Transition Metal-Free Trans Hydroboration of Alkynoic Acid Derivatives: Experimental and Theoretical Studies

Article abstract of DOI:10.1021/acs.joc.8b01493

We report a phosphine-catalyzed trans hydroboration of alkynoate esters and amides. The reaction proceeds under mild conditions with exclusive (E)-selectivity to afford (E)-β-boryl acrylates and (E)-β-boryl acrylamides in good to excellent yields. The reaction is tolerant of a variety of functional groups and allows efficient access to novel oxaboroles as well as a pargyline derivative (MAO inhibitor). Theoretical calculations suggest an internal hydride generates a phosphonium allenoxyborane followed by the formation of a key phosphonocyclobutene intermediate that collapses in a stereoselective, rate-limiting step.

Full text of DOI:10.1021/acs.joc.8b01493

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Article
Transition metal-free trans hydroboration of alkynoic
acid derivatives: Experimental and theoretical studies
Russell Fritzemeier, Ashley Gates, Xueying Guo, Zhenyang Lin, and Webster L Santos
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b01493 • Publication Date (Web): 09 Jul 2018
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The Journal of Organic Chemistry
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Transition metal-free trans hydroboration of alkynoic acid deriva-
tives: Experimental and theoretical studies
Russell Fritzemeier†, Ashley Gates†, Xueying Guo‡, Zhenyang Lin‡, Webster L. Santos†*
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†Department of Chemistry, Virginia Tech, Blacksburg, VA 24061, USA
‡Department of Chemistry, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong
SAR, China
Supporting Information Placeholder
O
pinB
• >30 examples
N
O
Et3P
H-Bpin
• trans products
• organocatalytic
• transition metal free
• DFT studies
H
O
R
H3CO
pinB
HO
X
pinB
R
O
X
B
O
rt, 1-4 h
N
X = OR, NR2
H
OCH3
H
F
H
ABSTRACT: We report a phosphine-catalyzed trans hydroboration of alkynoate esters and amides. The reaction proceeds under
mild conditions with exclusive (E) selectivity to afford (E)-β borylacrylates and (E)-β borylacrylamides in good to excellent yields.
The reaction is tolerant of a variety of functional groups and allows efficient access to novel oxaboroles as well as a pargyline de-
rivative (MAO inhibitor). Theoretical calculations suggest an internal hydride generate a phosphonium allenoxyborane followed by
the formation of
a key phosphonocyclobutene intermediate that collapses in a stereoselective, rate-limiting step.
Scheme 1. Approaches to trans hydroboration of alkynes
INTRODUCTION
Organoboron compounds are ubiquitous in organic chem-
istry due to the versatility of the C-B bond, as they efficiently
undergo a wide variety of useful transformations, most notably
the Suzuki-Miyaura cross-coupling reaction.1 Alkenyl-
boronates in particular are excellent substrates for such cross-
coupling reactions.2 Interest in organoboron compounds for
medicinal applications highlights their significance not only as
synthetic intermediates, but also as end products.3 Therefore,
development of novel methods is warranted.
A. metal-catalyzed trans
hydroborations of terminal alkynes
H
H
B
H-B, M cat.
R1
H
R1
M = Rh, Ru, Ir, Cu, Co
B. Ru-catalyzed trans
hydroborations of internal alkynes
H
R2
[Ru], pinB-H
R1
R2
R1
Bpin
C. Pd-catalyzed trans
hydroboration of enynes
Synthesis of alkenylboronates is typically achieved
through the hydroboration of alkynes; however, addition oc-
curs almost exclusively in a cis fashion.4 Overcoming classical
cis addition has proven to be somewhat challenging. The trans
hydroboration of terminal alkynes has seen varying degrees of
success with examples reported using Rh,5 Ru,6 Ir,5 Cu,7 and
Co8 catalysts as well as one report of a transition metal-free
borenium cation-mediated reaction (Scheme 1A).9 Examples
of trans hydroboration of internal alkynes are even more lim-
ited. For example, Fürstner reported an elegant cationic Ru-
catalyzed trans hydroboration of alkynes (Scheme 1B).10 DFT
studies suggested the formation of a key ruthenium metallacy-
clopropene intermediate in the mechanism.11 Further, a stere-
oselective trans hydroboration of 1,3-enynes enabled by 1,4-
azaborine-based phosphine-Pd complexed was demonstrated,12
which was supported by DFT studies (Scheme 1C).13 Finally,
Au-catalyzed trans hydroboration of propargylamines to form
cyclic aminoboranes has been described by Shi and co-
workers (Scheme 1D).14 Unfortunately, transition-metal free
trans hydroboration of internal alkynes examples are severely
lacking. A few examples of transition metal-free
H
R1
R3
R1
R2
1. [Pd], catB-H
Bpin
2. pinacol
R3
R2
D. Au-catalyzed trans
hydroboration of propargylamines
R2
R2
H
1. NaBH3CN
R3
N
H
R3
N
H
B
R1
R1
2. Au cat.
CN
H
E. metal-free trans
hydroboration of internal alkynes
H
R
9-BBN
R
N
N
B
F. this work
nBu
3P cat.
O
O
rt, 1 h
R
X
pinB
R
X
O
H
B
H
X = OR, NR2
O
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The Journal of Organic Chemistry
Scheme 2. Hydroboration of alkynoate estersa
Page 2 of 10
Table 1. Optimization of reaction conditionsa
1
2
3
4
5
6
7
8
O
O
R2
O
O
nBu
catalyst (0.1 equiv)
3P (0.1 equiv)
O
pinB
R2
pinB
R1
OCH3
O
+
pinB-H
neat or solvent
OCH3
neat or solvent
rt, 1 h
+
pinB-H
R1
O
H
rt, 1 h
H
1
2
1a
2a
O
pinB
O
pinB
pinB
entry
solvent
neat
catalyst
PBu3
-
% yieldb
88 (87)c
H3C
OCH3
OCH3
OCH3
H
H
1
2
H
H
H3C
2a,
87%
2b
, 87%
2c
, 81%
neat
0
59
74
0
9
O
pinB
O
O
3
THF
neat
Cy3P
PEt3
pinB
pinB
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
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27
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30
31
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42
43
44
45
46
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49
50
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53
54
55
56
57
58
59
60
OCH3
OCH3
OCH3
4
H
H
H
H3CO
OCH3
2d
, 86%
5
THF
neat
PPh3
2f
, 85%
2e
, 75%
6
P(OEt)3
P(t-Bu)3
PBu3
PBu3
PBu3
trace
0
O
O
pinB
pinB
Cl
O
pinB
Cl
OCH3
OCH3
7
neat
OCH3
H
H
H
Cl
8
THF
MeCN
toluene
86
80
84
b,d
2i
, 32%
2g
, 66%
2h
, 67%
O
pinB
9
O
O
F
O
pinB
pinB
OCH3
OCH3
OCH3
OCH3
10
H
H
H
F3C
F
d
2l
, 36%
2j
, 61%
2k
, 58%
11
12
THF
THF
IMes
ICy
0
0
O
pinB
H3C
O
pinB
pinB
OEt
H3C
OCH3
, 73% (84:16 E:Z)
H
H
H
(68:32 E:Z)c
b
c
c
a
2n
, 70%
pinB
2m
2o
, 54% (77:23 E:Z)
General procedure: methyl 3-phenylpropiolate (0.34 mmol)
and pinacolborane (0.37 mmol), followed by catalyst (0.034
mmol) at rt under nitrogen for 1 h. b NMR yields. c Isolated yield.
