Synthesis of Chemically and Configurationally Stable Monofluoro Acylboronates: Effect of Ligand Structure on their Formation, Properties, and Reactivities

Article abstract of DOI:10.1021/jacs.5b00822

The recent disclosures of two classes of acylborons, potassium acyltrifluoroborates (KATs) and N-methyliminodiacetyl (MIDA) acylboronates, demonstrated that certain acylboron species can be both remarkably stable and uniquely reactive. Here we report new classes of ligands for acylboronates that have a significant influence on the formation, properties, and reactivities of acylboronates. Our systematic investigations identified a class of neutral, monofluoroboronates that can be prepared in a one step, gram-scale fashion from readily accessible KATs. These monofluoroboronates are stable to air, moisture, and silica gel chromatography and can be easily handled without any special precautions. X-ray crystallography, NMR spectroscopy, and HPLC studies showed that they are tetravalent, configurationally stable B-chiral acylboronates. Significantly, the ligands on the boronate allow for fine-tuning of the properties and reactivity of acylboronates. In amide-forming ligation with hydroxylamines under aqueous conditions, a considerable difference in reactivity was observed as a function of ligand structure. The solid-state structures suggested that subtle steric and conformational factors modulate the reactivities of the acylboronates.

Full text of DOI:10.1021/jacs.5b00822

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Article
Synthesis of Chemically and Configurationally Stable
Monofluoro Acylboronates: Effect of Ligand Structure
on their Formation, Properties and Reactivities
Hidetoshi Noda, and Jeffrey W. Bode
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.5b00822 • Publication Date (Web): 27 Feb 2015
Downloaded from http://pubs.acs.org on March 6, 2015
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Synthesis of Chemically and Configurationally Stable
Monofluoro Acylboronates: Effect of Ligand Structure on their
Formation, Properties and Reactivities
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Hidetoshi Noda and Jeffrey W. Bode*
LaboratoriumfurOrganischeChemie, Department of Chemistry and Applied Biosciences, ETH−Zurich, 8093 Zurich, Switzerꢀ
land
ABSTRACT:The recent disclosures of two classes of acylborons– potassium acyltrifluoroborates (KATs) and MIDA acylꢀ
boronates – demonstrated that certain acylboron species can be both remarkably stable and uniquely reactive. Here we report new
classes of ligandsfor acylboronatesthat have a significant influence on the formation, properties and reactivitiesofacylboronates.
Our systematic investigationsidentified a class of neutral, monofluoroboronates that can be prepared in a onestep, gram scale fashꢀ
ion from readily accessible KATs. These monofluoroboronates are stable to air, moisture, and silica gelchromatography and can be
easily handled without any special precautions. Xꢀray crystallography, NMR spectroscopy, and HPLC studiesshowed that they areꢀ
tetravalent, configurationally stable Bꢀchiral acylboronates. Significantly, the ligands on the boronate allow for fineꢀtuning of the
properties and reactivity of acylboronates. In amideꢀforming ligation with hydroxylamines under aqueous conditions,a consideraꢀ
bledifference inreactivity was observed as a function of ligand structure.The solidstate structuressuggested thatsubtle steric and
conformational factorsmodulate the reactivities of the acylboronates.
