Highly selective nickel-catalyzed methyl-carboxylation of homopropargylic alcohols for α-alkylidene-γ;-butyrolactones

Article abstract of DOI:10.1021/ol202520x

A first practical Ni(0)-catalyzed highly stereoselective methyl-carboxylation of homopropargylic alcohols with ZnMe₂ and CO₂ for the efficient synthesis of α-alkylidene-γ;- butyrolactones is described. The reaction may be applied to

Full text of DOI:10.1021/ol202520x

ORGANIC
LETTERS
2011
Vol. 13, No. 22
6046–6049
Highly Selective Nickel-Catalyzed
Methyl-Carboxylation of Homopropargylic
Alcohols for r-Alkylidene-
γ-butyrolactones
Suhua Li† 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 Lu,
Shanghai 200062, P. R. China
masm@sioc.ac.cn
Received September 16, 2011
ABSTRACT
A first practical Ni(0)-catalyzed highly stereoselective methyl-carboxylation of homopropargylic alcohols with ZnMe2 and CO2 for the efficient
synthesis of R-alkylidene-γ-butyrolactones is described. The reaction may be applied to other alkynols.
During the last 10 years, there have been tremendous
developments in CO2 activation. Mainly three types of
transition-metal-catalyzed CO2 activation reactions form-
ing new carbonÀcarbon bonds have been developed:1
(1) the carboxylation of organometallic reagents
(Sn,2 B,3 Zn4), aryl bromides,5 arenes,6 or terminal CÀH
bonds of alkynes7 affording carboxylic acids (Scheme 1, eq 1);
(2) the carboxylation of unsaturated hydrocarbons such as
(5) Correa, A.; Martın, R. J. Am. Chem. Soc. 2009, 131, 15974.
(6) (a) Boogaerts, I. I. F.; Nolan, S. P. J. Am. Chem. Soc. 2010, 132,
8858. (b) Zhang, L.; Cheng, J.; Ohishi, T.; Hou, Z. Angew. Chem., Int.
Ed. 2010, 49, 8670. (c) Boogaerts, I. I. F.; Fortman, G. C.; Furst,
M. R. L.; Cazin, C. S. J.; Nolan, S. P. Angew. Chem., Int. Ed. 2010,
49, 8674. (d) Mizuno, H.; Takaya, J.; Iwasawa, N. J. Am. Chem. Soc.
2011, 133, 1251. For transition metal-free carboxylation of ArÀH see:
(e) Vechorkin, O.; Hirt, N.; Hu, X. Org. Lett. 2010, 12, 3567.
(7) (a) Gooßen, L. J.; Rodrıguez, N.; Manjolinho, F.; Lange, P. P.
Adv. Synth. Catal. 2010, 352, 2913. (b) Yu, D.; Zhang, Y. Proc. Natl.
Acad. Sci. U. S. A. 2010, 107, 20184. For synthesis of 2-alkynoates see:
(c) Zhang, W.; Li, W.; Zhang, X.; Zhou, H.; Lu, X. Org. Lett. 2010, 12,
4748.
(8) For reports on 20 mol % of Ni(cod)2-catalyzed alkylative carboxy-
lation of alkynes with DBU (10 equiv) via a cyclometalation mechanism,
see: (a) Shimizu, K.; Takimoto, M.; Sato, Y.; Mori, M. Org. Lett. 2005, 7,
195. (b) Shimizu, K.; Takimoto, M.; Sato, Y.; Mori, M. Synlett 2006, 3182.
(9) (a) For a report on 1À3 mol % of Ni(cod)2 catalyzed hydro-
carboxylation of alkynes via a direct hydrometalation mechanism, see:
Li, S.; Yuan, W.; Ma, S. Angew. Chem., Int. Ed. 2011, 50, 2578. (b) For a
CuF-catalyzed hydrocarboxylation reaction, see: Fujihara, T.; Xu, T.;
Semba, K.; Terao, J.; Tsuji, Y. Angew. Chem., Int. Ed. 2011, 50, 523.
(10) Williams, C. M.; Johnson, J. B.; Rovis, T. J. Am. Chem. Soc.
2008, 130, 14936.
† Chinese Academy of Sciences.
‡ East China Normal University.
(1) For recent reviews, see: (a) Louie, J. Curr. Org. Chem. 2005, 9,
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Dalton Trans. 2010, 39, 3347. (g) Boogaerts, I. I. F.; Nolan, S. P. Chem.
