Allene carboxylates as dipolarophiles in Rh-catalyzed carbonyl ylide cycloadditions

Article abstract of DOI:10.1002/chem.200902208

Face-to-face: Allene carboxylates can serve as efficient dipolarophiles for Rh-catalyzed carbonyl ylide cycloadditions (see scheme). The endo and exo products arise from cycloaddition on the same face of the allene, but opposite faces of the dipole. This facial selectivity results in the formation of two of the four possible diastereomers.

Full text of DOI:10.1002/chem.200902208

DOI: 10.1002/chem.200902208
Allene Carboxylates as Dipolarophiles in Rh-Catalyzed Carbonyl Ylide
Cycloadditions
Laxmidhar Rout and Andrew M. Harned*[a]
Foregoing their past as structural oddities and molecules
of only fundamental interest, allenes have proven them-
selves as valuable synthetic building blocks and reaction in-
termediates.[1] In part, the interest in these molecules stems
from their axial chirality,[2] which has tremendous potential
in the realm of stereoselective synthesis (Figure 1).[1,3] We
was employed to control the stereochemical outcome of di-
polar cycloadditions (e.g. 1!3).[5,6] There were also rather
limited examples of allenes being used in carbonyl ylide cy-
cloadditions.[7] Herein we report that carboxylate-functional-
ized allenes can serve as dipolarophiles for carbonyl ylides
and that excellent levels of allene facial selectivity can be
achieved.
Our first task was to determine the feasibility of using
electron-deficient allenes as dipolarophiles. To test this we
examined the Rh-catalyzed cycloaddition between diazocar-
bonyl compound 1a and the achiral allene 2a (Table 1). At-
tempting the reaction in CH2Cl2 or 1,2-dichloroethane
(DCE) did not result in product formation, even at elevated
temperatures (Table 1, entries 1–3). However, running the
reaction in refluxing toluene formed 3 and 4 in a 2.5:1 dia-
stereomeric ratio (Table 1, entry 4). Gratifyingly, the two
diastereomers could be separated and their identity was de-
termined by the magnitude of the allylic coupling con-
stants.[8] Running the reaction in benzene resulted in a
slightly diminished yield with no dramatic improvement on
Figure 1. General modes of reactivity with axially chiral allenes and their
application to carbonyl ylide cycloadditions.
Table 1. Optimization of reaction conditions.[a]
have recently begun a program aimed at utilizing the unique
structural features of axially chiral allenes to predictably
control the stereochemical outcome of cycloaddition reac-
tions[4] as the key step in the synthesis of various natural
products. We are particularly interested in cycloaddition re-
actions for which catalyst control of stereochemistry would
be difficult, either from a mechanistic standpoint or due to
substrate instability.
Entry
Temp [8C]
Solvent
Time [h]
Yield [%][b]
Upon scanning the literature we were surprised to find a
dearth of examples in which the axial chirality of allenes
1
2
3
4
5
6
7
8
25
40
60
110
70
80
CH2Cl2
CH2Cl2
DCE
toluene
C6H6
24
24
24
12
16
9
–
–
–
82
74
80
85
86
[a] Dr. L. Rout, Prof. A. M. Harned
Department of Chemistry
20:1 DCE/C6H6
20:1 DCE/C6H6
20:1 DCE/C6H6
University of Minnesota
Minneapolis, Minnesota 55455 (USA)
Fax : (+1)612-626-7541
65
18
0.5
150[c]
[a] Ratio of 3:4 determined by 1H NMR spectroscopy of crude product.
[b] Combined yield of products, which were separable by chromatogra-
phy. [c] Microwave heating (power=150 W, temperature=1508C).
E-mail: harned@umn.edu
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200902208.
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Chem. Eur. J. 2009, 15, 12926 – 12928

