Sequenced reactions with samarium(II) iodide. Sequential intramolecular Reformatsky/nucleophilic acyl substitution reactions for the synthesis of medium-sized carbocycles

Article abstract of DOI:10.1021/jo020027w

Samarium(II) iodide was used to access eight- and nine-membered carbocycles via a domino reaction comprised of a Reformatsky reaction followed by a nucleophilic acyl substitution reaction. This method represents a general and efficient approach to a variety of highly functionalized, stereodefined carbocycles.

Full text of DOI:10.1021/jo020027w

J . Org. Chem. 2002, 67, 3459-3463
3459
Sequ en ced Rea ction s w ith Sa m a r iu m (II) Iod id e. Sequ en tia l
In tr a m olecu la r Refor m a tsk y/Nu cleop h ilic Acyl Su bstitu tion
Rea ction s for th e Syn th esis of Med iu m -Sized Ca r bocycles
Gary A. Molander,* Giles A. Brown, and Isabel Storch de Gracia
Roy and Diana Vagelos Laboratories, Department of Chemistry, University of Pennsylvania,
Philadelphia, Pennsylvania 19104-6323
gmolandr@sas.upenn.edu
Received J anuary 11, 2002
Samarium(II) iodide was used to access eight- and nine-membered carbocycles via a domino reaction
comprised of a Reformatsky reaction followed by a nucleophilic acyl substitution reaction. This
method represents a general and efficient approach to a variety of highly functionalized,
stereodefined carbocycles.
In tr od u ction
framework.7 Because of the well-known entropic and
enthalpic factors associated with the formation of medium-
sized rings, these carbon-carbon bond-forming reactions
are considered quite challenging.8 In fact, the number of
general methods for preparing medium-sized carbocycles
by cyclization or cycloaddition (annulation) reactions from
acyclic precursors is relatively small.7a,9 Methods that
have been developed to access this type of carbon
framework10 include oxy-Cope rearrangements,11 Whar-
ton/Grob fragmentations,12 metathesis reactions,13 transi-
tion metal-catalyzed cycloaddition reactions,14 and a
variety of SmI2 sequenced reactions.3b,15
Samarium(II) iodide (SmI2) was introduced to the
organic chemistry community as a reducing agent over
20 years ago.1 Since that time it has become the reagent
of choice for a variety of selective reactions.2 Many of the
earlier reports concentrated on the use of SmI2 as a
reductive coupling agent for a single transformation.
However, it soon became apparent that this unique
reagent could also be employed for a variety of sequential
processes.3 Further enhancing the scope of SmI2 in any
domino reaction is the ability to adjust the reactivity and/
or selectivity of the process by varying different reaction
parameters. For example, catalysts,1,4 solvent effects,5 or
photochemical irradiation of the reaction mixture6 can
all be utilized to advantage in carrying out desired
transformations. This ability to adjust the reaction
conditions while using SmI2 greatly facilitates its use for
a variety of sequential processes (both radical and
anionic) because the reductant can be selectively tuned
for each individual step of a multistep process.
On the basis of previous studies in our laboratories,
an additional domino process leading to medium-sized
rings was visualized. When SmI2 is used as the promoter
for an intramolecular Reformatsky reaction, the observed
products are stereodefined lactones.16 Because lactones
(7) (a) Petasis, N. A.; Patane, M. A. Tetrahedron 1992, 48, 5757. (b)
Oishi, T.; Ohtsuks, Y. In Studies in Natural Products Synthesis; Atta-
ur-Rahman, Ed.; Elsevier: Amsterdam, 1989; Vol. 3, p 73. (c) Rigby,
J . H. In Studies in Natural Products Synthesis; Atta-ur-Rahman, Ed.;
Elsevier: Amsterdam, 1993; Vol. 12, p 233.
(8) Illuminati, G.; Mandolini, L. Acc. Chem. Res. 1981, 14, 95.
(9) Molander, G. A. Acc. Chem. Res. 1998, 31, 603.
