Annulations via dianions: Formation of five-, six- and seven-membered rings

Article abstract of DOI:10.1055/s-2005-864836

Phosphonium salts bearing an electron-withdrawing group at the γ-position form dianions that react with bis-electrophiles to generate five-, six-, and seven- membered rings.

Full text of DOI:10.1055/s-2005-864836

LETTER
951
Annulations via Dianions: Formation of Five-, Six- and Seven-Membered
Rings
A
G
nnulations via
D
e
ianions orge A. Kraus,* Sarathy Kesavan
Department of Chemistry, Iowa State University, Ames, IA 50011, USA
E-mail: gakraus@iastate.edu
Received 18 January 2005
chemistry of dianions has been collated into a useful book
and a comprehensive review.13
Abstract: Phosphonium salts bearing an electron-withdrawing
group at the g-position form dianions that react with bis-electro-
philes to generate five-, six-, and seven- membered rings.
We prepared phosphonium salts 4a and 4b by the reaction
of triphenylphosphine with 4-bromobutyronitrile or ethyl
4
Key words: dianions, bis-electrophiles, annulation
-bromobutyrate (Figure 2).14 In the dianion derived by
reaction of 4a or 4b with a strong base, the nitrile or ester
anion should be the more reactive anion. This is supported
As part of a program to develop terpene-based antiviral
1
by many reports of ylide formation from either 4a or 4b
agents, we needed an efficient synthetic route to natural
with one equivalent of base.1
5–17
The dianions from
products such as illudin S (1) and pseudolaric acid (2).2
,3
phosphonium salts 4a and 4b were generated using either
lithium diisopropylamide (LDA) or lithium tetramethylpi-
peridide (LiTMP) at temperatures ranging from –78 °C to
In the case of compound 1, the well-documented acid la-
bility of cyclopropyl carbinols plus the ready availability
of 1,1-diacetylcyclopropane led us to evaluate a [3+3] an-
nulation route. We report herein that alcohols such as 3
can be readily generated by the dianion-based annulation
described below (Figure 1).
–
20 °C. With either 4a or 4b, the use of LiTMP at –20 °C
afforded significantly better yields than LDA.
Br–
G
4a G = CN
O
O
Ph P
4b G = CO Et
3
2
G
HO
Me
HO
CO2H Me
O
Figure 2
OH
OH
OH
Me
HO2C
Me
The reactions of 4a and 4b with base and 1,3-diketones
are illustrated in Table 1. In addition to studying the reac-
tions of 4a and 4b with 1,1-diacetylcyclopropane, we also
studied reactions with 2,2-diacetylpropane and 1,1-diace-
tylcyclopentane. The isolated yields obtained through our
optimized conditions are good and the one-step reaction is
direct and amenable to scale up to prepare gram quantities
of products.
1
2
3
Figure 1
Most 4-acyl cyclohexenes are prepared by Diels–Alder
reactions. There are only a few examples where these
compounds are prepared by bringing together two three-
carbon units. Moohoff has reacted unsaturated aldehydes
4
5
with b-keto phosphonates to form cyclohexenones. Na- Hydroxy ester 5a was a mixture of diastereomers in a ratio
jera has used dianions of sulfones to generate six-mem- of 5:1, as evidenced by proton NMR. Hydroxy nitrile 5b
6
bered rings. Mordini has reported a novel allylic stannane was a single compound as evidenced by a single methyl
7
reagent which functions as a dianion equivalent. Molan- resonance at d = 1.27 ppm. Hydroxy nitrile 5c was a 3:1
der has communicated an innovative approach to the syn- mixture of diastereomers. Compound 5d was also one
thesis of six-membered rings by use of a,b-epoxy stereoisomer.
aldehydes and iodomethyl-substituted allylic silanes.8
Ishikawa and coworkers have described a generally appli-
cable tandem Michael addition/Claisen cyclization proto-
col to generate six-membered rings in good to excellent
18
The readily available keto aldehyde 6 was also studied.
Reaction with the dianions of 4a and 4b followed by Jones
oxidation of the resulting alcohols provided 7a and 7b in
3% and 48% yields, respectively. Since the aldehyde is
the more electrophilic site, the production of 7a and 7b
confirms our assessment of the relative reactivity of the
dianions.