Introduction
Acylboranesand acylboronates are an intriguingclass of comꢀ
pounds whose remarkable properties and reactivity have only
recently been recognized. This stands incontrast to the substanꢀ
tial body of literature on alkyl, aryl, alkenyl and alkynyl boron
compounds, for which extensive synthetic studies and imꢀ
portant reactions have long been recognized.1Acylboronshave
been proposed as intermediates in some transformations,2 but
the assumed instability of acylborons3 prevented organic
chemists from isolating and characterizing these molecules.4,5
Indeed, in 2005 Stevenson noted that “no verified examples of
acylboron derivatives had ever been isolated and theoretical
calculations suggested that acylboranes were highly reactive
species and prone to rearrangement.”6,7
In 2007 Yamashita, Nozaki and their colleagues reported
the first fully characterized acylboron 1 using a carefully deꢀ
signed nucleophilic boryl anion (Figure 1a).8In 2010, acollaboꢀ
rative team consisting of Curran, Lacôte and coꢀworkers also
reported acylborane2 from an Nꢀheterocyclic carbene stabiꢀ
lized nucleophilic borane (Figure 1b).9 The syntheses of these
ligandꢀstabilized acylborons were landmark achievements in
this area, but these studies did not explore their synthetic poꢀ
tential. Recently, insertion of carbon monoxide into Piers´
borane10 was realized by the aid of a frustrated Lewis pair, and
Figure 1. Reported fully characterized acylborons. Dipp = 2,6ꢀ
(iPr)2C6H4.
formylborane 3 was isolated as a pyridineꢀcoordinated adduct,
althoughits synthetic utility was not well studied (Figure 1c).11
tuted acylboronates are benchꢀstable and readily handled mateꢀ
rials, making them suitable for further transformations.
In 2010, Molander et al. synthesized a singleexampleof a
potassium acyltrifluoroborate (KAT,4) from an acyl anion
equivalent and an electrophilic boron source, followed by
treatment withaqueous KHF2 (Figure 1d).12Yudin documented
a multistep synthesis of Nꢀmethyliminodiacetyl (MIDA) acylꢀ
boronates 5 and demonstrated their downstream transforꢀ
mations (Figure 1e).13 These reports establishedthat tetrasubstiꢀ
Our interests in acylborons arose from ourrecent discloꢀ
surethat KATs undergo extremely fast amideꢀforming ligations
with hydroxylamines in water.14,15Following this discovery, we
reported the syntheses of a variety of KATs on gram scale
either from aldehydes16 or aryl halides.17 We also devised a
convenient route to MIDA acylboronates from their correꢀ
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sponding KATs in one step and found that they possess even
from Schiff base ligand 6a
higher reactivity towards hydroxylamines than KATs. Unforꢀ
tunately MIDA acylboronates werefound to be less stable in
water, limiting their application in bioconjugation reactions.18
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The successful amide forming reactions of MIDA acylꢀ
boronate clearly demonstrated that a suitable ligand on the
boron atom could alter the stability and reactivity of acylꢀ
borons by modulating their physical and chemical properties.
These findings encouraged us to explore further ligands on the
acylborons in hopes of realizing the kind of ligandꢀmodulated
reactivity
commonly
observed
in
metalꢀpromoted
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tion.19We hypothesized that other new acylboron species could
be generated from KATs by following a similar protocol to the
one we identified for the facile formation of MIDA acylꢀ
boronates.
Here we report our studiestowards expanding the chemical
space of acylboronates,20 including the first systematic studies
on the role of the boron ligands on the formation, properties,
and reactivities of acylboronates. The acylboronates prepared
during the course of these studies are tetravalent, monofluoro,
configurationally stableBꢀchiral boron species;allare stable
under air, in water and on silica gel. They react smoothly with
hydroxylaminesunder aqueous conditionsto give amides.
Anotable difference of reactivity was observed between strucꢀ
turally similar boronates, shedding light on the mechanism of
the amide formation with hydroxylamines.
Scheme2. Selected examples of acylboronates from biden-
tate ligandsa
Results and discussion
Boron ligands.Atthe outset of our investigations, we estabꢀ
lished strict criteria for properties of our desired acylboronates.
They must be stable to air, water and silica gel chromatogꢀ
raphy.Most reported acylborons required a glove box for their
preparation. KATs are not amenable to purification by normal
phase silica gel chromatography, andMIDA acylboronates
gradually decompose in water. Our efforts to find a suitable
ligand on the boron began with tridentate MIDA analogs. As in
our reported synthesis of MIDA acylboronates from KATs,
BF3•Et2O was slowly added to a suspension of KAT and TMSꢀ
activatedligand in dry acetonitrile under a nitrogen atmosꢀ
phere.Many possible permutations of MIDA ligand were
screened, including its elongated variants and different substitꢀ
uents on the nitrogenatom (Figure 2).21 Surprisingly, this proꢀ
cedure was successful only for the formation of the parent
MIDA acylboronate 5; any deviation from this structure resultꢀ
ed in the formation of unstable adducts that could not be isoꢀ
lated or characterized.
aReaction conditions: 4a (1.0 equiv), TMSꢀligand (1.0 equiv),
BF3•Et2O (1.0 equiv), CH3CN (0.1 M), 23 °C.
aReaction conditions: 4a (1.0 equiv), TMS2ꢀ6 (1.0 equiv),
BF3•Et2O (1.0 equiv), CH3CN (0.1 M), 23 °C.
The first successful formation of a new acylboronate came
with tridentate Schiff base ligand 6.The obtained adduct was
neither the expected bicyclic boronate 8a nor the fiveꢀ
membered ring boronate 9a,butratherthe sixꢀmembered acylꢀ
boronate 7a that retained one of the fluoride ligands (Scheme
1).22,23The structure of 7a was assigned based on a control exꢀ
periment (see the Supporting Information, Scheme S1), and
further supported by the Xꢀray structure of 10a (vide infra).
This result led us to investigate bidentate ligands that could
form a sixꢀmembered ring. We were pleased to find that many
of them formed stable acylboronates that satisfied the desired
criteria. Selected examples are shown in Scheme 2. As exꢀ
pected, acylboronate 10a was obtained from the Schiff base
ligand derived from 2ꢀhydroxyꢀ1ꢀnaphthaldehyde. This boroꢀ
nate possesseda sixꢀmembered ring containing the phenol oxyꢀ
gen and the imine sp2ꢀnitrogen. Another sp2ꢀnitrogen donor
can be used to obtain
a stable acylboronate; 2ꢀ(2´ꢀ
pyridyl)phenol14 also formed sixꢀmembered acylboronate 11a
with the phenol oxygen and the pyridine nitrogen. In addition,
a nitrogen atom is not essential to construct a sixꢀmembered
boronate; 8ꢀhydroxyquinolinꢀNꢀoxide also gave the acylꢀ
boronate 12a through the Nꢀoxide and the phenol, although the
Figure 2. Selected MIDA derivativesthat did not form a stable
complex
Scheme 1. Formation of six-membered acylboronate 7a
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complexation was not as clean and unidentified products were the product yield. We expect that substrate specific optimizaꢀ
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formed along with 12a. Furthermore, other classes of oxygen
donors are compatible with the acylboronate formation. Picoꢀ
linic acid derived hydroxamic acid was a suitableligand to
form the stable acylboronate 13a. The structures of 10a,
11a,13aand the pꢀCl analog 12d, all were unambiguously esꢀ
tablished by Xꢀray crystallography (Figure 3). These acylꢀ
boronates were easily converted back to the corresponding
KATsin excellent yields by treatment with aqueous KHF2 at
tionsor alternative fluorophiles will avoid the formation of the
undesired adducts and increase the product yield. Acylꢀ
boronates15a, 16a, 17a,18a and 24a also provided a crystal
suitable for Xꢀray diffraction (Figure 4 and the Supporting
Information Figure S5).