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r
10.1021/ol202520x
Published on Web 10/18/2011
2011 American Chemical Society

alkynes,8,9 alkenes,10 1,3-dienes,11 bis-1,3-dienes,12 and
allenes13 also affording carboxylic acids (Scheme 1, eq 2);
and (3) the cycloaddition of CO2 and diynes affording
pyrones (Scheme 1, eq 3).14 Thus, activation of CO2 is still
mostly limited to the simple substrates for preparation of
simple carboxylic acids except for those noted in ref 14.
intramolecular transmetalation of intermediate A in the
presence of ZnMe2, forming intermediate B (Scheme 3). In
addition, the cyclic structure of intermediate C may also
increase the reactivity of its CÀZn bond with the Aresta’s
complex D because of the release of the ring strain to form
R-alkylidene-γ-butyrolactones E-2efficiently via lactonization.
Scheme 1. Transition-Metal-Catalyzed CO2-Activation Form-
ing CÀC Bonds
Scheme 3. Concept for the Synthesis of γ-Butyrolactones based
on the Previous Mechanistic Study Reported in Ref 9a
In 2005, Mori et al. reported catalytic alkylative carboxy-
lation of alkynes by using 20 mol % of Ni(cod)2 and 10
equiv of DBU with moderate regioselectivity via a cyclo-
metalation mechanism.8 However, to the best of our knowl-
edge, alkyl-carboxylation, which would be very efficient
for the synthesis of stereodefined fully substituted R,β-
unsaturated alkenoic acids, has not been well established.
Recently, we have developed a hydrocarboxylation of
alkynes with a unique mechanism by using ZnEt2 as the
hydride source via β-elimination.9a We reasoned that the
protocol may be easily extended to methylcarboxylation
by following the established reaction conditions for al-
kynes in MeCN and 3-butynyl tosylamides in DMSO
reported in ref 9a. However, as shown in Scheme 2, the
methylcarboxylation of phenyl-substituted alkynes in MeCN
or 4-phenylbutynyl tosylamide in DMSO all yielded the
corresponding carboxylic acids in unsatisfactory yields
and poor regioselectivity (for further results, see Table S1
in the Supporting Information).
As we know, R-methylene- or alkylidene-γ-butyrolac-
tone is a commonly observed structural unit in many biolo-
gically active natural products (Figure 1)15 showing anti-
cancer, antimalarial, antiviral, antibacterial, antifungal,
and anti-inflammatory activities.16,17 The exo-cyclic dou-
ble bond is not only responsible for their interesting
biological properties but also serves as a functional group
for further manipulations in organic synthesis.18 In this
paper, we report our recent realization of such a concept.
(14) Synthesis of pyrones using 5 mol % of Ni(cod)2, 10 mol % of IPr-
NHC in 1 atm of CO2, see: (a) Louie, J.; Gibby, J. E.; Farnworth, M. V.;
Tekavec, T. N. J. Am. Chem. Soc. 2002, 124, 15188. Using 5À10 mol %
of Ni(cod)2 and 10À20 mol % of phosphine ligand (P(n-C8H17 3
) and
dppb) in 50 kg/cm2 of CO2 at 100À120 °C see:(b) Tsuda, T.; Morikawa,
S.; Sumiya, R.; Saegusa, T. J. Org. Chem. 1988, 53, 3140. For examples
when 10 mol % or more of Ni(cod)2 was used see:(c) Tsuda, T.;
Morikawa, S.; Saegusa, T. J. Chem. Soc., Chem. Commun. 1989, 9.
(d) Tsuda, T.; Morikawa, S.; Hasegawa, N.; Saegusa, T. J. Org. Chem.
1990, 55, 2978. (e) Tekavec, T. N.; Arif, A. M.; Louie, J. Tetrahedron
2004, 60, 7431.
Scheme 2. Methylcarboxylation of Phenyl-Substituted Alkynes
or 4-Phenyl-3-butynyl Tosylamide
(15) (a) Fan, X.; Zi, J.; Zhu, C.; Xu, W.; Cheng, W.; Yang, S.; Guo,
Y.; Shi, J. J. Nat. Prod. 2009, 72, 1184. (b) Sheu, J.-H.; Ahmed, A. F.;
Shiue, R.-T.; Dai, C.-F.; Kuo, Y.-H. J. Nat. Prod. 2002, 65, 1904.
