Halogen-Bond-Induced Consecutive Csp3-H Aminations via Hydrogen Atom Transfer Relay Strategy

Article abstract of DOI:10.1021/acs.orglett.0c00081

The utilization of a halogen bond in a number of chemical fields is well-known. Surprisingly, the incorporation of this useful noncovalent interaction in chemical reaction engineering is rare. We disclose here an uncommon use of halogen bonding to induce intermolecular C_sp³-H amination while enabling a hydrogen atom transfer relay strategy to access privileged pyrrolidine structures directly from alkanes. Mechanistic studies support the presence of multiple halogen bond interactions at distinct reaction stages.

Full text of DOI:10.1021/acs.orglett.0c00081

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Letter
3
Halogen-Bond-Induced Consecutive Csp −H Aminations via
Hydrogen Atom Transfer Relay Strategy
Fan Wu, Jeewani P. Ariyarathna, Navdeep Kaur, Nur-E Alom, Maureen L. Kennell, Omar H. Bassiouni,
and Wei Li*
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ABSTRACT: The utilization of a halogen bond in a number of
chemical fields is well-known. Surprisingly, the incorporation of
this useful noncovalent interaction in chemical reaction engineer-
ing is rare. We disclose here an uncommon use of halogen bonding
to induce intermolecular Csp3−H amination while enabling a
hydrogen atom transfer relay strategy to access privileged
pyrrolidine structures directly from alkanes. Mechanistic studies
support the presence of multiple halogen bond interactions at distinct reaction stages.
ature’s ability to use noncovalent interactions (NCIs) to
regulate crucial biological processes has long inspired
a similar transformation via the requisite N−I bond formation
(Scheme 1b).13 Herein, we disclose a rare halogen bonding
charge-transfer complex induced nitrogen radical formation
from sulfonamides to initiate a HAT relay process, a strategy
that is not amenable to nitrene-based technology. In turn,
multiple Csp3−H aminations can take place to convert alkanes
into pyrrolidines, a privileged pharmaceutical motif.
Among the many facets of XB, our work is inspired by the
charge-transfer component postulated by the works of
Mulliken.14 We were curious if this XB character could,
under visible-light-mediated conditions, elicit heteroatom
radical formation with simple nitrogen sources to conduct
hydrogen atom abstraction chemistry (Scheme 1c). In this
case, we sought a simple halogen bond donor that could be
used to engage the Lewis basic sulfonamides in halogen
bonding. Upon visible light irradiation, nitrogen-centered
radical formation could take place via a halogen bonding
charge-transfer complex. Radical abstraction of a suitable
hydrogen atom, followed by iodination and substitution with
sulfonamide, would then install the first C−N bond. We
reasoned that an ensuing nitrogen relay process could occur via
N
us.1 For example, halogen bond (XB) interactions have been
indicated to play an essential role in the recognition of thyroid
hormones by their cognate proteins (Scheme 1a).2 Over the
past few decades, this seemingly “exotic” interaction has grown
in popularity and has been widely recognized in material and
drug design and in crystal engineering.3 Yet only recently
chemical researchers have started to contemplate how to
synchronize this useful NCI to guide chemical reactions.4
Exciting early works in this area by Bolm, Huber, Takemoto,
Tan, Yeung, and others have mostly centered on the use of
halogen bonding as Lewis acid equivalents or anion
receptors.5−7 Particularly, a series of interesting studies by
Huber and co-workers has laid the mechanistic foundation that
halogen bonding, and not other interactions, is responsible for
the rate acceleration in a number of model reaction settings.7
Distinctively, we sought to use this NCI to engineer
unconventional chemical reactions. A particular process we
are interested in, the use of XB to access reactive radical
species for selective C−H functionalization, remains largely
unexplored.8
̈
visible-light-mediated Hofmann−Loffler−Freytag (HLF) re-
The selective replacement of Csp3−H with Csp3−N bond, a
ubiquitous motif in medicinal chemistry, is an intensely
pursued research area.9 The current state of the art for
intermolecular Csp3−H amination is the transition-metal-
catalyzed nitrene insertion or transfer chemistry.10 Another
complementary yet unified strategy that has garnered
significant momentum recently is the radical-based approach
to evoke hydrogen atom transfer (HAT) processes.11 Despite
recent progress in intermolecular C−H amination via HAT,
the use of a versatile and convenient nitrogen source is highly
desirable with limited examples.12 During the progress of our
action.15 This HAT relay process would afford us a unique
route to pyrrolidines as part of our program to assemble
heterocycles from feedstock chemicals.16
Our experiments commenced with finding suitable con-
ditions for the initial benzylamination process. Evaluation of a
Received: January 8, 2020
work, we became aware of an elegant report by the Muniz
̃
group using PhI(O2CAr)2 as a terminal reagent to accomplish
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35). Additionally, this reaction could be applied for the direct
and regioselective C−H amination of a number of natural
products and pharmaceuticals including the drug molecule
Celebrex (Scheme 2, products 36−38).19
Scheme 1. Background on Halogen Bond and
Intermolecular Csp3-H Aminations
Encouraged by the benzylamine scope, we proceeded with n-
pentylbenzene to test our nitrogen relay strategy. Gratifyingly,
the nitrogen relay productpyrrolidine 39was generated in
a reasonable 46% yield.20 Hence, two consecutive aminations
of Csp3−H bonds with variable bond dissociation energies
(BDEs), in a single reaction operation, provided us a versatile
and modular strategy to synthesize pyrrolidines. Excited by this
finding, we further extended the substrate scope to a range of
other pyrrolidine products in moderate yields (Scheme 2,
products 40−46). We were delighted to observe that even the
drug Celebrex could readily participate in this reaction,
generating the desired pyrrolidine 47 in 48% yield and
highlighting the application of this protocol in late-stage
pharmaceutical functionalization.
