Synthesis of 1,1′-diarylethanes and related systems by displacement of trichloroacetimidates with trimethylaluminum

Article abstract of DOI:10.1021/acs.joc.8b00027

Benzylic trichloroacetimidates are readily displaced by trimethylaluminum under Lewis acid promoted conditions to provide the corresponding methyl substitution product. This method is a convenient way to access 1,1′-diarylethanes and related systems, which play a significant role in medicinal chemistry, with a number of systems owing their biological activity to this functionality. Most benzylic substrates undergo ready displacement, with electron deficient systems being the exception. The use of an enantiopure imidate showed significant racemization, implicating the formation of a cationic intermediate.

Full text of DOI:10.1021/acs.joc.8b00027

Subscriber access provided by MT ROYAL COLLEGE
Note
Synthesis of 1,1'-Diarylethanes and Related Systems by
Displacement of Trichloroacetimidates with Trimethylaluminum
Nivedita S. Mahajani, and John Daniel Chisholm
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00027 • Publication Date (Web): 24 Feb 2018
Downloaded from http://pubs.acs.org on February 25, 2018
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a service to the research community to expedite the dissemination
of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in
full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully
peer reviewed, but should not be considered the official version of record. They are citable by the
Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore,
the “Just Accepted” Web site may not include all articles that will be published in the journal. After
a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web
site and published as an ASAP article. Note that technical editing may introduce minor changes
to the manuscript text and/or graphics which could affect content, and all legal disclaimers and
ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or
consequences arising from the use of information contained in these “Just Accepted” manuscripts.
The Journal of Organic Chemistry is published by the American Chemical Society.
1155 Sixteenth Street N.W., Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 36
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Synthesis of 1,1’ꢀDiarylethanes and Related Systems
by Displacement of Trichloroacetimidates with
Trimethylaluminum.
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
Nivedita S. Mahajani and John D. Chisholm*
Department of Chemistry, Syracuse University, 1ꢀ014 Center for Science and Technology,
Syracuse, NY 13244
jdchisho@syr.edu
RECEIVED DATE (to be automatically inserted after your manuscript is accepted if
required)
HN
AlMe3 (3 equiv)
AlCl3 (1 equiv)
49-92% yield
Ar
CCl3
Ar
R = Ar, Alkyl or H
O
Me
DCM, 0 °C - rt
R
R
Abstract
Benzylic trichloroacetimidates are readily displaced by trimethylaluminum under Lewis acid
promoted conditions to provide the corresponding methyl substitution product. This method is a
convenient way to access 1,1’ꢀdiarylethanes and related systems, which play a significant role in
medicinal chemistry, with a number of systems owing their biological activity to this
functionality. Most benzylic substrates undergo ready displacement, with electron deficient
1
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 36
1
2
3
4
5
6
systems being the exception. Use of an enantiopure imidate showed significant racemization,
implicating the formation of a cationic intermediate.
7
8
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
Trichloroacetimidates are often used to activate alcohols as leaving groups, commonly
being displaced by heteroatom nucleophiles like alcohols,1 carboxylic acids,2 thiols3 and amines.4
This chemistry is especially important in the synthesis of carbohydrates.5 Imidate displacement is
facilitated by rearrangement of the leaving group to trichloroacetamide, providing an additional
thermodynamic driving force to drive the displacement. The imidate structure also features a
basic nitrogen, which is readily activated by catalytic amounts of Brønsted or Lewis acids.
Trichloroacetimidates are easily formed from alcohols from the inexpensive trichloroacetonitrile,
and the imidates can be generated in situ,6 providing a method to use inexpensive and readily
available alcohols as alkylating agents under mild conditions.
While the use of imidates to form ethers, sulfides and substituted amines has become well
known, it is more rare to displace trichloroacetimidates with carbon nucleophiles. As
trichloroacetimidates are typically activated with Lewis acids, a carbon nucleophile must be
compatible with these conditions. Typically, these substitutions are limited to FriedelꢀCrafts type
processes with electron rich aromatic rings acting as nucleophiles,3h,7 although there have been
reports of silyl enol ethers, allylsilanes and allylstannanes being effective nucleophiles under
Lewis acid catalysis.6b,8 Currently there are no reports on the displacement of
trichloroacetimidates with stoichiometric amounts of alkylmetal reagents.
Recently investigations into increasing the scope of nucleophiles that may be used in the
displacement of trichloroacetimidates were undertaken. This project began as a new entry into
the synthesis of 1,1’ꢀdiarylethane systems, as 1,1’ꢀdiarylethanes are an important functionality in
2
ACS Paragon Plus Environment

Page 3 of 36
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
many biologically active molecules9 like those shown in Figure 1.10 Typically these systems are
accessed by hydrogenation of an alkene,11 displacement of a leaving group (like a halide,12
ammonium salt13 or ether14) or through FriedelꢀCrafts processes,15 however displacement of the
imidate may also provide access to these systems if a compatible alkylmetal nucleophile could be
invoked.
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
Me
Me Me
H
Me
N
N
N
HN
1
demiditraz (2)
(pesticide)
CO2Me
antitumor agent
Me
Me
OMe
OMe
MeO
S
F
NMe2
R
OMe
3 R = H, antiviral agent
5
4 R = OH, antitumor agent
anti-insomnia agent
Figure 1. Biologically Active 1,1’-Diarylethanes
A survey of the literature suggested that trimethylaluminum may be a good candidate for
this study as this reagent is readily available. Additionally, trimethylaluminum addition reactions
are tolerant of and accelerated by exogenous Lewis acids,16 which are also known to facilitate
trichloroacetimidate displacements. Trimethylaluminum has been used as a source of methyl
anion previously to displace halides,17 sulfonates,17b,18 and Meldrum’s acid derivatives.19 This
reagent has also been shown to open benzylic epoxides20 and benzylic sulfites,21 with the
addition of the new methyl group occurring preferentially at the benzylic position in these cyclic
systems. Yields in these displacements and ring openings tend to be highest when the leaving
group is tertiary or benzylic,17c,22 and most studies indicate that the trimethylaluminum is adding
to carbocations that are formed in situ. This mechanism is supported by the rearrangement of
some tertiary allylic chlorides during the addition reaction.23
Initially, the reaction of trimethylaluminum with diphenylmethyl trichloroacetimidate 6a
was studied (Table 1). Solvent effects were observed to be prevalent in the substitution, as only
3
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 36
1
2
3
4
5
6
7
8
9
DCM provided 1,1ꢀdiphenylethane 7a in appreciable yield at room temperature (entries 1ꢀ5).
More polar solvents like Et2O, THF and MeCN may coordinate to the trimethylaluminum and
lower reactivity, reducing conversion. Alternatively, the less polar toluene may disfavor
formation of the diphenylmethyl carbocation, which may be necessary for product formation.
Heating the reaction in toluene did provide some product, however no conversion was observed
in refluxing THF. In order to improve the yield, the use of Lewis acid promoters was explored.
Initially TMSOTf and BF3•OEt2 were evaluated, as these Lewis acids are commonly employed
with trichloroacetimidates.16a,16c,16d With TMSOTf, however, the major product was the
rearranged trichloroacetamide 8a, and this product was also a significant in the reaction with
BF3•OEt2. This product has recently been observed to occur when trichloroacetimidate 6a is
treated with a Lewis acid.24 A number of other Lewis acids were then screened for their ability to
facilitate the substitution reaction (entries 11ꢀ15) at the expense of the rearrangement. From these
results aluminum trichloride emerged as the most promising promoter, providing the desired
product 7a in a 91% yield (entry 11). Omission of the trimethylaluminum was also explored,
with mainly rearrangement of the imidate to the acetamide being observed under these
conditions (entry 16), as has been described previously.24
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
4
ACS Paragon Plus Environment

Page 5 of 36
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Table 1. Addition of Trimethylaluminum to Trichloroacetimidate 6a
HN
O
Ph
Ph
CCl3
Ph
Ph
Ph
Ph
CCl3
AlMe3
O
6a
Me
7a
NH
8a
solvent
entry
1
2
3
4
conditionsa
toluene, rt, 24h
DCM, rt, 4h
Et2O, rt, 24 h
THF, rt, 18 h
promoterb yield 7a yield 8a
0
68
0
0
13
0
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
0
5
6
7
MeCN, rt, 30 min
toluene, reflux, 22 h
DCM, reflux, 22h
0
60
13
25
0
23
27
0
8
THF, reflux, 22 h
9c
DCM, rt, 30 min TMSOTf
0
50
63d
8
10c
11c
12c
13c
14c
15c
16
DCM, rt, 30 min BF3•OEt2 37d
DCM, rt, 30 min
DCM, rt, 30 min
DCM, rt, 30 min
DCM, rt, 30 min
DCM, rt, 30 min Sc(OTf)3
DCM, rt, 30 min AlCl3
AlCl3
SnCl2
ZnF2
ZnI2
91
56d
68
68
45
0
44d
0
0
0
60e
aAlMe3 (1.5 equiv) was added at 0 °C and then the reaction was warmed to the reported temperature. One equiv
b
c
d
1
e
of the Lewis acid was added. 3 Equiv of AlMe3 was used. Ratio of products observed in the crude H NMR. No
AlMe3 was added.
The scope of the displacement with respect to trichloroacetimidate was then investigated
(Table 2). Initially diarylmethaneꢀtype trichloroacetimidates bearing different functionality on
the aromatic rings were evaluated. Alkyl, aryl and methoxy functionalized aromatic substrates all
provided the corresponding methylated products in good yield (entries 2ꢀ5). In the case of the
methoxy containing imidate 6e some rearrangement (28%) to the corresponding
trichloroacetamide was observed. In the other examples in Table 2 only trace amounts of the
rearranged product was observed, evidently this rearrangement is most competitive in highly
activated electron rich systems. The conditions were also compatible with aryl halides (entries 6ꢀ
8). Incorporation of stronger electron withdrawing groups on one of the aromatic rings was also
tolerated in the diarylmethyl imidate substitutions, with nitro and trifluoromethyl groups not
troubling the displacement (entries 9 and 10). These results are similar to FriedelꢀCrafts reactions
that have been reported with electronꢀpoor trichloroacetimidates, which also proceed in good
yield.25 Larger bicyclic aromatic systems like naphthalene and benzothiophene were
5
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 36
1
2
3
4
5
6
7
8
incorporated without issue (entries 11ꢀ14). The synthesis of the benzothiophene containing 1,1’ꢀ
diarylethane 7n is notable, as this compound is an intermediate in the synthesis of
benzothiophene 5, a compound designed to treat insomnia.26
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
Table 2. Addition of Trimethylaluminum to Trichloroacetimidates
HN
O
AlMe3 (3 equiv)
AlCl3 (1 equiv)
R1
R2
R1
R2
R1
R2
CCl3
CCl3
O
6
Me
7
NH
8
DCM, 0 °C - rt
entry
1
2
3
4
5
6
7
8
R1
Ph
4ꢀMePh
2ꢀMePh
4ꢀ(Ph)Ph
4ꢀOMePh
3ꢀClPh
4ꢀBrPh
3ꢀFPh
4ꢀNO2Ph
3,5ꢀCF3Ph
2ꢀnaphthyl
1ꢀnaphthyl
R2
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Yield
91 (7a)
65 (7b)
70 (7c)
91 (7d)
64a (7e)
92 (7f)
86 (7g)
87 (7h)
66 (7i)
95 (7j)
57 (7k)
57 (7l)
57 (7m)
9
10
11
12
13 3ꢀbenzothienyl Ph
14 3ꢀbenzothienyl 4ꢀFPh 71 (7n)
15
16
17
18
4ꢀ(Ph)Ph
4ꢀ(Ph)Ph
4ꢀ(Ph)Ph
2ꢀnaphthyl
Me
87 (7o)
nꢀBu 97 (7p)
iꢀPr 90b (7q)
Et
Et
H
H
H
H
H
H
H
H
60 (7r)
62 (7s)
19 3ꢀbenzothienyl
20
21
22
23
24
3,4ꢀOMePh
4ꢀOMePh
4ꢀ(Ph)Ph
1ꢀnaphthyl
2ꢀnaphthyl
92c,d (7t)
52c,e (7u)
81c,f (7v)
60c,f (7w)
49c,g (7x)
62c,h (7y)
0 (7z)
25 3ꢀbenzothienyl
26
27
4ꢀNO2Ph
Ph2CH
0 (7aa)
aSome rearrangement product 8e (28%) was also isolated. bReaction started at ꢀ20 °C and allowed to warm to rt. cNo
d
e
aluminium trichloride was added. Reaction performed for 15 min at 0 °C. Reaction performed for 15 min at ꢀ20
°C. Reaction performed for 4 h at 0 °C. Reaction started at ꢀ10 °C and allowed to warm to 5 °C. Reaction
performed for 30 min at ꢀ20 °C.
f
g
h
With the success of diarylmethyl trichloroacetimidates in the methylation reaction,
attention was focused on less activated substrates. Additionally, the diarylmethanes cannot
undergo competing elimination reactions, so some systems that could be susceptible to
elimination were evaluated (Table 2, entries 15ꢀ19). Most of these substrates performed well,
including the hindered substrate 6q. Substitution with imidate 6q had to be started at a lower
6
ACS Paragon Plus Environment

