One-Pot C-H Arylation/Lactamization Cascade Reaction of Free Benzylamines

Article abstract of DOI:10.1021/acs.joc.0c00542

An efficient method has been developed for the synthesis of seven-membered biaryl lactams involving Pd-catalyzed, native amine-directed, ortho-arylation of benzylamines followed by in situ lactamization. This cascade sequence is enabled by the use of 2-iodobenzoates, which facilitates C-H arylation from the free amine under conditions that typically require an improved directing group approach. This reaction is characterized by a broad substrate scope with good functional group tolerance. The need for an ester versus carboxylic acid-functionalized coupling partner is also explored, as is the potential for synthesizing eight-membered biaryl lactams. Various applications are also investigated, including access to the aza-brassinolide core.

Full text of DOI:10.1021/acs.joc.0c00542

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Article
One Pot C#H Arylation/Lactamization Cascade Reaction of Free Benzylamines
Pratibha Chand-Thakuri, Vinod G. Landge, Mohit Kapoor, and Michael C. Young
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c00542 • Publication Date (Web): 22 Apr 2020
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Page 1 of 21
The Journal of Organic Chemistry
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One Pot C‒H Arylation/Lactamization Cascade Reaction of Free
Benzylamines
Pratibha Chand-Thakuri, Vinod G. Landge, Mohit Kapoor,† Michael C. Young*
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Department of Chemistry & Biochemistry, School of Green Chemistry & Engineering, The University of Toledo, 2801 W.
Bancroft St., Mailstop 602, Toledo, OH 4606.
R
NH2
PdII
R
NH
O
I
AgI
R'O2C
Ligand Free
Coupling Partner
Accelerated




Haloesters/Acids as
Coupling Partners
Scalable
ABSTRACT: An efficient method has been developed for the synthesis of seven-membered biaryl lactams involving Pd-catalyzed,
native amine-directed, ortho-arylation of benzylamines followed by in situ lactamization. This cascade sequence is enabled by use of
2-iodobenzoates, which facilitates C–H arylation from the free amine under conditions that typically require an improved directing
group approach. This reaction is characterized by a broad substrate scope with good functional group tolerance. The need for an ester
versus carboxylic acid-functionalized coupling partner is also explored, as is the potential for synthesizing eight-membered biaryl
lactams. Various applications are also investigated, including access to the aza-brassinolide core.
Introduction
of serving as a native directing group for C–H activation, gave
a stable dimeric species that required a higher temperature to
turnover to product, whereas CO2 could lead to a more reactive
intermediate. Based on these results, we wondered whether or
not the free amine could be available during the reaction for a
cascade in the presence of a suitable electrophile,13 such as an
ester group installed during the C–H arylation step (Scheme 1).
Compared with substrates previously used for the ortho-
arylation of benzylamines,11,12 pre-coordination of the ester
moiety could lower the barrier to C–I bond activation, allowing
the free benzylamine to serve as a satisfactory DG at a lower
temperature, but also potentially without the addition of a
transient DG.
Cascade reactions are multistep processes in which the
product or intermediate of an initial reaction acts as a starting
material for additional reactions that can occur, thus reducing
the number of steps required for the synthesis of complex
products.1 Though many organometallic cascade reactions
involve a C–H activation step,2 it is rare that these reactions are
initiated by C–H activation.3 However, if a nucleophilic
directing group (DG) could be utilized to first perform C‒H
functionalization, the nucleophile should be able to
subsequently intercept a newly-installed electrophile to achieve
a multistep reaction.4 Primary amines, though nucleophilic, are
often regarded as poor directing groups for C–H activation due
to issues with oxidation as well as the propensity to form
catalytically-inactive complexes,5 and there are therefore
limited examples of native amine-directed C‒H activation
reactions.6 As a result many approaches using static7 or
transient8 directing groups have been developed.
Scheme 1. Proposed Strategy for Benzylamine C–H
Arylation/Lactamization Cascade.
R1
NH
R1
O
Pd
CO2R'
I
NH2
R2
+
Along these lines, our group has recently explored CO2 as a
highly sustainable transient DG to access free amine C–H
activation products.10 While ortho-C–H arylation of
benzylamines had been achieved previously without a transient
DG by Daugulis,11 the high temperature (130 ºC) and use of
trifluoroacetic acid as solvent led to partial protection of the
amine moiety as the solvent amide. By adding CO2, we found
that the reaction could be performed effectively at a mere 100
ºC, and the free amine products obtained in generally good
yields.12 We rationalized that the benzylamine, though capable
R2
NH2
O
HOAc
OR
NH2H2N
Pd
O
Pd
OAc
OAc
O
O
RO
Proposed Arylation Intermediate
Acid-Mediated
Lacamization
The proposed cascade reaction between benzylamines and 2-
iodobenzoate esters would give rise to diarylazepinones. These
seven-membered lactams are important in a number of different
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Scheme
2.
Benzylamine
Substrate
Scope
of
C–H
biologically-relevant small molecules, including Glycogen
Synthase Kinase-3 and γ-Secretase inhibitors.14 However,
despite numerous organometallic approaches to the synthesis of
azepinones,15 incorporation of two arenes into the backbone is
rare.16 Our initial hypothesis was the conversion in situ to the
carbamaic acid was expected to facilitate C‒H arylation, while
equilibration back to the amine would allow the subsequent
lactamization16 (under acidic conditions this wouldn’t require
strong base or exceedingly high temperatures).17 However, the
presence of the ortho-ester was expected to potentially lower
the reaction temperature with CO2, or even negate its use
outright.
Arylation/Lactamization. Isolated yields. Reactions performed at
0.15 mmol scale with 3 equiv. of ethyl 2-iodobenzoate. Reactions
performed in duplicate and the average yields reported.
1
2
3
4
5
6
7
8
2 R3
R
Pd(OAc)2 (10 mol%)
AgOAc (2 equiv.)
R1
NH2
R3
I
NH
CO2Et
+
O
R2
R1
AcOH, 100 ºC, 14h
F
F
Me
Et
iPr
NH
9
Me
Me
Me
Me
Me
F
F
NH
NH
NH
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O
O
O
O
Results and Discussion
To determine the optimal reaction conditions we chose 2-(m-
tolyl)propan-2-amine as a model substrate. Using Pd(OAc)2 as
a catalyst, AgTFA as an additive, and AcOH as a solvent, we
were able to observe the desired product in 58% yield (Table 1,
Entry 1) in the presence of ~5 equivalents of CO2. Using
AgOAc as additive instead of AgTFA dramatically increased
the yield up to 96% (Entry 2). We had previously used a
mixture of HFIP/AcOH for the CO2-promoted arylation, but
found it was notably less effective with ethyl 2-iodobenzoate as
coupling partner using either AgTFA or AgOAc (Entries 3 and
4). Using only HFIP as solvent also led to reasonable, although
reduced, yield of the desired lactam product (Entry 5).
Considering that Daugulis had demonstrated the ortho-arylation
of benzylamines in trifluoroacetic acid at 130 ºC, we wondered
whether or not the one pot reaction could be achieved using his
conditions – notably the answer is yes, although the yield of the
desired lactam product was not nearly as high, even when the
reaction was run for a longer period of time (Entry 6). When
we performed a control reaction in the absence of added CO2,
comparable yields of product were obtained (Entry 7). Upon
reperforming controls from our original work, we confirmed
that CO2 was necessary for ethyl 4-iodobenzoate, but
surprisingly not for the 2-substituted ester. To control for
potential pre-absorption of CO2 by the amine or solvent, the
amine in acetic acid was sparged with N2 for 1h prior to setting
up the reaction, but this had a negligible effect on the overall
yield observed (Entry 8). We therefore concluded that these
transformations could be achieved simply by using the amine
as a native directing group at 100 ºC, likely due to chelation-
assistance in the oxidation to the C–I bond.
1a, 86%
1b, 90%
1c, 89%
1d, 64%
Me
F
Me
F
F
Me
nBu
Hex
NH
Ph
Me
Me
Cl
NH
NH
NH
O
O
O
O
1e, 84%
1f, 73%
Me
1g, 78%
Me
1h, 89%
Me
Me
Me
Me
NH
Me
Me
Et
Me
Ph
MeO
O
NH
NH
NH
O
O
O
1i, 98%
1j, 92%
Me
1k, 85%
Me
1l, 82%
Et
Et
NH
Me
Me
NH
MeO
Et
NH
BnO
NH
O
O
O
O
1m, 79%
Me
1n, 80%
1o, 72%
Br
1p, 62%
Cl
Me
NH
Me
Me
F
Br
NH
NH
NH
O
O
F
O
O
1q, 82%
1r, 85%
1s, 82%
1t, 79%
F
F3C
NH
NH
NH
NH
O
O
O
O
1w, 67%
Br
1x, 59%
1u, 77%
Cl
1v, 62%
F3C
Cl
MeO
O
NH
NH
NH
NH
Table 1. Optimization of One Pot C–H Arylation/Lactamization
Cascade. Reactions performed at 0.15 mmol scale with 3 equiv. of
ethyl 2-iodobenzoate. Reactions performed in duplicate and the
F
O
O
O
a
average yields reported. Reaction performed without CO2 or H2O,
1y, 55%
OCHF2
1z, 53%
1aa, 77%
1ab, 52%
NPr2
b
with 10 equiv. of aryl halide, and at 130 ºC. Reaction performed
O
c
without CO2 or H2O. Reaction performed without CO2 or H2O, and
O
Me
NH
reaction was sparged with N2 prior to heating.
NH
NH
NH
O
O
O
Me
Me
Me
Pd(OAc)2 (10 mol%)
O
NH
Me Me
NH2
Ag Salt (2 equiv.)
I
Me
+
O
1ac, 72%
1ae, 54%
99% e.s.
1ad, 52%
1af, 45%
47% e.s.
CO2 (5 equiv.)
H2O (4 equiv.)
EtO2C
Solvent, 100 ºC, 14h
Using the optimized conditions, we were able to isolate the
model product in good yield (Scheme 2, 1a). Yields were
determined throughout by running reactions in at least
duplicate, and the average reported. Given the challenges with
mono- and di-arylation, we initially explored substrates with
steric-blocking groups at the o or m position of the benzylamine.
Short to medium length carbon chains at the α-position were
tolerated under our reaction conditions with good to excellent
Entry
Solvent
Ag-salt
NMR Yield (%)
1
AcOH
AcOH
AgTFA
AgOAc
AgTFA
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
58
96
25
70
78
42
>96
94
2
3
HFIP/AcOH(1:1)
HFIP/AcOH(1:1)
HFIP
4
5
6a
7b
8c
TFA
AcOH
AcOH
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The Journal of Organic Chemistry
yields (1b – 1f), and exclusive γ-C(sp2)‒H selectivity was
Next we focused on exploring the scope of the reaction with
1
2
3
4
5
6
7
8
observed, even in the presence of potentially competitive δ-
C(sp2)‒H positions (1g). Chloro (1h) as well as a variety of
electron rich substituents (1l – 1p) on the benzylamine were
also tolerated in the reaction. We were pleased to find that the
cascade cyclization also worked with less substituted α-
secondary (1q – 1u) as well as α-primary benzylamines (1v –
1ad) under the same reaction conditions. It is worth noting that
we observed minor formation of the acetamides with α-primary
benzylamines, likely as a consequence of the less sterically
hindered amines reacting with the solvent. This is the primary
reason for the lower yields with the less substituted substrates.
When we subjected (R)-(+)-1-(1-naphthyl)ethylamine to the
reaction, the lactam product was recovered with complete
retention of configuration (1ae). Meanwhile, a more acidic α-
aminoamide substrate gave the lactam product, but with only
45% es during the reaction (1af), a notable challenge with these
epimerizable substrates.6a The presence of the β-chelating
moiety allowed selective mono-arylation in this example. In the
absence of such a group, however, a mixture of mono- and di-
arylation with concomitant lactam formation was observed (see
Supporting Information for details).
respect to the 2-iodobenzoate coupling partner (Scheme 3),
using 2-(m-tolyl)propan-2-amine as the amine substrate. We
were able to prepare the lactam products with a wide variety of
fluorinated, chlorinated, and even brominated iodobenzoate
substrates with fair to excellent yield (2a – 2h). The reaction
could also be performed with ethyl diiodobenzoate with
arylation at the 2-iodo position exclusively (2i). The selectivity
of the oxidative addition to the C‒I bond can be rationalized as
being directed by the ortho-ester group. Iodobenzoates bearing
electron poor groups such as trifluoromethyl (2j) and nitro (2k)
groups, as well as electron rich groups such as methyl (2l),
methoxy (2m and 2n), and trifluoromethoxy (2o) were all
tolerated under our reaction conditions. Even a highly activated
trimethoxybenzoate substrate could participate in the reaction
(2p). We were delighted to see that this reaction could even be
extended to lactam formation with heterocyclic esters, such as
iodofuran (2q) and iodothiophene (2r) derivatives.
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We considered that using the ortho-iodobenzoic acids would
represent a more straightforward and attractive approach to
synthesizing these lactam products. There were some obvious
challenges to this, including the ability of PdII to C‒H activate
benzoic acids,18 as well a recent report where decarboxylation
occurred when an ortho-halobenzoic acid was used as a
coupling partner for C–H arylation.19 Despite these potential
pitfalls, we were able to generate the desired lactam products
directly with 2-iodobenzoic acid derivatives (Scheme 4). A
slight increase in yield was observed when we used a mixture
of solvents, HFIP:AcOH (1:1), instead of AcOH. Notably the
yields are lower compared to those starting from the 2-
iodobenzoate derivatives, however, this direct approach may be
valuable in situations where preconversion of the carboxylic
acid to the ester is challenging or otherwise undesirable.
Scheme 3. ortho-Iodobenzoate Substrate Scope of C–H
Arylation/Lactamization. Isolated yields. Reactions performed at
0.15 mmol scale with 3 equiv. of ethyl 2-iodobenzoate. Reactions
performed in duplicate and the average yields reported.
Me
Me
NH2
I
Me
Pd(OAc)2 (10 mol%)
AgOAc (2 equiv.)
Me
CO2R1
NH
+
Me
Me
R2
O
AcOH, 100 ºC, 14h
R1 = Me or Et
R2
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
NH
NH
NH
NH
Scheme 4. ortho-Iodobenzoic Acid Substrate Scope of C–H
Arylation/Lactamization. Isolated yields. Reactions performed at
0.15 mmol scale with 3 equiv. of ethyl 2-iodobenzoate. Reactions
performed in duplicate and the average yields reported.
O
O
O
O
Cl
Cl
2b, 92%
F
Cl
2a, 87%
2c, 47%
Me
2d, 94%
2 R3
R
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Pd(OAc)2 (10 mol%)
AgOAc (2 equiv.)
R1
NH2
R2
I
NH
NH
NH
NH
NH
CO2H
O
O
O
O
F
O
R1
+
R4
R3
1:1 HFIP/AcOH
100 ºC, 14h
F
R4
F
Br
2h, 87%
F
2g 70%
F
Me
NH
Cl
Me
2e, 65%
2f, 57%
Me
Me
Me
F
Me
Me
NH
Me
Me
Me
Me
Me
Me
NH
Me
Me
NH
Me
Me
Me
Me
O
O
O
O
NH
NH
NH
NH
O
O
O
O
1q, 38%
Me
1i, 67%
Me
1a, 62%
NH
1t, 42%
F
Me
Me
Me
I
CF3
NO2
Me
Me
Me
2k, 26%
2l, 98%
2i, 82%
Me
2j, 94%
Me
NH
NH
NH
Me
Me
Me
Me
Me
Me
O
O
O
Me
O
NH
NH
NH
O
O
O
Cl
OMe
2m, 48%
OCF3
1ae, 28%
1v, 59%
2b 45%
99% e.s.
OMe
2m, 96%
Me
OMe
2n, 83%
MeO
2o, 32%
Me
Considering the utility of the transformation to form seven-
membered lactams, the thought that it might also be appropriate
for synthesizing even more highly-strained eight-membered
biaryl lactams20 was investigated. We first attempted the
transformation using the sterically-hindered substrate ethyl 2’-
iodophenylacetate. Perhaps unsurprisingly, the presence of the
ortho-substituent effectively shut down the C‒H arylation
reaction, and no biaryl formation was observed (Scheme 5a).
Me
Me
Me
Me
Me
Me
Me
NH
NH
NH
O
O
O
S
MeO
O
OMe
MeO
2p, 72%
2r, 54%
2q, 27%
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Unlike the benzoate ester, which can putatively coordinate to targeted. The benzylic position was surprisingly recalcitrant to
1
2
3
4
5
6
7
8
the transition metal and enhance oxidative addition to the C‒I
bond,21 the larger chelate size coupled with the weaker
coordinative ability of the acetate ester precludes similar
reactivity.
oxidation with a variety of oxidants and catalysts. However,
portion-wise treatment of the lactam with NBS and AIBN was
able to furnish imide 6 in fair yield. While the lactam moiety
was not particularly sensitive to nucleophiles such as hydrazine
or fully reduced by treatment with LiAlH4 (both in refluxing
solvent), it could be converted into thioamide 7 by addition of
Lawesson’s Reagent.
We next tried the corresponding acid, believing that the
stronger chelating ability of the free acid (upon deprotonation)
would allow 2’-phenylacetic acid to participate in the reaction.
Notably, the crude reaction mixture contained both starting
materials due to poorer conversion, as well as the C‒H arylation
product, and 3 as well as the carboxylic acid hydrolysis product
of 3. Though the other components were determined from the
crude NMR, 3 could be isolated in low yield (Scheme 5b). We
envision that this product comes from the desired C‒H arylation
and lactamization. However, due to the increased strain, an
unusual β-nitrogen elimination occurs,22 though the mechanism
is currently unknown.
In addition to the potential uses of the unsaturated biaryl
lactams themselves, we reasoned that reduction of the arenes
could allow facile access to the aza-brassinolides, which have
been investigated for multiple uses.23 To access the core
aromatic structure, 4-bromoindanone was subjected to a
Rosenmund-von Braun reaction, and the resulting nitrile 8 was
reduced, with concomitant reduction of the ketone, and then the
amine was Boc protected to give 9. Deprotection of the Boc
group with trifluoroacetic acid gave the benzylamine precursor
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
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27
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43
44
45
46
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51
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53
54
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59
60
10
which
when
subjected
to
the
key
C‒H
Scheme 5. Towards Synthesis of Eight-Membered Lactams Using
2‘-Iodophenylacetic Acid Substrates.
arylation/lactamization reaction furnished 11. Lactam 11 can
then in principle be reduced to give the aza-brassinolide core,
although notably the technology is currently lacking to achieve
the trans-selective hydrogenation.24 Consequently, we are
currently exploring this transformation and its application to the
total synthesis of members of the brassinolide family.
Me
Me
a)
Me
Pd(OAc)2 (10 mol%)
AgOAc (2 equiv.)
I
CO2Et
NH2
NH
O
Me
Me
+
+
Me
AcOH, 100 ºC, 14h
Scheme 7. Synthetic Applications of Seven-Membered Biaryl
Lactam Products.
b)
Me
Pd(OAc)2 (10 mol%)
AgOAc (2 equiv.)
I
CO2H
NH2
Me
Me
F3C
Me
Me
HFIP/AcOH (7:3), 100 ºC, 14h
NH
O
F3C
F3C
Bn
O
H2N
3, 24%
O
N
NH
a.
c.
S
Our previous report on the ortho-arylation of benzylamines
did not show any evidence of lactamization when ethyl 2-
iodobenzoate was coupled with secondary benzylamines.12 The
modified conditions were anticipated to allow the preparation
of these more substituted biarylazepinones. Using a variety of
different secondary benzylamines, however, no lactam products
could be identified, only the initial C‒H arylation products.
Attempts to reoptimize the conditions for these less sterically-
accessible substrates failed to facilitate the desired cascade
reaction. Interestingly, we did find one outlier – when an N-
propylbenzylamine was used in the reaction, a lactam product
was observed in good yield (Scheme 6). Surprisingly, there was
no sign of the propyl chain by NMR, and subsequent analysis
by X-ray crystallography showed that the propyl group had
fallen off (4). Given the inability to access any other lactam
products from secondary amines, we propose that the propyl
group must fall off before the reaction, possibly due to oxidation
and deallylation or hydrolysis if the intermediate formed is an
imine.
b.
7, 82%
5, 95%
O
F3C
NH
O
6, 47%
OH
O
O
OH
d.
e.
f.
8, 56%
OAc
9, 70%
NHBoc
10, 73%
NH2
Br
CN
OAc
H
H
H
H
g.
10
H
aza-Brassinolide
H
N
H
N
11, 42%
Core
H
O
O
a) NaH (2.0 equiv.), BnBr (1.3 equiv.), DMF, RT; b) NBS (8.0 equiv.),
AIBN (80 mol%), MeCN, 82 ºC; c) Lawesson’s Reagent (1.1 equiv.),
PhMe, 110 ºC. d) CuCN (2.5 equiv.), CuI (50 mol%), DMF, 120 ºC; e)
NiCl2 (20 mol%), (Boc)2O (2 equiv.), NaBH4 (7 equiv.), MeOH, RT;
f) TFA, DCM, RT; g) Pd(OAc)2 (10 mol%), ethyl 2-iodobenzoate (3
equiv.), AgOAc (2 equiv.), AcOH, 100 ºC.
Scheme 6. Results of Using an N-Propyl Secondary Amine
Substrate.
ArI (3 equiv.)
Pd(OAc)2 (10 mol%)
AgOAc (2 equiv.)
F
Me
nPr
Et
Et
NH
An important consideration for synthetic organometallic
methodology is to ensure scalability – especially in systems that
may contain some heterogeneity. Using a 40 mL sealed tube,
we attempted to scale the reaction from 0.15 mmol scale up to
7.5 mmol scale. Gratifyingly, even under these modified
conditions 1i could still be obtained in 70% isolated yield
(Scheme 8). This represents an increase of 50 times the reaction
scale, suggesting that the reaction can be scaled up effectively
despite the fact that not all of the silver dissolves during the
reaction.
F
HN
O
Me
AcOH, 100 ºC, 14h
4, 78%
Because secondary benzylamines generally did not work in
the reaction, we sought to prepare a tertiary lactam 5 by
postsynthetic alkylation of the lactam product 1x (Scheme 7).
This was achieved by deprotonation with NaH and treatment
with BnBr. Following up on this other derivatives were
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The Journal of Organic Chemistry
probe this, we prepared 12 (Scheme 9). Notably, when the
Scheme 8. Reaction Scale-Up
1
2
3
4
5
6
amide was subjected to the reaction conditions, no lactam
product was formed, and the starting material was recovered
nearly quantitatively. This supports that the C–H preceeds
amide formation in this protocol.
Me Me
NH
Me
Pd(OAc)2 (10 mol%)
AgOAc (2.0 equiv.)
Me
NH2
I
Me
CO2Et
O
Me
+
AcOH, 100 ºC, 14h
Scheme 9. Potential Role of Amide Intermediate
15.0 mmol Scale (100 x Scale-Up)
1i, 70%
2.64 g recovered
F3C
Pd(OAc)2 (10 mol%)
AgTFA (2 equiv.)
O
NH
O
7
8
9
F3C
N
H
With a synthetic protocol in hand, our last goal was to
understand why the simple arylation reaction was high yielding
only in the presence of added CO2, while the present
arylation/lactamization does not require CO2. Based on our
previous work,12 we knew that CO2 likely prevents the
formation of the bis-palladium dimers (Figure 1, I and II). We
had reasoned that dimer II was simply too stable to oxidize in
the presence of a simple aryl iodide. However, due to the ability
of the ester group to coordinate to the catalyst (III), we propose
that the rate of oxidative addition is enhanced and this means
that even the more stable dimer is able to participate in the
reaction with this specific aryl halide at the lower reaction
temperature to generate a high valent Pd-species (IV) which is
capable of undergoing reductive elimination to generate the C–
H arylation intermediate V. Ligand exhange from the dimer
brings another substrate into the cycle, liberating the free amine
intermediate. Although the condensation between two amides
requires strong activation,16c the η-carboxyamine is expected to
readily eliminate the alcohol under acidic conditions to form the
product lactam.16a,b
AcOH, 100 ºC, 14h
I
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Conclusion
In conclusion, we have demonstrated a robust protocol for the
one pot C–H arylation and lactamization of benzylamine
substrates. The protocol works on α-tertiary, α-secondary, and
α-primary amines, and can work with a variety of both benzoate
ester and benzoic acid coupling partners. The seven-membered
lactam products can be converted into more advanced
derivatives, and the method can potentially be used as an entry
into natural product synthesis. The fact that the reaction doesn’t
require CO2 or any other form of transient directing group, as
we had originally assumed, suggests that careful use of oxidant
may be enough to allow the simple free amine to serve as a
native directing group.
A more complete mechanistic
understanding of these reactions is currently underway in our
lab.
Experimental
1
General Information. H, 13C, and 19F spectra were recorded
Figure 1. Proposed Reaction Mechanism
on either a Varian Inova 400 MHz NMR spectrometer, a Varian
Inova 600 MHz NMR spectrometer, or a Bruker Avance 600
MHz NMR spectrometer, and were processed using
MestReNova by Mestrelab Research S.L. Proton (1H) chemical
shifts are reported in parts per million () with respect to
tetramethylsilane (TMS, =0), and referenced internally with
respect to the protio solvent impurity.26 Proton-decoupled
Carbon (13C{1H}) chemical shifts are reported in parts per
million () with respect to tetramethylsilane (TMS, =0), and
referenced internally with respect to the carbon signal of the
solvent. Fluorine (19F) chemical shifts are reported in parts per
million () and referenced internally with respect to
hexafluorobenzene included neat in an insert tube (C6F6, =-
164.9). Deuterated NMR solvents were obtained from
Cambridge Isotope Laboratories, Inc., Andover, MA, and used
without further purification. Electro Spray Ionization Mass
spectra were recorded on either an Agilent 6530 LC Q-TOF
mass spectrometer using electrospray ionization with
fragmentation voltage set at 115 V or lower for sensitive
substrates, and processed with an Agilent MassHunter
Operating System, or on a Waters SYNAPT G2-Si High
Definition Mass Spectrometer. For limited cases where ESI
data could not be obtained, CI was performed using a Water
AutoSpec. Single crystal data were collected on a Bruker Apex
Duo using Apex 3 software for data collection and processing.
Anhydrous solvents were purchased from Sigma-Aldrich
Chemical Company, St. Louis, MO, and pulled through an LC
Technologies Solvent Drying System under “bone dry” N2. All
other materials were obtained from Sigma-Aldrich Chemical
Company, St. Louis, MO, Combi-Blocks, San Diego, CA,
Oakwood Chemical, Estill, SC, Alfa Aesar, Ward Hill, MA,
Acros Organic, Geel, Belgium, or TCI, Tokyo, Japan, and were
used as received. Optimization reactions under CO2 pressure
HOAc
ROH
NH2
Pd(OAc)2
NH2
O
HOAc
OR
NH
O
O
H2N
Pd
NH2
HOAc
NH2
O
O
Pd
O
AcO
I
O
H2N
Pd
NH2
O
H2N
NH2
Pd
O
O
RO
O
O
Pd
O
Pd
O
O
AcO
II
V
OAc
O
H2N
Pd
O
H2N
Pd
NH2
OAc
O
NH2
Pd
OAc
O
Pd
I
O
O
OR
III
OR
IV
AgI
AgOAc
Based on our proposed mechanism, we envisioned that
intramolecular lactamization would be favored, and is less
likely to occur prior to the C–H arylation event. However, the
conditions are potentially harsh enough for amide-formation to
occur first. We had observed isolable amounts of the acetamides
from reaction of the α-primary benzylamines with the acetic
acid solvent, and so a similar mechanism where the amine first
reacts with the ester, followed by oxidative addition of Pd to the
C–I bond and subsequent intramolecular C–H activation. To
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Page 6 of 21
were performed using 2 dram vials from Qorpak with PTFE temperature under a nitrogen atmosphere. The suspension was
1
2
3
4
5
6
7
8
lined caps (GLA-00984).
cooled to -5 °C, followed by dropwise addition of a 1:2 mixture
of TFA: DCM (8.4 equiv. of TFA) under vigorous stirring over
a period of 15 min. The resulting suspension was stirred at 0 °C
for an additional 1-2 h. The reaction mixture was quenched with
distilled H2O, followed by the dropwise addition of a 1:1
mixture of 14% aqueous NH4OH solution (5 mL). After 30 min,
the reaction mixture was extracted with CH2Cl2 (20 mL), and
the organic layer was washed with H2O, brine, and dried over
Na2SO4. The filtrate was concentrated in vacuo and the crude
azide was used in the next step without further purification.
Notes on the Use of Azides. Many of the starting materials in
this study were prepared by a well-established two step
procedure where an alcohol is combined in dichloromethane
with sodium azide, followed by addition of excess of
trifluoroacetic acid in dichloromethane. This procedure
produces hydrazoic acid in situ, and as a result should be given
great care.27 Furthermore, use of dichloromethane can lead to
explosive diazidomethane. Keeping the concentration and
temperature low is critical to prevent formation of this
compound. Although using chloroform may obviate some of
these risks, we found that more reliable yields were obtained by
using dichloromethane as the solvent.
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To a solution of the azide (1 equiv.) in anhydrous THF
(10 mL) was added LiAlH4 (1.05 equiv.) portion wise at 0 °C
under a nitrogen atmosphere. The reaction mixture was stirred
at room temperature for 3-4 h, and then quenched by dropwise
addition of 1.0 M aqueous NaOH. The reaction mixture was
then portioned between Et2O and 1.0 M aqueous HCl. The
aqueous layer was treated with 28% aqueous NH4OH solution,
followed by extraction with CH2Cl2 (2 x 10 mL). The filtrate
was concentrated in vacuo and the residual amine was purified
by flash column chromatography, if necessary.
.
.
The reaction should always be run on relatively small
scale, as HN3 is a powerful explosive.
The reaction should always be kept cold while HN3 is
present, as its exothermic decomposition can lead to
explosions.
.
The reaction should always be kept relatively dilute, and
efforts should be made to prevent any concentration
through solvent loss throughout the duration of the
reaction.
Method B. General Procedure for Synthesis of
Benzylamines Bearing an α-Secondary Center. Following
our previous method,12 to a solution of the carbonyl compound
(1 equiv.) in methanol (10 mL) was added ammonium acetate
(10 equiv.) at room temperature under a nitrogen atmosphere.
After the reaction mixture was stirred for 90 min at room
temperature, NaBH3CN (1 equiv) was added portion wise. The
reaction mixture was stirred for 24-48 h at room temperature,
followed by dilution with NaOH solution (1.0 M, 10 mL). After
stirring for 30 min at room temperature, the reaction mixture
was then portioned between Et2O and 1.0 M HCl. The aqueous
layer was basified with 28% aqueous NH4OH solution (pH 8.0),
and then extracted with CH2Cl2 (2 x 10 mL). The filtrate was
concentrated in vacuo and the residual amine was purified by
flash column chromatography.
.
.
Because HN3 is highly volatile, the reaction should be
performed in a fume hood under a nitrogen atmosphere.
It is important to fully neutralize all hydrazoic acid to
ensure it is not present during the work-up, and to
furthermore ensure that all waste is disposed of into
containers that will not collect any acids or transition
metals, as this can lead to explosions from formation of
HN3 as well as various metal-nitrides. These containers
should be well labeled, and it is safest if their volume is
small, and that they are not stored for long periods of time.
The organoazide products are expected to be stable at room
temperature, but care should also be taken to not heat them
excessively. In our hands, the reaction mixtures and purified
products are always kept at room temperature or below, and
once purified the organoazides are used immediately and are
not stored.
2-(2-Fluorophenyl)propan-2-amine (S-1). Method A used. o-
Fluoroacetophenone (500 mg) and iodomethane (1.8 equiv.)
were used. Product was purified by acid/base workup and
recovered as a colorless oil (0.44 g, 79% yield), which was
found to match the data in literature.12 1H NMR (400 MHz,
CDCl3) δ 7.47 – 7.39 (m, 1H), 7.21 (ddd, J = 9.8, 7.6, 3.3 Hz,
1H), 7.12 – 7.06 (m, 1H), 7.05 – 6.98 (m, 1H), 1.79 (s, 2H).
Synthesis of Amine Substrates
Method A. General Procedure for Synthesis of
Benzylamines Bearing an α-Tertiary Center. Following our
previous reported method,12 an oven dried 50 mL round bottom
flask was added freshly ground magnesium turnings (2.5
equiv.) and a single crystal of iodine. The flask was placed
under N2, followed by addition of diethyl ether (10 mL). After
the stirring for 15 min at room temperature, the organohalide
(1.8 equiv.) was added dropwise. The reaction mixture was
refluxed for 1 h, followed by cooling to ~0-5 °C. After cooling,
the appropriate ketone (1 equiv.) was added as an ether solution
in a dropwise manner, ensuring to maintain a low temperature.
After stirring for 4-5 h at 0 °C, the reaction mixture was
quenched with saturated aqueous ammonium chloride (NH4Cl)
and extracted with diethyl ether (3 x 10 mL). The combined
organic layer was washed with brine, dried over Na2SO4 (s), and
concentrated in vacuo to give the crude alcohol product, which
was used for the next step without any further purification.
2-(3-Fluorophenyl)propan-2-amine (S-2). Method A used. m-
Fluoroacetophenone (500 mg) and iodomethane (1.8 equiv.)
were used. Product was purified by acid/base workup and
recovered as a colorless oil (0.44 g, 79% yield), which was
found to match the data in literature.28 1H NMR (600 MHz,
CDCl3) δ 7.28 – 7.23 (m, 2H), 7.23 – 7.19 (m, 1H), 6.91 – 6.84
(m, 1H), 1.50 (s, 2H), 1.45 (s, 6H).
2-(3-Fluorophenyl)butan-2-amine (S-3). Method A used. m-
Fluoroacetophenone (500 mg) and iodoethane (1.8 equiv.) were
used. Product was purified by acid/base workup and recovered
as a yellow oil (0.49 g, 81% yield)which was found to match
the data in literature.12 1H NMR (600 MHz, CDCl3) δ 7.31 –
7.27 (m, 1H), 7.23 – 7.17 (m, 2H), 6.93 – 6.88 (m, 1H), 1.83 –
1.77 (m, 1H), 1.74 – 1.68 (m, 1H), 1.55 (br s, 2H), 1.45 (s, 3H),
0.75 (t, J = 7.4 Hz, 3H).
To a solution of the alcohol (1 equiv.) in anhydrous
CH2Cl2 (10 mL), NaN3 (2.2 equiv.) was added at room
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The Journal of Organic Chemistry
2-(2-Fluorophenyl)-3-methylbutan-2-amine (S-4). Method A 2-(3-Methylphenyl)butan-2-amine (S-10). Method A used.
1
2
3
4
5
6
7
8
used. o-Fluoroacetophenone (500 mg) and 2-Iodopropane (1.8
equiv.) were used. Product was purified on silica gel in
CH2Cl2/MeOH (95:5) and recovered as a colorless oil (0.50 g,
76% yield). 1H NMR (600 MHz, CDCl3) δ 7.43 (td, J = 8.2, 1.7
Hz, 1H), 7.19 (dddd, J = 7.4, 6.8, 3.3, 1.1 Hz, 1H), 7.08 (ddd, J
= 7.4, 4.3, 0.8 Hz, 1H), 6.99 (ddd, J = 12.9, 8.1, 1.0 Hz, 1H),
2.32 (heptd, J = 6.8, 1.5 Hz, 1H), 1.59 (s, 2H), 1.45 (d, J = 0.8
Hz, 3H), 0.86 (d, J = 6.8 Hz, 3H), 0.77 (d, J = 6.9 Hz, 3H).
13C{1H} NMR (151 MHz, CDCl3) δ 160.9 (d, J = 245.5 Hz),
136.1 (d, J = 11.2 Hz), 128.0 (dd, J = 19.1, 7.1 Hz), 123.8 (d, J
= 3.2 Hz), 116.5, 116.3, 57.7 (d, J = 3.9 Hz), 36.1 (d, J = 3.8
Hz), 25.2 (d, J = 3.2 Hz), 17.6 (d, J = 13.9 Hz).19F NMR (376
MHz, CDCl3) δ -108.7 (m). HRMS (ESI-TOF) m/z: [M + H]+
Calcd for C11H17FN 182.1340; Found 182.1343.
m-Methylacetophenone (500 mg) and iodoethane (1.8 equiv.)
were used. Product was purified by acid/base workup and
recovered as a colorless oil (0.45 g, 81% yield). 1H NMR (600
MHz, CDCl3) δ 7.49 (d, J = 7.7 Hz, 1H), 7.31 – 6.93 (m, 3H),
2.59 (s, 3H), 1.96 (dq, J = 15.0, 7.5 Hz, 1H), 1.86 (dq, J = 14.7,
7.5 Hz, 1H), 1.54 (s, 3H), 0.76 (t, J = 7.5 Hz, 3H). 13C{1H}
NMR (151 MHz, CDCl3) δ 145.6, 135.8, 132.8, 126.7, 126.5,
125.7, 56.6, 35.4, 30.4, 23.1, 9.1. HRMS (ESI-TOF) m/z: [M +
H]+ Calcd for C11H18N 164.1434; Found 164.1436.
9
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15
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18
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2-([1.1’-Biphenyl]-3-yl)propan-2-amine (S-11). Method A
used. 3-Acetylbiphenyl (500 mg) and iodomethane (1.8 equiv.)
were used. Product was purified by acid/base workup and
recovered as a yellow oil (0.38g, 71% yield) which was found
to match the data in literature.29 1H NMR (600 MHz, CDCl3) δ
7.77 (t, J = 1.7 Hz, 1H), 7.64 (d, J = 7.5 Hz, 2H), 7.52 (dd, J =
7.7, 1.4 Hz, 1H), 7.50 – 7.41 (m, 4H), 7.38 (t, J = 7.4 Hz, 1H),
1.68 (s, 2H), 1.57 (s, 6H).
2-(2-Fluorophenyl)hexan-2-amine (S-5). Method A used. o-
Fluoroacetophenone (500 mg) and iodobutane (1.8 equiv.) were
used. Product was purified by acid/base workup and recovered
as a yellow oil (0.51 g, 74% yield) which was found to match
the data in literature.12 1H NMR (400 MHz, CDCl3) δ 7.43 –
7.38 (m, 1H), 7.22 – 7.17 (m, 1H), 7.08 (td, J = 7.6, 1.3 Hz, 1H),
6.99 (ddd, J = 12.8, 8.1, 1.3 Hz, 1H), 1.95 – 1.87 (m, 1H), 1.81
– 1.73 (m, 3H), 1.50 (s, 3H), 1.28 – 1.20 (m, 2H), 1.12 – 1.01
(m, 2H), 0.83 (t, J = 7.3 Hz, 3H).
2-(3-Methoxyphenyl)propan-2-amine (S-12). Method
A
used. m-Methoxyacetophenone (500 mg) and iodomethane (1.8
equiv.) were used. Product was purified by acid/base workup
and recovered as a yellow oil (0.35 g, 65% yield) which was
found to match the data in literature.28 1H NMR (600 MHz,
CDCl3) δ 7.43 – 7.06 (m, 1H), 7.07 (dd, J = 4.9, 3.2 Hz, 2H),
6.88 – 6.67 (m, 1H), 3.82 (s, 3H), 1.71 (s, 2H), 1.48 (s, 6H).
2-(2-Fluorophenyl)octan-2-amine (S-6). Method A used. o-
fluoroacetophenone (500 mg) and iodohexane (1.8 equiv.) were
used. Product was purified on silica gel in CH2Cl2/MeOH (95:5)
and recovered as a colorless oil (0.55 mg, 68% yield) which was
found to match the data in literature.12 1H NMR (400 MHz,
CDCl3) δ 7.45 – 7.34 (m, 1H), 7.24 – 7.16 (m, 1H), 7.08 (t, J =
7.5 Hz, 1H), 6.99 (dd, J = 12.8, 8.0 Hz, 1H), 1.96 – 1.83 (m,
1H), 1.80 – 1.72 (m, 3H), 1.49 (s, 3H), 1.20 (br s, 6H), 1.13 –
1.01 (m, 2H), 0.83 (t, J = 6.6 Hz, 3H).
2-(3-Methoxyphenyl)butan-2-amine (S-13). Method A used.
m-Methoxyacetophenone (500 mg) and iodoethane (1.8 equiv.)
were used. Product was purified by acid/base workup and
recovered as a yellow oil (0.40 g, 68% yield) which was found
to match the data in literature.12 1H NMR (600 MHz, CDCl3) δ
7.26 – 7.20 (m, 1H), 7.05 – 6.96 (m, 1H), 6.78 – 6.72 (m, 1H),
3.80 (s, 3H), 1.83 – 1.74 (m, 1H), 1.76 – 1.65 (m, 1H), 1.43 (s,
3H), 0.74 (t, J = 7.4 Hz, 3H).
2-(2-Fluorophenyl)-1-phenylpropan-2-amine (S-7). Method
A used. o-Fluoroacetophenone (500 mg) and benzyl bromide
(1.8 equiv.) were used. Product was purified on silica gel in
CH2Cl2/MeOH (98:2) and recovered as a light yellow oil (0.71
g, 85% yield) which was found to match the data in literature.12
1H NMR (400 MHz, CDCl3) δ 7.26 – 7.21 (m, 2H), 7.19 – 7.16
(m, 3H), 7.12 – 7.06 (m, 1H), 7.04 – 7.01 (m, 1H), 6.96 – 6.93
(m, 2H), 3.27 (d, J = 13.1 Hz, 1H), 3.08 (d, J = 13.1 Hz, 1H),
1.65 (br s, 2H), 1.57 (s, 3H).
2-(3-(Benzyloxy)phenyl)propan-2-amine (S-14). Method A
used. 3'-Benzyloxyacetophenone (500 mg) and iodomethane
(1.8 equiv.) were used. Product was purified by acid/base
workup and recovered as a yellow oil (0.40 g, 75% yield) which
was found to match the data in literature.28 1H NMR (600 MHz,
CDCl3) δ 7.46 (dd, J = 7.9, 0.9 Hz, 2H), 7.43 – 7.37 (m, 2H),
7.36 – 7.32 (m, 1H), 7.27 (t, J = 8.0 Hz, 1H), 7.19 – 7.16 (m,
1H), 7.11 (ddd, J = 7.8, 1.8, 0.8 Hz, 1H), 6.85 (ddd, J = 8.2, 2.5,
0.7 Hz, 1H), 5.08 (s, 2H), 1.61 (s, 2H), 1.49 (s, 3H).
2-(3-Chorophenyl)propan-2-amine (S-8). Method A used. m-
Chloroacetophenone (500 mg) and iodomethane (1.8 equiv.)
were used. Product was purified on silica gel in CH2Cl2/MeOH
(97:3) and recovered as a yellow oil (0.44 g, 81% yield) which
was found to match the data in literature.12 1H NMR (400 MHz,
CDCl3) δ 7.49 (t, J = 1.9 Hz, 1H), 7.36 (dt, J = 8.0, 0.8 Hz, 1H),
7.23 (t, J = 7.8 Hz, 1H), 7.17 (dt, J = 7.6, 1.2 Hz, 1H), 1.55 (s,
2H), 1.46 (s, 6H).
