Effect of Terminal Alkylation of Aryl and Heteroaryl Hydrazines in the Fischer Indole Synthesis

Article abstract of DOI:10.1021/acs.joc.1c00203

The effect of alkylation on the terminal position of aryl and heteroaryl hydrazines in the Fischer indole synthesis was examined. Compared to their unalkylated counterparts, reactions using alkylated hydrazines provided indole products with higher yields and faster rates. The reactions can be conducted at lower temperatures and are compatible with acid-sensitive functionality. The terminally alkylated hydrazines were readily prepared by a new two-step sequence and held as stable hydrazinium salts. The mild formation of the salts along with the favorable Fischer indole reaction conditions highlights the potential of this approach in later-stage synthetic use.

Full text of DOI:10.1021/acs.joc.1c00203

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Effect of Terminal Alkylation of Aryl and Heteroaryl Hydrazines in
the Fischer Indole Synthesis
Michael A. Schmidt*
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ABSTRACT: The effect of alkylation on the terminal position of aryl and
heteroaryl hydrazines in the Fischer indole synthesis was examined. Compared to
their unalkylated counterparts, reactions using alkylated hydrazines provided indole
products with higher yields and faster rates. The reactions can be conducted at lower
temperatures and are compatible with acid-sensitive functionality. The terminally
alkylated hydrazines were readily prepared by a new two-step sequence and held as
stable hydrazinium salts. The mild formation of the salts along with the favorable
Fischer indole reaction conditions highlights the potential of this approach in later-
stage synthetic use.
a way to reduce the severity of the reaction conditions. We
hypothesized that terminal alkylation of the arylhydrazine can
facilitate key aspects of the transformation. For example, an N-
alkylated hydrazine is expected to be more nucleophilic and
would not be capable of forming a stable hydrazone
intermediate. More subtle benefits were also considered. They
include a more favorable tautomerization from 3 to 4,4 easier
access to the reactive conformer (i.e., 4), and a greater stability of
the [3,3] sigmatropic rearrangement product 5.5 This
modification would be traceless, as the alkyl group would depart
with the amine in the final stage of the reaction (i.e., 5 to 6)
without the need for further processing of the indole. Such an
approach has scarcely any precedent and no systematic or
synthetic study, being used only as a mechanistic probe in the
study of the Fischer indole synthesis.6 In this work, we describe
our investigation of this strategy. First, we report the synthesis of
a range of terminal N-alkyl hydrazines and then test their
reactivity in Fischer indole reactions.
INTRODUCTION
■
The Fischer indole synthesis is an enduringly popular method
for the construction of a wide range of indoles.1 Since its initial
report ∼140 years ago,2 a tremendous amount of research has
elucidated many idiosyncratic features of the reaction.1,3 In
practice, this reaction is limited to relatively simple substrates
because of the harsh conditions commonly used (excess acid/
Lewis acid, elevated temperatures). We considered terminal
alkylation of the arylhydrazine starting material 1 (Scheme 1) as
Scheme 1. Fischer Indole Reaction (Top); Methylated
Hydrazine Shown with Mechanistic Details (Bottom, This
Work)
RESULTS AND DISCUSSION
■
Synthesis of the N-Alkylhydrazine Salts. We explored a
two-step approach that yielded the N-alkyl hydrazine substrates
as HCl or HBF4 salts (Figure 1). The copper or palladium cross-
coupling reaction of aryl or heteroaryl bromides with
commercially available 1-methyl-1-Boc hydrazine (7) provided
N′-Boc-N′-methyl-N-arylhydrazine products. The copper con-
ditions recently reported by Singer et al.7 (CuI, L1, K2CO3,
Special Issue: Excellence in Industrial Organic Syn-
thesis 2021
Received: January 27, 2021
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Figure 1. Preparation of the terminally methylated hydrazine salts.
DMSO) worked well for unencumbered substrates (Figure 1).
For more challenging substrates, the palladium-catalyzed
conditions developed by Mauger and Mignani8 (Pd(OAc)2, X-
Phos, NaOH, tert-amyl alcohol) for the formation of N-aryl
benzophenone hydrazones proved successful. Even these
conditions fared poorly though, with 1-bromo-2,6-dichloroben-
zene (18% isolated yield after 16 h), so for this particular
substrate 44 (vide infra), we prepared it via terminal formylation
of 2,6-dichlorophenylhydrazine, methylation, and deprotection/
salt formation in a similar way to the reported conditions.6a The
Boc groups in compounds 8Boc−17Boc were removed with
concomitant salt formation under the action of either TMSCl in
methanol or HBF4·OEt2 in toluene. The salts studied herein
were stable, free-flowing, easily filterable solids.9
While methyl-substituted hydrazine 7 is readily available, we
prepared others in the series10 to examine the effect of the alkyl
chain in the Fischer indole reaction. These variants were coupled
to bromobenzene and deprotected affording salts in an
analogous manner: Et 8Et (52% overall), i-Pr 8i‑Pr (42% overall),
Bn 8Bn (48% overall), please see the Experimental Section for
more details.
Table 1. Effect of Different Terminal Substitution on the
Fischer Indole Reaction
b
entry
salt
temp/time
isolated yield or (solution yield)
1
2
3
4
5
6
7
R1 = Me 8
R1 = H 8H
R1 = Me 8
R1 = Et 8Et
R1 = i-Pr 8i‑Pr
R1 = Bn 8Bn
8Boc
50 °C/20 min
50 °C/240 min
23 °C/24 h
23 °C/24 h
23 °C/24 h
23 °C/24 h
96%
93%
(99%)
(89%)
(27%)
(99%)
90%
a
50 °C/1 h
a
1.50 equiv of TMSCl was added, and the reaction was run at 0.45 M.
Solution yield refers to the yield at the end of the reaction as
b
determined by calibrated HPLC analysis.
intermediate hydrazone by LC-MS. This precipitation may be a
contributing factor in the 12-fold increased reaction time (240
min) needed to form 19. The higher alkyl groups (8Et, 8i‑Pr, 8Bn)
were compared to 8 Table 1, entries 3−6), and a striking
sensitivity of the reaction rate was observed.9 Gratifying, the
most accessible salt, 8, was highly effective (99% solution yield)
over 8Et (89% solution yield) or 8i‑Pr (27% solution yield). The
benzyl analogue 8Bn also proceeded well (99% solution yield),
similar to 8. The performance of 8Bn may be attributed to subtle
effects on the pKa of the intermediates. Ethanol was the
preferred solvent over MeCN, DMF, DCM, and THF, affording
the highest yield of 19 in the shortest reaction times.9
Alkylated Hydrazines in the Fischer Indole Reaction.
We examined the Fischer indole transformation using the
alkylated analogues of phenylhydrazine (i.e., 8) (Table 1). To
simplify our studies, the reactions were carried out without
additional acids or Lewis acids. We used 4-phenylcyclohexanone
(18) as a representative carbonyl compound. A reaction using an
equimolar amount of 8 and 18 in ethanol (0.63 M) provided
indole 19 in 96% yield after 20 min at 50 °C. At 23 °C, the
reaction took 24 h to reach completion (99%). The expected
1
byproduct, methylamine hydrochloride, was detected by H
NMR spectroscopy of the crude reaction mixture.9 We did not
observe any intermediates (i.e., 3 or 4) by LC-MS, and the
reaction was homogeneous. This was in stark contrast to the
reaction of the desmethylated phenylhydrazine 8H with 18
(Table 1, entry 2). We observed rapid precipitation of the
It is noteworthy that the Boc-protected methylhydrazine
precursor 8Boc (Table 1, entry 7) could be used directly in the
Fischer indole reaction under acidic conditions (0.45 M ethanol,
1.00 equiv of 8Boc, 1.50 equiv of TMSCl, 50 °C, 1 h), affording
B
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Table 2. Fischer Indole Reaction of Sensitive Ketone 20 and Diketone 22
a
Please see the Experimental Section for exact conditions.
19 in 90% isolated yield. This single-step option may be useful if
isolation of the salt is problematic.
(i.e., Scheme 1, 3 to 4) and the indole product distribution
(Table 3, entry 1). As a control experiment, we heated 28 for 24
h at 50 °C in deuterated ethanol, and 1H NMR spectroscopy was
used to monitor deuterium incorporation. The methylene
adjacent to the p-nitrophenyl group incorporated deuterium
(74.5%) over the methylene adjacent to the p-methoxyphenyl
group (∼1%), indicating enolization of the carbon adjacent to
the p-nitrophenyl group (Table 3, 28D) was facile. The electron-
rich arylhydrazine salt 10 reacted with 28 to provide indole 29 in
83% yield over 22 h at 80 °C (Table 3, entry 1a). Other indole
isomers were not detected by LC-MS. Two-dimensional NMR
spectroscopy confirmed the structure, suggesting that the
product arises out of an enehydrazine in conjugation with the
p-methoxyphenyl group. A reaction under a Curtin−Hammett
scenario could explain this result (Table 3). The corresponding
parent desmethyl salt 10H afforded the indole product 29,
exclusively, in 69% yield, though the rate was significantly faster
(1.5 h versus 22 h), possibly due to reduced steric interactions
throughout the reaction (Table 3, entry 1c).13
To investigate a Curtin−Hammett scenario, the reaction of
10 and 28 was run in deuterated ethanol, and we obtained indole
29 with 71% deuterium incorporation at the methylene position.
A control experiment reveals 29 does not incorporate deuterium
under the reaction conditions. In addition, salt 10 was reacted
with truncated 1-aryl-2-propanones 31 and 32. As expected, the
reaction of 10 with 31 (Table 2, entry 2) was rapid and clean,
forming product 33 in 30 min (78%), while reaction with 32
(Table 3, entry 3) was slower, necessitating 4 h to form product
34 (85%).
Scope and Limitations. The effect of the hydrazine
alkylation on the Fischer indole reaction was evaluated by
directly comparing against the parent desmethylated aryl- or
heteroaryl- hydrazine. As before, an equimolar ratio of hydrazine
salt and carbonyl compound was used, no additional acids or
Lewis acids were added, and identical concentration and
temperatures were used unless noted.
The reaction of 8 with acid-sensitive 4-hydroxy-4-phenyl-
cyclohexanone (20) proceeded efficiently to provide indole 21
in 93% yield after 24 h at 23 °C (Table 2, entry 1a). With the
desmethyl salt 8H, we observed rapid precipitation of the
hydrazone (identified by LC-MS) and a slow conversion to 21,
affording only 53% after 1 week with an incomplete reaction
(Table 2, entry 1b). At 50 °C, the reaction with 8H was
homogeneous and faster (7 h), though only a 79% yield of 21
was obtained (Table 2, entry 2c). Despite the improved kinetics,
multiple impurities were observed. These impurities are likely
formed by oligomerization stemming from the tertiary benzylic
alcohol in 20 or 21.
We examined subtle effects on the carbonyl group with 7-
acetyl-1-tetralone 22 (Table 2, entry 2a).11 Salt 9 reacted cleanly
with diketone 22 over 26 h at 80 °C affording exclusively the
indole 23 in 88% yield. Using desmethyl salt 9H, indole 23 was
formed in 69% yield, though the reaction was far more complex
(Table 2, entry 2b).9 1H NMR spectroscopy and LC-MS
analysis of the reaction after 5 min revealed four products in
addition to the starting materials and the desired product. Two
products were identified as the isomeric monohydrazones (24
and 25 2:1 molar ratio, respectively). The remaining two minor
products were bishydrazone 26 and the hydrazone of the indole
product 27. We conclude that 9H can reversibly react with the
unique carbonyl groups of 22 and selectively forms product 23.
An electronically differentiated ketone 28 was prepared12 to
examine the relationship between the ease of tautomerization
Conversely to 10, the reaction of electron-poor arylhydrazine
salt 11 with 28 at 80 °C for 4 h consumed all of 11 and led to
multiple products (Table 3, entry 1b). Only Neber-like product
30 could be identified in 6% yield.14 Under identical conditions,
the parent desmethyl salt 11H was very sluggish to react with 28,
and after 24 h, both starting materials mostly remained (Table 3,
entry 1d).
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Table 3. Fischer Indole Studies on an Electronically Differentiated Ketone 22
a
Please see the Experimental Section for exact conditions.
Dinitro salt 11 was also reacted with 31 and 32. In the case of
31 (Table 3, entry 4), four products were isolated. Two products
were an inseparable mixture of ketones 35 and 36 (54:46 ratio,
respectively, 15% combined yield), another was 3,5-dinitroani-
line (37, 61%), and the final product was the desired indole 38
(14%). The reaction of 11 with 32 (Table 3, entry 5) was slow at
80 °C, and multiple products were observed. A major byproduct
was 37 and a yellow solid identified as the hydrazone 39 (7%),
indicating N-demethylation took place. The difficulty of
electron-deficient arylhydrazines to engage in the Fischer indole
synthesis is known3a and was observed with methylated
hydrazines; the major pathway being the dissociative fragmen-
tation of the N-N bond to an aniline and an oxidized carbonyl
compound.
performed in ethanol at 75 °C, though transesterification of the
isopropyl ester with the solvent could be observed by LC-MS
(∼5−10%). The addition of 0.5 equiv of pyridine was found to
suppress transesterification while maintaining the desired
reaction. By switching the solvent to 1-butanol and performing
the reaction at 90 °C, complete consumption of 12 was
observed. Analysis of the reaction by LC-MS indicated that 12 is
consumed faster than ketone 40. It was found that salt 12 is not
stable under the reaction conditions and is degraded to multiple
products. A major byproduct was identified as tricycle 42 (2%
isolated yield).9 The yield of indole 41 was improved by adding
an additional 1.00 equiv 12 and 0.50 equiv pyridine after 10 h.
This protocol provided indole 41 in 54% yield and with no
erosion of enantiopurity (94:6 er). The reaction of 12H with 40
in 1-butanol at 90 °C led down a drastically different pathway,
rapidly (2 h) forming the lactam 43 as the major product (50%),
with only trace amounts of the desired product (Table 4, entry
1b).
2-Hydrazinothiophenes are an interesting class of non-
benzenoid heterocycles capable of engaging carbonyl com-
pounds in a Fischer-like reaction.15 The reaction of thiophene
salt 12 with ketone 40 (94:6 er, Table 4, entry 1a)16 was initially
D
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Table 4. Fischer Indole Studies of Nonstandard Hydrazine Salts
a
b
c
Please see the Experimental Section for exact conditions. 1-Butanol was used as the solvent. 1.00 equiv of salt 12 and 0.50 equiv of pyridine were
d
used, and this charge was repeated after 10 h. Isopropanol was used as the solvent.
2,6-Dichlorophenyl hydrazine salt 44, as a free base, can be
used in a Fischer indole synthesis with cyclohexanone in
benzene at room temperature.6a A complex mixture of products
is formed, due to the chlorine atom inhibiting facile rear-
omatization post [3,3] sigmatropic rearrangement (see Table 4,
46 C2-chlorine).1a,6a Substrate 44 was examined under our
conditions. (Table 4, entry 2a). The reaction of 44 with 18 in
ethanol at 50 °C by LC-MS revealed a complicated mixture of
products from the incorporation of the solvent. By switching to
isopropanol, we could identify 45 as the major component
(33%), monochloro 47 (8%), and 48 (11%). Indoles 49 and 50
were observed in 1% and 2%, respectively. We hypothesized that
the prevalence of dichloro products arises from the exogenous
chloride brought in as the HCl salt. The free chloride can attack
intermediate 46 at the 3, 4, or 5 positions (Table 4, 46), leading
to products 49, 45, or 48, respectively.17 The desmethylated salt
44H, as expected, rapidly (<30 min) formed the hydrazone,
though converted very slowly over 6 days to indole products
(Table 4, entry 2b). The distribution of products was similar to
44 (19%, 45;14% ,47; 4%, 48; trace, 49; 1%, 50), though the
yield of product 45 was lower.
Azaindoles are an important class of pharmaceutically relevant
heterocycles, and the electron-rich subset is accessible via the
Fischer indole synthesis.18 The initial reaction of 1-(2-methoxy-
3-pyridyl)-2-methylhydrazine bishydrochloride (132HCl) with
hexanal (51, 1.10 equiv) for 2 h at 50 °C afforded a mixture with
four major products (Figure 2, entry a). The desired 6-azaindole
52 (47%) was identified along with desmethyl azaindole 53
(8%). Two other unexpected products were the N-methyl
azaindole product 54 (9%) and the ethoxylated 4-azaindole
isomer 55 (11%).17,19
Figure 2. Fischer indole reaction of 13 and 51 (top). Proposed
formation of 54 (below).
prepared the tetrafluoroborate salt form 13, and any subsequent
substrate with a 2-methoxypyridine structure was also prepared
as a tetrafluoroborate salt (Figure 1, 13, 14, and 16). The
reaction of 13 with 51 for 2 h at 50 °C afforded product 52 in
We expected desmethyl product 53 to be formed by
demethylation via chloride ion. Treatment of 52 with TMSCl
in ethanol at 50 °C revealed that 53 was formed. We, therefore,
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Table 5. Fischer Indole Reactions of Salts 14 and 15
a
b
Please see the Experimental Section for exact conditions. 1-Butanol was used as the solvent.
46% yield, along with 54 (11%) and 55 (15%) (Figure 2, entry
b). Product 53 was eliminated. Intrigued by the formation of N-
methyl azaindole 54, we prepared two deuterium-labeled salts,
Functional aldehyde equivalents such as lactols can be used in
the Fischer indole reaction. The reaction of salt 15 with
isochroman-3-ol24 (61) at 80 °C for 24 h afforded the desired
product 62 (30%) (Table 5, entry 2a). The N-methylated
product 63 was also isolated (4%). We observed ethyl benzyl
ethers 64 and 65 by LC-MS; therefore, we changed the solvent
to tert-amyl alcohol, expecting to eliminate these ethers. We
noted that the reaction appeared to boil and build pressure at 80
°C. We speculate that the conditions cause the dehydration of
the solvent to form amylene (bp 35−38 °C). We identified one
major intermediate, the hemiaminal 68 by LCMS and 1H NMR
spectroscopy, though the majority of the mass balance was
multiple unidentified byproducts. Performing the reaction in
isopropanol reduced the number of ether impurities, and we
obtained 62 in 34% yield and 63 in 2% yield. Besides a small
amount of the isopropyl ether 66 (4% yield), we also identified
benzyl chloride 67 (4% yield) and the aniline 69 (13% yield)
byproducts. The parent desmethyl salt 15H was reacted with 61
for 48 h at 80 °C (Table 5, entry 2b). A complex mixture of
multiple, low quantity products were observed. The expected
hydrazone intermediate was identified by LC-MS analysis as the
major species and converted inefficiently to product 62 (13%).
Encouraged by the heightened reactivity offered by
methylation, we examined pyridylhydrazines that are considered
challenging substrates for the synthesis of azaindoles (Table
6).18a,b We screened the reaction of salt 16 with three different
carbonyl compounds, 1-hexanal (51), ethyl pyruvate (56), and
4-tert-butylcyclohexanone (70). Only in the case of 70 did we
observe any indole products. We observed nondescript
decomposition with ethyl pyruvate and aldol-like dimerization
products with hexanal. The reaction of salt 16 with 70 after 8 h at
90 °C in 1-butanol led to product 71 in 97% yield (Table 6, entry
1a). We did not observe any indole N-methylated byproducts.
20
21
13OCD3 and 13NHCD3
.
These two substrates clearly showed
that the methyl on the indole nitrogen of 54 comes from the
terminal methyl group of the initial hydrazine salt.9 Inter-
molecular exchange of methylamine was ruled out by spiking a
reaction of 13NHCD3 with unlabeled methylammonium tetra-
fluoroborate. The 54 product of this reaction contained only the
indole N-CD3 label. A final experiment using 15N-labeled salt
1315N was performed,22 and the 54 product was found to be
unlabeled. The sum of these results point toward an intra-
molecular transfer of the methylamine group and would be an
example of a Fischer indole reaction where, subsequent to the
[3,3] rearrangement, the core heteroaryl nitrogen is lost, rather
than the side chain nitrogen.23 The reaction with the parent
desmethyl hydrazine salt 13H, under identical conditions, took
30 h to reach completion, affording 52 in 55% yield along with
55 (16%) (Figure 2, entry c). The inability to form 54 is likely
responsible for the higher yield.
