Rearrangement of epoxynitriles: A convenient homologation of acyclic and cyclic ketones to carboxylic acids

Article abstract of DOI:10.1021/jo025737g

A convenient two-step homologation of both aliphatic and aromatic ketones to the corresponding carboxylic acid has been developed. First ketones were converted to epoxynitriles with the Darzens reaction. Second, a Lewis acid mediated rearrangement of these epoxynitriles with lithium bromide was achieved to give homologated secondary alkanoic acids (as well as aryl-alkanoic) in good yields. The mechanism and the scope of the rearrangement reaction were investigated. This strategy constitutes a two- step homologation of ketones to secondary carboxylic acids.

Full text of DOI:10.1021/jo025737g

Rea r r a n gem en t of Ep oxyn itr iles: A
Con ven ien t Hom ologa tion of Acyclic a n d
Cyclic Keton es to Ca r boxylic Acid s
Neil F. Badham,*,† Wilford L. Mendelson,†
‡
†
‡
†
Andrew Allen, Ann M. Diederich, Drake S. Eggleston,
†
‡
‡
J ohn J . Filan, Alan J . Freyer, Lewis B. Killmer, J r.,
†
†
†
Conrad J . Kowalski, Li Liu, Vance J . Novack,
Frederick G. Vogt, Kevin S. Webb, and J ennifer Yang
‡
†
F IGURE 1. Retrosynthesis of SB-207499 from a ketone
GlaxoSmithKline Pharmaceuticals, 709 Swedeland Road,
King of Prussia, Pennsylvania 19406
precursor.
SCHEME 1. Wh ite’s Meth od ology for
Alk yl-Su bstitu ted Ep oxyn itr iles
neil_f_badham@gsk.com
Received March 19, 2002
Abstr a ct: A convenient two-step homologation of both
aliphatic and aromatic ketones to the corresponding car-
boxylic acid has been developed. First ketones were con-
verted to epoxynitriles with the Darzens reaction. Second,
a Lewis acid mediated rearrangement of these epoxynitriles
with lithium bromide was achieved to give homologated
secondary alkanoic acids (as well as aryl-alkanoic) in good
yields. The mechanism and the scope of the rearrangement
reaction were investigated. This strategy constitutes a two-
step homologation of ketones to secondary carboxylic acids.
SCHEME 2. Attem p ted Rea r r a n gem en t of
Ep oxyn itr ile 3
Secondary alkanoic acids are found in bile acids, as
well as several important nonsteroidal antiinflammatory
agents (e.g ibuprofen). We were interested in preparing
quantities of SB-207499 by an efficient strategy. SB-
2
07499 is in clinical trails for COPD (chronic obstructive
pulmonary disease) and asthma. One approach to this
secondary cyclohexane carboxylate (Figure 1) could be
homologation of a cyclohexanone precursor.
epoxynitrile from a ketone by using the Darzens reaction9
followed by rearrangement to give the secondary car-
boxylic acid. This methodology has been successfully
demonstrated by White.10
There are various methodologies in the literature for
the homologation of a ketone to a secondary carboxylic
acid in two or three steps. Representative methodologies
Initially we focused our attention on White’s conditions
for alkyl-substituted epoxynitriles and their conversion
to aliphatic secondary acids (Scheme 1). We successfully
prepared epoxynitrile 3 in 73% yield (Scheme 2) under
1
have involved intermediates such as enol ethers, epox-
2
3
4
ides, cyanohydrins, R,â-unsaturated sulfones, ketene
5
6
7
thioacetals, glycidic esters, nitriles, and R-acetoxyacry-
lonitriles8 to add the one-carbon unit. These existing
methodologies have been limited by their high cost or low
efficiency and throughput for a scalable process. One
underutilized strategy has been the formation of an
11
modified phase transfer conditions. However, in at-
tempting to use White’s conditions (Scheme 1) to give the
acid 1a , exposure to anhydrous HCl resulted in decom-
position of compound 3 without formation of White’s
disclosed intermediates.
Thus we tried other conditions for rearrangement of 3
which did not require strong acid. In the same publica-
tion, White had disclosed conditions specific for rear-
rangement of aryl-substituted epoxynitriles (Scheme 3).