(c) Smith, A. B., III; Toder, B. H.; Carroll, P. J.; Donohue, J.
J. Crystallogr. Spectrosc. Res. 1982, 12, 309. (d) Aoyagi, Y.; Yamazaki,
A.; Nakatsugawa, C.; Fukaya, H.; Takeya, K.; Kawauchi, S.; Izum, H.
Org. Lett. 2008, 10, 4429.
(16) For comprehensive reviews, see: (a) Grieco, P. A. Synthesis 1975,
67. (b) Hoffman, H. M. R.; Rabe, J. Angew. Chem., Int. Ed. Engl. 1985,
24, 94. (c) Sarma, J. C.; Sharma, R. P. Heterocycles 1986, 24, 441.
(d) Petragnani, N.; Ferraz, H. M. C.; Silva, G. V. J. Synthesis 1986, 157.
(e) Kitson, R. R. A.; Millemaggi, A.; Taylor, R. J. K. Angew. Chem., Int.
Ed. 2009, 48, 9426.
(17) (a) De Bernardi, M.; Garlaschelli, L.; Toma, L.; Vidari, G.; Vita-
Finzi, P. Tetrahedron 1991, 47, 7109. (b) Vidari, G.; Lanfranchi, G.;
Pazzi, N.; Serra, S. Tetrahedron Lett. 1999, 40, 3063. (c) Tesaki, S.;
Kikuzaki, H.; Yonemori, S.; Nakatani, N. J. Nat. Prod. 2001, 64, 515.
(d) Baraldi, P. G.; Nunez, M. C.; Tabrizi, M. A.; Clercq, E. D.; Balzarini,
We reasoned that the OH group in the readily available
homopropargylic alcohols may be acting as the directing
group to increase the regioselectivity because of the
(11) Takaya, J.; Sasano, K.; Iwasawa, N. Org. Lett. 2011, 13, 1698.
(12) (a) Takimoto, M.; Mori, M. J. Am. Chem. Soc. 2002, 124, 10008.
(b) Takimoto, M.; Nakamura, Y.; Kimura, K.; Mori, M. J. Am. Chem.
Soc. 2004, 126, 5956.
ꢀ
J.; Bermejo, J.; Estevez, F.; Romagnoli, R. J. Med. Chem. 2004, 47, 2877.
(e) Janecki, T.; Bzaszczyk, E.; Studzian, K.; Janecka, A.; Krajewska, U.;
Rozalski, M. J. Med. Chem. 2005, 48, 3516. (f) Romagnoli, R.; Baraldi,
P. G.; Tabrizi, M. A.; Bermejo, J.; Estevez, F.; Borgatti, M.; Gambari,
ꢀ_
ꢀ
(13) (a) Takimoto, M.; Kawamura, M.; Mori, M.; Sato, Y. Synlett
2005, 2019. (b) Takaya, J.; Iwasawa, N. J. Am. Chem. Soc. 2008, 130, 15254.
R. J. Med. Chem. 2005, 48, 7906. (g) Oh, S.; Jeong, I. H.; Shin, W.-S.;
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Org. Lett., Vol. 13, No. 22, 2011
6047

Table 2. Synthesis of R-Alkylidene-γ-butyrolactones by Methyl-
Lactionization of Homopropargylic Alcoholsa
entry
R1/R2/R3/R4
Ph/H/H/H (1a)
yield of E-2 (%)b
Figure 1. Natural products bearing the R-alkylidene-γ-butyro-
lactone substructure.
