Aryl- and alkenyllithium preparations and copper-catalyzed reaction between the derived magnesium reagents and the monoacetate of 4-cyclopentene-1,3-diol

Article abstract of DOI:10.1021/ol0501065

(Chemical Equation Presented) Aryl- and alkenyllithiums, prepared by halogen-lithium exchange with lithium, exchange with n-(or t-)BuLi, stannane-lithium exchange with n-BuLi, and direct lithiation with n-BuLi, were transformed into magnesium reagents wit

Full text of DOI:10.1021/ol0501065

ORGANIC
LETTERS
2005
Vol. 7, No. 7
1319-1322
Aryl- and Alkenyllithium Preparations
and Copper-Catalyzed Reaction between
the Derived Magnesium Reagents and
the Monoacetate of
4-Cyclopentene-1,3-diol
Kenya Nakata and Yuichi Kobayashi*
Department of Biomolecular Engineering, Tokyo Institute of Technology,
Box B-52, 4259 Nagatsuta-cho, Midori-ku, Yokohama 226-8501, Japan
ykobayas@bio.titech.ac.jp
Received January 18, 2005
ABSTRACT
Aryl- and alkenyllithiums, prepared by halogen
n-BuLi, and direct lithiation with n-BuLi, were transformed into magnesium reagents with MgCl2 and subjected to CuCN-catalyzed reaction
with the title monoacetate. Except for the halogen lithium exchange with n-BuLi, the other preparations of the lithium anions were found to
be compatible with the CuCN-catalyzed reaction to afford SN2-type products efficiently.
−lithium exchange with lithium, exchange with n-(or t-)BuLi, stannane−lithium exchange with
−
Although preparation of the monoacetate of 4-cyclopentene-
1,3-diol (1) was established in the late 1980s,1 this compound
had not actively been used as a starting compound in organic
synthesis before we started our investigation2 due to the lack
of an efficient reaction for installation of a carbon moiety
onto the cyclopentene ring. Recently, we have developed a
reagent system for arylation of 1 consisting of a chlorine-
based Grignard reagent (ArMgCl) and a CuCN catalyst,
which proceeds in SN2 fashion to produce 2 (eq 1).2b,3 The
SN2 preference is unusual among copper-assisted reactions.4
Later, the reaction was expanded to bromine-based Grignard
reagents (ArMgBr) of low regioselectivity by adding MgCl2
or LiCl in the ArMgBr/CuCN catalyst system.5
(1) (a) Sugai, T.; Mori, K. Synthesis 1988, 19-22. (b) Laumen, K.;
Schneider, M. P. J. Chem. Soc., Chem. Commun. 1986, 1298-1299. (c)
Laumen, K.; Schneider, M. Tetrahedron Lett. 1984, 25, 5875-5878. (d)
Wang, Y.-F.; Chen, C.-S.; Girdaukas, G.; Sih, C. J. J. Am. Chem. Soc.
1984, 106, 3695-3696. (e) Deardorff, D. R.; Myles, D. C.; MacFerrin, K.
D. Tetrahedron Lett. 1985, 26, 5615-5618. (f) Deardorff, D. R.; Myles,
D. C. In Organic Syntheses; Freeman, J. P., Ed.; Wiley: New York, 1993;
Collect. Vol. 8, pp 13-16.
(2) (a) Kobayashi, Y. Curr. Org. Chem. 2003, 7, 133-147. (b) Ainai,
T.; Ito, M.; Kobayashi, Y. Tetrahedron Lett. 2003, 44, 3983-3986. (c)
Hattori, H.; Abbas, A. A.; Kobayashi, Y. Chem. Commun. 2004, 884-
885. (d) Kobayashi, Y.; Murugesh, M. G.; Nakano, M.; Takahisa, E.;
Usmani, S. B.; Ainai, T. J. Org. Chem. 2002, 67, 7110-7123.
In connection with this research project, we targeted
organomagnesium chlorides derived from RLi (4) and MgCl2.
10.1021/ol0501065 CCC: $30.25
© 2005 American Chemical Society
Published on Web 03/08/2005

