Acyloxyphosphonium versus aminophosphonium intermediates: Application to the synthesis of N-acylbenzotriazoles

Article abstract of DOI:10.1002/ejoc.201403076

In attempts to convert carboxylic acids directly into N-acylbenzotriazoles by using Ph3P/I2 as an acid-activating system, the outcome of the reaction is reversed from no reaction to almost quantitative yield of the expected product simply by switching the order of the addition of the reagents to the presumed acyloxyphosphonium intermediate. If triethylamine was present before treatment with 1H-benzotriazole, anhydride was always exclusively generated without a detectable amount of the expected product. However, if the base was applied after the addition of 1H-benzotriazole, the reaction proceeded smoothly to afford N-acylbenzotriazoles in good to excellent yields within short reaction times. 31P NMR spectroscopy revealed the presence of a benzotriazophosphonium species in preventing the formation of the anhydride by attack of the carboxylate anion at the acyl function of the acyloxyphosphonium salt.

Full text of DOI:10.1002/ejoc.201403076

Job/Unit: O43076
/KAP1
Date: 02-10-14 14:24:24
Pages: 5
SHORT COMMUNICATION
DOI: 10.1002/ejoc.201403076
Acyloxyphosphonium versus Aminophosphonium Intermediates: Application to
the Synthesis of N-Acylbenzotriazoles
[a]
[a]
[a]
Chuthamat Duangkamol, Sirilak Wangngae, Mookda Pattarawarapan, and
Wong Phakhodee*[
a]
Keywords: Synthetic methods / Carboxylic acids / Triphenylphosphine / Iodine / Reactive intermediates
In attempts to convert carboxylic acids directly into N-acyl- able amount of the expected product. However, if the base
benzotriazoles by using Ph
3
P/I
2
as an acid-activating system,
was applied after the addition of 1H-benzotriazole, the reac-
tion proceeded smoothly to afford N-acylbenzotriazoles in
the outcome of the reaction is reversed from no reaction to
almost quantitative yield of the expected product simply by
switching the order of the addition of the reagents to the pre-
sumed acyloxyphosphonium intermediate. If triethylamine
was present before treatment with 1H-benzotriazole, an-
hydride was always exclusively generated without a detect-
3
1
good to excellent yields within short reaction times. P NMR
spectroscopy revealed the presence of a benzotriazophos-
phonium species in preventing the formation of the an-
hydride by attack of the carboxylate anion at the acyl func-
tion of the acyloxyphosphonium salt.
Introduction
N-Acylbenzotriazoles are versatile and efficient neutral
acylating agents that have been used as substitutes for the
corresponding acid chlorides in N-, C-, S-, and O-acylation
[
1]
reactions. The classical method for their preparation in-
volves treating 1H-benzotriazole (BtH) with acid chlorides.
In this case, the requisite acid chlorides have to be prepared
in one step prior to reacting with BtH. Alternatively, N-
acylbenzotriazoles can be synthesized directly from carb-
oxylic acids by reacting an acid salt with sulfonylbenzotri-
Scheme 1. Synthesis of N-acyloxybenzotriazoles.
[
2]
azole derivatives (Scheme 1, a) or through in situ genera-
tion of the acid chloride with thionyl chloride before treat-
presumably through formation of highly reactive acylphos-
phonium intermediates.
[
3]
ment with an excess amount of BtH (Scheme 1, b). Al-
though the N-acylbenzotriazoles are generally obtained in
good yields, the reactions still suffer from some limitations,
including the use of corrosive or expensive reagents, long
reaction times, and the requirement for high temperatures.
Recently, a combination of Ph P and I was introduced
3
2
as a new acid-activating system in the synthesis of amides
[
9]
and Weinreb amides. The reaction is believed to proceed
through an acyloxyphosphonium intermediate that is gen-
erated upon mixing a carboxylic acid with Ph P and I in
Triphenylphosphine (Ph P) is a very attractive reagent
3
2
3
[
4]
the presence of iPr NEt. This method is very promising, as
possessing widespread applications in organic synthesis.
2
the reagents are inexpensive, readily available, and easy to
handle. Thus, in searching for an alternative route toward
N-acylbenzotriazoles, it seems feasible that similar condi-
tions could be adopted to promote the direct conversion of
carboxylic acids into their benzotriazole derivatives
Owing to a strong affinity toward oxygen, PPh has been
3
used along with a number of additives such as N-bromosuc-
[
5]
[6]
cinimide, hypervalent iodine(III) reagents, I2/Zn(OTf)2
[7]
(
Tf = trifluoromethylsulfonyl), and diethyl azodicarboxyl-
ate (Mitsunobu reaction) in promoting the direct conver-
sion of carboxylic acids into amides, esters, and thioesters,
[8]
(Scheme 1, c).
