Radical cyclizations of cyclic ene sulfonamides occur with β-elimination of sulfonyl radicals to form polycyclic imines

Article abstract of DOI:10.1021/ja408387d

Radical cyclizations of cyclic ene sulfonamides provide stable bicyclic and tricyclic aldimines and ketimines in good yields. Depending on the structure of the precursor, the cyclizations occur to provide fused and spirocyclic imines with five-, six-, and seven-membered rings. The initial radical cyclization produces an α-sulfonamidoyl radical that undergoes elimination to form the imine and a phenylsulfonyl radical. In a related method, 3,4-dihydroquinolines can also be produced by radical translocation reactions of N-(2- iodophenylsulfonyl)tetrahydroiso-quinolines. In either case, very stable sulfonamides are cleaved to form imines (rather than amines) under mild reductive conditions.

Full text of DOI:10.1021/ja408387d

Article
pubs.acs.org/JACS
Radical Cyclizations of Cyclic Ene Sulfonamides Occur with
β‑Elimination of Sulfonyl Radicals to Form Polycyclic Imines
Hanmo Zhang, E. Ben Hay, Steven J. Geib, and Dennis P. Curran*
Department of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, United States
S
* Supporting Information
ABSTRACT: Radical cyclizations of cyclic ene sulfonamides
provide stable bicyclic and tricyclic aldimines and ketimines in
good yields. Depending on the structure of the precursor, the
cyclizations occur to provide fused and spirocyclic imines with
five-, six-, and seven-membered rings. The initial radical
cyclization produces an α-sulfonamidoyl radical that undergoes
elimination to form the imine and a phenylsulfonyl radical. In a
related method, 3,4-dihydroquinolines can also be produced by radical translocation reactions of N-(2-iodophenylsulfonyl)-
tetrahydroiso-quinolines. In either case, very stable sulfonamides are cleaved to form imines (rather than amines) under mild
reductive conditions.
sulfonyl alkyl radicals in Figure 1a is commonly applied to make
alkenes from β-functionalized sulfones, allyl sulfones and
alkenyl sulfones.2 The example reaction from Zard is a typical
addition/fragmentation reaction of an allyl sulfone.3
INTRODUCTION
■
The quintessential reaction of β-sulfonyl radicals is fragmenta-
tion to form a sulfonyl radical and a multiple bond.1 Such β-
elimination reactions have broad synthetic utility. The radical
prior to fragmentation can be centered on either carbon or
nitrogen (Figure 1). For example, the elimination reaction of β-
Carbon−nitrogen double bonds can also be made by two
different kinds of sulfonyl radical eliminations. The elimination
of β-sulfonyl aminyl and related radicals has been developed by
Kim and others into a useful method to make assorted imines,
hydrazones and, as exemplified in Figure 1b, oximes.4
The reverse positioning of the sulfonyl group and the radical
(β-elimination of a sulfonyl group from an α-sulfonamidoyl
radical; Figure 1c) is less common and has a checkered history.
Often, this history involves reactions of N-alkenylsulfonamides,
hereafter called ene sulfonamides. In 1959, McKusick and co-
workers reported that the isomerization of ene sulfonamide 1 to
β-sulfonyl enamine 2 was induced by X-rays (Figure 2a).5 This
isomerization can also be triggered by photolysis or thermolysis
with AIBN, and studies supported a sulfonyl radical addition/
elimination mechanism.5c
More recently, Zard6 and Renaud7 have introduced trans-
formations based on carbon-radical additions to functionalized
ene-sulfonamides to make functionalized ketones or hetero-
cycles, depending on the associated functional groups. In an
example from Renaud7 (Figure 2b), treatment of in situ
generated catechol borane 3 (the radical precursor) with ene
sulfonamide 4 and di-t-butyl hydroperoxide (DTHP) gave α-
ketoester 5 in 20% overall yield from 1-octene (the precursor of
3).
Murphy has also observed that N-sulfonyl groups are lost in
several transformations.8For example, treatment of diazonium
ion 9 with tetrakisdimethylaminoethylene (TDAE) provided
indole 10 in 33% yield (Figure 2c) as one of several products.8b
Figure 1. Three classes of radicals that can undergo β-elimination of
sulfonyl radicals to make CC and CN bonds.
Received: August 13, 2013
Published: October 10, 2013
© 2013 American Chemical Society
16610
dx.doi.org/10.1021/ja408387d | J. Am. Chem. Soc. 2013, 135, 16610−16617

Journal of the American Chemical Society
Article
Figure 3. Tin hydride cyclizations of similar ene sulfonamides give
contrasting results.
some reactions combine to suggest that even if this elimination
does occur at times, it is not very efficient.
We now report that we have found strong evidence in the
search for evidence of β-sulfonyl radical eliminations from α-
sulfonamidoyl radicals. Specifically, we have isolated members
of a family of stable imines, the primary products of such
reactions, in good yields. The elimination has good synthetic
potential because a strong N−SO2Ar bond is cleaved under
mild conditions with concomitant ring formation. We also
introduce a radical translocation variant that has value as a new
deprotection reaction. Lastly, we revisit the contrasting results
of Cossy and Somfai to better understand whether β-sulfonyl
radical eliminations are involved.
