Solvomercuration and demercuration of alkenes on solid-phase

Article abstract of DOI:10.1016/S0040-4039(01)01804-4

The first report of alkoxy and amino mercuration of alkenes on solid-phase is reported. The organomercurial has been transformed into alkanes, iodo ethers and Giese adducts in good yield. Cleavage by mild acid treatment released the product from the solid

Full text of DOI:10.1016/S0040-4039(01)01804-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 8383–8386
Solvomercuration and demercuration of alkenes on solid-phase†
Sadagopan Raghavan,* K. A. Tony and S. Ramakrishna Reddy
Organic Division I, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 24 April 2001; revised 12 September 2001; accepted 21 September 2001
Abstract—The first report of alkoxy and amino mercuration of alkenes on solid-phase is reported. The organomercurial has been
transformed into alkanes, iodo ethers and Giese adducts in good yield. Cleavage by mild acid treatment released the product from
the solid-support in excellent purity. © 2001 Elsevier Science Ltd. All rights reserved.
The merit of solid-phase synthesis of small organic
molecules is well recognized and is extensively
employed in drug discovery programs.1 The solid-phase
synthesis of small organic molecules depends greatly on
the adaptation of solution reactions to solid-phase,
which requires considerable effort and time, mainly due
to the different requirements and properties of the two
phases. There is an ever increasing need to find strategi-
cally important processes which are efficient and lead to
greater structural variation in a shorter period of time.
The electrophile-mediated functionalisation of alkenes2
is one such reaction which affords products with vicinal
functionalities that can be further transformed by
replacement with hydrogen, substitution via radical
intermediates, nucleophilic substitution and b-elimina-
tion. We wish to disclose herein for the first time,
amino mercuration3 and alkoxy mercuration3 of alke-
nes tethered to the solid-support, followed by demercu-
ration that includes reduction, halogenation and the
Giese reaction, of the organomercurial.
The attempted reduction of the mercurial 2a using the
standard conditions, sodium borohydride in the pres-
ence of aqueous sodium hydroxide,5 in THF followed
by cleavage from the solid support using 25% TFA in
DCM, afforded the reduction product along with size-
able amounts of eugenol arising from elimination. After
much experimentation, lithium borohydride6 in THF
was found to be the reagent of choice for reduction to
afford 5a after cleavage in 80% yield. Attempted Giese
reaction of the amino mercurial 2a with sodium boro-
hydride and excess acrylonitrile (50 equiv.) in solvents
like DMF,7 THF and DCM in the presence and in the
absence of aqueous sodium hydroxide, followed by
cleavage from the solid support afforded only trace
amounts of the adduct 6a. The reduction product was
the major component under these reaction conditions.
Finally, when the reaction was performed in
dimethoxyethane using sodium borohydride in the pres-
ence of aqueous sodium hydroxide under nitrogen,8
followed by cleavage, the desired product 6a was
obtained in 65% yield. The eugenol ether 1 was reacted
in a similar fashion with morpholine to afford mercuric
compound 2b, which underwent smooth reduction with
lithium borohydride to afford 5b in 70% yield after
cleavage. The carbonꢀcarbon bond formation reaction
employing conditions identical to that used for 2a
proceeded without incident to yield 6b in 60% yield
(Scheme 1).
Eugenol and 3-hydroxybenzoic acid allyl ester were
anchored to Wang resin through the phenolic group
using the Mitsunobu protocol.4 Treatment of the alkene
1 with aniline (6 equiv.) and mercuric trifluoroacetate (3
equiv.) in dry THF under a nitrogen atmosphere at rt
overnight afforded the amino mercurial 2a after filtra-
tion and washing the resin (Scheme 1). The difference
in the FT-IR data of 1 and 2a point to complete
reaction. Mercuric trifluoroacetate was used primarily
due to its solubility in organic solvents that swell
polystyrene based resins and its enhanced reactivity.
The polymer bound allyl ester 7 was converted to the
amino mercurial 8, which was reduced with sodium
borohydride in THF to afford the amine 11 after
cleavage. Lithium borohydride was not used for fear of
reductive cleavage. The Giese reaction afforded
aminonitriles 12 after cleavage, employing the condi-
tions detailed earlier (Scheme 2).
Keywords: alkoxy mercuration; amino mercuration; demercuration;
solid-phase; Wang resin.
