In situ generation and nucleophilic capture of 1,n-dial equivalents from 1,n-dioates (α,ω-diesters)

Article abstract of DOI:10.1055/s-2006-926465

A procedure is described for the in situ generation of functional equivalents of glutaric, succinic, and malonic dialdehydes. DIBAL-H reduction of the corresponding 1,n-dioates followed by in situ addition of a nucleophilic trapping agent allows for one-p

Full text of DOI:10.1055/s-2006-926465

1572
SHORT PAPER
In situ Generation and Nucleophilic Capture of 1,n-Dial Equivalents from
1,n-Dioates (a,w-Diesters)
1
, n-Dial Equiva
h
lents from
a
o
,
w
-Diesters mas R. Hoye,* Lucas C. Kopel, Troy D. Ryba
Department of Chemistry, University of Minnesota, Minneapolis, Minnesota 55455, USA
Fax +1(612)6267541; E-mail: hoye@chem.umn.edu
Received 15 November 2005
cess of a compatible trapping nucleophile (Nu-Met).
Abstract: A procedure is described for the in situ generation of
functional equivalents of glutaric, succinic, and malonic dialde-
hydes. DIBAL-H reduction of the corresponding 1,n-dioates fol-
lowed by in situ addition of a nucleophilic trapping agent allows for
Species 5 (Scheme 1) contains a pair of tetrahedral inter-
mediates, which we envisioned collapsing to aldehydes,
upon warming, at different moments in time. If each reac-
one-pot, bidirectional homologation. Olefination and Grignard ad- tive aldehyde, once exposed, was rapidly trapped by Nu-
dition classes of reactions are specifically demonstrated.
Met, then species 7 would arise via 6 without the interven-
tion of 1 or 2 (and the associated issues). Previous reports
in which simple monoesters have been subjected to
DIBAL-H/Horner–Emmons,1 DIBAL-H/Mukaiyama al-
dol,2 DIBAL-H/Grignard,3 and LiBH4/Grignard4 tandem
reactions, provided precedent. Here we report results that
demonstrate this strategy.
Key words: nucleophilic additions, hydrides, reductions, tandem
reactions, Wittig reactions
The two aldehyde groups in 1,n-dials, especially those of
the succinic and glutaric families (1, Figure 1), are notori-
ous for their tendencies to engage one another through in-
tramolecular reaction. This phenomenon influences
reactivity at the second aldehyde, a requirement for sym-
metrical chain elongation. Internal hydrate formation (see
2, Figure 1) or addition of a nucleophilic species (Nu–) to
one of the free aldehydes and subsequent intramolecular
adduct formation with the second (cf., 3, Figure 1) are
common examples of this situation. One strategy for cir-
cumventing these problems is to expose the two aldehyde
functional groups sequentially, rather than in parallel.
While this is cumbersome and inefficient if it requires
protecting group or oxidation-state differentiation of the
two termini (i.e., multiple manipulations), a viable in situ
release of each aldehyde in the presence of a suitable trap-
ping nucleophile would not suffer from these drawbacks.
O
O
Product
R1O
OR1
n
4
Met
Nu
Met
Nu
O
O
DIBAL-H (2 equiv)
–78 °C
n
7
Met
Nu
AlBu2
OR1
Bu2Al
R1O
AlBu2
O
1) Nu-Met
(2.2 equiv)
O
O
O
OR1
2) warm
n
n
5
6
Scheme 1
HO
O
OH Nu
O
OH
OHC
CHO
R1O2C
CO2R1
We chose to study (Scheme 2) double Horner–Emmons (4
→ 10) and double Grignard additions (4 → 11) using
phosphonates 8 and allylmagnesium chloride (9) as repre-
sentative trapping nucleophiles, Nu-Met.
