Iron-Catalyzed Hydroamination and Hydroetherification of Unactivated Alkenes

Article abstract of DOI:10.1021/acs.orglett.9b00427

The hydrofunctionalization of alkenes, explored for over 100 years, offers the potential for a direct, atom-economical approach to value-added products. While thermodynamically favored, the kinetic barrier to such processes necessitates the use of catalysts to control selectivity and reactivity. Modern variants typically rely on noble metals that require different ligands for each class of hydrofunctionalization, thereby limiting generality. This Letter describes a general iron-based system that catalyzes the hydroamination and hydroetherification of simple unactivated olefins.

Full text of DOI:10.1021/acs.orglett.9b00427

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Iron-Catalyzed Hydroamination and Hydroetherification of
Unactivated Alkenes
Paul T. Marcyk and Silas P. Cook*
Department of Chemistry, Indiana University, 800 East Kirkwood Avenue, Bloomington, Indiana 47405-7102, United States
S
* Supporting Information
ABSTRACT: The hydrofunctionalization of alkenes, ex-
plored for over 100 years, offers the potential for a direct,
atom-economical approach to value-added products. While
thermodynamically favored, the kinetic barrier to such
processes necessitates the use of catalysts to control selectivity
and reactivity. Modern variants typically rely on noble metals that require different ligands for each class of
hydrofunctionalization, thereby limiting generality. This Letter describes a general iron-based system that catalyzes the
hydroamination and hydroetherification of simple unactivated olefins.
Of the first-row transition metal-catalyzed methods, copper
he hydrofunctionalization of alkenes offers a direct
Tmethod to forge beneficial carbon−heteroatom bonds. and iron catalysts offer the most generality. While copper
catalysts can require specific ligands9 or substrates10 for
Starting from abundant alkene or alkyne building blocks, the
thermodynamically favorable addition1 of a hydrogen−
difficult hydrothiolation reactions, simple iron salts can be used
under “ligandless” conditions to provide Markovnikov
heteroatom bond (H−N, H−O, or H−S) across a unit of
unsaturation builds molecular complexity succinctly. Within
selectivity.8 Furthermore, iron(III) salts enable the hydro-
functionalization of styrene derivatives or strained alkenes to
the context of hydrofunctionalization, hydroamination is the
form carbon−nitrogen,11,12 carbon−oxygen,13 and carbon−
sulfur14 bonds under different sets of conditions. Similar
approaches rely on Brønsted acids,15−17 such as trifluorome-
thanesulfonic acid18 or those generated in situ from metal
triflate salts.19−24 In spite of these advances, functionalizing
unactivated alkenes with iron(III) catalysts is limited to
intramolecular reactions.25−28 Previously, we have disclosed a
powerful, yet mild, iron system capable of catalytically
activating aliphatic alcohols toward substitution reactions.29−31
In our studies of alcohol substitution with sulfonamide
nucleophiles, reaction monitoring revealed that cyclohexanol
can undergo an iron-promoted E1 elimination, forming
cyclohexene.32 The in situ-generated alkene also proved
competent in the reaction. Enticed by this promising lead,
we postulated that alkene could be used directly in
hydrofunctionalization reactions. Here, we report a general
iron catalyst capable of the intermolecular hydrofunctionaliza-
tion of unactivated alkenes with sulfonamides, alcohols, and
select thiols (Figure 1b).
most studied,2 with less attention given to hydroetherification3
and hydrothiolation.4 Traditionally, precious metals such as
palladium, rhodium, ruthenium, and gold have been used to
activate the π-system (Figure 1a).5 Recently, earth-abundant,
first-row transition metals have enabled unique variants of
these reactions,6,7 with iron offering new vistas in hydro-
functionalization over a diverse range of X−H bonds.8
To begin, we evaluated the hydroamination of cyclohexene
with p-toluenesulfonamide in the presence of select acid
catalysts (Table 1). Strong Lewis acids, such as AlCl3, were
unable to promote the desired reaction (Table 1, entry 1).
Likewise, mild Lewis acid FeCl3 provided only trace yield
(Table 1, entry 2). The combination of FeCl3 with non-
coordinating silver salts33 greatly enhanced the Lewis acidity of
the iron catalyst, providing the hydroamination product in
Figure 1. (a) Hydroamination, hydroetherification, and hydro-
thiolation require different conditions for each reaction. (b) This
work offers a single catalyst for sulfonamides, alcohols, and a
thiophenol.
Received: January 31, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b00427
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 1. Evaluation of Acid Catalysts
Scheme 1. Hydroamination with Sulfonamide Nucleophiles
a
entry
catalyst
yield (%)
1
2
3
AlCl3
FeCl3
AgSbF6
0
<5
0
4
5
6
7
8
9
10
11
12
FeCl3w/3 AgSbF6
FeCl3 w/3 AgAsF6
FeCl3 w/3 AgBF4
FeCl3 w/3 AgOTf
FeCl3·6H2O w/3 AgSbF6
FeBr3 w/3 AgSbF6
FeCl2 w/2 AgSbF6
HSbF6
78
82
43
17
58
79
33
0
b
c
HCI
0
68
42
d
13
14
FeCl3 w/3 AgSbF6
FeCl3 w/3 AgSbF6
e
a
b
NMR yields using 1,3,5-trimethoxybenzene standard. 65−75%
c
d
aqueous solution. 12 M concentrated. Cs2CO3 (0.15 equiv) added.
e
2,6-Di-tert-butyl-4-methylpyridine (0.15 equiv) added.
modest-to-good yields (Table 1, entries 4−10). While the
combination of FeCl3 with AgAsF6 gave marginally higher yield
(Table 1, entry 5), AgSbF6 (Table 1, entry 4) was chosen due
to the significantly lower cost compared to AgAsF6. Catalytic
amounts of strong Brønsted acids, such as an aqueous solution
of HSbF6 (Table 1, entry 10) or concentrated HCl (Table 1,
entry 11), were unable to promote hydroamination.
Furthermore, the reaction does not seem to be driven by
“hidden Brønsted acid catalysis”34 as evidenced by product
formation in the presence of Cs2CO3 (Table 1, entry 13) and
2,6-di-tert-butyl-4-methylpyridine (Table 1, entry 14).23,35
While these bases imposed a slight decrease in yield, the
retention of catalytic activity suggests that iron is the primary
catalyst.
Scheme 2. Alkene Scope for Hydroamination
With suitable conditions for the hydroamination of cyclo-
hexene, a variety of sulfonamide nucleophiles were evaluated
(Scheme 1). Sulfonamides were a privileged amine source for
our catalytic system. Other amine classes such as electron-
deficient anilines, amides, and carbamates provided no
hydroamination products, likely due to strong binding to the
iron catalyst (see Supporting Information). The highest yields
were achieved with p-toluenesulfonamide (1a) affording
hydroamination product (2a) in good yield, even on 5 mmol
scale. Similar sulfonamides, such as o-toluenesulfonamide (1b)
and benzenesulfonamide (1c), gave reasonable yields. More
easily removable 2-nitrobenzenesulfonamide (1d) was toler-
ated.36 Sterically bulky (1e), electron-rich (1f), as well as
electron-poor (1g−h) sulfonamides gave moderate-to-good
yields. Heterocycles, such as the thiophene in 1i, could be
incorporated as in 1i. Additionally, secondary sulfonamides 1j
and 1k produced tertiary amine products (2j−k) in modest
yields.
With a wide range of viable sulfonamides, we next evaluated
the scope of alkenes (Scheme 2). Smaller cyclic alkenes
cyclopentene (3a) and cycloheptene (3b) worked well, while
larger cyclooctene and cyclododecane surprisingly failed to
produce product (data not shown). Strained norbornene (3c)
reacted smoothly to afford 4c in 80% yield. Unsymmetric
alkenes, such as 1-hexene (3d), gave a mixture of the 2- and 3-
substituted products (4d), likely through a carbocation
rearrangement.37 Ester-containing substrates (3e) appear to
inhibit the reaction, producing relatively low yields. More
B
DOI: 10.1021/acs.orglett.9b00427
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
reactive trisubstituted alkenes (3f−j) proceeded in moderate-
to-good yields. Cyclic, trisubstituted alkenes (3f−g) gave
superior yields with FeCl3 alone. The modest yields of this
substrate class are due to competitive dimerization of the
alkene. Furthermore, the addition of AgSbF6 led to increased
dimerization and gave little to no hydroamination products.
