Evidence for a Radical Mechanism in Cu(II)-Promoted SnAP Reactions

Article abstract of DOI:10.1055/s-0037-1611670

Saturated nitrogen heterocycles can be found with increasing abundance in bioactive molecules despite a limited number of methods to access these scaffolds. However, the coupling of recently introduced SnAP [tin (Sn) amine protocol] reagents with a wide r

Full text of DOI:10.1055/s-0037-1611670

SYNLETT
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Georg Thieme Verlag Stutt-
gart · New
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2019, 30,
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M. U. Luescher, J. W. Bode
Letter
Synlett
Evidence for a Radical Mechanism in Cu(II)-Promoted SnAP
Reactions
Michael U. Luescher1
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SnBu3
O
SnBu3
O
H
CuII
polar mechanism
CuII
Jeffrey W. Bode*
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Laboratory of Organic Chemistry (LOC), Department of
Chemistry and Applied Biosciences (D-CHAB), ETH Zurich,
8093 Zurich, Switzerland
O
N
radical clock SnAP
bode@org.chem.ethz.ch
C–Sn oxidation,
radical mechanism
Cu(II)! A Lewis acid, transmetalating agent, or C–Sn bond oxidant?
Dedicated to a great mentor and teacher – Rick L. Danheiser
Published as part of the 30 Years SYNLETT – Pearl Anniversary
Issue
Received: 14.12.2018
Accepted after revision: 10.01.2019
Published online: 05.02.2019
with the addition of strong nucleophiles to C=N functional-
ities, e.g. aza-enolization or poor functional group toler-
ance,3 SnAP reagents with their -heteroatom C(sp3)–Sn
nucleophiles have emerged as valuable tools in the prepara-
tion of functionalized unprotected saturated heterocycles
suitable for immediate further elaboration.2
DOI: 10.1055/s-0037-1611670; Art ID: st-2018-b0805-l
License terms:
Abstract Saturated nitrogen heterocycles can be found with increas-
ing abundance in bioactive molecules despite a limited number of
methods to access these scaffolds. However, the coupling of recently in-
troduced SnAP [tin (Sn) amine protocol] reagents with a wide range of
aldehydes and ketones has proven to be a reliable, practical, and versa-
tile one-step approach to saturated N-heterocycles. While effective, the
lack of mechanistic understanding limits efforts to develop new catalyt-
ic and enantioselective variants. To distinguish between a polar or radi-
cal mechanism, we assessed Lewis and Brønsted acids, radical trapping
experiments, and radical clock SnAP reagents reinforcing the current
understanding of the SnAP protocol as a radical cyclization.
R
R'
Y
SnBu3
Y
R'
R
R
O
R
aldehydes & ketones 0.1–1.0 equiv Cu(II)
NH2
N
H
CH2Cl2–HFIP, r.t.
> 30 SnAP reagents
C-substituted
N-heterocycles
endo-
cyclization
(ket)imine
formation
Y = CH2, O, S, NBoc
R' = H, Me, Et, OMOM, NHBoc
> 200 examples
Scheme 1 SnAP chemistry: Cu(II)-mediated preparation of unprotect-
ed functionalized saturated nitrogen heterocycles
Key words SnAP reagents, N-heterocycles, morpholines, cyclization,
radical clock, mechanism
Tin (Sn) amine protocol (SnAP) reagents are simple
building blocks used for the direct transformation of alde-
hydes and ketones into saturated five- to nine-membered
N-heterocycles such as substituted unprotected pyrroli-
dines, (thio)morpholines, piperazines, piperidines, oxaze-
panes, and diazepanes (Scheme 1).2 The SnAP protocol is
distinguished by a broad substrate scope tolerating aromat-
ic, heteroaromatic, and aliphatic aldehydes, including sub-
strates bearing various functional groups such as unpro-
tected indoles, phenols, esters, nitriles, and halides under
simple, robust, and consistent reaction conditions.
The key C–C bond forming reaction featured in SnAP
chemistry relies on the addition of an organotin species to
an imine, an underutilized transformation because of the
poor electrophilicity of unfunctionalized and therefore un-
activated imines. Circumventing the poor electrophilicity of
imines through the use of an intramolecular reaction and
avoiding the fundamental problems that are associated
Circumstantial evidence, including the reluctance of
chelating imines as 3 to participate in the reaction (Scheme
2, a) and the ability to conduct the SnAP chemistry under
photocatalytic conditions,4 strongly supports a radical
mechanism. We have therefore favored a mechanistic
scheme for the Cu-promoted reactions in which CuII acts as
a one-electron oxidant.2a While this radical-based mecha-
nism for the SnAP reagents rationalizes most of the obser-
vations, further studies were required to strengthen our
proposal.
