Scope and mechanism of a true organocatalytic beckmann rearrangement with a boronic acid/perfluoropinacol system under ambient conditions

Article abstract of DOI:10.1021/jacs.8b01618

Catalytic activation of hydroxyl functionalities is of great interest for the production of pharmaceuticals and commodity chemicals. Here, 2-alkoxycarbonyl- and 2-phenoxycarbonyl-phenylboronic acid were identified as efficient catalysts for the direct and chemoselective activation of oxime N-OH bonds in the Beckmann rearrangement. This classical organic reaction provides a unique approach to prepare functionalized amide products that may be difficult to access using traditional amide coupling between carboxylic acids and amines. Using only 5 mol % of boronic acid catalyst and perfluoropinacol as an additive in a polar solvent mixture, the operationally simple protocol features mild conditions, a broad substrate scope, and a high functional group tolerance. A wide variety of diaryl, aryl-alkyl, heteroaryl-alkyl, and dialkyl oximes react under ambient conditions to afford high yields of amide products. Free alcohols, amides, carboxyesters, and many other functionalities are compatible with the reaction conditions. Investigations of the catalytic cycle revealed a novel boron-induced oxime transesterification providing an acyl oxime intermediate involved in a fully catalytic nonself-propagating Beckmann rearrangement mechanism. The acyl oxime intermediate was prepared independently and was subjected to the reaction conditions. It was found to be self-sufficient; it reacts rapidly, unimolecularly without the need for free oxime. A series of control experiments and ¹⁸O labeling studies support a true catalytic pathway involving an ionic transition structure with an active and essential role for the boronyl moiety in both steps of transesterification and rearrangement. According to ¹¹B NMR spectroscopic studies, the additive perfluoropinacol provides a transient, electrophilic boronic ester that is thought to serve as an internal Lewis acid to activate the ortho-carboxyester and accelerate the initial, rate-limiting step of transesterification between the precatalyst and the oxime substrate.

Full text of DOI:10.1021/jacs.8b01618

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Scope and Mechanism of a True Organocatalytic Beckmann Rear-rangement
with a Boronic Acid / Perfluoropinacol System under Ambient Conditions
Xiaobin Mo, Timothy D. R. Morgan, Hwee Ting Ang, and Dennis G Hall
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 22 Mar 2018
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Journal of the American Chemical Society
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Scope and Mechanism of a True Organocatalytic Beckmann Rear-
rangement with a Boronic Acid / Perfluoropinacol System under
Ambient Conditions
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Xiaobin Mo‡, Timothy D. R. Morgan‡, Hwee Ting Ang, and Dennis G. Hall*
Department of Chemistry, University of Alberta, Edmonton, Alberta, T6G 2G2, Canada
Supporting Information
ABSTRACT: Catalytic activation of hydroxyl functionalities is of great interest for the production of pharmaceuticals and comꢀ
modity chemicals. Here, 2ꢀalkoxycarbonylꢀ and 2ꢀphenoxycarbonylꢀphenylboronic acid were identified as efficient catalysts for the
direct and chemoselective activation of oxime NꢀOH bonds in the Beckmann rearrangement. This classical organic reaction proꢀ
vides a unique approach to prepare functionalized amide products that may be difficult to access using traditional amide coupling
between carboxylic acids and amines. Using only 5 mol% of boronic acid catalyst and perfluoropinacol as an additive in a polar
solvent mixture, the operationally simple protocol features mild conditions, displays a broad substrate scope, and a high functional
group tolerance. A wide variety of diaryl, arylꢀalkyl, heteroarylꢀalkyl and dialkyl oximes react under ambient conditions to afford
high yields of amide products. Free alcohols, amides, carboxyesters, and many other functionalities are compatible with the reaction
conditions. Investigations of the catalytic cycle revealed a novel boronꢀinduced oxime transesterification providing an acyl oxime
intermediate involved in a fully catalytic nonꢀselfꢀpropagating Beckmann rearrangement mechanism. The acyl oxime intermediate
was prepared independently and was subjected to the reaction conditions. It was found to be selfꢀsufficient; it reacts rapidly, uniꢀ
molecularly without the need for free oxime. A series of control experiments and 18O labeling studies support a true catalytic pathꢀ
way involving an ionic transition structure with an active and essential role for the boronyl moiety in both steps of transesterificaꢀ
tion and rearrangement. According to 11B NMR spectroscopic studies, the additive perfluoropinacol provides a transient, electroꢀ
philic boronic ester that is thought to serve as an internal Lewis acid to activate the orthoꢀcarboxyester and accelerate the initial,
rateꢀlimiting step of transesterification between the preꢀcatalyst and the oxime substrate.
