Iron-catalyzed intermolecular hydroamination of styrenes

Article abstract of DOI:10.1021/ol5013907

An iron-catalyzed formal hydroamination of alkenes has been developed. It features O-benzoyl-N,N-dialkylhydroxylamines as the electrophilic nitrogen source and cyclopentylmagnesium bromide as the reducing agent for intermolecular hydroamination of styrene

Full text of DOI:10.1021/ol5013907

Letter
pubs.acs.org/OrgLett
Iron-Catalyzed Intermolecular Hydroamination of Styrenes
C. Bryan Huehls, Aijun Lin, and Jiong Yang*
Department of Chemistry, Texas A&M University, College Station, Texas 77843-3255, United States
S
* Supporting Information
ABSTRACT: An iron-catalyzed formal hydroamination of alkenes has
been developed. It features O-benzoyl-N,N-dialkylhydroxylamines as
the electrophilic nitrogen source and cyclopentylmagnesium bromide
as the reducing agent for intermolecular hydroamination of styrene
and derivatives with good yield and excellent Markovnikov
regioselectivity. The reaction presumably proceeds through the iron-
catalyzed hydrometalation of styrene followed by electrophilic
amination with the electrophilic O-benzoylhydroxylamine.
mines are an important class of organic compounds because
of their ubiquity in bulk chemicals, materials, and bioactive
would be compatible with the low-valent iron species presumably
formed during the functionalization of unactivated alkenes. We
were also not aware of precedents of iron-catalyzed hydro-
amination reactions using electrophilic amination reagents.7,8
Herein we report the results of our study, which led to an
approach for iron-catalyzed formal hydroamination of unac-
tivated alkenes using the electrophilic O-benzoyl-N-hydroxyl-
amines as the nitrogen source and cyclopentylmagnesium
bromide as the reducing agent (Scheme 1, eq 2).
A
compounds.1 Among the numerous methods for synthesis of
amines, addition of H-NR2 across unactivated double bonds, i.e.,
the so-called hydroamination of alkenes (Scheme 1, eq 1),
Scheme 1. Hydroamination of Alkenes
Our research commenced with screening iron−ligand systems
for the formal electrophilic hydroamination of styrene (1a) using
O-benzoyl-N-hydroxypiperidine (2a) (Table 1). The initial
results were disappointing as only a small amount of the desired
product (3a) was formed when a solution of 1a and 2a in THF
was treated with FeCl2, the iminopyridine ligand L1 or L2, and
cyclopentylmagnesium bromide (not shown). Speculating that
the reducing reaction conditions might be detrimental to 2a, we
hypothesized that the yield of the reaction might be improved by
the slow addition of 2a. Indeed, under otherwise identical
reaction conditions, 3a was obtained in 34% and 55% yields with
the iminopyridine ligand L1 and L2, respectively, when O-
benzoyl-N-hydroxylpiperidine was slowly added via a syringe
pump (Table 1, entries 1 and 2). The regioselectivity of the
reaction was excellent as none of the isomeric anti-Markovnikov
hydroamination product was observed. A number of common
bidentate and tridentate ligands were screened under similar
conditions (L3−L8, entries 3−10) with the bis(imino)pyridine
(PDI) L8 being found to be superior to the others giving 3a in
71% yield. The hydroamination reaction could be reproduced
when FeCl2 of high purity (99.99%) was used (entry 9).9 The
desired product 3a could also be formed, but with minimal
enantiomeric excess when the chiral tridentate ligands L9 and
L10 were employed (entries 10 and 11).10 Other Grignard
reagents were also tested in the reaction, and each of them gave
3a as the product, but with varying efficiency. The lowest yield
represents a particularly effective approach as it allows efficient
preparation of alkylamines from readily available substrates. A
number of catalytic systems have been developed over the
decades for this transformation.2 However, despite all the
advances, significant challenges remain as many of these catalytic
systems are hampered by the limited substrate scope, the reliance
on precious and/or toxic transition metals, or elevated reaction
temperatures. Thus, new approaches for the hydroamination of
alkenes, particularly those through alternative reaction pathways,
are attractive because of their potential of complementary
reactivities, selectivities, and efficiencies compared with the
existing methods.
