Unexpected regioselectivity switch: Organophosphine-triggered reactions of cyclopropene-1,1-dicarboxylates with aldehydes

Article abstract of DOI:10.1021/ol401324z

With tris(4-methoxyphenyl)phosphine as the nucleophilic reagent, the readily available cyclopropene-1,1-dicarboxylates undergo a ring-opening reaction to generate a Wittig-type intermediate, which would react with aromatic aldehydes to yield (E)-5-aryl-2-(methoxycarbonyl)-2,4-pentadienoates. It is interesting to observe that the regioselectivity of the ring-opening reaction is switched.

Full text of DOI:10.1021/ol401324z

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Unexpected Regioselectivity Switch:
Organophosphine-Triggered Reactions
of Cyclopropene-1,1-dicarboxylates
with Aldehydes
Shengjun Ni,† Jie Chen,† and Shengming Ma*,†,‡
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, 345 Lingling Lu, Shanghai 200032,
P. R. China, and Shanghai Key Laboratory of Green Chemistry and Chemical Process,
Department of Chemistry, East China Normal University, 3663 North Zhongshan Road,
Shanghai 200062, P. R. China
masm@sioc.ac.cn
Received May 13, 2013
ABSTRACT
With tris(4-methoxyphenyl)phosphine as the nucleophilic reagent, the readily available cyclopropene-1,1-dicarboxylates undergo a ring-opening
reaction to generate a Wittig-type intermediate, which would react with aromatic aldehydes to yield (E)-5-aryl-2-(methoxycarbonyl)-2,4-
pentadienoates. It is interesting to observe that the regioselectivity of the ring-opening reaction is switched.
Cyclopropenes, highly strained yet readily accessible
carbocyclic molecules, have been shown to possess useful
reactivity in organic synthesis.1 Over the past several years,
more attention has been paid to the reactions of cyclopro-
penes: a variety of nucleophiles may add to the strained
CdC bond2 or open the strained three-membered ring.3
In addition, a series of nonmetallic O-, S-, N-, P-based
nucleophiles have been reacted with cyclopropenes.4
In 2007, Gevorgyan and co-workers reported a phos-
phine-catalyzed sila-MoritaÀBaylisÀHillman reaction of
cyclopropenes, in which no ring-opening reaction was
(3) For reports on the ring-opening reactions of cyclopropenes, see:
(a) Wang, Y.; Fordyce, E. A. F.; Chen, F. Y.; Lam, H. W. Angew. Chem.
2008, 120, 7460. Angew. Chem., Int. Ed. 2008, 47, 7350. (b) Giudici, R.;
Hoveyda, A. H. J. Am. Chem. Soc. 2007, 129, 3824. (c) Smith, M. A.; Richey,
H. G. Organometallics 2007, 26, 609. (d) Nakamura, I.; Bajracharya, G. B.;
