Stereoselective cyclizations mediated by functionalized organomagnesium reagents and catalyzed by cobalt or copper salts

Article abstract of DOI:10.1016/S0040-4039(02)00839-0

The iodine-magnesium exchange reaction with i-PrMgCl allows a mild preparation of functionalized arylmagnesium compounds bearing a leaving group in the molecule. With the appropriate transition-metal catalyst (a copper or cobalt salt), cyclization reactions occur leading to five- or six-membered ring systems in good yields.

Full text of DOI:10.1016/S0040-4039(02)00839-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 4875–4879
Stereoselective cyclizations mediated by functionalized
organomagnesium reagents and catalyzed by cobalt or
copper salts
Florian F. Kneisel, Yasunari Monguchi, Kolja M. Knapp, Hendrik Zipse and Paul Knochel*
Department Chemie, Ludwig-Maximilians-Universita¨t Mu¨nchen, Butenandtstrasse 5-13, Building F, D-81377 Mu¨nchen, Germany
Received 23 April 2002; revised 29 April 2002; accepted 30 April 2002
Abstract—The iodine–magnesium exchange reaction with i-PrMgCl allows a mild preparation of functionalized arylmagnesium
compounds bearing a leaving group in the molecule. With the appropriate transition-metal catalyst (a copper or cobalt salt),
cyclization reactions occur leading to five- or six-membered ring systems in good yields. © 2002 Elsevier Science Ltd. All rights
reserved.
Recently, we have shown that the iodine–magnesium
exchange reaction is a general method for preparing
functionalized aryl-, heteroaryl- and alkenyl-magnesium
reagents.1,2 Since this method allows the preparation of
a wide range of Grignard reagents bearing electrophilic
functionalities, we envisioned the preparation of hetero-
cycles from substrates of type 1 or 2. Reaction with
i-PrMgCl should selectively afford the corresponding
organomagnesium reagents of type 3 and 4, which may
undergo a ring closure reaction either directly or in the
presence of a transition-metal catalyst,3 leading to
products of type 5 or 6 (Scheme 1).
First, we examined the reaction of the three aromatic
iodides 7–9. In all cases, the iodine–magnesium
exchange in the presence of i-PrMgCl (1.0 equiv.) was
fast and complete at −30°C within 1 h. Upon warming
of the intermediate Grignard reagent to room tempera-
ture, the cyclized product 10 or 11 was obtained in
variable yields, depending on the reaction conditions
(Scheme 2). Thus, the magnesium species derived from
the bromide 7 furnishes 2,3-dihydrobenzofuran 104 in
42% yield. When the diiodide 8 was subjected to the
same reaction conditions the heterocycle 10 was
obtained in 65% yield. Addition of a 1 M solution of
Scheme 1. Reagents and conditions: (i) THF, i-PrMgCl, −20°C; (ii) transition-metal catalysis (copper or cobalt salt).
* Corresponding author.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00839-0

4876
F. F. Kneisel et al. / Tetrahedron Letters 43 (2002) 4875–4879
1) i-PrMgCl (1.0 equiv),
O
O
THF, -30°C, 1 h
Y
2) 25°C, 2 h
3) add. or not
I
7: Y=Br
8: Y=I
CuCN · 2LiCl (1 mol%)
10: 42-87% (see text)
1) i-PrMgCl (1.0 equiv),
THF, -30°C, 1 h
O
I
O
2) CuCN · 2LiCl (1 mol%)
25°C, 2 h
I
9
11: 84%
SO2Ph
N
SO2Ph
N
1) i-PrMgCl (1.0 equiv),
THF, -30°C, 1 h
Br
2) CuCN · 2LiCl (1 mol%)
25°C, 2 h
I
12
13: 87%
Scheme 2.
the THF soluble copper salt CuCN·2LiCl5 (1 mol%)
promoted a smooth cyclization, affording 10 in 79%
yield starting from 7 and 87% yield starting from the
diiodide 8, demonstrating the efficient catalysis of
copper salts in these intramolecular SN2 reactions.6,7
These results confirm that the substitution reactions
are more efficient with alkyl iodides than with alkyl
bromides.
warming up to room temperature the yield of the
cyclized product could be increased to 65% and even
to 83% at 45°C, showing that under these conditions,
the sensitive ethyl ester function does not react with
the Grignard reagent. We have also studied the stere-
ochemistry of the cyclization step. We prepared the
tosylates 14a, 17 and 20 in optically enriched form in,
respectively, 60, 57 and 42% ee, by using the method
of Jacobsen.9 After cyclization induced by the addi-
tion of CuCN·2LiCl (10–25 mol%), the products 16a,
19 and 22 were obtained in 83, 41 and 46% yield and
in 60, 57 and 42% ee, showing that the reaction
occurs with complete inversion of configuration6,7,10
(Scheme 3). Next, we turned our attention toward the
cyclization of substrates of type 23 bearing an allylic
acetate as leaving group. We prepared cis-23, trans-23
and trans-24 using the method of Ba¨ckvall.11 Thus,
the sodium salt of the sulfonamide 25a was treated
(25°C, 16 h) with the allylic chloride 26 in the pres-
ence of Pd(dba)2 (10 mol%) and PPh3 (40 mol%),
affording the precursor cis-23 in 76% yield. On the
other hand, treatment of 25a–b with the allylic chlo-
ride 26 in the presence of K2CO3 (1.2 equiv.) in
DMSO (80°C, 22 h) gave the corresponding acetates
trans-23 and trans-24 in 89 and 35% yield, respec-
tively.
In the presence of CuCN·2LiCl (1 mol%), the Grig-
nard reagent derived from 9 underwent ring closure
to chroman 11 in 84% yield (Scheme 2). Interestingly,
these conditions could be used with nitrogen-function-
alized substrates. The iodosulfonamide 12 was con-
verted
under
standard
conditions
to
the
corresponding intermediate Grignard reagent (i-
PrMgCl, THF, −30°C, 1 h). After treatment with
CuCN·2LiCl (1 mol%) a smooth cyclization occurred
(25°C, 2 h) leading to the sulfonylated 1,2,3,4-tetra-
hydro-quinoline 13 in 87% yield. We have examined
functionalized substrates such as the readily available
tosylates 14a–b which contain an ester functionality.
In both cases, the I–Mg exchange reaction proceeded
smoothly at −20°C within 1 h, leading to the corre-
sponding Grignard reagents 15a–b. In the case of the
diiodide 14b, only
observed.
a mono I–Mg exchange is
The treatment of cis-23 and trans-23 with i-PrMgCl
(1.1 equiv. in THF, −10°C, 16 h) furnished the corre-
sponding Grignard reagent as expected. Whereas
trans-23 underwent cyclization leading quantitatively
to the cis carbazole derivate 27, the Grignard reagent
derived from cis-23 did not undergo ring closure.
However, the addition of CuCN·2LiCl (50 mol%) led
to cyclization (25°C, 15 h) in quantitative yield.
The ester and tosylate functions of both substrates
are compatible with the conditions of the iodine–mag-
nesium exchange; 10 mol% of the catalyst
(CuCN·2LiCl) was used. In a preliminary experiment
with 14a,8 the reaction was kept at 0°C for 12 h after
the addition of CuCN·2LiCl and 16a was obtained in
50% yield. By performing the same reaction and