We have previously shown that substoichiometric
amounts of radical inhibitors such as BHT or TEMPO retard-
ed the reaction and alkoxamines arising from possible in-
termediate radicals were obtained by using stoichiometric
amounts of TEMPO.2a With use of SnAP M for the prepara-
tion of morpholines rather than SnAP TM for the prepara-
tion of thiomorpholines as in our original publication, the
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M. U. Luescher, J. W. Bode
Letter
Synlett
radical inhibitor experiments were repeated here by using
SnAP reagents with lower oxidation potentials (Scheme 2,
b) and similar results were obtained.
In this report, we describe our investigations into fur-
ther separating H+- and Lewis acid-mediated mechanisms
from a reaction pathway involving single-electron species
with a radical clock SnAP reagent aimed to trap possible in-
termediate radicals further down the reaction after a suc-
cessful cyclization.
As a Lewis acid-mediated mechanism was excluded in
earlier experiments,2a,b investigations aimed at elucidating
the possibility of a Brønsted acid-mediated SnAP reaction
mechanism were carried out (Table 1).
The standard SnAP reaction (Table 1, entry 1) involves
the addition of stoichiometric quantities of a weak base,
2,6-lutidine, that is proposed to act as a ligand and form the
active copper species. Leaving out 2,6-lutidine, which could
interfere with a potential Brønsted acid-mediated mecha-
nism, resulted in a decreased yield of the desired product 7
(entry 2). Furthermore, other Lewis acids known to be a
source of triflic acid8 were unsuccessful in mediating the
SnAP cyclization leaving Cu(OTf)2 as the sole active media-
tor under these conditions (entries 2–5). To further dismiss
a Brønsted acid-mediated mechanism, the addition of ex-
cess 2,6-di-t-butylpyridine, a weak base that binds protons
but is unable to coordinate to metal centers because of the
sterically demanding t-butyl groups,9 only retarded the re-
action, affording the desired product in moderate amounts
(entry 6). Experiments in which TfOH was used in place of
Although the observation of alkoxyamine adduct 5 from
the addition of TEMPO is indicative of a radical process, it
could also arise from an unproductive side reaction, such as
the disproportionation of an organo–copper intermediate
after transmetalation or trapping of an oxonium after fur-
ther redox reactions.5,6 Bærends, for example, has shown
that CuX2∙TEMPO can behave as an ionic electrophile by sin-
gle-electron pairing of CuX2 and TEMPO forming a reactive
oxidant that releases Cu(I) and a nucleophile–TEMPO ad-
duct after the reaction with a two-electron nucleophile.7
The isolation of such an adduct might therefore represent a
side reaction that is not connected to the productive Cu(II)-
mediated conversion, emphasizing the need for additional
experiments aimed at elucidating the mechanism of the
SnAP reaction.
Furthermore, a Lewis acid-mediated mechanism can be
excluded on the basis of the aforementioned experiments
and failure to afford the desired product in previous experi-
ments. However, investigations aimed at separating Lewis
and Brønsted acid mechanisms needed to be carried out to
further exclude a polar mechanism because Cu(OTf)2 with
its weakly coordinating counterions is known to be a source
of triflic acid (TfOH) acting as a Brønsted acid under condi-
tions proposed to involve metal catalysis.8
a) Chelating substrates using SnAP morpholine 6
1.0 equiv Cu(OTf)2
1.0 equiv 2,6-lutidine
O
SnBu3
O
O
SnBu3
N
via
N
N
H
N
CH2Cl2–HFIP, r.t.
N
N
LnCu
1
2
3
traces using
standard conditions
b) Proposed radical mechanism using SnAP reagents with isolation of TEMPO adduct 5
1) TEMPO
O
N
SnBu3
O
(CF3)2CH–OH
2) NaBH4, MeOH
R
N
H
R
– Bu3SnOCH(CF3)2
Cu(I)
4
Me
Me
Cu(II)
N
O
O
Me Me
O
O
O
N
H
CF3
N
H
R
N
RR
Cu(II)
N
H
R
5
H
PRODUCT
this work
radical clock experiments
Scheme 2 Experiments supporting a role for Cu(OTf)2 as an oxidant rather than as a Lewis acid; see Supporting Information for more detailed TEMPO
and BHT studies
Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–G

C
M. U. Luescher, J. W. Bode
Letter
Synlett
Table 1 Screening for Brønsted Acid-Mediated Cyclization
PhBox ligands.2e Likewise, enantiomerically enriched -bis
substituted SnAP-eX reagents afforded racemic 2,3-disub-
stituted piperidines by using the standard conditions.2f
O
N
SnBu3
O
SnBu3
RCHO, 3 Å MS
O
cond.
