Tf2O-TMDS combination for the direct reductive transformation of secondary amides to aldimines, aldehydes, and/or amines

Article abstract of DOI:10.1007/s11426-016-0224-5

The direct partial reduction of highly stable secondary amides to more reactive aldimines and aldehydes is a challenging yet highly demanding transformation. In this context, only three methods have been reported. We report herein an improved version of the Charette’s method. Our protocol consists of activation of secondary amides with triflic anhydride/2-fluoropyridine, and partial reduction of the resulting intermediates with 1,1,3,3-tetramethyldisiloxane (TMDS), which delivered aldimines or aldehydes upon acidic hydrolysis. Aromatic amides were reduced to the corresponding aldimines in 85%–100% NMR yields, and yields (NMR) from aliphatic amides were 72%–86%. Acidic hydrolysis of the aldimine intermediates afforded, in one-pot, the corresponding aldehydes in 80%–96% yields. A simple protocol was established to isolate labile aldimines in pure form in 92%–96% yields. The improved method gave generally higher yields as compared to the known ones, and features the use of cheaper and more atom-economical TMDS as a chemoselective reducing agent. In addition, a convenient extraction protocol has been established to allow the isolation of amines, which constitutes a mild method for the N-deacylation of amides, another highly desirable transformation. The extended method retains the advantages of the original method of Charette in terms of mild conditions, good functional group tolerance, and excellent chemoselectivity.

Full text of DOI:10.1007/s11426-016-0224-5

SCIENCE CHINA
Chemistry
• ARTICLES •
doi: 10.1007/s11426-016-0224-5
Tf2O-TMDS combination for the direct reductive transformation
of secondary amides to aldimines, aldehydes, and/or amines
Qi-Wei Lang†, Xiu-Ning Hu† & Pei-Qiang Huang*
Department of Chemistry, Fujian Provincial Key Laboratory of Chemical Biology, Collaborative Innovation Center of Chemistry for Energy
Materials, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen 361005, China
Received May 13, 2016; accepted June 3, 2016; published online October 31, 2016
The direct partial reduction of highly stable secondary amides to more reactive aldimines and aldehydes is a challenging yet
highly demanding transformation. In this context, only three methods have been reported. We report herein an improved ver-
sion of the Charette’s method. Our protocol consists of activation of secondary amides with triflic anhydride/2-fluoropyridine,
and partial reduction of the resulting intermediates with 1,1,3,3-tetramethyldisiloxane (TMDS), which delivered aldimines or
aldehydes upon acidic hydrolysis. Aromatic amides were reduced to the corresponding aldimines in 85%–100% NMR yields,
and yields (NMR) from aliphatic amides were 72%–86%. Acidic hydrolysis of the aldimine intermediates afforded, in one-pot,
the corresponding aldehydes in 80%–96% yields. A simple protocol was established to isolate labile aldimines in pure form in
92%–96% yields. The improved method gave generally higher yields as compared to the known ones, and features the use of
cheaper and more atom-economical TMDS as a chemoselective reducing agent. In addition, a convenient extraction protocol
has been established to allow the isolation of amines, which constitutes a mild method for the N-deacylation of amides, another
highly desirable transformation. The extended method retains the advantages of the original method of Charette in terms of
mild conditions, good functional group tolerance, and excellent chemoselectivity.
secondary amides, amide activation, partial reduction, aldimines, N-deacylation
Citation:
Lang QW, Hu XN, Huang PQ. Tf2O-TMDS combination for the direct reductive transformation of secondary amides to aldimines, aldehydes, and/or
amines. Sci China Chem, doi: 10.1007/s11426-016-0224-5
lenging. The versatility of both aldimines and aldehydes in
1 Introduction
organic synthesis rends nevertheless such transformation
highly desirable. In fact, very few examples of the chem-
oselective reduction of secondary amides to aldimines/
aldehydes have been reported [5–8] (Scheme 1). In 1993,
Ganem’s group [5] reported the seminal selective reduction
of secondary lactams to aldimines with Schwartz reagent
(Cp2ZrHCl). The second method appeared seventeen years
later, in 2010, Charette and co-workers [6] communicated a
controlled and chemoselective reduction of secondary am-
ides to aldimines and aldehydes utilizing triflic anhydride
(Tf2O) as an amide activating agent and Et3SiH as a reduc-
ing reagent. The first catalytic partial reduction of second-
ary amides to aldimines has been achieved in 2012 by
The reduction of amides is a fundamental transformation in
organic synthesis [1], which has attracted considerable at-
tention in recent years due to the need to develop mild, se-
lective, and environmental benign methods for pharmaceu-
tical industry [2]. Those efforts have accumulated in several
mild and versatile methods [3]. Among them some are for
the reduction of secondary amides to amines [4]. However,
partial reduction of highly stable secondary amides to yield
more reactive aldimines and/or aldehydes remains chal-
†These authors contributed equally to this work.
*Corresponding author (email: pqhuang@xmu.edu.cn)
© Science China Press and Springer-Verlag Berlin Heidelberg 2016
chem.scichina.com link.springer.com

2
Lang et al. Sci China Chem December (2016) Vol.59 No.12
Brookhart and co-workers [7]. In addition to the abovemen-
tioned one-pot methods, Nikonov et al. [8] have developed
a two-step method consisting of amide activation in form of
iminoyl chlorides and catalytic reduction.
