Combined rhodium-catalyzed carbon-hydrogen activation and β-carbon elimination to access eight-membered rings

Article abstract of DOI:10.1002/anie.200904527

(Figure Presented) Enlargel C-H bond activation and β-carbon elimination are combined in a net intramolecular hydroacylation of alkylidenecyclobutanes and alkylideneazetidines in the presence of rhodium catalysts, affording eight-membered-ring compounds in high yield (see scheme). This study demonstrates the possibility of exploiting the strain energy of azetidines through β-carbon elimination in new transition-metal-catalyzed reactions.

Full text of DOI:10.1002/anie.200904527

Communications
DOI: 10.1002/anie.200904527
À
C H Activation
Combined Rhodium-Catalyzed Carbon–Hydrogen Activation and
b-Carbon Elimination to access Eight-Membered Rings**
Damien Crꢀpin, James Dawick, and Christophe Aꢁssa*
À
Transition-metal-catalyzed activation of otherwise inert C H
À
and C C bonds is widely recognized as a very promising
strategy for the development of sustainable synthetic chemis-
try.[1,2] In this context, b-carbon elimination of putative penta-
=
rhodacycles, having an exocyclic C O double bond, has been
used in the design of reactions to promote the ring enlarge-
ment of non-functionalized cyclobutanes into larger rings
[Eqs. (1) and (2)].[3] Both approaches relied on the insertion
of rhodium catalysts into particularly strained cyclobutenones
and cyclobutanones, respectively. In contrast, we now disclose
the outcome of an alternative strategy which relies on stable
À
À
aldehydes as precursors in a C H/C C activation sequence
(Scheme 1).
Scheme 1. Working hypothesis.
hypothesized that this rational design would be applicable to
aldehyde-tethered 3-alkylideneazetidines (X = NR3) to afford
eight-membered heterocycles.
We found that exposure of substrate 1a to [{Rh(coe)2Cl}2]
(2.5 mol%;
coe = cyclooctene)
and
P(pMeOC6H4)3
(10 mol%) in ethylene-saturated 1,2-dichloroethane (1,2-
DCE) at 808C (Method I) gave cyclooctenone 2a in 94%
yield (Scheme 2). Encouraged by this result, we explored
Encouraged by our recent report of intramolecular
hydroacylation of aldehyde-tethered alkylidenecyclopro-
panes,[4] we anticipated that aldehyde-tethered alkylidenecy-
clobutanes A (X = CR1R2) would undergo the following
sequential steps: C H activation to give B,[5] hydrometalation
À
=
of the C C double bond in B to give C, b-carbon elimination
of C to give D, and finally reductive elimination of D to give
the eight-membered carbocycle E.[6] This approach would
complement previous reports of the formation of eight-
membered carbocycles which relied on b-carbon elimination
of nickel cyclobutanolates[7] or rhodium-catalyzed b-carbon
elimination of vinyl cyclobutanones.[8] Moreover, given the
similar strain energy of azetidines and cyclobutanes,[9] we
Scheme 2. Rhodium-catalyzed rearrangement of aldehyde-tethered
alkylidenecyclobutane 1a into cyclooctenone 2a.
alternative reaction conditions to avoid the need for satu-
ration of the solution with ethylene.[10] We observed that
cationic rhodium complexes were much more active and
enable full conversions without requiring the presence of
ethylene, giving 2a more rapidly and in good yield. Hence,
treatment of 1a with [{Rh(coe)2Cl}2] (2.5 mol%), AgBF4
(5 mol%), and P(pMeOC6H4)3 (10 mol%) in 1,2-DCE at
808C for 30 minutes gave 2a in 89% yield (Method II),[11]
whereas using precatalyst [Rh(nbd)2]BF4 (5 mol%; nbd =
norbornadiene) in the presence of binap (5 mol%; binap =
2,2’-bis(disphenylphosphino-1,1’-binaphthyl)[12] in acetone at
[*] D. Crꢀpin, J. Dawick, Dr. C. Aꢁssa
Department of Chemistry, University of Liverpool
Crown Street, L69 7ZD (England)
Fax: (+44)151-794-3588
E-mail: aissa@liverpool.ac.uk
[**] D.C. thanks the EPSRC for financial support for students. C.A. is
grateful to Research Councils UK and the University of Liverpool for
financial support. We thank the EPSRC National Mass Spectrometry
Service Centre for some measurements.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200904527.