NH2
N
H
CH2Cl2, r.t., 4 h
quant.
O
N
SnBu3
O
1) Cu(OTf)2, 2,6-lutidine, CH2Cl2–HFIP
2) NaBH4, MeOH
6
7
CF3
CF3
SnAP M
N
H
86%
Entry Conditionsa
Resultsb
+ Bu3SnOCH(CF3)2 (stoich.)
CF3
CF3
7
4
1c
Cu(OTf)2 (1.0 equiv), 2,6-lutidine
(1.0 equiv)
88% with 100% conv.
isolated side products:a
F3C
via
CF3
2
3
4
5
6
Cu(OTf)2 (1.0 equiv)
Bi(OTf)3 (1.0 equiv)
Yb(OTf)3 (1.0 equiv)
Sc(OTf)3 (1.0 equiv)
65% with 100% conv.
≤ 5% with ≤ 10% conv.
≤ 5% with ≤ 5% conv.
≤ 5% with ≤ 5% conv.
OH
O
O
O
O
ox.
N
H
N
H
N
N
CF3
CF3
CF3
CF3
8
9
Cu(OTf)2 (1.0 equiv), 2,6-di-t-butylpyridine 21% with 30% conv.
(2.5 equiv)
Scheme 3 Side product formation through an oxidative mechanism.
a Dimeric structures were not detected in the crude 1H NMR spectrum
as confirmed through independent synthesis (see Supporting Informa-
tion).
7
8
9
TfOH (1.0 equiv)
TfOH (2.5 equiv)
TfOH (2.5 equiv)e
TfOH (5.0 equiv)
≤ 5% with 28%d
ca. 5% with 52%d
6% with 48%d
Organostannanes are known to undergo bond fragmen-
tation upon one-electron oxidation giving an organic
radical and a stannylium cation fragment,10,11 a fragment
that was previously isolated as the HFI -adduct 4.2e Not sur-
prisingly, unsymmetrically substituted stannanes would
lead to the formation of the most stable organic radical
upon such oxidative fragmentations affording an - hetero-
atom-stabilized alkyl radical by using SnAP reagents. There-
fore, the postulated mechanistic picture (Scheme 2, b) in
which the C–Sn bond is oxidized through a Cu(II) species is
proposed to involve an -heteroatom-stabilized carbon-
centered radical. Such a radical is proposed to react in an
intramolecular reaction with the imine LUMO being located
on the azomethine carbon forming a nitrogen-centered
radical.
Trapping of such an open-shell intermediate would pro-
vide strong support for a radical cyclization. On the basis of
this assumption and to provide further evidence that a free
radical intermediate is generated during the SnAP reaction,
radical clock experiments aimed at trapping the proposed
nitrogen-centered radical were conducted. With the knowl-
edge that the addition of N-centered radicals onto alkenes
in general is relatively slow, fragmentations that produce a
relatively stable imine -bond were investigated over the
addition of N-centered radicals onto olefins.12 To make sure
that our radical indicator reactions are fast enough to com-
pete with processes that intercept the proposed intermedi-
ates, an SnAP reagent for nitrogen radical fragmentation
with known fast kinetics was designed.13
10
ca. 6% with 93%d
a Reactions were conducted on a 0.15 mmol scale at 23 °C for 8 h in
CH2Cl2–HFIP (4:1, 0.05 M).
b NMR yields and conversion (conv.) from 1H NMR spectroscopic measure-
ments of unpurified reaction mixtures with 1,3,5-trimethoxybenzene as an
additional internal standard added after the reaction.
c Standard SnAP conditions.
d Imine hydrolysis as a side reaction.
e Slow addition over 8 h.
Cu(OTf)2 afforded some product (entries 7–10). Although
Cu(OTf)2 is known to be a source of slowly released TfOH in
certain protic reaction media, there seems to be no correla-
tion between the addition of TfOH at the beginning of the
reaction or over the course of it (entries 8–10). This indi-
cates that, although some product formation through a H+-
mediated mechanism could occur, on the basis of our cur-
rent understanding we exclude polar mechanisms as the
principal source of product formation.
