α-Quaternary Mannich Bases through Copper-Catalyzed Amination-Induced 1,2-Rearrangement of Allylic Alcohols

Article abstract of DOI:10.1002/chem.201702428

A novel copper-catalyzed amination-induced 1,2-rearrangement reaction of allylic alcohols has been developed under simple and mild conditions. The commercially available N-fluorobenzenesulfonimide (NFSI) is employed as an amination reagent. In this transformation, not only alkyl, but also aryl substituents can efficiently undergo 1,2-carbon atom migration, thereby providing an efficient and powerful route to prepare a wide range of α-quaternary Mannich bases. The reaction features a broad substrate scope, operational simplicity, and excellent practicality.

Full text of DOI:10.1002/chem.201702428

A Journal of
Accepted Article
Title: α-Quaternary Mannich Bases through Copper-Catalyzed
Amination-Induced 1,2-Rearrangement of Allylic Alcohols
Authors: Wei-Zhi Weng, Jian-Guo Sun, Ping Li, and Bo Zhang
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To be cited as: Chem. Eur. J. 10.1002/chem.201702428
Link to VoR: http://dx.doi.org/10.1002/chem.201702428
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10.1002/chem.201702428
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COMMUNICATION
α-Quaternary Mannich Bases through Copper-Catalyzed
Amination-Induced 1,2-Rearrangement of Allylic Alcohols
Wei-Zhi Weng, Jian-Guo Sun, Ping Li,* and Bo Zhang*
Abstract:
A
novel copper-catalyzed amination-induced 1,2-
rearrangement reaction of allylic alcohols has been developed under
simple and mild conditions. The commercially available N-
fluorobenzenesulfonimide (NFSI) is employed as an amination
reagent. In this transformation, not only alkyl, but also aryl
substituents can efficiently undergo 1,2-carbon atom migration,
thereby providing an efficient and powerful route to prepare a wide
range of α-quaternary Mannich bases. The reaction features a broad
substrate scope, operational simplicity, and excellent practicality.
Scheme 1. Amination and fluorination of allylic alcohols with NFSI.
β-Amino ketones and aldehydes (Mannich bases) are highly
important and useful compounds, which have received
considerable attention because of their widespread application
as versatile synthetic intermediates and building blocks in
organic synthesis.[1] Moreover, studies have disclosed that many
Mannich bases and their derivatives show excellent bioactivity
such as analgesic, antihypertensive, or cytotoxic activity.[2]
Consequently, there is continuing interest in the development of
synthetic methods for their preparation. In general, Mannich
bases without a quaternary center can be readily obtained
through Mannich reaction[1] and Aza-Michael addition reaction[3].
However, methods for the efficient synthesis of Mannich bases
bearing an all-carbon quaternary center that are of considerable
synthetic importance[4] have hardly been reported.[5] Therefore,
the development of new and efficient approaches for preparing
Mannich bases with an all-carbon quaternary center is highly
desirable and remains a challenging issue.
preparation of Mannich bases with the concomitant formation of
an α-quaternary center has been virtually unexplored.[5d]
Nitrogen-centered radicals play an important role in organic
synthetic chemistry.[10] Great progress has recently been made
in nitrogen-centered radical-initiated vicinal difunctionalization of
alkenes.[11] Inspired by these reports, and combined with our
interest in radical amination reactions,[12] we envisioned that a
nitrogen-centered radical might be able to add to the double
bond of an allylic alcohol providing a carbon-centered radical
which then undergoes 1,2-rearrangement, thereby providing
access to α-quaternary Mannich bases. Herein, we report a
copper-catalyzed amination-induced 1,2-rearrangement reaction
of allylic alcohols using N-fluorobenzenesulfonimide (NFSI) as a
nitrogen-radical precursor to deliver various Mannich bases with
the concomitant creation of an α-quaternary center under simple
and mild conditions (Scheme 1).
