γ,δ,ε-C(sp3)-H Functionalization through Directed Radical H-Abstraction

Article abstract of DOI:10.1021/jacs.5b02065

Aliphatic amides are selectively functionalized at the γ- and δ-positions through directed radical 1,5 and 1,6 H-abstractions, respectively. The initially formed γ- or δ-lactams are intercepted by N-iodosuccinimide and trimethylsilyl azide, leading to double and triple C-H functionalizations at the γ-, δ-, and ε-positions. This new reactivity is exploited to convert alkyls into amino alcohols and allylic amines.

Full text of DOI:10.1021/jacs.5b02065

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Communication
#, #, #-C(sp3)-H Functionalization through A Directed Radical H-Abstraction
Tao Liu, Tian-Sheng Mei, and Jin-Quan Yu
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.5b02065 • Publication Date (Web): 27 Apr 2015
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, δ, ε-C(sp3)–H Functionalization through A Directed Radical H-Abstraction
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Tao Liu, Tian-Sheng Mei and Jin-Quan Yu*
†Department of Chemistry, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, California 92037
RECEIVED DATE (automatically inserted by publisher); yu200@scripps.edu
Scheme 1. Initial Design and Unexpected Results
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Abstract: Aliphatic amides are selectively functionalized at
the  and positions through a directed radical 1,5 and 1,6-
H-abstraction. The initially formed - or -lactams are
intercepted by NIS and TMSN3 leading to di- and tri- C–H
functionalizations at the , , and positions. This new
reactivity is exploited to convert alkyls into amino alcohols
and allylic amines.
Pd-catalyzed -C–H functionalizations of aliphatic acids using
directing groups have been extensively studied in the past decade.
A diverse range of transformations have been developed using
both Pd(II)1, Pd(0)2 and other transition metal catalysts.3 In
contrast, -C–H functionalizations are still rare.4 Inspired by
pioneering studies on 1,5 and 1,6-H-abstraction,5, 6 we questioned
whether the reactivity and selectivity of these radical abstraction
could be harnessed to develop wide range of catalytic C–H
functionalization reactions of aliphatic acids or amides. An
extensive literature survey revealed two potential challenges. First,
radical abstractions of - or -C–H bonds of aliphatic amides have
a
Condition A: 1a (0.1 mmol), NIS (3 equiv.), DCE (1 mL), 100 oC, air, 14 h.
only been demonstrated for C–H bond adjacent to an oxygen
Condition B: 1a (0.1 mmol), PhI(OAc)2 (1.5 equiv.), I2 (1.5 equiv.), DCE, r.t., air,
atom.6d Second, the vast majority of the reactions initiated by
b
c
48 h. Isolated yield. For substrate 1a, isolated yield of 2a is 92% (condition A)
and 89% (condition B); for substrate 1b, isolated yield of 2b is 62% (condition A). d
Product structure is confirmed by X-ray crystallographic analysis.
nitrogen radicals leads to cyclization (eq 1)6e instead of
intermolecular functionalizations with the exception of a few
examples involving amine substrates.6c This suggests that the
facile cyclization pathway might be difficult to prevent. Herein
we report an empirically discovered a sequential radical -, or -
C–H lactamization and subsequent reaction with NIS and TMSN3
to give -iodo--lactams or , -dehydrogenated -lactams.
Structural elaborations of these highly functionalized lactams
allows for an overall conversion of simple alkyls into di-
functionalized olefins, amino alcohols or tri-functionalized allylic
amines.
Table 1. Screening of Protecting Groups a,b
Our initial efforts to trigger the radical H-abstraction by the
amide were guided by the conditions used for radical cyclization
of toluenesulfonyl protected amines.6e We choose to use our
N-heptafluorotolyl amide (PG1) directing group1b anticipating this
would accommodate subsequent functionalizations with a metal
catalyst if the -carbon centered radical is formed and intercepted
by the metal. Through an extensive survey of radical initiators,
iodine sources, solvents and other parameters (see Supporting
Information for details), it was found that a combination of
PhI(OAc)2 and I2 facilitated the desired lactamization reaction of
1a to give the -lactamization product 2a in excellent yield
(Scheme 1A). Next, we sought to identify an appropriate metal
catalyst or reagent that can intercept the -carbon centered radical
prior to the cyclization thereby achieving a general intermolecular
a Conditions: 1 (0.1 mmol), NIS (4 equiv.), TMSN3 (4 equiv.), DCE (1 mL), 100 oC,
air, 14 h. Yields were determined by 1H NMR analysis of the crude reaction
b
mixture using CH2Br2 as an internal standard.