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Chemie
568C for 3.5 hours afforded the desired compound in 85%
yield (Method III). This optimization study gave us a set of
three reactions conditions (Methods I–III) which could be
used on a variety of substrates, thereby demonstrating the
general applicability of the reaction design outlined above.
Hence, aromatic cyclooctenone 2b was isolated in excel-
lent yields from precursor 1b, using either neutral or cationic
rhodium catalysts (Table 1, entries 1 and 2). Additional
substitution on the carbon–carbon double bond of the
alkylidenecyclobutane moiety shut down the reactivity of all
catalytic systems tested, and substrate 1c was recovered
mostly intact after 24 hours (Table 1, entry 3). In contrast,
substituents on the ring of the alkylidenecyclobutane moiety
of substrates 1d and 1e (Table 1, entries 4 and 5) were
tolerated, giving compounds 2d and 2e, respectively, in good
yields, although slightly higher catalyst loadings and pro-
longed reaction times were necessary. Substitution on the
tether (Table 1, entries 6–8) was also compatible with the
diverse reaction conditions tested, and treatment of substrates
1 f and 1g afforded compounds 2 f and 2g, respectively, in
good yields without alteration of the diastereomeric ratios;
these ratios were initially equimolar for 1 f and 1g.
catalyst (Scheme 3).[12] The conversion of (E)-1h was com-
plete within 48 hours and 2h was obtained in excellent yield
(Scheme 3a). In contrast, conversion of (Z)-1h under the
Scheme 3. Apparent regioconvergence of the rearrangement. Reaction
of a) (E)-1h and b) (Z)-1h.
We then examined the regioselectivity of this transforma-
tion with both E and Z isomers of substrate 1h and observed
that both isomers were converted into the same cycloocte-
none 2h when treated with our optimal cationic rhodium
same reaction conditions did not go to completion, and 2h
was isolated in 53% yield (Scheme 3b). We first hypothesized
that this regioconvergence might be a result of the isomer-
=
ization of the C C double bond prior to rearrangement.
However, (E)-1h was not present in the recovered starting
material (30%), and treating (Z)-1h under the same reaction
conditions and then stopping the reaction after 4 hours or
18 hours showed incomplete conversion into 2h (3% and
20%, respectively by 1H NMR analysis) without any trace of
(E)-1h. Although we cannot yet completely rule out that a
putative isomerization of (Z)-1h into (E)-1h occurs at a much
slower rate than the rearrangement of (E)-1h into 2h, other
mechanistic rationales must be investigated before a conclu-
sion can be reached. In this regard, it is noteworthy that this
apparent regioconvergence was not observed using Method I.
Hence, treating (E)-1h with a neutral rhodium catalyst at
1208C gave 2h in only 30% yield, whereas (E)-1h was
recovered in 50% yield. Isomer (Z)-1h was more reluctant to
undergo the rearrangement under the same neutral condi-
tions, and we recovered (Z)-1h mostly intact (70% yield),
without a trace of (E)-1h according to 1H NMR analysis. The
cationic nature of the rhodium catalyst used in Scheme 3
therefore seems critical to the observed regioconvergence.
No reaction was observed when a pyridine group was
embedded within the substrate. We reasoned that this could
be because of the irreversible trapping of the active catalyst
by the lone pair of electrons on the nitrogen atom. Accord-
ingly, this limitation was easily circumvented by alkylation of
the pyridine and counteranion exchange [Eq. (3)]. Hence,
substrate 3 afforded compound 4 in yields ranging from 70 to
75% in the presence of cationic rhodium catalysts.
À
Table 1: Rhodium-catalyzed C H activation/b-carbon elimination to
access cyclooctenones.[a]
Entry
Substrate
Product
Method
t [h]
Yield [%]
1
2
3
1b (R=H)
1b (R=H)
1c (R=Me)
2b
2b
2c
I
II
–
17
0.5
24
92
89
0[c]
[b]
4
5
1d
1e
2d
2e
II[d]
16
22
69[e]
79
II[f]
6
7
1 f
1 f
2 f
2 f
I[g]
86
25
75
III[d]
71[h]
8
1g
2g
III[d]
24
75
The detrimental effect of the lone pair of electrons, on the
nitrogen atom, upon reactivity prompted us to install
electron-withdrawing groups on the nitrogen atom of alde-
hyde-tethered 3-alkylideneazetidines when we turned our
attention to these substrates (Scheme 4). However, treating
[a] Yields of isolated products. [b] All methods (I–III) employed 10 mol%
catalyst. [c] Recovered 1c in 87–95% yield. [d] Used 5 mol% catalyst.
