Iridium-mediated isomerization-cyclization of bicyclic Pauson-Khand derived allylic alcohols

Article abstract of DOI:10.1021/jo8017439

(Chemical Equation Presented) Treatment of 2-(toluene-4-sulfonyl)-2,3,4,4a, 5,6-hexahydro-1H-[2]pyrindin-6-ol 10, accessed from the diastereoselective Luche reduction of a Pauson-Khand derived bicylic cyclopentenone, with a catalytic amount of (1,5-cycloo

Full text of DOI:10.1021/jo8017439

SCHEME 1. The Directed Hydrogenation of Alkenols
Iridium-Mediated Isomerization-Cyclization of
Bicyclic Pauson-Khand Derived Allylic Alcohols
Yvonne Kavanagh, C´ıara M. Chaney, Jimmy Muldoon, and
Paul Evans*
Centre for Synthesis and Chemical Biology, School of
Chemistry and Chemical Biology, UniVersity College Dublin,
Dublin 4, Ireland
paul.eVans@ucd.ie
ReceiVed August 6, 2008
this would be an attractive method for the synthesis of densely
functionalized trans-fused bicycles, of the type trans-5, pos-
sessing 4-contiguous stereogenic centers, and as such would
prove complementary to standard hydrogenation. As in the case
of 2, this type of reduction has been reported to proceed
stereoselectively generating the cis-fused ring architecture where
n ) 1 (i.e. cis-5).4 Methods for achieving the trans-architecture
related to this type of system are of interest since it is found in
several naturally occurring compounds.5
Bicyclic compounds of the type 4 may be accessed, typically
in good yields, from the corresponding enyne 6 following a
Pauson-Khand reaction (PKR)6 and a Luche reduction.7 The
latter process has been shown to proceed in related systems with
high levels of diastereoselectivity.8
To investigate the feasibility of this directed, diastereoselec-
tive reduction approach bicyclic cyclopentenone 9 was prepared
in 4-steps following an initial Mitsunobu reaction between
propargyl alcohol 7 and N-(tert-butoxycarbonyl)-p-toluene-
sulfonamide.9 Subsequent removal of the tert-butoxycarbonyl
(Boc) group and alkylation with butenyl bromide gave enyne
8. Pauson-Khand cycloaddition was effected under standard
conditions6 which entailed initial formation of the dicobalt
hexacarbonyl-alkyne complex followed by promotion with
4-methylmorpholine N-oxide (NMO).10 The resulting bicyclic
cyclopentenone 9 was then treated with sodium borohydride in
the presence of cerium(III) chloride heptahydrate7,8 to stereo-
selectively form allylic alcohol 10. The relative stereochemistry
of the stereogenic centers was probed by nuclear Overhauser
effect experiments. A degassed solution of allylic alcohol 10
Treatment of 2-(toluene-4-sulfonyl)-2,3,4,4a,5,6-hexahydro-
1H-[2]pyrindin-6-ol 10, accessed from the diastereoselective
Luche reduction of a Pauson-Khand derived bicylic cyclo-
pentenone, with a catalytic amount of (1,5-cyclooctadi-
ene)(pyridine)(tricyclohexylphosphine)iridium(I) hexafluo-
rophosphate 1 (Crabtree’s catalyst) under a hydrogen
atmosphere resulted in the formation of 4-(toluene-4-sulfo-
nyl)-2-oxa-4-azatricyclo[5.2.1.03,8]decane 12 as a single
diastereoisomer. This process is likely to proceed via an
initial Ir(I)-mediated isomerization of the alkene to form an
N-sulfonyl enamine 11, followed by cyclization. Evidence
to support this came when, after short reaction periods, 11
was isolated, characterized spectroscopically, and on resub-
mission to the reaction conditions formed 12.
