Ligand-Free Iron-Catalyzed Regioselectivity-Controlled Hydroboration of Aliphatic Terminal Alkenes

Article abstract of DOI:10.1021/acscatal.0c02731

The control of regioselectivities has been recognized as the elementary issue for alkene hydroboration. Despite considerable progress, the specificity of alkene substrates or the adjustment of ligands was necessary for specific regioselectivities, which r

Full text of DOI:10.1021/acscatal.0c02731

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Article
Ligand-Free Iron-Catalyzed Regioselectivity-
Controlled Hydroboration of Aliphatic Terminal Alkenes
Wei Su, Rui-Xiao Qiao, Yuan-Ye Jiang, Xiao-Li Zhen, Xia Tian,
Jian-Rong Han, Shi-Ming Fan, Qiushi Cheng, and Shouxin Liu
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.0c02731 • Publication Date (Web): 18 Sep 2020
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ACS Catalysis
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Ligand-Free Iron-Catalyzed Regioselectivity-Controlled
Hydroboration of Aliphatic Terminal Alkenes
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Wei Su,*, † Rui-Xiao Qiao,‡ Yuan-Ye Jiang,# Xiao-Li Zhen,† Xia Tian,† Jian-Rong Han,† Shi-Ming
Fan,‡ Qiushi Cheng, † Shouxin Liu*, ‡
† School of Science, Hebei University of Science and Technology, Shijiazhuang, 050022, China
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‡ Hebei Key Laboratory of Molecular Chemistry for Drug, Hebei University of Science and Technology, Shijiazhuang, 050022,
China
# School of Chemistry and Chemical Engineering, Qufu Normal University, Qufu, 273100, China
ABSTRACT: The control of regioselectivities has been recognized as the elementary issue for alkene hydroboration. Despite considerable
progress, the specificity of alkene substrates or the adjustment of ligands were necessary for specific regioselectivities, which restrict the
universality and practicability. Herein, we report a ligand-free iron-catalyzed regiodivergent hydroboration of aliphatic terminal alkenes that
obtains both Markovnikov and anti-Markovnikov hydroboration products in high regioselectivities. Notably, solvents and bases were shown
to be crucial factors influencing the regioselectivities and further studies suggested the iron-boron alkoxide ate complex is the key
intermediate that determines the unusual Markovnikov regioselectivity. Terminal alkenes with diverse structures (mono-substituted and 1,1-
disubstituted, open-chain and exocyclic) underwent the transformation smoothly. The reaction does not require the addition of auxiliary
ligands and it can be performed on a gram scale, thus providing an efficient and sustainable method for the synthesis of primary, secondary,
and tertiary alkyl borates.
Key Words: iron catalysis, hydroboration, alkenes, alkyl borates, regioselectivity, ligand-free
Scheme 1. Markovnikov Hydroboration of Aliphatic
Terminal Alkenes
INTRODUCTION
Alkylboron compounds are not only widely employed as
intermediates in organic synthesis1, they are also applied in the field
of pharmaceuticals because of their intrinsic biological activities2.
Therefore, synthetic methods that can be used to construct
alkylboron compounds in an efficient and sustainable manner have
been studied widely3. Since the seminal work reported by Brown in
19564, the hydroboration of alkenes has evolved into the most
powerful strategy for the synthesis of alkylboron compounds. As
the elementary factor influencing product structures, the control of
the regioselectivity has always been the core issue in hydroboration
of alkenes. In most of the catalyzed and uncatalyzed approaches5,
alkene hydroboration commonly follows anti-Markovnikov
regioselectivity to afford the corresponding linear alkylboron
compounds (Scheme 1a). However, the metal-catalyzed
hydroboration of aryl-substituted alkenes gave the reverse
Markovnikov regioselectivity with catecholborane (HBcat) or
pinacolborane (HBpin) as hydrogen and boron source, mainly
because of the electronic bias of the vinyl group (Scheme 1b, i)6.
Furthermore, the regiospecific hydroboration of internal alkenes
was achieved through the introduction of directing groups7 or
remote electronic effects8 in alkene substrates (Scheme 1b, ii).
