An Oxyboration Route to a Single Regioisomer of Borylated Dihydrofurans and Isochromenes

Article abstract of DOI:10.1021/acs.joc.8b01790

An oxyboration reaction that employs B-O σ bonds as addition partners to C-C π bonds to form borylated dihydrofurans and isochromenes has been developed. By nature of the mechanism, the reaction produces exclusively one borylated regioisomer, in contrast to and/or complementary to alternative routes that produce these borylated heterocycles via C-H activation. Access to the borylative heterocyclization route is demonstrated from alcohols directly or from a hydroboration-oxyboration sequence starting from the corresponding ketone, forming the heterocyclic core and installing the boron in one synthetic step. Catechol boronates were directly used as coupling partners in the in situ Suzuki cross-coupling reactions without transesterification to pinacol boronates.

Full text of DOI:10.1021/acs.joc.8b01790

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Article
An Oxyboration Route to a Single Regioisomer
of Borylated Dihydrofurans and Isochromenes
Kim N. Tu, Chao Gao, and Suzanne A. Blum
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b01790 • Publication Date (Web): 25 Jul 2018
Downloaded from http://pubs.acs.org on July 26, 2018
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The Journal of Organic Chemistry
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An Oxyboration Route to a Single Regioisomer of Borylated
Dihydrofurans and Isochromenes
Kim N. Tu, Chao Gao, and Suzanne A. Blum*
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Department of Chemistry, University of California, Irvine, Irvine, California 92697–2025, United States
ABSTRACT: An oxyboration reaction that employs B–O σ bonds as addition partners to C–C π bonds to form borylated dihydroꢀ
furans and isochromenes has been developed. By nature of the mechanism, the reaction produces exclusively one borylated regioiꢀ
somer, in contrast to and/or complementary to alternative routes that produce these borylated heterocycles via C–H activation. Acꢀ
cess to the borylative heterocyclization route is demonstrated from alcohols directly or from a hydroboration–oxyboration sequence
starting from the corresponding ketone, forming the heterocyclic core and installing the boron in one synthetic step. Catechol boroꢀ
nates were directly used as coupling partners in the in situ Suzuki cross coupling reactions without transesterification to pinacol
boronates.
INTRODUCTION
Borylated heterocycles are versatile synthetic intermediates,
such as building blocks for drug discovery and for the syntheꢀ
sis of materials.1,2 The common approach to constructing
borylated heterocycles is through construction of the heterocyꢀ
cle followed by borylation in a separate synthetic step.3 A
method for constructing the heterocyclic core and installing
the boron in one synthetic step through a borylative heterocyꢀ
clization reaction would be synthetically appealing due to its
complementary bond disconnections, regiochemistry, and
functional group tolerance.4–11 Herein we develop oneꢀstep
cyclative oxyboration routes to two Oꢀheterocycle classes,
dihydrofurans and isochromenes, for which existing iridiumꢀ
catalyzed C–H activation–borylation methods provide unsatisꢀ
factory or complementary regioselectivity.12,13
Scheme 1. Comparison of Previous Method and Oxyꢀ
boration Method
We describe the motivation for developing an approach to
each of these two O-heterocyclic cores separately in more
detail: Substituted 2,3ꢀdihydrofurans are found in a range of
natural and synthetic products such as Aflatoxin B1,14 with
many exhibiting interesting biological activity.15–21 Yet curꢀ
rently, there is only one report on the synthesis of borylated
dihydrofurans, by Miyaura.12 That reported iridiumꢀcatalyzed
C–H activation–borylation method proceeded with low regiꢀ
oselectivity, however (Scheme 1). Given that the regioselecꢀ
tivity of oxyboration is dictated by the cyclization step, in
contrast, we envisioned that an alternative borylative heteroꢀ
cyclization strategy may overcome the challenge of poor regiꢀ
oselectivity in the synthesis of this compound class.4–6,9
Synthetic methods to borylated isochromenes, specifically,
are synthetically appealing because such compounds could be
further functionalized through established crossꢀcoupling reacꢀ
tions.33,34 There are, however, limited examples for the generaꢀ
tion of borylated isochromenes, by Miyaura,12,13 again via
iridiumꢀcatalyzed C–H activation/borylation. In that case, exꢀ
clusive access to the 3ꢀborylated isochromene was reported,
whereas we envisioned that the borylative heterocyclization
described here would access the complementary 4ꢀborylated
isochromene. The development of an oxyboration route to
dihydrofurans and isochromenes will now be described in
sequence, providing the chronology of the investigations and
allowing for comparison and contrast between the two ring
systems.
Similarly, isochromenes are common cores in biologically
active compounds, including natural products and pharmaceuꢀ
ticals.22–32 Due to their ubiquity,22,23,25–28 developing synthetic
methods from simple and readily available starting materials
has been the focus of ongoing research.22,23,25
RESULTS AND DISCUSSION
As part of prior oxyboration studies, we had previously
identified an initial condition that resulted in goldꢀcatalyzed
formation of a borylated dihydrofuran, albeit in low yield.4
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This reaction was an extension of our work accessing other tion. We hypothesized that the phenyl ring in direct conjugaꢀ
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ring systems through oxyboration reactions, wherein we idenꢀ
tified that quenching the gold catalyst at the end of the reacꢀ
tion resulted in higher product yields,4 including on scale.35
Yet optimization studies herein in the dihydrofuran system
(Scheme 2) found the opposite result. Quenching the active
gold catalyst using triphenylphosphine at the end of the reacꢀ
tion was detrimental to the integrity of the desired product,
causing decomposition of the product after 15 h; thus we hereꢀ
in optimized conditions that were absent of triphenyphosphine.
Furthermore, the cyclization reaction (2a to 3a) was particuꢀ
larly sensitive to temperature. Reactions at 40 °C or 50 °C
tion with the alkyne might slow the desired cyclization relative
to the rate of catalyst decomposition. This hypothesis was
tested by changing to benzyl substituents (i.e., removing the
direct conjugation); the reaction then indeed proceeded in
good yields for electronꢀrich or neutral benzyl groups (4h, 4i
and 4j). However, substitution with electronꢀpoor benzyl
groups (substrate leading to attempted formation of 4k and 4l,
CF3 and COOCH3, respectively), led to the corresponding diꢀ
hydrofurans 5 with a hydrogen in the place of the desired boꢀ
ron (Figure 1; plausibly arising from protodeborylation) as the
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major reaction products as determined by H NMR spectroꢀ
1
produced similar H NMR spectroscopy yields, but reactions
scopic analysis of the crude reaction mixtures of correspondꢀ
1
at 60–100 °C resulted decreased yields of desired product by
promoting product decomposition. Transesterification of the
moistureꢀsensitive catechol boronic ester to the benchꢀstable
pinacol boronic ester (Bpin) at ambient temperature was perꢀ
formed for final product isolation.5–9
ing 3k and 3l. These relatively low H NMR spectroscopy
yields of 3k and 3l could not be determined accurately due to
overlap between the resonances corresponding to the desired
oxyboration product and undesired protiated product. The
minor desired catechol boronates in these cases nevertheless
did not undergo successful transesterification to isolable pinaꢀ
col boronates, possibly due to the presence of reactive byprodꢀ
ucts under these conditions.
Scheme 2. 3ꢀBorylated Dihydrofurans Substrate Scopea
Figure 1. Undesired dihydrofurans without boron, 5.
For the conjugated substrates (R2 = aryl), which displayed
conversions <50%, we considered an alternative formal
borylation method. In this method, an electrophilic boron reaꢀ
gent (ClBcat4–9 identified by our laboratory, or BCl3 identified
by Ingleson10,11) activates the C–C π bond and promotes a
cyclization–demethylation sequence, without requiring forꢀ
mation of a B–O σ bond in the starting material. We decided
to test this alternative route with alkynyl ether 6 as a substrate
and ClBcat and BCl3 as activating agents. Desired product 8
did not form, but rather partial conversion occurred to a speꢀ
cies giving rise to a 11B NMR spectroscopy signal at 11–12
ppm, consistent with tetracoordinated boron, which still mainꢀ
tained the methyl group as depicted in compounds 7a and 7b43
(eq 1). This lack of completed formal borylative heterocyclizaꢀ
tion reactivity is consistent with our proposed model, in which
substrate classes with pKa of the corresponding heteroatom–H
bonds (in this case RO–H) that are greater than 10 have higher
potential for successful direct borylation (through B–O σ
bonds) than for formal borylation (through intermolecular
activation by external boron electrophiles followed by
dealkylation).9
Under the optimized reaction conditions, the substrate scope
was examined (Scheme 2). The oxyboration method tolerated
functional groups including fluoride (4d), electronꢀrich (4e, 4i,
4j) and electronꢀpoor aryl groups (4g), and aliphatic substituꢀ
tion (4a–4c). The reaction tolerated cyclopropyl (4c), a fragꢀ
ment of interest in pharmaceutical discovery.36–41 In contrast to
palladiumꢀcatalyzed routes to borylated heterocycles,42 the
optimized oxyboration route tolerated bromoarenes (4f), grantꢀ
ing the opportunity for a subsequent crossꢀcoupling reaction at
that orthogonal functional group. The borylative cyclization
step for these substrates provided intermediate 3 in moderateꢀ
toꢀquantitative 1H NMR spectroscopy yields of a single regioiꢀ
somer, which was then transesterified to benchꢀstable 4. The
reaction is not compatible with electronꢀrich R1 as no converꢀ
sion to 3 was observed when R1 = pꢀanisyl (See Supporting
Information (SI) for more information). Due to the synthetic
difficulty of accessing the requisite starting material, no subꢀ
stitution at the 4ꢀposition was attempted.
Me
O
O
ClBcat
50 100 °C
p-tolyl
Me
p-tolyl
Me
[B]
O
O
p-tolyl
p-tolyl
(1)
or
+MeCl
[B]
BCl3, 25 °C
[B]
7b
6
7a
or
8
consistent structures
not observed
[B] = Bcat, BCl2
11B NMR peak at 12 ppm for
ClBcat and 11 ppm for BCl3
Next, the oxyboration route to borylated isochromenes was
investigated. The same catalyst was found to be optimal in this
case (Scheme 3; see Supporting Information (SI) for full cataꢀ
lyst optimization details). The primary challenge in the extenꢀ
sion of the method to the synthesis of borylated isochromenes
occurred upon attempted product isolation (Table 1). These
products showed sensitivity at both the benzylic carbon and
the carbon–boron bond, indicated by positions 1 and 4 in
structure 11.
Aryl substitution at R2, however, resulted in a reaction that
did not fully consume 2, stopping at less than 50% consumpꢀ
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The Journal of Organic Chemistry
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Scheme 3. 4ꢀBorylated Isochromenes
Scheme 4. 4ꢀBorylated Isochromene Substrate Scopea
First, 11a was chosen as the model compound for product
9
isolation optimization. Examination of the crude reaction mixꢀ
ture by H NMR spectroscopy showed that cyclization was
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successful (>95% conversion). In contrast to the dihydrofuran
systems, attempted formation of the analogous isochromene
Bpin product 14a from 11a through transesterification proved
unsuccessful as the product decomposed upon exposure to air
(Table 1, entry 2).
The model substrate was switched to 11b, which had the
benzylic position hindered. With the new substrate, the resultꢀ
ing Bpin product 14b could be isolated. However, the C–Bpin
bond was not as robust as in the dihydrofuran systems, resultꢀ
ing in a formation of the protodeborylated product (15) upon
exposure of the product to air for 5 d (Table 1, entry 3; see
Supporting Information (SI) for full details). Consistent with
the reports from Suginome44 and Wang45, it was found that
transformation with 1,8ꢀdiaminonaphthalene (as Bdan) proꢀ
vided a viable isolation method, imparting the desired air staꢀ
bility (Table 1, entry 4 and 5, 12a and 12b).
The 1H NMR yield of 12a (94%) was high, however, signifꢀ
icant material was lost upon attempted isolation (34%), preꢀ
sumably due to the instability of the (nonꢀmethylꢀsubstituted)
benzylic carbon during flash column chromatography. The
similarly low yield of 12i (24%) further suggested the instabilꢀ
ity of this unsubstituted product class.
We were inspired by the work of Nöth47 to examine if inꢀ
termediate 10b could be generated directly from 16 via reducꢀ
tive hydroboration (Scheme 5). This reaction proceeded at 50
˚C for 5 h in the presence of 2 equiv HBcat. Removing excess
HBcat under reduced pressure, followed by oxyboration, proꢀ
duced the desired isochromene product (12b) in 68% yield.
Thus, ketones can serve as complementary starting materials
via a hydroboration–oxyboration sequence.
Table 1. Isolation Methods
Scheme 5. Synthesis of Isochromenes via Hydroboraꢀ
tion–Oxyboration
entry
substrate boron ligand [B]
benzylic
stability
B C
stability
–
exchange
(%)a
1
2
3
4
0
BF3K N/A
N/A
N/A
5 d
stable
stable
11a
11a
11b
11a
11b
>99
>99
>99
>99
Bpin
Bpin
18 h
stable
We next turned attention to closer examination of the regiꢀ
oisomeric characterization of product class 12. Compound 11
(Bcat cyclization product) was regioisomerically pure on the
Bdan stable
Bdan stable
5
a
Calculated through ratio of products to starting material in
1
basis of H NMR spectroscopic analysis of the crude reaction
1H NMR spectra
mixture. Similar cyclization reactions that generate the alternaꢀ
Under standard reaction conditions of 4 h at 100 ˚C, with
isolation as Bdan, the substrate scope was investigated
(Scheme 4). Products 12c, 12e, 12f, and 12g demonstrated the
reaction’s tolerance of alkyl and aryl chlorides and fluorides.
Products 12d and 12e contained a cyclopropyl and a trifluoꢀ
romethyl group, respectively, which are desirable for the synꢀ
thesis of pharmaceuticals and biologically active molecules.36–
tive 5ꢀmembered products (e.g., 17 type) have been reported,
1
however, and the H NMR spectroscopy differentiation beꢀ
tween the 5ꢀ and 6ꢀmembered ring products may not be
straightfoward.25,48 To establish which regioisomer was generꢀ
ated under the oxyboration route, a structure elucidation study
was done (Scheme 6). Substrate 9b was subjected to standard
oxyboration conditions, and the product was deliberately proꢀ
todeborylated via an acidic workup to make one of the two
possible regioisomers, 15 or 17, which was then purified. The
1H NMR spectrum of this sample was consistent with that
reported for 15.25 This material was then subjected to ozonolyꢀ
sis. 1H NMR spectroscopic analysis of the ozonolysis products
established the presence of only 18 in both the crude and puriꢀ
fied samples, and thus that the 6ꢀmembered product (15) was
the only cyclization product (corresponding to the 6ꢀ
membered ring structures shown in Scheme 4).
40,46
Formation of compound 12e required harsher conditions
(120 ˚C, 18 h), plausibly due to the strong electronꢀ
withdrawing ability of the trifluoromethyl group adjacent to
the oxygen, hindering nucleophilic cyclization. A similar reꢀ
sult was observed with 12g, wherein an electronꢀwithdrawing
group that was para to the nucleophile resulted a slower cyꢀ
clization reaction (100 ˚C, 19 h). The successful synthesis of
isopropyl 12h, however, showed that a more sterically hinꢀ
dered nucleophile could be tolerated in this intramolecular
reaction.
