Orthogonal synthesis of indolines and isoquinolines via aryne annulation

Article abstract of DOI:10.1021/ja0780582

Described in this report is the development of two unique methodologies exploiting the reactivity of arynes. Reaction of N-carbamoyl-functionalized enamine derivatives with benzyne affords substituted indolines. An orthogonal reactivity is uncovered when related enamine derivatives are modified as amides, such that isoquinolines are formed as the product of condensation with benzyne. This latter transformation is applied to a concise total synthesis of the opiate alkaloid papaverine. Copyright

Full text of DOI:10.1021/ja0780582

Published on Web 01/15/2008
Orthogonal Synthesis of Indolines and Isoquinolines via Aryne Annulation
Christopher D. Gilmore, Kevin M. Allan, and Brian M. Stoltz*
DiVision of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California 91125
Received October 21, 2007; E-mail: stoltz@caltech.edu
Scheme 1.
Aryne cycloaddition reactions have a long history dating back
to early reports of Diels-Alder reactions1 and [2+2] cyclodimer-
izations.2,3 Additionally, aryne cyclizations have proved to be an
exceptional method for gaining metal-free access to heterocyclic
molecules.4,5 On the basis of our recent success in the area of
benzyne C-C insertion reactions,6 we sought to develop a series
of aryne annulations using readily available N-acyl dehydroamino
esters. Herein, we report two orthogonal addition reactions that
directly produce either indolines or isoquinolines by reaction of
arynes with differentially substituted enamines (Scheme 1). Given
the prevalence of these heterocycles within countless bioactive
Table 1. Synthesis of Indolinesa
molecules, this methodology will provide new avenues toward
substances relevant to the advancement of human medicine.
Our initial investigations focused on implementing N-carbamoyl
dehydroalanine esters in the annulation reactions. These substrates,
when reacted with silyl aryl triflates7 in the presence of fluoride
sources, produced an indoline adduct arising from a formal [3+2]
cycloaddition (Table 1).8,9 Optimization of standard reaction
parameters identified Bu4NPh3SiF2 (TBAT) and THF as the best
fluoride source and solvent, respectively.
Importantly, the reaction produces a range of substituted indolines
(entries 1-3) by reaction of O-t-Bu carbamate substrates with
symmetrical and nonsymmetrical aryne precursors.10,11 Moreover,
a dehydrophenylalanine derivative proved competent under the
reaction conditions, affording the corresponding 1,2,3-trisubstituted
a Performed by treating 2.0 mmol silyl aryl triflate and 1.0 mmol ene
indoline as a single isolated diastereomer (entry 4). Interestingly,
carbamate with TBAT (2.0 mmol) in THF (50 mL) at 23 °C for 6 h.
b Isolated as a 2.3:1 mixture of 4- and 7-methoxyindolines.
an unexpected cis stereochemical relationship is observed, which
suggests that protonation occurs from the less-hindered face of the
adduct enolate, anti to the bulky â-substituent. Although the
formation of these products suffers generally from modest yields,
our reaction provides a rapid and straightforward synthesis of
functionalized indolines by a direct addition process.12
In order to probe the effect of aryne substitution on reactivity,
methyl 2-acetamidoacrylate was added to a variety of functionalized
arynes to produce 6-, 7-, and 8-substituted isoquinolines (Table 3).
Interestingly, ortho-functionalized arynes bearing the inductively
electron-withdrawing methoxy substituent provided a single product
(entry 1).10,11 In the case of a meta methyl aryne, the product was
observed as a 1:1 mixture of isomers (entry 2). Finally, electron-
rich (entries 3, 4) and electron-poor (entry 5) arynes each perform
well in the reaction and provide ready access to functionalized
isoquinolines.
Having developed this powerful condensation reaction for
generating isoquinolines, we sought to demonstrate its utility in a
rapid total synthesis of papaverine16 (Scheme 2), a clinically used
non-narcotic antispasmotic agent that is a biosynthetic precursor
of several pavine natural products and one of the four major
constituents of opium.17 Our synthesis began with the condensation
of homoveratric acid (1) and serine methyl ester‚HCl (2), followed
by elimination to provide N-acyl enamine 3.18 In the key step,
enamide 3 undergoes dehydrative addition to the aryne produced
from silyl aryl triflate 4 to furnish isoquinoline 5 in 70% yield.
Last, saponification and thermal decarboxylation19 afforded papav-
erine (6) in 29% overall yield in three steps from commercially
available materials, marking the shortest reported synthesis of this
important alkaloid.20,21
Upon discovering that carbamate derivatives could produce
formal [3+2] cycloadducts, we broadened our search to include
other dehydroamino esters, specifically enamide variants (Table 2).
Again, an addition reaction occurred between the aryne and the
enamine derivative; however, in this case the adduct was an
isoquinoline.13 This product arises via a [4+2] addition reaction
between the N-acyl enamine and aryne followed by dehydrative
aromatization.14 Under optimized conditions (TBAT, THF, 23 °C,
6 h), reaction of benzyne and N-acetyl dehydroalanine ester
produced methyl 1-methylisoquinoline-3-carboxylate in 87% yield
(entry 1). We have found the scope of this reaction to be quite
broad and have successfully synthesized a range of structurally
diverse, polyfunctionalized isoquinoline derivatives. Notably, this
reaction tolerates a variety of substitution R to the amide carbonyl,
including alkyl (entries 1-5), aryl (entry 6), and several heteroatom-
functionalized alkyl groups (entries 7-9). Importantly, alkyl
substituents can be added in place of an ester on the enamine moiety
(entries 10, 11). In fact, the enamine may even be incorporated
within a carbocycle, providing access to a number of tricyclic
isoquinoline derivatives (entries 12-15).15
9
1558
J. AM. CHEM. SOC. 2008, 130, 1558-1559
10.1021/ja0780582 CCC: $40.75 © 2008 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Synthesis of Isoquinolines from 2-(TMS)phenyl Triflatea
papaverine. The utilization of this methodology in more complex
settings is currently underway in our laboratories and will be
reported in due course.
Acknowledgment. The authors thank Abbott, Amgen, Bristol-
Myers Squibb, Merck, and Caltech for generous funding.
Supporting Information Available: Experimental details. This
material is available free of charge via the Internet at http://pubs.acs.org.
References
(1) (a) Wittig, G.; Pohmer, L. Angew. Chem. 1955, 67, 348. (b) Wittig, G.;
Hoffmann, R. W. Chem. Ber. 1962, 95, 2718-2728. (c) Kornfeld, E. C.;
Barney, P.; Blankley, J.; Faul, W. J. Med. Chem. 1965, 8, 342-347.
(2) (a) Baker, W. Nature 1942, 150, 210-211. (b) Schafer, M. E.; Berry, R.
S. J. Am. Chem. Soc. 1965, 87, 4497-4501. (c) Porter, G.; Steinfeld, J.
I. J. Chem. Soc. A 1968, 877-878.
(3) For reviews on the use of arynes in organic synthesis, see: (a) Kessar, S.
V. In ComprehensiVe Organic Synthesis; Trost, B. M.; Fleming, I., Eds.;
Pergamon Press: New York, 1991; Vol. 4, pp 483-515. (b) Pellissier,
H.; Santelli, M. Tetrahedron 2003, 59, 701-730. (c) Wenk, H. H.;
Winkler, M.; Sander, W. Angew. Chem., Int. Ed. 2003, 42, 502-528.
(4) For examples of aryne annulation approaches to the synthesis of
heterocycles, see: (a) Nair, V.; Kim, K. H. J. Org. Chem. 1975, 40, 3784-
3786. (b) Yoshida, H.; Shirakawa, E.; Honda, Y.; Hiyama, T. Angew.
Chem., Int. Ed. 2002, 41, 3247-3249. (c) Zhao, J.; Larock, R. C. J. Org.
Chem. 2007, 72, 583-588. (d) Beltra´n-Rodil, S.; Pen˜a, D.; Guitia´n, E.
Synlett 2007, 1308-1310.
(5) For recent examples of metal-free syntheses of benzannulated heterocycles,
see: (a) Movassaghi, M.; Hill, M. D. J. Am. Chem. Soc. 2006, 128,
14254-14255. (b) Movassaghi, M.; Hill, M. D.; Ahmad, O. K. J. Am.
Chem. Soc. 2007, 129, 10096-10097.
(6) Tambar, U. K.; Stoltz, B. M. J. Am. Chem. Soc. 2005, 127, 5340-5341.
(7) (a) Himeshima, Y.; Sonoda, T.; Kobayashi, H. Chem. Lett. 1983, 1211-
1214. (b) For a facile two-step preparation of o-silylaryl triflates from
the corresponding o-bromophenols, see: Pen˜a, D.; Cobas, A.; Pe´rez, D.;
Guitia´n, E. Synthesis 2002, 1454-1458.
a Performed by treating 2.0 mmol 2-(TMS)phenyl triflate and 1.0 mmol
enamide with TBAT (2.0 mmol) in THF (100 mL) at 23 °C for 6-8 h.
Table 3. Isoquinoline Synthesis from Methyl 2-Acetamidoacrylatea
(8) For examples of [3+2] cycloadditions with arynes, see: (a) Del Mazza,
D.; Reinecke, M. G. J. Chem. Soc., Chem. Commun. 1981, 124-125. (b)
Matsumoto, K.; Katsura, H.; Uchida, T.; Aoyama, K.; Machiguchi, T. J.
Chem. Soc., Perkin Trans. 1996, 1, 2599-2602. (c) Raminelli, C.; Liu,
Z.; Larock, R. C. J. Org. Chem. 2006, 71, 4689-4691. (d) Jin, T.;
Yamamoto, Y. Angew. Chem., Int. Ed. 2007, 46, 3323-3325.
(9) For enamine cycloadditions with arynes, see: (a) Gingrich, H. L.; Huang,
Q.; Morales, A. L.; Jones, M., Jr. J. Org. Chem. 1992, 57, 3803-3806.
(b) Crews, P.; Beard, J. J. Org. Chem. 1973, 38, 522-528.
(10) For results highlighting aryne regioselectivity, see: (a) Xin, H. Y.; Biehl,
E. R. J. Org. Chem. 1983, 48, 4397-4399. (b) Han, X. Y.; Jovanovic,
M. V.; Biehl, E. R. J. Org. Chem. 1985, 50, 1334-1337. (c) Biehl, E. R.;
Razzuk, A.; Jovanovic, M. V.; Khanapure, S. P. J. Org. Chem. 1986, 51,
5157-5160.
(11) For computational studies of aryne electronic properties, see: Johnson,
W. T. G.; Cramer, C. J. J. Am. Chem. Soc. 2001, 123, 923-928.
(12) For other examples of direct indoline synthesis, see: (a) Yip, K.-T.; Yang,
M.; Law, K.-L.; Zhu, N.-Y.; Yang, D. J. Am. Chem. Soc. 2006, 128, 3130-
3131. (b) Ganton, M. D.; Kerr, M. A. Org. Lett. 2005, 7, 4777-4779. (c)
Moutrille, C.; Zard, S. Z. Tetrahedron Lett. 2004, 45, 4631-4634.
(13) For classical syntheses of isoquinolines, see: (a) Doebner, O. Justus
Liebigs Ann. Chem. 1887, 242, 265-289. (b) Bischler, A.; Napieralski,
B. Ber. Dtsch. Chem. Ges. 1893, 26, 1903-1912. (c) Pictet, A.; Gams,
A. Ber. Dtsch. Chem. Ges. 1910, 113, 2384-2391. (d) Bevis, M. G.;
Forbes, E. J.; Uff, D. C. Tetrahedron 1969, 25, 1585-1589.
(14) Doebner, O. Justus Liebigs Ann. Chem. 1887, 242, 265.
(15) Attempts to expand the substrate scope by simply employing N-vinyl
acetamide met with exclusive arylation at the enamine olefin terminus,
see: Ramtohul, Y. K.; Chartrand, A. Org. Lett. 2007, 9, 1029-1032.
(16) Isolation of papaverine: Merck, G. Liebigs Ann. Chem. 1848, 66, 125-
128.
a Performed by treating 2.0 mmol silyl aryl triflate and 1.0 mmol enamide
with TBAT (2.0 mmol) in THF (100 mL) at 23 °C for
6-8 h.
Scheme 2. Total Synthesis of Papaverine
(17) (a) Bentley, K. W. In The Isoquinoline Alkaloids; Ravindranath, B., Ed.;
Harwood Academic Publishers: Amsterdam, 1998; pp 107-122. (b)
Bentley, K. W. Nat. Prod. Rep. 2005, 22, 249-268.
(18) Goodall, K.; Parsons, A. F. Tetrahedron Lett. 1995, 36, 3259-3260.
(19) Stanforth, S. P.; Tarbit, B.; Watson, M. D. Tetrahedron 2004, 60, 8893-
8897.
(20) For previous total syntheses of papaverine, see: (a) Pictet, A.; Finkelstein,
M. Ber. Dtsch. Chem. Ges. 1909, 42, 1979-1989. (b) Rosenmund, K.
W.; Nothnagel, M.; Riesenfeldt, H. Ber. Dtsch. Chem. Ges. 1927, 60,
392-398. (c) Mannich, C.; Walther, O. Arch. Pharm. 1927, 265, 1-11.
(d) Galat, A. J. Am. Chem. Soc. 1951, 73, 3654-3656. (e) Wahl, H. Bull.
Soc. Chim. Fr. 1950, 17, 680. (f) Popp, F. D.; McEwen, W. E. J. Am.
Chem. Soc. 1957, 79, 3773-3777. (g) Hirsenkorn, R. Tetrahedron Lett.
1991, 32, 1775-1778.
In summary, we have developed a direct, metal-free, and
divergent process for the synthesis of diversely substituted indolines
and isoquinolines by the coupling reaction of N-acyl dehydroamino
esters with arynes. This methodology exploits orthogonal modes
of reactivity displayed by differentially substituted enamine deriva-
tives in the presence of arynes. Finally, we have applied this
chemistry to a concise total synthesis of the opiate alkaloid
(21) Decarboxylated products of this type (e.g., 6) constitute those originally
targeted in the N-vinyl acetamide case (see ref 15), thereby circumventing
the undesired ene reactivity previously displayed by these substrates.
JA0780582
9
J. AM. CHEM. SOC. VOL. 130, NO. 5, 2008 1559