2-(Naphthalen-2-yl)butan-2-amine (S-15). Method A used. 2-
Acetonaphthone (500 mg) and iodoethane (1.8 equiv.) were
used. Product was purified by acid/base workup and recovered
as a yellow oil (0.34 g, 58% yield), and that was unstable under
ESI-MS conditions. 1H NMR (600 MHz, CDCl3) δ 7.90 (s, 1H),
7.86 – 7.80 (m, 3H), 7.57 (dd, J = 8.6, 1.9 Hz, 1H), 7.50 – 7.43
(m, 2H), 1.93 (dq, J = 15.0, 7.5 Hz, 1H), 1.82 (dq, J = 14.8, 7.4
Hz, 1H), 1.62 (s, 2H), 1.55 (s, 3H), 0.76 (t, J = 7.4 Hz, 3H).
13C{1H} NMR (151 MHz, CDCl3) δ 146.2, 133.3, 132.1, 128.2,
127.9, 127.5, 126.0, 125.6, 124.5, 123.6, 55.5, 37.5, 30.9, 8.8.
HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C14H18N 200.1434;
Found 200.1437.
2-(3-Methylphenyl)propan-2-amine (S-9). Method A used.
m-Methylacetophenone (500 mg) and iodomethane (1.8 equiv.)
were used. Product was purified by acid/base workup and
recovered as a colorless oil (0.43 g, 77% yield), which was
found to match the data in literature.12 1H NMR (400 MHz,
CDCl3) δ 7.34 (s, 1H), 7.30 (d, J = 7.9 Hz, 1H), 7.23 (t, J = 7.7
Hz, 1H), 7.05 (d, J = 7.3 Hz, 1H), 2.38 (s, 3H), 1.49 (s, 6H).
1-Ethyl-1,2,3,4-tetrahydronaphthalen-1-amine
(S-16).
Method A used. α-Tetralone (500 mg) and iodoethane (1.8
equiv.) were used. Product was purified by acid/base workup
and recovered as a yellow oil (0.36 g, 60% yield). 1H NMR (600
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MHz, CDCl3) δ 7.44 (d, J = 7.8 Hz, 1H), 7.18 (dd, J = 11.1, 3.8 manner. The reaction mixture was stirred overnight at room
1
2
3
4
5
6
7
8
Hz, 1H), 7.12 (td, J = 7.4, 1.1 Hz, 1H), 7.06 (d, J = 7.5 Hz, 1H),
2.88 – 2.70 (m, 2H), 2.02 – 1.93 (m, 1H), 1.89 – 1.80 (m, 3H),
1.73 (dq, J = 14.6, 7.4 Hz, 1H), 1.68 – 1.61 (m, 1H), 0.85 (t, J
= 7.5 Hz, 3H). 13C{1H} NMR (151 MHz, CDCl3) δ 144.4,
136.7, 129.1, 126.3, 126.2 (d, J = 2.1 Hz), 53.3, 36.5, 36.0, 30.4,
19.7, 8.8. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C12H18N
176.1434; Found 176.1437.
temperature followed by concentrating in vacuo to give a white
residue. The crude residue was treated with ethyl acetate (30
mL) and stirred for 30 min at room temperature. The solid was
filtered off and washed with additional ethyl acetate. The
combined filtrate was concentrated in vacuo to afford the crude
amide as colorless oil.
The Boc-protected crude amide was dissolved in dry
CH2Cl2 and trifluoroacetic acid (5.0 equiv.) was added at room
temperature under an N2 atmosphere. After the reaction mixture
was stirred for 2.0 hours at room temperature, the organic
solvent was evaporated in vacuo. The reaction mixture was
treated with aqueous sodium hydroxide (1.0 M, 20 mL) and
stirred for 30 min. The reaction mixture was then extracted with
CH2Cl2 (2 × 10 mL), dried over Na2SO4, and concentrated to
give the crude product as a colorless oil, which was subjected
to column chromatography on silica gel in hexanes/EtOAc
(20:80) and amine was recovered as a light yellow oil (1.0 g,
1-(3-Fluorophenyl)ethan-1-amine (S-17). Method B used. 3'-
Fluoroacetophenone (500 mg) was used. Product was purified
by acid/base workup and recovered as a yellow oil (0.43 g, 86%
yield) which was found to match the data in literature.30 1H
NMR (600 MHz, CDCl3) δ 7.31 – 7.26 (m, 1H), 7.13 (d, J = 7.7
Hz, 1H), 7.09 (d, J = 10.0 Hz, 1H), 6.93 (td, J = 8.3, 2.1 Hz,
1H), 4.15 (q, J = 6.6 Hz, 1H), 3.28 (s, 2H), 1.41 (d, J = 6.6 Hz,
3H).
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1-(3-Bromophenyl)ethan-1-amine (S-18). Method B used. 3'-
Bromoacetophenone (500 mg) was used. Product was purified
by acid/base workup and recovered as a yellow oil (0.29 g, 57%
yield) which was found to match the data in literature.12 1H
NMR (400 MHz, CDCl3) δ 7.48 (s, 1H), 7.33 (d, J = 7.5 Hz,
1H), 7.24 (d, J = 7.4 Hz, 1H), 7.16 (t, J = 7.7 Hz, 1H), 4.05 (q,
J = 6.4 Hz, 1H), 1.48 (s, 2H), 1.33 (d, J = 6.4 Hz, 3H).
59% yield)which was found to match the data in literature.12 1
H
NMR (400 MHz, CDCl3) δ 7.37 – 7.27 (m, 5H), 4.65 (s, 1H),
3.54 – 3.45 (m, 1H), 3.17 – 3.05 (m, 2H), 2.93 – 2.86 (m, 1H),
2.01 (brs, 2H), 1.61 – 1.42 (m, 3H), 1.28 – 1.15 (m, 1H), 0.84
(t, J = 7.4 Hz, 3H), 0.76 (t, J = 7.4 Hz, 3H).
2-(2-Fluorophenyl)-N-propylbutan-2-amine (S-22). To a 50-
mL round bottom flask charged with a stir bar was added the 2-
(2-fluorophenyl)butan-2-amine (500 mg), propionaldehyde
(1.5 equiv.), and 15 mL of chloroform. The reaction was stirred
at 60 ºC for 4 h and filtered over Na2SO4 after cooling. The
filtrate was concentrated in vacuo, followed by dissolution in
methanol (10 mL). Sodium borohydride (1.2 equiv) was added
portion wise, followed by stirring for 6 h. After stirring the
reaction was quenched with aq. NaOH. The aqueous layer was
extracted with diethyl ether (2 x 25 mL), dried over Na2SO4,
followed by concentration in vacuo. The residue was then
acidified using 1.2M hydrochloric acid, followed by subsequent
washing with diethyl ether (2 x 50 mL). The aqueous layer was
then made basic with ammonium hydroxide and extracted with
DCM (3 x 30 mL). After drying over Na2SO4, the organic layer
was concentrated in vacuo to give the secondary amine product
1-(2-Bromophenyl)ethan-1-amine (S-19). Method B used. 2'-
Bromoacetophenone (500 mg) was used. Product was purified
by acid/base workup and recovered as a yellow oil (0.29 g, 57%
yield)which was found to match the data in literature.31 1H NMR
(600 MHz, CDCl3) δ 7.55 – 7.48 (m, 1H), 7.30 (td, J = 7.5, 0.9
Hz, 1H), 7.10 – 7.03 (m, 1H), 4.49 (q, J = 6.6 Hz, 1H), 1.51 (s,
2H), 1.37 (d, J = 6.6 Hz, 3H).
1-(2-Chlorophenyl)ethan-1-amine (S-20). Method B used. 2'-
Chloroacetophenone (500 mg) was used. Product was purified
by acid/base workup and recovered as a yellow oil (0.31 g, 62%
yield), which was found to match the data in literature.12 1H
NMR (400 MHz, CDCl3) δ 7.51 (dd, J = 7.7, 1.3 Hz, 1H), 7.32
(dd, J = 7.9, 1.0 Hz, 1H), 7.28 – 7.23 (m, 1H), 7.15 (td, J = 7.7,
1.6 Hz, 1H), 4.53 (q, J = 6.6 Hz, 1H), 1.56 (s, 2H), 1.38 (d, J =
6.6 Hz, 3H).
1
as a colorless oil (0.63 g, 75% yield). H NMR (600 MHz,
CDCl3) δ 7.30 – 7.25 (m, 1H), 7.24 – 7.18 (m, 1H), 7.09 (td, J
= 7.6, 1.3 Hz, 1H), 6.99 (ddd, J = 13.1, 8.1, 1.2 Hz, 1H), 2.39
(ddd, J = 10.2, 8.9, 5.8 Hz, 1H), 2.15 (ddd, J = 10.6, 8.5, 6.4 Hz,
1H), 1.92 (dq, J = 14.9, 7.5 Hz, 1H), 1.80 (dq, J = 14.9, 7.7 Hz,
1H), 1.55 – 1.37 (m, 5H), 0.85 (t, J = 7.4 Hz, 3H), 0.72 (t, J =
7.5 Hz, 3H). 13C{1H} NMR (151 MHz, CDCl3) δ 161.6 (d, J =
245.9 Hz), 129.7 (d, J = 5.2 Hz), 128.4 (d, J = 9.1 Hz), 123.8
(d, J = 3.3 Hz), 116.3, 116.1, 45.3, 34.1 (d, J = 3.1 Hz), 23.9,
23.7, 12.0, 8.9. 19F NMR (376 MHz, CDCl3) δ -111.4. HRMS
(ESI-TOF) m/z: [M + H]+ Calcd for C13H21FN 210.1653; Found
210.1657.
(S)-2-Amino-N,N-dipropyl-2-phenylacetamide
(S-21).
Following our previous procedure,12 NaOH (330 mg, 1.1 equiv)
in a mixture of H2O/t-BuOH (8.0 + 4.5 mL) was prepared in a
50 mL round bottom flask. L-(+)-Phenyl glycine (1.13 g, 1.0
equiv.) was added to the flask, and the reaction was stirred at
room temperature. After 15 min, (Boc)2O (1.1 equiv.) was
added in a dropwise manner. The reaction mixture was stirred
overnight followed by removal of volatiles in vacuo. The
resulting oily residue was diluted with dichloromethane,
washed with water, and concentrated to give Boc-protected
phenyl glycine. The crude residue was subjected to column
chromatography on silica gel and hexanes/EtOAc (40:60) as
eluent to obtain purified Boc-protected phenyl glycine.
Synthesis of Iodo(hetero)arylcarboxylic Acids.
Medthod A. General Procedure for Synthesis of Ethyl
Esters from 2-Iodobenzoic Acids via Fischer Esterification.
2-iodobenzoic acid (1 equiv.) was added to a 50 mL round
bottom flask, followed by anhydrous ethanol (25 mL). Acetyl
chloride (1.5 equiv.) was added dropwise, followed by
refluxing overnight. The reaction was cooled, followed by
evaporating in vacuo. The residue was triturated in sat.
NH4OH(aq), followed by extracting with dichloromethane (3 x
Boc-protected phenyl glycine (1.0 equiv.) was added to an
oven dried round bottom flask and dry CH2Cl2 was added to it
under an N2 atmosphere. Dicyclohexylcarbodiimide (DCC, 1.0
equiv.) was added to the reaction mixture in one portion. The
reaction mixture was cooled to 0°C and stirred for 15 minutes
under N2 atmosphere followed by the addition of appropriate
amine (1.0 equiv.) as a solution in dry CH2Cl2 in a dropwise
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The Journal of Organic Chemistry
25 mL). The organic phase was rinsed once with sat. NH4OH(aq)
,
followed by drying over Na2SO4, and evaporating in vacuo to
give the desired product.
Hz), 126.4 (d, J = 3.2 Hz), 118.1 (d, J = 25.5 Hz), 82.8 (d, J =
27.1 Hz), 62.1, 14.3. 19F NMR (376 MHz, CDCl3) δ -85.7 (dd).
HRMS (CI) m/z: [M]+• Calcd for C9H8FIO2 293.9548; Found
293.9551.
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Method B. General Procedure for Synthesis of Ethyl Esters
from 2-Iodobenzoic Acids via SN2. 2-iodobenzoic acid (1
equiv.) and K2CO3 (2.5 equiv.) in 50 mL of DMF were stirred
at room temperature for 30 min. Iodoethane (1.5 equiv.) was
added portion wise to the reaction. The reaction was warmed to
50 °C for 3-4 h. After the reaction was completed (monitored
by TLC), reaction was diluted with EtOAc and washed with
water (3 x 50 mL). The organic layer was collected, dried over
Na2SO4 and concentrated in vacuo to give the desired products.
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Ethyl 4,5-difluoro-2-iodobenzoate (S-29). Method B used.
4,5-Difluoro-2-iodobenzoic acid (500 mg) was used. Product
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recovered as a yellow oil (467 mg, 85% yield). H NMR (600
MHz, CDCl3) δ 7.79 (dd, J = 9.5, 7.5 Hz, 1H), 7.72 (dd, J =
10.8, 8.1 Hz, 1H), 4.38 (q, J = 7.1 Hz, 2H), 1.40 (t, J = 7.2 Hz,
3H). 13C{1H} NMR (151 MHz, CDCl3) δ 164.4(d, J = 1.5 Hz),
151.7 (dd, J = 260.1, 13.0 Hz), 149.9 (dd, J = 251.9, 12.5 Hz),
131.4 (t, J = 4.4 Hz), 130.3 (d, J = 19.5 Hz), 120.4 (dd, J = 19.5,
1.3 Hz), 87.1 (dd, J = 6.3, 4.2 Hz), 62.3, 14.3. 19F NMR (376
MHz, CDCl3) δ -128.6 (m), 134.8 (ddd). HRMS (CI) m/z: [M]+•
Calcd for C9H7F2IO2 311.9453; Found 311.9464.
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Characterization Data. Ethyl 4-chloro-2-iodobenzoate (S-
23). Method A used. 4-Chloro-2-iodobenzoic acid (500 mg)
was used. Product recovered as a yellow solid (505 mg, 92%
yield). 1H NMR (600 MHz, CDCl3) δ 8.00 (d, J = 2.0 Hz, 1H),
7.76 (d, J = 8.4 Hz, 1H), 7.38 (dd, J = 8.4, 2.0 Hz, 1H), 4.39 (q,
J = 7.1 Hz, 2H), 1.40 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (151
MHz, CDCl3) δ 165.7, 141.0, 138.1, 133.5, 131.8, 128.3, 94.6,
62.1, 14.3. HRMS (CI) m/z: [M]+• Calcd for C9H8ClIO2
309.9252; Found 309.9254.
Ethyl 5-bromo-2-iodobenzoate (S-30). Method A used. 5-
bromo-2-iodobenzoic acid (500 mg) was used. Product
recovered as a brown solid (499 mg, 92% yield) which was
found to match the data in the literature.35 1H NMR (600 MHz,
CDCl3) δ 7.90 (d, J = 2.4 Hz, 1H), 7.81 (d, J = 8.4 Hz, 1H), 7.26
(dd, J = 8.4, 2.4 Hz, 1H), 4.39 (q, J = 7.1 Hz, 2H), 1.41 (t, J =
7.1 Hz, 3H).
Ethyl 5-chloro-2-iodobenzoate (S-24). Method A used. 5-
Chloro-2-iodobenzoic acid (500 mg) was used. Product
recovered as a yellow solid (495 mg, 90% yield). 1H NMR (600
MHz, CDCl3) δ 7.90 (dd, J = 8.4 Hz, 2.4 Hz, 1H), 7.77 (d, J =
2.4 Hz, 1H), 7.14 (dd, J = 8.4, 2.4 Hz, 1H), 4.40 (q, J = 7.1 Hz,
2H), 1.42 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (151 MHz, CDCl3)
δ 165.5, 142.5, 136.8, 134.6, 132.8, 131.1, 91.3, 62.3, 14.3.
HRMS (CI) m/z: [M]+• Calcd for C9H8ClIO2 309.9252; Found
309.9256.
Ethyl 2,5-diiodobenzoate (S-31). Method A used. 2,5-
Diiodobenzoic acid (2.00 g) was used. Product recovered as a
tan solid (2.11 g, 98% yield) which was found to match the data
in literature.36 1H NMR (400 MHz, CDCl3) δ 8.08 (d, J = 2.1
Hz, 1H), 7.68 (d, J = 8.3 Hz, 1H), 7.44 (dd, J = 8.3, 2.1 Hz, 1H),
4.40 (q, J = 7.1 Hz, 2H), 1.41 (t, J = 7.1 Hz, 3H).
Ethyl 2-iodo-5-(trifluoromethyl)benzoate (S-32). Method A
used. 2-Iodo-5-(trifluoromethyl)benzoic acid (500 mg) was
used. Product recovered as a yellow oil (468 mg, 86% yield).
1H NMR (600 MHz, CDCl3) δ 8.13 (d, J = 8.2 Hz, 1H), 8.02 (d,
J = 2.1 Hz, 1H), 7.38 (ddd, J = 8.3, 2.2, 0.5 Hz, 1H), 4.44 (q, J
= 7.2 Hz, 2H), 1.43 (t, J = 7.2 Hz, 3H). 13C{1H} NMR (151
MHz, CDCl3) δ 165.5, 142.2, 136.3, 130.8 (q, J = 33.5 Hz),
128.8 (q, J = 3.5 Hz), 127.7 (q, J = 3.8 Hz), 123.6 (q, J = 272.5
Hz), 98.6, 62.4, 14.3. 19F NMR (376 MHz, CDCl3) δ -61.5.
HRMS (CI) m/z: [M]+• Calcd for C10H8F3IO2 343.9516; Found
343.9510.
Ethyl 2-chloro-6-iodobenzoate (S-25). Method B used. 2-
Chloro-6-iodobenzoic acid (500 mg) was used. Product
recovered as a yellow oil (467 mg, 85% yield) which was found
to match the data in the literature.32 1H NMR (600 MHz, CDCl3)
δ 7.72 (dd, J = 8.0, 0.9 Hz, 1H), 7.38 (dd, J = 8.1, 0.9 Hz, 1H),
7.03 (t, J = 8.1 Hz, 1H), 4.46 (q, J = 7.2 Hz, 2H), 1.43 (t, J =
7.2 Hz, 3H).
Ethyl 5-fluoro-2-iodobenzoate (S-26). Method A used. 5-
Fluoro-2-iodobenzoic acid (500 mg) was used. Product
recovered as a yellow oil (508 mg, 92% yield) which was found
to match the data in the literature.33 1H NMR (600 MHz, CDCl3)
δ 7.93 (dd, J = 9.0, 5.4 Hz, 1H), 7.53 (dd, J = 9.3, 3.3 Hz, 1H),
7.03 – 6.77 (m, 1H), 4.40 (q, J = 7.4 Hz, 2H), 1.41 (t, J = 7.3
Hz, 3H).
Ethyl 2-iodo-5-nitrobenzoate (S-33). 2-Iodobenzoic acid (2.0
g, 8.06 mmol) was treated with conc. H2SO4 (9 mL), followed
by cooling to 0 ºC. Conc. HNO3 (3 mL) was then added slowly,
and the reaction was then heated to 110 ºC. After 46 h the
reaction was cooled, poured over ice, then filtered and dried.
The resulting solid was then recrystallized from EtOH, giving
Ethyl 2-fluoro-6-iodobenzoate (S-27). Method B used. 2-
Fluoro-6-iodobenzoic acid (500 mg) was used. Product
recovered as a yellow oil (486 mg, 88% yield) which was found
to match the data in the literature.34 1H NMR (600 MHz, CDCl3)
δ 7.74 – 7.49 (m, 1H), 7.18 – 6.98 (m, 2H), 4.45 (q, J = 7.2 Hz,
2H), 1.42 (t, J = 7.2 Hz, 3H).
intermediate as
a light yellow solid (1.64 g, 69%).
Subsequently, anhydrous EtOH (50 mL) was treated with acetyl
chloride (500 μL, 7.0 mmol), and 2-iodo-5-nitrobenzoic acid
(1.24 g, 4.23 mmol) was added, followed by heating under
reflux. After 24 h the reaction was cooled, then evaporated in
vacuo. The residue was triturated in sat. Na2CO3, followed by
extracting with dichloromethane (3 x 20 mL). The combined
organic phase was dried over MgSO4, then evaporated in vacuo
to give the desired product as a light yellow solid (801 mg, 59%)
with spectral data that corresponded to literature values.37 1H
NMR (400 MHz, CDCl3) δ8.59 (d, J = 2.7 Hz, 1H), 8.20 (d, J =
8.6 Hz, 1H), 7.96 (dd, J = 8.6, 2.7 Hz, 1H), 4.43 (d, J = 7.1 Hz,
2H), 1.44 (t, J = 7.1 Hz, 3H).