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Scheme 6. Structure Elucidation
Scheme 7. Downstream Functionalization
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Synthetic utility. A 6 mmol scale oxyboration reaction
smoothly afforded 1.43 g of 4a from 1a in 20 h at 40 °C
(75%). On this scale, a catalyst loading reduction to 1.8 mol %
was possible, as was a higher substrate concentration (eq 2).
To demonstrate the utility of oxyboration to produce
borylated building blocks that are suitable for downstream C–
C bondꢀforming reactions, in situ Suzuki crossꢀcoupling reacꢀ
tions were demonstrated on the Bcat intermediates of both
substrate classes. These reactions established that the transꢀ
esterification/boron group manipulation was not necessary in
cases where immediate downstream functionalization was
desired.
Scheme 8. Formal Total Synthesis of (±)ꢀXJP via Oxyꢀ
boration
As mentioned previously, borylated dihydrofurans were
found to be sensitive to high temperature during oxyboration
optimization. Yet procedures for Suzuki crossꢀcoupling reacꢀ
tions often require elevated temperatures of 70–100 °C.33,49
The conditions for mildꢀtemperature Suzuki crossꢀcoupling
reactions and mechanistic studies by Denmark50 motivated our
examination of cesium hydroxide monohydrate as a reagent
for promoting palladiumꢀcatalyzed crossꢀcoupling reactions of
Bcat intermediate 3a. Employment of this reagent combination
at ambient temperature resulted in the successful synthesis of
22 and 24 directly from catechol boronate 3a (77% and 56%
yield, respectively;Scheme 7).
A formal total synthesis of (±)ꢀXJP, an antihypertensive
natural product isolated from peels of Musa sapientum L,24
was also conducted. Commercially available substrate 27 was
transformed to 28, the substrate for oxyboration, in two steps
(Scheme 8, see Supporting Information (SI) for details). Subꢀ
sequent oxyboration followed by in situ H2O2 oxidation under
basic conditions generated the dimethylated (±)ꢀXJP (29) in
64% yield over three steps, finishing the formal total syntheꢀ
sis. Demethylation of 29 to afford (±)ꢀXJP has been previously
reported. 24
In the case of borylated isochromenes, yields in crossꢀ
coupling reactions were found to be highly dependent on
quantity of water employed in the reaction (Scheme 7). Addiꢀ
tion of some water accelerated the crossꢀcoupling reaction, but
excesses lead to decomposition of 11b through competing
protodeborylation. Optimized addition of 1.1 equiv of water,
with Pd(PPh3)4 and Cs2CO3, effectively catalyzed the crossꢀ
coupling reaction of 11b with aryl iodide 25 at 100 ˚C to afꢀ
ford 26 (66% yield over three steps from alkynyl benzyl alcoꢀ
hol 9b).
CONCLUSION
In conclusion, a method has been developed for preparing 3ꢀ
borylated dihydrofurans and 4ꢀborylated isochromenes via an
oxyboration reaction that generates exclusively one regioisoꢀ
mer, in contrast and/or compliment to alternative C–H activaꢀ
tion routes. The method can be scaled, and generates borylated
heterocycles suitable for downstream functionalization, as
highlighted in the Suzuki crossꢀcoupling of the catechol boroꢀ
nates and formal total synthesis of (±)ꢀXJP. The oxyboration
reaction toward borylated isochromenes can also harness the
corresponding ketones instead of benzyl alcohols as substrates.
The method provides a useful tool to access functionalized,
regioisomerically pure borylated dihydrofurans and isoꢀ
chromenes as building blocks for organic synthesis.
EXPERIMENTAL SECTION
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The Journal of Organic Chemistry
General Information. All reagents were used as received
identified by TLC, combined and concentrated in vacuo to
afford 1.
General Experimental Procedure B for the Synthesis of
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4
5
6
7
8
from commercial sources unless otherwise stated. 1,2ꢀ
Dimethoxylethane was purchased from Sigma–Aldrich in a
Sigma–Aldrich Sure/Seal™ bottle and used without further
purification. Tetrahydrofuran and triethylamine were dried by
passing through an alumina column under argon pressure on a
push still solvent system. Chloroform was dried over K2CO3,51
degassed using three freezeꢀpumpꢀthaw cycles, and vacuum
transferred before use. Tolueneꢀd8 and C6D6 were dried over
CaH2, degassed using three freezeꢀpumpꢀthaw cycles, and
vacuum transferred before use. Catecholborane51 was degassed
using three freezeꢀpumpꢀthaw cycles, and vacuum transferred
before use. Ozone was generated by a ClearWater Tech, LLC
Mꢀ1500 ozone generator. Cesium carbonate was dried by heatꢀ
ing at ca. 300 ˚C under vacuum (ca. 30 mTorr) for ca. 12 h,
and stored in a N2ꢀfilled glovebox. Manipulations were perꢀ
formed in a glovebox under nitrogen atmosphere unless othꢀ
erwise noted. Analytical thin layer chromatography (TLC) was
performed using Merck F250 plates and visualized under UV
irradiation at 254 nm, or using a basic aqueous solution of
potassium permanganate. Flash chromatography was conductꢀ
ed using a Teledyne Isco Combiflash® Rf 200 Automatic Flash
Chromatography System, and Teledyne Isco Redisep® 35– 70
ꢁm silica gel. All proton and carbon nuclear magnetic resoꢀ
nance (1H and 13C) spectra were recorded on a Bruker DRXꢀ
400 spectrometer, Bruker DRXꢀ500 spectrometer outfitted
with a cryoprobe, or a Bruker AVANCEꢀ600 spectrometer.
Boron nuclear magnetic resonance (11B NMR) spectra were
recorded on a Bruker AVANCEꢀ600 or on a Bruker DRXꢀ500
spectrometer. Fluorine nuclear magnetic resonance (19F NMR)
spectra were recorded on a Bruker DRXꢀ400 spectrometer or
on a Bruker AVANCEꢀ600 spectrometer. All coupling conꢀ
stants were measured in Hertz (Hz). Chemical shifts were reꢀ
ported in ppm and referenced to the residual protiated solvent
peak (δH = 7.26 ppm for CDCl3, δH = 2.08 ppm for d8ꢀtoluene,
δH = 7.16 ppm for C6D6 in 1H NMR spectroscopy experiments;
δC = 77.16 ppm for CDCl3, δC = 20.43 ppm for d8ꢀtoluene, δC
= 128.06 ppm for C6D6 in 13C NMR spectroscopy experiꢀ
ments), except compounds with Bdan where chemical shifts
were reported in ppm and referenced to TMS (δH = 0.00 ppm).
11B NMR and 19F NMR spectroscopy experiments were referꢀ
Alkynols 1h–j. Alkynols were prepared according to a literaꢀ
ture procedure, repeated here for convenience and clarity.53
Using a standard Schlenk line, to a flameꢀdried round bottom
flask was added terminal alkynol (0.450 mL, 6.00 mmol, 1.20
equiv) in dry THF (35 mL) via syringe, and cooled to ꢀ78 °C
under dynamic N2 atmosphere. To this cooled solution was
added nꢀbutyllithium (1.60 M solution in hexane) (7.8 mL, 13
mmol, 2.5 equiv) dropwise via syringe. The resulting suspenꢀ
sion was stirred at –78 °C for 1 h, followed by addition of a
solution of dry ZnBr2 (2.82 g, 12.5 mmol, 2.50 equiv) in dry
THF (10 mL) via syringe. The mixture was stirred at –78 °C
for 10 min, then warmed to 25 °C. The catalyst
Pd(DPEphos)Cl2 (35.8 mg, 0.0500 mmol, 1.00 mol%) and
benzyl bromide (5.00 mmol, 1.00 equiv) were added to the
clear reaction mixture via syringe at 25 °C and stirred at 40 °C
for 18 h. The reaction was quenched with 1.0 M hydrochloric
acid (1 × 10 mL). The aqueous layer was extracted with ether
(2 × 20 mL). The combined organic layers were washed with
sat. sodium bicarbonate (1 × 15 mL), dried over anhydrous
Na2SO4, filtered through filter paper, and concentrated in vacꢀ
uo. The resulting crude oil was purified by silica gel flash colꢀ
umn chromatography using an elution gradient from 100%
hexanes to 30% EtOAc in hexanes. Productꢀcontaining fracꢀ
tions were identified by TLC, combined and concentrated in
vacuo to afford 1.
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1-cyclopropyl-3-hexyn-1-ol (1c) was prepared using proceꢀ
dure A and obtained as light yellow oil (199 mg, 29% yield).
TLC (20% EtOAc/hexanes): Rf = 0.27, visualized by UV abꢀ
1
sorbance. H NMR (d8ꢀtoluene, 500 MHz): δ 2.94–2.89 (m,
1H), 2.36–2.26 (m, 2H), 1.97 (qt, J = 7.5, 2.5 Hz, 2H), 1.51 (d,
J = 4.0 Hz, 1H), 0.97 (t, J = 7.5 Hz, 3H), 0.83–0.77 (m, 1H),
0.28– 0.26 (m, 2H), 0.24–0.21 (m, 1H), 0.13–0.11 (m, 1H).
13C{1H}NMR (CDCl3, 125 MHz): δ 84.0, 76.6, 73.8, 28.3,
17.0, 14.4, 12.7, 2.4. HRMS (ESIꢀTOF) m/z calcd for
C9H14ONa ([M+Na]+) 161.0942, found 161.0944.
1-(4-fluorophenyl)-3-hexyn-1-ol (1d) was prepared using
procedure A and obtained as light yellow oil (303 mg, 32%
yield). TLC (20% EtOAc/hexanes): Rf = 0.22, visualized by
1
enced to the absolute frequency of 0 ppm in the H dimension
1
UV absorbance. H NMR (d8ꢀtoluene, 500 MHz): δ 7.03–7.00
according to the Xi scale. Highꢀresolution mass spectrometry
(HRMS (ESIꢀTOF)) data were obtained at the University of
California, Irvine.
(m, 2H), 6.77–6.73 (m, 2H), 4.44–4.41 (m, 1H), 2.33–2.32 (m,
2H), 1.93–1.88 (m, 2H), 1.82 (bs, 1H), 0.91 (td, J = 7.4, 3.0
Hz, 3H). 13C{1H}NMR (d8ꢀtoluene, 150 MHz): δ 162.2 (d, J =
93.4 Hz), 139.2, 127.4 (d, J = 8.1 Hz), 114.7 (d, J = 21.2 Hz),
84.3, 75.6, 71.8, 30.1, 13.9, 12.3. 19F{1H}NMR (d8ꢀtoluene,
565 MHz): δ –115.2. HRMS (ESIꢀTOF) m/z calcd for
C12H12FO ([MꢀH]ꢀ) 191.0872, found 191.0868.
General Experimental Procedure A for the Synthesis of
Alkynols 1c–g. Alkynols were prepared according to a literaꢀ
ture procedure, repeated here for convenience and clarity.52
Using a standard Schlenk line, to a flameꢀdried round bottom
flask was added zinc dust (1.63 g, 25.0 mmol, 5.00 equiv) and
I2 (1.27 g, 5.00 mmol, 1.00 equiv). The flask was capped with
septum and placed under dynamic N2. Then aldehyde (5.00
mmol, 1.00 equiv), and propargyl bromide (6.00 mmol, 1.20
equiv) in dry THF (50 mL) was added via syringes at 25 °C.
The resulting reaction mixture was sonicated at room temperaꢀ
ture for 4 h. The reaction was quenched with sat. ammonium
chloride (1 × 20 mL). The aqueous layer was extracted with
EtOAc (1 × 30 mL). The combined organic layers were
washed with brine (1 × 30 mL), dried over anhydrous Na2SO4,
filtered through filter paper, and concentrated in vacuo. The
resulting crude oil was purified by silica gel flash column
chromatography using an elution gradient from 100% hexanes
to 10% EtOAc in hexanes. Productꢀcontaining fractions were
1-(4-methylphenyl)-3-pentyn-1-ol (1e) was prepared using
procedure A and obtained as clear oil (175 mg, 20% yield). 1H
NMR (CDCl3, 600 MHz): δ 7.27 (d, J = 7.7 Hz, 2H), 7.16 (d,
J = 7.7 Hz, 2H), 4.78 (m, 1H), 2.59–2.52 (m, 2H), 2.34 (s 3H),
1.81 (s, 3H). This spectrum is in agreement with previously
reported spectral data.54
1-(4-bromophenyl)-3-hexyn-1-ol (1f) was prepared using
procedure A and obtained as light yellow oil (473 mg, 37%
yield). TLC (20% EtOAc/hexanes): Rf = 0.29, visualized by
1
UV absorbance. H NMR (CDCl3, 600 MHz): δ 7.47 (d, J =
8.4 Hz, 2H), 7.26 (d, J = 8.4 Hz, 2H), 4.79–4.76 (m, 1H),
2.62–2.50 (m, 2H), 2.44 (d, J = 3.0 Hz, 1H), 2.18 (qt, J = 7.2,
2.4 Hz, 2H), 1.12 (t, J = 7.8 Hz, 3H). 13C{1H}NMR (CDCl3,
150 MHz): δ 141.9, 131.6, 127.7, 121.7, 85.5, 75.0, 72.1, 30.2,
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The Journal of Organic Chemistry
14.2, 12.5. HRMS (ESIꢀTOF) m/z calcd for C12H12BrO ([Mꢀ
Page 6 of 17
pinacol boronate 4. All of the pinacol boronates 4a–4j are
missing one carbon signal in their corresponding 13C NMR
spectroscopy data. This carbon atom is assigned to the carbon
in the newly formed C–B σꢀbond. This is expected due to the
quadrupolar relaxation of boron.55
1
2
3
4
5
6
7
8
H]ꢀ) 251.0072, found 251.0081.
1-(methyl-4-formylphenyl)-3-hexyn-1-ol (1g) was prepared
using procedure A and obtained as yellow oil (330 mg, 28%
yield). TLC (20% EtOAc/hexanes): Rf = 0.15, visualized by
1
UV absorbance. H NMR (d8ꢀtoluene, 500 MHz): δ 8.04–8.01
Pinacol boronate (4a) was obtained as colorless oil using
(m, 2H), 7.18–7.16 (m, 2H), 4.46 (s, 1H), 3.51 (t, J = 2.5 Hz,
3H), 2.34–2.33 (m, 2H), 1.91–1.87 (m, 3H), 0.91 (t, J = 3.0
Hz, 3H). 13C{1H}NMR (d8ꢀtoluene, 125 MHz): δ 171.1, 153.4,
134.8, 134.7, 130.8, 89.7, 80.4, 77.1, 56.2, 35.1, 19.1, 17.4.
HRMS (ESIꢀTOF) m/z calcd for C14H16O3Na ([M+Na]+)
255.0997, found 255.0998.
