One-Step Trimethylstannylation of Benzyl and Alkyl Halides

Article abstract of DOI:10.1021/acs.joc.6b01883

Trialkylstannanes are good leaving groups that have been used for the formation of carbon-metal bonds to electrode surfaces for analyses of single-molecule conductivity. Here, we report the multistep synthesis of two amide-containing compounds that are of interest in studies of molecular rectifiers. Each molecule has two trimethylstannyl units, one linked by a methylene and the other by an ethylene group. To account for the very different reactivities of the parent halides, a new methodology for one-step trimethylstannylation was developed and optimized.

Full text of DOI:10.1021/acs.joc.6b01883

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Note
One-Step Trimethylstannylation of Benzyl and Alkyl Halides
Jianbing Jiang, Robert H. Crabtree, and Gary W. Brudvig
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b01883 • Publication Date (Web): 19 Sep 2016
Downloaded from http://pubs.acs.org on September 23, 2016
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One-Step Trimethylstannylation of Benzyl and Alkyl Halides
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Jianbing Jiang, Robert H. Crabtree* and Gary W. Brudvig*
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Department of Chemistry, Yale University, New Haven, Connecticut 06520, USA and
Energy Sciences Institute, Yale University, West Haven, Connecticut 06516, USA
*Corresponding Authors
robert.crabtree@yale.edu
gary.brudvig@yale.edu
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Abstract
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Trialkylstannanes are good leaving groups that have been used for the formation of
carbonꢀmetal bonds to electrode surfaces for analyses of singleꢀmolecule conductivity. Here, we
report the multiꢀstep synthesis of two amideꢀcontaining compounds that are of interest in studies
of molecular rectifiers. Each molecule has two trimethylstannyl units, one linked by a methylene
and the other by an ethylene group. To take account of the very different reactivities of the parent
halides, a new methodology for oneꢀstep trimethylstannylation was developed and optimized.
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The preparation of trialkylstannyl compounds is of broad importance due to their wide
applications in organic synthesis,1,2 their bioactivity3 and their surface attachment potential.4
Trialkylstannanes are common building blocks for construction of complex compounds, as
exemplified by Pdꢀmediated Stille coupling.2 Trialkylstannanes are also good leaving groups
facilitating the formation of carbonꢀmetal bonds for selfꢀassembled surface attachment.4ꢀ6 In
single molecule studies of molecular rectifiers between Au tips, CꢀAu bonds formed from
trimethyltin compounds gave improved performance compared with traditional methods.5,6 In
order to study the affect of unsymmetrical anchoring groups, it is necessary to synthesize
trialkylstannyl compounds with the SnR3 moieties linked asymmetrically to the molecular core,
such as by using a methylene linker on one end and an ethylene linker on the other (see 1 and 2
in Chart 1).
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Conventional methodologies for preparing trialkylstannyl compounds include either an
organotin nucleophile with an electrophilic counterpart, or an organotin electrophile with a
nucleophilic partner.7ꢀ13 Great efforts have been made to modulate the nucleophilicity or
electrophilicity of the trialkylstannyl unit to accommodate substrates with different reactivity.8ꢀ
12,14ꢀ16
Lipshutz et al.15 developed a method involving trimethylstannylmethylcuprate
[Me3Sn(Me)Cu(CN)Li2] which selectively delivered the trimethylstannyl moiety to a variety of
substrates. Oshima et al.14 prepared tributylstannylmanganate (R3SnMe3MnLi2) as a
trialkylstannylation reagent for several organic substrates. Uchiyama et al.16 used a polycyclic
aromatic hydrocarbonꢀcatalyzed method to prepare ambientꢀstable stannylꢀlithium (SnꢀLi)
compounds from different tin sources, and showed the high reactivity that resulted.
Molecular rectifiers are organic molecules, in which electron migration is favored in one
direction over the other.17 We have reported the synthesis of amideꢀcontaining compounds as
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molecular rectifiers with applications in solar energy conversion.18 The rectification property
measurements required the incorporation of anchoring groups on the molecules to attach to the
gold electrodes used in singleꢀmolecule break junction measurements.17,19,20 Several anchoring
groups have been reported,17,19,20 and one attractive type is RSnMe3. This transfers the R group
to Au and thus leads to the covalent attachment of the R group to a gold electrode surface. To
test asymmetric linkers, we needed to start from a precursor having halide groups of very
different reactivity. The two reported prior cases involve symmetrical compounds (I and II,
Chart 1) that contains either two benzyl or two alkyl trimethylstannyl units, different methods
being required for the synthesis of each.18
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Chart 1. Amido compounds with two trimethylstannyl groups.
Herein, we report the synthesis of two analogous compounds containing both a benzyl
and an alkyl trimethylstannyl unit at the opposite termini of each molecule (1 and 2, Chart 1).