0,1
0,1
0,1
0,1
1
2
3
4
Figure 1
O
O
We recently encountered the need to chain extend, in a
symmetrical fashion, various 3-oxygenated glutaralde-
hydes. With that and the above issues in mind, we consid-
ered whether a one-pot reduction–addition reaction
sequence would provide a solution. In particular, we
planned for an a,w-diester 4 to be treated sequentially and
at low temperature first, with two equivalents of diisobu-
tylaluminum hydride (DIBAL-H) and second, with an ex-
R1O
OR1
n
4
1) DIBAL-H, –78 °C
2) CH2=CHCH2MgCl 9
3) warm
2) (R2O)2P(O)CH(Na)CO2R2
8
3) warm
O
O
OH OH
R2O
OR2
n
n
10
11
SYNTHESIS 2006, No. 10, pp 1572–1574
x
x.
x
x
.
2
0
0
6
Advanced online publication: 27.04.2006
DOI: 10.1055/s-2006-926465; Art ID: M07605SS
© Georg Thieme Verlag Stuttgart · New York
Scheme 2

SHORT PAPER
1,n-Dial Equivalents from a,w-Diesters
1573
then warmed to r.t. and stirred for 2 h. Water (ca. 30 mL) and a sat-
urated solution of Rochelle’s salt (ca. 30 mL) were added and the
resulting mixture was stirred until the two layers were homoge-
neous. The aqueous layer was extracted with EtOAc (3 ×). The
combined organic layers were dried over Na2SO4. The solvent was
removed in vacuo, and the resulting material was purified via flash
chromatography (25% EtOAc–75% hexanes) to provide the di-
enoate product (1.48 g, 6.16 mmol, 91%).
The essential results are summarized in Table 1. Succi-
nate (entries 1 and 2) and glutarate (entries 3–5) esters
were excellent substrates and gave the corresponding di-
enoate esters 10 or 1,n-diols 11 in very good to excellent
yields. Of particular interest because of our more specific
motivation, the 3-triethylsilyloxyglutarate ester shown in
entry 5 was also well tolerated, without complication from
elimination reactions. Finally, the strategy is applicable to
malonate esters (entries 6 and 7), but not without compe-
tition from other events (see Table 1, note c). Thus, the
procedure is even applicable to the particularly challeng-
ing malonaldehyde case (i.e., for rapid preparation of 1,3-
dienes and -diols like those shown for products in entries
Triethyl Phosphonoacetate Sodium Salt (8-Et); Typical Proce-
dure
Triethyl phosphonoacetate (4.1 mL, 20 mmol) was added to a sus-
pension of NaH (0.46 g, 19 mmol) in THF (40 mL) at 0 °C. The
mixture was stirred until the evolution of H2 gas ceased (£10 min).
At this time the solution had become homogeneous. No-D 1H NMR
6 or 7), as long as lower efficiencies are acceptable. We analysis5 confirmed that a small amount of starting, non-deprotonat-
ed triethyl phosphonoacetate remained. In the case of entry 5, ex-
did not attempt to optimize this dimethyl malonate reac-
cess NaH remaining after sodiophosphonoacetate generation led to
tion.
decomposition of the desired product. It therefore was necessary to
In conclusion, we have provided a convenient way to
symmetrically elongate 1,n-dial equivalents via sequen-
tial reduction of the corresponding 1,n-dioates and addi-
tion of an appropriate nucleophile.
use a slight excess (0.05 equiv) of phosphonoacetate relative to
NaH.
Undeca-1,10-diene-4,8-diol (Entry 4); Typical Procedure
A solution of DIBAL-H in toluene (5.0 mL, 7.5 mmol) was slowly
added (over ca. 7 min) to a solution of dimethyl glutarate (0.50 mL,
3.4 mmol) in Et2O (13.6 mL) at –78 °C under N2. The internal tem-
perature was maintained below –70 °C. The mixture was stirred for
30 min at –78 °C. A solution of allylmagnesium chloride in Et2O
(3.7 mL, 7.5 mmol) was added at –78 °C. The reaction mixture was
then warmed to r.t. and stirred for 2 h. The mixture was quenched
with sat. NH4Cl solution at 0 °C. A saturated solution of Rochelle’s
salt was added at r.t., and the two-phase mixture was stirred for ap-
proximately 8 h. The aqueous layer was extracted with EtOAc (3 ×).
