Chemo-, Regio-, and Stereoselective Copper(II)-Catalyzed Boron Addition to Acetylenic Esters and Amides in Aqueous Media

Article abstract of DOI:10.1021/acs.joc.6b00648

Aqueous conditions were developed for conducting an open-to-air, copper(II)-catalyzed addition of pinBBdan to alkynoates and alkynamides. The simple and mild β-borylation protocol proceeds in a remarkably chemo-, regio-, and stereoselective fashion to aff

Full text of DOI:10.1021/acs.joc.6b00648

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Article
Chemo-, Regio-, and Stereoselective Copper(II)-Catalyzed Boron
Addition to Acetylenic Esters and Amides in Aqueous Media
Amanda K. Nelson, Cheryl L. Peck, Sean M. Rafferty, and Webster L Santos
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b00648 • Publication Date (Web): 22 Apr 2016
Downloaded from http://pubs.acs.org on April 25, 2016
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Chemo-, Regio-, and Stereoselective Copper(II)-Catalyzed Boron Addition to
Acetylenic Esters and Amides in Aqueous Media
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Amanda K. Nelson, Cheryl L. Peck, Sean M. Rafferty, and Webster L. Santos*
Department of Chemistry, Virginia Tech, Blacksburg, VA 24061
* Eꢀmail: santosw@vt.edu
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Abstract
Aqueous conditions were developed for conducting an openꢀtoꢀair, copper(II)ꢀcatalyzed
addition of pinBBdan to alkynoates and alkynamides. The simple and mild βꢀborylation
protocol proceeds in a remarkably chemoꢀ, regioꢀ, and stereoselective fashion to afford
1,8ꢀdiaminonaphthalene protected (Z)ꢀβꢀboryl enoates and primary, secondary and
tertiary enamides in good to excellent yields. These reactions demonstrate a high
tolerance toward a variety of alkyl, aryl, and heteroatom functional groups and provide
convenient access to a diverse range of vinylboronic acid derivatives.
Introduction
Vinylboronic acids and their derivatives serve as valuable intermediates in
organic synthesis, particularly with SuzukiꢀMiyaura cross coupling reactions to form
carbonꢀcarbon bonds.1 As a consequence, efficient and economical methods for their
preparation are essential. Access to these derivatives via borylation of alkynes with
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boron sources such as HBpin and bis(pinacolato)diboron (B2pin2) is well established
including uncatalyzed,2 transition metalꢀcatalyzed,3 and base/acid catalyzed4
processes.5 However, some have disadvantages such as the use of organic solvents
and precious transition metals such as platinum or palladium, and the production of
toxic byꢀproducts. Among the class of vinylboronic acid derivatives, routes to conjugated
vinylboronates bearing carbonyl groups is severely limited, and methods toward primary
and secondary amides are nonꢀexistent.6 Because of the utility of vinylboronic acids, the
development of simple, efficient, and sustainable methods for their installation is
important.
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Among the myriad of protecting groups for boron, the pinacol (pin) moiety is a
standout, popular choice because of its compatibility with numerous reaction conditions.
However, the 1,8ꢀdiaminonaphthyl group (dan), an alternative boron ligand, is emerging
as an orthogonal protecting group.7 This moiety is attractive because of its robustness
and compatibility, and it allows fine tuning of the reactivity of the boron center. For
example, chemoselective transformations of Bpin derivatives occur in the presence of
the Bdan group.7e,8 Therefore, novel methods to introduce Bdan into organic substrates
efficiently are valuable. A differentially protected diboron reagent, pinBBdan (1)10e has
been particularly useful for the incorporation of the Bdan substituent.8e,8g,9 For example,
elegant work by Fernandez and coꢀworkers reported the organocatalytic addition of 1 to
α,βꢀunsaturated carbonyls.9a Further, Hall and coꢀworkers pioneered a method to
incorporate Bdan on the vinylic βꢀcarbon of esters (Scheme 1).7c,10 The multiꢀstep
procedure, however, was limited to esters containing no substituents on the βꢀcarbon.10
Regardless, the copperꢀcatalyzed enantioselective conjugate borylation,8f alkylation,7c
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and reduction11 reactions developed demonstrate the utility of these compounds as
synthetic intermediates.
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Given our interest in developing sustainable methods for the borylation of
activated carbonꢀcarbon bonds12 and the paucity of borylation reactions in water,13 we
set out to contribute a simple, efficient, and environmentally friendly process for the
addition of Bdan to acetylenic carbonyl groups. Water is a notably enticing solvent
choice partly due to its costꢀeffectiveness, but moreover because it is not flammable or
toxic. Further, we wanted to capitalize on our initial finding that earth abundant and air
stable Cu(II) efficiently catalyzes the borylation of α,βꢀunsaturated carbonyls, affording
an environmentally and user friendly method.12a,14 The seminal work of Marder and coꢀ
workers,15 outlining the Ptꢀcatalyzed borylation of α,βꢀunsaturated ketones, propelled
other transition metalꢀcatalyzed and metalꢀfree investigations on βꢀborylation
reactions.16 Inspired by these contributions, we report the development of an efficient
and aqueousꢀbased method for generating structurally diverse 1,8ꢀdiaminonaphthalene
protected βꢀborylꢀα,βꢀunsaturated carbonyl compounds, including primary and
secondary amides (Scheme 1). In this strategy, we capitalize on the chemoselective
activation of the more Lewis acidic boron of Bpin by activating it with a Lewis base
(either water or 4ꢀpicoline) to form an sp2ꢀsp3 diboron intermediate, thereby facilitating
the efficient transfer of Bdan.12a,17
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Scheme 1. Approaches to Bdan vinylboronates.
Results and discussions
Preliminary studies utilized commercially available 2ꢀbutynoate (2a) and the previously
established aqueous borylation protocol of alkynoates with B2(pin)2.18 Under these
conditions, no reaction was observed, likely due to the insolubility of the pinBBdan
diboron reagent in water (Table 1, entry 1). Addition of an environmentally benign
alcohol, such as ethanol or 2ꢀpropanol, promoted solubility (entry 2ꢀ7). As such, the
reaction proceeds smoothly to provide the (Z)ꢀβꢀborylꢀα,βꢀunsaturated ester 3a as a
single regioꢀ and stereoisomer, which was verified by nuclear Overhauser effect (nOe)
experiments. The expected chemoselective transfer of Bdan to the β carbon was
observed as a consequence of the differential in Lewis acidity of each boron center,
allowing the conjugate addition of the 1,8ꢀdiaminonaphthyl borylꢀcopper complex
(Scheme 1). The optimal percentage of alcohol in the aqueous solvent system was
determined by monitoring the percent conversion over time (entries 2ꢀ5). We observed
a high conversion after 6 hours with 5% ethanol (entry 2). However, complete
conversion was achieved in a shorter period of time when the ethanol additive was
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Table 1. Optimization of reaction conditions.a
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conversionc
(yield)
entry solvent
time (h)
1
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4
5
6
7
H2O
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4
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6
6
4
0
5% EtOH/H2O
10% EtOH/H2O
15% EtOH/H2O
20% EtOH/H2O
10% MeOH/H2O
10% iPrOH/H2O
93
100 (86)
100
100
0
100 (85)
2 wt % TPGSꢀ750ꢀ
M/H2O
8
9
6
6
94
10% EtOH/H2O,
2% TPGSꢀ750ꢀM
10% EtOH/H2Od
10% EtOH/H2Oe
100 (86)
10
11
1
1
0
0
a
Reaction conditions: pinBBdan (0.52 mmol), 2ꢀbutynoate 2a (0.625 mmol), 4ꢀpicoline (5 mol %), CuSO4 (1 mol
%). b Exclusive stereoselectivity was obtained, as determined by GCꢀMS of the crude material and confirmed by nOe
c
d
of the isolated product. Conversion determined by monitoring the consumption of pinBBdan using GCꢀMS.
Without copper. e Without 4ꢀpicoline.
increased to 10% (entry 3). Higher percentages of the ethanol additive had a negative
effect on the rate of conversion, requiring 6 hours to reach completion (entries 4ꢀ5).