Yamamoto, Y. J. Org. Chem. 2003, 68, 2297. (e) Ma, S.; Zhang, J.; Cai,
Y.; Lu, L. J. Am. Chem. Soc. 2003, 125, 13954. (f) Wang, Y.; Lam, H. W.
J. Org. Chem. 2009, 74, 1353. (g) Fordyce, E. A. F.; Luebbers, T.; Lam,
H. W. Org. Lett. 2008, 10, 3993. (h) Ma, S.; Zhang, J.; Lu, L.; Jin, X.; Cai,
Y.; Hou, H. Chem. Commun. 2005, 909. (i) Chen, J.; Ma, S. J. Org. Chem.
2009, 74, 5595. (j) Chen, J.; Xin, N.; Ma, S. Tetrahedron Lett. 2009, 50,
3175. (k) Liu, Y.; Ma, S. Chem. Sci. 2011, 2, 811. (l) Liu, Y.; Ma, S. Org.
Lett. 2012, 14, 720.
(4) (a) Banning, J. E.; Prosser, A. R.; Alnasleh, B. K.; Smarker, J.;
Rubina, M.; Rubin, M. J. Org. Chem. 2011, 76, 3968. (b) Banning, J. E.;
Prosser, A. R.; Rubin, M. Org. Lett. 2010, 12, 1488. (c) Alnasleh, B. K.;
Sherrill, W. M.; Rubina, M.; Banning, J.; Rubin, M. J. Am. Chem. Soc.
2009, 131, 6906. (d) Prosser, A. R.; Banning, J. E.; Rubina, M.; Rubin,
M. Org. Lett. 2010, 12, 3968. (e) Ryabchuk, P.; Rubina, M.; Xu, J.;
Rubin, M. Org. Lett. 2012, 14, 1752. (f) Rubina, M.; Woodward, E. W.;
Rubin, M. Org. Lett. 2007, 9, 5501. (g) Alnasleh, B. K.; Sherrill, W. M.;
Rubin, M. Org. Lett. 2008, 10, 3231.
† Chinese Academy of Sciences.
‡ East China Normal University.
(1) For some recent reports, see: (a) Fox, J. M.; Yan, N. Curr. Org.
Chem. 2005, 9, 719. (b) Rubin, M.; Rubina, M.; Gevorgyan, V. Synthesis
2006, 1221. (c) Rubin, M.; Rubina, M.; Gevorgyan, V. Chem. Rev. 2007,
107, 3117. (d) Marek, I.; Simaan, S.; Masarwa, A. Angew. Chem. 2007,
119, 7508. Angew. Chem., Int. Ed. 2007, 46, 7364.
(2) For some representative reports on the reactions of the CdC
bond of cyclopropenes, see: (a) Nakamura, M.; Hirai, A.; Nakamura, E.
J. Am. Chem. Soc. 2000, 122, 978 and references therein. (b) Liao, L.;
Fox, J. M. J. Am. Chem. Soc. 2002, 124, 14322. (c) Trofimov, A.;
Rubina, M.; Rubin, M.; Gevorgyan, V. J. Org. Chem. 2007, 72, 8910 and
references therein. (d) Masarwa, A.; Stanger, A.; Marek, I. Angew.
Chem. 2007, 119, 8185. Angew. Chem., Int. Ed. 2007, 46, 8039. (e)
Tarwade, V.; Liu, X.; Yan, N.; Fox, J. M. J. Am. Chem. Soc. 2009, 131,
5382. (f) Yan, N.; Liu, X.; Fox, J. M. J. Org. Chem. 2008, 73, 563. (g)
Alnasleh, B. K.; Sherrill, W. M.; Rubin, M. Org. Lett. 2008, 10, 3231. (h)
Yin, J.; Chisholm, J. D. Chem. Commun. 2006, 632. (i) Pallerla, M. K.;
Fox, J. M. Org. Lett. 2005, 7, 3593. (j) Sherrill, W. M.; Rubin, M. J. Am.
Chem. Soc. 2008, 130, 13804. (k) Pallerla, M. K.; Fox, J. M. Org. Lett.
2007, 9, 5625.
r
10.1021/ol401324z
XXXX American Chemical Society

observed.5 Recently, we have observed the formation of
highly regioselective 2,3,5-trisubstituted furans via the
intermediacy of intermediates I and II (Scheme 1).6 In
principle, intermediate I should be in resonance with
Wittig-type intermediate III. Upon reacting with an alde-
hyde, 2,4-pentadienoates IV would be formed. Here, we
wish to report an unexpected observation in this area.
Table 1. Cascade Ring-Opening and Wittig-Type Reaction of 1a
with PhCHO under Different Reaction Conditionsa
yield
of
recovery
of 1a
(%)b
temp
t
3aa
Scheme 1. Possible Reaction Pathways
entry
phosphine
PCy3
solvent (°C) (h) (%)b
1
2
dioxane 150 34 12
dioxane 150 48 62
dioxane 150 26 69
dioxane 150 35 66
27
À
(4-MeC6H4)3P
3
(4-MeOC6H4)3P
(3,4-MeOC6H3)3P
À
4
À
5
(2,4,6-MeOC6H2)3P dioxane 150 35 N/D
À
6
(4-MeOC6H4)3P
(4-MeOC6H4)3P
(4-MeOC6H4)3P
(4-MeOC6H4)3P
(4-MeOC6H4)3P
toluene 150 28 65
DMF 150 31 N/D
CH3CN 100 28 43
À
7
À
8
37
55
100
À
9
CH2Cl2 70
THF 80
45 14
10
48 n.r.
11c (4-MeOC6H4)3P
dioxane 150 26 71
An initial attempt was conducted with the readily
available cyclopropene 1a and tricyclohexylphosphine.
However, after careful analysis of all the data, the expected
IV-type product 4aa was not formed; instead, isomeric
product (E)-3-butyl-2-(methoxycarbonyl)-5-phenyl-2,4-
pentadienoic acid methyl ester E-3aa was formed (Table 1,
entry 1). Electron-rich triarylphosphine derivatives such as
tris(p-tolyl)phosphine and tri(3,4-dimethoxyphenyl)phosphine
were more effective, and the yield was above 60% (Table 1,
entries 2À4). But to our disappointment, no desired product
was furnished when tri(2,4,6-trimethoxyphenyl)phosphine
was used (Table 1, entry 5). Further screening led to the
observation that tri(4-methoxyphenyl)phosphine was the
best, affording the crude product 3aa in 69% NMR yield
(Table 1, entry 3). When 1.2 equiv of cyclopropene 1a were
used, a 71% NMR yield of 3aa was obtained (Table 1,
entry 11).
a The reaction was conducted by using 0.4 mmol of 1a, 0.8 mmol of
PhCHO, and 0.4 mmol of phosphine in dioxane in a Schlenk tube with
a screw cap. b The yield was determined by 1H NMR spectroscopic
analysis with CH3NO2 as the internal standard. c 0.34 mmol of
(4-MeOC6H4)3P was used, with a 5% NMR yield of 5aa formed.
Table 2. Scope of Cascade Ring-Opening and Wittig-Type
Reaction of Cyclopropene-1,1-dicarboxylates with Aldehydesa
Then the solvent effect was examined: the yield was
slightly lower with toluene as solvent (Table 1, entry 6); the
reaction in DMF was complicated (Table 1, entry 7); a
lower yield was observed in CH3CN (Table 1, entry 8) and
CH2Cl2 (Table 1, entry 9);no reaction wasdetected inTHF
(Table 1, entry 10); and dioxane was proved to be the best
(Table 1, entry 3).
With the optimized conditions in hand (Table 1, entry 11),
the scope of the reaction was explored. When R1 is n-Bu and
R2 is H, the product 3aa was obtained in 64% isolated yield
(Table 2, entry 1). With R2 being substituents such as 4-NC,
3-NC, 2-NC (Table 2, entries 2À5), 4-F3C(Table 2, entry6),
4-MeO2C (Table 2, entry 7), 4-Cl, and 2,4-Cl (Table 2,
entries 8 and 9) to the aryl ring, the reaction proceeded
smoothly to afford the corresponding product in moderate
to good yields. For substrates with R2 being 4-Ph (Table 2,
entry 10), 3-MeO (Table 2, entry 11), and 4-Br (Table 2,
isolated
yield of
entry
R1
R2
H (2a)
t (h)
3 (%)
1b
2
3c
4
n-Bu (1a)
n-Bu (1a)
n-Bu (1a)
n-Bu (1a)
n-Bu (1a)
n-Bu (1a)
n-Bu (1a)
n-Bu (1a)
n-Bu (1a)
n-Bu (1a)
n-Bu (1a)
n-Bu (1a)
H (1b)
26
30
30
30
30
30
30
30
31
26
29
29
24
30
64 (3aa)
68 (3ab)
67 (3ab)
65 (3ac)
66 (3ad)
63 (3ae)
64 (3af)
65 (3ag)
64 (3ah)
62 (3ai)
57 (3aj)
65 (3ak)
61 (3ba)
63 (3ca)
4-NC (2b)
4-NC (2b)
3-NC (2c)
2-NC (2d)
4-F3C (2e)
4-MeO2C (2f)
4-Cl (2g)
2,4-Cl (2h)
4-Ph (2i)
3-MeO (2j)
4-Br (2k)
H (2a)
5
6
7
8
9
10
11
12
13b
14b
n-Pr (1c)
H (2a)
a The reaction was conducted by using 0.4 mmol of 1, 0.48 mmol of 2,
and 0.34 mmol of (4-MeOC6H4)3P in dioxane at 150 °C in a Schlenk tube
with a screw cap; a 2À5% NMR yield of 5 was formed in all the
reactions. b 0.8 mmol of 2 was used. c Conditions: 5.0 mmol of 1a were
used in this reaction.
(5) Chuprakov, S.; Malyshev, D. A.; Trofimov, A.; Gevorgyan, V.
J. Am. Chem. Soc. 2007, 129, 14868.
(6) Chen, J.; Ni, S.; Ma, S. Synlett 2011, 931.
B
Org. Lett., Vol. XX, No. XX, XXXX

