Scalable synthesis of enaminones utilizing Gold's reagents

Article abstract of DOI:10.1016/j.tet.2017.03.092

Several Gold's reagents were synthesized from cyanuric chloride and N,N-dialkylformamides. These synthetic equivalents of N,N-dimethylformamide dimethyl acetal were used in an optimized and scalable procedure for the regioselective synthesis of a variety

Full text of DOI:10.1016/j.tet.2017.03.092

Accepted Manuscript
Scalable synthesis of enaminones utilizing Gold's reagents
Alexander W. Schuppe, James M. Cabrera, Catherine L.B. McGeoch, Timothy R.
Newhouse
PII:
S0040-4020(17)30358-7
10.1016/j.tet.2017.03.092
TET 28598
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 16 February 2017
Revised Date: 27 March 2017
Accepted Date: 31 March 2017
Please cite this article as: Schuppe AW, Cabrera JM, McGeoch CLB, Newhouse TR, Scalable synthesis
of enaminones utilizing Gold's reagents, Tetrahedron (2017), doi: 10.1016/j.tet.2017.03.092.
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Scalable synthesis of enaminones utilizing Gold’s reagents
Alexander W. Schuppea, James M. Cabreraa, Catherine L. B. McGeocha, and Timothy R. Newhousea*
aDepartment of Chemistry, Yale University, 275 Prospect Street, New Haven, Connecticut 06520-8107, United
States

ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
Scalable synthesis of enaminones utilizing Gold’s reagents
Alexander W. Schuppea, James M. Cabreraa, Catherine L. B. McGeocha, and Timothy R. Newhousea*
a Department of Chemistry, Yale University, 275 Prospect Street, New Haven, Connecticut 06520-8107, United States
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Several Gold’s reagents were synthesized from cyanuric chloride and N,N-dialkylformamides.
These synthetic equivalents of N,N-dimethylformamide-dimethyl acetal were used in an
optimized and scalable procedure for the regioselective synthesis of a variety of enaminones
from ketone starting materials, whose utility was demonstrated by the stereoselective synthesis
of Rawal-type dienes.
Available online
2009 Elsevier Ltd. All rights reserved
.
Keywords:
Enaminones;
Rawal Diene;
Diels-Alder
1. Introduction
Fig. 1. Enaminone formation from ketones by multiple approaches
The use of dienes with electron-donating groups in the Diels-
Alder reaction leads to increased rates of reaction, thus allowing
for more mild reaction conditions and broader functional group
compatibility.1 In particular, Danishefsky- and Rawal-type
dienes,2-3 which possess two constructively oriented electron-
donating groups, have been widely used in natural product
synthesis.4-5 This is because of their ease of preparation,
increased reactivity toward thermal cycloadditions, and the utility
of the oxidation states introduced as the heteroatom substituents.
2-3 Both of these types of dienes have been conveniently prepared
by enolization and trapping of a β-substituted enone – a
methoxy-enone in the case of Danishefsky dienes and an
enaminone for Rawal dienes.2-3
a) Common reagents result in mixtures of isomers
NMe2
O
O
MeO
OMe
O
Me
Me
2
Me
Me
Me
or
Me2N
OtBu
NMe2
Me2N
4a
Me2N
1a
4b
3
b) Stepwise synthesis by methoxy enone diversification
O
i. (OMe)3CH, BF3 OEt2,
O
Enaminones, which are also powerful building blocks for
heterocycle formation and Michael addition-elimination
reactions,6-10 are usually accessed through functionalization of a
ketone directly with N,N-dimethylformamide dimethyl acetal (2,
DMF-DMA)11 or Bredereck’s reagent (3)12 as shown in Figure
1a. While this approach is simple and direct, it can lead to non-
selective enolization and thus constitutional isomeric products
wherein the two different ketone α-positions have been
functionalized (e.g. 4a and 4b). This problem has been
circumvented through stepwise enone formation via β-
elimination of an acetal formed from trimethylorthoformate,
followed by addition-elimination with dimethylamine (Figure
1b).13 It is noteworthy that this latter approach allows for the
synthesis of a wide variety
Me
i-Pr2NEt
Me
Me
ii. NaOAc
iii. Me2NH
1a
Me2N
4b
c) Direct, selective enaminone formation utilizing Gold's reagents
O
O
t-BuOLi
R
R
R
R
Cl
R'
R'
R'
1
N
N
N
5
N
R'
R'
R'
4
>90 g per batch
of β-amino substituted enones from a single β-methoxy enone
precursor.
Corresponding author. Tel.: +1-203-432-8316; fax: +1-203-
432-4900; e-mail: timothy.newhouse@yale.edu
During the course of a total synthesis of andirolide N,14 we
examined these conventional approaches for enaminone synthesis

2
Tetrahedron
and ultimately found the most scalable approach utilized the
equivalents of CO2 are produced, and thus caution should be
ACCEPTED MANUSCRIPT
aminomethylene electrophile equivalent (5), known as Gold’s
reagent.15-17 This approach allowed for the direct regio- and
diastereoselective functionalization of 2-butanone using Gold’s
reagent, a bench stable reagent which can be prepared in a single
step and purified by recrystallization.17 The straightforward
preparation of this valuable equivalent to DMF-DMA employs
inexpensive cyanuric chloride and DMF. In this report we
describe the synthesis of a small library of sterically and
electronically varied Gold’s reagents using readily available
formamides, and investigate their utility in enaminone synthesis.
exercised when this reaction is performed on large scale.
Careful control of the temperature was critical for minimizing
byproduct formation during the exothermic release of CO2.
Concomitant with the release of CO2 was a distinct change in
color of the reaction mixture to a dark red or brown, occurring at
a different temperature for each substrate. As a precaution, a
modified protocol involving a double-walled reflux condenser
and an oil-bubbler outlet was employed (see Supplementary
Materials) for the scalable synthesis of the parent methyl-
substituted Gold’s reagent (5a). While this procedure was
successful on a 50-gram scale to provide 120 g of 5a in 97%
yield, further optimization is likely necessary for larger scale
preparations due to the exotherm and gas release.
2. Results and discussion
2.1. Synthesis of a library of Gold’s reagents
In order to expand the synthetic utility of Gold’s reagents,
Using this protocol, a number of Gold’s reagents could be
prepared, as depicted in Scheme 1. Ethyl substitution on the
formamide yielded the corresponding ethyl Gold’s reagent (5b)
in 63% yield. Activated alkyl substituents, such as allyl (5c) and
benzyl (5d), were also tolerated in the synthesis of the
corresponding Gold’s reagents in 69% and 47% yield,
respectively. The synthesis of several reagents derived from
cyclic formamides proceeded well: pyrrolidine (5e), piperidine
(5f), morpholine (5g), and indoline (5h) Gold’s reagents were
synthesized in 74-91% yield. In order to observe complete
conversion for some of the more challenging substrates (5c, 5d,
5e, and 5g), fewer equivalents of the formamide were used
relative to cyanuric chloride. Purification of the Gold’s reagents
could be readily performed by simple trituration with
combinations of ethereal and hydrocarbon solvents.
various
[3-(dialkylamino)-2-azaprop-2-en-1-
ylidene]dialkylammonium chloride salts (5) were synthesized, in
addition to the one known tetramethyl analog (5a).17 The
synthesis of these reagents proceeded smoothly by heating one
equivalent of cyanuric chloride (6) and six equivalents of N,N-
dialkylformamide, either neat or using 1,4-dioxane as
Scheme 1. Formation of Gold’s reagents using formamides a-d
R
Cl
N
Cl
Cl
N
R
R
OHC
R
N
N
N
N
N
R
(6 equiv)
R
Cl
6
-CO2
∆
5
(1 equiv)
(3 equiv)
2.2. Development of optimized conditions for the
transformation of ketones to enaminones
Cl
Cl
Me
N
Me
Et
Et
N
N
N
N
N
With a library of novel Gold’s reagents in hand, we turned to
optimization of the conditions for enaminone formation (Table
1). Previous conditions described by Gupton and co-workers16a
employed using the newly synthesized Gold’s reagents were
ineffective, thus alternative reaction conditions were examined.