Unlike the copper(I)ꢀcatalyzed borylation reaction developed by Yun et al.,19 in which a
methanol additive increased the rate of the reaction, no reaction was observed in this
case (entry 6). Under these conditions, pinBBdan was insoluble and unable to
participate in the reaction. 2ꢀpropanol, on the other hand, was an adequate additive
(entry 7). Next, we explored the use of a nanomicellar surfactant, 2 wt % TPGSꢀ750ꢀ
M,20 as an alternative aqueous reaction media and found these conditions to be similar
to the 10% ethanol mixture (entries 8ꢀ9). In comparison, no improvement to the yield
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was observed with the addition of the surfactant to the EtOH/H2O mixture. As expected,
copper(II) and 4ꢀpicoline were needed for the efficient conversion to product (entries 10ꢀ
11). We opted to utilize copper(II) instead of copper(I) sources such as CuCl because of
solubility issues in water and oxidation to copper(II) upon exposure to air.12a Therefore,
the simpler conditions were determined to be optimal (entries 3 and 9).
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Under these optimized conditions, the functional group tolerance and scope of
the reaction was examined (Table 2). Overall, the borylation reaction rapidly installed
the Bdan functional unit onto the βꢀcarbon regioꢀ and stereoselectively, providing the
(Z)-stereoisomer in all cases. Various alkyl chains ranging from methyl to heptyl
substituents on the R1 position provided the products in high yields with short reaction
times (3a-d). The more sterically hindered tertꢀbutyl substituent did not affect the yield
nor the selectivity of the product (3e). Next, we examined various cyclic rings and
obtained high yields for the cyclopropyl (3f) and cyclohexyl (3h) substituents.
Unfortunately, the borylated product for ethyl 3ꢀcyclopentylpropiolate (3g) was only
obtained in 48% yield. Regioselectivity for βꢀborylation was demonstrated by applying
Table 2. Boryl Conjugate Addition to Substituted Alkynoatesa
entry
1
substrate
product
time (h)
4
yieldc
86
3a
3b
3c
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4
79
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3d
3e
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3f
4
8
83
48
3g
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3h
3i
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8
72
78
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3j
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77
79
3k
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3l
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85
82
O
3m
O
C3H7
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3n
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73
a Reaction conditions: pinBBdan (0.52 mmol), alkynoate 2 (0.625 mmol), 4ꢀpicoline (5 mol %) and CuSO4 (1 mol %). b Exclusive stereoselectivity was
obtained, as determined by GCꢀMS of the crude material and confirmed by nOe of the isolated product. c Averaged from 2 or more experiments.
the reaction conditions to the conjugated cycloꢀ hexꢀ3ꢀenꢀ1ꢀyne ester (2i) to give the (Z)ꢀ
α,β,γ,δꢀunsaturated diene in a 78% yield. When R1 contained an ether substituent, the
borylation proceeded smoothly to give 3j in a 77% yield. Next, we probed substituent
tolerance in the R2 position and found that substrates containing sterically bulky
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substituents, such as a phenyl ring and branched isobutyl group, are readily borylated to
provide good yields of the respective (Z)ꢀβꢀborylꢀα,βꢀunsaturated esters (3k-l). Finally,
we demonstrated the chemoselectivity of this reaction by examining unsaturation at the
R2 position. The borylation of hexynoate derivatives bearing allyl (2m) and propargyl
(2n) groups resulted in high yields of the βꢀborylated products, thus verifying that the
reaction occurs exclusively at the more activated alkyne.
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Prompted by the great success of the alkynoate substrates, we sought to expand
the substrate scope to include acetylenic amide derivatives. Amides have received
minimal attention as substrates due to their inherently low reactivity toward 1,4ꢀ
conjugate additions.21 In fact, methods to access (Z)ꢀβꢀborylꢀα,βꢀunsaturated amides
directly are not available. However, it has been suggested that acetylenic amides and
esters undergo 3,4ꢀsyn addition reactions.21d Gratifyingly, Weinreb amide 4a reacted
readily under our 10% ethanol aqueous conditions to provide the desired product 5a in
an 82% yield (Table 3, entry 1). We reꢀexamined the use of a surfactant to pursue an
increase in the reaction yield. When ethanol was replaced by the 2 wt % TPGSꢀ750ꢀM
surfactant, a drastically lower yield was obtained (entry 2). However, in contrast to the
alkynoate optimization results, when ethanol was employed in conjunction with the
surfactant, an excellent yield of 5a was obtained (91%, entry 3). As expected, the
reaction remained stereoselective for the (Z)ꢀisomer.
As the addition of the 2 wt % TPGSꢀ750ꢀM surfactant improved the yield, we
continued to use this aqueousꢀbased media to explore the scope and limitations of
alkynamide substrates (Table 4). A comparable, but slightly lower yield was obtained
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when the alkyl chain of the Weinreb amide was reduced from a hexyl (5a) to a methyl
substituent (5b).
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Table 3. Screening of solvent system for the
borylation of Weinreb amide.a
entry
Solvent
Yield
82
1
2
2
10% EtOH/H2O
2 wt % TPGSꢀ750ꢀM/H2O
61
10% EtOH/H2O, 2 wt %
TPGS_750ꢀM
91
a
Reaction conditions: pinBBdan (0.625 mmol),
alkynamide 4 (0.520 mmol), 4ꢀpicoline (5 mol %) in
b
ethanol (0.1mL) and CuSO4 (1 mol %). Determined by
1H NMR of the crude material and confirmed by nOe of
the isolated product.
A series of N,Nꢀdimethyl amide substrates were synthesized to explore further
the effects of substitutions on the alkyne. Substrates with aliphatic substituents on the
R1 position, such as propyl (4c) or hexyl (4d) groups, undergo βꢀborylations in good
yields. The branched tertꢀbutyl derivative also gave the desired product 5e
stereoselectively. Although this reaction does not reach completion after 48 h, a good
yield (71%) is still obtained. Additionally, the borylation of amides containing cyclic R1
Table 4. Conjugate addition to Weinreb amides and substituted alkynamides a
entry
1
Substrate
product
time (h) yieldc
5a
4
88
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2
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5b
5c
5d
10
85
76
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5
6
5e
5f
48
12
71
89
O
Me
N
Me
7
8
5g
5h
15
28
93
79
9
5i
5j
15
9
82
92
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12
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14
5k
5l
12
12
15
16
76
96
41
90
5m
5n
15
5o
9
93
a
Reaction conditions: pinBBdan (0.625 mmol), alkynamide 4 (0.520 mmol), 4ꢀpicoline (5 mol %) in ethanol (0.1 mL) and CuSO4 (0.9 mL, 1 mol %
dissolved in an aqueous solution of 2 wt % TPGSꢀ750ꢀM). Determined by 1H NMR of the crude material and confirmed by nOe of the isolated
b
product. c Averaged from 2 or more experiments.
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substituents proceeded smoothly and provided the desired products in excellent yields
(5f-h). Even 3ꢀcyclopentylꢀN,Nꢀdimethylpropiolamide (4f) afforded the borylation product
in an 89% yield, which was surprising given that the ester equivalent was low yielding.
The conjugated cyclohexꢀ3ꢀenꢀ1ꢀyne substituted N,Nꢀdimethylpropiolamide (4h) was
regioselectively borylated at the βꢀposition, providing the (Z)ꢀα,β,γ,δꢀunsaturated diene,
5h, in an 79% yield. Borylation of the methylene phenyl ether (4i) also proceeded
smoothly. Finally, we demonstrated that the steric bulk of the tertiary amide was well
tolerated with an alkynamide derivative of Dꢀproline (4j). This substrate readily
undergoes βꢀborylation to give the desired product in excellent yield (92%) and without
racemization of the chiral center.
