Ammonia free partial reduction of aromatic compounds using lithium di-tert-butylbiphenyl (LiDBB)

Article abstract of DOI:10.1021/jo0257593

The reduction of a series of hetero- and carbocyclic aromatic compounds under ammonia free conditions is described. By using LiDBB as a source of electrons, bis(methoxyethyl)amine (BMEA) as a protonating agent, and THF as a solvent, we were able to accomplish reductions more usually performed under Birch type conditions. Moreover, the use of these conditions was further enhanced by the tolerance of the reducing system toward reactive electrophiles that cannot be used successfully in ammonia.

Full text of DOI:10.1021/jo0257593

SCHEME 1
Am m on ia F r ee P a r tia l Red u ction of
Ar om a tic Com p ou n d s Usin g Lith iu m
Di-ter t-bu tylbip h en yl (LiDBB)
Timothy J . Donohoe* and David House
Dyson Perrins Laboratory, South Parks Road,
Oxford OX1 3QY, U.K.
timothy.donohoe@chem.ox.ac.uk
Received March 26, 2002
Abstr a ct: The reduction of a series of hetero- and carbo-
cyclic aromatic compounds under ammonia free conditions
is described. By using LiDBB as a source of electrons, bis-
(methoxyethyl)amine (BMEA) as a protonating agent, and
THF as a solvent, we were able to accomplish reductions
more usually performed under Birch type conditions. More-
over, the use of these conditions was further enhanced by
the tolerance of the reducing system toward reactive elec-
trophiles that cannot be used successfully in ammonia.
SCHEME 2
We have recently demonstrated that the conditions
traditionally used for accomplishing a Birch reduction of
both pyrroles and furans (i.e., Na or Li in ammonia) could
be replaced by an “ammonia free” variant that provides
a practicable alternative for partial reduction and reduc-
tive alkylation.1 In this new regimen, lithium naphtha-
lenide 2 provides the electrons, and bis(methoxyethyl)-
amine (BMEA) is a convenient acid.2 Our proposed
mechanism is shown, and we suspect that the reaction
proceeds via an intermediate, reactive, dianion species
B capable of deprotonating an amine. In designing this
system, our key premise was that the amine (BMEA)
should be acidic enough to protonate dianion B derived
from the heterocycle but not acidic enough to protonate
the monoanion (enolate C) that is subsequently formed,
Scheme 1. In this note, we wish to fully discuss the scope
of this method and report on a simple improvement that
can be made to the reducing system.
During further investigation of the partial reduction
of electron-deficient pyrroles, we discovered that substi-
tuting naphthalene for DBB (di-tert-butylbiphenyl)3 re-
sulted in a marked improvement in yield. Scheme 2
shows that the reductive alkylation of pyrrole 3 can now
be accomplished with a variety of electrophiles in yields
that rival those achieved in ammonia (see compounds
4-8); certainly, these reactions are much cleaner with
the new electron-transfer agent (LiDBB, formed by
addition of an electron to DBB). The use of diphenyl
disulfide (see compound 7) is a pertinent example of the
advantages of DBB as we could not isolate compound 7
pure from reductions involving naphthalene. This com-
pound is also noteworthy as we can find no examples in
the literature of disulfides being used as electrophiles in
any Birch reduction. Standard ammonia free conditions
involve the addition of Li metal (4 equiv), DBB (4 equiv),
and BMEA (1.2 equiv). As mentioned in our early report,1
one limitation of this methodology is a failure of the
enolate generated under ammonia free conditions to
displace unactivated alkylhalides such as butylbromide
(see compound 6): if these types of electrophile are
required, then the reductive alkylation must be per-
formed in ammonia.
One reason for the improvement in yield that is
obtained by switching from naphthalene to DBB may be
attributed to the increased steric bulk of the latter, which
disfavors radical coupling reactions between LiDBB and
other radical anions formed in solution.4 In addition, the
lower (more negative) reduction potential of DBB versus
naphthalene points to the conclusion that the radical
anion thus produced (LiDBB) will be a more powerful
reducing agent.4
In addition to its practicality in the laboratory, one
major advantage of this new reducing system is its ability
to allow reaction of enolates with reactive electrophiles.
Attempting to acylate an enolate (e.g., C) in liquid
ammonia, with an acid chloride, for example, results
cleanly in the formation of a protonated compound: HCl
produced from the reaction of the acid chloride with
ammonia is the culprit. However, under the ammonia
(1) (a) Donohoe, T. J .; Harji, R. R.; Cousins, R. P. C. Tetrahedron
Lett. 2000, 41, 1327. (b) Donohoe, T. J .; Harji, R. R.; Cousins, R. P. C.
