Direct Photocatalytic Synthesis of Medium-Sized Lactams by C?C Bond Cleavage

Article abstract of DOI:10.1002/anie.201808890

Reported is a novel two-step ring-expansion strategy for expeditious synthesis of all ring sizes of synthetically challenging (hetero)aryl-fused medium-sized lactams from readily available 5–8-membered cyclic ketones. This step-economic approach features a remote radical (hetero)aryl migration from C to N under visible-light conditions. Broad substrate scope, good functional-group tolerance, high efficiency, and mild reaction conditions make this procedure very attractive. In addition, this method also provides expedient access to 13–15-membered macrolactams upon an additional one-step manipulation. Mechanistic studies indicate that the reaction involves an amidyl radical and is promoted by acid.

Full text of DOI:10.1002/anie.201808890

A Journal of the Gesellschaft Deutscher Chemiker
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Accepted Article
Title: Direct Photocatalytic Synthesis of Medium-Sized Lactams
through C-C Bond Cleavage
Authors: Na Wang, Qiang-Shuai Gu, Zhong-Liang Li, Zhuang Li, Yu-
Long Guo, Zhen Guo, and Xin-Yuan Liu
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201808890
Angew. Chem. 10.1002/ange.201808890
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10.1002/anie.201808890
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Direct Photocatalytic Synthesis of Medium-Sized Lactams
through C–C Bond Cleavage
Na Wang+, Qiang-Shuai Gu+, Zhong-Liang Li, Zhuang Li, Yu-Long Guo, Zhen Guo, and Xin-Yuan Liu*
Abstract: We have developed a novel two-step ring-expansion
strategy for expeditious synthesis of all ring sizes of synthetically
challenging (hetero)aryl-fused medium-sized lactams from readily
available 5–8-membered cyclic ketones. This step-economic
approach is featured by a unique remote radical (hetero)aryl migration
from C to N under visible-light conditions. Broad substrate scope,
good functional group tolerance, high efficiency, and mild reaction
conditions make this protocol very attractive. In addition, this method
also provides expedient access to 1315-membered macrolactams
upon further one-step manipulation. Mechanistic study indicated that
the reaction involved amidyl radical and was promoted by acid.
ketone carbonyl group (N+1 expansion, Scheme 2a).[8] These
reactions feature short synthetic steps (1 to 2 steps) while
suffering from the difficulty in preparing the ketone starting
material, which itself has a medium-sized ring. As a result, such
reactions typically find applications in preparation of 7-membered
or smaller lactams. The second type includes a number of
protocols relying on a common mechanism: intramolecular
nucleophilic addition of N-nucleophile to ketone followed by a
retro-aldol type reaction (N+2, N+3, and N+4 expansion, Scheme
6b, 6i]
2b).[6a,
The third type is based on tandem nucleophilic
addition and oxy-2-azonia-Cope rearrangement (N+4 expansion,
Scheme 2c).[9] Both of these two types of expansion
methodologies are capable of inserting multiple atoms and thus
are amenable to practical preparation of a broad scope of lactams
(typically 9-membered and larger). Nonetheless, compared with
the first type, these two normally require multi-step preparation of
expansion substrates from cyclic ketones. Besides, all these three
types of methodologies fail to provide a practically efficient route
toward 8-membered lactams, which have raised recent synthetic
interests.[6h] With our continuing efforts[10] in developing radical-
initiated skeletal reorganization for the construction of carbo- and
heterocyclic systems,[11] we herein report a general and efficient
two-step N+3 ring-expansion strategy for convenient access to all
ring members of medium-sized, i.e., 8–11-membered, lactams
from readily available cyclic (hetero)aryl ketones under mild
visible-light conditions[12] (Scheme 2d) via a rare remote radical
(hetero)aryl migration from C to N.[13] On this basis, we have also
developed a N+4 ring-expansion strategy leading to 13–15-
membered macrolactams upon further one-step manipulation.
