Fluorine as a Traceless Directing Group for the Regiodivergent Synthesis of Indoles and Tryptophans

Article abstract of DOI:10.1021/jacs.8b08350

Despite ample evidence for the unique reactivity offered by hypervalent F-iodanes, mechanistic investigations fall far behind. In order to shed light on the unusual behavior of such F-reagents, we conducted computational and experimental studies on the chemodivergent transformation of styrenes. We identified the spirocyclic F-cyclopropane as the common intermediate for both the C,H-fluorination and C,H-amination pathways. The fate of this key compound is determined by the extent of cationic charge delocalization controlled by the N-substituents. Exploiting this phenomenon, a multitude of different transformations have become available, leading, i.e., to the regiodivergent synthesis of indoles and tryptophans.

Full text of DOI:10.1021/jacs.8b08350

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Article
Fluorine as a Traceless Directing Group for the
Regiodivergent Synthesis of Indoles and Tryptophans
Anna Andries-Ulmer, Christoph Brunner, Julia Rehbein, and Tanja Gulder
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b08350 • Publication Date (Web): 05 Sep 2018
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Fluorine as a Traceless Directing Group for the Regiodivergent
Synthesis of Indoles and Tryptophans
Anna Andries-Ulmer,[a]‡ Christoph Brunner, [a]‡ Julia Rehbein *[b] and Tanja Gulder*[a]
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aDepartment of Chemistry and Catalysis Research Center (CRC), Technical University of Munich, Lichtenbergstraße
4, 85748 Garching, Germany
bInstitute of Organic Chemistry, University of Regensburg, Universitätstraße 31, 93053 Regensburg, Germany
ABSTRACT: Despite ample evidence for the unique reactivity offered by hypervalent F-iodanes, mechanistic investigations
lack far behind. In order to shed light on the unusual behavior of such F-reagents, we conducted computational and experi-
mental studies on the chemodivergent transformation of styrenes. We identified the spirocyclic F-cyclopropane as the com-
mon intermediate for both the C,H-fluorination and C,H-amination pathway. The fate of this key compound is determined
by the extent of cationic charge delocalization controlled by the N-substituents. Exploiting this phenomenon, a multitude of
different transformations have become available, leading, i.a., to the regiodivergent synthesis of indoles and tryptophans.
Introduction
can likewise be observed in other F-iodane mediated
fluorinations, such as
Hypervalent λ3-iodane-mediated alkene functionaliza-
tions have significantly matured over the last years. To-
day, a manifold of different iodine-based reagents as well
as catalytic systems are available, allowing for the intro-
duction of a wide range of functionalities and thus giving
rise to highly versatile building blocks.1 In this context,
fluorinations have recently raised huge attention among
the synthetic community and iodane reagents1b and cata-
lysts2 have proven to be an exciting playground for the
discovery of new, fascinating and often unexpected reac-
tivities and selectivities.1a-e,2 The fluorobenziodoxole 4
constitutes such a prominent example3 that brought new
impetus in the field of electrophilic fluorinations. Since its
synthesis was reported only in 2013,4 4 has emerged to an
effective and broadly applicable source of fluorine with its
reaction scope spanning from difluorinations to intra-
and intermolecular fluorofunctionalizations4a,5 and even
radiofluorinations.5j,5k But besides simply being an inter-
esting alternative to established, electrophilic fluorination
reagents, like e.g. selectfluor (2) or N-fluoro pyridinium
salts 7, λ3-fluoro iodanes offer a completely new chemose-
lectivity thus unlocking novel, as yet not accessible chem-
ical space. Within our efforts to develop new and selective
halogenation methods,6 we recently reported on such an
example showcasing the unique reactivity addressable
with F-iodane 4 in the fluorocyclization of styryl ben-
zamides 3 (Scheme 1).5d,5i Treatment of substrate 3 with
iodane 4 initiated a fluorination/1,2-aryl migration/ring
closing cascade surprisingly giving rise to the formal sev-
en-endo cyclization product 5. Replacing 4 by other elec-
trophilic F sources, such as 2, solely afforded the benzox-
azines 1, as expected.5d Such a distinct fluorination behav-
ior is not restricted to this particular transformation, but
Scheme 1. Examples of chemoselective conversions
of styrenes 3 depending on the electrophilic F-
reagent.