Electrophilic amination reagents such as N-chloroamines and
hydroxylamine O-esters have emerged as versatile tools for
synthesis of substituted amines using nucleophilic substrates.3
Recently, we became interested in iron-catalyzed transforma-
tions in general and low-valent iron-catalyzed functionalization
of unactivated alkenes in particular because of the unique
reactivity of iron compared with other transition metals4 and the
high abundance and low toxicity of many iron salts.5 We
envisioned that the umpolung reactivity of these electrophilic
amination reagents might be exploited in low-valent iron-
catalyzed hydrometalation of double bonds for electrophilic
amination of unactivated alkenes.6 Unknown at the outset of our
research was whether these electrophilic amination reagents
Received: March 31, 2014
© XXXX American Chemical Society
A
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Letter
a
a
Table 1. Screening of Reaction Conditions
Table 2. Scope of O-Benzoyl-N,N-dialkylhydroxylamines
b
entry
[M]
FeCl2
L
RMgX
yield of 3a (%)
1
2
3
4
5
6
7
8
L1
L2
L3
L4
L5
L6
L7
L8
L8
L9
L10
L8
L8
L8
L8
L8
L8
L5
L5
C5H9MgBr
C5H9MgBr
C5H9MgBr
C5H9MgBr
C5H9MgBr
C5H9MgBr
C5H9MgBr
C5H9MgBr
C5H9MgBr
C5H9MgBr
C5H9MgBr
EtMgBr
34
55
60
49
48
55
<55
71
73
27
47
51
64
11
40
26
42
25
53
FeCl2
FeCl2
FeCl2
FeCl2
FeCl2
FeCl2
FeCl2
FeCl2
FeCl2
FeCl2
FeCl2
FeCl2
FeCl2
FeCl3
Fe(OAc)2
Fe(acac)3
CoCl2
NiCl2
a
The reactions were carried out using 1.4 mmol of the styrene, 0.07
mmol of FeCl2, 0.07 mmol of L8, 2.8 mmol of cyclopentylmagnesium
bromide, and 0.7 mmol of the O-benzoyl-N-hydroxylamines in 3 mL
c
b
9
of THF at 0 °C. Isolated yield.
10
11
12
13
14
15
16
17
18
19
yield, while the corresponding O-benzoyl-N-hydroxylamines of
azepane and morpholine gave 3c and 3d in 61% and 52% yield,
respectively. The O-benzoyl-N,N-dialkylhydroxylamines pre-
pared from acyclic secondary amines proved to be equally
effective in the reaction. Thus, good yields were obtained upon
reaction of styrene with the O-benzoyl-N,N-dialkylhydroxyl-
amines prepared from diethylamine, N-ethylbutylamine, and N-
benzylmethylamine to give the products in good yields (i.e., 3e in
80% yield, 3f in 65% yield, and 3g in 58% yield). To our surprise,
only a trace amount of 3h was formed when O-benzoyl-N,N-
dibenzylhydroxylamine was used, likely due to rapid decom-
position of the electrophilic amination reagent under the
reducing reaction conditions.
i-PrMgBr
t-BuMgBr
C5H9MgBr
C5H9MgBr
C5H9MgBr
C5H9MgBr
C5H9MgBr
a
Unless noted otherwise, the reactions were carried out with 10 mol %
of [M], 10 mol % of L, 2.0 equiv of styrene, 4 equiv of RMgBr, and 1.0
equiv of O-benzoyl-N-hydroxylpiperidine in THF at 0 °C. Isolated
yield. FeCl2 of 99.99% purity was used.
b
c
Further examination of the reaction showed that it is
compatible with substituted styrenes as well (Table 3). For
example, o-, m-, and p-methylstyrene all participated in the
hydroamination reactions. The yield of the reaction with the
ortho-substituted substrate (3k in 49% yield) was lower than
those of the other two isomers (3i in 66% yield and 3j in 62%
yield), possibly due to steric reasons. Para-substitution of styrene
with the tert-butyl group gave the hydroamination product 3l in
75% yield. Styrenes substituted with the electron-donating
methoxy group are also compatible with the reaction and showed
a trend similar to that of the methyl-substituted styrenes. The
hydroamination of m- and p-methoxy-substituted styrenes gave
3m and 3n in 55% and 55% yield, respectively. On the other
hand, a significantly reduced yield was observed when the
methoxy group was at the ortho-position (3o in 24% yield),
possibility because of the ability of the methoxy group to interfere
through coordination with the metal center of the intermediates.
(11%, entry 14) was observed with tert-butylmagnesium
chloride. It was followed by ethylmagnesium bromide (51%,
entry 12) and isopropylmagnesium bromide (64%, entry 13).
Thus, cylopentylmagnesium bromide remained the reagent of
choice. The desired product was also formed when other ferrous
and ferric salts were used even though none of them were as
effective (entries 15−17). Interestingly, NiCl2 was found to give
3a in a yield comparable to that of FeCl2 (entry 19), but CoCl2
was significantly less effective for the reaction (entry 18).
