Asymmetric synthesis of indole homo-Michael adducts via dynamic kinetic Friedel-Crafts alkylation with cyclopropanes

Article abstract of DOI:10.1021/ol4010646

An enantioconvergent Friedel-Crafts alkylation of indoles with donor-acceptor cyclopropanes is described. The reaction is catalyzed by pybox?MgI₂ and proceeds via a type I dynamic kinetic asymmetric transformation (DyKAT).

Full text of DOI:10.1021/ol4010646

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Asymmetric Synthesis of Indole
Homo-Michael Adducts via Dynamic
Kinetic FriedelꢀCrafts Alkylation
with Cyclopropanes
Steven M. Wales, Morgan M. Walker, and Jeffrey S. Johnson*
Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill,
North Carolina 27599-3290, United States
jsj@unc.edu
Received April 17, 2013
ABSTRACT
An enantioconvergent FriedelꢀCrafts alkylation of indoles with donorꢀacceptor cyclopropanes is described. The reaction is catalyzed by
pybox•MgI2 and proceeds via a type I dynamic kinetic asymmetric transformation (DyKAT).
Donorꢀacceptor (DꢀA) cyclopropanes are versatile
reagents for atom economical synthetic transformations.1
A particularly useful subset are those derived from 1,1-
dicarboxylate esters (or congeners) with vicinal carbon or
heteroatom donors. Under Lewis acid catalysis, these
materials function as homo-Michael acceptors in ring-
opening reactions2 and as zwitterion equivalents in (3 þ n)-
annulations.3 Productive oligomerization pathways4 and
umpolung reactivity modes have also emerged.5 Mechan-
istically, DꢀA cyclopropanes typically undergo stereo-
specificreactionthroughconfigurationallystableactivated
‘ion pair’ intermediates, resulting in inversion at the donor
site.6 As such, chirality transfer has been demonstrated in a
number of settings through deployment of optically active
cyclopropanes.2a,b,7 By contrast, more desirable strategies
to access enantioenriched products without preinstallation
of donor configuration are relatively rare. To this end, kinetic
resolutions of racemic cyclopropanes have been achieved
with nitrones,8 amines,9 and azomethine imines10 under
(1) Reviews: (a) Reissig, H.-U.; Zimmer, R. Chem. Rev. 2003, 103,
1151–1196. (b) Yu, M.; Pagenkopf, B. L. Tetrahedron 2005, 61, 321–347.
(c) Carson, C. A.; Kerr, M. A. Chem. Soc. Rev. 2009, 38, 3051–3060. (d)
Lebold, T. P.; Kerr, M. A. Pure Appl. Chem. 2010, 82, 1797–1812. (e)
Mel’nikov, M. Y.; Budynina, E. M.; Ivanova, O. A.; Trushkov, I. V.
Mendeleev Commun. 2011, 21, 293–301.
(2) Selected examples: (a) Lifchits, O.; Charette, A. B. Org. Lett.
2008, 10, 2809–2812. (b) Lifchits, O.; Alberico, D.; Zakharian, I.;
Charette, A. B. J. Org. Chem. 2008, 73, 6838–6840. (c) Sapeta, K.; Kerr,
M. A. Org. Lett. 2009, 11, 2081–2084.
(3) Recent examples: (a) Smith, A. G.; Slade, M. C.; Johnson, J. S.
Org. Lett. 2011, 13, 1996–1999. (b) Sathishkannan, G.; Srinivasan, K.
Org. Lett. 2011, 13, 6002–6005. (c) Qu, J. -P.; Liang, Y.; Xu, H.; Sun,
X. -L.; Yu, Z. -X.; Tang, Y. Chem.;Eur. J. 2012, 18, 2196–2201. (d)
Goldberg, A. F. G.; O’Connor, N. R.; Craig, R. A., II; Stoltz, B. M. Org.
Lett. 2012, 14, 5314–5317. (e) Humenny, W. J.; Kyriacou, P.; Sapeta, K.;
Karadeolian, A.; Kerr, M. A. Angew. Chem., Int. Ed. 2012, 51, 11088–
11091.
(4) (a) Ivanova, O. A.; Budynina, E. M.; Chagarovskiy, A. O.;
Trushkov, I. V.; Melnikov, M. Y. J. Org. Chem. 2011, 76, 8852–
8868. (b) Ivanova, O. A.; Budynina, E. M.; Chagarovskiy, A. O.;
Rakhmankulov, E. R.; Trushkov, I. V.; Semeykin, A. V.; Shimanovskii,
N. L.; Melnikov, M. Y. Chem.;Eur. J. 2011, 17, 11738–11742. (c)
Novikov, R. A.; Timofeev, V. P.; Tomilov, Y. V. J. Org. Chem. 2012, 77,
5993–6006.
(5) (a) Moran, J.; Smith, A. G.; Carris, R. M.; Johnson, J. S.; Krische,
M. J. J. Am. Chem. Soc. 2011, 133, 18618–18621. (b) Chagarovskiy,
A. O.; Ivanova, O. A.; Budynina, E. M.; Trushkov, I. V.; Melnikov,
M. Y. Tetrahedron Lett. 2011, 52, 4421–4425.
(6) (a) Cram, D. J.; Yankee, E. W. J. Am. Chem. Soc. 1970, 92, 6329–
6331. (b) Karadeolian, A.; Kerr, M. A. J. Org. Chem. 2007, 72, 10251–
10253. (c) Pohlhaus, P. D.; Sanders, S. D.; Parsons, A. T.; Li, W.;
Johnson, J. S. J. Am. Chem. Soc. 2008, 130, 8642–8650.
(7) Selected examples: (a) Pohlhaus, P. D.; Johnson, J. S. J. Am.
Chem. Soc. 2005, 127, 16014–16015. (b) Sapeta, K.; Kerr, M. A. J. Org.
Chem. 2007, 72, 8597–8599. (c) Jackson, S. K.; Karadeolian, A.; Driega,
A. B.; Kerr, M. A. J. Am. Chem. Soc. 2008, 130, 4196–4201. (d) Lebold,
T. P.; Leduc, A. B.; Kerr, M. A. Org. Lett. 2009, 11, 3770–3772. (e) de
Nanteuil, F.; Waser, J. Angew. Chem., Int. Ed. 2011, 50, 12075–12079. (f)
Benfatti, F.; de Nanteuil, F.; Waser, J. Chem.;Eur. J. 2012, 18, 4844–
4849.
r
10.1021/ol4010646
XXXX American Chemical Society

chiral Lewis acid catalysis, while the Trost group have
reported ligand controlled enantioconvergent cycloaddi-
tions of vinyl-cyclopropanes and olefins via allyl-palladium
intermediates.11 In a different realm, our laboratory has
demonstrated that cyclopropanes bearing donors with
electron-releasing substituents are suitable substrates
for type I dynamic kinetic asymmetric transformations
(DyKAT’s)12 by virtue of their increased rate of config-
urational inversion upon Lewis acid association.13,14 Here-
in, we now report the extension of our catalytic system
developed previously for DyKAT annulations of racemic
cyclopropanes 1 and dipolarophiles 2 to FriedelꢀCrafts
alkylation reactions (Figure 1).
entry tounderexplored chiralspace. Additional inspiration
came from Kerr’s findings that indoles readily cleave DꢀA
cyclopropanes under Lewis acid17 or H-bond activation18
in the racemic mode.
