Organic chemistry using weakly electrophilic salts: The reaction with nitrogen nucleophiles

Article abstract of DOI:10.3987/COM-08-S(D)69

The reaction of electrophilic salts, which were obtained by the treatment of acetals with TESOTf?2,4,6-collidine, with nitrogen nucleophiles was studied in detail. Treatment of the salts with potassium phthalimide afforded the corresponding N,O-acetals in

Full text of DOI:10.3987/COM-08-S(D)69

HETEROCYCLES, Vol. 79, 2009
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HETEROCYCLES, Vol. 79, 2009, pp. 1113 - 1120. © The Japan Institute of Heterocyclic Chemistry
Received, 9th October, 2008, Accepted, 1st December, 2008, Published online, 9th December, 2008. COM-08-S(D)69
DOI: 10.3987/COM-08-S(D)69
ORGANIC CHEMISTRY USING WEAKLY ELECTROPHILIC SALTS:
THE REACTION WITH NITROGEN NUCLEOPHILES†
Hiromichi Fujioka,* Ozora Kubo, Kento Senami, Kazuhisa Okamoto,
Takashi Okitsu, and Yasuyuki Kita*††
Graduate School of Pharmaceutical Sciences, Osaka University, 1-6, Yamada-oka,
Suita, Osaka, 565-0871, Japan. E-mail: fujioka@phs.osaka-u.ac.jp
Abstract – The reaction of electrophilic salts, which were obtained by the
treatment of acetals with TESOTf•2,4,6-collidine, with nitrogen nucleophiles was
studied in detail. Treatment of the salts with potassium phthalimide afforded the
corresponding N,O-acetals in good yields. The use of hydrazine in place of
potassium phthalimide gave the corresponding hydrazones. The reaction is very
mild and chemoselective, and acid-labile functional groups can tolerate these
conditions.
INTRODUCTION
Recently, we have been developing an organic chemistry using weakly electrophilic salts obtained by the
reaction of acetal compounds under triethylsilyl triflate (TESOTf) ―2,4,6-collidine conditions.1 Based on
initial results, we reported the efficient formation of O,O-mixed, O,S- and N,O-acetals (Scheme 1). The
O,O-mixed, O,S-acetals were prepared by the nucleophilic attack of alcohols and thiols or lithium
thiolates, respectively. On the other hand, amine nucleophiles, such as benzylamine and
N-methylbenzylamine, did not give the desired N,O-acetals, and the aldehydes derived from the starting
acetals were obtained. Only sodium azide or trimethylsilyl azide (TMSN3) gave the N,O-acetals, in which
the nitrogen unit was an azide.1f
We then studied in detail the reaction of the salts with other nitrogen nucleophiles and obtained some
interesting results. We now present our study on this subject.
†This paper is dedicated to the memory of the late Dr. John Daly.

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R2XH
(X = O, S)
OR1
OR1
OR1
OR1
TESOTf
N
OTf
or
R
N
XR2
N3
OR1
R
R
R
or NaN3
TMSN3
(reactive collidinium
salt, weak electrophile)
CH2Cl2, 0 oC
Scheme 1. Reaction of the collidinium salts with hetero nucleophiles
RESULTS AND DISCUSSION
The results of the reactions using benzylamine and N-methylbenzylamine, which afforded aldehydes, not
N,O-acetals, suggested two possibilities. One is the weak nucleophilicity of such amines. However, this
seemed to be unlikely, because the nucleophilicity of the nitrogen atom is usually much stronger than that
of the oxygen atom. Another possibility, the over reaction of N,O-acetals to iminium ions, which are
easily hydrolized to aldehydes (Scheme 2 shows the reaction using N-methylbenzylamine), then seemed
plausible.
OR1
OR1
N
OR1
H2O work-up
PhCH2NHMe
TESOTf
N
Me
Me
R
R
N
O
OR1
R
R
CH2Ph
CH2Ph
CH2Cl2, 0 oC
Scheme 2. Hypothesis of the result from the reaction with N-methylbenzylamine
To prove the hypothesis in Scheme 2, the reaction of decanal dimethyl acetal (1) and phthalimide as a
nitrogen nucleophile was examined hoping that the obtainable N,O-acetal would not give the iminium salt
due to the weak electron-donating ability of the nitrogen of phthalimide. TESOTf (2 equiv) was added to
a solution of 1 (1 equiv) and 2,4,6-collidine (3 equiv) in CH2Cl2 (0.1 M solution), and then the mixture
was stirred for 30 min at 0 °C. Treatment of the resulting solution with potassium phthalimide
O
KN
TESOTf
(2 equiv)
OMe
N
O
OMe
OMe
O
2 (3 equiv)
N
8
8
18-crown-6
(3 equiv)
1
O
(3 equiv)
CH2Cl2, 0 oC
3 (80%)
Scheme 3. The reaction of 1 with potassium phthalimide (2)

