Synthesis of ortho -haloaminoarenes by aryne insertion of nitrogen-halide Bonds

Article abstract of DOI:10.1021/jo502541t

A rapid and general access to ortho-haloaminoarenes has been developed by aryne insertion into N-chloramine, N-bromoamine, and N-iodoamine bonds via two complementary protocols harnessing fluoride-promoted 1,2-elimination of ortho-trimethylsilyl aryltriflates. Typically, electron-deficient N-chloramines effectively react with aryne intermediates generated at elevated temperature with CsF, while less stable N-haloamines are found more efficient under milder, TBAF-mediated aryne formation at room temperature. Both protocols demonstrate a good level of regioselectivity and functional group tolerance. Efforts to elucidate the mechanism of N-X insertion are also discussed. The practical value of this transformation is highlighted by rapid synthesis of novel analogues of the antipsychotic cariprazine.

Full text of DOI:10.1021/jo502541t

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Article
Synthesis of ortho-Haloaminoarenes by
Aryne Insertion of Nitrogen-Halide Bonds
Charles E. Hendrick, and Qiu Wang
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo502541t • Publication Date (Web): 11 Dec 2014
Downloaded from http://pubs.acs.org on December 24, 2014
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Synthesis of ortho-Haloaminoarenes by Aryne Insertion of Nitrogen-Halide
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Bonds
8
Charles E. Hendrick and Qiu Wang*
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Department of Chemistry, Duke University, Durham, North Carolina 27708
qiu.wang@duke.edu
NMe2
HN
O
X
X
N
X
R
insertion
R
+
N
R
R
R
R
N
R
N
in situ
formation
X = Cl, Br, or I
ortho-halo aminoarene
novel antipsychotic compounds
OTf
R
TMS
ABSTRACT
A rapid and general access to ortho-haloaminoarenes has been developed by aryne
insertion into N-chloramine, N-bromoamine, and N-iodoamine bonds via two complementary
protocols harnessing fluoride-promoted 1,2-elimination of ortho-trimethylsilyl aryltriflates.
Typically, electron-deficient N-chloramines effectively react with aryne intermediates generated
at elevated temperature with CsF while less stable N-haloamines are found more efficient under
milder, TBAF-mediated aryne formation at room temperature. Both protocols demonstrate a
good level of regioselectivity and functional group tolerance. Efforts to elucidate the mechanism
of N−X insertion are also discussed. The practical value of this transformation is highlighted by
rapid synthesis of novel analogs of the antipsychotic cariprazine.
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INTRODUCTION
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The ortho-haloaminoarene motif is an important pharmacophore in numerous bioactive
molecules and drugs.1 Representative examples include antipsychotics cariprazine and
aripiprazole (Abilify) as well as an anti-inflammatory CXCR3 inhibitor which all contain an
ortho-chloro-arylpiperazine as the primary pharmacophore (Figure 1). Furthermore, ortho-
haloaminoarenes are versatile synthetic intermediates in cross-coupling reactions, providing
facile access to biologically and industrially important products.2 Synthetic access to this class of
compounds is therefore of significant interest.
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O
NMe2
O
O
Cl
N
EtHN
Me
Cl
HN
Cl
HN
Cl
N
Cl
N
N
N
F
Cl
O
N
N
N
(
)
3
Cariprazine
Aripiprazole
CXCR3 Inhibitor
(antipsychotic)
(antipsychotic)
(anti-inflammatory)
Figure 1. Representative ortho-haloaminoarenes in pharmaceuticals.
Existing approaches to ortho-haloaminoarenes generally rely on stepwise C−N and C−X
bond formation. For example, electrophilic halogenation of aminoarenes represents a
straightforward strategy, however both ortho- and para-halogenated isomers are often observed
in poor regioselectivity.3 Transition-metal catalyzed ortho-directed halogenations provide
significant improvements in this regard, achieving excellent ortho selectivity with milder halide
sources. 4 Despite these advances, the need for noble metals and specific directing groups limits
the utility of these methods as a general synthetic strategy. Alternatively, Buchwald-Hartwig
coupling reactions between ortho-dihaloarenes and amines can yield ortho-haloaminoarene
products.2b,5 However, chemoselective aminations between similarly activated aryl halides is
challenging, limiting this strategy to less functionally complex arene scaffolds. The lack of an
effective and general strategy remains a challenge in preparing valuable ortho-haloaminoarenes.
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In our studies, we propose an insertion transformation between nitrogen-halide bonds
(N−X) and arynes as a direct approach to this important class of ortho-haloaminoarene
compounds (Scheme 1). This route circumvents the obstacles of previous stepwise methods
through simultaneous installation of both amine and halide functionalities in an innately ortho-
selective manner. The proposed transformation is inspired by the labile nature of N−X bonds,
which could undergo an insertion reaction with highly reactive arynes without transition metals.
For example, N-chloramines are known to cleave homolytically in the presence of acid to
undergo formal intramolecular insertions across simple olefins and alkynes.6 We expected that
such an intermolecular N−X bond and aryne insertion would be general and applicable to the
synthesis of a broad substrate scope of ortho-haloaminoarenes with a good functional group
compatibility and a high level of regioselectivity, benefiting from the synthetic advantages of
aryne chemistry.
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Scheme 1. Our approach to ortho-haloaminoarenes by aryne insertion of N–X bonds
OTf
R
X
X
R1
R1
NXS
H
TMS
N
R2
R
N
R2
R1
N
R2
X = Cl, Br, or I
CsF or TBAF
isolated or formed in situ
ortho-haloaminoarenes
Aryne intermediates have emerged as a powerful platform for the development of
numerous new transformations in the past two decades.7-8 Their reactivity is characterized by a
low-lying LUMO, arising from a strained π-bond, which facilitates insertion reactions into a
variety of σ-bonds for the preparation of complex ortho-difunctionalized arenes with predictable
regioselectivity.9 Kobayashi’s work on the ortho-trimethylsilyl aryltriflate system,10 has allowed
for the formation of reactive aryne intermediates with mildly basic fluoride. Such mild
conditions eliminate the need for strong bases or high temperatures necessary in other systems,
allowing the development of aryne chemistry coupled with sensitive substrates.11 In this study,
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we posited that the high reactivity of arynes could enable intermolecular amino-halogenation
from labile N-halide bonds, yielding diverse ortho-haloaminoarenes under milder conditions.
In a recent communication,12 we reported an insertion transformation between N-
chloramines and arynes to form ortho-chloroaminoarenes. Preliminary results indicated that
more reactive N-bromoamines and N-iodoamines were inefficient under these original
conditions. Herein, we describe our continued efforts to expand this insertion strategy as a more
general approach to ortho-haloaminoarenes, including the development of a complementary
milder protocol that features improved product yields for the more reactive N-bromoamines and
N-iodoamines, as well as electron-rich N-chloramines. Furthermore, we present extended studies
to investigate the mechanism of this insertion reaction. Finally, as a brief demonstration of the
utility of this method in organic synthesis and medicinal chemistry, we have also synthesized
novel analogs of the antipsychotic drug cariprazine.
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RESULTS AND DISCUSSION
Our studies on aryne insertion into N–X bonds began with the model substrates of
morpholine 1 and benzyne precursor 2 (Scheme 2). The initial reaction optimization revealed
that desired product 3a formed in 63% yield upon one-pot formation of N-chloromorpholine,
from the treatment of 1 with N-chlorosuccinimide, followed by exposure to 2 and CsF at 60 °C.
However, these conditions were found less tolerant to analogous N–Br bond insertion, with
desired ortho-bromoaminoarene 3b obtained only in 36% yield.
Scheme 2: CsF-promoted benzyne insertion of N-chloro- and N-bromomorpholines.a
X
1) NXS, MeCN, rt, 1 h
HN
O
2)
CsF, 60 °C
OTf
N
O
2
TMS
1
3a
3b
X = Cl, 63%
X = Br, 36%
aYields determined by 1H NMR spectroscopy with either CH2Br2 as a quantitative internal standard.
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To identify more general conditions for different N-halo bonds, we decided to use N-
bromomorpholine as a standard substrate to examine additional insertion conditions (Table 1).
In comparison to CsF, TBAF as the fluoride source led to the formation of 3b in a similar 33%
yield, along with protonation product 3’ in 15% yield (entries 1 and 2). When different solvents
were tested, toluene and t-BuOH were found ineffective while THF gave a higher yield of 3’ in
27% yield, indicating a higher overall conversion of 1 to N-arylated product (entries 3–5). At a
lower temperature (0 °C), the reaction gave a comparable yield of desired product 3b and a
reduced amount of 3’ (entry 6). Increasing the equivalence of benzyne precursor significantly
improved reaction efficiency (entries 7–9). In particular, excess of 2 compared to TBAF gave
markedly higher yields of 3b and a decreased amount of byproduct 3’ (entry 8). A further
increased amount of 2 could eliminate the formation of byproduct 3’, however with no
improvement for the formation of 3b (entry 9). Finally, the use of anhydrous TBAT as the
fluoride source decreased the formation of 3b (entry 10).