White’s synthetic approach for aryl-substituted epoxy-
nitriles was very attractive, since it involved a one-pot
rearrangement of the aryl precursors. However, applica-
tion of this methodology failed with our dialkyl-substi-
tuted epoxynitrile 3. For example, with White’s Lewis
*
To whom correspondence should be addressed. Fax: 610 270 4829.
Department of Synthetic Chemistry.
Department of Analytical Chemistry.
†
‡
(
(
(
1) Levine, S. G. J . Am. Chem. Soc. 1958, 80, 6150.
2) Corey, E. J .; Chaykovsky, M. J . Am. Chem. Soc. 1962, 84, 867.
3) (a) Eliel, E. L.; Freeman, J . P. Organic Syntheses; Wiley: New
York, 1963; Collect. Vol. IV, p 58. (b) Ruzicka, L.; Plattner, P. A.;
Heusser, H.; Meier, K. Helv. Chim. Acta 1947, 30, 1342.
(
4) Sch o¨ llkopf, U.; Schroder, R. Angew. Chem., Int. Ed. Engl. 1972,
1, 311.
5) Christensen, S. B.; Guider, A.; Forster, C. J .; Gleason, J . G.;
1
(
Bender, P. E.; Karpinski, J . M.; DeWolf, W. E., J r.; Barnette, M. S.;
Underwood, D. C.; Griswold, D. E.; Cieslinski, L. B.; Burman, M.;
Bochnowicz, S.; Osborn, R. R.; Manning, C. D.; Grous, M.; Hillegas, L.
M.; O’Leary Bartus, J .; Ryan, M. D.; Eggleston, D. S.; Haltiwanger, R.
C.; Torphy, T. J . J . Med. Chem. 1998, 41, 821.
4 3 4
acids, LiClO , Li(OOCCF ), and KHSO in toluene or
(9) Rosen, T. Compr. Org. Synth. 1991, 2, 409.
(
(
(
6) Newman, M. S.; Magerlein, B. J . Org. React. 1949, 5, 413.
7) Oldenziel, O. H.; van Leusen, A. M. Tetrahedron Lett. 1973, 1357.
8) J onczyk, A.; Fedorynski, M.; Zdrojewski, T. Polish J . Chem. 1997,
(10) (a) White, D. R.; Wu, D. K. J . Chem. Soc., Chem. Commun.
1974, 988. (b) White, D. R. U.S. Patents 3994964, 397431, and 4021478.
(11) J onczyk, A.; Fedorynski, M.; Makosza, M. Tetrahedron Lett.
1972, 2395.
7
1, 941.
1
0.1021/jo025737g CCC: $22.00 © 2002 American Chemical Society
Published on Web 06/21/2002
5
440
J . Org. Chem. 2002, 67, 5440-5443

TABLE 1. P r ep a r a tion of Ep oxyn itr ilesa
SCHEME 3. Wh ite’s Meth od ology for
Ar yl-Su bstitu ted Ep oxyn itr iles
SCHEME 4. Rea r r a n gem en t of Ep oxyn itr ile 3
xylene at reflux resulted in recovery of starting material.
We therefore extended our studies to other Lewis acids
and solvents with the hope that they could be applied to
substrate 3.
Ultimately we found a set of conditions that did work
for this pivotal transformation. The combination of
lithium bromide (or magnesium bromide) in DMF, aceto-
nitrile, and a small amount of water efficiently trans-
formed the cyclohexyl-epoxynitrile 3 into acids 112 in 75%
yield (Scheme 4). Moreover, we were successful in car-
rying out the above conversion of precursor 3 to SB-
2
07499 in the pilot plant.
Intrigued by this result, we wanted to see how general
this new rearrangement methodology was for other
alkyl-, alkenyl-, or aryl-substituted epoxynitriles. A selec-
tion of epoxynitriles 7-12 were synthesized (Table 1)
1
3
14
according to the methods of Stork, Svoboda, or Mon-
gelli.15 In the case of epoxynitrile 10 the reported method
a
All yields are isolated.
(
solid NaOH) was too slow in our hands to be practical,16
therefore the method implemented by Stork was used.
In all of these examples the epoxynitriles 7-12 could be
isolated in good yield. Epoxynitriles 7-12 were formed
as mixtures of cis and trans isomers. The mixtures were
treated under our rearrangement conditions (LiBr, DMF,
CH CN, H O, 90-95 °C, 24 h); we were pleased to find
3 2
that in most cases good yields of the secondary carboxylic
acids were obtained (Table 2).