In recent years, we have developed several methods for
the direct reductive transformation of amides [14,15]. In
particular, lately we have disclosed, on one hand, the one-
pot two-stage reduction [Tf2O/1,1,3,3-tetramethyldisiloxane
(TMDS); B(C6F5)3(cat.)] of secondary amides to amines
[16a], and on the other hand, the reductive (Tf2O/TMDS;
CsF) 1,3-dipolar cycloaddition of secondary amides with
dipolarophiles [16b]. The latter two reactions were assumed
to pass through the iminium intermediates A (Scheme 2).
Although Charette and co-workers [6] have previously re-
ported the seminal chemoselective reduction of secondary
amides using Tf2O/Et3SiH system (Scheme 1(b)), our alter-
native utilizing Tf2O/TMDS combination presents some
advantages in terms of the silane used. TMDS is a non-
toxic, cheap, and easy-to-handle reducing reagent. We re-
port herein the partial reduction of secondary amides to
yield aldimines or aldehydes by the Tf2O/TMDS combina-
tion. In addition, two convenient protocols have been establi-
shed for the efficient isolation of either aldimines or amines.
On the other hand, due to the lability of aldimines, their
isolation and purification remains a problem. The classical
purification method by distillation is a low-yielding tech-
nique, and unsuitable for small scale preparation. Ganem
and co-workers [5] have established a non-aqueous tech-
nique for the isolation of imines. However, the isolated
yields were only 25%–86%. Charette and co-workers [6]
have developed a protocol, which allowed them to isolate
aldimines in good to excellent yield. However, as noted by
Nikonov and Lee [8] that protocol is unsuitable for the iso-
lation of the aldimines prepared by other methods. Indeed,
the NMR yields of aldimines prepared by Nikonov’s two-
step methods were 90%–100%, while isolated yields
dropped to 40%–57% [8]. Thus efficient protocol for the
isolation of aldimines is elusive.
Additionally, in both organic synthesis and medicinal
chemistry, amides are used as versatile intermediates [9]
and protected form of amines [10], and as directing groups
for C–H functionalization [11]. Thus, methods for chemose-
lective N-deacylation of amides is demanding [9a,12],
which continues to attract the attention of many research
groups [9a,13]. Specifically, among the aforementioned
methods for the partial reduction of secondary amides, only
Ganem has, yet beautifully demonstrated the power of his
creative invention in organozirconium chemistry for manu-
facturing the major anticancer drug, paclitaxel [9a].
2 Experimental
2.1 Materials and method
Unless otherwise stated, reactions were performed in oven-
dried glassware under an argon atmosphere. Dichloro-
methane was distilled over calcium hydride under an argon
atmosphere. Silica gel (300–400 mesh) was used for flash
column chromatography, eluting with ethyl acetate/hexane.
Melting points were uncorrected.
Infrared spectra were measured using film KBr pellet
1
techniques. H and 13C NMR spectra were recorded at 500
and 125 MHz, respectively. Mass spectra were obtained
using electrospray ionization and an FT-ICR analyzer (ESI-
MS) for high resolution mass spectra (HRMS). Tf2O was
distilled over phosphorous pentoxide and was stored for use
within a week [15b].
2.1.1 General procedure for reduction of secondary am-
ides to aldimines (general procedure A)
Into a solution of an amide (1.0 mmol) in 4 mL of anhy-
Scheme 2 Direct reductive transformations of secondary amides using
Tf2O/TMDS combination.
Scheme 1 Known methods for the reduction of secondary amides to
aldimines/aldehydes.

Lang et al. Sci China Chem December (2016) Vol.59 No.12
3
drous dichloromethane was added 2-fluoropyridine (117mg,
103 μL, 1.2 mmol). After being cooled to 0 °C, trifluoro-
methanesulfonic anhydride (Tf2O) (310 mg, 185 μL, 1.1
mmol) was added dropwise via a syringe and the mixture
was stirred for 20 min. To the resulting mixture, 1,1,3,3-
tetramethyldisiloxane (TMDS) (94 mg, 124 μL, 0.7 mmol)
was added dropwise and the resulting mixture was stirred
for 10 min at 0 °C. The mixture was allowed warming up to
room temperature and stirred for 6 h.
Quenching with NaHCO3 (sat.): the reaction was
quenched by addition of 0.5 mL of a saturated aqueous so-
lution of sodium bicarbonate (NaHCO3) and diluted with 30
mL of dichloromethane. Then 1,3,5-trimethoxybenzene
(168.2 mg, 1.0 mmol) was added as internal standard. The
biphasic mixture was transferred to a separation funnel and
the layers were separated. The aqueous layer was extracted
with dichloromethane (5 mL×2). The combined organic
layers were dried over anhydrous sodium sulphate
(Na2SO4), filtered, and concentrated under reduced pressure.
Yields of crude imines were calculated by integration of 1H
NMR spectra.
ing mixture was stirred for 10 min at 0 °C. The mixture was
allowed to warm up to room temperature and stirred for 6 h.
Then 2 mL of 1 M HCl was added and the reaction mixture
was vigorously stirred at room temperature for 1–2 h. The
reaction was quenched with a saturated aqueous solution of
sodium bicarbonate (NaHCO3) and diluted with dichloro-
methane (30 mL). The biphasic mixture was transferred to a
separation funnel and the layers were separated. The aque-
ous layer was extracted with dichloromethane (5 mL×2).
The combined organic layers were dried over anhydrous
sodium sulphate (Na2SO4), filtered, and concentrated under
reduced pressure. The residue was purified by flash chro-
matography on silica gel (300–400 mesh) to give the corre-
sponding aldehyde.
2.1.4 General procedure for the one-pot deacylation of
secondary amides to amines and aldehydes (general proce-
dure D)
Into a solution of an amide (1.0 mmol) in 4 mL of anhy-
drous dichloromethane was added 2-fluoropyridine (117
mg, 103 μL, 1.2 mmol). After being cooled to 0 °C, trifluo-
romethanesulfonic anhydride (Tf2O) (310 mg, 185 μL, 1.1
mmol) was added dropwise via a syringe and the mixture
was stirred for 20 min. To the resulting mixture, TMDS (94
mg, 124 μL, 0.7 mmol) was added dropwise and the result-
ing mixture was stirred for 10 min at 0 °C. The mixture was
allowed to warm up to room temperature and stirred for 6 h.
Aqueous HCl solution (1 M, 10 mL) was added. The
mixture was warmed to rt and stirred for 2 h before addition
of 10 mL of a 25% ammonium hydroxide solution. The
organic layer was separated and the aqueous phase was
extracted with diethyl ether (10 mL×3). The combined
organic layers were washed with aqueous HCl solution (5
mL×3), the organic phases was dried over anhydrous
MgSO4, filtered, and concentrated under reduced pressure.
The residue was purified by flash column chromatography
on silica gel affording aldehyde. Another 25% ammonium
hydroxide (10 mL) was added to the aqueous phases, then
extracted with diethyl ether (10 mL×3). The combined
organic layers were washed with brine (5 mL), dried over
anhydrous Mg2SO4, filtered, and concentrated under
reduced pressure. To the residue was added a solution of
HCl in diethyl ether, and the resulting mixture was
concentrated under reduced pressure to afford the desired
amine as its hydrochloride salt.
Quenching with NaH: the solvent was removed through a
drying tube charged with anhydrous CaCl2 under reduced
pressure, then 4 mL of THF and NaH (60 mg, 2.5 mmol,
60% dispersion on mineral oil) were added. The resulting
suspension was stirred at r.t. for 20 min. Then 1,3,5-
trimethoxybenzene (168.2 mg, 1.0 mmol) was added as
internal standard. Yields of crude imines were calculated by
integration of 1H NMR spectra.
2.1.2 General procedure for the isolation of aldimines
(general procedure B)
After completion of partial reduction of a secondary amide
with 1,1,3,3-tetramethyldisiloxane as described above, the
solvent was removed through a drying tube charged with
anhydrous CaCl2 under reduced pressure. The residue was
washed with hexane (4 mL×3) to remove oxosilane. To the
washed residue were added a mixture of hexane/Et2O (4
mL/4 mL), and Et3N (210 μL, 1.5 mmol). The resultant
mixture was vigorously stirred at r.t. for 1–2 h to dissolve
imines. The supernatant was collected and the oily residue
was extracted with hexane (4 mL×2). The combined super-
natant and extracts were concentrated under reduced pres-
sure. The crude product was dried under vacuum at r.t. for
2–3 h to give a pure aldimine as determined by 1H NMR.
2.1.3 General procedure for the reductive transformation
of secondary amides to aldehydes (general procedure C)
2.2 Synthesis
Into a solution of an amide (1.0 mmol) in 4 mL of anhy-
drous dichloromethane was added 2-fluoropyridine (117
mg, 103 μL, 1.2 mmol). After being cooled to 0 °C, trifluo-
romethanesulfonic anhydride (Tf2O) (310 mg, 185 μL, 1.1
mmol) was added dropwise via a syringe and the mixture
was stirred for 20 min. To the resulting mixture, TMDS (94
mg, 124 μL, 0.7 mmol) was added dropwise and the result-
Following the general procedure A, the partial reduction of
amides 1a–1r yielded the corresponding aldimines 2a–2r,
respectively, whose yields, calculated by integrating the
corresponding 1H NMR spectra, are listed in Table 1.
2.2.1 (E)-N-Isopropyl-1-(4-nitrophenyl)methanimine (2f)
Following the general procedure B, imine 2f was obtained

4
Lang et al. Sci China Chem December (2016) Vol.59 No.12
as a brown solid (176 mg, yield: 92%). m.p.: 49–50 °C {lit.
9.89 (s, 1H); 13C NMR (CDCl3, 125 MHz), δ (ppm): 55.5,
114.3 (2C), 129.9, 131.9 (2C), 164.6, 190.8; MS (ESI, m/z):
159 (M+Na+).
[17]: 52–53 °C}; IR (film), νmax (cm–1): 2969, 2926, 1867,
1
1644, 1601, 1522, 1348, 1107, 853; H NMR (CDCl3, 500
MHz): δ 1.29 (d, J=6.3 Hz, 6H), 3.62 (septet, J=6.3 Hz,
1H), 7.88–7.92 (m, 2H), 8.24–8.27 (m, 2H), 8.39 (s, 1H);
13C NMR (CDCl3, 125 MHz), δ (ppm): 23.9 (2C), 61.9,
123.8 (2C), 128.7 (2C), 142.0, 148.8, 156.0; MS (ESI, m/z):
193 (M+H+).