Figure 2. Possible examples of sulfonyl radical eliminations to make
imine intermediates under nonreducing conditions.
All of the transformations in Figure 2 are multistep processes
that may or may not include sulfonyl radical elimination steps.
Take Renaud’s reaction (b), for example. Addition of the
radical derived from 3 to alkene 4 provides α-benzenesulfona-
midoyl radical 6. One sensible route to the product 5 is sulfonyl
radical elimination to an imine 7 followed by hydrolysis.
However, the conditions are oxidizing, so direct oxidation of 6
to a sulfonyl iminium ion 89 and then hydrolysis could provide
a path to the product 5 that does not involve sulfonyl radical
elimination.
The evidence for such sulfonyl radical eliminations under
reducing conditions is even less clear-cut, as shown by the two
examples in Figure 3.10 In an approach to (−)-kainic acid,
Cossy reported in 1999 that cyclization of enantiopure 11 with
tributyltin hydride unexpectedly provided imine 13 (Figure
3a).11 She had expected a cyclative hydrostannation to occur
starting with tin radical addition to the alkyne. The actual
product 13 was indeed cyclized, but it contained neither tin nor
the sulfonyl group. This, and Somfai’s result coming up in
Figure 3b, led Cossy to suggest that enamidyl radical 12 was the
key intermediate in this reaction.
RESULTS AND DISCUSSION
■
Discovery and Mechanism of the Imine-Forming
Reaction. We first encountered the imine-forming reaction
during pilot studies directed toward the synthesis of the
meloscine/epimeloscine (17a,b) class of natural products.13,14
The goal was to learn how to make the B-ring of ABD tricycles
like 18 by radical cyclizations and to determine the favored
configuration of such cyclizations when R ≠ H (Figure 4).
Somfai in turn had reported in 1994 that syringe pump
addition of tin hydride to ene sulfonamide 14 provided the
reduced spirocyclic sulfonamide 16 in 57% isolated yield.12
This reaction presumably involves α-sulfonamidoyl radical 15,
which apparently abstracts hydrogen from tin hydride even
under syringe pump conditions. Likewise, a homologue of 14
with a six-membered ring ene sulfonamide underwent reductive
cyclization in similar yield.
The collective evidence in Figures 2 and 3 for the β-sulfonyl
radical elimination reaction to form imines is circumstantial
because the direct products of such reactions are not isolated.
Further, the low yields and formation of competing products in
Figure 4. Structures of meloscine natural products 17 and target
tricyclic analogues 18.
Scheme 1 shows the synthesis of two key precursors and the
results of the first radical cyclizations. Initially we made
precursors like 23 by a reliable Stille coupling route (detailed in
the Supporting Information), but we later switched to the
Suzuki coupling route in Scheme 1 because it was more flexible
for varying substituents in target radical precursors. Coupling of
16611
dx.doi.org/10.1021/ja408387d | J. Am. Chem. Soc. 2013, 135, 16610−16617

Journal of the American Chemical Society
Article
Scheme 1. Syntheses of 23 and 24 Typify the Synthesis of the
Various Radical Precursors in This Study
Scheme 2. Radical Cyclizations to Ene Sulfonamides Provide
Stable Cyclic Aldimines
2-(pinacolatoboranyl)aniline 19 with readily available 4-iodo-1-
(phenylsulfonyl)-2,3-dihydro-1H-pyrrole 2015 provided aniline
21 in 79% yield. Reductive N-benzylation to give 22 (69%
yield) was followed by acylation with bromoacetyl bromide and
2-bromopropanoyl bromide. The α-bromoacetanilides 23 and
24 were obtained in 83 and 87% yields.
Bromoacetamide 23 has two axes that can provide rotational
isomers. Rotation of the NC(O) bond (a) is a standard
amide rotation that can provide E and Z isomers, while rotation
of the N−Ar bond (b) provides a pair of enantiomers. There is
only one set of signals in the 1H NMR spectrum of 23 (>95%),
which we assign to the depicted E-amide rotamer (CO and
N−Ar trans).16 All the geminal methylene protons of 23 are
diastereotopic, confirming that it is a mixture of enantiomers
about the N−Ar axis on the NMR time scale.
initiation18). The 80 °C experiment gave imine epimers 26a
and 26b as a 75/25 mixture in 63% isolated yield. This ratio
increased to 83/17 in the rt experiment, and the isolated yield
was 43%.
The configuration of the major isomer from cyclization of 24
was initially assigned as 26a based on NOESY experiments on
the mixture. Later we succeeded in crystallizing the major
diastereomer from the mixture, and its X-ray crystal structure
confirmed both the constitution and the configuration. This
structure, shown in Figure 5, provides clues as to why these
The corresponding α-bromopropanamide 24 adds a stereo-
center to the rotatable amide and N−Ar bonds, so four
diastereomers of 24 are possible.17 This amide is a 70/30
mixtures of diastereomers according to 1H NMR analysis.
These must be the E-rotamers of the two possible
diastereomers created by the stereocenter and the N−Ar axis.
