Practical metal-free C(sp3)-H functionalization: Construction of structurally diverse α-substituted N-benzyl and N-allyl carbamates

Article abstract of DOI:10.1002/anie.201310193

Described is a practical and universal C-H functionalization of readily removable N-benzyl and N-allyl carbamates, with a wide range of nucleophiles at ambient temperature promoted by Ph₃CClO₄. The metal-free reaction has an excellent functional-group tolerance, and displays a broad scope with respect to both N-carbamates and nucleophile partners (a variety of organoboranes and C-H compounds). The synthetic utility in target- as well as diversity-oriented syntheses is demonstrated. Strategic play: A direct functionalization of the title carbamates with a wide range of nucleophiles has been developed. The reaction proceeds efficiently at low temperature using Ph₃CClO₄ as an oxidant. Sensitive functional groups are tolerated, thus allowing applications in natural product synthesis, the construction of chemical libraries, and the discovery of potential anticancer targets.

Full text of DOI:10.1002/anie.201310193

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Communications
DOI: 10.1002/anie.201310193
Synthetic Methods
3
À
Practical Metal-Free C(sp ) H Functionalization: Construction of
Structurally Diverse a-Substituted N-Benzyl and N-Allyl
Carbamates**
Zhiyu Xie, Lei Liu,* Wenfang Chen, Hongbo Zheng, Qingqing Xu, Huiqing Yuan, and
Hongxiang Lou*
À
Abstract: Described is a practical and universal C H func-
tionalization of readily removable N-benzyl and N-allyl
carbamates, with a wide range of nucleophiles at ambient
temperature promoted by Ph3CClO4. The metal-free reaction
has an excellent functional-group tolerance, and displays
a broad scope with respect to both N-carbamates and
À
nucleophile partners (a variety of organoboranes and C H
compounds). The synthetic utility in target- as well as diversity-
oriented syntheses is demonstrated.
a-Substituted nitrogen-containing heterocycles (N-het-
erocycles), like tetrahydroisoquinolines (THIQs), tetrahydro-
quinolines (THQs), and piperidines, represent ubiquitous
structural motifs in numerous alkaloids exhibiting a wide
range of pharmacological activities.[1] Among them, 1-benzyl
Figure 1. Bioactive C1-substituted THIQs, THQs, and piperidines.
THIQs are the most widely distributed[1a] and serve as key
intermediates in the synthesis and biosynthesis[1c] of other
types of alkaloids. For instance, tetrahydropalmatine (THP),
isolated from Corydalis, has been demonstrated to possess
significant analgesic effects and have therapeutic potential for
heart disease and liver damage (Figure 1).[2a] Noscapine,
mediated by the sigma receptor agonist activity, is well known
for its antitussive effects, and reported to have promising
effects in the treatment of several cancers and hypoxic
ischemia in stroke patients.[2b] Besides the benzyl substruc-
ture, aryl and arylethyl substituents are often incorporated at
C1. Solifenacin (trade name Vesicare), a competitive antag-
onist preventing acetylcholine from binding to the human
muscarinic acetylcholine receptor, is used in the treatment for
overactive bladder.[2c] Methylphenidate, a piperidine ana-
logue, is known to be a psychostimulant drug for the
treatment of attention deficit hyperactivity disorder
(ADHD).[2d]
Inspired by the importance of these compounds in
modern pharmacology, significant efforts have been devoted
to their construction, and current syntheses mainly rely on
three strategies.[3] The two most frequently employed
approaches for the synthesis of C1-substituted N-heterocycles
are stereoselective cyclizations such as the Pictet–Spengler
condensation, and hydrogenation of the C1-substituted
imines as in the Bischler–Napieralski cyclization/reduction
sequence. Recently, introduction of a carbon unit to the a-
position of the N-heterocycles has been investigated as an
alternative to the first two traditional methods. In particular,
[*] Z. Xie, Prof. L. Liu, W. Chen, H. Zheng, Prof. H. Lou
Key Lab of Chemical Biology of Ministry of Education
School of Pharmaceutical Sciences, Shandong University
Jinan 250012 (China)
À
direct C H functionalization of N-heterocycles with a variety
of carbon nucleophiles presents an atom-economic protocol
without prior installation of activating groups, and is therefore
attractive.[4] A number of different approaches have been
established for electron-rich amines, especially N-arylated
THIQs and dimethylanilines, since the pioneering studies of
the groups of Murahashi and Li.[5,6] However, the difficulty in
removing the N-aryl group results in poor functional-group
E-mail: leiliu@sdu.edu.cn
louhongxiang@sdu.edu.cn
Homepage: http://www.pharm.sdu.edu.cn/szdw/Liu%20lei/3
/Liu_02/index.htm
Q. Xu, Prof. H. Yuan
School of Medicine, Shandong University
Jinan 250012 (China)
tolerance, and therefore limits the synthetic utility.[7] In sharp
[**] We are grateful to Dr. Paul E. Floreancig (University of Pittsburgh)
for helpful suggestions on the mechanism. Financial support from
the National Science Foundation of China (no. 21202093) and the
Young Scientist Foundation Grant of Shandong Province
(no. BS2013YY001) is greatly appreciated.