Crabtree’s iridium(I) catalyst 11 offers both enhanced reactiv-
ity in hydrogenation reactions, often enabling sterically chal-
lenging, substituted alkenes to participate that prove unreactive
under more standard, Wilkinson-type rhodium(I) catalysis and
also, as a consequence of coordination, delivery of hydrogen
in a diastereoselective fashion (efficient, diastereoselective
delivery of hydrogen has been reported to occur even with
tertiary alcohols).1b,2,3 A classic example of the power of this
approach was published by Stork and Kahne in which they
demonstrated that treatment of 2 with 1, under a hydrogen
atmosphere, gave trans-3 in 92% de (Scheme 1).3 In contrast,
under heterogeneous hydrogenation conditions (5 mol % Pd/C,
H2, MeOH) cis-3 was selectively formed. We envisaged that
(4) (a) Becker, D. P.; Nosal, R.; Zabrowski, D. L.; Flynn, D. L. Tetrahedron
1997, 53, 1. (b) Krafft, M. E.; Bonaga, L. V. R.; Wright, J. A.; Hirosawa, C. J.
Org. Chem. 2002, 67, 1233.
(5) Kam, T.-S.; Yoganathan, K.; Wei, C. J. Nat. Prod. 1997, 60, 673.
(6) For reviews see: (a) Brummond, K. M.; Kent, J. L. Tetrahedron 2000,
56, 3263. (b) Evans, P.; Kavanagh, Y. Modern Approaches to the Synthesis of
O- and N-Heterocycles; Kaufman, T. S., Larghi, E. L., Eds.; Research Signpost:
Kerala, India, 2007; Vol 2, pp 33-78.
(7) Gemal, A. L.; Luche, J.-L. J. Am. Chem. Soc. 1981, 103, 5454.
(8) (a) Clive, D. L. J.; Cole, D. C.; Tao, Y. J. Org. Chem. 1994, 59, 1396–
1406. (b) Lanver, A.; Schmalz, H.-G. Eur. J. Org. Chem. 2005, 1444.
(9) Trost, B. M.; Machacek, M. R.; Faulk, B. D. J. Am. Chem. Soc. 2006,
128, 6745.
(10) (a) Shambayti, S.; Crowe, W. E.; Schreiber, S. L. Tetrahedron Lett.
1990, 31, 5289. (b) Jeong, N.; Chung, Y. K.; Lee, B. Y.; Lee, S. H.; Yoo, S.-E.
Synlett 1991, 204.
(1) (a) Crabtree, R. H.; Felkin, H.; Morris, G. E. J. Organomet. Chem. 1977,
141, 205. (b) Crabtree, R. H.; Davis, M. W. J. Org. Chem. 1986, 51, 2655.
(2) For reviews concerning directed reactions, including hydrogenation of
alkenes see: (a) Hoveyda, A. H.; Evans, D.A.; Fu, G. C. Chem. ReV. 1993, 93,
1307. (b) Brown, J. M. Angew. Chem., Int. Ed. Engl. 1987, 26, 190.
(3) Stork, G.; Kahne, D. E. J. Am. Chem. Soc. 1983, 105, 1072.
10.1021/jo8017439 CCC: $40.75
Published on Web 10/08/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 8601–8604 8601

SCHEME 2. The Iridium(I) Mediated Conversion of Pauson-Khand Derived Allylic Alcohol 10 into Tricycle 12
in dichloromethane was then treated with Crabtree’s catalyst 1
(ca. 10 mol%) and stirred under an atmosphere of hydrogen
gas. After 1 h the formation of a nonpolar compound was
detected by thin layer chromatography. Purification of the crude
reaction mixture by flash column chromatography afforded this
material, which proved to be 12 (32%).11 The second compound
recovered from the column was N-sulfonyl enamine 11 (59%).
The reaction was repeated under identical conditions, albeit for
longer reaction periods, and in doing so it became clear that as
the time of reaction was increased the isolated yield of the
tricycle 12 increased and accordingly less of the enamine 11
was detected. For example, after 2 days 12 was obtained as the
sole product (95%).