Optimization efforts focused on variation of the base employed
along with modification of solvent and temperature (Table 1).
Me
Me
Et
Et
5a
5b
(63%)b
(97%)b
50 g scale
Cl
Cl
Bn
Bn
Table 1. Optimization of enaminone formationa
N
N
N
N
N
N
Bn
Bn
Cl
(1.1 equiv)
5c
(69%)c
5d
(47%)d
Et
Et
O
O
N
N
N
Et
Et
Cl
Me
Cl
5b
Et
Base (1.1 equiv)
23 → 60 ºC
12 h
N
N
N
N
N
N
N
Et
1b
4c
5e
(82%)b,d
5f
(85%)
% Yielda
Entry
Base
Solvent
1
2
3
4
5
6
MeONa
i-PrONa
t-BuONa
t-BuONa
t-BuOK
t-BuOLi
1
MeOH
i-PrOH
t-BuOH
THF
THF
THF
<5
29
0
24
<5
96
Cl
Cl
N
N
N
N
N
N
O
O
a
Yield determined by H-NMR analysis after aqueous work-up using 1,3,5-
5g
(91%)b,c
5h
(74%)
trimethoxybenzene as an internal standard.
aIsolated yield b1,4-dioxane was used as solvent (4 M) c3 equiv of formamide
was used d4 equiv of formamide was used.
When the previously described conditions using NaOMe in
MeOH16a or NaO-i-Pr in i-PrOH15 were employed for the
transformation of 1b to 4c, modest yields up to 29% were
observed (Entries 1 and 2). Alteration of the alkoxide base to
NaO-t-Bu in t-BuOH did not result in product formation (Entry
3). Use of THF as solvent resulted in an improved yield (Entry
solvent (5a, 5b, 5e, and 5g), to produce three equivalents of the
corresponding Gold’s reagent (5, Scheme 1). It should be noted
that during the course of this exothermic reaction three

4), and it was found that the optimal counterion of the tert-
DMA.17 Derivatization of commercially available terpene
compounds, dihydro-β-ionone and geranylacetone, with Gold’s
reagent (5h and 5f respectively) led to regioselective formation of
the heterocyclic enaminones 4k and 4l at the less hindered
primary position in 56% and 62% yield. Functionalization of γ-
butyrolactone with 5g resulted in the synthesis of the
morpholine-derived enaminone (4m) in 74% yield.
ACCEPTED MANUSCRIPT
butoxide base was lithium (Entry 6), which resulted in formation
of the product 4c in 96% yield. Metal amide bases (LiHMDS,
NaHMDS, KHMDS, LDA, and LiTMP) were also investigated
but led to only modest yields of enaminone 4c.
2.3. Substrate scope of the formation of enaminones with
Gold’s reagents
In order to demonstrate the scalability of the newly developed
reaction conditions, we applied them in the synthesis of
enaminone 4b, which was required for the total synthesis of
andirolide N. Reaction of 2-butanone (1a) and 5a on 1-mole
scale provided enaminone 4b in 73% yield after vacuum
distillation (Scheme 2B), which is a notable improvement over
the previously reported yield of 48%.14 The modified procedure
additionally replaced the alcoholic solvent used in reaction
workup with diethyl ether to allow for a facile extractive isolation
and recovery of product.
After the reaction conditions for enaminone formation had
been optimized with acetophenone, the generality of these
conditions was probed by testing the library of Gold’s reagents
(Scheme 2A). By using acetophenone to directly compare the
efficiency of enaminone formation with various Gold’s reagents,
it was found that the corresponding enaminones were prepared
(4c-4i) with similar efficiencies.
Scheme 2. Substrate scope of enaminone formationa
(1.1 equiv)
Cl
R3
2.4. Diastereoselective Rawal diene synthesis
R3
N
N
N
As a demonstration of the utility of enaminones, the substrate
4b was converted to the diastereomeric Rawal-type dienes 7a and
7b as shown in Table 2. While not previously examined in detail,
R3
R3
O
O
R1
5
R1
R2
R2
19-20
t-BuOLi (1.1 equiv)
R3
we hypothesized that the identities of the amide base and
23 → 60 ºC
THF (73%)
N
additives used would be crucial for controlling enoxysilane
geometry.21 Indeed, 7a and 7b could be formed
diastereoselectively through simply modifying these parameters.
1
4
R3
4c R3= Et (88%)
4d R3= allyl (65%)
4e R3= Bn (87%)
4f R3= pyrrolidine (88%)
4g R3= piperidine (75%)
4h R3= morpholine (84%)
4i R3= indoline (78%)
A.
O
Table 2. Diastereoselective Rawal diene synthesisa-e
Me
R3
O
TIPSO
TIPSO
N
Me
Me
R3
Base (1.1 equiv)
+
4c-i
TIPSCl (1.1 equiv)
Me2N
NMe2
7a
NMe2
7b
−78 → 0 ºC
O
O
4b
Me Me
Me
N
% Yielda
Entry
Base
LiTMP
Additives
E/Z Ratio
Me
1
LiCl,
DMPU
DMPUc
DMPU
none
DMPU
none
none
59%b
>20:1
Me
N
N
46%
74%
30%
63%b
23%
71%
92%
20:1
10:1
2:1
1:10
2:1
2
3
4
5
6
7
8
LiTMP
LiTMP
LiTMP
LiHMDS
LiHMDS
NaHMDS
KHMDS
Me
4k
4j
(94%)
osimertinib
precursor
(56%)
1:1
2:1
none
N
O
aYield determined by 1H-NMR analysis after aqueous work-up using 1,2,4,5-
tetramethylbenzene as an internal standard. bIsolated yield after vacuum
distillation. c4b was pre-mixed with TIPSCl (2 equiv) before addition of base.
Me
Me
O
N
Me
O
O
4l
(62%)
4m
(74%)
Formation of the E-diene (7a) could be performed selectively
(>20:1 E:Z) by deprotonation with lithium 2,2,6,6-
tetramethylpiperidine (LiTMP) in the presence of LiCl (0.3
equiv)21a and DMPU (1 equiv), with TIPSCl as the silylating
agent (Entry 1). Slightly diminished yield was observed using
inverse order of addition, wherein TIPSCl was pre-mixed with
DMPU (1 equiv) and 4b prior to the introduction of LiTMP
(Entry 2).22 LiCl was an essential additive for maintaining high
levels of diastereoselectivity – a 10:1 ratio was observed in its
absence (Entry 3), and exclusion of DMPU led to even further
diminished diastereoselectivity (2:1) (Entry 4). Reversal of the
diastereoselectivity to form the Z-diene (7b) in a 1:10 E:Z ratio
was observed when LiHMDS with DMPU was employed (Entry
5). Comparison of HMDS amides in the absence of DMPU
displayed similarly modest diastereoselectivities (Entries 6-8).20a
Although modest diastereoselectivity was observed with
KHMDS, these reaction conditions provided the highest yield
Cl
(1.1 equiv)
B.
Me
Me
N
N
N
O
O
Me
Me
Me
5
Me
Me
t-BuOLi (1.1 equiv)
Me
N
Me
> 90 g per batch
23 → 60 ºC
THF (73%)
mol scale
1a
a isolated yield
4b
The reaction conditions utilizing dimethyl Gold’s reagent (5a)
could be employed to synthesize an intermediate (4j) en route to
an FDA approved treatment for non-small cell lung carcinoma,
osimertinib,18b in 94% yield, which has previously been reported
to proceed in 84% yield using commercially available DMF-

4
Tetrahedron
ACCEPTED MANUSCRIPT
(Entry 8). Other lithium amides (LDA or LiNCy2 were less
successful.
4.2 Experimental procedures
The origin of diastereoselection is worthy of comment. While
4.2.1. Methyl Gold’s reagent (5a):
minimization of 1,3-diaxial interactions in chair-like transition
states or reactions that proceed via more open transition states are
generally used to rationalize diastereoselective enolate
[CAUTION!]: This reaction produces a large amount of CO2 gas
and thus appropriate reaction setup should be used (see
Supplementary Materials for pictures of reaction setup).
formation,23 these results suggest other factors may be operable.
20c
To a flame-dried 500-mL round-bottomed flask equipped with
a magnetic stir bar was added cyanuric chloride (50.0 g, 271
mmol, 1.0 equiv). The solid was diluted with 1,4-dioxane (67
mL, 4 M). To the stirred heterogeneous mixture was added N,N-
dimethylformamide (126 mL, 1.6 mol, 6 equiv) dropwise over 20
minutes at room temperature, which resulted in a pale yellow
heterogeneous mixture.
3. Conclusion
This report details the synthesis of a library of Gold’s reagents,
which were shown to be generally effective for ketone and ester
one-carbon homologation to form enaminones. An enaminone
recently employed in the synthesis of andirolide N14 was
prepared on mole scale and conditions were described to
selectively form E- and Z-Rawal-type dienes. We hope that the
development of these scalable processes will enable broader
application of Gold’s reagents to challenges in multistep
synthesis.
The reaction vessel was fitted with a flame-dried 45-cm double
walled reflux condenser with a mineral oil bubbler outlet
connected to the top of the condenser. The reaction apparatus
was transferred to a room temperature oil bath that was then
warmed to 90 ºC. When the oil bath temperature had reached 85
ºC (ca. 30 minutes), the reaction mixture turned dark red, and
exothermic release of CO2 commenced. After stirring at 90 ºC for
two additional hours, the reaction mixture was removed from the
oil bath and cooled to room temperature. Once at room
temperature, a dark brown solid formed. The crude brown solid
was purified by trituration with pentane (3 x 200 mL). The
resulting solid was dried under vacuum to provide the title
4. Experimental
4.1 General Experimental
General Experimental Procedures: All reactions were carried
out under an inert nitrogen atmosphere with dry solvents under
anhydrous conditions unless otherwise stated. All reactions were
capped with a rubber septum or Teflon-coated silicon microwave
cap unless otherwise stated. Stainless steel cannula or syringes
were used to transfer solvent, and air- and moisture- sensitive
liquid reagents. Reactions were monitored by thin-layer
chromatography (TLC) and carried out on 0.25 mm Merck silica
gel plates (60F-254) using UV light as the visualizing agent and
potassium permanganate, an acidic solution of p-anisaldehyde,
and Seebach as developing agents. Flash column chromatography
employed SiliaFlash P60 (40-60 µm, 230-400 mesh) silica gel
purchased from SiliCycle Inc.
Materials: All reaction solvents were purified using a Seca
solvent purification system by Glass Contour, with the exception
of methanol, iso-propyl alcohol, and tert-butyl alcohol. Methanol
was purified by distillation over magnesium, and anhydrous iso-
propyl alcohol, tert-butyl alcohol, and 1,4-dioxane were
purchased from Sigma Aldrich and used as received. N,N-
dicyclohexylamine, 2,2,6,6-tetramethylpiperidine, and DMPU
were distilled over CaH2. n-butyllithium (in hexanes) was
purchased from Sigma-Aldrich. The molarity of n-butyllithium
solutions were determined by titration with N-benzylbenzamide.
All other reagents were used as received without further
purification, unless otherwise stated.
1
compound as a light brown solid (127 g, 97%). H NMR (600
MHz, CDCl3): δ 9.79 (s, 2H), 3.40 (s, 6H), 3.21 (s, 6H) 13C
NMR (151 MHz, CDCl3): δ 168.4, 42.7, 36.2 IR (cm-1): 3389,
2933, 1604, 1417, 1341, 1124, 1065, 829, 531 ESI-HRMS
+
(m/z): [M-Cl]+ calc’d for C6H14N3 : 128.1182; found: 128.1183
4.2.2. Ethyl Gold’s reagent (5b):
To a flame-dried 25-mL round-bottomed flask equipped with a
magnetic stir bar was added cyanuric chloride (1.0 g, 5.4 mmol,
1.0 equiv) and the stirred solid was diluted with 1,4-dioxane (1.4
mL, 4 M). To the stirred heterogeneous mixture was added N,N-
diethylformamide (3.6 mL, 32.5 mmol, 6 equiv) dropwise over 5
minutes at room temperature. The reaction vessel was fitted with
an oven-dried reflux condenser and transferred to a room
temperature oil bath that was then warmed to 85 ºC. When the oil
bath temperature had reached 85 ºC the reaction mixture turned
dark red, and exothermic release of CO2 commenced. After
stirring at 85 ºC for two hours, the reaction was removed from
the oil bath and cooled to room temperature. Once at room
temperature, a dark brown solid formed. The crude brown solid
was purified by trituration with pentane (5 x 4 mL). The resulting
solid was concentrated under reduced pressure by rotary
evaporation to reveal the title compound as a light brown solid
(2.24 g, 63%). 1H NMR (500 MHz, CDCl3): δ 9.67 (s, 2H), 3.67
(q, J = 7.2 Hz, 4H), 3.62 (q, J = 7.2 Hz, 4H), 1.35 (t, J = 7.2 Hz,
6H), 1.23 (t, J = 7.2, Hz, 6H) 13C NMR (151 MHz, CDCl3): δ
167.5, 48.3, 41.8, 14.3, 12.4 IR (cm-1): 3408, 2977, 1706, 1586,
1446, 1341, 1273, 1234, 1138, 994, 764 ESI-HRMS (m/z): [M-
Instrumentation: All new compounds were characterized by
1
means of H-NMR, 13C-NMR, FT-IR (thin film from CH2Cl2),
and HR-MS. Copies of the H- and 13C-NMR spectra can be
1
found in the supplementary materials. NMR spectra were
recorded using a Varian 400 MHz NMR spectrometer, Varian
500 MHz NMR spectrometer, or a Varian 600 MHz NMR
1
spectrometer. All H-NMR data are reported in δ units, parts per
+
Cl]+ calc’d for C10H22N3 : 184.1808; found: 184.1807
million (ppm), and were calibrated relative to the signals for
residual chloroform (7.26 ppm) in deuterochloroform (CDCl3).