IMes = 1,3-bis(2,4,6-trimethylphenyl)-imidazolium; ICy = 1,3-
Dicyclohexylbenzimidazolium
O
pinB
O
O
pinB
OCH3
d (62:38 E:Z)c
OCH3
OCH3
H
H
H
,
Ph
2p
, 27%
2r 69%
89%, 2 h
2q,
O
O
pinB
pinB
O
trans diborations15, silaborations,15a, 16 and carboborations17 of
alkynes have been reported, but the corresponding hydrobora-
tions have remained elusive.18 Interestingly, the trans hydrob-
oration of internal alkynes can be effected using a pyridyl di-
recting group (Scheme 1E).19 Theoretical calculations supports
initial coordination of the pyridyl nitrogen to boron followed
by a hydride migration. The corresponding vinyl anion inter-
mediate promotes boryl transfer allowing formation of the
lower energy trans product.19
pinB
H3C
N
OCH3
OCH3
OCH3
H
H
H
N
,
2s,
65%
2t
60%
2u
, 38%
O
O
CH3
CH3
pinB
O
pinB
pinB
CH3
O
O
O
O
O
H
H
, 81%
H
2w
2x
, 82%
2v
, 87%
O
pinB
O
pinB
O
O
H
H
2z
The scarcity of transition metal-free trans hydroborations
and the limited substrate scope of known reactions demon-
strates the necessity for new methods. Furthermore, new pro-
tocols that utilize commercially available reagents such as
pinacolborane would be advantageous and desirable. Inspired
2y
, 86%
, 79%
a
General procedure: alkyne (1 equiv) and pinacolborane (1.1
equiv) followed by PBu3 (0.1 equiv) at rt under nitrogen for 1
hour unless otherwise indicated. Isolated yields shown. b 0.3 equiv
of PBu3.c Determined by GC. >99:1 E:Z selectivity unless stated
otherwise. d Incomplete conversion.
17a,
b
by previous phosphine-catalyzed addition to alkynes,15a,
we hypothesized that phosphine may be able to catalyze the
trans addition of pinacolborane to alkynoate esters. Herein, we
describe experimental and theoretical studies of this reaction
employing pinacolborane and catalytic amounts of trial-
kylphosphine (Scheme 1F). The atom efficient protocol pro-
ceeds with excellent regio- and stereoselectively in good to
excellent yields under mild conditions either neat or in the
presence of solvent.
(entries 3 and 4), albeit in lower yields. Unfortunately, tri-
phenylphosphine was unable to mediate the reaction, and none
of the desired product was observed (entry 5). Furthermore, no
borylated material was observed with triethylphosphite or tri-
tert-butylphosphine as the catalysts (entries 6 and 7). To inves-
tigate solvent effects, the reaction was performed in THF,
acetonitrile, and toluene and minimal reduction in yield as
determined (entries 8-10). In certain cases, solvent is useful in
dissolving both the starting material and catalyst (vide infra).
N-heterocyclic carbenes (NHCs) were inefficient as catalysts
(entries 11 and 12). Based on the catalyst screen, tri-n-
butylphosphine was deemed as the optimal additive (entry 1).
Confirmation of the (E)-stereoselectivity was performed with
2D-NOESY experiments. In addition, 11B NMR studies
showed a single peak at 30.1 ppm, suggesting the lack of in-
ternal coordination between boron and the carbonyl oxygen
RESULTS AND DISCUSSION
Upon initiating our studies, we were pleased to find that
addition of pinacolborane and 10 mol % tri-n-butylphosphine
to methyl 3-phenylpropiolate (1a) under neat conditions pro-
duced the corresponding (E)-borylcinnamate 2a in excellent
yield in an hour at room temperature (entry 1, Table 1). In the
absence of phosphine catalyst, no reaction was observed.20 In
addition, we found that tricyclohexylphosphine and tri-
ethylphosphine catalyzed the hydroboration reaction as well
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Scheme 3. Hydroboration of alkynamidesa
The Journal of Organic Chemistry
Scheme 4. Hydroboration of MAO inhibitor derivative
1
2
3
4
5
6
7
8
O
O
O
nBu
CH3
N
O
3P (0.5 equiv)
pinB
CH3
N
Cl
OCH3
OCH3
NR2
+
NR2
pinB-H
THF
BuLi
5
R
R
60 °C, 4 h
H
6
, 70%
pargyline
MAO inhibitor
4
3
pinB
H
H3C
pinB
O
nBu
3P (0.2 equiv)
N
O
OCH3
43% (86:14 E:Z)
O
pinB
pinB
O
pinB
THF, rt, 2 h
H
CH3
N
N
N
7,
H
H
CH3
H
H3C
Scheme 5. Synthesis of 2(5H)-oxaborolesa
4b
, 48%
4c
4a,
, 54%
46%
9
O
O
O
pinB
pinB
pinB
HO
B
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
O
(2 equiv)
O
H
NaBH4
CH3
OCH3
N
N
pinB
Ar
N
H
H
H
H
Ar
EtOH, rt, 30 min
H3CO
Cl
H
4f
, NR
4e,
46%
4d
, 53%
2
8
a
General procedure: alkynamide (1 equiv) and pinacolborane
(1.1 equiv), followed by tri-tert-butylphosphine (0.5 equiv) at 60
°C. Isolated yields shown. NR = no reaction.
HO
HO
B
HO
O
H
HO
B
O
O
H
B
O
B
H
H
H3CO
F
Cl
(see Supporting Information) in contrast to amides (vide in-
fra).
8a
, 77%
8d
, 70%
8b
, 77%
8c
, 80%
a General procedure: borylacrylate 2 (1 equiv) dissolved in EtOH
followed by NaBH4 (2 equiv) at rt for 30 min. Isolated yields
shown.
With optimized conditions (10 mol % tributylphosphine) in
hand, we evaluated the substrate scope with a variety of al-
kynoate esters 1a-1z (Scheme 2). Alkyl substitutions on aryl
rings were tolerated on various positions to afford products
2b-2d in excellent yields. Electron releasing substituents such
as a methoxy group were well tolerated (2e-2f). Furthermore,
alkynoates substituted with electron withdrawing substituents
on the phenyl ring such as chlorine, fluorine and trifluorome-
thyl groups (2g – 2l) were also able to undergo reaction, albeit
in slightly reduced yields. In addition, 3-alkyl substituted pro-
piolates were efficient substrates. Products bearing linear al-
kanes (2m-n) as well as cycloalkanes (2o-2q) were afforded in
good yields, although reduced stereoselectivity was observed
in 2m-2p. Regioselective addition of Bpin to the β vs the γ
carbon occurred in 2q. Moreover, other aryl functional units
served as good substrates. Biphenyl, naphthyl, quinolyl, indol-
yl, and benzodioxolyl groups (1r-1v) were transformed to the
desired alkenylboronic ester products in up to 87% yield. Sev-
eral attempts to hydroborate methyl propiolate were per-
formed, but no reaction was observed. To investigate the ef-
fect of the ester moiety, isopropyl and benzyl propiolates were
subjected to the reaction condition, which afforded 2w-2x in
excellent yield. Notably, in the presence of competing alkene
(1y) or alkyne (1z) substituents, chemoselective hydroboration
proceeded with the internal alkyne in excellent yield.
Scheme 6. Mechanistic studies
pinB
D
O
pinB
nBu
3P (0.1 equiv)
OCH3
rt, 1 h
(80% D incorporation)
D
9
2a
D
O
pinB
H
OCH3
1. nBu3P (0.1 equiv)
(observed by GC/MS)
H
rt, 15 min
2. MeOD
10
Treatment of 5 with methylchloroformate and butyllithium
afforded the requisite alkynamide 6. We were pleased to find
that the amine-bearing 6 was converted to the corresponding
borylated pargyline derivative 7 in 43% yield. Next, we sought
to demonstrate the utility of these substrates to the synthesis of
novel oxaboroles. Oxaboroles have recently gained much at-
tention, largely due to the success of the FDA approved drugs
Crisaborole (Eucrisa)22 and Tavaborole (Kerydin).23 Previous
methods to synthesize 2(5H)-oxaboroles required propargyl
alcohols, the products of which have non-H substitutions on
the 5-position.15b, 17c, 24 We observed that the ester substrates
underwent efficient reduction to the corresponding 3-
monosubstituted 2(5H)-oxaboroles 8a–8d in excellent yields
(Scheme 5). Reduction of (E)-β-borylacrylate products repre-
sents an efficient route to previously elusive oxaborole struc-
tures, which may prove to have unique biological activity.