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The acidic hydrogen of the amide functional group is also tolerated under these
mild conditions, as evidenced by 5k-o. To the best of our knowledge, borylation of
secondary and primary amides have never been reported.22 The secondary amides
were regioꢀ and stereoselectively borylated in good to excellent yields (5k-l). When the
steric demand of the amide substituent was increased from a methyl to a benzyl group,
the borylation of 4l proceeded nearly quantitatively (96%, 5l). Gratifyingly, the less
reactive carboxamides readily undergo borylation as well (4m-o). Excellent yields were
obtained when the R1 position was substituted with a propyl (5n) or hexyl (5o) alkyl
chain while a modest yield was obtained for methyl substituent (5m). Interestingly, a
trend of increasing product yield as the R1 substituent became larger was observed,
presumably as a consequence of the solubility of the starting material.
Conclusions
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In summary, we have developed a mild and efficient copper(II)ꢀcatalyzed βꢀ
borylation of alkynoates and alkynamides using an unsymmetrical diboron reagent,
pinBBdan. We demonstrate the chemoselective transfer of the less Lewis acidic Bdan
moiety, and notably borylated inherently unreactive secondary and primary amides. The
reaction is carried out under environmentally friendly conditions, which are openꢀtoꢀair
and employ an aqueous media. Catalytic amounts of an inexpensive air stable
copper(II) catalyst and commercially available amine base also makes this approach
cost effective.
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Experimental Section
General Information. All borylation reactions were carried out openꢀtoꢀair and
performed at least in duplicate. MilliꢀQ water was obtained using a UV water system.
Deꢀionized water was used straight from the house DI water tap and was not degassed
or further purified. Dry THF and DCM were obtained from a solvent purification system.
Copper sulfate pentahydrate, 4ꢀpicoline, TPGSꢀ750ꢀM, and other commercially
available reagents and substrates (2a-c) were purchased and used as received. CuSO4
stock solutions were prepared by dissolving 2.6 mg CuSO4 in 1 mL MilliꢀQ water or 2 wt
% TPGSꢀ750ꢀM. The unsymmetrical diboron reagent, pinBBdan, was synthesized
according to the literature.1 TLC analyses were performed using silica gel MF254 plates
or Silicycle aluminum backed silica gel Fꢀ254 plates and spots were visualized with UV
light and KMnO4 stain.
Instrumentation. 1H NMR spectra were recorded on either a 500 MHz or 400 MHz
spectrometer. Chemical shifts are reported in ppm with the solvent resonance as the
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internal standard (CDCl3: 7.26 ppm, (CD3)2SO: 2.50 ppm, (CD3)2CO: 2.05 ppm). Data
are reported as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q =
quartet, p = pentet, m = multiplet, dd = doublet of doublets, dt = doublet of triplets, br =
broad), coupling constants (Hz), and integration. 13C{1H}vNMR spectra were recorded
on either a 600 MHz, 500 MHz, or 400 MHz spectrometer. Chemical shifts are reported
in ppm with the solvent resonance as the internal standard (CDCl3: 77.16 ppm). The
carbon directly attached to boron may not be observed, except for three examples, due
to quadrupolar relaxation. 11B NMR spectra were recorded on a 400 MHz spectrometer.
Chemical shifts are reported in ppm using boron trifluoride diethyl etherate as an
external standard (BF3O(C2H5)2: 0 ppm). High resolution mass spectra (HRMS) were
performed on an LCꢀESIꢀTOF. Gas chromatography (GC) analyses were performed on
a GC system coupled to a mass selective detector and autosampler. Optical rotation
was determined using a polarimeter. Melting and boiling points were measured on a
melting point apparatus and uncorrected.
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General Procedure 1. Dry THF (6.58 mL, 0.612 M) and nonꢀ1ꢀyne (0.500 g, 4.02
mmol, 1.0 equiv.) were added to an oven dried nitrogen purged flask. The flask was
cooled to ꢀ78 °C using a dry iceꢀacetone cold bath. Next, nꢀbutyllithium (1.690 mL of 2.5
M in hexanes, 4.23 mmol, 1.05 equiv.) was added dropwise to the flask and allowed to
stir for 30 minutes. To the flask, ethyl chloroformate (0.450 g, 4.02 mmol, 1.0 equiv) was
then slowly added dropwise. The reaction temperature was held at ꢀ78 °C for 8ꢀ9 hours
and allowed to warm to room temperature overnight. The reaction was quenched with
saturated aqueous ammonium chloride (30 mL) and extracted with hexanes (3 x 5 mL).
The organic layer was then washed with DI water (5 x 10 mL), dried over sodium
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sulfate, filtered, and concentrated in vacuo. Column chromatography was used to purify
the product(s), eluting with hexanes and ethyl acetate.
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General Procedure 2. Dry THF (8.6 mL, 0.612 M) and pentꢀ1ꢀyne (0.50 mL, 5.27
mmol, 1.0 equiv.) were added to an oven dried nitrogen purged flask. The flask was
cooled to ꢀ78 °C using a dry iceꢀacetone cold bath. Next, nꢀbutyllithium (2.11 mL of 2.5
M in hexanes, 5.27 mmol, 1.0 equiv.) was added dropwise to the flask and allowed to
stir for 30 minutes. To the flask, phenyl chloroformate (643 ꢁL, 5.27 mmol, 1.0 equiv.)
was slowly added dropwise. The reaction temperature was held at ꢀ78 °C for 8ꢀ9 hours
and allowed to warm to room temperature overnight. The reaction was quenched with
saturated aqueous ammonium chloride (30 mL) and extracted with hexanes (3 x 5 mL).
The organic layer was then washed with DI water (5 x 10 mL), dried over sodium
sulfate, filtered, and concentrated in vacuo. Column chromatography was used to purify
the product(s), eluting with hexanes and ethyl acetate.
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General Procedure 3.2 Dry THF (27.2 mL, 0.2 M), methyl nonꢀ2ꢀynoate 3c (1.0 mL,
5.44 mmol, 1.0 equiv.), and N,Oꢀdimethylhydroxylamine (997 mg, 16.32 mmol, 3.0
equiv.) were added to an oven dried nitrogen purged flask. The flask was cooled to ꢀ20
°C using a sodium chloride ice bath and kept cold for 1 hour prior to the dropwise
addition of secꢀbutylmagnesium chloride (12.0 mL of 2 M in diethyl ether, 24.0 mmol,
4.4 equiv.). The consumption of the starting material was monitored by TLC. The
reaction was quenched with saturated aqueous ammonium chloride (20 mL). The
mixture was extracted with diethyl ether (3 x 10 mL). The combined extracts were
washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The
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product(s) were purified using column chromatography, eluting with hexanes and ethyl
acetate.
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General Procedure 4.2 Dry THF (10 mL, 0.5 M) and octꢀ1ꢀyne (500 mg, 4.54 mmol, 1.0
equiv.) were added to an oven dried nitrogen purged flask. The flask was cooled to ꢀ78
°C using a dry iceꢀacetone cold bath. Next, nꢀbutyllithium (1.8 mL of 2.5 M in hexanes,
4.54 mmol 1.0 equiv.) was added dropwise to the flask and allowed to stir for 30
minutes. This solution was transferred dropwise via cannula to a separate nitrogen dried
flask containing dry THF (10 mL) and dimethylcarbamic chloride (0.84 mL, 9.07 mmol
2.0 equiv.). The reaction temperature was held at ꢀ78 °C for 6 hours and allowed to
warm to room temperature overnight. The reaction was quenched with DI water (10 mL)
and extracted with hexanes (10 x 3 mL). The organic layer was then washed with DI
water (5 x 15 mL), dried over sodium sulfate, filtered, and concentrated in vacuo.
Column chromatography was used to purify the product(s), eluting with hexanes and
diethyl ether (4c) or hexanes and ethyl acetate (4d-i).
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General Procedure 5. Dry DCM (45.3 mL, 0.1 M) and hexynoic acid (0.50 mL, 4.53
mmol 1.0 equiv.) were added to an oven dried nitrogen purged flask and cooled to 0 °C.
Triethylamine (0.63 mL, 4.53 mmol, 1.0 equiv.) was added dropwise to the flask and
allowed to stir for 15 minutes before the dropwise addition of pivaloyl chloride (0.61 mL,
4.98 mmol 1.1 equiv.). The consumption of starting material was monitored by TLC.
