Intramolecular aminoboration of unfunctionalized olefins

Article abstract of DOI:10.1002/anie.201505489

A direct and catalyst-free method for the intramolecular aminoboration of unfunctionalized olefins is reported. In the presence of BCl₃ (1 equiv) as the sole boron source, intramolecular aminoboration of sulfonamide derivatives of 4-penten-1-am

Full text of DOI:10.1002/anie.201505489

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Angewandte
Communications
International Edition: DOI: 10.1002/anie.201505489
German Edition: DOI: 10.1002/ange.201505489
Synthetic Methods
Intramolecular Aminoboration of Unfunctionalized Olefins
Chun-Hua Yang, Yu-Shi Zhang, Wen-Wen Fan, Gong-Qing Liu, and Yue-Ming Li*
Abstract: A direct and catalyst-free method for the intra-
molecular aminoboration of unfunctionalized olefins is
reported. In the presence of BCl3 (1 equiv) as the sole boron
source, intramolecular aminoboration of sulfonamide deriva-
tives of 4-penten-1-amines, 5-hexen-1-amines, and 2-allylani-
lines proceeded readily without the use of any catalyst. The
boronic acids obtained after hydrolysis could be converted into
the corresponding pinacol borates in a straightforward manner
by treatment with pinacol under anhydrous conditions.
O
rganoboron compounds have found widespread applica-
Scheme 1. Inter- and intramolecular aminoboration reactions.
Bz=benzoyl, pin=pinacolato.
tion in a variety of carbon–carbon and carbon–heteroatom
coupling reactions.[1] Furthermore, boronic acid moieties have
emerged as important functional groups in biologically active
compounds. For example, an a-aminoboronic acid is a key
structure in the proteasome inhibitor Velcade (bortezomib),[2]
and b-aminoboronic acids have been used as a key subunit in
peptidomimetics with antitubercular activity.[3]
In the course of searching for new methods for the
À
amination of C C multiple bonds, we found that the intra-
molecular fluoroamination of unfunctionalized olefins was
possible with BF3 as the fluorine source and PhI(OAc)2 as the
reaction promoter.[12] We assumed that the direct amino-
Traditionally, organoboron compounds have been pre-
pared by transmetalation reactions between organometallic
compounds, such as organolithium and organomagnesium
reagents, and borates,[4] by the hydroboration of alkenes and
alkynes,[5] by the haloboration or aminoboration of alkynes,[6]
=
À
boration of C C double bonds should be possible if an N B
intermediate could be generated during the reaction. In this
context, an aminoboration reaction was proposed with
BF3·Et2O as the boron source. However, no desired amino-
boration product was detected when 1a was treated with
BF3·Et2O. Instead, a very slow intramolecular hydroamina-
tion reaction occurred, which was complete after 24 h at 608C
(Scheme 2).[13]
by the borylation of C X double bonds,[7] by the borylation of
=
C H/C X bonds, and by other miscellaneous methods.[9]
Recently, Hirano, Miura, and co-workers[10] and Tortosa and
co-workers[11] described the copper(I)-catalyzed simultaneous
[8]
À
À
À
addition of nitrogen and boron atoms to C C multiple bonds
or their equivalents for the preparation of aminoboron
compounds. In the presence of a catalytic amount of CuCl,
the intermolecular aminoboration of olefins with bis(pinaco-
lato)diboron and O-benzoyl N,N-dialkyl hydroxylamines
produced the corresponding b-aminoboron compounds in
good to excellent yields (Scheme 1a). We are interested in
developing new, straightforward procedures for the amino-
Scheme 2. Amination reactions involving BF3. Ts=p-toluenesulfonyl.
À
boration of C C multiple bonds. Herein, we report our recent
results on the direct and catalyst-free intramolecular amino-
=
boration of unfunctionalized C C double bonds (Sche-
me 1b).