This finding seemed to indicate that 11 gradually underwent
conversion into 12 as the reaction progressed, which was
corroborated when a purified sample of 11 was resubmitted to
the reaction in the presence of 5 mol % of 1. In this instance,
under a hydrogen atmosphere conversion of 11 into 12 (90%)
was observed over 16 h. Interestingly, in the absence of either
the catalyst, or indeed if the same process was carried out under
a nitrogen atmosphere, no conversion of 11 was detected.
Furthermore, when 10 was stirred with 10 mol % of 1 under a
nitrogen atmosphere no conversion into 11 was detected.
Treatment of enone 9, under identical conditions used to convert
10 to 11/12, also resulted in no change. In none of these studies
were the anticipated saturated products, of the type 5, resulting
from alkene hydrogenation observed. In relation to these findings
several examples of alkenyl isomerizations with 1 have been
observed in which the desired hydrogenation appears to be
slow.12
12. To this end, 12 was treated with allyltrimethylsilane in the
presence of BF3 ·OEt2 and gratifyingly 13, the product of
carbon-carbon bond formation, was isolated in good yield as
a single diastereoisomer whose stereochemistry was again
uncovered by the use of nuclear Overhauser effect NMR
experiments.
14
The identity and stereochemistry of the 6-oxa functional group
was next investigated (Scheme 2). Since alternative Lewis basic
groups2 have also been reported to interact with 1, compound
10 was first acetylated under standard conditions before 14 was
treated with 10 mol % of 1. After 1 h, proton NMR spectroscopy
indicated quantitative formation of 15 and after 3 h a mixture
of 15 and 16 was similarly detected in a 3:2 ratio. Initially it
was hoped that in the absence of the hydroxyl group responsible
for the cyclization reaction 11 to 12, directed hydrogenation
might have occurred to form the trans-ring junction. However,
hetereogeneous hydrogenation of this mixture gave only one
compound that proved to be cis-16. A Mitsunobu sequence was
then employed to invert the hydroxyl stereochemistry. Thus,
17 was prepared in 2-steps and its relative stereochemistry
probed by NOE experiments and comparison to 10. Treatment
of 17 with Crabtree’s catalyst 1 again gave the product 18 of
isomerization in 80% yield. In this example only a trace of the
reduced compound 19 was detected even after prolonged
reaction periods (15 h).
These examples clearly demonstrate that, for this type of
[4.3.0]-bicyclic structure, regioselective isomerization of the
trisubstituted alkene occurs more rapidly than addition of
hydrogen and that, as expected, the stereochemistry and identity
of the 6-oxa functionality governs any further reactivity. To
compare the reactions described above with the analogous
[3.3.0]-bicyclic system 20 was prepared from allylprop-2-
ynylamine15 via sulfonamide formation, PKR, followed by
Luche reduction (Scheme 3). In the event, treatment of 20 with
Crabtree’s catalyst 1 gave a mixture of compounds 21, 22, and
The overall conversion, 10 into 12, represents a diastereo-
selective C-H activation and since it is appreciated that N,O-
acetals participate in a range of further functionalization
reactions13 we were interested in considering the reactivity of
(11) CCDC reference no. 694620.
(12) For examples of alkene isomerization with 1 see: (a) Krel, M.;
Lallemand, J.-Y.; Guillou, C. Synlett 2005, 2043. (b) Sole´, D.; Urbaneja, X.;
Bonjoch, J. Org. Lett. 2005, 24, 5461.
(14) For a representative procedure see: Toumieux, S.; Compain, P.; Martin,
O. R.; Selkti, M. Org. Lett. 2006, 8, 4493.
(15) Li, Y.; Marks, T. J. J. Am. Chem. Soc. 1998, 120, 1757.
(13) Speckamp, W. N.; Moolenaar, M. J. Tetrahedron 2000, 56, 3817.
8602 J. Org. Chem. Vol. 73, No. 21, 2008

SCHEME 3. Conversion of 20 into Tricycle 23
in competition with the oxidative addition of hydrogen to form
an Ir(III) dihydride 34 required for alkenyl reduction.
Where n ) 1 results indicate that the formation of 30 is
favored and that this then undergoes conversion into 31, which
in turn may then undergo decomplexation to afford the
isomerized alkene products (11, 15, 18), or evidently cyclization
and hydrogen transfer to generate the tricycles 12, 23, and 27.
