Rhodium-catalyzed hydroformylation of cyclopropenes

Article abstract of DOI:10.1021/ja805059f

The first catalytic diastereo- and enantioselective hydroformylation of cyclopropenes was demonstrated. The reaction proceeds efficiently under very mild conditions and low catalyst loadings providing high yields of cyclopropylcarboxaldehydes. This novel methodology represents a convenient, atom-economic approach toward optically active cyclopropylcarboxaldehydes from readily available prochiral cyclopropenes.

Full text of DOI:10.1021/ja805059f

Published on Web 09/20/2008
Rhodium-Catalyzed Hydroformylation of Cyclopropenes
William M. Sherrill and Michael Rubin*
Department of Chemistry, UniVersity of Kansas and Center for EnVironmentally Beneficial
Catalysis, 1251 Wescoe Hall DriVe, Malott Hall, Lawrence, Kansas 66045-7582
Received July 1, 2008; E-mail: mrubin@ku.edu
Abstract: The first catalytic diastereo- and enantioselective hydroformylation of cyclopropenes was
demonstrated. The reaction proceeds efficiently under very mild conditions and low catalyst loadings
providing high yields of cyclopropylcarboxaldehydes. This novel methodology represents a convenient,
atom-economic approach toward optically active cyclopropylcarboxaldehydes from readily available prochiral
cyclopropenes.
Scheme 1. Synthetic Approaches toward Formylcyclopropanes
Introduction
Cyclopropylcarboxaldehydes are arguably some of the most
sought after compounds in the chemistry of small cycles. Not
only are they themselves important biologically active targets,1
but they also are extremely versatile synthons as the aldehyde
group can be readily transformed into a number of useful
functionalities.2 Established synthetic approaches toward these
important targets include various modes of [2 + 1] cycloaddi-
tions (Scheme 1, path a), such as Michael-initiated ring-closure
reaction (MIRC);3 the cyclization of conjugated aldehydes with
carbenoidequivalentsderivedfromdihalomethanes,4,5diazocompounds,6
nitrogen ylides,7 sulfur ylides,8 or arsonium ylides;9 as well as
functional group transformations in pre-existing cyclopropyl
rings, such as oxidation of cyclopropylmethanols (Scheme 1,
path b),10 reduction of cyclopropylcarboxylic acid derivatives
(Scheme 1, path c),11 and oxidative cleavage of the double bond
in vinylcyclopropanes (Scheme 1, path d).12 In light of the recent
advances in chemistry of cyclopropenes,13,14 we envisioned an
(1) See, for example: (a) Paul, V. J.; Fenical, W Science 1983, 221, 747.
(b) Zheng, G. C.; Hatano, M.; Ishitsuka, M. O.; Kusumi, T.; Kakisawa,
H. Tetrahedron Lett. 1990, 31, 2617. (c) Shuto, S.; Takada, H.;
Mochizuki, D.; Tsujita, R.; Hase, Y.; Ono, S.; Shibuya, N.; Matsuda,
A. J. Med. Chem. 1995, 38, 2964.
(2) For recent application of cyclopropyl carboxaldehydes in synthesis,
see: (a) Trost, B. M.; Hu, Y.; Horne, D. B. J. Am. Chem. Soc. 2007,
129, 11781. (b) White, J. D.; Martin, W. H. C.; Lincoln, C.; Yang, J.