Due to the unsymmetrical nature of both molecules, the synthetic strategy adopted here must be
totally different from the ones adopted for the two reported symmetrical counterparts I and II.18
In the present work, the methodology for introducing two trimethylstannyl units at two sites with
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different reactivity (benzyl vs. alkyl) was explored and optimized. The rectification efficiency of
the resulting compounds will be the focus of a subsequent paper, however.
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The preparation of target compound 1 was attempted using compound 4 as the key
intermediate (Scheme 1). Treatment of paraꢀsubstituted Nꢀmethylaniline with 4ꢀ
bromoethylbenzoyl chloride, which was prepared in situ by reaction of 4ꢀbromoethylbenzoic
acid with oxalyl chloride, afforded compound 3 in 75% yield (Scheme 1). Removal of the tertꢀ
butyldimethylsilyl (TBS) group was achieved with tetraꢀnꢀbutylammonium fluoride (TBAF).
However, the alkyl bromide was unexpectedly transformed to a styrene unit (side product 5,
Scheme 1), presumably due to the basic nature of the fluoride, which promoted the elimination
of HBr. Alternative conditions were explored using trifluoroacetic acid (TFA),21 but these failed
to remove the TBS unit.
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Scheme 1. Attempted synthesis of compound 1.
To avoid the use of the unsuitable TBS group, a synthetic strategy was adopted relying on
tetrahydropyranyl (THP), instead of TBS, to protect the hydroxyl group (Scheme 2). The key
intermediate 11 was prepared from 4ꢀaminobenzyl alcohol 6 via a multiꢀstep synthesis. Reaction
of 6 with trifluoroacetic anhydride in dichloromethane gave the diꢀtrifluoroacetyl–protected
compound 7. The ester unit of 7 was selectively hydrolyzed in quantitative yield under relatively
mild basic conditions that left the amide unit intact. Protection of the hydroxy group was
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achieved using THP in the presence of a catalytic amount of pꢀtoluenesulfonic acid monohydrate
(TsOH) to give compound 9, which was methylated with methyl iodide using sodium hydride as
base to give compound 10 in 78% yield. Deꢀacetylation of 10 was achieved in methanolic NaOH
solution at a modestly elevated temperature (50 °C) to give compound 11 in 91% yield. The
same reaction conditions as for the preparation of 3 were used here successfully to give
compound 12 in 69% yield. The hydroxyl group was unveiled by methanolic TsOH, and further
converted to benzyl bromide by an Appel reaction in 83% yield.
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Scheme 2. Synthesis of compound 13.
Benzyl and alkyl halides have greatly differing reactivity in almost all of their reactions
due to the special stability of the benzyl unit. Preparation of either benzyl or alkyl
trialkylstannanes has been reported,8,9,12,13 but no method is available to introduce R3Sn on both
benzyl and alkyl sites within a single molecule. Here, we explore and optimize a oneꢀstep
synthesis of R3Sn from both benzyl and alkyl halides by first forming a R3Sn anion, followed by
nucleophilic substitution. A variety of conditions (reagents, equivalents and reaction times) were
tested for optimization as listed in Table 1.
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n
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The initial conditions (Entry 1 in Table 1) involved the formation of Bu2Cu(CN)Li2 by
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mixing CuCN with two equivalents of BuLi, followed by addition of one equivalent of
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hexamethylditin to give Me3Sn(nBu)Cu(CN)Li2,15,22 which was expected to deliver the Me3Sn
unit both to the benzyl and the alkyl sites. However, only the monoꢀtrimethylstannylated product
14 and debrominated product 15 were observed, without detection of the desired product, 1, as
determined by highꢀresolution mass spectrometry (HRꢀMS) and proton nuclear magnetic
resonance (1H NMR). Elimination of CuCN from Entry 1 gave Me3SnLi as the nucleophile, but
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n
this still failed to give any improvement, presumably due to the excess BuLi causing lithiumꢀ
halogen exchange, rendering the benzyl and alkyl sites nucleophilic and affording the
debrominated products after acidic aqueous workꢀup.
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Table 1. Reaction conditions for trimethylstannylation of compound 13.a
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Productb,c
Entry
1
Reagents (equiv.)
Conditions
CuCN (3.3)
CuCN, nBuLi, –41 °C, 30 min →
hexamethylditin, –41 °C, 1 h →
13, –78 °C, 8 h
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15
nBuLi (6.6)
hexamethylditin (3.3)
nBuLi, –41 °C, 30 min →
hexamethylditin, –41 °C, 1 h →
13, –78 °C, 8 h
nBuLi (6.6)
hexamethylditin (3.3)
14
15
2
nBuLi (3.3)
1 (10%)
nBuLi, hexamethylditin, –41 °C, 40 min →
13, 8 h, 0 °C
nBuLi, hexamethylditin, –41 °C, 40 min →
13, 8 h, 0 °C
nBuLi, hexamethylditin, –41 °C, 40 min →
13, 30 min, 0 °C
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4
5
hexamethylditin (3.3)
14
nBuLi (2.1)
1 (32%)
hexamethylditin (2.1)
14
nBuLi (2.1)
1 (42%)
hexamethylditin (2.1)
14
aAll reactions were conducted in a Schlenk flask under N2 atmosphere; bproducts were confirmed
by 1H NMR and LCꢀMS; cisolated yields in the brackets.