Excluding a Lewis or Brønsted acid-mediated mecha-
nism, we started looking more closely into the idea of
Cu(OTf)2 acting as an oxidant, as proposed in the seminal
SnAP publication.2a The main side product isolated seems to
arise from intermediates in which the C–Sn bond was oxi-
dized to give an oxonium (Scheme 3). A free radical inter-
mediate, which could arise through direct C–Sn bond oxida-
tion or the disproportionation of in situ formed organo–
copper intermediate after transmetalation (rather than the
involvement of a polar two-electron species), was further
supported through the loss of stereochemical information
in reactions using -bis substituted SnAP reagents. Racemic
SnAP reagents bearing both a heteroatom and an alkyl sub-
stituent next to the organostannane group undergo stereo-
convergent cyclizations in combination with enantiopure
The unsubstituted cyclopropane analogue was synthe-
sized in a short reaction sequence (Scheme 4). Starting
from 1-amino-1-cyclopropane carboxylic acid, reduction,
nitrogen protection, alkylation, and deprotection provided
radical clock SnAP morpholine 14. To examine our hypothe-
sis, an imine formed from the radical clock SnAP reagent
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D
M. U. Luescher, J. W. Bode
Letter
Synlett
demonstrates for the first time that the proposed nucleop-
hilic -heteroatom-stabilized radical preferentially reacts in
a 6-endo-trig manner with a C=N double bond affording a
stabilized nitrogen-centered radical which is preferred over
the 5-exo-trig or 6-endo-trig addition onto an alkene. This
is also observed for the preparation of medium-sized N-
heterocycles with use of SnAP 3-Vinyl OA 24 by the 7-endo-
trig addition onto an imine which is preferred over the 5-
exo-trig or 6-endo-trig addition onto an internal alkene
(Scheme 6, b).
OH
OH
COOH
NH2
NaBH4, I2
Tr-Cl, Et3N
Bu3SnCH2I, NaH
DMF, 0 °C
THF, reflux
quant.
DMF, r.t.
75%
NH2
NH
C(Ph)3
10
11
12
O
SnBu3
O
SnBu3
AcOH, TFE
NH
NH2
CH2Cl2, r.t.
58% over two steps
C(Ph)3
14
13
radical clock SnAP M
The structure of cis-2,6-disubstituted morpholine 15
was confirmed in a short reaction sequence by using 2-
aminobutanol 26 (Scheme 6, c). By using a reported O-
stannylmethylation procedure of -disubstituted aminoal-
cohols,15b SnAP 3-Et M 27 reagent was prepared in one step
(Scheme 6, c). With use of the same cyclization conditions
as in the radical clock experiment, cis-2,6-disubstituted
morpholine 15 was obtained in 82%, confirming the struc-
ture of the ring-opened product isolated from the radical
clock experiment.
Finally, additional control experiments were performed
to confirm that the ring-opened products are the direct re-
sults of a radical cyclization and subsequent cyclopropane
fragmentation and test the stability of the cyclopropane
scaffold under the reaction conditions applied (Scheme 7).
Destannylated starting material and side products aris-
ing from C–Sn bond oxidation were detected, but no ring-
opened products were observed when the radical clock
SnAP 14 was subjected to the standard cyclization condi-
tions without prior imine formation (Scheme 7, a). Substi-
tuting the labile Bu3Sn group in SnAP 14 to remove a poten-
tial source of unwanted side reactions and focus on the
Scheme 4 Preparation of radical clock SnAP reagent
was employed under standard SnAP cyclization conditions.
As ring opening of the cyclopropane would afford unstable
imine products, NaBH4 reduction was performed on the
crude material. Subsequent detection and isolation of ring-
opened products arising from either reduction 15 or oxida-
tion 16 of the intermediate ring-opened radical reinforce
the proposal of an open-shell SnAP cyclization (Scheme 5).
The structures of the isolated products were confirmed
by their independent preparation (Scheme 6). The amino
alcohol required for the synthesis of the vinyl SnAP reagent
23 was obtained through a diastereoselective addition of
vinylmagnesium bromide to N-sulfinyl imine 1814 followed
by simultaneous amine and alcohol deprotection. Cycliza-
tion using SnAP morpholine reagent 23 under the same
conditions as in the radical clock experiment afforded cis-
2,6-disubstituted morpholine 16, confirming the structure
of the ring-opened product isolated from the radical clock
experiment (Scheme 6, a). Furthermore, SnAP 3-Vinyl M 23
Cu(OTf)2 (1.0 equiv)
2,6-lutidine (1.0 equiv)
H
O
SnBu3
O
N
SnBu3
O
N
O
N
3 Å MS
NO2
Me
O
NO2
Me
NO2
Me
NO2
Me
NH2
CH2Cl2, r.t.
CH2Cl2–HFIP, r.t.