Org. Lett. 2007, 9, 3481. (c) Al Dulayymi, J. R.; Baird, M. S.; Roberts,
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(e) Kalidindi, S.; Jeong, W. B.; Schall, A.; Bandichhor, R.; Nosse,
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Tetrahedron: Asymmetry 2007, 18, 1403. (c) Hartikka, A.; Arvidsson,
P. I. J. Org. Chem. 2007, 72, 5874. (d) Kunz, R. K.; MacMillan,
D. W. C. J. Am. Chem. Soc. 2005, 127, 3240. (e) Nowick, J. S.;
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9
13804 J. AM. CHEM. SOC. 2008, 130, 13804–13809
10.1021/ja805059f CCC: $40.75
2008 American Chemical Society

Rhodium-Catalyzed Hydroformylation of Cyclopropenes
A R T I C L E S
Scheme 2. Mechanistic Pathways for Different Processes
alternative approach to cyclopropylcarboxaldehydes via catalytic
hydroformylation15 of the cyclopropene double bond (Scheme
1, path e). We hoped to develop a mild, practical, and atom
economic protocol for the stereoselective installation of a new
carbon-carbon bond in the three-membered cycle, while
avoiding the use of reactive organometallic reagents invoked
inmostC-Cbondformingreactionsinvolvingcyclopropenes.12,16,17
To date, hydroformylation of cyclopropenes is represented
by a few stoichiometric reactions mediated by HMn(CO)5 or
HCo(CO)4, reported by Orchin and Noyori.18,19 Orchin first
demonstrated that 1,2-substituted cyclopropenes undergo hy-
droformylation in the presence of Mn- and Co-complexes to
afford low yields of aldehyde 3, accompanied by large amounts
of the reduction product 2 (eq 1). Application of micellar
catalysis allowed for improved yields of aldehydes (up to 93%);
however, this reaction produced mixtures of syn- and anti-
addition products.16c Later, Noyori investigated the hydroformy-
lation reaction using a stoichiometric HMn(CO)5 complex in
various solvents, including scCO2, yet was unsuccessful in
obtaining an aldehyde yield above 40%.17
Occurring in the Rh(I)-Catalyzed Hydroformylation of
Cyclopropenes
dimerization of cyclopropenes occurring in the presence of
electron-poor transition metal reagents (Scheme 2, Path III).20,21
These two dominating side processes do not allow efficient
incorporation of the carbonyl function into the final product,
leading instead to the formation of polymers and mixtures of
oligocarbocyclic hydrocarbons and ketones.22 To date, only one
highly selective carbonylative transformation involving cyclo-
propenes, the Pauson-Khand reaction, has been reported;
however, this process requires use of at least stoichiometric
amounts of metal carbonyl complexes.23
Herein we report the first examples of catalytic diastereo-
and enantioselective hydroformylation of prochiral cyclopro-
penes to produce tri- and tetrasubstituted cyclopropylcarboxal-
dehydes, proceeding under mild conditions and very low catalyst
loading (eq 2).
In line with the reasoning mentioned above, our initial
experiments demonstrated that treatment of 3-methyl-3-phenyl-
cyclopropene (4a) with syngas in the presence of standard
hydroformylation catalyst, Rh(acac)(CO)2, afforded quantita-
The long-standing challenge associated with the use of
coordinatively unsaturated electron-deficient transition metal
catalysts derived from metal carbonyl complexes in cyclopro-
pene chemistry lies in the significantly more facile migratory
insertion of cyclopropene into a metal-carbon bond (Scheme
2, Path II) as compared to the CO insertion step (Path I). Another
commonly encountered problem is a very fast formal [2 + 2]
(15) For recent reviews on catalytic hydroformylation of olefins, see: (a)
Nozaki, K. In New Frontiers in Asymmetric Catalysis; Koichi, M.,
Lautens, M, Eds.; Wiley: New York, 2007; pp 101-127. (b) Claver,
C.; Dieguez, M.; Pamies, O.; Castillon, S. Top. Organomet. Chem.
2006, 18, 35. (c) Leighton, J. L. In Modern Rhodium-Catalyzed
Organic Reactions; EvansP. A., Ed.; Wiley: New York, 2005; pp 93-
110. (d) Dieguez, M.; Pamies, O.; Claver, C. Tetrahedron: Asymmetry
2004, 15, 2113. (e) Breit, B. Acc. Chem. Res. 2003, 36, 264. (f) Breit,
B.; Seiche, W. Synthesis 2001, 1.
(16) For recent examples on additions of Grignard reagents to cyclopro-
penes, see: (a) Nakamura, M.; Hirai, A.; Nakamura, E. J. Am. Chem.
Soc. 2000, 122, 978. (b) Liao, L.; Fox, J. M. J. Am. Chem. Soc. 2002,
124, 14322. (c) Yang, Z.; Xie, X.; Fox, J. M. Angew. Chem., Int. Ed.
2006, 45, 3960. (d) Simaan, S.; Marasawa, A.; Bertus, P.; Marek, I.
Angew. Chem., Int. Ed. 2006, 45, 3963. See also ref 13a,c.
(17) For the Pd-catalyzed addition of terminal alkynes to cyclopropenes
proceeding under mild and neutral conditions, see: Yin, J.; Chisholm,
J. D. Chem. Commun. 2006, 632.
(12) (a) Pellicciari, R.; Marinozzi, M.; Macchiarulo, A.; Fulco, M. C.;
Gafarova, J.; Serpi, M.; Giorgi, G.; Nielsen, S.; Thomsen, C. J. Med.