n
Success was finally achieved by reducing the ratio of BuLi to hexamethylditin to 1:1
(3.3 eq, Entry 3). This at first gave the desired product in 10% yield. Further optimization raised
the yield to 32% (Entry 4). Finally, reducing the reaction time from 8 h to 30 min further
increased the yield to 42%, implying that we are dealing with a kinetic product that decays after
long reaction times. All the yields above are based on isolated products after fineꢀsilica column
chromatography. Reaction yields for side products 14 and 15 were not included due to the
presence of other inseparable minor impurities.
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Successful introduction of the trimethylstannyl units was confirmed by HRꢀMS, 1H NMR
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and C NMR. An expanded portion of the H NMR spectrum of compound 1 is displayed in
Figure 1 and shows the expected splitting patterns from the tin isotopes. 119Sn and 117Sn are the
most important isotopes among its three NMR active nuclei (115Sn, 117Sn and 119Sn, all with
I = ½). The benzyl –CH2– a protons were split by 119Sn and 117Sn, resulting in two broadened
satellite peaks with a coupling constant [J(H–119Sn) and J(H–117Sn)] of 64 Hz (Figure 1A). A
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similar splitting pattern was observed for the b protons with a J value of 56 Hz. The C NMR
spectrum also shows the splitting from 119Sn and 117Sn. The peaks from three methyl carbons A
and B attached to each Sn atom display two sets of satellite peaks with coupling constants
[J(C–119Sn) and J(C–117Sn)] of 1100 Hz for both carbons (Figure 1B). 119Sn NMR also gives two
distinct peaks for the two different Sn units (Figure 1C). All coupling constants observed above
are in good agreement with the reported values.23,24 HRꢀMS also shows interesting isotopic
distributions of the various tin isotopes. The observed spectrum is almost identical to the
simulated one, further confirming the presence of two Me3Sn units.
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CH3
Sn
CH3
C
H3
C
A
119Sn NMR
H3
C
a
I
Sn
a
H3
C
b
II
I
H3
C
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O
N
CH3
O
N
CH3
7
8
b
Sn
II
Sn
H
3C
CH3
CH3
H3C
CH3
CH3
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CH3
B
observed
D
580.0795
A
H3
C
Sn
578.0791
H3
C
582.0808
581.0819
B
A
B
579.0810
A
AB
576.0793
577.0806
584.0819
583.0832
O
N
CH3
575.0800
575 576 577 578 579 580 581 582 583 584
B
Sn
H
3C
CH3
calculated
CH3
575 576 577 578 579 580 581 582 583 584
m/z
Figure 1. 1H NMR (A), 13C NMR (B) and 119Sn NMR (C) spectra of compound 1 in CDCl3. (D)
HRꢀMS spectra of compound 1.
Scheme 3. Synthesis of compound 2.
The same strategy as we used for the synthesis of compound 1 was adopted to prepare
compound 2 (Scheme 3). THP protected Nꢀmethylanaline 16 was prepared according to a
previous procedure,18 and condensed with 4ꢀbromomethylbenzoic acid to give 17. Unexpected
benzyl halide exchanged occurred in this reaction to give benzyl chloride. The chloride
originated from either oxalyl chloride or sodium chloride during aqueous workꢀup. The same
THP deprotection and Appel reactions were conducted to give 18, and 19, respectively, in 95%
yield for both steps (Scheme 3). Trimethylstannylation of 19 using the optimized condition from
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1 (Entry 5 in Table 1) afforded 2 in 45% yield. The slightly higher yield than that for compound
1 (42%) presumably originated from ClꢀBr exchange, rendering the reactivity of benzyl chloride
closer to that of alkyl bromide.
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In conclusion, we have conducted a multiꢀstep synthesis for preparing amideꢀcontaining
compounds for future studies of these compounds as molecular rectifiers. In the synthesis of
these compounds, we developed an approach for oneꢀstep trimethylstannylation of benzyl and
alkyl halides in moderate yields. We believe this approach can be applied to other organic
substrates and lead to a variety of new symmetrical or unsymmetrical trialkylstannyl compounds.
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Experimental Section
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General information: All chemicals and solvents were commercially available and used
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as obtained, without further purification. H NMR spectra were recorded at a 400 MHz
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spectrometer, and C NMR spectra were recorded at a 100 MHz spectrometer. Chemical shifts
are reported as ppm from the internal reference tetramethylsilane (TMS). HRꢀMS was performed
on a QꢀTOF LC−MS with API by direct injection of a methanolic solution at ~0.5 mg/mL
concentration. NMR spectra are available in the Supporting Information.