The diastereomers cannot be separated by chromatography, so
the barrier to N−Ar bond rotation is less than about 22 kcal/
mol. Related diastereomers with higher N−Ar rotation barriers
have been separated and shown to give the same products on
radical cyclization.17a So separation is pointless because the two
diastereomers of 24 will give the same radical and hence the
same result on radical cyclization.
The results of tin hydride reactions with 23 and 24 are
summarized in Scheme 2. In a typical cyclization experiment, a
benzene solution of 23 (1 equiv, 0.01 M), Bu3SnH (3 equiv),
and AIBN (0.3 equiv) was heated at 80 °C for 30 min. The
starting material was consumed, and a single major new
product was evident on TLC analysis. Evaporation of the
solvent and flash chromatography provided the new product in
75% yield. This was not the expected product of reductive
cyclization (see 18 in Figure 2), but instead the stable
spirocyclic aldimine 25. The imine structure of 25 was clear
from the various spectra. For example, the sulfonyl group was
absent, and correlated resonances at 7.51 ppm (singlet) in the
1H NMR spectrum and 167.8 ppm in the 13C NMR are
diagnostic of the imine CH atoms. Other NMR and HRMS
data are fully consistent with structure 25.
Figure 5. X-ray crystal structure of 26a (left) along with standard
representation focusing on the lactam ring conformation and
substituents (right).
imines are so stable. The lactam ring (B) of 26a adopts a
distorted half-chair conformation in which the smaller imine
CH-group on the spiro carbon atom is pseudoequatorial and
the larger CH2-group is pseudoaxial. The larger group adopts
the pseudoaxial location because of A-strain19 and because
there are no 1,3-diaxial interactions. In the pseudoequatorial
location, the imine carbon atom is shielded by the fused
aromatic ring (especially the adjacent ortho-hydrogen) on one
side and by the substituents on C3 of the lactam on the other
side.
The mechanism for formation of these products is illustrated
in Figure 6a with the simpler precursor 23. A tributyltin radical
abstracts bromine from 23 to give α-amide radical 27, which
then undergoes 6-exo cyclization by adding to the β-carbon
atom of the ene sulfonamide. The resulting α-sulfonamidoyl
radical 28 ejects the phenylsulfonyl radical (PhSO2•) in a β-
fragmentation reaction to give imine 25. This imine is robust,
and it survives both heating with excess tin hydride (a potential
Cyclization of 24 was conducted under similar conditions at
both 80 °C (AIBN initiation) and room temperature (rt, Et3B
16612
dx.doi.org/10.1021/ja408387d | J. Am. Chem. Soc. 2013, 135, 16610−16617

Journal of the American Chemical Society
Article
a
Table 1. Scope of the New Imine Forming Reaction
Figure 6. Evidence for β-fragmentation: (a) suggested steps and
intermediates for formation of the imine and (b) possible fates of the
tin and sulfur reaction components (right).
ionic hydride source) and silica gel chromatography. It cannot
tautomerize to an enamine. Its isolation is strong evidence
implicating the β-elimination of α-sulfonamidoyl radicals
because it is the primary product this reaction.
Focusing on the phenylsulfonyl radical product1a,2a of the β-
fragmentation reaction, we can further speculate that this
abstracts a hydrogen atom from tin hydride to generate
tributyltin radical (Bu3Sn•) and benzenesulfinic acid
(PhSO2H).20a,b This is a chain transfer step provided that the
original bromine abstraction reaction by the tin radical (23 →
27) competes effectively with possible back hydrogen atom
transfer.21
a
Isolated yields after flash chromatography are recorded.
Benzenesulfinic acid is an unstable compound prone to
disproportionation and other reactions.2a And with a pKa of
about 2.7, it can also be expected to undergo an acid/base
reaction with Bu3SnH as shown in Figure 6b. If this reaction is
quantitative, then 2 equiv of Bu3SnH are needed for the overall
reaction. Indeed, the use of 1 equiv of Bu3SnH in the pilot
reductions in Scheme 1 did not provide high conversions of
precursor 24.22a Likewise, tin hydide addition/elimination
reactions of allyl sulfones require 2 equiv of tin hydride.23
This suggests that a significant amount of tin hydride is
consumed either by the indicated acid/base reaction or by
other reactions with the sulfur-derived product(s).20b
Scope of the Imine-Forming Reaction. Next we
surveyed the scope of the imine-forming reaction by varying
substituents and ring sizes, and the results of these studies are
summarized in Table 1. The precursors were all made by
suitable variations of the route outlined in Scheme 1, and
complete details (experimental procedures, characterization of
intermediates) are in the Supporting Information. The radicals
derived from the precursors in Table 1 may undergo the initial
cyclization at different rates. To maximize the chances for
cyclization rather than direct reductive debromination, we
switched to a standard syringe pump procedure for these
reactions. The crude products were purified by flash
chromatography to provide the isolated yields in Table 1.