* Corresponding author. E-mail: purush101@yahoo.com
† IICT Communication No 4788.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01804-4

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S. Ragha6an et al. / Tetrahedron Letters 42 (2001) 8383–8386
Scheme 1. (a) 3.0 equiv. Hg(OCOCF3)2, 6.0 equiv. R1R2NH, THF, rt, 16 h; (b) 3.0 equiv. LiBH4, THF, −23°C to rt, 16 h; (c)
8.0 equiv. NaBH4, aq. 1N NaOH, 50 equiv. acrylonitrile, DME, 0°C–rt, 16 h; (d) 25% TFA, DCM, rt, 12 h, 5a=80%, 5b=70%,
6a=65%, 6b=60%; (e) 3.0 equiv. Hg(OCOCF3)2, 3.0 equiv. ROH, DCM, rt, 16 h; (f) 3.0 equiv. LiBH4, THF, −23°C to rt, 16
h; (g) 3.0 equiv. I2, THF, rt, 12 h; (h) 25% TFA, DCM, rt, 12 h, 16a=85%, 16b=80%, 17a=90%, 17b=90%.
borohydride in the presence of a phase transfer catalyst,
or in DMF7 as the solvent. Treatment of the ethoxy
mercurial 13a with an excess of acrylonitrile under the
standard conditions afforded only traces of the Giese
adduct. The eugenol ether 1 was reacted in a similar
fashion with 2-methoxyethanol to afford 16b in 80%
yield after reduction and cleavage. Treatment of 13b
with iodine in THF afforded 17b in 90% yield. The
Giese reaction did not proceed to yield any of the
desired product with 13b also (Scheme 1). Although
CꢀC bond formation using alkoxy mercurial 13 failed,
the iodo functionality present in 15 would allow CꢀC
bond formation via a radical intermediate.
The alkoxy mercuration reaction was performed on
eugenol and trans-cinnamic acid anchored to Wang
resin. Treatment of alkene 1 with ethanol (3 equiv.) and
mercuric trifluoroacetate (3 equiv.) in dry DCM at rt
under nitrogen afforded the ethoxy mercurial 13a.
Reduction of 13a with lithium borohydride in THF
afforded 16a in 85% yield after cleavage (Scheme 1).
Treatment of 13a with iodine9 in THF afforded the
iodo ether 15a, which upon cleavage from the solid
1
support afforded iodo ether 17a in 90% yield. The H
NMR spectrum of 17a revealed only two protons in the
aromatic region that resonated as two singlets, not as
two meta-coupled doublets, thereby supporting the pro-
posed structure. The mass spectrum of 17a also sup-
ported the presence of two iodine atoms. Unlike
b-acetoxy mercurials,10 b-hydroxy and b-alkoxy
mercurials11 have been employed in carbonꢀcarbon
bond forming reactions with moderate success, particu-
larly using sodium trimethoxyborohydride12 or sodium
The polymer bound cinnamate ester 18 was converted
to the ethoxy mercurial 19, which was reduced with
tributyltin hydride13 in THF to afford b-alkoxy cin-
namic acid 22 after cleavage. Iodination of 19 pro-
ceeded cleanly to afford a single product 23 after

S. Ragha6an et al. / Tetrahedron Letters 42 (2001) 8383–8386
8385
Scheme 2. (a) 3.0 equiv. Hg(OCOCF3)2, 6.0 equiv. R1R2NH, THF, rt, 16 h; (b) 5.0 equiv. NaBH4, DME, 0°C–rt, 16 h; (c) 8.0
equiv. NaBH4, aq. 1N NaOH, 50 equiv. acrylonitrile, DME, 0°C–rt, 16 h; (d) 25% TFA, DCM, rt, 12 h, 11a=75%, 11b=70%,
12a=60%, 12b=50%.
cleavage (Scheme 3). Since the radical generated from 21
for 15 min at 0°C under a nitrogen atmosphere. DEAD
(1.82 g, 6.3 mmol, 3.0 equiv.) was added at 0°C and the
mixture stirred at rt for 16 h. The resin was collected by
filtration and washed successively with DMF (3×20 mL),
dioxane (3×20 mL), DCM (3×20 mL), 1:1 DCM/MeOH
(3×20 mL), MeOH (3×20 mL), DCM (3×20 mL) and
finally with ether (3×20 mL). Resin 1 was dried in vacuo
and used in the next step.
is not nucleophilic, the Giese reaction was not attempted.