Synthesis: 4-(2-Bromoethyl)-N-(4-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)-N-
methylbenzamide (3). To a suspension of 4ꢀbromoethylbenzoic acid (1.54 g, 6.74 mmol) in a
solvent mixture of CH2Cl2 (6.0 mL) and benzene (6.0 mL) was added oxalyl chloride (723 ꢁL,
8.43 mmol) and DMF (10 ꢁL, 0.77 mmol). The reaction mixture was stirred for 2 h under
nitrogen atmosphere. The solvent was removed under vacuum to give a yellow residue, which
was reꢀdissolved in benzene (6.0 mL). A solution of 4ꢀ(((tertꢀbutyldimethylsilyl)oxy)methyl)ꢀNꢀ
methylaniline (1.41 g, 5.62 mmol), triethylamine (2.35 mL, 16.9 mmol) and DMAP (35 mg, 0.29
mmol) in CH2Cl2 (6.0 mL) was then added to the benzene solution. The combined mixture was
stirred at room temperature for 16 h under nitrogen atmosphere. The reaction residue was diluted
with CH2Cl2, washed with aqueous NaHCO3, and extracted with CH2Cl2. The organic extracts
were combined, dried over Na2SO4 and chromatographed [silica, CH2Cl2/ethyl acetate (9:1)] to
afford a colorless oil (2.18 g, 75%). 1H NMR (400 MHz, CDCl3) δ 7.24 (d, J = 8.0 Hz, 2H), 7.17
(d, J = 8.0 Hz, 2H), 6.99 (d, J = 4.0 Hz, 2H), 6.97 (d, J = 4.0 Hz, 2H), 4.66 (s, 2H), 3.47 (s, 3H),
3.45 (t, J = 4.0 Hz, 2H), 3.05 (t, J = 4.0 Hz, 2H), 0.91 (s, 9H), 0.05 (s, 6H); 13C NMR (100 MHz,
CDCl3) δ 170.3, 143.6, 140.4, 139.8, 134.5, 129.1, 128.1, 126.9, 126.6, 64.4, 39.0, 38.5, 32.2,
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25.9, 18.4, –5.25; HRMS (ESI) m/z: (M + H)+ Calcd for C23H33BrNO2Si 462.1458, found
462.1438.
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4-(2,2,2-Trifluoroacetamido)benzyl 2’,2’,2’-trifluoroacetate (7). To a solution of 4ꢀ
aminobenzyl alcohol (1.23 g, 10 mmol) in anhydrous CH2Cl2 (250 mL) was added K2CO3
(6.91 g, 50 mmol) and trifluoroacetic anhydride (4.24 mL, 30 mmol) and the mixture was stirred
at room temperature under nitrogen for 1 h. The reaction mixture was washed with water and
extracted with CH2Cl2. The combined organic extract was dried over Na2SO4 and the solvent
was evaporated to yield a yellowꢀbrown solid (3.09 g, 98%). The compound was used for the
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next step without further purification. H NMR (400 MHz, DMSOꢀd6) δ 11.34 (s, 1H), 7.69 (d,
J = 12 Hz, 2H), 7.48 (d, J = 12 Hz, 2H), 5.39 (s, 2H); 13C NMR (100 MHz, CDCl3) δ 160.0,
135.9, 131.3, 129.9, 120.7, 115.0, 68.8; HRMS (ESI) m/z: (M + Na)+ Calcd for C11H7F6NO3Na
338.0222, found 338.0233.
2,2,2-Trifluoro-N-(4-(hydroxymethyl)phenyl)acetamide (8). To a solution of 7 (2.28 g,
7.23 mmol) in methanol (190 mL) was added a 2.0 M aqueous solution of potassium hydroxide
(36 ꢁL, 72 ꢁmol) and the mixture was stirred at 50 °C under nitrogen for 1 h. The solution was
cooled down to room temperature, and the solvent was evaporated under reduced pressure to
yield the desired product as a brown solid (1.58 g, 99%). It was used for the next reaction
without further purification. 1H NMR (400 MHz, DMSOꢀd6) δ 11.19 (s, 1H), 7.59 (d, J = 8.0 Hz,
2H), 7.32 (d, J = 8.0 Hz, 2H), 5.18 (t, J = 8.0 Hz, 1H), 4.46 (d, J = 8.0 Hz, 2H); 13C NMR
(100 MHz, CDCl3 + CD3OD) δ 142.7, 139.0, 131.5, 124.8, 121.3, 118.4, 67.8, 3.7; HRMS (ESI)
m/z: (M + Na)+ Calcd for C9H8F3NO2Na 242.0399, found 242.0402.
2,2,2-Trifluoro-N-(4-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)phenyl)acetamide (9).
