Highly efficient two-step synthesis of C-sp3-centered geminal diiodides

Article abstract of DOI:10.1021/ol047997l

(Chemical Equation Presented) Trisubstituted gem-diiodoalkenes of functionalized chains are efficiently reduced to the corresponding terminal geminal diiodides in high yields upon treatment with the diazene precursor, diethyl 4-(hydrazinosulfonyl)-benzyl phosphonate.

Full text of DOI:10.1021/ol047997l

ORGANIC
LETTERS
2004
Vol. 6, No. 25
4731-4734
Highly Efficient Two-Step Synthesis of
C-sp3-Centered Geminal Diiodides
Jean-Manuel Cloarec and Andre´ B. Charette*
De´partement de Chimie, UniVersite´ de Montre´al, P.O. Box 6128 Station Downtown,
Montre´al, Que´bec, Canada H3C 3J7
andre.charette@umontreal.ca
Received September 30, 2004
ABSTRACT
Trisubstituted gem-diiodoalkenes of functionalized chains are efficiently reduced to the corresponding terminal geminal diiodides in high
yields upon treatment with the diazene precursor, diethyl 4-(hydrazinosulfonyl)-benzyl phosphonate.
Geminal diiodides (RCHI2 where R is aryl or alkyl) are
precursors to various organometallic intermediates that can
be used as novel reagents to produce carbon-carbon bonds.1
It is extremely difficult to find an adequate substitute for
gem-diiodo compounds due to their unique reactivity. In
contrast, the use of functionalized gem-diiodo compounds
remains scarce in synthesis,2 mainly due to the lack of
suitable methods to access them when other functional groups
are present in a substrate.
Their usefulness in mechanistic investigations and their
synthetic potential have generated much interest in the
preparation of compounds containing gem-diiodides centered
on an sp3 carbon. This area of research extends from Myers’s
recent contribution3 to the pioneering work of Letsinger and
Kammeyer4b five decades ago. Synthetic methods in which
the oxidation state of the carbon is preserved3,4 or increased5
have shown low compatibility with functional groups and
usually require uncommon reagents in addition to the need
for tedious purification techniques. Presently, the most widely
used method is that involving the alkylation reaction of
CHI2Li with highly electrophilic partners (primary halides
or cyclic sulfates) since the reaction temperature has to be
kept quite low to avoid carbene formation.6 Isolation of the
(1) For leading references of selected topics, see below. Diastereoselective
cyclopropanation via R1CHI(ZnEt), see: (a) Scho¨llkopf, U.; Groth, U.;
Tiller, T. Liebigs Ann. Chem. 1991, 857-860. (b) Sugimara, T.; Katagiri,
T.; Tai, A. Tetrahedron Lett. 1992, 33, 367-368. Enantioselective synthesis
of allenes via R1CHI(ZnBu), see: (c) Varghese, J. P.; Zouev, I.; Aufauvre,
L.; Knochel, P.; Marek, I. Eur. J. Org. Chem. 2002, 4151-4158. Diastereo-,
enantioselective cyclopropanation via (R1CHI)2Zn, see: (d) Charette, A. B.;
Lemay, J. Angew. Chem., Int. Ed. Engl. 1997, 36, 1090-1092. Catalytic
diastereo-, enantioselective cyclopropanation via (R1CHI)2Zn, see: (e)
Denmark, S. E.; Christenson, B. L.; O’Connor, S. P; Murase, N. Pure Appl.
Chem. 1996, 68, 23-27. (E)-Olefination via R1CH(CrX)2, see: (f) Okazoe,
T.; Takai, K.; Utimoto, K. J. Am. Chem. Soc. 1987, 109, 951-953.
Diastereoselective cyclopropanation via R1CHI(SmI), see: (g) Molander,
G. A.; Etter, J. B. J. Org. Chem. 1987, 52, 3942-3944. Diasteroselective
alkylation of aldehydes via R1CHI(SmI2), see: (h) Matsubara, S.; Yoshioka,
M.; Utimoto, K. Angew. Chem., Int. Ed. Engl. 1997, 36, 617-618.
