A Hydrazone-Based exo-Directing-Group Strategy for β C-H Oxidation of Aliphatic Amines

Article abstract of DOI:10.1002/anie.201600912

Described is a new hydrazone-based exo-directing group (DG) strategy developed for the functionalization of unactivated primary β C-H bonds of aliphatic amines. Conveniently synthesized from protected primary amines, the hydrazone DGs are shown to site-selectively promote the β-acetoxylation and tosyloxylation via five-membered exo-palladacycles. Amines with a wide scope of skeletons and functional groups are tolerated. Moreover, the hydrazone DG can be readily removed, and a one-pot C-H acetoxylation/DG removal protocol was also discovered. All about the DGs: A hydrazone-based exo-directing group (DG) strategy is developed for the functionalization of unactivated primary β C-H bonds of aliphatic amines. The hydrazone DGs can be conveniently installed and removed, and promote β-acetoxylation and tosyloxylation via a five-membered exo-palladacycle. PG=protecting group, Ts=4-toluenesulfonyl.

Full text of DOI:10.1002/anie.201600912

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International Edition: DOI: 10.1002/anie.201600912
German Edition: DOI: 10.1002/ange.201600912
Synthetic Methods
À
A Hydrazone-Based exo-Directing-Group Strategy for b C H
Oxidation of Aliphatic Amines
Zhongxing Huang, Chengpeng Wang, and Guangbin Dong*
Dedicated to Professor Stephen F. Martin on the occasion of his 70th birthday
Abstract: Described is a new hydrazone-based exo-directing
group (DG) strategy developed for the functionalization of
À
unactivated primary b C H bonds of aliphatic amines. Con-
veniently synthesized from protected primary amines, the
hydrazone DGs are shown to site-selectively promote the b-
acetoxylation and tosyloxylation via five-membered exo-palla-
dacycles. Amines with a wide scope of skeletons and functional
groups are tolerated. Moreover, the hydrazone DG can be
À
readily removed, and a one-pot C H acetoxylation/DG
removal protocol was also discovered.
C
ontrol of site selectivity still represents a fundamental and
ongoing challenge for C H functionalization.[1] In particular,
given that aliphatic amines are ubiquitously found in
approved drugs and other biologically important com-
À
pounds,[2] site-selective C H functionalization of amines and
protected amines, such as amides, sulfonamides, and carba-
mates, undoubtedly holds significant potential for pharma-
ceutical and agrochemical applications.[3–10]
À
3
À
Figure 1. Amine-directed C(sp ) H functionalization. FG=functional
group.
It is known that the a position of aliphatic amines,
inherently activated by the adjacent nitrogen atom, can be
derivatized by a large collection of pathways (Figure 1a).[3]
Amide- and sulfonamide-type directing group (DG) strat-
to proceed by a deprotonation/migratory pathway.[10] Herein,
an approach for site-selective functionalization of unactivated
À
À
egies have been frequently employed to activate the g C H
primary b C H bonds of aliphatic amines is described to
bonds of amines via five-membered metallacycle intermedi-
ates.[4,5] To functionalize the remote d- and e-positions, either
[1,5] or [1,6] H abstraction through generation of highly
reactive nitrogen-centered radicals has proved to be a general
approach.[6] Moreover, Sanford and co-workers recently
reported a direct approach for hydroxylation and chlorination
of terminal positions of amines using platinum catalysis.[7]
Despite all these advances, methods that can site-selectively
proceed by using a hydrazone-based exo-type DG.[11]
3
À
Utilizing an oxime-based exo-DG, b C(sp ) H function-
alization of masked alcohols has been recently achieved by
our group.[12] We envisioned that this exo-directing strategy
could be extended to the b oxidation of amines through
development of a new hydrazone-based DG (Figure 2). It was
anticipated that the hydrazone B, prepared from the corre-
sponding monoprotected primary amine A, would guide
metalation at the primary b-position through forming a five-
membered exo-metallacycle (C), which should lead to b-
functionalized amines. The use of 2,6-dimethoxyphenyl as the
hydrazone substituent should prevent endo metalation and
stabilize the metallacycle.[12b,d,e] However, the challenges
associated with this strategy are twofold: 1) compared to
alcohols, amines are generally more coordinating and suscep-
tible to oxidation. Thus, to enable the desired site selectivity,
choosing an appropriate amine protecting group (PG)
becomes important. 2) Efficient installation and chemoselec-
À
functionalize unactivated b C H bonds of amines remain
underdeveloped. In 2006, Du Bois and co-workers reported
a rhodium-catalyzed intramolecular b C H amination by
À
nitrene insertion to form masked 1,2-diamines (Figure 1b).[8]
Gaunt and co-workers disclosed a novel free-amine-directed
b-functionalization, in which use of sterically hindered
secondary amines appears to be important.[9] In addition, b-
arylation of Boc-protected dialkylamines has been discovered
[*] Z. Huang, C. Wang, Prof. Dr. G. Dong
Department of Chemistry, University of Texas at Austin
100 East 24th street, Austin, TX 78712 (USA)
E-mail: gbdong@cm.utexas.edu
tive removal of the hydrazone DG through forming and
breaking an N N bond is nontrivial.