To a solution of 8 (1.4 g, 6.39 mmol) in anhydrous dichloromethane (128 mL) was added 3,4ꢀ
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dihydroꢀ2Hꢀpyran (641 ꢁL, 7.03 mmol) and TsOH (60.7 mg, 0.32 mmol). The mixture was
stirred under nitrogen at room temperature for 4 h. The mixture was washed with aqueous
NaHCO3 and extract with CH2Cl2. The combined organic extract was dried over Na2SO4 and the
solvent was evaporated under reduced pressure. The crude residue was purified by column
chromatography [(silica, CH2Cl2/EtOAc (9:1)] to yield the desired compound as a colorless oil
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(1.57 g, 81%). H NMR (400 MHz, CDCl3) δ 7.88 (br, 1H), 7.54 (d, J = 8.0 Hz, 2H), 7.40 (d,
J = 8.0 Hz, 2H), 4.77 (d, J = 12 Hz, 1H), 4.69 (t, J = 4.0 Hz, 1H), 4.49 (d, J = 12 Hz, 1H), 3.87–
3.93 (m, 1H), 3.52–3.57 (m, 1H), 1.52–1.90 (m, 6H); 13C NMR (100 MHz, CDCl3) δ 136.6,
134.3, 128.7, 120.4, 117.1, 114.2, 97.8, 68.1, 62.2, 30.5, 25.4, 19.3; HRMS (ESI) m/z: (M + Na)+
Calcd for C14H16F3NO3Na 326.0974, found 326.0955.
2,2,2-Trifluoro-N-methyl-N-(4-(((tetrahydro-2H-pyran-2-
yl)oxy)methyl)phenyl)acetamide (10). To a solution of 9 (1.28 g, 4.23 mmol) in anhydrous
THF (53 mL) under nitrogen was added sodium hydride (60 wt% dispersion in mineral oil,
194 mg, 4.85 mmol) and methyl iodide (395 ꢁL, 6.35 mmol) and the reaction mixture was stirred
under nitrogen at 45 °C for 2 h. The mixture was cooled down to room temperature and
quenched with water. The aqueous layer was extracted with ethyl acetate. The combined organic
layers were combined, dried over Na2SO4 and filtered. The filtrate was evaporated under reduced
pressure. Column chromatography [silica, CH2Cl2/EtOAc (19:1)] yielded the desired compound
as a colorless oil (1.05 g, 78%). 1H NMR (400 MHz, CDCl3) δ 7.42 (d, J = 8.0 Hz, 2H), 7.20 (d,
J = 8.0 Hz, 2H), 4.81 (d, J = 12 Hz, 1H), 4.72 (t, J = 4.0 Hz, 1H), 4.52 (d, J = 12 Hz, 1H), 3.86–
3.92 (m, 1H), 3.52–3.58 (m, 1H), 3.3 (s, 3H), 1.53–1.90 (m, 6H); 13C NMR (100 MHz, CDCl3) δ
154.7, 136.6, 134.3, 128.7, 120.4, 115.6, 97.8, 68.0, 62.2, 30.5, 25.5, 19.3; HRMS (ESI) m/z: (M
+ H)+ Calcd for C15H19F3NO3 318.1312, found 318.1308.
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N-Methyl-4-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)aniline (11). To a solution of 10
(1.06 g, 3.33 mmol) in methanol (50 mL) was added KOH (559 mg, 9.98 mmol) and the mixture
was stirred at room temperature under nitrogen for 3 h. The solvent was evaporated. The residue
was washed with water and extracted with ethyl acetate. The organic extract was dried over
Na2SO4 and the solvent was evaporated to yield a colorless oil (0.67 g, 91%). The obtained
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compound was used without further purification in the following step. H NMR (400 MHz,
CDCl3) δ 7.20 (d, J = 8.0 Hz, 2H), 6.59 (d, J = 8.0 Hz, 2H), 4.68 (t, J = 4.0 Hz, 1H), 4.67 (d,
J = 12 Hz, 1H), 4.40 (d, J = 12 Hz, 1H), 3.91–3.97 (m, 1H), 3.73 (br, 1H), 3.51–3.57 (m, 1H),
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1.53–1.90 (m, 6H); C NMR (100 MHz, CDCl3) δ 149.0, 129.7, 112.2, 97.2, 68.8, 62.2, 30.65,
30.78, 25.6, 19.5; HRMS (ESI) m/z: (M + H)+ Calcd for C13H20NO2 222.1489, found 222.1477.