Derivatives of citronellol, elaborated either with a tosylate
leaving group (3i) or protected with TIPS (3j), were tolerated
without nucleophilic displacement of the tosylate (4i) or
deprotection (4j). Additionally, 2,2-disubstituted alkenes, such
as 3k, could be used to produce 4k in serviceable yield.
We next sought to translate this methodology to form C−O
through hydroetherification reactions (Scheme 3). Under our
primary alcohols, such as n-pentanol (5f), were also competent
nucleophiles.
In a quest to expand the nucleophile scope to secondary
alcohols, phenols, and thiophenols, milder conditions were
employed. Since FeCl3 alone does not activate secondary
alcohols, these reactions could employ this cheap catalyst
system. Using strained alkene norbornene, the hydroether-
ification of secondary alcohols proceeded with good yields
(Scheme 3b). Secondary alcohol 4-phenylcyclohexanol (5g)
afforded the desired product 6g in excellent yield, while 4-
phenyl-2-butanol (5h) gave only modest yield. Additionally, p-
nitrophenol (5i) formed the hydroetherification product in
74% yield. The strongly withdrawing nitro group proved
critical to promote hydroetherication and inhibit Friedel−
Crafts side productseven p-fluorophenol led primarily to
Friedel−Crafts products (data not shown). Excitingly, p-
nitrothiophenol (5j) gave the desired hydrothiolation product
6i. Thiols represent a difficult substrate class since disulfide
formation competes under the reaction conditions.14
Scheme 3. Hydroetherification and Hydrothiolation
To evaluate the alkene scope for hydroetherification,
primary alcohol 5e was evaluated over a range of alkenes.
Similar to the hydroamination, small cyclic alkenes cyclo-
pentene (3a) and cycloheptene (3b), as well as strained
norbornene (3c) performed well. 1-Hexene (3d) produced a
mixture of carbocation-rearranged products. Trisubsituted
olefins produced moderate yields of the hydroetherification
products 7f−l. While 2-methyl-2-butene (3h) reacted
efficiently at 40 °C with only FeCl3, 2-methyl-2-pentene (3l)
proceeded in high yield at room temperature. Finally, tosylated
citronellol 3i afforded 7i without excess olefin (Scheme 4).
Scheme 4. Alkene Scope for Hydroetherification
reaction conditions, the combination of FeCl3 and AgSbF6 can
activate alcohols, leading to deleterious substitution reactions
instead of the desired hydroetherification products. To
eliminate this side reaction, primary alcoholsa challenging
substrate for substitution reactions32were chosen as the class
of nucleophile for hydroetherification (Scheme 3a). Primary
alcohols were less reactive than sulfonamides under our
catalytic conditions. In order to achieve suitable yields, excess
alkene was necessary. Primary alcohols with pendant benzene
rings (5a−b) gave the desired hydroetherification products
(6a−b) with the majority of the remaining mass balance being
recovered starting alcohol. Placing an electron-withdrawing
group on the pendant benzene ring, such as fluoride (5c),
bromide (5d), or nitro (5e), gave the highest yields. Simple
In summary, we have developed an efficient iron-based
catalytic system for the hydrofunctionalization of unactivated
alkenes. Using a simple, air- and moisture-tolerant catalyst, the
efficient construction of C−N, C−O, and C−S bonds can be
accomplished under the same conditions. This modular
approach functionalizes mono-, di-, and trisubstituted olefins
with a wide range of sulfonamides along with primary and
C
DOI: 10.1021/acs.orglett.9b00427
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b00427.
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AUTHOR INFORMATION
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Corresponding Author
*E-mail: sicook@indiana.edu.
ORCID
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Silas P. Cook: 0000-0002-3363-4259
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We acknowledge funds from Indiana University in partial
support of this work. We also gratefully acknowledge the NSF
CAREER Award (CHE-1254783). Eli Lilly & Co. and Amgen
supported this work through the Lilly Grantee Award and the
Amgen Young Investigator Award. P.T.M. was supported by
the Graduate Training Program in Quantitative and Chemical
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