Experimental and theoretical investigations into the unusual regioselectivity of 4,5-, 5,6-, and 6,7-indole aryne cycloadditions

Article abstract of DOI:10.1021/ol902415s

"Chemical Equation Presented" The 6,7-indolyne shows remarkable regioselectivity in its cycloaddition with 2-substituted furans. Electron-donating groups give predominantly the more sterically crowded product, while electron-withdrawing groups display the

Full text of DOI:10.1021/ol902415s

ORGANIC
LETTERS
2010
Vol. 12, No. 1
96-99
Experimental and Theoretical
Investigations into the Unusual
Regioselectivity of 4,5-, 5,6-, and
6,7-Indole Aryne Cycloadditions
Ashley N. Garr,† Diheng Luo,‡ Neil Brown,‡,§ Christopher J. Cramer,†
Keith R. Buszek,*,‡,§ and David VanderVelde§
Department of Chemistry and Supercomputing Institute, UniVersity of Minnesota,
207 Pleasant Street SE, Minneapolis, Minnesota 55455, Department of Chemistry,
UniVersity of MissourisKansas City, 205 Spencer Chemical Laboratories,
5100 Rockhill Road, Kansas City, Missouri 64110, and The UniVersity of Kansas
Center of Excellence in Chemical Methodologies and Library DeVelopment, Structural
Biology Center, 2121 Simons DriVe, Lawrence, Kansas 66047
buszekk@umkc.edu
Received October 27, 2009
ABSTRACT
The 6,7-indolyne shows remarkable regioselectivity in its cycloaddition with 2-substituted furans. Electron-donating groups give predominantly
the more sterically crowded product, while electron-withdrawing groups display the opposite regioselectivity. By contrast, 4,5- and 5,6-indolynes
show no regioselectivity. Optimized electronic structure calculations using the M06-2X density functional and 6-311+G(2df,p) basis set revealed
that the 6,7-indolynes are highly polar structures and that their cycloadditions have substantial electrophilic substitution character that leads
to the observed preference for contrasteric products.
Benzynes and other common arynes (e.g., naphthalynes and
pyridynes) have fascinated chemists for decades. Surpris-
ingly, arynes occurring at all three benzenoid positions of
the ubiquitous indole nucleus (indole arynes or indolynes
1-3, Figure 1) were, until recently, unknown. These newest
members of the aryne family represent, inter alia, potentially
attractive and powerful new tools for the total synthesis of
complex natural products such as the nodulisporic acids,1
trikentrins,2 herbindoles,2a,c and the teleocidins.3 (Figure 2).
We recently discovered the first successful and general route
to these reactive intermediates via metal-halogen exchange
Figure 1. Benzenoid indole aryne (indolyne) systems.
of o-dihalides4 and later via fluoride-induced decomposition
of o-silyltriflates.5 We subsequently examined the regiose-
(2) (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.
(3) (a) Dangel, B. D.; Godula, K.; Youn, S. W.; Sezen, B.; Sames, D.
J. Am. Chem. Soc. 2002, 124, 11856–11857. (b) Nakatsuka, S.; Matsuda,
T.; Goto, T. Tetrahedron Lett. 1987, 38, 3671–3674.
† University of Minnesota.
‡ University of MissourisKansas City.
§ University of Kansas.
(1) Synthetic studies, see: (a) Smith, A. B., III; Kuerti, L.; Davulcu,
A. H.; Cho, Y. S.; Ohmoto, K. J. Org. Chem. 2007, 72, 4611–4620.
10.1021/ol902415s  2010 American Chemical Society
Published on Web 12/04/2009

Scheme 2
.
Furan and Azide Cycloadditions with 4,5-, and
5,6-Indolynes
Figure 2. Examples of complex indole natural products.
Intrigued by these observations, we wished to identify the
fundamental electronic and steric parameters that account
for these fascinating reaction profiles. The information
obtained from this study will provide a better understanding
of the structure and reactivity of the indole aryne system.
