Iron-Catalyzed Borrowing Hydrogen C-Alkylation of Oxindoles with Alcohols

Article abstract of DOI:10.1002/cssc.201900799

A general and efficient iron-catalyzed C-alkylation of oxindoles has been developed. This borrowing hydrogen approach employing a (cyclopentadienone)iron carbonyl complex (2 mol %) exhibited a broad reaction scope, allowing benzylic and simple primary and secondary aliphatic alcohols to be employed as alkylating agents. A variety of oxindoles underwent selective mono-C3-alkylation in good-to-excellent isolated yields (28 examples, 50–92 % yield, 79 % average yield).

Full text of DOI:10.1002/cssc.201900799

Accepted Article
Title: Iron-Catalyzed Borrowing Hydrogen C-Alkylation of Oxindoles
Using Alcohols
Authors: Mubarak Dambatta, Kurt Polidano, Alexander Northey,
Jonathan Williams, and Louis Christian Morrill
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10.1002/cssc.201900799
ChemSusChem
COMMUNICATION
Iron-Catalyzed Borrowing Hydrogen C-Alkylation of Oxindoles
Using Alcohols
Mubarak B. Dambatta,[a] Kurt Polidano,[a] Alexander D. Northey,[a] Jonathan M. J. Williams,[b] and Louis
C. Morrill*[a]
Abstract: A general and efficient iron-catalyzed C-alkylation of
oxindoles has been developed. This borrowing hydrogen approach
employs a (cyclopentadienone)iron carbonyl complex (2 mol %) and
exhibits a broad reaction scope, allowing benzylic and simple
primary and secondary aliphatic alcohols to be employed as
alkylating agents. A variety of oxindoles undergo selective mono-
C(3)-alkylation in good to excellent isolated yields (28 examples, 50-
92% yield, 79% average yield).
A) Selected examples of biologically active C(3)-substituted oxindoles
H2N
Me
N
O
EtO2C
Ph
Ph
CN
NC
O
Br
F
O
O
O
N
H
N
H
N
H
(±)
(±)
F
cytostatic activity against
H460, MCF-7 and SF-268
cancer cell lines
HIV-1 non-nucleoside
reverse transcriptase
inhibitors
anti-inflammatory and
analgesic activity
Me
The oxindole framework is present in a diverse array of naturally
occurring compounds.[1] Furthermore, oxindoles that are mono-
or disubstituted at the C(3) position are commonly employed in
drug discovery programmes,[2] with examples including the
development of HIV-1 non-nucleoside reverse transcriptase
inhibitors, spircocyclic compounds with anti-cancer and anti-
inflammatory properties, and antagonists of progesterone and 5-
hydroxytryptamine7 (5-HT7) receptors (Scheme 1A). The
traditional method for alkylation of unprotected oxindoles
employs toxic alkyl halides and exhibits poor selectivity (mono-
vs. dialkylation, C- vs. N-alkylation) alongside the generation of
stoichiometric quantities of undesired byproducts.[3] An
alternative approach employs the borrowing hydrogen (BH)
principle, also known as hydrogen autotransfer, which allows
bench stable and inexpensive alcohols to be used as alkylating
agents, generating water as the sole byproduct.[4] Recent
progress in this area has provided alternatives to commonly
employed precious metal catalysts through the development of
catalysts based on earth-abundant first row transition metals.[5]
The BH alkylation of oxindoles using alcohols, which
selectively produces mono-C(3)-alkylation products, has been
reported using heterogeneous catalysis,[6] and by employing
homogeneous precious metal catalyst systems based on
ruthenium and iridium.[7] However, with respect to earth-
abundant first row transition metal catalysis, only sporadic
examples appear in the literature, in each case forming only a
F
N
O2N
O
O
N
NPh
N
H
H
(±)
(±)
5-hydroxytryptamine7 (5-HT7)
receptor antagonists
progesterone receptor
antagonists
B) Iron-catalyzed borrowing hyrogen C-alkylation of oxindoles (this work)
Me
N
Ph
well-defined bench stable
Fe(0) carbonyl complex
O
most abundant transition
metal in the Earth's crust
selective mono-C(3)-alkylation
benzylic and aliphatic alcohols
N
Me
(2 mol %)
Ph
Fe
R1
OC
CO
R2
O
OC
R2
PPh3, K2CO3
R3
R3
+
O
R1
OH
N
N
BH catalysis
R4
R4
28 examples
50-92% yield
79% average yield
+ H2O
Scheme 1. Oxindole importance and project overview work.