In summary, we have demonstrated alkoxy and amino
mercuration on solid-phase using a limited number of
examples. The organomercurials have been used success-
fully to access structurally diverse compounds through
CꢀC bond forming reactions, halogenation and reduc-
tion.
Amino mercuration: Mercuric trifluoroacetate (1.41 g,
3.3 mmol, 3.0 equiv.) and aniline (613 mg, 6.6 mmol, 6.0
equiv.) were added successively to the resin (820 mg, 1.35
m eq./g) suspended in THF (11 mL) and allowed to stir
at rt for 16 h under nitrogen. The resin was filtered and
washed as detailed earlier to afford resin 2a.
Typical experimental procedure
Mitsunobu reaction: Wang resin (1. 25 g, 1.7 m eq./g),
eugenol (1.72 g, 6.3 mmol, 3.0 equiv.) and PPh3 (2.75 g,
6.3 mmol, 3.0 equiv.) were gently stirred in NMP (11 mL)
Scheme 3. (a) 3.0 equiv. Hg(OCOCF3)2, 3.0 equiv. ROH, DCM, rt, 16 h; (b) 3.0 equiv. nBu3SnH, THF, 0°C–rt, 16 h; (c) 3.0
equiv. I2, THF, rt, 12 h; (d) 25% TFA, DCM, rt, 12 h, 22a=85%, 22b=70%, 23a=90%, 23b=90%.

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S. Ragha6an et al. / Tetrahedron Letters 42 (2001) 8383–8386
Reduction: The above resin (180 mg, 0.75 m eq./g) was
suspended in THF (2.50 mL) and LiBH4 (0.36 mL, 2
M/THF) was added at −23°C under nitrogen. The
reaction mixture was allowed to attain rt and allowed
to stir for 16 h. The resin was filtered and subjected to
the wash cycle as described earlier to afford 3a.
NMR (100 MHz, CDCl3) l 176.3, 140.9, 128.6, 128.0,
126.4, 77.8, 64.5, 43.4, 15.0. m/z (EI) 194, 165, 149.
Iodination: The resin 18 (295 mg, 0.94 m eq./g) was
suspended in dry THF (3 mL) and stirred at rt for 5
min. Iodine (205 mg, 0.8 mmol, 3.0 equiv.) in THF (1
mL) was added to the resin dropwise at rt under
nitrogen and allowed to stir at the same temperature
for a further 12 h. The resin was filtered and washed to
Cleavage: The resin 3a (145 mg) was treated with 25%
TFA in DCM (2 mL) at rt for 16 h. The resin was
filtered and washed thoroughly with DCM. The com-
bined filtrates were evaporated and the residue dis-
solved in ethyl acetate and washed successively with
satd aq. sodium bicarbonate, water, brine, dried over
sodium sulfate and evaporated to afford 5a (50 mg,
1
afford 21a. Cleavage afforded iodo ether 23a. H NMR
(200 MHz, CDCl3) l 7.30 (m, 5H), 4.50 (d, J=9.4 Hz,
1H), 4.40 (d, J=9.4 Hz, 1H), 3.38 (q, J=7.0 Hz, 2H),
1.18 (t, J=7.0 Hz, 3H). 13C NMR (100 MHz, CDCl3)
l 174.0, 137.2, 128.9, 128.7, 128.4, 81.1, 65.0, 26.8, 14.9.
m/z (EI) 193, 164.
1
80%). H NMR (200 MHz, CDCl3) l 7.14 (m, 2H),
6.80 (d, J=8.0 Hz, 1H), 6.67 (m, 2H), 6.60 (m, 3H),
5.40 (bs, 1H), 3.83 (s, 3H), 3.75 (m, 1H), 2.80 (dd,
J=10.6, 8.5 Hz, 1H), 2.70 (dd, J=10.6, 5.3 Hz, 1H),
1.06 (d, J=6.4 Hz, 3H). 13C NMR (100 MHz, CDCl3)
l 146.7, 146.4, 144.3, 130.1, 129.3, 122.3, 117.8, 114.3,
114.0, 112.1, 55.9, 50.0, 41.7, 20.1. m/z (EI) 257, 183.
Acknowledgements
S.R. is thankful to Dr. J. S. Yadav, Head, Org. Div. I
and Dr. K. V. Raghavan, Director, I.I.C.T, for their
constant support and encouragement. K.A.T. is thank-
ful to CSIR, New Delhi for a fellowship.
