Stereoselective Anti-Markovnikov Geminal Diamination and Dioxygenation of Vinylarenes Mediated by the Bromonium Ion

Article abstract of DOI:10.1002/ejoc.201600203

A straightforward method is reported for the stereoselective anti-Markovnikov geminal diamination and stoichiometric geminal dioxygenation of vinylarenes mediated by a bromonium ion. The role of the substituent on the nucleophile and the nucleophilicity of the heteroatom in the competing geminal and vicinal addition pathways has been described. The stereoselectivity of the geminal dioxygenation is dependent on the ring size of the product and the position of the substituent that induces the stereoselectivity. The migration of the phenyl group through a semi-pinacol rearrangement during the geminal addition process was confirmed by the results of deuterium labelling studies.

Full text of DOI:10.1002/ejoc.201600203

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DOI: 10.1002/ejoc.201600203
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Geminal Difunctionalization
Stereoselective Anti-Markovnikov Geminal Diamination and
Dioxygenation of Vinylarenes Mediated by the Bromonium Ion
Pandur Venkatesan Balaji[a] and Srinivasan Chandrasekaran*[a]
Abstract: A straightforward method is reported for the stereo- stereoselectivity of the geminal dioxygenation is dependent on
selective anti-Markovnikov geminal diamination and stoichio- the ring size of the product and the position of the substituent
metric geminal dioxygenation of vinylarenes mediated by a that induces the stereoselectivity. The migration of the phenyl
bromonium ion. The role of the substituent on the nucleophile group through a semi-pinacol rearrangement during the gemi-
and the nucleophilicity of the heteroatom in the competing nal addition process was confirmed by the results of deuterium
geminal and vicinal addition pathways has been described. The labelling studies.
Introduction
found as the key structural unit in a variety of biologically rele-
vant molecules,[1] including tryptamine-based alkaloids, and
Structural motifs that contain two heteroatoms attached to a have found applications in coordination chemistry[2] and asym-
single carbon atom are considered to be highly privileged scaf- metric catalysis.[3] In spite of their importance, available meth-
folds and hold a special place in heterocyclic chemistry. Com- ods for their preparation are scarce. This is a consequence of
pounds such as imidazolidines and dioxolanes, which contain the inherent impediment that is faced by forming two bonds
two nitrogen and two oxygen atoms, respectively, are widely from two different heteroatoms to a single carbon atom. Access
Figure 1. General approaches to the synthesis of geminal diheteroatom-functionalized compounds (PTSA = para-toluenesulfonic acid, NBS = N-bromosuccin-
imide, and OTf = trifluoromethanesulfonate).
[a] Department of Organic Chemistry, Indian Institute of Science,
to these compounds is generally achieved by a stepwise con-
Bangalore 560012, Karnataka, India
E-mail: scn@orgchem.iisc.ernet.in
https://orgchem.iisc.ernet.in/index.php/faculty/
81-srinivasan-chandrasekaran
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/ejoc.201600203.
densation of carbonyl compounds with nucleophiles using a
heteroatom substitution strategy (Figure 1, equation 1).[4]
The well-known bimetallic Wacker process, which is used ex-
tensively for the oxidation of alkenes into aldehydes or ketones,
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proceeds through an addition-elimination mechanism, but nally diaminated products 3b–3d efficiently in very good yields
studies are mostly limited to its use as an oxidation reaction.[5] with high stereo- and regioselectivity. However, unsubstituted
By using the Wacker process and modified Wacker conditions diamine 1e formed the geminal addition product 3ea as well
with other transition metals, oxidizing agents, and alcohols as as the vicinal addition product 3eb in an equal ratio (Table 1,
the solvents (when used in a large excess amount), geminally Entry 5).
dioxygenated products such as acetals and ketals have been
Table 1. Geminal diamination of vinylarenes.[a]
obtained.[6] Other methods can be mediated/catalyzed by iod-
ine/hypervalent iodine(III) reagents, for example, geminal dioxy-
genation reactions have been performed either by the addition
of the nucleophilic solvent or the transfer of a nucleophilic li-
gand to alkenes.[7] Because these protocols allow only the addi-
tion of simple alcohols or carboxylic acids to alkenes, they have
limited applicability.