The reaction of salt 14 with ethyl pyruvate (56, 1.10 equiv)
was very efficient, forming azaindole 57 in 90% yield after 15 h at
50 °C (Table 5, entry 1a). The isomeric azaindole 58 was
obtained in a 1% yield. While the remainder of the mass balance
was multiple unidentified products, one major byproduct was
hydrazone 59 in ∼5% yield. Interestingly, in this example, we did
not observe any N-methylated indole products. In stark contrast,
the desmethyl hydrazine 14H, under identical conditions, stalls
at the hydrazone 59 and does not convert to the product over 1
week of reaction time. Increasing the temperature to 80 °C for 8
days does not lead to product 57, hydrazone 59 was recovered in
62% yield, and the only observed indole product was the
desmethylated product 60 in 8% yield (Table 5, entry 1b).
F
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no indole was observed. We scaled the reaction with 2.00 equiv
of acetaldehyde diethyl acetal, but after 29 h, only a 16% yield of
74 was obtained. The use of a less electrophilic N,N-
dimethylhydrazone of acetaldehyde led to decomposition; no
indole or 74 was observed.
Table 6. Challenging Hydrazine Substrates
CONCLUSIONS
■
There are key advantages to using methylated hydrazines for a
Fischer indole reaction. The reactions can proceed at lower
temperatures and are often higher yielding with fewer
byproducts. For the reactions described herein, no additional
acid or Lewis acid was needed, and the substrate salt alone was
sufficiently reactive for the Fischer indole reaction to proceed by
warming in alcohol. These results allow for more sensitive
functionality to survive and bode well for the implementation of
a Fischer indole reaction in late-stage synthetic sequences. In
addition, the reactions were more likely to be homogeneous due
to the inability to form insoluble hydrazones. This aids in mass
transfer and improves the reaction rate. As a consequence of the
cleaner reaction profiles, product isolation is more straightfor-
ward.
The alkylated salts were readily prepared using a two-step
strategy. First, a flexible C−N cross-coupling reaction formed an
N-Boc-N-methyl arylhydrazine, which can be deprotected, and
the salt isolated in a direct-drop process. Additionally, the Boc-
intermediate can also be used directly in the Fischer indole
reaction without detriment, offering flexibility in the strategy.
a
Please see the Experimental Section for exact conditions.
EXPERIMENTAL SECTION
■
The desmethyl salt 16H took 30 h to reach full conversion,
though the yield was similar (95%) (Table 6, entry 1b).
General Remarks. All reactions were performed in round-bottom
flasks or vials, and stainless steel syringes were used to transfer liquids
(unless noted otherwise). To heat reactions, where noted, the flasks or
vials were inserted into appropriate aluminum reaction blocks
(Chemglass Optitherm blocks for flasks, Chemglass reactor pie-blocks
for vials). Flash column chromatography was performed on a Teledyne
ISCO CombiFlash Rf using silica gel (20−40 μm, Gold grade silica,
Unsubstituted 3-pyridyl methylhydrazine salt 17 was likewise
screened with 51, 54, and 70. Similarly to the reaction with 16,
only 70 afforded an indole product. The reaction of 17 with 70
after 10 h at 90 °C in 1-butanol afforded the expected 4-
azaindole product 72 in 67% yield The 6-azaindole isomer 73
was isolated in 6% yield (Table 6, entry 2a). We did observe a
trace amount of a methylated product in the course of the
reaction by LC-MS analysis. The desmethyl analogue 17H was
reacted under identical conditions, and while hydrazone
formation was rapid (<1 h by LC-MS analysis), the conversion
to the azaindole products was extremely slow, necessitating 2
weeks for complete conversion of the hydrazone (Table 6, entry
2b). Unlike the reaction with 17, the reaction with 17H and 70
produced many products, along with a significant amount of an
insoluble material. The azaindole 72 was isolated in a 13% yield.
The isomer 73 was detected in trace amounts
Teledyne ISCO). Organic solutions were concentrated on a Bu
Rotavapor R-143 at ∼20 Torr at 25−35 °C.
̈
chi
Commercial reagents and solvents were used as received. All
quantities expressed in the individual experiments are corrected for
purity as specified by the vendor. Arylhydrazine hydrochloride salts 8H,
9H, 17H, and 44H are commercially available. Salt 10H was prepared by
the method of Yu et al.;25 herein, we report the H NMR spectra.
1
Compounds 37, 58, 69, and 74 were confirmed by comparison of 1H
NMR spectra against purchased standards.
Reactions were monitored using a Shimadzu Nexera X2 UPLC
system equipped with a Shimadzu LCMS-2020 mass spectrometer. A
general method was used [Sample preparation: 20 μL reaction sample
diluted to 1.5 mL with 10 mM ammonium acetate in MeCN/water
(95:5 v/v%). Column: Agilent Poroshell EC-C18, 1.7 μm, 2.1 mm × 50
mm. Oven temperature: 40 °C. Injection volume: 1.0 μL. Flow rate: 1.0
mL/min. Detector wavelength: 220 nm. Mobile phase “A”: 10 mM
ammonium acetate in MeCN/water (5:95 v/v%). Mobile phase “B”: 10
mM ammonium acetate in MeCN/water (95:5 v/v%). Gradient, 0%
“B” ramp to 100% “B” over 4 min, then hold for 0.5 min]. Water content
was measured by coulometric titration (Karl Fischer titration) with a
Mitsubishi Chemical Analytech CA-310 Moisture meter. Proton
nuclear magnetic resonance (1H NMR) spectra were recorded with a
Bruker DPX 400 spectrometer and are recorded in parts per million
from internal tetramethylsilane on the δ scale and are referenced from
the residual protium in the NMR solvent (CHCl3, δ 7.27; C2D5HSO, δ
2.50; C2D3HO, δ 3.56, 1.11; CD2HOD, δ 3.31; C6D5H, δ 7.16). Data is
reported as follows: chemical shift [multiplicity (s = singlet, d = doublet,
t = triplet, q = quartet, m = multiplet), coupling constant(s) in hertz,
integration]. Carbon nuclear magnetic resonance (13C{1H} NMR)
spectra were recorded with a Bruker DPX 400 spectrometer and are
We explored the possibility of terminally methylated
hydrazines forming unsubstituted (i.e., C2,C3 = H) indoles
(Figure 3). Screening 8 with either acetaldehyde, acetaldehyde
diethyl acetal, or n-butyl vinyl ether in ethanol (10 mg/mL 8) at
80 °C for 24 h afforded the same major product in all cases,
which was identified as 2-methylquinoline (74). Product 74 may
̈
arise via a variant of the Skraup−Dobner−von Miller reaction,
Figure 3. Attempt to form parent indole.
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recorded in parts per million from internal tetramethylsilane on the δ
scale and are referenced from the carbon resonances in the NMR
solvent (CDCl3, δ 77.00; DMSO-d6, δ 39.51; MeOD-d4; δ 49.15; C6D6,
δ 128.39). Data is reported as follows: chemical shift [multiplicity (s =
singlet, d = doublet, t = triplet, q = quartet, m = multiplet), coupling
constant(s) in hertz]. Infrared data (FTIR) were obtained with an
Agilent Cary 630 FTIR spectrometer and are reported as follows:
[frequency of absorption (cm−1), intensity of absorption (a = apparent,
s = strong, m = medium, w = weak, br = broad). Melting points were
determined with a Thomas-Hoover capillary melting point apparatus.
High-resolution mass spectrometry (HRMS) was collected on an
Aglient Technologies 6230 series TOF LC/MS instrument or a Themo
LTQ-Orbitrap Discovery instrument. Optical rotations were measured
on a Reichert Polar3 Polarimeter. DSC measurements26 were
performed in a TA Instruments Q2000 DSC instrument, and data
was obtained as follows. Approximately 3−5 mg, recorded to 2 decimal
to an internal temperature of 4 °C with an ice−water bath, and a light
purge of nitrogen was applied to the headspace, venting to the back of
the hood. Chlorotrimethylsilane (8.75 mL, 67.48 mmol, 1.50 equiv)
was added dropwise at a rate such that the internal temperature did not
exceed 6.0 °C (10 min). The reaction mixture was warmed to room
temperature and stirred for 3 h. A crystalline slurry formed during the
process. The stirring was suspended, toluene (20 mL) was added, and
the meniscus was marked. Additional toluene (40 mL) was added, and
the slurry was concentrated in vacuo to the marked line. The slurry was
cooled to an internal temperature of 4 °C with an ice−water bath and
held for 30 min. The crystals were collected by filtration, washed with
toluene (2 × 20 mL), and then dried at an ambient temperature under
reduced pressure until a constant weight was achieved. Salt 8 was
obtained as white crystals (7.00 g, 98%) and was stored under nitrogen
at −20 °C. DSC (methanol/toluene), Tonset 125.98 °C, Tpeak 197.44 °C
(ΔHD 150.5 kJ/mol). 1H NMR (400 MHz, DMSO-d6): δ 11.40 (br s,
2H), 8.48 (br s, 1H), 7.29 (app t, J = 7.8 Hz, 2H), 7.15 (d, J = 8.2 Hz,
2H), 6.98 (t, J = 7.3 Hz, 1H), 2.75 (s, 3H). 13C{1H} NMR (101 MHz,
DMSO-d6): δ 143.6, 129.1, 122.3, 115.9, 33.8. IR (solid) (cm−1): 2672
(br m), 1457 (m), 1383 (m), 768 (s), 690 (s). HRMS (ESI): m/z [M +
H]+ calcd for C7H11N2, 123.0917; found, 123.0915.
̈
places, were accurately weighed into M20 gold-plated crucibles (TUV
̈
SUD Schweiz AG) rated to 217 bar. The crucibles were sealed under air
with the appropriate press (Schmidt Technologies Manual Press). After
equilibrating at 25 °C, the samples were heated at a rate of 4.0 °C per
min to a maximum temperature of 350 °C. Mass loss after completion
of the measurements was <1.0%. Data analysis was conducted using TA
Instruments Universal Analysis software version 4.5.0.5. Data is
reported as follows: (solvent system of isolation), Tonset corresponding
to the left-limit onset, Tpeak, (ΔHD: kJ/mol) of the major exo- or
endotherms.
Note! Many hydrazine salts exhibit proton NMR spectra with
extremely broadened resonances for the heteroatom-bonded protons
often leading to spectra with different than the theoretical amount of
protons. The data presented herein is reported as observed.
Caution! The carbon−nitrogen cross-coupling reactions are
sensitive toward air, especially so at their operating temperatures. To
monitor these reactions, they are first cooled to room temperature and
then sampled strictly under nitrogen with a nitrogen-purged stainless
steel needle and syringe. Sampling at elevated temperatures raises the
risk of prematurely terminating the reaction.
The higher alkyl derivatives 8Et, 8i‑Pr, and 8Bn were prepared
analogously, though the procedure was not optimized.
2-Ethyl-1-phenylhydrazine Hydrochloride (8Et): 3.17 mmol scale.
60% yield for the CN coupling and 87% yield for the HCl salt formation.
White solid (286 mg). 1H NMR (400 MHz, DMSO-d6): δ 11.11−11.21
(br m, 2H), 8.32−8.35 (br m, 1H), 7.31 (app t, J = 7.0 Hz, 2H), 7.11−
7.15 (m, J = 8.2 Hz, 2H), 6.99 (t, J = 7.3 Hz, 1H), 3.16 (q, J = 7.2 HZ,
2H), 1.27 (t, J = 7.3 HZ, 3H). 13C{1H} NMR (101 MHz, DMSO-d6): δ
143.6, 129.1, 122.1, 115.9, 42.9, 9.4. HRMS (ESI): m/z [M + H]+ calcd
for C8H13N2, 137.1073; found, 137.1070.
2-Isopropyl-1-phenylhydrazine Hydrochloride (8i‑Pr): 4.23 mmol
scale. 47% yield for the CN coupling and 90% yield for the HCl salt
formation. White solid (337 mg). 1H NMR (400 MHz, DMSO-d6): δ
11.13 (br s, 2H), 8.30 (br s, 1H), 7.29 (app t, J = 7.1 Hz, 2H), 7.18 (d, J
= 8.1 Hz, 2H), 6.97 (t, J = 7.1 Hz, 1H), 3.53 (septet, J = 6.5 Hz, 1H),
1.32 (d, J = 6.5 Hz, 6H). 13C{1H} NMR (101 MHz, DMSO-d6): δ
143.6, 129.0, 121.1, 116.0, 50.6, 17.3. HRMS (ESI): m/z [M + H]+
calcd for C9H15N2, 151.1230; found, 151.1227.
2-Benzyl-1-phenylhydrazine Hydrochloride (8Bn): 4.08 mmol scale.
62% yield for the CN coupling and 77% yield for the HCl salt formation.
White solid (396 mg). 1H NMR (400 MHz, DMSO-d6): δ 11.55 (br s,
2H), 8.49 (br s, 1H), 7.56−7.58 (m, 2H), 7.40−7.43 (m, 3H), 7.31
(app t, J = 7.9 Hz, 2H), 7.15 (d, J = 7.8 Hz, 2H), 6.98 (t, J = 7.3 Hz, 1H),
4.31 (s, 2H). 13C{1H} NMR (101 MHz, DMSO-d6): δ 143.6, 130.9,
130.5, 129.1, 129.0, 128.4, 122.0, 116.0, 51.4. HRMS (ESI): m/z [M +
H]+ calcd for C13H15N2, 199.1230; found, 199.1226.
2-Methyl-1-(4-chlorophenyl)hydrazine Hydrochloride (9). To a
dried flask equipped with a thermocouple were added copper(I) iodide
(591 mg, 3.10 mmol, 0.040 equiv), ligand L1 (1.13 g, 4.65 mmol, 0.060
equiv), and potassium carbonate (16.1 g, 116 mmol, 1.50 equiv). The
vessel was flushed and then maintained under a nitrogen atmosphere. 1-
Bromo-4-chlorobenzene (15.0 g, 77.6 mmol, 1.00 equiv) was added,
followed by hydrazine 7 (14.8 mL, 97.0 mmol, 1.25 equiv) and then
dimethyl sulfoxide (78 mL, deoxygenated by nitrogen sparging for 30
min, water content 454 ppm by Karl Fisher titration). The mixture was
heated to an internal temperature of 75 °C and stirred for 8 h. After
cooling to room temperature, the reaction mixture was filtered over a
pad of Celite (4.5 cm diameter, 1 cm height), and the pad was washed
with isopropyl acetate (2 × 50 mL). The mixture was poured into a 1.0
M aqueous solution of a pH 7 sodium phosphate buffer (100 mL),
forming a triphasic mixture (dark brown top layer, green middle layer,
blue bottom layer). The bottom two layers (green and blue) were
separated and extracted with isopropyl acetate (100 mL). The
combined organic extracts were washed with water (100 mL) and a
saturated, aqueous solution of brine (100 mL) and then dried over
anhydrous sodium sulfate. The drying agent was removed by filtration,
and the solution was concentrated in vacuo to afford a brown oil. The oil
was purified by flash column chromatography over silica gel (0−15%
ethyl acetate in hexanes gradient) to afford product 9Boc as a light yellow
Synthesis of N-Alkylated Hydrazine Salts. 2-Methyl-1-phenyl-
hydrazine Hydrochloride (8). To a dried flask equipped with a
thermocouple were added copper(I) iodide (480 mg, 2.52 mmol, 0.040
equiv), ligand L1 (917 mg, 3.78 mmol, 0.060 equiv), and potassium
carbonate (13.07 g, 94.58 mmol, 1.50 equiv). The vessel was flushed
and then maintained under a nitrogen atmosphere. Bromobenzene
(6.67 mL, 63.05 mmol, 1.00 equiv) was added, followed by hydrazine 7
(12.1 mL, 78.8 mmol, 1.25 equiv) and then dimethyl sulfoxide (63 mL,
deoxygenated by nitrogen sparging for 30 min, water content 396 ppm
by Karl Fisher titration). The mixture was heated to an internal
temperature of 75 °C and stirred for 8 h. After cooling to room
temperature, the reaction mixture was filtered over a pad of Celite (4.5
cm diameter, 1 cm height), and the pad was washed with isopropyl
acetate (2 × 50 mL). The mixture was poured into a 1.0 M aqueous
solution of a pH 7 sodium phosphate buffer (100 mL), forming a
triphasic mixture (dark brown top layer, green middle layer, blue
bottom layer). The bottom two layers (green and blue) were separated
and extracted with isopropyl acetate (100 mL). The combined organic
extracts were washed with water (100 mL) and a saturated, aqueous
solution of brine (100 mL) and then dried over anhydrous sodium
sulfate. The drying agent was removed by filtration, and the solution
was concentrated in vacuo to afford a brown oil. The oil was purified by
flash column chromatography over silica gel (0−15% ethyl acetate in
hexanes gradient) to afford product 8Boc as a white solid (12.34 g, 88%).
Rf (10% ethyl acetate in hexanes): 0.31 (UV). Mp (ethyl acetate/
1
hexanes): 76−78 °C. H NMR (400 MHz, DMSO-d6): δ 7.87 (br s,
1H), 7.16 (t, J = 7.9 Hz, 2H), 6.72 (t, J = 7.3 Hz, 1H), 6.58 (d, J = 7.7
Hz, 2H), 3.06 (s, 3H), 1.33 (br s, 9H). 13C{1H} NMR (101 MHz,
DMSO-d6): δ 155.4, 148.1, 128.8, 118.6, 111.7, 79.3, 37.1 (br), 27.8. IR
(solid) (cm−1): 3288 (m), 1674 (s), 1364 (s), 1155 (s) 752 (s). HRMS
(ESI): m/z [M + Na]+ calcd for C12H18N2NaO2, 245.1261; found,
245.1263.
The Boc hydrazine 8Boc (10.00 g, 44.99 mmol, 1.00 equiv) dissolved
in methanol (20 mL) after stirring for 15 min. The solution was cooled
H
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Article
solid (17.86 g, 90%). Rf (10% ethyl acetate in hexanes): 0.23 (UV). Mp
(ethyl acetate/hexanes): 66−69 °C. 1H NMR (400 MHz, DMSO-d6):
δ 8.07 (br s, 1H), 7.19 (d, J = 8.8 Hz, 2H), 6.59 (d, J = 8.8 Hz, 2H), 3.05
(s, 3H), 1.33 (br s, 9H). 13C{1H} NMR (101 MHz, DMSO-d6): δ
155.3, 147.1, 128.6, 122.0, 113.1, 79.5, 37.0 (br), 27.8. IR (solid)
(cm−1): 3284 (m), 1681 (s), 1360 (s), 1148 (s), 820 (s). HRMS (ESI):
m/z [M + H − C4H8]+ calcd for C8H10ClN2O2, 201.0425; found,
201.0425.
concentrated in vacuo to afford a rapidly crystallizing gel. Additional
toluene (20 mL) was added, and the mixture was concentrated in vacuo.
Toluene (20 mL) was added, and the crystals were collected by
filtration, washed with methyl tert-butyl ether (2 × 20 mL), and then
dried at an ambient temperature under reduced pressure until a
constant weight was achieved. Salt 10 was obtained as off-white
(yellowish) crystals (3.54 g, 91%) and was stored under nitrogen at −20
°C. DSC (methanol/toluene), Tonset 104.10 °C, Tpeak 202.31 °C (ΔHD
215.0 kJ/mol). 1H NMR (400 MHz, DMSO-d6): δ 11.00−11.40 (br m,
2H), 8.18−8.45 (br m, 1H), 6.34 (s, 1H), 6.31 (s, 1H), 6.15 (s, 1H),
3.71 (s, 6H), 2.75 (s, 3H). 13C{1H} NMR (101 MHz, DMSO-d6): δ
161.1, 145.5, 94.6, 94.3, 55.3, 33.8. IR (solid) (cm−1): 2628 (br), 1606
(m), 1465 (m), 1200 (s), 831 (s). HRMS (ESI): m/z [M + H]+ calcd
for C9H15N2O2, 183.1128; found, 183.1134.
