One-Pot Synthesis of α-Branched N-Acylamines via Titanium-Mediated Condensation of Amides, Aldehydes, and Organometallics

Article abstract of DOI:10.1021/acs.orglett.7b00082

A three-component, titanium-mediated synthesis of α-branched N-acylamines from commercial or readily accessible amides, aldehydes, and organometallic reagents is reported. The transformation proceeds under mild reaction conditions and tolerates a variety of functional groups (including nitrile, carbamate, olefin, basic amine, furan, and other sensitive heteroaromatics) to generate a large umbrella of α-branched N-acylamine products in high yields. The operationally practical procedure enables the use of this method in parallel chemical synthesis, a valuable feature that can facilitate the screening of bioactive molecules by medicinal chemists.

Full text of DOI:10.1021/acs.orglett.7b00082

Letter
pubs.acs.org/OrgLett
One-Pot Synthesis of α‑Branched N‑Acylamines via Titanium-
Mediated Condensation of Amides, Aldehydes, and Organometallics
Chunhui Dai,*,†,§ Julien Genovino,*,‡,§ Bruce M. Bechle,† Matthew S. Corbett,† Chan Woo Huh,†
Colin R. Rose,† Jianmin Sun,† Joseph S. Warmus,† and David C. Blakemore†
‡
†Neuroscience and Pain and Cardiovascular, Endocrine, and Metabolic Diseases, Pfizer Worldwide Medicinal Chemistry, Eastern
Point Road, Groton, Connecticut 06340, United States
S
* Supporting Information
ABSTRACT: A three-component, titanium-mediated synthesis of
α-branched N-acylamines from commercial or readily accessible
amides, aldehydes, and organometallic reagents is reported. The
transformation proceeds under mild reaction conditions and
tolerates a variety of functional groups (including nitrile,
carbamate, olefin, basic amine, furan, and other sensitive
heteroaromatics) to generate a large umbrella of α-branched N-acylamine products in high yields. The operationally practical
procedure enables the use of this method in parallel chemical synthesis, a valuable feature that can facilitate the screening of
bioactive molecules by medicinal chemists.
reaction partners such as boronic acids,6a alkanes,6b alkyl
α-Branched N-acylamines are highly prevalent motifs across all
halides,6c vinyl arenes,6d,e alcohols,6f,g or carbonyl compounds
(ketones/aldehydes).6h,i,k However, most of these new
methods suffer from a range of limitations such as harsh
reaction conditions (elevated temperatures, use of peroxides),
excess reagents, limited substrate scope, and the requirement of
preparing the starting building blocks.
areas of organic chemistry.1,2 Their synthesis has traditionally
relied upon the preactivation of carboxylic acids with coupling
reagents (including the use of anhydrides, carbodiimides,
hydroxybenzotriazole, or thionyl chloride) followed by their
condensation with a secondary amine.3 A standard alternative is
the hydrogenation of α-substituted enamides, yet it is limited by
the supply of this class of substrates that require preparation.4
In the past decade, new synthetic methods have emerged,
taking advantage of an alternate bond disconnection (Scheme
1a)5,6 via the coupling of primary amides with a variety of
A multicomponent transformation that takes advantage of
three readily available coupling partners could both improve
efficiency and enable access to a greater and more diverse
chemical space. Such chemical diversity is not as readily
accessible via traditional methods. For instance, amide bond
couplings are restricted by the limited scope of α-branched
hereroarylamines available. In addition, a three-component and
operationally practical method could allow the screening of
bioactive molecules via targeted parallel chemical synthesis, a
valuable approach in drug discovery. One such method is the
recent Bi(OTf)3-catalyzed aza-Friedel−Crafts of in situ
generated N-acylimine/N-acyliminium (Scheme 1b).6i This
elegant transformation is, however, restricted to electron-rich
arenes used in excess (3 equiv) that typically lead to
regioisomeric product mixtures.
Scheme 1. Access to α-Branched N-Acylamines
Herein, we report the first three-component Ti-mediated
synthesis of α-branched N-acylamines using a large variety of
aliphatic and (hetero)aromatic primary amides, aldehydes, and
organometallic reagents such as Grignards and organozincates
(Scheme 1c).
A previous report on the Ti-mediated condensation of
amides and aldehydes to generate sterically hindered enamides
in the presence of triethylamine prompted us to explore these
reaction conditions to access α-branched N-acylamines.7 We
Received: January 9, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b00082
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Letter
hypothesized that the putative N-acylimine or N,O-hemiaminal
enamide precursor could be trapped upon addition of a suitable
nucleophile to afford α-branched N-acyl amine products.
At the outset of our studies, we selected benzamide (1) and
benzaldehyde (2) as test substrates to optimize the reaction
conditions following the reported protocol using methylmag-
nesium bromide as a source of nucleophile (Table 1). The
Scheme 2. Ti-Mediated Coupling of Aromatic Amides and
Aldehydes Followed by MeMgBr Addition
a,b
Table 1. Optimization of the Ti-Mediated Three-
Component Condensation
a
a
b
entry Lewis acid solvent base MeMgBr temp (°C) yield (%)
1
2
3
4
5
TiCl4
DCE
THF
THF
THF
5
0
0
0
0
5
5
5
4
3
rt
rt
16
65
77
72
34
Ti(Oi-Pr)4
Ti(Oi-Pr)4
Ti(Oi-Pr)4
Ti(Oi-Pr)4
60
60
60
THF
a
b
Equivalents of reagent. Isolated yield.
conditions operative for the formation of enamides, TiCl4 (1.2
equiv) and NEt3 (5 equiv) in DCE at room temperature, only
afforded α-methyl-N-acylamine 3 in 16% isolated yield (entry
1). Several side products were observed under these reaction
conditions including the presumed N-acylimine and bis-N-acyl-
N,N-hemiaminal product resulting from the addition of a
second amide molecule as well as cinnamaldehyde well-known
to form under these reaction conditions.8 Further optimization
(for more details, see the Supporting Information) showed that
the reaction in THF using Ti(Oi-Pr)4 in place of TiCl4 and in
the absence of NEt3 led to a cleaner reaction profile with 65%
isolated yield (entry 2). These results hint to the key role of
Ti(Oi-Pr)4 (versus TiCl4) and the detrimental effect of the
base; both points are in sharp contrast with the conditions
reported for the formation of enamides.7 An increased yield
(77%) was observed when the reaction mixture was stirred at
60 °C for 1 h after Grignard addition (entry 3). The
stoichiometry of Grignard reagent also proved critical to ensure
the formation of product in high yields (entries 3−5).
With our optimized conditions in hand, the substrate scope
was investigated starting with electronically differentiated aryl
amides (Scheme 2a). The electronics of the aryl group did not
seem to impact the nucleophilicity of the amido group given
that both electron-rich (p-methyl, p-methoxy) and electron-
deficient (m-bistrifluoromethyl)benzamides worked equally
well to form N-acylamines 6a−c in 86%, 80%, and 80% yields.
Increased steric bulk at the ortho position (6d) did not impact
the yields significantly. p-Nitrobenzamide failed to give product
6e. This is consistent with the known propensity of Grignard
reagents to react with nitro-aromatics.9 The benzaldehyde
coupling partner appeared more sensitive to the electronics of
the ring. o- and p-methyl benzaldehydes (6f,g) worked equally
well along with electron-deficient benzaldehydes (6h−j),
presumably enhancing the electrophilicity of the carbonyl
group. However, an electron-rich substituent such as p-methoxy
(6k) did not impact the yield. Increasing aromatic electron-
density with the N,N-dimethylamino and the catechol motifs
still generated N-acylamines 6l and 6m, albeit in lower yields.10
In agreement with our optimization of conditions, the
a
Conditions: aldehyde (1.0 equiv), amide (1.05 equiv), Ti(i-OPr)4
b
(1.2 equiv), THF, 18 h, rt; MeMgBr (5.0 equiv), 60 °C, 1 h. Isolated
yields. Reaction carried out at room temperature. The reaction
mixture was also stirred at 60 °C for 1−3 h before Grignard addition.
c
d
transformation can be run at room temperature with minimal
loss of efficiency.
To our delight, a diverse set of heteroaromatics was tolerated
under the reaction conditions (Scheme 2b). For instance,
reaction of benzaldehyde with nicotinamide provided N-
acylamine 6n in 93% isolated yield. However, attempts to
B
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a,b
couple either picolinamide or pyrazine-2-carboxamide with
benzaldehyde failed to afford 6o and 6p, supposedly due to the
formation of a stable 5-membered titanacycle precluding any
further reaction. In contrast, heterocyclic aldehydes reacted
successfully to generate the products in remarkably good yields
considering the presence of several chelating atoms (N, O, S).