the fluoro lactonizations reported by Stuart and co-
workers.5b Although the F-iodane 4 closely resembles the
structure of the well-studied Togni reagent,7 it exhibits a
different mechanistic behavior: DFT calculations were
indicative for an activation of the F-iodane 4 proceeds via
coordination of H-bond donors or Lewis acids to the fluo-
rine rather than to the oxygen atom.8 Upon such an acti-
vation, 4 reacts with the alkene in an isomeriza-
tion/metathesis/nucleophilic substitution sequence.9
Although the exploration of the fundamental pathways in
these chemo- and regioselective fluorinations have lately
become subject of extensive investigations,8-10 the mecha-
nisms operative in such transformations are still far from
being understood. To harness the intriguing chemistry of
fluoro λ3-iodanes, the field now needs to advance from
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serendipity-driven to a more rational-based method de- With our aim to further discover the realm of fluorination
1
2
3
4
5
6
7
8
velopment, making detailed investigations on the princi-
ples operative here inevitable.
chemistry1b,12 mediated by 4, a comprehensive under-
standing of forming benzoxazepines 5 is necessary, in
particular the reasons for the exquisite chemo- and regi-
oselectivities. In order to answer these questions, we fur-
ther explored the substrate scope of the fluorocyclization
varying the N-substituent. Besides our former model
substrate 3a (Table 1, entry 1),5d the carbamate analog 3b
gave the corresponding benzoxazepine 5b as well, albeit
in poor 18% yield (entry 2). To our surprise, the corre-
sponding N-sulfonamide 3c showed no formation of 5 at
all. The N-tosylated 3-methylindole (12c, entry 3) was
isolated together with significant amounts of starting
material 3c. Instead of the C(sp2),H-fluorination of the
alkene moiety in 3 followed by rearrangement of the ani-
line ring, an exclusive C(sp2),H amination devoid of any
1,2-aryl shift took place, at least formally. One explanation
for this reactivity change might be the more nucleophilic
character at the N-atom in 3c as compared to the amides
3a and carbamates 3b (cf. Scheme 4). To test this hypoth-
esis, N-silyl 3e, N-Me 3f and the simple aniline derivative
3d were employed. All substrates indeed delivered the
corresponding 3-methylindoles 12d - 12f as the only prod-
ucts in excellent yields (entries 4 - 6). Interestingly, in-
stalling both an electron-withdrawing and -donating
group at the nitrogen, such as in N-methyl benzamide 3g,
the C,H-fluorination including the aryl shift constituted
the only reaction pathway again (entry 7).13
We therefore set out to look closer into the unusual fluor-
ination behavior of 4 with particular focus on the 1,2-aryl
shift that is responsible for the distinct chemoselectivity.11
During our experimental as well as theoretical investiga-
tions using the fluorocyclization of styryl benzamides 3 as
our model reaction, a mutual influence of the introduced
fluorine atom and the N-substituent R1 on the 1,2-aryl
shift was revealed (Scheme 2a). Harnessing this observed,
unique feature, a diverse set of regio- and chemodivergent
(cascade) reactions became available, all starting from the
same structural scaffold, the N-substituted styrene 3.
Besides being able to specifically target the formation of
fluorinated products 5, C,H oxidations to benzylic ketones
13 as well as C,H aminations to indoles with (ꢀ 12) and
without (ꢀ 14) scrambling of the substituents became
available. The utility of the developed methods was fur-
ther demonstrated by establishing a metal free, Cacchi-
type annulation that provided easy access to optically
pure, unnatural tryptophan analogs 16 (Scheme 2b).
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Scheme 2. Chemodivergent conversion of styrenes
3.
Table 1. N-Substituent dependent product selectivity
time
R
conversion
quant.
yielda
5 : 12b
[h]
90%
(77%)c
18%
1
a: Bz
0.25
100:0
2
3
b: Cbz
c: Tos
48
48
50%
24%
100:0
0:100
24%
quant.
4
5
6
7
d: H
e: TBDMS
f: Me
3
3
quant.
quant.
quant.
quant.
0:100
0:100
0:100
100:0e
(quant.)c
quant.d
(71%)c
quant.
