Intermolecular sp3-C-H Amination for the Synthesis of Saturated Azacycles

Article abstract of DOI:10.1021/acs.orglett.9b04096

The preparation of substituted azetidines and larger ring, nitrogen-containing saturated heterocycles is enabled through efficient and selective intermolecular sp³-C-H amination of alkyl bromide derivatives. A range of substrates are demonstrated to undergo C-H amination and subsequent sulfamate alkylation in good to excellent yield. N-Phenoxysulfonyl-protected products can be unmasked under neutral or mild basic conditions to yield the corresponding cyclic secondary amines. The preparative convenience of this protocol is demonstrated through gram-scale and telescoped multistep procedures. Application of this technology is highlighted in a nine-step total synthesis of an unusual azetidine-containing natural product, penaresidin B.

Full text of DOI:10.1021/acs.orglett.9b04096

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Intermolecular sp3‑C−H Amination for the Synthesis of Saturated
Azacycles
Kerry N. Betz,† Nicholas D. Chiappini,†,‡ and J. Du Bois*
Department of Chemistry, Stanford University, 337 Campus Drive, Stanford, California 94305, United States
S
* Supporting Information
ABSTRACT: The preparation of substituted azetidines and larger ring, nitrogen-containing saturated heterocycles is enabled
through efficient and selective intermolecular sp3-C−H amination of alkyl bromide derivatives. A range of substrates are
demonstrated to undergo C−H amination and subsequent sulfamate alkylation in good to excellent yield. N-Phenoxysulfonyl-
protected products can be unmasked under neutral or mild basic conditions to yield the corresponding cyclic secondary amines.
The preparative convenience of this protocol is demonstrated through gram-scale and telescoped multistep procedures.
Application of this technology is highlighted in a nine-step total synthesis of an unusual azetidine-containing natural product,
penaresidin B.
electron-withdrawing halogen group is unprecedented and
underscores recent advances in Rh-catalyzed amination.11−18
Typical methods for de novo azetidine synthesis include SN2
displacement reactions of mono- and dihalopropanes with alkyl
amines,6,7,19 aziridine ring expansions,6,7,20,21 thermal and
photochemical [2+2] cycloadditions,6,7,22,23 and Pd-catalyzed
C−N cross-couplings (see Table S2 for relevant compar-
isons).6,7,24,25 Our approach for constructing azetidine
derivatives involves selective, intermolecular C−H amination
of bromoalkanes to introduce the requisite nitrogen center
followed by ring closure. Accordingly, the potential scope of
this method is quite broad and extends beyond four-membered
ring synthesis.
Exploratory studies to develop a process for azetidine
synthesis were conducted with 1-bromo-3-phenylpropane 1a
(Table 1). The proximity of the electronegative Br group in 1a
to the benzylic site deactivates this position toward oxidation.
Consequently, a number of reported C−H amination
protocols fail to engage this substrate; others furnish small
amounts of the desired product in combination with
unidentifiable species (see Table S3 for relevant comparisons).
Using a recently disclosed amination protocol developed in our
lab,26 intermolecular C−H amination of 1a with phenyl
sulfamate (PhsNH2) proceeds in 64% yield to furnish 2a (23%
RSM). The intermediate bromoalkyl sulfamate ester efficiently
cyclizes upon treatment with a base to provide the
corresponding azetidine 3a (see Table S1 for optimization).
Through the application of this two-step sequence, 3a is
aturated azacycles are ubiquitous structural elements in
1
Snatural products. Cyclic amines also appear in designed
molecules because of the unique and disparate physicochem-
ical and topological properties of such heterocycles.2,3
Accordingly, numerous methods, which rely on both conven-
tional and modern C−N bond-forming tactics including C−H
oxidation, enable access to pyrrolidine and piperidine
derivatives.4−6 We have been interested in developing a
general protocol for assembling substituted azacycles of
differing ring size, with a specific focus on azetidine structures.
The value of such amines is considerable in synthesis,
pharmacology, and medicine.7−10 Herein, we present a method
for the preparation of small (n = 3−5) and medium (n = 6−8)
ring-sized azacycles that capitalizes on selective, intermolecular
sp3-C−H amination of brominated hydrocarbon substrates
(Scheme 1). The efficient functionalization of substrates in
which the desired site of C−H oxidation is proximal to an
Scheme 1. Selective Intermolecular C−H Amination for the
Preparation of Cyclic Amines, Including Polyfunctionalized
Azetidines
Received: November 19, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b04096
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Table 1. Cyclic Amine Synthesis through C−H Amination
Table 2. Optimized Protocol for Cyclic Amine Assembly
a
Reactions performed with 0.3 mmol of starting material and 0.3 mL
of t-BuCN for 6 h; values in parentheses represent percent recovered
b
starting material. Cyclization performed with 0.1 mmol of C−H
c
aminated product in 1 mL of DMF for 2 h. The product aziridine is
unstable to the reaction conditions; complete conversion of starting
d
1
material is observed by H NMR. Reaction conducted for 10 h at
ambient temperature. Piv = t-BuCO2−; Phs = PhOS(O)2−; DMF =
N,N−dimethylformamide.