5
9
yields. Wade has reported the chemistry of 1,3-dinitro-
1
0
propane dianions. Recently, Bose and Langer reported
the reaction of 1,1-diacetylcyclopropane with dianions of
1
1
b-diketones. Seebach has reported a useful [3+3] cy-
12
With the experimental conditions optimized for the gener-
ation of six-membered rings, we next investigated the
synthesis of five- and seven-membered rings. The results
of the additions of the dianions of 4a and 4b to symmetri-
cal 1,2-dicarbonyl compounds are depicted below in
Table 2.
clization of a nitroallylic ester with enamines. The
SYNLETT 2005, No. 6, pp 0951–0954
0
6.
0
4.
2
0
0
5
Advanced online publication: 23.03.2005
DOI: 10.1055/s-2005-864836; Art ID: S00605ST
©
Georg Thieme Verlag Stuttgart · New York

9
52
G. A. Kraus, S. Kesavan
LETTER
Table 1 Six-Membered Ring Formation
Me
O
O
R
R'
G
PPh3Br
+ Base +
R
R'
HO
Me
G
G
Base (temp., °C)
LDA (–78)
R, R¢
Yield (%)
CO Et
CH CH
23
27
54
61
65
59
5a
5a
5a
5b
5c
5d
2
2
2
2
2
CO Et
LDA-HMPA (–78)
LiTMP (–20)
LiTMP (–20)
LiTMP (–20)
LiTMP (–20)
CH CH
2
2
CO Et
CH CH
2
2
CN
CN
CN
Me, Me
CH CH
2
2
CH CH CH CH
2
2
2
2
CN
CO2Et
O
O
ox.
ox.
4
a
4b
HO
CHO
Me
Ph
Me
Me
2
LiTMP
Me
2 LiTMP
Me
Me
Ph
6
Ph
7
a
7b
Scheme 1
The yields of cyclopentenols ranged from fair to very Tetrahydrofuran was distilled over sodium benzophenone ketyl. All
experiments were performed under an argon atmosphere unless oth-
good. Alcohols 8a–d were 1:1 mixtures of diastereomers,
erwise noted. Nuclear magnetic resonance measurements were per-
as shown by proton NMR.
formed with either a Varian 300 MHz or Bruker 400 MHz
We also evaluated the synthesis of seven-membered rings instrument. High resolution mass spectra were recorded on a Kratos
using phthalaldehyde. The results are depicted in Table 3. model MS-50 spectrometer and low resolution mass spectra were
performed with a Finnegan 4023 mass spectrometer. Standard grade
silica gel (60 Å) was used for flash column chromatography. H–EA
refers to hexane–ethyl acetate.
Unfortunately, attempts to conduct this chemistry with
1
,4-diketones such as 2,5-hexanedione led to mixtures of
products.
The results above demonstrate that cyclizations using General Procedure for the Synthesis of Hydroxy Esters or
Hydroxy Nitriles
dianions derived from 4a and 4b can generate five-, six-,
To a solution of phosphonium salt (1.0 equiv) in 3 mL THF/mmol
and seven-membered rings. The functionalized ring sys-
of salt at –78 °C was added a solution of LiTMP generated using tet-
tems produced by the dianion annulations will be useful
for the synthesis of natural products.
ramethylpiperidine (2.1 equiv) and n-BuLi (2.0 equiv, 2.5 M solu-
tion in hexane) in 3 mL of THF/mmol of tetramethylpiperidine. The
temperature was allowed to rise to –20 °C and stirred at –20 °C for
a period of 90 min. The solution was then cooled to –78 °C and 2,2-
diacetylpropane (0.82 equiv) in THF was added. The solution was
warmed to 0 °C and was stirred for 1 h. The reaction was quenched
Table 2 Five-Membered Ring Formation
O
R
R
with sat. NH Cl solution. The organic layer was extracted with Et O
R
4
2
G
PPh3Br
+
Base
+
R
O
OH
Table 3 Seven-Membered Ring Formation
G
H
G
Base
LDA
R
Yield (%)
CHO
ox.
