New strategies in organic catalysis: The first enantioselective organocatalytic Friedel-Crafts alkylation [18]

Full text of DOI:10.1021/ja015717g

4370
J. Am. Chem. Soc. 2001, 123, 4370-4371
of an enantioselective conjugate pyrrole addition using chiral
amine or metal catalysts.
New Strategies in Organic Catalysis: The First
Enantioselective Organocatalytic Friedel-Crafts
Alkylation
Nick A. Paras and David W. C. MacMillan*
DiVision of Chemistry and Chemical Engineering
California Institute of Technology
Pasadena, California 91125
ReceiVed February 23, 2001
The metal-catalyzed addition of aromatic substrates to electron
deficient σ- and π-systems, commonly known as Friedel-Crafts
alkylation,1 has long been established as a powerful strategy for
C-C bond formation.2 Surprisingly, however, relatively few
asymmetric catalytic protocols have been reported that exploit
this venerable reaction manifold,3 despite the widespread avail-
ability of electron-rich aromatics and the chemical utility of the
accompanying products. In our recent studies, we reported that
the LUMO-lowering activation of R,â-unsaturated aldehydes via
the reversible formation of iminium ions with chiral imidazoli-
dinone 14 is a valuable platform for the development of enanti-
oselective organocatalytic Diels-Alder reactions5 (eq 1) and [3
+ 2] nitrone cycloadditions6 (eq 2). In this communication, we
To further demonstrate the value of our iminium-catalysis
strategy, we recently sought to develop an asymmetric Friedel-
Crafts variant that is currently unavailable using acid or metal
catalysis. In this context, it has been documented that R,â-
unsaturated aldehydes are poor electrophiles for pyrrole conjugate
addition due to the capacity of electron-rich aromatics to undergo
acid-catalyzed 1,2-carbonyl addition.8 As illustrated with the
calculated iminium ion model MM3-2,9 we expected R,â-
unsaturated iminium ions arising from chiral amine 1 to be inert
to 1,2-addition (pathway a) on the basis of steric constraints
imposed by the catalyst framework. As such, we assumed that
catalyst 1 might selectively partition heteroaromatic nucleophiles
toward a nonconventional and less sterically demanding 1,4-
addition manifold (pathway b) while enforcing high levels of
enantiocontrol in the carbon-carbon bond forming event.
Table 1. Effect of the Brønsted Acid Cocatalyst on the
Friedel-Crafts Alkylation of Cinnamaldehyde with N-Methyl
Pyrrole
demonstrate that this organocatalytic strategy is also amenable
to the enantioselective Friedel-Crafts alkylation of pyrroles with
R,â-unsaturated aldehydes to generate â-pyrrolyl carbonyls (eq
3), useful synthons for the construction of a variety of biomedical
agents.7 To our knowledge this study represents the first example
a Yields based upon isolation of the corresponding alcohol after
NaBH4 reduction. b Product ratios determined by chiral GLC. c Absolute
configuration assigned by chemical correlation to a known compound.
(1) Friedel, C.; Crafts, J. M. Bull. Soc. Chim. Fr. 1877, 27, 530.
(2) (a) Olah, G. A.; Krishnamurti, R.; Prakash, G. K. S. In ComprehensiVe
Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon Press: Oxford,
1991; Vol. 3, Chapter 1.8, p 293. (b) Roberts, R. M.; Khalaf, A. A. Friedel-
Crafts Alkylation Chemistry; Marcel Dekker: New York, 1984. (c) Friedel-
Crafts Chemistry; Olah, G. A., Ed.; Wiley: New York, 1973. (d) Friedel-
Crafts and Related Reactions; Olah, G. A., Ed.; Wiley-Interscience: New
York, 1963-65; Vols. 1-4.
(3) (a) Gathergood, N.; Zhuang, W.; Jorgensen, K. A. J. Am. Chem. Soc.
2000, 122, 12517. (b) Saaby, S.; Fang, X. M.; Gathergood, N.; Jorgensen, K.