C6D6 as solvent (81 mg, 85% yield). TLC (20%
EtOAc/hexanes): Rf = 0.71, visualized by UV absorbance. H
1
NMR (CDCl3, 600 MHz): δ 4.28 (t, J = 9.6 Hz, 2H), 2.69 (t, J
= 9.0 Hz, 2H), 2.42 (t, J = 7.2 Hz, 2H), 1.52 (sextet, J = 7.2
Hz, 2H), 1.25 (s, 12H), 0.90 (t, J = 7.2 Hz, 3H). 13C{1H}NMR
(CDCl3, 150 MHz): δ 172.5, 82.6, 70.6, 32.0, 29.8, 24.9, 20.9,
13.7. 11B{1H}NMR (CDCl3, 192 MHz): δ 30.2 (s). HRMS
(ESIꢀTOF) m/z calcd for C13H24BO3 ([M+H]+) 239.1819,
found 239.1824.
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13
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15
16
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25
26
27
28
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32
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47
48
49
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5-phenyl-3-hexyn-1-ol (1h) was prepared using procedure B
and obtained as yellow oil (129 mg, 16% yield). TLC (30%
EtOAc/hexanes): Rf = 0.33, visualized by KMnO4 stain soluꢀ
1
tion. H NMR (d8ꢀtoluene, 500 MHz): δ 7.18 (d, J = 7.5 Hz,
Pinacol boronate (4b) was obtained as colorless oil using
2H), 7.11–7.10 (m, 2H), 7.02 (s, 1H), 3.36 (t, J = 7.0 Hz, 2H),
3.31 (s, 2H), 2.17–2.13 (m, 2H). 13C{1H}NMR (d8ꢀtoluene,
125 MHz): δ 137.1, 137.2, 126.7, 124.7, 79.9, 79.5, 61.5, 25.2,
23.5. HRMS (ESIꢀTOF) m/z calcd for C11H12ONa ([M+Na]+)
183.0786, found 183.0783.
C6D6 as solvent (61 mg, 64% yield). TLC (20%
EtOAc/hexanes): Rf = 0.75, visualized by UV absorbance. H
1
NMR (CDCl3, 600 MHz): δ 4.68–4.63 (m, 1H), 2.82 (dd, J =
14, 9.6 Hz, 1H), 2.43–2.41 (m, 2H), 2.28 (dd, J = 14, 7.2 Hz,
1H), 1.29 (d, J = 6.6 Hz, 3H), 1.24 (s, 12H), 1.07 (t, J = 7.2
Hz, 3H). 13C{1H}NMR (CDCl3, 150 MHz): δ 173.1, 82.5,
78.6, 39.2, 25.0, 24.9, 22.0, 21.7, 12.4. 11B{1H}NMR (CDCl3,
192 MHz): δ 30.1 (s). HRMS (ESIꢀTOF) m/z calcd for
C13H23BO3 ([M]+) 238.1743, found 238.1743.
5-(m-anisyl)-3-hexyn-1-ol (1i) was prepared using proceꢀ
dure B and obtained as yellow oil (179 mg, 19% yield). TLC
(30% EtOAc/hexanes): Rf = 0.18, visualized by KMnO4 stain
1
solution. H NMR (C6D6, 600 MHz): δ 7.08 (t, J = 7.8 Hz,
1H), 6.98 (s, 1H), 6.90 (d, J = 7.8 Hz, 1H), 6.68 (d, J = 7.8 Hz,
1H), 3.39–3.33 (m, 7H), 2.19–2.16 (m, 2H). 13C{1H}NMR
(C6D6, 150 MHz): δ 160.5, 139.2, 129.7, 120.5, 114.1, 112.3,
79.9, 79.7, 61.4, 54.7, 25.4, 23.5. HRMS (ESIꢀTOF) m/z calcd
for C12H14O2Na ([M+Na]+) 213.0892, found 213.0894.
Pinacol boronate (4c) was obtained as colorless oil using
toluene as solvent (81 mg, 77% yield). TLC (20%
1
EtOAc/hexanes): Rf = 0.57, visualized by UV absorbance. H
NMR (CDCl3, 600 MHz): δ 4.00–3.99 (m, 1H), 2.78 (t, J = 11
Hz, 1H), 2.52–2.51 (m, 1H), 2.44–2.43 (m, 2H), 1.25 (s, 12H),
1.08 (s, 4H), 0.55 (s, 1H), 0.47 (s, 1H), 0.38 (s, 1H), 0.24 (s,
1H). 13C{1H}NMR (CDCl3, 150 MHz): δ 173.3, 86.5, 82.5,
27.3, 24.98, 24.95, 21.7, 16.0, 12.6, 3.3, 1.3. 11B{1H}NMR
(CDCl3, 192 MHz): δ 30.1 (s). HRMS (CIꢀTOF) m/z calcd for
C15H25BO3 ([M]+) 264.1900, found 264.1889.
5-(3,5-dimethoxyphenyl)-3-hexyn-1-ol (1j) was prepared usꢀ
ing procedure B and obtained as yellow solid (582 mg, 53%
yield). TLC (30% EtOAc/hexanes): Rf = 0.15, visualized by
KMnO4 stain solution. 1H NMR (d8ꢀtoluene, 600 MHz): δ 6.53
(d, J = 1.8 Hz, 2H), 6.35 (s, 1H), 3.38–3.36 (m, 8H), 3.32 (s,
2H), 2.17–2.14 (m, 2H). 13C{1H}NMR (d8ꢀtoluene, 125 MHz):
δ 161.6, 139.8, 106.4, 104.7, 99.0, 79.8, 79.6, 61.5, 54.7, 25.5,
23.6. HRMS (ESIꢀTOF) m/z calcd for C13H16O3Na ([M+Na]+)
243.0997, found 243.0996.
Pinacol boronate (4d) was obtained as light yellow oil using
toluene as solvent (97 mg, 76% yield). TLC (20%
1
EtOAc/hexanes): Rf = 0.53, visualized by UV absorbance. H
NMR (CDCl3, 600 MHz): δ 7.29 (t, J = 6.6 Hz, 2H), 7.02 (t, J
= 8.7 Hz, 2H), 5.48 (t, J = 9.3 Hz, 1H), 3.16 (dd, J = 14.4, 10.8
Hz, 1H), 2.66 (dd, J = 14.4, 7.8 Hz, 1H), 2.55–2.50 (m, 2H),
1.25 (d, J = 3.0 Hz, 12H), 1.15 (t, J = 7.8 Hz, 3H).
13C{1H}NMR (CDCl3, 150 MHz): δ 173.1, 163.1, 161.5,
139.4, 127.4, 115.4, 82.7, 82.5, 40.8, 25.0, 21.7, 12.5.
11B{1H}NMR (CDCl3, 192 MHz): δ 29.6 (s). 19F{1H}NMR
(CDCl3, 565 MHz): δ –115.4. HRMS (CIꢀTOF) m/z calcd for
C18H24BFO3 ([M]+) 318.1806, found 318.1804.
General Experimental Procedure for the Synthesis of
pinacol boronates 4. In an N2ꢀfilled glovebox, alkynol 1 (0.40
mmol, 1.0 equiv) was dissolved in 0.1 mL toluene or benzene
in a 1ꢀdram vial equipped with stir bar. Catecholborane (42.7
ꢁL, 0.400 mmol, 1.00 equiv) was added via gastight syringe to
this solution. The resulting solution was left uncapped to allow
the release of H2 gas and stirred at room temperature for 0.5 h,
then transferred via pipet to a 1ꢀ dram vial containing the cataꢀ
lyst IPrAuTFA (7.0 mg, 0.010 mmol, 2.5 mol%). The first vial
was rinsed with toluene (3 × 0.10 mL) and transferred to the
reaction mixture. The vial with the resulting suspension was
capped and the solution was stirred on a preheated hot plate at
40 °C over an appropriate time as determined by the NMR
spectroscopy yield study (see SI Section II).
Pinacol boronate (4e) was obtained as light yellow oil using
toluene as solvent (97 mg, 66% yield). TLC (20%
1
EtOAc/hexanes): Rf = 0.57, visualized by UV absorbance. H
NMR (d8ꢀtoluene, 600 MHz): δ 7.05–7.01 (m, 3H), 6.86 (d, J
= 7.2 Hz, 1H), 5.38 (dd, J = 10.2, 8.4 Hz, 1H), 3.23 (ddd, J =
15, 10.2, 1.8 Hz, 1H), 2.87 (ddd, J = 15, 8.4, 1.8 Hz, 1H), 2.25
(t, J = 1.8 Hz, 1H), 1.09 (d, J = 6.6 Hz, 12H). 13C{1H}NMR
(d8ꢀtoluene, 150 MHz): δ 168.8, 143.9, 137.9, 128.6, 128.3,
126.6, 123.0, 83.8, 82.5, 41.4, 25.0, 24.9, 21.3, 14.4.
11B{1H}NMR (d8ꢀtoluene, 192 MHz): δ 30.3 (s). HRMS (ESIꢀ
TOF) m/z calcd for C18H25BO3Na ([M+Na]+) 323.1798, found
323.1788.
The reaction vial was cooled to room temperature and a soꢀ
lution of pinacol (142 mg, 1.20 mmol, 3.00 equiv) in anhyꢀ
drous Et3N (0.84 mL, 6.00 mmol, 15.0 equiv) was added. The
resulting solution was stirred at 25 °C for 1 h. The vial conꢀ
taining the reaction mixture was then removed from the
glovebox. Volatiles were removed in vacuo. The resulting
light brown oil was purified by silica gel chromatography usꢀ
ing an elution gradient from 100% hexanes to 10% EtOAc in
hexanes. Solvents were removed in vacuo to afford the desired
Pinacol boronate (4f) was obtained as light yellow oil using
toluene as solvent (125 mg, 82% yield). TLC (20%
1
EtOAc/hexanes): Rf = 0.54, visualized by UV absorbance. H
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Page 7 of 17
The Journal of Organic Chemistry
the NMR scale. The bomb was moved inside the N2ꢀfilled
NMR (CDCl3, 600 MHz): δ 7.46 (d, J = 8.4 Hz, 2H), 7.20 (t, J
1
2
3
4
5
6
7
8
= 8.4 Hz, 2H), 5.46 (t, J = 9.0 Hz, 1H), 3.18 (dd, J = 15, 10.8
Hz, 1H), 2.64 (dd, J = 14.4, 7.8 Hz, 1H), 2.58–2.48 (m, 2H),
1.25 (d, J = 3.6 Hz, 12H), 1.15 (t, J = 7.8 Hz, 3H).
13C{1H}NMR (CDCl3, 150 MHz): δ 173.0, 142.7, 131.7,
127.4, 121.3, 82.7, 82.3, 40.8, 25.0, 21.6, 12.5. 11B{1H}NMR
(CDCl3, 192 MHz): δ 30.0 (s). HRMS (CIꢀTOF) m/z calcd for
C18H24BBrO3 ([M]+) 380.0987, found 380.0981.
glovebox. Pinacol (2.12 g, 18.0 mmol, 3.00 equiv) was disꢀ
solved in anhydrous Et3N (2.5 mL, 18 mmol, 3.0 equiv). The
resulting solution was added to the above reaction mixture via
syringe, and the resulting suspension was stirred at 25 °C for 1
h inside the N2ꢀfilled glovebox. The bomb was then removed
from the glovebox. Volatiles were removed in vacuo. The
resulting light brown oil was purified by silica gel chromatogꢀ
raphy using an elution gradient from 100% hexanes to 10%
EtOAc. Solvents were removed in vacuo to afford the desired
pinacol boronate 4a as a light yellow oil (1.42 g, 75% yield).
Spectral data were identical to those previously obtained for
this compound.
Pinacol boronate (4g) was obtained as colorless oil using
toluene as solvent (102 mg, 72% yield). TLC (20%
9
1
EtOAc/hexanes): Rf = 0.51, visualized by UV absorbance. H
10
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26
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36
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41
42
43
44
45
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47
48
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NMR (CDCl3, 600 MHz): δ 8.01 (d, J = 7.8 Hz, 2H), 7.38 (t, J
= 7.2 Hz, 2H), 5.55 (t, J = 8.4 Hz, 1H), 3.91 (s, 3H), 3.22 (t, J
= 12.6 Hz, 1H), 2.66 (dd, J = 14.4, 7.8 Hz, 1H), 2.60–2.51 (m,
2H), 1.24 (d, J = 3.6 Hz, 12H), 1.17 (t, J = 7.8 Hz, 3H).
13C{1H}NMR (CDCl3, 150 MHz): δ 173.0, 167.1, 148.9,
130.0, 129.3, 125.4, 82.7, 82.4, 52.2, 40.9, 31.7, 25.0, 22.8,
21.7, 14.3, 12.5. 11B{1H}NMR (CDCl3, 192 MHz): δ 29.7 (s).
HRMS (ESIꢀTOF) m/z calcd for C20H28BO5 ([M+H]+)
359.2034, found 359.2036.
Genral Experimental Procedure C for the preparation of 2ꢀ
alkynyl benzyl and 2′ꢀAlkynyl benzyl alcohols (9a, 9i).56
A
100 mL flameꢀdried and septumꢀcapped round bottom flask
was prepared and filled with N2 on a Schlenk line. Then, 2ꢀ
iodobenzyl alcohol (1.17 g, 5.00 mmol, 1.00 equiv),
PdCl2(PPh3)2 (0.175 g, 0.250 mmol, 5.00 mol %), and CuI
(95.0 mg, 0.500 mmol, 10.0 mol %) were quickly placed, reꢀ
spectively, into the 100 mL round bottom flask after the sepꢀ
tum was briefly removed. Then, the system was capped with
the septum again, followed by vacuumed on high vacuum for
ca. 5 min. Then, the system was refilled with N2 on a Schlenk
line. Then, tetrahydrofuran (25 mL) was added via a syringe
under N2 on the Schlenk line to make a homogeneous solution.
Then, the N2 inlet from the Schlenk line was replaced with a
N2ꢀfilled balloon, which was kept connected to the reaction
round bottom flask until the end of this reaction. To the resultꢀ
ing solution Et3N (1.4 mL, 10. mmol, 2.0 equiv) was added via
a syringe. The resulting solution was cooled to 0 ˚C in an ice
bath. At 0 ˚C, alkyne (7.5 mmol, 1.5 equiv) was added dropꢀ
wise via a syringe, followed by warming of the resulting soluꢀ
tion to 25 ˚C. The reaction solution was stirred at 25 ˚C under
N2 for 18 h or until all aryl iodide was consumed as shown by
TLC. The reaction was quenched with saturated NH4Cl(aq)
(20 mL), and the resulting organic layer was washed with
brine (10 mL). The aqueous layer was extracted with EtOAc
(3 × 10 mL), and the combined organic layers were dried over
MgSO4, and then filtered through a Celite® plug (Celite® in a
medium glass frit funnel). The filtrate was concentrated in
vacuo. The crude product was purified by silica gel flash colꢀ
umn chromatography.