Page 7 of 36
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
temperature, as when the reaction was started at 0 °C the alkene derived from elimination of the
imidate was the major product. Primary benzylic trichloroacetimidates (Table 2, entries 20ꢀ26)
were more reactive and did not require the addition of aluminum trichloride to provide the ethylꢀ
substituted aromatics in useful yields. In addition, many of the primary imidate substitutions
were initiated at low temperatures to avoid decomposition and/or elimination. In the case of 4ꢀ
nitrobenzyl trichloroacetimidate no reaction occurred, with only starting material being
recovered. Attempts to force substitution of imidate 6z by heating the reaction in DCE at reflux
also gave no reaction. The aliphatic imidate 6aa was also unreactive and only returned starting
material, highlighting the requirement for benzylic activation of the imidate.
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
Tertiary benzylic trichloroacetimidates and allylic trichloroacetimidates were also
evaluated as substrates (Scheme 1). Displacement of the tertiary benzylic trichloroacetimidate 9
(prepared from the known alcohol27) may provide an expeditious route to analogs of
physostigmine.28 Attempts to convert imidate 9 to the desired methyl compound were
unsuccessful, as only the corresponding chloride 10 was obtained. Although chloride
displacement of trichloroacetimidates is known with HCl,29 the formation of chloride 10 was
unexpected as trimethylaluminum typically is a better nucleophile than the chloride ion.
Attempts to achieve methyl substitution using other Lewis acid promoters with less nucleophilic
counterions (TMSOTf, Zn(OTf)2) provided starting material at room temperature or below.
Alternatively, heating chloride 10 with two equiv of trimethylaluminum in refluxing DCE only
returned starting material, and no methylation product was detected. While the displacement of
tertiary chlorides with trimethylaluminum has been reported, the reactions are slower in the
presence of Lewis basic functional groups like amides.17c This result was rationalized by
complexation of the trimethylaluminum to the carbamate leading to a slower substitution
7
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 36
1
2
3
4
5
6
7
8
9
reaction. In the more complex system 9 when the trimethylaluminum is complexed with the
carbamate, ester and sulfonamide, displacement by the methyl group may be decelerated leading
to the formation of chloride 10. The formation of chloride 10 also suggests that the
corresponding chlorides may be intermediates in the methyl displacement reaction. To
investigate this possibility, chlorodiphenylmethane was treated with trimethylaluminum (DCM
room temp, 0 °C – rt) which resulted in the formation of 1,1’ꢀdiphenylethane 7a in 65% yield,
supporting the possibility that if the chloride was formed it would be rapidly displaced by
trimethylaluminum. Attempts to isolate chlorodiphenylmethane by treating imidate 6a with
AlCl3 in DCM gave predominantly the rearrangement product, acetamide 8a (60% yield, Table
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
1
1, entry 16). Only trace amounts of chlorodiphenylmethane in the crude H NMR. We are
therefore unable to unambiguously assess whether the corresponding chloride is an intermediate
in the transformation, and it is also unclear why chloride displacement is favored over imidate
rearrangement or elimination for imidate 9.
Scheme 1. Attempted Methylation of 9 and Methylation of 11
HN
CCl3
AlMe3 (3 equiv)
AlCl3 (1 equiv)
CO2Me
CO2Me
O
Cl
NCO2Me
DCM, 0 °C - rt
NCO2Me
H
H
N
N
9
10 80%
SO2Ph
SO2Ph
Me
1) Cl3CCN, DBU
DCM
HO
NSO2Ph
NSO2Ph
12
63%
(2 steps)
NSO2Ph
13
not observed
2) AlMe3 (3 equiv)
AlCl3 (1 equiv)
DCM, 0°C
11
Evaluation of the imidate of allylic alcohol 11 was stymied by the instability of the
trichloroacetimidate, which readily decomposed. Adopting the procedure of Dalla and coꢀ
workers,6b where the imidate was formed and used without purification in the alkylation reaction,
gave alkene 12 as the sole product of the reaction in 63% yield over two steps. Interestingly,
none of the direct substitution product 13 was detected in the crude 1H NMR.
8
ACS Paragon Plus Environment

Page 9 of 36
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
As shown in Table 2, imidates that are precursors to relatively stable carbocations tend to
provide higher yields in the substitution reaction. This is consistent with the reaction proceeding
through an SN1ꢀtype pathway, where the imidate ionizes and the resulting cation is trapped by
the trimethylaluminum. Additionally, the formation of the more hindered allylic substitution
product 12 (Scheme 1) indicates that sterics is not a controlling factor in the substitution reaction,
which is also consistent with an SN1 pathway. To further test this hypothesis the enantioenriched
imidate (S)ꢀ15 was prepared from the known aminoalcohol30 and subjected to the reaction
conditions, providing the product 16 in 49% yield (Scheme 2). Analysis of the reaction product
by chiral HPLC showed a racemic mixture, providing further support for an SN1ꢀtype mechanism
being operative.
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
Scheme 2. Substitution Using a Chiral Trichloroacetimidate
CCl3
HN
O
OH
Cl3CCN (1.5 equiv)
DBU (20 mol %)
CH3
CH3
N
N
DCM, 0°C
S
SO2Ph
S
SO2Ph
15
>96:4 S:R
14
AlMe3 (3 equiv)
AlCl3 (1 equiv)
CH3
CH3
N
DCM, 0°C
S
SO2Ph
16 49%
50:50 S:R
The use of triethylaluminum as the nucleophile in the imidate substitution was also
briefly evaluated. In contrast to trimethylaluminum (Table 1, entry 2), treatment of imidate 6a
with triethylaluminum provided the rearranged acetamide 7a (60%) as the major product of the
reaction (Scheme 3). While a trace amount of the ethyl addition product 17 was observed, it was
contaminated with the reduction product diphenylmethane 18, which was difficult to separate.
This product may arise from βꢀhydride delivery, as has been observed in the reaction of
triethylaluminum with benzylic halides.17a Triethylaluminum has also been previously reported
to reductively open epoxides31 and reduce activated alcohols to alkanes32 through a similar
9
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 36
1
2
3
4
5
6
7
8
mechanism. Given the predominant rearrangement product, the added complexity of the
competitive reduction, and the difficulty in separating the ethyl addition and reduction products,
the use of triethylaluminum was not explored further.
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
Scheme 3. Use of Triethylaluminum in the Substitution
NH
NHCOCCl3
AlEt3
O
CCl3
+
+
DCM, rt
Ph
Ph
Ph
Ph
Ph
Ph
6a
Ph
8a
60%
17
trace
18
trace
Ph
The Lewis acid promoted addition of trimethylaluminum to trichloroacetimidates
provides a useful method for the transformation of alcohols to the corresponding methyl analogs.
This work represents the first conditions for the displacement of trichloroacetimidates with an
alkylmetal reagent. The transformation most likely proceeds through cationic intermediates, and
therefore performs best in benzylic or allylic systems. Increasing steric demands around the site
of rearrangement was detrimental to the yield of the transformation. This reaction is especially
useful in the synthesis of 1,1’ꢀdiarylethanes and related systems, which are important
functionality in drug discovery. The reactivity of trichloroacetimidates with other organometallic
reagents (specifically organozinc and organocopper reagents) is now being explored, and the
results of these studies will be reported in due course.
Experimental Section
General Procedure for Trichloroacetimidate Synthesis. A flame dried flask was charged with
the alcohol starting material (1 equiv) under argon. Dry DCM was then added to form a 0.5 M
solution, and the flask was cooled to 0 °C. 1,8ꢀDiazabicyclo[5.4.0]undecꢀ7ꢀene (0.2 equiv) was
then added to the solution, followed by trichloroacetonitrile (1.5 equiv). The reaction mixture
was monitored by TLC until no more alcohol starting material was detected. The reaction
10
ACS Paragon Plus Environment

Page 11 of 36
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
mixture was then concentrated in vacuo, and the residue was purified by silica gel column
chromatography using the listed solvent system to provide the desired trichloroacetimidates.
Imidates 6b, 6c, 6d, 6e, 6f, 6g, 6h, 6j, 6l, 6m, 6n, 6o, 6p, 6q, 6r, 6s, 6t, 6w, 6x, 6y, 6z, 6aa, 9
and 15 were synthesized from the corresponding alcohols using the general procedure. Imidates
6a,1c 6i,24 6k,33 6u,34 and 6v,35 were synthesized according to literature protocols.
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
(4‐Methylphenyl)(phenyl)methyl 2,2,2‐trichloroacetimidate (6b). Purified by silica gel
chromatography (10% ethyl acetate/ 1% triethylamine/ 89% hexanes). Viscous oil (1.17 g, 87%).
IR (DCM) 3340, 1662, 1286, 1066, 998 cmꢀ1; 1H NMR (400 MHz, CDCl3) δ 8.39 (s, 1H), 7.43ꢀ
7.41 (m, 2H), 7.36ꢀ 7.25 (m, 5H), 7.15 (d, J = 7.9 Hz, 2H), 6.91 (s,1H), 2.32 (s, 3H); 13C{1H}
NMR (100 MHz CDCl3) δ 161.3, 139.9, 137.8, 136.8, 129.2, 128.4, 127.9, 127.0, 126.8, 91.6,
81.3, 21.6. Anal. calcd for C16H14Cl3NO: C, 56.09; H, 4.12; N, 4.09. Found: C, 56.32; H, 3.84;
N, 4.44.
(2‐Methylphenyl)(phenyl)methyl 2,2,2‐trichloroacetimidate (6c). Purified by silica gel
chromatography (5% ethyl acetate/ 1% triethylamine/ 94% hexanes); Clear oil (2.38 g, 92%);
TLC Rf = 0.59 (10% ethyl acetate/90% hexanes); IR (DCM) 3339, 3053, 3032, 2983, 1664,
1
1286, 1265, 1075, 913, 741 cm–1; H NMR (400 MHz, CDCl3) δ 8.39 (brs, 1H), 7.46ꢀ7.43 (m,
13
1H), 7.38ꢀ7.28 (m, 5H), 7.24ꢀ7.16 (m, 3H), 7.12 (s, 1H), 2.37 (s, 3H); C{1H} NMR (100 MHz,
CDCl3) δ 161.3, 138.9, 137.5, 136.2, 130.5, 128.4, 128.1, 128.0, 127.3, 127.2, 126.1, 91.6, 79.0,
19.4. Anal. calcd for C16H14Cl3NO: C, 56.09; H, 4.12; N, 4.09. Found: C, 56.00; H, 3.96; N,
4.44.
[1,1'‐Biphenyl]‐4‐yl](phenyl)methyl 2,2,2-trichloroacetimidate (6d). Purified by silica gel
chromatography (1% triethylamine/ 99% hexanes); White solid (0.35 g, 75%); IR (DCM) 3339,
3052, 1664, 1493, 1265, 1075, 984, 798, 739, 703 cm–1; 1H NMR (300 MHz, CDCl3) δ 8.42 (brs,
11
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 36
1
2
3
4
13
1H), 7.58ꢀ7.29 (m, 14H), 6.97 (s, 1H). C{1H} NMR (100 MHz, CDCl3) δ 161.4, 141.0, 140.7,
5
6
7
8
139.8, 138.8, 128.9, 128.6, 128.2, 127.5, 127.4, 127.2, 127.0, 91.7, 81.3 (one aromatic resonance
was unresolved). Anal. calcd for C21H16Cl3NO: C, 62.32; H, 3.99; N, 3.46. Found: C, 62.50; H,
3.98; N, 3.59.
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
(4‐Methoxyphenyl)(phenyl)methyl 2,2,2‐trichloroacetimidate (6e). Purified by silica gel
chromatography (1% ethyl acetate/ 1% triethylamine/ 98% hexanes); Yellow viscous oil (1.32 g,
1
92%); IR (DCM) 3335, 1663, 1609, 1512, 1268, 1054, 915, 739 cm–1; H NMR (400 MHz,
13
CDCl3) δ 8.38 (s, 1H), 7.42ꢀ7.25 (m, 7H), 6.90ꢀ6.86 (m, 3H), 3.79 (s, 3H); C{1H} NMR (100
MHz, CDCl3) δ 161.4, 159.4, 140.0, 131.9, 128.6, 128.5, 127.9, 126.8, 113.9, 91.7, 81.2, 55.3.
Anal. calcd for C16H14Cl3NO2: C, 53.58; H, 3.93; N, 3.91. Found: C, 53.83; H, 3.67; N, 4.15.
(3-Chlorophenyl)(phenyl)methyl 2,2,2‐trichloroacetimidate (6f). Purified by silica gel
chromatography (5% ethyl acetate/ 1% triethylamine/ 94% hexanes); Viscous oil (1.23 g, 78%);
TLC Rf = 0.65 (10% ethyl acetate/90% hexanes); IR (DCM) 3341, 1664, 1354, 1266, 1007, 791,
720, 701 cm–1; 1H NMR (400 MHz, CDCl3) δ 8.44 (brs, 1H), 7.41 (d, J = 8.9 Hz, 3H), 7.37ꢀ7.21
(m, 6H), 6.90 (s, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 161.2, 141.9, 139.1, 134.5, 129.9,
128.7, 128.4, 128.3, 127.1, 127.0, 125.1, 91.4, 80.6. Anal. Calcd for C15H11Cl4NO: C, 49.62; H,
3.05; N, 3.86. Found: C, 49.85; H, 3.25; N, 4.00.
(4‐Bromophenyl)(phenyl)methyl 2,2,2‐trichloroacetimidate (6g). Purified by silica gel
chromatography (5% ethyl acetate/ 1% triethylamine/ 94% hexanes); White solid (2.08 g, 90%);
TLC Rf = 0.59 (10% ethyl acetate/90% hexanes); IR (DCM) 3054, 2986, 2305, 1667, 1487,
1
1421, 1265, 705 cm–1; H NMR (400 MHz, CDCl3) δ 8.43 (brs, 1H), 7.48 (d, J = 8.5 Hz, 2H),
7.34ꢀ7.29 (m, 7H), 6.89 (s, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 161.2, 139.2, 138.8, 131.7,
128.7, 128.6, 128.3, 126.9, 122.1, 91.4, 80.7. Anal. Calcd for C15H11BrCl3NO: C, 44.21; H, 2.72;
12
ACS Paragon Plus Environment

Page 13 of 36
The Journal of Organic Chemistry
1
2
3
4
N, 3.44. Found: C, 44.18; H, 2.98; N, 3.76.
5
6
7
8
(3-Fluorophenyl)(phenyl)methyl 2,2,2‐trichloroacetimidate (6h). Purified by silica gel
chromatography (5% ethyl acetate/ 1% triethylamine/ 94% hexanes); Clear oil (0.97 g, 56%);
TLC Rf = 0.61 (10% ethyl acetate/90% hexanes); IR (DCM) 3054, 1666, 1076, 999, 797, 735
cm–1; 1H NMR (400 MHz, CDCl3) δ 8.44 (brs, 1H), 7.43ꢀ7.41 (m, 2H), 7.38ꢀ7.28 (m, 4H), 7.21ꢀ
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
13
7.13 (m, 2H), 7.00ꢀ6.95 (m, 1H), 6.92 (s, 1H); C{1H} NMR (100 MHz, CDCl3) 162.8 (d, J =
245.1 Hz), 161.2, 142.3, 142.3, 139.1, 130.1, 130.0, 128.6, 128.3, 127.0, 122.5, 114.9 (d, J =
21.0 Hz), 113.9 (d, J = 22.2 Hz), 91.4, 80.6. Anal. Calcd for C15H11Cl3FNO: C, 51.98; H, 3.20;
N, 4.04. Found: C, 52.06; H, 3.02; N, 4.06.
[3,5‐Bis(trifluoromethyl)phenyl](phenyl)methyl 2,2,2-trichloroacetimidate (6j). Purified by silica
gel chromatography (10% ethyl acetate/ 1% triethylamine/ 89% hexanes); Offꢀwhite solid (1.25
g, 89%); TLC Rf = 0.52 (10% ethyl acetate/90% hexanes); IR (DCM) 3342, 1668, 1625, 1379,
963, 798 cmꢀ1; 1H NMR (400 MHz, CDCl3) δ 8.52 (s, 1H), 7.89 (s, 2H), 7.82 (1H), 7.42ꢀ7.36 (m,
5H), 7.03 (s, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 160.9, 142.5, 137.9, 132.0 (q, J = 45.0
Hz), 129.0, 128.9, 123.2 (q, J = 361.7 Hz), 122.1 (hept, J = 4.9 Hz), 91.1, 79.0 (two aromatic
resonances did not resolve). Anal. Calcd for C17H10Cl3F6NO: C, 43.95; H, 2.17; N, 3.01. Found:
C, 43.83; H, 2.07; N, 3.14.
(Naphthalen‐1‐yl)(phenyl)methyl 2,2,2-trichloroacetimidate (6l). Purified by silica gel
chromatography (1% triethylamine/ 99% hexanes); Clear oil (1.84 g, 70%); TLC Rf = 0.61 (10%
1
ethyl acetate/90% hexanes); IR (DCM) 3055, 1665, 1265, 1074, 981, 735 cm–1; H NMR (300
MHz, CDCl3) δ 8.47 (brs, 1H), 8.08ꢀ8.05 (m, 1H), 7.88ꢀ7.83 (m, 1H), 7.70 (s, 1H), 7.61 (d, J =
7.0 Hz, 1H), 7.49ꢀ7.44 (m, 5H), 7.37ꢀ7.29 (m, 3H ), 7.23 (s, 1H); 13C{1H} NMR (100 MHz,
CDCl3) δ 161.5, 139.1, 134.8, 133.9, 130.9, 129.1, 128.8, 128.5, 128.1, 127.3, 126.4, 126.0,
13
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 36
1
2
3
4
5
6
125.8, 125.2, 124.0, 91.6, 79.2. Anal. Calcd for C19H14Cl3NO: C, 60.26; H, 3.73; N, 3.70. Found:
C, 60.20; H, 3.85; N, 3.92.
7
8
9
(1-Benzothiophen-3-yl)(phenyl)methyl 2,2,2-trichloroacetimidate (6m). Purified by silica gel
chromatography (5% ethyl acetate/ 1% triethylamine/ 94% hexanes); Viscous oil (0.34 g, 61%);
IR (DCM) 3335, 1664, 1264, 702, 563, 484 cm–1; 1H NMR (400 MHz, CDCl3) δ 8.49 (brs, 1H),
7.86ꢀ7.84 (m, 1H), 7.78ꢀ7.75 (m, 1H), 7.52 (d, J = 7.0 Hz, 1H), 7.40ꢀ7.32 (m, 7H), 7.25 (s, 1H);
13C{1H} NMR (100 MHz, CDCl3) δ 161.4, 140.7, 138.2, 137.3, 134.5, 128.6, 128.5, 127.3,
125.9, 124.7, 124.3, 122.9, 122.7, 91.6, 77.2. Anal. Calcd for C17H12Cl3NOS: C, 53.08; H, 3.14;
N, 3.64. Found: C, 53.29; H, 2.92; N, 4.01.
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
(1‐Benzothiophen‐3‐yl)(4‐fluorophenyl)methyl 2,2,2-trichloroacetimidate (6n). Purified by silica
gel chromatography (5% ethyl acetate/ 1% triethylamine/ 94% hexanes); Clear oil (0.90 g, 71%);
TLC Rf = 0.76 (10% ethyl acetate/90% hexanes); IR (DCM) 3338, 3052, 1665, 1606, 1510,
1265, 1071 cmꢀ1; 1H NMR (300 MHz, CDCl3) δ 8.50 (brs, 1H), 7.87ꢀ7.83 (m, 1H), 7.72ꢀ7.68 (m,
1H), 7.52ꢀ7.47 (m, 2H), 7.37 (d, J = 0.9 Hz, 1H), 7.35ꢀ7.31 (m, 3H), 7.06 (tt, J = 9.8, 2.9 Hz,
13
2H); C{1H} NMR (100 MHz, CDCl3) δ 162.7 (d, J = 246.3 Hz), 161.3, 140.7, 137.1, 134.2,
134.0, 129.3 (d, J = 6.7 Hz), 125.7, 124.7, 124.3, 122.9, 122.6, 115.6 (d, J = 29.0 Hz), 91.5, 77.4.
Anal. Calcd for C17H11Cl3FNOS: C, 50.71; H, 2.75; N, 3.48. Found: C, 50.77; H, 2.70; N, 3.53.
1‐(1,1'‐Biphenyl]‐4‐yl)ethyl 2,2,2-trichloroacetimidate (6o). Purified by silica gel
chromatography (5% ethyl acetate/ 1% triethylamine/ 94% hexanes); Off white solid (1.06 g,
81%); IR (DCM) 3333, 1661, 1661, 798, 765, 702, 650 cm–1; 1H NMR (400 MHz, CDCl3) δ 8.33
(brs, 1H), 7.60ꢀ7.57 (m, 4H), 7.49 (d, J = 8.2 Hz, 2H), 7.43 (t, J = 7.3 Hz, 2H), 7.36ꢀ7.32 (m,
1H), 6.03 (q, J = 6.5 Hz, 1H), 1.69 (d, J = 6.6 Hz, 3H); 13C{1H} NMR (75 MHz, CDCl3) δ 161.7,
140.9, 140.8, 140.4, 128.8, 127.4, 127.3, 127.1, 126.3, 91.8, 77.0, 22.1. Anal. Calcd for
14
ACS Paragon Plus Environment

Page 15 of 36
The Journal of Organic Chemistry
1
2
3
4
C16H14Cl3NO: C, 56.09; H, 4.12; N, 4.09. Found: C, 56.00; H, 3.96; N, 4.44.
5
6
7
8
1‐(1,1'‐Biphenyl]‐4‐yl)pentyl 2,2,2-trichloroacetimidate (6p). Purified by silica gel
chromatography (5% ethyl acetate/ 1% triethylamine/ 94% hexanes); White solid (0.71 g, 60%);
TLC Rf = 0.68 (10% ethyl acetate/90% hexanes); IR (DCM) 3339, 2954, 2927, 2859, 1661, 1300
cm–1; 1H NMR (400 MHz, CDCl3) δ 8.27 (brs, 1H), 7.57 (d, J = 8.2 Hz, 4H), 7.47ꢀ7.32 (m, 4H),
7.34ꢀ7.32 (m, 1H), 5.87ꢀ5.84 (m, 1H), 2.12ꢀ2.03 (m, 1H), 1.92ꢀ1.84 (m, 1H), 1.51ꢀ1.34 (m, 4H),
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
13
0.90 (t, J = 7.2 Hz, 3H); C{1H} NMR (100 MHz, CDCl3) δ 161.7, 140.7, 140.7, 139.5, 128.7,
127.1, 127.1, 126.5, 91.8, 80.8, 36.6, 27.6, 22.4, 14.0 (one aromatic resonance was not resolved).
Anal. Calcd for C19H20Cl3NO: C, 59.32; H, 5.24; N, 3.64. Found: C, 59.58; H, 5.31; N, 3.45.
1‐(1,1'‐Biphenyl]‐4‐yl)‐2‐methylpropyl 2,2,2-trichloroacetimidate (6q). Purified by silica gel
chromatography (10% ethyl acetate/ 1% triethylamine/ 89% hexanes); White solid (2.00 g,
66%), TLC Rf = 0.42 (10% ethyl acetate/90% hexanes); IR (DCM) 3339, 2967, 1661, 1487,
1
1300, 1058, 990 cmꢀ1; H NMR (400 MHz, CDCl3) δ 8.16 (s,1H), 7.53ꢀ7.49 (m, 4H), 7.37ꢀ7.34
(m, 4H ), 7.28ꢀ7.26 (m, 1H), 5.52 (d, J = 7.1 Hz, 1H), 2.16 (octet, J = 6.8 Hz, 1H), 1.02 (d, J =
6.6 Hz, 3H), 0.86 (d, J = 6.8 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 161.8, 140.8, 140.7,
138.2, 128.8, 127.4, 127.3, 127.2, 126.9, 92.0, 85.6, 34.4, 19.0, 18.3. Anal. Calcd for
C18H18Cl3NO: C, 58.32; H, 4.89; N, 3.78. Found: C, 58.50; H, 4.69; N, 3.90.
1‐(Naphthalen‐2‐yl)propyl 2,2,2-trichloroacetimidate (6r). Purified by silica gel chromatography
(1% triethylamine/ 99% hexanes); Yellow oil (1.39 g, 96 %); TLC Rf = 0.62 (10% ethyl
1
acetate/90% hexanes); IR (DCM) 3332 ,2972, 1663, 1073, 831, 797, 704 cm–1; H NMR (300
MHz, CDCl3) δ 8.26 (brs, 1H), 7.85ꢀ7.81 (m, 4H), 7.52 (dd, J = 8.4, 1.6 Hz, 1H), 7.48ꢀ7.45 (m,
2H), 5.92 (m,1H), 2.20ꢀ2.09 (m, 1H), 2.05ꢀ1.94 (m, 1H), 1.03 (t, J = 7.4 Hz, 3H); 13C{1H} NMR
(100 MHz, CDCl3) δ 161.8, 137.5, 133.08, 133.06, 128.2, 128.0, 127.7, 126.2, 126.0, 125.4,
15
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 of 36
1
2
3
4
5
6
124.0, 91.9, 82.3, 29.8, 10.0. Anal. Calcd for C15H14Cl3NO: C; 54.49; H, 4.27; N, 4.24. Found:
C, 54.42; H, 4.36; N, 4.31.
7
8
9
1‐(1‐Benzothiophen‐3‐yl)propyl 2,2,2-trichloroacetimidate (6s). Purified by silica gel
chromatography (5% ethyl acetate/ 1% triethylamine/ 94% hexanes); Yellow viscous oil (2.38 g,
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
1
91%); IR (DCM) 3340, 2972, 1664, 1428, 1082, 976, 760 cmꢀ1; H NMR (300 MHz, CDCl3) δ
8.32 (brs, 1H), 7.94ꢀ7.91 (m, 1H), 7.85ꢀ7.82 (m, 1H), 7.45 (s, 1H), 7.37ꢀ7.30 (m, 2H), 6.24 (t, J
= 8.1 Hz, 1H), 2.30ꢀ2.02 (m, 2H), 1.02 (t, J = 9.8 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ
161.9, 140.7, 137.1, 134.9, 124.5, 124.1, 123.6, 122.9, 122.5, 91.9, 77.9, 28.1, 10.0. Anal. Calcd
for C13H12Cl3NOS: C, 46.38; H, 3.59; N, 4.16. Found: C, 46.03; H, 3.60; N, 3.95.
3,4-Dimethoxybenzyl 2,2,2-trichloroacetimidate (6t). Purified by silica gel chromatography (30%
ethyl acetate/ 1% triethylamine/ 69% hexanes); Yellow oil (3.00 g, 90%); TLC Rf = 0.28 (20%
ethyl acetate/ 80% hexanes); 1H NMR (400 MHz, CDCl3) δ 8.38 (brs, 1H), 7.01ꢀ6.98 (m, 2H),
6.87 (d, J = 8.1 Hz, 1H), 5.29 (s, 2H), 3.89 (s, 6H); C{1H} NMR (100 MHz, CDCl3) δ 162.4,
13
149.1, 149.0, 127.9, 120.8, 111.3, 111.0, 91.5, 70.8, 55.85, 55.83. Anal. Calcd for C11H12Cl3NO3:
C, 42.27; H, 3.87; N, 4.48. Found: C, 42.39; H, 3.59; N, 4.59.
1‐(Naphthalen‐1‐yl)ethyl 2,2,2-trichloroacetimidate (6w). Purified by silica gel chromatography
(10% ethyl acetate/ 1% triethylamine/ 89% hexanes); Light brown oil (5.64 g, 85%); TLC Rf =
0.56 (10% ethyl acetate / 90% hexanes); IR (DCM) 3338, 1662, 1512, 1301, 1085, 774, 648 cm–
1; H NMR (400 MHz, CDCl3) δ 8.47 (brs, 1H), 8.04 (d, J = 8.0 Hz, 1H), 7.87 (t, J = 7.4 Hz,
1
2H), 7.62 (d, J = 8.0 Hz, 1H), 7.56ꢀ7.44 (m, 3H), 5.77 (s, 2H); C{1H} NMR (75 MHz, CDCl3)
13
δ 162.8, 133.7, 131.6, 130.9, 129.5, 128.7, 127.3, 126.5, 126.0, 125.2, 123.7, 91.5, 69.5. Anal.
Calcd for C13H10Cl3NO: C, 51.60; H, 3.33; N, 4.63. Found: C, 51.83; H, 3.28; N, 4.77.
1‐(Naphthalen‐2‐yl)ethyl 2,2,2-trichloroacetimidate (6x). Purified by silica gel chromatography
16
ACS Paragon Plus Environment