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Table 1. TBAF-mediated Benzyne Insertion into N-bromomorpholine
Br
N
H
N
H
1) NBS, rt, 1 h
N
+
2) 2, F- source
O
O
O
1
3b
3'
entry
1
2
fluoride
(equiv)
solvent temp
(°C)
time
(h)
yield yield
3ba
36
3’a
trace
15
1
2
1
1
1.5
CsF (3)
MeCN
60
rt
rt
rt
rt
0
1
1
3
1.5 TBAF (1.5) MeCN
1.5 TBAF (1.5) toluene
1.5 TBAF (1.5) t-BuOH
33
3
1
N/D
16
4
1
<10 min N/D N/D
5
1
1.5 TBAF (1.5)
1.5 TBAF (1.5)
THF
THF
THF
THF
THF
THF
3
7
36
36
13
52
52
31
27
19
13
16
--
6
1
7
1.5
1
1
TBAF (1)
rt
rt
rt
rt
7
8
2.5 TBAF (1.5)
24
4
9
1
3
3
TBAF (1.5)
TBAT (1.5)
10
1
54
ND
aYields determined by 1H NMR spectroscopy with either CH2Br2 or DMF as a quantitative internal standard. TBAT
= tetrabutylammonium triphenyldifluorosilicate
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With these findings, we sought to compare the efficiency of both CsF- and TBAF-
mediated benzyne insertion reactions on different N-haloamines (Table 2). CsF-based conditions
proved more effective for N-chloromorpholine, providing 3a in 66% yield in comparison to 52%
under TBAF-mediated conditions. Rather, more reactive N-bromomorpholine underwent
insertion more effectively when TBAF was used, giving 3b in 44% isolated yield compared to
29% from the CsF-mediated reaction. For highly reactive N-iodomorpholine, desired insertion
product 3c was formed only under TBAF-conditions, albeit in 20% yield. When an extended
scope of amines was examined under both conditions, a general trend emerged from these results
(Table 2), indicating more stable, electron-deficient, N-chloramines favored CsF-based
conditions at elevated temperature while more reactive, electron-rich, substrates favored TBAF-
mediated conditions at room temperature. For example, the insertion reactions between benzyne
and various N-chloramines, including cyclic piperazines bearing an electron-withdrawing group,
all successfully delivered the ortho-chloroaminoarene products (4–9) with comparable efficiency
under CsF- and TBAF-promoted conditions. These results demonstrated good compatibility of
this transformation with various functional groups such as carbamates (4), sulfonamides (5),
amides (6–7), and ureas (8–9). When electronically rich cyclic amines, such as piperidine
derivatives and Boc-protected diazepane were examined, significant differences were observed
for the formation of desired ortho-chloroaminoarene products 10–13, with much higher yields
under TBAF-promoted reactions than the CsF-based reactions. Similar results were observed for
benzyne insertions into reactive N-bromo- and N-iodoamines, in which TBAF-conditions were
more effective than CsF-conditions. Although the reaction of N-iodoamines gave only 20% of
the desired ortho-iodoaminoarene 17, even under TBAF conditions, it is noteworthy that these
products are inaccessible by any other method so far, to our knowledge. Note that acyclic amines
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were poor substrates for either TBAF or CsF conditions, with <15% desired products observed.13
Although the insertion can be impeded by competing decomposition resulting from reactive or
sterically hindered intermediates at elevated temperatures, these results prove that benzyne
insertion into N-halo bonds is an effective strategy to rapidly access ortho-chloro-, ortho-bromo-,
and ortho-iodoaminoarenes.
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Table 2. Benzyne Insertion into Various N-Haloaminesa
X
1) NXS, solvent
H
R1
N
R2
R1
2) 2, fluoride source
N
R2
yield (%)a
(by CsF) (by TBAF)
ortho-halo aminoarene product
X
N
3a X = Cl
3b X = Br
3c X = I
66
29
52
44
20
O
ND
4 R = NBoc
63
58
53
5 R = NSO2Et
66b
Cl
N
6 R = N(CO)Ph
7 R = N(CO)Cyp
8 R= N(CO)NEt2
44
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60
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N
R
9 R= N(CO)N(C2H4O)
53
61
Cl
N
10 R = H
25
45
60
64
11 R = Ph
12 R = CO2Et
28
48c
R
Cl
N
13
32
47
NBoc
Br
N
14 R = NBoc
12
49
57
37
15 R = CHPh
16 R = CHCO2Et
ND
ND
R
I
17
ND
20
N
NBoc
aIsolation yields. Reaction conditions: step 1: amine (1.0 equiv), NXS (1.0 equiv), rt, 1 h; step 2: CsF-conditions: 2
(1.5 equiv), CsF (3.0 equiv), 60 °C, listed as entry 1 in Table 1; TBAF-conditions: 2 (2.5 equiv), TBAF (1.5 equiv),
rt, listed as entry 8 in Table 1. Results listed as products in isolation yields. ND = Not detected. bAverage of yields
from two runs. b 90% purity.
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Access to more diversely substituted ortho-aminoarenes was next investigated with
substituted aryne precursors under both CsF- and TBAF-mediated protocols (Table 3). The
reactions were performed using morpholine as the model substrate with aryne precursors bearing
electron-donating and electron-withdrawing functionalities at various positions. For the 3-
methoxybenzyne precursor, the insertion reactions with N-chloro- and N-bromomorpholine
yielded the desired ortho-haloaminoarenes 18 and 19 respectively under both conditions (entry
1). Notably, ortho-chloroaminoarene 18 was formed in a higher yield under CsF conditions than
TBAF conditions while ortho-bromoaminoarene 19 was formed in comparable efficiency under
both conditions. Similar results were observed for the insertion reaction of an asymmetric
napthylyne precursor, providing 20 and 21 with comparable efficiency in high regioselectivity
(entry 2). The insertion of electron-deficient 3-chlorobenzyne gave product 22 only in low yields
under either CsF or TBAF conditions, though a high regioselectivity was observed (entry 3).
Distal substitutions were unable to effect regioselectivity, leading to isolation of 23 as a 1:1
mixture of isomers (entry 4). Overall, arynes bearing multiple substitutions were well tolerated,
giving superb regioselectivity with both methods. A significant pattern could be observed
regarding substitution effects for these substrates, as the CsF method was found to be much more
effective for electron-deficient arynes (Table 3, entries 5 and 6) whereas the TBAF mediated
protocol significantly favored more electron-rich arynes (entries 7 and 8). These results indicate
the utility of both protocols towards accessing ortho-haloaminoarenes with diversely substituted
aryl scaffolds.
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Table 3. Aryne Scope for Insertion of N-Halomorpholines
6
7
8
1) NXS, solvent, rt, 1 h
X
H
N
R
O
2) aryne precursor, F- source
N
O
9
18-28
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Entry
1
Aryne Precursor
Product
MeO
X
CsF
TBAF
41%b
18 Cl
76%a
OMe
TMS
X
Br
35%a
38%c
19
N
OTf
O
2
TMS
OTf
20 Cl
63%
47%
47%d
50%
X
N
Br
21
O
Cl
Cl
OTf
X
22 Cl
22%e
18%f
3
TMS
N
O
X
N
OTf
4
5
Cl
48%g
59%
47%g
11%h
23
Me
Me
Me
TMS
O
Br
Br
X
N
OTf
24
Cl
Me
TMS
O
54%
37%
25%
27%
F
F
OTf
F
F
X
25 Cl
6
TMS
N
26
Br
O
OMe
OMe
TMS
OTf
X
N
7
8
27 Cl
28 Cl
34%
25%i
41%
39%
MeO
MeN
MeO
MeN
O
X
N
TMS
OTf
O
Reaction conditions. step 1: amine (1 equiv), NXS (1 equiv), MeCN, rt, 1 h; step 2: CsF- or TBAF-promoted
insertion conditions (listed as entry 1 and 8 in Table 1, respectively). Isolation yields. Major isomer is shown.
Regioselectivity (rs) is determined by 1H NMR spectroscopy. ars = 5:1. brs = 3:1. crs = 12:1. drs = 10:1. ers = 9:1. frs
= 6:1. grs = 1:1. hYield determined by 1H NMR spectroscopy. irs = 8:1.
To address the excess amount of aryne precursor used under TBAF-mediated insertion
reactions, especially when these materials are not readily accessible,10-11 we found that the
isolation of the N-haloamines typically led to improved efficiency of aryne precursor, despite the
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lower overall yield of the insertion products (Scheme 3). For example, the reaction of 2 and N-
chloromorpholine in MeCN with TBAF-effected N−Cl bond insertion in 40% yield while
isolation of the intermediate N-bromoamine provided 3a in 29% isolated yield. The electron-rich
indolyne substrate underwent insertion of N-chloro-N’-Boc-piperazine in higher efficiency under
such conditions than the CsF-mediated insertion conditions. Arynes bearing halide substituents
were also tolerated, yielding 30 with excellent regioselectivity in 21% yield. Despite reduced
overall yields, the synthetic utility of using isolated N-haloamines in the insertion reaction is
substantial, especially for heteroarynes and N-bromoamines.
