Synthesis of Hindered α-Amino Carbonyls: Copper-Catalyzed Radical Addition with Nitroso Compounds

Article abstract of DOI:10.1021/jacs.5b07860

The synthesis of sterically hindered anilines has been a significant challenge in organic chemistry. Here we report a Cu-catalyzed radical addition with in situ-generated nitroso compounds to prepare sterically hindered amines directly from readily available materials. The transformation is conducted at room temperature, uses abundant copper salts, and is tolerant of a range of functional groups.

Full text of DOI:10.1021/jacs.5b07860

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Communication
Synthesis of Hindered #-Amino Carbonyls: Copper-
Catalyzed Radical Addition with Nitroso Compounds
David J. Fisher, Leslie G. Burnett, Rocio Velasco, and Javier Read de Alaniz
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.5b07860 • Publication Date (Web): 28 Aug 2015
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Synthesis of Hindered α-Amino Carbonyls: Copper-Catalyzed
Radical Addition with Nitroso Compounds
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David J. Fisher, G. Leslie Burnett, Rocío Velasco and Javier Read de Alaniz*
Department of Chemistry & Biochemistry, University of California, Santa Barbara, California 93106, United States
Supporting Information Placeholder
amines.10 Although less developed, a powerful method
ABSTRACT: The synthesis of sterically hindered ani-
used for the synthesis of α-amino carbonyl compounds
bearing hindered anilines is electrophilic amination with
arylnitroso compounds (Figure 1b). Despite progress,
this approach suffers from several drawbacks: (1) the
reduced reactivity of arylnitroso compounds requires the
use of tin enolates11 or activated carbonyl compounds;12
(2) the N- vs. O-regioselectivity is often difficult to con-
trol.13
lines has been a significant challenge in organic chemis-
try. Here we report a Cu-catalyzed radical addition with
in situ generated nitroso compounds to prepare sterically
hindered amines directly from readily available materi-
als. The transformation is conducted at room tempera-
ture, uses abundant copper salts, and is tolerant of a
range of functional groups.
NHC(O)Ph
MeO
O
Me
Me
The construction of carbon–nitrogen bonds using
alkylation,1 amine-carbonyl reductive amination,2 C–N
cross-coupling3 and electrophilic amination4 has been
extensively explored over the past several decades. This
synthetic effort has been fueled by the prevalence of
nitrogen-based functional groups in natural products and
pharmaceutically relevant agents. Of these compounds,
sterically hindered anilines are of particular importance
in medicinal chemistry because these groups are known
to improve the lipophilicity and metabolic stability of
drug molecules.5 Despite these advantageous properties,
incorporation of sterically hindered anilines in medicinal
chemistry remains a noteworthy challenge.
N
N
N
N
H
F
N
O
1
2
CO2H
O
carfentanil
Me
N
N
H
N
BocN
Me
H
N
HN
Me
Me
N
H
O
3
4
a. Arylation of an amine derivative
R1
R1
N
C–N
X
N
+
R2
Y
R2
bond formation
Compounds containing sterically hindered anilines
generally fall into two categories (Figure 1), anilines
bearing α-substituted alkyl6 (1 and 3) and α-amino car-
bonyl compounds with N-containing quaternary stereo-
centers7 (2 and 4). As such, different approaches are
generally used to access these types of structural motifs.
The most common strategy to generate these scaffolds
relies on methods that construct the N-aryl bond using
an arylation of an amine derivative (Figure 1a). Initially,
these transformations relied heavily on highly reactive
organometallic reagents.8 However, more recently a
number of milder methods for the synthesis of hindered
anilines have been reported. For example, Lalic reported
an elegant approach using the copper-catalyzed coupling
of aryl boronic esters with O-benzoyl hydroxylamines9
and recently Buchwald reported the use of rational lig-
and design for the arylation of hindered primary
Y = H, Cl, OR
b. Electrophilic amination
O
O
electrophilic
O
R2
N
+
R1
N
R3
α-amination
R1
H
R2 R3
Figure 1. Examples of sterically hindered amines and strat-
egies for their preparation.
In considering a means to develop a general and
practical strategy for the synthesis of sterically hindered
amines we were drawn to the potential use of radical
transformations with nitroso compounds. Although ni-
troso compounds have been used for decades in radical
reactions such as spin trapping agents, surprisingly, their
use in synthesis remains rare.14 However, Baran and co-
workers recently described a very general approach for
the synthesis of amines by merging radical reactions
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with nitrosoarene compounds.15 This methodology is of
Page 2 of 6
addition would then form the persistent nitroxyl radical
1
2
3
4
5
6
7
8
particular relevance to our work and prompts us to dis-
close our results.
that could subsequently undergo another radical addition
to form 10.
2 R3
O
O
Ar
N
O
Ar
N
Given the importance of sterically hindered anilines
in medicinal chemistry and the difficulties associated
with their synthesis, we sought to develop a new method
that was mild, practical and highly functional group tol-
erant. In this communication, we describe our initial
efforts in this area using a copper-catalyzed radical addi-
tion with aryl nitroso compounds to access sterically
hindered α-amino carbonyl compounds. This new pro-
cess can be conducted at room temperature, uses readily
available starting materials, and an abundant copper salt
as a catalyst.