CꢀC bond formation: Resin 3a (180 mg, 0.75 m eq./g)
was suspended in DME and cooled to 0°C. Acryloni-
trile (0.8 mL, 12 mmol, 50 equiv.) was added. Sodium
borohydride (71 mg, 1.92 mmol, 8.0 equiv.) dissolved in
1N NaOH (1.92 mL) was added dropwise at 0°C under
nitrogen. The reaction mixture was allowed to attain rt
and stirred for 16 h. The resin was filtered and washed
as before to afford resin 4a.
References
1. For some leading articles refer: (a) Hermkens, P. H. H.;
Hamersma, H. J. Comb. Chem. 1999, 1, 307; (b) Brown,
R. C. D. J. Chem. Soc., Perkin Trans. 1 1998, 3293; (c)
Sammelson, R. E.; Kurth, M. E. Chem. Rev. 2001, 101,
137.
2. Block, E.; Schwan, A. L. Comprehensive Organic Synthe-
sis; Trost, B. M.; Fleming, I. Eds.; Pergamon: Oxford,
1991; Vol. 4, p. 329.
3. Larock, R. C. Solvomercuration/Demercuration in
Organic Synthesis; Springer-Verlag: Berlin, 1986.
4. Richter, L. S.; Gadek, T. R. Tetrahedron Lett. 1994, 35,
4705.
5. Brown, H. C.; Geoghegan, P. J. J. Org. Chem. 1970, 35,
1844.
The resin 4a was cleaved as was resin 3a to afford the
1
amino nitrile 6a. H NMR (200 MHz, CDCl3) l 7.20–
7.10 (m, 2H), 6.85–6.52 (m, 6H), 5.37 (bs, 1H), 3.82 (s,
3H), 3.66 (m, 1H), 2.85–2.75 (m, 2H), 2.35 (t, J=6.8
Hz, 2H), 1.85–1.50 (m, 4H). 13C NMR (100 MHz,
CDCl3) l 147.3, 146.5, 144.4, 129.4, 122.2, 119.3, 117.5,
114.4, 113.3, 112.2, 55.9, 53.1, 39.9, 33.2, 22.4, 17.0.
m/z (EI) 310, 270, 235.
Alkoxy mercuration: Resin 18 was prepared in the
same way as resin 1.
6. Takacs, J. M.; Helle, M. A.; Takusagawa, F. Tetrahedron
Lett. 1989, 30, 7321.
7. Barulenga, J.; Lopez-Prado, J.; Campos, P. J.; Asensio,
Reduction: The above resin (142 mg, 0.94 m eq./g) was
suspended in toluene (1.6 mL) and tributyltin hydride
(0.1 mL, 0.39 mmol, 3.0 equiv.) was added at 0°C
under nitrogen. The reaction mixture was allowed to
attain rt gradually overnight. The resin was filtered and
washed as detailed earlier to afford resin 20a.
G. Tetrahedron 1983, 39, 2863.
8. Yim, A.-M.; Vidal, Y.; Viallefont, P.; Martinez, J. Tetra-
hedron Lett. 1999, 40, 4535.
9. Jensen, F. R. Electrophilic Substitution of Organomercuri-
als; McGraw-Hill: New York, 1968.
10. Burke, S. D.; Fobare, W. F.; Armistead, D. M. J. Org.
Chem. 1982, 47, 3348.
11. (a) Giese, B.; Meister, J. Chem. Ber. 1977, 110, 2588; (b)
Giese, B.; Hueck, K. Tetrahedron Lett. 1980, 1829.
12. Robson, J. H.; Wright, G. F. Can. J. Chem. 1960, 38, 21.
13. Whitesides, G. M.; San Filippo, Jr., J. J. Am. Chem. Soc.
1970, 92, 6611.
Cleavage from the solid-support using 25% TFA–DCM
1
afforded 22a. H NMR (200 MHz, CDCl3) l 7.45–7.20
(m, 5H), 4.74 (dd, J=9.4, 4.7 Hz, 1H), 3.40 (q, J=7.0
Hz, 2H), 2.80 (dd, J=12.9, 9.4 Hz, 1H), 2.60 (dd,
J=12.9, 4.7 Hz, 1H), 1.20 (t, J=7.0 Hz, 3H). 13C