[
a] Department of Chemistry, Faculty of Science, Chiang Mai
Results and Discussion
University
2
39 Suthep Rd, Muang, Chiang Mai 50200, Thailand
E-mail: wongp2577@gmail.com
The amidation between benzoic acid and BtH mediated
by the Ph P/I system was investigated under the reported
http://www.chem.science.cmu.ac.th/user/view_profile.php?ps_
id=133
3
2
[
9]
conditions by using Et N as the base. Typically, benzoic
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201403076.
3
acid was added to a solution containing a 1:1 molar ratio
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1

Job/Unit: O43076
/KAP1
Date: 02-10-14 14:24:24
Pages: 5
C. Duangkamol, S. Wangngae, M. Pattarawarapan, W. Phakhodee
SHORT COMMUNICATION
3 2
of Ph P/I in CH Cl at 0 °C. The mixture was allowed to Table 1. Synthesis of N-acylbenzotriazole promoted by Ph P/I
.[a]
3
2
2
2
stir for 5 min at the same temperature before the dropwise
addition of Et N (2 equiv.), which was followed by the ad-
3
dition of BtH (1.1 equiv.). Unfortunately, it was found that
within 5 min of stirring at room temperature, benzoic acid
was completely consumed and benzoic anhydride was iso-
lated in 98% yield without any detectable amount of the
expected N-benzoylbenzotriazole product. A similar result
was also obtained upon replacing Et N with iPr NEt. Sev-
Entry
R
Time [h][b]
Yield [%]
[
2a]
1
2
3
4
5
6
7
8
9
C
6
H
5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
1
95
92
[
10]
2-CH
3-CH
4-CH
2-CH
4-CH OC H
3,4-(CH
2-ClC
3-ClC
4-ClC
3-O
4-O
3
3
3
3
C
C
C
6
6
6
H
H
H
4
4
[
1f]
97
3
2
[2a]
[2b]
4
85
77
93
99
86
91
84
70
36
77
eral attempts to adjust the reaction times before or after
adding BtH or changing the molar ratio of Ph P/I /benzoic
OC
6
H
4
[
[
[
11]
12]
1g]
2b]
3
2
3
6
4
C
3
O)
2
6
H
3
acid from 1:1:1 to 2:2:1 also failed to give satisfactory re-
sults.
Given that benzoic anhydride was always exclusively ob-
tained following the above-described procedure, we turned
our attention to examine the effect of the addition sequence 12
of the reagents on the reaction outcome. To our delight, it
was found that if BtH was added 10 min before treatment
6
6
6
H
4
H
H
[
4
[2b]
[1n]
1
1
0
1
4
2
NC
NC
6
H
H
4
[
[
2b]
1o]
2
6
4
1
1
1
1
3
4
5
2-naphthyl
0.5
0.5
1
0.5
1
5-phenylvaleryl
5-phenylvaleryl
hexanoyl
hexanoyl
octanoyl
37
86
51
with Et N, the expected N-benzoylbenzotriazole product
3
16
[
[
13]
was afforded in 81% yield after 30 min without the forma- 17
tion of benzoic anhydride. The best result (95% yield) was
97
99
14]
18
1
achieved with a prolonged acid-activation step for 30 min [a] Unless otherwise specified, the reactions were performed by
prior to adding BtH.
adding the carboxylic acid (0.41 mmol) to a mixture containing I
0.45 mmol) and Ph P (0.45 mmol) at 0 °C. The mixture was stirred
at 0 °C for 30 min before adding BtH (0.45 mmol), and the mixture
was stirred for another 10 min. After adding Et N (0.82 mmol),
the mixture was stirred at room temperature for the specified time.
2
(
3
To demonstrate the efficiency and versatility of the re-
vised protocol, a series of N-acylbenzotriazoles were syn-
thesized from aromatic and aliphatic carboxylic acids. Ac-
3
cording to Table 1, the reactions with aromatic acids, espe- [b] Time after the addition of Et
3
N.
cially those containing electron-donating groups (Table 1,
entries 2–7) generally proceeded smoothly to give the ex-
pected N-acylbenzotriazoles in good to excellent yields. solution turned light yellow and then changed to brown
Only in the case of 2-methoxybenzoic acid (Table 1, entry 5) after a few seconds. According to the 31P{H} NMR spectra
was a slightly lower yield of the corresponding product ob- (Figure 1, a,b), upon the addition of I , a slight shift in the
2
served, probably as a result of steric hindrance from the free phosphine signal from δ = –5.31 ppm to –5.83 ppm was
OMe group. Whereas halogen substituents (Cl) on the aro- observed with the appearance of two new resonances. The
matic ring of benzoic acid had little effect on the yield of upfield shift of the signal to δ = –17.07 ppm suggested the
the reaction (Table 1, entries 8–10), a strong electron-with- formation of a pentacoordinate phosphorus species be-
[
9,15]
drawing substituent (NO ), however, significantly decreased tween Ph P and I ,
whereas the downfield shift to δ =
2
3
2
the product yield even with extended reaction times 45.98 ppm was indicative of the presence of triphenylphos-
[
16,17]
(Table 1, entries 11 and 12). The reaction with relatively ste- phonium iodide.
Subsequent addition of benzoic acid
ric 2-naphthoic acid (Table 1, entry 13) also gave the desired to the Ph P/I mixture resulted in slight shifts of all signals,
3
2
product in moderate yield.
which could be accounted for by certain interactions be-
Aliphatic acids were found to be less effective than aro- tween the acid and the phosphorus species (Figure 1, c).
matic acids. Under the standard reaction conditions, the After the addition of BtH, the color of the reaction mixture
yields of the benzotriazole derivatives of 5-phenylvaleric changed from dark brown to light yellow, and a yellowish
acid and hexanoic acid were only 37 and 51%, respectively precipitate formed. The 31P{H} NMR spectrum of the
(
5
(
Table 1, entries 14 and 16). With prolonged reaction times, solution (Figure 1, d) showed a downfield shift of the signal
-phenylvaleric acid, hexanoic acid, and octanoic acid at δ = –17.64 ppm to –14.64 ppm with the appearance of
Table 1, entries 15, 17, and 18) gave the corresponding N- a new signal at δ = 36.13 ppm, which is characteristic of
[
17–19]
acylbenzotriazoles in high yields. On the basis of these re- compounds with a P–N bond.
This result strongly
sults, it is possible that π–π stacking interactions between indicated that the equilibrium was shifted toward the for-
the benzene ring of the aromatic acids and those of the mation of a benzotriazophosphonium species. The reaction
phosphine intermediate may be responsible for the rate en- mixture turned to a clear colorless solution immediately af-
31
hancement observed with the aromatic carboxylic acids.
ter the addition of Et N. The P{H} NMR spectrum of
3
To gain mechanistic insight into the reaction, a the mixture after about 20 min in the presence of base (Fig-
P{H} NMR spectroscopy experiment was performed to ure 1, e) showed the appearance of an exclusive signal at
3
1
monitor the phosphorus-containing intermediates in the δ = 29.28 ppm, which was attributed to the release of the
[
17]
ongoing reaction between benzoic acid and BtH. Upon Ph P=O byproduct upon complete conversion of benzoic
3
adding I to a solution of Ph P in CDCl , the color of the acid into N-benzoylbenzotriazole.
2
3
3
2
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O43076
/KAP1
Date: 02-10-14 14:24:24
Pages: 5
Acyloxyphosphonium versus Aminophosphonium Intermediates
3 2 3
Scheme 2. Proposed mechanism for the reaction mediated by the Ph P/I system if Et N is added before (route a) or after the addition
of BtH (route b).
presumably through attack of the carboxylate ion at the
phosphorus center of IV to form pentacoordinate species
[
20]
V. Intramolecular acyl substitution then gives the N-acyl-
benzotriazole with concomitant loss of Ph P=O.
3
It is important to note that anhydride formation has al-
ready been encountered in several reactions involving the
acyloxyphosphonium salt owing to competitive acyl substi-
tution with a highly nucleophilic carboxylate anion.[
Nevertheless, its formation was somehow under-em-
phasized and no further attempts were made to circumvent
this undesired side reaction. By using our developed proto-
col, the formation of anhydride is avoided, and aminophos-
phonium species IV is highly reactive and acts as a dual
activating agent for the nucleophilic acyl substitution of
carboxylic acids to provide the N-acylbenzotriazoles in high
yields.
8,9,15]
Figure 1. 31P{H} NMR monitoring of the progress of the reaction
between benzoic acid and BtH in CDCl
after the addition of I , (c) the reaction after the addition of
benzoic acid, (d) the reaction after 10 min past the addition of BtH,
and (e) the reaction after the addition of Et N.
