The phosphate-carboxylate mixed-anhydride method: A mild, efficient process for ester and amide bond construction

Article abstract of DOI:10.1016/j.tet.2012.04.103

A highly efficient carboxylate-phosphate anhydride pathway is described for the direct, economical synthesis of esters and amides from carboxylic acids and alcohols or amines. The reaction proceeds with retention of configuration with both chiral secondary alcohols and α-amino acid derivatives allowing access to useful chiral auxiliaries, ligands, and organocatalysts. Ester and amide products can be isolated directly in high yield due to the water soluble nature of the side products.

Full text of DOI:10.1016/j.tet.2012.04.103

Tetrahedron 68 (2012) 5415e5421
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The phosphateecarboxylate mixed-anhydride method: a mild, efficient process
for ester and amide bond construction
,
a
a
b
James McNulty a , Ramesh Vemula , Venkatesan Krishnamoorthy , Al Robertson
*
a Department of Chemistry, McMaster University, 1280 Main Street West, Hamilton, Ontario L8S 4M1, Canada
b Cytec Canada Inc., P.O. Box 240, Niagara Falls, Ontario L2E 6T4, Canada
a r t i c l e i n f o
a b s t r a c t
Article history:
A highly efficient carboxylateephosphate anhydride pathway is described for the direct, economical
synthesis of esters and amides from carboxylic acids and alcohols or amines. The reaction proceeds with
retention of configuration with both chiral secondary alcohols and a-amino acid derivatives allowing
access to useful chiral auxiliaries, ligands, and organocatalysts. Ester and amide products can be isolated
directly in high yield due to the water soluble nature of the side products.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 20 March 2012
Received in revised form 24 April 2012
Accepted 25 April 2012
Available online 2 May 2012
Keywords:
Acylation
Mixed-anhydride
Ester
Amide
Chiral amines
Organocatalysis
1. Introduction
the Mitsunobu3 esterification process, are especially sought. Mild
methods that achieve carboxylic acid activation resulting in re-
Acylation reactions of carboxylic acids with alcohols or amines
to form ester or amide derivatives represents one of the most im-
portant and commonly employed transformations in organic syn-
thesis.1,2 Large scale esterification processes are used for the
synthesis of a variety of end-products including, monomers, poly-
mers, plasticizers, and fragrance chemicals, many on an industrial
scale. Classic methods, such as Fischer esterification or the use of
activating agents, such as thionyl chloride proceed under highly
acidic conditions, while alkylation of carboxylate anions to give
esters can be performed under strongly basic conditions in dipolar
solvents2c or ionic liquids.2d While these methods are appropriate
for many simple carboxylate acylation reactions, the extreme
acidity or basicity required limits the scope and these reactions are
rarely employed in the synthesis of chiral and/or sensitive de-
rivatives. Acylation processes leading to high-value fine chemicals,
such as peptide derivatives, organocatalysts, pharmaceuticals,
pheromones, and fragrances require milder and more stringent
coupling protocols to achieve the desired chemo- and stereo-
selectivity. Situations that proceed with reliable stereocontrol in-
volving either inversion or retention of stereochemistry, such as in
tention of stereochemistry at the a-position of chiral carboxylic
acids and retention coupled to the use of chiral amines or alcohols
are also of great importance in amide and peptide bond forming
reactions and in the synthesis of natural products (lactones, dep-
sipeptides, lactams etc.). Several reagents are commonly employed
to achieve these purposes, as shown in Scheme 1, notable examples
being the use of carboxylate activating agents, such as DCC or EDC,
and Mitsunobu-type reagents based on Ph3P/DEAD or Bu3P/DIAD.
While effective in driving the acylation process, these reagents
unfortunately produce stoichiometric quantities of unwanted hy-
drated side products, such as DCCeurea and Ph3P]O/DEADH2
(Scheme 1) that complicate work-up and purification processes and
render the overall processes with low atom-economy.
The mixed-anhydride method for carboxylic group activation is
also well known, typically involving activation with a reactive acid
chloride, such as the Yamaguchi reagent.4 Mixed carbox-
ylateephosphate anhydrides have also been employed in acylation
reactions.5e7 Surprisingly, this process does not appear to be well
known and is rarely applied. The reactive reagent phenyl dichlor-
ophosphate has been exploited in both ester5 and thioester6 bond
forming processes. The use of less reactive, more selective
monochloro-disubstituted phosphates has also been reported,
mainly in the synthesis of macrocyclic lactones, through activation
of the corresponding seco-acid derivatives via the mixed
* Corresponding author. Tel.: þ1 905 525 9140x27393; fax: þ1 905 522 2509;
e-mail address: jmcnult@mcmaster.ca (J. McNulty).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2012.04.103

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J. McNulty et al. / Tetrahedron 68 (2012) 5415e5421
2. Results and discussion
To begin, we studied the model reaction of 4-nitrobenzoic acid
with the lipophilic alcohol n-dodecanol employing 1 equiv of
diethyl chlorophosphate 1. While no reaction occurred in
dichloromethane at rt in the presence of triethylamine, a significant
turnover was seen with the use of pyridine as a base at rt (Table 1,
entry 2), and more so upon warming (Table 1, entry 3). Switching to
neat pyridine as solvent allowed for complete conversion and iso-
lation of the ester in very high yield (entry 4). Thus neither the
more nucleophilic DMAP10 nor reagent 39 are required to effect
efficient esterification using the monochloro phosphate 1.
Table 1
Direct esterification of acids and alcohols with 1 in pyridine
O
O
Scheme 1. Methods for mild carboxylate activation and the stoichiometric formation
of side products (Cy¼cyclohexyl-, DCC¼dicyclohexylcarbodiimide, DEAD-
¼diethylazidodi-carboxylate).