G
PPh3Br
+ Base +
CN
CN
CN
CN
CN
Me
Me
Me
40
38
61
68
80
65
8a
CHO
G
LDA (HMPA)
LiTMP
8a
8a
8b
8c
8d
HO
G
Base (temp., °C)
LDA (–78)
Yield (%)
LiTMP
2-Furyl
Ph
CO
CO
CN
2
2
Et
Et
21
44
52
9a
LiTMP
LiTMP (–20)
LiTMP (–20)
9a
9b
CO Et
LiTMP
Ph
2
Synlett 2005, No. 6, 951–954 © Thieme Stuttgart · New York

LETTER
3 × 10 mL) and dried over MgSO . The crude product was purified
Annulations via Dianions
953
1
(
First isomer: H NMR (300 MHz, CDCl ): d = 7.44 (1 H, t, J = 1.5
4
3
by silica gel chromatography to afford the product.
Hz), 7.35 (1 H, s), 6.39 (1 H, d, J = 1.5 Hz), 6.33 (1 H, d, J = 1.2
Hz), 6.30 (1 H, t, J = 3.0 Hz), 3.50 (1 H, t, J = 8.7 Hz), 2.84–3.00 (2
Compound 5a
1
3
H, m). C NMR (75 MHz, CDCl ): d = 153.7, 148.1, 143.1, 142.8,
3
The crude product was purified on silica gel (H–EA = 5:1).
1
35.3, 126.7, 118.6, 111.5, 110.9, 108.1, 107.9, 83.0, 41.9, 34.4.
1
HRMS: m/z calcd for C H NO : 241.0739; found: 241.0746.
Major isomer: H NMR (300 MHz, CDCl ): d = 5.34 (1 H, m), 4.17
14 11
3
3
(
1
1 H, q, J = 7.2 Hz), 2.77 (1 H, d, J = 11.7 Hz), 2.33–2.41 (2 H, m),
.42 (3 H, m), 1.27 (3 H, t, J = 7.2 Hz), 1.25 (3 H, s), 1.01–1.1 (1 H,
1
Second isomer: H NMR (300 MHz, CDCl ): d = 7.34–7.38 (2 H,
3
m), 6.40–6.53 (1 H, m), 6.34–6.40 (2 H, m), 6.27–6.33 (1 H, m),
1
3
m), 0.80–0.90 (2 H, m), 0.49–0.52 (1 H, m). C NMR (75 MHz,
5
.98 (1 H, t, J = 3.0 Hz), 3.64 (1 H, t, J = 8.7 Hz), 2.98–3.02 (2 H,
CDCl ): d = 174.8, 136.2, 119.0, 70.1, 60.9, 49.3, 31.4, 27.7, 21.5,
13
3
m). C NMR (75 MHz, CDCl ): d = 152.7, 147.1, 143.1, 142.1,
3
1
9.0, 14.8, 8.3, 6.1.
1
34.3, 125.7, 117.6, 111.5, 110.9, 108.1, 107.9, 83.0, 41.9, 34.4.
1
Minor isomer: H NMR (300 MHz, CDCl ): d = 5.42 (1 H, br s),
3
Compound 8c
4
1
0
7
.18 (2 H, q, J = 7.2 Hz), 2.58–2.69 (2 H, m), 2.24–2.34 (1 H, m),
.42 (3 H, m), 1.30 (3 H, t, J = 7.2 Hz), 0.82–0.94 (1 H, m), 0.60–
The crude product was purified on silica gel (H–EA = 3:1).
.75 (3 H, m). 13C NMR (75 MHz, CDCl ): d = 175.0, 135.8, 119.3,
First isomer: H NMR (300 MHz, CDCl ): d = 7.18–7.45 (10 H, m),
1
3
3
1
3
0.3, 61.4, 49.0, 31.5, 26.4, 25.0, 19.0, 14.8, 8.3, 6.3. HRMS: m/z
6.45 (1 H, m), 3.38 (1 H, m), 2.70–2.98 (2 H, m). C NMR (75
calcd for C H O : 224.1412; found: 224.1415.