To test the feasibility of the proposed strategy, a practical
DG-installation method was first sought. Gratifyingly, when
NBzONH2 was employed as the electrophilic amination
reagent,[14] sec-butylamine was protected and aminated to
[13]
À
Homepage: http://gbdong.cm.utexas.edu/
Supporting information for this article can be found under:
http://dx.doi.org/10.1002/anie.201600912.
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Table 1: Optimized reaction conditions and control experiments.[a]
Entry Variations from the “standard conditions”
Yield Conv.
[%][b] [%][b]
1
2
3
4
5
without Pd(OAc)2
–
64
23
10
85
86
130 mol% instead of 230 mol% PhI(OAc)2
NFSI instead of PhI(OAc)2
KPS instead of PhI(OAc)2
200 mol% KPS and 20 mol% PhI(OAc)2 instead of 24 100
PhI(OAc)2
26 100
6
7
without LiOAc
LiCl instead of LiOAc
42 100
39 84
8
9
NaOAc instead of LiOAc
69 100
68 100
64 100
KOAc instead of LiOAc
10
11
12
13
14
15
without Ar1CHO[c]
without Ac2O
H2O instead of Ac2O
38
–
93
100
À
Figure 2. b C H oxidation of protected aliphatic amines.
100 mg 4 Š M.S. instead of Ar1CHO and Ac2O[d]
DCE/AcOH/Ac2O 4:4:1 instead of AcOH/Ac2O
one portion addition of Pd(OAc)2 and oxidant
<5 100
70 90
66 100
give a tosyl-protected hydrazine intermediate, which upon
condensation with 2,6-dimethoxybenzaldehyde (Ar1CHO)
provided the hydrazone 1a in 78% yield as a single E isomer
(Scheme 1a). Both NBzONH2 and Ar1CHO are commer-
cially available and can be prepared in bulk.[15] In addition to
this one-pot procedure, 1a can also be prepared by a con-
venient chromatography-free protocol from the correspond-
ing sulfonamide (Scheme 1b). This protocol is also general to
other sulfonamide substrates (see Table 2), and can be
operated on a multigram scale without need of chromatog-
raphy or isolation of the hydrazine intermediate.
[a] The reactions were run on a 0.1 mmol scale in 1.0 mL solvent.
[b] Yields determined by NMR spectroscopy using 1,1,2,2-tetrachloro-
ethane as the internal standard. [c] Ar1CHO was recovered in 11% yield
when no extra Ar1CHO was added. [d] DCE/AcOH (1:1) was used as the
solvent. KPS=potassium persulfate, M.S.=molecular sieves, NSFI=N-
fluorobenzenesulfonimide.
(20 mol%) as the additives (see equation in Table 1). Air can
be well tolerated, and a two-portion addition of the palladium
and oxidant was found to be beneficial. To understand the
role of each reactant, control experiments were conducted
(Table 1). As expected, palladium played a pivotal role in this
reaction (entry 1). While 2.3 equivalents of PhI(OAc)2 proved
to be optimal, the yield only dropped marginally with
1.3 equivalents of the oxidant (entry 2). In contrast, other
common oxidants, including KPS and NFSI, were less
effective (entries 3–5). Acetate additives were found to
facilitate the acetoxylation (entries 6–9).[16] In addition,
Ar1CHO and Ar1CN were identified as the major by-
products, presumably from the hydrolysis and elimination of
the DG, which was supported by the detrimental effect of
added water (entry 12). Thus, additional Ar1CHO and Ac2O
were intentionally employed to suppress hydrolysis of the
hydrazone DG. The extra aldehyde would disfavor the
hydrolysis equilibrium and Ac2O can remove adventitious
water. In contrast, the use of molecular sieves instead of
Ar1CHO and Ac2O was ineffective (entry 13). Finally, DCE
can be used as a cosolvent (entry 14), and the one-portion
addition procedure slightly decreased the yield (entry 15).
The scope of the b-acetoxylation reaction was then
examined under the optimized reaction conditions
(Table 2). First, a range of sulfonyl groups other than Ts can
be used as the PG for this transformation (2a–e), including
nosyl (2d) and SES[17] (2e) groups, which are known to be
removable under mild reaction conditions. Nevertheless,
Scheme 1. Installation of hydrazone DG. Ts =4-toluenesulfonyl.