HETEROCYCLES, Vol. 79, 2009
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(2) for 15 min at rt gave the N,O-acetal 3 in good yield (80%), whereas treatment of the resulting salt with
phthalimide did not give 3 at all due to the weak nucleophilicity of the nitrogen atom (Scheme 3).
The result in Scheme 3 showed that the hypothesis in Scheme 2 was correct. This was also proved by
getting hydrazone product 5, using hydrazine as a nitrogen nucleophile.2 Thus, the reaction of the salt,
which was prepared in the same way as Scheme 3, with 1-aminopiperidine (4) gave the hydrazone 5 in
moderate yield.
N
TESOTf
H2N
OMe
OMe
(2 equiv)
N
4 (2 equiv)
N
N
8
8
5 (52%)
1
(3 equiv)
CH2Cl2, 0 oC
Scheme 4. The reaction of 1 with hydrazine 4
Features of our organic chemistry using weakly electrophilic salts are 1) the reaction proceeds under
weakly basic conditions, which allow the presence of acid-labile functional group, and 2) the reaction is
highly chemoselective. These points and the generality of the reactions in Schemes 3 and 4 were proved
from the results in Table 1. The reaction using an acetal 6 having tert-butyldimethylsilyl (TBS) ether and
potassium phthalimide (2) as a nitrogen nucleophile afforded the N,O-acetal 9 in good yield (entry 1). The
use of 1-aminopiperidine (4) in place of 2 afforded the corresponding hydrazone 10 (entry 2). During the
reactions, TBS-ether unit was remained intact. Furthermore, even compound 7 having trityl (Tr) ether was
also available, and the corresponding N,O-acetal 11 and hydrazone 12 were obtained (entries 3 and 4). It
is noteworthy that the acid-labile trityl ether was tolerant during the reaction. High chemoselectivity was
shown from the reactions in entries 5 and 6. As a substrate, compound 8 having the acetal and ketal
functions in the same molecule was used. Since we have already proved the chemoselective formation of
the intermediates from the substrates having the acetal and ketal functions (see refs. 1a,b and 2), the
reaction smoothly proceeded to give the corresponding N,O-acetal 13 and hydrazone 14, both of which
have a ketal functional group.
CONCLUSION
We proved that electrophilic salts, prepared by the treatment of acetals with the TESOTf―2,4,6-collidine
combination, could react with nitrogen nucleophiles such as benzylamine and N-methylbenzylamine,
but the iminium species could not be isolated due to their instability against water. We then used
phthalimide and hydrazine as nitrogen nucleophiles and got the corresponding N,O-acetal and hydrazone

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in moderate to good yields. The reaction is mild and highly chemoselective, and an acid-labile functional
group can tolerate such conditions.
Table 1. Reaction of the acetals having another functional group
entry
acetal
N-nucleophile
product
yield
78%
O
OMe
N
TBSO
1
2
11
9
OMe
OMe
O
TBSO
11
6
2
3
4
2
58%a)
63%
TBSO
TrO
N
10
11
N
11
O
OMe
N
11
OMe
OMe
O
TrO
11
7
35%a)
66%
TrO
N
4
5
4
2
12
N
O
11
OTES
O
O
O
N
O
O
13
O
O
O
42%a)
N
N
8
6
4
O
O
14
a) 1H NMR yield.
EXPERIMENTAL
General techniques
1
13
The H and C NMR spectra were measured by 500 MHz, 300 MHz or 270 MHz spectrometers with
o
tetramethylsilane as an internal standard at 20-25 C. IR spectra were recorded by a diffuse reflectance
measurement of samples dispersed in KBr powder. Merck silica gel 60 was used for column
chromatography.
Acetals 11a-1c, 1f 61b-1c, 1f, 71c, 1f, and 81f are known in the literatures.