Chem. 2007, 50, 4630. (b) Pandey, R. K.; Lindeman, S.; Donaldson,
W. A. Eur. J. Org. Chem. 2007, 3829. (c) Melancon, B. J.; Perl, N. R.;
Taylor, R. E. Org. Lett. 2007, 9, 1425. (d) Barluenga, J.; de Prado,
A.; Santamaria, J.; Tomas, M. Chem.-Eur. J. 2007, 13, 1326. (e)
Deng, X.-M.; Cai, P.; Ye, S.; Sun, X.-L.; Liao, W.-W.; Li, K.; Tang,
Y.; Wu, Y.-D.; Dai, L.-X. J. Am. Chem. Soc. 2006, 128, 9730. (f)
Racouchot, S.; Sylvestre, I.; Ollivier, J.; Kozyrkov, Y. Y.; Pukin, A.;
Kulinkovich, O. G.; Salau¨n, J. Eur. J. Org. Chem. 2002, 2160. (g)
Fujita, M.; Hiyama, T.; Kondo, K. Tetrahedron Lett. 1986, 27, 2139.
(h) Halazy, S.; Krief, A. Tetrahedron Lett. 1981, 22, 4341. (i) Monpert,
A.; Martelli, J.; Gree, R.; Carrie, R. Tetrahedron Lett. 1981, 22, 1961.
(j) Holm, K. H.; Lee, D. G.; Skattebøl, L. Acta Chem. Scand., Ser. B:
Org. Chem. Biochem. 1978, B32, 693.
(18) (a) Nalesnik, T. E.; Orchin, M. J. Organomet. Chem. 1981, 222, C5.
(b) Nalesnik, T. E.; Freudenberger, J. H.; Orchin, M. J. Organomet.
Chem. 1982, 236, 95. (c) Matsui, Y.; Orchin, M. J. Organomet. Chem.
1983, 244, 369.
(19) Jessop, P. G.; Ikariya, T; Noyori, R Organometallics 1995, 14, 1510.
(20) For transition metal-catalyzed formal [2 + 2] cycloaddition of
cyclopropenes, see for example: (a) Lukin, K. A.; Zefirov, N. S. Zh.
Org. Khim. 1990, 26, 289.
(13) For recent reviews, see: (a) Marek, I.; Simaan, S.; Masarwa, A. Angew.
Chem., Int. Ed. 2007, 46, 7364. (b) Rubin, M.; Rubina, M.; Gevorgyan,
V. Chem. ReV. 2007, 107, 3117. (c) Rubin, M; Rubina, M.; Gevorgyan,
V. Synthesis 2006, 1221. (d) Fox, J. M.; Yan, N. Curr. Org. Chem.
2005, 9, 719.
(21) For the formation of metallacycles from cyclopropenes, see: (a)
Hashmi, A. S. K.; Grundl, M. A.; Bats, J. W.; Bolte, M Eur. J. Org.
Chem. 2002, 7, 1263, and refs cited therein. On oligomerization of
cyclopropenes in the presence of Rh(I), see: (b) Cetinkaya, B.; Binger,
P. Chem. Ber. 1982, 115, 3414.
(14) For recent examples, see: (a) Yan, N.; Liu, X.; Fox, J. M. J. Org.
Chem. 2008, 73, 563. (b) Rubina, M.; Woodward, E. W.; Rubin, M.
Org. Lett. 2007, 9, 5501. (c) Simaan, S.; Marek, I. Org. Lett. 2007, 9,
2569. (d) Chuprakov, S.; Malyshev, D. A.; Trofimov, A.; Gevorgyan,
V. J. Am. Chem. Soc. 2007, 129, 14868. (e) Marasawa, A.; Sranger,
A.; Marek, I. Angew. Chem., Int. Ed. 2007, 46, 8039.
(22) (a) Grobovenko, S. Ya.; Zlobina, V. A.; Surmina, L. S.; Bolesov, I. G.;
Lapidus, A. L.; Beletskaya, I. P. Metalloorg. Khim 1990, 3, 697. (b)
Binger, P.; Biedenbach, B. Chem. Ber. 1987, 120, 601. (c) Kireev,
S. L.; Smit, V. A.; Ugrak, B. I.; Nefedov, O. M. IzV. Akad. Nauk
SSSR, Ser. Khim. 1991, 2565.