Scheme 2. Single-Flask Procedure for Azetidine
a
Construction
a
Values in parentheses represent percent recovered starting material.
obtained in 62% overall yield (Table 1, entry 1). The
effectiveness of the amination reaction, which affords largely
product and recovered starting material, allows the cyclization
reaction to be telescoped in a single-flask procedure. Following
this protocol, pure azetidine 3a can be isolated in 49% yield
(Table S1; see Scheme 2 for more details).
To examine the generality of the amination method for
assembling cyclic amines of varying ring size, a systematic
analysis of reaction performance with phenyl-substituted
bromoalkanes was conducted. Azacycles 3−8 units in size
can be fashioned through our two-step sequence. For the most
part, C−H amination yields improve as the distance between
the Br-substituent and the benzylic center is increased;
nonetheless, even phenethyl bromide 1b can be oxidized in
40% yield to generate sulfamate 2b (Table 1, entry 2). The
cyclization event is consistently high yielding with the one
exception involving azocane 3f (Table 1, entry 6). As a final
note, reactions performed with alkyl mesylate substrates show
diminished product yields stemming from the inefficiency of
a
Reactions performed with 0.3 mmol of starting material and 0.3 mL
of t-BuCN for 6 h; values in parentheses represent percent recovered
starting material. Cyclization performed with 0.1 mmol of C−H
aminated product in 1 mL of DMF for 2 h. Product isolated as a
b
c
1:1.8 mix of diastereomers; cyclization was conducted on the pure
d
syn-diastereomer. Product isolated as a 1:1.1 mix of diastereomers.
e
Recovered starting material was not obtained due to the high
f
volatility of this compound. Product isolated as a 1:1 mix of
g
diastereomers. Product decomposition occurs on silica gel.
h
Amination gives a >10:1 mix of isomeric products; ring closure
was conducted on a pure sample of the isomer shown.
the amination reaction (Table 1, entries 1 and 5). Somewhat
surprisingly, this finding holds even for 6-phenylhexyl mesylate
(Table 1, entry 5), thus leaving in question an explanation for
the suboptimal performance of the amination reaction with
mesylate-derived starting materials.
B
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Phenoxysulfonyl (Phs) is a convenient and chromato-
graphically stable N-protecting group, which can be readily
removed to liberate the amine product (Scheme 3). Heating a
Phs-amine starting material in aqueous CH3CN or aqueous
pyridine cleaves the Phs group; both conditions afford the
desired amine in high purity following reversed-phase
chromatography (HPLC) or trituration of the oxalate salt.30
To demonstrate the synthetic utility of our method for
complex chemical synthesis, an unusual, azetidine-derived lipid
penaresidin B was identified as a natural product target
(Scheme 4).31 Penaresidin B consists of a densely function-
alized azetidine core with three contiguous stereocenters and a
distally hydroxylated alkane side chain. Several total syntheses
of penaresidin B32−34 and related congeners35−41 have been
described, all relying on early stage nitrogen incorporation
using starting materials such as Garner’s aldehyde42 and/or
multistep functional group interconversions to construct the
azetidine core. The shortest of the reported syntheses of
penaresidin B is 17 linear steps.34 Application of our C−H
amination/cyclization method streamlines access to this
natural product. Our route to penaresidin B capitalizes on
the performance of dioxolane substrates for C−H amination.
Beginning from enantiopure oxirane 5,43 addition of organo-
cuprate to the less hindered terminus yielded alcohol 6.
Protection of the alcohol group as the p-nitrobenzoyl ester was
intended to deactivate the carbinol C−H bond and the
proximal tertiary site toward C−H amination. Grubbs’ cross-
metathesis of 7 with commercially available (R)-2,2-dimethyl-
4-vinyl-1,3-dioxolane afforded olefin 8, which was subsequently
epoxidized to give 9 as an ∼7:1 mixture of diastereomeric
products.
Generation of the desired sulfamate ester 10 from 9
necessitated the development of a single-flask protocol for
sequential amination/reduction owing to problems with
isolation of the intermediate N,O-acetal. Subjecting 9 to
standard amination conditions followed by NaBH3CN
furnished aminoalcohol 10 as an ∼5:1 mixture favoring the
desired stereoisomer. This result is striking given the large
number of disparate C−H bonds in 9 and the adjacent
functional groups flanking the desired site of oxidation. This
includes the epoxide moiety, which, much like a neighboring
bromide group, strongly deactivates the C−H bond under-
going reaction. We anticipate that this amination/reduction
protocol will prove useful for the assembly of structurally
related amino-polyol motifs.
Scheme 3. Facile Phs Deprotection Affords N−H
a
Azetidines
a
Method A: H2O/CH3CN, 90 °C; product isolated as the CF3CO2H
salt following HPLC purification. Method B: H2O/pyridine; oxalate
salt of the product isolated by trituration.
To further explore the scope of our azacycle assembly
method and to demonstrate its utility for fine chemical
synthesis, substituted primary and secondary alkyl bromide
derivatives were subjected to the optimized protocol (Table 2).
C−H amination generally proceeds in yields ranging from 37
to 71%; subsequent ring closure is efficient and affords the
desired azacycle products. In several cases, Phs-protected cyclic
amines are obtained in high purity following aqueous workup
without recourse to silica gel chromatography (Table 2, entries
1, 4, and 5).
Substrates bearing benzylic (Table 2, entries 1−4), tertiary
(Table 2, entries 5−7 and 11), and protected carbinol C−H
bonds (Table 2, entries 8−10) are successfully converted to
the corresponding azacycles. The mild conditions for
cyclization are tolerant of base-sensitive functional groups,
including pinacolborane (Table 2, entry 2), N-Boc indole
(Table 2, entry 3), and esters (Table 2, entries 4 and 7).
Subjecting 1,3-dioxane and dioxolane-derived substrates
(Table 2, entries 8−10) to the two-step sequence affords
unusual N,O-acetal azetidines, which are amenable to further
modification.27,28 In addition, the stereospecificity of Rh-
catalyzed C−H amination makes available optically active
cyclic amines bearing tetrasubstituted centers (cf. entries 6 and
8).26,29 As highlighted previously (see Table 1), cyclic amines
of different ring sizes can be accessed using our amination/
cyclization technology. Entry 10 is notable in this regard, as the
glycerol-based substrate undergoes site-selective oxidation and
ring closure with K2CO3 to furnish an isolable, spirocyclic
aziridine N,O-acetal.
It is possible to conduct sequential C−H amination/
cyclization in a single flask with only a small diminution in
overall reaction performance (Scheme 2). This modified
protocol is convenient when isolation of the C−H amination
product is capricious, as is sometimes the case for N,O-acetal
and other derivatives.
Scheme 4. Asymmetric Synthesis of Penaresidin B
C
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To complete the synthesis of penaresidin B, epoxide 10 was
converted to bromohydrin 11 under the action of CeBr3.
Bromide displacement of 10 occurred regioselectively at C4
(penaresidin B numbering) to give 11 as the only detectable
product.44,45 The ordering of steps through this sequence
obviates the use of protecting groups and affords a single
bromohydrin regioisomer.
Novartis Pharmaceuticals for financial support of this work.
K.N.B. is grateful to the Evelyn Laing McBain Fellowship and
to the National Science Foundation for a Graduate Research
Fellowship. Mass spectra were obtained through the Vincent
Coates Foundation Mass Spectrometry Laboratory at Stanford
University.
Finally, ring closure of the azetidine followed by sulfamate
and nitrobenzoate deprotection yielded the desired target.
Removal of the Phs-protecting group in 12 proved to be more
challenging than with less functionalized azetidines (see
Scheme 3).46 Successful deprotection, however, was ultimately
achieved by adapting a procedure for cross-coupling of cyclic
sulfamate esters.47 Under nickel catalysis with MeMgBr,
displacement of the phenyl ring afforded the sulfated azetidine;
subsequent treatment with methanolic HCl furnished the
natural product. All told, the enantioselective synthesis of
penaresidin B proceeds in nine steps from commercial starting
materials, a substantial decrease in the overall step count
compared to previous efforts.
We have described reaction technology for the generation of
structurally diverse small- and medium-sized cyclic secondary
amines. This process capitalizes on site-selective, intermolec-
ular C−H amination to first introduce the obligatory nitrogen
center as a sulfamate ester. Efficient C−H oxidation is viable
across a range of functionalized propyl and longer chain alkyl
bromide starting materials, substrates that have not been
previously documented for amination reactions. We expect this
work to advance the utility of C−H amination for the
preparation of complex chemicals.
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.9b04096.
■
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AUTHOR INFORMATION
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Corresponding Author
*E-mail: jdubois@stanford.edu.
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Kerry N. Betz: 0000-0001-9118-5909
Nicholas D. Chiappini: 0000-0003-0469-1008
J. Du Bois: 0000-0001-7847-1548
Present Address
‡N.D.C.: Department of Chemistry, Princeton University,
Frick Chemistry Laboratory, Washington Road, Princeton, NJ
08544.
Author Contributions
†K.N.B. and N.D.C. contributed equally to this work.
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ACKNOWLEDGMENTS
■
The authors are grateful to Dr. T. Aaron Bedell (Stanford
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synthesis of penaresidin B. The authors thank the National
Science Foundation under the Center for Chemical Innovation
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