Diastereo-, enantioselective epoxidation via R1CHI(MgCl), see: (i) Schulze,
V.; Hoffmann, R. W. Chem.sEur. J. 1999, 5, 337-344. o-Alkylation of a
phenol via R1CHI(ZnEt), see: (j) Lehnert, E. K.; Sawyer, J. S.; MacDonald,
T. L. Tetrahedron Lett. 1989, 30, 5215-5218.
(3) Furrow, M. E.; Myers, A. G. J. Am. Chem. Soc. 2004, 126, 5436-
5445.
(4) From geminal dichloride. Use of FeCl3, see: (a) Miller, J. A.; Nunn,
M. J. Tetrahedron Lett. 1974, 15, 2691-2694. Use of AlCl3, see: (b)
Letsinger, R. L.; Kammeyer, C. W. J. Am. Chem. Soc. 1951, 73, 4476-
4476. Use of AlI3, see: (c) Anson, C. E.; Sheppard, N.; Powell, D. B.;
Norton, J. R.; Fisher, W.; Keiter, R. L.; Johnson, B. F. G.; Lewis, J.;
Bhattacharrya, A. K.; Knox, S. A. R.; Turner, M. L. J. Am. Chem. Soc.
1994, 116, 3058-3062. From an aldehyde. Use of P2I4, see: (d) Feshchenko,
N. G.; Kondratenko, N. V.; Yagupol’skii, L. M.; Kirsanov, A. V. Zh. Org.
Khim. 1970, 6, 190-190. Use of TMSI, see: (e) Jung, M. E.; Mossman,
A. B.; Lyster, M. A. J. Org. Chem. 1978, 43, 3698-3701. Use of Tf2O/
MgI2, see: (f) Garcia Martinez, A.; Herrera Fernandez, A.; Martinez
Alvarez, R.; Garcia Fraile, A.; Bueno Calderon, J.; Osio Barcina, J. Synthesis
1986, 1076-1078. From a triple bond, see: (g) Aufauvre, L.; Marek, I.;
Knochel, P. Chem. Commun. 1999, 2207-2208. From a diazo, see: (h)
Neuman, R. C. Jr.; Rahm. M. L. J. Org. Chem. 1966, 31, 1857-1859. See
also: (h) Pross. A.; Sternhell, S. Aust. J. Chem. 1970, 23, 989-1003.
(5) Gonzalez, C. C.; Kennedy, A. R.; Leon, E. I.; Riesco-Fagundo, C.;
Suarez, E. Angew. Chem., Int. Ed. 2001, 40, 2326-2328.
(2) For cyclopropanation using CH3CHI2, see: (a) Liu, P.; Jacobsen, E.
N. J. Am. Chem. Soc. 2001, 123, 10772-10773. Olefination using
C2H5CHI2, see: (b) Stragies, R.; Blechert, S. J. Am. Chem. Soc. 2000, 122,
9584-9591. Olefination using C13H27CHI2, see: (c) Johnson, D. V.; Felfer,
U.; Griengl, H. Tetrahedron 2000, 56, 781-790. Olefination using
(MeO)2CH(CH2)5CHI2, see: (d) Rechka, J. A.; Maxwell, J. R. Tetrahedron
Lett. 1988, 29, 2599-2600.
10.1021/ol047997l CCC: $27.50
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gem-diiodide from residual CH2I2 or the electrophile is not
always possible. Furthermore, the compounds containing
gem-diiodides are often highly unstable7 and can easily
undergo decomposition via the free carbene.8 In this com-
munication, we describe an efficient new mild route to
functionalized gem-diiodides. The method involves the
transformation of a carbonyl 1 into a gem-diiodoalkene9 2
that is then chemoselectively reduced under metal-free
reduction (Scheme 1).
in several ways, including one that has been reported to be
suitable to reduce alkynes with no over-reduction of a
carbon-iodine bond (Table 1, entry 4).11 After extensive
Table 1. Survey of Conditions for the Reduction of Geminal
Diiodoalkene 2f
Scheme 1. General Approach to 1,1-Diiodoalkanes
Previous examples involving the reduction of gem-
dihaloalkenes are limited to the specific case of gem-difluoro-
and dichloroalkenes that were reduced upon treatment with
H2 and Pd/C.10 We avoided harsh reduction conditions with
metal catalysts due to the sensitivity of both the starting
alkene and the resulting gem-diiodide. A wide range of gem-
diiodalkenes 2 were synthesized from aldehydes 1 (Scheme
2). The reductant “diazene” (HNdNH) that can be generated
Scheme 2. Synthesis of 1,1-Diiodoalkenesa
b
a See Supporting Information. 1H NMR of crude mixture.
experimentation to find an efficient set of conditions (Table
1),11 we were pleased to discover that the decomposition of
arylsulfonohydrazide is a suitable approach for the reduction
of diiodoalkene 2f. When the decomposition was promoted
(6) Displacement of primary halides by LiCHI2, see: (a) Charreau, P.;
Julia, M.; Verpeaux, J. N. Bull. Soc. Chim. Fr. 1990, 127, 275-282. Ring
opening of cyclic sulfates by LiCHI2, see: (b) Stiasny, H. C.; Hoffmann,
R. W. Chem.sEur. J.. 1995, 1, 619-624. Use of CHI3 as source of a “CI2”
unit, see: (c) Baker, R.; Castro, J. L. J. Chem. Soc., Perkin Trans. 1 1990,
47-65. (d) Seyferth, D.; Lambert, R. L. Jr. J. Organomet. Chem. 1973,
54, 123-130. See also: (e) Christoph, G. G.; Fleischer, E. B. J. Chem.
Soc., Perkin Trans. 2 1975, 600-603.
(7) Decomposition and/or â-elimination proceed upon exposure for hours
to H2O2, pyridine, HCl, or NaOH in water. â-Elimination with DBU, see:
Garcia Martinez, A.; Martinez Alvarez, R.; Martinez Gonzalez, S.;
Subramanian, R. L.; Conrad, M. Tetrahedron Lett. 1992, 33, 2043-2044.
(8) Using hν irradiation, see: (a) Miranda, M. A.; Perez-Prieto, J.; Font-
Sanchis, E.; Scaiano, J. C. Acc. Chem. Res. 2001, 34, 717-726. See also:
(b) Pienta, N. J.; Kropp, P. J. J. Am. Chem. Soc. 1978, 100, 655-657.
Using LAH, see: (c) Ashby, E. C.; Deshpande, A. K. J. Org. Chem. 1994,
59, 3798-3805.
(9) For selected references for the synthesis of trisubstituted gem-
diiodoalkenes, see: (a) Gavin˜a, F.; Luis, S. V.; Ferrer, P.; Costero, A. M.;
Marco, J. A. J. Chem. Res., Miniprint 1986, 2843-2852. (b) Dabdoub, M.
J.; Dabdoub, V. B.; Baroni, A. C. M. J. Am. Chem. Soc. 2001, 123, 9694-
9695. (c) Bonnet, B.; Le Gallic, Y.; Ple´, G.; Duhamel, L. Synthesis 1993,
1071-1073.
a For experimental details, see Supporting Information. Methods
used for the synthesis of geminal diiodoalkenes: A: PPh3, CI4,
DCM, rt, 2.5 h, 87%. B: PPh3, CHI3, t-BuOK, PhMe, -20 °C,
10-30 min, 37-69%. C: (EtO)2P(O)CH2I, I2, LiHMDS, -78 °C,
10 min, 33-79%. D: (EtO)2P(O)CHI2, LiHMDS, THF, -78 °C,
10 min, 62-87%. E: (EtO)2P(O)Me, I2, LiHMDS, THF, -78 °C,
10 min, 46%. F: Multistep routes, see Supporting Information.
4732
Org. Lett., Vol. 6, No. 25, 2004

by NaOAc (Table 1, entry 14), the desired gem-diiodide 3f
was obtained along with a sulfonylated byproduct 6f. When
gem-diiodoalkenes 2l and 2k were submitted to the reduction,
the corresponding byproducts 6l and 6k were generated.