Despite these results, Markovnikov hydroboration of aliphatic
terminal alkenes that can be obtained from petrochemical
feedstocks or synthesized in a straightforward manner remain
a) hydroboration of alkenes
H
uncatalyzed or
metal-catalyzed
[B]
+ "Boron Source"
HBR'R''
R
R
commonly as
anti-Markovnikov
R = alkyl, aryl etc.
or [B(OR')2]2
b) hydroboration for synthesis of branched alkyl borates
i. aryl-substituted alkenes as substrates:
BR'R''
Rh, Cu, Co, Fe,
Ni, Mn or Mg cat.
H
R'
+
HBR'R'
R'
ii. alkene substrates with directing or electronegative groups:
BR'R''
Rh, Ir or Cu cat.
FG
FG
R
FG
R
+
HBR'R''
n
n
H
=
directing groups or
n = 1, 2, 3
electronegative groups
c) Markovnikov hydroboration of unactivated terminal alkenes
i. Previous works:
Bpin
Cu- or Rh- catalyzed
elusive. Very recently, the research groups of Ito9,10
,
(Bpin)2
+
H
Alkyl
Alkyl
ligand-controlled
Montgomery11, Aggarwal12, and Shi13 independently realized Cu-
or Rh-catalyzed Markovnikov hydroboration of aliphatic alkenes
based on the addition of metal-boron intermediates to alkenes
(Scheme 1c, i). Although these efforts provide elegant methods for
the synthesis of branched alkyl borates, the scope of the reactions
with respect to alkenes are generally limited to monosubstituted
alkenes, and they require either expensive and multi-step
synthesized phosphine ligands or carbene ligands. To advance
beyond these limitations, the development of new efficient and
practical hydroboration reaction systems remains in demand.
Regiospecific
Mostly primary alkyl substitued alkenes
Using unavailable and toxic ligand



ii. This work:
R1
+
Bpin
R2
H
FeBr3, LiOtBu
MeOtBu, 40oC
Fe(OTs)3, LiOtBu
NMP, 80oC
R2
H
Bpin
R1
R1
R2
anti-Markovnikov
(Bpin)2
Markovnikov
Ligand-free

Regiodivergent (up to 99:1 and 1:99)
Bulky alkyl substituted and 1,1- disubstituted alkenes


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In recent years, iron-catalyzed transformations have attracted
obtained (see SI, Page 13). Lastly, when iron salts were omitted in
both MeOtBu and NMP, hydroboration products were not obtained
(entries 15, 16), and the diboration of alkenes was obseverd in NMP
while not in MeOtBu. According to previous work19, the diboration
of 1a in NMP should be promoted by the alkoxide base LiOtBu at
the relatively high temperature. From the above results, both
regioselective outcomes clearly can be achieved in excellent levels
and the course of the reaction can be determined by the choice of
conditions in the iron-catalyzed system. The effect of trace amounts
of other metals in the iron salts on the reaction was ruled out.
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renewed interest not only because of its high natural abundance,
low cost, and limited toxicity, but also because its catalytic
properties differ from those of other transition metals14. Especially
in the field of olefin functionalization, a series of unprecedented
and practical transformation have been achieved by iron-catalysis15.
Regarding the hydroboration of alkenes, since Ritter reported iron-
catalyzed 1,4-hydroboration of 1,3-dienes in 200916a, a variety of
iron catalysts have been developed, providing sustainable and
efficient tools for alkene hydroboration by using HBpin16 or
(Bpin)217 as boron source. Nevertheless, in terms of substrate range
or selectivity, these iron-catalyzed hydroboration reactions did not
surpass the effects achieved by other metals (Scheme 1a & 1b).
Given the unique nature and enormous potential of iron catalysis,18
we envisioned that iron-catalysis would be a feasible strategy to
expand the concept of alkene hydroboration, both in the scope of
alkene substrates and the regulatory mechanism of
regioselectivities. Herein, we describe a ligand-free iron-catalyzed
regiodivergent hydroboration of aliphatic terminals alkenes
(Scheme 1c, ii). Either Markovnikov or anti-Markovnikov
hydroboration products could be obtained in high regioselectivities
(98:2 vs. 2:98) by regulation of solvent, base, and other reaction
parameters. Interestingly, the adoption or not of the ate form of
iron-boron intermediates was suggested to be a key factor that
determines the regioselectivity. Finally, a series of terminal alkenes
with a range of structures including primary, secondary, and tertiary
alkyl substituted alkenes, 1,1-disubstituted alkenes and even 2-
methylideneadamantane, were found to be compatible with this
reaction.
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Table 1. Optimization of Reaction Conditionsa
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PMPO
PMPO
Bpin
TM cat. (10 mol%)
Base
Solvent , 50 oC, Ar
2a
+ (Bpin)2
PMPO
+
1a
Bpin
0.1 mmol 0.2 mmol
3a
Entry
Fe cat.
Base (equiv)
Solvent
Yield
2a/3ac
(%)b
51
23
37
63
65
67
78
95
29
34
62
18
77
50
0
1
2
FeCl2
FeCl2
LiOtBu (2)
LiOtBu (2)
LiOtBu (2)
LiOtBu (2)
LiOtBu (2)
LiOtBu (1.5)
LiOtBu (3)
LiOtBu (3)
LiOMe(3)
Dioxane
THF
10:90
16:84
3:97
83:17
89:11
2:98
98:2
98:2
43:57
55:45
76:24
74:26
98:2
2:98
–
3
FeCl2
MeOtBu
DMA
4
FeCl2
5
FeCl2
NMP
RESULTS AND DISCUSSION
6d
FeBr3
FeCl2
MeOtBu
NMP
Development of iron-catalyzed hydroboration of aliphatic
alkenes. We initially attempted iron-catalyzed hydroboration using
p-methoxyphenyl protected 3-methyl-3-buten-1-ol (1a) as the
substrate and (Bpin)2 as the boron source (Table 1). When the
substrates were treated with FeCl2 and LiOtBu in 1,4-dioxane at 50
C for 18 h, the hydroboration product was obtained in 51% GC
yield with good anti-Markovnikov regioselectivity (2a/3a = 10:90,
entry 1). On this basis, the solvent effect was tested. With ethers as
solvent, the hydroboration tended to follow anti-Markovnikov
regioselectivity (entries 1–3). In particular, with MeOtBu as
solvent, excellent anti-Markovnikov regioselectivity was achieved
(37%, 2a/3a = 3:97, entry 3). Upon optimization of the reaction
conditions, the anti-Markovnikov hydroboration product was
obtained in improved yield and regioselectivity (67%, 2a/3a = 2:98,
entry 6). In contrast, the more desirable Markovnikov
hydroboration product was predominantly obtained using amide
solvents (entries 4 and 5). By increasing the amount of both (Bpin)2
and LiOtBu and elevating the temperature, the yield and
Markovnikov regioselectivity were both improved to excellent
levels (78%, 2a/3a = 98:2, entry 7). We also test the effect of iron
salts, and the anions of iron salts were shown to have little influence
on the regioselectivity (page S6-S7). Fe(OTs)3 was found to be the
best choice in NMP (entry 8). Notably, both the anion and cation in
the base play important roles in determining the yield and
regioselectivity (entries 8–12), which suggests the involvement of
an iron alkoxide ate as a key catalytic intermediate18c, 19 (entries 8-
10). The reaction proceeded with undiminished yield and
regioselectivity using high-purity FeCl2 (99.99%) (entry 13, 14),
while the use of other metal chlorides (copper, nickel, cobalt,
manganese and palladium) led to low reactivities, and anti-
Markovnikov product was mainly obtained with NMP as solvent
(see SI, Page S13-S14 ). To exclude the possible borane-catalyzed
process20, the reactions with BH3 as catalyst or HBpin as boron
source were also conducted, and no hydroboration products were
7e
8e
Fe(OTs)3
Fe(OTs)3
Fe(OTs)3
Fe(OTs)3
Fe(OTs)3
FeCl2
NMP
9e
NMP
10e
11e
12e
13e, f
14d, f
15d
16e
LiOiPr (3)
NMP
NaOtBu (3)
KOtBu (3)
LiOtBu (3)
LiOtBu (1.5)
LiOtBu (1.5)
LiOtBu (3)
NMP
NMP
NMP
FeCl2
MeOtBu
MeOtBu
NMP
–
–
0
–
aReaction conditions: alkene 1a (0.1 mmol), (Bpin)2 (0.2 mmol),
iron salt or other metal salt (0.01 mmol), and base were stirred in
solvent (0.5 mL) at 50 C for 18 h. bCombined yields of 2a and 3a
c
determined by GC analysis. Determined by GC analysis of the
crude reaction mixtures. dUsing FeBr3 (0.02mmol), 40 C for 36 h.
eUsing (Bpin)2 (0.25mmol), 80 C. fUsing FeCl2 (99.99%)
purchased from Sigma–Aldrich.
Substrate scope of aliphatic alkenes. With the optimum
conditions in hand, the generality of the Markovnikov
hydroboration was investigated (Scheme 2). We found that
Markovnikov hydroboration generally proceeded with a range of
yields and regioselectivities that correlated with the steric hindrance
imparted by the substituents on the vinyl group. The 1,1-
disubstituted open-chain alkenes containing a methyl group were
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converted into the corresponding tertiary alkyl borates with
Diminished yields were observed when the substituents on the vinyl
group presented more steric bulk (2s, 2t, 2u), although the
regioselectivity remained excellent. Interestingly, 2-methylene
adamantine gave the corresponding product in good yield and
regioselectivity. In addition to 1,1-disubstituted alkenes, mono-
substituted alkenes were also investigated. The regioselectivity
reduced from excellent (2w, 2x) to good (2y), and then to moderate
(2z, 2aa), when the alkyl substituent was changed from 3 to 2 and
to 1, respectively. In contrast, for the Cu- and Rh-catalyzed
versions, 1 alkyl substituted alkenes usually gave good
regioselectivities, whereas 2 and 3 alkyl substituted alkenes
reacted with lower regioselectivities9-13. Furthermore, the reaction
tolerated a variety of functional groups, including phenyl ether (2a,
2e–h), 2-methylnaphthalene ether (2b), benzyl ether (2c), silicon
ether (2d), fluoro (2e), trifluoromethyl (2f), trifluoromethoxy (2g),
phenylborate (2h), sulfonamide (2l), amide (2m, 2q, 2r), amine
(2u), thioether (2n), sulfone (2o), and ketal (2p) groups, as well as
some pharmaceutically important cycles, such as indole (2i), furan
(2r), cyclopropane (2q), and amantadine (2v, 2w). Benefiting from
the good functional group tolerance, an estrone derivate could also
be converted into the corresponding tertiary alkyl borate derivative,
albeit with moderate diastereomeric ratio (d. r. = 67:33). Finally,
the hydroboration of 2a could be scaled up to 5 mmol with a
reduced iron-catalyst loading of 2.5%, thereby demonstrating the
robustness and practical application of this method.
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excellent yields and regioselectivities (2a–j). Methylene substituted
cycloalkanes also reacted in high yield and regioselectivity in the
Markovnikov
Scheme 2. Iron-Catalyzed Markovnikov Hydroborationa
Fe(OTs)3 (10 mol%)
LiOtBu (0.6 mmol)
NMP (1 mL), 80 oC, Ar
Bpin
R2
R1
H
+
(Bpin)2
R1
R2
0.2 mmol 0.5 mmol
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PMPO
2a
5 mmol,b
Bpin
NapO
Bpin
, 76%, 96:4
BnO
Bpin
, 75%, 97:3
, 78%, 98:2
2b
2c
74%, 98:2
2e
, R' = F, 80%, 98:2
R'
2f
, R' = CF3, 72%, 96:4
TBDPSO
Bpin
2g
2h
, R' = OCF3, 68%, 96:4
, R' = Bpin, 58%, 94:6
O
Bpin
2d
, 82%, 98:2
MeO
Bpin
Bpin
N
Bpin
tBu
2k b
,
73%, 97:3
2i
2j
, 69%, 98:2
, 64%, 98:2
d.r. = 55:45
Bpin
Bpin
Bpin
Bpin
O
O
2o
S
We then tested the scope of the iron-catalyzed anti-Markovnikov
hydroboration (Scheme 3). All the 1,1-disubstituted, 1, 2, and 3
alkyl mono-substituted terminal alkenes reacted in moderate yield
with high regioselectivity. Although many anti-Markovnikov
hydroboration strategies have been established, the reaction
described herein offers a further alternative method.
TsN
CbzN
S
2l
2m
2n
, 65%, 97:3
, 77%, 97:3
, 85%, >99:1
, 71%, 98:2
Bpin
Bpin
Bpin
O
O
N
N
O
O
2q
O
2p
2r
, 78%, 99:1
Bpin
, 64%, 98:2
, 57%, 96:4
Scheme
3.
Iron-Catalyzed
anti-Markovnikov
Bpin
Hydroborationa
Bpin
N
Ph
FeBr3 (20 mol%)
LiOtBu (0.3 mmol)
MeOtBu (1 mL), 40 oC, Ar
H
R1
2s
2t
2u
, 47%, 98:2
, 73%, 97:3
, 52%, 97:3
Bpin
Bpin
+
(Bpin)2
R1
R2
R2
Bpin
0.2 mmol 0.4 mmol
Bpin
Bpin
Bpin
Bpin
Bpin
PMPO
3a
NapO
3b
TBDPSO
3d
, 54%, 11:89
2w
2x
2y
, 80%, 95:5
, 82%, 96:4
, 74%, 89:11
Bpin
2v
, 76%, 90:10
, 54%, 2:98
, 60%, 1:99
Bpin
Bpin
R
BocN
2ab
Bpin
2z c
,
73%, 66:34
2aa
, 77%, 86:14
, 71%, <1:99
Bpin
Bpin
O
, 3e
MeO
R = F
R = OCF3
, 61%, 3:97;
3j
, 45%, 3:97
, 3g
, 69%, 2:98;
H
H
H
H
H
H
Bpin
Bpin
BnO
BnO
CbzN
3m
PivO
3ae
Bpin
, 65%, 1:99
estrone derivative
2ac
, 45%, 96:4
d.r. = 67:33
3w
, 41%, 3:97
Bpin
, 65%, 8:92
Bpin
Bpin
aReaction conditions: alkene (0.2 mmol), (Bpin)2 (0.5 mmol),
Fe(OTs)3 (0.02 mmol), LiOtBu (0.6 mmol) were stirred in NMP (1
mL) at 80 C for 18 h. Isolated yields are shown here and the
products is partially decomposed during isolation process. The
regioselectivity was determined by GC analysis of the crude
reaction mixtures. bFe(OTs)3 (2.5 mol%) was used.
3x
3y
3z
, 67%, 4:96
, 51%, 3:97
, 62%, 1:99
aReaction conditions: alkene (0.2 mmol), (Bpin)2 (0.4 mmol), FeBr3
(0.04 mmol), LiOtBu (0.3 mmol) were stirred in MeOtBu (1 mL) at
40 C for 36 h. Isolated yields are shown here and the products is
partially decomposed during isolation process. The regioselectivity
was determined by GC analysis of the crude reaction mixtures.
hydroboration (2k–r); however, methylene substituted cyclobutane
gave complete anti-Markovnikov regioselectivity (2ab).
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Scheme 4. Mechanism Studies
5
6
7
8
a) experiments of the deuterated alkene
c) addition of proton sources
Bpin
CD2H
CD2
standard condition 1
standard condition 1
addtives (1 e.q.)
2a 3a
+
PMP
2ad
PMP
PMPO
9
1ad D: 92%
,
D: 90%
, 73%, 97:3,
PMP
Entry
additives
Yield
1
2
3
4
5
6
10
11
12
13
14
15
16
17
18
19
20
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22
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60
CD2
standard condition 2
Bpin
H2O
41%
MeOH EtOH iPrOH tBuOH tBuOHa
PMP
1ad D: 92%
D
D
50%
58%
69%
86%
93:7
45%
91:9
3ad
D: 89%
,
, 43%, 2:98,
2a:3a
54:46 61:39 69:31 79:21
b) protodeboration reactions
Bpin
e) control experiments of Markovnikov hydroboration
standard condition 1
5
2a 3a
Bpin
+
or
standard condition 2
PMPO
> 95%
Recovery
Fe(OTs)3
LiOtBu
0%
5
+
(Bpin)2
2a 3a
PMPO
i. using
+
NMP (0.5 mL), Ar, 80 o
C
d) experiments with deuterated solvents and additives
0.1 mmol
LiOtBu (0.3 mmol) (Bpin)2 (0.25 mmol)
Fe(OTs)3 (10 mol%)
LiOtBu (0.3 mmol)
+(Bpin)2 (0.25 mmol)
,
Bpin
Fe(OTs)3 (mol %)
5
10
25
50
PMPO
PMPO
CH2D
D: 94%
d9-DMA (0.5 mL), 80 o
C
Yield
94%
98:2
95%
98:2
70%
94:6
57%
82:18
0.1 mmol
2ae-1
, 71%, 98:2,
2a 3a
:
Bpin
Fe(OTs) (10 mol %) (Bpin)2 (0.25 mmol)
ii.using
,
3
standard condition 1
PMPO
CH2D
+ tBuOD (X equiv)
PMPO
LiOtBu
(mmol) 0.10
0.15
0.20
46%
92:8
0.25
70%
96:4
0.30
0.35
92%
98:2
2ae-2
2ae-3
D: 0%
D: 0%
X = 2,
X = 5,
FeBr3 (20 mol%)
, 45%, 92:8,
, 33%, 92:8,
Yield
2a 3a
37%
44%
95%
98:2
:
84:16
90:10
LiOtBu (0.15 mmol)
Fe(OTs) (10 mol %) LiOtBu (0.25 mmol)
D
iii. using
,
3
Bpin
+(Bpin)2 (0.2 mmol)
d8-THF (0.5 mL), 40 o
PMPO
PMPO
0.1 mmol
(Bpin) 2 (mmol)
Yield
0.2
0.3
0.4
C
3af-1
D: 8%
, 37%, 11:89,
D
79%
97:3
53%
94:6
44%
89:11
2a:3a
standard condition 2
Bpin
PMPO
+ tBuOD (X equiv)
PMPO
-
-
OtBu
OtBu
PinBFeOtBu
PinB-Bpin +
PinBFeOtBu
Li+
Li+
+
3af-2
3af-3
D: 31%
D: 54%
X = 2,
X = 5,
, 27%, 12:88,
, 26%, 12:88,
pinB-Bpin
Standard conditions 1 as shown in Scheme 2. Standard conditions 2 as shown in Scheme 3. a tBuOH (2 equiv) was used.