Cyclization of 2-bromo-2-methylpropanamide 29, a more
substituted analogue of 23 and 24, provided imine 30 with a
quaternary center adjacent to the spirocenter in 81% yield
(entry 1). Precursors 31 and 33 have a six-membered ene
sulfonamide ring, one without (31) and one with (33)
additional methyl groups on the carbon bearing the radical
precursor. Isolated yields of six-membered cyclic imines 32 and
34 were 73 and 50% (entries 2 and 3). These precursors all
form spirocyclic aldimines on tin hydride reaction. The
precursor 35 bears an additional ethyl group on the α-carbon
atom of the ene sulfonamide. This gives spirocyclic ketimine
product 36 in 61% yield.
Finally, we prepared a 2-bromo-2-methylpropanamide
precursor 37 that has the ene sulfonamide as part of a seven-
membered ring. Cyclization of 37 provided imine 38 with
spirofused six- and seven-membered rings in 40% isolated yield
(entry 5). In this seven-membered ring series, the geminal
dimethyl group adjacent to the spiro-carbon was important for
product stability.22b In contrast, the five- and six-membered
imines were stable regardless of amide substitution pattern.
16613
dx.doi.org/10.1021/ja408387d | J. Am. Chem. Soc. 2013, 135, 16610−16617

Journal of the American Chemical Society
Article
Imine products predominated in every case in Scheme 2 and
Table 1, so this suggests that the β-fragmentation reaction of
the intermediate α-sulfonamidoyl radicals is rather general. All
the imines in Table 1 were again stable and easily isolable.
Overall, this is an appealing method to make functionalized
spirocyclic imines.
Imine-Formation by Radical Translocation. If β-
fragmentation is a core reaction of α-sulfonamidoyl radicals,
then it should be possible to make such radicals by another
route and again observe the formation of imines. We chose
radical translocation24 to generate such radicals based in part on
Murphy’s minor product in Figure 2c.25 However, we used
halide rather than diazo radical precursors to retain the
opportunity for tin hydride mediated reactions.
The dihydroisoquinoline product 44 arises from a sequence
of iodine atom abstraction to give aryl radical 45 followed by
radical translocation to give 46 and then β-fragmentation to
give the imine functional group embedded in the products 44.
These results show that the imine-forming reaction is a
characteristic of α-sulfonamidoyl radicals that is independent of
their method of generation. Beyond that, such reactions could
have value in synthesis. Sulfonyl groups are attractive N-
protecting groups because sulfonamides are so stable.26 The
knock on N-sulfonyl groups is that they are hard to remove by
either hydrolysis or reduction.27 Here the 2-halosulfonyl group
functions as “self-oxidizing protecting group”;28 it is removed
under mild reductive conditions to give a valuable imine
product that is oxidized on the carbon skeleton with respect to
the precursor.
Understanding the Contrasting Prior Results. To
complete the study, we came full circle to the contrasting
results of Cossy and Somfai (Figure 3). Recall that starting
from similar ene sulfonamide precursors, Cossy obtained a
fused imine 13 lacking the N-sulfonyl group,11 but Somfai
obtained a standard reduced spricycle 16 retaining the N-
sulfonyl group.12
The results of four simple but informative experiments are
summarized in Scheme 3. Reduction of N-(2-bromophenyl-
Scheme 3. Radical Translocation Reactions Lead to
Oxidative Removal of N-(2-Halosulfonyl) Groups Under
Mild Reductive Conditions Provided That the Precursors
Have Suitably Activated C−H Bonds
Figure 7 shows possible products in tin hydride reactions of
Cossy’s substrate 11. At issue is which functional group in 11 is
Figure 7. Products in the cyclization of 11 depend on which functional
group is the precursor in the cyclization and which is the acceptor.
Path (a), the alkyne is the precursor and the ene sulfonamide is the
acceptor. Path (b), the ene sulfonamide is the precursor and the alkyne
is the acceptor. The isolated product 13 is a secondary product of path
(a) derived from 49, not a primary product from reductive
desulfonylation path (b).
sulfonyl)pyrrolidine 39 and the corresponding piperidine
homologue 40 with Bu3SnH at 80 °C under the usual thermal
conditions provided principally the directly debrominated
products 41 and 42. We suspected that these products formed
because the radical translocation (a 1,5-hydrogen atom transfer
reaction) failed, not because the elimination reaction failed.
To address this problem, we made the two N-(2-halophenyl-
sulfonyl)tetrahydroisoquinolines 43a (X = I) and 43b (X = Br).
These have a pair of C−H bonds that are additionally activated
for radical translocation by the adjacent aryl ring. Reduction of
43a,b with Bu3SnH under the standard thermal conditions
followed by flash chromatography provided the stable 3,4-
dihydroisoquinoline 44 in 55 and 46% yield, repectively.
the radical precursor in the cyclization and which is the radical
acceptor. Cossy had planned a hydrostannation reaction in
which the alkyne is the radical precursor and the ene
sulfonamide is the acceptor, path (a) (going downward from
11). Addition of tributyltin radical to 11 gives alkenyl radical
47. The expected final product of cyclization of 47 at that time
was reduced alkenyl stannane 48, but this was not isolated.
