Development of a protocol for eight- and nine-membered ring synthesis in the annulation of sp2,sp3-hybridized organic dihalides with keto esters

Article abstract of DOI:10.1021/jo001195w

A protocol has been developed in which annulation reactions of various dihalides with keto esters can be carried out to provide entry to eight- and nine-membered carbocycles. In this process wherein one alkenyl- or aryl bromide and a tethered alkyl chloride comprise the organic dihalide, a selective metal - halogen exchange reaction between the sp²-hybridized bromide and an organolithium initiates the process. Transmetalation to an organoytterbium reagent generates a species that undergoes selective carbonyl addition to the ketone of the keto ester, creating a lactone intermediate. Subjection of the resulting chloroalkyl lactone to intramolecular reductive coupling with samarium(II) iodide completes the desired annulation.

Full text of DOI:10.1021/jo001195w

J . Org. Chem. 2000, 65, 8333-8339
8333
Develop m en t of a P r otocol for Eigh t- a n d Nin e-Mem ber ed Rin g
Syn th esis in th e An n u la tion of sp 2,sp 3-Hybr id ized Or ga n ic
Dih a lid es w ith Keto Ester s
Gary A. Molander* and Christoph Ko¨llner
Roy and Diana Vagelos Laboratories, Department of Chemistry, University of Pennsylvania,
Philadelphia, Pennsylvania 19104-6323
gmolandr@sas.upenn.edu
Received August 7, 2000
A protocol has been developed in which annulation reactions of various dihalides with keto esters
can be carried out to provide entry to eight- and nine-membered carbocycles. In this process wherein
one alkenyl- or aryl bromide and a tethered alkyl chloride comprise the organic dihalide, a selective
metal-halogen exchange reaction between the sp2-hybridized bromide and an organolithium
initiates the process. Transmetalation to an organoytterbium reagent generates a species that
undergoes selective carbonyl addition to the ketone of the keto ester, creating a lactone intermediate.
Subjection of the resulting chloroalkyl lactone to intramolecular reductive coupling with samari-
um(II) iodide completes the desired annulation.
In tr od u ction
forming a part of bicyclic or tricyclic frameworks.7 The
synthesis of such structures often requires application
of carbon-carbon bond-forming reactions and is still
considered quite challenging. Entropic factors, together
with transannular interactions that inhibit cyclization,
conspire to make the construction of medium-sized rings
difficult.8 As evidence of this, the number of general
methods for preparing medium-sized carbocycles by
cyclization or cycloaddition (annulation) reactions from
acyclic precursors is relatively small.7a,9
We have previously employed SmI2 to promote a
sequential intermolecular carbonyl addition/intramolecu-
lar nucleophilic acyl substitution sequence, generating
seven- through nine-membered monocyclic, bicyclic, and
tricyclic ring systems with good yields and high dia-
stereoselectivities.10 This domino process consisted of an
intermolecular reaction followed by an intramolecular
ring expansion that resulted in a formal [m + n] cyclo-
addition, starting from extremely simple, readily avail-
able substrates. We have shown that the intermolecular
reaction between a chloroiodoalkane and a keto ester
leads to a chloroalkyl-substituted lactone via an initial
carbonyl addition reaction (Scheme 1).
Since the first use of samarium(II) iodide (SmI2) as a
reducing agent in organic synthesis 20 years ago,1 this
remarkable reductant has been utilized in a variety of
selective reactions.2 Although many of the early studies
focused on single transformations, it subsequently be-
came evident that SmI2 was an ideal reductive coupling
agent for sequential processes.3 This provides a major
advantage compared to other reductants such as Mg, Zn,
Cr(II), and Bu3SnH. In addition to its ability to promote
a wide array of useful organic reactions (both radical and
anionic processes), one of the unique benefits of SmI2 is
its adjustable reactivity through solvent effects,4 by the
addition of catalysts,1,5 and even through irradiation of
reaction mixtures.6 This feature greatly facilitates the
sequencing of reactions because the reductant can be
selectively tuned for each individual step of a multistep
process.