Mechanistic investigations. To gain insight on the reaction
mechanism, several additional experiments were performed. When
deuterated alkene 1ad was used as the reaction substrate, no
migration of deuterium was observed under either of the standard
conditions used for Markovnikov or anti-Markovnikov
regioselectivities (Scheme 4a). This result suggested that
elimination of iron and -H followed by the addition of [FeH] to
alkenes is unlikely.
iPrOH, EtOH, MeOH and H2O, the yield and Markovnikov
regioselectivity gradually decreased (entries 1-5); c) the more
proton source was added, the more the yield decreased (entries 5,
6). The result indicates that the alcohol can undergo anion exchange
with the reaction intermediate, and the anion influences yield and
regioselectivity significantly.
To make clear the source of the hydrogen, we performed the
reactions in deuterated solvents or with tBuOD as the deuterated
additive (Scheme 4d). With d9-DMA as solvent, the deuteration rate
of Markovnikov product 2ae-1 was 94%, and either 0.2 mmol or
0.5 mmol tBuOD was added, the deuteration rates of 2ae-2 and 2ae-
3 were both 0% in NMP. These results illustrated that, in
Markovnikov hydroboration, the “H atom” is coming from the
amide solvent and hydrogen atom transfer (HAT) is preferred to be
underwent rather than boration-protonation. To our knowledge, the
common hydrogen sources in iron-catalyzed HAT are hydrosilicon
compounds15b-f, and amides are the first time to be indicated as the
Next, we submitted alkene diboration substrate 5 to the reaction
under both two standard conditions and observed no
protodeboration products (Scheme 4b); thus,
a diboration–
protodeboration mechanism was excluded9, 21
.
Different from Cu- or Rh-catalyzed hydroboration in which
alcohols just acted as proton sources9-13, in iron-catalyzed
Markovnikov hydroboration, additional H2O or alcohols have
significant effects on the yield and regioselectivity (Scheme 4c): a)
on the whole, both of yield and Markovnikov regioselectivity
hydrogen source.
deuteration rate of anti-Markovnikov product 3af-1 was 8%, while
However, with d8-THF as solvent, the
t
decreased when proton sources were added; b) From BuOH to
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ACS Catalysis
when 0.2 mmol or 0.5 mmol tBuOD were added in MeOtBu, the
mixture by 1H-NMR and 13C-NMR. The product 2ag was proposed
to be formed by the iron-catalyzed hydrogen atom transform of 1ag
and followed three-membered ring-opening boration process. The
product 3ag was proposed to be formed by initiated migration
insertion of [FeBpin] intermediate to the vinyl of 1ag, and followed
ring-opening and protonation process. These results suggested that
the Markovnikov regioselectivity was dictated by HAT process,
while the anti-Markovnikov regioselectivity was controlled by the
addition of [FeBpin] to alkenes. However, the radical-closing
reactions with 1ah only gave the straightforward hydroboration
products 2ah and 3ah (Scheme 5b). These results were coursed by
the slower rate of ring-closing process compared to the boration
(Markovnikov) and protonation (anti-Markovnikov).