Triethylamine (917 mg, 9.06 mmol, 2.0 equiv.) was added dropwise to a separate
nitrogen dried flask containing dry DCM (45.3 mL, 0.1 M) and Dꢀproline methyl ester
hydrochloride (585 mg, 4.53 mmol, 1.0 equiv.). The solution was stirred at room
temperature for 1 hour prior to being added dropwise to the initial flask via cannula. The
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reaction mixture was allowed to warm to room temperature overnight. DI water (15 mL)
was used to quench the reaction. Subsequently, the product(s) were extracted with
DCM (3 x 10 mL). The organic layer was then washed with DI water (2 x 10 mL), 10%
NaOH (3 x 10 mL), brine, dried with sodium sulfate, and concentrated in vacuo. Column
chromatography was used to purify the product(s), eluting with hexane and ethyl
acetate. The resulting products were > 97% pure and used as is for the βꢀborylation
reaction.
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General Procedure 6.2 Methyl nonꢀ2ꢀynoate 3c (600 mg, 3.57 mmol 1.0 equiv.) and
MeOH (28.5 mL, 0.1 M) were added to an oven dried nitrogen purged flask. To the
reaction mixture, an excess of 28ꢀ30% ammonium hydroxide (36.8 mL, 267 mmol, 75
equiv.) was added dropwise and allowed to stir at room temperature for 6 h (4m-n) or
17 h (4o). The consumption of the starting material was monitored by TLC. The
aqueous based solvent from the crude reaction mixture was concentrated in vacuo to
provide an offꢀwhite colored solid. The mixture was dissolved in ethyl acetate and rinsed
with DI water (3 x 10 mL). The combined extracts were washed with brine, dried over
sodium sulfate, filtered, and concentrated in vacuo. The solid was solubilized in a
minimal amount of diethyl ether at room temperature then hexanes was added slowly
until the solution became cloudy. The crude solution was sealed with parafilm and
stored at 5 °C overnight. The precipitate was filtered and the obtained crystals were
washed with cold hexanes. After being dried on high vacuum, the final product(s) were
obtained as white crystals. The compounds were recrystallized using diethyl ether and
hexanes.
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General Procedure 7: β-Borylation of Alkynoates with pinBBdan (3a-n). In a 2
dram vial were added pinBBdan 1 (153 mg, 0.520 mmol, 1.0 equiv.), 4ꢀpicoline (2.55
ꢂL, 0.026 mmol, 0.05 equiv.) and ethyl butꢀ2ꢀynoate 2a (66 ꢂL, 0.625 mmol, 1.2 equiv.).
Then, 0.5 mL of 2.6 mg/mL CuSO4 stock solution (prepared with MilliꢀQ water), 0.4 mL
MilliꢀQ water, and 0.1 mL 200 proof ethanol (9:1 ratio, 0.52 M) were added down the
sides of the reaction vessel. Care was taken to ensure that solid reagents were not
splashed on the sides of the vial. The reaction mixture was heated to 50 °C and stirred
vigorously. The reaction was monitored for completion by TLC. In many cases, the
product and borylating reagent exhibited the same Rf; therefore, GCꢀMS was used to
determine complete consumption of the borylating reagent in these cases. After the
reaction was found to be complete, 2 mL of ethyl acetate was added to quench the
reaction. The product was extracted using ethyl acetate (3 x 10 mL). The combined
extracts were then washed with DI water (5 x 10 mL) and brine. The organic layer was
dried over sodium sulfate, filtered, and concentrated in vacuo. Column chromatography
was used to purify the borylated product, eluting with hexanes and ethyl acetate.
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General Procedure 8: β-Borylation of Alkynamides with pinBBdan (5a-o). In a 2
dram vial were added pinBBdan 1 (183 mg, 0.624 mmol, 1.2 equiv.), 4ꢀpicoline (2.55
ꢂL, 0.026 mmol, 0.05 equiv.), NꢀmethoxyꢀN-methylnonꢀ2ꢀynamide 4a (103 mg, 0.520
mmol, 1.0 equiv.). Then, 0.5 mL of 2.6 mg/mL CuSO4 stock solution (prepared with
aqueous 2 wt % TPGSꢀ750ꢀM), 0.4 mL aqueous 2 wt % TPGSꢀ750ꢀM, and 0.1 mL 200
proof ethanol (9:1 ratio, 0.52 M) were added down the sides of the reaction vessel. Care
was taken to ensure that solid reagents were not splashed on the sides of the vial. The
reaction mixture was heated to 50 °C and stirred vigorously. The reaction was
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monitored for completion by TLC. In some cases, the product and acetylenic amide
exhibited the same Rf; therefore, GCꢀMS was used to determine the complete
consumption of the starting material in these cases. After the reaction was found to be
complete, 2 mL of ethyl acetate was added to quench the reaction. The product was
extracted using ethyl acetate (3 x 10 mL). The combined extracts were then washed
with DI water (5 x 10 mL) and brine. The organic layer was dried over sodium sulfate,
filtered, and concentrated in vacuo. Column chromatography was used to purify the
borylated product, eluting with hexanes and ethyl acetate (5a-l) or diethyl ether and
ethyl acetate (5m-o).
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Ethyl dec-2-ynoate (2d). Synthesized according to general procedure 1. The title
compound was isolated in a 96% yield (758 mg) as a yellow liquid. TLC Rf = 0.33 in
100% hexanes. 1H and 13C{1H}NMR are consistent with literature.3
Ethyl 4,4-dimethylpent-2-ynoate (2e). Synthesized according to general procedure 1
(4.77 mmol scale). The title compound was isolated in a 66% yield (485 mg) as a
colorless liquid (bp 182.7 °C). TLC Rf = 0.31 in 100% hexanes. 1H NMR (400 MHz,
CDCl3) δ 4.20 (q, J = 7.1 Hz, 2H), 1.29 (t, J = 7.1 Hz, 3H), 1.27 (s, 9H); 13C{1H}NMR
(101 MHz, CDCl3) δ 154.3 (C), 96.5 (C), 72.0 (C), 61.9 (CH2), 30.1 (CH3), 27.6 (C), 14.2
(CH3). HRMS (APCI+): Calcd for C9H14O2 [M+H]+: 155.1067, Found 155.1059.
Ethyl 3-cyclopropylpropiolate (2f). Synthesized according to general procedure 1
(2.36 mmol scale). The title compound was isolated in an 87% yield (285 mg) as a
yellow liquid (bp 148.9 °C). TLC Rf = 0.35 in 19:1 / hexanes:EtOAc. 1H NMR (400 MHz,
CDCl3) δ 4.15 (q, J = 7.1 Hz, 2H), 1.39 – 1.28 (m, 1H), 1.25 (t, J = 7.1 Hz, 3H), 0.93 –
0.81 (m, 4H); 13C{1H}NMR (101 MHz, CDCl3) δ 153.9 (C), 93.1 (C), 68.6 (C), 61.8
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(CH2), 14.1 (CH3), 9.3 (CH2), ꢀ0.5 (CH). HRMS (APCI+): Calcd for C8H11O2 [M+H]+:
139.0754, Found 139.0753.
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Ethyl 3-cyclopentylpropiolate (2g). Synthesized according to general procedure 1
(3.39 mmol scale). The title compound was isolated in a 70% yield (396 mg) as a
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colorless liquid (bp 207.1 °C). TLC Rf = 0.41 in 19:1 / hexanes:EtOAc. H NMR (400
MHz, CDCl3) δ 4.18 (q, J = 7.1 Hz, 2H), 2.74 – 2.67 (m, 1H), 1.94 – 1.89 (m, 2H), 1.75 –
1.61 (m, 4H), 1.60 – 1.49 (m, 2H), 1.27 (t, J = 7.1 Hz, 3H); 13C{1H}NMR (101 MHz,
CDCl3) δ 154.1 (C), 93.4 (C), 72.8 (C), 61.8 (CH2), 33.1 (CH2), 29.8 (CH), 25.3 (CH2),
14.2 (CH3). HRMS (APCI+): Calcd for C10H15O2 [M+H]+: 167.1067, Found 167.1065.