In the case of compound 7 the cis- and trans-epoxyni-
triles were separated. Rearrangement of both isomers
separately gave identical results (products/reaction times).
This result suggested a mechanism that involved a
common intermediate for the rearrangement of both cis-
and trans-epoxynitriles. Most substrates showed com-
plete reaction within 12-24 h, with very few impurities
observed. Hydrogen cyanide was liberated as a byproduct
of the rearrangement and care was taken when handling
the reaction and subsequent workup and disposal of
waste.
Increasing the steric bulk R to the epoxynitrile proved
deleterious and no reaction was observed for either the
isopropyl epoxynitrile 11 or the tert-butyl epoxynitrile 12.
Starting material was recovered in either case. These
results suggested that steric factors are critical. It was
(
12) Allen, A.; Diederich, A. M.; Mendelson, W.; Liu, L. PCT Int.
Appl. 1998, 9834584.
13) Stork, G.; Worrall, W. S.; Pappas, J . J . J . Am. Chem. Soc. 1960,
2, 4315.
14) Svoboda, J .; Kocfeldova, Z.; Palecek, J . Collect. Czech. Chem.
Commun. 1988, 53, 822.
15) Mongelli, N.; Animati, F.; D’Alessio, R.; Zuliani, L.; Gandolfi,
C. Synthesis 1988, 310.
16) Zakharova, N. I.; Gutnikova, N. P.; Bekker, A. R.; Filippova,
T. M.; Miropol’skaya, M. A.; Samokhvalov, G. I. J . Org. Chem. USSR
Engl. Trans.) 1986, 21, 1870.
(
8
(
(
(
(
J . Org. Chem, Vol. 67, No. 15, 2002 5441

TABLE 2. Rea r r a n gem en t P r od u cts fr om th e
SCHEME 5. P r op osed Mech a n ism for th e
Rea r r a n gem en t of Bisa lk yl-Su bstitu ted
Ep oxyn itr iles
a
Ep oxyn itr iles
SCHEME 6. P r op osed Mech a n ism for F or m a tion
of Com p ou n d 16
acid (Lewis acid promoted ring opening/hydride shift) it
would be expected that epoxynitriles 11 and 12 would
rearrange readily to give acid products. This was not
observed, thus this alternative mechanism is considered
unlikely.
Water was found to be essential for the rearrangement
reaction. We believe it is required to hydrolyze the
proposed intermediate acyl-nitriles, e.g. compound 19
(Scheme 5). In the absence of water, acyl-nitrile dimer
products were formed almost exclusively instead of the
acid product. Such dimers are known to be formed from
acyl-nitriles in the presence of HCN.19 To ensure acid
product formation, water (1.5-3.0% w/w) was added at
the start of the reaction, leading to the desired transfor-
mation of epoxynitrile to acid rather than producing
unwanted dimer products.
When the rearrangement was extended to an R,â-
unsaturated epoxynitrile 10, the desired acid product was
not formed. Instead, a rather unstable R,â,γ,δ-unsatur-
ated aldehyde 16 was isolated (1:1 mixture of cis and
trans isomers) (Scheme 6). Isolation of the unsaturated
aldehydes indicated that the double bond in epoxynitrile
10 had participated in the rearrangement.
a
All yields are isolated.
also found that aryl-substituted epoxynitriles rearrange
to give acids. Thus, compound 8 rearranged to give
ibuprofen (14).17 A proposed mechanism for the rear-
rangement is given for the bisalkyl-substituted epoxyni-
triles in Scheme 5.
In our proposed mechanism, bromide attacks the
epoxide at the quaternary position either in a S 1 or S 2
N N
fashion to give intermediate 17, which then undergoes
loss of elements of HBr to give the enol or enolate 18.
This enol or enolate may be protonated to give compound
9, which undergoes hydrolysis in situ to give compound
5. In support of the mechanism, in the case of compound
, intermediates were isolated and identified in which
Our proposed mechanism for formation of compound
16 (Scheme 6) is consistent with the results found with
1
1
3
2
0
3 4
Ph SiClO for selective isomerization of glycidates.