1
71 (E-2a)
82 (E-2b)
71 (E-2c)
52 (E-2d)
82 (E-2e)
64 (E-2f)
61 (E-2g)
54 ((E, E)-2h)
77 (E-2i)
74 (E-2j)
78 (E-2k)
90 (E-2l)
90 (E-2m)
68 (E-2n)
2
p-MeOC6H4/H/H/H (1b)
p-EtO2CC6H4/H/H/H (1c)
p-BrC6H4/H/H/H (1d)
R-naphthyl/H/H/H (1e)
2-thienyl/H/H/H (1f)
nC5H11/H/H/H (1g)
(E)-1-hexenyl/H/H/H (1h)
Ph/Ph/H/H (1i)
3
4
5
6
7c
8
Table 1. Optimization of Conditions for Methyl-Lactonization
of 1aa
9
10
11
12
13
14
Ph/H/Me/H (1j)
Ph/H/Et/H (1k)
Ph/H/Ph/H (1l)
p-MeOC6H4/H/Ph/Me (1m)
Ph/H/Me/Me (1n)
entry Ni(cod)2 (mol %) time/h temp/°C yield of E-2a (%)b
a Reaction conditions: The reaction was carried out with 0.5 mmol of
1, 1 mol % of Ni(cod)2 (1.4 mg, 0.005 mmol), 1.5 equiv of CsF (113.9 mg,
0.75 mmol), 3 equiv of ZnMe2 (1.2 M in toluene, 1.25 mL), and a balloon
of CO2 (about 1 L) in 3 mL of CH3CN at 50 °C. b Isolatedyield. c 2 mol %
of Ni(cod)2 was used, and the reaction time was 13 h.
1c
2d
3e
4
3
14
2.0
50
50
50
50
30
40
60
70
50
50
50
50
50
50
50
28
57
55
76
72
67
73
73
54
75
71
67
67
80
78
3
3
2.0
2.0
3
5
3
16
6
3
3.5
1.5
0.75
2.0
2.0
2.0
2.0
1.5
6.0
It deserves to be mentioned that the lactonization was
complete after the concentration of the crude product and
the regioselectivity of methylative carboxylation of alkynols
was very high (g97:3, if any on the basis of the 1H NMR
analysis of the crude products after lactonization).
Next, the scope of the reaction was examined (Table 2).
Aryl substituted homopropargylic alcohols gave moderate
to excellent yields of E-2 (Table 2, entries 1À6 and 9À14),
whereas n-pentyl- and (E)-1-hexenyl-substituted alkynols
produced moderate yields of E-2g and E-2h (Table 2,
entries 7 and 8). Ester- (Table 2, entry 3), conjugated ene-
(Table 2, entry 8), and p-Br-substituted phenyl (Table 2,
entry 4) homopropargylic alcohols may all be successfully
applied to afford E-2c, E-2h, and E-2d in moderate to good
yields.
7
3
8
9f
3
3
10g
11h
12i
13
14
15j
3
3
3
5
1
0.25
17.3
a Reaction conditions: The reaction was carried out with 0.5 mmol of
1a, the indicated amount of Ni(cod)2, 1.5 equiv of CsF, 3 equiv of ZnMe2
(1.20 M in toluene, 1.25 mL), and a balloon of CO2 (about 1 L) in 3 mL of
CH3CN at the indicated temperature. b NMR yield. c DMSO was used as
the solvent, and 1a was recovered in 37% NMR yield. d DMF was used
as the solvent. e NMP was used as the solvent. f 2 equiv of ZnMe2 were
used, and 1a was recovered in 24% NMR yield. g 4 equiv of ZnMe2 were
used. h 3.0 equiv of CsF were used. i 1.0 equiv of CsF was used. j 1a was
recovered in 5% NMR yield.
Furthermore, to our delight, the scope of substrates is
not just limited to linear homopropargaylic alcohols; fused
bicyclic R-alkylidene-γ-butyrolactones (trans,E)-2o could
also be synthesized through this method efficiently
(Scheme 4, eq 1). A similar strategy may also be applied to
Weinitiated thisstudy by using 4-phenyl-3-butynol 1aas
the starting point. Interestingly, the slow methyl-lactoniza-
tion reaction of alkynol 1a in DMSO9a did afford E-2a,
albeit in 28% yield (Table 1, entry 1). However, the regio-
and stereoselectivity are excellent. Optimization on the
solvent (Table 1, entries 2À4), temperature (Table 1, en-
tries 5À8), amount of ZnMe2 (Table 1, entries 9À10), CsF
(Table 1, entries 11À12), and catalyst loading (Table 1,
entries 13À15) was then conducted with the optimal con-
ditions being established as follows: homopropargylic
alcohol 1a was treated with 1 mol % Ni(cod)2, 1.5 equiv of
CsF, and 3.0 equiv of ZnMe2 in CH3CN in 50 °C to afford
E-2a, indicating a dramatic solvent effect (Table 1, entry 14).9a
(18) (a) De, D.; Seth, M.; Bhaduri, A. P. Synthesis 1990, 956.
(b) Ohta, T.; Miyake, T.; Seido, N.; Kumobayashi, H.; Takaya, H.