Ethyl 3-cyclohexylpropiolate (2h). Synthesized according to general procedure 1
(4.59 mmol scale). The title compound was isolated in a 55% (434 mg) yield as a
1
colorless oil (bp 249.8 °C). TLC Rf = 0.58 in 9:1 / hexanes:EtOAc. H NMR (400 MHz,
CDCl3) δ 4.21 (q, J = 7.1 Hz, 2H), 2.55 – 2.46 (m, 1H), 1.88 – 1.80 (m, 2H), 1.76 – 1.67
(m, 2H), 1.55 – 1.46 (m, 3H), 1.35 – 1.27 (m, 3H), 1.30 (t, J = 7.1 Hz, 3H); 13C{1H}NMR
(101 MHz, CDCl3) δ 154.2 (C), 93.0 (C), 73.2 (C), 61.9 (CH2), 31.6 (CH2), 29.0 (CH),
25.7 (CH2), 24.8 (CH2), 14.2 (CH3). HRMS (ESI+): Calcd for C11H17O2 [M+H]+:
181.1223, Found 181.1223.
Ethyl 3-(cyclohex-1-en-1-yl)propiolate (2i). Synthesized according to general
procedure 1 (4.71 mmol scale). The title compound was isolated in a 78% yield (656
mg) as a yellow liquid. TLC Rf = 0.44 in 19:1 / hexanes:EtOAc. 1H and 13C{1H}NMR are
consistent with literature.3
Ethyl 4-phenoxybut-2-ynoate (2j). Synthesized according to general procedure 1
(3.90 mmol scale). The title compound was isolated in a 55% yield (438 mg) as a white
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solid. TLC Rf = 0.46 in 9:1 / hexanes:EtOAc. H and C{1H}NMR are consistent with
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Phenyl hex-2-ynoate (2k). Synthesized according to general procedure 2. The title
compound was isolated in a 75% yield (739 mg) as a pale yellow liquid (bp 283.9 °C).
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TLC Rf = 0.36 in 19:1 / hexanes:EtOAc. H NMR (400 MHz, CDCl3) δ 7.42 – 7.36 (m,
2H), 7.30 – 7.23 (m, 1H), 7.15 – 7.12 (m, 2H), 2.38 (t, J = 7.1 Hz, 2H), 1.71 – 1.60 (m,
2H), 1.05 (t, J = 7.4 Hz, 3H); 13C{1H}NMR (101 MHz, CDCl3) δ 152.2 (C), 150.3 (C),
129.6 (CH), 126.4 (CH), 121.6 (CH), 92.3 (C), 73.0 (C), 21.2 (CH2), 20.9 (CH2), 13.6
(CH3). HRMS (APCI+): Calcd for C12H13O2 [M+H]+: 189.0910, Found 189.0902.
Isobutyl hex-2-ynoate (2l). Synthesized according to general procedure 2. The title
compound was isolated in an 86% yield (763 mg) as a pale yellow liquid (bp 219.1 °C).
1
TLC Rf = 0.48 in 19:1 / hexanes:EtOAc. H NMR (400 MHz, CDCl3) δ 3.93 (d, J = 6.8
Hz, 2H), 2.31 (t, J = 7.1 Hz, 2H), 2.02 – 1.92 (m, 1H), 1.66 – 1.55 (m, 2H), 1.00 (t, J =
7.4 Hz, 3H), 0.94 (d, J = 6.8 Hz, 6H); C{1H}NMR (101 MHz, CDCl3) δ 154.2 (C), 89.4
13
(C), 73.4 (C), 71.9 (CH2), 27.7 (CH), 21.2 (CH2), 20.8 (CH2), 19.2 (CH3), 13.6 (CH3).
HRMS (APCI+): Calcd for C10H17O2 [M+H]+: 169.1223, Found 169.1217.
Allyl hex-2-ynoate (2m). Synthesized according to general procedure 2. The title
compound was isolated in a 67% yield (539 mg) as a yellow liquid (bp 208.9 °C). TLC Rf
= 0.42 in 19:1 / hexanes:EtOAc. 1H NMR (400 MHz, CDCl3) δ 5.98 – 5.87 (m, 1H), 5.30
– 5.25 (m, 1H), 5.39 – 5.32 (m, 1H), 4.65 (dt, J = 5.9, 1.3 Hz, 2H), 2.31 (t, J = 7.1 Hz,
2H), 1.67 – 1.56 (m, 2H), 1.0 (t, J = 7.4 Hz, 3H); 13C{1H}NMR (101 MHz, CDCl3) δ 153.7
(C), 131.4 (CH), 119.3 (CH2), 90.0 (C), 73.2 (C), 66.4 (CH2), 21.2 (CH2), 20.8 (CH2),
13.6 (CH3). HRMS (APCI+): Calcd for C9H13O2 [M+H]+: 153.0910, Found 153.0901.
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But-2-yn-1-yl hex-2-ynoate (2n). To a mixture of hexꢀ2ꢀynoic acid (500 mg, 4.46 mmol,
1.3 equiv.) in DCM (32.4 mL, 0.1 M), butꢀ2ꢀynꢀ1ꢀol (0.26 mL, 3.43 mmol, 1.0 equiv.) was
added followed by the solution of DMAP (41.9 mg, 0.343 mmol, 0.1 equiv.) in DCM (1.8
mL, 0.2 M). The solution was cooled to 0 °C and stirred for 15 minutes prior to the
addition of DCC (0.751 mL, 4.80 mmol, 1.4 equiv.). The consumption of the starting
material was monitored by TLC. After 6 hours, the reaction mixture was filtered through
a short plug of silica, which was rinsed with hexanes (3 x 10 mL). The filtrate was
concentrated in vacuo to provide the final product 2n as a colorless liquid in a 93% yield
(522 mg).
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(bp >235 °C (decomp)). TLC Rf = 0.38 in 19:1 / hexanes:EtOAc. H NMR (400 MHz,
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CDCl3) δ 4.71 (q, J = 2.4 Hz, 2H), 2.31 (t, J = 7.1 Hz, 2H), 1.85 (t, J = 2.4 Hz, 3H),
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1.66 – 1.55 (m, 2H), 1.01 (t, J = 7.4 Hz, 3H); C{1H}NMR (101 MHz, CDCl3) δ 153.4
(C), 90.9 (C), 84.3 (C), 73.0 (C), 72.7 (C), 54.2 (CH2), 21.3 (CH2), 21.0 (CH2), 13.8
(CH3), 4.0 (CH3). HRMS (APCI+): Calcd for C10H13O2 [M+H]+: 165.0910, Found
165.0907.
N-Methoxy-N-methylnon-2-ynamide (4a). Synthesized according to general
procedure 3. The title compound was isolated in a 90% yield (966 mg) as a pale yellow
oil. TLC Rf = 0.40 in 4:1 / hexanes:EtOAc. 1H and 13C{1H}NMR are consistent with the
literature.5
N-Methoxy-N-methylbut-2-ynamide (4b). Synthesized according to general procedure
3. The title compound was isolated in a 55% yield (380 mg) as a colorless oil. TLC Rf =
0.34 in 3:2 / hexanes:EtOAc. 1H and 13C{1H}NMR are consistent with the literature.6
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N,N-Dimethylhex-2-ynamide (4c). Synthesized according to general procedure 4. The
title compound was isolated in a 91% yield (575 mg) as a pale yellow oil (bp <210 °C
(decomp)). TLC Rf = 0.26 in 7:3 / hexanes:EtOAc. 1H NMR (400 MHz, CDCl3) δ 3.19 (s,
3H), 2.95 (s, 3H), 2.33 (t, J = 7.1 Hz, 2H), 1.60 (m, 2H), 1.01 (t, J = 7.3 Hz, 3H);
13C{1H}NMR (101 MHz, CDCl3) δ 155.0 (C), 93.1 (C), 74.3 (C), 38.5 (CH3), 34.2 (CH3),
21.5 (CH2), 21.0 (CH2), 13.7 (CH3). HRMS (ESI+): Calcd for C8H14NO [M+H]+:
140.1070, Found 140.1075.