rare, and, oftentimes, preꢀactivation of the hydroxyl (i.e., toꢀ
sylation) is required. Compared to the use of inorganic Lewis
INTRODUCTION
New catalytic modes of functional group activation can unlock
unique reactivity in organic molecules and lead to novel bondꢀ
forming processes. When applied to safe and readily available
substrates like alcohols and carboxylic acids, efficient and
atomꢀeconomical methods can be developed that byꢀpass the
use of toxic halide derivatives or stoichiometric reagents.[1] In
this regard, the concept of boronic acid catalysis (BAC) exꢀ
ploits the tempered Lewis acidity of boronic acids along with
their ability to form reversible covalent bonds with hydroxyl
functionalities, thereby providing an opportunity for tempoꢀ
rary activation of C–O bonds. Several applications of BAC
have been demonstrated by our group and others.[2] For inꢀ
stance, we reported direct boronic acidꢀcatalyzed transposiꢀ
tion[3] and substitutions[4] of allylic alcohols, and Friedelꢀ
Crafts alkylation of neutral arenes with readily available alꢀ
lylic and benzylic alcohols.[5] With a view to expand BAC
towards other dehydrative reactions of hydroxylꢀcontaining
functional groups, we considered the direct Beckmann rearꢀ
rangement of ketoximes into secondary amides.[6] In its classiꢀ
cal form, the Beckmann rearrangement is promoted by strong
protic acids.[7] This important transformation is at the heart of
the industrial synthesis of lactam monomers for the manufacꢀ
ture of nylon, and it also finds utility in the discovery and proꢀ
duction of pharmaceuticals.[8] Mild catalytic manifolds are
acids, organocatalysis offers notable advantages such as
broader functional group compatibility and operational simꢀ
plicity (ie., airꢀ and moisture tolerance).
a. Classical Beckmann Rearrangement
OH
O
O
N
H2NOH
H2SO4
H2O
NH
b. Organocatalytic Beckmann Rearrangement Variants
O
P
Cl
n-Pr
O
O
O
N
N
O
P
R1HN
R2
n-Pr
n-Pr
P
Mes
cyclopropenium
Mes
Cl
N
Cl
O
O
O
OH
R2
+
N
cyanuric chloride
T3P
O
R1
> 60 °C
NHR2
R1
c. Boronic Acid Catalyzed Beckmann Rearrangement
B(OH)2
CO2R
OH
O
N
O
1a: R = Me, 1b: R = Ph
+
NHR2
R2
R1HN
R2
R1
R1
CH3NO2:(CF3)2CHOH
25 -50 ℃
Figure 1. Classical and organoꢀmediated/catalyzed Beckmann
Rearrangement procedures.
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Reported procedures for the Beckmann rearrangement emꢀ Table 1. Optimization of Boronic Acid Catalyzed Beckmann
1
2
3
4
5
6
7
8
ploying organic compounds as promoters, such as cyanuric
chloride,[9] BOPCl,[10] triphosphazene,[11] tosyl chloride,[12]
propylphosphonic anhydride (T3P),[13] TFA[14] or cyclopropeꢀ
nium salts[15] require an acid coꢀcatalyst or elevated temperaꢀ
tures (60ꢀ100 °C) to achieve effective activation of oximes
(Figure 1). Many of these reagents have been shown to act
merely as initiators of the Beckmann rearrangement through a
selfꢀpropagating mechanism involving a nitrilium intermediꢀ
ate, and are therefore not true catalysts.[12,15] These limitations,
coupled with the significance of the Beckmann rearrangement
as a unique method for the synthesis of amides, warrant the
development of new organocatalytic procedures that can operꢀ
ate at or near ambient temperature for a wider variety of subꢀ
strates. Herein, using the BAC concept, we report a direct
Beckmann rearrangement procedure that displays high funcꢀ
tional group tolerance under ambient conditions for diaryl,
arylꢀalkyl, heteroarylꢀalkyl and dialkyl oximes, affording high
yields of amide products.
Rearrangement
B(OH)2
F3C CF3
F3C CF3
HO OH
OH
N
CO2R
O
Ph
1a: R = Me, or 1b: R = Ph
N
H
Me
Ph
Me
perfluoropinacol
CH3NO2/HFIP (x:y),
temp, time, [M]
2a
3a
entry[a] cat.
mol
(%)
x:y
[M]
T
t (h)
3a[b]
(%)
(ºC)
9
1
10
10
10
10
10
10
10
5
1:4
1:2
1:1
4:1
1:4
1:4
1:4
1:4
1:4
1:4
1:4
1:4
0.5
0.5
0.5
0.5
1.0
1.0
1.0
1.0
1.0
1.0
1.0
0.5
50
50
50
50
50
rt
72
72
72
72
72
24
24
24
6
100
93
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1a
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
2
3
79
4
60
5
87
6
72
7[c]
8[d]
9[d]
10[d]
11[f]
12
rt
94
rt
93[e]
37[e]
94
RESULTS AND DISCUSSION
5
rt
Optimization of Reaction Conditions. The initial optimizaꢀ
tion focused on the identification of effective boronic acids
capable of mediating the prototypic Beckmann rearrangement
of oxime 2a into amide 3a (Table 1). Over 20 functionalized
aryl boronic acids[16] were screened in different solvents (see
SI). Only 2ꢀmethoxycarbonylphenyl boronic acid (1a) providꢀ
ed a significant amount of the amide product. It was found to
transform oxime 2a into amide 3a in good yield in a solvent
mixture of 4:1 hexafluoroisopropanol (HFIP) and nitromeꢀ
thane at 50 °C after 72 hours (entry 1). The use of HFIP is
vital to the reaction, and a higher conversion is achieved with
a higher proportion of HFIP (entries 2ꢀ4). Further optimization
showed that the concentration could be increased up to 1.0 M,
thus providing substantial solvent economy without underminꢀ
ing the reaction yield (entry 5). However, the reaction exhibitꢀ
ed lower efficiency when decreasing the reaction time and
temperature (entry 6). We hypothesized that, in addition to
providing a polar reaction medium, HFIP could form an elecꢀ
tronꢀpoor boronic ester and modulate the Lewis acidity of the
boron atom. To this end, a catalytic amount of perfluoroꢀ
pinacol was added to promote a more stable cyclic boronic
ester. Satisfactorily, product 3a formed in higher conversion at
room temperature after 24 hours (entry 7). With perfluoroꢀ
pinacol, catalyst loading could be decreased to 5 mol%, afꢀ
fording 3a in high yield (entry 8). Further optimization of the
boronic acid (see SI) led to the use of phenoxy ester 1b, which
considerably shortened the reaction time providing 3a in high
yield after only 6 hours (entries 9ꢀ10). It is noteworthy that the
reaction appears to tolerate trace water (entry 11 vs entry 8),
and the use of molecular sieves was found to have a negligible
effect (see SI). Solvents need no exhaustive drying with this
5
rt
6
5
rt
24
72
86
20
50
0
1c
(R=H)
aReaction conditions: 0.5 mmol of oxime were dissolved in the
b
1
indicated solvent mixture. Yields were determined by H NMR
analysis of reaction mixture using 1,4ꢀdinitrobenzene as internal
c
standard. Reaction was run with 10 mol% of perfluoropinacol.
