+): [M
+
Na]+ 690.1843. C34H30ClN7NaO6 requires
690.1838); νmax 1688, 1597, 1513, 1333, 1121, 745 cm−1; δH
(300 MHz, CHCl3) (two regioisomers 1 : 1); 9.95 (0.5H, s, CHO).
9.90 (0.5H, s, CHO), 8.50 (1H, s, ArH), 8.20–8.15 (1H, m, ArH),
8.05–8.00 (1H, m, ArH), 7.95–7.90 (1H, m, ArH), 7.80–7.75 (1H,
m, ArH), 7.45 (1H, d, J 13.0, ArH), 7.30–7.24 (3H, m, ArH),
7.15–7.05 (1H, m, ArH), 6.90–6.85 (1H, m, ArH), 6.80 (1H, d,
J 12.0, ArH), 6.75 (1H, d, J 12.0 ArH), 4.85 (1H, d, J 14.0, CH),
5.50–4.50 (5H, m, OCH and NCH), 4.10–3.80 (5H, m, NCH +
OMe), 3.35–3.00 (1H, m, NCH), 2.60–2.40 (1H, m, NCH), 1.15
(3H, t, J 6.5, CH3), 0.88 (3H, t, J 6.5, CH3); δC (125 MHz, CDCl3)
190.9, 190.8, 154.1, 153.8, 153.0, 152.8, 152.6, 152.5, 151.7,
151.3, 150.7, 150.5, 149.5, 147.3, 144.8, 144.7, 144.5, 134.3,
133.5, 133.0, 132.8, 132.8, 132.3, 131.5, 130.8, 129.1, 129.1,
129.0, 128.0, 127.0, 126.6, 126.0, 124.7, 122.6, 118.1, 116.0,
118.1, 113.1, 112.1, 111.4, 110.7, 109.9, 62.1, 60.8, 60.1, 58.6,
56.4, 50.4, 50.3, 46.0, 45.4, 11.8; m/z (ES-API+) 690.2
([M + Na]+).
1725, 1688, 1605, 1574, 1223, 1133, 966, 684 cm−1
;
δH (500 MHz, CHCl3) (two regioisomers ca. 3 : 2); 9.89 (1H, s,
CHO), 8.30–8.25 (0.4H, brs, NH or OH; by HSQC, minor
regioisomer), 8.12 (0.4H, s, CH, minor regioisomer),
8.10–8.05 (0.6H, brs, NH or OH; by HSQC, major regio-
isomer), 7.95 (0.6H, s, CH, major regioisomer), 7.50–7.45
(1H, m, ArH), 7.42 (0.6H, s, ArH, major regioisomer),
7.35–7.30 (1H, m, ArH), 7.25–7.15 (2H, m, ArH), 6.95–6.85
(2H, m, ArH), 6.82–6.80 (1.8H, m, ArH, 1 × major, 3 × minor
regioisomer), 6.65 (0.6H, d, J 10.0, ArH, major regioisomer),
5.88 (0.4H, d, J 13.0, OCH, minor regioisomer), 5.75 (0.6H,
d, J 13.0, OCH, major regioisomer), 5.52 (0.4H, d, J 12.0,
OCH, minor regioisomer), 5.35–5.25 (1H, m, OCH), 5.25
(0.6H, d, J 13.0, OCH, major regioisomer), 5.05–4.95 (1H, m,
0.4 OCH, minor regioisomer + 0.6 OCH, major regioisomer),
3.98 (1.2H, s, OCH3, minor regioisomer); 3.88 (1.8H, s,
OCH3, major regioisomer), 1.65 (1H, brs, OH); δC (125 MHz,
CDCl3), 191.3 (CH), 191.2 (CH), 162.6 (C), 162.3 (C), 157.7
PEG-2000 azide cycloadduct 23
This compound is novel.