HETEROCYCLES, Vol. 79, 2009
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General Procedure for Preparation of N,O-Acetals 3, 9, 11, and 13
2,4,6-Collidine (3.0 equiv) and TESOTf (2.0 equiv) were added to a solution of an acetal in CH2Cl2 (0.1
M) at 0 oC under N2. The reaction mixture was stirred for 30 min at the same temperature. After checking
disappearance of the substrate on TLC, potassium phthalimide (2) (3.0 equiv) and 18-crown-6 (3.0 equiv)
were added to the reaction mixture and the solution was stirred at rt. Disappearance of the polar
component was ascertained by TLC. The mixture was quenched with H2O and extracted with CH2Cl2.
The organic layer was dried over Na2SO4, filtered, and evaporated in vacuo. The residue was purified by
flash SiO2 column chromatography to give an N,O-acetal.
General Procedure for Preparation of Hydrazones 5, 10, 12, and 14
2,4,6-Collidine (3.0 equiv) and TESOTf (2.0 equiv) were added to a solution of an acetal in CH2Cl2 (0.1
M) at 0 oC under N2. The reaction mixture was stirred for 30 min at the same temperature. After checking
disappearance of the substrate on TLC, 1-aminopiperidine (4) (2.0 equiv) was added to the reaction
o
mixture and the solution was stirred at 0 C. Disappearance of the polar component was ascertained by
TLC. The mixture was quenched with H2O (2.0 mL) and extracted with CH2Cl2. The organic layer was
dried over Na2SO4, filtered, and evaporated in vacuo. The residue was purified by flash SiO2 column
chromatography to give a hydrazone. It containes the aldehyde, which is difficult to be separated from the
hydrazone. The yield of the hydrazone was determined by 1H NMR. Purification in several times by flash
SiO2 column chromatography gave pure hydrazone.
Experiment in Scheme 3: According to the general procedure, treatment of 1 (37.0 mg, 0.183 mmol)
with 2,4,6-collidine (73 µL, 0.549 mmol), TESOTf (83 µL, 0.366 mmol), 2 (101.6 mg, 0.549 mmol), and
18-crown-6 (145.0 mg, 0.549 mmol) gave 3 (48.3 mg, 80%). Eluent; hexanes-AcOEt (10/1). 3: Colorless
oil; IR (KBr) 2926, 1776, 1717, 1350, 1115 cm-1; 1H NMR (300 MHz, CDCl3) δ 0.78 (3H, t, J = 6.0 Hz),
1.16-1.43 (14H, m), 2.05-2.26 (2H, m), 3.31 (3H, s), 5.24 (1H, t, J = 6.9 Hz), 7.69-7.75 (2H, m),
7.82-7.88 (2H, m); 13C NMR (68 MHz, CDCl3) δ 14.9, 23.4, 26.2, 29.8, 30.0, 30.2, 32.6, 33.1, 57.2, 84.4,
124.1, 132.1, 134.8, 168.6. Anal. Calcd for C19H27NO3: C, 71.80; H, 8.57; N, 4.41. Found: C, 72.06; H,
8.64; N, 4.29.
Experiment in Scheme 4: According to the general procedure, treatment of 1 (41.3 mg, 0.204 mmol)
with 2,4,6-collidine (81 µL, 0.612 mmol), TESOTf (92 µL, 0.408 mmol), and 4 (44 µL, 0.408 mmol)
gave 5 (25.2 mg, 52 %). Eluent; hexanes-AcOEt (10/1). 5: Colorless oil; IR (KBr) 2928, 2855, 1609,
1
1454, 1360 cm-1; H NMR (300 MHz, CDCl3) δ 0.88 (3H, t, J = 6.3 Hz), 1.22-1.35 (12H, m), 1.42-1.52
(4H, m), 1.66-1.74 (4H, m), 2.19-2.26 (2H, m), 2.89-2.92 (4H, t like), 6.95 (1H, t, J = 5.4 Hz); 13C NMR

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HETEROCYCLES, Vol. 79, 2009
(68 MHz, CDCl3) δ 14.1, 22.6, 24.1, 25.3, 27.6, 29.2, 29.3, 29.4, 29.5, 31.9, 33.2, 52.9, 141.8; HRMS
(FAB) calcd for C15H31N2 (M++H) 239.2487, found 239.2482.
Experiments in Table 1
Entry 1: According to the general procedure, treatment of 6 (47.2 mg, 0.131 mmol) with 2,4,6-collidine
(52 µL, 0.393 mmol), TESOTf (59 µL, 262 mmol), 2 (73.3 mg, 0.396 mmol), and 18-crown-6 (102.2 mg,
0.387 mmol) gave 9 (48.3 mg, 78%). Eluent; hexanes-AcOEt (8 /1). 9: Colorless oil; IR (KBr) 2928,
1
1776, 1715, 1325, 1099 cm-1; H NMR (270 MHz, CDCl3) δ 0.04 (6H, s), 0.89 (9H, s), 1.24-1.52 (18H,
m), 2.09-2.29 (2H, m), 3.35 (3H, s), 3.59 (2H, t, J = 6.4 Hz), 5.27 (1H, t, J = 7.1 Hz), 7.74-7.77 (2H, m),
7.87-7.90 (2H, m); 13C NMR (68 MHz, CDCl3) δ –5.3, 18.3, 25.4, 25.8, 26.0, 29.4 (2C), 29.5, 29.6, 32.3,
32.8, 56.5, 63.3, 83.7, 123.5, 131.6, 134.2, 168.1; HRMS (FAB) calcd for C27H46NO4Si (M++H)
476.3196, found 476.3193.
Entry 2: According to the general procedure, treatment of 6 (74.3 mg, 0.206 mmol) with 2,4,6-collidine
(81 µL, 0.618 mmol), TESOTf (93 µL, 0.412 mmol), and 4 (44 µL, 0.412 mmol) gave 10 (47.1 mg, 58%).
Eluent; hexanes-AcOEt (10/1). 10: Colorless oil; IR (KBr) 2855, 1603, 1556, 1454, 1097 cm-1; 1H NMR
(300 MHz, CDCl3) δ 0.00 (6H, s), 0.85 (9H, s), 1.22-1.30 (14H, m), 1.37-1.48 (6H, m), 1.61-1.69 (4H, m),
2.14-2.21 (2H, m), 2.86 (t like, J = 5.4 Hz), 3.55 (t, J = 6.6), 6.90 (1H, J = 5.7 Hz); 13C NMR (75 MHz,
CDCl3) δ -5.3, 18.4, 24.1, 25.3, 25.8, 26.0, 27.6, 29.2, 29.4, 29.5 (3C), 29.6, 32.9, 33.3, 53.0, 63.3, 141.8;
HRMS (FAB) calcd for C23H49N2OSi (M++H) 397.3614, found 397.3610.
Entry 3: According to the general procedure, treatment of 7 (58.2 mg, 0.119 mmol) with 2,4,6-collidine
(47 µL, 0.357 mmol), TESOTf (54 µL, 0.238 mmol), 2 (66.8 mg, 0.361 mmol), and 18-crown-6 (95.2 mg,
0.360 mmol) gave 11 (45.6 mg, 63%). Eluent; hexanes-AcOEt (6 /1). 11: Colorless oil; IR (KBr) 2930,
1776, 1713, 1348, 1070 cm-1; 1H NMR (270 MHz, CDCl3) δ 1.21-1.65 (18H, m), 2.04-2.31 (2H, m), 3.03
(2H, t, J = 6.4 Hz), 3.34 (3H, s), 5.27 (1H, t, J = 7.0 Hz), 7.18-7.31 (9H, m), 7.42-7.45 (6H, m), 7.72-7.75
13
(2H, m), 7.86-7.89 (2H, m); C NMR (68 MHz, CDCl3) δ 25.4, 26.2, 29.0, 29.4 (2C), 29.5 (2C), 30.0,
32.3, 56.5, 63.6, 83.7, 86.2, 123.5, 126.7, 127.6, 128.7, 131.6, 134.2, 144.5, 168.1; HRMS (FAB) calcd
for C40H45NO4Na (M++Na) 626.3246, found 626.3246.
Entry 4: According to the general procedure, treatment of 7 (96.4 mg, 0.197 mmol) with 2,4,6-collidine
(78 µL, 0.592 mmol), TESOTf (89 µL, 0.395 mmol), and 4 (43 µL, 0.395 mmol) gave 12 (36.1 mg, 35%).
Eluent; hexanes-AcOEt (10/1). 12: Colorless oil, IR (KBr) 2930, 2855, 1597, 1448, 1069, cm-1, 1H NMR
(270MHz, CDCl3) δ 1.24-1.37 (16H, m), 1.42-1.52 (2H, m), 1.55-1.73 (6H, m), 2.18 (2H, m), 2.90 (4H, t
like), 3.03 (3H, t, J = 5.7 Hz), 6.94 (3H, t, J = 5.7 Hz), 7.18-7.31 (9H, m), 7.41-7.46 (6H, m); 13C NMR
(68 MHz, CDCl3) δ 24.2, 25.3 (2C), 26.3, 27.6, 29.2, 29.5 (3C), 29.6, 30.0, 33.3, 53.0, 63.7, 86.2, 126.8,