The 1,2-carbon atom migration reactions of allylic alcohols,
which proceed through cationic (semipinacol) rearrangements or
radical (neophyl) rearrangements, have presented an attractive
and powerful strategy for the synthesis of valuable β-
functionalized ketones, which are widely utilized intermediates
for natural product synthesis.[6] For example, tandem
halogenation/semipinacol-type rearrangements of allylic alcohols
with strong electrophilic halogen reagents as promoters have
been extensively studied for the synthesis of diversely β-
halogenated ketones.[7] In addition, elegant radical-mediated
semipinacol- or neophyl-type rearrangements have been
developed for the conversion of allylic alcohols into the
corresponding β-functionalized ketones using visible-light
mediated[8] and metal or metal-free oxidation[9]. Despite these
reported advances, to the best of our knowledge, amination-
induced 1,2-rearrangement reaction of allylic alcohols for the
To achieve the goal above, some challenges need to be
addressed: 1) NFSI is a well-known electrophilic fluorinating
reagent[13], which can induce tandem fluorination/semipinacol-
type rearrangement of allylic alcohol to produce fluorinated
product I rather than the desired aminated product.[7j] 2) the side
reaction of direct intramolecular nucleophilic attack of alcohol
onto the carbocation is one key challenge, which would lead to
epoxide II.[8j] 3) the cationic intermediate has a tendency to
undergo deprotonation to form enamine III.[14] With these
challenges in mind, we first investigated the amination/ring
expansion reaction of 1-(1-phenylvinyl)cyclobutanol 1a for the
formation of 2a. Because nitrogen-centered radical can be
generated by reaction of NFSI with CuI salts[15,16], we first
examined the reaction in the presence of CuI as a catalyst and
o
1,10-phenanthroline L1 as a ligand in DCE at 70 C. After 12
hours, we were pleased to find that the desired product 2a was
formed in 64% yield (Table 1, entry 1). The structure of 2a was
confirmed by X-ray analysis (see the Supporting Information).[17]
Interestingly, possible byproducts I-III were not observed in this
reaction. Encouraged by this result, we next surveyed various
ligands L2-L7 (Table 1, entries 2-7). These results showed that
6,6'-dimethyl-2,2'-bipyridine L7 is the best ligand for this
transformation, which afforded 2a in 83% yield (Table 1, entry 7).
Reactions with various CuI salts including CuCl, CuBr, Cu2O,
[a]
W.-Z. Weng, J.-G. Sun, Prof. P. Li, Prof. Dr. B. Zhang
State Key Laboratory of Natural Medicines
China Pharmaceutical University
24 Tongjia Xiang, Nanjing 210009, China
E-mail: zb3981444@cpu.edu.cn; liping2004@126.com
Supporting information for this article is given via a link at the end
of the document.
This article is protected by copyright. All rights reserved.

10.1002/chem.201702428
Chemistry - A European Journal
COMMUNICATION
CuTC, [(MeCN)4Cu]BF4, and CuOTf provided 2a in 49-86%
yields, showing that CuCl performs best (Table 1, entries 8-13).
Solvent effects were also examined, and DCE was found to be
optimal (Table 1, entries 14-17). The reaction did not occur at
room temperature (Table 1, entry 18). When the reaction was
run under air, 2a was obtained in 26% yield (Table 1, entry 19).
Notably, decreasing the CuCl and ligand loading to 5 mol% still
give 2a in good yield (Table 1, entry 20). However, no product
was observed in the absence of the copper catalyst or ligand,
implying that both the copper salt and ligand are essential for the
success of this reaction (Table 1, entries 21 and 22).
corresponding ring expanded products 2n and 2o in moderate
yields. Furthermore,
a more challenging seven-membered
substrate 1p was also tested, and the product 2p was formed in
31% yield.
Table 1. Optimization of reaction conditions.[a]
Entry
Catalyst
Ligand
Solvent
Yield [%][b]
Scheme 2. Scope of allylic alcohols 1. Reaction conditions: 1 (0.30 mmol),
CuCl (10 mol%), L7 (10 mol%), and NFSI (0.45 mmol) in DCE (2.0 mL) at 70
oC under N2 for 12 h. Yields of isolated products are given.