dReaction was run with 5 mol% perfluoropinacol. Isolated yield.
e
f50 mol% of water was added to the solvent.
Examination of Substrate Scope. A representative panel of
36 aromatic and alkyl substituted oximes were tested in the
boronic acid catalyzed Beckmann rearrangement under the
optimal conditions from Table 1 (entry 8 or 10) using 1a or 1b
as the catalyst. As shown in Scheme 1, in most cases the reacꢀ
tion proceeded efficiently at room temperature for both aryl
and alkyl substituted substrates. As demonstrated with 3a, this
BAC procedure maintains its efficiency on gramꢀscale. A
range of functional groups were found to be fully tolerant of
these reaction conditions. A phenolꢀcontaining substrate unꢀ
derwent the rearrangement in 93% yield (2k). As shown with
products 3lꢀ3r, halide, alcohol, amide, carboxyester, and niꢀ
trile groups are compatible. Moreover, a variety of common
protecting groups were also tolerated, including acid sensitive
Boc (2j) and Ts (2aa) groups. Pharmaceutically relevant hetꢀ
eroaromatic substrates also reacted efficiently, including the
use of free pyrrole (2y) and indole (2z). These unprotected
substrates offer significant synthetic advantage, in terms of
step and atom economy, over amidation methods that require
protected heterocycles. Hindered heteroaromatic amides like
3y are unprecedented and would be difficult to prepare using
standard amide coupling methods. The temperature sensitive
enamide 3ab was obtained in high yield under ambient condiꢀ
tions with this procedure. The steroid pregnenolone oxime 2aj
underwent the Beckmann rearrangement in 76% yield even
without protection of the alcohol. Cyclohexanone oxime 2ag,
a notoriously challenging substrate,[9ꢀ12,15] gave a 65% yield
under more forcing conditions. Additionally, the superiority of
simple
experimental
procedure.
Interestingly,
2ꢀ
carboxyphenylboronic acid (1c) is ineffective (entry 12).
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Journal of the American Chemical Society
aReactions performed on 0.5 mmol scale. Yields are reported
catalyst 1b over 1a is clearly evidenced by the examples of
b
after isolation unless otherwise noted; Gram scale, 30 h; cOxime
1
2
3
4
5
6
7
8
oximes 2l, 2u, and 2af. As expected, aromatic oximes with
electronꢀwithdrawing substituents are less reactive due to their
inferior migratory aptitude. Although carboxyesterꢀsubstituted
aromatic ketone 2r was successful at elevated temperature, no
product was observed when the highly deactivated oxime 2s
was used under various conditions. Oxime 2w was also unreꢀ
active, presumably due to catalyst inhibition from chelation of
the boronic acid to the orthoꢀamine and the oxime moieties.
was formed as a mixture of isomers, for ratios see SI, however,
d
unless noted, a single amide product was observed; The minor
e
product resulted from migration of R2; Yield was determined by
1H NMR analysis of the reaction mixture with 1,4ꢀdinitrobenzene
f
g
h
as internal standard; 50 ºC; 80 ºC; With 10 mol% boronic acid
and diol; iWith 30 mol% boronic acid and diol; j20 mol% boronic
acid, CH3NO2/HFIP (1:1), 50 ºC, 24 h; kHFIP, 50 ºC, 24 h.
9
Several of the oximes used in this study were formed as mixꢀ
tures of E/Z isomers. Notably, in almost all cases the mixture
of oximes resolved to a single major product with generally
excellent selectivity based on the expected migratory aptitude
of the R1 and R2 groups. The nonꢀstereospecific nature of this
Beckmann rearrangement method probably originates from the
rapid interconversion of E and Z oximes under the reaction
conditions.[17]
Scheme 1. Substrate Scope of Boronic Acid Catalyzed Beckꢀ
mann Rearrangementa
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
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58
59
60
boronic acid 1a/1b (5 mol%)
perfluoropinacol (5 mol%)
OH
O
N
R1
N
H
R2
R2
R1
CH3NO2:HFIP = 1:4
rt, 24 h, [1.0 M]
2
3
O
O
O
O
Ph
Ph
Ph
Ph
N
H
N
H
N
H
N
H
Due to the ability of HFIP to facilitate ionic reactions[18] the
BAC conditions were compared with some of the most active
Beckmann rearrangement promoters reported. When T3P and
TFA were applied to a subset of oxime substrates, the results
were clearly inferior to the new BAC method (Scheme 2). In
fact, rearrangement of even the simplest of oximes, 2a, failed
with the use of catalytic or even stoichiometric amounts of
TFA. [19] These results demonstrate that the exceptional activiꢀ
ty of boronic acid catalysts 1a/1b is not simply due to the unuꢀ
sual solvent system employed or to the presence of adventiꢀ
tious acid.