PEG2000-azide 24 (25 mg, 12.5 µmol) and alkyne 16 (C), 157.5 (C), 155.9 (C), 153.8 (C), 152.7 (C), 152.5 (C), 151.4
(3.0 mg, 12.5 µmol) were added together in deuterated chloro- (C), 147.5 (C), 142.5 (CH), 141.1 (CH), 136.0 (C). 134.9 (C),
form (0.5 mL) and the reaction left at r.t. (ca. 0.025 M in both 132.7 (C), 132.5 (C), 131.6 (CH), 130.9 (CH), 130.8 (CH),
reagents). The progression of the reaction was monitored 129.4 (C), 128.9 (C), 128.5 (CH), 128.1 (CH), 127.2 (C), 126.7
daily. The final product was also analysed by GPC, ca. 14 days (C), 122.5 (CH), 122.1 (CH), 118.9 (C), 118.5 (C), 115.2 (CH),
for 100% conversion. The stacked spectra and the graph of 114.9 (CH), 113.0 (CH), 111.1 (C), 111.0 (C), 110.9 (CH).
conversion/time, as well as GPC data, are in the ESI.† 110.7 (CH), 110.1 (CH), 103.6 (CH), 103.5 (CH), 67.1 (CH2),
Characteristic peaks of product were observed as follows: δH 63.2 (CH2), 60.7 (CH2), 58.4 (CH2), 56.2 (CH3), 56.1 (CH3);
(300 MHz, CDCl3) (ca. 1 : 1 ratio) 9.82 + 9.80 (1H, s × 2, CHO), m/z (ES-API+) 520.0 ([M + Na]+).
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Alcohol 19/benzyl azide Cycloadduct 28
washed with sat. aq. NaHCO3 (3 × 5 mL), and dried over
MgSO4. Purification by column chromatography (silica; EtOAc/
Hex; 20 : 80 → 50 : 50) afforded 35 as a waxy green solid
(128 mg, 0.22 mmol, 66%). Mp 67–73 °C. (Found (ESI)
[M + H]+, 572.2212. C32H34N3O5S requires 572.2214). νmax
2923, 2784, 1587, 1489, 1234, 1102, 1003 and 757 cm−1
;
δH (500 MHz, CDCl3) 8.52 (1H, d, J 8.5, ArH), 8.31–8.23 (2H, m,
ArH), 7.54–7.48 (1H, m, ArH), 7.45–7.37 (2H, m, ArH),
7.22–7.15 (3H, m, ArH), 7.08 (1H, d, J 7.5, ArH), 6.79 (1H, d,
J 2.0, ArH), 6.53 (1H, d, J 1.9, ArH), 4.62–4.49 (2H, m, OCH2),
4.43–4.27 (2H, m, OCH2), 3.90 (3H, s, OCH3), 3.45 (2H, d, J 5.3,
NCH2), 2.95 (2H, t, J 5.6, NCH2), 2.85 (6H, s, N(CH3)2).
δC (126 MHz, CDCl3) 154.5, 153.3, 152.1, 141.5, 136.9, 136.1,
135.9, 134.7, 132.1, 130.5, 130.0, 129.9, 129.7, 129.3, 128.6,
124.4, 123.3, 123.3, 122.7, 118.8, 115.3, 110.9, 87.7, 86.2, 63.7,
60.4, 55.9, 53.0, 47.3, 45.5, 42.6. m/z (ESI) 570 ([M + H]+, 100%)
and 606 ([M + Na]+, 10%); UV-Vis (MeCN) λmax (ε/M−1 cm−1):
This compound is novel.
Alcohol 19 (30 mg, 0.096 mmol) and benzyl azide 20
(13 mg, 12 μL, 0.096 mmol) were stirred in MeCN (0.6 mL) for
5 days, monitoring each day by TLC (0.16 M in each reagent).
At the end of this time the solvent was removed under vacuum
and the product purified by flash chromatography on silica gel
(hexane : EtOAc, 7 : 3) to yield the product 28 as a white solid
(40 mg, 0.093 mmol, 97%). TLC hexane : EtOAc, 7 : 3, silica,
Rf 0.1; M.p. 126–129 °C; (found (ESI+): [M + Na]+ 452.1579.
C25H23N3NaO4 requires 452.1581); νmax 1589, 1492, 1444, 1423,
1335, 1273, 1161, 1138, 1108, 1004, 845, 798, 721 cm−1
;
338 (10 500), 234 ((36 200) nm; fluorescence (MeCN; λex
367 nm); λem 510 nm.