Samarium(II) iodide has proven to be a useful reagent
in the synthesis of medium-sized carbocycles. These
carbocycles are structural units present in a wide range
of natural products, existing either as isolated rings or
Preferential reactivity of the iodide over the chloride
provided high regioselectivity in the initial step. High
chemoselectivity for reaction of the initially formed
organosamarium species at the aldehyde or ketone in
preference to the ester was observed. Reaction of the
chloroalkyl-substituted lactone via an intramolecular
nucleophilic acyl substitution ended the sequential reac-
tion pathway and afforded the desired carbocyclic hy-
droxy ketones. We also demonstrated that a complemen-
tary construction of medium-sized carbocycles was feasible
(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. Aldrichimica 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) 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.; Candiani, I.; Colombo, M.; Franzoi, L.; Bedeschi, A. Tetrahedron
Lett. 1995, 36, 949. (f) Hamann, B.; Namy, J .-L.; Kagan, H. B.
Tetrahedron 1996, 45, 14225.
(5) (a) Molander, G. A.; McKie, J . A. J . Org. Chem. 1991, 57, 3132.
(b) Machrouhi, F.; Hamann, B.; Namy, J .-L.; Kagan, H. B. Synlett 1996,
633.
(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.
(7) (a) Petasis, N. A.; Patane, M. A. Tetrahedron 1992, 48, 5757. (b)
Oishi, T., Ohtsuka, Y., Atta-ur-Rahman, Ed.; Elsevier: Amsterdam,
1989; Vol. 3, p 73. (c) Rigby, J . H., 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) Molander, G. A.; Alonso-Alija, C. J . Org. Chem. 1998, 63, 4366.
10.1021/jo001195w CCC: $19.00 © 2000 American Chemical Society
Published on Web 11/01/2000

8334 J . Org. Chem., Vol. 65, No. 24, 2000
Molander and Ko¨llner
Sch em e 1
Sch em e 4
lithium compound 1b-Li with ethyl levulinate 2a af-
forded the desired lactone in a yield of only 28% (Scheme
4).
Sch em e 2
Unfortunately, these initial reaction conditions ap-
peared nearly optimal in terms of the organolithium
nucleophile. For example, we varied the concentration
of 2a added (neat or as a solution in THF) and the order
of the addition (2a added to 1b-Li or the inverse addi-
tion). Use of other solvents such as Et2O and other bases
(t-BuLi) did not increase the yield. The major product
isolated was always (2-chloroethyl)benzene. Thus it
seems likely that deprotonation of the keto ester is
occurring under these conditions to form an enolate and
(2-chloroethyl)benzene. The enolate is subsequently pro-
tonated in the aqueous workup to give the starting keto
ester. A brief survey of the literature uncovered few
successful reactions of organolithiums with ethyl levu-
linate,15 and in none of these reports were aryllithiums
employed.
Literature precedent indicated that more success might
be achieved with organomagnesium reagents.16 Thus a
Li-Mg-exchange reaction was effected by treating the
organolithium with solid anhydrous MgBr2.17 After the
MgBr2 was completely dissolved the keto ester was
added, but only a small amount of the product could be
isolated in this unoptimized procedure (eq 1). Most of the
material obtained was again (2-chloroethyl)benzene. We
did not explore the direct reaction between the dihalide
1b and Mg metal to obtain a Grignard solution. The lack
of chemoselectivity of Mg toward the dihalide was
perceived to be a significant potential problem.
Sch em e 3
using iodo esters and (chloroalkyl)cycloalkanones in an
efficient one-pot annulation reaction.11 This reaction
sequence also involved intermolecular carbonyl addition
followed by an intramolecular nucleophilic acyl substitu-
tion reaction.
The drawback of both of these processes was that only
alkyl halides could be employed. Aryl and alkenyl halides
are relatively resistant to reduction by SmI2,12 and the
sp2-hybridized radicals generated under these conditions
typically abstract hydrogen from THF more rapidly than
electron transfer from SmI2 can produce the correspond-
ing organosamarium.4a,13 Consequently, only reduction
products are observed (Scheme 2).