R
then
SmI2
OH
N
Cu cat.
Br
R1
+
H
R1
R1
O
R1
H
Ar
R2 R3
8
R2 R3
R2 R3
11
O
9
10
Proposed pathway
Cu(I)
radical addition
A
9
– redox-neutral
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Cu(II)
– room temperature
– catalytic copper
– high functional
group tolerance
O
Ar
N
O
A
O
radical
addition
R3
+
R1
O
R1
N
Ar
R2 R3
C
R2
B
persistent radical
Figure 2. Proposed Cu-catalyzed radical addition with in
situ generated nitroso compounds.
Our recent work on photocontrolled atom transfer
radical polymerization (ATRP) led us to explore the
coupling between alkyl halides and nitrosobenzene.16
We were particularly drawn to the Cu-based catalysts
used in the mechanistically related radical trap-assisted
atom transfer radical coupling (ATRC), in which Cu(I)
catalysts can propagate radical reactions between two
functionalized polymer chain ends and a radical trapping
agent such as nitrosobenzene by undergoing single elec-
tron transfer with alkyl halides.17 The key step in ATRC
is the formation of a persistent nitroxyl radical,18 which
is stable enough to steer the reaction away from unwant-
ed radical side reactions, such as disproportionation and
radical-radical coupling. The persistent radical enables
the efficient coupling between two polymer chain ends.
To this end, we conducted the reaction using 5 mol
% CuCl2 as the catalyst and phenylhydroxylamine as the
nitroso precursor (see ESI Table S1). Unfortunately, us-
ing this redox-neutral protocol only a trace amount of
amine 7 was isolated. However, the low yield was due to
a competitive condensation reaction between the in situ
generated nitrosobenzene and excess phenylhydroxyla-
mine, a good nucleophile. To our gratification, further
optimization revealed that slow addition of phenylhy-
droxylamine (5 h) and increasing the equivalents of the
ligand pentamethyldiethylenetriamine (PMDTA) from
0.5 to 1.8 resulted in the formation of 7 in 73% yield.
With a general catalytic protocol in place (5 mol %
CuCl2, 1.8 equiv of PMDTA, rt, THF), we next set out to
demonstrate the broad applicability of this new approach
for a library of α-bromocarbonyl compounds. Various
esters and amides were reacted with phenylhydroxyla-
mine under optimized reaction conditions to generate the
α-amino adducts in excellent yields (Table 1). It is worth
noting that modifications to the addition rate (5 to 10 h)
of the phenylhydroxylamine were necessary to obtain
good yields with the amide derived α-bromocarbonyl
compounds due to their decreased reactivity compared
to the corresponding esters. The mild reaction conditions
and radical nature of this transformation translate to a
high degree of functional group compatibility. For ex-
ample, the acid labile TMS protecting group was well
tolerated, affording the desired product (14) in 87%
yield. Compounds bearing an alkene or terminal alkyne,
such as 15 and 16, were also compatible. The
Cu(I)/PMDTA complex selectively reduced the α-
bromo-carbon bond in the presence of an aryl bromide
(17), enabling the synthesis of sterically hindered ani-
lines that could be used in subsequent cross-coupling
reactions. The reaction could be used to rapidly access
racemic N-containing quaternary stereocenters (19) in
good yield (75%). Unprotected alcohols and amides are
well tolerated (22–24), eliminating the need to use pro-
tecting group chemistry. Of note, Weinreb amides result
100 mol % Cu(0)
O
50 mol % PMDTA
O
O
Ph
N
+
Br
(eq 1)
N
EtO
Ph
THF, N2, rt
then SmI2
EtO
H
Me Me
Me Me
7
5
6
With this in mind, we began by studying the reac-
tion of ethyl α-bromoisobutyrate 5 and nitrosobenzene 6
in THF (eq 1). Using standard stoichiometric Cu(0)
ATRP conditions19 and introducing Sm-mediated reduc-
tion of the N–O adduct, the desired amine 7 was isolated
in 87% yield. Even though copper is abundant and inex-
pensive, we sought to render the reaction catalytic; an
ongoing challenge in the field of metal-catalysis is low-
ering catalyst loading and/or removal of residual metals.
The significance of this arises in part from the known
toxicity of metal salts and the cost of removal from late-
stage target compounds. Although the catalyst loading
for ATRP can be decreased using reducing agents that
regenerate Cu(I) in situ such as glucose, tin(II) 2-
ethylhexanoate,20 ascorbic acid,21 and zerovalent metals
including Cu, Zn, Mg, and Fe,22 we envisaged that an
unexplored, yet practical redox-neutral alternative could
be utilized (Figure 2). By replacing the nitrosoarene with
an N-aryl hydroxylamine, the Cu(I) necessary for the
formation of the carbon centered radical (A) could be re-
generated via a Cu(II)-catalyzed oxidation of N-aryl hy-
droxylamine. This would result in the formation of ni-
trosobenzene (B), the radical trapping species. Radical
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in the direct formation of the methyl amide (22) because this scaffold could serve as a valuable building block for
1
2
3
4
5
6
7
8
the N–O bond of the Weinreb amides are also reduced
by SmI2. Presumably, other reduction conditions could
be used to avoid this reduction if necessary. Alternative-
ly, the morpholine amide could be used as a Weinreb
amide surrogate and in this case a 92% yield of the de-
sired product was isolated.23
non-aniline derived sterically hindered amines.
Having demonstrated the initial scope of the reac-
tion with a variety of α-bromocarbonyl compounds, we
focused our efforts next on the incorporation of different
N-aryl hydroxylamines (Table 2).24 Phenylhydroxyla-
mines substituted at the para- and meta-position with
electron donating and electron withdrawing groups de-
liver the desired product in excellent yield 28–33. Both
α-bromo amides and esters are compatible with the dif-
ferent N-aryl hydroxylamines.
Table 1. Scope of the α-bromocarbonyls.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 2. Scope of the N-aryl hydroxylamines.
a
Isolated yields calculated based on 8 as the limiting re-
agent.
To illustrate the utility of this catalytic method for
the preparation of biologically active hindered amine
molecules, we applied it to the synthesis of 35 (Scheme
1), a precursor to the 4-anilidopiperidine class of opioid
analgesics that include carfentanil (2), which is a veteri-
nary sedative for large animals, and remifentanil, a gen-
eral anesthetic.25 The most common method to prepare
carfentanil and its analogs (see ESI), relies on harsh
acidic and basic conditions, as well as high temperatures
that force the use of protecting groups and reduce the
efficiency of the overall process.26 Using a radical-based
approach with α-bromocarbonyl 34, available in 1-step
from readily available material, and in situ generated
nitroso compounds (Scheme 1a), the reaction can be
conducted at room temperature, is high yielding, and is
compatible with acid labile protecting groups such as
Boc. This useful handle would allow for the synthesis of
carfentanil derivatives that often vary at the piperidine
nitrogen.27 Moreover, this approach provides entry into
the late-stage construction of the N-containing quater-
nary stereocenters, which provides new opportunities for
medicinal chemists that were previously difficult. To
a
Isolated yields calculated based on 8 as the limiting re-
agent. b Reaction conducted with stoichiometric amounts of
Cu(0) and nitrosobenzene was used (see ESI). c See ESI for
details.
While the catalytic copper conditions proved gen-
eral, stoichiometric copper conditions were advanta-
geous with α-bromophenylacetate 20 and the primary α-
bromo amide 24. For 20 a 38% yield was obtained using
the catalytic conditions and for 24 the stoichiometric
conditions were required because the activation of the
free amide was prohibitively slow with the catalytic
conditions. Finally, this methodology can be used to ac-
cess the primary amine (27) in good yield. In this case
commercially available 2-methyl-2-nitrosopropane was
used, which can be deprotected using methanesulfonic
acid (see ESI for details). This is noteworthy because
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further explore the utility of the Cu-catalyzed radical
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addition with arylnitroso compounds, we synthesized 39
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highlight the compatibility with arylbromides, where a
late-stage cross-coupling reaction could be used to ac-
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9
MeO
O
MeO
O
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OH
Br
H
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b
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N
OH
O
39, 98%
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SmI2. b) 1.6 equiv phenylboronic acid, 6 mol % Pd(PPh3)4,
2 equiv K2CO3, dioxane, H2O.
In summary, we have developed a general method
for the construction of α-amino carbonyl compounds
containing sterically hindered anilines. This transfor-
mation occurs under mild conditions, uses inexpensive
copper salts and allows the conversion of simple starting
materials to complex products containing nitrogen qua-
ternary stereocenters in high yields. The reaction toler-
ates a range of functional groups such as aryl halides,
alkynes, alkenes, amides, esters, and unprotected alco-
hols and we anticipate that this methodology will find
widespread application in both academia and industry.
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Supporting Information. Experimental procedures, sup-
1
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AUTHOR INFORMATION
Corresponding Author
(15) Gui, J.; Pan, C.-M.; Jin, Y.; Qin, T.; Lo, J. C.; Lee, B. J.;
Spergel, S. H.; Mertzman, M. E.; Pitts, W. J.; La Cruz, T. E.;
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B. E.; Read de Alaniz, J.; Fors, B. P.; Hawker, C. J. J. Am. Chem. Soc.
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Valente, C. J.; Schellenberger, A. M.; Tillman, E. S. Macromolecules
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javier@chem.ucsb.edu
Funding Sources
The authors declare no competing financial interests.
ACKNOWLEDGMENT
Financial support from UCSB and Amgen is gratefully
acknowledged. D. F. thanks Mellichamp Sustainability Fel-
lowship and R. V. thanks Junta de Castilla y León and
Fondo Social Europeo for a PIRTU fellowship. NMR in-
strumentation was supported by the NIH Shared Instrumen-
tation Grant (SIG): 1S10OD012077-01A1.
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O
H
N
O
OH
N
copper catalyzed
+
Br
R2 R3
R1
Ar
R1
H
Ar
R2 R3
22 examples
78% average yield
O
O
R3
+
N
R1
Ar
R2
alkyl radical nitrosoarenes
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