9
J. AM. CHEM. SOC. VOL. 130, NO. 41, 2008 13805

A R T I C L E S
Sherrill and Rubin
Table 1. Rh(I)-Catalyzed Hydroformylation of 3,3-Disubstituted Cyclopropenes
c
R1
R2
R3
Rxn time, hrs (4:Rh ratio)a
Yield of 5, %
dr (5:6)b
1
2
3
4
5
6
7
8
9
Ph
Me
Me
Me
CH2OMOM
CH2OAc
CO2Me
Me
H
H
H
H
H
H
H
H
4a
4b
4c
4d
4e
4f
4g
4h
4i
18 (1500:1)
18 (1500:1)
18 (100:1)
36 (1500:1)
36 (1500:1)
18 (1500:1)
36 (1500:1)
72 (1500:1)
18 (100:1)
5a
5b
5c
5d
5e
5f
5g
5h
5i
87
11:1
8:1
12:1
10:1
7:1
p-Cl-C6H4
p-F-C6H4
Ph
Ph
Ph
CO2Me
CMe2OBn
Ph
71d
91d
72
75
90d
64
1:1
24:1
e
Me
Me
91
-
Me
80d
7:1f
a dppf:Rh molar ratio of 2:1 was employed. b Determined by 1H NMR analysis of crude reaction mixtures. c Isolated yields of a major diastereomer
d Combined isolated yields of two diastereomers. e A single diastereomer 5h was obtained. f Regioselectivity of >10:1 was observed.
tively dimeric product 7 (eq 3). Attempts to suppress the
unwanted cyclization by saturating the coordination sphere of
the transition metal with monodentate phosphine ligands24a,22b
were unsuccessful (eq 3). Next, we tested several bidentate
diphosphine ligands24c,d anticipating their chelating effect would
help stabilize the catalytically active Rh(I) species in a more
saturated form. It was found that employment of dppm, dppp,
and dppb in combination with Rh(acac)(CO)2 allowed for
suppressing of the redundant cyclization; however, it did not
promote the hydroformylation reaction, leading instead to
complete recovery of cyclopropene 4a (eq 3). In contrast, the
Rh(acac)(CO)2/dppe combination produced the desired product
5a in low yield, whereas the analogous complex with a more
rigid ferrocenyl backbone (dppf) provided complete conversion
of 4a into formylcyclopropanes 5a and 6a (eq 3). The hydro-
formylation reaction proceeded very diastereoselectively af-
fording less sterically hindered aldehyde 5a as a major product.
Remarkably, no products of ring-opening were detected in this
reaction. On the basis of the ligand effect observed, it would
be reasonable to propose that the reaction is very sensitive to
the ligand bite angle; however, the enhanced catalytic activity
of the dppf complex might also be explained by the increased
electronic density provided by the ferrocenyl backbone.
isolated yield. It was found that as little as 0.067 mol% of Rh(I)
was enough to drive this reaction to completion under very mild
conditions (Table 1, entry 1). Efficient isolation of products
could be achieved either by column chromatography or by direct
vacuum distillation of the reaction mixtures. The scope of this
novel transformation was examined on a series of 3,3-disub-
stituted cyclopropenes (Table 1). Cyclopropenes 4b-c bearing
substituted aryl groups at C3 reacted uneventfully to provide
the corresponding aldehydes 5b-c (entries 2-3). Both acetal
(entry 4) and ester (entry 5) protecting groups for a primary
alcohol function were perfectly compatible with the reaction
conditions: the corresponding aldehydes 5d and 5e were
obtained in high yield and good selectivity. The diastereose-
lectivity of this transformation is largely controlled by steric
factors. Thus, the reaction of electron-deficient cyclopropene
4f provided a nearly equimolar mixture of two diastereomeric
cyclopropylcarboxaldehydes 5f and 6f due to the similar
effective size of the substituents at C3 (entry 6). At the same
time, the analogous ester derivative bearing a small Me-group
at C3 (4g) reacted very selectively (entry 7). Finally, the
substrate possessing a very bulky Bn-protected tertiary alcohol
function (4h) provided a single diastereomer of formylcyclo-
propane 5h (entry 8). We also tested the hydroformylation
reaction of 1,3,3-trisubstituted cyclopropene 4i, which represents
a more challenging model, as it can potentially produce four
different products in the syn-specific addition and, therefore,
requires simulataneous control of facial and regioselectivity. It
was found that standard reaction conditions using 0.067 mol%
of Rh-catalyst did not produce any reaction with 4i, presumably,
due to the increased steric demand in the substrate. However,
increasing catalyst loading to 1 mol% provided tetrasubstituted
cyclopropane 5i in good yield and high regio- and diastereo-
selectivity (entry 9).
Preparative scale hydroformylation of 4a also proceeded
smoothly under these conditions providing aldehyde 5a in high
Naturally, having in hand efficient conditions for the dias-
tereoselective hydroformylation, we were very intrigued by the
possibility of performing an asymmetric hydroformylation of
prochiral cyclopropenes (eq a). We began our optimization25
by testing several commercially available ligands, which were
shown to produce high enantioselectivities in the asymmetric
hydroformylation (AHF) of styrene.26 However, all of these
ligands provided unsatisfactory results in the hydroformylation
of cyclopropene 4a. Thus, Ph-BPE (L1),25 reported by Klosin
as one of the best-performing ligands for the AHF of terminal
(23) (a) Kireev, S. L.; Smit, V. A.; Ugrak, B. I.; Nefedov, O. M. Bull.
Acad. Sci. USSR (Engl. Transl.) 1991, 2240. (b) Witulski, B.;
Go¨ssmann, M. Synlett 2000, 1793. (c) Marchueta, I.; Verdaguer, X.;
Moyano, A.; Pericas, M. A.; Riera, A. Org. Lett. 2001, 3, 3193. (d)
Pericas, M. A.; Balsells, J.; Castro, J.; Marchueta, I.; Moyano, A.;
Riera, A.; Vazquez, J.; Verdaguer, X. Pure Appl. Chem. 2002, 74,
167. (e) Nu¨ske, H.; Bra¨se, S.; de Meijere, A. Synlett 2000, 1467. (f)
Pallerla, M. K.; Fox, J. M. Org. Lett. 2005, 7, 3593.
(24) For use of these ligands in low-p ressure hydroformylation of olefins,
see for example: (a) Hjortkjaer, J.; Toromanova-Petrova, P J. Mol.
Catal. 1989, 50, 203. (b) Choukroun, R.; Gervais, D.; Kalck, P.;
Senocq, F. J. Organomet. Chem. 1987, 335, C9. (c) Rajurkar, K. B.;
Tonde, S. S.; Didgikar, M. R.; Joshi, S. S.; Chaudhari, R. V. Ind.
Eng. Chem. Res. 2007, 46, 8480. (d) Rosales, M.; Gonzalez, A.;
Guerrero, Y.; Pacheco, I.; Sanchez-Delgado, R. A. J. Mol. Cat. A 2007,
270, 241.
(25) Typical procedure described on page SI9 (Supporting Information)
was used for optimization of the asymmetric hydroformylation, except
that dppf was substituted with an equimolar amount of the corre-
sponding chiral ligand.
9
13806 J. AM. CHEM. SOC. VOL. 130, NO. 41, 2008

Rhodium-Catalyzed Hydroformylation of Cyclopropenes
A R T I C L E S
Table 2. 2. Ligand Screening in the Asymmetric Hydroformylation of 3-Methyl-3-phenylcyclopropene (4a)
#
Ligand
conv, % (NMR)
drc (5a:6a)
eed (5a), %
ee (6a), %
eee(b:l) in the AHF of styrene
1
2
3
4
5
6
7
8
(R,R,R,R)-Ph-BPE (L1)
(R)-BINAPINE (L2)
(R,R,S,S)-Tangphos (L3)
(R,R,S,S)-DUANPHOS (L4)
(S,S,S,S)-Me-DUPHOS (L5)
(R,R,R,R)-iPr-DUPHOS (L6)
CatASium m(R) (L7)
Josiphos J001-1 (L8)
Josiphos J002-1 (L9)
Josiphos J003-1 (L10)
Josiphos- J008-1 (L11)
Josiphos- J010-1 (L12)
Walphos W001-1 (L13)
Walphos W002-1 (L14)
Taniaphos T001-1 (L15)
Taniaphos T003-1 (L16)
Taniaphos T021-1 (L17)
Mandyphos M001-1 (L18)
Mandyphos M004-1 (L19)
(R)-BINAP (L20)
100
49
100
100
6
12:1
13:1
2.9:1
14:1
4:1
13:1
-
14:1
10.6:1
18.5:1
14:1
27:1
5.4:1
10.3:1
7:1
-42
+18
+31
+8
-10
-18
-
+14
+56
+24
+16
-19
+50
+42
-43
-47
N/D
N/D
-73
-13
-1
-3
+1
-24
-3
N/D
+43
-
-6
-41
-7
-20
-4
+33
+28
-34
-36
N/D
N/D
+23
+28
+19
-10
-
+77
+78
N/D
+78
+64
-3
+10
+47
+55
+22
N/D
+27
+10
-
-94 (44.6:1)27
+94 (9.5:1)27
+65 (14.9:1)27a
