Synthesis of sterically hindered enamides via a Ti-mediated condensation of amides with aldehydes and ketones

Article abstract of DOI:10.1039/c2cc32538a

The first TiCl₄-mediated condensation of secondary amides with aldehydes and ketones has been achieved. The reaction proceeds at room temperature and is complete within 5 h in most cases. The optimized procedure used 5 equiv of an amine base hi

Full text of DOI:10.1039/c2cc32538a

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COMMUNICATION
Synthesis of sterically hindered enamides via a Ti-mediated condensation
of amides with aldehydes and ketonesw
´
Julien Genovino, Bharat Lagu, Yaping Wang and B. Barry Toure*
Received 9th April 2012, Accepted 30th April 2012
DOI: 10.1039/c2cc32538a
The first TiCl4-mediated condensation of secondary amides with
aldehydes and ketones has been achieved. The reaction proceeds
at room temperature and is complete within 5 h in most cases.
The optimized procedure used 5 equiv of an amine base hinting
that the in situ activation of both the amide and the Lewis acid is
required. The reaction affords polysubstituted (E)-enamides.
or anhydrides in this reaction has not been reported. The
conversion of carbonyl compounds to enamides is advantageous
due to their long shelf life, low cost and ease of access. Herein,
we present a new route to polysubstituted enamides that uses
readily available amides and carbonyl compounds. The reaction
proceeds at room temperature (and even below), and is complete
mostly within 5 h.
Enamides1 are an emerging class of substrates for the synthesis
of chiral amines via asymmetric hydrogenation2 and more
importantly for the synthesis of saturated and unsaturated
heterocycles.3 Considering the extensive patent coverage of
heterocyclic moieties in the pharmaceutical industry, access to
new heterocycles or those with unusual substitution patterns is
increasingly needed.4 From a synthetic viewpoint, a variety of
reaction strategies to synthesize enamides have been disclosed
in the literature.5 The most widely applicable routes to enamides
remain the Cu- and Pd-catalyzed processes developed by
Buchwald,5o Porco,5p Ma5q and others5k–q and more recently
refined by Batey.5k With the exception of Batey’s procedure, which
still uses excess amount of the precious organotrifluoroborate salts
(2–5 equiv.), these transition metal catalyzed reactions require high
temperature, very strong bases, and careful exclusion of air. It
should be noted that these methods are not applicable to the
synthesis of hindered enamides due to the limited supply of
complex vinyl halides/borates and/or the difficulty to synthesize
them. Recently, a two-step procedure based on the Heck arylation
of preformed enamides was introduced as a potential solution
to this problem, although only b-amidoacrylates were extensively
investigated.5n Overall, the synthesis of sterically congested
enamides still represents an unsolved synthetic problem.
There has been a long standing interest in converting
carbonyl compounds into enamides.3h,6 The most widely used
procedures uses p-TsOH in refluxing toluene over a long period of
time (1–5 days).6a Broadly speaking, hindered substrates do not
work well under these conditions.3h More recently, a chemical
development group at Boehringer Ingelheim6d has successfully
converted ketones into N-acetyl enamides using ammonia and
acetic anhydride at room temperature. The use of other amines
A preliminary screening was carried out using 2-pyrrolidinone
and cyclohexanecarboxaldehyde (entry 1, Table 1). We aimed at
identifying conditions that would promote this very sterically
demanding condensation reaction at a mild temperature. The
use of a strong Lewis acid was thought to be essential in order to
overcome the low inherent nucleophilicity associated with
amides by analogy to the use of p-TSA under the previously
mentioned condition.6a BF3ÁOEt2, Zn(OTf)2, AlCl3, MgCl2,
Ti(Oi-Pr)4 and TiCl4 all failed to promote the desired reaction.