14
radical clock SnAP M
O
O
N
No cyclized product with intact cyclopropyl detected
Structures confirmed by independent synthesis
Yields refer to isolated material
+ e + H
NaBH4
NO2
NO2
Me
N
H
Me
Me
Me
15
ca. 3%
O
O
N
NaBH4
– e – H
NO2
Me
NO2
Me
N
H
16
10%
Scheme 5 Radical clock SnAP reaction to detect nitrogen-centered radicals upon successful cyclization
Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–G

E
M. U. Luescher, J. W. Bode
Letter
Synlett
O
S
O
S
O
S
a)
t-Bu
t-Bu
NH2
OH
t-Bu
O
N
NH
NH2 • HCl
PPTS (cat.), MgSO4
MgBr
Tr-Cl, Et3N
NaH, Bu3SnCH2I
DMF, 0 °C, 3 h
HCl
H
H
NH
PhH, –78 °C
MeOH, r.t.
DMF, r.t.
CH2Cl2, r.t.
75%
OPMB
OPMB
OPMB
OH
C(Ph)3
97%, dr ≥ 20:1
79% over two steps
17
18
19
20
21
b)
1) RCHO
1) RCHO
2) Cu(OTf)2,
2,6-lutidine
2) Cu(OTf)2,
O
SnBu3
O
SnBu3
O
O
O
AcOH, TFE
2,6-lutidine
SnBu3
NO2
Me
N
NH
NH2
N
H
NH2
NH
N
CH2Cl2, r.t.
76%, dr ≥ 20:1
48%, dr ≥ 20:1
N
C(Ph)3 44% over two steps
24
22
23
SnAP 3-Vinyl M
16
25
SnAP 3-Vinyl OA
7 steps (40% overall) a
c)
3 New SnAP reagents
1) RCHO
OH
O
SnBu3
2) Cu(OTf)2,
Cyclization products are idential to isolated materials
in the radical clock experiments
O
2,6-lutidine
NaH, Bu3SnCH2I
NH2
NO2
Me
NH2
6- And 7-endo-trig cyclization onto imine preferred over 5-exo-
or 6-endo-trig cyclization onto olefins
N
H
DMF, 0 °C, 3 h
82%, dr ≥ 20:1
Me
Me
Me
88%
26
27
SnAP 3-Et M
15
Scheme 6 Preparation of radical clock SnAP products by using alkyl- and alkenyl-SnAP reagents. a See Supporting Information for the preparation of
SnAP 3-Vinyl OA 24
a) Radical clock SnAP reagent stability test
was observed by using 29 either as the imine or as the sec-
ondary amine after imine reduction, again supporting our
proposal of a radical-based SnAP cyclization.
Cu(OTf)2 (1.0 equiv)
2,6-lutidine (1.0 equiv)
O
SnBu3
no ring-opened products detected!
NH2
CH2Cl2–HFIP, r.t.
Considering the above results and the additional prop-
erties of HFIP to assist in intermolecular electron-transfer
reactions through stabilization of radical cations, which ex-
tends their lifetime and facilitates subsequent fragmenta-
tions,16 through an HFIP nucleophile-assisted cleavage of a
stannane radical cation,17 also seen in organosilane-cation
radicals,18 strong support is found for the current proposal
of a radical cyclization using SnAP reagents (Scheme 2, b).
The fact that little conversion is observed without the addi-
tion of HFIP2a and the finding that Bu3Sn–OCH(CF3)2 4 is
formed in a 1:1 ratio to the desired N-heterocycle2e further
reinforce this mechanistic proposal, which might also be
driven by the formation of the thermodynamically strong
Sn–O bond (ca. 550 kJ mol–1) vs. Sn–C (ca. 235 kj mol–1) that
could facilitate fragmentation.19
14
b) Radical clock SnAP analogue stability test
OH
O
Me
AcOH, TFE
O
Me
RCHO, 3 Å MS
ethyl iodide, NaH
DMF, 0 °C
NH
NH
NH2
CH2Cl2, r.t.
36%
CH2Cl2, r.t.
72%
C(Ph)3
C(Ph)3
12
28
29
volatile
O
N
Me
Cu(OTf)2, 2,6-lutidine, CH2Cl2–HFIP, r.t.
or 1) NaBH4, MeOH
NO2
Me
2) Cu(OTf)2, 2,6-lutidine, CH2Cl2–HFIP, r.t.
In conclusion, several observations documented in
these studies are consistent with the initial mechanistic
proposal of the SnAP protocol as a radical-based method.20
As Cu(OTf)2 is known to be a source of triflic acid, investiga-
tions on the role of a Brønsted acid-mediated mechanism
allowed us to exclude this, as well as a Lewis acid-mediated
process. Taken together, the further evidence of the radical-
based nature of SnAP chemistry will guide ongoing efforts
to develop new variants and selective catalysts.
no ring-opened products detected!
Scheme 7 Cyclopropane imine stability studies under SnAP cyclization
conditions. These results demonstrate that SnAP reactions are not in-
duced by redox reactions of the imine.
stability of the imine and secondary amine of potential
(ethoxymethyl)cyclopropanamine
prepared (Scheme 7, b). No cyclopropane fragmentation
product,
29
was
Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–G

F
M. U. Luescher, J. W. Bode
Letter
Synlett
Funding Information
(15) (a) Luescher, M. U.; Jindakun, C.; Bode, J. W. Org. Synth. 2018, 95,
345. (b) Luescher, M. U.; Jindakun, C.; Bode, J. W. Org. Synth.
2018, 95, 357.
(16) (a) Yoshida, J.-I.; Kataoka, K.; Horcajada, R.; Nagaki, A. Chem.
Rev. 2008, 108, 2265. (b) Yoshida, J.-I.; Izawa, M. J. Am. Chem.
Soc. 1997, 119, 9361. (c) Eberson, L.; Hartshorn, M. P.; Persson,
O.; Radner, F. Chem. Commun. 1996, 2105.
This work was supported by the European Research Council (ERC
Starting Grant No. 306793-CASAA).
E
uro
p
e
a
n
R
esearc
h
C
o
u
n
c
i
l(3
0
6
7
9
3-C
A
S
A
A)
Acknowledgment
(17) Luo, P.; Dinnocenzo, J. P. J. Org. Chem. 2015, 80, 9240.
(18) Dockery, K. P.; Dinnocenzo, J. P.; Farid, S.; Goodman, J. L.; Gould,
I. R.; Todd, W. P. J. Am. Chem. Soc. 1997, 119, 1876.
We thank the MS Service and NMR Service of the Laboratory of
Organic Chemistry at ETH Zurich for analysis.
(19) Dean, J. A. In Lange’s Handbook of Chemistry; McGraw-Hill: New
York, 1999, 15th ed., 4.41–4.53.
(20) General Procedure SnAP Protocol
Supporting Information
Imine formation: To a solution of the SnAP reagent (0.50
mmol, 1.00 equiv) in CH2Cl2 or acetonitrile (3.0 mL) at r.t. was
added the corresponding aldehyde (0.50 mmol, 1.00 equiv) and
3 Å or 4 Å MS powder (ca. 50 mg). The reaction mixture was
stirred at r.t. for 4 h and filtered through a short layer of Celite
(CH2Cl2 rinse). The filtrate was concentrated under reduced
pressure to afford the pure air-stable imine that was used in the
next step without further purification.
SnAP cyclization: Separately, anhydrous Cu(OTf)2 (0.50 mmol,
1.00 equiv) was suspended in CH2Cl2–HFIP (3:1; 8.0 mL). 2,6-
Lutidine (0.50 mmol, 1.00 equiv) was added and the resulting
bluish suspension was stirred at r.t. for 1 h to afford a dark green
suspension. A solution of the imine (0.50 mmol, 1.00 equiv) in
CH2Cl2 (2.0 mL) was added in one portion and the resulting
mixture was stirred at r.t. for 12 h. The reaction mixture was
diluted with CH2Cl2 (20 mL), treated with a solution of 12% aq
NH4OH and brine (1:1, 20 mL), and stirred vigorously for 20 min
at r.t. The layers were separated, and the aqueous layer was
extracted with CH2Cl2 (2 x 5 mL). The combined organic layers
were washed with H2O (2 x 5 mL) and brine (10 mL), dried with
anhydrous Na2SO4, filtered, and concentrated. Purification by
flash column chromatography afforded the desired C-substi-
tuted unprotected morpholines.
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1611670.
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References and Notes
(1) Present address: Michael. U. Luescher, Department of Chemis-
try and Chemical Biology (CCB), Harvard University, Cambridge,
MA 02138, United States of America
(2) (a) Vo, C.-V. T.; Mikutis, G.; Bode, J. W. Angew. Chem. Int. Ed.
2013, 52, 1705. (b) Luescher, M. U.; Vo, C.-V. T.; Bode, J. W. Org.
Lett. 2014, 16, 1236. (c) Vo, C.-V. T.; Luescher, M. U.; Bode, J. W.
Nat. Chem. 2014, 6, 310. (d) Geoghegan, K.; Bode, J. W. Org. Lett.
2015, 17, 1934. (e) Luescher, M. U.; Bode, J. W. Angew. Chem. Int.
Ed. 2015, 54, 10884. (f) Luescher, M. U.; Bode, J. W. Org. Lett.
2016, 18, 2652.
(3) Hideto, M.; Ueda, M.; Naito, T. Synlett 2004, 1140.
(4) Jindakun, C.; Hsieh, S.-Y.; Bode, J. W. Org. Lett. 2018, 20, 2071.
