Stereoselective geminal difunctionalization of vinyl arenes mediated by the bromonium ion

Article abstract of DOI:10.1039/c3cc46003g

An anti-Markovnikov geminal oxyamination of styrenyl alkenes in an intermolecular fashion using the umpolung strategy mediated by the bromonium ion is reported. Isotope labeling studies confirm the migration of the phenyl group in the semipinacol rearrang

Full text of DOI:10.1039/c3cc46003g

ChemComm
View Article Online
View Journal | View Issue
COMMUNICATION
Stereoselective geminal difunctionalization of
vinyl arenes mediated by the bromonium ion†
Cite this: Chem. Commun., 2014,
50, 70
Pandur Venkatesan Balaji and Srinivasan Chandrasekaran*
Received 6th August 2013,
Accepted 24th October 2013
DOI: 10.1039/c3cc46003g
www.rsc.org/chemcomm
An anti-Markovnikov geminal oxyamination of styrenyl alkenes in
an intermolecular fashion using the umpolung strategy mediated by
the bromonium ion is reported. Isotope labeling studies confirm the
migration of the phenyl group in the semipinacol rearrangement.
Difunctionalization of alkenes is a preeminent strategy used in organic
synthesis which has been extensively studied and widely utilized as a
transformative tool and has profound utiltity in various branches of
chemistry.1 The much studied 1,2-difunctionalization (vicinal) of
alkenes involves a simple addition across the double bond.2–7 Whereas
the geminal difunctionalization of alkenes is an intricate process, where
the single sp2 carbon of the CQC bond gets difunctionalized. The
addition of two nucleophiles to the electron rich alkene moiety,
especially in a geminal fashion, still remains challenging. Most of the
reported methods utilize the modified Wacker process8 and are limited
to simple oxidation9,10 and use of tethered nucleophiles to form
heterocycles in an intramolecular fashion.11 No promising reagent
system other than the Wacker type is available yet.
The methods that are available for the geminal difunctionaliza-
tion of alkenes in an intermolecular process using stoichiometric
nucleophiles are very scarce. Especially the intermolecular geminal
oxyamination of alkenes still remains obscure and to the best of our
knowledge it has not yet been reported under non-Wacker condi-
tions.12 In this context, we report the first non-Wacker method for
the intermolecular geminal oxyamination of alkenes using the
umpolung strategy mediated by the bromonium ion through a
semipinacol rearrangement (Scheme 1).
Scheme 1 Geminal difunctionalization of alkenes.
Then we sought to increase the electrophilicity of the
bromonium ion to facilitate this addition. After some optimization,
we found that in the presence of NBS, which is activated by AgOTf,
N-Ts-phenylalaninol 1a and styrene 2a effectively reacted to provide a
single product within 1 h in a very good yield (88%).13 We were
thrilled to find that the product formed was a 5-membered oxazo-
lidine 3a (Scheme 2) with excellent diastereoselectivity, formed by the
addition of the nitrogen and oxygen atoms to the same carbon rather
than the expected morpholine derivative E1 which comes from
vicinal addition.
This method allows the straightforward stereoselective umpolung
installation of two new heteroatoms into a single carbon of an
alkene in a domino process. Attracted by the novelty and the
potential of this addition process, further studies were taken up to
understand the scope and limitation of this protocol.
We originally intended to add 1,2-dinucleophiles (such as
1,2-aminoalcohol or 1,2-diol) across the double bond of alkenes to get
1,4-heterocycles by an annulation process. To examine the feasibility
of this addition, we first attempted to add N-Ts-phenylalaninol 1a to
styrene 2a using NBS as the electrophilic bromine source and there
was no observable product formed.
First the effect of substituents in the aminoalcohols on the
stereoselectivity of addition was studied and the results are summar-
ized in Table 1. The N-Ts-aminoalcohol 1b, the norephedrine derived
Department of Organic Chemistry, Indian Institute of Science, Bangalore-560012, India.