We eventually found that thermal decomposition of
commercially available 4-methylbenzenesulfono hydrazide
in refluxing 2-methoxyethanol (bp 124 °C) gave an encour-
aging conversion (Table 1, entry 18). It is widely accepted
that diazene decomposes during the reduction process as soon
as it is formed and that it may reduce the alkene through a
pericyclic six-membered ring-type transition structure.12
Sulfinic acid byproduct undergoes a known thermal re-
arrangement to afford compounds that are often difficult to
separate from the desired alkane.12a,13,14a To solve this
purification problem, many have used a polymer-supported
arylsulfonohydrazide14 or polymer-supported alkenes.14b,15
We opted to modify the reagent by introducing a polar
substituent at the para position to allow easy removal of the
byproducts. We eventually found that the introduction of a
diethylphosphonate group16 on the aryl moiety of the reagent
led to a compound with the desired properties. Furthermore,
this phosphonate does not interfere in the reduction process,
and a simple filtration of the cooled reaction mixture through
a pad of silica gel afforded the desired diiodo compound
without any residual sulfur-containing byproducts. The
Table 2. Preparation of Geminal Diiodides via the Reduction
of Geminal Diiodoalkenes Using 7
1
a Determined by H NMR of the crude reaction mixture. b 2-Methoxy-
ethanol was used as the solvent. c 2-Methoxyethyl ether was used as the
solvent. d Reaction was run at 162 °C. e o-Xylene was used as solvent.
f Reaction was run in a sealed tube with microwave irradiation at 144 °C.
g Reaction was run in a sealed tube with microwave irradiation at 162 °C.
h 1-Methylnaphthalene was used as the solvent. i Added in one portion.
j To the mixture was added 1 equiv of the reagent every 90 min. k To the
mixture was added 0.25 equiv of the reagent every 10 min. l To the mixture
was added 1 equiv of the reagent every 10 min. m Decomposition was
Figure 1. Arylsulfonohydrazide derivatives.
efficiency of 7 as a reducing agent was compared with
reagents 8a-c (Table 2). The variation of the para substituent
on the aryl group of the reagent had little effect on the level
of conversions of 2f into 3f as long as this group was
compatible with the reducing conditions.
1
observed by H NMR.
In 2-methoxyethanol, reagent 8a was slightly less effective
in comparison with the parent compound 8b (entry 1 vs 4).
Conversely, the corresponding reagent 8c bearing a p-NO2
group gave a conversion slightly higher than with 8b (entry
4 vs 5). Although the conversion with 7 was slightly lower
than those observed with 8b and 8c (entry 6), we were
confident that we could improve the yield by increasing the
number of equivalents of the reagent. It is also worth
mentioning that 2-methoxyethanol could be substituted for
2-methoxyethyl ether (entry 9), o-xylene (entries 12 and 17),
or 1-methylnaphthalene (entry 18). This solvent modification
is especially useful for substrates that are potentially sensitive
to nucleophilic solvents. Further optimization led us to
establish suitable conditions to obtain the desired gem-
diiodides 3b and 3f in 78 and 76% yield. High conversions
were observed for both substrates when using 4-6 equiv of
sulfonohydrazide 7 (entries 10, 11, 20, 22). However, the
portionwise addition of the reducing agent was proven to
be crucial. Much lower conversions were observed if the
(10) For gem-dichloroalkene, see: (a) Blinn, R. C.; Gunther, F. A. J.
Am. Chem. Soc. 1950, 72, 1399-1401. For gem-difluoroalkene, see: (b)
Kitazume, T.; Ohnogi, T; Miyauchi, H.; Yamazaki, T. J. Org. Chem. 1989,
54, 5630-5632.
(11) For ref see Supporting Information.
(12) Leading references, see: (a) Hu¨nig, S.; Mu¨ller, H. R.; Thier, W.
Angew. Chem., Int. Ed. Engl. 1965, 4, 271-280. (b) Pasto, D. J.; Taylor,
R. T. Org. React. 1991, 40, 91-155. Theorical studies for the outcome of
diazene, see: (c) Pasto, D. J.; Chipman, D. M. J. Am. Chem. Soc. 1979,
101, 2290-2296. (d) Pasto, D. J. J. Am. Chem. Soc. 1979, 101, 6852-
6857. (e) Tang, H. R.; McKee, M. L.; Stanbury, D. M. J. Am. Chem. Soc.
1995, 117, 8967-8973.
(13) Dewey, R. S.;Van Tamelen, E. E. J. Am. Chem. Soc. 1961, 83,
3729-3729.
(14) (a) Emerson, D. W.; Emerson, R. R.; Joshi, S. C.; Sorensen, E. M.;
Turek, J. E. J. Org. Chem. 1979, 44, 4634-4640. (b) Gavin˜a, F.; Gil, P.;
Palazo´n, B. Tetrahedron Lett. 1979, 20, 1333-1336.
(15) (a) Lacombe, P.; Castagner, B.; Gareau, Y.; Ruel, R. Tetrahedron
Lett. 1998, 39, 6785-6786. (b) Nang, T. D.; Katabe, Y.; Minoura, Y.
Polymer 1976, 17, 117-120.
(16) For the synthesis, see: (a) Herweh, J. J. Org. Chem. 1966, 31, 4308-
4312. For blowing agent properties by thermal decomposition, see: (b)
Herweh. J. U.S. Patent 3761544, 1973.
Org. Lett., Vol. 6, No. 25, 2004
4733

tively mild reducing conditions (Table 3). The generation
of a gem-diiodide in the presence of Cbz-protected primary
amines (3g), unprotected alcohols (3h), ethers (3e, 3f),
sulfones (3j), esters (3k, 3l), pyrroles (3s), thienyl groups
(3t), nitro groups (3o), nitriles (3n), and chlorides (3i) is very
effective under the reaction conditions, and high yields of
the desired products were obtained. Alkenes or alkynes are
obviously among the groups that are not compatible under
these reducing conditions. Although 2-methoxyethanol could
be used as the solvent for this reaction, it was not suitable
for substrates bearing silyl protecting groups (2m) since these
were cleaved under the reaction conditions. Attempts to
reduce a substrate containing a primary iodine (2u) led to a
SN2 reaction of this group by the solvent (9). gem-Diiodides
bearing relatively acidic â-protons were surprisingly stable
(3r, 3s), and â-elimination (and subsequent reduced mono-
iodide) products were observed only in small quantities.
In conclusion, an alternative and practical route to
synthetically useful terminal gem-diiodides was described.
The unprecedented reduction of gem-diiodoalkenes was
performed using a novel p-substituted arylsulfonohydrazide
reagent. The method shows excellent functional group
compatibility, and high yields of the products were observed.
The use of these precursors in the cyclopropanation reaction
of alkenes is in progress and will be reported in due course.
Table 3. Preparation of Geminal Diiodides via the Reduction
of Geminal Diiodoalkene Using 7a
a Typical procedure: gem-dihaloalkene 2a-t and sulfonohydrazide 7 (1
equiv) were heated under reflux for 10 min in o-xylene (1.0 M). An
additional 3 equiv of 7 was added in 3 portions over 30 min. The mixture
was cooled to room temperature, filtered through a pad of silica gel, and
concentrated, affording pure material by 1H NMR. b Isolated yield of
analytically pure 1,1-diodoalkane. c Yield obtained was 75% when per-
formed on a 3 g scale. d Up to 8% of the monoiodide was observed.
e Conversion ) 85%.
Acknowledgment. This work was supported by NSERC
(Canada) and Universite´ de Montre´al. We also acknowledge
Dr. Tan Phan Viet and Sylvie Bilodeau for technical support,
as well as Philippe Murphy for performing some experi-
ments.
reagent was not added portionwise over a long period of
time. The reaction could also be run at relatively high
concentration (entries 9, 14, 20 and 22).
This optimal set of reaction conditions was then applied
to several 1,1-diiodoalkenes to illustrate the generality of the
reaction and its functional group tolerance under the rela-
Supporting Information Available: Experimental pro-
cedures, characterization data, and spectra (1H and 13C NMR,
IR, HRMS) for the new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL047997L
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Org. Lett., Vol. 6, No. 25, 2004