3 3
: (a) Ph P, (b) the solution
2
3
Conclusions
In summary, the significance of the addition sequence of
the reagents in the reaction involving an acyloxyphosphon-
ium intermediate was demonstrated. By simple alteration of
the addition order of the amine base and BtH, carboxylic
acids can be readily converted into N-acylbenzotriazoles in
high yields in short reaction times without the formation of
the anhydride by product. In the absence of base, the pres-
ence of benzotriazophosphonium salt IV clearly indicates
that nucleophilic attack by nitrogen at the phosphorus cen-
ter of the phosphonium salts was more favorable, which
allows for more controlled activation of the acid through
the pentacoordinate species V. This strategy could be poten-
tially useful in enhancing the outcomes of various reactions
involving carboxylic acids and related functionalities. Stud-
ies toward this direction are in progress and will be reported
in due course.
On the basis of these results, mechanistic details for the
reactions following the different addition sequence of the
reagents were proposed (Scheme 2). Upon mixing Ph3P
with I , pentacoordinate phosphorus species I is predomi-
2
nantly formed, and a small amount of phosphonium iodide
II is generated. Treatment with a carboxylic acid leads to
slow formation of acyloxyphosphonium salt III. However,
in the presence of Et N (Scheme 2, route a), the equilibrium
3
is rapidly shifted toward intermediate III, which undergoes
rapid nucleophilic displacement with the carboxylate anion
to give the anhydride side product. As a result, upon ad-
dition of BtH, no further reaction proceeds because of the
insufficient reactivity of the anhydride under the applied
conditions.
Upon treating the reaction mixture with BtH in the ab-
sence of base (Scheme 2, route b), tetracoordinate benzotri-
azophosphonium species IV is predominantly formed, be-
cause BtH is a stronger nucleophile than carboxylic acid.
Supporting Information (see footnote on the first page of this arti-
cle): Experimental details, including complete experimental pro-
1
13
Upon the addition of the amine base, the carboxylic acid is cedures and copies of the H NMR and C NMR spectra of all
rapidly deprotonated and undergoes condensation with IV described compounds.
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3

Job/Unit: O43076
/KAP1
Date: 02-10-14 14:24:24
Pages: 5
C. Duangkamol, S. Wangngae, M. Pattarawarapan, W. Phakhodee
SHORT COMMUNICATION
[
[
4] a) D. H. Valentine Jr., J. H. Hillhouse, Synthesis 2003, 317–334;
b) L. F. Pedrosa, Synlett 2008, 1581–1582.
5] a) P. Froyen, Tetrahedron Lett. 1997, 38, 5359–5362; b) P. Gopi-
nath, R. S. Vidyarini, S. Chandrasekaran, J. Org. Chem. 2009,
Acknowledgments
This work was supported by the Chiang Mai University, Center
of Excellence for Innovation in Chemistry (PERCH-CIC) and by
Thailand’s Office of the Higher Education Commission (National
Research University Project).
7
4, 6291–6294; c) P. Gopinath, C. Debasree, R. S. Vidyarini, S.
Chandrasekaran, Tetrahedron 2010, 66, 7001–7011.
[6] J. Tian, W.-C. Gao, D.-M. Zhou, C. Zhang, Org. Lett. 2012,
14, 3020–3023.
[
[
7] N. Mamidi, D. Manna, J. Org. Chem. 2013, 78, 2386–2396.
8] a) J. McNulty, A. Capretta, V. Laritchev, J. Dyck, A. J. Robert-
son, J. Org. Chem. 2003, 68, 1597–1600; b) J. McNulty, A. Cap-
retta, V. Laritchev, J. Dyck, A. J. Robertson, Angew. Chem. Int.
Ed. 2003, 42, 4051–4054; Angew. Chem. 2003, 115, 4185–4188;
c) D. L. Hughes, R. A. Reamer, J. Org. Chem. 1996, 61, 2967–
2971.
[1] For recent examples, see: a) A. R. Katritzky, B. V. Rogovoy, N.
Kirichenko, V. Vvedensky, Bioorg. Med. Chem. Lett. 2002, 12,
1
809–1811; b) A. R. Katritzky, K. Suzuki, S. K. Singh, H.-Y.
He, J. Org. Chem. 2003, 68, 5720–5723; c) X. Wang, Y. Zhang,
Synth. Commun. 2003, 33, 2627–2634; d) A. R. Katritzky,
A. A. A. Abdel-Fattah, M. Wang, J. Org. Chem. 2003, 68, [9] A. Kumar, H. K. Akula, M. K. Lakshman, Eur. J. Org. Chem.
4
932–4934; e) A. R. Katritzky, A. A. A. Abdel-Fattah, M.
2010, 2709–2715.
Wang, J. Org. Chem. 2003, 68, 1443–1446; f) A. R. Katritzky, [10] K. Nain Singh, A. Kaur, Synth. Commun. 2005, 35, 2935–2937.
