Isomerization of N-Allyl Amides to Form Geometrically Defined Di-, Tri-, and Tetrasubstituted Enamides

Article abstract of DOI:10.1021/jacs.7b00564

Enamides represent bioactive pharmacophores in various natural products, and have become increasingly common reagents for asymmetric incorporation of nitrogen functionality. Yet the synthesis of the requisite geometrically defined enamides remains problematic, especially for highly substituted and Z-enamides. Herein we wish to report a general atom economic method for the isomerization of a broad range of N-allyl amides to form Z-di-, tri-, and tetrasubstituted enamides with exceptional geometric selectivity. This report represents the first examples of a catalytic isomerization of N-allyl amides to form nonpropenyl disubstituted, tri- and tetrasubstituted enamides with excellent geometric control. Applications of these geometrically defined enamides toward the synthesis of cis vicinal amino alcohols and tetrasubstituted α-borylamido complexes are discussed.

Full text of DOI:10.1021/jacs.7b00564

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Article
Isomerization of N-Allyl Amides to Form Geometrically
Defined Di-, Tri-, and Tetrasubstituted Enamides.
Barry M. Trost, James J. Cregg, and Nicolas Quach
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.7b00564 • Publication Date (Web): 02 Mar 2017
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Isomerization of N-Allyl Amides to Form Geometrically Defined Di-,
Tri-, and Tetrasubstituted Enamides.
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Barry M. Trost*, James J. Cregg, Nicolas Quach
Department of Chemistry, Stanford University, Stanford, California, 94305-5080, United States
Supporting Information Placeholder
Structure-activity relationship (SAR) studies have demon-
strated the necessity of the enamide group, and of a specific
enamide geometry, for excellent potency. Both the E, and
less thermodynamically stable Z enamide isomers are wide-
ly represented within natural product scaffolds.
ABSTRACT: Enamides represent bioactive pharmacophores
in various natural products, and have become increasingly
common reagents for asymmetric incorporation of nitrogen
functionality. Yet the synthesis of the requisite geometri-
cally defined enamides remains problematic, especially for
highly substituted and Z-enamides. Herein we wish to re-
port a general atom economic method for the isomerization
of a broad range of N-allyl amides to form Z-di-, tri-, and
tetrasubstituted enamides with exceptional geometric selec-
tivity. This report represents the first examples of a catalyt-
ic isomerization of N-allyl amides to form non-propenyl
disubstituted, tri- and tetrasubstituted enamides with excel-
lent geometric control. Applications of these geometrically
defined enamides towards the synthesis of cis vicinal ami-
no alcohols and tetrasubstituted α-borylamido complexes
are discussed.
Traditional methods for the synthesis of enamides include
acylation of imines, Curtius rearrangement of unsaturated
acyl azides and condensation of amides with aldehydes.
Unfortunately, these methods often give poor yields, low
E:Z selectivities, and require harsh reaction conditions.10
Attractive alternatives have been developed, including the
metalation of ynamides11 and the hydroamidation of termi-
nal alkynes,12 however these methods currently lack broad
substrate scopes. Metalations generally require cyclic ter-
tiary amides or carbamates, which are difficult to remove,
and hydroamidations are limited to the synthesis of 1,2-
disubstituted enamides. For the total synthesis of complex
synthetic targets both methods have been largely overshad-
owed by the Cu and Pd catalyzed cross coupling of vinyl
halides and triflates with amides,13-16 which currently repre-
sents the most general protocol for the synthesis of geomet-
rically defined enamides. However, these couplings still
suffer from a number of limitations. The synthesis of the
requisite geometrically defined vinyl halides or triflates,
especially for highly substituted acyclic systems, is often
problematic.17 Furthermore, basic conditions, elevated tem-
peratures and an excess of one coupling partner are often
required.10 Other nucleophilic positions, such as free alco-
hols, primary amides, and phenols, are usually protected as
they can react competitively.8c Finally, additional cross
coupling handles, such as boronic esters or acids, as well as
vinyl or aryl halides and triflates are generally incompati-
ble.
INTRODUCTION: Enamides are stable, highly polarized,
electron rich double bonds that are excellent substrates for
incorporation of nitrogen functionality. They are commonly
utilized in asymmetric hydrogenations,1 cycloadditions,2
cyclopropanations,3 halo functionalizations,4 heterocycle
synthesis,5 carbonyl and imine additions,6 and transition
metal mediated C-C bond formations.7 In addition, en-
amides are important pharmacophores in various bioactive
natural products that display a range of anti-cancer, anti-
fungal, and cytotoxic properties (Figure 1).8-9
O
H
N
HO
HO
NH
O
O
OH
O
O
O
OH
HN
O
NH
CONH2
O
N
H
HN
O
O
HO
OH
O
NH
O
TMC-95A
Proteasome
inhibitor
Apicularen A
Anti-cancer
OH
O
The transition metal catalyzed isomerization of N-allyl
amides to enamides could provide an alternative, however,
it routinely gives modest to poor E:Z selectivities.18 This is
not surprising, as reports of highly selective metal cata-
lyzed isomerizations of any alkenes to give the thermody-
namically less stable Z isomers,19 as well as higher order
trisubstituted alkenes are rare.20 For enamides, there is a
single report of forming the thermodynamically less stable
Z-propenyl enamides selectively (>20:1 Z:E).21 However, it
Salicylihalamide A
Anti-cancer
O
O
O
OMe
OMe
NH2
NH
O
O
O
O
O
H
N
O
O
N
H
HN
PM060184
Anti-cancer (clinical trials)
O
Crocacin A
Antibacterial, cytotoxic, and anti-fungal
Figure 1: Bioactive Enamide Natural Products
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Journal of the American Chemical Society
Page 2 of 9
is limited to 4 examples with little functionality, and the Our interest in the Ru catalyzed isomerization of N-allyl
1
2
3
4
5
6
7
8
authors note that the isomerization is entirely Z selective in
“some” cases but do not comment on when this selectivity
is diminished. Additionally there are no reports of forming
higher order acyclic enamides, such as non propenyl, tri- or
tetrasubstituted enamides with exceptional geometric con-
trol through a metal catalyzed isomerization of N-allyl am-
ides. Herein we wish to report a remarkably general isom-
erization methodology for the synthesis of disubstituted
(including both propenyl and non propenyl), tri-, and
tetrasubstituted acyclic enamides with excellent geometric
selectivity. The methodology is completely atom economic,
displays excellent functional group tolerance, employs neu-
tral conditions, requires easily accessible N-allyl amides,
uses a commercially available catalyst, and can be run un-
der atmospheric conditions (Figure 2). The conserved spa-
tial orientation across all substitution patterns investigated
likely arises from using a highly unsaturated ruthenium
catalyst with three open coordination sites.22 Preliminary
evidence suggests that this unsaturation allows for amide
coordination to enhance both reactivity and selectivity. In
contrast, traditional isomerization methodologies towards
enamides, and olefins in general, have largely focused on
ligand design to create a steric bias for kinetic selectivities
in the product-determining step.18-20
amides was initiated when we observed an enamide isom-
erization byproduct during our examination of more reac-
tive disubstituted olefins in the alkene-alkyne coupling
reaction shown below (eq.1).23
O
O
6% CpRu(CH3CN)3PF6
NH
H
N
+
eq. 1
N
H
+
Acetone, 3h
O
Expected
Unexpected
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When an amide, instead of a carbamate-directing group,
was used, an enamide product formed competitively. While
the initial result was obtained in acetone we found DMF to
give the highest conversions and yields. The
CpRu(CH3CN)3PF6 catalyst was found to be differential for
this transformation. When we investigated substitution at
R1, we found the isomerization gave excellent geometric
selectivities (>20:1) in all cases (Table 1). We were excited
to see that vinyl boronic esters (2d,2e), and aryl halides
(2b) were tolerated, since they are functional groups that
would likely be reactive under Cu or Pd cross coupling
conditions. Tertiary amides (1g) were unreactive under
these conditions, only giving back starting material.
Table 1: Trisubstituted Enamides
O
O
6% CpRu(CH3CN)3PF6
R1
R1
N
H
R2
Metal Isomerizations of Allyl Amidesref. 18a
N
H
R2
DMF, rt 16h
1a-1f
O
M=Ru,
Rh, Ir,
Fe, Co,
Ni
2a-2f
O
[M] or [M-H]
Product (yield %)a,b
R1
N
Product (yield %)a,b
R1
N
Substrate
Substrate
R2
R2
O
Generally give poor E:Z selectivity
O
O
O
B
O
O
O
S
O
N
H
ArO2S
N
H
Single Reference for Z-Propenyl Enamidesref. 21
B
O
N
H
O
N
H
1a
F
2a 80%
Cl
1% [RuCl2(1,5-COD)]x,
1% 2,4-di-t-butylphenyl phosphite,
Cl
O
2e 78%
1e
O
Br
O
O
R1
N
R2
O
O
O
O
S
O
N
O
O
R1
N
10% CaH2, 80-110oC,THF or Dioxane
H
ArO2S
N
H
Ar
Only 4 examples
R2
N
H
O
N
H
1b
2b 75%
1f
2f 94%
NR
Previously Unknown Geometrically Selective Isomerizations:
NHCOR2
NHCOR2
NHBz
2c 89%c
NHBz
NHCOR2
NHCOR2
NBz
Allyl Amide
Enamide
R4
R1
1c
R1
R4
R1
R1
[M] or
[M-H]
R3
R3
1g
O
B
O
NHCOR2
R1
NHCOR1
NHCOR2
R1
NHCOR
B
O
O
NHBz
NHBz
2d 99%
R2
R4
R4
R1
R3
1d
R3
aOlefin Selectivity >20:1 by NMR. NOE effects were used to assign geometry
bYields are of isolated material. c12% Ru
Cp
This Work:
R1
H
Ru
O
R4
N
H
NHCOR1
NHCOR1
3-12% CpRu(CH3CN)3PF6
DMF, rt, 1-16h
R2
R3
R2
R4
R2
R4
We next examined whether monosubstituted terminal N-
allyl amides could be selectively isomerized under the
same conditions (Table 2). Gratifyingly they also reacted
with exceptional geometric selectivity to give the thermo-
dynamically less stable Z-enamides in excellent yields. In
these cases very minor peaks that may be attributed to the
minor trans isomer were visible, however the Z:E ratio in
these instances was still exceptional (>20:1). Additionally,
when the reaction was run in d7-DMF, it clearly showed
that the selectivity for the conversion of 3a to 4a was al-
ways excellent (>20:1), and that chromatography was not
leading to any enrichment of the Z:E ratio that could ac-
count for the excellent selectivities after purification (See
SI for Spectra). Subsequent optimization showed that for
this olefin substitution pattern, conversion of 3a to 4a was
>95% complete after 3h using only 3% catalyst.
Highly unsaturated
CpRu catalyst essential for
high selectivity
R3
R3
Amide and C-R4 are always Cis in product
Excellent Functional Group Tolerance
O
R
O
OH
OTBS
H
N
NHBoc
Including free
alcohols and cross
coupling handles!
OMe
RHN
N
H
O
R
O
O
O
O
HN
B
R
OTBS
R
OH
Br
Single Catalyst System gives Di-, Tri-, and Tetrasubstituted
Enamides (>20:1)
NHCOR1
NHCOR2
NHCOR
NHCOR1
CpRu(CH3CN)3PF6
NHCOR2
R2
R4
R4
R1
R1
R2
R4
R1
R3
R3
R3
First example of an isomerization of any acyclic olefin to form a tetrasubstituted
olefin with excellent geometric selectivity.
Figure 2: Isomerization of N-Allyl Amides
RESULTS AND DISCUSSION:
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Journal of the American Chemical Society
Z-propenyl enamides have been utilized as excellent sub-
isolated enamide 5b in excellent yield as a single olefin
isomer.
strates for a number of reported asymmetric reactions, 7,24a
however there synthesis remains difficult. There is a single
report of using Cu catalysis for the coupling of Z-propenyl
1
2
3
4
5
6
7
8
OH
O
HO
O
O
N
H
O
o
HN
O
TBSO
O
N
H
TBSO
O
N
H
bromide with amides but requires 24h at 100 C and gives
N
H
HO
12% CpRu(CH3CN)3PF6
DMF, rt 16h
NH
NH
CO2Me
5b 69%
only moderate yields.25 The base mediated isomerization of
allyl benzamide (3a) has been reported to give a 1:1 mix-
ture of E:Z isomers.24b The alternative hydroamidation of
terminal alkynes for the synthesis of Z-enamides has not
been applied to propenyl systems.11
HN
O
CONH2
eq. 2
CO2Me
O
BocHN
BocHN
NH
5a
O
TMC-95A
For the synthesis of non-propenyl Z-enamides we next ex-
amined whether 1,2 disubstituted N-allyl amides were ef-
fective substrates (Table 3). The isomerization of amides
6a and 6b gave enamides 6b and 7b with excellent Z-
selectivity (>20:1). Additionally, enamide 7b was formed
with excellent regioselectivity, as no isomerization towards
the silyl ether was detected. A number of Z-enamide natu-
ral products contain a hydroxyl group in the same spatial
orientation (Figure 1), and this is highlighted for natural the
natural product oximidine II (Table 3). The isomerization
of 6a and 7a represent the first reports of a metal catalyzed
isomerization of non-propenyl 1,2-disubstituted N-allyl
amides towards Z-enamides with excellent geometric selec-
tivity.
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Table 2: Disubstituted Propenyl Enamides
O
O
6% CpRu(CH3CN)3PF6
N
H
R1
N
H
R1
DMF, rt 16h
3a-3f
4a-4f
Product (yield %)a,b
Substrate
Substrate
Product (yield %)a,b
O
O
O
H
N
N
N
H
N
H
H
4a
80%, >95%c
>95%d
O
3b
3a
4b 99%
O
O
O
O
N
Br
N
H
N
H
N
H
H
3d
Br
4d 93%
3c
4c 89%
O
O
N
H
NHBoc
N
H
NHBoc
3e
4e 74%
Table 3: Disubstituted Non-Propenyl Enamides
O
O
X% CpRu(CH3CN)3PF6
aOlefin Selectivity >20:1 by NMR. NOE effects were used to assign geometry
bYields are of isolated material. c6% catalyst NMR conversion after 1h,
d3% catalyst NMR conversion after 3h
N
H
R1
N
H
R1
DMF, rt 16h
R2
6b-7b
6a-7a
R2
Substrate
X %
Product (yield %)a,b
O
O
When we examined the isomerization of terminal allyl
Boc-amine 3g we found that it gave a lower conversion (70
%), and surprisingly gave a modest selectivity for the E
isomer (5:1 E:Z) (Figure 3). Interested in finding an alter-
native amide group that may serve as an easily cleavable
protecting group, we next examined formamide 3h. Grati-
fyingly isomerization of 3h gave enamide 4h in excellent
yield and with ~19:1 (Z:E) geometric selectivity. The
formamide group is a useful amine protecting group, as
N
H
N
H
10%
OH
6a
6b 90%
O
O
NOCH3
O
HN
O
O
N
H
Oximidine II
OH
N
H
10%
TBSO
7a
TBSO
7b 55%
aOlefin Selectivity >20:1 by NMR.. NOE effects were used to assign geometry
bYields are of isolated material.
Next, we examined whether branching at the allyl position
was tolerated (Table 4). The branched N-allyl amide 8a
isomerized to the stereodefined enamide 9a in excellent
yield and as a single isomer. No protection of the resultant
allylic alcohol was necessary, and no additional isomeriza-
tion towards the free alcohol to form an aldehyde was ob-
served. Alanine was chosen as the amide group, as similar
enamide motifs are present in a number of natural products
including the antibiotic A-3302-A (Table 4).27 This result
illustrated that substitution at all three positions of the allyl
are tolerated. Therefore we next attempted the isomeriza-
tion of amides 8b and 8c (Table 4), which simultaneously
contained branching and an additional olefin substitution.
well as
a
stable precursor to isocyanates and
formamidines.26 Vinyl-formamides are an important subu-
nit in a number of bioactive natural products (Figure 3).
Boc-protected amines are less reactive and give modest E selectivity
O
O
10% CpRu(CH3CN)3PF6
DMF, rt 16h
70% conversion
~5:1 E:Z
N
H
O
N
H
O
3g
4g
But N-formyl is highly reactive and Z selective
O
O
3% CpRu(CH3CN)3PF6
Useful prtoecting group foramines
H
>95% conversion, ~19:1 Z:E
N
H
N
H
H
DMF, rt 3h
4h
3h
O
NC
OH
OH
H
N
R
O
H
NH
O
O
Melanocin A
9 nm vs. B16 melanoma cells
Mycalolide B
actin polymerization inhibitor
(IC50=10-50 nM)
Figure 3: Formamide Directing Groups
In order to further display the utility of this process and
highlight its functional group tolerance, we synthesized
dipeptide 5a containing the functional motif seen in TMC-
95A (Figure 1)(eq. 2).8 Gratifyingly after isomerization we
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Page 4 of 9
dicylohexylborane.32 We were especially pleased to find
that no protection of the free N-H was required, suggesting
that transmetalation of Cy2BNR2 with HBpin is facile.
Table 4: Additional Substitution Patterns
R4
R4
R5
O
O
1
2
R3
R2
X% CpRu(CH3CN)3PF6
DMF, rt 16h
R3
R2
N
H
R1
N
R1
H
9a-9d
R5
8a-8d
3
4
5
6
7
8
9
X %
12%
Product (yield %)a,b
Substrate
However, our initial attempts to isomerize 10a proved dif-
ficult. The problem appeared to arise from the instability of
the product, and crude NMR spectra after aqueous extrac-
tion suggested protodeborylation might be the culprit. Sur-
prisingly when we monitored the isomerization reaction by
NMR, the process was almost complete within 1h to give
enamide 10b. However there was ~10% of enamide 4a
from protodeborylation (Figure 5). NOE experiments of the
crude solution indicated that the only isomer formed was
the Z-enamide 10b. Next we examined the isomerization of
N-allyl amide 11a, and once again, the reaction was com-
plete within 1h to give a single isomer (Figure 5). In this
case no protodeborylation of enamide 11b was observed.
Finally, we examined the isomerization of N-allyl amide
12a (Figure 5). The reaction was once again complete with-
in 1h, highlighting the exceptional rate enhancement in
reactivity afforded by the terminal pinacol ester.33 However,
NMR analysis indicated ~75% protodeborylation after 1h,
HO
HO
O
O
NHR
H
N
NHBoc
OtBu
O
N
H
N
H
O
O
O
HN
HN
8a
9a 76%
O
NH
O
O
O
N
H
N
H
10%
Antibiotic A-3302-A
8b
9b 72%
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
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O
O
Geometrically Selective
Isomerizaiton to form a
Tetrasubstituted Olefin!
N
N
H
10%
12%
H
8c
9c, 88%
O
N
H
NR
8d
aOlefin Selectivity >20:1 by NMR. NOE effects were used to assign geometry
bYields are of isolated material.
Enamides 9b and 9c were both formed with excellent geo-
metric selectivity (>20:1) and in high yield. Product 9c
represents the first example of forming a geometrically
defined tetrasubstituted enamide through an isomerization
process. The synthesis of the analogues geometrically de-
fined vinyl halide or triflate necessary for cross coupling
would be especially daunting.28 To the best of our
knowledge this isomerization also represents the first ex-
ample of any olefin isomerization to form an acyclic
tetrasubstituted olefin in a geometrically defined fashion.
β,β-disubstituted N-allyl amides (8d) were unreactive un-
der these reaction conditions.
o
so we subsequently heated the reaction at 80 C for 20
minutes to complete the protodeborylation process, provid-
ing tetrasubstituted enamide 12b in excellent isolated yield
and as a single geometrical isomer.
Di-
3% CpRu(CH3CN)3PF6
4 Å mol molecular sieves
1h, rt, DMF,
NHBz
NHBz
NHBz
+
(10:1)(10b:4a)
PinB
PinB
10a
4a
10b >20:1 (Z:E)
88% conversion
Tri-
PinB
PinB
PinB
PinB
6% CpRu(CH3CN)3PF6
NHBz
NHBz
11a
No observed
proteodeborylation
Allyl boron compounds have been extensively studied as
reagents in organic synthesis. They readily undergo stereo-
specific allylations of aldehdyes,29 and can be utilized as
coupling partners in various C-C bond forming reactions.30
Thus, we became interested in exploring whether substrates
bearing terminal alkenyl boronates could be isomerized
effectively and with excellent geometric selectivity. We
envisioned rapid access to the necessary staring materials
by hydroboration and diborylation of propargyl amides
(Figure 4). This, in addition, to the already demonstrated β-
borylation31 to give 1d and 1e, would provide all three vi-
nyl boronate starting materials in a single step from com-
mercial or easily prepared starting materials.
1h, rt, DMF
>95% conversion
11b, >20:1 (Z:E)
Tetrasubstituted
C5H11
(3:1)(12b:12c) after 1h rt
C5H11
C5H11
PinB
6% CpRu(CH3CN)3PF6
PinB
PinB
NHBz (>20:1)(12b:12c) after
NHBz
12b
NHBz
+
heating to 80 oC.
85% isolated yield 12b
>20:1 (Z:E)
1h, rt, DMF
>95% conversion
PinB
PinB
12c
12a
Figure 5: Isomerization of Vinyl Boronates
Although various γ-substituted allyl boronates have been
utilized as allylating reagents,34 there are only 2 reports of
synthesizing or using acyclic E-(γ-amidoallyl) boron com-
pounds,35,36 and no reports of synthesizing the acyclic Z-(γ-
amidoallyl) boronate or borane (Figure 6). 37 Thus, we were
especially interested in utilizing enamides 10b and 11b as
allylating reagents. The addition of benzaldehyde to the
crude reaction mixture of 10b in DMF, followed by heating
at 70 oC over 16h gave moderate conversion to amino alco-
hol 10c with >20:1 dr. However we were disappointed with
the observed protodeborylation of compound 10b under the
standard conditions. Thus, we examined whether less polar
solvents were amenable to the isomerization process. We
hoped that they would result in less protodeborylation, as
well as provide greater reactivity in the allylboration step.
Gratifyingly 5 equivalents of DMF relative to substrate in
DCM gave a clean isomerization and suppressed proto-
deborylation to minimal levels, allowing for allylation at a
lower temperature and with improved yield (>20:1 dr.)
(Figure 6).38 DMF may act as a ligand to stabilize and turn-
over the catalyst, since the enamide products likely serve as
R
NHCOR
O
10% Cy2BH, HBpin
cat CuCl, NaOtBu,
cat HPtBu3BF
PinB
NHBz
N
R
neat, rt, 1h
92% yield
H
1.2 equiv. MeOH,
PinBBPin
PinB
10a
1d-1e
commercially available
or easily prepared
0 oC-rt, 1.5h
see Table 1
cat Pt(PPh3
PinBBPin
)
4
DMF 70 o
4h-on
C
R
PinB
PinB
NHCOR
11a, 12a
Figure 4: Vinyl Boronates Substrate Synthesis
Gratifyingly, we found that the starting vinyl boronate 10a
could be synthesized in near quantitate yield by the reaction
of propargyl amide with neat pinacol borane and catalytic
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Journal of the American Chemical Society
good ligands. Next we attempted the addition of aldehyde There are few examples of non-metal catalyzed heteroatom
directed hydroborations using BR2H regents.41-42 Therefore,
the exceptional selectivity observed for the hydroboration
of 9c with BH3 as compared to all other examples with en-
amides, is noteworthy. Further studies will hopefully eluci-
date additional mechanistic details and may lead to a gen-
eral α-selective hydroboration of enamides resulting in
highly valuable α-boryl amido complexes.
1
2
3
4
5
6
7
8
to the crude solution of trisubstituted enamide 11b in DMF,
followed by heating at 70 C over 16h. The reaction gave
very clean conversion to give cis amino alcohol 11c with
>20:1 dr.
o
OH
O
R2B
NR1R2
R2
NR1R2
H
R2
O
Unknown
then:
This work:
9
The amidoborane product (14b) exhibited unusual stability,
which likely arises from chelation of the amide group to
form a stable tetravalent borane.43-44 Analogous tetravalent
amino carboxy and cyano boranes have been extensively
investigated as isoelectronic analogs of protonated amino
acids. They show diverse biological properties, including
antitumor, antiosteoporotic, anti-inflammatory, and hypoli-
pidemic activities.45 However, examples of hydrolytically
stable amide chelated boranes have been largely unex-
plored. Given the increasing interest in α-borylamides46 we
attempted to convert the borane 14b into a boronate ester.
Amidoborane 14b was easily converted to the catechol
ester 15 by heating in the presence of excess catechol in
toluene (Figure 7). The α-borylamide motif has been
shown to interact with serine residues to form tetravalent
boronates that mimic the transition state structures ob-
served during proteasome activity. The α-boryldipeptide
bortezomib was the first proteasome inhibitor to be tested
in humans and is marketed for use against multiple myelo-
ma and mantle cell lymphoma. Synthetically, α-
borylamides also display differential, and oftentimes en-
hanced, reactivity for metal catalyzed cross coupling reac-
tions.47
OH
Ph
H
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
6% CpRu(CH3CN)3PF6
73% yield
>20:1 dr
PinB
NHBz
NHBz
10a
48 h, 30 o
C
DCM (0.2M)
5 equiv. DMF
10c
then:
O
O
Trisubstituted allylation reagent:
NHBz
PinB
PinB
6% CpRu(CH3CN)3PF6
1h, rt, DMF
O
59% yield
CO2Et
>20:1 dr
NHBz
11a
PinB
16h, 70 o C, DMF
OH
11c
Figure 6: One-Pot Allylation
No protodeborylation of enamide 11b was observed under
the isomerization or allylation conditions. The lower yield
is due to the instability of the product 11c to purification.
HYDROBORATION OF TETRASUBSTITUTED EN-
AMIDE:
The synthesis of tetrasubstituted acyclic enamides is rare,
and therefore there is little information on their reactivity
under standard synthetic transformations such as hydrobo-
ration. Given that we could easily synthesize tetrasubstitut-
ed enamide 9c, we attempted the hydroboration of 9c ex-
pecting to get the amino alcohol 14a (Figure 7). The highly
polarized nature of enamides has traditionally resulted in
excellent selectivity for the β position irrespective of the
enamide substituent pattern.39 However, we were surprised
to find that, under traditional hydroboration conditions, we
instead formed the product from α addition to give the α-
borylamido complex 14b. Mechanistically the reversal in
selectivity may arise from the increased A1,3 strain experi-
enced for tetrasubstituted enamides.40 To minimize strain,
rotation of the Cvinyl-N bond could lead to intramolecular
delivery of borane through coordination with the amide
oxygen becoming faster than intermolecular addition of the
borane to the tetrasubstituted enamide.
MECHANISTIC PROPOSAL:
The conserved spatial orientation of the original olefin and
amide across all substrates examined suggests an isomeri-
zation mechanism involving a chelation controlled C-H
activation. When we added 1 catalyst equivalent of PPh3 to
our standard conditions we obtained a ~1:1 E:Z mixture of
enamide isomers for the isomerization of allyl benzamide
3a. Additionally work by Grotjahn using a hemilabile bi-
dentate ligand is reported to give the E isomer as the only
product.18b This suggests the selectivity in our case requires
three open coordination sites on the CpRu catalyst. The
precatalyst CpRu(CH3CN)3PF6 rapidly loses the acetoni-
trile ligands upon solvation and readily forms complexes
with alkenes.22 Simultaneous coordination of the amide and
olefin to the highly unsaturated Ru catalyst (I) followed by
C-H abstraction to give intermediate II is likely the prod-
uct-determining step (Figure 8). Reductive elimination
forms enamide III and subsequent ligand exchange with
additional N-allyl amide V gives the desired enamide IV.
H
O
O
O
H
B
1) 3 equiv. BH3THF
THF, 0 ˚C-rt, 2h
N
H
N
H
N
H
HO
14a
9c
2) NaOH, H2O2, rt, 30 mins
14b
Expected:
Not Observed
89% yield
H
Amine Carboxy and Cyano Boranes
Stable to silica gel chromatography.
Stable to NaOH, H2O2
11B shift 4.34 ppm(CDCl3) characteristic of
tetracoordinate boron.
O
H
B
H
H
H
H
N
H
B
OR
B
R3
N
R3N
N
O
Strong B-H IR stretches (2250-2400 cm-1
)
14b
antitumor, antiosteoporotic, anti-inflammatory,
and hypolipidemic properties
O
H
O
X equiv. catechol
B
O
H
B
O
O
OH
B
H
N
N
Toluene, rt-80 o
C
N
H
H
N
H
OH
15
17.66 ppm 11B (Toluene)
10 equiv. 100% conversion 5 mins
2 equiv. >90% conversion, 5h
O
14b
5.35 ppm 11B (Toluene)
Bortezomib
proteasome inhibitor
approved for multiple myeloma
Figure 7: Hydroboration of tetrasubstituted enamide to
form α-borylamido complex
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Page 6 of 9
R
O
O
Proposed Mechanism:
R
CpRu(CH3CN)3PF6
H
N
Cp
Ru
R
R
R
R
R
N
H
R
1
2
3
4
5
6
7
8
NCCH3
H3CCN
B
Opposite Spatial
Orientation of
Enamide
NCCH3
O
A
+ V
-3 CH3CN
O
CpRu(CH3CN)3PF6
R
R
N
H
R
N
H
R
Cp
H
Ru
O
R4
A
NHCOR4
R1
N
C
H
R3
R2
R1
R3
I
If Alkene-Alkyne coupling proceded via C-H activation to form Ru-allyl:
O
R2
V
O
R
R
H
N
H
R
Cp
R
R
NHCOR
Ru
N
H
R
4
carbometalation
R
R
RE
NHCOR4
O
R
R
Ru
Cp
N
R
R3
L
D
H
R1
R3
R2
Ru
9
R
R
II
H
2L
R2
Cp
Cp
IV
I
NHCOR4
R3
Ru
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Never Observed
II
R1
R2
III
L=ligand
Figure 9: Additional Mechanistic Consideration
CONCLUSION:
H
H
NCOR4
R3
CH3 NCOR
See 1g
See 8d
R
R
R3
R2
VI
VII
R2
Methyl Substitution on N or Cis in orginal olefin
leads to complete lack of reactivity
In summary, we have reported a general method for the
synthesis of geometrically defined di-, tri-, and tetrasubsti-
tuted enamides. The starting olefin substation pattern de-
termines the resultant enamide geometry. The breadth of
starting olefin substitution patterns that are reactive, includ-
ing 1,1-disubstituted (Table 1), monosubstituted (Table 2),
1,2-disubstituted (Table 3), branching (Table 4), 1,1,2-
trisubstituted (Figure 5), and 1,1,2-trisubstitued with
branching (Figure 5), is remarkable. The reactivity and
geometric selectivity that is observed likely arises from the
role of chelation in the mechanism to both control the ge-
ometry and improve the reactivity. In this regard the highly
unsaturated precatalyst CpRu(CH3CN)3PF6 was found to be
differential. The method displays exceptional chemoselec-
tivity, as demonstrated by the large number of functional
groups that are compatible, including aryl halides, free al-
cohols, and boronic esters. These functionalities would be
difficult to incorporate using Cu catalyzed cross couplings
towards enamides. Additionally, other alkene functionali-
ties (Figure 8, 16 and 17)(3d, Table 2), which could pose
difficulties for other metal catalyzed isomerizations, are
tolerated. The isomerization of vinyl boronates (10a and
11a, Figure 6) provides rapid access to Z-enamide allylat-
ing regents for forming cis vicinal amino alcohols. Addi-
tionally, an unusual regioselectivity for hydroboration of
enamides has been observed, and represents a novel route
to α-borylamides. We believe this method should provide a
complementary approach to Cu and Pd catalyzed C-N cou-
plings towards geometrically defined enamides and pro-
vides the desired products with much greater atom econo-
my.
Competition Experiments:
NHBz
3a
1 equiv
4a
NHBz
10% CpRu(CH3CN)3PF6
16
NHBz
16
3a
NHBz
:
DMF, rt , 1h
NHBz
1 equiv
1
0.82
< 0.05
17
3a
4a
NHBz
1 equiv
1 equiv
OH
10% CpRu(CH3CN)3PF6
DMF, rt , 1h
NHBz
NHBz
3a
17
O
OH
<0.05
1
:
0.86
:
O
Figure 8: Mechanistic Proposal
When methyl is substituted for the N-H (VI)(see 1g, Table
1), or cis to the N-allyl amide (VII)(see 8d, Table 4) the
reaction produces no product. This supports the proposed
mechanism, since both substitutions would lead to addi-
tional A1,3-strain in the proposed π-allyl intermediate. The
importance of both coordination of the amide and double
activation of the C-H (allylic and α to the amide) is sup-
ported by competition experiments between allyl ben-
zamide 3a and either 16 or 17. Terminal alkenes 16 and 17
both contain chelating groups which could provide access
to chelate structures similar to proposed intermediate I,
however, do not contain a doubly activated C-H. In both
cases conversion of N-allyl amide 3a to enamide 4a was
complete within an hour, while both 16 and 17 remained
almost completely unreacted. Finally, the lack of reactivity
associated with allyl silyl ethers, which also contain a dou-
bly activated C-H, but not the same chelating ability, again
supports the requirement for both chelate structure I and a
doubly activated C-H.
Interestingly, the enamide geometry observed from the
alkene-alkyne coupling (B) (Figure 9), compared to that
obtained through the isomerization process (C), supports
the assertion that in the case of the alkene-alkyne coupling
a ruthenacyclopentene intermediate is operative.23 An alter-
native mechanism involving a C-H activation to give in-
termediate I, followed by carbometalation II, and reductive
elimination, would be expected to give product D, which
has never been observed. This suggests that when an al-
kyne is present, the observed products B and C arise from
two different mechanistic pathways.
ASSOCIATED CONTENT
Supporting Information. Experimental details, compound
characterization data, and spectra. This material is available
free of charge via http://pubs.acs.org
AUTHOR INFORMATION
Corresponding Author
bmtrost@stanford.edu
Notes
The authors declare no competing financial interest.
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Journal of the American Chemical Society
52. This paper describes the isomerization of tertiary N-allyl am-
ACKNOWLEDGMENT
1
2
3
4
5
6
7
8
ides to enamides, providing enamides with generally modest E:Z
selectivities from 95:5 to 20:80. There is a single example that
reports 0:100 E:Z (compound 2d), however the compound is not
reported in the experimental and we were unable to find any addi-
tional experimental information.
22. CH3CN ligands are readily displaced providing highly unsatu-
rated catalyst upon solvation. For review see: Trost, B. M.; Fred-
eriksen, M. U.; Rudd, M. T. Angew. Chem. Int. Ed. 2005, 44,
6630–6666.
23 Trost, B. M.; Cregg, J. J. J. Am. Chem. Soc. 2015, 137, 620–
623.
24. (a) Hashimoto, T.; Nakatsu, H.; Takiguchi, Y.; Maruoka, K. J.
Am. Chem. Soc. 2013, 135, 16010–16013. (b) For the synthesis of
the enamide see: Fisher, L. E.; Muchowski, J. M.; Clark, R. D. J.
Org. Chem. 1992, 57, 2700.
25. Min, G. K.; Skrydstrup, T. J. Org. Chem. 2012, 77, 5894–
5906.
26. (a) Tu, S.; Zhang, C. Org. Process Res. Dev. 2015, 19, 2045–
2049. (b) Lei, M.; Ma, L.; Hu, L. Tetrahedron Lett. 2010, 51,
4186–4188.
27. Lin, Z.; Schmidt E. W. J. Med. Chem. 2011, 54, 3746–3755.
28. In this case methyl vs. ethyl would need to be differentiated.
Attempting to differentiate benzyl from phenyl for the synthesis
of tetrasubstituted vinyl triflates has been shown. However it is
extremely sensitive to electronics of the aromatic ring. D. J. Wal-
lace; Campos K. R.; Shultz C. S.; Spindler F. Org. Process Res.
Dev., 2009, 13, 84–90.
We thank the NIH (GM-033049) and the NSF (NSF CHE-
1360634) for their generous support of our programs.
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O
O
12% CpRu(CH3CN)3PF6
HN
HN
DMF, rt, 16h
13
~30% conversion
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NHCOR1
R4
NHCOR1
R2 R4
NHCOR2
R1
NHCOR
3%-12% CpRu(CH3CN)3PF6
DMF, rt 1-16h
NHCOR2
R1
1
2
3
4
5
6
R2
R4
R1
R3
R3
R3
Single Catalyst System gives Di-, Tri-, and Tetrasubstituted Enamides (>20:1)
Useful Products:
H
H
B
O
R
OH
6% CpRu(CH3CN)3PF6
3 equiv. BH3THF
NHBz
Ph
PinB
NHBz
R
N
H
then:
O
R
NHBz
59-73% >20:1 d.r.
89%
H
R
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