The Boc hydrazine 9Boc (15.00 g, 58.43 mmol, 1.00 equiv) was
dissolved in methanol (30 mL) after stirring for 15 min. The solution
was cooled to an internal temperature of 4 °C with an ice−water bath,
and a light purge of nitrogen was applied to the headspace, venting to
the back of the hood. Chlorotrimethylsilane (11.5 mL, 87.64 mmol,
1.50 equiv) was added dropwise at a rate such that the internal
temperature did not exceed 6.0 °C (15 min). The reaction mixture was
warmed to room temperature and stirred for 5 h. A crystalline slurry
formed during the process. The stirring was suspended, toluene (30
mL) was added, and the meniscus was marked. Additional toluene (60
mL) was added, and the slurry was concentrated in vacuo to the marked
line. The slurry was cooled to an internal temperature of 4 °C with an
ice−water bath and held for 30 min. The crystals were collected by
filtration, washed with toluene (2 × 30 mL), and then dried at an
ambient temperature under reduced pressure until a constant weight
was achieved. Salt 9 was obtained as white crystals (10.82 g, 96%) and
was stored under nitrogen at −20 °C. DSC (methanol/toluene), Tonset
118.79 °C, Tpeak 190.04 °C (ΔHD 164.2 kJ/mol). 1H NMR (400 MHz,
DMSO-d6): δ 11.36 (br s, 1H), 8.58 (br s, 1H), 7.36 (app d, J = 8.8 Hz,
2H), 7.13 (app d, J = 8.9 Hz, 2H), 2.76 (s, 3H). 13C{1H} NMR (101
MHz, DMSO-d6): δ 142.6, 129.0, 126.0, 117.6, 33.8. IR (solid) (cm−1):
2658 (m), 1491 (m), 1092 (m), 820 (s), 663 (s). HRMS (ESI): m/z
[M + H]+ calcd for C7H10ClN2, 157.0527; found, 157.0527.
2-Methyl-1-(3,5-dimethoxyphenyl)hydrazine Hydrochloride (10).
To a dried flask equipped with a thermocouple were added copper(I)
iodide (170 mg, 0.894 mmol, 0.040 equiv), ligand L1 (325 mg, 1.34
mmol, 0.060 equiv), and potassium carbonate (4.63 g, 33.52 mmol,
1.50 equiv). The vessel was flushed and then maintained under a
nitrogen atmosphere. 1-Bromo-3,5-dimethoxybenzene (5.00 g, 22.34
mmol, 1.00 equiv) was added, followed by hydrazine 7 (4.27 mL, 27.93
mmol, 1.25 equiv) and then dimethyl sulfoxide (22 mL, deoxygenated
by nitrogen sparging for 30 min, water content 709.760 ppm by Karl
Fisher titration). The mixture was heated to an internal temperature of
75 °C and stirred for 16 h. After cooling to room temperature, the
maroon reaction mixture was filtered over a pad of Celite (3 cm
diameter, 1 cm height) (air exposure turns the reaction mixture green),
and the pad was washed with isopropyl acetate (3 × 25 mL). The
mixture was poured into a 0.5 M aqueous solution of a pH 7 sodium
phosphate buffer (50 mL), forming a triphasic mixture (dark brown top
layer, green middle layer, blue bottom layer), and the bottom two layers
(green and blue) were separated and extracted with isopropyl acetate
(50 mL). The combined organic extracts were washed with water (50
mL) and a saturated, aqueous solution of brine (50 mL) and then dried
over anhydrous sodium sulfate. The drying agent was removed by
filtration, and the solution was concentrated in vacuo to afford a brown
oil. The oil was purified by flash column chromatography over silica gel
(0−25% ethyl acetate in hexanes gradient) to afford product 10Boc as a
light yellow oil (5.90 g, 94%). Rf (20% ethyl acetate in hexanes): 0.30
(UV). 1H NMR (400 MHz, DMSO-d6): δ 7.87 (br s, 1H), 5.90 (t, J =
1.8 Hz, 1H), 5.73 (s, J = 2.0 Hz, 2H), 3.66 (s, 6H), 3.03 (s, 3H), 1.35 (br
s, 9H). 13C{1H} NMR (101 MHz, DMSO-d6): δ 161.7, 155.9, 150.5,
91.4, 90.8, 79.9, 55.3, 37.5, 28.4. IR (thin film) (cm−1): 3325 (w), 1696
(m), 1599 (m), 1144 (s), 816 (m). HRMS (ESI): m/z [M + H]+ calcd
for C14H23N2O4, 283.1652; found, 283.1659.
2-Methyl-1-(3,5-dinitrophenyl)hydrazine Hydrochloride (11). To
a dried flask equipped with a thermocouple were added copper(I)
iodide (153 mg, 0.802 mmol, 0.040 equiv), ligand L1 (291 mg, 1.20
mmol, 0.060 equiv), and potassium carbonate (4.15 g, 30.06 mmol,
1.50 equiv). The vessel was flushed and then maintained under a
nitrogen atmosphere. 1-Bromo-3,5-dinitrobenzene (5.00 g, 20.04
mmol, 1.00 equiv) was added, followed by hydrazine 7 (3.83 mL,
25.05 mmol, 1.25 equiv) and then dimethyl sulfoxide (20 mL,
deoxygenated by nitrogen sparging for 30 min, water content 709.306
ppm by Karl Fisher titration). The mixture was heated to an internal
temperature of 75 °C and stirred for 5 h. After cooling to room
temperature, the black reaction mixture was filtered over a pad of Celite
(3 cm diameter, 1 cm height), and the pad was washed with isopropyl
acetate (3 × 50 mL). The mixture was poured into a 0.5 M aqueous
solution of a pH 7 sodium phosphate buffer (50 mL), and the layers
were separated with the aid of a flashlight. The aqueous layer was
extracted with isopropyl acetate (3 × 50 mL). The combined organic
extracts were washed with water (50 mL) and a saturated, aqueous
solution of brine (50 mL) and then dried over anhydrous sodium
sulfate. The drying agent was removed by filtration, and the solution
was concentrated in vacuo to afford a black residue. The residue was
purified by flash column chromatography over silica gel (0−30% ethyl
acetate in hexanes gradient) to afford product 11Boc as a red oil that
crystallized to a yellow solid (5.56 g, 94%). Rf (20% ethyl acetate in
1
hexanes): 0.25 (UV). Mp (ethyl acetate/hexanes): 115−116 °C. H
NMR (400 MHz, DMSO-d6): δ 9.19 (s, 1H), 8.16 (t, J = 1.8 Hz, 1H),
7.70 (d, J = 1.7 Hz, 2H), 3.13 (s, 3H), 1.38 (br s, 9H). 13C{1H} NMR
(101 MHz, DMSO-d6): δ 154.8, 150.4, 148.9, 110.5, 107.1, 80.6, 37.1
(br), 27.7 (br). IR (solid) (cm−1): 1688 (s), 1543 (s), 1346 (s), 1144
(s), 726 (s). HRMS (ESI): m/z [M + H]+ calcd for C12H17N4O6,
313.1143; found, 313.1152.
The Boc hydrazine 11Boc (5.00 g, 16.01 mmol, 1.00 equiv) was
dissolved in methanol (50 mL). The solution was cooled to an internal
temperature of 2.5 °C with an ice−water bath, and a light purge of
nitrogen was applied to the headspace, venting to the back of the hood.
Chlorotrimethylsilane (4.15 mL, 32.02 mmol, 2.00 equiv) was added
dropwise at a rate such that the internal temperature did not exceed 5.0
°C (15 min). The reaction mixture was warmed to room temperature
and stirred for 15 h, whereupon yellow needles formed. The solvent was
concentrated in vacuo by 80%, then toluene (20 mL) was added, and the
solution was concentrated again in vacuo by 80%. Additional toluene
(15 mL) was added, and the crystals were collected by then dried at an
ambient temperature under reduced pressure until a constant weight
was achieved. Salt 11 was obtained as beige needles (3.87 g, 97%) and
was stored under nitrogen at −20 °C. DSC (methanol/toluene), Tonset
155.35 °C, Tpeak 187.73 °C (ΔHD 275.5 kJ/mol), Tpeak 312.00 °C (ΔHD
312.8 kJ/mol). 1H NMR (400 MHz, DMSO-d6): δ 10.00−12.00 (br s,
2H), 9.55 (br s, 1H), 8.31 (s, 1H), 8.26 (s, 2H), 2.81 (s, 3H). 13C{1H}
NMR (101 MHz, DMSO-d6): δ 148.6, 146.6, 114.5, 110.2, 34.4. IR
(solid) (cm−1): 2658 (br), 1536 (s), 1338 (s), 1174 (w), 723 (s).
HRMS (ESI): m/z [M + H]+ calcd for C7H9N4O4, 213.0618; found,
213.0623.
The Boc hydrazine 10Boc (5.00 g, 17.71 mmol, 1.00 equiv) was
dissolved in methanol (10 mL). The solution was cooled to an internal
temperature of 1 °C with an ice−water bath, and a light purge of
nitrogen was applied to the headspace, venting to the back of the hood.
Chlorotrimethylsilane (3.44 mL, 26.57 mmol, 1.50 equiv) was added
dropwise at a rate such that the internal temperature did not exceed 5.0
°C (15 min). The reaction mixture was warmed to room temperature
and stirred for 15 h. Toluene (10 mL) was added, and the solution was
Ethyl 5-(2-Methylhydrazinyl)thiophene-2-carboxylate Sesquihy-
drochloride (12). To a dried flask equipped with a thermocouple were
added copper(I) iodide (318 mg, 1.67 mmol, 0.040 equiv), ligand L1
(606 mg, 2.50 mmol, 0.060 equiv), and potassium carbonate (8.73 g,
I
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62.5 mmol, 1.50 equiv). The vessel was flushed and then maintained
under a nitrogen atmosphere. Ethyl 5-bromothiophene-2-carboxylate
(10.0 g, 41.7 mmol, 1.00 equiv) was added, followed by hydrazine 7
(7.97 mL, 52.1 mmol, 1.25 equiv) and then dimethyl sulfoxide (62.5
mL, deoxygenated by nitrogen sparging for 30 min, water content
207.336 ppm by Karl Fisher titration). The mixture was heated to an
internal temperature of 80 °C and stirred for 14 h. After cooling to room
temperature, the reaction mixture was filtered over a pad of Celite (4.5
cm diameter, 1 cm height), and the filter was washed with
dichloromethane (2 × 100 mL). The mixture was poured into a 0.50
M aqueous solution of a pH 7 sodium phosphate buffer (100 mL), and
the layers were separated. The aqueous layer was extracted with
dichloromethane (2 × 50 mL). The combined organic extracts were
washed with water (100 mL) and a saturated, aqueous solution of brine
(100 mL) and then dried over anhydrous sodium sulfate. The drying
agent was removed by filtration, and the solution was concentrated in
vacuo to afford a dark oil. The oil was purified by flash column
chromatography over silica gel (0−25% ethyl acetate in hexanes
gradient) to afford product 12Boc as a red gel (10.42 g, 83%). After
extended storage (>2 mo) at 4 °C, the material crystallized. Rf (15%
ethyl acetate in hexanes): 0.27 (UV). Mp (ethyl acetate/hexanes): 74−
75 °C. 1H NMR (400 MHz, CDCl3): δ 7.52 (d, J = 4.0 Hz, 1H), 6.54
(br s, 1H), 6.20 (d, J = 4.0 Hz, 1H), 4.29 (q, J = 7.1 Hz, 2H), 3.21 (s,
3H), 1.45 (s, 9H), 1.34 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (101 MHz,
CDCl3): δ 162.6, 161.9, 155.5, 134.2, 119.7, 106.2, 81.8, 60.6, 37.3,
28.1, 14.3. IR (thin film) (cm−1): 3276 (br w), 1677 (br m), 1450 (m),
1148 (s), 1085 (s). HRMS (ESI): m/z [M + H]+ calcd for C13H21N2O4,
301.1216; found, 301.1219.
The Boc hydrazine 12Boc (8.00 g, 26.63 mmol, 1.00 equiv) was
dissolved in methanol (16 mL). The solution was cooled to an internal
temperature of 2.3 °C with an ice−water bath, and a light purge of
nitrogen was applied to the headspace, venting to the back of the hood.
Chlorotrimethylsilane (8.70 mL, 66.58 mmol, 2.50 equiv) was added
dropwise at a rate such that the internal temperature did not exceed 5.0
°C (15 min). The reaction mixture was warmed to room temperature
and stirred for 2.5 h. A crystalline slurry formed during the process. The
stirring was suspended, toluene (16 mL) was added, and the meniscus
was marked. Additional toluene (40 mL) was added, and the slurry was
concentrated in vacuo to the marked line. The slurry was cooled to an
internal temperature of 4 °C with an ice−water bath and held for 30
min. The crystals were collected by filtration, washed with toluene (2 ×
16 mL), and then dried at an ambient temperature under reduced
pressure until a constant weight was achieved. Salt 12 was obtained as
bone-colored crystals (5.92 g) and was stored under nitrogen at −20
°C. The exact protonation state of the salt was difficult to determine by
NMR spectroscopy due to broad resonances. The solid was found to be
78.3 wt % free base (4.64 g) by quantitative NMR. The theoretical yield
of the free base is 5.33 g, corresponding to a corrected, isolated yield of
87%. This observed potency of 78.3% did not correspond to a
monohydrochoride (84.6 wt %) or a dihydrochloride (73.3 wt %) salt
but rather a sesquihydrochloride (78.5 wt %). As calculated as a
sesquihydrochloride salt, this would represent an 87% isolated yield of
the salt 12 having 99.7 wt % purity. DSC (methanol/toluene), Tonset
125.98 °C, Tpeak 148.95 °C (ΔHD144.6 kJ/mol). 1H NMR (400 MHz,
DMSO-d6): δ 9.80−12.30 (br s, 1.5H), 9.47 (br s, 1H), 7.56 (d, J = 4.0
Hz, 1H), 6.76 (d, J = 3.9 Hz, 1H), 4.23 (q, J = 7.1 Hz, 2H), 2.75 (s, 3H),
1.26 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (101 MHz, DMSO-d6): δ
161.4, 154.2, 133.7, 122.7, 113.4, 60.7, 34.0, 14.3. IR (solid) (cm−1):
3168 (w), 2691 (m), 1696 (m), 1457 (m). 1260 (s), 1085 (s). HRMS
(ESI): m/z [M + H]+ calcd for C8H13N2O2S, 201.0692; found,
201.0692.
sodium hydroxide (2.89 g, 71.48 mmol, 1.40 equiv), 3-bromo-2-
methoxypyridine (6.31 mL, 51.06 mmol, 1.00 equiv), and hydrazine 7
(9.77 mL, 63.82 mmol, 1.25 equiv) were added sequentially, and the
mixture was heated to an internal temperature of 90 °C under a
nitrogen atmosphere. The initially dark solution becomes a reddish
slurry, then a black suspension. After 2 h, the mixture is cooled to room
temperature and filtered through a pad of Celite (4.5 cm diameter, 1 cm
height), and the pad was washed with dichloromethane (3 × 50 mL).
The combined filtrates were concentrated in vacuo to afford a dark oil.
The oil was purified by flash column chromatography over silica gel (0−
25% ethyl acetate in hexanes gradient). The product 13Boc was isolated
as a syrup that, upon storage, at 4 °C slowly (1−2 days) solidifies to a
waxy solid (12.30 g, 95%). Rf (25% ethyl acetate in hexanes): 0.55
1
(UV). Mp (ethyl acetate/hexanes): 49−51 °C. H NMR (400 MHz,
DMSO-d6): δ 7.55 (br s, 1H), 7.52 (dd, J = 4.9, 1.6 Hz, 1H), 6.84 (dd, J
= 7.6, 5.0 Hz, 1H), 6.75 (dd, J = 7.6, 1.3 Hz, 1H), 3.88 (s, 3H), 3.05 (s,
3H), 1.32 (br s, 9H). 13C{1H} NMR (101 MHz, DMSO-d6): δ 155.2,
151.3, 134.8, 131.7, 117.2, 116.2, 79.5, 52.7, 36.8 (br), 27.8. IR (solid)
(cm−1): 3358 (w), 1692 (s), 1364 (s), 1148 (s), 805 (m). HRMS
(ESI): m/z [M + H]+ calcd for C12H20N3O3, 254.1499; found,
254.1497.
The Boc hydrazine 13Boc (12.30 g, 48.56 mmol, 1.0 equiv) was
dissolved in toluene (61.5 mL). The solution was cooled to an internal
temperature of 5 °C with an ice−water bath, and a light purge of
nitrogen was applied to the headspace, venting to the back of the hood.
The tetrafluoroboric acid-diethyl ether complex (14.4 mL, 101 mmol,
2.08 equiv) was added dropwise under vigorous stirring at a rate such
that the internal temperature did not exceed 6 °C (1 h), forming a
grainy slurry. Rapid addition of the acid will cause gelling; though after
further agitation, it will break down to a slurry. The slurry was aged for
an additional 1 h at room temperature. The product was collected by
filtration, washed with toluene (2 × 61 mL), and then dried at an
ambient temperature under reduced pressure until a constant weight
was achieved. The salt 13 was obtained as a light beige solid (15.64 g)
and was stored under nitrogen at −20 °C. The exact protonation state
of the salt (i.e., mono or bistetrafluoroborate) was difficult to determine
by NMR spectroscopy due to broad resonances. The solid was 45.1 wt
% as analyzed by quantitative NMR as the free base, corresponding to
7.05 g. The theoretical yield of the free base is 7.44 g, corresponding to a
corrected, isolated yield of 95%. As calculated as a bistetrafluoroborate
salt, this would represent a 95% isolated yield of the salt 13 having 96.8
wt % purity. DSC (toluene), Tonset 107.27 °C, Tpeak 165.44 °C (ΔHD
185.1 kJ/mol). 1H NMR (400 MHz, DMSO-d6): δ 10.58 (br s, 2H),
7.83 (dd, J = 5.0, 1.5 Hz, 1H), 7.31 (dd, J = 7.6, 1.5 Hz, 1H), 7.08 (v br s,
integration impeded by broadening), 7.01 (dd, J = 7.6, 5.1 Hz, 1H),
3.94 (s, 3H), 2.86 (s, 3H). 13C{1H} NMR (101 MHz, DMSO-d6): δ
153.6, 140.0, 127.5, 123.3, 117.6, 54.0, 34.8. IR (solid) (cm−1): 3127
(br), 1561 (m), 1271 (m), 984 (s), 764 (m). HRMS (ESI): m/z [M +
H]+ calcd for C7H12N3O, 154.0975; found, 154.0970.
The labeled compounds (13OCD3, 13NHCD3, and 1315N) were
prepared analogously.
2-(Methoxy-d3)-3-(2-methylhydrazinyl)pyridinium Bistetrafluor-
oborate (13OCD3): 10.47 mmol scale. 96% yield for the CN coupling
and 84% yield for the HBF4 salt formation. White solid (3.13 g, 42.2 wt
% calculated as free base). 1H NMR (400 MHz, DMSO-d6): δ 10.59 (br
s, 2H), 7.84 (dd, J = 5.0, 1.5 Hz, 1H), 7.32 (dd, J = 7.6, 1.5 Hz, 1H), 7.02
(dd, J = 7.7, 5.0 Hz, 1H), 6.79 (v br s, integration impeded by
broadening), 2.86 (s, 3H). 13C{1H} NMR (101 MHz, DMSO-d6): δ
153.7, 140.1, 127.5, 123.4, 117.7, 53.3 (app septet, J = 22.5 Hz), 34.9.
HRMS (ESI): m/z [M + H]+ calcd for C7H9D3N3O, 157.1163; found,
157.1167.
2-Methoxy-3-(2-methylhydrazinyl)pyridinium Bistetrafluorobo-
rate (13). To a dried flask equipped with a thermocouple was added
tert-amyl alcohol (200 mL, water content 145.9 ppm by Karl Fisher
titration). The solvent was deoxygenated by nitrogen sparging for 30
min, and then palladium acetate (351 mg, 1.53 mmol, 0.030 equiv) and
X-Phos (1.51 g, 3.06 mmol, 0.060 equiv) were added against a current
of nitrogen. The suspension was heated to an internal temperature of 65
°C (temperature ramp took 15 min), forming a very dark solution, and
then cooled to room temperature, forming a light slurry. Powered
2-Methoxy-3-(2-(methyl-d3)hydrazinyl)pyridinium Bistetrafluor-
oborate (13NHCD3): 6.11 mmol scale. 92% yield for the CN coupling
and 89% yield for the HBF4 salt formation. White solid (1.74 g, 44.4 wt
% calculated as free base). 1H NMR (400 MHz, DMSO-d6): δ 10.57 (br
s, 2H), 8.06 (br s, 1H), 7.83 (dd, J = 4.9, 1.5 Hz, 1H), 7.31 (dd, J = 7.6,
1.4 Hz, 1H), 7.01 (dd, J = 7.4, 5.2 Hz, 1H), 3.94 (s, 3H). 13C{1H} NMR
(101 MHz, DMSO-d6): δ 154.1, 140.2, 127.9, 124.1, 118.1, 54.6, 34.6
(app septet, J = 21.3 Hz). HRMS (ESI): m/z [M + H]+ calcd for
C7H9D3N3O, 157.1163; found, 157.1168.