Table 1. Protecting Group Screeninga,b
entry
PG (4)
Me (4a)
product
yield (%)c
erd
1
2
3
4
5
6
7
8
9
5a
5b
5c
5d
5e
5f
85e,f
77e,g
22
62.5:37.5
76:24
nd
CH2Ph (4b)
CHPh2 (4c)
Boc (4d)
0
ꢀ
SiMe2Ph (4e)
SiMe2(t-Bu) (4f)
SiMe2(c-Hex) (4g)
SiEt3 (4h)
67e
76e
51
91.5:8.5
91:9
nd
5g
5h
5i
61
nd
Si(i-Pr)3 (4i)
35
nd
a Reactions performed with 1.0 equiv of 1a ([1a]0 = 0.05 M) and
1.5ꢀ1.7 equiv of 4. b 100% consumption of 1a in <24 h in all cases.
c Determined by 1H NMR spectroscopy with mesitylene as the internal
standard. d Determined by chiral HPLC analysis. e Isolated yield. f The
(3 þ 2)-annulation product was also isolated in 10% yield. g The (3 þ 2)-
annulation product was also isolated in 16% yield.
Figure 1. Proposed asymmetric FriedelꢀCrafts alkylation.
The ubiquitous indole nucleophile15 was an ideal start-
ing point for these investigations. We were interested in
developing a homologue of the extensively studied asym-
metricconjugate addition ofindoles toarylidine malonates
and related carbonyl Michael acceptors,16 as a potential
Our opening experiment was performed with N-Me-indole
and cyclopropane 1a under our previously optimized condi-
tions for asymmetric cycloadditions (L1 = (S,S)-4-Cl-(t-Bu)-
pybox),13a,b providing the desired alkylation product 5a in a
modest but encouraging 62.5:37.5 er (Table 1, entry 1).
Subsequent attempts to improve the enantioselectivity using
pybox and DBFOX ligands derived from other amino
alcohols were unsuccessful;19 thus we proceeded to explore
modulations of the N-protecting group (PG).20 We rea-
soned that more sterically encumbered and/or electronically
deactivating N-substituents would be required for the ob-
ligatory background ‘racemization’ of 1a to become com-
petitive with the rate of alkylation and began testing this
hypothesis with the moderately sized benzyl group (Table 1,
entry 2). After observing an increase in the er, we introduced
a second Ph group by way of the benzhydryl moiety, but
this change dramatically lowered the yield (entry 3). Not
surprisingly,18 the Boc group diminished the indole reactiv-
ity even further to the point that decomposition/oligomer-
ization of 1a was the sole reaction pathway (entry 4). Useful
levels of both yield and enantioselectivity were eventually
(8) (a) Sibi, M. P.; Ma, Z.; Jasperse, C. P. J. Am. Chem. Soc. 2005,
127, 5764–5765. (b) Kang, Y.-B.; Sun, X.-L.; Tang, Y. Angew. Chem.,
Int. Ed. 2007, 46, 3918–3921.
(9) Zhou, Y.-Y.; Wang, L.-J.; Li, J.; Sun, X.-L.; Tang, Y. J. Am.
Chem. Soc. 2012, 134, 9066–9069.
(10) Zhou, Y.-Y.; Li, J.; Ling, L.; Liao, S.-H.; Sun, X.-L.; Li, Y.-X.;
Wang, L.-J.; Tang, Y. Angew. Chem., Int. Ed. 2013, 52, 1452–1456.
(11) (a) Trost, B. M.; Morris, P. J. Angew. Chem., Int. Ed. 2011, 50,
6167–6170. (b) Trost, B. M.; Morris, P. J.; Sprague, S. J. J. Am. Chem.
Soc. 2012, 134, 17823–17831.
(12) Steinreiber, J.; Faber, K.; Griengl, H. Chem.;Eur. J. 2008, 14,
8060–8072.
(13) (a) Parsons, A. T.; Johnson, J. S. J. Am. Chem. Soc. 2009, 131,
3122–3123. (b) Parsons, A. T.; Smith, A. G.; Neel, A. J.; Johnson, J. S.
J. Am. Chem. Soc. 2010, 132, 9688–9692. (c) Campbell, M. J.; Johnson,
J. S.; Parsons, A. T.; Pohlhaus, P. D.; Sanders, S. D. J. Org. Chem. 2010,
75, 6317–6325.