Pinacol boronate (4h) was obtained as white solid using
toluene as solvent (59 mg, 53% yield). TLC (40%
1
DCM/hexanes): Rf = 0.26, visualized by UV absorbance. H
NMR (C6D6, 500 MHz): δ 7.51 (d, J = 7.5 Hz, 2H), 7.20 (t, J =
7.5 Hz, 2H), 7.07 (t, J = 7.5 Hz, 1H), 4.02 (s, 2H), 3.92 (t, J =
9.5 Hz, 2H), 2.67 (t, J = 9.5 Hz, 2H), 1.12 (s, 12H).
13C{1H}NMR (C6D6, 125 MHz): δ 171.4, 139.1, 129.4, 128.6,
126.6, 82.7, 70.8, 35.0, 32.3, 25.0. 11B{1H}NMR (C6D6, 192
MHz):
δ 30.5 (s). HRMS (ESIꢀTOF) m/z calcd for
C17H23BO3Na ([M+Na]+) 309.1641, found 309.1645.
Pinacol boronate (4i) was obtained as colorless oil using
toluene as solvent (79 mg, 63% yield). TLC (30%
1
EtOAc/hexanes): Rf = 0.52, visualized by UV absorbance. H
NMR (C6D6, 600 MHz): δ 7.21–7.13 (m, 3H), 6.71 (d, J = 7.8
Hz, 1H), 4.01 (s, 2H), 3.95–3.91 (m, 2H), 3.36 (d, J = 1.8 Hz,
3H), 2.68 (t, J = 9.6 Hz, 2H), 1.13 (d, J = 2.4 Hz, 12H).
13C{1H}NMR (C6D6, 150 MHz): δ 171,4. 160.4, 140.6, 129.5,
121.9, 115.4, 112.2, 82.7, 70.8, 54.7, 35.0, 32.3, 25.0.
11B{1H}NMR (C6D6, 192 MHz): δ 30.4 (s). HRMS (ESIꢀTOF)
m/z calcd for C18H25BO4Na ([M+Na]+) 339.1747, found
339.1735.
Pinacol boronate (4j) was obtained as yellow solid using
toluene as solvent (91 mg, 66% yield). TLC (40%
(2-(hex-1-yn-1-yl)phenyl)methanol (9a): Prepared according
to general procedure C, and purified by flash column chromaꢀ
tography (silica, 15% EtOAc in hexane) to afford a brown
1
DCM/hexanes): Rf = 0.22, visualized by UV absorbance. H
NMR (C6D6, 600 MHz): δ 6.49 (d, J = 2.0 Hz, 2H), 6.32 (t, J =
2.0 Hz, 1H), 4.28 (t, J = 9.5 Hz, 2H), 3.77 (s, 6H), 3.71 (s,
2H), 2.71 (t, J = 9.5 Hz, 2H), 1.28 (s, 12H). 13C{1H}NMR
(CDCl3, 150 MHz): δ 170.2, 160.8, 140.8, 107.0, 98.7, 82.8,
71.0, 55.4, 34.7, 31.8, 25.0. 11B{1H}NMR (CDCl3, 192 MHz):
δ 30.0 (s). HRMS (ESIꢀTOF) m/z calcd for C19H27BO5Na
([M+Na]+) 369.1853, found 369.1866.
1
liquid (0.80 g, 85% yield). H NMR (CDCl3, 500 MHz): δ
7.44–7.33 (m, 2H), 7.32–7.18 (m, 2H), 4.79 (d, J = 6.3 Hz,
2H), 2.46 (t, J = 7.1 Hz, 2H), 2.07 (s, 1H), 1.66–1.56 (m, 2H),
1.55–1.44 (m, 2H), 0.96 (t, J = 7.3, 1.2 Hz, 3H). This spectrum
is in agreement with previously reported spectral data.56
General Experimental Procedure D for the preparation of 2ꢀ
alkynyl benzyl and 2′ꢀAlkynyl benzyl alcohols (9b–d, 9f).56,57
A 100 mL flameꢀdried and septumꢀcapped round bottom flask
containing a stir bar was prepared and filled with N2 on a
Schlenk line. Then 2′ꢀiodoacetophenone (1.0 equiv),
PdCl2(PPh3)2 (5 mol%), and CuI (10 mol%) were placed, reꢀ
spectively, to the 100 mL round bottom flask after the septum
was briefly removed. Then, the system was capped again with
the septum and vacuumed with a high vacuum. Then, the sysꢀ
tem was refilled with N2 on a Schlenk line. Tetrahydrofuran
(0.2 M) was added under N2 on the Schlenk line via a syringe.
Then, the N2 inlet from the Schlenk line was replaced with a
Gramꢀscale preparation of 4a. The gramꢀscale oxyboraꢀ
tion reaction was conducted in a 100ꢀmL bomb equipped with
a stir bar in a N2ꢀfilled glovebox. A flameꢀdried 100ꢀmL bomb
with a stir bar was charged with alkynol 1a (0.672 g, 6.00
mmol, 1.00 equiv) together with C6D6 (4.6 mL) was added via
syringe. To the resulting rapidly stirring suspension was added
catecholborane (0.64 mL, 6.0 mmol, 1.0 equiv) via syringe.
The bomb was sealed, and the suspension was stirred at room
temperature for 30 min. The bomb was removed from the
glovebox and placed in a preheated oil bath at 40 °C until full
consumption of starting materials was achieved (18 h). This
time was chosen based on the time required for conversion on
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N2ꢀfilled balloon, which was kept connected to the reaction 20% EtOAc in hexane) to afford a light yellow liquid (0.45 g,
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round bottom flask until the end of this reaction. To the resultꢀ
ing solution Et3N (2.0 equiv) was added. The resulting soluꢀ
tion was cooled to 0 ˚C in an ice bath. At 0 ˚C, alkyne (1.5
equiv) was added dropwise, followed by warming of the reꢀ
sulting solution to 25 ˚C. The reaction solution was stirred at
25 ˚C under N2 for 18 h or until all aryl iodide was consumed
as shown by TLC (ca. 10% EtOAc in hexane). The reaction
was quenched with saturated NH4Cl(aq) (20 mL), and the reꢀ
sulting organic layer was washed with brine (10 mL). The
aqueous layer was extracted with EtOAc (3 × 10 mL), and the
combined organic layers were dried over MgSO4, and then
filtered through a Celite® plug (Celite® in a medium glass frit
funnel). The filtrate was concentrated in vacuo. The crude
product was purified by silica gel flash column chromatogꢀ
raphy to afford 2′ꢀalkynylacetophenones as described separateꢀ
ly in the SI. 2′ꢀAlkynylacetophenone (1.0 equiv) was placed
into a flameꢀdried 100 mL round bottomed flask with a stir
bar. Then, the round bottom flask was capped with a septum,
and the system was vacuumed under high vacuum. Then, the
system was refilled with N2 on a Schlenk line. Under N2 on the
Schlenk line, EtOH was added via a syringe to produce a
0.1 M solution. The resulting solution was cooled to 0 ˚C. At
0 ˚C, NaBH4 (2.0–4.0 equiv) was added, and the reaction was
stirred at 0 ˚C for 10 min. Then, the N2 inlet from the Schlenk
line was replaced with a N2ꢀfilled balloon, which was kept
connected to the reaction round bottom flask until the end of
this reaction. The reaction was then warmed to 25 ˚C and
stirred at this temperature under N2 18 h before it was
quenched with saturated NH4Cl(aq) (20 mL), and the resulting
organic layer was washed with brine (20 mL). Then, the aqueꢀ
ous layer was extracted with EtOAc (3 × 10 mL), followed by
combining all organic layers. The combined organic layers
were then dried over MgSO4, and then filtered through a
Celite® plug (Celite® in a medium glass frit funnel), and the
filtrate was concentrated in vacuo to afford the crude product,
which was then purified by flash column chromatography as
described separately for each substrate below.
68% yield). H NMR (CDCl3, 600 MHz): δ 7.50 (d, J = 7.8
Hz, 1H), 7.38 (d, J = 7.6, 1H), 7.32 (t, J = 7.5, 1H), 7.20 (td, J
= 7.5, 1.3 Hz, 1H), 5.29 (q, J = 6.1 Hz, 1H), 3.72 (t, J = 6.9,
2H), 2.66 (t, J = 6.8 Hz, 2H), 2.28–1.98 (m, 3H), 1.51 (d,
J = 6.6 Hz, 3H). 13C{1H}NMR (CDCl3, 151 MHz): δ 147.4,
132.5, 128.5, 127.1, 124.7, 120.8, 93.3, 79.4, 68.6, 43.8, 31.5,
24.0, 17.2. HRMS (ESIꢀTOF) m / z calcd for C13H15ClONa
([M+Na]+) 245.0709, found 245.0700.
1-(2-(cyclopropylethynyl)phenyl)ethan-1-one (SI-3d): Preꢀ
pared according to general procedure D, and purified by flash
column chromatography (silica, 10% EtOAc in hexane) to
afford a yellow oil (0.34 g, 93% yield). The molecular strucꢀ
ture was shown in the Supporting Information. 1H NMR
(CDCl3, 500 MHz): δ 7.66 (ddd, J = 7.5, 1.5, 0.5 Hz, 1H),
7.48–7.43 (m, 1H), 7.42–7.35 (m, 1H), 7.35–7.24 (m, 1H),
2.70 (s, 3H), 1.50 (tt, J = 8.2, 5.0 Hz, 1H), 0.95–0.80 (m, 4H).
This spectrum is in agreement with previously reported specꢀ
tral data.59
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1-(2-(cyclopropylethynyl)phenyl)ethan-1-ol (9d): Prepared
according to general procedure D (2.0 equiv NaBH4 used), and
purified by flash column chromatography (silica, 15% EtOAc
1
in hexane) to afford a yellow liquid (0.27 g, 76% yield). H
NMR (CDCl3, 500 MHz): δ 7.46 (dd, J = 7.9, 1.2 Hz, 1H),
7.35 (dd, J = 7.7, 0.8 Hz, 1H), 7.28 (t, J = 7.6 Hz, 1H), 7.21–
7.13 (m, 1H), 5.29–5.21 (m, 1H), 2.16 (d, J = 4.2 Hz, 1H),
1.53–1.44 (m, 4H), 0.94–0.85 (m, 2H), 0.87–0.75 (m, 2H).
13C{1H}NMR (CDCl3, 151 MHz): δ 147.5, 132.5, 128.2,
127.1, 124.7, 121.2, 98.9, 73.5, 68.7, 23.8, 8.9, 0.4. HRMS
(ESIꢀTOF) m / z calcd for C13H14ONa ([M+Na]+) 209.0942,
found 209.0937.
2-(hex-1-yn-1-yl)benzaldehyde (SI-5): was prepared accordꢀ
ing to general procedure D, and purified by flash column
chromatography (silica, 10% EtOAc in hexane) to afford a
yellow liquid (0.40 g, 86% yield). The molecular structure was
1
shown in the Supporting Information. H NMR (CDCl3, 500
MHz): δ 10.54 (s, 1H), 7.89 (d, J = 7.7 Hz, 1H), 7.58–7.44 (m,
2H), 7.38 (t, J = 7.3 Hz, 1H), 2.49 (t, J = 7.1 Hz, 2H), 1.68–
1.58 (m, 2H), 1.56–1.44 (m, 2H), 0.97 (t, J = 7.4, 1.6 Hz, 3H).
This spectrum is in agreement with previously reported specꢀ
tral data.60
1-(2-(hex-1-yn-1-yl)phenyl)ethan-1-ol (9b): Prepared acꢀ
cording to general procedure D (4.0 equiv NaBH4 used), and
purified by flash column chromatography (silica, 10% EtOAc
in hexane) to afford a light yellow liquid (0.92 g, 91% yield).
1H NMR (CDCl3, 500 MHz): δ 7.48 (d, J = 7.9 Hz, 1H), 7.38
(d, J = 7.7 Hz, 1H), 7.30 (t, J = 7.6 Hz, 1H), 7.19 (t,
J = 7.6 Hz, 1H), 5.29 (t, J = 5.7 Hz, 1H), 2.46 (t, J = 7.1 Hz,
2H), 2.19 (d, J = 4.1 Hz, 1H), 1.66–1.57 (m, 2H), 1.54–1.44
(m, 5H), 0.96 (t, J = 7.3 Hz, 3H). This spectrum is in agreeꢀ
ment with previously reported spectral data.58
2,2,2-trifluoro-1-(2-(hex-1-yn-1-yl)phenyl)ethan-1-ol (9e):
Prepared according to a modified reported procedure.61 In a
N2ꢀfilled glovebox, 2ꢀ(hexꢀ1ꢀynꢀ1ꢀyl)benzaldehyde (SIꢀ5,
0.400 g, 2.15 mmol, 1.0 equiv) was dissolved into DME (10.8
mL, 0.200 M) in a flameꢀdried 100 mL round bottomed flask,
followed by addition of CsF (0.163 g, 1.07 mmol, 0.50 equiv)
and a stir bar. Then, the reaction flask was capped with a sepꢀ
tum, and removed from the glovebox. The resulting solution
was cooled to 0 ˚C under N2 on a Schlenk line. Then, TMSCF3
(0.32 mL, 2.2 mmol, 1.0 equiv) was added dropwise via a
syringe, and the reaction was warmed to 25 ˚C and stirred
under N2 on the Schlenk line. Upon the full consumption of the
starting material (ca. 17 h) as shown by TLC (ca. 10% EtOAc
in hexane), the reaction was quenched by adding 10% HCl(aq)
(10 mL), and the aqueous layer was extracted with EtOAc
(3 × 10 mL). The organic layers were combined and dried over
MgSO4. The drying agent was then removed via filtration
through a Celite® plug (Celite® in a medium glass frit funnel),
and the filtrate was concentrated in vacuo. The residue was
purified via a flash column chromatography (silica, 10%
EtOAc in hexane) to afford a yellow oil (0.37 g, 68% yield).
1H NMR (CDCl3, 500 MHz): δ 7.59–7.53 (m, 1H), 7.45 (dd, J
1-(2-(6-chlorohex-1-yn-1-yl)phenyl)ethan-1-one
(SI-3c):
Prepared according to general procedure D, and purified by
flash column chromatography (silica, 15% EtOAc in hexane)
to afford an orange oil (0.61 g, 93% yield). The molecular
1
structure was shown in the Supporting Information. H NMR
(CDCl3, 600 MHz): δ 7.69–7.65 (m, 1H), 7.49 (dd, J = 7.6, 1.4
Hz, 1H), 7.41 (td, J = 7.6, 1.4 Hz, 1H), 7.35 (td, J = 7.6, 1.4
Hz, 1H), 3.74 (t, J = 6.3 Hz, 2H), 2.72–2.64 (m, 5H), 2.13–
2.05 (m, 2H). 13C{1H}NMR (CDCl3, 151 MHz): δ 200.7,
141.1, 134.3, 131.3, 128.6, 127.9, 122.1, 94.3, 80.7, 43.8,
31.3, 30.0, 17.3. HRMS (ESIꢀTOF) m / z calcd for C13H14ClO
([M+H]+) 221.0733, found 221.0738.