4-(2-Bromoethyl)-N-methyl-N-(4-(((tetrahydro-2H-pyran-2-
yl)oxy)methyl)phenyl)benzamide (12). To a suspension of 4ꢀbromoethylbenzoic acid (1.16 g,
5.04 mmol) in benzene (30 mL) was added oxalyl chloride (520 ꢁL, 6.05 mmol) and DMF (8 ꢁL,
0.62 mmol). The reaction mixture was stirred for 2 h under nitrogen atmosphere. The solvent
was removed under vacuum to give a yellow residue, which was reꢀdissolved in benzene
(6.0 mL). A solution of 11 (744 mg, 3.36 mmol), triethylamine (1.4 mL, 10.1 mmol) and DMAP
(20 mg, 0.16 mmol) in CH2Cl2 (6.0 mL) was then added to the benzene solution. The combined
mixture was stirred at room temperature for 16 h under nitrogen atmosphere. The reaction
residue was diluted with CH2Cl2, washed with brine, and extracted with CH2Cl2. The organic
extracts were combined, dried over Na2SO4 and chromatographed [silica, CH2Cl2/ethyl acetate
1
(19:1)] to afford a colorless oil (1.5 g, 69%). H NMR (400 MHz, CDCl3) δ 7.25 (d, J = 8.0 Hz,
2H), 7.22 (d, J = 8.0 Hz, 2H), 7.00 (d, J = 8.0 Hz, 4H), 4.71 (d, J = 12 Hz, 1H), 4.64 (t,
J = 4.0 Hz, 1H), 4.42 (d, J = 12 Hz, 1H), 3.83–3.89 (m, 1H), 3.44–3.54 (m, 6H), 3.06 (t,
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J = 8.0 Hz, 2H), 1.51–1.87 (m, 6H); C NMR (100 MHz, CDCl3) δ 170.3, 144.1, 140.5, 136.7,
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134.5, 129.1, 128.4, 128.0, 126.7, 97.9, 68.1, 62.2, 39.0, 32.1, 30.5, 25.4, 19.4; HRMS (ESI)
m/z: (M + H)+ Calcd for C22H27BrNO3 432.1169, found 432.1139.
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4-(2-Bromoethyl)-N-(4-(hydroxymethyl)phenyl)-N-methylbenzamide (4). To
a
solution of 12 (210 mg, 0.486 mmol) in methanol (2.43 mL) was added TsOH (9.2 mg,
48.6 ꢁmol). The resulting mixture was stirred at room temperature under nitrogen for 3 h.
Aqueous NaHCO3 was added to the reaction mixture, and the resulting solution was extracted by
CH2Cl2. The organic extract was combined, dried and chromatographed [silica, CH2Cl2/ethyl
1
acetate (7:3)] to afford a colorless oil (164 mg, 97%). H NMR (400 MHz, CDCl3) δ 7.20–7.24
(m, 4H), 6.99–7.02 (m, 4H), 4.63 (s, 2H), 3.47 (s, 3H), 3.46 (t, J = 8.0 Hz, 2H), 3.06 (t,
J = 8.0 Hz, 2H), 1.76 (br, 1H); 13C NMR (100 MHz, CDCl3) δ 170.4, 144.1, 140.5, 139.2, 134.4,
129.1, 128.1, 127.6, 126.9, 64.5, 39.0, 38.5, 32.3, 29.7; HRMS (ESI) m/z: (M + H)+ Calcd for
C17H18BrNO2 348.0594, found 348.0583.
4-(2-Bromoethyl)-N-(4-(bromomethyl)phenyl)-N-methylbenzamide (13). To
a
solution of 4 (82 mg, 0.24 mmol) in anhydrous CH2Cl2 (2.35 mL) was added carbon
tetrabromide (117 mg, 0.35 mmol) and triphenylphosphine (92.6 mg, 0.35 mmol) and the
mixture was stirred at 0 °C under nitrogen. The mixture was further stirred at room temperature
for 4 h. The reaction mixture was chromatographed [silica, CH2Cl2/ethyl acetate (9:1)] to yield
the desired product as a colorless oil (80 mg, 83%). 1H NMR (400 MHz, CDCl3) δ 7.23–7.26 (m,
4H), 6.98–7.03 (m, 4H), 4.41 (s, 2H), 3.48 (s, 3H), 3.47 (t, J = 8.0 Hz, 2H), 3.07 (t, J = 8.0 Hz,
2H); 13C NMR (100 MHz, CDCl3) δ 170.3, 144.8, 140.7, 135.9, 134.2, 129.9, 129.1, 128.2,
127.0, 39.0, 38.4, 32.6, 32.3; HRMS (ESI) m/z: (M + Na)+ Calcd for C17H17Br2NONa 431.9569,
found 431.9540.
