Chemoselective reductive alkynylation of tertiary amides by Ir and Cu(i) bis-metal sequential catalysis

Article abstract of DOI:10.1039/c6cc05318a

We report herein a convenient and versatile method for the direct reductive alkynylation of tertiary amides to give propargylic amines through sequential Ir-catalysed hydrosilylation-Cu(i)-catalysed alkynylation. The reactions proceed chemoselectively at the amide group in the presence of several sensitive functional groups including the very reactive aldehyde group on either the amide or the alkyne coupling partner. The method is general for tert-amides with or without α-hydrogen.

Full text of DOI:10.1039/c6cc05318a

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DOI: 10.1039/C6CC05318A
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Chemoselective Reductive Alkynylation of Tertiary Amides by Ir
and Cu(I) Bis‐metal Sequential Catalysis
Pei‐Qiang Huang,*a,b Wei Ou,a and Feng Hana
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
We report herein a convenient and versatile method for the direct with
–hydrogens have been employed as substrates in all
reductive alkynylation of tertiary amides to give propargylic these methods.4‐7
amines through sequential Ir‐catalysed hydrosilylation ‐ Cu(I)‐ Propargylic amines are a class of versatile building blocks in organic
catalysed alkynylation. The reactions proceed chemoselectively at synthesis and medicinal chemistry.1f,g,8 The catalytic synthesis of
the amide group in the presence of several sensitive functional these important structures has been extensively investigated in the
groups including the very reactive aldehyde group on either the last 15 years.8,10 These efforts have resulted in several highly
amide or the alkyne coupling partner. The method is general for efficient and powerful methodologies.8‐11 However, to the best of
tert‐amides with or without ‐hydrogen.
our knowledge, the access of propargylic amines through the direct
catalytic reductive alkynylation of amides and lactams has hitherto
been unknown. Considering the widespread use of amides as
versatile synthetic intermediates in the synthesis of alkaloids and
medicinal agents,1,2a and the fact that amides are products of
numerous powerful synthetic methodologies,12 the catalytic
transformation of amides leading to C‐C bond formation is highly
desirable. Except for one report,13 the known methods for the
reductive alkynylation of amides are stepwise and require
additional steps to convert amides/ lactam to more reactive
thioamides/ lactams,1f,g,14 and selenoamides.15 As a continuation of
our research program on the direct transformation of amides,3b,e,g‐i
we report herein a bis‐metallic Ir and Cu(I)‐catalysed reductive
alkynylation of common tertiary amides with or without an –
hydrogen to give propargylic amines (Scheme 1, b).
Reductive alkylation of amides is an essential transformation in the
synthesis of alkaloids and nitrogen‐containing medicinal agents.1,2a,b
However, due to the poor electrophilicity of the amide carbonyl
group, those transformations frequently require the use of highly
reactive organometallic reagents (e.g. RLi and RMgX) and harsh
conditions, which lead to low chemoselectivity and poor functional
group tolerance. Consequently, multi‐step methods are being
routinely employed instead.1a,b,f,g
Within the context of developing efficient synthetic methods,
the step‐economical direct transformation of amides has
attracted considerable attention in recent years, leading to the
accumulation of a host of synthetically useful methods.2,3
Despite the advances, catalytic C‐C bond forming reactions
that employ common amides as substrates remain rare and
challenging. Recently, based on Nagashimas iridium‐catalysed
transformation of amides to enamines (Scheme 1, a),4 Dixon,
and Chida/ Sato have independently developed a catalytic
intramolecular reductive nitro‐Mannich‐type reaction,5 and a
chemoselective reductive nucleophilic addition to N‐
methoxyamides.6 Very recently, Chida/ Sata have reported an
iridium‐catalysed
reductive
transformation
of
N
‑
hydroxyamides to nitrones.7 However, only tert‐amides
a. Department of Chemistry and The Key Laboratory for Chemical Biology of Fujian
Province, iChEM (Collaborative Innovation Center of Chemistry for Energy
Materials), College of Chemistry and Chemical Engineering, Xiamen University,
Xiamen, Fujian 361005 (P.R. China).E‐mail: pqhuang@xmu.edu.cn
b. State Key Laboratory of Elemento‐Organic Chemistry, Nankai University, Tianjin
300071, P. R. China.
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
Scheme 1. a. Nagashima’s catalytic reduction of amides to
enamines; b. bis‐metal sequential catalytic transformation of
amides with C‐C bond formation.