Tetrahedron Lett. 2000, 41, 1331.
(2) Donohoe, T. J .; Guyo, P. M.; Harji, R. R.; Helliwell, M.; Cousins,
R. P. C. Tetrahedron Lett. 1998, 39, 3075.
(3) (a) Cohen, T.; Kreethadumrongdat, T.; Liu, X.; Kulkarni, V. J .
Am. Chem. Soc. 2001, 123, 3478. (b) Holy, N. L. Chem. Rev. 1974, 74,
243. (c) DBB is commercially available in quantities up to 25 g but is
easily prepared on a 100 g scale by Friedel-Crafts alkylation of
biphenyl, see Supporting Information: Curtis, M. D.; Allred, A. L. J .
Am. Chem. Soc. 1965, 87, 2554.
(4) (a) Freeman, P. K.; Hutchinson, L. L. Tetrahedron Lett. 1976,
1849. (b) Freeman, P. K.; Hutchinson, L. L. J . Org. Chem. 1980, 45,
1924.
10.1021/jo0257593 CCC: $22.00 © 2002 American Chemical Society
Published on Web 05/29/2002
J . Org. Chem. 2002, 67, 5015-5018
5015

SCHEME 3a
SCHEME 4a
a
Key: (i) Li, DBB, BMEA, THF, -78 °C; (ii) BrCH2CO2t-Bu;
(iii) PhCOCl; (iv) MeOCOCl.
free conditions, the concentration of amine is kept quite
low and enolate C does react with acid chlorides (and
other reactive electrophiles) before protonation takes
place. The chemistry in Scheme 3 shows the reductive
alkylation (9), acylation (10), and carboxylation (12) of
pyrroles 3 and 11 with a range of reactive electrophiles
that we have not been able to use successfully at all in
liquid ammonia.
a
Key: (i) Li, DBB, BMEA, THF, -78 °C; (ii) PhCH2Br; (iii) MeI;
(iv) MeOCOCl.
SCHEME 5a
With the superiority of DBB over naphthalene clearly
established, we next examined reduction of electron
deficient furans under these conditions and found that,
disappointingly, the reductive alkylation of furan derived
ester 13 was not particularly high yielding with either
naphthalene or DBB as the electron carrier.7 Suspecting
that the ester group may have been attacked by nucleo-
philes generated in situ, we also examined partial reduc-
tion of pyrrolidine amide 15; here, we were able to isolate,
for the first time, a byproduct from the reaction (a 1,2-
diketone, ArCOCOAr, Ar ) 2-furyl). Presuming that this
compound was formed via an acyloin type of coupling,
we decided to minimize this unwanted side reaction by
increasing the steric bulk of the amide nitrogen. Conse-
quently, hindered amide 17 was prepared and subjected
to ammonia free reductive alkylation, quenching with
benzyl bromide so as to allow a direct comparison with
the ester and pyrrolidine amide derivatives, Scheme 4.
The result was a high yielding reaction that gave desired
product 18 in 84% yield. (This result also fits with our
experience regarding the partial reduction of furans;
here, we found that bulky, amide derived, auxiliaries
attached to furan gave higher yields during reductive
alkylation (ammonia) than their pyrrolidine amide coun-
terparts. See ref 7.) Further exploitation of this amide
allowed compounds 19 and 20 to be prepared in two high
yielding reduction reactions.
a
Key: (i) Li, DBB, BMEA, THF, -78 °C; (ii) BrCH2CO2t-Bu;
(iii) MeOCOCl; (iv) (E)-PhCHdCHCH2Br; (v) BnBr.
tion reaction is not just limited to transformations of
electron deficient heterocycles.
Despite its versatility, some aromatic compounds that
were subjected to the ammonia free conditions did not
give clean reactions: we were unable to partially reduce
2-cyanofuran, methyl benzoate, tert-butylphenyl sulfox-
ide, or tert-butylphenyl sulfone under these conditions.9
Of these substrates, the first two could be partially
reduced (and then alkylated) in liquid ammonia.
In theory, this reaction could be made catalytic in DBB
because the arene is regenerated as LiDBB donates an
electron to the substrate.10 Some preliminary experi-
ments showed that this was indeed the case; for example,
the reduction of 3 with Li (4 equiv) and DBB (50 mol %)
gave pyrroline 4 in 49% yield after alkylation with BnBr.