transition metals is required and would represent a valuable
addition to the synthetic toolbox. To this end, herein we report
the use of a bench stable (cyclopentadieneone)iron(0) carbonyl
complex (2 mol %) for the selective mono-C(3)-alkylation of
various oxindoles using both benzylic and simple primary and
secondary aliphatic alcohols as alkylating agents (Scheme
1B).[9]
To commence our studies, we selected the C(3)-benzylation
of oxindole 2 with benzyl alcohol 1 (1.2 equiv.) as a model
system (Table 1). After extensive optimization,[10] it was found
minor component of
a
broader study.[8] As such, the
development of a general catalytic BH C-alkylation of oxindoles
using well-defined complexes based on earth-abundant first row
that
a
BH
system
composed
of
bench
stable
(cyclopentadieneone)iron(0) carbonyl complex 3 (2 mol %),[11]
triphenylphosphine (4 mol %) to form the active catalyst, K2CO3
(0.5 equiv.) as base in xylenes ([2] = 0.5 M) at 150 °C for 24 h,
enabled the efficient C-benzylation of 2, giving 4 in 97% NMR
yield and 90% isolated yield (entry 1).[12] Importantly, only 1.2
equivalents of the alkylating agent and substoichiometric
quantities of base were required for complete conversion, giving
a high atom economy process.[13] No alkylation occurs in the
absence of iron precatalyst 3 (entry 2), with only 26% conversion
observed in the absence of K2CO3 (entry 3). The PPh3-bound
[Fe] precatalyst 5 could be employed, accessing 4 in 95% NMR
yield (entry 4), verifying it as a plausible catalytic intermediate
(c.f. Scheme 3). Interestingly, from the iron complexes employed
[a]
[b]
M. B. Dambatta, K. Polidano, A. D. Northey, Dr L. C. Morrill
Cardiff Catalysis Institute, School of Chemistry, Cardiff University,
Main Building, Park Place, Cardiff, CF10 3AT, UK
E-mail: MorrillLC@cardiff.ac.uk
Prof. J. M. J. Williams
Department of Chemistry, University of Bath, Claverton Down, Bath,
BA2 7AY, UK
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
http://XXXX
Information about the data that underpins the results presented in
this article, including how to access them, can be found in the
Cardiff University data catalogue at under:
http://XXXX (accessed XXXX)
This article is protected by copyright. All rights reserved.

10.1002/cssc.201900799
ChemSusChem
COMMUNICATION
Table 1: Optimization of the Fe-catalyzed oxindole C-benzylation.[a]
quantity of K2CO3 (entry 13), highlighted that catalytic quantities
of base (10 mol %) can be employed, accessing 4 in 88% NMR
yield. Employing toluene as solvent (entry 14), increasing the
reaction concentration (entry 15), lowering reaction temperature
(entry 16), reducing reaction time (entry 17), or reducing the
catalyst loading (entry 18), all lowered the efficiency of the iron-
catalyzed mono-C(3)-benzylation of 2.
Me
N
Ph
O
N
Me
3, L = CO
5, L = PPh3
Ph
Fe
OC
L
OC
Ph
O
[Fe] precatalyst 3 (2 mol %)
PPh3 (4 mol %)
K2CO3 (0.5 equiv.)