(14) Tang has recently reported a DyKAT annulation of electron-
rich DꢀA cyclopropanes and cyclic enol silyl ethers; see: Xu, H.; Qu,
J. -P.; Liao, S.; Xiong, H.; Tang, Y. Angew. Chem., Int. Ed. 2013, 52,
4004–4007.
(15) For a review on the electrophilic functionalization of indoles,
see: Bandini, M.; Eichholzer, A. Angew. Chem., Int. Ed. 2009, 48, 9608–
9644.
(16) Selected examples: (a) Zhou, J.; Tang, Y. J. Am. Chem. Soc.
2002, 124, 9030–9031. (b) Evans, D. A.; Fandrick, K. R.; Song, H.-J.;
Scheidt, K. A.; Xu, R. J. Am. Chem. Soc. 2007, 129, 10029–10041. (c)
Liu, L.; Ma, H.; Xiao, Y.; Du, F.; Qin, Z.; Li, N.; Fu, B. Chem. Commun.
2012, 48, 9281–9283.
(18) Emmett, M. R.; Kerr, M. A. Org. Lett. 2011, 13, 4180–4183.
(19) Ad-pybox, Ph-pybox, Bn-pybox, Inda-pybox, Ph-DBFOX, and
(t-Bu)-DBFOX all provided 5a in er’s of <53:47.
(20) The absence of a PG resulted in side products of N-alkylation.
(21) For examples of N-TBS-indoles in asymmetric catalysis, see: (a)
Terada, M.; Yokoyama, S.; Sorimachi, K.; Uraguchi, D. Adv. Synth.
Catal. 2007, 349, 1863–1867. (b) Matsuzawa, H.; Kanao, K.; Miyake, Y.;
Nishibayashi, Y. Org. Lett. 2007, 9, 5561–5564. (c) Cai, Y.; Zhu, S. -F.;
Wang, G. -P.; Zhou, Q. -L. Adv. Synth. Catal. 2011, 353, 2939–2944.
(17) (a) Harrington, P.; Kerr, M. A. Tetrahedron Lett. 1997, 38,
5949–5952. (b) Grover, H. K.; Lebold, T. P.; Kerr, M. A. Org. Lett.
2011, 13, 220–223.
B
Org. Lett., Vol. XX, No. XX, XXXX

obtained upon experimentation with silyl PGs (entries 5ꢀ9),
with TBS providing optimal results (entry 6).21
Having established TBS as a suitable PG, we proceeded
to examine a set of 4-X-(t-Bu)-pybox ligands (Table 2,
entries 1ꢀ5). Consistent with our previous studies,13 optimum
results were obtained with halo substitution, although the
notably higher yield with L2 (X = Br, entry 2) made this the
particular ligand of choice for further experimentation.22,23
We continued by reducing the indole equivalents from 1.7
to 1.1 (entry 6) or using the indole as the limiting reagent
(entry 7); however, these alterations provided no advantage.
In our previous experience,13b deviations from dimethyl ester
activation have produced comparable but inferior results;
thus we were not surprised to re-encounter this trend with the
dibenzyl analogue 1b (Table 2, entry 8). In this alkylation
manifold, however, a notable increase in er occurred with the
diisopropyl ester 1c (entry 9), although ultimately we chose to
continue with dimethyl malonate-derived cyclopropanes due
to yield considerations.