We have developed a strategy for the two-step homolo-
gation of ketones to secondary carboxylic acids. This
1
8
bromide had added to the dialkyl portion of the epoxide.
Also if the lithium bromide was acting only as a Lewis
(
19) For example: (a) Tate, B. E.; Bartlett, P. D. J . Am. Chem. Soc.
(
17) Ebbers, E. J .; Ariaans, G. J . A.; Bruggink, A.; Zwanenburg, B.
Tetrahedron: Asymmetry 1999, 10, 3701.
18) This compound gave satisfactory analysis by NMR and mass
spectroscopy.
1956, 78, 5575. (b) Oku, A.; Nakaoji, S.; Kadono, T.; Imai, H. Bull.
Chem. Soc. J pn. 1979, 52, 2966.
(20) Torii, S.; Inokuchi, T.; Kusumoto, M.; Matsumoto, S.; Okada,
H. Chem. Lett. 1991, 2009.
(
5
442 J . Org. Chem., Vol. 67, No. 15, 2002

efficient protocol produces secondary carboxylic acids in
good to high yield. The rearrangement reaction is unfa-
vorable for alkyl-ketones with hindered aliphatic sub-
stituents R to the epoxynitrile. The course of the rear-
rangement was found to be different in the case of an
R,â,γ,δ-unsaturated epoxynitrile. Finally, water was
found to be essential for the rearrangement reaction. In
its absence, the secondary carboxylates are not produced.
with 3 N HCl. This was then extracted with ether. The organic
layers were combined and dried with Na SO . The solution was
2
4
filtered and concentrated in vacuo. The crude mixture was
chromatographed on silica gel (ether:hexane 2:3) to give 2-meth-
yl-heptanoic acid (13) (0.296 g, 62.8%) as a colorless oil. These
22
data are consistent with published data.
2
-Meth ylh ep ta n oic a cid (13): IR (neat) 3100-2500, 1708,
-
1
1
1243 cm ; H (400 MHz, CDCl
3
) δ 2.48 (1H, m), 1.69 (1H, m),
1.46 (1H, m), 1.30 (6H, m), 1.18 (3H, d, J ) 7.0 Hz), 0.90 (3H, t,
1
3
J ) 6.8 Hz); C (100 MHz, CDCl
3
) δ 183.62, 39.39, 33.46, 31.65,
6.76, 22.44, 16.76, 13.95, 13.92. Anal. Calcd for C : C,
6.63; H, 11.18. Found: C, 66.76; H, 10.89.
2
6
8 16 2
H O
Exp er im en ta l Section
Rea r r a n gem en t of a n r,â-Un sa tu r a ted Ep oxyn itr ile.
-[Cycloh ex-2-en yl]id en ep r op a n a l (16): A solution of 2,3-
Wa r n in g: Hydrogen cyanide will be released in the rear-
rangement of epoxynitriles 3 and 7-12. All cyanide safety
precautions should be taken during handling of reaction solu-
tions, purification, and waste disposal of contaminated materials.
Rep r esen ta tive Da r zen s Rea ction . 2,3-Ep oxy-3-m eth yl-
octa n en itr ile (7): To a solution of 2-heptanone (5.74 g, 7.0 mL,
2
epoxy-3-[cyclohex-1-enyl]butanenitrile (11) (2.00 g, 12.3 mmol),
LiBr (2.10 g, 24.18 mol), DMF (10 mL), CH CN (10 mL), and
O (0.45 mL, 25.0 mmol) was stirred overnight at 91 °C. The
reaction was cooled, diluted with Et O, and washed with H
and then dried over Na SO . The solution was filtered and
3
H
2
2
2
O
5
2
0.3 mmol) and ClCH CN (3.82 g, 3.2 mL, 50.6 mmol) was added
2
4
concentrated in vacuo. The crude reaction mixture was chro-
matographed on silica gel (ether:pentane 1:9) to give an unstable,
colorless oil, 2-[cyclohex-2-enyl]idene-propanal (16) (0.320 g,
dropwise potassium tert-butoxide (1 M in t-BuOH, 50.3 mL, 50.3
mmol) over 45 min. The reaction was stirred overnight under
nitrogen at ambient temperature. The reaction solution was then
filtered through a plug of silica gel, which was then washed with
ether. The crude mixture was concentrated in vacuo and
chromatographed on silica gel (ether:hexane 1:9) to give 2,3-
epoxy-3-methyloctanenitrile (7) (5.217 g, 68.2%) as a colorless
-
1
1
9.2%). IR (neat) 1664, 1648, 1612, 1582 cm
cis-2-[Cycloh ex-2-en yl]id en ep r op a n a l: 1H (400 MHz,
CDCl ) δ 10.26 (1H, s), 7.16 (1H, dt, J ) 2.1, 10.4 Hz), 6.17 (1H,
m), 2.47 (2H, m), 2.18 (2H, m), 1.76 (2H, m), 1.72 (3H, d, J )
.
3
2
1
13
oil. These data are consistent with published data.
cis-2,3-Ep oxy-3-m eth ylocta n en itr ile: IR (neat) 2245, 1250
3
0.8 Hz); C (100 MHz, CDCl ) δ 189.82, 151.90, 136.80, 129.72,
122.25, 28.35, 25.71, 21.73, 10.47.
cm- ; H (400 MHz, CDCl
(
1
1
) δ 3.23 (1H, s), 1.76 (2H, m), 1.54
tr a n s-2-[Cycloh ex-2-en yl]id en ep r op a n a l: 1H (400 MHz,
3
1
3
2H, m), 1.38 (3H, s), 1.36 (4H, m), 0.93 (3H, t, J ) 9.9 Hz);
100 MHz, CDCl ) δ 116.29, 63.55, 47.62, 34.53, 31.53, 24.84,
2.42, 19.96, 13.86. Anal. Calcd for C 15NO: C, 70.55; H, 9.87;
C
CDCl ) δ 10.16 (1H, s), 6.54 (1H, dt, J ) 2.1, 10.1 Hz), 6.27 (1H,
3
1
3
(
3
m), 2.84 (2H, m), 2.22 (2H, m), 1.76 (2H, m), 1.74 (3H, s);
C
2
9
H
(100 MHz, CDCl ) δ 191.14, 150.30, 139.11, 129.35, 126.65,
3
N, 9.14. Found: C, 70.44; H, 9.87; N, 9.14.
26.27, 24.68, 22.37, 9.82. Due to the compound’s instability, CHN
analysis was not possible.
tr a n s-2,3-Ep oxy-3-m eth ylocta n en itr ile: IR (neat) 2245,
-
1
1
1
1
250 cm ; H (400 MHz, CDCl
.54 (3H, s), 1.39 (6H, m), 0.90 (3H, t, J ) 6.9 Hz); C (100 MHz,
) δ 116.43, 63.55, 46.87, 36.12, 31.46, 24.44, 22.42, 18.49,
3.86. Anal. Calcd for C 15NO: C, 70.55; H, 9.87; N, 9.14.
3
) δ 3.23 (1H, s), 1.61 (2H, m),
13
Ack n ow led gm en t. We thank Professor A. I. Meyers
for helpful suggestions and discussions during this
work.
CDCl
1
3
9
H
Found: C, 70.26; H, 9.74; N, 9.21.
Rep r esen ta tive Rea r r a n gem en t Rea ction . 2-Meth ylh ep -
ta n oic a cid (13): 2,3-Epoxy-3-methyloctanenitrile (7) (0.500 g;
Su p p or tin g In for m a tion Ava ila ble: Procedures for the
preparation and full characterization of compounds 1, 3, 8-12,
14, and 15. This material is available free of charge via the
Internet at http://pubs.acs.org.
3
.26 mmol), LiBr (0.426 g, 4.90 mmol), CH
2.5 mL), and H O (110 µL, 6.11 mmol) were heated and stirred
overnight at 91 °C. The reaction was then cooled and diluted
with EtOAc and washed with H O. The aqueous layer was
separated and the pH of the aqueous layer was adjusted to 2
3
CN (2.5 mL), DMF
(
2
2
J O025737G
(
21) Mongelli, N.; Animati, R. D.; Zuliani, L.; Gandolfi, C. Synthesis
(22) Aurell, M. J .; Domingo, L. R.; Mestres, R.; Munos, E.; Zaragoza,
R. J . Tetrahedron 1999, 55, 815.
1
988, 310.
J . Org. Chem, Vol. 67, No. 15, 2002 5443