In addition to esters, we were pleased to discover that ter-
tiary alkynamides were able to undergo hydroboration, albeit
higher catalyst load and higher temperature were required
(Scheme 3). For example, pyrrolidine (3a) and dimethylamine
(3b) derivatives were hydroborated in good yield. Consistent
with our previous studies,15c boron-oxygen coordination is
suggested by the presence of a single peak at ~14 ppm in the
11B NMR spectra, a chemical shift characteristic of quater-
nized neutral boron (see Supporting Information for details).
Arylalkynamides 3c-3e bearing electron donating as well as
electron withdrawing groups underwent the transformation in
~50% yield. Finally, no hydroboration product was observed
in the case of the corresponding N-methyl secondary amide
derivative (4f).
To gain insight into the mechanism of the trans hydrobora-
tion reaction, we performed deuterium labeling experiments
(Scheme 6). Treatment of 2a with deuteropinacolborane af-
forded deuterated product 9, suggesting pinacolborane is the
source of hydrogen. Interestingly, if the reaction is quenched
in deuterated methanol prior to completion, we observed for-
mation of deuterated methyl cinnamate 10 suggesting that 9
can also undergo deuterodeboration.
To establish a complete catalytic cycle, we also carried out
density functional theory (DFT) calculations (Scheme 7) (see
Supporting Information for the computational details). Figure
1 shows the energy profile calculated for the feasible reaction
To demonstrate the utility of the developed reaction condi-
tions, we applied the hydroboration reaction to the monoamine
oxidase (MAO) inhibitor pargyline (5, Scheme 4).21
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Page 4 of 10
mechanism. In light of previous reports demonstrating β- state corresponds to the ring expansion from a four-membered
addition of trialkylphosphines to acetylenic esters,25 we sur-
mised that PMe3 first nucleophilically attacks the β-carbon of
the unsaturated ester 1 to form A, followed by addition of the
Lewis acid pinacolborane to the terminal oxygen of A to give
B. Hydride migration to the α-carbon can proceed to generate
intermediate C, which is supported by experimental deuter-
ation studies (Scheme 7). C has a resonance structure C-a with
a single bond between the α-carbon and the ester group that
allows rotation along the single bond to facilitate a new phos-
phorous-carbon bond formation and achieve a four-membered
ring phosphono-cyclobutene intermediate D. As the boron
center in D is Lewis acidic, migration of the phosphorus-
carbon bond to form a new boron-β-carbon bond results in a
high energy transition state to afford E. The release of PMe3
generates an internally coordinated intermediate F, which
leads to the trans hydroboration product 2.
ring D towards a more stable five-membered ring E forming
the β-carbon-boron bond. This is the step that also governs the
stereoselectivity of the reaction.
1
2
3
4
5
6
7
8
Scheme 7. Proposed Catalytic Cycles
O
pinB
R
OR1
O
pinB
R
H
2
OR1
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
H
F
O
OR1
R
PMe3
1
O
pinB
OR1
O
pinB
Me3P
O
R
R
Me3P
PMe3
OR1
In another possibility, a resonance structure of C in C-b
can allow the attack a negatively charged β−carbon to a Lewis
acidic boron center to yield five-membered ring E1 (Scheme
7). However, to achieve this, the π−bond between α−carbon
and the ester group in C-b must be broken through rotation to
form the trans-intermediate D1. Many attempts to locate the
transition state of this rotation were not successful, and all
attempted calculations led to transition state TSC-D, linking
intermediates C and D.
H
R
OR1
A
H
E
E1
pinB
H
Path II
Path I
pinB
Me3P
O
pinB
H
pinB
O
OR1
O
OR1
R
H
R
OR1
H
D1
PMe3
Me3P
R
B
D
A possible pathway that leads to D1 can occur through D.
The cyclization affords E1 (Path II, marked in blue), which
allows the release of PMe3 to generate F, a common interme-
diate with Path I. Our calculations indicate that Path II is less
favorable than Path I (Figure 1). According to the energy pro-
files, the overall reaction free energy barrier of Path II (the
energy difference between C and TSD-D1) is 1.8 kcal/mol less
favored than Path I, which is 30.5 kcal/mol (the energy differ-
ence between C and TSD-E). The rate-determining transition
pinB
H
O
OR1
pinB
H
pinB
O
PMe3
O
R
H
OR1
OR1
C
R
R
PMe3
C-a
PMe3
C-b
Bpin
MeO
pinB
O
O
O
H
pinB
H
H
O
OMe
OMe
pinB
Ph
O
PMe3
TSD-D1
OMe
Ph
H
Ph
OMe
Path I
Ph
Me3P
PMe3
TSB-C
Me3P
pinB
TS1-A
PMe3
TSD-E
Path II
Ph
O
TSA-B
OMe
H
23.5
22.4
14.3
20.9
(10.7)
(-6.3)
(-16.1)
(-8.0)
PMe3
TSC-D
Ph
pinB
H
PMe3
12.7
12.5
pinB
11.3
10.7
(-2.5)
O
Ph
(-17.8)
(-17.9)
(-18.7)
O
OMe
Ph
Me3P
Ph
Bpin
O
pinB
Bpin
Me3P
Ph
H
O
1.9
PMe3
TSE-F
O
0.0
(0.0)
H
Me3P
OMe
(-28.9)
A
OMe
Ph
Me3P
pinB
O
OMe
TSE1-F
H
H
OMe
O
OMe
TSD1-E1
H
B
OMe
-17.9
Ph
(-48.5)
1a
PMe3
Ph
pinB
-18.0
-18.8
O
-17.6
D
(-48.6)
(-51.9)
H
(-48.4)
-22.0
OMe
PMe3
O
pinB
Ph
-25.3
PMe3
(-54.1)
(-57.1)
Me3P
H
Ph
Bpin
OMe
pinB
pinB
H
O
Ph
O
H
TSF-2
-32.5
O
C
H
(-65.3)
OMe
OMe
pinB
OMe
-39.0
-39.3
O
Ph
D1
(-57.6)
Ph
Ph
(-57.6)
PMe3
C-a
PMe3
C-b
-42.2
(-59.8)
OMe
PMe3
Bpin
O
Me3P
Ph
H
pinB
O
O
pinB
Ph
E
Ph
OMe
OMe
H
OMe
H
E1
H
2a
F
Figure 1. Energy profile calculated at B3LYP/6-31G** for the proposed mechanism of trans hydroboration of methyl 3-phenylpropiolate.
The solvation-corrected relative free energies and relative electronic energies (in parentheses) are given in kcal/mol.
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The Journal of Organic Chemistry
In conclusion, we have developed a novel protocol for the
1H), 7.42 (d, J = 8.5 Hz, 1H), 7.28 (d, J = 8.5 Hz, 1H), 7.09 (s,
1H), 6.49 (s, 1H), 3.82 (s, 3H), 3.79 (s, 3H); 13C NMR (100
MHz, CDCl3) δ 155.2, 130.6, 128.4, 127.5, 126.4, 109.8,
109.8, 102.0, 89.9, 79.2, 52.8, 33.2. HRMS: (ESI) m/z: [M +
H]+ calcd for C13H12NO2 214.0863; Found 214.0863.
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7
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hydroboration of alkynoate esters and amides under mild con-
ditions. The organocatalytic reaction proceeds in a chemose-
lective fashion and leads to trans hydroborated derivatives that
can be elaborated to a variety of products, including here-to-
fore inaccessible 3-monosubstituted 2(5H)-oxaboroles. The
detailed computational analysis of the proposed mechanism is
in agreement with experiment. Current efforts are directed
towards extending the method to borylations of primary and
secondary alkynamides and their applications in biological
systems.
General procedure for the synthesis of alkynamide sub-
strates 3a – 3f. To a round bottom flask with stir bar was add-
ed the ester substrate (1 equiv, 3.0 mmol) followed by purging
with N2(g). Dry THF (20 mL) was then added followed by pyr-
rolidine (2 equiv, 6 mmol) and the mixture was allowed to stir
at room temperature for 4 hours. The reaction mixture was
diluted in ethyl acetate (20 mL) and water (20 mL). The or-
ganic layer was washed with brine, dried over sodium sulfate,
and concentrated in vacuo to afford a yellow oil. The crude
product was then subjected to silica chromatography (40%
ethyl acetate in hexanes) to afford the product as a white solid.