Ethyl 3-fluoro-2-iodobenzoate (S-28). Method B used. 3-
Fluoro-2-iodobenzoic acid (500 mg) was used. Product
1
recovered as a yellow oil (497 mg, 90% yield). H NMR (600
MHz, CDCl3) δ 7.53 (d, J = 7.7 Hz, 1H), 7.35 (td, J = 7.9, 5.3
Hz, 1H), 7.19 – 7.14 (m, 1H), 4.41 (q, J = 7.1 Hz, 2H), 1.41 (t,
J = 7.1 Hz, 3H). 13C{1H} NMR (151 MHz, CDCl3) δ 166.1 (d,
J = 2.5 Hz), 162.1 (d, J = 244.9 Hz), 138.2, 129.8 (d, J = 8.2
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Ethyl 2-iodo-5-methylbenzoate (S-34). Method A used. 2- 9.9 mmol) and I2 (2.51 g, 9.9 mmol). The reaction was allowed
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Iodo-5-methylbenzoic acid (500 mg) was used. Product
recovered as a yellow oil (526 mg, 95% yield) which was found
to match the data in the literature.36 1H NMR (600 MHz, CDCl3)
δ 7.82 (d, J = 8.1 Hz, 1H), 7.59 (d, J = 1.9 Hz, 1H), 6.95 (dd, J
= 8.1, 2.2 Hz, 1H), 4.38 (q, J = 7.1 Hz, 2H), 2.32 (s, 3H), 1.40
(t, J = 7.1 Hz, 3H).
to stir at RT in the dark. After 15 h the reaction was filtered,
followed by washing with Na2S2O3(aq), then drying over Na2SO4
and evaporating in vacuo. The crude residue was added to
absolute ethanol (50 mL) which had been pre-treated with
acetyl chloride (1 mL). The reaction was heated under reflux for
24h. After cooling, the reaction was evaporated in vacuo. The
crude reaction was subjected to column chromatography over
silica gel using 10:1 hexanes/EtOAc, given the desired product
as a tan oil (1.39 g, 40%). 1H NMR (600 MHz, CDCl3) δ 7.13
(s, 1H), 4.38 (d, J = 7.1 Hz, 2H), 3.89 (s, 3H), 3.87 (s, 3H), 3.85
(s, 3H), 1.40 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (151 MHz,
CDCl3) δ 166.8, 153.9, 153.5, 144.8, 131.7, 110.3, 83.7, 61.9,
61.2, 60.9, 56.4, 14.3. HRMS (CI) m/z: [M]+• Calcd for
C12H15IO5 365.9959; Found 365.9955.
Ethyl 2-iodo-5-methoxybenzoate (S-35). Method A used. 2-
Iodo-5-methoxybenzoic acid (500 mg) was used. Product
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recovered as a yellow oil (495 mg, 90% yield). H NMR (600
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MHz, CDCl3) δ 7.82 (d, J = 8.7 Hz, 1H), 7.33 (d, J = 3.1 Hz,
1H), 6.74 (dd, J = 8.7, 3.1 Hz, 1H), 4.40 (q, J = 7.1 Hz, 2H),
3.81 (s, 3H), 1.41 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (151 MHz,
CDCl3) δ 166.6, 159.6, 141.9, 136.4, 119.2, 116.5, 82.5, 61.9,
55.7, 14.4. HRMS (CI) m/z: [M]+• Calcd for C10H11IO3
305.9747; Found 305.9751.
Ethyl 2-iodofuran-3-carboxylate (S-39). According to a
known procedure,39 furan-3-carboxylic acid (1.0 g, 8.9 mmol)
in anhydrous THF (200 mL) under a nitrogen atmosphere
cooled to -78 °C was added nBuLi (22.3 mmol, 1.6 M in
hexanes) dropwise. Reaction was brought to room temperature
after half an hour. Again, reaction was cooled to -78 °C and
iodine (12.5 g, 49.1 mmol) as a solution in anhydrous THF (30
mL) was added dropwise to the reaction mixture. Reaction was
brought to room temperature again and let the reaction stir for
2 h. Reaction was quenched by adding water (dropwise) and the
organic solvents were removed in vacuo. The aqueous solution
was acidified using 1.2M hydrochloric acid solution and
extracted with EtOAc (3 x 20 mL). The combined organic phase
was dried over Na2SO4 and concentrated in vacuo. Desired
product was obtained (62% yield) and was used in the next step
without further purification.
Ethyl 2-iodo-4,5-dimethoxybenzoate (S-36). Method B used.
2-Iodo-4,5-dimethoxybenzoic acid (500 mg) was used. Product
recovered as a yellow solid (517 mg, 90% yield). 1H NMR (600
MHz, CDCl3) δ 7.42 (s, 1H), 7.38 (s, 1H), 4.38 (q, J = 7.1 Hz,
2H), 3.91 (s, 3H), 3.90 (s, 3H), 1.41 (t, J = 7.1 Hz, 3H). 13C{1H}
NMR (151 MHz, CDCl3) δ 165.7, 151.9, 148.8, 126.6, 123.8,
113.9, 84.6, 61.6, 56.4, 56.2, 14.4. HRMS (CI) m/z: [M]+• Calcd
for C11H13IO4 335.9853; Found 335.9865.
Ethyl 2-iodo-6-(trifluoromethoxy)benzoate (S-37). Based on
a modified procedure for the ortho-iodination of aromatic
acids,38 2-(trifluoromethoxy)benzoic acid (1.69 g, 8.2 mmol),
Pd(OAc)2 (180 mg, 0.80 mmol), diacetoxyiodobenzene (5.28 g,
16.4 mmol), and I2 (4.16 g, 16.4 mmol) were combined in a 60
mL sealed tube, followed by blanketing with N2. Anhydrous
dimethylformamide (20 mL) was added, followed by sealing
the tube and heating to 110 ºC in an oil bath. After 48 h the
reaction was cooled, followed by treating with Na2SO3(aq), and
stirring for 1h. The mixture was then poured into 1.2M HCl(aq)
followed by extracting with dichloromethane (4 x 30 mL). The
combined organic was dried over Na2SO4, followed by
evaporation in vacuo. The residue was triturated in a mixture of
hexanes and 1M NaOH(aq), followed by washing with additional
hexanes (4 x 25 mL). The aqueous phase was acidified with
conc. HCl(aq), followed by extraction with dichloromethane (3 x
20 mL). The crude mixture, which showed ~80% conversion to
the iodide, was added to acetonitrile (20 mL), followed by ethyl
iodide (659 μL, 8.2 mmol) and potassium carbonate (2.27 g,
16.4 mmol). The reaction was heated under reflux for 24h,
followed by pouring into deionized water (100 mL) and
extracting with dichloromethane (3 x 20 mL), followed by
drying over Na2SO4. The reaction was evaporated in vacuo,
giving a mixture of yellow oil and solid. The mixture was
treated with hexanes, then filtered through a silica plug.
Concentration gave the desired product as a yellow oil (925 mg,
Method A was used for esterification of 2-iodofuran-3-
carboxylic acid (500 mg). Product recovered as a yellow oil
(503 mg, 90% yield). 1H NMR (600 MHz, CDCl3) δ 7.57 (d, J
= 2.0 Hz, 1H), 6.74 (d, J = 2.1 Hz, 1H), 4.33 (q, J = 7.1 Hz, 2H),
1.37 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (151 MHz, CDCl3) δ
162.3, 148.3, 124.2, 112.6, 98.0, 60.9, 14.4. HRMS (CI) m/z:
[M]+• Calcd for C7H7IO3 265.9434; Found 265.9435.
Synthesis of Biaryl Lactams.
Standard conditions for the synthesis of Biaryl Lactams
starting from Ethyl 2-Iodobenzoates. Reactions performed in
duplicate, and the total mass/percent yield over two reactions
reported. A 7.5 mL vial was charged with Pd(OAc)2 (3.4 mg,
0.015 mmol, 0.1 equiv), silver acetate (50.1 mg, 0.30 mmol, 2
equiv), organohalide (0.45 mmol, 3.0 equiv), amine (0.15
mmol, 1 equiv), and acetic acid (1.0 mL). The vial was sealed
with a PTFE lined cap and stirred at room temperature for 15
min. After 15 min of stirring, the reaction mixture was heated
in a pie-block at 100 °C under stirring for 12-15 h. After cooling
to room temperature, the reaction mixture was made basic with
ammonium hydroxide solution up to pH = 8. The reaction
mixture was stirred for 15 minutes followed by extraction with
dichloromethane (3 × 10 mL). The organic layer was washed
with brine and dried over Na2SO4. The filtrate was concentrated
under vacuo and further purified by flash column
chromatography over silica (Hexanes:EtOAc unless otherwise
specified) to give the desired lactam product.
1
31%). H NMR (400 MHz, CDCl3) δ7.72 (d, J = 8.0 Hz, 1H),
7.27 (d, J = 8.4 Hz, 1H), 7.11 (t, J = 8.2 Hz, 1H), 4.43 (q, J =
7.1 Hz, 2H), 1.38 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (151 MHz,
CDCl3) δ 165.3, 145.7, 137.4, 134.3, 131.7, 120.3 (q, J = 259.8
Hz), 120.0, 92.6, 62.5, 14.0. 19F NMR (376 MHz, CDCl3) δ -
55.7 (d). HRMS (CI) m/z: [M]+• Calcd for C10H8F3IO3
359.9465; Found 359.9471.
Ethyl 2-iodo-3,4,5-trimethoxybenzoate (S-38). 3,4,5-
Trimethoxybenzoic acid (2.00 g, 9.43 mmol) was added to
chloroform (30 mL), followed by silver trifluoroacetate (2.19 g,
Characterization data.
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The Journal of Organic Chemistry
8-Fluoro-7,7-dimethyl-6,7-dihydro-5H-dibenzo[c,e]azepin-
mg, 84% yield). Rf = 0.5 (hexanes/EtOAc = 1:1). 1H NMR (600
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5-one (1a). Reaction time 14 h, purified by hexanes:EtOAc
(60:40). Product recovered as white solid (65.8 mg, 86% yield).
Rf = 0.5 (hexanes/EtOAc = 1:1). 1H NMR (600 MHz, CDCl3)
δ 7.98 (dd, J = 7.7, 1.3 Hz, 1H), 7.59 (td, J = 7.6, 1.4 Hz, 1H),
7.49 (ddd, J = 10.3, 8.3, 1.1 Hz, 2H), 7.33 (td, J = 7.9, 4.9 Hz,
1H), 7.28 (dd, J = 7.7, 1.4 Hz, 1H), 7.08 (ddd, J = 13.2, 8.1, 1.5
Hz, 1H), 6.49 (s, 1H), 1.92 (d, J = 10.1 Hz, 3H), 1.30 (s, 3H).
13C{1H} NMR (151 MHz, CDCl3) δ 168.9, 158.5 (d, J = 247.3
Hz), 140.8 (d, J = 4.3 Hz), 139.1 (d, J = 3.1 Hz), 132.7, 131.9,
131.8 (d, J = 11.2 Hz), 130.0, 129.8, 128.9 (d, J = 10.5 Hz),
128.4, 128.1 (d, J = 2.8 Hz), 117.0 (d, J = 27.5 Hz), 54.4 (d, J =
3.8 Hz), 31.8 (d, J = 17.7 Hz), 27.9. 19F NMR (376 MHz,
CDCl3) δ -109.5 (m). HRMS (ESI-TOF) m/z: [M + H]+ Calcd
for C16H15FNO 256.1132; Found 256.1122.
MHz, CDCl3) δ 7.96 (dd, J = 7.7, 1.3 Hz, 1H), 7.58 (td, J = 7.6,
1.4 Hz, 1H), 7.49 (td, J = 7.6, 1.2 Hz, 1H), 7.44 (dd, J = 7.8, 1.0
Hz, 1H), 7.33 (td, J = 7.9, 5.0 Hz, 1H), 7.27 (d, J = 10.1 Hz,
1H), 7.08 (ddd, J = 13.2, 8.1, 1.4 Hz, 1H), 6.26 (s, 1H), 1.86 (d,
J = 10.0 Hz, 3H), 1.71 – 1.51 (m, 1H), 1.41 (dd, J = 17.2, 8.0
Hz, 1H), 1.21 – 1.02 (m, 1H), 1.00 – 0.85 (m, 3H), 0.57 (t, J =
7.0 Hz, 3H). 13C{1H} NMR (151 MHz, CDCl3) δ 168.8, 159.2
(d, J = 247.1 Hz), 140.7, 139.2, 132.7, 131.8, 131.6 (d, J = 11.2
Hz), 129.9, 129.5, 128.9 (d, J = 10.5 Hz), 128.4, 128.1 (d, J =
2.0 Hz), 116.9 (d, J = 27.8 Hz), 57.8 (d, J = 3.6 Hz), 38.0, 28.8
(d, J = 18.0 Hz), 26.8, 22.5, 13.7. 19F NMR (376 MHz, CDCl3)
δ -109.4 (m). HRMS (ESI-TOF) m/z: [M + H]+ Calcd for
C19H21FNO 298.1602; Found 298.1607.
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8-Fluoro-7-hexyl-7-methyl-6.7-dihydro-5H-
9-Fluoro-7,7-dimethyl-6,7-dihydro-5H-dibenzo[c,e]azepin-
5-one (1b). Reaction time 14 h, purified by hexanes:EtOAc
(60:40). Product recovered as white solid (68.9 mg, 90% yield).
Rf = 0.5 (hexanes/EtOAc = 1:1). 1H NMR (600 MHz, CDCl3) δ
7.99 (dd, J = 7.7, 1.2 Hz, 1H), 7.59 (ddd, J = 7.8, 7.4, 1.5 Hz,
1H), 7.53 – 7.45 (m, 3H), 7.14 – 7.08 (m, 2H), 6.66 (s, 1H), 1.77
(s, 3H), 1.24 (s, 3H). 13C{1H} NMR (151 MHz, CDCl3) δ 169.5,
162.6 (d, J = 248.1 Hz), 147.5 (d, J = 6.5 Hz), 138.3, 133.8 (d,
J = 3.3 Hz), 133.3 (d, J = 8.3 Hz), 133.0, 131.8, 130.2, 129.3,
128.0, 114.7 (d, J = 21.0 Hz), 110.9 (d, J = 23.2 Hz), 53.6 (d, J
= 1.4 Hz), 29.9, 26.5. 19F NMR (376 MHz, CDCl3) δ -111.9 (m).
HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C16H15FNO
256.1132; Found 256.1128.
dibenzo[c,e]azepin-5-one (1f). Reaction time 14 h, purified by
hexanes:EtOAc (60:40). Product recovered as white solid (52.6
1
mg, 73% yield). Rf = 0.56 (hexanes/EtOAc = 1:1). H NMR
(600 MHz, CDCl3) δ 7.96 (dd, J = 7.7, 1.0 Hz, 1H), 7.58 (td, J
= 7.6, 1.3 Hz, 1H), 7.49 (td, J = 7.6, 1.1 Hz, 1H), 7.43 (dd, J =
7.8, 0.9 Hz, 1H), 7.32 (qd, J = 7.9, 3.9 Hz, 1H), 7.27 (d, J = 6.3
Hz, 1H), 7.13 – 7.02 (m, 1H), 6.42 (s, 1H), 1.86 (d, J = 10.1 Hz,
3H), 1.58 (td, J = 13.5, 4.4 Hz, 1H), 1.45 – 1.37 (m, 1H), 1.18
– 1.10 (m, 1H), 1.10 – 1.02 (m, 2H), 0.99 – 0.82 (m, 5H), 0.74
(t, J = 7.3 Hz, 3H). 13C{1H} NMR (151 MHz, CDCl3) δ 168.9,
159.2 (d, J = 247.1 Hz), 140.7 (d, J = 4.2 Hz), 139.2, 132.7,
131.8, 131.6 (d, J = 11.1 Hz), 129.9, 129.4, 128.9 (d, J = 10.5
Hz), 128.3, 128.1 (d, J = 2.4 Hz), 116.9 (d, J = 27.7 Hz), 57.8
(d, J = 3.8 Hz), 38.2, 31.3, 29.0, 28.7 (d, J = 17.9 Hz), 24.5,
22.5, 14.1. 19F NMR (376 MHz, CDCl3) δ -109.4 (m). HRMS
(ESI-TOF) m/z: [M + H]+ Calcd for C21H24FNNaO 348.1734;
Found 348.1736.
7-Ethyl-9-fluoro-7-methyl-6.7-dihydro-5H-
dibenzo[c,e]azepin-5-one (1c). Reaction time 14 h, purified by
hexanes:EtOAc (60:40). Product recovered as white solid (71.9
mg, 89% yield). Rf = 0.5 (hexanes/EtOAc = 1:1). 1H NMR (600
MHz, CDCl3) δ 7.98 (d, J = 7.6 Hz, 1H), 7.58 (t, J = 7.2 Hz,
1H), 7.53 – 7.44 (m, 3H), 7.14 – 7.07 (m, 2H), 6.35 (s, 1H), 1.69
(s, 3H), 1.54 (q, J = 7.4 Hz, 2H), 0.61 (t, J = 7.4 Hz, 3H).
13C{1H} NMR (151 MHz, CDCl3) δ 169.4, 162.6 (d, J = 248.0
Hz), 147.0 (d, J = 6.5 Hz), 138.3, 133.7 (d, J = 3.1 Hz), 133.3
(d, J = 8.2 Hz), 133.0, 131.8, 130.0, 129.2, 128.0, 114.7 (d, J =
21.0 Hz), 112.0 (d, J = 23.2 Hz), 57.2, 30.0, 26.2, 9.3. 19F NMR
(376 MHz, CDCl3) δ -112.1 (m). HRMS (ESI-TOF) m/z: [M +
H]+ Calcd for C17H17FNO 270.1294; Found 270.1303.
7-Benzyl-8-fluoro-7-methyl-6.7-dihydro-5H-
dibenzo[c,e]azepin-5-one (1g). Reaction time 14 h, purified by
hexanes:EtOAc (60:40). Product recovered as white solid (77.5
mg, 78% yield). Rf = 0.6 (hexanes/EtOAc = 1:1). 1H NMR (600
MHz, CDCl3) δ 8.10 (d, J = 7.6 Hz, 1H), 7.65 (dd, J = 7.6, 1.0
Hz, 1H), 7.61 – 7.52 (m, 2H), 7.42 – 7.31 (m, 2H), 7.19 – 7.12
(m, 3H), 7.03 (ddd, J = 13.3, 7.4, 2.0 Hz, 1H), 6.80 – 6.73 (m,
2H), 6.28 (s, 1H), 2.94 (d, J = 13.7 Hz, 1H), 2.77 (d, J = 13.7
Hz, 1H), 1.76 (d, J = 10.2 Hz, 3H). 13C{1H} NMR (151 MHz,
CDCl3) δ 168.8, 159.3 (d, J = 248.0 Hz), 140.7 (d, J = 4.0 Hz),
139.2 (d, J = 3.0 Hz), 136.4, 133.0, 132.2, 130.9 (d, J = 11.0
Hz), 130.4, 130.3, 129.8, 129.3 (d, J = 10.6 Hz), 128.7, 128.2
(d, J = 2.7 Hz), 128.1, 126.9, 117.0 (d, J = 27.9 Hz), 58.2 (d, J
= 4.1 Hz), 43.5, 28.8 (d, J = 18.4 Hz). 19F NMR (376 MHz,
CDCl3) δ -108.2 (m). HRMS (ESI-TOF) m/z: [M + H]+ Calcd
for C22H19FNO 332.1445; Found 332.1449.
8-Fluoro-7-isopropyl-7-methyl-6.7-dihydro-5H-
dibenzo[c,e]azepin-5-one (1d). Reaction time 14 h, purified by
hexanes:EtOAc (60:40). Product recovered as white solid (54.4
mg, 64% yield). Rf = 0.5 (hexanes/EtOAc = 1:1). 1H NMR (600
MHz, CDCl3) δ 7.97 (d, J = 7.7 Hz, 1H), 7.57 (dd, J = 10.9, 4.3
Hz, 1H), 7.47 (t, J = 7.5 Hz, 1H), 7.42 (d, J = 7.8 Hz, 1H), 7.33
(td, J = 7.9, 5.0 Hz, 1H), 7.28 (d, J = 7.7 Hz, 1H), 7.08 (ddd, J
= 13.3, 8.1, 1.1 Hz, 1H), 6.23 (s, 1H), 2.08 (dq, J = 13.5, 6.7 Hz,
1H), 1.71 (d, J = 10.0 Hz, 3H), 0.79 (d, J = 6.8 Hz, 3H), 0.64
(d, J = 6.8 Hz, 3H). 13C{1H} NMR (151 MHz, CDCl3) δ 168.7,
159.7 (d, J = 247.0 Hz), 140.2 (d, J = 3.9 Hz), 139.3 (d, J = 2.8
Hz), 132.4, 132.3, 132.0, 130.1, 129.3, 128.9 (d, J = 10.6 Hz),
128.3, 128.3, 116.8 (d, J = 28.1 Hz), 61.7 (d, J = 3.9 Hz), 31.4,
22.0 (d, J = 18.6 Hz), 18.3, 16.2. 19F NMR (376 MHz, CDCl3)
δ -108.7 (m). HRMS (ESI-TOF) m/z: [M + H]+ Calcd for
C18H19FNO 284.1440; Found 284.1450.
9-Chloro-7,7-dimethyl-6.7-dihydro-5H-dibenzo[c,e]azepin-
5-one (1h). Reaction time 14 h, purified by hexanes:EtOAc
(60:40). Product recovered as white solid (72.5 mg, 89% yield).
Rf = 0.5 (hexanes/EtOAc = 1:1). 1H NMR (600 MHz, CDCl3) δ
7.99 (dd, J = 7.7, 1.1 Hz, 1H), 7.59 (ddd, J = 7.8, 7.4, 1.5 Hz,
1H), 7.52 – 7.46 (m, 3H), 7.40 – 7.36 (m, 2H), 6.91 (s, 1H), 1.79
(s, 3H), 1.22 (s, 3H). 13C{1H} NMR (151 MHz, CDCl3) δ 169.5,
146.9, 138.1, 136.2, 134.3, 133.2, 132.8, 131.8, 130.2, 129.2,
128.3, 128.0, 123.8, 53.7, 29.8, 26.5. HRMS (ESI-TOF) m/z:
[M + H]+ Calcd for C16H15ClNO 272.0837; Found 272.0842.
