Copper-promoted/catalyzed C-N and C-O bond cross-coupling with vinylboronic acid and its utilities

Article abstract of DOI:10.1016/S0040-4039(03)01037-2

The mildest method of N-vinylation has been discovered. The synthetic utilities of the N- and O-vinylated products include protecting group, cyclopropanation and Grubbs' ring closure metathesis reactions.

Full text of DOI:10.1016/S0040-4039(03)01037-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 4927–4931
Copper-promoted/catalyzed CꢀN and CꢀO bond cross-coupling
with vinylboronic acid and its utilities
Patrick Y. S. Lam,* Guillaume Vincent, Damien Bonne and Charles G. Clark
Bristol-Myers Squibb Co., PO Box 5400, Princeton, NJ 08543-5400, USA
Received 19 December 2002; revised 17 April 2003; accepted 22 April 2003
Abstract—The mildest method of N-vinylation has been discovered. The synthetic utilities of the N- and O-vinylated products
include protecting group, cyclopropanation and Grubbs’ ring closure metathesis reactions. © 2003 Elsevier Science Ltd. All rights
reserved.
Copper-promoted carbonꢀnitrogen (CꢀN) and car-
bonꢀoxygen (CꢀO) oxidative-coupling reactions of NH/
OH-containing substrates with arylboronic acids have
emerged as a powerful synthetic methodology since the
initial reports.1 This novel methodology is characterized
by the mild reaction conditions (room temperature,
weak base, in air) and is useful for the synthesis of
nitrogen- and oxygen-containing compounds found in
pharmaceuticals, crop-protection chemicals and mate-
rial sciences. Many extensions and applications of this
new methodology have been reported.2–6
vinylamines or ethers are also useful synthetic
intermediates.
A variety of NH/OH-substrates were reacted with
trans-1-hexenylboronic acid in the presence of pyridine/
triethylamine and copper(II) acetate (stoichiometric or
10 mol% copper) under five different conditions, as
shown in Table 1: (A) stoichiometric Cu(OAc)2 in air;
(B) catalytic Cu(OAc)2/O2; (C) catalytic Cu(OAc)2/
TEMPO in air; (D) catalytic Cu(OAc)2/pyridine N-
oxide in air; (E) catalytic [Cu(OH)·TMEDA]2Cl2/O2
(Collman conditions3c). All NH-containing substrates
(entries 1–5) afford very good yields under stoichiomet-
ric conditions with retention of the trans-configura-
tion.13 These substrates are also capable of undergoing
oxidative-coupling under catalytic conditions. For benz-
imidazolinone 2 (entry 1), catalytic Cu(OAc)2/O2 (61%)
is the best system. Similarly for 2-pyridinone 4 (entry 2)
Cu(OAc)2/O2 (96%) works best. For benzimidazole 6
(entry 3) and indazole 8 (entry 4), Cu(OAc)2/pyridine
N-oxide (90 and 88%, respectively) is the superior sys-
tem. For phthalimide 10 (entry 5) we found that the
Collman3c system, [Cu(OH)·TMEDA]2Cl2/O2, gave the
best yield. Although Cu(OAc)2/TEMPO is one of the
best catalytic systems for aryl boronic acid cross-cou-
pling, it surprisingly gave poor results for the vinyl-
boronic acid cross-coupling. The O-vinylation of
3,5-di-t-butyl phenol 10 (entry 6) required a stoichio-
metric amount of copper(II) acetate to afford a 52%
yield of the corresponding trans vinyl ether.