1
2
3
4
5
6
7
8
CuI
CuI
CuI
CuI
CuI
CuI
CuI
L1
L2
L3
L4
L5
L6
L7
L7
L7
L7
L7
L7
L7
L7
L7
L7
L7
L7
L7
L7
none
L7
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
64
80
trace
23
27
44
83
86
74
83
64
49
63
54
0
To explore the scope of the reaction further, and investigate
whether 1,2-migration of an aryl group can be induced during
the amination process of allylic alcohol, we turned our attention
to α-aryl substituted allylic alcohols (Scheme 3). Gratifyingly,
under the optimized reaction conditions, various α,α-diaryl allylic
alcohols underwent the desired 1,2-aryl migration smoothly to
generate the corresponding products 4a-c in up to 70% yield.
When the reactions were carried out on α-aryl-α-alkyl allylic
alcohols, only the 1,2-aryl shift occurred regardless of the nature
of the alkyl group (4d-g). The structure of 4d was determined by
X-ray analysis (see the Supporting Information).[18] Intriguingly,
when unsymmetrical α,α-diaryl allylic alcohol 3h was employed
as substrate, the more electron-deficient phenyl group migrated
CuCl
CuBr
Cu2O
CuTC
[(MeCN)4Cu]BF4
CuOTf
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
none
9
10
11
12
13
14
15
16
17
18[c]
19[d]
20[e]
21
22
DCE
MeCN
DMF
1,4-dioxane
toluene
DCE
DCE
DCE
DCE
DCE
0
trace
0
26
80
0
0
[a] Reaction conditions: 1a (0.30 mmol), catalyst (10 mol%), ligand (10 mol%),
and NFSI (0.45 mmol) in solvent (2.0 mL) at 70 oC under N2 for 12 h. [b]
Isolated yields. [c] The reaction was performed at rt. [d] The reaction was
performed under air. [e] Using 5 mol% of CuCl and 5 mol% of L7.
With optimized reaction conditions in hand, the scope and
limitations of this transformation were examined (Scheme 2).
Various electron-donating and electron-withdrawing substituents
on the aromatic ring of 1-(1-arylvinyl)cyclobutanol were well
tolerated, and the corresponding products 2b-j were obtained in
up to 85% yield. Moreover, oxa-cyclobutanol 1k was shown to
be compatible under the current reaction conditions, leading to
the desired product 2k in good yield. Notably, the amination/ring
expansion reaction proceeded smoothly for alkyl-substituted
substrates. For example, 1-(prop-1-en-2-yl)cyclobutanol and 1-
(3-phenylprop-1-en-2-yl)cyclobutanol were readily converted to
the targeted products 2l and 2m in moderate yields due to some
side reactions. To evaluate the ring-expansion ability of this
reaction, we next investigated different allylic cycloalkanols. As
shown in Scheme 2, the less strained five- and six-membered
substrates 1n and 1o reacted readily with NFSI to give the
Scheme 3. Scope of allylic alcohols 3. Reaction conditions: 1 (0.30 mmol),
CuCl (10 mol%), L7 (10 mol%), and NFSI (0.45 mmol) in DCE (2.0 mL) at 70
oC under N2 for 12 h. Yields of isolated products are given. [a] The yield is
reported for major product as shown. [b] The ratio of 4h and its isomer was
determined by 1H NMR analysis of the crude product.
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10.1002/chem.201702428
Chemistry - A European Journal
COMMUNICATION
preferentially to produce the product 4h. This result indicated
that the 1,2-aryl migration might proceed via a radical pathway
(neophyl rearrangement).[19] Besides α-quaternary β-amino
ketones, the novel transformation can also be applied to the
preparation of α-quaternary β-amino aldehydes. As shown in
Scheme 3, a wide range of α-monosubstituted allylic alcohols
carrying different aryl substituents consistently afforded the
desired products 4i-p in moderate to good yields regardless of
their electronic properties. Finally, we showed that 9-(1-
phenylvinyl)-9H-fluoren-9-ol 3q is also viable substrate, which
gave the 1,2-migration product 4q in 40% yield. In all cases,
none of byproducts I-III was isolated.
bond of allylic alcohol 1 or 3 provides the carbon-centered
radical C. When both R2 and R3 are alkyl substituents, C is
further oxidized by B to form the carbocation D along with
fluoride anion, thereby regenerating the active dinuclear CuII-CuII
catalyst A. Deprotonation by fluoride anion and sequential 1,2-
alkyl shift of D affords the product 2. If R3 is an aryl substituent, a
neophyl rearrangement via a spiro[2,5]octadienyl radical E might
predominate, which leads to the radical F. The proposed
pathway is in line with our experimental result (see 4h). SET
from F to B with concomitant deprotonation by fluoride anion
delivers the product 4. This process allows the regeneration of
the active catalyst A.
Preliminary mechanistic studies revealed that a nitrogen-
centered radical addition pathway is likely involved in these
reactions. Under the optimized conditions, formation of 2a and
4e from 1a and 3e were completely suppressed in the presence
of 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) and 2,6-di-tert-
butyl-4-methylphenol (BHT) as radical scavengers [Scheme 4a,
Eq. (1) and (2)]. Moreover, when the reactions were conducted
In summary, we have presented a novel copper-catalyzed
amination-induced 1,2-rearrangement reaction of allylic alcohols,
in which the commercially available NFSI was used as an
amination reagent. In this transformation, 1,2-alkyl or aryl
migration efficiently occurred through
a cationic pathway
(semipinacol rearrangement) or a radical pathway (neophyl
rearrangement). The protocol provides a simple and efficient
approach to access a wide range of α-quaternary Mannich
bases under mild conditions. Reactions that are easy to conduct
show a broad substrate scope and good functional group
tolerance. Further application of this reaction is in progress.
in the presence of 1,1-diphenylethylene as a radical trapper[14]
,
only traces of the desired products 2a and 4e were observed,
and adduct 5 was formed in good yield [Scheme 4a, Eq. (3) and
(4)]. Based on these experimental observations, a plausible
mechanism is proposed in Scheme 4b. First, an active dinuclear
CuII-CuII catalyst A is generated from the CuCl precatalyst and
NFSI through Cl/F exchange reactions.[20] Subsequently, A
reduces NFSI via one-electron F atom transfer pathway to
produce a reactive bis-sulfonylamidyl radical and a dinuclear
CuII−CuIII intermediate B.[15,21,22] Radical addition onto the double
Acknowledgements
This work is financially supported by the National Natural
Science Foundation of China (21642014), the Natural Science
Foundation of Jiangsu Province (BK20160743), the Program for
Jiangsu Province Innovative Research Team, the 111 Project
(B16046), and the Project Program of State Key Laboratory of
Natural Medicines (SKLNMZZYQ201602).
Keywords: copper • migration • amination • Mannich bases •
radical reactions
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[17] CCDC 1522583 contains the supplementary crystallographic data for
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This article is protected by copyright. All rights reserved.

10.1002/chem.201702428
Chemistry - A European Journal
COMMUNICATION
COMMUNICATION
W.-Z. Weng, J.-G. Sun, P. Li,* and B.
Zhang*
Page No. – Page No.
α-Quaternary Mannich Bases through
Copper-Catalyzed
Amination-Induced
1,2-Rearrangement of Allylic Alcohols
A novel copper-catalyzed amination-induced 1,2-rearrangement reaction of allylic
alcohols has been achieved under simple and mild conditions. This transformation
exhibits a broad substrate scope and good functional group tolerance. A variety of
Mannich bases containing an α-quaternary center are readily prepared in moderate
to excellent yields using the title reaction.
This article is protected by copyright. All rights reserved.