-79 (13:1)28
+44 (16:1)29b
-83 (12:1)29b
-61(15.4:1)26
-39 (11.9:1)27
-43 (5.4:1)27
+47 (7.1:1)27
+55 (24.2:1)27
100
0
82
80
95
100
23
100
100
96
100
<1
<1
100
84
72
52
0
86
70
50
100
86
4
36
64
100
100
2
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
+44 (2.4:1)27
12:1
-
-
+24 (5.6:1)27
+10 (6.6:1)27
+28(10.2:1)27
27:1
12:1
13:1
20:1
-
15:1
22:1
31:1
25:1
12:1
13:1
34:1
13:1
15:1
36:1
9:1
(R)-Tol-BINAP (L21)
(R)-Xyl-BINAP (L22)
CTH-(R)-BINAM (L23)
(R)-SYNPHOS (L24)
+14
-
-2 (2.1:1)27
+19 (11:1)27
-64
-68
-53
-74
-36
-8
-45
-41
-27
-13
N/D
-16
-5
-
-
+13
+2
-
+36
N/D
+2
+12
-
(R)-SOLPHOS (L25)
(R)-Xyl-SOLPHOS (L26)
(R)-C3-TUNEPHOS (L27)
(R)-DIFLUOROPHOS (L28)
BIPHEP SL-A101 (L29)
BIPHEP SL-A109 (L30)
(R)-Cl-MeO-BIPHEP (L31)
CTH-R-P-PHOS (L32)
CTH-R-Xyl-P-PHOS (L33)
(R,R)-NORPHOS (L34)
(R,R)-DIOP (L35)
(S,S)-CHIRAPHOS (L36)
(S)-PHANEPHOS (L37)
(S)-Xyl-PHANEPHOS (L38)
CARBOPHOS (L39)
(R,R)-BINAPHANE (L40)
(R)-SDP (L41)
CTH-R-SpiroP (L42)
CatASium I (L43)
CatASium T2 (L44)
CatASium DR (L45)
Rhophos P001-2 (L46)
+17 (15.7:1)27
+13 (1.5:1)27b
-2 (16.8:1)4,30
100
91
0
0
30
8
10:1
16:1
-
-
11:1
6:1
-
0
+20
-
-50
N/D
0
-6
-
+8 (8.8:1)27
+6 (6:1)27
-34 (8.2:1)27
0
-
5:1
90
<1
7
50
0
+14 (2:1)27
+29 (4.2:1)27
+26 (8.7:1)27
+10 (18.5:1)27
4.4:1
13:1
-
a A Rh:L ratio of 1:1.2 was employed. See ref 27. b In the cited literature the opposite enantiomers of these ligands were employed; accordingly, the
opposite enantiomers of the products were obtained. c Determined by 1H NMR analysis of crude reaction mixtures. d Negative values of ee are provided
when the levorotatory (R,R)-enantiomer was obtained as major product. Positive values of ee indicate the predominant formation of the dextrorotatory
(S,S)-product. e Negative and positive values of ee indicate the predominant formation of (-)-R and (+)-S enantiomer, respectively.
olefins, provided 5a with 42% ee only (Table 2, entry 1).
Another highly reputed AHF ligand BINAPINE (L2) afforded
18% ee in the reaction with 4a (entry 2). Further optimization
demonstrated that, generally, all C2-symmetric phospholane
ligands provided significantly lower enantioselectivities than
those observed in the AHF of styrenes (entries 3-7). Next, we
screened a series of C1-symmetric ligands with planarly chiral
ferrocene backbone (L8-L19). This family of ligands,31 pos-
sesses great structural diversity and a wide spectrum of
electronic properties. Here again, it was found that several
ligands showing respectable selectivities in hydroformylation
of styrenes, demonstrated less than satisfying results in the
reaction with 4a (entries 10,11). And Vice Versa, the “obvious
outsiders” unexpectedly produced promising enantioselectivities
(entry 19). While not comprehensive, this screening clearly
demonstrated that the existing immense experience in ligand
optimization acquired through the AHF of terminal olefins
cannot be directly applied to the hydroformylation of small
cycles. Such a discrepancy is not surprising, considering the
significant difference in geometry, electronic properties, and
reactivity of the two types of substrates.