Page 17 of 36
The Journal of Organic Chemistry
1
2
3
4
(10% ethyl acetate/ 1% triethylamine/ 89% hexanes); White solid (1.89 g, 99%), TLC Rf = 0.70
5
6
1
(20% ethyl acetate/80% hexanes); IR (DCM) 3335, 3053, 1665, 1305, 1081, 817, 649 cm–1; H
7
8
9
NMR (400 MHz, CDCl3) δ 8.42 (brs, 1H), 7.90 (s, 1H), 7.87ꢀ7.84 (m, 3H), 7.54 (dd, J = 8.4, 1.4
Hz, 1H), 7.50ꢀ7.48 (m, 2H), 5.50 (s, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ 162.6, 133.2,
133.1, 132.9, 128.4, 128.0, 127.7, 127.0, 126.3, 126.3, 125.5, 91.4, 70.9. Anal. Calcd for
C13H10Cl3NO: C, 51.60; H, 3.33; N, 4.63. Found: C, 51.71; H, 3.52; N, 4.84.
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
(1‐Benzothiophen‐3‐yl)methyl 2,2,2-trichloroacetimidate (6y). Purified by silica gel
chromatography (10% ethyl acetate/ 1% triethylamine/ 89% hexanes); Off white solid (1.92 g,
68%); TLC Rf = 0.48 (10% ethyl acetate/90% hexanes); IR (DCM) 3340, 3052, 2984, 2304,
1664, 1460, 1295, 1265, 1076, 799, 737, 705 cmꢀ1; 1H NMR (400 MHz, CDCl3) δ 8.46 (brs, 1H),
7.88ꢀ7.86 (m, 2H), 7.56 (s, 1H), 7.43ꢀ7.36 (m, 2H), 5.57 (s, 2H); 13C{1H} NMR (75 MHz,
CDCl3) δ 162.7, 140.5, 137.8, 130.3, 126.5, 124.7, 124.4, 122.9, 122.0, 91.0, 65.3. Anal. Calcd
for C11H8Cl3NOS: C, 42.81; H, 2.61; N, 4.54. Found: C, 43.17; H, 2.43; N, 4.61.
4-Nitrobenzyl 2,2,2-trichloroacetimidate (6z). Purified by silica gel chromatography (20% ethyl
acetate/ 1% triethylamine/ 79% hexanes); Yellow solid (3.75 g, 97%); TLC Rf = 0.23 (10% ethyl
1
acetate / 90% hexanes); H NMR (400 MHz, CDCl3) δ 8.50 (s, 1H), 8.25 (d, J = 8.7 Hz, 2H),
7.61 (d, J = 8.8 Hz, 2H), 5.45 (s, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ 162.1, 147.8, 142.7,
127.9, 123.8, 90.9, 69.1. Anal. Calcd for C9H7Cl3N2O3: C, 36.33; H, 2.37; N, 9.42. Found: C,
36.27; H, 2.30; N, 9.48.
2,2‐Diphenylethyl 2,2,2-trichloroacetimidate (6aa). Purified by silica gel chromatography (5%
ethyl acetate/ 1% triethylamine/ 89% hexanes); Clear oil (0.31 g, 87%); IR (DCM) 3337, 1663,
1081, 798 cmꢀ1; TLC Rf = 0.68 (10% ethyl acetate/90% hexanes); 1H NMR (400 MHz, CDCl3) δ
8.30 (s, 1H), 7.32ꢀ7.20 (m, 10H), 4.81 (d, J = 7.3 Hz, 2H), 4.54 (t, J = 7.2 Hz, 1H); 13C{1H}
17
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 18 of 36
1
2
3
4
5
6
NMR (100 MHz, CDCl3) δ 162.8, 141.0, 128.5, 128.4, 126.8, 91.3, 71.6, 49.5. Anal. Calcd for
C16H14Cl3NO: C, 56.09; H, 4.12; N, 4.09. Found: C, 55.93; H, 3.92; N, 4.07.
7
8
(2S,3aS,8aS)-dimethyl
8-(phenylsulfonyl)-3a-(2,2,2-trichloro-1-iminoethoxy)-3,3a,8,8a
-
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
tetrahydropyrrolo[2,3-b] indole-1,2(2H)-dicarboxylate (9). Purified by silica gel
chromatography (40% ethyl acetate/ 1% triethylamine/ 59% hexanes); White foamy solid (0.08
21
g, 60%); TLC R = 0.57 (50% ethyl acetate/50% hexanes); [ ] = +85.1 (c = 1.6, CHCl3); IR
̾
f
1
(DCM) 3434, 2090, 1642 cm–1; H NMR (400 MHz, CDCl3, 50 °C) δ 8.49 (s, 1H), 7.98 (d, J =
7.2 Hz, 2H), 7.54ꢀ7.44 (m, 4H), 7.39ꢀ7.30 (m, 2H), 7.07 (td, J = 7.7, 1.1 Hz, 1H), 6.71 (s, 1H),
4.83 (d, J = 9.0 Hz, 1H), 3.51 (brs, 3H), 3.26 (s, 3H), 3.17 (d, J = 12.9 Hz, 1H), 3.03 (dd, J =
12.8, 9.2 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3, 50 °C) δ 170.3, 159.1, 154.4, 144.8, 144.4,
132.5, 131.5, 129.0, 127.7, 126.6, 125.5, 124.3, 116.3, 93.4, 90.8, 81.6, 58.6, 52.7, 52.2, 39.3.
Anal. Calcd for C22H20Cl3N3O7S: C, 45.81; H, 3.49; N, 7.28. Found: C, 45.95; H, 3.37; N, 7.31.
3‐(N‐Methylbenzenesulfonamido)‐1S‐(thiophen‐2‐yl)propyl 2,2,2‐trichloroacetimidate (15).
Purified by silica gel chromatography (20% ethyl acetate/ 1% triethylamine/ 79% hexanes);
25
Yellow oil (0.25 g, 85%); TLC R = 0.62 (40% ethyl acetate/60% hexanes); [ ] = +32.5 (c =
̾
f
0.4, DCM); IR (DCM) 3375, 1693, 1335, 1163, 1109, 834 cm–1; 1H NMR (400 MHz, CDCl3) δ
8.46 (brs, 1H), 7.81ꢀ7.79 (m, 2H), 7.63ꢀ7.52 (m, 3H), 7.31 (dd, J = 5.1, 1.1 Hz, 1H), 7.18 (d, J =
3.4 Hz, 1H), 7.01 (q, J = 3.6 Hz, 1H), 6.28 (q, J = 4.9 Hz, 1H), 3.21 (t, J = 6.9 Hz, 2H), 2.81 (s,
3H), 2.47ꢀ2.38 (m, 1H), 2.32ꢀ2.24 (m, 1H); 13C{1H} NMR (100MHz, CDCl3) δ 161.1, 141.4,
137.4, 132.7, 129.1, 127.4, 126.6, 126.5, 125.7, 91.4, 73.5, 46.8, 35.5, 35.3. Anal. Calcd for
C16H17Cl3N2O3S2: C, 42.16; H, 3.76; N, 6.15. Found: C, 42.16; H, 3.82; N, 6.12. The
enantiomeric purity of this material was verified by NMR using the chiral shift reagent Europium
tris[3ꢀ(heptafluoropropylhydroxymethylene)ꢀ(+)ꢀcamphorate] i.e. Eu(hfc)3. The addition of 0.8
18
ACS Paragon Plus Environment

Page 19 of 36
The Journal of Organic Chemistry
1
2
3
4
1
equiv of Eu(hfc)3 gave separation of the imidate NH peak at ~8.4 ppm in the H NMR (see
5
6
supporting spectra for details).
7
8
9
General Procedures for the Displacement of Trichloroacetimidates with
Trimethylaluminum.
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
Method A. Aluminium trichloride (1 eq) was dissolved in dry DCM (0.162 M) under argon in a
flame dried flask. Trimethylaluminium (3 equiv, 2M in hexanes) was slowly added and the
mixture was stirred for 5 min. After cooling to 0 °C the trichloroacetimidate (1 equiv) was added.
The reaction mixture was then allowed to warm to rt. After 15 min the reaction was quenched
with 10% aq. HCl. The mixture was poured into water and extracted with DCM (3x). The
combined organic extracts were dried (Na2SO4), filtered, and concentrated in vacuo. The residue
was then purified by silica gel chromatography using the eluent listed for each example.
Compounds 7a, 7b, 7c, 7d, 7e, 7f, 7g, 7h, 7i, 7j, 7k, 7l, 7m, 7n, 7o, 7p, 7r, 7s, 10, and 16 were
obtained by this method.
Method B. Trimethylaluminium (3 equiv, 2M in hexanes) was suspended in dry DCM (0.162
M) under argon in a flame dried flask. The temperature of the reaction was then cooled to the
temperature noted in Table 2. The trichloroacetimidate was the added. The reaction was
monitored by TLC, and quenched with the addition of 10% aq. HCl after the time listed in Table
2. The quenched mixture was poured into water and extracted with DCM (3x). The organic
extracts were then dried using Na2SO4, filtered, and concentrated. The residue was purified by
silica gel chromatography using the eluent listed for each example. Compounds 7q, 7t, 7u, 7v,
7w, 7x, 7y were obtained using this method.
1,1- Diphenylethane (7a).36 Purified by silica gel chromatography (1% ethyl acetate/ 99%
1
hexanes); Clear viscous oil (0.04 g, 91%); H NMR (400 MHz, CDCl3) δ 7.20ꢀ7.08 (m, 10H),
19
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 20 of 36
1
2
3
4
13
4.07 (q, J = 7.2 Hz, 1H), 1.56 (d, J = 7.2 Hz, 3H); C{1H} NMR (100 MHz, CDCl3) δ 146.4,
5
6
128.4, 127.7, 126.1, 44.8, 21.9.
7
8
1-Phenyl-1-(p-tolyl)ethane (7b).36 Purified by silica gel chromatography (1% ethyl acetate/ 99%
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
hexanes). Clear oil (0.03 g, 65%); TLC Rf = 0.74 (100% hexanes); H NMR (400 MHz, CDCl3)
δ 7.29ꢀ7.07 (m, 9H), 4.12 (q, J = 7.2 Hz, 1H), 2.3 (s, 3H), 1.62 (d, J = 7.2 Hz, 3H); 13C{1H}
NMR (100 MHz, CDCl3) δ 146.6, 143.4, 135.5, 129.0, 128.3, 127.6, 127.5, 125.9, 44.4, 21.9,
21.0.
1-Phenyl-1-(o-tolyl)ethane (7c).11c Purified by silica gel chromatography (100% hexanes). Clear
viscous oil (0.08 g, 70%); TLC Rf = 0.83 (10% ethyl acetate/90% hexanes); 1H NMR (400 MHz,
CDCl3) δ 7.27ꢀ 7.11 (m, 9H), 4.30 (q, J = 7.2 Hz, 1H), 2.22 (s, 3H), 1.60, (d, J = 7.2 Hz, 3H);
13C{1H} NMR (75 MHz, CDCl3) δ 146.3, 144.0, 136.2, 130.5, 128.4, 127.8, 126.8, 126.2, 126.1,
125.9, 41.1, 22.2, 19.8.
4-(1-Phenylethyl)biphenyl (7d).37 Purified by silica gel chromatography (1% ethyl acetate/ 99%
1
hexanes); Clear viscous oil (0.04 g, 91%); TLC Rf = 0.69 (10% ethyl acetate/90% hexanes); H
NMR (400 MHz, CDCl3) δ 7.55 (dd, J = 8.4, 1.4 Hz, 2H), 7.51ꢀ7.49 (m, 2H), 7.40 (t, J = 7.3 Hz,
13
2H), 7.32ꢀ7.16 (m, 8H), 4.18 (q, J = 7.2 Hz, 1H), 1.67 (d, J = 7.2 Hz, 3H); C{1H} NMR (100
MHz, CDCl3) δ 146.2, 145.5, 141.0, 139.0, 128.7, 128.4, 128.0, 127.6, 127.1, 127.0, 127.0,
126.1, 44.5, 21.9.
4-(1-Phenylethyl)anisole (7e).38 Purified by silica gel chromatography (1% ethyl acetate/ 99%
1
hexanes); Clear viscous oil (0.03 g, 64%); TLC Rf = 0.37 (10% ethyl acetate/90% hexanes); H
NMR (400 MHz, CDCl3) δ 7.29ꢀ7.12 (m, 7H), 6.83ꢀ6.81 (m, 2H), 4.10 (q, J = 7.2 Hz, 1H), 3.77
(s, 3H), 1.61 (d, J = 7.2 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 157.8, 146.8, 138.6, 128.5,
128.3, 127.5, 125.9, 113.7, 55.2, 43.9, 22.1.
20
ACS Paragon Plus Environment