(71%)c
12
12
quant.
g: Me, Bz
(85%)c,13
The reactions were carried out using styrene 1 (0.10 mmol,
1.0 eq.) and 0.12 mmol fluorine reagent 4 (1.2 eq.) in 0.50 mL
1
MeCN (0.2M
) at rt. aThe yield was determined by H NMR of
the crude product using an internal standard. bThe ratio was
determined from the crude 1H-NMR spectrum. cIsolated
yield. dThe N-desilylated product 12d was obtained. eThe
Results and Discussion
Mechanistic Investigations
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R3
F
I
O
corresponding ketone 13g was isolated as the benzoxazepini-
Me
3
4Å MS,
MeCN, rt
Me
Me
R4
um product rapidly hydrolyzed upon work up.13 Tos: p-
toluene sulfonic acid, Piv: Pivaloyl, Cbz: benzyl carbamate,
Bz: benzoyl, TBDMS: tert-butyldimethylsilyl.
1
2
3
4
5
6
7
8
NHR1
N
R
R2
4
3
12
Me
To test if this observation also holds true for styrenes 3
bearing different functional groups, we treated a small,
but structurally diverse library of 13 selected derivatives 3
with the F-iodane 4 (Scheme 3). Throughout, no 1,2-aryl
shift occurred and the 3-substituted indoles 12 were iso-
lated in good to excellent yields as the only products.14
These results unambiguously prove that the observed
reactivity is the result of a general phenomenon.15,16
Me
Me
N
N
N
Me
Tos
H
12f
71%
,
12c
57%a
12d
,
,
3d
from : quant
from : 71%
OTBS
3e
9
Me
Me
Me
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O
O
N
N
N
Tos
Tos
Tos
12h
78%a
,
12i
12j,
,
Rearrangement was observed again when the benzoic
acid amide 3r was used as a substrate. The 3-fluorinated
isochroman imine 17 was formed in 71%, a result being
counterintuitive to a mechanism involving a phenonium
ion intermediate as proposed earlier.5d,9 These results,
however, together with those obtained earlier5d clearly
show that the chemoselectivity is completely independent
of the electronic properties of the aromatic moiety. Prod-
uct formation is instead exclusively determined by the N-
substituent. This phenomenon was only observed when
the hypervalent F-iodane 4 was employed. Interestingly,
using other iodanes, like e.g., the chloro and bromo ana-
logs of 4, led again to a complete switch in chemoselectiv-
ity now solely yielding the six-membered benzoxazines 1
(see Scheme 1 and SI). These results impressively confirm
the different and unique reactivity pattern triggered by
the fluoro iodane 4, not only when compared to other
electrophilic F-reagents such as 2.
66%a
65%a
Et
Me
Me
Me
N
H
N
N
H
Me
H
12k
89%b
12m
,
74%b
Me
,
12l
,
64%b
Me
Me
Me
Cl
NC
Ph
N
N
H
N
H
N
F3C
H
H
12n
12p
,
61%b
,
12o
55%b
,
12q
65%b
,
68%b
Me
F
I
O
4Å MS,
MeCN, rt
Me
Me
Me
F
O
O
71%
3r
4
17r
NHPh
NPh
The reactions were carried out using styrene 1 (0.20 mmol,
1.0 eq,) and 0.24 mmol fluorine reagent 4 (1.2 eq.) in 1.00 mL
a
MeCN (0.2
M
) at rt. The reaction was conducted at 60 °C.
b0.7 eq. 4 was used together with 5 eq. pyridinium p-toluene
soulfonate (PPTS).
Scheme 3. Formation of 3-substituted indoles 12
and the 3-fluoro isochroman derivative 17.
Intrigued by the obtained results and to further harness
the observed chemoselectivity, a more detailed investiga-
tion on the mechanistic course was initiated. Addressing
the correlation of product selectivity with the electronic
nature of the N-substituents, computations were con-
ducted for substrates 3a (R = Bz) and 3f (R = Me), which
lead to opposed chemoselectivities under identical reac-
tion conditions (cf. Table 1). In principle, two reaction
pathways can be envisioned (Scheme 4). Path A gives 3-
methyl indole 12 as the single product via activation of the
nitrogen atom. In this case, the nucleophilic nitrogen first
reacts with the electrophilic iodine atom in 4, giving the
hypervalent iodonium ion J_mF after fluoride cleavage.
The now electrophilic nitrogen in J_mF is attacked in-
tramolecularly by the olefin moiety, furnishing the carbo-
cation L which is then transferred into the 3-methylindole
12 by proton abstraction. Such a mechanistic scenario17
was already suggested earlier.15,16a,b As an alternative, the
C,C double bond can be activated by 4 in a two-step pro-
cess providing access to reactive compounds B and C that
should lead, in principle, to both the 3- and 2-methyl
indole 12 and 14 or to the corresponding benzoxazepines 5
due to the ambivalent nucleophilicity of the amide group.
If the mechanism proceeds via path B, the product selec-
tivity would be determined by the electrophilicity of the
cyclopropyl carbon atoms of C.
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1
2
3
4
Scheme 4. Possible mechanisms for the conversion
of 1,1-disubstituted styrenes 3.
F
5
6
Me
Me
Me
Ar
I
4
+
4
+
7
8
9
A
NR
I
NHR
path B
path A
NH
R
(neutral)
J
3
F
Ar
R
ΔGⱡ [kcal/mol]
ΔRG [kcal/mol]
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F
-
1
a: Bz
f: Me
23.5
22.5
-8.7
-9.1
Me
F
Me
IAr
2
NH
B
NR
I
R
As for both substrates, 3a and 3f, the cyclopropyl com-
pound C is accessible kinetically and thermodynamically,
the inherent reactivity of C must be the key to explain the
chemoselectivity. Therefore, the electronic and nuclear
structure of C were analyzed in more detail: According to
NBO analysis for R = Me, intermediate C fashions a prop-
er σ bond between C2 and C7 (Scheme 5, right) and exists
rather as an imine C_Me, delocalizing the nitrogen atom
lone pair and thereby reducing its availability to act as a
nucleophile. This is not only reflected in the bond length
and bond orders (cf. Figure 1), but also in the partial
charges (see SI). Translating the electronic structure into
the HASAB concept, the lower polarization of the reac-
tion centers suggests that the nitrogen atom adds prefer-
ably to the less polarized C8 position that is also less ste-
rically hindered.
(neutral)
J_mF
Ar
- ArI
- ArI
F
7
Me
Me
8
NH
R
N
R
C
L
F
Me
Me
3
2
and/
or
Me
N
N
N
R
R
R
12
14
C_dep
(neutral)
DFT computations18 showed that for this specific sub-
strate class 3 the electrophilic activation of the nitrogen
by 4 is in general strongly endergonic from 3 and 4 to J or
J_mF and thus thermodynamically less favorable when
compared to path B (for details see SI). Consequently,
only the alternative activation pathway B was examined in
more detail. Suggested intermediates A - C were fully
optimized for R = Me, Bz and Tos (see SI). It is known
from the experimental work that the substrate is con-
sumed within minutes without significant product for-
mation implying low barriers for the first reaction step(s).
The crucial intermediate that might explain the variation
in product selectivity as a function of the N-substituent R
was deemed to be intermediate C, which can, in principle,
be attacked by the intramolecular nucleophile either at
C7 or C8. To elucidate a potential rational why the elec-
trophilic site changes by varying R and consequently the
product selectivity, the inherent reactivity of C was ex-
plored. One could argue that C is only built in case of R =
Bz, where 5 occurs as the single product, whereas for R =
Me no rearrangement process is needed and the postulat-
ed C would not be necessary. Calculations showed, how-
ever, that the activation barrier as well as the driving force
for furnishing C is independent of R. This suggests C as a
common intermediate irrespective of the N-substituent
(Table 2).19
Scheme 5. Intermediates C determining the chemo-
divergency in a step-wise process.
Plotted NBOs of the carbocationic center C7 and the local-
ized lone pair of the nitrogen atom and oxygen atom for
C_open_Bz (left) and of the C7-C2 σ-bond and the delocal-
ized lone pair, like e.g., the iminium π-bond for C_Me
(right).
Table 2. Calculations of ΔGⱡ and ΔRG for the for-
mation of the spirocyclic intermediate C_dep.
In contrast, visualization of the natural bond orbitals for
R = Bz supported a sp²-hybridized C7 atom with an empty
p-orbital pointing towards the π-cloud of the adjacent
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benzene ring (Scheme 5, left). The transformation of 3a
thus proceeds via the α-fluoro carbocation20 C_open,
1
2
3
4
5
6
7
8
9
which is stabilized by the 2p non-bonded electron-pair
back bonding of the F atom. Nucleophilic trapping of
C_open_Bz can occur only at C7, exclusively delivering
the formally rearranged benzoxazepine 5 as observed.
Hammett analysis of the C,H fluorination nicely supports
the results of the calculations and thus of a positive
charge being formed in the rate determining step in the
pathway to benzoxazepines 5 (see SI). The Lewis basic
carbonyl oxygen, which points directly to the carbocation
at C7, further alleviates the positive charge in C_open_Bz
(see Scheme 7). If this stabilization is missing, such as in
lactam 3s, the reaction takes place without a 1,2-aryl shift,
giving the 3-indole 12s (48% yield, Scheme 6a) with no 2-
indole detectable at all.
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Scheme 6. Control experiments
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Scheme 7. Comparison of the cyclization pathways for the iminium ion C (left) and the imine C_dep to furnish
the corresponding benzoxazepine D or D_dep indicating a preference of the iminium ion pathway (left).
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Cheng et al. postulated – based on computations only - a
mechanism of the cyclization proceeding solely via
C_Bz_dep to D_Bz_dep. For matters of comparison we
9
considered both pathways, via C_Bz and C_Bz_dep to-
wards D_Bz and D_Bz_dep, respectively. The activation
barriers clearly favor the pathways via C_Bz. Although
deprotonation of C_Bz would certainly enhance the nu-
cleophilicity of the nitrogen atom in C and hence in prin-
ciple allow for a facile cyclization towards the indole di-
rectly, the cyclization energy for C_Bz to the transient
D_Bz is almost barrier free (Scheme 7) implying that this
reaction path cannot be suppressed under the standard
reaction conditions. Moreover, the low cyclization barrier
Figure 1. Correlation of the extent of the carbocationic char-
acter and product selectivity.
hints at C being present in very low concentrations.
Having found evidence for the hypothesis that the carbo-
cationic character at the fluorinated carbon atom (C7) in
the common intermediate C determines the product se-
lectivity and that the carbocation C_open is the preferred
form for R = Bz and the iminium C for R = Me, it is now
interesting to search for substrates that, in principle,
provide access to both mechanistic pathways. This would
give the possibility to prepare either 5/14 or 12 depending
on the reaction conditions. Looking at the geometries,
NBO charges, and orbitals of the intermediate of N-tosyl
styrene 3c its electronic structure lies between that of 3a
and 3f with regard to its carbocationic/imine character
(Figure 1 and SI). This should lead to an ambivalent be-
havior if our correlation holds true. Indeed, if the reaction
mixture was treated with an acidic additive, thus shifting
the equilibrium from C_dep to C and as a consequence to
C_open, a 58:42-mixture of the regioisomers 12 and 14
was detectable (Scheme 6b).
Cascade Reactions to Benzylic Ketones and Indols
directed by Fluoride
With this mechanistic insight in mind, we got intrigued
by the idea to harness the selective formation of the α-
fluoro carbocation 11 in organic synthesis. Exploiting the
introduced halogen atom as a traceless directing group
and thus the reactivity of the α-fluorinated carbocation 11,
a plethora of novel transformations should be accessible,
a concept Nature actually is applying with great success.21
Probing this concept we next set out to trap 11 by H2O,
which was simply achieved by using the standard condi-
tions for the C,H fluorination but omitting the molecular
sieve. The F-carbocation 11 collapsed rapidly upon nucle-
ophilic attack of water to give exclusively the benzyl ke-
tone 13. Such metal free oxidative rearrangements facili-
tated by hypervalent iodanes have ample precedence in
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literature.22 These methods, however, often suffer from
14 resulting from an aryl migration were isolated with
1
2
3
4
5
6
7
8
harsh conditions necessary to get satisfying conversions
and often deliver regioisomeric product mixtures. This
metal free Wacker-type process triggered by 4 delivered
the ketones 13 in 63% to even quantitative yield under
mild conditions, even in the absence of the amide func-
tionality (10 examples, Scheme 8). Only for the cyclohex-
ene derivative 3aa the displacement of the hypernucleo-
fug occurred via ring contraction and not via a 1,2-aryl
migration, giving the cyclopentane 13aa.
excellent yields of up to 96%. This result again confirmed
a mechanism via an F carbocation 11 rather than a phe-
nonium ion. Besides several amides 3, the corresponding
carbamates 3 were likewise capable of undergoing this
transformation and even trisubstituted alkenes 3aq – 3au
were smoothly converted to the rearranged heterocycles
14aq – 14au. This oxidative process is characterized by a
broad functional group tolerance, including diverse alkyl,
aryl, heteroaryl, halide, alkoxy, hydroxy and amine sub-
stituents at various positions, and thus exceeds that of
related metal-mediated transformations.23 The unique
chemoselectivity of 4 was impressively proven once again,
as styrenes 3 treated with other known hypervalent
iodanes, like e.g., the Koser reagent, always provided a
mixture of 2- and 3-functionalized indoles 12 and 14.15
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Scheme 8. Substrate scope for the formation of
benzylic ketones 13.
Scheme 9. Synthesis of C2-substituted indoles 14
applying a 4-fold cascade reaction.
The reactions were carried out using styrene 1 (0.20 mmol,
1.0 eq,) and 0.24 mmol fluorine reagent 4 (1.2 eq.) in 1.00 mL
MeCN (0.2M
). The reaction was conducted at art and b60°C.
The o-nitrogen substituted ketones 13a, 13t – 13x are of
particular versatility, as they can serve as starting materi-
als in indole syntheses. As the F-iodane 4 already showed
a high functional group tolerance and the reaction to 13
proceeded under mild conditions, we were intrigued by
the idea to add a cyclocondensation step to this fluorina-
tion/1,2-aryl migration/water addition sequence. Such a
quadruple reaction cascade not only enables a chemo- but
also a regiodivergent conversion of 3. Now indoles 14 are
produced that are orthogonal in their substitution pattern
to heterocycles 12 built via the imine pathway (see
Scheme 3). Slightly acidic conditions were necessary to
facilitate the cyclocondensation (cf. SI). The best results
were achieved by adding catalytic amounts camphorsul-
phonic acid (CSA, 50 mol%) to the reaction mixture. Only
activation but no exchange of the fluoride in 4 by the CSA
was observed (see SI). Experiments using 13C-labelled 3a
together with NMR studies unambiguously corroborated
that the indole 14 is generated following the envisaged 4-
fold cascade reaction (cf. SI). With these conditions to
easily generate 2-substituted indoles 14 with high yields in
hand, a survey of structurally different 1,1-substituted
olefins 3 as substrates was conducted to elucidate the
scope of this transformation (Scheme 9). Regardless of
the electronic nature of the aromatic portion, only indoles
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Scheme 10. F-Iodane 4 triggered cascade reaction to
unnatural tryptophan analogs 16.
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The reactions were carried out using styrene 1 (0.10 mmol,
1.0 eq,), 0.12 mmol fluorine reagent 4 (1.2 eq.) and 0.05 mmol
CSA (0.5 eq.) in 0.50 mL MeCN (0.2M). The reaction was
a
b
c
conducted at rt and 60°C. Decomposition of the electron-
rich heterocycle occurred during purification.
Conclusions
With the mechanistic studies described above, the func-
tionalization of alkenes using F-iodane 4 evolved from a
phenomenon, relying on simple molecular properties, to a
concept that now allows for predicting product for-
mation. Computational and experimental investigations
disclosed the spiro compound C as the common key in-
termediate for the C,H-fluorination, C,H-oxidation, and
C,H-amination of styrenes 3. Depending on the electronic
nature of intermediate C, in particular the extent of its
carbocationic character at C7, different downstream
routes are accessible that give access to even different
compound classes from the very same structural scaffold
under identical reaction conditions. This insight on the
mechanism allowed for the first time a streamlined and
rational reaction design. With the selective trapping of
the F carbocation 11, pathways to exploit the in situ in-
stalled F atom as a traceless directing group were discov-
ered, paving the way to chemo- and regiodivergent syn-
thetic routes, even when structurally complex molecules,
such as the amino acid precursors 15, were employed. This
concept should be easily transferable to other substrate
classes thus now allowing to discover new, as yet unex-
plored structural space. Overall, an important piece of the
puzzle explaining the marvelous and, as yet, often surpris-
ing reactivity of hypervalent fluoro iodanes was provided
that offers new opportunities to explore the unprecedent-
ed chemistry of hypervalent iodanes in the future.
The reactions were carried out using styrene 1 (0.20 mmol,
1.0 eq,), 0.24 mmol fluorine reagent 4 (1.2 eq.) and 0.10 mmol
CSA (0.5 eq.) in 1.00 mL MeCN (0.2M). The reaction was
a
b
c
conducted at rt and 60°C. The O-TBDMS protected sub-
strate 3aw was used as substrate.