With this simple C−H amination protocol in hand, we were
interested in understanding the role of the halogen bond in the
reaction mechanism. First, we conducted a series of UV−vis
studies to elucidate the presence of potential charge-transfer
complexes of NIS with a variety of sulfonamides (Figure 1a).
As expected, neither NIS nor the sulfonamide provided any
absorption peaks in the visible light range. When NIS mixed
with the sulfonamides, an absorption peak (∼500 nm) started
to appear. Interestingly, the intensity of this peak seemed to
correlate well with the electronic properties of the
sulfonamides with a decreasing order of intensity as follows:
PMBSO2NH2, TsNH2, PhSO2NH2, and NsNH2. This study
revealed that the extent of interaction between the sulfonamide
and NIS increased as the electron-donating capability of the
sulfonamide increased. This observation is reminiscent of the
“outer” and “inner” complexes postulated by Mulliken and
Person to account for the extent of charge transfer.21
Importantly, we conducted a concentration-dependent UV−
vis study with TsNH2 and NIS, in which a high degree of linear
correlation between the UV−vis absorbance and the TsNH2
concentration was observed (Figure 1b and Supporting
Information). Furthermore, we conducted the control
reactions shown in Figure 1c, which suggest that the ionic
variety of halogen bond donors revealed that N-iodosuccina-
mide (NIS) was optimal. Under a 26 W compact fluorescent
light (CFL) source, the reaction produced product 1 in 87%
isolated yield (Scheme 2, product 1). Examination of different
sulfonamides revealed that a wide range of alkyl and aryl
sulfonamides proceeded effectively under the standard reaction
conditions (Scheme 2, products 2−12). For example, simple
methyl, trichloroethoxyl, cyclopropyl, and camphor sulfona-
mides were all well-tolerated in this reaction (Scheme 2,
products 5 and 8−10). Less steric-demanding N-methyl and
N-butyl sulfonamides were also viable substrates (Scheme 2,
products 6 and 7). Interestingly, heteroaromatic sulfonamides
were also suitable substrates for product formations (Scheme
2, products 13−16). Control reactions revealed that NIS was
essential and that electron-deficient sulfonamides were poor
substrates.17
For the benzyl substrate scope, we observed consistent high
yields for a wide range of para- and ortho-substituted
ethylbenzenes (Scheme 2, products 17−24). In cases,
substrates containing acidic C−H bonds or cross-coupling
functionalities such as protected amines, ketones, or halogens
proceeded smoothly (Scheme 2, products 18 and 21−23).
Substrates with functional groups such as NPhth on the alkyl
chain and adamantane were efficient in furnishing the desired
C−H amination products (Scheme 2, products 25−27).18
Alkylbenzenes with sterically congested tertiary and cyclic
benzyl positions could also afford the desired products in good
yields (Scheme 2, products 28−30). Furthermore, molecules
with multiple benzylic C−H bonds could be differentiated with
high regioselectivity (Scheme 2, products 31 and 32).
Diarylmethanes worked exceptionally well in this reaction
regardless of the electronic nature (Scheme 2, products 33−
conversion to the N−I bond proposed in Muniz’s work is
̃
highly inefficient here with NIS in dark conditions. Important
additional 15N NMR studies revealed a downfield shift of the
nitrogen signal of TsNH2 (Figure 1d).22 These collective
studies suggested the presence of electron donor−acceptor
complex A of halogen bonding between NIS and the
sulfonamides that is ultimately responsible for the absorption
band observed in our UV−vis studies.23
Kinetic analysis of several substituted ethylbenzenes
provided a Hammett plot with a ρ value close to −1,
indicating kinetic acceleration of the rate-limiting step with
more electron-donating substrates (Supporting Information).