HETEROCYCLES, Vol. 79, 2009
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127.7, 128.7, 141.8, 144.5; HRMS (FAB) calcd for C36H49N2O (M++H) 525.3845, found 525.3790.
Entry 5: According to the general procedure, treatment of 8 (33.0 mg, 0.145 mmol) with 2,4,6-collidine
(57 µL, 0.435 mmol), TESOTf (65 µL, 0.290 mmol), 2 (80.3 mg, 0.434 mmol), and 18-crown-6 (114.8
mg, 0.434 mmol) gave 13 (47.0 mg, 66%). Eluent; hexanes-AcOEt (3 /1). 13: Colorless oil; IR (KBr)
2934, 1776, 1712, 1348, 1103 cm-1; 1H NMR (270 MHz, CDCl3) δ 0.54 (6H, q, J = 7.9 Hz), 0.90 (9H, t, J
= 7.9 Hz), 1.23-1.55 (5H, m), 1.70-1.79 (4H, m), 2.02-2.10 (1H, m), 2.21-2.31 (1H, m), 3.51-3.59 (2H,
13
m), 3.70-3.74 (2H, m), 3.92 (4H, s), 5.52 (1H, t, J = 7.0 Hz), 7.73-7.77 (2H, m), 7.86-7.89 (2H, m); C
NMR (68 MHz, CDCl3) δ 4.2, 6.7, 29.9 (2C), 32.9, 34.2, 38.6, 61.7, 64.1, 70.3, 80.8, 108.8, 123.5, 131.6,
134.2, 168.0; HRMS (FAB) calcd for C26H40NO6Si (M++H) 490.2625, found 490.2603.
Entry 6: According to the general procedure, treatment of 8 (45.9 mg, 0.201 mmol) in CH2Cl2 (1.0 mL,
0.2 M) with 2,4,6-collidine (79 µL, 0.603 mmol), TESOTf (91 µL, 0.402 mmol), and 4 (65 µL, 0.603
mmol) gave the mixture of 2,4,6-collidine and 14. Since 14 was unstable and hard to be separated from
2,4,6-collidine, the yield of 14 (42%) was determined by 1H NMR. Eluent; hexanes-AcOEt (100/1 to 2/1).
1
14: Yellow oil; IR (KBr) 2939, 1603, 1447, 1375, 1105 cm-1; H NMR (300 MHz, CDCl3) δ 1.26-1.76
13
(15H, m), 2.18 (2H, t, J = 6.3 Hz), 2.91 (4H, m), 3.94 (4H, s), 6.96 (1H, t, J = 5.7 Hz); C NMR (75
MHz, CDCl3) δ 24.1, 25.3, 30.0, 34.4, 35.6, 39.5, 52.9, 64.2 (2H), 108.9, 140.0; HRMS (FAB) calcd for
C15H27N2O2 (M++H) 267.2073, found 267.2076.
ACKNOWLEDGEMENTS
This work was financially supported by Grants-in-Aid for Scientific Research (A) and (B) and
Grant-in-Aid for Scientific Research for Exploratory Research from Japan Society for the Promotion of
Science.
REFERENCES AND NOTES
††Present address: College of Pharmaceutical Sciences, Ritsumeikan University, 1-1-1 Nojihigashi,
Kusatsu, Shiga, 525-8577
1. a) H. Fujioka, Y. Sawama, N. Murata, T. Okitsu, O. Kubo, S. Matsuda, and Y. Kita, J. Am. Chem.
Soc., 2004, 126, 11800; b) H. Fujioka, T. Okitsu, Y. Sawama, N. Murata, R. Li, and Y. Kita, J. Am.
Chem. Soc., 2006, 128, 5930; c) H. Fujioka, T. Okitsu, Y. Sawama, T. Ohnaka, and Y. Kita, Synlett,
2006, 18, 3077; d) H. Fujioka, T. Okitsu, T. Ohnaka, Y. Sawama, O. Kubo, K. Okamoto, and Y. Kita,
Adv. Synth. Catal., 2007, 349, 636; e) H. Fujioka, T. Ohnaka, T. Okitsu, O. Kubo, K. Okamoto, Y.
Sawama, and Y. Kita, Heterocycles, 2007, 72, 529; f) H. Fujioka, T. Okitsu, T. Ohnaka, R. Li, O.

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Kubo, K. Okamoto, Y. Sawama, and Y. Kita, J. Org. Chem., 2007, 72, 7898.
2. Hydrazone compounds are more stable than imine compounds against water. The utility of the
hydrazone compounds was demonstrated. For examples, see a) H. Takahashi, K. Tomita, and H.
Otomasu, J. Chem. Soc., Chem. Commun., 1979, 668; b) D. Enders, H. Shubert, and C. Nubling,
Angew. Chem., Int. Ed. Engl., 1986, 25, 1109; c) S. E. Denmark, T. Weber, and D. W. Piotrowsky, J.
Am. Chem. Soc., 1987, 109, 2224.