All 13C-NMR data are reported in ppm relative to CDCl3 (77.16
4.2.3. Allyl Gold’s reagent (5c):
1
ppm) and were obtained with H decoupling unless otherwise
To a flame-dried 25-mL round-bottomed flask equipped with a
magnetic stir bar was added cyanuric chloride (1.0 g, 5.4 mmol,
1.0 equiv). To the stirred solid was added N,N-diallylformamide24
(2.03 g, 16.3 mmol, 3.0 equiv) dropwise over 5 minutes at room
temperature. The reaction vessel was fitted with an oven-dried
reflux condenser and transferred to a room temperature oil bath
that was then warmed to 100 ºC. When the oil bath temperature
stated. The following abbreviations or combinations thereof were
used to explain the multiplicities: s = singlet, d = doublet, t =
triplet, q = quartet, br = broad, m = multiplet, and a = apparent.
All IR spectra were taken on an FT-IR/Raman Thermo Nicolet
6700. High resolution mass spectra (HR-MS) were recorded on a
Bruker microTOF mass spectrometer using ESI-TOF
(electrospray ionization-time of flight).

had reached 80 ºC the reaction mixture gradually turned dark
164.6, 51.2, 47.6, 25.0, 24.2 IR (cm-1): 3392, 2975, 1706, 1581,
1450, 1306, 1110, 855 ESI-HRMS (m/z): [M-Cl]+ calc’d for
C10H18N3 : 180.1495; found: 180.1495
ACCEPTED MANUSCRIPT
brown, and exothermic release of CO2 commenced. After stirring
at 100 ºC for one hour, the reaction was removed from the oil
bath and cooled to room temperature. Once at room temperature,
a black oil formed, which was washed with Et2O (5 x 5 mL), and
the ethereal layer was discarded. The oil was concentrated under
reduced pressure by rotary evaporation to reveal the title
+
4.2.6. Piperidine Gold’s reagent (5f):
To a flame-dried 25-mL round-bottomed flask equipped with a
magnetic stir bar was added cyanuric chloride (270 mg, 1.47
mmol, 1.0 equiv). To the stirred solid was added 1-
formylpiperdine (1.0 g, 8.8 mmol, 6.0 equiv) dropwise over 5
minutes at room temperature. The reaction vessel was fitted with
an oven-dried reflux condenser and transferred to a room
temperature oil bath that was then warmed to 100 ºC. Once the
oil bath temperature had reached 90 ºC, the reaction mixture
gradually turned a dark brown color and exothermic release of
CO2 commenced. After stirring at 100 ºC for two hours, the
reaction was removed from the oil bath and cooled to room
temperature. Once at room temperature, a red-orange solid
formed.
1
compound as a black oil (1.51 g, 69%). H NMR (600 MHz,
CDCl3): δ 9.86 (s, 2H), 5.86–5.80 (m, 2H), 5.73–5.67 (m, 2H),
5.40–5.38 (m, 3H), 5.33 (at, J = 9.6 Hz, 3H), 5.25 (ad, J = 17.4
Hz, 2H), 4.23 (dd, J = 25.8, 6.6 Hz, 8H) 13C NMR (151 MHz,
CDCl3): δ 168.7, 130.5, 129.3, 122.1, 120.8, 55.5, 48.8 IR (cm-
1): 3390, 2932, 2077, 1709, 1572, 1441, 1418, 1332, 1235, 1170,
+
929, 844 ESI-HRMS (m/z): [M-Cl]+ calc’d for C14H22N3 :
232.1808; found: 232.1828
4.2.4. Benzyl Gold’s reagent (5d):
To a flame-dried 25-mL round-bottomed flask equipped with a
magnetic stir bar was added cyanuric chloride (752 mg, 3.33
mmol, 1.0 equiv). To the stirred solid was added N,N-
dibenzylformamide (1.0 g, 32.5 mmol, 4.0 equiv) in one portion
at room temperature. The reaction vessel was fitted with an oven-
dried reflux condenser and transferred to a room temperature oil
bath that was then warmed to 120 ºC. Once the oil bath
temperature had reached 75 ºC, the solids gradually melted to
form a red-orange solution, and exothermic release of CO2
commenced. After stirring at 120 ºC for one hour, the reaction
was removed from the oil bath and cooled down to room
temperature. Once at room temperature, a yellow-orange solid
formed.
To the reaction vessel containing the crude red solid was added
THF (2 mL), and the mixture was heated to reflux until complete
dissolution of solid was observed. Once the solid dissolved,
hexanes (6 mL) was added, and a red solid formed. The mixture
was allowed to slowly cool to room temperature and the red solid
was washed with hexanes/THF (2:1, 2 x 6 mL), and concentrated
under reduced pressure to yield the title compound as a red solid
1
(928 mg, 85%). H NMR (600 MHz, CDCl3): δ 9.71 (s, 2H),
3.75 (adt, J = 15.6, 5.4 Hz, 8H), 1.78– 1.72 (m, 8H), 1.69–1.66
(m, 4H) 13C NMR (151 MHz, CDCl3): δ 166.4, 53.1, 45.4, 26.6,
25.5, 23.9 IR (cm-1): 3398, 2940, 1588, 1449, 1362, 1335, 1222,
1113, 1024, 1000 ESI-HRMS (m/z): [M-Cl]+ calc’d for
+
To the reaction vessel containing the crude yellow solid was
added THF (2 mL) and the mixture was heated to reflux until
complete dissolution of solid was observed. Once the solid
dissolved, hexanes (6 mL) was added and a yellow solid
precipitated after cooling to room temperature. The liquid was
decanted and the resulting solid was triturated with hexanes/THF
(2:1, 2 x 6 mL). Residual solvent was removed by concentration
under reduced pressure to yield the title compound as a yellow
C12H22N3 : 208.1808; found: 208.1808
4.2.7. Morpholine Gold’s reagent (5g):
To a flame-dried 25-mL round-bottomed flask equipped with a
magnetic stir bar was added cyanuric chloride (1.2 g, 6.5 mmol,
1.0 equiv) and the stirred solid was diluted with 1,4-dioxane (1.6
mL, 4 M). To the stirred heterogeneous mixture was added 4-
formylmorpholine (1.9 mL, 19 mmol, 3 equiv) dropwise over 5
minutes at room temperature. The reaction vessel was fitted with
an oven-dried reflux condenser and transferred to a room
temperature oil bath that was then warmed to 85 ºC. Once the oil
bath temperature had reached 85 ºC, the reaction mixture turned a
dark red color and exothermic release of CO2 commenced. After
stirring at 85 ºC for one hour, the reaction was removed from the
oil bath and cooled to room temperature. Once at room
temperature, a brown oil formed. The crude oil was purified by
washing with Et2O/pentane (3:1, 2 x 4 mL). The ethereal layer
was discarded and the oil was dried under vacuum overnight
(ca.100 mtorr) to reveal the title compound as a brown solid
1
solid (1.47 g, 47%). H NMR (600 MHz, CDCl3): δ 10.63 (s,
2H), 7.44–7.33 (m, 16H), 7.14–7.13 (m, 4H), 4.74 (s, 4H), 4.71
(s, 4H) 13C NMR (151 MHz, CDCl3): δ 169.7, 133.2, 132.9,
129.4, 129.3, 129.3, 129.1, 128.8, 128.4, 56.5, 48.9 IR (cm-1):
1589, 1568, 1496, 1453, 1344, 1215, 755, 701 ESI-HRMS
+
(m/z): [M-Cl]+ calc’d for C30H30N3 : 432.2458; found: 432.2434
4.2.5. Pyrrolidine Gold’s reagent (5e):
To a flame-dried 25-mL round-bottomed flask equipped with a
magnetic stir bar was added cyanuric chloride (1.0 g, 5.4 mmol,
1.0 equiv) and diluted with 1,4-dioxane (1.4 mL, 4 M). To the
stirred heterogeneous mixture was added 1-formylpyrrolidine
(2.1 mL, 22 mmol, 4.0 equiv) dropwise over 5 minutes at room
temperature. The reaction vessel was fitted with an oven-dried
reflux condenser and transferred to a room temperature oil bath
that was then warmed to 85 ºC. Once the oil bath temperature had
reached 50 ºC, a white precipitate formed in the yellow reaction
mixture. When the oil bath temperature reached 85 ºC the
reaction mixture turned dark red, and exothermic release of CO2
commenced. After stirring at 85 ºC for two hours, the reaction
was removed from the oil bath and cooled to room temperature.
Once at room temperature, a red-brown oil formed. The crude
brown solid was purified by trituration with pentane (3 x 5 mL).
The pentane layer was discarded and the oil was concentrated
under reduced pressure by rotary evaporation to reveal the title
1
(2.18 g, 91%). H NMR (600 MHz, CDCl3): δ 9.87 (s, 2H),
3.90–3.88 (at, J = 4.2 Hz, 4H), 3.87–3.84 (m, 8H), 3.76 (at, J =
4.8 Hz, 4H) 13C NMR (151 MHz, CDCl3): δ 167.1, 67.1, 66.1,
51.8, 45.2 IR (cm-1): 3386, 2931, 1709, 1585, 1442, 1341, 1261,
1235, 1174, 1110, 1021, 856, 617 ESI-HRMS (m/z): [M-Cl]+
+
calc’d for C10H18N3O2 : 212.1394; found: 212.1393
4.2.8. Indoline Gold’s reagent (5h):
To a flame-dried 25-mL round-bottomed flask equipped with a
magnetic stir bar was added cyanuric chloride (128 mg, 1.13
mmol, 1.0 equiv). To the stirred solid was added 1-
formylindoline (1.0 g, 6.79 mmol, 6.0 equiv)25 in one portion at
room temperature. The reaction vessel was fitted with an oven-
dried reflux condenser and transferred to a room temperature oil
bath that was then warmed to 115 ºC. Once the oil bath
temperature had reached 75 ºC, the solids gradually melted to
form an orange mixture, which turned dark red at 95 ºC and
1
compound as a red-brown solid (1.9 g, 82%). H NMR (400
MHz, CDCl3): δ 9.64 (s, 2H), 3.90 (t, J = 6.4 Hz, 4H), 3.64 (t, J =
6.4 Hz, 4H), 2.05–2.02 (m, 8H) 13C NMR (151 MHz, CDCl3): δ

6
Tetrahedron
ACCEPTED MANUSCRIPT
exothermic release of CO2 commenced. After stirring at 115 ºC
The title compound was prepared according to the general
for one hour, the reaction was removed from the oil bath and
cooled to room temperature. Once at room temperature, an
orange solid formed.
procedure with acetophenone (23 µL, 0.20 mmol, 1.0 equiv) and
allyl Gold’s reagent (5c, 59 mg, 0.22 mmol, 1.1 equiv) then
heated at 65 ºC for 12 hours. The crude oil was purified by flash
column chromatography on silica gel (ethyl acetate/hexanes=
20% to 45%) to yield the title compound (29.5 mg, 65%) as a
To the reaction vessel containing the crude orange solid was
added THF (2 mL) and the mixture was heated to reflux until
complete dissolution of solid was observed. Once the solid
dissolved, hexanes (6 mL) was added, and an orange solid
precipitated after cooling to room temperature. The liquid was
decanted and the resulting solid was triturated with hexanes/THF
(2:1, 2 x 6 mL). Residual solvent was removed by concentration
under reduced pressure to yield the title compound as an orange
1
yellow oil. Rf: 0.14 (30% ethyl acetate/hexanes) H NMR (600
MHz, CDCl3): δ 7.88–7.85 (m, 3H), 7.46–7.39 (m, 3H), 5.84 (d,
J = 12.6 Hz, 1H), 5.83–5.75 (m, 2H), 5.26 (d, J = 10.2 Hz, 2H),
5.22 (d, J = 16.9 Hz, 2H), 3.92–3.84 (m, 4H) 13C NMR (151
MHz, CDCl3): δ 189.2, 153.2, 140.6, 133.0, 131.1, 130.6, 128.3,
127.7, 119.2, 118.1, 93.2, 58.6, 50.6 IR (cm-1): 2922, 2853, 2214,
1597, 1581, 1546, 1447, 1365, 1274, 1312, 1206, 1051, 1024,
997, 703 ESI-HRMS (m/z): [M+H]+ calc’d for C15H18NO+:
228.1383; found: 228.1382
1
solid (782 mg, 74%). H NMR (600 MHz, CDCl3): δ 11.12 (s,
2H), 8.08 (d, J = 10.2 Hz, 2H), 7.38 (t, J = 9.0 Hz, 2H), 7.29 (d, J
= 9.0 Hz, 2H), 7.27–7.24 (m, 2H), 4.34 (t, J = 9.0 Hz, 4H), 3.33
(t, J = 9.0 Hz, 4H) 13C NMR (151 MHz, CDCl3): δ 160.8, 139.6,
133.6, 129.3, 128.3, 126.0, 114.5, 48.3, 27.5 IR (cm-1): 3368,
2933, 1681, 1602, 1575, 1416, 1342, 1123, 766 ESI-HRMS
4.2.12. Dibenzyl enaminone of acetophenone (4e):
The title compound was prepared according to the general
procedure with acetophenone (23 µL, 0.20 mmol, 1.0 equiv) and
benzyl Gold’s reagent (5d, 103 mg, 0.22 mmol, 1.1 equiv) then
heated at 65 ºC for 12 hours. The crude oil was purified by flash
column chromatography on silica gel (Et2O/DCM= 2% to 10%)
to yield the title compound (57.2 mg, 87%) as an orange solid.
(m/z): [M-Cl]+ calc’d for C18H18N3 : 276.1495; found: 276.1495
+
4.2.9. General procedure for enaminone formation:
An evacuated flame-dried 5-mL microwave vial equipped with
magnetic stir bar was brought into a glovebox. Once in the
glovebox, the flask was filled with nitrogen atmosphere. Solid
LiO-t-Bu (17.6 mg, 0.22 mmol, 1.1 equiv) was added and the vial
was sealed. The reaction vessel was removed from the glovebox,
and the vial was evacuated and backfilled with nitrogen three
times.
To the reaction vessel containing stirred solid LiO-t-Bu, was
added THF (0.4 mL, 0.5 M) at room temperature. To the stirred
reaction mixture was added the corresponding ketone (0.2 mmol,
1.0 equiv) dropwise over one minute at room temperature. After
stirring at room temperature for 30 minutes, the corresponding
Gold’s reagent (0.22 mmol, 1.1 equiv) was added in one portion.
The reaction vessel was sealed with a Teflon vial microwave cap,
and transferred to a pre-warmed oil bath set to 65 ºC. After
stirring for the stated time, the reaction was removed from the oil
bath, cooled to room temperature, and diluted with sat. aq. NH4Cl
(5 mL). The layers were separated, and the aqueous layer was
extracted with chloroform (3 x 5 mL). The combined organics
were washed with brine (5 mL), dried over anhydrous sodium
sulfate, filtered, and concentrated under reduced pressure by
rotary evaporation to give crude enaminone. Purification by flash
column chromatography on silica gel or trituration afforded the
title compound.