The full scope of the Fe-catalyzed BH C(3)-alkylation of
oxindoles was explored, starting with the C-alkylation of oxindole
2 (Scheme 2A/B).[16] Using the optimized reaction conditions
(Table 1, entry 1) a variety of substituted benzylic alcohols can
be employed as alkylating agents, giving the corresponding
mono-C(3)-alkylated oxindoles in excellent isolated yields
(products 4 and 11−24, 52-91% yield). Within the alcohol,
sterically encumbered aryl units such as o-tolyl and 1-naphthyl
were tolerated in addition to electron-donating (4-OMe, 4-OBn)
and electron-withdrawing (4-CF3, 4-CN) substituents. The
catalytic system exhibits chemoselectivity, tolerating the
reducible nitrile and alkene moieties present within products 19
and 20. 4-Iodobenzyl alcohol was employed as the alkylating
agent, incorporating an additional functional handle into oxindole
21 for subsequent elaboration via established cross-coupling
methods.[17] Furan-2-ylmethanol and thiophene-2-ylmethanol
were both compatible with this methodology, incorporating an
additional heterocycle into products 23 and 24, which were
formed in 77% and 84% isolated yield, respectively. We were
pleased to discover that less activated simple aliphatic alcohols
can also be employed as alkylating agents in this process
(products 25−31, 53-84% yield). In each case, the alcohol was
used as solvent in order to obtain high isolated yields of the
mono-C(3)-alkylated oxindoles. Under otherwise identical
reaction conditions, decan-1-ol, butan-1-ol, ethanol and
methanol were all successfully utilized as alkylating agents. 1,4-
Butanediol was also employed as the alkylating agent,
accessing mono-C(3)-alkylated oxindole 29 in 53% isolated yield,
with no dialkylation products observed. Remarkably, it was
found that unactivated secondary alcohols propan-2-ol and
butan-2-ol, were also tolerated, giving alkylated oxindoles 30
and 31 in excellent isolated yields. This is a rare example of
secondary alcohol compatibility as alkylating agents in BH
catalysis employing earth-abundant first row transition metal
+
OH
O
Ph
150 ºC, xylenes, 24 h
"standard" conditions
N
H
N
H
4
1 (1.2 equiv.)
TMS
2
Ph
Ph
TBDMS
Ph
Ph
O
O
X
O
O
TMS
TBDMS
Fe
Fe
Fe
Fe
OC
OC
OC
OC
OC
OC
OC
10
CO
CO
CO
CO
OC
6
7
8, X = NTs; 9, X = O
entry
variation from “standard” conditions
none
yield[b] (%)
97 (90)
< 2
1
2
no [Fe] precatalyst 3
3
no K2CO3
26
95
18
5
4[c]
5 (2 mol %) instead of 3
6 (2 mol %) instead of 3
7 (2 mol %) instead of 3
8 (2 mol %) instead of 3
9 (2 mol %) instead of 3
10 (2 mol %) instead of 3
no PPh3 activator
5
6
7
5
8
5
9
5
10
11
12
13
14
15
16
17
18[d]
90
92
85
88
91
93
86
92
73
Me3NO (4 mol %) instead of PPh3
Cs2CO3 (0.5 equiv) instead of K2CO3
K2CO3 (0.1 equiv)
toluene instead of xylenes
[2] = 1 M
130 °C
reaction time = 6 h
[Fe] precatalyst 3 (1 mol %)
[a] Reactions performed using 1 mmol of oxindole 2 and bench-grade
xylenes. [2] = 0.5 M. [b] Yield after 24 h as determined by 1H NMR
analysis of the crude reaction mixture with 1,3,5-trimethylbenzene as the
internal standard. Isolated yield given in parentheses. [c] no PPh3. [d] 2
mol % of PPh3.
catalysts.[18] Unfortunately, despite examining
a range of
alternative reaction conditions, benzylic alcohols containing nitro
or ketone functional groups, allylic alcohols, propargylic alcohols
and bulkier secondary alcohols (e.g. 1-phenylethan-1-ol) were
found to be incompatible with this C-alkylation procedure.
Next, we explored the scope of the reaction with respect to
variation within the oxindole component (Scheme 2C).
Employing the optimized reaction conditions (Table 1, entry 1) a
variety of substituted oxindoles undergo efficient and selective
mono-C(3)-alkylation with benzyl alcohol (products 32−37, 50-
92% yield). Oxindoles containing halogen substitution at the 5-
position (5-Br, 5-Cl and 5-F) in addition to N-methyl, N-benzyl
and N-phenyl substitution were all well tolerated. Barbituric acids
are a class of activated amide that have been shown to
participate as competent nucleophiles in homogeneous BH
alkylation processes employing precious metal catalysts.[19]
Using [Fe] precatalyst 3 (4 mol %), it was found that a selection
in this study, it was found that (cyclopentadienone)iron carbonyl
precatalysts 3 and 5, which contain a more electron-rich
cyclopentadienone framework, were uniquely effective for the
desired transformation, with the use of alternative iron
precatalysts 6-10 resulting in low to negligible formation of
alkylated oxindole 4 (entries 5-9).[14] The reaction can be
performed in the absence of PPh3, albeit in a slightly diminished
yield, indicating thermal activation of the precatalyst occurs at
150 °C (entry 10).[11] Substituting triphenylphopshine for
trimethylamine N-oxide (4 mol %),[15] also had a slightly negative
impact on the reaction (entry 11). Employing Cs2CO3 as base
resulted in lower conversion to 4 (entry 12). Lowering the
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10.1002/cssc.201900799
ChemSusChem
COMMUNICATION
Me
N
Ph
Ph
O
N
Me
Fe
OC
CO
OC
R1
R2
O
[Fe] precatalyst 3 (2 mol %)
PPh3 (4 mol %)
K2CO3 (0.5 equiv.)
R2
28 examples (50-92% yield)
selective mono-C(3)-alkylation
benzylic and aliphatic alcohols
R3
R3
+
O
150 ºC, xylenes, 24 h
"standard" conditions
R1
OH
N
N
R4
R4
(1.2 equiv.)
A) Alcohol scope (22 examples)
B) Incompatible alcohols
Me
Me
OH
Me
O2N
O
O
O
O
O
N
H
N
H
N
H
O
N
H
N
H
OH
N
H
Me
4, 90%
11, 87%
12, 78%
13, 90%
14, 91%
15, 91%
OMe
OBn
CF3
CN
I
O
Ph
OH
OH
O
O
O
O
O
O
N
H
N
H
N
H
N
N
N
H
H
H
16, 86%
17, 90%
18, 89%
19, 83%
20, 52%
21, 91%
O
O
S
25, R = n-dec, 59%a
26, R = n-Bu, 71%a
27, R = Et, 79%a
F
R
Ph
28, R = Me, 61%a
Me
O
29, R = (CH2)4OH, 53%a
30, R = i-Pr, 80%a
O
O
N
H
N
N
N
Ph
OH
31, R = s-Bu, 84%a,b,(1:1 d.r.)
H
H
H
22, 88%
23, 77%
24, 84%
C) Oxindole scope (6 examples)
D) C-alkylation of barbituric acid derivatives (5 examples)
O
E) Incompatible amides
When R1= Ph
[Fe] precatalyst 3
(4 mol %)
PPh3 (8 mol %)
32, X = Br, R = H, 80%
38, R2= Me, 60%
39, R2= c-Hex, 7c5%
40, R2= Bn, 57%
When R2= Me
Ph
O
O
O
O
33, X = Cl, R = H, 92%
34, X = F, R = H, 50%
35, X = H, R = Me, 75%
36, X = H, R = Bn, 80%
37, X = H, R = Ph, 75%
X
R2N
O
NR2
R2N
O
NR2
+
R1
(1.2 equiv.)
OH
HN
TsN
150 ºC
xylenes, 24 h
O
41, R1 = 4-OMeC6H4, 50%c
42, R1 = 4-MeC6H4, 73%
N
R
O
R1
Scheme 2. Scope of the Fe-catalyzed C-alkylation of oxindoles. Reactions performed using 1 mmol of oxindole starting material and bench-grade xylenes. All
yields are isolated yields after chromatographic purification. Reagents and conditions: [a] alcohol used as solvent; [b] [Fe] precatalyst 3 (4 mol %), PPh3 (8
mol %); [c] K2CO3 (0.5 equiv.).
of N-alkyl barbituric acid derivatives undergo efficient C(5)-
monoalkylation, giving products 38−42 in 50-75% isolated yield
(Scheme 2D). This iron-catalyzed process is the first example of
a BH alkylation of barbituric acid derivatives employing an earth-
abundant transition metal catalyst. Unfortunately, piperdin-2-one
and 1-tosylpiperdin-2-one were found to be incompatible with
this protocol, with complex reaction mixtures obtained across a
range of reaction conditions explored.
