Organotin hydride catalyzed carbon-carbon bond formation: Radical-mediated reductive cyclization of enals and enones

Full text of DOI:10.1021/jo951827s

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J . Org. Chem. 1996, 61, 4-5
Sch em e 1. Red u ctive Cycliza tion w ith
Or ga n otin Hyd r id e Ca ta lyzed
Ca r bon -Ca r bon Bon d F or m a tion :
Ra d ica l-Med ia ted Red u ctive Cycliza tion of
En a ls a n d En on es
Stoich iom etr ic Bu 3Sn H
David S. Hays and Gregory C. Fu*
Department of Chemistry, Massachusetts Institute of
Technology, Cambridge, Massachusetts 02139
Received October 16, 1995
Radical reactions are now employed routinely by
synthetic organic chemists.1 Many of these transforma-
tions are mediated by a stoichiometric quantity of Bu3-
SnH. Motivated both by an awareness of the toxicity of
triorganotin species2 as well as by an interest in asym-
metric catalysis,3 we have initiated a program focused
on the design of new processes in which organotin
hydrides are used as catalysts rather than as stoichio-
metric reagents. In this paper, we report the develop-
ment of a Bu3SnH-catalyzed, PhSiH3-mediated carbon-
carbon bond-forming reaction, the reductive cyclization
of enals and enones (eq 1).
Sch em e 2. P r op osed Ca ta lytic Cycle for Tin
Hyd r id e-Ca ta lyzed , Silicon Hyd r id e-Med ia ted
Red u ctive Cycliza tion
independently reported that silicon hydrides react with
tin alkoxides to afford tin hydrides and silyl ethers (eq
2).9,10 Two known reactions, run in sequence, thus
provide the basis for a new catalytic process (Scheme 2).11
Several groups have reported that enals and enones
undergo reductive cyclization4 by a free radical chain
process upon treatment with a stoichiometric quantity
of Bu3SnH (Scheme 1).5,6 In the first step, a tributyltin
radical adds to the carbonyl group to produce a tin ketyl.
Addition of this ketyl to the pendant olefin affords a new
radical, which abstracts a hydrogen atom from Bu3SnH
to generate the reductive cyclization product (1).
Employing Bu3SnH as a catalyst for this transforma-
tion requires the use of a stoichiometric amount of a
second metal hydride capable of regenerating Bu3SnH
from tributyltin alkoxide 1.7,8 Several workers have
As illustrated in Table 1, we have established that Bu3-
SnH does indeed effectively catalyze the silicon hydride-
mediated reductive cyclization of enals and of enones.
Thus, treatment of unsaturated aldehydes or ketones
with 5-15 mol % of (Bu3Sn)2O12-14 and 0.5 equiv of
PhSiH3 (radical initiator, 2 equiv of EtOH,16 refluxing
15
benzene or toluene) affords the desired cyclic products
in good yields.17
(1) For leading references, see: (a) Hart, D. J . Science 1984, 223,
883-887. (b) Giese, B. Radicals in Organic Synthesis: Formation of
Carbon-Carbon Bonds; Pergamon: New York, 1986. (c) Curran, D.
P. Synthesis 1988, 417-439, 489-513. (d) Regitz, M.; Giese, B. Houben-
Weyl, Methoden der Organischen Chemie; Georg Thieme Verlag:
Stuttgart, 1989. (e) Motherwell, W. B.; Crich, D. Free Radical Chain
Reactions in Organic Synthesis; Academic: New York, 1992.
(2) For leading references, see: Pereyre, M.; Quintard, J .-P.; Rahm,
A. Tin in Organic Synthesis; Butterworths: Boston, 1987; Chapter 1.
(3) (a) Catalytic Asymmetric Synthesis; Ojima, I., Ed.; VCH: New
York, 1993. (b) Noyori, R. Asymmetric Catalysis in Organic Synthesis;
Wiley: New York, 1994.
This new catalytic carbon-carbon bond-forming pro-
cess efficiently generates both five- (Table 1, entries 1-4)
and six-membered rings (entries 5 and 6).18 Cyclization
proceeds more readily when the remote position of the
(9) (a) Reference 7. (b) Itoi, K. Fr. Patent 1,368,522, 1964. Itoi, K.;
Kumano, S. Kogyo Kagaku Zasshi 1967, 70, 82-86. (c) Hayashi, K.;
Iyoda, J .; Shiihara, I. J . Organomet. Chem. 1967, 10, 81-94. (d)
Bellegarde, B.; Pereyre, M.; Valade, J . Bull. Soc. Chim. Fr. 1967, 3082-
3083.
(10) For a mechanistic study, see: Pijselman, J .; Pereyre, M. J .