We explored the scope of the reaction using O-benzoyl-N,N-
dialkylhydroxylamines prepared from various secondary amines
for the hydroamination of styrene under the optimized
conditions (Table 2). The reaction appeared to be general and
gave the products in good to moderate yields and excellent
Markovnikov selectivity (Table 2). For example, the reaction of
styrene with O-benzoyl-N-hydroxylpyrrolidine gave 3b in 70%
B
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a
Table 3. Scope of the Styrene Derivatives
Scheme 2. Some Mechanistic Studies
bromide (and likely cyclopentylmagnesium bromide as well) is
irreversible under the reaction conditions. Interestingly, only a
trace amount of 3a was formed upon reaction of the
independently prepared Grignard reagent 4 and 2a with and
without FeCl2-L8 (eq 3), suggesting that the Grignard reagent
itself is not the reactive intermediate of the reaction.
On the basis of these experimental findings, a proposed
mechanism of the reaction is shown in Scheme 3. Alkylation of
Scheme 3. Proposed Reaction Mechanism
a
The reactions were carried out using 1.4 mmol of the styrene, 0.07
mmol of FeCl2, 0.07 mmol of L8, 2.8 mmol of cyclopentylmagnesium
bromide, and 0.7 mmol of the O-benzoyl-N-hydroxylamines in 3 mL
b
c
of THF at 0 °C. Isolated yield. Only 3a was isolated, likely due to
reductive dechlorination. The yield was not determined.
The reaction proved to be compatible with the electron-
withdrawing fluorine substituent as 3p was obtained in moderate
yield (46%) when 4-fluorostyrene was used. 4-Chlorostyrene
also underwent the hydroamination reaction, but with 3a as the
only isolated product due to dechlorination under the reducing
reaction conditions.11 Attempts for the hydroamination of 4-
trifluoromethylstyrene to form 3r gave an untraceable reaction
mixture. The hydroamination of α- and β-methylstyrene afforded
the products in low yield only (<5%). No hydroamination
product was formed when aliphatic terminal alkenes were used
(not shown).
To better understand the mechanism of the reaction, the
hydroamination of styrene with 2a was also carried out using
excess d5-ethylmagnesium bromide. Such a combination of
reagents led to formation of d3-3a (Scheme 2, eq 1), which was
consistent with the report by Greenhalgh and Thomas that the
iron-catalyzed hydrometalation of styrene using ethylmagnesium
bromide is rapid and reversible.6 However, only one deuterium
was incorporated (i.e., d1-3a) when d7-isopropylmagnesium
bromide was used as the hydride source (eq 2), suggesting that
the hydrometalation of styrene with isopropylmagnesium
FeCl2 with the Grignard reagent forms organoferrate A.
Coordination of this intermediate with styrene followed by β-
hydride elimination of the Grignard alkyl group gives iron
hydride complex C, which undergoes hydrometalation with
styrene to form D.12 The tertiary amine product is formed upon
reaction of D with O-benzoyl-N-hydroxyamine leaving the iron
benzoate E.13 Further reaction of E with the Grignard reagent
regenerates A and completes the catalytic cycle.
In summary, we report an operationally simple iron-catalyzed
umpolung hydroamination reaction. This transformation
employs the electrophilic O-benzoyl-N-hydroxylamine as the
source of nitrogen and cyclopentylmagnesium bromide as the
reducing agent for the hydroamination of styrenes to give tertiary
amines in good yield and excellent Markovnikov regioselectivity.
To the best of our knowledge, this transformation represents the
first example of iron-catalyzed hydroamination of alkenes using
electrophilic nitrogen sources.
C
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Letter
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ASSOCIATED CONTENT
* Supporting Information
Experimental details and NMR spectra of new compounds. This
material is available free of charge via the Internet at http://pubs.
acs.org.
■
S
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: yang@mail.chem.tamu.edu.
Notes
(d) Sherry, B. D.; Furstner, A. Acc. Chem. Res. 2008, 41, 1500−1511.
̈
The authors declare no competing financial interest.
(e) Czaplik, W. M.; Mayer, M.; Cvengros, J.; von Wangelin, J. A.
ChemSusChem 2009, 2, 396−417. (f) Nakamura, E.; Yoshikai, N. J. Org.
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ACKNOWLEDGMENTS
We thank the National Science Foundation (CHE-1150606) and
the Robert A. Welch Foundation (A-1700) for financial support.
■
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