The combined organic layers were dried over Na2SO4. The solvent
was removed in vacuo, and the resulting material was purified via
(2E,7E)-Diethyl Nona-2,7-dienedioate (Entry 3); Typical Proce-
dure
A solution of DIBAL-H in toluene (10.0 mL, 15 mmol) was slowly
added (over ca. 15 min) to a solution of dimethyl glutarate (1.0 mL,
6.8 mmol) in Et2O (27 mL) at –78 °C under N2. The internal tem-
perature was maintained below –70 °C (internal temperature
probe). The mixture was stirred for 30 min at –78 °C. A solution of
the phosphonoacetate anion (20 mmol, preparation described be-
low) was added via cannula at –78 °C. The reaction mixture was
Table 1 Results of Sequential Reaction of Starting Diesters with i) DIBAL-H and ii) Either Phosophonate Anion 8 or Allylmagnesium Chlo-
ride (9)
Entry
1
Starting diester
Nucleophilea
8-Et
Product
Yield (%)b
75
Comments
EtO2C
EtO2C
94:6
(E,E:E,Z)
CO2Etn
CO2Et
2
9
73
dr ca. 1:1
(13C NMR)
OH
EtO2C
CO2Et
OH
3
4
8-Et
9
91
71
95:5
(E,E:E,Z)
EtO2C
CO2Et
MeO2C
MeO2C
CO2Me
dr ca. 1:1
(13C NMR)
CO2Me
OH
OH
5
OTES
8-Me
87
98:2
(E,E:E,Z)
OTES
MeO2C
MeO2C
MeO2C
CO2Me
MeO2C
EtO2C
CO2Me
6c
7
8-Et
9
18
41
–
CO2Et
CO2Me
CO2Me
dr ca. 1:1
(13C NMR)
OH OH
a See Scheme 2.
b Isolated following purification by silica gel chromatography.
c Varying ratios of deconjugated (1,4-) and conjugated (1,3-) dienes were obtained; isomerization to the latter, more stable isomer generally
occurred upon handling and storage.
Synthesis 2006, No. 10, 1572–1574 © Thieme Stuttgart · New York

1574
T. R. Hoye et al.
SHORT PAPER
flash chromatography (50% EtOAc–50% hexanes) to provide the
desired product (0.44 g, 2.4 mmol, 71%).
13C NMR (125 MHz, CDCl3): d = 166.7, 145.0, 123.5, 70.1, 51.5,
40.1, 6.9, 4.9.
HRMS (ESI): m/z [M + Na]+ calcd for C17H30O5NaSi: 365.1760;
found: 365.1793.
(2E,6E)-Diethyl Octa-2,6-dienedioate6 (Entry 1)
TLC: Rf = 0.6 (25% EtOAc–75% hexanes).
1H NMR (500 MHz, CDCl3): d = 6.87–7.01 (br dt, J = 6.0, 16.0 Hz,
2 H, H3, H6), 5.86 (d, J = 15.0 Hz, 2 H, H2, H7), 4.19 (q, J = 7.0,
7.0, 7.0 Hz, 4 H, CH2Me), 2.33–2.46 (m, 4 H, H4, H5), 1.29 (t, J =
7.5, 7.5 Hz, 6 H, CH3).
(2E,4E)-Diethyl Hepta-2,4-dienedioate (Entry 6)
TLC: Rf = 0.7 (25% EtOAc–75% hexanes).
1H NMR (500 MHz, CDCl3): d = 7.27 (dd, J = 10.0, 15.0 Hz, 1 H,
H3), 6.27 (dd, J = 10.0, 15.0 Hz, 1 H, H4), 6.19 (dt, J = 7.0, 14.0 Hz,
1 H, H5), 5.85 (d, J = 15.0 Hz, 1 H, H2), 4.20 [q, J = 7.5 Hz, 2 H,
C(1)(=O)OCH2Me], 4.16 [q, J = 7.5 Hz, 2 H, C(8)(=O)OCH2Me],
3.20 (d, J = 7.0 Hz, 2 H, H7), 1.30 [t, J = 7.0 Hz, 3 H, (OCH2CH3)a],
1.27 [t, J = 7.0 Hz, 3H, (OCH2CH3)b].