We reasoned that a base may be required to activate the amide,
and/or facilitate the tautomerization of the transiently formed
N-acyl iminium intermediate. When NEt3 was combined to
the above Lewis acids, again no reaction was observed with
BF3ÁOEt2 and Zn(OTf)2 while AlCl3, MgCl2, and Ti(Oi-Pr)4
only afforded varying amount of N-acyl hemiaminal intermediate
(see supporting information). Gratifyingly, TiCl4 enabled the
formation of the desired enamide 1 in very good isolated yield
(73%). To the best of our knowledge this is the first time that a
Lewis acid has been used to make enamides from amide
nucleophiles at room temperature. We next turned our atten-
tion to the nature of the base, which proved more critical than
expected. DIPEA, DBU, and Cs2CO3 all appeared inferior in
yields while DABCO, t-BuONa, and NaOH did not promote
any reaction (see supporting information). Further optimiza-
tion revealed that the amount of NEt3 (i.e. 5 equiv. as opposed
to 1, 2.5, and 10 equiv.) was crucial to achieve a good yielding
transformation. This preliminary screening informed our
choice to use the TiCl4/Et3N combination. Ti-complexes with
an amine base are known to promote a range of synthetic
transformations, oftentimes tolerating the presence of very
sensitive substrates.7
Next, we explored the substrate scope of this new transformation
(Table 1). 2-Pyrrolidinone was reacted with a range of aldehydes
of different steric hinderance starting with cyclopentane- and
cyclooctane-carboxaldehydes. In both cases the desired products
were obtained in moderate to good yield (49 and 62% respectively,
entry 1). To probe the steric effect in acyclic series, we started our
Novartis Institutes for Biomedical Research (NIBR)–250
Massachusetts Avenue, Cambridge 02139, MA, USA.
E-mail: barry.toure@novartis.com; Tel: +1 617 8714197
w Electronic Supplementary Information (ESI) available. See DOI:
10.1039/c2cc32538a
c
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Chem. Commun., 2012, 48, 6735–6737 6735

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Table 1 Ti-mediated condensation of amides with aldehydes
the corresponding enamide 10 in very good yield (75% at
60 1C in DCE, 46% at rt, entry 6). Primary amides proved
equally reactive although the corresponding products were
isolated in low yield due primarily to stability issues (entry 7).
To explore the access to even more complex enamides, we
investigated the applicability of this methodology to ketone
substrates (Table 2). Without any optimization, we were pleased
that 2-pyrrolidinone could be condensed with an unsymmetrical
ketone to form a,b-disubstituted enamide 14 in good yield and very
high stereoselectivity (entry 1). Interestingly, no loss of reactivity
was observed in the formation of enamide 14 compared to
the condensation with the less hindered phenylacetaldehyde
(51% vs. 46% yield – Table 2, entry 1 vs. table 1, entry 3).
Entry
1
Enamide product
Yielda (%)
73,15c
49b
1: n = 1,
2: n =0,
3: n = 3
62
As observed for the coupling with aldehydes, moving from
2-pyrrolidinone to an oxazolidinone coupling partner did
not influence the yield or the stereoselectivity of the reaction
(14 vs. 15, entry 1, Table 2). Noteworthy, enamide 15 was
obtained (E)-stereoselectively as opposed to Park’s protocol5n
that affords the complementary (Z)-isomer. Acetophenone
also proved to be a good substrate to afford the geminal
bis-substituted enamide 16 (80% NMR yield, 52% isolated).
