SnAP reagents for the transformation of aldehydes into substituted thiomorpholines - An alternative to cross-coupling with saturated heterocycles

Article abstract of DOI:10.1002/anie.201208064

It's a SnAP! The transformation of aldehydes into N-unsubstituted 3-thiomorpholines provides a convenient alternative to metal-catalyzed cross-coupling reactions, which are generally unsuited to the functionalization of saturated N-heterocycles. A copper-mediated radical cyclization is the key to the mild conditions, high functional group tolerance, and broad substrate scope offered by these reagents. Copyright

Full text of DOI:10.1002/anie.201208064

Angewandte
Chemie
DOI: 10.1002/anie.201208064
Saturated Heterocycles
SnAP Reagents for the Transformation of Aldehydes into Substituted
Thiomorpholines—An Alternative to Cross-Coupling with Saturated
Heterocycles**
Cam-Van T. Vo, Gediminas Mikutis, and Jeffrey W. Bode*
Saturated N-heterocycles are increasingly common scaffolds
for the discovery and development of biologically active small
molecules.[1] Unlike their aromatic counterparts, they cannot
be easily appended to a substrate by cross-coupling reactions.
The most reliable method for constructing 2-aryl piperidines
and pyrrolidines is an effective but laborious lithiation,
transmetallation, and Pd-catalyzed cross-coupling.[2] Unfortu-
nately, this method is not well-suited for cross-coupling
morpholines, thiomorpholines, or piperazines. Researchers
have therefore sought to identify new synthetic methods for
the preparation of substituted, saturated N-heterocycles by
ꢀ
C H functionalization. For example, the groups of Naka-
mura,[3] Sames,[4] MacMillan,[5] Maulide,[6] and others[7] have
reported a-arylation of N-heterocycles, but these reactions
require N-aryl substituents that are difficult to remove or
further elaborate.
Herein, we disclose SnAP reagents for the facile con-
version of aldehydes into N-unprotected, 3-thiomorpholines
(Figure 1). This strategy has the potential to be a general
approach to installing saturated heterocycles using aldehydes
as a synthetic handle. Its successful execution relies on the use
of radical chemistry to overcome a long-standing challenge in
ꢀ
organic synthesis: C C bond-forming addition to unactivated
primary imines.[8]
At the outset of our studies, we established two key design
parameters for reaction development. First, we required that
our approach deliver N-unprotected heterocycles directly
from the reaction. Second, we wanted the N-heterocycle
substituents to be derived from a stable, widely available
functional group, ideally halide, aldehyde, or organoboronic
acid. After several unsuccessful attempts, our studies led us to
Figure 1. Approaches to cross-coupling with saturated heterocycles.
Boc=tert-butoxycarbonyl, Fg=functional group.
ꢀ
an unusual approach: intramolecular C C bond-forming
radical cyclization of an imine bearing a pendant nucleophilic
carbon.
For our initial studies, we selected the preparation of
3-substituted thiomorpholines from aldehydes, as there are
presently very few methods for their synthesis.[9] Amino
tributylstannane 1 (SnAP-TM)[10] is readily obtained in one
step by S-alkylation of 2-aminoethanethiol with commercially
available tributyl(iodomethyl)-stannane.[11] Condensation
with an aldehyde gives the corresponding imine, which we
endeavored to cyclize to give N-unprotected 3-thiomorpho-
lines. The poor electrophilicity of this imine, which lacks
either the N-sulfonyl or N-aryl group typically found in imine
electrophiles, presented numerous challenges. Initial attempts
with stannane–lithium exchange or Lewis acid induced
cyclization proved unsuccessful (Table 1, entry 1). Inspired
by reports from the group of Kagoshima on the intermolec-
ular addition of organostannanes to N-phenyl or N-para-
methoxyphenyl imines using stoichiometric Cu(OTf)2,[12] we
[*] C.-V. T. Vo, G. Mikutis, Prof. Dr. J. W. Bode
Laboratorium fꢀr Organische Chemie, Department of Chemistry
and Applied Biosciences, ETH Zꢀrich
Wolfgang Pauli Strasse 10, 8093 Zꢀrich (Switzerland)
E-mail: bode@org.chem.ethz.ch
Homepage: http://www.bode.ethz.ch
[**] This work was supported by an ETH Research Grant (ETH-12 11-1).
We are grateful to Drs. Xiangyang Zhang and Bernd Schweizer of
ETH (Zꢀrich) for mass spectrometry and for X-ray crystallographic
structural determination. SnAP=tin (Sn) amine protocol.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201208064.
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Table 1: Optimization of reaction conditions.[13]
Entry[a] Solvent
Additive
T [8C] Yield[b] [%]
1
2
3
4
5
6
7
8
THF
nBuLi
–
–
–
0!RT
RT
60
95
60
0
ClC2H4Cl
ClC2H4Cl
toluene
HFIP
ClC2H4Cl
tBuOH
NR
35
44
55
33
15
trace
65
38
75
74
76
–
HCl
KHCO3
60
60
1:1 ClC2H4Cl/HFIP 1,10-phenanthroline 60
1:1 ClC2H4Cl/HFIP 2,6-di-tBu-pyridine
1:1 ClC2H4Cl/HFIP pyridine
1:1 ClC2H4Cl/HFIP 2,6-lutidine
4:1 ClC2H4Cl/HFIP 2,6-lutidine
4:1 CH2Cl2/HFIP
9
60
60
60
60
RT
10
11
12[c]
13
2,6-lutidine
[a] All reactions were performed on a 0.05 mmol scale by adding
a solution of 2a into a mixture of Cu(OTf)2 (0.05 mmol), additive
(0.05 mmol), and CaSO4 in the solvent (0.05m) and stirring for 12 h.
[b] Yield determined by 1H NMR spectroscopy with benzyl methyl ether
as an internal standard. [c] Reaction performed at 608C for 2 h.
HFIP=hexafluoroisopropyl alcohol, NR=no reaction.
examined the cyclization of imine 2a under these conditions.
At room temperature, no cyclization product was detected
(Table 1, entry 2), but at 608C a small amount of the desired
product was obtained (Table 1, entry 3). Further optimization
of the conditions was unproductive until we found that
hexafluoroisopropyl alcohol (HFIP) significantly improved
the yield (55% yield) and diminished the formation of side
products (Table 1, entry 5). Other polar solvents (MeOH,
tBuOH) failed to give similar improvement and we attributed
the beneficial effects of HFIP to activation of the imine by
protonation. Anhydrous conditions, which deterred imine
hydrolysis, could be conveniently achieved by the addition of
anhydrous CaSO4 to the reaction mixture. To further improve
the reactivity, monodentate and bidentate ligands for copper,
including 1,10-phenanthroline, 2,6-di-tert-butylpyridine, 2,6-
lutidine, and pyridine were tested, with 2,6-lutidine offering
the best results (Table 1, entry 11). Using this ligand in
a mixture of HFIP and CH2Cl2 or ClC2H4Cl as solvent, the
cyclization was complete after 2 h at 608C or 12 h at room
temperature (Table 1, entry 12–13).
Scheme 1. Conversion of aldehydes into thiomorpholines with SnAP-
TM. All reactions were performed on a 0.50 mmol scale with Cu(OTf)2
(0.50 mmol), 2,6-lutidine (0.50 mmol), and CaSO4 at RT for 12 h.
Yields shown are of isolated, analytically pure products following
column chromatography. [a] reactions performed in 4:1 ClC2H4Cl/HFIP
at 608C for 2 h. MS=molecular sieves.
unbranched aliphatic aldehydes were observed, but in lower
yields, presumably owing to facile enamine formation.
We also investigated the more substituted SnAP reagents
4 and 5, prepared from rac-cysteine ethyl ester and rac-
penicillinamine methyl ester, respectively. Under the stan-
dard conditions, these reagents coupled with representative
aldehydes to give the more substituted thiomorpholines 6a–d
in good yields and high diastereoselectivity (Figure 2). The cis
relative stereochemistry was confirmed by X-ray crystallo-
graphic analysis of 6a. We presently ascribe the high
diastereoselectivities observed in these cases to equilibration
of an initially formed diastereomeric mixture to the thermo-
dynamically favored cis product. Further studies of this
process, including the use of enantiopure starting materials
and efforts to modulate the diastereoselectivity are ongoing.
Kagoshima et al. proposed a role for the CuII as a Lewis
acid in the the nucleophilic addition of a-thioalkyl stannanes
With the optimized reaction conditions in hand, we
explored the transformation of various aldehydes into
N-unprotected
3-thiomorpholines
with
SnAP-TM
1 (Scheme 1). This occurred smoothly with a broad scope of
aldehydes (aryl, heteroaryl, and alkyl aldehydes). Both
electron-poor and electron-rich substituents on aryl rings
gave good yields. Functional groups, including organohalides,
protected alcohols, amines, and esters, were tolerated under
the reaction conditions. The reactions succeeded with meta-
or para-heteroaryl substrates, but failed with ortho-heteroaryl
aldehydes. Imines prepared from pivalaldehyde, isobutyral-
dehyde, glyoxal, and chloral also afforded thiomorpholine
products in good to moderate yields. Products from
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Scheme 3. Proposed mechanism for copper-mediated cyclization.
prior studies on ring closures of imines with pendant vinyl and
aryl radicals.[15]
Figure 2. SnAP reagents for the synthesis of functionalized thiomor-
pholines. The d.r. was determined by 1H NMR analysis of unpurified
reaction mixtures. [a] The diastereomers could be separated by flash
column chromatography.
The reaction of carbon radicals with imines may be
related to the recent work of Molander et al.[16] and Baran
et al.[17] on oxidative C C bond formation between aromatic
ꢀ
N-heterocycles and radicals generated from organoboronic
acids or their derivatives. In these transformations, a stoichio-
metric amount of oxidant is needed to reform the aromatic
ring. In principle, our cyclization should be catalytic in CuII,
but we believe that the coordination of the unprotected
thiomorpholine product to the CuII leads to catalyst inhib-
ition. The addition of sacrificial metal salts that can exchange
the bound copper make possible the use of substoichiometric
amounts of Cu(OTf)2, but currently with poor turnover.
Efforts to render this cyclization catalytic and to employ
chiral ligands are ongoing. The similarities between this
cyclization and the coupling of organoboronic acids with
heteroaromatic compounds also suggest that organoboranes
or organosilanes could serve as surrogates for the organo-
stannanes in SnAP reagents.
to N-phenyl or N-para-methoxyphenyl imines.[12] We were
therefore surprised that 2-pyridylaldehyde and related sub-
strates, which should chelate CuII, showed poor reactivity
(Scheme 2a). Likewise, other metal salts and Lewis acids,
including Zn(OTf)2 and BF3·OEt2, failed to promote cycliza-
tion. These results led us to postulate an alternative mech-
In conclusion, we have developed SnAP reagents for the
transformation of aldehydes into N-unprotected 3-thiomor-
pholines. The use of a radical cyclization overcomes the long-
standing problem of the poor electrophilicity of unactivated
imines. This method is effective on a wide range of aldehydes,
including electron-rich and electron-poor aryl, heteroaryl,
and alkyl aldehydes, as well as glyoxylates. We anticipate that
this strategy will be rapidly extended to a family of SnAP
reagents for generating other N-unprotected saturated het-
erocycles, including morpholines, piperazines, and diaze-
panes. The ease of execution, mild reaction conditions, and
functional group tolerance mirror the convenience of metal-
catalyzed cross-coupling reactions, and provides access to
saturated N-heterocycles not currently accessible by tradi-
tional methods.
Scheme 2. Experiments supporting a role for Cu(OTf)2 as an oxidant
rather than as a Lewis acid.
anism. Organostannanes are well-known to form carbon-
centered radicals under oxidative conditions,[14] thus suggest-
ing a mechanism in which CuII acts as an oxidant. To test this
hypothesis, TEMPO (1.5 equiv) was added into reaction. No
cyclization product was obtained and trapped compound 8
was observed. The reduction of 8 to amine 9 allowed us to
isolate and characterize this adduct (Scheme 2b).
On the basis of these results, we proposed a mechanism
for cyclization that features the generation and cyclization of
a carbon radical (Scheme 3). Iminotributylstannane I under-
goes protonation and one-electron oxidation with Cu(OTf)2,
leading to the formation of CuI and radical cation II. The
a-thio radical II cyclizes with the intramolecular imine to
form radical cation III, which is reduced by CuI to generate
copper(II) complex IV. The observed 6-endo cyclization,
rather than the competing 5-exo cyclization, is consistent with
Experimental Section
To a solution of the SnAP-TM reagent 1 (0.50 mmol, 1.00 equiv) in
CH2Cl2 (2.5 mL, 0.25m) was added aldehyde (0.50 mmol, 1.00 equiv)
and 4 ꢀ molecular sieves. The reaction mixture was stirred at RT for
2 h, filtered through a layer of celite and concentrated under reduced
pressure to provide imine 2. Separately, Cu(OTf)2 (0.50 mmol,
1.00 mmol) was added to a solution of 2,6-lutidine (0.50 mmol,
1.00 equiv) in HFIP (2 mL) and stirred at RT for 1 h. CaSO4 (50 mg)
was added to the reaction mixture, followed by imine 2 in CH2Cl2
(8 mL), and stirred at RT for 12 h. The reaction was quenched with
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sat. aq. NaHCO3 (5 mL), followed by 10% aq. NH4OH (3 mL) and
stirred vigorously for 15 min. The mixture was extracted with CH2Cl2
(3 ꢁ 30 mL), washed with H2O (3 ꢁ 30 mL) and brine, dried over
Na2SO4, filtered, and concentrated. Purification by flash column
chromatography (0.1% NEt3 was added to the mobile phase)
delivered the N-unprotected 3-thiomorpholine 3.
[6] I. D. Jurberg, B. Peng, E. Wçstefeld, M. Wasserloos, N. Maulide,
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Mitchell, A. Peschiulli, N. Lefevre, L. Meerpoel, B. U. W. Maes,
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Received: October 7, 2012
Published online: December 23, 2012
[9] Most existing methods for thiomorpholine synthesis require the
substituted 1,2-aminothiol as the starting material; for examples,
see: a) G. N. Ziakas, E. A. Rekka, A. M. Gavalas, P. T. Elefther-
iou, P. N. Kourounakis, Bioorg. Med. Chem. 2006, 14, 5616 –
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Keywords: aldehydes · cross-coupling · nitrogen heterocycles ·
radical reactions · thiomorpholines
.
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