1
2
3
4
5
6
7
8
deuteration rates of 3af-2 and 3af-3 were respectively 31% and
54%, which indicated that the hydrogen has a multiple source in the
anti-Markovnikov hydroboration.
A series of control experiments were performed to clarify how the
reaction was influenced by each parameter subtly (Scheme 4e).
When Fe(OTs)3 (10 mol%) was used, only the Markovnikov
regioselectivity increased with an increase in the amount of LiOtBu.
When LiOtBu (0.3 mmol) was used, the Markovnikov
regioselectivity decreased with an increase in the amount of
Fe(OTs)3. These results indicate that an increase in the amount of
LiOtBu relative to the amount of Fe(OTs)3 led to better
Markovnikov regioselectivity. Together with the results presented
in Table 1, entries 8–12, we propose that an iron-boron alkoxide ate
is the key intermediate that determines the Markovnikov
regioselectivity and that the generation of a non-ate iron-boron
intermediate mainly leads to the formation of the anti-Markovnikov
products. To confirm the inference, control experiments in which
(Bpin)2 competed with iron-boron intermediate in forming the ate
salt with LiOtBu were performed. The results showed that an
increase in the amount of (Bpin)2 led to a reduction in the level of
Markovnikov regioselectivity, which is consistent with our
proposed mechanism.
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
Scheme 6. Reactions of Substrates Containing Aryl
Bromide/Iodide
in NMP
O
O
Bpin
standard condition 1
X
H
1ai
2ai
, 32%
X = Br,
, 0.2 mmol
X = Br,
1aj
2ai
, 44%
X = I,
, 0.2 mmol
X = I,
in MeOtBu
Scheme 5. Radical Clock Reactions
O
O
standard condition 2
Bpin
a) radical ring-opening reactions:
X
X
H
Fe(OTs)3 (10 mol%)
LiOtBu (0.6 mmol)
1ai
3ai
X = Br,
, 0.2 mmol
X = Br,
, 51%, 4:96
Bpin
1aj
3aj
X = I,
, 0.2 mmol
X = I,
, 41%, 4:96
(Bpin)2 (0.5 mmol)
Standard conditions 1 as shown in Scheme 2. Standard conditions
2 as shown in Scheme 3.
NMP (1 mL), 80oC, Ar
1ag
2ag
, 0.2 mmol
, yield: 34%, mixture
proposed process:
1ag
Unexpected results were observed with the substrates containing
aryl bromide/iodide (Scheme 6). In MeOtBu, the aryl bromid and
iodide (1ai & 1aj) underwent the anti-Markovnikov hydroboration
to give the corresponding products 3ai, 3aj; however, in NMP, both
1ai and 1aj gave the dehalogenated hydroboration product 2ai. The
dehalogenation was proposed to be initialed by the single electron
transfer22, which illustrated the ironboron intermediate formed in
NMP is capable of the ability to catalyze single electron transfer
process; meanwhile, the dehalogenation via iron-hydride
intermediate is also possible23.
H
H
HAT
Bpin [Fe]
+
Bpin
•
Ph
Ph
Bpin-[Fe]-H
Bpin
H
FeBr3 (20 mol%)
LiOtBu (0.3 mmol)
(Bpin)2 (0.4 mmol)
MeOtBu (1 mL), 40oC, Ar
3ag
, yield: 24%, mixture
1ag
, 0.2 mmol
proposed process:
1ag
Based on the above results and Uchiyama’s previous work in which
KFe(OtBu)3 was proven as a single-electron-transfer catalyst19a, we
propose a plausible reaction mechanism (see SI, page S30).