entry 12), the reaction could also occur in moderate yields.
As could be seen in Table 2, the position of CN on the
phenyl ring had a limited effect on the yield (Table 2, entries
2À5). In addition, when R2 is H, if R1 is H or n-C3H7, the
reaction is also working and the yield is 61% or 63%,
respectively (Table 2, entries 13 and 14). To test the practic-
ability, the reaction was carried out in gram scale (5.0 mmol)
of 1a, 2b (6.0 mmol), and tri(4-methoxyphenyl)phosphine
(4.3 mmol) to afford the desired product 3ab in 67% yield
(Table 2, entry 3).
With LB-phos8 as the ligand, a cross-coupling reaction
could proceed smoothly between 3ag and PhB(OH)2 with
64% of the product 3ai (Scheme 3).
Scheme 3
The X-ray diffraction study of 3ai clearly proves the
configuration of CdC bond in the molecule and the
regioselectivity of the ring-opening reaction (Figure 1).7
In an effort to shed further light on the mechanism,
control experiments were conducted. Under the conditions
used in our previous report,6 5aa was obtained in 91%
yield (eq a, Scheme 4); under the standard conditions in the
absence of benzaldehyde 2a in this study, we only observed
4% of 5aa (eq b, Scheme 4) while the reaction of cyclo-
propene 1a in the presence of aldehyde 2a under the
standard conditions afforded 63% of 3aa together with
3% of 5aa (eq c, Scheme 4).
Figure 1. ORTEP structure of 3ai.
Scheme 4. Control Experimentsa
Heteroaromatic aldehydes could also be applied to this
reaction. When 0.8 mmol of 2-furaldehye was used to react
with 0.4 mmol of 1a and 0.34 mmol of (4-MeOC6H4)3P,
67% of 3al could be isolated (Scheme 2). Citronellal
and cyclohexanecarboxaldehyde proved to be ineffec-
tive in the reaction with 1a, and no starting material was
recovered.
Scheme 2
b
a 0.5 mmol of 1a was used in all the reactions. The yield was
determined by 1H NMR spectroscopic analysis with CH3NO2 as the
internal standard.
A plausible mechanism for this transformation is de-
picted in Scheme 5. Initial attack of the tri(4-methoxy-
phenyl)phosphine at the less-substituted sp2 carbon atom
of cyclopropene 1 results in the formation of zwitterionic
phosphonium adduct V. Due to the presence of the CdC
bond, V is in resonance with Wittig-type intermediate VI.
Based on the results shown in Scheme 4, we reasoned that
the reversed selectivity for the first step may be caused by
the much higher reactivity of intermediate VI toward
aldehydes as compared to intermediate III due to the steric
effect (Scheme 1). Thus, intermediate VI reacts with
(7) Crystal data for compound 3ai: C24H26O4, MW = 378.45,
monoclinic, space group P2(1), final R indices [I > 2 σ(I)], R1
0.0472, wR2 = 0.1223, R indices (all data), R1 = 0.0593, wR2
=
=
˚
˚
˚
0.1310, a = 6.2434(5) A, b = 8.0127(7) A, c = 21.1301(18) A, R =
3
˚
90°, β = 90.262(2)°, γ = 90°, V = 1057.05(15) A , T = 293 (2) K, Z = 2,
reflections collected/unique: 6377/4106 [R(int) = 0.0195], number of
observations [>2σ(I)] 3264; parameter: 256. Supplementary crystal-
lographic data have been deposited at the Cambridge Crystallographic
Data Center (CCDC 918034).
€
€
(8) (a) Lu, B.; Fu, C.; Ma, S. Tetrahedron Lett. 2010, 51, 1284. (b) Lu,
€
B.; Fu, C.; Ma, S. Chem.;Eur. J. 2010, 16, 6434. (c) Ma, S.; Lu, B.; Fu,
C. International Patent, Application No. PCT/CN2009/001527. (d) Lu,
€
B.; Li, P.; Fu, C.; Xue, Li.; Lin, Z.; Ma, S. Adv. Synth. Catal. 2011, 353,
100.
Org. Lett., Vol. XX, No. XX, XXXX
C

Finally, elimination of the Ar3PO furnishes the (E)-2,4-
pentadienoates 3.
Scheme 5. A Plausible Mechanism
In conclusion, we have developed a new methodology to
synthesize highly stereoselective (E)-5-aryl-2-(methoxy-
carbonyl)-2,4-pentadienoates from the nucleophilic ring-
opening reaction of cyclopropene-1,1-dicarboxylates with aro-
matic aldehydes with a switch of the regioselectivity. Further
studies of this reaction are being conducted in our laboratory.
Acknowledgment. Financial support from the National
Basic Research Program of China (2009CB825300) and
National Natural Science Foundation of China (21232006)
is greatly appreciated. We thank Dengke Ma in our group
for reproducing the results presented in Table 2, entries 2,
11 and in Scheme 2.
Supporting Information Available. General procedure
and spectroscopic data. This material is available free of
charge via the Internet at http://pubs.acs.org.
aldehyde 2 to generate the Wittig-type cyclic intermediate
VII, which is preferred over VIII due toits sterichindrance.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX