Preparation of polyfunctional arylmagnesium reagents bearing a triazene moiety. A new carbazole synthesis

Article abstract of DOI:10.1021/ol0505454

(Chemical Equation Presented) The reaction of iodo- or bromo-substituted aryltriazenes with i-PrMgCl·LiCl generates the corresponding magnesiated derivatives which react with various electrophiles (acid chlorides, 3-iodoenones, allylic halides, aldehydes)

Full text of DOI:10.1021/ol0505454

ORGANIC
LETTERS
2005
Vol. 7, No. 13
2543-2546
Preparation of Polyfunctional
Arylmagnesium Reagents Bearing a
Triazene Moiety. A New Carbazole
Synthesis
Ching-Yuan Liu and Paul Knochel*
Department Chemie und Biochemie, Ludwig-Maximilians-UniVersita¨t, Butenandtstrasse
5-13, 81377, Mu¨nchen, Germany
paul.knochel@cup.uni-muenchen.de
Received March 12, 2005
ABSTRACT
The reaction of iodo- or bromo-substituted aryltriazenes with i-PrMgCl‚LiCl generates the corresponding magnesiated derivatives which
react with various electrophiles (acid chlorides, 3-iodoenones, allylic halides, aldehydes) affording polyfunctional triazenes. They can be
readily converted to the corresponding polyfunctional aryl iodides. This new synthetic strategy was applied to prepare functionalized car-
bazoles.
The triazene functionality (ArNdN-NR2) is a convenient
way to protect a diazonium salt and to carry this reactive
functionality through several steps. It has also proved its
utility as a linker in solid-phase combinatorial syn-
thesis.1 Of special synthetic interest is its conversion to an
iodide function under mild conditions.2 Recently, we
have developed a general halogen-magnesium exchange
reaction using the mixed Mg/Li reagent i-PrMgCl‚LiCl.3
Both aryl iodides and bromides undergo a halogen-
magnesium exchange under mild conditions. Since this
exchange reaction tolerates many functional groups, we
have examined the compatibility of an I/Mg exchange
Scheme 1
(1) For reviews, see: (a) Kimball, D. B.; Haley, M. M. Angew. Chem.,
Int. Ed. 2002, 41, 3338. (b) Moore, J. S. Acc. Chem. Res. 1997, 30, 402.
(c) Bra¨se, S. Acc. Chem. Res. 2004, 37, 805. See also: (d) Nicolaou, K. C.;
Li, H.; Boddy, C. N. C.; Ramanjulu, J. M.; Yue, T. Y.; Natarajan, S.; Chu,
X. J.; Bra¨se, S.; Ru¨bsam, F. Chem. Eur. J. 1999, 5, 2584. (e) Enders, D.;
Rijksen, C.; Bremus-Ko¨bberling, E.; Gillner, A.; Ko¨bberling, J. Tetrahedron
Lett. 2004, 45, 2839. (f) Lormann, M. E. P.; Dahmen, S.; Avemaria,
F.; Lauterwasser, F.; Bra¨se, S. Synlett 2002, 915. (g) Kimball, D. B.;
Herges, R.; Haley, M. M. J. Am. Chem. Soc. 2002, 124, 1572. (h) Kimball,
D. B.; Weakley, T. J. R.; Haley, M. M. J. Org. Chem. 2002, 67, 6395.
(i) Gross, M. L.; Blank, D. H.; Welch, W. M. J. Org. Chem. 1993, 58,
2104.
10.1021/ol0505454 CCC: $30.25
© 2005 American Chemical Society
Published on Web 05/20/2005

