Multiple rhodium-catalyzed cleavages of single C-C bonds

Article abstract of DOI:10.1021/ol400266g

The Rh(I)-catalyzed intramolecular hydroacylation of cis and trans asymmetrically substituted alkylidenecyclobutanes proceeds according to three mechanistic pathways. As shown by deuterium-labeling experiments, the mechanism accounting for the rearrangeme

Full text of DOI:10.1021/ol400266g

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Multiple Rhodium-Catalyzed Cleavages of
Single CꢀC bonds
ꢀ
Christophe A¨ıssa,* Damien Crepin, Daniel J. Tetlow, and Kelvin Y. T. Ho
University of Liverpool, Chemistry Department, Crown Street, L69 7ZD, Liverpool,
United Kingdom
aissa@liverpool.ac.uk
Received January 29, 2013
ABSTRACT
The Rh(I)-catalyzed intramolecular hydroacylation of cis and trans asymmetrically substituted alkylidenecyclobutanes proceeds according to
three mechanistic pathways. As shown by deuterium-labeling experiments, the mechanism accounting for the rearrangement of the cis isomers
includes the cleavage of three carbonꢀcarbon bonds and a remarkable transannular 3-exo-trig carbometalation.
A better mechanistic understanding of the factors con-
trolling the regioselectivity of the transition-metal-cata-
lyzed activation of single carbonꢀcarbon (CꢀC) bonds is
crucial in view of future applications of this strategy in
synthesis.1 Whileboththree-andfour-memberedcycloalk-
anes are particularly apt to undergo CꢀC bond cleavage in
the presence of transition metals, the regioselectivity of the
β-C elimination of transient cyclobutylcarbinyl metals has
rarely been studied.2 Recently, we reported that treatment
of alkylidenecyclobutanes (ACBs) 1 and 2 (R = -(CH2)2-
C6H3-3,4-Cl2) with a rhodium catalyst3 leads to the for-
mation of eight-membered ring ketone 3 as a single
regioisomer (Scheme 1).4,5 The rearrangement of 1 into 3
could be explained by the following sequential steps:
formation of Rh(III)-acyl-hydrido intermediate A,6 syn
coplanar migratory insertion toward cyclobutylcarbinyl B,7
bond rotation toward C, syn coplanar β-carbon elimination
to give D, and finally reductive elimination (Scheme 2). Our
assumption that the opening of the cyclobutane ring in C is a
syn coplanar process is based on the numerous examples of
syn coplanar transition-metal-catalyzed β-C elimination of
cyclopropane derivatives.8 Applying the same rationale to
ACB 2 would have led us to predict the formation, not of 3,
but its regioisomer, via β-carbon elimination from F, rotamer
of E (Scheme 2). Hence, how can we explain the regioconver-
gent rearrangement of ACBs 1 and 2? Importantly, while the
conversion of 1 was complete, the conversion of 2 was more
ꢁ
(1) (a) Necas, D.; Kotora, M. Curr. Org. Chem. 2007, 11, 1566. (b)
Rubin, M.; Rubina, M.; Gevorgyan, V. Chem. Rev. 2007, 107, 3117. (c)
Seiser, T.; Cramer, N. Org. Biomol. Chem. 2009, 7, 2835. (d) Murakami,
M.; Matsuda, T. Chem. Commun 2011, 47, 1100. (e) Aıssa, C. Synthesis
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Chem., Int. Ed. 2011, 50, 7740.
(2) (a) Catellani, M.; Chiusoli, G. P.; Dradi, E.; Salerno, G.
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Chem. Soc. 2002, 124, 11578. (f) Wender, P. A.; Correa, A. G.; Sato, Y.;
Sun, R. J. Am. Chem. Soc. 2000, 122, 7815.
(5) For examples of eight-membered ring ketones formed by rho-
dium-catalyzed intramolecular hydroacylation, see: (a) Aloise, A. D.;
Layton, M. E.; Shair, M. D. J. Am. Chem. Soc. 2000, 122, 12610. (b)
Bendorf, H. D.; Collela, C. M.; Dixon, E. C.; Marchetti, M.; Matunokis,
A. N.; Musselman, J. D.; Tiley, T. A. Tetrahedron Lett. 2002, 43, 7031.
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Int. Ed. 2012, 51, 11548.