On the basis of the abovementioned literature precedents, our goal
was to develop a direct, sequential catalytic hydrosilylation ‐
alkynylation of common tert‐amides. Although Nagashima‘s
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method (Scheme 1, a)4 has been developed and applied only for
tert‐amides containing –hydrogens,5‐7 we wondered if this method
could be extended to include common tert‐amides without an –
Table 1. Direct reductive alkynylation of common tert‐amides
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without ‐hydrogen by sequential catalysis.DOI: 10.1039/C6CC05318A
hydrogen as substrates. Thus,
a toluene solution of N,N‐
dimethylbenzamide (1a) was treated with a catalytic amount of
Vaska’s complex [IrCl(CO)(PPh3)2, 1 mol%], 1.2 equiv of TMDS, 1.2
equiv of phenylacetylene, and 5 mol% of CuBr.9b To our delight, the
desired propargylamine 3a was obtained in 89% yield after being
stirred at room temperature for 12 h. Similarly, reaction of amide
1b with the two‐step, one‐pot reductive alkynylation reaction of
aliphatic amides 1c and 1d (the structures of all amides and alkynes
used are listed in the Electronic Supplementary Information)
produced the corresponding propargylic amines 3c and 3d in 60%,
and 80% yield, respectively. The relatively low yield of 3c could be
attributed to the steric hindrance of the amide substrate. The
reaction of sterically hindered N,N‐diisopropylbenzamide 1e also
provided the corresponding amine (3e) in a moderate yield (67%),
much lower than those of sterically un‐cumbered N,N‐
Ph
Me
N
Ph
Ph
Ph
Me
Bn
Me
Me
Me
Me
Ph
N
4-MePh
N
N
Me
Me
Me
Bn
3b: 90%[a]
3a: 89%[a]
3c: 60%[a]
3d: 80%[a]
Ph
EtO
OEt
Ph
Ph
dimethylbenzamide
(1a)
and
N,N‐diallylbenzamide
(1f).
Me
Functionalized alkyne 2b participated in the reaction to afford
amine 3g in an excellent yield (91%). On the other hand, amides
bearing either electron‐rich groups such as furan‐2‐yl (1h) and
benzo[b]thiophen‐2‐yl (1i), or electron‐poor groups such as para‐
nitrophenyl (1j) all reacted similarly to give the corresponding
amines 3h, 3i, and 3j in 80%, 81%, and 77% yield, respectively.
After examining the steric and electronic effects, we explored
the chemoselectivity and functional group tolerance.4,6,9e The
mild reductive alkynylation reaction showed remarkable
functional group tolerance and chemoselectivity as
Me
Ph
N
Me
Bn
N
Ph
N
Ph
N
O
Me
Me
Me
Me
3h: 80%[a]
3g: 91%[a]
3f: 85%[a]
3e: 67%[a]
Ph
Ph
Ph
Me
N
Me
Me
N
N
Me
S
Me
Me
O2N
CN
demonstrated by the formation of products 3j
– 3p. The
3i: 81%[a]
3k: 80%[a]
3j: 77%[a]
reaction tolerated redox‐sensitive functional groups such as
nitro (3j), cyano (3k), and aldehyde (3l), and common nitrogen
protecting groups such as Boc (3m) and Cbz (3n). It is well
known that amides are far less reactive than aldehydes.
However, under the current conditions, the reaction of an
aldehyde‐containing substrate took place chemoselectively at
the carbonyl of the amide instead of that of the aldehyde
leading to the isolation of amino aldehyde 3l in 64% yield,
along with the (aldehyde group) concomitantly reduced
product 3l’ in 8% yield. Moreover, the reductive alkynylation
reaction is fully compatible with an Boc‐protected amine that
contains an acidic proton (NHBoc, 1o) affording the desired
product 3o in excellent yield (89%). Interestingly, the reaction
of an amide bearing a free hydroxyl group (1p) yielded the O‐
silylated product 3p in 52% yield when 2.0 equiv of TMDS was
used. It is worth mentioning that o‐cyanobenzamide 1k is a
product of metal‐catalysed C‐H cyanation.12e
Ph
Ph
Ph
Me
Me
Ph
N
N
N
N
O
Me
Me
P
3m: P = Boc, 92%[a]
3n: P = Cbz, 95%[a]
3l: 64%[a]
3l': 8%[a]
H
OH
Ph
Ph
Ph
(dr=20:1)[d]
CO2Me
(S)
(S)
H
Ph
N
Ph
NHBoc
N
Me
SiH
Me
Me
Me
O
N
Ph
Si
O
3q:75%[a,c]
3o: 89%[a]
3p[b] : 52%[a]
Ph
Ph
TMS
(dr=15:1)[d]
(dr=17:1)[d]
(dr=17:1)[d]
We next investigated the stereoselectivity of the reductive
alkynylation reaction. For this purpose, benzamide derivatives
CO2Me
(S)
CO2Me
(S)
CO2Me
H
H
H
(S)
derived from ethyl (S)‐prolinate 1q
– 1s were selected as
(S)
N
(S)
N
(S)
Ph
N
substrates. These functionalized substrates also provided
opportunities for the further examination of the functional
group tolerance and chemoselectivity of the reaction. The
reductive phenylacetylenation of amido ester 1q proceeded
Br
NC
3r: 78%[a,c]
3t: 85%[a,c]
3s: 79%[a,c]
chemoselectively at the amido group to give
diastereomeric mixture from which the major diastereomer 3q
a 20:1
[a] Isolated yield. [b] 2.0 equiv of TMDS used. [c] yield for the major diastereomer.