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N,N-Dimethylnon-2-ynamide (4d). Synthesized according to general procedure 4. The
title compound was isolated in a 78% yield (642 mg) as a yellow oil. TLC Rf = 0.18 in
1:1 / hexanes:EtOAc. 1H and 13C{1H}NMR are consistent with the literature.2
N,N-4,4-Tetramethylpent-2-ynamide (4e). Synthesized according to general
procedure 4. The title compound was isolated in a 68% yield (473 mg) as an offꢀwhite
solid (mp 64.0 – 64.8 °C). TLC Rf = 0.39 in 3:2 / hexanes:EtOAc. 1H NMR (400 MHz,
CDCl3) δ 3.17 (s, 3H), 2.94 (s, 3H), 1.27 (s, 9H); 13C{1H}NMR (101 MHz, CDCl3) δ 155.0
(C), 100.3 (C), 72.7 (C), 38.5 (CH3), 34.2 (CH3), 30.3 (CH3), 27.8 (C). HRMS (ESI+):
Calcd for C9H16NO [M+H]+: 154.1226, Found 154.1222.
3-Cyclopentyl-N,N-dimethylpropiolamide (4f). Synthesized according to general
procedure 4. The title compound was isolated in an 85% yield (638 mg) as a light brown
liquid (bp >250 °C (decomp)). TLC Rf = 0.34 in 3:2 / hexanes:EtOAc. 1H NMR (400
MHz, CDCl3) δ 3.16 (s, 3H), 2.93 (s, 3H), 2.75 (p, J = 7.3 Hz, 1H), 2.00 – 1.88 (m, 2H),
1.77 – 1.62 (m, 4H), 1.61 – 1.53 (m, 2H); 13C{1H}NMR (101 MHz, CDCl3) δ 155.0 (C),
97.1 (C), 73.6 (C), 38.4 (CH3), 34.1 (CH3), 33.3 (CH2), 30.1 (CH), 25.1 (CH2). HRMS
(ESI+): Calcd for C10H16NO [M+H]+: 166.1226, Found 166.1227.
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3-Cyclohexyl-N,N-dimethylpropiolamide (4g). Synthesized according to general
procedure 4. The title compound was isolated in a 64% yield (521 mg) as a white solid
(mp 51.0 – 51.8 °C). TLC Rf = 0.35 in 3:2 / hexanes:EtOAc. 1H NMR (400 MHz, CDCl3)
δ 3.19 (s, 3H), 2.96 (s, 3H), 2.61 – 2.49 (m, 1H), 1.89 – 1.64 (m, 4H), 1.57 – 1.30 (m,
6H); 13C{1H}NMR (101 MHz, CDCl3) δ 155.0 (C), 96.7 (C), 74.0 (C), 38.5 (CH3), 34.1
(CH3), 31.8 (CH2), 29.2 (CH), 25.8 (CH2), 24.8 (CH2). HRMS (ESI+): Calcd for
C11H18NO [M+H]+: 180.1383, Found 180.1387.
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3-(Cyclohex-1-en-1-yl)-N,N-dimethylpropiolamide (4h). Synthesized according to
general procedure 4 (9.1 mmol scale). The title compound was isolated in a 94% yield
(1.56 g) as an offꢀwhite solid (mp 41.6 – 42.6 °C). TLC Rf = 0.36 in 3:2 /
hexanes:EtOAc. 1H NMR (400 MHz, CDCl3) δ 6.36 – 6.31 (m, 1H), 3.18 (s, 3H), 2.97 (s,
3H), 2.18 – 2.09 (m, 4H), 1.68 – 1.54 (m, 4H); 13C{1H}NMR (101 MHz, CDCl3) δ 155.1
(C), 139.8 (CH), 119.2 (C), 92.4 (C), 79.5 (C), 38.5 (CH3), 34.2 (CH3), 28.5 (CH2), 26.0
(CH2), 22.1 (CH2), 21.3 (CH2). HRMS (ESI+): Calcd for C11H15NO [M+H]+:
178.1226, Found 178.1224.
N,N-Dimethyl-4-phenoxybut-2-ynamide (4i). Synthesized according to general
procedure 4. The title compound was isolated in a 21% yield (194 mg) as a yellow oil
(bp <180 °C (decomp)). TLC Rf = 0.41 in 1:1 / hexanes:EtOAc. 1H NMR (400 MHz,
CDCl3) δ 7.33 – 7.27 (m, 2H), 7.03 – 6.95 (m, 2H), 4.85 (s, 2H), 3.07 (s, 3H), 2.94 (s,
3H); 13C{1H}NMR (101 MHz, CDCl3) δ 157.4 (C), 153.7 (C), 129.7 (CH), 122.0 (CH),
115.1 (CH), 86.0 (C), 79.9 (C), 55.9 (CH2), 38.3 (CH3), 34.2 (CH3). HRMS (ESI+): Calcd
for C12H14NO2 [M+H]+: 204.1019, Found 204.1023.
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Methyl hex-2-ynoyl-D-prolinate (4j). Synthesized according to general procedure 5.
The title compound was isolated in a 64% yield (645 mg, 1:1 mixture of rotamers) as a
colorless viscous oil (bp > 235 °C (decomp)). TLC Rf = 0.44 in 3:2 / hexanes:EtOAc. In
the NMR spectra, the second rotamer is designated by * and the overlapping rotamer
peaks are designated by †. 1H NMR (400 MHz, CDCl3) δ 4.63 (dd, J = 8.7, 3.2 Hz, 1H),
4.50* (dd, J = 8.7, 3.8 Hz, 1H), 3.84 – 3.54† (m, 10H), 2.33 (t, J = 7.0 Hz, 2H), 2.28* (t, J
= 7.0 Hz, 2H), 2.25 – 2.19 (m, 1H), 2.14 – 1.89† (m, 7H), 1.66 – 1.51† (m, 4H), 1.02 (t, J
= 7.3 Hz, 3H), 0.98* (t, J = 7.3 Hz, 3H); 13C{1H}NMR (101 MHz, CDCl3) δ 172.4 (C),
172.0* (C), 153.1 (C), 152.9* (C), 92.3 (C), 92.1* (C), 74.8 (C), 74.7* (C), 60.7 (CH),
57.9* (CH), 52.3 (CH3), 52.2* (CH3), 48.4 (CH2), 45.7* (CH2), 30.6 (CH2), 29.7* (CH2),
24.1 (CH2), 23.1* (CH2), 21.2 (CH2), 21.1* (CH2), 20.7 (CH2), 20.6* (CH2), 13.4 (CH3),
13.3* (CH3). HRMS (ESI+): Calcd for C12H18NO3 [M+H]+: 224.1281, Found 224.1297.
N-Methylhex-2-ynamide (4k). Synthesized according to general procedure 5. The title
compound was isolated in a 68% yield (386 mg, 9:1 mixture of rotamers) as a white
solid. TLC Rf = 0.41 in 3:2 / hexanes:EtOAc. 1H and 13C{1H}NMR are consistent with the
literature.7
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N-Benzylhex-2-ynamide (4l). Synthesized according to general procedure 5. The title
compound was isolated in a 53% yield (483 mg, 9:1 mixture of rotamers) as a white
solid (mp 44.2 – 45.1 °C). TLC Rf = 0.29 in 4:1 / hexanes:EtOAc. In the NMR spectra,
the minor rotamer is designated by * and the overlapping rotamer peaks are designated
by †. 1H NMR (400 MHz, CDCl3) δ 7.39 – 7.26† (m, 10H), 6.06 (br s, 1H), 6.00* (br s,
1H), 4.60* (d, J = 6.6 Hz, 2H), 4.47 (d, J = 5.9 Hz, 2H), 2.33* (t, J = 7.1 Hz, 2H), 2.26 (t,
J = 7.1 Hz, 2H), 1.57† (m, J = 7.2 Hz, 4H), 0.99 (t, J = 7.3 Hz, 3H), 0.98* (t, J = 7.3 Hz,
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3H); 13C{1H}NMR (101 MHz, CDCl3) δ 153.6† (C), 137.7* (C), 137.5 (C), 128.9* (CH),
128.8 (CH), 128.0 (CH), 127.9* (CH), 127.8 (CH), 127.2* (CH), 87.9† (C), 75.6† (C),
47.4* (CH2), 43.9 (CH2), 21.4 (CH2), 21.3* (CH2), 21.0* (CH2), 20.7 (CH2), 13.7 (CH3),
13.6* (CH3). HRMS (ESI+): Calcd for C13H16NO [M+H]+: 202.1226, Found 202.1234.