OH
O
1 (1.0 eq)
9
+
+
HO
9
O2N
O2N
Entry
Base (equiv)
Reaction conditions
Isolated yield of 8a (%)
phosphateecarboxylate anhydride in the presence of base.7 This
method has continued to escape attention7a despite the ready
availability of the required reagents.
1
2
3
4
Et3N (2.5 equiv)
Py (2.5 equiv)
Py (2.5 equiv)
Py (2.5 equiv)
CH2Cl2, 20 ꢀC, 12 h
CH2Cl2, 20 ꢀC, 6 h
CH2Cl2, 40 ꢀC, 6 h
70 ꢀC, 6 h
0
48
55
91
We have been interested in the development of novel carboxylic
acid activating agents and conditions for controlled esterification
over a number of years2d,8 and were attracted to a publication9
describing an activated derivative of the mild phosphorylating
agent diethyl chlorophosphate 1. This method, outlined in Scheme 2,
was reported to require reagent 3 and the process based on the
formation of an activated 6-oxo-6H-pyridazin-1-yl phosphorylating
agent 4 from the reaction of 1 with 3. This reagent reacts with the
carboxylic acid to form the mixed anhydride 2, subsequently pro-
ceeding to give the ester 5 upon addition of the desired alcohol
derivative.
From this initial process we developed a generally effective
procedure for the esterification process and work-up protocol. In
the general reaction, use of a 1:1 ratio of carboxylic acid and alcohol
and 1.05 equiv of diethyl chlorophosphate 1 reacted in neat pyri-
dine at 70 ꢀC successfully and all reactions were complete within
3 h. The overall scope of this acylation method is presented in Table
2. The table reports isolated yields for the chromatographically
purified esters. Under these conditions, a range of aromatic,
unsaturated and aliphatic carboxylic acids, including -hindered
acids, could readily be condensed with alcohols (Table 2). For ex-
ample, -menthol readily reacted with the phosphate-activated
a,b-
a
L
cinnamic acid derivative giving the methyl cinnamate ester in
good yield and with complete retention of stereochemistry (Table
2, entry 4). In addition, N-protected
a-amino acids (Table 2, entry
6) could also be coupled with alcohols including
ing a single diastereomeric product. All of the results confirmed
that the reaction proceeds with retention of stereochemistry on
L
-menthol, yield-
Scheme 2. Formation of phosphateecarboxylate mixed anhydride 2 via the use of
reagent 3 and diethyl chlorophosphate.9
both the part of the chiral secondary alcohol and
a-amino car-
boxylic acid stereogenic centers. The successful participation of 2-
phenylethanol 6c (entries 3 and 7, Table 2) in the reaction pro-
vided 2-phenylethylesters in good yield without styrene formation,
again indicating that no activation of the alcohol occurs. The re-
action was successful with primary and secondary alcohols, failing
only in the case of tertiary butanol. The esterification of the pro-
The requirement of the activated intermediate 4 in this chem-
istry drew our attention for two reasons, first of all the requirement
of reagent 3 was not convincing mechanistically and secondly the
situation appeared reminiscent of some of the lactonization diffi-
culties encountered with the use of the Yamaguchi macro-
lactonization method. In problematic cases, Yonemitsu and co-
workers10 reported that the use of excess DMAP and mild heating,
so as not to promote symmetrical carboxylic anhydride formation,
was highly effective in promoting the mixed-anhydride pathway. In
an initial communication from our group,8e we demonstrated that
reagent 3 is not required, and that a pyridine base alone allowed
formation of the mixed- anhydride 2 directly from 1 and the car-
boxylic acid. Herein we report our complete findings on the suc-
cessful activation of this pathway using only pyridine. The method
allows for the straightforward and direct synthesis of a range of
esters and amides, with retention of stereochemistry at any ster-
eogenic centers present when employing chiral alcohols or amines.
Product purification can be achieved through simple aqueous/or-
ganic solvent partition. The relatively high atom-economy, ease of
product isolation and low cost of reagents11 make the phospha-
teecarboxylate method an attractive alternative in controlled ester
and amide bond-forming processes.
tected
a
-amino acid 5k and phenylacetate 5d with L-menthol (en-
tries 12 and 13) allowed access to the useful chiral auxiliary
functionalized derivatives 8l and 8m. A further advantage in using
the diethyl chlorophosphate 1 process is that the reagent can be
employed directly in the presence of the alcohol in pyridine. Most
likely, the more nucleophilic carboxylate anion attacks the acti-
vated derivative of 1 to form the mixed anhydride, in preference to
the alcohol. No diethyl phosphate esters have been observed from
the direct reaction of the alcohols with 1.
The reaction of the same diethyl phosphate-activated carboxylic
acid anhydrides with amines could also be carried out effectively,
however the process required a small change to the procedure. The
overall reaction was not successful when done in the initial pres-
ence of the amine as diethylphosphoramide side products were
obtained, no doubt due to the higher nucleophilicity of the amine.
This issue was easily resolved through sequential addition of the
amine to the activated acid. This general protocol completely

J. McNulty et al. / Tetrahedron 68 (2012) 5415e5421
5417
suppressed phosphoramide formation and resulted in high yields
of the desired condensed amide products. This protocol proved to
be general for all primary and secondary amines investigated and
overall results are summarized in Table 3. The process allows rapid
access to synthetically useful Weinreb11a,b amide derivatives as well
Table 2
Synthesis of ester derivatives using the phosphateecarboxylate mixed-anhydride
method
Entry
1
R-CO2H
R-OH 6
Product 8
Yielda (%) 8
as the amide adducts from both chiral a-amino ester derivatives as
O
O
O
the amine component and with N-protected acids as the carboxylic
acid component. In view of the current interest of prolinamide and
derived products in asymmetric organocatalysis,11c we focussed on
HO
6a
9
OH
91
9
O2N
O2N
O2N
8a
5a
formation of amide derivatives from N-Boc-protected- -proline 5e.
