Regioselectivity of birch reductive alkylation of biaryls

Article abstract of DOI:10.1021/ol051377i

(Chemical Equation Presented) The regioselectivity of the Birch reductive alkylation of polysubstituted biaryls has been investigated. Results indicate that regioselectivity is affected by the electronic nature of substituents on both aromatic rings. The

Full text of DOI:10.1021/ol051377i

ORGANIC
LETTERS
2005
Vol. 7, No. 21
4557-4560
Regioselectivity of Birch Reductive
Alkylation of Biaryls†
Raphae1l Lebeuf, Fre´de´ric Robert, and Yannick Landais*
UniVersite´ Bordeaux-I, Laboratoire de Chimie Organique et Organome´tallique, 351,
Cours de la Libe´ration, F-33405 Talence Cedex, France
y.landais@lcoo.u-bordeaux1.fr
Received June 13, 2005
ABSTRACT
The regioselectivity of the Birch reductive alkylation of polysubstituted biaryls has been investigated. Results indicate that regioselectivity is
affected by the electronic nature of substituents on both aromatic rings. The electron-rich 3,5-dimethoxyphenyl moiety is selectively reduced
and then alkylated, while phenols and aniline are not dearomatized under these conditions. Biaryls possessing a phenol moiety are alkylated
on the second ring, providing that the acidic proton has been removed prior to the Li/NH3 reduction.
Galanthamine and crinine alkaloids 1 and 2 isolated from
Amaryllidaceae1 and morphine alkaloids such as 32 or
strychnine 43 are all made up of an arylcyclohexane moiety
connected to an ethylamino chain through a quaternary
stereocenter (marked 9) (Scheme 1). These natural products
possess a wide range of biological activity and have been
the subject of intense research for many years. In the course
of our continuing interest in desymmetrization processes,4
we envisaged a general strategy to access these different
classes of alkaloids on the basis of the desymmetrization of
arylcyclohexa-2,5-dienes of type I.5
substituted biaryl precursor. While the Birch reduction of
biaryl compounds has been well studied,7 the corresponding
Birch reductive alkylation has been relatively unexplored.8
This probably stems from the lack of regioselectivity that
could be predicted from Li/NH3 reduction of unsymmetrical
biaryls and by the difficulty in controlling alkylation vs
protonation of the resulting carbanion. We thus carefully
Scheme 1. Arylcyclohexa-2,5-diene Core of Several Alkaloids
It was anticipated that these building blocks could be
prepared through a Birch reductive alkylation6 of a suitably
† Dedicated to Prof. Michel Pereyre on the occasion of his 65th birthday.
(1) (a) Martin, S. F. The Amaryllidaceae Alkaloids in The Alkaloids;
Academic Press: New York, 1987; Vol. 30. (b) Hoshino, O. The
Amaryllidaceae Alkaloids in The Alkaloids; Academic Press: New York,
1998; Vol. 51, pp 324-424.
(2) Zezula, J.; Hudlicky, T. Synlett 2005, 388-405.
(3) (a) Bonjoch, J.; Sole´, D. Chem. ReV. 2000, 100, 3455-3482. (b)
Creasey, W. A. Monoterpenoid Indole Alkaloids (Saxton, J. E., Ed.) In
The Chemistry of heterocyclic Compounds; Taylor, E. C., Ed.; Wiley: New
York, 1994; Supplement to Vol. 25, Part 4, pp 715-754.
(4) (a) Angelaud, R.; Babot, O.; Charvat, T.; Landais, Y. J. Org. Chem.
1999, 64, 9613-9624. (b) Abd. Rahman, N.; Landais, Y. Curr. Org. Chem.
2002, 6, 1369-1395. (c) Landais, Y.; Zekri, E. Eur. J. Org. Chem. 2002,
4037-4053.
(5) Martin, S. F.; Campbell, C. L. J. Org. Chem. 1988, 53, 3184-3190.
(6) (a) Rabideau, P. W.; Marcinow, Z. Org. React. 1992, 42, 1-334
and references therein. (b) Mander, L. N. Synlett 1991, 134-144.
10.1021/ol051377i CCC: $30.25
© 2005 American Chemical Society
Published on Web 09/13/2005