J
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2-Methoxy-3-(2-methylhydrazinyl-1-15N)pyridinium Bistetra-
fluoroborate (1315N): 4.37 mmol scale. 86% yield for the CN coupling
and 90% yield for the HBF4 salt formation. White solid (1.20 g, 43.4 wt
% calculated as free base). 1H NMR (400 MHz, DMSO-d6): δ 10.58 (br
s, 2H), 8.04 (br s, 2H), 7.84 (dd, J = 5.0, 1.5 Hz, 1H), 7.31 (d, J = 7.6 Hz,
1H), 7.01 (dd, J = 7.6, 5.1 Hz, 1H), 3.94 (s, 3H), 2.86 (d, J = 2.6 Hz,
3H). 13C{1H} NMR (101 MHz, DMSO-d6): δ 153.8 (d, J = 2.9 Hz),
140.1, 127.7 (d, J = 7.3 Hz), 123.7, 117.8, 54.3, 35.0. HRMS (ESI): m/z
[M + H]+ calcd for C7H1215NN2O, 155.0945; found, 155.0951.
2-Methoxy-5-(2-methylhydrazinyl)pyridinium Bistetrafluorobo-
rate (14). To a dried pear-shaped flask equipped with a thermocouple
was added tert-amyl alcohol (100 mL, water content 150.9 ppm by Karl
Fisher titration). The solvent was deoxygenated by nitrogen sparging
for 30 min, and then palladium acetate (347 mg, 1.52 mmol, 0.030
equiv) and X-Phos (1.49 g, 3.03 mmol, 0.060 equiv) were added against
a current of nitrogen. The suspension was heated to an internal
temperature of 65 °C (temperature ramp took 15 min), forming a very
dark solution, and then cooled to room temperature, forming a slight
slurry. Separately, to a dried 500 mL round-bottomed flask were added
powered sodium hydroxide (2.83 g, 70.74 mmol, 1.40 equiv), 5-bromo-
2-methoxypyridine (6.88 mL, 50.53 mmol, 1.00 equiv), and hydrazine 7
(9.66 mL, 63.16 mmol, 1.25 equiv) under nitrogen. The dark palladium
mixture in the pear-shaped flask was transferred to the round-bottomed
flask using a wide bore (16 gauge) cannula. The cherry red suspension
was heated to an internal temperature of 90 °C under nitrogen. The
mixture changes from a cherry red suspension to a thick, pinkish-beige
suspension and then finally to a black slurry. After 3 h, the mixture is
cooled to room temperature and filtered through a pad of Celite (4.5 cm
diameter, 1 cm height), and the pad was washed with tert-amyl alcohol
(2 × 20 mL). The combined filtrates were concentrated in vacuo to
afford a dark oil. The oil was purified by flash column chromatography
over silica gel (0−60% ethyl acetate in hexanes gradient). The product
14Boc was isolated as a thick, tan syrup (11.76 g, 92%). Rf (30% ethyl
copper(I) iodide (397 mg, 2.08 mmol, 0.040 equiv), ligand L1 (758 mg,
3.13 mmol, 0.060 equiv), and potassium carbonate (10.91 g, 78.18
mmol, 1.50 equiv). The vessel was flushed and then maintained under a
nitrogen atmosphere. 2-Bromo-5-methoxypyridine (6.54 mL, 52.12
mmol, 1.00 equiv) was added, followed by hydrazine 7 (9.97 mL, 65.2
mmol, 1.25 equiv) and then dimethyl sulfoxide (52 mL, deoxygenated
by nitrogen sparging for 30 min, water content 655.8 ppm by Karl
Fisher titration). The mixture was heated to an internal temperature of
80 °C and stirred for 16 h. After cooling to room temperature, the
reaction mixture was filtered over a pad of Celite (4.5 cm diameter, 1 cm
height), and the pad was washed with isopropyl acetate (2 × 50 mL).
The mixture was poured into a 1.0 M aqueous solution of a pH 7
sodium phosphate buffer (100 mL), forming a triphasic mixture (dark
brown top layer, green middle layer, blue bottom layer). The bottom
two layers (green and blue) were separated and extracted with isopropyl
acetate (100 mL). The combined organic extracts were washed with
water (100 mL) and a saturated, aqueous solution of brine (100 mL)
and then dried over anhydrous sodium sulfate. The drying agent was
removed by filtration, and the solution was concentrated in vacuo to
afford a brown oil. The oil was purified by flash column
chromatography over silica gel (0−30% acetone in hexanes gradient)
to afford product 15Boc as a white solid (11.18 g, 85%). Rf (15% acetone
in hexanes): 0.19 (UV). Mp (acetone/hexanes): 96−97.5 °C. 1H NMR
(400 MHz, DMSO-d6): δ 8.16 (br s, 1H), 7.82 (d, J = 2.8 Hz, 1H), 7.26
(dd, J = 8.9, 2.8 Hz, 1H), 6.49 (d, J = 8.9 Hz, 1H), 3.72 (s, 3H), 3.06 (s,
3H), 1.28 (br s, 9H). 13C{1H} NMR (101 MHz, DMSO-d6): δ 155.7
(br), 153.5, 149.6, 133.2, 124.8, 107.1, 79.2 (br), 55.9, 37.3 (br), 27.9.
IR (solid) (cm−1): 3217 (br w), 1700 (s), 1364 (m), 1141 (s), 823 (s).
HRMS (ESI): m/z [M + H]+ calcd for C12H20N3O3, 254.1499; found,
254.1507.
The Boc hydrazine 15Boc (10.00 g, 39.48 mmol, 1.00 equiv) was
dissolved in methanol (50 mL) and then cooled to an internal
temperature of 0.5 °C with an ice−water bath, and a light purge of
nitrogen was applied to the headspace, venting to the back of the hood.
Chlorotrimethylsilane (15.2 mL, 118.4 mmol, 3.00 equiv) was added
dropwise at a rate such that the internal temperature did not exceed
+5.0 °C (30 min). The reaction mixture was allowed to warm to room
temperature and was stirred for 15 h, forming a white slurry after 30
min. The stirring was suspended, the meniscus was marked, and then
toluene (50 mL) was added. The mixture was concentrated to the
marked line; then additional toluene (50 mL) was added. The slurry
was stirred for 30 min; then the crystals were isolated by filtration and
then dried at an ambient temperature under reduced pressure until a
constant weight was achieved. Salt 15 was obtained as a light beige solid
(8.85 g) and was stored under nitrogen at −20 °C. The exact
protonation state of the salt (i.e., mono or bishydrochloride) was
difficult to determine by NMR spectroscopy due to broad resonances.
The solid was 64.5 wt % as analyzed by quantitative NMR as the free
base, corresponding to 5.71 g. The theoretical yield of the free base is
6.05 g, corresponding to a corrected, isolated yield of 94%. As calculated
as a bishydrochloride salt, this would represent a 94% isolated yield of
the salt 15 having 95.1 wt % purity. DSC (methanol/toluene), Tonset
147.29 °C, Tpeak 196.84 °C (ΔHD 234.9 kJ/mol). 1H NMR (400 MHz,
DMSO-d6): δ 8.79−12.36 (br m, 3H), 7.85 (d, J = 2.9 Hz, 1H), 7.47
(dd, J = 9.1, 2.9 Hz, 1H), 6.91 (d, J = 9.0 Hz, 1H), 3.77 (s, 3H), 2.74 (s,
3H). 13C{1H} NMR (101 MHz, DMSO-d6): δ 150.9, 149.2, 129.7,
127.5, 111.2, 56.3, 35.3. IR (solid) (cm−1): 2479 (br w), 1629 (w),
1349 (w), 1278 (s), 842 (m). HRMS (ESI): m/z [M + H]+ calcd for
C7H12N3O, 154.0975; found, 154.0979.
1
acetate in hexanes): 0.50 (UV). H NMR (400 MHz, DMSO-d6): δ
7.72 (br s, 1H), 7.52 (d, J = 2.7 Hz, 1H), 7.06 (dd, J = 8.8, 2.9 Hz, 1H),
6.68 (d, J = 8.8 Hz, 1H), 3.75 (s, 3H), 3.07 (s, 3H), 1.33 (br s, 9H).
13C{1H} NMR (101 MHz, DMSO-d6): δ 157.7, 155.4, 139.1, 129.9,
125.0, 110.3, 79.5, 52.8, 37.3 (br), 27.8. IR (thin film) (cm−1): 3302
(w), 1692 (m), 1487 (m), 1364 (m), 1148 (s). HRMS (ESI): m/z [M +
H]+ calcd for C12H20N3O3, 254.1499; found, 254.1506.
The Boc hydrazine 14Boc (9.25 g, 36.52 mmol, 1.00 equiv) was
dissolved in toluene (46 mL). The solution was cooled to an internal
temperature of 0.2 °C with an ice−water bath, and a light purge of
nitrogen was applied to the headspace, venting to the back of the hood.
The tetrafluoroboric acid-diethyl ether complex (11.0 mL, 76.69 mmol,
2.10 equiv) was added dropwise under vigorous stirring at a rate such
that the internal temperature did not exceed 5 °C (1 h), forming a
grainy slurry. Rapid addition of the acid will cause gelling; though after
further agitation, it will break down to a slurry. The slurry was aged for
an additional 1.5 h at room temperature. The product was collected by
filtration, washed with ethyl acetate (2 × 25 mL), and then dried at an
ambient temperature under reduced pressure until a constant weight
was achieved. If toluene is used as the cake wash, the salt will clump
upon storage. The salt 14 was obtained as a light beige solid (11.79 g)
and was stored under nitrogen at −20 °C. The exact protonation state
of the salt (i.e., mono or bistetrafluoroborate) was difficult to determine
by NMR spectroscopy due to broad resonances. The solid was 45.1 wt
% as analyzed by quantitative NMR as the free base, corresponding to
5.32 g. The theoretical yield of the free base is 5.59 g, corresponding to a
corrected, isolated yield of 95%. As calculated as a bistetrafluoroborate
salt, this would represent a 95% isolated yield of the salt 14 having 97.0
wt % purity. DSC (toluene), Tonset 123.68 °C, Tpeak 192.55 °C
(ΔHD182.5 kJ/mol). 1H NMR (400 MHz, DMSO-d6): δ 10.46 (br s,
2H), 7.98 (d, J = 2.8 Hz, 1H), 7.54 (dd, J = 8.9, 2.9 Hz, 1H), 6.89 (d, J =
8.8 Hz, 1H), 3.83 (s, 3H), 2.78 (br s, 3H). 13C{1H} NMR (101 MHz,
DMSO-d6): δ 160.7, 136.8, 133.8, 132.7, 111.3, 54.0, 34.3. IR (solid)
(cm−1): 3157 (br), 1565 (m), 1025 (s), 1006 (s), 839 (m). HRMS
(ESI): m/z [M + H]+ calcd for C7H12N3O, 154.0975; found, 154.0979.
5-Methoxy-2-(2-methylhydrazinyl)pyridinium Bishydrochloride
(15). To a dried flask equipped with a thermocouple were added
2-Methoxy-6-(2-methylhydrazinyl)pyridinium Bistetrafluorobo-
rate (16). To a dried flask equipped with a thermocouple were added
copper(I) iodide (310 mg, 1.59 mmol, 0.040 equiv), ligand L1 (580 mg,
2.39 mmol, 0.060 equiv), and potassium carbonate (8.35 g, 59.81
mmol, 1.50 equiv). The vessel was flushed and then maintained under a
nitrogen atmosphere. 2-Bromo-6-methoxypyridine (5.00 mL, 39.87
mmol, 1.00 equiv) was added, followed by hydrazine 7 (7.63 mL, 49.84
mmol, 1.25 equiv) and then dimethyl sulfoxide (40 mL, deoxygenated
by nitrogen sparging for 30 min, water content 205.85 ppm by Karl
Fisher titration). The mixture was heated to an internal temperature of
80 °C and stirred for 1 h. After cooling to room temperature, the
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reaction mixture was filtered over a pad of Celite (4.5 cm diameter, 1 cm
height), and the pad was washed with isopropyl acetate (2 × 76 mL).
The mixture was poured into a 0.5 M aqueous solution of a pH 7
sodium phosphate buffer (76 mL), and the layers were separated. The
aqueous layer was extracted with isopropyl acetate (76 mL), and the
combined organic extracts were washed with water (76 mL) and a
saturated, aqueous solution of brine (76 mL) and then dried over
anhydrous sodium sulfate. The drying agent was removed by filtration,
and the solution was concentrated in vacuo to afford a green-brown oil.
The oil was purified by flash column chromatography over silica gel (0−
20% ethyl acetate in hexanes gradient) to afford product 16Boc as a
colorless oil that rapidly crystallized (9.21 g, 91%). Rf (15% ethyl acetate
in hexanes): 0.43 (UV). Mp (ethyl acetate/hexanes): 74−75.5 °C. 1H
NMR (400 MHz, DMSO-d6): δ 8.50 (s, 1H), 7.44 (t, J = 7.8 Hz, 1H),
6.09 (d, J = 7.9 Hz, 1H), 6.04 (d, J = 7.8 Hz, 1H), 3.74 (s, 3H), 3.08 (s,
3H), 1.28 (br s, 9H). 13C{1H} NMR (101 MHz, DMSO-d6): δ 162.9,
157.8, 156.0 (br), 140.1, 98.9, 97.6, 79.2 (br), 52.4, 37.3 (br), 27.8. IR
(solid) (cm−1): 3317 (m), 1674 (s), 1364 (m), 1141 (s), 757 (m).
HRMS (ESI): m/z [M + H]+ calcd for C12H20N3O3, 254.1499; found,
254.1505.
The Boc hydrazine 16Boc (5.00 g, 19.74 mmol, 1.00 equiv) was
dissolved in toluene (25 mL). The solution was cooled to an internal
temperature of 1.2 °C with an ice−water bath, and a light purge of
nitrogen was applied to the headspace, venting to the back of the hood.
The tetrafluoroboric acid-diethyl ether complex (5.62 mL, 40.47 mmol,
2.05 equiv) was added dropwise under vigorous stirring at a rate such
that the internal temperature did not exceed 5 °C (1 h), forming a
grainy slurry. Rapid addition of the acid will cause gelling; though after
further agitation, it will break down to a slurry. The slurry was aged for
an additional 1.5 h at room temperature. The product was collected by
filtration, washed with ethyl acetate (2 × 10 mL), and then dried at an
ambient temperature under reduced pressure until a constant weight
was achieved. If toluene is used as the cake wash, the salt will clump
upon storage. Ssalt 16 was obtained as a white solid (5.99 g) and was
stored under nitrogen at −20 °C. The exact protonation state of the salt
(i.e., mono or bistetrafluoroborate) was difficult to determine by NMR
spectroscopy due to broad resonances. The solid was 45.8 wt % as
analyzed by quantitative NMR as the free base, corresponding to 2.74 g.
The theoretical yield of the free base is 3.02 g, corresponding to a
corrected, isolated yield of 91%. As calculated as a bistetrafluoroborate
salt, this would represent a 91% isolated yield of the salt 16 having 98.3
wt % purity. DSC (toluene), Tonset 104.39 °C, Tpeak 192.91 °C (ΔHD
214.4 kJ/mol). 1H NMR (400 MHz, DMSO-d6): δ 10.67 (br s, 3 H),
9.25 (br s, 1H), 7.64 (t, J = 7.9 Hz, 1H), 6.38 (app t, J = 7.3 Hz, 2H),
3.88 (s, 3H), 2.87 (s, 3H). 13C{1H} NMR (101 MHz, DMSO-d6): δ
163.3, 153.9, 141.8, 102.2, 101.0, 54.1, 35.6. IR (solid) (cm−1): 3112
(w), 1632 (m), 1286 (m), 1002 (s), 782 (m). HRMS (ESI): m/z [M +
H]+ calcd for C7H12N3O, 154.0975; found, 154.0979.
3-(2-Methylhydrazinyl)pyridinium Bishydrochloride (17). To a
dried flask equipped with a thermocouple were added copper(I) iodide
(477 mg, 2.51 mmol, 0.040 equiv), ligand L1 (911 mg, 3.76 mmol,
0.060 equiv), and potassium carbonate (13.12 g, 93.99 mmol, 1.50
equiv). The vessel was flushed and then maintained under a nitrogen
atmosphere. 3-Bromopyridine (6.10 mL, 62.66 mmol, 1.00 equiv) was
added, followed by hydrazine 7 (12.00 mL, 78.33 mmol, 1.25 equiv)
and then dimethyl sulfoxide (63 mL, deoxygenated by nitrogen
sparging for 30 min, water content 96.40 ppm by Karl Fisher titration).
The mixture was heated to an internal temperature of 80 °C and stirred
for 3 h. After cooling to room temperature, the reaction mixture was
filtered over a pad of Celite (4.5 cm diameter, 1 cm height), and the pad
was washed with isopropyl acetate (2 × 100 mL). The mixture was
poured into a 0.5 M aqueous solution of a pH 7 sodium phosphate
buffer (100 mL), and layers were separated. The aqueous layer was
extracted with isopropyl acetate (100 mL). The combined organic
extracts were washed with water (50 mL) and a saturated, aqueous
solution of brine (50 mL) and then dried over anhydrous sodium
sulfate. The drying agent was removed by filtration, and the solution
was concentrated in vacuo to afford a brown oil. The oil was purified by
flash column chromatography over silica gel (0−100% ethyl acetate in
hexanes gradient) to afford product 17Boc as a golden brown gel (11.56
g, 83%). Rf (75% ethyl acetate in hexanes): 0.38 (UV). 1H NMR (400
MHz, DMSO-d6): δ 8.19 (s, 1H), 7.96−7.97 (m, 2H), 7.19 (dd, J = 8.2,
4.6 Hz, 1H), 6.94 (ddd, J = 8.3, 2.7, 1.3, 1H), 3.09 (s, 3H), 1.33 (br s,
9H). 13C{1H} NMR (101 MHz, DMSO-d6): δ 155.2, 144.1 (br), 139.9,
134.5, 123.7 (br), 118.1, 79.7, 37.2 (br), 27.8. IR (thin film) (cm−1):
3299 (br w), 1700 (s), 1364 (m), 1148 (s), 7.08 (w). HRMS (ESI): m/
z [M + H]+ calcd for C11H18N3O2, 224.1394; found, 224.1399.
The Boc hydrazine (11.56 g, 39.48 mmol, 1.00 equiv) was dissolved
in methanol (23 mL) then cooled to an internal temperature of 2.3 °C
with an ice−water bath and a light purge of nitrogen was applied to the
headspace, venting to the back of the hood. Chlorotrimethylsilane (17.0
mL, 129.4 mmol, 2.50 equiv) was added dropwise at a rate such that the
internal temperature did not exceed +5.0 °C (30 min). The reaction
mixture was allowed to warm to room temperature and was stirred for
15 h. Toluene (23 mL) was added, then the stirring was suspended, and
the meniscus was marked. Additional toluene (46 mL) was added, and
the mixture was concentrated to the marked line. The slurry was cooled
to an internal temperature of 3.5 °C with an ice−water bath and was
stirred for 30 min. The crystals were isolated by filtration, washed with
toluene (2 × 23 mL), and then dried at an ambient temperature under
reduced pressure until a constant weight was achieved. The salt 17 was
obtained as a light beige solid (8.95 g) and was stored under nitrogen at
−20 °C. The exact protonation state of the salt (i.e., mono or
bishydrochloride) was difficult to determine by NMR spectroscopy due
to broad resonances. The solid was 61.4 wt % as analyzed by
quantitative NMR as the free base, corresponding to 5.50 g. The
theoretical yield of the free base is 6.38 g, corresponding to a corrected,
isolated yield of 86%. As calculated as a bishydrochloride salt, this
would represent an 86% isolated yield of the salt 17 having 97.8 wt %
purity. DSC (methanol/toluene), Tonset 124.83 °C, Tpeak 218.25 °C
(ΔHD 142.4 kJ/mol). 1H NMR (400 MHz, DMSO-d6): δ 12.83 (br s,
3H), 9.83 (br s, 1H), 8.63 (d, J = 1.7 Hz, 1H), 8.44 (br d, J = 5.1 Hz,
1H), 8.19 (dd, J = 8.4, 1.5 Hz, 1H), 7.92 (dd, J = 8.6, 1.5 Hz, 1H), 2.81
(s, 3H). 13C{1H} NMR (101 MHz, DMSO-d6): δ 143.5, 133.9, 130.2,
127.28, 127.25, 34.0. IR (solid) (cm−1): 2564 (br w), 1629 (w), 1561
(m), 805 (m), 675 (m). HRMS (ESI): m/z [M + H]+ calcd for
C6H10N3, 124.0869; found, 124.0871.
