Addition of terminal alkynes to α-ketone esters to synthesize α-tertiary-hydroxy esters promoted by zinc and an alkyl halide

Article abstract of DOI:10.1016/j.tetlet.2015.09.144

A convenient method to synthesize various α-tertiary-hydroxy esters at room temperature has been developed. This method uses the readily available and inexpensive Zn powder in combination with an alkyl halide to promote the addition of alkynes to α-ketone

Full text of DOI:10.1016/j.tetlet.2015.09.144

Tetrahedron Letters xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Addition of terminal alkynes to
a-ketone esters to synthesize
a-tertiary-hydroxy esters promoted by zinc and an alkyl halide
b,
Wen Zhang a, Yuan Cao a, Wei Chen c, Gang Zhao a, , Lin Pu
⇑
⇑
a College of Chemical Engineering, Sichuan University, Chengdu 610065, China
b Department of Chemistry, University of Virginia, Charlottesville, VA 22904-4319, USA
c Chengdu Zepletech Inc., Chengdu 610041, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A convenient method to synthesize various
developed. This method uses the readily available and inexpensive Zn powder in combination with an
alkyl halide to promote the addition of alkynes to -ketone esters with no need to exclude air or mois-
a-tertiary-hydroxy esters at room temperature has been
Received 11 August 2015
Accepted 29 September 2015
Available online xxxx
a
ture. It has also been extended to promote the reaction of alkynes with a variety of aldehydes and other
electron-deficient ketones.
Keywords:
Ó 2015 Elsevier Ltd. All rights reserved.
a
-Ketone ester
Alkynes
-Tertiary-hydroxy esters
Zinc
a
Addition of terminal alkynes to
a
-ketone esters is a very useful
OH
R'[M]
-R'H
R''COCO2R'''
method to generate
a-tertiary-hydroxy carboxylic acid derivatives
R
H
R
[M]
R
R''
CO2R'''
R'' = aryl or alkyl
that can be used to prepare a number of organic compounds with
interesting biological functions.1–8 Generally, the reaction is con-
ducted by deprotonation of a terminal alkyne with a strong base
such as an alkyl lithium reagent or an alkyl zinc reagent followed
α-tertiary-hydroxy esters
Scheme 1. Alkyne addition to
a
-ketone esters to form
a
-tertiary-hydroxy esters.
by nucleophilic addition to an
a
-ketone ester (Scheme 1).1–5
Because of the high sensitivity of these reagents toward air and
moisture, these reactions require rigorously dry and air-free condi-
tions. The use of Zn(OTf)2 in the presence of Et3N and a chiral
amino alcohol reagent6 as well as other methods7,8 have also been
developed to promote the alkyne addition to a-ketone esters. We
are interested in exploring a direct use of the inexpensive and
PhCOCO2Me
OH
Ph
CO2Me
Zn, MeI
1
Ph
Ph
H
a solvent a solvent
step 1
step 2
2
much more easily manageable zinc powder in combination with
Scheme 2. Zn-Promoted addition of phenyl acetylene to the
form the -tertiary-hydroxy ester 2.
a-ketone ester 1 to
an alkyl halide to promote the addition of alkynes to
esters. Herein, we wish to report that when Zn and MeI or EtI are
used, the reaction of terminal alkynes with -ketone esters can
be carried out in air with no need to rigorously dry the system. This
allows -tertiary-hydroxy esters to be prepared efficiently under
a-ketone
a
a
were conducted in two steps at room temperature in air unless
indicated otherwise. In the first step, phenyl acetylene was com-
bined with the activated Zn powder and MeI in a solvent which
was stirred until the disappearance of Zn (ꢀ2 h). Then, 1 and a sol-
vent were added, and the reaction was allowed to proceed for 12 h.
As shown in entries 1 and 2, when CH2Cl2 was used in both steps 1
and 2 even with the addition of the Lewis acid Ti(OiPr)4 (entry 2),
no product was obtained. Changing the solvent to THF (step 1)
and Et2O (step 2) gave no product (entry 3) except with the addi-
tion of Ti(OiPr)4 which generated the product in low yield (entry 4).
Although there was no product formation when NMP was used in
both steps 1 and 2 (entry 5), when the solvent of the second step
a
very mild conditions. We further find that the addition of terminal
alkynes to a variety of aldehydes can also be conducted smoothly
under the same conditions.
We first studied the reaction of phenyl acetylene with the
a-ketone ester 1 under various conditions (Scheme 2). Table 1
summarizes the reaction conditions explored. All the reactions
⇑
Corresponding authors.
E-mail addresses: gzhao@scu.edu.cn (G. Zhao), lp6n@virginia.edu (L. Pu).
http://dx.doi.org/10.1016/j.tetlet.2015.09.144
0040-4039/Ó 2015 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Zhang, W.; et al. Tetrahedron Lett. (2015), http://dx.doi.org/10.1016/j.tetlet.2015.09.144

2
W. Zhang et al. / Tetrahedron Letters xxx (2015) xxx–xxx
Table 1
Table 2
Reaction conditions for the addition of phenyl acetylene to 1a
Zn-promoted reaction of alkynes with other carbonyl compoundsa
Entry
Alkyne/Zn/RI/1
RI
Solvent of
step 1
Solvent of
step 2
Yield (%)
Entry
Alkyne
Aldehyde
Isolated yield (%)
1
2
3
4
CHO
CHO
CHO
90
64
83
85
1
4:6:12:1
4:6:12:1
4:6:12:1
4:6:12:1
4:6:12:1
4:6:12:1
4:6:12:1
4:6:12:1
4:6:12:1
4:6:12:1
4:6:12:1
4:6:12:1
4:6:12:1
4:6:12:1
3:4:8:1
MeI
MeI
MeI
MeI
MeI
MeI
MeI
MeI
MeI
MeI
MeI
MeI
MeI
MeI
MeI
MeI
MeI
MeI
EtI
CH2Cl2
CH2Cl2
THF
CH2Cl2
CH2Cl2
Et2O
Et2O
NMP
Hexane
Toluene
THF
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
No productg
2b
3
No productg
No productg
F
4b
5
6
7
8
THF
43
NMP
NMP
NMP
NMP
NMP
DMF
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
No producth
Cl
Br
80
87
76
92
72
61
77
86
CHO
9
10
11c
12d
13e
14f
15
16
17
18
19
CHO
5
61
O
No productg
6
7
8
9
CHO
60
85
95
81
84
34
33
Trace
91
3:1:2:1
O2N
CHO
1:6:12:1
1:0.5:1:1
4:6:12:1
CHO
O
The bold entries are the optimized conditions.
Br
CHO
4
a
The following general conditions were used unless indicated otherwise. Step 1:
activated Zn (3 mmol, 196.1 mg), MeI (6 mmol, 851.6 mg) or EtI (6 mmol,
935.8 mg), phenylacetylene (2 mmol, 204.3 mg), a solvent (0.5 mL). Stirring at room
temperature in air until Zn disappeared (ꢀ2 h). Step 2: a solvent (5 mL) and 1
(0.5 mmol, 82.1 mg) were added and the reaction was allowed to proceed at room
temperature for 12 h.
10
89
55
CF3
O
11b
Ti(OiPr)4 (1 equiv) was added.
Unactivated Zn powder was used.
Step 1 was extended to over 12 h.
Phenyl acetylene and 1 were added in step 2.
All the components were mixed in one step.
Both Zn and 1 remained.
Zn disappeared and 1 remained.
b
c
a
Conditions of entry 9 in Table 1 were applied unless indicated otherwise.
AlCl3 (2 equiv) was added after step 1 and step 2 was allowed to proceed for
48 h.
d
b
e
f
g
h
a dilute HCl solution), MeI (6 mmol) and NMP (0.5 mL) were com-
bined in air and the resulting mixture was stirred at room temper-
ature until the disappearance of Zn (ꢀ2 h). Then, an
a-ketone ester
was changed to others such as hexane, THF, toluene, and CH2Cl2,
good yields of the desired product 2 were obtained (entries 6–9).
Among these reactions, entry 9 using CH2Cl2 as the solvent in step
2 gave the highest yield. Further variation of the conditions of
entry 9 all led to reduced yield (entries 10–14), including the
change of NMP to DMF in entry 10; the use of unactivated Zn pow-
der in entry 11; the extension of the reaction time of step 1 to 12 h
in entry 12; the addition of both phenyl acetylene and 1 in step 2 in
entry 13; and the combination of all the components in one step in
entry 14 which gave no product. Entries 15–18 show that reducing
the amount of the alkyne, Zn, and MeI all led to reduced yield. We
further found that EtI could be used to replace MeI to give the same
excellent yield under the same conditions (entry 19).
(0.5 mmol) in CH2Cl2 (5 mL) was added. After stirred for ꢀ12 h, the
reaction was complete as shown by TLC. A saturated ammonia
chloride solution (10 mL) was added and the organic phase was
separated. The water phase was extracted with CH2Cl2. The com-
bined organic phase was washed with saturated sodium chloride
solution and dried with anhydrous sodium sulfate. After concen-
tration and column chromatograph on silica gel eluted with petro-
leum ether/ethyl acetate (10:1), the desired
ester product was obtained.
a-tertiary-hydroxy
We have further extended the application of the above method
to the reaction of alkynes with aldehydes and other ketones.9 As
the results summarized in Table 2 show, in the presence of Zn
and MeI, good yields are obtained for the reaction of aryl and alkyl
alkynes with aromatic and aliphatic aldehydes to generate the cor-
responding secondary propargylic alcohols in air at room temper-
ature. For the electron deficient trifluoromethyl phenyl ketone in
entry 10, a good yield of the tertiary alcohol product was obtained.
However, for a non electron-deficient ketone in entry 11, addition
of a Lewis acid complex was necessary in order to promote the
reaction.
We have used the optimized conditions of entry 9 as described
above to synthesize several
a-tertiary-hydroxy esters and the
results are shown in Figure 1. It demonstrates that this Zn-pro-
moted method can be applied to the reactions of both aryl and
alkyl alkynes with aryl or alkyl
a-ketone esters in good yields.
Thus, various -tertiary-hydroxy esters can be prepared readily
a
at room temperature with no need to exclude air or moisture.
The general procedure for this Zn-promoted alkyne addition to
In summary, we have developed a convenient method to syn-
thesize a-tertiary-hydroxy esters at room temperature. This reac-
a
-ketone esters is given below. To a 25 mL round-bottom flask, an
alkyne (2 mmol), zinc powder (3 mmol, activated by washing with
OH
OH
OH
OH
Me
CO2Me
84%
Br
CO2Me
CO2Me
CO2Me
92%
Figure 1. Various
70%
71%
-ketone esters.
a
-tertiary-hydroxy esters prepared by using the Zn-promoted alkyne addition to
a
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W. Zhang et al. / Tetrahedron Letters xxx (2015) xxx–xxx
3
129–132; (c) Gray, P. J.; Motherwell, W. B.; Sheppard, T. D.; Whitehead, A. J.
Synlett 2008, 2097–2100; (d) Ivanov, I. K.; Parushev, I. D.; Christov, V. C.
Heteroatom Chem. 2013, 24, 322–331.
tion uses the readily available and inexpensive Zn powder in com-
bination with MeI or EtI and can be conducted in air without using
a rigorously dry condition. This method significantly improves the
currently available ones and it can also be extended to promote the
reaction of alkynes with aldehydes and other electron-deficient
ketones.