The b-acetoxylation reaction was investigated initially
using 1a as the model substrate. After a careful evaluation of
various reaction parameters, the desired 1,2-amino alcohol 2a
was isolated in 73% yield with Pd(OAc)2 as the catalyst,
PhI(OAc)2 as the oxidant, and LiOAc (1 equiv) and Ar1CHO
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Table 2: Scope of the b-acetoxylation.[a]
common and versatile functional groups, including cyclo-
propane (2t), aryl bromide (2r), electron-deficient olefin
(2s), phthalimide (2u), and silyl ether (2p), were also
tolerated. It is worth noting that, for the Amphetamine-
3
À
derived substrate, the C(sp ) H bond was selectively ace-
À
toxylated over the more reactive ortho-aryl C H bond (2v),
and represents a feature which is distinct from the amide-
directed reactions.[18] Nevertheless, attempts to activate
À
methylene C H bonds using this strategy remained unsuc-
cessful (2w and 2x).[19]
The acetoxylation reaction proved to be scalable, and on
a larger scale the palladium loading can be significantly
reduced [Eq. (1)]. In addition, the hydrazone DG can be
efficiently removed to give the protected 1,2-amino alcohol 3
À
through cleavage of the N N bond with zinc powder
(Scheme 2a). Given that this cleavage reaction can also use
Scheme 2. Removal of the DG and PG.
HOAc/Ac2O as the solvent, a convenient one-pot acetoxyla-
tion/DG removal sequence was achieved simply by adding
zinc to the reaction mixture after completion of the b-
acetoxylation step (Scheme 2b). Furthermore, the Ts group in
3 can be efficiently switched to a more labile trifluoroacetyl
(TFA) group under mild reaction conditions.[20]
[a] Reactions were run on a 0.15 mmol scale. [b] 400 mol% of PhI(OAc)2
were used. [c] Drug from which the substrate was directly derived (see
the Supporting Information for details). TIPS=triisopropylsilyl,
TMS=trimethylsilyl.
amide- or carbamate-type PGs remained challenging for this
transformation, likely because of their enhanced Lewis
basicity which inhibits the cyclopalladation step. Substrates
with various alkyl scaffolds afforded the desired acetoxylation
products (2 f–k) in good yields. The oxidation is selective for
À
the primary b C H bonds over either secondary/tertiary b-
3
À
positions or more remote primary positions. The hydrazone
substrates can be directly derived from a number of approved
drugs, such as Rimantadine (2l), Forthane (2k), Mexiletine
(2n), and Amphetamine (2v), in simple operations without
chromatography. Slower reactions were observed for sub-
strates with adjacent coordinating groups, for example, esters
(2o) and ethers (2m and 2n). Nevertheless, moderate to good
yields were obtained after an longer reaction time. Several
More recently,
a
b C(sp ) H sulfonyloxylation/SN2
approach was developed for the diverse functionalization of
masked alcohols.[12c] Thus, it was expected that a similar
strategy could be adopted for late-stage diversification of
aliphatic amines using a hydrazone DG, and in turn should
expedite analogue preparation. Indeed, starting with
Amphetamine, a chromatography-free three-step sequence
afforded the hydrazone 5 in 72% yield, wherein a quinoline-
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Keywords: amines · C H activation · hydrazones · oxidation ·
palladium
How to cite: Angew. Chem. Int. Ed. 2016, 55, 5299–5303
Angew. Chem. 2016, 128, 5385–5389
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was isolated in 52% yield. As expected, 6 can be rapidly
derivatized by SN2 reactions to introduce various functional
groups, including sulfide, ether, bromide, and azide groups
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In summary, a hydrazone-based DG strategy is described
À
to realize the b C H functionalization of aliphatic amines. A
number of key features can be noted: first, from common
primary amines, an efficient chromatography-free or one-pot
procedure was made available to install the DG. Second,
through forming a hydrazone-directed exo-palladacycle, the
À
b C H oxidation occurred site- and chemoselectively. Finally,
the DGs can be easily removed either in a separate step or
through a one-pot acetoxylation/reduction sequence. Consid-
ering the critical role of nitrogen-containing aliphatic moi-
eties in pharmaceutical and agrochemical research, this
hydrazone-based approach should offer new strategies to
synthesize functionalized amines. Efforts to expand substrate
and reaction scope, particularly regarding the activation of
À
[5] For a recent g-C H functionalization of 1,2-amino alcohols, see:
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M. J. Gaunt, Nat. Chem. 2015, 7, 1009.
À
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more challenging methylene C H bonds, are currently
underway.
Acknowledgments
We thank the CPRIT, Frasche Foundation, ACS PRF, and the
Welch Foundation (F-1781) for funding. G.D. is a Searle
Scholar and Sloan Fellow. Dr. Michael Young is thanked for
providing chemicals and X-ray crystallography. We also
acknowledge Yan Xu for providing chemicals, and Dr.
Vincent Lynch for X-ray crystallography. Johnson Matthey
is thanked for a generous donation of palladium salts.
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À
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À
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[21] The use of 2,6-dimethoxyphenyl-based DG proved much less
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[22] CCDC 1449052 contains the supplementary crystallographic
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Received: January 26, 2016
Revised: February 24, 2016
Published online: March 22, 2016
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