However, extensive studies have shown that this subs-
toichiometric reaction is rather capricious and generally
leads to low yields (we have evidence to suggest that a
background reaction between the DBB and BMEA is
responsible, possibly involving a reactive dianion of the
electron carrier formed when a relatively large excess of
lithium is present11). Therefore, we recommend that the
stoichiometric procedure should be used in preparative
reactions.
Finally, the reduction of carbocyclic aromatics was
explored using LiDBB. Benzonitrile 21 proved to be the
most versatile benzenoid examined, and this could be
reduced successfully to furnish compounds 22-24, Scheme
5.8 In addition, benzamide 25 also proved to be a viable
substrate under ammonia free conditions, clearly showing
that this new method of accomplishing the partial reduc-
(5) (a) Donohoe,T. J .; Guyo, P. M. J . Org. Chem. 1996, 61, 7664. (b)
Donohoe, T. J .; Guyo, P. M.; Beddoes, R. L.; Helliwell, M. J . Chem.
Soc., Perkin Trans. 1 1998, 667.
(6) Donohoe, T. J .; Ace, K. W.; Guyo, P. M.; Helliwell, M.; McKenna,
J . Tetrahedron Lett. 2000, 41, 989.
(7) (a) Donohoe, T. J .; Helliwell, M.; Stevenson, C. A.; Ladduwahetty,
T. Tetrahedron Lett. 1998, 39, 3071. (b) Donohoe, T. J .; Calabrese, A.
A.; Stevenson, C. A.; Ladduwahetty, T. J . Chem. Soc., Perkin Trans. 1
2000, 3724.
(9) Donohoe, T. J .; House, D. Unpublished work.
(10) Ramo´n, D. J .; Yus, M. J . Chem. Soc., Chem. Commun. 1991,
398. See also: Yus, M.; Ramo´n, D. J . Eur. J . Org. Chem. 2000, 225
and references therein.
(11) Brooks, J . J .; Rhine, W.; Stucky, G. D. J . Am. Chem. Soc. 1972,
94, 7346. See also: Yus, M.; Herrera, R. P.; Guijarro, A. Tetrahedron
Lett. 2001, 42, 3455.
(8) Schultz, A. G.; Macielag, M. J . Org. Chem. 1986, 51, 4983.
5016 J . Org. Chem., Vol. 67, No. 14, 2002

electrophile (3.0 mmol) was added dropwise, at which point the
turquoise color disappeared. The solution was stirred for a
further 2-10 min (depending on the electrophile), and saturated
ammonium chloride solution (5 mL) was added. The reaction
mixture was poured into a separating funnel containing dilute
hydrochloric acid (1 M) and ethyl acetate. The layers were
separated, and the aqueous layer was extracted with two further
portions of ethyl acetate. The combined organic extracts were
dried over MgSO4, and the solvent was removed under reduced
pressure to give a crude product. Purification was achieved by
chromatography on silica gel eluting initially with petroleum
ether (40-60 °C) to remove the DBB. (DBB may be recycled by
recrystallization from methanol.) The solvent polarity was then
increased to yield the target material (typically 10-20% Et2O
or EtOAc).
While alternative electron carriers and proton sources
have been screened without further improvement in
yield, current work aims to use cyclic voltametry to
investigate the reduction potentials of various substrates
and electron carriers to determine the optimum working
difference between them; the results of this study will
be reported in due course.
To conclude, we have shown that introduction of DBB
as an electron carrier in the ammonia free conditions for
partial reduction of aromatic compounds leads to a
significant increase in yield. The scope of this new
reaction has been explored, and it now encompasses not
just electron deficient heterocycles but also benzenoid
aromatics. Besides practicability, one of the main advan-
tages of this sequence is its ability to tolerate reaction of
enolates with sensitive electrophiles: these do not work
at all in ammonia, and this gives us access to a wide
range of compounds that could not be prepared directly
via the Birch reduction.