E-mail: scn@orgchem.iisc.ernet.in; Fax: +91 80 2360 2423; Tel: +91 80 2293 2404
† Electronic supplementary information (ESI) available: Experimental procedures and
spectral data of compounds 1a–1t and 3a–3t. CCDC 942034 and 942035. For ESI and
crystallographic data in CIF or other electronic format see DOI: 10.1039/c3cc46003g
Scheme 2 Oxazolidine formation by the addition of N-Ts-phenylalaninol 1a
to styrene 2a.
70 | Chem. Commun., 2014, 50, 70--72
This journal is ©The Royal Society of Chemistry 2014

View Article Online
Communication
ChemComm
Table 1 Effect of substituents in the aminoalcohol on the stereoselectivity
of additiona,b
Entry Amino alcohol
1
Product
Yieldc (%)
75
2
3
72
79
Scheme 3 Proposed mechanism for the addition of 1,2-aminoalcohols to
styrene.
4
5
65d
nitrogen can undergo a 6-exo-tet cyclization (Path-A) to give morpho-
line E (vicinal addition) and (ii) the phenyl group can render
neighbouring group assistance to facilitate bromide ion departure
to form a transient phenonium ion F.15 The species F then readily
undergoes a semipinacol rearrangement involving the migration of
the phenyl group, which is favoured by the formation of the planar
oxonium ion G, which finally gets cyclized in a 5-endo-trig fashion to
give oxazolidine H. In the reaction of unsubstituted N-Ts-
aminoalcohol (e.g. 1e) (when R = H) both the pathways become
possible, whereas in the case of substituted N-Ts-aminoalcohols like
1a–d (when R a H) path-B dominates due to steric interactions (D,
Scheme 3) and forms only the oxazolidine as the product. The
mechanism shown above also explains the greater control over the
stereoselectivity offered by the geminal substituent of nitrogen than
that of oxygen, since the former heteroatom gets added at the
cyclization step.
74b,e
65b, f
6
a
Conditions: 1 equiv. (0.2 mmol) of amino alcohol, 1.2 equiv. of 2a, 1.2 equiv.
of NBS, 1.4 equiv. of AgOTf, CH2Cl2, rt, 60 min. b 1f and 1g: rt, 30 min.
c Isolated yields. d Ratio of 3ea :3eb is 2 : 1. e d.r = 1 : 1.7. f d.r = 1 : 1.5.
1c and the bicyclic 2-N-Ts-indanol 1d provided the oxazolidines 3b,
3c and a tricyclic, linearly fused oxazolidine 3d, respectively, as the
sole product with excellent diastereoselectivity at the newly formed
endocyclic stereogenic center (entries 1–3, Table 1). The X-ray
diffraction analysis of the product 3b provided a robust proof for
the oxazolidine structure assigned.14
Interestingly, when the simple unsubstituted N-Ts-aminoalcohol
1e was treated with styrene (NBS, AgOTf, CH2Cl2, rt) [entry 4, Table 1]
it yielded a mixture of two different heterocycles, 6-membered
morpholine 3ea and 5-membered oxazolidine 3eb in a 2 : 1 ratio,
which are formed by the vicinal and geminal addition respectively.
However, when the 1-substituted N-Ts-aminoalcohols 1f and 1g
were reacted with styrene under the reaction conditions the corre-
sponding oxazolidines were obtained in good yields with moderate
diastereoselectivity (d.r. = 1 : 1.7 for 3f; d.r. = 1:1.5 for 3g). This
decrease in the diastereoselectivity can be attributed to the lack of
geminal substituents at the annulating nucleophile.
In light of the above observations, we propose a mechanism as
depicted in Scheme 3 for this stereoselective intermolecular geminal
difunctionalization of styrenes. Initially the NBS activated by AgOTf
delivers an electrophilic bromonium ion, which gets added to the
electron rich p-bond of vinyl benzene A (styrene) to form a bridged
bromonium ion B. This gets equilibrated to the more stable open
benzylic carbocation C. The hydroxyl group of the nucleophile adds
intermolecularly to this carbocation C in a rate determining step to
give a bromobenzylether intermediate D. The bromogroup of ether D
gets activated by Ag; at this stage the intramolecular reaction can
take place via two kinetically controlled pathways. (i) The tethered
Since we envisaged that this addition process must involve a
benzylic carbocationic intermediate (C, Scheme 3) and also a
semipinacol rearrangement (F, Scheme 3) by a Whitmore 1,2
shift of the phenyl group, the effect of the substituent in the
migrating phenyl group of styrene on the course of the reaction
was studied and the results are shown in Table 2.
The p-methyl substituted styrene 2h and 2,4,6-trimethyl substituted
styrene 2i gave the corresponding oxazolidines 3h and 3i, respectively,
in good yields and high diastereoselectivity as observed for styrene 2a.
Interestingly, the substrates with electron withdrawing groups
p-bromo 2j and the p-fluoro 2k also gave the products 3j and 3k,
respectively, in high yields. In the case of m-Cl-styrene 2l the oxazo-
lidine 3l was obtained along with the uncyclized bromoether (inter-
mediate D, Scheme 3). The highly electron deficient m-NO2 styrene 2m
failed to undergo the addition reaction. This relative decrease/absence
of reactivity of electron deficient styrenes to undergo oxidative
addition-cum-annulation provides additional support for the interme-
diacy of the benzylic carbocation and the migration of the nucleophile.
Next, the influence of stereochemistry of olefin on the
diastereoselectivity of product formation was examined and
the results are depicted in Scheme 4.
Intriguingly, when the diastereomeric alkenes of b-methylstyrene
2n and 2o were subjected to this addition (NBS, AgOTf, CH2Cl2, rt)
This journal is ©The Royal Society of Chemistry 2014
Chem. Commun., 2014, 50, 70--72 | 71

View Article Online
ChemComm
Communication
Table 2 Effect of substituents in the phenyl group of styrene in the
annulation processa,b,c
Scheme 6 Synthesis of pseudoprolines from styrene.
In conclusion, the first report on the non-Wacker inter-
molecular geminal oxyamination of vinyl arenes (styrenes)
through a domino process is described. This highly stereo-
selective oxidative geminal addition is found to involve a
semipinacol rearrangement. The diastereomeric alkenes were
found to show stereoconvergence in the product formation.
The migration of the phenyl group in the semipinacol rearran-
gement was confirmed by deuterium labeling studies. The
efficacy of this method was exemplified in the synthesis of
pseudoprolines from styrene.
a
b
c
d
Conditions: the same as Table 1. 3m: rt, 12 h. 3l: rt, 4 h. Isolated
e
yields. Uncyclized bromoether = 29%.
We thank Mr. Amol G. Dikundwar and Prof. T. N. Guru Row
for their help in X-ray crystal structure determination of com-
pounds 3b and 3n. P.V.B. thanks IISc for an Int.PhD Fellowship
and CSIR, India, for a CSIR-SRF fellowship. S.C. thanks DST,
India, for a JC Bose Fellowship.
Notes and references
1 E. Block and A. L. Schwan, in Comprehensive Organic Synthesis, ed. B. M.
Trost and I. Fleming, Pergamon, Oxford, 1st edn, 1991, vol. 4, p. 329.
2 (a) A. Wang, H. Jiang and H. Chen, J. Am. Chem. Soc., 2009,
131, 3846; (b) L. Emmanuvel, T. M. A. Shaikh and A. Sudalai, Org.
Lett., 2005, 7, 5071; (c) R. B. Woodward and F. V. Brutcher Jr., J. Am.
Chem. Soc., 1958, 80, 209.
Scheme 4 Stereoconvergence of diastereomeric alkenes.
they were found to furnish oxazolidine 3n as the sole product with
the same stereochemistry at both the newly formed endocyclic and
exocyclic stereogenic centers. The observed stereoidentity of the
products formed strongly implies the convergence of the diastereo-
meric intermediates formed from the diastereomeric olefins. It is
pertinent to speculate that the rotation of the Ca–Cb bond (inter-
mediate C, Scheme 3) of the open or weakly bound carbocation
causes the loss of stereogenicity of the olefin, which eventually
causes the loss of stereospecificity through stereoconvergence.
To follow the trajectory of the migration process, the b,b-di-
deuterated-styrene 2p was chosen as the olefin for investigation.