This knowledge in turn should result in more versatile
strategies and benefits for complex molecule total synthesis.
We began our investigation by examining a series of
2-substituted furans featuring electron-donating straight chain
alkyl, branched alkyl, and aryl groups and electron-
withdrawing groups (Table 1).8 The electron-donating groups
lectivity of indolynes in Diels-Alder reactions with 2-sub-
stituted furans.5a These studies quickly led to the first
application of indolynes in the construction of natural
products and culminated in a concise and efficient total
synthesis of (()-cis-trikentrin A and the (()-herbindoles A
and B.6 This work and recently that of Garg clearly validated
the utility of indolynes to gain quick access to architecturally
challenging structures.7
During the course of these investigations, we were
surprised to find that 2-substituted furans in particular
displayed a striking regioselectivity when paired with the
6,7-indolynes (Scheme 1).5a
Table 1. Regioselective 6,7-Indolyne Cycloadditions with
2-Substituted Furans
Scheme 1
.
Regioselective 6,7-Indolyne Cycloadditions with
2-Substituted Furans
entry
furan, R
19
20
yield, %
1
2
3
4
5
6
Me
Et
i-Pr
t-Bu
Ph
80
84
94
98
>99
<1
20
16
6
2
<1
>99
89
90
88
91
92
83
SO2Ph
Using 2-t-butylfuran, for example, the contrasteric product
11 was formed in at least a 15:1 preference over the alternate
regioisomer. Even with the less sterically demanding 2-me-
thylfuran, there was a 4:1 preference for the indicated isomer.
Analysis of the products by various 2D NMR methods
(COSY, NOESY, HMBC, and HSQC) allowed for the
unequivocal assignment of the structures.
By contrast, there was no preference for either regioisomer
in the 4,5- and 5,6-indolyne cycloaddition examples involv-
ing 2-t-butylfuran. In each case, a nearly 1:1 ratio of
cycloadducts was formed in excellent yield (Scheme 2).5a
(entries 1-5) showed a remarkable preference for the more
crowded cycloadduct 19, while the opposite regiochemistry
was found for an electron-withdrawing case (entry 6).
In earlier studies involving the reaction of monosubstituted
3-benzynes with 2-substituted furans (Me, Et, i-Pr, t-Bu),9
regioselectivity correlated well with the strength of induc-
tively electron-withdrawing groups such as F and OMe on
the benzyne to favor contrasteric products, while it was
reversed with inductively electron-donating groups such as
Me.
(4) Buszek, K. R.; Luo, D.; Kondrashov, M.; Brown, N.; VanderVelde,
D. Org. Lett. 2007, 9, 4135–4137.
(8) 2-Methyl-, 2-ethyl-, and 2-t-butylfuran are readily available from
commercial sources. The others were prepared as follows. (a) 2-i-
Propylfuran: see ref 8c. (b) 2-Phenylfuran: Negishi, E.; Takahashi, T.; King,
A. O. Org. Synth. 1988, 66, 67–72. (c) 2-Phenylsulfonylfuran: Malanga,
C.; Aronica, L. A.; Lardicci, L. Synth. Commun. 1996, 26, 2317–2327.
(9) (a) Giles, R. G. F.; Sargent, M. V.; Sianipar, H. J. Chem. Soc., PT1
1991, 1571–1579. (b) Newman, M. S.; Kannan, R. J. Org. Chem. 1976,
41, 3356–3359. (c) Gribble, G. W.; Keavy, D. J.; Branz, S. E.; Kelly, W. J.;
Pals, M. A. Tetrahedron Lett. 1988, 29, 6227–6230.
(5) (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 4,5-indolyne formation and further cycloaddition reactions have
subsequently been reported by Garg: (b) Bronner, S. M.; Bahnck, K. B.;
Garg, N. K. Org. Lett. 2009, 11, 1007–1010.
