Visible-Light-Mediated Remote γ-C(sp3)-H Functionalization of Alkylimidates: Synthesis of 4-Iodo-3,4-dihydropyrrole Derivatives

Article abstract of DOI:10.1021/acs.orglett.8b02022

An efficient and environmentally friendly synthetic approach toward functionalized dihydropyrrole derivatives is reported. The developed protocol proceeds via chemoselective intramolecular N-C bond formation of alkylimidates through 1,5-hydrogen atom transfer from in situ generated imidate N-radicals. The major advantage of this designed strategy lies in the choice of starting materials, mild reaction conditions, high chemo- and diastereoselectivity, clean source of energy, and good functional group tolerance. Further, 4-iododihydropyrroles could be easily transformed into a variety of useful derivatives.

Full text of DOI:10.1021/acs.orglett.8b02022

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Visible-Light-Mediated Remote γ‑C(sp3)−H Functionalization of
Alkylimidates: Synthesis of 4‑Iodo-3,4-dihydropyrrole Derivatives
Yogesh Kumar, Yogesh Jaiswal, and Amit Kumar*
Department of Chemistry, Indian Institute of Technology Patna, Bihta 801106, Bihar, India
S
* Supporting Information
ABSTRACT: An efficient and environmentally friendly syn-
thetic approach toward functionalized dihydropyrrole derivatives
is reported. The developed protocol proceeds via chemoselective
intramolecular N−C bond formation of alkylimidates through
1,5-hydrogen atom transfer from in situ generated imidate N-
radicals. The major advantage of this designed strategy lies in the
choice of starting materials, mild reaction conditions, high
chemo- and diastereoselectivity, clean source of energy, and good functional group tolerance. Further, 4-iododihydropyrroles
could be easily transformed into a variety of useful derivatives.
he design of sustainable and efficient synthetic strategies
that utilize ubiquitous and readily available starting
dihydropyrroles from readily available starting materials
under mild reaction conditions.
T
materials and satisfy the parameters of green chemistry is a
highly desirable and continuous effort in contemporary organic
synthesis. Functionalized N-heterocycles are important and key
structural motifs that are present in many natural products and
high-value synthons for pharmaceutical industries.1,2 The
function of nitrogen-containing compounds critically depends
on their characteristic structures, so the late-stage functional-
ization of these molecules is of high research priority in drug
discovery.1−3 N-Heterocycles containing a five-membered
nucleus, for example, pyrroles4 and dihydropyrroles,5 are
privileged scaffolds and play important roles across various
fields of science. As a result, numerous elegant synthetic
strategies have been designed for their synthesis.4,5 Most of the
developed protocols extensively use oxime derivatives as key
precursors under either metal-catalyzed conditions or photo-
chemical conditions (Figure 1).6
In the recent past, a photochemical approach has emerged as
a powerful, clean, alternative technique for making C−C and
C−X (where X = N, O, S) bonds. In particular, visible-light-
mediated late-stage functionalization of unreactive (γ or δ)
C(sp3)−H bonds through chemoselective 1,5-hydrogen-atom-
transfer (HAT) is an attractive research priority for the
chemical industries.7−13 Recently, several research groups, e.g.,
Leonori,9 Studer,10 Nevado,11 and Muniz,12 have designed
very effective protocols for the functionalization of unreactive
C(sp3)−H distal bonds viz. the generation of iminyl or amidyl
radicals under a single-electron-transfer (SET) approach using
photoredox catalysts.7−14 A major obstacle in these strategies is
the cost of the overall reactions and limited availability of
photoredox catalysts. Hence, a photochemical reaction without
any costly additional metal-based-photocatalyst is a significant
research field in organic chemistry. Very recently, the groups of
Nagib13b and He15 have reported methods for the synthesis of
valuable 1,2-amino alcohols via radical-mediated intramolecu-
lar β-N−C bond formation of alkylimidate derivatives (Scheme
1A,B).
Taking inspiration from their pioneering works and our
research interest in the development of new synthetic
protocols for important heterocyclic molecules,16 we envisaged
that appropriately functionalized alkylimidates could ideally
serve as a source of imidate N-radicals under visible-light
conditions, which would eventually activate remote γ-C(sp3)−
H bonds selectively via a thermodynamically favorable 1,5-
HAT leading to a variety of functionalized dihydropyrrole
derivatives. Herein, we report the development of novel,
transition-metal-free, visible-light induced, chemoselective
intramolecular γ-C(sp3)−H amidation reactions of alkylimi-
Figure 1. General scheme for the synthesis of dihydropyrrole
derivatives.
Despite several well-decorated methods available in the
literature, the major challenges associated with these reported
protocols are (a) the need of elaborated steps to access starting
materials and (b) the need for a metal-based-catalyst or
photocatalyst (difficult to remove from the reaction mixtures
and eventually responsible for toxicity). Considering these
facts, there is a need to develop a convenient, efficient, and
cost-effective method for the synthesis of functionalized
Received: July 4, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b02022
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 1. Imidate Radical-Directed Intramolecular
Table 1. Optimization of the Reaction Conditions
Chemoselective Distal N−C Bond Formation
b
entry MI (X equiv) oxidants (Y equiv)
solvent
yield of 2a (%)
1
2
3
4
5
6
7
8
9
1o
11
12
13
14
NaI (3.0)
KI (3.0)
PIDA (3.0)
PIDA (3.0)
PIDA (3.0)
PIFA(3.0)
PIDA (3.0)
PIDA (3.0)
PIDA (4.0)
PIDA (5.0)
PIDA (4.0)
PIDA (4.0)
PIDA (4.0)
PIDA (4.0)
PIDA (4.0)
CH3CN
CH3CN
CH3CN
CH3CN
CH2Cl2
1,4-dioxane
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
64
48
0
NH4I (3.0)
NaI (3.0)
NaI (3.0)
NaI (3.0)
NaI (4.0)
NaI (5.0)
NaI (4.0)
NaI (4.0)
NaI (4.0)
NaI (4.0)
0
trace
46
71
62
54
30
75
0
c
d
e
f
0
0
NaI (4.0)
a
Reaction conditions: imidate 1a (0.3 mmol), MI (X equiv), oxidant
(Y equiv), and solvent (3.0 mL) were irradiated under degassed
dates, including an unexpected C−I bond formation (Scheme
1C). To the best of our knowledge, use of alkylimidates as a
key precursor for the straightforward synthesis of function-
alized dihydropyrroles by intramolecular γ-N−C bond
formation has not been reported to date.
b
conditions at rt using 12 W blue LED for 18 h. Isolated yield of the
c
product 2a. Reaction was performed with 12 W white LED.
d
e
Reaction was performed with 12W green LED. Reaction was
f
performed with 12 W(×2) blue LED. Reaction was performed in the
dark.
At the outset, we selected 4-phenylbutylimidate 1a as a
model substrate as it possesses a benzylic C−H bond at the γ-
position to the imidate (−NH) group. To generate an imidate
N-radical, a combination of NaI/PIDA (in situ generation of
triiodide, Nagib protocol)13 was employed to form an N−I
bond, and blue LED light (λmax = 455 nm) was used to
dissociate the N−I bond. Under these selected conditions,
when the reaction was carried out in CH3CN for 18 h,
unexpectedly, we obtained 4-iododihydropyrrole 2a in 64%
yield with moderate diastereoselectivity (dr 3.2:1, entry 1,
Table 1). The outcome of this reaction was quite interesting
because it not only enables chemoselective N−C bond
formation but also allows the formation of a C−I bond.
Hence, several reaction parameters were optimized to increase
the overall efficiency of this designed protocol, and the results
are tabulated in Table 1 (for detailed optimization studies, see
the Supporting Information (SI)).17 After careful optimization,
the reaction conditions described in Table 1, entry 11, were
selected for the further exploration. Notably, in the absence of
light, NaI, and PIDA, no product formation was observed,
which further demonstrates their importance in this cascade
reaction (entries 12−14).