(10) (a) Stach, H.; Hesse, M. Tetrahedron 1988, 44, 1573. (b) Mehta,
G.; Singh, V. Chem. Rev. 1999, 99, 881. (c) Boivin, J .; Pothier, J .;
Ramos, L.; Zard, S. Z. Tetrahedron Lett. 1999, 40, 9239. (d) Lee, T. V.;
Roden, F. S.; Porter, J . R. J . Chem. Soc., Perkin Trans. 1 1989, 2139.
(e) MacDonald, T. L.; O’Dell, D. E. J . Org. Chem. 1981, 46, 1501. (f)
Suginome, H.; Kondoh, T.; Gogonea, C.; Singh, V.; Goto˜, H.; Osawa,
E. J . Chem. Soc., Perkin Trans. 1 1995, 69.
(11) (a) Bluthe, N.; Malacria, M.; Gore, J . Tetrahedron 1984, 40,
3277. (b) J anardhanam, S.; Shanmugam, P.; Rajagopalan, K. Synth.
Commun. 1993, 23, 311. (c) J anardhanam, S.; Rajagopalan, K. J . Chem.
Soc., Perkin Trans. 1 1992, 2727. (d) Clive, D. L. J .; Russel, C. G.; Suri,
S. J . Org. Chem. 1982, 47, 1632.
(12) (a) Grob, C. A. Angew. Chem., Int. Ed. Engl. 1969, 8, 535. (b)
Grob, C. A.; Baumann, W. Helv. Chim. Acta 1955, 38, 594. (c) Wharton,
P. S.; Hiegel, G. A. J . Org. Chem. 1965, 30, 3254. (d) Garst, M. E.;
Roberts, V. A.; Prussin, C. J . Org. Chem. 1982, 47, 3969. (e) Amann,
C. M.; Fisher, P. V.; Pugh, M. L.; West, F. G. J . Org. Chem. 1998, 63,
2806. (f) Caine, D.; McCloskey, C. J .; Van Derveer, D. J . Org. Chem.
1985, 50, 175. (g) Zhang, W.; Dowd, P. Tetrahedron Lett. 1996, 37,
957. (h) Tietze, L.-F.; Reichert, U. Angew. Chem., Int. Ed. Engl. 1980,
19, 830. (i) Westen, H. H. Helv. Chim. Acta 1964, 47, 575. (j) Patel, H.
A.; Dev, S. Tetrahedron 1981, 37, 1577.
(13) (a) Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413. (b)
Fu¨rstner, A. Top. Catal. 1997, 4, 285. (c) Schuster, M.; Blechert, S.
Angew. Chem., Int. Ed. Engl. 1997, 36, 2036. (d) Fu¨rstner, A.; Thiel,
O. R.; Ackermann, L.; Schanz, H.-J .; Nolan, S. P. J . Org. Chem. 2000,
65, 2204.
The development of efficient and novel approaches to
medium-sized carbocycles is a worthy endeavor for
organic chemists. Medium-sized carbocycles are incor-
porated into a variety of natural products either as
isolated moieties or as part of a bicyclic or polycyclic
(1) Girard, P.; Namy, J .-L.; Kagan, H. B. J . Am. Chem. Soc. 1980,
102, 2693.
(2) (a) Molander, G. A. Org. React. 1994, 46, 211. (b) Soderquist, J .
A. Aldrichim. Acta 1991, 24, 15. (c) Molander, G. A. Chem. Rev. 1992,
92, 29. (d) Sasaki, M.; Collin, J .; Kagan, H. B. New J . Chem. 1992, 16,
89.
(3) (a) Molander, G. A.; Harris, C. R. Chem. Rev. 1996, 96, 307. (b)
Molander, G. A.; Harris, C. R. Tetrahedron 1998, 54, 3321.
(4) (a) Molander, G. A.; McKie, J . A. J . Org. Chem. 1992, 57, 3132.