Medium-sized lactams (8–11-membered rings)[1] are found in
a wide range of natural products and molecules of biological
significance, such as decursivine, lyngbyatoxin, rhazinilam, and
other biologically active compounds[2] (Scheme 1). Nevertheless,
efficient access to such skeletons remains a challenging topic due
to unfavourable transannular interactions and entropic/enthalpic
reasons.[3] The ring expansion strategy dispenses with the high-
dilution technique commonly required for a direct head-to-tail
cyclization strategy[4] and is also more flexible for accessing a full
range of ring sizes compared with a cycloaddition strategy.[5] Thus,
the development of such ring expansion methods has been
thriving for decades.[6]
We started our investigation by finding that treatment of 1A
(Table 1, R1 = H, R2 = m-CF3, n = 1), readily prepared from
Scheme 1. Biologically active medium-sized lactams.
Among others, ketone has served as an excellent platform for
developing several types of practical ring-expansion
methodologies toward medium-sized lactams.[7] The first type
encompasses the classic Beckmann rearrangement, Schmidt
rearrangement and bicyclic oxaziridine rearrangement as well as
their variants, in which one nitrogen atom is inserted aside the
[a] N. Wang, Z. Li, Y.-L. Guo, Prof. Dr. X.-Y. Liu*
Department of Chemistry and Shenzhen Grubbs Institute, Southern
University of Science and Technology, Shenzhen 518055, China
E-mail: liuxy3@sustc.edu.cn
Website: http://liuxy.chem.sustc.edu.cn/
N. Wang, Prof. Dr. Z. Guo
College of Materials Science & Engineering, Key Laboratory of
Interface Science and Engineering in Advanced Materials, Ministry of
Education, Taiyuan University of Technology, Shanxi, 030024, China
Dr. Q.-S. Gu, Dr. Z.-L. Li
Academy for Advanced Interdisciplinary Studies, Southern University
of Science and Technology, Shenzhen, 518055, China.
[+] These authors contribute equally to this work.
Supporting information for this article is given via a link at the end of
the document.
Scheme 2. Ring-expansion strategies for synthesis of medium-sized lactams
from ketone.
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Table 1: Scope of medium-sized lactams fused with aryl rings.[a]
commercially available 1-tetralone in one step (see SI for details),
with photocatalyst Ru(bpy)3Cl26H2O (1.5 mol%) and
acetoxybenziodoxole (BI-OAc, 1.5 equiv) under blue LED
irradiation in 1,2-dichloroethane (DCE) at room temperature
afforded 9-membered lactam 2A in 83% isolated yield (Table S1,
entry
1 and Table 1a). Upon further reaction condition
optimization (see Table S1 for details), we found that the cyclic
benziodoxole structure was essential for the reaction, because
hydroxylbenziodoxole (BI-OH) (Table S1, entry 2) was only
slightly less effective than BI-OAc while acyclic PhIO as well as
molecular oxygen failed to afford the desired product (Table S1,
entries 3 and 4). In addition, control experiments demonstrated
that photocatalyst, BI-OAc, and light are all indispensable for the
current reaction (Table S1, entries 10–12).
Subsequently we investigated the generality of this reaction
under the optimal conditions (Table 1). We first examined the
effect of substituents on the aryl ring of the aniline moiety. A
variety of substrates bearing electron-withdrawing groups, such
as trifluoromethyl, fluoro, and carbonyl groups, on either the para-
or meta-position of the aniline were suitable for the reaction to
afford desired products 2A–2E in 44–87% yields. More
importantly, substrates bearing phenyl rings unsubstituted (1F) or
substituted by slightly electron-releasing groups (1G–1H) or a
naphthalene ring (1I) all worked well to afford 2F–2I in 42–82%
yield. Unfortunately, the reaction of substrate 1J with a strong
electron-donating group (-OMe) afforded no expected product,
likely due to undesired oxidative decomposition. We next
investigated the effect of substituents on the aryl ring of the
tetrahydronaphthalene moiety. Both electron-withdrawing (2K–
2M) and –releasing (2N) groups were well tolerated to provide
expanded lactams in good yields. However, substrates 1O
exhibited a sluggish reaction rate, possibly caused by the
disfavoured steric interaction between the ortho-Me group with
the expanding ring.
[a] Reaction conditions: 1 (0.20 mmol), Ru(bpy)3Cl26H2O (0.003 mmol), BI-OAc
(0.30 mmol) in DCE (2 mL) at room temperature under irradiation of blue LED.