Since 4 is accessible by several methods6 such as halogen-
lithium exchange with lithium, exchange with n-(or t-)BuLi,
stannane-lithium exchange, and direct lithiation, these
preparations were expected to raise the synthetic potential
of the CuCN-catalyzed reaction of 1. For example, the
organolithium alternation serves sterically defined alkenyl
anions without loss of the stereochemical integrity of the
precursors. In this regard, partial loss of the olefin geometry
in Grignard preparation from the alkenyl halides and Mg
seems difficult to suppress.7 Herein, we present in situ
preparations of aryl- and alkenyllithiums (4) according to
the methods mentioned above and the CuCN-catalyzed
reaction of 1 with the derived magnesium reagents. Except
for the halogen-lithium exchange of ArX with n-BuLi, the
preparations of 4 were compatible with the subsequent
reaction. Furthermore, we elucidated a reason for the different
results among the preparations and established a guideline
for the successful installation using 4.
With RMgCl in mind as a necessary source for performing
the SN2-type reaction with the CuCN catalyst, PhLi (4a) (3
equiv of monoacetate 1) in cyclohexanes-Et2O (2:1), which
was prepared by halogen-lithium exchange with lithium,8
was added to an ice-cold mixture of MgCl2 (2-5 equiv)9 in
THF. After 15 min, CuCN (0.3 equiv) and, again after 20-
30 min, monoacetate 1 (1 equiv) were added to the mixture,
and the reaction was carried out at 0 °C for 1 h to obtain the
results summarized in Table 1. For comparison, the native
regioselectivity but also suppressed the nucleophilic attack
to the Ac carbon (entries 2-5 vs entry 1). Among the entries,
4-5 equiv of MgCl2 provided the best results in terms of
the yield of 2a and the regioselectivity (2a over 3a) as shown
in entries 4 and 5.
The best reaction conditions found above were applied to
PhLi (4a) prepared in situ from PhX (X ) I, Br, SnBu3) by
several methods. First, 4a was prepared in the usual manner
from PhI by halogen-lithium exchange with n-BuLi and
subjected to the reaction with 1. Surprisingly, the expected
product 2a was not produced (Table 2, entry 1); instead,
Table 2. Phenylation of Monoacetate 1 Using PhLi Derived
from PhX or PhSnBu3 and BuLia
ratio
yield conversion
entry
source of PhLib (equiv)
of 2:3 of 2, %c
of 1, %c
1
2
3
4
5
PhI (3), n-BuLi (3.3)
PhBr (3), n-BuLi (3.3)
PhI (3), t-BuLi (6.0)
PhBr (3), t-BuLi (6.0)
-
-
92:8
92:8
0
0
<10d
<10d
100
100
100
94 (91)
90 (85)
PhSnBu3 (3.6), n-BuLi (3.6) >95:<5 86 (74)
a CuCN-catalyzed reactions were carried out with PhMgCl‚LiCl (3-3.6
equiv) prepared from PhLi (4a) (3-3.6 equiv) and MgCl2 (4 equiv) (THF,
0 °C, 1 h). b PhLi (4a) was prepared in situ from the source indicated in
the table. c Yield and conversion were determined by 1H NMR analysis.
Isolated yields are indicated in parentheses. d Instead, starting 1 and
1
butylbenzene were confirmed by H NMR spectroscopy.
butylbenzene (n-Bu-Ph), though volatile, was detected in
the crude reaction mixture with recovered monoacetate 1 by
1H NMR spectroscopy. A similar result was also observed
in entry 2 using the anion derived from PhBr and n-BuLi.
We postulated that n-BuX (X ) I, Br), coproduced with 4a
by the halogen-lithium exchange, substantially consumed
PhMgCl by the CuCN-catalyzed coupling reaction before
addition of 1 even within 30 min (Scheme 1).11
Table 1. Phenylation of Monoacetate 1a
ratio
of 2a:3a
yield
conversion
entry
additive
equiv
of 2a, %b
of 1, %b
1
2
3
4
5
-
-
2
3
4
5
65:35
75:25
86:14
>95:<5
>95:<5
22
26
51
78 (75)
85 (72)
100c
55d
64d
100
100
MgCl2
MgCl2
MgCl2
MgCl2
a Reaction was conducted with PhLi (4a) (3 equiv) in the presence or
absence of the additive and CuCN (0.3 equiv) in THF at 0 °C for 1 h.
b Yield and conversion were determined by 1H NMR analysis. Isolated yields
are indicated in parentheses. c Major products were Ph2C(OH)Me and the
corresponding diol. d Starting 1 was recovered.
Scheme 1. Reaction Courses of PhLi Generated by
Halogen-Lithium Exchangesa
property of the 4a/CuCN catalyst was also examined (entry
1).10 As can be seen, MgCl2 not only altered the native low
(3) Compounds 2 (R ) aryl, alkenyl) have been synthesized from
cyclopentene monoepoxide, but in low regioselectivities: (a) Marino, J.
P.; Ferna´ndez de la Pradilla, R.; Laborde, E. J. Org. Chem. 1987, 52, 4898-
4913. (b) Tueting, D. R.; Echavarren, A. M.; Stille, J. K. Tetrahedron 1989,
45, 979-992. (c) Tucci, F. C.; Chieffi, A.; Comasseto, J. V.; Marino, J. P.
J. Org. Chem. 1996, 61, 4975-4989.
(4) (a) Lipshutz, B. H. In Organometallics in Synthesis; Schlosser, M.,
Ed.; Wiley: New York, 1994; Chapter 4. (b) Lipshutz, B. H. In Organo-
metallics in Synthesis, 2nd ed.; Schlosser, M., Ed.; Wiley: New York, 2002;
Chapter 6. (c) Helmchen, G.; Ernst, M.; Paradies, G. Pure Appl. Chem.
2004, 76, 495-506.
a Results are summarized in Table 2.
(5) Kobayashi, Y.; Nakata, K.; Ainai, T. Org. Lett. 2005, 7, 183-186.
(6) (a) Schlosser, M. In Organometallics in Synthesis; Schlosser, M.,
Ed.; Wiley: New York, 1994; Chapter 1. (b) Schlosser, M. In Organo-
metallics in Synthesis, 2nd ed.; Schlosser, M., Ed.; Wiley: New York, 2002;
Chapter 1.
(7) Ref 5 in: Sapountzis, I.; Dohle, W.; Knochel, P. Chem. Commun.
2001, 2068-2069.
To support this hypothesis, n-BuX (X ) I, Br) (3 equiv
of 1) was added externally to the solution of PhLi (3 equiv)
(8) We thank Kanto Kagaku, Japan for providing us this information.
(9) Prepared freshly from Mg and Cl(CH2)2Cl in a ratio of 1:3.
1320
Org. Lett., Vol. 7, No. 7, 2005

in cyclohexanes-Et2O, which was prepared by the halogen-
lithium exchange with Li, and the resulting solution was
mixed first with MgCl2 (4 equiv) for 15 min and then with
CuCN (30 mol %) for 20-30 min. The mixture thus prepared
upon reaction with 1 afforded 2a in 0-32% yields with
n-Bu-Ph (32-100%) and 1 (54-97%) (Scheme 2).
conversion into the magnesium species, 4b afforded the SN2-
type product 2b in 82% isolated yield with >95% regio-
selectivity (Scheme 3). In a similar way, 2-furyllithium 4c13
Scheme 3. Reaction of 1 with Reagents Derived from 4b or
4c (3 equiv), MgCl2 (4 equiv), and CuCN (30 mol %)
Scheme 2. Results Supporting the Side Reaction of PhMgCl
with n-BuX by Using PhLi (3 equiv to 1), n-BuX or Cl(CH2)2Cl
(3 equiv), CuCN (30 mol %), and 1 (1 equiv)
Since n-BuX was confirmed to consume PhMgCl, one
might expect a similar interference by Cl(CH2)2Cl, which
was used for the preparation of MgCl2 from Mg. Although
the successful results of Table 1, entries 4 and 5, precluded
such an interference, additional evidence was provided by
external addition of Cl(CH2)2Cl to the pure PhMgCl and
subsequent reaction with 1, which afforded the normal
coupling product 2a in good yield (Scheme 2, the lower
equation).
The above results suggested successful phenylation of 1
with PhLi (4a) prepared from PhX by halogen-lithium
exchange with t-BuLi, since LiX and isobutene, coproduced
with PhLi, would be inert in the desired reaction (see Scheme
1). In practice, the t-BuLi alternation was proved to be the
case. Thus, 4a (3 equiv of 1), produced from PhX (X ) I,
Br) and t-BuLi, was combined with MgCl2 (4 equiv), and
the subsequent CuCN-catalyzed reaction with 1 produced
2a in good yields and high regioselectivity (Table 2, entries
3 and 4). The efficiency thus observed was comparable to
that obtained with the PhLi/MgCl2/CuCN catalyst (Table 1,
entries 4 and 5).
derived from furan and n-BuLi furnished 2c efficiently.
The synthetic advantage of using an organostannane as a
source of alkenyllithium was highlighted by alkenylation of
1. Thus, cis-alkenyllithium 4d was prepared from cis-
alkenylstannane 5 and n-BuLi and subjected to the CuCN-
catalyzed reaction with 1 after in situ conversion into the
organomagnesium chloride to afford 2d in 65% yield with
>95% regioselectivity (Scheme 4). Similarly, trans-alkenyl-
Scheme 4. Reaction of 1 with Reagents Derived from 4d or
4e (3 equiv), MgCl2 (4 equiv), and CuCN (30 mol %)
Preparation of PhLi (4a) by the stannane-lithium ex-
change of PhSnBu3 and n-BuLi was also expected to be
compatible with the CuCN-catalyzed reaction of 1. Thus,
4a was produced from PhSnBu3 and n-BuLi in THF at 0 °C
for 30 min, and subsequent reaction with 1 after transforma-
tion into PhMgCl produced 2a with good efficiency (Table
2, entry 5), which is as high as that of entry 4 in Table 1.
Another compatible preparation of ArLi would be direct
lithiation of aromatic compounds with n-BuLi, which was
proven by using the aryl anion 4b derived from the MOM
ether of phenol by ortho lithiation with n-BuLi.12 After
stannane 6 produced 2e as well. No product crossover by
2e was observed in the 1H NMR spectra of 2d and vice versa.
In comparison with the previous alkenylation with lithium
alkenylborates/nickel catalyst2d (85-89% yield, 83-86%
regioselectivity), the present method is more efficient and
the reagent preparation is simpler than that of the borates,
which took three steps from the alkenyllithiums.
(10) Reactions with Ph2Cu(CN)Li2 (3 equiv) and PhCu(CN)Li (3 equiv)
in THF at 0 °C to room temperature afforded a mixture of products among
which the corresponding diol was the major component.
(11) Nova´k, J.; Salemink, C. A. Synthesis 1983, 597-598.
(12) (a) Snieckus, V. Chem. ReV. 1990, 90, 879-933. (b) Townsend, C.
A.; Bloom, L. M. Tetrahedron Lett. 1981, 40, 3923-3924.
The alkenyl protocol was applied to prostaglandin syn-
thesis (Scheme 5). Alkenyl stannane 7 was prepared by
(13) Ramanathan, V.; Levine, R. J. Org. Chem. 1962, 27, 1216-1219.
Org. Lett., Vol. 7, No. 7, 2005
1321