13C NMR (125 MHz, CDCl3): d = 166.5, 147.0, 122.5, 60.4, 30.6,
14.4.
HRMS (ESI): m/z [M + Na]+ calcd for C12H18O4Na: 249.1103;
found: 249.1103.
13C NMR (125 MHz, CDCl3): d = 170.7, 167.0, 143.8, 134.3, 131.5,
121.4, 61.1, 60.4, 38.3, 14.4, 14.3.
Deca-1,9-diene-4,7-diol7 (Entry 2)
TLC: Rf = 0.6 (50% EtOAc–50% hexanes).
HRMS (ESI): m/z [M + Na]+ calcd for C11H16O4Na: 235.0946;
found: 235.0958.
1H NMR (500 MHz, CDCl3, mixture of diastereomers): d = 5.68–
5.90 (two overlapping dddd, J = 7.0, 8.0, 10.0, 17.0 Hz, 2 H, H2,
H9), 5.11–5.19 (m, 4 H, H1, H10), 3.64–3.76 [br s (W1/2h = 19 Hz)
2 H, H4, H7], 2.38 (br s, OH), 2.30 (two overlapped br ddd, J = 6.0,
6.0, 13.0 Hz, H3b, H3b¢, H8b, H8b¢), 2.20 (two overlapped app
dddd, J = 1.0, 8.0, 8.0, 14.0 Hz, H3a, H3a¢, H8a, H8a¢), 2.13 (br s,
OH), 1.64–1.75 (m, 2 H, H5a, H6a), 1.50–1.62 (m, 2 H, H5b, H6b).
Nona-1,8-diene-4,6-diol10 (Entry 7)
TLC: Rf = 0.5 (50% EtOAc–50% hexanes).
1H NMR (500 MHz, CDCl3, mixture of diastereomers): d = 5.82
(dddd, J = 7.0, 7.0, 10.0, 17.0 Hz, 2 H, H2, H8), 5.15 (br d, J = 16.0
Hz, 2 H, H1Z, H9Z), 5.14 (br d, J = 11.0 Hz, 2 H, H1E, H9E), 4.01
(app p, J = 6.0 Hz, 2 H, H4, H6), 2.36 (br s, 2 × OH), 2.28 (ddddd,
J = 1.0, 1.0, 7.0, 7.0, 14.0 Hz, 2 H, H3a, H7a), 2.27 (ddddd, J =1.0,
1.0, 7.0, 7.0, 14.0 Hz, 2 H, H3b, H7b), 1.66 (t, J = 6 Hz, 2 H, 2 ×
H5).
13C NMR (125 MHz, CDCl3, mixture of diastereomers): d = 135.3,
118.2, 71.5*, 71.0**, 42.6*, 42.3**, 33.8*, 32.9** (*one diastere-
omer, **the other diastereomer),
HRMS (ESI): m/z [M + Na]+ calcd for C10H18O2Na: 193.1205;
found: 193.1191.
13C NMR (125 MHz, CDCl3, from the mixture of diastereomers):
d = 134.9*, 134.5**, 118.1**, 118.0*, 71.9**, 68.2*, 42.6**, 42.1*,
41.8**, 41.6* (* = anti and ** = syn diastereomer).
(2E,7E)-Diethyl Nona-2-7-dienedioate8 (Entry 3)
TLC: Rf = 0.7 (25% EtOAc–75% hexanes).
HRMS (ESI): m/z [M + Na]+ calcd for C9H16O2Na: 179.1048; found
(from the diastereomeric mixture): 179.1050.
1H NMR (500 MHz, CDCl3): d = 6.93 (dt, J = 6.5, 15.5 Hz, 2 H, H3,
H7), 5.83 (d, J = 16.0 Hz, 2 H, H2, H8), 4.19 (q, J = 7.0 Hz, 4 H,
CH2Me), 2.24 (dt, J = 7.0, 7.0 Hz, 4 H, H4, H6), 1.64 (p, J = 7.0 Hz,
2 H, H5), 1.29 (t, J = 7.5 Hz, 6 H, CH3).
Acknowledgment
13C NMR (125 MHz, CDCl3): d = 166.6, 148.2, 122.1, 60.4, 31.6,
26.5, 14.4.
This investigation was supported by a grant awarded by the DHHS
(GM-65597).
HRMS (ESI): m/z [M + Na]+ calcd for C13H20O4Na: 263.1259;
found: 263.1263.
References
Undeca-1,10-diene-4,8-diol9 (Entry 4)
TLC: Rf = 0.3 (50% EtOAc–50% hexanes).
(1) Takacs, J. M.; Helle, M. A.; Seely, F. L. Tetrahedron Lett.
1986, 27, 1257.
1H NMR (500 MHz, CDCl3, mixture of diastereomers): d = 5.83
(dddd, J = 7.0, 8.0, 10.0, 17.0 Hz, 2 H, H2, H10), 5.12–5.17 (m, 4
H, H1, H11), 3.64–3.70 (m, 2 H, H4, H8), 2.31 (br dt, J = 6.0, 13.0
Hz, 2 H, H3a, H9a), 2.15 (ddd, J = 7.5, 7.5, 14.5 Hz, 2 H, H3b, H9b),
1.45–1.77 (m, 8 H, H5, H6, H7, OH).
(2) Sasaki, M.; Yudin, A. K. Synlett 2004, 2443.
(3) Burke, S. D.; Deaton, D. N.; Olsen, R. J.; Armistead, D. M.;
Blough, B. E. Tetrahedron Lett. 1987, 28, 3905.
(4) Comins, D. L.; Herrick, J. J. Tetrahedron Lett. 1984, 25,
1321.
(5) Hoye, T. R.; Aspaas, A. W.; Eklov, B. M.; Ryba, T. D. Org.
Lett. 2005, 7, 2205.
(6) Murphy, P. J.; Williams, H. L.; Hibbs, D. E.; Hursthouse, M.
B.; Malik, K. M. A. Tetrahedron 1996, 52, 8315.
(7) Baylon, C.; Heck, M. P.; Mioskowski, C. J. Org. Chem.
1999, 64, 3354.
13C NMR (125 MHz, CDCl3, mixture of diastereomers): d = 135.1
(+), 135.1 (–), 117.9, 117.8, 70.7, 70.6, 42.2, 42.0, 36.7, 36.5, 21.8,
21.7.
HRMS (ESI): m/z [M + Na]+ calcd for C11H20O2Na: 207.1361;
found: 207.1370.
(8) Villieras, J.; Rambaud, M.; Graff, M. Synth. Commun. 1986,
16, 149.
(9) Einhorn, C.; Luche, J. L. J. Organomet. Chem. 1987, 322,
177.
(2E,7E)-Dimethyl 5-(Triethylsilyloxy)nona-2,7-dienedioate
(Entry 5)
TLC: Rf = 0.25 (10% EtOAc–90% hexanes).
(10) (a) Rychnovsky, S. D.; Griesgraber, G.; Zeller, S.; Skalitzky,
D. J. J. Org. Chem. 1991, 56, 5165. (b) Samoshin, V. V.;
Gremyachinskiy, D. E.; Smith, L. L.; Bliznets, I. V.; Gross,
P. H. Tetrahedron Lett. 2002, 43, 6329.
1H NMR (300 MHz, CDCl3): d = 6.94 (dt, J = 7.5, 15.3 Hz, 2 H, H3,
H7), 5.86 (dt, J = 1.5, 15.6 Hz, 2 H, H2, H8), 3.93 (tt, J = 5.7, 11.4
Hz, 1 H, H5), 3.73 (s, 6 H, CO2Me), 2.36 (nfom, 4 H, H4, H6), 0.95
[t, J = 7.8 Hz, 9 H, Si(CH2CH3)3], 0.59 [q, J = 7.8 Hz, 6 H,
Si(CH2CH3)3]; nfom = non-first-order multiplet.
Synthesis 2006, No. 10, 1572–1574 © Thieme Stuttgart · New York