=
δH (500 MHz, CHCl3) (two regioisomers 3 : 2); 7.45–7.40 (1H,
m, ArH), 7.40–7.70 (10H, m, ArH), 5.95 (0.4H, d, J 8.0, CH,
minor regioisomer), 5.70–5.55 (2H, m, CH), 5.45–5.25 (2H, m,
CH), 5.05 (0.6H, d, J 14.0, CH, major regioisomer), 4.90 (0.4H,
d, J 16.0, CH, minor regioisomer). 4.70 (0.4H, d, J 12.0, CH,
minor regioisomer). 4.62 (0.6H, d, J 13.0, CH, major regio-
isomer), 4.58 (1.2H, brs, OCH2Ar, 2 × major regioisomer), 4.54
(0.8H, brs, OCH2Ar, 2 × minor regioisomer), 3.82 (1.4H, s,
OCH3, minor regioisomer), 3.80 (1.6H, s, OCH3, major regio-
isomer), 2.20 (1H, brs, OH). δC (125 MHz, CDCl3) 152.7 (C),
152.4 (C), 151.0 (C), 150.9 (C), 145.5 (C), 144.9 (C), 143.8 (C),
143.7 (C), 136.5 (C), 135.7 (C), 134.0 (C), 133.1 (C), 131.7 (C),
130.9 (C), 130.5 (C), 129.8 (CH), 128.5 (CH), 128.1 (C), 127.9
(C), 127.8 (CH), 127.7, (CH), 127.4 (CH), 127.3 (CH), 126.8
(CH), 126.2 (CH), 124.8 (CH), 123.5 (CH), 121.1 (CH), 112.0
(CH), 110.1 (CH), 110.0 (CH), 109.4 (CH), 66.2 (CH2), 64.0
(CH2), 63.9 (CH2), 61.4 (CH2), 59.8 (CH2), 56.5 (CH2), 55.0
(CH3), 54.8 (CH3), 51.9 (CH2), 50.9 (CH2).
2,4-Dimethyl-3-ethyl BoDIPY strained alkyne 36
This compound is novel.
To a solution of alkyne 16 (100 mg, 0.340 mmol, 1.0 eq.) in
DCM (22 mL) was added 3-ethyl-2,4-dimethylpyrrole (87.3 mg,
0.1 mL, 0.71 mmol, 2.1 eq.), at which point the solution
became red, TFA (3.9 mg, 2 µL, 34 µmol, 0.1 eq.) was added,
resulting in the formation of a green solution which was
stirred for 3 h, during which time it returned to a red colour.
The solution was then washed with a saturated solution of
NaHCO3 (20 mL), turning the organic layer yellow, and brine
(20 mL). The organic layer was then dried over MgSO4, which
was subsequently removed by filtration, and the solvent was
evaporated. The residue was then dissolved in toluene
(12.3 mL) and a suspension of DDQ (84 mg, 0.37 mmol,
1.1 eq.) in toluene (6 mL) was added, resulting in the solution
turning purple. The mixture was then stirred for 1 h before
TEA (141 mg, 0.20 mL, 1.4 mmol, 4.1 eq.) was added along
with BF3·Et2O (290 mg, 0.25 ml, 2.04 mmol, 6.0 eq.) and the
mixture was refluxed at 75 °C for 45 min. The mixture was
then cooled before being filtered through a silica plug eluted
with DCM. The resultant solution was then concentrated
under vacuum to afford the crude product. The product was
m/z (ES-API+) 452.0 ([M + Na]+). The reaction was followed
over time in a separate run using alcohol 19 (15 mg,
0.050 mmol) and benzyl azide (6.5 mg, 0.050 mmol) in CDCl3
(0.4 mL) ([19] ca. 0.13 M). The conversion/time graph for a sep-
arate reaction is in the ESI.†
01Dansyl amine alkyne 35
This compound is novel.