We reasoned that BF3 would interact with the sulfonamide
substrate 1a to form a Lewis pair with either the nitrogen or
oxygen atom of the sulfonamido group. The formation of an
[*] C.-H. Yang, Y.-S. Zhang, W.-W. Fan, Dr. G.-Q. Liu, Prof. Dr. Y.-M. Li
Stake Key Laboratory of Medicinal Chemical Biology, College of
Pharmacy and Tianjin Key Laboratory of Molecular Drug Research
Nankai University
À
N BF2 bond is difficult owing to the high dissociation energy
À
of B F bonds. Instead, Lewis acid mediated reactions took
place, and the hydroamination product was isolated. Given
Tianjin 300071 (P.R. China)
E-mail: ymli@nankai.edu.cn
À
that the dissociation energy of a B Cl bond is lower than that
À
of a B F bond, we reasoned that different reactions should
Prof. Dr. Y.-M. Li
take place if BCl3 was used instead of BF3 under similar
reaction conditions. To test this assumption, we added
a stoichiometric amount of BCl3 to a solution of 1a. After
12 h at room temperature, the desired aminoboration product
2a was obtained (Scheme 3). The structure of 2a was
confirmed by X-ray diffraction.
CAS Key Laboratory of Synthetic Chemistry of Natural Substances
Shanghai Institute of Organic Chemistry
Chinese Academy of Sciences
345 Lingling Road, Shanghai 200032 (P.R. China)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201505489.
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Chemie
boronates were isolated in good overall yields (Table 1).
The reaction was not affected significantly by the Thorpe–
Ingold effect (compare the formation of products 3a, 3 f, 3h,
Table 1: Direct intramolecular aminoboration of unfunctionalized N-(4-
pentenyl)sulfonamides.[a]
Scheme 3. Direct intramolecular aminoboration of 1a.
Encouraged by this result, we optimized the conditions for
this direct intramolecular aminoboration reaction. Prelimi-
nary results indicated that the reaction medium was crucial
for the reaction. Haloalkane solvents were generally suitable,
and 1,2-dichloroethane (DCE) gave the most promising
result. This solvent was then used as the reaction medium
for further studies. Polar aprotic solvents, such as THF, 1,4-
dioxane, DMF, and acetonitrile, were not suitable for the
reaction, possibly as a result of their strong interaction with
BCl3 and subsequent deactivation of the latter. When the
reaction was carried out in toluene, the expected amino-
boration product was also obtained. However, the removal of
toluene was difficult as compared to the removal of DCE, and
reaction in toluene was not pursued further. No significant
rate difference was observed when the reaction was carried
out at 308C instead of 258C. Therefore, subsequent reactions
were carried out at room temperature without special control
of the reaction temperature. A reaction with BBr3 as the
boron source gave a similar result. Studies with BBr3 were not
continued owing to the relatively difficult conditions needed
to handle the reagent.
Entry
R1
R2
Product
Yield [%][b]
1
2
3
4
Ph
Ph
Ph
Ph
Ts
Ms
3a
3b
3c
3d
74
86
44
84
o-NO2C6H4SO2
p-NO2C6H4SO2
5
86
À
À
À
6
7
8
(CH2)5
Ts
Ms
Ts
Ms
3 f
3g
3h
3i
3j
3k
3l
83
45
61
44
68
55
63
40
À
(CH2)5
Me
Me
Me
H
9
10
11
12
13
p-NO2C6H4SO2
Ts
PhSO2
H
H
p-NO2C6H4SO2
3m
[a] Reactions conditions: 1 (1 mmol), BCl3 (1 mmol), DCE (10 mL),
argon atmosphere. [b] Yield of the isolated product. Ms=methanesul-
fonyl.
Having established optimal reaction conditions, we also
studied the effect of the protecting group on the course of the
reaction. We found that the basicity and nucleophilicity of the
nitrogen atom were crucial factors. When the amino group
was protected with a tosyl group, the aminoboration product
was obtained in good yield. Other protecting groups, such as
benzyl, acetyl, trifluoroacetyl, and tert-butoxycarbonyl (Boc)
groups, were not suitable, and no aminoboration product was
detected when substrates bearing these protecting groups
were subjected to the reaction. Deprotection occurred with
the isolation of the corresponding primary amine when a Boc-
protected substrate was used. These results indicated that for
the aminoboration to proceed, the amino/amido group must
have balanced basicity/nucleophilicity. Strongly nucleophilic
amino/amido groups will interact more strongly with BCl3,
thus leading to the deactivation of both the nitrogen and the
boron atom.
and 3k).[15] Substrates with substituents on the main chain,
À
À
such as 2,2-diphenyl (substrate 1a), (CH2)5 (substrate 1 f),
or 2,2-dimethyl (substrate 1h), were transformed efficiently
into the desired aminoboration products, and the amino-
boration of substrates without substituents on the main chain
(substrates 1k–m) also gave the corresponding aminobora-
tion products in satisfactory yields (Table 1, entries 11–13).
Substrate 1e did not undergo the aminoboration reaction.
Instead, the Friedel–Crafts alkylation product 3e was isolated
in high yield (Table 1, entry 5).[13] A gram-scale synthesis of
2a was also carried out to test the scalability of the method:
The aminoboration of 1a on a 5.0 mmol scale afforded
boronic acid 2a in 83% yield. Furthermore, functional-group
transformations by oxidation, amination, and Suzuki coupling
reactions were possible.[16]
As the purification of boronic acids on a silica-gel column
is sometimes problematic, the obtained boronic acids were
converted into the corresponding boronates[14] to facilitate
product purification. A variety of N-(4-pentenyl)sulfonamide
substrates 1 were subjected to the intramolecular amino-
boration reaction. After complete consumption of the starting
material, the reaction mixture was carefully treated with
water, and the crude product was separated from the mixture
and treated with pinacol and magnesium sulfate to give the
corresponding pinocol boronate. Reactions of p-toluene-,
methane-, 2-nitrobenzene-, and 4-nitrobenzenesulfonamide
substrates all proceeded readily, and the corresponding
We next turned our attention to the intramolecular
aminoboration of N-(5-hexenyl)sulfonamide substrates 4.
Reactions of N-(5-hexenyl)sulfonamide substrates 4 generally
proceeded less efficiently than those of N-(4-pentenyl)sulfon-
amide substrates 1, possibly as a result of the disfavored
entropic nature of the cyclization reactions.[17] However,
aminoboration products 5 were still isolated in moderate to
good yields under the optimized conditions (Table 2).
Following the synthesis of [(4,4-diphenyl-1-tosylpyrroli-
din-2-yl)methyl]boronic acid (2a), 2-(4,4,5,5-tetramethyl-
[1,3,2]dioxaborolan-2-ylmethyl)pyrrolidines
(3),
and
2-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-ylmethyl)piperi-
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Table 2: Direct intramolecular aminoboration of unfunctionalized N-(5-
We carried out control experiments to study the possible
formation of HCl during the aminoboration reaction. Two
reactions were examined under the standard aminoboration
conditions, and sodium carbonate was added to one of the two
reaction mixtures. The reactions were carried out in an ice–
water bath and were sampled every 10 min. The study showed
that reactions in the presence of Na2CO3 proceeded slightly
faster than reactions without the base (Table 4). This result
hexenyl)sulfonamides.[a]
Entry
R1
R2
Product
Yield [%][b]
1
2
3
4
5
6
7
8
9
Ph
Ph
Ph
À
Ts
Ms
5a
5b
5c
5d
5e
5 f
5g
5h
5i
58
70
50
54
65
67
86
56
61
63
76
54
Table 4: Control experiments with and without a base.[a]
p-NO2C6H4SO2
Ts
Ms
p-NO2C6H4SO2
Ts
Ms
o-NO2C6H4SO2
Ts
PhSO2
À
À
(CH2)5
À
(CH2)5
À
À
(CH2)5
Me
Me
Me
H
Entry
Reaction time
[min]
Yield [%][b,c]
10
11
12
5j
5k
5l
A
B
H
H
1
2
3
4
5
6
10
20
30
40
50
60
43
48
53
57
61
64
47
55
58
61
66
72
p-NO2C6H4SO2
[a] Reaction conditions: 4 (1 mmol), BCl3 (1 mmol), DCE (10 mL), argon
atmosphere. [b] Yield of the isolated product.
dines (5), we also investigated the synthesis of different 2-
(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-ylmethyl)-2,3-dihy-
dro-1H-indoles 7 by this method. The desired aminoboration
products 7a–f were isolated in moderate overall yields, and
the reaction was not overly sensitive to the electronic effect of
substituents on the benzene ring (Table 3).
[a] Reactions were carried out with 1a (0.5 mmol) and BCl3 (0.5 mmol) in
CDCl3 (5 mL), with or without Na2CO3, in an ice–water bath. [b] The yield
of 2a was determined by NMR spectroscopy with 1,3,5-trimethoxyben-
zene (0.33 mmol) as the internal standard. [c] Conditions A: The
reaction was carried out in the absence of Na2CO3. Conditions B: The
reaction was carried out in the presence of Na2CO3.
Table 3: Direct intramolecular aminoboration of N-(2-allylphenyl)-
possibly supports the assumption of the formation of HCl
during the reaction. Removal of HCl from the reaction system
sulfonamides.[a]
À
should help to move the equilibrium to the N BCl2 side and
speed up the reaction.
NMR spectroscopic experiments were also carried out to
study the interaction between BCl3 and the sulfonamide
functional group. As a direct NMR spectroscopic study on the
interaction between the substrate and BCl3 was difficult
owing to the fast conversion of the starting material into the
aminoboration product, N-methyl-p-toluenesulfonamide
Entry
R1
R2
Product
Yield [%][b]
1
2
3
4
5
6
H
Ts
Ts
Ts
Ts
7a
7b
7c
7d
7e
7 f
78
69
29
41
51
67
Me
MeO
Cl
Me
Cl
1
(TsNHMe) was used as a model substrate. H NMR spectra
showed that the sulfonamide signals changed significantly
after the addition of BCl3. Similarly, the 11B NMR signal of
BCl3 changed significantly after the addition of TsNHMe. We
reasoned that this change was due to the strong interaction
between BCl3 and the sulfonamide. DFT calculations were
also carried out. Preliminary results indicated that the
departure of HCl from the Lewis adduct was the rate-limiting
step. However, this step was energetically favored both
kinetically and thermodynamically. The intramolecular ami-
noboration step was found to be a fast step with a low energy
barrier.[16]
On the basis of previously reported results and these
preliminary studies, we propose a possible reaction pathway
for the intramolecular aminoboration reaction in Scheme 4:
When BCl3 is mixed with the substrate, it interacts with the
sulfonamide nitrogen atom to form an LA···NHRTs adduct
p-NO2C6H4SO2
p-NO2C6H4SO2
[a] Reaction conditions: 6 (1 mmol), BCl3 (1 mmol), DCE (10 mL), argon
atmosphere. [b] Yield of the isolated product.
The formation of the Friedel–Crafts alkylation product 3e
rather than the corresponding aminoboration product when
the trisubstituted substrate 1e was subjected to the reaction
(Table 1) indicated the formation of a carbenium cation
intermediate. The carbenium cation could be formed by
=
protonation of the substituted C C double bond with HCl
when the corresponding carbenium cation intermediate
showed enough stability. Reactions of terminal alkenes
could proceed through the aminoboration pathway since the
formation of the corresponding secondary carbenium cation
would be slow and less favored.
À
A. The elimination of HCl from A to give an N BCl2
intermediate B is the rate-limiting step. It is also a fast step,
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Scheme 4. A tentative reaction pathway for the intramolecular amino-
boration reaction.
and the addition of a base had little effect on the course of the
1
reaction. A downfield shift of the H NMR signals for the
methylene hydrogen atoms adjacent to the nitrogen atom was
observed owing to the attachment of an electron-withdrawing
boron group to the nitrogen atom. Intramolecular amino-
boration similar to a hydroboration reaction then occurred to
give product C, which could be hydrolyzed to afford the final
aminoboration product D. We propose that when the
=
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a carbenium cation intermediate, which was captured by the
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3e.[13]
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In summary, we have described the direct intramolecular
aminoboration of a variety of N-(4-pentenyl)-, N-(5-hexenyl)-
, and N-(2-allylphenyl)sulfonamide substrates by treatment
with BCl3. In the presence of BCl3 (1 equiv) as the sole boron
source, direct intramolecular aminoboration of these unfunc-
tionalized olefins proceeded readily at room temperature
without the use of a catalyst to give the corresponding boronic
acids in good yields. The boronic acids could be readily
converted into boronates, and the obtained boronates could
be further functionalized by oxidation, amination, and Suzuki
coupling reactions. The good yields, mild reaction conditions,
and straightforward reaction procedure make this trans-
formation an attractive method for the synthesis of a variety
of useful N-heterocyclic boronic acids and boronates.
Acknowledgements
We acknowledge financial support from the National Natural
Science Foundation of China (NSFC 20972072, NSFC
21272121).
Keywords: aminoboration · boronic acids · boronic esters ·
Suzuki cross-coupling · synthetic methods
How to cite: Angew. Chem. Int. Ed. 2015, 54, 12636–12639
Angew. Chem. 2015, 127, 12827–12830
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Received: June 15, 2015
Revised: August 4, 2015
Published online: September 1, 2015
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