1-(2,6-Dichlorophenyl)-2-methylhydrazinium Hydrochloride
(44). The precursor was prepared as in ref 6a. For the final step,
removal of the N-formyl group, the following procedure was followed. A
solution of N′-(2,6-dichlorophenyl)-N-methylformylhydrazide (8.00 g,
36.5 mmol, 1.00 equiv) in ethanol (16.0 mL) was cooled to an internal
temperature of 2.3 °C whereupon a light slurry formed. Chloro-
trimethylsilane (9.5 mL, 73.0 mmol, 2.00 equiv) was added slowly at a
rate such that the internal temperature did not exceed 5.0 °C (∼10
min). The slurry was warmed to room temperature during which, at
approximately 10 °C, a yellow solution formed. After 30 min, the
product began to crystallize from solution. After stirring for a total of 2
h, a 50 vol% solution of ethanol in toluene (24 mL) was added, and the
slurry was cooled to an internal temperature of 1.8 °C with an ice−
water bath and held for 30 min. The crystals were collected by washed
with toluene (2 × 16 mL). After drying to a constant weigh under a
vacuum, salt 44 was isolated as white crystals (6.42 g, 77%) and was
stored under nitrogen at −20 °C. DSC (ethanol/toluene), Tonset 163.70
°C, Tpeak 225.26 °C (ΔHD 148.7 kJ/mol). 1H NMR (400 MHz,
DMSO-d6): δ 10.93 (br m, 2H), 7.72 (br s, 1H), 7.55−7.58 (m, 2H),
7.36 (t, J = 8.1 Hz, 1H), 2.81 (s, 3H). 13C{1H} NMR (101 MHz,
DMSO-d6): δ 136.0, 132.6, 129.6, 129.1, 36.2. IR (solid) (cm−1): 3213
(w), 2572 (w), 1573 (m), 1446 (m), 1144 (m), 779 (s). HRMS (ESI):
m/z [M + H]+ calcd for C7H8Cl2N2, 191.0137; found, 191.0142.
Synthesis of Unalkylated Hydrazine Salts. 3,5-Dimethoxyphe-
nylhydrazine Hydrochloride (10H): white solid. 1H NMR (400 MHz,
DMSO-d6): δ 10.22 (br s, 1H), 8.24 (br s, 1H), 6.20 (d, J = 1.2 Hz, 2H),
6.10 (t, J = 2.0 Hz, 1H), 3.70 (s, 6H).
3,5-Dinitrophenylhydrazine Hydrochloride (11H). Caution! The
stability of product 11H toward friction and shock was not investigated.
Caution must be exercised with this compound. To a dried flask was
added copper(I) iodide (122 mg, 0.641 mmol, 0.040 equiv), ligand L1
(232 mg, 0.958 mmol, 0.060 equiv), potassium carbonate (3.32 g, 24.02
mmol, 1.50 equiv), 1-bromo-3,5-dinitrobenzene (4.00 g, 15.87 mmol,
L
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1.00 equiv) and tert-butyl carbazate (2.64 g, 19.98 mmol, 1.25 equiv).
The vessel was flushed and then maintained under a nitrogen
atmosphere. DMSO (16 mL, deoxygenated by nitrogen sparging for
30 min, water content 141.811 ppm by Karl Fisher titration) was added.
The mixture stirred at room temperature for 3 days. When attempting
to run this reaction at 75 °C, we observed significant pressure build-up
and a greatly reduced yield of product (2.7%). The reaction mixture was
filtered over a pad of Celite (4.5 cm diameter, 1 cm heightt), and the
pad was washed with isopropyl acetate (2 × 40 mL). The mixture was
poured into a 0.5 M aqueous solution of a pH 7 sodium phosphate
buffer (120 mL), and layers were separated with the aid of a flashlight.
The aqueous layer was extracted with isopropyl acetate (3 × 20 mL).
The combined organic extracts were washed with water (80 mL) and a
saturated, aqueous solution of brine (80 mL) and then dried over
anhydrous sodium sulfate. The drying agent was removed by filtration,
and the solution was concentrated in vacuo to afford a black oil. The oil
was purified by flash column chromatography over silica gel (0−40%
ethyl acetate in hexanes gradient). Fractions were pooled that contained
the desired molecular weight (298.96 g/mol) and concentrated in vacuo
to afford the product as a dark gel (2.21 g). We did not fully characterize
this product.
The dark gel from above was dissolved in methanol (22 mL) then a
light purge of nitrogen was applied to the headspace, venting to the back
of the hood. Chlorotrimethylsilane (2.00 mL, 15.0 mmol, 2.00 equiv)
was added dropwise over 5 min. The reaction mixture was allowed to
stir for 24 h, forming a thick precipitate. Toluene (22 mL) was added,
and the precipitate was collected by filtration. The cake was washed
with toluene (2 × 11 mL) and dried at an ambient temperature under
reduced pressure until a constant weight was achieved. The product
11H was obtained as a bone-colored solid (860 mg, 23% from aryl
bromide) and was stored in a plastic vial, not glass, under nitrogen at
−20 °C. DSC (methanol/toluene), Tonset 204.43 °C, Tpeak 233.39 °C
(ΔHD: − 658.04 kJ/mol). 1H NMR (400 MHz, DMSO-d6): δ 10.53 (br
s, 2H), 9.48 (br s, 1H), 8.31 (m, 1H), 8.18 (m, 1H), 6.19 (br s, 1H).
13C{1H} NMR (101 MHz, DMSO-d6): δ 148.4, 148.0, 113.6, 109.5. IR
(solid) (cm−1): 3291 (w), 2878 (br m), 1532 (s), 1131 (s), 1088 (m).
HRMS (ESI): m/z [M + H]+ calcd for C6H7N4O4, 199.0462; found,
199.0460.
solids were collected by filtration, washed with toluene (2 × 10 mL),
and dried at an ambient temperature under reduced pressure until a
constant weight was achieved. The product 13H was obtained as a white
solid (4.34 g). The solid was 42.8 wt % as analyzed by quantitative
NMR as the free base, corresponding to a product that was obtained in
81% yield and 97 wt % purity. The NMR spectrum was similar to the
bishydrochloride. 1H NMR (400 MHz, DMSO-d6): δ 9.90 (br s, 3H),
7.77 (dd, J = 5.0, 1.4 Hz, 1H), 7.20 (dd, J = 7.7, 1.4 Hz, 1H), 6.99 (dd, J
= 7.6, 5.0 Hz, 1H), 3.93 (s, 3H). 13C{1H} NMR (101 MHz, DMSO-
d6): δ 152.6, 138.6, 129.4, 120.8, 117.2, 53.6.
5-Hydrazinyl-2-methoxypyridinium Bistetrafluoroborate (14H).
The free base (5-hydrazinyl-2-methoxypyridine) was prepared
according to Cook.27 5-Hydrazinyl-2-methoxypyridine (6.20 g, 44.6
mmol, 1.00 equiv) was stirred in toluene (56 mL) forming a red
suspension. The tetrafluoroboric acid-diethyl ether complex (13.0 mL,
93.6 mmol, 2.10 equiv) was added dropwise under vigorous stirring
over 1 h. A dark, gummy precipitate separated. The toluene was
decanted from the gum, and ethyl acetate (56 mL) was added. The
mixture was stirred for 14 h, becoming a slurry. The solids were
collected by filtration, washed with ethyl acetate (2 × 10 mL), and dried
at an ambient temperature under reduced pressure until a constant
weight was achieved. The product 14H was obtained as a reddish-brown
solid (10.18 g). The solid was 40.6 wt % as analyzed by quantitative
NMR as the free base, corresponding to a product that was obtained in
73% yield and 92.0 wt % purity. The NMR spectrum was consistent
with the product 14H. 1H NMR (400 MHz, DMSO-d6): δ 9.82 (br s,
4H), 7.89 (d, J = 2.7 Hz, 1H), 7.46 (dd, J = 8.9, 2.9 Hz, 1H), 6.86 (d, J =
8.9 Hz, 1H), 3.82 (s, 3H). 13C{1H} NMR (101 MHz, DMSO-d6): δ
159.5, 136.4, 132.8, 130.5, 111.1, 54.2.
2-Hydrazinyl-5-methoxypyridinium Bishydrochloride (15H). A
solution of the commercially available free base, 2-hydrazinyl-5-
methoxypyridine (80 wt %, 1.00 g, 5.75 mmol, 1.00 equiv) in methanol
(5.0 mL), was cooled in an ice-water bath for 10 min, then
chlorotrimethylsilane (2.2 mL, 17.2 mmol, 3.0 equiv) was added
dropwise over 10 min. The reaction mixture was allowed to warm to
room temperature and stir for 1 h. The slurry was filtered, and the solids
were washed with methyl tert-butyl ether (2 × 5 mL) to afford salt 15H
as a tan solid (1.09 g). The solid was 60.8 wt % as analyzed by
quantitative NMR as the free base (663 mg), corresponding to a
product that was obtained in 89% yield and 92.7 wt % purity. The NMR
Ethyl 5-Hydrazinylthiophene-2-carboxylate Hydrochloride (12H).
Di-tert-butyl 1-(5-ethoxycarbonylthiophen-2-yl)hydrazine-1,2-dicar-
boxylate was prepared according to Moody.15 To a solution of di-
tert-butyl 1-(5-ethoxycarbonylthiophen-2-yl)hydrazine-1,2-dicarboxy-
late (3.28 g, 8.49 mmol, 1.00 equiv) in methanol (6.5 mL) was charged
chlorotrimethylsilane (3.30 mL, 25.5 mmol, 3.00 equiv) over 5 min.
After 1 h, a thick precipitate was formed, and an additional charge of
chloromethylsilane (3.30 mL, 25.5 mmol, 3.00 equiv) and methanol
(6.5 mL) was added. After an additional 6 h, methanol (6.5 mL) was
added to the thick precipitate. The slurry stirred for an additional 17 h
(23 h total). The slurry was filtered, and the needles were washed with
methanol (2 × 7 mL) to afford the product as an off-white (peach) solid
(1.20 g). Unlike 12, this compound was found to be a monohydro-
chloride.
1
spectrum was consistent with the product 15H. H NMR (400 MHz,
DMSO-d6): δ 9.77 (br s, 5H), 7.87 (d, J = 2.6 Hz, 1H), 7.44 (dd, J = 9.1,
2.9 Hz, 1H), 6.90 (d, J = 9.0 Hz, 1H), 3.77 (s, 3H). This compound had
concentration-dependent instability in DMSO solution, complicating
13C NMR spectra acquisition. The solution stability was better in
methanol, and resonances were confirmed by 2D HSQC and HMBC
spectroscopy. 1H NMR (400 MHz, MeOD-d4): δ 7.63 (dd, J = 9.4, 2.7
Hz, 1H), 7.58 (dd, J = 2.7, 0.6 Hz, 1H), 6.96 (dd, J = 9.4, 0.6 Hz, 1H),
3.83 (s, 3H). 13C{1H} NMR (101 MHz, MeOD-d4): δ 152.3, 151.2,
134.8, 121.5, 113.4, 57.2.
2-Hydrazinyl-6-methoxypyridinium Bistetrafluoroborate (16H). A
solution of the commercially available free base, 2-hydrazinyl-6-
methoxypyridine (745 mg, 5.09 mmol, 1.00 equiv) in toluene (4.0
mL), was cooled in an ice-water bath to an internal temperature of 5.0
°C. The tetrafluoroboric acid-diethyl ether complex (1.48 mL, 10.7
mmol, 2.10 equiv) was added dropwise under vigorous stirring over 15
min. A dark red, gummy precipitate separated that broke down into a
free-flowing slurry after 30 min of stirring. The slurry was filtered, and
the solids were washed with methyl tert-butyl ether (2 × 8 mL) to afford
salt 16H as reddish solids (1.37 g). The solid was 44.0 wt % as analyzed
by quantitative NMR as the free base (603 mg), corresponding to a
product that was obtained in 81% yield and 99.5 wt % purity. The NMR
1H NMR (400 MHz, DMSO-d6): δ 10.39 (br s, 3H), 9.40 (br s, 1H),
7.54 (d, J = 4.2 Hz, 1H), 6.54 (d, J = 4.0 Hz, 1H), 4.22 (q, J = 7.1 Hz,
2H), 1.26 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (101 MHz, DMSO-d6): δ
161.6, 157.0, 133.8, 120.7, 110.0, 60.5, 14.3. IR (solid) (cm−1): 3168
(w), 2691 (m), 1696 (s), 1457 (m), 1260 (s). HRMS (ESI): m/z [M +
H]+ calcd for C7H11N2O2S, 187.0536; found, 187.0538.
3-Hydrazinyl-2-methoxypyridinium Bistetrafluoroborate (13H).
The dihydrochloride salt was prepared according to Houk and
Garg.18b The salt (3.50 g, 16.5 mmol, 1.00 equiv) was partitioned
between dichloromethane (50 mL) and a solution of 1 N aqueous
sodium hydroxide (50 mL). The layers were split, the aqueous layer was
extracted with dichloromethane (2 × 25 mL), and the combined
organic layers were dried over anhydrous sodium sulfate, filtered, and
concentrated in vacuo to afford the free base as a tea-colored oil (2.12 g,
92%).
1
spectrum was consistent with the product 16H. H NMR (400 MHz,
DMSO-d6): δ 9.92 (br s, 3H), 8.99 (br s, 1H), 7.61 (app t, J = 7.9 Hz,
1H), 7.46 (br s, 1H), 6.38 (d, J = 7.8 Hz, 1H), 6.35 (d, J = 7.9 Hz, 1H),
3.88 (s, 3H). 13C{1H} NMR (101 MHz, DMSO-d6): δ 163.1, 155.1,
141.4, 101.4, 100.7, 53.8.
The free base was dissolved in toluene (15 mL), and the
tetrafluoroboric acid-diethyl ether complex (4.73 mL, 33.0 mmol,
2.00 equiv) was added dropwise under vigorous stirring over 1 h. The
Synthesis of Indoles and Byproducts. 3-Phenyl-2,3,4,9-
tetrahydro-1H-carbazole (19). From 8, to a vial containing 8 (500
mg, 3.15 mmol, 1.00 equiv) and ketone 18 (560 mg, 3.15 mmol, 1.00
M
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equiv) was added absolute ethanol (5.0 mL, deoxygenated by nitrogen
sparging for 20 min). The mixture was placed under nitrogen heated to
an internal temperature of 50 °C for 20 min. The mixture was then
cooled to room temperature, and the solvent was concentrated in vacuo
to afford a residue. To the residue was added water (5.0 mL), and the
resulting slurry was stirred for 10 min. The solids were isolated by
filtration, then dried at 50 °C under vacuum until a constant weight was
achieved. Product 19 was isolated as a white powder (746 mg, 96%).
From 8Boc, to a vial containing 8Boc (200 mg, 0.900 mmol, 1.00
equiv) and ketone 18 (160 mg, 0.900 mmol, 1.00 equiv) was added
absolute ethanol (2.0 mL, deoxygenated by nitrogen sparging for 20
min), followed by chlorotrimethylsilane (180 μL, 1.35 mmol, 1.50
equiv). The mixture was placed under nitrogen heated to an internal
temperature of 50 °C for 1 h. The mixture was then cooled to room
temperature, and the solvent was concentrated in vacuo to afford a
residue. To the residue was added water (5.0 mL), and the resulting
slurry was stirred for 10 min. The solids were isolated by filtration,
washed with water (3 × 5.0 mL), and then dried at 50 °C under vacuum
until a constant weight was achieved. Product 19 was isolated as a white
powder (200 mg, 90%). This compound’s spectra matched the
literature report.28 1H NMR (400 MHz, CDCl3): δ 7.75 (br s, 1H), 7.46
(d, J = 7.6 Hz, 1H), 7.34−7.39 (m, 4H), 7.32 (d, J = 8.0 Hz, 1H), 7.24−
7.28 (m, 1H), 7.16 (app t, J = 7.4 Hz, 1H), 7.10 (app t, J = 7.3 Hz, 1H),
3.08−3.15 (m, 2H), 2.91−2.98 (m, 1H), 2.81−2.87 (m, 2H), 2.22−
2.26 (m, 1H), 2.10−2.20 (m, 1H). 13C{1H} NMR (101 MHz, CDCl3):
δ 146.7, 136.0, 133.6, 128.4, 127.5, 127.3, 126.2, 121.0, 119.2, 117.7,
110.4, 110.2, 41.1, 30.3, 29.2, 23.4. HRMS (ESI): m/z [M + H]+ calcd
for C18H18N, 248.1434; found, 248.1432.
3-Phenyl-2,3,4,9-tetrahydro-1H-carbazol-3-ol (21). To a round-
bottomed flask were added salt 8 (1.00 g, 6.30 mmol, 1.00 equiv) and
ketone 20 (1.20 g, 6.30 mmol, 1.00 equiv). Absolute ethanol (10 mL,
deoxygenated by nitrogen sparging for 20 min) was added, and the
mixture was stirred at room temperature. The reaction initially becomes
homogeneous and then a white precipitate forms. After 24 h, the solvent
was evaporated and the product was purified by flash column
chromatography over silica gel using a 0−70% ethyl acetate in hexanes
gradient. The indole 21 was isolated as a white solid (1.54 g, 93%).
Repeating the reaction with phenylhydrazine hydrochloride (8H, 300
mg) under similar conditions (50 °C) for 7 h afforded 428 mg (79%) of
21. Rf (20% ethyl acetate in hexanes): 0.26 (UV). Mp (ethyl acetate/
hexanes): 152.5−153.5 °C. 1H NMR (400 MHz, DMSO-d6): δ 10.66
(br s, 1H), 7.54 (app d, J = 7.3 Hz, 2H), 7.30−7.34 (m, 3H), 7.25 (d, J =
8.0 Hz, 1H), 7.22 (app t, J = 7.3 Hz, 1H), 6.99 (app t, J = 7.1 Hz, 1H),
6.92 (app t, J = 7.1 Hz, 1H), 5.04 (s, 1H), 3.08 (d, J = 15.8 Hz, 1H),
2.88−2.96 (m, 1H), 2.82 (d, J = 15.8 Hz, 1H), 2.54 (dt, J = 16.4, 4.8 Hz,
1H), 2.23 (ddd, J = 14.0, 9.3, 5.7 Hz, 1H), 1.98 (dt, J = 12.8, 5.2 Hz,
1H). 13C{1H} NMR (101 MHz, DMSO-d6): δ 149.7, 136.1, 133.6,
127.7, 127.4, 126.2, 125.1, 120.0, 118.0, 117.0, 110.5, 107.1, 71.7, 35.9,
35.6, 20.3. IR (solid) (cm−1): 3515 (m), 3288 (br), 1211 (m), 749 (s),
693 (s). HRMS (ESI): m/z [M + H]+ calcd for C18H18NO, 264.1383;
found, 264.1382.
(9H, 200 mg) under identical conditions afforded 287 mg of 23, which
was 78.5 wt % by quantitative NMR (225 mg, 69% corrected). Rf (30%
ethyl acetate in hexanes): 0.47 (UV). Mp (ethanol/water): 252−254
°C. Mp (recrystallized, tetrahydrofuran): 264−265 °C. Character-
1
ization was performed on the recrystallized material. H NMR (400
MHz, DMSO-d6): δ 11.85 (s, 1H), 8.27 (d, J = 1.6 Hz, 1H), 7.80 (dd, J
= 7.8, 1.7 Hz, 1H), 7.56 (d, J = 2.0 Hz, 1H), 7.44 (d, J = 7.8 Hz, 1H),
7.40 (d, J = 8.6 Hz, 1H), 7.10 (dd, J = 8.6, 2.1 Hz, 1H), 3.07 (app t, J =
7.6 Hz, 2H), 2.92 (app t, J = 7.5 Hz, 2H), 2.62 (s, 3H). 13C{1H} NMR
(101 MHz, DMSO-d6): δ 197.4, 141.6, 135.63, 135.61, 133.9, 128.9,
128.5, 127.6, 127.0, 123.7, 121.8, 120.5, 117.8, 112.9, 111.1, 28.9, 26.6,
18.7. IR (solid) (cm−1): 3273 (m), 1659 (s), 1409 (s), 1247 (s), 820
(m). HRMS (ESI): m/z [M + H]+ calcd for C18H15ClNO, 296.0837;
found, 296.0836.
4,6-Dimethoxy-2-(4-nitrobenzyl)-3-phenyl-1H-indole (29). To a
round-bottomed flask were added ketone 28 (1.00 g, 3.51 mmol, 1.00
equiv) and salt 10 (766 mg, 3.51 mmol, 1.00 equiv). Absolute ethanol
(10 mL, deoxygenated by nitrogen sparging for 20 min) was added, and
the mixture was heated to an internal temperature of 80 °C under a
nitrogen atmosphere. After 22 h, the deep red reaction mixture was
cooled to room temperature, and the crystalline slurry was concentrated
in vacuo to afford reddish-brown solids. The solids were broken down
and stirred in water (10 mL) for 30 min, then filtered. The cake was
washed with additional water (2 × 5 mL) and deliquored on the filter
until a sandy, free-flowing solid was obtained (∼10 min). The solids
were dissolved off the filter with dichloromethane (∼20 mL), and the
solvent was concentrated in vacuo. The residue was slurried in toluene
(10 mL) for 10 min and concentrated in vacuo. The sample was placed
under nitrogen, toluene (5.0 mL) was added, and the mixture was
brought to reflux, forming a dark red solution. Heating was
discontinued, heptane (2.0 mL) was added, and the solution was
allowed to cool to room temperature. At an internal temperature of
approximately 53 °C, crystallization began. Once the slurry reached
room temperature, it was stirred for an additional 15 min; then the red
crystals were isolated by dried at room temperature under reduced
pressure until a constant weight was achieved (1.22 g, 83%). Repeating
this reaction with 3,5-dimethoxyphenylhydrazine hydrochloride (10H,
136 mg) under identical conditions (1.5 h) afforded the indole 29 as red
crystals (193 mg, 69%). Rf (25% ethyl acetate in hexanes): 0.35 (UV).
1
Mp (toluene/heptane): 142−145 °C. H NMR (400 MHz, DMSO-
d6): δ 10.96 (s, 1H), 8.14 (d, J = 8.4 Hz, 2H), 7.33 (d, J = 8.4 Hz, 2H),
7.20 (d, J = 8.4 Hz, 2H), 6.88 (d, J = 8.4 Hz), 6.45 (s, 1H), 6.14 (s, 1H),
4.08 (s, 2H), 3.76 (s, 3H), 3.75 (s, 3H), 3.62 (s, 3H). 13C{1H} NMR
(101 MHz, DMSO-d6): δ 157.4, 156.4, 153.9, 148.4, 146.0, 137.2,
131.4, 129.7, 129.2, 128.0, 123.6, 113.8, 112.7, 111.0, 91.4, 87.0, 55.2,
54.9, 31.4. IR (solid) (cm−1): 3396 (m), 1506 (s), 1345 (m), 1148 (m),
801 (s). HRMS (ESI): m/z [M + H]+ calcd for C24H23N2O5, 419.1601;
found, 419.1587.
1-Ethoxy-1-(4-methoxyphenyl)-3-(4-nitrophenyl)propan-2-one
(30): dark oil (6%). Rf (20% ethyl acetate in hexanes): 0.34). 1H NMR
(400 MHz, DMSO-d6): δ 8.12 (d, J = 8.7 HZ, 2H), 7.31 (d, J = 8.7 Hz,
4H), 6.96 (d, J = 8.8 Hz, 2H), 5.01 (s, 1H), 4.08 (d, J = 16.9 Hz, 1H),
3.99 (d, J = 17.0 Hz, 1H), 3.76 (s, 3H), 3.45 (dq, J = 16.8, 7.0 Hz, 2H),
1.17 (t, J = 7.0 Hz, 3H). 13C{1H} NMR (101 MHz, DMSO-d6): δ
205.1, 159.3, 146.3, 142.7, 131.0, 128.7, 123.1, 114.1, 85.7, 64.3, 55.1,
43.8, 15.1. HRMS (ESI): m/z [M + H]+ calcd for C18H20NO5,
330.1336; found, 330.1347.
4,6-Dimethoxy-3-(4-methoxyphenyl)-2-methyl-1H-indole (33).
To a suspension of the salt 10 (100 mg, 0.457 mmol, 1.00 equiv) in
ethanol (1.00 mL, deoxygenated by nitrogen sparging for 30 min) was
added ketone 31 (71.8 μL, 0.457 mmol, 1.00 equiv), and the mixture
was heated to an internal temperature of 80 °C for 30 min. The mixture
was cooled to approximately 50 °C, and water (2.00 mL) was added.
The slurry was cooled to room temperature and stirred for 30 min. The
product 33 was isolated as a beige solid (106 mg, 78%). Rf (20% ethyl
acetate in hexanes): 0.26 (UV). Mp (ethanol/water): 164−165 °C. 1H
NMR (400 MHz, DMSO-d6): δ 10.83 (s, 1H), 7.23 (d, J = 8.7 Hz, 2H),
6.89 (d, J = 8.7 Hz, 2H), 6.42 (d, J = 2.0 Hz, 1H), 6.11 (d, J = 2.0 Hz,
1H), 3.77 (s, 3H), 3.74 (s, 3H), 3.61 (s, 3H), 2.23 (s, 3H). 13C{1H}
NMR (101 MHz, DMSO-d6): δ 156.9, 155.8, 153.4, 136.7, 131.5,
1-(8-Chloro-6,11-dihydro-5H-benzo[a]carbazol-2-yl)ethan-1-
one (23). To a round-bottomed flask were added salt 9 (1.00 g, 5.18
mmol, 1.00 equiv) and ketone 22 (957 mg, 1.00 equiv). Absolute
ethanol (10 mL, deoxygenated by nitrogen sparging for 20 min) was
added, and the mixture was sealed under nitrogen and heated to an
internal temperature of 80 °C for 26 h. The initial slurry dissolved, and
then a yellow precipitate formed after 30 min. The yellow slurry was
allowed to cool to room temperature, and then the solvent was removed
in vacuo. The yellow powder was broken down with a spatula and
slurried in water (10 mL) for 10 min, then filtered, and washed with
water (2 × 5 mL). Product 23 was dried at 50 °C under a vacuum until a
constant weight was achieved. The dried indole 23 (1.45 g) was found
to be 93 wt % by quantitative NMR (1.35 g, 88% corrected yield).
Further purification was hampered by the insolubility of the product,
though it can be recrystallized by dissolving in boiling tetrahydrofuran
(20 mL/g 23), allowing cooling to room temperature, standing for 24 h,
slowly removing 25% of the solvent in vacuo, and finally collecting the
large yellow plates by filtration. The recovery is typically 80% of theory.
Repeating the reaction with 4-chlorophenylhydrazine hydrochloride
N
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128.9, 128.5, 112.5, 112.0, 111.0, 91.1, 86.8, 55.2, 54.9, 54.8, 11.8. IR
(solid) (cm−1): 3332 (br m), 1558 (m), 1457 (m), 1196 (s), 1126 (s).
HRMS (ESI): m/z [M + H]+ calcd for C18H20NO3, 298.1438; found,
298.1449.
30 min) was added ketone 32 (75.9 mg, 0.457 mmol, 1.00 equiv), and
the mixture was heated to an internal temperature of 80 °C for 24 h.
The mixture was cool to room temperature and concentrated in vacuo.
The residue was partitioned between a 1.0 M aqueous solution of a pH
7 sodium phosphate buffer (15 mL) and ethyl acetate (15 mL). The
layers were separated with the aid of a flashlight, and any rag layer or
solid precipitates were retained in the organic phase. The organic layer
was dried over anhydrous sodium sulfate, filtered, and concentrated in
vacuo to afford a dark residue. The crude was purified by flash column
chromatography over silica gel (0−40% ethyl acetate in hexanes
gradient) to afford 23.1 mg of a dark yellow solid, approximately 80%
pure by NMR. This material was further purified by bringing a
suspension of the material in methanol (7 mL) to reflux and then
cooling and concentrating to ∼5 mL under a stream of nitrogen. The
product 39 was isolated as fine yellow needles (9.9 mg, 7%). The E
configuration of the hydrazone was determined by nOesy analysis. A
cross peak was observed between the proton on the nitrogen and the
methyl group adjacent to the hydrazone. Rf (40% ethyl acetate in
4,6-Dimethoxy-2-methyl-3-(4-nitrophenyl)-1H-indole (34). To a
suspension of the salt 10 (100 mg, 0.457 mmol, 1.00 equiv) in ethanol
(1.00 mL, deoxygenated by nitrogen sparging for 30 min) was added
ketone 32 (86.2 mg, 0.457 mmol, 1.00 equiv), and the mixture was
heated to an internal temperature of 80 °C for 4 h. The mixture was
cooled to approximately 50 °C, and water (2.00 mL) was added. The
slurry was cooled to room temperature and stirred for 30 min. The
product 34 was isolated as deep red crystals (125 mg, 88%). Rf (50%
ethyl acetate in hexanes): 0.66 (UV). Mp (ethanol/water): 195−197
°C. 1H NMR (400 MHz, DMSO-d6): δ 11.25 (s, 1H), 8.19 (d, J = 8.9
Hz, 2H), 7.58 (d, J = 8.9 Hz, 2H), 6.48 (d, J = 1.8 Hz, 1H), 6.21 (d, J =
1.8 Hz, 1H), 3.77 (s, 3H), 3.68 (s, 3H), 2.34 (s, 3H). 13C{1H} NMR
(101 MHz, DMSO-d6): δ 156.4, 153.2, 144.4, 143.9, 137.0, 131.7,
131.0, 110.9, 110.1, 91.8, 87.0, 55.2, 54.9, 12.1. IR (solid) (cm−1): 3362
(br w), 1592 (m), 1491 (m), 1327 (s), 1107 (s). HRMS (ESI): m/z [M
+ H]+ calcd for C17H17N2O4, 313.1183; found, 313.1196.
1
hexanes): 0.50 (UV). Mp (methanol): 211 °C (decomposition). H
NMR (400 MHz, DMSO-d6): δ 9.99 (s, 1H), 8,21 (d, J = 8.7 Hz, 2H),
8.08−8.15 (m, 3H), 7.56 (d, J = 8.6 Hz, 2H), 3.81 (s, 2H), 1.92 (s, 3H).
13C{1H} NMR (101 MHz, DMSO-d6): δ 149.2, 148.7, 148.1, 146.3,
3-(4-Methoxyphenyl)-2-methyl-4,6-dinitro-1H-indole (38). To a
suspension of the salt 11 (100 mg, 0.457 mmol, 1.00 equiv) in ethanol
(1.00 mL, deoxygenated by nitrogen sparging for 30 min) was added
ketone 31 (62.3 μL, 0.457 mmol, 1.00 equiv), and the mixture was
heated to an internal temperature of 80 °C for 2 h. The mixture was cool
to room temperature and concentrated in vacuo. The residue was
partitioned between a 1.0 M aqueous solution of a pH 7 sodium
phosphate buffer (10 mL) and ethyl acetate (10 mL). The layers were
separated, and the organic layer was dried over anhydrous sodium
sulfate, filtered, and concentrated in vacuo to afford a dark residue. The
crude was purified by flash column chromatography over silica gel (0−
40% ethyl acetate in hexanes gradient) to afford three products of
increasing polarity. The first product to elute was a 54:46 (35/36) ratio
of products as a yellow solid (20.3 mg combined mass, 15%). The
second product was 3,5-dinitroaniline (37, 44.9 mg, 61%) as a yellow
solid, and the third product was the indole 38 (18.2 mg, 14%) as a red
145.9, 130.4, 123.4, 111.3, 106.4, 43.9, 16.0. IR (solid) (cm−1): 3340
(w), 1536 (s), 1502 (m), 1338 (s), 727 (m). HRMS (ESI): m/z [M +
H]+ calcd for C15H14N5O6,360.0939; found, 360.0936.
Ethyl (S)-4-(1-tert-Butylsulfonamido)-2-isopropoxy-2-oxoethyl-5-
phenyl-6H-thieno[2,3-b]pyrrole-2-carboxylate (41). To a round-
bottomed flask were added ketone16 40 (1.00 g, 2.81 mmol, 1.00
equiv, 94:6 er) and thiophene salt 12 (720 mg, 2.81 mmol, 1.00 equiv).
1-Butanol (7.20 mL, deoxygenated by nitrogen sparging for 30 min)
was added, followed by pyridine (114 μL, 1.41 mmol, 0.50 equiv), and
the mixture was heated to an internal temperature of 90 °C under a
nitrogen atmosphere. After 10 h, the reaction was cooled to room
temperature, and an additional charge of salt 12 (720 mg, 2.81 mmol,
1.00 equiv) and pyridine (114 μL, 1.41 mmol, 0.50 equiv) were added
under a nitrogen atmosphere. The mixture was stirred at an internal
temperature of 90 °C for an additional 14 h, after which it was cooled to
room temperature and concentrated in vacuo. The residue was
partitioned between water (10 mL) and ethyl acetate (10 mL). The
layers were separated, and the aqueous layer was extracted with ethyl
acetate (2 × 5 mL). The combined organic layers were dried over
anhydrous sodium sulfate, filtered, and concentrated in vacuo to afford a
dark orange-brown gel. The gel was purified by flash column
chromatography over silica gel (0−50% ethyl acetate in hexanes
gradient) to afford a semipure product contaminated with 43. We
observed a white precipitate in a stretch of early eluting fractions. These
fractions were collected and concentrated in vacuo to afford a dark
yellow solid. This yellow solid was slurried in methyl tert-butyl ether (10
mL) and filtered to afford a bone-colored solid (20 mg) identified as
pyridine 42 (2% with respect to total 12 charged). The semipure
product 41 was subjected to additional purification by flash column
chromatography over silica gel (0−5% methyl tert-butyl ether in
dichloromethane) to afford pure 41, which tenaciously retains methyl
tert-butyl ether. Drying in a vacuum oven for 48 h at 50 °C afforded a
light yellow foam (770 mg, 54%, 94:6 er).
Repeating this reaction with desmethyl salt 12H (313 mg, 1.41 mmol,
1.00 equiv), ketone 40 (500 mg, 1.41 mmol, 1.00 equiv) in 1-butanol
(3.60 mL, deoxygenated by nitrogen sparging for 30 min) at an internal
temperature of 90 °C for 2 h under nitrogen, led to formation of the
cyclized product 43. The expected hydrazone from condensation of
12H and 40, and the desired product 43 were both observed in the
reaction mixture in low to trace amounts. After reaction workup as
above, and purification of the crude by flash column chromatography
over silica gel (5 to 35% ethyl acetate in hexanes gradient), the product
was isolated semipure as a red gel. Methanol (25 mL) was added to the
gel and the mixture was brought to a boil for 5 min. Cooling to room
temperature caused 43 to crystallize as fine white needles that were
collected by Buchner filtration, and washed with methanol (2 × 5 mL)
(325 mg, 50%). Rf (25% ethyl acetate in hexanes): 0.28 (UV). Rf (5%
methyl tert-butyl ether in dichloromethane): 0.50. [α]2D2 +107.4° (c 10.0
1
solid. Rf (40% ethyl acetate in hexanes): 0.32 (UV). H NMR (400
MHz, DMSO-d6): δ 12.81 (s, 1H), 8.56 (d, J = 2.0 Hz, 1H), 8.46 (d, J =
2.0 Hz, 1H), 7.10 (d, J = 8.6 Hz, 2H), 6.96 (d, J = 8.6 Hz, 2H), 3.80 (s,
3H), 2.43 (s, 3H). 13C{1H} NMR (101 MHz, DMSO-d6): δ 158.0,
146.1, 139.6, 139.0, 136.0, 130.4, 125.9, 121.9, 113.8, 113.3, 111.61,
111.58, 55.0, 12.7. IR (solid) (cm−1): 3325 (br w), 1498 (m), 1342
(m), 1323 (m), 1245 (s). HRMS (ESI): m/z [M + H]+ calcd for
C16H14N3O5, 28.0928; found, 328.0929.
1-((3,5-Dinitrophenyl)amino)-1-(4-methoxyphenyl)propan-2-
one (35) and 2-((3,5-Dinitrophenyl)amino)-1-(4-methoxyphenyl)-
propan-1-one (36). Rf (25% ethyl acetate in hexanes): 0.42 (UV). The
resonances due to the 3,5-dinitroaniline fragment could not be assigned
conclusively to a methoxyphenylpropanone backbone. Data for the
backbones are as follows. 1H NMR (400 MHz, DMSO-d6) 35: δ 7.44
(d, J = 8.6 Hz, 2H), 6.99 (d, J = 8.4 Hz, 2H), 5.68 (d, J = 7.1 Hz, 1H),
3.74 (s, 3H), 2.10 (s, 3H). 13C{1H} NMR (101 MHz, DMSO-d6) 35: δ
203.5, 159.2, 129.1, 128.1, 114.6, 64.9, 55.1, 26.7. 1H NMR (400 MHz,
DMSO-d6) 36: δ 8.14 (d, J = 8.9 Hz, 2H), 7.10 (d, J = 8.8 Hz, 2H), 5.53
(app pentet, J = 7.2 Hz, 1H), 3.88 (s, 3H), 1.49 (d, J = 6.8 Hz, 3H).
13C{1H} NMR (101 MHz, DMSO-d6) 36 δ: 197.8, 163.7, 131.0, 127.1,
1
114.2, 55.6, 52.4, 18.4. The remaining resonances are as follows. H
NMR (400 MHz, DMSO-d6): δ 7.95 (br t, J = 2.0 Hz, 1H), 7.93 (br t, J
= 2.0 Hz, 1H), 7.89 (br s, 2H), 7.86 (br s, 2H), 7.79 (d, J = 7.1 Hz, 1H),
7.43 (d, J = 7.8 Hz, 1H). 13C{1H} NMR (101 MHz, DMSO-d6): δ
149.5, 148.9, 148.7, 148.6, 112.0 (br), 111.5 (br), 104.6, 104.3. HRMS
(ESI): m/z [M − H]− calcd for C16H14N3O6, 344.0888; found,
344.0886.
3,5-Dinitroaniline (37). This compound’s 1H NMR spectrum
matched a commercially available sample. Rf (20% ethyl acetate in
1
hexanes): 0.31 (UV). H NMR (400 MHz, DMSO-d6): δ 7.90 (br s,
1H), 7.74 (d, J = 2.0 Hz, 2H), 6.52 (br s, 2H).
(E)-1-(3,5-Dinitrophenyl)-2-(1-(4-nitrophenyl)propan-2-ylidene)-
hydrazine (39). To a suspension of the salt 11 (100 mg, 0.457 mmol,
1.00 equiv) in ethanol (1.00 mL, deoxygenated by nitrogen sparging for
O
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Article
mg/mL, methanol). 1H NMR (400 MHz, DMSO-d6): δ 12.09 (s, 1H),
8.15 (s, 1H), 8.13 (d, J = 8.0 Hz, 1H), 7.60 (app d, J = 7.5 Hz, 2H), 7.53
(app t, J = 7.6 Hz, 2H), 7.43 (app t, J = 7.3 Hz, 1H), 5.23 (d, J = 8.7 Hz,
1H), 4.90 (septet, J = 6.2 Hz, 1H), 4.30 (q, J = 7.1 Hz, 2H), 1.32 (t, J =
7.1 Hz, 3H), 1.20 (d, J = 6.2 Hz, 3H), 1.08 (d, J = 6.2 Hz, 3H), 1.06 (s,
9H). 13C{1H} NMR (101 MHz, DMSO-d6): δ 170.2, 162.9, 138.3,
138.1, 131.6, 128.88, 128.84, 128.16, 128.14, 127.0, 124.6, 109.4, 68.9,
60.6, 58.7, 53.3, 23.5, 21.4, 21.3, 14.4. IR (solid) (cm−1): 3276 (br w),
1722 (m), 1685 (m), 1513 (m), 1282 (s), 1070 (s). HRMS (ESI): m/z
[M + NH4]+ calcd for C24H34N3O6S2, 524.1884; found, 524.1875.
Diethyl Dithieno[2,3-b:3′,2′-e]pyridine-2,6-dicarboxylate (42). A
positive NOE was observed between the singlet at 8.60 ppm and the
singlet at 8.11 ppm. Rf (20% ethyl acetate in hexanes): 0.39 (UV). 1H
NMR (400 MHz, CDCl3): δ 8.60 (s, 1H), 8.11 (s, 2H), 4.46 (q, J = 7.1
Hz, 4H), 1.45 (t, J = 7.1 Hz, 6H). 13C{1H} NMR (101 MHz, CDCl3): δ
163.0, 162.2, 133.8, 130.1, 129.5, 127.8, 62.1, 14.3. IR (solid) (cm−1):
1703 (s), 1528 (m), 1286 (m), 1066 (s), 731 (s). HRMS (ESI): m/z
[M + H]+ calcd for C15H14NO4S2, 336.0359; found, 336.0358.
(ESI): m/z [M + H]+ calcd for C18H16Cl2N, 316.0654; found,
316.0664.
8-Chloro-3-phenyl-2,3,4,9-tetrahydro-1H-carbazole (47): 70%,
light yellow crystals. Rf (5% ethyl acetate in hexanes): 0.44 (UV). Mp
1
(ethyl acetate/hexanes): 108−109 °C. H NMR (400 MHz, DMSO-
d6): δ 11.05 (s, 1H), 7.29−7.40 (m, 5H), 7.18−7.25 (m, 1H), 7.06 (d, J
= 7.6 Hz, 1H), 6.89−6.96 (m, 1H), 2.79−3.07 (m, 4H), 2.69 (dd, J =
15.1, 10.6 Hz, 1H), 1.98−2.15 (m, 2H). 13C{1H} NMR (101 MHz,
DMSO-d6): δ 146.5, 135.8, 132.8, 129.1, 128.3, 126.9, 126.0, 119.6,
119.1, 116.2, 115.2, 109.6, 40.5, 29.8, 29.1, 23.0. IR (solid) (cm−1):
3448 (m), 1487 (m), 1323 (m), 1178 (m), 999 (m). HRMS (ESI): m/z
[M + H]+ calcd for C18H17ClN, 282.1044; found, 282.1055.
7,8-Dichloro-3-phenyl-2,3,4,9-tetrahydro-1H-carbazole (48):
66%, white solid. Rf (5% ethyl acetate in hexanes): 0.36 (UV). Mp
1
(ethyl acetate/hexanes): 170−172 °C. H NMR (400 MHz, DMSO-
d6): δ 11.27 (s, 1H), 7.30−7.41 (m, 5H), 7.19−7.27 (m, 1H), 7.12 (d, J
= 8.3 Hz, 1H), 2.80−3.08 (m, 4H), 2.63−2.74 (m, 1H), 1.98−2.12 (m,
2H). 13C{1H} NMR (101 MHz, DMSO-d6): δ 146.4, 136.9, 133.7,
128.3, 127.4, 126.9, 126.1, 122.4, 119.8, 117.0, 113.3, 110.0, 40.3, 29.7,
28.8, 23.0. IR (solid) (cm−1): 3452 (m), 1450 (m), 1319 (w), 1159
(m), 1003 (w). HRMS (ESI): m/z [M + H]+ calcd for C18H16Cl2N,
316.0654; found, 316.0665.
Ethyl 5-(5-(tert-Butylsulfonamido)-6-oxo-3-phenyl-5,6-dihydro-
pyridazin-1(4H)-yl)thiophene-2-carboxylate (43). Rf (25% ethyl
1
acetate in hexanes): 0.29 (UV). Mp (methanol): 174−176 °C. H
NMR (400 MHz, DMSO-d6): δ 7.94−7.97 (m, 2H), 7.70 (d, J = 4.0 Hz,
1H), 7.69 (s, 1H), 7.50−7.59 (m, 3H), 7.39 (d, J = 4.3 Hz, 1H), 4.70
(ddd, J = 12.7, 8.8, 7.2 Hz, 1H), 4.28 (q, J = 7.1 Hz, 2H), 3.47 (dd, J =
16.9, 6.8 Hz, 1H), 3.20 (dd, J = 16.9, 12.8 Hz, 1H), 1.35 (s, 9H), 1.30 (t,
J = 7.1 Hz, 3H). 13C{1H} NMR (101 MHz, DMSO-d6): δ 164.0, 162.0,
154.3, 148.0, 134.4, 132.4, 130.8, 128.8, 126.6, 124.4, 114.5, 60.6, 59.2,
49.7, 31.4, 23.8, 14.2. IR (solid) (cm−1): 1681 (br m), 1442 (m), 1245
(s), 1122 (s), 1088 (s). HRMS (ESI): m/z [M + H]+ calcd for
C21H26N3O5S2, 464.1308; found, 464.1300.
5,8-Dichloro-3-phenyl-2,3,4,9-tetrahydro-1H-carbazole (49):
37%, white crystals. Rf (5% ethyl acetate in hexanes): 0.36 (UV). Mp
1
(ethyl acetate/hexanes): 156−158 °C. H NMR (400 MHz, DMSO-
d6): δ 11.42 (s, 1H), 7.28−7.38 (m, 4H), 7.17−7.26 (m, 1H), 7.03 (d, J
= 8.2 Hz, 1H), 6.92 (d, J = 8.1 Hz, 1H), 3.32 (br dd, J = 15.1, 4.2 Hz,
1H), 2.93−3.01 (m, 1H), 2.80−2.93 (m, 3H), 1.94−2.09 (m, 2H).
13C{1H} NMR (101 MHz, DMSO-d6): δ 146.4, 137.3, 133.6, 128.4,
126.9, 126.1, 125.4, 122.8, 120.2, 119.4, 114.2, 109.4, 40.5, 31.0, 29.0,
23.1. IR (solid) (cm−1): 3422 (m), 1461 (m), 1319 (m), 1147 (s), 1129
(m). HRMS (ESI): m/z [M + H]+ calcd for C18H16Cl2N, 316.0654;
found, 316.0669.
6,8-Dichloro-3-phenyl-2,3,4,9-tetrahydro-1H-carbazole (45). To
a round-bottomed flask was added salt 44 (1.00 g, 4.40 mmol, 1.00
equiv) and ketone 18 (781 mg, 4.40 mmol, 1.00 equiv). Isopropanol
(10 mL, deoxygenated by nitrogen sparging for 30 min) was added, and
the mixture was heated to an internal temperature of 50 °C under
nitrogen. A green-black solution formed. After 3 h, the reaction mixture
was cooled to room temperature and concentrated in vacuo to afford a
dark residue. The residue was partitioned between ethyl acetate (10 m)
and water (10 mL), and the layers were separated. The now reddish
organic layer was dried over anhydrous sodium sulfate, filtered, and
concentrated in vacuo. The crude was purified by flash column
chromatography over silica gel (0−10% ethyl acetate in hexanes
gradient) to afford two products. The first product to elute was pure 47
(104 mg, 8%) as a white solid. The second was a golden oil containing a
mixture of product (673 mg). By quantitative NMR: 45 (462 mg, 33%),
48 (154 mg, 11%), 49 (14.8 mg, 1%), and 50 (37 mg, 2%). Repeating
this reaction with 2,6-dichlorophenylhydrazine hydrochloride (44H,
1.00 g) under identical conditions for 6 days afforded the following: 45
(280 mg, 19%), 47 (183 mg, 14%), 48 (57 mg, 4%), 49 (<1%, trace),
and 50 (16.7 mg, 1%).
Preparation of Authentic Markers 45, 47−50. A general procedure
was followed, and 1.00 g of the parent hydrazine hydrochloride salt and
18 (1.00 equiv) were heated in ethanol (10 mL/g hydrazine salt) to 80
°C for 1 h. The reaction was cooled to room temperature and then
partitioned between EtOAc (15 mL/g) and a saturated aqueous
solution of sodium bicarbonate (10 mL/g). The organic layer was
separated, dried over anhydrous sodium sulfate, filtered, and
concentrated in vacuo to afford a solid residue. The residue was
purified by flash column chromatography over silica gel (0−10% ethyl
acetate in hexanes gradient) to afford the desired indole.
8-Chloro-6-isopropoxy-3-phenyl-2,3,4,9-tetrahydro-1H-carba-
zole (50). Rf (5% ethyl acetate in hexanes): 0.26 (UV). Mp (ethyl
1
acetate/hexanes): 114−115 °C. H NMR (400 MHz, DMSO-d6): δ
10.83 (s, 1H), 7.30−7.36 (m, 4H), 7.18−7.24 (m, 1H), 6.86 (d, J = 2.1
Hz, 1H), 6.71 (d, J = 2.1 Hz, 1H), 4.49 (septet, J = 6.1 Hz, 1H), 2.94−
3.04 (m, 1H), 2.76−2.94 (m, 3H), 2.64 (dd, J = 15.2, 10.5, 1H), 1.95−
2.12 (m, 2H), 1.22 (d, J = 6.0 Hz, 6H). 13C{1H} NMR (101 MHz,
DMSO-d6): δ 151.0, 146.5, 136.6, 128.9, 128.4, 128.2, 126.8, 126.0,
115.0, 111.1, 109.3, 102.7, 70.6, 40.5, 29.8, 29.2, 23.1, 21.9. IR (solid)
(cm−1): 3336 (br m), 1588 (m), 1208 (m), 1114 (s), 965 (m). HRMS
(ESI): m/z [M + H]+ calcd for C21H23ClNO, 340.1463; found,
340.1468.
3-Butyl-7-methoxy-1H-pyrrolo[2,3-c]pyridine (52). To a round-
bottomed flask was added salt 13 (1.00 g, 45.1 wt % calculated as free
base, 2.94 mmol, 1.00 equiv). Absolute ethanol (10 mL, deoxygenated
by nitrogen sparging for 20 min) was added, followed by freshly distilled
hexanal (51, 406 μL, 3.24 mmol, 1.10 equiv), and the homogeneous
solution was heated to an internal temperature of 50 °C under a
nitrogen atmosphere for 2 h. The solution was cooled to room
temperature and poured into a 0.5 M aqueous solution of a pH 7
sodium phosphate buffer (20 mL). The solution was extracted with
ethyl acetate (2 × 15 mL). The combined organic extracts were dried
over anhydrous sodium sulfate, filtered, and concentrated in vacuo to
afford a dark residue. The residue was purified by flash column
chromatography over silica gel (0−25% ethyl acetate in hexanes
gradient). The desired product 52 was isolated as a white solid (280 mg,
46%). N-Methyl analogue 54 was isolated as a colorless oil (69 mg,
11%) and the 4-azaindole 55 was isolated as a light tan oil that became a
wax upon standing (95 mg, 15%). Repeating the reaction with 3-
hydrazinyl-2-methoxypyridinium bistetrafluoroborate (13H, 300 mg,
42.8% calculated as free base) under identical conditions for 30 h
afforded the desired indole 52 as a white solid (104 mg, 55%) and the 4-
azaindole 55 as a light tan oil that became a wax upon standing (33 mg,
16%). Rf (15% ethyl acetate in hexanes): 0.34 (UV). Mp (ethyl acetate/
hexanes): 73−75 °C. 1H NMR (400 MHz, DMSO-d6): δ 11.35 (br s,
1H), 7.59 (d, J = 5.8 Hz, 1H), 7.17 (br s, 1H), 7.10 (d, J = 5.6 Hz, 1H),
3.98 (s, 3H), 2.64 (t, J = 7.6 Hz, 2H), 1.59 (quintet, J = 7.5 Hz, 2H),
6,8-Dichloro-3-phenyl-2,3,4,9-tetrahydro-1H-carbazole (45):
40%, white crystals. Rf (5% ethyl acetate in hexanes): 0.35 (UV). Mp
1
(ethyl acetate/hexanes): 126−127 °C. H NMR (400 MHz, DMSO-
d6): δ 11.31 (s, 1H), 7.39 (d, J = 1.6 Hz, 1H), 7.28−7.37 (m, 4H),
7.18−7.26 (m, 1H), 7.13 (d, J = 1.6 Hz, 1H), 2.79−3.06 (m, 4H), 2.65
(dd, J = 15.1, 10.5 Hz, 1H), 1.95−2.14 (m, 2H). 13C{1H} NMR (101
MHz, DMSO-d6): δ 146.3, 137.8, 131.5, 129.4, 128.3, 126.9, 126.1,
122.8, 119.0, 115.8, 115.6, 109.7, 40.2, 29.7, 28.7, 23.0. IR (solid)
(cm−1): 3437 (m), 1469 (m), 1293 (m), 1073 (m), 700 (s). HRMS
P
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1.33 (quintent, J = 7.4 Hz, 2H), 0.90 (t, J = 7.3 Hz, 3H). 13C{1H} NMR
(101 MHz, DMSO-d6): δ 150.7, 133.6, 133.0, 124.7, 120.4, 115.4,
108.5, 52.4, 32.2, 24.2, 21.9, 13.8. IR (solid) (cm−1): 1625 (m), 1375
(s), 1297 (s), 1077 (m), 1039 (m). HRMS (ESI): m/z [M + H]+ calcd
for C12H17N2O, 205.1335; found, 205.1334.
(ESI): m/z [M + H]+ calcd for C11H13N2O3, 221.0921; found,
221.0928.
Ethyl 5-Methoxy-1H-pyrrolo[2,3-c]pyridine-2-carboxylate (58).
This compound’s 1H NMR spectrum matched a commercially available
1
sample. Rf (10% acetone in dichloromethane): 0.29 (UV). H NMR
(400 MHz, C6D6): δ 8.09 (s, 1H), 7.92 (br s, 1H), 6.97 (s, 1H), 6.86 (d,
J = 1.0 Hz, 1H), 4.04 (q, J = 7.1 Hz, 2H), 3.98 (s, 3H), 1.98 (t, J = 7.2
Hz, 3H).
3-Butyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (53). Note
that this compound was wot observed when methylhydrazine 13 or
hydrazine 13H was used as the HBF4 salt. Rf (10% methanol in
dichloromethane): 0.44 (UV). Mp (methanol/dichloromethane):
Ethyl (E)-2-(2-(6-Methoxypyridin-3-yl)hydrazinylidene)-
propanoate (59). The E configuration of the hydrazone was
determined by nOesy analysis. A cross peak was observed between
the proton on the nitrogen and the methyl group adjacent to the
hydrazone. Rf (5% methanol in dichloromethane): 0.49 (UV). Mp
(methanol/dichloromethane): 118−119 °C. 1H NMR (400 MHz,
DMSO-d6): δ 9.80 (s, 1H), 8.08 (d, J = 2.7 Hz, 1H), 7.62 (dd, J = 8.9,
2.8 Hz, 1H), 6.79 (d, J = 8.8 Hz, 1H), 4.18 (q, J = 7.1 Hz, 2H), 3.80 (s,
3H), 2.04 (s, 3H), 1.26 (t, J = 7.1 Hz, 3). 13C{1H} NMR (101 MHz,
DMSO-d6): δ 164.8, 158.6, 135.9, 132.0, 131.7, 125.7, 110.5, 60.2, 53.0,
14.2, 11.7. IR (solid) (cm−1): 3284 (m), 1662 (m), 1368 (m), 1144 (s),
1029 (s). HRMS (ESI): m/z [M + H]+ calcd for C11H16N3O3,
238.1186; found, 238.1181.
Ethyl 5-Hydroxy-1H-pyrrolo[3,2-b]pyridine-2-carboxylate (60). Rf
(5% methanol in dichloromethane): 0.23 (UV). 1H NMR (400 MHz,
DMSO-d6): δ 12.11 (br s, 1H), 11.47 (br s, 1H), 7.57 (d, J = 9.5 Hz,
1H), 6.48 (d, J = 1.6 Hz, 1H), 6.25 (d, J = 9.5 Hz, 1H), 4.29 (q, J = 7.1
Hz, 2H), 1.30 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (101 MHz, DMSO-
d6): δ 161.8, 160.5, 130.4, 128.2, 125.4, 121.2, 118.4, 98.8, 60.4, 14.2. IR
(solid) (cm−1): 3183 (br w), 1681 (m), 1569 (m), 1211 (m), 812 (m).
HRMS (ESI): m/z [M + H]+ calcd for C10H11N2O3, 207.0764; found,
207.0769.
1
234−235 °C. H NMR (400 MHz, DMSO-d6): δ 11.58 (br s, 1H),
10.78 (br s, 1H), 7.04 (d, J = 2.3 HZ, 1H), 6.83 (t, J = 6.1 Hz, 1H), 6.41
(d, J = 6.8 Hz, 1H), 2.55 (t, J = 7.5 Hz, 2H), 1.54 (quintet, J = 7.5 Hz,
2H), 1.32 (app sextet, J = 7.4 Hz, 2H), 0.89 (t, J = 7.3 Hz, 3H). 13C{1H}
NMR (101 MHz, DMSO-d6): δ 155.1, 129.4, 123.9, 123.8, 123.7,
116.9, 32.5, 24.1, 21.9, 13.8. IR (solid) (cm−1): 3131 (br), 1644 (s),
1398 (s), 1103 (m), 749 (s). HRMS (ESI): m/z [M + H]+ calcd for
C11H15N2O, 191.1179; found, 191.1186.
3-Butyl-7-methoxy-1-methyl-1H-pyrrolo[2,3-c]pyridine (54). Rf
1
(15% ethyl acetate in hexanes): 0.53 (UV). H NMR (400 MHz,
DMSO-d6): δ 7.57 (d, J = 5.6 Hz, 1H), 7.17 (s, 1H), 7.08 (d, J = 5.6 Hz,
1H), 3.97 (s, 3H), 3.95 (s, 3H), 2.61 (t, J = 7.5 Hz, 2H), 1.58 (quintet, J
= 7.5 Hz, 2H), 1.33 (quintet, J = 7.4 Hz, 2H), 0.90 (t, J = 7.4 Hz, 3H).
13C{1H} NMR (101 MHz, DMSO-d6): δ 151.2, 133.8, 133.6, 130.1,
120.7, 114.4, 108.7, 52.6, 35.5, 32.1, 23.9, 21.9, 13.8. IR (solid) (cm−1):
1610 (m), 1543 (m), 1312 (s), 1249 (m), 805 (m). HRMS (ESI): m/z
[M + H]+ calcd for C13H19N2O, 219.1492; found, 219.1499.
3-Butyl-5-ethoxy-1-methyl-1H-pyrrolo[3,2-b]pyridine (55). Rf
1
(15% ethyl acetate in hexanes): 0.47 (UV). H NMR (400 MHz,
DMSO-d6): δ 10.75 (br s, 1H), 7.60 (d, J = 8.7 Hz, 1H), 7.22 (d, J = 2.3
Hz, 1H), 6.47 (d, J = 8.6 Hz, 1H), 4.32 (q, J = 7.0 Hz, 2H), 2.66 (t, J =
7.5 Hz, 2H), 1.67 (quintet, J = 7.5 Hz, 2H), 1.23−1.39 (m, 5H), 0.91 (t,
J = 7.3 Hz, 3H). 13C{1H} NMR (101 MHz, DMSO-d6): δ 158.0, 141.2,
124.8, 124.5, 122.0, 114.4, 104.1, 60.2, 31.8, 23.2, 21.9, 14.7, 13.8. IR
(solid) (cm−1): 3179 (br), 1565 (m), 1248 (s), 1107 (s), 719 (s).
HRMS (ESI): m/z [M + H]+ calcd for C13H19N2O, 219.1492; found,
219.1499.
2-(5-Methoxy-1H-indol-3-yl)phenylmethanol (62). To a round-
bottomed flask were added salt 15 (1.00 g, 64.5 wt % calculated as free
base, 4.21 mmol, 1.00 equiv) and isochroman-3-ol (61, 632 mg, 4.21
mmol, 1.00 equiv). Isopropanol (10 mL, deoxygenated by nitrogen
sparging for 30 min) was added, and the mixture was heated to an
internal temperature of 80 °C, forming a light yellow solution. After 24
h, the mixture was cooled to room temperature and concentrated in
vacuo to afford a yellow-brown residue. The residue was partitioned
between a 0.5 M aqueous solution of a pH 7 sodium phosphate buffer
(30 mL) and isopropyl acetate (15 mL). The layers were separated, and
the aqueous layer was extracted with isopropyl acetate (2 × 15 mL).
The combined organic extracts were dried over anhydrous sodium
sulfate, filtered, and concentrated in vacuo to afford a yellow-brown oil.
The crude was purified by flash column chromatography over silica gel
(0−100% ethyl acetate in dichloromethane gradient) to afford the
product 62 as an off-white (beige) solid (367 mg, 34%). The N-methyl
analogue 63 was isolated as a golden brown gel (27.6 mg, 2%). The
isopropyl ether product 66 was isolated as a dark residue (53.3 mg, 4%).
The benzyl chloride product 67 was isolated impure. It was
subsequently slurried in methanol (4 mL) then isolated by filtration
to afford 67 as an off-white (yellow) solid (43.5 mg, 4% yield). Aniline
69 was isolated as a dark residue (67.8 mg, 13%). Repeating this
reaction with 2-hydrazinyl-5-methoxypyridinium bishydrochloride
(15H, 400 mg, 60.8 wt % calculated as free base) and isochroman-3-
ol (61) under identical conditions for 48 h afforded the product 62
(60.5 mg, 13%). Rf (50% ethyl acetate in dichloromethane): 0.17 (UV).