Scheme 2. Synthesis of Functionalized Carbazoles 6a and 6b
Scheme 3. Plausible Mechanism of the Cabazole Formation
to the polyfunctional magnesiated triazene (1c; entries
6-8) which reacts with electrophiles leading to the ester-
substituted triazenes 3f, 3g, and 3h in 78-86%. A similar
transformation is also achieved for a cyano-substituted
iodoaryltriazene (2d) providing the Grignard reagent (1d)
and the acylated products 3i (86%; entry 9) and 3j (85%;
entry 10). Finally, not only triazenes bearing a halogen in
the ortho-position undergo a halogen/magnesium exchange
smoothly, but also 1-(4-iodophenylazo)pyrrolidine (2e) reacts
with i-PrMgCl‚LiCl (-40 °C, 40 min) affording the corre-
sponding magnesiated triazene 1e. Its direct reaction with
EtCHO provides the benzylic alcohol 3k (90%; entry 11).
A copper-catalyzed acylation leads to the ketone 3l
(88%; entry12).
with a triazene moiety. We have found that in the case of
the reaction of iodotriazene with i-PrMgCl the triazene group
reacted, and no arylmagnesium reagent was formed. How-
ever, by using the more reactive exchange reagent i-PrMgCl‚
LiCl, this exchange reaction proceeds smoothly. Herein, we
wish to report the preparation of polyfunctional arylmag-
nesium reagents bearing a triazene functionality of type 1
starting from the aromatic halides of type 2 (X ) I or Br)
and leading to polyfunctional triazenes such as 3 which
can be converted to the polyfunctional iodides 4, allowing
an effective functionalization of aromatic derivatives
(Scheme 1).
The triazenes of type 3 are readily converted to the
corresponding aryl iodides using either a reaction in a
sealed-tube with MeI2a,b,d (15 equiv, 120 °C, 24-48 h;
method A) or in refluxing CH2Cl2 with TMSI (2 equiv,
4-6 h; method B) in 70-90% yield; see Table 2. Various
functional groups such as ketones, enones or an ester are
tolerated. In the case of a benzylic alcohol such as 3k, a
dehydration is observed leading to the iodostyrene 3j in 85%
yield (entry 10).
Thus, 1-(2,6-dibromophenylazo)pyrrolidine (2a) obtained
from 2,6-dibromoaniline in 95% yield (see the Supporting
Information) reacts with i-PrMgCl‚LiCl (1.05 equiv, -40
to -15 °C, 3.5 h) affording the expected arylmagnesium
derivative 1a (see entries 1-4 of Table 1). After a trans-
metalation with CuCN‚2LiCl,4 the resulting copper reagent
is readily allylated giving the triazene 3a (78%; entry 1 of
Table 1). Acylation of the copper derivatives of 1a or 1b
with acyl, heteroaryl or aliphatic acid chlorides furnishes the
expected ketones 3b (82%; entry 2), 3c (85%; entry 3) or
3e (82%; entry 5). An addition-elimination reaction with
3-iodo-2-cyclohexen-1-one leads to the triazene 3d in
80% yield (entry 4). Starting with 1-(2-iodo-4-carbo
ethoxyphenylazo)-pyrrolidine (2c), the reaction with
i-PrMgCl‚LiCl is complete within 40 min at -40 °C leading
Using our method, we have developed a new carbazole
synthesis.5 Starting from the Grignard reagents 1a and
1c, we performed
a
Negishi cross-coupling6 with
1,2-diiodobenzene leading to the derived polyfunctional
(2) (a) Moore, J. S.; Weinstein, E. J.; Wu, Z. Tetrahedron Lett. 1991,
32, 2465. (b) Wu, Z.; Moore, J. S. Tetrahedron Lett. 1994, 35, 5539.
(c) Ku, H.; Barrio, J. R. J. Org. Chem. 1981, 46, 5239. (d) Wan, W. B.;
Chiechi, R. C.; Weakley, T. J. R.; Haley, M. M. Eur. J. Org. Chem.
2001, 3485.
(3) (a) Krasovskiy, A.; Knochel, P. Angew. Chem., Int. Ed
2004, 43, 3333. (b) Kopp, F.; Krasovskiy, A.; Knochel, P. Chem. Commum.
2004, 2288. (c) Ren, H.; Krasovskiy, A.; Knochel, P. Org. Lett. 2004, 6,
4215. See also: (d) Knochel, P.; Dohle, W.; Gommermann, N.; Kneisel,
F. F.; Kopp, F.; Korn, T.; Sapountzis, I.; Vu, V. A. Angew. Chem., Int. Ed.
2003, 42, 4302.
(4) Knochel, P.; Yeh, M. C. P.; Berk, S. C.; Talbert, J. J. Org. Chem.
1988, 53, 2390.
(5) Kno¨lker, H. S.; Reddy, K. R. Chem. ReV. 2002, 102, 4303.
2544
Org. Lett., Vol. 7, No. 13, 2005

Table 1. Polyfunctional Aryl Triazenes of Type 3 Obtained by the Reaction of the Grignard Reagents 1 with Electrophiles
a Isolated yield of analytically pure product.
biphenyls 5a (88%) and 5b (80%). The reaction of com-
pound type 5 with i-PrMgCl‚LiCl (1.1 equiv, -40 °C, 1 h)
provides the functionalized carbazoles 6a (75%) and
6b (70%). The evaporation of i-PrI resulting from the I/Mg-
exchange is important before heating (50 °C, 2 h). Otherwise,
unwanted cross-coupling products with i-PrI are observed
(Scheme 2). A tentative mechanism of the cyclization
involving the formation of a hydroxylamine derivative as
side-product is described in Scheme 3.
In summary, we have shown that the reaction of iodo- or
bromo-substituted aryltriazenes with i-PrMgCl‚LiCl gener-
ates magnesiated derivatives which react with various
electrophiles (acid chlorides, 3-iodoenones, allylic halides,
and aldehydes) to afford polyfunctional triazenes which can
be readily converted to the corresponding polyfunctional aryl
iodides. As an application of the versatility of these prod-
(6) (a) Green, L.; Chauder, B.; Snieckus, V. J. Heterocycl. Chem. 1999,
36, 1453. (b) Negishi, E.; Valente, L. F.; Kobayashi, M. J. Am. Chem. Soc.
1980, 102, 3298. (c) Kobayashi, M.; Negishi, E. J. Org. Chem. 1980, 45,
5223. (d) Negishi, E. Acc. Chem. Res. 1982, 15, 340. (e) Tamaru, Y.; Ochiai,
H.; Nakamura, T.; Yishida, Z. Tetrahedron Lett 1986, 27, 955. (f) Klement,
I.; Rottla¨nder, M.; Tucker, C. E.; Majid, T. N.; Knochel, P.; Venegas, P.;
Cahiez, G. Tetrahedron 1996, 52, 7201.
(7) Typical Procedure 1: Preparation of 3f. To a solution of triazene
2c (187 mg, 0.5 mmol) in THF (0.5 mL) was slowly added i-PrMgCl‚LiCl
(0.26 mL, 0.53 mmol, 2.05 M in THF) at -40 °C. The reaction mixture
was continuously stirred at -40 °C for 40 min. A complete conversion to
the Grignard reagent (1c) was observed as indicated by GC analysis of
hydrolyzed reaction aliquots. CuCN‚2LiCl (0.5 mmol, 0.5 mL, 1.0 M in
THF) was added dropwise at -40 °C, and then the reaction mixture
was slowly warmed to -30 °C over 30 min. Benzoyl chloride
(0.75 mmol) in THF (0.1 mL) was added, and the mixture was stirred at
-30 °C for 1 h and then warmed to rt and stirred again for 1 h before the
addition of aq NH3 (2 mL). The aqueous phase was extracted with diethyl
ether (2 × 10 mL). The organic fractions were washed with brine (10 mL),
dried (MgSO4), and concentrated in vacuo. Purification by flash chroma-
tography (pentane/ether ) 2:1) yielded the pure product 3f (137 mg, 78%)
as yellow crystals.
(8) Typical Procedure 2: Preparation of 6a. To a solution of compound
5a (228 mg, 0.5 mmol) in THF (0.25 mL) was slowly added i-PrMgCl‚
LiCl (0.26 mL, 0.53 mmol, 2.0 M in THF) at -40 °C. The reaction mixture
was continuously stirred at -40 °C. After 1 h, isopropyl iodide resulting
from the I/Mg exchange was evaporated in vacuo (evaporation was done
twice, 1 h for each time). Then the mixture was heated to 55 °C for 2 h
after addition of fresh THF (1.5 mL). The mixture was cooled to rt and
quenched as usual. The aqueous phase was extracted with ether
(2 × 5 mL). The organic fractions were washed with brine (5 mL), dried
(MgSO4), and concentrated in vacuo. Purification by flash chromatography
(pentane/ether ) 32:1) yielded the pure product 6a (92 mg, 75%) as a white
solid.
Org. Lett., Vol. 7, No. 13, 2005
2545

Table 2. Polyfunctional Aryl Iodides Obtained by the Iodolysis of Triazenes of Type 3 with CH3I (Method A) or TMSI (Method B)
a Isolated yield of analytically pure product. b Prepared according to Method A: CH3I, 120 °C, 24-48 h. c Prepared according to Method B: (CH3)3SiI,
CH2Cl2, reflux, 4-6 h.
ucts,we also have developed a new synthesis of function-
alized carbazoles.
Supporting Information Available: Experimental pro-
cedures and full characterization of all compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Acknowledgment. We thank the Fonds der Chemischen
Industrie for financial support. We thank Boehringer-
Ingelheim (Vienna) and Chemetall (Frankfurt) for the gener-
ous gift of chemicals.
OL0505454
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Org. Lett., Vol. 7, No. 13, 2005