Di-tert-butyl Ethynylimidodicarbonate as a General Synthon for the β-Aminoethylation of Organic Electrophiles: Application to the Formal Synthesis of Pyrrolidinoindoline Alkaloids (±)-CPC-1 and (±)-Alline

Article abstract of DOI:10.1021/acs.joc.0c00781

The reagent di-tert-butyl ethynylimidodicarbonate is demonstrated as a β-aminoethyl anion synthetic equivalent. It can be used to install ethyleneamine groups by exploiting its terminal alkyne reactivity with common organic electrophiles. Reactions exemplified with this terminal ynimide reagent include additions to imines, aldehydes, ketones, pyridinium salts, Michael acceptors, epoxides, and Pd-catalyzed Sonogashira couplings. Subsequent regioselective [3 + 2] cycloadditions of the alkynyl-imides (ynimides) generate N,N-di-Boc imide-functionalized triazole and isoxazole heterocycles. Reduction of the ynimides with Pd-catalyzed hydrogenation generates ethyleneimides with easily removable N,N-di-Boc-carbamate protecting groups, allowing for a flexible ynimide-based approach to ethyleneamine installation. The utility of this two-step aminoethylation strategy was demonstrated in the short formal syntheses of pyrrolidinoindoline alkaloids (±)-CPC-1 and (±)-alline. Analogously, the reagent (N,N,N′)-tri-Boc 2-ethynylhydrazine serves as a β-hydrazinoethyl anion synthetic equivalent.

Full text of DOI:10.1021/acs.joc.0c00781

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Article
Di-tert-butyl Ethynylimidodicarbonate as a General Synthon for the #-
Aminoethylation of Organic Electrophiles: Application to the Formal
Synthesis of Pyrrolidinoindoline Alkaloids (±)-CPC-1 and (±)-Alline
Ramsay Beveridge, Yiwei Hu, Bruce Gregoire, and Robert A Batey
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c00781 • Publication Date (Web): 04 Jun 2020
Downloaded from pubs.acs.org on June 4, 2020
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Di-tert-butyl Ethynylimidodicarbonate as a General
Synthon for the -Aminoethylation of Organic
b
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Electrophiles: Application to the Formal Synthesis of
Pyrrolidinoindoline Alkaloids (±)-CPC-1 and (±)-Alline
Ramsay E. Beveridge, Yiwei Hu, Bruce Gregoire, and Robert A. Batey*
Davenport Research Laboratories, Department of Chemistry, University of Toronto, 80
St. George St., Toronto, ON, Canada, M5S 3H6
Corresponding Author E-mail: rob.batey@ utoronto.ca
Phone/Fax: (416)-978-5059
RECEIVED DATE (to be automatically inserted after your manuscript is accepted
if required according to the journal that you are submitting your paper to)
TITLE RUNNING HEAD: Di-tert-butyl Ethynylimidodicarbonate as a General Synthon
for the β-Aminoethylation of Organic Electrophiles: Application to the Formal Synthesis
of Pyrrolidinoindoline Alkaloids (±)-CPC-1 and (±)-Alline
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Table of Contents Graphic:
O
X
Boc
Ph
N(Boc)2
N
N(Boc)2
H
N
0
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0
N(Boc)2
(i) E+
Boc
X = OH, NHTs
CO
2
Et
N
equivalent to
2
(ii) H , Pd/C
R O
2
OH
1
2
R = Me, R = Me, (±)-CPC-1
–
NMe
NH2
N(Boc)
2
1
2
R = H, R = H, (±)-Alline
H
R1
Abstract:
The reagent di-tert-butyl ethynylimidodicarbonate is demonstrated as a β-aminoethyl
anion synthetic equivalent. It can be used to install ethyleneamine groups by exploiting
its terminal alkyne reactivity with common organic electrophiles. Reactions exemplified
with this terminal ynimide reagent include additions to imines, aldehydes, ketones,
pyridinium salts, Michael acceptors, epoxides, as well as Pd-catalyzed Sonogoshira
couplings. Subsequent regioselective [3+2] cycloadditions of the alkynyl-imides
(
ynimides) generate N,N-di-Boc imide functionalized triazole and isoxazole heterocycles.
Reduction of the ynimides with Pd-catalyzed hydrogenation generates ethyleneimides
with easily removable N,N-di-Boc-carbamate protecting groups allowing for a flexible
ynimide based approach to ethyleneamine installation. The utility of this two-step
aminoethylation strategy was demonstrated in the short formal syntheses of
pyrrolidinoindoline alkaloids (±)-CPC-1 and (±)-alline. Analogously, the reagent
(N,N,N’)-tri-Boc 2-ethynylhydrazine, serves as a β-hydrazinoethyl anion synthetic
equivalent.
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Introduction:
b-Substituted ethylamines are a common structural motif found in natural
products and a privileged scaffold in pharmaceutical development. Acyclic examples
include neurotransmitters such as dopamine and serotonin, the serotonin/norepinephrine
reuptake inhibitors duloxetine, fluoxetine, and atomoxetine, and the beta-3 adrenergic
receptor agonist mirabegron (Figure 1). More commonly, the b-substituted ethylamine
motif is embedded within a ring, such as in the tetrahydroquinoline VMAT2 inhibitor
valbenazine, the pyrroloiminoquinone discorhabdin B, the antiplatelet clopidogrel, or in
complex alkaloids such as ibogamine, ibogaine, cephalotaxine, lamellarin L,
galanthamine, and strychnine. In addition, there are many examples of targets
incorporating further substitution at either the a- or b-positions of the β-ethyleneamine
fragment.
1
1
1
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The de novo synthesis of b-substituted ethylamines 1 typically relies upon one of
three key disconnections (Figure 2a). C–N bond disconnection is a powerful approach,
1
2
3
through for example reductive amination, Gabriel amination, or hydroamination
strategies. However, this disconnection does not readily allow for diversification of the b-
substituent. Disconnection of the a-C–C bond can be achieved, for example, through the
4
5
use of a-amino anion equivalents such as cyanide or nitromethane anion followed by
subsequent reduction. Disconnection of the b-C–C bond can occur through the use of
either electrophilic or nucleophilic β-ethyleneamine fragments. For example, the
metallated intermediate 2 serves as an equivalent to the nucleophilic synthon 3. The
challenge in the latter case is that fragmentation via E1cB elimination of the protected
6
amino group can occur (i.e., 4) for Mg based intermediates 2. More stable versions of
7
8
type 2 reagents include alkylboronate and alkylzinc aminoethylation examples but these
species are mostly limited to the generation of phenethylamine products. To overcome
these issues, we envisaged the use of b-anionic or metallated ynamides 5 (which are
incapable of E1cB elimination) as stable and versatile reagents for β-ethyleneamine
installation. Such intermediates would be accessible from the corresponding terminal
ynamides, and act as synthetic equivalents to either the reduced nucleophilic β-
aminoethylene synthon 3 (following reduction) or unsaturated synthon 6 (Figure 2b).
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OH
H
HO
HO
NH2
N
S
N
O
NH2
N
H
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Dopamine
Mirabegron (MyrbetriqTM
)
MeO
MeO
N
S
H
O
Me
O
N
OMe
O
N
H
O
H N
2
S
Cl
Valbenazine (IngrezzaTM
)
Duloxetine (CymbaltaTM
O
)
Clopidogrel (PlavixTM
)
HO
X
O
N
H
N
N
MeO
O
Et
O
N
H
HO
HO
MeO
Lamellarin L
ibogamine (X = H)
ibogaine (X = OMe)
MeO
Cephalotaxine
OH
MeO
H C
3
N
Me
O
HN
S
N
N
OH
N
H
Br
O
N
O H
H
H
O
OMe
Galanthamine
O
H
Discorhabdin B
Strychnine
Figure 1. Representative b-substituted ethylamine natural product and pharmaceutical
molecules containing ethyleneamine fragments.
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α-disconnection
R1
R2
1
(
a)
N
H
β-disconnection
1
1
1
1
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C–N disconnection
(
b)
M
P1
P1
–
equivalent to
equivalent to
–
N
NH2
N
P2
P2
3
4
2
P1
N
P2
–
NH2
–
NH2
M
5
3
6
Figure 2. (a) Three disconnections for b-substituted ethylamine synthesis. (b)
Nucleophilic β-aminoethylene synthetic equivalents 2 and 5.
Ynamides are stable N-substituted alkynes which have become popular reagents
9
for selectively incorporating amine functional groups in organic molecules. In particular,
the utility of these polarized 1-amido-alkynes have been exemplified in natural product
total synthesis applications via N-alkynyl cycloaddition and cyclization reactions.10 In
contrast to the familiar use of ynamides in ring-forming reactions, terminal ynamide
species, required for the formation of 5, remain surprisingly under-utilized in additions to
common organic electrophiles. Previous work in this area includes ynamide Sonogashira
couplings,11 ynamide-acetylide addition to carbonyl groups,12,13 and copper-catalyzed
ynamide addition to acid-chlorides and pyridinium salts.14 More recently, a powerful
copper-catalyzed enantioselective addition of N-sulfonamide protected terminal ynamides
15
to isatins was disclosed while this manuscript was in preparation. While useful, these
examples have the limitation of using N-substituted alkynes possessing urethane,
sulfonamide or indole groups on nitrogen which are not easily deprotected or transformed
into other amine functional groups (e.g., primary amines). Furthermore, there appear to
be no examples of terminal ynamide nucleophiles reacting with other common
electrophiles such as epoxides and Michael acceptors.
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We envisaged the use of a terminal ynamide 7 which on deprotonation and
trapping with an electrophile or cross-coupling would form the ynamide 8. Subsequent
reduction to 9 and deprotection would lead to the formation of the primary amine 10 or
the substituted variant 11. This would represent both a powerful approach to
functionalized ynamide synthesis, and when combined with subsequent alkyne reduction
would serve as a general route to install β-ethyleneamine groups (Scheme 1). Our prior
studies on the use of Boc-protected ynehydrazides16 suggested that the use of di-Boc
protected precursors 12 or 13 could potentially serve as synthetic equivalents to the β-
ethyleneamine synthon 3 or β-ethylenehydrazine synthon 14, respectively. Herein, we
describe our initial investigation into the utility of terminal ynamide and ynehydrazide
reagents 12 or 13, including a general exploration of their reactivity. The di-tert-butyl
ethynylimidodicarbonate 12 is demonstrated to be a general β-aminoethyl anion synthon
and is applied to the total syntheses of two pyrrolidinoindoline alkaloids.
0
1
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5
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7
8
9
0
1
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8
9
0
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9
0
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0
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9
0
P1
N
P1
N
(
i) Base / Metallation
ii) Electrophile, E
P2
P2
[H]
H
E
E
(
8
7
deprotect
E
P2
P2
or
E
N
P1
NH
2
N
H
9
10
11
Boc
N
–
–
equivalent to
Boc
NH2
H
H
12
3
Boc
N
Boc
NH2
N
equivalent to
N
H
Boc
1
3
14
Scheme 1. General concept of Boc-protected ynamide acetylide anions as β-
ethyleneamine and β-ethylenehydrazine synthetic equivalents.
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Results and Discussion:
Initial studies on the use of ynehydrazides, formed by the addition of acetylides to
di-t-butylazodicarboxylate (DBAD), had revealed that the Boc groups provided stable N-
substituted alkyne species and could be readily deprotected after manipulation of the
alkyne.16 We similarly reasoned that the tri-Boc protected terminal ynehydrazide 13
could serve as an equivalent to either of the synthons 3 or 14 (following alkyne reduction
and, in the former case, reductive cleavage of the N–N bond). To evaluate the terminal
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
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4
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5
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5
5
5
5
5
5
6
0
1
2
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8
9
0
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2
3
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7
8
9
0
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2
3
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9
0
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0
1
7
ynehydrazide approach to aminoethylation, the pyrrolidinoindoline alkaloids (±)-CPC-1
1518,19 and (±)-alline 1620,21 were chosen as targets. Briefly, we envisaged an approach
utilizing addition of the lithium acetylide 17 (formed by deprotonation of 13) to an N-
protected isatin 18 (Scheme 2). Subsequent alkyne reduction and hydrazine N–N bond
cleavage of 19 to 20, followed by a reductive cyclization was envisaged to then afford 15
or 16.
2
H
2
R O
R O
N
Boc
N
O
Me
N
R1
N
H
reductive
cyclization
2
0
R1
1
2
1
1
5 R = R = Me, (±)-CPC-1
1
2
alkyne reduction
and N–N bond cleavage
6 R = R = H, (±)-Alline
Boc
N
Boc
ynehydrazide
carbonyl addition
N
N(Boc)2
Li
17 Boc
NBoc
2
O
R O
O
N
O
N
R1
1
8
19
R1
Scheme 2. Proposed ynehydrazide aminoethylation approach to pyrrolidinoindoline
alkaloids
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6
Toward this goal, we were pleased to observe that the tri-Boc-protected terminal
ynehydrazide 13 could be easily prepared in gram-scale quantities through the addition of
lithiated trimethysilylethyne to di-tert-butylazodicarboxylate (DBAD), and subsequent
0
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2
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9
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0
trapping with (Boc) O and TBAF deprotection (Scheme 3). Addition of 13 as its lithium
2
acetylide to N-Me isatin ketone 18a followed by methylation afforded 19a in good yield.
Isatin ynehydrazide 19a could be mono-deprotected to 20a using catalytic magnesium
perchlorate.22 Reduction of the alkyne group of 20a occurred to give hydrazide 22a.
However, attempts to then cleave the N‒N bond under a variety of conventional
conditions were unsuccessful. A major side product observed in many of the reduction
reactions attempted was the undesired reductive cleavage of the methyl ether a- to the
isatin amide.
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(
i) n-BuLi (1.2 equiv)
THF, -78 °C to rt
H
Boc
N
TMS
Boc
H
+
N
Boc
(ii) Boc O (1.5 equiv)
(iii) TBAF (2.0 equiv)
2
Boc
N
N
Boc
1
3
5
1% (3 steps)
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
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8
9
0
1
2
3
4
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6
7
8
9
0
Boc
Boc
N
N
(
i) 13 (1.5 equiv)
n-BuLi (1.5 equiv)
THF, -78 °C to rt
O
MeO
Boc (i) Mg(ClO4)2
(10 mol %)
O
O
(
ii) Me SO (2 equiv)
MeCN
55 °C, 4 h
N
2
4
N
rt, 16 h
Me
Me
9a
6% (2 steps)
1
8a
1
7
Boc
Boc
N
Boc
N
Boc
N
MeO
H
(ii) H , Pd/C
MeO
N
2
EtOAc, rt, 24 h
H
O
O
2
1a
N
N
Me
Me
2
2a
5
3% (2 steps)
H
N
MeO
Boc
various conditions
O
e.g., SmI , NaNaphth,
Zn/HOAc, Raney Ni
2
N
20a
Me
Scheme 3. Unsuccessful ynehydrazide approach to (±)-CPC-1
Although unsuccessful in the synthesis of the target alkaloid CPC-1 15, these results
provided a proof-of-concept for using ynehydrazide 13 as a reagent for
hydrazinoethylation which may be valuable for other applications including heterocycle
generation. To illustrate this concept, compound 22a was directly elaborated to
pyrazoles23 23a and 23b, demonstrating how reagent 13 can further function as an
ethylenepyrazole building block (Scheme 4).
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R1
Me
O
Boc
Boc
Me
N
N
MeO
N
MeO
N
O
O
4N HCl/dioxane
H
O
+
MeOH
80 °C, 30 min
Me
Me
N
N
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9
0
Me
22a
R1
Me
1
2
2
3a (R = H) 52%
3b (R = Cl) 30%
1
Scheme 4. Conversion of compound 22a to ethylenepyrazoles 23a and 23b
We next revisited our pyrrolidinoindoline synthetic strategy with the goal of using
an alternative ynamide derivative for the key aminoethylation. Drawing a parallel with
2
Gabriel amination strategies which utilize phthalimide or di-Boc-imide nucleophiles as
masked amines, our efforts focused on investigating imide functionalized alkynes as
ethyleneamine synthons. In this regard, we were particularly attracted to the previously
reported N,N-di-Boc terminal ynimide 1224 because it appeared straightforward to
prepare, and possessed flexible Boc carbamate protecting groups which should be easy to
remove or manipulate.25 Under slightly modified conditions to those described
2
4
previously, ynimide 12 was prepared in synthetically useful quantities via addition of
di-tert-butyl-iminodicarboxylate 24 to alkynyl-iododium triflate reagents 25 with mild
heating (Scheme 5).
Scheme 5. Synthesis of di-tert-butyl ethynylimidodicarbonate ynimide reagent 12 from
alkynyliodonium triflate reagents 25
With ynimide 12 in hand, we revisited our terminal N-linked alkyne aminoethylation
concept in additions to protected isatins toward the synthesis of the alkaloids (±)-CPC-1
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1
5 and (±)-alline 16. In contrast to our prior ynehydrazide results in this area, attempts to
generate the lithium-acetylide of 12 with n-BuLi or LDA followed by trapping with N-
Me-isatin resulted in unsatisfactory carbonyl addition. Ultimately, a slight modification
of literature conditions for room temperature formation of Zn-acetylides using a
1
1
1
1
1
1
1
1
1
1
2
2
2
2
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3
4
5
6
7
8
9
0
Et
Zn/HMPA mixture26 was found to allow for clean addition of 12. Functionalized
2
ynimide 26 was obtained after tertiary alcohol methylation (Scheme 6). Importantly, this
ynimide strategy was successful in completing the formal total synthesis of
pyrrolidinoindoline (±)-CPC-1 15 via hydrogenation and Mg(ClO
4
2
) catalyzed imide
2
2
mono-Boc deprotection to provide ethyleneamine compound 20a which is known to
undergo reductive cyclization to the target alkaloid.19b
Scheme 6. Formal synthesis of (±)-CPC-1 using an ynimide aminoethylation approach
The related alkaloid (±)-alline 16 was then accessed in a similar fashion via Zn-
acetylide addition of ynimide 12 to N-benzyl isatin to give 27 (Scheme 7). Subsequent
hydrogenation/deprotection afforded intermediate 28. The formal synthesis was realized
by reductive cyclization with LiAlH to provide compound 29 which is known to
4
undergo benzyl deprotection to provide the target alkaloid.19b
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9
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Scheme 7. Formal synthesis of (±)-alline using an ynimide aminoethylation approach
These results illustrate how the N,N-di-boc imide group is a superior ynamide
alkyne substituent versus other commonly used sulfonamide or urethane groups, because
its flexibility toward deprotection or conversion to other amine functional groups. Based
on these results, we investigated the generality of this ynimide based aminoethylation
strategy using 12 as an acetylide nucleophile with a variety of other common
electrophiles. The Zn-acetylide of 12 was found to undergo reaction with other carbonyl
species including aldehydes, ketones and imines (Scheme 8). Only activated imines like
those possessing an N-sulfonyl group were found to be reactive with the Zn-acetylide of
12, and attempts to alkynylate aldehydes with 12 under catalytic conditions27 were
unsuccessful.
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Scheme 8. Reaction of di-tert-butyl ethynylimidodicarbonate ynimide 12 with carbonyl
and sulfonylimine electrophiles
Di-tert-butyl ethynylimidodicarbonate 12 was also found to participate in a
2
8
copper-catalyzed multicomponent N-acyl pyridinium salt reaction providing access to
interesting ynimide functionalized dihydroquinoline 31 and dihydroisoquinoline 32
compounds (Scheme 9). Although two regioisomeric addition sites exist in the quinoline
case, only the 1,2-addition product 31 was observed which is consistent with previous
observations using other alkyne additions.28
Scheme 9. Copper-catalyzed reaction of di-tert-butyl ethynylimidodicarbonate ynimide
12 with heteroaromatic N-acyliminium ions
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The first examples of terminal ynamide addition to epoxide and Michael acceptor
electrophiles were also achieved with ynimide reagent 12 (Schemes 10 and 11). For
addition of 12 to epoxides, the Yamaguchi conditions29 were found to be generally
optimal for formation of 33. Poor regioselectivity (~1:1) was observed with styrene oxide
which did not improve using alternative conditions. In addition, attempts to facilitate a
Michael addition of ynimide 12 using rhodium catalysis were unsatisfactory and resulted
in a complex mixture of products. However, 1,4-addition of 12 could be achieved via
reaction of the Zn-acetylide in combination with TBDMSOTf activation of the Michael
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0
3
0
acceptor. In order to reveal the desired ketone products 34, tetrabutylamonnium fluoride
was used to cleave the silyl-enol ether intermediates due to the acidic sensitivity of the
ynimide fragment.
Scheme 10. Reaction of di-tert-butyl ethynylimidodicarbonate ynimide 12 with epoxides
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O
O
LiHMDS (1.5 equiv)
Boc
Boc
ZnBr (1.5 equiv)
2
H
N
34a, n = 1, 62%
34b, n = 2, 57%
TBDMSOTf (1.5 equiv)
n
n
1
2
THF, -78 °C to -44 °C
(1.5 equiv)
Boc
N
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
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2
2
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0
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3
4
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6
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8
9
0
Boc
Scheme 11. Reaction of di-tert-butyl ethynylimidodicarbonate ynimide 12 with enones
Ynimide 12 was also functionalized with acyl and aryl groups using metal-
catalyzed Sonogashira conditions to give the coupled products 35 (Scheme 12). Efficient
ynimide arylation was only observed using aryl iodides as coupling partners as the use of
aryl-bromides resulted in low amounts of desired aryl-coupled ynimide product, possibly
as a result of competing metal facilitated oxazolinone cyclization of N-Boc alkyne 12.24
Scheme 12. Sonogoshira couplings with di-tert-butyl ethynylimidodicarbonate ynimide
1
2
To exemplify the generality of an alkynyl-imide aminoethylation strategy, a
variety of the functionalized alkynyl-imides prepared above were reduced using simple
Pd/C hydrogenation conditions. This approach afforded the corresponding ethyleneamine
products 36 (Scheme 13). Importantly, expanded access to aminoethyl structures
including valuable diamine and amino-alcohol products demonstrates how this ynimide
reaction sequence is differentiated from other aminoethylation strategies which typically
only provide access to aryl-functionalized ethyleneamines.7,8 In addition, the di-Boc
group can be readily deprotected into the fully deprotected amine, or the mono-Boc
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5
6
carbamates using catalytic Mg(ClO
4
)
2
, which in turn can be converted into N-
methylamines by reduction with LiAlH
4
, vide supra.
0
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9
0
Scheme 13. Aminoethylation products 36
ethynylimidodicarbonate ynimide reagent 12
derived from
di-tert-butyl
In addition to aminoethylation, the ynimide reagent 12 can also be used to
incorporate the convenient and flexible Boc-imide group in pharmaceutically relevant
heterocycles through the use of subsequent [3+2] cycloadditions. For example, copper-
3
1
catalyzed [3+2] cycloaddition reaction of 12 with azides, affords 4-substituted 1,2,3-
triazoles 37 functionalized with the easily de-blocked di-Boc imide group (Scheme 14).
Furthermore, application of Fokin’s ruthenium catalyzed conditions32 results in a
complete regioselectivity switch to provide 5-imide substituted 1,2,3-triazoles 38
(
Scheme 15). This interesting electronically biased regioselectivity outcome with
ruthenium is consistent with Fokin’s observations and other related [3+2] results.16a
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8
9
0
Scheme 14. Cu-catalyzed synthesis of 4-imide-functionalized triazoles from di-tert-butyl
ethynylimidodicarbonate ynimide 12
Scheme 15. Ru-catalyzed synthesis of 5-imide functionalized triazoles from di-tert-butyl
ethynylimidodicarbonate ynimide 12
In a related fashion, di-Boc ynimide 12 can also be used to generate imide
functionalized isoxazoles such as 39 (Scheme 16). Again, a complete regioselectivity
switch in isoxazole formation is observed using Fokin’s ruthenium catalyzed conditions33
versus copper-catalysis, to afford the regioisomeric adduct 40.
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8
9
0
Scheme 16. Catalytic synthesis of imide-functionalized isoxazoles from di-tert-butyl
ethynylimidodicarbonate ynimide 12
As an illustration of the simplicity with which these di-Boc imide functionalized
heterocycles can be deprotected and exploited, amide and amine functionalized triazoles
4
1 and 42 were synthesized via a Boc-group deprotection / acylation or reductive
amination strategy, respectively (Scheme 17). In this regard, ynimide 12 is shown to be a
more flexible reagent for heterocycle amine-functionalization via introduction of the di-
Boc imide group versus conventional ynamide cycloadducts possessing sulfonamide or
urethane nitrogen-functionality.
Scheme 17. Deprotection and reaction of Boc-imide functionalized triazoles
Conclusion
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Di-tert-butyl ethynylimidodicarbonate reagent 12 is a useful precursor to generate
functionalized internal ynimides as well as di-Boc imide functionalized triazole and
isoxazole heterocycles. The ynimide products included in this report were constructed
using new examples of ynamide acetylide reactivity with carbonyl groups, imines,
epoxides, Michael acceptors, and pyridinium ions. Importantly, ynimide 12 is
demonstrated to function as an ethyleneamine building block via simple hydrogenation of
internal ynimide products resulting in straightforward access to useful aminoethylated
structures including alkaloid natural products. Future work in this area includes the
investigation of asymmetric ynimide carbonyl alkynylations as well as using reagent 12
to prepare other alkaloids through possible epoxide opening or 1,4-addition strategies.
Analogous chemistry is also possible using the tri-Boc protected terminal ynehydrazide
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
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9
0
1
3, which serves as a synthetic equivalent to a nucleophilic β-hydrazinoethyl anion
synthon. Overall, we hope that this study will encourage others to consider terminal
ynamide acetylide disconnections in complex molecule syntheses.
Experimental Section:
THF was dried over sodium benzophenone-ketyl and toluene and acetonitrile
were dried over calcium hydride and distilled fresh under nitrogen atmosphere before use
and transferred via syringe using standard techniques unless otherwise stated. The
following reagents were prepared according to previously reported literature conditions:
N-hydroxybenzimidoyl chloride,34 1-methylindoline-2,3-dione35 and 1-benzylindoline-
,3-dione,36 1-oxaspiro[2.5]octane,37 (E)-N-benzylidene-4-methylbenzenesulfonamide,38
2
methyl 2-azidoacetate,39 and aryl-azides.40 All other reagents including catalysts,
LiHMDS (1.0 M in THF), KHMDS (0.5 M in toluene), Tf O (1.0 M in CH Cl ), Et Zn
1.0 M in hexanes), alkynes, di-tert-butyl-azodicarboxylate, epoxides, Michael acceptors,
benzoyl-chloride, aryl-halides, aldehydes (passed through short plug of basic Al
immediately prior to use), ketones and benzyl azide were purchased from Aldrich or
VWR and used as received unless otherwise stated. NMR solvent (CDCl with TMS
2
2
2
2
(
2
O
3
3
internal standard) was purchased from Cambridge Isotopes Lab Inc. and used as received.
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1
13
1
All products were characterized by H NMR and C NMR, IR and HRMS. H
1
3
NMR and C NMR were recorded on Varian Mercury 300 MHz, Varian Mercury 400
MHz, and Bruker 500 MHz spectrometers. Chemical shifts are expressed in ppm values
1
and H NMR spectra are referenced to 0.00 ppm for Me
4
Si (TMS) and solvent residual
0
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13
peak of 2.50 ppm for d
6
-DMSO. C NMR spectra are referenced to 77.00 ppm for CDCl
3
and 39.52 ppm for d
6
-DMSO. Peak multiplicities are designated by the following
abbreviations: s, singlet; br.s, broad singlet; d, doublet; t, triplet; q, quartet; m, multiplet;
r, rotomers; J, coupling constant in Hz. If a coupling pattern can be assigned as a
combination of multiplicities, then the listed abbreviations are combined to provide an
appropriate descriptor for the observed patterns (e.g., dt–doublet of triplets). IR spectra
were obtained on a Shimadzu FTIR-8400S with samples loaded as thin films on NaCl
plates neat or with CH
2
Cl as indicated. Mass spectra were obtained by the University of
2
Toronto mass spectral facility (AIMS); high resolution mass spectra (HRMS) were
recorded on an AEI MS3074 spectrometer. Melting points were obtained on a Fisher-
Johns melting point apparatus and are uncorrected. Flash column chromatography was
performed on silica gel (60 Å, 230-400 mesh, obtained from Silicycle Inc.) using reagent
grade EtOAc and hexanes as eluent (gradient elution 0-100% EtOAc unless otherwise
stated). Analytical thin-layer chromatography (TLC) was performed on pre-coated
aluminum-backed silica gel plates (Alugram SIL G/UV254 purchased from Silicycle
Inc.) and visualized with a UV lamp (254 nm) or KMnO stain and heating.
4
Tri-tert-butyl 2-ethynylhydrazine-1,1,2-tricarboxylate (13)
In a nitrogen flushed 250 mL flask capped with a rubber septa was charged THF
(30 mL) and ethynyltrimethylsilane (1.42 mL, 10.0 mmol, 1.0 eq.) under N and cooled
2
to -78 °C in a dry ice/acetone bath. A solution of n-BuLi (4.80 mL of a 2.5 M solution in
hexanes, 12.0 mmol, 1.2 eq.) was then added dropwise over 1-2 min and the resulting
mixture stirred at -78 °C for 15 min. A solution of DBAD (di-t-butyl-azodicarboxylate,
3.45 g, 15.0 mmol, 1.5 eq.) in THF (15 mL) was then added over 1-2 min and the cooling
bath removed and the mixture allowed to warm to room temperature and stirred at room
temperature for 30 min. The reaction mixture was then re-cooled to -78 °C and Boc O
2
(1.83 g, 15.0 mmol, 1.5 eq.) in THF (6 mL) added and the cooling bath removed and the
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mixture allowed to warm to room temperature and stirred at room temperature for 30
min. The reaction mixture was then quenched by addition of saturated NH
mL) and diluted with EtOAc (100 mL) and water (20 mL) and the layers separated. The
organic extract was dried (MgSO ), filtered through a Si plug topped with Celite (2” tall x
” wide) using EtOAc (50 mL) to wash/elute and the filtrate concentrated under reduced
4
Cl (aq.) (30
4
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
pressure to provide 3.90 g of a yellow oil. The resulting crude residue was dissolved in
THF (20 mL) and cooled to 0 °C and treated with tetra-n-butyl-ammonium fluoride
(
TBAF, 18.2 mL of a 1M solution in THF, 18.2 mmol, ~2.0 eq.) and stirred for 45 min in
the ice/water bath. The reaction mixture was then diluted with water (100 mL) and
extracted with Et O (2 x 300 mL). The organic extracts were combined, washed with
water (50 mL) then saturated NaCl (aq.) (25 mL), dried (MgSO ), filtered and
2
4
concentrated under reduced pressure. The crude residue was then purified through silica
gel chromatography (gradient elution 0-100 % EtOAc in hexanes) to provide compound
1
3 (1.80 g, 51% yield over 2 steps) as a yellow oil. R
f
= 0.37 (20% EtOAc/hexanes); IR
-1
1
(
neat, cm ) 3272, 2981, 2936, 2148, 1807, 1750, 1478, 1456, 1393, 1146, 1002, 847; H
13
1
NMR (400 MHz, CDCl ) d 3.08 – 2.93 (1H, r, m), 1.43–1.60 (27H, m); C{ H} NMR
3
(
101 MHz, CDCl
3
) d 149.0, 148.7, 84.4, 74.3, 60.7, 60.1, 27.90, 27.84; HRMS (EI) m/z:
Na, 379.1839; Found, 379.1852.
+
[M + Na] Calcd for C17
H
28
N
2
O
6
Tri-tert-butyl-2-((3-methoxy-1-methyl-2-oxoindolin-3-yl)ethynyl)hydrazine-1,1,2-
tricarboxylate (19a)
Terminal ynehydrazide 13 (535 mg, 1.5 mmol, 1.5 eq.) was dissolved in THF (5 mL) and
cooled to -78 °C in a dry ice/acetone bath. A solution of n-BuLi (0.60 mL of a 2.5 M
solution in hexanes, 1.5 mmol, 1.5 eq.) was then added dropwise over 1-2 min and the
resulting mixture stirred at -78 °C for 15 min. A solution of N-Me isatin (161 mg, 1.0
mmol, 1.0 eq.) in THF (2 mL) was then added and the cooling bath removed and the
mixture allowed to warm to room temperature. After stirring for 1 h at room temperature
dimethylsulfate (0.24 mL, 2.5 mmol, 2.5 eq.) was added and the mixture stirred at room
temperature for a further 3 h. The reaction mixture was then diluted with water (25 mL)
and EtOAc (75 mL) and the phases separated. The aqueous phase was extracted again
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1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
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5
5
5
5
5
5
5
6
with EtOAc (50 mL) and the organic extracts combined and washed with saturated NaCl
(aq.) (10 mL), dried (MgSO
crude residue was then purified through silica gel chromatography (gradient elution 0-
00 % EtOAc in hexanes) to provide compound 19a (407 mg, 76% yield over 2 steps) as
an orange oil after vacuum line drying to remove residual dimethylsulfate. R = 0.38
4
), filtered and concentrated under reduced pressure. The
1
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
f
-1
(40% EtOAc/hexanes); IR (neat, cm ) 3059, 2981, 2935, 2258, 1801, 1730, 1700, 1622,
1
1
478; H NMR (400 MHz, CDCl
3
) d 7.38–7.50 (1H, m), 7.29–7.37 (1H, m), 7.02–7.12
(
1H, m), 6.78–6.85 (1H, m), 3.58–3.66 (3H, r, m), 3.12–3.23 (3H, r, m), 1.40–1.55 (27H,
m); 13C{ H} NMR (101 MHz, CDCl
1
) d 171.3, 151.0, 148.86, 148.79, 143.1, 130.4,
3
128.0, 124.8, 123.1, 108.6, 84.7, 84.51, 84.46, 80.3, 74.3, 67.5, 52.9, 28.1, 27.9, 27.8,
6.3; HRMS (EI) m/z: [M + NH , 549.2924; Found, 549.2910.
]+ Calcd for C27
2
4
H
41
N
4
O
8
Di-tert-butyl
1-(2-(3-methoxy-1-methyl-2-oxoindolin-3-yl)ethyl)hydrazine-1,2-
dicarboxylate (22a)
Compound 19a (215 mg, 0.405 mmol, 1.0 eq.) was dissolved in MeCN (5 mL) and
Mg(ClO
4
)
2
(9 mg, 0.04 mmol, 0.1 eq.) was added and the flask fitted with a reflux
1
condenser and placed in a 55 °C oil bath. After 4 h, H NMR of an aliquot showed
conversion to the imide mono-Boc deprotected product. The reaction mixture was cooled
to room temperature and concentrated under reduced pressure. The crude residue was
dissolved in EtOAc (40 mL) and filtered through a Celite pad and concentrated under
reduced pressure again to provide 180 mg (quant. yield) of the crude mono imide-Boc
deprotected intermediate. The crude residue thus obtained was dissolved in EtOAc (10
mL) and Pd/C added (90 mg 10% w/w, ~0.2 eq. Pd). The flask was capped with a rubber
septa and purged with N
2
for 2 min. then a balloon of H attached and purged for 5 min
2
before a fresh H balloon attached and the mixture stirred at room temperature overnight.
2
After 24 h, the reaction mixture was filtered through Celite using EtOAc (40 mL) to
wash/elute and concentrated under reduced pressure. The crude residue was then purified
through silica gel chromatography (gradient elution 0-100 % EtOAc in hexanes) to
provide compound 22a (94 mg, 53% yield over 2 steps) as a yellow oil. R = 0.36 (40%
f
-1
EtOAc/hexanes); IR (neat, cm ) 3322, 3057, 3001, 2938, 2828, 2253, 1743, 1662, 1603,
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1
476; H NMR (400 MHz, CDCl
3
) d 7.25–7.44 (2H, m), 7.00–7.21 (1H, m), 6.84 (1H, d,
J = 6.0 Hz), 6.28–6.58 (1H, r, m), 3.26–3.65 (2H, m), 3.18 (3H, s), 2.99 (3H, s), 2.28–
13
1
2.48 (1H, m), 2.07–2.26 (1H, m), 1.28–1.52 (18H, m); C{ H} NMR (101 MHz, CDCl )
3
d 176.1, 155.0, 154.6, 144.2, 130.1, 128.0, 124.2, 123.2, 108.5, 81.7, 80.8, 77.2, 52.5,
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
+
4
3.4, 34.3, 28.2, 28.1, 26.1; HRMS (EI) m/z: [M + H] Calcd for C22
H
34
N
3
6
O , 436.2448;
Found, 436.2441.
3
-(2-(3,5-Dimethyl-1H-pyrazol-1-yl)ethyl)-3-methoxy-1-methylindolin-2-one (23a)
Compound 22a (45 mg, 0.103 mmol, 1.0 eq.) was dissolved in MeOH (1 mL) in a capped
microwave vial and 2,4-pentanedione added (15.5 mg, 0.016 mL, 0.154 mmol, 1.5 eq.)
followed by addition of 4N HCl in dioxane (0.5 mL). The mixture was stirred at room
temperature for 30 min then placed in an 80 °C oil bath for 30 min. The reaction was
cooled to room temperature and the volatiles removed under an air stream. The crude
residue was then partitioned between CH
2
Cl
2
(40 mL) and saturated NaHCO
3
(aq.) (10
mL) and the phases separated. The organic phase was dried (MgSO
4
), filtered and
concentrated under reduced pressure and the crude residue purified through silica gel
chromatography (gradient elution 0-100 % EtOAc in hexanes) to provide compound 23a
-
1
(
16.2 mg, 52% yield) as a yellow oil. R
f
= 0.09 (60% EtOAc/hexanes); IR (CH
2
Cl
2
, cm )
1
3
091, 2981, 2930, 2827, 1720, 1612, 1553, 1471, 1372, 1347, 1121, 1094, 754; H NMR
(
400 MHz, CDCl
3
) d 7.34 (1H, app td, J = 7.5, 1.0 Hz), 7.28 (1H, d, J = 7.0 Hz), 7.10
(1H, app t, J = 7.5 Hz), 6.84 (1H, d, J = 8.0 Hz), 5.71 (1H, s), 4.10–4.30 (2H, m), 3.21
(
3H, s), 3.03 (3H, s), 2.40 (1H, ddd, J = 14.0, 10.5, 6.0 Hz), 2.27 (1H, ddd, J = 14.0, 10.0,
13
1
5
.5 Hz), 2.20 (3H, s), 2.15 (3H, s); C{ H} NMR (101 MHz, CDCl ) d 175.4, 147.2,
3
1
43.7, 138.8, 130.0, 126.7, 124.3, 123.1, 108.4, 104.8, 81.0, 53.0, 42.8, 37.8, 26.1, 13.4,
+
10.9; HRMS (EI) m/z: [M + H] Calcd for C17
H N
22 3
2
O , 300.1712; Found, 300.1711.
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1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
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4
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5
5
5
5
6
3
-(2-(4-Chloro-3,5-dimethyl-1H-pyrazol-1-yl)ethyl)-3-methoxy-1-methylindolin-2-
one (23b)
An identical procedure used for the preparation of compound 23a using compound 22a
(
39 mg, 0.090 mmol, 1.0 eq.) and 3-chloro-2,4-pentanedione (17 mg, 0.014 mL, 0.127
mmol, 1.4 eq.) provided compound 6 (9.2 mg, 30% yield) as a yellow wax. R = 0.17
, cm ) 3080, 2931, 2828, 1722, 1612, 1471, 1373,
) d 7.35 (1H, app td, J = 7.5, 1.5 Hz),
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
f
-1
(
60% EtOAc/hexanes); IR (CH
2
Cl
2
1
1
7
348, 1124, 1092, 753; H NMR (400 MHz, CDCl
3
.26–7.29 (1H, m), 7.10 (1H, app td, J = 7.5, 1.0 Hz), 6.84 (1H, d, J = 8.0 Hz), 4.11–4.31
(2H, m), 3.21 (3H, s), 3.02 (3H, s), 2.39 (1H, ddd, J = 14.0, 10.0, 6.0 Hz), 2.24 (1H, ddd,
1
3
1
J = 14.0, 10.0, 6.0 Hz), 2.18 (3H, s), 2.13 (3H, s); C{ H} NMR (101 MHz, CDCl
3
) d
1
2
75.3, 144.2, 143.7, 135.1, 130.1, 126.6, 124.2 (2C), 123.1, 108.5, 80.8, 53.0, 43.9, 37.7,
+
6.2, 11.2, 9.2; HRMS (EI) m/z: [M + H] Calcd for C17
H21ClN
3
2
O , 334.1322; Found,
334.1327.
Di-tert-butyl-iminodicarboxylate (24)
Di-tert-butyl-iminodicarboxylate is commercially available but can also be conveniently
4
1
prepared according to the following adaptation of a literature protocol: NH
0.0 mmol, 1.0 eq.) was added to a 0 ºC solution of Boc O (18.70 g, 85.78 mmol, 4.29
eq.) in MeCN (20 mL) and a solution of DMAP (4.90 g, 40.0 mmol, 2.0 eq.) in MeCN
(65 mL) was added dropwise by addition funnel over 30 min under N and the mixture
4
Cl (1.07 g,
2
2
2
was allowed to stir overnight, warming to room temperature. After 18 h, the reaction
mixture was concentrated under reduced pressure and the resulting residue was
partitioned between Et
separated. The organic extract was washed again with 5% aqueous citric acid (50 mL)
then with saturated NaHCO (aq.) (2 x 50 mL) followed by saturated NaCl (aq.) (25 mL),
dried (MgSO ), filtered and concentrated under reduced pressure to provide N,N,N-tri-
2
O (150 mL) and 5% aqueous citric acid solution (50 mL) and
3
4
tert-butyl iminotricarboxylate (4.98 g, 79% yield) as a waxy solid. N,N,N-Tri-tert-butyl-
tri-iminocarboxylate (4.90 g, 15.46 mmol, 1.0 eq.) was dissolved in MeOH (20 mL) and
hydrazine-monohydrate (3.0 mL, 61.8 mmol, 4.0 eq.) was added under N at room
2
temperature. The reaction mixture was stirred for 4 h at room temperature then diluted
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with Et
2
O (100 mL) and washed with 10% HCl (aq.) (2 x 25 mL) followed by saturated
NaHCO
3
(aq.) (2 x 25 mL), dried (MgSO ), filtered and concentrated under reduced
4
pressure to provide compound 9 (3.05 g, 91% yield) as a white solid.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
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4
4
4
4
5
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5
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5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
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8
9
0
1
2
3
4
5
6
7
8
9
0
Di-tert-butyl ethynylimidodicarbonate (12)
From terminal alkynyl iodonium salt 25a: A suspension of PhI(OAc) (5.96 g, 18.5
2
mmol, 1.0 eq.) in CH
2
Cl
2
(10 mL) at 0 ºC was treated with Tf
2
O (9.25 mL of a 1.0 M
solution in CH Cl , 9.25 mmol, 0.5 eq.) under N
2
2
2
. This mixture was stirred for 30 min in
the ice bath then tributyl(ethynyl)stannane (5.80 g, 18.5 mmol, 1.0 eq.) was added by
syringe and the reaction mixture stirred for 90 min in the cooling bath. The volatiles were
then removed on a rotary evaporator followed by brief vacuum line drying (5 min). The
residue thus obtained was slurried in Et
2
O (5 mL) and the solids filtered off using Et O
2
(25 mL) to wash to provide the terminal alkynyl iodonium salt 25a (6.19 g, 88% yield) as
a white solid which should be reacted within 2-3 h of preparation.
Di-tert-butyl-iminodicarboxylate 24 (868 mg, 4.0 mmol, 1.0 eq.) in a N flushed flask
2
was dissolved in toluene (118 mL) and cooled to 0 ºC and KHMDS (8.40 mL of a 0.5 M
solution in toluene, 4.20 mmol, 1.05 eq.) was added. After stirring for 30 min, freshly
prepared terminal alkynyl iodonium salt 25a (2.72 g, 7.20 mmol, 1.8 eq.) was added in
one portion and the mixture was removed from the cooling bath and after warming to
room temperature (20 min) the flask was placed in a 45 ºC oil bath with a reflux
condenser. After 16 h, the reaction mixture was cooled to room temperature and filtered
through a short plug of Celite using toluene (75 mL) to wash/elute and the filtrate was
concentrated under reduced pressure. The resulting crude residue was purified through
silica gel chromatography (gradient elution 0-100 % EtOAc in hexanes) to provide
compound 12 (525 mg, 55% yield) as a yellow oil.
From TMS-alkynylphenyliodonium triflate 25b: TMS-alkynylphenyliodonium triflate
was prepared following a literature protocol,42 the following is representative: a
suspension of PhI(OAc)
Page 25 of 54
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(12.9 g, 40.0 mmol, 1.0 eq.) in CH
2
Cl (20 mL) at 0 ºC was
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1
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1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
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3
3
3
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3
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4
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4
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4
4
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5
5
5
5
5
5
5
6
treated with Tf
This mixture was stirred for 30 min in an ice bath then bis-trimethylsilylacetylene (6.8 g,
.08 mL, 40.0 mmol, 1.0 eq.) was added by syringe and stirred for 1 h in an ice bath, then
the volatiles were removed under reduced pressure followed by brief vacuum line drying
5 min). The residue thus obtained was slurried in Et O (20 mL) and the solids filtered off
using Et O (25 mL) to wash to provide TMS-alkynylphenyliodonium salt 25b (14.8 g,
2% yield) as a white solid.
2
O (20.0 mL of a 1.0 M solution in CH
2
Cl
2
, 20.0 mmol, 0.5 eq.) under N
2
.
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(
2
2
8
Di-tert-butyl-iminodicarboxylate 24 (2.65 g, 12.21 mmol, 1.0 eq.) in a N
flask was dissolved in toluene (400 mL) and cooled to 0 ºC and KHMDS (25.6 mL of a
.5 M solution in toluene, 12.8 mmol, 1.05 eq.) was added. After stirring for 30 min,
2
flushed 1-L
0
TMS-alkynylphenyliodonium salt 25b (13.74 g, 30.5 mmol, 2.5 eq.) was added in two
equal portions over 30 min and the mixture was removed from the cooling bath and after
warming to room temperature (20 min) the flask was placed in a 65 ºC oil bath with an
attached reflux condenser. After 15 h, the reaction mixture was cooled to room
temperature and filtered through a short plug of Celite and the filtrate was concentrated
under reduced pressure. The resulting crude residue was dissolved in THF (10 mL) and
cooled to 0 ºC and treated with tetra-n-butyl-ammonium fluoride (TBAF, 24.4 mL of a
1
M solution in THF, 24.4 mmol, ~2 eq.) and stirred for 15 min in the cooling bath then
stirred for 1 h at room temperature. The reaction mixture was then diluted with water
(100 mL) and extracted with Et O (2 x 200 mL). The organic extracts were combined,
washed with water (3 x 50 mL) then with saturated NaCl (aq.) (25 mL), dried (MgSO ),
2
4
filtered and concentrated under reduced pressure. The crude residue was then purified
through silica gel chromatography (gradient elution 0-100 % EtOAc in hexanes) to
provide compound 12 (1.52 g, 51% yield) as a yellow oil. R = 0.45 (20%
f
-1
EtOAc/hexanes); IR (neat, cm ) 3281, 2982, 2937, 2156, 1805, 1766, 1479, 1456, 1396,
1
1
371, 1348, 1309, 1244, 1138, 846; H NMR (300 MHz, CDCl
3
) d 2.99 (1H, s), 1.54
) d 149.6, 85.0, 71.6, 62.6, 27.7; HRMS (EI)
, 259.1658; Found, 259.1655.
13
1
(18H, s); C{ H} NMR (101 MHz, CDCl
3
m/z: [M + NH
4
]+ Calcd for C12
H
23
N
2
O
4
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Di-tert-butyl-((3-methoxy-1-methyl-2-oxoindolin-3-yl)ethynyl)-imidocarbonate (26)
A N
mmol, 2.0 eq.) and HMPA (72 mg, 0.07 mL, 0.40 mmol, 2.0 eq.) in toluene (1.0 mL) was
treated with Et Zn (0.40 mL of a 1 M solution in hexanes, 0.40 mmol, 2.0 eq.) at room
2
purged flask containing di-tert-butyl ethynylimidodicarbonate 12 (96 mg, 0.40
2
1
1
1
1
1
1
1
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1
1
2
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2
2
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2
2
2
2
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4
4
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5
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0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
temperature. After stirring for 2 h, 1-methylindoline-2,3-dione (32 mg, 0.20 mmol, 1.0
eq.) in toluene (1.0 mL) was added and the reaction mixture was stirred at room
temperature overnight. After 14 h, dimethyl sulfate (50 mg, 0.038 mL, 0.40 mmol, 2.0
eq.) was added and the reaction mixture stirred at room temperature for 3 h. Then,
saturated NH
were extracted with EtOAc (50 mL). The organic extract was washed with 1M NaOH (3
x 10 mL), dried (MgSO ), filtered and concentrated under reduced pressure. The crude
residue was purified through silica gel chromatography (pre-treated with 1% Et N in
4
Cl (aq.) (5 mL) and H
2
O (5 mL) were added in that order and organics
4
3
hexanes, using gradient elution 0-100% EtOAc in hexanes) to provide compound 26 (45
-1
mg, 54% yield) as a yellow oil. R
f
= 0.48 (40% EtOAc/hexanes); IR (CH
2
Cl
2
, cm ) 2982,
1
2
938, 2829, 2268, 1809, 1770, 1728, 1614, 1471, 1371, 1238, 1136, 1105, 1018, 845; H
NMR (400 MHz, CDCl ) d 7.41–7.46 (1H, m), 7.34 (1H, app td, J = 8.0, 1.0 Hz), 7.05–
3
1
3
1
7
.11 (1H, m), 6.82 (1H, d, J = 8.0 Hz), 3.64 (3H, s), 3.19 (3H, s), 1.49 (18H, s); C{ H}
NMR (126 MHz, CDCl
3
) d 171.3, 148.8, 143.1, 130.4, 127.8, 124.7, 123.1, 108.6, 85.0,
+
7
6.9, 74.2, 69.5, 53.2, 27.7, 26.2; HRMS (EI) m/z: [M + Na] Calcd for C22
H
28
N
2
6
O Na,
439.1839; Found, 439.1846.
tert-Butyl (2-(3-methoxy-1-methyl-2-oxoindolin-3-yl)ethyl)carbamate (20a)
To a solution of compound 26 (18 mg, 0.043 mmol, 1.0 eq.) dissolved in EtOAc (5 mL)
was added Pd/C (9.0 mg of 10% w/w dry) and the flask was capped with a rubber septa
and purged with N
2
then purged with a balloon of H
2
(5 min) and stirred at room
temperature under a balloon of H
2
for 12 h. The reaction flask was then purged with N
2
and the reaction mixture filtered through Celite using EtOAc (40 mL) to wash/elute and
the filtrate concentrated under reduced pressure. The resulting crude residue (18 mg) was
dissolved in MeCN (3 mL) and Mg(ClO
4
) (2.1 mg, 0.0086 mmol, 0.2 eq.) was added
2
and the flask was placed in a 55 ºC oil bath with a reflux condenser under N for 2.5 h.
2
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2
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5
6
The reaction mixture was cooled to room temperature and the volatiles removed under
reduced pressure and the crude residue was purified through silica gel chromatography
(
gradient elution 0-100 % EtOAc in hexanes) to provide compound 20a (10.8 mg, 78%
-1
yield) as a gum. R
f
= 0.31 (40% EtOAc/hexanes); IR (CH
2
Cl
2
, cm ) 3364, 2976, 2933,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
828, 1713, 1614, 1500, 1472, 1367, 1348, 1250, 1173; H NMR (400 MHz, CDCl
3
) d
7.30–7.39 (2H, m), 7.10–7.15 (1H, m), 6.85 (1H, d, J = 8.0 Hz), 4.92 (1H, br s), 3.23–
1
3
1
3
.33 (2H, m), 3.21 (3H, s), 3.01 (3H, s), 2.08 (2H, t, J = 6.5 Hz), 1.41 (9H, s); C{ H}
NMR (101 MHz, CDCl
3
) d 175.8, 155.8, 143.7, 130.0, 126.8, 124.4, 123.2, 108.6, 81.9,
+
7
9.0, 53.0, 37.4, 35.4, 28.4, 26.2; HRMS (EI) m/z: [M + H] Calcd for C17
H
25
N
2
4
O ,
321.1814; Found, 321.1822.
Di-tert-butyl ((3-hydroxy-1-benzyl-2-oxoindolin-3-yl)ethynyl)-imidocarbonate (27)
A N
mg, 0.40 mmol, 2.0 eq.) and HMPA (0.07 mL, 0.40 mmol, 2.0 eq.) in toluene (1.0 mL)
was treated with Et Zn (0.40 mL of a 1 M solution in hexanes, 0.40 mmol, 2.0 eq.) at
room temperature. After stirring for 2 h, 1-benzylindoline-2,3-dione (47 mg, 0.20 mmol,
.0 eq.) in toluene (1.0 mL) was added and the reaction mixture was stirred at room
temperature overnight. After 16 h, saturated NH Cl (aq.) (5 mL) and then H O (5 mL)
were added and the organics extracted with EtOAc (50 mL), dried (MgSO ), filtered and
2
purged flask containing di-tert-butyl ethynylimidodicarbonate compound 12 (96
2
1
4
2
4
concentrated under reduced pressure. The crude residue was purified through silica gel
chromatography (gradient elution 0-100 % EtOAc in hexanes) to provide compound 27
-1
(
59 mg, 61% yield) as a yellow oil. R
f
= 0.37 (40% EtOAc/hexanes); IR (CH
2
Cl , cm )
2
3
379, 3063, 2982, 2933, 2268, 1809, 1778, 1738, 1614, 1489, 1468, 1373, 1267, 1240,
1
1170, 1138, 1109, 982; H NMR (400 MHz, CDCl
3
) d 7.51 (1H, dd, J = 7.6, 1.0 Hz),
7
7
.27–7.36 (5H, m), 7.22 (1H, app td, J = 7.8, 1.2 Hz), 7.03–7.11 (1H, m), 6.71 (1H, d, J =
.8 Hz), 4.80–4.98 (2H, m), 3.60 (1H, s), 1.49 (18H, s); 13C{ H} NMR (101 MHz,
) d 173.7, 148.8, 142.0, 135.1, 130.3, 128.84, 128.80, 127.8, 127.1, 124.6, 123.5,
109.8, 85.1, 75.6, 71.8, 69.3, 44.0, 27.7; HRMS (EI) m/z: [M + NH
]+ Calcd for
, 496.2448; Found, 496.2453.
1
CDCl
3
4
C
27
H
34
N
3
O
6
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tert-Butyl-(2-(1-benzyl-3-hydroxy-2-oxoindolin-3-yl)ethyl)carbamate (28)
To compound 27 (35 mg, 0.073 mmol, 1.0 eq.) dissolved in EtOAc (5 mL) was added
Pd/C (16 mg of 10% w/w dry) and the flask was capped with a rubber septa and purged
with N
2
, then purged with a balloon of H
2
(5 min) and stirred at room temperature under a
and the reaction
1
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0
1
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0
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0
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8
9
0
balloon of H
2
for 32 h. Then, the reaction flask was purged with N
2
mixture filtered through Celite using EtOAc (40 mL) to wash/elute and the filtrate
concentrated under reduced pressure. The resulting crude residue (29 mg) was dissolved
in MeCN (3 mL) and Mg(ClO
was placed in a 55 º oil bath with a reflux condenser under N
portion of Mg(ClO (1.3 mg, 0.006 mmol, 0.1 eq.) was added and heating continued for
h. The reaction mixture was then cooled to room temperature, the volatiles removed
4
)
2
(1.3 mg, 0.006 mmol, 0.1 eq.) was added and the flask
2
for 3 h then a further
)
4 2
2
under reduced pressure and then the crude residue was purified through silica gel
chromatography (gradient elution 0-100 % EtOAc in hexanes) to provide compound 28
, cm-1)
(
17.2 mg, 62% yield) as a white wax. R
f
= 0.27 (40% EtOAc/hexanes); IR (CH
2
Cl
2
1
3
366, 3061, 2976, 2930, 1720, 1614, 1489, 1468, 1367, 1251, 1175; H NMR (400 MHz,
CDCl
3
) d 7.41 (1H, dd, J = 7.4, 0.8 Hz), 7.26–7.35 (5H, m), 7.21 (1H, app td, J = 7.8, 1.2
Hz), 7.02–7.11 (1H, m), 6.73 (1H, d, J = 7.8 Hz), 4.74–5.01 (3H, m), 3.26–3.38 (2H, m),
1
3
1
3
.22 (1H, br s), 2.08–2.26 (2H, m), 1.43 (9H, s); C{ H} NMR (126 MHz, CDCl ) d
3
1
77.8, 156.0, 142.2, 135.4, 129.8, 128.9, 127.8, 127.3, 127.2, 124.1, 123.3, 109.7, 79.4,
+
75.4, 43.8, 38.3, 35.6, 28.4; HRMS (EI) m/z: [M + Na] Calcd for C22
H
26
N
2
4
O Na,
4
05.1784; Found, 405.1785.
8-Benzyl-1-methyl-1,2,3,3a,8,8a-hexahydropyrrolo[2,3-b]indol-3a-ol (29)
Compound 28 (15.5 mg, 0.0406 mmol, 1.0 eq.) was charged to a flask and N
5 min, then dissolved in THF (3 mL) and cooled to 0 ºC in an ice/water bath. LiAlH
then added under N (0.14 mL of a 2.0 M solution in THF, 0.28 mmol, 7.0 eq.) and the
reaction mixture was stirred 15 min, then placed in a 65 ºC oil bath with a reflux
condenser under N for 14 h. The mixture was then cooled to room temperature and
quenched by addition of MeOH (1.0 mL) followed by stirring for 30 min. H O (1.0 mL)
2
purged for
4
was
2
2
2
was then added and the mixture stirred for an additional 30 min. The resulting slurry was
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