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Scheme 3: Insertion of N-Haloamines with Aryne Precursor in Stoichiometric Amounta
X
OTf
X
TBAF (1.5 equiv)
MeCN, rt, 1-24 h
R
N
+
R
N
Z
TMS
Z
Br
X
N
Cl
Me
Cl
N
N
Me
N
Z
NBoc
NBoc
3a X = Cl, Z = O; 40% (66%)
14 X = Br, Z = NBoc; 29% (29%)
29 20% (trace)
30 21% (34%)
a
Reaction conditions: N-chloro or N-bromoamine (1 equiv), aryne precursor (1 equiv), TBAF (1.5 equiv), MeCN, rt.
Isolated yields shown. As a comparison, the yields indicated in the parenthesis are those obtained under the CsF-
based one-pot method (aryne precursor 1.5 equiv).
To understand the mechanism for the formation of ortho-chloroaminoarenes, we initially
explored two possible reaction pathways: (1) a radical driven mechanism involving homolytic
cleavage of the N-halide bond and addition to benzyne; and (2) an initial nucleophilic addition
followed by electrophilic capture of the halide via a short-lived zwitterionic intermediate
(Scheme 4). Previously N-chloramine addition across alkenes and alkynes were reported as
radical mediated processes, thus an analogous radical process was suspected in this
transformation.14 When TEMPO as a radical scavenger was added to the reaction however, no
change was observed on reaction efficiency or trapping of TEMPO by an aryl radical species
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(Scheme 4, A). An intermolecular radical cascade could be ruled out based upon these results as
well as the tolerance of activated benzylic protons (e.g. 11 and 15) in the insertion reactions. To
identify whether the nitrogen or chloride of the N-chloroamines initiated the insertion reaction,
sterically hindered N-chloro-2,2,6,6-tetramethylpiperidine was tested with an aryne precursor,
however no reaction occurred, suggesting the dependence of the insertion on nitrogen
nucleophilicity (Scheme 4, B). Indeed, the regioselective outcome observed in our insertion
reactions is consistent with that reported for nucleophilic additions of amines to unsymmetrical
arynes,9c-e,15 indicating that the insertion may occur in a polar pathway directed by nucleophilic
addition of the nitrogen. However, it remained unclear as to the radical or polar nature of the
subsequent aryl-chloride bond formation. To probe this question, an aryne precursor bearing a 3-
O-allyl moiety was prepared as a radical trap, poised to undergo cyclization in the presence of
even short-lived radicals at the 2-position. Upon exposure of this mechanism probe to N-
chloromorpholine under TBAF-based insertion conditions in MeCN, both aminochlorination
product 32 and cyclized byproduct 32’ were observed (Scheme 4, C). The formation of 32’ is
suggestive of some radical character at the 2-position in the insertion reaction pathway while the
low efficiency of this reaction and the observed preference for C−Cl over C−C bond formation
(32 vs. 32’) prevents complete dismissal of a polar pathway.
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Based upon the current information, a possible mechanism is proposed (Scheme 4d): the
initial nucleophilic attack of the nitrogen of the N-haloamine (I) to the electrophilic aryne would
lead to the formation of activated quaternary N-haloamine (II). This intermediate (II) could
undergo direct halogenation by the resultant ortho-carbanion to give the product (V).
Alternatively, the weak N-halide bond can cleave homolytically, providing an aminium and
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halide radical (III), which would lead to the more stable aryl radical (IV) then facilitate
halogenation by the previously formed halide radical to give the product (V).
Scheme 4. Mechanistic Studies
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N
Cl
N
O
N
1) NCS (1 equiv), MeCN, 1 h
HN
(a)
+
O
2) 2 (1.5 equiv), TEMPO (2 equiv)
CsF (3 equiv), 60 °C
O
O
1 equiv
52%a
ND
TMS
Cl
(2.5 equiv)
OTf
Cl
Cl
(b)
Cl
N
N
+
+
TBAF (1.5 equiv), THF, 50 h
N
quantitative
recoverya
1 equiv
ND
ND
O
O
TMS
OTf
O
Cl
31
Cl
N
Cl
(c)
+
N
(X equiv)
+
other products
O
N
TBAF (1.5 equiv), MeCN
O
O
1 equiv
32
32'
28%b (32 : 32' = 2:1)
(d) Proposed mechanism
X
R1
N
R2
X
N
R1
I
II
R2
X
R1
III
N
R2
X
X
R1
N
R2
R1
N
R2
IV
V
ortho-haloaminoarene
aYields determined by H NMR spectroscopy with CH2Br2 as a quantitative internal standard. Isolation yield of a
1
b
mixture.
Given the synthetic value and operational simplicity of this facile approach to access
highly substituted ortho-haloaminoarenes, we next prepared several novel analogs of the
antipsychotic cariprazine as part of our ongoing interest in neurologically active aminoarenes
(Scheme 5). Starting from commercially available N-Boc-piperazine, the insertion reactions in
Scheme 3 led to the formation of 29 and 30 as two novel ortho-chloroaminoarenes. Thus, the
preparation of the new cariprazine analogs 34 and 35 was readily achieved by the removal of the
Boc group followed by reductive amination with 33. Note that both 34 and 35 would be
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particularly difficult to access otherwise. This example demonstrated aryne insertion reaction of
N-haloamines as a valuable method for the rapid synthesis of pharmaceutically important ortho-
haloaminoarenes and its synthetic utility in medicinal chemistry and drug discovery. Future
structure-activity relationship studies of these novel analogs will provide valuable information
toward the discovery of novel antipsychotic properties.
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Scheme 5. Rapid Synthesis of Novel Analogs of the Antipsychotic Cariprazine
NMe2
HN
O
MeN
MeN
Cl
N
1) HCl, Et2O, rt
Cl
N
2) TEA, NaHB(OAc)3, DCE, rt
H
O
N
NBoc
O
29
33
NMe2
34, 64%
N
H
NMe2
O
Br
Cl
HN
Br
1) HCl, Et2O, rt
Cl
N
2) TEA, NaHB(OAc)3, DCE, rt
Me
N
Me
H
O
N
NBoc
O
30
N
H
NMe2 33
35, 60%
CONCLUSION
A transition-metal-free aryne insertion of nitrogen-halide bonds has been described for
the synthesis of ortho-haloaminoarene compounds. This formal ortho-haloamination of arynes
can be achieved as a one-pot protocol directly starting from amines, by a facile halogenation with
N-halosuccinimides. Insertion of the corresponding N-chloro, N-bromo, or N-iodoamines with
aryne intermediates formed in situ provide the ortho-haloaminoarene products in moderate to
good yields. Two complementary conditions have been established to effect this insertion on a
broad scope of amine and aryne substrates, employing either CsF or TBAF to promote 1,2-
elimination of ortho-trimethylsilyl aryltriflates for the in situ formation of arynes. Reactions with
electron-deficient N-chloramines are more efficient under CsF-mediated aryne forming
conditions, whereas more reactive N-chloramines, as well as N-bromo- and N-iodoamines
strongly prefer mild TBAF-mediated conditions. Both CsF and TBAF protocols demonstrated
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good compatibility with various functional groups such as halides, carbamates, amides, ureas,
and esters. Mechanism studies indicated that the reaction is initiated by the nitrogen moiety,
while the presence of a short-lived aryl radical was identified as a partial contributor in the
reaction mechanism by an intramolecular mechanism probe. Furthermore, the modular synthesis
of novel analogues of antipsychotic cariprazine demonstrated the synthetic value and potential of
this transformation in medicinal chemistry and drug discovery.
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EXPERIMENTAL SECTION
General Experimental Information. Unless otherwise noted, reactions were performed without
exclusion of air or moisture. All commercially available reagents and solvents were used as
received unless otherwise stated. N-chlorosuccinimide (NCS) and N-bromosuccinimide (NBS)
were recrystallized from boiling water then dried under vacuum and stored in a desiccator. N-
iodosuccinimide (NIS) was recrystallized from boiling 1,4-dioxane with CCl4 then dried under
vacuum and stored in a desiccator. Analytical thin-layer chromatography (TLC) was performed
using aluminum plates pre-coated with 0.25 mm of 230–400 mesh silica gel impregnated with a
fluorescent indicator (254 nm). TLC plates were visualized by exposure to ultraviolet light
and/or exposure to KMnO4 or vanillin stain. Organic solutions were concentrated in vacuo using
a rotary evaporator. Column chromatography was performed with silica gel (60 Å, standard
grade). Nuclear magnetic resonance spectra were recorded at ambient temperature (unless
otherwise stated) on 400 MHz or 500 MHz spectrometers. All values for proton chemical shifts
are reported in parts per million (δ) and are referenced to the residual protium in CDCl3 (δ 7.26).
All values for carbon chemical shifts are reported in parts per million (δ) and are referenced to
the carbon resonances in CDCl3 (δ 77.0). NMR data are represented as follows: chemical shift,
multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, quin = quintet, m = multiplet, br =
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broad), coupling constant (Hz), and integration. Infrared spectroscopic data are reported in
wavenumbers (cm-1) with only select peaks shown. High-resolution mass spectra were obtained
using a liquid chromatography-electrospray ionization and time-of-flight mass spectrometer.