-C–H functionalization method.
While all efforts to trap the -carbon centered radical with various
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Cu, Pd and Ni catalysts were not fruitful, the attempt to perform a
Scheme 3. Synthetic application of δ-iodo -lactam 3
radical -azidation led to a surprising finding. In the presence of
TMSN3, the reaction of 1a with NIS in DCE afforded -iodo -
lactam 3a in which both - and -C–H bonds are functionalized
(Scheme 1, B). This reactivity was further investigated with a
range
of
amide
directing
groups.
While
N-methoxy and N-alkyl amides did not give rise to any product,
N-phenyl and N-sulfonyl amides are generally reactive (Table 1).
The highly acidic N-heptafluorotolyl (PG1) and the N-para-
trifluoromethyl phenylsulfonyl (PG2) amides are more effective
affording the -iodo -lactams in 86% and 72% yields
respectively (Table 1).
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Table 2. , Iodolactamization of Aliphatic Amidesa,b
Scheme 2. Preliminary Mechanistic Investigations
O
NIS (4.0 equiv)
R1
R3
H
R1
H
N
TMSN3 (4.0 equiv)
H
N
PG
PG
DCE (0.1M)
R2
R4
air, 100 oC, 14h
I
R2
O
R3
R4
1
3
Substrate
Product
Substrate
Product
O
O
H
Me
H
N
H
N
N
PG2
N
PG2
H
H
PG2
PG2
I
I
Me
O
O
H
H
O
H
c
1c
Me
3c
1h
3h, 70%
, 72%, 53%
O
H
H
N
Me
O
H
N
PG2
PG2
H
N
N
Me
I
PG1
Me
Me
PG1
I
Me
O
O
1d
3d, 71%d
1i
Me
3i, 72%
O
O
H
N
H
H
H
H
Me
H
N
PG2
H
N
PG1
H
H
N
PG1
PG2
Me
I
Me
Me
n-Pr
n-Pr
O
O
I
Me
1j
3j, 61%d
1e
3e, 53%e
O
O
Me
H
Et
H
N
AcO
H
N
OAc
O
N
PG2
N
PG1
H
H
PG2
PG1
I
Et
Me
I
Me
Me
d
1f
3f, 63%
1k
3k
, 62%
O
O
N
H
N
TcpN
Me
H
NTcp
O
PG2
PG1
N
PG2
N
PG1
H
H
O
I
I
Me
3l, 72%f, g
1g
3g, 48%
1l
a Conditions: 1 (0.1 mmol), NIS (4 equiv.), TMSN3 (4 equiv.), DCE (1 mL), 100 oC,
1
Monitoring the reaction by H NMR and isolation of -lactam
b
c
d
air, 14 h. Isolated yields. Run on gram-scale. Obtained as a mixture of
2c by shortening the reaction to 2 h suggests that 2c is initially
formed as the intermediate which then reacts with TMSN3 and
NIS to give iodo lactam 3c (Scheme 2, A). Apparently, the in situ
generated azide radical7 triggers a -C–N bond scission to give
theterminal double bond and subsequent radical cyclization
affords 3c (Scheme 2, B). Alternatively, the radical intermediate I
could abstract a hydrogen from 2c to initiate a radical chain
reaction to produce 4b which undergoes standard
iodolactamization8 to give 3c. The iodolactamization step is
verified by subjecting a synthetic standard 4b to the reaction
conditions to give 3c (Scheme 2, C). Importantly, the iodo lactam
3a and 3b can be converted to ,-desaturated amide 4a and 4b
respectively, thus leading to a method for dehydrogenation
(Scheme 3).9, 10 In addition, the iodo lactam 3c protected with
para-trifluoromethyl phenylsulfonyl group (PG2) is subjected to
methanolysis conditions to give 5 containing a synthetically
useful 1,2-amino alcohol motif.
e
f
diastereomers (3:2). Obtained as a mixture of diastereomers (7:6). Obtained as a
g
mixture of diastereomers (2:1). Tcp = tetrachlorophthalimide. One pot procedure
for substrate 1l: NIS (2 equiv.), 100 oC, air, 8h; I2 (3 equiv.) and
TMSN3 (4 equiv.), 100 oC, 14h.