(3) The active rhodium catalyst was prepared by hydrogenation of
[Rh(nbd)(BINAP)]BF4 in acetone (nbd = norbornadiene, BINAP =
2,20-bis(disphenylphosphino-1,10-binaphthyl)); see: Fairlie, D. P.; Bosnich,
B. Organometallics 1988, 7, 946.
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J. Am. Chem. Soc. 1980, 102, 5824.
r
10.1021/ol400266g
XXXX American Chemical Society

sluggish and this substrate was recovered in 30% yield
without isomerization of the cis trisubstituted olefin. These
results suggested that the observed regioconvergent ring
cleavage should be accounted for by a more refined mecha-
nistic rationale.
Scheme 1. Regioconvergent Ring Opening of ACBs
We initiated our investigations by examining the reactivity
of deuterium-labeled substrates displaying the same alkyl side
chain on the cyclobutane ring (R = -(CH2)2-C6H3-3,4-Cl2).
We observed a quantitative transfer of the deuterium atom
from its initial position in aldehydes 1D and 2D (Scheme 1) to
the same carbon atom of the olefin in cyclooctenone 3D,
although the reaction of 2D was much slower and led to a
mixture of decarbonylation products alongside 3D and re-
covered 2D.9 To our surprise, we also observed that the
methylene moieties in R and β positions of the aldehyde
group in 4 quantitatively exchanged their positions in the
rhodium-catalyzed rearrangement delivering 5 after full con-
version (eq 1). Conversely, we verified that the rearrangement
of aldehyde 6 into ketone 7 occurred under the same reaction
conditions without concomitant migration of the methylene
groups (eq 2). The position of the deuterated methylene was
ascertained in each case by comparison of the 13C NMR
spectra of compounds 3, 5, and 7. These results suggest that
trans and cis ACBs 1 and 2 underwent a regioconvergent
intramolecular hydroacylation toward 3 through specific and
very distinct mechanistic pathways, in which the less sterically
congested CꢀC bond of the cyclobutane ring was cleaved.
Scheme 2. β-C Elimination of Cyclobutylcarbinyl Metal
Intermediates in the Regioconvergent Ring Opening of ACBs
the deuterium-labeling experiments conducted with2D and
4 are in better agreement with the following mechanism
(Scheme 3). As discussed previously and depicted in
Scheme 2, insertion of the catalyst into the CꢀH bond of
the aldehyde group of cis ACB 2 followed by syn coplanar
hydrometalation would give E. Bond rotation toward G
instead of F would align the carbonꢀrhodium bond and
the less sterically hindered CꢀC bond of the cyclobutane
ring for a syn coplanar β-C elimination providing trans no-
narhodacycle H (Scheme 3). Then, carbon monoxide extru-
sion and reinsertion would lead to I and then J. Examples of
such extrusion/reinsertion equilibrium involving smaller rho-
dacycles are well-known.10,11 We propose that J would then
undergo a transannular syn coplanar 3-exo-trig carborhodation
The results obtained with 1D and 6 can be explained by
the sequence of reactions involving intermediates AꢀD,
already depicted in Scheme 2. In contrast, the outcomes of
(8) Co: (a) Atkins, M.; Golding, B. T.; Bury, A.; Johnson, M. D.;
Sellars, P. J. J. Am. Chem. Soc. 1980, 102, 3630. Pd: (b) Owczarzyk, Z.;
Lamaty, F.; Vawter, E. J.; Negishi, E. J. Am. Chem. Soc. 1992, 114,
10091. (c) Rawal, V. H.; Michoud, C. J. Org. Chem. 1993, 58, 5583. (d)
Feutren, S.; McAlonan, H.; Montgomery, D.; Stevenson, P. J. J. Chem.
(10) (a) Fairlie, D. P.; Bosnich, B. Organometallics 1988, 7, 936. (b)
Barnhart, R. W.; Bosnich, B. Organometallics 1995, 14, 4343. (c)
Tanaka, K.; Fu, G. C. Chem. Commun. 2002, 684. (d) Bjørnstad, V.;
Undheim, K. Synthesis 2008, 962. (e) Tanaka, K.; Okazaki, E.; Shibata,
Y. J. Am. Chem. Soc. 2009, 131, 10822.
(11) The temporary increase of strain energy during the formation of
I might be compensated by intramolecular coordination to the olefin;
see: Cedeno, D. L.; Sniatynsky, R. Organometallics 2005, 24, 3882 and
pertinent references cited therein.