Accordingly, we performed an independent search for the
best catalytic system. To this end, we performed screening of
a few more sets of commercially available chiral diphosphine
ligands, which included a group of C2-symmetric ligands with
a flexible axially chiral backbone (L20-L33, entries 20-33),
and several other types of chiral ligands featuring both flexible
and rigid scaffolds (L34-L46, entries 34-46). Although no
9
J. AM. CHEM. SOC. VOL. 130, NO. 41, 2008 13807

A R T I C L E S
Sherrill and Rubin
Figure 1. Proposed stereomodels for the Rh/(R)-C3-TUNEPHOS-catalyzed hydroformylation.
Table 3. Rh-Catalyzed Asymmetric Hydroformylation of
3,3-Disubstituted Cyclopropenes
promising results were obtained in the latter case, the screening
of the former group appeared to be more rewarding. Thus,
promising results were obtained for SYNPHOS (L24, entry 24),
SOLPHOS (L25, entry 25), and DIFLUOROPHOS (L28, entry
28), while the best conversion and enantioselectivity were
attained in the presence of C3-TUNEPHOS (L27, entry 27).
Notably, C3-TUNEPHOS was previously reported to be a
marginal ligand for the AHF of styrene.27
#
R1
4:[Rh] ratio dr (5:6) ee (5), % yield, % [R]D (conc., CH2Cl2)
The following rationale, based on molecular mechanics
modeling (UUF), was used to account for the origins of
diastereo- and enantioselectivity in the asymmetric hydroformy-
lation reaction (stereomodels A1 and A2, Figure 1).32 As
mentioned above, the facial selectivity of the reaction is
controlled by sterics, as the approach of the rhodium hydride
species predominantly occurs from the less hindered face of
the cyclopropene (i.e., syn- to a smaller substituent, Figure 1).
The absolute stereochemistry of the process is determined by
1
2
3
4
5
CO2Me
4g 750:1
22:1
74
57
74
83
68
63
82
86
54
78
-109.8 (c 1.17)
-24.6 (c 1.25)
-114.3 (c 1.42)
-137.8 (c 0.64)
-128.1 (c 1.56)
CMe2OBn 4h 375:1 5 only
Ph
p-Cl-C6H4 4b 375:1
p-Me-C6H4 4j 750:1
4a 750:1
25:1
17:1
17:1
the relative orientation of the cyclopropene in the resulting
rhodium complex (A1 vs A2). Molecular modeling suggests
the two pseudoequatorial phenyl rings at the phosphorus atoms
of (R)-C3-TUNEPHOS obstruct quadrants II and IV (shaded
in gray in Figure 1), while quadrants I and III, with the
pseudoaxial phenyl groups slightly tilted back, remain relatively
unhindered.33 Accordingly, the orientation of the cyclopropene
in the trigonal bipyramidal rhodium complex A1 is such that it
minimizes the unfavorable interaction of the small substituent
“S” with the phenyl groups of the ligand, favoring complex A1
vs A2, which explains the absolute stereochemistry of the
obtained products 5a (Figure 1).34
To investigate the scope of the asymmetric hydroformylation
reaction, we tested a series of cyclopropenes possessing different
substituents at C3 in the presence of Rh/C3-TUNEPHOS
catalyst (Table 3). It was found that the enantioselectivity of
this reaction depended significantly on the substrate nature. Thus,
phenyl- and ester-substituted cyclopropenes 4g and 4a provided
the corresponding formylcyclopropanes with 74% ee (entries
1,3), while hydroformylation of cyclopropene 4h possessing a
(26) For a review, see: (a) Agbossou, F.; Carpentier, J.; Mortreux, A. Chem.
ReV. 1995, 95, 2485 See, also. (b) van der Vlugt, J I.; Paulusse, J. M. J.;
Zijp, E. J; Tijmensen, J. A.; Mills, A. M.; Spek, A. L.; Claver, C.;
Vogt, D. Eur. J. Inorg. Chem. 2004, 4193. (c) Ewalds, R.; Eggeling,
E. B.; Hewat, A. C.; Kamer, P. C. J.; van Leeuwen, P. W. N. M.;
Vogt, D. Chem.-Eur. J. 2000, 6, 1496. (d) Dieguez, M.; Pereira,
M. M.; Masdeu-Bulto, A. M.; Claver, C.; Bayon, J. C. J. Mol. Cat. A
1999, 143, 111. (e) Deng, C.; Ou, G.; She, J.; Yuan, Y. J. Mol. Cat.