The power of the established method was further demon-
strated by its application to structurally complex, chiral
substrates 15 (Scheme 10). The synthesis of several
isotryptophan derivatives 16a -16d with various substitu-
ents at the aryl moiety succeeded in very good 42% – 78%
yields. No loss of optical purity was detectable during this
annulation event, making this method perfectly suited for
a late stage introduction of the indole nucleus in complex
substrates and thus a metal free Cacchi-type cyclization
procedure possible.
ASSOCIATED CONTENT
Supporting Information Available: Additional studies,
experimental procedures, compound characterization and
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Journal of the American Chemical Society
Cortes Gonzalez, M. A.; Nordeman, P.; Bermejo Gomez, A.;
copies of NMR spectra are available free of charge via the
Meyer, D. N.; Antoni, G.; Schou, M.; Szabo, K. J., Chem.
Commun. 2018, 54, 4286-4289; (k) Yang, B.; Chansaenpak, K.;
Wu, H.; Zhu, L.; Wang, M.; Li, Z.; Lu, H., Chem. Commun. 2017,
53, 3497-3500.
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Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
(6)
(a) Arnold, A. M.; Pöthig, A.; Drees, M.; Gulder, T., J.
Am. Chem. Soc. 2018, 40, 4344-4353; (b) Fabry, D. C.; Stodulski,
M.; Hoerner, S.; Gulder, T., Chem. Eur. J. 2012, 18, 10834-10838;
(c) Ulmer, A.; Stodulski, M.; Kohlhepp, S. V.; Patzelt, C.; Poethig,
A.; Bettray, W.; Gulder, T., Chem. Eur. J. 2015, 21, 1444-1448; (d)
Patzelt, C.; Pöthig, A.; Gulder, T., Org. Lett. 2016, 18, 3466-3469;
(e) Stodulski, M.; Goetzinger, A.; Kohlhepp, S. V.; Gulder, T.,
Chem. Commun. 2014, 50, 3435-3438; (f) Stodulski, M.; Kohlhepp,
S. V.; Raabe, G.; Gulder, T., Eur. J. Org. Chem. 2016, 2016, 2170-
2176.
* julia.rehbein@uni-regensburg.de
* tanja.gulder@tum.de
ORCID
9
Tanja Gulder: 0000-0003-4870-226
Julia Rehbein: 0000-0001-9241-0637
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(7)
Charpentier, J.; Fruh, N.; Togni, A., Chem. Rev. 2015,
Author Contributions
115, 650-682.
‡These authors contributed equally.
(8)
(a) Zhou, B.; Xue, X.-s.; Cheng, J.-p., Tetrahedron Lett.
2017, 58, 1287-1291; (b) Zhou, B.; Yan, T.; Xue, X.-S.; Cheng, J.-P.,
Org. Lett. 2016, 18, 6128-6131.
ACKNOWLEDGMENT
(9)
Yan, T.; Zhou, B.; Xue, X.-S.; Cheng, J.-P., J. Org. Chem.
2016, 81, 9006-9011.
This work was funded by the Emmy-Noether (DFG, T.G.: GU
1134-3 and J.R.: RE 3630/1-1) and Heisenberg (DFG, GU 1134-4)
program of the German Research Foundation (DFG). We
thank P. Bestler, R. Schütt, and R. Fisch for technical sup-
port.
(10)
(a) Zhang, J.; Szabó, K. J.; Himo, F., ACS Catal. 2017, 7,
1093-1100; (b) Mai, B. K.; Szabo, K. J.; Himo, F., ACS Catal. 2018,
8, 4483-4492.
(11)
It is noteworthy that aryl migrations are generally
widespread among hypervalent iodane chemistry, but normally
constitute undesired side reactions leading to regioisomeric
product mixtures. For examples on the formation of regioismers
due to 1,2-aryl migration process, please see: (a) Boye, A. C.;
Meyer, D.; Ingison, C. K.; French, A. N.; Wirth, T., Org. Lett.
2003, 5, 2157-2159; (b) Prakash, O.; Pahuja, S.; Goyal, S.; Sawhney,
S. N.; Moriarty, R. M., Synlett 1990, 337-338 and ref. 18
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