A. Angew. Chem., Int. Ed. 2000, 39, 4114. (c) Jensen, K. M.; Thorhauge, J.;
Hazell, R. G.; Jørgensen, K. A. Angew. Chem., Int. Ed. 2001, 40, 160.
(4) Derived in two steps from (S)-phenylalanine.
(5) Ahrendt, K. A.; Borths, C. J.; MacMillan, D. W. C. J. Am. Chem. Soc.
2000, 122, 4243.
(6) Jen, W. S.; Wiener, J. J. M.; MacMillan, D. W. C. J. Am. Chem. Soc.
2000, 122, 9874.
(7) (a) Kleemann, A.; Engel, J.; Kutscher, B.; Reichert, D. Pharmaceutical
Substances, 4th ed.; Thieme: Stuttgart; New York, 2001. (b) (S)-Ketorolac:
Guzman, A.; Yuste, F.; Toscano, R. A.; Young, J. M.; Vanhorn, A. R.;
Muchowski, J. M. J. Med. Chem. 1986, 29, 589. (c) Viminol: Della Bella,
D. Boll. Chim. Farm. 1972, 111, 5.
Our enantioselective catalytic Friedel-Crafts alkylation was
first evaluated using N-methyl pyrrole with (E)-cinnamaldehyde
and a series of benzyl imidazolidinone‚HX salts 1. As revealed
in Table 1, this reaction was successful with a variety of amine
catalysts (entries 1-5) to provide the desired conjugate addition
adduct with moderate to excellent enantioselectivity (80-93%
ee).10 It is important to note that products arising from 1,2-iminium
addition were not observed in these reactions, in accord with our
(8) (a) Gupta, R. R.; Kumar, M.; Gupta, V. Heterocyclic Chemistry;
Springer-Verlag: Heidelberg, 1999; Vol 3. (b) Strell, A.; Kalojanoff, R. Chem.
Ber. 1954, 87, 1954.
(9) Monte Carlo simulation, MM3 force-field; Macromodel V6.5.
(10) A broad range of Brønsted acid cocatalysts have been evaluated: HCl,
77% ee; p-TSA, 42% ee; TfOH, 55% ee.
10.1021/ja015717g CCC: $20.00 © 2001 American Chemical Society
Published on Web 04/13/2001

Communications to the Editor
J. Am. Chem. Soc., Vol. 123, No. 18, 2001 4371
Table 2. Organocatalyzed Friedel-Crafts Alkylation between
N-Methyl Pyrrole and Representative R,â-Unsaturated Aldehydes
Table 3. Organocatalyzed Friedel-Crafts Alkylation between
R,â-Unsaturated Aldehydes and Representative Pyrroles
entry
R
temp (°C)
time (h)
% yielda
% eeb,c
1
2
3
4
5
6
7
Me
Pr
i-Pr
Ph
4-MeOPh
CH2OBn
CO2Me
-60
-50
-50
-30
-30
-60
-50
72
72
72
42
104
72
83
81
80
87
79
90
72
91d
90
91
93
91
87d
90e
104
a Yields based upon isolation of the corresponding alcohol after
NaBH4 reduction. b Ratios determined by chiral GLC or HPLC.
c Absolute stereochemistry determined by chemical correlation or by
analogy. d Using 10 mol % catalyst 1d. e Using catalyst 1a.
mechanistic postulate. An enantioselectivity/temperature profile
documents that optimal enantiocontrol is achieved with catalyst
1d at -30 °C to afford substituted pyrrole (S)-3 in 93% ee and
87% yield (entry 5). The superior levels of asymmetric induction
and reaction efficiency exhibited by the TFA salt 1d prompted
us to select this catalyst for further exploration.
The scope of the organocatalytic Friedel-Crafts alkylation
between N-methyl pyrrole and various R,â-unsaturated aldehydes
has been investigated (Table 2). Significant variation in the steric
contribution of the olefin substituent (R ) Me, Pr, i-Pr, entries
1-3) is possible without loss in yield or enantioselectivity (g80%
yield, g90% ee). The reaction is also tolerant of â-aromatic
substituents on the olefin component (entries 4-5, g79% yield,
91-93% ee). As revealed in entries 6 and 7, the reaction can
accommodate electron-deficient aldehydes that do not readily
participate in iminium formation (R ) CH2OBn, 87%ee; R )
CO2Me, 90% ee). To demonstrate the preparative utility, the
addition of N-methyl pyrrole to cinnamaldehyde was performed
on a 25 mmol scale with catalyst 1d to afford (S)-3 in 93% ee
and 87% yield.
This amine-catalyzed Friedel-Crafts alkylation is also general
with respect to pyrrole architecture (Table 3). Variation in the
N-alkyl group (R1 ) H, Me, Bn, allyl, entries 1-4) is possible
without loss in yield or enantioselectivity (g74% yield, 89-93%
ee). Incorporation of alkyl substituents at the C(2)-pyrrole position
reveals that increased π-nucleophilicity has little influence on
reaction selectivity (entry 5, 87% yield, 90% ee).11,12 In accordance
with established heteroaromatic addition methodology,8a the use
of C(3)-substituted pyrroles results in regioselective alkylation
of the more hindered C(2)-aromatic site (entry 6, 98:2 C(2):C(5)
selectivity) with excellent levels of enantiocontrol (97% ee).
A further illustration of the utility of this organocatalytic
Friedel-Crafts alkylation is presented in the reaction of N-methyl
pyrrole with excess crotonaldehyde (eq 4). The central issue in
this reaction is that of catalyst-controlled alkylation at both C(2)
and C(5) of the aromatic nucleophile to provide enantioselective
access to C2-symmetric pyrrole adducts. As outlined in eq 4,
formation of the 2,5-disubstituted pyrrole 4 is accomplished in
98% ee and 90:10 selectivity for the desired C2-isomer (83%
yield). This concept can be further advanced to the implementation
of two discrete R,â-unsaturated aldehydes to provide the non-
symmetrical disubstituted pyrrole 5 in 99% ee and 90:10 anti
selectivity (eq 5, 72% yield over two steps). Interestingly, we
expect this enantioselective bisalkylation technology to be of
a Yields based upon isolation of the corresponding alcohol after
NaBH4 reduction. b Ratios determined by chiral GLC or HPLC.
c Absolute stereochemistry determined by chemical correlation or by
analogy. d Using catalyst 1d. e Using catalyst 1c. f Using catalyst 1a.
particular value for the construction of ligands for use in
asymmetric organometallic catalysis.
Finally, with regard to the operational advantages of organo-
catalysis, it is important to note that (i) the sense of asymmetric
induction observed in all cases was readily anticipated by the
calculated iminium ion model MM3-2 in accord with previous
studies,5,6 and (ii) all of the alkylations described herein were
performed under an aerobic atmosphere, using wet solvents and
an inexpensive bench-stable catalyst.
In summary, we have further established LUMO-lowering
organocatalysis as a broadly useful concept for asymmetric
synthesis in the context of the Friedel-Crafts alkylation. A full
account of this survey will be forthcoming.
Acknowledgment. Financial support was provided by kind gifts from
Dupont, GlaxoWellcome, Johnson and Johnson, and Merck.
(11) Only products arising from regioselective alkylation of the pyrrole
C(5) position were observed in these cases.
(12) Aromatic systems that are electron-deficient relative to pyrrole were
found to be poor substrates for these alkylation reactions. A new organocata-
lytic Friedel-Crafts protocol that is specifically selective for indoles, furans,
and thiophenes has recently been developed in our laboratory and will be
reported in due course.
Supporting Information Available: Experimental procedures and
spectral data for all compounds are provided (PDF). This material is
available free of charge via the Internet at http://pubs.acs.org.
JA015717G