L
As shown in Table 3, a wide range of functionalized prolinamide
derivatives are readily available using this method.
O
HO
6b
O
2
3
4
5a
88
80
86
8b
Table 3
O
OH
O
Synthesis of amide derivatives using the phosphateecarboxylate mixed-anhydride
method
OH
O
6c
8c
Yielda (%) 9
5b
Entry
1
R-CO2H
R0-NH2
7
Product 9
O
O
O
O
N
O
HN
OH
O
O
OH
OH
79
.HCl
Cl
Cl
MeO
O
5c
7a
6d
9a
5g
8d
O
OH
O
O
O
O
O
O
O
H2N
.HCl
2
3
5a
N
H
80
77
HO
6e
4
4
5
6
79
88
O
O
O
8e
O
O
O2N
9b
7b
5d
O
OH
HN
O
O
N
Boc
5e
5g
N
6d
O
N
Boc
7c
O
MeO
9c
8f
N
O
4
5
5e
5e
7c
76
79
O
O
N
O
Boc
4
9d
7
8
6c
82
88
.
HO
O
4
8g
5f
N
HN
7d
N
Boc
O
O
O
9e
OH
6d
O
H
N
5h
N
6
7
5e
5e
56
79
8h
H N
O
Boc
7e
9f
O
H
9
5b
6d
6d
6d
72
67
81
O
N
H N
N
Boc
O
7f
8i
9g
H
O
H2N
O
N
10
11
12
8
9
5e
5e
75
79
N
O
O
OH
O
O
Boc
7g
5i
9h
8j
H
N
H2N
N
Boc
O
OH
7h
9i
O
5j
8k
H
H2N
N
N
Boc
10
5e
62
O
O
O
O
O
7i
9j
N
O
N
O
6d
6d
77
75
OH
O
O
O
5k
8l
a
Isolated yields reported after silica-gel chromatography.
O
O
O
13
5d
O
While several reports on the preparation of N-Boc-protected
prolinamide derivatives appear in the literature,26,27 a considerable
lack of NMR data appears in support of the characterization of these
compounds. Not surprisingly, all of the N-Boc prolinamides 9dej
(Table 3, entries 4e10) were observed by NMR to exist as a mixture
of two rotamers in ratios varying from 50:50 to 70:30. This fact
8m
a
Isolated yields reported after silica-gel chromatography.

5418
J. McNulty et al. / Tetrahedron 68 (2012) 5415e5421
complicates the full NMR spectral assignment of these derivatives
particularly at low field (200e300 mHz). Nonetheless, we were able
to fully resolve and characterize both amide rotamers in each in-
stance (600 mHz) and report the 1H and 13C NMR data separately
for each in the experimental section.
In terms of process-chemistry, a major advantage provided by
the use of this phosphateecarboxylate mixed-anhydride method is
that the ester and amide products can be isolated in all cases in-
vestigated so far by simple solvent removal and partition between
ethyl acetate and aqueous sodium bicarbonate solution. The crude
ester and amide products appear uncontaminated and can be used
directly in subsequent reactions. In order to quantify yields, the
data reported in Tables 2and 3 are of chromatographically pure
ester and amide products and are considered to be minimum yields.
In order to illustrate further from this process-chemistry view, Fig.1
depicts the ‘crude’ and ‘pure’ 1H NMR spectra obtained of the amide
to remove the hydrated side products shown at the bottom of
Scheme 1.
Finally, in order to extend this method toward the synthesis of
chiral tertiary amines, and, as further evidence that the NMR data
reported for the prolinamide derivatives represents the amide
conformers in each case, we investigated the reduction of the
N-Boc-proline-morpholinamide derivative 9d. As depicted in
Scheme 3, reduction in THF using lithium aluminum hydride pro-
ceeded slowly to yield the single tertiary diamine 9k as the sole
product. In addition to confirming that the NMR complications are
simply due to the existence of the rotamers, this overall process can
now be extended to allow ready access to chiral tertiary amines.
Such tertiary amines are of much interest in catalysis as ligands and
directly as catalysts in Lewis-base mediated asymmetric organo-
catalysis, for example, in BayliseHilman and related reactions.11d,e
9d from the reaction of N-Boc-L-proline and morpholine via the
LiAlH4, THF
N
O
N
O
phosphateecarboxylate process (Table 3, entry 4). Upon comple-
tion of the reaction, solvent removal and partition between ethyl
acetate and aqueous bicarbonate (see experimental), the crude 1H
NMR obtained is recorded as shown (Fig. 1, top). Amide 9d is ob-
served as a 55:45 mixture of two rotamers as described, and very
little else. Purification of ‘crude’ 9d over silica-gel leads to isolation
of the pure material in 76% yield the 1H NMR of which is repro-
duced (Fig. 1, bottom) showing removal of only minor baseline
contaminants. This process contrasts sharply to other coupling re-
agents commonly used to effect this transformation, such as DCC or
Bu3P/DIAD, which absolutely require chromatographic purification
N
Boc
N
Reflux, 2 h
O
9d
9k
Scheme 3. Synthesis of chiral tertiary diamine.
3. Conclusion
In conclusion, we describe a general acylation process utilizing
diethyl chlorophosphate in pyridine to mediate formation of
a
phosphateecarboxylate mixed-anhydride intermediate. This
straightforward procedure contrasts with earlier phospha-
teecarboxylate protocols that required the use of adjuvants, such as
39 (Scheme 1) and/or DMAP.10 The process is applicable to the
synthesis of a wide range of general ester and amide derivatives and
allows rapid entry to useful chiral auxiliaries, ligands and amines
suitable for organocatalysts. The reaction takes place selectively in
the presence of an alcohol and sequentially in the presence of
amines allowing access to useful ester, amide and peptide ana-
logues. Purification is technically simple since there are no hydrated
organic side products (such as DEADH2, Ph3PO, DCCeurea etc.) to
contend with, all side products are either volatile or water soluble
allowing for the straightforward isolation of high purity products.
Simply removing solvents and work up from aqueous sodium bi-
carbonate/ethyl acetate yields the ester or amide product in rela-
tively high purity (>95% in all cases so far investigated) without
chromatographic purification. Diethyl chlorophosphate is readily
available in quantity at approximately one-third the cost of the
standard Yamaguchi reagent. In contrast to coupling reagents, such
as DCC or DIAD, the reagent is stable indefinitely stored on the
bench. The phosphateecarboxylate process is thus highly attractive
in view of its simplicity as well as both economical and process-
chemistry considerations. The use of phosphateecarboxylate mixed
anhydrides is almost totally overlooked in acylation chemistry. We
hope that the full description of this process and demonstration of
its applicability and potential so far will result in adoptation and
consideration of the method by the wider synthetic community.
Work in our laboratories continues with the exploration of the re-
activity of the lesser reactive chlorophosphates with a view to
expanding their chemical utility and in use of proline-derived sec-
ondary and tertiary amines described in organocatalytic reactions.
4. Experimental
4.1. General information
Reactions were carried out under an argon atmosphere in oven-
dried glassware. Melting points (uncorrected) were measured on
a Gallenkamp melting point apparatus. Diethyl chlorophosphate
Fig. 1. Comparison of 1H NMR spectrum (600 mHz) of N-Boc-morpholinyl-L-prolina-
mide 9d obtained after aqueous/organic solvent partition (top) and subsequent puri-
fication over silica-gel chromatography (bottom).

J. McNulty et al. / Tetrahedron 68 (2012) 5415e5421
5419
was obtained from Cytec and Aldrich. All other fine chemicals were
obtained from Aldrich and used without further purification. Pyr-
idine, triethylamine and dichloromethane were distilled freshly
over CaH2. Silica-gel Merck (70e230 mesh) was used for column
chromatography and silica-gel SIL G/UV254 for TLC (Macher-
eyeNagel). 1H and 13C NMR spectra were recorded on a Bruker AV
200 or AV 600 spectrometer using TMS as internal standard.
4.22e4.32 (m, 2H), 7.21e7.30 (m, 5H). 13C NMR (CDCl3):
36.6, 36.8, 64.7, 126.5, 126.6, 128.4, 128.5, 128.9, 129.0, 137.9, 177.1.
d
18.9, 33.9,
4.3.4. (E)-((1R,2S,5R)-2-Isopropyl-5-methylcyclohexyl) 3-(4-
chlorophenyl)acrylate (8d).12a Colorless oil; ½a 2D5
ꢂ55.9 (c 0.47,
ꢁ
CHCl3); 1H NMR (CDCl3):
d 0.75e1.30 (m, 11H), 1.40e2.09 (m, 6H),
4.76 (dt, 1H), 6.36 (dd, J¼16 Hz, 1H), 7.34e7.49 (m, 4H), 7.58 (dd,
Chemical shifts are reported in units of
d
(parts per million) and
J¼16 Hz, 1H). 13C NMR (CDCl3):
d 16.3, 20.7, 22.0, 23.4, 26.3, 31.4,
34.2, 40.9, 47.2, 74.4, 119.3, 129.1, 129.2, 133.0, 142.9, 166.3.
coupling constants (J) are expressed in hertz. CIMS were run on
a Micromass Quattro Ultima spectrometer fitted with a direct in-
jection probe (DIP) with ionization energy set at 70 eV and HRMS
(CI) were performed with a Micromass Q-Tof Ultima spectrometer.
Optical rotations were determined on a PerkineElmer 241 polar-
imeter installed with a l589 sodium lamp.
4.3.5. Heptyl 2-(benzo[d][1,3]dioxol-5-yl)acetate (8e). Colorless liq-
uid; 1H NMR (CDCl3):
d
0.80 (t, J¼7.2 Hz, 3H), 1.19 (br s, 8H), 1.51 (m,
2H), 3.45 (s, 2H), 3.90 (t, J¼7.2 Hz, 2H), 5.87 (s, 2H), 6.66e6.72 (m,
3H). 13C NMR (CDCl3):
14.1, 22.6, 25.9, 28.6, 28.9, 31.8, 41.1, 65.1,
d
101.1, 108.3, 109.8, 122.4, 127.8, 146.7, 147.0, 171.9. EIMS (70 eV): m/z
(%): 279 (15) [Mþ1], 278 (60) [Mþ], 180 (10), 135 (100); HRMS (EI):
m/z calcd for C16H22O4: 278.1518; found: 278.1500.
4.2. General procedures
4.2.1. General procedure for ester syntheses Table 2. (a) Typical
procedure for the synthesis of
a mixture of 4-chlorocinnamic acid (0.365 g, 2.00 mmol) and
-menthol (0.312 g, 2.00 mmol) in pyridine (3.0 mL) was added
L
-menthol-4-chloro cinnamate, 8d: to
4.3.6. (S)-1-tert-Butyl-2-((1R,2S,5R)-2-isopropyl-5-methyl-cyclo-
hexyl) pyrrolidine-1,2-dicarboxylate (8f).16 Viscous oil; ½a 2D5
ꢂ92 (c
ꢁ
L
0.1, CHCl3); 1H NMR (600 MHz; CDCl3, a mixture of two rotamers in
diethyl chlorophosphate (0.320 mL, 2.10 mmol) slowly at rt in an
atmosphere of argon, and the reaction mixture was stirred at rt for
about 30 min. The heterogenous mixture was heated at 70 ꢀC under
argon atmosphere for 3 h, during which the reaction mixture be-
came homogeneous. Pyridine was removed in vacuo, and the resi-
due partitioned between ethyl acetate (15.0 mL) and saturated
sodium bicarbonate (5.0 mL). After stirring well (10 min), the or-
ganic layer was separated, dried over anhyd Na2SO4 and the solvent
evaporated in vacuo to yield the crude product. In all cases, crude
products were >95% pure by 1H NMR. Purification of 8d over silica-
gel (5% ethyl acetate in hexane) afforded 0.552 g, 86% yield of pure
product 8d.12a
the ratio 72:28):
d
0.75 (3Hꢃ 28/100, d, J¼6.8 Hz, CMe), 0.80 (3Hꢃ
72/100, d, J¼6.8 Hz, CMe), 0.83e1.15 (m, 15H), 1.31e1.38 (m, 6H),
1.42 (9Hꢃ 72/100, s, OtBu),1.45 (9Hꢃ 28/100, s, OtBu),1.63e1.72 (m,
4H), 1.81e2.02 (m, 5H), 2.12e2.30 (m, 2H), 3.34e3.57 (m, 2H),
4.06e4.19 (m, 3H), 4.23 (dd, 0.72H, J¼3.2, 8.9 Hz), 4.28 (dd, 0.28H,
J¼3.2, 8.9 Hz), 4.67e4.73 (m, 1H). 13C NMR (CDCl3):
d 15.7, 16.2, 20.8,
20.9, 22.0, 22.8, 23.2, 23.4, 25.5, 26.1, 28.3, 28.4, 31.1, 31.4, 31.5, 34.1,
34.2, 34.3, 40.8, 42.6, 46.4, 46.5, 46.8, 48.4, 48.6, 59.2, 63.4, 63.5,
74.7, 79.1, 79.2, 79.9, 154.3, 172.7.
4.3.7. 2-Phenylethyl octanoate (8g).17 Colorless oil; 1H NMR
(CDCl3):
2.24e2.36 (m, 2H), 2.88e3.04 (m, 3H), 4.19e4.33 (m, 2H), 7.20e7.35
(m, 5H). 13C NMR (CDCl3):
14.1, 22.7, 24.9, 24.98, 28.99, 29.1, 31.7,
d
0.85 (t, J¼7.0 Hz, 3H), 1.25 (br s, 8H), 1.58 (m, 2H),
4.2.2. General procedure for amide syntheses Table 3. (b) Typical
d
procedure for the synthesis of
L-N-(4-nitro-benzoyl)-Val-OMe, 9b:
34.4, 35.2, 63.8, 63.9, 126.6, 126.7, 128.6, 128.9, 129.1, 137.2, 174.1.
to a mixture of 4-nitrobenzoic acid (0.334 g, 2.00 mmol) in pyridine
(3.0 mL) was added slowly diethyl chlorophosphate (0.32 mL,
2.10 mmol) at rt in an atmosphere of argon, and the reaction mixture
4.3.8. (1R,2S,5R)-2-Isopropyl-5-methylcyclohexyl-2-methyl-buta-
noate (8h).20 Colorless oil; ½a 2D5
ꢁ
ꢂ42.3 (c 0.4, CHCl3); 1H NMR
was stirred at rt for about 45 min. To this was then added
L-valine
(CDCl3): d 1.01e1.17 (m, 19H), 1.32e1.45 (m, 2H), 1.63e1.73 (m, 2H),
methylester hydrochloride (0.335 g, 2.00 mmol) in one lot, and the
reaction mixture was heated to 70 ꢀC under argon atmosphere for
5 h. After completion of the reaction, pyridine was removed in vacuo
and the residue partitioned between ethyl acetate (15.0 mL) and
saturated sodium bicarbonate solution (5.0 mL) and stirred well for
about 10 min. The organic layer was separated, dried over anhyd
Na2SO4, and the solvent was evaporated in vacuo yielding the crude
product. Purification of 9b over silica-gel (5% ethyl acetate in hex-
ane) afforded 0.448 g, 80% yield of pure product 9b.12b
1.82e1.99 (m, 2H), 2.44e2.58 (m, 1H), 4.59 (dt, J¼4.4, 10.8 Hz, 1H);
13C NMR (CDCl3):
d
16.2, 19.0, 19.1, 20.8, 22.1, 23.4, 26.2, 31.4, 34.3,
40.9, 47.1, 73.8, 176.8.
4.3.9. (1R,2S,5R)-2-Isopropyl-5-methylcyclohexyl
isobutyrate
(8i).21 Colorless oil; ½a 2D5
ꢁ
ꢂ7.5 (c 0.2, CHCl3); 1H NMR (CDCl3):
d
0.73e1.15 (m, 16H), 1.38e2.00 (m, 8H), 2.28e2.38 (m, 1H),
4.60e4.73 (m, 1H). 13C NMR (CDCl3):
d 11.6, 16.0, 16.1, 16.8, 20.8,
22.0, 23.2, 23.3, 26.1, 26.7, 26.9, 29.7, 31.3, 34.3, 40.8, 40.9, 41.4, 41.6,
46.9, 73.7, 176.3.
4.3. Characterization data for all ester and amide derivatives
reported in Tables 2and 3
4.3.10. (1R,2S,5R)-2-Isopropyl-5-methylcyclohexylacetate
(8j).22 Colorless oil; ½a 2D5
ꢁ
ꢂ7.5 (c 0.1, CHCl3); 1H NMR (CDCl3):
4.3.1. Dodecyl 4-nitrobenzoate (8a).13 White solid (mp: 41e42 ꢀC).
d
1.02e1.90 (m, 19H), 2.00 (s, 3H), 4.60e4.73 (m, 1H). 13C NMR
1H NMR (CDCl3):
d
0.84 (t, J¼7.2 Hz, 3H), 1.26 (br s, 20H), 1.75e1.86
(CDCl3):
170.7.
d 16.4, 20.8, 21.4, 22.1, 23.5, 26.3, 31.4, 34.3, 40.9, 47.0, 74.2,
(m, 2H), 4.33 (t, J¼7.2 Hz, 3H), 8.19e8.31 (m, 5H). 13C NMR (CDCl3):
d
14.3, 22.9, 26.1, 28.8, 29.4, 29.5 (several overlapped peaks), 29.7,
29.8, 32.1, 66.3, 123.7, 130.8, 136.1, 164.9.
4.3.11. (1R,2S,5R)-2-Isopropyl-5-methylcyclohexylbenzoate
(8k).23 Colorless oil; ½a 2D5
ꢁ
ꢂ86 (c 0.4, CHCl3); 1H NMR (CDCl3):
4.3.2. Butyl 4-nitrobenzoate (8b).8a,14a White solid (mp: 37e38 ꢀC).
d
0.91e2.17 (m,19H), 4.88 (dt, J¼4.2,10.6 Hz,1H), 7.40e7.59 (m, 3H),
1H NMR (CDCl3):
d
0.96 (t, J¼7.2 Hz, 3H),1.43e1.51 (m, 2H),1.72e1.86
8.04 (d, J¼8.0 Hz, 2H). 13C NMR (CDCl3):
d 16.6, 20.9, 22.1, 23.7, 26.5,
(m, 2H), 4.35 (t, J¼7.2 Hz, 3H), 8.18e8.32 (m, 4H). 13C NMR (CDCl3):
31.5, 34.4, 41.0, 47.3, 74.9, 128.4, 129.6, 130.9, 132.8, 166.2.
d
13.4, 18.9, 29.4, 30.3, 65.5, 123.3, 130.4, 135.6, 150.2, 164.5.
4.3.12. (1R,2S,5R)-2-Isopropyl-5-methylcyclohexyl-1,3-dioxo-iso-
4.3.3. Phenethyl isobutyrate (8c).15 Colorless oil; 1H NMR (CDCl3):
1.12 (d, J¼7.0 Hz, 6H), 2.41e2.60 (m, 1H), 2.91e3.04 (m, 2H),
indoline-2-carboxylate (8l).24 White solid; mp: 69e71 ꢀC; ½a 2D5
ꢂ58
ꢁ
d
(c 0.1, CHCl3); 1H NMR (CDCl3):
d 0.78e2.06 (m, 18H), 4.42 (s, 2H),

5420
J. McNulty et al. / Tetrahedron 68 (2012) 5415e5421
4.68 (dt, J¼4.4, 10.8 Hz, 1H), 7.73e7.92 (m, 4H). 13C NMR (CDCl3):
d
0.83 (t, J¼6.8 Hz, 3H), 1.20e1.28 (m, 6H), 1.41e1.47 (m, 11H),
1.81e2.31 (m, 4H), 3.16e3.38 (m, 4H), 4.21 (s, 1H), 6.88 (br s,1H); 13C
NMR (151 MHz, CDCl3) 14.04, 22.57, 23.77, 24.63, 26.57, 28.42, 29.54,
29.72, 31.11, 31.50, 39.40, 41.73, 59.88, 80.40, 155.89,171.87; Rotamer
0.83 t, J¼6.8 Hz, 3H), 1.21e1.27 (m, 6H), 1.41e1.47 (m, 11H),
1.81e2.31 (m, 4H), 3.16e3.38 (m, 4H), 4.17 (s, 1H), 6.03 (br s, 1H); 13C
NMR (151 MHz, CDCl3) 14.04, 22.57, 23.77, 24.63, 26.57, 28.42, 29.54,
d
16.3, 20.8, 22.0, 23.4, 26.3, 31.4, 34.1, 39.2, 40.7, 46.98, 76.3, 123.6,
132.1, 134.2, 166.9, 167.6. EIMS (70 eV): 344.185 (Mþ1).
d
4.3.13. (1R,2S,5R)-2-Isopropyl-5-methylcyclohexyl-2-(benzo[d]-[1,3]
B
d
dioxol-5-yl)acetate (8m). Colorless oil; ½a D25
ꢁ
ꢂ63 (c 0.2, CHCl3); 1H
NMR (CDCl3): d 0.75e1.30 (m, 12H), 1.40e2.09 (m, 6H), 3.50 (s, 2H),
d
4.60 (dt, J¼4.2, 10.8 Hz, 1H), 5.93 (s, 2H), 6.72e6.78 (m, 3H). 13C
29.72, 31.11, 31.50, 39.40, 41.73, 61.42, 80.40, 154.84, 172.49. HRMS
(EI): m/z calcd for C16H30N2O3: 298.2256; found: 298.2254.
NMR (CDCl3): d 16.3, 20.8, 22.1, 23.4, 26.2, 31.4, 34.3, 40.8, 41.4, 47.1,
74.7, 101.0, 108.3, 109.7, 122.4, 128.0, 146.6, 147.7, 171.3. HRMS (EI):
m/z calcd for C19H26O4: 318.1831; found: 318.1841.
4.3.21. (S)-1-tert-Butyl-2-(cyclohexylcarbamoyl)pyrrolidine-1-
carboxylate(9h).27 White solid; ½a 2D5
ꢁ
ꢂ52.5 (c 0.2, MeOH); 1H NMR
4.3.14. N,4-Dimethoxy-N-methylbenzamide (9a).18 Pale yellow liq-
(600 MHz, CDCl3) a mixture of rotamers formed in the ratio 55:45;
uid; 1H NMR (CDCl3):
d 3.36 (s, 3H), 3.56 (s, 3H), 3.85 (s, 3H), 6.88 (d,
Rotamer A
2.05e2.30 (m, 1H), 3.26e3.39 (m, 2H), 3.70 (s, 1H), 4.13 (s, 1H), 5.84
(br s, 1H); 13C NMR (151 MHz, CDCl3)
23.75, 24.61, 24.88, 25.55,
28.41, 31.16, 33.31, 47.09, 61.41, 80.46, 154.83, 171.50; Rotamer B
1.12e1.32 (m, 5H), 1.40 (s, 9H), 1.51e1.80 (m, 8H), 2.05e2.30 (m,
1H), 3.26e3.39 (m, 2H), 3.70 (s, 1H), 4.18 (s, 1H), 6.86 (br s, 1H); 13C
NMR (151 MHz, CDCl3) 23.75, 24.61, 24.88, 25.55, 28.41, 31.16,
d 1.12e1.32 (m, 5H), 1.40 (s, 9H), 1.51e1.80 (m, 8H),
J¼8.0 Hz, 2H), 7.71 (d, J¼8.0 Hz, 2H). 13C NMR (CDCl3):
d 33.8, 55.3,
60.9, 113.2, 113.5, 125.9, 130.5, 132.1, 161.5, 169.4.
d
4.3.15. (S)-Methyl-3-methyl-2-(4-nitrobenzamido)butanoate
(9b).12b Pale yellow liquid; ½a 2D5
ꢁ
þ17 (c 0.1, CHCl3); 1H NMR (CDCl3):
d
d
0.95e1.03 (m, 6H), 2.19e2.38 (m, 1H), 3.79 (s, 3H), 4.74e4.81 (m,
1H), 6.79 (d, 1H), 7.95 (d, J¼8.0 Hz, 2H), 8.27 (d, J¼8.0 Hz, 2H). 13C
d
32.81, 47.86, 61.41, 80.46, 155.75, 170.87. HRMS (EI): m/z calcd for
C16H28N2O3: 296.2100; found: 296.2108.
NMR (CDCl3):
165.4, 172.5.
d 18.0, 19.0, 31.6, 52.5, 57.8, 123.9, 128.4, 139.7, 149.8,
4.3.16. (4-Methoxyphenyl)(morpholino)methanone (9c).19 Colorless
4.3.22. (S)-1-tert-Butyl-2-(benzylcarbamoyl)pyrrolidine-1-
oil; 1H NMR (CDCl3):
d
3.67 (br s, 8H), 3.82 (s, 3H), 6.88 (d, J¼8.0 Hz,
carboxylate(9i).26 White solid; ½a 2D5
ꢁ
ꢂ51.5 (c 0.2, MeOH); 1H NMR
2H), 7.35 (d, J¼8.0 Hz, 2H). 13C NMR (CDCl3):
d 55.4, 66.9, 113.8,
(600 MHz, CDCl3) a mixture of rotamers formed in the ratio 60:40;
127.3, 129.3, 160.9, 170.5.
Rotamer A
4.28e4.33 (m, 2H), 4.45 (s, 1H), 4.57 (s, 1H), 7.26e7.33 (m, 5H); 13C
NMR (151 MHz, CDCl3) 24.77, 28.41, 29.81, 43.44, 47.24, 80.61,
127.49, 128.76, 128.33, 155.72, 172.06; Rotamer B 1.37 (s, 9H),
1.88e2.39(m, 4H), 3.35e3.43(m, 2H), 4.28e4.33 (m, 2H), 4.45 (s,1H),
6.37 (br s,1H), 7.26e7.33 (m, 5H); 13C NMR (151 MHz, CDCl3)
23.86,
d 1.40 (s, 9H), 1.88e2.39 (m, 4H), 3.35e3.43 (m, 2H),
4.3.17. (S)-1-[tert-Butoxycarbonyl]-2-morpholinocarbonyl-pyrroli-
d
dine (9d). White solid; ½a D25
ꢁ
ꢂ53 (c 0.2, MeOH); 1H NMR (600 MHz,
d
CDCl3) a mixture of two rotamers in the ratio 55:45; Rotamer A
d
1.42 (s, 9H), 1.77e1.85 (m, 2H), 1.93e2.15 (m, 2H), 3.36e3.72 (m,
d
10H), 4.60 (dd, J¼8.3, 2.8 Hz, 1H); 13C NMR (151 MHz, CDCl3)
28.41, 31.19, 43.44, 47.24, 80.61,127.49,128.76,138.33,154.64,172.36.
d
24.23, 29.81, 42.40, 45.97, 46.77, 56.16, 66.61, 66.97, 79.56, 154.50,
171.01; Rotamer B
d 1.37 (9H, s), 1.77e1.85 (m, 2H), 1.93e2.15 (m,
4.3.23. (S)-1-tert-Butyl (2S)-2-[(4-methoxyphenyl)carbamoyl] pyr-
2H), 3.36e3.72 (m, 10H), 4.48 (dd, J¼8.5, 3.5 Hz, 1H); 13C NMR
rolidine-1-carboxylate (9j). White solid; ½a D25
ꢁ
ꢂ84 (c 0.2, MeOH); 1H
(151 MHz, CDCl3)
d 23.54, 28.49, 30.53, 42.30, 45.70, 46.53, 56.68,
NMR (600 MHz, CDCl3) a mixture of rotamers formed in the ratio
66.61, 67.07, 79.56, 153.84, 171.9 HRMS (EI): m/z calcd for
C14H24N2O4: 284.1736; found: 284.1739.
70:30; Rotamer A
2H), 3.73 (s, 3H), 4.45 (s, 1H), 6.76e6.77 (m, 2H), 7.37e7.39 (m, 2H),
9.32 (br s,1H); 13C NMR (151 MHz, CDCl3)
24.66, 27.71, 31.12, 42.74,
55.46, 60.44, 80.74, 114.03, 121.16, 131.79, 154.63, 156.32, 169.85;
Rotamer B 1.46 (s, 9H), 1.86e2.01 (m, 4H), 3.34e3.44 (m, 2H), 3.73
(s, 3H), 4.28 (s, 1H), 6.76e6.77 (m, 2H), 7.37e7.39 (m, 2H), 7.81 (br s,
1H); 13C NMR (151 MHz, CDCl3)
24.00, 27.71, 31.12, 42.74, 55.46,
d 1.46 (s, 9H), 1.86e2.42 (m, 4H), 3.34e3.44 (m,
d
4.3.18. (S)-1-tert-Butyl-2-(piperidin-1-ylcarbonyl)pyrrolidine-1-
carboxylate(9e).25 White solid; ½a 2D5
ꢁ
ꢂ52 (c 0.2, MeOH); 1H NMR
d
(600 MHz, CDCl3) a mixture of two rotamers in the ratio 55:45;
Rotamer A
d 1.40 (9H, s), 1.48e1.64 (m, 6H), 1.78e1.82 (m, 2H),
d
1.91e1.97 (m, 1H), 2.06e2.14 (m, 1H), 3.05 (dd, J¼10.7, 7.0 Hz, 1H),
3.26e3.74 (m, 5H), 4.51 (dd, J¼8.6, 3.4 Hz, 1H); 13C NMR (151 MHz,
61.86, 80.74,114.03,121.16,130.68,154.63,155.98,170.80. HRMS (EI):
m/z calcd for C17H24N2O4: 320.1736; found: 320.1743.
CDCl3) d 23.48, 24.64, 28.51, 26.54, 28.60, 30.61, 43.19, 46.38, 56.96,
79.34, 154.09, 170.69; Rotamer B
d 1.37 (9H, s), 1.48e1.64 (m, 6H),
4.3.24. (S)-4[(1-Methyl-2-pyrrolidinyl)methyl]morpholine
(9k).28 LiAlH4 (0.053 g, 1.40 mmol) was suspended in dry THF
(3.00 mL) and cooled to 0 ꢀC under nitrogen. Compound 9d
(0.200 g, 0.70 mmol) dissolved in THF (3.00 mL) was slowly added
and then heated to reflux for 2 h. Then the reaction mixture was
cooled to 0 ꢀC and quenched by dropwise addition of saturated
aqueous Rochelle’s salt. The organic and aqueous phases were
separated and the aqueous phase was extracted with EtOAc
(3ꢃ20 mL). The organic layer was dried over MgSO4, filtered and
1.78e1.82 (m, 2H), 1.91e1.97 (m, 1H), 2.06e2.14 (m, 1H), 3.32e3.57
(m, 5H), 3.94e4.01 (m, 1H), 4.65 (dd, J¼8.6, 2.5 Hz, 1H); 13C NMR
(151 MHz, CDCl3)
d 24.14, 26.54, 24.64, 28.51, 28.60, 29.87, 43.24,
46.24, 56.56, 79.34, 154.54, 170.45.
4.3.19. (S)-1-tert-Butyl-2-[(2-phenylethyl)carbamoyl] pyrrolidine-1-
carboxylate (9f).26 White solid; ½a 2D5
ꢁ
ꢂ71.5 (c 0.2, MeOH); 1H
NMR (600 MHz, CDCl3) a mixture of two rotamers in the ratio
55:45; Rotamer A
2H), 3.32e3.50 (m, 4H), 4.24 (s, 1H), 6.84 (br s, 1H), 7.17e7.29 (m,
5H); 13C NMR (151 MHz, CDCl3)
24.57, 28.47, 31.07, 35.84, 40.59,
47.15, 60.15, 80.46, 126.52, 128.78, 139.07, 155.87, 172.03; Rotamer B
1.42 (s, 9H), 1.72e2.30 (m, 4H), 2.74e2.82 (m, 2H), 3.32e3.50 (m,
4H), 4.17 (s, 1H), 6.04 (br s, 1H), 7.17e7.29 (m, 5H); 13C NMR
(151 MHz, CDCl3) 23.68, 28.47, 31.07, 35.84, 40.59, 47.15, 61.45,
d 1.42 (9H, s), 1.72e2.30 (m, 4H), 2.74e2.82 (m,
evaporated to provide the title compound as an yellow oil; ½a D25
ꢁ
ꢂ45 (c 0.2, MeOH); 1H NMR (600 MHz, CDCl3)
d 1.50e1.58 (m, 1H),
d
1.66e1.76 (m, 2H),1.93e1.96 (m,1H) 2.16 (td, J¼9.6, 7.6 Hz,1H), 2.24
(dd, J¼12.0, 7.0 Hz, 1H), 2.30 (dt, J¼7.3, 6.1 Hz, 1H), 2.40 (s, 3H), 2.44
(d, J¼3.6 Hz, 4H), 2.50 (dd, J¼12.0, 5.1 Hz, 1H), 3.04 (ddd, J¼9.3, 7.6,
1.9 Hz, 1H), 3.68 (t, J¼4.7 Hz, 4H); 13C NMR (151 MHz, CDCl3)
d
d
d
22.73, 30.92, 41.68, 54.54, 57.96, 62.62, 64.42, 61.74.
126.52, 128.78, 138.62, 154.79, 172.67.
Acknowledgements
4.3.20. (S)-1-tert-Butyl-2-(hexylcarbamoyl)pyrrolidine-1-
carboxylate (9g). White solid; ½a D25
ꢁ
ꢂ50.5 (c 0.2, MeOH); 1H NMR
We thank NSERC, Cytec Canada Inc. and McMaster University for
financial support of this work.
(600 MHz, CDCl3) a mixture of rotamers in the ratio 60:40; Rotamer A

J. McNulty et al. / Tetrahedron 68 (2012) 5415e5421
5421
13. Cao, Y.-Q.; Wu, G.-Q.; Li, Y.-B.; Dai, Z.; Chen, B.-H. Synth. Commun. 2006, 36,
3353e3358.
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