A 2007, 270, 76. (f) Clarkson, G. J.; Ansell, J. R.; Cole-Hamilton,
D. J.; Pogorzelec, P. J.; Whittell, J.; Wills, M. Tetrahedron: Asymmetry
2004, 14, 1787. (g) Reetz, M. T.; Oka, H.; Goddard, R. Synthesis
2003, 12, 1809. (h) Pamies, O.; Net, G.; Ruiz, A.; Claver, C.
Tetrahedron: Asymmetry 2001, 12, 3441. (i) Deerenberg, S.; Kamer,
P. C. J.; van Leeuwen, P. W. N. M. Organometallics 2000, 19, 2065.
(j) Solinas, M.; Gladiali, S.; Marchetti, M. J. Mol. Cat. A 2005, 226,
141. (k) Shibahara, F.; Nozaki, K.; Hiyama, T. J. Am. Chem. Soc.
2003, 125, 8555. (l) Bonafoux, D.; Hua, Z.; Wang, B.; Ojima, I. J.
Flourine Chem. 2001, 112, 101. (m) Dieguez, M.; Ruiz, A.; Claver,
C. TA Tetrahedron: Asymmetry 2001, 12, 2827. (n) Cobley, C. J.;
Klosin, J.; Qin, C.; Whiteker, G. T. Org. Lett. 2004, 19, 3277.
(27) See, for example: Axtell, A. T.; Klosin, J; Abboud, K. A Organome-
tallics 2006, 25, 5003.
(28) Sherrill, W. M.; Rubin, M. Unpublished results.
(29) Axtell, A.; Cobley, C. J.; Klosin, J.; Whiteker, G. T.; Zanotti-Gerosa,
A.; Abboud, K. A. Angew. Chem., Int. Ed. 2005, 44, 5834.
(30) Dieduez, M.; Pereira, M.; Claver, C.; Bayon, J. C. J. Mol Cat A. 1999,
143, 111.
(33) The steric environment in these stereomodels resembles that described
by a Halpern for the mechanism of the Rh-catalyzed asymmetric
hydrogenation in the presence of a structurally related (R)-BINAP
ligand. See: Halpern, J Science 1982, 217, 401.
(31) Merchandized by Solvias Inc.
(34) Assignment of absolute configuration for non-racemic compound 5a
was performed by chemical transformation of this product into
2-methyl-2-phenylcyclopropylmethanol with known absolute config-
uration. Absolute configurations of all other compounds were assigned
by analogy to 5a. See Supporting Information for details.
(32) Analogous systems were successfully employed for predicting the
stereochemical outcome in the Rh-catalyzed asymmetric hydroformy-
lation of styrenes. Clark, T. P.; Landis, C. R.; Freed, S. L.; Klosin, J.;
Abboud, K. A J. Am. Chem. Soc. 2005, 127, 5040.
9
13808 J. AM. CHEM. SOC. VOL. 130, NO. 41, 2008

Rhodium-Catalyzed Hydroformylation of Cyclopropenes
A R T I C L E S
benzyl-protected tertiary alcohol function afforded aldehyde 5h
with only moderate ee of 57% (entry 2). Remarkably, in the
hydroformylation of the 3-arylcyclopropene series (Table 3,
entries 3-5), introduction of an electron-withdrawing substituent
in the para-position of the aryl ring led to a notable improvement
of enantioselectivity (entry 4), whereas installation of an
electron-donating group resulted in deterioration of ee (entry
5). The reasons for this unusual electronic effect are not yet
completely understood. Further work to improve the enantiose-
lectivity of this asymmetric transformation, and to understand
the origins of the observed significant electronic effect on the
enantioinduction of hydroformylation, is currently underway in
our laboratories.
allowed for complete suppression of the dominating side
processes, and permitted design of a novel, efficient catalytic
carbonylative transformation amenable for scale-up production.
This methodology opens new avenues toward efficient prepara-
tion of optically active cyclopropylcarboxaldehydes, valuable
building blocks for synthetic chemistry.
Acknowledgment. Financial support from the University of
Kansas and the National Science Foundation (EEC-0310689) is
gratefully acknowledged. We also thank Solvias, Inc. for a gift of
chiral ligands.
Supporting Information Available: Experimental details.
Complete ref 11d. This material is available free of charge via
the Internet at http://pubs.acs.org.
In conclusion, we demonstrated the first catalytic diastereo-
and enantioselective hydroformylation of prochiral cyclopro-
penes proceeding under very mild conditions and low loadings
of the Rh(I)-catalyst. Optimization of the reaction protocol
JA805059F
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J. AM. CHEM. SOC. VOL. 130, NO. 41, 2008 13809