[d] ratio determined by 1H NMR of the crude reaction mixture.
was isolated in 78% yield.
2 | J. Name., 2012, 00, 1‐3
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Similarly, excellent chemoselectivities and diastereoselectivities (dr
= 17:1, 15:1, and 17:1) were also observed for the reactions of
trimethylsilylacetylene with 1q, and phenylacetylene with the
bromo‐, cyano‐substituted prolinates 1r and 1s, which afforded the
major diastereomers 3r, 3s and 3t in 78%, 79%, and 85% yield,
respectively. Note that in the latter two reactions, the bromo,
cyano, and ester groups remained intact during the reductive
alkynylation process. The relative stereochemistry of the major
diastereomer 3q was assigned to be S,S by comparing the NMR data
with those reported by Tu,9d and Che9e (two diastereomers of ethyl
ester of 3q, cf. Electronic supplementary information), and those of
3r ‐ 3t were assigned accordingly.
View Article Online
DOI: 10.10E3t9O/C6CCO0E5t318A
[IrCl(CO)(PPh3)2] (1 mol%)
O
TMDS (2.0 equiv), rt, 10 min
Bn
N
n-C14H29
CuBr (5 mol %), rt
Me
Bn
H
CH(OEt)2 (2b)
N
n-C14H29
1t
94%
(gram-scale)
Me
3u
O
10% Pd/C, H2
Bn
95%
N
i-Bu
conc. HCl
MeOH
[IrCl(CO)(PPh3)2] (1 mol%)
Bn
TMDS (2.0 equiv), tol.
rt, 10 min
1u
CuBr (5 mol %)
CO2Me
n-C14H29
N
H
CO2Me
After the successful development of catalytic reductive alkynylation
of amides without –hydrogen, we turned our attention to extend
the reaction to amides bearing –hydrogen atoms. Moreover, to
further examine the scope of the alkynes, functionalized ones were
employed. Thus, the reductive alkynylation of amide 1t with
propiolaldehyde diethylketal 2b furnished the propargylic amine 3u
in 94% yield (Scheme 2). This gram‐scale reaction used 2 equiv. of
TMDS instead of the usual 1.2 equiv. Subsequent reduction of 3u
with H2 and Pd/C could be combined with the reductive
alkynylation in one‐pot to give the alkaloid (±)‐bgugaine (4)16
(Scheme 2). Bgugaine is an alkaloid isolated from the tubers of
Arisaum vulgare and has been showed to be a strong hepatotoxin
with antibacterial and antimycotic activities.16 Methyl propiolate
could also be used for the direct reductive alkynylation to afford
propargylic amine 3v in 88% yield even on a 5 mmol scale.
Remarkably, the direct reductive alkynylation with an acetylene
bearing an unprotected aldehyde group underwent smooth
reaction to afford the desired amino aldehyde 3w in 67% yield.
We next undertook a preliminary mechanistic study. For this
purpose, 1H NMR of starting amide 1v (spectrum A, cf. SI), its
mixture with TMDS (spectrum B, cf. SI), and the mixture formed 10
min after addition of the Ir catalyst (spectrum C, Figure 1), were
recorded. The spectrum C showed that the starting amide was
Me
2d
-bgugaine (4)
88%
Bn
CHO
i-Bu
N
Bn
3v
[IrCl(CO)(PPh3)2] (1 mol%)
TMDS (2.0 equiv), rt, 10 min
O
Me
Bn
N
CuBr (5 mol %), rt
Bn
Bn
N
H
C6H4-CHO-p (2e) Me
1v
67%
3w Bn
Scheme 2. Direct catalytic reductive alkynylation of tert‐amides
containing ‐hydrogens.
IrCl(CO)(PPh3)3 (cat.)
O
(cat.)
IrCl(CO)(PPh3)3
O
OSi
R1
R2
H
R1
R1
N
R2
N
R2
R2
or
R1
N
R3
N
R3
R3
H)
TMDS
TMDS
R3
A
B (no H)
amides without
amides bearing
an H (1t - 1v)
or
H (1a-1s)
R
R
CuBr
Br
Br
D
or
D
Cu
R
H
Cu
completely consumed ( = 2.06, q) with the clean formation of
‐H
C
R1
R2
R2
1
enamine A‐v (enamine‐H = 6.07, d). On the other hand, the H NMR
R1
N
R3
N
spectra of starting benzamide 1b (spectrum A’, cf. SI), an amide
without an ‐hydrogen, its mixture with TMDS (spectrum B’, cf. SI),
and the mixture formed 30 min after the addition of the Ir‐catalyst
(spectrum C’, Figure 2), indicated that the amide (NMe‐H = 2.64, s)
R
R
H
R3
E
E'
+
OH
OH
H
2
R1
R2
Si
Si
R
N
was transformed cleanly to give hemiaminal silyl ether B‐b (NCHO
=
CuBr
or
H
R3
5.61, s). On the basis of the above‐mentioned information, a
plausible mechanism of the reaction is depicted in Scheme 3. Upon
coordination with CuBr, terminal hydrogen in alkyne C becomes
more acidic and was deprotonated with either enamine A or
hemiaminal silyl ether intermediate B to generate an alkynylide ion
D and an iminium intermediate E or E’. The scenario of the reaction
between C and A is in analogy with that proposed by Knochel.10a,c
The addition of the alkynylide ion D to the iminium ions E/ E’ then
gives F/ F’, which, after work‐up, affords the propargylic amines 3.
In summary, we have demonstrated that the Ir‐catalysed
hydrosilylation of tert‐amides is compatible with the Cu(I)‐
catalysed alkynylation reaction. On the basis of this finding, we
have developed a mild, sequential catalysis method for the
direct reductive alkynylation of tert‐amides to give propargylic
amines.
R
3u - 3w
R
R1
R2
N
R3
or
R2
H
CuBr
R1
N
R3
3a - 3t
R2
F
R1
N
R3
CuBr
F'
Scheme 3. Plausible mechanism for the bis‐metallic Ir and Cu(I)‐
catalysed reductive alkynylation of tert‐amides.
The method is broad in scope allowing the employment of
aromatic as well as aliphatic tert‐amides with or without
hydrogen and bearing functional groups with diverse
electronic and steric properties. The method also shows
‐
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excellent 1,3‐asymmetric induction. The reaction exhibits
remarkable chemoselectivity at the least reactive amide group,
and is compatible with several sensitive functional groups such
as aldehyde, cyano, ester, and nitro groups on either the
amide or alkyne partners.
General procedure for the reductive alkynylation of amides.
Into
a
dried 10‐mL round‐bottom flask containing
IrCl(CO)(PPh3)2 (1 mol %, weighted in a glove box) were added
a toluene (5 mL) solution a tert‐amide (1.0 mmol) and TMDS
9
(1.2 mmol) or TMDS (2.0 mmol) (for amides with
at rt. After being stirred for 30 min (for amides without
hydrogen) or 10 min (for amides with ‐hydrogen), the
‐hydrogen)

‐

resulting solution and an alkyne (1.2 mmol) were added to a
suspension of CuBr (5 mol %) in toluene (3 mL). The mixture
was stirred for 12 h at rt, and concentrated under reduced
pressure. The residue was purified by flash chromatography on
10 For enantioselective alkynylation reactions, see: (a) C. Koradin,
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2535‐2538; (b) C. Wei and C.‐J. Li, J. Am. Chem. Soc., 2002, 124,
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silica gel to afford the corresponding propargylic amine 3.
The authors are grateful for financial support from the
National Natural Science Foundation of China (21332007), and
the Program for Changjiang Scholars and Innovative Research
Team in University (PCSIRT) of Ministry of Education, China.
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2
3
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