ꢀ
Soc., Perkin Trans. 1 2000, 1129. (e) Bennasar, M. L.; Zulaica, E.; Sole,
D.; Roca, T.; Garcıa-Dıaz, D.; Alonso, S. J. Org. Chem. 2009, 74, 8359.
Ni: (f) Pinke, P. A.; Stauffer, R. G.; Miller, R. G. J. Am. Chem. Soc. 1974,
96, 4229. (g) Miller, R. G.; Pinke, P. A.; Stauffer, R. D.; Golden, H. J.;
Baker, D. J. J. Am. Chem. Soc. 1974, 96, 4211. (h) Pinke, D. A.; Miller,
R. G. J. J. Am. Chem. Soc. 1974, 96, 4221. Ru: (i) Trost, B. M.; Toste,
F. D.; Shen, H. C. J. Am. Chem. Soc. 2000, 122, 2379. (j) Trost, B. M.;
Shen, H. C. Org. Lett. 2000, 2, 2523. (k) Trost, B. M.; Shen, H. C. Angew.
Chem., Int. Ed. 2001, 40, 1313. (l) Trost, B. M.; Shen, H. C.; Horne,
D. N.; Toste, F. D.; Steinmetz, B. G.; Koradin, C. Chem.;Eur. J. 2005,
11, 2577. Rh: (m) Wender, P. A.; Dyckman, A. J.; Husfeld, C. O.;
Kadereit, D.; Love, J. A.; Rieck, H. J. Am. Chem. Soc. 1999, 121, 10442.
(n) Wender, P. A.; Dyckman, A. J. Org. Lett. 1999, 1, 2089. (o) Aıssa, C.;
(12) (a) Zhang, Y.; Negishi, E.-i. J. Am. Chem. Soc. 1989, 111, 3454.
(b) Grigg, R.; Dorrity, M. J.; Malone, J. F. Tetrahedron Lett. 1990, 31,
1343. (c) Grigg, R.; Sridharan, V.; Sukirthalingam, S. Tetrahedron Lett.
1991, 32, 3855. (d) Meyer, F. E.; Parsons, P. J.; de Meijere, A. J. Org.
Chem. 1991, 56, 6487. (e) Oppolzer, W.; Pimm, A.; Stammen, B.; Hume,
W. E. Helv. Chim. Acta 1997, 80, 623. (f) Oh, C. H.; Kang, J. H.; Rhim,
C. Y.; Kim, J. H. Chem. Lett. 1998, 375. (g) de Meijere, A.; von
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Furstner, A. J. Am. Chem. Soc. 2007, 129, 14836.
(9) kH/kD = 1.10ꢀ1.25 was measured in parallel experiments con-
ducted with 1 and 1D. Attempts of similar measurements with 2 and 2D
led to inconclusive results due to the decomposition of the catalyst by
partial decarbonylation of the substrate.
€
Zezschwitz, P.; Brase, S. Acc. Chem. Res. 2005, 38, 413. (h) Grigg, R.;
Sakee, U.; Sridahran, V.; Sukirthalingam, S.; Thangavelauthum, R.
Tetrahedron 2006, 62, 9523.
B
Org. Lett., Vol. XX, No. XX, XXXX

toward K. Examples of 3-exo-trig carbometalation reactions
of transition metal species are abundant in the litera-
ture,8aꢀh,12 and several involve rhodium species.13 However,
the rearrangement of J into K is the first example of the
transannular variant of a 3-exo-trig carbometalation. Equili-
bration between rotamers K and L would explain how, after
syn coplanar β-C elimination from L to cis nonarhodacycle
Mand reductive elimination,14 the methylene groups in Rand
β positions of the aldehyde group in 4 have exchanged their
position in this otherwise regioconvergent rearrangement.
Table 1. Regioselectivity of β-C Elimination in the
Rh-Catalyzed Hydroacylation of Substituted ACBs
entry
R
8 (E/Z)
yielda
9/10b
1
nC7H15
8a (1.5:1)
8b (1.5:1)
8c (3:1)
61%
69%
92%
51%c
93%
81%d
90%
60%f
93%
24%g
67%h
>20:1
>20:1
4.2:1
1:2.3
>20:1
1:1.3e
>20:1
<1:20
>20:1
12:1
2
-(CH2)3NTs(nPr)
Ph
3
Scheme 3. Mechanistic Rationale Accounting for the Results of
the Deuterium-Labeling Experiments with cis ACBs
4
Ph
8c (<1:20)
8d (19:1)
8d (<1:20)
8e (>20:1)
8e (<1:20)
8f (>20:1)
8f (<1:20)
8g (1:3.3)
5
C6H4-2-OBn
C6H4-2-OBn
C6H4-4-OBn
C6H4-4-OBn
C6H3-2,4-Cl2
C6H3-2,4-Cl2
C6H4-4-CO2Me
6
7
8
9
10
11
1:1.3e
a Combined isolated yield of 9 and 10. b Otherwise noted, this ratio
was determined by 1H NMR of the crude material. c 8c (Z only) was
recovered in 13% yield. d 8d (Z only) was recovered in 8% yield. e Ratio
determined from isolated yields of 9 and 10. f Isolated yield of 10e only;
8e (Z only) was recovered in 21% yield. g Isolated yield of 9f only; 8f
(Z only) was recovered in 39% yield. h 8g (E/Z = 1:6) was recovered in
5% yield after 90 h. Ts = 4-tolylsulfonyl.
recovered without isomerization of the trisubstituted ole-
fin, in up to 39% yield in the case of the least reactive
substrate 8f (entry 10). Moreover, the regioselectivity of
the reactions of cis 8cꢀ8g depended on the nature of the
substituent (entries 4, 6, 8, 10, and 11).
Hence, only one single CꢀC bond is cleaved in the
intramolecular hydroacylation of trans ACBs (Scheme 2,
AꢀD), whereas three single CꢀC bonds are cleaved in the
rearrangement of their cis isomers (color-coded in red,
Scheme 3, GꢀM). In both rearrangements, the minimiza-
tion of steric interactions between the substituent located
on the cyclobutane ring and the ligand sphere in inter-
mediates C and G would dictate the regioselectivity of the
β-C elimination step.
Having established a plausible mechanism for the regio-
convergent ring opening of substituted ACBs in intramo-
lecular hydroacylation, we examined the generality of this
remarkable transformation (Table 1). As it was the case for
1 and 2 (Scheme 1), we observed that the treatment of
mixturesof cis and trans isomersofalkyl-substitutedACBs
8a and 8b led to the formation of a single regioisomer 9a
and 9b, respectively (Table 1, entries 1 and 2). Moreover,
all trans isomers of aryl-substituted 8cꢀ8g underwent the
reaction according to intermediates AꢀD (Scheme 2) and
afforded 9cꢀ9g in excellent yields, without noticeable
influence of the electronic or steric nature of the substitu-
ents located on the cyclobutane ring (Table 1, entries 3, 5,
7, 9, and 11). Conversely, cis 8cꢀ8g reacted more slowly
than their trans isomers and the starting material was
These results enabled us to further refine the mechanistic
rationale depicted in Schemes 2 and 3. Hence, the cis isomers
of aryl-substituted ACBs can undergo the reaction accord-
ing to two competing catalytic cycles, where the equilibrium
between intermediates EꢀG is pivotal (Scheme 4). We
assume that minimization of steric interactions favors β-C
elimination through intermediates G and H, leading even-
tually to 9. However, steric congestion can be compensated,
and even overridden, by electronic stabilization of the
organorhodium intermediates, which would favor the β-C
elimination of intermediate F toward secondary nonarho-
dacycle N. From the results listed in Table 1, the degree of
electronic influence of substituents R on the formation of
regioisomer 10 from cis 8cꢀ8g follows the order C6H4-4-OBn
(15) It was not possible to obtain samples of pure cis or trans 8g.
However, on the basis of the results obtained with trans 8cꢀ8f, it is
reasonable to assume that pure trans 8g would give up to 90% of 9g,
which would equate to a 1:4.2 ratio of compounds 9g and 10g produced
by the cis isomer of 8g in entry 11.
(16) For examples of such stabilization, see: (a) Mak, K. W.; Chan,
K. S. J. Am. Chem. Soc. 1998, 120, 9686. (b) Mak, K. W.; Xue, F.; Mak,
T. C. W.; Chan, K. S. J. Chem. Soc., Dalton Trans. 1999, 3333. (c)
Settambolo, R.; Pucci, S.; Bertozzi, S.; Lazzaroni, R. J. Organomet.
Chem. 1995, 489, C50. (d) Settambolo, R.; Caiazzo, A.; Lazzaroni, R.
J. Organomet. Chem. 1996, 506, 337.
(13) (a) Nishihara, Y.; Yoda, C.; Osakada, K. Organometallics 2001,
20, 2124. (b) Nishihara, Y.; Yoda, C.; Itazaki, M.; Osakada, K. Bull.
Chem. Soc. Jpn. 2005, 78, 1469. (c) Miura, T.; Sasaki, T.; Harumashi, T.;
Murakami, M. J. Am. Chem. Soc. 2006, 128, 2516.
(14) See ref 5a for an example of a similar rearrangement of hexa-
rhodacycle intermediates leading to cyclooctenones.
(17) In contrast, a phenyl ring is not able to direct in a similar fashion
the rhodium-catalyzed ring opening of 4-cyclopropyl-2-cyclobutenones,
see: Huffman, M. A.; Liebeskind, L. S. J. Am. Chem. Soc. 1993, 115,
4895.
Org. Lett., Vol. XX, No. XX, XXXX
C

Scheme 4. Mechanistic Rationale for the Regioselective Ring
Opening of cis Aryl-Substituted ACBs
Scheme 5. Retention of Configuration in CꢀC Cleavage and
Reductive Elimination
The rearrangement of a 3.3:1 mixture of trans and cis iso-
mers of racemic 1120 led to the formation of 12 and 13 in 75%
and 9% yield, respectively (Scheme 5). Although the rearran-
gement of a mixture enriched in the cis olefin (E/Z = 1:8) was
more sluggish, it led predominantly to 13 in 33% yield,
accompanied by 8% of 12 and 33% of recovered starting
material (E/Z < 1:20) (Scheme 5). Importantly, as inferred
from a large pseudodiaxal coupling constant, compound 13
was obtained only as an anti diastereomer from cis olefin 11,
indicating that β-C elimination of intermediate F and subse-
quent reductive elimination of intermediate O (Scheme 4)
occurred with retention of configuration.
In conclusion, we have demonstrated that the rhodium-
catalyzed intramolecular hydroacylation of cis and trans
asymmetrically substituted ACBs proceeds according to
three catalytic pathways. Overall, we anticipate that our
results will help in understanding the regioselectivity of
other metal-catalyzed CꢀC bond cleavage processes.
. C6H4-4-CO2Me > Ph > C6H4-2-OBn . C6H3-2,4-Cl2.15
It is likely that the polarized carbonꢀrhodium bond
(CδꢀꢀRhδþ) of secondary rhodium N is better stabilized
by an electron-withdrawing substituent such as phenyl than
by an alkyl chain.16,17 This stabilization would be accentuated
in the reaction of cis 8g. Although such stabilization is not
possible with an electron-rich para-benzyloxyphenyl substi-
tuent, the reaction of cis 8e gave only 10e. In this case, we
propose that an η2 interaction between the aryl substituent
and the metal would favor the ring enlargement from F to N.
Results of theoretical studies have suggested that a similar
interaction favors the cleavage of the most sterically hindered
CꢀC bond in the samarium-promoted ring opening of
phenyl-substituted methylenecyclopropane, both kinetically
and thermodynamically.18 A similar explanation has been
proposed for the organolanthanide-catalyzed regioselective
hydroamination of the same reagent, which also proceeds by
cleavage of the most sterically hindered CꢀC bond.19 In the
case of cis 8d and 8f, electronic stabilization is less relevant
because of the increased steric hindrance.
Acknowledgment. We are grateful for the financial
support from EPSRC (DTA studentships to D.C. and K.
Y.T.H.), the Leverhulme Trust (RPG198), RCUK, and
the University of Liverpool.
(18) Tobisch, S. Chem.;Eur. J. 2005, 11, 3113.
(19) Ryu, J.-S.; Li, G. Y.; Marks, T. J. J. Am. Chem. Soc. 2003, 125,
12584.
(20) ACB 11 was prepared from anti 2,3-bisphenylcyclobutanone,
itself obtained according to a slight modification of a known procedure
reported by Ghosez and coworkers in Falmagne, V. J-B.; Escudero, J.;
Taleb-Sahraoui, S.; Ghosez, L. Angew. Chem. 1981, 93, 926. See
Supporting Information.
Supporting Information Available. Detailed experimen-
tal procedures and characterization of all new com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX