Preparation of α,β-unsaturated diazoketones employing a Horner-Wadsworth-Emmons reagent

Article abstract of DOI:10.1021/jo1021844

A new method for the preparation of α,β-unsaturated diazoketones from aldehydes and a Horner-Wadsworth-Emmons reagent is reported. The method was applied to the short synthesis of two substituted pyrrolidines.

Full text of DOI:10.1021/jo1021844

pubs.acs.org/joc
diazoketones have proven to be very promising as multi-
Preparation of r,β-Unsaturated Diazoketones
functional intermediates,6-17 two recent examples being the
asymmetric aziridination of vinyl diazoketones described
by Wulff6 and the syntheses of trisubstituted γ-butyrolac-
tones by Brueckner.7,8 Although there are many efficient methods
to prepare diazoketones,1,2,18 very few19-23 can be extended
to the synthesis of the R,β-unsaturated diazoketones, and
this is likely responsible for their limited application in synthesis.
In fact, with the exception of the Danheiser23 deformylating
procedure, none of the other methods19-22 is general and
suitable for the synthesis of unsaturated diazoketones. For
example, the most useful methodology to prepare diazoketones,
involving diazomethane acylation in the presence of acyl
chlorides or mixed anhydrides, is not generally good for the
synthesis of the R,β-unsaturated diazoketones.19 This is because
dipolar cycloaddition to the conjugated double bond rapidly
occurs, resulting in the formation of pyrazolines.24
Employing a Horner-Wadsworth-Emmons Reagent
Vagner D. Pinho and Antonio C. B. Burtoloso*
´
Instituto de Quımica de Sao Carlos, Universidade de
Sa~o Paulo, CEP 13560-970, Sa~o Carlos, SP, Brazil
~
antonio@iqsc.usp.br
Received September 3, 2010
Herein, we present a simple procedure to prepare these
unsaturated diazocarbonyl compounds from a range of aldehydes
and a 3-diazo-2-oxopropylphosphonate, employing a Horner-
Wadsworth-Emmons (HWE) reaction. Furthermore, we
also demonstrate the utility of these unsaturated diazoketones
as bifunctional building blocks by preparing two substituted
pyrrolidines in just two steps.
We started our work by preparing diethyl 3-diazo-2-
oxopropylphosphonate 1 from (diethylphosphono)acetic acid25
(Table 1) as described by Mikityuk26 and with the goal to
evaluate it as a new HWE diazo reagent. Unfortunately,
employing Mikityuk’s protocol, we could only obtain low
yields of compound 1 (entry 1, Table 1). Given that no other
work was described toward the preparation of 1 to date, we
developed an improved synthesis as depicted in Table 1.
Diazophosphonate 1 proved to be very difficult to prepare
initially. This was due to the extreme instability or lack of
reactivity of the activated (diethylphosphono)acetic acids
toward diazomethane. Among all the conditions described in
Table 1, diazomethane acylation from an acyl chloride
proved to be the best, since the other activated carboxylic
acids (entries 8-12) were not suitable for this transforma-
tion. After these improvements, phosphonate 1 could be
easily synthesized in 70% yield as a stable yellow oil.27
A new method for the preparation of R,β-unsaturated
diazoketones from aldehydes and a Horner-Wadsworth-
Emmons reagent is reported. The method was applied to
the short synthesis of two substituted pyrrolidines.
The chemistry of diazo compounds has shown, over the
years, a multitude of applications in the field of organic
synthesis.1-5 Some of these applications include the insertion
of diazocarbonyl compounds into C-H and X-H (X = N,
O, S, P, Se) bonds, cyclopropanation reactions, dipolar cyclo-
additions, ylide formation, and the Wolff rearrangement.
In view of the wide array of transformations that diazocarbon-
yls can accomplish, it speaks to the importance of methods
which provide these substrates efficiently and with vast struc-
tural diversity. Among the different types of diazocarbo-
nyl substrates found in the literature to date, R,β-unsaturated
(1) Ye, T.; McKervey, M. A. Chem. Rev. 1994, 94, 1091.
(2) Doyle, M. P.; McKervey, M. A.; Ye, T. Modern Catalytic Methods for
Organic Synthesis with Diazo Compounds: From Cyclopropanes to Ylides;
New York, 1998.
(16) Ceccherelli, P.; Curini, M.; Marcotullio, M. C.; Rosati, O.; Wenkert,
E. J. Org. Chem. 1990, 55, 311.
(3) Singh, G. S. Curr. Org. Synth. 2005, 2, 175.
(4) Ferreira, V. F. Curr. Org. Chem. 2007, 11, 177.
(5) Zhang, Z.; Wang, J. Tetrahedron 2008, 64, 6577.
(6) Deng, Y.; Lee, Y. R.; Newman, C. A.; Wulff, W. D. Eur. J. Org. Chem.
2007, 13, 2068.
(17) Muller, P.; Maitrejean, E. Collect. Czech. Chem. C. 1999, 64, 1807.
(18) Maas, G. Angew. Chem., Int. Ed. 2009, 48, 8186.
(19) Wotiz, J. H.; Buco, S. N. J. Org. Chem. 1955, 20, 210.
(20) Harmon, R. E.; Sood, V. K.; Gupta, S. K. Synthesis 1974, 8, 577.
(21) Regitz, M.; Menz, F.; Liedhegener, A. Liebigs Ann. Chem. 1970, 739, 174.
(22) Doyle, M. P.; Dorow, R. L.; Terpstra, J. W.; Rodenhouse, R. A.
J. Org. Chem. 1985, 50, 1663.
(7) Kapferer, T.; Brueckner, R. Eur. J. Org. Chem. 2006, 9, 2119.
(8) Kapferer, T.; Brueckner, R.; Herzig, A.; Koenig, W. A. Chem. Eur.
J. 2005, 11, 2154.
;
(9) Cainelli, G.; Galletti, P.; Garbisa, S.; Giacomini, D.; Sartor, L.;
Quintavalla, A. Bioorg. Med. Chem. 2003, 11, 5391.
(10) Rowlands, G. J.; Barnes, W. K. Tetrahedron Lett. 2004, 45, 5347.
(11) Cainelli, G.; Giacomini, D.; Galletti, P.; Quintavalla, A. Eur. J. Org.
Chem. 2003, 9, 1765.
(12) Clark, J. S.; Hodgson, P. B.; Goldsmith, M. D.; Street, L. J. J. Chem.
Soc., Perkin Trans. 1 2001, 24, 3312.
(13) Danheiser, R. L.; Cha, D. D. Tetrahedron Lett. 1990, 31, 1527.
(14) Ujvary, I.; Prestwich, G. D. J. Labelled Compd. Radiopharm. 1990,
28, 167.
(23) Danheiser, R. L.; Miller, R. F.; Brisbois, R. G.; Park, S. Z. J. Org.
Chem. 1990, 55, 1959.
(24) Unless starting from the R,β-dialkylated or β,β-dialkylated R,β-
unsaturated acids.
(25) Teichert, A.; Jantos, K.; Harms, K.; Studer, A. Org. Lett. 2004, 6,
3477–3480.
(26) Mikityuk, A. D.; Kashemirov, B. A.; Khokhlov, P. S. Zh. Obshch.
Khim. 1987, 57, 1669.
(27) We exhaustively tested many classical conditions to prepare acid
chlorides, but the only condition that provided acceptable yields of 1
was refluxing the carboxylic acid with freshly distilled oxalyl chloride in
chloroform.
(15) Fang, F. G.; Prato, M.; Kim, G.; Danishefsky, S. J. Tetrahedron Lett.
1989, 30, 3625.
DOI: 10.1021/jo1021844
r
Published on Web 12/14/2010
J. Org. Chem. 2011, 76, 289–292 289
2010 American Chemical Society

Pinho and Burtoloso
JOCNote
TABLE 1. Optimization Studies for the Preparation
of Diazophosphonate 1
TABLE 3. Synthesis of Diazoketones 12-21 from Aldehydes 2-11 and
HWE Reagent 1 (Method J)
entry activation method
126 acyl chloridea
activation conditions
yield (%)
1. SOCl2, 25 °C, 3 h
1. SOCl2, 50 °C, 3 h
18
0
5
2
3
4
5
6
acyl chloridea
acyl chloridea
acyl chloridea
acyl chloridea
acyl chloridea
acyl chloridea
1. SO2Cl2, 25 °C, 3 h
2. PCl5, THF, 25 °C, 1 h
1. (COCl)2, 25 °C, 2 h
0
20
25
70
0
0
0
1. (COCl)2, DCM, 25 °C, 2 h
1. (COCl)2, CHCl3, reflux, 2 h
7
8
acyl phosphoniumb 1. PPh3, NBS, THF, 0 °C, 1 h
9
10
acyl ureab
acyl mesylatesb 1. MsCl, CH3CN, TEA, 0 °C, 1 h
1. DCC, THF, 25 °C, 1 h
11 mixed anhydrideb,c 1. ClCO2Et, TEA, DCM, 0 °C, 1 h
0
0
12 mixed anhydrideb,c
1. TFAA, CHCl3, reflux, 2 h
aAfter the activation of (diethylphosphono)acetic acid, the solvent
was concentrated and the residue dissolved in dry THF prior to its
addition to a ethereal diazomethane solution (3 equiv). bEthereal diazo-
methane solution (3 equiv) was added directly in the reaction flask after
carboxylic acid activation. c12 h reaction after diazomethane addition.
TABLE 2. Evaluation of the HWE Reaction between
Diazophosphonate 1 and Benzaldehyde
entry method
base
solvent
T (°C)
0 (2 h)
yield (%)
1a,b
2a,c
3a,c
4 a,c
5 a,c
6 a,c
7 a,c
8a,d
9a,e
10 f
A
B
C
D
E
F
G
H
I
Ba(OH)2
NaH
NaH
LiHMDS THF
NaHMDS THF
KHMDS THF
THF
THF
PhMe
57
60
62
38
60
56
60
37
14
91
-78 (1 h) to 0 (1 h)
-78 (1 h) to 0 (1 h)
-78 (1 h) to 0 (1 h)
-78 (1 h) to 0 (1 h)
-78 (1 h) to 0 (1 h)
-78 (1 h) to 0 (1 h)
BuLi
THF
CH3CN 25 (24 h)
THF
THF
DIPEA
K2CO3
NaH
25 (48 h)
-78 (1 h) to 0 (1 h)
J
a1.0 equiv of phosphonate 1. b0.8 equiv of the base. c1.1 equiv of the
aAll liquid aldehydes were freshly distilled prior to use. bAll yields
refer to purified products after flash chromatography.
base. d3.0 equiv of the base and 1.0 equiv of LiCl as additive. e1.0 equiv
of 18-crown-6 ether as additive. 2.0 equiv of the phosphonate 1 and
2.2 equiv of NaH.
f
provided similar yields for the reaction with benzaldehyde,
method B furnished the best yields when extended to other
aldehydes. From Table 2, it is also clear that solvent effects
had no substantial influence in the yield of the HWE reaction
(entries 2 and 3), but counterion effects had (entries 4-6).
Since method B provided a very clean HWE reaction, we
thought that the 60% yield may be related to the degradation
of phosphonate 1 during the reaction. To verify that, we
decided to adjust method B by using 2 equiv of 1. To our
delight, under these conditions (entry 10), a 91% yield could
be obtained for the HWE reaction.
With an improved method for the synthesis of 1 in hand,
we turned our attention to find the best conditions for the
Horner-Wadsworth-Emmons reaction employing phos-
phonate 1 and benzaldehyde as a model (Table 2). Initially,
after studying some classical conditions28-33 for the HWE
reaction, we found that method B (NaH as a base) proved
to be the optimal. Although methods A, C, and E-G also
(28) Wadsworth, W. S.; Emmons, W. D. J. Am. Chem. Soc. 1961, 83,
1733.
(29) Paterson, I.; Yeung, K.; Smaill, J. Synlett 1993, 774.
Employing method J (2 equiv of 1), aldehydes 2-11 were
converted to the respective R,β-unsaturated diazoketones34
12-21 with isolated yields ranging from 50 to 91%. Table 3
illustrates these results from branched and unbranched aliphatic
ꢀ
(30) Grison, C.; Geneve, S.; Halbin, E.; Coutrot, P. Tetrahedron 2001, 57,
4903.
(31) Blanchette, M. A.; Choay, w.; Davis, J. T.; Essenfeld, A. P.; Masamune,
S.; Roush, W. R.; Sakai, T. Tetrahedron Lett. 1984, 25, 2183.
(32) Lee, E. S.; Lee, W. G.; Yun, S.; Rho, S. H.; Im, I.; Yang, S. T.;
Sellamuthu, S.; Lee, Y. J.; Kwon, S. J.; Park, O. K.; Jeon, E.; Park, W. J.;
Kim, Y. Biochem. Biophys. Res. Commun. 2007, 358, 7–11.
(33) Lee, K.; Jackson, J. A.; Wiemer, D. F. J. Org. Chem. 1993, 58, 5967.
(34) Only the E isomer was detected.
290 J. Org. Chem. Vol. 76, No. 1, 2011

Pinho and Burtoloso
JOCNote
SCHEME 1. Coupled Diazoketone 22 Observed when 1.0 equiv
of 1 Was Employed
from R,β-unsaturated diazoketones, no nitrogen atom pro-
tection is necessary when N-alkylpyrrolidines are desired, a
drawback that is often encountered when these compounds
are prepared from amino acid-derived diazoketones.
In summary, a new method for the preparation of R,β-
unsaturated diazoketones from commercially available or
easily accessed aldehydes and a new Horner-Wadsworth-
Emmons reagent is reported. The method can be extended to
the synthesis of structurally diverse unsaturated diazo-
ketones and will complement the Danheiser deformylating
protocol. To demonstrate the application of these diazo-
ketones, a short synthesis of two substituted pyrrolidines was
also accomplished.
Experimental Section
3-Diazo-2-oxopropylphosphonate 1. (Diethylphosphono)acetic
acid25 (2.10 g, 10.8 mmol, 1 equiv) was added to a 50.0 mL
flame-dried round-bottom flask, followed by the addition of dry
toluene (3 ꢀ 15.0 mL) for azeothropic removal of moisture. Next,
dry chloroform (27.0 mL) was added and the system cooled to 0 °C.
Freshly distilled oxalyl chloride (2.83 mL, 32.4 mmol, 3 equiv) was
then added dropwise to the reaction vessel and the solution stirred
at reflux for 2 h. After this period, the solvent and volatiles were
removed on the rotary evaporator, and the resultant residue was
dissolved in dry tetrahydrofuran (THF) (11.0 mL). (Caution: The
acid chloride from (diethylphosphono)acetic acid is very unstable, and
care should be exercised during these operations to avoid its hydrolysis.)
Next, the acid chloride solution was added by cannula to a cooled
(0 °C) and freshly prepared 0.4 M ethereal solution of diazomethane
(67.0 mL, 2.5 equiv)41 and the reaction allowed to stir at room tem-
perature for 2 h. After that, the solvent was removed via rotary eva-
porator and the residue purified by flash column chromatography
(gradient 50% AcOEt/hexane and then 100% AcOEt) to furnish
the diazophosphonate 1 (1.65 g, 70%) as a yellow oil:42 1H NMR
(200 MHz, CDCl3) δ 5.61 (1H, s), 4.16 (4H, m), 2.95 (2H, d, J=
21.7 Hz), 1.34 (6H, td, J = 7.0, 0.6 Hz); 13C NMR (50 MHz,
CDCl3) 173.0, 145.1, 34.3, 21.4, 13.6; IR (neat, cm-1) 2108, 1633,
1359, 1249, 1045, 972; HRMS (ESI) calcd for C7H13N2NaO4P
[Mþ Na]þ 243.0511, found 243.0515; Rf 0.27 (10% MeOH/EtOAc).
General Procedure for the HWE Reaction. (E )-1-Diazo-4-
phenylbut-3-en-2-one 12 (Method J). To a suspension of NaH
(60% in mineral oil) (13.0 mg, 0.33 mmol, 2.2 equiv) in dry THF
(0.5 mL), under argon atmosphere and at 0 °C, was added a
0.3 M solution of diethyl 3-diazo-2-oxopropylphosphonate
(66.0 mg, 0.30 mmol, 2.0 equiv) in dry THF. After being stirred
for 15 min at this temperature, the system was cooled to -78 °C,
and then a 0.2 M solution of freshly distilled benzaldehyde (16.0 mg,
0.15 mmol, 1.0 equiv) in dry THF was added dropwise. After 1 h,
the -78 °C cooling bath was replaced with ice-water and the
mixture stirred for an additional 1 h. Next, a saturated aqueous
NH4Cl solution (10 mL) was added to the reaction vessel and the
aqueous layer extracted with dichloromethane (3 ꢀ 6 mL). The
combined organic layers were then dried over Na2SO4, filtered,
and evaporated in a rotary evaporator. Purification by flash
column chromatography (12% AcOEt/Hexanes) afforded di-
azoketone 12 (47.0 mg, 91%) as a stable yellow solid: 1H NMR
(200 MHz, C6D6) δ 7.63 (d, J=15.9 Hz, 1H), 7.07-6.99 (m, 5H),
6.22 (d, J=15.9 Hz, 1H), 4.40 (s, 1H); C NMR (50 MHz, CDCl3) δ
SCHEME 2. Synthesis of Pyrrolidines 24 and 26 from
R,β-Unsaturated Diazoketones 12 and 19
aldehydes, aromatic aldehydes, and aminoaldehydes. It is
interesting to note that the use of excess of the phosphonate 1
seems to be crucial for the success of these reactions. In fact,
besides the formation of unsaturated diazoketones in lower
yields (20-80), the use of only 1 equiv of 1 can led in some
cases to the formation of coupled diazoketones.35 This fact
was observed during the HWE reaction with very reactive
aldehydes such as 4-nitrobenzaldehyde (Scheme 1).
To show the applicability of the present method and
another utility of this class of unsaturated diazocarbonyls,
diazoketones 12 and 19 were readily converted in two steps in
the functionalized pyrrolidinones 24 and 26 after Michael
addition12 in the presence of benzylamine and rhodium-
catalyzed N-H insertion (Scheme 2).36
Pyrrolidinones such as 24 and 26 are important building
blocks in the pharmaceutical industry and are highly useful
synthetic intermediates to be applied in the total synthesis
of natural pyrrolidines.37-40 Furthermore a vast library of
pyrrolidines can be synthesized with this method just by
varying the aldehyde and amine in the HWE and Michael
addition reactions, respectively. It is also noteworthy that,
(35) For a precedent that shows a similar type of coupling between ethyl-
diazoacetate and aldehydes, see: Erhunmwunse, M. O.; Steel, P. G. J. Org.
Chem. 2008, 73, 8675.
184.2, 140.7, 130.3, 128.9, 128.2, 123.6, 56.1; IR (KΒr, cm-1
)
ꢁ
(36) Desai, P.; Aube, J. Org. Lett. 2000, 2, 1657.
(37) Dewick, P. M. Medicinal Natural Products: A Biosynthetic Approach;
Wiley: New York, 2002.
(38) O’Hagan, D. Nat. Prod. Rep. 2000, 17, 435.
(39) Daly, J. W.; Spande, T. F.; Garraffo, H. M. J. Nat. Prod. 2005, 68,
1556.
(41) Very recently, a new procedure of diazoketone syntheses employing
only one equivalent of diazomethane has been described: Pace, V.; Verniest,
G.; Sinisterra, J.; Alcantara, A. R; De Kimpe, N. J. Org. Chem. 2010, 75,
5760.
(40) Achenbach, T. V.; Slater, E. P.; Brummerhop, H.; Bach, T.; Muller,
R. Antimicrob. Agents Chemother. 2000, 44, 2794.
(42) Lowering the reaction scale by too much and/or not using freshly
prepared diazomethane caused the yield to drop to 46-50%.
J. Org. Chem. Vol. 76, No. 1, 2011 291

Pinho and Burtoloso
JOCNote
3070, 2098, 1637, 1583, 1448, 1369, 1149, 973, 757; HRMS (ESI)
calcd for C10H9N2O [M þ H]þ 173.0715, found 173.0712; mp
63-66 °C; Rf 0.30 (25% EtOAc/hexanes).
facilities (in special to Dr. Sylvana C. Miguel Agustinho). We
also thank Dr. Ross Denton (University of Nottingham) for
reading and discussion of the manuscript.
Acknowledgment. We thank FAPESP (Research Sup-
~
Supporting Information Available: Experimental proce-
dures, spectroscopic data, and copies of NMR spectra for all
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
porting Foundation of the State of Sao Paulo) for financial
support and a fellowship to V.D.P. We also thank CNPq
for research fellowship to A.C.B.B. and IQSC-USP for
292 J. Org. Chem. Vol. 76, No. 1, 2011