The absence of 48 led to the suggestion that the observed
product 13 arose from a cyclization in which the ene
sulfonamide was the radical precursor and the alkyne was the
radical acceptor, path (b) (going to the right from 11). This is a
reductive desulfonylation, not a hydrostannation. The problem
with this suggestion is that the conversion of 11 to 12 is a
16614
dx.doi.org/10.1021/ja408387d | J. Am. Chem. Soc. 2013, 135, 16610−16617

Journal of the American Chemical Society
Article
homolytic substitution reaction at a sulfonyl group, a reaction
that is widely thought to be unfavorable.29 Previous suggestions
of such reactions have been refuted both experimentally30 and
computationally.31 However, the focus of much of this prior
work has been on substitution of sulfonyl groups by second-
row radicals (especially carbon radicals) rather than tin radicals.
In contrast, homolytic substitutions at sulfur atoms in lower
oxidation states (for example, ArSR and ArS(O)R) with carbon,
tin, and other radicals are common.32
With the hindsight provided by the new results, we can see
that Cossy’s original line of thinking (the alkyne is the
precursor, path (a)) could well be correct. However, we now
see that the expected product of the tin radical addition to the
alkyne is imine 49 resulting from sulfonyl radical elimination
rather than reduced sulfonamide 48 from hydrogen transfer.
Could it be that imine 49 was formed in Cossy’s reaction and
then protodestannylated to 13 by the in situ generated
benzenesulfinic acid?33
Figure 8. Syringe pump addition of tin hydride to 14 gives not one but
two products: one stable to chromatography (16) and one unstable
(52).
To address this issue, we synthesized bromide 50 (Scheme
4) as described fully in the Supporting Information. The
a
Scheme 4. Tin Hydride Reduction of 50
however, the ratio trend was consistent: the unstable product
was always major and the stable product was always minor.
In a typical syringe pump experiment, the stable product was
isolated in 15% yield by flash chromatography and proved to be
Somfai’s reduced product 16 retaining the N-sulfonyl group.
The 1H NMR spectra of several crude mixtures recorded before
chromatography showed that the unstable product was
spirocyclic imine 52.35 For example, the protons of the N−
CH2 group resonated as a doublet of triplets, J = 2.1 and 6.9 Hz
a
The bromide, not the ene sulfonamide, functions as a radical
1
at 3.86 ppm, in the H NMR spectrum. When an integration
standard was added (1,3,5-trimethoxybenzene), the calculated
yield of the imine 52 was typically 45−60%.
precursor.
Syringe pump experiments like these are difficult to
reproduce in the best of cases because there are many variables.
And the cyclization of 14 is far from a best case scenario for two
reasons. First, the benzenesulfinic acid byproduct is a good
hydrogen atom donor that is nicely matched with the α-
sulfonylamidoyl radical 15 for polarity reverse catalysis.36 This
acid may be consumed less efficiently under syringe pump
conditions because tin hydride is always deficient. Thus, the
syringe pump procedure might provide more powerfully
reducing conditions rather than less. Second, alkyl bromides
are electrophiles and ene sulfonamides are nucleophiles, so
nonradical reactions may compete, especially under the long
heating involved in the syringe pump procedure.
To mitigate the first problem, we switched to the standard
fixed concentration conditions so that tin hydride is never
deficient during the reaction course.37 To eliminate the
possibility of a competing intramolecular SN2 reaction, we
replaced the bromide 14 by the analogous phenylselenide 53.
The results of two key experiments with 53 are summarized
in Scheme 5. In both experiments, 53 (0.01 M) was reduced
with 3 equiv of tin hydride at 80 °C (AIBN initiation). After 30
min, TLC analysis showed that the precursor was largely
consumed. In the first reaction, the solvent was evaporated and
the crude product was dissolved in CDCl3 with an integration
standard. The major product was imine 52 in 60% yield.
Resonances from the reduced product 16 were not evident in
this spectrum.
bromine atom in 50 that replaces the alkyne in 11 can only
serve as a radical precursor, not a radical acceptor. Thus, the
origin of any cyclized product formed in reduction of 50 is
straightforward to determine.
Reduction of 50 with Bu3SnH was conducted at room
temperature under conditions similar to Cossy’s (Et3B
initiation). The major product was the imine 51 (Scheme 4),
which was isolated in 54% yield by flash chromatography and
fully characterized. Clearly in substrate 50, the bromide
functioned as the radical precursor and the ene sulfonamide
functioned as the radical acceptor.
The results of this experiment suggest that the imine product
13 in Cossy’s reaction was formed by the path (b) in Figure 7
with the steps of (1) tin radical addition to the alkyne 11 to
give 47, (2) 5-exo cyclization, and (3) β-fragmentation to
eliminate the sulfonyl group and form the imine 49. Finally, (4)
ionic protodestannylation of this primary product 49 produces
the isolated product 13.
With new understanding of Cossy’s reaction, it is now
Somfai’s result (no imine formation in Figure 3b) that with
hindsight looks out of place. Thus, we resynthesized bromide
14 by Somfai’s published procedures12 to revisit its cyclization
chemistry.
Syringe pump addition of tributyltin hydride to bromide 14
as described by Somfai gave somewhat variable results, as
summarized in Figure 8 and described more fully in the Ph.D.
thesis of H. Zhang.34 Two products were consistently formed:
an unstable product and stable product. The inconsistencies
were with percent conversion and the ratio of the two products;
In the second reaction, a solution of sodium borohydride in
ethanol was added after tin hydride treatment to reduce any
imine present to an amine. This crude mixture was exposed to
16615
dx.doi.org/10.1021/ja408387d | J. Am. Chem. Soc. 2013, 135, 16610−16617

Journal of the American Chemical Society
Article
nylsulfonyl)-tetrahydroisoquinolines. Accordingly, readily avail-
able N-(2-halophenylsulfonyl) groups can now serve as so-
called self-oxidizing protecting groups,28 although C−H bonds
that are activated toward 1,5-hydrogen transfer seem to be an
important prerequisite. As with the cyclative transformation,
very stable sulfonamides are cleaved to form imines (rather
than amines) under mild reductive conditions.
Scheme 5. Results of Tin Hydride Reactions of
Phenylselenide 53 and Alcohol 55
Imines are synthetic intermediates in a vast collection of two-
component and multicomponent addition reactions.38 By far
the most common way to make imines, whether stable species
or transient reaction intermediates, is by the condensation of
aldehydes or ketones with amines.39 The ability to made imines
by a sulfonyl radical elimination, especially when coupled with a
prior radical reaction (here, the cyclizations), provides a
powerful alternative to the usual condensation route that
differs both in the bonds that are formed and in the reaction
conditions. These differences promise to offer expanded
opportunities for imine chemistry in synthesis.
benzoyl chloride and pyridine, and then the resulting product
was purified by flash chromatography to provide benzamide 54
in 59% yield.
ASSOCIATED CONTENT
* Supporting Information
■
S
These results show that the formation of imine 51 by
sulfonyl radical elimination is more rapid than hydrogen atom
abstraction from tin hydride under fixed tin hydride conditions
and syringe pump conditions. We understand why Somfai did
not observe the imine 51 (because he purified his products by
flash chromatography), though we are not sure why he isolated
about 30% more reduced product 16 from his syringe pump
experiment than we typically observed. From the vantage point
of the β-fragmentation reaction, the key observation is that the
cyclization results with 14 are generally consistent with Cossy’s
prior results and with our new results.
Details of all new experiments, spectral data, and crystal data
(CIF). This material is available free of charge via the Internet
at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
curran@pitt.edu
■
Notes
The authors declare no competing financial interest.
Finally, to test whether ene sulfonamides are competent
radical precursors at all under these conditions, we treated
alcohol 55 (Scheme 5) with tributyltin hydride under the
standard thermal conditions (80 °C). No new products was
detected, and most of the starting material was recovered. Thus,
the sulfonyl groups of ene sulfonamides are not subject to facile
homolytic substition reactions by tin radicals.29−31
ACKNOWLEDGMENTS
We thank the National Institutes of Health and the National
Science Foundation for funding.
■
REFERENCES
■
(1) (a) Chatgilialoglu, C.; Bertrand, M. P.; Ferreri, C. In Sulfur-
Centered Radicals; Alfassi, Z. B., Ed.; Wiley: West Sussex, 1999; pp
311−354. (b) Bertrand, F.; Le Guyader, F.; Liguori, L.; Ouvry, G.;
Quiclet-Sire, B.; Seguin, S.; Zard, S. Z. C. R. Acad. Sci., Ser. IIc: Chim.
2001, 4, 547−555. (c) Rosenstein, I. In Radicals in Organic Synthesis,
1st ed.; Renaud, P., Sibi, M., Eds.; Wiley-VCH: Weinheim, 2001; Vol
1, pp 50−71.
(2) (a) Chatgilialoglu, C. In Chemistry of Sulphones and Sulphoxides;
Patai, S., Rappoport, Z., Eds.; Wiley: Chichester, 1988; pp 1089−1113.
(b) Bertrand, M. P. Org. Prep. Proced. Int. 1994, 26, 257−290.
(3) Le Guyader, F.; Quiclet-Sire, B.; Seguin, S.; Zard, S. Z. J. Am.
Chem. Soc. 1997, 119, 7410−7411.
(4) (a) Kim, S.; Lee, I. Y.; Yoon, J.-Y.; Oh, D. H. J. Am. Chem. Soc.
1996, 118, 5138−5139. (b) Kim, S.; Yoon, J. Y. J. Am. Chem. Soc.
1997, 119, 5982−5983. (c) Kim, S.; Kim, N.; Yoon, J. Y.; Oh, D. H.
Synlett 2000, 1148−1150. Such eliminations can also be used to make
CO and CN bonds. For example, (d) Kim, S. G.; Jin, R. C. Synlett
1992, 629−630. (e) Lee, J. Y.; Lim, K.-C.; Meng, X.; Kim, S. Synlett
2010, 2010, 1647−1650.
(5) (a) Stacey, F. W.; Sauer, J. C.; McKusick, B. C. J. Am. Chem. Soc.
1959, 81, 987−992. (b) Graftieaux, A.; Gardent, J. Tetrahedron Lett.
1972, 13, 3321−3324. (c) Hertler, W. R. J. Org. Chem. 1974, 39,
3219−3223.