7-Butyl-8-fluoro-7-methyl-6.7-dihydro-5H-
dibenzo[c,e]azepin-5-one (1e). Reaction time 14 h, purified by
hexanes:EtOAc (60:40). Product recovered as white solid (74.9
7,7,9-Trimethyl-6.7-dihydro-5H-dibenzo[c,e]azepin-5-one
(1i). Reaction time 14 h, purified by hexanes:EtOAc (60:40).
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Product recovered as white solid (73.8 mg, 98% yield). Rf = 0.5
[M+H]+ Found: 282.1480. HRMS (ESI-TOF) m/z: [M + H]+
Calcd for C18H20NO 282.1489; Found 282.1480.
(hexanes/EtOAc = 1:1). 1H NMR (600 MHz, CDCl3) δ 7.99 (dd,
J = 7.7, 1.2 Hz, 1H), 7.60 – 7.55 (m, 1H), 7.53 (dd, J = 7.8, 1.2
Hz, 1H), 7.45 (dd, J = 11.2, 4.6 Hz, 2H), 7.23 (d, J = 7.9 Hz,
1H), 7.20 (s, 1H), 6.59 (s, 1H), 2.42 (s, 3H), 1.79 (s, 3H), 1.23
(s, 3H). 13C{1H} NMR (151 MHz, CDCl3) δ 169.7, 145.1,
139.3, 138.0, 134.9, 133.1, 131.7, 131.6, 130.1, 129.3, 128.7,
127.6, 124.0, 53.9, 30.0, 26.9, 21.5. HRMS (ESI-TOF) m/z: [M
+ H]+ Calcd for C17H18NO 252.1383; Found 252.1377.
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9-(Benzyloxy)-7,7-dimethyl-6.7-dihydro-5H-
dibenzo[c,e]azepin-5-one (1n). Reaction time 14 h, purified by
hexanes:EtOAc (40:60). Product recovered as white solid (82.4
1
mg, 80% yield). Rf = 0.45 (hexanes/EtOAc = 1:1). H NMR
(600 MHz, CDCl3) δ 7.98 (dd, J = 7.8, 1.2 Hz, 1H), 7.57 (td, J
= 7.7, 1.4 Hz, 1H), 7.53 – 7.40 (m, 7H), 7.37 – 7.34 (m, 1H),
7.03 (d, J = 2.5 Hz, 1H), 7.00 (dd, J = 8.5, 2.6 Hz, 1H), 6.51 (s,
1H), 5.12 (s, 2H), 1.75 (s, 3H), 1.24 (s, 3H). 13C{1H} NMR (151
MHz, CDCl3) δ 169.7, 158.7, 146.7, 139.1, 136.7, 132.9, 132.7,
131.8, 130.5, 130.1, 129.1, 128.9, 128.4, 127.7, 127.4, 112.8,
111.4, 70.4, 53.9, 29.9, 26.7. HRMS (ESI-MS): calcd. 344.1650
[M+H]+ Found: 344.1666. HRMS (ESI-TOF) m/z: [M + H]+
Calcd for C23H22NO2 344.1645; Found 344.1666.
9
7-Ethyl-7,9-dimethyl-6.7-dihydro-5H-dibenzo[c,e]azepin-5-
one (1j). Reaction time 14 h, purified by hexanes:EtOAc
(60:40). Product recovered as white solid (73.2 mg, 92% yield).
Rf = 0.5 (hexanes/EtOAc = 1:1). 1H NMR (600 MHz, CDCl3) δ
7.95 (dd, J = 7.7, 1.4 Hz, 1H), 7.56 (td, J = 7.6, 1.4 Hz, 1H),
7.45 (td, J = 7.5, 1.1 Hz, 1H), 7.34 (dd, J = 7.8, 0.9 Hz, 1H),
7.29 (dd, J = 7.6, 1.4 Hz, 1H), 7.23 (t, J = 7.6 Hz, 1H), 7.17 (dd,
J = 7.5, 1.1 Hz, 1H), 6.25 (s, 1H), 2.60 (s, 3H), 1.87 (s, 3H),
1.65 (dq, J = 14.8, 7.4 Hz, 1H), 1.49 (dq, J = 14.7, 7.4 Hz, 1H),
0.64 (t, J = 7.4 Hz, 3H). 13C{1H} NMR (151 MHz, CDCl3) δ
168.9, 144.5, 141.8, 139.6, 133.7, 133.6, 131.8, 131.5, 130.4,
128.7, 127.7, 127.2, 61.3, 31.5, 30.2, 25.7, 9.2. HRMS (ESI-
MS): calcd. 266.1544 [M+H]+ Found: 266.1538. HRMS (ESI-
TOF) m/z: [M + H]+ Calcd for C18H20NO 266.1539; Found
266.1538.
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7-Ethyl-7-methyl-6.7-dihydro-5H-dibenzo[c]naphtha[2,3-
e]azepin-5-one (1o). Reaction time 14 h, purified by
hexanes:EtOAc (40:60). Product recovered as white solid (65.1
1
mg, 72% yield). Rf = 0.55 (hexanes/EtOAc = 1:1). H NMR
(600 MHz, CDCl3) δ 8.03 – 7.99 (m, 2H), 7.88 (t, J = 8.5 Hz,
2H), 7.80 (s, 1H), 7.68 – 7.60 (m, 2H), 7.57 – 7.47 (m, 3H), 6.34
(s, 1H), 1.85 (s, 3H), 1.63 (tq, J = 14.3, 7.1 Hz, 2H), 0.63 (t, J =
7.4 Hz, 3H). 13C{1H} NMR (151 MHz, CDCl3) δ 169.7, 142.6,
139.5, 136.1, 133.1, 132.7, 132.4, 132.0, 131.3, 129.9, 129.8,
128.1, 127.9, 127.9, 127.0, 126.8, 123.3, 57.8, 30.6, 26.6, 9.5.
HRMS (ESI-MS): calcd. 302.1544 [M+H]+ Found: 302.1547.
HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C21H20NO
302.1539; Found 302.1547.
7,7-Dimethyl—9-phenyl-6.7-dihydro-5H-
dibenzo[c,e]azepin-5-one (1k). Reaction time 14 h, purified by
hexanes:EtOAc (60:40). Product recovered as white solid (79.9
mg, 85% yield). Rf = 0.6 (hexanes/EtOAc = 1:1). 1H NMR (600
MHz, CDCl3) δ 8.02 (dd, J = 7.8, 0.8 Hz, 1H), 7.66 – 7.59 (m,
7H), 7.52 – 7.46 (m, 3H), 7.42 – 7.37 (m, 1H), 6.44 (s, 1H), 1.87
(s, 3H), 1.29 (s, 3H). 13C{1H} NMR (151 MHz, CDCl3) δ 169.6,
145.6, 141.1, 140.7, 139.0, 136.7, 133.1, 132.2, 131.8, 130.2,
129.4, 129.1, 128.0 127.9, 127.4, 126.8, 122.2, 54.1, 30.1, 26.9.
HRMS (ESI-MS): calcd. 314.1544 [M+H]+ Found: 314.1541.
HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C22H20NOo
314.1539; Found 314.1541.
3a-Ethyl-2,3,3a,4-tetrahydrobenzo[e]naphtho[1,8-
bc]azepin-5(1H)-one (1p). Reaction time 14 h, purified by
hexanes:EtOAc (50:50). Product recovered as white solid (51.5
1
mg, 62% yield). Rf = 0.55 (hexanes/EtOAc = 1:1). H NMR
(600 MHz, CDCl3) δ 7.99 (dd, J = 7.7, 1.3 Hz, 1H), 7.57 (td, J
= 7.8, 1.4 Hz, 1H), 7.51 (dd, J = 7.8, 1.1 Hz, 1H), 7.45 (td, J =
7.6, 1.3 Hz, 1H), 7.35 (dd, J = 7.7 Hz, 1.1 Hz, 1H), 7.29 (t, J =
7.6 Hz, 1H), 7.19 – 7.15 (m, 1H), 6.21 (s, 1H), 2.95 – 2.88 (m,
1H), 2.83 (dt, J = 16.5, 5.2 Hz, 1H), 2.29 – 2.16 (m, 1H), 1.93
– 1.82 (m, 1H), 1.78 (dtdd, J = 13.0, 8.3, 4.7, 2.3 Hz, 1H), 1.74
– 1.68 (m, 1H), 1.61 – 1.54 (m, 1H), 1.50 (dq, J = 14.7, 7.3 Hz,
1H), 0.64 (t, J = 7.4 Hz, 3H). 13C{1H} NMR (151 MHz, CDCl3)
δ 169.9, 140.9, 140.0, 138.4, 136.0, 133.0, 131.8, 130.0, 129.7,
129.5, 129.5, 127.8, 127.4, 56.2, 37.1, 31.1, 28.7, 19.2, 8.7.
HRMS (ESI-MS): calcd. 278.1544 [M+H]+ Found: 278.1510.
HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C19H20NO
278.1539; Found 278.1544.
9-Methoxy-7,7-dimethyl-6.7-dihydro-5H-
dibenzo[c,e]azepin-5-one (1l). Reaction time 14 h, purified by
hexanes:EtOAc (40:60). Product recovered as white solid (65.7
mg, 82% yield). Rf = 0.4 (hexanes/EtOAc = 1:1). 1H NMR (600
MHz, CDCl3) δ 7.97 (dd, J = 7.7, 1.2 Hz, 1H), 7.56 (td, J = 7.7,
1.4 Hz, 1H), 7.49 (t, J = 8.0 Hz, 2H), 7.43 (td, J = 7.7, 1.2 Hz,
1H), 6.96 – 6.91 (m, 2H), 6.73 (s, 1H), 3.86 (s, 3H), 1.77 (s,
3H), 1.23 (s, 3H). 13C{1H} NMR (151 MHz, CDCl3) δ 169.8,
159.5, 146.7, 139.1, 132.8, 131.7, 130.3, 130.1, 129.1, 127.3,
111.9, 110.5, 55.5, 53.9, 29.9, 26.7. HRMS (ESI-MS): calcd.
268.1337 [M+H]+ Found: 268.1337. HRMS (ESI-TOF) m/z:
[M + H]+ Calcd for C17H18NO 268.1332; Found 268.1337.
9-Fluoro-7-methyl-6.7-dihydro-5H-dibenzo[c,e]azepin-5-
one (1q). Reaction time 14 h, purified by hexanes:EtOAc
(50:50). Product recovered as white solid (59.3 mg, 82% yield).
Rf = 0.45 (hexanes/EtOAc = 1:1). 1H NMR (600 MHz, CDCl3)
δ 8.00 (d, J = 7.8 Hz, 1H), 7.64 – 7.57 (m, 1H), 7.57 – 7.47 (m,
3H), 7.12 (td, J = 8.3, 2.6 Hz, 1H), 7.09 (dd, J = 9.5, 2.6 Hz,
1H), 6.67 (s, 1H), 4.37 (p, J = 6.1 Hz, 1H), 1.68 (d, J = 6.9 Hz,
3H). 13C{1H} NMR (151 MHz, CDCl3) δ 169.9, 162.9 (d, J =
248.5 Hz), 144.3 (d, J = 6.7 Hz), 137.1, 134.8 (d, J = 3.2 Hz),
133.6, 131.7 (d, J = 8.3 Hz), 131.6, 130.0, 129.1, 128.2, 115.1
(d, J = 21.4 Hz), 109.9 (d, J = 22.8 Hz), 47.5 (d, J = 1.4 Hz),
16.6. 19F NMR (376 MHz, CDCl3) δ -111.6 (td). HRMS (ESI-
TOF) m/z: [M + H]+ Calcd for C15H13FNO 242.0976; Found
242.0972.
7-Ethyl-9-methoxy-7-methyl-6.7-dihydro-5H-
dibenzo[c,e]azepin-5-one (1m). Reaction time 14 h, purified
by hexanes:EtOAc (40:60). Product recovered as white solid
(66.6 mg, 79% yield). Rf = 0.4 (hexanes/EtOAc = 1:1). 1H NMR
(600 MHz, CDCl3) δ 7.97 (dd, J = 7.7, 0.9 Hz, 1H), 7.55 (td, J
= 8.1, 1.1 Hz, 1H), 7.48 (d, J = 8.8 Hz, 2H), 7.41 (t, J = 7.5 Hz,
1H), 6.94 (m, 2H), 6.40 (s, 1H), 3.87 (s, 3H), 1.69 (s, 3H), 1.54
(ddd, J = 14.5, 7.2, 1.5 Hz, 2H), 0.60 (t, J = 7.4 Hz, 3H. 13C{1H}
NMR (151 MHz, CDCl3) δ 169.7, 159.4, 146.1, 139.1, 132.8,
132.7, 131.7, 130.2, 129.9, 129.0, 127.3, 111.8, 111.7, 57.4,
55.5, 30.2, 26.1, 9.4. HRMS (ESI-MS): calcd. 282.1494
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The Journal of Organic Chemistry
9-Bromo-7-methyl-6.7-dihydro-5H-dibenzo[c,e]azepin-5- 245.7 Hz), 141.6 (d, J = 3.5 Hz), 136.7 (d, J = 2.8 Hz), 133.7,
1
2
3
4
5
6
7
8
one (1r). Reaction time 14 h, purified by hexanes:EtOAc
(50:50). Product recovered as white solid (76.7 mg, 85% yield).
Rf = 0.45 (hexanes/EtOAc = 1:1). 1H NMR (600 MHz, CDCl3)
δ 8.04 – 7.96 (m, 1H), 7.62 – 7.58 (m, 1H), 7.56 (dd, J = 8.2,
2.0 Hz, 1H), 7.54 – 7.49 (m, 3H), 7.42 (d, J = 8.2 Hz, 1H), 6.70
(d, J = 5.6 Hz, 1H), 4.35 (p, J = 6.8 Hz, 1H), 1.68 (d, J = 6.9
Hz, 3H). 13C{1H} NMR (151 MHz, CDCl3) δ 167.8, 142.0,
135.8, 134.9, 131.8, 129.6, 129.5, 129.3, 128.0 127.0, 126.6,
123.8, 120.7, 45.5, 14.5. HRMS (ESI-MS): calcd. 302.0180
[M+H]+ Found: 302.0180. HRMS (ESI-TOF) m/z: [M + H]+
Calcd for C15H13BrNO 302.0175; Found 302.0180.
131.5, 130.6, 129.5 (d, J = 8.8 Hz), 129.2, 128.7, 126.2 (d, J =
17.0 Hz), 125.2 (d, J = 3.3 Hz), 114.9 (d, J = 22.5 Hz), 36.2 (d,
J = 5.3 Hz).19F NMR (376 MHz, CDCl3) δ -119.4 (m). HRMS
(ESI-MS): calcd. 228.0819 [M+H]+ Found: 228.0845. HRMS
(ESI-TOF) m/z: [M + H]+ Calcd for C11H18N 164.1434; Found
164.1436.
9-Fluoro-6.7-dihydro-5H-dibenzo[c,e]azepin-5-one
(1w).
Reaction time 14 h, purified by hexanes:EtOAc (50:50).
Product recovered as white solid (45.6 mg, 67% yield). Rf =
9
1
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
0.45 (hexanes/EtOAc = 1:1). H NMR (600 MHz, CDCl3) δ
8.10 (s, 1H), 8.00 (dd, J = 7.8, 1.1 Hz, 1H), 7.59 (ddd, J = 7.8,
7.4, 1.5 Hz, 1H), 7.55 (dd, J = 8.6, 5.4 Hz, 1H), 7.53 – 7.48 (m,
2H), 7.12 (td, J = 8.5, 2.7 Hz, 1H), 7.00 (dd, J = 8.5, 2.7 Hz,
1H), 4.16 (dd, J = 14.7, 5.8 Hz, 1H), 3.94 (dd, J = 14.8, 7.0 Hz,
1H). 13C{1H} NMR (151 MHz, CDCl3) δ 171.4, 162.5 (d, J =
249.2 Hz), 141.1 (d, J = 7.2 Hz), 136.9, 135.0 (d, J = 3.3 Hz),
133.5, 131.5, 131.3 (d, J = 8.3 Hz), 130.4, 129.1, 128.2, 115.5
8-Bromo-7-methyl-6.7-dihydro-5H-dibenzo[c,e]azepin-5-
one (1s). Reaction time 14 h, purified by hexanes:EtOAc
(50:50). Product recovered as white solid (54.3 mg, 82% yield).
Rf = 0.45 (hexanes/EtOAc = 1:1). 1H NMR (600 MHz, CDCl3)
δ 8.00 (d, J = 7.7 Hz, 1H), 7.60 (t, J = 8.2 Hz, 2H), 7.53 – 7.46
(m, 3H), 7.25 (t, J = 7.9 Hz, 1H), 6.89 (d, J = 7.2 Hz, 1H), 5.18
(p, J = 7.5 Hz, 1H), 1.18 (d, J = 7.4 Hz, 3H). 13C{1H} NMR
(151 MHz, CDCl3) δ 169.6, 141.8, 139.7, 137.6, 133.4, 132.5,
131.8, 130.7, 130.3, 129.9, 129.4, 128.6, 122.3, 51.2, 18.1.
HRMS (ESI-MS): calcd. 302.0180 [M+H]+ Found: 302.0178.
HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C11H18N 164.1434;
Found 164.1436.
(d, J = 21.2 Hz), 113.9 (d, J = 21.9 Hz), 44.8 (d, J = 0.9 Hz). 19
F
NMR (376 MHz, CDCl3) δ -112.3 (td). HRMS (ESI-MS):
calcd. 228.0819 [M+H]+ Found: 228.0822. HRMS (ESI-TOF)
m/z: [M + H]+ Calcd for C11H18N 164.1434; Found 164.1436.
9-(Trifluoromethyl)-6.7-dihydro-5H-dibenzo[c,e]azepin-5-
one (1x). Reaction time 14 h, purified by hexanes:EtOAc
(50:50). Product recovered as white solid (49.0 mg, 59% yield).
Rf = 0.4 (hexanes/EtOAc = 1:1). 1H NMR (600 MHz, CDCl3) δ
8.04 (d, J = 7.5 Hz, 1H), 7.73 – 7.68 (m, 2H), 7.64 (t, J = 7.5
Hz, 1H), 7.59-7.55 (m, 3H), 7.53 (s, 1H), 4.25 (dd, J = 14.1, 2.8
Hz, 1H), 4.06 (dd, J = 14.3, 4.7 Hz, 1H). 13C{1H} NMR (151
MHz, CDCl3) δ 170.7, 142.5, 139.7, 136.4, 133.8, 131.7, 130.6,
130.3 (q, J = 33.2 Hz), 130.1, 129.3, 129.2, 125.6 (q, J = 3.6
Hz), 124.0 (q, J = 272.2 Hz), 123.8 (q, J = 3.5 Hz), 44.9. 19F
NMR (376 MHz, CDCl3) δ -60.8. HRMS (ESI-MS): calcd.
278.0787 [M+H]+ Found: 278.0793. HRMS (ESI-TOF) m/z:
[M + H]+ Calcd for C11H18N 164.1434; Found 164.1436.
8-Chloro-7-methyl-6.7-dihydro-5H-dibenzo[c,e]azepin-5-
one (1t). Reaction time 14 h, purified by hexanes:EtOAc
(50:50). Product recovered as white solid (61.0 mg, 79% yield).
Rf = 0.45 (hexanes/EtOAc = 1:1). 1H NMR (600 MHz, CDCl3)
δ 8.01 (dd, J = 8.1, 1.4 Hz, 1H), 7.61 – 7.57 (m, 1H), 7.50 (dd,
J = 10.9, 4.4 Hz, 2H), 7.43 (ddd, J = 16.5, 7.9, 1.2 Hz, 2H), 7.32
(t, J = 7.9 Hz, 1H), 7.17 (d, J = 7.4 Hz, 1H), 5.21 (p, J = 7.5 Hz,
1H), 1.18 (d, J = 7.4 Hz, 3H). 13C{1H} NMR (151 MHz, CDCl3)
δ 169.8, 140.3, 139.7, 137.4, 133.6, 131.7, 131.6, 130.3, 129.8,
129.8, 129.1, 128.9, 128.5, 47.7, 18.2. HRMS (ESI-MS): calcd.
258.0685 [M+H]+ Found: 258.0673. HRMS (ESI-TOF) m/z:
[M + H]+ Calcd for C11H18N 164.1434; Found 164.1436.
8-Chloro-10-fluoro-6.7-dihydro-5H-dibenzo[c,e]azepin-5-
one (1y). Reaction time 14 h, purified by hexanes:EtOAc
(50:50). Product recovered as yellow solid (21 mg, 55% yield).
Rf = 0.3 (hexanes/EtOAc = 1:1). 1H NMR (600 MHz, CDCl3) δ
8.03 (dd, J = 7.7, 1.3 Hz, 1H), 7.62 (td, J = 7.6, 1.5 Hz, 1H),
7.56 (td, J = 7.6, 1.3 Hz, 1H), 7.52 (dd, J = 7.7, 1.1 Hz, 1H),
7.26 (d, J = 3.9 Hz, 1H), 7.19 (ddd, J = 10.7, 8.7, 2.5 Hz, 2H),
4.65 (dd, J = 15.2, 7.0 Hz, 1H), 3.95 (dd, J = 15.2, 6.3 Hz, 1H).