Alkynamides 3a,41 3b,42 and 3f43 are known compounds.
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EXPERIMENTAL
General Experimental Information. All reagents and
solvents were purchased from commercially available sources
unless noted otherwise. THF, toluene, and DCM were dried
using the Innovative Technology Pure Solv-MD solvent puri-
fication system. Flash chromatography was performed using
SiliaFlash P60 40-63 um, 60 A. TLC analyses were performed
using Silicycle aluminum backed silica gel F254 plates. NMR
spectra were obtained using a Bruker Avance II 500 MHz,
Agilent 400-MR 400 MHz, or a Varian Inova 400 MHz spec-
1-(Pyrrolidin-1-yl)-3-(p-tolyl)prop-2-yn-1-one
(3c).
1
White solid, 57% (350 mg). H NMR (400 MHz, CDCl3) δ
7.43 (d, J = 8.1 Hz, 2H), 7.15 (d, J = 7.9 Hz, 2H), 3.72 (t, J =
6.8 Hz, 2H), 3.52 (t, J = 7.0 Hz, 2H), 2.36 (s, 3H), 2.00 – 1.90
(m, 4H). 13C NMR (101 MHz, CDCl3) δ 153.0, 140.5, 132.5,
129.4, 117.6, 89.2, 82.4, 77.2, 48.3, 45.5, 25.5, 24.9, 21.8.
HRMS: (ESI) m/z: [M + H]+ calcd for C14H16NO 214.1226;
Found 214.1214.
1
trometer. Chemical shifts are reported in δ ppm. H and 13C
NMR spectra are referenced using an internal standard (CDCl3
or TMS). Chemical shifts for 11B spectra are referenced using
BF3•OEt2 as an external standard. ESI mass spectra were ac-
quired using an Agilent 6220 TOF LC-MS. EI mass spectra
and GC-MS experiments were performed using an Agilent
7890 Series GC system coupled to an HP 5975 Mass Selective
Detector.
3-(4-Methoxyphenyl)-1-(pyrrolidin-1-yl)prop-2-yn-1-
1
one (3d). White solid, 40% (360 mg). H NMR (400 MHz,
CDCl3) δ 7.48 (d, J = 9.0 Hz, 2H), 6.86 (d, J = 9.0 Hz, 2H),
3.82 (s, 3H), 3.72 (t, J = 6.8 Hz, 2H), 3.52 (t, J = 7.0 Hz, 2H),
2.00 – 1.89 (m, 4H). 13C NMR (101 MHz, CDCl3) δ 161.0,
153.2, 134.3, 114.3, 112.6, 89.3, 82.1, 55.5, 48.3, 45.4, 25.5,
24.9. HRMS: (ESI) m/z: [M + H]+ calcd for C14H16NO2
230.1176; Found 230.1161.
General Procedure for the synthesis of alkynoate ester
susbtrates 1a – 1z. Dry THF (20 mL) was added to the termi-
nal acetylene (1 equiv, 5.0 mmol) in a round bottom flask
equipped with a stir bar. The solution was cooled to -78 °C
(dry ice/acetone bath) and butyllithium (2.5M in hexanes, 5.0
mmol) was added dropwise and stirred. After 15 minutes me-
thyl chloroformate (1 equiv, 5.0 mmol) was added dropwise to
the mixture at -78 °C and stirred for 2 hours. The reaction was
then diluted with ethyl acetate, and water was added. The or-
ganic layer was washed with brine and dried over anhydrous
sodium sulfate. Concentration in vacuo yielded a yellow oil
which, upon purification by column chromatography (1:10,
ethyl acetate:hexanes), yielded the corresponding ester. Esters
1a,26 1b,27, 1c,28 1d,29 1e,30 1f,31 1g,30 1i,32 1j,30 1k,33 1l,30 1m,34
1o,35 1p,36 1q,27 1r,37 1s,37 1v,37 1w,31 1x,31 1y,38 1z,39 and 640
are known compounds. Compound 1n was purchased com-
mercially and used directly.
3-(4-Chlorophenyl)-1-(pyrrolidin-1-yl)prop-2-yn-1-one
(3e). White solid, 48% (220 mg). 1H NMR (400 MHz, CDCl3)
δ 7.46 (d, J = 8.8 Hz, 2H), 7.33 (d, J = 8.8 Hz, 2H), 3.71 (t, J =
6.8 Hz, 2H), 3.53 (t, J = 7.0 Hz, 2H), 1.95 (s, 4H). 13C NMR
(101 MHz, CDCl3) δ 152.6, 136.3, 133.7, 129.0, 119.2, 87.5,
83.6, 77.2, 48.3, 45.5, 25.5, 24.9. HRMS: (ESI) m/z: [M + H]+
calcd for C13H13ClNO 234.0680; Found 234.0665.
General procedure for the hydroboration of alkynoate
esters to form (E)-β borylacrylates 2a – 2z. Alkynoate ester
(0.34 mmol, 1.0 equiv.) was added to a flame dried 2-neck
round bottom flask with a stir bar. The flask was then filled
with N2(g) by purging for 30 minutes. Solid esters were dis-
solved in 50 µL dry THF, while oils were reacted neat. Pina-
colborane (0.37 mmol, 1.1 equiv.) followed by tri-n-
butylphosphine (0.034 mmol, 0.1 equiv.) were added to the
vial at room temperature. The reaction was then allowed to stir
at room temperature for 60 minutes. The reaction mixture was
then directly loaded onto silica gel and purified by column
chromatography (0-10% ethyl acetate in hexanes) to yield the
product as a colorless oil.
Methyl 3-(3-chlorophenyl)propiolate (1h). Clear oil,
67% (319 mg). H NMR (400 MHz, CDCl3) δ 7.56 (t, J = 1.8
1
Hz, 1H), 7.50 – 7.39 (m, 2H), 7.31 (t, J = 7.9 Hz, 1H), 3.84 (s,
3H). 13C NMR (101 MHz, CDCl3) δ 154.2, 134.7, 132.8,
131.2, 131.1, 130.0, 121.4, 84.7, 81.2, 53.1. HRMS: (ESI)
m/z: [M + H]+ calcd for C10H8ClO2 195.0207; Found
195.0203.
Methyl
(E)-3-phenyl-3-(4,4,5,5-tetramethyl-1,3,2-
Methyl 3-(quinolin-6-yl)propiolate (1t). Light yellow
solid, 35% (228 mg). H NMR (400 MHz, CDCl3) δ 8.93 (s,
dioxaborolan-2-yl)acrylate (2a). Colorless oil, 87% (85 mg).
1H NMR (400 MHz, CDCl3) δ 7.54 – 7.46 (m, 2H), 7.42 –
7.32 (m, 3H), 6.44 (s, 1H), 3.79 (s, 3H), 1.42 (s, 12H); 13C
NMR (101 MHz, CDCl3) δ 168.5, 138.7, 129.3, 128.9, 127.3,
125.7, 84.5, 52.0, 25.2; 11B NMR (128 MHz, CDCl3) δ 30.3.
HRMS: (ESI) m/z: [M + H]+ calcd for C16H22BO4 289.1609;
Found 289.1588.
1
1H), 8.13 – 8.03 (m, 3H), 7.78 (s, 1H), 7.43 (s, 1H), 3.84 (s,
3H); 13C NMR (101 MHz, CDCl3) δ 154.2, 152.1, 148.4,
136.0, 133.9, 131.9, 130.1, 127.6, 122.1, 117.7, 85.7, 81.1,
52.9, 52.9. HRMS: (ESI) m/z: [M + H]+ calcd for C13H10NO2
212.0706; Found 212.0717.