2. (a) Use n-BuLi: Selnick, H. G.; Barrow, J. C.; Nantermet, P. G.; Williams, P. D.;
Stauffer, K. J.; Sanderson, P. E.; Rittle, K. E.; Morrissette, M. M.; Wiscount, C. M.;
Tran, L. O.; Lyle, T. A.; Staas, D. D. PCT Int. Appl. WO2002050056, 2002.; (b)
Agami, C.; Cases, M.; Couty, F. J. Org. Chem. 1994, 59, 7937–7940.
3. Use LDA and MgCl2: Toscano, M. D.; Payne, R. J.; Chiba, A.; Kerbarh, O.; Abell, C.
ChemMedChem 2007, 2, 101–112.
4. Use Me2Zn or Et2Zn: (a) Infante, R.; Gago, A.; Nieto, J.; Andrés, C. Adv. Synth.
Catal. 2012, 354, 2797–2804; (b) Gou, S.-H.; Chen, X.-H.; Xiong, Y.; Feng, X.-M. J.
Org. Chem. 2005, 70, 5732–5736.
5. Use Me3Ga: Jiang, H.-L.; Lin, A.-J.; Peng, H.; Zhu, Y.-H.; Pan, Y.; Zhu, C.-J.; Cheng,
Y.-X. Synlett 2011, 2039–2042.
Acknowledgment
Partial supports of this work from the Specialized Research
Fund for the Doctoral Program of Higher Education in China are
gratefully acknowledged. We also thank the Sichuan University
High Level Talent Project and Sichuan Province 1,000 Talents Plan
Project for financial support.
6. Use Zn(OTf)2: (a) Jiang, B.; Chen, Z.-L.; Tang, X.-X. Org. Lett. 2002, 4, 3451–3453;
(b) Sorger, K.; Stohrer, J. Ger. Offen 2005. 10359702.
7. Rh-catalyzed addition: (a) Dhondi, P. K.; Carberry, P.; Choi, L. B.; Chisholm, J. D. J.
Org. Chem. 2007, 72, 9590–9596; (b) Dhondi, P. K.; Chisholm, J. D. Org. Lett. 2006,
8, 67–69; (c) Wang, T.; Niu, J.-L.; Liu, S.-L.; Huang, J.-J.; Gong, J.-F.; Song, M.-P.
Adv. Synth. Catal. 2013, 355, 927–937; (d) Song, M.-P.; Wang, T.; Gong, J.-F.; Niu,
J.-L.; Hao, X.-Q. Faming Zhuanli Shenqing 2012. 102746343; (e) Takashi, O.;
Takahito, K.; Yosuke, T.; Takahiro, K.; Takanori, I.; Takayuki, Y.; Hajime, M.;
Hisao, N.; Kazushi, M. Angew. Chem., Int. Ed. 2011, 50, 6296–6300.
8. AgF catalyzed addition to CF3COCO2Me Deng, G.-J.; Li, C.-J. Synlett 2008, 1571–
1573.
9. Selected reviews on alkyne additions to carbonyl compounds: (a) Smith, M.;
March, J. March’s Advanced Organic Chemistry, 6th ed.; Wiley: New York, 2007. p.
1360; (b) Frantz, D. E.; Fässler, R.; Tomooka, C. S.; Carreira, E. M. Acc. Chem. Res.
2000, 33, 373–381; (c) Pu, L. Tetrahedron 2003, 59, 9873–9886; (d) Cozzi, P. G.;
Hilgraf, R.; Zimmermann, N. Eur. J. Org. Chem. 2004, 20, 4095–4105; (e) Lu, G.; Li,
Y.-M.; Li, X.-S.; Chan, A. S. C. Coord. Chem. Rev. 2005, 249, 1736–1744; (f) Trost, B.
M.; Weiss, A. H. Adv. Synth. Catal. 2009, 351, 963–983.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2015.09.
144.
References and notes
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3157–3159; (b) Mayrargue, J.; Avril, J. L.; Miocque, M. Bull. Soc. Chim. Fr. 1984,
Please cite this article in press as: Zhang, W.; et al. Tetrahedron Lett. (2015), http://dx.doi.org/10.1016/j.tetlet.2015.09.144