CONCLUSIONS
■
Tin hydride mediated radical cyclizations of ene sulfonamides
are general reactions that provide bicyclic and tricyclic
aldimines and ketimines in good yields. Depending on the
structure of the precursor, the cyclizations occur in 5-exo or 6-
exo modes to provide fused or spirocyclic imines. With the
exception of the small spirocyclic imine 52, all of the cyclic
imines herein are robust compounds that are not reduced
ionically by tin hydride under the reaction conditions and that
are readily purified by flash chromatography. Reinvestigation of
the contrasting prior results from Cossy11 and Somfai12 showed
that imine products predominated in both cases.
Mechanistically, the initial radical cyclization produces an α-
sulfonamidoyl radical that undergoes elimination to form the
imine and a phenylsulfonyl radical. This β-elimination reaction
has been postulated in the past based on the structures of
downstream products that have been isolated in related
reactions (Figures 2 and 3). The isolation of the many primary
imine products in this work does not prove that imines are
intermediates in all of these prior reactions. However, it
cements the case for the β-elimination as a core reaction of α-
sulfonamidoyl radicals.
(6) (a) Quiclet-Sire, B.; Wendeborn, F.; Zard, S. Z. Chem. Commun.
2002, 0, 2214−2215. (b) Quiclet-Sire, B.; Tran, N. D. M.; Zard, S. Z.
Org. Lett. 2012, 14, 5514−5517.
(7) Darmency, V.; Renaud, P. Chimia 2005, 59, 109−110.
(8) (a) Bommezijn, S.; Martin, C. G.; Kennedy, A. R.; Lizos, D.;
Murphy, J. A. Org. Lett. 2001, 3, 3405−3407. (b) Mahesh, M.;
In a related method, 3,4-dihydroquinolines can also be
produced by radical translocation reactions of N-(2-halophe-
16616
dx.doi.org/10.1021/ja408387d | J. Am. Chem. Soc. 2013, 135, 16610−16617

Journal of the American Chemical Society
Article
Murphy, J. A.; LeStrat, F.; Wessel, H. P. Beilstein J. Org. Chem. 2009, 5,
1.
(9) Curran, D. P.; Guthrie, D. B.; Geib, S. J. J. Am. Chem. Soc. 2008,
(31) Aitken, H. M.; Hancock, A. N.; Schiesser, C. H. Chem. Commun.
2012, 48, 8326−8328.
(32) (a) Crich, D. Helv. Chim. Acta 2006, 89, 2167−2182.
(b) Schiesser, C. H. Chem. Commun. 2006, 4055−4065. (c) Li, C.
In Encyclopedia of Radicals in Chemistry, Biology and Materials;
Chatgilialoglu, C., Studer, A., Eds.; Wiley: New York, 2012; Vol 1,
pp 943−964. (d) Jasch, H.; Hienrich, M. R. In Encyclopedia of Radicals
in Chemistry, Biology and Materials; Chatgilialoglu, C., Studer, A., Eds.;
Wiley: New York, 2012; Vol 2, pp 529−560.
130, 8437−8445.
(10) Murphy also observed a minor desulfonylation product that
might arise from sulfonyl radical elimination in an unusual reductive
indole-forming reaction; see ref 7a.
(11) Cossy, J.; Cases, M.; Pardo, D. G. Tetrahedron 1999, 55, 6153−
6166.
(12) Ahman, J.; Somfai, P. J. Chem. Soc., Perkin Trans. 1 1994, 1079−
1082.
(13) Zhang, H.; Curran, D. P. J. Am. Chem. Soc. 2011, 133, 10376−
10378.
(33) Buchi, G.; Wuest, H. Tetrahedron Lett. 1977, 18, 4305−4306.
̈
̈
(34) Zhang, H. Ph.D. Thesis, University of Pittsburgh, 2013.
(35) This compound has been previously isolated and also described
to be unstable. See: Burk, R. M.; Overman, L. E. Heterocycles 1993, 35,
205−225.
(14) (a) Overman, L. E.; Robertson, G. M.; Robichaud, A. J. J. Am.
Chem. Soc. 1991, 113, 2598−2610. (b) Selig, P.; Herdtweck, E.; Bach,
T. Chem.Eur. J. 2009, 15, 3509−3525. (c) Hayashi, Y.; Inagaki, F.;
Mukai, C. Org. Lett. 2011, 13, 1778−1780. (d) Feldman, K. S.;
Antoline, J. F. Org. Lett. 2012, 14, 934−937.
(36) (a) Roberts, B. P. Chem. Soc. Rev. 1999, 28, 25−35. (b) Crich,
D.; Grant, D.; Krishnamurthy, V.; Patel, M. Acc. Chem. Res. 2007, 40,
453−463.
(37) Syringe pump experiments with phenyl selenide 53 gave similar
results to bromide 14. Imine 52 was typically the major crude product,
but reduced product 15 was a significant minor product.
(38) (a) Yus, M.; Gonzalez-Gomez, J. C.; Foubelo, F. Chem. Rev.
2011, 111, 7774−7854. (b) Choudhury, L. H.; Parvin, T. Tetrahedron
2011, 67, 8213−8228. (c) Kobayashi, S.; Mori, Y.; Fossey, J. S.; Salter,
M. M. Chem. Rev. 2011, 111, 2626−2704.
(39) (a) Pawlenko, S. In Organic Nitrogen Compounds with a C,N-
Double Bond, 4th ed.; Klamann, D., Hagemann, H., Eds.; Georg
Thieme Verlag: Stuttgart, 1990; Vol E14b, pp 222−281. (b) Abbaspour
Tehrani, K.; De Kimpe, N. In Compounds with Two Carbon−
Heteroatom Bonds: Heteroatom Analogues of Aldehydes and Ketones;
Pawda, A., Bellus, D., Eds.; Georg Thieme Verlag: Stuttgart, 2004; Vol
27, pp 245−312.
(15) Kiewel, K.; Luo, Z.; Sulikowski, G. A. Org. Lett. 2005, 7, 5163−
5165.
(16) (a) Itai, A.; Toriumi, Y.; Saito, S.; Kagechika, H.; Shudo, K. J.
Am. Chem. Soc. 1992, 114, 10649−10650. (b) Curran, D. P.; Hale, G.
R.; Geib, S. J.; Balog, A.; Cass, Q. B.; Degani, A. L. G.; Hernandes, M.
Z.; Freitas, L. C. G. Tetrahedron: Asymmetry 1997, 8, 3955−3975.
(17) (a) Guthrie, D. B.; Geib, S. J.; Curran, D. P. J. Am. Chem. Soc.
2011, 133, 115−122. (b) Mandel, J.; Pan, X.; Hay, E. B.; Geib, S. J.;
Wilcox, C. S.; Curran, D. P. J. Org. Chem. 2013, 78, 4083−4089.
(18) Miura, K.; Ichinose, Y.; Nozaki, K.; Fugami, K.; Oshima, K.;
Utimoto, K. Bull. Chem. Soc. Jpn. 1989, 62, 143−147.
(19) Hoffmann, R. W. Angew. Chem., Int. Ed. Engl. 2000, 39, 2055−
2070.
(20) (a) Chatgilialoglu, C.; Alberti, A.; Ballestri, M.; Macciantelli, D.;
Curran, D. P. Tetrahedron Lett. 1996, 37, 6391−6394. (b) Another
possible outcome is that the sulfonyl radicals eventually dimerize. The
products of such reactions would probably also react with tin hydrides.
See: Chatgilialoglu, C.; Lunazzi, L.; Ingold, K. U. J. Org. Chem. 1983,
48, 3588−3589.
(21) (a) Chatgilialoglu, C.; Newcomb, M. In Advances In
Organometallic Chemistry; West, R., Hill, A. F., Eds.; Academic Press:
San Diego, 1999; Vol 44, pp 67−112. (b) Vleeschouwer, F. D.;
Speybroeck, V. V.; Waroquier, M.; Geerlings, P.; Proft, F. D. J. Org.
Chem. 2008, 73, 9109−9120.
(22) (a) With 2 equiv of tin hydride, small amounts of starting
material sometimes remained in pilot experiments, so we settled on 3
equiv for the preparative experiments. (b) Cyclization of the related 2-
bromoacetamide analogue provided a crude spirocyclic imine product
that was not stable to handling or isolation.
(23) Ueno, Y.; Ohta, M.; Okawara, M. J. Organomet. Chem. 1980,
197, C1−C4.
(24) (a) Curran, D. P.; Kim, D.; Liu, H. T.; Shen, W. J. Am. Chem.
Soc. 1988, 110, 5900−5902. (b) Snieckus, V.; Cuevas, J. C.; Sloan, C.
P.; Liu, H.; Curran, D. P. J. Am. Chem. Soc. 1990, 112, 896−898.
(c) Robertson, J.; Pillai, J.; Lush, R. K. Chem. Soc. Rev. 2001, 30, 94−
103. (d) Denes, F.; Beaufils, F.; Renaud, P. Synlett 2008, 2389−2399.
(25) Murphy, J. A.; Roome, S. J. J. Chem. Soc., Perkin Trans. 1 1995,
1349−1358.
(26) (a) Kocienski, P. J. Protecting Groups; Georg Thieme Verlag:
Stuttgart, 1994. (b) Greene, T. W.; Wuts, P. G. M. Protective Groups in
Organic Synthesis, 3rd ed.; Wiley-Interscience: New York, 1999.
(27) (a) Knowles, H. S.; Parsons, A. F.; Pettifer, R. M.; Rickling, S.
Tetrahedron 2000, 56, 979−988. (b) Viaud, P.; Coeffard, V.; Thobie-
Gautier, C.; Beaudet, I.; Galland, N.; Quintard, J.-P.; Le Grognec, E.
Org. Lett. 2012, 14, 942−945.
(28) Curran, D. P.; Yu, H. S. Synthesis 1992, 123−127.
(29) Kampmeier, J. A.; Evans, T. R. J. Am. Chem. Soc. 1966, 88,
4096−4097.
(30) Crich, D.; Hutton, T. K.; Ranganathan, K. J. Org. Chem. 2005,
70, 7672−7678.
16617
dx.doi.org/10.1021/ja408387d | J. Am. Chem. Soc. 2013, 135, 16610−16617