the nickel-catalyzed alkenylation2d in 76% yield with >95%
regioselectivity, and transformed into ∆7-PGA1 methyl ester
(9), which is an antitumor agent found by Suzuki and
Noyori.15 Although the efficiency of the respective methods
is comparable, the present reaction is advantageous in terms
of the reagent preparation (vide ante).
Scheme 5. Synthesis of Prostaglandin Intermediate 2f
In summary, the CuCN-catalyzed arylation of 1 with aryl-
MgCl to afford the SN2 product 2 was expanded to aryl and
alkenyllithium anions, which were prepared through halogen-
lithium exchange with lithium, exchange with t-BuLi,
stannane-lithium exchange with n-BuLi, and direct lithiation
with n-BuLi. However, the lithium anion prepared by the
usual halogen-lithium exchange with n-BuLi was not
compatible with the CuCN-catalyzed reaction. The reason
for the failure was elucidated and is informative for other
Cu-catalyzed reactions.
Acknowledgment. This work was supported by a Grant-
in-Aid for Scientific Research from the Ministry of Educa-
tion, Science, Sports, and Culture, Japan.
hydrostannation of the corresponding acetylene14 and con-
verted into the magnesium reagent 8 by the stannane-lithium
exchange with n-BuLi followed by transmetalation of the
resulting 4f with MgCl2. Reaction of 1 and 8 thus prepared
proceeded cleanly with the CuCN catalyst to produce 2f
exclusively in 74% yield. Previously, 2f was synthesized by
Supporting Information Available: Typical experimen-
tal procedures, compound characterization, and copies of
spectra. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL0501065
(15) (a) Kato, T.; Furushima, M.; Kurozumi, S.; Noyori, R. Cancer Res.
1986, 46, 3538-3542. (b) Noyori, R.; Suzuki, M. Science 1993, 259, 44-
45.
(14) Nicolaou, K. C.; Veale, C. A.; Webber, S. E.; Katerinopoulos, H.
J. Am. Chem. Soc. 1985, 107, 7515-7518.
1322
Org. Lett., Vol. 7, No. 7, 2005