General Procedure for CsF-Mediated N-Haloamination of Arynes
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To a solution of the amine (0.20 mmol, 1 equiv) in MeCN (2.0 mL) in a 1-dram vial, was added
N-halosuccinimide (0.20 mmol, 1.0 equiv). The mixture was stirred in the dark at room
temperature for 1 h, after which aryne precursor (0.30 mmol, 1.5 equiv) and CsF (91 mg, 0.60
mmol, 3.0 equiv) were added. The resulting mixture was placed on a pre-heated 60 °C hot plate
and stirred vigorously. The reaction was monitored by TLC analysis for complete consumption
of N-chloramine (typically 1–2 h). Then the reaction mixture was filtered through a pad of
Celite, and washed with dichloromethane. The filtrate was concentrated and the resulting residue
was redissolved in organic solvent (dichloromethane or ethyl acetate, 15 mL) and washed with a
saturated aqueous solution of Na2CO3 (5 mL). The aqueous layer was extracted with organic
solvent of choice (dichloromethane or ethyl acetate, 10 mL × 3). The combined organic layers
were washed with brine (5 mL), dried over Na2SO4, and filtered. The filtrate was concentrated in
vacuo. The crude material was purified by flash column chromatography. Occasionally, further
purification was performed by recrystallization using hot hexanes or kugelrohr distillation (as
indicated).
General Procedure for TBAF-mediated N-haloamination of arynes
To a solution of the amine (0.20 mmol, 1.0 equiv) in anhydrous THF, was added N-
halosuccinimide (0.20 mmol, 1.0 equiv) under nitrogen. The mixture was stirred in the dark for 1
h at room temperature. Aryne precursor (0.50 mmol, 2.5 equiv) was then added followed by the
dropwise addition of a solution of TBAF (1.0 M, THF, 0.30 mL, 0.30 mmol, 1.5 equiv). After
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stirring in the dark at room temperature for 24 h, the reaction was quenched with a saturated
aqueous solution of Na2CO3 (5 mL) and diluted in dichloromethane (15 mL). The aqueous layer
was extracted with dichloromethane (5 mL × 2). The combined organic layers were dried over
Na2SO4 and then filtered. The filtrate was added directly onto silica gel without prior
concentration and the resulting silica mixture was purified by flash column chromatography.
Occasionally, further purification was performed by recrystallization from hot hexanes or
kugelrohr distillation (as indicated).
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TBAF-mediated ortho-haloamination protocol using isolated N-haloamines (Scheme 3).
To a solution of N-haloamine (0.40 mmol, 1.0 equiv) in anhydrous THF, was added aryne
precursor (0.40 mmol, 1.0 equiv) followed by the dropwise addition of a solution of TBAF (1.0
M, THF, 0.6 mL, 0.6 mmol, 1.5 equiv). After stirring in the dark at room temperature for 24 h,
the reaction was quenched with a saturated aqueous solution of Na2CO3 (5 mL) and diluted in
dichloromethane (15 mL). The aqueous layer was extracted with dichloromethane (5 mL × 2).
The combined organic layers were dried over Na2SO4 and then filtered. The filtrate was added
directly onto silica gel without prior concentration and the resulting silica mixture was purified
by flash column chromatography. Occasionally, further purification was performed by
recrystallization from hot hexanes or kugelrohr distillation (as indicated).
4-(2-Chlorophenyl)-morpholine (3a). Isolation by flash column chromatography (10% ethyl
acetate−hexanes). The title compound was obtained as a white solid (130.8 mg, 66%) from the
CsF promoted conditions, as a clear oil (20.4 mg, 52%) from the one-pot TBAF conditions, and
as a clear oil (31.8 mg, 40%) from the procedure using isolated N-chloramine. Rƒ = 0.32 (10%
ethyl acetate–hexanes); 1H NMR (400 MHz, CDCl3): δ 7.39 (dd, J = 8.0, 1.2 Hz, 1H), 7.26 (ddd,
J = 8.0, 1.2, 0.8 Hz, 1H), 7.05 (dd, J = 8.0, 1.6 Hz, 1H), 7.01 (ddd, J = 8.0, 1.6, 0.8 Hz, 1H), 3.90
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(t, J = 4.6 Hz, 4H), 3.08 (t, J = 4.6 Hz, 4H); 13C NMR (100 MHz, CDCl3): δ 149.0, 130.7, 128.7,
127.6, 123.9, 120.2, 67.1, 51.6; FTIR (thin film), cm-1 2853, 1479, 1115, 1069, 761; HRMS-ESI
(m/z) Calcd for (C10H13ClNO) ([M+H]+): 198.0680; found: 198.0681.
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4-(2-Bromophenyl)morpholine (3b). Isolation by flash column chromatography (5% ethyl
acetate−hexanes). The title compound was obtained as a colorless oil (14.0 mg, 29%) from the
CsF promoted conditions and as a white solid (21.5 mg, 44%) from the one-pot TBAF
1
conditions. Rƒ = 0.35 (10% ethyl acetate–hexanes); H NMR (400 MHz, CDCl3): δ 7.58 (d, J =
8.0 Hz, 1H), 7.29 (t, J = 7.6 Hz, 1H), 7.05 (d, J = 8.0 Hz, 1H), 6.93 (t, J = 7.6 Hz, 1H), 3.89 (t, J
13
= 4.4 Hz, 4H), 3.05 (t, J = 4.4 Hz, 4H); C NMR (100 MHz, CDCl3): δ 150.1, 133.7, 128.2,
124.4, 120.7, 119.7, 67.0, 51.9; FTIR (thin film), cm-1 2817, 1473, 1225, 1110, 1038, 931, 757;
HRMS-ESI (m/z) Calcd for (C10H13BrNO) ([M+H]+): 242.0175; found: 242.0175.
4-(2-Iodophenyl)morpholine (3c). Isolated by flash column chromatography (5% ethyl
acetate−hexanes). The title compound was obtained as a clear oil (11.7 mg, 20%) from the one-
pot TBAF conditions. Rƒ = 0.55 (20% ethyl acetate–hexanes); 1H NMR (400 MHz, CDCl3): δ
7.86 (d, J = 6.4 Hz, 1 H), 7.35−7.31 (m, 1H), 7.04 (d, J = 6.4 Hz, 1H), 6.82 (t, J = 6.4 Hz, 1H),
13
3.89 (s br, 4H), 2.99 (s br, 4H); C NMR (125 MHz, CDCl3): δ 153.0, 140.1, 129.2, 125.6,
121.0, 98.1, 67.2, 52.7; FTIR (thin film), cm-1 2957, 1578, 1468, 1114, 1013, 932, 760; HRMS-
ESI (m/z) Calcd for (C10H13INO) ([M+H]+): 290.0036; found: 290.0037.
4-(2-Chlorophenyl)piperazine-1-tert-butyl-carboxylate (4). Isolation by flash column
chromatography (15% ethyl acetate−hexanes). The title compound was obtained as a yellow
solid (32.5 mg, 63%) from the CsF promoted conditions and as a yellow solid (34.6 mg, 58%)
from the one-pot TBAF conditions. Rƒ = 0.64 (30% ethyl acetate–hexanes); 1H NMR (400 MHz,
CDCl3): δ 7.36 (dd, J = 8.0, 1.6 Hz, 1H), 7.22 (ddd, J = 8.0, 7.2, 1.6 Hz, 1H), 7.01 (dd, J = 7.6,
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1.6 Hz, 1H), 6.98 (ddd, J = 7.6, 7.2, 1.6 Hz, 1H), 3.59 (t, J = 4.8 Hz, 4H), 2.98 (t, J = 4.8 Hz,
5
6
13
4H), 1.48 (s, 9H); C NMR (125 MHz, CDCl3, 60 ˚C): δ 154.9, 1493, 130.7, 129.1, 127.6,
7
8
9
124.0, 120.6, 79.7, 51.3, 44.1, 28.5; FTIR (thin film), cm-1 2974, 1693, 1479, 1246, 1169, 1036,
760; HRMS-ESI (m/z) Calcd for (C15H22ClN2O2) ([M+H]+): 297.1364; found: 297.1357.
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1-(2-Chlorophenyl)-4-(ethylsulfonyl)piperazine (5). Isolation by flash column chromatography
(20% ethyl acetate−hexanes). The title compound was obtained as a white solid (31.2 mg, 54%,
and 45.2 mg 78% on two individual runs) from the CsF promoted conditions and as a white solid
1
(30.7 mg, 53%) from the one-pot TBAF conditions. Rƒ = 0.72 (50% ethyl acetate–hexanes); H
NMR (400 MHz, CDCl3): δ 7.37 (dd, J = 8,0, 1.6 Hz, 1H), 7.24 (ddd, J = 8.0, 7.2, 0.8, 1H),
7.03−6.99 (m, 2H), 3.48 (t, J = 4.8 Hz, 4H), 3.11 (t, J = 4.8 Hz, 4H), 3.01 (q, J = 7.6 Hz, 2H),
13
1.41 (t, J = 7.6 Hz, 3H); C NMR (100 MHz, CDCl3): δ 148.5, 130.7, 128.9, 127.7, 124.4,
120.7, 51.2, 46.1, 43.8, 7.8; FTIR (thin film), cm-1 2827, 1479, 1323, 1144, 949, 748; HRMS-
ESI (m/z) Calcd for (C12H18ClN2O2S) ([M+H]+): 289.0772; found: 289.0772.