3a (1a): 93%
3a (1a): 94%b
3c (1a): 93% (3:1)c,d
3d (1a): 90%c
3b (1a): 94%
X
O
O
O
O
MeO
Ph
N
N
H
N
H
N
H
H
3i (1a): 70%c X = BocHN, 3j (1a): 88%
X = HO, 3k (1a): 93%
ortho: 3f (1a): 96%
meta: 3g (1a): 86%
para: 3h (1a): 72%
para: 3h (1b): 92%
3e (1a): 90%
X
X
X
O
O
O
N
H
N
H
N
H
X = MeO2C, 3r (1b): 53%g
X = F3C, 3s (1a/1b): 0%
X = Br, 3l (1a): 0%
(1b): 85%
X = HO, 3n (1a): 82%;
Scheme 2. Comparison of Organocatalysts for the Beckmann
Rearrangement in CH3NO2/HFIPa
(1b): 96%
X = F, 3m (1a): 81%
(1b): 92%
X = MeCOHN, 3o (1a): 85%
X = MeO2C, 3p (1a): 99%
OH
O
N
catalyst (5 mol%)
R1
R2
X = NC, 3q (1a): 83%; (1b): 92%
N
H
R2
R1
CH3NO2:HFIP = 1:4
rt, 24 h, [1.0 M]
2
3
S
O
O
O
O
O
S
N
H
N
H
N
H
N
H
N
H
Br
O
O
O
1a/diol: 0%
1b/diol: 85%
T3P: 23%
1a/diol: 93%
3v (1a): 94%d
3t (1a): 99%j
3u (1a): 0%
(1b): 74%d
3w (1a/1b): 0%
1b/diol: 90%b
T3P: 76%
TFA: 0%
N
H
N
H
3l
3a
HN
O
RN
O
MeN
O
O
F
Ph
N
N
H
N
H
N
H
O
O
1a/diol: 81%
1b/diol: 92%
T3P: 66%
1a/diol: 49%
1b/diol: 74%
T3P: 57%
H
Ph
Ph
N
H
N
H
3y (1a): 43%c,j R = H, 3z (1a): 80%
R = Ts, 3aa (1a): 99%f,h
3x (1a): 87%d,f
3ab (1a): 49%
(1b): 74%
3m
3ab
O
O
O
O
1a/diol: 85%
1b/diol: -
T3P: 54%
O
1a/diol: 0%
1b/diol: 98%
T3P: 0%
Ph
N
H
Ph
Ph
N
H
N
H
N
H
N
H
N
H
3ac (1a): 74%f,h
3ad (1a): 84%
3ae (1a): 85%c
3af (1a): 0%
(1b): 98%
3ae
3af
aReactions performed on 0.5 mmol scale. Yields are reported after
b
isolation unless otherwise noted; Reaction was complete after 6
HN
O
h.
O
O
O
H
NH
NH
HO
H
H
NH
Chemical Orthogonality with Alcohols. Electronꢀpoor arylꢀ
boronic acids are excellent catalysts for the activation of cerꢀ
tain alcohols in FriedelꢀCrafts reactions.[5] We were interested
in evaluating the potential of 1a to act as a chemoselective
activator of oxime NꢀOH units. To this end, boronic acid 1a
3ag (1b): 65%e,g,i 3ah (1a): 96%f
3aj (1a): 98%k
3ai (1a): 96%f
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and oxime 2a were subjected to FriedelꢀCrafts benzylation
Scheme 4. Mechanistic Control Experiments[a,b]
1
2
3
4
5
6
7
8
conditions with pꢀxylene and alcohol 4 as competing subꢀ
strates (Scheme 3).[5b] Remarkably, only the amide 3a was
formed along with a good recovery of 2a and alcohol 4. None
of the expected FriedelꢀCrafts product (5) was observed. This
result highlights the potential of BAC in orthogonal catalysis
of reactions with substrates containing multiple hydroxylꢀ
containing functional groups.
R
a.
CO2H
catalyst (20 mol%)
OH
Me
EDC HCl (20 mol%)
DMAP (5 mol%)
O
R = B(OH)2, 52%
R = NO2, trace
R = CF3, trace
R = H, trace
N
Ph
N
H
Me
Ph
CH3NO2:HFIP = 1:1,
50 °C, 24 h, 1.0 M
3a
2a
b.
O
N
Ph
Me
O
9
OH
Me
R
O
R = B(OH)2 (A), 101%c
R = B(pin), 72%
R = H, n.r.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
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31
32
33
34
35
36
37
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40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 3. Chemoselectivity of Boronic Acid Catalyst 1a
N
Ph
catalyst (20 mol%)
N
H
Me
Ph
CH3NO2:HFIP = 1:1,
50 °C, 24 h, 1.0 M
OH
Me
OH
Me
O
2a
3a
N
N
Ph
N
Me
Ph
Ph
H
c.