Page 21 of 36
The Journal of Organic Chemistry
1
2
3
4
1-Chloro-3-(1-phenylethyl)benzene (7f). Purified by silica gel chromatography (1% ethyl acetate/
5
6
99% hexanes); Clear viscous oil (0.11 g, 92%); IR (DCM) 3434, 2090, 1642 cm–1 ;2968,1594,
7
8
1
1493, 1475, 1426, 1082, 791; TLC Rf = 0.73 (10% ethyl acetate/90% hexanes); H NMR (400
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
MHz, CDCl3) δ 7.30ꢀ7.26 (m, 2H), 7.20ꢀ7.13 (m, 5H), 7.09ꢀ7.07 (m, 2H), 4.10 (q, J = 7.2 Hz,
1H), 1.61 (d, J = 7.2 Hz, 3H); 13C{1H} NMR (75 MHz, CDCl3) δ 148.5, 145.5, 134.2, 129.7,
128.6, 127.8, 127.6, 126.4, 126.3, 125.9, 44.6, 21.7. Calcd for C14H13Cl: C, 77.59; H, 6.05;
Found: C, 77.33; H, 5.76
1-Bromo-4-(1-phenylethyl)benzene (7g).39 Purified by silica gel chromatography (100%
1
hexanes); Clear viscous oil (0.11 g, 86%); TLC Rf = 0.71 (10% ethyl acetate/90% hexanes); H
NMR (400 MHz, CDCl3) δ 7.38 (d, J = 8.4 Hz, 2H), 7.27 (t, J = 7.7 Hz, 2H), 7.21ꢀ7.16 (m, 3H),
13
7.07 (d, J = 8.4 Hz, 2H), 4.09 (q, J = 7.2 Hz, 1H), 1.60 (d, J = 7.2 Hz, 3H); C{1H} NMR (75
MHz, CDCl3) δ 145.7, 145.4, 131.5, 129.4, 128.5, 127.6, 126.3, 119.9, 44.3, 21.8.
1-Fluoro-3-(1-phenylethyl)benzene (7h). Purified by silica gel chromatography (100% hexanes);
1
Clear viscous oil (0.04 g, 87%); TLC Rf = 0.66 (100% hexanes); H NMR (400 MHz, CDCl3) δ
7.30ꢀ7.26 (m, 2H), 7.23ꢀ7.17 (m, 4H), 6.99 (d, J = 7.7 Hz, 1H), 6.92ꢀ6.83 (m, 2H), 4.13 (q, J =
13
7.2 Hz, 1H), 1.62 (d, J = 7.2 Hz, 3H); C{1H} NMR (75 MHz, CDCl3) δ 163.0 (d, J = 244.5
Hz), 149.0, 145.6, 129.7, 128.5, 127.6, 126.3, 123.3, 114.5 (d, J = 22.5 Hz), 112.8 (d, J = 22.4
Hz), 44.5, 21.7. Anal. Calcd for C14H13F: C, 83.97; H, 6.54. Found: C, 83.88; H, 6.22.
1-Nitro-4-(1-phenylethyl)benzene (7i).40 Purified by silica gel chromatography (1% ethyl acetate/
1
99% hexanes); Yellow oil (0.08 g, 66%); TLC Rf = 0.55 (10% ethyl acetate/90% hexanes); H
NMR (400 MHz, CDCl3) δ 8.06 (d, J = 8.8, Hz, 2H), 7.29 (d, J = 8.6 Hz, 2H), 7.24 (t, J = 7.1
13
Hz, 2H), 7.18ꢀ7.12 (m, 3H), 4.18 (q, J = 7.2 Hz, 1H), 1.60 (d, J = 7.2 Hz, 3H); C{1H} NMR
(100 MHz, CDCl3) δ 154.1, 146.4, 144.5, 128.7, 128.5, 127.6, 126.7, 123.7, 44.7, 21.5.
21
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 22 of 36
1
2
3
4
5
6
7
8
9
1‐(1‐Phenylethyl)‐3,5‐bis(trifluoromethyl)benzene (7j). Purified by silica gel chromatography
(100% hexanes); Clear viscous oil (0.13 g, 95%); TLC Rf = 0.57 (100% hexanes); IR (DCM)
2801, 1420, 1374, 1280, 1173, 1134, 897, 701 cm–1; 1H NMR (400 MHz, CDCl3) δ 7.71 (s, 1H),
7.76 (s, 2H), 7.32 (t, J = 7.2 Hz, 2H), 7.25ꢀ7.18 (m, 3H), 4.26 (q, J = 7.2 Hz, 1H), 1.68 (d, J =
7.2 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) 148.9, 144.2, 131.7 (q, J = 44.6 Hz)), 128.9,
127.8 (q, J = 3.4 Hz), 127.5, 126.9, 123.5 (q, J = 361.0 Hz), 120.3 (hept, J =5.2), 44.7, 21.6.
Anal. Calcd for C16H12F6: C, 60.38; H, 3.80. Found: C, 60.65; H, 3.75.
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-(1-Phenylethyl)-naphthalene (7k).41 Purified by silica gel chromatography (100% hexanes);
1
Clear viscous oil (0.07 g, 57%); TLC Rf = 0.52 (100% hexanes); H NMR (400 MHz, CDCl3) δ
7.79ꢀ7.76 (m, 2H), 7.72 (d, J = 8.5 Hz, 1H), 7.69 (s, 1H), 7.42ꢀ7.38 (m, 2H), 7.30ꢀ7.24 (m, 5H),
13
7.20ꢀ7.16 (m, 1H), 4.30 (q, J = 7.2 Hz, 1H), 1.72 (d, J = 7.2 Hz, 3H); C{1H} NMR (75 MHz,
CDCl3) δ 146.3, 143.8, 133.6, 132.2, 128.5, 128.0, 127.81, 127.78, 127.62, 126.9, 126.2, 126.0,
125.4, 44.9, 21.8 (one aromatic resonance was not resolved).
1-(1-Phenethyl)-naphthalene (7l).42 Purified by silica gel chromatography (2% ethyl acetate/
98% hexanes); Clear viscous oil (0.07 g, 57%); TLC Rf = 0.73 (10% ethyl acetate/90% hexanes).
1H NMR (400 MHz, CDCl3) δ 8.02ꢀ7.04 (m, 1H), 7.84ꢀ7.82 (m, 1H), 7.73 (d, J = 7.6 Hz, 1H),
7.47ꢀ7.39 (m, 4H), 7.25ꢀ7.22 (m, 4H), 7.17ꢀ7.13 (m, 1H), 4.91 (q, J = 7.1 Hz, 1H), 1.76 (d, J =
7.1 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 146.6, 141.5, 134.0, 131.7, 128.7, 128.4, 127.6,
127.0, 125.9, 125.8, 125.4, 125.3, 124.3, 123.9, 40.5, 22.5.
3-(1-Phenylethyl)-benzo[b]thiophene (7m).43 Purified by silica gel chromatography (2% ethyl
1
acetate/ 98% hexanes); White foam (0.07 g, 57%); TLC Rf = 0.38 (100% hexanes); H NMR
(400 MHz, CDCl3) δ 7.83ꢀ7.81 (m, 1H), 7.55ꢀ7.53 (m, 1H), 7.29ꢀ7.15 (m, 8H), 4.43 (q, J = 7.1
Hz, 1H), 1.73 (d, J = 7.1 Hz, 3H); 13C{1H} NMR (75 MHz, CDCl3) δ 145.4, 140.7, 140.6, 138.6,
22
ACS Paragon Plus Environment