13C{1H} NMR (151MHz, CDCl3) δ 170.5, 161.7 (d, J = 250
Hz), 142.6 (d, J = 9 Hz), 136.2 (d, J = 2 Hz), 133.7, 133.0 (d, J
= 3.3 Hz), 132.4 (d, J = 12 Hz), 131.6, 130.5, 129.3, 129.0,
116.2 (d, J = 24 Hz), 115.6 (d, J = 23 Hz), 40.2. 19F NMR (376
MHz, CDCl3) δ -111.8 (t). HRMS (ESI-MS): calcd. 262.0429
[M+H]+ Found: 262.0433. HRMS (ESI-TOF) m/z: [M + H]+
Calcd for C11H18N 164.1434; Found 164.1436.
2,3,3a,4-tetrahydrobenzo[e]naphtho[1,8-bc]azepin-5(1H)-
one (1u). Reaction time 14 h, purified by hexanes:EtOAc
(50:50). Product recovered as a white solid (29 mg, 77%). Rf =
0.5 (hexanes/EtOAc = 1:1). 1H NMR (600 MHz, CDCl3) δ 8.00
(dd, J = 7.8, 0.8 Hz, 1H), 7.62 (d, J = 5.0 Hz, 1H), 7.57 (pd, J =
7.8, 1.5 Hz, 2H), 7.49 (ddd, J = 7.8, 6.8, 1.9 Hz, 1H), 7.38 (d, J
= 7.6 Hz, 1H), 7.31 (t, J = 7.6 Hz, 1H), 7.18 (d, J = 7.5 Hz, 1H),
4.25 (td, J = 6.0, 2.8 Hz, 1H), 2.91 (dt, J = 16.3, 3.8 Hz, 1H),
2.79 (ddd, J = 16.3, 10.7, 5.4 Hz, 1H), 2.19 – 2.09 (m, 1H), 2.09
– 1.99 (m, 1H), 1.99 – 1.84 (m, 2H). 13C{1H} NMR (151MHz,
CDCl3) δ 170.4, 139.1, 138.2, 137.0, 135.2, 133.9, 131.2, 129.7,
129.2, 129.0, 128.0, 127.7, 127.6, 46.9, 29.6, 28.6, 18.9. HRMS
(ESI-MS): calcd. 250.1226 [M+H]+ Found: 250.1232. HRMS
(ESI-TOF) m/z: [M + H]+ Calcd for C11H18N 164.1434; Found
164.1436.
10-Chloro-9-(trifluoromethyl)-6.7-dihydro-5H-
8-Fluoro-6.7-dihydro-5H-dibenzo[c,e]azepin-5-one
(1v).
dibenzo[c,e]azepin-5-one (1z). Reaction time 14 h, purified by
hexanes:EtOAc (50:50). Product recovered as yellow solid (25
mg, 53% yield). Rf = 0.4 (hexanes/EtOAc = 1:1). 1H NMR (600
MHz, CDCl3) δ 8.04 (dd, J = 7.7, 1.2 Hz, 1H), 7.96 (s, 1H), 7.73
(s, 1H), 7.70 – 7.52 (m, 4H), 4.19 (dd, J = 14.9, 5.7 Hz, 1H),
4.04 (dd, J = 14.9, 7.0 Hz, 1H). 13C{1H} NMR (151 MHz,
CDCl3) δ170.7, 143.7, 137.8, 135.1, 134.0, 132.4, 132.2, 131.9,
130.8, 129.7, 129.2, 127.6 (q, J = 30.8 Hz), 126.1 (q, J = 5.5
Hz), 122.7 (q, J = 273 Hz), 44.2. 19F NMR (376 MHz, CDCl3)
Reaction time 14 h, purified by hexanes:EtOAc (50:50).
Product recovered as white solid (42.2 mg, 62% yield). Rf =
1
0.45 (hexanes/EtOAc = 1:1). H NMR (600 MHz, CDCl3) δ
8.02 (dd, J = 7.8, 1.1 Hz, 1H), 7.61 (ddd, J = 7.8, 7.2, 1.4 Hz,
1H), 7.57 (dd, J = 7.8, 1.3 Hz, 1H), 7.55 – 7.51 (m, 1H), 7.42 –
7.34 (m, 2H), 7.12 (ddd, J = 9.2, 6.9, 2.4 Hz, 1H), 6.83 (s, 1H),
4.52 (dd, J= 15.1, 7.1 Hz, 1H), 3.93 (ddd, J = 15.1, 6.0, 1.8 Hz,
1H). 13C{1H} NMR (151 MHz, CDCl3) δ 170.9, 158.4 (d, J =
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δ -62.8. HRMS (ESI-MS): calcd. 312.0398 [M+H]+ Found:
Hz, 1H), 7.92 – 7.87 (m, 2H), 7.66 (d, J = 8.6 Hz, 1H), 7.65 –
312.0406. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C11H18N
164.1434; Found 164.1436.
7.62 (m, 1H), 7.61 – 7.56 (m, 2H), 7.55 – 7.48 (m, 2H), 7.44 (d,
J = 7.9 Hz, 1H), 5.46 (p, J = 7.5 Hz, 1H), 1.33 (d, J = 7.4 Hz,
3H). 13C{1H} NMR (151 MHz, CDCl3) δ 170.3, 139.1, 138.9,
134.8, 133.7, 133.1, 131.6, 130.3, 130.1, 129.3, 129.0, 128.7,
128.6, 127.9, 127.2, 126.4, 122.6, 45.8, 18.7. HRMS (ESI-MS):
calcd. 274.1226 [M+H]+ Found: 274.1237. HRMS (ESI-TOF)
m/z: [M + H]+ Calcd for C11H18N 164.1434; Found 164.1436.
1
2
3
4
5
6
7
8
8-bromo-6,7-dihydro-5H-dibenzo[c,e]azepin-5-one (1aa).
Reaction time 14 h, purified by hexanes:EtOAc (50:50).
Product recovered as white solid (33 mg, 77% yield). Rf = 0.3
(hexanes/EtOAc = 1:1). 1H NMR (400 MHz, CDCl3) δ 8.00 (dd,
J = 6.7, 2.6 Hz, 1H), 7.58 (dd, J = 11.9, 4.5 Hz, 2H), 7.54 – 7.44
(m, 3H), 7.40 (s, 1H), 7.25 (dd, J = 11.8, 4.0 Hz, 1H), 4.67 (dd,
J = 15.0, 6.9 Hz, 1H), 4.02 (dd, J = 15.0, 6.4 Hz, 1H). 13C{1H}
NMR (151 MHz, CDCl3) δ 170.7, 141.2, 138.3, 137.4, 133.7,
132.3, 131.4, 130.3, 129.6, 129.2, 129.1, 128.8, 121.9, 77.4,
76.9, 43.9. HRMS (ESI-MS): calcd. 288.0019 [M+H]+ Found:
288.0023. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C11H18N
164.1434; Found 164.1436.
(S)-7-Oxo-N,N-dipropyl-6,7-dihydro-5H-
9
dibenzo[c,e]azepin-5-carboxamide (1af). Reaction time 14 h,
purified by hexanes:EtOAc (1:8). Product recovered as white
solid (23 mg, 46% yield). Rf = 0.5 (hexanes/EtOAc = 1:8). 1H
NMR (600 MHz, CDCl3) δ 8.03 (d, J = 7.7 Hz, 1H), 7.62 (d, J
= 3.8 Hz, 2H), 7.59 (dd, J = 7.7, 0.9 Hz, 1H), 7.56 – 7.50 (m,
1H), 7.46 (td, J = 7.6, 1.1 Hz, 2H), 7.36 (td, J = 7.6, 1.2 Hz,
1H), 7.12 – 7.06 (m, 1H), 4.98 (d, J = 6.1 Hz, 1H), 3.68 (ddd, J
= 13.4, 10.1, 5.6 Hz, 1H), 3.17 (ddd, J = 13.3, 10.1, 5.8 Hz, 1H),
2.92 – 2.77 (m, 2H), 1.74 – 1.68 (m, 2H), 1.48 – 1.38 (m, 1H),
1.35 (ddt, J = 13.9, 9.3, 6.9 Hz, 1H), 0.98 (t, J = 7.4 Hz, 3H),
0.61 (t, J = 7.4 Hz, 3H). 13C{1H} NMR (151 MHz, CDCl3) δ
167.7, 167.0, 138.4, 137.7, 137.0, 134.4, 131.5, 130.4, 130.2,
129.2, 128.8, 128.6, 128.6, 123.6, 54.0, 49.3, 48.0, 21.9, 20.9,
11.7, 11. HRMS (ESI-MS): calcd. 337.1911 [M+H]+ Found:
337.1917. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C11H18N
164.1434; Found 164.1436.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
9-Methoxy-6.7-dihydro-5H-dibenzo[c,e]azepin-5-one (1ab).
Reaction time 14 h, purified by hexanes:EtOAc (50:50).
Product recovered as white solid (37.3 mg, 52% yield). Rf = 0.3
(hexanes/EtOAc = 1:1). 1H NMR (600 MHz, CDCl3) δ 7.99 (dd,
J = 7.7, 1.2 Hz, 1H), 7.59 – 7.54 (m, 1H), 7.54 – 7.50 (m, 2H),
7.47 – 7.42 (m, 1H), 7.13 (s, 1H), 6.97 (dd, J = 8.5, 2.7 Hz, 1H),
6.83 (d, J = 2.6 Hz, 1H), 4.22 (dd, J = 14.7, 6.0 Hz, 1H), 3.91
(dd, J = 14.7, 7.0 Hz, 1H), 3.86 (s, 3H). 13C{1H} NMR (151
MHz, CDCl3) δ 171.5, 159.7, 140.5, 137.7, 133.3, 131.5, 131.4,
130.8, 130.3, 128.9, 127.5, 113.9, 112.5, 55.6, 45.3. HRMS
(ESI-MS): calcd. 240.1019 [M+H]+ Found: 240.1029. HRMS
(ESI-TOF) m/z: [M + H]+ Calcd for C11H18N 164.1434; Found
164.1436.
2-Chloro-7,7,9-trimethyl-6.7-dihydro-5H-
dibenzo[c,e]azepin-5-one (2a). Reaction time 14 h, purified by
hexanes:EtOAc (50:50). Product recovered as white solid (74.6
mg, 87% yield). Rf = 0.5 (hexanes/EtOAc = 1:1). 1H NMR (600
MHz, CDCl3) δ 7.94 (d, J = 8.4 Hz, 1H), 7.54 (d, J = 2.1 Hz,
1H), 7.45 – 7.36 (m, 2H), 7.25 – 7.22 (m, 1H), 7.20 (s, 1H), 6.45
(s, 1H), 2.42 (s, 3H), 1.79 (s, 3H), 1.26 (s, 3H). 13C{1H} NMR
(151 MHz, CDCl3) δ 168.7, 145.0, 141.1, 138.8, 137.7, 133.6,
131.8, 131.5, 131.4, 129.1, 128.9, 127.7, 124.2, 53.9, 30.0, 27.1,
21.6. HRMS (ESI-MS): calcd. 286.0993 [M+H]+ Found:
286.1003. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C11H18N
164.1434; Found 164.1436.
8-(Difluoromethoxy)-6,7-dihydro-5H-dibenzo[c,e]azepin-5-
one (1ac). Reaction time 14 h, purified by hexanes:EtOAc
(50:50). Product recovered as yellow solid (30 mg, 72% yield).
Rf = 0.3 (hexanes/EtOAc = 1:1). 1H NMR (400 MHz, CDCl3) δ
8.01 (d, J = 7.7 Hz, 3H), 7.68 – 7.49 (m, 9H), 7.44 (dt, J = 15.6,
7.2 Hz, 6H), 7.19 (d, J = 7.8 Hz, 3H), 6.89 (s, 3H), 6.59 (t, J =
73.4 Hz, 4H), 4.58 (dd, J = 15.0, 7.0 Hz, 3H), 3.90 (dd, J = 15.0,
6.3 Hz, 3H). 13C{1H} NMR (151MHz, CDCl3) δ 170.9, 146.5,
141.5, 136.9, 133.7, 131.6, 131.5, 130.4, 129.2, 129.1, 128.8,
127.1, 119.5, 116.2 (t, J = 261.8 Hz), 37.3.19F NMR (376 MHz,
CDCl3) δ -81.2 (dd). HRMS (ESI-MS): calcd. 276.0831
[M+H]+ Found: 276.0839. HRMS (ESI-TOF) m/z: [M + H]+
Calcd for C11H18N 164.1434; Found 164.1436.
3-Chloro-7,7,9-trimethyl-6.7-dihydro-5H-
dibenzo[c,e]azepin-5-one (2b). Reaction time 14 h, purified by
hexanes:EtOAc (50:50). Product recovered as white solid (78.8
mg, 92% yield). Rf = 0.5 (hexanes/EtOAc = 1:1). 1H NMR (600
MHz, CDCl3) δ 7.98 (d, J = 2.3 Hz, 1H), 7.53 (dd, J = 8.4, 2.4
Hz, 1H), 7.48 (d, J = 8.4 Hz, 1H), 7.40 (d, J = 7.8 Hz, 1H), 7.22
(dd, J = 8.5, 0.7 Hz, 1H), 7.21 (s, 1H), 6.68 (s, 1H), 2.42 (s, 3H),
1.79 (s, 3H), 1.25 (s, 3H). 13C{1H} NMR (151 MHz, CDCl3) δ
168.4, 144.9, 138.5, 137.8, 134.5, 133.8, 133.8, 131.7, 131.4,
130.7, 129.9, 128.8, 124.3, 53.9, 29.9, 27.0, 21.5. HRMS (ESI-
MS): calcd. 286.0993 [M+H]+ Found: 286.0982. HRMS (ESI-
TOF) m/z: [M + H]+ Calcd for C11H18N 164.1434; Found
164.1436.
6,7,9,10-tetrahydro-5H-benzo[c]benzofuro[6,5-e]azepin-5-
one (1ad). Reaction time 14 h, purified by hexanes:EtOAc
(50:50). Product recovered as white solid (39.2 mg, 52% yield).
Rf = 0.4 (hexanes/EtOAc = 1:1). 1H NMR (600 MHz, CDCl3) δ
7.99 (dd, J = 7.8, 1.2 Hz, 1H), 7.60 – 7.55 (m, 1H), 7.55 – 7.50
(m, 2H), 7.50 – 7.45 (m, 1H), 7.11 (s, 1H), 7.00 (s, 1H), 4.85 –
4.43 (m, 2H), 4.12 (dd, J = 14.8, 5.9 Hz, 1H), 3.88 (dd, J = 14.8,
6.9 Hz, 1H), 3.24 (t, J = 8.7 Hz, 2H). 13C{1H} NMR (151 MHz,
CDCl3) δ 171.2, 160.6, 139.1, 138.1, 133.6, 131.9, 131.4, 130.2,
129.1, 128.0, 127.1, 123.5, 110.3, 71.7, 44.8, 29.6. HRMS (ESI-
MS): calcd. 252.1019 [M+H]+ Found: 252.1024. HRMS (ESI-
TOF) m/z: [M + H]+ Calcd for C11H18N 164.1434; Found
164.1436.
4-Chloro-7,7,9-trimethyl-6.7-dihydro-5H-
dibenzo[c,e]azepin-5-one (2c). Reaction time 14 h, purified by
hexanes:EtOAc (50:50). Product recovered as white solid (40.3
mg, 47% yield). Rf = 0.5 (hexanes/EtOAc = 1:1). 1H NMR (600
MHz, CDCl3) δ 7.48 (dd, J = 8.0, 1.2 Hz, 1H), 7.46 – 7.41 (m,
2H), 7.37 (dd, J = 7.8, 1.2 Hz, 1H), 7.23 – 7.20 (m, 1H), 7.18
(s, 1H), 6.41 (s, 1H), 2.41 (s, 3H), 1.76 (s, 3H), 1.20 (s, 3H).
13C{1H} NMR (151 MHz, CDCl3) δ 167.0, 145.7, 140.7, 138.5,
134.1, 133.2, 132.3, 131.2, 131.0, 129.8, 128.8, 127.9, 124.2,
54.2, 30.0, 26.4, 21.6. HRMS (ESI-MS): calcd. 286.0993
(R)-1-Methyl-1,2-dihydro-3H-dibenzo[c]naphthop2,1-
e]azepin-3-one (1ae). Reaction time 14 h, purified by
hexanes:EtOAc (50:50). Product recovered as white solid (44.3
mg, 54% yield). Rf = 0.5 (hexanes/EtOAc = 1:1). 1H NMR (600
MHz, CDCl3) δ 8.11 (d, J = 8.5 Hz, 1H), 8.08 (dd, J = 7.8, 1.2
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The Journal of Organic Chemistry
[M+H]+ Found: 286.0998. HRMS (ESI-TOF) m/z: [M + H]+
Calcd for C11H18N 164.1434; Found 164.1436.
3-Bromo-7,7,9-trimethyl-6.7-dihydro-5H-
1
2
3
4
5
6
7
8
dibenzo[c,e]azepin-5-one (2h). Reaction time 14 h, purified by
hexanes:EtOAc (50:50). Product recovered as white solid (86.2
mg, 87% yield). Rf = 0.5 (hexanes/EtOAc = 1:1). 1H NMR (600
MHz, CDCl3) δ 8.13 (d, J = 2.2 Hz, 1H), 7.69 (dd, J = 8.4, 2.2
Hz, 1H), 7.43 – 7.37 (m, 2H), 7.25 – 7.19 (m, 2H), 6.77 (s, 1H),
2.41 (s, 3H), 1.79 (s, 3H), 1.25 (s, 3H). 13C{1H} NMR (151
MHz, CDCl3) δ 168.3, 144.9, 138.5, 138.2, 134.7, 134.7, 133.8,
132.9, 131.3, 130.9, 128.9, 124.3, 121.8, 53.9, 29.9, 27.0, 21.5.
HRMS (ESI-MS): calcd. 330.0488 [M+H]+ Found: 330.0499.
HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C11H18N 164.1434;
Found 164.1436.
3-Fluoro-7,7,9-trimethyl-6.7-dihydro-5H-
dibenzo[c,e]azepin-5-one (2d). Reaction time 14 h, purified by
hexanes:EtOAc (50:50). Product recovered as white solid (75.9
mg, 94% yield). Rf = 0.5 (hexanes/EtOAc = 1:1). 1H NMR (600
MHz, CDCl3) δ 7.69 (dd, J = 9.2, 2.8 Hz, 1H), 7.52 (dd, J = 8.7,
5.3 Hz, 1H), 7.39 (d, J = 7.7 Hz, 1H), 7.30 – 7.26 (m, 1H), 7.23
– 7.19 (m, 2H), 6.87 (s, 1H), 2.41 (s, 3H), 1.80 (s, 3H), 1.24 (s,
3H). 13C{1H} NMR (151 MHz, CDCl3) δ 168.5, 162.1 (d, J =
248.3 Hz), 144.8, 138.1, 135.6 (d, J = 3.2 Hz), 135.0 (d, J = 6.7
Hz), 133.9, 131.4, 131.3 (d, J = 7.5 Hz), 128.8, 124.2, 118.9 (d,
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
J = 21.4 Hz), 116.6 (d, J = 23.2 Hz), 54.0, 29.9, 26.8, 21.5. 19
F
3-Iodo-7,7,9-trimethyl-6.7-dihydro-5H-dibenzo[c,e]azepin-
5-one (2i). Reaction time 14 h, purified by hexanes:EtOAc
(50:50). Product recovered as white solid (92.7 mg, 82% yield).
Rf = 0.5 (hexanes/EtOAc = 1:1).1H NMR (600 MHz, CDCl3) δ
8.31 (d, J = 2.0 Hz, 1H), 7.89 (dd, J = 8.3, 2.0 Hz, 1H), 7.39 (d,
J = 7.8 Hz, 1H), 7.28 – 7.25 (m, 1H), 7.22 (d, J = 7.8 Hz, 1H),
7.20 (s, 1H), 6.44 (s, 1H), 2.42 (s, 3H), 1.79 (s, 3H), 1.26 (s,
3H). 13C{1H} NMR (151 MHz, CDCl3) δ 168.1, 144.8, 140.6,
138.8, 138.7, 138.6, 134.6, 133.9, 131.3, 131.0, 128.9, 124.3,
93.1, 54.0, 30.0, 27.1, 21.6. HRMS (ESI-MS): calcd. 378.0349
[M+H]+ Found: 378.0359. HRMS (ESI-TOF) m/z: [M + H]+
Calcd for C11H18N 164.1434; Found 164.1436.
NMR (376 MHz, CDCl3) δ -112.7 (m). HRMS (ESI-MS):
calcd. 270.1289 [M+H]+ Found: 270.1292. HRMS (ESI-TOF)
m/z: [M + H]+ Calcd for C11H18N 164.1434; Found 164.1436.
4-Fluoro-7,7,9-trimethyl-6.7-dihydro-5H-
dibenzo[c,e]azepin-5-one (2e). Reaction time 14 h, purified by
hexanes:EtOAc (50:50). Product recovered as white solid (52.5
mg, 65% yield). Rf = 0.5 (hexanes/EtOAc = 1:1).1H NMR (600
MHz, CDCl3) δ 7.50 (td, J = 8.1, 5.5 Hz, 1H), 7.45 (d, J = 7.8
Hz, 1H), 7.29 (d, J = 7.8 Hz, 1H), 7.22 (dd, J = 7.8, 0.9 Hz, 1H),
7.19 (s, 1H), 7.18 – 7.14 (m, 1H), 6.51 (s, 1H), 2.41 (s, 3H),
1.77 (s, 3H), 1.24 (s, 3H). 13C{1H} NMR (151 MHz, CDCl3) δ
165.3, 160.9 (d, J = 255.9 Hz), 145.4, 141.1 (d, J = 1.5 Hz),
138.6, 134.0 (d, J = 2.3 Hz), 132.0 (d, J = 9.7 Hz), 131.4, 128.8,
125.0 (d, J = 3.4 Hz), 124.2, 121.9 (d, J = 11.3 Hz), 115.5 (d, J
= 22.4 Hz), 54.0, 30.0, 26.6, 21.6. 19F NMR (376 MHz, CDCl3)
δ -111.6 (dd). HRMS (ESI-MS): calcd. 270.1289 [M+H]+
Found: 270.1293. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for
C11H18N 164.1434; Found 164.1436.