This styrene containing two deuteriums and a phenyl group at
the vicinal position, under these oxidative addition conditions, got
transformed into an oxazolidine 3p containing the exocyclic methyl-
ene group constituting two deuteriums and a phenyl group on the
same carbon (Scheme 5). This result unequivocally confirms the
migration of the phenyl group from the hydrogen attached carbon
(Ca, migration origin) to the di-deuterium attached carbon (Cb,
migration terminus) through a semipinacol rearrangement (inter-
mediates D–G, Scheme 3).
3 T. J. Donohoe, C. K. A. Callens, A. Flores, A. R. Lacy and A. H. Rathi,
Chem.–Eur. J., 2011, 17, 58.
˜
´
4 (a) K. Muniz and C. Martınez, J. Org. Chem., 2013, 78, 2168;
(b) F. Cardona and A. Goti, Nat. Chem., 2009, 1, 269.
5 S. D. R. Christie and A. D. Warrington, Synthesis, 2008, 1325.
6 (a) U. Farid and T. Wirth, Angew. Chem., Int. Ed., 2012, 51, 3462;
(b) V. A. Schmidt and E. J. Alexanian, J. Am. Chem. Soc., 2011,
133, 11402; (c) H. M. Lovick and F. E. Michael, J. Am. Chem. Soc.,
2010, 132, 1249.
7 (a) S. E. Denmark, W. E. Kuester and M. T. Burk, Angew. Chem., Int.
Ed., 2012, 51, 10938; (b) L. Zhou, D. W. Tay, J. Chen, G. Y. C. Leung
and Y.-Y. Yeung, Chem. Commun., 2013, 49, 4412.
8 J. Tsuji, Synthesis, 1984, 369.
9 (a) P. Teo, Z. K. Wickens, G. Dong and R. H. Grubbs, Org. Lett., 2012,
14, 3237; (b) C. N. Cornell and M. S. Sigman, Org. Lett., 2006, 8, 4117;
(c) J. Chen and C.-M. Che, Angew. Chem., Int. Ed., 2004, 43, 4950;
(d) H. Kikuchi, K. Kogure and M. Toyoda, Chem. Lett., 1984, 341.
10 (a) U. Farid, F. Malmedy, R. Claveau, L. Albers and T. Wirth, Angew.
Chem., Int. Ed., 2013, 52, 7018; (b) M. A. Kumar, P. Swamy,
M. Naresh, M. M. Reddy, C. N. Rohitha, S. Prabhakar,
A. V. S. Sarma, J. R. P. Kumar and N. Narender, Chem. Commun.,
2013, 49, 1711; (c) A. D. Chowdhury and G. K. Lahiri, Chem.
Commun., 2012, 48, 3448; (d) A. M. Balija, K. J. Stowers, J. Schultz
and M. S. Sigman, Org. Lett., 2006, 8, 1121; (e) T. Hosokawa, T. Ohta,
S. Kanayama and S.-I. Murahasi, J. Org. Chem., 1987, 52, 1758.
11 R. M. McDonald, G. Liu and S. S. Stahl, Chem. Rev., 2011, 111, 2981.
The potency and the expediency of this geminal oxidative
addition were exemplified in the straightforward synthesis of
pseudoprolines 3q and 3t from styrene 2a in a single pot with a 12 (a) A. F. Ward and J. P. Wolfe, Org. Lett., 2011, 13, 4728;
(b) L. D. Elliott, J. W. Wrigglesworth, B. Cox, G. C. Lloyd-Jones and
very high stereoselectivity (Scheme 6).
K. I. Booker-Milburn, Org. Lett., 2011, 13, 728.
13 When the reaction was performed with the lesser equivalents
(catalytic) of NBS (0.2 equiv.) or AgOTf (0.2 equiv.), the yield of the
product was found to decrease proportionally. For optimization data
refer to ESI†.
14 CCDC 942034 and 942035 contain the supplementary crystallo-
graphic data for the compunds 3b and 3n.
15 D. J. Cram, J. Am. Chem. Soc., 1952, 84, 2129.
Scheme 5 Deuterium labeling study.
72 | Chem. Commun., 2014, 50, 70--72
This journal is ©The Royal Society of Chemistry 2014