Unlike geminal dioxygenation reactions, an insufficient num-
ber of available methods exist for the geminal diamination of
alkenes. The geminal diaminated unit of tryptamine-based mol-
ecules is commonly accessed by an intramolecular cyclization
of the tethered amine to the indole unit.[8] The Michael-type
addition of amines to the electron-deficient olefins has also
been utilized for the synthesis of geminal diaminated com-
pounds.[9] Geminal dioxygenated and diaminated compounds
are also synthesized by multistep cycloaddition reactions using
the ring strain of epoxides and aziridines.[10] The highly studied
and routinely used vicinal difunctionalization of alkenes allows
only the installation of two heteroatoms at the adjacent
carbons atoms.[11] In this context, we recently reported the
bromoniun ion mediated geminal aminooxygenation and the
hypervalent iodine mediated geminal diamination and
aminooxygenation of vinylarenes (Figure 1, equation 2).[12]
Our previous work on the use of NBS/AgOTf for the geminal
aminooxygenation of alkenes was the first report of such a
transformation under non-Wacker conditions.[12a] Hence, we
were keen to study the scope and limitations of this method
for the geminal diamination and dioxygenation of vinylarenes,
despite our recent report of a metal-free process[12b] for the
geminal diamination of alkenes. Herein, we present the results
of a detailed study of the bromonium ion mediated simple one-
pot intermolecular geminal diamination and stereoselective
geminal dioxygenation of vinylarenes (Figure 1, equation 3).
[a] Reagents and conditions: diamine 1a–1e (0.30 mmol, 1 equiv.), 2a
(1.5 equiv.), NBS (1.2 equiv.), AgOTf (1.4 equiv.), and solvent (3 mL); Ts = p-
tolylsulfonyl. [b] Isolated yield.
As a result of the substituent of diamines 1a–1d (Table 1,
Entries 1–4) and steric reasons, the SN2-type endocyclization
(see below, Scheme 3, path B, vicinal addition) is much slower
than the addition to the oxonium ion (see below, Scheme 3,
path A, geminal addition). However, because of the absence of
steric effects in unsubstituted diamine 1e (Table 1, Entry 5), the
SN2-type endocyclization and the addition to the oxonium ion
are equally favored, which results in the formation of products
3ea and 3eb in an equal ratio.
Results and Discussion
We commenced our studies by first examining the feasibility
of the challenging diamination of vinylarenes under previously
reported conditions, which involved a bromonium ion medi-
ated oxidative addition[12a] (with NBS and AgOTf; Table 1).
After the successful geminal diamination of vinylarenes, we
When we attempted to add the diamine [i.e., N,N′-ditosyl-1,2- studied the stoichiometric geminal addition of 1,2-diols
diaminopropane (1a)] to styrene (2a; NBS, AgOTf, CH2Cl2, room (Table 2). The reaction of 1,2-diol 4a also exclusively formed
temp.), we were pleased that the reaction proceeded to form geminal addition product 5a as a mixture of diastereomers
imidazolidine 3a as the sole product with very high stereo- upon its addition to styrene (2a) under the same conditions
selectivity (Table 1, Entry 1). It is worth noting that under these (NBS, AgOTf, CH2Cl2, room temp.; Table 2, Entry 1). The other
conditions the two amino groups were added in an anti-Mark- monosubstituted 1,2-diols 4b and 4c were also found to give
ovnikov fashion. Enantiopure diamines such as N,N′-ditosyl- geminal addition products 5b and 5c as a mixture of diastereo-
phenylethylenediamine (1b), N,N′-ditosyl-3-phenyl-1,2-diamino- mers. Unlike the unsubstituted diamine (Table 1, Entry 5) and
propane (1c), and N,N′-ditosyl-3-isopropyl-1,2-diaminopropane an unsubstituted amino alcohol[12a] under the same conditions,
(1d) derived from phenylglycine, phenylalanine, and isoleucine, unsubstituted 1,2-ethanediol (4d) surprisingly gave only gemi-
respectively, also exclusively formed the corresponding gemi- nal addition product 5d (Table 2, Entry 4). This observation
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demonstrates the important role of the nucleophilicity of the Entries 3 and 4; cf. Table 2, Entry 2]. ꢀ-Propyl-substituted 1,3-
heteroatom in the control of the competing geminal and vicinal diol 4m gave the 2,5-disubstituted 1,3-dioxane 5m as a mixture
addition pathways.
of diastereomers when treated with styrene (2a) under the reac-
tion conditions (Table 3, Entry 5).
Table 2. Geminal addition of 1,2-diols to vinylarenes.[a]
Table 3. Geminal addition of 1,3-diols to vinylarenes.[a]
[a] Reagents and conditions: diols 4i–4m (0.50 mmol, 1 equiv.), 2a (1.2 equiv.),
NBS (1.2 equiv.), AgOTf (1.2 equiv.), and solvent (4 mL). [b] Isolated yield.
The cis stereochemistry was assigned to the newly formed
chiral center of 1,3-dioxane 5l on the basis of the high confor-
mational free energy (–ΔG°) of the 4-alkyl-substituted 1,3-diox-
ane system.[13] From 1D and 2D NOE experiments, the positive
correlations observed between the axial H-2/H-4/H-6 atoms fur-
ther confirmed the assigned relative stereochemistry of the
acetal stereocenter in 5l (Scheme 1).[14]
[a] Reagent and conditions: diols 4a–4h (0.50 mmol, 1 equiv.), 2a (1.2 equiv.),
NBS (1.2 equiv.), AgOTf (1.2 equiv.), and solvent (4 mL). [b] dr = diastereomeric
ratio. [c] Isolated yield.
trans-1,2-Dimethyl-1,2-ethanediol (4e) and the cis-1,2-di-
methyl-1,2-ethanediol (4f) formed the corresponding fully sub-
stituted dioxolanes 5e and 5f, respectively, in good yields. Diols
4g and 4h, which were derived from L-tartaric acid and meso-
tartaric acid, respectively, and contain dicarboxylic acid ester
groups also underwent the geminal addition smoothly to pro-
vide the corresponding dioxolanes 5g and 5h (NBS, AgOTf,
CH2Cl2, room temp.; Table 2, Entries 7 and 8].
After studying the addition of 1,2-diols to vinylarenes, we
examined the reactivity of 1,3-diols in this addition reaction
(Table 3). The addition of unsubstituted 1,3-propanediol (4i)
and ꢀ,ꢀ-diethyl-1,3-propanediol (4j; NBS, AgOTf, CH2Cl2, room
temp.) to styrene (2a) gave only the corresponding geminal
addition products 5i (cf. Table 2, Entry 4 and Table 1, Entry 5)
and 5j (Table 3, Entries 1 and 2). Interestingly, unlike the 1,2-
Scheme 1. 1D and 2D NOE correlations observed for compound 5l.
Because of its similarity to 5l, the cis stereochemistry was
diols, α-methyl-substituted 1,3-diols 4k and 4l, upon reaction also assigned to the acetal chiral center of 5k. These results
with styrene (2a), provided the corresponding 2,4-disubstituted clearly indicate that the stereoselectivity of the geminal dioxy-
1,3-dioxanes 5k and 5l with very high stereoselectivity (Table 3, genation is dependent on the ring size of the product (cf.
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Table 3, Entry 4 and Table 2, Entry 2) and the position of the The reaction of diol 4e with ꢀ,ꢀ-dideuterated styrene 2v (NBS,
substituent that induces the stereoselectivity of the reaction (cf. AgOTf, CH2Cl2, room temp.) furnished the ꢀ,ꢀ-dideuterio
Table 3, Entry 4 and Table 3, Entry 5).
phenyl-substituted dioxolane 5v as the sole product in good
yield (Scheme 2).
We then decided to study the effect of substituted styrenes
on the reactivity of the geminal addition reaction (Table 4).