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N-Methyl-4-(2-(trimethylstannyl)ethyl)-N-(4-
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((trimethylstannyl)methyl)phenyl)benzamide (1). A solution of hexamethylditin (171 ꢁL,
0.823 mmol) in anhydrous THF (3.0 mL) was purged with nitrogen and cooled down to –40 °C
using an acetonitrile/dry ice cooling bath. nꢀButyllithium (293 ꢁL, 2.2 M in hexanes,
0.778 mmol) was added dropwise to the suspension and the mixture was stirred at –40 °C for
40 min under nitrogen. A solution of 13 (94 mg, 0.229 mmol) in anhydrous THF (3.0 mL) was
added dropwise and the mixture was further stirred at –40 °C for 30 min under nitrogen. The
reaction was quenched with a saturated aqueous ammonium chloride solution. The mixture was
extracted with ethyl acetate, and the organic phase was dried over Na2SO4 and the solvent was
evaporated. The crude residue was purified by column chromatography [silica, hexanes/ethyl
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acetate (17:3)] to yield the desired compound as a colorless oil (55.6 mg, 42%). H NMR
(400 MHz, CDCl3) δ 7.18 (d, J = 8.0 Hz, 2H), 6.94 (d, J = 8.0 Hz, 2H), 6.77–6.83 (m, 4H), 3.44
(s, 3H), 2.71 (d, J = 8.0 Hz, 2H), 2.23 (s, 2H), 1.04 (d, J = 8.0 Hz, 2H), –0.01 (s, 9H), –0.06 (s,
9H); 13C NMR (100 MHz, CDCl3) δ 170.6, 146.8, 141.8, 140.4, 133.3, 129.0, 127.1, 127.0,
126.9, 38.4, 32.3, 19.8, 12.2, 10.0, 10.3; HRMS (ESI) m/z: (M + H)+ Calcd for C23H36NOSn2
582.0835, found 582.0810. Compounds 14 and 15 were also isolated on the same column
chromatography. The yields are not reported here due to the presence of minor impurities in each
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sample. Compound 14: H NMR (400 MHz, CDCl3) δ 7.21 (d, J = 8.0 Hz, 2H), 7.0 (d, J = 8.0
Hz, 2H), 6.97 (d, J = 8.0 Hz, 2H), 6.91 (d, J = 8.0 Hz, 2H), 3.45 (s, 3H), 2.75 (t, J = 8.0 Hz, 2H),
2.27 (s, 3H), 1.08 (t, J = 8.0 Hz, 2H), –0.08 (s, 9H); HRMS (ESI) m/z: (M + H)+ Calcd for
C20H28NOSn 418.1187, found 418.1205. Compound 15: 1H NMR (400 MHz, CDCl3) δ 7.22 (d, J
= 8.0 Hz, 2H), 7.02 (d, J = 8.0 Hz, 2H), 6.98 (d, J = 8.0 Hz, 2H), 6.91 (d, J = 8.0 Hz, 2H), 3.45
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(s, 3H), 2.55 (q, J = 8.0 Hz, 2H), 2.28 (s, 3H), 1.15 (t, J = 8.0 Hz, 3H); HRMS (ESI) m/z: (M +
H)+ Calcd for C17H20NO 254.1539, found 254.1555.
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4-(Chloromethyl)-N-methyl-N-(4-(2-((tetrahydro-2H-pyran-2-
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yl)oxy)ethyl)phenyl)benzamide (17). To a suspension of 4ꢀbromomethylbenzoic acid (1.08 g,
5.04 mmol) in CH2Cl2 (8.0 mL) was added oxalyl chloride (780 ꢁL, 9.08 mmol) and DMF
(20 ꢁL, 1.54 mmol). The reaction mixture was stirred for 3 h under nitrogen atmosphere to give a
yellow suspension. Benzene (8.0 mL) was added, and the mixture was stirred for another 2 h.
The solvent was removed under vacuum to give a yellow residue, which was reꢀdissolved in
benzene (6.0 mL). A solution of 16 (791 mg, 3.36 mmol), triethylamine (1.4 mL, 10.1 mmol)
and DMAP (20 mg, 0.16 mmol) in CH2Cl2 (6.0 mL) was then added to the benzene solution.
The combined mixture was stirred at room temperature for 16 h under nitrogen atmosphere. The
reaction residue was diluted with CH2Cl2, washed with brine, and extracted with CH2Cl2. The
organic extract was combined, dried over Na2SO4 and chromatographed [silica, CH2Cl2/ethyl
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acetate (19:1)] to afford a colorless oil (678 mg, 52%). H NMR (400 MHz, CDCl3) δ 7.28 (d,
J = 8.0 Hz, 2H), 7.17 (d, J = 8.0 Hz, 2H), 7.10 (d, J = 8.0 Hz, 2H), 6.94 (d, J = 8.0 Hz, 2H), 4.54
(t, J = 4.0 Hz, 1H), 4.47 (s, 2H), 3.85–3.91 (m, 1H), 3.67–3.73 (m, 1H), 3.51–3.57 (m, 1H),
13
3.34–3.46 (m, 4H), 2.83 (d, J = 8.0 Hz, 2H), 1.44–1.80 (m, 6H); C NMR (100 MHz, CDCl3)
δ 169.9, 142.8, 138.6, 137.8, 135.9, 129.8, 129.1, 127.8, 126.6, 98.7, 67.9, 63.3, 45.5, 35.7, 30.6,
25.4, 19.4; HRMS (ESI) m/z: (M + H)+ Calcd for C22H27ClNO3 388.1674, found 388.1643.
4-(Chloromethyl)-N-(4-(2-hydroxyethyl)phenyl)-N-methylbenzamide (18). To
a
solution of 17 (110 mg, 0.248 mmol) in methanol (1.42 mL) was added TsOH (5.5 mg,
28.4 ꢁmol). The resulting mixture was stirred at room temperature under nitrogen for 2 h.
Aqueous NaHCO3 was added to the reaction mixture, and the resulting solution was extracted by
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CH2Cl2. The organic extract was combined and dried over Na2SO4 to afford a colorless oil
(82 mg, 95%). 1H NMR (400 MHz, CDCl3) δ 7.27 (d, J = 8.0 Hz, 2H), 7.17 (d, J = 8.0 Hz, 2H),
7.07 (d, J = 8.0 Hz, 2H), 6.95 (d, J = 8.0 Hz, 2H), 4.46 (s, 2H), 3.77 (t, J = 8.0 Hz, 2H), 3.45 (s,
3H), 2.77 (t, J = 8.0 Hz, 2H), 1.88 (br, 1H); 13C NMR (100 MHz, CDCl3) δ 170.0, 142.9, 138.7,
137.3, 135.9, 129.8, 129.1, 127.9, 126.9, 63.3, 45.5, 38.5, 29.7; HRMS (ESI) m/z: (M + H)+
Calcd for C17H19ClNO2 304.1099, found 304.1070.
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N-(4-(2-Bromoethyl)phenyl)-4-(chloromethyl)-N-methylbenzamide (19). To
a
solution of 18 (87 mg, 0.29 mmol) in anhydrous CH2Cl2 (2.87 mL) was added carbon
tetrabromide (143 mg, 0.43 mmol) and triphenylphosphine (113 mg, 0.43 mmol) and the mixture
was stirred at 0 °C under nitrogen. The mixture was further stirred at room temperature for 3.5 h.
The reaction mixture was chromatographed [silica, CH2Cl2/ethyl acetate (19:1)] to yield the
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desired product as a colorless oil (100 mg, 95%). H NMR (400 MHz, CDCl3) δ 7.27 (d,
J = 8.0 Hz, 2H), 7.18 (d, J = 8.0 Hz, 2H), 7.07 (d, J = 8.0 Hz, 2H), 6.98 (d, J = 8.0 Hz, 2H), 4.48
13
(s, 2H), 3.50 (d, J = 8.0 Hz, 2H), 3.48 (s, 3H), 3.09 (d, J = 8.0 Hz, 2H); C NMR (100 MHz,
CDCl3) δ 169.9, 143.4, 138.8, 137.3, 135.8, 129.5, 129.1, 127.9, 126.9, 45.5, 38.5, 38.4, 32.6;
HRMS (ESI) m/z: (M + H)+ Calcd for C17H18BrClNO 366.0333, found 366.0348.
N-Methyl-N-(4-(2-(trimethylstannyl)ethyl)phenyl)-4-
((trimethylstannyl)methyl)benzamide (2). A solution of hexamethylditin (140 ꢁL,
0.676 mmol) anhydrous THF (3.2 mL) was purged with nitrogen and cooled down to –40 °C
using an acetonitrile/dry ice cooling bath. nꢀButyllithium (255 ꢁL, 2.2 M in hexanes,
0.676 mmol) was added dropwise to the suspension and the mixture was stirred at –40 °C for
40 min under nitrogen. A solution of 19 (118 mg, 0.322 mmol) in anhydrous THF (3.2 mL) was
added dropwise and the mixture was further stirred at –40 °C for 30 min under nitrogen. The
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cooling bath was then removed, and the reaction mixture was then slowly allowed to warm up to
room temperature and stirred for 45 min. The reaction was quenched with a saturated aqueous
ammonium chloride solution. The mixture was extracted with ethyl acetate, and the organic
phase was dried over Na2SO4 and the solvent was evaporated. The crude residue was purified by
column chromatography [silica, hexanes/ethyl acetate (17:3)] to yield the desired compound as a
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colorless oil (83.9 mg, 45%). H NMR (400 MHz, CDCl3) δ 7.12 (d, J = 8.0 Hz, 2H), 7.02 (d,
J = 8.0 Hz, 2H), 6.90 (d, J = 8.0 Hz, 2H), 6.73 (d, J = 8.0 Hz, 2H), 3.45 (s, 3H), 2.74 (t,
13
J = 8.0 Hz, 2H), 2.22 (s, 2H), 1.08 (t, J = 8.0 Hz, 2H), –0.02 (s, 9H), –0.04 (s, 9H); C NMR
(100 MHz, CDCl3) δ 171.0, 145.5, 143.3, 143.0, 130.5, 129.2, 128.4, 126.6, 125.7, 38.5, 32.0,
20.6, 12.3, –10.0, –10.2; HRMS (ESI) m/z: (M + H)+ Calcd for C23H36NOSn2 582.0835, found
582.0818.
Acknowledgement
This work was supported by grants from the U.S. Department of Energy (DEꢀFG02ꢀ
07ER15909), and a generous grant from the TomKat Foundation. We would like to thank
Terence Wu and Mousumi Ghosh of the Yale West Campus Analytical Core staff for help with
instrumentation.
Supporting Information.
The Supporting Information is available free of charge on the ACS Publications website
at http://pubs.acs.org/journal/joceah.
NMR spectra of compounds 1–4, 7–13 and 17–19.
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References
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