7,7,9-Trimethyl-3-(trifluoromethyl)-6.7-dihydro-5H-
dibenzo[c,e]azepin-5-one (2j). Reaction time 14 h, purified by
hexanes:EtOAc (50:50). Product recovered as white solid (90.0
mg, 94% yield). Rf = 0.5 (hexanes/EtOAc = 1:1). 1H NMR (600
MHz, CDCl3) δ 8.28 (d, J = 1.5 Hz, 1H), 7.90 – 7.73 (m, 1H),
7.67 (d, J = 8.2 Hz, 1H), 7.44 (d, J = 7.8 Hz, 1H), 7.28 – 7.24
(m, 1H), 7.24 (s, 1H), 6.62 (s, 1H), 2.44 (s, 3H), 1.81 (s, 3H),
1.24 (s, 3H). 13C{1H} NMR (151 MHz, CDCl3) δ 168.4, 145.2,
142.7, 139.2, 133.6, 133.5, 131.8, 129.9, 129.9 (q, J = 33.3 Hz).
129.0, 128.1 (q, J = 3.6 Hz), 127.4 (q, J = 3.8 Hz), 124.4, 123.9
(q, J = 272.2 Hz), 54.0, 30.0, 27.2, 21.6. 19F NMR (376 MHz,
CDCl3) δ -60.9. HRMS (ESI-MS): calcd. 342.1076 [M+H]+
Found: 342.1089. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for
C11H18N 164.1434; Found 164.1436.
1-Fluoro-7,7,9-trimethyl-6.7-dihydro-5H-
dibenzo[c,e]azepin-5-one (2f). Reaction time 14 h, purified by
hexanes:EtOAc (50:50). Product recovered as white solid (46.0
mg, 57% yield). Rf = 0.5 (hexanes/EtOAc = 1:1). 1H NMR (600
MHz, CDCl3) δ 7.77 (dd, J = 7.7, 0.7 Hz, 1H), 7.53 (dd, J = 7.9,
6.1 Hz, 1H), 7.41 (td, J = 8.0, 5.0 Hz, 1H), 7.33 (ddd, J = 10.6,
8.2, 1.3 Hz, 1H), 7.24 (s, 1H), 7.21 – 7.18 (m, 1H), 6.67 (s, 1H),
2.42 (s, 3H), 1.78 (s, 3H), 1.25 (s, 3H). 13C{1H} NMR (151
MHz, CDCl3) δ 168.5 (d, J = 3.4 Hz), 158.7 (d, J = 248.6 Hz),
145.5, 138.6, 135.7, 133.1 (d, J = 7.7 Hz), 128.9 (d, J = 9.0 Hz),
127.8, 127.3, 127.2, 125.8 (d, J = 3.4 Hz), 124.3, 119.2 (d, J =
24.5 Hz), 54.0, 30.0, 26.6, 21.7. 19F NMR (376 MHz, CDCl3) δ
-113.4 (m). HRMS (ESI-MS): calcd. 270.1289 [M+H]+ Found:
270.1298. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C11H18N
164.1434; Found 164.1436.
7,7,9-Trimethyl-3-nitro-6.7-dihydro-5H-
dibenzo[c,e]azepin-5-one (2k). Reaction time 14 h, purified by
hexanes:EtOAc (50:50). Product recovered as white solid (23.1
mg, 26% yield). Rf = 0.5 (hexanes/EtOAc = 1:1). 1H NMR (600
MHz, CDCl3) δ 8.84 (s, 1H), 8.38 (d, J = 8.6 Hz, 1H), 7.74 (d,
J = 8.6 Hz, 1H), 7.46 (d, J = 7.8 Hz, 1H), 7.28 (d, J = 7.9 Hz,
2H), 6.85 (s, 1H), 2.45 (s, 3H), 1.84 (s, 3H), 1.25 (s, 3H).
13C{1H} NMR (151 MHz, CDCl3) δ 167.1, 147.0, 145.6, 145.4,
140.1, 132.8, 131.9, 130.6, 129.1, 126.0, 125.7, 124.6, 53.9,
29.9, 27.5, 21.6. HRMS (ESI-MS): calcd. 297.1234 [M+H]+
Found: 297.1235. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for
C11H18N 164.1434; Found 164.1436.
2,3-Difluoro-7,7,9-trimethyl-6.7-dihydro-5H-
dibenzo[c,e]azepin-5-one (2g). Reaction time 14 h, purified by
hexanes:EtOAc (50:50). Product recovered as white solid (60.3
mg, 70% yield). Rf = 0.5 (hexanes/EtOAc = 1:1). 1H NMR (600
MHz, CDCl3) δ 7.83 (dd, J = 10.8, 8.3 Hz, 1H), 7.35 (dd, J =
10.0, 7.7 Hz, 2H), 7.24 – 7.20 (m, 2H), 6.86 (s, 1H), 2.41 (s,
3H), 1.80 (s, 3H), 1.26 (s, 3H). 13C{1H} NMR (151 MHz,
CDCl3) δ 167.7, 152.1 (dd, J = 253.8, 12.9 Hz), 149.6 (dd, J =
250.9, 12.8 Hz), 144.9, 138.8, 137.0 (dd, J = 6.4, 3.9 Hz), 133.0,
131.4, 130.0, 128.9, 124.4, 119.4 (d, J = 18.8 Hz), 118.0 (d, J =
18.4 Hz), 53.9, 29.9, 27.0, 21.5. 19F NMR (376 MHz, CDCl3) δ
-130.8 (m), -137.0 (m). HRMS (ESI-MS): calcd. 288.1194
[M+H]+ Found: 288.1207. HRMS (ESI-TOF) m/z: [M + H]+
Calcd for C11H18N 164.1434; Found 164.1436.
3,7,7,9-Tetramethyl-6.7-dihydro-5H-dibenzo[c,e]azepin-5-
one (2l). Reaction time 14 h, purified by hexanes:EtOAc
(50:50). Product recovered as white solid (78.0 mg, 98% yield).
Rf = 0.55 (hexanes/EtOAc = 1:1).1H NMR (600 MHz, CDCl3)
δ 7.80 (d, J = 1.0 Hz, 1H), 7.43 (dd, J = 7.8, 1.8 Hz, 2H), 7.38
(dd, J = 8.0, 1.4 Hz, 1H), 7.21 (dd, J = 8.5, 0.7 Hz, 1H), 7.19 (s,
1H), 6.58 (s, 1H), 2.44 (s, 3H), 2.41 (s, 3H), 1.78 (s, 3H), 1.24
(s, 3H). 13C{1H} NMR (151 MHz, CDCl3) δ 169.9, 144.8,
137.7, 137.6, 136.6, 134.9, 132.7, 132.6, 131.4, 130.4, 129.3,
128.6, 124.0, 53.9, 30.0, 26.8, 21.5, 21.1. HRMS (ESI-MS):
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calcd. 266.1539 [M+H]+ Found: 266.1544. HRMS (ESI-TOF)
CDCl3) δ 165.1, 154.9, 142.0, 141.7, 140.1, 128.6, 127.1, 125.3,
m/z: [M + H]+ Calcd for C11H18N 164.1434; Found 164.1436.
124.9, 118.0, 111.8, 54.6, 28.9, 21.9. HRMS (ESI-MS): calcd.
242.1176 [M+H]+ Found: 242.1180. HRMS (ESI-TOF) m/z:
[M + H]+ Calcd for C11H18N 164.1434; Found 164.1436.
1
2
3
3-Methoxy-7,7,9-trimethyl-6.7-dihydro-5H-
dibenzo[c,e]azepin-5-one (2m). Reaction time 14 h, purified
by hexanes:EtOAc (50:50). Product recovered as white solid
(80.9 mg, 96% yield). Rf = 0.4 (hexanes/EtOAc = 1:1).1H NMR
(600 MHz, CDCl3) δ 7.50 (d, J = 2.9 Hz, 1H), 7.45 (d, J = 8.6
Hz, 1H), 7.40 (d, J = 7.8 Hz, 1H), 7.22 – 7.19 (m, 1H), 7.18 (s,
1H), 7.13 (dd, J = 8.6, 2.9 Hz, 1H), 6.59 (s, 1H), 3.91 (s, 3H),
2.40 (s, 3H), 1.78 (s, 3H), 1.24 (s, 3H). 13C{1H} NMR (151
MHz, CDCl3) δ 169.5, 159.0, 144.5, 137.3, 134.6, 134.0, 132.1,
131.2, 130.8, 128.6, 124.0, 119.2, 113.2, 55.7, 54.0, 30.0, 26.7,
21.5. HRMS (ESI-MS): calcd. 282.1489 [M+H]+ Found:
282.1491. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C11H18N
164.1434; Found 164.1436.
4
5
6
7
8
9
6,6,8-trimethyl-5.6-dihydro-4H-benzo[c]thieno[3,2-
e]azepin-4-one (2r). Reaction time 14 h, purified by
hexanes:EtOAc (50:50). Product recovered as white solid (41.6
mg, 54% yield). Rf = 0.4 (hexanes/EtOAc = 1:1). 1H NMR (600
MHz, CDCl3) δ 7.57 (d, J = 5.1 Hz, 1H), 7.54 (d, J = 7.8 Hz,
1H), 7.38 (d, J = 5.2 Hz, 1H), 7.24 (s, 1H), 7.21 (dd, J = 7.9, 0.9
Hz, 1H), 6.24 (s, 1H), 2.41 (s, 3H), 1.60 (s, 6H). 13C{1H} NMR
(151 MHz, CDCl3) δ 164.3, 143.0, 142.8, 138.8, 133.7, 130.1,
130.1, 130.0, 128.6, 128.4, 125.2, 54.4, 28.5, 21.6. HRMS (ESI-
MS): calcd. 258.0947 [M+H]+ Found: 258.0950. HRMS (ESI-
TOF) m/z: [M + H]+ Calcd for C11H18N 164.1434; Found
164.1436.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2,3-Dimethoxy-7,7,9-trimethyl-6.7-dihydro-5H-
dibenzo[c,e]azepin-5-one (2n). Reaction time 14 h, purified by
hexanes:EtOAc (50:50). Product recovered as white solid (77.5
mg, 83% yield). Rf = 0.3 (hexanes/EtOAc = 1:1).1H NMR (600
MHz, CDCl3) δ 7.50 (s, 1H), 7.42 (d, J = 7.8 Hz, 1H), 7.21 (dd,
J = 8.5, 0.7 Hz, 1H), 7.19 (s, 1H), 6.98 (s, 1H), 6.56 (s, 1H),
3.98 (d, J = 2.2 Hz, 6H), 2.41 (s, 3H), 1.78 (s, 3H), 1.26 (s, 3H).
13C{1H} NMR (151 MHz, CDCl3) δ 169.3, 151.4, 148.5, 144.8,
137.7, 134.8, 133.2, 131.1, 128.6, 125.5, 124.0, 112.2, 111.7,
56.2 (d, J = 7.1 Hz), 53.9, 29.9, 26.5, 21.5. HRMS (ESI-MS):
calcd. 312.1594 [M+H]+ Found: 312.1596. HRMS (ESI-TOF)
m/z: [M + H]+ Calcd for C11H18N 164.1434; Found 164.1436.
Standard conditions for the synthesis of Biaryl Lactams
Starting from 2-Iodobenzoic Acids. Reactions performed in
duplicate, and the total mass/percent yield over two reactions
reported. A 7.5 mL vial was charged with Pd(OAc)2 (3.36 mg,
0.015 mmol, 0.10 equiv), silver acetate (50.07 mg, 0.30 mmol,
2.0 equiv), organohalide (0.45 mmol, 3.0 equiv), amine (0.15
mmol, 1.0 equiv), HFIP (0.5 mL), and acetic acid (0.5 mL). The
vial was sealed with a PTFE lined cap and stirred at room
temperature for 15 min. After 15 min of stirring, the reaction
mixture was heated in a pie-block at 100 °C under stirring for
12-15 h. After cooling to room temperature, the reaction
mixture was made basic with ammonium hydroxide solution up
to pH = 8. The reaction mixture was stirred for 15 minutes
followed by extraction with dichloromethane (3 × 10 mL). The
organic layer was washed with brine and dried over Na2SO4.
The filtrate was concentrated in vacuo and further purified by
flash column chromatography over silica (Hexanes:EtOAc) to
give the desired lactam product.
7,7,9-trimethyl-(4-trifluoromethoxy)-6.7-dihydro-5H-
dibenzo[c,e]azepin-5-one (2o). Reaction time 14 h, purified by
hexanes:EtOAc (50:50). Product recovered as white solid (32.2
mg, 32% yield). Rf = 0.4 (hexanes/EtOAc = 1:1). 1H NMR (600
MHz, CDCl3) δ 7.55 (t, J = 8.1 Hz, 1H), 7.48 – 7.43 (m, 2H),
7.37 – 7.34 (m, 1H), 7.24 – 7.20 (m, 1H), 7.20 (s, 1H), 6.55 (s,
1H), 2.41 (s, 3H), 1.77 (s, 3H), 1.20 (s, 3H). 13C{1H} NMR (151
MHz, CDCl3) δ 165.5, 147.1, 145.6, 140.9, 138.7, 133.7, 131.4
(d, J = 3.9 Hz), 128.8, 128.0, 128.0, 124.3, 121.3, 120.7 (q, J =
257.9 Hz), 54.0, 29.9, 26.3, 21.6. 19F NMR (376 MHz, CDCl3)
δ -55.4. HRMS (ESI-MS): calcd. 336.1206 [M+H]+ Found:
336.1211. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C11H18N
164.1434; Found 164.1436.
Results.
7,7,9-Trimethyl-6.7-dihydro-5H-
dibenzo[c,e]azepin-5-one (1i). 2-(m-tolyl)propan-2-amine
(0.15 mmol) and 2-iodobenzoic acid (0.45 mmol) were used.
Reaction time 14 h, purified by hexanes:EtOAc (50:50).
Product recovered as white solid (50.6 mg, 67% yield). Rf = 0.5
(hexanes/EtOAc = 1:1). Characterization data previously listed
(vide supra).
1,2,3-Trimethoxy-7,7,9-trimethyl-6.7-dihydro-5H-
dibenzo[c,e]azepin-5-one (2p). Reaction time 14 h, purified by
hexanes:EtOAc (50:50). Product recovered as white solid (73.1
mg, 72% yield). Rf = 0.3 (hexanes/EtOAc = 1:1). 1H NMR (600
MHz, CDCl3) δ 7.55 (d, J = 7.9 Hz, 1H), 7.31 (s, 1H), 7.19 (s,
1H), 7.15 – 7.12 (m, 1H), 6.35 (s, 1H), 3.98 (s, 3H), 3.95 (s,
3H), 3.48 (s, 3H), 2.40 (s, 3H), 1.76 (s, 3H), 1.29 (s, 3H).
13C{1H} NMR (151 MHz, CDCl3) δ 169.0, 152.7, 150.8, 145.5,
144.7, 137.4, 133.4, 129.3, 129.2, 127.5, 127.1, 123.6, 108.6,
61.4, 60.7, 56.2, 54.1, 30.1, 26.1, 21.6. HRMS (ESI-MS): calcd.
342.1700 [M+H]+ Found: 342.1702. HRMS (ESI-TOF) m/z:
[M + H]+ Calcd for C11H18N 164.1434; Found 164.1436.
8-Fluoro-7,7-dimethyl-6.7-dihydro-5H-dibenzo[c,e]azepin-
5-one (1a). 2-(2-fluorophenyl)propan-2-amine (0.15 mmol)
and 2-iodobenzoic acid (0.45 mmol) were used. Reaction time
14 h, purified by hexanes:EtOAc (50:50). Product recovered as
white solid (47.5 mg, 62% yield). Rf = 0.5 (hexanes/EtOAc =
1:1). Characterization data previously listed (vide supra).
8-Chloro-7-methyl-6.7-dihydro-5H-dibenzo[c,e]azepin-5-
one (1t). 1-(2-chlorophenyl)ethan-1-amine (0.15 mmol) and 2-
iodobenzoic acid (0.45 mmol) were used. Reaction time 14 h,
purified by hexanes:EtOAc (50:50). Product recovered as white
solid (32.5 mg, 42% yield). Rf = 0.45 (hexanes/EtOAc = 1:1).
Characterization data previously listed (vide supra).
6,6,8-trimethyl-5.6-dihydro-4H-benzo[c]furo[2,3-e]azepin-
4-one (2q). Reaction time 14 h, purified by hexanes:EtOAc
(50:50). Product recovered as white solid (19.5 mg, 27% yield).
Rf = 0.4 (hexanes/EtOAc = 1:1). 1H NMR (600 MHz, CDCl3) δ
7.78 (d, J = 7.9 Hz, 1H), 7.47 (d, J = 1.9 Hz, 1H), 7.24 (dd, J =
7.9, 0.7 Hz, 1H), 7.22 (s, 1H), 6.93 (d, J = 1.9 Hz, 1H), 5.86 (s,
1H), 2.42 (s, 3H), 1.63 (s, 6H). 13C{1H} NMR (151 MHz,
9-Fluoro-7-methyl-6.7-dihydro-5H-dibenzo[c,e]azepin-5-
one (1q). 1-(3-fluorophenyl)ethan-1-amine (0.15 mmol) and 2-
iodobenzoic acid (0.45 mmol) were used. Reaction time 14 h,
purified by hexanes:EtOAc (50:50). Product recovered as white
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The Journal of Organic Chemistry
solid (27.8 mg, 38% yield). Rf = 0.45 (hexanes/EtOAc = 1:1.
Characterization data previously listed (vide supra).
Synthesis of C–H Arylation/Lactamization/Dealkylation
Product 7-Ethyl-8-fluoro-7-methyl-6,7-dihydro-5H-
1
2
3
4
5
6
7
8
9
dibenzo[c,e]azepin-5-one (4). A 7.5 mL vial was charged with
Pd(OAc)2 (3.36 mg, 0.015 mmol, 0.1 equiv), silver acetate
(50.07 mg, 0.30 mmol, 2 equiv), ethyl 2-iodobenzoate (0.45
mmol, 3 equiv), 2-(2-fluorophenyl)-N-propylbutan-2-amine
(0.15 mmol, 1 equiv), and acetic acid (1 mL). The vial was
sealed with a PTFE lined cap and stirred at room temperature
for 15 min. After 15 min of stirring, the reaction mixture was
heated in a pie-block at 100 °C under stirring for 14 h. After
cooling to room temperature, the reaction mixture was made
basic with ammonium hydroxide solution up to pH = 8. The
reaction mixture was stirred for 15 minutes followed by
extraction with dichloromethane (3 × 10 mL). The organic
layer was washed with brine and dried over Na2SO4. The filtrate
was concentrated in vacuo and further purified by flash column
chromatography over silica (1:1 Hexanes:EtOAc). Product
recovered as a tan solid (63.0 mg, 78% yield). Rf = 0.5
(hexanes/EtOAc = 1:1). 1H NMR (600 MHz, CDCl3) δ 7.97 (dd,
J = 7.7, 1.4 Hz, 1H), 7.58 (td,J = 7.6, 1.4 Hz, 1H), 7.49 (td, J =
7.6, 1.0 Hz, 1H), 7.44 (dd, J = 7.8, 0.7 Hz, 1H), 7.33 (td, J =
7.9, 5.0 Hz, 1H), 7.28 (d, J = 7.7 Hz, 1H), 7.08 (ddd, J = 13.2,
8.1, 1.3 Hz, 1H), 6.27 (s, 1H), 1.85 (d, J = 10.0 Hz, 3H), 1.66
(dq, J = 14.5, 7.7 Hz, 1H), 1.47 (dq, J = 14.4, 7.2 Hz, 1H), 0.63
(t, J = 7.3 Hz, 3H). 13C{1H} NMR (151 MHz, CDCl3) δ 168.8,
159.4 (d, J = 247.1 Hz), 140.7, 139.1, 132.6, 131.9, 131.3 (d, J
= 11.0 Hz), 130.0, 129.5, 128.9 (d, J = 10.5 Hz), 128.4, 128.2,
116.9 (d, J = 27.8 Hz), 58.2, 31.2, 28.2 (d, J = 18.1 Hz), 9.2. 19F
NMR (376 MHz, CDCl3) δ -109.3 (m). HRMS (ESI-MS):
calcd. 270.1289 [M+H]+ Found: 270.1296. HRMS (ESI-TOF)
m/z: [M + H]+ Calcd for C11H18N 164.1434; Found 164.1436.
(R)-1-Methyl-1,2-dihydro-3H-benzo[c]naphtho[2,1-
e]azepin-3-one (1ae). (R)-1-(naphthalen-1-yl)ethan-1-amine
(0.15 mmol) and 2-iodobenzoic acid (0.45 mmol) were used.
Reaction time 14 h, purified by hexanes:EtOAc (50:50).