1-(2-(6-chlorohex-1-yn-1-yl)phenyl)ethan-1-ol (9c): Preꢀ
pared according to general procedure D (4.0 equiv NaBH4
used), and purified by flash column chromatography (silica,
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The Journal of Organic Chemistry
J = 2.0 Hz, 1H), 7.37 (dd, J = 8.2, 2.0 Hz, 1H), 7.19 (d, J = 8.2
= 7.0, 2.1 Hz, 1H), 7.39–7.28 (m, 2H), 5.63–5.54 (m, 1H),
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7
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2.85 (d, J = 5.8 Hz, 1H), 2.45 (t, J = 7.1 Hz, 2H), 1.66–1.43
(m, 4H), 0.96 (t, J = 7.3 Hz, 3H). 13C{1H}NMR (CDCl3, 151
MHz): δ 135.4, 132.7, 129.2, 128.1, 127.5, 125.6, 123.9, 96.5,
77.7, 71.0 (q, J = 32 Hz), 30.8, 22.1, 19.3, 13.7. 19F{1H}NMR
(CDCl3, 565 MHz): δ ꢀ77.74 (d, J = 6.8 Hz). HRMS (ESIꢀ
TOF) m / z calcd for C14H14F3O ([MꢀH]ꢀ) 255.0997, found
255.0999.
Hz, 1H), 4.98–2.47 (m, 6H). This spectrum is in agreement
with previously reported spectral data.64
4-chloro-2-(hex-1-yn-1-yl)-N-methoxy-N-methylbenzamide
(SI-8): was prepared according to general procedure D from
SIꢀ7, and purified by flash column chromatography (silica,
30% EtOAc in hexane) to afford a brown oil (1.2 g, 92%
yield). The molecular structure was shown in the Supporting
1
1-(5-fluoro-2-(hex-1-yn-1-yl)phenyl)ethan-1-one
(SI-3f):
Information. H NMR (CDCl3, 600 MHz): δ 7.41 (d, J = 2.0
Prepared according to general procedure D, and purified by
flash column chromatography (silica, 5% EtOAc in hexane) to
afford a brown liquid (0.47 g, 71% yield). The molecular
Hz, 1H), 7.33–7.20 (m, 2H), 3.41 (br d, J = 109.2 Hz, 6H),
2.40 (dd, J = 7.4, 6.7 Hz, 2H), 1.61–1.52 (m, 2H), 1.50–1.36
(m, 2H), 0.93 (td, J = 7.3, 0.7 Hz, 3H). 13C{1H}NMR (CDCl3,
125 MHz): δ 168.5, 136.4, 134.0, 131.2, 127.1, 122.7, 95.1,
76.5, 60.5, 31.8, 30.0, 21.3, 18.5, 13.0. HRMS (ESIꢀTOF)
m / z calcd for C15H19ClNO2 ([M+H]+) 280.1104, found
280.1100.
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1
structure was shown in the Supporting Information. H NMR
(CDCl3, 500 MHz): δ 7.46 (dd, J = 8.6, 5.5 Hz, 1H), 7.36–7.33
(m, 1H), 7.12–7.09 (m, 1H), 2.73 (s, 3H), 2.45 (t, J = 7.1 Hz,
2H), 1.64–1.52 (m, 2H), 1.54–1.42 (m, 2H), 0.93 (t, J = 7.2
Hz, 3H). This spectrum is in agreement with previously reꢀ
ported spectral data.62
1-(4-chloro-2-(hex-1-yn-1-yl)phenyl)ethan-1-one
(SI-9):
was prepared according to a modified literature procedure.65
The molecular structure was shown in the Supporting Inforꢀ
mation. To a solution of SIꢀ8 (1.19 g, 4.25 mmol, 1.0 equiv)
in dry THF (21 mL, 0.2 M) in a 100 mL flameꢀdried septumꢀ
capped round bottom flask with a stir bar was added MeMgBr
(2.1 mL of a 3.0 M Et2O solution, 6.37 mmol, 1.5 equiv)
dropwise via a syringe at 0 ˚C under N2 on a Schlenk line. The
resulting solution was warmed to 25 ˚C, and stirred at this
temperature for 2.0 h under N2 on the Schlenk line. Then, the
reaction was quenched with saturated NH4Cl(aq) (20 mL). The
resulting organic layer was washed with brine (20 mL). Then,
the aqueous layer was extracted with EtOAc (3 × 15 mL),
followed by combining all organic layers. The combined orꢀ
ganic layers were then dried over MgSO4, and then filtered
through a Celite® plug (Celite® in a medium glass frit funnel),
and the filtrate was concentrated in vacuo to afford the crude
product, which was then purified by flash column chromatogꢀ
raphy (10% EtOAc in hexane) to afford a yellow oil (0.73 g,
73%). 1H NMR (CDCl3, 500 MHz): δ 7.63 (d, J = 8.4 Hz, 1H),
7.47 (d, J = 2.1 Hz, 1H), 7.29 (dd, J = 8.4, 2.1 Hz, 1H), 2.70
(s, 3H), 2.46 (t, J = 7.1 Hz, 2H), 1.77–1.57 (m, 2H), 1.52–1.41
(m, 2H), 0.95 (t, J = 7.3 Hz, 3H). 13C{1H}NMR (CDCl3,
126 MHz): δ 200.0, 139.2, 137.5, 133.8, 130.1, 128.0, 124.5,
98.6, 79.0, 30.5, 30.2, 22.2, 19.5, 13.7. HRMS (ESIꢀTOF) m /
1-(5-fluoro-2-(hex-1-yn-1-yl)phenyl)ethan-1-ol (9f): Preꢀ
pared according to general procedure D (2.0 equiv NaBH4
used), and purified by flash column chromatography (silica,
10% EtOAc in hexane) to afford a yellow oil (0.36 g, 76%
1
yield). H NMR (CDCl3, 500 MHz): δ 7.34 (dd, J = 8.5, 5.7
Hz, 1H), 7.22 (dd, J = 9.9, 2.8 Hz, 1H), 6.87 (td, J = 8.3, 2.7
Hz, 1H), 5.32–5.22 (m, 1H), 2.44 (t, J = 7.0 Hz, 2H), 2.11 (d,
J = 4.0 Hz, 1H), 1.65–1.55 (m, 2H), 1.55–1.43 (m, 5H), 0.96
(t, J = 7.3 Hz, 3H). 13C{1H}NMR (CDCl3,151 MHz): δ 162.6
(d, J = 248 Hz), 150.3 (d, J = 7 Hz), 134.1 (d, J = 8 Hz), 117
(d, J = 3 Hz), 114 (d, J = 22 Hz), 112.1 (d, J = 23 Hz), 95.3,
77.4, 68.4, 30.9, 23.8, 22.2, 19.30, 13.7. 19F{1H}NMR (CDCl3,
565 MHz): δ ꢀ111.08– ꢀ111.23 (m). HRMS (ESIꢀTOF) m / z
calcd for C14H17FONa ([M+Na]+) 243.1161, found 243.1167.
4-Chloro-2-iodo-N-methoxy-N-methylbenzamide
(SI-7):
was prepared according to a modified reported procedure.63
The molecular structure was shown in the Supporting Inforꢀ
mation. A 100 mL flameꢀdried septumꢀcapped round bottom
flask containing a stir bar was prepared. Then, 4ꢀchloroꢀ2ꢀ
iodobenzoic acid (SIꢀ6) (1.41 g, 5.00 mmol, 1.0 equiv) was
placed in the 100 mL round bottom flask, followed by capping
the system with a septum. Then, the system was vacuumed
under high vacuum, and refilled with N2 on a Schlenk line.
Then, MeCN (21 mL, 0.2 M) was added under N2 under N2 on
the Schlenk line. To the resulting solution, 4ꢀ(4,6ꢀdimethoxyꢀ
z
calcd for C14H15ClONa ([M+Na]+) 257.0709, found
257.0711
1-(4-chloro-2-(hex-1-yn-1-yl)phenyl)ethan-1-ol (9g): Preꢀ
1,3,5ꢀtriazinꢀ2ꢀyl)ꢀ4ꢀmethylꢀmorpholinium
chloride
(DMTMM; 1.66 g, 6.00 mmol, 1.2 equiv), Nꢀ
methylmorpholine (1.0 mL, 10.0 mmol, 2.0 equiv), and
MeO(Me)NH•HCl (0.585 g, 6.0 mmol, 1.2 equiv) were quickꢀ
ly added, respectively, under N2 on the Schlenk line at 25 ˚C
after the septum was briefly removed. Once the addition of
chemicals was done, the septum was quickly returned. Then,
the resulting mixture was stirred at 25 ˚C under N2 with a N2ꢀ
filled balloon for 18 h. Then, the solvent was removed in vacꢀ
uo, and the resulting residue was dissolved in EtOAc (20 mL).
The new solution was washed with 1 M HCl(aq) (1 × 20 mL),
deionized H2O (1 × 15 mL), and brine (1 × 15 mL). The aqueꢀ
ous phases were combined and extracted with EtOAc (1 × 15
mL), followed by combining all resulting organic phases. The
combined organic phases were then dried over MgSO4, and
then filtered through a Celite® plug (Celite® in a medium glass
frit funnel). The filtrate was concentrated in vacuo to afford
the crude product, which was purified by flash column chroꢀ
matography (40% EtOAc in hexane) to afford a light yellow
pared according to general procedure D from SIꢀ9 (3.0 equiv
NaBH4 used), and purified by flash column chromatography
(silica, 10% EtOAc in hexane) to afford a colorless oil (0.62 g,
84% yield). 1H NMR (CDCl3, 500 MHz): δ 7.43 (d,
J = 8.4 Hz, 1H), 7.35 (d, J = 2.3 Hz, 1H), 7.31–7.21 (m, 1H),
5.25 (qd, J = 6.4, 3.4 Hz, 1H), 2.45 (t, J = 7.1 Hz, 2H), 2.09 (d,
J = 3.8 Hz, 1H), 1.69–1.55 (m, 2H), 1.53–1.42 (m, 5H), 0.96
(t, J = 7.3 Hz, 3H). 13C{1H}NMR (CDCl3, 126 MHz): δ 145.9,
132.6, 132.0, 128.3, 126.2, 123.0, 97.1, 77.3, 68.2, 30.8, 24.0,
22.2, 19.4, 13.7. HRMS (ESIꢀTOF) m / z calcd for
C14H17ClONa ([M+Na]+) 259.0865, found 259.0868.
1-(2-(hex-1-yn-1-yl)phenyl)-2-methylpropan-1-ol (9h): Preꢀ
pared according to reported procedure.65 A solution of SIꢀ5
(0.452 g, 2.43 mmol, 1.00 equiv) in dry THF (4.8 mL, 0.50 M)
in a 100 mL flameꢀdried septumꢀcapped round bottom flask
equipped with a star bar was cooled to 0 ˚C under N2 on a
Schlenk line. To the cooled solution, iPrMgBr (2.9 mL of a 1.0
M THF solution, 2.9 mmol, 1.2 equiv) was added dropwise at
0 ˚C via a syringe. The resulting solution was warmed to
1
oil (1.5 g, 93%). H NMR (CDCl3, 500 MHz): δ 7.84 (d,
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Page 10 of 17
25 ˚C, and stirred at this temperature for 2.0 h under N2. Then, ing to general procedure E, and purified by flash column
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7
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the reaction was quenched with saturated NH4Cl(aq) (20 mL),
and the resulting organic layer was washed with brine
(20 mL). Then, the aqueous layer was extracted with EtOAc
(3 × 10 mL), followed by combining all organic layers. The
combined organic layers were then dried over MgSO4, and
then filtered through a Celite® plug (Celite® in a medium glass
frit funnel), and the filtrate was concentrated in vacuo to afꢀ
ford the crude product, which was then purified by flash colꢀ
umn chromatography (15% EtOAc in hexane) to afford a yelꢀ
chromatography (silica, 35% DCM in hexane) to afford a
white foam (0.048 g, 34% yield). 1H NMR (CDCl3,
500 MHz): δ 7.23–7.12 (m, 5H), 7.09 (dd, J = 8.4, 1.1 Hz,
2H), 7.06–7.01 (m, 1H), 6.35 (dd, J = 7.2, 1.1 Hz, 2H), 5.84
(s, 2H), 5.06 (s, 2H), 2.56–2.20 (m, 2H), 1.61 (tt, J = 8.9, 6.8
Hz, 2H), 1.40 (dq, J = 14.7, 7.4 Hz, 2H), 0.94 (t, J = 7.3 Hz,
3H). 13C{1H}NMR (CDCl3, 151 MHz): δ 161.4, 141.3, 136.5,
133.9, 128.3, 127.7, 127.7, 125.9, 124.1, 123.7, 119.9, 117.9,
106.0, 68.6, 34.3, 30.5, 29.8, 22.6, 14.1. 11B{1H}NMR
(CDCl3, 193 MHz): δ 30.21. HRMS (ESIꢀTOF) m / z calcd for
C23H24BN2O ([M+H]+) 355.1986, found 355.1979.
1
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low oil (0.12 g, 21%). H NMR (CDCl3, 600 MHz): δ 7.44–
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39
40
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43
44
45
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59
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7.39 (m, 1H), 7.37 (dd, J = 7.7, 1.3 Hz, 1H), 7.32–7.26 (m,
1H), 7.18 (td, J = 7.6, 1.4 Hz, 1H), 4.84 (dd, J = 6.6, 4.7 Hz,
1H), 2.45 (t, J = 7.0 Hz, 2H), 2.18–2.06 (m, 1H), 2.03 (dd, J =
4.8, 0.7 Hz, 1H), 1.71–1.56 (m, 2H), 1.53–1.43 (m, 2H), 1.00
(d, J = 6.7 Hz, 2H), 0.96 (t, J = 7.3 Hz, 3H), 0.88 (d, J = 6.9
Hz, 3H). 13C{1H}NMR (CDCl3, 151 MHz): δ 145.6, 132.4,
127.8, 126.9, 126.4, 122.0, 95.6, 78.9, 77.8, 34.7, 31.0, 22.2,
19.7, 19.4, 17.8, 13.8. HRMS (ESIꢀTOF) m / z calcd for
C16H22ONa ([M+Na]+) 253.1568, found 253.1563.
2-(3-butyl-1-methyl-1H-isochromen-4-yl)-2,3-dihydro-1H-
naphtho[1,8-de][1,3,2]diazaborinine (12b): Prepared accordꢀ
ing to general procedure E, and purified by flash column
chromatography (silica, 25% DCM in hexane) to afford a
white solid (0.114 g, 78% yield). 1H NMR (CDCl3, 600 MHz):
δ 7.20–7.11 (m, 6H), 7.08 (d, J = 8.2 Hz, 1H), 7.05 (d, J = 7.2
Hz, 1H), 6.35 (d, J = 7.2 Hz, 2H), 5.83 (s, 2H), 5.20 (q, J = 6.5
Hz, 1H), 3.05–2.12 (m, 2H), 1.70–1.58 (m, 5H), 1.49–1,35 (m,
2H), 0.94 (t, J = 7.3 Hz, 3H). 13C{1H}NMR (CDCl3, 151
MHz): δ 159.6, 141.4, 136.5, 133.1, 132.1, 127.9, 127.6,
126.0, 124.0, 123.5, 119.9, 117.9, 106.0, 73.6, 34.5, 30.3,
22.6, 20.0, 14.1. 11B{1H}NMR (CDCl3, 193 MHz): δ 30.05.
HRMS (ESIꢀTOF) m / z calcd for C24H25BN2O ([M]+)
368.2065, found 368.2066.
(2-(phenylethynyl)phenyl)methanol (9i): Prepared according
to general procedure C, and purified by flash column chromaꢀ
tography (silica, 15% EtOAc in hexane) to afford a light yelꢀ
low solid, and the resulting solid was further purified with hot
hexane (ca. 40–60 ˚C, ca. 3 mL) to afford a white solid (0.58
1
g, 56% yield). H NMR (CDCl3, 500 MHz): δ 7.61–7.45 (m,
4H), 7.42–7.34 (m, 4H), 7.30 (t, J = 7.3 Hz, 1H), 4.93 (d, J =
6.5 Hz, 2H), 2.07 (t, J = 6.4 Hz, 1H). This spectrum is in
agreement with previously reported spectral data.56
2-(3-(3-chloropropyl)-1-methyl-1H-isochromen-4-yl)-2,3-
dihydro-1H-naphtho[1,8-de][1,3,2]diazaborinine (12c): Preꢀ
pared according to general procedure E, and purified by flash
column chromatography (silica, 25% DCM in hexane) to afꢀ
ford a white solid (0.098 g, 63% yield). 1H NMR (CDCl3, 600
MHz): δ 7.23–7.13 (m, 5H), 7.08 (dd, J = 15.2, 6.9 Hz, 3H),
6.36 (d, J = 7.3 Hz, 2H), 5.93 (s, 2H), 5.22 (q, J = 6.6 Hz, 1H),
3.63 (t, J = 5.8 Hz, 2H), 2.62–2.50 (m, 2H), 2.19–2.07 (m,
2H), 1.63 (d, J = 6.8 Hz, 3H). 13C{1H}NMR (CDCl3, 151
MHz): δ 157.3, 141.3, 136.4, 132.8, 132.1, 128.0, 127.7,
126.4, 124.3, 123.5, 119.9, 117.9, 106.0, 73.7, 44.5, 31.6,
30.3, 19.9. 11B{1H}NMR (CDCl3, 193 MHz): δ 30.01. HRMS
(ESIꢀTOF) m / z calcd for C23H22BClN2ONa ([M+Na]+)
411.1416, found 411.1403.
General Experimental Procedure E for the Synthesis of
pinacol boronates 12. In a N2ꢀfilled glovebox, to a oneꢀdram
vial containing alkynyl benzylic alcohols (0.400 mmol,
1.0 equiv) was added HBcat (42.6 µL, 0.400 mmol, 1.0 equiv),
followed by rinsing walls of the vial with 0.05 mL toluene,
and the resulting solution was left in the glovebox uncapped to
allow the release of H2 gas at 25 ˚C for 1.5 h. Then, the resultꢀ
ing substrate solution was transferred to a separate oneꢀdram
vial containing IPrAuTFA (7.0 mg, 0.010 mmol, 2.5 mol %)
and a stir bar, followed by rinsing the first oneꢀdram vial with
3.5 mL toluene, and the rinse was combined with the reaction
solution in the second oneꢀdram vial. The reaction vial was
capped. Then, the reaction mixture was heated to 100 ˚C (or
120 ˚C for 10e) with stirring at this temperature for 4 h (18 h
for 10e, and 19 h for 10g). The resulting solution was cooled
to 25 ˚C, followed by addition of 1,8ꢀdiaminonaphthalene
(126 mg, 0.800 mmol, 2.0 equiv) and Et3N (0.84 mL,
6.0 mmol, 15 equiv). The vial used for weighting 1,8ꢀ
diaminonaphthalene was rinsed with 0.20 mL toluene, and the
resulting solution was combined with the reaction solution,
followed by capping the reaction vial again. The reaction was
stirred at 25 ˚C for 18 h. Once the isolation reaction was done
as determined by TLC (20–40% DCM in hexane), the reaction
vial was removed from the glovebox, and the reaction was
quenched with saturated NH4Cl(aq) (5 mL). Then, the resultꢀ
ing organic layer was washed with brine (5 mL). The aqueous
layer was then extracted with EtOAc (3 × 5 mL), followed by
combining all organic layers. The combined organic layers
were then dried over MgSO4, which was then filtered with a
Celite® plug (Celite® in an M glass frit funnel), and the filtrate
was concentrated in vacuo to afford the crude product, which
was then purified by flash column chromatography.
2-(3-cyclopropyl-1-methyl-1H-isochromen-4-yl)-2,3-
dihydro-1H-naphtho[1,8-de][1,3,2]diazaborinine (12d): Preꢀ
pared according to general procedure E, and purified by flash
column chromatography (silica, 25% DCM in hexane) to afꢀ
ford a white foam (0.086 g, 61% yield). 1H NMR (CDCl3, 500
MHz): δ 7.22–7.10 (m, 5H), 7.07 (dd, J = 8.3, 1.0 Hz, 2H),
7.02 (d, J = 7.4 Hz, 1H), 6.36 (dd, J = 7.3, 1.1 Hz, 2H), 5.94
(s, 2H), 5.09 (q, J = 6.5 Hz, 1H), 1.89–1.80 (m, 1H), 1.54 (d, J
= 6.5 Hz, 3H), 1.03–0.92 (m, 2H), 0.76–0.61 (m, 2H).
13C{1H}NMR (CDCl3, 151 MHz): δ 158.8, 141.5, 136.5,
133.4, 132.1, 128.0, 127.7, 125.6, 123.5, 123.4, 119.9, 117.9,
106.0, 73.6, 29.9, 19.6, 14.3, 5.9, 5.2. 11B{1H}NMR (CDCl3,
193 MHz): δ 30.23. HRMS (ESIꢀTOF) m / z calcd for
C23H21BN2O ([M]+) 352.1751, found 352.1741.
2-(3-butyl-1-(trifluoromethyl)-1H-isochromen-4-yl)-2,3-
dihydro-1H-naphtho[1,8-de][1,3,2]diazaborinine (12e): Preꢀ
pared according to general procedure E, and purified by flash
column chromatography (silica, 25% DCM in hexane) to afꢀ
ford a white foam (0.119 g, 70% yield). 1H NMR (CDCl3, 500
MHz): δ 7.23 (t, J = 7.6 Hz, 1H), 7.16 (d, J = 7.6 Hz, 2H),
7.10 (dd, J = 9.3, 6.2 Hz, 3H), 7.05 (d, J = 8.4 Hz, 2H), 6.29
(d, J = 7.4 Hz, 2H), 5.73 (s, 2H), 5.45 (q, J = 7.6 Hz, 1H),
2.59–2.15 (m, 2H), 1.79–1.49 (m, 2H), 1.42–1.24 (m, 2H),
2-(3-butyl-1H-isochromen-4-yl)-2,3-dihydro-1H-
naphtho[1,8-de][1,3,2]diazaborinine (12a): Prepared accordꢀ
ACS Paragon Plus Environment

Page 11 of 17
The Journal of Organic Chemistry
0.90 (t, J = 7.4 Hz, 3H). 13C{1H}NMR (CDCl3, 151 MHz): δ
136.3, 134.0, 129.2, 128.5, 128.4, 128.4, 128.2, 127.7, 127.7,
126.7, 124.4, 124.2, 119.8, 117.9, 106.1, 68.9. 11B{1H}NMR
(CDCl3, 193 MHz): δ 30.30. HRMS (ESIꢀTOF) m / z calcd for
C25H19BN2O ([M]+) 374.1595, found 374.1586.
1
2
3
4
5
6
7
8
157.8, 141.1, 136.4, 133.1, 130.1, 127.8, 127.1, 126.4, 124.9,
123.0, 120.6, 120.0, 118.1, 106.2, 74.5 (q, J = 32 Hz), 34.22,
29.87, 22.41, 14.03. 11B{1H}NMR (CDCl3, 193 MHz): δ
29.59. 19F NMR (CDCl3, 565 MHz): δ –78.48 (d, J = 7.3 Hz).
HRMS (ESIꢀTOF) m / z calcd for C24H22BF3N2O ([M]+)
422.1782, found 422.1792.
3-butyl-4-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)-1H-
isochromene(14a): Prepared according to a literature proceꢀ
dure from compound 11a.9 Compound 11a was prepared acꢀ
cording to general procedure E. In a N2ꢀfilled glovebox, pinaꢀ
col (0.142 g, 1.20 mmol, 3.0 equiv) was dissolved into Et3N
(0.84 mL, 3.0 mmol, 15 equiv), and the resulting solution was
transferred to 11a. The resulting reaction solution was capped
and stirred in the glovebox for 1 h at 25 ˚C. Then, the reaction
vial was removed from the glovebox, and the solvent was reꢀ
moved in vacuo. The resulting residue was purified by flash
chromatography (15% DCM in hexane) to afford a yellow oil
(0.070 g, 56% yield). 1H NMR (CDCl3, 500 MHz): δ 7.69 (d, J
= 7.8 Hz, 1H), 7.29–7.21 (m, 1H), 7.15–7.08 (m, 1H), 6.99 (d,
J = 7.4 Hz, 1H), 4.98 (s, 2H), 2.63 (t, J = 7.6 Hz, 2H), 1.67–
1.57 (m, 2H), 1.46–1.32 (m, 2H), 1.38 (s, 12H), 0.97 (t, J = 7.4
Hz, 3H). 13C{1H}NMR (CDCl3, 126 MHz): δ 170.8, 133.9,
128.1, 127.6, 125.4, 124.6, 123.6, 83.0, 68.9, 33.5, 31.2, 25.0,
22.68, 14.1. 11B{1H}NMR (CDCl3, 160 MHz): δ 31.75.
2-(3-butyl-7-fluoro-1-methyl-1H-isochromen-4-yl)-2,3-
dihydro-1H-naphtho[1,8-de][1,3,2]diazaborinine (12f): Preꢀ
pared according to general procedure E, and purified by flash
column chromatography (silica, 25% DCM in hexane) to afꢀ
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
ford a white solid (0.120 g, 77% yield). H NMR (CDCl3, 600
MHz): δ 7.17 (td, J = 7.8, 2.0 Hz, 2H), 7.14–7.09 (m, 3H),
6.87 (tt, J = 8.6, 2.3 Hz, 1H), 6.79 (dt, J = 9.1, 2.4 Hz, 1H),
6.37 (dd, J = 7.2, 1.8 Hz, 2H), 6.02–5.73 (m, 2H), 5.16 (q, J =
6.5 Hz, 1H), 2.40–2.31 (m, 2H), 1.75–1.53 (m, 5H), 1.45–1.37
(m, 2H), 1.00 (t, J = 7.4 Hz 3H). 13C{1H}NMR (CDCl3, 151
MHz): δ 161.3 (d, J = 245 Hz), 158.7 (d, J = 2 Hz), 141.2,
136.3, 134.1 (d, J = 7 Hz), 129.2 (d, J = 3 Hz), 127.7, 125.4
(d, J = 7.6 Hz), 119.8, 117.9, 114.3 (d, J = 21 Hz), 110.7 (d, J
= 23 Hz), 106.0, 73.1 (d, J = 2 Hz), 34.3, 30.2, 22.5, 19.6,
14.2. 11B{1H}NMR (CDCl3, 193 MHz): δ 30.29. 19F{1H}NMR
(CDCl3, 565 MHz): δ –115.93– –116.15 (m). HRMS (ESIꢀ
TOF) m / z calcd for C24H24BFN2O ([M]+) 386.1970, found
386.1966.
2-(3-butyl-1-methyl-1H-isochromen-4-yl)-4,4,5,5-
tetramethyl-1,3,2-dioxaborolane (14b): Prepared according to
a literature procedure from compound 11b.9 Compound 11b
was prepared according to general procedure E. In a N2ꢀfilled
glovebox, pinacol (70.9 mg, 0.600 mmol, 3.0 equiv) was disꢀ
solved into Et3N (0.42 mL, 3.0 mmol, 15 equiv), and the reꢀ
sulting solution was transferred to 11b. The resulting reaction
solution was stirred in the glovebox for 1 h at 25 ˚C. Then, the
reaction vial was removed from the glovebox, and the solvent
was removed in vacuo. The resulting residue was purified by
flash chromatography (5% to 100% DCM in hexane) to afford
a yellow oil (22.3 mg, 34% yield). 1H NMR (CDCl3, 600
MHz): δ 7.65 (dd, J = 7.9, 1.1 Hz, 1H), 7.20 (td, J = 7.6,
1.4 Hz, 1H), 7.11 (td, J = 7.4, 1.2 Hz, 1H), 6.98 (d, J = 7.4 Hz,
1H), 5.09 (q, J = 6.5 Hz, 1H), 2.73–2.44 (m, 2H), 1.65–1.53
(m, 5H), 1.44–1.30 (m, 14H), 0.94 (t, J = 7.4 Hz, 3H).
13C{1H}NMR (CDCl3, 151 MHz): δ 169.0, 133.2, 132.0,
127.8, 125.5, 124.9, 122.9, 83.0, 74.0, 33.7, 30.9, 25.0, 22.7,
19.6, 14.1. 11B{1H}NMR (CDCl3, 193 MHz): δ 31.37.
2-(3-butyl-6-chloro-1-methyl-1H-isochromen-4-yl)-2,3-
dihydro-1H-naphtho[1,8-de][1,3,2]diazaborinine (12g): Preꢀ
pared according to general procedure E, and purified by flash
column chromatography (silica, 25% DCM in hexane) to afꢀ
1
ford a white solid (0.108 g, 67% yield). H NMR (CDCl3, 600
MHz): δ 7.17 (t, J = 7.8 Hz, 2H), 7.11 (dd, J = 7.0, 2.5 Hz,
4H), 6.96 (d, J = 8.4 Hz, 1H), 6.38 (d, J = 7.2 Hz, 2H), 5.83 (s,
2H), 5.17 (q, J = 6.5 Hz, 1H), 2.35 (tt, J = 9.9, 5.0 Hz, 2H),
1.79–1.52 (m, 5H), 1.39 (sext, J = 7.4 Hz, 2H), 0.94 (t, J = 7.3
Hz, 3H). 13C{1H}NMR (CDCl3, 151 MHz): δ 160.9, 141.2,
136.4, 135.1, 133.6, 130.2, 127.8, 125.7, 124.7, 123.7, 119.9,
118.1, 106.2, 73.3, 34.5, 30.2, 22.5, 19.9, 14.2. 11B{1H}NMR
(CDCl3, 193 MHz): δ 30.09. HRMS (ESIꢀTOF) m / z calcd for
C24H24BClN2O ([M]+) 402.1674, found 402.1677.