N-(2-Aminoethyl)-5-(dimethylamino)naphthalene-1-sulfona- purified by column chromatography using an eluent of 2 : 8
mide 34 (100 mg, 0.34 mmol) was added to aldehyde strained EtOAc : pet. ether to afford the pure product 36 as a red/green
alkyne 16 (100.3 mg, 0.34 mmol) in THF (1 mL) and heated to metallic solid (128 mg, 0.225 mmol, 66%). (Found (ESI)
reflux for two hours. The reaction was cooled to ambient tem- [M + Na]+ 591.2609 C34H35BF2N2NaO3 requires 591.2601;
perature, NaBH4 (25.7 mg, 0.68 mmol) was added and stirred vmax 2962, 2928, 2868, 1536, 1454, 1315, 1182, 972 and
for 18 hours. The reaction was diluted with EtOAc (5 mL), 960 cm−1; δH (500 MHz, CDCl3) 7.38 (1H, t, J 7.5, ArH),
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7.17–7.22 (1H, m, ArH), 7.14 (1H, d, J 7.9, ArH), 6.87 (1H, d, BoDIPY strained alkyne 38
J 1.5, ArH), 6.78 (1H, d, J 1.7, ArH), 4.62–4.71 (1H, m, CHH),
4.46 (2H, d, J 13.9, 2 × CHH), 4.31–4.39 (1H, m, CHH), 3.89
(3H, s, OCH3), 2.54 (3H, s, CH3), 2.51 (3H, s, CH3), 2.35 (2H, q,
J 7.5, CH2CH3), 2.29 (2H, q, J 7.6, CH2CH3), 1.64 (3H, s, CH3),
1.45 (3H, s, CH3), 1.03 (3H, t, J 7.6, CH2CH3), 0.97 (3H, t,
J 7.5, CH2CH3); δC (125 MHz, CDCl3) 154.4, 154.1, 153.8, 153.7,
142.7, 139.5, 138.7, 138.2, 138.0, 135.3, 132.7, 131.7, 131.6,
This compound is novel.
130.8, 130.7, 129.4, 124.3, 124.1, 122.6, 111.2, 87.2, 86.1, 63.3,
To a solution of aldehyde 16 (100 mg, 0.340 mmol, 1.0 eq.)
in DCM (22 mL) pyrrole (47 mg, 0.71 mmol, 2.1 eq.), TFA
(3.8 mg, 34 µmol, 0.1 eq.) was added and the solution was
stirred for 3 h. The solution was then washed with a saturated
solution of NaHCO3 (20 mL) and brine (20 mL). The organic
layer was then dried over MgSO4, which was subsequently
removed by filtration, and the solvent evaporated. The residue
was then dissolved in toluene (12.3 mL) and a suspension of
DDQ (84 mg, 0.37 mmol, 1.1 eq.) in toluene (6 mL) was added.
The mixture was then stirred for 1 h before TEA (141 mg,
1.4 mmol, 4.1 eq.) was added along with BF3·Et2O (290 mg,
2.04 mmol, 6.0 eq.) and the mixture was refluxed at 80 °C for
45 min. The mixture was then cooled to rt, before being
filtered through a silica plug eluted with DCM. The resulting
solution was then concentrated under vacuum to afford the
crude product. The crude product was purified by flash
column chromatography to afford the pure product 38 as an
orange/green metallic solid (42 mg, 0.089 mmol, 26%).
60.5, 56.1, 17.2, 17.1, 14.7, 14.6, 12.5, 11.8 and 11.4;
δF (376 MHz, CDCl3) −146.53–−145.15 (brm); m/z (ESI) 591
([M + Na]+). Fluorescence (MeCN; λex = 524 nm); λem = 534 nm;
UV-Vis (MeCN) λmax (ε/M−1 cm−1): 520 (14 700) nm.
2,4-Dimethyl BoDIPY Strained alkyne 37
This compound is novel.
To a solution of aldehyde 16 (100 mg, 0.340 mmol, 1.0 eq.)
in DCM (22 mL), 2,4-dimethylpyrrole (67 mg, 0.71 mmol,
2.1 eq.), TFA (3.8 mg, 34 µmol, 0.1 eq.) was added and the
solution was stirred for 3 h. The solution was then washed
with a saturated solution of NaHCO3 (20 mL) and brine
(20 mL). The organic layer was then dried over MgSO4, which
was subsequently removed by filtration, and the solvent evap-
orated. The residue was then dissolved in toluene (12.3 mL)
and a suspension of DDQ (84 mg, 0.37 mmol, 1.1 eq.) in
toluene (6 mL) was added. The mixture was then stirred for 1 h
before TEA (141 mg, 1.4 mmol, 4.1 eq.) was added along with
BF3·Et2O (290 mg, 2.04 mmol, 6.0 eq.) and the mixture was
refluxed at 80 °C for 45 min. The mixture was then cooled to
rt, before being filtered through a silica plug eluted with DCM.
The resulting solution was then concentrated under vacuum to
afford the crude product. The crude product was purified by
flash column chromatography to afford the pure product 37 as
an orange/green metallic solid (38 mg, 0.074 mmol, 22%). Rf =
0.44 (Hexane–EtOAc 3 : 1); (found (ESI)) [M + Na]+ 535.1983.
C30H27BF2N2NaO3 requires 535.1980; vmax 2955, 2922, 2853,
1536, 1504, 1456, 1264 and 964 cm−1; δH (500 MHz, CDCl3)
7.35–7.41 (1H, m, ArH), 7.23–7.25 (1H, m, ArH), 7.17–7.22 (1H,
m, ArH), 7.11–7.16 (1H, m, ArH), 6.86 (1H, s, ArH), 6.77 (1H, s,
ArH), 6.03 (1H, s, MeCCHCMe), 5.97 (1H, s, MeCCHCMe), 4.66
(1H, d, J 15.4, CHH), 4.40–4.48 (2H, m, 2 × CHH), 4.33 (1H, d,
J 15.4, CHH), 3.88 (3H, s, OCH3), 2.56 (3H, s, CH3), 2.53 (3H, s,
Rf
= 0.55 (DCM); (found (ESI)) [M +
Na]+ 479.1351
C26H19BF2N2NaO3 requires 479.1354; vmax 1545, 1410, 1385,
1261, 1114, 1078 and 956 cm−1; δH (500 MHz, CDCl3) 7.94 (2H,
brs, 2 × NCHCHCH), 7.40–7.45 (1H, m, ArH), 7.27–7.31 (2H, m,
ArH), 7.23–7.26 (1H, m, ArH), 7.20–7.22 (1H, m, ArH) 7.18–7.20
(2H, m, ArH + NCHCHCH), 7.08–7.10 (1H, m, NCHCHCH),
6.59 (2H, brs, 2 × NCHCHCH), 4.71 (1H, d, J 15.4, CHH), 4.62
(1H, d, J 15.4, CHH), 4.50 (1H, d, J 15.4, CHH), 4.41 (1H, d,
J 15.4, CHH), 3.97 (3H, s, OCH3); δC (125 MHz, CDCl3) 154.5,
153.2, 146.8, 145.1, 143.9, 137.3, 134.9, 131.7, 129.8, 126.7,
127.0, 124.4, 122.6, 118.6, 113.6, 87.2, 86.7, 63.7, 60.6, 56.1;
m/z (ESI) 479 ([M + Na]+; fluorescence (MeCN; λex = 508 nm);
λem = 519 nm; UV-Vis (MeCN) λmax (ε/M−1 cm−1): 497
(58 563) nm.
(Me, Et, Me) BoDIPY clicked product 39 and 40
CH3); δC (125 MHz, CDCl3) 155.5, 155.4, 154.4, 154.2, 143.5, These compounds are novel. We have not confirmed which
142.9, 141.0, 138.2, 135.2, 131.5, 131.3, 130.7, 129.4, 124.3, regioisomer is which, however tentative assignments have
123.8, 122.6, 121.2, 121.1, 110.8, 87.2, 86.1, 63.2, 60.5, 56.1, been made; full details are in the ESI.†
14.5 and 14.1; m/z (ESI) 535 ([M + Na]+); fluorescence (MeCN;
To a solution of (Me, Et, Me) BoDIPY alkyne (28.4 mg,
λex = 504 nm); λem = 510 nm; UV-Vis (MeCN) λmax (ε/M−1 cm−1): 0.05 mmol, 1 eq.) in CDCl3 (0.5 mL), benzylazide (0.56 mg,
498 (18 407) nm.
5.2 µL, 0.05 mmol, 1 eq.) was added. The reaction was followed
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1
by H NMR. The solvent was then removed under vacuum to Characterisation RTP and Dan Lester for providing access to
give the crude product. This was then purified by flash column the GPC and TGA instruments described in the General
chromatography (eluent EtOAc–Hexane gradiant 1 : 4–1 : 1), to Experimental. Crystallographic data were collected using an
give the pure products 39 and 40 in a 1 : 1 ratio as two isolable instrument (described in the General Experimental) purchased
regioisomers A (first to elute) and B (second to elute). through support from Advantage West Midlands (AWM) and
Regioisomer A: (13 mg, 0.0185 mmol, 37%). Rf
= 0.4 the European Regional Development Fund (ERDF).
(EtOAc–Hexane 1 : 1); (found (ESI)) [M + Na]+ 724.3238.
C41H42BF2N5NaO3 requires 724.3248; νmax 2960, 2923, 2853,
1539, 1472, 1314, 1181, 973 and 751 cm−1; δH (500 MHz,
CDCl3) 7.29–7.33 (3H, m, ArH), 7.21–7.25 (1H, m, ArH), 7.16
(1H, d, J 8.4, ArH), 7.09–7.14 (2H, m, ArH), 7.04 (1H, d, J 7.0,
ArH), 6.95, (1H, t, J 7.4, ArH), 6.87 (1H, s, ArH), 6.82 (1H, s,
ArH), 5.75 (1H, d, J 15.6, NCHH), 5.49 (1H, d, J 14.3, OCHH),
5.51 (1H, d, J 12.8, OCHH), 5.43 (1H, d, J 15.6, NCHH), 5.19
(1H, d, J 14.3, OCHH), 4.77 (1H, d, J 12.8, OCHH), 3.87 (3H, s,
OCH3), 2.54 (3H, s, CH3), 2.52 (3H, s, CH3), 2.25–2.38 (4H, m,
2 × CH2CH3),1.52 (3H, s, CH3), 1.45 (3H, s, CH3) 1.03 (3H, t,
J 7.4, CH2CH3), 0.98 (3H, t, J 7.4, CH3); δC (125 MHz, CDCl3)
154.0, 152.5, 146.9, 145.2, 145.2, 139.4, 135.1, 134.3, 132.9,
132.5, 131.7, 130.6, 129.1, 129.0, 128.7, 128.4, 127.0, 122.4,
121.7, 113.4, 111.5, 63.0, 61.4, 56.2, 52.0, 23.6, 17.1, 12.5, 11.9
References
1 Strained alkynes. (a) J. D. Thomas, H. Cui, P. J. North,
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and 11.6; m/z (ESI) 724 ([M + Na]+); fluorescence (MeCN; λex
=
528 nm); λem = 535 nm; UV-Vis (MeCN) λmax (ε/M−1 cm−1): 521
(14 466) nm. Regioisomer B: (13 mg, 0.0185 mmol, 37%). Rf =
0.3 (EtOAc–Hexane 1 : 1); (Found (ESI)) [M + Na]+ 724.3245
C41H42BF2N5NaO3 requires 724.3241; νmax 2960, 2923, 2853,
1539, 1472, 1314, 1181, 973 and 751 cm−1; δH (500 MHz,
CDCl3) 7.42–7.46 (3H, m, ArH), 7.27–7.33 (3H, m, ArH), 7.16
(1H, d, J 8.4, ArH), 7.01–7.06 (1H, m, ArH), 6.90–6.93 (2H, m,
ArH), 6.86, (1H, d, J 2.0, ArH), 6.73 (1H, d, J 2.0, ArH), 6.82
(1H, s, ArH), 5.80 (1H, d, J 11.6, OCHH), 5.73 (1H, d, J 14.3,
NCHH), 5.53 (1H, d, J 14.3, NCHH), 5.38 (1H, d, J 14.5, OCHH),
5.02 (1H, d, J 14.5, OCHH), 4.95 (1H, d, J 11.6, OCHH), 3.91
(3H, s, OCH3), 2.49–2.55 (6H, m, 2 × CH3), 2.24–2.37 (4H, m,
2 × CH2CH3), 1.53 (3H, s, CH3), 1.39 (3H, s, CH2CH3),
0.94–1.06 (6H, m, 2 × CH3); δc (125 MHz, CDCl3) 153.9, 153.8,
147.3, 144.6, 139.7, 134.3, 133.4, 133.1, 131.4, 130.8, 129.5,
129.3, 129.0, 128.9, 128.8, 127.6, 127.0, 122.3, 122.1, 113.5,
112.1, 67.6, 58.1, 56.3, 52.9, 17.1, 12.5, 12.0, 11.6; m/z (ESI) 724
([M + Na]+); fluorescence (MeCN; λex = 528 nm); λem = 535 nm;
UV-Vis (MeCN) λmax (ε/M−1 cm−1): 521 (14 466) nm.
Conflicts of interest
There are no conflicts to declare.
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Acknowledgements
We thank EPSRC for funding of RCK through a project grant
(Ref. EP/M006670/1) and EPSRC/AstraZeneca for funding SF
through an NPIF PhD studentship, EPSRC are thanked for sup-
porting AM through the Warwick Impact Acceleration Account
(IAA EP/K503848/1) and Warwick University for support of
project student ZD. We are grateful for the Polymer
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