But-2-ynamide (4m). Synthesized according to general procedure 6. The title
compound was isolated in a 65% yield (193 mg) as offꢀwhite crystals. TLC Rf = 0.48 in
1:1 / hexanes:EtOAc. 1H and 13C{1H}NMR are consistent with the literature.8
Hex-2-ynamide (4n). Synthesized according to general procedure 6. The title
compound was isolated in a 43% yield (170 mg) as white crystals (mp 80.5 – 81.5 °C).
TLC Rf = 0.28 in 1:1 / hexanes:EtOAc. 1H NMR (400 MHz, CDCl3) δ 6.33 (br s, 1H),
5.80 (br s, 1H), 2.29 – 2.23 (m, 2H), 1.63 – 1.51 (m, 2H), 1.02 – 0.95 (m, 3H);
13C{1H}NMR (101 MHz, CDCl3) δ 155.3 (C), 89.0 (C), 75.1 (C), 21.3 (CH2), 20.7 (CH2),
13.6 (CH3). HRMS (ESI+): Calcd for C6H10NO [M+H]+: 112.0757, Found 112.0755.
Non-2-ynamide (4o). Synthesized according to general procedure 6. The title
compound was isolated in an 81% yield (443 mg) as white crystals. TLC Rf = 0.40 in 1:1
/ hexanes:EtOAc. 1H and 13C{1H}NMR are consistent with the literature.2
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Ethyl (Z)-3-(1H-naphtho[1,8-de][1,3,2]diazaborinin-2(3H)-yl)but-2-enoate (3a).
Synthesized according to general procedure 7. The title compound was isolated in 80ꢀ
89% yields (116 mg, 126 mg, and 130 mg) as a yellow solid (mp 85.7 – 87.2 °C). TLC
Rf = 0.34 in 9:1 / hexanes:EtOAc. 1H NMR (400 MHz, CDCl3) δ 7.11 (dd, J = 8.2, 7.4
Hz, 2H), 7.04 (dd, J = 8.2 Hz, 4J = 1.0 Hz, 2H), 6.35 (dd, J = 7.4 Hz, 4J = 1.0 Hz, 2H),
6.22 (q, 4J = 1.7 Hz, 1H), 5.80 (br s, 2H), 4.22 (q, J = 7.2 Hz, 2H), 2.30 (d, 4J = 1.7 Hz,
3H), 1.33 (t, J = 7.2 Hz, 3H); 13C{1H}NMR (101 MHz, CDCl3) δ 166.2 (C), 140.7 (C),
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136.4 (C), 127.7 (CH), 125.7 (CH), 120.2 (C), 118.3 (CH), 106.3 (CH), 60.1 (CH2), 16.6
(CH3), 14.5 (CH3); 11B NMR (128 MHz, CDCl3) δ 28.58. HRMS (ESI+): Calcd for
C16H18BN2O2 [M+H]+: 281.1456, Found 281.1450.
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Ethyl (Z)-3-(1H-naphtho[1,8-de][1,3,2]diazaborinin-2(3H)-yl)hex-2-enoate (3b).
Synthesized according to general procedure 7. The title compound was isolated in 78ꢀ
80% yields (124 mg and 129 mg) as a yellow solid (mp 102.5 – 104 °C). TLC Rf = 0.44
in 9:1 / hexanes:EtOAc. 1H NMR (400 MHz, CDCl3) δ 7.12 (dd, J = 8.3, 7.2 Hz, 2H),
7.05 (dd, J = 8.3 Hz, 4J = 1.0 Hz, 2H), 6.35 (dd, J = 7.2 Hz, 4J = 1.0 Hz, 2H), 6.19 (t, 4J =
0.7 Hz, 1H), 5.78 (br s, 2H), 4.22 (q, J = 7.2 Hz, 2H), 2.80 – 2.72 (m, 2H), 1.58 – 1.47
(m, 2H), 1.33 (t, J = 7.2 Hz, 3H), 0.99 (t, J = 7.3 Hz, 3H); 13C{1H}NMR (101 MHz, CDCl3)
δ 166.0 (C), 140.7 (C), 136.4 (C), 127.7 (CH), 125.2 (CH), 120.1 (C), 118.2 (CH), 106.3
(CH), 60.1 (CH2), 32.4 (CH2), 23.2 (CH2), 14.5 (CH3), 14.4 (CH3); 11B NMR (128 MHz,
CDCl3) δ 28.86. HRMS (ESI+): Calcd for C18H22BN2O2 [M+H]+: 309.1769, Found
309.1759.
Methyl (Z)-3-(1H-naphtho[1,8-de][1,3,2]diazaborinin-2(3H)-yl)non-2-enoate (3c).
Synthesized according to general procedure 7. The title compound was isolated in 84ꢀ
92% yields (147 mg, 152 mg, and 162 mg) as a yellow solid (mp 75.1 – 76.3 °C). TLC
Rf = 0.44 in 9:1 / hexanes:EtOAc. 1H NMR (400 MHz, CDCl3) δ 7.14 (dd, J = 8.3, 7.3
Hz, 2H), 7.07 (dd, J = 8.3 Hz, 4J = 1.0 Hz, 2H), 6.36 (dd, J = 7.3 Hz, 4J = 1.0 Hz, 2H),
6.19 (t, 4J = 0.7 Hz, 1H), 5.83 (br s, 2H), 3.78 (s, 3H), 2.83 – 2.76 (m, 2H), 1.54 – 1.28
(m, 8H), 0.94 – 0.88 (m, 3H); 13C{1H}NMR (101 MHz, CDCl3) δ 166.4 (C), 140.6 (C),
136.3 (C), 127.6 (CH), 124.3 (CH), 120.1 (C), 118.1 (CH), 106.3 (CH), 51.2 (CH3), 31.7
(CH2), 30.5 (CH2), 29.9 (CH2), 29.7 (CH2), 22.7 (CH2), 14.2 (CH3); 11B NMR (128 MHz,
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CDCl3) δ 28.85. HRMS (ESI+): Calcd for C20H26BN2O2 [M+H]+: 337.2082, Found
337.2078.
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Ethyl (Z)-3-(1H-naphtho[1,8-de][1,3,2]diazaborinin-2(3H)-yl)dec-2-enoate (3d).
Synthesized according to general procedure 7. The title compound was isolated in 78ꢀ
88% yields (141 mg, 152 mg, and 168 mg) as a yellow solid (mp 40 – 41 °C). TLC Rf =
0.55 in 9:1 / hexanes:EtOAc. 1H NMR (400 MHz, CDCl3) δ 7.12 (dd, J = 8.3, 7.3 Hz,
2H), 7.05 (dd, J = 8.3 Hz, 4J = 1.0 Hz, 2H), 6.35 (dd, J = 7.3 Hz, 4J = 1.0 Hz, 2H), 6.17 (t,
4J = 0.7 Hz, 1H), 5.79 (br s, 2H), 4.22 (q, J = 7.2 Hz, 2H), 2.80 – 2.73 (m, 2H), 1.55 –
1.22 (m, 13H), 0.91 – 0.86 (m, 3H); 13C{1H}NMR (101 MHz, CDCl3) δ 166.0 (C), 140.7
(C), 136.4 (C), 127.7 (CH), 125.0 (CH), 120.2 (C), 118.2 (CH), 106.3 (CH), 60.1 (CH2),
31.9 (CH2), 30.5 (CH2), 30.1 (CH2), 30.0 (CH2), 29.3 (CH2), 22.8 (CH2), 14.4 (CH3), 14.2
(CH3); 11B NMR (128 MHz, CDCl3) δ 28.90. HRMS (ESI+): Calcd for
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C22H30BN2O2 [M+H]+: 365.2395, Found 365.2382.