2-(3-butyl-1-isopropyl-1H-isochromen-4-yl)-2,3-dihydro-
1H-naphtho[1,8-de][1,3,2]diazaborinine (12h): Prepared acꢀ
cording to general procedure E, and purified by flash column
chromatography (silica, 25% DCM in hexane) to afford a
white solid (0.108 g, 67% yield). 1H NMR (CDCl3, 600 MHz):
δ 7.13–7.05 (m, 5H), 7.03 (d, J = 8.3 Hz, 2H), 6.93 (d, J = 7.3
Hz, 1H), 6.27 (d, J = 7.2 Hz, 2H), 5.74 (s, 2H), 4.76 (d, J = 6.6
Hz, 1H), 2.33 (td, J = 7.3, 4.1 Hz, 2H), 2.27–2.18 (m, 1H),
1.70–1.52 (m, 2H), 1.44–1.29 (m, 2H), 1.07 (d, J = 6.7 Hz,
3H), 0.97–0.83 (m, 6H). 13C{1H}NMR (CDCl3, 151 MHz): δ
159.4, 141.4, 136.4, 133.4, 129.4, 127.8, 127.7, 125.5, 125.3,
124.0, 119.9, 117.8, 106.0, 82.8, 34.7, 31.3, 30.2, 22.6, 19.4,
18.1, 14.1. 11B{1H}NMR (CDCl3, 193 MHz): δ 29.93. HRMS
(ESIꢀTOF) m / z calcd for C26H30BN2O ([M+H]+) 397.2456,
found 397.2425.
1-(2-(hex-1-yn-1-yl)phenyl)ethan-1-one (16): Prepared acꢀ
cording to general procedure D, and purified by flash column
chromatography (silica, 10% EtOAc in hexane) to afford a
1
brown oil (0.92 g, 92% yield). H NMR (CDCl3, 500 MHz): δ
7.68–7.62 (m, 1H), 7.48 (dd, J = 7.6, 1.4 Hz, 1H), 7.39 (td, J =
7.5, 1.5 Hz, 1H), 7.32 (td, J = 7.6, 1.4 Hz, 1H), 2.72 (s, 3H),
2.46 (t, J = 7.1 Hz, 2H), 1.66–1.56 (m, 2H), 1.54–1.43 (m,
2H), 0.95 (t, J = 7.3 Hz, 3H). 13C{1H}NMR (CDCl3, 151
MHz): δ 201.3, 141.2, 134.1, 131.2, 128.4, 127.7, 122.6, 97.0,
79.8, 30.7, 30.2, 22.2, 19.6, 13.8. HRMS (ESIꢀTOF) m / z
calcd for C14H16ONa ([M+Na]+) 223.1099, found 223.1096.
Structure elucidation. Oxyboration was performed acꢀ
cording to general procedure E, except the isolation portion in
the general procedure E was not conducted. Instead, after cyꢀ
clization, 1 M HCl(aq) (10 mL) was used to quench the reacꢀ
tion and to protodeborate the product in situ. Then, the organic
layer was washed with brine (1 × 15 mL), and all aqueous
layers were combined and extracted with EtOAc (3 × 5 mL).
The organic layers were combined. The combined organic
phases were then dried over MgSO4, and then filtered through
a Celite® plug (Celite® in a medium glass frit funnel), and the
filtrate was concentrated in vacuo to afford the crude product.
2-(3-phenyl-1H-isochromen-4-yl)-2,3-dihydro-1H-
naphtho[1,8-de][1,3,2]diazaborinine (12i): Prepared accordꢀ
ing to general procedure E, and purified by flash column
chromatography (silica, 10% EtOAc in hexane) to afford a
white solid (0.036 g, 24% yield). 1H NMR (CDCl3, 600 MHz):
δ 7.87–7.78 (m, 2H), 7.45 (dd, J = 7.6, 1.3 Hz, 1H), 7.42–7.36
(m, 3H), 7.35–26 (m, 3H), 7.25–7.15 (m, 2H), 7.13 (d, J = 8.2
Hz, 2H), 6.31 (d, J = 7.1 Hz, 2H), 5.83 (s, 2H), 5.29 (s, 2H).
13C{1H}NMR (CDCl3, 151 MHz): δ 157.9, 141.1, 136.4,
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 17
1
An H NMR spectrum of the crude reaction mixture showed
only one regioisomer of product. The crude product was then
purified by flash column chromatography (15% EtOAc in
(5 mL). The resulting organic layer was washed with brine
1
2
3
4
5
6
7
8
(5 mL). Then, the aqueous layer was extracted with EtOAc (3
× 5 mL), followed by combining all organic layers. The comꢀ
bined organic layers were then dried over MgSO4, and then
filtered through a Celite® plug (Celite® in an M glass frit funꢀ
nel), and the filtrate was concentrated in vacuo to afford the
crude product, which was then purified by flash column chroꢀ
matography (silica, 25% DCM in hexane) to afford a white
solid (0.100 g, 68% yield). 1H NMR spectroscopic data
matched that previously obtained from 12b (see above).
hexane) to afford
a light yellow oil (0.041 g, 50%).
1H NMR (CDCl3, 500 MHz): δ 7.17 (td, J = 7.4, 1.3 Hz, 1H),
7.11 (td, J = 7.5, 1.4 Hz, 1H), 6.99 (d, J = 7.3 Hz, 1H), 6.92
(dd, J = 7.4, 1.3 Hz, 1H), 5.61 (s, 1H), 5.20 (q, J = 6.5 Hz,
1H), 2.18 (t, J = 7.5 Hz, 2H), 1.81–1.49 (m, 5H), 1.46–1.34
(m, 2H), 0.94 (t, J = 7.3 Hz, 3H). 13C{1H}NMR (CDCl3,
126 MHz): δ 157.2, 131.8, 131.4, 127.8, 125.8, 123.3, 122.7,
100.3, 74.1, 33.7, 29.2, 22.5, 19.9, 14.1. This spectrum was in
agreement with previously reported spectral data for 15 by a
different laboratory.10
9
5-propyl-4-(p-tolyl)-2,3-dihydrofuran (22) Compound 3a
was prepared according to the procedure described above,
except for the isolation step, and stored in a vial in d8ꢀtoluene
inside the N2ꢀfilled glovebox without purification. The conꢀ
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
For further analysis, likely compound 15 (or perhaps 17)
(0.0408 g, 0.200 mmol, 1.0 equiv) made in the previous step
was dissolved in DCM (2.5 mL, 0.08 M) in a one dram vial
with a stir bar, and the resulting solution was cooled to –78 ˚C.
Then, O3 was passed through the cooled solution until the soꢀ
lution became dark blue (ca. 5 min.). To the resulting dark
blue solution, a solution of PPh3 (0.0682 g, 0.260 mmol,
1.3 equiv) in DCM (0.7 mL, 0.4 M) as a quench was added
dropwise at –78 ˚C, and the resulting solution was stirred at 25
˚C for 3 h. Then, the solvent was removed in vacuo, and the
resulting residue was purified by flash column chromatogꢀ
raphy (5% EtOAc in hexane) to afford a transparent oil
1
centration of the solution of 3a was calculated by H NMR
spectroscopy using an internal standard. Phenanthrene as inꢀ
ternal standard (4.5 mg, 0.025 mmol) was dissolved in d8ꢀ
toluene (0.4 mL) in a 1ꢀdram vial. To this solution was added
a small aliquot of 3a in d8ꢀtoluene (10. ꢁL) using gasꢀtight
syringe. The mixture was then transferred to a J. Young tube
and removed from glovebox. The concentration of the stock
solution of 3a was calculated based on the integration ratio
between the known phenanthrene and the unknown stock soluꢀ
1
tion using H NMR spectroscopy. This solution was used in
the next step.
1
(0.022 g, 47%). H NMR (CDCl3, 500 MHz): δ 10.27 (s, 1H),
The crossꢀcoupling procedure was adapted from a literature
procedure.50 In a N2ꢀfilled glovebox, to a oneꢀdram vial (“reacꢀ
tion vial”) containing 4ꢀiodotoluene (43.6 mg, 0.200 mmol,
1.0 equiv) was added CsOH•H2O (100.8 mg, 0.6002 mmol,
3.0 equiv) and 3a from the stock solution above (0.240 mmol,
1.2 equiv) via gasꢀtight syringe. XPHOSꢀPdꢀG3 (6.8 mg,
0.0080 mmol, 0.040 equiv) was dissolved in THF (0.1 mL)
and transferred via pipet to the reaction vial. The vial containꢀ
ing the Pd catalyst was rinsed with THF (0.1 mL) and the rinse
was also added via pipet to the reaction vial. A stir bar was
added to the reaction vial. The vial was capped and the soluꢀ
tion was stirred at 25 °C for 2.5 d. Then the reaction vial was
removed from glovebox and solution was diluted with Et2O (1
mL). The reaction mixtued was filtered through a pad of
Celite®. The reaction vial and the Celite® were rinsed with
Et2O (2 mL). The filtrate was concentrated in vacuo, and puriꢀ
fied by flash chromatography (30% DCM in hexane) to afford
a colorless oil (31 mg, 77% yield). TLC (40% DCM/hexanes):
Rf = 0.53, visualized by UV absorbance. 1H NMR (CDCl3, 500
MHz): δ 7.13 (m, 4H), 4.34 (t, J = 9.0 Hz, 2H), 3.00 (t, J = 9.0
Hz, 2H), 2.36 (t, J = 8.0 Hz, 2H), 2.33 (s, 3H), 1.62 (sext, J =
7.5 Hz, 2H), 0.96 (t, J = 7.5 Hz, 3H). 13C{1H}NMR (CDCl3,
125 MHz): δ 154.1, 134.9, 133.4, 129.1, 126.3, 108.2, 68.0,
34.2, 29.3, 21.2, 20.7, 14.1. HRMS (CIꢀTOF) m/z calcd for
C14H18O ([M]+) 202.1358, found 202.1355.
7.90–7.76 (m, 1H), 7.66–7.54 (m, 2H), 7.46 (ddd, J = 7.4, 6.1,
2.5 Hz, 1H), 6.67 (q, J = 6.6 Hz, 1H), 2.35 (td, J = 7.6, 3.6 Hz,
2H), 1.77–1.49 (m, 5H), 1.44–1.29 (m, 2H), 0.91 (t, J = 7.4
Hz, 3H). 13C{1H}NMR (CDCl3, 126 MHz): δ 192.5, 172.9,
144.8, 134.2, 133.1, 132.7, 128.0, 126.1, 68.7, 34.4, 27.1,
22.9, 22.4, 13.8. HRMS (ESIꢀTOF) m / z calcd for
C14H18O3Na ([M+Na]+) 257.1154, found 257.1154. These
1
spectra indicated the product to be 18, and H NMR spectral
information of both the crude and purified fractions did not
match previously reported spectra of 1911 or 2012. It was conꢀ
cluded that the only product was 18.
HydroborationꢀOxyboration. In a N2ꢀfilled glovebox, to a
oneꢀdram vial containing 16 (0.0801 g, 0.400 mmol, 1.0
equiv) was added HBcat (85.2 µL, 0.800 mmol, 2.0 equiv) and
a stir bar. The walls of the vial were rinsed with 0.05 mL toluꢀ
ene, and the vial was capped. Then, the resulting solution was
heated at 50 ˚C for 5.0 h with stirring. Then, the resulting
solution was concentrated under high vacuum (ca. 10 mTorr)
for 1.5 h at 25 ˚C in the glovebox. This process completed the
hydroboration step.
In a separate oneꢀdram vial in the glovebox, IPrAuTFA (7.0
mg, 0.010 mmol, 2.5 mol %) was dissolved into 0.4 mL toluꢀ
ene, and the resulting catalyst solution was transferred into the
substrate vial containing the hydroboration product, and a stir
bar was added. The reaction vial was then capped. The reacꢀ
tion mixture was heated to 100 ˚C with stirring for 4 h. This
process completed the oxyboration step.
5-(2-propyl-4,5-dihydrofuran-3-yl)benzo[d][1,3]dioxole
(24): Compound 3a was prepared according to the procedure
described above, except for the isolation step, and stored in a
vial in d8ꢀtoluene inside the N2ꢀfilled glovebox without purifiꢀ
cation. The concentration of the solution of 3a was calculated
by 1H NMR spectroscopy using an internal standard. Phenanꢀ
threne as internal standard (4.5 mg, 0.025 mmol) was disꢀ
solved in d8ꢀtoluene (0.4 mL) in a 1ꢀdram vial. To this solution
was added a small aliquot of 3a in d8ꢀtoluene (10. ꢁL) using
gasꢀtight syringe. The mixture was then transferred to a J.
Young tube and removed from glovebox. The concentration of
the stock solution of 3a was calculated based on the integraꢀ
tion ratio between the known phenanthrene and the unknown
In order to replace Bcat with Bdan, the resulting solution
was cooled to 25 ˚C, followed by addition of 1,8ꢀ
diaminonaphthalene (126 mg, 0.800 mmol, 2.0 equiv) and
Et3N (0.84 mL, 6.0 mmol, 15 equiv). The vial used for
weighting 1,8ꢀdiaminonaphthalene was rinsed with 0.20 mL
toluene, and the rinse was combined with the reaction soluꢀ
tion. The reaction vial was capped again, and the reaction was
stirred at 25 ˚C for 18 h. Once the exchange reaction was
done, the reaction vial was removed from the glovebox, and
the reaction mixture was quenched with saturated NH4Cl(aq)
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The Journal of Organic Chemistry
1
stock solution using H NMR spectroscopy. This solution was
used in the next step.
113.7, 73.6, 31.3, 29.7, 26.8, 22.5, 19.9, 14.0. HRMS (ESIꢀ
TOF) m / z calcd for C22H24O2Na ([M+Na]+) 343.1674, found
343.1671.
1
2
3
4
5
6
7
8
9
The crossꢀcoupling procedure was adapted from a literature
procedure.50 In a N2ꢀfilled glovebox, to a oneꢀdram vial (“reacꢀ
tion vial”) containing 23 (49.6 mg, 0.200 mmol, 1.0 equiv)
was added CsOH•H2O (100.8 mg, 0.6002 mmol, 3.0 equiv)
and 3a from the stock solution above (0.240 mmol, 1.2 equiv)
via gasꢀtight syringe. XPHOSꢀPdꢀG3 (6.8 mg, 0.0080 mmol,
0.040 equiv) was dissolved in THF (0.1 mL) and transferred
via pipet to the reaction vial. The vial containing the Pd cataꢀ
lyst was rinsed with THF (0.1 mL) and the rinse was also addꢀ
ed via pipet to the reaction vial. A stir bar was added to the
reaction vial. The vial was capped and the solution was stirred
at 25 °C for 2.5 d. Then the reaction vial was removed from
glovebox and solution was diluted with Et2O (1 mL). The reꢀ
action mixture was filtered through a pad of Celite®. The reacꢀ
tion vial and the Celite® were rinsed with Et2O (2 mL). The
filtrate was concentrated in vacuo and purified by flash chroꢀ
matography (30% DCM in hexane) to afford a colorless oil
(26 mg, 56% yield). TLC (40% DCM/hexanes): Rf = 0.45,
A mixture of (6ꢀiodoꢀ2,3ꢀdimethoxyphenyl)methanol (SIꢀ
11) and (5ꢀiodoꢀ2,3ꢀdimethoxyphenyl)methanol (SIꢀ11′) was
prepared according to a modified literature procedure.13,14 In a
flameꢀdried 250 mL round bottom flask, 2,3ꢀdimethoxybenzyl
alcohol 27 (0.389 g, 2.30 mmol, 1.0 equiv) and AgTFA (0.508
g, 2.30 mmol, 1.0 equiv) were dissolved in dry CHCl3 (8 mL)
under N2 on a Schlenk line. To the resulting solution, a soluꢀ
tion of I2 (0.584 g, 2.30 mmol, 1.0 equiv) in 40 mL dry CHCl3
was added dropwise under N2. The resulting mixture was
stirred at 25 ˚C under N2 for 18 h. Then, the reaction mixture
was filtered through a Celite® plug (Celite® in an M glass frit
funnel), and the filtration cake was rinsed with DCM (3 × 10
mL). Then, all organic solutions were combined, and washed
with saturated NaHCO3(aq) (1 × 10 mL) and brine (1 × 10
mL). Then the combined organic layers were then dried over
MgSO4, and then filtered through a Celite® plug (Celite® in an
M glass frit funnel), and the filtrate was concentrated in vacuo.