(5) Paderes, M. C.; Belding, L.; Fanovic, B.; Dudding, T.; Keister, J. B.;
Chemler, S. R. Chem. Eur. J. 2012, 18, 1711.
(6) Vogler, T.; Studer, A. Synthesis 2008, 1979.
(7) Michel, C.; Belanzoni, P.; Gamez, P.; Reedjik, J.; Baerends, E. J.
Inorg. Chem. 2009, 48, 11909.
Spectral Data for Selected Compounds
(8) (a) Youn, S. W.; Jang, S. S.; Lee, S. R. Tetrahedron 2016, 72, 4902.
(b) Dang, T. T.; Boeck, F.; Hintermann, L. J. Org. Chem. 2011, 76,
9353. (c) Tschan, M. J.-L.; Thomas, C. M.; Strub, H.; Carpentier,
J.-F. Adv. Synth. Catal. 2009, 351, 2496. (d) Wabnitz, T. C.; Yu,
J.-Q.; Spencer, J. B. Chem. Eur. J. 2004, 10, 484.
3-(4-(Trifluoromethyl)phenyl)morpholine (7): Yield: 98.5 mg
(86%); clear colorless oil; IR (thin film): 3313, 3068, 2961, 2912,
2889, 2852, 1676, 1603, 1584, 1398, 1365, 1335, 1232, 1105
cm–1 1H NMR (400 MHz, CDCl3):  = 7.59 (d, J = 8.2 Hz, 2 H),
;
7.52 (d, J = 8.2 Hz, 2 H), 3.99 (dd, J = 10.0, 3.2 Hz, 1 H), 3.93–3.85
(m, 1 H), 3.81 (dd, J = 11.1, 3.2 Hz, 1 H), 3.65 (td, J = 11.1, 2.7 Hz,
1 H), 3.35 (dd, J = 11.1, 10.0 Hz, 1 H), 3.14 (td, J = 11.6, 3.3 Hz, 1
H), 3.01 (dt, J = 11.8, 2.0 Hz, 1 H), 1.90 (br s, NH); 13C NMR (100
MHz, CDCl3):  = 144.7 (q, JCF = 1.40 Hz), 130.1 (q, JCF = 32.4 Hz),
127.7, 125.6 (q, JCF = 3.72 Hz), 124.2 (q, JCF = 272.2 Hz), 73.6,
67.4, 60.3, 46.5; Rf = 0.18 (hexanes/EtOAc 1:1); ESI-HRMS: m/z
[M + H] calcd for C11H13F3N1O1: 232.0944; found: 232.0946.
(9) Brown, H. C.; Kanner, B. J. Am. Chem. Soc. 1966, 88, 986.
(10) Luo, P.; Dinnocenzo, J. P. J. Org. Chem. 2015, 80, 9240.
(11) (a) Yoshida, J.-I.; Kataoka, K.; Horcajada, R.; Nagaki, A. Chem.
Rev. 2008, 108, 2265. (b) Glass, R. S.; Radspinner, A. M.; Singh,
W. P. Tetrahedron 1992, 114, 4921. (c) Yoshida, J.-I.; Ishichi, Y.;
Nishiwaki, K.; Shiozawa, S.; Isoe, S. Tetrahedron Lett. 1992, 33,
2599. (d) Yoshida, J.-I.; Maekawa, T.; Murata, T.; Matsunaga, S.-I.;
Isoe, S. J. Am. Chem. Soc. 1990, 112, 1962.
(±)–cis-3-Ethyl-5-(4-methyl-3-nitrophenyl)
morpholine
(12) Musa, O. M.; Horner, J. H.; Shahin, H.; Newcomb, M. J. Am. Chem.
Soc. 1996, 118, 3862.
(15): Yield: 102 mg (82%, d.r. > 20:1); colorless oil; IR (thin
film): 2963, 2932, 2878, 2848, 1528, 1454, 1349, 1105cm–1; H
1
(13) (a) Newcomb, M. Encyclopedia of Radicals in Chemistry, Biology
and Materials; Vol. 1; Chatgilialoglu, C.; Studer, A., Eds.; Wiley:
Chichester, UK, 2012, 107–124. (b) Beckwith, A. L. J.; Bowry, V.
W. J. Am. Chem. Soc. 1994, 116, 2710. (c) Newcomb, M. Tetrahe-
dron 1993, 49, 1151. (d) Griller, D.; Ingold, K. U. Acc. Chem. Res.
1980, 13, 317.
(14) (a) Chen, Y.; Goldberg, F. W.; Xiong, J.; Wang, S. Synthesis 2015,
47, 679. (b) Crimmins, M. T.; Shamszad, M. Org. Lett. 2007, 9,
149. (c) Barrow, J. C.; Ngo, P. L.; Pellicore, J. M.; Selnick, H. G.;
Nantermet, P. G. Tetrahedron Lett. 2001, 42, 2051. (d) Tang, T. P.;
Volkman, S. K.; Ellman, J. A. J. Org. Chem. 2001, 66, 8772.
NMR (400 MHz, CDCl3):  = 8.03 (d, J = 1.8 Hz, 1 H), 7.52 (dd, J =
7.9, 1.8 Hz, 1 H), 7.29 (d, J = 7.9 Hz, 1 H), 4.01 (dd, J = 10.2, 3.2
Hz, 1 H), 3.84 (dd, J = 10.9, 3.0 Hz, 1 H), 3.78 (dd, J = 11.0, 3.2 Hz,
1 H), 3.28–3.14 (m, 2 H), 2.96–2.85 (m, 1 H), 2.56 (s, 3 H), 1.89
(br s, NH), 1.50–1.27 (m, 2 H), 0.94 (t, J = 7.5 Hz, 3 H); 13C NMR
(100 MHz, CDCl3):  = 149.5, 147.4, 140.3, 132.9, 132.7, 132.0,
123.4, 73.2, 72.0, 59.7, 56.8, 25.5, 20.2, 10.1; Rf = 0.30 (hex-
anes/EtOAc 1:1); ESI-HRMS: m/z [M + H]+ calcd for C13H19N2O3:
251.1390; found: 251.1394.
Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–G

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M. U. Luescher, J. W. Bode
Letter
Synlett
(3S,5R)-3-(4-Methyl-3-nitrophenyl)-5-vinylmorpholine (16):
(±)-cis-3-[4-(1H-1,2,4-Triazol-1-yl)phenyl]-6-vinyl-1,4-oxaz-
epane (25): Yield: 64.5 mg (48%, d.r. > 20:1); colorless oil; IR
(thin film): 3433, 2938, 2857, 1638, 1522, 1280, 1144, 983, 836
cm–1; 1H NMR (400 MHz, CDCl3):  = 8.53 (s, 1 H), 8.09 (s, 1 H),
7.63 (d, J = 8.5 Hz, 2 H), 7.51 (d, J = 8.5 Hz, 2 H), 5.91 (ddd, J =
17.3, 10.5, 8.1 Hz, 1 H), 5.14–5.00 (m, 2 H), 4.13–3.97 (m, 3 H),
3.56 (dd, J = 12.4, 9.6 Hz, 1 H), 3.43 (dd, J = 13.0, 10.5 Hz, 1 H),
3.24 (dd, J = 13.9, 4.9 Hz, 1 H), 3.12 (dd, J = 13.9, 3.5 Hz, 1 H),
2.77–2.66 (m, 1 H), 2.09 (br s, NH); 13C NMR (100 MHz, CDCl3): 
= 152.7, 141.6, 141.0, 138.8, 136.4, 128.6, 120.3, 115.6, 80.6,
75.5, 66.3, 51.9, 47.2; Rf = 0.21 (hexanes/EtOAc 2:1); mp = 70–
72 °C; ESI-HRMS: m/z [M + H]+ calcd for C14H19N4O1: 271.1553;
found: 271.1558.
Yield: 94.4 mg (76%, d.r. > 20:1); colorless oil; IR (thin film):
2988, 2849, 1738, 1528, 1275, 1261, 1102 cm–1 1H NMR (400
;
MHz, CDCl3):  = 8.06 (d, J = 1.8 Hz, 1 H), 7.55 (dd, J = 7.9, 1.8 Hz,
1 H), 7.30 (d, J = 7.9 Hz, 1 H), 5.77 (ddd, J = 17.3, 10.4, 6.8 Hz, 1
H), 5.35 (dt, J = 17.3, 1.4 Hz, 1 H), 5.23–5.12 (m, 1 H), 4.07 (dd,
J = 10.2, 3.2 Hz, 1 H), 3.81 (td, J = 10.4, 3.2 Hz, 2 H), 3.65–3.50
(m, 1 H), 3.33–3.19 (m, 2 H), 2.58 (s, 3H), 1.93 (br s, NH); 13C
NMR (100 MHz, CDCl3):  = 149.5, 140.1, 136.5, 133.1, 133.0,
132.0, 123.5, 117.6, 72.9, 71.3, 59.2, 58.6, 20.3; Rf = 0.68 (hex-
anes/EtOAc 1:1); ESI-HRMS: m/z [M + H]+ calcd for C13H17N2O3:
249.1234; found: 249.1231.
Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–G