expected to occur selectively at the tertiary carbon center, the
subsequent H-abstraction by the azide radical at the -carbon
center could occur at either methyl or the ethyl group leading to
different products. The exclusive formation of 3d (Table 2)
containing the newly installed iodide on the methylene carbon
suggests that the radical abstraction by the azide radical occurs
selectively at the methylene carbon (Scheme 2, B). Similarly,
product 3e was obtained with substrate 1e. This method also
allows access to synthetically useful iodinated spiro lactams 3g
and 3h from 1g and 1h respectively.
For substrates containing substituents at the  and  positions,
low yields (~40%) were obtained when the para-trifluoromethyl
phenylsulfonyl (PG2) protecting group was used. Thus, 1i-1l
containing N-heptafluorotolyl (PG1) protecting groups were
prepared for testing. We found that the desired bicyclic δ iodo
lactam (3i) was formed in 72% yield. Other amides containing
methyl, acetoxy and tetrachlorophthalimide at α or β carbons are
The smooth conversion of the iodo lactam products to more
useful olefin and 1,2-amino alcohol motifs prompted us to
examine the scope of this transformation. Substrate 1d containing
both a methyl and ethyl group at the -position was subjected to
the reaction conditions. While the first lactamization event is
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all compatible, giving the desired products in good yields (3j-3l).
Scheme 5. Synthetic Application of δ, ε Vinyl Lactams
4
5
6
7
8
9
Notably, 3l can be converted to , -unsaturated chiral amino acid,
providing a new method to functionalize leucine. Since previous
protocols for functionalizing leucine via radical H-abstraction are
O
Me
O
PG2
NaOMe (5.0 equiv)
MeOH (0.1M), rt.
N
OMe
6c,
9
HN
directed by the amino group,
the use of this amide as a
Me
PG2
, 88%
Drug analogue
directing group in reaction provides a complimentary method to
7a
8
dehydrogenate leucine.
O
Vigabatrin
(brand name Sabril)
To investigate whether this protocol can be extended to the
functionalizations of , -C–H bonds, we prepared amide
substrates 6a-6d containing tertiary C–H bonds at the  position
(Table 3). Interestingly, 6a was converted to , -dehydrogenated
-lactam 7a under the standard conditions. Apparently, the olefin
intermediate bearing a radical on the nitrogen center derived from
the initially formed -lactam underwent the facile intramolecular
radical abstraction at the allylic carbon center, leading to the
cyclization product 7a (Scheme 4). The initial formation of the -
lactam instead of the -lactam can be attributed to the higher
reactivity of the tertiary C–H bonds at the -position. The -
methylene C–H bond in 6b is selectively functionalized in the
presence of the -methyl C–H bond. Cyclopentyl (6c) and
cyclohexyl (6d) are also compatible, albeit affording lower yields.
A minor product derived from the radical abstraction of the -
methyl C–H bond was also obtained with the cyclic substrate 7d.
Importantly, these lactam products can be readily converted to
synthetically useful , -desaturated -aminoesters as shown in
Scheme 5. For example, 7a is converted to 8, a compound that is
closely related to Vigabatrin.
OH
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NH2
In conclusion, we have developed a protocol to functionalize ,
, ε-C–H bonds of aliphatic acids via a radical 1,5 and 1,6-H-
abstraction. The terminal alkyl groups of aliphatic amides are
converted to olefins, amino alcohols and allylic amines.
Acknowledgements. We gratefully acknowledge The Scripps
Research Institute and the NIH (NIGMS, 2R01GM084019) for
financial support.
Supporting Information Available: Experimental procedures and
spectral data for all new compounds (PDF). This material is available
free of charge via the Internet at http://pubs.acs.org.
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o
aConditions: 6 (0.1 mmol), NIS (4 equiv.), TMSN3 (4 equiv.), DCE (1 mL), 100 C,
b
c
air, 14 h.
Isolated yields.
The structure of 7a is confirmed by X-ray
d
e
crystallographic analysis. Obtained as a mixture of isomers (5:1). Obtained as a
mixture of isomers (3:1).
Scheme 4. Proposed Mechanism for the Formation of δ, ε
Vinyl Lactams
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