Ethyl 5-Methoxy-1H-pyrrolo[3,2-b]pyridine-2-carboxylate (57).
To a round-bottomed flask was added salt 14 (1.00 g, 45.1 wt %
calculated as free base, 2.94 mmol, 1.00 equiv). Absolute ethanol (10
mL, deoxygenated by nitrogen sparging for 20 min) was added,
followed by ethyl pyruvate (56, 367 μL, 3.24 mmol, 1.10 equiv), and the
homogeneous solution was heated to an internal temperature of 50 °C
under a nitrogen atmosphere for 15 h. The solution was cool to room
temperature and concentrated in vacuo. The residue was partitioned
between a 0.5 M aqueous solution of a pH 7 sodium phosphate buffer
(15 mL) and isopropyl acetate (10 mL). The layers were separated, and
the aqueous layer was extracted with isopropyl acetate (10 mL). The
combined organic extracts were dried over anhydrous sodium sulfate,
filtered, and concentrated in vacuo to afford a yellow solid. The crude
was purified by flash column chromatography over silica gel (0−100%
ethyl acetate in hexanes gradient) to afford product 57 as an off-white
(beige) solid (585 mg, 90%). The remaining chromatography fractions
eluting after the product were concentrated in vacuo and purified by
flash column chromatography over silica gel (5−15% acetone in
dichloromethane gradient) to afford the 6-azaindole isomer 58 as a light
yellow solid (4.9 mg, 1%). Compound 58′s 1H NMR spectrum
matched a commercially available sample. Repeating the reaction with
5-hydrazinyl-2-methoxypyridinium bistetrafluoroborate (14H, 1.00 g,
40.6% calculated as the free base) under similar conditions (80 °C, 8
days) afforded, after flash column chromatography over silica gel (0−
10% methanol in dichloromethane gradient) the hydrazone 59 as a
golden-colored solid (427 mg, 62%) and the desmethylated indole 60
as a beige solid (49 mg, 8%). Rf (25% ethyl acetate in hexanes): 0.46
(UV). Mp (ethyl acetate/hexanes): 134−135 °C. 1H NMR (400 MHz,
DMSO-d6): δ 12.01 (br s, 1H), 7.76 (d, J = 8.9 Hz, 1H), 7.01 (s, 1H),
6.76 (d, J = 8.9 Hz, 1H), 4.35 (q, J = 7.1 Hz, 2H), 3.87 (s, 3H), 1.34 (t, J
= 7.1 Hz, 3H). 13C{1H} NMR (101 MHz, DMSO-d6): δ 161.0, 159.9,
140.4, 128.3, 126.8, 124.0, 109.5, 106.2, 60.6, 52.9, 14.3. IR (solid)
(cm−1): 3317 (m), 1685 (s), 1521 (m), 1204 (s), 775 (s). HRMS
1
Mp (ethyl acetate/dichloromethane): 150−151 °C. H NMR (400
MHz, DMSO-d6): δ 11.72 (br s, 1H), 8.02 (d, J = 2.7 Hz, 1H), 7.62 (d, J
= 2.4 Hz, 1H), 7.57−7.61 (m, 1H), 7.41−7.47 (m, 1H), 7.39 (d, J = 2.7
Hz, 1H), 7.29−7.37 (m, 2H), 5.14 (t, J = 5.3 Hz, 1H), 4.48 (d, J = 5.4
Hz, 2H), 3.79 (s, 3H). 13C{1H} NMR (101 MHz, DMSO-d6): δ 151.0,
143.8, 139.8, 133.3, 132.8, 129.6, 128.6, 127.0, 126.2, 125.9, 118.5,
112.3, 109.4, 61.2, 55.9. IR (solid) (cm−1): 3355 (br w), 1580 (w),
1200 (m), 1029 (m), 757 (s). HRMS (ESI): m/z [M + H]+ calcd for
C15H15N2O2, 255.1128; found, 255.1136.
(2-(5-Methoxy-1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)phenyl)-
1
methanol (63). Rf (50% ethyl acetate in dichloromethane): 0.43. H
NMR (400 MHz, C6D6): δ 8.37 (d, J = 2.7 Hz, 1H), 7.62 (dd, J = 7.1,
1.5 Hz, 1H), 7.52 (dd, J = 7.3, 1.4 Hz, 1H), 7.41 (d, J = 2.7 Hz, 1H), 7.24
(app quintd, J = 7.5, 1.5 Hz, 2H), 7.08 (s, 1H), 4.63 (s, 2H), 3.40 (s,
Q
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The Journal of Organic Chemistry
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Article
3H), 3.26 (s, 3H), 2.86 (br s, 1H). 13C{1H} NMR (101 MHz, C6D6): δ
152.6, 144.4, 140.3, 134.65, 134.57, 131.08, 129.9, 129.5, 128.2, 127.4,
120.4, 112.9, 110.8, 63.8, 56.1, 31.3. IR (solid) (cm−1): 3280 (br w),
1491 (m), 1215 (m), 1029 (m), 757 (s). HRMS (ESI): m/z [M + H]+
calcd for C16H17N2O2, 269.1285; found, 269.1289.
107.1, 101.2, 52.5, 44.6, 32.0, 27.1, 24.0, 23.2, 21.6. IR (solid) (cm−1):
3354 (m), 2948 (m), 1621 (w), 1215 (s), 1025 (s), 809 (s). HRMS
(ESI): m/z [M + H]+ calcd for C16H23N2O, 259.1805; found,
259.1811.
8-(tert-Butyl)-6,7,8,9-tetrahydro-5H-pyrido[3,2-b]indole (72). To
a round-bottomed flask were added salt 17 (1.00 g, 61.4 wt % calculated
as free base, 4.99 mmol, 1.00 equiv) and 4-tert-butylcyclohexanone (70,
777 mg, 4.99 mmol, 1.00 equiv). n-Butanol (10 mL, deoxygenated by
nitrogen sparging for 30 min) was added, and the mixture was heated to
an internal temperature of 90 °C, forming a light yellow solution. After
10 h, a dark orange solution formed. The mixture was cooled to room
temperature and concentrated in vacuo to afford a yellow-brown
residue. The residue was partitioned between dichloromethane (10
mL) and a saturated aqueous solution of sodium bicarbonate (10 mL).
The pH of the aqueous later was 9. The layers were separated, and the
aqueous layer was extracted with dichloromethane (2 × 10 mL). The
combined organic layers were dried over anhydrous sodium sulfate,
filtered, and concentrated in vacuo. The residue was purified by flash
column chromatography over silica gel (0−20% methanol in dichloro-
methane gradient) to afford the product 72 as an off-white (beige) solid
(765 mg, 67%. The fractions containing the minor product were
combined and concentrated in vacuo to afford a beige solid. This
appeared to be some sort of salt form of 73. The salt was partitioned
between a saturated, aqueous solution of sodium bicarbonate (5 mL)
and dichloromethane (5 mL). The layers were separated, and the
aqueous layer was extracted with dichloromethane (5 mL). The
combined organic layers were dried over anhydrous sodium sulfate,
filtered, and concentrated in vacuo to afford the isomeric 6-azaindole 73
as an off-white solid (69 mg, 6%). This reaction was repeated with 3-
hydrazinylpyridinium bishydrochloride (17H, 319 mg) under identical
conditions. In this case, the conversion of the hydrazone to the product
was very slow taking 2 weeks for full conversion of the hydrazone. At
reaction completion, there was a thick precipitate of an unidentified,
highly insoluble material that needed to be filtered off. Work up and
purification as above afforded the indole 72 as a beige solid (49.9 mg,
13%). The isomeric 6-azaindole 73 was identified as a trace product in
the reaction, though it was not found during isolation. Rf (10%
methanol in dichloromethane): 0.49. Mp (methanol/dichlorome-
thane): 232−233 °C. 1H NMR (400 MHz, DMSO-d6): δ 10.86 (s, 1H),
8.16 (d, J = 4.5 Hz, 1H), 7.56 (d, J = 7.6 Hz, 1H), 6.95 (dd, J = 7.9, 4.6
Hz, 1H), 277−2.90 (m, 2H), 2.65−2.77 (m 1H), 2.31 (dd, J = 14.1,
10.9 Hz, 1H), 2.07 (dd, J = 11.0, 5.0 Hz, 1H), 1.28−1.54 (m, 2H), 0.97
(s, 9H). 13C{1H} NMR (101 MHz, DMSO-d6): δ 145.3, 140.8, 138.9,
128.8, 116.9, 115.1, 109.1, 44.7, 32.3, 27.4, 24.2, 23.9, 21.3. IR (solid)
(cm−1): 2944 (w), 1480 (w), 1412 (m), 1360 (m), 764 (s). HRMS
(ESI): m/z [M + H]+ calcd for C15H21N2, 229.1699; found, 229.1705.
6-(tert-Butyl)-6,7,8,9-tetrahydro-5H-pyrido[3,4-b]indole (73). Rf
(10% methanol in dichloromethane): 0.35. Mp (methanol/dichloro-
3-(2-(Isopropoxymethyl)phenyl)-5-methoxy-1H-pyrrolo[2,3-b]-
1
pyridine (66). Rf (50% ethyl acetate in dichloromethane): 0.57. H
NMR (400 MHz, DMSO-d6): δ 11.72 (br s, 1H), 8.02 (d, J = 2.7 Hz,
1H), 7.60 (d, J = 2.6 Hz, 1H), 7.54 (br d, J = 7.3 Hz, 1H), 7.27−7.43 (m,
3H), 4.40 (s, 2H), 3.79 (s, 3H), 3.59 (app septet, J = 6.1 Hz, 1H), 1.09
(d, J = 6.1 Hz, 6H). 13C{1H} NMR (101 MHz, DMSO-d6): δ 151.0,
143.8, 136.5, 133.7, 133.3, 129.8, 129.7, 127.6, 126.0, 125.9, 118.5,
112.2, 109.4, 70.3, 67.6, 55.9, 22.0. HRMS (ESI): m/z [M + NH4]+
calcd for C18H24N3O2, 314.1863; found, 314.1870.
3-(2-(Chloromethyl)phenyl)-5-methoxy-1H-pyrrolo[2,3-b]-
1
pyridine (67). Rf (50% ethyl acetate in dichloromethane): 0.66. H
NMR (400 MHz, DMSO-d6): δ 11.83 (br s, 1H), 8.05 (d, J = 2.6 Hz,
1H), 7.59−7.67 (m, 2H), 7.46−7.49 (m, 2H), 7.36−7.41 (m, 2H), 4.78
(s, 2H), 3.79 (s, 3H). 13C{1H} NMR (101 MHz, DMSO-d6): δ 151.0,
143.8, 135.3, 134.2, 133.6, 131.0, 130.6, 128.8, 127.0, 125.4, 118.5,
111.8, 109.1, 55.9, 45.3. IR (solid) (cm−1): 3116 (br w), 1491 (w),
1215 (m), 1032 (m), 749 (s). HRMS (ESI): m/z [M − H]− calcd for
C15H12ClN2O, 271.0644; found, 271.0649.
2-(2-(Isochroman-3-yl)-2-methylhydrazinyl)-5-methoxypyridine
(68). This product was isolated from a different experiment run in tert-
amyl alcohol. 1H NMR (400 MHz, DMSO-d6): δ 7.77 (d, J = 2.9 Hz,
1H), 7.26 (dd, J = 9.0, 2.9 Hz, 1H), 7.11−7.17 (m, 2H), 7.02−7.11 (m,
2H), 6.81 (d, J = 8.9 Hz, 1H), 6.37−6.61 (m, 1H), 6.51 (br s, 1H), 4.90
(d, J = 15.0 Hz, 1H), 4.77 (d, J = 15.0 Hz, 1H), 4.51 (dd, J = 10.0, 3.4
Hz, 1H), 3.72 (s, 3H), 3.01 (dd, J = 16.3, 10.0 Hz, 1H), 2.73 (d, J = 16.0
Hz, 1H), 2.66 (s, 3H). 13C{1H} NMR (101 MHz, DMSO-d6): δ 155.1,
149.2, 134.4, 133.5, 133.2, 128.2, 126.4, 125.7, 124.8, 123.9, 106.9, 90.2,
66.7, 55.9, 38.5 (obscured by DMSO, identified by HSQC), 30.6.
UPLCMS (LRMS, ESI): m/z [M + H]+ calcd for C16H20N3O2, 286.2;
found, 286.2.
5-Methoxypyridin-2-amine (69). This compound’s 1H NMR
1
spectrum matched a commercially available sample. H NMR (400
MHz, DMSO-d6): δ 7.63 (d, J = 3.1 Hz, 1H), 7.09 (dd, J = 8.9. 3.1 Hz,
1H), 6.41 (d, J = 8.9 Hz, 1H), 5.42 (br s, 2H), 3.67 (s, 3H).
6-(tert-Butyl)-2-methoxy-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]-
indole (71). To a round-bottomed flask was added salt 16 (1.00 g, 45.8
wt % calculated as free base, 2.99 mmol, 1.00 equiv) and 4-tert-
butylcyclohexanone (70, 466 mg, 2.99 mmol, 1.00 equiv). n-Butanol
(10 mL, deoxygenated by nitrogen sparging for 30 min) was added, and
the mixture was heated to an internal temperature of 90 °C, forming a
light yellow solution. After a total of 8 h, the mixture was cooled to room
temperature and concentrated in vacuo to afford a yellow-brown
residue. The residue was partitioned between dichloromethane (10
mL) and a saturated aqueous solution of sodium bicarbonate (10 mL).
The layers were separated, and the aqueous layer was extracted with
dichloromethane (2 × 5 mL). The combined organic layers were dried
over anhydrous sodium sulfate, filtered, and concentrated in vacuo to
afford a yellow solid. The solids were slurried in 10 v/v% methyl tert-
butyl ether in hexanes (10 mL) for 15 min. The solids were collected by
Buchner filtration to afford 685 mg of a light beige powder. The mother
liquor was concentrated in vacuo to afford a red gel that was purified by
flash column chromatography over silica gel (0−5% methanol in
dichloromethane gradient). Fractions containing the product were
combined and concentrated in vacuo to afford additional product 71
(65 mg) as beige solids. The total amount of 71 isolated was 750 mg
(97%).
1
methane): 215−216 °C (dec). H NMR (400 MHz, DMSO-d6): δ
11.12 (br s, 1H), 8.54 (br s, 1H), 8.00 (br d, J = 3.2 Hz, 1H), 7.34 (br d,
J = 4.8 Hz, 1H), 2.63−2.90 (m, 3H), 2.31 (app t, J = 12.9 Hz, 1H), 2.07
(dd, J = 11.4, 4.2 Hz, 1H), 1.29−1.53 (m 2H), 0.97 (s, 9H). 13C{1H}
NMR (101 MHz, DMSO-d6): δ 139.1, 137.2, 133.2 (br), 132.9, 131.4,
112.0 (br), 108.4, 44.8, 32.3, 27.4, 24.2, 23.6, 21.7. IR (solid) (cm−1):
2948 (w), 1573 (m), 1364 (m), 1141 (m), 801 (s). HRMS (ESI): m/z
[M + H]+ calcd for C15H21N2, 229.1699; found, 229.1705.
2-Methylquinoline (74). A mixture of salt 8 (500 mg, 3.15 mmol,
1.00 equiv), acetaldehyde diethyl acetal (920 μL, 6.30 mmol, 2.00
equiv), and ethanol (5.0 mL) was heated to an internal temperature of
80 °C under nitrogen for 29 h. The reaction was cooled to room
temperature, then poured into a saturated, aqueous solution of sodium
bicarbonate (10 mL), and extracted with dichloromethane (1 × 10 mL,
then 2 × 5 mL). The combined organic extracts were dried over
anhydrous sodium sulfate, filtered, and concentrated in vacuo to afford a
dark oil. The oil was purified by flash column chromatography over
silica gel (0−25% ethyl acetate in hexanes gradient) to give a semipure
product. A second purification by flash column chromatography over
silica gel (0−2% ethyl acetate in dichloromethane gradient) afforded 74
as a light yellow oil (73.4 mg, 16%) that was identical to a commercially
available sample.
Repeating this reaction with 2-hydrazinyl-6-methoxypyridinium
bistetrafluoroborate (16H, 380 mg, 44.0 wt % calculated as free base)
under identical conditions (30 h) afforded the indole 71 as an orange
solid (296 mg, 95%). Rf (15% ethyl acetate in hexanes): 0.35. Mp
1
(hexanes): 167−168 °C (dec). H NMR (400 MHz, DMSO-d6): δ
10.97 (br s, 1H), 7.65 (d, J = 8.3 Hz, 1H), 6.40 (d, J = 8.3 Hz, 1H), 3.82
(s, 3H), 2.55−2.77 (m, 3H), 2.27 (app dd, J = 13.0, 12.0 Hz, 1H), 2.03
(dd, J = 11.4, 4.0 Hz, 1H), 1.30−1.51 (m, 2H), 0.95 (s, 9H). 13C{1H}
NMR (101 MHz, DMSO-d6): δ 159.0, 145.8, 131.2, 127.9, 113.7,
R
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Article
(8) Mauger, C.; Mignani, G. The Synthesis of Important
Pharmaceutical Building Blocks by Palladium-Catalyzed Coupling
Reaction: Access to Various Arylhydrazines. Adv. Synth. Catal. 2005,
347, 773.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.1c00203.
■
sı
(9) For details, please see the Supporting Information.
(10) Brosse, N.; Pinto, M. F.; Jamart-Grégoire, B. New Synthesis of
1,1-Substituted Hydrazines by Alkylation of N-Acyl- or N-Alkylox-
ycarbonylaminophthalimide Using the Mistunobu Protocol. J. Org.
Chem. 2000, 65, 4370.
Rate experiments, ligand byproduct identification,
1
stability studies and isotope labeling experiments, H
and 13C{1H} NMR spectra, and DSC traces (PDF)
(11) We briefly examined an aldehyde/ketone competition reaction
with the nonenolizable aldehyde, 4-propanoylbenzaldehyde with 8, and
did not observe any indole products. Instead, higher molecular weight
products were observed, possibly arising from aldol-like reactions.
Compound 8 remained unchanged.
AUTHOR INFORMATION
Corresponding Author
Michael A. Schmidt − Bristol Myers Squibb Company,
Chemical Process Development, New Brunswick, New Jersey
08903, United States; orcid.org/0000-0002-4880-2083;
Email: Michael.Schmidt@bms.com
■
(12) House, H. O.; Berkowitz, W. F. The Stereochemistry of the
Neber Rearrangement. J. Org. Chem. 1963, 28, 2271. For step 4 of this
synthesis, we instead dehydrated using p-TsOH (5 mol%) in refluxing
toluene (8.8 mL/g) with a Dean−Stark trap to collect the water over 1
h. After cooling to room temperature, the reaction mixture was washed
with a saturated, aqueous solution of sodium bicarbonate (5 mL/g),
water (5 mL/g) and then a saturated aqueous solution of brine (5 mL/
g). The organic layer was dried over anhydrous sodium sulfate, filtered,
and concentrated in vacuo to afford a brown mass that was dissolved in a
minimum of 2 vol% triethylamine in toluene and passed through a plug
of silica (23 g silica/g crude), eluting with 2 vol% triethylamine in
toluene. The solution was collected from the column until just before a
yellow colored band eluted. Concentration of the filtrate in vacuo
affords light yellow crystals of the olefin.
(13) Terminal nitrogen methylation is expected to reduce the
equilibrium constant of the initial bimolecular step (i.e., 1 + 2 → 3),
especially for acyclic ketones. Hine, J.; Evangelista, R. A. Iminium-Ion
Formation and Deuterium Exchange by Acetone in the Presence of
Pyrrolidine, Pyrazolidine, Isoxazolidine, and Their Acyclic Analogues. J.
Am. Chem. Soc. 1980, 102, 1649.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.1c00203
Notes
The author declares no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Dr. Gregory Beutner, Dr. Hester Dang, Dr. John
Schultz, Dr. Steven Wisniewski, and Dr. Michael Zacuto for
reviewing this manuscript. We thank Dr. Ben Cohen, Dr. Simon
Leung, and Dr. Shasha Zhang for assistance in obtaining and
interpreting DSC measurements. We are grateful to Mr. Michael
Peddicord for assistance obtaining mass spectrometric data.
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