2.2.6 4-Bromobenzaldehyde (3e)
Following the general procedure C, the reaction of amide 1e
(242 mg, 1.0 mmol) gave, after flash column chromatog-
raphy on silica gel (eluent: EtOAc/Hexane=1:15), the
known aldehyde 3e (178 mg, yield: 96%) as a white solid.
m.p.: 58–59 °C {lit. [18]: 57–59 °C}; IR (film), νmax (cm–1):
3080, 2856, 1921, 1694, 1586, 1384, 1285, 1204, 1156,
2.2.2 (E)-4-[(Isopropylimino)methyl]benzonitrile (2i)
Following the general procedure B, imine 2i was obtained
as a white solid (162 mg, yield: 94%). m.p.: 35–36 °C; IR
(film), νmax (cm–1): 2969, 2929, 2867, 2228, 1709, 1643,
1
1065, 1010, 812; H NMR (CDCl3, 500 MHz), δ (ppm):
7.67–7.71 (m, 2H), 7.73–7.77 (m, 2H), 9.98 (s, 1H); 13C
NMR (CDCl3, 125 MHz), δ (ppm): 129.8, 131.0 (2C), 132.4
(2C), 135.1, 191.0 ppm; MS (ESI, m/z): 207 (M+Na+).
1
1465, 1382, 1301, 1143, 834; H NMR (CDCl3, 500 MHz),
δ (ppm): 1.27 (d, J=6.3 Hz, 6H), 3.60 (septet, J=6.3 Hz,
1H), 7.67–7.71 (m, 2H), 7.82–7.85 (m, 2H), 8.33 (s, 1H);
13C NMR (CDCl3, 125 MHz), δ (ppm): 23.9 (2C), 61.8,
113.5, 118.6, 128.4 (2C), 132.3 (2C), 140.3, 156.4;
HRMS-ESI calcd for [C11H12N2+H]+ (M+H)+: 173.1073;
found: 173.1073.
2.2.7 4-Nitrobenzaldehyde (3f)
Following the general procedure C, the reaction of amide 1f
(208 mg, 1.0 mmol) gave, after flash column chromatog-
raphy on silica gel (eluent: EtOAc/Hexane=1:15), the
known aldehyde 3f (124 mg, yield: 82%) as a white solid.
m.p.: 104–105 °C {lit. [18]: 101–103 °C}; IR (film) νmax
(cm–1): 3106, 2847, 1708, 1605, 1534, 1349, 1197, 1104,
2.2.3 (E)-N-Isopropyl-1-(naphthalen-2-yl)methanimine (2j)
Following the general procedure B, imine 2j was obtained
as a white solid (186 mg, yield: 94%). m.p.: 72–73 °C; IR
(film), νmax (cm–1): 2967, 2917, 2861, 1635, 1467, 1358,
1
817, 739; H NMR (CDCl3, 500 MHz), δ (ppm): 8.07–8.11
(m, 2H), 8.39–8.42 (m, 2H), 10.18 (s, 1H); 13C NMR
(CDCl3, 125 MHz), δ (ppm): 124.3, 130.4, 140.0, 151.1,
190.3 ppm; MS (ESI, m/z): 174 (M+Na+).
1
1145, 968, 865, 827, 750; H NMR (CDCl3, 500 MHz), δ
(ppm): 1.31 (d, J=6.3 Hz, 6H), 3.60 (septet, J=6.3 Hz, 1H),
7.47–7.53 (m, 2H), 7.82–7.90 (m, 3H), 7.96–8.00 (m, 1H),
8.03 (s, 1H), 8.45 (s, 1H); 13C NMR (CDCl3, 125 MHz), δ
(ppm): 24.2 (2C), 61.8, 124.0, 126.3, 126.9, 127.8, 128.3,
128.5, 129.5, 133.1, 134.1, 134.5, 158.4; HRMS-ESI calcd
for [C14H15N+H]+ (M+H)+: 198.1277; found: 198.1276.
2.2.8 Methyl 4-formylbenzoate (3g)
Following the general procedure C, the reaction of amide 1g
(221 mg, 1.0 mmol) gave, after flash column chromatog-
raphy on silica gel (eluent: EtOAc/Hexane=1:15), the
known aldehyde 3g (148 mg, yield: 90%) as a white solid.
m.p.: 61–62 °C {lit. [18]: 60–62 °C}; IR (film), νmax (cm–1):
3026, 2962, 2886, 1724, 1686, 1436, 1389, 1287, 1200,
2.2.4 (E)-N-(2,3-Dihydro-1H-inden-2-yl)-1-phenylmetha-
nimine (2p)
1
1108, 1013, 852, 808, 756, 685; H NMR (CDCl3, 500
Following the general procedure B, imine 2p was obtained
as a white solid (212 mg, yield: 96%). m.p.: 54–55 °C; IR
(film), νmax (cm–1): 3063, 3023, 2937, 2901, 2845, 1641,
MHz), δ (ppm): 3.97 (s, 3H), 7.94–7.97 (m, 2H), 8.18–8.21
(m, 2H), 10.11 (s, 1H); 13C NMR (CDCl3, 125 MHz), δ
(ppm): 52.5, 129.4 (2C), 130.1 (2C), 135.0, 139.1, 166.0,
191.6; MS (ESI, m/z): 187 (M+Na+).
1
1482, 1450, 1384, 1306, 1061, 742; H NMR (CDCl3, 500
MHz), δ (ppm): 3.10–3.25 (m, 4H), 4.28–4.36 (m, 1H),
7.16–7.20 (m, 2H), 7.22–7.26 (m, 2H), 7.38–7.44 (m, 3H),
7.73–7.78 (m, 2H), 8.39 (s, 1H); 13C NMR (CDCl3, 125
MHz), δ (ppm): 40.1 (2C), 71.3, 124.5 (2C), 126.4 (2C),
128.2 (2C), 128.6 (2C), 130.6, 136.2, 142.0 (2C), 159.9;
HRMS-ESI calcd for [C16H15N+H]+ (M+H)+: 222.1277;
found: 222.1275.
2.2.9 4-Formylphenyl acetate (3h)
Following the general procedure C, the reaction of amide 1h
(221 mg, 1.0 mmol) gave, after flash column chromatog-
raphy on silica gel (eluent: EtOAc/Hexane=1:15), the
known aldehyde 3h [19] (141 mg, yield: 86%) as a colorless
oil. IR (film), νmax (cm–1): 2833, 2735, 1764, 1701, 1597,
1
1503, 1372, 1300, 1198, 1158, 1012, 910, 856; H NMR
2.2.5 4-Methoxybenzaldehyde (3c)
(CDCl3, 500 MHz), δ (ppm): 2.34 (s, 3H), 7.26–7.30 (m,
2H), 7.90–7.94 (m, 2H), 9.99 (s, 1H); 13C NMR (CDCl3,
125 MHz), δ (ppm): 21.1, 122.3 (2C), 131.1 (2C), 133.9,
155.2, 168.7, 190.9; MS (ESI, m/z): 187 (M+Na+).
Following the general procedure C, the reaction of amide 1c
(193 mg, 1.0 mmol) gave, after flash column chromatog-
raphy on silica gel (eluent: EtOAc/Hexane=1:15), the
known aldehyde 3c (122 mg, yield: 90%) as a colourless oil.
IR (film), νmax (cm–1): 2838, 2739, 1688, 1600, 1511, 1313,
2.2.10 4-Cyanobenzaldehyde (3i)
1
Following the general procedure C, the reaction of amide 1i
1259, 1160, 1025, 833; H NMR (CDCl3, 500 MHz), δ
(188 mg, 1.0 mmol) gave, after flash column chromatog-
(ppm): 3.89 (s, 3H), 6.99–7.03 (m, 2H), 7.82–7.86 (m, 2H),

Lang et al. Sci China Chem December (2016) Vol.59 No.12
5
raphy on silica gel (eluent: EtOAc/Hexane=1:15), the
known aldehyde 3i (115 mg, yield: 88%) as a white solid.
m.p.: 100–101 °C {lit. [20]: 97–100 °C}; IR (film), νmax
(cm–1): 3094, 3049, 2848, 2746, 2230, 1705, 1606, 1572,
the first stage of our previous two methods depicted in
Scheme 2, has been investigated [16], the conditions estab-
lished therein [Tf2O (1.1 equiv.)/2-F-Pyr. (1.2 equiv.), 20
min at 0 °C, TMDS (0.7 equiv.), 10 min at 0 °C, 6 h at r.t.]
were adopted for the present investigation. Thus we first
focused our attention on the quenching and isolation proto-
col of aldimines. We opted for 1,3,5-trimethoxybenzene as
1
1385, 1297, 1265, 1202, 1172, 832, 736; H NMR (CDCl3,
500 MHz), δ (ppm): 7.85–7.88 (m, 2H), 7.99–8.03 (m, 2H),
10.11 (s, 1H); 13C NMR (CDCl3, 125 MHz), δ (ppm): 117.6,
117.7, 129.8 (2C), 132.9 (2C), 138.7, 190.6; MS (ESI, m/z):
154 (M+Na+).
1
an internal reference for determining yields by H NMR
technique. In the event, amide 1a was successively treated
with Tf2O, 2-F-Pyr., TMDS, and the reaction was quenched
by addition of aqueous NaHCO3 (sat.) or K2CO3 (s) (Table
1). The yields were determined to be 98% and 90%, respec-
tively. Thus aqueous NaHCO3 (sat.) was employed for
quenching the reaction.
2.2.11 (Z)-3-Chloro-3-phenyl-2-[(tetrahydrofuran-2-yl)me-
thyl]acrylaldehyde (3s)
Following the general procedure C (activated at –78 °C for
20 min, then 0 °C for 5 min), the reaction of amide 1s [21]
(46 mg, 0.15 mmol) gave, after flash column chromatog-
raphy on silica gel (eluent: EtOAc/Hexane=1:15), aldehyde
3s (32 mg, yield: 81%) as a colorless oil. IR (film), νmax
(cm–1): 3061, 2924, 2870, 1723, 1677, 1604, 1445, 1263,
To examine the scope of the method, the partial reduc-
tions of a series of N-isopropyl aroyl amides were under-
taken, and the results are summarized in Table 1. As can be
seen from Table 1, the partial reduction reactions of ben-
zamide derivatives 1a–1o gave the corresponding aldimines
2a–2o in 76%–100% NMR yields. For benzamide deriva-
tives bearing an electron-donating group, the corresponding
aldimines are stable and detected as the sole products (en-
tries 2 and 3, Table 1). For those bearing electron-with-
drawing groups, while imines were formed in goods yields,
a substantial amount (8%–18% NMR yields) of the corre-
sponding hydrolytic products, namely aldehydes were ob-
served (entries 4–9). The electron-rich aroyl amides 1j and
1k gave imines 2j and 2k in excellent yields (both in 93%
yield, entries 10 and 11). The reactions of N-cyclohexyl,
N-n-butyl, N-(2,3-dihydro-1H-inden-2-yl), and N-(pent-4-
yn-1-yl)benzamide derivatives produced the corresponding
imines in 84%–86% NMR yields (entries 12–15).
To inhibit the hydrolysis of aldimines (to aldehydes)
during the NMR monitoring of the reaction, NaH was used
as a base to replace aqueous NaHCO3, and the yields
(NMR) of aldimines improved to 89%–99% (entries 4–10
and 12–14, Table 1). The method was next extended to ali-
phatic secondary amides (entries 16–18), and the corre-
sponding imines were formed in yields of 72%–86%
(NMR).
To tackle the problem of isolation of labile aldimines, an
extraction protocol was developed (cf. the experimental
section, general procedure B) which allowed, as exampled
in Table 2, the isolation of aldimines 2f, 2i, 2j, and 2n in
excellent yields (92%–96%).
We next turned our attention to the one-pot transfor-
mation of secondary amides to aldehydes. This was
achieved by one-pot amide activation (Tf2O, 2-F-Pyr.), par-
tial reduction (TMDS), and acidic hydrolysis with 1 M HCl.
As can be seen from Table 3, the corresponding aldehydes
3c and 3e–3i were obtained in 81%–96% yields. Notewor-
thy is that sensitive functional groups such as Br, NO2,
CO2Me, OAc, CN survived from both the reduction and
acidic hydrolytic conditions. The mildness and chemoselec-
tivity of the method were further demonstrated by the
1
1167, 1063, 878, 767, 720; H NMR (CDCl3, 500 MHz), δ
(ppm): 1.30–1.39 (m, 1H), 1.69–1.82 (m, 2H), 1.87–1.96
(m, 1H), 2.41 (ddd, J=13.4, 8.8, 0.8 Hz, 1H), 2.50 (dd,
J=13.4, 4.5 Hz, 1H), 3.64 (t, J=6.8 Hz, 2H), 3.93–4.00 (m,
1H), 7.39–7.46 (m, 3H), 7.50–7.56 (m, 2H), 10.40 (d, J=0.8
Hz, 1H); 13C NMR (CDCl3, 125 MHz), δ (ppm): 25.5, 31.5,
33.8, 67.5, 76.9, 128.4, 128.5, 129.7, 134.3, 137.7, 149.7,
192.2; HRMS-ESI calcd for [C14H15ClO2+Na]+ (M+Na)+:
273.0653; found: 273.0652.
2.2.12 2,3-Dihydro-1H-inden-2-amine hydrochloride salt
(5t)
Following the general procedure D, amine hydrochloride
salt 5t was obtained as a white solid (154 mg, yield: 91%).
Decompose at 205 °C. IR (film) νmax (cm–1): 3436, 3020,
1
2965, 2917, 1653, 1592, 1570, 1496, 1174, 1076, 754; H
NMR (400 MHz, DMSO-d6), δ (ppm): 2.95 (dd, J=15.8, 4.0
Hz, 2H), 3.16 (dd, J=15.8, 6.9 Hz, 2H), 3.86 (s, 1H),
6.95–7.29 (m, 4H), 8.14–8.82 (br s, 3H); 13C NMR (100
MHz, DMSO-d6), δ (ppm): 37.2, 50.3, 124.6 (2C), 126.9
(2C), 139.8 (2C); MS (ESI, m/z): 134 (M+H+).
2.2.13 Phenylmethanamine hydrochloride salt (5u)
Following the general procedure D, amine hydrochloride
salt 5u was obtained as a white solid (120 mg, yield: 84%).
Decompose at 219 °C. IR (film), νmax (cm–1): 3446, 3184,
2994, 2676, 2560, 1653, 1589, 1465, 1456, 1381, 1215,
1
1103, 1056, 874, 746; H NMR (400 MHz, DMSO-d6), δ
(ppm): 3.88 (s, 2H), 7.12–7.54 (m, 5H), 8.30–8.78 (br s,
3H); 13C NMR (100 MHz, DMSO-d6), δ (ppm): 42.0, 128.2,
128.3 (2C), 128.8 (2C), 133.9 ppm; MS (ESI, m/z): 108
(M+H+).
3 Results and discussion
Given that the partial reduction of secondary amides, being

6
Lang et al. Sci China Chem December (2016) Vol.59 No.12
Table 1 Direct reduction of secondary amides to aldimines a)
Table 3 One-pot transformation of secondary amides to aldehydes a)
Yield (%) b)
Combined
yield (%) b)
Entry
Amide (1)
Yield (%) b)
90/83 c)
Yield (%) b)
86
2
3
2
0
0
1
2
3
4
5
6
1a R=H
98 c)
99 c)
100
99
1b R=Me
3c
3e
3h
3i
1c R=OMe 100 c)
100
1d R=CF3 78 c)/94 d) 16 c)/4 d) 94 c)/98 d)
1e R=Br 86 c)/99 d) 12 c)/1 d) 98 c)/100 d)
1f R=NO2 76 c)/91 d) 18 c)/8 d) 94 c)/99 d)
96
82
88
1g
7
85 c)/96 d)
9 c)/2 d)
94 c)/98 d)
R=CO2Me
1h R=OAc 81 c)/94 d) 15 c)/0 d) 96 c)/94 d)
1i R=CN 88 c)/94 d)
1s d)
3f
8
9
8 c)/3 d)
96 c)/97 d)
90
81
10
11
12
1j
1k
1l
93 c)/96 d)
93 c)
6 c)/1 d)
99 c)/97 d)
3g
3s
a) Conditions: Tf2O (1.1 equiv.), 2-F-Pyr. (1.2 equiv.), 0 °C, 20 min;
TMDS (0.7 equiv.), 0 °C to r.t., 6 h; then 1 M HCl, 2–3 h; b) isolated yield;
c) quenched with silica gel; d) activated at –78 °C for 20 min, then at 0 °C
for 5 min.
2
95
85 c)/89 d) 12 c)/3 d) 92 c)/97 d)
84 c)/91 d) 7 c)/2 d) 91 c)/93 d)
smooth reduction of the Jiang’s multi-functionalized α,β-
unsaturated secondary amide 1s [21] which produced alde-
hyde 3s in 81% yield.
13
14
1m
1n
86 c)/95 d) 14 c)/2 d) 100 c)/97 d)
To further extend the scope of the method, a convenient
extraction protocol was established (cf. the experimental
section), which allowed the isolation of both or either
amines/aldehydes. Thus, as illustrated by amides 1t and 1u
(Scheme 3), by employing the partial reduction reaction and
extraction protocol (general procedure D), amine 5t and p-
anisaldehyde (3c), as well as amine 5u and p-anisaldehyde
(3c), were isolated in yields of 91%/88%, and 84%/79%,
respectively. This one-pot reaction thus constitutes a mild
method for the N-deacylation of secondary amides.
15
16
1o
1p
85 c)
77 d)
4
2
89
79
17
18
1q
1r
72 d)
86 d)
2
74
98
12
a) Conditions: Tf2O (1.1 equiv.), 2-F-Pyr. (1.2 equiv.), 0 °C, 20 min;
TMDS (0.7 equiv.), 0 °C to r.t., 6 h; b) yields determined by H NMR
1
using 1,3,5-trimethoxybenzene as an internal standard; c) quenched with
NaHCO3 (sat.); d) quenched with NaH.
4 Conclusions
Table 2 Isolated yield of aldimines a)
In summary, a versatile protocol for the direct reductive
transformation of common secondary amides to aldimines,
Aldimines
Yield (%) b)
92
Aldimines
Yield (%) b)
94
2i
2f
2j
94
96
2n
Scheme 3 One-pot transformation of secondary amides to aldehydes and
amines. Conditions: Tf2O (1.1 equiv.), 2-F-Pyr. (1.2 equiv.), 0 °C, 20 min;
TMDS (0.7 equiv.), 0 °C to r.t., 6 h; then 1 M HCl, 2–3 h.
a) Conditions: Tf2O (1.1 equiv.), 2-F-Pyr. (1.2 equiv.), 0 °C, 20 min;
TMDS (0.7 equiv.), 0 °C to r.t., 6 h; b)isolated yield.

Lang et al. Sci China Chem December (2016) Vol.59 No.12
7
11 For a review, see: a) Chen X, Engle KM, Wang DH, Yu JQ. Angew
Chem Int Ed, 2009, 48: 5094–5115. For selected recent examples,
see: b) Sun K, Li Y, Zhang Q. Sci China Chem, 2015, 58:
1354–1358; c) Wang B, He G, Chen G. Sci China Chem, 2015, 58:
1345–1348; d) Zhao S, Chen FJ, Liu B, Shi BF. Sci China Chem,
2015, 58: 1302–1309; e) Shi XY, Dong XF, Fan J, Liu KY, Wei JF,
Li CJ. Sci China Chem, 2015, 58: 1286–1291
12 Reeves JT, Tan Z, Reeves DC, Song JJ, Han ZS, Xu Y, Tang W,
Yang BS, Razavi H, Harcken C, Kuzmich D, Mahaney PE, Lee H,
Busacca CA, Senanayake CH. Org Process Res Dev, 2014, 18:
904–911
13 For selected examples, see: a) Wang AE, Chang Z, Liu YP, Huang
PQ. Chin Chem Lett, 2015, 24: 1055–1058; b) Sultane PR, Mete TB,
Bhat RG. Org Biomol Chem, 2014, 12: 261–264; c) Kita Y, Nishii Y,
Onoue A, Mashima K. Adv Synth Catal, 2013, 355: 3391–3395; d)
Shimizu Y, Morimoto H, Zhang M, Ohshima T. Angew Chem Int Ed,
2012, 51: 8564–8567; e) Shimizu Y, Noshita M, Mukai Y, Morimoto
H, Ohshima T. Chem Commun, 2014, 50: 12623–12625; f) Bechara
WS, Pelletier G, Charette AB. Nat Chem, 2012, 4: 228–234; g)
Koenig SG, Vandenbossche CP, Zhao H, Mousaw P, Singh SP, Ba-
kale RPA. Org Lett, 2009, 11: 433–436; h) Spaggiari A, Blaszczak
LC, Prati F. Org Lett, 2004, 6: 3885–3888
14 For selected transformations of tertiary amides, see: a) Huang PQ,
Wang Y, Xiao KJ, Huang YH. Tetrahedron, 2015, 71: 4248–4254; b)
Huang PQ, Geng H, Tian YS, Peng QR, Xiao KJ. Sci China Chem,
2015, 58: 478–482; c) Mao ZY, Huang SY, Gao LH, Wang AE,
Huang PQ. Sci China Chem, 2014, 57: 252–264
aldehydes, and amines has been disclosed. Comparing to the
original method of Charette, our protocol features the em-
ployment of TMDS, a non-toxic, cheap (containing two
usable hydride in a molecule), and easy-to-handle reducing
reagent, and afforded aldimines or aldehydes in higher
yields for most cases. In addition, a simple protocol has
been established to isolate labile aldimines in high purity
and in high yields. This method has also been extended to
the N-deacylation of amides. On account of the versatility of
aldimines, aldehydes, and amines, this extended method
will find application in organic synthesis and medicinal
chemistry.