[e] Recovered 1d in 16% yield. [f] Used 10 mol% catalyst. [g] Used
15 mol% catalyst. [h] Recovered 1 f in 16% yield. Bn=benzyl.
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Communications
of alkylidenecyclobutanes is currently ongoing in our labo-
ratories.
Received: August 13, 2009
Revised: November 11, 2009
Published online: December 10, 2009
Keywords: alkylideneazetidines · alkylidenecyclobutanes ·
.
À
À
C C activation · C H activation · intramolecular hydroacylation
À
[1] For recent reviews about C H bond activation, see: a) F.
Kakiuchi, N. Chatani, Adv. Synth. Catal. 2003, 345, 1077 – 1101;
b) R. G. Bergman, Nature 2007, 446, 391 – 393; c) L. Ackermann,
Top. Organomet. Chem. 2007, 24, 36 – 60.
À
[2] For selected reviews about C C bond activation, see: a) B.
Rybtchinski, D. Milstein, Angew. Chem. 1999, 111, 918 – 932;
Angew. Chem. Int. Ed. 1999, 38, 870 – 883; b) M. Murakami, M.
Makino, S. Ashida, T. Matsuda, Bull. Chem. Soc. Jpn. 2006, 79,
1315 – 1321; c) D. Necas, M. Kotora, Curr. Org. Chem. 2007, 11,
1566 – 1591; d) Y. J. Park, J.-W. Park, C.-H. Jun, Acc. Chem. Res.
2008, 41, 222 – 241; e) T. Seiser, N. Cramer, Org. Biomol. Chem.
2009, 7, 2835 – 2840.
[3] a) M. A. Huffman, L. S. Liebeskind, J. Am. Chem. Soc. 1993,
115, 4895 – 4896; b) M. Murakami, K. Takahashi, H. Amii, Y. Ito,
J. Am. Chem. Soc. 1997, 119, 9307 – 9308.
[4] C. Aꢀssa, A. Fꢁrstner, J. Am. Chem. Soc. 2007, 129, 14836 –
14837.
À
[5] The insertion of rhodium into the C H bond of aldehydes has
Scheme 4. Preparation of eight-membered heterocycles through
rhodium-catalyzed rearrangement of aldehyde-tethered 3-alkylidene-
azetidines. a) Compound 7 reacts under either of two sets of reaction
been extensively documented, see: a) J. W. Suggs, J. Am. Chem.
Soc. 1978, 100, 640 – 641; b) V. Ritleng, C. Sirlin, M. Pfeffer,
Chem. Rev. 2002, 102, 1731 – 1769; c) M. A. Garralda, Dalton
Trans. 2009, 3635 – 3645.
À
À
conditions. b) Aryl-containing substrates also undergo the C H/C C
activation sequence. Ts=para-toluenesulfonyl.
[6] For alternative approaches to seven- and eight-membered-ring
ketones through intramolecular hydroacylation, which rely on
the rearrangement of hexarhodacycle intermediates, see:
a) A. D. Aloise, M. E. Layton, M. D. Shair, J. Am. Chem. Soc.
2000, 122, 12610 – 12611; b) Y. Sato, Y. Oonishi, M. Mori, Angew.
Chem. 2002, 114, 1266 – 1269; Angew. Chem. Int. Ed. 2002, 41,
1218 – 1221; c) Y. Oonishi, M. Mori, Y. Sato, Synthesis 2007,
2323 – 2336; d) Y. Oonishi, J. Ogura, Y. Sato, Tetrahedron Lett.
2007, 48, 7505 – 7507. For approaches relying on coordination by
an heteroatom, see: e) H. D. Bendorf, C. M. Colella, E. C.
Dixon, M. Marchetti, A. N. Matunokis, J. D. Musselman, T. A.
Tiley, Tetrahedron Lett. 2002, 43, 7031 – 7034; f) M. M. Coulter,
P. K. Dornan, V. M. Dong, J. Am. Chem. Soc. 2009, 131, 6932 –
6933.
amide 5 or carbamate 6 with rhodium catalysts according to
Methods I–III gave poor results, and some decomposition was
observed. In contrast, changing the protective group to a tosyl
(4-toluenesulfonyl) group gave much better results. Hence,
compound 8 was isolated in good yields after exposure of 7 to
either neutral or cationic rhodium catalysts according to
Methods I and III (Scheme 4a). Similarly, aromatic substrate
9 gave 10 in good yield upon isolation (Scheme 4b).