examined the scope of such reductive alkylations through a
general survey of the conditions that could allow for both a
control of the alkylation vs protonation processes and the
regioselectivity of the reduction. We report here our pre-
liminary studies on this regioselective Birch alkylation of
biaryls and the utility of this strategy to access alkaloids of
the crinine family.
We envisioned that a careful choice of the nature of R
and R′ substituents on the biarylic precursor of I (Scheme
1) would allow the regioselective reduction of one arene over
the other. We thus investigated first the reduction of biaryls
having only one substituted arene (Scheme 2). Reduction of
occurring predominantly on the methoxy-substituted ring. It
is interesting to note that these results are in line with the
relative reduction rates of simple monosubstituted arenes,
which follow the order ArOMe > ArH > ArOH.6a,9 We then
carried out the reduction on biaryl 910 bearing two methoxy
groups and found that reduction occurred in high yield with
complete regiocontrol, leading to symmetrical diene 10a,b,
irrespective of the nature of the electrophile.
The above studies were then extended to the reduction/
alkylation of biaryls having a 3,5-dimethoxyphenyl group,
the other aromatic ring being substituted with hydroxy and
methoxy groups (Scheme 3). As expected, Birch reduction
Scheme 3. Birch Reductive Alkylation of Polysubstituted
Scheme 2. Birch Reductive Alkylation of Biaryls with One
Biaryls
Substituted Arene
of biaryl 11 led to the alkylated product 12 in high yield. In
comparison, biaryl 13 produced an inseparable mixture of
alkylated product 14 (which also lost a methoxy group) and
starting material in a 1:1 ratio (1H NMR). This indicates that
electron transfer followed by protonation is not regioselective
in this case, occurring both on 3,4- and 3,5-dimethoxyphenyl
rings.
Methoxy groups ortho or para to an activating group (here
the second arene) are known to be good leaving groups under
such reaction conditions. It was thus decided to replace the
p-OMe group in 13 by a OH group, which should be a poorer
leaving group.6 This proved to be the case since phenols 15
and 17 led to exclusive reduction on the 3,5-dimethoxyphenyl
ring, but with no or only partial alkylation (Scheme 4). For
instance, 15 led to 38% of alkylated product 16, along with
51% of the reduced diene (not shown), while 17 led only to
the reduced product in 51% yield and recovered starting
material (21%). The large amount of reduced product is
attributed to the protonation of the carbanionic intermediate
by the acidic phenolic proton, protonation thus competing
with alkylation (Vide infra).11 This problem was eventually
solved by performing Li/NH3 reduction on biaryls 15 and
17, after prior deprotonation of the phenol with n-BuLi (1.1
equiv). Under these conditions, Birch reductive alkylation
commercially available biphenyl 5 was carried out in Li/
NH3 at -33 °C. Reduction occurred regioselectively on the
unsubstituted ring to provide the alkylated product 6, albeit
in a moderate 44% yield (along with 23% recovered 5 and
some polymeric byproducts). The same reaction carried out
on the methylated analogue 7 led to a 77:23 mixture of
alkylated products 8a,b, with the reduction and alkylation
(7) (a) Birch, A. J.; Nadamuni, G. J. Chem. Soc., Perkin Trans. 1 1974,
545-552. (b) Tanaka, H.; Takamura, Y.; Shibata, M.; Ito, K. Chem. Pharm.
Bull. 1986, 34, 24. (c) Marcinow, Z.; Clawson, D. K.; Rabideau, P. W.
Tetrahedron 1989, 45, 5441-5448. (d) Rabideau, P. W.; Huser, D. L.;
Nyikos, S. J. Tetrahedron Lett. 1980, 21, 1401. (e) Lindow, D. F.; Harvey,
R. G. J. Am. Chem. Soc. 1971, 93, 3786-3787.
(8) (a) Mu¨ller, P. M.; Pfister, R. HelV. Chim. Acta 1973, 66, 771-779.
(b) Rabideau, P. W.; Peters, N. K.; Huser, D. L. J. Org. Chem. 1981, 46,
1593-1597. (c) Guo, Z.; Schultz, A. G. Org. Lett. 2001, 3, 1177-1180.
(9) The relative rates of reduction of two separate arenes may differ from
the order observed if these arenes were conjugated.
(10) Biaryls 13 and 23 were prepared using a Suzuki coupling. Biaryls
15, 17, 21a,b having a 3,5-dimethoxyphenyl moiety are more conveniently
prepared on a large scale using a four-step one-pot sequence (see the
Supporting Information).
(11) Addition of excess lithium (3.3 equiv) led to the same result.
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Org. Lett., Vol. 7, No. 21, 2005