Yields of isolated products are given. [b] Reaction time is 24 h. [c] Reaction time
is 12 h. Phth = phthaloyl.
containing substrates 8A and 8B were effectively transformed to
the corresponding pyridyl-fused medium-sized lactams 9 and 10,
respectively, in satisfactory yields under the optimized conditions
(Table 2). Similarly, an array of 2-quinolyl-fused substrates 8C–
8F reacted smoothly to afford a small library of 9- to 11-membered
medium-sized lactams 12–14 in 63–70% yields. The structure of
12 was confirmed by X-ray crystallographic analysis (see Figure
S1 in SI).[14] In addition, a labile electron-rich thiophenyl ring in
substrate 8C survived our oxidative reaction conditions to deliver
Subsequently, we explored the scope for the expanding ring.
As mentioned above, 8-membered lactams are exceptionally
recalcitrant to practical preparation by known expansion methods
based on ketone. To our delight, substrate 1P featuring a yet-to-
expand five-membered ring was applicable for the expansion
process to provide 8-membered lactam 3 in 70% yield, albeit with
an elongated reaction time. Meanwhile, substrate 1Q possessing
a 7-membered ring underwent the desired expansion smoothly to
give 10-membered lactam 4. More encouragingly, substrate 1R
bearing an 8-membered ring delivered 11-membered lactam 5 in
60% yield with an extended reaction time. Furthermore, the
expansion of substrates 1Sa, 1Sb, and 1T having additional fused
aryl rings within the backbones of the expanding rings proceeded
straightforwardly to afford 8-membered lactams 6a/6b and 10-
membered lactam 7 in good yields, respectively (Table 1b and 1c).
All these excellent results are in great support for the potential
wide application of the current protocol in constructing a rich
diversity of medium-sized lactams.
Table 2: Scope of medium-sized lactams fused with heteroaryl rings.[a]
Encouraged by these exciting results, we speculated that
heteroaryl ketone might also be compatible with our current
protocol, thus enabling facile assembly of heteroaryl-fused
medium-sized lactams. Gratifyingly, both 2-pyridyl- or 4-pyridyl-
[a] Reaction conditions: 8 (0.20 mmol), Ru(bpy)3Cl26H2O (0.003 mmol), BI-OAc
(0.30 mmol) in DCE (2 mL) at room temperature under irradiation of blue LED.
Yields of isolated products are given.
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desired lactam 11, albeit in low yield.
(Figure S2 in SI). In addition, the cyclic voltammetry study on
reduction potential indicated benziodoxolonyl radical (BI·)
together with a carboxylic acid (ca. ≥ 2.0 V for 2-iodobenzoic
acid vs Fc/Fc in DCE) rather than Ru(III) (0.95 V vs Fc/Fc in
DCE) likely oxidized the substrates (1.41 V for 1A and 1.58
V for 1C vs Fc/Fc in DCE) to amidyl radical species. The
indispensable role of carboxylic acid was substantiated by greatly
accelerated reaction rates in presence of stoichiometric amounts
of side products acetic acid and 2-iodobenzoic acid (Figures S3–
4 in SI) and significantly diminished yield in presence of base (less
than 15% yield after overnight stirring, see SI for details).
To demonstrate the application potential of this strategy,
versatile transformations were performed. The aryl group of 6b
was successfully removed to release the free lactam 15 in 49%
overall yield (Scheme 3a), thus validating the applicability of our
protocol in synthesis of naturally occurring or biologically active
medium-sized secondary lactams (Scheme 1).[2] Furthermore,
upon treatment of 2F with DMFDMA and subsequent cyclization
of the obtained enamine intermediate with p-tolylhydrazine, the
fused pyrazole 16 was generated in 61% yield (Scheme 3b). Most
importantly, we developed a further one-step N+4 ring-expansion
strategy for access to a range of macrolactams from the obtained
-keto lactams.[6] As such, the reaction of 911-membered -keto
lactams with 3-bromopropylamine afforded 1315-membered
lactams 1719 in 3044% yields (Scheme 3c). Besides, other
common and useful manipulations, such as tandem ketone
reduction and dehydration, nucleophilic addition to ketone with
allyl Grignard reagent, and Suzuki coupling of aryl bromide with
an aryl boronic acid, of our prepared medium-sized lactams were
also readily effected (Scheme S1 in SI).
Scheme 4. Mechanistic study.