In the present contribution we outline a means to
circumvent this problem using a two-step synthetic
approach (Scheme 3). We have developed a procedure
whereby organoytterbiums are generated in situ from
easy accessible organolithiums and are utilized as nu-
cleophiles in the first step of a two-step reaction, with a
SmI2-promoted process completing the transformation.
Resu lts a n d Discu ssion
The desired process was initially tested with readily
available aryl dihalide 1b and keto ester 2a . Parham et
al.14 have shown that selective metalation of 1-bromo-2-
(2-chloroethyl)benzene 1b at low temperatures (-100 °C)
is virtually quantitative. However, reaction of the organo-
(14) (a) Parham, W. E.; J ones, L. D.; Sayed, Y. A. J . Org. Chem.
1976, 41, 1184. (b) Parham, W. E.; Bradsher, C. K.; Reames, D. C. J .
Org. Chem. 1981, 46, 4804.
(11) Molander, G. A.; Machrouhi, F. J . Org. Chem. 1999, 64, 4119.
(12) Kunishima, M.; Hioki, K.; Kono, K.; Sakuma, T.; Tani, S. Chem.
Pharm. Bull. 1994, 42, 2190.
(13) (a) Fevig, T. L.; Elliot, R. L.; Curran, D. P. J . Am. Chem. Soc.
1988, 110, 5064. (b) Molander, G. A.; Kenny, C. J . Am. Chem. Soc.
1989, 111, 8236. (c) Molander, G. A.; Harring, L. S. J . Org. Chem. 1990,
55, 6171. (d) Inanaga, J .; Ujikawa, O.; Yamaguchi, M. Tetrahedron
Lett. 1991, 32, 1737. (e) Matsukawa, M.; Inanaga, J .; Yamaguchi, M.
Tetrahedron Lett. 1987, 28, 1737.
(15) (a) Boeckman, R. K., J r.; Bruza, K. J . Tetrahedron 1981, 37,
3997. (b) Molander, G. A.; Mautner, K. J . Org. Chem. 1989, 54, 4042.
(16) (a) Arnold, R. T.; Buckley, J . S.; Richter, J . J . Am. Chem. Soc.
1947, 69, 2322. (b) Kazmierczak, F.; Helquist, P. J . Org. Chem. 1989,
54, 3988. (c) Mukherji, S. M.; Vig, O. P.; Singh, S.; Bhattacharyya, N.
K. J . Org. Chem. 1953, 18, 1499. (d)) Tamai, Y.; Akiyama, M.;
Okamura, A.; Miyamo, S. J . Chem. Soc., Chem. Commun. 1992, 9, 687.
(17) Markies, P. R.; Villena, A.; Akkerman, O. S.; Bickelhaupt, F.;
Smeets, W. J . J .; Spek, A. L. J . Organomet. Chem. 1993, 463, 7.

Annulation of sp2,sp3-Hybridized Organic Dihalides
J . Org. Chem., Vol. 65, No. 24, 2000 8335
Although the reaction of 1b-Li with MgBr2 and 2a was
not subjected to exhaustive optimization, the initial result
was significantly discouraging that other organometallic
compounds were explored. Organolanthanide reagents
have made a significant impact on selective organic
synthesis and in particular on those reactions involving
carbonyl addition reactions. For example, organocerium
reagents derived from a variety of organolithium reagents
show little enolization in their reactions with carbonyl
substrates.18 The Li-Ce-exchange reaction is well-known
and has been applied to many organic transformations.2c
Reaction of anhydrous CeCl3 with organolithium or
organomagnesium reagents leads to organocerium inter-
mediates that are less basic than their organometallic
precursors. One advantage of the cerium reagents com-
pared to the lithium or magnesium reagents is that it is
easy to follow the reaction as it proceeds to completion.
The organocerium compounds are in most cases bright
orange or yellow. After the reaction with an electrophile
is complete, the color fades, leaving a white suspension.