(2RS)-Isop r op yl 1-(ter t-Bu tyloxyca r bon yl)-2-ben zyl-2,5-
d ih yd r op yr r ole-2-ca r boxyla te, 4. By method B, pyrrole 3 (253
mg, 1.0 mmol) and benzyl bromide (596 µL, 5.0 mmol) gave the
title compound as a solid (277 mg, 80%) after chromatography
[(i) light petrol; (ii) light petrol-10% Et2O]; 1H NMR (300 MHz,
CDCl3) δ 7.25-7.15 (m, 6 H), 7.12-7.05 (m, 4 H), 5.71 (dt, J 6.4
and 2.0 Hz, 1 H), 5.67 (dt, J 6.0 and 2.0 Hz, 1 H), 5.58 (dt, J 6.4
and 2.0 Hz, 1 H), 5.51 (dt, J 6.4 and 2.4 Hz, 1 H), 5.08 (sp, J 6.0
Hz, 1 H), 5.02 (sp, J 6.4 Hz, 1 H), 4.15 (dt, J 15.6 and 2.4 Hz, 1
H), 4.03 (dt, J 15.6 and 2.0 Hz, 1 H), 3.79 (d, J 13.6 Hz, 1 H),
3.59 (d, J 13.6 Hz, 1 H), 3.51 (dt, J 15.2 and 2.4 Hz, 1 H), 3.35
(dt, J 15.2 and 2.0 Hz, 1 H), 3.25 (d, J 13.6 Hz, 1 H), 3.21 (d, J
13.6 Hz, 1 H), 1.56 (s, 9 H), 1.51 (s, 9 H), 1.30 (d, J 6.0 Hz, 3 H),
1.25 (d, J 6.0 Hz, 3 H), 1.25 (d, J 6.4 Hz, 3 H), and 1.24 (d, J 6.0
Hz, 3 H); 13C NMR (101 MHz, CDCl3) δ 171.5, 171.3, 153.3,
136.9, 136.5, 130.7, 130.5, 129.5, 129.4, 128.4, 128.3, 127.8, 127.5,
126.4, 126.1, 80.6, 79.5, 76.0, 75.7, 69.1, 68.7, 54.9, 54.6, 39.1,
38.3, 28.6, 28.5, 21.9, 21.7, and 21.7; IR (film) 2979, 1734, 1702,
and 1394 cm-1; CIMS m/z (rel intensity) 346 (41%, MH+), 290
(100), 246 (22) and 158 (21); C20H28NO4 requires M, 346.2018,
Exp er im en ta l Section
Gen er a l. Tetrahydrofuran was distilled before use from
sodium-benzophenone ketyl radical under an argon atmosphere.
All reactions were carried out under argon using oven-dried
glassware. Proton and carbon NMR spectra were recorded on
Fourier transform spectrometers using an internal deuterium
lock. Chemical shifts are quoted in parts per million (ppm)
downfield of tetramethylsilane. Coupling constants J are quoted
in hertz and are not rationalized. Both the proton and carbon
NMR spectra of compounds 4-12 exhibit doubling of some
signals because of the presence of Boc group rotamers. Infrared
spectra were recorded on an FTIR spectrophotometer. Positive
ion chemical ionization (CI) mass spectra and accurate mass data
were recorded.
found MH+, 346.2025; mp 67-69 °C. Anal. Calcd for C20H27
-
NO4: C, 69.54; H, 7.88; N, 4.05. Found: C, 69.71; H, 8.00; N,
4.02.
(2RS)-Isop r op yl 1-(ter t-Bu tyloxyca r bon yl)-2-p h en ylsu l-
fa n yl-2,5-d ih yd r op yr r ole-2-ca r boxyla te, 7. By method B,
pyrrole 3 (253 mg, 1.0 mmol) and diphenyl disulfide (545 mg,
2.5 mmol) gave the title compound as a solid (190 mg, 52%) after
chromatography [(i) light petrol; (ii) light petrol-10% Et2O]; 1H
NMR (300 MHz, CDCl3) δ 7.52-7.23 (m, 10 H), 5.76-5.62 (m, 4
H), 5.16 (sp, J 6.2 Hz, 1 H), 5.08 (sp, J 6.2 Hz, 1 H), 4.05 (dt, J
15.9 and 1.9 Hz, 1 H), 3.95 (dt, J 15.8 and 1.5 Hz, 1 H), 3.24 (dt,
J 16.1 and 1.7 Hz, 1 H), 2.92 (dt, J 15.9 and 1.7 Hz, 1 H), 1.61
(s, 9 H), 1.53 (s, 9 H), 1.33 (d, J 6.2 Hz, 6 H), and 1.29 (d, J 6.3
Hz, 6 H); 13C NMR (75 MHz, CDCl3) δ 167.9, 167.8, 152.3, 151.4,
138.2, 137.8, 130.7, 130.5, 129.3, 129.1, 129.0, 128.3, 128.1, 127.8,
127.7, 84.3, 84.3, 81.4, 80.2, 70.2, 70.1, 54.5, 54.3, 28.3, 28.2,
21.6, 21.6, 21.5, and 21.4; IR (film) 2979, 2934, 1739, 1706, 1382,
1264, 1156, and 1104 cm-1; CIMS m/z (rel intensity) 364 (10%,
MH+), 254 (69), 215 (25), and 198 (100); C19H26NO4S requires
M, 364.1582, found MH+, 364.1581; mp 81-82 °C (dec). Anal.
Calcd for C19H25NO4S: C, 62.79; H, 6.93; N, 3.85; S, 8.82.
Found: C, 62.80; H, 6.67; N, 3.97; S, 8.53.
(2RS)-Isop r op yl 1-(ter t-Bu tyloxyca r bon yl)-2-(ter t-bu tyl)-
m et h ylca r b oxyla t e-2,5-d ih yd r op yr r ole-2-ca r b oxyla t e, 9.
By method B, pyrrole 3 (253 mg, 1.0 mmol) and tert-butyl
bromoacetate (369 µL, 2.5 mmol) gave the title compound as an
oil (280 mg, 76%) after chromatography [(i) light petrol; (ii) light
petrol-20% Et2O]; 1H NMR (400 MHz, CDCl3) δ 5.98 (dt, J 6.4
and 2.0 Hz, 1 H), 5.92 (dt, J 6.4 and 2.0 Hz, 1 H), 5.79 (dt, J 6.4
and 2.4 Hz, 1 H), 5.70 (dt, J 6.4 and 2.0 Hz, 1 H), 5.01 (sp, J 6.4
Hz, 1 H), 4.96 (sp, J 6.0 Hz, 1 H), 4.32 (dt, J 15.2 and 2.4 Hz, 1
H), 4.25 (dt, J 15.6 and 2.8 Hz, 1 H), 4.16 (dt, J 15.2 and 2.4 Hz,
1 H), 4.11 (dt, J 15.2 and 2.4 Hz, 1 H), 3.24 (d, J 14.4 Hz, 1 H),
3.14 (d, J 14.0 Hz, 1 H), 3.03 (d, J 14.4 Hz, 1 H), 2.93 (d, J 14.0
Hz, 1 H), 1.47 (s, 9 H), 1.47 (s, 9 H), 1.40 (s, 9 H), 1.40 (s, 9 H),
1.25 (d, J 6.4 Hz, 3 H), 1.20 (d, J 6.4 Hz, 3 H), 1.20 (d, J 6.0 Hz,
3 H), and 1.19 (d, J 6.0 Hz, 3 H); 13C NMR (101 MHz, CDCl3) δ
170.6, 170.4, 169.7, 169.3, 153.1, 153.0, 129.6, 129.4, 128.2, 128.0,
80.6, 80.5, 80.0, 79.8, 73.4, 73.0, 69.3, 69.0, 54.9, 54.7, 40.6, 39.5,
Gen er a l P r oced u r es for Am m on ia -F r ee Bir ch Red u c-
t ion s. Met h od A: Gen er a t ion of LiDBB Solu t ion s b y
Son ica tion . Freshly cut lithium wire (28 mg, 4.0 mmol) was
hammered out into a foil, cut into several small strips, and
placed in a Schlenk tube containing DBB (1.1 g, 4.0 mmol). The
tube was evacuated and purged with argon several times.
Tetrahydrofuran (25 mL, freshly distilled from sodium-ben-
zophenone) was added, and the contents of the Schlenk tube
were sonicated in a ice-water bath, adding ice regularly to keep
the bath temperature below 5 °C. Gradually, the solution became
turquoise, characteristic of the DBB radical-anion. The LiDBB
solution was sonicated until no lithium foil remained (typically
2-4 h). The LiDBB solution was cooled to -78 °C and stirred
vigorously.
Meth od B: Gen er a tion of LiDBB Solu tion s fr om Acti-
va ted Lith iu m P ow d er . Freshly cut lithium wire (28 mg, 4.0
mmol) was hammered out into a foil, cut into several small
strips, and placed in a Schlenk tube containing DBB (1.1 g, 4.0
mmol) and some glass “antibumping” granules. The tube was
evacuated and purged with argon several times. The contents
of the Schlenk tube were then stirred with maximum vigor until
the lithium foil had been completely reduced to a powder
(typically 0.5-2 h). (For the lithium to be ground efficiently, it
is important to select a magnetic bead whose length is close to
the internal diameter of the Schlenk tube.) CAUTION: This
powder is extremely reactive and will catch fire on contact with
water. The Schlenk tube was cooled to -78 °C under a positive
pressure of argon, and tetrahydrofuran (25 mL, freshly distilled
from sodium-benzophenone) was added, immediately resulting
in a dark turquoise solution.
Once the LiDBB solution was formed, by either Method A or
B, the substrate (1.0 mmol) and bis(methoxyethyl)amine (BMEA)
(180 µL, 1.2 mmol) in freshly distilled THF (10 mL) were added
dropwise over a period of 2-5 min. The turquoise color persisted
throughout the course of the substrate addition. The reaction
mixture was stirred at -78 °C for a further 30 min, and the
J . Org. Chem, Vol. 67, No. 14, 2002 5017

28.4, 28.3, 28.0, 21.7, 21.6, and 21.6; IR (film) 2979, 1732, 1706,
and 1393 cm-1; CIMS m/z (rel intensity) 370 (43%, MH+), 314
(100), 282 (36), and 258 (36); C19H32NO6 requires M, 370.2230,
found MH+, 370.2238.
(2RS)-N,N-Diisop r op yl 2-Ca r b om et h oxy-2,5-d ih yd r o-
fu r a n -2-ca r boxa m id e, 20. By method B, furan 17 (195 mg, 1.0
mmol) and methyl chloroformate (270 µL, 3.5 mmol) gave the
title compound as a solid (213 mg, 84%) after chromatography
[(i) light petrol; (ii) light petrol-20% EtOAc]; 1H NMR (200 MHz,
CDCl3) δ 6.09 (dt, J 6.0 and 1.2 Hz, 1 H), 6.04 (dt, J 6.0 and 2.0
Hz, 1 H), 4.87 (ddd, J 13.2, 2.4, and 1.6 Hz, 1 H), 4.78 (ddd, J
13.2, 2.4, and 2.0 Hz, 1 H), 4.23 (sp, J 6.8 Hz, 1 H), 3.76 (s, 3 H),
3.33 (sp, J 6.8 Hz, 1 H), 1.39 (d, J 6.8 Hz, 3 H), 1.36 (d, J 6.8
(2RS)-Isop r op yl 1-(ter t-Bu t yloxyca r b on yl)-2-b en zoyl-
2,5-d ih yd r op yr r ole-2-ca r boxyla te, 10. By method B, pyrrole
3 (253 mg, 1.0 mmol) and benzoyl chloride (350 µL, 3.0 mmol)
gave the title compound as an oil (240 mg, 67%) after chroma-
1
tography [(i) light petrol; (ii) light petrol-20% Et2O]; H NMR
Hz, 3 H), 1.16 (d, J 6.8 Hz, 3 H), and 1.02 (d, J 6.8 Hz, 3 H); 13
C
(400 MHz, CDCl3) δ 7.83-7.76 (m, 4 H), 7.63-7.43 (m, 2 H),
7.41-7.32 (m, 4 H), 6.17 (dt, J 6.4 and 2.0 Hz, 2 H), 6.10 (dt, J
6.0 and 2.4 Hz, 2 H), 5.13 (sp, J 6.4 Hz, 1 H), 5.12 (sp, J 6.0 Hz,
1 H), 4.50 (dt, J 16.4 and 2.0 Hz, 1 H), 4.39 (dt, J 16.4 and 2.0
Hz, 1 H), 4.35-4.31 (m, 2 H), 1.34 (d, J 6.0 Hz, 3 H), 1.32 (s, 9
H), 1.30 (d, J 6.0 Hz, 3 H), 1.28 (d, J 6.0 Hz, 3 H), 1.24 (d, J 6.0
Hz, 3 H), 1.18 (s, 9 H); 13C NMR (101 MHz, CDCl3) δ 192.5,
167.4, 153.0, 135.7, 132.7, 131.9, 130.1, 129.9, 129.3, 129.3, 128.4,
128.3, 128.3, 127.9, 82.5, 81.4, 80.4, 69.6, 53.9, 53.6, 28.1, 27.6,
21.7, and 21.6; IR (film) 2981, 1745, 1706, and 1392 cm-1; CIMS
m/z (rel intensity) 360 (4%, MH+), 304 (23), 244 (18), 171 (21),
154 (100), and 153 (24); C20H26NO5 requires M, 360.1811, found
MH+, 360.1813. Anal. Calcd for C20H25NO5: C, 66.83; H, 7.01;
N, 3.90. Found: C, 67.01; H, 7.01; N, 3.98.
NMR (50 MHz, CDCl3) δ 171.0, 166.7, 129.1, 127.6, 95.2, 77.3,
52.7, 48.6, 46.4, 20.7, 20.2, 20.0, and 19.6; IR (film) 2968, 1752,
1735, 1649, and 1443 cm-1; CIMS m/z (rel intensity) 256 (45%,
MH+), 196 (100), and 130 (46); C13H22NO4 requires M, 256.1549,
found MH+, 256.1542; mp 90-91 °C.
(1RS)-1-[(ter t-Bu tyl)m eth yl Ca r boxyla te]-cycloh exa -2,5-
d ien yl-1-ca r bon itr ile, 22. By method B, benzonitrile 21 (102
µL, 1.0 mmol) and tert-butyl bromoacetate (443 µL, 3.0 mmol)
gave the title compound as an oil (175 mg, 80%) after chroma-
tography [(i) light petrol; (ii) light petrol-10% EtOAc]; 1H NMR
(300 MHz, CDCl3) δ 6.02 (dt, J 10.2 and 3.4 Hz, 2 H), 5.83 (dt,
J 10.2 and 1.9 Hz, 2 H), 2.78-2.70 (m, 2 H), 2.65 (s, 2 H), and
1.51 (s, 9 H); 13C NMR (75 MHz, CDCl3) δ 167.4, 127.6, 123.5,
120.5, 81.9, 46.0, 34.3, 27.9, and 25.5; IR (film) 2235, 1732, and
1154 cm-1; CIMS m/z (rel intensity) 237 (100%, MNH4+), 220
(38, MH+), 181 (28), and 164 (16); C13H18NO2 requires M,
220.1338, found MH+, 220.1333.
(2RS)-1-(ter t-Bu tyloxyca r bon yl)-2-d im eth oxyca r bon yl-
2,5-d ih yd r op yr r ole, 12. By method B, pyrrole 11 (225 mg, 1.0
mmol) and methyl chloroformate (193 µL, 2.5 mmol) gave the
title compound as a solid (173 mg, 61%) after chromatography
[(i) light petrol; (ii) light petrol-20% Et2O]; 1H NMR (300 MHz,
CDCl3) δ 6.12 (dt, J 6.0 and 2.1 Hz, 1 H), 6.08 (dt, J 6.2 and 2.0
Hz, 1 H), 5.87 (dt, J 6.1 and 2.1 Hz, 1 H), 5.84 (dt, J 6.2 and 2.2
Hz, 1 H), 4.35 (t, J 2.1 Hz, 2 H), 4.30 (t, J 1.9 Hz, 2 H), 3.82 (s,
6 H), 3.81 (s, 6 H), 1.52 (s, 9 H), and 1.45 (s, 9 H); 13C NMR (75
MHz, CDCl3) δ 167.7, 130.3, 130.2, 126.6, 126.5, 80.9, 54.2, 54.1,
(1RS)-1-Meth oxyca r bon yl-cycloh exa -2,5-d ien yl-1-ca r bo-
n itr ile, 23. By method B, benzonitrile 21 (102 µL, 1.0 mmol)
and methyl chloroformate (386 µL, 5.0 mmol) gave the title
compound as an oil (94 mg, 58%) after chromatography [(i) light
1
petrol; (ii) light petrol-10% Et2O]; H NMR (200 MHz, CDCl3)
52.9, 52.8, 28.2, and 28.0; IR (film) 1756, 1710, and 1393 cm-1
;
δ 6.20-6.09 (m, 2 H), 5.88-5.77 (m, 2 H), 3.85 (s, 3 H), and 2.82-
CIMS m/z (rel intensity) 286 (7%, MH+), 247 (33), 230 (100),
186 (77), and 126 (46); C13H19NO6Na requires M, 308.1110, found
MNa+, 308.1106; mp 71-73 °C.
2.74 (m, 2 H); 13C NMR (50 MHz, CDCl3) δ 167.2, 129.5, 119.4,
117.5, 54.1, 43.6, and 25.4; IR (film) 2242, 1749, and 1254 cm-1
;
CIMS m/z (rel intensity) 181 (100%, MNH4+) and 118 (16);
C9H13N2O2 requires M, 181.0977, found MNH4+, 181.0974.
(2RS)-N,N-Diisop r op yl 2-Ben zyl-2,5-d ih yd r ofu r a n -2-ca r -
boxa m id e, 18. By method B, furan 17 (195 mg, 1.0 mmol) and
benzyl bromide (415 µL, 3.5 mmol) gave the title compound as
a solid (241 mg, 84%) after chromatography [(i) light petrol; (ii)
(1RS)-1-(3′-P h en yl-p r op -2′-en yl)-cycloh exa -2,5-d ien yl-1-
ca r b on it r ile, 24. By method B, benzonitrile 21 (102 µL, 1.0
mmol) and cinnamyl bromide (493 mg, 2.5 mmol) gave the title
compound as an oil (147 mg, 67%) after chromatography [(i) light
petrol; (ii) light petrol-5% Et2O]; 1H NMR (400 MHz, CDCl3) δ
7.40-7.30 (m, 4 H), 7.28-7.22 (m, 1 H), 6.51 (br d, J 16.0 Hz, 1
H), 6.20 (dt, J 15.2 and 8.0 Hz, 1 H), 6.02-5.95 (m, 2 H), 5.74-
5.68 (m, 2 H), 2.75 (dtt, J 23.2, 3.2, and 2.0 Hz, 1 H), 2.65 (dtt,
J 23.2, 3.2, and 2.0 Hz, 1 H) and 2.64 (dd, J 7.6 and 1.6 Hz, 2
H); 13C NMR (101 MHz, CDCl3) δ 136.8, 135.1, 128.6, 127.7,
127.5, 126.3, 124.1, 122.4, 121.3, 44.6, 37.0, and 25.7; IR (film)
3030, 2231, 1598, and 1494 cm-1; CIMS m/z (rel intensity) 239
(100%, MNH4+), 117 (49), and 91 (8); C16H19N2 requires M,
239.1548, found MNH4+, 239.1544.
1
light petrol-20% EtOAc]; H NMR (200 MHz, CDCl3) δ 7.31-
7.15 (m, 5 H), 6.09 (dt, J 6.0 and 2.6 Hz, 1 H), 5.74 (dt, J 6.0
and 1.6 Hz, 1 H), 4.92 (sp, J 6.6 Hz, 1 H), 4.57 (ddd, J 12.8, 2.6,
and 1.8 Hz, 1 H), 4.33 (ddd, J 12.8, 2.6, and 1.8 Hz, 1 H), 3.35
(sp, J 6.6 Hz, 1 H), 3.19 (d, J 14.0 Hz, 1 H), 3.03 (d, J 13.6 Hz,
1 H), 1.42 (d, J 6.6 Hz, 3 H), 1.37 (d, J 6.6 Hz, 3 H), 1.14 (d, J
6.6 Hz, 3 H) and 1.05 (d, J 6.6 Hz, 3 H); 13C NMR (101 MHz,
CDCl3) δ 171.9, 136.3, 132.0, 130.6, 127.8, 126.4, 125.7, 96.7,
77.2, 48.1, 46.5, 44.5, 20.9, 20.6, 20.5, and 20.3; IR (film) 2966,
1620, and 1440 cm-1; CIMS m/z (rel intensity) 288 (100%, MH+),
196 (72), and 159 (79); C18H26NO2 requires M, 288.1964, found
MH+, 288.1976; mp 64-65 °C.
(2RS)-N,N-Diisop r op yl 2-Meth yl-2,5-d ih yd r ofu r a n -2-ca r -
boxa m id e, 19. By method B, furan 17 (195 mg, 1.0 mmol) and
methyl iodide (218 µL, 3.5 mmol) gave the title compound as an
oil (135 mg, 64%) after chromatography [(i) light petrol; (ii) light
petrol-20% EtOAc]; 1H NMR (200 MHz, CDCl3) δ 6.13 (dt, J
6.0 and 2.4 Hz, 1 H), 5.87 (dt, J 6.0 and 1.6 Hz, 1 H), 4.81 (sp,
J 6.4 Hz, 1 H), 4.69 (ddd, J 12.8, 2.0 and 1.6 Hz, 1 H), 4.64 (ddd,
J 12.8, 2.4 and 1.6 Hz, 1 H), 3.35 (sp, J 6.4 Hz, 1 H), 1.50 (s, 3
H), 1.40 (d, J 6.8 Hz, 3 H), 1.37 (d, J 6.8 Hz, 3 H), 1.19 (d, J 6.8
Hz, 3 H), and 1.16 (d, J 6.8 Hz, 3 H); 13C NMR (101 MHz, CDCl3)
δ 172.7, 133.6, 124.6, 92.9, 75.6, 48.1, 46.3, 25.4, 20.6, 20.5, 20.5,
and 20.5; IR (film) 2968, 1630, and 1438 cm-1; CIMS m/z (rel
intensity) 212 (100%, MH+), 130 (31), and 83 (12); C12H22NO2
requires M, 212.1651, found MH+, 212.1643.
Ack n ow led gm en t. We thank the EPSRC (Grant
GR/N19946) for supporting this project and Pfizer for
unrestricted financial support. Part of this work was
carried out at the University of Manchester.
Su p p or tin g In for m a tion Ava ila ble: Preparation of DBB;
1
data for compounds 5, 6, syn/anti-8, 14, 16, 26; copies of H
NMR spectra for compounds 6, anti-8, 9, 18, 19, 20, 22, 23,
24. This material is available free of charge via the Internet
at http://pubs.acs.org.
J O0257593
5018 J . Org. Chem., Vol. 67, No. 14, 2002