Based on the mechanistic study discussed above, a plausible
mechanism is proposed in Scheme 5. The reaction was initiated
2+*
3+
by oxidation of the photoexcited Ru(bpy)3 to Ru(bpy)3 by BI-
OAc to generate BI·.[17] Substrate 1 was then oxidized by BI·
together with carboxylic acid originating from either unproductive
decomposition of BI-OAc or the reaction itself to provide amidyl
radical I.[18] The amidyl radical I would subsequently attack the
(hetero)aryl ring to form a new C–N bond in intermediate II,
followed by selective C–C bond cleavage to furnish the neutral
ketyl radical III. Single-electron oxidation of the neutral ketyl
3+
radical III by Ru(bpy)3 would deliver the medium-sized lactam
2+
and regenerate Ru(bpy)3
.
Scheme 3. Versatile transformations. DMFDMA = N,N-Dimethylformamide
dimethyl acetal.
Our initial mechanistic study revealed significant inhibition of
the reaction of 1A by 2,2,6,6-tetramethylpiperidin-1-oxyl
(TEMPO), indicating a possible radical process (See Scheme S2
in SI). In addition, the possible involvement of amidyl radical[15]
was firstly supported by the formation of hydroamination products
2U and d-2U from 1U, featuring an anilide moiety the same with
that in substrate 1C, under the otherwise optimized conditions
except that solvent was changed to CHCl3/CDCl3 (Scheme 4a).
The reaction was reminiscent of reported radical hydroamination
mediated by amidyl radical,[16] likely via a pathway involving 5-
exo-trig
intramolecular
cyclization
followed
by
hydrogen/deuterium abstraction from CHCl3/CDCl3. The
formation of amidyl radical was further supported by a slight
electronic effect of substitution on the aniline ring favouring
electron-releasing groups (Scheme 4b), as reported in
literature.[16a] As for the generation of amidyl radical, the
luminescence quenching experiments revealed that BI-OAc
rather than substrate 1A effectively quenched the excited Ru(II)
Scheme 5. A plausible mechanistic pathway.
In summary, we have successfully developed a novel
photocatalytic ring-expansion strategy for direct synthesis of a
variety of synthetically challenging 8–11-membered (hetero)aryl-
fused lactams from readily available cyclic ketones through a rare
remote radical (hetero)aryl migration from C to N. The present
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[7]
[8]
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protocol exhibits broad substrate scope, good functional group
tolerance, high yield, and mild reaction conditions, all of which
warrant a great potential for wide application in preparation of
medium-sized lactams. Further versatile transformations of the
obtained medium-sized lactams, particularly the one-step ring
expansion to macrolactams, have also been demonstrated to
ensure a broad impact of this methodology in various related
areas. Detailed mechanistic studies revealed a carboxylic acid-
promoted pathway for generation of amidyl radical with I(III)
reagents under visible light irradiation conditions.
[9]
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Acknowledgements
Financial support from the National Natural Science Foundation
of China (nos. 21722203, 21831002, 21801116 and 21572096),
Shenzhen special funds for the development of biomedicine,
internet, new energy, and new material industries
(JCYJ20170412152435366 and JCYJ20170307105638498), and
Shenzhen Nobel Prize Scientists Laboratory Project (C17213101)
is greatly appreciated.
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Keywords: amidyl radical • C–C bond cleavage • ketones •
medium-sized lactams • ring expansion
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[14] The X-ray crystallographic coordinates for 12 has been deposited at the
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The
Cambridge
Crystallographic
Data
Centre
via
http://www.ccdc.cam.ac.uk/.
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Chem. 2007, 2007, 437.
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Entry for the Table of Contents (Please choose one layout)
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N. Wang, Q.-S. Gu, Z.-L. Li, Z. Li, Y.-L.
Guo, Z. Guo, X.-Y. Liu*
Page No. – Page No.
Direct Photocatalytic Synthesis of
Medium-Sized Lactams through C–C
Bond Cleavage
Growing ring under light: A two-step ring-expansion strategy for expedite
synthesis of all ring sizes of synthetically challenging (hetero)aryl-fused medium-
sized lactams from readily available 5–8-membered cyclic ketones has been
developed. The key step involves an uncommon remote radical (hetero)aryl
migration from C to N via C–C bond cleavage under mild visible light irradiation
conditions.
This article is protected by copyright. All rights reserved.