This includes motifs such as furans (6q−s), imidazole (6t),
pyrazole (6u), pyridines (6v,w), pyrazine (6x), isothiazole (6y),
oxazole (6z), and pyrrole (6aa). The low yields observed in
some instances were either due to the difficult isolation/shelf
stability of the prepared starting aldehydes (6y) or the
increased steric hindrance (6aa).11
Scheme 4. Grignards and Organozincates Addition
To further demonstrate the substrate scope of this method,
we continued our study with aliphatic substrates (Scheme 3).
Scheme 3. Condensation of Aliphatic Amides and
a,b
Aldehydes
a
Conditions: aldehyde (1.0 equiv), amide (1.05 equiv), Ti(i-OPr)4
b
(1.2 equiv), THF, 16 h, rt, MeMgBr (5.0 equiv), rt, 1 h. Isolated
yields. The corresponding organiczinc was used in place of the
Grignard reagent. The product was isolated as a mixture of two
diastereomers. NaBH4 was used as nucleophile in place of the
c
d
e
organometallic reagent.
80% isolated yield. Grignard or organozinc sources of phenyl
and benzyl derivatives all proceeded smoothly to form the
products in moderate to excellent yields (11d−g; 64−88%).
Vinyl- and propargylmagnesium bromides reacted as well
(11h,i) and provided reasonable yields. In addition, α-branched
N-acyl propargylic amines (similar to 11i) are known to cyclize
under mild conditions (catalytic FeCl3, DCE, 80 °C or
IPrAuCl, AgNTf2, DCM, rt) to form oxazoles,13 which makes
this method an alternate and highly versatile strategy to access
trisubstituted oxazoles. The use of a reductant such as NaBH4
as nucleophile enabled the isolation of N-acylamine 11j in 94%
yield.
a
Conditions: aldehyde (1.0 equiv), amide (1.05 equiv), Ti(i-OPr)4
b
(1.2 equiv), THF, 18 h, rt; MeMgBr (5.0 equiv), 60 °C, 1 h. Isolated
yields. Isolated as a mixture of two diastereomers.
c
While the exact reaction mechanism remains under
investigation, we presume that the amide adds to the Ti(Oi-
Pr)4−aldehyde complex to initially form a six-membered N-acyl
N,O-acetal titanocycle 12 (Figure 1). At this point, it is possible
Aliphatic linear and α-branched amides were all suitable
substrates that led to a highly efficient coupling (9a−e). The
bulkier adamantane-1-carboxamide led to slightly diminished
yield (9f). α-Proton-containing aliphatic aldehydes such as
linear 4-phenylbutyraldehyde and α-branched cyclohexanecar-
boxaldehyde successfully afforded the desired products (9g,h)
in spite of the competing enamide formation. It is noteworthy
that the hindered 2-methyl-2-phenyl-1-propanal reacted as
efficiently as benzaldehyde to form 9i in 55% yield.12
To maximize the potential of this three-component reaction,
we finally decided to explore a range of commercially available
Grignard and organozinc reagents (Scheme 4). Even though
Grignard reagents with α-hydrogens can undergo β-hydride
elimination giving rise to an olefin and a titanohydride complex,
ethyl- and isopropylmagnesium bromide both reacted smoothly
to form N-acylamines 11a and 11b in 48% and 50% yields,
respectively. The use of an organozinc equivalent (i-PrZnCl) to
form 11b did not impact the yield (53%) significantly.
Organozincates were demonstrated to be generally efficient
under these reaction conditions; for instance, cyclopropylzinc
chloride was used to generate N-acylamine 11c in a remarkable
Figure 1. Putative reaction intermediates.
that key imine intermediate 13 is formed via deprotonation of
the nitrogen proton by the Grignard reagent. Such an
intermediate is likely to undergo a reaction mechanism similar
to Ellman’s 1,2-addition of Grignard reagents to sulfinimines.14
It is also possible that chelate 14 is generated in situ given that
N-acyl-O-isopropyl N,O-acetal 15 was isolated on several
occasions (see the SI). The formation of related N,O-acetals
under similar reaction conditions is known in the literature.15
C
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Letter
(5) The new methods that have appeared in the last decade seem to
indicate a paradigm shift in the synthesis of amides;see: Pattabiraman,
V. R.; Bodel, J. W. Nature 2011, 480, 471.
When N,O-acetal 15 was submitted to the reaction conditions
with MeMgBr with or without the titanium Lewis acid, full
conversion to the desired methylated product was observed.