After reaction of 1b-Li with solid CeCl3 and subsequent
addition of a solution of 2a in THF, the desired chloro-
alkyl lactone 3a was obtained in a respectable yield of
56% (eq 1). The best yield, however, was achieved
employing another lanthanide salt, tris(trifluoromethane-
sulfonato)ytterbium [Yb(OTf)3, ytterbium(III) triflate]. In
an earlier study19 we had used organoytterbium reagents
derived from Yb(OTf)3 and organolithium or Grignard
reagents in carbonyl addition reactions. When the organo-
ytterbium reagents were added to the chiral aldehydes
or ketones, exceptionally high diastereofacial selectivities
were observed. One further advantage of Yb(OTf)3 is its
relatively good solubility in THF, which ensures a fast
and complete reaction with the organolithium reagents.
When Yb(OTf)3 in THF at -78 °C was treated with 1
equiv of 1b-Li, an intensely colored burgundy solution
of the organoytterbium was produced. Upon addition of
a solution of 2a in THF and slow warming to room
temperature the color faded at ca. -30 °C, providing a
nearly colorless solution. Aqueous workup and silica gel
chromatography provided the lactone 3a in an isolated
yield of 70% (eq 1). This was by far the best result under
all tested conditions with different metal exchange reac-
tions.
SmI2 were necessary to complete the reaction, an excess
of SmI2 increased the yield. Therefore in this study 4
equiv of SmI2 were typically used for the second step of
the reaction sequence. Under these conditions 3a was
transformed in the annulated product 4a in a yield of
91%.
To explore the scope and limitations of the two-step
annulation reaction, a diverse array of substrates were
subjected to the protocol. All dihalides in this study had
as a common feature a bromo substituent attached to an
sp2-center and a chloroalkyl side chain. The keto esters
were acyclic or cyclic, and both chiral and achiral
examples were examined. The different substrate com-
binations tested for this study are outlined in Table 1.
All of the substrates were either commercially avail-
able or were prepared using literature procedures (see
Experimental Section). The two exceptions were the
dihalides 1420 and 19. Substrate 14 was generated by
reaction of 5-chloropent-1-yne with BBr3 at -78 °C, which
afforded a (Z/ E)-mixture of the bromoboration product.21
Subsequent cleavage of the boron-vinyl bond was
achieved using acetic acid in pentane. This two-step
procedure provided 14 in an overall yield of 57% (eq 3).
Substrate 19 was generated in 69% yield from (Z)-4-
bromopent-3-en-1-ol22 using thionyl chloride and N,N-
dimethylaniline as base (eq 4).
It should be noted at this point that all attempts to
complete the annulation process in a “one-pot” transfor-
mation were unsuccessful. Thus direct addition of SmI2
to the chloroalkyl lactone generated in situ by the
Yb(OTf)3 method failed to produce the desired annulated
product. Additionally, all attempts to utilize an interme-
diate organosamarium species generated by addition of
SmI3 to the initial organolithium reagent failed to provide
the selectivities necessary for a clean conversion to the
intermediate lactone.
To complete the annulation reaction, therefore, the
isolated lactone 3a was subjected to a SmI2-promoted
reaction under similar conditions to those previously
utilized.10,11 Reduction of the chloroalkyl lactone with
SmI2 and subsequent nucleophilic acyl substitution in the
presence of a catalytic amount of NiI2 and irradiation
with visible light proved to be the most successful
conditions (eq 2). Although theoretically only 2 equiv of
With regard to the results displayed in Table 1, a few
general comments are in order. First, all of the annula-
tion products in Table 1 were isolated in their hemiketal
form, with no detectable evidence (NMR) for equilibration
with the open hydroxy ketone. With a few exceptions, the
yields were good to excellent. As might be expected,
formation of the nine-membered rings proved more
troublesome than the eight-membered rings. All of the
products where a new stereocenter was formed were
obtained as single diastereomers. This was demonstrated
1
by H and 13C NMR analysis as well as by fused silica
capillary GC analysis of the crude reaction mixtures.
Because all of the stereochemistry of the annulation
process is determined in the initial carbonyl addition
reaction, these results provided further evidence of the
(20) Takahashi, K.; Takagi, J .; Ishiyama, T.; Miyaura, N. Chem. Lett.
2000, 126.
(21) Lappert, M. F.; Prokai, B. J . Organomet. Chem. 1964, 1, 384.
(22) Kocienski, J .; Pritchard, M.; Wadman, S. N.; Whitby, R. J .;
Yeates, C. L. J . Chem. Soc. Perkin Trans. 1 1992, 3419.
(18) Collins, S.; Hong, Y.; Hoover, G. J .; Veit, J . R. J . Org. Chem.
1990, 55, 3565.
(19) Molander, G. A.; Burkhardt, E. R.; Weinig, P. J . Org. Chem.
1990, 55, 4990.

8336 J . Org. Chem., Vol. 65, No. 24, 2000
Molander and Ko¨llner
Ta ble 1. La n th a n id e-P r om oted Tw o-Step An n u la tion Rea ction s betw een Dih a lid es a n d Keto Ester s

Annulation of sp2,sp3-Hybridized Organic Dihalides
J . Org. Chem., Vol. 65, No. 24, 2000 8337
Sch em e 5
Sch em e 7
Sch em e 6
Sch em e 8
surprising result (Scheme 5). The reaction resulted in a
mixture of the desired annulation product 25 and the
unexpected unsaturated acid 26.
Although we have no evidence to confirm the mecha-
nism of this transformation, it may result from an
unusual 1,5-hydrogen atom transfer to afford a primary,
R-alkoxy radical. Subsequent reduction of this radical by
SmI2 and â-elimination would lead to the observed
product (Scheme 6).
In addition to the keto esters, we also employed two
aldehyde esters in the annulation process. Reaction of
the dihalide 1b with aldehyde ester 27 gave only a
moderate yield of the lactone 28 (Scheme 7). Subsequent
reaction with SmI2 provided a 70% yield of the expected
product 29 that was in equilibrium with its opened
hydroxy ketone isomer 30. The ratio of the two isomers
was approximately 4:1 (29:30). This was the only com-
pound where such an equilibrium was observed. As
pointed out above all of the keto ester annulated products
appeared to exist exclusively in the hemiketal form.
We also employed aldehyde ester 31 in the reaction
with the dihalide 1b to afford lactone 32 in moderate
yield (56%, Scheme 8). Unfortunately, reaction of 32 with
SmI2 provided a complex reaction mixture from which
no annulation product could be isolated.
Finally, reaction of the 1,3-substituted dihalide 33 with
2a cleanly delivered the lactone 34. However, after
reaction with SmI2, only the (m-tolyl)lactone was isolated
and this in a yield of only 11% (Scheme 9). Much of the
crude material from this reaction after aqueous workup
could not be eluted from the silica gel column. Presum-
ably, after reduction of the chloroalkyl chain to the
organosamarium an intermolecular rather than an intra-
molecular nucleophilic acyl substitution reaction took
place, yielding polymeric material. Although eight-
membered ring systems incorporating a 1,3-substituted
benzene ring are known,17,24 undoubtedly the strain of
exceptionally good diastereoselectivity engendered by
organoytterbium reagents in carbonyl addition reac-
tions.19 Single-crystal X-ray structural analysis of com-
pounds 7d , 10c, and 21 confirmed the expected trans
fusion between the two carbocyclic rings resulting from
attack of the organoytterbium species trans to the side
chain on the cyclic keto ester in the first step of the two-
step reaction sequence. This expected stereochemical
outcome is in agreement with our earlier study.10
Use of substrate 8b for the first step synthesis of 9a
and 9c (entries 7 and 9) yielded products that showed
very broad signals in the 1H NMR spectra at room
temperature. Hindered rotation about the aryl-lactone
single bond in the molecule appeared to be responsible
for these broad signals, because at higher temperatures
(80 °C in DMSO-d6) the rotation barrier was exceeded
1
and sharp signals in the H as well as in the 13C NMR
spectra were obtained. As expected the NMR spectra of
the two corresponding annulation products 10a and 10c
showed no such abnormal behavior and were clearly
resolved at room temperature in CDCl3.
Intermediate 9a could not be obtained analytically
pure, as we were not able to remove one impurity despite
several attempts with column chromatography. In the
end, 9a was subjected to the SmI2-promoted annulation
reaction as obtained after the purification (87% pure as
measured by GC). After the annulation reaction and
column chromatography, only a single product (the
expected 10a ) was isolated.
The Br-Li-exchange reaction of the alkenyl bromide
substrates 14 and 19 (entries 12-15) were performed
using 2 equiv of t-BuLi according to a known procedure.23
Although the yield of the SmI2 reaction to form 16 and
23 (entries 12 and 15) were lower than those generally
observed, no significant differences in the use of alkenyl
bromide derivatives compared to their aryl bromide
counterparts were noted.
Reaction of 1a with 2b led cleanly to the chloroalkyl
lactone 24, but the subsequent SmI2 reaction gave a
(24) (a) J enneskens, L. W.; de Kanter, F. J . J .; Turkenburg, L. A.
M.; de Boer, H. J . R.; de Wolf, W. H.; Bickelhaupt, F. Tetrahedron 1984,
40, 4401. (b) Wijsman, G. W.; van Es, D. S.; de Wolf, W. H.;
Bickelhaupt, F. Angew. Chem., Int. Ed. Engl. 1993, 32, 726.
(23) Neumann, H.; Seebach, D. Chem. Ber. 1978, 111, 2785.

8338 J . Org. Chem., Vol. 65, No. 24, 2000
Molander and Ko¨llner
at -100 °C for 10 min and then transferred via a dry-ice-cooled
cannula to a solution of 758 mg (1.21 mmol) of anhydrous
Yb(OTf)3 in 25 mL of THF at -78 °C. The solution turned to
a deep burgundy color and was stirred at -78 °C for 30 min.
Addition of a solution of ethyl levulinate (2a ) in 10 mL of THF
via cannula yielded a lighter red color. While warming to room
temperature during 3 h, the color of the solution changed to
pale yellow. After an additional 2 h at room temperature, the
reaction was hydrolyzed with saturated aqueous NaHCO3. The
organic phase was separated, and the aqueous phase was
extracted with Et2O. The combined organic extracts were
washed with brine and dried over MgSO4. After removal of
solvent, the residue was purified by flash chromatography
(silica gel, 3:1 hexanes-ethyl acetate) to provide 182 mg (70%)
of 3a : 1H NMR (500 MHz, CDCl3) δ 7.35 (m, 1H), 7.25 (m,
3H), 3.79 (m, 1H), 3.70 (m, 1H), 3.31 (m, 1H), 3.13 (m, 1H),
2.59-2.74 (m, 2H), 2.47-2.56 (m, 2H), 1.72 (s, 3H); 13C NMR
(125 MHz, CDCl3) δ 175.7, 142.1, 134.8, 131.9, 128.0, 127.1,
125.2, 87.5, 44.8, 37.2, 35.8, 29.3, 28.4; IR (neat) 2974, 1770
cm-1; HRMS calcd for C13H16ClO2 (MH+): 239.0839, found
239.0841; LRMS (CI) m/z 239 MH+ (100), 173 (57), 137 (67).
1-Meth yl-13-oxa tr icyclo[8.2.1.02,7]tr id eca -2(7),3,5-tr ien -
10-ol (4a ). Gen er a l P r oced u r e for th e Syn th esis of Hy-
d r oxy Cycloa lk a n on es. To a suspension of 537 mg (3.57
mmol) of samarium metal in 25 mL of THF at 0 °C was added
911 mg (3.40 mmol) of diiodomethane. The suspension was
stirred 1 h at 0 °C and 2 h at room temperature. To the
resulting deep blue SmI2 solution was added 21 mg (0.068
mmol) of NiI2 and then a solution of 204 mg (0.85 mmol) of 3a
in 10 mL of THF via cannula. After the addition of the
substrate, the reaction mixture was irradiated with visible
light (250 W krypton lamp) for 4 h while the temperature was
maintained below 25 °C. The resultant mixture was hydrolyzed
with a saturated aqueous solution of Rochelle’s salt. The
organic phase was separated, and the aqueous phase was
extracted with Et2O. The combined organic extracts were
washed with brine and dried over MgSO4. After removal of
solvent, the residue was purified by flash chromatography
(silica gel, 3:1 hexanes-ethyl acetate) to provide 159 mg (91%)
of 4a : 1H NMR (500 MHz, CDCl3) δ 7.26 (m, 1H), 7.14 (m,
3H), 3.12 (m, 1H), 2.89 (m, 1H), 2.72 (s, 1H), 2.11-2.22 (m,
5H), 2.03 (m, 1H), 1.81 (s, 3H); 13C NMR (125 MHz, CDCl3) δ
146.8, 138.7, 131.4, 127.0, 126.1, 124.6, 107.6, 83.5, 39.7, 39.0,
38.5, 31.9, 28.4; IR (neat) 3395 cm-1; HRMS calcd for C13H17O2
(MH+): 205.1229, found 205.1227; LRMS (CI) m/z 205 MH+
(14), 187 (100), 169 (18).