(6) Buszek, K. R.; Brown, N.; Luo, D. Org. Lett. 2009, 11, 201–204.
(7) Tian, X.; Huters, A. D.; Douglas, C. J.; Garg, N. K. Org. Lett. 2009,
11, 2349–2351.
Org. Lett., Vol. 12, No. 1, 2010
97

To characterize this phenomenon in additional detail,
electronic structure calculations were undertaken to predict
the structures and reactivities of the N-methyl-4,5-, 5,6-, and
6,7-indolynes with furan and 2-alkylfurans. Similar calcula-
tions were also undertaken for the benzofuran and ben-
zothiophene analogues of the indolynes as these heterocycles
may prove useful for the construction of other interesting
natural (or unnatural) products. With respect to methodology,
all structures were optimized using the M06-2X density
functional10 and 6-311+G(2df,p) basis set11 as implemented
in MN-GFM,12 a locally modified version of the Gaussian03
software package.13 Analytical frequency calculations were
employed to characterize the nature of all gas-phase struc-
tures as minima or transition states. In select instances, the
effects of diethyl ether solvation were taken into account
using the SMD14 implicit solvation model.
Table 2. ∆Gq Values in kcal/mol for the Reaction of Indolynes
with Substituted Furans
entry
aryne
furan, R
∆Gq (a)
∆Gq (b)
Table 2 lists the activation free energies computed for the
reaction of the N-methylindolynes with the furans. With
unsubstituted furan, ∆Gq is similar for the 4,5- and 5,6-
indolyne isomers, and slightly smaller for the 6,7-isomer.
Considering 2-t-butylfuran, the predicted free energies of
activation are reduced by 3-4 kcal/mol compared to reaction
with furan itself in the 4,5- and 5,6-indolyne cases. Regi-
oselection becomes possible upon 2-substitution of the furan,
and the differential free energies of activation in these two
instances are predicted to be 1 kcal/mol or less. In the 6,7-
indolyne case, by contrast, a free energy of activation similar
to those for 4,5 and 5,6 is predicted for the formation of
26a (which is equivalent to 19 but lacks the 3-phenyl
substituent), but no transition-state (TS) structure for the
formation of 26b (corresponding to desphenyl 20) could be
locatedsthe approach of the furan to the indolyne led
smoothly and without barrier to the final tetracyclic product
in every instance.
1
2
3
4
5
6
7
8
9
21
22
23
21
22
23
23
23
23
H
H
H
t-Bu
t-Bu
t-Bu
Me
Et
10.5
10.0
8.7 (8.4)a
6.3
7.3
6.9
6.1
b
7.0 (8.0)
9.2 (9.4)
9.0 (9.4)
9.7 (10.3)
7.5 (7.8)
7.8 (8.2)
7.6 (8.2)
i-Pr
a Values in parentheses include continuum ethereal solvation effects.
b No barrier to reaction is predicted in the gas phase or continuum solution.
of the latter in each case, with the margin being largest (2.1
kcal/mol) for R ) i-Pr. Ethereal solvation effects on the free
energies of activation are predicted from the SMD continuum
model to be 1 kcal/mol or smaller in every instance and to
have no influence on regioselection.
Inspection of the TS structures for the formation of 26b
with the smaller alkyl groups provides insight into the failure
to find such a TS structure for t-Bu. There are significant
steric interactions between the N-Me group of the indolyne
and the 2-alkyl group on the furan so that the bond forming
to the 6 position is substantially shorter than that to the 7
position. The difference in the two formation bond lengths
becomes increasingly long as the substituent is varied from
Me to Et to i-Pr. This increase, however, is probably not
associated with larger steric bulk since each of these furan
2-alkyl substituents orients a C-H bond toward the N-methyl
group to minimize steric clash. Instead, it becomes clear from
consideration of the preference for 26b over 26a and
inspection of partial atomic charges that the 6,7-“cycload-
dition” has substantial electrophilic substitution character.
Thus, the electron-poor indolyne attacks the 2-substituted
furan to generate the more stable 2-alkyldihydrofurylcarbe-
nium ion. As the 2-substituent is varied from Me to Et to
i-Pr, the increased stabilization provided by the larger alkyl
groups increases this character and leads to increased
regioselection and increased electrophilic substitution char-
acter so that bond formation becomes decreasingly synchro-
nous. Thus, it appears that in the case of R ) t-Bu the
combination of unavoidably increased sterics (there is no
longer a C-H bond that can be disposed toward the N-Me
group) and enhanced carbenium ion stabilization switches
To better understand this point, the reactions of other
2-alkylfurans with 23 were modeled. With R ) Me, Et, or
i-Pr, TS structures for formation of 26b could be found in
every instance. Interestingly, the differential free energies
of activation for formation of 26a vs 26b favored formation
(10) Zhao, Y.; Truhlar, D. G. Theor. Chem. Acc. 2008, 120, 215–241.
(11) Hehre, W. J.; Radom, L.; Schleyer, P. v. R.; Pople, J. A. Ab Initio
Molecular Orbital Theory; Wiley: New York, 1986.
(12) Zhao, Y.; Truhlar, D. G. MN-GFM Version 4.1; University of
Minnesota: Minneapolis, 2008.
(13) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb,
M. A.; Cheeseman, J. R.; Montgomery, J. A., Jr.; Vreven, T.; Kudin, K. N.;
Burant, J. C.; Millam, J. M.; Iyengar, S. S.; Tomasi, J.; Barone, V.;
Mennucci, B.; Cossi, M.; Scalmani, G.; Rega, N.; Petersson, G. A.;
Nakatsuji, H.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.;
Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Klene, M.; Li,
X.; Knox, J. E.; Hratchian, H. P.; Cross, J. B.; Bakken, V.; Adamo, C.;
Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.;
Cammi, R.; Pomelli, C.; Ochterski, J. W.; Ayala, P. Y.; Morokuma, K.;
Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Zakrzewski, V. G.; Dapprich,
S.; Daniels, A. D.; Strain, M. C.; Farkas, O.; Malick, D. K.; Rabuck, A. D.;
Raghavachari, K.; Foresman, J. B.; Ortiz, J. V.; Cui, Q.; Baboul, A. G.;
Clifford, S.; Cioslowski, J.; Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz,
P.; Komaromi, I.; Martin, R. L.; Fox, D. J.; Keith, T.; Al-Laham, M. A.;
Peng, C. Y.; Nanayakkara, A.; Challacombe, M.; Gill, P. M. W.; Johnson,
B.; Chen, W.; Wong, M. W.; Gonzalez, C.; Pople, J. A. Gaussian 03,
revision D.01; Gaussian, Inc.: Wallingford, CT, 2004.
(14) (a) Marenich, A. V.; Cramer, C. J.; Truhlar, D. G. J. Phys. Chem.
B 2009, 113, 6378–6396. (b) Marenich, A. V.; Hawkins, G. D.; Liotard,
D. A.; Cramer, C. J.; Truhlar, D. G. GESOL-version 2008, University of
Minnesota, Minneapolis, 2008.
98
Org. Lett., Vol. 12, No. 1, 2010

the mechanisms for a highly asynchronous but still concerted
cycloaddition to a “stepwise” electrophilic substitution and
subsequent ring closure. We place “stepwise” in quotes here
because no TS structures nor intermediates can be located
in either the gas phase or ethereal continuum solution for
this process. To the extent that the reaction has an actual
free energy of activation, it is likely associated with the
displacement of discrete solvent molecules between the
reacting partners that is not included in the present compu-
tational models, which otherwise are in reasonable quantita-
tive agreement for predicted regioselection in 26a and 26b
compared to 19 and 20.
Table 3. ∆Gq Values in kcal/mol for the Reaction of
Benzofurans and -Thiophenes with Substituted Furans
Support for the polarization of the 6,7-indolyne that makes
the 6 position substantially more electrophilic than the 7
position may be obtained from inspection of atomic polar
tensor partial charges15 and the molecular geometry. Thus,
C(6) is predicted to have a charge 0.26 au more positive
than C(7), and the C(5)C(6)C(7) bond angle is predicted at
the M06-2X level to be 135.3° while the C(6)C(7)C(7a) angle
is predicted to be 117.2°. The former value is more consistent
with carbocationic character, while the latter is more
consistent with carbanionic character. For comparison, the
corresponding bond angles in the analogous indyne (i.e., the
hydrocarbon generated by replacing the N-methyl group with
a methylene) are predicted at the DFT level to be 128.2 and
125.5°.16 Thus, the C(6)-C(7) bond is strongly polarized
in the expected direction by the nearby C(7a)-N bond dipole.
At the M06-2X level, the C(7a)-N bond dipole is
predicted to lead to some polarization of the formal triple
bonds in the 4,5- and 5,6-indolynes as well, although to a
substantially smaller degree than in the 6,7 case (cf. entries
4 and 5 in Table 2). The failure to observe any regioselection
under experimental conditions (reactions of Scheme 2) may
reflect reduced polarization associated with the 3-phenyl
group in the experimental substrate, or some degree of
solvent leveling of the gas-phase predictions, or simply
overpolarization predicted at the DFT level, but the effect
in any case is predicted to be only about 1 kcal/mol.
Given the substantial synthetic utility of the indolyne
cycloadditions, we modeled the analogous cycloadditions of
furan and 2-t-butylfuran with benzofuran and benzothiophene;
results are presented in Table 3. Very similar reactivity
profiles are predicted for all three heterocyclic systems, with
the benzofuran case being predicted to have the lowest free
energies of activation by a small margin, as would be
expected given the greater electrophilicity of this heterocycle.
This suggests that synthetic efforts based on these other
heterocycles should be equally fruitful.
entry
aryne, X
furan, R
∆Gq (a)
∆Gq (b)
1
2
3
4
5
6
7
8
27, O
28, O
29, O
27, O
28, O
29, O
27, S
28, S
29, S
27, S
28, S
29, S
H
H
H
t-Bu
t-Bu
t-Bu
H
H
H
9.2
9.1
7.3
4.9
5.8
6.2
9.6
8.9
8.4
5.4
5.5
5.8
6.4
4.9
a
9
10
11
12
t-Bu
t-Bu
t-Bu
6.5
4.8
a
a No barrier to reaction is predicted in the gas phase or continuum
solution.
cycloaddition reactions. Dipolar effects can induce regiose-
lection with asymmetrically substituted dienes when polar-
ization of the benzyne triple bond imparts substantial
asynchronous electrophilic substitution character to the initial
bond forming step.
Acknowledgment. We acknowledge support of this work
by the National Institutes of Health, NIGMS, Grant R01
GM069711 (KRB), and the National Science Foundation,
CHE06-10183 (CJC). Additional support 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). We
thank Dee Tanaka for synthetic technical assistance and Nalin
Chandrasoma and Lincoln Maina for additional NMR
acquisition.
Supporting Information Available: NMR and other
spectroscopic data for compounds used in this study and
experimental details for their preparation as well as optimized
cartesian coordinates for all computed structures. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Benzynes derived from benzannulated heterocycles are
thus revealed to be powerful synthetic tools for the construc-
tion of highly functionalized tetracycles through [4 + 2]
(15) Cioslowski, J. J. Am. Chem. Soc. 1989, 111, 8333.
(16) Cramer, C. J.; Thompson, J. J. Phys. Chem. A 2001, 105, 2091–
2098.
OL902415S
Org. Lett., Vol. 12, No. 1, 2010
99