Table 2. Additional Optimization Studiesa,b
entry
R0 (1)
product
L
yield (%)c
erd
91:9
1
Me (1a)
Me (1a)
Me (1a)
Me (1a)
Me (1a)
Me (1a)
Me (1a)
Bn (1b)
i-Pr (1c)
5f
5f
5f
5f
5f
5f
5f
5j
5k
L1
L2
L3
L4
L5
L2
L2
L2
L2
76e
81f
53
2
90.5:9.5
83:17
3
4
81
86:14
5
72
85:15
6g
7h
8
73
89.5:10.5
90.5:9.5
90:10
94.5:5.5j
69i
80e
75e
Figure 2. Substrate scope.a
9
substituents.25 In these instances, the slower rates of alkyla-
tion led to a greater extent of unproductive decomposition
of 1a. More sterically demanding 2- and 7-methylindoles
were well tolerated. In the former case a marginal decrease
in enantioselectivity occurred, presumably as a consequence
of the increased indole nucleophilicity.18 As observed
by Kerr26 and Ila,27 the presence of a 3-methyl substituent
induced cyclization of the putative intermediate giving
pentannulation product 5s in a useful er, albiet in modest
yield and with endo diastereoselectivity.28
a Reactions performed with 1.0 equiv of 1 ([1]0 = 0.05 M) and 1.7
equiv of 4f. b 100% consumption of 1 in <24 h in all cases except entry 7.
c Determined by 1H NMR spectroscopy with mesitylene as the internal
standard. d Determined by chiral HPLC analysis. e Isolated yield from a
single trial. f Average isolated yield of two trials. g With 1.1 equiv of N-
i
TBS-indole. h With 2.0 equiv of 1a and 1.0 equiv of 4f. Isolated yield
based on indole. j Er of TBS-deprotected derivative.
With optimized conditions established, the scope of
the asymmetric FriedelꢀCrafts alkylation was examined
(Figure 2). A range of indoles with electronically diverse
substituents provided the desired enantioenriched alkyla-
tion products.24 Yields were generally high with the excep-
tion of electron-deficient indoles bearing halo or ester
Dynamic cyclopropane reactivity was extended to sub-
strates bearing thienyl (1d), benzo[d][1,3]dioxol-5-yl (1e),
(26) (a) Kerr, M. A.; Keddy, R. G. Tetrahedron Lett. 1999, 40, 5671–
5675. (b) England, D. B.; Kuss, T. D. O.; Keddy, R. G.; Kerr, M. A.
J. Org. Chem. 2001, 66, 4704–4709. (c) England, D. B.; Woo, T. K.; Kerr,
M. A. Can. J. Chem. 2002, 80, 992–998.
(27) Venkatesh, C.; Singh, P. P.; Ila, H.; Junjappa, H. Eur. J. Org.
Chem. 2006, 5378–5386.
(28) Higher levels of endo diastereoselectivity (up to 100:1) were
obtained with aryl donors by Kerr and Ila in racemic preparations with
Yb(OTf)3 and BF3 respectively; see refs 26 and 27.
(22) See the Supporting Information for solvent screening results.
(23) In the absence of molecular sieves, slightly lower yields were
observed and 1 partially isomerized (<5%) to alkenes.
(24) Only traces of (3 þ 2)-annulation products were observed. These
impurities were easily removed by flash chromatography (higher Rf).
(25) Under the standard conditions, an experiment with 1-benzyl-5-
bromoindole provided the alkylation product in 64% yield and 86:14 er.
Org. Lett., Vol. XX, No. XX, XXXX
C

Table 3. Stereochemical Experimentsa
conversion
(%)b
yield
(%)b
er recovered
1h (R:S)c
er 5z
(R:S)c,d
cyclopropane
rac-1h
S-1h
61
87
16
49
75
10
94:6
86.5:13.5
>99.5:0.5
3:97
7.5:92.5
>99.5:0.5
R-1h
Figure 3. Unsuccessful cyclopropane donors.a
a Reactions performed with 1.0 equiv of 1h ([1h]0 = 0.05 M) and 1.7
equiv of 4f. b Determined by 1H NMR spectroscopy with mesitylene as
the internal standard. c Determined by chiral HPLC analysis. d Er of
TBS-deprotected derivative.
styrenyl (1f), and furanyl (1g) donors, all of which in fact
provided alkylation products with higher enantiopurity than
obtained with test substrate 1a. Among these, 1d provided the
best results (up to 96% yield and 97:3 er). Of note, all reactions
proceeded with complete cyclopropane consumption within
24 h, with the exception of those giving 5s and 5v, which
required ca. 3 d. All products were stable to silica gel
chromatography, and subsequent TBS-deprotection was rou-
tine with aqueous acid.29 Exemplary secondary transforma-
tions have been documented for racemic analogues.17a,18,26a
Under the optimized conditions, we have thus far been
unable to effectively alkylate N-TBS-indole with electron-
rich cyclopropanes bearing 2-OMePh and phthalimido30
substituents (Figure 3). In both cases cyclopropane reac-
tivity is sluggish, presumably due to steric shielding of the
electrophilic site. In contrast, with nitrogen-bearing carbon-
based donors including 4-NMe2Ph4a and N-Bn-indol-
3-yl,4b cyclopropane decomposition has been problematic
(Figure 3). Other aryl nucleophiles in combination with 1a
as an alkyating agent have also been explored, albeit with
limited success. Furan and thiophene are unreactive, while
N-Bn- and N-TBS-pyrroles have provided low yields
(30ꢀ40%) of alkylation products as regioisomeric mixtures
arising from substitution at both the 2- and 3-positions of
the pyrrole ring.
inversion.31 In accord with this precedent, a crystal of
alkylation product 5f (generated from an enriched sample
of98:2er) was determinedtohavethe (R)-configurationby
X-ray crystallography.32,33 To gain further insight, phenyl-
cyclopropane 1h was utilized as a mechanistic probe owing
to its configurational stability to Lewis acids (Table 3).13 Not
surprisingly, deployment of racemic-1h under the standard
conditions resulted in a kinetic resolution whereby enriched
(R)-1h was returned, while stereospecific alkylations were
observed with the (S) and (R) enantiomers. A significant rate
preference was conferred for (S)-1h.
Taken collectively with our previous data13 and Kerr’s
findings,34 these results point conclusively toward an en-
antioconvergent FriedelꢀCrafts alkylation proceeding
by a type I DyKAT, whereby stereospecific nucleophilic
trapping of the Lewis acid activated (S)-cyclopropane
occurs through a transient diastereomic intermediate.
In summary, we have reported a dynamic kinetic asym-
metric FriedelꢀCrafts alkylation of indoles with DꢀA
cyclopropanes, providing homo-Michael adducts in moder-
ate to high enantiopurity. The identification of TBS as a
suitable PG ensured the smooth transition of our previously
established DyKAT conditions to this alkylation setting.
Efforts to uncover new stereoselective transformations of
DꢀA cyclopropanes are ongoing in our laboratory.
Our previous mechanistic studies13 of L1/L2•MgI2 cat-
alyzed formal cycloadditions have elucidated a type I
DyKAT whereby nucleophilic attack occurs on the tran-
sient cyclopropane (S)-1 to furnish products of donor site
Acknowledgment. We thank the NSF (CHE-0749691)
for financial support. S.M.W. acknowledges the American
Australian Association for an Amgen Fellowship. X-ray
crystallography was performed by Dr. Peter White
(UNCꢀCH).
(29) See the Supporting Information for selected examples.
(30) Benfatti, F.; de Nanteuil, F.; Waser, J. Org. Lett. 2012, 14, 386–
389. See also refs 7e and 7f.
(31) For cyclopropanes 1d and 1g, the CahnꢀIngoldꢀPrelog prio-
rities change because of the thienyl and furanyl group; thus it is the (R)
enantiomers that are reactive.
(32) CCDC 932134 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge from
the Cambridge Crystallographic Centre via www.ccdc.cam.ac.uk/da-
ta_request/cif.
(33) The absolute configurations of other reaction products were
assigned by analogy.
Supporting Information Available. Experimental de-
tails and analytical data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(34) The indole-ring opening of enantiopure vinyl- and phenyl-cyclo-
propane diesters was also found to be stereospecific under Zn(NTf2)2
catalysis; see ref 17b.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX