Titanium(IV) isopropoxide as an efficient catalyst for direct amidation of nonactivated carboxylic acids

Article abstract of DOI:10.1055/s-0032-1316993

Secondary and tertiary amides are formed in high yields, in an efficient and environmentally benign titanium(IV) isopropoxide catalyzed direct amidation of carboxylic acids with primary and secondary amines. Georg Thieme Verlag Stuttgart ? New York.

Full text of DOI:10.1055/s-0032-1316993

LETTER
▌2201
letter
Titanium(IV) Isopropoxide as an Efficient Catalyst for Direct Amidation of
Nonactivated Carboxylic Acids
Catalytic Amide Formation
Helena Lundberg, Fredrik Tinnis, Hans Adolfsson*
Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University, 106 91 Stockholm, Sweden
Fax +46(8)154908; E-mail: hansa@organ.su.se
Received: 25.05.2012; Accepted after revision: 03.07.2012
amides without any racemization of chiral starting materi-
Abstract: Secondary and tertiary amides are formed in high yields,
als at 70 °C in THF in the presence of molecular sieves as
in an efficient and environmentally benign titanium(IV) isoprop-
a water scavenger. During the same time and in parallel to
oxide catalyzed direct amidation of carboxylic acids with primary
our work, Williams and co-workers also reported that
ZrCl4 along with ZrCp2Cl2 were efficient catalysts for the
direct amidation between carboxylic acids and primary
and secondary amines, at 110 °C in toluene.8 The group of
Yamamoto has previously reported that group IV metal
complexes can be used as catalysts for catalytic esterifica-
tion of carboxylic acids with alcohols.5j,10
and secondary amines.
Key words: amides, titanium, catalysis, carboxylic acids, amines
The amide bond is a common functional group in both
natural and synthetic compounds. Approximately 25% of
all pharmaceuticals available on the global market are es-
timated to contain at least one amide bond,1 and environ-
mentally benign and inexpensive methods for amide-bond
synthesis are highly valuable. Amides can be synthesized
from the corresponding ammonium salts at high tempera-
tures.2 Substrates with stereocenters or sensitive function-
al groups are, however, likely to racemize or decompose
under harsh thermal conditions, and a multitude of differ-
ent coupling reagents utilizing milder reaction conditions
have been developed for the formation of amides.3 All
coupling-reagent methods are based on activation of the
carboxylic acid using stoichiometric amounts of reagents,
which leads to a poor atom economy for the processes.
The extensive use of coupling reagents on industrial scale,
resulting in stoichiometric amounts of waste, is one of the
reasons to why the formation of amides without poor
atom-economy reagents, was ranked as the most challeng-
ing task in organic chemistry by the American Chemical
Society Green Chemistry Institute.4 A limited number of
catalytic protocols for direct amidation of nonactivated
carboxylic acids and amines have been reported. Various
boron-based catalysts have been shown to allow for mild-
er reaction conditions and, in general, most secondary and
certain tertiary amides can be prepared in good to excel-
lent yields. However, partial racemization of enantiomer-
ically pure starting materials is a general drawback with
these catalysts.5 There are also reports on enzymatic pro-
tocols with a limited substrate scope6 and a few reported
protocols on metal catalysis at high reaction tempera-
tures,7,8 where the thermal background reaction can be ex-
pected to be significant. We have recently demonstrated
that zirconium(IV) chloride is an efficient catalyst for the
direct amidation of nonactivated carboxylic acids with
both primary and secondary amines.9 The operationally
simple reactions resulted in excellent yields of a range of
In our previous study on direct amidation of carboxylic
acids with primary and secondary amines, we found that
zirconium tetrachloride efficiently catalyzed the transfor-
mation. We became interested to see if this was a general
feature of early transition-metal complexes and decided to
evaluate a series of metal chlorides and alkoxides as cata-
lysts for the formation of N-benzyl phenylacetamide (3a,
Scheme 1 and Table 1), under the reaction conditions and
workup methods we have reported earlier.9
O
O
catalyst (10 mol%)
NH2
+
Bn
Bn
Bn
N
THF, 70 °C, 0.4 M
500 mg MS (4 Å)
Bn
OH
H
Scheme 1 Direct catalytic amide formation of nonactivated carbox-
ylic acids
Interestingly, it was found that several of the examined
Lewis acids were active catalysts, with seven complexes
giving rise to isolated yields around 90% (Table 1, entries
2–8). Titanium tetrachloride displayed lower activity (Ta-
ble 1, entry 1), and Y(Oi-Pr)3 (Table 1, entry 9) did not
show any activity at all. In the latter case, the yield is in
the same range as the thermal background reaction (Table
1, entry 11). The use of the vanadium complex VO(OEt)3
resulted in low conversion and a mixture of products (Ta-
ble 1, entry 10).
The possibility of using several different Lewis acid cata-
lysts in this user-friendly amidation protocol, where the
reaction mixture is simply filtered through a pad of silica
to yield analytically pure amides in most cases, makes this
amidation methodology highly attractive and practical.
Since titanium isopropoxide is an inexpensive and widely
used chemical compound found in most research labora-
tories, we decided to further evaluate this complex as a
catalyst for the direct amide formation. The amidation re-
action was found to proceed smoothly in several solvents
at a concentration of 0.4 M, and worked best under an
SYNLETT 2012, 23, 2201–2204
Advanced online publication: 17.08.2012
DOI: 10.1055/s-0032-1316993; Art ID: ST-2012-B0452-L
© Georg Thieme Verlag Stuttgart · New York
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6

2202
H. Lundberg et al.
LETTER
could be scaled up to 20 mmol at a concentration of 1.6 M
with respect to the amine without any decrease in yield
(Table 2, entry 4).
Table 1 Lewis Acid Catalyst Screen for the Direct Amidation of
Phenyl Acetic Acid with Benzylaminea
Entry
Catalyst
Isolated yield (%)
The relatively nontoxic solvent THF was chosen as reac-
tion medium for a substrate screening (Table 3). As can be
seen in Table 3, secondary and tertiary amides with differ-
ent functional groups were formed in good to excellent
yields with catalytic amounts of Ti(Oi-Pr)4. The enantio-
merical excess of the chiral starting materials was fully re-
tained in the formed amides 3r, 3s, and 3t (Table 3, entries
18–20), as determined by chiral HPLC. However, the
more labile stereocenter in ibuprofen, situated in both α-
position and benzylic position, underwent partial racemi-
zation, and the resulting amide 3q was found to have an
enantiomeric excess of 83% (Table 3, entry 17). The for-
mation of tertiary amides required a higher reaction tem-
perature (100 °C), and a catalyst loading of 20 mol%.
Under these conditions, compounds 3aa–ac were isolated
in good yields (Table 3, entries 27–29). Unfortunately,
even at these conditions, the bulky N,N-dihexylamine as
well as aniline turned out to be problematic substrates
when reacted with phenylacetic acid, resulting in 20% of
amide product and trace amounts, respectively. Benzoic
acid as well as the sterically hindered Boc-protected ami-
no acids required 20 mol% catalyst loading and 1.5 equiv-
alents of acid in order to reach good yields (Table 3,
entries 9, 18, and 19). Cyclohexanecarboxylic acid, ada-
mantanecarboxylic acid, and cinnamic acid were all run at
100 °C to generate good to moderate yields (Table 3, en-
tries 11–13). The thermal background reaction in the ami-
dation reactions depends strongly on the nature of the
substrates, the choice of solvent and, most importantly,
the reaction temperature. This observation was also re-
ported by Williams and co-workers, who described that
substantial thermal background reactions occur for a large
number of substrates at temperatures of 110 °C and
above.10 To determine the extent of thermal amidation oc-
curring for amide 3a under the reaction conditions pre-
sented in this study, a control experiment was performed,
resulting in a 10% yield (Table 1, entry 11). This result
can be compared to 69% yield of the same amide, formed
under thermal conditions, as reported by Grosjean et al.
for the same substrate,11 indicating that the high yields of
amides in Table 3 at 70 °C is the result of true catalysis.12
1
2
TiCl4
68
91
Ti(Oi-Pr)4
Ti(OBu)4
ZrCl4
3
89
4
>99
93
5
Zr(OEt)4
Zr(Ot-Bu)4
Hf(Ot-Bu)4
Nb(OEt)5
Y(Oi-Pr)3
VO(OEt)3
–
6
93
7
89
8
88
9
13b
21b,c
10
10
11
a Reaction conditions: phenylacetic acid (1.2 mmol), benzylamine
(1 mmol), catalyst (10 mol%), and activated 4 Å MS (0.5 g) in dry
THF (amine concentration 0.4 M) at 70 °C in a sealed tube under N2
atmosphere. Reaction time 24 h.
b NMR yield.
c Mixture of products.
inert atmosphere (Table 2, entry 2 vs. 3). No significant
difference in yield was seen when the amidation was per-
formed in a sealed tube or under regular reflux conditions
in a round-bottomed flask equipped with condenser (Ta-
ble 2, entries 1 and 2, respectively) under nitrogen
atmosphere. Furthermore, it was found that the reaction
Table 2 Solvent Screeninga
Entry
Solvent
Isolated yield (%)
1
2b
3b,c
4d
5
THF
91
90
67
91
75
89
68
93
63
86
THF
THF
THF
MeCN
toluene
DMSO
CH2Cl2
DMF
6
Table 3 Substrate Screeninga
7
Entry Amide
Number Isolated yield
(%)a
8
9
O
1
2
3a
3b
91
79
Ph
10
1,4-dioxane
N
Ph
H
a Reaction conditions: phenylacetic acid (1.2 mmol), benzylamine
(1 mmol), Ti(Oi-Pr)4 (10 mol%), and 4 Å MS (0.5 g), in dry solvent
(amine concentration 0.4 M) at 70 °C in a sealed tube under N2 atmo-
sphere.
O
N
H
Ph
b Reflux conditions in round-bottomed flask with condenser.
c Regular atmosphere.
d Phenylacetic acid (20 mmol), benzylamine (24 mmol), Ti(Oi-Pr)4
(10 mol%) and 4 Å MS (5 g) in dry THF (amine concentration 1.6 M)
at 70 °C in a sealed tube under N2 atmosphere.
Synlett 2012, 23, 2201–2204
© Georg Thieme Verlag Stuttgart · New York

LETTER
Catalytic Amide Formation
2203
Table 3 Substrate Screeninga (continued)
Table 3 Substrate Screeninga (continued)
Entry Amide
Number Isolated yield
(%)a
Entry Amide
Number Isolated yield
(%)a
Br
O
O
3
3c
3d
3e
85
99
99
18b
3r
3s
78c
78c
N
Ph
N
H
Ph
H
N
Boc
O
O
O
4
5
Ph
N
Ph
O
H
19b
N
H
Ph
HN
Boc
O
O
N
H
Ph
20b
21
3t
81
97
Ph
N
Ph
H
O
S
O
O
O
6
7
3f
94
88
Ph
S
N
Ph
Ph
H
Ph
Ph
Ph
S
3u
N
H
O
3g
N
H
O
22
23
24
3v
3w
3x
96
91
88
N
H
O
O
8
3h
72
N
Ph
H
O
O
N
H
O
9
3i
3j
82c
81
Ph
N
Ph
H
O
O
O
Ph
Ph
N
H
10
N
H
Ph
O
O
25
26
3y
3z
71
79
N
H
80e
N
Ph
11
3k
H
O
O
Ph
Ph
H
N
Ph
N
H
10
12
13
14
3l
65e
61e
75
O
74d
O
O
N
27
3aa
3m
3n
Ph
Cl
N
Ph
O
H
O
O
O
Ph
Ph
28
29
3ab
3ac
69d
76d
N
N
N
Ph
H
Cl
O
15
16
3o
3p
92
93
F3C
Boc
N
Ph
O
H
O
a Reaction conditions: carboxylic acid (1.2 mmol), benzyl amine
(1 mmol), Ti(Oi-Pr)4 (10 mol%), and 4 Å MS (0.5 g), in dry THF
(substrate concentrations 0.4 M) at 70 °C in a sealed tube under N2 at-
mosphere.
H
N
N
Ph
H
O
b No racemization was detected with chiral HPLC (AD column).
c Carboxylic acid (1.5 mmol) and Ti(Oi-Pr)4 (20 mol%).
d Carboxylic acid (1.5 mmol) and Ti(Oi-Pr)4 (20 mol%) at 100 °C.
e Reaction temperature 100 °C.
17
3q
80f
N
H
Ph
f Carboxylic acid (c 0.2 M) and Ti(Oi-Pr)4 (20 mol%). Product ee
(83%) was determined with chiral HPLC (IA column).
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 2201–2204

2204
H. Lundberg et al.
LETTER
J.; Pearlman, B. A.; Wells, A.; Zaksh, A.; Zhang, T. Y.
To conclude, we have demonstrated that several early
transition-metal complexes are efficient catalysts for the
direct amidation of nonactivated carboxylic acids with
amines. Secondary and tertiary amides were readily
formed in good to excellent yields with a general and op-
erationally simple protocol using the easily handled and
inexpensive titanium(IV) isopropoxide as catalyst.
Green Chem. 2007, 9, 411.
(5) (a) Charville, H.; Jackson, D.; Hodges, G.; Whiting, A.
Chem. Commun. 2010, 46, 1813. (b) Al-Zoubi, R. M.;
Marion, O.; Hall, D. G. Angew. Chem. Int. Ed. 2008, 47,
2876. (c) Arnold, K.; Davies, B.; Hérault, D.; Whiting, A.
Angew. Chem. Int. Ed. 2008, 47, 2673. (d) Maki, T.;
Ishihara, K.; Yamamoto, H. Tetrahedron 2007, 63, 8645.
(e) Ishihara, K.; Ohara, S.; Yamamoto, H. J. Org. Chem.
1996, 61, 4196. (f) Arnold, K.; Batsanov, A. S.; Davies, B.;
Whiting, A. Green Chem. 2008, 10, 124. (g) Arnold, K.;
Davies, B.; Giles, R. L.; Grosjean, C.; Smith, G. E.; Whiting,
A. Adv. Synth. Catal. 2006, 348, 813. (h) Maki, T.; Ishihara,
K.; Yamamoto, H. Org. Lett. 2006, 8, 1431. (i) Starkov, P.;
Sheppard, T. D. Org. Biomol. Chem. 2011, 9, 1320.
(j) Ishihara, K. Tetrahedron 2009, 65, 1085.
(6) (a) Ulijn, R. V.; Baragaña, B.; Hallning, P. J.; Flitsch, S. L.
J. Am. Chem. Soc. 2002, 124, 10988. (b) Litjens, M. J. J.;
Straathof, A. J. J.; Jongejan, J. A.; Heijnen, J. J. Tetrahedron
1999, 55, 12411. (c) Van Rantwijk, F.; Hacking, M. A. P. J.;
Sheldon, R. A. Monatsh. Chem. 2000, 131, 549.
(7) (a) Shteinberg, L. Y.; Kondratov, S. A.; Shein, S. M. Zh.
Org. Khim. 1988, 1968. (b) Shteinberg, L. Y.; Kondratov, S.
A.; Shein, S. M. Zh. Org. Khim. 1989, 1945. (c) Nordahl, Å.;
Carlson, R. Acta Chem. Scand. B 1988, 28. (d) Chaudhari, P.
S.; Salim, S. D.; Sawant, R. V.; Akamanchi, K. G. Green
Chem. 2010, 12, 1707. (e) Tamaddon, F.; Aboee, F.; Nasiri,
A. Catal. Commun. 2011, 16, 194. (f) Hosseini-Sarvari, M.;
Sodagar, E.; Doroodmand, M. M. J. Org. Chem. 2011, 76,
2853.