(b) Machrouhi, F.; Hamann, B.; Namy, J .-L.; Kagan, H. B. Synlett 1996,
633. (c) Miller, R. S.; Sealy, J . M.; Shabangi, M.; Kuhlman, M. L.;
Fuchs, J . R.; Flowers, R. A., II. J . Am. Chem. Soc. 2000, 122, 7718.
(5) (a) Inanaga, J .; Ishikawa, M.; Yamaguchi, M. Chem. Lett. 1987,
1485. (b) Ruder, S. M. Tetrahedron Lett. 1992, 33, 2621. (c) Hasegawa,
E.; Curran, D. P. J . Org. Chem. 1993, 58, 5008. (d) Namy, J .-L.;
Colombo, M.; Kagan, H. B. Tetrahedron Lett. 1994, 35, 1723. (e) Cabri,
W.; Canadiani, I.; Colombo, M.; Franzoi, L.; Bedeschi, A. Tetrahedron
Lett. 1995, 36, 949. (f) Hamann, B.; Namy, J .-L.; Kagan, H. B.
Tetrahedron 1996, 52, 14225.
(6) (a) Skene, W. G.; Scaiano, J . C.; Cozens, F. L. J . Org. Chem. 1996,
61, 7918. (b) Ogawa, A.; Sumino, Y.; Nanke, T.; Ohya, S.; Sonoda, N.;
Hirao, T. J . Am. Chem. Soc. 1997, 119, 2745. (c) Ogawa, A.; Ohya, S.;
Hirao, T. Chem. Lett. 1997, 275.
10.1021/jo020027w CCC: $22.00 © 2002 American Chemical Society
Published on Web 04/19/2002

3460 J . Org. Chem., Vol. 67, No. 10, 2002
Molander et al.
Ta ble 1. Sequ en tia l Refor m a tsk y/Nu cleop h ilic Acyl
Su bstitu tion Rea ction s Med ia ted by Sa m a r iu m (II) Iod id e
Sch em e 1
are substrates for SmI2-promoted ring expansion reac-
tions, the SmI2-promoted Reformatsky reaction could be
utilized as the initial component of a two-step sequence
leading to medium-sized carbocycles. Thus, an intramo-
lecular Reformatsky-type reaction followed by a nucleo-
philic acyl substitution reaction seemed likely to lead
directly from acyclic substrates to highly functionalized,
stereodefined eight- and nine-membered carbocycles. In
the present contribution we outline the actualization of
this novel combination of reactions resulting in the
synthesis of an array of medium-sized carbocycles (Scheme
1).
Resu lts a n d Discu ssion
To test the generality of the SmI2-mediated sequential
process a series of acyclic and cyclic substrates were
synthesized and subjected to optimized reaction condi-
tions. Compounds 1-3 and 5-13 (Table 1) were synthe-
sized via an initial boron-catalyzed aldol reaction with
the appropriate ketone and aldehyde (Scheme 2).17 The
resulting â-hydroxy ketones were treated with bro-
moacetyl bromide in the presence of pyridine at 0 °C to
provide the bromoacetate derivatives. These acetates
were subjected to sodium iodide in boiling acetone to give
the desired diiodides via a double Finkelstein reaction.
Because of the sensitivity of 3-chloropropanal, in the case
of substrate 4 the aldol reaction was carried out using
3-((tert-butyldimethylsilyl)oxy)propanal.18 The resulting
aldol product was then deprotected using TBAF to give
the diol which was selectively mesylated at the primary
(14) (a) Wender, P. A.; Ihle, N. C. J . Am. Chem. Soc. 1986, 108, 4678.
(b) Wender, P. A.; Ihle, N. C.; Correia, C. R. D. J . Am. Chem. Soc.
1988, 110, 5904. (c) Wender, P. A.; Nuss, J . M.; Smith, D. B.; Sua´rez-
Sobrino, A., Vågberg, J .; Decosta, D.; Bordner, J . J . Org. Chem. 1997,
62, 4908. (d) Wender, P. A.; Takahashi, H.; Witulski, B. J . Am. Chem.
Soc. 1995, 117, 4720. (e) Wender, P. A.; Dyckman, A. J .; Husfeld, C.