Scheme3. Boronate group scopewithsubstitutedligandsa
,
slightly elevated temperatures.24 25
9
In analogy to transition metal catalysis, we anticipated that
subtle changes to the ligand on boron could modulate the
properties and reactivities of the acylboronates. To investigate
this hypothesis, we prepared a number of derivatives of 11a by
similar procedures.26 The complexation proved remarkably
general with respect to the boronate moiety, and a wide range
of acylboronates was obtained from various substituted ligands
(Scheme 3). An array of methyl substituted regioisomers 15a–
19a were obtained in moderate to good yield. Variation of the
electronic nature of the substituent had little influence on the
reaction outcome, and 20a was formed equally well. Extended
aromatic systems on the ligand were also tolerated, delivering
the desired acylboronates 21a–24a with the same level of reacꢀ
tion efficiency.In contrast, the acylboronate 25a derived from
(±)ꢀ1ꢀ(2´ꢀhydroxyꢀ1´ꢀnaphthyl)isoquinoline failed to be isolatꢀ
ed; 25a was observed by NMR and highꢀresolution mass specꢀ
trometry experiments on the unpurified reaction mixtures, but
was rather unstable towards silica gel.27In general, the substitꢀ
uent at 3ꢀ or 3´ꢀposition rendered acylboronates less stable than
11a (e.g.: 15a, 21a and 22a).Nevertheless, all compounds exꢀ
cept 25a were purified by silica gel column chromatography
and analyzed in pure form. In all cases, the major byproducts
were the difluoroboronates derived from BF3•Et2O and TMSꢀ
activated ligands without involving an acyl moiety, decreasing
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aReaction conditions: 4a (1.0 equiv), TMSꢀligand (1.0 equiv),
BF3•Et2O (1.0 equiv), CH3CN (0.1 M), 23 °C.
a)
b)
c)
d)
Figure 3.Solid state structures of 10a, 11a, 12d and 13a. ORTEP, ellipsoids are set at a 50% probability. All hydrogen atoms have
been removed for clarity.
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Figure 4.Solid state structures of 18a and 24a. ORTEP, ellipsoids are set at a 50% probability. All hydrogen atoms have been removed
for clarity. Selected bond lengths (Å) and angles (°). (a) 18a: O2–C5 1.239(3), N1–B1 1.615(3), B1–C5 1.642(3), O2–C5–B1 118.4(2),
O1–B1–N1 110.8(2), N1–C11–C12–C4 5.1(3), O2–C5–B1–N1 23.1(2). (b)24a: O2–C5 1.229(2), N1–B5 1.593(2), B5–C5 1.639(3),
O2–C5–B5 120.6(2), O1–B5–N1 109.4(1), N1–B5–C5–C6 6.62(2), N1–C14–C3–C4 7.3(2).
Scheme4. Acyl group scope with ligand 14a
Scope of acylboronate synthesis.The scope of the acyl
group was also investigated (Scheme 4). Aromatic KATs were
smoothly converted into the corresponding acylboronates reꢀ
gardless of the nature of substituents. Aromatic halides, nitriles
and terminal alkynes were tolerated.Heteroaromatic KATs can
also participate in this transformation, and 11gwasformed
equally well. Aliphatic monofluoroacylboronate 11h wasisoꢀ
lated in 79% yield after silica gel column purification. The
higher yield for the aliphatic substrate was attributed to a more
stable acyldifluoroborane intermediate – generated from the
KAT and BF3•Et2O – than that of the aromatic counterparts,
leading to less decomposition.28 For 11a, the isolated yield was
comparable when performed on a gram scale (5.0 mmol scale,
1.05 g of 11a), confirmingthe robustness of this complexation.
Properties of acylboronates.A summary of structural data
from NMR spectroscopy and Xꢀray analysis ispresentedin
Table 1, in comparison with known acylborons.For all acylꢀ
boronates, the peaks forthe carbonyl group in the13CꢀNMR
aReaction conditions: 4 (1.0 equiv), TMSꢀ14 (1.0 equiv),
spectra appeared around 220 to 250 ppm as a broad peak due
BF3•Et2O (1.0 equiv), CH3CN (0.1 M), 23 °C. b5.0 mmol scale.
to the quadrupolar relaxation of 11B. These low field shifts are
in good agreement with reported acylboranes and acylꢀ
boronates.8,11,14,18The peaks of aliphatic carbonyls were shifted
even lower than their aromatic counterparts by greater than 10
ppm (4dvs4i, 5avs5hand 11avs11h). The newly synthesized
acylboronates all display signals between +0.2 and+2.9 ppm in
the11BꢀNMR spectra, indicating a tetravalent boron species.29
tetrasubstituted boron and a suitably arranged ligand to coordiꢀ
nate to the boron center are presumably important for their
stability. Since the conformation of ligands is restricted to
tightly bind to the boron center in a bidentate fashion, only the
fluorine atom and the acyl groupareflexible to minimize unfaꢀ
vorable structural effects caused by ligands in the boronate
moiety. This fact is clearly reflected by a wide span of torsion
angles O–C(sp2)–B–F in thesemonofluoroacylboronates.
Amongacylboronates that contain a different class of ligands
(10a, 11a, 12d and 13a), the angles are in the range beꢀ
tween113.23 ° in11a and 166.90 ° in10a. More strikingly, even
among structurally similar acylboronates, the angles cover a
relatively broad range from 112.90 ° in16a to 143.87 ° in18a.
This angle difference must result from a function of ligand
structures, but is not obviously correlated with the different
reactivity of acylboronates observed in the amide forming ligaꢀ
tion with hydroxylamines (vide infra).
In the solid state, C=O bond lengths of 10a (1.226 Å), 11a
(1.235 Å), 12d (1.234 Å) and 13a (1.229 Å) are closer to that
of benzophenone (1.223 Å)30 rather than phenyl benzoate
(1.194 Å).31 In contrast to trisubstituted acylboron 1, C–B, B–
O and B–N bond lengths of thesearein the range of typicaltetꢀ
raꢀsubstituted boron species.32Figure 5 presents a side view of
11a from the biaryl plane, which clearly shows a pyramidal
structure of the boron. In order to coordinate to the tetrahedral
boron, the biaryl moiety in the ligand is slightly twisted, with
an angle of 13.17 °. The O1–B1–N1 angle is 107.9 °, close to
the optimal 109.5 °. Indeed, in all monofluoroacylboronates in
Table 1, the corresponding angles formed by the boron atom
and two coordinating groups in the ligand, either O–B–N or
O–B–O, are between 105.1 °in13a and 110.8 ° in18a. A
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1
2
Figure 6. Chiral reverse phase HPLC spectra of 11a. Daicel
Chiralpak ADꢀRH, 20ꢀ95% CH3CN in 20 min.
3
4
5
Table 2. Half-life of acylboronates under aqueous condi-
tionsa
Table 1. Summary of NMR chemical shifts and bond
lengths/torsion angles of acylborons in solid state
6
7
8
9
Entry
1
Acylꢀ[B]
4a (KAT)
5a (MIDA)
11a
Temp (°C)
t1/2
NMR [ppm]
Solvent
C6D6
Xꢀray [Å] or [°]
Acyl–
23
23
23
50
23
23
23
23
23
23
23
23
23
23
Not observedb
12 min
24 h
13Ca
218
11B
C=O
O–C–B–F
[B]
1b
4dc
2
+21.8
–0.8
1.241
1.240
—
3
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
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d6ꢀacetone 234
9.65
110.06
130.51
—
4
3.3 h
1.0 h
18 h
11a
5
15a
4ic
d6ꢀDMSO 246
–1.9
+5.4
+4.2
+1.7
+2.1
+0.6
+0.2
+2.2
+2.0
+2.0
+2.2
+2.6
+2.9
—
6
16a
5ad
5hd
10a
11a
11h
12d
13a
15a
16a
17a
18a
24a
CD3CN
CD3CN
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
226
239
227
229
243
227
227
229
229
229
229
228
—
—
7
17 h
17a
8
4.8 h
20 h
18a
—
—
9
19a
1.226
1.235
—
166.90
113.23
—
10
11
12
13
14
10 h
20a
1.5 h
4.3 h
12 h
21a
22a
1.234
1.229
1.235
1.234
1.238
1.239
1.229
149.81
120.58
113.45
112.90
133.34
143.87
125.35
23a
15 h
24a
aDetermined by 1HꢀNMR. 0.042 M, 9:1 d6ꢀDMSO/D2O. Bn2O
was used as an internal standard.bEven after 3 days, <5% deꢀ
composition was observed.