However, a carbocation buildup during the rate-limiting step
was not likely based on the small ρ value.24 This mechanistic
analysis was supported by the subsequent intermolecular
kinetic isotopic effect (KIE) studies using substrates 48 for
product 49 (Figure 2a). In this case, the observed KIE was 7.7,
suggesting that the C−H abstraction step was the rate-limiting
step. To further clarify the reaction mechanism, we conducted
a series of control experiments. In the absence of light, the
reaction afforded less than 5% yield, suggesting that ambient
light was crucial. The absence of NIS, as expected, resulted in
B
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Scheme 2. Substrate Scope
a
Standard reaction conditions: NIS (300 mol %), dichloromethane (DCM), 26 W CFL, rt, 16 h. Product ratios were determined for crude
b
c
1
mixtures based on H NMR. Reported yields were isolated yields. Standard reaction conditions: NIS (500 mol %), 36 h. PMB stands for para-
d
e
f
methoxybenzene. Yields reported in bracket are benzylamine products from crude 1H NMR. dr ranges from 1:1 to 1.2:1. dr is greater than 95:5.
no reaction at all. The absence of NH2Ts afforded neither the
desired product nor the iodoethylbenzene intermediate,
illustrating the requirement of NH2Ts for the hydrogen atom
abstraction process. Additionally, we introduced iodoethylben-
zene 50 for the amination process (Figure 2b). Interestingly,
NH2Ts alone with 50 only resulted in 2% yield under dark
conditions. However, with the addition of NIS, NH2Ts and 50
afforded the amination products 51 and 52 in 94% combined
yield under light and 83% combined yield under dark
conditions. Furthermore, the addition of catalytic or
stoichiometric iodine resulted in marginal formation of 51,
suggesting that NIS was the halogen bonding activation
species. Importantly, the addition of NIS to 2-iodopropane
caused both carbon signals to shift.25 These studies suggested
that a second halogen bond complex with NIS was likely
generated to facilitate the substitution reaction.
On the basis of our mechanistic evidence, we tentatively
propose the following mechanism (Figure 3). First, a halogen
bond complex A initiates visible light absorption. Upon
photoexcitation and charge transfer, the complex C ultimately
extrudes the nitrogen-centered radical D and iodine, which
may also exist in equilibrium with the N−I intermediate E.26
The resulting heteroatom radical D can then abstract the
benzylic C−H bond to form radical F. The likely role of iodine
is to recombine with F to produce 1-iodoethylbenzene. A
second halogen bonding between 1-iodoethylbenzene and NIS
C
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Figure 3. Proposed reaction mechanism.
compared to halonium processes and, instead, identifiable with
nitrogen-centered radical additions to alkenes (Scheme 3).28 In
a
Scheme 3. Regioselective Bromoamination of Alkenes
Figure 1. UV−Vis studies and control reactions.
a
With NIS, these reactions also produced the desired products albeit
in lower yields, most likely due to product stability issues.
this case, the use of N-bromosuccinamide (NBS), with visible
light, enabled several classes of olefins to undergo nitrogen
radical additions to provide the desired products (Scheme 3,
products 53−56). Importantly, this strategy could be applied
to complex alkene structures with great yields and
regioselectivity (Scheme 3, product 57−59). Notably, the
alkene addition process also revealed a high degree of
chemoselectivity, in which only the electron-rich alkene
addition product 59 was observed in the presence of an
electron-deficient olefin.
Figure 2. KIE studies and control experiments.
We have disclosed a practical protocol to directly furnish a
nitrogen-centered radical, most likely via visible light excitation
of a halogen bond charge-transfer complex. This process
utilizes simple and abundant sulfonamides as the nitrogen
source to accomplish the direct and site-selective C−H
amination of a range of alkanes. Importantly, this reaction is
amenable for a HAT relay strategy to access pyrrolidine
structures via two consecutive C−H aminations of alkanes with
variable BDEs. The utility of the nitrogen-centered radical is
further showcased in the alkene amino-halogenation process to
provide complementary regiochemistry to conventional
halonium-based processes. Most excitingly, we believe this
results in the formation of another complex G, which activates
the 1-iodoethylbenzene for the nucleophilic substitution to
generate the final product 1.27 A similar process can be
proposed for the subsequent HLF reaction to generate the
pyrrolidine products.
The use of a halogen source and a nucleophile, in alkene
halofunctionalization reactions, often affords reactivity and
regioselectivity pertaining to halonium chemistry. On the
contrary here, we have shown that the regioselectivity patterns
obtained are opposite to that of halonium-related pathways.
Specifically, we observed a highly regiodivergent outcome
D
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work will open interesting avenues to consider how to engage
electron donor−acceptor complexes enhanced by potential
halogen bonding for the engineering of unconventional
chemical reactions.
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c00081.
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Experimental procedure and characterization data for
the products (PDF)
AUTHOR INFORMATION
Corresponding Author
■
Wei Li − Department of Chemistry and Biochemistry, School of
Green Chemistry and Engineering, The University of Toledo,
Toledo, Ohio 43606, United States; orcid.org/0000-0001-
8524-217X; Email: Wei.Li@utoledo.edu
Authors
Fan Wu − Department of Chemistry and Biochemistry, School of
Green Chemistry and Engineering, The University of Toledo,
Toledo, Ohio 43606, United States
Jeewani P. Ariyarathna − Department of Chemistry and
Biochemistry, School of Green Chemistry and Engineering, The
University of Toledo, Toledo, Ohio 43606, United States
Navdeep Kaur − Department of Chemistry and Biochemistry,
School of Green Chemistry and Engineering, The University of
Toledo, Toledo, Ohio 43606, United States
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2014, 57, 10257−10274. (b) Yi, H.; Zhang, G.; Wang, H.; Huang, Z.;
Wang, J.; Singh, A. K.; Lei, A. Chem. Rev. 2017, 117, 9016−9085.
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Chem. Rev. 2017, 117, 9247−9301. (b) Du Bois, J. Org. Process Res.
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Arnold, F. H. Nat. Chem. 2017, 9, 629−634. (k) Wu, X.; Yang, K.;
Zhao, Y.; Sun, H.; Li, G.; Ge, H. Nat. Commun. 2015, 6, 6462. For a
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(a) Sharma, A.; Hartwig, J. F. Nature 2015, 517, 600−604.
(b) Huang, X.; Bergsten, T. M.; Groves, J. T. J. Am. Chem. Soc.
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Nur-E Alom − Department of Chemistry and Biochemistry,
School of Green Chemistry and Engineering, The University of
Toledo, Toledo, Ohio 43606, United States
Maureen L. Kennell − Department of Chemistry and
Biochemistry, School of Green Chemistry and Engineering, The
University of Toledo, Toledo, Ohio 43606, United States
Omar H. Bassiouni − Department of Chemistry and
Biochemistry, School of Green Chemistry and Engineering, The
University of Toledo, Toledo, Ohio 43606, United States
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c00081
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We would like to dedicate this work to Prof. D. W. C.
MacMillan (Princeton Univ.) for his 52nd birthday. We thank
the Univ. of Toledo for a startup grant. We thank Dr. Y. W.
Kim (Univ. of Toledo) for NMR assistance. G.-S. S. Shyam
(Univ. of Toledo) and Z. (M.) Wang at Environmental
Analysis Service Center (Univ. of Cincinnati) are acknowl-
edged for collecting high-resolution mass spectrometry data.
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(17) Electron-deficient sulfonamides such as 4-(trifluoromethyl)-
benzenesulfonamide and trifluoromethanesulfonamide provided 6%
and 9% yields, respectively.
(18) Other nonbenzylic C−H bonds from 2-methylpentane, THF,
and cyclohexane were also tested to provide corresponding yields of
7%, 25%, and 0%. The lower yields of the amination products can be
attributed to a combination of inefficient C−H bond abstraction and/
or nucleophile substitution processes.
(19) The site selectivity is likely due to the increased steric
hindrance, which resulted in slower HAT process at the tertiary
benzylic.
(20) For selected reviews on challenges and perspectives in C−H
functionalization: (a) Hartwig, J. F. J. Am. Chem. Soc. 2016, 138, 2−
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(21) Mulliken, R. S.; Person, W. B.; Molecular Complexes: A Lecture
and Reprint Vol.; Wiley-Interscience: New York, 1969.
(22) For detailed information and spectra, please refer to page 107
of the Supporting Information.
(23) At this stage, we cannot distinguish whether the absorption
band around 500 nm is from the donor−acceptor complex or from
iodine.
(24) Anslyn, E. V.; Dougherty, D. A. In Modern Physical Organic
Chemistry; University Science: Sausalito, CA, 2006; pp 445−453.
(25) The reason we used 2-iodopropane instead of compound 50 for
the NMR studies was because compound 50 quickly decomposed in
the presence of NIS, while 2-iodopropane was stable. For detailed
information, please refer to pages 105 and 106 of the Supporting
Information. In addition, we tested (1-iodooctyl)benzene and NIS
with several other nucleophiles including TMSCF3 (No reaction),
TMSN3 (45%), and BnOH (50%).
F
https://dx.doi.org/10.1021/acs.orglett.0c00081
Org. Lett. XXXX, XXX, XXX−XXX