conditions, to the alkylated diene 24 in reasonable yield,
along with some reduced product (∼20%).
Scheme 4. Birch Reductive Alkylation of Biaryls with a m- or
p-Phenol Group
These results may be rationalized following the mechanism
summarized in Scheme 6. Regioselectivity in Birch reduction
Scheme 6. Tentative Mechanistic Rationale of the Birch
Reductive Alkylation of Biaryls
occurred smoothly at -78 °C, producing the desired dienes
16 and 18 in excellent yields (Scheme 4). Interestingly, under
these conditions, phenol 19 also led to alkylated product 20,
albeit in a modest 48% yield. This last example demonstrates
that it is possible, through a careful tuning of the nature of
the substituents on the aromatic ring, to alkylate selectively
the substituted arene (as in 10b) or the unsubstituted one
(as in 20), starting from closely related biaryls 9 and 19,
respectively. This simple protocol is also of interest as it
provides a ready access to dienes such as 16, which are
precursors of pallidine 3 and other morphine analogues.
While this protocol was found efficient and reproducible
with phenol in meta and para positions relative to the biaryl
linkage, such was not the case with o-phenols, which were
reduced in good yields but were reluctant to undergo further
alkylation (Scheme 5). For instance, o-phenol 21a and 21b
is determined during the first step, involving protonation of
the radical anion A, formed through electron transfer from
Li to the biaryl system, and during the second protonation
of the cyclohexadienyl anion C. In line with kinetic studies
and calculations by Zimmerman et al.,12 we propose that
protonation occurs first at the site of highest electron density
(C4) to provide the most stable radical species B. This would
explain the tendency to transfer electrons regioselectively
to the most electron-rich arene, which is also more proficient
at stabilizing a radical species. A second transfer of electron
onto B would then lead to carbanion C, which may then be
alkylated. In the presence of a better source of proton than
NH3 (i.e., phenol or NHR), protonation of C contends with
alkylation to provide reduced products (R′ ) H). Without
any proton source, ammonia is too weak an acid to protonate
the benzylic carbanion and alkylation may ensue. Formation
of a dianion intermediate D has also been proposed in the
Birch reduction of biaryls and should not be ruled out.13 In
this case, protonation of D could also occur at (C4) to provide
the most stable anion C.
Scheme 5. Birch Reductive Alkylation of Biaryls with
o-Phenol or Amino Groups
Finally, reduction during Birch reduction of biaryls pos-
sessing an o-phenol substituent (i.e., 21a,b) may result from
an increase in the basicity of carbanion C due to an oxanion-
carbanion repulsion.14 Successful reductive alkylation of
(12) (a) Zimmerman, H. E.; Wang, P. A. J. Am. Chem. Soc. 1993, 115,
2205-2216 and references therein. (b) Lindow, D. F.; Cortez, C. N.; Harvey,
R. G. J. Am. Chem. Soc. 1972, 94, 5406-5412.
(13) (a) Mu¨llen, K.; Huber, W.; Neumann, G.; Schnieders, C.; Unterberg,
H. J. Am. Chem. Soc. 1985, 107, 801-807. (b) Mu¨llen, K. Angew. Chem.,
Int. Ed. Engl. 1987, 26, 204-217.
led to the reduced diene 22a and 22b in excellent yield after
deprotonation with 1.1 equiv of n-BuLi. In sharp contrast,
N-Boc-protected o-aminobiaryl 23 led, under the same
Org. Lett., Vol. 7, No. 21, 2005
4559

which was then directly submitted to Pictet-Spengler
cyclization using Echenmoser’s salt,16 affording 27 in five
steps and 20% overall yield from biaryl 19.
Scheme 7. Access to Crinine-Type Alkaloids
In summary, we report here on the preliminary investiga-
tions on regioselective Birch reductive alkylation of biaryls.
The reactivity profile of a series of biarylic systems has thus
been established, demonstrating that reduction of poorly
activated arenes can be followed by alkylation through a
careful choice of substituents. This is to our knowledge the
first Birch reductive alkylations of polysubstituted biaryls.
This complements nicely the well-known Birch reductive
alkylation of benzoic and heterocyclic esters and amides.17
The process is applicable to a large variety of biarylic systems
and is readily amenable to large scale synthesis. This strategy
can offer a rapid entry toward useful building blocks for the
synthesis of alkaloids. Desymmetrization of these dienes is
actively pursued in our laboratory and will be reported in
due course.
biaryl 23 would support such a hypothesis as, in this case,
delocalization of the nitrogen negative charge on the Boc
carbonyl function would reduce this repulsion and thus allow
the alkylation. A subtle change in the structure of the starting
biaryl (ortho vs meta OH group) thus makes the anion C
resistant (or not) to protonation by NH3. Our attempts to carry
out Birch reductive alkylation on 21a,b without ammonia
have so far been unsuccessful.
We finally established the utility of this strategy for the
synthesis of alkaloids such as those depicted above (Scheme
1) through a rapid access to a crinine analogue 27, starting
from diene 20 (Scheme 7). The phenol group of 20 was first
protected and the cyano group reduced using LiAlH4-AlCl3
to produce 25 in good overall yield. The piperidine ring of
the crinine skeleton was easily assembled through olefin
hydroamination using a catalytic amount of LDA.15 This
produced the desired intermediate 26 as a single isomer,
Acknowledgment. We gratefully acknowledge the CNRS,
MENRT (grant to R.L.), the Institut Universitaire de France,
and COST-D28 for financial support. We also thank Dr. C.
Guillou (ICSN, Gif sur Yvette) for fruitful discussions.
Supporting Information Available: Detailed experi-
mental procedures and spectral and analytical data for all
dienes and precursors. This material is available free of
charge via the Internet at http://pubs.acs.org.
OL051377I
(15) (a) Ates, A.; Quintet, C. Eur. J. Org. Chem. 2003, 1623-1626. (b)
Trost, B. M.; Tang, W. J. Am. Chem. Soc. 2003, 125, 8744-8745. (c) van
Otterlo, W. A. L.; Pathak, R.; de Koning, C. B.; Fernandes, M. A.
Tetrahedron Lett. 2004, 45, 9561-9563.
(16) (a) Schkeryantz, J. M.; Pearson, W. H. Tetrahedron 1996, 52, 3107-
3116. (b) Keck, G. E.; Webb II, R. R. J. Am. Chem. Soc. 1981, 103, 3173-
3177.
(17) (a) Schultz, A. G. Chem. Commun. 1999, 1263-1271 and references
therein. (b) Donohoe, T. J.; House, D. J. Org. Chem. 2002, 67, 5015-
5018. (c) Donohoe, T. J.; Johnson, D. J.; Mace, L. H.; Bamford, M. J.;
Ichihara, O. Org. Lett. 2005, 7, 435-437. (d) Gopalan, A.; Magnus, P. J.
Org. Chem. 1984, 49, 2317-2321.
(14) A loss of conjugation between the benzylic carbanion at C1 and
the neighboring arene due to a non planarity of the system may also increase
the basicity of the carbanion.
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