J. Org. Chem. 1995, 60, 357. (c) Arcadi, A.; Chiarini, M.; Marinelli, F.;
ꢁ
Berente, Z.; Kollar, L. Org. Lett. 2000, 2, 69. (d) Otto, A.; Liebscher, J.
Synthesis 2003, 1209. (e) Gasperi, T.; Loreto, M. A.; Tardella, P. A.;
ꢂ
Veri, E. Tetrahedron Lett. 2003, 44, 4953. (f) Castulık, J.; Marek, J.;
Mazal, C. Tetrahedron 2001, 57, 8339. (g) Otto, A.; Ziemer, B.;
Liebscher, J. Synthesis 1999, 965. (h) Otto, A.; Ziemer, B.; Liebscher,
J. Eur. J. Org. Chem. 1998, 2667. (i) Otto, A.; Abegaz, B.; Ziemer, B.;
Liebscher, J. Tetrahedron: Asymmetry 1999, 10, 3381. (j) Nishimura, K.;
Tomioka, K. J. Org. Chem. 2002, 67, 431. (k) Read de Alaniz, J.; Rovis,
T. J. Am. Chem. Soc. 2005, 127, 6284.
6048
Org. Lett., Vol. 13, No. 22, 2011

o-ethynylphenols 3a and 3b for the synthesis of 2(3H)-
benzofuranones E-4a and E-4b in good to excellent yields
(Scheme 4, eq 2). (E)-4-(1-Phenyl ethylidene)-3-isochro-
manone E-6 was produced in 58% yield from (2-(phenyle-
thynyl)phenyl)methanol (5) (Scheme 4, eq 3). To check the
practicality, this reaction was scaled up to 1 g (5 mmol) of
1o affording E-2o in 97% yield (Scheme 4, eq 1).
reasoned that the deprontonation of this functionality with
the zinc reagent makes the interaction between the oxygen
atom and Zn much stronger than that of tosylamide with
Zn;9a thus, the OH group acts as a much better activating/
directing group for the yield of CO2 fixation as well as the
regioselectivity (see Scheme 3). For the role of CsF, we
reasoned that it is increasing the reactivity of the alkenyl
zinc intermediate toward CO2.19 Because of the ready
availability of various homopropargylic alcohols, excellent
catalytic activity, high regio- and stereoselectivity, and
good compatibility of various functional groups, this
transformation will be a useful and practical method for
highly selective synthesis of natural and unnatural lactones
with synthetic or biological potentials, which opens new
and efficient ways for CO2 activation. However, it should
be noted that such nonmethyl alkyl- or arylative is still a
challenge.20 Further studies in this area are being pursued
in this laboratory.21
Scheme 4. Synthesis of Fused Lactones
Acknowledgment. Financial support from the National
Basic Research Program of China (2011CB808705),
National Natural Science Foundation of China (20732005),
and Project for Basic Research in Natural Science Issued
by Shanghai Municipal Committee of Science (No. 08dj-
1400100) is greatly appreciated. We thank Ms. Zhao Fang
in this group for reproducing the results presented in entry
4 of Table 2, eq 3 of Scheme 4.
In conclusion, we have successfully developed the first
example of transition-metal-catalyzed highly regio- and
stereoselective alkylative carboxylation of alkynes with
CO2 under the catalysis of just 1À2 mol % of Ni(cod)2.8
For the unique character of the directing OH group, we
Supporting Information Available. Spectroscopic data,
1
general procedure, and H/13C NMR spectra of all the
products. This material is available free of charge via the
Internet at http://pubs.acs.org.
(20) When ZnEt2 was used instead of ZnMe2 in the reaction with 1a
under the standard conditions presented in entry 14 of Table 1, only
20% of ethyl-carboxylation products were obtained together with 69%
of the hydro-carboxylation products on the basis of 1H NMR analysis.
(21) The terminal alkynes do not work well in this catalytic system.
(19) For reports on additives increasing the activity of organic zincs,
see: (a) Metzger, A.; Schade, M. A.; Knochel, P. Org. Lett. 2008, 10,
1107. (b) Metzger, A.; Bernhardt, S.; Manolikakes, G.; Knochel, P.
Angew. Chem., Int. Ed. 2010, 49, 4665. (c) Ref 4d.
Org. Lett., Vol. 13, No. 22, 2011
6049