With these optimized reaction conditions in hand, we next
evaluated the scope of this transformation via visible-light-
mediated remote γ-C(sp3)−H activation. Alkylimidates con-
taining different O-alkyl groups in the alkoxy group, for
instance, trifluoroethyl, trichloroethyl, ethyl, n-propyl, and
isopropyl groups (1b−f, Scheme 2) instead of the methyl
moiety, were also employed under the optimized reaction
conditions, and the corresponding 4-iodo-3,4-dihydropyrroles
(2b−f) were isolated in moderate yields (54 to 61%). In
general, we observed that the reaction proceeds very well with
methyl- and trifluoroethyl-substituted butylimidates (1a and
1b). Interestingly, when the reactions were carried out with
ethyl-, n-propyl-, and isopropyl-substituted alkylimidates (1d−
f), which contain two possible sites of γ-C−H functionalization
via 1,5-HAT, the chemoselective products were formed along
with some unidentified compounds. The observed chemo-
selectivity could be explained on the basis of the C−H BDE
(BDE: bond dissociation energy) for the benzyl over the
methyl or ethyl groups. This high-level selectivity is an
attractive feature of this developed method. Indeed, when the
reaction was carried out with 1 mmol of 1a under the standard
reaction conditions, the desired product 2a was obtained in
58% yield along with some uncharacterized compounds.
Further, 4-arylbutylimidates 1g−k containing electron-donat-
ing groups (EDGs), such as methyl, ethyl, tert-butyl, and
methoxy, at the meta and para positions of the phenyl ring
reacted well under the standard conditions and gave the
corresponding products in moderate to good yields (50−70%,
Scheme 2, entries 2g−k) with excellent diastereoselectivity (dr
19:1).
The 2,4-trans diastereoselectivity was unambiguously con-
firmed by NMR techniques. The NOESY spectrum of 2a
shows no correlations between peaks of H-2 and H-4 protons;
however, a strong correlation was observed between signals of
H-2′ and H-4′ protons of other diastereomers, confirming the
stereochemical relationship between two functional groups
(for details, see the SI).17 Similarly, 4-arylbutylimidates (1n
and 1o) bearing a halo functional group such as fluoro at the
para position of the aromatic ring gave the desired products in
moderate yields (49−56%, entries 2n and 2o). The
substituents on the aryl ring had no apparent effect on the
outcome of the reaction. In addition, the substrate scope of
this protocol was further extended for the synthesis of the
heteroaryl derivative, which was procured in a low yield of 36%
(entry 2p). Having demonstrated the generality of the
developed protocol with alkylimidates containing benzylic
C−H bonds, we next turned our attention to more challenging
and unbiased substrates, for instance, long-chain aliphatic
B
DOI: 10.1021/acs.orglett.8b02022
Org. Lett. XXXX, XXX, XXX−XXX

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Scheme 2. Substrate Scope for 4-Iodo-3,4-dihydropyrrole
Derivatives
Scheme 3. Control Experiments
a,b
to the imidate (−NH) was subjected to optimize conditions.
Impressively, only one of the methylene groups was activated
to form the desired product 2x (28%) along with many
uncharacterized products (Scheme 3b). This result illustrates
that the γ-C−H bond of the nitrile sides of the imidate (−NH)
group could be selectively activated over the alcohol domain.
In addition, when the reactions were performed with other
sodium halide salts such as NaCl and NaBr in place of NaI
under the standard conditions, no desired product was
obtained (Scheme 3c), and a complex reaction mixture was
observed on a TLC plate. Next, we attempted to detect the
1
reaction intermediates by using H NMR and HRMS analysis
(Scheme 3d, for details, see the SI).17 Specifically, when 1a was
subjected to the standard conditions for 3 h, intermediates 4 or
4′ and 5 were detected ([M + H]+ ion peaks at m/z =
304.0183 and 176.1066, respectively) by mass spectrometry,
which eventually corresponds to either N-iodobutylimidate 4
or 4-iodophenylbutanimidate 4′ and 1-pyrroline 5. Further-
more, it was possible to isolate the key intermediate 5 from the
reaction mixture and unambiguously characterize it by NMR
and HRMS measurements (for details, see the SI).17
Moreover, when isolated intermediate 5 was further subjected
to similar conditions, we obtained the C-4 halogenated 1-
pyrroline 2a in 80% yield. These additional control experi-
ments implied that in situ generated IOAc (from NaI and
PIDA) plays a dual role in this reaction to form the weak N−I
bond (BDE: N−I = 38.0 kcal/mol)13c,19 that is broken under
these mild reaction conditions and to be the source of
electrophilic iodonium ion. To the best of our knowledge, this
is the first example that showcases the dual ability of iodine
monoacetate in visible-light-mediated γ-C−H amidation.
On the basis of the above control experiments and previous
literature reports,7−13 a plausible reaction mechanism is
proposed in Scheme 4. First, the imidate group (−NH) of
1a reacts with NaI/PIDA via in situ generated IOAc13c,20
a
b
For reaction conditions, see entry 11 of Table 1. Isolated yields of
1
the products. The diastereomeric ratios (dr) were determined by H
NMR analysis of reaction mixtures and are given in parentheses.
c
Reaction was carried out on a 1.0 mmol scale.
imidates containing stronger C−H bonds (BDE: benzylic 90
kcal/mol vs aliphatic 97 kcal/mol).13b,18 The imidates
containing unbiased secondary γ-C−H bonds (1q−u), when
subjected to similar reaction conditions, gratifyingly provided
the desired dihydropyrroles, albeit in low yields (26 to 44%,
entries 2q−u) with high diastereoselectivity. Subsequently, the
substrate scopes of this protocol were further extended with
sterically hindered alkylimidates. The reaction works equally
well for α-disubstituted imidates (1v−w) and afforded the
desired products in good yields (61−62%, entries 2v−w).
To investigate the mechanistic aspects of this reaction, a few
additional control experiments were carried out, and the results
are summarized in Scheme 3. When the reaction of
alkylimidate 1a was carried out in the presence of a
stoichiometric amount of radical scavengers such as TEMPO
and BHT, the desired transformation was completely inhibited
(Scheme 3a). This observation suggests that the reaction
probably proceeds by the radical pathway. In order to check
the chemoselectivity in this transformation, a suitable imidate
1x containing two methylene (−CH2) groups at the γ-position
17
1
(confirmed by H NMR measurements, see the SI) to give
N-iodobutylimidate 4, which undergoes N-I homolytic
cleavage under visible-light conditions to afford imidate N-
radical A. Subsequently, 1,5-HAT from the γ-C−H bond to the
imidate radical A provides carbon radical B. This species B
abstracts an iodine atom from 4 via a radical-chain reaction to
generate iodinated intermediate 4′. Intramolecular nucleo-
philic attack of the imidate (−NH) group onto the C−I bond
C
DOI: 10.1021/acs.orglett.8b02022
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Letter
chiral dihydropyrroles from alkylimidates by employing NaI/
PIDA and blue LED visible light. The overall reaction proceeds
via chemoselective intramolecular N−C bond formation
through 1,5-hydrogen atom transfer followed by nucleophilic
attack of enamine species to the iodine monoaceate. In situ
generated imidate N-radical selectively activates remote γ-
C(sp3)−H bonds over the other C(sp3)−H bonds. This
strategy enables the formation of not only intramolecular N−C
bonds but also intermolecular C−I bonds, which could be
further functionalized into important, high-value derivatives.
The synthetic application of this developed protocol is
currently under investigation in our laboratory.
Scheme 4. Proposed Reaction Mechanism
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b02022.
Experimental procedure, H NMR, 13C {1H}, COSY,
HSQC, and NOESY NMR spectra of the products, and
control experiment results (PDF)
1
leads to the five-membered key intermediate 1-pyrroline 5.
Subsequently, pyrroline 5 will give the desired 4-iodo-3,4-
dihydropyrrole product 2a via tautomerization of 5 to C,
followed by the nucleophilic attack of enamine species C to the
iodine monoaceate (IOAc). Notably, the observed high trans
selectivity could be explained from the proposed transition
state TS-I and TS-II. Minimization of the steric interaction
between the hydrogen and phenyl moiety leads to
thermodynamically favored TS-I over TS-II.
Apparently, the presence of an iodo or alkoxy moiety in the
dihydropyrrole products makes venerable synthetic precursors
that are well suited for further manipulation. Hence, we
selected 4-iodo-2,3-dihydropyrrole 2a to transform it into
various useful products (Scheme 5). Nucleophilic substitution
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: amitkt@iitp.ac.in, amitktiitk@gmail.com.
ORCID
Amit Kumar: 0000-0002-1683-7740
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the CSIR (02(0229)/15/EMR-
II), New Delhi, and the Indian Institute of Technology Patna.
Y.K. and Y.J. thank IIT Patna for an Institute Research
Fellowship. We also acknowledge IIT Patna for providing the
NMR facilities and SAIF-IIT, Patna, for HRMS facilities.
Scheme 5. Synthetic Manipulations of 4-Iodo-3,4-dihydro-
2H-pyrrole
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experiment.
F
DOI: 10.1021/acs.orglett.8b02022
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