To conclude, we developed the first three-component
condensation of amides, aldehydes, and organometallic reagents
to form α-branched N-acylamines in good to high yields. The
method is highly versatile with a broad substrate scope, and
each of the three coupling partners is commercially available or
easily prepared. The high level of diversity achievable with this
operationally practical one-step protocol is well suited to the
fast screening of chemical matter in small library format to
progress medicinal chemistry projects efficiently. The use of
differentiated nucleophiles to expand the chemical diversity of
the products is currently under investigation in our laboratory.
(6) (a) Rossi, S. A.; Shimkin, K. W.; Xu, Q.; Mori-Quiroz, L. M.;
Watson, D. A. Org. Lett. 2013, 15, 2314. (b) Tran, B. L.; Li, B.; Driess,
M.; Hartwig, J. F. J. Am. Chem. Soc. 2014, 136, 2555. (c) Do, H.-Q.;
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using styrene was reported: Rosenfeld, D. C.; Shekhar, S.; Takemiya,
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(f) Apsunde, T. D.; Trudell, M. L. Synthesis 2014, 46, 230. (g) Das,
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3521. (h) Rubio-Perez, L.; Sharma, P.; Perez-Flores, F. J.; Velasco, L.;
Arias, J. L.; Cabrera, A. Tetrahedron 2012, 68, 2342. (i) Schneider, A.
E.; Manolikakes, G. J. Org. Chem. 2015, 80, 6193. (j) α-Banched N-
acylamines were not exemplified in the ruthenium-catalyzed oxidative
coupling of amines and primary alcohols in the presence of a hydrogen
acceptor; see: Watson, A. J. A.; Maxwell, A. C.; Williams, J. M. J. Org.
Lett. 2009, 11, 2667. (k) Le Gall, E.; Pignon, A.; Martens, T. Beilstein J.
Org. Chem. 2011, 7, 997.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b00082.
(7) Genovino, J.; Lagu, B.; Wang, Y.; Toure,
2012, 48, 6735.
́
B. B. Chem. Commun.
Reaction optimization details, procedures, and full
characterization of the products (PDF)
(8) The enal byproduct is formed via Ti-mediated oxidation of
triethylamine to the corresponding iminium with subsequent
tautomerization to the enamine, which adds to the starting aldehyde;
see: Bharathi, P.; Periasamy, M. Org. Lett. 1999, 1, 857.
(9) Bartoli, G.; Bosco, M.; Dalpozzo, R. Tetrahedron Lett. 1985, 26,
115.
AUTHOR INFORMATION
Corresponding Authors
■
(10) Chelation of the dimethylamino group or the catechol motifs
with titanium metal may interfere with the desired transformation.
(11) Amide bond cleavage of the heterocyclic products under acidic
conditions may also be a cause for the lower yields.
*E-mail: chunhui.dai@pfizer.com.
*E-mail: julien.genovino@pfizer.com.
ORCID
(12) When the amide coupling partner was replaced by urea or
carbamate starting materials, no reaction was observed. Similarly, the
use of acetophenone provided no reaction.
(13) (a) Senadi, G. C.; Hu, W.-P.; Hsiao, J.-S.; Vandavasi, J. K.; Chen,
C.-Y.; Wang, J.-J. Org. Lett. 2012, 14, 4478. (b) Bay, S.; Baumeister, T.;
Hashmi, A. S. K.; Roder, T. Org. Process Res. Dev. 2016, 20, 1297.
(14) (a) Liu, G.; Cogan, D. A.; Ellman, J. A. J. Am. Chem. Soc. 1997,
119, 9913. (b) Cogan, D. A.; Liu, G.; Ellman, J. Tetrahedron 1999, 55,
8883.
(15) For the formation and reactivity of similar N-acyl-N,O-acetals,
see: (a) Li, G.; Fronczek, F. R.; Antilla, J. C. J. Am. Chem. Soc. 2008,
130, 12216. (b) Li, M.; Luo, B.; Liu, Q.; Hu, Y.; Ganesan, A.; Huang,
P.; Wen, S. Org. Lett. 2014, 16, 10. (c) Breuer, S. W.; Bernath, T.; Ben-
Ishai, D. Tetrahedron 1967, 23, 2869.
Julien Genovino: 0000-0001-5879-2491
Author Contributions
§C.D. and J.G. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Dr. Justin Stroh (Pfizer) for HRMS determination as
well as Dr. Chris J. Helal (Pfizer) and Dr. Vincent Mascitti
(Pfizer) for helpful discussions.
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DOI: 10.1021/acs.orglett.7b00082
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