F. F. Kneisel et al. / Tetrahedron Letters 43 (2002) 4875–4879
OTos OTos
4877
O
O
O
X
i
iii
X
I
X
MgCl
CO2Et
CO2Et
CO2Et
14a: X=H
14b: X=I
15a: X=H
15b: X=I
16a: 83%
16b: 85%
OTos
OTos
O
O
O
R
I
R
ClMg
R
iii
i
CO2Et
CO2Et
CO2Et
14a: R=Me; 60% ee
17: R=Bu; 57% ee
15a: R=Me
18: R=Bu
16a: 83%; 60% ee
19: 41%; 57% ee
O
O
O
ClMg
I
OTos
OTos
ii
iv
CO2Et
CO2Et
CO2Et
22: 46%; 42% ee
20: 42% ee
21
Scheme 3. Reagents and conditions: (i) THF, i-PrMgCl, −20°C, 1 h; (ii) THF, i-PrMgCl, −10°C, 10 h; (iii) CuCN·2LiCl (10
mol%), −20°C to 25°C or 45°C, 12 h; (iv) CuCN·2LiCl (25 mol%), −10°C to 45°C, 12 h.
Alternatively, we found that by adding Co(acac)2
(10 mol%) instead of CuCN·2LiCl, a similar ring
closure reaction occurred (−10°C, 17 h) leading to 27
in >95% yield.
explains the preferential cyclization of the trans-iso-
mers 23 and 24.
In summary, we have shown that polyfunctionalized
arylmagnesium compounds bearing a primary halide
or a secondary tosylate can be readily prepared by an
iodine–magnesium exchange. A smooth cyclization
reaction occurs after the addition of a catalytic
amount of CuCN·2LiCl. These ring closures occur
with complete inversion of configuration. In the case
of allylic acetates, an anti-substitution (SN2%) occurs
directly from the Grignard intermediate. The cycliza-
tion of the substrate requiring syn-substitution only
took place in the presence of copper or cobalt salts.
Similarly, the ester-substituted substrate trans-24 was
converted into the cis-tetrahydrocarbazole 28, after
successive treatment with i-PrMgCl (1.1 equiv., −
10°C, 1 h) and a catalytic amount of CuCN·2LiCl
(50 mol%, −20°C, 4 h), in 69% yield. In the absence
of CuCN·2LiCl, the heterocycle 28 was obtained in
56% yield (Scheme 4). These results indicate that an
intramolecular anti-SN2%-substitution reaction has a
low activation energy. In the case of the cis-substrate
23, anti-substitution would provide a carbazole con-
taining a higher energy trans-ring junction. This
explains the preferential cyclization of the trans-iso-
mers 23 and 24. An estimate of the cis/trans energy
difference using Boltzmann-averaged enthalpies for all
conformers within a 40 kJ/mol window leads to a
preference for cis-27 of 20.6 kJ/mol. Provided that
this energy difference is also descriptive of the SN2
transition states leading to 27, this corresponds to a
cis/trans product ratio of 150 000:1.12 This also
Acknowledgements
We thank the DFG (Leibniz-Program) and the Fonds
der Chemischen Industrie for generous financial sup-
port. We thank Chemetall GmbH (Frankfurt),
Degussa AG (Hanau) and BASF AG for the gener-
ous gift of chemicals.

4878
F. F. Kneisel et al. / Tetrahedron Letters 43 (2002) 4875–4879
Cl
OAc
26
R
I
OAc
26, i
iii
N
Ts
H
H
R
I
R
cis-23: 76%
NH
Ts
N
Ts
25a: R=H
25b: R=CO2Et
27: R=H; 95%
R
I
OAc
28: R=CO2Et; 69%
iv
26, ii
N
Ts
trans-23: R=H; 89%
trans-24: R=CO2Et; 35%
Scheme 4. Reagents and conditions: (i) Pd(PPh3)4 (10 mol%), rt, 16 h; (ii) K2CO3, DMSO, 80°C, 22 h; (iii) i-PrMgCl, CuCN·2LiCl
or Co(acac)2 cat.; (iv) i-PrMgCl, −10°C to rt, anti-substitution.
References
lowing an analogous literature procedure (Sy, W.-W.
Synth. Commun. 1992, 22, 3215–3219). The second step
was an etherification following an analogous literature
procedure (Buisson, J.-P.; Demerseman, P. J. Hetero-
cyclic Chem. 1995, 32, 17–24) using 2-chloroacetone as
the electrophile. The keto function was reduced with
1.0 equiv. NaBH4 at −25°C in MeOH. Tosylation of
the alcohol with toluene-4-sulfonic anhydride in
dichloromethane in the presence of NEt3 at room tem-
perature resulted in the formation of 14a and 14b.
9. Enantiomerically enriched cyclization precursors 14a, 17
and 20 were prepared as described in Ref. 8, see also:
Ready, J. M.; Jacobsen, E. N. J. Am. Chem. Soc. 1999,
121, 6086–6087.
1. (a) Jensen, A. E.; Dohle, W.; Sapountzis, I.; Lindsay,
D. M.; Vu, V. A.; Knochel, P. Synthesis 2002, 565–569;
(b) Boudier, A.; Bromm, L. O.; Lotz, M.; Knochel, P.
Angew. Chem., Int. Ed. 2000, 39, 4415–4435; (c) Boy-
mond, L.; Rottla¨nder, M.; Be´rillon, L.; Lepreˆtre, A.;
Varchi, G.; Avolio, S.; Laaziri, H.; Que´guiner, G.;
Cahiez, G.; Knochel, P. Chem. Eur. J. 2000, 6, 767–
770.
2. For a selective halogen–magnesium exchange reaction
using organomagnesium-ate complexes, see: Inoue, A.;
Kitagawa, K.; Shinokubo, H.; Oshima, K. J. Org.
Chem. 2001, 66, 4333–4339.
3. Wakabayashi, K.; Yorimitsu, H.; Oshima, K. J. Am.
10. Hanessian, S.; Thavonekham, B.; DeHoff, B. J. Org.
Chem. 1989, 54, 5831–5833.
11. Ba¨ckvall, J. E.; Nystro¨m, J. E.; Nordberg, R. E. J. Am.
Chem. Soc. 1985, 107, 3676–3686.
Chem. Soc. 2001, 123, 5374–5375.
4. For an alternative way to prepare 2,3-dihydrofurans,
see for example: (a) Kuwabe, S.; Torraca, K. E.; Buch-
wald, S. L. J. Am. Chem. Soc. 2001, 123, 12202–12206;
(b) Inoue, K.; Sawada, A.; Shibata, I.; Baba, A. Tetra-
hedron Lett. 2001, 42, 4661–4663.
12. Geometry optimization was performed at the HF/6-
31G(d) level of theory. Zero point vibrational energies
and thermal corrections to enthalpies were also calcu-
lated at this level with a scaling factor of 0.89. Refined
energy differences were then computed through single
point calculations at the Becke3LYP/6-31G(d)//HF/6-
31G(d) level and combined with the HF/6-31G(d) ther-
mal corrections to yield enthalpy differences at 298 K.
The strong preference for cis-27 is quite insensitive to
the theoretical methods used, as neglect of thermal cor-
rections or the use of HF instead of B3LYP energies
leads to essentially the same result. All calculations
were performed with Gaussian 98.13
5. Knochel, P.; Yeh, M. C. P.; Berk, S. C.; Talbert, J. J.
Org. Chem. 1988, 53, 2390–2392.
6. For intermolecular SN2 substitution reactions, see: (a)
Lipshutz, B. H.; Wilhelm, R. S. J. Am. Chem. Soc.
1981, 103, 7672–7674; (b) Lipshutz, B. H.; Wilhelm, R.
S.; Kozlowski, J. A.; Parker, D. J. Org. Chem. 1984,
49, 3928–3938.
7. For a review, see: Lipshutz, B. H.; Sengupta, S. Org.
React. 1992, 41, 135–631.
8. The tosylates 14a–b were prepared starting from ethyl
4-hydroxybenzoate. The first step was an iodination fol-

F. F. Kneisel et al. / Tetrahedron Letters 43 (2002) 4875–4879
4879
13. Gaussian 98, Revision A.6, Frisch, M. J.; Trucks, G.
W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.;
Cheeseman, J. R.; Zakrzewski, V. G.; Montgomery, J.
A., Jr.; Stratmann, R. E.; Burant, J. C.; Dapprich, S.;
Millam, J. M.; Daniels, A. D.; Kudin, K. N.; Strain,
M. C.; Farkas, O.; Tomasi, J.; Barone, V.; Cossi, M.;
Cammi, R.; Mennucci, B.; Pomelli, C.; Adamo, C.;
Clifford, S.; Ochterski, J.; Petersson, G. A.; Ayala, P.
Y.; Cui, Q.; Morokuma, K.; Malick, D. K.; Rabuck,
A. D.; Raghavachari, K.; Foresman, J. B.; Cioslowski,
J.; Ortiz, J. V.; Stefanov, B. B.; Liu, G.; Liashenko, A.;
Piskorz, P.; Komaromi, I.; Gomperts, R.; Martin, R.
L.; Fox, D. J.; Keith, T.; Al-Laham, M. A.; Peng, C.
Y.; Nanayakkara, A.; Gonzalez, C.; Challacombe, M.;
Gill, P. M. W.; Johnson, B.; Chen, W.; Wong, M. W.;
Andres, J. L.; Gonzalez, C.; Head-Gordon, M.;
Replogle, E. S.; Pople, J. A. Gaussian, Inc., Pittsburgh,
PA, 1998.