N-Vinylation has previously been carried out by a
variety of methods including mercuric acetate/sulfuric
acid-catalyzed vinylation of benzimidazoles with vinyl
acetate,7 alkylation of benzimidazoles with dibromo-
ethane followed by elimination,8a palladium(II)-cata-
lyzed vinylation of amides with electron-deficient acryl-
ates and analogs,9a palladium(0)-catalyzed vinylation
with vinyl bromides9b and triflates,9c copper(I) thio-
phenecarboxylate-catalyzed vinylation of amides with
vinyl iodides10 and cesium hydroxide-catalyzed addi-
tion of alcohols and amine derivatives to alkynes and
styrenes.11
The drawbacks of these methods are elevated tempera-
tures and a lack of generality and/or substrate scope. In
an effort to expand our copper(II) acetate oxidative-
coupling chemistry, we have discovered that a novel
stereospecific N/O-vinylation can be accomplished with
vinylboronic acid under mild reaction conditions.12
These N-vinylated products are not easily accessible via
the classical enamine condensation route. The resulting
We hypothesize that the mechanism (Scheme 1) of the
reaction involves a rapid coordination and dissolution
of copper(II) acetate by the NH substrate to form the
amine-copper(II) complex A. Transmetallation of the
* Corresponding author. E-mail: patrick.lam@bms.com
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01037-2

4928
P. Y. S. Lam et al. / Tetrahedron Letters 44 (2003) 4927–4931
vinylboronic acid with A gives the amine-vinyl-cop-
per(II) complex B which may very slowly reductively
eliminate to afford C. Alternatively, and most proba-
bly, B undergoes air oxidation to yield the correspond-
ing higher oxidation-state copper(III) complex D14
which can undergo more efficient reductive elimination
to give C.
good yield for 3 (66%, entry 1), 11 (79%, entry 2) and
13 (75%, entry 3). In general, these products are
difficult to obtain by simple alkylation with cyclopropyl
iodide (Table 3).
The N/O-vinylated products are also useful intermedi-
ates for Grubbs’ ring closure metathesis reaction16
(RCM) to generate novel heterocycles (Scheme 2). Het-
erocycles 22 and 2417 can be obtained in 4518 and 44%
yield, respectively. To the best of our knowledge, 22 is
the first demonstration of RCM with electron-rich N-
vinyl substrate.
With the success of the facile generation of vinylamines
and ether, we decided to explore the synthetic utilities
of these products. The vinyl group is useful as a pro-
tecting group7b,8 (Table 2). The cleavage of the vinyl
group is simply achieved by mild acid treatment for 3
(entry 1), 13 (entry 2) and 9a (entry 3). However, for 11
(entry 4) and 7 (entry 5) acidic treatment at 70°C did
not result in deprotection. These vinyl groups can be
removed by ozonolysis.
In conclusion, N/O-vinylation has been achieved in
good yields through the oxidative-coupling of vinyl-
boronic acid with NH/OH-containing substrates in
presence of stoichiometric or catalytic copper(II) ace-
tate. This efficient and extremely mild method gives
N-vinylated products which are not easily accessible via
the classical enamine condensation route. We continue
to explore the mechanism and scope of this powerful
The Simmons–Smith reaction15 is an efficient method
for synthesizing cyclopropylamine or ether from the
products of the N/O-vinylation. This reaction gave
Table 1. CꢀN and CꢀO bond cross-coupling of vinyl boronic acid and NH- or OH-containing substrates
a
Conditions: (A) 1.1 equiv. Cu(OAc)2 in air. (B) 0.1 equiv. Cu(OAc)2 and O2. (C) 0.1 equiv. Cu(OAc)2, 1.1 equiv. TEMPO in air. (D) 0.1 equiv.
Cu(OAc)2, 1.1 equiv. pyridine N-oxide in air. (E) 0.1 equiv. [Cu(OH)TMEDA]2Cl2 and O2.
b DMF as solvent.

P. Y. S. Lam et al. / Tetrahedron Letters 44 (2003) 4927–4931
4929
Scheme 1. Possible Mechanism of N-vinylation with trans-1-hexenylboronic acid.
Table 2. Cleavage of the vinyl group (protecting group)
Conditions: A=HCl 2 M in MeOH:dioxane (1:1); B=(1) O3/MeOH/−78°C, (2) Me2S/rt.

4930
P. Y. S. Lam et al. / Tetrahedron Letters 44 (2003) 4927–4931
Table 3. Cyclopropanation of N-vinyl substrates
674–676; (b) Lam, P. Y. S.; Clark, C. G.; Saubern, S.;
Adams, J.; Winters, M. P.; Chan, D. M. T.; Combs, A.
Tetrahedron Lett. 1998, 39, 2941–2944; (c) Evans, D. A.;
Katz, J. L.; West, T. R. Tetrahedron Lett. 1998, 39,
2937–2940; (d) Chan, D. M. T.; Monaco, K. L.; Wang,
R.-P.; Winters, M. P. Tetrahedron Lett. 1998, 39, 2933–
2936.
2. (a) Chan, D. M. T.; Monaco, K. L.; Li, R.; Bonne, D.;
Clark, C. G.; Lam, P. Y. S. Tetrahedron Lett. 2003, 44,
3863–3865; (b) Lam, P. Y. S.; Bonne, D.; Vincent, G.;
Clark, C. G.; Combs, A. P. Tetrahedron Lett. 2003, 44,
1694–1697; (c) Lam, P. Y. S.; Vincent, G.; Bonne, D.;
Clark, C. G. Tetrahedron Lett. 2002, 43, 3091–3094; (d)
Lam, P. Y. S.; Deudon, S.; Hauptman, E.; Clark, C. G.
Tetrahedron Lett. 2001, 42, 2427–2429; (e) Lam, P. Y. S.;
Deudon, S.; Averil, K. M.; Li, R.; He, M.; DeShong, P.;
Clark, C. G. J. Am. Chem. Soc. 2000, 122, 7600–7601.
3. For catalytic copper, see: (a) Lam, P. Y. S.; Vincent, G.;
Clark, C. G.; Deudon, S.; Jadhav, J. K. Tetrahedron Lett.
2001, 42, 3415–3418; (b) Kwong, F. Y.; Klapars, A.;
Buchwald, S. L. Org. Lett. 2002, 4, 581–584; (c) Collman,
J. P.; Zhong, M.; Zhang, C.; Costanzo, S. Org. Lett.
2001, 66, 7892–7897 and references cited therein.
Scheme 2. Vinylation of NH/OH-containing substrates:
application for Grubbs’ ring closure metathesis reaction.
4. For solid-phase version of N-arylation, see: (a) Combs,
A. P.; Tadesse, S.; Rafalski, M.; Haque, T. S.; Lam, P. Y.
S. J. Comb. Chem. 2002, 4, 179–182; (b) Combs, A. P.;
Rafalski, M. J. Combinatorial Chem. 2000, 2, 29–32; (c)
Combs, A. P.; Saubern, S.; Rafalski, M.; Lam, P. Y. S.
Tetrahedron Lett. 1999, 40, 1623–1626.
copper-promoted C-heteroatom oxidative-coupling
reaction with organometalloids.
Acknowledgements
5. For S-arylation, see: (a) Savarin, C.; Srogl, J.; Liebe-
skind, L. S. Org. Lett. 2002, 4, 4309–4312; (b) Herradura,
P. S.; Pendola, K. A.; Guy, R. K. Org. Lett. 2000, 2,
2019–2022. For O-arylation, see: (c) Quach, T. D.; Batey,
R. A. Org. Lett. 2003, 5, 1381–1384; (d) Evans, D. A.;
Katz, J. L.; Peterson, G. S.; Hinterman, T. J. Am. Chem.
Soc. 2001, 123, 12411–12413; (e) Simon, J.; Salzbrunn, S.;
Surya Prakash, G. K.; Petasis, N. A.; Olah, G. A. J. Org.
Chem. 2001, 66, 633–634. (f) Decicco, C. P.; Song, Y.;
Evans, D. A. Org. Lett. 2001, 3, 1029–1032; (g) Petrassi,
We thank Dr. Paul S. Anderson, Dr. Carl P. Decicco
and Dr. Ruth R. Wexler for their support of this
research.
References
1. (a) Lam, P. Y. S.; Clark, C. G.; Saubern, S.; Adams, J.;
Averill, K.; Chan, D. M. T.; Combs, A. P. Synlett 2000,

P. Y. S. Lam et al. / Tetrahedron Letters 44 (2003) 4927–4931
4931
H. M.; Sharpless, K. B.; Kelly, J. W. Org. Lett. 2001, 3,
139–142; (h) Jung, M. E.; Lazarova, T. I. J. Org. Chem.
1999, 64, 2976–2977. For N-arylation, see: (i) Collot, V.;
Bovy, P. R.; Rault, S. Tetrahedron Lett. 2000, 41, 9053–
9057; (j) Mederski, W. W. K. R.; Lefort, M.; Germann,
M.; Kux, D. Tetrahedron 1999, 55, 12757–12770; (k)
Cundy, D. J.; Forsyth, S. A. Tetrahedron Lett. 1998, 39,
7979–7982.
equiv.), 3 mL of dry dichloromethane, triethylamine (93
mL, 0.667 mmol, 2.0 equiv.), 1-ethyl-2-benzimidazolinone
2 (54 mg, 0333 mmol, 1.0 equiv.), cupric acetate (6.1 mg,
0.033 mmol, 0.1 equiv.) and TEMPO (57.3 mg, 0.367
mmol, 1.1 equiv.). The reaction was allowed to stir under
air at room temperature for 12 h. The reaction was
quenched by a solution of 50 mL of NH3 in MeOH (2 M).
The solvent was evaporated under reduced pressure and
the residue was dissolved in 3 mL of dichloromethane
and purified by silica gel chromatography (eluent: 7%
methanol/chloroform) to give 49.5 mg (61% yield, >95%
purity) of 1-ethyl-3-hexen-1%-yl-2-benzimidazolinone 3:
1H NMR (CDCl3) l 7.26 (m, 1H), 7.11 (m, 2H), 7.00 (m,
1H), 7.11 (d, J=14.5 Hz, trans, 1H), 6.12 (m, J=14.5 Hz,
trans, 7.3 Hz, 1H), 3.94 (q, J=7.3 Hz, 2H), 2.23 (m, 2H),
1.54–1.40 (m, 4H), 1.36 (t, J=7.4 Hz, 3H), 0.94 (t, J=7.3
Hz, 3H); HRMS calcd for C15H21N2O (M+H)+ m/e
245.1654 found m/e 245.1646.
6. (a) Kang, S.-K.; Lee, S.-H.; Lee, D. Synlett 2000, 1022–
1024; (b) Fedorov, A. Y.; Finet, J.-P. Tetrahedron Lett.
1998, 39, 7979–7982; (c) Arnauld, T.; Barton, D. H. R.;
Doris, E. Tetrahedron 1997, 53, 4137–4144; (d) Lopez-
Alvarado, P.; Avendano, C.; Menendez, J. C. J. Org.
Chem. 1995, 60, 5678 and references cited therein.
7. (a) Xiang, Y.; Chen, J.; Schinazi, R. F.; Zhao, K. Biorg.
Med. Chem. Lett. 1996, 6, 1051–1054; (b) Chen, Y. L.;
Hedberg, K. G.; Guarino, K. J. Tetrahedron Lett. 1989,
30, 1067–1068.
8. (a) Iddon, B.; Hartley, D. J. Tetrahedron Lett. 1997, 38,
4647–4650; (b) Greene, T. W.; Wuts, P. G. M. Protecting
Group in Organic Synthesis, 3rd ed.; John Wiley & Sons:
New York, p. 619.
9. (a) Hosokawa, T.; Takano, M.; Kuroki, Y.; Murahashi,
S.-I. Tetrahedron Lett. 1992, 33, 6643–6645; (b) Lebedev,
A. Y.; Izmer, V. V.; Kazyul’kin, D. N.; Beletskaya, I. P.;
Voskoboynikov, A. Z. Org. Lett. 2002, 4, 623–626; (c)
Willis, M. C.; Brace, G. N. Tetrahedron Lett. 2002, 43,
9085–9088.
10. (a) Shen, R.; Porco, J. A. Org. Lett. 2000, 2, 1333–1336
and references cited therein; (b) Ogawa, T.; Kiji, T.;
Hayami, K.; Suzuki, H. Chem. Soc. Jpn. 1991, 1443–
1446.
11. Tzalis, D.; Koradin, C.; Knochel, P. Tetrahedron Lett.
1999, 40, 6193–6195.
12. We have preliminary found that b-styrylboronic acid is a
good vinylating agent during our catalytic copper acetate
chemistry work.3a We have also found that azeotroping a
mixture of benzimidazole and n-hexanal resulted in no
N-vinylation (enamine formation), only decomposition of
the aldehyde starting material. We have observed little
electronic effect of the vinylboronic acids (4-methoxy-b-
styrylboronic acid, 91% yield; b-styrylboronic acid, 79%
yield; 4-trifluoromethyl-b-styrylboronic acid, 83% yield)
with benzimidazole, similar to arylboronic acids.1b
13. Representative catalytic N-vinylation procedure (condition
C) for 1-ethyl-3-hexen-1%-yl-2-benzimidazolinone 3: To a
20 mL vial equipped with a CaSO4 drying tube was
14. Crystal structure of a related Cu(III) has recently been
determined: Hayashi, H.; Pujinami, S.; Nagatomo, S.;
Ogo, S.; Suzuki, Y.; Kitagawa, T. J. Am. Chem. Soc.
2000, 122, 2124–2125.
15. Yang, Z.; Lorentz, J. C.; Shi, Y. Tetrahedron Lett. 1998,
39, 8621–8624. (This reaction gave no product for 5, 7
and 9a.)
16. (a) Delgado, M.; Martin, J. D. Tetrahedron Lett. 1997,
38, 6299–6300; (b) Fujiruma, O.; Fu, G. C.; Grubbs, R.
H. J. Org. Chem. 1994, 59, 4029–4031; (c) Miller, S. J.;
Kim, S.-H.; Chen, Z.-R.; Grubbs, R. H. J. Am. Chem.
Soc. 1995, 117, 2108–2109.
17. Sturino, C. F.; Wong, J. C. Y. Tetrahedron Lett. 1998,
39, 9623–9626.
18. Experimental procedure for RCM to give 3,4-dihydro-
benzo[4,5]imidazo[1,2-a]pyridine 22: N-vinylbenzimidazole
derivative 21 (254 mg, 1.28 mmol) was added to a
homogeneous brown solution of Grubbs’s catalyst 26
(217 mg, 0.25 mmol) in 10 mL of dry benzene under
argon. The resulted mixture was stirred at 80°C for 1 h,
at which time TLC showed the reaction to be completed.
The reaction mixture was opened to air and stirred for 15
min before it was concentrated. Flash chromatography
(silica gel 230–400 mesh, 50% ethyl acetate in hexane)
yielded 98 mg of product (45% yield, >95% purity). 1H
NMR (CDCl3) l 7.72–7.69 (m, 1H), 7.37–7.33 (m, 1H),
7.28–7.22 (m, 2H), 7.03 (d, J=7.7 Hz, cis, 1H), 5.63–5.57
(q, J=7.7 Hz, cis, 1H), 3.19 (t, J=8.1 Hz, 2H), 2.59–2.52
(m, 2H). HRMS calcd for C11H10N2 (M+H)+ m/e
170.0844 found m/e 170.0842.
,
added in sequence 33 mg of 4 A molecular sieves, trans-1-
hexen-1-ylboronic acid 1 (85.2 mg, 0.667 mmol, 2.0