1
Rf: 0.30 (5% Et2O/DCM) H NMR (500 MHz, CDCl3): δ 8.18
(d, J = 12.5 Hz, 1H), 7.85 (d, J = 7.5 Hz, 2H), 7.46–7.32 (m, 9H),
7.22 (d, J = 7.0 Hz, 3H), 6.02 (d, J = 13.0 Hz, 1H), 4.47 (brs,
2H), 4.38 (brs, 2H) 13C NMR (151 MHz, CDCl3): δ 189.4, 154.3,
140.4, 135.9, 135.3, 131.2, 129.1, 128.8, 128.7, 128.3, 128.0,
127.7, 127.4, 93.3, 59.5, 50.9 IR (cm-1): 3028, 2923, 1641, 1597,
1580, 1544, 1452, 1361, 1201, 1076, 1050, 1025, 754, 698 ESI-
HRMS (m/z): [M+H]+ calc’d for C23H22NO+: 328.1696; found:
328.1703
4.2.13. Pyrrolidine enaminone of acetophenone (4f):
The title compound was prepared according to the general
procedure with acetophenone (23 µL, 0.20 mmol, 1.0 equiv) and
pyrrolidine Gold’s reagent (5e, 47 mg, 0.22 mmol, 1.1 equiv)
then heated at 65 ºC for 12 hours. The crude oil was purified by
flash column chromatography on silica gel (ethyl
acetate/hexanes= 30% to 60%) to yield the title compound (57.2
mg, 88%) as a tan solid. Rf: 0.12 (50% ethyl acetate/hexanes) 1H
NMR (500 MHz, CDCl3): δ 8.03 (d, J = 12.5 Hz, 1H), 7.89 (d, J
= 7.0, 2H), 7.46–7.39 (m, 3H), 5.68 (d, J = 12.5 Hz, 1H), 3.57
(brs, 2H), 3.29 (brs, 2H), 2.04 (brs, 2H), 1.95 (brs, 2H) 13C NMR
(151 MHz, CDCl3): δ 188.4, 150.0, 140.5, 130.8, 128.1, 127.5,
93.1, 52.4, 47.0, 25.2 IR (cm-1): 2917, 2849, 1639, 1582, 1548,
1364, 1341, 1272, 1218, 1052, 757 ESI-HRMS (m/z): [M+H]+
calc’d for C13H16NO+: 202.1226; found: 202.1222
4.2.10. Diethyl enaminone of acetophenone (4c):
The title compound was prepared according to the general
procedure with acetophenone (23 µL, 0.20 mmol, 1.0 equiv) and
ethyl Gold’s reagent (5b, 47 mg, 0.22 mmol, 1.1 equiv) then
heated at 65 ºC for 12 hours. The crude oil was purified by flash
column chromatography on silica gel (ethyl acetate/hexanes=
30% to 60%) to yield the title compound (35.3 mg. 88%) as a tan
4.2.14. Piperidine enaminone of acetophenone (4g):
The title compound was prepared according to the general
procedure with acetophenone (23 µL, 0.20 mmol, 1.0 equiv) and
piperidine Gold’s reagent (5f, 54 mg, 0.22 mmol, 1.1 equiv) then
heated at 65 ºC for 12 hours. The crude oil was purified by flash
column chromatography on silica gel (ethyl acetate/hexanes=
40% to 70%) to yield the title compound (32.4 mg, 75%) as a
light yellow solid. Rf: 0.15 (50% ethyl acetate/hexanes) 1H
NMR (500 MHz, CDCl3): δ 7.88 (d, J = 7.0 Hz, 2H), 7.78 (d, J =
12.5 Hz, 1H), 7.45–7.38 (m, 3H), 5.81 (d, J = 12.5 Hz, 1H), 3.36
(brs, 4H), 1.66 (brs, 6H) 13C NMR (126 MHz, CDCl3): δ 189.1,
153.2, 140.8, 130.9, 128.2, 127.5, 91.3, 24.2 IR (cm-1): 2937,
2854, 1638, 1597, 1581, 1544, 1462, 1448, 1367, 1312, 1275,
1209, 1116, 1053, 1024, 881, 704, 660 ESI-HRMS (m/z):
[M+H]+ calc’d for C14H18NO+: 216.1383; found: 216.1386
1
solid. Rf: 0.19 (65% ethyl acetate/hexanes) H NMR (600 MHz,
CDCl3): δ 7.88 (d, J = 7.2 Hz, 2H), 7.82 (d, J = 12.6 Hz, 1H),
7.46–7.40 (m, 3H), 5.77 (d, J = 12.6 Hz, 1H), 3.38–3.27 (m, 4H),
1.24 (t, J = 6.0 Hz, 6H) 13C NMR (151 MHz, CDCl3): δ 188.9,
152.5, 140.9, 130.9, 128.2, 127.6, 91.8, 50.7, 42.9, 15.0, 11.7 IR
(cm-1): 2975, 2929, 2280, 2188, 2177, 2025, 1992, 1981, 1959,
1640, 1598, 1582, 1547, 1469, 1365, 1282, 1219, 1078, 658 ESI-
HRMS (m/z): [M+H]+ calc’d for C13H18NO+: 204.1383; found:
204.1384
4.2.11. Diallyl enaminone of acetophenone (4d):

4.2.15. Morpholine enaminone of acetophenone (4h):
6.5 Hz, 2H), 1.64 (s, 3H), 1.61–1.56 (m, 2H), 1.45–1.42 (m, 2H),
ACCEPTED MANUSCRIPT
1.02 (s, 6H) 13C NMR (126 MHz, CDCl3): δ 198.7, 144.1, 139.3,
136.8, 131.0, 128.1, 127.7, 125.7, 122.8, 108.8, 100.5, 48.1, 42.4,
40.0, 35.2, 32.9, 28.7, 27.7, 24.2, 20.0, 19.7 IR (cm-1): 2923,
2863, 1665, 1583, 1300, 1262, 1111, 748, 703 ESI-HRMS (m/z)
[M+H]+ calc’d for C22H30NO+: 324.2322; found: 324.2346
The title compound was prepared according to the general
procedure with acetophenone (23 µL, 0.20 mmol, 1.0 equiv) and
morpholine Gold’s reagent (5g, 54 mg, 0.22 mmol, 1.1 equiv)
then heated at 65 ºC for 12 hours. The crude oil was purified by
flash column chromatography on silica gel (ethyl
acetate/hexanes= 60% to 80%) to yield the title compound (36.3
mg, 84%) as a brown oil. Rf: 0.13 (70% ethyl acetate/hexanes)
1H NMR (500 MHz, CDCl3): δ 7.88 (d, J = 7.5 Hz, 2H), 7.73 (d,
J = 12.6 Hz, 1H), 7.47–7.40 (m, 3H), 5.88 (d, J = 12.6 Hz, 1H),
3.76 (at, J = 4.8 Hz, 4H), 3.40 (at, J = 4.2 Hz, 4H) 13C NMR
(151 MHz, CDCl3): δ 189.3, 152.9, 140.3, 131.3, 128.3, 127.6,
92.6, 66.3 IR (cm-1): 2922, 2853, 1641, 1597, 1582, 1547, 1444,
1372, 1313, 1283, 1207, 1115, 1055, 1022, 927, 885, 760, 705,
4.2.19. Piperidine enaminone of geranylacetone (4l):
The title compound was prepared according to the general
procedure with geranylacetone (15 µL, 0.20 mmol, 1.0 equiv)
and piperidine Gold’s reagent (5f, 54 mg, 0.22 mmol, 1.1 equiv)
then heated at 65 ºC for 2 hours. The crude oil was purified by
flash column chromatography on silica gel (ethyl
acetate/hexanes= 40% to 60%) to yield the title compound (27.2
mg, 62%) as a yellow solid. Rf: 0.29 (60% ethyl acetate/hexanes)
1H NMR (500 MHz, CDCl3): δ 7.48 (d, J = 12.8 Hz, 1H), 5.14–
5.06 (m, 3H), 3.23 (brs, 4H), 2.34–2.28 (m, 4H), 2.07–2.02 (m,
3H), 1.97–1.94 (m, 1H), 1.67–1.58 (m, 15H) 13C NMR (126
MHz, CDCl3): δ 198.2, 151.3, 135.6, 131.4, 124.7, 124.5, 123.9,
39.8, 32.1, 26.9, 26.8, 25.8, 25.8, 24.5, 24.4, 24.2, 23.5, 17.8,