Page 23 of 36
The Journal of Organic Chemistry
1
2
3
4
128.6, 127.4, 126.3, 124.2, 123.8, 122.8, 122.5, 121.5, 39.6, 22.4.
5
6
7
8
3-(1-(4-Fluorophenyl)ethyl)-benzo[b]thiophene (7n).14a Purified by silica gel chromatography
(100% hexanes); Clear viscous oil (0.09 g, 71%); TLC Rf = 0.76 (10% ethyl acetate/ 90%
hexanes); 1H NMR (400 MHz, CDCl3) δ 7.80 (d, J = 7.5 Hz, 1H), 7.49 (d, J = 7.7 Hz, 1H), 7.27ꢀ
7.13 (m, 5H), 6.91 (t, J = 8.7 Hz, 2H), 4.39, (q, J = 7.0 Hz, 1H), 1.67 (d, J = 7.1 Hz, 3H);
13C{1H} NMR (75 MHz, CDCl3) δ 161.5 (d, J = 242.3 Hz), 141.2, 140.8, 140.4, 138.5, 128.9,
124.3, 123.9, 122.9, 122.5, 121.6, 115.4 (d, J = 21.7 Hz), 38.9, 22.5.
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
4-Isopropylbiphenyl (7o).44 Purified by silica gel chromatography (100% hexanes); Clear viscous
oil (0.10 g, 87%); TLC Rf = 0.55 (100% hexanes); 1H NMR (400 MHz, CDCl3) δ 7.57 (d, J = 7.2
Hz, 2H), 7.51 (d, J = 8.2 Hz, 2H), 7.40 (t, J = 7.4 Hz, 2H), 7.30 (t, J = 7.3 Hz, 3H), 2.94 (hept, J
= 6.9 Hz, 1H), 1.28 (d, J = 7.0 Hz, 6H); 13C{1H} NMR (100 MHz, CDCl3) δ 148.1, 141.3, 138.8,
128.8, 127.2, 127.1, 127.0, 126.9, 33.9, 24.1.
1-(1-Methylpentyl)-4-phenyl-benzene (7p). Purified by silica gel chromatography (100%
hexanes); Clear viscous oil (0.12 g, 97%); TLC Rf = 0.64 (100% hexanes); IR (DCM) 3027,
1
2957, 2926, 2856, 1486, 1455, 1008, 837, 732 cm–1; H NMR (400 MHz, CDCl3) δ 7.60ꢀ7.58
(m, 2H), 7.52 (d, J = 8.2 Hz, 2H), 7.42 (t, J = 7.4, Hz, 2H), 7.34ꢀ7.30 (m, 1H), 7.26ꢀ7.24 (m,
2H), 2.72 (hextet, J = 6.8 Hz, 1H), 1.65ꢀ1.56 (m, 2H), 1.33ꢀ1.15 (m, 7H), 0.87 (t, J = 6.9 Hz,
13
3H); C{1H} NMR (100 MHz, CDCl3) δ 147.2, 141.2, 138.7, 128.7, 127.4, 127.0, 126.9, 39.6,
38.2, 30.0, 22.8, 22.3, 14.1 (one aromatic resonance was unresolved). Anal. Calcd for C18H22: C,
90.70; H, 9.30. Found: C, 90.79; H, 9.37.
4-(3-methylbutan-2-yl)-1,1'-biphenyl (7q). Purified by silica gel chromatography (100%
hexanes); Clear viscous oil (0.065 g, 90%); TLC Rf = 0.45 (100% hexanes); IR (DCM) 3416,
2960, 2872, 1598, 1486 cmꢀ1; 1H NMR (400 MHz, CDCl3) δ 7.61 (d, J = 7.7 Hz, 2H), 7.53 (d, J
23
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 24 of 36
1
2
3
4
5
6
7
8
9
= 8.2 Hz, 2H), 7.44 (t, J = 7.4 Hz, 2H), 7.33 (t, J = 7.3 Hz, 1H), 7.25 (d, J = 9.1Hz, 2H), 2.50
(quintet, J = 7.1 Hz, 1H), 1.81 (octet, J = 6.6 Hz, 1H), 1.29 (d, J = 7.0 Hz, 3H), 0.98 (d, J = 6.6
Hz, 3H), 0.82 (d, J = 6.6 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 146.3, 141.2, 138.6,
128.7, 128.1, 127.02, 127.00, 126.8, 46.6, 34.5, 21.3, 20.2, 18.9 . Anal. Calcd for C17H20: C,
91.01; H, 8.99. Found: C, 91.18; H, 8.75.
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-(1-Methylpropyl)-naphthalene (7r).14a Purified by silica gel chromatography (100% hexanes);
1
Clear viscous oil (0.07 g, 60%); TLC Rf = 0.71 (100% hexanes); H NMR (400 MHz, CDCl3) δ
7.80ꢀ7.75 (m, 3H), 7.60 (s, 1H), 7.41 (qd, J = 6.9, 1.4 Hz, 2H), 7.33 (dd, J = 8.5, 1.6 Hz, 1H ),
2.75 (sextet, J = 7.0 Hz, 1H), 1.74ꢀ1.62 (m, 2H), 1.31 (d, J = 6.9 Hz, 3H), 0.84 (t, J = 7.4 Hz,
3H); 13C{1H} NMR (100 MHz, CDCl3) δ 145.1, 133.6, 132.2, 127.8, 127.6, 127.5, 125.9, 125.7,
125.2, 125.0, 41.8, 31.0, 21.9, 12.3.
3-(1-Methylpropyl)-benzo [b] thiophene (7s).14a Purified by silica gel chromatography (100%
1
hexanes); Clear viscous oil (0.07 g, 62%); TLC Rf = 0.65 (100% hexanes); H NMR (400 MHz,
CDCl3) δ 7.86ꢀ7.84 (m, 1H), 7.79ꢀ7.77 (m, 1H), 7.38ꢀ7.30 (m, 2H), 7.06 (s, 1H), 3.09 (sextet, J =
6.8 Hz, 1H), 1.89ꢀ1.79 (m, 1H), 1.71ꢀ1.60 (m, 1H), 1.35 (d, J = 6.9 Hz, 3H), 0.93 (t, J = 7.4 Hz,
13
3H); C{1H} NMR (75 MHz, CDCl3) δ 142.5, 140.7, 138.9, 124.0, 123.7, 122.9, 121.9, 119.6,
34.7, 29.8, 20.3, 12.0.
4-Ethyl-1,3-dimethoxybenzene (7t).45 Purified by silica gel chromatography (5% ethyl acetate/
95% hexanes); Clear viscous oil (0.08 g, 92%); TLC Rf = 0.66 (20 ethyl acetate/80% hexanes).
1H NMR (400 MHz, CDCl3) δ 6.80 (d, J = 8.6 Hz, 1H), 6.74ꢀ6.73 (m, 2H), 3.88 (s, 3H), 3.85 (s,
3H), 2.60 (q, J = 7.6 Hz, 2H), 1.23 (t, J = 7.6 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ
148.8, 147.0, 137.0, 119.5, 111.3, 111.3, 56.0, 55.8, 28.5, 15.8.
4-Ethylanisole (7u).46 Purified by silica gel chromatography (4% ethyl acetate/ 96% hexanes);
24
ACS Paragon Plus Environment

Page 25 of 36
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Clear viscous oil (0.05 g, 52%); TLC Rf = 0.78 (10% ethyl acetate/ 90% hexanes); 1H NMR (400
MHz, CDCl3) δ 7.10 (d, J = 8.5 Hz, 2H), 6.82 (d, J = 8.6 Hz, 2H), 3.77 (s, 3H), 2.58 (q, J = 7.6
Hz, 2H), 1.20 (t, J = 7.6 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 157.7, 136.4, 128.7,
113.8, 55.3, 28.0, 15.9.
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
4-Ethylbiphenyl (7v).44 Purified by silica gel chromatography (1% ethyl acetate/ 99% hexanes);
1
Clear viscous oil (0.09 g, 81%); TLC Rf = 0.68 (100% hexanes); H NMR (400 MHz, CDCl3)
7.59ꢀ7.57 (m, 2H), 7.52ꢀ7.50 (d, J = 7.5 Hz, 2H), 7.42 (t, J = 7.4 Hz, 2H), 7.33ꢀ7.26 (m, 3H),
13
2.69 (q, J = 7.6 Hz, 2H), 1.27 (t, J = 7.6 Hz, 3H). C{1H} NMR (100 MHz, CDCl3) δ 143.4,
141.2, 138.6, 128.7, 128.3, 127.1, 127.0, 127.0, 28.5, 15.6.
1-Ethylnapthalene (7w).47 Purified by silica gel chromatography (100% hexanes); Clear viscous
oil (0.062 g, 60%); TLC Rf = 0.66 (100% hexanes); 1H NMR (400 MHz, CDCl3) δ 8.04 (d, J =
8.2 Hz, 1H), 7.85ꢀ7.83 (m, 1H), 7.69 (d, J = 8.1 Hz, 1H), 7.52ꢀ7.44 (m, 2H), 7.40 (t, J = 7.2 Hz,
1H), 7.33 (d, J = 6.9 Hz, 1H), 3.12 (q, J = 7.5 Hz, 2H), 1.38 ( t, J = 7.6 Hz, 3H); 13C{1H} NMR
(75 MHz, CDCl3) δ 140.3, 133.9, 131.8, 128.8, 126.4, 125.7, 125.4, 124.9, 123.8, 25.9, 15.1 (one
aromatic resonance was unresolved).
2-Ethylnapthalene (7x).48 Purified by silica gel chromatography (100% hexanes); Clear viscous
oil (0.05 g, 49%); TLC Rf = 0.62 (100% hexanes); 1H NMR (400 MHz, CDCl3) δ 7.79ꢀ7.74 (m,
3H), 7.60 (s, 1H), 7.41ꢀ7.33 (m, 2H), 7.33 (dd, J = 8.4, 1.2 Hz, 1H), 2.80 (q, J = 7.6 Hz, 2H),
13
1.31 (t, J = 7.6 Hz, 3H); C{1H} NMR (100 MHz, CDCl3) δ 141.7, 133.7, 131.9, 127.8, 127.6,
127.4, 127.1, 125.8, 125.5, 125.0, 29.0, 15.5.
3-Ethyl-benzo[b]thiophene (7y).49 Purified by silica gel chromatography (100% hexanes); Clear
1
viscous oil (0.08 g, 62%); TLC Rf = 0.57 (100% hexanes); H NMR (400 MHz, CDCl3) δ 7.85ꢀ
7.83 (m, 1H), 7.74ꢀ7.72 (m, 1H), 7.38ꢀ7.30 (m, 2H), 7.06 (s, 1H), 2.85 (qd, J = 7.5, 1.0 Hz, 2H),
25
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 26 of 36
1
2
3
4
13
1.36 (t, J = 7.5 Hz, 3H); C{1H} NMR (75 MHz, CDCl3) δ 140.6, 139.1, 138.7, 124.2, 123.8,
5
6
122.9, 121.7, 120.2, 21.8, 13.4.
7
8
9
1,2‐Dimethyl (2S)‐8‐(benzenesulfonyl)‐3a‐chloro‐1H,2H,3H,3aH,8H,8aH‐pyrrolo[2,3‐b] indole ‐
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
1,2‐dicarboxylate (10). Purified by silica gel chromatography (20% ethyl acetate/ 80% hexanes);
24
White solid (0.06 g, 80%); [ ]
= +38.2 (c = 1.2, DCM); TLC Rf = 0.33 (50% ethyl
̾
1
acetate/50% hexanes ); H NMR (400 MHz, CDCl3) δ 7.78 (d, J = 7.7 Hz, 2H), 7.58 (d, J = 8.1
Hz, 1H), 7.49 (t, J = 7.3 Hz, 1H), 7.40ꢀ7.34 (m, 3H), 7.22 (d, J = 7.2 Hz, 1H), 7.14 (t, J = 7.5 Hz,
1H), 6.20 (s, 1H), 4.66 (d, J = 8.7 Hz, 1H), 3.70 (s, 3H), 3.13 (s, 3H), 3.09ꢀ3.12 (m, 1H), 2.95ꢀ
2.86 (m, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 170.0, 154.3, 142.2, 139.0, 133.3, 132.1,
131.3, 128.9, 127.3, 125.8, 124.4, 118.4, 86.3, 71.4, 59.3, 53.1, 52.3, 43.0. HRMS (ESI) (m/z):
calcd for C20H19ClN2O6SNa (M+Na+): 473.0544. Found: 473.0541.
N‐Methyl‐N‐[3‐(thiophen‐2‐yl)butyl]benzenesulfonamide (16). Purified by silica gel
chromatography (20% ethyl acetate/ 80% hexanes); Clear oil (0.070 g, 49%), TLC Rf = 0.62
(50% ethyl acetate/ 50% hexanes); IR (DCM) 2923, 1446, 1340, 1164, 735, 691 cm–1; 1H NMR
(400 MHz, CDCl3) δ 7.67 (d, J = 7.2 Hz, 2H), 7.49 (t, J = 7.3 Hz, 1H), 7.43 (t, J = 7.7 Hz, 2H),
7.06ꢀ7.04 (m, 1H), 6.84 (t, J = 3.5 Hz, 1H), 6.75 (d, J = 3.3 Hz, 1H), 3.07 (sextet, J = 6.9 Hz,
1H), 2.93 (td, J = 7.4, 1.9 Hz, 2H), 2.63 (s, 3H), 1.84ꢀ1.71 (m, 2H), 1.27 (d, J = 6.9 Hz, 3H);
13C{1H} NMR (100 MHz, CDCl3) δ 150.6, 137.5, 132.5, 129.0, 127.4, 126.6, 123.1, 122.8, 48.4,
37.0, 34.9, 32.6, 23.1. Anal. Calcd for C15H19NO2S2: C, 58.22; H, 6.19; N, 4.53. Found: C,
58.10; H, 6.14; N, 4.89; Chiral HPLC analysis: OJ column (hexane/iꢀPrOH = 91/9, 0.9 mL/min,
254 nm, 25 °C): tr = 20.4, 22.2 min.
1‐(Benzenesulfonyl)‐1,2,3,4‐tetrahydropyridin‐4‐ol (11). IBX (1.170 g, 4.17 mmol) was
dissolved in dry DMSO (3.3 ml) and warmed to 75 °C for 5 min. The known 1ꢀ
26
ACS Paragon Plus Environment

Page 27 of 36
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
(benzenesulfonyl)ꢀ4ꢀpiperidone50 (0.500 g, 2.08 mmol) was added and the reaction was allowed
to proceed for 14 h at 75 °C. The reaction mixture was then poured into sat. aq. NaHCO3
solution and partitioned with ethyl acetate. The organic phase was then filtered through Celite
with ethyl acetate, and then the filtrate was washed with water and brine. The organic layer was
then dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by silica gel
chromatography (40 % ethyl acetate/ 60% hexanes) to provide crude 1ꢀ(benzenesulfonyl)ꢀ2,3ꢀ
dehydroꢀ4ꢀpiperidone as an offꢀwhite solid (0.297 g, 60%). A portion of this solid (0.200 g, 0.83
mmol) was then dissolved in 2 mL of MeOH. The reaction was cooled to 0°C and CeCl3•7H2O
(0.313 g, 0.83 mmol) was added followed by NaBH4 (0.032 g, 0.83 mmol). Reaction mixture
was then allowed to warm to room temperature. After 30 min the reaction was poured into water
and extracted with ethyl acetate (3x). The combined organic layers were then dried (Na2SO4),
filtered and concentrated. The residue was purified by silica gel chromatography (50% ethyl
acetate/ 50% hexanes) to provide alcohol 11 as white solid (0.191 g, 95%).
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
11. TLC Rf = 0.20 (40% ethyl acetate/ 60% hexanes); IR (DCM) 3398, 1643, 1446, 1170, 935
cm–1; 1H NMR (300 MHz, CDCl3) δ 7.80ꢀ7.78 (m, 1H), 7.63ꢀ7.50 (m, 3H), 6.81 (d, J = 8.3 Hz,
1H), 5.13 (ddd, J = 8.3, 4.8, 1.1 Hz, 1H), 4.12 (brs, 1H), 3.73ꢀ3.66 (m, 1H), 3.14 (td, J = 11.9,
3.2 Hz, 1H), 1.86ꢀ1.64 (m, 3H); 13C{1H} NMR (75 MHz, CDCl3) 137.9, 133.1, 129.3, 127.7,
127.0, 108.8, 59.9, 39.2, 30.0. Anal. Calcd for C11H13NO3S: C, 55.21; H, 5.48; N, 5.85. Found:
C, 54.82; H, 5.40; N, 6.25.
1‐(Benzenesulfonyl)‐4‐methyl‐1,2,3,4‐tetrahydropyridine (12). Alcohol 11 (0.150 g, 0.632 mmol)
was dissolved in 1.1 mL of dry DCM under argon. The reaction was cooled to 0 °C and DBU (20
µL, 0.131 mmol) was added followed by trichloroacetonitrile (70 µL, 0.698 mmol). The reaction
mixture was then allowed to warm to rt and stirred for 15 min. In a separate flask AlCl3 (84 mg,
27
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 28 of 36
1
2
3
4
5
6
7
8
9
0.632 mmol) was dissolved in DCM (2 mL) and AlMe3 (0.94 mL, 2M in hexanes, 1.92 mmol)
was added. After 5 min the solution containing the trimethylaluminum was added to the imidate
formed in the first solution at 0°C. After 5 min the reaction was quenched with 1 M HCl and the
mixture extracted with DCM (3x). The combined organic layers were then dried (Na2SO4),
filtered and concentrated. The residue was purified by silica gel chromatography (15% ethyl
acetate/ 85% hexanes) to provide alkene 12 as yellow oil (94 mg, 63%).
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
12. TLC Rf = 0.25 (20% ethyl acetate/ 80% hexanes); IR (DCM) 3033, 2974, 2931, 1446, 1328,
1279,1213, 1164, 1105, 980 cm–1; 1H NMR (400 MHz, CDCl3) δ 7.83 (d, J = 7.2 Hz, 2H), 7.55
(t, J = 7.6 Hz, 1H), 7.47 (t, J = 7.6 Hz, 2H), 5.67ꢀ5.57 (m, 2H), 4.44 (brs, 1H), 3.85 (dd, J = 5.9,
1.4 Hz, 1H ), 3.19ꢀ3.12 (m, 1H), 1.97ꢀ1.79 (m, 2H), 1.26 (d, J = 6.8 Hz, 3H). 13C{1H} NMR (100
MHz, CDCl3) δ 141.5, 132.3, 129.4, 129.0, 126.8, 124.4, 49.6, 37.8, 23.7, 20.4. Anal. Calcd for
C12H15NO2S: C, 60.73; H, 6.37; N, 5.90. Found: C, 60.46; H, 6.46; N, 5.86.
N‐[3S‐Hydroxy‐3‐(thiophen‐2‐yl)propyl]‐N‐methylbenzenesulfonamide
(14).
(S)ꢀ3ꢀ
(Methylamino)ꢀ1ꢀ(2ꢀthienyl) propanꢀ1ꢀol51 (0.200 g, 1.17 mmol) was dissolved in dry DCM (5
mL) and cooled to 0 °C. Pyridine (0.113 ml, 1.46 mmol) was then added followed by
benzenesulfonyl chloride (0.246 mg, 1.39 mmol). The reaction mixture was then allowed to
warm to rt and stirred for 14 h. The reaction mixture was then poured into water and extracted
with ethyl acetate (3x). This organic extracts were then dried (Na2SO4), filtered, concentrated in
vacuo. Purification by silica gel chromatography (40% ethyl acetate/ 60% hexanes) gave
sulfonamide S1 as a white solid (0.33 g, 90%).
24
14. TLC R = 0.45 (40% ethyl acetate/ 60% hexanes); [ ] = ꢀ7.4 (c = 0.8, DCM); IR (DCM)
̾
f
1
3499, 2925, 1446, 1331, 1160, 1089, 737, 691 cm–1; H NMR (300 MHz, CDCl3) δ 7.74ꢀ7.71
(m, 2H), 7.61ꢀ7.48 (m, 3H), 7.30 (d, J = 5.0 Hz, 1H), 6.98 (dd, J = 5.0, 3.5 Hz, 1H), 6.93 (dd, J =
28
ACS Paragon Plus Environment

Page 29 of 36
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
3.4, 1.0 Hz, 1H ), 4.49 (dd, J = 8.1, 5.3 Hz, 1H), 3.24ꢀ 3.14 (m, 1H), 2.85ꢀ2.73 (m, 1H), 2.62 (s,
3H), 2.14ꢀ2.01 (m, 1H), 1.93ꢀ 1.82 (m,1H). 13C{1H} NMR (75 MHz, CDCl3) δ 144.7, 137.4,
132.5, 129.0, 127.4, 126.7, 126.4, 125.5, 71.8, 47.3, 36.8, 34.9. Anal. Calcd for C14H17NO3S2: C,
54.00; H, 5.50; N, 4.50. Found: C, 53.72; H, 5.82; N, 4.38.
Supporting Information Available
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
Copies of 1H and 13C{1H} NMR spectra and chiral HPLC data for compound 16. This material is
available free of charge via the Internet at http:// pubs.acs.org.
Author Information
Corresponding Author
*Eꢀmail: jdchisho@syr.edu
Notes
The authors declare no competing financial interest.
Acknowledgements
Financial support was provided in part by the National Institute of General Medical Sciences
(R15ꢀGM116054). Acknowledgement is also made to the Donors of the American Chemical
Society Petroleum Research Fund for a New Directions award in support of this research (54823ꢀ
ND1). NMR spectra were obtained at Syracuse University using instrumentation acquired with
the assistance of the National Science Foundation (CHEꢀ1229345).
References:
1.
(a) Iversen, T.; Bundle, D. R. J. Chem. Soc., Chem. Commun. 1981, 1240. (b) Wessel, H.ꢀ
P.; Iversen, T.; Bundle, D. R. J. Chem. Soc. Pekin 1 1985, 2247. (c) Ali, I. A. I.; El
29
ACS Paragon Plus Environment