MHz, CDCl ): d = 146.2, 142.5, 132.9, 129.2, 128.9, 128.6, 128.2,
13
20
3
3
1
27.4, 127.2, 125.4, 119.1, 87.01, 46.3, 34.2. HRMS: m/z calcd for
Compound 5b
C H NO: 261.1154; found: 261.1156.
l8 l5
The crude product was purified on silica gel (H–EA = 5:1).
1
Second isomer: H NMR (300 MHz, CDCl ): d = 7.18–7.45 (10 H,
m), 6.40 (1 H, m), 3.58 (1 H, m), 2.71–2.98 (2 H, m). C NMR (75
MHz, CDCl ): d = 146.2, 143.5, 131.9, 129.1, 128.7, 128.6, 128.1,
1
3
1
H NMR (300 MHz, CDCl ): d = 5.04 (1 H, br s), 2.99 (1 H, dd,
13
3
J = 11.6 Hz, J = 6.0 Hz), 2.23–2.78 (2 H, m), 1.92–2.01 (2 H, m),
3
1
3
1
.51–1.81 (6 H, m), 1.38–1.50 (3 H, m), 1.27 (3 H, s). C NMR (75
27.4, 127.2, 125.4, 119.1, 87.01, 45.3, 33.2. HRMS: m/z calcd for
MHz, CDCl ): d = 142.5, 121.4, 115.8, 74.3, 53.9, 37.1, 36.4, 31.0,
3
C H NO: 261.1154; found: 261.1158.
l8 l5
2
2
8.8, 28.4, 27.8, 20.3, 19.8. HRMS: m/z calcd for C H NO:
13 19
05.1467; found: 205.1469.
Compound 8d
The crude product was purified on silica gel (H–EA = 4:1).
Compound 5c
1
First isomer: H NMR (300 MHz, CDCl ): d = 7.15–7.30 (10 H, m),
3
The crude product was purified on silica gel (H–EA = 5:1 to 3:1).
6
.45 (1 H, m), 3.71 (2 H, m), 3.57 (1 H, t, J = 8.4 Hz), 2.98–3.10 (1
1
Major isomer: H NMR (300 MHz, CDCl ): d = 5.32 (1 H, br s),
3
H, m), 2.71–2.22 (1 H, m), 0.95 (3 H, t, J = 7.2 Hz).
2
.92 (1 H, dd, J = 7.8, 4.5 Hz), 2.50–2.60 (1 H, m), 2.30–2.40 (1 H,
1
Second isomer: H NMR (300 MHz, CDCl ): d = 7.15–7.30 (10 H,
3
m), 1.42 (3 H, m), 1.32 (3 H, s), 1.00–1.10 (1 H, m), 0.80–0.95 (2
H, m), 0.60–0.70 (1 H, m). C NMR (75 MHz, CDCl ): d = 136.0,
1
3
m), 6.43 (1 H, m), 3.61–3.78 (2 H, m), 3.47 (1 H, t, J = 8.4 Hz),
3
2
.98–3.10 (1 H, m), 2.71–2.22 (1 H, m), 0.95 (3 H, t, J = 7.2 Hz).
1
20.9, 117.7, 70.3, 34.5, 28.6, 27.5, 24.2, 18.9, 8.3, 6.7. HRMS:
m/z calcd for C H NO: 177.1154; found: 177.1156.
11
15
General Procedure for the Synthesis of 7a, 7b, 9a or 9b
1
Minor isomer: H NMR (300 MHz, CDCl ): d = 5.40 (1 H, br s),
3
To a solution of phosphonium salt (1.0 equiv) in 3 mL THF/mmol
of salt at –78 °C was added a solution of LiTMP generated using tet-
ramethylpiperidine (2.1 equiv) and n-BuLi (2.0 equiv, 2.5 M solu-
tion in hexane) in 3 mL of THF/mmol tetramethylpiperidine. The
temperature of solution was allowed to rise to –20 °C and stirred at
2
.86 (1 H, t, J = 6.0 Hz), 2.50–2.52 (2 H, m), 1.45 (3 H, m), 1.23 (3
H, s), 1.13–1.20 (1 H, m), 0.78–0.90 (2 H, m), 0.68–0.72 (1 H, m).