O
O
1a (20 mol%)
p-xylene (5.0 equiv)
2a (31%)
3a (62%)
N
Ph
2a (1 equiv)
O
OR
3a
(100%)
+
+
Me
CH3NO2:HFIP = 1:4
rt, 30 min
CH3NO2/HFIP (1:4)
0.5 M, 50 °C, 24 h
B(OH)2
B(OR)2
OH
A
R = H or CH(CF3)2
Br
aReaction conditions: 0.5 mmol of oxime were dissolved in the
indicated solvent mixture without further precautions. bYields
Br
5 (0%)
+ 4 (97% recovery)
4 (1 equiv)
1
were determined by H NMR analysis of reaction mixture using
c
1,4ꢀdinitrobenzene as internal standard. Reaction was run with
the conditions of Table 1, entry 10.
Investigation of the ortho-Boronyl Group. Preliminary exꢀ
periments were performed in order to shed light on the mechaꢀ
nism. The unique structure and reactivity of 2ꢀ
methoxy/phenoxycarbonylꢀphenylboronic acids 1a and 1b led
us to propose the formation of a oꢀboronyl oxime ester (A in
Scheme 4c) as the key intermediate for this Beckmann rearꢀ
rangement procedure. Oxime esters were shown by Kuhara in
the early 1900s to be suitable precursors in the Beckmann
rearrangement.[20] To support the intermediacy of an oxime
ester, several control experiments were conducted. 2ꢀ
Carboxyphenylboronic acid was found to be inactive under
various conditions (see Table 1 and SI). However, when the
reaction was performed in the presence of an esterification
reagent to form the acyl oxime in situ, a moderate (52%) yield
of amide product 3a was observed (Scheme 4a). Removing or
replacing the boronyl group with other electron withdrawing
groups (e.g. NO2 and CF3) led to no product formation, which
suggests a Lewis acidic role for the orthoꢀboronyl. Oxime
ester A was prepared independently and shown to efficiently
catalyze the rearrangement, which supports its intermediacy
(Scheme 3b). Protecting catalyst 1a with pinacol before use
resulted in only a trace amount of product (see SI). However,
when the pinacol boronate of A was subjected to the standard
reaction conditions, 72% of amide 3a was observed (Scheme
3b). Altogether these results indicate that a Lewis acidic boroꢀ
nate can facilitate the downstream Beckmann rearrangement,
but a free boronic acid is preferred for effecting the oxime
transesterification. When oxime ester A was exposed to the
reaction solvent, spontaneous rearrangement occurred, formꢀ
ing 3a and a mixture of the carboxylic acid and HFIP ester of
the catalyst. The selfꢀsufficiency and high reactivity of A supꢀ
port a unimolecular Beckmann rearrangement that does not
require a second molecule of oxime as needed in the selfꢀ
propagating ‘nitrilium’ mechanism.[12,15]
Studies of the Role of HFIP and Perfluoropinacol. Use of
HFIP as solvent has proven to be beneficial for cationic proꢀ
cesses such as the Beckmann rearrangement.[17] In addition to
its role as a polar solvent, we suspected that HFIP could also
engage in reversible boronic ester formation with catalyst 1a
thus providing a highly electrophilic and Lewis acidic boron
center (see SI). This idea led to the use of coꢀcatalytic perꢀ
fluoropinacol, which presumably forms a more stable 5ꢀ
membered boronic ester (Table 1, entries 7ꢀ10). The partial
formation of a reactive perfluoropinacol boronate is supported
by NMR studies (Figure 2). Mixtures of boronic acid 1a (δ =
30 ppm) and increasing amounts of perfluoropinacol in nitroꢀ
methaneꢀd3 were subjected to 11B NMR measurement (equaꢀ
tion 1). A large shift in the 11B NMR from 30 ppm to 15 ppm
supports the presence of a tetrahedral boron atom arising from
the coordination between the carbonyl and the Lewis acidic
boron. The perfluoropinacol boronate was prepared indeꢀ
pendently from 1a (equation 2), and it was also subjected to
NMR analysis. The same characteristic 11B NMR shift of 15
ppm confirms its formation in the titration studies. Downfield
1
shifts in the H and 13C NMR signals for the carbonyl and
methoxy groups also suggest an increase in the electrophilicity
of the ester (Scheme 5a). These interactions are likely responꢀ
sible for facilitating the transesterification and promoting the
subsequent Beckmann rearrangement.
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Although the role of the boronyl unit in the actual rearrangeꢀ
a. Titration experiments of 1a with perfluoropinacol using 11B NMR
F3C CF3
1
ment is unclear, it is reasonable to assume that carboxyl coorꢀ
dination to the electrophilic boronate turns the acyl unit into a
very reactive leaving group and thus facilitates the bond miꢀ
gration process (see TS in Scheme 5b). Other electronꢀ
withdrawing substituents such as nitro (cf. Scheme 3a) are
incapable of this sort of internal Lewis acidꢀpromoted activaꢀ
tion. The rearranged acyl imidate B eventually releases the
amide product (D) via exchange with another molecule of
oxime. Acyl imidate B is expected to be a significantly more
reactive ester compared to 1a/1b and acyl oxime A. Thus, it
reacts rapidly by transesterification with oxime substrate to
recycle the effective catalyst, acyl oxime A. When no more
oxime is available, esterification with HFIP, a much weaker
2
3
4
5
6
7
8
9
F3C
CF3
B(OH)2
CO2Me
F3C CF3
F3C CF3
CD3NO2
rt, 18 h
O
O
B
(1)
+
CO2Me
HO OH
1a
perfluoropinacol
(1.0-3.0 equiv)
(
11B: 30 ppm)
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16
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18
19
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23
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49
50
51
52
53
54
55
56
57
58
59
60
1
nucleophile, leads to C, which was detected by MS and H
NMR (see SI).