16.1. IR (cm-1): 2924, 2855, 2348, 2166, 1610, 1563, 1447, 1369,
1239, 1100, 1026, 983, 852, 765 ESI-HRMS (m/z): [M+H]+
calc’d for C19H32NO+: 290.2478; found: 290.2501
662 ESI-HRMS (m/z): [M+H]+ calc’d for C13H16NO2 :
218.1176; found: 218.1179
+
4.2.16. Indoline enaminone of acetophenone (4i):
The title compound was prepared according to the general
procedure with acetophenone (23 µL, 0.20 mmol, 1.0 equiv) and
indoline Gold’s reagent (5h, 69 mg, 0.22 mmol, 1.1 equiv) then
heated at 65 ºC for 12 hours. The crude oil was purified by flash
column chromatography on silica gel (ethyl acetate/hexanes=
60% to 80%) to yield the title compound (39.1 mg, 78%) as a
yellow solid. Rf: 0.19 (20% ethyl acetate/hexanes) 1H NMR (500
MHz, CDCl3): δ 8.41 (d, J = 12.4 Hz, 1H), 7.96 (d, J = 7.1 Hz,
1H), 7.51–7.43 (m, 3H), 7.20 (d, J = 7.7 Hz, 2H), 7.10 (d, J = 7.9
Hz, 1H), 6.98 (t, J = 7.4 Hz, 1H), 6.04 (d, J = 12.6 Hz, 1H), 3.94
(t, J = 8.4 Hz, 2H), 3.26 (t, J = 8.4 Hz, 2H) 13C NMR (151 MHz,
CDCl3): δ 189.1, 143.9, 141.5, 140.0, 131.5, 131.2, 128.4, 128.1,
127.8, 125.7, 123.2, 109.2, 96.6, 48.3, 27.7 IR (cm-1): 2924,
1643, 1579, 1542, 1598, 1496, 1258, 1208, 1052, 883, 747, 703
ESI-HRMS (m/z): [M+H]+ calc’d for C17H16NO+: 250.1226;
found: 250.1221
4.2.20. Morpholine enaminone of γ-butyrolactone (4m):
The title compound was prepared according to the general
procedure with γ-butyrolactone (44 µL, 0.20 mmol, 1.0 equiv)
and morpholine Gold’s reagent (5g, 54 mg, 0.22 mmol, 1.1
equiv) then heated at 65 ºC for 6 hours. The crude oil was
purified by flash column chromatography on silica gel (ethyl
acetate/hexanes= 40% to 60%) to yield the title compound (36.4
mg, 74%) as
a
yellow solid.
Rf: 0.15 (90% ethyl
1
acetate/hexanes) H NMR (400 MHz, CDCl3): δ 7.11 (t, J = 2.0
Hz, 1H), 4.27 (t, J = 7.6 Hz, 2H), 3.72 (t, J = 4.4 Hz, 4H), 3.42 (t,
J = 4.4 Hz, 4H), 3.01 (dd, J = 8.0, 2.0 Hz, 2H) 13C NMR (151
MHz, CDCl3): δ 175.5, 145.2, 88.2, 66.6, 64.6, 49.8, 26.2 IR
(cm-1): 2922, 2855, 1723, 1622, 1445, 1363, 1270, 1230, 1158,
1114, 1021, 1003, 863, 747 ESI-HRMS (m/z): [M+H]+ calc’d
4.2.17. Osimertinib precursor (4j):
The title compound was prepared according to the general
procedure with N-Me-3-acetylindole25 (35 mg, 0.20 mmol, 1.0
equiv) and morpholine Gold’s reagent (5a, 36 mg, 0.22 mmol,
1.1 equiv) then heated at 65 ºC for 2 hours. The yellow oil was
washed with pentane (3 x 2 mL), the pentane layer was
discarded, and the oil was dried under vacuum (ca.100 mtorr) to
reveal the title compound as a yellow-orange foam (43.2 g, 94%).
+
for C9H14NO3 : 184.0968; found: 184.0980
4.2.21. Scalable synthesis of dimethyl enaminone of 2-butanone
(4m):
To a flame-dried 5-L round-bottomed flask equipped with a
magnetic stir bar was added solid LiO-t-Bu (88.1 g, 1.1 mol, 1.1
equiv). To the stirred solid, was added THF (2.0 L, 0.5 M) via
cannula, and this mixture was allowed to stir at room temperature
for 10 minutes to allow for complete dissolution of LiO-t-Bu
solid. 2-butanone (72.1 g, 1.0 mol, 1.0 equiv) was added
dropwise at room temperature to the reaction mixture over 15
minutes, resulting in a light yellow mixture. After stirring at
room temperature for 30 minutes, methyl Gold’s reagent (5a, 182
g, 1.1 mol, 1.1 equiv) was added in 5 portions over 30 minutes.
The reaction vessel was fitted with an oven-dried reflux
condenser and transferred to a heating mantle that was then
warmed to a gentle reflux.
1
Rf: 0.12 Ethyl acetate H NMR (400 MHz, CDCl3): δ 8.40–8.37
(m, 1H), 7.76 (d, J = 12.5 Hz, 1H), 7.67 (s, 1H), 7.33–7.25 (m,
3H), 5.64 (d, J = 12.5 Hz, 1H), 3.81 (s, 3H), 3.00 (brs, 6H) 13C
NMR (151 MHz, CDCl3): δ 184.9, 152.0, 137.5, 133.0, 126.9,
123.2, 122.7, 122.6, 122.2, 121.6, 118.3, 109.5, 94.1, 33.4 IR
(cm-1): 2919, 1635, 1574, 1549, 1523, 1466, 1369, 1331, 1225,
1081, 1048, 1011, 884, 791, 748, 574 ESI-HRMS (m/z): [M+H]+
calc’d for C14H17N2O+: 229.1335; found: 229.1336
4.2.18. Indoline enaminone of dihydro-β-ionone (4k):
The title compound was prepared according to the general
procedure with dihydro-β-ionone (42 µL, 0.20 mmol, 1.0 equiv)
and indoline Gold’s reagent (5h, 69 mg, 0.22 mmol, 1.1 equiv)
then heated at 65 ºC for 1.5 hours. The crude oil was purified by
flash column chromatography on silica gel (ethyl
acetate/hexanes= 10% to 30%) to yield the title compound (36.4
mg, 56%) as a yellow solid. Rf: 0.22 (20% ethyl acetate/hexanes)
1H NMR (500 MHz, CDCl3): δ 8.12 (d, J = 13.0 Hz, 1H), 7.18
(d, J = 7.5 Hz, 2H), 7.01 (d, J = 8.0 Hz, 1H), 6.94 (t, J = 7.4 Hz,
1H), 5.34 (d, J = 13.0 Hz, 1H), 3.82 (t, J = 8.5 Hz, 2H), 3.23 (t, J
= 8.5 Hz, 2H), 2.55–2.52 (m, 2H), 2.37–2.33 (m, 2H), 1.92 (t, J =
After stirring at reflux for 12 hours, the reaction apparatus was
removed from the heating mantle and allowed to cool to room
temperature. Once at room temperature, the reaction was diluted
with sat. aq. NH4Cl (2.5 L) and chloroform (3 L). The layers
were separated, and the aqueous layer was extracted with
chloroform (3 x 2 L). The combined organics were washed with
brine (5 mL), dried over anhydrous sodium sulfate, filtered, and
concentrated under reduced pressure by rotary evaporation to
give the crude enaminone as a black oil. The black oil was
purified by fractional distillation through a 5 cm vigreux column

8
Tetrahedron
to reveal the title compound as a yellow liquid (92.3 g, 73%).
backfilled with nitrogen three times. The Schlenk adaptor was
ACCEPTED MANUSCRIPT
Boiling point: 82 ºC at 200 mtorr Rf: 0.11 (90% ethyl
acetate/hexanes) 1H NMR (400 MHz, CDCl3): δ 7.50 (d, J = 12.7
Hz, 1H), 5.01 (d, J = 12.7 Hz, 1H), 2.90 (brs, 6H), 5.01 (d, J =
12.7 Hz, 1H), 2.33 (q, J = 7.5 Hz, 2H), 1.09 (t, J = 7.5 Hz, 3H)
13C NMR (151 MHz, CDCl3): δ 199.0, 152.3, 95.3, 44.8, 36.9,
30.4 10.0 IR (cm-1): 2931, 2053, 1562, 1433, 1354, 1283, 1221,
1103, 1036, 979, 763 ESI-HRMS (m/z): [M+H]+ calc’d for
C7H14NO+: 128.1070; found: 128.1001
replaced with a rubber septum and placed under a nitrogen
atmosphere.
To the stirred solid LiHMDS was added THF (16 mL, 0.5 M)
and then placed in a saturated dry-ice acetone bath cooled to –78
ºC. Enaminone 4b (1.0 g, 7.9 mmol, 1.0 equiv) was added
dropwise over 5 minutes to the reaction mixture at –78 ºC, which
resulted in an orange mixture. After stirring at –78 ºC for 30
minutes, DMPU (2.9 mL, 24 mmol, 3.0 equiv) was added
dropwise over 5 minutes, which resulted in a light orange
reaction mixture.
4.2.22. E-Diene (7a):
Once 30 minutes had elapsed, TIPSCl (1.9 mL, 8.6 mmol, 1.1
equiv) was added dropwise to the reaction mixture over 5
minutes, which resulted in a yellow reaction mixture. The
reaction vessel was transferred to a 0 ºC ice-water bath.
After stirring at 0 ºC for 2 hours, sat. aq. NH4Cl (10mL) was
added and the layers were separated. The aqueous layer was
extracted with pentane (3 x 25 mL). The combined organics were
washed with sat. aq. NaHCO3 (20 mL), brine (3 x 30 mL), dried
over anhydrous sodium sulfate, filtered, and concentrated under
reduced pressure by rotary evaporation to yield an orange oil as a
1:11 (E:Z) mixture of diastereomers. The crude mixture was
purified by rapid fractional distillation (<5 minutes) with a heat
gun to reveal the title compound as a yellow liquid (1:10 E:Z, 1.4
g, 63%) Boiling point: 80–84 ºC at 200 mtorr Rf: 0.8 (5%
To a flame-dried 100-mL round-bottomed flask equipped with
a magnetic stir bar was added LiCl (100.1 mg, 2.36 mmol, 0.3
equiv). The reaction flask was placed under vacuum and heated
with a heat gun for 2 minutes and then back filled with nitrogen
(This process was repeated three times). After the flask was
cooled to room temperature, the flask was back filled with
nitrogen and diluted with THF (26 mL, 0.3M).
2,2,6,6-tetramethylpiperidine (1.6 mL, 9.43 mmol, 1.2 equiv)
was added dropwise over 5 minutes at room temperature to the
vigorously stirred reaction mixture. The reaction vessel was
transferred to a –20 ºC dry-ice acetone bath. After stirring at this
temperature for 10 minutes, n-BuLi (3.5 mL, 8.7 mmol, 1.1
equiv) was added dropwise over 5 minutes, which resulted in a
pale yellow solution. Once 25 minutes had elapsed, the reaction
was cooled to –78 ºC in a saturated dry-ice acetone bath, and
DMPU (0.95 mL, 7.9 mmol, 1.0 equiv) was added dropwise over
2 minutes, which resulted in a light orange mixture. The reaction
mixture was allowed to stir at –78 ºC for 30 minutes.
1
Et2O/0.5% Et3N/pentane) H NMR (600 MHz, CDCl3): δ 6.37
(d, J = 13.5 Hz, 1H), 4.73 (d, J = 13.5 Hz, 1H) 4.43 (q, J = 8.4
Hz, 1H), 2.65 (s, 6H), 1.62 (d, J = 6.8 Hz, 3H), 1.26–1.20 (m,
3H), 1.13 (s, 9H), 1.12 (s, 9H) 13C NMR (151 MHz, CDCl3): δ
150.8, 139.5, 98.8, 98.3, 40.8, 18.3, 13.8 IR (cm-1): 2943, 2865,
1993, 1648, 1580, 1464, 1350, 1329, 1193, 1039, 937, 882, 937,
801 ESI-HRMS (m/z): [M+H]+ calc’d for C16H34NOSi+:
284.2404; found: 284.2403
In a separate flame-dried 25-mL round-bottomed flask was
added enaminone 4b (1.0 g, 7.9 mmol, 1.0 equiv) that was then
diluted with THF (5 mL, 1.6 M). This solution was added
dropwise over 5 minutes at –78 ºC to the vigorously stirred
reaction mixture, which resulted in a red-orange reaction mixture.
After stirring at –78 ºC for 30 minutes, a solution of TIPSCl (1.7
mL, 7.7 mmol, 0.98 equiv) in THF (10 mL, 7.7M) was added to
the reaction mixture dropwise over 5 minutes, which resulted in a
light yellow solution. Following stirring at –78 ºC for 10 minutes,
the reaction vessel was transferred to a 0 ºC ice-water bath.
After stirring at 0 ºC for 2 hours, sat. aq. NH4Cl (10mL) was
added and the layers were separated. The aqueous layer was
extracted with pentane (3 x 25 mL). The combined organics were
washed with sat. aq. NaHCO3 (20 mL), brine (3 x 30 mL), dried
over anhydrous sodium sulfate, filtered, and concentrated under
reduced pressure by rotary evaporation to yield an orange oil as
a >20:1 (E:Z) mixture of diastereomers. The crude mixture was
purified by rapid fractional distillation (<5 minutes) with a heat
gun to reveal the title compound as a yellow liquid (>20:1 E:Z,
1.32 g, 59%) Boiling point: 80–84 ºC at 200 mtorr Rf: 0.8 (5%
Acknowledgments
Yale University and the NSF (GRF to A.W.S.) are acknowledged
for financial support. C. L. B. M. gratefully acknowledges the
Arthur Fleischer Undergraduate Summer Research Fellowship in
Chemistry.
References and notes
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1H), 2.72 (s, 6H), 1.57 (d, J = 8.4 Hz, 3H), 1.23–1.17 (m, 3H),
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