A. A. Shestopalov, K. Suzuki, Synthesis 2004, 1806–1813; g)
A. R. Katritzky, C. Cai, K. Suzuki, S. K. Singh, J. Org. Chem.
[11] I. Nakamura, T. Nemoto, N. Shiraiwa, M. Terada, Org. Lett.
2009, 11, 1055–1058.
2
004, 69, 811–814; h) A. R. Katritzky, A. A. A. Abdel-Fattah,
[12] T. Asakawa, A. Hiza, M. Nakayama, M. Inai, D. Oyama, H.
Koide, K. Shimizu, T. Wakimoto, N. Harada, H. Tsukada, N.
Oku, T. Kan, Chem. Commun. 2011, 47, 2868–2870.
[13] M. C. V. Nagel, T. Heinze, Polym. Bull. 2010, 65, 873–881.
A. V. Gromova, R. Witek, P. J. Steel, J. Org. Chem. 2005, 70,
9
211–9214; i) A. R. Katritzky, K. Suzuki, Z. Wang, Synlett
2005, 1656–1665; j) A. R. Katritzky, K. Widyan, K. Kirich-
enko, J. Org. Chem. 2007, 72, 5802–5804; k) D. Lim, F. Fang, [14] A. R. Katritzky, Z. Wang, S. Slavov, M. Tsikolia, D. Dobchev,
G. Zhou, D. M. Coltart, Org. Lett. 2007, 9, 4139–4142; l) X.
Wang, W. Wang, Y. Wen, L. He, X. Zhu, Synthesis 2008, 3223–
N. G. Akhmedov, C. D. Hall, U. R. Bernier, G. G. Clark, K. J.
Linthicum, Proc. Natl. Acad. Sci. USA 2008, 105, 7359–7364.
228; m) G. Zhou, D. Lim, F. Fang, D. M. Coltart, Synthesis [15] S. Bae, M. K. Lakshman, J. Org. Chem. 2008, 73, 1311–1319.
[16] I. Tornieporth-Oetting, T. Klapoetke, J. Organomet. Chem.
1989, 379, 251–257.
[17] S. P. Morcillo, L. Alvarez de Cienfuegos, A. J. Mota, J. Justicia,
R. Robles, J. Org. Chem. 2011, 76, 2277–2281.
mun. 2010, 40, 3669–3677; o) A. R. Katritzky, S. R. Tala, N. E.
Abo-Dya, K. Gyanda, B. E.-D. M. El-Gendy, Z. K. Abdel-Sa-
mii, P. J. Steel, J. Org. Chem. 2009, 74, 7165–7167; p) Z. Xia,
X. Lv, W. Wang, X. Wang, Tetrahedron Lett. 2011, 52, 4906– [18] H.-J. Cristau, A. Hammami, E. Manginot, E. Torreilles, Phos-
4910.
phorus Sulfur Silicon Relat. Elem. 1998, 134/135, 475–486.
[
[
19] S. Paul, S. Panda, D. Manna, Tetrahedron Lett. 2014, 55, 2480–
[
2] a) A. R. Katritzky, N. Shobana, J. Pernak, A. S. Afridi, W. Q.
Fan, Tetrahedron 1992, 48, 7817–7822; b) A. R. Katritzky, H.-
Y. He, K. Suzuki, J. Org. Chem. 2000, 65, 8210–8213.
2483.
20] J. Zaloom, M. Calandra, D. C. Roberts, J. Org. Chem. 1985,
50, 2601–2603.
[
3] A. R. Katritzky, Y. Zhang, S. K. Singh, Synthesis 2003, 2795–
Received: August 14, 2014
2
798.
Published Online: ᭿
4
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O43076
/KAP1
Date: 02-10-14 14:24:24
Pages: 5
Acyloxyphosphonium versus Aminophosphonium Intermediates
Carboxylic Acid Conversion
C. Duangkamol, S. Wangngae,
M. Pattarawarapan,
W. Phakhodee* ................................. 1–5
Acyloxyphosphonium versus Aminophos-
phonium Intermediates: Application to the
Synthesis of N-Acylbenzotriazoles
In synthesizing N-acylbenzotriazoles by
using Ph P/I as an acid activator, an-
hydride is exclusively generated upon ad-
ding Et N to the presumed acyloxyphos-
phonium intermediate before treatment
with 1H-benzotriazole (BtH). In the ab-
sence of base, benzotriazophosphonium
iodide is predominantly formed, which rap-
idly reacts with carboxylate ions to afford
N-acylbenzotriazoles in good to excellent
yields.
3
2
Keywords: Synthetic methods / Carboxylic
acids / Triphenylphosphine / Iodine / Reac-
tive intermediates
3
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5