General Catalytic Amidation Procedure
Phenylacetic acid (163 mg, 1.2 mmol) and flame-dried 4 Å MS
(500 mg) was placed in an oven-dried vial equipped with a stirring
bar and sealed with a crimp-on cap. The atmosphere was exchanged
for N2, dry THF (2.5 mL) was added, and the reaction vessel was
put in an oil bath at 70 °C. After 5 min, Ti(OiPr)4 (30 μL, 0.1 mmol)
was added, and the mixture was stirred for an additional 15 min.
Benzylamine (0.11 mL, 1 mmol) was added, and after 24 h, the re-
action mixture was filtered through a pad of silica, eluted with 100
mL solvent (EtOAc–Et3N = 200:1) and concentrated under reduced
pressure to afford analytically pure amide 3a (205 mg, 91%).
Acknowledgment
We are grateful for financial support from the Swedish Research
Council, the Carl Trygger Foundation and the K & A Wallenberg
Foundation.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SnoIufproig
(8) Allen, C. L.; Chhatwal, A. R.; Williams, J. M. J. Chem.
Commun. 2012, 48, 666.
m
iotSrat
ungIifoop
r
t
(9) Lundberg, H.; Tinnis, F.; Adolfsson, H. Chem.–Eur. J. 2012,
18, 3822.
References and Notes
(10) (a) Ishihara, K.; Ohara, S.; Yamamoto, H. Science 2000,
290, 1140. (b) Ishihara, K.; Nakayama, M.; Ohara, S.;
Yamamoto, H. Synlett 2001, 1117. (c) Ishihara, K.;
Nakayama, M.; Ohara, S.; Yamamoto, H. Tetrahedron 2002,
58, 8179. (d) Nakayama, M.; Sato, A.; Ishihara, K.;
Yamamoto, H. Adv. Synth. Catal. 2004, 346, 1275. (e) Sato,
A.; Nakamura, Y.; Maki, T.; Ishihara, K.; Yamamoto, H.
Adv. Synth. Catal. 2005, 347, 1337. (f) Nakamura, Y.; Maki,
T.; Wang, X.; Ishihara, K.; Yamamoto, H. Adv. Synth. Catal.
2006, 348, 1505.
(1) Ghose, A. K.; Viswanadhan, V. N.; Wendoloski, J. J.
J. Comb. Chem. 1999, 1, 55.
(2) (a) Perreux, L.; Loupy, A.; Volatron, F. Tetrahedron 2002,
58, 2155. (b) Gelens, E.; Smeets, L.; Sliedregt, L. A. J. M.;
Van Steen, B. J.; Kruse, C. G.; Leurs, R.; Orru, R. V. A.
Tetrahedron Lett. 2005, 46, 3751. (c) Wang, Q.; Yang, X.-
J.; Liu, F.; You, Q.-D. Synth. Commun. 2008, 38, 1028.
(d) Gooßen, L. J.; Ohlmann, D. M.; Lange, P. P. Synthesis
2009, 160. (e) Charville, H.; Jackson, D. A.; Hodges, G.;
Whiting, A.; Wilson, M. R. Eur. J. Org. Chem. 2011, 5981.
(3) (a) Han, S.; Kim, Y. Tetrahedron 2004, 60, 2447.
(b) Valeur, E.; Bradley, M. Chem. Soc. Rev. 2009, 38, 606.
(4) Constable, D. J. C.; Dunn, P. J.; Hayler, J. D.; Humphrey, G.
R.; Leazer, J. L.; Linderman, R. J. Jr.; Lorenz, K.; Manley,
(11) Grosjean, C.; Parker, J.; Thirsk, C.; Wright, A. R. Org.
Process Res. Dev. 2012, 16, 781.
(12) See ref. 9 for a more extensive list of values for thermal
amidation at 70 °C.
Synlett 2012, 23, 2201–2204
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