Ethyl (Z)-4,4-dimethyl-3-(1H-naphtho[1,8-de][1,3,2]diazaborinin-2(3H)-yl)pent-2-
enoate (3e). Synthesized according to general procedure 7. The title compound was
isolated in 73ꢀ89% yields (122 mg and 149 mg) as a white solid (mp 102.3 – 103.3 °C).
TLC Rf = 0.51 in 9:1 / hexanes:EtOAc. 1H NMR (400 MHz, CDCl3) δ 7.13 (dd, J = 8.4,
7.3 Hz, 2H), 7.06 (dd, J = 8.4 Hz, 4J = 1.0 Hz, 2H), 6.33 (dd, J = 7.3 Hz, 4J = 1.0 Hz,
2H), 5.95 (s, 1H), 5.66 (br s, 2H), 4.23 (q, J = 7.2 Hz, 2H), 1.34 (t, J = 7.2 Hz, 3H), 1.30
(s, 9H); 13C{1H}NMR (101 MHz, CDCl3) δ 168.2 (C), 140.7 (C), 136.3 (C), 127.7 (CH),
124.0 (CH), 119.7 (C), 118.0 (CH), 106.1 (CH), 60.7 (CH2), 36.1 (C), 30.7 (CH3), 14.3
(CH3); 11B NMR (128 MHz, CDCl3) δ 29.76. HRMS (ESI+): Calcd for
C19H24BN2O2 [M+H]+: 323.1925, Found 323.1927.
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Ethyl (Z)-3-cyclopropyl-3-(1H-naphtho[1,8-de][1,3,2]diazaborinin-2(3H)-yl)acrylate
(3f). Synthesized according to general procedure 7. The title compound was isolated in
80ꢀ87% yields (128 mg, 132 mg, and 139 mg) as a white solid (mp 125.7 – 127.2 °C).
TLC Rf = 0.37 in 9:1 / hexanes:EtOAc. 1H NMR (400 MHz, CDCl3) δ 7.10 (dd, J = 8.3,
7.2 Hz, 2H), 7.04 (dd, J = 8.3 Hz, 4J = 1.0 Hz, 2H), 6.31 (dd, J = 7.2 Hz, 4J = 1.0 Hz,
2H), 6.03 (d, 4J = 0.9 Hz, 1H), 5.62 (br s, 2H), 4.21 (q, J = 7.1 Hz, 2H), 3.04 – 2.96 (m,
1H), 1.31 (t, J = 7.1 Hz, 3H), 1.03 – 0.97 (m, 2H), 0.72 – 0.67 (m, 2H); 13C{1H}NMR (101
MHz, CDCl3) δ 166.6 (C), 140.4 (C), 136.3 (C), 127.7 (CH), 123.6 (CH), 120.0 (C),
118.3 (CH), 106.3 (CH), 60.0 (CH2), 14.5 (CH3), 13.6 (CH), 8.7 (CH2); 11B NMR (128
MHz, CDCl3) δ 28.75. HRMS (ESI+): Calcd for C18H20BN2O2 [M+H]+: 307.1612, Found
307.1599.
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Ethyl (Z)-3-cyclopentyl-3-(1H-naphtho[1,8-de][1,3,2]diazaborinin-2(3H)-yl)acrylate
(3g). Synthesized according to general procedure 7. The title compound was isolated in
45ꢀ51% yields (88 mg and 79 mg) as a white solid (mp 112.5 – 113.2 °C). TLC Rf = 0.47
in 9:1 / hexanes:EtOAc. 1H NMR (400 MHz, CDCl3) δ 7.12 (dd, J = 8.3, 7.2 Hz, 2H),
7.05 (dd, J = 8.3 Hz, 4J = 1.0 Hz, 2H), 6.33 (dd, J = 7.2 Hz, 4J = 1.0 Hz, 2H), 6.03 (d, 4J
= 1.0 Hz, 1H), 5.66 (br s, 2H), 4.20 (q, J = 7.1 Hz, 2H), 3.93 – 3.81 (m, 1H), 2.04 – 1.94
(m, 2H), 1.80 – 1.63 (m, 4H), 1.52 – 1.39 (m, 2H), 1.32 (t, J = 7.1 Hz, 3H); 13C{1H}NMR
(101 MHz, CDCl3) δ 166.1 (C), 140.5 (C), 136.3 (C), 127.7 (CH), 124.2 (CH), 119.9 (C),
118.2 (CH), 106.2 (CH), 60.0 (CH2), 41.6 (CH), 33.4 (CH2), 25.9 (CH2), 14.4 (CH3); 11B
NMR (128 MHz, CDCl3) δ 29.55. HRMS (ESI+): Calcd for C20H24BN2O2 [M+H]+:
335.1925, Found 335.1922.
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Ethyl (Z)-3-cyclohexyl-3-(1H-naphtho[1,8-de][1,3,2]diazaborinin-2(3H)-yl)acrylate
(3h). Synthesized according to general procedure 7. The title compound was isolated in
69ꢀ75% yields (125 mg, 130 mg, 132 mg, and 136 mg) as a white solid (mp 137.1 –
137.6 °C). TLC Rf = 0.50 in 9:1 / hexanes:EtOAc. 1H NMR (400 MHz, CDCl3) δ 7.12 (dd,
J = 8.3, 7.2 Hz, 2H), 7.05 (dd, J = 8.3 Hz, 4J = 1.0 Hz, 2H), 6.33 (dd, J = 7.2 Hz, 4J = 1.0
Hz, 2H), 5.96 (d, 4J = 0.9 Hz, 1H), 5.63 (br s, 2H), 4.20 (q, J = 7.2 Hz, 2H), 3.57 – 3.45
(m, 1H), 1.82 – 1.67 (m, 5H), 1.46 – 1.12 (m, 8H); 13C{1H}NMR (101 MHz CDCl3) δ
166.0 (C), 140.5 (C), 136.3 (C), 127.7 (CH), 123.2 (CH), 119.9 (C), 118.1 (CH), 106.2
(CH), 60.0 (CH2), 40.5 (CH), 33.0 (CH2), 26.3 (CH2), 26.1 (CH2), 14.4 (CH3); 11B NMR
(128 MHz, CDCl3) δ 29.35. HRMS (ESI+): Calcd for C21H26BN2O2 [M+H]+:
349.2082, Found 349.2068.
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Ethyl (Z)-3-(cyclohex-1-en-1-yl)-3-(1H-naphtho[1,8-de][1,3,2]diazaborinin-2(3H)-
yl)acrylate (3i). Synthesized according to general procedure 7. The title compound was
isolated in 75ꢀ82% yields (136 mg and 147 mg) as a dark yellow solid (mp 120 – 121.5
°C). TLC Rf = 0.45 in 9:1 / hexanes:EtOAc. 1H NMR (400 MHz, CDCl3) δ 7.11 (dd, J =
8.3, 7.3 Hz, 2H), 7.03 (dd, J = 8.3 Hz, 4J = 1.0 Hz, 2H), 6.34 (dd, J = 7.3 Hz, 4J = 1.0 Hz,
2H), 6.11 (s, 1H), 5.81 (br s, 2H), 5.42 (m, 1H), 4.19 (q, J = 7.2 Hz, 2H), 2.20 – 2.06 (m,
4H), 1.78 – 1.64 (m, 4H), 1.30 (t, J = 7.2 Hz, 3H); 13C{1H}NMR (101 MHz, CDCl3) δ
156.9 (C), 140.8 (C), 138.1 (C), 136.5 (C), 127.7 (CH), 125.0 (CH), 122.4 (CH), 120.2
(C), 118.2 (CH), 106.3 (CH), 60.3 (CH2), 28.6 (CH2), 25.3 (CH2), 23.0 (CH2), 22.2 (CH2),
14.5 (CH3); 11B NMR (128 MHz, CDCl3) δ 27.95. HRMS (ESI+): Calcd for
C21H24BN2O2 [M+H]+: 347.1925, Found 347.1915.
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