Sch em e 9
the desired eight-membered ring is too high to permit
its formation by the current technique.
Con clu sion s
A two-step annulation process to synthesize eight- and
nine-membered monocyclic, bicyclic, and tricyclic hydroxy
ketones has been developed. In contrast to earlier reports
this method allows one to employ sp2-hybridized bromo
derivatives for the incorporation of alkenyl or aryl
moieties in the carbocycles. This extension was made
possible by using organoytterbium reagents prepared in
situ from organolithiums and Yb(OTf)3 in a carbonyl
addition reaction followed by a SmI2-promoted nucleo-
philic acyl substitution reaction. Use of these organo-
ytterbium species provided the products with complete
diastereoselection. Consequently, this method seems
promising for the synthesis of a variety of medium-sized
ring platforms.
Exp er im en ta l Section
Rea gen ts. Tetrahydrofuran (THF) was distilled immedi-
ately prior to use from benzophenone ketyl under N2. Ytter-
bium(III) triflate (Yb(OTf)3 hydrate), 1.6 M n-BuLi solution
in hexanes, 1.7 M t-BuLi solution in pentane, samarium metal,
diiodomethane, nickel(II) iodide (NiI2), 5-chloropent-1-yne, 1.0
M BBr3 solution in CH2Cl2, thionyl chloride, N,N-dimethyl-
aniline, as well as the substrates 2a , 2b, 5b, and 33 were
purchased from Aldrich Chemicals. Anhydrous Yb(OTf)3 was
obtained according to a literature procedure.25 The substrates
1a -c,14a,26 5a ,27 8a ,b,28 1129 and (Z)-4-bromopent-3-en-1-ol22
were synthesized as reported earlier. Standard benchtop
techniques were employed for handling air-sensitive re-
agents,30 and all reactions were carried out under N2.
5-[2-(2-Ch lor oeth yl)p h en yl]-5-m eth yld ih yd r ofu r a n -2-
on e (3a ). Gen er a l P r oced u r e for th e Syn th esis of Ch lo-
r oa lk yl La cton es. To a solution of 265 mg (1.21 mmol) of
1-bromo-2-(2-chloroethyl)benzene (1b) in 10 mL of THF at
-100 °C was added dropwise 0.76 mL of a 1.6 M n-BuLi-
solution in hexanes. The resulting clear solution was stirred
2-Br om o-5-ch lor op en t-1-en e (14). To a solution of 4.43 g
(43.2 mmol) of 5-chloropent-1-yne in 25 mL of CH2Cl2 at -78
°C was added 43.2 mL of a 1.0 M solution of BBr3 in CH2Cl2
during 20 min. The solution was warmed to room temperature
and stirred for an additional 1 h. After careful hydrolysis with
water, the organic phase was separated, and the aqueous
phase was extracted with CH2Cl2. The combined organic
extracts were dried over MgSO4. After removal of solvent, the
residue (a mixture of the title compound and an E/ Z-mixture
of 2-bromo-5-chloropent-1-en-1-yl)dibromoborane was sus-
pended in 300 mL of pentane. After addition of 10 mL of AcOH,
the suspension was heated to reflux for 4 h. After careful
neutralization with saturated NaHCO3 solution, the organic
phase was separated, and the aqueous phase was extracted
with Et2O. The combined organic extracts were washed first
with saturated NaHCO3 solution and then with brine and
dried over MgSO4. After removal of solvent, the residue was
purified via Kugelrohr distillation (10 mmHg, 70 to 80 °C) to
provide 4.50 g (57%) of the title compound 14, which rapidly
turned brown on standing. No correct elemental analysis nor
(25) Forsberg, J . H.; Spaziano, V. T.; Balasubramanian, T. M.; Liu,
G. K.; Kinsley, S. A.; Duckwort, C. A.; Poteruca, J . J .; Brown, P. S.;
Miller, J . L. J . Org. Chem. 1987, 52, 1017.
(26) Ponton, J .; Helquist, P.; Conrad, P. C.; Fuchs, P. L. J . Org.
Chem. 1981, 46, 118.
(27) (a) Marschall, H.; Vogel, F.; Weyerstahl, P. Chem. Ber. 1974,
107, 2852. (b) Molander, G. A.; Harris, C. R. J . Am. Chem. Soc. 1995,
117, 3705.
(28) (a) Cotarca, L.; Delogu, P.; Maggioni, P.; Nardelli, A.; Bianchini,
R.; Sguassero, S. Synthesis 1997, 328. (b) Andrew, D.; Hastings, D. J .;
Weedon, A. C. J . Am. Chem. Soc. 1994, 116, 10870. (c) Lee, G. H.;
Choi, E. B.; Lee, E.; Pak, C. S. J . Org. Chem. 1994, 59, 1428.
(29) de Diesbach, H.; Klement, O. Helv. Chim. Acta 1941, 24, 158.
(30) Brown, H. C. Organic Syntheses via Boranes; Wiley: New York,
1975.
1
HRMS could be obtained. H NMR (500 MHz, CDCl3) δ 5.63
(m, 1H), 5.44 (d, J ) 1.6 Hz, 1H), 3.54 (t, J ) 6.3 Hz, 2H),
2.58 (m, 2H), 2.01 (m, 2H); 13C NMR (125 MHz, CDCl3) δ 132.4,
118.1, 43.3, 38.3, 30.3; IR (neat) 2958, 1629 cm-1; LRMS (CI)
m/z 184 (24), 120 (82), 103 (100).
(Z)-2-Br om o-5-ch lor op en t-2-en e (19). A solution of 210
mg (1.27 mmol) of (Z)-4-bromopent-3-en-1-ol, 257 mg (2.16
mmol) of thionyl chloride and 262 mg (2.16 mmol) of N,N-
dimethylaniline in 4 mL of CHCl3 was heated to reflux

Annulation of sp2,sp3-Hybridized Organic Dihalides
J . Org. Chem., Vol. 65, No. 24, 2000 8339
overnight. The cooled solution was hydrolyzed with 2 N HCl.
The organic phase was separated, and the aqueous phase was
extracted with Et2O. The combined organic extracts were
washed first with 2 N HCl and then with brine and dried over
MgSO4. After removal of the solvent, the residue was purified
via Kugelrohr distillation (10 mmHg, 50 to 60 °C) to provide
160 mg (69%) of the title compound 19, which rapidly turned
brown on standing. No correct elemental analysis nor HRMS
for a Postdoctoral Fellowship. We gratefully acknowl-
edge the National Institutes of Health (GM35249) and
Merck & Co., Inc. for their generous support. We also
thank Dr. Pat Carroll for performing the X-ray crystal
structure determinations.
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures and structural data for all compounds not described
within the text. X-ray crystal structure data for compounds
7d , 10c, and 21. 1H and 13C NMR spectra from all compounds
for which no elemental analyses were obtained. This material
is available free of charge via the Internet at http://pubs.acs.org.
1
could be obtained. H NMR (500 MHz, CDCl3) δ 5.71 (m, 1H),
3.53 (t, J ) 6.8 Hz, 2H), 2.60 (m, 2H), 2.30 (m, 3H); 13C NMR
(125 MHz, CDCl3) δ 125.2, 124.7, 43.0, 34.7, 28.8; IR (neat)
2958 cm-1; LRMS (CI) m/z 184 (4), 154 (100), 135 (12), 133
(11).
Ack n ow led gm en t. C. Ko¨llner is indebted to the
Deutscher Akademischer Austauschdienst (Germany)
J O001195W