O.; Kadereit, D., Love, J . A.; Rieck, H. J . Am. Chem. Soc. 1999, 121,
10442. (f) Wender, P. A.; Correa, A. G.; Sato, Y., Sun, R. J . Am. Chem.
Soc. 2000, 122, 7815. (g) Yet, L. Chem. Rev. 2000, 100, 2963.
(15) (a) Tinant, B.; Feneau-Dupont, J .; Declercq, J . P.; Ates, A.;
Marko, I. E. Bull. Soc. Chim. Belg. 1997, 106, 297. (b) Molander, G.
A.; Le Hue´rou, Y.; Brown, G. A. J . Org. Chem. 2001, 66, 4511. (c)
Molander, G. A.; Machrouhi, F. J . Org. Chem. 1999, 64, 4119. (d)
Molander, G. A.; Alonso-Alija, C. J . Org. Chem. 1998, 63, 4366.
(16) Molander, G. A.; Etter, J . B.; Harring, L. S.; Thorel, P.-J . J .
Am. Chem. Soc. 1991, 113, 8036.
(17) (a) O’Brien, P.; Porter, D. W.; Smith, N. M. Synlett 2000, 1336.
(b) Dolbier, W. R.; Rong, X. X.; Bartberger, M. D.; Koroniak, H.; Smart,
B. E.; Yang, Z.-Y. J . Chem. Soc., Perkin Trans. 2 1998, 219.
(18) Ihara, M.; Katsumata, A.; Setsu, F.; Tokunaga, Y.; Fukumoto,
K. J . Org. Chem. 1996, 61, 677.
a
b
Complex mixture. Isolated as a 32:1 mixture of diastereo-
mers. c Isolated as an 8.6:1 mixture of diastereomers.

Sequenced Reactions with Samarium(II) Iodide
J . Org. Chem., Vol. 67, No. 10, 2002 3461
Sch em e 2a
a
Key: (a) (C6H11)2BCl, NEt3, or (Bu)2BOTf, Hunig’s base; (b)
bromoacetyl bromide, pyr; (c) NaI.
Sch em e 3a
F igu r e 1. Empirical transition structure models for the SmI2-
promoted cyclization of â-haloacetoxy ketones.
The diastereoselectivity of this sequential process has
its origins in the initial SmI2-promoted Reformatsky
reaction.16 The diastereoselectivity in the SmI2-promoted
Reformatsky reaction is believed to result from the
formation of a highly organized reaction intermediate by
coordination of the oxophilic Sm(III) species to the
carbonyl of the ketone starting material. The usual
Zimmerman-Traxler chair transition structures must be
adjusted for this particular transformation because of the
bicyclic nature of the transition structures.19 Using this
modified paradigm, boat transition structures (B and D,
Figure 1) are higher in energy than the chair transition
structures (A and C) because of the usual unfavorable
interactions associated with the former. Additionally,
conformational analyses have established that Z ester
rotamers are substantially favored over the correspond-
ing E ester rotamers.20 If this preference asserted itself
in the transition state of the intramolecular Reformatsky
reaction, involvement of the chair transition structures
would be even more favored. Finally, all equatorial A is
more stable than C, accounting for the observed sense
of diastereoselection.
a
Key: (a) (C6H11)2BCl, NEt3; (b) TBAF; (c) MsCl, NEt3; (d)
bromoacetyl bromide, pyr; (e) NaI.
alcohol. The secondary alcohol was then acetylated with
bromoacetyl bromide, and the resulting compound was
subjected to the standard Finkelstein conditions to afford
the desired substrate 4 for the sequential protocol
(Scheme 3).
Initial optimization studies involved bromoacetate 1.