Initially, iron(II or III) salts react with (Bpin)2 and LiOtBu to form
the iron(II)-boron di-tert-butoxide ate intermediate A1
Li+[FeBpin(OtBu)2]- in NMP and iron(II)-boron tert-butoxide
intermediate B1[FeBpinOtBu] in MeOtBu. We propose that the ate
ironboron intermediate A1 could be stabilized by coordination of
the carbonyl oxygen atoms of NMP to the lithium ion24. In MeOtBu,
intermediate B1 adds to the alkene to produce the intermediate B2
with Bpin on the terminal carbon and iron on the internal carbon,
then the organoiron intermediate B2 undergo protonation to form
the anti-Markovnikov product. In NMP, the ate intermediate A1
performs as the single-electron-transfer catalyst and reacts with
NMP to generate the iron hydride intermediate A2
H·[FeBpin(OtBu)2]. The HAT occurs with A2 to the alkene to form
the more stabilized tertiary radical and FeBpin(OtBu)2 (A3), then
the tertiary radical reacts with intermediate A3 to give the
Markovnikov hydroboration product. Given the diversity of
oxidation, spin states and coordination modes accessible by iron,
especially in the ligand-free environment, the mechanism presented
Bpin
Bpin
protonation
+
3ag
[Fe]
Ph
Ph
[Fe]-Bpin
[Fe]
b) radical ring-closing reactions:
Bpin
Fe(OTs)3 (10 mol%)
LiOtBu (0.6 mmol)
(Bpin)2 (0.5 mmol)
NMP (1 mL), 80oC, Ar
2ah
, yield: 58%, r.r = 95:5
no ring-closing product
1ah
, 0.2 mmol
FeBr3 (20 mol%)
LiOtBu (0.3 mmol)
Bpin
(Bpin)2 (0.4 mmol)
3ah
, yield: 54%, r.r = 3:97
no ring-closing product
MeOtBu (1 mL), 40oC, Ar
1ah
, 0.2 mmol
Furthermore, we performed the radical clock reations. The radical
ring-opening reactions were conducted by using 1ag as substrate
(Scheme 5a). With NMP or MeOtBu as solvent, the ring-opening
products 2ag or 3ag was respectively detected from the isolated
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Page 6 of 9
L., Steel, P. G., Marder, T. B. Zinc-catalyzed borylation of primary,
now is sketchy and the detailed version needs further efforts to
elucidate25.
secondary and tertiary alkyl halides with alkoxy diboron reagents at room
temperature. Angew. Chem. Int. Ed. 2014, 53, 1799-1803. (g) Atack, T. C.,
Cook, S. P. Manganese-catalyzed borylation of unactivated alkyl chlorides.
J. Am. Chem. Soc. 2016, 138, 6139-6142. (h) Cheng, Y., Mück-Lichtenfeld,
C., Studer, A. Metal-free radical borylation of alkyl and aryl iodides. Angew.
Chem. Int. Ed. 2018, 57, 16832-16836. (i) Wu, J., He, L., Noble, A.,
Aggarwal, V. K. Photoinduced deaminative borylation of alkylamines. J.
Am. Chem. Soc. 2018, 140, 10700-10704. (j) Friese, F. W., Studer, A.
Deoxygenative borylation of secondary and tertiary alcohols. Angew. Chem.
Int. Ed. 2019, 58, 9561-9564.
1
2
3
4
5
6
7
8
CONCLUSION
In summary, we have developed an iron-catalyzed regiodivergent
hydroboration methodology that can be applied to aliphatic
terminal alkenes. The regioselectivity was shown to be determined
by the solvent and base used, and further studies revealed that the
iron-boron alkoxide ate salt was the vital intermediate for
Markovnikov regioselectivity. We believe that these results provide
crucial examples that expand our understanding of mechanisms
involving iron catalysis. The phosphine- and carbene-ligand-free
reaction features abundant, low cost, and low-toxicity iron catalyst,
and offers wide scope with respect to terminal alkenes, which
provides an efficient and sustainable method for synthesizing all
primary, secondary, and tertiary alkyl borates. Further studies on
iron-catalyzed alkene boration functionalization and related
mechanism are under way.
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ASSOCIATED CONTENT
Supporting Information
This information is available free of charge on the ACS
Publications website.
Supplementary data, experimental procedures, and analytical data
for all new compounds.
AUTHOR INFORMATION
Corresponding Author
Email for Wei Su: weisu@hebust.edu.cn;
Email for Shouxin Liu: chlsx@hebust.edu.cn.
Note
The authors declare no competing financial interest.
ACKNOWLEDGEMENT
The authors thank the NSFS (21901059, 21978067, 21702119), Natural
Science Foundation of Hebei Province (B2018208079, B2018208093) and
two Start-up Grants from Hebei University of Science and Technology for
Wei Su and Qiushi Cheng.
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R1
Bpin
R2
H
FeBr3, LiOtBu
MeOtBu, 40oC
Fe(OTs)3, LiOtBu
NMP, 80oC
R2
H
Bpin
R1
R1
+
R2
(Bpin)2
anti-Markovnikov
Markovnikov
Ligand-free

Regiodivergent (up to 99:1 and 1:99)
Bulky alkyl substituted and 1,1- disubstituted alkenes


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