Cyclic ketones were also investigated. Simple dihydronaphthalen-
1-yl oxazolidinones were previously prepared in very good yield
via an arene-ynamide cyclization protocol,8 wherein the precursor
must be prepared via a multi-step sequence. Here, we can
access a more complex derivative in one step from commercially
54c E only
30
2
3
4: n = 3
46 E only
15c
5: R = H
43 Z : E
30c 1 : 1.3
6: R = Me
4
5
7
35 E only
8: R = H
9: R = Ph
54
14c
54
Table 2 Ti-mediated condensation of amides with ketones
75b,d
NMR yield/isolated
yield (%)
6
10
Entry Enamide product
20b
17b
8e
11, Ar = Ph,
12, Ar = (p-CF3)Ph,
13, Ar = (o-Me)Ph,
7
1
a
Standard condition: TiCI4 (1.2 equiv.), NEt3 (5 equiv.), 0 1C to r.t.,
X= C, R = Ph
X = O, R = Ph
X = O, R = H
14 51/nd E only
15 50/(45) E onlya
16 80/52
b
c
d
DC., 2–16 h. NMR yield. Using DBU. 75% at 60 1C in DCE.
Heating did not prove beneficial for other substrates. NMR yield
only, not purified.
e
investigation with a simple heptanal system. To our surprise,
the yield of the reaction was very low (30%, entry 2). However
the yield of the reaction nearly doubled when DBU was used
as a base in lieu of Et3N firmly establishing the strong
dependence of this reaction on the nature/strength of the base.
When 2-phenyl acetaldedyde was used as substrate, the desired
product was isolated in 46% yield (entry 3) under the standard
reaction conditions against 15% for the DBU protocol. A
similar trend was observed with 2-phenyl propanal (entry 4).
Taken together, these results suggest that a small base should
be used when condensing hindered substrates, whereas a
strong base is preferred for unhindered aldehydes. In addition,
erosion of stereoselectivity was observed when a branched
aldehyde was used (1.3 : 1 E, Z ratio, entry 3). The reaction is
also compatible with the use of carbamates affording the
oxazolidinone adduct 8 in moderate yield (entry 5). Remark-
ably, 4–phenyloxazolidinone performed equally well in this
union between two highly hindered substrates (entry 5, 54%).
Acyclic secondary amide N-methyl benzamide also afforded
2
n = 1, X = C, R, R2 = H, R1 = Br 17 54/43
n = 1, X = O, R, R1 = H, R2 = Br 18 54/49
n = 0, X = C, R = F, R1, R2 = H 19 46/38
3
20 32/19
4
21 18/11 E onlya
a
The olefin geometry of 14 confirmed by nOe, geometry of 15 and 21
were assigned by analogy to 14; nd = not determined.
c
6736 Chem. Commun., 2012, 48, 6735–6737
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available starting materials. For instance, oxazolidinone reacted
with halogenated dihydronaphtalenone to afford 17 in 43%
isolated yield (entry 2). The presence of an ether functionality is
also compatible with our reaction conditions (entry 2) as
well as the use of indanone derivatives (entry 2). Finally,
we attempted to access unprecedented tetrasubstituted and
halogenated enamides. In both cases, desired products 20 and
21 could be isolated without any optimization albeit in low
yield (entries 3 and 4).
3 Selected examples of heterocyclic syntheses, access to pyrimidines:
(a) A. Estrada, J. P. Lyssikatos, F. St-Jean and P. Bergeron, Synlett,
2011, 16, 2387; (b) access to pyridones: L. Carles, K. Narkunan,
S. Penlou, L. Rousset, D. Bouchu and M. A. Ciufolini, J. Org. Chem.,
2002, 67, 4304; (c) H. Imase, K. Noguchi, M. Hirano and K. Tanaka,
Org. Lett., 2008, 10, 3563; (d) access to pyrimidin-4-ones: J. M.
Ramanjulu, M. P. DeMartino, Y. Lan and R. Marquis, Org. Lett.,
2010, 12, 2270; (e) access to pyrrolidinone/chiral 4-hydroxy piperidines/
chiral 1H-Pyrrol-2(3H)-one: S. Tong, D.-X. Wang, L. Zhao, J. Zhu and
M.-X. Wang, Angew. Chem., Int. Ed., 2012, 51, 1 and references therein;
(f) G. J. Brizgys, H. H. Jung and P. E. Floreancig, Chem. Sci., 2012,
3, 438; (g) access to chiral pyrrolidines: R. Matsubara, N. Kawai and
S. Kobayashi, Angew. Chem., 2006, 118, 3898; (h) access to isoquinolin-
1-(2H)-ones: C.-C. Chen, L.-Y. Chen, R.-Y. Lin, C.-Y. Chu and
S. A. Dai, Heterocycles, 2009, 78, 2979; (i) access to pyridines:
T. Lechel, J. Dash, C. Eidamshaus, I. Brudgam, D. Lentz and H.-U.
Reissig, Org. Biomol. Chem., 2010, 8, 3007; (j) M. Movassaghi, M. D.
Hill and O. K. Ahmad, J. Am. Chem. Soc., 2007, 129, 10096; (k) access
to pyrroles: M. R. Rivero and S. L. Buchwald, Org. Lett., 2007, 9, 973.
4 W. R. Pitt, D. R. Parry, B. G. Perry and C. R. Groom, J. Med.
Chem., 2009, 52, 2952.
5 Curtius rearrangement of a,b-unsaturated acyl azides: (a) B. B. Snider
and F. B. Song, Org. Lett., 2000, 2, 407; (b) elimination of b-hydroxy-
a-silyl amides: A. Furstner, C. Brehm and Y. Cancho-Grande, Org.
Lett., 2001, 3, 3955; (c) condensation of aldehydes or ketones with
nitriles: Z. Rappoport, The Chemistry of Enamines, John Wiley &
Sons, Chichester, UK, 1994, p. 1441 Ru-catalyzed amidation of
alkynes; (d) T. Kondo, A. Tanaka, S. Kotachi and Y. Watanabe,
J. Chem. Soc. Chem. Commun., 1995, 413; (e) L. J. Gooßen,
J. E. Rauhaus and G. Deng, Angew. Chem., 2005, 117, 4110 (Angew.
Chem., Int. Ed., 2005, 44, 4042); (f) Fe- and Rh-catalyzed isomeriza-
tion of N-allylamides: J. K. Stille and Y. Becker, J. Org. Chem., 1980,
45, 2139; (g) S. Sergeyev and M. Hesse, Synlett, 2002, 1313;
(h) S. A. Sergeyev and M. Hesse, Helv. Chim. Acta, 2003, 86, 750;
(i) Rh-catalyzed carbozincation and hydrozincation of ynamides:
B. Gourdet, M. E. Rudkin, C. A. Watts and H. W. Lam, J. Org.
Chem., 2009, 74, 7849; (j) B. Gourdet and H. W. Lam, J. Am. Chem.
Soc., 2009, 131, 3803; (k) Cu-catalyzed amidation of potassium
alkenyltrifluoroborate salts: Y. Bolshan and R. A. Batey, Angew.
Chem., Int. Ed., 2008, 47, 2109; (l) for Pd-catalyzed Heck reaction:
ref. 2b; for Pd-catalyzed amidation of enol triflates, or tosylates:
A. Klapars, K. R. Campos, C.-Y. Chen and R. P. Volante, Org.
Lett., 2005, 7, 1185; (m) D. J. Wallace, D. J. Klauber, C.-Y. Chen
and R. P. Volante, Org. Lett., 2003, 5, 4749; (n) Pd-mediated Heck
arylation: Y. Liu, D. Li and C.-M. Park, Angew. Chem., Int. Ed.,
2011, 50, 7333; (o) for Cu-catalyzed coupling between amides and
alkenyl halides: L. Jiang, G. E. Job, A. Klapars and S. L. Buchwald,
Org. Lett., 2003, 5, 3667; (p) R. Chen and J. Porco, Org. Lett., 2000,
2, 1333; (q) X. Pan, Q. Cai and D. Ma, Org. Lett., 2004, 6, 1809.