1
3
C NMR (75 MHz, CDCl ): d = 136.5, 121.2, 117.5, 70.1, 38.6,
3
2
1
9.5, 28.2, 22.1, 18.9, 7.9, 7.4. HRMS: m/z calcd for C H NO:
77.1154; found: 177.1151.
11 15
–
–
20 °C for a period of 90 min. The solution was then cooled to
78 °C and 2,2-diacetylpropane (0.82 equiv) in THF was added.
Compound 5d
The solution was warmed to 0 °C and was stirred for 1 h. The reac-
The crude product was purified on silica gel (H–EA = 5:1).
tion was quenched with sat. NH Cl solution. The organic layer was
4
1
H NMR (300 MHz, CDCl ): d = 5.16 (1 H, br s), 3.13 (1 H, dd,
extracted with Et O (3 × 10 mL) and dried over MgSO . The crude
3
2
4
J = 11.6, 6.0 Hz), 2.18–2.50 (2 H, m), 1.64–1.64 (3 H, m), 1.32 (3
product was purified on silica gel to afford the product.
1
3
H, s), 1.08 (3 H, s), 1.04 (3 H, s). C NMR (75 MHz, CDCl ): d =
3
The crude product was flushed through a pad of silica to get crude
mixture. The mixture was dissolved in 4 mL of acetone and 2.7 M
Jones reagent (1.0 equiv) was added at 0 °C. After stirring for 30
min, it was quenched with 1 mL of i-PrOH. The solvent was evap-
1
41.72, 121.7, 116.7, 73.6, 42.5, 35.6, 28.4, 23.7, 20.6, 20.4, 19.5.
HRMS: m/z calcd for C H NO: 179.1310; found: 179.1312.
1
1
17
Compound 8a
orated, dissolved in 5 mL of H O and extracted with EtOAc (3 × 10
2
The crude product was purified on silica gel (H–EA = 4:1).
mL). The organic layer was dried with MgSO and the crude prod-
4
1
First isomer: H NMR (300 MHz, CDCl ): d = 5.49 (1 H, br s), 3.12
3
uct was purified by silica gel chromatography (H–EA = 5:1).
(
2 H, t, J = 6.7 Hz), 2.49–2.78 (2 H, m), 1.71–1.78 (3 H, m), 1.49 (3
1
3
Compound 7a
H, s). C NMR (75 MHz, CDCl ): d = 144.5, 125.2, 120.5, 84.4,
3
1
4
2.3, 33.6, 24.8, 11.9.
H NMR (300 MHz, CDCl ): d = 7.28–7.40 (3 H, m), 7.11–7.15 (2
3
1
H, m), 5.61 (1 H, dd, J = 5.7, 2.4 Hz), 4.06 (1 H, dd, J = 11.7, 6.7
Second isomer: H NMR (300 MHz, CDCl ): d = 5.39 (1 H, br s),
3
1
3
Hz), 2.71–3.03 (2 H, m), 1.42 (3 H, s), 1.25 (3 H, s). C NMR (75
MHz, CDCl ): d = 203.0, 147.9, 139.5, 129.3, 128.2, 128.1, 127.7,
22.0, 116.6, 48.8, 38.2, 30.2, 27.2, 22.8. HRMS: m/z calcd for
C H NO: 225.1157; found: 225.1157.
2
1
8
1
.98 (2 H, t, J = 6.7 Hz), 2.49–2.78 (2 H, m), 1.71–1.78 (3 H, m),
.49 (3 H, s). 13C NMR (75 MHz, CDCl ): d = 143.7, 122.9, 119.9,
3
3
1
3.1, 41.2, 33.5, 22.8, 11.7. HRMS: m/z calcd for C H NO:
37.0841; found: 137.0843.
8
11
1
5
l5
Compound 7b
Compound 8b
The crude product was purified on silica gel (H–EA = 4:1).
1
H NMR (300 MHz, CDCl ): d = 12.62 (1 H, s), 7.25–7.30 (3 H, m),
3
7
.15–7.18 (2 H, m), 5.51 (1 H, t, J = 3.6 Hz), 4.27 (2 H, q, J = 7.2
Hz), 3.01 (2 H, d, J = 3.6 Hz), 1.32 (3 H, t, J = 7.2 Hz), 1.29 (6 H,
Synlett 2005, No. 6, 951–954 © Thieme Stuttgart · New York

9
54
G. A. Kraus, S. Kesavan
LETTER
s). 13C NMR (75 MHz, CDCl ): d = 175.6, 172.7, 143.6, 141.4,
(5) Moorhoff, C.; Schneider, D. F. Tetrahedron Lett. 1987, 28,
559.
3
1
29.8, 127.5, 126.7, 122.3, 93.6, 60.5, 39.86, 25.7, 25.1, 14.4.
HRMS: m/z calcd for C H O : 272.1412; found: 272.1416.
(6) Najera, C.; Sansona, J. Tetrahedron 1994, 50, 3491.
1
7
20
3
(
7) Innocenti, A.; Dembech, P.; Mordini, A.; Ricci, A.; Seconi,
G. Synthesis 1991, 267.
8) Molander, G.; Shubert, C. J. Am. Chem. Soc. 1987, 109, 576.
Compound 9a
It was purified on silica gel using (H–EA = 3:1).
(
1
(9) Ishikawa, T.; Kadoya, R.; Arai, M.; Takahashi, H.; Kaisi, Y.;
H NMR (300 MHz, CDCl ): d = 7.98 (1 H, t, J = 6.0 Hz), 7.23–7.43
3
Mizuta, T.; Yoshikai, K.; Saito, S. J. Org. Chem. 2001, 66,
(3 H, m), 6.57 (1 H, d, J = 7.5 Hz), 6.17–6.24 (1 H, m), 4.28 (2 H,
8000.
q, J = 7.2 Hz), 2.60 (1 H, d, J = 5.1 Hz), 1.34 (3 H, t, J = 7.2 Hz).
1
3
(10) Wade, P. A.; Kondracki, P. A.; Carroll, P. J. J. Am. Chem.
Soc. 1991, 113, 8807.
11) Bose, G.; Langer, P. Tetrahedron Lett. 2004, 45, 3861.
12) Seebach, D.; Missbach, M.; Calderari, G.; Eberle, M. J. Am.
Chem. Soc. 1990, 112, 7625.
C NMR (75 MHz, CDCl ): d = 171.8, 167.5, 137.7, 134.0, 133.2,
3
1
29.8, 129.7, 129.5, 128.7, 126.6, 102.0, 61.2, 21.6, 14.5. HRMS:
(
(
m/z calcd for C H O : 230.0943; found: 230.0948.
l4 14
3
Acknowledgment
(13) (a) Thompson, C. M. Dianion Chemistry in Organic
Synthesis; CRC Press: Boca Raton, 1994. (b) Langer, P.;
Freiburg, W. Chem. Rev. 2004, 104, 4125.
We thank Iowa State University for partial support of this research.
(
14) Cristau, H. J.; Beziat, Y.; Niangoran, C. E.; Christol, H.
Synthesis 1987, 648.
15) Turos, E.; Boy, K.; Ren Xiao, F. J. Org. Chem. 1992, 57,
References
(
(
(
1) Kraus, G. A.; Ogutu, H. Tetrahedron 2002, 58, 7391.
2) Matsumoto, T.; Shirahama, H.; Ichikara, A.; Fukuoka, Y.;
Takahashi, Y.; Mori, Y.; Watanabe, M. Tetrahedron 1965,
6667.
(16) Beaulieu, P. L.; Duceppe, J. S.; Johnson, C. J. Org. Chem.
1991, 56, 4196.
2
1, 2671.
(17) Beaulieu, P. L.; Schiller, P. W. Tetrahedron Lett. 1988, 29,
2019.
(18) Inukai, T.; Yoshizawa, R. J. Org. Chem. 1967, 32, 404.
(
(
3) Xu, R.-S. Stud. Nat. Prod. Chem. 2000, 21, 729.
4) Evans, D. A.; Johnson, J. S. In Comprehensive Asymmetric
Catalysis; Jacobsen, E. N.; Pfaltz, A.; Yamamoto, H., Eds.;
Springer: New York, 1999, Vol. 3, 1177.
Synlett 2005, No. 6, 951–954 © Thieme Stuttgart · New York