Organomet. Chem. 1973, 63, 139-157.
(4) Corey, E. J .; Pyne, S. G. Tetrahedron Lett. 1983, 24, 2821-2824.
For a review, see: J asperse, C. P.; Curran, D. P.; Fevig, T. L. Chem.
Rev. 1991, 91, 1237-1286.
(5) Early work: (a) Beckwith, A. L. J .; Roberts, D. H. J . Am. Chem.
Soc. 1986, 108, 5893-5901. (b) Ardisson, J .; Ferezou, J . P.; J ulia, M.;
Pancrazi, A. Tetrahedron Lett. 1987, 28, 2001-2004. (c) Sugawara,
T.; Otter, B. A.; Ueda, T. Tetrahedron Lett. 1988, 29, 75-78.
(6) Enholm was the first to systematically explore the scope of this
reaction: (a) Enholm, E. J .; Prasad, G. Tetrahedron Lett. 1989, 30,
4939-4942. (b) Enholm, E. J .; Burroff, J . A. Tetrahedron Lett. 1992,
33, 1835-1838.
(7) A polar variant of this strategy (catalytic tin hydride, stoichio-
metric silicon hydride) has been applied to the reduction of carbonyl
groups. For an early report, see: Nitzsche, S.; Wick, M. Angew. Chem.
1957, 69, 96. For a suggestion that radical-mediated reactions might
be susceptible to this approach, see: Lipowitz, J .; Bowman, S. A.
Aldrichim. Acta 1973, 6, 1-6.
(11) For titanium-catalyzed reductive cyclization of δ,ꢀ-unsaturated
enals and enones to cyclopentanols: (a) Kablaoui, N.; Buchwald, S. L.
J . Am. Chem. Soc. 1995, 117, 6785-6786. (b) Crowe, W. E.; Rachita,
M. J . J . Am. Chem. Soc. 1995, 117, 6787-6788.
(12) For all of the substrates illustrated in Table 1, very little (<3%)
reductive cyclization is observed in the absence of (Bu3Sn)2O under
otherwise identical conditions.
(13) (Bu3Sn)2O serves as a convenient and inexpensive source of Bu3-
SnH (treatment of (Bu3Sn)2O with PhSiH3/EtOH in benzene at room
temperature results in clean formation of 2 equiv of Bu3SnH). Reduc-
tive cyclizations in which catalytic amounts of Bu3SnH are used in
place of (Bu3Sn)2O provide yields and stereoselectivities essentially
identical to those reported in Table 1.
(14) Table 1, entries 1, 2, and 4: 5 mol % (Bu3Sn)2O; entry 6: 10
mol % (Bu3Sn)2O; entries 3 and 5: 15 mol % (Bu3Sn)2O.
(15) Preliminary efforts to employ polymethylhydrosiloxane (PMHS)
as the stoichiometric reducing agent predominantly afforded uncyclized
alcohol (1,2-reduction), along with small amounts (<25%) of the
reductive cyclization product.
(8) For Bu3SnH-catalyzed, borohydride-mediated radical dehaloge-
nation processes, see: (a) NaBH4: Corey, E. J .; Suggs, J . W. J . Org.
Chem. 1975, 40, 2554-2555. (b) NaBH3CN: Stork, G.; Sher, P. M. J .
Am. Chem. Soc. 1986, 108, 303-304 (carbon-carbon bond-forming
reactions).
0022-3263/96/1961-0004$12.00/0 © 1996 American Chemical Society

Communications
J . Org. Chem., Vol. 61, No. 1, 1996
5
Ta ble 1. Bu 3Sn H-Ca ta lyzed Red u ctive Cycliza tion of
En a ls a n d En on es
observe essentially the same diastereoselectivities when
we conduct the reactions under the catalyzed conditions
as when we run them with stoichiometric Bu3SnH,6a
a
result consistent with the catalytic reaction proceeding
by the pathway outlined in Scheme 2.
We have begun to explore the development of Bu3SnH-
catalyzed variants of related radical-based transforma-
tions.20 For example, Enholm has reported that activated
dienes undergo intramolecular coupling upon treatment
with 3 equiv of tributyltin hydride.21 We have found that
this reaction can be effected with 5 mol % of (Bu3Sn)2O
and 0.5 equiv of PhSiH3 in comparable yield and stereo-
selectivity (eq 3).
In summary, we have developed a new Bu3SnH-
catalyzed carbon-carbon bond-forming process, the radi-
cal-mediated reductive cyclization of enals and enones.
Ongoing investigations include the following: further
examination of the scope of this reaction,6b including
application to the synthesis of heterocycles;22 the pursuit
of mechanistic studies; the development of Bu3SnH-
catalyzed variants of other tin ketyl-mediated processes;
and the design and synthesis of chiral, nonracemic
organotin hydride catalysts.
a
Product ratios are based on analysis by capillary gas chroma-
tography and/or 1H NMR. Yields refer to isolated mixtures of the
b
cis and trans products and are the average of two runs. c 29% 1,2-
reduction is observed.
Ack n ow led gm en t. Support has been provided by
the Camille and Henry Dreyfus Foundation (New
Faculty Award in Chemistry to G.C.F.), the National
Science Foundation (predoctoral fellowship to D.S.H.;
Young Investigator Award to G.C.F., with funding from
Amoco, Berlex, Hoechst Celanese, Merck, Pfizer, Rohm
& Haas, and Upjohn), and the American Cancer Society
(J unior Faculty Research Award to G.C.F.). Acknowl-
edgment is made to the donors of the Petroleum
Research Fund, administered by the American Chemi-
cal Society, for partial support of this research.
olefin bears a radical-stabilizing substituent (e.g., ester
or phenyl, entries 1 and 2); otherwise, a significant
quantity of uncyclized alcohol resulting from 1,2-reduc-
tion of the aldehyde is produced (29%; entry 3).6a,19 We
(16) In some of the reactions that we have explored, a somewhat
lower yield of cyclic product is observed if EtOH is not present. The
following data suggested to us that the addition of EtOH would
facilitate the regeneration of Bu3SnH, which might in turn improve
the efficiency of the reductive cyclization: (1) exchange of alcohols with
tin alkoxides is rapid at room temperature (ref 2, Chapters 2 and 11),
and (2) primary tin alkoxides are more readily reduced by silanes than
are secondary or tertiary tin alkoxides (ref 9b). Thus, we believe that,
in the presence of EtOH, Bu3SnH is regenerated through reduction of
Bu3SnOEt.
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures and compound characterization data (16 pages).
(17) Sample experimental details (Table 1, entry 5): To a solution
of the enal (184 mg, 1.00 mmol) in benzene (2.0 mL) in a 10 mL seal-
able Schlenk tube was added (Bu3Sn)2O (76 µL, 0.15 mmol), PhSiH3
(62 µL, 0.50 mmol), ethanol (117 µL, 2.00 mmol), and AIBN (16 mg,
0.10 mmol in 200 µL of benzene) under an atmosphere of nitrogen.
The container was sealed, shaken, and immersed in an 80 °C oil bath.
After 6.5 h, TLC analysis indicated that no starting material remained.
The reaction mixture was treated with TBAF (3.0 mL of a 1.0 M
solution in THF; 1 h at rt) and then subjected to workup with 2 M
HCl (15 mL) and ether. The combined organic extracts were dried
(MgSO4), filtered, and concentrated to afford a crude mixture of trans
hydroxy ester and cis lactone. The residue was dissolved in CH2Cl2
(10 mL), a catalytic quantity of TsOH was added, and the solution
was stirred for 20 h at rt, at which time GC analysis indicated that all
of the trans hydroxy ester had lactonized. The reaction mixture was
concentrated and then purified by flash chromatography to afford 103
mg (74%) of an analytically pure mixture of cis and trans lactones as
a colorless oil (1.1:1 trans:cis by 1H NMR).
J O951827S
(19) We observe the formation of a similar quantity of 1,2-reduction
product under the stoichiometric reductive cyclization conditions (1.2
equiv of Bu3SnH, no PhSiH3).
(20) For example, see: (a) Conjugate reduction of R,â-unsaturated
carbonyls: Pereyre, M.; Valade, J . Compt. Rend. 1965, 260, 581-584.
(b) Reductive cyclization of keto-oximes: Naito, T.; Tajiri, K.; Harimoto,
T.; Ninomiya, I.; Kiguchi, T. Tetrahedron Lett. 1994, 35, 2205-2206.
Kiguchi, T.; Tajiri, K.; Ninomiya, I.; Naito, T.; Hiramatsu, H. Tetra-
hedron Lett. 1995, 36, 253-256. (c) Conjugate reduction/intramolecular
aldol: Enholm, E. J .; Xie, Y.; Abboud, K. A. J . Org. Chem. 1995, 60,
1112-1113.
(21) (a) Enholm, E. J .; Kinter, K. S. J . Am. Chem. Soc. 1991, 113,
7784-7785. (b) Enholm, E. J .; Kinter, K. S. J . Org. Chem. 1995, 60,
4850-4855.
(22) For example, see: Lee, E.; Tae, J . S.; Chong, Y. H.; Park, Y.
C.; Yun, M.; Kim, S. Tetrahedron Lett. 1994, 35, 129-132.
(18) We have not yet explored the generation of other ring sizes.