The resulting residue was purified by flash column chromatogꢀ
raphy (silica, 25% EtOAc in hexane) to afford a white solid
(0.387 g, 57% yield). The products obtained were a mixture of
major product, (6ꢀiodoꢀ2,3ꢀdimethoxyphenyl)methanol (SIꢀ
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
visualized by UV absorbance. H NMR (CDCl3, 500 MHz): δ
6.78 (d, J = 8.0 Hz, 1H), 6.74 (d, J = 1.5 Hz, 1H), 6.68 (dd, J =
8.0, 1.5 Hz, 1H), 5.94 (s, 2H), 4.32 (t, J = 9.5 Hz, 2H), 2.96 (t,
J = 9.5 Hz, 2H), 2.33 (t, J = 7.5 Hz, 2H), 1.60 (sext, J =
7.5 Hz, 2H), 0.96 (t, J = 7.5 Hz, 3H). 13C{1H}NMR (CDCl3,
125 MHz): δ 154.1, 134.9, 133.4, 129.1, 126.3, 108.2, 68.0,
34.2, 29.3, 21.2, 20.7, 14.1. HRMS (ESIꢀTOF) m/z calcd for
C14H17O3 ([M+H]+) 233.1178, found 233.1181.
11),
and
minor
product
(5ꢀiodoꢀ2,3ꢀ
dimethoxyphenyl)methanol (SIꢀ11′). The ratio SIꢀ11:SIꢀ11′
1
was 2:1 according to H NMR spectroscopy. For the major
1
product, H NMR (CDCl3, 500 MHz): δ 7.53 (d, J = 8.7 Hz,
1H), 6.65 (d, J = 8.7 Hz, 1H), 4.81 (d, J = 6.9 Hz, 2H), 3.86–
3.83 (m, 6H), 2.29 (t, J = 6.4 Hz, 1H). For the minor product,
1H NMR (CDCl3, 500 MHz): δ 7.33–7.27 (m, 1H), 7.15 (d, J =
2.1 Hz, 1H), 4.64 (d, J = 6.9 Hz, 2H), 3.94–3.88 (m, 6H), 2.07
(t, J = 6.4 Hz, 1H). These spectra are in agreement with previꢀ
ously reported spectral data.13
1-(4-(3-butyl-1-methyl-1H-isochromen-4-yl)phenyl)ethan-1-
one (26): First, intermediate 11b was prepared according to
general procedure E from 9b (0.040 g, 0.20 mmol, 1.0 equiv)
(with the exception that no isolation was performed). Instead
of isolation, once 11b was prepared in the glovebox, the reacꢀ
tion solution was cooled to 25 ˚C and transferred into a one
dram vial (“reaction vial”) containing Pd(PPh3)4 (23.1 mg,
0.0200 mmol, 10. mol %), Cs2CO3 (0.196 g, 0.600 mmol, 3.0
equiv), and a stir bar. Compound 1ꢀ(4ꢀiodophenyl)ethanꢀ1ꢀone
25 (0.591 g, 0.240 mmol, 1.2 equiv) was dissolved in 0.15 mL
toluene, and the resulting solution was transferred to the reacꢀ
tion vial. Then, the vials for 11b and 25 were each rinsed with
0.5 mL toluene, and all the rinses were combined into the reꢀ
action vial. The reaction vial was capped with a cap with a
septum and sealed with black tape before it was taken out
from the glovebox. Outside the glovebox, deionized water (4.0
µL, 0.22 mmol, 1.1 equiv) was quickly added via a 10 µL
airtight syringe, followed by hearting the resulting solution to
100 ˚C and stirred at this temperature vigorously (to ensure
mixing of the water droplet) for 24 h. Then, the reaction was
quenched with aqueous saturated NH4Cl (5 mL). The resulting
organic layer was washed with brine (5 mL). Then, the aqueꢀ
ous layer was extracted with EtOAc (3 × 5 mL), followed by
combining all organic layers. The combined organic layers
were then dried over MgSO4, and then filtered through a
Celite® plug (Celite® in an M glass frit funnel), and the filtrate
was concentrated in vacuo to afford the crude product, which
was then purified by flash column chromatography (silica, 4%
EtOAc in hexane) to afford a light yellow oil (0.042 g, 66%)
1H NMR (CDCl3, 600 MHz): δ 8.02 (d, J = 7.9 Hz, 2H), 7.36
(d, J = 7.9 Hz, 2H), 7.15 (t, J = 7.4 Hz, 1H), 7.12–7.05 (m,
2H), 6.53 (d, J = 7.7 Hz, 1H), 5.27 (q, J = 6.5 Hz, 1H), 2.66 (s,
3H), 2.14–2.03 (m, 2H), 1.67 (d, J = 6.5 Hz, 3H), 1.59–1.42
(m, 2H), 1.31–1.20 (m, 2H), 0.81 (t, J = 7.3 Hz, 3H).
13C{1H}NMR (CDCl3, 126 MHz): δ 198.0, 153.8, 142.9,
135.9, 132.4, 131.9, 131.7, 128.7, 127.7, 126.3, 123.2, 122.4,
A
Mixture
of
(2,3ꢀdimethoxyꢀ6ꢀ(propꢀ1ꢀynꢀ1ꢀ
yl)phenyl)methanol (28) and (2,3ꢀdimethoxyꢀ5ꢀ(propꢀ1ꢀynꢀ1ꢀ
yl)phenyl)methanol (28′) was prepared according to a modiꢀ
fied general procedure C: To a 100 mL flameꢀdried round
bottom flask, the mixture of SIꢀ11 and SIꢀ11′ (0.387 g,
1.30 mmol, 1.0 equiv), PdCl2(PPh3)2 (0.046 g, 0.066 mmol, 5.0
mol %) and CuI (0.025 g, 0.013 mmol, 10. mol %), Et3N (2.6
mL, 19. mmol, 2.0 equiv), and a stir bar were mixed under N2
on a Schlenk line, followed by cooling the resulting mixture to
0 ˚C. At 0 ˚C, propyne (2.6 mL of a 1.0 M THF solution, 2.6
mmol, 2.0 equiv) was added via a syringe under N2 on a
Schlenk line. The reaction mixture was warmed to 25 ˚C, and
stirred at 25 ˚C under N2 for 18 h. The reaction was quenched
with saturated NH4Cl(aq) (20 mL), and the resulting organic
layer was washed with brine (10 mL). The aqueous layer was
extracted with EtOAc (3 × 10 mL), and the combined organic
layers were dried over MgSO4, and then filtered through a
Celite® plug (Celite® in a medium glass frit funnel), and the
filtrate was concentrated in vacuo. The crude product was
purified by flash column chromatography (silica, 25% EtOAc
in hexane) to afford a brown solid (0.261 g, 97% yield). The
1
ratio 28:28′ was 2:1 according to H NMR spectroscopy. For
1
28, H NMR (CDCl3, 600 MHz): δ 7.15 (d, J = 8.5 Hz, 1H),
6.79 (d, J = 8.5 Hz, 1H), 4.85 (d, J = 6.9 Hz, 2H), 3.89–3.86
(m, 6H), 2.52 (t, J = 6.9 Hz, 1H), 2.07 (s, 3H). 13C NMR
(CDCl3, 126 MHz): δ 152.6, 136.2, 128.6, 124.1, 115.2, 111.8,
1
88.5, 77.2, 61.5, 59.2, 55.9, 4.6. For 28′, H NMR (CDCl3,
600 MHz): δ 6.99 (d, J = 1.9 Hz, 1H), 6.91 (d, J = 2.0 Hz,
1H), 4.64 (d, J = 6.4 Hz, 2H), 3.87–3.84 (m, 6H), 2.12–2.08
(m, 1H), 2.04 (s, 3H). 13C{1H}NMR (CDCl3, 126 MHz): δ
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The Journal of Organic Chemistry
Page 14 of 17
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Larsen, M. A.; Hartwig, J. F. IridiumꢀCatalyzed C–H Borylation
of Heteroarenes: Scope, Regioselectivity, Application to Lateꢀ
Stage Functionalization, and Mechanism. J. Am. Chem. Soc.
2014, 136, 4287–4299.
Hirner, J. J.; Faizi, D. J.; Blum, S. A. Alkoxyboration: Ringꢀ
Closing Addition of B–O σ Bonds across Alkynes. J. Am. Chem.
Soc. 2014, 136, 4740–4745.
Chong, E.; Blum, S. A. Aminoboration: Addition of B–N σ
Bonds across C–C π Bonds. J. Am. Chem. Soc. 2015, 137,
10144–10147.
Tu, K. N.; Hirner, J. J.; Blum, S. A. Oxyboration with and
without a Catalyst: Borylated Isoxazoles via B–O σꢀBond
Addition. Org. Lett. 2016, 18, 480–483.
Faizi, D. J.; Issaian, A.; Davis, A. J.; Blum, S. A. CatalystꢀFree
Synthesis of Borylated Lactones from Esters via Electrophilic
Oxyboration. J. Am. Chem. Soc. 2016, 138, 2126–2129.
Faizi, D. J.; Davis, A. J.; Meany, F. B.; Blum, S. A. Catalystꢀ
Free Formal Thioboration to Synthesize Borylated
Benzothiophenes and Dihydrothiophenes. Angew. Chem. Int.
Ed. 2016, 55, 14286–14290.
152.2, 146.9, 134.5, 119.8, 116.2, 111.8, 85.3, 79.4, 61.1,
59.2, 55.9, 4.5. HRMS (ESIꢀTOF) m / z calcd for C12H14O3Na
([M+Na]+) 229.0841, found 229.0841. This mixture was used
for the next step without further purification.
1
2
3
4
5
6
7
8
(4)
(5)
(6)
(7)
(8)
7,8-Dimethoxy-3-methylisochroman-4-one (29): First, inꢀ
termediate SIꢀ11 was prepared according to general procedure
E (see SI) to generate the mixture of 28 and 28′ (0.130 g,
0.400 mmol, 1.0 equiv) (with the exception that no isolation
was performed). Instead of isolation, once the mixture of 28
and 28′ was prepared, the reaction solution was cooled to 25
˚C and transferred into a 25 mL Schlenk tube in the glovebox.
A stir bar was also added into the Schlenk tube. Then, this
tube was sealed and taken out of the glovebox and attached to
a Schlenk line. In order to avoid decomposition of the delicate
Bcat product, it was kept under N2 on the Schlenk line until
0.82 mL NaOH (0.21 mL of a 3.0 M aqueous solution,
0.64 mmol, 1.6 equiv), and H2O2 (0.17 mL of a 30. wt % soluꢀ
tion in H2O, 0.64 mmol, 1.6 equiv) were then sequentially and
quickly added, and the resulting mixture was stirred at 25 ˚C
for 1.5 h. Once the reaction was done as determined by TLC
(ca. 15% EtOAc in hexane), it was quenched with saturated
NH4Cl(aq) (5 mL). The resulting organic layer was washed
with brine (5 mL). Then, the aqueous layer was extracted with
EtOAc (3 × 5 mL), followed by combining all organic layers.
The combined organic layers were then dried over MgSO4,
and then filtered through a Celite® plug (Celite® in an M glass
frit funnel), and the filtrate was concentrated in vacuo to afꢀ
ford the crude product, which was then purified by flash colꢀ
umn chromatography (silica, 15% EtOAc in hexane) to afford
a white solid (0.038 g, 64% yield based on the actual amount
of 28 present in the reaction, which was calculated based on
1H NMR spectroscopy of the starting material using the ration
9
10
11
12
13
14
15
16
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Issaian, A.; Tu, K. N.; Blum, S. A. Boron–Heteroatom Addition
Reactions via Borylative Heterocyclization: Oxyboration,
Aminoboration, and Thioboration. Acc. Chem. Res. 2017, 50,
2598–2609.
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Warner, A. J.; Lawson, J. R.; Fasano, V.; Ingleson, M. J.
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Formation of C(Sp
) Boronate Esters by Borylative
Cyclization of Alkynes Using BCl 3. Angew. Chem. Int. Ed.
2015, 54, 11245–11249.
Warner, A. J.; Churn, A.; McGough, J. S.; Ingleson, M. J. BCl3ꢀ
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Kikuchi, T.; Takagi, J.; Isou, H.; Ishiyama, T.; Miyaura, N.
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Kikuchi, T.; Takagi, J.; Ishiyama, T.; Miyaura, N. Iridiumꢀ
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1
of the two regioisomers). H NMR (CDCl3, 600 MHz): δ 7.84
(14)
(15)
(d, J = 8.7 Hz, 1H), 6.94 (d, J = 8.6 Hz, 1H), 5.13 (d,
J = 15.7 Hz, 1H), 4.80 (d, J = 15.7 Hz, 1H), 4.19 (qd, J = 6.7,
1.1 Hz, 1H), 3.94 (s, 3H), 3.84 (s, 3H), 1.50 (d, J = 6.7 Hz,
3H). 13C{1H}NMR (CDCl3, 126 MHz): δ 195.0, 157.0, 143.3,
124.2, 123.3, 111.3, 77.9, 77.4, 63.0, 56.0, 15.8, 7.9. HRMS
(ESIꢀTOF) m / z calcd for C12H14O4Na ([M+Na]+) 245.0790,
found 245.0788. The spectral information is in agreement with
previously reported spectral data.
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a Novel Series of Tricyclic Dihydrofuran
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Highly Potent and SubtypeꢀSelective PPARα Agonists with
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Freire, C. P. V.; Ferreira, S. B.; de Oliveira, N. S. M.; Matsuura,
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ASSOCIATED CONTENT
The Supporting Information is available free of charge on the
ACS Publications website at http://pubs.acs.org.
Optimization studies and experimental procedures for synthesis of
precursors, and 1H, 11B, 13C and 19F NMR spectra (PDF).
AUTHOR INFORMATION
(19)
(20)
Corresponding Author
* blums@uci.edu
ACKNOWLEDGMENT
We thank the National Science Foundation (CHEꢀ1665202) and
the University of California, Irvine (UCI), for funding. We thank
Mr. Darius Vrubliauskas (UCI) for assisting the ozonolysis.
(21)
(22)
Lipshutz, B. H. FiveꢀMembered Heteroaromatic Rings as
Intermediates in Organic Synthesis. Chem. Rev. 1986, 86, 795–
819.
Mancuso, R.; Mehta, S.; Gabriele, B.; Salerno, G.; Jenks, W. S.;
Larock, R. C. A Simple and Mild Synthesis of 1 H ꢀ
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Dihydroisobenzofurans by the Iodocyclization of 2ꢀ(1ꢀ
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The Journal of Organic Chemistry
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