As indicated from the Xꢀray structures, these acylboronates
are the first examples ofBꢀchiral acylborons; stable Bꢀchiral
boronates themselves have not been widely explored.33In order
to determine if they are configurationally stable, enantiomers
of the boronate 11a were separated ona reverse phase chiral
HPLC column and the collected peaks were reinjected. Neither
racemization nor decomposition wasobserved even after incuꢀ
bating at 50 °C in MeOH (Figure 6).34 The robustness of the
boron chiral center encouragesthe use of this class of Bꢀchiral
acylboronates for asymmetric synthesis in future applicaꢀ
tions.35,36 As a solid, 11a can be stored on the bench without
special precautions for at least 6 months.
aPeak for the carbonyl group. bRef8. cRef14. dRef18.
The stability of the acylboronates under the KAT ligation
conditions was examined more closely by exposing 11a and its
derivatives to a 9:1 d6ꢀDMSO/D2O solution. The mixtures
were analyzed by 1HꢀNMR using Bn2O as an internal standard
and the decomposition rate of the acylboronates was processed
by pseudoꢀfirst order kinetics. Table 2 showsthe t1/2 of various
acylboronates from the fitted curves.KAT 4a was completely
stable under the conditions and it was difficult to determine its
halfꢀlife (entry 1).37 On the other hand, MIDA acylboronate 5a
was found to be the least stable acylboronates in Table 2, and
quickly decomposed upon exposure to water (entry 2). At
room temperature, monofluoroboronate11aslowly underwent
hydrolysis (entry 3); a faster rate of decomposition was obꢀ
served at 50 °C (entry 4). As we noticed during its preparation,
the substituent at 3ꢀposition made the complex significantly
less stable (entries 5 and 11). The difference in the stability
between 21a and 22a suggests that sterics is not the sole facꢀ
torbehind their instability (entries 11 and 12). This wasalso
suggestedby the results from Meꢀsubstituted19a and Clꢀ
substituted20a at the same position.Mesubstituent at less
crowded position had little influence on the stability (entries 6,
Figure 5. Side view of 11a. ORTEP, ellipsoids are set at a
50% probability. Most hydrogen atoms have been removed for
clarity.
5
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equimolar ratio of 11b and 4ꢀmethylbenzoylboronate was
Scheme 5. Reactivity of acylboronates in amide formation
with hydroxylamine 26a
1
2
3
combined with 1.0 equiv hydroxylamine 26in aqueous DMSO
at 23 °C, and the product ratio was determined by HPLC analꢀ
ysis.
(a) Competitive amide formation between acylboronates
4
5
6
7
8
9
The
acylboronate24aderived
from
10ꢀ
hydroxybenzo[h]quinoline showed significantly lower reactiviꢀ
ty than any other compounds evaluated. On the other hand, the
introduction of a substituent at the 6ꢀposition on the pyridine
ring enhanced its reactivity, making 18aeven superior to the
MIDA acylboronate under these conditions, albeit being slightꢀ
ly less stable than 11a.
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
Mechanism of the amide formation.In addition to the
hydrolytic stability in Table 2, the ground state energies were
calculated by DFT method. The calculations of a series of
acylboronates at the B3LYP/6ꢀ31+G(d, p) level of theory indiꢀ
cated that the instability of 18a was not the sole factor for its
higher reactivity; less stable 15a showed lower reactivity than
(b) List of evaluated acylboronates
,
18a.38 39 This indication opposes the involvement of a decomꢀ
posed but reactive intermediate such as an acyl boronic acid,
and favors a mechanism employing intact monofluoroboroꢀ
nates. This is also consistent with the mechanistic studies preꢀ
viously conducted with MIDA acylboronates.
