N. Brown et al. / Tetrahedron Letters 50 (2009) 7113–7115
7115
R4
Ar
metal–halogen exchange with n-BuLi at the 7-bromo position
and subsequent elimination to give the 6,7-indolyne, followed by
cycloaddition with dienes. The remaining 4-bromo position is then
available for further elaboration using well-known cross-coupling
protocols. This heretofore unrecognized reaction orthogonality
renders the 4,6,7-tribromoindole a versatile platform for the total
synthesis of natural products, and holds enormous potential for
the construction of diverse small-molecule libraries. We are pres-
ently exploiting this latter application for use in library develop-
ment. The results of these efforts will be reported in due course.
R3
R2
R4
R3
R2
R3
R2
N
R1
27
N
N
R1
R1
Suzuki
28
26
Negishi
(R3)2Zn
ArB(OH)2
Stille
R3
Br
R3
12
N
R2
R1
Acknowledgments
Heck
R4
Sonogashira
R4
Buchwald-
Hartwig
Z
Z
We acknowledge support of this work by the National Institutes
of Health, NIGMS, Grant R01 GM069711 (K.R.B.). Additional sup-
port of this work was provided by the NIH, NIGMS, Grant P50
GM069663 via the University of Kansas Chemical Methodologies
and Library Development Center of Excellence (KU-CMLD).
HNR4R5
R3
R2
NR4R5
R3
R2
R3
R2
N
R1
29
N
N
R1
R1
31
30
References and notes
Figure 3. Cross-coupling manifolds in the 4-bromoindole scaffold.
1. For recent total syntheses, see: (a) Jackson, S. K.; Kerr, M. A. J. Org. Chem. 2007,
72, 1405–1411; (b) Huntley, R. J.; Funk, R. L. Org. Lett. 2006, 8, 3403–3406; (c)
Jackson, S. K.; Banfield, S. C.; Kerr, M. A. Org. Lett. 2005, 7, 1215–1218; (d)
MacLeod, J. K.; Monahan, L. C. Tetrahedron Lett. 1988, 29, 391–392.
2. (a) Nakatsuka, S.; Matsuda, T.; Goto, T. Tetrahedron Lett. 1987, 38, 3671–3674;
(b) Nakatsuka, S.; Matsuda, T.; Goto, T. Tetrahedron Lett. 1986, 27, 6245–6248;
(c) Nakatsuka, S.; Masuda, T.; Asano, O.; Terame, T.; Goto, T. Tetrahedron Lett.
1986, 27, 4327–4330.
3. Moreno, O. A.; Kishi, Y. J. Am. Chem. Soc. 1996, 118, 8180–8181.
4. Muratake, H.; Natsume, M. Tetrahedron Lett. 1987, 28, 2265–2268.
5. Buszek, K. R.; Luo, D.; Kondrashov, M.; Brown, N.; VanderVelde, D. Org. Lett.
2007, 9, 4135–4137.
6. (a) Brown, N.; Luo, D.; VanderVelde, D.; Yang, S.; Brassfield, A.; Buszek, K. R.
Tetrahedron Lett. 2009, 50, 63–65; Another o-silyltriflate method for indolyne
formation and further cycloaddition reactions has subsequently been reported:
(b) Bronner, S. M.; Bahnck, K. B.; Garg, N. K. Org. Lett. 2009, 11, 1007–1010.
7. Buszek, K. R.; Brown, N.; Luo, D. Org. Lett. 2009, 11, 201–204.
Br
OMe
p-MeOPhB(OH)2 (2.2 eq)
Pd2(dba)3 (4 mol%)
t-Bu3P•HBF4 (16 mol%)
DIEA (2.2 eq)
N
TBS
23
THF, 65 ºC, 3 h
57%
N
H
32
Scheme 5. Suzuki–Miyaura coupling with 4-bromoindoles.
8.
A synthesis of the bicyclic scaffold of N-methylwelwit-indolinone C
isothiocyanate via indolyne cyclization has been reported: Tian, X.; Huters, A.
D.; Douglas, C. J.; Garg, N. K. Org. Lett. 2009, 11, 2349–2351.
Br
9. (a) Bartoli, G.; Palmieri, G. Tetrahedron Lett. 1989, 30, 2129–2132; (b) Bartoli,
G.; Bosco, M.; Dalpozzo, R.; Palmieri, G.; Marcantoni, E. J. Chem. Soc. PT1 1991,
2757–2761; (c) Bosco, M.; Dalpozzo, R.; Bartoli, G.; Palmieri, G.; Petrini, M. J.
Chem. Soc., Perkin Trans. 2 1991, 657–663; (d) Dalpozzo, R.; Bartoli, G. Curr. Org.
Chem. 2005, 9, 163–178.
3,4-dimethylaniline (1.2 eq)
Pd2(dba)3 (4 mol%)
t-Bu3P•HBF4 (16 mol%)
Cs2CO3 (1.5 eq)
glyme, 85 ºC, 24 h
27%
HN
N
TBS
23
10. All new compounds reported herein exhibited satisfactory 1H NMR, 13C NMR,
high resolution mass spectral, or elemental analysis data consistent with their
structures. 15: 1H NMR: d 8.28 (d, 1H, J = 6.2 Hz); d 7.80 (d, 1H, J = 6.4 Hz); d
6.60 (br s, 2H, NH2). 13C NMR: d 141.2, 140.8, 128.2 (2 C), 112.7, 106.8.
Mp = 127.8–129.3 °C; 16: 1H NMR: d 7.98 (d, 1H, J = 2.2 Hz); d 7.76 (d, 1H,
J = 2.2 Hz). 13C NMR: 138.8, 128.8, 126.5, 121.6, 116.3. Mp = 83.5–84.8 °C; 17:
N
H
33
Scheme 6. Buchwald–Hartwig coupling of anilines with 4-bromoindoles.
1H NMR: d 8.46 (br s, 1H, NH); d 7.53 (s, 1H); d 7.28 (m, 1H); d 6.65 (m, 1H). 13
C
NMR: d 153.3, 128.2, 126.7, 125.7, 117.2, 114.1, 106.5, 104.7. Mp = 97.0–
99.0 °C; 18: 1H NMR: d 7.62 (s, 1H); d 7.43 (d, 1H, J = 3.6 Hz); d 6.71 (d, 1H,
J = 3.3 Hz); d 0.99 (s, 9H); d 0.73 (s, 6H). 13C NMR: d 140.7, 135.4, 133.4, 127.6,
119.4, 113.7, 108.0, 106.2, 27.4, 19.9, 2.2. Mp = 90.5–91.6 °C; 23: 1H NMR: d
7.34 (s, 1H); 7.22 (d, 1H, J = 3.3 Hz); d 6.92 (m, 1H); d 6.84 (m, 1H); d 6.64 (d,
1H, J = 3.5 Hz); d 4.48 (s, 1H); d 3.98 (s, 1H); d 2.36–2.26 (m, 2H); d 1.04 (s, 9H);
d 0.69 (s, 3H); d 0.61 (s, 3H). 13C NMR: d 148.6, 145.0, 142.0, 136.9, 134.2, 132.4,
130.8, 118.6, 109.2, 105.4, 70.4, 51.0, 50.6, 26.6, 19.4, À1.5, À1.8. Mp = 114.1–
115.2 °C.
conventional catalyst and ligand combinations to achieve even the
stated yields. Although cross-coupling reactions with haloindoles
are certainly precedented,14 their yields, along with other hetero-
arenes, tend to be highly variable, and usually low.15 In our sys-
tems, annulation leads to a more electron-rich bromoarene, and
this factor is also known to suppress yields in many cases. We
are continuing to pursue improved conditions in support of our
library objectives.
11. Coe, J. W.; Wirtz, M. C.; Bashore, C. G.; Candler, J. Org. Lett. 2004, 6, 1589–1592.
12. This product is identical in all respects to that previously reported by us (see
Ref. 7).
13. (a) González-Bobes, F.; Fu, G. C. J. Am. Chem. Soc. 2006, 128, 5360–5361; (b)
Zhou, J.; Fu, G. C. J. Am. Chem. Soc. 2004, 126, 1340–1341; (c) Netherton, M. R.;
Fu, G. C. Angew. Chem., Int. Ed. 2002, 41, 3910–3912.
14. Billingsley, K.; Buchwald, S. L. J. Am. Chem. Soc. 2007, 129, 3358–3366.
15. Tyrell, E.; Brookes, P. Synthesis 2004, 4, 469–483.
In conclusion, we have devised a shorter, improved route to ( )-
cis-trikentrin A that utilizes an efficient tandem 6,7-indolyne
cycloaddition/Negishi coupling sequence. We have shown that
the 4,6,7-tribromoindole system appears to undergo selective