Acknowledgments This work was supported by the National Natural
Science Foundation of China (21332007) and Xiamen University.
Conflict of interest The authors declare that they have no conflict of
interest.
1
2
Seyden-Penne J. Reductions by the Alumino- and Borohydrides in
Organic Synthesis. 2nd Ed. New York: Wiley, 1997
Constable DJC, Dunn PJ, Hayler JD, Humphrey GR, Leazer HL Jr,
Linderman RJ, Lorenz K, Manley J, Pearlman BA, Wells A, Zaks A,
Zhang TY. Green Chem, 2007, 9: 411–420
3
4
For a recent review, see: Smith AM, Whyman R. Chem Rev, 2014,
114: 5477–5510
15 For selected transformations of secondary amides, see: a) Geng H,
Huang PQ. Tetrahedron, 2015, 71: 3795–3801; b) Huang PQ, Huang
YH, Xiao KJ, Wang Y, Xia XE. J Org Chem, 2015, 80: 2861−2868;
c) Huang PQ, Lang QW, Wang AE, Zheng JF. Chem Commun, 2015,
51: 1096−1099; d) Huang PQ, Ou W, Ye JL. Org Chem Front, 2015,
2: 1094−1106; e) Zheng JF, Qian XY, Huang PQ. Org Chem Front,
2015, 2: 927−935; f) Wang AE, Chang Z, Sun WT, Huang PQ. Org
Lett, 2015, 17: 732–735; g) Zheng JF, Xie ZQ, Chen XJ, Huang PQ.
Acta Chim Sinica, 2015, 73: 705−715; h) Huang PQ, Huang YH,
Geng H, Ye JL. Sci Rep, 2016, 6: 28801
For selected examples, see: a) Hanada S, Tsutsumi E, Motoyama Y,
Nagashima H. J Am Chem Soc, 2009, 131: 15032–15040; b) Reeves
JT, Tan Z, Marsini MA, Han ZS, Xu Y, Reeves DC, Lee H, Lu BZ,
Senanayake CH. Adv Synth Catal, 2013, 355: 47–52; c) Li Y, Molina
de La TJA, Grabow K, Bentrup U, Junge K, Zhou S, Brückner A,
Beller M. Angew Chem Int Ed, 2013, 52: 11577–11580; d) Di Gioia
ML, Belsito EL, Leggio A, Leotta V, Romio E, Siciliano C, Liguori
A. Tetrahedron Lett, 2015, 56: 2062–2066; e) Sakai N, Takeoka M,
Kumaki T, Asano H, Konakahara T, Ogiwara Y. Tetrahedron Lett,
2015, 56: 6448–6451
16 a) Huang PQ, Lang QW, Wang YR. J Org Chem, 2016, 81:
4235−4243; b) Huang PQ, Lang QW, Hu XN. J Org Chem, 2016,
doi: 10.1021/acs.joc.6b01080; c) Huang PQ, Geng H. Org Chem
Front, 2015, 2: 150−158; d) Xiang SH, Xu J, Yuan HP, Huang PQ.
Synlett, 2010: 1829−1832
5
6
a) Schedler DJA, Godfrey AG, Ganem B. Tetrahedron Lett, 1993,
34: 5035–5038; b) Schedler DJA, Li J, Ganem B. J Org Chem, 1996,
61: 4115–4119; c) Spletstoser JT, White JM, Tunoori AR, Georg GI.
J Am Chem Soc, 2007, 129: 3408–3419
Pelletier G, Bechara WS, Charette AB. J Am Chem Soc, 2010, 132:
12817–12819
Cheng C, Brookhart M. J Am Chem Soc, 2012, 134: 11304–11307
Lee SH, Nikonov GI. Dalton Trans, 2014, 43: 8888–8893
a) Ganem B, Franke, RR. J Org Chem, 2007, 72: 3981–3987; b)
Song L, Liu K, Li C. Org Lett, 2011, 13: 3434–3437
17 Chen CW, Tseng MC, Hsiao SK, Chen WH, Chu YH. Org Biomol
Chem, 2011, 9: 4188–4193
7
8
9
18 Iinuma M, Moriyama K, Togo H. Tetrahedron, 2013, 69: 2961–2970
19 Schiaffo CE, Dussault PH. J Org Chem, 2008, 73: 4688–4690
20 Kornblum N, Fifolt MJ. Tetrahedron, 1989, 45: 1311–1322
21 Huang L, Wang Q, Wu W, Jiang H. J Org Chem, 2014, 79: 7734–
7739
10 Wuts PGM, Greene TW. Protective Groups in Organic Synthesis. 4th
Ed. Hoboken: Wiley-Interscience, 2006. 773–789