6 (a) C. A. Zezza and M. B. Smith, Synth. Commun., 1987, 17, 729;
(b) ref. 3k; (c) for reductive acylation of ketoximes: M. J. Burk,
G. Casy and N. B. Johnson, J. Org. Chem., 1998, 63, 6084; (d) for
an access to enamides via acylation of imines: J. T. Reeves, Z. Tan,
Z. S. Han, G. Li, Y. Zhang, Y. Xu, D. C. Reeves, N. C. Gonnella,
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Ed., 2012, 51, 1400 and references therein.
While the detailed mechanistic picture of this reaction
remains unclear, several lines of evidence point to a mechanism
distinct from the classic p-TSA catalyzed enamide synthesis
reactions. First, the reaction does not proceed in the absence of
an organic base. Second, weaker Lewis acids only afforded
N-hemiaminal intermediates in the presence of the base. Third,
the reaction showed a strong dependence on the nature/strength
of the base; for unhindered carbonyl substrates the yield of the
reaction increases with the use of stronger bases whereas for
hindered carbonyl compounds steric considerations prevailed.
Taken together, these observations paint a mechanistic picture
that is consistent with a tandem aza-aldol/E2-elimination
mechanism. Finally, the optimal reaction conditions required
the use of 5 equiv of the base. Under this scenario, the
displacement of the chloride by excess base to generate a
Ti-NEt3 adduct, an even stronger Lewis acid, is plausible.9
Indeed, the activation of Lewis acids by Lewis bases is a
known concept that has been well described in the literature
especially for weak Lewis acids such as SbCl4, SiCl4, or Se
derivatives.10 The metal center in the resulting adduct is thought
to be more electropositive than without base. By analogy and
even though such activation does not seem to be reported for
Ti(IV) complexes, it appeared plausible to us to think that the
strong inherent acidity of TiCl4 may generally hide its activation
by Lewis bases, and thus be less visible than for weak acids
(e.g. SiCl4). This Lewis base activation would only become
beneficial for reactions of high activation energy where TiCl4
alone is not sufficient to promote the transformation.
We have developed a convenient condensation of secondary
amides with a variety of carbonyl compounds in one step at
room temperature using the unique combination of TiCl4 and
NEt3 to generate polysubstituted enamides in moderate to
good yields. We expect the new enamides synthesized herein to
find application in asymmetric hydrogenations,2 and the
synthesis of diverse heterocyclic cores.3
7 (a) G. Koch, O. Loiseleur, D. Fuentes, A. Jantsch and
K.-H. Altmann, Org. Lett., 2002, 4, 3811; (b) C. M. Hayward,
D. Yohannes and S. J. Danishefsky, J. Am. Chem. Soc., 1993,
115, 9345; (c) W. A. White and H. Weingarten, J. Org. Chem.,
1967, 32, 213.
8 Y. Zhan, R. P. Hsung, X. Zhang, J. Huang, B. W. Slafer and
A. Davis, Org. Lett., 2005, 7, 1047.
9 Cationic Ti species, see: (a) G. W. Fowles and R. A. Hoodless,
J. Chem. Soc., 1963, 33; (b) A. M. Chapman and D. F. Wass,
Dalton Trans, 2012, DOI: 10.1039/c2dt30168g.
Novartis Office of Education, Diversity, and Inclusion and
Patience Moyo are acknowledged.
Notes and references
1 For reviews on the synthetic use of enamides: (a) K. Gopalaiah and
H. B. Kagan, Chem. Rev., 2011, 111, 4599.
2 (a) D. Pena, A. J. Minnaard, J. G. De Vries and B. L. Feringa,
J. Am. Chem. Soc., 2002, 124, 14552; (b) P. Harrison and G. Meek,
Tetrahedron Lett., 2004, 45, 9277; (c) P. Dupau, P. Le Gendre,
C. Bruneau and P. H. Dixneuf, Synlett, 1999, 11, 1832.
10 S. E. Denmark and T. W. Wilson, Angew. Chem., Int. Ed., 2012,
51, 3236 and references therein.
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 6735–6737 6737