Based on our previous studies with MIDA acylboronates, a
plausible mechanistic pathway is depicted in Scheme 6. The
initial addition of the hydroxylamine to the carbonyl group
forms tetrahedral intermediate 27, which is in equilibrium with
iminium species 28. The hemiaminal 27 can undergo a conꢀ
certed elimination, followed by a tautomerization to form the
amide. We previously postulated that a higher concentration of
the productive, tetrahedral intermediate in equilibrium was key
for the higher reactivity of MIDA acylboronates than KATs;
the stability of the iminium intermediate derived from either
MIDA acylboronates or KATs determined the position of equiꢀ
librium, and regulated the overall kinetics of the amide forꢀ
mation.
(c) Relative reactivity to 11ab
339
350
300
250
200
150
100
100
50
2
11 15 16 17 18 19 20 21 22 23 24
0
4
5
Scheme 6. Possible mechanistic pathway for the amide
formation of acylboronate and hydroxylamine
aReaction conditions: 11b (1.0 equiv), 4ꢀmethylbenzoylboronate
(1.0 equiv), 26 (1.0 equiv), 8:1 DMSO/H2O, 23 °C. bDetermined
by HPLC. In the reactivity chart, 11a was set to 100 as a
standard substrate.
7 and 9). In all cases, the bidentate, monofluoroacylboronates
were much more stable than the MIDA variants and should be
sufficiently stable for most applications.
Reactivity of acylboronates in amide-forming liga-
tions.We evaluated the reactivity of the newly prepared acylꢀ
boronates inamideꢀforming ligations with hydroxylamines. In
spite of the stability observed above, all acylboronates smoothꢀ
ly formed amides with Oꢀcarbamoylhydroxylamine26, but
their reactivity varied depending on the ligand structure. The
modularity of the ligand structures in acylboronates such as
10a and 11a presents an opportunity to obtain information
about a structureꢀreactivity relationship; KAT has little chance
for a systematic modification, and it was difficult to prepare
acylboronates from MIDA analogs.
In the course of the investigation, we found that slight
modifications of the ligand structure in 11a can have a draꢀ
matic effect on theirreaction rate in amideꢀforming ligation.
The relative reactivity of various 4ꢀmethylbenzoylboronates in
comparison to 11a is illustrated in Scheme 5c; KAT 4a and
MIDA acylboronate 5aare also included for reference. An
The reactivity difference between 18aand 24acan also be
explained by different concentrations of the tetrahedral interꢀ
mediates. Higher reactivity of 18aarises from the less stable
nature of the iminium species due to the steric hindrance of the
methyl group on the ligand. This is similar to ground state
destabilization found in enzyme catalysis.40
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bode@org.chem.ethz.ch
Xꢀray crystallography supports this conjecture.The solid
state structures of 24a, 11a and 18anotably differ in B–N bond
lengths, 1.593, 1.602 and 1.615 Å respectively (Figures3 and
4). A longer B–N bond makes the boron atom more sp2ꢀlike41
and presumably leads to a less stable acylboronate.The obꢀ
served tendency can be understood by the following: 1) the B–
N bond in 18ais longer so as to minimize steric repulsions
between the carbonyl and the methyl group at the 6ꢀposition,
and 2) the B–N bond in 24ais shorter because linking the biarꢀ
yl backbone makes the complex sterically more compact, causꢀ
ing less steric repulsions.42 Since both E and Z isomers of
28are more susceptible to steric hindrance than the parent
acylboronates,43 we conclude that a subtle steric factor on the
ligand leads to notable differences in the reactivity for the amꢀ
ide formation.
1
2
3
4
5
6
7
8
Funding Sources
This work was supported by ETH Zürich.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
We thank the NMR service and the MS service of the Laboratoriꢀ
umfürOrganischeChemie at ETHZürich for analyses. Dr. Nils
Trapp and Dr. Michael Wörleare gratefully acknowledged for the
acquisition of Xꢀray structures.
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REFERENCES
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Conclusions
In summary, we have prepared a series of new acylboronates
and identified a novel class of ligands suitable for fineꢀtuning
of the properties and reactivities of acylboronates.44The one
step synthesis from KATsis robust and scalable, making it
possible to prepare a wide range of acylboronates derived from
either aromatic or aliphatic precursors and a variety of bidenꢀ
tate ligands. These monoꢀfluoroacylboronates arestable to air,
water and chromatography on normal phase silica gel. The
stableacylborons possess a tetravalent boron and a suitably
structured ligand that can coordinate tightly to the sp3ꢀboron
center, both of which arelikelykey for their high stability.
Many acylboronates afforded a crystal suitable for Xꢀray difꢀ
fraction.45Solid state structures and NMR analysis showed they
are the firstBꢀchiral acylboronates reported in the literature.
Their configurational stability in protic solvents was conꢀ
firmed, suggesting a possibility for asymmetric synthesis.All
acylboronates prepared in this study reacted with hydroxylaꢀ
mines to form amides, butsubstantial differencesinreactivities
were observed as a function ofligand structures. Xꢀray crystalꢀ
lographysuggested that the ligand modulates the B–N bond
length, which is associated with steric factors in the complex.
The difference in the reactivity is likely to arise from ground
state destabilization of the unfavorable intermediate, leading to
a higher concentration of the productive intermediate. Thisꢀ
gives useful insights into the reaction mechanismof this amide
formation.
(6)Stevenson, P. J. INComprehensive Organic Functional Group
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A deeper understanding ofthe effects of theligand on the
formation, properties and reactivities of acylboronates is essenꢀ
tial for further improvement of acylboron–hydroxylamine amꢀ
ide formation. Current efforts in our group are following this
line of investigation, particularly with regard to the conditions
for amideꢀforming ligations.The stable nature of acylboronates
will enable further applications such as traceless modulation of
chemoselective amideꢀforming ligations and bioconjugaꢀ
tions.46This study also establishes acylboronates as rich and so
far underexplored class of organoborons ripe for further develꢀ
opment and exploration.
ASSOCIATED CONTENT
Supporting Information. Experimental procedures, supplemenꢀ
tary results, CIF files for all Xꢀray structures, and spectroscopic
data for new compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
(8)(a) Yamashita, M.; Suzuki, Y.; Segawa, Y.; Nozaki, K. J. Am.
Chem. Soc.2007, 129, 9570–9571. (b) Segawa, Y.; Suzuki, Y.; Yamaꢀ
shita, M.; Nozaki, K. J. Am. Chem. Soc.2008, 130, 16069–16079.
AUTHOR INFORMATION
Corresponding Author
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(36) Preliminary results showed that the kinetic resolution of 11a
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(25) MIDA acylboronate was also converted back to KAT at 23 °C
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(26) Analogs of 10a were also easily prepared. See the Supporting
Information for details.
(27) Almost no diastereoselectivity was observed on the formation
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(39) See the Supporting Information for details.
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(41) The tetrahedral characters (THC) of 24a, 11a and 18a are
1
2
3
4
5
6
7
8
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(42) The distances between the carbonyl oxygen and the adjacent
hydrogen on the ligand are 3.05 Å for 18a and 3.38 Å for 24a.
(43)A substituent also makes the tetrahedral intermediate 27 less
stable, but one of the diastereomers of 27 should be less sensitive
towards sterics and likely more favorably formed.
(44)Preliminary results suggest that these ligands can also moduꢀ
late properties and reactivities of nonꢀacyl boronates. The selective
Suzuki–Miyaura cross coupling between an aryl boronic acid and a
monofluoroboronate was easily achieved under anhydrous basic conꢀ
ditions.
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(45) CCDC 1044728–1044736 contain the supplementary crystalꢀ
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bridge Crystallographic Data Centre.
(46) (a) Hackenberger, C. P. R.; Schwarzer, D. Angew. Chem. Int.
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TOC graphic (4.73 x 8.45 cm)
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