In conclusion, we have demonstrated that by using simple
and stable aldehydes as starting materials, the strain energy of
simple cyclobutanes and azetidines can be exploited through
rhodium-catalyzed b-carbon elimination. To the best of our
knowledge, previous reports of metal-mediated ring opening
of azetidines are extremely scarce and describe only b-
nitrogen elimination.[13] Hence, the b-carbon elimination of
azetidines proposed between putative intermediates C and D
(Scheme 1), and exemplified herein in Equation (3), suggests
the possibility of new transition-metal-catalyzed reactions
with these substrates. Moreover, this study opens new access
to eight-membered rings and expands the scope of rhodium-
catalyzed intramolecular hydroacylation.[6,14] Additional
mechanistic investigation of the regioconvergent ring opening
[7] M. Murakami, S. Ashida, T. Matsuda, J. Am. Chem. Soc. 2006,
128, 2166 – 2167.
[8] P. A. Wender, A. G. Correa, Y. Sato, R. Sun, J. Am. Chem. Soc.
2000, 122, 7815 – 7816.
[9] Strain energy of cyclobutane = 26.3 kcalmolÀ1 (from K. B.
Wiberg in The Chemistry of cyclobutanes (Eds.: Z. Rappoport,
J. F. Liebman), Wiley, New York, 2005, chap. 1, pp. 4 – 5). The
strain energy of azetidine is estimated at 26.2 kcalmolÀ1, see:
S. W. Benson in Thermochemical Kinetics, Wiley, NewYork,
1968, p. 184.
[10] Miller and co-workers postulated that ethylene could block one
coordination site on rhodium and hence prevent the decarbon-
ylation.of the substrate; see: R. Campbell, Jr., C. F. Lochow,
K. P. Vora, R. G. Miller, J. Am. Chem. Soc. 1980, 102, 5824 –
5830. However, in the absence of ethylene, the reaction depicted
in Scheme 2 (using Method I) did not proceed, but we did not
observe any decarbonylation, even with 50 mol% catalyst.
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[11] Treatment of 1a with only AgBF4 (10 mol%) or with AgBF4
(10 mol%) and P(pMeOC6H4)3 (10 mol%) in refluxing 1,2-
DCE led to complete degradation of the starting material.
[12] The ligand exchange between nbd and binap was facilitated by
bubbling H2 (16.7 equiv per Rh) through the solution using a
syringe and stirring for 1 hour before the solution was added to
the substrate.
[13] Opening of azetidinium salts with organolithium derivatives,
see: a) M. T. Wills, I. E. Wills, L. Von Dollen, B. L. Butler, J.
Porter, A. G., Jr. Anderson, J. Org. Chem. 1980, 45, 2489 – 2498;
b) F. Couty, F. Durat, G. Evano, D. Prim, Tetrahedron Lett. 2004,
45, 7525 – 7528. Opening of vinylazetidines with Co2(CO)8, see:
c) D. Roberto, H. Alper, J. Am. Chem. Soc. 1989, 111, 7539 –
7543.
[14] For leading references on rhodium-catalyzed intramolecular
hydroacylation, see: a) K. Sakai, J. Ide, O. Oda, N. Nakamure,
Tetrahedron Lett. 1972, 13, 1287 – 1290; b) R. C. Larock, K.
Oertle, G. F. Potter, J. Am. Chem. Soc. 1980, 102, 190 – 197;
c) D. P. Fairlie, B. Bosnich, Organometallics 1988, 7, 936 – 945;
d) D. P. Fairlie, B. Bosnich, Organometallics 1988, 7, 946 – 954;
e) K. Tanaka, G. C. Fu, J. Am. Chem. Soc. 2001, 123, 11492 –
11493; f) K. Tanaka, G. Fu, J. Am. Chem. Soc. 2002, 124, 10296 –
10297; g) K. Tanaka, G. Fu, J. Am. Chem. Soc. 2003, 125, 8078 –
8079; h) K. Takeishi, K. Sugishima, K. Sasaki, K. Tanaka, Chem.
Eur. J. 2004, 10, 5681 – 5688; i) K. Tanaka, K. Sasaki, K. Takeishi,
M. Hirano, Eur. J. Org. Chem. 2007, 5675 – 5685.
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