We postulated that the attenuated reactivity of the alkyl
chloride would allow the desired SmI2-promoted Refor-
matsky reaction to occur selectively, and only with
photochemical irradiation6 would the SmI2 be activated
enough to reduce the chloride and undergo the desired
nucleophilic acyl substitution reaction. As can be seen
from Table 1, entry 1, addition of substrate 1 to a solution
4b
of SmI2 in the presence of 2% NiI2 followed by irradia-
tion gave the desired medium-sized carbocycle in a yield
of only 39%. The use of other additives such as Fe-
(DBM)3 or LiCl4c instead of NiI2 failed to improve the
4a
Increasing the carbon chain length by one methylene
unit (Table 1, entry 3) by using 5-bromopentenal17b as
the aldehyde in the initial aldol reaction provided the
desired nine-membered carbocycle 15 as a single di-
astereomer in 76% yield. Varying the ketone used in the
aldol reaction to either acetophenone or pinacolone
provided a range of different substrates that underwent
the SmI2-promoted tandem sequence to afford both eight-
and nine-membered carbocycles in good yields as single
diastereomers (Table 1, entries 5-8). The relative ster-
eochemistry of compounds 16 and 19 was determined by
X-ray crystallography. The sense of diastereoselection
observed is consistent with a chair transition structure
in the initial Reformatsky reaction as outlined above.
When the SmI2-promoted sequential process was at-
tempted with substrate 4, the desired seven-membered
ring carbocycle was not observed and only a complex
mixture was obtained (Table 1, entry 4). It seems likely
in this case that the strain engendered in creating a
bicyclo[3.2.1] intermediate upon attack of the organosa-
marium at the mildly electrophilic lactone cannot be
overcome, and side reactions result. Attempted formation
yield of the reaction.
During the first phase of our studies, 2.5 equiv of SmI2
was used to convert 1 cleanly and nearly quantitatively
to the intermediate (chloropropyl)-â-hydroxyvalerolactone
product. Subsequently, TLC was utilized to monitor the
reaction, wherein the lactone could be observed because
it was more polar than the starting material but less
polar than the final product. Using this analytical
technique revealed that the initial Reformatsky reaction
was indeed proceeding smoothly. Thus, the low yield of
the overall process was attributed to an ineffective
nucleophilic acyl substitution. In an effort to improve the
global yield of the transformation, substrate 1 was
converted to substrate 2 via a simple Finkelstein reac-
tion. Thus, the more easily reduced alkyl iodide was
expected to improve the nucleophilic acyl substitution
component of the two-step transformation.15c Addition of
the diiodide 2 to a solution of SmI2 containing 2% NiI2
at -78 °C generated the intermediate lactone in situ.
Upon warming of the solution to room temperature, an
alkylsamarium species was generated by reaction of SmI2
with the alkyl iodide. This species reacted via a nucleo-
philic acyl substitution reaction with the lactone gener-
ated in the previous step to provide the observed medium-
sized carbocycle in 90% yield as a single diastereomer
after isolation by silica gel chromatography. The relative
stereochemistry was assigned by comparison to products
16 and 19 (vide infra).
(19) Zimmerman, H. E.; Traxler, M. D. J . Am. Chem. Soc. 1957,
79, 1920.
(20) (a) Wiberg, K. B.; Laidig, K. E. J . Am. Chem. Soc. 1987, 109,
5935. (b) Wang, X. B.; Houk, K. N. J . Am. Chem. Soc. 1988, 110, 1870.
(c) Mark, H.; Baker, T.; Noe, E. A. J . Am. Chem. Soc. 1989, 111, 6551.
(d) J ung, M. E.; Gervay, J . Tetrahedron Lett. 1990, 31, 4685.

3462 J . Org. Chem., Vol. 67, No. 10, 2002
Molander et al.
residual CHCl3 was applied as an internal standard (δ ) 7.27
of a 10-membered carbocycle via substrate 9 served to
demonstrate another limitation of the method. This time
entropic effects were presumably to blame. Again a
complex mixture of products was generated (Table 1,
entry 9).
1
ppm) for H spectra while the CDCl3 signal served as internal
standard (δ ) 77.23 ppm) for 13C spectra. Standard flash
chromatography procedures were followed using 32-63 mm
silica gel.23 Tetrahydrofuran (THF) and diethyl ether (Et2O)
were distilled immediately prior to use from sodium benzophe-
none ketyl under Ar. Samarium metal was 99.9% and -40
mesh. CH2I2 was distilled under Ar and stored over copper
granules. NiI2 powder was 99.999%. Standard benchtop tech-
niques were employed for handling air-sensitive reagents,24
and all air-sensitive reactions were carried out under N2.
Gen er a l P r oced u r e for th e Syn th esis of â-Hyd r oxy
Keton es. 7-Ch lor o-4-h yd r oxyh ep ta n -2-on e. To a solution
of acetone (1.06 g, 18.30 mmol) in 35 mL of Et2O was added
dicyclohexylboron chloride (4.48 g, 21.12 mmol) at 0 °C,
followed by the dropwise addition of NEt3 (2.85 g, 28.15 mmol).
The resulting white suspension was stirred at 0 °C for 3.5 h.
The suspension was then cooled to -78 °C, and a solution of
4-chlorobutanal (1.50 g, 14.08 mmol) in 15 mL of Et2O was
added over 5 min. The reaction mixture was stirred at -78
°C for 2 h and then stored in a freezer at -30 °C for 12 h. The
reaction mixture was then quenched with pH 7 buffer and
methanol and cooled to 0 °C, and 30 mL of H2O2 (30% v/v)
was added dropwise. The mixture was stirred at 0 °C for 1 h
and then diluted with 100 mL of H2O. The aqueous layer was
extracted with CH2Cl2, and the organic extracts were combined
and washed with brine and then dried with MgSO4. Flash
chromatography (30% EtOAc/petroleum ether) yielded 1.56 g
(67%) of the title compound as a colorless oil: 1H NMR (CDCl3,
500 MHz) δ 4.09-4.04 (m, 1H), 3.63-3.54 (m, 2H), 3.11 (d, J
) 3.0 Hz, 1H), 2.65 (dd, J ) 17.9, 2.7 Hz, 1H), 2.56 (dd, J )
17.9, 9.0 Hz, 1H), 2.18 (s, 3H), 2.01-1.94 (m, 1H), 1.88-1.82
(m, 1H), 1.61-1.56 (m, 2H); 13C NMR (CDCl3, 125 MHz) δ
210.0, 66.9, 50.1, 45.2, 33.5, 30.9, 28.8; IR (film) νmax 3436, 1712
cm-1; HRMS (CI+) calcd for (M + H)+ C7H14O2Cl 165.0682,
found 165.0690.
The threo substrate 10 was synthesized using the
standard aldol protocol employing dicyclohexylboron
chloride and triethylamine to afford the desired aldol
product in 68% yield as a 10:1 mixture of anti and syn
isomers.21 To obtain erythro substrate 11, reversal of the
aldol selectivity was realized by carrying out the reaction
using dibutylboryl triflate and Hunig’s base which pro-
vided the aldol product in 66% yield as an 8:1 mixture of
syn and anti isomers.22 Both of these mixtures of aldol
products were elaborated to the desired substrates (10
and 11) for the sequential process via the standard
sequence of reactions described previously. When these
substrates were exposed to the SmI2-promoted reaction
conditions (excess SmI2 and 2% NiI2), they both reacted
smoothly to afford the desired eight-membered car-
bocycles in moderate yields as mixtures of diastereomers
(Table 1, entries 10 and 11). The attenuation of diaste-
reoselectivity in the initial Reformatsky reaction for the
erythro isomer has been observed previously.16
The final class of substrates studied were those in
which a ring was already incorporated into the initial
structure. It was anticipated that these substrates would
provide stereodefined bicyclic products after the SmI2-
promoted sequential process. Substrates 12 and 13 were
both synthesized according to the standard sequence of
reactions outlined previously. The aldol reactions were
carried out using cyclopentylhexylboron triflate21b to give
the desired aldol products as a mixture of threo and
erythro isomers. A simple recrystallization from Et2O/n-
pentane gave exclusively the threo isomers. The structure
of the threo aldol product from cyclohexanone and 4-chlo-
robutanal was confirmed by X-ray cystallography. When
these substrates were exposed to the SmI2 reaction
conditions, they both gave the expected bicyclic products
in good yields, and only one diastereomer was observed
in each case (Table 1, entry 12 and 13). The relative
stereochemistry of product 23 was confirmed by X-ray
crystallography.
Gen er a l P r oced u r e for th e Acetyla tion of â-Hyd r oxy
Keton es w ith Br om oa cetyl Br om id e. 4-(Br om oa cety-
loxy)-7-ch lor oh ep ta n -2-on e (1). To a solution of 7-chloro-
4-hydroxyheptan-2-one (1.00 g, 6.07 mmol) in 30 mL of
anhydrous CH2Cl2 at 0 °C was added pyridine (0.96 g, 12.15
mmol) followed by bromoacetyl bromide (1.84 g, 9.11 mmol).
The resulting suspension was stirred for 2 h at 0 °C and then
quenched with 40 mL of 1 N HCl. The mixture was extracted
with CH2Cl2. The organic extracts were combined and washed
with brine and then dried with MgSO4. Flash chromatography
(20% EtOAc/petroleum ether) yielded 1.53 g (88%) of the title
compound as a colorless oil (1): 1H NMR (CDCl3, 500 MHz) δ
5.36-5.31 (m, 1H), 3.79 (s, 2H), 3.56 (t, J ) 6.1 Hz, 2H), 2.84
(dd, J ) 17.0, 7.0 Hz, 1H), 2.66 (dd, J ) 17.7, 5.6 Hz, 1H),
2.18 (s, 3H), 1.87-1.74 (m, 4H); 13C NMR (CDCl3, 125 MHz) δ
204.9, 166.7, 71.4, 47.3, 44.4, 31.3, 30.5, 28.1, 25.7; IR (film)
Con clu sion
max 1732, 1716 cm-1; HRMS (CI+) calcd for (M + H)+ C9H15O3-
A samarium(II) iodide-promoted sequential cyclization
protocol has been developed that provides an efficient
approach to the synthesis of functionalized medium-sized
carbocycles. This method involves the samarium(II)
iodide-promoted Reformatsky reaction followed by a
nucleophilic acyl substitution reaction to afford stereo-
defined medium-sized carbocycles with high yields under
mild conditions.
ν
ClBr 284.9893, found 284.9895.
Gen er a l P r oced u r e for th e F in k elstein Rea ction . 7-
Iod o-4-(iod oa cetyloxy)h ep ta n -2-on e (2). To a solution of
1 (1.00 g, 3.50 mmol) in 30 mL of acetone was added NaI (2.62
g, 17.51 mmol). The solution was heated at reflux for 16 h and
cooled to room temperature, and 50 mL of water was added.
The aqueous phase was extracted with CH2Cl2 (3 × 35 mL).
The organic extracts were combined and washed with brine
and then dried with MgSO4. Purification by flash chromatog-
raphy (20% EtOAc/petroleum ether) afforded 1.33 g (89%) of
2 as a pale yellow oil: 1H NMR (CDCl3, 500 MHz) δ 5.31-
5.28 (m, 1H), 3.65 (ABq, νAB ) 11.9 Hz, J ) 10.2 Hz, 2H), 3.22-
3.18 (m, 2H), 2.81 (dd, J ) 16.9, 6.9 Hz, 1H), 2.64 (dd, J )
16.9, 5.7 Hz, 1H), 2.18 (s, 3H), 1.92-1.87 (m, 2H), 1.81-1.71
(m, 2H); 13C NMR (CDCl3, 125 MHz) δ 204.9, 168.4, 70.9, 47.4,
Exp er im en ta l Section
1
Gen er a l P r oced u r es. H and 13C NMR were recorded at
500 and 125 MHz for proton and carbon, respectively. CDCl3
was employed as the solvent unless stated otherwise, and
34.9, 30.7, 29.1, 6.0, -5.3; IR (film) νmax 1734, 1717 cm-1
;
(21) (a) Brown, H. C.; Dhar, R. K.; Bakshi, R. K.; Pandiarajan, P.
K.; Singaram, B. J . Am. Chem. Soc. 1989, 111, 3441. (b) Brown, H. C.;
Dhar, R. K.; Bakshi, R. K.; Ganesan, K.; Singaram, B. J . Org. Chem.
1992, 57, 499. (c) Ganesan, K.; Brown, H. C. J . Org. Chem. 1993, 58,
7162.
HRMS (CI+) calcd for (M + Na)+ C9H14O3I2Na 446.8930, found
446.8947.
(22) (a) Evans, D. A.; Vogel, E.; Nelson, J . V. J . Am. Chem. Soc.
1979, 101, 6120. (b) Evans, D. A.; Nelson, J . V.; Vogel, E., Taber, T. R.
J . Am. Chem. Soc. 1981, 103, 3099.
(23) Still, W. C.; Kahn, M.; Mitra, A. J . Org. Chem. 1978, 43, 2923.
(24) Brown, H. C. Organic Syntheses via Boranes; Wiley: New York,
1975.

Sequenced Reactions with Samarium(II) Iodide
J . Org. Chem., Vol. 67, No. 10, 2002 3463
Gen er a l P r oced u r e for th e Sequ en ced Rea ction s Us-
in g Sa m a r iu m (II) Iod id e. Samarium metal (0.88 g, 5.85
mmol) was added under a flow of N2 to an oven-dried flask. A
50 mL volume of THF was added, the suspension was cooled
to 0 °C, and CH2I2 (1.34 g, 5.0 mmol) was added. The mixture
was stirred at room temperature for 4 h, and NiI2 (2% mol)
was added. After being stirred for 5 min, the deep-blue solution
was cooled to -78 °C and the substrate (1 mmol) in 10 mL of
THF was added over 5 min. After the initial starting material
was consumed (TLC or GC analysis), the reaction mixture was
warmed to room temperature and stirred for 12 h. The
resultant solution was quenched with a saturated aqueous
solution of Rochelle’s salt (potassium sodium tartrate) and
extracted with Et2O. The organic extracts were combined and
washed with 30 mL of brine and dried over MgSO4.
1.64 (m, 4H), 1.52-1.47 (m, 1H), 1.32 (dd, J ) 13.9, 4.5 Hz,
1H), 1.25-1.22 (m, 1H), 1.20 (s, 3H); 13C NMR (CDCl3, 125
MHz) δ 95.5, 70.1, 69.6, 47.6, 38.1 (2C), 29.8, 28.3, 16.8; IR
(film) νmax 3468 cm-1; HRMS (CI+) calcd for (M + H)+ C9H17O3
173.1178, found 173.1184.
Ack n ow led gm en t. We gratefully acknowledge the
National Institutes of Health (Grant GM 35249) for
their generous support. We thank Mr. J effery Lee for
synthesizing several intermediates and also the Minis-
terio de Educacio´n y Cultura (Spain) for a fellowship to
I.S.d.G. We also thank Dr. Patrick J . Caroll for perform-
ing the X-ray crystal structure determinations.
(1R*,3S*,5R*)-3-Hyd r oxy-3-m eth yl-9-oxa bicyclo[3.3.1]-
n on a n -1-ol (14). This was prepared from 2 (424 mg, 1.0 mmol)
according to the general procedure described above to afford,
after flash chromatography (50% EtOAc/petroleum ether), 14
(155 mg, 90%) as a colorless oil: 1H NMR (CDCl3, 500 MHz)
δ 4.58 (br s, 1H), 4.50-4.48 (m, 1H), 3.93 (br s, 1H), 2.07-
1.96 (m, 2H), 1.85 (d, part of ABq, J ) 14.9 Hz, 1H), 1.73-
Su p p or tin g In for m a tion Ava ila ble: Full experimental
details, 1H and 13C NMR spectra for all compounds, and X-ray
structural data for 16, 19, and 23. This material is available
free of charge via the Internet at http://pubs.acs.org.
J O020027W