Table 4. Effect of substituent on styrenes on the geminal dioxygenation.[a]
Scheme 2. Deuterium labelling study.
In light of the above observations, we have proposed a plau-
sible mechanism for the bromonium ion mediated geminal di-
amination and dioxygenation of vinylarenes (Scheme 3). First,
the electrophilic bromenium ion is added to A by using NBS,
which is activated by AgOTf, to form the highly reactive bromo-
nium ion B. The more stable ꢀ-bromo benzylic carbocation C
was formed upon equilibration with bromonium ion B. The nu-
cleophile (diol/diamine) then attacks the ꢀ-bromo benzylic car-
bocation C to give acylic ꢀ-bromo ether or amine D. The inter-
action of the Ag atom with the bromine of intermediate D
makes the C–Br bond highly labile. The reaction can then take
two different kinetically favored pathways for the addition of
the nucleophile to the emerging carbocation (Scheme 3, paths
A and B).
The anchimeric assistance furnished by the phenyl group at-
tached α to the heteroatom facilitates the bromide ion as a
leaving group to give phenoniun ion E (Scheme 3, path A). The
migration of phenyl group to the methylene carbon is favored
by the donation of the lone pair electrons of the heteroatom
to the carbocation, which gives rise to the formation of the
more stable oxonium/amidonium ion F. The annulation step,
by the addition of the tethered nucleophile to the stabilized
carbocation, eventually furnishes the five-membered hetero-
cycle G in an overall geminal difunctionalization of styrene. The
departure of bromide ion from intermediate D could also be
facilitated by the addition of the tethered nucleophile to the
electrophilic methylene carbon (Scheme 3, path B) before
phenyl migration occurs through the competing pathway.
The geminal diamination of a substituted diamine was found
to follow path A only (Table 1, Entries 1–4). However, in the
case of unsubstituted diamine 1e, both the competing geminal
and vicinal addition pathways were found to occur (Table 1,
Entry 5).
These results indicate the substituents on the diamines con-
trol whether the reaction proceeds through a geminal or vicinal
addition pathway. However, the diols, irrespective of their sub-
stituents, were found to proceed through the geminal addition
pathway only (Scheme 3, path A). This observation suggests
that the nucleophilicity of the heteroatom involved in the final
step controls the pathway of addition (cf. Table 1, Entry 5, and
Table 2, Entry 4). The formation of ꢀ,ꢀ-dideuterio phenyl-substi-
tuted dioxolane 5v as the sole product in the reaction of ꢀ,ꢀ-
dideuterated styrene 2v with diol 4e (NBS, AgOTf, CH2Cl2, room
temp.; Table 4, Entry 9) strongly suggests that the possible for-
mation of a phenonium ion and subsequent phenyl migration
[a] Reagents and conditions: diol 4e (0.50 mmol, 1 equiv.), 2n–2v (1.2 equiv.),
NBS (1.2 equiv.), AgOTf (1.2 equiv.), and solvent (4 mL). [b] Isolated yield.
[c] Inseparable mixture of diastereomers.
The o-, m-, and p-alkyl-substituted styrenes 2n, 2o, and 2p,
respectively, along with 2,4,6-trimethylstyrene (2q) were found
to form the corresponding geminal addition products 5n–5q
(Table 4, Entries 1–4), smoothly upon reaction with 1,2-diol 4e
under the addition reaction conditions (NBS, AgOTf, CH2Cl2,
room temp.).
Interestingly, the electron-withdrawing substituents on sty-
renes 2r and 2s also facilitated this oxidative addition to give
the respective products 5r and 5s efficiently (NBS, AgOTf,
CH2Cl2, room temp.). Under the same conditions, 1,2-diol 4e
was successfully added to trans-stilbene (2t) and trans-ꢀ-meth-
ylstyrene (2u) to provide the corresponding dioxolane 5t and a
diastereomeric mixture of dioxolane 5u in good yields (Table 4,
Entries 7 and 8).
Deuterium labeling studies were then conducted to gain in- through a semi-pinacol rearrangement is occurring during the
sight into the mechanism of this oxidative geminal addition. course of the geminal addition process.
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