Product recovered as white solid (23 mg, 28% yield). Rf = 0.5
(hexanes/EtOAc = 1:1. Characterization data previously listed
(vide supra).
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8-Fluoro-6.7-dihydro-5H-dibenzo[c,e]azepin-5-one (1v). 2-
fluorobenzylamine(0.15 mmol) and 2-iodobenzoic acid (0.45
mmol) were used. Reaction time 14 h, purified by
hexanes:EtOAc (50:50). Product recovered as white solid (40.5
mg, 59% yield). Rf
= 0.45 (hexanes/EtOAc = 1:1).
Characterization data previously listed (vide supra).
3-Chloro-7,7,9-trimethyl-6,7-dihydro-5H-
dibenzo[c,e]azepin-5-one
(2b).
2-(m-tolyl)propan-2-
amine(0.15 mmol) and5-chloro-2-iodobenzoic acid (0.45
mmol) were used. Reaction time 14 h, purified by
hexanes:EtOAc (50:50). Product recovered as white solid (38.6
mg, 45% yield). Rf
= 0.5 (hexanes/EtOAc = 1:1).
Characterization data previously listed (vide supra).
3-Methoxy-7,7,9-trimethyl-6,7-dihydro-5H-
dibenzo[c,e]azepin-5-one (2m). 1-(3-fluorophenyl)ethan-1-
amine (0.15 mmol) and2-iodo-5-methoxybenzoic acid (0.45
mmol) were used. Reaction time 14 h, purified by
hexanes:EtOAc (50:50). Product recovered as white solid (40.6
mg, 48% yield). Rf
= 0.4 (hexanes/EtOAc = 1:1).
Characterization data previously listed (vide supra).
Synthesis of Lactam N-Alkylation Product 6-Benzyl-9-
(trifluoromethyl)-6,7-dihydro-5H-dibenzo[c,e]azepin-5-one
(5). 9-(Trifluoromethyl)-6,7-dihydro-5H-dibenzo[c,e]azepin-5-
one (0.1 mmol) was dissolved in 1 mL of dry DMF under
nitrogen. The solution was cooled to 0 °C and sodium hydride
(60% dispersion in mineral oil) (2 equiv.) was added to it
portion wise. The resulting suspension was stirred for 15 min at
the same temperature. Benzyl bromide (1.3 equiv.) was then
added drop wise and the solution was stirred overnight at room
temperature. The completion of the reaction was confirmed by
checking TLC and the excess of sodium hydride was quenched
by adding 1 mL of water at 0 °C. The organic layer was
extracted with ethyl acetate followed by multiple washes with
water. The combined organic layer was concentrated under
reduced pressure and the pure product was obtained as a tan
solid (35mg, 95%).1H NMR (600 MHz, CDCl3) δ 8.10 (dd, J =
7.7, 1.5 Hz, 1H), 7.70 (d, J = 8.1 Hz, 1H), 7.63 (dd, J = 8.1, 1.1
Hz, 1H), 7.58 (dtd, J = 23.3, 7.4, 1.5 Hz, 2H), 7.53 (dd, J = 7.6,
1.3 Hz, 1H), 7.32 – 7.27 (m, 3H), 7.27 – 7.23 (m, 2H), 7.01 (s,
1H), 4.89 (d, J = 14.6 Hz, 1H), 4.78 (d, J = 14.6 Hz, 1H), 4.34
(d, J = 14.9 Hz, 1H), 3.99 (d, J = 14.9 Hz, 1H). 13C{1H} NMR
(151 MHz, CDCl3) δ 168.3, 142.1, 138.3, 137.0, 135.9, 135.1,
131.2, 130.9, 129.8 (q, J = 32.6 Hz), 129.3, 129.0, 128.8, 128.8,
128.6, 128.1, 125.5 (q, J = 3.6 Hz), 123.9 (q, J = 272.3 Hz),
123.7 (q, J = 3.7 Hz), 50.7, 49.9. 19F NMR (376 MHz, CDCl3)
δ -60.8. HRMS (ESI-MS): calcd. 368.1257 [M+H]+ Found:
368.1265. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C11H18N
164.1434; Found 164.1436.
Derivatization of and Reactions of Biaryl Lactams.
Synthesis of C–H Arylation/Lactamization/β-Nitrogen
Elimination Product 2-(2'-(Prop-1-en-2-yl)-[1,1'-biphenyl]-
2-yl)acetamide (3). A 7.5 mL vial was charged with Pd(OAc)2
(3.36 mg, 0.015 mmol, 0.10 equiv), silver acetate (50.07 mg,
0.30 mmol, 2 equiv), 2-(2-iodophenyl)acetic acid (0.45 mmol,
3 equiv), 2-(m-tolyl)propan-2-amine (0.15 mmol, 1 equiv),
HFIP (0.7 mL), and acetic acid (0.3 mL). The vial was sealed
with a PTFE lined cap and stirred at room temperature for 15
min. After 15 min of stirring, the reaction mixture was heated
in a pie-block at 100 °C under stirring for 14 h. After cooling to
room temperature, the reaction mixture was made basic with
ammonium hydroxide solution up to pH = 8. The reaction
mixture was stirred for 15 minutes followed by extraction with
dichloromethane (3 × 10 mL). The organic layer was washed
with brine and dried over Na2SO4. The filtrate was concentrated
in vacuo and further purified by flash column chromatography
over silica (1:1 Hexanes:EtOAc). Product was observed as a tan
solid (19.1 mg, 24% yield). Rf = 0.55 (hexanes/EtOAc = 1:1).
1H NMR (600 MHz, CDCl3) δ 7.35 – 7.29 (m, 2H), 7.27 (dd, J
= 7.5, 2.0 Hz, 1H), 7.22 – 7.19 (m, 1H), 7.12 (s, 1H), 7.10 (dd,
J = 7.7, 1.2 Hz, 1H), 7.05 (d, J = 7.7 Hz, 1H), 5.01 – 4.88 (m,
1H), 4.83 (dd, J = 1.9, 0.8 Hz, 1H), 3.52 (s, 2H), 2.39 (s, 3H),
1.60 (dd, J = 1.2, 0.8 Hz, 3H). 13C{1H} NMR (151 MHz,
CDCl3) δ 174.9, 145.0, 141.9, 141.1, 136.4, 134.4, 130.7, 129.8,
129.6, 129.1, 128.5, 126.8, 126.5, 126.0, 115.2, 37.3, 22.5, 20.3.
HRMS (ESI-MS): calcd. 252.1383 [M+H]+ Found: 252.1391.
HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C11H18N 164.1434;
Found 164.1436.
Synthesis
of
Lactam
Oxidation
Product
3-
(Trifluoromethyl)-5H-dibenzo[c,e]azepine-5,7(6H)-dione
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The Journal of Organic Chemistry
Page 18 of 21
(6). 9-(Trifluoromethyl)-6,7-dihydro-5H-dibenzo[c,e]azepin-5- mmol) and NiCl2·6H2O (143 mg, 0.6 mmol). NaBH4 (800 mg,
1
2
3
4
5
6
7
8
one (0.1 mmol) was dissolved in acetonitrile (5 mL) and N-
bromosuccinimide (4 equiv.) was added to it followed by the
addition of AIBN (40 mol%). The mixture was refluxed
overnight and then cooled. Again, N-bromosuccinimide (4
equiv.) and AIBN (40 mol%) was added to the reaction mixture
and stirred under reflux for a further 14 h. Reaction was cooled,
and solvent was concentrated in vacuo and further purified by
flash column chromatography over silica (4:1 Hexanes:EtOAc)
to get the desired product. Product recovered as a white solid
(13.5 mg, 47% yield). Rf = 0.6 (hexanes/EtOAc = 4:1). 1H NMR
(600 MHz, CDCl3) δ 8.56 (s, 1H), 8.42 (d, J = 1.4 Hz, 1H), 8.17
(dd, J = 7.9, 1.2 Hz, 1H), 7.94 (dd, J = 8.3, 1.7 Hz, 1H), 7.86
(d, J = 8.3 Hz, 1H), 7.80 – 7.71 (m, 2H), 7.64 (ddd, J = 8.0, 7.1,
1.5 Hz, 1H). 13C{1H} NMR (151 MHz, CDCl3) δ 166.9, 166.2,
139.5, 134.9, 133.7, 132.1, 131.8, 131.2, 131.2 (q, J = 33.8 Hz),
130.6, 130.0, 129.7 (q, J = 3.4 Hz), 129.2 (q, J = 3.9 Hz), 123.5
(q, J = 272.5 Hz). 19F NMR (376 MHz, CDCl3) δ -61.3. HRMS
(ESI-MS): calcd. 292.0580 [M+H]+ Found: 292.0589. HRMS
(ESI-TOF) m/z: [M + H]+ Calcd for C11H18N 164.1434; Found
164.1436.
21.0 mmol) was then added in small portions over 30 min. The
reaction was exothermic and effervescent. The resulting
reaction mixture containing a finely divided black precipitate
was allowed to warm to room temperature and left to stir for a
further 24 h. The solvent was removed in vacuo and extracted
with dichloromethane and dried over Na2SO4. The crude
reaction mixture was purified by flash column chromatography
to yield 9 as a white solid (552 mg, 70%). Rf = 0.3 (PE/EA =
1
1:6). H NMR (600 MHz, CDCl3) δ 7.30 (d, J = 7.4 Hz, 1H),
9
7.19 (t, J = 7.5 Hz, 1H), 7.14 (d, J = 7.4 Hz, 1H), 5.17 (t, J =
6.1 Hz, 1H), 4.89 (s, 1H), 4.24 (t, J = 4.6 Hz, 2H), 3.07 – 2.91
(m, 1H), 2.79 – 2.68 (m, 1H), 2.50 – 2.38 (m, 1H), 1.96 – 1.85
(m, 1H), 1.44 (s, 9H). 13C{1H} NMR (151 MHz, CDCl3) δ 155.9,
145.7, 141.6, 134.6, 127.3, 127.2, 123.5, 79.6, 76.2, 42.4, 35.5,
28.5, 28.0. HRMS (ESI-MS): calcd. 262.1449 [M-H]- Found:
262.1447. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C11H18N
164.1434; Found 164.1436.
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60
4-(Aminomethyl)-2,3-dihydro-1H-inden-1-ol Boc-protected
amine (10). (500 mg, 1.9 mmol) was dissolved in dry CH2Cl2
(10 mL) and trifluoroacetic acid (8 mL) was added at room
temperature under an N2 atmosphere. After the reaction was
stirred for 2 h at room temperature, the volatiles were removed
in vacuo. The reaction mixture was treated with sodium
hydroxide (1.0 M, 20 mL) and stirred for 30 min. The reaction
mixture was extracted with CH2Cl2, dried over Na2SO4, and
concentrated in vacuo to give the crude product as a colorless
oil, which was subjected to column chromatography on silica
gel using CH2Cl2/MeOH (95:5) to give product 10 as a colorless
Synthesis of Thioamide Product 9-(Trifluoromethyl)-6,7-
dihydro-5H-dibenzo[c,e]azepine-5-thione
(7).
9-
(Trifluoromethyl)-6,7-dihydro-5H-dibenzo[c,e]azepin-5-one
(0.1 mmol) was dissolved in toluene (5 mL) and Lawesson's
reagent (1.1 equiv.) was added. The obtained mixture was
heated under reflux overnight, and the completion of the
reaction was confirmed by checking TLC. Solvent was
concentrated in vacuo and further purified by flash column
chromatography over silica (4:1 Hexanes:EtOAc) to get desired
product. Product recovered as a yellow solid (24.0 mg, 82%
1
oil (226 mg, 73%). Rf = 0.2 (DCM/MeOH = 95:5). H NMR
(600 MHz, CDCl3) δ 7.31 (d, J = 7.0 Hz, 1H), 7.25 – 7.21 (m,
2H), 5.28 – 5.19 (m, 1H), 3.80 (d, J = 5.8 Hz, 2H), 3.02 (ddd, J
= 15.9, 8.5, 4.8 Hz, 1H), 2.82 – 2.73 (m, 1H), 2.54 – 2.43 (m,
1H), 2.02 – 1.91 (m, 1H), 1.83 (s, 2H). 13C{1H} NMR (151 MHz,
CDCl3) δ145.6, 141.1, 139.1, 127.5, 126.5, 122.9, 76.3, 43.9,
35.7, 28.0. HRMS (ESI-MS): calcd. 164.1070 [M+H]+ Found:
164.1073. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C11H18N
164.1434; Found 164.1436.
1
yield). Rf = 0.7 (hexanes/EtOAc = 4:1). H NMR (600 MHz,
CDCl3) δ 9.12 (s, 1H), 8.33 (dd, J = 7.9, 1.2 Hz, 1H), 7.73 (s,
2H), 7.60 (td, J = 7.6, 1.3 Hz, 1H), 7.56 – 7.47 (m, 3H), 4.29
(dd, J = 14.3, 6.4 Hz, 1H), 4.18 (dd, J = 14.3, 6.4 Hz, 1H).
13C{1H} NMR (151 MHz, CDCl3) δ 199.7, 142.4, 138.5, 138.2,
134.1, 132.8, 131.5, 130.6 (q, J = 32.9 Hz), 130.1, 129.2, 129.0,
126.0 (q, J = 3.6 Hz), 123.9 (q, J = 272.4 Hz), 123.7 (q, J = 3.6
Hz), 48.7.19F NMR (376 MHz, CDCl3) δ -60.8. HRMS (ESI-
MS): calcd. 294.0559 [M+H]+ Found: 294.0570. HRMS (ESI-
TOF) m/z: [M + H]+ Calcd for C11H18N 164.1434; Found
164.1436.
3-Oxo-1,2,3,10,11,12-hexahydrobenzo[e]indeno[4,5-
c]azepin-10-yl acetate (11). General procedure for C–H
arylation/lactamization used, product purified by column
chromatography (hexanes/EtOAc) to give product as a brown
solid (19 mg, 42% yield) as a mixture of diastereomers (likely
due to atropisomerism of the seven-membered lactam). Rf = 0.2
(PE/EA = 1:7). 1H NMR (600 MHz, CDCl3) δ 8.05 – 7.92 (m,
1H), 7.61 – 7.55 (m, 2H), 7.53 – 7.46 (m, 3H), 6.24 (dt, J = 7.2,
3.7 Hz, 1H), 4.22 – 4.11 (m, 1H), 4.06 (dt, J = 14.9, 6.0 Hz,
1H), 3.28 – 3.10 (m, 1H), 2.98 (dddd, J = 53.6, 15.7, 8.7, 4.5
Hz, 1H), 2.64 – 2.47 (m, 1H), 2.28 – 2.15 (m, 1H), 2.08 (d, J =
2.5 Hz, 3H). 13C{1H} NMR (151 MHz, CDCl3) δ = 171.2,
171.1, 141.4, 141.1, 140.9, 140.0, 139.9, 137.8, 135.1, 133.7,
133.6, 131.5, 131.4, 130.3, 129.4, 129.3, 129.0, 128.9, 128.3,
125.7, 125.6, 78.5, 78.1, 41.1, 32.4, 28.9, 28.9, 21.5. HRMS
(ESI-MS): calcd. 308.1281 [M+H]+ Found: 308.1287. HRMS
(ESI-TOF) m/z: [M + H]+ Calcd for C11H18N 164.1434; Found
164.1436.
Synthesis of aza-BrassinolidePrecursor 4-Cyanoindanone
(8). Based on a modification of a known procedure,40 4-
bromoindanone (1.0 g, 4.74 mmol), CuI (451 mg, 2.37 mmol)
and CuCN (1.06 g, 11.8 mmol) were combined in anhydrous
DMF (5 mL) in a 35 mL sealed tube with a Teflon stopper,
followed by heating to 120 ºC. The reaction was cooled after 24
h, followed by dilution with EtOAc (125 mL) and subsequent
filtration through celite. The reaction mixture was evaporated
in vacuo and subsequently recrystallized from EtOAc to give
the product as a light brown solid (436 mg, 58%). 1H NMR (600
MHz, CDCl3) δ 7.93 (d, J = 7.7 Hz, 1H), 7.86 (d, J = 7.5 Hz,
1H), 7.50 (t, J = 7.6 Hz, 1H), 3.32 – 3.27 (m, 2H), 2.79 – 2.74
(m, 2H). 13C{1H} (151 MHz, CDCl3) δ 204.6, 157.8, 138.2,
137.7, 128.3, 128.1, 116.2, 111.5, 35.9, 25.3.
tert-Butyl
(1-hydroxy-2,3-dihydro-1H-inden-4-
Scale-Up Experiment. 7,7,9-trimethyl-6,7-dihydro-5H-
dibenzo[c,e]azepin-5-one (1i). A 40 mL sealed tube (Ace
Glassware) was charged with Pd(OAc)2 (168 mg, 0.75 mmol,
0.10 equiv), silver acetate (2.50 g, 15.0 mmol, 2.0 equiv), ethyl
yl)methylcarbamate (9). To a stirred solution of 1-oxo-2,3-
dihydro-1H-indene-4-carbonitrile 8 (500 mg, 3.0 mmol) in dry
methanol (30 mL), cooled to 0 ºC, were added Boc2O (1.3 g, 6
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The Journal of Organic Chemistry
Crystallographic data for 2g
4-iodobenzoate (45.0 mmol, 3.0 equiv), 2-(m-tolyl)propan-2-
1
2
3
4
5
6
7
8
Crystallographic data for 2r
Crystallographic data for 4
amine (15.0 mmol, 1.0 equiv), and acetic acid (7 mL). The tube
was sealed and stirred at room temperature for 15 min. After 15
min of stirring, the reaction mixture was heated in an oil bath at
100 °C under stirring for 12 h. After cooling to room
temperature, the reaction mixture was made basic with
ammonium hydroxide solution up to pH = 8. The reaction
mixture was stirred for 15 minutes followed by extraction with
dichloromethane (3 ×10 mL). The organic layer was washed
with brine and dried over Na2SO4. The filtrate was concentrated
under vacuo and further purified by flash column
chromatography over silica (Hexanes:EtOAc). Product
recovered as white solid (2.64 g, 70% yield). Rf = 0.5
(hexanes/EtOAc = 1:1).
AUTHOR INFORMATION
Corresponding Author
* Michael C. Young: michael.young8@utoledo.edu
Present Addresses
†Author is presently an Assistant Professor at Chitkara University.
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Author Contributions
The manuscript was written through contributions of all authors. /
All authors have given approval to the final version of the
manuscript.
Synthesis of Amide 12. 2-Iodobenzoic acid (1.56 g, 6.28
mmol) and HCTU (2.83 g, 6.85 mmol) were combined in
MeCN (25 mL), followed by addition of Et3N (1.92 mL, 13.7
mmol). It is noteworthy that HCTU can lead to strong
anaphylaxis.41 The reaction was stirred for 6h, upon which time
the mixture was observed to have solidified. 2-
Fluorobenzylamine (650 μL, 5.71 mmol) was dissolved in
MeCN (10 mL), and this was added to the reaction mixture,
which was stirred for an additional 18 h. The reaction mixture
was then poured into 0.33 M KOH(aq)(150 mL), followed by
extraction with dichloromethane (3 x 25 mL). The combined
organic phase was dried over Na2SO4, then evaporated in vacuo.
The residual solid was recrystallized from EtOAc to give the
desired product as a tan solid (1.59 g, 78% yield).1H NMR (600
MHz, CDCl3) δ 7.85 (dd, J = 8.0, 0.7 Hz, 1H), 7.50 (td, J = 7.6,
1.6 Hz, 1H), 7.41 – 7.35 (m, 2H), 7.32 – 7.27 (m, 1H), 7.14 (td,
J = 7.5, 1.0 Hz, 1H), 7.12 – 7.05 (m, 2H), 6.11 (s, 1H), 4.70 (d,
J = 5.9 Hz, 2H). 13C{1H} NMR (151 MHz, CDCl3) δ 169.3,
161.3 (d, J = 246.3 Hz), 142.0, 140.1, 131.4, 130.9 (d, J = 4.2
Hz), 129.7 (d, J = 8.2 Hz), 128.5, 128.3, 124.7 (d, J = 14.8 Hz),
124.5 (d, J = 3.6 Hz), 115.6 (d, J = 21.2 Hz), 92.5, 38.3 (d, J =
3.8 Hz).19F NMR (376 MHz, CDCl3) δ -117.1 (m). HRMS (ESI-
MS): calcd. 354.9869 [M+H]+ Found: 354.9881. HRMS (ESI-
TOF) m/z: [M + H]+ Calcd for C11H18N 164.1434; Found
164.1436.
Notes
In addition to being available in the Supporting Information, all
crystallographic data has been deposited with the Cambridge
Crystallographic Database (1968313, 1968314, and 1968315).
Conflicts of Interest
This work is partially covered by US patent US20190185392,
held by MCY and MK.
ACKNOWLEDGMENT
The authors wish to acknowledge financial support through start-
up funds from The University of Toledo, as well as a generous grant
from the ACS Herman Frasch Foundation (830-HF17). The authors
wish to acknowledge Dr. Zhiquiang (Mark) Wang at the
Environmental Analysis Service Center, University of Cincinnati,
Ms. Sandhya Adhikari at The University of Toledo, and Dr. Ian
Riddington at The University of Texas
– Austin’s Mass
Spectrometry Facility for collecting high resolution mass
spectrometry data. Dr. Kristin Kirschbaum is acknowledged for
advice in collecting single crystal X-ray diffraction data.
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ASSOCIATED CONTENT
Supporting Information.
The Supporting Information is available free of charge via the
Internet at http://pubs.acs.org.” and includes:
1
Selectivity experiment data, chiral HPLC data, H and 13C NMR
spectra
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Page 20 of 21
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