(4-(2-Chlorophenyl)piperazin-1-yl)(phenyl)methanone (6). Isolation by flash column
chromatography (20% ethyl acetate−hexanes). The title compound was obtained as a yellow
solid (26.5 mg, 44%) from the CsF promoted conditions and as a yellow solid (36.1 mg, 60%)
from the one-pot TBAF conditions. Rƒ = 0.26 (30% ethyl acetate–hexanes); 1H NMR (400 MHz,
CDCl3): δ 7.43 (m, 5H), 7.37 (dd, J = 7.6, 1.2 Hz, 1H), 7.23 (ddd, J = 7.6, 7.2, 1.6 Hz, 1H),
13
7.02–6.98 (m, 2H), 3.38 (br d, 4H), 3.05 (br d, 4H); C NMR (100 MHz, CDCl3): δ 170.4,
148.6, 135.7, 130.7, 129.7, 128.9, 128.5, 127.6, 127.1, 124.3, 120.5; 13C NMR (125 MHz,
C6D5CD3, 80 °C) 51.5, 45.2; FTIR (thin film), cm-1 2918, 1628, 1478, 1227, 1039, 1011, 761;
HRMS-ESI (m/z) Calcd for (C17H18ClN2O) ([M+H]+): 301.1102; found: 301.1105.
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(4-(2-Chlorophenyl)piperazin-1-yl)(cyclopropyl)methanone (7). Isolation by flash column
chromatography (30% ethyl acetate−hexanes). The title compound was obtained (1:1 ratio of two
conformers) as a yellow oil (26.5 mg, 53%) from the CsF promoted conditions and as a clear oil
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(26.3 mg, 50%) from the one-pot TBAF conditions. Rƒ = 0.56 (50% ethyl acetate–hexanes); H
NMR (400 MHz, CDCl3): δ 7.38–7.36 (m, 1H), 7.23 (ddd, J = 8.8, 8.0, 1.6 Hz, 1H), 7.0 (m, 2H),
3.83 (br d, 4H), 3.04 (br d, 4H), 1.78 (tt, J = 8.0, 4.8 Hz, 1H), 1.03–1.00 (m, 2H), 0.80–0.77 (m,
2H); 13C NMR (100 MHz, CDCl3): δ 172.1, 148.7, 130.7, 128.9, 127.6, 124.2, 120.5, 51.7, 51.0,
45.8, 42.4, 11.0, 7.4; FTIR (thin film), cm-1 2819, 1636, 1479, 1227, 1032, 760; HRMS-ESI
(m/z) Calcd for (C14H18ClN2O) ([M+H]+): 265.1102; found: 265.1102.
4-(2-Chlorophenyl)-N,N-diethylpiperazine-1-carboxamide (8). Isolation by flash column
chromatography (30% ethyl acetate−hexanes). The title compound was obtained as a yellow oil
(31.2 mg, 53%) from the CsF promoted conditions and as a yellow oil (31.1 mg, 53%) from the
one-pot TBAF conditions. Rƒ = 0.30 (30% ethyl acetate–hexanes). 1H NMR (400 MHz, CDCl3):
δ 7.36 (dd, J = 8.0, 1.6 Hz, 1H), 7.22 (ddd, J = 8.0, 7.6, 1.6 Hz, 1H), 7.02 (dd, J = 8.0, 1.6 Hz,
1H), 6.98 (ddd, J = 8.0, 7.6, 1.6 Hz, 1H), 3.41 (t, J = 4.8 Hz, 4H), 3.23 (q, J = 7.2 Hz, 4H), 3.04
(t, J = 4.8 Hz, 4H), 1.14 (t, J = 7.2 Hz, 6H); 13C NMR (100 MHz, CDCl3): δ 164.4, 149.0, 130.6,
128.8, 127.6, 123.9, 120.5, 51.1, 47.2, 41.8, 13.2; FTIR (thin film), cm-1 2920, 1641, 1479, 1229,
1038, 760; HRMS-ESI (m/z) Calcd for (C15H23ClN3O) ([M+H]+): 296.1524; found: 296.1524.
(4-(2-Chlorophenyl)piperazin-1-yl)(morpholino)methanone (9). Isolation by flash column
chromatography (ethyl acetate) followed by kugelrohr distillation. The title compound was
obtained as a white solid (32.9 mg, 53%) from the CsF promoted conditions and as a white solid
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(37.4 mg, 61%) from the one-pot TBAF conditions. Rƒ = 0.35 (ethyl acetate). H NMR (400
MHz, CDCl3) δ 7.37 (dd, J = 8.0, 1.6 Hz, 1H), 7.22 (ddd, J = 8.0, 7.2, 1.6 Hz, 1H), 7.00 (m, 2H),
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4H); C NMR (100 MHz, CDCl3) δ 163.8, 148.9, 130.7, 127.6, 124.1, 120.5, 66.6, 51.1 47.4,
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46.9; FTIR (thin film), cm-1 2850, 1639, 1410, 1226, 1113, 1026, 760; HRMS-ESI (m/z) Calcd
for (C15H21ClN3O2) ([M+H]+): 310.1317; found: 310.1318.
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1-(2-Chlorophenyl)piperidine (10). Isolation by flash column chromatography (10%
dichloromethane–hexanes). The title compound was obtained as a colorless oil (9.7 mg, 25%)
from the CsF promoted conditions and as a colorless oil (17.4 mg, 45%) from the one-pot TBAF
conditions. Rƒ = 0.27 (10% dichloromethane–hexanes); 1H NMR (400 MHz, CDCl3): δ 7.35 (dd,
J = 8.0, 1.6 Hz, 1H), 7.20 (ddd, J = 8.0, 7.6, 1.6 Hz, 1H), 7.04 (dd, J = 8.0, 1.6 Hz, 1H), 6.93
(ddd, J = 8.0, 7.6, 1.6 Hz, 1H), 2.97 (t, J = 2.8 Hz, 4H), 1.75 (quin., J = 2.8 Hz, 4H), 1.58 (quin.,
J = 2.8 Hz, 2H); 13C NMR (125 MHz, CDCl3): δ 150.6, 130.5, 128.9, 127.4, 123.2, 120.4, 52.9,
26.2, 24.3; FTIR (thin film), cm-1 2937, 1588, 1479, 1233, 756; HRMS-ESI (m/z) Calcd for
(C11H15ClN) ([M+H]+): 196.0888; found: 196.0888.
1-(2-Chlorophenyl)-4-phenylpiperidine (11). Isolation by flash column chromatography using
a gradient of (5% dichloromethane–hexanes to 5% ethyl acetate–hexanes). The title compound
was obtained as a white solid (15.0 mg, 28%) from the CsF promoted conditions and as a white
solid (34.2 mg, 60%) from the one-pot TBAF conditions. Rƒ = 0.26 (5% ethyl acetate–hexanes);
1H NMR (400 MHz, CDCl3) δ 7.40-7.30 (m, 5H), 7.26-7.21 (m, 2H), 7.11 (d, J = 7.2 Hz, 1H),
6.98 (t, J = 7.8 Hz, 1H), 3.53 (d, J = 12.0 Hz, 2H), 2.79 (t, J = 10.8 Hz, 2H), 2.67 (tt, J = 11.8,
4.2 Hz, 1H), 2.08-1.92 (m, 4H); 13C NMR (125 MHz, CDCl3) 150.4, 146.2, 130.6, 128.9, 128.4,
127.5, 126.9, 126.2, 123.4, 120.5, 52.6, 42.5, 33.7; FTIR (thin film), cm-1 2934, 1586, 1478,
1382, 758, 700; HRMS-ESI (m/z) Calcd for (C17H19ClN) ([M+H]+): 272.1201; found: 272.1202.
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Ethyl-1-(2-chlorophenyl)piperidine-4-carboxylate (12). Isolation by flash column
chromatography (5% hexanes–ethyl acetate). The title compound was obtained as a colorless oil
(25.0 mg, 90% purity, 42%) from the CsF promoted conditions and as a colorless oil (34.5 mg,
64%) from the one-pot TBAF conditions. Rƒ = 0.38 (10% ethyl acetate–hexanes); 1H NMR (400
MHz, CDCl3) δ 7.35 (dd, J = 8.0, 1.2 Hz, 1H), 7.20 (ddd, J = 8.0, 7.6, 1.6 Hz, 1H), 7.03 (d, J =
7.6 Hz, 1H), 6.95 (t, J = 7.6 Hz, 1H), 4.17 (q, J = 7.2 Hz, 2H), 3.37 (d, J = 11.6 Hz, 2H), 2.71
(td, J = 11.6, 2.8 Hz, 2H), 2.44 (tt, J = 10.4, 4.6 Hz, 1H), 2.01-1.96 (m, 4H), 1.28 (t, J = 7.2 Hz,
3H); 13C NMR (125 MHz, CDCl3) δ 175.0, 149.8, 130.5, 129.0, 127.4, 123.5, 120.5, 115.7, 60.4,
51.2, 40.9, 28.5, 14.2; FTIR (thin film), cm-1 2953, 1730, 1588, 1480, 1310, 1169, 1041, 757;
HRMS-ESI (m/z) Calcd for (C14H19ClNO2) ([M+H]+): 268.1099; found: 268.1098.
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4-(2-Chlorophenyl)-1,4-diazepane-1-tert-butyl-carboxylate (13). Isolation by flash column
chromatography (5% ethyl acetate−hexanes). The title compound was obtained as a colorless oil
(20.2 mg, 32%) from the CsF promoted conditions and as a colorless oil (28.9 mg, 47%) from
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the one-pot TBAF conditions. Rƒ = 0.52 (20% ethyl acetate–hexanes); H NMR (500 MHz,
CDCl3, 50 °C): δ 7.34 (d, J = 7.5 Hz, 1H), 7.16 (t, J = 7.5 Hz, 1H), 7.08 (d, J = 7.5 Hz, 1H), 6.92
13
(t, J = 7.5 Hz, 1H), 3.61 (s br, 4H), 3.22−3.17 (m, 4H), 2.03−2.01 (m, 2H), 1.48 (s, 9H); C
NMR (125 MHz, CDCl3, 50 °C) As a mixture of conformers: δ 155.5, 151.1, 130.6, 129.1,
127.4, 123.4, 122.2, 79.4, 55.5, 54.6, 54.4, 48.3, 48.0, 46.2, 45.3, 28.6; FTIR (thin film), cm-1
2972, 1690, 1480, 1157, 1088, 753; HRMS-ESI (m/z) Calcd for (C16H24ClN2O2) ([M+H]+):
311.1521; found: 311.1526.
4-(2-Bromophenyl)piperazine-1-tert-butyl-carboxylate (14). Isolated by Flash Column
Chromatography (5% ethyl acetate–hexanes). The title compound was obtained as a colorless oil
(8.5 mg, 12%) from the CsF promoted conditions, as a colorless oil (33.2 mg, 49%) from the
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one-pot TBAF conditions, and as a colorless oil (20.4 mg, 29%) from the isolated N-bromoamine
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procedure; Rƒ = 0.65 (30% ethyl acetate–hexanes); H NMR (400 MHz, CDCl3) δ 7.56 (d, J =
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8.0 Hz, 1H), 7.27 (t, J = 8.0 Hz, 1H), 7.02 (d, J = 8.0 Hz, 1H), 6.93 (t, J = 8.0 Hz, 1H), 3.60 (t, J
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= 4.6 Hz, 4H), 2.97 (t, J = 4.6 Hz, 4H), 1.48 (s, 9H); C NMR (125 MHz, CDCl3, 60 °C) δ
1.54.9, 150.4, 133.8, 128.3, 124.6, 121.0, 120.0, 79.8, 51.6, 28.4; FTIR (thin film), cm-1 2923,
1689, 1585, 1474, 1163, 757; HRMS-ESI (m/z) Calcd for (C15H22BrN2O2) ([M+H]+): 341.0859;
found: 341.0860.
1-(2-bromophenyl)-4-phenylpiperidine (15). Isolated by flash column chromatography using a
gradient of (5% dichloromethane–hexanes to 5% ethyl acetate–hexanes). The title compound
was obtained as an orange solid (36.2 mg, 57%) from the one-pot TBAF conditions. Rƒ = 0.26
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(5% ethyl acetate–hexanes) H NMR (400 MHz, CDCl3) δ 7.57 (d, J = 8.0 Hz, 1H), 7.35–7.20
(m, 6H), 7.09 (d, J = 8.0 Hz, 1H), 3.49 (d, J = 11.6 Hz, 2H), 2.69 (td, J = 11.6, 2.4 Hz, 2H), 2.65
13
(tt, J = 8.0, 4.0 Hz, 1H); C NMR (125 MHz, CDCl3) 151.4, 146.2, 133.7, 128.4, 128.1, 126.9,
126.2, 124.0, 121.0, 120.1, 53.0, 42.5, 33.7; FTIR (thin film), cm-1 2933, 1586, 1474, 1382, 759,
699; HRMS-ESI (m/z) Calcd for (C17H19BrN) ([M+H]+): 316.0695; found: 316.0695.
Ethyl-1-(2-bromophenyl)piperidine-4-carboxylate (16). Isolated by flash column
chromatography (5% ethyl acetate–hexanes). The title compound was obtained as a colorless oil
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(23.0 mg, 37%) from the one-pot TBAF conditions. Rƒ = 0.38 (10% ethyl acetate–hexanes); H
NMR (400 MHz, CDCl3) δ 7.55 (dd, J = 8.0, 1.6 Hz, 1H), 7.25 (ddd, J = 8.0, 7.2, 1.6 Hz, 1H),
7.03 (dd, J = 8.0, 1.6 Hz, 1H) 6.89 (ddd, J = 8.0, 7.2, 1.6 Hz, 1H), 4.17 (q, J = 7.2 Hz, 2H), 3.35
(d, J = 12.0 Hz, 2H), 2.70 (td, J = 12.0, 3.6 Hz, 2H), 2.43 (tt, J = 10.4, 4.8 Hz, 1H), 2.05–1.92
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(m, 4H), 1.28 (t, J = 7.2 Hz, 3H); C NMR (125 MHz, CDCl3) δ 175.0, 151.2, 133.7, 128.1,
124.2, 121.0, 120.1, 60.4, 51.7, 40.9, 28.5, 14.2; FTIR (thin film), cm-1 2952, 1726, 1586, 1474,
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1166, 1043, 756; HRMS-ESI (m/z) Calcd for (C14H19BrNO2) ([M+H]+): 312.0594; found:
312.0593.
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4-(2-iodophenyl)piperazine-1-tert-butyl-carboxylate (17). Isolated by flash column
chromatography (5% ethyl acetate−hexanes). The title compound was obtained as a clear oil
(15.8 mg, 20%) from the one-pot TBAF conditions. Rƒ = 0.55 (20% ethyl acetate–hexanes); 1H
NMR (500 MHz, CDCl3): δ 7.86 (dd, J = 8.0, 1.5 Hz, 1H), 7.34−7.30 (m, 1H), 7.01 (d, J = 7.5
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Hz, 1H), 6.82 (td, J = 7.5, 1.5 Hz, 1H), 3.63 (s br, 4H), 2.93 (s br, 4H), 1.49 (s, 9H); C NMR
(125 MHz, CDCl3, 60 °C): 155.0, 153.4, 140.2, 129.2, 125.7, 121.2, 98.5, 79.7, 52.4, 44.3, 28.5;
FTIR (thin film), cm-1 2924, 1696, 1469, 1417, 1245, 1170; HRMS-ESI (m/z) Calcd for
(C15H22IN2O2) ([M+H]+): 389.0720; found: 389.0727.
4-(2-Chloro-6-methoxyphenyl)morpholine (18) and 4-(2-Chloro-3-methoxyphenyl)-
morpholine (18’). Isolation by flash column chromatography (10% ethyl acetate−hexanes). The
title compound was obtained as a white solid (34.9 mg, 76%, a 5:1 mixture) from the CsF
promoted conditions and as a white solid (18.8 mg, 41%, a 3:1 mixture) from the one-pot TBAF
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conditions. Rƒ = 0.44 (20% ethyl acetate–hexanes); H NMR (400 MHz, CDCl3): δ 7.25 (d, J =
8.6 Hz, 1H, 18) 7.19 (t, J = 8.2 Hz, 1H, 18’), 6.71–6.68 (m, 2H, 18), 6.58 (d, J = 2.8 Hz, 1H,
18’), 6.53 (dd, J = 8.6, 2.8 Hz, 1H, 18), 3.89 (s, 3H, 18’), 3.88 (t, J = 4.8 Hz, 4H, 18 and 18’),
3.78 (s, 3H, 18), 3.05 (t, J = 4.8, 4H, 18 and 18’); 13C NMR (100 MHz, CDCl3): δ 156.2, 150.5,
130.9, 127.3, 117.0, 112.5, 108.1, 107.2, 106.9, 67.2, 67.1, 56.3, 55.5, 51.8, 51.6; FTIR (thin
film), cm-1 2852, 1472, 1270, 1115, 1093, 1044, 777; HRMS-ESI (m/z) Calcd for (C11H14ClNO2)
([M+H]+): 228.0786; found: 228.0785.
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4-(2-Bromo-3-methoxyphenyl)morpholine (19) and 4-(2-Bromo-6-methoxyphenyl)-
morpholine (19’). Isolated by flash column chromatography (5% ethyl acetate−hexanes). The
title compound was obtained as a colorless oil (19.3 mg, 35%, a 5:1 mixture) from the CsF
promoted conditions and as a colorless oil (21.0 mg, 38%, a 12:1 mixture). Rƒ = 0.44 (20% ethyl
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acetate–hexanes); H NMR (400 MHz, CDCl3) δ 7.44, (d, J = 8.6 Hz, 1H, 19’), 7.24 (t, J = 8.0
Hz, 1H, 19), 6.71 (d, J = 8.0 Hz, 1H, 19), 6.62 (d, J = 8.0 Hz, 1H, 19), 6.61 (d, J = 2.6 Hz, 1H,
19’), 6.50 (dd, J = 8.6, 2.6 Hz, 1H, 19’), 3.89 (s, 3H, 19), 3.88 (t, J = 4.4 Hz, 4H, 19 and 19’),
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3.78 (s, 3H, 19’), 3.05 (t, J = 4.4 Hz, 4H, 19 and 19’); C NMR (100 MHz, CDCl3) δ 159.8,
157.1, 151.9, 151.2, 134.0 (2C), 128.3, 113.2, 110.1, 109.1, 109.0, 107.8, 107.2, 67.2, 56.4, 55.5,
52.2, 52.0; FTIR (thin film), cm-1 2852, 1469, 1267, 1114, 1091, 1045, 776; HRMS-ESI (m/z)
Calcd for (C11H15BrNO2) ([M+H]+): 272.0281; found: 272.0285.
4-(1-Chloronaphthalen-2-yl)morpholine (20). Isolation by flash column chromatography (10%
ethyl acetate−hexanes). The title compound was obtained as a white solid (31.0 mg, 63%) from
the CsF promoted conditions and as a white solid (23.2 mg, 47%, a 10:1 mixture) from the one-
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pot TBAF conditions. Rƒ = 0.42 (20% ethyl acetate–hexanes); H NMR (400 MHz, CDCl3): δ
8.39 (d, J = 8.8 Hz, 1H), 7.89 (d, J = 8.0 Hz, 1H), 7.76 (d, J = 8.8 Hz, 1H), 7.58–7.54 (m, 1H),
7.46–7.42 (m, 1H), 7.34 (d, J = 8.8 Hz, 1H), 3.95 (t, J = 4.4 Hz, 4H), 3.18 (t, J = 4.4 Hz, 4H);
13C NMR (125 MHz, CDCl3): δ 146.2, 132.0, 131.0, 127.9, 127.7, 127.2, 125.0, 124.2, 124.0,
119.5, 67.3, 51.8; FTIR (thin film), cm-1 2852, 1503, 1367, 1114; HRMS-ESI (m/z) Calcd for
(C14H15ClNO) ([M+H]+): 248.0836; found: 248.0837.
4-(1-Bromonaphthalen-2-yl)morpholine (21). Isolation by flash column chromatography (5%
ethyl acetate−hexanes). The title compound was obtained as a pink solid (27.3 mg, 47%) from
the CsF promoted conditions and as a pink solid (29.3 mg, 50%) from the one-pot TBAF
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conditions. Rƒ = 0.42 (20% ethyl acetate–hexanes); 1H NMR (400 MHz, CDCl3): δ 8.31 (d, J =
8.0 Hz, 1H), 7.80 (t, J = 8.0 Hz, 2H), 7.56 (ddd, J = 8.0, 6.8, 1.2 Hz, 1H), 7.46–7.42 (m, 1H),
7.35 (d, J = 8.8 Hz, 1H), 3.95 (t, J = 4.4 Hz, 4H), 3.16 (t, J = 4.4 Hz, 4H); 13C NMR (125 MHz,
CDCl3): δ 148.0, 133.3, 131.5, 128.7, 127.9, 127.5, 127.0, 125.2, 120.1, 118.6, 67.3, 52.3; FTIR
(thin film), cm-1 2851, 1499, 1252, 1114, 987, 810, 749; HRMS-ESI (m/z) Calcd for
(C14H15BrNO) ([M+H]+): 292.0332; found: 292.0340.
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4-(2,3-Dichlorophenyl)morpholine (22) and 4-(2,6-Dichlorophenyl)morpholine (22’).
Isolation by flash column chromatography (10% ethyl acetate−hexanes). The title compound was
obtained as a colorless oil (10.3 mg, 22%, a 9:1 mixture) from the CsF promoted conditions and
as a colorless oil (8.4 mg, 18%, a 6:1 mixture) from the one-pot TBAF conditions. Rƒ = 0.36
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(20% ethyl acetate–hexanes); H NMR (400 MHz, CDCl3): δ 7.19–7.14 (m, 2H, 22 and 22’),
6.95 (dd, J = 7.0, 2.6 Hz, 1H, 22), 3.88 (t, J = 4.8 Hz, 4H, 22 and 22’), 3.16 (t, J = 4.8 Hz, 4H,
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22’), 3.04 (t, J = 4.8 Hz, 4H, 22); C NMR (125 MHz, CDCl3): δ 151.0, 134.1, 127.5, 124.8,
118.5, 67.1, 66.6, 51.7, 49.0; FTIR (thin film), cm-1 2854, 1578, 1446, 1237, 1117, 956, 779;
HRMS-ESI (m/z) Calcd for (C10H12Cl2NO) ([M+H]+): 232.0290; found: 232.0292.
4-(2-Chloro-5-methylphenyl)morpholine (23) and 4-(2-chloro-4-methylphenyl)morpholine
(23’). Isolation by flash column chromatography (10% ethyl acetate−hexanes). The title
compound was obtained as a colorless oil (20.3 mg, 48%, a 1:1 mixture) from the CsF promoted
conditions and as a colorless oil (19.8 mg, 47%, a 1:1 mixture) from the one-pot TBAF
conditions. Rƒ = 0.53 (20% ethyl acetate–hexanes); 1H NMR (400 MHz, CDCl3): δ 7.23 (d, J =
8.0 Hz, 1H, 23), 7.20 (d, J = 1.6 Hz, 1H, 23’), 7.03 (dd, J = 8.0, 1.6 Hz, 1H, 23’), 6.93 (d, J =8.4
Hz, 1H, 23), 6.84 (s, 1H, 23), 6.80 (d, J = 8.0 Hz, 1H, 23’), 3.87–3.86 (m, 8H, 23+23’), 3.04 (t, J
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= 4.4 Hz, 4H, 23’), 3.02 (t, J = 4.8 Hz, 4H, 23); C NMR (100 MHz, CDCl3): δ 148.6, 146.5,
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137.6, 131.1, 128.2, 124.6, 121.0, 120.0, 67.2, 51.8, 51.7, 21.1, 20.4; FTIR (thin film), cm-1
2852, 1496, 1135, 1115, 1039; HRMS-ESI (m/z) Calcd for (C11H15ClNO) ([M+H]+): 212.0837;
found: 212.0836.
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4-(3-Bromo-2-chloro-5-methylphenyl)morpholine (24). Isolated by flash column
chromatography (10% ethyl acetate−hexanes). The title compound was obtained as a white solid
1
(34.5 mg, 59%) from the CsF promoted conditions. Rƒ = 0.35 (20% ethyl acetate–hexanes); H
NMR (400 MHz, CDCl3): δ 7.18 (d, J = 1.2 Hz, 1H), 6.78 (d, J = 1.2 Hz, 1H), 3.87 (t, J = 4.6
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Hz, 4H), 3.02 (t, J = 4.6 Hz, 4H), 2.29 (s, 3H); C NMR (125 MHz, CDCl3): δ 150.4, 138.2,
128.6, 126.2, 123.9, 120.1, 67.1, 51.8, 20.9; FTIR (thin film), cm-1 2852, 1441, 1250, 1113, 883;
HRMS-ESI (m/z) Calcd for (C11H14BrClNO) ([M+H]+): 289.9942; found: 289.9937.
4-(2-Chloro-4,5-difluorophenyl)morpholine (25). Isolation by flash column chromatography
(10% ethyl acetate−hexanes). The title compound was obtained as a pale yellow solid (25.0 mg,
54%) from the CsF promoted conditions and as a white solid (11.7 mg, 25%) from the one-pot
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TBAF conditions. Rƒ = 0.54 (20% ethyl acetate–hexanes); H NMR (400 MHz, CDCl3): δ 7.22
(dd, J = 9.8, 8.0 Hz, 1H), 7.87 (dd, J = 11.8, 8.0 Hz, 1H), 3.86 (t, J = 4.4 Hz, 4H), 3.98 (t, J = 4.4
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Hz, 4H); C NMR (125 MHz, CDCl3): δ 149.2 (dd, JC-F = 250, 12.5 Hz), 145.9 (dd, J = 250,
12.5 Hz), 145.8, 123.4 (d, J = 12.5 Hz), 119.2 (d, J = 12.5 Hz), 109.3 (d, J = 12.5 Hz), 66.9,
51.7; FTIR (thin film), cm-1 2856, 1494, 1200, 1165, 1115, 799; HRMS-ESI (m/z) Calcd for
(C10H11ClF2NO) ([M+H]+): 234.0492; found: 234.0491.
4-(2-Bromo-4,5-difluorophenyl)morpholine (26). Isolated by flash column chromatography
(5% ethyl acetate−hexanes). The title compound was obtained as a white solid (21.1 mg, 37%)
from the CsF promoted conditions and as a white solid (15.3 mg, 27%) from the one-pot TBAF
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conditions. Rƒ = 0.54 (20% ethyl acetate–hexanes); 1H NMR (400 MHz, CDCl3): δ 7.44 (dd, J =
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9.6, 8.4 Hz, 1H), 6.89 (dd, J = 11.8, 7.4 Hz, 1H), 3.87 (t, J = 4.4 Hz, 4H), 2.97 (t, J = 4.4 Hz,
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4H); C NMR (125 MHz, CDCl3): δ 149.7 (dd, JC-F = 250, 12.5 Hz), 147.2, 146.2 (dd, JC-F
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250, 12.5 Hz), 122.1 (d, JC-F =12.5 Hz), 113.1, 109.8 (d, JC-F = 12.5 Hz), 67.0, 52.1; FTIR (thin
film), cm-1 2855, 1493, 1199, 1115, 896; HRMS-ESI (m/z) Calcd for (C10H11BrF2NO)
([M+H]+): 277.9987; found: 277.9992.
4-(2-Chloro-3,5-dimethoxyphenyl)morpholine (27). Isolation by flash column chromatography
(10% ethyl acetate−hexanes). The title compound was obtained as a white solid (17.4 mg, 34%)
from the CsF promoted conditions and as a white solid (21.2 mg, 41%) from the one-pot TBAF
conditions. Rƒ = 0.32 (20% ethyl acetate–hexanes); 1H NMR (400 MHz, CDCl3): δ 6.28 (d, J =
2.6 Hz, 1H), 6.25 (d, J = 2.6 Hz, 1H), 3.88–3.86 (m, 7H), 3.81 (s, 3H), 4.04 (t, J = 4.4 Hz, 4H);
13C NMR (100 MHz, CDCl3): δ 159.2, 156.7, 150.8, 108.7, 98.1, 94.1, 67.1, 56.2, 55.4, 51.7;
FTIR (thin film), cm-1 2957, 1455, 1202, 1113, 1043; HRMS-ESI (m/z) Calcd for
(C12H17ClNO3) ([M+H]+): 258.0899; found: 258.0886.
4-(4-Chloro-1-methyl-1H-indol-5-yl)morpholine (28) and 4-(5-chloro-1-methyl-1H-indol-4-
yl)morpholine (28’). Isolation by flash column chromatography (5% ethyl acetate−hexanes).
The title compound was obtained as a white solid (25.3 mg, 25%, an 8:1 mixture) from the CsF
promoted conditions and as a white solid (19.6 mg, 39%) from the one-pot TBAF conditions. Rƒ
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= 0.36 (20% ethyl acetate–hexanes); H NMR (400 MHz, CDCl3): δ 7.20 (dd, J = 8.8, 0.4 Hz,
1H, 28), 7.15 (d, J = 7.6 Hz, 1H, 28’), 7.07 (d, J = 2.8 Hz, 1H, 28), 7.05 (d, J = 8.8 Hz, 1H, 28),
7.01 (d, J = 3.2 Hz, 1H, 28’), 6.60 (d, J = 7.6 Hz, 1H, 28’), 6.56 (dd, J = 2.8, 0.4 Hz, 1H, 28),
6.46 (dd, J = 3.2, 0.4 Hz, 1H, 28’, 3.95 (t, J = 4.8 Hz, 4H, 28’), 3.92 (t, J = 4.6 Hz, 4H, 28), 3.78
(s, 3H, 28’), 3.77 (s, 3H, 28), 3.24 (t, J = 4.8 Hz, 4H, 28’, 3.06 (t, J = 4.6 Hz, 4H, 28); 13C NMR
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(100 MHz, CDCl3): δ 141.3 (2C), 134.2 (2C), 129.9, 128.6, 127.3, 122.2, 120.5 (2C), 114.9,
108.0 (2C), 106.1, 104.3, 99.8, 67.5 (2C), 52.6 (2C), 51.9 (2C), 33.1 (2C); FTIR (thin film), cm-1
2852, 1478, 1253, 1252, 1114; HRMS-ESI (m/z) Calcd for (C13H16ClN2O) ([M+H]+): 251.0946;
found: 251.0946.
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4-(3-Bromo-2-chloro-5-methylphenyl)piperazine-1-tert-butyl-carboxylate (29). Isolation by
flash column chromatography (5% ethyl acetate−hexanes) followed by kugelrohr distillation.
The title compound was obtained as a waxy white solid (66.5 mg, 34%) from the CsF promoted
conditions and as a colorless oil (33.9 mg, 21%) from the isolated N-chloramine protocol. Rƒ =
0.60 (20% ethyl acetate–hexanes); 1H NMR (400 MHz, CDCl3): δ 7.17 (s, 1H), 6.75 (s, 1H), 3.58
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(t, J = 4.4 Hz, 4H), 2.95 (t, J = 4.4 Hz, 4H), C NMR (100 MHz, CDCl3, one carbon did not
resolve): δ 154.7, 150.4, 138.1, 128.6, 126.2, 123.7, 120.3, 79.7, 51.3, 28.4, 20.8; FTIR (thin
film), cm-1 2974, 1686, 1478, 1418, 1233, 1121; HRMS-ESI (m/z) Calcd for (C16H23BrClN2O2)
([M+H]+): 389.0626; found: 389.0626.
4-(4-Chloro-1-methyl-1H-indol-5-yl)piperazine-1-tert-butyl-carboxylate (30). Isolation by
flash column chromatography (5% ethyl acetate−hexanes) followed by recrystallization from hot
hexanes. The title compound was obtained as a yellow solid (87.2 mg, 20%) from the isolated N-
chloramine protocol. Rƒ = 0.63 (50% ethyl acetate–hexanes); 1H NMR (400 MHz, CDCl3): δ 7.18
(d, J = 8.8 Hz, 1H), 7.06 (d, J = 3.2 Hz, 1H), 7.01 (d J = 8.8 Hz, 1H), 6.56 (d, J = 3.2 Hz, 1H),
3.77 (s, 3H), 3.63 (t, J = 4.4 Hz, 4H), 2.99 (t, J = 4.4 Hz, 4H). 1.50 (s, 9H); 13C NMR (125 MHz,
CDCl3, 60 ˚C): δ 154.9, 141.4, 134.4, 129.8, 128.6, 120.7, 115.2, 107.9, 99.9, 79.4, 52.2, 44.4,
32.8, 28.5; FTIR (thin film), cm-1 2974, 1686, 1478, 1418, 1233, 1121; HRMS-ESI (m/z) Calcd
for (C18H25ClN3O2) ([M+H]+): 350.1630; found: 350.1631.
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Synthesis of Aryne Precursors
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Known aryne precursors were synthesized as previously described.16
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3-(Allyloxy)-2-(trimethylsilyl)phenyl trifluoromethanesulfonate (31). To a vigorously stirring
solution of 1-allyloxy-2-bromoresorcinol17 (1.14 g, 5.00 mmol, 1.0 equiv) in THF (10 mL), was
added dropwise HMDS (0.806 g, 5.00 mmol, 1.0 equiv) under nitrogen. The reaction mixture
was heated to reflux for 4 h until gas evolution had fully ceased. Upon cooling down to room
temperature, the reaction mixture was concentrated to remove remaining HMDS and ammonia.
Without further purification, the crude material was dissolved in THF (35 mL), cooled down to
−94 °C, and added dropwise n-BuLi (2.2 mL, 2.5 M, 5.50 mmol, 1.1 equiv) over 10 minutes at
−94 °C. The reaction was allowed to slowly warm to −78 °C over 40 minutes, cooled back down
to −94 °C and next added dropwise Tf2O (1.69 g, 6.00 mmol, 1.2 equiv) over 10 minutes. Upon
the complete addition, the reaction was again allowed to warm to −78 °C over 40 minutes. Then
the reaction mixture was quenched with the slow addition of a mixture of saturated aqueous
solution of NaHCO3 and H2O (5 mL, 1:1) at −78 °C, and upon further warmed up to room
temperature, followed by another addition of saturated aqueous solution of NaHCO3 and H2O (20
mL, 1:1) and Et2O (70 mL). The aqueous layer was extracted with Et2O (50 mL × 3). The
combined organic layers were dried over MgSO4, and filtered. The filtrate was concentrated. The
resulting residue was purified by flash column chromatography (10% dichloromethane−hexanes)
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to yield 31 as a clear oil (1.10 g, 62% yield). Rf = 0.58 (5% ethyl acetate–hexanes); H NMR
(500 MHz, CDCl3): δ 7.34 (t, J = 8.0 Hz, 1H), 6.94 (d, J = 8.0 Hz, 1H), 6.81 (d, J = 8.0 Hz, 1H),
6.04 (ddt, J = 17.5, 10.5, 5.5 Hz, 1H), 5.41 (ddd, J = 17.5, 3.0, 1.5 Hz, 1H), 5.31 (ddd, J = 10.5,
3.0, 1.0 Hz, 1H), 4.56 (ddd, J = 5.5, 1.5, 1.0 Hz, 2H), 0.38 (s, 9H); 13C NMR (125 MHz, CDCl3):
δ 164.5, 154.7, 132.5, 131.6, 121.0, 118.8 (q, JC−F = 318 Hz), 118.1, 112.9, 110.5, 69.5, 0.8;
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