In the case of n ) 0, presumably due to the extra strain
associated with the [3.3.0] bicyclic system, 32 may also be
formed, which leads to the formation of 22 on tautomerization.
This sequence of events implies a relatively slow oxidative
addition of hydrogen to Ir(I) forming the Ir(III) dihydride species
34 required for hydrogenation of the alkene.
An alternative pathway involving the addition of Ir(III)
dihydride across the double bond followed by ꢀ-hydride
elimination was also considered. However, in this instance it
would appear surprising that intermediates such as 35 would
not rapidly generate the products of direct hydrogenation on
reductive elimination.
SCHEME 4. Conversion of 26 into Tricycle 27
In summary, we have uncovered and studied an unusual
isomerization-cyclization sequence that appears to be mediated
by an iridium species derived from Crabtree’s catalyst. The key
to observing this sequence is that formal addition of two
hydrogen atoms across the trisubstituted, bicyclic alkenes used
in this study appears to be slow under the conditions studied.
Future work involves ascertaining the role, if any, played by
the heteroatom in the isomerization process and further applica-
tion of these novel N,O- and O,O-acetals in the kind of ring-
opening chemistry exemplified by the stereoselective transfor-
mation 12 to 13. In relation to these future studies an
enantioselective PKR-based method for the formation of this
type of structure has recently been reported.17
the tricycle 23, albeit in low yield (7%). None of the N-sulfonyl
enamine, which, based on the study summarized in Scheme 2,
presumably facilitates the formation of 23, was detected in this
example. The relative stereochemistry between the ring junction
in compounds 21 and 22 was elucidated by oxidation of the
alcohol 21, which formed 22, and hydrogenation (Pd/C, H2, not
shown) of 20 and the PKR adduct, which formed 21 and 22,
respectively.
Compound 23 possessed similar spectral properties to its
congener 12 and, pleasingly, underwent a similar opening of
the N,O-acetal to generate 24, again as a single major dia-
stereoisomer.
The formation of 21 and 22 in this sequence (these types of
compounds were not observed during the studies illustrated in
Scheme 2) is probably explained by the increased strain of the
[3.3.0]-bicycle and the influence this has on the reactivity of
the bridging trisubstituted alkene.
As Scheme 4 illustrates, the same sequence may be success-
fully applied to compounds possessing alternative functional
groups to the N-sulfonyl examples previously discussed. Thus,
26 (prepared following the PKR and Luche reduction of 4-but-
1-enyloxyprop-2-yne 25)16 gave 27 in moderate yield on
treatment of with 10 mol % of 1. The lower yields observed in
this sequence may reflect the increased volatility of these lower
molecular weight ether-containing compounds.
A possible mechanistic rationale, based on the sequence
presented by Guillou and co-workers,12a may be suggested
(Scheme 5). Under an atmosphere of hydrogen following
reduction and subsequent loss of COD the cationic iridium(I)
species 1 generates a 12 valence electron cationic Ir(I) species
28. Association of this cationic species to the trisubstituted
alkenes employed in this study serves to generate key complex
29 which may or may not be ligated to the hydroxyl group. It
seems reasonable that at this stage regioselective insertion into
one of two allylic carbon-hydrogen bonds serves to generate
Ir(III) π-allyl complexes 30 and 32, a step that appears to occur
Experimental Section
(1R*,3R*,7S*,8R*)-4-(Toluene-4-sulfonyl)-2-oxa-4-azatricyclo[5.2.1.03,8]-
decane (12) and (4aS*,6R*)-2-(Toluene-4-sulfonyl)-3,4,4a,5,6,7-
hexahydro-2H-[2]pyrindin-6-ol (11). A solution of alcohol 10 (156
mg, 0.53 mmol, 1 equiv) in dichloromethane (20 cm3) was degassed
with a steady stream of N2 for 10 min. To this Crabtree’s catalyst
1 (20 mg, 0.025 mmol, 5 mol %) was added. Stirring was continued
under an atmosphere of H2 for 15 h. Solvent removal followed by
direct purification by flash column chromatography (cyclohexane
f cyclohexane-EtOAc; 1:1) afforded 12 as a colorless solid (78
mg, 51%) [crystals suitable for X-ray crystallography11 were formed
from gradual evaporation of a saturated solution of 12 in dichlo-
romethane]: mp 108 °C; Rf 0.65 (cyclohexane-EtOAc; 1:1); δH
(400 MHz, CDCl3) 1.35-1.40 (1H, m, 10-CH2), 1.52 (1H, d, J )
10.0 Hz, 9-CH2), 1.67-1.72 (2H, m, 6-CH2, 10-CH2), 1.87-1.89
(1H, m, 9-CH2), 1.91-1.96 (1H, m, 6-CH2), 2.22-2.28 (2H, m,
7-CH, 8-CH), 2.42 (3H, s, CH3), 2.78-2.85 (1H, m, 5-CH2),
3.45-3.49 (1H, m, 5-CH2), 4.24 (1H, s, 1-CH2), 5.77 (1H, s,
3-CH2), 7.28 (2H, d, J ) 8.0 Hz, ArH), 7.70 (2H, d, J ) 8.0 Hz,
ArH) ppm; δC (100 MHz, CDCl3) 21.5 (CH3), 26.5 (CH2), 28.8
(CH), 34.4 (CH2), 34.8 (CH2), 38.8 (CH2), 41.2 (CH), 77.8 (CH),
85.6 (CH), 127.8 (CH), 129.6 (CH), 135.9 (C), 143.2 (C) ppm;
υ
max (film) 2989, 2926, 1597, 1454, 1333, 1159, 1091, 1041, 998,
907, 867, 817, 762, 662; m/z C15H20NO3S requires 294.1164 (MH+,
100%); found 294.1178 (+4.8 ppm). Further elution gave 11 as an
amorphous solid (56 mg, 36%): Rf 0.30 (cyclohexane-EtOAc; 1:1);
δH (400 MHz, CDCl3) 1.13-1.19 (2H, m, 4-CH2, 5-CH2),
1.96-2.01 (1H, m, 4-CH2), 2.16-2.22 (3H, m, 4-CH2, 4a-CH,
(17) (a) Hiroi, K.; Watanabe, T.; Kawagishi, R.; Abe, I. Tetrahedron:
Asymmetry 2000, 11, 797. (b) Gibson, S. E.; Kaufmann, K. A. C.; Loch, J. A.;
Steed, J. W.; White, A. J. P. Chem. Eur. J. 2005, 11, 2566.
(16) Trost, B. M.; Xie, J. J. Am. Chem. Soc. 2006, 128, 6044.
J. Org. Chem. Vol. 73, No. 21, 2008 8603

SCHEME 5. Possible Mechanistic Rationale for the Crabtree Catalyst Mediated Isomerization-Cyclization Sequence
7-CH2), 2.42 (3H, s, CH3), 2.63 (1H, dd, J ) 7.0, 15.8 Hz, 7-CH2),
2.80 (1H, dt, J ) 3.0, 12.5 Hz, 3-CH2), 3.85 (1H, dt, J ) 3.0, 12.5
Hz, 3-CH2), 4.28-4.34 (1H, m, 6-CH), 6.51 (1H, s, 1-CH), 7.29
(2H, d, J ) 8.0 Hz, ArH), 7.64 (2H, d, J ) 8.0 Hz, ArH) ppm; δC
(100 MHz, CDCl3) 21.5 (CH3), 27.2 (CH2), 35.3 (CH), 38.8 (CH2),
41.4 (CH2), 43.6 (CH2), 71.9 (CH), 117.8 (CH), 124.6 (CH), 127.0
(CH), 129.6 (CH), 134.6 (C), 143.5 (C) ppm; υmax (film) 3492,
3415, 2926, 2856, 2250, 1677, 1598, 1494, 1454, 1339, 1259, 1164,
1092, 1047, 977 cm-1; m/z C15H20NO3S requires 294.1164 (MH+,
100%); found 294.1151 (-4.4 ppm). Following the procedure
described above alcohol 10 (42 mg; 0.140 mmol, 1 equiv) in
dichloromethane (10 cm3) was treated with 1 (11 mg, 0.014 mmol,
10 mol%) under a hydrogen atmosphere. After stirring for 48 h
gradient elution flash column chromatography (cyclohexane to
cyclohexane-EtOAc; 3:1) yielded 12 (40 mg, 95%) with data in
accord to that reported above.