Methyl 3-(1-methyl-1H-indol-5-yl)propiolate (1u). Yel-
low oil, 74% (294 mg). 1H NMR (400 MHz, CDCl3) δ 7.91 (s,
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Methyl (E)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-
yl)-3-(p-tolyl)acrylate (2b). Colorless oil, 87% (109 mg). H
cdcl3) δ 167.7, 138.6, 132.2, 131.1, 130.2, 129.9, 129.3, 126.9,
1
84.5, 52.1, 24.9; 11B NMR (128 MHz, CDCl3) δ 29.9. HRMS:
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3
4
5
6
7
8
NMR (400 MHz, CDCl3) δ 7.39 (d, J = 8.2 Hz, 2H), 7.17 (d, J
= 8.5 Hz, 2H), 6.42 (s, 1H), 3.78 (s, 3H), 2.35 (s, 3H), 1.42 (s,
12H); 13C NMR (101 MHz, CDCl3) δ 168.6, 139.5, 135.9,
129.6, 127.2, 124.7, 84.5, 52.0, 25.2, 21.4; 11B NMR (128
MHz, CDCl3) δ 30.2. HRMS: (ESI) m/z: [M + H]+ calcd for
C17H24BO4 303.1765; Found 303.1770.
(ESI) m/z: [M + H]+ calcd for C16H21BClO4 323.1216; Found
323.1195.
Methyl (E)-3-(4-fluorophenyl)-3-(4,4,5,5-tetramethyl-
1,3,2-dioxaborolan-2-yl)acrylate (2j). Colorless oil, 61%
(109 mg) 1H NMR (400 MHz, CDCl3) δ 7.51 – 7.42 (m, 2H),
7.03 (t, J = 8.7 Hz, 2H), 6.37 (s, 1H), 3.77 (s, 3H), 1.40 (s,
12H); 13C NMR (101 MHz, CDCl3) δ 168.4, 164.7, 162.2,
134.7, 129.1, 125.5, 115.9, 115.7, 84.5, 52.0, 25.1; 11B NMR
(128 MHz, CDCl3) δ 30.7. HRMS: (ESI) m/z: [M + H]+ calcd
for C16H21BFO4 307.1514; Found 307.1521.
Methyl (E)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-
1
yl)-3-(m-tolyl)acrylate (2c). Colorless oil, 81% (143 mg). H
9
NMR (400 MHz, CDCl3) δ 7.31 – 7.11 (m, 4H), 6.42 (s, 1H),
3.77 (s, 3H), 2.33 (s, 3H), 1.41 (s, 12H); 13C NMR (101 MHz,
CDCl3) δ 168.5, 138.6, 138.4, 130.0, 128.7, 127.9, 125.4,
124.3, 84.4, 51.9, 25.1, 21.5; 11B NMR (128 MHz, CDCl3) δ
30.8. HRMS: (ESI) m/z: [M + H]+ calcd for C17H24BO4
303.1765; Found 303.1760.
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Methyl (E)-3-(2-fluorophenyl)-3-(4,4,5,5-tetramethyl-
1,3,2-dioxaborolan-2-yl)acrylate (2k). Colorless oil, 58% (47
1
mg). H NMR (400 MHz, CDCl3) δ 7.42 (td, J = 7.8, 1.7 Hz,
1H), 7.31 – 7.24 (m, 1H), 7.14 – 7.01 (m, 2H), 6.55 (s, 1H),
3.77 (s, 3H), 1.38 (s, 13H); 13C NMR (101 MHz, CDCl3) δ
168.1, 161.7, 159.2, 130.7, 130.7, 129.8, 129.8, 128.9, 128.9,
126.7, 126.6, 124.5, 124.4, 116.3, 116.1, 52.1, 25.2; 11B NMR
(128 MHz, CDCl3) δ 30.6. HRMS: (ESI) m/z: [M + H]+ calcd
for C16H21BFO4 307.1514; Found 307.1518.
Methyl
(E)-3-(4-(tert-butyl)phenyl)-3-(4,4,5,5-
tetramethyl-1,3,2-dioxaborolan-2-yl)acrylate (2d). Color-
1
less oil, 86% (98 mg). H NMR (400 MHz, CDCl3) δ 7.44 (d,
J = 8.8 Hz, 2H), 7.38 (d, J = 8.8 Hz, 2H), 6.44 (s, 1H), 3.78 (s,
3H), 1.43 (s, 13H), 1.32 (s, 9H); 13C NMR (101 MHz, CDCl3)
δ 168.7, 152.6, 135.8, 127.1, 125.8, 124.7, 84.5, 52.0, 34.9,
31.4, 25.3; 11B NMR (128 MHz, CDCl3) δ 30.4. HRMS: (ESI)
m/z: [M + H]+ calcd for C20H30BO4 345.2237; Found
345.2239.
Methyl (E)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-
yl)-3-(4-(trifluoromethyl)phenyl)acrylate (2l). Off-white
1
solid, 36% (36 mg). H NMR (400 MHz, CDCl3) δ 7.61 (q,
4H), 6.45 (s, 1H), 3.81 (s, 3H), 1.41 (s, 13H); 13C NMR (101
MHz, CDCl3) δ 168.1, 142.4, 131.1, 130.8, 127.9, 127.5,
125.8, 122.8, 110.2, 84.8, 52.3, 25.1; 11B NMR (128 MHz,
CDCl3) δ 30.5. HRMS: (ESI) m/z: [M + H]+ calcd for
C17H21BF3O4 357.1483; Found 357.1490.
Methyl (E)-3-(2-methoxyphenyl)-3-(4,4,5,5-tetramethyl-
1,3,2-dioxaborolan-2-yl)acrylate (2e). Colorless oil, 75% (75
mg). 1H NMR (400 MHz, CDCl3) δ 7.35 – 7.27 (m, 2H), 6.94
(td, J = 7.5, 1.1 Hz, 1H), 6.87 (dd, J = 8.2, 1.0 Hz, 1H), 6.49
(s, 1H), 3.81 (s, 3H), 3.76 (s, 3H), 1.38 (s, 12H); 13C NMR
(101 MHz, CDCl3) δ 167.9, 157.3, 130.4, 129.6, 129.3, 128.3,
121.2, 111.2, 84.1, 55.6, 51.8, 25.3; 11B NMR (128 MHz,
CDCl3) δ 30.2. HRMS: (ESI) m/z: [M + H]+ calcd for
C17H24BO5 319.1714; Found 319.1730.
Methyl (E)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-
yl)hex-2-enoate (2m). Colorless oil, 54% (99 mg). 1H
NMR (400 MHz, CDCl3) δ 5.98 (s, 1H), 3.69 (s, 3H), 2.28 –
2.18 (m, 2H), 1.49 (h, J = 7.4 Hz, 2H), 1.33 (s, 13H), 0.90 (t, J
= 7.4 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 168.3, 125.7,
84.1, 51.7, 38.0, 25.0, 21.3, 14.0; 11B NMR (128 MHz,
CDCl3) δ 31.1. HRMS: (ESI) m/z: [M + H]+ calcd for
C13H24BO4 255.1765; Found 255.1772.
Methyl (E)-3-(4-methoxyphenyl)-3-(4,4,5,5-tetramethyl-
1,3,2-dioxaborolan-2-yl)acrylate (2f). Colorless oil, 85% (92
1
mg). H NMR (400 MHz, CDCl3) δ 7.45 (d, J = 8.7 Hz, 2H),
6.88 (d, J = 8.8 Hz, 2H), 6.38 (s, 1H), 3.81 (s, 3H), 3.77 (s,
3H), 1.42 (s, 12H); 13C NMR (101 MHz, CDCl3) δ 168.8,
160.7, 131.1, 128.8, 123.4, 114.3, 84.5, 55.4, 51.9, 25.3. 11B
NMR (128 MHz, CDCl3) δ 30.4. HRMS: (ESI) m/z: [M + H]+
calcd for C17H24BO5 319.1714; Found 319.1727.
Ethyl (E)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-
yl)but-2-enoate (2n). Colorless oil, 70% (380 mg) (70:30
1
E:Z). H NMR (400 MHz, CDCl3) δ 6.42 – 6.40 (q, 0.43H),
6.02 – 5.95 (m, 1H), 4.14 (m, 3H), 2.13 (s, 1H), 1.91 (s, 3H),
1.32 (s, 12H), 1.28 – 1.18 (m, 12H). 13C NMR (101 MHz,
CDCl3) δ 167.9, 166.3, 130.7, 127.0, 84.2, 84.0, 60.5, 59.9,
24.9, 24.8, 21.2, 16.4, 14.4. 11B NMR (128 MHz, CDCl3) δ
30.6. HRMS: (ESI) m/z: [M + H]+ calcd for C12H22BO4
241.1608; Found 241.1622.
Methyl (E)-3-(4-chlorophenyl)-3-(4,4,5,5-tetramethyl-
1,3,2-dioxaborolan-2-yl)acrylate (2g). White solid, 66% (75
mg). 1H NMR (400 MHz, CDCl3) δ 7.42 (d, 2H), 7.33 (d, 2H),
6.40 (s, 1H), 3.79 (s, 3H), 1.40 (s, 12H); 13C NMR (101 MHz,
CDCl3) δ 168.3, 137.2, 135.3, 129.1, 128.5, 126.2, 84.7, 52.1,
25.2; 11B NMR (128 MHz, CDCl3) δ 30.25. HRMS: (ESI)
m/z: [M + H]+ calcd for C16H21BClO4, 323.1219; Found
323.1205.
Methyl (E)-3-cyclopropyl-3-(4,4,5,5-tetramethyl-1,3,2-
dioxaborolan-2-yl)acrylate (2o). Colorless oil, 73% (148
mg). 1H NMR (400 MHz, CDCl3) δ 6.07 (s, 1H), 3.70 (s, 3H),
1.72 – 1.61 (m, 1H), 1.34 (s, 13H), 0.92 – 0.80 (m, 4H); 13C
NMR (101 MHz, CDCl3) δ 168.4, 123.3, 84.4, 51.7, 25.2,
18.1, 8.4; 11B NMR (128 MHz, CDCl3) δ 30.4. HRMS: (ESI)
m/z: [M + H]+ calcd for C13H22BO4 253.1608; Found
253.1604.
Methyl (E)-3-(3-chlorophenyl)-3-(4,4,5,5-tetramethyl-
1,3,2-dioxaborolan-2-yl)acrylate (2h). White solid, 67% (58
1
mg). H NMR (400 MHz, CDCl3) δ 7.46 (s, 1H), 7.40 – 7.32
(m, 1H), 7.35 – 7.24 (m, 3H), 6.40 (s, 1H), 3.78 (s, 3H), 1.40
(s, 12H); 13C NMR (101 MHz, CDCl3) δ 168.2, 140.5, 134.8,
130.1, 129.2, 127.3, 126.8, 125.3, 84.7, 52.2, 25.1; 11B NMR
(128 MHz, CDCl3) δ 30.5. HRMS: (ESI) m/z: [M + Na]+ calcd
for C16H20BClNaO4 345.1059; Found 345.1038.
Methyl
(E)-3-cyclohexyl-3-(4,4,5,5-tetramethyl-1,3,2-
dioxaborolan-2-yl)acrylate (2p). Colorless oil, 27% (30 mg).
1H NMR (400 MHz, CDCl3) δ 5.98 (s, 1H), 3.70 (s, 3H), 2.23
– 2.13 (m, 1H), 1.82 – 1.72 (m, 4H), 1.73 – 1.60 (m, 2H), 1.36
(s, 13H), 1.31 – 1.08 (m, 7H); 13C NMR (101 MHz, CDCl3) δ
168.7, 124.0, 84.1, 51.7, 44.8, 32.1, 26.4, 26.2, 25.2. 11B NMR
(128 MHz, CDCl3) δ 31.1. HRMS: (ESI) m/z: [M + Na]+ calcd
for C16H27BNaO4 317.1898; Found 317.1879.
Methyl (E)-3-(2-chlorophenyl)-3-(4,4,5,5-tetramethyl-
1,3,2-dioxaborolan-2-yl)acrylate (2i). White solid. 32% (30
mg). 1H NMR (400 MHz, CDCl3) δ 7.42 – 7.20 (m, 4H), 6.38
(s, 1H), 3.79 (s, 3H), 1.35 (s, 12H); 13C NMR (101 MHz,
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Methyl
(E)-3-(cyclohex-1-en-1-yl)-3-(4,4,5,5-
22.1; 11B NMR (128 MHz, CDCl3) δ 30.1. HRMS: (ESI) m/z:
[M + Na]+ calcd for C18H25BNaO4 339.1741; Found 339.1744.
1
2
3
4
5
6
7
8
tetramethyl-1,3,2-dioxaborolan-2-yl)acrylate (2q). Color-
less oil, 89% (109 mg). 1H NMR (400 MHz, CDCl3) δ 6.12 (s,
1H), 5.99 (s, 1H), 3.69 (s, 3H), 2.22 – 2.08 (m, 4H), 1.70 –
1.49 (m, 4H), 1.37 (s, 12H); 13C NMR (101 MHz, CDCl3) δ
169.2, 137.6, 136.7, 120.3, 84.1, 51.6, 26.7, 25.4, 25.4, 22.4,
21.8; 11B NMR (128 MHz, CDCl3) δ 30.8. HRMS: (ESI) [M +
Benzyl
(E)-3-phenyl-3-(4,4,5,5-tetramethyl-1,3,2-
dioxaborolan-2-yl)acrylate (2x). White solid, 82% (89 mg).
1H NMR (400 MHz, CDCl3) δ 7.54 – 7.46 (m, 2H), 7.43 –
7.28 (m, 8H), 6.50 (s, 1H), 5.24 (s, 2H), 1.43 (s, 12H); 13C
NMR (101 MHz, CDCl3) δ 168.0, 138.7, 135.9, 129.3, 128.9,
128.7, 128.5, 128.4, 127.3, 125.8, 84.6, 66.8, 25.2; 11B NMR
(128 MHz, CDCl3) δ 30.6. HRMS: (ESI) m/z: [M + H]+ calcd
for C22H26BO4 365.1923; Found 365.1924.
H]+ calcd for C16H26BO4 293.1922; Found 293.1919.
Methyl
(E)-3-([1,1'-biphenyl]-4-yl)-3-(4,4,5,5-
tetramethyl-1,3,2-dioxaborolan-2-yl)acrylate (2r). White
solid, 69% (65 mg). 1H NMR (400 MHz, CDCl3) δ 7.64 – 7.54
(m, 6H), 7.45 (t, J = 7.9 Hz, 2H), 7.40 – 7.31 (m, 1H), 6.50 (s,
1H), 3.81 (s, 3H), 1.45 (s, 12H); 13C NMR (101 MHz, CDCl3)
δ 168.6, 142.1, 140.5, 137.7, 129.0, 127.8, 127.7, 127.6,
127.2, 125.5, 84.6, 52.1, 25.3; 11B NMR (128 MHz, CDCl3) δ
30.7. HRMS: (ESI) m/z: [M + H]+ calcd for C22H26BO4
365.1919; Found 365.1947.
9
Allyl
(E)-3-phenyl-3-(4,4,5,5-tetramethyl-1,3,2-
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
dioxaborolan-2-yl)acrylate (2y). Colorless oil, 86% (78 mg).
1H NMR (400 MHz, CDCl3) δ 7.53 – 7.46 (m, 2H), 7.41 –
7.31 (m, 3H), 6.47 (s, 1H), 6.04 – 5.89 (m, 1H), 5.36 (dq, J =
17.2, 1.6 Hz, 1H), 5.25 (dq, J = 10.4, 1.3 Hz, 1H), 4.70 (dt, J =
5.8, 1.5 Hz, 2H), 1.42 (s, 12H); 13C NMR (101 MHz, CDCl3) δ
167.8, 138.7, 132.3, 129.3, 128.9, 127.3, 125.8, 118.6, 84.6,
65.6, 25.2; 11B NMR (128 MHz, CDCl3) δ 30.4. HRMS: (ESI)
m/z: [M + H]+ calcd for C18H24BO4 315.1765; Found
315.1761.
Methyl (E)-3-(naphthalen-2-yl)-3-(4,4,5,5-tetramethyl-
1,3,2-dioxaborolan-2-yl)acrylate (2s). White solid, 65% (46
1
mg). H NMR (400 MHz, CDCl3) δ 7.97 (s, 1H), 7.86 – 7.78
Prop-2-yn-1-yl
(E)-3-phenyl-3-(4,4,5,5-tetramethyl-
(m, 3H), 7.62 (dd, J = 8.6, 1.7 Hz, 1H), 7.49 (dt, J = 6.2, 3.4
Hz, 2H), 6.58 (s, 1H), 3.82 (s, 3H), 1.46 (s, 12H); 13C NMR
(101 MHz, CDCl3) δ 168.6, 136.1, 133.7, 133.4, 128.6, 128.6,
1,3,2-dioxaborolan-2-yl)acrylate (2z). Colorless oil, 79%
(103 mg). 1H NMR (400 MHz, CDCl3) δ 7.53 – 7.45 (m, 2H),
7.41 – 7.32 (m, 3H), 6.48 (s, 1H), 4.81 (d, J = 2.5 Hz, 2H),
2.49 (s, 1H), 1.42 (s, 14H); 13C NMR (101 MHz, CDCl3) δ
167.1, 138.5, 129.5, 128.9, 127.3, 124.9, 84.7, 77.7, 75.2,
52.4, 25.2; 11B NMR (128 MHz, CDCl3) δ 30.3. HRMS: (ESI)
m/z: [M + H]+ calcd for C18H22BO4 313.1609; Found
313.1619.
127.8, 127.7, 126.9, 126.6, 125.8, 124.4, 84.6, 52.1, 25.25; 11
B
NMR (128 MHz, CDCl3) δ 30.5. HRMS: (ESI) m/z: [M + H]+
calcd for C20H24BO4 339.1766; Found 339.1774.
Methyl
(E)-3-(quinolin-6-yl)-3-(4,4,5,5-tetramethyl-
1,3,2-dioxaborolan-2-yl)acrylate (2t). White solid, 60% (68
1
mg). H NMR (400 MHz, CDCl3) δ 8.91 (dd, J = 4.2, 1.7 Hz,
Methyl
(E)-4-(benzyl(methyl)amino)-3-(4,4,5,5-
1H), 8.13 (d, J = 1.3 Hz, 1H), 8.08 (d, J = 8.8 Hz, 1H), 7.93
(d, J = 2.0 Hz, 1H), 7.85 (dd, J = 8.8, 2.1 Hz, 1H), 7.41 (dd, J
= 8.3, 4.2 Hz, 1H), 6.58 (s, 1H), 3.82 (s, 3H), 1.45 (s, 13H).
13C NMR (101 MHz, CDCl3) δ 168.4, 151.1, 148.6, 136.9,
136.6, 130.2, 128.2, 127.1, 126.9, 121.8, 84.8, 52.2, 25.2. 11B
NMR (128 MHz, CDCl3) δ 30.7. HRMS: (ESI) m/z: [M + H]+
calcd for C19H23BNO4 340.1718; Found 340.1730.
tetramethyl-1,3,2-dioxaborolan-2-yl)but-2-enoate (7). Puri-
fied as a mixture of E:Z isomers (86:14) by diluting crude oil
in hexanes and extracting product with methanol. Colorless
1
oil, 43% (34 mg). H NMR (400 MHz, CDCl3) δ 7.38 – 7.20
(m, 6H), 6.22 (s, 1H), 3.72 (s, 3H), 3.47 (s, 2H), 3.23 (s, 2H),
2.15 (s, 3H), 1.38 (s, 12H). 13C NMR (101 MHz, CDCl3) δ
167.7, 138.9, 129.2, 128.2, 127.0, 126.3, 84.3, 62.9, 62.4,
51.7, 42.7, 25.0. 11B NMR (128 MHz, CDCl3) δ 31.0. HRMS:
(ESI) m/z: [M + K]+ calcd for C19H28BKNO4 384.1746; Found
384.1775.
Methyl
(E)-3-(1-methyl-1H-indol-5-yl)-3-(4,4,5,5-
tetramethyl-1,3,2-dioxaborolan-2-yl)acrylate (2u). Off-
white solid, 38% (60 mg). 1H NMR (400 MHz, CDCl3) δ 7.79
(d, J = 1.7 Hz, 1H), 7.41 (dd, J = 8.6, 1.7 Hz, 1H), 7.29 (d, J =
8.6 Hz, 2H), 7.05 (d, J = 3.1 Hz, 1H), 6.49 (s, 1H), 6.47 (s,
1H), 3.79 (s, 3H), 3.78 (s, 3H), 1.45 (s, 13H); 13C NMR (101
MHz, CDCl3) δ 169.0, 137.4, 130.2, 129.8, 128.8, 123.1,
121.1, 120.7, 109.6, 102.0, 84.4, 51.9, 33.1, 25.3; 11B NMR
(128 MHz, CDCl3) δ 30.9. HRMS: (ESI) m/z: [M + H]+ calcd
for C19H25BNO4 342.1871; Found 342.1872.
General procedure for the hydroboration of alkyna-
mides to produce (E)-β borylacrylates 4a – 4e. Alkynamide
(0.30 mmol, 1.0 equiv.) was added to a flame dried 2-neck
round bottom flask with a stir bar. The flask was then filled
with N2(g) by purging for 30 minutes. Dry THF was then added
(0.5 mL). Pinacolborane (0.33 mmol, 1.1 equiv.) followed by
tri-n-butylphosphine (0.15 mmol, 0.5 equiv.) were added to
the vial at room temperature. The reaction was then allowed to
stir at 60 °C for 4 hours. The reaction mixture was then direct-
ly loaded onto silica gel and purified by column chromatog-
raphy (40% ethyl acetate in dichloromethane) to yield the
product as a white solid.
Methyl
(E)-3-(benzo[d][1,3]dioxol-5-yl)-3-(4,4,5,5-
tetramethyl-1,3,2-dioxaborolan-2-yl)acrylate (2v). White
solid, 87% (71 mg). 1H NMR (400 MHz, CDCl3) δ 7.05 – 6.97
(m, 2H), 6.79 (dd, J = 7.8, 0.6 Hz, 1H), 6.34 (s, 1H), 5.97 (s,
2H), 3.77 (s, 3H), 1.41 (s, 12H); 13C NMR (101 MHz, cdcl3) δ
168.7, 148.8, 148.3, 132.8, 124.0, 122.2, 108.6, 107.0, 101.4,
84.5, 52.0, 25.2; 11B NMR (128 MHz, CDCl3) δ 30.7. HRMS:
(ESI) m/z: [M + H]+ calcd for C17H22BO6 333.1507; Found
333.1524.
(E)-3-Phenyl-1-(pyrrolidin-1-yl)-3-(4,4,5,5-tetramethyl-
1,3,2-dioxaborolan-2-yl)prop-2-en-1-one (4a). White solid,
1
46% (42 mg). H NMR (400 MHz, CDCl3) δ 7.72 – 7.65 (m,
2H), 7.38 – 7.27 (m, 3H), 6.35 (s, 1H), 3.71 (t, J = 6.9 Hz,
2H), 3.63 (t, J = 6.9 Hz, 2H), 2.08 – 1.88 (m, 4H), 1.26 (s,
12H). 13C NMR (101 MHz, CDCl3) δ 171.3, 138.8, 128.9,
128.1, 127.9, 118.6, 80.5, 47.4, 47.1, 26.2, 25.6, 24.4. 11B
NMR (128 MHz, CDCl3) δ 14.0. HRMS: (ESI) m/z: [M + H]+
calcd for C19H27BNO3 328.2082; Found 328.2101.
Isopropyl
(E)-3-phenyl-3-(4,4,5,5-tetramethyl-1,3,2-
dioxaborolan-2-yl)acrylate (2w). Colorless oil, 81% (94 mg).
1H NMR (400 MHz, CDCl3) δ 7.54 – 7.45 (m, 2H), 7.40 –
7.27 (m, 3H), 6.41 (s, 1H), 5.11 (hept, J = 6.3 Hz, 1H), 1.42 (s,
12H), 1.28 (d, J = 6.3 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ
167.8, 138.8, 129.1, 128.8, 127.3, 126.8, 84.4, 68.3, 25.2,
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(E)-N,N-Dimethyl-3-phenyl-3-(4,4,5,5-tetramethyl-
Page 8 of 10
J = 8.3 Hz, 2H), 7.43 (s, 1H), 7.32 (d, J = 8.5 Hz, 2H), 4.85 (s,
1H), 4.68 (s, 2H). 13C NMR (101 MHz, CDCl3) δ 147.90,
134.28, 133.34, 128.83, 128.26, 105.30, 71.79. 11B NMR (128
MHz, CDCl3) δ 32.8. HRMS: (ESI) m/z: [M - H]- calcd for
C9H7BClO2 193.0223; Found 193.0229.
1
2
3
4
5
6
7
8
1,3,2-dioxaborolan-2-yl)acrylamide (4b). White solid, 48%
1
(39 mg). H NMR (400 MHz, CDCl3) δ 7.70 (d, J = 8.2 Hz,
2H), 7.33 (q, J = 7.2, 6.4 Hz, 3H), 6.50 (s, 1H), 3.18 (d, J =
4.0 Hz, 6H), 1.28 (s, 13H). 13C NMR (101 MHz, CDCl3) δ
173.4, 138.7, 129.0, 128.1, 127.8, 117.0, 77.2, 37.3, 26.1. 11B
NMR (128 MHz, CDCl3) δ 13.7. HRMS: (ESI) m/z: [M +
Na]+ calcd for C17H24BNNaO3 324.1730; Found 324.1745.
3-(4-Fluorophenyl)-1,2-oxaborol-2(5H)-ol (8d). White
solid, 70% (40 mg). 1H NMR (400 MHz, CDCl3) δ 7.69 – 7.58
(m, 2H), 7.37 (s, 1H), 7.10 – 6.99 (m, 2H), 6.09 (d, J = 7.8 Hz,
1H), 4.71 (s, 2H). 13C NMR (101 MHz, CDCl3) δ 163.49,
161.04, 148.96, 146.76, 131.81, 128.38, 115.49, 115.27,
71.60. 11B NMR (128 MHz, CDCl3) δ 32.9. HRMS: (ESI)
m/z: [M - H]- calcd for C9H7BFO2 177.0529; Found 177.0536.
(E)-1-(Pyrrolidin-1-yl)-3-(4,4,5,5-tetramethyl-1,3,2-
dioxaborolan-2-yl)-3-(p-tolyl)prop-2-en-1-one (4c). White
9
1
solid, 54% (52 mg). H NMR (400 MHz, CDCl3) δ 7.60 (d, J
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
= 8.1 Hz, 2H), 7.13 (d, J = 7.9 Hz, 2H), 6.32 (s, 1H), 3.68 (t, J
= 6.9 Hz, 2H), 3.60 (t, J = 6.9 Hz, 2H), 2.33 (s, 3H), 2.06 –
1.85 (m, 5H), 1.26 (s, 12H). 13C NMR (101 MHz, CDCl3) δ
171.3, 139.0, 135.8, 128.8, 127.9, 117.7, 80.4, 47.3, 47.0,
26.2, 25.5, 24.4, 21.5. 11B NMR (128 MHz, CDCl3) δ 14.0.
HRMS: (ESI) m/z: [M + H]+ calcd for C20H29BNO3 342.2239;
Found 342.2256.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website.
(E)-3-(4-Methoxyphenyl)-1-(pyrrolidin-1-yl)-3-(4,4,5,5-
tetramethyl-1,3,2-dioxaborolan-2-yl)prop-2-en-1-one (4d).
White solid, 53% (41 mg). 1H NMR (400 MHz, CDCl3) δ 7.71
(d, J = 8.9 Hz, 2H), 6.87 (d, J = 8.9 Hz, 2H), 6.31 (s, 1H), 3.82
(s, 3H), 3.71 (t, J = 6.9 Hz, 2H), 3.62 (t, J = 6.9 Hz, 2H), 2.08
– 1.88 (m, 4H), 1.29 (s, 13H). 13C NMR (101 MHz, CDCl3) δ
171.5, 160.7, 131.3, 129.8, 116.4, 113.6, 80.5, 55.4, 47.3,
47.1, 26.4, 25.6, 24.5. 11B NMR (128 MHz, CDCl3) δ 13.8.
HRMS: (ESI) m/z: [M + H]+ calcd for C20H29BNO4 358.2188;
Found 358.2172.
Spectroscopic data for all new compounds and deuterium labeling
experimental (PDF).
Computational details (DFT) of reaction mechanism (PDF).
AUTHOR INFORMATION
Corresponding Author
* santosw@vt.edu
Author Contributions
(E)-3-(4-Chlorophenyl)-1-(pyrrolidin-1-yl)-3-(4,4,5,5-
tetramethyl-1,3,2-dioxaborolan-2-yl)prop-2-en-1-one (4e).
Purified by preparatory TLC (100% EtOAc). White solid,
The manuscript was written through contributions of all authors.
ORID
1
46% (27 mg). H NMR (400 MHz, CDCl3) δ 7.63 (d, J = 8.7
Webster L. Santos: 0000-0002-4731-8548
Hz, 2H), 7.31 (d, J = 8.7 Hz, 2H), 6.34 (s, 1H), 3.72 (t, J = 6.9
Hz, 2H), 3.64 (t, J = 6.9 Hz, 2H), 2.10 – 1.90 (m, 4H), 1.56 (s,
3H), 1.26 (s, 13H). 13C NMR (101 MHz, CDCl3) δ 171.1,
137.2, 134.9, 129.3, 128.4, 118.8, 80.6, 47.5, 47.2, 26.2, 25.6,
24.5. 11B NMR (128 MHz, CDCl3) δ 13.8. HRMS: (ESI) m/z:
[M + H]+ calcd for C19H26BClNO3 362.1692; Found 362.1696.
ACKNOWLEDGMENT
We acknowledge financial support by the National Science
Foundation (CHE‐1414458) and the Research Grants Council
of Hong Kong (16304017).
General procedure for the synthesis of oxaboroles 8a –
8d. To a round-bottom flask equipped with a stir bar was add-
ed hydroboration product (0.3 mmol, 1 equiv) and dissolved in
ethanol (3 mL). Sodium borohydride (0.6 mmol, 2 equiv) was
added and the mixture was allowed to stir for 30 minutes at
room temperature. The mixture was concentrated in vacuo to
afford an off-white solid, which was then purified via column
chromatography to afford the final product as a white solid.
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1
solid, 77% (92 mg). H NMR (400 MHz, CDCl3) δ 7.59 (d, J
= 8.8 Hz, 2H), 7.32 (s, 1H), 6.90 (d, J = 8.9 Hz, 2H), 4.83 (s,
1H), 4.67 (s, 2H), 3.82 (s, 3H). 13C NMR (101 MHz, CDCl3) δ
160.9, 159.2, 145.8, 128.1, 114.1, 71.8, 55.4. 11B NMR (128
MHz, CDCl3) δ 33.1. HRMS: (ESI) m/z: [M - H]- calcd for
C10H10BO3 189.0723; Found 189.0715.
3-Phenyl-1,2-oxaborol-2(5H)-ol (8b). White solid, 77%
(45 mg). 1H NMR (400 MHz, CDCl3-d) δ 7.65 (d, J = 8.4 Hz,
2H), 7.43 – 7.32 (m, 3H), 7.30 – 7.23 (m, 1H), 6.45 (s, 1H),
4.71 (s, 2H). 13C NMR (101 MHz, CDCl3) δ 147.4, 135.9,
128.7, 127.6, 126.9, 71.8. 11B NMR (128 MHz, CDCl3) δ 32.6.
HRMS: (ESI) m/z: [M - H]- calcd for C9H8BO2 159.0623;
Found 159.0597.
3-(4-Chlorophenyl)-1,2-oxaborol-2(5H)-ol (8c). White
1
solid, 80% (89 mg). H NMR (400 MHz, CDCl3-d) δ 7.58 (d,
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