Scheme 5. Proposed Catalytic Cycle of Boronic Acid Cataꢀ
lyzed Beckmann Rearrangement
a. Boron activated transesterification with oxime:
OMe
O
CO2Me
B(OH)2
perfluoropinacol
B
O
O
1a
CF3
CF3
1H (O-Me): 3.9 ppm
13C (C=O): 170.0 ppm
11B (Ar-B): 30.0 ppm
F3C
CF3
OH
N
1H (O-Me): 4.5 ppm
13C (C=O): 183.0 ppm
11B (Ar-B): 15.0 ppm
Me
δ+
H
Ph
Ph
Me
Me
O
b. Synthesis of the perfluoropinacol boronate
O
N
F3C CF3
O
F3C
CF3
B(OH)2
δ-
B
F3C CF3
Dean-Stark
O
O
CO2Me
OR
B
+
RO
F3C
CF3
(2)
slow
toluene, reflux, 24 h
CO2Me
HO OH
ester activation
(R2 = perfluoropinacolato)
1a
(1.0 mmol)
perfluoropinacol
(1.0 equiv)
95% (11B: 15 ppm)
b. Beckmann rearrangement:
O
Ph
Figure 2. Titration of boronic acid 1a with various amounts of
N
H
Me
(product)
perfluoropinacol via 11B NMR.
O
N
Ph
Me
D
O
B(OR)2
Mechanistic Proposal: True Catalysis vs Self-propagation.
Based on the above experiments, a catalytic cycle is proposed
in Scheme 5. The catalyst undergoes boronic ester formation
with perfluoropinacol resulting in a more electrophilic boron
center, which mediates the oxime transesterification by actiꢀ
vating the carboxyester and affording catalytic intermediate A
(Scheme 5a). This boronꢀassisted oxime transesterification is
likely to be the rateꢀlimiting step, a notion supported by the
superiority of preꢀcatalyst 1b with a better leaving group
(OPh). Based on the ability of A to rearrange spontaneously
and quantitatively in the absence of free oxime (cf. Scheme
4c), this boronic acid induced Beckmann rearrangement likely
proceeds via a fully catalytic, unimolecular mechanism. The
reactivity of A does not support a stepwise bimolecular selfꢀ
propagating mechanism involving the reaction of a free niꢀ
trilium ion with oxime substrate.[21] This sort of stepwise proꢀ
cess has been previously shown to lead to dimerized side
products with other organocatalysts.[9,12b] These byproducts
were not observed when 1a was used as the catalyst with cyꢀ
clohexanone oxime, which further supports the proposed
mechanism when using 1a/1b as catalytic species.[22]
OH
Me
A (acyl oxime)
(R =CH(CF3)2 or
Ph
N
perfluoropinacolato)
Ph
N
O
B
Transesterification
Me
OH
N
O
Beckmann
Rearrangement
Me
OR
Ph
RO
TS
O
Me
O
CF3
CF3
Ph
HFIP
O
N
O
B(OR)2
B (acyl imidate)
B(OR)2
C
A qualitative reaction progress kinetic analysis of the rearꢀ
rangement step was performed by monitoring the decomposiꢀ
tion of acyl oxime A into products C and D by LCꢀMS and
UV detection (Figure 3). This study confirmed the rapid transꢀ
formation of acyl oxime (A) into the amide and HFIP ester
products at ambient temperature. Decay of A does not show
the linear relationship expected of a zeroꢀorder rearrangement.
This observation is most likely explained by the involvement
of HFIP as a reactant in the probable rateꢀlimiting transesteriꢀ
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fication of the acyl imidate intermediate (B), a step required to
of the 18O label was observed, and the 18O ended up partitionꢀ
1
2
3
4
5
6
7
8
release C and D. When used as solvent, HFIP thus leads to a
pseudoꢀfirstꢀorder situation that is reminiscent of the exponenꢀ
tial profiles of Figure 3.
ing into HFIP ester C* (35%) and amide product D* (59%). A
negligible amount (<2%) of carboxylic acid E was observed.
These results confirm that the oxime oxygen atom is the one
being incorporated into the amide product, not water, and it
also rules out the selfꢀpropagating pathway commonly operaꢀ
tive with other organocatalysts. Control analysis with authenꢀ
tic 2ꢀcarboxyphenylboronic acid (E) confirmed that if it
formed, carboxylic acid E or its boronate form would be easily
detected under the LCꢀMS conditions utilized (see SI). To
confidently rule out the selfꢀpropagated mechanism, an asꢀ
sumption deduced by the absence of 2ꢀcarboxyphenylboronic
acid (E) from the reaction mixture, it was necessary to confirm
that E is unable to convert to C under the reaction conditions.
Indeed, subjecting 2ꢀcarboxyphenylboronic acid (E) with and
without oxime 2a in HFIP did not lead to the formation of the
HFIP ester C (Scheme 7).
Thus, product D* can only form through the fully catalytic,
nonꢀselfꢀpropagating mechanism. Partitioning of the 18O label
into C* and D* is in closer agreement with the ionic pathway.