dd, J ) 2.0, 13.0 Hz, 5-CH2), 1.40-1.45 (1H, m, 4-CH2), 1.52
(1H, dq, J ) 6.0, 13.0, 7-CH2), 1.64 (1H, dq, J ) 4.5, 13.0 Hz,
4-CH2), 1.79-1.85 (1H, m, 7a-CH), 1.91-1.99 (3H, m, 4a-CH,
5-CH2, 7-CH2), 2.06-2.13 (1H, m, CH2), 2.18-2.25 (1H, m, CH2),
2.33 (3H, s, CH3), 2.80 (1H, td, J ) 3.0, 13.0 Hz, 3-CH2),
3.56-3.61 (1H, m, 3-CH2), 3.90 (1H, dd, J ) 6.0, 9.0 Hz, 1-CH),
4.23-4.29 (1H, m, 6-CH), 4.88-4.93 (2H, m, CH2), 5.54-5.63
(1H, m, CH), 7.20 (2H, d, J ) 8.0 Hz, ArH), 7.63 (2H, d, J ) 8.0
Hz, ArH) ppm; δC (100 MHz, CDCl3) 21.4 (CH3), 27.4 (CH2), 31.9
(CH), 36.3 (CH2), 37.7 (CH2), 39.8 (CH2), 40.0 (CH), 41.6 (CH2),
53.7 (CH), 72.0 (CH), 117.3 (CH2), 126.9 (CH), 129.5 (CH), 135.0
(CH), 138.3 (C), 142.8 (C) ppm; υmax (film) 3512, 3414, 3076, 2926,
2867, 2255, 1641, 1598, 1495, 1461, 1442, 1384, 1335, 1315, 1267,
1160, 1091, 1061, 1018, 969, 917, 815, 737 cm-1; m/z C18H26NO3S
requires 336.1633 (MH+, 100%); found 336.1635 (+0.5 ppm).
(1S*,4aS*,6R*,7aR*)-1-Allyl-2-(toluene-4-sulfonyl)-octahydro-
[2]pyrindin-6-ol (13). Under an atmosphere of nitrogen, boron
trifluoride·diethyletherate (0.4 cm3, 2.96 mmol, 10 equiv) was
added to a solution of the tricyclic ether 12 (87 mg, 0.29 mmol, 1
equiv) and allyltrimethylsilane (0.18 cm3, 1.18 mmol, 4 equiv) in
dichloromethane (15 cm3) at rt. The mixture was stirred for 15 h,
before NaHCO3 (15 cm3) was added. Ether (3 × 20 cm3) was used
to the extract and the combined extracts were dried over MgSO4
and filtered then solvent was removed in vacuo. The crude material
was purified by flash column chromatography (cyclohexane-EtOAC;
1:1) giving 13 (85 mg, 85%) as a colorless solid: mp 130 °C; Rf
0.30 (cyclohexane-EtOAc; 1:1); δH (400 MHz, CDCl3) 1.30 (1H,
Acknowledgment. We would like to acknowledge financial
support from the Science Foundation Ireland and the University
College Dublin. Additionally Dr. Helge Mu¨ller-Bunz is thanked
for X-ray crystallography and Dr. Dilip Rai for mass spectrometry.
Supporting Information Available: Experimental details,
copies of proton and carbon NMR spectra, and the X-ray
structure of 12. This material is available free of charge via the
Internet at http://pubs.acs.org.
JO8017439
8604 J. Org. Chem. Vol. 73, No. 21, 2008