COMMUNICATION
the diastereoselectivity (Table 1, entry 5). After further in-
vestigating the affect of solvent,[9] we found that the reactivi-
ty in DCE could be restored with aromatic additives. The
best results were obtained in 20:1 DCE/C6H6 at 658C
(Table 1, entry 7).[10] Other Rh sources, did not offer any ad-
to afford higher diastereoselectivity than those with ethyl
esters, while 1a seems to be better than 1b. In general, the
size of the R2 group of 2 seems to have a relatively minor
affect on the diastereoselectivity.
vantage over [Rh2ACHTUNGTRENNUNG
(OAc)4],[9] but running the reaction under
Table 2. Investigating the scope of the allene.[a]
microwave irradiation considerably reduced the reaction
time without affecting the diastereoselectivity (Table 1,
entry 8). It is not clear how the aromatic additives are help-
ing the reaction, but other groups have found aromatic sol-
vents to be beneficial to carbonyl ylide cycloadditions.[11]
The success of these preliminary experiments allowed us
to consider the use of internal allenes as dipolarophiles.
Analysis of the four possible transition states reveals an in-
teresting consequence associated with the use of these al-
lenes (Scheme 1). The major endo[12] and major exo transi-
tion states involve approach of the less hindered face of the
allene to opposite faces of the dipole, forming 5 and 6, re-
spectively. The minor endo and exo transition states involve
approach of the dipole to the more hindered face of the
allene, forming 7 and 8. At first glance it may seem like the
major and minor paths lead to enantiomeric products, but
upon closer inspection one finds that 5 and 6 are actually
diastereomers of 7 and 8. Based on this analysis we predicted
that only two of the products (i.e. 5 and 6) would be feasi-
ble.
Entry
1
R1
Et
Allene
Method
A
5:6[b]
Yield [%][c]
64[d]
2.8:1
2
3
4
tBu
Et
B
A
A
3.4:1
2.7:1
2.8:1
88
50[d]
82
tBu
5
6
tBu
Et
A/B
A
4.0:1
90
To our delight we found that allenes 2c–2j were compati-
ble with the reaction and only two of the possible diastereo-
mers were formed (Table 2). The observed levels of diaste-
reoselectivity (2.7:1 to 4.1:1) are similar to those previously
observed for carbonyl ylide cycloadditions with acrylate di-
polarophiles.[11a,13] Though there are exceptions (Table 2,
compare entries 1 and 3), allenes with benzyl esters seemed
3.0:1
93
7
Et
A
>3:1[e]
>3:1[e]
>3:1[e]
>3:1[e]
2.8:1
78[d]
72[d]
60[d]
55[d]
88
8
tBu
tBu
Et
A
9
A
10
11
12
13
14
A
tBu
tBu
tBu
tBu
B
A
3.1:1
53[d]
78
A
4.1:1
A
2.8:1
50[d]
[a] Method A: conventional heating, 658C, 12 h. Method B: microwave
heating (power=150 W, temperature=1508C), 30 min. [b] Determined
by 1H NMR spectroscopy of crude product. [c] Combined yield of prod-
ucts, which were separable by chromatography. [d] Only trace amounts of
6 could be isolated. The indicated yield is the isolated yield of the major
product 5. [e] An accurate determination of the product ratio in the
crude material could not be made.
Scheme 1. Transition state analysis.
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www.chemeurj.org
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A. M. Harned and L. Rout
[3] For recent examples, see: a) J. A. Marshall, H. R. Chobanian, J. Org.
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[5] For reviews on the use of allenes in 1,3-dipolar cycloaddiitons, see:
a) G. Broggini, G. Zecchi, Gazz. Chim. Ital. 1996, 126, 479–488;
b) M. Murakami, T. Matsuda in Modern Allene Chemistry (Eds.: N.
Krause, A. S. K. Hashmi), Wiley-VCH, Weinheim, 2004, pp. 727–
815.
[6] For an review on asymmetric 1,3-dipolar cycloadditions, see: K. V.
Gothelf, K. A. Jørgensen in Synthetic Applications of 1,3-Dipolar
Cycloaddition Chemistry Toward Hetereocycles and Natural Prod-
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[7] a) D. M. Hodgson, F. Le Strat, Chem. Commun. 2004, 822–823;