Finally, reduction of 43 by the iron-hydrogen complex gives
C(3)-alkylated product 4 with regeneration of the active iron
complex.
In conclusion, we have developed a general and efficient Fe-
catalyzed C-alkylation of oxindoles using benzylic and simple
primary and secondary aliphatic alcohols as alkylating agents
via the borrowing hydrogen approach. A variety of oxindoles
undergo selective mono-C(3)-alkylation in excellent isolated
yields (28 examples, 50-92% yield, 79% average yield). Ongoing
studies are focused on further applications of earth-abundant
first row transition metals in catalysis and these results will be
reported in due course.
To obtain insight into the reaction mechanism, α,β-
unsaturated amide 43 was synthesized and subjected to the
“standard” C-alkylation reaction conditions, which produced 4 in
71% NMR yield, indicating that 43 is a plausible reaction
intermediate (Scheme 3A). In line with this observation, and
previous related investigations,[11]
a
plausible reaction
mechanism initiates with CO decoordination of [Fe] precatalyst 3
by PPh3 to form the active iron complex, which abstracts
hydrogen from benzyl alcohol in the presence of base to form
the required transient reactive benzaldehyde intermediate
(Scheme 3B). Subsequent nucleophilic attack of oxindole 2
generates β-hydroxy amide 44 that undergoes rapid base-
catalyzed E1cB dehydration to form α,β-unsaturated amide 43.
Acknowledgements
We gratefully acknowledge the School of Chemistry, Cardiff
University for generous support, TETFund for
a
Ph.D.
studentship (M.B.D.), the EPSRC-funded Bath/Bristol/Cardiff
Catalysis Centre for Doctoral Training (K.P., EP/L016443/1), and
This article is protected by copyright. All rights reserved.

10.1002/cssc.201900799
ChemSusChem
COMMUNICATION
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The authors declare no conflict of interest
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A) Evidence supporting an α,β-unsaturated amide intermediate
Ph
Ph
O
[Fe] precatalyst 3 (2 mol %)
PPh3 (4 mol %)
K2CO3 (0.5 equiv.)
+
OH
O
Ph
150 ºC, xylenes, 24 h
N
H
N
H
4, 71%a
1 (1.2 equiv.)
43
B) Plausible mechanism
Me
N
Ph
O
N
Me
3, L = CO
5, L = PPh3
Ph
L
Fe
OC
OC
Ph
O
- L
Ph
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O
N
H
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Me
Ph
Fe
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OC
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Ph
Ph
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N
Me
O
N
H
43
Fe
H
OC
H
OC
HO
Ph
+ base
base + H2O
base
O
O
N
H
N
H
44
2
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Keywords: iron catalysis • borrowing hydrogen • alkylation •
oxindoles • alcohols
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Entry for the Table of Contents
Layout 2:
COMMUNICATION
Mubarak B. Dambatta, Kurt Polidano,
Andrew D. Northey, Jonathan M. J.
Williams and Louis C. Morrill*
Page No. – Page No.
Iron-Catalyzed Borrowing Hydrogen
C-Alkylation of Oxindoles Using
Alcohols
I’m only borrowing it!: A general and efficient iron-catalyzed C-alkylation of
oxindoles has been developed. This borrowing hydrogen approach employs a
(cyclopentadienone)iron carbonyl complex (2 mol %) and exhibits a broad reaction
scope, allowing benzylic and simple primary and secondary aliphatic alcohols to be
employed as alkylating agents. A variety of oxindoles undergo selective mono-C(3)-
alkylation in good to excellent isolated yields (28 examples, 50-92% yield, 79%
average yield).
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