3
À
contrast, the functionalization of the C(sp ) H bond adjacent
to readily removable amide or carbamate moieties proved to
be much more challenging, probably owing to the reduced
reactivity, and only a few examples have been disclosed so
far.[8] The scope with respect to the nucleophile reported for
each method is notably limited, and often focuses on only one
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201310193.
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particular class. Moreover, the procedures usually require
harsh reaction conditions (high temperature, strong acid, neat
condition, etc.), the use of metals, and long reaction times, all
of which are generally disadvantageous for achieving asym-
metric variants because of the high probability of racemiza-
tion at the benzyl position.[6k] Therefore, the development of
and trityl ions.[10c–g] While the tropylium cation (C7H7BF4) did
not facilitate the reaction, Ph3CSbCl6 afforded the product in
51% yield (entries 3 and 4). The counterion of the trityl
cation proved to be crucial for the reaction efficiency, and
[11]
Ph3CClO4
gave an 87% yield after 2 hours at room
temperature (entries 4–8). Reaction optimization experi-
ments identified CH2Cl2 as the best solvent, and CBz as the
ideal amine protecting group (entries 8–11).
À
a universal, mild, and efficient method for direct C H
functionalization of N-carbamate hetreocycles with a wide
range of nucleophiles will not only provide a new strategy for
natural product synthesis but also facilitate the quick
construction of N-heterocycle libraries having structural
variation at the C1-position for the discovery of novel,
Examination of the scope with respect to organoborane
partners has revealed that a broad range of nucleophiles are
amenable to the reaction (Table 2). Electronically varied
benzyl, allyl, alkenyl, alkynyl, and aryl trifluoroborate salts
are compatible with the oxidation system and deliver the
desired THIQ 4 in good to excellent yields. The use of
corresponding boronate esters (2i, 2m, and 2q) and boronic
acids (2j) provides comparable results to those of the
potassium trifluoroborates, except for the benzyl boronate
ester 2b, and this is probably due to an oxidative decom-
position under the reaction conditions.[9g] The secondary
potassium benzyltrifluoroborates 2e and 2 f also efficiently
provide the branched benzyl THIQs, another important core
unit within a multitude of biologically active natural products
such as noscapine (Figure 1). Classically, the arylation of N-
acyliminium ions requires strong nucleophiles, such as
organometallic reagents and p-rich arenes.[12] As shown in
Table 2, the reaction is efficient not only for the p-rich aryl
(2u,v) and heteroaryl trifluoroborates (2y,z), but also for p-
neutral (2w) and p-deficient (2x) arylboranes, though the
latter two require slightly elevated temperatures. The N-
heteroaryltrifluoroborate 2za does not afford the desired
product. Several commonly seen functionalities were toler-
ated, including halogens (2d, 2o, and 2x), benzyl ethers (2s),
and silyl ethers (2t), and such moieties can serve as additional
functional handles.
biologically interesting small molecules. Herein, we present
3
À
a metal-free C(sp ) H functionalization of N-benzyl and N-
allyl carbamates with diverse nucleophiles by triphenylcarbe-
nium perchlorate (Ph3CClO4) oxidation.
The widespread availability and unique nucleophilicity of
organoboranes have attracted growing interest in exploring
new chemistry beyond the Suzuki–Miyaura coupling, includ-
ing a-vinylation of aldehydes,[9a] transition metal catalyzed
additions of boronic acids or boroxines to epoxides,[9b]
oxocarbenium and N-acyliminium ions,[9c–d] Lewis acid medi-
ated dialkyl ether synthesis from organotrifluoroborates and
acetals,[9e–f] and C H arylation of quinones and electron-
À
deficient hererocycles such as pyridine and pyrimidine.[9h–j]
Therefore, initially we examined the benzylation of the N-acyl
THIQ 1 with potassium benzyltrifluoroborate (2a) at room
temperature for reaction optimization (Table 1). A variety of
commonly used oxidants for N-aryl THIQs, such as DDQ,
PhI(OAc)2, Na2S2O8, CAN, O2, and TBHP resulted in no
reaction (entry 1). TEMPO oxoammonium salt[8b] (T+BF4
;
À
TEMPO = 2,2,6,6-tetramethylpiperidin-1-oxyl) gave the
desired product in 23% yield after 24 hours (entry 2). We
then explored the carbocation oxidants, such as tropylium[10a,b]
After demonstrating the generality of the organoboranes
as nucleophiles, we next explored the scope of carbamate
substrates 5 with 2a (Table 2). Structurally and electronically
varied cyclic N-benzyl carbamates worked efficiently to
afford the desired benzylation products in excellent yields
(6a–f). Dihydroisoquinoline (DHIQ; 6g) was also a compe-
tent substrate for the transformation. Additionally, cyclic N-
allyl carbamates proved to be suitable substrates. Electroni-
cally varied N-carbamate dihydroquinolines (DHQs; 6h–j)
and dihydropyridine (DHP; 6k) were also tolerated. Given
the variety of known protocols that utilize the enamine
moiety in DHIQ (6g) and DHP (6k) as a reactive handle for
further functionalization, such as cycloadditions, alkylations,
oxidations, and reductions,[13a] the direct construction of C1-
substituted N-carbamate DHIQs and DHPs could provide
opportunities to develop a structurally and stereochemically
diverse library of alkaloid-like compounds through diversity-
oriented synthesis.[13] Besides the cyclic substrates, electroni-
cally varied acyclic N-benzyl carbamates (6l–n) and N-allyl
Table 1: Model reaction optimization.[a]
Entry
Oxidant
R1
Solvent
t [h]
Yield [%][b]
1
2
3
4
5
6
7
8
oxidants[c]
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
CH3
CH2Cl2
CH2Cl2
solvent[d]
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
24
24
24
2
2
2
2
2
24
2
2
<5
23
<5
51
45
33
48
87
<5
91
0
T+BF4
À
C7H7BF4
Ph3CSbCl6
Ph3CBF4
Ph3COTf
Ph3CPF6
Ph3CClO4
Ph3CClO4
Ph3CClO4
Ph3CClO4
9
10
11
OBn
OtBu
[a] The reaction was carried out with 1 (0.2 mmol), 2a (0.4 mmol), and
oxidant (0.2 mmol) in solvent (2.0 mL) at room temperature for the
indicated periods. [b] Yield of isolated product. [c] DDQ, PhI(OAc)2,
Na2S2O8, CAN, O2/CuCl2, and TBHP/CuBr2. [d] CH2Cl2 or CH3CN.
CAN=ceric ammonium nitrate, DDQ=2,3-dichloro-5,6-dicyano-1,4-
benzoquinone, TBHP=tert-butyl hydrogen peroxide, Tf=trifluoro-
methanesulfonyl.
À
carbamate (6o) also serve as precursors for the direct C H
benzylation. To the best of our knowledge, this is the first
À
example of direct C H functionalization of N-allyl carba-
mates such as cyclic DHQ and DHP, and acyclic (5o)
substrates to date.
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Table 2: The scope of organoboranes and N-heterocycles.[a]
Table 3: The scope of CDC reactions.[a]
[a] The reaction was carried out with 1a (0.2 mmol) and Ph3CClO4
(0.2 mmol) in CH2Cl2 (2.0 mL) followed by 7 (0.5 mmol) at 08C or RT for
0.5–8 h. [b] 1.0 mmol acetaldehyde was employed. [c] 7 was added after
the oxidation with 2,6-dichloropyridine (0.4 mmol).
(CDC)[5] under the same reaction conditions (Table 3).
Interestingly, the CDC reactions of 1a with a number of
carbon nucleophiles including aldehydes (8a–c), and aro-
matic and aliphatic ketones (8d–h), together with p-rich
arenes (8i–k) and heteroarenes (8l,m), proceed smoothly at
room temperature to deliver the products in good to excellent
yields.
À
The universal and mild method for the C H functional-
ization of readily removable carbamates led us to investigate
its application to the enantioselective synthesis of bioactive
natural products (Scheme 1). The carbamate 9, prepared in
one step from 6,7-dimethoxy-THIQ and 8-phenylmenthyl
chloroformate,[14] was subjected to the standard reaction
conditions with organoboranes 2c and 2n at À908C to give
excellent yields of benzylated (10; d.r. = 13:1) and alkyny-
lated (11; d.r. = 10:1) THIQs, respectively. Subsequently, the
major diastereomers of 10 and 11 were separated, and further
transformed into three molecules through a single- or two-
step modification. The compound 10 reacted with LiAlH4 and
MeLi to furnish 12 and 13, respectively, with efficient
recovery of the chiral auxiliary 15 (86% and 80%).[15]
Sequential reduction of 11 with the H2 on Pd/C and LiAlH4
afforded 14 in 64% yield from 9.[15a] The alkyne 4s was
converted into the tricyclic 16 by hydrogenation and HBF4-
mediated Mitsunobu reaction in 56% yield.[16]
[a] Unless otherwise specified, the reaction was carried out with 1a or 5
(0.2 mmol), 2 (0.4 mmol), and Ph3CClO4 (0.2 mmol) in CH2Cl2 (2.0 mL)
at RT for 2 h. [b] Nucleophiles were added once the oxidation process
was complete. [c] Reaction was performed at 408C. [d] Reaction was
performed at 608C. CBz=benzyloxycarbonyl, TBS=tert-butyldimethyl-
silyl, TMS=trimethylsilyl,
As discussed above, a small N-heterocycle library with
structural variation at the C1-position was rapidly constructed
À
using this universal C H functionalization protocol with
a wide range of nucleophiles (Tables 2 and 3; see the
Supporting Information). The cytotoxicities of these com-
pounds in human prostate cancer (PC3 and DU145), doce-
taxel-resistant prostate cancer (PC3R), and human liver
À
The successful C H functionalization of N-benzyl and N-
allyl carbamates with organoborane nucleophiles prompted
us to explore the feasibility of cross-dehydrogenative coupling
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Figure 2. Mechanistic studies for carbamate oxidation by Ph3CClO4.
however, can be well explained by a hydride transfer
process.[18] Lastly, the coupling efficiency was not affected
by 1 equivalent of the radical inhibitor 2,6-di-tert-butyl-4-
methylphenol (BHT) or TEMPO, thus suggesting that
a radical intermediate might not be involved in the reaction.
In the tropylium-mediated amine oxidation, formation of an
electron donor–acceptor (EDA) complex was proposed for
Scheme 1. Synthetic applications. DIAD=diisopropyl azodicarboxylate.
À
the tropylium ion and aryl ring in the substrate before C H
cleavage.[10b,19] Therefore, we envision the formation of an
EDA complex between Ph3C+ and the aryl ring (see 18),
followed by an irreversible[10c] one-step hydride abstraction to
generate the N-acyliminium ion 19 for subsequent nucleo-
philic addition.
carcinoma (HepG2) cell lines were evaluated using the MTT
assay. While most of them did not show any cytotoxicity
towards DU145 and HepG2 cell lines (IC50 > 50 mm), some of
them exhibit inhibitory activity towards PC3 and PC3R cells
(see the Supporting Information). The C1-arylethynyl THIQs
4l-NH[17] (9.8 Æ 0.5 mm) and 4o-NH (9.0 Æ 1.6 mm) show com-
parable potency as cisplatin (8.0 Æ 0.5 mm) towards PC3R
cells, whereas our compounds are sevenfold less potent
(18.8 Æ 0.5 mm and 21.2 Æ 2.7 mm) than cisplatin (2.79 Æ
0.5 mm) against PC3 cells. These preliminary results not only
suggest that C1-arylethynyl THIQs are promising anticancer
hits worthy of further exploration, but also demonstrate the
practicability of the facile method in chemical library
In summary, we have developed a practical and universal
À
C H functionalization of readily removable N-benzyl and N-
allyl carbamates with a wide range of nucleophiles at ambient
temperature promoted by Ph3CClO4. The metal-free reaction
has an excellent functional-group tolerance, and displays
a broad scope with respect to both N-carbamates and
organoborane partners. CDC reactions with a variety of
À
C H nucleophiles were also achieved. The synthetic utility of
the reactions in target-oriented synthesis was exemplified by
the enantioselective synthesis of three bioactive molecules.
The facile method is also practical for diversity-oriented
synthesis and the discovery of biologically interesting small
molecules, as demonstrated by the rapid access to a small N-
heterocycle library with structural variation at C1, and the
discovery of C1-arylethynyl THIQs as selective anticancer
hits. We envision that the mild method outlined herein will
provide a platform for future efforts in the development of
construction and drug discovery.
+
À
In the Ph3C -mediated C H oxidations, a hydride abstrac-
tion mechanism to give carbenium ions was prevalent, but no
mechanistic experiment was performed.[10c–i] Therefore,
kinetic isotope studies were conducted and several aspects
of the data merit further comment. Firstly, the substrates
À
showed a kinetic isotope effect, thus suggesting that the C H
bond cleavage is involved in the rate-determining step
(Figure 2). Secondly, the intermolecular KIE (2.4) for 1a is
lower than its intramolecular one (6.1), thus indicating that
À
catalytic asymmetric C H functionalization of a variety of N-
carbamates.
À
a reactive intermediate is formed prior to C H cleavage, and
its formation is not rapidly reversible.[18] Thirdly, the more
reactive substrate, 5 f, shows a lower intramolecular KIE (3.8)
than the less reactive 1a (6.1). This implies that bond cleavage
is easier for substrates which react more quickly, and is
Received: November 24, 2013
Published online: March 5, 2014
À
counter to the observation for DDQ-mediated C H cleavage
which proceeds through radical cation intermediates and
À
Keywords: antitumor agents · organoboranes · C
H functionalization · nitrogen heterocycles · synthetic methods
.
initiated by a single-electron transfer.[18c] The phenomenon,
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