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Figure 2. a) Key NOE enhancements. b) Selected HMBC cross peaks.
Although many of the diastereomeric products were sepa-
rable by chromatography, none were solid at room tempera-
ture. Thus, extensive 2D NMR and NOE spectroscopic anal-
ysis were performed on the cycloaddition products of 1a
and 2d in order to confirm the bicyclic structure
(Figure 2).[14] Both diastereomers exhibited NOE enhance-
ment of both methyl groups upon irradiation of the methyne
ꢀ
C H, establishing the stereochemistry of the olefin, indicat-
ing that the cycloaddition proceeds with high facial selectivi-
ty with respect to the allene. We were also able to confirm
the exo relationship of the minor diastereomer, owing to the
NOE enhancements observed on the ethylene bridge. The
endo relationship of the major diastereomer was inferred by
[8] S. Sternhell, Q. Rev. Chem. Soc. 1969, 23, 236–270.
[9] See the Supporting Information.
[10] The increased temperatures required for these reactions, relative to
related carbonyl ylide cycloadditions, may be due to the increased
steric requirements of the allene relative to olefins and alkynes.
[11] a) A. Padwa, G. E. Fryxell, L. Zhi, J. Am. Chem. Soc. 1990, 112,
3100–3109; b) D. M. Hodgson, A. H. Labande, F. Y. T. M. Pierard,
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3603–3606.
ꢀ
the lack of NOE enhancements between the methyne C H
and the ethylene bridge, as well as the significant downfield
shift of HC; presumably a result of the proximity of the ester
moiety.
In conclusion, we have shown that allene carboxylates can
serve as dipolarophiles in carbonyl ylide cycloadditions.
These reactions proceed with high allene facial selectivity to
give only two of the four possible diastereomers. Unfortu-
nately, there are few methods available for the enantioselec-
tive construction of electron-deficient allenes,[15] so we
cannot comment on the level of chirality transfer that would
be observed.[16] We are currently working to address this sit-
uation and will report these results in due course.
[12] We are defining endo to be the product with the CO2R3 group anti
to the oxo bridge, as proposed by Padwa in reference [11a].
[13] C.-Y. Zhou, W.-Y. Yu, C.-M. Che, Org. Lett. 2002, 4, 3235–3238.
[14] While this analysis was only performed on the structures shown in
Figure 2, all of the isolated products had very similar spectral char-
acteristics within each diastereomeric series.
[15] a) J. A. Marshall, M. A. Wolf, E. M. Wallace, J. Org. Chem. 1997, 62,
367–371; b) T. M. V. D. Pinho e Melo, A. L. Cardoso, A. M. d’A.
Rocha Gonsalves, J. Costa Pessoa, J. A. Paix¼o, A. M. Beja, Eur. J.
Org. Chem. 2004, 4830–4839; c) C.-Y. Li, X.-B. Wang, K.-L. Sun, Y.
Tang, J.-C. Zheng, Z.-H. Xu, Y.-G. Zhou, L.-X. Dai, J. Am. Chem.
Soc. 2007, 129, 1494–1495; d) H. Liu, D. Leow, K.-W. Huang, C.-H.
Tan, J. Am. Chem. Soc. 2009, 131, 7212–7213.
Acknowledgements
We thank the University of Minnesota for financial support and Dr. Leti-
tia Yao for NMR assistance.
[16] We attempted to use Marshallꢄs Pd-catalyzed carbonylation of prop-
argylic mesylates (Ref. [15a]) in order to construct enantioenriched
2e. Unfortunately, in our hands this method produced (S)-2e with
moderate enantiopurity (72% ee). Because the diastereomeric rela-
tionship between 5 and 7 (and 6 and 8) would complicate the deter-
mination of the enantiomeric excess in the product, we prefer to
employ allenes with higher enantiopurity.
Keywords: allenes
cycloaddition · diazo compounds
· axial chirality · carbonyl ylides ·
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VCH, Weinheim, 2004; b) S. Ma, Chem. Rev. 2005, 105, 2829–2872.
[2] For reviews of chiral allenes, see: a) R. Rossi, P. Diversi, Synthesis
1973, 25–36; b) M. Ogasawara, Tetrahedron: Asymmetry 2009, 20,
259–271.
Received: August 7, 2009
Published online: November 5, 2009
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Chem. Eur. J. 2009, 15, 12926 – 12928