With the highly polar solvent used, it is reasonable to envisage
that an asynchronous rearrangement through a shortꢀlived ion
pair consisting of the carboxylate and the piꢀcomplex could
occur. The slight deviation from a nonꢀequal distribution of the
label (ie., 59:35 as opposed to 47:47), may be rationalized
through two possible explanations (Scheme 8). Because the
16O oxygen is coordinated to the boron atom, the 18O label is
initially more “free” to collapse with the piꢀcomplex and form
the acyl imidate, thus leading to a disproportionate amount of
18O label into amide D* (Scheme 8a). Alternatively, provided
formation of the acyl imidate is reversible, complex kinetic
isotopic effects and/or equilibrium isotopic effects could maniꢀ
fest and play a role leading to a small bias in favor of C/D*
over C*/D. Nevertheless, with proportions of labeled B* and
C* that are quite similar, the rearrangement mechanism is
consistent with the ionic pathway and a true catalytic cycle
involving 1a/1b as preꢀcatalysts and acyl oxime A as the efꢀ
fective catalytic species.
O
O
Me
N
Ph
Me
Ph
O
O
N
B(OH)2
B(OH)2
B (acyl imidate)
A (acyl oxime)
9
10
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48
49
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53
54
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57
58
59
60
(HO)2B
O
CF3
CF3
O
HFIP
+
Ph
O
N
H
rt, 20 min
D (amide)
C (HFIP ester)
400
300
200
100
0
A
C
D
0
5
10
15
20
Time (min)
Figure 3. Reaction progress kinetic analysis of the model Beckꢀ
mann rearrangement of the acyl oxime (A) of acetophenone. Relaꢀ
tive peak areas on the graph are not normalized.
To further support the proposed Beckmann rearrangement
mechanism, an isotope labeling study was conducted using
18Oꢀlabeled acyl oxime (Scheme 6). If the rearrangement is
unimolecular with ionic character, the label should distribute
about equally into amide product D* and HFIP ester C*. If the
rearrangement step is concerted, depending on the migrating
oxygen of the carboxylate unit, the label should be observed
exclusively in amide D* or, if 1,3ꢀmigration of the carboxylate
is preferred, it will be observed in HFIP ester C*. With a selfꢀ
propagating pathway, the label should be incorporated solely
into carboxylic acid E* (1c). Acyl oxime A* was synthesized
as a 2,2ꢀdimethylpropanediol boronate with a 18O label onto
the sp3 oxygen. It was prepared with 51% 18O incorporation
using a 18Oꢀlabeled acetophenone oxime 2a* made according
to a literature procedure.23 The results of this experiment,
which was analyzed by HPLCꢀMS (selected ion monitoring
mode), are shown in Scheme 6. Acyl oxime B* was treated in
HFIP in the presence of a small amount of water to allow in
situ boronate hydrolysis to the more reactive boronic acid. In
our reaction optimization (cf., Table 1), water was shown not
to significantly affect this Beckmann rearrangement proceꢀ
dure. Moreover, the presence of water in this investigation
would allow us to confirm or rule out adventitious water as
being the origin of the oxygen atom in the amide product. In
the event, with A* normalized as 100% 18O, less than 6% loss
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Scheme 6. Rearrangement of 18OꢀLabeled Oxime 2a*
1
2
3
4
5
6
7
18O
18O
Ph
(HO)2B
CF3
CF3
(HO)2B
O
N
Ph
HFIP
N
H
O
[B*]
+
18OH
or
D*
C*
{*35%}
{*59%}
Ionic (asynchronous) pathway
8
9
18O
(HO)2B
O
(HO)2B
O
CF3
CF3
HFIP
HFIP
Ph
N
Ph
[B*]
[B*]
18O
O
+
N
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
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46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
O
O
H
H2O
B
O
(HO)2B
O
C
D*
(10 equiv)
Ph
N
N
Ph
18O
18O
or
O
HFIP
50 °C, 6 h
(HO)2B
CF3
CF3
O
Ph
18O
boronic ester of A*
(51% 18O incorporation)
(HO)2B
A* (acyl oxime) {*100%}
Ph
O
N
H
N
+
18O
C*
D
Concerted pathway
(HO)2B
(HO)2B
O
O
O
Ph
oxime
18OH
18OH
+
N
N
Ph
+
H
nitrilium
D
E*
E*
Self-propagation pathway
Scheme 7. Control reactions: nonꢀformation of C from 1c
a. With oxime 2a
O
CF3
CF3
B(OH)2
CO2H
O
OH
Me
HFIP
N
Ph
O
CONCLUSION
+
N
H
Me
+
Ph
rt, 30 min
B(OR)2
In summary, we have identified 2ꢀmethoxy/2ꢀphenoxyꢀ
carbonylꢀphenylboronic acids 1a/1b with catalytic perfluoroꢀ
pinacol as chemoselective organocatalysts for the Beckmann
rearrangement under mild conditions at ambient temperature.
This operationally simple protocol requires no inert atmosꢀ
phere or preꢀdrying of solvents and displays a broad scope of
oxime substrates and a high functional group tolerance. Mechꢀ
anistic studies suggest a novel organocatalytic pathway initiatꢀ
ed by facile boron mediated transesterification of an oxime,
followed by a unimolecular Beckmann rearrangement. The
boronyl unit of catalyst 1a/1b plays an active role in both steps
of this unique and selective mode of N–OH bond activation. In
light of the selfꢀsufficiency and high reactivity of intermediate
A, and 18O labeling studies, this work identifies a true organoꢀ
catalytic Beckmann rearrangement mechanism and further
expands the scope and utility of the BAC concept.
1c
2a
3a
C
b. Without oxime
O
CF3
CF3
B(OH)2
CO2H
O
HFIP
rt, 30 min
Ph
O
+
N
H
Me
B(OR)2
1c
3a
C
Scheme 8. Possible pathways for uneven C*:D* proportions
ASSOCIATED CONTENT
Supporting Information. Experimental details, analytical and
spectral reproductions for the prepared compounds. The Supportꢀ
ing Information is available free of charge on the ACS Publicaꢀ
tions website.
AUTHOR INFORMATION
Corresponding Author
*Eꢀmail: dennis.hall@ualberta.ca
Author Contributions
‡These authors contributed equally.
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(22) In contrast, formation of the dimer side product of cyclohexaꢀ
none oxime was confirmed by H NMR and HRMS when TsCl was
used as an activator under the same reaction conditions (see SI).
(23) Pusterla, I.; Bode, J. W. Angew. Chem. Int. Ed. 2012, 51, 513ꢀ
516.
Funding Sources
1
1
2
3
No competing financial interests have been declared.
ACKNOWLEDGMENT
4
5
6
7
X. M. thanks Alberta Innovates – Health Solutions for a Graduate
Studentship. This research was generously funded by the Natural
Science and Engineering Research Council of Canada (Discovery
Grant to D. G. H.) and the University of Alberta
8
9
REFERENCES
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Chem. Soc. 2016, 138, 10762ꢀ10765.
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(5) (a) Ricardo, C. L.; Mo, X.; McCubbin, J. A.; Hall, D. G. Chem.
Eur. J. 2015, 21, 4218ꢀ4223; (b) Mo, X.; Yakiwchuk, J.; Dansereau,
J.; McCubbin, J. A.; Hall, D. G. J. Am. Chem. Soc. 2015, 137, 9694ꢀ
9703.
(6) Gawley, R. E. Org. React. 1988, 35, 1ꢀ420.
(7) Beckmann, E. Ber. Dtsch. Chem. Ges. 1886, 19, 988ꢀ993.
(8) Examples: (a) Production route to paracetamol: Davenport, K.G.;
Hilton, C. B. Process for producing Nꢀacylꢀhydroxy aromatic amines,
United States Patent. US4524217, 18 Jun 1985; (b) (+)ꢀCodeine:
White, J. D.; Hrnciar, P.; Stappenbeck, F. J. Org. Chem. 1999, 64,
7871ꢀ7884. For other examples see: (c) Holth, T. A. D.; Hutt, O. E.;
Georg, G. I. Beckmann Rearrangements and Fragmentations in Or-
ganic Synthesis. In Molecular Rearrangements in Organic Synthesis
(Eds.: C. M. Rojas), John Wiley & Sons, Inc., 2015, pp. 111ꢀ150.
(9) Furuya, Y.; Ishihara, K.; Yamamoto, H. J. Am. Chem. Soc. 2005,
127, 11240ꢀ11241.
(10) Zhu, M.; Cha, C.; Deng, W. ꢀP.; Shi. X. ꢀX. Tetrahedron Lett.
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(11) Hashimoto, M.; Obora, Y.; Sakaguchi, S.; Ishii, Y. J. Org. Chem.
2008, 73, 2894ꢀ2897.
(12) (a) Pi, H. ꢀJ.; Dong, J. ꢀD.; An, N.; Du, W.; Deng, W. ꢀP. Tetra-
hedron 2009, 65, 7790ꢀ7793; (b) An, N.; Tian, B. ꢀX.; Pi, H. ꢀJ.;
Eriksson, L. A.; Deng, W. ꢀP. J. Org. Chem. 2013, 78, 4297ꢀ4302 (c)
Tian, B. ꢀX.; An, N.; Deng, W. ꢀP.; Eriksson, L. A. J. Org. Chem.
2013, 78, 6782ꢀ6785.
(13) Augustine, J. K.; Kumar, R.; Bombrun, A.; Mandal, A. B.
Tetrahedron Lett. 2011, 52, 1074ꢀ1077.
(14) Ronchin, L.; Vavasori, A.; Bortoluzzi, M. Catal. Commun. 2008,
10, 251ꢀ256: TFA is employed as a stoichiometric promoter.
(15) Vanos, C. M.; Lambert, T. H. Chem. Sci. 2010, 1, 705ꢀ708.
(16) Focus was placed mainly on oꢀfunctionalized aryl boronic acids
with various ortho substitution (Y = F, Br, I, CF3, NO2, CN, CHO,
CO2H, CONH2, CO2Me, etc).
(17) Pereira, M. M. A.; Santos, P. P. Rearrangements of hydroxyla-
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F., Eds.; John Wiley & Sons, Ltd., 2009; pp. 343ꢀ498.
(18) Shuklov, I. A.; Dubrovina, N. V.; Börner, A. Synthesis, 2007,
2925ꢀ2943.
(19) For attempted Beckmann rearrangement with TFA under various
other conditions, see SI.
(20) (a) Kuhara, Mem. Coll. Sci. Eng. Kyoto Imp. Univ. 1906, 1, 254;
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TOC Graphic
1
2
3
4
5
B(OH)2
OH
O
N
R1
CO2Ph
BAC
R2
N
H
R2
via
R1
BAC 1b (5 mol%)
6
7
8
9
R2
O
True catalysis
Broad scope
R1
N
R1
O
O
N
R2
Chemoselective
Mild conditions
Simple procedure
O
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B(OR)2
B(OR)2
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